CZ224597A3 - Tricyclic diazepine derivatives - Google Patents

Abstract

Tricyclic compound of general formula (I) as defined herein which exhibit antagonist activity at V1 and/or V2 receptors and exhibit in vivo vasopressin antagonist activity, methods for using such compounds in treating diseases characterized by excess renal reabsorption of water, and process for preparing such compounds.

Description

Tricyclic diazepine derivatives

Technical field

The invention relates to tricyclic diazepine derivatives having the ability to antagonize vasopressin and thus can be used for the treatment of congestive heart failure, coronary vasoconstriction, excessive renal water absorption and the like.

BACKGROUND OF THE INVENTION [0002] The locus of plasma pituitary gland, which is detected in arteries when ingested.

Vasopressin is released from the posterior ia and in response to elevated osmosis of the blood vessel is detected by the appropriate receptors in the brain of blood volume and blood loss, which receptors for volume reduction and baroreoeptors

This hormone exerts its effect through two receptor-deficient receptor subtypes, V receptors in blood vessels and a recipe in kidney epithelia. Restriction of urine production that is forged by V receptors _? helps maintain normal csmotiocyte blood plasma, blood volume and blood pressure.

ova 'i' c s ~ i? ° or lacquer

Vasopressin is involved in some cases in congestive heart failure, in which peripheral resistance is increased. Antagonists may decrease V ₅ A systemic vascular resistance, increase cardiac output and prevent coronary vasoconstriction induced by vasopressin.

Thus, in conditions where vasopressin induces an increase in total peripheral resistance and changes in local blood flow, V ₁ receptor antagonists can be used to treat these conditions. These substances lower blood pressure and may therefore also be useful in the treatment of some types of elevated blood pressure.

• · · ·

Receptor blockade may also be beneficial in the treatment of certain diseases where the renal clearance of free water is too high. The decrease in urine production is controlled by the secretion of vasopressin (antidiuretic hormone) in the hypothalamus, which then binds to specific renal channel receptors. This binding stimulates adenylyl cyclase and affects the cell areas facing the lumen of the channels. Thus, receptor antagonists may modulate fluid retention in congestive heart failure, liver cirrhosis, nephritic syndrome, central nervous system injury, lung disease and sodium deficiency.

Increases in vasopressin concentration occur in congestive heart failure, which is more common in the elderly with chronic heart failure. In patients with decreased sodium, heart failure and increased vasopressin concentration, receptor antagonists may have a beneficial effect by promoting free water excretion by antagonizing the effect of the anti-diuretic hormone. Due to the biochemical and pharmacological effects of the hormone, these agents can be expected to be used to treat and / or prevent elevated blood pressure, cardiac insufficiency, coronary artery convulsions, cardiac ischemia, renal vascular convulsions, liver cirrhosis, congestive heart failure, nephritic syndrome , cerebral edema, cerebral ischemia, cerebral hemorrhage, thrombosis, and abnormal water retention conditions.

Vasopressin antagonists of the peptide family have been described by M. Manning et al., J. Med. Chem., 35, 382 (1992); M. Manning et al., J. Med. Chem.,

35, 3895 (1992); H. Gavras and B. Lammek, U.S. Pat. U.S. Patent No. 5,070,187, 1991 to M. Manning and W. H. Sawyer, U.S. Pat. U.S. Patent No. 5,055,448, 1991 to F. E. Ali, U.S. Pat. U.S. Patent No. 4,766,108, 1938 to R. R. Ruffolo et al., Drug News

and Persoective, 4 (4), 217, May 1991. P. D. Williams et al. have described potent hexapeptide-type oxytocin antagonists in J. Med. Chem., 35, 3905, 1992, they also have a weak antagonist effect against vasopressin since they can bind to the V 1 and V 2 receptors. These peptides are not effective when administered orally and many peptides do not antagonize vasopressin selectively, since they also have a partial agonist effect.

Recently, non-peptide vasopressin antagonists have been described in Y. Yamamura et al., Science, 252, 579, 1991, Y. Yamamura et al., 3r. J. Pharmacol., 105, 737 (1992), Ogawa et al., (Otsuka Pharm Co., LTD). 514,567-Al, E? 382 185-A2, WO 91/05549 and U.S. Pat. No. 5,253,510, and WO 9/44545 (Yamanouchi Pharm. CO., Ltd., WO 94/20473,

WO 94/12476 and WO 94/14796 (Fujisawa Co., Ltd., E-620215-Al Ogawa et al. (Otsuka Pharm. Co.) ΞΡ 470514A) discloses carbostyria derivatives and pharmaceutical compositions containing them. Oxytocin and vasopressin antagonists have been described by Merck and Co., MG 3ock and? 0. Williams,? 533242A, MG 3cck et al.,? 533244A, J.

M. Erb, D. F. Verber, P. D. Wiiiians, ΞΡ 533240A and K. Gilbert et al., ΞΡ 533243A.

Premature birth can cause newborn health problems and increased mortality, with the peptide hormone oxytccin being a key mediator that can affect the delivery mechanism. Based on its pharmacological effect, the hormone antagonists may be suitable for preventing premature labor according to Β. Ξ. Evans et al., J. Med. Chem.,

35, 3919 (1992); J. Med. Chem., 36, 3993, 1993, and references cited therein. It is an object of the present invention to provide compounds which antagonize the peptide hormone oxytocin and are suitable for the prevention of premature labor.

The present invention is based on the discovery that the pharmaceutical derivatives have an antagonistic effect of V t and / or v t and are capable of antagonistic pressin. They also antagonize the same substances

SUMMARY OF THE INVENTION

According to the invention, there are formed rivals of the general formula ioybio diazepine de-

XC 1 represents a group 2, Ξ. OCK, C 1 -C 6, N-alkyl o

1 to 3 carbon atoms, 3H- (alkyl of i to 3 carbon atoms CKNH- (alkyl of 1 to 3); i ík) , CHITrh, £ CHN ( alkyl of 1 to 3 carbon atoms) CHC- (alkyl of 1 to 3 carbon atoms), CHS- (alkyl of 1 to 3 atoms

A-3 carbon), wherein n is an integer of 0 to 2, is bite

R.

or

R.

Where m is an integer from 1 to 2, provided that when Y is - (CH 2) ^ and n = 2, m may also be 3 and

Y is - (CH-) and n = 2, m has a meaning different from 2.2 n-chlorine atoms, -30, to 3 carbon atoms, -NHCQ1 to 3, 3 atoms

R @ - represents a hydrogen atom, a halogen atom, i.e. Promu, fluorine or iodine, OH, -S-alkyl of 1 to 3 carbon, -SH, -SO-alkyl of 1 to 3 carbon atoms - alkyl of 1 to 3 atoms carbon -C0- (alkyl of 1 carbon atom), -CF ^, C1-C3-alkyl, -C 1-3 carbon atoms, MC ?, _-ΝΗ ρ, - (C1-C3 (C1-C4 alkyl), -M- (alkyl of carbon atoms) -SC4MH-, -SC4NH-alkyl of 1 to carbon, or -30C-NH2-alkyl _; N- (C 1 -C 3 alkyl) means hydrogen, chlorine, bromine, fluorine or iodine, -OH, C 1 -C 3 alkyl, C 1 -C 3 alkyl or

R 1 and R 2 together form methylenedioxy or ethylenedioxy,

R 6 represents a group

AND"

- CAr where

Ar is one of the groups

ς

R _d is hydrogen, alkyl of 1 to 3 carbon atoms or -CO- (alkyl of 1 to 3 carbon atoms),

R _q and R? are hydrogen, alkyl or alkoxy of 1 to 3 carbon atoms or halogen;

R 'is o

(a) any of the groups

• ···· ····································································· · · ··· ··· ··· ·· 9, «

- Ί -NSO _? - (alkyl of 3 to 8 carbon atoms),

-NSO ₂ - (alkenyl of 3 to 3 carbon atoms), ί

I i

R a

II

-NH-C-O- (C 3 -C 3 alkyl),

(C 3 -C 3 alkyl),

Μ,.

-MH-C 3- (alkenyl of 3 to 3 carbon atoms) »»

-MH-C- (C 3 -C 3 alkenyl) wherein the alkyl and alkenyl moieties may be straight or branched, cycloalkyl means cycloalkyl of 3 to 8 carbon atoms, cyclohexenyl or cyclopentenyl,

R is hydrogen, methyl, ethyl, any of the groups

R.

R.

- (CZCc - N - (Gí - Jq - N O

- (CH 2) p -O- (C 1 -C 3 alkyl) -CH 2 CH 2 OH, q represents an integer of 1, 2 3 thereof,

R. represents a hydrogen atom, CH, its -C, H_,

About what

h) a group of formula

- X - R kae

R is alkyl it _in vždv alkenyl of 3 to 8 carbon Xu atoms, - (CH) - (cycloalkyl of 3-5 carbon atoms, P · d), one of the groups

R.

Λ - (CH.). -;

R_

R,

II.

<'7

N

R.

/ '

- ((¾

R.

, _! _ '

O p is an integer from 0 to 3,

X stands for 0, S, NH, NCH,, · ··· ·

C = o or chemical bond,

R ^ and R? c) a group of the general formula

R.

- N - CC where R stands for, a sky or aikenvi with a direct sky and a branched string with a generalized uniz. <U.

Straight-chain or branched -O-alkyl or -Q-alkenyl of 3 to 3 carbon atoms, hydrofuran or ZezrahydroZhiophene;

// 'w »

W // or -CH ₂ -K *, where K 'represents a halogen atom, OH tetrahydrofuran, tetrahydrothiophene or a heterocyclic group of the formula zD - Ν \

G =?

where

D, Ξ, F and G are carbon or nitrogen, wherein the carbon atoms are optionally substituted with substituents selected from halogen, alkoxy of 1 to 2 carbon atoms, -CO- (alkyl of 1 to 3 carbon atoms), CH2, alkyl of Or (C 1 -C 3 alkyl, hydroxy and C 1 -C 3 alkyl);

R and R, are as defined above,

d) a group of the formula “N-CCCHAr

O-C 1 -C 3 alkyl

-S-alkyl of 1 to 1; carbon atoms;

-S- (CHL Z ^R

Z σ

R._

R.

- NHCK,) _q _ _N

- O- N ·

where

R represents a halogen atom, an alkyl of 1 to 3 carbon atoms, -Q-alkyl of 1 to 3 carbon atoms, and a hydroxy group;

R ^ is as defined above,

Ar is one of the groups

R and R- independently represent hydrogen, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, -OF.

-CN, -OK, -SCr ₃ , -OCF ₃ , halogen, NO 2, amino or NH-alkyl of 1 to 3 carbon atoms, or -N- (alkyl of 1 to 3 carbon atoms) ₃ , or - N (R _Q ) (CK ₂ ) 4 -N- (R _Q ) ₂ ,

W 'is O, S, NH, N-alkyl of 1 to 3 carbon atoms, NCO- (alkyl of 1 to 3 carbon atoms), NSO4-alkyl of 1 to 3 carbon atoms),

R '_ means any one of the groups 25 means a group

of the general formula

phenyl, optionally substituted by one or two substituents selected from the group consisting of alkyl or alkoxy of 1 to 3 carbon atoms, halogen, amino or (C1 -C3) alkylamino,) a membered aromatic (unsaturated) heterocyclic ring containing one heteroatom from oxygen, nitrogen or sulfur groups; · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

3) 6-membered aromatic (unsaturated) heterocyclic ring containing 1 nitrogen atom,

4) a 5- or 6-membered aromatic (unsaturated) heterocyclic ring containing 2 nitrogen atoms,

5) a 5-membered aromatic (unsaturated) heterocyclic ring containing 1 nitrogen atom and in addition an oxygen or sulfur atom, wherein:

The 5-membered or 6-membered heterocyclic ring is optionally substituted with an alkyl radical of 1 to 3 carbon atoms, a formyl group, a group of the formula

- (CH.) N

B is a halogen atom or an alkoxy group having 1 to 3 carbon atoms.

A fused heterocyclic ring may be, for example, a furan, pyrrole, pyrazole, thiophene, thiazole oxazole, imidazole, pyrimidine or pyridine ring, which may be unsubstituted or substituted.

In the group of compounds of formula I, some subgroups of substances are more preferred in a broad sense. Preferred are, for example, those compounds in which it is a group

O li

-CAr and Ar means the group ····

- 14 · · 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 19 19 19 19 · ·· ·· ·

R _T

R.

wherein R g, R _g and _R? as defined above.

Particularly preferred are those compounds wherein R 8 is a group

O

II

-Car and Ar are selected from groups

r _;

R,

R. stands for NHCOAr where Ar stands for

- 15 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

9 9 9 9

9 9 9 9 ·

Wherein Rg, Rg, Rg ₅ and W are as defined above.

Also broadly preferred are those compounds wherein in formula I, Y is - (CH 2) -, n = 0 or 1, AB is a group or ^N " ^{, CK} 2 ^! m

R.

R.

and R, R, R ", R_, R, R 'and R _n are as defined above, and 4 3 0 / o JU m represents an integer of 1 or 2 respectively.

Particularly preferred are those compounds of formula (I) wherein Y is - (CH 2) -, n = 1 and A-3 is neo; m = 1 sky

R.

R.

J

R 8 represents a group

O il

-Scrap

An is one of the groups

- 16 R_ stands for 5

NCOAr, neoo

-NCCCK. Ar, -NCON -Ar '

R.

R, R. and W are as defined above,

Si o

R g and R _g substituents are preferably in the ortho position selected from the group CF_, Cl, OCH_ CH "SCH _O or _o or 0CF

Ar 'is a disubstituted derivative in which R g and R g independently represent Cl, OCHg, CHg or F.

Another very preferred group of compounds of formula I are those wherein Y is - (CHg), n = or 0, and

- 17 π z means phenyl, substituted phenyl, thiophene, furan, pyrrole or pyridine ring,

AB means! Cr, _n - ^N or m = 1 if η = 1 or m = 2 if n = 0 means a group

O

Where Ar is a group

And Rg represents a group

R a

-NCOAr ’,

- MXCH, Ar where Ar is one of the groups

importance.

W 'N

Rgt- and W have the above

Particularly preferred are compounds of the formula

where m = integer 1 or 2,

R 6 and R 6 have the same meaning as above, R 8 is the group · · · ·

- 19 O

-CAr where Ar is one of the groups

R.

//

NHCOR2a;

R_ means o

and

R_ \\ I // '-γΝ

R, —R.

-NCQAr ', m.p.

R

NCO (C 1-6) _n cycloalkyl, R 3

-NCONArj NCOCrúAr ', -XR. _n

R. R.

wherein cycloalkyl means cycloalkyl of 3 to 6 carbon atoms, cyclchexenyl or cyclopentenyl,

Ar is one of the groups

independently represent hydrogen, methyl or ethyl; and

- 20 · 4 · 4 · 4 · 4 · I · r · I

Rg, R _? , R, Rg, R, Rgg, X and w 'are as defined above.

Particularly preferred are also compounds of the general formulas

* 3 where integer is 1 or 2,

R and R? have the above meaning,

R.

means SKUOin

O

II

-CAr where Ar is any of the skuoin

R>

□

NHZOR., A

R.

R,

R 6 is 6

NCOAr, NCO (CH _{2) n} -cycloalkyl, and R

R · • · · · · · ·

- 21 · · · · · ek ek ek ek ek ek ek ek 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21 21

-NCONAr ',

NCOCHyV, -XR _{1 (r}

R a

O

II

-MH-C-O- (alkyl of 3 to 3 carbon atoms), n

-MK-3- (alkyl of 3 to 3 carbon atoms), lt

-MH-C-O- (alkenyl of 3 to 3 carbon atoms),

II

-MH-C- (C 3 -C 3 alkenyl), wherein the alkyl and aikenyl radicals may be straight or branched, cycloalkyl, especially C3 -C3 cycloalkyl, cyclohexenyl or cyclopentenyl,

Ar is one of the groups

R _r independently ^R 8 ^'R 9' is hydrogen, ^R _10, R _25, X and W 'are methyl or ethyl, and as hereinbefore defined • • · · · ·

Compounds of formula I may be prepared as shown in Scheme 1 by reacting tricyclic derivatives of formula 3a or 3b with substituted or unsubstituted 6-nitropyridine-3-carbonyl chloride of formula 4 to form intermediates 5a and 5b. Reduction of the nitro group in these intermediates gives the 6-amino-3-pyridinylcarbonyl derivatives 6a and 6b. Reduction of the nitro group in said intermediates may be accomplished by catalytic reduction, for example with hydrogen or a mixture of hydrazine and ethanol in the presence of palladium on charcoal, or chemical reduction, for example with stannous chloride and ethanol or zinc in acetic acid or titanium chloride. The conditions are chosen such that other functional groups in the molecule are retained.

Reaction of compounds of formula 6a and 6b with aroyl chloride, heteroaroyl chloride, arylsulfonyl chloride, diarylphosphinyl chloride, diphenoxyphosphinyl chloride, alkylcarbonyl chloride, alkenylcarbonyl chloride, alkoxycarbonyl chloride, alkenyloxycarbonyl chloride, alkylsulfonyl chloride or alkenylsulfonylbenzyl or alkenylsulfonylbenzyl 1, the novel compounds according to the invention of formulas 8a and 8b are obtained. The reaction may be carried out in a solvent such as chloroform, dichloromethane, dioxane, tetrahydrofuran, toluene and the like in the presence of a tertiary base such as triethylamine, diisopropylethylamine or pyridine at 0 to 50 ° C. When more than one aroyl, heteroaryl, arylsulfonyl group and the like are introduced in the course of the reaction, the other of these groups can be removed by a gentle treatment such as a dilute solution of sodium or potassium hydroxide in a lower alkanol to give products of formula 8a and 8b.

- 23 ·· · · ·

no ₂

5a

5b

Scheme 1 - cont.

4 · 4 · I · I · · · · · · · · · · · · · · · · · ·

NH,

6b

R.

Ar'COCI

Af'CH ₂ COC!

alkyl (CH ₂ ) _n COCl

AfNCOCt

2a

2b

R8 = -NHCOAr '; -NHCONAr '; · ΝΗΟΟ (ΟΗ ₂ ) _η cycloalkyl

-NHCOCH ₂ Ar '

6a »· · · ·

Scheme 1 - cont aUcyi (C ₃ -C _g) COCl alkyl (C ₃ -C ₃₎ O-COC

alkenyl (C8-C8) -COC1;

alkenyl, (Cg-Cg) -CCOCI alkyl (C ₃ -C _g) SO ₂ C aikenvi (C - - _C) SQ., C

J 0 4

• · · ** · · ·

cont.

R.

□

8a

3b = -NHCOalkenyl (C 8 -C 8) -NHSO ₂ alkyl (C ₃ -C 8),

NHCOalkyl (C ₃ -Cg) - ₂ NHCO alkyl (C ₃ -C _G) • NHCO ₂ alkenyl (C ₃ -Cg)

NHSO ₂ alkenyl (C ₃ -C 8)

-NHSO

• · · ·

By reacting tricyclic derivatives of formula 6a or 6b with a carbamoyl derivative of formula 9 or an isocyanate derivative of formula 10, the resulting products of formulas 11a and 11b can be obtained by the method of Scheme 2 below. These compounds of formula I antagonize the efficacy of vasopressin and / or oxytocin.

In these compounds, R 8 is a group

-NKCONAr ’

R.

and R _x is hydrogen, methyl or eohyl.

• • •

- 23 Diagram

Sa - O

C 1 -C -Na '

I or ί 0 = C = NAr '

NHCONAr

Y

11b

Reaction of tricyclic derivatives of formula 3a and 3b with 6-chloro or 6-fluoropyridine-3-carbonyl chloride of formula 12 yields intermediates of formula 13a and 13b according to Scheme 3.

- 29 Diagram 3

Intermediates 13a and 13b can be reduced with a compound of formula 14, a derivative of R 1, X 2 ^, wherein R 1, R 2 is as defined above, and X is O, S, NH or NCH ₀ to give compounds 15a and 15b according to Scheme 4.

·····························

- 30 Diagram 4

13a

13b

R

-N

3 3 i 5c

Compounds of formula I wherein Y, A-S, Z,

R, R. and R_ are as defined above and R 12 in the meaning _of ^3-1

-COAr can be represented by the formula

R_

Wherein each symbol is as defined above, may be prepared by the method of Scheme 5 by first preparing the pyridinyl portion of Formula 16 to be attached to the tricyclic benzazepine moiety of the final product molecule.

The preformed pyridinyl moiety 16 can be activated by reaction with peptide coupling reagents, but is preferably activated by conversion to pyridine-3-carbonyl chlorides of formula 17. The coupling is carried out in an inert solvent such as chloroform, dichloromethane, tetrahydrofuran, dioxane. , toluene and the like in the presence of a tertiary amine such as triethylamine. The reaction can also be carried out in pyridine or in alkylpyridine derivatives.

• ··

- 32 Diagram

The starting materials of formulas 3a and 3b of Scheme 1 can be obtained by methods known in the literature. For example, some intermediate products such as 6,11-dihydro-5H-dibenz (b, e) azepines and substituted derivatives may be prepared according to L. H. Werner et al., J. Med. Chem., 8, 74-80, 1965,

A. W. H. Wardrop et al., J. Chem. Soc., Perkins Trans I, 1279-1285 (1976).

····

Substituted 5,11-dihydrodibenz [b, e] azepin-6-one can be prepared by methods known in the literature, for example, according to J. Schmutz et al., Helv. Chim. Acta, 48, 336, 1965 and then reduced to substituted 6,11-dihydro-5H-dibenz (b, e) azepines by treatment with lithium aluminum hydride, borane, borane / dimethylsulfide or other reagents capable of reducing the amidcarbonyl group to a methylene group. The 10,11-dihydrobenz- [b, f] 1,4] thiazepines, which are also intermediates, can be prepared, for example, by K. Brewster et al., J. Chem. Soc. Perkin I, 1286, 1976. Reduction of the dibenz (b, f [1,4] oxazepines according to A. W. H.

Wardrop et al., J. Chem. Soc. Perkin Trans.I, 1279, 1976, and dibenz / b, f [1,4] oxazepin-11 (1H) -ones as well as dibenz / b, f [1,4] thiazepin-11 (10H) -ones according to J. Schmutz et al., Helv. Chim. Acta, 48, 336, 1965 may be accomplished by treatment with lithium aluminum hydride in inert solvents such as dioxane and the like. The tricyclic 6,7-dihydro-5H-dibenz (b, d) azepine intermediates of formula (30) can also be prepared by methods known in the literature, for example, by T. Oht et al., Tetrahedron Lett., 26, 5811, 1985, Wiesner and et al., J. Amer. Chem. Soc., 77, 675, 1955, derivatives of these compounds can be prepared by the reactions shown in Scheme 7. Reduction of nitro compounds of formula 31 followed by ring closure affords lactams of formula 32, which are then reduced to give tricyclic azepines of formula 33.

The 5,11-dihydro-6H-pyrido [3,2-c] l benzazepines can also be prepared according to literature, for example, J. Firl et al., Liebigs Ann. Chem., 469, 1989. 11H-pyrido [2,3-b] 1,4] benzodiazepin-6 (5H) -ones have been described in J. F. F. Liegeois et al., J. Med. Chem., 36, 2107, 1993, these derivatives can be reduced to the corresponding 11H-pyrido [2,3-b] 1,4] benzodiazepines. Synthesis of tricyclic 1,4,5,10-tetrahydropyrazolo [4,3-c] l benzodiazepine and

34 of its 3-chlorinated derivative have been described in G. Palazzino et al., J. Heterocyclic. Chem., 26, 71,

1989. 4,10-Dihydro-5H-thieno [3,2-c] -benzazepine and 9,10-dihydro-4H-thieno [2,3-c] -benzazepine of formula 21a and 21b may be prepared by coupling tributyltin derivatives of formulas 19 and 20 to 2-nitrobenzyl bromide in the presence of tetrakis (triphenylphosphine) palladium (0) as shown in Scheme 6.

Subsequent coupling of intermediates 24 to give the tricyclic azepine of formula 25 reduces the nitro group to give the 6-aminonicotinoyl derivative of formula 26.

This derivative is then reacted with the appropriate acid chloride as shown in Scheme 7 to give the products of Formula 27 and 27a.

Scheme 7 also depicts the synthesis of tricyclic azepine intermediates of formulas 30 and 33. Tricyclic lactam derivatives of formulas 29 and 32 may be prepared by reduction of nitro-containing intermediates of formulas 28 and 31 followed by ring closure in the corresponding amino derivatives. can be reduced by treatment with lithium aluminum hydride LAH or borane to give tricyclic azepine derivatives of formulas 30 and 33.

• · · · · · · · · · · ·

- 35 S c h e m 6

21b ···· · · · · · · · · · · · · · · ·

- 36 Diagram 7

Τ

• ·

Scheme 7 - cont.

zs

Ar'COCI or Ar'CH ₂ COCI or

Ar'NCOCI

R b or cycloalkyl - (CF 3 - COCl)

• ········· · t · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ·

- 38 Scheme 7 - cont.

alkenyl (Cg-Cg) COalkenyl (Cg-Cg) COCOalkyl (Cg-Cg) SO2 'alkenyl (Cg-Cg) SO2-

I · I · I · · · · · · ·

Scheme pokrač - cont.

(1) H _2, Pd / C

->.

(2) ring closure

LAH or

(2) ring closure

ο Ar ¹ 24

The tricyclic intermediates of formula 42 for the preparation of certain compounds of formula I wherein Y is -CIL- and m = 1 may be prepared according to Scheme 8. Suitable i-nitro-2-chloro or 1-nitro-2-bromo-heterocyclic derivatives of formula 25 are reacted with an alkylllithium reagent, for example tert-butyllithium, sec-butyllithium or n-octyllithium, to exchange a halogen atom to give an intermediate of formula 37, which is then reacted with an anhydride of formula 38. In this case, R &lt; 2 &_gt; Scheme t-butyl, sec-butyl, n-butyl, 2,6-dimethylpiperidine or non-nucleophilic dialkylamine with steric hindrance. The nitroderivatives of formula 39 are then reduced by treatment with hydrogen in the presence of a suitable catalyst or by chemical processes, for example zinc in acid.

Of acetic acid, titanium tetrachloride and the like to amino derivatives of formula 40 which are intermediates for the next reaction. The ring closure of the cyclic lactam of Formula 41 can be readily accomplished by heating in xylene or other inert solvent at a temperature in the range of 100 to 200 ° C. The cyclic lactams of formula 41 can be readily reduced with borane in tetrahydrofuran or a mixture of borane and dimethylsulfide in tetrahydrofuran or lithium aluminum hydride in a suitable solvent such as dioxane to give the tricyclic derivatives of formula 42.

Alternatively, phenyllithium derivatives of formula (37b) prepared by lithiation of protected benzaldehyde derivatives or lithiation of benzaldehyde derivatives with protected 2-chloro- or 2-bromo groups can be reacted with compounds of formula (38b) wherein Z is as defined above. The derivatives of formula 38b can be prepared by conventional procedures, for example by ring closure in 1-amino-2-carboxyhero-aromatic compounds or in 1-amino-2-benzoic acid derivatives with acetic anhydride as shown in Scheme 8.

• · · ·

- 42 Figure 8

• · · ·

1

£ 2

As shown in Scheme 9, tricyclic derivatives of Formula 42 can also be prepared by treating palladium or copper compounds with halogenated derivatives of Formula 43 to give tricyclic lactam derivatives of Formula 4a. Reduction of the lactam carbonyl group yields intermediates of Formula 42. Ring closure of derivatives of Formula 45 with activated copper or palladium reagents yields lactam derivatives of Formula 47. Ullmann reaction of halogenated heterocyclic compounds and 2-bromonitrobenzene and related reactions with low valency palladium compounds, as (Pd(PPh.p ₄ ) and PdCl ₂ (PPh ₃ ) ₂ are known synthetic procedures described in N. Shimizu et al., Tetrahedron Lett., 34, 3421, 1993 and in the literature, M. M. Ali. and more,

44 Tetrahedron, 37, 8117, 1992, and in the aforementioned literature and v

J. Stavenuiter et al., Heterocycles, 26, 2711, 1987 and in the literature.

Scheme 9

• · · ·

The tetrahydro-1H-1-benzazepin-5-one derivatives of formula 51 and the tetrahydro-1H-1-benzazepine-2,5-diones of formula 52 are valuable compounds for the preparation of tricyclic heterocyclic compounds of formulas 53 and 54 as intermediates according to the scheme below 10. Tetrahydrobenzazepin-5-one derivatives of formulas 51 and 52 can be processed to hydroxymethylene derivatives or reacted with Vilsmeier reagent or N, N-dimethylformamide dimethylacetal to form a dimethylaminomethylene derivative. The construction of heterocyclic rings from alpha-hydroxymethylenketone derivatives by reaction with hydrazine, N-methylhydrazine, hydroxylamine or formamidine to form pyrazole, N-methylpyrazole, oxazole or pyrimidine derivatives is a conventional procedure described in the literature, for example Vilsmeier formylation is described in Tetrahedron, 49, 4015 4034, 1993, and the publications mentioned, and ring formation is described in J. Heterocyclic Chem., 29, 1214, 1992 and references cited therein.

Substituted and unsubstituted tetrahydrobezazepin-2-one derivatives are known compounds which can be prepared by reacting alpha-tetralone derivatives with sodium azide in an acidic medium according to J. Chem. Soc., 456, 1937 or Tetrahedron, 49, 1807, 1993 (Schmidt reaction). Reduction of the tetrahydro-1H-benzazepin-2-one derivatives affords the tetrahydro-1H-benzazepine compounds of formula 48, the acylation of which affords the compounds of formula 49. Oxidation of the Γ1-acyltetrahydro-1H-benzazepine compounds of formula 49 to

The 5-one derivatives are a known oxidation procedure, as described, for example, in R. L. Augustine and W. G. Pierson, J. Org., Chem., 34, 1070, 1969.

Synthesis of 3,4-dihydro-1H-1-benzazepine-2,5-dione derivatives, which can be represented by Formula 52 and wherein. R 1b represents a hydrogen atom already described in the literature as well

46 as the conversion of 3,4-dihydro-1H-1-benzazepine-2,5-dione compounds to 4 - [(dimethylamino) methylene] -3,4-dihydro-1H-1-benzazepine-2,5-dione derivatives with N, N-dimethylformamide and dimethylacetal (WY Chen and NW Gilman, J. Heterocyclic. Chem., 20, 663, 1983). This publication describes a process for the preparation of 2-methyl-5,7-dihydropyrimido [5,4-d] -1-benzazepin-6- (6H) -one compounds which can then be reduced to remove the kanamonyl group of the lactam, thereby to yield tnicyclic derivatives of formula 54 wherein Z is a pyrimidine ring.

I · · · »

► · · · ······ · · · · ·

- Δ, Ί -

^ (C 8 H 9 C 0 O 0 O)

O a: R ₁₅ = (CH ₃ ) ₃ CCO

(CH ₃ ) ₂ S = O

KMnO,

• · · ·

- 48 Scheme 10 - cont.

- 49 Scheme 11 ► · · ··· <

• · · I · · · · ·

in

- 50 · · 50 · 50

57b

NHCCR ^

59a

NHCCF? G

59b • ·· ·

Compounds means a group in which the group -COAr in the meaning of R

R.

can be prepared according to Scheme 11. The tricyclic derivatives of formulas 3a and 3b are reacted with a substituted or unsubstituted z-L-nitrobenzoyl chloride of formula 55 to give derivatives 56a and 56b. Reduction of the nitro group in these derivatives affords 4-aminobenzoyl intermediates of formula 57a and 57b, which are then reacted with an acid chloride of formula 58 to give products of formula 59a and 59b.

Compounds in which the group -COAr in the meaning of R1 represents a group

R.

may be prepared by reacting tricyclic azepines 3a and 3b with a substituted benzoyl chloride of formula 60 according to Scheme 12 to give products 61a and 61b. Similarly, reaction of heteroaroyl chlorides of formula 62, 63 or 64 with tricyclic azepines of formula 3a and 3b yields products 65a and 65b with aryl groups as shown in Scheme 13.

• · · ·

Scheme 13

The following examples illustrate the practice of the invention but are not intended to limit its scope.

-É-Σ ___ Ε- £ _2_Ζ-θ_ £ _® J2_i ___ Z_2_2_á_l_e_z_u

Reference Example 1

Preparation of 6,11-dihydro-5H-dibenz- (b, e) -azepine

Mixture prepared by mixing 48.52 g (0.20 mol) of 2-aminobenzophenone-2-carboxylic acid; and 500.0 ml of xylene, are heated at reflux for 67.0 hours.

Then the reaction mixture is cooled to room temperature; and filtered. and the solid is washed with xylene.

43.30 g (yield 97.80%) of 5H-dibenz- [b, e] -azepine-6,11-dione are obtained; in the form of a slightly brown / crystalline substance. Melting point: 245.0-248.0 ° C

To the above compound (4.46 g) (0.020 mol); in 25.0 ml of tetrahydrofuran, 12.0 ml (0.12 mol) of a ten molar solution of boron-dimethylsulfide in tetrahydrofuran is added. Then, an additional 10.0 mL of tetrahydrofuran was added to the resulting reaction mixture, and the mixture was stirred overnight; and then heated at reflux for 4.0 hours to dissolve the solid particles. After cooling the mixture, 15.0 ml of methanol are added dropwise; and the reaction mixture is concentrated in vacuo. Then 50.0 ml of 2N sodium hydroxide solution was added to the residue, and the reaction mixture was heated at reflux for 2.0 hours.

Then the solid is filtered, washed with water, air dried; and then shaken with dichloromethane. The extract is dried with sodium sulfate; and the solvent is removed.

3.25 mg (83.0% yield) of the title compound are obtained as a crystalline solid.

117.0-122.0 ° C

Melting point :

·· ····

- 55 Reference Example 2

Preparation of 2-chloro-5H-dibenz- [b, e] -azepine-6,11-dione

A mixture prepared by mixing 1.0 g (450.0 mmol) of 5H-dibenz- [b, e] -azepine-6,11-dione in 50.0 ml of glacial acetic acid (partial suspension); chlorine gas was bubbled through the reaction mixture and the temperature of the reaction mixture rose to 38.0 ° C. P then determines _a stationary when the temperature of the mixture decreases reskční obviates the white-colored precipitate as a solid. After filtration, 0.40 g of a solid is obtained which is a 1: 8 mixture of the starting material of the desired product.

Subsequent standing of the filtrate gave 0.10 g of the desired product as a crystalline solid.

Melting point: 289.0-293.0 ° C

Reference Example 3

Preparation of 10,11-dihydro-N, N-dimethyldibenz- [b, f] [1,4] -ozazepine-2-sulfonamide

To mixture _t prepared by mixing 5.88 g of 10,11-dihydro-N, N-dimethyl-11-oxodibenz- [B, f] -1,4] -oxazepine-2-sulfonamide; in 5.0 ml of tetrahydrofuran, 20.0 ml of a molar solution of borane-dimethylsulfide in tetrahydrofuran is added.

The resulting reaction mixture was stirred overnight; and then heated under reflux for 2.0 hodin.Poté mixture is cooled: and diluted _in 10.0 ml of methanol. After the following and ames ae ápěf, thicken.

the mixture was concentrated again with methanol; 20.0 ml of 2N sodium hydroxide solution was added to this mixture; and the reaction mixture is heated again

- 56 • · · · · ·

at reflux for 2.0 hours. Then shake the mixture with dichloromethane; The extract obtained is dried over magnesium sulphate and then filtered.

The filtrate obtained is poured over a thin layer of water-containing magnesium silicates; and the filter layer is washed with dichloromethane.

The filtrate was concentrated to give 4.80 g of crystalline solid.

Melting point: 99.0 - 102.0 ° C

Recrystallization of the above; 3.96 g of the desired product are obtained in the form of a crystalline solid, from a mixture of diisopropyl ether and dichloromethane.

Melting point: 109.0 - 110.0 ° C

Mass Spectroscopy (FAB):

305 (+ H)

Analytical evaluation of the compound of formula C C HH ^ gN ^O ^S: Calculated: C, 59.20; H, 5.30; N, 9.20; S 10,60%

Found: C, 57.60; H, 5.2. S 10,10%

Reference Example 4

Preparation of 2-chloro-5,6-dihydrophenanthridine

Solution prepared by dissolving 2,62 g (17,0 mmol)

Chlorine gas was bubbled for 10 minutes in 6- (5H) -phenanthridinone, in 120.0 ml of acetic acid, and heated to 70 ° C. The reaction mixture was then allowed to cool to room temperature

- 57 rooms; and then filtered. Filtration gave 1.35 g of crystalline material.

Melting point: 310.0 - 318.0 ° C

To 1.57 g of the above substance described in the previous section of Reference Example 4; in 25.0 ml of tetrahydrofuran, 12.0 ml of a 10 molar solution of boron-dimethylsulfide in tetrahydrofuran is added. The resulting reaction mixture was heated to reflux for 18.0 hours; 15.0 ml of methanol are then added thereto after cooling. The mixture is then concentrated in vacuo _; and 50.0 mL of 2N sodium hydroxide solution was added to the residue. The mixture was heated at reflux for 2.0 hours, and after filtering off the solid, it was washed with water and air dried.

The desired product is obtained, in which neither the amount obtained nor the yield is indicated; and no analytical data. The product is obtained as a solid.

Reference Example 5

Preparation of 9-chloro-5H-dibenz- [b, e] -azepine-6,11-dione

Mixture prepared by mixing 11.50 g of 5H-dibenz- (b, e) -azepine

6,11-dione; and 600.0 ml glacial acetic acid; The mixture is heated on a steam bath until all solid particles have dissolved. Chlorine gas is added to the resulting solution (ϊΟ, ΟθΟ) by bubbling chlorine through said solution until a solid precipitate is formed.

Then the mixture is allowed to reach room temperature; and filtered. 7.30 g of the desired product are obtained.

Melting point

290.0-295.0 ° C

Reference Example 6

Preparation of 9-chloro-6,11-dihydro-5H-dibenz- (b, e) -azepine

To a mixture prepared by mixing 7.28 g of 9-chloro-5H-dibenz [b, e] -azepine-6,11-dione; in 25.0 ml of tetrahydrofuran, under argon atmosphere, was added 8.50 ml of boron-dimethylsulfide (10 molar) / tetrahydrofuran.

The resulting reaction mixture was stirred at room temperature for 18.0 hours; and then, after the addition of 30.0 ml of tetrahydrofuran, the mixture is heated to reflux for 3.0 hours until all solids have dissolved. The reaction mixture was then cooled to room temperature and then 25.0 ml of methanol was added dropwise.

After removal of the volatiles under vacuum from the mixture, the residue was mixed with 100.0 ml of 2N sodium hydroxide solution; and the mixture is heated at reflux overnight; and then filtered.

Shake the solid with dichloromethane; and the extract obtained is washed with a 2 N / citrophonic acid solution (

2-hydroxypropane-1,2,3-tricyclic); followed by water and then dried over sodium sulphate.

Removal of the solvent yielded 4.20 g of solid which, after mechanical work-up and removal with ethyl acetate: hexane (1: 2), afforded the title product as a crystalline solid.

Melting point 137.0-141.0 ° C

Reference Example 7

Preparation of 10,11-dihydrodibenz- [b, f] 1,4] -thiazepine

59 Ku mixture prepared by mixing 3.30 g of 10,11-dihydro-11-oxodibenz- [b, f] 1,4] -thiazepine; in 25.0 ml of tetrahydrofuran, 4.0 ml of a 10 molar solution of borane-dimethylsulfide in tetrahydrofuran are added. The resulting reaction mixture is stirred at room temperature for 10.0 hours; and after addition of 50.0 ml of anhydrous methanol, the solvent is removed. After this operation is repeated with another 30.0 ml of methanol; and its removal to give white colored crystals which is purified by silica gel chromatography using hexane: chloroform: ethyl acetate (2: 1: 1); as eluent.

The title product is obtained, with no weight or yield. The product is obtained in the form of a white crystalline solid.

Melting point 145.0-14S, 0 ° C

In an analogous manner to that described in the preceding Reference Example 7; the following compounds of Reference Examples 8 to 17 may also be prepared;

Reference Example 8

Preparation of 4-methyl-10,11-dihydrodibenz- [b, f] 1,4] -thiazepine

Reference Example 9

Preparation of 4-chloro-10,11-dihydrodibenz- [b, f] 1,4] -thiazepine

- 50 - ...... ..

Reference Example 10

Preparation of 2-methyl-11,11-dihydrodibenz- [b, f] [1,4] thiazepine

Reference Example 11

Preparation of 2-chloro-10,11-dihydrodibenz- [b, f] 1,4] -thiazepine

Reference Example 12

Preparation of 2-methoxy-10,11-dihydrodibenz- [b, f] 1,4] -thiazepine

Reference Example 13

Preparation of 8-chloro-10,1-1-dihydrodibenz- [b, f] [1,4] thiazepine

Reference Example 14

Preparation of 4,8-dichloro-10,11-dihydrodibenz- [b, f] 1,4] -thiazepine

Reference Example 15

Preparation of 8-chloro-4-methyl-1,1,1-dihydrodibenz- [b, f] 1,4] thiazepine

Reference Example 16

Preparation of 8-methoxy-10,11-dihydrodibenz- [b, f] 1,4] -thiazepine

Reference Example 17

• · · · · · · · ·

Preparation of 7-chloro-4-methyl-10,11-dihydrodibenz- [b, f] 1,4] thiazepine

In a similar manner to that described in Reference Example 3J, the following compounds listed in Reference Examples 18 to 29ζ may also be prepared.

Reference Example 18

Preparation of 2-chloro-10,11-dihydrodibenz- [b, f] [1,4] oxazepine

Reference Example 19

Preparation of 2-methyl-10,11-dihydrodibenz- [b, f] [1,4] oxazepine

Reference Example 20

Preparation of 4-chloro-10,11-dihydrodibenz- [b, f] [1,4] oxazepine

Reference Example 21

Preparation of 3-methyl-10,11-dihydrodibenz- [b, f] [1,4] oxazepine

Reference Example 22

Preparation of 7-chloro-10,11-dihydrodibenz- [b, f] -1,4-oxazepine

- 62 Reference Example 23

Preparation of 8-chloro-10,11-dihydrodibenz- [p, f] [1,4] oxazepine

Reference Example 24

Preparation of 2,4-dichloro-10,11-dihydrodibenz- [b, f] 1,4] -oxezepine

Reference Example 25

Preparation of 4,8-dichloro-10,11-dihydrodibenz- [b, f] [1,4] oxazepine

Reference Example 26

Preparation of 4-chloro-8-methyl-10,11-dihydrodibenz- [b, f] [1,4] oxazepine

Reference Example 27

Preparation of 4-methyl-7-chloro-10,1-dihydrodienzene [b, f] 1,4] oxazepine

Reference Example 28

Preparation of 1-chloro-4-methyl-10,11-dihydrodibenz- [b, f] 1,4] oxazepine

Reference Example 29

Preparation of 2-fluoro-10,11-dihydrodibenz- [b, f] [1,4] oxazepine

Reference Example 30

Preparation of N- (2-iodophenyl) -2-iodophenylacetamide

A solution prepared by dissolving 13.32 g (0.03 mol) of 2-iodophenylacetic acid in 75.0 ml of thionyl chloride was heated at reflux for 2.0 hours; then the volatiles are removed from the reaction mixture under vacuum. Toluene (3x) is then added to the residue; and after each addition the solvent is evaporated under vacuum; to give 2-iodophenylacetyl chloride as a gummy substance (0.05 mol) to which was added a mixture of toluene and dichloromethane (1: 1); in which 1 1, 0 g (0.05 mol) of 2-iodenilin is contained _; and 0.10 moles of diisopropylamine.

The reaction mixture was stirred at room temperature overnight; and then the solvent is removed. The residue is dissolved in dichloromethane; and the resulting solution is washed successively with a 1N hydrochloric acid solution; saturated aqueous sodium bicarbonate; and brine; and then dried over sodium sulfate.

After removal of the solvent, the residue was recrystallized from a mixture of methanol and ether.

16.0 g of the desired product are obtained in the form of a brown-colored crystalline solid.

Melting point: 160.0-163.0 ° C

Reference Example 31

Preparation of 2-iodo-N- (2-iodophenyl) -benzenethanamine

To the mixture prepared by suspending 1.39 g (3.0 mmol)

2-iodo-N- (2-iodophenyl) -benzeneacetamide; in 30% ml of a mixture of tetra64 hydrofuran and dichloromethane (1: 1); 3.75 ml of 2.0 molar borane-dimethylsulfide in tetrahydrofuran was added to the resulting suspension. The resulting reaction mixture was quenched. stirred at room temperature for 1.0 hour; and then heated at reflux for 16.0 hours.

The reaction mixture is then added after cooling; drop by drop; slowly water until it stops evolving gas.After removing the volatile components under vacuum; The aqueous residue was basified with 2N sodium hydroxide solution.

The reaction mixture was then shaken with 50.0 ml of ether; and the extract obtained is washed with brine, and then dried with sodium sulfate. Then the solution is filtered through a thin layer of magnesium silicate containing water; and the filter layer is washed with ether; and the filtrate was evaporated. The solid residue obtained is washed with isooctane to give 1.20 g of a white solid which is recrystallized from diethyl ether: hexane; The title compound is obtained in the form of a white crystalline solid.

Reference Example 32

Preparation of N- (4-nitrobenzoyl-N- (2-iodophenyl) -2-iodobenzenethylamine).

To a solution prepared by dissolving 0.90 g of 2-iodo-N- (2-iodophenyl) -benzenethanamine; in 4.0 ml of tetrahydrofuran, 0.41 g of triethylamine is added; and 0.57 g of 4-nitrobenzoyl chloride.

The resulting reaction mixture was stirred at room temperature for 2.0 hours; and then the solvent is removed from the mixture under vacuum. The residue was dissolved in ethyl acetate: dichloromethane (5: 1); and the resulting solution is washed successively with 1N hydrochloric acid solution; saturated aqueous solution

Sodium bicarbonate; and brine; Then the solution is filtered through a thin layer of magnesium silicate containing water, and after evaporation of the filtrate, the solid residue is worked up mechanically and taken up with diethyl ether and hexane.

1.10 g of the expected product are obtained in the form of a white solid.

Reference Example 33

Preparation of 3,4-dihydro-1 H -1-benzazepine-2,5-dione

To the mixture prepared by mixing 225.0 ml of glacial acetic acid; and 8.50 mL of concentrated sulfuric acid; 49.54 g (0.30 mol) of 2-nitroscetophenone are added; and 47.02 g (0.50 mol) of hydrated glyoxylic acid (2-oxoethanoic acid). The resulting reaction mixture was heated at 100 ° C for 16.0 hours. Then the mixture was cooled and poured onto crushed ice. After the ice has dissolved, the reaction mixture is filtered; and the solid product is washed with chilled water. The solid was recrystallized from dichloromethane / hexane.

20.10 g of 3- (2-nitrobenzoyl) -acrylic acid are obtained in the form of a white crystalline solid.

Melting point: 153.0-158.0 ° C

A solution prepared by dissolving 9.0 g of the above substance; in 80.0 ml of ethanol and 1.60 g of palladium on charcoal; is hydrogenated in a Parr hydrogenation apparatus under 20 psi of hydrogen pressure for 20 hours. The reaction mixture is then filtered through diatomaceous earth and the solvent is removed.

The residue (7.0 g) was chromatographed on silica using _a

- 66 • ·

hexane: ethyl acetate (1: 1) as eluent.

4.0 g of 3- (2-aminobenzoyl) -propionic acid are obtained; in the form of an orange colored solid.

Melting point: 103.0 - 107.0 ° C

A mixture prepared from 0.50 g of the above material * 0.36 ml of triethylamine and 0.43 ml of diethoxyphosphinyl cyanide; in 20.0 mL of dichloromethane, was stirred at room temperature for 5 days.

After removal of the solvent from the mixture, ethyl acetate is added to the residue, and the mixture is washed successively with water; 2N citric acid solution; 1M sodium bicarbonate solution; and with a cord; and then dried over sodium sulphate.

After removal of the solvent, the residue is purified by chromatography on silica gel using ethyl acetate; hexane (1: 1) as eluent.

0.190 g of the desired product is obtained in the form of a slightly brown, crystalline solid.

Melting point: 168.0-170.0 ° C

Reference Example 34

Preparation of 4 - [(dimethylamino) methylene] -3,4-dihydro-1H-1-benzazepine-2,5-dione

After mixing 0.250 g (1.43 mmol) of 3,4-dihydro-1H-1-benzazepine-2,5-dione; and 5.50 mL (4.53 g, 41.50 mmol) of N, N-dimethylformamide, the dimethyl acetal is heated at 90.0 ° C for 1.50 hours. The reaction mixture is then cooled, diluted with diethyl ether; and filtered. The solid product is washed thoroughly with diethyl ether, and dried.

0.26 g of the title compound is obtained as a brown colored crystalline solid.

Melting point: 203.0 - 205.0 ° G

Reference Example 35

Preparation of 2-methyl-6,7-dihydro-5H-pyrimido- (5,4-d) - (1) -benzazepine

To a solution prepared by dissolving 0.308 g (3.26 mmol) of acetamidine hydrochloride; in 15.0 ml of methanol, treated in an argon atmosphere _of '0.176 g (3.26 mmol) of sodium methoxide; and 0.50 g (2.17 mmol) of 4 - [(dimethylamino) -methylene] -1,2,3,4-tetrahydro-5H-1- (0.5 mmol) was added to the mixture. benzazepine-2,5-dione; and the mixture was stirred at room temperature overnight.

Then the mixture (containing a thick precipitate) was diluted with 3.0 mL methanol and cooled; The filtrate is concentrated to dryness; and chloroform is added to the residue and the original solid to be combined. The resulting mixture was washed with water; and the separated organic layer is mixed with activated carbon and then filtered through a thin layer of magnesium silicate containing water. The filtrate is evaporated.

0.41 g of crystalline material is obtained.

Melting point: 257.0-258.0 ° C

To the resulting product whose preparation is described above, _R was added 5 equivalents of lithium hydride in aioaxanu; and the mixture was heated for 24.0 hours.

Obtained as the title compound as a solid.

• ··

Reference Example 36

Preparation of 5,6-dihydropyrrolo [2,3-b] 1,4] -benzothiazepine

To a suspension prepared from 11.67 g of 2-thiobenzoic acid; in a mixture of 32.0 ml of ethanol; and 11.0 ml of water, 12.72 g of sodium bicarbonate in solid form are added in portions. Of 2-chloro-3-nitropyridine. The mixture was then heated at reflux for 2.0 hours; The mixture is then cooled and concentrated in vacuo. The remaining aqueous solution is diluted with 15.0 ml of water; acidify with a 2N hydrochloric acid solution; and then shaken twice with 250.0 ml of ethyl acetate. Concentration of the extract in vacuo gave a yellow colored solid residue which was dissolved in a minimum amount of ethyl acetate while heating on a steam bath. The resulting solution was cooled overnight and filtered to give 2.50 g of starting material.

The filtrate is concentrated; It is cooled and filtered after filtration

12.50 g of 2- (3-nitro-2-pyridinylthio) -benzoic acid; in the form of a yellow colored solid.

The above (5.0 g), and 0.75 g of palladium on charcoal; in 60.0 ml of ethanol, was stirred in a Parr hydrogenation apparatus at 10 psi of hydrogen for 13.0 hours. The mixture was then filtered through diatomaceous earth; and the filter cake was washed with 200.0 mL of dichloromethane. The combined filtrates were evaporated in vacuo to give a solid which was treated mechanically and taken up with ethanol; and filtered to give 3.60 g yellow solid _r.

This solid (3.0 g) is again hydrogenated with presence- ⁺ and palladium on charcoal (0.50 g) in 50.0 ml of ethanol, and 30.0 ml of acetic acid under a pressure of 310.28 psi of hydrogen, after for 18.0 hours. Then the mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol.

···· • · ·

The combined filtrates are concentrated in vacuo; to give 1.60 g of a solid.

The above material was again reduced in 25.0 ml of N, N-dimethylformamide, in the presence of 0.80 g of palladium on charcoal, under 50 psi of hydrogen. 0.57 g of solid was obtained, which was recrystallized from ethyl acetate 3e. .

0.28 g of 2- (3-amino-2-pyridinylthio) -benzoic acid is obtained.

The above compound (0.20 g) was heated in 2-hydroxypyridine at 170.0 ° C to give 5,6-dihydroxypyrido- [2,3-b] 1,4] -benzothiazepine as a yellow solid of a colored solid which is reacted with borane dimethylsulfide, in a manner analogous to that described in Reference Example 3 above.

The title product is obtained in the form of a solid.

Reference Example 37

Preparation of 2-nitro-2-carboxy-diphenylamine

The solid mixture, prepared from 13.70 g of anthranilic acid, 20.20 g of o-bromonitrobenzene, 13.80 g of anhydrous potassium carbonate, and 0.10 g of metallic copper, is heated in an oil bath at 200.0 ° C with stirring. ; for 2.0 hours. The reaction mixture is then cooled, and the solid is washed 3 times with 100.0 ml of ether. The solid is then dissolved in hot water; and filtered.

The filtrate obtained is acidified with 40.0 ml of hydrochloric acid; and the resulting solid is isolated 8 dried.

20.50 g of the desired product are obtained, m.p. ___ · e e e e e e * * * *

- 70 in the form of a solid.

Melting point: 262.0-265.0 ° C

Reference Example 38

Preparation of 2-amino-2 ^from - carboxy-diphenylamine

The solution, prepared by dissolving 7.30 g of 2-nitro-2-carboxydiphenylamine in 50.0 ml of methanol, is hydrogenated at 10 psi for 24.0 hours in the presence of 10% palladium on active carbon. The mixture is filtered through diatomaceous earth and the filtrate is evaporated to dryness under vacuum.

6.60 g of the desired product are obtained in the form of a solid.

Melting point: 72.0-75.0 ° C

Reference example. 39

Preparation of 5,11-dihydro-10H-dibenz- [b, e] -1,4] -diazepin-11-one

Mixture prepared by mixing 6.60 g of 2-amino-2-carboxydiphenylamine; in 300.0 ml of xylene, heated at reflux for 20 hours. After evaporating the xylene under vacuum, the remaining residue is evaporated from 210.0 ml of toluene under vacuum; and the residue is evaporated again from 50.0 ml of chloroform. The residue is dissolved in 10.0 ml of tetrahydrofuran and added to 400.0 ml of hexane; pre-cooled with ice. The resulting solid is isolated.

4.30 g of the desired product are obtained as a solid.

Melting point: 121.0 - 123.0 ° C

Reference Example 40

Preparation of 5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepine

To the solution prepared by mixing 4.30 g of 5,11-dihydro-10H-dibenz- [b, e] -1,4] diazepin-11-one; in 50.0 ml of tetrahydrofuran, is added under stirring, under a nitrogen atmosphere, and with cooling to 0 ° C; 4.0 ml of a 10 molar solution of dimethylsulfidoborane complex in tetrahydrofuran. The cooling bath (ice-cooled) is removed after 30.0 minutes; The reaction mixture was stirred at room temperature for 18.0 hours.

Then the reaction mixture is cooled in an ice-cooled bath; and 30.0 ml of anhydrous methanol are added dropwise; and then the reaction mixture is evaporated to dryness under vacuum. Add another 30.0 mL of methanol; the mixture is again evaporated to give a residue which, after mixing with 30.0 ml of 40% sodium hydroxide solution, is heated to 110.0 ° C for 45 minutes; and then cooled to room temperature.

The reaction mixture is then diluted with 200.0 ml of water, shaken 3x with 100.0 ml of dichloromethane. The combined extracts are washed with 1N hydrochloric acid; and 0,5 N sodium hydroxide solution. The organic phase is dried and evaporated to dryness in vacuo ·

3.20 g of the desired product are obtained.

114.0-116.0 ° C

Melting point ::

Reference Example 41

Preparation of 5H-dibenz- [b, e] -azepine-6,11-dione

A mixture prepared from 2.50 g of 2-eminobenzophenone-2-carboxylic acid; in 50.0 ml xylene; The mixture was heated to reflux with stirring for 23.0 hours. The reaction mixture was then filtered.

1.82 g of the desired product are obtained in the form of a solid.

Reference Example 42

Preparation of 2-chloro-5H-dibenz- [b, e] -azepine-6,11-dione

A mixture prepared from 1.0 g of 5H-dibenz- (b, e) -sepin-6.11 dione; in 50.0 ml of acetic acid, stirred; and while stirring, chlorine gas is bubbled through until the reaction mixture is saturated. In this operation, the temperature of the mixture is raised to 38.0 ° C. On standing (a precipitate was formed from the reaction mixture, which was filtered off, washed with hexane) and air-dried.

0.62 g of a solid is obtained, which is purified by chromatography to give the title product as a solid.

Melting point: 289.0-293.0 ° C

Reference Example 43

73 Preparation of 2-chloro-6,11-dihydro-5H-dibenz- (b, e) -azepine

To a mixture prepared from 7.28 g of 2-chloro-5H-dibenz- [b, e] azepine-6,11-dione; in 25.0 mL of anhydrous tetrahydrofuran; added dropwise; in an argon atmosphere; 8.50 mL (10 M) of boron dimethyl sulfide in tetrahydrofuran.

The resulting reaction mixture was then stirred at room temperature for 18.0 hours; and then heated at reflux for 3.0 hours; and then cooled to room temperature.

while stirring vigorously, 25.0 ml of methanol are carefully added to the mixture; followed by 100.0 ml of 2N sodium hydroxide solution. Thereafter, the reaction mixture was heated to reflux for 24.0 hours; and the solid which was collected, dissolved in d ^ _fl .chořmethanu, washed with 2N HCl citrónovýma subsequently dried sodným.Poté volatiles evaporated in vacuo.

4.16 g of residue are obtained, which is recrystallized from ethyl acetate-hexane.

2.05 g of the desired product are obtained as a crystalline solid.

Mp 137.0-141.0 ° C

Reference Example 44

Preparation of 2- [2- (tributylstannyl) -3-thienyl] -1,3-dioxolane

To a solution prepared by dissolving 15.60 g (0.10 mol) of 2- (3-thienyl) -1,3-dioxolane; in 100.0 ml of anhydrous ether, n-butyllithium (1.48N; in hexane) was added dropwise under a nitrogen atmosphere, with stirring at room temperature;

74.30 ml). After the reaction mixture was heated to reflux for 15 minutes, the mixture was cooled to minus 78.0 ° C; and 34.18 g of tributylstannyl chloride (0.105 mol) / in 100.0 ml of dried tetrahydrofuran are added dropwise. At the end of this operation, the reaction mixture was allowed to reach room temperature; and the solvent was evaporated. 100.0 ml of hexane are then added to the residual oily consistency; and the resulting precipitate (lithium chloride) is filtered off. Then the filtrate is evaporated; and the residue distilled under reduced printing.

34.16 g (77% yield) of the title product are obtained, m.p.

Reference Example 45

Preparation of 2- (2 - [(2-nitrophenyl) methyl] -3-thienyl] -1,3-dioxolane

A mixture of 2- (2- (tributylstannyl) -3-thienyl) -1,3-dioxolane (8.80 g, 20 mmol); 4.50 g (22.0 mmol) of 2-nitrobenzyl bromide; and tetrakis- (triphenylphosphine) -palladium (0) (200.0 mg) / heated to reflux; in a nitrogen atmosphere; in degassed toluene; at the end of said operation, the reaction mixture is allowed to reach room temperature; and then filtered through diatomaceous earth. Thereafter, toluene is concentrated under reduced pressure; and the product was isolated by silica gel chromatography eluting with 30% ethyl acetate / hexane.

4.50 g of the desired product are obtained in the form of a viscous liquid.

Mass Spectroscopy (M ⁺ ): 292.0;

Reference Example 46

Preparation of 4,10-dihydro-5H-thien- [3,2-c] 1-benzazepine

A solution prepared by dissolving 4.0 g of 2- [2 - [(2-nitrophenyl) methyl] -3-thienyl-1,3-dioxolane} in 50.0 ml of acetone} and 50.0 ml of 90% acetic acid. , is heated from constant stirring to 60 ° C.

To this reaction mixture was slowly added 10.0 g of zinc dust, after which the reaction mixture was stirred for 6.0 hours. The reaction mixture was then filtered (and the residue was washed with acetone) and concentrated. The residue is shaken with chloroform and thoroughly washed with water.

The separated organic layer was dried over sodium sulphate and concentrated after filtration. The product was isolated by column chromatography on silica gel, eluting with 20% ethyl acetate / hexane.

2.0 g of the expected product are obtained in the form of a slightly yellow-colored solid.

Melting point: S6.0 ° C

Mass Spectroscopy (M +): 202.0}

Reference example 4T ⁷

Preparation of 4,5-dihydro-4,4-dimethyl-2- [3 - [(2-nitrophenyl) methyl] -2-thienyl] -oxazole

To the solution prepared by dissolving 4,50 g (25 mmol)

4,5-dihydro-4,4-dimethyl-2- (: 2-thienyl) -oxazole} in anhydrous ether is added at a temperature of minus 70.0 ° C under a nitrogen atmosphere. ····················································

76 drop by drop, 11.0 ml n-butyllithium solution (2.5 molar in hexane). The reaction mixture was then stirred at minus 78.0 ° C for 45.0 minutes; and then, drop by drop, 8.30 g of tri-n-butylsulfanyl chloride (25.0 mmol) in dried ether. Then the reaction mixture was stirred at room temperature for 1.0 hour; and then mix quickly with water.

Then the mixture is shaken with ether, washed thoroughly with water, dried, and concentrated. The product obtained is sufficiently pure to be used for the next reaction.

An oily consistency product, i.e., 4,5-dihydro-4,4-dimethyl-2- [3- (tributylatannyl) -2-thienyl] oxazole; mixes with

5.50 g (25 mmol) of 2-nitrobenzyl bromide, in toluene; and the mixture 3e is heated to reflux in the presence of 200.0 mg of tetrakis (triphenylphosphine) palladium (0); for 16.0 hours. At the end of said operation, the reaction mixture is allowed to reach room temperature; and filtered.

After removal of toluene under reduced pressure, a brown-colored oily consistency product is isolated _from silica gel column chromatography, eluting with 30% ethyl acetate in hexane.

5.70 g of the desired product are obtained.

Mass Spectroscopy (M &lt; + &gt;): 316, OJ

Reference Example 48

Preparation of 9,10-dihydro-4H-thien- [3,2-c] -1-benzazepin-10-one

A solution prepared by dissolving 5.0 g of 4,5-dihydro-4,4-dimethyl-2- [3 - [(2-nitrophenyl) methyl] -2-thienyl] -O-8-azole; in a mixture (100.0 mL) of acetone and water (3: 1); and containing 30.0 ml of a 1N hydrochloric acid solution; is heated at reflux below • *

- 77 reflux condenser, for 24,0 hours.

The reaction mixture was concentrated, and the residue was dissolved in glacial acetic acid (100 ml). To this solution, with stirring, at 70.0 ° C, was slowly added 10.0 g of zinc rust, and the reaction mixture was further stirred at 70.0 ° C for 6.0 hours. the mixture is cooled to room temperature; After removal of the acetic acid under reduced pressure, the residue obtained is shaken with chloroform, and the chloroform layer is then dried and concentrated.

2.90 g of the desired product are obtained in the form of a brown solid.

Mass Spectroscopy (M +): 215, OJ

Reference Example 49

Preparation of 9,10-dihydro-4H-thien- [2,3-c] -1-benzazepine

A solution prepared from 2.0 g of 9,10-dihydro-4H-thien- [2,3-b] benzazepin-10-one; and 500.0 mg lithium aluminum hydride in tetrahydrofuran; with stirring at reflux for 4.0 hours. At the end of this operation, the reaction mixture is carefully mixed with ice-cold water and then shaken with chloroform.

The organic layer is washed thoroughly with water, and dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by silica gel column chromatography, using 30% ethyl acetate in hexane as eluent.

1.20 g of the desired product are obtained as a bright yellow solid.

Mass Spectroscopy (M ⁺ ): 202, OJ • · · ·

Reference Example 50

Preparation of 2-methylfuran-carbonyl chloride

The mixture prepared from 4.0 g of methyl 2-methylfuran-3-carboxylate is 30.0 ml of 2N sodium hydroxide solution; and 15.0 ml of methanol, heated at reflux for 1.50 hours. After this operation, the solvent is removed in vacuo, and the resulting solid is shaken with dichloromethane, which is discarded. Then the solid residue is dissolved in water, and the resulting solution is acidified with a 2N citric acid solution, which precipitates a solid, which is washed with water and dried.

1.05 g of 2-methylfuran-3-carboxylic acid is obtained, in crystalline form.

The above compound, (0.95 g) is 3.0 mL of thionyl chloride; Heat at reflux for 1.0 h. To remove the solvent, add to the residue 3 x 20.0 ml toluene each; and after removal of the solvent, the title product is obtained in the form of an oily consistency _ς

Reference Example 51

Preparation of 2- / 2- (tributylstannyl) -3-thienyl / -1,3-dioxolane

To a solution prepared by dissolving 15.60 g (0.10 mol) of 2- (3-thienyl) -1,3-dioxolane; in 100.0 ml of anhydrous ether is added dropwise, with stirring, and under a nitrogen atmosphere, at room temperature; 74.30 ml of a solution of (1.48 N) n-butyllithium in hexane.When the reaction mixture was heated to reflux for 15 minutes, the mixture was cooled to minus. • · · · · · · ·

78.0 ° C, and then 34.18 g (0.105 mol) of n-butylstannyl chloride solution are added dropwise; in 100.0 ml of dried tetrahydrofuran. After this operation is complete, the reaction mixture is allowed to warm to room temperature; and the solvent is evaporated.

To the residual oily consistency obtained, 100.0 ml of hexane are added, and the resulting precipitate (lithium chloride) is filtered off. The filtrate is evaporated and the residue is distilled under reduced pressure.

34.16 g (77% yield) of the title product are obtained.

Reference Example 52

Preparation of methyl 6-aminopyridine-3-carboxylate

Hydrogen chloride gas was bubbled through for 25.0 minutes into 400 ml of dry methanol, cooled in an ice-cooled bath. 30.0 g of 6-aminopyridine-3-carboxylate were added to the methanol saturated with hydrogen chloride. ; and heating the resulting reaction mixture at 90.0 ° C; with stirring, for 2.0 hours, all solid particles being dissolved.

After removal of the solvent under vacuum, the solid residue obtained is dissolved in 100.0 ml of water; and the acidic solution is neutralized with a saturated aqueous sodium bicarbonate solution (solid is removed) / and the mixture is filtered after cooling.

30.0 g of the desired product are obtained in the form of a white crystalline solid.

150.0-154.0 ° C

Melting point :

9999 9 99 99 9999 9 9 9 9 9 9 t 99 99 99 9 9

9 9 9 9 9

999999 9 9 9 9 9 9 9 9

- 80 Reference Example 53

Preparation of 6 - [(5-fluoro-2-methylbenzoyl) -amino] -pyridine-3-carboxylic acid

To the mixture prepared by mixing 4.50 g of methyl 6-quinopyridine-3-carboxylate and 5.53 ml of triethylamine in 40.0 ml of dichloromethane cooled in an ice-cooled bath is added 6.38 g.

5-fluoro-2-methylbenzoyl chloride, in 10.0 mL of dichloromethane.

The resulting reaction mixture was stirred under argon; and at room temperature for 18.0 hours; and then another 3.40 g of 5-fluoro-2-methylbenzoyl chloride was added.

After the mixture is stirred at room temperature for 3.0 hours; The mixture was filtered, and 3.0 g of methyl 6 - [[beta] - (5-fluoro-2-methylbenzoyl) - amino] pyridine-3-carboxylate was obtained.

After concentrating the filtrate to dryness, the residue is worked up mechanically and taken up in hexane with ethyl acetate; to give an additional 9.0 g of the bis-acetylated product.

A mixture of 12.0 g of the above-mentioned methyl 1-6 - [(bis (5-fluoro-2-methylbenzoyl)] - amino) pyridine-3-carboxylate is treated with 60.0 ml of a 1: 1 mixture of methanol and tetrahydrofuran After stirring at room temperature for 16.0 hours, the reaction mixture was concentrated in vacuo and, after dilution with 25.0 ml of water, cooled and acidified with 1N hydrochloric acid. Then the mixture was filtered, and the solid was washed with water.

6.30 g of the expected product are obtained in the form of a white solid.

In analogy to the above Reference Example 53J, the following 6 - [(arylamino) -pyridine-3-carboxylic acid] 6 - [(heteroaroyl) -amino] -pyridine] may be prepared by substitution with the appropriate aroyl chloride, heteroarlyl chloride, cycloalkanoyl chloride, phenylacetyl chloride and the corresponding acid chloride. -3-carboxylic acids and related

6- (acetylated) -amino / -pyridine-3-carboxylic acid.

Reference Example 54

Preparation of 6 - [(3-methyl-2-thienylcarbonyl) -amino] -pyridine-3 carboxylic acid

Reference Example 55

Preparation of 6 - [(2-methyl-3-thienylcarbonyl) -amino] -pyridine-3-carboxylic acid

Reference Example 56

Preparation of 6 - [(3-methyl-2-furanylcarbonyl) -amino] -pyridine-3-carboxylic acid

Reference Example 57

Preparation of 6 - [(2-methyl-3-furanylcarbonyl) -amino] -pyridine-3-carboxylic acid

Reference Example 58

Preparation of 6 - [(3-fluoro-2-methylbenzoyl) -amino] -pyridine-3-carboxylic acid

- 82 Reference example 59

Preparation of 6 - [(2-methylbenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 60

Preparation of 6 - [(2-chlorobenzovl) -amino] -pyridine-3-carboxylic acid

Reference Example 61

Preparation of 6 - [(2-fluorobenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 62

Preparation of 6 - [(2-chloro-4-fluorobenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 63

Preparation of 6 - [(2,4-dichlorobenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 64

Preparation of 6- (4-chloro-2-fluorobenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 65

• ·

Preparation of 6- / (3,4,5-trimethoxybenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 66

Preparation of 6 - [(2,4-difluorobenzoyl) amino] -pyridine-3-carboxylic acid

Reference Example 67

Preparation of 6- [(2-bromobenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 68

Preparation of 6 - [(2-chloro-4-nitrobenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 69

Preparation of 6 - [(tetrahydrofuran-2-carbonyl) -amino] -pyridine-3-carboxylic acid

Reference Example 70

Preparation of 6 - [(tetrahydrothienyl-2-carbonyl) -amino] -pyridine-3-carboxylic acid

Reference Example 71

Preparation of 6 - [(cyclohexylcarbonyl) -amino] -pyridine-3-carboxylic acid

- 84 Reference example 72

Preparation of 6 - [(cyclohex-3-en-carbonyl) -amino] -pyridine-3-carboxylic acid

Reference Example 73

Preparation of 6 - [(5-fluoro-2-methylbenzeneacetyl) -amino] -pyridine-3-carboxylic acid

Reference Example 74

Preparation of 6 - [(2-chlorobenzeneacetyl) amino] -pyridine-3-carboxylic acid

Reference Example 75

Preparation of 6 »[(cyclopentylcarbonyl) -amino] -pyridine-3-carboxylic acid

Reference Example 76

Preparation of 6 - [(cyclohexylacetyl) -amino] -pyridine-3-carboxylic acid

Reference Example

Preparation of 6 - [(3-methyl-2-thienylacetyl) -amino] -pyridine-3-carboxylic acid

Reference Example 78 ·· ····

Preparation of 6- [(2-Methyl-1-3-thienylacetyl) -amino] -pyridine-3-carboxylic acid

Reference Example

Preparation of 6 - [(3-methyl-2-furanylation of ethyl) -sino] -pyridine-3-carboxylic acid

Mp 288.0-290.0 ° C

Reference Example 80

Preparation of 6 - [(2-Methyl-3-furyl-acetyl) -emino] -pyridine-3-carboxylic acid

Reference Example 81

Preparation of 6 - [(3-methyl-2-tetrahydro-thienylacetyl) -amino] -pyridine-3-carboxylic acid

Reference Example 82

Preparation of 6 - [(2-methyl-3-tetrahydro-thienyl-acetyl) -pyridine-3-carboxylic acid]

Reference Example 83

Preparation of 6 - [(2,5-dichlorobenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 84

···· «

Preparation of 6 - [(3,5-dichlorobenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 85

Preparation of 6 - [(2-methyl-4-chlorobenzoyl) -amino] -oyridine-3-carboxylic acid

Reference Example 86

Preparation of 6 - [(2,3-dimethylbenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 87

Preparation of 6 - [(2-Methoxybenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 88

Preparation of 6 - [(2-trifluoromethoxybenzoyl) -amino] -pyridine-3 carboxylic acid

Reference Example 89

Preparation of 6 - [(4-chloro-2-methoxybenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 90

Preparation of 6- / (2- (trifluoromethyl) -benzoyl) -amino) -pyridine-3 carboxylic acid

Reference Example 91

Preparation of 6 - [(2,6-dichlorobenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 92

Preparation of 6 - [(2,6-dimethylbenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 93

Preparation of 6 - [(2-methylthiobenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example

Preparation of 6 - [(4-fluoro-2- (trifluoromethyl) -benzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example

Preparation of 6 - [(2,3-dichlorobenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 96

Preparation of 6 - [(4-fluoro-2-methylbenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 97 • • • • • • • • • • • • • • • • • •

Preparation of 6 - [(2,3,5-trichlorobenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 98

Preparation of 6 - [(5-fluoro-2-chlorobenzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example

Preparation of 6 - [(2-fluoro-5- (trifluoromethyl) -benzoyl) -amino] -pyridine-3-carboxylic acid

Reference Example 100

Preparation of 6 - [(5-fluoro-2-methylbenzoyl) -amino] -pyridine-carbonyl chloride

The mixture prepared by mixing 6.20 g of 6 - [(5-fluoro-2-methylbenzoyl) -amino] -pyridine-3-carboxylic acid and 23.0 ml of thionyl chloride is refluxed for 1.0 hour. A further 12.0 ml of thionyl chloride was added to the reaction mixture, and the mixture was heated at reflux for 0.50 hours.

The reaction mixture was then concentrated to dryness under vacuum and 30.0 ml of toluene were added to the residue.

9 9 9 99 9 9 9 9 9 9 9 9 10 11 12 13 14 15 16 17 18 19 20

99999 999 99 99

- 89, the operation with addition and subsequent removal of toluene is repeated once more.

7.70 g of the desired product are obtained as a crude solid.

In an analogous manner to that described in the preceding Reference Example 100; the following 6 (acyl) amino) -pyridine-3-carbonyl chlorides can also be prepared (Reference Examples 101 to 147).

Reference Example 101

Preparation of 5 - [(3-methyl-2-thienylcarbonyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 102

Preparation of 6 - [(2-methyl-3-thienylcarbonyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 103

Preparation of 6 - [(3-methyl-2-furanylcarbonyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 104

Preparation of 6 - [(2-methyl-3-furanylcarbonyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 105

Preparation of 6- [(3-fluoro-2-methylbenzoyl) -emino] -pyridine-3-carbonyl chloride

Reference Example 106

Preparation of 6 - [(2-methylbenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 107

Preparation of 6 - [(2-chlorobenzoyl) amino] pyridine-3-carbonyl chloride

The above compound was obtained as white _r kry3 tslické substance.

Reference Example 10S

Preparation of 6 - [(2-fluorobenzoyl) amino] -pyridine-3-carbonyl chloride

Reference Example 109

Preparation of 6 - [(2-chloro-4-fluorobenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 110

Preparation of 6 - [(2,4-dichlorobenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 111

Preparation of 6 - [(4-chloro-2-fluorobenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 112

Preparation of 6 - [(3,4,5-trimethoxybenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 113

Preparation of 6 - [(2,4-difluorobenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 114

Preparation of 6 - [(2-bromobenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 115

Preparation of 6 - [(2-chloro-4-nitrobenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 116

Preparation of 6 - [(tertrahydrofuranyl-2-carbononyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 117

Preparation of 6 - [(tetrahydrothien, yl-2-carbonyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 118

Preparation of 6 - [(cyclohexylcarbonyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 119

Preparation of 6 - [(cyclohex-3-en-carbonyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 120

Preparation of 6 - [(2-methylbenzeneacetyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 121

Preparation of 6 - [(2-chlorobenzeneacetyl) -amino] -pyridine-2-carbonyl chloride

Reference Example 122

Preparation of 6 - [(cyclopentylcarbonyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 123

Preparation 6 - / (cyclohexylacetyl) -a ^i! Nino / pyridine-3-carbonyl chloride

Reference Example 124

Preparation of 6 - [(3-methyl-2-thienylcarbonyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 125

Preparation of 6 - [(2-methyl-3-thienylacetyl) -emino] -pyridine-3-carbonyl chloride

Reference Example 126

Preparation of 6 - [(3-methyl-2-furanylation-yl) -amino] -pyridine-3-carbonyl chloride

Reference Example 127

Preparation of 6 - [(2-methyl-3-furanylacetyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 128

Preparation of 6 - [(2-methyl-5-fluorobenzeneacetyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 129

Preparation of 6 - [(3-Methyl-2-tetrahydro-thienylacetyl) -amino] -pyridine

3-carbonyl chloride

Reference Example 130

Preparation of 6 - [(2-methyl-3-tetrahydrothienylacetyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 131

Preparation of 6 - [(2,5-dichlorobenzoyl) -araino] -pyridine-3-carbonyl chloride

Reference Example 132

Preparation of 6 - [(3,5-dichlorobenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 133

Preparation of 6 - [(2-methyl-4-chlorobenzoyl) -amino] -pyridine-3-carbonyl 1-chloride

Reference Example 134

Preparation of 6 - [(2,3-dimethylbenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 135

Preparation of 6 - [(2-methoxybenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 136

Preparation of 6 - [(2-Trifluoromethoxybenzoyl) amino] -pyridine-2-carbonyl chloride

- 95 Reference example 137

Preparation of 6 - [(4-chloro-2-thoxybenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 138

Preparation of 6 - [(2- (trifluoromethyl) -benzoyl] -amino) -pyridine-3-carbonyl chloride

Reference Example 139

Preparation of 6 - [(2,6-diethylbenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 140

Preparation of 6 - [(2,6-dimethylbenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example

Preparation of 6 - [(2-methylthiobenzoyl) -amino] -pyridine-3-carbonyl chloride

Reference Example 142

Preparation of 6 - [(4-fluoro-2- (trifluoromethyl) -benzoyl) -8mino] -pyridine-3-carbonyl chloride

Reference Example 143 • · ·

96 Preparation of 6 - [(2,3-dichlorobenzoyl) -amino] -pyridine-3-carbonyl chloride • ··

Reference Example 144

Preparation of b - [(4-Fluoro-2-methylbenzoyl) -emino] -pyridine-3-carbonyl chloride

Reference Example 145

Preparation of 6 - [(2,3,5-trichlorobenzoyl) -amino] -pyridine-3-carbonyl chloride reference example 146

Preparation of 6 - [(5-fluoro-2-chlorobenzoyl) -anone] -pyridine-3-carbonyl chloride

Reference Example 147

Preparation of 6 - [(2-fluoro-5- (trifluoromethyl) -benzoyl) -emino] -pyridine-3-carbonyl chloride

In a similar manner to that described in Reference Example 53 * above, the following .beta.-acetylated products may also be prepared which have been purified by silica gel chromatography and are shown, together with the general structural formula, in Taoulace A; published on the next page.

The aforementioned compounds can then be hydrolyzed to acids in analogy to the procedure described in Reference Example 53 above. published on other pages.

Reference Example 172

Preparation of 6-amino-5-bromopyridine-3-carboxylic acid

To a solution prepared by dissolving 13.80 g (0.10 mol) of 6-aminonicotinic acid (b-emino-3-pyridinecarboxylic acid) J in 100.0 ml of glacial acetic acid, slowly add a mixture of 16.0 g 5.0 ml of 0.10 mol of bromine, in 20.0 ml of acetic acid. The resulting reaction mixture was stirred for 8.0 hours at room temperature; and then the acetic acid is removed under reduced pressure.

The yellow-colored residue was dissolved in water; and then carefully neutralized with 30% sodium hydroxide solution. The solid was filtered, and washed with water.

18.0 g of the title product are obtained as a solid.

Mass Spectroscopy (M ⁺ ): 218, OJ

Reference Example 173

Preparation of methyl 6-amino-5-bromopyridine-3-carboxylate in 100.0 ml of saturated methanolic hydrogen chloride solution dissolved 10.0 g (50.0 mmol) of 6-amino-5-bromopyridine carboxylic acid, and the resulting reaction mixture was warms behind

- 98 · · 98 98 98 98

Table A

H,

Rerer. pr. C Rl R ₂ * 3 r ₄ X M " * Λ £ Γ'- 'i '4 3 S 5 1 ’J a r * -'- and? i 1 - <- <ir- I «-. ccm r r '4 - ídt 1 · - - - • · d ~ n - - 4. s- - r : í j 1 .. «-“ í - - 1 - 1 - - ’- • 1 · , ->. i - 1 - 1 312 1 ' - 13- · - · 1 year · - 1 - 1 - | r 1 - - 3 15 9 1 CH? 1 1 1: -: Ξ r 4 6 -

M is a molecular ion in the FAB mass spectrum • ·

Table B

Ref. pr.č. Rl r ₂ 8 · 3 r ₄ X M ” cm .. ? ς X | «Y- · cm · - 152 CHj r - · OF'! 1 cc?: -! Q £ - ^? 154 Cl 1 1 1 1 - / · * Γ ” 1 - 1 · - · 1 ·. · ~ ^ í 1 1 and . A / < O v * 7 £ 3 r ¹ - - \ 170 1 CH-. 1? - 1 - 1 *** ' 1 1 1 1 1 1 - -

M ⁺ is the molecular ion in the FA3 mass spectrum.

I »

After refluxing the methanol for 24.0 hours. After the methanol is removed from the mixture under reduced pressure, the residue is dissolved in ice-cold water. The resulting aqueous solution is neutralized with 0.1N sodium hydroxide solution, and the solid which separated was filtered off, then washed well with water and air dried.

There was obtained 10.0 g of the desired product as a solid.

Mass Spectroscopy (M ⁺ ): 231.0;

Reference Example 174

Preparation of 6 - [(2-methylbenzeneacetyl) -amino] -pyridine-3-carboxylic acid

ICu of the mixture cooled to 0 ° C; and prepared by mixing 5.0 g of methyl 6-8minopyridine-3-carboxylate; and 12.60 ml of N, N-diisopropylethylamine in 40.0 ml of dichloromethane are added a solution prepared by dissolving 12.20 g of 2-methylbenzeneacetyl chloride in 10.0 ml of dichloromethane.

The resulting reaction mixture was then stirred under argon at room temperature overnight. The mixture was then diluted with 200.0 mL of dichloromethane; and with 50.0 ml of water and the organic layer was separated. Then, the organic phase is washed successively with 50.0 ml of 1M sodium bicarbonate solution and 50.0 ml of brine; and then dried over sodium sulphate.

Then, the mixture is filtered through a thin layer of magnesium silicate containing water; and the filtrate was evaporated to dryness. The residue (9.0 g) was chromatographed on silica gel, eluting with hexane: ethyl acetate (3: 1).

8.60 g of solid are obtained.

·· «···

- 101

The above-mentioned substance obtained in the preceding operation, i. predominantly methyl 6 - [[bis (2-methylbenzeneacetyl)] - amino] -pyridine-3-carboxylate} is dissolved in 60.0 mL of tetrahydrofuran: methanol (1: 1)} and 23.0 mL ml of 5N sodium hydroxide solution. The reaction mixture was stirred at room temperature overnight and then concentrated under vacuum. 25.0 ml of water was added to the residue, and the mixture was stirred and acidified with cold 1N hydrochloric acid. Then the mixture was cooled. The solid was filtered off and washed with water.

5.90 g of a white solid are obtained.

Reference Example 175

Preparation of 6 - [(2-methylbenzeneacetyl) -amino] -pyridine-3-carbonyl chloride

A mixture prepared by mixing 4.50 g of 6 - [(2-methylbenzeneacetyl) -amino] -pyridine-3-carboxylic acid} and 25.0 ml of thionyl chloride; 3e is heated under reflux for 1.0 hour; and then concentrated to dryness under vacuum.

To the residue is added 20.0 ml of toluene; This toluene operation is repeated once more and the resulting solid residue is dried at room temperature under vacuum.

5.30 g of the desired product are obtained in the form of a gray-colored solid, m.p.

Reference Example 176

102 • ···············································

Preparation of [1,1'-biphenyl] -2-biphenylcarbonyl chloride

A mixture prepared by mixing 5.60 g of (1,1-biphenyl) -2-carboxylic acid and 29.0 ml of thionyl chloride; Heat on a steam bath for 0.50 hours. The volatiles are then removed from the reaction mixture under vacuum; and 40.0 ml of toluene are added to the residue, which is then evaporated. This toluene operation is repeated once more, 'and is carried out under vacuum.

6.80 g of the desired product are obtained in the form of a yellow oil.

Reference Example 177

Preparation of methyl 6 - [bis - ([1,1-biphenyl] -2-carbonyl)] -amino] pyridine-3-carboxylate

To the cooled solution to 0 ° C; připrěvaného dissolving 2.64 g of methyl 6-aminopyridine-3-karbox.ylátu _/ and 5.50 ml of diisopropylethylamine in 30.0 ml of dichloromethane; added under argon, 6.80 g of (1,1-biphenyl) -2-carbonyl chloride; in 10.0 ml of dichloromethane. The resulting reaction mixture was stirred at room temperature for 2.0 days; and then diluted with 120.0 ml of dichloromethane / and 50.0 ml of water.

After separation, the organic layer is washed sequentially with 50.0 ml of a 1Τ. sodného sodium bicarbonate solution; and 50.0 ml of brine, and then dried with sodium sulfate. The mixture was then filtered through a thin pad of magnesium silicate / containing water, and the filtrate was concentrated in vacuo to a solid residue which was recrystallized from ethyl acetate.

6.20 g of the expected product are obtained in the form of a white crystalline solid.

Melting point: 180.0-188.0 ° C

Reference Example 178

Preparation of 6 - [(1,1-Biphenyl / -2-ylcarbonyl)] - amino] -pyridine-3-carboxylic acid

To a mixture of 6.0 g of methyl 6 - [bis - [(1,1-biphenyl) -2-1-carbonyl]] -amino] -pyridine-3-carboxylate, * in 40.0 ml of methanol; and 30.0 ml of tetrahydrofuran, cooled to 0 ° C, slowly added 18.0 ml of 2N sodium hydroxide solution.

The resulting reaction mixture was stirred at room temperature overnight; and then the pH of the mixture is adjusted to pH 5.0 with glacial acetic acid. Thereafter, the reaction mixture is concentrated, then acidified with 1N hydrochloric acid to a pH of 2.0 to 3.0; and then shaken with 250.0 ml of ethyl acetate.

The extract obtained is washed with 50.0 ml of brine, dried over sodium sulphate and then the solvent is removed in vacuo. The residue, as a white solid, was worked up mechanically and taken up with 15.0 ml of ethyl acetate.

3.35 g of the expected product are obtained in the form of a white crystalline solid.

Melting point: 215.0-217.0 ° C

Reference Example 179

Preparation of 6- (1,1'-biphenyl) -2-yl-carbonyl) -amino] -pyridine-3-carbonyl chloride

- 104

The mixture, prepared by mixing 1.90 g of 6 - [(1,1-biphenyl) -2-ylcarbonyl) -amino] -pyridine-3-carboxylic acid, and 9.0 ml of thionyl chloride, is heated to reflux for 3 hours. for 1.0 hour and then concentrated to dryness.

To the residue is added 15.0 ml of toluene, which is then evaporated in vacuo; and this toluene operation is repeated once more.

2.10 g of the desired product are obtained in the form of a light brown oil.

Reference Example 180

Preparation of 6 - [(Cyclohexylcarbonyl) -araino] -pyridine-3-carboxylic acid

To a solution cooled to 0 ° C; and prepared by dissolving 5.0 g of methyl 6-aminopvridine-3-carboxylate; and 12.60 ml of diisopropylethylamine; in 50.0 ml of dichloromethane, a solution prepared from 9.70 ml of cyclohexylcarbonyl chloride in 10.0 ml of dichloromethane is added under an argon atmosphere.

The resulting reaction mixture was stirred at room temperature overnight; and then diluted by the addition of 200.0 ml of dichloromethane; and 60.0 ml of water. After separation, the organic layer is washed with 60.0 mL of brine; and dried with sodium sulfate. The mixture is then filtered through a thin layer of magnesium silicate with water content, and the filtrate is concentrated under vacuum.

12.80 g of solid are obtained.

The above solid, prepared in the previous step, was cooled to 0 ° C in tetrahydrofuran: methanol (1: 1) and then 62.0 ml of 2N sodium hydroxide solution was added.

• ·· · β

• · a

105

The resulting reaction mixture was stirred at room temperature for 3.0 hours, then neutralized with 10.0 ml of glacial acetic acid and then concentrated in vacuo. Thereafter, the mixture (containing the solids) was acidified with 1N hydrochloric acid solution. to pH 1.0; and shake first with 250.0 ml of ethyl acetate; and then twice with 100.0 ml of ethyl acetate.

The combined extracts were washed with 100.0 ml of brine; dried with sodium sulfate; and concentrated to a white / solid which was then mechanically treated and taken up with hexane.

6.50 g of the desired product are obtained in the form of a white solid.

Reference Example 181

Preparation of methyl 2- (4-ethoxy-oxobutyl) aminobenzoate

Mixture prepared by mixing 19.20 g of methyl 2-aminobenzoate; and 9.60 g of ethyl? -bromobutyrate; was heated at 80.0-85.0 ° C for 24.0 hours. The mixture was then cooled to room temperature and filtered. The solid was washed with dichloromethane; and the filtrate is washed successively with 1N ammonium chloride solution; with water; 1N sodium bicarbonate solution; and finally with brine.

After removal of the solvent, an oily consistency is obtained which is distilled; and a fraction boiling at 45.0 to 75.0 ° C; and 130.0-160.0 ^o C13e collected and discarded

The residue was the title product (55.40 g) obtained as an oil.

- 106 -

Reference Example 182

Preparation of methyl 2- [N- (4-ethoxy-4-oxobutyl) -N- (2-methylphenylsulfonyl) amino] benzoate

Mixture prepared by mixing 2.65 g of methyl 2 - [(4-ethoxy-4-oxobutyl) amino] benzoate 2.0 g of 2-methylphenylsulfonyl chloride and pyridine; Heat on a steam bath for 16.0 hours. The reaction mixture was concentrated in vacuo (pyridine was removed) and 1N hydrochloric acid was added.

The mixture was then shaken with dichloromethane and the extract washed successively with 1N hydrochloric acid; water; with 1M sodium bicarbonate; brine; and then dried over sodium sulfate. The mixture is filtered through a thin layer of magnesium silicate containing water; and the filtrate was evaporated.

3.80 g of solid are obtained, which are recrystallized from ethanol; to give the title compound as a crystalline solid

Melting point: 100.0 - 102.0 ° C

Reference Example 183

Preparation of methyl and ethyl 1,2-dihydro-5-hydroxy-1 - [(4-methylphenyl) sulfonyl] -3H-1-benzazepine-4-carboxylate

To the mixture prepared by mixing 0.448 g of potassium tert-butoxide (butoxide); in 2.0 mL of tetrahydrofuran cooled to 0 ° C * 0.838 g of methyl 2- [N- (4-ethoxy-4-oxobutyl) -N- (2-methylphenylsulfonyl) amino] benzoate was added; in 12.0 mL of tetrahydrofuran.

The resulting reaction mixture was stirred under a nitrogen atmosphere at 0 ° C for 4.0 hours. It is then poured into water and neutralized with 2N citric acid solution. The mixture was then shaken with dichloromethane. and the extract obtained is washed successively with water and brine, and dried over magnesium sulphate.

The extract is then filtered through a thin layer of magnesium silicate containing water; and the filtrate is concentrated to dryness.

0.58 g of the expected product is obtained; of the title product, in the form of a mixture of methyl and ethyl esters.

Reference Example 184

Preparation of 1,2,3,4-tetrahydro-1 - [(2-methylphenyl) -sulfonyl] -5H-benzazepin-5-one

A mixture of 30.0 g of methyl 1-ethyl-1,2-dihydro-5-hydroxy-1 '(4-methylphenyl) sulfonyl] -3H-1-benzazepine-4-carboxylate; in a mixture of 1 - 1.0 ml concentrated hydrochloric acid; and 171.0 ml of glacial / acetic acid were heated under reflux for 24 hours.

Another 170.0 ml of concentrated hydrochloric acid was added to the reaction mixture; and the mixture was heated at reflux for an additional 24.0 hours. The mixture was then concentrated to near dryness in vacuo; diluted with water; and the resulting solution was adjusted to pH 8.0 with a saturated aqueous solution of sodium bicarbonate _/ pH. Then the mixture is shaken with dichloromethane, and the extract is washed successively with water and brine; and dried with sodium sulfate.

The resulting solution is filtered through a thin layer of water-containing magnesium silicate; and the filtrate was evaporated.

12.0 g of the expected product are obtained in the form of a brown oil.

- 108

Reference Example 185

Preparation of 4 - [(dimethylamino) -methylene] -1,2,3,4-tetrhydro-1 / (2-methylphenyl) sulfonyl] -5H-1-benzazepin-5-one

A mixture prepared by mixing 1.89 g of 1,2,3,4-tetrahydro-1 [(2-methylphenyl) sulfonyl] -5H-1-benzazepin-5-one; and 2.47 ml of tert-butoxy-bis- (dimethylamino) -methane (Bredericks reagent); in 10.0 ml of dichloromethane, was heated under an argon n steam bath / for 16.0 hours.

The reaction mixture is then concentrated to dryness in vacuo, and the residue is dissolved in dichloromethane. The solution is filtered through a thin layer of magnesium silicate / containing water and the filter layer is washed with a mixture of 5% ethyl acetate in dichloromethane. After concentrating the filtrate to dryness, the residue (1.96 g) is recrystallized from dichloromethane-hexane to give 0.85 g of the desired product as a crystalline solid.

Melting point: 180.0-150.0 ° C

A second crop of crystalline desired product was obtained (0.85 g) after treatment of the mother liquors; and an additional 0.30 g is obtained after washing the magnesium silicate / containing water * with ethyl acetate.

Reference Example 186

Preparation of 1,4,5,6-tetrahydro-6 - [(2-methylphenyl) -sulfonyl] pyrazole- (4) _; 3-d // 1 / -benz of pin • · · 9 • · · ·

109

Mixture prepared by mixing 1,55 g of 4 - [(dimethylamino) methylene] -1,2,3,4-tetrahydro-1 - [(2-methylphenyl) sulfonyl] -5H-1-benzazepin-5-one 0, 25 ml hydrazine; and 60.0 ml of ethanol, are heated under reflux in an argon atmosphere on a steam bath for 2.0 hours.

After allowing the reaction mixture to stand at room temperature overnight, the solvent is removed in vacuo.

The mixture is filtered through a thin layer of magnesium silicate containing water and the filtrate is evaporated.

1.40 g of the desired product are obtained in the form of a crystalline solid.

Melting point: 76.0-79.0 ° C

When carrying out the above reaction on a larger scale, with 18.29 g of 4-Adimethylamino) -methylene- (1,4-tetrahydro-1,2-methyl-phenyl) -sulfonyl-5H-1-benzazepin-5-one; the product in dichloromethane is filtered through a thin layer of magnesium silicate containing water; The filter cake is then washed with ethyl acetate. The resulting filtrate 3e is concentrated.

16.50 g of the expected product are obtained, which product is obtained by thin layer chromatography; eluting with silica gel ₍ and hexane: ethyl acetate 1: 2); shows one spot.

Reference Example 187

Preparation of 1,4,5,6-tetrahydro-pyrazole- [4,3-d] -benzazepine

- 110

A mixture prepared by mixing 1.0 g of 1,4,5,6-tetrahydro-6 [(2-methylphenyl) -sulfonyl] -pyrazole- [4,3-d] -benzazepine; in a mixture of 60.0 ml of 40% (v / v) sulfuric acid; in glacial acetic acid is heated at 60.0 ° C for 12.0 hours until the tosyl group is degraded. The reaction mixture was poured into 100.0 ml of ice and water, while cooling. It is then added portionwise to the mixture while maintaining the temperature below 30 ° C;) with vigorous stirring; solid sodium hydroxide; and the pH is adjusted to pH 8.0

Then the mixture was shaken with 3 ethyl acetate, and the extract was dried with sodium sulfate, and the solvent was evaporated.

The title compound is obtained as a solid, m.p.

Reference Example 188

Preparation of 10,11-dihydrobenz- [b, f] 1,4] -oxazepine

To a slurry prepared from 7.35 g of lithium aluminum hydride in 100.0 ml of tetranydrofuran; 10.0 g of dibenz- [b, f] [1,4] oxazepin-10 &lt; 11 &gt; After addition of an additional 100.0 mL of tetrahydrofuran, the reaction mixture was heated to reflux for 6.0 hours and then stirred at room temperature overnight.

Thereafter, to the cooled mixture was added, dropwise, 40 ml of water.

7.50 ml of 15% sodium hydroxide solution, and 3 x 7.50 ml of water each. Then the reaction mixture is filtered, and the filter cake is washed with tetrahydrofuran and dichloromethane. The filtrate is concentrated to dryness under vacuum; 10.10 g of solid are obtained, which is dissolved in dichloromethane, and the solution obtained is filtered through a thin layer of magnesium silicate containing water.

111

Then the filter cake is washed with dichloromethane; and the filtrate is concentrated to dryness. 8.90 g of solid are obtained, which is recrystallized from dichloromethane-hexane.

7.50 g of the title compound are obtained as a crystalline solid.

Melting point: 69.0-71.0 ° C

Reference Example 189

Preparation of pyrido [2,3-b] 1,4] benzoxazepin-6 (5H) -one

Mixture prepared by mixing 21,40 g of phenyl salicylate *

25.71 g of 3-amino-2-chloropyridine and 20.0 ml of 1,2,4-trichlorobenzene were heated under reflux for 1.0 hour under argon, and the liberated phenol and hydrogen chloride were simultaneously collected (distilled off) from the reflux mixture / into 1N sodium hydroxide solution.

The still hot reaction mixture was poured into 200.0 ml of ethanol, and the resulting precipitate was collected by filtration. Then, it was washed with ethanol, and dried.

Recrystallization of the residue from methanol: dimethylformamide (6: 1) gave 6.0 g of the desired product.

Melting point: 268.0-270.0 ° C

Reference Example 190

- 112

Preparation of 5,6-dihydropyrido [2,3-b] 1,4] -benzoxazepine

Mixture prepared by mixing 2.80 g of pyrido [2,3-b] 1,4] benzoxazepin-6 (5H) -one 10.0 ml of tetrahydrofuran; and 3.0 mL of a 10 molar solution of borane dimethyl sulfide in tetrahydrofuran, was stirred at room temperature overnight; and then heated at reflux for 3.0 hours.

The reaction mixture was then added dropwise to the reaction mixture under argon; 5.0 ml methanol; and after removal of the solvent under vacuum, methanol is added to the mixture again. After removal of the solvent under vacuum, 12.0 ml of 2N sodium hydroxide solution was added to the residue. The reaction mixture was then heated at reflux for 2.0 hours; and then shaken with ethyl acetate. The extract was washed with 2N citric acid solution; then with water, and finally with brine; and dried with sodium sulfate.

The mixture is then filtered through a thin layer of magnesium silicate containing water; and the filtrate is concentrated to dryness under vacuum. The residue was chromatographed on a column (2 '' x 18 '); silica gel, (32 ° g); eluent hexane: ethyl acetate (1: 1);

0.78 g of the desired product is obtained as a crystalline solid.

Melting point 172.0-174.0 ° C

Reference Example 191

Preparation of N- (2-hydroxyphenyl) -2-chloro-3-p-pyridinecarboxamide

Analogous to that described in J. Med.Ohem., 37,519 (1944); a solution prepared from 1.09 g of 2-aminophenol in 15.0 ml of tetrahydrofuran was added dropwise to the solution.

- 113 mixture of 2.10 g triethylamine / δ 2.33 g 2-chloropyridine-3-carbonyl chloride. hydrochloride in 10.0 ml tetrahydrofuran.

The reaction mixture was stirred under argon at room temperature for one hour; and then refluxed for a further 1.0 hours. After removal of the solvent under vacuum (the residue was mechanically treated) and taken up with water.

The solid product is filtered off; and washed with water.

1.02 g of solid is obtained, which, after recrystallization from 2-propanol, yields the title product as a crystalline solid.

Melting point: 145.0-146.0 ° C

Reierence example 192

Preparation of pyrido [2,3-b] 1,5-benzoxazepin-5 (6H) -one

Mixture prepared by mixing 13.0 g of N- (2-hydroxyphenyl) -2-chloro-3-pyridinecrboxamide; and 2.82 g of sodium methoxide, in 100.0 ml of N, N-dimethylformamide, was heated under reflux, under an argon atmosphere, for 3.0 hours.

0.50 g of sodium methoxide are then added to the reaction mixture; and the mixture is heated to reflux for 2.0 hours; and then stirred at room temperature for 2.0 days.

After removal of the solvent under high vacuum; the obtained reddish brown colored residue is mechanically processed; and removed with methanol (chilled). Then the mixture was filtered, and the solid product was washed with chilled methanol.

5.0 g of the expected product are obtained in the form of a white solid.

114

Melting point

250.0-253.0 ° C

Reference Example 193

Preparation of 5,6-dihydropyrido- [2,3-b] 1,5-benzoxazepine

To a slurry, prepared by mixing 0.886 g of lithium aluminum hydride in 20.0 ml of tetrahydrofuran; added in portions, with stirring; 1.65 g of pyridine [2,3-b] 1,5] benzoxazepin-5 (6H) -one] and the resulting reaction mixture was diluted with 30.0 mL of tetrahydrofuran, and heated to reflux; in an argon atmosphere; for 18.0 hours.

Then 1.0 ml of water, 1.0 ml of 15% sodium hydroxide solution were added successively to the reaction mixture; and 3 x 1.0 ml of water; and the mixture was filtered. The solid is shaken with shichloromethane, and this extract is poured over a thin layer of magnesium silicate / containing water. The obtained filtrate 3e is concentrated to dryness.

The title compound is obtained as a crystalline solid.

Melting point: 125.0 - 129.0 ° C

Reference Example

Preparation of 9,10-dihydro-4H-thieno- (2,3-cis) -benzs from pin

To a solution prepared by dissolving 9.0 g of 4,5-dihydro-4,

4-Dimethyl-2- (2-thienyl) -oxazole] in 200.0 mL of tetrahydrofuran, and cooled to minus 78 ° C, is added 2.50 molar

- 115 ·· ···· solution of n-butyllithium in hexane.

The resulting reaction mixture was stirred at minus 78.0 ° C for 15.0 minutes; and then at 0 ° C for 30.0 minutes. 6.0 g of 2-methylbenzoxazepin-4-one are then added with stirring; and the mixture is stirred at room temperature for 16.0 hours; then it is mixed with ice-cold water, and shaken with chloroform. The extract is concentrated to dryness; and 100.0 ml of 40% sulfuric acid was added to the residue. The reaction mixture was then heated to reflux for 4.0 hours; and after cooling to room temperature, it is filtered.

There was obtained 9,10-dihydro-4,10-dioxo-4H-thieno [2,3-c] benzazepine as a solid which was washed with water to give a crystalline solid (2). , 50 g).

The above product was dissolved in dry tetrahydrofuran (100 ml), and lithium tetrahydroaluminium (1.0 g) was added to the solution. The mixture was heated at reflux for 16 hours; ice-cooled water is added dropwise thereto. The reaction mixture is then diluted with water; and shaken with chloroform: methanol (3: 1); and the extract is dried with magnesium sulfate.

After removal of the solvent, the residue was chromatographed over silica gel, eluting with ethyl acetate: hexane (1: 1).

1.80 g of the desired product are obtained in the form of a solid.

Mass Spectroscopy (Cl): 202.0 (Μ + H)

Reference Example 195

- 116 ··

Preparation of methyl -4 - [((1,1'-biphenyl) -2-carbonyl) amino] -3-methoxybenzoate

Mixture prepared by mixing 10.0 g of (1,1'-biphenyl) -2-carboxylic acid; in 75.0 ml of dichloromethane; and 12.52 g of oxalyl chloride, stirred at room temperature for 15.0 hours. Evaporation of the volatiles under vacuum gave 11.06 g of an oily consistency.

A portion of 2.16 g of the above-mentioned oil-like compound was treated with 1.81 g of methyl-4-amino-3-methoxybenzoate} and 1.30 g of N, N-diisopropylethylminine under stirring with 25.0 ml of dichloromethane. and at room temperature for 18.0 hours. The reaction mixture was then washed successively with water (δ with a saturated aqueous solution of sodium bicarbonate) and the separated organic phase was dried over sodium sulfate.

The organic layer is then poured over magnesium silicate _/ containing water; and hexane is added to the filtrate at boiling.

3.20 g of the desired product are obtained as a crystalline solid.

Melting point: 115.0-117.0 ° C

Reference Example 196

Preparation of methyl 4 - [((1,1-biphenyl) -2-carbonyl) amino] -2-chlorobenzoate

A solution prepared by dissolving 2.37 g of (1,1-biphenyl) -2-carbonyl chloride in 10.0 ml of dichloromethane is added dropwise to an ice-cooled solution prepared from 1.84 g of methyl 4-amino-2-chlorobenzoate; and 1.49 g of M, N-diisopropyl

117 • ··

of ethylamine in 50.0 ml of dichloromethane.

The resulting reaction mixture was stirred at room temperature for 18.0 hours; and then washed successively with water and saturated aqueous sodium bicarbonate; and then the separated organic layer is dried over sodium sulfate.

The organic phase is poured over a layer of magnesium silicate with water content; and hexane is added to the mixture at boiling.

1.10 g of the expected product are obtained in the form of a crystalline solid.

Melting point: 132.0-134.0 ° C

Mass Spectroscopy (M ⁺ H): 365.0;

Reference Example 197

Preparation of 4 - [((1,1-biphenyl) -2-carbonyl) amino] -2-chlorobenzoic acid

Mixture prepared by mixing 3.0 g of methyl 4 - [(1,1-biphenyl) -2-carbonyl) amino] -2-chlorobenzoate; in 75.0 ml of absolute ethanol; and 2.0 mL of 10N sodium hydroxide solution; Heat on a steam bath for 3.0 hours. Upon addition of water, a solution is formed which is shaken with chloroform. The separated aqueous phase is acidified with acetic acid; and recovering the resulting solid product; and then dried in vacuo at 50 ° C.

The desired product is obtained (0.10 g; as a crystalline solid).

217.0-219.0 ° C

Melting point :

118

Reference Example 198

Preparation of 4 - [((1,1-biphenyl) -2-carbonyl) amino] -3-methoxybenzoyl chloride

The solution, prepared by mixing 2.69 g of 4 - [(1,1biphenyl) -2-carbonyl] -amino] -3-methoxybenzoic acid in 5.0 ml of thionyl chloride, is heated on a steam bath, under argon atmosphere, for a period of time. 1.0 hours.

Removal of the volatiles under vacuum gave a residue which was then slurried in hexane.

2.58 g of the expected product are obtained; in the form of a solid, crystalline substance.

Melting point: 121.0-123.0 ° C

Mass Spectroscopy (M +): 361, OJ

Reference Example 199

Preparation of methyl 4- ([(1,1-biphenyl) -2-carbonyl) amino] benzoate

A mixture prepared by mixing 10.0 g of (1,1-biphenyl) 2-carboxylic acid in 75.0 ml of dichloromethane; and 12.52 g of oxalyl chloride; is stirred at room temperature for 18.0 hours.

After evaporation of volatiles from the mixture (in vacuo ^ _(gave 11.66 g of an oil ,.

A portion of 7.50 g of the above-mentioned oily substance, in 25.0 ml of di-methanol, is added dropwise to a solution prepared by dissolving 4.53 g of methyl 4-aminobenzoate and 4.30 g of N, N-diisopropylethylamine; in 100.0 ml of dichloromethane at 0 ° C.

- 119

The reaction mixture was stirred at room temperature for 18 hours, then washed sequentially with water and saturated aqueous sodium bicarbonate; and after separation, the organic layers are dried with sodium sulfate.

The organic phase is then poured over magnesium silicate containing water; and hexane is added while boiling.

8.38 g of the expected product are obtained; of the title product as a solid, crystalline solid.

Melting point: 163.0-165.0 ° C

Reference Example 200

Preparation of 4 - [(1,1-biphenyl) -2-carbonyl] amino] benzoic acid.

A total of 3.15 g of methyl 4 - [(1,1-biphenyl) -2-carbonyl) amino] benzoate, was heated under reflux for 8.0 hours in 100.0 ml of ethanol; and 2.50 ml of 10N sodium hydroxide solution. After cooling, the reaction mixture is acidified with (R) acid; and isolating and drying the desired product.

2.90 g of the desired title compound are obtained? of said product as a solid.

Melting point: 246.0-249.0 ° C

Mass Spectroscopy (M + H): 318.0;

Reference Example 201

- 120

4 - / (/ 1.1 ^from biphenyl / -2-carbonyl) amino / benzoyl chloride

Mixture prepared by mixing 1.39 g of 4 - [((1,1-biphenyl) -2-carbonyl) -amino] -benzoic acid; in 2.0 ml thionyl chloride; was heated on a pen bath for 1.0 ° C. Thereafter, cooled hexane was added to the mixture; and isolate, and dry.

1.34 g of the desired product are obtained.

Melting point 118.0 - 120.0 ° C

Reference Example 202

Preparation of 2- (phenylmethyl) -benzoyl chloride

Mixture prepared by mixing 5.0 g of 2- (phenylmethyl) benzoic acid; in 5.0 ml thionyl chloride; The mixture is heated on a steam bath for 1.0 h.

5.74 g of the expected product are obtained in the form of an oily substance.

MS (+): 227.0; (as methyl ester)

Reference Example 203

Preparation of methyl -4- [2- (phenylmethyl) -benzoyl] -amino] -benzoate ········

121 ···

To a mixture of 3.03 g of methyl 4-aminobenzoate and 3.12 g of N, N-diisopropylethylamine in 75.0 ml of dichloromethane is added 5.54 g of 2- (phenylmethyl) -benzoyl chloride, and the reaction mixture is stirred at room temperature. The mixture was washed sequentially with water and a saturated aqueous solution of sodium bicarbonate; and the organic layer is dried over sodium sulfate after separation.

The organic phase is then poured over magnesium silicate containing water (2X) and hexane is added to the filtrate at boiling.

5.04 g of the desired product are obtained as a crystalline solid.

Melting point: 138.0-139.0 ° C

Reference Example 204

4 - / (2- (f ^c phenylmethyl) benzoyl / amino / sodium benzoate

A mixture prepared by mixing 4 methyl (phenylmethyl) benzoyl / -emino] benzoate; in 100.0 ml of absolute ethanol with 3.50 ml of 10N sodium hydroxide solution, is heated on a steam bath for 3.0 hours. The aqueous phase is then filtered; and the resulting solid is isolated and dried.

4.25 g of the expected product are obtained.

Melting point: 340.0 - 346.0 ° C

Reference Example 205

122

Preparation of 4- [2- (phenylmethyl) -benzoyl] -amino] -benzoic acid

Susperize, prepared by mixing 4.0 g of sodium 4 - [2- (phenylmethyl) benzoyl / amino] benzoate; in water, adjusted to pH 5 with 0.1 by addition of acetic acid and the solid which is isolated by filtration; is dried at. temperature 80.0 ° C under vacuum.

3.75 g of the expected product are obtained.

Melting point: 246.0-247.0 ° C

Mass Spectroscopy (M +): 332, OJ

Reference Example 206

Preparation of 4- [2- (phenylmethyl) -benzoyl] -amino] -toenzovl chloride

The mixture, prepared by mixing 2.0 g of 4- [2- (phenylmethyl) benzoyl] -amino) benzoic acid, with 2.0 ml of thionyl chloride, is heated on a steam bath for 1.0 hour.

The volatiles were then evaporated under vacuum.

1.53 g of the desired product are obtained as an oil.

Mass Spectroscopy (14+): 346, OJ (as methyl ester)

Reference Example 207

Preparation of methyl 4 - [(2-phenylmethyl) -benzoyl] -amino] -2-chlorobenzoate

- 123

The mixture, prepared by mixing 5.0 g of 2- (phenylmethyl) benzoic acid; in 5.0 ml of thionyl chloride, is heated on a steam bath for 1.0 hour. g of an oily consistency.

A portion (2.85 g) of the above oil, in 25.0 mL of dichloromethane; was added to a solution prepared from 1.85 g of methyl 4-amino-2-chlorbenzoátuya 1.65 g of N, N-diisopropyl) ziaTAin§y and ^{z i 'r} taí'o reaction? ^{, the} mixture was stirred at room temperature for 18.0 hours. The mixture was then washed successively with water and a saturated aqueous solution of sodium bicarbonate; and the separated organic layer is dried with sodium sulfate.

The organic phase is passed through 2 times over magnesium silicate containing water; and hexane is added to the filtrate at boiling.

2.96 g of the desired product are obtained in the form of a crystalline solid.

Melting point: 133.0-135.0 ° C

Mass spectroscopy ([delta]): 380.0;

Reference Example 208

Preparation of methyl-4 - [(2-phenylmethyl) -benzoyl] -amino] -3-methoxybenzoate

The solution prepared by dissolving 2.85 g of 2- (methylmethyl) benzoyl chloride in 25.0 ml of dichloromethane is added dropwise to an ice-cooled solution of 1.84 g of methyl 4-amino-3-methoxybenzoate. ; in 50.0 ml of dichloromethane.

The resulting reaction mixture was then stirred at room temperature for 18.0 hours, and then washed sequentially with water and water.

124 a saturated aqueous solution of sodium bicarbonate; After separation, the organic layer is dried over sodium sulfate. The organic phase is then poured over a layer of magnesium silicate containing water; and hexane is added to the filtrate while boiling.

2.20 g of the desired product are obtained as a crystalline solid.

Melting point: 129.0 - 131.0 ° C

Mass Spectroscopy (M +): 376, Q * Reference Example 209

Preparation of 2-chloro-4 - [(2-phenylmethyl) -benzoyl] -emino] -benzoic acid

Mixture prepared by mixing 2.80 g of methyl 2-chloro-4 - [(2-phenylethyl) benzoyl] aminobenzoate; in 75.0 ml of absolute ethanol and 1.84 ml of 10N sodium hydroxide solution; Heat in a steam bath for 3.0 hours.

Upon addition of water, a solution is formed which is shaken with dichloromethane. After separation, the aqueous phase is acidified with acetic acid; and the resulting solid is collected and dried under vacuum at 80 ° C.

2.60 g of the desired product are obtained as a crystalline solid.

Melting point: 184.0 - 187.0 ° C

Mass Spectroscopy (M + H): 366.10;

β · · ·

125

• · · · · ·

Reference Example 210

Preparation of 3-methoxy-4 - [(2-phenylthyl) -benzoyl] -amino] -benzoic acid

Mixture prepared by mixing 2.05 g of methyl 4 - [(2-phenylmethyl) -benzoyl] -amino] -3-methoxybenzoate; in 75.0 ml of absolute ethanol and 1.40 ml of 10N sodium hydroxide solution are heated in a steam bath for 3.0 hours.

After addition of water, the resulting solution was shaken with dichloromethane; and after separation, the aqueous phase is acidified with acetic acid; and recovering the resulting solid; and dried under vacuum at 80.0 ° C,

1.87 g of the desired product are obtained in the form of a crystalline solid.

Melting point: 176.0-17S, 0 ° C

Mass Spectroscopy (M + H): 362, OJ

Reference Example 211

Preparation of 3-methoxy-4 - [(2-phenylmethyl) -benzyl] -amino] -benzoyl chloride

Mixture prepared by mixing 1.71 g of 3-methoxy-4 - [(2-phenylmethyl) -benzoyl] -amino] -benzoic acid; in 2.0 ml of thionyl chloride, was heated in a steam bath, under argon atmosphere, for 1.0 hour. After addition of hexane, the resulting solid was isolated and dried.

1.71 g of the desired product are obtained in the form of a solid, crystalline solid.

- 126

Melting point: 130.0-135.0 ° C

Mass Spectroscopy (M +): 376.0; (as methyl ester)

Reference Example 212

Preparation of [4- (trifluoromethyl) -1,1-biphenyl] -2-carbonyl chloride

Mixture prepared by mixing 5.0 g of 4- (trifluoromethyl) [1,1-biphenyl] -2-carboxylic acid; in 5.0 ml of thionyl chloride, heated in a steam bath; under argon, * for 1.0 hour.

After addition of hexane, the resulting solid is isolated and dried.

5.36 g of the desired product are obtained as a colorless oil.

Mass Spectroscopy (M +): 220, OJ (as methyl ester)

Reference Example 213

Preparation of methyl 4- ([(4- (trifluoromethyl) / 1,1-biphenyl) carbonyl) amino] benzoate

A solution prepared by dissolving 3.13 g of 4- (trifluoromethyl) [1,1'-biphenyl] -2-carbonyl chloride] in 25.0 ml of dichloromethane is added dropwise to an ice-cooled solution of 1.84 g of methyl 1-4-aminobenzoate. and 1.43 g of H, N-diisopropylethylamine, v

- 127 50,0 ml dichloromethane.

The resulting reaction mixture was stirred at room temperature for 18.0 hours; and then washed with water; followed by a saturated aqueous solution of sodium bicarbonate; and the separated organic layer is dried with sodium sulfate. The organic phase is then poured over a layer of magnesium silicate / containing water; and hexane is added to the filtrate at boiling.

3.36 g of the expected product are obtained in the form of a crystalline solid.

Melting point: 164.0-165.0 ° C

Mass Spectroscopy (M +): 396;

Reference Example 214

Preparation of 3-methoxy-4- _from ^a (/ 4 (trifluoromethyl) / 1 1bifenyl / 2-carbonyl) -amino / benzoyl chloride

The mixture prepared by mixing 2.0 of 3-methoxy-4 / ([4- (trifluoromethyl) [1,1-biphenyl] -2-carbonyl) amino] -benzoic acid in 20.0 ml of thionyl chloride is heated to steam bath, under argon atmosphere, for 1.0 hour.

After addition of hexane, the resulting solid is isolated and dried.

1.92 g of the desired product are obtained in the form of a crystalline solid.

Melting point :

136.0-138.0 ° C • · · ·

- 128 Reference example 215

Preparation of 3-methoxy-4 - [((4-trifluoromethyl) [1,1'-biphenyl] -2-carbonyl) amino] benzoic acid

A mixture 3,7S g of methyl 3-methoxy-4 / (/ 4 ^of trifluoromethyl) - / 1 14 Biphenyl / -2-ksrbon.yl) amino / benzoate; in 75.0 ml of absolute ethanol, and 2.20 ml of 10N sodium hydroxide solution, are heated in a steam bath for 3.0 hours.

After addition of water, a solution is obtained which is shaken with dichloromethane. After separation, the aqueous phase is acidified with acetic acid, and the resulting solid is dried under vacuum at 80 ° C.

3.49 g of the desired product are obtained in the form of a crystalline solid.

Melting point: 213.0 - 215.0 ° C

Reference Example 216

Preparation of methyl 3-methoxy-4 - [((4-trifluoromethyl) - [1,1-biphenyl] 2-carbonyl) amino] benzoate

Solution prepared by dissolving 3,56 g / 4- (trifluoromethyl)

- (1,1-Biphenyl) -2-carbonyl chloride] in 25.0 ml of dichloromethane is added dropwise to an ice-cooled solution of 1.81 g of methyl 14-amino-3-methoxybenzoate and 1.62 g of Ν, di-diisopropylethylamine in 50, 0 ml of dichloromethane. The reaction mixture was stirred at room temperature for 18.0 hours; and then washed successively with water; and a saturated aqueous sodium bicarbonate solution.

After separation, the organic layer is dried over sodium sulfate and then poured over a layer of water-containing magnesium silicate.

• ·

129 Add hexane to the filtrate while boiling.

3.90 g of the desired product are obtained in the form of a crystalline solid.

Melting point: 112.0 - 113.0 ° C

Reference Example 217

Preparation of 2-chloro-4 - [([4- (trifluoromethyl)] - (1,1-biphenyl) -2-kerbonyl] -Qmino] -benzenesulfonate

Mixture prepared by mixing 1,39 g of 2-chloro-4 - [([4- (trifluoromethyl) - [1,1-biphenyl] -2-carbonyl) amino] benzoic acid ”in 2,0 ml thionyl chloride is heated in a steam bath for 1.0 hour. The reaction mixture is concentrated in vacuo to a residue which was added to the chilled hexane and the resulting p ^c: Loading was isolated and dried.

1.39 g of the title product are obtained.

Reference Example 218

Preparation of 2-chloro-4 - [(4 - (trifluoromethyl) - [1,1-biphenyl] -2-carbonyl) amino] benzoic acid

Mixture prepared by mixing 3.83 g of methyl 2-chloro-4 - [([4- (trifluoromethyl) -1,1-biphenyl] -2-carbonyl) amino] benzoate; ve

75.0 ml of absolute ethanol and 2.20 ml of 10N sodium hydroxide solution are heated in a steam bath for 3.0 hours.

130

After addition of water, a solution is obtained which is shaken with dichloromethane. After separation, the aqueous phase is acidified with acetic acid; and the resulting solid is dried under vacuum at 80.0 ° C.

3.42 g of the desired product are obtained in the form of a solid, crystalline solid.

Mp: 187.0-189.0 ° C

Reference Example 219

Preparation of methyl 2-chloro-4 - [([4- (trifluoromethyl) -1,1-diphenyl] -2-pyridyl] amino] benzoate

Solution prepared by dissolving 3.56 g of 4- (trifluoromethyl) [1,1-biphenyl] -2-carbonyl chloride; in 10.0 ml of dichloromethane, 1.86 g of methyl 2-chloro-4-aminobenzoate are added dropwise to an ice-cooled solution; and 1.60 g of Ν, Ν-diisopropylethylamine, in 50.0 mL of dichloromethane.

The reaction mixture was stirred at room temperature for 18.0 hours; and then washed successively with water; and a saturated aqueous sodium bicarbonate solution; and the organic layer is dried over sodium sulfate after separation. The organic phase is then poured over a layer of magnesium silicate containing water, γ (3x), and hexane is added to the filtrate at boiling.

4.0 g of the expected product are obtained in the form of a crystalline solid.

Melting point :

130.0-132.0 ° C

- 131

Reference Example 220

Preparation of 4 - [(4- (trifluoromethyl) - [1,1-biphenyl] -2-carbonyl) amino] benzoic acid

A mixture of 3.0 g of methyl-4 - / (/ 4 (trifluoromethyl) - / 1 1 ^/ biphenyl / -2-ylcarbonyl) amino / benzoate · ,. in 75.0 ml of absolute ethanol and 2.0 ml of 10N sodium hydroxide solution; 3e was heated in a steam bath for 3.0 hours.

After addition of water, the solution is shaken with dichloromethane; and the aqueous phase, after separation, is acidified with acetic acid. The resulting solid is isolated; and dried under vacuum at 50 ° C.

2.93 g of the expected product are obtained in the form of a crystalline solid.

Melting point: 243.0-245.0 ° C

Mass Spectroscopy (M &lt; + &gt;): 3S5, OJ

Reference Example 221

Preparation of methyl-6- [3- (2-methylpyridinyl) -carbonyl] -amino] -pyridine-3-carboxylate

To a solution prepared by swelling 3.0 g of methyl 6-amino pyridine-3-carboxylate; and 4.0 mL of N, N-diisopropylethylamine; in 100.0 ml of dichloromethane, a solution of 6.40 g of 2-methylpyridine-3-carbonyl chloride in 25.0 ml of dichloromethane is added dropwise (while stirring the reaction mixture). Then the mixture was stirred at room temperature for 2.0 hours and then rapidly mixed with water.

• ·

The separated organic layer was washed with water; It is dried over magnesium sulphate and evaporated under vacuum. The residue is stirred with ether; and the resulting solid is collected and then air dried.

6.80 g of the desired product are obtained.

Mass Spectroscopy (M &lt; + &gt;): 390, OJ

Reference Example 222

Preparation of 6- [3- (2-methylpyridinyl) -carbonyl] -omino] -pyridine-3-carboxylic acid

To a solution prepared by dissolving 6.50 g of methyl 6H- 3- (2-methylpyridinyl) carbonyl / amino / pyridine-3-carboxylate; in 100.0 mL of tetrahydrofuran: methanol (1: 1); 20.0 ml of 5N sodium hydroxide solution are added.

The resulting reaction mixture was stirred overnight; and then evaporated in vacuo until a solid residue is obtained which is dissolved in water and neutralized with acetic acid. The separated solid product was filtered and air dried.

3.0 g of the expected product are obtained.

Mass Spectroscopy (M +): 257.0;

Reference Example 223

Preparation of methyl 1-6 - [(1,1,1-biphenyl) -2-carbonyl] -amino] -pyridine-3-carboxylate

- 133

To a solution prepared by dissolving 1.50 g of methyl 6-aminopyridine-3-carboxylate; in 100.0 ml of dichloromethane, 3.0 ml of H, N-diisopropylethylamine are added at room temperature. A solution of 2.50 g of (1,1-biphenyl) -2-carbonyl chloride was added slowly, with stirring, to the resulting reaction mixture. The reaction mixture was then stirred at room temperature for 4.0 hours; then quickly mix with water. After separation, the organic layer is washed thoroughly with water, dried over anhydrous magnesium sulphate, filtered and dried under vacuum to a solid residue which, after trituration with ether, is filtered and dried.

3.0 g of the expected product are obtained.

Mass Spectroscopy (M +): 332, OJ

Reference Example 224

Preparation of 6 - [(1,1-biphenyl) -2-carbonyl] amino] -pyridine-3-carboxylic acid

To a solution prepared by dissolving 2.50 g of methyl 6 - [(1,1-biphenyl) -2-carbonyl) amino] -pyrine-3-carboxylate; in 50.0 mL of tetrahydrofuran: methanol (1: 1); 10.0 ml of 5N sodium hydroxide solution are added with stirring; and the reaction mixture is stirred at room temperature for 16 hours.

The reaction mixture is then concentrated in vacuo; and dissolving the residue in water; and neutralized with acetic acid. The separated colorless solid is filtered off; and air dried.

2.0 g of the expected product are obtained.

Mass Spectroscopy (M +): 315.0;

····

- 134 ·· ·

Reference Example 225

Preparation of methyl 2- (2-pyridinyl) benzoate

Mixture prepared by mixing 12.0 g of methyl 2- (iodomethyl) benzoate 20.0 g of n-butylstannane and 2.0 g of tetrakis (triphenylphosphine) palladium (0); The reaction mixture was concentrated in vacuo to a residue which was purified by silica gel column chromatography using ethyl acetate: hexane (1: 1) as eluent.

5.50 g of the expected product are obtained as an oil.

Mass Spectroscopy (M &lt; + &gt;): 213, OJ

Reference Example 226

Preparation of 3- (2-pyridinyl) -benzoic acid

The mixture prepared by mixing 3.0 g of methyl 2- (2-pyridinyl) benzoate and 600.0 mg of sodium hydroxide in 50.0 ml of methanol: water (9: 1); The mixture was heated to reflux for 4.0 hours. The reaction mixture is then concentrated in vacuo, and the residue is dissolved in 50.0 ml of cooled water.

The resulting solution is neutralized with glacial acetic acid, and the resulting product is filtered off, washed with water, and dried.

2.50 g of the desired product are obtained.

Mass Spectroscopy (M + 1): 200, OJ

135 Example 1

Preparation of N- [5- (dibenz- [b, f] 1,4] oxazepin-10 (11H) -ylcarbonyl)

- 2-pyridinyl / -5-fluoro-2-methylbenzamide

To a solution prepared by dissolving 0.39 g of 10,11-dihydrodibenz- [b, f] 1,4] oxazepine and 1.10 ml of triethylamine; in 5.0 ml of dichloromethane, 1.17 g of 6 - [(5-fluoro-2-methylbenzoyl) amino] pyridine-3-carbonyl chloride is added.

The resulting reaction mixture 3e was stirred under argon; and at room temperature, * for 16.0 hours, and then diluted with 50.0 mL of dichloromethane, * and 20.0 mL of water. After separation, the organic layer was washed sequentially with 20.0 ml of 1M sodium bicarbonate solution / and with 20.0 ml of brine, and then dried over sodium sulfate. Then the mixture is filtered through a thin layer of magnesium silicate containing water and the filtrate is concentrated to dryness under vacuum.

The chromatographic zbytek.se ^R U is silica gel, eluting with ethyl acetate: hexane (1: 1) as eluant, and ZIS Ka is a solid which is crystallized from ethyl acetate.

0.335 g of the expected product is obtained in the form of an off-white solid, crystalline solid.

Melting point: 180.0-136.0 ° C

Example 2

Preparation of N- (5- (1,9,10-dihydro-4H-thien- [2,3-c] -1-benzazepin-9-yl) -carbonyl) -2-pyridinyl / -5-fluoro-2- methylbenzamide

In an analogous manner to that described in the preceding Example 1J, 9,10-dihydro-4H-thien- [2,3-c] -1,136 is reacted in dichloromethane, benzazepine in the presence of and 6 - [(5-fluoro-2-methylbenzoyl) -amino] -pyridine-3-carbonyl chloride.

The title compound is obtained in the form of a yellow, non-crystalline solid.

Example 3

Preparation of N- [5 - [(4,10-dihydro-5H-thien- [3,2-c] -1-benzazepin-5-ylcarbonyl) -2-pyridinyl-5-fluoro-2-methylbenzamide]

In an analogous manner to that described in Example 1 above; a mixture of 4,10-dihydro-5H-thien- [3,2-c] -1-benzazepine and triethylamine is reacted; in dichloromethane, with 6 - [(5-fluoro-2-methylbenzoyl) amino] pyridine-3-carbonyl chloride.

The desired product is obtained in the form of a solid.

Example 4

Preparation of N- [5- (Pyrido- [2,3-b] [1,4] benzoxazepin-5 (1H) -ylcarbonyl) -2-pyridinyl] -5-fluoro-2-methylbenzamide

In an analogous manner to that described in Example 1 above, 5,6-dihydro-p-pyridine [2,3-b] 1,4] -benzoxazepine, in dichloromethane, in the presence of triethylamine, is reacted with 6 - [(5- fluoro-2-methylbenzoyl) amino / pyridine-3-carbonyl chloride.

• ·

- 137 ··· ·· • · ·· ····

The title compound is obtained in white, solid, solid; crystalline substance product, in the form

Melting point

157.0-1S9.0 ° C

Example 5

Preparation of N- [5- (p-pyrido- [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -2-p-pyridinyl] -5-fluoro-2- me thy lbe nzamid

In an analogous manner to that described in Example 1 above; react 5,6-dihydro- [2,3-b] 1,5] -benzoxazepine with 6 - [(5-fluoro-2-methylbenzoyl) -emino] dichloromethane, ‘in the presence of triethyl amine.

The title product is obtained as a non-crystalline solid.

Example 6

Preparation of N- [5 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -2-pyridinyl] -5-fluoro-2-methylbenzamide

In an analogous manner to that described in Example 1 above, 6,11-dihydro-5H-dibenz- [b, e] -szepine, in dichloromethane, in the presence of triethylamine; with 6 - [(5-fluoro-2-methylbenzoyl) -amino] -pyridine-3-carbonyl chloride.

The desired product is obtained as a solid.

- 138 ··· ·· ·· ·

Example 7

Preparation of N- (5- (4,5-dihydro-2-methylpyrazole- [4,3-d] -) - 1-benzazepin-6 (2H (-yl) carbonyl-2-pyridinyl) -5-fluoro- Of 2-methylbenzamide

In an analogous manner to that described in Example 1 'above, 2,4,5,6-tetrahydro-2-methylpyrezole- [4,3-d] 1-benzazepine, in dichloromethane, is reacted in the presence of triethylamine; C6 - / (5-fluoro-2-methylbenzoyl) -smino / pyridine-3-karbon- ^'T lchloridem.

The desired above-mentioned oroduct is obtained in the form of a solid.

Example 8

Preparation of N- [5 - [(6,7-dihydro-5H-dibenz- [b, d] -azepin-5-yl) carbonyl] -2-pyridinyl] -5-fluoro-2-methylbenzamide

In an analogous manner to that described in Example 1 * above, 6,7-dihydro-5H-dibenz- (E, d) -azepine is reacted in dichloromethane, in the presence of triethylamine, with < 6 - / (5-fluoro-2- methylbutyl ^{C-fluorobenzoyl)} -emino / -pytidin-3-carbonyl chloride.

The desired product is obtained.

Example 9

Preparation of N- [5 - [(4,5-dihydro-6H-thien- [3,2-d] l-benzzepin-6-yl) carbonyl] -2-pyridinyl] -5-fluoro-2-methylbenzamide · · ······························································ ·

139 In an analogous manner to that described in Example 1 above; reacted with 4,5-dihydro-6H-thien- [3,2-d] 1-benzazepine; in dichloromethane. in the presence of triethylamine ;, with 6 - / (5-fluoro-2-methy1benzoyl) amino / beta _{T-naphthyridine-3} ka rbony lchloridem.

The desired product is obtained in the form of a solid.

Example 10

Preparation of N- [5 - [(5,10-dihydro-4H-thien- [3,2-c] -2-benzazepin-4-yl) carbonyl] -2-p-pyridinyl] -5-fluoro-2- methylbenzamide

In an analogous manner to that described in Example 1 above; 5,10-dihydro-4H-thien- [3,2-c] -2-benzazepine is reacted; in dichloromethane, in the presence of triethylamine; with 6 - [(5-fluoro-2-methylbenzyol) -amino] -pyridine-3-carbonyl chloride.

The desired product is obtained as a solid.

Example 11

Preparation of N- [5 - [(4,5-dihydropyrazole- [4,3-d] -1-benzazepin-6 (1H) -yl) carbonyl] -2-piperidinyl] -5-fluoro-2 -methylbenzamide

To a solution prepared by mixing 0.20 mole of 1,4,5,6-tetrahydropyrazole- [4,3-d] -1-benzszepine; and 0.80 moles of triethylamine, 0.42 moles of 6 - [(5-fluoro-2-methylbenzoyl) -emino] pyridine-3-carbonyl chloride is added; in 15.0 ml of dichloromethane.

- 140 • · · · ···

The resulting reaction mixture was stirred under argon for 16.0 hours; and then diluted with 25.0 ml of dichloromethane, and then washed successively with water and 1M sodium bicarbonate solution, then dried over sodium sulphate.

After removal of the solvent, the obtained residue was stirred in methanol: tetrahydrofuran (1: 1); together with 1N sodium hydroxide solution; for 5.0 hours. The reaction mixture is then neutralized with acetic acid; Water was added to the obtained residue 3e, and the mixture was shaken with ethyl acetate. The extract was washed successively with water and 1N hydrochloric acid; 171 with sodium bicarbonate solution, and then dried with sodium sulfate.

P _by removing the solvent from the mixture under vacuum and the residue chromatographed on silica gel using ethyl acetate hexane ::, Avid® eluent.

The desired product is obtained in the form of a solid, m.p.

Example 12

Preparation of N- [5 - [(6,11-dihydro-5K-dibenz- [b] N-azepin-5-yl) carbonyl] -2-pyridinyl] -1,1-biphenyl] -2-carboxamide

To a solution cooled to 0 ° C; and prepared by mixing 0.239 g of 6,11-dihydro-5H-dibenz- (b, e) -azepine; and 625.0 ml triethylamine; in 3.50 ml of dichloromethane is added a solution prepared by dissolving 0.657 g of 6 - [(1,1-biphenyl) -2-ylcarbonyl) amino] -3-pyridinecarbonyl chloride in 1.50 ml of dichloromethane.

The resulting reaction mixture was stirred under argon; at room temperature for 1, 0 hours and then diluted with 40.0

• 9

141 ml of dichloromethane; and 20.0 ml of water. After separation of the organic layer, this phase is washed sequentially with 20.0 ml of 1M sodium bicarbonate solution; and with 20.0 ml of brine; and forcibly dried with sodium sulfate.

The solution is filtered through a thin layer of water-containing magnesium silicates and the filtrate is concentrated to dryness under vacuum. The solid residue is chromatographed on silica gel, eluting with ethyl acetate: hexane (1: 1); as eluent. A glassy consistency product is obtained, which is recrystallized from ethyl acetate.

0.395 g of the desired product is obtained in the form of a white crystalline solid.

Melting point: 134.0-142.0 ° C

Example 13

Preparation of N- [5 - [(4,5-dihydro-2-methylpyrazole- [4,3-6] [1] -cenzazepin-6 (2H) -yl) carbonyl] -2-p-yynyl] 1,1'-Biphenyl / -2-carboxamide

In an analogous manner to that described in Example 12 above; 2,4,5,6-tetrahydro-2-methylpyrazole- [4,3-d] -1-benzazepine is reacted; with 6 - [(1,1-biphenyl) -2-ylcarbonyl] amino] -3-pyridinecarbonyl chloride.

The desired product is obtained as a solid.

Example 14

142

Preparation of N- [5 - [(6,7-dihydro-5H-dibenz- [b, d] ssepin-5-yl] carbonyl] -2-pyridinyl [1,1-biphenyl] -2-carboxamate

In an analogous manner to that described in Example 12 above; react with 6,7-dihydro-5H-dibenz- [b, d] azepinj with 6 - [(1,1-biphenyl) -2-ylcarbonyl] amino] -3-pyridinecarbonyl chloride.

The desired product is obtained. in the form of a solid.

Example 15

Preparation of N- [5- (U, 5-dihydro-6H-thien- [3,2-b] -1-benzazepin-6-yl) carbonyl] -2-pyridinyl [1,1-biphenyl] -2- carboxamide

In an analogous manner to that described in Example 12 above; 4,5-dihydro-6H-thien- [3,2-d] -1-benzazepinine is reacted with 6 / ((1,1-biphenyl) -2-yl-carbonyl) -amino) -3-pyridinecarbonyl chloride .

The title product is obtained in the form of a solid.

Example 16

Preparation of N- [5 - [(5,10-dibyl-4H-thien- [3,2-c] -2-benzazepin-4-yl) carbonyl] -2-pyridinyl] -1,1-biphenyl] -2-carboxamide

143 In an analogous manner to that described in Example 12J, 5,1O-dihydro-4H-thien- [3,2-c] -2-benzazepine was reacted; with 6 '((1,1-biphenyl) -2-ylcarbonyl) -emino] -3-pyridinecarbonyl chloride.

The desired product is obtained in the form of a solid, m.p.

Example 17

Preparation of N- [5 - [(9,10-dihydro-4H-thien- [2,3-c] -1-benzazepin-9-yl) carbonyl] -2-pyrimidinyl- [1,1] biphenyl] -2-carboxammonium

Following the process described in Example 12 was reacted with 5,1O-dihydro-4H-thieno / 2,3-c // 1 / benzazepine 6 / (/ 1.1 ^from biphenyl / -2-yl- (carbonyl) -amino] -3-pyridinecarbonyl chloride.

The desired non-indicated product is obtained in the form of a solid,

Example 18

Preparation of N- [5- (1,4,10-dihydro-5H-thien- [3,2-c] -1-benzazepin-5-yl) carbonyl] -2-pyridinyl [1,1-biphenyl] -2-carboxamide

In an analogous manner to that described in Example 12J above, 4,10-dihydro-5H-thien- [3,2-c] -1-benzazepinine is reacted with 6 ((1,1 ^z -biphenyl) -2-) - (yl-carbonyl) -araino] -3-pyridinecarbonyl chloride.

• · ·

144 form of the solid, the desired title compound / product is obtained.

Example 19

Preparation of N- (5 - [(4,5-dihydropyrazole- [4,3-d] 1-benzazepin-6 (1H) -yl) carbonyl] -2-pyridinyl- (1,1-biphenyl) - Of 2-carboxamide

In an analogous manner to that described in Example 11J above, 1,4,5,6-tetrshydropyrazole- [4,3-d] -1-benzazepine is reacted with

6 - [(1,1-biphenyl) -2-ylcarbonyl] amino-3-pyridinecarbonyl chloride.

The title product is obtained in the form of a solid.

Example 20

Preparation of N- [5 - [(6,1-Dibyro-5H-pyrido [2,3-b] 1,5] -benzodiazepin-6-yl) -carbonyl] -2-piperazin-2-yl] - (Ridinyl) -2-methylfuran-3-carboxamide

To a solution cooled to 0 ° C; and prepared by mixing 0.296 g of 6,11-dihydro-5H-pyridine [2,3-b] 1,5-benzodium and 624.0 ml of triethylamine; in 3.0 mL of dichloromethane is added a solution prepared by dissolving 6 - [(2-methyl-3-furanylcarbonyl) amino] -3-pyridinecarbonyl chloride * in 4.0 mL of dichloromethane. The resulting reaction mixture was stirred at room temperature for 16 hours and then the solvent was removed in vacuo.

• ·

145 To the residue obtained is added 1T sodium bicarbonate solution; and the resulting mixture was shaken with ethyl acetate.

The extract is washed successively with water; then with sodium bicarbonate solution; and brine, followed by drying with sodium sulfate.

Fo removal of the solvent under vacuum; the remaining residue is chromatographed on silica gel; using ethyl acetate: hexane as the eluent.

The desired product is obtained in the form of a solid, m.p.

Example 21

Preparation of N- [5- (5 (6H) -phenanthridinyl) -carbonyl] -2-pyridinyl-2-methylfuran-3-carboxamide

In an analogous manner to that described in Example 20J above, 5,6-dihydro-phenanthridine; with 6 - [(2-methyl-3-furanylcarbonyl) amino] -3-pyridinecarbonyl chloride.

The desired product is obtained as a solid.

Example 22

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-methylfuran-3-carboxamide

- 146

In an analogous manner to that described in Example 20 above; react with 5,11-dihydro-1H-dibenz- [b, e] [1,4] aiazepine] with 6 '(2-methyl-3-furanylcarbonyl) -amino] -3-pyridinecarbonyl chloride.

The desired product is obtained in the form of a solid.

Example 23

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -1,1-biphenyl] -2 -carboxamide

In an analogous manner to that described in Example 12 above; 5,11-dihydro-1H-dibenz- [b, e] [1,4] diazepine is reacted; 6 / (/ 1,1-biphenyl-enes ^{of the} LZ-2-yl-carbonyl / -9niino / -3-pyridinkyrbonylchlori chloride.

The desired product is obtained as a solid.

Example 24

Preparation of 5- (4- (4-butyloxy-benzoyl-5,11-dihydro-5H-dibenz) b, e) -azepine

To a solution prepared by dissolving 6,11-dihydro-5H-dihydro-5H-dibenz- [b, e] azepine (0.12 g, 0.60 mmol) in 2.0 mL of dichloromethane; 0.12 g (1.20 mmol) of triethyl is added first.

147 amine, followed by 0.15 g (0.72 mmol) of 4-butoxybenzoyl chloride. The resulting reaction mixture was stirred at room temperature for about 2.0 hours; and then stirred with 4.0 ml of 1N sodium hydroxide solution. The mixture was then shaken with ethyl acetate (10 mL); and the extract is washed successively with 1N sodium hydroxide solution; followed by brine (5.0 mL); The solution is filtered through a pad of magnesium silicate containing water; and the filtrate is evaporated, and the crude material is worked up mechanically and taken up with isooctane.

0.24 g of the expected product is obtained in the form of a white solid.

Mass spectroscopy (CI): 372.0; ('' H ⁺ )

Example 25

Preparation of 10 - ((1,1-biphenyl) -4-ylcarbonyl) -5,11-dihydro-10H-dibenz- [b, e] 1,4] diazepine

To a solution prepared by dissolving 0.50 g of 5,11-dihydro-10H-dibenz- [b, e] -1,4] diazepine; in 50.0 ml of dichloromethane; and 12.0 ml of diisopropyl thylamine, and cooled to 0 ° C; a solution prepared by dissolving 0.67 g (1,1-biphenyl) -4-carbon tetrachloride is added dropwise; in 50.0 ml of dichloromethane, and the resulting reaction mixture was stirred at room temperature for 16.0 hours. At the end of this operation, an additional 0.30 g (1,1-biphenyl) -4-carbonyl chloride was added to the mixture; in 30.0 ml of dichloromethane, and the mixture is stirred again at room temperature for 16.0 hours.

The volatile components are then centrifuged from the mixture under vacuum; and the residue was dissolved in 150.0 ml of chloroform

148 was washed with 50.0 ml water; and then, after drying with sodium sulfate *, the solvent is removed.

The remaining residue is chromatographed on silica gel, eluting with ethyl acetate: hexane (1: 5), followed by ethyl acetate: hexane (1: 3).

0.86 g of the desired product is obtained in the form of a solid.

Melting point: 152.0-154.0 ° C

Mass spectroscopy (CI): 377.0; ('.Ή ⁺ ) Example 1

Preparation of 10 - ((1,1-biphenyl) -4-yl-carbonyl) -10,1-1-dihydrodibenz (b, f) -1,4-oxazepine

To a solution prepared by dissolving 1.0 g of 10,11-dihydrodibenz- [b, f] 1,4] oxazepine; and 7.0 ml of triethylminine; in 30.0 ml of dichloromethane, ’and cooled to 0 ° C,‘ add, dropwise, 2.0 g (1,1-biphenyl) -4-carbon, yl chloride, dropwise. The resulting reaction mixture was stirred at room temperature for 16.0 hours and then diluted with 50.0 mL of chloroform.

the mixture is washed successively with 30.0 ml of water each time; 2N hydrochloric acid solution; with water; with a saturated aqueous solution of sodium bicarbonate; and again with water; and then dried over sodium sulphate.

Removal of the solvent under vacuum gave 1.60 of the desired product as a yellow solid.

• · ·

149

Mp 93.0-95.0 ° C

Mass Spectroscopy (Cl): 378.0 (MK ⁺ )

Example 27

Preparation of 9 - ([1,1-biphenyl] -4-ylcarbonyl) -9,10-dihydro-4H-thien- [2,3-c] -1-benzezepine

In an analogous manner to that described in Example 26 above; was reacted with 9,10-dihydro-4H-thien- [2,3-c] -1-benzazepine with 1,1-biphenyl] -4-carbonyl chloride.

The title product is obtained as a yellow solid.

Mass Spectroscopy (Cl): 381.0 (R).

Example 28

Preparation of 5 - ((1,1-biphenyl) -4-ylcarbonyl) -6,7-dihydro-5H-dibenz (b, d) -azepine

In an analogous manner to that described in Example 26 above; 6,7-dihydro-5H-dibenz- (b, d) -azepine is reacted; with (1,1-biphenyl) 4-carbonyl chloride.

The title product is obtained as a solid.

- 150 ··· · 9 · 9 ···················

Example 29

Preparation of 6 - ([1,1-biphenyl] -4-ylcarbonyl) -5,11-dihydro-6H-pyrido [2,3-e] -1-benzazepine

In an analogous manner to that described in Example 26 above, 5,1 1-dihydro-6H-β-pyrido [2,3-e] -benzazepine is reacted with 1,1,1-biphenyl) -4-carbonyl chloride

The desired product is obtained in the form of a foam,

Example 30

Preparation of 5 - ((1,1biphenyl) -4-ylcarbonyl) -5,6-dihydropyrido [2,3-b] 1,4] benzothiazepine

In an analogous manner to that described in Example 26J above, 5,6-dihydropyrido- [2,3-b] [1,4] benzothiazepine] was reacted with (1,1-biphenyl) -4-carbonyl chloride.

The title product is obtained in the form of a solid, m.p.

Example 31

Preparation of 10 - ((1,1-biphenyl) -4-ylcarbonyl) -10,11-dihydro- [b, f] [1,4] thiazepine (I)

In a similar manner to that described in Example 26 above, 10,11-dihydro- [b, f] 1,4] -thiazepine is reacted; with (1,1-biphenyl) 4-carbonyl chloride.

_R The desired title product, as a solid.

Example 32

Preparation of 10- (4-benzoylbenzoyl) -10,11-dihydrobenz- [b, f] 1,4] oxazepine

In an analogous manner to that described in Example 26 above, 10.1 1-dihydrobenz- [b, f] [1,4] ^z- oxazepine; with 4- (benzovl) benzoyl chloride.

The title product is obtained in the form of a light-colored solid.

Melting point: 103.0-1.6 ° C

Mass Spectroscopy (Cl): 406.0 (MH ⁺ )

Example 33

Preparation of 5- (4-benzoylbenzoyl) -5,6,11,12-tetrahydrobenz- (b, f) azocine

In an analogous manner to that described in Example 26 above; 5,6,11,12-tetrshydrobenz- (b, f) -azocine is reacted; with 4- (benzoyl) ·

C · ·

9 9

9 9 9

9

9 9

- 152 with benzoyl chloride.

The desired product is obtained as a solid.

Melting point: 89.0-92.0 ° C

Mass Spectroscopy (Cl): 418.0 (MH ⁺ )

Note:

In the following Examples 34-44; yields are not given; and neither analytical; and other data.

Example 34

Preparation of 10- [4- (benzoylbenzoyl) -10,11-dihydro- [b, 1H] -thiazepine

In an analogous manner to that described in Example 26 above; 10,11-dihydro- [b, f] 1,4] -thiazepine is reacted; with 4- (benzoyl) chloride.

The desired product is obtained as a solid.

Example 35

Preparation of 5- [4- (benzoylbenzoyl)] - 5,11-dihydro-6H-pyrido [2,2-e] [1] benzazepine

153

In an analogous manner to that described in Example 26 above; 5,6-dihydropyrido [2,3-b] 1,4] -benzothiazepine is reacted; with 4- (benzoyl) -benzoyl chloride.

The desired product is obtained as a solid.

Example 36

Preparation of 6 - [(4-benzoylbenzoyl)] - 5,11-dihydro-6H-pyrido [2,3-e] [1] benzazepine

In an analogous manner to that described in Example 26J above, 5,11-dihydro-6H-pyrido [2,3-e] -1-benzazepine; with 4- (benzoyl) -benzoyl chloride.

The title product is obtained as a solid »

Example 37

Preparation of 5 - [(4-benzolobenzoyl)] - 3-6,7-dihydro-5H-dihenz- (b, d) azepine

In an analogous manner to that described in Example 26 above; 6,7-dihydro-5H-dibenz- (b, d) -azepine is reacted; with 4- (benzoyl) benzoyl chloride.

The desired, title product _t as a solid.

154

Example 38

Preparation of 9 - [(4-benzoylbenzoyl)] - 9.1 C-dihydro-4H-thien- [2,3-c] [1] benzazepine

In an analogous manner to that described in Example 26 above; 9,10-dihydro-4H-thien- [2,3-c] -1-benzazepine is reacted; with 4 (benzoyl) -benzoyl chloride.

The desired product is obtained in the form of a solid.

Example 39

Preparation of 5 - [(4-benzoylbenzoyl)] - 4,1 O-dihydro-5H-thien- [3,2-c] [1] benzazepine

In an analogous manner to that described in Example 26J above, 4,10-dihydro-5H-thien- [3,2-c] -1-benzzepinjone was reacted with 4- (benzoyl) -benzoyl chloride.

The desired product is obtained in the form of a solid.

Example 40

Preparation of 5 - ([1,1-biphenyl] -4-yl-carbonyl) -4,1-dihydro-5H-thi [3,2-C] -1-benzazepine

In an analogous manner to that described in Example 26 above; reacted with 4,1Q-dihydro-5H-thien- [3,2-c] 1-benzzepine; with (1,14-biphenyl) -4-carbonyl chloride.

• ·

99 9

- 155 ZÍ3ká the desired _R ,, title product as a solid.

Example 41

Preparation of 6 - ((1,1-diphenyl) -4-ylcarbonyl) -1,4,5,6-tetrahydropyrrole- [4,3-d] -1-benzepepine

In an analogous manner to that described in Example 26J, 2 mmol of 1,4,5,6-tetrahydropyrrole- [4,3-d] -1-benzazepine are reacted. The product is stirred in methanol with 2N sodium hydroxide solution for 16.0 hours, and then the reaction mixture is concentrated and shaken with ethyl acetate.

The extract was washed with an IP solution of citric acid; then with sodium bicarbonate; and water; and then dried over sodium sulfate, and the solvent is removed.

The desired product is obtained as a solid.

Example 42

Preparation of N- [4 - [(5,6-dihydropyrazole- [4,3-d] -1-benzazepin-6 (1H) -yl) carbonyl] -3-chlorophenyl] -1,1-biphenyl] -2-carboxamide

In an analogous manner to that described in Example IIJ above, 6- (2-chloro-4-aminobenzoyl) -1,4,5,6-tetrahydropyrazole- [4,3-d] -1-benzazepine was reacted with (1,1 * - Biphenyl) -4-carbonyl chloride

The desired product is obtained in the form of a solid.

156 Example 43

Preparation of N- [4 - [(5,6-dihydropyrazolo- [4,3-d] 1-benzazepin-6 (1H) -ylcarbonyl] -3-chlorophenyl] -2- (dimethylamino) -pyridine- 3carboxamide

In an analogous manner to that described in Example 12 above, 6- (2-chloro-4-aminobenzoyl) -1,4,5,6-tetrahydripyrazole- [4,3-d] benzazepine; with 2- (dimethylamino) -pyridine-3-carbonyl chloride.

The desired product is obtained in the form of a solid.

Example 44

Preparation of N- [4- [(5,6-dihydropyrazolo [4,3-d] 1-benzazepin-6 (1H) -yl) carbonyl] phenyl] -2- (dimethylamino) pyridine -3- [arboxamide]

In an analogous manner to that described in Example 11j above, 6- (4-aminobenzoyl) -1,4,5,6-tetrahydro-pyrazolo [4,3-d] benzzepine was reacted with 2- (dimethyleminopyridine-3-carbonyl chloride).

The desired product is obtained as a solid.

Example 45

Preparation of N- [5- (5,6,11,12-tetrahydrobenz- [b, f] -azocin-5-yl) carbonyl] -2-pyridinyl] -5-fluoro-2-methylbenzamide

- 157

To the mixture prepared by mixing 0.246 g of 5,6,11,12-tetrahydro-benzo [b, f] azocin and 695.0 ml of triethylamine; in 5.0 ml of dichloromethane cooled to 0 ° C; 0.586 g of 6 - [(5-fluoro-2-methylbenzoyl) amino] pyridine-3-carbonyl chloride is added thereto with stirring; and the resulting reaction mixture was stirred under argon for 16.0 hours.

After dilution with 50.0 ml of dichloromethane; and with 20.0 ml of water, the organic layer is separated; s washed successively with 20.0 ml of (R) sodium bicarbonate solution; and brine. and then dried over sodium sulfate. The solution obtained is poured over a thin layer of magnesium silicate with water; and the filtrate is concentrated to dryness under vacuum.

The residual residue (450.0 mg) was further processed by preprative plates by silica gel chromatography. The product was obtained as a solid which was recrystallized from ethyl acetate.

0.20 g of the expected product is obtained in the form of a white crystalline solid.

Melting point: 198.0 - 200.0 ° C

Example 46

Preparation of N- [4- (dibenz- [b, f] [1,4] oxazepine-10 (11H) -ylcarbonyl) phenyl] -1,1-biphenyl] -2-carboxamide

To a mixture prepared by mixing 0.197% of 10,11-dihydrodibenz- [b, f] 1,4] oxazepine; and 0.402 g of 4 - [((1,1-biphenyl) -2-carbonyl) -amino] -benzoyl chloride; ^in: 5, -0 'ml (chilled in an ice bath) * dichloromethane, was added dropwise 0.154 g of N, N-diisopropylethylamine in 2.0 mL of dichloromethane.

The reaction mixture was stirred under argon at room temperature for 2.0 hours.

- 158 water; and the organic phase, after separation, is washed successively with 2N sodium carbonate solution; with water, and brine; and then dried over sodium sulfate.

The mixture is then filtered through a thin layer of magnesium silicate containing water, and the filter cake is washed with dichloromethane. The filtrate is then concentrated to dryness; to give 0.65 solid, which was purified by silica gel thick layer chromatography using hexane: ethyl acetate (2: 1) as eluent.

0.110 g of the expected product is obtained in the form of a glassy substance.

Melting point: 107.0 - 122.0 ° C

Analytical evaluation of the compound

Found: C, 80.80; H, 4.90; N 6,00%

Example 47

Preparation of N- [4- (dibenz- [b, f] [1,4] oxazepin-10 (11H) -ylcarbonyl) 3-chlorophenyl] -1,1-biphenyl] -2-carboxamide

Mixture prepared by mixing 0.263 g of 10,11-dihydro-10 (4-amino-2-chlorobenzoyl) -dibenz- [b, f] [1,4] oxazepine; 0.195 g (1,1biphenyl) -2-carbonyl chloride; and 0.116 g of N, N-diisopropylethylminine; in 7.0 ml of dichloromethane, stirred at room temperature for 3.0 hours. The mixture was then poured into water and shaken with dichloromethane.

The extract obtained is washed successively with 2N sodium carbonate solution; with water; and with brine, and then dried with sodium sulphate.Then, the rottok is filtered through a thin layer of magnesium silicate, containing water, and the filter cake is filtered.

- 159 -

The filtrate was concentrated to dryness, and the resulting yellow solid was purified by chromatography on a thick silica gel pad using 1: 1 hexane: ethyl acetate as eluent.

0.12 g of the desired product is obtained in the form of a yellowish-colored solid of glassy character.

145.0-188.0 ° C

Analytical evaluation of the compound:

Found: C, 73.60; H, 4.60; N 5.00 *, Cl 6.40%

Example. 48

Preparation of N- [5- (dibenz- [b, f] [1,4] oxazspin-10 (11II) T.yl-carbonyl) -2-pyridinyl] -5-fluoro-2-methylbenzamide

In an analogous manner to that described in Example 46 above; is reacted with 10,11-dihydrobenz- [b, f] (1,4) oxazepine, in dichloromethane, with 2 - [(2-methyl-5-fluorobenzoyl) amino] -5-pyridinylcarbonyl chloride, in the presence of Ν, Ν-diisopropylethylamine.

The desired product is obtained as a solid, crystalline solid.

Melting point 180.0-186.0 ° C

The following compounds (Example 49) can be prepared in an analogous manner to that described in Example 46J above

53J • · · ·

160 Example 43

Preparation of N- [4- (dibenz- [b, f] [1,4] oxazepin-10 (11H) -ylcarbonyl) phenyl] -2- (2-pyridinyl) -benzamide

Example 50

Preparation of N- [4- (dibenz- [b, f] 1,4] oxazepin-10 (11H) -ylcarbonyl) phenyl] -2- (3-pyridinyl) -benzamide

Example 51

Preparation of N- [4- (dibenz- [b, f] 1,4] -oxazepin-10 (11H) -ylcarbonyl) phenyl] -2- (4-pyridinyl) -benzamide

Example 52

Preparation of 4- [4- (dibenz- [b, f] [1,4] oxazepin-10 (11H) -yl-Xarbonyl)

3-chlorophenyl / -2- (2-thienyl) - oenzamino Example 53

Preparation of N- (4-dibenz- [b, f] [1,4] oxazepin-10 (11H) -yl-carbonyl) 3-chlorophenyl] -2- (3-thienyl) -benzamide

In an analogous manner to that described in Example 48 above; the compounds of Examples 54 to 64 may also be prepared;

• ·

- 161 Example 54

Preparation of N- [5- (aibenz - [b, f] 1,4] -oxszepin-10 (11H) -yl-kerbonyl)

- 2-pyridinyl / -2-chloro-5-fluorobenzamide

Example 55

Preparation of N- [5- (dibenz- [b, f] 1,4] oxazepin-10 (11H) -yl-carbonyl)

2-pyridinyl-2-methyl-3-fluorobenzamide

Fig. 1 a d 56

Preparation of N- [5- (dibenz- [b, f] 1,4] -oxczepin-10 (11H) -ylcarbonyl)

- 2-pyridinyl / -2-methylbenzamide

Example 57

Preparation of N- [5- (dibenz- [b, f] [1,4] oxezepine-10 (11I-1) -yl-carbonyl)

2-pyridinyl / -2-chloro-3-pyridinylkerboxamide

Example 58

Preparation of R- [5- (dibenz- [b, f] [1,4] oxazepine-10 (11H) -ylcarbonyl)

2-pyridinyl / -2-h, hydroxybenzamide

Example 59

Preparation of N- [5- (dibenz- [b, f] [1,4] oxszepin-10 (11H) -yl-carbonyl)

2-pyridinyl-2- (dimethylamino) -benzamide

Example 60 • ·

- 162

Preparation of N- [5- (dibenz- [b, f] [1,4] oxazepin-13 (1H) -yl-carbonyl) -2-pyridinyl] -2- (dimethylemino) -3-pyridinylcarboxamide

Example 61

Preparation of N- [5- (dibenz- [b, f] [71,4] -oxazepine-10 (11H) -ylcarbonyl)

- 2-pyridinyl / -2-fluoro-5-chlorobenzamide

Example 62

Preparation of N- [5- (dibenz- [b, f] 1,4] -oxazepine-13 (1H) -vl-carbononyl)

- 2-pyridinyl- (1,1 ^z - biphenyl) -2-kerboxamide

Example 63

Preparation of N- [5- (dibenz- [b, f] 1,4] -oxazepin-10 (1 H) -yl-carbonyl)

- 2-pyridinyl / -2- (3-pyridinyl) -benzamide

Example 64

Preparation of N- [5- (dibenz- [b, f] [1,4] oxazepin-10 (11H) -ylcarbonyl) -2-pyridinyl] -3- (2-pyridinyl) benzamide

Example 65

Preparation of N- [5- (dibenz- [b, f] 1,4] -oxazepin-13 (11H) -yl-crtonyl) -2-pyridinyl] -2- (4-pyridinyl) benzamide

Example 66

• ·

163

Preparation of N- [5- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -2-pyridinyl] -1,1-biphenyl] -2-carboxsmide

Mixture prepared by mixing 0.198 g of 5,6-dihydropyrido [2,3-b] 1,5-benzoxazepine] 0.155 g of N, N-diisopropylethine; and 0.404 g of 6 - [(1,1-biphenyl) -2-carbonyl] -amino] -pyridine-3-carbonyl chloride in 12.0 ml of dichloromethane, stirred at room temperature for 3.50 hours. The reaction mixture was then poured into water and shaken with chloroform.

The extract obtained is washed successively with 2N sodium carbonate solution with water and brine, and then dried over sodium sulphate. The solution is then poured over a thin layer of magnesium silicate. containing water, and the filtrate is concentrated to dryness after the filter cake is washed with hexane: ethyl acetate (1 r 2)

The desired amount (not shown) is obtained; in the title product, in the form of a glassy solid.

Melting point: 107.0-114.0 ° C

Analytical evaluation of the compound:

Found: C, 74.40; H, 5.70; N £, 80%

Example 67

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxszepin-6 (5H) -ylcarbonyl) -3-chlorophenyl] -1,1-biphenyl] -2-carboxamate

A mixture prepared by mixing 0.189 g of 5,6-hydropyrido [2,3b] [1,5] -benzoxazepine] 0.155 g of N, N-diisopropyl-thylamine and 0.444 g of 4 - [( _1'- 1-biphenyl)] The 2-carbonyl) amino] -2-chlorobenzoyl chloride, in 12.0 mL of dichloromethane, was stirred at room temperature for 2.50 hours.

164

The reaction mixture was poured into water; and extracted with dichloromethane. The extract obtained is readily extracted with 2N solution. sodium carbonate *,. The solution was allowed to flow through a thin layer of magnesium silicate containing water; washing the filter cake with 50.0 ml of a 1: 2 mixture of hexane and ethyl acetate; and the filtrate is concentrated to dryness.

The residue obtained is worked up mechanically and recovered.

and taken up with ether; ádaný; The title product, in the form of a solid melting point:

205.0-21.0 ° C

Analysis Found: C, 72.30;

and an ·> - ->

N, 7.90; Cl

6.701

In an analogous manner to that described in Example 66 above; the compounds shown in Examples 68-87 may also be prepared;

Example 68

Preparation of N - [5- (Pyrido- [2,3-c] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -3-pyridinyl] - [1,1-biphenyl] -2-carboxsmide

Example 69

Preparation of N- [5- (Pyrido- [2,3-b] 1,5] -benzoxazepin-6 (5H) -yl-carbonyl) -2-pyridinyl] -2-chlorobenzamide

- 165 Example 70

Preparation of N- [5- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-chloro-5-fluorobenzamide

Example 71

N- / 5- (pvrido- / 2,3-b // 1,5 / 6--benzoxszepin (dk) -yl-carbonyl corr) -2-pyridinyl / ^z -2-hvdroxybe nzamidu

Example 72

Preparation of N- [5- (p-pyrido- [2,3-b] 1,5] -benzoxszepin-6 (5K) -ylcarbonyl) -2-pyridinyl] -2,5-difluorobenzamide

Example 73

Preparation of N- [5- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -yl-carbonyl) -2-pyridinyl] -2-methylbenzamide

Example 74

Preparation of N- [5- (p, yrido- [2,3-b] [1,5] -benzoxezepin-6 (5H) -yl-carbonyl) -2-pyridinyl-2- (methylemino) -benzamide

Example 75

Preparation of N- [5- (pyrido [2,3-b] 11,5] -benzoxazepin-6 (5H) -ylcarbonyl) -2-pyridinyl] -2- (methylamino) -benzamide

Example 76

- 166

Preparation of N- [5- (pyrido- [2,3-b] [1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -2-pyridinyl] -2- (aminomethyl) -benzamide

Example 77

Preparation of N- [5- (Pyrido- [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -2-p-yridinyl] -2-methoxybenzamide

Example 78

Preparation of N- [5- (pyrido- [2,3-b] 1,5] -benzoxszepin-6 (5H) -ylcarbonyl) -2-p-pyridinyl] -2-chloro-5-fluorobenzamide

Example 79

Preparation of N- [5- (pyrido- [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-methyl-3-fluorobenzamide

Example SO

Preparation of N- [5- (Pyrido- [2,3-b] 1,5] -benzoxazepin-6 (5K) -ylcarbonyl) -2-pyridinyl] -2-fluoro-6-chlorobenzamide

Example 81

Preparation of N- [5- (p-pyrido- [2,3-b] [1,5] -benzoxazepine-6 (5H) -v-carbonyl) -2-pyridinyl] -2,6-dichlorobenzamide

Example 82

Preparation of N - _[ 5- (Pyrido- [2,3-b] 1,5] -benzoxszepin-6 (5H) -yl-tertbonyl) -2-pyridinyl] -2,5-dimethylbenzamide

- 167

Example 83

Preparation of N- [5- (Pyrido- [2,3-b] 1,5] -benzoxazepin-6 (5H) -yl-carbonyl) -2-pyridinyl] -2-chloro-3-pyridinylcarboxaniide

Example. 84

N- / 5- (pyrido / 2,3-b // 1,5 / -benzoxezepin-6 (5H) - yl _t-carbonyl) -2-pyridinyl-2- (methylamino) -3- pyridinylcarboxamide

Example 85

Preparation of N- [5- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -2-pyridinyl] -2- (dimethylamino) -3-pyridinylcarboxsmide

Example 86

Preparation of N- [5- (Pyrido- [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl] -2-pyridinyl] -2- (aminomethyl) -4- pvridinylksrboxsmid

Example. 87

Preparation of N- [5- (pyrido- [2,3-b] 1,5] -benzoxszepin-o (5H) -ylcarbonyl) -2-pyridinyl] -2- (dimethylamino) -4-pyridinylksrboxamide

In an analogous manner to that described in Example 67 above; it is also possible to prepare the compounds listed in Examples 88-108 below. and no other analytical data.

· · · · «« ««

• ·

- 168

Example 88

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -3-chloro-6-methylphenyl] -1,1-biphenyl] -2-carboxamide

Example 89

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -3,6-dimethylphenyl] -1,1-biphenyl] -2 -carboxamide

Example 90

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepine-6 (5H) -v-carbonyl) -2-methylphenyl] -1,1-biphenyl] -2-carboxamide

Example 91

Preparation of N- [4- (p-pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -yl-carbonyl) -2-chlorophenyl] -1,1-biphenyl-2 -carboxamide

Example 92

Preparation of N- [4- (pyrido- [2,3-b] 1,5] -benzoxazepin-6 (5K) -ylcarbonyl) -3-chloro-6-methylphenyl] -2- (2-thienyl) -benzamide

Example 93

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -3,6-dimethylphenyl] -2- (3-thienyl) - benzemide

Example 94 • ············

- 169

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl] -3-methylphenyl] -2- (2- thi e ny1) -be nzami du ·· ··· *

Example 95

Preparation of N- [4- (p-pyrido- [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -3-chlorophenyl] -2- (2-thienyl) - benzamide

Example. 96

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -3-chlorophenyl] -2- (3-thienyl) benzamide

Example 97

Preparation of N- [4- (pyrido- [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -3-chlorophenyl] -2- (2-furanyl) -benzamide

Example 98

Preparation of N- [4- (p-pyrido- [2,3-b] [1,5] -benzoxazepin-6 (5K) -ylcarbonyl) -3-chlorophenyl] -2- (2-pyridines) -benzamide

Example 99

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -yl-carbonyl) -3-chloro-phenyl] -2- (3-pyridinyl) -benzamide

Example 100

- 170

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazpein-6 (5H) -ylcarbonyl) -2-chlorophenyl] -2- (4-pyridinyl) benzamide

Example 101

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxszepin-6 (5K) -ylcarbonyl) -3-chlorophenyl] -2- (3-furanyl) -benzamide

Example 102

Preparation of N- / 4- (pyrido _of 2,3-1 // 1,5 / benzoxazepin-6 (5H) -yl -carbonyl) -3-methylphenyl-biphenyl // 1,1 / 2-carboxamide

Example 103

Preparation of N- [4- (pyrido [2,3- f] [1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -3-methylphenyl] -2- (3-thienyl) -benzamide

Example 104

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H-1-ylcarbonyl) -3-methylphenyl] -2- (2-pyridinyl) -benzamide

Example 105

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -3-methylphenyl] -2- (3-pyridinyl) - benzamide

Example 106

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -3-methylphenyl] -2- (4-pyridinyl) -benzamide • ·

171 Example 107

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -3-methylphenyl] -2- (2-furanyl) -benzamide

Example 108

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -3,6-dimethylphenyl] -2- (2-thienyl) -benzamide

Analogous to the procedure described above in Example 67; it is also possible to prepare the compounds listed in Examples 109 to 129J below, in which the yields are not shown either; and no marginal or other additional information.

Example 109

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepine-S (5H) -ylcarbonyl) -3-fluoro-6-methylphenyl] -1,1-biphenyl] - Of 2-carboxamide

Example 110

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -yl-carbonyl) -3,6-dichlorophenyl] -1,1-biphenyl] -2- carboxamide

Example 111

Preparation of N- / 4- (pyrido / 2,3-b // 1,5 / benzoxazepin-6 (5H) -yl-carbonyl bony · 1) -3- fluorophenyl // ^1> 1-biphenyl / -2 -ksrboxamide

- 172 · · 172 172 172 172 172 172 172 172 172 172 172 172 172 172 172 172 172 172 172 172 172 172 172 172 172 · · · · ····················· · 9

Example 112

Preparation of N- [4- (pyrido- [2,3-b] 1,5] -benzoxazepin-6 (5K) -ylcarbonyl) -phenyl] -1,1-biphenyl] -2-carboxamide

Example 113

Preparation of N- [4- (pyrido [2,3-b] 1,5] benzoxazepin-6 (5H) -ylcarbonyl) phenyl] -2- (2-thienyl) benzamide

Example. 114

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxszepin-6 (5H) -ylcarbonyl) -phenyl] -2- (3-thienyl) -benzamide

Example 115

Preparation of N- [4- (pyrrolo [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -phenyl] -2- (2-thienyl) -benzsmiau

Example 116

Preparation of N- / 4- (pyrido / 2,3-b // 1,5 / benzoxazepin-6 (5H) -yl -carbonyl) -3-fluo ^R phenyl / -2- (2-thienyl) -henzamide

Example 117

Preparation of N- (4-Pyrrolo [2,3-b] 1,5] -benzoxazepin-o (5H) -yl-carbonyl) -phenyl] -2- (3-thienyl) -benzamide

Example 118 • ·

- 173 • · · · · · · · · · · · · · · · · · · · ·

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (pH) -ylcarbonyl) -phenyl] -2- (2-furanyl) -benzamide

Example 119

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazpein-o (5H) -ylcarbonyl) -phenyl] -2- (2-pyridinyl) -benzamide

Example 120

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -phenyl] -2- (3-pyridinyl) -benzamide

Example 121

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxazepin-6 (5H) -ylcarbonyl) -phenyl] -2- (4-pyridinyl) -benzamide

Example 122

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxezepin-5 (5H) -ylcarbonyl) -3-fluorophenyl] -2- (3-furanyl) -benzamide

Example 123

Preparation of N- (4-Pyrido- [2,3-b] 1,5] -benzoxazepine-6 (5H) -v-carbonyl) -3-methyl-6-fluorophenyl- (1,1-biphenyl) - Of 2-crboxamide

Example 124

Preparation of N- [4- (pyrido- [2,3-b] 1,5] -benzoxszpein-6 (5H) -ylcarbonyl) -2-methylphenyl] -2- (2-furanyl) -benzamide

9

174

Example 25

Preparation of N- [4- (pyrido- [2,3-b] - (1,5) -benzoxazepin-6 (5K) -ylcarbonyl) -3-methylphenyl] -2- (3-furanyl) -benzamide

Example 126

Preparation of N- [4- (p-pyrido- [2,3-b] - [1,5] benzoxazepin-6 (5H) -ylcarbonyl) -3,6-dimethylphenyl] -2- (3-pyridinyl) - benzamide

Example 127

Preparation of N- [4- (pyrido- [2,3-b] [1,5] -benzoxszepin-6 (5H) -ylcarbonyl) -3,6-dichlorophenyl] -2- (4-pyridinyl) -benzamide

Example 128

Preparation of N- [4- (pyrido [2,3-b] 1,5] -benzoxezepin-6 (5K) -ylcarbonyl) -phenyl] -2- (3-fluoro) benzamide

Example 129

Preparation of N- [4- (pyrido- [2,3-b] 1,5] -benzoxszepin-o (5K) -ylcarbonyl) -3-fluorophenyl] -2- (2-thienyl) benzamide

Example 130

Preparation of N- [5- (Pyrido- [2,3-b] [1,4] benzoxazepine-5 (6H) -carbonyl) -2-pyridinyl] -5-fluoro-2-methylbenzamide

In an analogous manner to that described in Example 46 above;

5,6-dihydropyrido [2,3-b] 1,4] -benzoxazepine (1 mol) is reacted with · · · · ···· · · · · · · · · · · · · · · · · · · · · R-7 r- · ·········· · · · ·

175 with 2- [(2-methyl-5-fluorobenzoyl) amino] -5-pyridinylcarbonyl chloride (1.0 mmol); in dichloromethane; in the presence of Ν, Ν-diisopropylethylamine (3.0'mmoles).

The desired product is obtained in the form of a solid; glassy character.

Example 131

Preparation of N- [5- (pyrido [2,3-b] 1,4] benzoxazepin-5 (6H) -ylcarbonyl) -2-pyridinyl] -1,1-biphenyl] -2-carboxamide

In an analogous manner to that described in Example 66 above; 0.198 g of 5,6-dihydropyrido [2,3-b] [1,4] benzoxazepine is reacted with 0.404 g of 6 - [(1,1-biphenyl) -2-carbonyl] amino] -pyridine- 3-carbonvlchloride; in dichloromethane; in the presence of 0.155 g of K, N-diisopropylethylamine.

The title product is obtained in the form of a solid;

Example 132

Preparation of N- [4- (p-pyrido- [2,3-a] [1,4] benzoxazepin-5 (6H) -ylcarbonyl) -3-chlorophenyl-1- (1,1-biphenyl)] -2-carboxamide

In an analogous manner to that described in Example 66 above;

0.198 g of 5,6-dihydropyrido- [2,3-b] 1,4] -benzoxazepine is reacted with 0.444 g of 4 - [([1,1-biphenyl] -2-carbonyl) -emino] -2-chlob ^t: nzoyl chloride; in dichloromethane; in the presence of N, N-diisopropylethylamine.

The desired product is obtained; in the form of a solid.

- 176 Example

Preparation of N- [4- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -phenyl] - [1,1,1-biphenyl] -2-kax ' boxsmióu

To a mixture prepared by mixing 10.55 g of 6,11-dihydropyrido / ^from 2,3-b // 1, 5 / benzodiazepine-5 (6H) -one; in 40.0 ml of tetrahydrofuran, 15.0 ml of a 10 molar borendimethylsulfide solution is added; in tetrahydrofuran. The resulting reaction mixture was stirred at room temperature:

lobu no ·:

the vinegar is heated at reflux by a reflux condenser; under argon atmosphere for 4.0 hours.

An additional 40.0 mL of tetrahydrofuran was then added to the mixture, and the mixture was heated to reflux overnight.

Thereafter, 12.0 ml of ethanol are added to the cooled reaction mixture; and the solvent is removed.

To the remaining residue was added 30.0 ml of 2K sodium hydroxide solution, and the resulting residue was stirred for 30 minutes. solution was heated to r ^r -fluxu reflux; in an argon atmosphere; every 2.0 hours. The mixture was shaken with ethyl acetate; The separated aqueous phase is made alkaline with 2N sodium hydroxide solution and then shaken with ethyl acetate. The extract is washed successively with wasp, brine and then dried with sodium sulfate.

This solution is filtered through a thin layer of water-containing magnesium silicate and the filtrate is concentrated to dryness.

• ·

- 177

4.65 g of a brown solid are obtained, which solid is purified by chromatography on silica gel; and solids are obtained. A portion (4.85 g) of this crude product 3e was treated mechanically with ether.

2.6S g of 6,11-dihydropyrido [2,3-b] 1,5-benzodiszepine is obtained; in the form of a solid.

Mixture prepared by mixing 3.296 g of 6,11-dihydropyrido [2,3-b] 1,5-benzodiazepine; obtained in the above step (3.604 g of 4 - [(1,1-biphenyl) -2-carbonyl) -amino] benzoyl chloride) and 0.232 g of Ν, Ν-diisopropylethylamine) in 6.0 ml of dichloromethane are stirred. at room temperature for 1.50 hours. The reaction mixture is then poured into water; and shaken with dichloromethane. The mixture was washed successively with water (saturated aqueous sodium bicarbonate solution) with water, then dried over sodium sulfate.

The solution thus obtained was filtered through a thin pad of water-containing magnesium silicate and the filtrate was concentrated to dryness. The residue was purified over a thick pad of silica gel using hexane: ethyl acetate (1: 2) as eluent. eluent?

The solid obtained is recrystallized from ethyl acetate.

The title product is obtained in the form of an off-white crystalline solid.

Melting point

220.0-221.0 ° C

Example 134

Preparation of N- [4- (6,11-dihydropyrido- [2,3-b] [1,5] benzodiazepine-6 (5H) -ylcarbonyl) -3-chlorophenyl] -1,1-biphenyl] -2- carboxamide • · * ·

- 178 Mixture prepared by mixing 0,197 g of 6,11-dihydropvrio / 2,

3-b [1,5] -benzodiszpeine; 0.444 g of 4 - [([1,1-biphenyl] -2-carbonyl) amino] -2-chlorobenzoyl chloride; and 0.155 g of N, N-diisopropylethylamine; in 6.0 ml of dichloromethane, stirred at room temperature for 1.5 hours. The reaction mixture is then poured into water and shaken with dichloromethane. The extract is washed successively with water; a saturated aqueous solution of sodium bicarbonate is again treated with water, and brine; and then dried over sodium sulphate. The solution thus obtained is filtered through a thin layer of magnesium silicate containing water and the filtrate is concentrated to dryness.

The residue was chromatographed on a thick layer of silica gel, using a pad, eluting with hexane: ethyl acetate 1: 2).

0.160 g of the desired product is obtained in the form of a solid.

Melting point 147.0-165.0 ° C

Analytical evaluation of the compound:

Found: C, 72.10; N, 9.10; Cl 6.30 1

Example 135

Preparation of N- [4- (6,11-dihydropyrrolo [2,3-b] 1,5] -benzodiazepine-6 (5H) -yl-carbonyl) -phenyl] -1,1-biphenyl] -2-carboxamide. HCl

To 50.0 ml of anhydrous and cooled methanol; Hydrogen chloride gas was injected for 15.0 minutes. Also taken with 25.0 ml of the methanolic hydrogen chloride thus prepared; to 0.30 g of 4- (6,11-dihydropyrido [2,3-b] [1,5] -benzodiszepin-6 (5H-4-ylcarbonyl) -phenyl] - 1,1-biphenyl) -2- and thus prepared

• · · ·

179 reaction mixture, stirred at 0 ° C for 0.50 hours; and then heated to room temperature.

After removal of the solvent, the solid residue is dried under vacuum; to give 0.31 g of the desired product as a solid. Melting point: 195.0-21.0 ° C

In an analogous manner to that described in Example 134J above, 6,11-dihydropyrido- [2,3-b] [1,5] -benzodiezepine, with the appropriate substituted or unsubstituted ((arylcarbonyl) amino) -benzoyl chloride, may be prepared; or with an appropriate (substituted or unsubstituted) (arylcarbonyl) -amino] -pyridinylcarbonyl chloride, followed by the compounds listed in Examples 136 to 217 ',

Example 136

Preparation of N- [4- ($, 11-dihydropyrido- [2,3-b] 1,5] -benzodxazepin-6 (5H) -yl-carbonyl] -3-chlorophenyl] -2- (2-thienyl) -benzamide

Example 137

Preparation of N- [4- (6,11-dihydropyrido [2,3-b] 1,5] -tenzodiazpein-6 (5H) -yl-carbonyl] -3-chlorophenyl] -2- (3-thienyl) -benzamide

Example 138

Preparation of N- [4- (5,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5K) -yl] -carbonyl] -1H-chloro-6-methylphenyl 1- [2- (2-thienyl) benzamide]

180

Example 139

Preparation of N- / 4- (6-dihydro-pyrido _r 11 / 2,3-b // 1,5 / -benzodiazpein6 (5H) -yl a carbonyl group) -feny1 / -2- (2-thienyl) -benzamide

Example HO

Preparation of N - [- (6,11-dihydropyrido- [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl] -phenyl] -2- (3-thienyl) -benzamide

Example 141

Preparation of N- [4- (6,11-dihydropyrido-3 ', 3-b] 1,5' -benzodiazepine-6 (5H) -ylcarbonyl) -3-methylphenyl] -2- (2-thienyl) -benzamide

Example 14 2

Preparation of N- [4- (6,11-dihydropyrido- [2,3-b] 1,5] -benzodiszepine-6 (5H) -yl-carbonyl] -3,6-dimethyl-phenyl] -2- (2-thienyl) -benzamide

Example 143

Preparation of N- [4- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -3-methylphenyl] -1,1-biphenyl] -2- ksrboxamide

Example 144

Preparation of N- [4- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5h) -ylcarbonyl) -3,6-dimethylphenyl] -1,1-biphenyl] - 2-ksrbox amide

Example 145

- 181

Preparation of N - [4- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -3,6-dichlorophenyl] -1,1-biphenyl] - 2-carboxamide

Example 146

Preparation of 11- [4- (6,11-Dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -3-methyl-6-chlorophenyl] -1,1-biphenyl -2-carboxsmid

Example 147

Preparation of N- [4- (6,11-Hydropyrido [2,3-b] 1,5] benzodiszepine-6 (5H) -ylcarbonyl) -3-chloro-6-fluorophenyl] - (1,1- biphenyl) -2-carboxamide

Example 148

Preparation of N- [4- (6,11-dibydropyrido [2,3- b] 1,5] -benzodiazepin-6 (5H) -yl-3-carbonyl) -2-methylphenyl] - (1,1-biphenyl) -2 -carboxamide

Example 149

Preparation of N- [4- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiszepine-6 (5H) -yl-carbonyl) -2-chlorophenyl] - (1,1-diphenyl) -2- carboxamide

Example 150

Preparation of N- [4- (6,11-dihydropyrido- [2,3-b] 1,5] -benzodiazepine-6 (5K) -ylcarbonyl] -phenyl] -2- (2-pyridinyl) -benzsmide

Example 151

182 Preparation of N- [4- (6,11-dihydropyrrolo [2,3-b] 1,5] -benzodiazepine-6 (5H) -yl-carbonyl) -phenyl] -2- (3-pyridinyl) -benzamide ·· · ·

Example 152

Preparation of N- [4- (6,11-dihydropyrido- [2,3-b] [1,5] benzodiazepine-6 (5H) -ylcarbonyl) -phenyl] -2- (4-pyridinyl) -benzamide

Example 153

Preparation of N- [4- (6,11-dihydropyrido- [2,3-b] [1,5 ^] benzodiszepine-6 (5H) -ylcarbonyl) -3-chlorophenyl] -2- (2-pyridine). yl) benzamide

Example 154

Preparation of N- [4- (6,11-dihyropropido- [2,3-b] [1,5] benzodiezepin-6 (5H) -yl-carbonyl) -3-chlorophenyl] -2- (3-pyridinyl) -benzamide

Example 155

Preparation of N- [4- (6,11-di-piperidido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl] -3-chlorophenyl] -2- (4-pyridinyl) 1-benzamide

Example. 156

Preparation of N- [4- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepime (5H) -yl] carbonyl) -3-methylphenyl] -2- (2-pyridinyl) benzamide

Example. 157

Preparation of N- [4- (6,11-dihydropyrido [2,3-b] [1,5] benzodiazepine-6 (5H) -yl-carbonyl) -3-methylphenyl] -2- (3-pyridinyl) -benzemide

- 183

Example 158

Preparation of N- [4- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -3-methylphenyl] -2- ( 4-p-pyridinyl) -benzamide

Example 159

Preparation of 11- [4- (6,11-Dihydropyrido [2,3-b] 1,5] -benzodiazepin-6 (5) -yl] -carbonyl) -3-methyl-6-fluorophenyl] -2- (2-thienyl) -benzamide

Example 160

Preparation of 11- [4- (6,11-dihydropyrido [2,3-b] [1,5] benzodiazepine-6 (5H) -ylcarbonyl) -3,6-dimethylphenyl] -2- (2-pyridinyl) ) -benzcmide

Example 161

Preparation of N- [4- (6,11-dihydropyrido [2,3-b] [1,5] -benzoyl) (5H) -yl-carbonyl) -3,6-dimethylphenyl] - 2- (3-pyridinyl) -benzsmide

Example 162

Preparation of N- [4- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -yl] carbonyl) -5,6-dimethylphenyl] -2- (4- pyridinyl) benzamide

Example 163

Preparation of N- [4- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5K-yl) -carbonyl] -2-methoxy-pyridine-3-carboxamide

Example 164 ····

- 184

Preparation of N- [4- (6,11-dihydropyrido- [2,3-b] [1,5] benzodiazepine-6 (5H ') -ylcarbonyl) -3-chlorophenyl) -2-methylthiopyridine-3 -carboxamide

Fig. 1 a d 165

Preparation of 11- [4- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -3-methylphenyl] -2-methylpyridine-3-carboxamide

Example 166

Preparation of 11- [4- (6,11-Dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H; -ylcarbonyl) -3,6-dimethylphenyl) -2-methylpyridine-3-carboxammonium

Example 167

Preparation of 11- [4- (6,11-Dihydropyrido- [2,3-b] 1,5] -benzodiazepine-6 (5H) -yl-carbonyl) -phenyl] -2-methyl-pyridine-3-carboxamide

Example 168

Preparation of 11- [4- (6,11-Dihydropyrido- [2,3-b] 1,5] -benzodiezepin-6 (5H) -yl-carbonyl) -3-chloro-phenyl] -2-methyl-pyridine-3-carboxamide

Example 169

Preparation of N- [4- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -3-chloro-6-methylphenyl] -2-fluoropyridine-3-carboxamide

- 185 -

Example 170

Preparation of N- [4- (6,11-dihydropyrido- [2,3-b] [1,5] benzodiazepine-6 (5H) -ylcarbonyl) -3-chlorophenyl] -2-fluoropyridine-3-carboxamide

Example 171

Preparation of N- [4- (6,1-dihydropyrido [2,3-b] ^[ 1,5] benzodiazepine-6 (5H) -ylcarbonyl) -2-methylphenyl] -2-chloropyridine-3-carboxsmide

Example 172

K - [4- (1,1-dihydropyrido [2,3-b] 1,5] -benzodiszepine-6 (5H) -ylcarbonyl) -3,6-dimethylphenyl] -2-chloro-pyridine -3-carboxamide

Fig. 1 a d 173

Preparation of N- [4- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -phenyl] -3-methylpyridine-2-carboxamide

Example 174

Preparation of N- [4- (6,11-Dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -3-chlorophenyl] -3-methylpyridin-2 -carboxaniidu

Example 175

Preparation of N- [4- (6,11-dihydropyrido [2,3,5] 1,5] -benzothiazepine-6 (5H) -ylcarbonyl) -3-chlorophenyl ^] -2-chloropyridine-3-carboxamide

Example 176

186

Preparation of N- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -1,1-biphenyl] -2- carboxamide

Example 177

Preparation of N- [5- (6,11-Dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2- (2-thienyl) -benzamide

Example. 178

Preparation of N- [5- (5,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2- (3-thienyl) -benzamide

Example 179

Preparation of N- (5-C6,11-dihydropyrido [2,3-b] 1,5) -benzodiszepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-fluorobenzamide

Example 180

Preparation 11- [5- (6,11-dihydropyrido [2,3-b] [1,5] benzodiazepine-6 (5K) -ylcarbonyl) -2-pyridinyl] -2- (2-pyridinyl) - benzamide

Example 181

Preparation of N- [5- (5,11-dihydropyrido [2,3-b] 1,5] benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2- (3-p-pyridinyl) -benzsmid

Example 182

Preparation of (1- / 5- (6,1-Dihydropyrido [2,3-b] [1,5] benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl) -2- (4-pyridinyl) -benzamide

- 187

Example 183

N- / 5- (6 _F 11-dihydro-pyrido / 2,3-b // 1,5 / -benzodiszepin6 (5H) -yl-carbonyl) -2-pyridinyl / -2- (2-furanyl) -benzamide

Example 184

Preparation of N- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2- (3-furanyl) -benzamide

Example 185

Preparation of N- [5- (6,11-dihydropyriao [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -3-chloropyridine-2-carboxamide

Example 186

Preparation of N- [5- (6,11-Dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-methylpyridine-3-carboxamide

Example 187

Preparation of N- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -5-fluoro-2-methylbenzamide

Example 188

Preparation of N- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-chlorobenzemide

Example 189

188

Preparation of N- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-chloro-5-fluorobenzamide

Example 190

Preparation of N- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-methylbenzamide

Example 191

Preparation of N- [5- (6,11-dihydropyrido- [2,3-b] [1,5] benzodiszepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2,5-dimethylbenzamide

Example 192

Preparation of N- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-chloro-4-fluorobenzamide

Example 193

Preparation of N- [5- (5,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-chloro-6-fluorobenzamide

Example 194

Preparation of N- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazpeine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-methyl-3-fluorobenzamide

Example 195

Preparation of N- [5- (1,1,1-dihydro-pyrido [2,3-b] 1,5] -benzodiazpeine-6 (5K) -ylcarbonyl) -2-pyridinyl] -2-hydroxybenzamide

- 189

4 · 4 · · · · · · · · · · · · · · · · ·

Example 196

Preparation of N- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl-2-acetyloxybenzamide

Example 197

Preparation of N - [5- (6,11-Dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-aminobenzamide

Example 198

Preparation of Ν- [5- (β, 11-Dihydropyrido [2,3-b] 1,5] -benzoisiszepin-6 (5H) -yl-1-carbonyl) -2-pyridinyl] -2- ( me thy la no) -benzs mi du

Example 199

Preparation of N- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazpeine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2- (dimethylamino) -benzamide

Example 200

Preparation of N- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine (5K) -ylcarbonyl) -2-pyridinyl] -2-aminomethylbenzamide

Example 201

Preparation of N- [5- (6,11-dihydropyrrolo [2,3-b] 1,5] -benzodiezepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2- (diethylamino) -benzamide

Example 202

190

Preparation of N- [5- (6,11-Dihydropyrido [2,3-b] 1,5] -benzodiazpeine-6 (5H-5-carbonyl) -2-pyridinyl] -2- (dimethylaminomethyl) - benzamide

Example 203

Preparation of N- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazpein [(5H) -ylcarbonyl] -2-pyridinyl] -2- (methylthio) benzamide

Example 204

Preparation of N- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-chloropyridine-3-carboxamide

Example 205

Preparation of N- [5- (6,11-dihydropyrido [2,3-l] 1,5] -benzoaiszpeine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-fluoropvridine-3-carboxemide

Example 206

Preparation of N- (5-C6,11-dihydropyrido [2,3-b] 1,5] -benzisisepepine (5H) -yl-carbononyl) -2-pyridinyl] -2-methoxy-pyridine-3-carboxamide

Example 207

Preparation of N- [5- (6,11-dihydropyrido [2,3-l] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-methylthiopyridine-3-carboxamide

Example 208 • ·

- 191

Preparation of N '- [5- (6,11-dihydropyrido [2,3-b] [1,5] benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-aminopyridine-3-carboxamide

Example 209

Preparation of N- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-methyl-pyridin-3 -k5rboxamide

Example 210

Preparation of N- [5- (6,1-Dihydropyrrolo [2,3-b] [1,5] benzodiazepine-6 (5R) -ylcarbonyl) -2-pyrrolidinyl] -2-dimethylamino-pyridine -3 carboxamide

Example 211

Preparation of N- [5- (6,11-dihydropyrido- [2,3-b] 1,5] -benzoothiazepine-6 (5H) -yl-carbonyl) -2-pyridinyl] -thiophene-2-carboxamide

Example 212

Preparation of N - [5- (6,11-Dihydropyrido [2,3-b] 1,5] -benzodiazepin-6 (5H) -yl-carbonyl) -2-pyridinyl] -1H-phenyl-3-carboxamide

Example 213

Preparation of N- (5-C6,11-dihydropyrido [2,3-b] [1,5] -benzodiazepine-6 (5H) -yl-carbonyl) -2-pyridinyl] furan-2-kerboximidamide

Example 2U • ·

- 192 • · · ·

Preparation of 11- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5H) -ylcarbonyl] -2-pyridinyl] -2-methylthiophene-3-carboxamide

Example 215

Preparation of N- [5- (6,11-dihydropvrido- [2,3-b] 1,5] -benzodiazepine-6 (5H) -yl-carbonyl) -2-pyridinyl] -3-methylthiophene-2-carboxamide

Example 216.

Preparation of 11- [5- (6,11-Dihyaropyrido [2,3-b] [1,5] -benzosiazepine-6 (5H) -ylcarbonyl) -2-pyridinyl] -2-chloro-thiophene- 3-carboxamide

Example 217

Preparation of 11- [5- (6,11-dihydropyrido [2,3-b] 1,5] -benzodiazepine-6 (5E) -yl-carbonyl-2-pyridinyl] -2-methylthiophene-3-carboxeoid

Example 218

Preparation 11- (4 -) (5,11-Dihydro-1H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-chlorophenyl] - (1,1-biphenyl) -2-carboxamide

Mixture prepared by mixing 0,196 g of 5,11-dihydro-1H-dibenz- (b, e [1,4] -diazepine) 0.155 g of N, N-diisopropylethylamine) and 0.444 g of 4 - [(1,1-biphenyl) - Of 2-carbonyl) amino (2-chlorobenzoyl chloride) in 12.0 mL of dichloromethane, was stirred at room temperature overnight. The reaction mixture was then poured into water; and shaken with dichloromethane. The extract obtained is washed successively with 211 solution. potassium carbonate, water, brine, and dried over sodium sulfate.

the nozzle is filtered through a thin layer of water-containing magnesium silicate, and the filtrate is concentrated to dryness.

- 193 -

• ··

The residue is worked up mechanically and taken up with ether; and the solvent is removed. Thereafter, the residue is mechanically worked up; and taken up with dichloromethane.

0.31 g of the desired title product _(as a solid.

Melting point: 158.0-184.0 ° C

Analytical evaluation of the compound of formula ^ 33 ^ 24 ^^ 3 ^ 2 * ^ 2θ

Found: C, 73.70; H, 4.60; N, 7.50; Cl 6,90%

In an analogous manner to that described in Example 218J above, 5,11-dihydro-1H-dibenz- [b, e] -diazepine may be prepared; with appropriately substituted or unsubstituted (arylcarbonyl) amino amino benzyl chloride; or, respectively, substituted or non-substituted [(srylcarbonyl) 8-amino] -pyridinylcarbonyl chloride, the following compounds listed in Examples 219 to 300;

Example 219

Preparation of N- (4 -) (5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) -carbonyl] -phenyl] - (1,1'-biphenyl) -2- ksrboxamide

Example 220

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-methylphenyl [1,1-biphenyl] - 2-carboxsmid

- 194

P t: k 'l and d 221

Preparation of N- / 4 - / (5,11-dihydro-10H-dibenz / b, e // 1,4 / -diazepin10-1yl) carbonyl / -3,6-dimethyl thylfenyl // 1 ₁ 1-biphenyl -2-carboxamide

Example 222

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-chlorophenyl] -2- (2-thienyl) - benzamide

Example 223

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-chlorophenyl] -2- (3-thienyl) - benzamide

Example 224

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-chlorophenyl] -2- (3-furanyl) - benzamide

Example 225

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-chlorophenyl] -2- (2-furanyl) - benzamide

Example 226

Preparation of N- (4 -) (5,11-dihydro-10H-dibenz- (b, e) -1,4) -diazepine

10-yl) carbonyl / -3-methylphenyl] -2- (2-thienyl) -benzamide

Example 227 • ·

195

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-methylphenyl] -2- (3-thienyl) -benzamide

Example 228

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-methylphenyl] -1,1-biphenyl] -2 -carboxamide

Example 229

Preparation of N- [4 - [(5,11-dihydro-1H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3,6-dimethylphenyl] -1,1-biphenyl] -2-carboxamide

Example 230

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-methyl-6-chlorophenyl] -1,1- biphenyl / -2-carboxamide

Example 231

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-chloro-6-fluorophenyl] -1,1- biphenyl / -2-carboxamide

Example 232

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-methylphenyl [1,1-biphenyl] -2 -carboxamide

Example 233

- 196 • · ··· ·

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-chloro-6-methylphenyl] -1,1- biphenyl / -2-carboxamide

Example 234

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-chlorophenyl] -1,1-biphenyl] -2 -ksrboxamide

Example 235

Preparation of N- [4 - [(5 ' _, 11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -phenyl] -2- (2-pyridinyl) -benzamide

Example 236

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -phenyl] -2- (3-pyridinyl) -benzamide

Example 237

Preparation of N- (4 -) (5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -phenyl] -2- (4-pyridinyl) - benzamide

Example 238

Preparation of N- [4 - [(5,11-dihydro-1H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-chlorophenyl] -2- (2-pyridinyl) - benzamide

Example 239

197 Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] -1,4] -diszepin-10-yl) carbonyl] -3-chlorophenyl] -2- ( 3-pyridinyl) -benzamide

Example 240

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-chlorophenyl] -2- (4-pyridinyl) - benzamide

Example 241

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] -diszepin-10-yl) carbonyl] -3-methylphenyl] -2- (2- pyridinyl) -benzamide

Example 242

Preparation of N - [4 - [(5,11-dihydro-10H-dibenz- [b, e] -1,4] -diszepin-10-yl) carbonyl] -3-methylphenyl] -2- (3) -pyridinyl) -benzamide

Example 1 a.d 243

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-methylphenyl] -2- (4- pyridinyl) -benzamide

Example 244

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3,6-dimethylphenyl] -2- ^(2-T p -ridinyl) -benzamide

Example 245

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3,6-dimethylphenyl] -2 - (3-pyridinyl) -benzamide

Example 246

Preparation of N- [4 - [(5,11-dihydro-1H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3,6-dimetbylphenyl] -2- (4-pyridinyl) -benzamide

198

Example 247

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] -diszepin-10-yl) carbonyl] -phenyl] -2-phenylmethyl) -benzamide

Example 248

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] -1,4] -diezepin-10-yl) carbonyl] -phenyl] -2- (3-chlorophenylmethyl) -benzamide

Example 249

Preparation of N- (4 -) (5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-chlorophenyl] -2- (phenylmethyl) benzamide

Example 250

Preparation of N- (4 -) (5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-chlorophenyl] -2-methoxypyridine-3-carboxamide

Example 251

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-chlorophenyl] -2- (methylthio) -pyridine- 3-carboxamide

Example 252 ·· ····

- 199

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-methylphenyl] -2-methylpyridin-3 -carboxamide

Example 253

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-methylphenyl] -3-methylpyridin-2- carboxamide

Example 254

Preparation of N- [4 - [(5,11-dihydro-1H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-methylphenyl] -2-chloropyridine-3-carboxamide

Example 255

Preparation of N- [4 - [(5,11-dihydro-1H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3,6-dimethylphenyl] -2-phenyl luorpyridine-3-carboxamide

Example 256

Preparation of N- [4 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -3-methyl-6-chlorophenyl] -2-chloropyridine-3-carboxamide

Example 257

Preparation of N- (5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -1,1-biphenyl] -2-carboxamide 280.0-285.0 ° C

Melting point :

··

Example 258

Preparation of N- (5 -) (5,11-dihydro-10H-dibenz- [b, e] 1,4] -diazepine

10-yl) carbonyl / -2-pyridinyl / -2- (2-thienyl) benzamide

200

Example 259

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2- (3-thienyl) - henzamide

Example 260

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2- (2-furanyl) - benzamide

Example 261

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2- (2-pyridinyl) -benzamide

Example 262

Preparation of N- [5 - [(5,11-dihydro-1H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2- (3-pyridinyl) - benzamide

Example 263

Preparation of N- [5 - [(5,11-dihydro-1H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2- (4-pyridinyl) -benzamide

Example 264 ··············

201 Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2- (2-furanyl) -benzamide

Example 265

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] -diszepin-10-yl) carbonyl] -2-pyridinyl] -2- (3-furanyl) - benzamide

Example 266

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-methoxypyridine-6-carboxamide

Example 267

Preparation of N- [5- (5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -pyridine-3-carboxamide

Example 268

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-pyridicarboxamide

Example 269

Preparation of N- [5- (5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-methyl-5-fluorobenzamide

Example 270

PREPARATION OF N- [5 - [(5,11-Dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-chlorobenzamide

202

Example 271

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-chloro-5-fluorobenzamide

Example 272

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-methylbenzamide

Example 273

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2,5-dimethylbenzamide

Example 274

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) -carbonyl] -2-pridinyl] -2-chloro-4. 5f luorbenzamide

Example 275Preparation of N- [5 - [(5 ' _, 11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-chloro 6-fluorobenzamide

Example 27

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-methyl-3-fluorobenzamide

Example 277 • · ·

- 203

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-hydroxybenzamide

Example 278

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-piperidinyl] -2-acetyloxybenzamide

Example 279

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-aminobenzamide

Example 280

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] -rdiazepin-10-yl) carbonyl] -2-pyridinyl] -2- (methylamino) - benzamiču

Example 281

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2- (aminomethyl) benzamide

Example 282

Preparation of N- [5 - [(5,1-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2- (dimethylethyl) lamino) -benzamide

Example 283

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-chloropyridine-3-carboxamide ·

- 204

Example 284

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-fluoropyridine-3-carboxamide

Example 285

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-piperidinyl] -2-methoxypyridine-3- (carboxamide

Example 286

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2- (methylthio) -pyridine- 3-carboxamide

Example 287

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-aminopyridine-3- carboxamide

Example 288

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) -carbonyl] -2-pyridines] -2- (methylamino) -pyridine -3-carboxamide

Example 289

Preparation of N- (5- (5,11-dihydro-10H-dibenz- [b, e] -1,4) -diazepine (aryl) -carbonyl] -2-pyridinyl] - (dimethylamino) -pyridin-3 -carboxamide • · · ·

- 205 Example 29σ

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -2-methylthiophene-3- carboxamide

Example 300

Preparation of N- [5 - [(5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepin-10-yl) carbonyl] -2-pyridinyl] -3-methylthiophene-2- carboxamide

Example 301

Preparation of N- [4 - [(6,11-dihydro-5H-chibenz- [b, e] -azepin-5-yl) carbonyl] -phenyl] - [1,1-biphenyl] -2-carboxamide

A mixture prepared by mixing 6,11-dihydro-5H-dibenz- [b, e] azepine (0.195 g) J and 0.41 g of 4 - [(1,1-biphenyl) -2-carbonyl) amino] benzoyl chloride; and 0.155 g of N, N-diisopropylethylamine in 12.0 ml of dichloromethane are stirred at room temperature for 3.0 hours. The reaction mixture is then poured into water; and shake with dichloromethane. Wash the extract successively with water; saturated aqueous sodium bicarbonate, again with sodnéhoj vodouj Solan Kouji 3e and dried over sodným.Zmíněný extract was filtered through a thin layer of silicate _{hořečnstého,:} comprising water, and the filter cake was washed with dichloromethane three.

The filtrate is concentrated to dryness; to give 0.66 g; a yellow solid, which is chromatographed on thick layer silica gel plates; eluent hexane-ethyl acetate (1.5: 1).

0.165 g of dichloromethane: ethyl acetate is recrystallized from the desired product as a crystalline solid.

Melting point :

224.0-225.0 ° C • ··

206

Example 302

Preparation of N- (4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) -carbonyl] -3-chlorophenyl] - (1,1-biphenyl) -2 -carboxamide

The mixture prepared by mixing 0.195 g of 6,11-dihydro-5H-dibenz- (b, e) -azepine is 0.444 g of 4 - [(1,1-biphenyl) -2-carbonyl] -amino] -2-chlorobenzoyl chloride; 0.155 g of Ν, Ν-diisopropylethylamine, and stirred at room temperature for 3.0 hours.

Then the reaction mixture is poured into water; The extract was washed successively with water and saturated aqueous sodium bicarbonate; again with water and then brine, followed by drying with sodium sulfate.

After removal of the solvent from the extract, the residue obtained is chromatographed on thick layer chromatography silica gel plates using hexane: ethyl acetate (1.5-0.5); as eluent.

0.32 g of the desired product is obtained as a crystalline solid.

Melting point: 120.0 - 125.0 ° C

In an analogous manner to that described in Example 302J above, 6,11-dihydro-5H-dibenz- (b, e) -azepine can be prepared; with appropriately substituted, ´ or unsubstituted 4 - [(arylcarbonyl) amino] benzoyl chloride; or respectively substituted or unsubstituted 6 - [(arylcarbonyl) amino] pyridine-3-carbonyl chloride; the following compounds exemplified in Examples 303 to 351;

• · · ·

207 Example 303

Preparation of N- [4 - [(6,11-dihydro-5H-dibenzyl- [b, e] -azepin-5-yl) carbonyl] -phenyl] -2- (2-thienyl) -benzamide

Example 304

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -phenyl] -2- (3-thienyl) -benzamide

Example 305

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -8-zepin-5-yl) carbonyl] -phenyl] -3,6-dichlorophenyl] -2- (2-thienyl) -benzamide

Example 306

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -8-zepin-5-yl) carbonyl] -3-chlorophenyl] -2- (2-thienyl) benzamide

Example 307

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-chlorophenyl] -2- (3-thienyl) benzamide

Example 308

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-chloro-6-methylphenyl] -2- (2-thienyl) - benzamide

Example 309

- 208

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-methylphenyl] -2- (2-thienyl) -benzamide

Example 310

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3,6-dimethylphenyl] -2- (2-thienyl) -benzamide

Example 311

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-methylphenyl] - [1,1-biphenyl] -2- carboxamide

Example 312

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -ezepin-5-yl) carbonyl] -3,6-dimethylphenyl] - [1,1-biphenyl] -2- carboxamide

Example 313

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-methyl-6-chlorophenyl] - [1,1-biphenyl] - 2-carboxaniide

Example 314

Preparation of N- (4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-chloro-6-methylphenyl] - [1,1,1-biphenyl] -2-carboxamide

Example 315

Preparation of N- (4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-methylphenyl] - (1,1-biphenyl) -2 -carboxamide

209 Example 316

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -2-chlorophenyl] - [1,1'-biphenyl] -2-carboxamide

Example 317

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -phenyl] -2- (2-pyridinyl) -benzamide

Example 318

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -phenyl] -2- (3-pyridinyl) -benzamide

Example 319

Preparation of N- [4 - [(b, 11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -phenyl] -2- (4-pyridinyl) -benzamide

Example 320

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-chlorophenyl] -2- (2-pyridinyl) benzamide

Example 321

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl)] -3-carbonyl] -4-chlorophenyl] -2- (3-pyridinyl) -benzamide

Example 322

210 Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-methylphenyl] -2- (2-pyridinyl) benzamide

Example 323

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-methylphenyl] -2- (3-pyridinyl) benzamide

Example 324

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3,6-dimethylphenyl] -2- (2-pyridinyl) -benzamide

Example 325

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3,6-dimethylphenyl] -2- (3-pyridinyl) benzamide

Example 3.26

Preparation of N- [4 - [(6,11-dihydro-5H-chibenz- [b, e] -azepin-5-yl) carbonyl] -3,6-dimethylphenyl] -2- (4-pyridinyl) -benzamide

Example 327

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-chlorophenyl] - (3-methylthio-1,1-biphenyl) - Of 2-carboxamide

Example 328

- 211 • · · · · ·

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-chlorophenyl] - (3-methoxy-1,1-biphenyl) - Of 2-carboxamide

Example 329

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -phenyl] - [4-dimethylamino-1,1-biphenyl] -2- carboxamide

Example 330

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-methylphenyl] - (3-chloro-1,1-biphenyl) - Of 2-carboxamide

Example 331

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-chlorophenyl] -2- (3-furanyl) benzamide

Example 332

Preparation of N- (4 -) (6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -phenyl] -2- (2-furanyl) -benzamide

Example 333

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] phenyl] - (3-chloro-1,1-biphenyl) - Of 2-carboxamide

Example 334

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-chlorophenyl] - (3-chloro-1,1-biphenyl) - 2-carboxamide • · ·· ····

- 212 Example 335

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3- (6-ethylphenyl) - [3-chloro-1,1-biphenyl] -2-carboxamide

Example 336

Preparation of N- (4 - [(6,11-dihydro-5H-dibenz- [b, e] -sepin-5-yl) carbonyl] -2-pyridinyl] - (3-chloro-1,1-biphenyl) - Of 2-carboxamide

Example 337

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -3-chlorophenyl] -4,4-fluoro-1, 1-biphenyl / -2-carboxamide

Example 338

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -2-pyridinyl] -2-chloropyridine-3-carboxamide

Example 339

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -2-pyridinyl] -2-fluoropyridine-3-carboxamide

Example 340

Preparation of N- [4 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -2-pyridinyl] -2-quinopyridine-3-carboxamide

Example 341

Preparation of N- [5 - [(6,11-dihydro-5H-dibenz- [b, e] -sepin-5-yl) carbonyl] -2-pyridinyl] -2- (methylamino) pyridine-3- Carboxamide ···· · · ·

213

Example 342

Preparation of N- [5 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -2-pyridinyl] -2- (dimethylamino) -pyridine- 3-carboxamide

Example 343

Preparation of N- [5 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -2-pyridinyl] -4-methylthiophene-2-carboxamide

Example 344

N- / 5 - / (6,11-dihydro-5H-dibenz / b, e / azepine-5-yl) carbonyl / -2-pyridinyl / methylthi ^x -2-phen-3-carboxamide

Example 345

Preparation of N- [5 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -2-pyridinyl] -2-chlorobenzamide

Example 346

Preparation of N- [5 - [(6,11-dihydro-5H-dibenz- [b, e] -zepin-5-yl) carbonyl] -2-pyridinyl] -2-chloro-5-fluorobenzamide

Example 347

Preparation of N- (5 -) (6,11-dihydro-5H-dibenz- [b, e-azepin-5-yl) carbonyl] -2-pyridinyl] -2-chloro-6-fluorobenzamide

- 214

Example 348

Preparation of N- [5 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -2-pyridinyl] -2-methyl-3-fluorobenzamide

Example 349

Preparation of N- [5 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -2-pyridinyl] -2- (methylamino) benzamide

Example 350

Preparation of N- [5 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -2-pyridinyl] -2-hydroxybenzamide

Example 351

Preparation of N- [5 - [(6,11-dihydro-5H-dibenz- [b, e] -azepin-5-yl) carbonyl] -2-pyridinyl] -2- (aminomethyl) benzamide

Example 352

Preparation of N- [5 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4-benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -5-fluoro-2 -methylbenzamide

In an analogous manner to that described in Example 1 above; 6,11-dihydro-5H-pyrido [2,3-b] 1,4] -benzodiazepine (2.0 mmol) is reacted; with 2.10 mmol of 6 - ((5-fluoro-2-methylbenzoyl) -amino) -pyridine-3-carbonyl chloride in the presence of 4.0 mmol of triethylamine in dichloromethane;

The desired product is obtained as a solid.

·· · · · · · ·

- 215

Melting point: 102.0 - 104.0 ° C

Example 353

Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] -3-chlorophenyl] - / 1,1 -biphenyl / -2-carboxamide

In an analogous manner to that described in Example 134J, 6,11-dihydro-5H-pyrido [2,3-b] 1,4] -benzociazepine (0.197 g) was reacted with 0.444 g of 4 - [(1, 1-Biphenyl [2-carbonyl] amino] -2-chlorobenzoyl chloride in the presence of 0.155 g of N, N-diisopropylmethylamine in 12.0 ml of dichloromethane.

The desired title product is obtained,

In an analogous manner to that described in Example 352J above, 6,11-dihydro-5H-pyrido [2,3-b] 1,4] -benzodiazepine can be prepared with an appropriately substituted; or unsubstituted 4 '(arylcarbonyl) -amino] -benzoyl chloride; or an appropriately substituted or unsubstituted 6 - [(arylcarbonyl) -amino] -pyridine-3-carbonyl chloride, the following compounds shown in Examples 354; to 395.

Example 354

216 Preparation of N- [4 - [(6,11-dihydro-5H-pyrido- [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] -phenyl] - / 1,1 -biphenyl / -2-carboxamide

Example 355

Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] phenyl] -2- (2-thienyl) -benzamide

Example 356

Preparation of N- (4- (6,11-dihydro-5H-pyrido- [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] -3-methylphenyl] - [1,1] biphenyl / -2-carboxamide

Example 357

Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] -3-methyl-6-chlorophenyl] - (1,1-biphenyl) -2-carboxamide

Example 358

Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] -3,6-dimethylphenyl] - / 1 , 1-biphenyl / -2-carboxamide

Example 359

Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -3-methylphenyl] -2- ( 2-thienyl) -henzamide

Example 360 ·· ····

217 Preparation of N- [4 - [(6,1 1-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -3-chlorophenyl] -2 - (2-thienyl) -benzamide ···· · · ·

Example 361

Preparation of N- [4 - [(6,11-Dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl] carbonyl] -phenyl] -2 - (2-pyridinyl) -benzamide

Example 362

Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] phenyl] -2- (3- pyridinyl) -benzamide

Example 363

Preparation of N- [4 - [(6,11-Dihydro-5H-pyrido [2,3-b] [1,4] benzodiiazepin-5-yl) carbonyl] -3-chlorophenyl] -2- (2 (pyridinyl) -benzamide

Example 364

Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -3-chlorophenyl] -2- (3) -pyridinyl) -benzamide

Example 365

Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -3-methylphenyl] -2 - (2-pyridinyl) -benzamide

Example 366

Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] -benzodiazepin-5-yl) carbonyl] -5,9-dimethylphenyl -2- (3-pyridinyl) -benzamide

218 Example 367

Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] phenyl] -2- (4- pyridinyl) -benzamide

Example 368

Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] phenyl] -2-chloropyridin-3 -carboxamide

Example 369

Preparation of N- (4- (C6,11-dihydro-5H-pyrido- [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl) phenyl] -2-fluoropyridine-3- ksrboxamide

Example 370

Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -3-chlorophenyl] -2-chloropyridine -3-carboxamide

Example 371

Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] -benzodiazepin-5-yl) carbonyl] phenyl] -2H-methoxypyridic- 3-carboxamide

Example 372

Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -3-methylphenyl] -2- ( methylthio) -pyridine-3-carboxamide

Example 373 • ·

219 Preparation of N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] -henzodiazepin-5-yl) carbonyl] -3-methylphenyl] -2- chloropyridine-3-carboxamide

Example 374

Preparation of N- [4 - [(6,11-dihydro-5H-pyrrolo [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] phenyl] -2-aminopyridine-3- kerboxamide

Example 375

Preparation of N- (5R - [(6,11-Dihydro-5H-pyrido [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] - / 1 1,1-biphenyl / -2-carboxamide

Example 376

Preparation of N- [5 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -2- ( 2-thienyl) -benzamide

Example 377

Preparation of N - N - ((6,11-dihydro-5H-pyrido- [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -2- (3) -thienyl) -benzamide

Example 378

Preparation of N - N - ((6,11-dihydro-5H-pyrido- [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -2- (2 -pyridinyl) -benzamide

Example 379

Preparation of N- [3 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -2- (3) -pyridinyl) -benzamide

- 220

Example d 380

Preparation of N- [5 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] -benzoduazin-5-yl) carbonyl] -2-pyridinyl] -2- ( 4-pyridinyl) -benzamide

Example 381

Preparation of N- (5 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -2- ( 2-furanyl) -benzsmide

Example 382

Preparation of N- (5 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] -benzodiazepin-5-yl) carbonyl] -2-piperidinyl] - 2- (3-furanyl) -benzamide

Example 383

N- / 5 - / (6,11-dihydro-5H-pyrido / 2,3-b // 1,4 / -benzodiazepine pi _n -5-yl) carbonyl / -2-pyridinyl / -2- cjjlorbenzamide

Example 384

N- / 5 - / (6,11-dihydro-5H-pyrido / 2,3-b // 1,4 / -benzodiazepine _5_yl pi _n) -carbonyl / -2-pyridinyl / -2-chloro-5 -fluorobenzamide

Example 385

Preparation of N- [5 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -2,5 -dimethylbenzamide

Example 386

-221 Preparation of N- [5 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] -benzodiazepin-5-yl) carbonyl] -2-p-pyridinyl -2-chloro-6-fluorobenzamide

Example 387

Preparation of N- [5 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -2- methyl-3-fluorobenzamide

Example 388

Preparation of N- [5 - [(6,11-dihydro-5H-pyrido- [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -2-hydroxybenzamide

Example 389

Preparation of N- [5 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -2-aminobenzamide

Example 390

Preparation of N- (5 -) (6,11-dihydro-5H-pyrido [2,3-b] 1,4] -benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -2- ( methylamino) -benzamide

Example 391

Preparation of N- [5 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -2- ( dimethylamino) -benzamide

Example 392

Preparation of N- [5 - [(6,11-dihydro-5H-pyrido- [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -2-chloropyridine -3-carboxamide • ·

222

Example 393

Preparation of N- (5- [6,11-dihydro-5H-pyrido- [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -2- (dimethylamino) -pyridine-3-carboxamide

Example 394

Preparation of N- [5- (6,11-dihydro-5H-pyrido- [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -2-methylthiophen-3 -carboxamide

Example 395

Preparation of N- [5 - [(6,11-Dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl] -3-methylthiophene- Of 2-carboxamide

Example 396

Preparation of N- (4 - [(4,5-dihydropyrazole- [4,3-d] l-benzyl-1H-piperidin-6 (1H) -yl) carbonyl) phenyl] 1,1-biphenyl] -2-carboxamide

Mixture prepared by mixing 0,278 g of 4,5-dihydropyrazole-4,

3-dH-benzazepine; 1.11 g of 4 - [((1,1-biphenyl) -2-carbonyl) amino] benzoyl chloride; and 0.426 g of Ν, Ν-diisopropylethylamine in 12.0 ml of dichloromethane: tetrahydrofuran (1: 1), was stirred at room temperature overnight. The reaction mixture is then poured into water; and shaken with dichloromethane. The extract was washed successively with 2N sodium carbonate solution; with water; and brine, and dried over sodium sulfate.

After removal of the solvent from the extract under vacuum, it is obtained

1.45 g of solid to which 25.0 ml of methanol: tetrahydrofuran (1: 1) was added; and to this mixture was added 2.78 mL

2N sodium hydroxide solution.

223 ^times , the prepared reaction mixture was stirred at room temperature for 3.5 hours. After removal of the solvent from the mixture under vacuum; water is added to the residue; and the mixture was shaken with dichloromethane. The extract is washed successively with water; 0.5N citric acid solution; again with water, then brine, and the extract dried with sodium sulfate.

^The solution is poured over a thin layer of water-containing magnesium silicate, and the filtrate is concentrated to dryness. The residue (0.95 g) is mechanically recovered _from and taken up in ether: dichloromethane.

0.17 g of the desired product is obtained as a crystalline solid.

Melting point: 255.0-260.0 ° C

Analytical evaluation of the compound of formula C11H11N1O2O2O: Found: C, 75.90; H 5.10J N 10.80%

Example 397

Preparation of N - [4 - [(4,5-dihydropyrazole- [4,3-d] -1-benzazepin-6 (1 H) -yl) -carbonyl] -3-chlorophenyl] - (1,1-biphenyl) -2-carboxamide

Mixture prepared by mixing 0,185 g of 4,5-dihydropyrazole-4,

3-d H -benzazepine 0.814 g of 4 - [((1,1-biphenyl) -2-carbonyl) amino] chlorobenzoyl chloride; and 0.284 g of N, N-diisopropylethylamine, in 9.0 ml of dichloromethane: tetrahydrofuran (1: 1), are stirred at room temperature overnight. The reaction mixture was poured into water; and extracted with dichloromethane. The extract was washed with 2N sodium hydroxide solution; followed by water _from and brine, and then dried over sodium sulphate.

After removal of the solvent under vacuum; to give 0.99 g • · · ·

224 residue, as a solid to which is added, after mixing 9 15.0 ml methanol: tetrahydrofuran (1: 1); 1.75 ml of 2N sodium hydroxide solution; and the reaction mixture was stirred at room temperature for 2.0 hours.

After removal of the volatile components under vacuum; shake the mixture with chloroform; the extract obtained is washed successively with a 1N citric acid solution; with water; and brine, followed by drying with sodium sulfate.

The solution is then filtered through a thin layer of magnesium silicate, containing water, and the filtrate is concentrated to dryness. The residue (0.76 g) was chromatographed on silica gel silica gel plates, eluting with hexane: ethyl acetate (1: 2).

0.37 g of the expected product is obtained in the form of a white solid.

Melting point: 172.0 - 202.0 ° C

Analytical evaluation of the compound, in the form of 1/2 hydrate:

Found: C, 70.10; H, 5.00; N, 9.80; Cl 6,40%

Example 398

Preparation of N- (5 - [(4,5-dihydropyrazole- [4,3-d] -1-benzazepin-6 (1H) -yl) carbonyl] -2-pyridinyl] - (1,1-biphenyl) -2-carboxamide

In an analogous manner to that described in Example 396 above; 0.10 mmol of 4,5-dihydropyrazole- [4,3-d] -1-benzazepine is reacted; with 0.21 mmol 6 - [(1,1-biphenyl) -2-carbonylamino] -pyridine-3-carbonyl chloride.

After recrystallization from ethyl acetate: hexane, the title product is obtained in the form of a slightly brown color.

- 225 • ··, solids,

Melting point: 228.0 - 234.0 ° C (as white colored crystals)

Example 399

Preparation of N- [5 - [(4,5-dihydropyrazole- [4,3-d] -1-benzazepin-6 (1H) -yl) carbonyl] -2-pyridinyl] -5-fluoro-2-methylbenzamide

In an analogous manner to that described in Example 396 above; 0.10 mmol of 4,5-dehydropyrazole- [4,3-d] -1-benzazepine is reacted with 0.21 mmol of 6 - [(5-fluoro-2-methylbenzoyl) amino] -2-pyridine

3-carbonyl chloride.

The desired product was obtained as a brown solid (0.15 g).

Melting point: 126.0-176.0 ° C

MASS (FAB): 442.0 (M ⁺ H).

Example 400

Preparation of N- [5- (4H-thien- [3,4-b] 1,5] -benzodiazepin-9 (1OH) -yl2-pyridinyl] -5-fluoro-2-methylbenzamide

In an analogous manner to that described in J. Med. Chem .; 22, 725 (1979), 9,10-dihydro-4H-thien- [3,4b] 1,5-benzodiazepin-10 (9H) -one was soldered.

* <···· · · · · · · · · · · · · · · · ·

226 The above intermediate (4.80 g) was dissolved in tetrahydrofuran using a nitrogen atmosphere; to this solution, 4.20 g of lithium aluminum hydride was added portionwise with stirring. The resulting reaction mixture was heated to reflux for 18 hours, and then mixed with water added dropwise. The mixture was shaken with chloroform, and the obtained extract was filtered through diatomaceous earth.

The organic layer was washed with 200.0 mL water, dried over sodium sulfate, and the solvent was removed.

The residue, in the form of an oily consistency, is chromatographed on plates provided with a thick layer of silica gel using chloroform as the eluent.

1.20 g of 9,10-dihydro-4H-thien- [3,4-b] 1,5-benzodiazepine is obtained as a solid.

The above compound (0.50 g) was reacted with 1.06 g of 6 - [(5-fluoro-2-methylbenzoyl) -amino] -pyridine-3-carbonyl chloride hydrochloride, * in dichloromethane, which contains 7.0 ml of NN-diisopropylethylamine.

The reaction mixture was stirred at room temperature for 16.0 hours and then washed successively with water; 1N hydrochloric acid solution; with a saturated aqueous sodium bicarbonate solution, again with aqueous, and finally dried with sodium sulfate.

After removal of the solvent, the residue was purified by silica gel chromatography; eluent ethyl acetate: hexane (1: 3).

1.10 g of the expected product are obtained in the form of a solid.

Melting point: 89.0-92.0 ° C

Example 401 • · · · ··· «·

- 227

Preparation of N- [4- (4H-thien- [3,4-b] 1,5] -benzodiazepin-9 (10H) -yl) phenyl] - [1,1-biphenyl] -2-carboxamide

In an analogous manner to that described in Example 400 above; 9,10-dihydro-4H-thien- [3,4-b] 1,5] -benzodiazepine is reacted; with

4 - [(1,1-biphenyl) -2-carbonyl] -amino] -benzoyl chloride.

The desired product is obtained.

Example 402

Preparation of N- (4- (4H-thien- [3,4-b] 1,5) -benzodiazepin-9 (1H) -yl) 3-chlorophenyl] - (1,1-biphenyl) -2-carboxamide

In analogy to the procedure described above for Example 400; 9,10-dihydro-4H-thien- [3,4-b] 1,5] -benzodiazepine is reacted; with 4 - [((1,1-biphenyl) -2-carbonyl) amino] -2-chlorobenzoyl chloride.

The desired product is obtained.

Example 403

Preparation of N- [5- (4H-thien- [3,4-b] 1,5] -benzodiazepin-9 (1H) -yl) 2-pyridinyl] - [1,1-biphenyl] -2-carboxamide

In an analogous manner to that described in Example 400 above; 9,10-dihydro-4H-thien- [3,4-b] 1,5] -benzodiazepine is reacted; with

• · ··· ···· ··· ·· ····

- 228

6 - [(1,1-biphenyl) -2-carbonyl] -amino] -pyridine-3-carbonyl chloride.

The desired product is obtained,

Example 404

Preparation of 5,11-dihydro- [4- (2-thienyl) -benzoyl] -1OH-dibenz- [b, e] 1,4] diazepine

Mixture prepared by mixing 3.0 g of 4- (2-thienyl) benzoic acid; and 30.0 mL of sulfonyl chloride, was heated to reflux for 45 minutes.

After removal of the solvent, the residue is dissolved in tetrachloromethane; and after removal of the solvent under vacuum (2X) / was obtained

4- (2-thienyl) -benzoyl chloride.

To the cooled solution (to 0 ° C); prepared by dissolving 2.0 g of 5,11-dihydro-10H-dibenz- [b, e] [1,4] diazepine; and 7.0 ml of R, N-diisopropylethylamine in 30.0 ml of dichloromethane and added dropwise a solution prepared by dissolving 3.15 g of 4 (2-thienyl) -benzoyl chloride in 30.0 ml of dichloromethane. The reaction mixture was stirred at room temperature for 16.0 hours; and then diluted with 50.0 ml of chloroform. The solution thus prepared is washed with 30.0 ml of water each time; 2N hydrochloric acid solution; saturated aqueous sodium bicarbonate; and water; and then dried over sodium sulfate.

After removal of the solvent in vacuo, the residue (3.10 g) was chromatographed on a silica gel column; eluting with hexane: ethyl acetate (2: 1).

1.80 g of the desired product are obtained in the form of a solid.

- 229

Melting point: 114.0 - 116.0 ° C

Example 405

Preparation of 5,11-dihydro-10- [4- (3-thienyl) -benzoyl] -1OH-dibenz (b, e) - (1,4) -diazepine

To a mixture prepared by mixing 2.0 g of 5,11-dihydro-10H-dibenz- [b, e] 1,4] -diazepine and 7.0 ml of N, N-diisopropylethylamine in 30.0 ml of dichloromethane; a solution prepared by dissolving 3.15 g of 4- (3-thienyl) -benzoyl chloride is added dropwise; in 30.0 ml of dichloromethane.

The resulting reaction mixture was stirred at room temperature for 16.0 hours; and then diluted with 50.0 ml of dichloromethane. The solution obtained is washed with 30.0 ml of water each time; 2N hydrochloric acid solution; saturated aqueous sodium bicarbonate; and again with water, followed by drying with sodium sulfate.

After removal of the solvent in vacuo, the residue was purified by silica gel chromatography; using hexane: ethyl acetate as eluent.

The desired product is obtained as a solid.

• · ·

- 230 Rat liver receptor binding assay

Plasma membranes of rat liver cells expressing vasopressin receptor subtypes are isolated using a sucrose gradient as described by Lesko et al., 1973. The membranes are then rapidly suspended in 50.0 mM Tris.HCl buffer pH 7, 4, containing 0.2% bovine serum albumin, BSA and 0.1 mM phenylmethylsulfonyl fluoride, PMSF, and then the membranes are kept frozen at -70 ° C until binding attempts.

In these experiments, 100 ml of 100.0 mM Tris.HCl buffer containing 10.0 mM MgCl 4, 0.2% BSA, inactivated by heat and the following mixture of protease inhibitors are added to the wells of a 96 well microtiter plate: leupaptin 1 0 mg%, aprotinin 1.0 mg%, 1,10-phenanthroline 2, C mg%, tryptis inhibitor 10.0 mg% and in addition 0.1 mM PMSF, 20.0 ml (phenylalanyl-3.4.5 - ³ H) -vasopressin (SA 45.1 Ci / mmol) at a concentration of 0.8 mM, the reaction is initiated by the addition of 80 ml tissue membranes containing 20 mg protein. The plates were allowed to stand for 120 minutes at room temperature to reach equilibrium. Non-specific samples are assayed in the presence of 0.1 mM unlabeled phenylalanylvasopressin antagonist, which is added in a volume of 20.0 mL.

Test substances were dissolved in 50% dimethylsulfoxide, DMSO and added in a volume of 20.0 mL to a final incubation volume of 200 mL. After binding, the contents of each well are filtered using a Brandel instrument (Gaithersburg, MD). The radioactivity retained on the filter material disc by the ligand-receptor complex is determined by liquid scintillation counting using a Packard LS counter with a 65% tritium efficiency. The data obtained is analyzed to obtain IC ₅₀ values using a competition program, Lundon-2 (Lundon Software,

OH), the results are summarized in Table I.

• ·

- 231 Rat kidney marrow receptor binding assays

Rat kidney marrow tissue is removed, cut into small portions and placed in 0.154 mM sodium chloride solution containing 1.0 mM EDTA and the liquid phase changes until the solution is clear and clear of blood. The tissue is homogenized in a 0.25 M sucrose solution containing 1.0 mM EDTA and the liquid phase is mixed with 0.1 mM PMSF, using a Potter-Elvehjem homogenizer with Teflon sand. The resulting homogenate is filtered through four layers of mull. The filtrate is again homogenized using a tightly-located piston homogenizer. The resulting homogenate is centrifuged at 1500 g for 15 minutes. The pellet is discarded and the supernatant is again centrifuged at 40,000 g for 30 minutes. The resulting pellet consists of a darker inner part and an outer pinkish part. This lighter outer part was suspended in a small amount of 50.0 mM Tris.HCl buffer pH 7.4. Protein content is determined according to Lowry et al., J. Biol. Chem., 1953. The membrane suspension is stored at -70 ° C in 50.0 mM Tris.HCl buffer containing 0.2% inactivated BSA and 0.1 mM PMSF in 1.0 ml aliquots containing 10.0 mg. protein per ml of suspension until testing.

A 96-well microtiter plate was used to store 100.0 mL of 100.0 mM Tris.HCl buffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl _2, and the following mixture of protease inhibitors : leupeptin 1.0 mg%, aprotinin 1.0 mg%, 1,10-phenanthroline 2.0 mg%, trypsin inhibitor 10.0 mg% and 0.1 mM PMSF and in addition

O Q

20.0 ml of H-Arginine -vasopressin (S.A. 75.0 Ci / mmol) at a concentration of 0.8 nM, the reaction is initiated by the addition of 80.0 ml membranes containing 200.0 mg of protein. The plates were allowed to stand for 120 minutes at room temperature to reach equilibrium. Non-specific binding is determined in the presence of 1.0 mM unlabeled ligand added in a volume of 20 ml. Test substances are dissolved in 50% DMSO and added in a volume of 20.0 ml to the end. ·· ··· · · ·· ·

- 232 ml incubation volume of 200 ml. After binding, the contents of each well are filtered using a Brandel instrument (Gaithersburg, MD). The radioactivity retained on the filter disc by the ligand-receptor complex is determined by a Packard LS liquid scintillation counter with an efficacy for 65% tritium. Data are analyzed to obtain an ICg of ₀ using the Lundon-2 competition program (Lundon Software; OH), results are shown in Table I.

Experiments with radiolabeled ligand binding and human platelet membranes

a) Preparation of platelet membranes

Platelet-rich frozen PRP obtained from Hudson Valley Blood Services is grown at room temperature (manufactured by Hudson Valley Blood Services, Westchester Medical Center, Valhalla, NY). The tubes containing PRP were centrifuged at 4 ° C and 16,000g for 10 minutes and the supernatant discarded. The plates were suspended in an equal volume of 50.0 mM tris.HCl pH 7.5 containing 120 mM sodium chloride and 20.0 mM EDTA. Then the suspension is centrifuged again at 16,000 g for 10 minutes. The washing step is repeated once more. Then the wash liquid is discarded and the disrupted pellets are homogenized in a low ionic strength buffer, 5.0 mM tris.HCl, pH 7.5 containing 5.0 mM EDTA. The homogenate is centrifuged for 10 minutes at 39,000 g. The pellet is resuspended in 70.0 mM Tris.HCl, pH 7.5, and then centrifuged for 10 minutes at 39,000 g. 1.0 mM tris.HCl at pH 7.4 containing 120 mM NaCl and 5.0 mM KCl to give 1.0-2.0 mg protein per ml suspension.

• ·

- 233 b) Binding to vasopressin receptor subtype in human platelet membranes

A 96 well microtiter plate is used, 100 ml of 50.0 mM tris.HCl containing 0.2% BSA and the above protease inhibitor mixture are used. Then add 20 ml 38

H-ligand (Arg Vasopressin, Manning) to a final concentration in the range of 0.01 to 10.0 nM. Binding is initiated by the addition of 80.0 ml of a plate suspension containing approximately 100 mg protein. The reagents are mixed by sucking several times into a re-dispensing pipette. Non-specific binding is measured in the presence of unlabeled 1.0 mM ligand (Manning or Arg Vasopressin). The mixture was allowed to stand for 90 minutes at room temperature. After this time, the mixture was quickly filtered with suction through GF / B filters using a Brandel. The radioactivity retained on the filter disc is determined by adding scintillation fluid, using a scintillation counter to determine the results.

Binding to LV-2 mouse fibroblast cell membrane membranes following cDNA transfection for expression of human Vβ receptor for vasopressin

a) Preparation of membranes

175 ml flasks; containing a continuous cell layer is aspirated to remove the culture medium. The cell layer was then rinsed with 2 x 5 ml of phosphate buffered saline, PBS, and the liquid was aspirated. Finally, 5 ml of enzyme-free dissociation Hank's solution (Specialty Media, Inc., Lafayette, NJ) was added and the bottles were allowed to stand for 2 minutes. The contents are then poured into a centrifuge tube and the material centrifuged at 300 g for 15 minutes. The Hank's solution is aspirated and the cell material is aspirated.

- 234 is homogenized using a polytron set to step 6 for a total of 10 seconds in 10.0 mM tris.HCl, pH 7.4 containing 0.25 M sucrose and 1.0 mM EDTA. The homogenate is centrifuged at 1500 g for 10 minutes to remove the membranes. The supernatant is centrifuged at 100,000 g for 60 minutes to deposit the receptor protein. The pellet is resuspended in a small volume of 50.0 mM tris.HCl, pH 7.4. The protein content is determined by Lowry and the receptor membranes are suspended in 50.0 mM Tris.HCl buffer containing 0.1 mM phenylmethylsulfonyl fluoride, PMSF with 0.2% BSA to provide 2.5 mg receptor protein per ml suspension.

b) Receptor binding

96-well microtiter plates are used in the tests to which 100.0 ml of 100.0 mM Tris.HCl buffer containing 0.2% heat-inactivated BSA are added.

10.0 mM magnesium chloride and the following mixture of protease inhibitors: leupeptin 1.0 mg%, aprotinin 1.0 mg%, 1,10-phenenthroline 2.0 mg%, trypsin inhibitor 10.0 mg% and in addition 0.1 mM PMSF, 20.0 ml of ³ H-Arginine ⁸ vasopressin (SA 75.0 Ci / mmol) at a concentration of 0.8 nM and the reaction is started by adding 80.0 ml membranes containing 200.0 mg protein. The plates were allowed to stand for 120 minutes at room temperature to reach equilibrium. Non-specific binding is determined in the presence of 1.0 mM unlabeled ligand added in a volume of 20 ml. Test substances were dissolved in 50% DMSO and added in a volume of 20.0 mL in a final incubation volume of 200 mL. At the end of the binding, the contents of p

each well was filtered using a Brandel instrument (Gaithersburg, MD). The radioactivity retained on the filter disc by the ligand-receptor complex is determined by liquid scintillation counting using a Packard LS counter with an efficacy of 65% tritium. The data obtained are analyzed to determine ICg ₀ values using the Lundon-2 competition program (Lundon Software, OH), the results are shown in Table I.

235 Determination of the potency of the V ₂ antagonist for vasopressin in waking rats under water loading

The awake rats are dosed orally at doses of 0.1 to 100 mg / kg or vehicle only.

Two to four rats are used for each substance. After 1 hour, argininevasopressin (AVP, antidiuretic hormone, ADH) dissolved in peanut oil at 0.4 mg / kg is then administered intraperitoneally. Two rats in each experiment were given only peanut oil as a control. After a further 20 minutes, the rats were orally administered with 20 ml / kg of deionized water and were individually placed in metabolic cages equipped with a funnel and a graduated glass cylinder to measure the amount of urine over 4 hours. Urine volume and osmotic pressure are measured using an osmometer (Fiske Assoc., Norwood, CA). The amount of sodium, potassium and chloride in the urine is determined using electrodes in a Beckman E3 (Electrolye 3). Decreased urine volume and increase in osmotic pressure compared to AVP controls indicate the efficacy of the test substances.

Efficacy of vasopressin antagonists in waking rats

The awake rats are fastened upside down with elastic straps. The tail root area is locally killed using 0.2 ml of 2% procaine. Under aseptic conditions, the ventral caudal artery is then accessed, into which a cannula of PE 10 and 20 (after heat treatment) is inserted into the lower abdominal aorta. The cannula is fixed, heparinized (1000 J / ml) and the wound is closed with one or two Dexon 4-0 sutures. In the same way, the cannula is also inserted into the caudal vein for administration of the active ingredients. The duration of the surgery is approximately 5 minutes. If necessary, an additional amount of 2% procaine or lidocaine is added.

• · * ·

The animals are then placed upright in plastic cages. The cannula is connected to a Statham P23Db pressure transducer and blood pressure fluctuations recorded. The rise in systolic blood pressure in response to the administration of 0.01 and 0.2 units of vasopressin (350 International Units = 1 mg) is recorded prior to administration of any active substance, then the test substances are administered orally at a dose of 0.1 to 100 mg / kg at volume of 10 ml / kg or intravenously 0.1 to 30 mg / kg in a volume of 1 ml / kg. Vassopressin injections are then repeated after 30, 60, 90, 120, 180, 240 and 300 minutes. Antagonism by the drug is calculated as a percentage compared to the response to vasopressin prior to drug administration, which is considered to be 100%.

Binding to the oxytocin receptor

a) Preparation of membranes

Female Spraque-Dawley rats weighing 200-250 g were injected intramuscularly (i.m.) with diethylstilbestrol, DES at a dose of 0.3 mg / kg. The rats are euthanized with pentobarbital after 18 hours. The uteri are removed, removed from fat and connective tissue and rinsed in 50 ml of physiological saline. Tissues from six rats are homogenized in 50 ml of 0.01 mM tris.HCl containing 0.5 mM dithiothreitol and 1.0 mM EDTA after adjustment to pH 7.4 using polytrene set to step 6, the tissues are left three times pass, each time for 10 seconds. The homogenate is then passed through two layers of mule and the filtrate is centrifuged at 1000 g for 10 minutes. The clear supernatant is discarded and centrifuged again at 165,000 g for a total of 30 minutes. The resulting deposit containing oxytocin receptors is resuspended in 50.0 mM tris.HCl containing 5.0 mM MgCl 2, pH 7.4 to give a suspension containing 2.5 mg protein / ml. This sus3 pension is used to monitor H-oxytocin binding.

- 237 (b) Binding of radiolabeled ligand

3

Binding of 3,5-H-oxytocin (HOT) to its receptor is performed on microtiter plates using different concentrations of labeled oxytocin in a buffer containing 50.0 mM tris.HCl at pH 7.4 and 5.0 mM MgClg, mixture of protease inhibitors: BSA 0.1 mg, aprotinin 1.0 mg, 1,10-phenanthroline 2.0 mg, trypsin 10.0 mg and, in addition, PMSF 0.3 mg per 10 ml of buffer solution. Non-specific binding is determined in the presence of 1.0 µM unlabeled oxytocin. The binding reaction was terminated after 60 minutes at 22 ° C by rapid filtration through a glass fiber filter using a Brandel instrument (Biomedical Research and Development Laboratories, Inc., Gaithesburg,

MD). Competition assays are performed at steady state using 1.0 nM labeled oxytocin and varying concentrations of drug. The concentration of účinnéΙΟ of the active substance that displaces 50% of the labeled oxytocin at its receptor is calculated using the Lundon-2 computer program (Lundon Software, Inc., Ohio, USA).

The results of the above experiments are summarized in Table I below.

x represents binding to the Vβ receptor subtype from human platelets and xx represents binding to membranes of the mouse fibroblast cell line LV-2 after transfection of the cDNA for expression of the human V ₂ receptor.

- 238 • ··

Table I

Binding to rat liver V receptors and rat kidney marrow V ₂ receptors or binding to receptors and ex. No IC _5Q (nM) IC- ₀ (gM)

Γ • ·

- 239 Table I - cont.

ex. formula

ΙΟ ₅₀ (μΜ)

^V 2

ICgQ (H> M)

90%, µM

1% (µM)

100% (LuM) * 26% CICLM)

40% (luM)> / • ·

- 240 ex.

Table I - cont.

formula

ΙΟ ₅₀ (μΜ)

46% GiiM) at ₂

29% CLOuM)

242 ···· · · ·

Table II

Activity of vasopressin pno receptor antagonist in waking rats after water loading

Ex. dose N urine volume osmotic pressure mg / kg ml / 4 h. MOsm / kg

78 13.3 + 0.3 229 ± 6 5í5í 6 12.1 + 1 497 ± 53 4 12.4 + 0.8 361 ± 30 Okay 76 2 + 0.2 1226 ± 58 26 10 2 4,5 1058 45 10 2 6.6 979 4 10 2 6.8 878 2 10 2 16.5 591 32 10 2 9.3 726 2 10 2 16.5 591 24 10 2 4.3 1492 27 Mar: 10 2 3.3 1317

x Inspection after water loading

Water load control + DMSO (10%) (20%)

AVP control

···· · ·· ··· ··

243

Test for anti-diuretic effect (V ₉ ) in waking rats with free access to water before, but not during, the experiment

Male or female Spraque-Dawley (Charles

River Laboratories, Inc., Kingston, NY) with normal blood pressure and a weight of 400-450 g were fed Laboratory Rodent Feed 5001 (PMI Feeds, Inc., Richmond, IN) during the experiment, water was administered ad libitum. On the day of the experiment, the rats were housed individually in metabolic cages equipped with a steel septum to separate the stool from the urine and a funnel for collecting urine. Oral active substances, vehicle or comparator were administered orally. Rats were not fed food or water during the experiment. After drug administration, urine was collected for 4 hours in calibrated cylinders. Urine volume was recorded. Urine osmotic pressure was determined using an Fiske osmometer (Fiske Associates, Norwood, MA, 02062). The urine content was analyzed for Na ⁺ , K ⁺ and Cl content using specific electrodes for these ions and Beckman E3 (Electrolyte 3). The carrier medium for the active ingredients was 20% DMSG in 2.5% pre-cooked starch.

The results of these experiments are summarized in Table IV below.

All rats were dosed at 10 ml / kg by gavage.

244 pressure

Table IV

Ex. no. dose mg / kg N urine volume ml / 4 h. osmotic MOsm / kg X 16 710 ± 2 981 ± 34 47 10 2 22.0 394 66 10 2 17.0 442 67 10 2 21.5 402 134 10 2 40.5 333 3 2 28 396 1 2 18.2 596 133 10 2 27.5 234 135 10 2 39.5 284 3 2 26.8 391 1 2 19.5 526 176 10 2 12.8 567 218 10 2 34 222 257 10 2 22.5 317 301 10 2 41.5 363 302 10 2 40 356 352 10 2 9.3 779 396 10 2 21.8 238 397 10 2 29.8 288 398 10 2 20.5 316 399 10 2 17.0 404 400 10 2 24.8 270 404 10 2 6 909

- 245 Table III

Oxytocin Binding Assay

Přikl.č. dose / UM inhibition% IC ₅₀ / µM 1 1 12 - 2 10 86 1.1 4 10 20 May - 12 10 76 0.61 24 10 97 1,8 25 10 94 0,113 26 10 73 2.5 27 Mar: 1 83 - 32 10 88 1,8 33 1 37 - 45 1 54

The compounds of the invention may be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. Such salts include, for example, salts with anonganic acids, for example hydrochloric, sulfuric, nitric, phosphoric, or organic acids, such as acetic, oxalic, succinic and maleic acids. Other possible salts include alkali metal or alkaline earth metal salts such as sodium, potassium, calcium or magnesium salts or salts with organic bases. The compounds of the invention may also be used in the form of esters, carbamates or other suitable conventional prodrug forms which, when administered, release the active moiety.

• · · ·

When used for the above purposes, the compounds of the invention may be admixed with at least one pharmaceutically acceptable carrier, diluent, diluent and the like and administered orally in the form of, for example, tablets, capsules, dispersible powders, granules or suspensions containing, for example, 0.05 to 5% of a suspending agent, syrups containing, for example, 10 to 50% sugar, elixirs containing, for example, 20 to 50% ethanol and the like or parenterally in the form of sterile injectable solutions or suspensions containing 0.05 to 5% suspending agent in isotonic medium. Such pharmaceutical compositions may contain, for example, 25 to 90% by weight of the active ingredient in combination with a carrier, more usually an active compound content of 5 to 60% by weight.

Effective dosages of a compound of the invention may vary depending upon the compound employed, the mode of administration, and the severity of the disease being treated. In general, satisfactory results can be obtained using daily doses of 0.5 to 500 mg / kg, preferably in divided doses, usually 2 to 4 times a day or in the form of a controlled release dosage form. The total daily dose for large mammals is 1 to 100, preferably 2 to 80 mg. Dosage forms for internal administration contain 0.5-500 mg of active ingredient in admixture with a solid or liquid pharmaceutical carrier. For example, several divided doses may be administered daily and the dose may be reduced depending on the results achieved during treatment.

The active compounds may be administered orally, intravenously, intramuscularly or subcutaneously. Solid carriers include starch, lactose, dibasic calcium phosphate, microcrystalline cellulose, sucrose and kaolin; liquid carriers are, for example, sterile water, polyethylene glycols, nonionic surfactants and edible oils such as corn, peanut and sesame oil, depending on the nature of the active substance and the chosen method

247 submissions. Adjuvants commonly used for this purpose, such as flavorings, colorants, preservatives and antioxidants such as vitamin E, ascorbic acid, BHT, and BHA, may be used in the manufacture of the pharmaceutical compositions.

In view of the ease and convenience of preparation and administration, the preferred pharmaceutical compositions are in particular solid compositions, in particular tablets and capsules, filled in powder form or liquid forms. Oral administration of the active compounds is particularly preferred.

However, the active compounds according to the invention can also be administered parenterally, including intraperitoneally. Solutions or suspensions of the active compounds in free form or in the form of pharmaceutically acceptable salts may be prepared in water, optionally in admixture with a wetting agent, for example hydroxypropylcellulose. It is also possible to prepare dispersions of the active compounds, for example in glycerol, in liquid polyethylene glycols or in mixtures of these with various oils. Under conditions of storage and use, these compositions should contain preservatives to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions as well as sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the dosage forms must be sterile and must be fluid to the extent that they can be administered by syringe. They must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria or fungi. The carrier can be a solvent or dispersion medium containing, for example, water, an alcohol such as glycerol, propylene glycol or liquid polyethylene glycol, including mixtures thereof and vegetable oil.

• · · ·

248

The novel tricyclic non-peptide compounds of the present invention antagonizing vasopressin can be used to treat conditions in which it is desirable to lower vasopressin levels, such as congestive heart failure, conditions in which the renal water is too high re-absorbed and in conditions with increased vascular resistance and with narrowing of the coronary vessels.

Particularly suitable are the active compounds according to the invention for the treatment and / or prevention of elevated blood pressure, cardiac insufficiency, coronary vascular spasm, insufficient oxygen supply of the cardiac muscle, renal vascular spasm, liver cirrhosis, congestive heart failure, nephritic syndrome, cerebral edema, cerebral ischemia, stroke, thrombosis associated with bleeding and all disease states associated with water retention.

The compounds of the invention that antagonize oxytoxin can also be used to prevent premature labor, which causes considerable problems in the neonate, including neonatal mortality.

Claims (5)

1. Tricyclic diazepine derivatives of the general formula I E-W> means (C ?H),, C, NK NK, NCGCK-, N-alkyl of 1 to 3 carbon atoms, CK-alkyl of 1 to 3 carbon atoms, CHNK- (alkyl of 1 to 3 carbon atoms), GKNK -. CKN (C 1 -C 3 alkyl) (C 1 -C 3 alkyl), C 3 -C 3 alkyl (C 1 -C 3), where n is an integer of G to 3, denotes a group R. something ^ - (¾) _f R. • · - 250 where m is an integer from 1 to 2, provided that if Y is - (CHp) ^ and n = 2, m may also be 3 and Y is - (CH-) and n = 2, m has a meaning different from 2.2 n R @ 1 represents a hydrogen atom, a halogen atom, i.e. chlorine, bromine, fluorine or iodine, OH, -S-alkyl of 1 to 3 carbon atoms, -3H, -SO-alkyl of 1 to 3 carbon atoms, -30-, -alkyl of 1 to 3 carbon atoms, -CO- (alkyl of 1 to 3 carbon atoms), -CF-, alkyl of 1 to 3 carbon atoms, -G-alkyl of 1 to 3 carbon atoms, -NO2, - NK-, -NHC3- (alkyl of 1 to 3 carbon atoms), -N- (alkyl of 1 to 3 carbon atoms) -3O ₂ NH-alkyl duties; or -30-N- (alkyl of 1 to 3 carbon atoms) R 1 represents a hydrogen, chlorine, bromine, fluorine or iodine atom, -OH, C 1 -C 3 alkyl, C 1 -C 3 alkyl or R ^ and R ^ together form a methylthio or ethylenedioxy group, R 6 represents a group - CAr where Ar is one of the groups X-R. :O - 251 ·· ···· «« · · · · · · · · · · · · · · · · · · · · R_ R _d is hydrogen, alkyl of 1 to 3 carbon atoms, or -CO- (alkyl of 1 to 3 carbon atoms), R (- and Rg) are each hydrogen, alkyl or alkoxy having from 1 to 3 carbon atoms or halogen, R 'is o (a) any of the groups -N'COAr AND R a - ncon-a R. -NCOCrMAť 4. N-SOI R a • ·· ·· - '252 -'lSO _? (alkyl of 3 to 8 carbon atoms), J R • NSO ₂ - (C 3 -C 8 alkenyl) i AND AND R -NH-C-Q- (C 3 -C 8 alkyl), II,. -MK-C- (alkyl of 3 to 8 carbon atoms), alkenyl of 3 to 8 carbon atoms), -NH-C- (C 3 -C 3 alkenyl) wherein the alkyl and alkenyl radicals may be straight or branched, cycloalkyl means cycloalkyl of 3 to 8 carbon atoms, cyclohexenyl or cyclopentenyl, R represents a hydrogen atom, methyl, ethyl, one of ss and a scouin R. - (CrUq-N (CR) q-N) R. - (CH,% - N - 253 - (CH3) g-O- (C1-C3 alkyl) or -CHgCHgOK, q represents an integer of 1, 2 or 3, R. represents a hydrogen atom, CHg or -C-, Η-, b) a group of formula -X - R where R _1Z> is alkyl or alkenyl of vždv 3-8 atomeo 10 ^JJ atoms, - (CH) - (cycloalkyl of 3 to δ carbon atoms), a group selected from R. lu "\ // R_ R_ R. -O-J at— * - (CH.). N R _from th ' O p is an integer from 0 to 3, X stands for 0, S, NH, NCH _O , - 254 ζ = 0 or chemical bond., R 8 and R 8 are as defined above, c) a group of the general formula R. wherein R is alkyl, or alkenyl having a direct sky and ⁷ and isomers of carbon. a branched chain of -O-alkyl or -O-alkenyl with a straight or branched chain of 2 to 8 carbon atoms each, hydrofuran or tetrahydrothiophene, any of: a scouin or -CH₂-K ', where K' represents a halogen atom, OH tetrahydrofuran, tetrahydrothiophene or a heterocyclic group of the formula - 255 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · -N Αχ G-? where D, Ε, E and G are carbon or nitrogen, the three carbon atoms being optionally substituted by halogen, C 1 -C 2 alkoxy, -C 0- (C 1 -C 3 alkyl), CEO. alkyl of 1 to 3 carbon atoms or -30 "- (alkyl of 1 to 3 carbon atoms, hydroxy and hydroxy); R_ and R. are as defined above, d) a group of the general formula R I ^a - N-GCGHAr R -O-C-alkyl of 1 to 2 carbon atoms alkyl of 1 to 2 carbon atoms -R._ -s-ø-n - _N -NHíCHj. -CON R. - o-c-n-n - rííí,) _and ·· · • ··· • ·· • * it · - 256 wherein is halogen, alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms or hydroxy, and R ^ is as defined above, Ar is one of the groups R and R _n are independently hydrogen, alkyl oi 3 azomech 9-3 alkyl, O-alkyl of 1 to 3 carbons, S-alkyl of 1-3 carbon atoms, -C? ₃ , -ON, -OH, -SCr ₃ , -OCR ₃ , halogen, NO 2, amino or NH-alkyl of 1 to 2 carbon atoms or -N- (alkyl of 1 to 2 carbon atoms) _2, or -N (R 1) . _{q) (CK?) q} -N (R _{q) 2,} W 'is O, S, NH, N-C 1 -C 3 alkyl, NCO- (C 1 -C 3 alkyl), NSO ₂ - (C 1 -C 3 alkyl),' 25 is any of the groups • · - a group of the formula zO is 1) phenyl, optionally substituted by one or two substituents from the group consisting of alkyl or alkoxy of 1 to 3 carbon atoms, halogen, amino or (C1-C3) alkylamino, 2) 5-membered aromatic (unsaturated) heterocyclic ring containing one heteroatom selected from oxygen, nitrogen or sulfur; - 258 3) 6-membered aromatic (unsaturated) heterocyclyl ring containing 1 nitrogen atom; 4) a 5- or 5-membered aromatic (unsaturated) non-heterocyclic ring containing 2 nitrogen atoms, (5) a 5-membered aromatic (unsaturated) heterocyclic ring containing 1 nitrogen atom and additionally oxygen atom or sulfur atom, wherein: The 5-membered or 6-membered heterocyclic ring is optionally substituted with an alkyl moiety of 1 to 3 carbon, an aryl group, a linear group - (C.N. R. accmem of halogen or alkoxy of carbon. as well as the pharmaceutically acceptable salts, esters and precursor forms thereof. 2. A compound according to claim 1 wherein zO is a phenyl ring optionally substituted by one or two of C1 -C3 alkyl, halogen, amino, C1 -C3 alkoxy, alkylamino. of 1 to 3 carbon atoms - 259, and n, m, W, X, Y, AB, R _A, R _Fe R _£ R, R _3, R _4, R _e, R g, _R? , Rg, Rg, R _lo, RGG, are as defined in claim 1. 3. A compound according to claim 1 wherein zO is a 6-membered aromatic (unsaturated) heterocyclic group containing one nitrogen atom and n, m, W, X, Y, A-B, R @ _q , R @ 1 ^ 2 '^ 3' ^ 4 '^ 5' ^ 6 '^ 7' ^ 3 '^ 9' ^ 10 '^ 25 ^ma ^ ^! Said in claim i. circle □ I know 4. A compound according to claim 1, wherein the group represents a 6-membered aromatic (unsaturated) heterocyclic ring containing 2 nitrogen atoms and Y, A-3, R, R, R, R, R, R, R and R. , 3 O X No. of » R g, R g, R y, R g, R _q , R q, R gg are as defined in claim 1. 5. A compound according to claim 1 wherein zO is a 5-membered aromatic (unsaturated) heterocyclic ring containing one sulfur heteroatom and Y, A-B, R, R, R., R, 3 0 -L <_ Rg, _R4, Rg, Rg, Ry, Rg, Rg, R _lo RGG have the meanings given in claim 1. • · · · · · · 260. The compound of claim 1 wherein zO is a 5-membered aromatic (unsaturated) moiety containing one oxygen heteroatom and Y, &lt; RTI ID = 0.0 &gt; 2, &lt; / RTI &gt; '8' '9' '10' '25 in claim 1. heterocyclic ring, AB, R _a , R- ₃ , R, are as defined herein7. A compound of formula I according to claim 1, wherein the group represents a 5-membered aromatic (unsaturated) heterocyclic ring containing one nitrogen atom and Y, A-3, R, R 1, R ₃ , R ₃ , R ₃ , R ₃ . _4, R _5, Rg, _R , Rg, R _q, R _lo RGG have the meanings given in claim 1. A compound of formula I according to claim 1, wherein the group represents a 5-membered aromatic (unsaturated) heterocyclic ring containing one nitrogen heteroatom and Y, AB, R, R, _q , R 6, R 8, R 8, R ₄ , Rg, Rg, R _? , Rg, _Rg, R _lo RGG have the meanings given in claim 1. - 261 9. A compound according to claim 1 wherein the group is a fused 5-membered aromatic (unsaturated) heterocyclic ring containing one nitrogen heteroatom and one sulfur heteroatom and Y, AB, R _{and &gt}; R &lt; _{f &gt};, R &lt; 6 &gt; _? R _g, R _4, R g, R _g, R 6, R 8, R 8, R ₁₀ , R ₁₀ , are as defined in claim 1. 10. A compound according to claim 1 wherein the group is a 5-membered aromatic (unsaturated) heterocyclic ring containing 1 nitrogen atom and 1 oxygen atom and Y, AB, R, ρ pp '3' 9 '10 '25 _and R ^^ R _L, Rg, Rg, _R4, Rg are as defined in claim 1 11. A compound of the formula I as claimed in claim 1, in which the group zO O represents a phenyl ring optionally substituted by one or two substituents from C1-C3 alkyl, halogen, amino, C1-C3 alkoxy or C1-C3 alkylamino, - 262 Y represents any one of -CK ^ -, -CH- (C1-C3) • c - NH _2, -CHNH- (C1-C3 alkyl), -OHN (CH3) ₂ , -CHN (C ₂ H ₁ ) ₂ , -CHO- (C 1 -C 3 alkyl), -CHS- (alkyl of 1 to 3 carbon atoms), A-3, YYYYYYY ₌ , YY, and Y-30 are as defined in claim 1. R R R 9 '10'; noecneno v; The group of claim 1, wherein the group represents a 6-olene aromatic (unsaturated) heterocyclic ring containing one nitrogen atom, Y is one of groups d f ' -CH- (C 1 -C 3 alkyl), -CHNH _2> AND -CHNH- (alkyl of 1 to 3 carbon atoms), -OHN, ₁₂ , -CHN (C ₂ H ₅ ) ₂ , -CHO- (C 1 -C 3 alkyl), -CHS- (alkyl of 1 to 3 carbon atoms), and 263 A-3. _And B, R _o, R _{3 in R>} r _4, r., R., R_, r., R ₃ are as defined in claim 1. 13. A compound of the formula I as claimed in claim 1 in which the group O is an S-membered aromatic (unsaturated) nicerocyclic ring containing two nitrogen atoms. Y is -CH, -, -CH- (C 1 -C 3 alkyl), -CHNH ?, -CHNH- (C 1 -C 3 alkyl), -CHN (CH ₂ ) ₂ , -Hn (C ₂ H, -) -, -CHO- (C 1 -C 3 alkyl), -CHS- (alkyl of 1 to 3 carbon atoms), and A-3, R, R, Rp R ₂ , R g, R ₄ , R ₅ > R g ^R 7 ' ^R 3' ^R 9 - ^R 10 '' 21 'and' b '' 1 '2' * 3 have the meaning as set forth in claim 1. 14. A compound of the formula I as claimed in claim 1, in which the group: - 264 means a 5-membered aromatic (unsaturated) heterocyclic ring containing one sulfur heteroatom and Y represents one of the groups -CH- (alkyl of 1 to 3 carbon atoms), -CHNH-, -CHNH- (C 1 -C 3 alkyl), -CHN (CH _q ) ₂ · -CHO- (C 1 -C 3 alkyl), -CHO- (C 1 -C 3 alkyl), -CHS- (alkyl of 1 to 3 carbon atoms), and 4-3 3 YYYYYYYYY? R if, -Λ-, -v ~ »-» 3 t · ^ν * · i 2. 0 '' 1 '' 4L 'Z' O have the meaning given in claim 1. 15. A compound of the formula I as claimed in claim 1 in which the moiety is a 5-membered aromatic (unsaturated) heterocyclic ring containing one oxygen heteroatom and Y is -CH 1 -, i. L -CH- (C 1 -C 3 alkyl), -CHNH 3, -CHNK- (C 1 -C 3 alkyl), -CHN (CH ₂ ) ₂ , -chn (c ₂ h ₅ ) ₂ -CHO- (C 1 -C 3 alkyl), 265 -CHS- (alkyl of 1 to 3 carbon atoms), and A = 3, R ^, R, _Q , R ^, R _? R @ 1 R @ 2 R @ 1 R @ 2 R @ 2 R @ 2 R @ 2 R @ 2 'are as defined in claim 1. 10 ’* 25 16. A compound of the formula I as claimed in claim 1, in which the group O is a 5-membered aromatic (unsaturated) heterocyclic ring containing one nitrogen heteroatom and Y is selected from -CE 2 -, 1 K- (C 1 -C 3 alkyl), -CHNH ₂ , I / -CHNH- alkyl (1-3 carbon atoms), -CKN (CH _{a) 2>} l | -CHN (C ₂ K 3) ₂ , -CHO- (C 1 -C 3 alkyl), AND -CHS- (alkyl of 1 to 3 carbon atoms), and A-3, R_, R _q, R _{1, R?} R ₃ , R ₆ , R ₆ , R ₆ , R ₆ , R ₆ , R ₆ , R ₆ , R ₆ , R 6, R ₆ and R 6 are as defined in claim 1. 17. A compound according to claim 1, wherein the group of the formula zO - 266 represents a 5-membered aromatic (unsaturated) heterocyclic ring containing 2 nitrogen heteroatoms and Y represents one of the groups * I -CH- (C 1 -C 3 alkyl), -CHNH 4, I _f I -CHNH- (C 1 -C 3 alkyl), -CHN (CH 3) -, -CHC (C 1 H -, C 1 -C 3 -alkyl of 1 to 3 carbon atoms), -CHS- (alkyl of 1 to 3 carbon atoms), A-3, R _a, R _b, R, R ~, R, R, R_, R ", _R? R 8, R 8, R 10, R 10, R 8, are as defined in claim 1 18. A compound of formula (I) according to claim 1 wherein the group is a fused 5-membered aromatic (unsaturated) heterocyclic ring containing one nitrogen heteroatom and one sulfur heteroatom, and Y represents one of the groups -CH2-, 1,1 -CH- (alkyl of 1 to 3 carbon atoms), -CHNKg, I i -CHNK- (alkyl of 1 to 3 carbon atoms), -CHN (CKg) ₂ , - 267 -i ^t HN (C H _{C) 9-Calkyl} -enoate of 1-3 carbon atoms), -CHS- (alkyl of 1 to 3 carbon atoms), and A-3, R _a, R _q, R _r R _2, R, R _4th ^R 5> ^R g ^'R 7- ^R 3' O ^{R 'R} io' ^R 25 are as defined in claim 1. 19. A compound according to claim 1, wherein zO is a 5-membered aromatic (unsaturated) heterocyclic ring containing 1 nitrogen heteroatom and 1 oxygen heteroatom, and Y represents one of the groups -CH- (C 1 -C 2 alkyl); -CHNH- (C 1 -C 3 alkyl), -CRM (C 1 -C ₂ ) ₂ , -CHN _(C2 -4_) ₂ -CHC- (alkyl oi 3alkyl) -CHS- (C 1 -C 2 alkyl), and ^{A 3} ' ^R a' ^R b ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R o ' ^R 7' ^R 3 ' ^R 9' ^R 10 ' ^R 25 are as defined in claim 1. • ·· · - 268 - 20. A compound of the formula I as claimed in claim 1, in which zO is a phenyl ring optionally substituted by one or two of C1 -C3 alkyl, halogen, amino, C1 -C3 alkoxy or alkylamino. of 1 to 3 carbon atoms, Y is - (CH3), n = 0 and A-B, R, R, R, R, R, 2 n a b 1 2 3 R ₄ , RR _& , R _? Rg, RRR ₂₅ are as defined in claim 1. 21. A compound according to claim 1 wherein zO is a 6-membered aromatic (unsaturated) heterocyclic ring containing one nitrogen atom. Y is - (CH_), n = 0 and A-B, R, R, R, R, R, ΓΊ cl D X d o _R4, Rg, Rg, _R? , Rg, _Rg, R, R ₂₅ are as defined in claim 1. 22. A compound of the formula I as claimed in claim 1, in which the group zO 269 means a 6-membered aromatic (unsaturated) heterocyclic ring containing 2 nitrogen atoms, Y is - (CH) n = 0 and AB, R, R, R, R_, R έ x n cl 0 3 3 ^R 4 ^'R 5' ^R g> ^R 7 ^»R g> ^R g, ^R io ^'R 25 ^{mA her} Ý ^known, stated in claim 1. 23. A compound according to claim 1, wherein the group represents a 5-membered aromatic (unsaturated) heterocyclic ring containing one sulfur heteroatom. Y is - (CH) n = 0 and AB, R, R, RRR "£ Π 5 l 0 l 3 of ^R 4 ^'R 5' ^R g ^'R 7' ^R g> ^R g> ^R] _q. RGG ^ma ^ ^{characterized known,} stated in claim 1. 24. The compound of claim 1 wherein the group is a 5-membered aromatic (unsaturated) heterocyclic ring containing one oxygen heteroatom. Y represents a group - (CH) ^, n = 0 and AB, RR, _RX, Rg, Rg, ^R 4> ^R g> ^Rg, Rg, Rg, Rg, R] _q ^R 25 are as defined in of claim 1. - 270 ···· 25. A compound according to claim 1 wherein the group is a 5-membered aromatic (unsaturated) heterocyclic ring containing one nitrogen atom, Y is - (CH) n = 0 and AB, R, RR, rr RP to -. . ' ^{u 1} - ^J 4 ’b year 1. R, R, R, R _n, R _n, R _IQF R ₅ are as defined in ná26. A compound of the formula I as claimed in claim 1 wherein the zO group is a 5-membered aromatic (unsaturated) heterocyclic ring containing 2 nitrogen heteroatoms, Y stands for - (CH) n = 0 and AB, RRr 'a' b '1' 2 ' ^K 3' ^R 4 ' ^R 5' ^R 6 ' ^R 7' ^R 8 ' ^R 9' ^R 10 ' ^R 25 ^{v 2nam} , as claimed in claim 1. 27. A compound of the formula I as claimed in claim 1, in which the group EMI1.0 is a compound of formula (I) - 271 means a 5-membered aromatic (unsaturated) heterocyclic ring containing one nitrogen heteroatom and one sulfur atom, Y is - (CH _O), n = 0 and A-3, R, R, R., R_, R_, O 3 O X X 5 R _4, R _5, Rg, _R , Rg, _{Rg, R10,} RGG have the meanings given in claim 1. 28. A compound according to claim 1, wherein the zO1 group is a 5-membered aromatic (unsaturated) heterocyclic ring containing one nitrogen heteroatom and one oxygen atom. Y is - (CH-), n = C and A-3, R, R, R, R, R 8a and o x c j _R4, Rg, Rg, _R? , R g, R _g, R _Q, R ₂ g are as defined in claim 1. 29. A compound of the formula I as claimed in claim 1, in which the group zO O represents a phenyl or substituted phenyl ring, Y represents a group selected from 0, S, NH, NC0CH "or N-alkyl 1 to 3 carbon atoms, and A-3, R, R _phenyl, Rg, Rg, Rg, R _4, R _K, Rg, Rg, Rg , Rg, Rθ, R have. as defined in claim 1. - 272 • ·· · 30. A compound of the formula I as claimed in claim 1, in which the moiety is a 6 membered aromatic (unsaturated) heterocyclic ring containing one nitrogen atom. Y is selected from O, S, NH, NCOCH 8 or N-alkyl of 1 to 3 carbon atoms, and A-B, R, R, R, R, R, R, R, R x, R x, C x, R _g , R _? , Rg, _Rg, R, Q, Rg ₅ have the meanings given in claim 1. 31. A compound of formula I according to claim 1 wherein the group is a 6-membered aromatic (unsaturated) heterocyclic ring containing two nitrogen heteroatoms, Y represents některou.ze group 0, S, NH, NCOCH ₀ N-alkyl or 1-3 carbon atoms, and AB, R, R₁, R₅, R₆, R₆, R₅, R₆, Rg, R _? , Rg, _Rg, R, RGG and s as defined in claim 1. 32. A compound according to claim 1, wherein the group represents a 5-membered aromatic (unsaturated) heterocyclic ring containing one atom. 273 • « Y represents některou.ze group 0, S, NH, or N-NCOCHg alkyl having 1 to 3 carbon atoms, and AB, _and R, RR, Rg, R, _R4, Rg, ^R 6 ^'R 7' ^R g ^'R g ^'R io' ^R @ 25 ^mA as defined in claim 1. 33. A compound according to claim 1, wherein the group is a 5-membered aromatic (unsaturated) heterocyclic ring containing one oxygen atom. 34. A compound according to claim 1, wherein the group represents a g-membered aromatic (unsaturated) heterocyclic ring containing one nitrogen atom. Y represents některou.ze group 0, S, NH, or N-NCOCHg alkyl having 1 to 3 carbon atoms, and AB, _and R, R _Fe, R _2, R _3, R _4, R _s, ^R 6 ^'R 7' ^R g ' ^R g' ^{R 10} ' ^R 25 as defined in claim 1. 35. A compound of the formula I as claimed in claim 1, in which the group R @ 1 is a compound of formula (I) - 274 4444 4 ···· · ·· ·· 4 4 4 4 4 4 4 444 4 4 4 4 4 4 4 4 4 4 4 4 444 444 444 44 44 4 means a 5-membered aromatic (unsaturated) heterocyclic ring containing 2 nitrogen heteroatoms, Y represents některou.ze group 0, S, NH, or N-NCOCHg alkyl having 1 to 3 carbon atoms, and AB, R, R₁, R₂, R g, R _g, R _4, R, R g, R g, R g, R _g, RGG, RGC as defined in claim 1. A compound of formula I according to claim 1, wherein the group is a 5-membered aromatic (unsaturated) heterocyclic ring containing one nitrogen heteroatom and one sulfur atom, Y represents některou.ze group 0, S, NH, or N-NCOCHg alkyl having 1 to 3 carbon atoms, and AB, R, R, _Q, Rg, Rg, _{Rg, R4,} Rg. R g, R g, R g, R g, R g _Q , R gg are as defined in claim 1. A compound of formula I according to claim 1, wherein zO is a 5-membered aromatic (unsaturated) heterocyclic ring containing one nitrogen heteroatom and one oxygen atom, Y is selected from O, S, NH, NCOCH 8 or N-alkyl of 1 to 3 carbon atoms and AB, R, R 6, R 8, R 8, R 8, R ₄ , R 8, R g, R g, R g, R g, R gg, R g, are as defined in claim 1. 275 A compound according to claim 1 wherein: Y is any one of - (CHg) wherein n = 0 or! AND -CH- (alkyl of 1 to 3 carbon atoms), -CHNHg, I I -CHNH- (C1-C3), -CHN (CH _q) g i I -CHN (C 8 H 8) g, -CHO- (C 1 -C 3 alkyl), 1, -CHS- (alkyl of 1 to 3 carbon atoms), R 8 represents a group O where Ar is any of the skuoin R. R. and R @ ¹ , // ¹ W x — R. :and R_ R. ! // ^- \\ 'XHZCR-, R. • · · · · · · · · · · · · · · · - 276 Rg means one of the groups -NCOAr ' • R NCO _(CH?) · -Cycloalkyl, R -NCOCH-Ar I * i R -NCONAr, -X-R10 R R. á 3 Ar is one of the groups R, R. R. R. I 0 Νϋΰ-Λ / w R. O 'αW means an oxygen or sulfur atom and A-3, R _a , R, _q , R ₁ , R ₂ , R ₄ , R-, R _? , Rg, _Rg, R, RGG, X and SKUD ina have the meanings given in claim 1. 39. A compound of the formula I as claimed in claim 1 in which Y represents one of the groups I ý -CH- (alkyl of 1 to 3 carbon atoms), -CKMK ₇ , 277 -CHNH- (alkyl of 1 to 3 carbon atoms), -CKN (CrM) ₂ . -CHN (C 1 H 2) 4, -CHO- (C 1 -C 2 alkyl), -CH 2 - (C 1 -C 3 alkyl), represents a group O II -r> where Ar is one of the groups R4χ R_ R. I —x -. < AND. M-x-R. ^Q R. Rg means one of the groups • · - 278 -NCOAr, R -NCO (CH ₇ ) _n -cycloalkyl, -NCOCn ~ Ar R -NCONAr, -X-S, wherein Ar is one of the groups R, Rc RR. TO. steed. AB, R _a, R _b, R₁, R _2, R _4, R _{5, R?} , R _g , R _g , R ₂₅ , R ₂₅ , X a W represents an oxygen or sulfur atom; and AB, R, R _b, R₁, R _2, and a cycloalkyl group of from are as defined in claim 1. 40. A compound of formula I as claimed in claim 1, wherein: -CH- (C 1 -C 3 alkyl), -CKNbM, -CHNK- (alkyl of 1 to 3 carbon atoms), -CHN (CK _q ) ,, 3 2 ^: Y stands for any of the groups -CH? -, · · · · · · · · - 279 -CHO- (alkyl of 1 to 3 carbon atoms), - wHS- (alkyl of 1 to 3 carbon atoms), R 8 represents a group O II -CAr where Ar is one of the groups R. Rg is one of the groups -NCOAr, -NC0 (CK _{7) n} -cycloalkyl, -NCOCK-Ar '-NCONAr, -X ^ ₁₀ I -'II 280 wherein Ar is any of the groups W represents an oxygen or sulfur atom, the zO group represents a phenyl ring optionally substituted by one or two substituents from the alkyl group having 1 to 3 carbon atoms, a halogen atom, an amino group, an alkoxy group having 1 to 3 carbon atoms or an alkylamino group having 1 to 3 carbon atoms; A 3, R _a , R _b , R ₁ , ^R 2 ' ^R 4' ^R 5 ' ^R 7' ^R 8 ' ^R 9' ^{R 1} 'cycloalkyl are as defined in claim 1. 41. Tricyclic diazepine derivatives of the general formula I according to claim 1, wherein Y is - (CH_) -, wherein 2 n n = 0, R _q is o 1! -CAr where Ar stands for one of the groups • · · · · · · ···· · · · · · - 281 R. I J ÍL R. RA ίϊ_γ_ \> ^x A o R 1 is one of the groups o -NCOAr '. -NCO (CH ₇ ) _n -cycloalkyl, R R And i -NCOCK-Ar, -NCONAR, -XR, _Q L ^R. And where Ar 'is one of the groups V 4 · 4 · 4 · 4 - 282 w represents an oxygen or sulfur atom, the group represents a phenyl ring optionally substituted by one or two substituents from the alkyl group having 1 to 3 carbon atoms, a halogen atom, an amino group, an alkoxy group having 1 to 3 carbon atoms or an alkylamino group having 1 to 3 carbon atoms , ^A-3 ' ^R and' * b '* 1' * 2 '* 4' ^R 5 ' ^R ?' ^R 5 ' ^{R 10} ' cycloalkyl are as defined in claim 1. 42. A compound according to claim 1, wherein Y is one of O, S, NH, NCOCH _q or C 1 -C 3 alkyl, R 8 represents a group - 283 R. R 1 is one of O -NCOAr ', -NCO (CE-L) _n -cycloalkyl, R R a i -NCOCrMAr ', -NCONAr, -X- ^ g! ! and R, R, A where Ar 'is one of the groups W * represents an oxygen or sulfur atom, the zO group represents a phenyl ring optionally substituted by one or two substituents from the alkyl group having 1 to 3 carbon atoms, a halogen atom, an amino group, an alkoxy group having 1 to 3 carbon atoms or an alkylamino group having 1 to 3 carbon atoms , A- ^B ' ^R and' ^R b ' ^R 1' ^R 2 ' ^R 4' ^R 5 ' ^R 7' ^R 8 ' ^R 9' ^R 10 ' ^R 25' ^{X and} cycloalkyl are as defined in claim 1. 284 43. Tricyclic diazepine derivatives of the general formula I according to claim 1, wherein Y is - (CH _O) - in which the 2 nn = 0, R 8 represents a group -CAr where Ar is one of the groups R. R. \ ¹ / □ í ^X í R. wX-R. R. R. 'XHZCR.A L_v_' <Ro RRq means one of the groups -NCOAr, -NCOfCl 4 H -cycloalkyl, R, R -NCOCKAr I ” AND R. -NCQNAr, -X-R R R. and 3 285 wherein Ar is any of the groups W represents an oxygen or sulfur atom, a group means 6-membered containing one aromatic nitrogen atom (unsaturated) hecerocyclic ring A-3, R, R, R _n, R ', R. , R -, R R R R ^and X and and 1 2 ’4’ 5 ’ 7 8 9 10 ’25 cycloalkyl are as defined in claim 1. 44. A compound according to claim 1, wherein Y is -CH2-. R 8 represents a group II -CA- 'where Ar stands for any of the groups R. \, / “ ^R o -X R. - 286 R. RR. H2CR-. 'OF AND -R. :O X = - R 6 is any of the group o X-R-, -NCQAr - NCO _{(CH?) N} -cycloalkyl, -NCCONAr 'i R a -NCONAr -X-R wherein Ar is one of the groups W represents an oxygen or sulfur atom, a group - 287 20 means a 6-membered aromatic (unsaturated) heterocyclic ring containing one nitrogen atom / ¹ A-3, R, ^R d ' ^R 1' 2 ' ^R 5' ^R 7 ' ^R 5' ^R 9 ' ^R 10 cycloalkyl are as defined in claim 1. 45. The compound - of the formula I according to claim 1 wherein Y is - _(CH?) -, where n = O, R _q is a group wherein Ar is a group R / T ₇ ^: X RR // '\\ X — R. • Q —X-R. R. R. -, T-XHZCR-. Her. J_V_P Rv = -X-R. : a · * · · · · · · · · · · · · · · · · · · · · · · · · - 288 Rg means one of the groups -NCOAr ' R -NCO (CH ₇ ) _n - cycloalkyl, -NCOCHnAr R -NCONA, -X-R,: wherein Ar is any of the group R. TO. ί \ " R, W represents a hydrogen atom or a sulfur atom; Means a 5-membered aromatic (unsaturated) heterocyclic ring containing one sulfur atom, AB, S _2, B _4, S _5, R _7th ,, ₃ , r ₉ , and _l0 . _25, in and cycloalkyl are as defined in claim i. • · · · · · · 289 46. The compound of claim 1 wherein Y is -CH-. R 8 represents the group III -CAr where Ar is one of the groups Rg is one of the groups -NCOAr, -NCO (CH3) _n cycloalkyl, R R λ a -NCOCK ^ Ar -NCONAr, -XR _in I * i * K-o - 290 where Ar stands for one of the groups ········ · 9 · · · · · + 0¾ 'ϋ-R A> w R, W represents an oxygen or sulfur atom, the group zO denotes a 5-membered aromatic (unsaturated) without reaching one sulfur atom, a cyclic ring, A-3, R, R, R 'R R R F' and '1' 2 '5' 7 '3' 9 'ykioalkyl are as defined in claim 1. 48. A compound according to claim 1, wherein m is an integer of 1 or 2. 291 R is hydrogen, halogen, i.e. chlorine, bromine, fluorine or iodine, OK, -S-alkyl of 1 to 3 carbon = 0 ₂ - carbon, -SK, -30 -alkyl C1 to 3 carbon atoms -alky1 o 1 to 3 atomeo h of carbon, -03- (alkyl o i atoms carbon), OF , alkyl of 1 to 3 atoms ϊ -O-alkyl o 1 to 3 carbon atoms, -NC, -NK,, - (alkyl o 1 to 3 atome (N-alkyl) atoms carbon)? d * * "> NH 4 -SO 2 NH-alkyl of 1 to 4 or -50, N- (alkyl and 7 carbon atoms), λ, is depressed by hydrogen, chlorine, bromine, fluorine or iodine. —OC, alkyl of 1 to 3 carbon atoms, O-alkyl of 1 to 3 carbon atoms, or R 1 and R 2 together form methylenedioxy or ethylenedioxy, R. vain skuoir.u II / * · T r * where Ar represents any of the skuoin R, R. 292 represents an aram of hydrogen, an alkyl or alkoxy group, or a carbon atom; · · · · - 293 ·························· (SO 3 -alkyl of 3 to 8 carbon atoms),) AND R (NSO 4 -alkenyl of 3 to 3 carbon atoms) i and AND R -NH-CO- (alkyl of 3 to 3 carbon atoms), alkyl of 3 to 8 carbon atoms (alkenyl of 3 to 3 carbon atoms), alkenyl of 3 to 3 carbon atoms, wherein alkyl and alkyl are substituted. oyl residues may be straight or branched chain, cycloalkyl means cycloalkyl of 3 to 6 carbon atoms, cyclohexenyl or cycloperenyl; R is hydrogen, methyl, ethyl, one of - (CH 2 -M, - (CH 2) -, R. - (CH.A-N - (CCq- N O \ _ / • · · · · · · · · · - 294 - (Ch 2) 2 ^- O- (C 1 -C 3 alkyl) or -CH ₂ CH ₂ OH, q represents an integer of 1, 2 or 3, R. represents a hydrogen atom, CE. or -C, E_, 3 2 o b) a group of the formula wherein R @ ₂ denotes alkyl or alkenyl of 3 to 3 carbon atoms, - (CE) - (cycloalkyl of 2 to 5 carbon atoms), one of the groups -X - R • ch. -: \\; // R_ R. N R. / R. / ir ^- - i —A \\ -η- <> O p is an integer from 0 to 3, X is O, S, NH, MCH. - 295 Q = O or chemical bond, R _q and R g are as defined above, c) a group of the formula R znamená, alkyl or straight-chained alkenyl having from 2 to 3 carbon atoms. Straight-chain or branched -O-alkyl or -C-aikenyl having from 2 to 3 carbon atoms, tetrahydrofuran or tetrahyarothiophene, one or a group -CHg-K, where K represents a halogen atom, OH, tetrahydrofuran, tetrahydrothiophene or a heterocyclic group of the formula ·· ··· · - 296 -Ν \ G = F where 9 9 9 9 9 9 98 9 9 9 D, Ξ, F and G are carbon or nitrogen, wherein: the carbon atoms are optionally substituted with a substituent; selected from halogen, C1-C3-alkoxy, -33- (C1-C3-alkyl), CHC, C1-C3-alkyl or -33- (C1-C3-alkyl) -hydroxy and 2. and R _x are as defined above; -O-C-alkyl of 1 to 3 carbon atoms -S-alkyl ^0-3% I and j are carbon -3-CHL-R. / c R. -NHiCH). -CGN R. 'Ru - NHCH) _ _t \ j - O- (CH3). - N Ru / 2 · · / / / / / / / / / / / / / / / / / / / / / - 297 where R _c is halogen, alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms, or hydroxy; and R is as defined above, Ar is one of the groups R @ 1 and R @ 2 independently represent a C atom, a C 1-3 alkyl, a C 1-3 alkyl, a C 1-3 alkyl, -CF 3 -alkyl; -ON, -OH, -SCFg, -QCF, halogen, NC 1, amino, or NH-C 1 -C 3 alkyl or -N- (C 1 -C 2 alkyl) _2, or -N (R1) (CH3) -N- (R.), O 2 OO 1 'means O, S, NH, N-alkyl of 1 to 2 carbon atoms, NCO- (alkyl of 1 to 3 carbon atoms), NSO ₂ - (alkyl of 1 to 3 carbon atoms), means any of the groups ························································ And the pharmaceutically acceptable salts of these compounds. 48. A compound according to claim 1, wherein Y is O, S, NH or N-alkyl of 1 to 3 carbon atoms, - 299 R., represents a hydrogen atom, a halogen atom, i.e., chlorine, bromine, fluorine or iodine, OH, -3-alkyl of 1 to 2 atoms carbon, -3H, -30-alkyl of 1 to 3 carbon atoms . -30, -alkyl o C 1 - C 3 alkyl; ŽiZ si atoms alkyl) having from 1 to 3 atoms carbon -O-alkyl of 1 to 3 carbon atoms, -MC, -MH, di -MHCO- - (alkyl (1 to 3 carbon atoms); 1 2.Ž 2 atoms -30, MH, -50, NH-alkenyl of 1 to 10 carbon atoms; i i i X 2 carbon moss or -30 .-, 11- (alkyl carbon atoms), R, denoted by aze of hydrogen, chlorine, bromine, z.uoru something yoga. -OH, alkyl of 1 to 3 carbon atoms, C-alkyl of 1 to 3 carbon atoms or R 1 and R 2 together form mesylenedioxycycline or ethylenedi xy with a 1n moiety, R, denotes sxuclnu - CAr where Ar is any of the skuoin R- R. RR. " R. ' - 300, · · · · · · R, R _d is hydrogen, alkyl of 1 to 3 carbon atoms or -33- (alkyl of 1 to 3 carbon atoms), R @ 1 and H @ - are each hydrogen, alkyl or alkoxy having 1 to 3 carbon atoms or halogen, R- represents O a; some of the skuoin • · · · · ft 301 -NSO 2 - (C 3 -C 3 alkyl), I AND R -NSO 8 - (C 3 -C 3 alkenyl), i AND R! L -NK-C-O- (alkyl of 3 to 8 carbon atoms), clay -NH-Co 3 to 8 carbon atoms II -NH — 3-O- (alkenyl of 3 to 8 carbon atoms), II -NH-C- (C 3 -C 3 alkenyl) wherein the alkyl and alkenyl radicals may be straight or branched, cycloalkyl means cycloalkyl of 3 to 6 carbon atoms, cyclohexenyl or cyclopentenyl, R is hydrogen, methyl, ethyl, any of the 51 moieties R. - (CH) d-N &lt; - &gt; - CH3) - N - (CH) d - NO - (CH ₂ ) ₂ -Q- (alkyl filled with -CH ₂ CH ₂ OH, o means whole; R. represents an o atom (b) the group represented by alkyl means alkyl, - (CH, carbon), some - CH. '. 302 (1 to 3 carbon atoms) or 1, 2 or 3, hydrogen, CH. or -C.H_, 2 2 2 -X or alkenyl of 3 to 8 atoms) - (C 3 -C 3 -alkenyl) exuo p represents the whole R, - (CH.). Η I - i N R. / - (CH.). - (CH 2; R. ) ') O number 0 to 3, / \\ \ \ \ R_ // X is O, S, WH, WCH. , - 303 C = Q or chemical bond, / and R? have the above meaning, c) a group of the formula or a group -CH2-K, wherein K represents a halogen atom, OH, tetrahydrofuran, tetrahydrothiophene or a heterocyclic group of the formula - 304 \ / G =? where O, Ξ, F and G are carbon or nitrogen, the carbon atoms being optionally substituted with substituents selected from the group consisting of halogen, alkoxy of 1 to 3 carbon atoms, -00- (alkyl of 1 to 3 carbon atoms), CHO, alkyl, etc. - (C 1 -C 3 alkenyl, hydroxy and C 1 -C 3 alkenyl); R 'and R' are as defined above for the general formula N- CCCHAr -O-C-alkyl of 1 to 3 carbon atoms -S-alkyl of 1 to 3 carbon atoms -S-CHi, -NHCE, -CQN, R. R. R " - NHCK.) _And - n -O- (CH, L-N; R. • · · · · · · · · · · · · · - 3-5 where R @ - is halogen, C1 -C3 alkyl, - C1 -C3 alkyl or hydroxy; R is as defined above, Ar 'means any of the groups! R. « Kne'N is also hydrogen, alkyl. R and R _{q are} independently up to 3 carbon atoms, 0-alkyl of 1 to 3 carbon atoms, S-alkyl of 1 to 3 carbon atoms, -C-, -CN, -OH, -3CF-, -OCF ,, halogen, NC ₂ O -7 neoo amino group -NH-alkyl of 1-3 carbon acomec.n ne'oo -N- (alkyl oi 3alkyl) _2> or -N (R _{<0) (CH2)} -N (R ^) ₂ , W 'is O, S, NH, N-C 1 -C 3 alkyl, NCO- (C 1 -C 3 alkyl), NSO ₂ - (C 1 -C 3 alkyl), R represents one of groups d i) and pharmaceutically acceptable salts thereof. 50. A compound according to claim 1, N- [5- (6,11-dihydro-5H-dibenz [b, e] azepin-5-yl) carbonyl] -2-pyridinyl] (1,1-biphenyl) ) -2-carboxamide. 51. A compound according to claim 1, N- [5 - [(6,11-dihydro-5H-dibenz [b, e] azepin-5-yl) carbonyl] -2-pyridinyl] -2-dimethylaminopyridine-3- carboxamide. 52. A compound according to claim 1, N- [5 - [(9,10-dihydro-4H-thieno [2,3-c] benzazepin-9-yl) carbonyl] -2-pyridinyl] ( 1,1-biphenyl) -2-carboxamide. 53. A compound according to claim 1, N- [5 - [(9,10-dihydro-4H-thieno [2,3-c] benzazepin-9-yl) carbonyl] -2-pyridinyl] -2. -dimethylaminopyridine-3-carboxamide. 54. A compound according to claim 1, N- [5- [(4,10-dihydro-5H-thieno [3,2-c] benzazepin-5-yl) carbonyl] -2-pyridinyl] (1, 2, 3, 4, 3, 4, 3, 4, 3). 1'-biphenyl) -2-carboxamide. · • ft ft ft ft 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 9 9 99 99 9 9 9 9 9 307. The compound of claim 1, N- [5 - [(4,10-dihydro-5H-thieno [3,2-c] benzazepin-5-yl) carbonyl] -2-pyridinyl]. -2-dimethylaminopyridine-3-carboxamide. The tricyclic diazepine derivative according to claim 1, N- (5- [9,10-dihydro-4H-thieno [2,3-c] benzazepin-9-yl) carbonyl] -2-pyridinyl] -5-fluoro-2-methylbenzamide. The tricyclic diazepine derivative according to claim 1, N- [5 - [(4,10-dihydro-5H-thieno [3,2-b] benzazepin-5-yl) carbonyl] -2-pyridinyl] -5-fluoro-2-methylbenzamide. 58. A compound according to claim 1, N- [5 - [(4,5-dihydropyrazolo [4,3-d] l] benzazepin-6- (1H) -yl) carbonyl] -2-pyridinyl [-2] -dimethylaminopyridine-3-carboxamide. The tricyclic diazepine derivative according to claim 1, N- [5 - [(4,5-dihydropyrazolo [4,4-d] benzazepin-6- (1H) -yl) carbonyl] -2-pyridinyl] -5-fluoro-2-methylbenzamide. The tricyclic diazepine derivative according to claim 1, N- [5- (pyrido) 2,3-b] [1,4] benzoxazepine-5- (6H) -ylcarbonyl) -2-pyridinyl] -5-fluoro-2-methylbenzamide. 61. A pharmaceutical composition for the treatment of diseases in which the renal water is absorbed too much, to treat congestive heart failure, liver cirrhosis, nephrotic syndrome, central nervous system disorders, lung diseases and hyponatraemia in mammals comprising: a pharmaceutical carrier and, as an active ingredient, a tricyclic diazepine derivative according to claim 1. 62. A method of treating diseases in which there is too high re-absorption of water in the kidney, congestive 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 9999 99 9 9 99 99 - 308 heart failure, liver cirrhosis, nephrotic syndrome, central nervous system disorders, lung diseases and hyponatraemia in mammals, In step 2e, an effective amount of a tricyclic diazepine derivative according to claim 1 is administered. 63. A process for the preparation of the tricyclic diazepine derivatives of the general formula (I), which is represented by the group (CH3) 4, C, 3. NK, MCGCH3, M-azyl. 1 to 3 carbon atoms, CH- (alkyl of 1 to 2 atoms), CHNH- (alkyl of 1 to 2 carbon atoms), CHNK, CHN (alkyl of 1 to 3 carbon atoms), CHQ- (alkyl of 1 to 2 carbon atoms) up to 3 carbon atoms), CH 2 - (alkyl of 1 to 2 carbon atoms), wherein n is an integer of 0 to 2, A-3 is - (CH 2) - N AND R. or ’(CH,) R_ J 2 that Y is - (CH, - 309 where m is an integer of 1, provided that, if n = 2, m may also be 3 and Y is - (CH 2) and n = 2, m has a meaning different from 2, 2 n R ^ represents a hydrogen atom, a halogen atom, i.e. chlorine, bromine, fluorine or iodine, OH, -S-alkyl of 1 to 3 carbon atoms, -SK, -SO-alkyl of 1 to 3 carbon atoms, -30 ^- alkyl of 1 to 3 carbon atoms, -CO- (alkyl of 1 to 2 carbon atoms), -CF _q , alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms, -MCp, -, - ? HCO- (alkyl of 1 to 3 carbon atoms), -M- (alkyl of 1 to 2 carbon atoms)?, -SC-, ΜΗΜΗ, -SO ^NH-alkyl of 1 to 3 carbon atoms or -30 _? N- (C 1 -C 3 alkyl) R _? represents a hydrogen, chlorine, bromine, fluorine or iodine azide, -CH, alkyl of 1 to 3 carbon atoms, C-alkyl of 1 to 2 carbon atoms, or R-! and R g together form mesylenedioxy or ezethylenedioxy, R 1 represents a group> 1 - CAr where Ar stands for one of the groups, · · · · · · - 310 - x-R, ',' _And R is hydrogen, alkyl of 1-3 carbon atoms or -CO- (alkyl oi 3alkyl) R @ 1 and R @ 2 denote a hydrogen atom, an aikvi or an alkoxy group having from 1 to 3 carbon atoms or a halogen atom, R @ - is a; any of the groups • · · - 311 -NSO ₂ - (alkyl of 3 to 8 carbon atoms), I ' AND R " 5. -NSO ₂ - (C 3 -C 8 alkenyl) i AND AND R 'a II -NK-C-O- (alkyl of 3 to 8 carbon atoms); -MK-3- (C 3 -C 8 alkyl), -NK-C-O- (alkenyl of 3 to 3 carbon atoms); -NK-C- (alkenyl of 3 to 8 carbon atoms), wherein the alkyl and alkenyl zoyls may be straight or branched, cycloalkyl means cycloalkyl of 3 to 3 carbon atoms, cyclohexenyl or cyclopentsnyl, R is hydrogen, methyl, ethyl, any of, and groups r. / ³ - (GJJq-N ^, R. - (CH.): - N - (G-1) q - N O - 312 - (CKg) β-O- (alkyl of 1 to 3 carbon atoms) or -CHgCHgOH, q represents an integer of 1, 2 or 3, R 1 represents a hydrogen atom, CH. or -C.H_. o 3 2c ' b) a group of formula where Him means alkyl or alkenyl always of 3 to 8 atoms carbon, - (CH. ) - (cvkloaíkvl o 3 o up to 5 atoms carbon), some the era of skuoin - • CH.), to. / - \ Λ \\ R. -CH.), C / CH). R. ó o p is an integer from 0 to 3, X is O, S, NH, NCH-; - 313 C = 0 or chemical bond, / R_ and R? have the above meaning, c) a group of the general formula R. o j - N - 030 where R is an alkyl or aikenvi 3 a direct sky cut through a branched chain always having 3 to 3 carbon atoms. Straight-chain or branched -O-alkyl or -O-alkenyl of 3 to 3 carbon atoms, tetrahydrofuran or tetrahydrothiophene; tetrahydrothiophene or a heterocyclic group of the formula - 314 Αχ G = F where D, Ξ, F and G are carbon or nitrogen, the carbon atoms being optionally substituted with halogen, C 1 -C 3 alkoxy, -03- (C 1 -C 3 alkyl), CKQ. alkyl of 1 to 3 carbon atoms or -33, - (alkyl of 1 to 3 carbon atoms); C 3 -C 3 hydroxy; R and R, are as defined above, and o d) a group of the general formula R i a i - N-CCCHAř -O-C-alkyl of 1 to 3 carbon atoms -3-alkyl of 1 to 3 carbon atoms; R. R " R " - O - Ci,!. - N - NK (CK.) ₀ • · · - 315 where R _c is halogen, alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms, or hydroxy; and R is as defined above, Ar means one of the skuoin to. 11 ₍ N and R _{q are} independently hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkyl, C 1 -C 3 alkyl, -CF. -CN, -CH, -SCFg, -QCF., Halogen, NO? amino or NH-alkyl; of 1 to 3 carbon atoms or -N- (alkyl of 1 to 3 carbon atoms), or of the group -N (R 1) (CH) -N- (R 1) 2; , NH, N-C 1 -C 3 alkyl, NCO- (C 1 -C 3 alkyl), NSO 3 -C 1 -C 3 alkyl), ^L 25 is any of the groups of the formula zO means 1) phenyl, optionally substituted by one or two alkyl or alkoxy substituents of 1 to 3 carbon atoms, halogen, amino or (C1 -C3) alkylamino, 2) a 5-membered aromatic (unsaturated) heterocyclic ring containing one heteroatom selected from the group consisting of oxygen, nitrogen or sulfur; - 317 i · 3) S-membered aromatic (unsaturated) heterocyclic ring containing 1 nitrogen atom, a) Ξ- or S-Chien aromatic (unsaturated) heterocyclic ring containing 2 nitrogen atoms, 3) a 5-membered aromatic (unsaturated) heterocyclic ring containing 1 nitrogen atom and in addition an oxygen or sulfur atom, wherein: The 5-membered or S-membered heterocyclic ring is optionally substituted with an alkyl residue of 1 to 3 carbon atoms, a dormyl group, a halogen atom or an alkoxy group of 1 to 3 carbon atoms, characterized by reacting a compound of the formula H 318 wherein each symbol is as defined above, with a compound of the formula A r-C-Q wherein this formula represents an aroyl chloride or arylcarboxylic acid, activated by conversion to a mixed anhydride or by the action of a peptide binding reagent, to form a tricyclic diazepine derivative of Formula I. 64. The compound of Claim 1 wherein the formula is hydrogen; a halogen atom, denotes chlorine, bromine, fluorine or iodine, CK, -3 carbon, -Sri, -30-alkyl of 1 to 3 -alkyl of 1 to 3 carbon atoms, alkyl of 1 to 3 carbon atoms, -30 , -00- (C 1 -C 3 alkyl) -O-alkyl of 1 to - (C 1 -C 3 alkyl) carbon, or -30, -OF, C 1 -C 2 alkyl, 3-carbon atoms, -MC, -Mt-K, -NKCC2 carbon atoms), - > 1- (alkyl of 1 to 3, -SO2-NK, -30, NK-alkyl of 1 to ₂ N atoms ₎ (C 1 -C 2 alkyl) "means a hydrogen, chlorine, bromine, fluorine or iodine atom, -OK, C 1 -C 2 alkyl, O-C 1-2 alkyl, or - 319 _{g of} R and R together form methyier.dicxyskupinu or ethylendioxyskup well, R _g represents a group II - CAr where Ar is one of the groups R. iU. R- R. R. R. _P : a X is O, S, -NCH3 or -NH, R is independently selected from hydrogen, alkyl of 1 to 3 carbon atoms, any of the groups - 320 R. • ·· I ··· ·· · · · · · · · · · · I ·· - (Cnjg - \, - (Cnjg -, \ * \ -! R. - (ΟΗ ₂₎ ^ - ΟΗ or -0- (C1-C3), wherein q represents 1, 2 or 3 atom unamena vocixu, oxa a_xy_:: ebo -30- (Alkyl of 1 to 2 carbon by atomeon um. λ_ and t._ denote a voxix atom, 2m neoo and <xysxuction. C 1 to C 2 or haloeen, R 10 : n am e n a (i) any of the skuoins -ěíCQAr I l R NCON-AR ' NCZ (C 1-6 -cycloalkyl) R -NCSC-LAr, m.p. AND R i N-SO. R 9 ························· 999 ·· · ··· · - 321 -NSO 3 - (C 3 -C 3 alkyl), -NSO ₂ - (alkenyl of 3 to 3 carbon atoms), I I -NH-C-O- (C 3 -C 3 alkyl), II - ΊΚ-3- (alkyl of 3 to 3 carbon atoms), u -NH-3-O- (alkenyl of 3 to 3 carbon atoms), ζ-Λ II -NH-3- (C 3 -C 3 alkenyl), wherein the alkyl and aikenyl radicals may have a straight or branched chain, eycloalkyl means a cycloalkyl of 3 to 6 carbon atoms, cyclohexenyl or cyclopentenyl, R represents a hydrogen atom, methyl, ethyl, one of ss 3. skuoin - (CH.) D-N R. / ³ R. - CH-A-N - (CHH-N O • · · · * • · · - (CH3) p-O- (C1-C3 alkyl) or -CH ₂ CH ₂ OH, q represents an integer of 1, 2 or 3, R. represents a hydrogen atom, CH, or -C, H ^, b) a group of formula -X-R _1q , where R, g is alkyl or alkenyl having from 3 to 3 carbon atoms, - (CH3) - (cycloalkyl of 3 to 3 carbon atoms), one of the groups to. \\: // ÍL ÍL -;whose). - R. -c-η o p is an integer from C to 3, X represents O, S, NK, NCH ,, • · - 323 (2 = O or chemical bond, R _q and R g are as defined above, c) a group of the general formula AND - N - COJ means straight or branched chain alkyl or alkenyl of 3 to 3 carbon atoms in each case. Straight-chain or branched -O-alkenyl or -O-alkenyl of 3 to 3 carbon atoms in each case; or tetrahybrothicine, one of the groups In // \\ / // CH. \\ /? or a group -CH 2 -K, where K * represents a halogen atom, OH, tetrahydrofuran, tetrahydrothiophene or a heterocyclic group of the formula - 324 \ / C- =? • · ·· · where D, Ξ, F and G are carbon or nitrogen, the carbon atoms being optionally substituted with substituents from the group halogen, C1-C3 alkoxy, -33- (C1-C3 alkyl), CHC, alkyl or C1-4 alkyl; up to 3 carbon atoms or -33; γ-3 carbon atoms, hydroxy and γ-C atoms ?. and R. are as defined above for formula (c) II O-C 1 -C 3 alkyl -3-alkyl of 1 to 6 carbon atoms; R, -ΝΗ (Οΰ). - CON'Rs - NHCK 1) _and - O - (Cl 2 - ;; - N R - 325 wherein it represents a halogen atom, an alkyl of 1 to 3 carbon atoms, an -O-alkyl of 1 to 3 carbon atoms or a hydroxy group, and R is as defined above, Ar is one of the groups R and R _{q are} independently hydrogen, alkyl or alkyl; 3 to 3 carbon atoms, O-alkyl of 1 to 3 carbon atoms, S-alkyl of 1 to 3 carbon atoms, -OF ,, -CN, -OH, -SCF ₃ , -OCF ₃ , halogen, NO ₂ amino or NH-alkyl of 1 to 3 carbon atoms or -N- (alkyl of 1 to 3 carbon atoms) -, or -N (R 1) (CH 2) -N- (R) -, o 2 q 0 2 W * is O, S, NH, N-C 1 -C 3 alkyl, NCO- (C 1 -C 3 alkyl), NSO ₂ - (C 1 -C 3 alkyl), is selected from the group consisting of: ··· ······· · · ···· ······ ··· ·· ·· · 326 and a pharmaceutically acceptable salt thereof. Tricyclic diazepine derivatives according to claim 1 R. where • · · · - 327 R. represents a hydrogen atom, a halogen atom, ro represents chlorine, bromine, fluorine or iodine, OH, -S-alkyl of 1 to 3 carbon atoms,--, -SO-alkyl of 1 to 3 carbon atoms, -SO , -alkyl of 1 to 3 carbon atoms, -00- (alkyl of 1 to 3 carbon atoms), -CFg, alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms, —NC ,, - NHp, -MKC3- (alkyl of 1 to 3 carbon atoms), -N-alkyl of 1 to 3 carbon atoms) g, -SOpNH ,, -50, NH-alkyl of 1 to 3 carbon atoms or -SOpN- (alkyl of 1 to 3 carbon atoms), R 1 represents a hydrogen, chlorine, bromine, fluorine or iodine atom, -OH, alkyl of 1 to 3 carbon atoms, O-alkyl of 1 to 3 carbon atoms, or R. and R, the scoleones form mesyldicin or ethylene glycol, R. znamena sxucznu AND" - CA; where Ar is one of the skuoins R- R_: o R. R. R is independently selected from hydrogen, alkyl of 1 to 3 carbon atoms, any of the groups - (C-Lh-N R. / ³ -(SCRAP. -C (C 6 -C 18) - (CH _n ) -OH or - (CH 2) -O- (C 1 -C 3 alkyl), 2 q 2 and q is 1 or 2, R _d represents a hydrogen atom, an alkyl of 1 to 3 carbon atoms or a -C 3 - (alkyl of 1 to 3 carbon atoms), R @ 1 and R @ 2 are each hydrogen, alkyl or alkoxy of 1 to 3 carbon atoms or halogen; R 'o from 3.m sns. (a) any of the skuoins -NCOAr, -NCON-Ar, -NCO (CL-) _n -cycloalkyl, R. R, -MS3 '- (aalkenyl of 2 to 3 carbon atoms), - (C 2 -C 3 -alkyl (2 to 3 carbon atoms), alkyl of 2 to 3 carbon atoms) -NH-3-3- (aalkenyl of 2 az and carbon atoms), -NH-3- (C 3 -C 3 -alkenyl) -alkyl, wherein the alkyl and alkenyl radicals may be straight or branched, cycloalkyl means cycloalkyl of 3 to 6 carbon atoms, cycloftexer. or cyclope.nteny 1, - 330 R represents a hydrogen atom, methyl, ethyl, one of s and a group - (GH) d-N - (CH 2 - N 7), - (CH.X- N - (C <) d - N p - (CH.) - 3- (alkyl of 1 to 5-olo) -CH.CH.OH, 3 carbon atoms) or skuc is an integer of 1, 2 or 3, is hydrogen, CH. or -C.H- -X-R, .., koe. means an alkyl or alkenyl group having from 3 to 3 carbon atoms, - (CH3) n- (cycloalkyl of 3 to 3 carbon atoms), one of the groups k. k. R_ · · · · · · · · · · · · · · · · · - 331 R. Η Ν R. / ' If t * R. / G is an integer of G to 3, X is 0, 3, NK, NCH, q or a chemical bond, R_ and R- are as defined above, ** / * (c) a compound of the formula R, alkyl or arylalkyl with straight or branched chain having from 3 to 3 carbon atoms in each case, 3 to 3 carbon atoms; , tetrahydrofuran or tetrahydrothiophene, any of the groups in question. - 332 ¢ - // \\ // / * ι * * or the group -OH.-K, where K represents a halogen atom, OH, X is a tetrahydrofuran, cetrahydro chloride, or a heterocyclic group of formula n ·> / \ / C- =? where 0, Ξ,? and O is carbon or nitrogen, wherein the carbon atoms are optionally substituted with halogen, C 1 -C 3 alkoxy, -C 3 - (C 1 -C 3 alkyl), CHO, C 1 -C 3 alkyl or -00- (alkyl of 1 to 3 carbon atoms, hydroxy and R 'and FL, are as defined above, d) a compound of the general formula - 333 R * - N- CCCHAR R Ό-Μ-alkyl of 1 to 3 carbon atoms -3-alkyl of 1 to 1 acoms carbon; N 'R, R. -NHC-γ-N - O- (G... .- N 'R. where atomeon λ. means aCom halogen, alkyl of 1 to about carbon, -3-alkyl of 1 to 3 carbon atoms or hydroxy; and R is as defined above, o Ar 'is one of the groups R. KxK í ’1 1 '! - 334 - R g and R _g are independently hydrogen, alkyl of 1-3 carbon atoms, 0-alkyl of 1 to 3 carbons, S-alkyl oi to 3 carbon atoms, -CR ,, -CN, -OK, -SCFg, -OCR, halogen, NO ₂ amino or NH-alkyl of 1 to 3 carbon atoms or -N- (alkyl of 1 to 3 carbon atoms), or -N (R); _{(CK?) and} -N- (R, _Q)?, W is 0, 3, NH, N-C 1 -C 3 alkyl, NCO- (C 1 -C 3 alkyl), NSC, - (C 1 -C 3 alkyl), R, g stands for \\ // 1 ^ \ h- R. and pharmaceutically acceptable salts thereof. - 335 56. The tricyclic diazepine derivatives according to claim 1, of the formula or wherein R. means and it m hydrogen, as follows: bromine, f luo ** · i -Ί or iodine. carbon, f - * 0-aikyi o -alkyl o - 52 J atoms atoms uhl í ku) · “· * · t —‘- z j. f -O-alkyl i 52 3 atomeo. - (alkyl 0 - 52 3 atoms atoms uhí í i # -. '· - j 2 ’~ ^ C, NH carbon n ebc -30 N - (alkyl r.amena omoru, 3 atcmeor. carbon, -30, MH, -30, NH-α, α, α, az 3. atcmec: Denotes hydrogen, chlorine, bromine, fluorine or poison, -OH, alkyl of 1 to 3 carbon atoms, C-alkyl of 1 to 3 carbon atoms, or R, together form a methylenedioxy group or ethylenedioxy group i.t. - CAr where Ar stands for one of the skua in ·· ···· R_: o R is independently selected from hydrogen or halogen or alkyl of 1 to 3 carbon atoms, -c • · · - 337 - (CHg) q -OH or - (CHg) -O- (alkyl of 1 to 3 carbon atoms), wherein q is an integer of 1 or 2, H ₄ represents a hydrogen atom, an alkyl of 1 to 3 carbon atoms or -33- (an alkyl of 1 to 3 carbon atoms), R @ 1 and R @ 8 are each hydrogen, alkyl or alkoxy having 1 to 3 carbon atoms or halogen; (a) any of the skuoins -NCOAr ' AND R -NCOCX-Ar ' -NCON-Ar. R_ About i- • · · · · · · · · 338 -NSO 4 -alkyl of 3 to 8 carbon atoms), -NSO 4 -C 3 -alkenyl); -NH-C-O- (C 3 -C 8 alkyl), I I -MK-C- (alkyl of 3 to 8 carbon atoms), II -NK-C-O- (C 3 -C 3 alkenyl), I I -NK-C- (C 3 -C 8 alkenyl) wherein the alkyl and alkyl radicals may be straight or branched, cycloalkyl means cycloalkyl of 3 to 6 carbon atoms, cyclohexenyl or cyclopentenyl, R is hydrogen, methyl, ethyl, or a group - (CrOq-N R. / ° R. - (CHýq— N · · · · · · - 339 - (CH 2) p -O- (C 1 -C 3 alkyl) or -CH ₂ CH ₂ OK, o. represents an integer of 1, 2 or 3; R, _q represents a hydrogen atom, CHg or -C2Hg, b) a group of formula -Y _ P ^rt 10 'where R., is alkyl or alkenyl of 3 to 3 carbon atoms, - (CH 3) - (both 3 to 5 carbon atoms and p uhlíku carbon), any of p is an integer of 0 to 3, X is O, S, NH, NCH 3, I • · · · - 340 ζ = 0 or chemical bond, R, _ and R? have the above meaning, c) a group of the general formula R. o? and - N - CCJ where R „represents a straight-chain or branched chain alkyl or alkenyl of 3 to 3 carbon atoms, an -O-alkyl or straight-chained or branched-chain alkenyl of 3 to 3 carbon atoms, tetrahydrofuran or tetrahydrothiophene , one of the skuo in \ y // λ // ll / CH. W // or -CH 2 -K, where K represents a halogen atom, OH, tetrahydrofuran, tetrahydrothiophene or a heterocyclic group of the formula ## STR6 ## * · · · · · · · · · - 341 \ G = F where D, E, F and G are carbon or nitrogen, the carbon atoms being optionally substituted by halogen, C1-C3 alkoxy, -33- (C1-C3 alkyl), CHO, C1-alkyl or (C 1 -C 3 alkyl, hydroxy and C 1 -C 3 alkyl); R and R. have the above meanings, and o d) a group of formula - N-CCCHAr O-C 1 -C 3 -alkyl; -3-alkyl of 1 to 3 carbon atoms • R, -S-CR1 - CON. - ΝΗ £ Κ,) _α - n / ^R » - o - (CH 2), - N / R. / 3 in - and / - 342 where R ^ represents a halogen atom, an alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms or a hydroxy group; and R is as defined above, Ar means one of the skunols R g and R _a are independently hydrogen, alkyl of 1-3 carbon atoms, C-alkyl of 1 to 3 carbons, S-alkyl of I to 3 carbon atoms, -CF ,, -CN, -OH, -SOF, -OCF, halogen, NC _? amino or NH-alkyl of 1 to 3 carbon atoms or -N- (alkyl of 1 to 3 carbon atoms), or the group -N (R) (CH) -N- (R), o 2 and o 2 is O, S, NH, N-alkyl of 1 to 3 carbon atoms, NCO- (alkyl of 1 to 3 carbon atoms), NSC1-alkyl of 1 to 3 carbon atoms), R1 represents any of the groups 25 i The pharmaceutically acceptable salts of these compounds are included in the invention. 67. The compound of claim 1 wherein - 344 R, represents a hydrogen atom, a halogen atom, i.e. chlorine, bromine, fluorine or iodine, OK ,. -3-alkyl of 1 to 2 carbon atoms, -SK, -SO-alkyl of 1 to 3 carbon atoms, -30, -alkyl of 1 to 3 carbon atoms, -CO-alkyl of 1 to 3 carbon atoms), OF, alkyl of 1 to 3 carbon atoms, -3-alkyl of 1 to 3 carbon atoms, -ΝΟ, -MK-, -NKCO- (alkyl of 1 to 3 carbon atoms), -M- (alkyl of 1 to 3 carbon atoms) ₇ , -SG- , ΜΚ-, -3O _? NK-alkyl of 1 to 3 carbon atoms or -30gN- (alkyl of 1 to 3 carbon atoms) R @ 1 represents hydrogen, chlorine, bromine, fluorine iodine, -OK, C1 -C3 alkyl, C1 -C3 alkyl or R. and R &apos; s together form a methylene-dioxy group or an ethyleneoxy group, i.e. a group H CAr where Ar is any of the skuoin R. EL - 345 ·· ···· RI * R is independently selected from hydrogen or halogen, C 1 -C 3 alkyl, or groups - (Οί) α-Ν -CH.q- n - (G -) q - N - (CH 2) -OH or - (CH 3) -O- (alkyl of 1 to 3 carbon atoms), and. Represents 1, 2 or 3, represents a hydrogen atom, alkyl. of 1 to or -30- (alkyl of 1 to 3 carbon atoms), R @ 1 represents a hydrogen atom, an alkyl of 1 to 3 carbon atoms, or a carbon atom, in each case a gene, Ro means - 3 ^ 6 any group -NCOAr ', i R i NCON-aZ R. σ NCO (CL.) _N R Λ • cvkloaikyl -MSG? - (mech carbon alkyl), -MSO ₂ - (alkenyl of 3 to 3 carbon atoms), AND AND AND R a -MH-C-G- (C 3 -C 3 alkyl), It -ME-C- (alkyl of 3 to 3 carbon atoms), -NH-C-O- (C 3 -C 3 alkenyl), - _L T _R -C- (alkenyl of 3 to 3 acomecn Union) - wherein the alkyl and alkenyl radicals may be straight or branched, cycloalkyl means cycloalkyl of 3 to 6 carbon atoms, cyclohexenyl or cyclopentenyl, R is hydrogen, methyl, ethyl, one of the C1 groups LU - (CH) a-N - (CH) c-N / -CH - (Ch; g- n - (CH.); X is Z) or Wk. q represents an integer i, 2 or 3, represents a hydrogen atom, CH. or -O.H_, b) a group of formula -X - R. wherein is alkyl or alkenyl in carbon, - (CH 2) n - (cycloalkyl carbon), one of groups of up to 3, and at least one atom. EL R / ^: - 348 - R_ / tCň.) R. / ¹ p is an integer from 0 to 3, X is 0, 2, NK, NCR, q, or a chemical bond, R and R_ are as defined above, o) a group of the general formula AND AND - M - c: where denotes R _a , alkyl or al ke nyl with direct heaven branched chain always o -5 up to 8 atoms carbon, -O-alkyl or -O-alkenyl with direct or rozvěve- chain always by 3 to and carbon atoms ku, tetra- hydrofuran or tetrahydrothiophene; - 349 - or a group -CH.-X, wherein X represents a halogen atom, OH, tetrahydrofuran, tetrahycrochiophene or a heterocyclic group of the formula —NC · koe 0, Ξ, R and G represent carbon atom n carbon atoms are optionally substituted by halogen atom, alkoxy carbon atom, -30- (alkyl of 1 to 3 carbon atoms, alkyl of 1 to 3 carbon atoms or nitrogen), with the same substituents (1 to 3 carbon atoms), CHO, - (alkyl of 1 to 1) C 3 -C 3 hydroxy; R and R are as defined above, and o (d) a group of the general formula ^: NHCH) '- _t \ j -O- (CHJ- ⁿ to. wherein is halogen, alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms, or hydroxy; and R. has the above meaning, o Ar * is one of the groups Κ- R. -K · ··· · ·· ·· 9999 . 9 999999 9 999,999 9 9 9 ·· · 9,999,999 • 9 9 9 9 9 999 9999 99 9 - 351 3 and R 8 are independently hydrogen, alkyl of up to 3 carbon atoms, C-alkyl of 1 to 3 carbon atoms, S-alkyl of 1 to 3 carbon atoms, -C 18 -CN, -OK, -SOF, , -OCR ,, halogen, NO? ,, amino neoo MK-alkyl oi to 3 carbon atomecn neoo -N- (alkyl oi to 3 carbon unzixu or -N (R ^) (CKY) _q -N- ( R) ₂ represents 0, S, NK, N-alkyl and 3 oi atomecn un NC0- (alkyl of 1-3 carbon atoms), NSC, - (al 1 to 3 carbon atoms), _ alkyl Iku R11 is one of u5 and and pharmaceutically acceptable salts thereof. • · · 352 The tricyclic diazepine derivatives according to claim 1, of formula or Wherein A-B is a scouin -CH ₂ -N or N-CH, R. R. is hydrogen, halogen, i.e. chlorine, bromine, fluorine or iodine, OK, -3-alkyl of 1 to 3 carbon atoms, -3K, -5G-alkyl of 1 to 3 carbon atoms, -30-alkyl of 1 to 3 carbon atoms, up to 3 carbon atoms, -CO- (alkyl of up to 3 carbon atoms), -OR 1, alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms, -NC 2, -NK 2, -NKCC- (alkyl of 1 to 3 carbon atoms), -N- (alkyl of 1 to 3, ₂ , 3, ₃ , 3, ₃ , 3, ₃ , 3, ₃ , 3, ₃ , 3, ₃ , 3 ₎ ; carbon atoms) », -SO-.NK _n -30» Oi NH-alkyl-C3 sky -30gN- (alkyl of 1-3 carbon atoms) », is hydrogen, chlorine, bromine, fluorine or iodine, -OK, alkyl of 1 to 3 carbon atoms, O-alkyl of 1 to 3 carbon atoms, or R 6 and R 8 together form a methylenedioxy or ethylenedioxy group, R 6 represents a group Z o tf - CAr O ^x a »s_ // Λ vo R. R is independently selected from hydrogen, halogen, alkyl of 1 to 3 carbon atoms or one of the groups - (CHa-N R. / ³ R. - (C2 (COq-N - (CH 2) -OH or - (CH 2) -O- (C 1 -C 3 alkyl), 2 q 2 q q represents an integer of 1, 2 or 3, 9900 9 99 9 9 9 9 9 9 9 - 359 9 99 9 R _d is hydrogen, alkyl of 1 to 3 carbon atoms, or -CO- (alkyl of 1 to 3 carbon atoms), R @ 1 and R @ 2 denote a hydrogen atom, an alkyl or alkoxy group having from 1 to 3 carbon atoms or a halogen atom, R 'is o (a) any of the groups -NCQAr ', -NCQN-Ar, -NCO (CQ) _n -cycloalkyl, R R. R - N-SQ, QH- - 355 -NSO4-alkyl of 3 to 8 carbon atoms), -NSC> _2- (alkenyl of 3 to 8 carbon atoms), AND I o Π,. -NH-C-O- (C 3 -C 8 alkyl), II -NH-C- (C 3 -C 8 alkyl), -NH-C-O- (alkenyl of 3 to 8 carbon atoms), II -NH-C- (C 3 -C 8 alkenyl) wherein the alkyl and alkenyl radicals may be straight or branched, cycloalkyl means cycloalkyl of 3 to 6 carbon atoms, cyclohexenyl or cyclopentenyl, R is hydrogen, methyl, ethyl, any of the groups - (CH3) q-N R. / ° R. - (CK) q-N O - 356 • · ··· · - (CHg) (O-C 1 -C 3 alkyl) or -CHgCHgOK, q is an integer of 1, 2 or 3, R 1 represents a hydrogen atom, CH, or -Ο, Η, O O <O b) a group of formula -X - R where R is alkyl or alkenyl of up to 8 carbon atoms, - (CHg) - (cycloalkyl carbon), one of the groups and atomeon - (CH.), -; , ^R ~ \ v / R / w ? _ R. - (CH II N R. _ / ¹ - (CH), R. HERE O p is an integer from 0 to 3, X is O, S, NH, NCH 3, 357 (2 = Q or chemical bond, Rg and R? have the above meaning, c) a group of the general formula R, - N - COJ where J is R, alkyl or alkenyl with a straight or di-3. branched chain of from 3 to 3 carbon atoms, -O-alkyl or -O-alkenyl of straight or branched chain of from 3 to 8 carbon atoms, tetrahydrofuran or tetranydrothiophene, one of the groups or the group -CH ₂ -K, where K represents a halogen atom, OH, tetrahydrofuran, tetrahydrothiophene or a heterocyclic group of the formula - 358 - where D, E, F and G are carbon or nitrogen, wherein the carbon atoms are optionally substituted with halogen, C1-C3 alkoxy, -C0- (C1-C3 alkyl), CHG, alkyl o (C 1 -C 3 alkyl, hydroxy and C 1 -C 3 alkyl); R _& apos _; and R, _q are as defined above, d) a group of the formula “N-COCHAr -O-C-alkyl of 1 to 3 carbon atoms -S-alkyl of 1 to 3 carbon atoms. -, --NH (CE,) ₃ - CCN R. ^{n R} b - NKíCH,) - n - O - (CH 2) - N. R. 7 3 ···· - 359 ··: where: R _q is halogen, alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms, or hydroxy; R, _q is as defined above, Ar is one of the groups R _R and R are independently hydrogen, alkyl of 1 with 9-3 carbon atoms, O-alkyl of 1 to 3 carbons, S-alkyl of 1 to 3 carbon atoms, -CF ^, -CN, -OH, -SCF4, -OCF4, halogen, MCg amino or NH-alkyl of 1 to 3 carbon atoms or -N- (alkyl of 1 to 3 carbon atoms) ₂ , or -N (R) (CH 2) -N- (R) -, b 2 qod W represents O, S, NH, N-alkyl of 1 to 3 carbon atoms, NCO- (alkyl of 1 to 3 carbon atoms), NSO ₂ - (alkyl of 1 to 3 carbon atoms), R ₂ 5 stands for any of the groups: - - - - - - - - - - - - - - · · · ··· · 4 · ··· - 360 q '' Β You E-pharmaceutically acceptable salts of these compounds. 69. A compound according to claim 1 of the formula EMI3.0 wherein: EMI3.0 [0027] wherein: EMI3.0 [0000] e-y \ _ where n - 0 of him 1 γ means, kub A-B represents a group R. and where m is an integer from 1 to 2, provided that if Y is - (CK) ^ ana 2, m can also be 3 and if v is - (CH) an = 2 has m meaning different from 2, 2 n represents a hydrogen atom, a halogen atom, which means chlorine, bromine, fluorine or poison, OH, -3-alkyl of 1 to 3 carbon atoms, -3H, -30-alkyl of 1 to 3 carbon atoms, -30? alkyl of 1 to 3 carbon atoms, -00- (alkyl of 1 to 3 carbon atoms), -CF, alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms, -NC2, -NH -NHCO- (alkyl of 1 to 3 carbon atoms), -N- (alkyl of 1 to 3 carbon atoms), -30.NH., -30-NH-alkyl of 1 to 3 atoms XJZ of carbon or -30? N- (alkyl of 1 to 3 carbon atoms)? Means hydrogen, chlorine, bromine, fluorine or iodine, -OK, alkyl of 1 to 3 carbon atoms, C-alkyl of 1 to 3 or Rg together form a mechylenedioxysuccin or ethylenedioxysuDi.nu, meaning a skuoin where Ar is one of the groups R. j O H - CAr K- represents a hydrogen atom, an alkyl or a -33-alkyl of 1 to 3 atoms is hydrogen. C 1 -C 3 carbon atoms and ur. .xo xy about buy .osen.u, from suggestions, and any of the groups -NCQAuý - NCCN-Ar 1 -N'CO (G 1 -) _n -cycloalkyl 1, -s ·· ···· -MSO- (alkyl of 3 to 3 carbon atoms), I I R a - (‘ISO. - (alkenes of 3 to 3 carbon atoms), -MH-O- (and carbon tetras), -MH-3- (alkyl of 3 to 3 carbon atoms), -MH-O-O- (alkenyl o 3 to 3 carbon atoms) -MH-O- (alkenyl of 3 to 3 carbon atoms), wherein the alkyl and alkenyl radicals may be straight or branched, cycloalkyl known: cycloalkyl of 3 to 6 carbon atoms, cycichexenyl or cyclopentenyl, - 364 R represents a hydrogen atom, methyl, ethyl, one of the groups - (CKH-N) R. / ³ (C-LJc— R. - (CH.X- N - (CHHq-N -O-taikyi o-az X '' - X1_ · uh-LAu atoms; neoo skuo means all cis i neoo o, R. represents a hydrogen atom, CH. or a scouin v; R 1 represents alkyl or aikenvi; carbon, -CH 2 - (cycloalkyl): ; up to 3 atomeo; 5 azomecn - • (CH - ·. - k, // // · · · · 9 · · · - 365 R, -;what. <'2 N R. / ' -;what. R. / o p means the whole path O -W - .w W, X is 0, 5, NK, MCH-., (3 = 0 or chemical bond, R @ 1 and R @ 2 are as defined above. of a group of formula nn is R R, an alkyl or a straight chain branched alkenyl having from 3 to 2 carbon atoms each. -O-alkyl or -O-alkenyl with a straight or di-branched chain having from 2 to 3 carbon atoms in each case; hydrofuran or tetrahydro iron, any of: skuo in - 366 - or a group -CK ^ -X ´, wherein X * represents a halogen atom, OH, tetrahydrofuran, tetrahydroquiophene or a heterocyclic group of formula '\! G =? xce 0, Ξ,? and G represents a carbon or nitrogen atom, the carbon atoms being optionally substituted by a halogen atom, an alkoxy group and a carbon atom, -00- (alkyl of 1 to 3 carbon atoms), 0 alkyl of 1 to 3 carbon atoms, or -00- (alkyl) 3 carbon atoms, hydroxy and t R and R. have the above meaning. and a compound of the formula Ί · · · · 367- Ν-CCCHA-G-C · alkyl ο 1 to 3 carbon atoms -3-alkyl of 1 to 3 carbon atoms --S - (-) - R, R. NHCH). _G - _N -NKCH.). -C0n '• R, - O- (CH.). R. R, where R is halogen, alkyl, -O-alkyl of 1 to 3, and hydroxy; R. has the abovementioned meaning, o Ar is a non-crosstalk from groups c a 3-carbon sword or sky 368 and R, independently represent hydrogen, alkyl of 1 to 3 carbon atoms, 3-alkyl of 1 to 3 carbon atoms. S-alkyl of 1 to 3 carbon atoms, -CR, -CM, -CH, -3CR, -OCR, halogen, MC, amino or C 1 -C 3 -alkyl or -M- (C 1 -C 3 -alkyl) or -M (R) (CH3) -M- (R), □-CC £ means G, 3, MH, M-C 1 -C 3 alkyl, NCO- (C 1 -C 3 alkyl), NSO 3 - (alkyl of 1 to 3 carbon atoms), R1 represents one of the groups Wz \ // W // Q Γ7 «· 369 and pharmaceutically acceptable salts of these compounds. 70. A compound according to claim 1 of the formula R wherein Y is O, S, NH or N-alkyl of 1 to 3 carbon atoms, It means a hydrogen atom, a halogen atom, that is, a chlorine, bromine, fluorine or iodine. OH, -3-alkyl. (C--C au-C u-Ciky-CF-Ciky-Ciky-Ciky-Ciky-Ciky-Ciky-Ciky-Ciky-Ciky-Ciky-Ciky-Ciky alkyl); 1-3 carbon atoms, -3-alkyl of 1-3 carbon atoms, -N3-, -NH2-, -NH33- (alkyl of 1-3 carbon atoms), -N- (alkyl of up to 3 carbon atoms) -, -3G-NH2, -3C-NH-alkyl of 1 to 2 carbon atoms or -3-Ν-alkyl. o 1 to denote hydrogen, chlorine, bromine, -OK, alkyl of 1 to 3 carbon atoms, carbon atoms, or carbon atoms; O-alkyl R, together form methylenedioxy or ethylenedioxy, is a group - CAr where Ar is any of the skuoin - 370 R. R. —N R. R. R. R @ 1 is a hydrogen atom, alkyl having 1 to 2 carbon atoms of -00-; an alkyl of 1 to 3 atoms. ur._ ixu; , R @ 1 and R @ 2 are hydrogen, alkyl or alkyl or carbon or halogen. means any of the skuoin -NCQAr ' AND R NCQN-Ar NCQ (C-), _n R ykloaikyl, R R. R_ 371 -N-i NSO ₂ - (alkenyl of 3 to 8 carbon atoms) it -MH-3- (3 to 3 acoms alkyl), -MH-3- (3 to 3 acoms alkyl), -MH-3-3- (alkenyl of 3 to 3 carbon atoms), -MH-3- (C3 -C3 alkenyl), wherein the alkyl and alkenyl moieties may have straight or branched chain, cycloalkyl means cycloalkyl of 3 to 6 carbon atoms, cyclohexenyl or cyclopentenyl, R is hydrogen, methyl, ethyl, some of the group 3, skuoin - (CCa-N - 372 - (CHR a -N 4 '- (C 1 A - N - (CH) q-N 0 (CH 2), -C- (alkyl α 1 to in -CH, CH, CH, umix atoms) or a total of 1, 2 or 3, i.e. a atom of the formula x, <as sign and _. <er.v_ vzz ·. carbon, CH, cycloalkyl of 2 to 5 carbon atoms); - • C // ÍL R_ R. R. / ^: -ch.;. -ch.). R. / ^j W of '···· - 373 - p is an integer from 0 to 3, X is O, S, NH, NCK, Or a chemical bond, and have the above-mentioned wcnam. □ / ^u o) a group of the general formula R. AND The branched chain KOS is a branched chain of always 3-alkyl or -O-alkenyl chain of 3 to 2-hydreturane or tetrahydroxylamine. 374 or a -CK2 -K group. wherein K represents a halogen atom, OH, tetrahydrofuran, tetrhydrothiophene or a heterocyclic group of the formula ## STR3 ## D, Ξ, F and O are carbon or nitrogen, p carbon atoms are optionally substituted with halogen, alkoxy of 1 to 3 carbon, -00- (alkyl of 1 to 3 carbon atoms), CHC alkyl of 1 to 3 carbon atoms or -00, - (alkyl of 3 carbon atoms, hydroxy and the substituents are as defined above). ..nu ooeone.no formula N-CCCH -r Gal alkyl of 1 to 3 carbon atoms -3-alkyl of 1 to 3 carbon atoms -5- (CHL-, \ j NHCH). -CON R. - NHCH) _q - nz ⁵ » - O - (CHL - ^N / 2 - where it is halogen, alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms or hydroxy; and R, _q is as defined above, Ar is one of the groups R, W R 8 and R _q independently represent hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkyl, C 1 -C 3 alkyl, -CF _q , -CN, -OK, -SCF1, -OCF3, halogen, NOg amino or NH-alkyl of 1 to 3 carbon atoms or -N- (alkyl of 1 to 3 carbon atoms) or -N (R, (CH 2) -N- (R) 2, q 2 W represents O, S, NH, N-C 1 -C 3 alkyl, NCO- (C 1 -C 3 alkyl), MSO 6 (C 1 -C 3 alkyl), means one of the groups »· ··· « - 376 λζ // \\ / / \\ // 'N v W // 'S. and their pharmaceutically acceptable salts. 71. A compound according to claim 1, wherein Y is O, S, NH or N-C1-C3 alkyl, A-B is a group A-S is -CH, —N or N — CH, i R, · · · · I 377 R @ 1 is hydrogen, halogen, i.e., bromine, fluorine or iodine; OK, -S-alkyl of 0 to 3 carbon atoms, -3K, -30-alkyl of 1 to 3 carbon atoms. -C 1-6 -alkyl of 1 to 3 carbon atoms, -03--. alkyl of 0 to 3 carbon atoms), -Cr _q , alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms, -MC ,, -ME, -MKCC- (alkyl of 1 to 3 carbon atoms) -30, NH, -ΞΟ, ΜΚ-alkyl or azoc umix atom neoc-1C, N- (aqt means hydrogen, chlorine, bromine, fluorine) po, -OK, alkyl of 1 to 2 carbon atoms, O-alkyl of 1 to 3 carbon atoms Rt: c_eoh; : xvsku: tveri methvlehdioxvsxu wasted skuc mu mm λ · - car where Ar represents one of the groups' • —R. —R. :and Her. J-v_, ₇ V / -to ς - 378 - R _d is hydrogen, alkyl of 1 to 3 carbon atoms or -C 3 - (alkyl of 1 to 3 carbon atoms), R @ 1 and R @ 2 are hydrogen, alkyl is an alkoxy group having from 1 to 3 carbon atoms or halogen, R. means o some of the skuoin -NCQA AND R NCON-AR ' AND -NCOCHAr NCO (CHL I * R R_ I O R- - 379 NSO 3 - (C 3 -C 8 alkyl), ί AND R • NSO8-Calkenyl of 3 to 8 carbon atoms), -NH-C-O- (C 3 -C 8 alkyl), 0 11 -NH-O- (alkyl of 3 to 8 carbon atoms); -NH-3-O- (alkenyl of 3 to 3 carbon atoms), Rf. C tt -NH-O- (alkenyl of 3 to 3 carbon atoms), wherein the alkyl and alkenyl radicals may have a straight or branched chain, cycloalkyl or cycloalkyl of 3 to 6 carbon atoms, cyclohexenyl or cyclopentenyl, R represents a hydrogen atom, methyl, ethyl, a 2 cl group - (GH) o-N • · · - 380 ·· ···· - (CHp) 2 -O- (alkyl of 1 to 3 carbon atoms) or -CHgCHgOK, o represents an integer of 1, 2 or 3, R. represents a hydrogen atom, CH, or -C-Hj, O b) a compound of formula - ^x - ^R 10 ka R. - represents alkyl or alkenyl (in each case of a carbon, carbon), by any of the groups of at least 3: carbon, - (CH-) - (cycloalkyl of 3 to 5 carbon atoms); Λ-CH- '. \\; //! // í <R_ RtCH). - (CH;;. '1 i <2 N R, AND R / ml O p is an integer from 0 to 3, X stands for O, S, ΜΗ, NCK ', ·· ·· ·· ···· - 381 · »38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 O or chemical bond, Rg and _R7 are as defined above, c) a group of formula rt. i zramena .-. alxvi and branched chain by in each case 3 to 2, and straight-chain-3-alkyl or -3-alkenyl by in each case 3 to 3 atoms of hydrofuran or tetrahydrothiofer. a carbon or branched carbon atom, a tetrano or one of -CKg-X ', wherein K' represents a halogen atom, OH tetrahydrofuran, tetrahydrothiophene or a heterocyclic group of the formula - 382 -N \ C- = where D, Z, F and G are carbon or nitrogen, wherein the carbon atoms are optionally substituted with halogen, C1-C2 alkoxy, -G0- (C1-C3 alkyl), CHG, C1-alkyl (C 1 -C 3 alkyl, hydroxy and C 1 -C 3 alkyl); R 'and Rg are as defined above, d) a compound of the formula C 1 -C 3 -alkyl -3-alkyl of 1 to 2 carbon atoms R, -č CK.I-N - NHCHj. - CON R. 'R. - NH4CH3) - n - o- (CH3). - N zS / ^R > - 383 wherein is halogen, alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms or hydroxy; and R1 is as defined above, o Ar 'is one of i R. h- and R _{3 are} independently hydrogen, C 1 -C 3 alkoxy, C 0 -C 3 alkyl, C 3 -C 3 alkyl, C 1 -C 3 alkyl, -CN, -CH, -SCRg, -OCR, halogen, NC? amino or C 1 -C 3 -alkyl or -M- (C 1 -C 3 alkyl) / g, or -N (R) (CKg) _σ -Ν- (R ^) ₂ , denotes 0, S, NH, N-C 1 -C 3 alkyl, NCO- (C 1 -C 3 alkyl), NSC ₂ - (C 1 -C 3 alkyl), R is any of 2c - 385 R ₁ is hydrogen, halogen, i.e., cMet, racing circuit, fluorine or iodine, OH, -5-alkyl of 1 to 3 carbon carbon, -3H , -30-alkyl o 1 to 3 atomeo ‘« Ί t 1 F * i · ku, -30.- -alkyl o 1 up to 3 atoms carbon ? —SX - \ Ikyi o 1 to 3 atoms uhi -OF., and i kyl c i to 3 atomeo h carbon, -O-alkyl 'C * 2 - - »τγ »Λ £ h uhi í ku, -NO. , -NH. - (alkyl o 1 up to 2 atoms uhi ík u), -M- alkv 1 o 1 to 3 atoms uhi -30.NH »-C J X ₂ NH-acyl up to 3 atoms or -50.N-alkyl - clay * R. stands for hydrogen, chlorine, bromine, fluorine or joou, -OH, alkyl of 1 to 3 carbon atoms, O-alkyl of 1 to 3 carbon atoms, or R. and R, taken together to form methylenedloxy or eohylenoxy with a group, meaning sxuoin means nexe R. R ZN: o X-R R_ - 386 r ₃ _ // ¹ h NHZCÍC i RN: ' ^X ~ * v R _d is hydrogen, alkyl of 1 to 3 carbon atoms, or -CO- (alkyl of 1 to 3 carbon atoms), R_ and R _? are hydrogen, alkyl or C1 -C3 alkoxy or halogen. R 1 is o (a) any of the groups -NCOAr, -NCON-Ar, NCO (CH3) _n R Λ cycloalkyl, R. -NCOCH, A.r ' _z Μ 'l' O! L -N-? AND R ·· · · · · · - 387 -NSO ₂ - (C 3 -C 8 alkyl), -NSO ₂ - (alkenyl of 3 to 8 carbon atoms), II -NH — 3-O- (alkyl of 3 to 3 carbon atoms), up to 3 carbon atoms) -NH-C-O- (C 3 -C 3 alkenyl), O II -MH-C- (C 3 -C 3 alkenyl) wherein the alkyl and alkenyl radicals may be straight or branched, cycloalkyl means cycloalkyl of 3 to 6 carbon atoms, cyclohexenyl or cyclopentenyl, R is hydrogen, methyl, ethyl, any of the 3 &lt; 1 &gt; - (CH3) c-N groups R. R. - (CH. (C - N - (CH 2) q - N O 388 - (CH 2) 4 - O- (C 1 -C 3 alkyl) or -CH.CH.OH, with 2 q being an integer of 1, 2 or 3, R. represents a hydrogen atom, CH, or -C (H), (I) and also a group of the formulas - X - R koe R,. -V represents alkyl or alkenyl; carbon, - (CH 2) - (carbon-alkenyl) or a carbon atom; az and azcmeor With p atoms, the integer is 0 to 3, X stands for 0, S, MH, MCH ,, - 389 ^X y = O or chemical bond, R. and Rg are as defined above, c) a group of the general formula R. is denoted by the term "hydrofure sku in". and a straight chain having from 3 to 3 carbon atoms or a straight or branched-chain O-alkenyl having from 3 to 3 carbon atoms, tetrane or tetrahydrothiophene, one of the following: or a group -CHg-K, wherein d 'represents a halogen atom, OH, tetrahydrofuran, tetrahydrothiophene or a heterocyclic group of the formula 390 - Ν E \ / G = F where D, E, F and C- are carbon or nitrogen, wherein the carbon atoms are optionally substituted with substituents from the group consisting of halogen, alkoxy of 1 to 3 carbon atoms, -00- (alkyl of 1 to 3 carbon atoms). CKC. alkyl of 1 to 2 carbon atoms or -00, - (alkyl of 1 to 3 carbon atoms, hydroxy and R and R. are as defined above. a o ' (d) common skuoin -O-C-alkyl of 1 to 2 carbon atoms -3-alkyl of 1 to 2 carbon atoms - 3 CEL / A -R. R. -NHíCKj. -CON R " - NHCH) _and _ R. • · · · · · · · · · · · · - 391 where R ^ is halogen, alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms or hydroxy; and R1 is as defined above, o Ar is one of the groups R 'and R' are independently hydrogen, alkyl or alkyl; 3 to 3 carbon atoms, O-alkyl of up to 3 carbon atoms, S-alkyl of 1 to 3 carbon atoms, -Or-, -ON, -OH, -SC: ₃ , -OCRg, halogen, NO ₂ amino or C 1 -C 3 -alkyl, or -M- (C 1 -C 3 -alkyl), or -N (R 2 -alkyl); (CH 2) -N- (R) 2, o 2 q 0 4 W represents O, S, NH, N-alkyl of 1 to 3 carbon atoms, NCO- (alkyl of 1 to 3 carbon atoms), NSO 8 -alkyl of 1 to 3 carbon atoms), R represents one of the groups And pharmaceutically acceptable salts of these compounds. 73. The compound of claim 72 wherein A-B is a group N — CK-; ll R 6 is o II ^- CAr where Ar is any of the groups - 384 / "V" \ \\ of // ^ _ // // / / \ v // \ And pharmaceutically acceptable salts thereof. 72. A compound according to claim 1, wherein Y is O, S, NH or N-alkyl and A-B is a group 1 to 3 carbon atoms, CH. or AND R. J N— CH, - AND R. J And Y, R _and R, _q , R 6, R 6, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, are as defined in claim 72. ^R S ' ^R 9' ^R 1O ' 74. The compound of claim 72 wherein A-B is a group N-CH 2 -; R, Y represents an oxygen atom and R, R, R, R,, R ", R", R ", and c 1 2 3 4 as defined in claim 72. R, R, 5 ’6’ 7 ’3’ R 8, R 8 q, R 8 r 11 ® J 75. The compound of claim 72 wherein A-B is a group N - CHyR, represents a group O II -Scrap - 394 - wherein Ar represents one of the groups Y represents an oxygen atom and a ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' R, R _? , Rg, Rg, R _1q, RGG are as defined in Claim 72nd The tricyclic diazepine derivatives of claim 72, wherein A-B is a group N - CH.—; R. Y is NH, and ^R a ' ^R b' ^R c ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R 6 ' ^R 7' ^R 8 ' ^R 9' ^R 10 'are as defined in claim 72. 77. The compound of claim 72 wherein A-3 is a group N - CH3 -; AND R 8 represents a group O II -CAr ················································ · E · t ··· »·· · · · · · · - 395 where Ar is one of the groups Y is NH and ^R a ' ^R b' ^R c ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R 5 ' ^R 7' ^R 3 ' ^R 9' ^R 10 ' ^R 25 are as defined above in claim 72. 78. The tricyclic diazepine derivatives of formula I of formula (I) Λ r *. represents (CH3) n, C, 3. NH, NC3 CH3, M- and n-y. L to 2 carbon atoms. CH- (alkyl of 1 to 2 atoms), CHNH- (alkyl of 1 to 3 carbon atoms), CHNH. CHN (C 1 -C 2 alkyl), CHQ-alkyl: up to 3 carbon atoms), CH 2 - (alkyl duties; carbon), wherein n is an integer from 0 to 2, azome: A-3 stands for Scuoin - (CH-K-N ...! EL rtebo R_ - 396 where m is an integer from 1 to 2, provided that when Y is - (CR 1) 2 and n = 2, m may also be 3 and Y is - (CR_) and n = 2, m has a meaning different from 2.2 n R. is hydrogen, such as bromine, fluorine or iodine, carbon, -SK, -SC-alkyl (o-alkyl of 1 to 3 carbon atoms), -CF _q , and -O-alkyl of 1 to 3 atomeo - (alkyl (1 to 3 carbon atoms), -5C, YH, carbon or -3C, N- (halogen, i.e., chlorine, OH, -S-alkyl of 1 to 3 carbon atoms, -30 , carbon, -00- (alkyl of 1 to 3 alkyl of 1 to 3 carbon atoms, h carbon, -NO1, -ΝΉ, -NKC3 carbon), -M- (alkyl of 1 to 3 alkyl of 1 up to 3 carbon atoms), R " Z is hydrogen, chlorine, bromine, -OR, alkyl of 1 to 3 carbon atoms, carbon or fluorine, or alkyl of 1 to 3 R 'is formed solely by methylenedioxysuccin or ethylenedioxyu, meaning CAr where Ar is any of the skuoin R. 1 J R. WITH R_ • ···· Ί · · - 397 ··· 9 · ···· · · · · · · · · · · · · · · · · · R- R. - <, 'NHZCR. # ^ rX-R. \ 70 Ν: X-R,: α R _d is hydrogen, alkyl of 1 to 3 carbon atoms, or -C 1-6 alkyl of 1 to 3 carbon atoms; R @ 7 and R @ 7 are hydrogen, alkyl or alkoxy in which: jm na_oženu. rto znamena (a) any of the skuoins -NCOAr; and R - NCON-Ar. -NCO (CH-) -cycloalkyl; ⁿ R -NCOC-OAr '. t. -N-SOR -N-? AND R - 398 -NSO ₂ - (C 3 -C 8 alkyl), -NSO8-Calkenyl of 3 to 3 carbon atoms), -NH-C-O- (alkyl of 3 to 3 carbon atoms), -NH-C- (alkyl of 3 to 3 carbon atoms) I I -NK-C-3- (C 3-5 alkenyl alkenyl), II -NK-3- (3 to 3 carbon aikenvi), wherein the alkyl and alkenyl residues may be straight or branched chain, cycloalkyl means cycloalkyl of 2 to carbon atoms, cyclohexenyl or cyclopentenyl, R stands for hydrogen azide, methyl, ethyl, some of the ss and the group is - (CH) c-n, - GH) q -, - (CHh - N - (CH) < 3 &gt; N 99 99 9999 t 9 9 9 99,999 9 • · · - 399 - (CKg) 2 -O- (alkyl of 1 to 3 carbon atoms) or -CHgCHgOK, o is an integer of 1, 2 or 3, R. represents a hydrogen atom, CH- or -C.H-, o0-20 b) a group of formula -X-R R @ 1 - represents alkyl or alkenyl by carbon, - (C1 -C6) - (cycloalkyl at [beta] carbon), by one of the following groups: R. • CH-). \, // \\ i // R_ R_ -OHI). R. O p is an integer from 0 to 3, X is O, S, ΜΗ, MCH ,, - 400 · · · · · · · · · · · · · · · · · · · · · · · 0 - q or chemical bond, R <. and R ₇ are as defined above, o) a compound of formula R. - M - CC represents R „, alkyl or alkenyl with a straight or branched chain of 2 to 5 carbon atoms. -C-alkyl or straight-chained or branched-chain alkenyl of 2 to 3 carbon atoms each, viscous hydrofuran or tetrahyrothiophene, some of which may be present r. or a group -CH ₂ -K *, where K 'represents a halogen atom, OH, tetrahydrofuran, tetrahydrothiophene or a heterocyclic group of the formula - 401 Λ - Ε Ε \ / C- = F where D, Ξ, R and C- represent a carbon or nitrogen atom, the carbon atoms being optionally substituted by halogen, an alkoxy group having 1 to 3 carbon atoms, -00- (alkyl having 1 to 3 carbon atoms), CH3, alkyl having 1 to 3 carbon atoms; C 1 -C 3 alkyl or -03, - (C 1 -C 3 alkyl, hydroxy and C 1 -C 3 alkyl) R and R. are as defined above, and ^JJ d) a group of the general formula - N- CCCHAR -O-C-alkyl of 1 to 3 carbon atoms -Ξ-alkyl, o az. carbon atoms -S-OU- _N , R / 0 • R -NHfCH3; -CON '' R. - NH (CH 2) _and - n - O - (CH 2) - ^N 'R. - 402 where R is halogen, C 1 -C 3 alkyl, C 1 -C 3 -alkyl or hydroxy; and R1 is as defined above, o Ar 'is one of the groups R and R independently represent hydrogen, alkyl of 1 3 9-3 carbon atoms, O-alkyl of 1 to 3 atomecn alkyl, S-alkyl of 1-3 carbon atoms, ₂ -GR, -ON, -OH, -SCR ₃ , -OCR ₃ - halogen, NO ₂ amino or NH-alkyl of 1 to 3 carbon atoms or -N- (alkyl of 1 to 3 carbon atoms), or -N ( R- _O) (CH _{2) q} -N (R ^) _2, W 'is O, S, NH, N-alkyl of 1-3 carbon atoms, NCO (alkyl of 1-3 carbon atoms), NSO ₂ - (-alkyl of 1-3 carbon atoms), ^L 25 represents either of R '3 and R represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom and optionally substituted alkyl radical of 1-3 carbon atoms, a formyl radical, a group of the formula ~ _{(CH2) q} N 404 with a halogen atom or a C 1 -C 3 alkoxy group, and pharmaceutically acceptable salts, esters and precursors thereof. 79. Tricyclic diazepine derivatives of the general formula wherein It means skucir.u (CH,). 3. NH, HCCCH, N-alkyl of 1 to 3 carbon atoms, CH- (alkyl of 1 to 3 carbon atoms), CKNH- (alkyl of 1 to 3 carbon atoms), CHNH ,, CHN (C 1 -C 3 alkyl), CHC- (C 1 -C 3 alkyl); (1 to 3 carbon atoms), CHS- (C1-C3 alkyl), wherein r. is an integer of 0 to 2, denotes a group - (Cl · -? · N R. or N-Chlorophenol). " R. 405 represents a hydrogen atom, a halogen atom, i.e. chlorine, bromine, fluorine or iodine. OH, -3-alkyl of 1 to 3 carbon atoms, -3H, -30-alkyl of 1 to 3 carbon atoms, -30, -alkyl of 1 to 3 carbon atoms, -OC-alkyl of 1 to 3 carbon atoms} C1-C3 alkyl; -O-alkyl of 1 to 3 carbon atoms, -NO 1, -HH, -MH 3 O- (alkyl of 1 to 3 carbon atoms), -N-alkyl of 1 to 3 carbon atoms), -30,? (C1-C3, NH-alkyl of 1 to 3 carbon atoms or -30, (C1-C3 alkyl) of 1 to 3 carbon atoms) having a hydrogen, chlorine, bromine or fluorine atom other than: OH, alkyl of 1 to 3 carbon atoms; 3 carbon atom, -Can carbon or R. ZOleor.e tvert methy.er.zzoxysxupm .oxvskucine, r.eo: R. means that where Ar is one of the groups R. I J to. 406 ·· · · ···· Rxhzoc ΕΝ: X - R. _r represents a hydrogen atom, an alkyl of 1 to about carbon atoms or -00- (alkyl of 1 to 3 carbon atoms), R @ 1 and R @ 2 denote hydrogen, alkyl or alkoxy or a halogen atom; (a) any of the groups -NCOAr '* NCON-Ar, -NCO (C 6 -) 4 -cycloalkyl, • 444 ·· 4 • 444 - 407 4 4 4 4 4 4 44 444 « 4 · NSOg-C 3 -C 3 -alkyl), -NSO 6 - (C 3 -C 8 alkenyl), II -NH-C-O- (alkyl of 3 to 3 carbon atoms), -NH-C- (C 3 -C 3 alkyl), -NK-C-O- (C 3 -C 3 alkenyl), II -NK-C- (C 3 -C 3 alkenyl) wherein the alkyl and alkenyl radicals may be straight or branched, cycloalkyl means cycloalkyl of 3 to 3 carbon atoms, cyclohexenyl or cyclopentenyl, R represents a hydrogen atom, methyl, ethyl, any of the groups and a group - (CK / KJ-N (CHJa— R, - (CHM O '‘\ _! • · · · · · · · · · · · · · · · · · · · · · · - 408 - (CH3) g-O- (C1-C3 alkyl) or -CHgCHgOH, q represents an integer of 1, 2 or 3, R 8 represents a hydrogen atom, CH 6 or -C _? H_, b) a group of formula -X - R kae denotes alkyl or alkenyl in each case from 2 to 8 atcmec: carbon, - (CH.) - (C 3 -C 8 alkenyl), by any of the groups - • ch.; ·, -; r, RK. / ^: R_ R. - (CH), Z O N R. / ' - (CH), - C-i Λ— - R. / o p is an integer from 0 to 3, X is O, S, NH, NCH About ’• · - 409 c = 0 or chemical bond, R and R_ have the above-mentioned knowledge; c) a group of the general formula AND - M - C3J where R, alkyl or branched chain is in each case a -O-alkyl or -O-alkenyl chain of from 3 to g each hydrofuran or tetranydrothiocenyl lkenyi 3 is a straight or branched chain carbon atom of 3 to 8 carbon atoms, a straight or branched carbon atom, a setra, one or a group -CHg-K where K represents a halogen atom, OH, tetrahydrofuran, tetrahydrothiophene or a heterocyclic group ··· · ·································································· ··· ·· ·· · - 410 - where D, E, F and G are carbon or nitrogen, wherein the carbon atoms are optionally substituted with substituents from the group halogen, alkoxy of 1 to 3 carbon atoms, -00- (alkyl of 1 to 3 carbon atoms), CHO, alkyl or or (C 1 -C 3) alkyl, hydroxy and C 1 -C 3 alkyl; R_ and R. are as defined above, SL O d) a compound of the general formula C 1 -C 3 -alkyl having 1 to 3 carbon atoms -S-alkyl of 1 to (carbon atoms; .R. R. S Cr, 1 _-N , -NK (C C) -CON R. - NH (Crp) _and - _N -O- (CK,) .- N R. ·················································································· β » - 411 where R _q is halogen, alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms, or hydroxy; R ^ is as defined above, Ar is one of the groups R g and R _{independently} represent hydrogen, alkyl oi to 3 carbon atoms, O-alkyl of I to 3 carbon atoms, alkyl of 1 to 3 carbon atoms ,,-OF -ON, -OH, -SCFg, -OCFg, halogen, NO ₂ amino or NH-alkyl of 1 to 3 carbon atoms or -N- (alkyl of 1 to 3 carbon atoms) _2, or -N (R 2). (CH 2) -N- (R), o 2 and od W represents O, S, NH, N-C 1 -C 3 alkyl, NCO- (C 1 -C 3 alkyl), NSO ₂ - (C 1 -C 3 alkyl), R, ₅ means one of the groups ·················· ΙΛ. and pharmaceutically acceptable salts thereof. 80. The compound of claim 79 wherein A-B is i ( N- CKR. f <2 stands for o AND! ^- CAr R, NHCOR-. and Y, R _a , R b, R c, R j, R j, R 3, Ru, R j, R g, R p, R g, R q, R jq, R-15 are as defined in claim 79. t - 413 81. The compound of claim 79 wherein A-B is a group N = CH, -; R, Y is - (CHg) - and ^R a ' ^R ' o ' ^R c' ^R 1 ' ^R 2' ^R 3 ' ^R 4' ^R 5 ' ^R o' ^R 7 ' ^R S' ^R 9 ' ^R 10' ^R 25 are as defined in claim 79. 82. The compound of claim 79 wherein A-3 is a group N = CH, -; R. Y represents an oxygen atom and _And R, R ^, R ^,, Rg, Rg, R, _Rc, Rg, Ry, Rg, Rg, R are as defined in claim 79th 83. Tricyclic diazepine derivatives according to wherein A-B is a group 10 ' ^R 25 of the claim N— CKR, Y represents NH and • · · · - 414 ^R and ' ^R ' o ' ^H c' * 1 ' ^R 2' ^R 3 ' ^R 4' ^R 5 ' ^R 5' ^R 7 ' ^R 8' ^R 9 ' ^R 10' ^R 25 have the meaning given in claim 79. 84. The compound of claim 79 wherein A-B is a group N— CH, - R. R 8 represents a group O - CAr where Ar is one of the groups R. I 3 R, R. NHCOR ,, R. / Y denotes - (CH) -, R _b, R _c, R g, R g, R g, R _4, R, Rg ^{»R7» R} g> ^R g> ^R x ₀ ^'R 25 are as defined in Claim 79 85. The compound of claim 79 wherein A-B is a group O II -Scrap Rg stands for • · - 415 where Ar is one of the groups R. NHCOR, Y represents an oxygen atom and ^R a ' ^R b' ^R c ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R 5 ' ^R 7' ^R 8 ' ^R 9' ^R 10 ' ^R 25 have the meaning , recited in claim 79. 86. The compound of claim 79 wherein A-B is a group R 8 represents a group N— CKRO II -CAr where Ar stands for one of the groups R ‘. R. O AA R. • NHCOR-. Y is NH and ^R a ' ^R b' ^R c ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R 6 ' ^R 7' ^R 8 ' ^R 9' ^R 10 ' ^R 25 are as defined above in claim 79. - 416 9 · · · * · * · * * 87. Tricyclic diazepine derivatives of formula I KG; means sxupzru (CH3) n, 0, 2. YH. HCCCH 3, N-α-xy, 1 to 2 carbon atoms. CH- (C1-C2 alkyl), CHNH- (C1-C2 alkyl), CHMH ,, CHN (alkyl of 1 to 3 and 2 to 2 carbon atoms), 3HS- (alkyl of 1 carbon), wherein n is an integer of 0 to 2 CHC- (alkyl o 3. Z J stands for - (CrJA-N ') R. something N-CHJ, R. t u r \> where m is an integer from 1 to 2, provided that if Y is - (CH ’and n = 2, m can also be 3 and Y is - (CH 2) n = 2, has m meaning, different cd 2 2 n - ^J C 9 · 9 9 - 417 represents a hydrogen atom, a halogen atom, i.e. chlorine, bromine, fluorine or iodine, OK, -3-alkyl of 1 to 3 carbon atoms, -3H, -SO-alkyl of 1 to 3 carbon atoms. -30, -alkyl of 1 to 3 carbon atoms, -CO- (alkyl of 1 to 3 carbon atoms), -CR1, alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms, -MC , -MK, -MKCO- (alkyl of 1 to 3 carbon atoms), -M-1 alkyl of 1 to 3 carbon atoms), -50, MK,, -50, NH-alkyl of 1 to 3; or (Cec-C alkyl alkyl) alkyl, represents a hydrogen, chlorine, bromine, fluorine, iodo, -CH, (C až-C alkyl) alkyl, (C až-C alkyl) alkyl group; Or 5 carbon atoms R. and R, formed solely by methylene oxide or ethylene oxide, R 1 represents a group 0 I » - CAr where Ar is any R. I> R. R Vj R_ · ··· · · · · · · · · · · · · · - 418 - NHOCR. /> ^X_R 10 N: • X-R. '0 R _d is hydrogen, alkyl of 1 to 3 carbon atoms, or -CO- (alkyl of 1 to 3 carbon atoms), R 8 and R 8 are hydrogen, alkyl or alkoxy of 1 to 3 carbon atoms or halogen, R 'is o (a) any of the groups -NCOAr, AND R a - ncon-aZ ~ NCO (CH-) -cycloalkyl, 1 * ^π RR 1 ⁰ R and -NCOCHOAr, AND R a C-SO-CZ-O R R_ / O II -N-R AND R a • · · · · · · · · · NSO 8 - (C 3 -C 8 alkyl), NSO 8 - (C 8 -C 8 -alkenyl), H -NH-C-O- (C 3 -C 3 alkyl), AND" -MK-C- (aqvi of 3 to 8 carbon atoms), (3 to 3 carbon atoms) AND" -NK-C- (C 3 -C 3 -alkenyl), wherein the alkyl and aikenyl radicals may be straight-chain or branched, cycloalkyl being cycloalkyl of 3 to 6 carbon atoms, cyclohexenyl or cyclopentenyl, R is hydrogen, methyl, ethyl, Z; Sl. skuc in R. / ³ - (CE.) A -, - (Cn,) a - M 'O Λ · · · - 420 - (CH ^) ,, - 0- (alkyl of 1-3 carbon atoms) or -CH ₂ CH ₂ OK, q is an integer 1, 2 or 3, R. represents a hydrogen atom, CH- or -C.H_. o 3 2 2 b) a group of formula -o ^R 10> where R (q) is alkyl or alkenyl of 3 to 8 carbon atoms, (CH3) - (C 3 -C 5 alkenyl), any of p being an integer of 0 to 3, X stands for 0, S, ΜΗ, MCH - 421 ¢ 2— O or chemical bond, R. and R1 are as defined above, b / c) a group of the general formula R. - M - COJ where J represents R, an alkyl or an alkenyl of a straight or branched chain having from 3 to 3 carbon atoms. -O-alkyl or -O-alkenyl with a straight chain of 3 to 3 carbon atoms, tetrahydrofuran or tetranydrothiophene, one of the groups; or -CH -X * wherein X * is halogen, OH. tetrahydrofuran, tetrahydrothiophene or a heterocyclic group of the formula 422 \ / c =? where D, E, F and G are carbon or nitrogen, wherein the carbon atoms are optionally substituted with substituents from the group consisting of halogen, alkoxy of 1 to 2 carbon atoms, -CO- (alkyl of 1 to 3 carbon atoms), CHC. alkyl of 1 to 3 carbon atoms or -CO, - (alkyl of 1 to 3 carbon atoms, hydroxy and R and R, have the above meaning, and ^J d) a group of the general formula - N-CCCH II -O-C-alkyl of 1 to 3 carbon atoms -Ξ-alkyl of 1 to 3 carbon atoms - NH (CH) _and n _ R, • · · · - 423 where R _q is halogen, alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms, or hydroxy; R ^ is as defined above, Ar is one of the groups R- and R- independently represent hydrogen, alkyl of 1 to 2 carbon atoms, O-alkyl of 1 to 3 carbon atoms, S-alkyl of 1 to 3 carbon atoms, -OF ,, -CN, -OK, -3CF-, -OCF, halogen, NO 2, amino or NH-alkyl of 1 to 3 carbon atoms or -W- (alkyl of 1 to 3 carbon atoms), or - N (R) (CH 2) -N- (R), o 2 σ o 2 W is O, S, NH, N-C 1 -C 3 alkyl, NCO- (C 1 -C 3 alkyl), MSO 1 -C 3 alkyl (C 1 -C 3), means one of the '25' groups And the group represents a 5-membered aromatic (unsaturated) heterocyclic ring containing one sulfur heteroatom and optionally substituted with a C 1 -C 3 alkyl radical, a formyl radical, with a < ^C h> group CN q A is halogen or C1-C3 alkoxy, and pharmaceutically acceptable salts, esters and precursors thereof. • · · · - 425 • 9 • 9 • 9 88. Tricyclic diazepine derivatives of the formula wherein Y is - (CHg) -, O, S, NH or N-alkyl of 1 to 3 carbon atoms, A-B represents a group - CH.- N or N- CHR. R. is hydrogen, halogen, i.e., chlorine, bromine, fluorine or iodine, OH, -3-alkyl of 1 to 3 carbon atoms, -3H, -30-alkyl of 1 to 3 carbon atoms, -30-alkyl of L Ξ to carbon atoms, alkyl of ¹ -CO- l to 3 carbon atoms) -of option., alkyl of 1 to 3 carbon atoms, -0-alkyl of 1-3 carbon atcmecn, -NC · ?, -NH? , -NHCO- (alkyl of 1 to 3 carbon atoms), -N-alkyl of 3 to 3 carbon atoms), -30-NH-, -SO4NH-alkyl of 1 to 3 carbon atoms or -30? -N ( alkyl of 1 to 3 carbon atoms R ^ represents a hydrogen, chlorine, bromine, fluorine or iodine atom -OH, alkyl of 1 to 3 carbon atoms, O-alkyl of 1 to 3 carbon atoms, or R @ 1 and R @ 2 taken together are methyl, dioxo or ethyl; Rg means a group II Scrap - 426 where Ar is a skuoin R. R, JJA x About k_ RI RV-_ 5 ^'to d is hydrogen, alkyl of 1 to about carbon uruiku -C0- or (alkyl of 1 to 3 carbon uhzixu ;, R and R_ are hydrogen, alkyl or aixoxy skuo Nou 'tr 5 ** / ^Mn of 1 to 3 carbon atoms or halogen. R. means o (a) any of the groups -N-CQAr, -NCOKAr. -NCO (C 1-6) _n -eyloalkyl * ^L S ΙΛ - (alkyl o I ' AND R to 3 carbon atoms), -NSO 3 - (C 3 -C 3 -alkyl); I ' ^k a O ”„ ....., -NH-3-O- (alkyl of 3 to 3 unix atoms), y-O- (alkyl of 2 to 3 carbon atoms), -NH-3-0- (alkenyl of 3 to about 3 carbon un ± o. <U) '· _a ~ C- -NK (alkenyl of 3-3 carbon atoms), the alkyl and alkenyl radicals may be straight or branched, chain, cycloalkyl means cycloalkyl of 3 to 6 carbon atoms, cyclohexenyl or cyclopentenyl, R represents a hydrogen atom, methyl, ethyl, any of the groups and a group - 428 - (G1) q-N, - (G1q), R - (C (G - y - (C 1-6) ₂ -O- (alkyl of 1 to 3 carbon atoms) or a group -ck _? ch ₂ sts, p is an integer of 1, 2 or 3, R. represents a hydrogen atom, CH, or -3, -. n j; o) a group of the formula wherein R 10 represents alkyl or alkenyl of carbon, - (CH 3) - (cycloalkyl of 3 carbon), any of the groups 3 atoms ternech R- (GO. -G-ý. N R. O' -CH? R. / l, U \ R O - 429 p is an integer from 0 to 3, X is O, S, NH, NCH., Q - q or a chemical bond; R _g and R "are as defined above, c) a group of the formula Where R is alkyl or alkenyl in each of 2 to 3 straight or tertiary carbon chains. -O-alkyl or -O-alkenyl with in each case 2 to 3 hydrofuran or tetrahydro straight or branched carbon atoms, tetra hiofe, one of the groups IN? γ-· ·········· 430 or a group -CHg-K tetrahydrofuran, tet a group of the formula wherein X 'represents an atom found, OH anydrothiophene or heterocyxic; C =? where O, 7, 7 and C- are carbon or nitrogen, the carbon atoms being optionally substituted by halogen, C1-C3 alkoxy, -30- (C1-C3 alkyl), CH3. alkyl of 1 to 3 carbon atoms or -CO, -, alkyl of 1 to 3 carbon atoms, hydroxy and R and R. have the above meaning, and o 'd! of a compound of formula - N-CCCHAr -alkyl of 1 to 3 carbon atoms -3-alkyl of 1 to 3 carbon atoms R. -o-echi- _n . -nh (c: h) -cqn ' R, / ' - O- (CH3). 'R, • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · - 431 where R _c represents a halogen atom, an alkyl of 1 to 3 carbon atoms, -O-alkyl of 1 to 3 carbon atoms or a hydroxy group and has the meaning given above, Ar is one of the groups R. I ’i R. R @ 1 and R @ 2 independently represent hydrogen, alkyl of 1 to 3 carbon atoms, O-alkyl of 1 to 3 carbon atoms, S-alkyl of 1 to 3 carbon atoms, -OF '; -CN, -OH, -SCRg, -OCFg, halogen, NC2amino or NH-alkyl of 1 to 3 carbon atoms or -N- (alkyl of 1 to 3 carbon atoms) ^, or -N (R)) ( CH 2) -N- (R 2). o 2 q o 2 W is O, S, NH, N-C 1 -C 3 alkyl, NCO- (C 1 -C 3 alkyl), NSO 3 - (C 1 -C 3 alkyl), ^L 25 is one of the groups And pharmaceutically acceptable salts thereof. A compound according to claim 88, wherein A-B is ν-κκΙ R. represents a group O -CAr where Ar is any of R_ / 4 4 4 4 4 4 4 4 4 4 • • · · · 4 44 44 44 4 433 ^Y ' ^R a' ^R b ' ^R c' ^R l ' ^R 2' ^R 3 ' ^R 4' ^R 5 ' ^R 6' ^R 7 ' ^R 8' ^R 9 ' ^R 10' R ₂₅ are as defined in claim 88. The tricyclic diazepine derivatives of claim 88, wherein A-3 is a group I i N — CK-; I i R. Y is - (CHg) - and ^R a ' ^R b' ^R o ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R 6 ' ^R 7' ^R 8 ' ^R 9' ^R 10 ' ^R 25 are as defined in claim 88. 91. The compound of claim 88 wherein A-3 is i Ň- CK-; R. j Y is Q 1) and ^R a ' ^R b' ^R c ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R 6 ' ^R 7' ^R 8 ' ^R 9' ^R 10 ' ^R 25 have the meaning referred to in claim 88. 92. The compound of claim 88 wherein A-B is a group Ni— CK434 Y is NH, and ^R a ' ^R b' ^R c ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ⁿ 6 ' ^R 7 * ^R 8' ^R 9 ' ^R 10' ^R 25 are as defined above in claim 88. 93. The compound of claim 88 wherein A-3 is a group N — Cru—; R. J R 8 represents a group II CAr where Ar is any of the groups R. i 3 R- i <_ NHCOR— Y is - (CH3) - and _Ra, Rg, R q ^»R V ^R 2 ^'R 3' ^R 4 ^'R 5' ^R 6 ^'R 7' ^R 8 ^'R 9' ^R are as defined in claim 88th 94. Tricyclic diazepine derivatives according to wherein A-B is a group 10 ' ^R 25 of Claim 88 · »nároku>>> nároku nároku nároku nároku nároku nároku nároku nároku nároku nároku nároku nároku nároku nároku nároku nároku nároku nároku nároku nároku · · ·· ···· R 8 represents a group - 435 Ν— CtL— R. O II -CAr where Ar is one of the groups R // ^_ A R. - \, / - ‘V - /, i - VHCOIU lu. RY is NH and ^R and ' ^R '' ^R '' ^R '' ^R '' ^R '' ^R '' ^R '' ^R '' ^R '' ^R '' ^R '' ^R 9' ^R 10 ' ^R 25 have the meaning referred to in claim 88. 95. The compound of claim 88 wherein A-B is a group N — CK-R. J R 8 represents a group -Scrap Where Ar represents any of the groups Y represents an oxygen atom and ^R a ' ^R b' ^R c ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R 6 ' ^R 7' ^R 3 ' ^R 9' ^R 10 ' ^R 25 have the meaning given above in claim 38. 96. A compound according to claim 1, N- [4- (dibenz / b, f [1,4] oxazepin-10 (11H) -ylcarbonyl) -phenyl] (1,1'-biphenyl) -2-carboxamide. . 97. A compound according to claim 1, N- [4- (dibenz / b, f [1,4] oxazepin-10 (11H) -ylcarbonyl) -3-chlorophenyl] (1,1'-biphenyl) -2 -carboxamide. 98. The compound of claim 1, N- [5- (dibenz [B, f] [1,4] oxazepin-10 (11H) -ylcarbonyl) -2-pyridinyl] -5-fluoro-2-methylbenzamide. 99. The compound of claim 1, N- [5- (dibenz [b, f] [1,4] oxazepin-10 (11H) -ylcarbonyl) -2-pyridinyl] -2- (4-pyridinyl) benzamide. . 100. A compound according to claim 1, N- [5- (pyrrolo [2,3-a] [1,5] benzoxazepin-6 (5H) ylcarbonyl) -2-pyridinyl] (1,1'-biphenyl) - 2-carboxamide. 101. A compound according to claim 1, N- [5- (pyrido [2,3-b] 1,4-benzoxazepin-5 (R) -ylcarbonyl) -2-pyridinyl] (1,1'-biphenyl) -2-carboxamide. • 9 437 102. A compound according to claim 1, N- [4- (pyrido [2,3-b] [1,4] benzoxazepin-5 (6H) -ylcarbonyl) -3-chlorophenyl] (1,1 ' -biphenyl). -2-carboxamide. 103. A compound according to claim 1, N- [4- (6,11-dihydropyrido [2,3-b] [1,5] benzodiazepin-6 (5H) -ylcarbonyl) -phenyl] (1,1'-). biphenyl) -2-carboxamide. 104. A compound according to claim 1, N- [4- (6,11-dihydropyrido) -2,3-b] [1,5] benzodiazepin-6 (5H) -ylcarbonyl) -3-chlorophenyl] (1, 2). 1'-biphenyl) -2-carboxamide. 105. The compound of claim 1, [beta] - [4- (δ, 11-dihydropyrido [2,3-b] 1,5] -benzodiazepin-6 (5H) -ylcarbonyl) phenyl] (1,1'-). biphenyl) -2-carboxamide hydrochloride. 106. A compound according to claim 1, N- [4 - [(5,11-dihydro-10H-dibenz- [1,2,4] diazepin-10-yl) carbonyl] -3-chlorophenyl]. N- (1,1-biphenyl) -2-carboxamide. 107. A compound according to claim 1, N- [4 - [(5,11-dihydro-10H-dibenz [b, e] [1,4] diazepin-10-yl) carbonyl] phenyl] (1,1-biphenyl). ) -2-carboxamide. 108. A compound according to claim 1, N- (4 - [(5,11-dihydro-10 [beta] -dibenz) b, e [1,4] diazepin-10-yl) carbonyl] -3-methylphenyl] (1, 2, 3, 4, 3, 4, 4, 4). 1'-biphenyl) -2-carboxamide. 109. A compound according to claim 1, N- [4 - [(5,11-dihydro-10H-dibenz [b, e] [1,4] diazepin-10-yl) carbonyl] -2-methylphenyl] ( 1,1-biphenyl) -2-carboxamide. 110. A compound according to claim 1, N- [4 - [(5,11-dihydro-1H-dibenz) b, e [1,4] diazepin-10-yl) carbonyl] -2-chlorophenyl] ( 1,1'-biphenyl) -2-carboxamide. - 438 111. The tricyclic diazepine derivative according to claim 1, N- [4 - [(6,11-dihydro-5H-dibenz [b, e] azepin-5-yl) carbonyl] phenyl] (1,1-biphenyl) - 2-carboxamide. 112. A compound according to claim 1, N- [4 - [(6,11-dihydro-5H-dibenz [b, e] -azepin-5-yl) carbonyl] -3-chlorophenyl] (1,1- biphenyl) -2-carboxamide. 113. A compound according to claim 1, N- [4 - [(6,11-dihydro-5H-dibenz [b, e] azepin-5-yl) carbonyl] -3-methylphenyl] (1,1'-). biphenyl) -2-carboxamide. 114. The compound of claim 1, N- [4 - [(6,11-dihydro-5H-dibenz [b, e] -azepin-5-yl) carbonyl] -2-chlorophenyl] (1,1 '). (biphenyl) -2-carboxamide. 115. The compound according to claim 1, N- [5 - [(6,11-dihydro-5H-pyrido [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] -2-pyridinyl]. -5-fluoro-2-methylbenzamide. 116. A compound according to claim 1, N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] -3-chlorophenyl. N- (1,1-biphenyl) -2-carboxamide. 117. The compound of claim 1, N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] 1,4] benzodiazepin-5-yl) carbonyl] phenyl] (1). 1,1-biphenyl) -2-carboxamide. 118. A compound according to claim 1, N- [4 - [(6,11-dihydro-5H-pyrido [2,3-b] [1,4] benzodiazepin-5-yl) carbonyl] -3- methylphenyl / (1,1'-biphenyl) -2-carboxamide. 119. A compound according to claim 1, N- [4 - [(4,5-dihydropyrazolo [4,3-d] l] benzazepin-6 (1H) -yl) carbonyl] phenyl] (1,1-biphenyl). -2-carboxamide. • · · · · · · · · · · - 439 120. A compound according to claim 1, N- [4 - [(4,5-dihydropyrazolo [4,3-d] l] benzazepin-6 (1H) -yl) carbonyl] -3-chlorophenyl] (1). , 1'-biphenyl) -2-carboxamide. 121. A compound according to claim 1, N- [5 - [(4,5-dihydropyrazolo) -4,3-d] benzazepin-6 (1H) -yl] carbonyl] -2-pyridinyl] ( 1,1-biphenyl) -2-carboxamide. 122. The compound of claim 1, N- [5 - [(4,5-dihydropyrazolo [4,3-d] l] benzazepin-6 (1H) -yl) carbonyl] -2-pyridinyl] -5 -fluoro-2-methylbenzamide. 123. A compound according to claim 1, N- [5- (4H-thieno [3,4-b] [1,5] benzodiazepin-9 (10H) -yl) -2-pyridinyl] -5-fluoro-2. -methylbenzamide. 124. A compound according to claim 1, N- [4- (4H-thieno [3,4-b] [1,5] benzodiazepin-9 (10H) -yl) phenyl] - (1,1'-biphenyl) -2-carboxamide. 125. The compound of claim 1, N- [4- (4H-thieno [3,4-b] [1,5] benzodiazepin-9 (10H) -yl) -3-chlorophenyl] (1,1'-). biphenyl) -2-carboxamide. 126. The compound of claim 1, N- [5- (4H-thieno [3,4-b] [1,5] benzodiazepin-9 (10H) -yl) -2-pyridinyl] (1,1'-). biphenyl) -2-carboxamide. 127. The tricyclic diazepine derivative of claim 1, 5.11-dihydro-10- [4- (2-thienyl) benzoyl] -10H-dibenz (B, e / 1,4) diazepine. 128. The tricyclic diazepine derivative of claim 1, 5.11-Dihydro-10- [4- (3-thienyl) benzoyl] -10H-dibenz] b, e [1,4] diazepine. • · · · 440 129. The compound of claim 79, wherein A-B is -CH2- R. J R _g represents a group Wherein Ar is any of the groups defined in claim 79. 130. The tricyclic diazepine derivative of claim 79 wherein A-B is a group -ch._ _n iL Y is - (CH ₂ ) - and ^R a ' ^R b' ^R o ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R 6 'are as defined in claim 79. R _? R _g, R _g, R _1q, R ₂₅ 441 131. The tricyclic diazepine derivatives of claim 79, wherein A-B is a group AND -CH, -n R. □ Y represents an oxygen atom and R _a . R _b , R _c . R _v ^and 3- * 4 ' ^K 5' ^R 6 ' ^R 7' ^R 8 ' ^R 9' ^R 10 ' ^R 25 have the meaning given in claim 79. 132. The tricyclic diazepine derivatives of claim 79 wherein A-3 is a group -CK-N R. J Y is NH, and ^R a ' ^R h' ^R c ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R 6 ' ^R 7' ^R 8 ' ^R 9' ^R 10 ' ^R 25' have the meaning , recited in claim 79. 133. The compound of claim 79, wherein A-B is a group I - CH.-Ν ’ R, R 8 represents a group -CAr • · · · - 442 wherein Ar represents any of the groups R. R, Y is - (CHg) - and ^R a ' ^R b' ^R c ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R 5 ' ^R 7' ^R 8 ' ⁵ 9' ^R 10 ' ^R 25 are as defined in claim 79. 134. The tricyclic diazepine derivatives of claim 79 wherein A-3 is a group I - CH. - N R. J R 8 represents a group O II -CAr where Ar is one of the groups R. O R, 443 Y is oxygen and ^R &apos; ^R d ^R c ^'R L' ^R 2 ^'R 3' ^R 4 ^'R 5' ^R 6 ^'R 7' ^R 3 ^'R 9' ^R 10 ^'R 25 are as defined in Claim 79. 135. The compound of claim 79 wherein A-B is a group R. R 8 represents a group O II -CAr where Ar is one of the groups Y is NH and ^R a ' ^R b' ^R c ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R 6 ' ^R 7' ^R 8 ' ^R 9' ^R 10 ' ^R 25 are as defined above in claim 79. 136. The tricyclic diazepine derivatives of claim 88 wherein A-B is a group - 444 R _g represents a group _CH, -n r. O II -CAr where Ar is one of the groups R. and Y, R _a , R 2, R _c , R 1, R ₂ , R 8. ^R 4> ^R 5> ^R 5> ^R 7 ' ^R g> ^R g' ^R 10 ' R _2g are as defined in claim 88. 137. The compound of claim 88 wherein A-B is a group R. j Y is - (CH ₂ ) - and ^R a ' ^R 1' ^R c ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R 6 ' ^R 7' ^R 8 ' ^R 9' ^R 10 ' ^R 25 are as defined in claim 88. 445 • φ ·· ···· · · · · · 138. The compound of claim 88 wherein A-B is a group -CK-N R. J Y represents an oxygen atom and R _a , ^R b ' ^R c' ^R 1 '2' ^R 3 ' ^R 4' ^R 5 ' ^R 6' ^R 7 ' ^R 8' have the meaning given in claim 88. R _g, R _1q, R ₂₅ 139. The compound of claim 88, wherein A-B is - CK - R. Y is NH and ^R a ' ^R b' ^R o ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R 6 ' ^R 7' ^R 3 ' ^R 9' ^R 10 ' ^R 25 are as defined above in claim 88. 140. The compound of claim 88 wherein A-B is a group I - TA, —n ' R. J R 8 represents the group "CAr O II - 446 - Y is - (CHg) - and ^R a ' ^R b' ^R c ' ^R 1' ^R 2 ' ^R 3 * ^R 4' ^R 5 ' ^R 6' ^R 7 ' ^R 8' ^R 9 ' ^R 10' ^R 25 are as defined in claim 88. 141. The tricyclic diazepine derivatives of claim 88 wherein A-B is a group AND —CH, - iL J R 8 represents a group O II -Scrap - 447 ··· «• · · Y is NH and ^R ' ^R H + ^R c ^'R L' ^R 2 ^'R 3' ^R 4 ^'R 5' ^R 6 ^'R 7' ^R 8 ^'R 9' ^R 10 ^'R 25 are as defined in Claim 88. 142. The tricyclic diazepine derivatives of claim 88 wherein A-B is a group I, CC-N R. R 8 represents a group O II — Ar where Ar is any of the groups R, O Rt Y represents an oxygen atom and ^R a ' ^R b' ^R c ' ^R 1' ^R 2 ' ^R 3' ^R 4 ' ^R 5' ^R 5 ' ^R 7' ^R 8 ' ^R 9' ^R 10 ' ^R 25 have the meaning given above in claim 88.