FI78475B - FOERFARANDE FOER FRAMSTAELLNING AV FARMAKOLOGISKT VAERDEFULLA BENSO-HETEROCYKLISKA FOERENINGAR. - Google Patents

Description

Method for the preparation of pharmacologically valuable benzoheterocyclic compounds - Förfarande för framställning av farma kologisi värdefulla benzo-heterocykliska föreningar 78475

The invention relates to a process for the preparation of pharmacologically valuable benzoheterocyclic compounds of the formula I

O

A \ HN 0

B

Vv CH-CH-NH-R3

R1 'OH

wherein / R 5 A is a single bond, a group C or -CH 2 -CH 2 "\ r 4

R 1 is OH, O-acyl or chlorine, R 2 is hydrogen, methyl or ethyl, CH 2 - (CH 2) m 'N R 7. R 3 is -C-CH 2 - / or -C- (CH 2) n -R 9 r 6 R 8 (II) (III) m 2, 3 or 4, n 1, 2 or 3, R 4 is hydrogen, lower alkyl, 2 78475 R 5 is hydrogen, lower alkyl and in addition, if R4 is hydrogen, phenyl,

R 9, R 7 7a r 8 are independently hydrogen or methyl, R 9 is hydrogen, Ar, OAr, NH-CO-Ar Ar is - R 10 "@CB 11 R 12 R 10 * R 11 'r 12 (which may be the same or different) are hydrogen , hydroxy, methyl, methoxy, halogen, methylenedioxy, NH-R13, CONH2f R13 is hydrogen, acyl or lower alkylsulfonyl; as racemates, enantiomers and optionally as diastereomeric antipode pairs, in each case as free bases or also as acid addition salts.

In the invention, "lower alkyl" means an alkyl group having 1 to 4 carbon atoms, "halogen" fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine, "acyl" an optionally substituted aliphatic carboxylic acid having up to 6 carbon atoms, an optionally substituted group or an optionally substituted benzoyl group .

In a preferred embodiment of the invention, 3,78475 A is a single bond = CH 2, = CH (CH 3), = O (013) 2 or = CH (C 2 H 5),

R 1 is OH or O-acyl in the m- or p-position relative to the side chain, R 2 is H, CH 3 or C 2 H 5, R 3 is as defined above for groups II and III, m is 2 or 3, n is 1, 2 or 3,

R 9, R 7 * R 8 are hydrogen or methyl, R 9 is H, Ar, NH-CO-Ar,

Ar is a group of formula IV, 2-pyridyl or 4-pyridyl,

R10 is H, OH, CH3, together with the group Rn also methylenedioxy,

R 11 is H, OH, CH 3, together with the group R 10 also methylenedioxy,

R12 is H,

R 13 is acetyl or methanesulfonyl.

Particularly preferred compounds are those in which A is = C (CH3) 2 or -CH2- R1 is OH in the p- or m-position relative to the side chain, R2 is H, CH3 or C2H5, 78475 4 R3 is isopropyl, tert-butyl, cyclopentyl, 1-methyl-cyclopentyl or a group of formula III, n is 1 or 2, R7, R8 is hydrogen or methyl, R9 is phenyl, 4-hydroxyphenyl, 2-pyridyl, 4-pyridyl, 2-hydroxyphenyl,

NH-CO, NH-CO

CH3

- (Q) -oh - 0H

CH3 CH3

German application 28 33 140 describes compounds in which the group corresponding to the substituent R9 of our application is always a nitrogen-bonded heterocyclic group. The compound closest to our application is the third compound on page 31, the first compound on page 32, the fourth compound on page 43, and the second compound on page 44. However, these known compounds have not been shown to have the benefits of the compounds described in our application. Above all, the compounds according to the invention have a better resorption ratio (i.e. the ratio of the effect of oral and intravenous dosing) in addition to which the compounds have only a small heart rate-increasing effect.

German application publication 20 05 134 describes compounds in which the side chain is in a different position than in the compounds according to our application. In addition, the new compounds always have two substituents on the aromatic ring. In addition, the group -N does not correspond to the meaning of our application, nor does R 4 (Formula III) correspond to the meanings of the known compounds. The compounds described in our application differ in at least three respects from the reference publication, which therefore cannot be close to the preparation method described in our application. In addition, the publication mentions a different field of use for the compounds than in our application.

German application publication 24 29 253 describes compounds in which the side chain is in a different position than in the compounds according to our application. Apparently, this has a major effect on the pharmacological properties of the compounds, as the compounds of the references are useful in the treatment of blood pressure and circulatory disorders.

German application 26 09 645 describes compounds in which the group Q-CnH2n ~ corresponds to the group R3 in the present application. As is apparent from the formulas Ha and Hb of the reference publications, the group Q denotes a heterocycle containing a nitrogen atom. In addition, the examples also make no reference to the substitutions according to the invention.

CA £ 0.51515 (Smith Kline) describes compounds of which compound II appears to be only a modification of compound I. In Compound II, in the aromatic ring, (a) the side chain is in a different position than the compounds described in the application and (b) does not contain additional substituents such as the compounds described in our application. In addition, the publication makes no mention of the efficacy of the compounds.

CA 93, 132 488 (Merck) describes benzimidazole derivatives having no additional substituents on the benzene ring.

According to the invention, the new compounds are prepared by methods known per se.

6 73475 a) Reduction of compounds of formula V.

O

\ _A

HN

/ == (1 * 2 (V) <Zjr> R1 where A,, R2 and R1 have the same meaning as above »however, the phenolic OH groups may also be protected by a hydrogen-genolytically cleavable group.

The reduction is carried out under reaction conditions in a sufficiently stable solvent, e.g. a lower alcohol such as ethanol. Suitable reducing agents are hydrogen and hydrogenation catalysts (such as palladium, platinum, Raney nickel) or hydrides (such as sodium borohydride or diborane). By appropriate selection of the reducing agent (catalytic reduction or reduction with hydrides), the formation of the erythro or threo form is preferred. Hydrogenolytically cleavable protecting groups, e.g. benzyl or substituted benzyl, optionally present in the central amino groups or the phenolic hydroxyl group, are removed in the usual manner during or after the reduction.

The novel compounds of the formula V used as starting materials can be obtained by methods known per se, as shown in the following reaction scheme: 7 78475

0oN OH 02N OH

ÖFriedel-Crafts A --- \? 2 - * HO-X \ -C0-CH2 -►

° 2 ^ ° H H2N OH

1_ 'r2 \ _I r2

Bz-O- ^ ^ -CO-CH2 -> 32-0 - / ^ - 00- ^ C1CO-CR.R-C1 ^ I mnr \ πρη

Bz = benzyl XlCO-OPh

Ph = phenyl R 0 0 R 4 rr 1 | A "V 5 X \ HN 0 HN 0 V = <? 2> = (f2

Bz-O- / \ -C0-CH2 Bz-O-Z \ -C0-CH2 Βγ2 Br2: / / 0 0 rl !!

/ “- ^ r5 / X

HN 0 HN 0 \ r- - / R, \ ------ / R2

Bz-O- / ^ -CO-CH-Br BzO - CO-CH-Br (VI) (VII) 8 78475

The corresponding bromoketones having an (protected) OH group in the m-position relative to the side chain can be obtained as follows:

OH OH

^ -co-ch2 -i. sf ^ -co-cI2 OH Bz-0

02N OH H2N OH

-J. / “VcO-CH 2 _C S> -C0-CH 2 /

Bz-0 Bz-0 o * "" "; i

A A I

/ —A: r5 aa HN 0 HN 0 R2 ν = \ K2 <\ -CO-CH9 <\ -C0-CH ~; ·; y_y 2 3z-0 Bz-0

V 'V

f \ 4 II

™ aR5 Ao \ - / r2 \ = \ P2 AA-CoAsr <_Pv-CO-CH-Br

Bz-0 Bz- ° (VIII) (IX) 9 78475 Bromoketones of formula X obtained by this or other conventional methods 0

La / \ ® /,> = <I2 (X) <\ -CO-CH-Br X- / (X) R1 wherein A, and R2 have the same meaning as above / wherein, however, the phenolic OH groups may be hydrogenolytically protected cleavable groups such as benzyl may be reacted with amines of formula XI R 'HN-R3 (XI) wherein R1 is as defined above and R' is hydrogen or a hydrogenolytically cleavable group such as benzyl or substituted benzyl, Va to 0

V_A

™ y_ / ° i2 1 '- CH - N - Rj (Va) ^ 0 wherein A, R1, R2, R3 and R' have the same meaning as above. The reaction takes place in a suitable solvent such as acetonitrile, ethyl acetate, in the presence of an acid scavenger such as sodium carbonate or an excess of amines. The protecting groups in the reaction product can then be removed in or after the further reaction.

(b) Phenylglyoxals or hemiacetals of formula XII 10 78475

_. o HN 'o / ^ "X-CO-Q

X_ / (XII).

R 1 wherein R 1 and A have the same meaning as above and Q is

/ OH CH

x O-lower alkyl is reacted with amines of formula XIII under the conditions of reductive amination h2n-r3 (XIII), which is as defined above.

Instead of components XII and XIII, the Schiff bases of the formula XIV which may be present as intermediates can also be reduced.

Complex hydrides, preferably sodium borohydride, or hydrogen and a hydrogenation catalyst such as platinum, palladium, nickel are used as reducing agents.

u 78475 The phenolic hydroxy groups in the starting materials may be unprotected by conventional hydrogenolytically cleavable groups. These protecting groups can be removed in the usual manner during or after hydrogenolytic reduction.

The final products are obtained in which R2 is hydrogen.

The compounds of formula XII used as starting materials can be obtained from acetophenone derivatives of formula XV 0 A \ NH 0 (XV) 'COCH3 R1 wherein

R1 and A have the same meaning as above, by oxidation with selenium dioxide in aqueous dioxane. Cryoxals or hemiacetals are obtained depending on whether they are crystallized from water or lower alcohols.

The amines of formula XIII are known and can be easily obtained by conventional methods.

12,78475

The compounds obtained according to a) to b) can, if desired, be separated into enantiomers, optionally also diastereomers into antipode pairs, by conventional methods, and the bases obtained first can be converted into acid addition salts, the acid addition salts obtained first into bases or salts with other acids.

The compounds of the invention can be used as medicaments. They have e.g. broncholytic, antispasmodic and antiallergic effect and increase ciliary function and attenuate inflammatory exudative reactions. They can therefore be used in all forms of asthma and bronchitis, urticaria, conjunctivitis, hay fever and colds. They are still relaxants of the uterine muscles and are suitable for preventing labor problems. The compounds may also be used to treat cardiovascular disorders, e.g., hypertension, peripheral vascular disease, and arrhythmias. Other effects observed include inhibition of gastric secretion and an antidepressant effect in the central nervous system.

The therapeutic and prophylactic dose depend on the nature and severity of the disease and the route of administration.

For adults, the following dosages are appropriate for the indications given.

13,78475

The amounts administered as broncholytics are 0.05 to 5 mg orally, 0.01 to 1.0 mg in-halos and 0.02 to 0.5 mg subcutaneously.

For uterine use, 10-50 mg or ampoules (10 ml) containing 0.1-1 mg as an infusion solution are used orally.

Ampoules of 20 to 100 mg or i.m. for injection in an amount of 20 to 40 mg are used orally to dilate blood vessels. Antihypertensive agents are administered orally from 200 mg to 1.8 g.

The pharmaceutical preparations contain the active ingredients, pharmaceutically acceptable carriers and possibly other therapeutic ingredients.

Broncholytes can thus be combined with theophyllines, parasympatholytics (e.g. ipratropium bromide), secretolytes (e.g. bromhexine), musculotropic spasmolytics (e.g. papaverine), corticosteroids and antiallergic agents. Uterine relaxants are possible in combination with corticoids.

Capsules, tablets, solutions and suspensions are suitable for oral administration. In pulmonary administration, a dry powder with a particle diameter of 0.5-7 γ is best introduced into the bronchial region by means of propellants. Parenteral administration is best accomplished as sterile isotonic aqueous solutions. For topical use, solutions, creams, ointments, emulsions and sprays are used.

The compounds of the invention can also be used to increase the growth rate of meat-producing animals, e.g. pigs, cattle, sheep, chickens, geese. Feed utilization is greatly improved and, in addition, the quality of the meat is better and its fat content lower than if no new compounds were used.

ΐ4 78475

Furmulointiesimerkit:

tablets

Tablet composition: active ingredient according to the invention 20 mg colloidal silicic acid 10 mg milk sugar 118 mg potato starch 60 mg polyvinylpyrrolidone 6 mg

Nacellulose glycolate 4 mg magnesium stearate 2 mg 22 mg

The ampoules

Composition of the solution per ampoule: active ingredient according to the invention 10 mg sorbitol 40 mg distilled water ad 10 ml Suppositories Composition of the suppository: active ingredient according to the invention 100 mg suppository mass (cocoa butter) 1600 mg 1700 mg

Inhalation powder

Each hard gelatin capsule is filled with 0.5 mg of the active ingredient according to the invention and 19.5 mg of lactose having a particle diameter of between 0.5 and 7.

Pharmacological studies shall use standard experimental methods and experimental animals or organs. Pharmacologically, the compounds according to the invention differ in some very clear respects from 78475 commercial products of the same indication. In addition to a good duration of action, they have, for example, a particularly clear selectivity between broncholysis and an increase in heart rate. Thus, for example, the compound of Example 1 has an EDggi.v of an increase in heart rate in guinea pigs. / yg / kg / more than ten times as high as broncholysis ED ^ qI.v. / yg / kg /, which is only 0.045 yg / kg. The resorption ratio is also generally favorable. Thus, for example, the resorption coefficient Εϋ, - ^ ρ.ο of compound 7 in Table 3.

The ED50i’v · is only 1.1, so the oral effect is practically equal to the intravenous effect. LD50 values are, e.g., in mice, so much above the therapeutic dose that the therapeutic width is good.

The following examples further illustrate the invention without, however, limiting it, since the reaction conditions can be significantly changed without affecting the result.

The solvent from which the following compounds are crystallized, depending on which, still contains a certain amount of solvent bound to the crystal. The melting points given are uncorrected.

Method 1

Example 1 HO-M-CH-CH 2 N 2 O 2 NHCH (CH 3) 2 16.1 g 5'-benzyloxy-8 '- (1-oxo-2-bromobutyl) 2H-1,4-Benzooxazin-3- (4H) -one and 7.5 g of isopropylamine are stirred for four hours at 60 [deg.] C. in 100 ml of acetonitrile, acidified with concentrated hydrochloric acid and added to 100 ml of water to give 5 ml of water. 1-Benzyloxy-8 '- (1-oxo-2-isopropylamino-butyl) -2H-1,4-benz-78475 16 oxazin-3- (4H) -one hydrochloride (melting point 229-232 ° C) 6 g of this compound are debenzelated in methanol with the addition of 5'-hydroxy-8 '- (1-oxo-2-isopropylamino-butyl) -2H-1,4-benzoxazin-3- (4H) -one as a catalyst. hydrochloride dihydrate (m.p. 242-245 ° C) Hydrogenation of 3.3 g of this compound in methanol using platinum as a catalyst gives 3 g of erythro-5'-hydroxy-8 '- (1-hydroxy-2-isopropylamino-butyl) -2H -1,4-benzoxazin-3- (4H) -one hydrochloride hydrate (yield 90% of theory), m.p. 208-210 ° C.

Example 1a Method 30 -CH-CH-NH-CH (CH 2) 2 x (threo) 32.4 g of 5'-benzyloxy-81- (1-oxo-2-bromobutyl) -2H-1,4 -benzoxazin-3- (4H) -one and 72 g of benzylisopropylamine are stirred for 15 hours at 100 ° C. After addition of water, the precipitated oil is taken up in ether and diluted with petroleum ether; 5'-Benzyloxy-8 '- (1-oxo-2-benzylisopropylamino-butyl) -2H-1,4-benzoxazin-3- (4H) -one crystallizes.

g of sodium borohydride are added to 11.6 g of this compound in a mixture of 60 ml of ethanol and 60 ml of acetonitrile and stirred for three hours. Then 250 ml of ice water and 100 ml of ethyl acetate are added. Sodium borohydride is decomposed with concentrated acetic acid with stirring and made alkaline with concentrated ammonia solution, the ethyl acetate phase is separated, dried and evaporated in vacuo, the oily residue is dissolved in ether, cooled and the precipitated threo-5'-benzyloxy-8 '- (1-hydroxy-2-hydroxy-2-hydroxy-2-hydroxy-2-hydroxy-2 ) -2H-1,4-benzoxazin-3- (4H) -one (mp 89-92 ° C) is removed by suction.

17,78475 4.8 g of this compound are hydrogenated in 100 ml of methanol using palladium on carbon as a catalyst. When the hydrogen consumption has ceased, the catalyst is filtered off with suction, the mother liquor is evaporated off on a rotary evaporator, the oily residue is dissolved in acetone / ethanol and acidified with a calculated amount of hydrochloric acid. The solution is diluted with ether and the precipitated threo-5'-hydroxy-81- (1-hydroxy-2-isopropylamino-butyl) -2H-1,4-benzoxazin-3- (4H) -one hydrochloride (yield 74% of theory). ) is separated by suction; after reprecipitation from methanol / ether, the melting point is 202-205 ° C.

Example 2 10 H, \ = / CH3 H0_ \ J2-ch-cH2 -NH-C-CH, X HCl OH CH2 10 g 5'-benzyloxy-8 '- (1-oxo-2-bromoethyl) -2H-1,4-benzoxazin-3- (4H) -one and 8.75 g of benzyl tert-butylamine are refluxed for 3 hours in 100 ml of acetonitrile. After cooling, the precipitated crystals are filtered off with suction and washed with 200 ml of warm water. The crystals are acidified in acetonitrile with ethereal hydrochloric acid; after dilution with ethyl acetate 5'-benzyloxy-81- (1-oxo-2-benzyl-tert-butylamino-ethyl) -2H-1,4-bentoxazin-3- (4H) -one hydrochloride (m.p. 185-189 °) C) precipitates.

7 g of this compound are debenzylated at 5 bar and at 50 ° C in 100 ml of methanol 5'-hydroxy-8 '(1-oxo-2-tert-butylaminoethyl) -2H-1,4-benzoxazin-3 - (4H) -one hydrochloride (melting point 237-240 ° C) using palladium on carbon as catalyst.

Catalytic hydrogenation of 2.2 g of this compound with methanol in platinum gives 1.6 g of 5'-hydroxy-8 '- (1-hydroxy-2-tert-butylaminoethyl) -2H-1,4-benzoxazine-3- (4H) -one hydrochloride (yield 72.5% of theory), m.p. 185-187 ° C.

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Method 2 Example 3

O

HN ~ \) CH

X HCl OH CH 3 5 g 5'-benzyloxy-8 '- (1-oxo-2-hydroxy-2-ethoxy-ethyl) -2H-1,4-benzoxazin-3- (4H) -one, 2.2 g 1,1-Dimethyl-3-phenylpropylamine and 50 ml of alcohol are heated for 3 hours at 50-60 ° C. After cooling the reaction mixture, the precipitated Schiff's base (melting point 138-140 ° C) is separated by suction.

1 g of sodium borohydride is added to 4.5 g of this compound in 100 ml of alcohol and stirred for 2 hours at room temperature. 100 [mu] l of water are added and then the 5'-benzyloxy-8 '- [1-hydroxy-2- (4-phenyl-2-methyl-butylamino) -ethyl] -2H-1,4-benzoxazin-3- (4H) -one (melting point 162-164 ° C) and hydrochloride are prepared with ethereal hydrochloric acid (melting point 205-207 ° C).

Catalytic hydrogenation of this compound with a palladium-carbon catalyst in 50 ml of methanol under normal conditions gives 2.7 g of 51-hydroxy-81- [1-hydroxy-2- (4-phenyl-2-methyl-butylamino) -ethyl / -2H-1,4-benzoxazin-3- (4H) -one hydrochloride (melting point 159-161 ° C), yield 90% of theory.

Example 4 H λΖ / CH3 ^ 5 ^ -ch-ch2-nh-c-ch3 x HCl CL iH3 24 7 8 4 75 5.8 g of 61-chloro-8 '- (1-oxo-2-hydroxy-2- ethoxy-ethyl) -2H-1,4-benzoxazin-3- (4H) -one, 1.5 g of tert-butylamine, 60 ml of dioxane and 60 ml of alcohol are heated at 50 ° C for 2 hours.

It is then cooled and 2 g of sodium borohydride are added to the solution at 10-20 ° C. The solution is stirred for one hour at room temperature, then poured into 500 ml of ice water and covered with 150 ml of ethyl acetate. Sodium borohydride is decomposed with concentrated acetic acid with stirring and then made alkaline with aqueous ammonia. The ethyl acetate-thiphasic phase is separated off, dried over sodium sulphate and evaporated in vacuo, the oily residue is dissolved in 15 ml of alcohol, acidified with ethereal hydrochloric acid and the precipitated 6'-chloro-8 * - (1-hydroxy-2- (tert-butylamino) ethyl) / -2H-1,4-benzoxazin-3- (4H) -one hydrochloride (yield 38% of theory) is filtered off with suction. Resuspend twice with methanolic activated carbon, after which the compound has a melting point above 300 ° C (base melting point 173-177 ° C).

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0 -P

P VO

C (0 <N

(0 Ή (0 ·· co <#> co

X

m o m XIX O-o-o i

X

z esi

X

o (0 i

> XX

1 -ςώ * o * * x (0 o Z r- 28 78475 η τι · ιλ oo

1 u ro (N (Ti O

UI O r- «- (N

•B

e (u i i i i <d -p rH UI O O (N m 3 -H ro (N «Ti o

CO Qj · - i— CN

Iti id ή X o a 3

O U) K

• m KK ro - «J O O o O UI i— (ro OO K i-i

CU U) UK U <N ro U

0.Ö KU KK K K

id id u

XX X X

«U o 0)

O -P

-p (N oo o LO

C (d Tr tj rt ro id ή "id ··

U) dP

(Jj ς ςο ψ sT1> O «o M 5 <o« m 5-5 5-ώ-5 i ° 9 g1 i V · <-> -o— δ-ό-5 xx J. i * T! I X 5 —f11 «vj <do V 5 x

> '3- XX V V

(0 5 - 0 0-0 X x XX

! .JpO Λ »J & £ $ x X fi O ° x o: <ö = x

K

1 · - o 1- 0 oo σν ^ 2 29 78475

Method 3 Example 5

O

Q ~ CH-CH2-NHC2H5 X HCl OH ^ H

4.3 g of 51-benzyloxy-81- (1-hydroxy-2-benzylethylaminoethyl) -2H-1,4-benzooxazin-3- (4H) -one hydrochloride (melting point 232-235 ° C) are hydrogenated in 125 ml methanol by adding 0.5 g of 5% palladium on carbon. After the calculated amount of hydrogen has elapsed, the catalyst is filtered off and the solution is distilled under reduced pressure. Trituration of the residue with acetonitrile gives 2.5 g of 5'-hydroxy-81- (1-hydroxy-2-ethylamino-ethyl) -2H-1,4-benzoxazin-3- (4H) -one hydrochloride (yield 86.7 % of theory) with a melting point of 240-242 ° C after reprecipitation from ethanol / ether.

Example 6 0 H0 ° / 0 HO-Q> -CH-CH2-NH-C-CH2-CH2-NHC

OH CH 3 3 N) H

6.3 g of 4'-benzyloxy-7 '- [1-hydroxy-2- (4-picolinic acid amido-2-methyl-2-butylamino) ethyl] -2-benzoxazolinone (m.p. 130-133 ° C) are hydrogenated in 125 ml. in methanol by adding 1 g of 5% palladium on carbon. After cessation of hydrogen consumption, the catalyst 30 78475 is filtered off and the clear solution is evaporated off under reduced pressure on a rotary evaporator. The oily residue is dissolved in 10 ml of alcohol and 0.58 g of formic acid is added to the solution. Precipitated 4'-hydroxy-71- [1-hydroxy-2- (4-picolinic acid amido-2-methyl-2-butylamino) ethyl] -2-benzoxazolinone formate (yield 78.5% of theory, melting point 166-168UC ) is separated by suction after 5 hours.

3i 78475 οο Γ ~ ro

ICJO -rf <N

1/10! N <N * “e qj i 1 1 3 -P _

r-H (Λ LO VO O

3 -rH O M "^ 03 (¾> M fN * ~

>; rH -H Ή Λ H

CO O Ή O rH O -H

O 3 pp. 0 Λ0 Λ0

• o tn 0 «C CU G S * S

«J 3 3 3 3 3 * · 3 X -P X -P ^ +!

OtO 3d) 3 Φ 3 Φ

Cu w ή ^ CU G O'- O'- O'- 3 3 3 3 3 Κ ^ κί W X Φ X 3Χ Μ

O

Φ, ρ tn o C 3 00 i "^ (tf * rj fl5 ·· en c *> £ ____________________

•B

•B

4J

•B

0 ΕΛ 1 o

> 1 CM

01 g. XM «f T ro O ro X 1 P xix ro o ro ^ 3 o - o - ox 1 x ^„ Φ 1 0-0-0 ω u ro 3 a- 1 x 1 x -H ± x 0-0- 0 3 1 Z 'X CM I ^

3 X CSJ

6 o X '1 I O ^ C ro x x 1 ^ Φ 3 XO-O XX 0 -H> Oi 0-0' _

-X 3 ro _ I I

]! · 4ώ. _ςώ.

Φ H M X

H 3 e H 05 Φ ro O _______________ 3 Λ5 ---- -P .X P 3

Φ rH

C 3 O - o »

<H Z

78475 32 π σι σ

I U 03 CM O

wo »- SN CN

-B

E ft) I I I

(0 + J

I-I (/ 1 03 VO 30

3 -H 00 fj O

(Λ ft Γ- <N (N

0 Λ m m a Λί Ή (d CO .C O 0

0 3 W Oj C

I (Λ · Η Ή Ci C

id w id ro *> (0 o: ft) Λ Λ Ο w (0> rd rd C W M i — f r-1

CC 3 <- O O

Id (0 3 3 3 k λ: ε x w w c

O

tl) 0-3 tn -Po oo C fO r »oo oo rd -H r- fd ·· m <#>

X

o Φ m IL, x x -r # =? T = = ^ z == X 1 1 G ^ ^ 1 = = 5 O -o 1 1

> I XX XX

(0 I (_) - O 0-0 1 -Co «-φό · ^

* x X

id «0 -r tn to 53 33 78475 mo oo mi U r- 'vn r- Γ' WO T- T- T- £ 03 II 1 1 <0 -P 5 H ID -¾1 tn un O: <u 3 H r- tn f— r- £ οι a «- <- 3 o> (0 03 ', ¾ i — I · Η CO O 0 ·· -Ι li 0 3 aa oi o • n oi Qj 0-4 03 0> (0 03> £ - (0 Λ X! 3

O 01 (13 (0 no ΊΊ O

Q, 03 -H> —I - tx tt c o o <- ™ £ (0 (0 3 3 ^ 2 K x 03 03 X * - X3 p o 03

O -P

o tn o tn G c i "cr \ ^ ftj · Η φ ** U) cfto

0 Q O

CM 00 CM

n: 31 x 0 ° 1 1 i

CM CM

X ^ X

m co co cnocn n cj o-> -c i □: I I x x I x <_> - c_> - o to - co - <o <o - co - to 1 4- 'x 3E x z z z

t 1 I

CM ^ CM

3 x z e:> o 0 «o

nj I I I

n3 xx xx rX CO - O Y "O <0-0 |“ ίφ «ςφ - ^ Φ x s 0 r- oo σ '2 34 78475 i« o rid · η 1 U ί ·> id

aj O »-: <d A

H P

e o) i <u

id -P -PO

rH to ro: id in 3 -H a oi ai a. Φ T- <d id Λί Ή

CO O OI

os a cu o

• Γ-Ν tn Qj CL -P H

id 4 J) rl

- Id JC -C w -H

O <Λ (d (0 id -rl

Oj C / l rH I — IM

CU C O O - -P

Id ro 3 3 -H

3 ΛΙ w ω X C

M

O

0)

0 -P

-PO x> C <d r- id -h id · ai &> 0

CM

x 0 ro

I X

cm ro o ro

X X I X

ro O ro o-O-O

Xl X l

0-0-0 X

1 z

X I

Z CM

_ <1 X

§ CM O

M X '

2 ° XX

1 f- · _c & '.

x

O

- 55 o t— 35 78 475 o <n I u m oo vo w o <n «-» -

•B

E O) I I 1

rO -P

—I to cm oo σ · '3 · Η in r— m (Λ Dj in * “

(0 (0 M H

C O _ _

0 3 O O

• nm <N S1 e e e as ^ nj m m O tn O O <n m Οι to co cn \ * n. C m n »- η ι- ίί c a ac y

E Ai CJ U X EX

«U o 0) O -P <- <-„

4J <n Γ '<N

C nJ (0 · Η (0 W <#>.?. = 0

-jO "3 5 aT? sT

3? ° isj O - 0—0 5 ”V 5" - δ χ "έ S ° -v- 5-4- ° i

<e z 5 JN

(0 I z K

a: nJ ·, 0 s V S Ϊ *

C EE I O-O

0) 0—0 5‐0 l s jJO- »Λ0 __ g O m m 5S <- *” 36 78475 I υ co o

B

e o)

(0 -P

H CO 3 · Η CO O.

(0 rd »H M O (5 3 O CO -n (CJ O tn Dj«

Dj D (0 flJ

X M _______-__

U

O

(1)

0 -P -P

C (Ö <TJ -h cO ·· en (#> ___-____— κ \ _ a JT * O 33

O ™ V

CO 0 = 9 ^ A Λ λ

U kj V

Y *> 5 V 'f ™ aT1 sa * ^ ä s A S S ms

Ci> 2 S I cc i

33 I OJ ώ Tm K

N S O o 0—0> u ~ · jjj aa a cc 3 p V- ° V- ° 1 / ° v \ ΛΛ / ° γ \ <u; 3 <Y \ J γΛ / γΛ / «Λ o o S 38 38 O ld to f" 2 37 78475 I υ

05 O

e φ rt -P rH 05 3 CO Oj rt

rt i-H

M O

a - 3 o w • n · * rt O 05 a 05 O. 3 rt rt DC Λί _ 14

O

05

0 + J + J

C rt rt ή rt · * CO (#> 5 «ΙΛ 1 a s Q v

^ V ^ XaT «'S

I C \ l ^ Jm tt * π υ ϋ- *?

V M S

> v- ° I ΛΛ a 33 PS, <f- ° K o * / V \> r ^ o = o rt

rt. £ »I

1 ° '° \ o) a o o λ: 2 ro po rt * aa 01 0 oo o> 2 <- <“38 78475

The following are intermediates of formula V which can be obtained according to the scheme above.

39 78475

U

0 0) 4-> tn

• H CN

Qj ^ CM 'T

03 CN CN ΙΛ

• rt CN (N

g i § I '

rH O

J3 rf 00 O

cn cn T- * o

CN CN

CÖ (0 O

M r-t <N

a 0 ®

0 0 CN

• O 03 X Η Ή «. (0 υ υ

o 03 rH X X

a 03 u

Q * G X

ta ta

X M

Oi Oi ro \ ro

X X

O o ^ v-p O · to x a x s a f

af f sf! a ** V

CNJS CM X «VÄ B

o_cj> 0-0 0-0-g cjfasO c ^ -o γ «ο

/ ° VS / S / S

fö / 30 = VA / ° \ Λ / AAA2

S i S i S

§ s 40 7 8 4 7 5

U

O

<υ + J (N ΓΊ tn rs

• H (N (N

04 tn i i

B

E o oo n3 «-

H CN (N

O

swim

iti (ti O

X r-i (N

a o x

oo <N

ri tn x -h - (0 u 0 w r-l ® α tn u

04 C X

(ti (ti X X

n KV E g E O w

O s— 'K

I 9 A O

cvi _ 1 El

EXE OJ E E

o_o_S υ_υ_§

Cjfc = o c ^ = o Λγ \ / ° γ \ 1 ^ A ^ s s 4i 78475

U

O

Q) r- Γ "4J \ o

CO r- CM

•B

cm I I

in • H co ro g m 1¾ 1— m

F-I

3 in (0 (0 J4 H C 0 O 3 • n in r— \ «. Cu o 0 co rH ac 04 w u 04 c s

<0 CO

e λ;

CM

CM

EC

m o * "S '

o K

w o o · m2 _ »

S I K 'I

cm® a a u_o 0-0 (jsO Cjpso

/ γ \ f ° yS

1 ~ s.AJ ° = vA ^ § § 42 78475 o o a) oo 4-> m in in

•B

Λ I

in H rr g un o id cm m i — I ΓΊ 3 tn m m Ä h c o O 3 • n in - id

O in i — i rH

0j tn u U

a e k ® cd id a ΠΛ C \ ύ x i mz <m x as i υ_υ cvi a; T o — u

0 = 0 I

/ γ \ / νζ

* d I

s ä-V -AAy o x * as. o as

Claims (4)

43 78475 A process for the preparation of pharmacologically valuable benzo-heterocyclic compounds of the formula I is 0} ~ \ HN 0) = {? 2 \ Y, // CH-CH-NH-R, ^ / LJ / 3 wherein / Rs A is simple a bond, a group C or -CH2-CH2- ^ R4 R1 is OH, O-acyl or chlorine, R2 is hydrogen, methyl or ethyl, CH2 "(CH2> m N R7 R3 is -C-CH2- ^ or -C- (CH2) n-R9 R6 r8 (li) (III) m 2, 3 or 4, n 1, 2 or 3, R4 is hydrogen, lower alkyl, R5 is hydrogen, lower alkyl and in addition, if R4 is hydrogen, phenyl, Rg , R 7 and R 8 are independently hydrogen or methyl, R 9 is hydrogen, Ar, OAr, NH-CO-Ar 44 78 475 "is ~ EglQ) '- £ Q) Wi R 10 -11 (IV) R 12 R 10, R 11, R R 2 (which may be the same or different) are hydrogen, hydroxy, methyl, methoxy, halogen, methylenedioxy, NH-R 13, CONH 2, R 13 is hydrogen, acyl or lower alkylsulfonyl; as racemates, enantiomers and optionally diastereomeric antipode pairs, in each case as free bases or also as acid addition salts, characterized in that a) the compound of the formula V is reduced with hydrogen and a hydrogenation catalyst or hydride in which R 1 to R 0 have the same meaning as above, in a solvent sufficiently stable under the reaction conditions, in which case the phenolic OH groups may also be protected by hydrogenolytically cleavable protecting groups, and optionally thereafter cleaving the remaining protecting groups, or that b) phenylglyoxal or hemiacetal of formula XII 0 h \ HN 0 y = y (vh), R 178475 wherein R 1 and A are as defined above, however, the phenolic OH groups may be protected by hydrogenolytically cleavable protecting groups and Q is -CHO or -CH (OH) -O-lower alkyl, is reacted with a compound of formula VIII with the amine H2N-R3 (VIII), wherein R3 is as defined above, wherein the OH groups which may be present may be protected by hydrogenolytically cleavable protecting groups, under reductive amination conditions using a complex hydride or hydrogen and a hydrogenation catalyst as a reducing agent and optionally after cleavage of the remaining protecting groups, or if desired the compounds obtained according to a) to b) are separated by conventional means, optionally also as diastereomeric antipode pairs, the bases obtained first are converted into acid addition salts, the acid addition salts obtained first into bases or salts with other acids. Compounds of formula V used as starting material 0 JL A H N V0 (V), M, Jh-NH-R3 XJ-I H wherein A, R1, R2 and R3 have the same meaning as above. 78475 A process for the preparation of pharmacologically active benzo-heterocyclic derivatives with the formula I 0 HN 0 \ - / (I) / V \\ ^ ΛΓ “CH-CH-NH-R3 s * - 'OH där ^ R5 A is not published The group * C or -CH2-CH2- Xr4 R1 is OH, O-acyl or chloro, R2 is a derivative, methyl or ethyl, CH2- <CH2> „r> v R7 R3 is -C-CH2- 'or -C- (CH2) n ** R9 r6 r8 (II) (III) m2, 3 or 4, n 1, 2 or 3, R4 is a residue, alkyl of R5, alkyl of R5, alkyl of och dessutom, savida R4 is a substance, phenyl , R6 * r7 and Rg are listed as varandra or methyl, R9, Ar, OAr, NH-CO-Ar 47 78475 "" -Ä · -® N or R10 R12 RIO, Rh, R12 oler olika), aryl, hydroxy, methyl, methoxy, halogen, methylenedioxy, NH-R13, CONH2, R13 is aryl, acyl ellgre alkylsulfonyl; in the form of a racemic, enantiomeric and optionally diastereomeric antipod, i respectively fall i in the form of a fracher base or a single addition, in which case a third is formed, (a) in the case of the lower form V 0, h \) ”(_ r> A- R N - '0 to 1 Ά, R 1, R 2 and R 3 are the same as in the case of reductions of the hydrogen and hydrogenation catalysts or hydrides and under the reaction conditions to give stable coloring matters of the phenolic OH group on the sphere of the hydrogen backbone of the hydrogen ring. after this event, in particular, there is a specific group of compounds, or in the case of (b) phenylglyoxal or a haloacetal with the formula XII 0 h \ HN 0 y = / (vh),, A> C ° 'Q Ri