DD149066A5 - Benzazepine DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of benzazepine derivatives for use as medicaments. The aim is the preparation of benzazepine derivatives with improved pharmacological, in particular sedative and anxiolytic activity. According to the invention, pyrimido-2-benzazepines of the general formula I are prepared in which A is one of the groups a to d. The substituents have the meaning given in claim 1.

Description

The invention relates to a process for the preparation of novel benzazepine derivatives. , '.

The compounds according to the invention have valuable pharmacological properties, in particular sedative and anxiolytic activity. They are used as ^Medicinal Products "

Characteristic of the known technical solutions

Various pharmacologically useful benzazepines have become known from US Pat. Nos. 4,028,381, 4,022,800 and 4,022,801.

Object of the invention

The aim of the invention is to provide a simple and economical process for the preparation of new benzazepine derivatives. with improved pharmacological activity.

Explanation of the essence of the invention

The invention is based on the object, new benzazepine derivatives with improved pharmacological activity,

21 * 7.1980

AP C 07 D / 218 921

56 971/11

especially sedative and anxiolytic activity and methods for their production.

According to the invention pyrimido-2-benzazepines of the general formula

E ¹

manufactured,

wherein A a of the groups I y γ- C Λ C Ca) Γ cb)

and

cc)

lower

R is hydrogen, chlorine, bromine, lower alkyl, the group

NR R ⁵ , the group -CH ₀ -CO-R ⁷ , the group

AQ -NH (CH ₀₎ NR Ή ', hydroxy, lower alkoxy, mercapto or lower alkylmercapto, R is hydrogen, amino or di (lower) alkylamino, R ^ is hydrogen, lower acyloxy or hydroxy, X is hydrogen, halogen, trifluoromethyl, Ethyl, a-hydroxyethyl or acetyl, Y is hydrogen or halogen, R and R are each hydrogen or lower alkyl or, together with the nitrogen atom, a 5- to 7-membered heterocycle which is an oxygen or sulfur

atom or the group ^ may contain N-lower alkyl, R

Hydrogen, lower alkoxy or NR R ⁹ , R and R ⁹ each

Is hydrogen or lower alkyl, η is 0 or 1 and m is 1 to 7, with the proviso that

1 2

(i) at least one of R and R is hydrogen;

(ii) when R is lower acyloxy or hydroxy, A is (a), X is hydrogen, halogen, trifluoromethyl, ethyl or acetyl and when R is the group -NH (CH ₂ ) _m NR R ⁹ , R and R ^{9 are} each lower

Alkyl;

(p

^{9 is} R ⁸ and R ^{9 is} alkyl; and

(iii) if A group (d) and R are the group

NR ⁸ R ⁹ , R ⁸ and R ^{9 are} lower

(iv) when η 1, R is hydrogen, lower alkyl, lower alkoxy, chloro, bromo or the group -CHp-CO-R '(wherein R ^{7 has the} above meaning) and A is group (a) or (b);

and pharmaceutically acceptable acid addition salts thereof. These compounds show pharmacological activity as anxiolytics and sedatives.

In the present specification, the term "lower alkyl" refers to straight-chain or branched carbons of hydrogen groups having 1-7, preferably 1-4, carbon atoms, such as methyl, ethyl, propyl, isopropyl, and the like.

21 δ 92 1 "3- AP C .07 D / 218 921

56 971/11

Unless otherwise specified, "the term" halogen "refers to the four forms fluorine, chlorine, iodine and bromine.

The terms "lower alkoxy" and "lower alkylmercapto" refer to radicals of the formula -O-lower alkyl or -S-lower alkyl, where "lower alkyl" is to be understood as defined above.

If the ^A usdruck "Ifucleophile of heteroatom or carbon-type" is used, so that agents are meant, as described in Belgian Pat. No. 833,249, whose content is to be regarded as incorporated herein.

The term "pharmaceutically acceptable salts" includes salts with both inorganic and organic pharmaceutically acceptable strong acids such as sulfuric acid, hydrochloric acid,

Nitric acid, methanesulfonic acid and p-toluenesulfonic acid. Such salts can be readily prepared by one skilled in the art, when envisioning the art and the nature of the compound to be salted.

Among the compounds of formula I above, preferred are those wherein A ^G roup (a) and η 0 mean. Particularly preferred are those compounds of formula I wherein

A group (a), η 0 and

οι ι

R and Ir are each hydrogen and R is hydrogen, lower alkyl, the group ITR R (in which R and R are each hydrogen or lower alkyl), hydroxy, chlorine, bromine, the group -UH- (CH ₂ ) _m LIR ⁸ R ⁹ (in which R ⁸ and R ^{9 are} each lower alkyl) or the group -CH ₂ -CO-R ⁷ (in which R ^{7 has the} above meaning), with particular importance being given to hydrogen of R, amino and lower alkyl being particularly preferred;

or

2 3 1

R is hydrogen, R is hydroxy and R is hydrogen,

1} 5 ή lower alkyl or the group NR R (wherein R and R are each hydrogen or lower alkyl);

c or

° ι ο 2

R and R are each hydrogen and R is amino or

Di (lower) alkylaraino, with dimethylamine being the preferred di (lower) alkylamino group.

Furthermore, among the compounds of the formula I, preference is given to those in which X is halogen, chlorine being particularly preferred, and / or Y being hydrogen, chlorine or fluorine.

 , 5 A particularly preferred compound in the context of the present invention is the 9-chloro-7- (2-chlorophenyl) -

Further examples of preferred compounds in the context of the present invention are

-9-chloro-7 - (? - fluorophenyl) -5H-pyrimido [5, ⁱ Jd] [2] benzazepine;

-9-chloro ~ 7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5, M-d] [2] benzazepine;

-9-chloro-7- (2-fluorophenyl) -N, N-dimethyl-5H-pyrimido [5,1-d] [2] benzazepine-4-amine;

-9-chloro-7- (2-; fluorophenyl) -5H-pyrimido [5,4-d] [2] -benzazepine-2-ol; and

*. '-9-Chloro-N, N-dimethyl-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine-2-amine. "

The compounds of the formula I and pharmaceutically acceptable acid addition salts thereof can be prepared according to the invention by reacting 35

a) a compound of the general formula

r: n α ri r. r \. fs \ ir \

218

II

wherein X and Y have the above meaning and R

Hydrogen, lower alkyl or NRΠ, where R

ο -

and R have the above meaning,

cyclized or -b) a compound of the general formula

wherein X, Y and R have the above meaning, dehydrated or

30 c) a compound of the general formula

-6 ^ 0.1980 * 84 0 29 G

HR ²¹

IV

wherein X and Y have the above meaning and ρ 0 or

21

1 and R are di (lower) alkylamino,

reacted with cyanamide or

15 d) 'a compound of the above general formula IV with a compound of the general formula

NH

NH,

Wherein R is hydrogen, mercapto, lower

Qq Q

Alkylmercapto, lower alkyl or NR R, wherein R

q is 25 and R has the meaning given above,

translates or

e) a compound of the general formula

-6.FEß.1980 * S4O29O

218 92t

Ia

1 2 in which X, Y, R and R have the above meaning,

reduced or

f) a compound of the general formula

ib

1 2 in which X, Y, R and R have the above meaning,

lower alkylated or

g) a compound of the general formula

ic

in which X, Y and R have the above meaning and R is hydrogen, lower alkyl, hydroxy, lower alkoxy,

4151/41 NR R (wherein R and R are each hydrogen or

lower alkyl or, together with the nitrogen atom, a 5- to 7-membered heterocycle which may contain an oxygen atom), chlorine,

7 bromine or the group -CHp-CO-R '(where R is the above

Meaning, with the proviso that at least one of R and R must be hydrogen, oxidized or

h) a compound of the general formula

id

(OIL

wherein X, Y and ρ have the above meaning and R is mercapto or hydroxy, lower alkylated or

r Γ rn ι Γι π η

r i \

218 921

i) a compound of the general formula

Ie

wherein X, Y and ρ have the above meaning, converted into the corresponding 2-hydroxy compound or

k) a compound of the general formula

HO

-N

If

wherein X and Y have the above meaning, converted into a corresponding 2-chloro or 2-bromo compound or

1) a compound of the general formula

"C cm 1 η : η .. c r, (\ ο α r.

18 9

1 S in which X, Y and ρ have the above meaning and R

Chlorine or bromine means

with hydrogen sulfide, with a lower alkyl mercaptan, with a lower alkanol, with a compound of the formula HNR R ₁ in which R and R have the above meaning, with

a compound of the formula H ₉ N- (CH ₉ ) NR R, wherein R, ο c d. m

R and m have the above meaning, or with the carbanion of a compound of formula

/

OR

71

CH ₂ XOR ⁷ '

or

COR ⁷¹ CH ₂ COR

71 21

wherein R is lower alkoxy and R above

Has meaning, implements or

m) a compound of the general formula

rrr ρ, ι η λ η r r rcii ^v e r ^v

ί 8

71 in which R, X, Y and p have the above meaning,

converted into the corresponding free acid or a corresponding amide, lower alkylamide or di-lower alkylamide or

n) a compound of the general formula

ii

wherein Y and R ⁴ * have the above meaning, R is hydrogen, chlorine, bromine, lower alkyl, the group

h c

NR R ^J , the group -CH-CO-R, the group -NH (CH ₂ ) _m NR ^Ö1 R ⁹¹ , hydroxy, lower alkoxy, mercapto or lower alkylmercapto, X ^{1 is} hydrogen, halogen,

81 Q1 trifluoromethyl, ethyl or acetyl and R and R ^

i | C

each lower alkyl and R, R and R above

Possession of property, with the proviso that at least

16 is one of R and R is hydrogen,

with a Niederacylierungsmittel brings to reaction or

o) a compound of the general formula

Ik

In which X ', Y, R and R have the above meaning 31

and "R Acyloxy means, with the proviso,

1 fi that at least one of R and R is hydrogen

is, hydrolyzed or

p) a compound of the general formula

wherein X, Y and R have the above meaning, R is hydrogen, lower alkyl, the group NR R

1

y, pp

Group -CH ₂ -CO-R ⁷ , the group NH- (CH ₂ ) _m NR ⁸ R ⁹ , hydroxy, lower alkoxy, mercapto or lower alkylmercapto means and R \ R ^, R

and

have the above meaning, with the proviso that

At least one of R 'and R is hydrogen,

deoxygenated or

218 921

q) from a compound of the general formula

III ¹

2 ^ "

wherein X, Y and R have the above meaning and R

Hydrogen, lower alkyl, lower alkoxy, chloro, bromo or the group -CH ₂ -CO-R ⁷ (wherein R ^{7 is the} above

Meaning) and Z is hydrogen or an easily cleavable acyl group, with the proviso

1 ß O

that at least one of R and R is hydrogen, the elements of H-Z removed or

r) converting a compound of the formula I into a pharmaceutically acceptable acid addition salt.

It should be understood and understood by those skilled in the art that when the compound to be subjected to any of the above-mentioned reactions contains, in addition to the group (s) involved in the reaction, groups which may be vulnerable under the conditions of such a reaction, either it is necessary to use a method for carrying out such a reaction which does not attack such a vulnerable group (if such a method is suitable) or such a vulnerable group is protected before the reaction is carried out and after which the protective group must be removed again.

The above process variants a) and b) and the preparation of the starting materials required for this purpose are described by way of example by the following reaction procedure:

Scheme I illustrates where X, Y and R are as above

have:

218 921

Reaction scheme I

-π γγπ iGP.ru ^ r, η <) Q γ »·

The compounds VI, VII and VIII belong to known classes of substances. A method for their preparation is explained for the sake of completeness.

5 VI> V II

The well-known compound of formula VI is reacted with copper (I) cyanide after it has previously been sequentially treated with sulfuric acid, sodium nitrite and, optionally, sodium tetrafluoroborate. Subsequently, the mixture is treated with an alkali metal hydroxide, e.g. Sodium hydroxide or potassium hydroxide, hydrolyzed at reflux temperature.

15 VII-- »V III

The compound of formula VIII forms in the reaction of the carboxylic acid of formula VII with methanol in the presence of an acidic catalyst such as sulfuric acid at about the reflux temperature of methanol for about 3-18 hours.

VIII ^ ix

The compound of formula VIII is then treated with 1-chloro-2,3-epoxypropane or other suitable epoxy-type ketalizing reagents such as ethylene oxide and 1,2-epoxypropane in the presence of a Lewis acid such as aluminum chloride, boron trifluoride or preferably tin tetrachloride , in an inert organic solvent such as toluene, carbon tetrachloride or benzene. The reaction temperature is conveniently between about 2O ⁰ C and 11O ⁰ C, preferably at about 25 ⁰ C.

35 ix> χ

This is followed by treating the compound of formula IX

with acetonitrile (CH-CN) in the presence of an alkali metal azide, such as sodium amide or · potassium amide / in liquid ammonia in the presence of an inert organic solvent, such as diethyl ether, tetrahydrofuran or dioxane. The reaction temperature may be between about the reflux temperature of liquid ammonia and room temperature.

XI

The compound of formula X is then reacted with a dialkoxyacetal of dimethylformamide, such as dimethylformamide dimethylacetal. Suitable reaction temperatures are between about 25 ⁰ C and 120 ⁰ C, with the reflux temperature of the dimethyl acetal preferred

15 is.

XI ± XI I

The conversion of the compounds of the formula XI into the compounds of the formula I comprises 2 stages, namely reaction with a suitable acid addition salt of an amidine or guanidine of the formula

NH 25 ^ ₁₁ I / _Ya

NH ₂

11 "

³⁰ in which R has the above meaning,

and acid hydrolysis of the ketal function. When X and Y are both hydrogen, the acidic hydrolysis of the ketal function preferably occurs before the reaction with the amidine or guanidine salt; if, on the other hand, X and / or Y are different from hydrogen, the acid hydrolysis of the ketal function preferably takes place after the reaction with the amidine or guanidine salt. Intermediates must be from the

Removed reaction mixture 'before continuing to work.

The reaction with a suitable acid addition salt of an amidine or guanidine of the formula Va, such as formamidine acetate, acetamidine hydrochloride, guanidine carbonate or a substituted guanidine carbonate is conveniently carried out in an aprotic polar organic solvent, such as dimethyl sulfoxide, in a temperature range of about 25 C to 125 ⁰ C, preferably in a range of about 9O ⁰ C to 95 ⁰ C.

The hydrolysis of the ketal function takes place by means of an aqueous, inorganic acid, such as sulfuric acid, phosphoric acid or, preferably, a hydrohalic acid, such as hydrochloric acid, in the presence of a lower alkyl alcohol as solvent, preferably ethanol. The reaction is carried out at about room temperature.

20 XII ·

The compound of formula II forms in the hydrogenation of the compound of formula XII in the presence of a metal catalyst, such as platinum, palladium or Raney nickel, and spontaneously cyclizes to compound In. The hydrogenation may be carried out in a suitable organic solvent, such as lower alkyl alcohols or lower alkylcarboxylic acids, e.g. Acetic acid. Depending on the reaction conditions used for this hydrogenation, a dihydropyrimido compound of the formula III can be formed in addition to or instead of the compound of the formula In. This dihydropyrimido compound can be prepared by treatment with a mild oxidizing agent, such as manganese dioxide, air or the like, in the compound of the invention.

35 mel In being convicted.

Verf.ahrensvariante c) is in the sense of an example

illustrated by the following Reaction Scheme II

Reaction scheme II

I-,)

io

ip

IVa ·

Io and Id

The compound of formula IVa is known, see for example US Pat. Nos. 3,947,585, 4,022,800 and 4,028,381. The compound is converted to an alcohol (C ₁ -C _14), for example ethanol, at a temperature between about 25 ⁰ C and 8O ⁰ C, preferably at the reflux temperature of the alcohol used, with Cyanaraid to the reaction.

This gives a mixture of the amino compound and the Ν, Ν-disubstituted amino compound, which can be separated, for example, by fractional crystallization and / or chromatography.

Process variant d) involves the reaction of a compound of the formula IV with an amidine

1 8 921

- 20 -

or guanidine salt or with thiourea or an S-lower alkyl isothiourea. For the reaction with the amidine or guanidine salt, any inert organic solvent may be used, such as dioxane, tetrahydrofuran or dimethylformamide, and the reaction temperature may be between about room temperature and the reflux temperature of the solvent, with about room temperature being preferred. The reaction with thiourea or with an S-lower alkyl isothiourea may be carried out in the presence of an alcoholic, e.g. methanolic, solution of an alkali metal alkoxide, e.g. Sodium ethoxide. The reaction may be carried out between about 0 C and 65 C, preferably at about room temperature.

Process variants e) and f) are illustrated by way of example by the following Reaction Scheme III, in which R has the above meaning:

Reaction scheme III

X-lower alkyl-Y

In yio 'and In or Io' - ^ =

By treating the compound of formula In (see Reaction Scheme I) with a reducing agent such as zinc in acetic acid at a reaction temperature of about ⁰ to 20 C -JJO obtained Io. ¹ As the solvent, a halogenated hydrocarbon such as methylene chloride may be used.

By treating the compound of the formula In or Io 'with hydrogen in the presence of platinum oxide or prehydrogenated platinum oxide and in acetic acid as the solvent, XIII is obtained. The reaction is usually carried out at about room temperature.

Other reducing agents suitable for process variant e) include sodium cyanoborohydride, sodium borohydride and the like.

In some cases, mixtures of the 6,7-dihydro and the 4,5 , 6,7-tetrahydro compounds are obtained. The mentioned ¹ J, 5,6,7-Tetrahydroverbindungen also show useful activities on the central nervous system.

25 Io ^ ^ ¹

In der.Behandlung.temperatur treatment of the compound of formula Io ¹ with formaldehyde in formic acid with heating, example, the dihydro compound is methylated. The methylation can also be carried out, for example, with methyl iodide, dimethyl sulfate or the like.

Lower alkyl substituents other than methyl are obtained using suitable alkyl halides, sulfates, alkyl sulfonates, tosylates, or the like in a solvent such as dimethylformamide, tetrahydrofuran, or the like.

drofuran, glyme and diglyme or ethereal solvents, or using suitable aldehydes under reductive reaction conditions.

Process variant g) is illustrated by way of example by the following Reaction Scheme IV, wherein R has the above meaning:

2t 8 921

-zn -

Reaction scheme IV

The compound of formula In is treated with a suitable oxidizing agent such as metachloroperbenzoic acid in an inert organic solvent such as methylene chloride. The reaction can be carried out between about 0 C and room temperature, preferably at about room temperature. The reaction time can be varied, depending on whether one desires as the product, the N-oxide or the di-N-oxide. When the reaction time is between about 2 and 25 hours, one obtains predominantly the N-oxide Iq; if, on the other hand, the reaction time is between about 50 hours and about 60 hours, then predominantly the di-N-oxide Ir is formed.

According to process variant h), a mercapto or hydroxy group is lower alkylated by methods known per se ,. The alkylation of the mercapto group is conveniently carried out by means of a suitable alkyl halide in the presence of a mixture of an alkali metal hydroxides, such as sodium hydroxide, and an alcohol (C ₁ -Cw), such as ethanol. The reaction may preferably be carried out at 20 x about room temperature.

The alkylation of the hydroxy group is conveniently carried out by means of a dialkyl sulfate, such as dimethyl or diethyl sulfate, under basic conditions, for example in the presence of sodium hydroxide. The reaction may be carried out between about 0 C and 65 C, preferably at about room temperature.

The conversion of a 2-amino compound into the corresponding 2-hydroxy compound according to process variant i) can be carried out by means of an acid, such as sulfuric acid. The reaction temperature may vary between about 25 ° C and 125 ⁰ C, with about 100 ⁰ C as Reaktionstemperatur.bevorzugt is. 35

Other methods that can be used for this conversion include alkaline hydrolysis and

Substitution of diazonium salts.

The conversion of a 2-hydroxy compound into the corresponding 2-chloro or bromo compound according to process variant k) can be carried out with a suitable chlorinating agent, such as phosphorus trichloride at the reflux temperature of the mixture, or with a suitable brominating agent, such as phosphoryl bromide or phosphorus pentabromide, between about room temperature and reflux temperature by-

10 are led.

According to process variant 1), the chlorine or bromine atom in the 2-position of the compound of formula Ig by nucleophilic substitution with different nucleophiles of the heteroatom and the carbon type, such as methanol, 3-dimethylaminopropylamine, methylamine, dimethylamine, N-methylpiperazine the carbanion of malonic acid diethyl ester and the like are replaced; It is possible to react in an inert polar organic solvent, such as dimethylformamide.

20 mamid, between about 0 C and the reflux temperature of the

Working solvent, preferably at room temperature.

The conversion of a compound of the formula Ih into the corresponding free acid according to the process variant

m) is conveniently carried out by hydrolysis under alkaline conditions, for example by means of an alkali or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide or the like, in the presence of a suitable ..lösungsmittels, for example a lower

30 alkanols, such as ethanol.

The conversion of a compound of the formula Ih into a corresponding amide according to process variant m) can be carried out either by treatment with ammonia or a suitable mono- or di-lower alkylarain at room temperature or elevated temperature (conveniently about 50-13O ⁰ C) in the presence an inert organic solution

21 a 921 _ _2T _

by means of such as a lower alkanol, e.g. Ethanol, or by hydrolysis to the corresponding free acid, conversion of this free acid into a reactive derivative such as an acid chloride or a mixed anhydride, and subsequent treatment of this reactive derivative with ammonia or a suitable mono- or di-lower-alkylamine.

Process variants n) and o) are illustrated by way of example by the following Reaction Scheme V, in which X ¹ , Y, R and R have the above meaning:

21 β 921

Reaction scheme V

• Ν

Iu

The compound of formula Is may be reacted with an acid anhydride of a suitable carboxylic acid, such as acetic or trifluoroacetic anhydride. The reaction is preferably carried out at about the reflux temperature of the anhydride used. Instead of an acid anhydride, an acid chloride may also be used

 10

It Iu

The compound of formula It can be reacted with an alkali metal carbonate, for example with sodium or potassium carbonate in an alcohol (C ₁ -Cj), such as methanol, at a temperature between about ⁰ ° C and 65 ° C, preferably at about room temperature , Other reaction conditions suitable for this step include the use of alkali metal hydroxides, for example, sodium or potassium hydroxide, and an alcohol (C.C.sub.1) in the presence of water or, otherwise, acid hydrolysis using an aqueous mineral acid, such as hydrochloric acid or sulfuric acid. in a solvent such as tetrahydrofuran or dioxane, and in a

Reaction temperature between about O ⁰ C and room temperature, preferably at OC. ,

The deoxygenation according to process variant p) can be carried out by methods known per se, for example by means of reagents such as phosphorus trichloride, tri-lower alkyl phosphites (for example triethyl phosphite), hexachlorodisilane, Raney nickel and the like.

Process variant q) and the preparation of the starting materials required therefor are illustrated by way of example by the following Reaktionssc'hema VI, wherein X, Y and R have the above meaning and Z 'one

21a 921

easily cleavable acyl group means:

92 1

Reaction scheme VI

.21 β 92 1

χιν

This transformation involves acylation using a suitable acylating agent which provides the readily cleavable acyl group Z ¹ , such as trifluoroacetyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, the mixed anhydride of formic and acetic acid, ethyl chloroformate, benzyloxycarbonyl chloride and the like. The conditions for carrying out such an acylation are familiar to any person skilled in the art.

XIV> XV

The compound of formula XIV is reacted with a suitable oxidizing agent, such as metachloroperbenzoic acid in an inert organic solvent, such as methylene chloride. The reaction may be carried out between about 0 C and about room temperature, preferably at about room temperature. The reaction time is about 40-60 hours.

XV

The acyl group Z ¹ is cleaved by methods known per se and familiar to any person skilled in the art. Of course, the choice of the method used depends on the nature of the acyl group Z '. For example, the trifluoroacetyl or ethoxycarbonyl

group are removed by alkaline hydrolysis, the Formylgru.ppe by acid hydrolysis, the benzyloxycarbonyl group using hydrogen bromide u.s.w.

XVI or XV> Iw ·

The conversion of XVI into Iw involves dehydrogenation, which is carried out by methods known per se.

can v.'denden, for example by Azodicarbonsäurediäthylester or by N-Halog = ning (preferably N-bromination) and subsequent dehydrohalogenation under alkaline conditions, for example by means of a tert. Amines, such as triethylamine.

When Z 'in formula XV is a group such as tosyl or mesyl, elimination of H-Z' can be carried out under alkaline conditions, for example by means of an alkali metal alkoxide in the corresponding alkanol, such as methanolic sodium methoxide.

If the 7H isomer of the compound of the formula Iw has formed, it may be isomerized to the compound of the formula Iw by treatment with a suitable base, for example with methanolic sodium methoxide.

For the sake of completeness, the preparation of those among 'the' intermediates of formula IV, wherein ρ is 1, is illustrated by way of example by the following Reaction Scheme VII, wherein X and Y have the above meanings:

21 8 92 t

Reaction scheme VII

HN (CH ₃ J ₂

XVII

XIX

rr mi r- 0. ". C f. ί \ (s ί '\ Γ.

8 92 1

The compound of formula XVII can with a peracid such as Metachlorbenzoesaure, are brought in an inert organic solvent, eg a halogenated hydrocarbon such as methylene chloride, or an ether for the reaction .. The reaction can be carried out between about O ⁰ C and 4O ⁰ C with room temperature being preferred. The Produktgeraisch can then be separated by fractional crystallization. Thin-layer chromatographic analysis shows the presence of both products

10 on.

The compound of formula XVIII may be reacted with dimethylformamide dimethyl acetal in an inert solvent such as halogenated hydrocarbons, e.g. Methylene chloride, dimethylformamide or high-boiling ether, are reacted. The reaction temperature can be between

approximately

is.

about 0 C and 100 C, with room temperature being preferred

The pyrimido-2-benzazepines of the above formula I and their pharmaceutically acceptable acid addition salts are useful as a remedy and are characterized by sedative and anxiolytic activity. These compounds can be used in the form of conventional pharmaceutical preparations; for example they may be mixed with common organic or inorganic inert carriers suitable for parenteral or enteral administration, for example with water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gum arabic, polyalkylene glycols, petrolatum or the like. They may be administered as conventional pharmaceutical forms, for example as solid forms such as tablets, dragees, capsules, suppositories or the like, or as liquid forms such as solutions, suspensions or emulsions. In addition, the pharmaceutical compositions containing the compounds according to the invention can be used in conventional pharmaceutical operations, such as

21 8 921 - 36 -

rilization, and they may contain conventional pharmaceutical excipients, such as preservatives, stabilizers, wetting agents, emulsifiers, salts for varying the osmotic pressure or buffers. The preparations may also contain other therapeutically valuable substances.

The table below shows the results obtained when the compounds enumerated below were subjected to certain well-known tests such as the inclined plane test, the control test, the unanesthetized cat test and the antipentemethylene tetrazole test (metrazolate test), as well as their toxicity:

A: 9-Chloro-7- (2-chlorophenyl) -2-methyl-5 H -pyriraido [5,4-d] [2] benzazepine

B: 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5, ⁱ } -d] [2] benzazepine

C: 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5, ¹ id] [2] benzazepine-JJ-arain

D: 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-2-methyl-5H-pyrimido [5, 0 - 0] [2] benzazepine dihydrochloride

E: 9-chloro-7- (2-chlorophenyl) -H, 5,6,7-tetrahydro-2-ethyl-ethyl

IH-pyri.midofSjH-d] [2] benzazepine dihydrochloride · 30

F: 9-chloro-7-2-chloro-phenyl) -6,7-dihydro-2,6-dimethyl-5H-pyrimido [5,... D ] [2] benzazepine-methanesulfonate (1: 2)

G: 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-ol

H: 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benza-

21 6,921 " ³⁷ "

zepin

I: 9-chloro-7- (2-fluorophenyl) -2-methoxy-5H-pyrimido [5,4-d] [2] benzazepine

K: 9-chloro-7- (2-fluorophenyl) -N, N-dimethyl-5H-pyrimido- [5, 4-d] [2] benzazepine-2-amine

r γγγ · ι η ° η. t ^: r \ r \ r.

TABLE

connection A Inclined plane mouse (ED ₅₀ ) Combat test mouse (effective dose) Unanästh. Cat (smallest effective dose) Metrazo1 Mouse (ED) mq / kg p.o. Toxicity mouse ( ^DI v _o > P-O. . 450 mg / kg i.p. B > 4OO mg / kg p.o. IO mg / kg p.o. 0.5 mg / kg p.o. 0.74 mg / kg p.o. > 1000 mg / kg p.o. > 1OOO mg / kg i.p. C 215 mg / kg p.o. 2.5 mg / kg p.o. 2.5 mg / kg p.o. O.59 mg / kq p.o. > 1000 mg / kg p.o. > 100 mg / kg i.p. ι D > 400 mg / kg p.o. 3.125mg / kg p.o. 1 mg / kg p.o. O.52 mg / kq p.o. > 1000 mg / kg p.o. 350 mg / kg i.p. OO "" co e > 4OO mg / kg p.o. 5O mg / kg p.o. 2.3 mg / kg p.o. > 1000 mg / kg p-o., 170 mg / kg i.p. F > 4OO mg / kg p.o. > 2OO mg / kg p.o. 34 mg / kg p.o. 650 mg / kg p.o. . 4 5O mg / kg i.p. G > 4OO mg / kg p.o. > 100 mg / kg p.o. > 20 mg / kg p.o. 7.7 mg / kg p.o. > 1000 mg / kg P-O. . > 1OOO mg / kg i.p. H > 4OO mg / kg p.o. 50 mg / kg p.o. 20 mg / kg p.o. 6.3 rng / kg p.o. > 1000 mg / kg P-O. . > 1OOO mg / kg i.p. I > 4OO mg / kg p.o. 2 mg / kg p.o. 1. mg / kg p.o. O.37 mg / kg p.o. 9OO mg / kg p.o. > 1OOO mg / kg i.p. K > 400 mg / kg p.o. 30 mg / kg p.o. 20 mg / kg p.o. 2.6 mg / kg p.o. > 1000 mg / kg p.o. > 1OOO mg / kg i.p. > 4OO mg / kg p.o. IO mg / kg p.o. Ϊ0 mg / kg p.o. 1.1 > 1000 mg / kg ·

-39 »21.7.1980

AP C 07 D / 218 921 56 971/11

A suitable pharmaceutical dosage unit may contain between about 1 to about 500 mg of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, with a dosage range of from about 1 mg to about 100 mg for oral administration and a dosage range of from about 1 mg to about 50 mg is preferred for parenteral administration. In each individual case, however, the person performing or monitoring the administration of the compounds in question must tailor the dosage according to their professional judgment to the individual requirements. It should be noted that the above dosages are given by way of example only and in no way limit the scope and practice of the present invention.

The term "dosage unit" as used in the present specification refers to individual pharmaceutical units which are suitable as unit doses of nipples and each of which contains a predetermined amount of the active ingredient which has been calculated such that: it results in the desired "therapeutic effect" together with the requisite pharmaceutical diluent, carrier or vehicle.

Example of execution ".

The following examples are intended to illustrate but not limit the invention. "All temperatures are in degrees centigrade unless otherwise specified.

- ίο -21 8 921

example 1

A stirred under argon suspension of 10 g (0.032 mol) of 8-chloro-3,4-dihydro-4- [(dimethylamino) methylene] -1-phenyl-5H-2-benzazepin-5-one and 8.5 g ( 0.047 mol) of guanidine carbonate in 250 ml of methanol is added at room temperature in a portion with 5.1 g (0.094 mol) of sodium methylate. After 10 minutes, 150 ml of methylene chloride are added and after 2 hours and 4 hours, respectively, the same portions of sodium and guanidine carbonate. After stirring overnight, the mixture is diluted with 250 ml of methylene chloride, washed with water, dried over sodium sulfate and evaporated in vacuo. The residue "crystallizes from ethanol and gives brownish crystals of the mp 209-210 ° C. By recrystallizing a sample of 2-amino-9-chloro-7-phenyl-5H-pyrimido [5,4-d] [2] benzazepine from methylene chloride / Ethyl acetate gives whitish prisms of Srap. 210-211 °.

20 Example 2

A stirred under argon suspension of 16 g (0.047 mol) of 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one and 12 , 5 g (0.07 mol) of guanidine carbonate in 460 ml of methanol is added at room temperature in a portion with 7.5 g (0.14 mol) Natriuramethylat. After 10 minutes, 290 ml of methylene chloride are added and after 2 hours and 4 hours, respectively, the same portions of sodium and guanidine carbonate. After stirring overnight, the mixture is diluted with 460 ml of methylene chloride, washed with water, dried over sodium sulfate and evaporated in vacuo. The residue crystallizes from ethanol / methylene chloride and gives 2-amino-9-chloro-7 - (- 2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine as whitish crystals of mp. 245-248 ° , -

A warm solution of the above product in 100 ml of methanol / methylene chloride (1: 1) is filtered and concentrated to half its volume on the steam bath. The filtrate is treated with 5 ml of a 5.7N ethanolic hydrochloric acid solution and allowed to stand for 2 hours at room temperature. The corresponding dihydrochloride is filtered off, washed with ethanol and at the. Air dried. The pale yellow crystals have a mp of 232-237 °.

Example 3

A stirred under argon suspension of 1.6 g (0.005 mol) of 8-chloro-3,4-dihydro- ⁱ l- [(dimethylamino) methylene] -1-phenyl-5H-2-benzazepin-5-one and 0, 7 g (0.0075 mol) of acetamidine hydrochloride in 50 ml of methanol is added at room temperature in a portion with 0.8 g (0.015 mol) of sodium methylate. After 10 minutes, 30 ml of methylene chloride are added and after 2 hours and 4 hours, respectively, the same portions of Natriuramethylat and acetamidine hydrochloride. After stirring overnight, the mixture is diluted with 50 ml of methylene chloride, washed with water, dried over sodium sulfate and evaporated in vacuo. Crystallize by taking up the residue in 20 ml of warm hexane and allow to cool. By removal of the solvent still receives a second portion benzazepine 9-chloro-2-methyl-7-phenyl-5K-pyrimido [5, ⁱ id] [2]. Recrystallization from hexane (activated carbon) gives whitish crystals of mp. '120-122 °. ,

' Example 4 ·'

A stirred under argon suspension of 5.1 g (0.015 mol) of 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one and 2.1 g (0.0225 mol) of acetamidine hydrochloride in 150 ml of methanol is added at room temperature in a 2.4 g (0.045 mol) portion.

21 8 92t

- 1 * 2 -

Sodium methylate added. After 10 minutes, 90 ml of methylene chloride are added and after 2 hours or ¹ hour respectively, the same portions of sodium and acetamidine hydrochloride. After stirring overnight, the mixture is diluted with 150 ml of methylene chloride, washed with water, dried over sodium sulfate and evaporated in vacuo. Recrystallization of the residue from hexane (activated charcoal) gives 9-chloro-7- (2-fluorophenyl) -2-methyl-

-d] [2] benzazepine as a white crystal

Example 5

10 l of the m. 10 ^ -107 °.

A. · Solution of 7.0 g (0.0204 mole) of 8-chloro-1- (2-fluorophenyl) -3, ^{1 J-dihydro-1} IC (dimethylaraino) methylene] - 5H-2-benzazepin-5-one and 3.5 g (0.0833 mol) of cyanamide in 300 ml of absolute ethanol is heated to boiling for 18 hours under reflux and then evaporated to dryness. After washing with water, the residue is filtered off and recrystallized 2 times from methanol, thereby obtaining the Ν, Ν-dimethylaraino compound. After concentrating the filtrates, the resulting precipitate is filtered off and recrystallized from methanol, thereby obtaining the amino compound. After evaporation of the filtrates, the residue is taken up in methylene chloride and chromatographed on Florisil. Elution with methylene chloride gives a further portion of the N, N-dimethylamino compound. A sample of 9-chloro-7- (2-fluorophenyl) -N, N-dimethyl-5H-pyriraido [5,4-d] [2] benzazepine-amine is recrystallized from methylene chloride / ether to give white needles of mp. 175 -180 °.

Subsequently, the column with a 5 percent. Solution of ether eluted in methylene chloride and then with ether. Evaporation of the ether fractions and recrystallization of the residue from methanol gives another * portion of the araino compound. A sample of 9-chloro-7- (2-fluoro

- -113 -

phenyl) -5H-pyrimido [5,4-d] [2] benzazepine-4-amine is recrystallized from methanol to give white prisms of mp. 2-2-247 °. '

To a solution of 0.2 g (0.5 mmol) of the N, N-dimethylamino compound in 5 ml of methanol is added 0.05 g (0.5 mmol) of methanesulfonic acid. After removal of the solvent, the oily residue is crystallized from isopropanol. Recrystallization from methanol / ether gives the corresponding methanesulfonic acid salt as yellow prisms of mp 190-195 °.

Example 6

A solution of 2.0 g (7.19 mmol) of [2- (2-fluorobenzoyl) -4-chlorobenzoic acid] in ¹ ml of methanol and 0.3 ml of sulfuric acid is refluxed for 10 hours and subsequently evaporated. The residue is partitioned between 50 ml of methylene chloride and 30 ml of dilute ammonium hydroxide solution, the organic phase separated, dried and evaporated. The resulting oil is dissolved in 20 ml of methylene chloride and filtered through 25 g Florisil eluting with methylene chloride. The obtained after evaporation of the solvent OeI is crystallized from ether and recrystallized from methylene chloride / ether / petroleum. This gives 2- (2-fluorobenzoyl) -4-ehlorbenzoesäure methyl ester as white rods of mp. 115-116.

30 Example 7

To a solution of 47 g (0.16 mol) of methyl 2- (2-fluorobenzoyl) -4-chlorobenzoate in 350 ml of dry toluene is added 21.4 ml (0.18 mol) of tin tetrachloride. After 5 hours, a solution of 24 ml (0.308 mol) of 1-chloro-2,3-epoxypropane in 25 ml of toluene is added with stirring over a period of 30 minutes. After 18 hours

21 8 921

another 12 ml (0.15 l- ¹ mol) of 1-chloro-2,3-epoxypropane are added over a period of 15 minutes. After 4 hours, the batch is cooled in an ice bath and basified with concentrated ammonium hydroxide solution. It is then filtered through Celite while washing with toluene. The combined filtrates are washed with 20Ö ml of water, dried over sodium sulfate and evaporated. The OeI thus obtained is taken up in 100 ml of methylene chloride and chromatographed on 500 g .Alox.

Elution with 4 1 methylene chloride / petroleum ether (2: 1) gives an OeI whose purity (TLC) is about 90 to 9536, h'ine sample is recrystallized from ether / petroleum to give 4-chloro-1- [4- chloromethyl-2- (2-fluorophenyl) -1,3-dioxolan-2-yl] benzoic acid methylester

15 as white prisms of mp. 117-122 °.

Example 8

To 800 ml of liquid ammonia is added a small piece of sodium and a few crystals of iron II nitrate. Subsequently, over a period of 30 minutes, 8.7 g (0.378 mol) of sodium are added with stirring and 15 minutes later, a solution of 20.1 ml (0.378 mol) of acetonitrile in 70 ml of ether over a period of 15 minutes. After 10 minutes, a solution of 56 g (0.145 mol) of the final product from Example 7 in 250 ml of ether is added over a period of 10 minutes. After 2 hours, add 700 ml of ether and let the ammonia evaporate overnight. After addition of ice, the reaction is made acidic with acetic acid and neutralized with saturated sodium bicarbonate solution. The aqueous phase is separated off and shaken out with 500 ml of ether. The combined ethereal phases are washed with 200 ml of semisaturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The residue is taken up in 150 ml of methylene chloride and filtered over 400 g of Florisil while rinsing with 1.5 l of MeOH.

921

thylenchlorid. The OeI thus obtained has a purity (DC) of 90-95 *.

ItS g of this product are heated with Ν, Ν-dimethylformamide dimethyl acetal for 90 minutes under reflux to boiling and then evaporated to dryness. After trituration of the residue with 300 ml of ice water is decanted and the remaining OeI taken up in 300 ml of methylene chloride, washed with 200 ml of water and dried over sodium sulfate. Evaporation of the solution and crystallization of the residue from methylene chloride / ether to obtain the final product. The mother liquors are evaporated, taken up in 100 ml of methylene chloride and filtered over 300 * g Florisil, eluting with 400 ml of methylene chloride and 1.5 1 ether. From methylene chloride / ether, crystalline 2- [4-chloromethyl-2- (2-fluorophenyl) -1,3-dioxolan-2-yl], -a- [(dimethylamino) -methylene] -A-OXo- ( ¹ J-chlorophenylpropionitrile Recrystallization of an analytical sample yields whitish prisms, mp 143-1M7 °, and the mother liquors contain the final product as OeI, whose purity (DC) is about 852.

Example 9

A solution of 1.0 g (0.00223 mol) of the final product of Example 8 in 8 ml of dry dimethylsulfoxide is added with ITg molecular sieve (Type 5A) and 0.7 g (0.00389 mol) of guanidine carbonate. The mixture is kept for 5 hours with stirring at 90-95 ⁰ C, cooled and treated with 50 ml of methylene chloride. The solution is decanted from the solid, with repeated washing with methylene chloride and water. After separating the aqueous phase, the organic phase is washed twice with dilute sodium chloride solution, dried over sodium sulfate and evaporated. The residue is chromatographed on 4 silica gel thick-layer plates (methylene chloride /

2t 8 921. ".

sigester, 3: 1, rf 0.4). 2-Amino-4- [2- [4- (chloromethyl) -2- (2-fluorophenyl) -1,3-dioxolan-2-yl] -4-chlorophenyl] pyrimidine-5-carbonitrile crystallizes from methanol to give whitish Prisms of the Mp. 184-191 °. 5

Example 10

A solution of 0.2 g (0.448 mmol) of the final product from Example 9 in 20 ml of methanol and 10 ml of 3N hydrochloric acid is heated to boiling for 20 minutes under reflux and then evaporated. After partitioning the residue between 50 ml of methylene chloride and 30 ml of dilute ammonium hydroxide solution, the organic phase is dried, concentrated and filtered through 15 g Florisil, eluting with 200'ml ether. The resulting 2-amino-4- [2- (2-fluorobenzoyl) -4-chlorophenyl] pyrimidine-5-carbonitrile is recrystallized from methylene chloride / ether / petrol and gives white prisms, mp. 151-157 °.

Example 11

A solution of 50 ml (0.142 mmol) of the end product from Example 10 in 10 ml of acetic acid is added with little Raneynickel and hydrogenated for 2.5 hours. After filtration over Celite and evaporation, the residue is partitioned between 30 ml of methylene chloride and 15 ml of dilute ammonium hydroxide solution. The organic phase is separated, dried over sodium sulfate and evaporated.

The residue is then taken up in ethanol, heated to boiling for 1 hour under reflux and evaporated to dryness. The resulting solid is chromatographed on a silica gel thick-layer plate (ethyl acetate / ethanol, 20: 1, rf 0.3). 2-Amino-9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine crystallizes from ether and has a mp of 243-248 °, the mixed melting point with authentic material

from example 2, 2HH-2HQ is ⁰ .

Example 12

A solution of 33 g (0.138 mol) of methyl 2-benzoylbenzoate in 200 ml of dry carbon tetrachloride is treated with 10.1 ml (0.13 mol) of 1-chloro-3, ίΐ-epoxypropane. After cooling in an ice-bath, a solution of 1.5 ml (0.013 mol) of tin tetrachloride in 10 ml of carbon tetrachloride is added with stirring over a period of 20 minutes. After standing over the weekend, add the same portions of 1-chloro-2,3-epoxypropane and tin tetrachloride. After a further 18 hours, the reaction mixture is cooled in an ice bath and neutralized with concentrated ammonium hydroxide solution. The precipitate is filtered off with washing with methylene chloride, the combined filtrates are washed with 150 ml of water, dried over sodium sulfate and evaporated. The resulting OeI is taken up in 100 ml of methylene chloride and chromatographed on 500 g of neutral Alox. Elution with 3 l of methylene chloride gives 2- [iJ- (chloromethyl) -2-phenyl-1, 3-dioxolan-2-yl] benzoic acid methyl ester as OeI whose purity (DC) about 95? is. Crystallization and recrystallization of a sample of ether / petroleum ether result in white rods of the mp 90-91.

Example 13

To 75 ml of liquid ammonia is added with stirring a small amount of sodium and a few crystals of iron II riitrat. Over a period of 20 minutes, the solution is treated with 1.15 g (0.0502 mol) of sodium and 5 minutes later with a solution of 2.9 ml (0.050 mol) of acetonitrile in 10 ml of ether. Subsequently, a solution of 6.6 g (0.0198 mol) of the end product from Example 12 in 40 ml of ether is added dropwise. After 2 hours

21 8 921

The mixture is mixed with 100 ml of ether, the ammonia is evaporated, 100 g of ice are added, acidified with acetic acid and neutralized with saturated sodium bicarbonate solution. The organic phase is separated off and the aqueous phase is extracted by shaking with ether. The combined organic extracts are washed with 100 ml of water, dried over sodium sulfate and evaporated. The remaining OeI is taken up in 15 ml of methylene chloride and filtered while rinsing with methylene chloride, over 100 g of Florisil. The crude 2- [4- (chloromethyl) -2-phenyl-1,3-dioxolan-2-yl] -β-oxobenzene propionitrile is used in the next step without further purification.

A "solution" of 20 g (0.0585 mol) of the above product in 75 ml of Ν, Ν-dimethylformamide dimethyl acetal is refluxed for 90 minutes and then evaporated to dryness.After.Zerreiben the oily residue with ice water decanted off and the residue is partitioned between 150 ml of methylene chloride and 150 ml of water.The organic phase is dried over sodium sulphate, concentrated and filtered through 150 g of Florisil, eluting with ether, giving the crude 2- [4- (chloromethyl) -2-one obtained in this way -phenyl-1,3-dioxolan-2-yl] -a - [(dimethylamino) -methylene] -β-o-benzolpropionitrile crystallized from ethanol A sample is recrystallised from methylene chloride / ether to give white prisms of the mp 107- 110 °.

Example IH, ₃₀

A solution of 2.0 g (0.00504 mol) of the end product from Example 13 in 10 ml of methylene chloride is mixed with 10 ml of methanol and 2 ml (0.0192 mol) of a 9.6N ethanolic hydrochloric acid solution remove the solvent and partition the residue between 50 ml of methylene chloride and 30 ml of a saturated sodium bicarbonate solution. After separating and drying

the organic phase over sodium sulfate is evaporated. The oily residue (1.5 g) is taken up in 30 ml of methanol and admixed with 1.5 g (0.00833 mol) of guanidine carbonate. The solution is stirred for 90 minutes and then heated for a further 2 hours under reflux to boiling. After evaporating and distributing the residue between 50 ml of methylene chloride and 30 ml of dilute ammonium hydroxide solution, the organic phase is dried over sodium sulfate and filtered over 50 g Florisil, eluting with 200 ml of methylene chloride, and β00 ml of ether. From the methylene chloride fraction is obtained after recrystallization from methylene chloride / petroleum ether 1-0xo-3-phenyl-1H-indene-2-carbonitrile as yellow rods of mp. 173-175 °.

From the ether fraction is obtained by crystallization from methylene chloride / petroleum ether 2-amino- ^J 4- (2-benzoylphenyl) pyrimidine-5-carbonitrile, mp 195-199. An analytical sample is recrystallized from methanol and

20 gives whitish prisms of the mp. 197-200.

Example 15

A solution of 3.1 g (0.0103 mol) of 2-Araino- ⁱ l- (2-benzoylphenyDpyrimidin-5-carbonitrile in 60 ml of glacial acetic acid is added to a teaspoon Raney nickel and hydrogenated for 8.5 hours, then filtered over Celite and the solvent is removed, after partitioning the residue between 50 ml of methylene chloride and 30 ml of dilute ammonium hydroxide solution, the organic phase is dried over sodium sulphate and evaporated, and the resulting oil is taken up in 75 ml of methanol and refluxed for 15 minutes , evaporated and dissolved in 100 ml of methylene chloride, then 3 g of activated manganese dioxide are added with stirring, and the mixture is refluxed for 30 minutes. After filtration and evaporation, the residue obtained is filtered.

r Γ Γ π ι η ^r :, ιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιι

2t 8 921

was chromatographed on 100 g Florisil. First eluted with 300 ml of methylene chloride then with 500 ml of ether and 1.5 1 of ethyl acetate. From the ethyl acetate fraction is obtained by recrystallization from methylene chloride / ether white rods of mp. 239-242 °. The mother liquors and the ether fraction yield, after evaporation and chromatography on silica gel thick-layer plates with ethyl acetate / methanol (20: 1) as eluant, another portion of 7-phenyl-5H-pyrimido [5,4-d] [2] benzazepine-2 amine. By recrystallization of an analytical sample of ether to obtain white prisms, mp. 201-205 °, which rearrange after cooling to rods of mp 240-243 °.

Example 'i6

In 5 equal portions, 5.5 g (58 mmol) of acetamidine hydrochloride and 15 ml (62 mmol) of a 4,12 M methanolic solution of sodium methylate, over a period of 3 hours, are added to a solution of 3.5 g (10 mmol). 8-Chloro-1- (2-chlorophenyl) -3,4-dihydro-M - [(dimethylamino) methylene] -5H-2-benzazepin-5-one in 140 ml of methanol and 140 ml of methylene chloride. The mixture is diluted with water and extracted by shaking with methylene chloride. After washing the methylene chloride solution with water, drying over sodium sulfate and evaporation in vacuo to give a yellow-brown OeI. By taking up the oil in 10 ml (10 mmol) of a 1M methanesulfonic acid solution in methanol and precipitating the salt by addition of ether, 9-chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido is obtained [5, ¹ id] [2] benzazepine as yellow prisms of mp 193-197 °. After recrystallization to methanol / ether resulting yellow prisms, mp. 197-198 °.

rrn mo η, c r. r \ r on.

• Example 17

In 5 equal portions are added 21 g (200 mmol) of formamidine acetate and 32.5 ml (135 mmol) of a 4,12M ethanolic solution of sodium methylate over a period of 3 'hours to a solution of 7.2 g (20 mmol ) 8-Chloro-1- (2-chlorophenyl) -3,4-dihydro- ⁱ } - [(dimethylamino)) methylene] -5H-2-benzazepin-5-one in 270 ml of methanol and 270 ml of methylene chloride. After diluting the solution with water and extracting with methylene chloride, the organic phase is washed with water, dried over sodium sulfate and evaporated in vacuo to give a yellow-brown OeI. Purification of crude 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine is carried out by column chromatography on 100 g of silica gel, eluting with methylene chloride / ethyl acetate (1: 1). and gives crystals of mp 122-124 °. By recrystallization au3,. Aether one receives pale yellow prisms of the form. 122-125.

20 Example 18

A mixture of 3.5 g (10 mmol) of 1- (2-chlorophenyl) -3,3-dihydro-ty-f-dimethylamine) methylene] -5H-2-benzazepin-5-one, 4.8 g (40 mmol) Isobutyraraidine hydrochloride, 10 ml (41 mmol) of a 4.12M methanolic solution of sodium methoxide and 100 ml of methanol is stirred for 2 hours at room temperature. The mixture is diluted with water and extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated in vacuo to give a yellow oil. Crystallization from ether gives 9-chloro-7- (2-chlorophenyl) -2-isopropyl, 1-5H-pyriraido [5,4-d] [2] benzazepine as a yellow solid of mp 127-129 °. By recrystallization from ether / petroleum ether to obtain colorless rods of mp.

35 127-129 °.

218 921

Example 19

In 2 equal portions is added 14, ¹ I g (80 mmol) of guanidine carbonate and 20 ml (82 mmol) of a 4,12M methanolic sodium methoxide solution (over a period of 90 minutes to a solution of 3.6 g 10 mmol ) 8-Chloro-1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethyl-amino) -methylene] -5H-2-benzazepin-5-one in 100 ml of methanol. After dilution of the mixture with water and shaking with methylene chloride, the organic phase is dried over sodium sulfate and evaporated in vacuo. The resulting yellow OeI crystallized from methylene chloride to give a white solid, mp. 240-241 °. Recrystallization from ether / methylene chloride gives 2-amino-9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine as colorless needles, mp. 240-241 °.

Example 20

In 4 equal portions, 7.2 g (76 mmol) of acetamidine hydrochloride and 18 ml (80 mmol) of a 4,46 M methanolic sodium methylate solution are added over a period of 3 hours to a solution of 4.5 g (14 mmol) 1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one in 180 ml of methanol and 180 ml of methylene chloride. After dilution of the mixture with water and shaking with methylene chloride, the organic phase is washed with water, dried over sodium sulfate and evaporated in vacuo. After taking up the yellow-brown oil in a mixture of 15 ml of isopropanol and 1.3 g (14 mmol) of methanesulfonic acid, it is evaporated in vacuo. The residue is crystallized from ether / methylene chloride to give 7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5,4-d] [2] benzazepine methanesulfonate as a yellow solid of mp. 147-151 Recrystallization from ether / methylene chloride gives the corresponding hemihydrate as yellow prisms of mp 159-160 °.

Example 21

In 5 equal portions are added 9.0 g (95 mmol) of acetamidine hydrochloride and 22.5 ml (0.1 mol) of a * J, 46M methanolic sodium methoxide solution, over a period of 3 hours, to a solution of 4 , 5 g (15 mmol) of 1-phenyl-3, ^ -dihydro- ¹ ! - [(dimethylaraino) -ethylene] -5H-2-benzazepin-5-one in 18O ml of methanol and 180 ml of methylene chloride. The methylene chloride phase is washed with water, dried over sodium sulfate and concentrated in vacuo. steamed. After dissolving the resulting OeIs in excess 6 percent. Methanolic hydrochloric acid solution is evaporated to dryness in vacuo. Crystallization of the residue from ether / methylene chloride gives 2-methyl-7-phenyl-5H-pyrimido [5, - d] [2] benzazepine dihydrochloride as a white solid of mp 211-221 °. Recrystallization from methanol / ether gives' white platelets of mp. 217-227 °.

20 Example 22

A solution of 2.0 g (5.6 mmol) of 9-chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5, d] [2] benzazepine and 2.2 g (10 , 8 mmol) of m-chloroperbenzoic acid (85%) in 100 ml of methylene chloride is stirred for 21 hours at room temperature. After vortexing with cold dilute sodium hydroxide solution, the organic phase is dried over sodium sulfate and evaporated to dryness in vacuo. Purification of 9-chloro-7- (2-chlorophenyl) -2 '-methyl-5H-pyrimido [5, ^l l-dl [2] benzazepin-6-oxide is carried out by filtration' .- tion over 25 g Silica gel with elution with 1000 ml of ether / methylene chloride (1: 1), thereby obtaining a colorless solid, mp. 215-216 °.

21 8 921 ~ ⁵ * '

Example 23

A solution of 3.8 g (10.7 mmol) of 9-chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5,4-d] [2] benzazepine and 9.6 g (47 in mol) of m-chloroperbenzoic acid (8536) in 400 ml of methylene chloride is stirred for 55 hours at room temperature. After washing the organic phase with cold dilute sodium hydroxide solution is dried over sodium sulfate and evaporated to dryness in vacuo.

The purification of 9-chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5,4-d] [2] benzazepine-3,6-dioxide is carried out by filtration over 25 g of silica gel under Elui® ren with 400 ml of ether / methylene chloride (1: 1) and 200 ml of methylene chloride / methanol (9: 1), thereby obtaining a colorless solid.

₁₅ bodies from the m. "241-243 °.

Example 24

A mixture of 3.7 g (10.5 mmol) of 9-chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5,4-d] [2] benzazepine, 1.3 g of zinc dust, 40 ml of acetic acid and 90 ml of methylene chloride are stirred for 30 minutes between -15 and -20. After filtration over Hyflo, the mixture is basified with cold dilute sodium hydroxide solution and extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated in vacuo to give a yellow oil. This OeI crystallizes from excess 6 percent. methanolic hydrochloric acid solution and gives 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-2-methyl-5H-pyrimido [5,4-d] [2] benzazepine dihydrochloride as a white solid of mp. 272-274 °. By recrystallization from methanol to obtain colorless rods of mp. 272-274 °.

A sample of the above material is partitioned between dilute sodium hydroxide solution and methylene chloride. The organic phase is dried over sodium sulfate and

21 8 92! -55 -

evaporated to dryness in vacuo. The residue crystallizes from ether and gives the free base as cream-colored prisms of mp. 176-177 °.

If the reaction is carried out in acetic acid with a prehydrogenated platinum oxide catalyst, 2 equivalents of hydrogen are taken up and, after working up, the tetrahydro compound described in Example 40 is obtained. Such tetrahydro compounds also develop

10 beneficial effects on the central nervous system.

Example 25

A mixture of 18.6 g (61 mmol) of 8-chloro-3,4-dihydro-1- (2-chlorophenyl) -5H-2-benzazepin-5-one and 149 ml of dimethylformamide dimethyl acetal is allowed to stand for 12 hours 50 heats After removal of the solvent in vacuo, the residue from ether / methylene chloride is crystallized to yield 8-chloro-1 -. (2-chlorophenyl) -3, ¹ J-dihydro - ^ - i (dimethylamino) methylene] - 5H-2-benzazepin-5-one as a yellow solid, mp 170 ° -171 ° C. Recrystallization from ether gives yellow prisms of the mp 170-171 °.

25 Example 26

A mixture of 3.4 g (12.5 mmol) of 1- (2-chlorophenyl) -3,4-dihydro-5H-2-benzazepin-5-one and 28 ml of dimethylformamide-diraethylacetal is boiled under reflux for 2 hours heated. After concentration of the mixture in vacuo, the solid obtained is triturated with ether and gives a brown solid, mp. 155-157 °. Recrystallization from methylene chloride / ether gives 1- (2-chlorophenyl) -3,4-dihydro-4- [(dimethylamino) methylene] -5H-2-benzasepin-5-one as yellow prisms, mp 158-159 °.

21 8 921

Example 27 *

A mixture of 5.2 g (22 mmol) of 3,4-dihydro-1-phenyl-5H-2-benzazepin-5-one and 43 ml of dimethylformamide dimethyl acetal is refluxed for 4 hours. The mixture is evaporated to dryness in vacuo. After crystallization of the residue from ether to give Si ^ dihydro-i-phenyl-iJ-t (dimethylamino) methylene] -5H-2-benzazepin-5-one as a yellow solid of mp.

I3I-I33 ⁰ · Recrystallization from ether gives yellow prisms, mp. 131-132.

Example 28

A mixture of 1.1 g (3.0 mmol) of 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5, Ud] [2] benzazepine-2-thiol, 1.0 mL (10 mmol) of dimethyl sulfate , 20 ml of 1N sodium hydroxide solution and 10 ml of ethanol is stirred for 15 minutes at room temperature. The mixture is diluted with water and extracted by shaking with methylene chloride. After drying the organic phase over sodium sulfate and evaporation in vacuo, an OeI is obtained, which is prepared from ether 9-chloro-7- (2-chlorophenyl) -2- (methylthio) -5H-pyrimido [5,4-d] [2] Benzazepine as colorless prisms, mp. 187-188 ° results.

Example 29

By dissolving equivalent amounts of the product from Example 28 and methanesulfonic acid in methanol and subsequent precipitation of the salt by addition of ether, 9-chloro-7- (2-chlorophenyl) -2- (methylthio) -5H-pyrimido [5.4- d] [2] benzazepine-methanesulfonate. After recrystallization from ethanol resulting in cream-colored needles, mp. 165-166 °.

.21 8: 921 - 57 -

Example 30

A mixture of 2.8 g (7.8 mmol) of 8-chloro-1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one, 2.8 g (37 mmol) of thiourea, 8.0 ml (32 mmol, oil) of a 4.0M methanolic sodium methylate solution and 80 ml of methanol are stirred for 18 hours at room temperature. After diluting the mixture with water and extracting with ether, the aqueous phase is neutralized with acetic acid and extracted by shaking with methylene chloride. The methylene chloride phase is dried over sodium sulfate and evaporated in vacuo, with a. Yellow solid of mp 238-239 ° is obtained. Recrystallization from tetrahydrofuran gives 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5, d] [2] benzazepine-2-thiol as yellow crystals of mp ⁰

Example 31

A solution of 1.2 g (0.00354 mol) of 9-chloro-7- (2-fluorophenyl) -2-amino-5H-pyrimido [5,4-d] [2] benzazepine in 20 ml of concentrated sulfuric acid and 20 ml of water is heated to reflux for 12 hours under reflux and then cooled. After addition of ice, the mixture is basified with ammonium hydroxide solution and extracted with 100 ml of methylene chloride. The precipitated solids are filtered off and recrystallized from methylene chloride / methanol, thereby obtaining 9-chloro-. 7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-ol as white prisms, mp. 297-299 ° (dec.). After drying and evaporating the methylene chloride extract, the residue is crystallized from methylene chloride / methanol to obtain an additional portion of product.

35 Example 32

A solution of 1.0 g (0.00294 mol) 9-chloro-7- (2-

218 921

fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine-2-ol in 5 ml of phosphorus oxychloride is heated for 4 hours on the steam bath and then evaporated to dryness. The solid is crystallized from methylene chloride / ether and partitioned between 50 ml of methylene chloride and 40 ml of saturated sodium bicarbonate solution. After drying and evaporation of the organic phase, the residue is crystallized from ether. Recrystallization from methylene chloride / ether gives 2,9-dichloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine as white prisms of mp 157-160 °.

Example 33

A solution of 1 g (0.00279 mol) of 2,9-dichloro-7-. (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine in 4 ml of Ν, Ν-dimethylformamide is cooled in an ice bath and saturated with methylamine. After 64 hours at room temperature, 50 ml of ice-water are added and the precipitate is filtered off. The precipitate is partitioned between 50 ml of methylene chloride and 50 ml of water. The organic phase is washed with 25 ml of semisaturated brine, dried and evaporated to dryness. After crystallization of the oil from ether is first recrystallized from methylene chloride / ether and then methanol. This gives 9-chloro-N-methyl-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-amine as white prisms, mp. 172-179 °.

, Example 34

A solution of 4.0 g (0.0112 mol) of 2,9-dichloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2-benzazepine in 15 ml of Ν, Ν-dimethylformamide is added in a Cooled ice bath and saturated with dimethylamine. After 18 hours at room temperature, 80 ml of ice-water are added and the precipitate is filtered off. By 2xliges recrystallization

Methanol is obtained 9-chloro-N, N-dimethyl-7- (2-fluorophenyl) -5H-pyrimido [5, * Jd] [2] benzazepin-2-amine al.s-weis.se rods of mp 175th -179 °.

5 Example 35

To 3.5 g (0.00978 mol) of 2,9-dichloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine in 7 ml of Ν, Ν-dimethylformamide are added Ice cooling Added 2.7 ml (0.0215 mol) of 3-dimethylamino-propylamine. After 66 hours at room temperature, it is mixed with 50 ml of ice-water and filtered off. The precipitate is taken up in 50 ml of methylene chloride, washed with UO ml of water and evaporated. After taking up the oil in dilute hydrochloric acid, the solution is adjusted to pH 2 with ammonium hydroxide. After extracting the acidic solution with 2 times 50 ml of methylene chloride each time, the aqueous phase is made basic with ammonium hydroxide and shaken out with 75 ml of methylene chloride. After drying and evaporation of the methylene chloride phase, the residue is crystallized from ether / petroleum ether. Recrystallization from the same solvent mixture gives 9-chloro-7- (2-fluorophenyl) -N- (3-N ', N-dimethylaminopropyl) -5H-pyriraido [5, Ud] [2jbenzazepin-2-amine as white needles of the mpt. 90-101 °. '

Example 3 6

To 1.0 g (0.00279 mol) of 2,9-dichloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine in 25 ml of methanol are added 0.18 g ( 0.00335 mol) of sodium methylate and stirred for 18 hours. After evaporation, the solid residue is taken up in 50 ml of methylene chloride, washed with 40 ml of water, dried and evaporated to dryness in vacuo. After recrystallization of the residue from ether / petroleum ether and ether to give 9-chloro-2-methoxy-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine as white prisms of mp. 137- 141 °.

2t 8 921

Example 37 . ,

A mixture of 34.2 g (0.1 mol) of 8-chloro-3,4-dihydro-1- (2-fluorophenyl) -4- [(dichloroamino) methylene] -5H-2-benzazepin-5-one, 62.4 g (0.6 mol) of formamidine acetate, 35 g (0.63 mol) of sodium methylate and 700 ml of methanol are stirred for 3 hours at room temperature, with simultaneous introduction of nitrogen. After diluting the mixture with water and extracting with methylene chloride, the organic phase is dried over sodium sulfate and evaporated in vacuo. The resulting red oil is suspended in boiling hexane. After decorating the still hot hexane solution, allow to cool, precipitating 9-chloro-7- (2-fluorophenyl) -5H-pyriraido [5,4-d] [2] benzazepine and filtering. Recrystallization "from cyclohexane gives whitish crystals of mp. 123-125 °.

Example 33

A solution of 3.2 g (10 mmol) of 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine, 3 g (15 mmol) of m-chloroperbenzoic acid (85 * ) in 100 ml of methylene chloride is stirred for ¹ hour at room temperature. The reaction mixture is washed with an excess of cold, dilute sodium hydroxide solution, dried over sodium sulfate and filtered through Hyflo. The filtrate is evaporated to dryness in vacuo. Crystallization of the residue from methylene chloride / ether gives crude 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine 6-oxide of mp. 185-186 °. After recrystallization from methylene chloride / ether, the pure product of mp. 187-188 °.

Example 39

A mixture of 2.5 g (7.4 mmol) of 9-chloro-7- (2-

21 8 921

fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine 6-oxide and 50 ml of acetic anhydride are heated to your steam bath for 2k hours. After evaporation of the mixture and crystallization of the residue from methylene chloride / ether to give the crude product of mp. 197-198 °. By Um- -. crystallize from methylene chloride / ether to give the pure 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5, ¹ Jd] [2] benzazepin-5-ol-acetate as cream-colored prisms, mp. 200-201 ° ,

example HO

A solution of 3.8 g (10.7 mmol) of 9-chloro-7- (2-chlorophenyl) -2-methyl-5H-pyriraido [5,4-d] [2] benzazepine in 50 ml of acetic acid at room temperature and normal pressure, using 0.5 g of prehydrogenated platinum oxide as the catalyst. After 3 hours and a shot of about. 500 ml of hydrogen (about 2 equivalents) is filtered off from the catalyst. The filtrate is evaporated to dryness in vacuo and the residue taken up in methylene chloride, washed with an excess of dilute, cold sodium hydroxide solution and dried over sodium sulfate. The methylene chloride phase is diluted with excess methanolic hydrochloric acid solution and evaporated in vacuo. The residue is triturated with isopropanol and filtered off. By Umkristallsieren from methanol, pure 9-chloro-7- obtained (2-chlorophenyl) - ^l i, 5,6,7-tetrahydro-2-methyl-1H-pyrimido [5, ^i} d] [2 jbenza-

zepin hydrochloride of mp. -275-2.76 °. 30 ·

Example Mi -

It is preferable to add a period of 2 hours to 28 g (150 mmol) of guanidine carbonate and 38 ml (150 mmol) of an iM, 09M methanolic sodium methylate solution in 2 equal portions to a solution of 7.0 g (20 mmol) of 8-Chlpr -1- (2-fluorophenyl) -3 ^ - dihydro-4 - [(dimethylamine) -

218 921

methylene] -5H-2-benzazepin-5-one-2-oxide in 210 ml of methanol. After dilution of the mixture with water and extraction with methylene chloride, the organic phase is dried over sodium sulfate and evaporated in vacuo to give a red solid. Recrystallization from methanol / ethyl acetate gives 2-amino-9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine-6-oxide as fine, yellow needles of mp. 320-323 °.

.10 - Example k2

A mixture of ¹ l (11 mmol) of 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-2-methyl-5H-pyrimido [5,4-d] [2] benzazepine, 2 ml 88 percent Formic acid and 2 ml 37.5 percent.

Formaldehyde solution is heated on the steam bath for 3 hours. The reaction mixture is poured onto an excess of dilute, ice-cold sodium hydroxide solution and extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated to dryness in vacuo. The residue crystallizes from ether and gives the crude product of mp 155-156 °. Recrystallization from ether gives pure 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-2,6-dimethyl-5H-pyrimido [5, 4-d] [2] .benzazepine as colorless prisms of Mp 156-157 °.

Example * J3

Method A: A mixture of 7.2 g (25 mmol) of 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-5H-2-benzazepin-5-one and 50 ml of dimethylformamide dimethyl acetal is added during 1 Hour heated to reflux under reflux. Evaporation of the mixture in vacuo gives brownish crystals. Recrystallization from ether gives 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-4 - [(dimethylamino) methyls] -5H-2-benzazepin-5-one as yellow prisms of the mp. 233 °.

Method B: A mixture of 10 g (35 mmol) crude

21 8 921 - it -

S, ² -dihydro-1- (2-fluorophenyl) -SH-a-5-one and 10 g (84 mmol) dimethylformamide dimethyl acetal in 10 ml of dimethylformamide are stirred for 12 hours at room temperature. The resulting precipitate is filtered off and washed successively with ethanol and ether, resulting in brownish crystals which are identical in all respects with authentic material.

Example 44 10

The preparation of 8-chloro-1-phenyl-3,4-dihydro-4 - [(dimethylaraino) methylene] -5H-2-benzazepin-5-one is carried out in the same manner as the preparation of 8-chloro-1 (2-fluorophenyl) -3,4-dihydro-4 - [(dimethylaraino) methylene] -. 5H-2-benzazepin-5-one (Method A) to yield yellow prisms of mp. I8O-I83 ^0th

Example 45

A mixture of 6.4 g (22 mmol) of 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-5H-2-benzazepin-5-one and 6.4 g (34 mmol) of m-chloroperbenzoic acid in 350 ml of methylene chloride is stirred for 2 hours at room temperature. The methylene chloride solution is washed with saturated sodium bicarbonate solution and water, dried over sodium sulfate and evaporated in vacuo. The yellow OeI is crystallized from ether / petroleum ether and gives whitish prisms of mp. 166-168 °. Recrystallization from ether / methylene chloride gives 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-5H-2-benzazepin-5-one-2-oxide as colorless prisms, mp. 168-170 °.

Example 46

The preparation of 8-chloro-1- (2-chlorophenyl) -3,4-dihydro-5H-2-benzazepin-5-one-2-oxide is carried out in the same manner as the preparation of 8-chloro-1 ( 2-fluorphe-

21 8 921 - «-

nyl) -3,4-dihydro-5H-2-benzazepin-5-one-2-oxide and gives yellow prisms, mp. 184-187 °.

example hl

A mixture of 3.4 g (11 mmol) of 8-chloro-1- (2-fluorophenyl) -3, U-dihydro-5H-2-benzazepin-5-one-2-oxide and 26 ml of dimethylformamide dimethylacetal is added during Stirred for 12 hours at room temperature. After dilution of the mixture with ether and filtration of the precipitate gives a yellow solid of mp 175-178. Recrystallization from ether / ethyl acetate gives 8-chloro-1- (2-fluorophenyl) -3, U-dihydro-U-Udimethylamine) -methylene] -5H-2-benzazepin-5-one-2-oxide as yellow needles

15 of the m. 193-19 ^ °.

Example U8

The preparation of 8-chloro-1- (2-chlorophenyl) -3,4-dihydro-UC (dimethylamino) methylene] -5H-2-benzazepin-5-one-2-oxide is carried out in the same manner as the preparation of 8-chloro-1- (2-fluorophenyl) -3, .U-dihydro- ⁱ l- [(dimethylamino) methylene] -5H-2-benzazepin-5-one-2-oxide and gives yellow prisms, 196-198 °. 25

Example M9

A mixture of 1 g (2.8 mmol) 8-chloro-1- (2-chlorophenyl) -U- [(dimethylamino) methylene] -3,4-dihydro-5, H-2-benzazepin-5-one 2-oxide, 1.0 g (11 mmol) of acetaraidine hydrochloride and 2.0 ml (9.9 mmol) of a 4.46M methanolic sodium methoxide solution in a mixture of 20 ml of methanol and 20 ml of methylene chloride is added during 2 hours Room temperature stirred. After diluting the mixture with water and extracting with methylene chloride, the organic phase is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. Around-

21 8 921 -s -

crystallize the residue from ether / methylene chloride gives 9-chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrdmido [5,4-d] [2] benzazepine 6-oxide as a colorless solid of the mp. 215- 216 °.

Example 50

A solution of 3.7 g (9.7 mmol) of 9-chloro-7 ~ (2-fluorophenyl) -5H-pyrimido [5, * 4-d] [2] benzazepine-5-ol acetate in 25 ml of tetrahydrofuran , 50 ml of methanol and 2 ml of 3N sodium hydroxide solution is stirred for 0.5 hours at room temperature. The Reaktionsgemiaoh is poured onto ice water and extracted with methylene chloride. The organic phase is separated, dried over sodium sulfate and evaporated to dryness in vacuo. The residue crystallizes from methylene chloride / ether to give crude 9-chloro-7- (2-fluorophenyl) -5H-pyriraido [5, U-d] [2] benzazepine-5-ol of mp. 186-1.88. Recrystallization from ether / methylene chloride results in cream-colored prisms

20 of the m. 196-198 °.

Example 51

A solution of 6.8 g (20 mmol) of 9-chloro-7- (2-chlorophenyl) -5H-pyriraido [5, ¹ Jd] [2 jbenzazepine, 6 g (30 mmol) of m-chloroperbenzoic acid (85 ° C) 200 ml of methylene chloride is stirred for H hours at room temperature. The mixture is washed with excess, cold, dilute sodium hydroxide solution, dried over sodium sulfate and filtered through Hyflo. After evaporation of the filtrate in vacuo, the residue is crystallized from methylene chloride / ether and gives the crude product of mp. 228-229 ° · By recrystallization from methylene chloride / ether to give 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [ 5, ¹ ld] [2] benzazepine-6-oxide, mp. 216-217 °.

218 921 * ⁶⁶ '

Example 52

A mixture of 3 g (8 mmol) of 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine 6-oxide and 50 ml of acetic anhydride is placed on the steam bath for 22 hours heated. After evaporating the reaction mixture, the residue is crystallized from methylene chloride / ether to give 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5, ¹ i · d] [2] benzazepin-5-ol-acetate from Mp. 211-212 °.

Recrystallization from the same solvent mixture gives pure product as colorless prisms, mp. 211-212 °.

Example 53

A solution of 4.8 g (12 mmol) 6-chloro-7- (2-chloro)

phenyl) -5H-pyrimido [5, ¹ ld] [2] benzazepine-5-ol-acetate in 50 ml of tetrahydrofuran, 50 ml of methanol and 4 ml of 3N sodium hydroxide is stirred for 30 minutes at room temperature.

The reaction mixture is poured into ice-water and extracted with methylene chloride. The organic phase is separated, dried over sodium sulfate and evaporated to dryness in vacuo. By crystallizing the residue from methylene chloride / ether to give 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-5-ol, mp. 105-117 ° · The pure Product is obtained by recrystallization from methylene chloride / acetone, resulting in colorless prisms of mp. 17 * 1-175 °.

³⁰ Example 5 **

A solution of 3.0 g (0.00838 mol) of 2,9-dichloro-7- (2-fluorophenyl) -5H-pyrimido [5, ⁱ td] [2] benzazepine in 8 ml of Ν, Ν-dimethylformamide is added 2 g (0.020 mol) of N-methylpiperazine are added. After 20 hours, 40 ml of ice-water are added and the resulting precipitate is filtered off. After distributing the solid between 50 ml of methyl

218 921

lenchloride and 50 ml of 1N hydrochloric acid, the pH of the aqueous phase is adjusted to 1-2 with ammonium hydroxide. The resulting precipitate is filtered off and recrystallized twice from methanol to give white prisms of mp 187-194. The acidic aqueous phase is basified with ammonium hydroxide and extracted with 100 ml of methylene chloride. The methylene chloride solution is dried and evaporated. The resulting OeI is acidified with 1N hydrochloric acid and the pH is adjusted to 1-2 with ammonium hydroxide. After cooling and filtration, the precipitate is recrystallized from methanol to give another portion of 9-chloro-7- (2-fluorophenyl) -2- ( ¹ -methyl-1-piperazinyl) -5H-pyrimido [5, 4 d] [2] benzazep in-hydrochloric !.

15

Ex iel 55

To 25 ml of methanol are added 1.0 £ (0.00279 mol) of 2,9-: dichloro-7- (2-f luor phenyl) -5H-py rim idol 5, ^* d] [2 jbenzaze-

~ C pin and 0.18 g (0.00335 mol) of sodium methylate. The reaction mixture is stirred for 18 hours and then evaporated to dryness. The solid residue is taken up in 50 ml of methylene chloride, washed with 40 ml of water, dried and evaporated .. By crystallization and recrystallization of the residue from ether / petroleum ether and recrystallization from ether to give 9-chloro-2-methoxy-7- ( 2-fluorophenyl) -5H-pyrimido [5, ^I ld j [2] benzazepine as white prisms of mp. 137-1 ^ 1.

Ex iel 56

1.9 g (16.8 mmol) of potassium tert-butoxide are added under nitrogen to 20 ml of diethyl malonate with stirring, followed by 2.0 g (5.59 mmol) of 2,9-dichloro-7- (2 -fluorophenyl) -5H-pyrimido [5,4-d] [2 jbenzazepine. The reaction mixture is kept for 2 hours at 110 ° and for k hours at 1 ^ 0 °. After adding ice

21 8 921 - ⁶⁸ -

is acidified with concentrated hydrochloric acid and extracted with 100 ml of ether. The ethereal phase is extracted with 25 ml of 3N hydrochloric acid. The combined acidic extracts are made basic with ammonium hydroxide and shaken twice with 100 ml of ether. The ethereal solution is dried, filtered through charcoal and concentrated to a small volume. After addition of petroleum ether, the 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5, ¹ id] [2] benzazepine-2-acetic acid ethyl acetate is filtered off and recrystallized from the same solvents, thereby obtaining white rods of the m. 98-103 °.

Example 57

A solution of 4.0 g (9.76 mmol) of ethyl 9-chloro-7- (2-fluorophenyl-SH-pyrimido) -4-d] [2] benzazepine-2-acetic acid in 30 ml of ethanol and 25 ml of 1N sodium hydroxide solution The reaction mixture is partitioned between 75 ml of water and 75 ml of ether, the basic extract is acidified with acetic acid and extracted twice with 100 ml of methylene chloride, after evaporation the resulting oil is crystallized from methanol and from methylene chloride Recrystallized from ether / petroleum ether to give 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine-2-acetic acid as whitish prisms of mp 138-140 °.

Example 58

For 10 minutes, methylamine is passed through a solution of 2.6 g (6.34 mmol) of 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine-2-acetic acid ethyl ester in 60 ml of ethanol. The mixture is allowed to stand for 18 hours, the reaction mixture is evaporated and the residue is partitioned between 75 ml of methylene chloride and 50 ml of water. After drying and evaporation of the organic phase, the residue is crystallized from methylene chloride / ether.

2t 8 92?

Recrystallization from the same Lösungsmitteige- 'mixed' is obtained 9-chloro-7- (2-fluorophenyl) -N-methyl-5H-pyrimidotS ^ -d] [2] benzazepine-2-acetamide as white rods of mp 175th -177 °.

Example 59

A mixture of 90.5 g (0.25 mol) of 8-chloro-1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one, 100 g (0.96 mol) of formamidine acetate and 1.0 l of formamide are heated on the steam bath for 16 hours. After cooling the reaction mixture to 0 °, the precipitate obtained is filtered off, washed with water and dried to constant weight, giving 9-chloro-7- (2-chlorophenyl) -5H-pyriraido [5,4-d]. [2] benzazephrine as whitish crystals of mp 120-121 °.

Example 60

A mixture of 0.4 g (1, VmMoI) of 8-chloro-1- (2-f-fluoro or phenyl) -3, U -di-hydro- ¹ J- [(dimethylamino) -methlylene [-5H-2 benzazepine-5-one-2-oxide, 1.0 g (9.6 mmol) of formamidine acetate and 20 ml of formamide are heated on the steam bath for 6 hours. The reaction mixture is poured onto ice and shaken out with methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulfate and evaporated in vacuo. By addition of ether / methylene chloride, the residue crystallizes to give 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine 6-oxide as whitish crystals of mp. 188 °.

Example 61

A. Mixture of O , U g (1.1 mmol) 8-chloro-1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylaraino) methylene] -5H-2-benzazepine-5-one-2 oxide and 1.0 g (9.6 mmol) of formaldehyde

21 8 921

mid-acetate in 20 ml of formamide is heated on the steam bath for 7 hours. The mixture is poured onto ice and extracted with methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is triturated with ether to give 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine 6-oxide · as a whitish solid of the mp. 215-217 °.

10 Example 62

A mixture of 0.5 g (1.3 mmol) of 9-chloro-7- (2-chlorophenyD-SH-pyrimidotSjM-d] [2] benzazepine 6-oxide, 1.0 ml (10 mmol) of phosphorus trichloride and 20 The mixture is refluxed for 3 hours and then cooled to give ice, basified with ammonium hydroxide and extracted with methylene chloride, the methylene chloride phase is washed with water, dried over sodium sulphate and evaporated in vacuo by addition of ether and gives 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine as colorless prisms, mp. 121-123 °.

Example 63 25

A mixture of 0.5 g (1.5 mmol) of 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine 6-oxide, 1.0 ml (10 mmol) of phosphorus trichloride and 20 ml of methylene chloride is refluxed for 2 hours.

It is poured on ice, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulfate and evaporated in vacuo. From ether, 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine gives rise to a whitish crisis.

³⁵ stalle of the m. 122-124 °.

Example 6U .

A mixture of 1.5 g ( ¹ mmol) of 8-chloro-1- (2-fluorophenyl) -3,1- ⁱ -dihydro- ¹ l- [(dimethylamino) methylene] J-5H-2-benzazepin-5-one 2-oxide, 1.5 g (20 mmol) of thiourea and 5 ml of a 4M methanolic sodium carbonate solution in 30 ml of methanol are stirred for 5 hours at room temperature. The reaction mixture is poured into water and extracted with ether. The aqueous phase is washed with,

Acidified and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulfate and evaporated in vacuo. The residue is triturated with methylene chloride to give an orange solid. Recrystallization from methylene chloride gives 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine-2-thiol-6-oxide as orange crystals of mp 323-325 ° (Zers.).

Example 65

20 '"

A mixture of 68 g (0.2 mol) of 9-chloro-7- (2-chloro)

phenyl) -5K "pyrimido [5,4-d] [2] benzozepine, 27 g zinc dust, 250 ml acetic acid and 600 ml methylene chloride is stirred for 2 hours at -30 ° C. The mixture is poured over Hyflo into a stirred mixture of 600 ml filtered concentrated ammonium hydroxide solution and 500 ml of ice.The methylene chloride phase is separated, dried over sodium sulfate and evaporated in vacuo.The residue is crystallized from methylene chloride / ether to give 9-chloro-7- (2-chlorophenyl) -6, 7 Dihydro-5H-pyrimido [5 , 'Hd] [2 jbenzazepine as a colorless solid, recrystallized from ether / methylene chloride to give colorless needles, mp 169-170 °.

35 Example 66

A solution of 1H, 5 g (42 mmol) of 9-chloro-7- (2 × chloro)

21 8 921 -72.

phenyl) -6,7-dihydro-5H-pyrimido [5 / ^I td] [2] benzazepine, 14.5 g (76 mmol) of p-toluenesulfonyl chloride, 30 ml of pyridine and 0.3 g of 4-dimethylaminopyridine in 300 ml of methylene chloride is stirred for 24 hours at room temperature. The mixture is washed with an excess of cold, dilute hydrochloric acid and dilute sodium hydroxide solution. After drying the methylene chloride solution over sodium sulfate and evaporation in vacuo, the residue is crystallized from methylene chloride / ether. This gives 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-6 - [(4-methylphenyl) sulfonyl] -5H-pyrimido [5,4-d] [2] benzazepine as a white solid of the mp. 200-201 °. Recrystallization from ether / methylene chloride gives the pure product as colorless prisms vpra mp 200-201 °.

15 '

Example 67

At 0 °, a solution of 6.4 g (19 mmol) of 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-5H-pyrimido [5,4-d] [2] benzazepine and Add 10 ml (12.8 mmol) of pyridine in 75 ml of methylene chloride dropwise with 5.0 ml (35 mmol) of trifluoroacetic anhydride. The mixture is stirred for 1 hour and poured into cold, dilute hydrochloric acid. The methylene chloride solution is separated, washed with saturated brine, dried over sodium sulfate and evaporated in vacuo. The residue is crystallized from ether and gives pink crystals of mp. 178-179 °. Recrystallization from ether gives 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-6- (trifluoroacetyl) -5H-pyrimido [5,4-d] [2] benzazepine as whitish crystals of Mp.. 179-180 °.

Example 68

A solution of 7.6 g (15 mmol) of 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-6 - [(4-methylphenyl) sulfonyl] -5H-pyrimidoC5 ,. ¹ id] [2] benzazepine and 4.0 g (20 mmol) m-chloro

Perbenzoic acid in 300 'ml of methylene chloride is stirred for 48 hours at room temperature. The mixture is washed with cold, dilute sodium hydroxide solution and saturated brine. The methylene chloride solution is dried over sodium sulfate and evaporated to dryness in vacuo. The residue (8.2 g) is purified by column chromatography on 20 g of silica gel, eluting with methylene chloride and then with ethyl acetate, giving 2.0 g of the starting material as a colorless solid from the methylene chloride fraction Ethyl acetate fraction gives 2.1 g of 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-6- [(4-methylphenyl) sulfonyl] -5H-pyrimido [5.4- d] [2] benzazepine-3-oxide as a whitish solid of the mp. 2 ^ 2-2 ^ 3 · By recrystallization from

Aether / methylene chloride gives colorless crystals of mp. 243-244 °.

Example 69

Method A-: A mixture of 2.0 g (3.9 mmol) of 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-6 - [(4-methylphenyl) sulfonyl] -5H-pyrimido [5., 4-d] [2] benzazepine-3-oxide and 8 ml of a 4M methanolic sodium ethoxide solution in 130 ml of tetrahydrofuran and 18.O ml of methanol is stirred for 19 hours at room temperature. The mixture is poured onto cold brine and extracted with methylene chloride. The organic phase is washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue is purified by column chromatography on 20 g of silica gel, eluting with ether / methylene chloride (1: 4) and methanol / methylene chloride (1: 9). Evaporation of the ethanol / methylene chloride fraction gives 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine-3-oxide as a white solid. Recrystallization from methylene chloride / ether gives long, colorless prisms of mp. 189-190 °.

218921

Method B: A mixture of. * 1.5 g (4.3 mmol) 9-

benzazepine-3-oxide, 6 ml of a 5 per cent. Methylene chloride solution of bromine and 600 ml of methylene chloride is stirred for 30 minutes at room temperature. The mixture is basified by the addition of 4.5 ml (32 mmol) of triethylamine and stirred for 10 minutes. The mixture is washed with saturated brine, dried over sodium sulfate and evaporated in vacuo, the residue is purified by column chromatography on 50 g silica gel eluting with methylene chloride, ethyl acetate and finally with tetrahydrofuran / methylene chloride (3: 7) contains a colorless solid of mp 242-244 °

15 is a compound which is isomeric to the desired product,

'regarding the imine bond. The tetrahydrofuran / methylene chloride fraction contains 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine-3-oxide as colorless prisms, mp. 189-190 °.

Example 70

The preparation of 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-6- (trifluoroacetyl) -5H-pyrimido [5,4-d] [2] benzazepine-3-oxide occurs in the same manner such as the preparation of 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-6 - [(4-methylphenyl) sulfonyl] -5H-pyrimido [5,4-d] [2] benzazepine-3 oxide and gives colorless crystals of mp. 209-211 °.

³⁰ Example 71

A mixture of 4.9 g (11 mmol) of 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-6- (trifluoroacetyl) -5H-pyrimido [5,4-d] [2] benzazepine. 3-oxide, 50 ml of 3N sodium hydroxide solution, 100 ml of ethanol and 100 ml of tetrahydrofuran is stirred for 30 minutes at room temperature. The mixture is concentrated in vacuo to a small volume, and the resulting

precipitate filtered off. This gives a colorless solid of mp 259-260. Recrystallization from tetrahydrofuran gives 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-5H-pyrimido [5,4-d] [2] benzazepine-3-oxide as colorless crystals of mp 263 -2611 degrees.

Example A

MANUFACTURE OF TABLETS (wet granulation)

Ingredient mg / tablet mg / tablet mg / tablet mg / tablet

parts 5  r 10 25 1. 2-amino-8- '1 chloro-7- (2- fluorophenyl) - 5H-pyriraido [5,4 d] [2] b e η ζ a ζ e ρ i η ·. or 7-phenyl-5H-pyridine mido [5,4-d] ben, 7 azepin-2-amine 232 • 261 280 2. Lactose 202 35 45 55 2. Modified 25 Strength 25 30 35 * J. Vorgelatini- 20 strength - - - 5. Distilled Water q.s. 3 fj 5 6. Magnesium 2 stearate 300 mg 350 mg 400 mg Tablet 250 mg mass . ,

Mix ingredients 1-4 in a suitable blender and granulate with plenty of water for a good one

2t 8 921

Consistency to receive. After milling, it is dried in a suitable oven. Then it is ground and mixed with magnesium stearate for 3 minutes. Finally, the mixture is pressed by machine into tablets of appropriate size.

Example B

MANUFACTURE OF TABLETS (direct compression) "

Ingredient mg / tablet mg / TabLette mg / tablet mg / tablet

parts 5 10 25 1. 2-amino-9 · 1 chloro-7- (2- fluorophenyl) - 5H-pyrimido [5,4 d] [2] benzazepine or 7-Phenyl-5K-pyridine mido [5,4-d] benz- azepin-2-amine 217 212 181 2. Lactose 221 45 55 3. Avicel U5 30 30 35 H. strength (direct 30 compressible) 3 _3 H 5. Magnesium 3 stearate 300 mg 300 mg 300 mg Tablets - 300 mg mass

Mix ingredient 1 with an equivalent amount of lactose. Subsequently, this mixture is well mixed with the ingredients 3 »4 and the rest of ingredient 2. After adding magnesium stearate, mix for 3 minutes. The mixture is finally mechanically

Tablets of corresponding size pressed.

Example C5. PREPARATION OF CAPSULES

Ingredient mg / tablet mg / tablet mg / tablet mg / tablet ' parts

1. 2-Amino-9-1-chloro-7- (2-fluorophenyl) -5H-pyrimido [5, ^I id] [2] benzazepine or

7-phenyl-5H-pyrimido [5, d] benzazepin-2-amine 2. Lactose 203

3. Strength 30 .1. Talk 15

25

5. Aerosol OT

Filling weight of the capsules

250 rag

293 , 5 32Ö 372 5 35 HO 30 15 20 20 1 , 5 2 2, 5

350 mg

400 mg U50 mg

Ingredients 1, 2, 3 and 5 are well mixed in a suitable blender. After the addition of talc is in turn mixed well and the mixture is bottled with a suitable industrial machine ³⁰ Neten in capsules.

Claims (4)

invention claim 1 · Process for the preparation of pyrimido-2-benzazepines of the general formula where A is one of the groups and Lower alkyl (C) R is hydrogen, chlorine, bromine, lower alkyl, the group NR ⁴ R ⁵ , the group -CH ₀ CO-R ⁷ , the group -ITH (CH ₀ ) Im ⁸ R ⁹ , R 1 is hydroxy, lower alkoxy, mercapto or lower alkylmercapto, R is hydrogen, amino or bis (lower) alkylamino, R is hydrogen, lower acyloxy or hydroxy, ZY / oxygen, halogen, trifluoromethyl, ethyl, C 1 -C 6 -hydroxyethyl or acetyl, YV / a hydrogen or halogen, R and R 'are each hydrogen or lower alkyl or, together with the nitrogen atom, a 5- to 7-membered heterocycle which is an oxygen or sulfur atom or the group R may be hydrogen, lower alkoxy or NR R, R and R are each hydrogen or lower alkyl, η is 0 or 1 and m is 1 to 7, with the proviso that -79-. *. 07/21/1980 AP C 07 D / 218 56 971/11 1 ? (i) at least one of R and R is hydrogen; (ii) when R ^ is lower acyloxy or hydroxy, A ^u roup (a), X is hydrogen, halogen, trifluoromethyl, ethyl or acetyl and, if R is ¹ group -im (CH ₂ ) _m IIR ⁸ R ⁹ , R ⁸ and R ^{9 are} never ^ denote alkyl; (iii) when A group (d) and R ^{1 are} the group DQ 8 9 R ^, R and H are lower alk mean yl; and ' (iv) when η is 1, R is hydrogen, lower alkyl, lower alkoxy, chloro, bromo or the 7 7 group -CHp-CO-R (in which R has the above meaning) and A represents group (a) or (b); and of pharmaceutically acceptable S ^.: iureadditlons: mln of which, gel-: characterized by .tan a) a compound of the general formula B ¹¹ wherein Z and Y have the above meaning and R is hydrogen, lower alkyl or HR ⁸ R ^, wherein R ⁸ and R ^ have the above meaning, is cyclized or 21 8 DV 4008/301 k b) a compound of the general formula III wherein X, Y and R have the above meaning, dehydrated or c) a compound of the general formula HR ²¹ IV wherein X and Y have the above meaning and ρ O or 21 1 and R are di (lower) alkylamino, reacted with cyanamide or 30 d) a compound of the above general formula IV with a compound of the general formula NH NHR 1ΛΛ ,! f- 21 8 DV .4θΟ8 / λΟ1 k 12 - wherein R is hydrogen, mercapto, lower Alkyl racercapto, lower alkyl or NR R ⁹ . wherein R ⁸ and R have the meaning above, implies or implements , e) a compound of the general formula Ia 1 2 wherein X, Y, R and R have the above meaning, reduced or f) a compound of the general formula 1 in which X, Y, R and R have the above meaning, lower alkylated or g) a compound of the general formula 21 8 921 - 82 - DV 4008/301 k ic 2 13 wherein X, Y and R have the above meaning and R ^J Hydrogen, lower alkyl, hydroxy, lower alkoxy, ^{11 4 51} each hydrogen or ssers NR ¹¹¹ R ⁵¹ (which ¹ and R lower alkyl or, together with the nitrogen atom, a 5- to 7-membered heterocycle which may contain an oxygen atom), chlorine, 7 denotes bromine or the group -CHp-CO-R (in which R has the above meaning), with the proviso that at least one of R and R is hydrogen must be 20, oxidized or h) a compound of the general formula id wherein X, Y and ρ have the above meaning and R is mercapto or hydroxy, lower alkylated or 8 92 t i) DV 4008/301 k a compound of the general formula 10 15 25 30 Ie in which X, Y and ρ have the above meaning, converted into the corresponding 2-hydroxy compound or k) a compound of the general formula wherein X and Y have the above meaning, converted into a corresponding 2-chloro or 2-bromo compound or 1) a compound of the general formula 35 21 8 921 DV 4008/301 k ₃ 15 wherein X, Y and ρ have the above meaning and R Chlorine or bromine means
with hydrogen sulfide, with a lower alkyl mercaptan, with a lower alkanol, with a compound of the formula Ii κ h c
HNR R, in which R and R have the above meaning, with 8 Q 8 a compound of the formula H ₀ N- (CH ₅ ) NR R, wherein R, ο cam R and m have the above meaning, or with the carbanion a compound of the formula / OR 71 or CH ₂ ^N COR ⁷¹ CH ₂
^N COR 71 71 21 wherein R is lower alkoxy and R above Has meaning, implements or m) a compound of the general formula R71-CO-CH2 ih DV 4008/301 k 71
wherein R, X, Y and p have the above meaning, converted into the corresponding free acid, or in a corresponding amide, Niederalkylaraid or di-lower alkylamide or n) a compound of the general formula 10 ii wherein Y and R have the above meaning, R is hydrogen, chlorine, bromine, lower alkyl, the group MR ¹¹ R ⁵ , the group -CH-CO-R ⁷ , the group -NH (CH ₂ ) _m : iR ⁸ⁱ R ⁹¹ , Hydroxy, lower :; Alkoxy, mercapto. or lower alkyl mercapto, X 'WaoserstoiT, halogen, - pi · η i trifluoromethyl, ethyl or acetyl and R 'and R are each lower alkyl and R, R and R' above Possession, with dor r'a:>:; ~ abo, that :; mi n.ion sound s 1 ^: ft ? one of R and R is hydrogen,. '' reacts with a Niederacylierungsmittel or o) a compound of the general formula 30 35 21 8 921 86. DV 4008/301 k 1 fi 0 wherein X ^f , Y ₁ R and R have the above meaning and R means lower acyloxy, with the proviso that at least one of R and R is hydrogen, hydrolyzed or p) a compound of the general formula 10 1520 2 17 in which X, Y and R have the above meaning, R ' h c hy 25 Hydrogen, lower alkyl, the group MR R
Group -CH ₂ -CO-R ⁷ , the group MH- (CH ₂ ) 1 LR ⁸ R ⁹
droxy, lower alkoxy, mercapto or lower
Alkylmercapto means and R, R ^, R ⁷ _f R ^ _unc j r9 have the above meaning, with the proviso that 17?
at least one of R and R is hydrogen, deoxygenated or 30 DV 4008/301 k q) - from an association of the general formula 10 v orin X, Y and R have the above meaning and R is hydrogen, lower alkyl, lower alkoxy, chlorine, "7 7 Bromine or the group -CHp-CO-R; (where R is the above Meaning) and Z is hydrogen or an easily cleavable acyl group, with the proviso 1 P ο that at least one of R and R is hydrogen, the elements removed from H-Z or .. r) converting a compound of the formula I into a pharmaceutically acceptable acid addition salt. 30 35 21 8 921 -88- 21.7.1980   , * AP C 07 D / 218 56 971/11 2, Process according to item 1, characterized in that compounds of the formula I, wherein A is the group (b), R is amino, η 0, C is hydrogen, halogen having an atomic number of at most 35 or trifluoromethyl and Y is hydrogen or halogen with a Atomic number of at most 35, and that these compounds according to process variant d), wherein 2 and Y have the above meaning and H ²¹ D:
interpret, manufacture. 21 12 and R dimethylamines, ρ 1 and R amino Process according to item 1, characterized in that compounds of the formula I in which R is hydrogen, ^u , OQ Q Bromine, lower alkyl, the group NR R ⁷ (wherein R and Br are each hydrogen or lower alkyl), the group -CHg-CO-R '(where R' is lower alkoxy), bialkylaminoalkylamino, hydroxy, lower alkoxy, mercapto or ρ
lower alkylmercapto and R is hydrogen, amino or Dimethylamines, with the proviso that (i) when A is group (b), (c) or (d) or when group (a) and R are lower acyloxy or hydroxy, RV / oxygen, lower alkyl or NR ⁸ R ⁹ ; and (ii) when η is 1, A is the group (b); or pharmaceutically acceptable acid addition salts thereof produces and that one operates according to process variants a), b), k) or r); or that one 21 works according to process variant c), where R is dirnethylamino and ρ O; or that one 21 operates according to method variant d), wherein R Dimethylamines and R hydrogen, mercapto, QQ denote alkyl or NR R ^y , with the proviso 12
, that ρ is O, if R means mercapto or if * 12 It Amino, X hydrogen, halogen with an atomic -89- / - "21.7 · T 980 AP C 07 D / 218 ¹ 921 56 971/11 35 or trifluoromethyl and YY / oxygen or halogen with an atomic number not exceeding 35; or that one operates according to process variant e) or f), wherein R is hydrogen, lower alkyl or NR ⁸ R ⁹ and R ^{2 is} hydrogen; or that according to process variant g) 13
works, where R ^ is hydrogen, lower alkyl or 8 9 * 2
And R is hydrogen - KR R ^7; or that one operates according to process variant h) or i), where ρ is 0; or that one operates according to process variant 1), wherein a compound of formula Ig, wherein ρ is 0, in a corresponding compound of formula I, wherein R is lower alkoxy, lower alkylamino, di-lower alkylamino, dialkylaminoalkyl 71 amino or ^u roup -CHpGOR means is transferred; or that one operates according to process variant n) or o), where R is hydrogen, 8 9 2
Alkyl or NR R and R are hydrogen. 4. The method according to item 1, characterized in that one produces compounds of formula I, wherein A is group (a) and η is 0. 5. The method according to item 4, characterized in that one 2 3 Compounds of formula I wherein R and R ije hydrogen and R hydrogen, lower alkyl, 45 ^ the group Hr 4r 5 (in which R 1 and R 1 are each hydrogen or lower alkyl, hydroxy, chlorine, bromine, the group -NH (CH ₀ ; NR ⁸ R ⁹ (in which R ⁸ and R ^{9 are} each lower alkyl) C. HI rj or the group -CH ₂ -CO-R '. Process according to point 5 »characterized in that compounds of the formula I are prepared in which hydrogen peroxide, 21 8 921 -90- 21.7.1980 , , AP C 07 D / 218 921 56 971/11 Amino or lower alkyl means » 7 · Method according to item 4, characterized in that Compounds of formula I are prepared in which R is hydrogen T 1 Substance, R ^ hydroxy and R is hydrogen, lower alkyl or the group ITR ^ hr (wherein R ^ and R * are each hydrogen or lower alkyl). , 8 · Method according to item 4, characterized in that 1 3 Compounds of formula I, wherein R and R are each ρ
Hydrogen and R is amino or di-lower alkylamino. 9 · Method according to item 8, characterized in that 2 compounds of formula I wherein R is dimethyl amino means. 10. The method according to any one of items 4 to 9 »characterized by preparing compounds of formula I wherein X is halogen. 11, method according to item 10, characterized in that compounds of formula I are prepared, wherein. X ^ hlor means. Method according to one of the items 4 to 11, characterized in that compounds of the formula I are prepared in which Y is hydrogen, chlorine or fluorine. 13 · Method according to item 1, characterized in that 9-chloro-7-C 2-chlorophenyl) -SH-pyrimido, 4-d7Z "27-benzazepine. t; " -91-. 21.7,1980 AP C 07 D / 218 921 56 971/11 14β Method according to item 1, characterized in that 9-chloro-.7 "(2-.fluorophenyl) -5H ~ pyrimido [5,4-dJ [^ benzazepine prepared 15 · The method of item 1, characterized in that 9 ~ ^c ~ hlor 7- (2 ~ chlorophenyl) -2-methyl-5H ~ pyrirnido- [5,4-d] [2lbenzazepin "manufactured. 16 · Method according to item 1, characterized in that 9-chloro-7-ί'2-fluorophenyl) ~ l · I, l ^ -dilτ ^ ithyl-5H-pyridinium (5,4-d] r2jbenzazepin ~ -4 ~ ainin manufactures » Process according to item 1, characterized in that one prepares S-OHI- or-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-ol. 18. The method according to item 1, characterized in that 9-chloro-ii, K-di-Tiiethyl-7- (2-fluorophenyl -) - 5H-pyrira? Ldo ·? [5 »4-d [[2" [benza7epin-2 ~ amine produced] 19 · Process for the preparation of medicaments, in particular for use as anxiolytics and edativa, characterized in that one brings a compound of the general formula I defined in point 1 or a pharmaceutically acceptable acid addition salt thereof in a galenic dosage form.