NO153138B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PYRIMIDOBENZOAZEPINE DERIVATIVES - Google Patents

Abstract

Pyrimido-2-benzazepines of the formula <IMAGE> wherein A is one of the groups <IMAGE> R<1> is hydrogen, chlorine, bromine, lower alkyl, the group NR<4>R<5>, the group -CH2-CO-R<7>, the group -NH(CH2)mNR<8>R<9>, hydroxy, lower alkoxy, mercapto or lower alkyl mercapto, R<2> is hydrogen, amino or di-lower alkyl amino, R<3> is hydrogen, lower acyloxy or hydroxy, X is hydrogen, halogen, trifluoromethyl, ethyl alpha -hydroxy ethyl or acetyl, Y is hydrogen or halogen, R<4> and R<5> each are hydrogen or lower alkyl or, together complete a five to seven membered heterocyclic ring, R<7> is hydroxy, lower alkoxy or NR<8>R<9>, R<8> and R<9> each are hydrogen or lower alkyl, n is 0 or 1 and m is 1 to 7, with certain provisos, and pharmaceutically acceptable acid addition salts thereof, exhibit pharmacological utility as anxiolytics and sedatives.

Description

The present invention relates to an analogue process for the production of new therapeutically effective pyrimido-2-benzazepines with the general formula

where A is one of the groups 1 4 5 R is hydrogen, chlorine, bromine, lower alkyl, the group NR R , • 7 8 9

the group -CH2-CO-R , the group -NH(CH2)mNR R , hydroxy, lower alkoxy, mercapto or lower alkyl-mercapto,

3

R is hydrogen, lower acyloxy or hydroxy, X is hydrogen or halogen, Y is hydrogen or halogen, R 4 and R^ are each hydrogen or lower alkyl or form together with the common nitrogen atom 4-methyl-1-piperazinyl,

7 8 9 8 9

R is hydroxy, lower alkoxy or NR R , R and R are each hydrogen or lower alkyl, n is 0 or 1 and m is 1-7, with the proviso that

(i) when R 3 is lower acyloxy or hydroxy, A is

1 8 9 the group (a), and if R is the group -NH(CH-) R R 8 9 R and R are each lower alkyl; 1 8 9 -(ii) when A is the group (d) and R is the group -NH(CH9) R R ,

8 9

R and R are each lower alkyl; and

(iii) when n is 1, R"'" is hydrogen, lower alkyl, lower R al7 coecr syso, m colovren, fobrr om angeiltletr ) and ruA ppeen r g-rCHupz^p-eCn O-R (a7) (hevlolreri (b ) ;

and pharmaceutically acceptable acid addition salts thereof. These compounds have pharmacological effects as anxiolytic and sedative agents.

In the above-mentioned compounds, the term "lower alkyl" means straight-chain or branched hydrocarbon groups with from 1-7 carbon atoms, preferably 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, etc.

The term "halogen" means all four forms thereof, i.e. fluorine, chlorine, iodine and bromine unless otherwise expressly stated.

The terms "lower alkoxy" and "lower alkyl-mercapto" denote a residue with the formula -O-lower alkyl and -S-lower alkyl, respectively, where lower alkyl is as previously stated..

Where the term "heteroatom" or "carbon atom nucleophiles" is used, residues as described in Belgian Patent No. 833,249 are meant.

The term "pharmaceutically acceptable salts" is used for

to denote 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 easily be formed, taking into account the prior art and the nature of the compound, by one skilled in the art.

Related therapeutically active compounds are known from BRD publication no. 2 524 048. The activity of three such compounds was compared with compounds according to the present invention (see pp. 30 and 33). From this it appears that the compounds according to the present invention are, on the whole, quantitatively superior and surprisingly exhibit a particularly pronounced activity, i.a. in the metrazol sample.

A particularly popular compound according to the invention is 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine.

According to the present invention, compounds of formula I and pharmaceutically acceptable acid addition salts thereof can be prepared by

a) cyclization of a compound of the general formula

where X and Y are as above, and R"^ is hydro-8 9 8 9

gene, lower alkyl or NR R where R and R are as above,

or

b) dehydrogenation of a compound with the general

"formula"

where X, Y and R^ are as indicated above, or c) the origin of a compound of the general formula

where X and Y are as above, p is 0 or 1

21

and R is di-lower alkylamino,

with cyanamide,

or

d) turnover of a compound with the general formula

IV above, with a compound of the general formula

where R <12> is hydrogen, mercapto, lower alkyl mercapto, 8 9 8" 9 lower alkyl or NR R where R and R are as above,

or

e) reduction of a compound of the general formula

where X, Y and R"'" are as above,

or

f) lower alkylation of a compound of the general formula

where X, Y, and.R^ are as above indicated,

or

g) oxidation of a compound of the general formula

13

where X bg Y is as indicated above and R is hydrogen, lower alkyl, hydroxy, lower alkoxy, NR<41>R<51> (where R<41> and R<51> are each hydrogen or

7 lower alkyl, chlorine, bromine or the group -CH -CO-R

(where R 7 is as above),

or

h) lower alkylation of a compound of the general formula

where X, Y and p are as indicated above and R 14 is mercapto

or hydroxy,

or

i) transfer of a compound of the general formula

where X, Y and p are as above,

in the corresponding 2-hydroxy compound,

or

k) transfer of a compound of the general formula

where X and Y are as above,

in a corresponding 2-chloro or bromo compound, or

1) treatment of a compound with the general formula

15

where X, Y and p are as above and R is

chlorine or bromine,

with hydrogen sulphide, with a lower alkyl mercaptan, with a lower alkanol, with a compound of formula HNR^R^ where

4 5

R and R are as above, with a compound with

8 9 8 9

formula H0N-(CHo)NR R , where R , R and m are as above or with the carbanion of a compound of the formula

7-1 21 where R is lower alkoxy and R is as indicated above, followed by saponification and decarboxylation of the thus obtained intermediate, or m) transfer of a compound of the general formula

71

where R , X, Y and p are as indicated above,

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

or

n) turnover of a compound with the general formula

wherein X and Y are as above, R^ is hydrogen, chlorine, bromine, lower alkyl, the group NR4R^, the group

-CH2-CO-R<7>, the group -NH (CH^NR^R91, hydroxy<y,> lower alkoxy, mercapto or lower alkylmercapto, R<81> and R<91> are each lower alkyl, and R4, R<5> and R<7>

is as stated above,

with a lower acylating agent or

o) hydrolysis of a compound of the general formula

16 31 where X<1>, Y, and R are as stated above and R

is lower acyloxy,

or else

p) deoxygenation of a compound of the general formula

17 where X and Y are as indicated above, R is 4 5 hydrogen, lower alkyl, the group NR R , the group 7 8 9 -CH2-CO-R , the group NH-(CH2)m-NR R , hydroxy, lower alkoxy, mercapto or lower alkyl mercapto and R4,

5 7 8 9

R , R , R and R are as indicated above,

or

q) removing elements H-Z from a compound of the general formula

18

where X and Y are as indicated above, R is hydrogen, lower alkyl, lower alkoxy, chlorine, bromine or

7 7

the group -CH2-CO-R (where R is as stated above) and Z is hydrogen or an easily cleavable acyl group

and

optionally transferring a compound of formula I prepared above into a pharmaceutically acceptable acid addition salt.

It will be obvious to a person skilled in the art that when the compound

which is to be subjected to one of the above-mentioned reactions^ contains, in addition to the groups included in the reaction, groups W which may be sensitive under such reaction conditions, either such a method must be used which does not affect such sensitive groups if such a method exists, or such sensitive groups must be protected before the reaction is carried out^ and the protecting group must then be removed.

The embodiments a) and b) above and the preparation of the starting materials are illustrated in exemplary form by the following reaction scheme I where X, Y and R<11> are as above: Compounds VI, VII and VIII are generically known compounds. A method of making them is included for completeness.

VI > VII

The compound with formula VI is a previously known compound which is reacted with copper (II) cyanide after prior treatment with sulfuric acid, sodium nitrite and possibly sodium tetrafluoroborate in series. The mixture is then hydrolysed with an alkali metal hydroxide, e.g. sodium or potassium hydroxide at reflux temperature.

VII VIII

The compound of formula VIII is formed by reacting the carboxylic acid of formula VII with methanol in the presence of an acid catalyst, such as sulfuric acid around the methanol's reflux temperature for approx. 3-18 hours.

VIII > IX

The compound of formula VIII is then reacted with 1-chloro-2,3-epoxypropane or other suitable epoxide ketalizing agents such as ethylene oxide and 1,2-epoxypropane in the presence of a Lewis acid such as aluminum chloride or boron trifluoride or preferably stannous chloride in an inert organic solution. agent such as toluene, carbon tetrachloride or benzene. Suitable reaction temperatures are from approx. 20°C to 110°C, but around 25°C is preferred.

IX > X

The compound of formula IX is then reacted with a^ethonitrile (CH^CN) in the presence of an alkali metal amide such as sodium or potassium amide in liquid ammonia in the presence of an inert organic solvent such as diethyl ether, tetrahydrofuran or dioxane. The reaction temperature can. vary from around the reflux temperature for liquid ammonia to room

perature.

X > XI

The compound of formula X is then reacted with a dimethoxy acetal of dimethylformamide such as dimethylformamide-dimethylacetal. Suitable reaction temperatures are from approx. 25°C - 120°C, the reflux temperature for dimethyl acetal being preferred.

XI > XII

The conversion of the compounds of formula XI into the compounds of formula XII involves two steps, namely reaction with an appropriate acid addition salt of an amidine or guanidine of the formula

wherein R is as above,

and acid hydrolysis of the ketal function. When X and Y are both hydrogen, the acid hydrolysis of the ketal function is preferably carried out before the reaction with amidine or the guanidine salt, but when X and/or Y is different from hydrogen, the acid hydrolysis of the ketal function is preferably carried out after the reaction with amidine or the guanidine salt. By-products that are formed must be removed from the reaction mixture before proceeding.

The reaction with an expedient acid addition salt

of an amidine or guanidine of formula Va such as formamidine acetate, acetamidine hydrochloride, guanidine carbonate or a substituted guanidine carbonate proceeds well in an aprotic polar organic solvent such as dimethylsulfoxide in a temperature range from approx. 25°C - 125°C, preferably 90° - 95°C.

The ketal function is hydrolysed by means of an aqueous inorganic acid such as sulfuric acid, phosphoric acid or preferably a hydrogen halide acid such as hydrochloric acid in the presence of a lower alkyl organic alcohol solvent, preferably ethanol. The reaction is carried out at around room temperature.

XII II

The compound of formula II is formed by 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 the compound In. The hydrogenation can also be carried out in a suitable organic solvent such as lower alkyl organic alcohols or lower alkyl carboxylic acids, e.g. acetic acid. Depending on the conditions during the aforementioned hydrogenation, a dihydropyrimido compound of formula III is formed in addition to, or instead of, the compound of formula In. This dihydropyrimido compound can be converted to the compound of formula In by treatment with a mild oxidizing agent, such as manganese dioxide, air, etc.

Embodiment c) is illustrated e.g. by the following reaction scheme II:

IVa > Io and lp

The compound with formula IVa is previously known, see e.g. U.S. Patent Nos. 3,947,585, 4,022,800 and 4,028,381. The compound is reacted with cyanamide in a C^ to C^ alcohol, e.g. ethanol at a temperature between 25°C and 80°C, the reflux temperature for the relevant alcohol being preferred.

A mixture of the amino compound and the N,N-disubstituted amino compound is obtained which can be separated, e.g.

by fractional crystallization and/or chromatography.

Process variant d) above includes the reaction of a compound of formula IV with an amidine or guanidine salt or with thiourea or an S-lower alkyl isothiourea. For the reaction with the amidine or the guanidine salt, any inert organic solvent such as dioxane, tetrahydrofuran or dimethylformamide can be used at a reaction temperature from around room temperature to the reflux temperature of the solvent, but around room temperature is preferred. The reaction with thiourea or with an S-lower alkyl isothiourea can be carried out in the presence of an alcoholic, e.g., methanolic solution of an alkali metal alkoxide, e.g. sodium methoxide. The reaction can be carried out at between 0°C and 65°C, but around room temperature is preferred.

The process variants e) and f) are illustrated in exemplary form by the following reaction scheme III, where R is as above:

In » Io' and In or Io' » XIII

The compound of formula In (see reaction scheme I) is treated with a reducing agent such as zinc in acetic acid at a reaction temperature from approx. -40°C to 20°C and gives Io'. The solvent used can be a halogenated hydrocarbon such as methylene chloride.

The compound of formula In or Io' is reacted with hydrogen

in the presence of platinum oxide or previously hydrogenated platinum oxide and glacial acetic acid as solvent and gives XIII. The reaction is normally carried out at around room temperature.

Other applicable reducing agents for process variant

e) includes sodium cyanoborohydride, sodium borohydride etc.

In many cases, mixtures of 6,7-dihydro and

The 4,5,6,7-tetrahydro compounds. These 4,5,6,7-tetrahydro compounds also have useful CNS properties.

Io<1> > lp'

The compound of formula Io<1> is reacted with formaldehyde in formic acid under heating, e.g. around reflux temperature for methylation of the dihydro compound. Methylation can also be carried out with e.g. methyl iodide, dimethyl sulfate, etc.

Lower alkyl substituents other than methyl can be prepared by using the corresponding alkyl halides, sulfates, alkyl sulfonates, tosylates, etc. in a solvent such as dimethylformamide, tetrahydrofuran, glyme and diglyme, or ether solvents or by using the appropriate aldehydes under reducing reaction conditions.

Process variant g) is illustrated, for example, by the following reaction scheme IV where R<11> is as above:

The compound of formula In is reacted with a suitable oxidizing agent such as metachloroperbenzoic acid in an inert organic solvent such as methylene chloride. The reaction can be carried out at between approx. 0°C and room temperature, with around room temperature being preferred. The reaction time can be varied depending on whether the N-oxide or the di-N-oxide product is desired. The N-oxide

Iq is mainly formed when the reaction time is varied between approx. 2 and 25 hours, while the di-N-oxide Ir is mainly formed when the reaction time is between approx. 40 and 60 hours.

According to process variant h) above, lower alkylation

a mercapto or hydroxy group by methods known per se. The alkylation of the mercapto group is readily carried out by means of the corresponding alkyl halide in the presence of a mixture of an alkali metal hydroxide, such as sodium hydroxide, and a to C 1 alcohol, such as ethanol. The reaction can preferably be carried out at around room temperature.

The alkylation of the hydroxy group is easily carried out with a dialkyl sulfate such as dimethyl or diethyl sulfate under basic conditions, e.g. in the presence of sodium hydroxide. The reaction can be carried out from approx. 0°C - 65°C, around room temperature being preferred.

The transfer of a 2-amino compound into the corresponding 2-hydroxy compound according to method variant i) above can be carried out with the aid of an acid, such as sulfuric acid. Reaction st emper a turn can be varied from approx. 25°C - 125°C, with around 100°C being the preferred temperature.

Other methods that can be used for the conversion are alkaline hydrolysis and substitution of diazonium salts.

The conversion of a 2-hydroxy compound into the corresponding 2-chloro or bromine compound according to process variant k) above can be carried out respectively with a suitable chlorinating agent such as phosphorus trichloride at reflux temperature for the mixture, and with a suitable bromination reagent such as phosphoryl bromide or phosphorus pentabromide at from approx. room temperature to

backflow.

According to method variant 1) above, the chlorine or bromine atom in the 2-position in the compound of formula Ig can be replaced by nucleophilic substitution with various heteroatom and carbon atom nucleophiles such as methanol, 3-dimethylaminopropylamine, methylamine, dimethylamine, N-methylpiperazine, the carbanion of diethylmalonate, etc. in an inert polar organic solvent such as dimethylformamide at from 0°C to the reflux temperature of the solvent, preferably at room temperature by reacting the compound 1g with a carbanion of the formula listed under 1) an intermediate product is obtained which is then transferred into a compound with formula I by saponification with a base, e.g. potassium tert.-butoxide, and decarboxylation by heating to e.g. 100-160°C.

The conversion of a compound of formula Ih into the corresponding free acid according to process variant m) above is easily carried out by hydrolysis under alkaline conditions, e.g. using an alkali or alkaline earth metal hydroxide,

such as sodium or potassium hydroxide or the like, in the presence of a suitable solvent such as a lower alkanol, e.g. ethanol.

The conversion of a compound of formula Ih into a corresponding amide according to process variant m) above can be carried out either by treatment with ammonia or a corresponding mono- or di-lower alkylamine at room temperature or at a higher temperature (preferably approx. 50 - 130°C) in the presence of an inert organic solvent such as a lower alkanol, e.g. ethanol, or by hydrolysis to the corresponding free acid, conversion of the 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 corresponding mono- or di-lower alkylamine .

Method variants n) and o) are illustrated as examples

11 31

by the following reaction scheme V where X , Y, R and R

is as above:

Ice > It

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

It > lu

The compound of formula It can be reacted with an alkali metal carbonate such as sodium or potassium carbonate in a C-| to alcohol, such as methanol at a temperature from approx. 0 C - 65°C, around room temperature being preferred. Other suitable reaction conditions for this step include the use of alkali metal hydroxides, e.g. sodium or potassium hydroxide, and one to alcohol in the presence of water, or in the alternative, an acid hydrolysis using an aqueous mineral acid such as hydrochloric or sulfuric acid with a 16sing agent1 such as THF or dioxane at a reaction temperature from approx. 0°C

to room temperature, but 0°C is preferred.

The deoxygenation according to method variant p) above can be carried out by methods known per se, e.g. by means of reagents such as phosphorus trichloride, trilower alkyl phosphites (e.g. triethyl phosphite), hexachlorodisilane, Raney nickel etc.

Process variant q) above and the preparation of the starting materials for this are illustrated in the form of an example

18

by the following reaction scheme VI, in which X, Y and R are as above and Z<1> is an easily cleavable acyl group:

Iv XIV

This transfer involves an acylation using a suitable acylating agent to give the easily cleavable acyl group Z', such as trifluoroacetyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, the mixed anhydride of formic acid and acetic acid, ethyl chloroformate, benzyloxycarbonyl chloride, etc.. The conditions for carrying out an acylation of this type will be well known to a 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 must be run at between approx. 0°C and room temperature, but room temperature is preferred. The reaction time is between approx. 40 and 60 hours.

XV > XVI

The acyl group Z<1> is cleaved off by methods known per se, which are well known to the person skilled in the art. The choice of the method to be used obviously depends on the nature of the acyl group Z<1>. Thus, e.g. the trifluoroacetyl or ethoxycarbonyl groups are removed by alkaline hydrolysis, the formyl group by acid hydrolysis and the benzyloxycarbonyl group by means of hydrogen bromide etc.

XVI or XV > Iw

The conversion of XVI into Iw comprises a dehydrogenation which can be carried out by known methods, e.g. by means of diethylazo-dicarboxylate or by N-halogenation (preferably N-bromination) followed by a dehydrohalogenation under alkaline conditions, e.g. using a tertiary amine such as triethylamine.

When Z<1> in formula XV is a group such as tosyl or mesyl,

an elimination of H-Z' can be carried out under alkaline conditions, e.g. by means of an alkali metal alkoxide in then corresponding alkanol such as methanolic sodium methoxide.

Any 7H-isomer of the compound of formula Iw which is formed can be isomerized to the compound of formula Iw by treatment with a suitable base, e.g. methanolic sodium methoxide.

For the sake of completeness, the production of such among the intermediates of formula IV in which p is 1 is exemplarily illustrated by the following reaction scheme VII where X and Y are as above: The compound of formula XVII can be reacted with a peracid such as methachloroperbenzoic acid in an inert organic reaction agent1 such as a halogenated hydrocarbon, e.g. methylene chloride, or an ether. The reaction can be carried out from approx. 0°C - 40°C, but room temperature is preferred. The mixture of products can then be separated from each other by fractional crystallization. Analysis by thin layer chromatography shows the presence of both products.

The compound of formula XVIII can be reacted with dimethylformamide dimethyl acetal in an inert solvent such as a halogenated hydrocarbon, e.g. methylene chloride, or dimethylformamide or high-boiling ethers. The reaction temperature can vary from approx. 0°C - 100°C, but room temperature is preferred.

The pyrimido-2-benzazepines of formula I above and their pharmaceutically acceptable acid addition salts are useful as pharmaceuticals and are characterized by activity as sedative and anxiolytic agents. These compounds can be used in the form of conventional pharmaceutical preparations, e.g. the aforementioned compounds can be mixed with conventional organic or inorganic inert pharmaceutical carriers suitable for parenteral or enteral administration such as e.g. water gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gum, polyalkylene glycols, vaseline etc. They can be given in conventional pharmaceutical forms, e.g. solid forms, such as tablets, dragees, capsules, suppositories etc., or in liquid forms such as solutions, suspensions or emulsions.

Furthermore, the pharmaceutical mixtures containing compounds according to the invention can be subjected to conventional pharmaceutical treatments such as sterilization and can contain conventional pharmaceutical excipients such as preservatives, stabilizers, wetting agents, emulsifying agents, salts for adjusting osmotic pressure or buffers. The mixtures may also contain other therapeutically active materials.

The following table shows results that were obtained when

the following compounds underwent certain well-known tests such as the inclined screen test, the foot shock test, the unanesthetized cat test, and the antipentamethylenetetrazole (metrazole) test, as well as indications regarding toxicity: Comparative compounds X, Y, Z are related compounds ( German interpretation document 25 24 048).

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

B: 9-chloro-7-(2-chlorophenyl)-5H-pyrim.ido[5, 4-d] [2 Jbenzazepine

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

D: 9-chloro-7-(2-chlorophenyl)-6,7-dihydro-2-methyl-5H-pyrimido[5,4-d][2]benzazepine dihydrochloride

F: 9-chloro-7-(2-chlorophenyl)-6,7-dihydro-2,6-dimethyl-5H-pyrimido[5,4-d][2]benzazepine-methanesulfonic acid salt (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]benzazepine

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]benzazepin-2-amine

L: 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido-[5,4-d][2]-benzazepine;

M: 9-chloro-7-(2-fluorophenyl)-N-methyl-5H-pyrimido-[5,4-d]-[2]benzazepine-2-acetamide;

N: 9-chloro-7-(2-chlorophenyl)-5H-pyrimido-[5,4-d][2]benz-zepin-5-ol-acetate:

0: 9-chloro-7-(2-chlorophenyl)-5H-pyrimido-[5,4-d][2]benz azepin-5-ol; P: 9-chloro-7-(2-chlorophenyl)-5H-pyrimido-[5,4-d][2]benz azepine-6-oxide; Q: 9-chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido-[5,4-d ]- [2]benzazepine-3,6-dioxide. Previously known compounds (German Offenlegungs-schrift_2:.524i048)_ X: 8-chloro-6-phenyl-1,4-dihydro-pyrazole-[4,3-d][2]benz azepine; Y: 8-chloro-6-(2-fluorophenyl)-1,4-dihydro-1-methylpyrazole- [4,3-d][2]benzazepine; Z: 8-chloro-2-methyl-6-phenyl-2H,4H-pyrazole-[4,3-d][2]- benzazepine hydrochloride

A suitable pharmaceutical dosage unit can contain from approx. 1 - 500 mg of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof with a dosage range from approx. 1 mg to 100 mg preferred for oral administration and a dosage range from approx. 1 mg to 50 mg for parenteral administration. For each patient, however, the particular dosage range must be adapted to individual requirements and the judgment of the person who administers or supervises the administration of the aforementioned compounds. It must be pointed out that the dosages described here are only examples and in no way limit the scope or practice of the present invention.

The term "dosage unit" as used in this specification refers to pharmaceutical defined units suitable as unit dosages for mammals and each containing a predetermined amount of active material calculated to produce the desired therapeutic effect in conjunction with the necessary pharmaceutical diluent, carrier or excipient.

The following examples are illustrative, but not limiting of the invention. All temperatures are given in centigrade unless otherwise stated.

Example 1 2-amino-9-chloro-7-phenyl-SH-pyrimidorS, 4-dl\ 2 Ibenzazepine

A stirred suspension of 10 g (0.032 mol) of 8-chloro-3,4-dihydro-4-(dimethylaminomethylene)-1-phenyl-5H-2-benzazepin-5-one and 8.5 g (0.047 mol) of guanidine carbonate in 250 ml of methanol was treated at room temperature under argon with 5.1 g (0.094 mol) of sodium methylate in one portion. 150 ml of methylene chloride was added after 10 min. and the rowing continued. The same amount of sodium methylate and guanidine carbonate was added two or more times at 2 hour intervals and stirring was continued overnight. After dilution with 250 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from ethanol gave light brown crystals: m.p. 209 - 210°C. Recrystallization of a sample from methylene chloride/ethyl acetate gave off-white prisms: m.p. 210 - 211°C.

Example 2

2- amino- 9- chloro- 7-( 2- fluorophenyl)- 5H- pvirimidor5, 4- dl[ 21-benzazepine

A stirred suspension of 16 g (0.047 mol) of 8-chloro-1-(2-fluoro-phenyl)-3,4-dihydro-4[(dimethylamino)methyl]-5H-2-benzazepin-5-one and 12, 5 g (0.07 mol) of guanidine carbonate in 460 ml of methanol was treated at room temperature under argon with 7.5 g

(0.14 mol) of sodium methylate in one portion. Methylene chloride (290 ml) was added after 10 min. and rowing was continued. Equal amounts of sodium methylate and guanidine carbonate were added twice more at 2 hour intervals and stirring was continued overnight. After dilution with 460 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated under reduced pressure. Recrystallization of the residue from an ethanol/methylene chloride solution gave off-white crystals: m.p. 245 - 248°C.

The dihydrochloride salt.

A hot solution of the above final product in 100 ml of 1:1 methanol/methylene chloride was filtered and evaporated on a steam bath to half its volume. The filtrate was treated with 5 ml of 5.7 N ethanolic hydrogen chloride solution and kept at room temperature for 2 hours. The pale yellow crystals were filtered, washed with ethanol and air dried to give the dihydrochloride salt, m.p. 232 - 237°C.

Example 3

9- chloro- 2- methyl- 7- phenyl- 5H- pyrimidoT5, 4- dlf 2Ibenzazepine

A suspension of 1.6 g (0.005 mol) of 8-chloro-3,4-dihydro-4-(dimethylaminomethylene)-1-phenyl-5H-2-benzazepin-5-one and 0.7 g (0.0075 mol ) acetamidine hydrochloride in 50 ml of methanol was

stirred at room temperature, under argon, and treated with 0.8 g (0.015 mol) sodium methylate in one portion. After stirring for 10 min. 30 ml of methylene chloride was added and stirring was continued. An additional 0.8 g (0.015 mol) of sodium methylate and 0.7 g (0.0075 mol) of acetamidine hydrochloride were added after 2 hours. The addition of 0.015 mol sodium methylate and 0.0075 mol acetamidine hydrochloride was repeated after a further 2 hours and stirring at room temperature was continued overnight. After dilution with 50 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated under reduced pressure. Crystallization took place when the residue was dissolved in 20 ml of hot hexane and cooled. Evaporation of the solvent gave a further yield of product. Recrystallization from hexane (activated carbon) gave off-white crystals, m.p. 120 - 122°C.

Example 4

9- chloro- 7-( 2- fluorophenyl)- 2- methyl- 5H- pyrimidor5. 4- dlF 2Ibenzazepine

A suspension of 5.1 g (0.015 mol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepine-5-

on and 2.1 g (0.0225 mol) of acetamidine hydrochloride in 150 ml of methanol were stirred at room temperature under argon and treated

with 2.4 g (0.045 mol) of sodium methylate in one portion. After stirring for 10 min. 90 ml of methylene chloride was added and stirring was continued. An additional 2.4 g (0.045 mol) of sodium methylate and 2.1 g (0.0225 mol) of acetamidine hydrochloride were added after 2 hours. The addition of 0.045 mole of sodium methylate and 0.0225

mol of acetamidine hydrochloride was repeated after a further 2 hour interval and stirring was continued overnight at room temperature. After dilution with 150 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated under reduced pressure. Recrystallization of the residue from hexane (activated charcoal) gave white crystals, m.p. 104 - 107°C.

Example 5

9- chloro- 7-( 2- fluorophenyl)- 5H- pvrimido[ 5, 4- dlf 2] benzazepine- 2-amine and 9- chloro- 7-( 2- fluorophenyl)- N, N- dimethyl- 5H- pyrimido -[ 5, 4- dl[ 2 Jbenzazepine- 4- amine

A solution of 7.0 g (0.0204 mol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one and 3.5 g (0.0833 mol) of cyanamide in 300 ml of absolute ethanol was refluxed for 18 hours and evaporated to dryness. The residue was washed with water, filtered and recrystallized

twice from methanol to give the N,N-dimethylamino compound. The filtrates were concentrated; filtered and recrystallized

from methanol to give the amino compd. The filtrates were evaporated, dissolved in dichloromethane and chromatographed over Florisil. The column was eluted with dichloromethane which was evaporated

and crystallized from methanol giving additional N,N-dimethylamino compound. A sample was recrystallized from dichloromethane/ether giving white needles, m.p. 175 - 180°C.

The column was then eluted with a 5% solution of ether in dichloromethane and then with ether. The ether fraction was evaporated and crystallized from methanol to give additional amino compound. A sample was recrystallized from methanol giving white prisms, m.p. 2 42 - 2 47°C.

To a solution of 0.2 g (0.5 mmol) of the N,N-dimethylamino compound in 5 ml of methanol was added 0.05 g (0.5 mmol) of methanesulfonic acid. The methanol was evaporated and the oil was crystallized from isopropanol and recrystallized from methanol/ether giving yellow prisms, m.p. 190 - 195°C.

Intermediate 1

2-(2-fluorobenzoyl)-4-chlorobenzoic acid, methyl ester

A solution of 2.0 g (7.19 mmol) [2-(2-fluorobenzoyl)-4-chlorobenzoic acid], in 40 ml methanol and 0.3 ml sulfuric acid was refluxed for 10 hours and then evaporated. The rest was for-

partitioned between 50 ml of dichloromethane and 30 ml of dilute ammonium hydroxide, and the organic layer was dried and evaporated. The resulting oil was dissolved in 20 ml of dichloromethane, filtered through 25 g of Florisil and eluted with dichloromethane. The solvent was evaporated and the oil crystallized

from ether and recrystallized from dichloromethane/ether/petroleum which gives . white sticks, m.p. 115 - 116°C.

Intermediate product 2

4- chloro- 2-[ 4-( chloromethyl)- 2-( 2- fluorophenyl)- 1, 3- dioxolan- 2-yl] benzoic acid methyl ester

To a solution of 47 g (0.16 mol) of intermediate

product 1 in 350 ml of dry toluene was added to 21.4 ml (0.18 mol) of stannous chloride, and after 5 hours a solution of 24 ml

(0.308 mol) of 1-chloro-2,3-epoxypropane in 25 ml of toluene added with stirring over a period of 30 min. After 18 hours, a further 12 ml (0.154 mol) of 1-chloro-2,.3-epoxypropane added over a period of 15 min. After 4 hours, the reaction was cooled in an ice bath and basified with concentrated ammonium hydroxide. The reaction was filtered through celite, and the celite was washed with toluene. The combined filtrates were washed with 200 ml of water, dried over sodium sulfate and evaporated. The resulting oil was dissolved in 100 ml of dichloromethane and chromatographed through 500 g of alumina. The column was eluted with 4 L of dichloro-

methane/kerosene:.- (2/1) which gives an oil which was approx* 90-95% pure by TLC. A sample was crystallized and recrystallized from ataL/petroleum ether which gives white prisms, m.p. 117 - 122 C.

Intermediate product 3

2- f 4- chloromethyl- 2-( 2- fluorophenyl)- 1, 3- dioxolane- 2- vll- <x f ( dimethylamino) mstvlenl-( 3- oxo-( 4- chlorophenyl) propanenitrile

A little sodium was added to 800 ml of liquid ammonia and

a few crystals of ferric nitrate. The total amount of 8.7 g (0.378 mol) of sodium was added with stirring over a period of 30 min., and after 15 min. a solution of 20.1 ml (0.378 mol) of acetonitrile in 70 ml of ether was added over a period of 10 min. The reaction was stirred for 2 hours and then 700 ml of ether was added. After allowing the ammonia to evaporate overnight, ice was added and the reaction acidified with acetic acid. It was neutralized with a saturated sodium bicarbonate solution, and the water was separated and re-extracted with 500 ml of ether. The combined ether layers were washed with brine (200 mL), dried over sodium sulfate and evaporated to dryness. The crude oil was dissolved in 150 ml of dichloromethane and filtered through 400 g of Florisil. The column was eluted with 1.5 1 of dichloromethane which gives an oil which was approx. 90 - 95% pure by TLC.

48 g of the oil was refluxed and stirred for 90 min. with N,N-dimethylformamide-dimethyl acetal and the mixture was then evaporated to dryness. The residue was triturated with 300 ml of ice water which was then decanted. The remaining oil was dissolved in 300 ml of dichloromethane, washed with 200 ml of water, and then dried over sodium sulfate. The solution was evaporated and the residue was crystallized from dichloromethane/ether giving the final product. The filtrates were evaporated, dissolved in 100 ml of dichloromethane and filtered through 300 g of Florisil. Elution with dichloromethane (400 ml) and ether (1.5 L) gave, after evaporation and then crystallization from dichloromethane/ether, the final product. The filtrates contained the end product as an oil which became approx. 85% pure by TLC. An analytical sample was recrystallized from the same solvents, giving grey-

white prisms, m.p. 143 - 147°C.

Intermediate product 4

2- amino- 4-\ 2 -\ 4-( chloromethyl)- 2-( 2- fluorophenyl)- 1, 3- dioxolan-2- yl1- 4- chlorophenyl] pyrimidine- 5- carbonitri1

To a solution of 1.0 g (0.00223 mol) of intermediate

product 3 in 8 ml of dry dimethylsulphoxide was added 4 g of the molecular sieves (type 5A) and 0.7 g (0.00389 mol) of guanidine carbonate. The reaction was stirred at 90-95°G for 5 hours, cooled and 50 ml of dichloromethane was added. The leaching was decanted and the solids were washed with dichloromethane and water several times. They collected ; solutions were separated, and the organic layer was washed with dilute brine (2x), then dried over sodium sulfate and concentrated to a

small volume. This solution was developed on 4 silica gel thick layer plates in dichloromethane/ethyl acetate (3/1). The tape

at Rf 0.4 was removed and crystallized and recrystallized from methanol giving off-white prisms, m.p. 184.- 191°C.

Intermediate 5

2- amino- 4- r 2-( 2- fluorobenzoyl)- 4- chlorophenyl]- pyrimidine- 5-carbonitrile

A solution of 0.2 g (0.448 mmol) of intermediate

product 4 in 20 ml of methanol and 10 ml of 3N hydrochloric acid was refluxed for 20 min. and the solvent was evaporated. The residue was distributed between 50 ml of dichloro-

methane and 30 ml of dilute ammonium hydroxide, and the organic layer was dried, concentrated and filtered through 15 g of Florisil. The column was "eluted with 200 ml of ether which was concentrated, filtered and recrystallized from dichloromethane/ether/petroleum ether which "gives white prisms, m.p. 153 - 157°C.

Example 6

2- amino- 9- chloro- 7-( 2- fluorophenyl)- 5H- pyrimido[ 5, 4- d][ 2]-benzazepine'

A solution of 50 mg (0.142 mmol) of intermediate

product 5 in 10 ml acetic acid was treated with 1/4 spatula of Raney nickel and hydrogenated for 2.5 hours. The reaction was filtered through celite, evaporated and partitioned between 30 mL of dichloromethane and 15 mL of dilute ammonium hydroxide. The organic layer was dried with sodium sulfate, evaporated and the residue was refluxed in ethanol for 1 hour and then evaporated to dryness. The solid was dissolved in dichloromethane and developed on a thick layer of silica gel plate in ethyl acetate/ethanol (20/1). The band of Rf 0.3 was removed and crystallized from ether to give white prisms, m.p.

243 - 248°C, and a mixed melting point of 244 - 248°C with authentic material obtained as in Example 2.

Intermediate 6 2- f 4- ( chloromethyl) - 2- f phenyl- 1, 3- dioxolan- 2- yl~ lbenzoic acid, methyl ester

To an opening--5V-y (0^36• isel) 2-benzoylbeneic acid methyl ester in 200 ml of dry carbon tetrachloride was added

10.1 ml (0.13 mol) of 1-chloro-3,4-epoxypropane. The reaction was cooled in an ice bath and a solution of 1.5 ml (0.013 mol) stannous chloride in 10 ml carbon tetrachloride was added with stirring over a 20 min. period. The reaction was allowed to stand over the weekend, and then the same amount of l-chloro-2,3-epoxy-propane and stannous chloride were added. After 18 hours, the reaction was cooled in an ice bath and neutralized with concentrated ammonium hydroxide. The precipitate was filtered off and washed with dichloromethane and the combined filtrates were washed with ■■ 15 Cml. water, dried over sodium sulfate and evaporated. The resulting oil was dissolved in 100 ml of dichloromethane and chromatographed through 500 g of neutral alumina. Elution with 3 1 of dichloromethane gave the final product as an oil which became approx. 95% pure by TLC. Crystallization and recrystallization of a small sample from ether/petroleum ether gave white rods, m.p. 90 - 91°C.

Intermediate product 7

2- f 4- ( chloromethyl) - 2- f envl- 1, 3- dioxolan- 2- yl l- a- 1 ( dimethylamino) methylenel- 3- oxo- benzenepropanenitrile

To a solution of 75 ml of liquid ammonia while stirring

was added a small bit of na trimm'and a few crystals of iron (ilOnitrate. A total of 1.15 g (0.0502 mol) of sodium was added over a period

in 20 min., and after 5 min. became a solution of 2.9 ml

(0.050 mol) of acetonitrile in 10 ml of ether added dropwise. A solution of 6.6 g (0.0198 mol) of intermediate 6 in 40 ml of ether was added dropwise, and after 2 hours 100 ml of ether was added and the ammonium oxide was allowed to evaporate. About.

100 g of ice was added to the reaction which was then acidified with acetic acid, followed by neutralization with a saturated solution of sodium bicarbonate. The aqueous layer was separated and extracted once more with ether. The combined ether layers were washed with 100 ml of water, dried over sodium sulfate and evaporated. The oil, was dissolved.. in..15. ml dichloromethane .and fil-

filtered through 100 g of Florisil. Elution with dichloromethane and evaporation gave 2-[4-(chloromethyl)-2-phenyl-1,3-dioxolan-2-yl-(3-oxo-benzenepropanenitrile) which was used without further purification.

A solution of 20 g (0.0585 mol) of the above-mentioned propanenitrile in 75 ml of N,N-dimethylformamide dimethyl acetal was refluxed and stirred for 90 min. and evaporated to dryness. The oil was triturated with ice water which was decanted, and the residue

was distributed between. 150 ml of dichloromethane and 150 ml of water. The organic layer was dried with sodium sulfate, concentrated and filtered through 150 g of Florisil. The column was eluted with ether which was evaporated and the resulting oil was crystallized from ethanol to give the final product. A sample was recrystallized from dichloromethane/ether to give white prisms, m.p. 107 - 110°C.

Intermediate 8

2-amino-4-(2-benzoylphenyl)pyrimidine-5-carbonitrile and 1-oxo-3-phenyl-1H-indene-2-carbonitrile

To a solution of 2.0 g (0.00504 mol) of intermediate

product 7 in 10 ml of dichloromethane, 10 ml of methanol and 2 ml (0.0192 mol) of 9.6 N ethanolic hydrogen chloride were added. After 90 min. the solvent was evaporated and the oil was partitioned between 50 ml of dichloromethane and 30 ml of a saturated sodium bicarbonate solution. The organic layer was dried with sodium sulfate and evaporated. 1.5 g of the oil obtained was dissolved in 30 ml of methanol, and 1.5 g (0.00833 mol) of guanidine carbonate was added. The solution was stirred for 90 min.

and then refluxed for 2 hours. The reaction was evaporated and then partitioned between 50 ml of dichloromethane and 30 ml of dilute ammonium hydroxide. The organic layer was dried with sodium sulfate and filtered through 50 g of Florisil. The column was eluted with dichloromethane (200 mL) and then ether (300 mL). The dichloromethane fraction was evaporated, crystallized and then recrystallized from dichloromethane/petroleum ether which gives the indene as yellow rods, m.p. 173 - 175°C.

The ether fraction was evaporated and crystallized from dichloromethane/petroleum ether which gives the pyrimidine, m.p. 195 - 199°C. An analytical sample was recrystallized from methanol which gives grey-white prisms, m.p. 197 - 200°C.

Example 7

7- phenyl- 5H- pyrimidoTS, 4- d][ 2] benzazepine- 2- amine

A solution of 3.1 g (0.0103 mol) of the pyrimidine compound in nellcin product 8 in 60 ml of glacial acetic acid was treated with 1 teaspoon of Raney nickel and then hydrogenated for 8.5 hours. The reaction was filtered through celite and evaporated. The filtrate was partitioned between 50 ml of dichloromethane and 30 ml of dilute ammonium hydroxide, and the organic layer was dried with sodium sulfate and evaporated. The resulting oil was refluxed in 75 ml of methanol for 15 min, evaporated and dissolved in 100 ml of dichloromethane. This was treated with 3 g of activated manganese dioxide and then refluxed and stirred for 30 min. The reaction was filtered, concentrated and chromatographed over 100 g of Florisil. The column was eluted with 300 ml of dichloromethane, 500 ml of ether and 1.5 L of ethyl acetate. The ethyl acetate fraction was evaporated and the oil was crystallized from ether and recrystallized from dichloromethane/ether to give white rods, m.p. 239 - 242°C. The filtrates and the ether fraction from the column were evaporated and developed on silica gel thick layer plates in ethyl acetate/methanol (20/1) which gives further product. An analytical sample was recrystallized from ether to give white prisms, m.p. 201 - 205°C which is converted into rods, m.p. 240 - 243°C.

Example 8

9- chloro- 7-( 2- chlorophenyl)- 2- methyl- 5H- pyrimido[ 5, 4- dlf2lbenz-a zepine

In 5 equal portions, 5.5 g (58 mmol) of acetamidine hydrochloride and 15 ml (62 mmol) of a 4.12 M methanol solution of sodium methoxide were added over 3 hours to a solution of 3.5 g (10 mmol) 8 -chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one in 140 ml of methanol and 140 ml of methylene chloride. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give an amber oil. The resulting amber oil was dissolved in 10 ml (10 mmol) of a 1 M methanol solution of methanesulfonic acid and the resulting salt was precipitated by addition of ether giving yellow prisms, m.p. 193 - 197°C. Recrystallization from a mixture of methanol and ether gave yellow prisms, m.p.

197 - 198°C.

Example 9

9- chloro- 7-( 2- chlorophenyl)- 5H- pyrimido[ 5, 4- dl[ 2Ibenzazepine

In 5 equal portions, 21 g (200 mmol) of formamidine acetate and 32.5 ml (135 mmol) of a 4.12 M methanol solution of sodium methoxide were added over the course of 3 hours to a solution of 7.2 g (20 mmol) of 8- chloro-1-(2-chlorophenyl)-3,4-dihydro-[(dimethylamino)methylene]-5H-2-benzazepin-5-one in 270 ml of methanol and 270 ml of methylene chloride. The reading was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an amber oil. Purification by column chromatography (100 g silica gel, eluent 1:1 methylene chloride and ethyl acetate) gave the final product m.p. 122 ~ 124 "C. Recrystallization from ether gave pale yellow prisms, mp 122 - 125°C.

Example 10

9- chloro- 7-( 2- chlorophenyl)- 2- isopropyl- 5H- pyrimidoi_ 5, 4- d li 2 Ibenzaze-p_in

A mixture of 3.5 g (10 mmol) of (8~chloro)-1-(2-chlorophenyl)-3,d-dihydro-4-[(dimethylamino)methylene-1-5H-2-benzazepin-5-one, 4 .8 g

(40 mmol) of isobutyramide hydrochloride, 10 ml (41 mmol) of a 4.12 M methanolic solution of sodium methoxide and 100 ml of methanol were stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with methylene chloride. The mefcylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oil. Crystallization of the oil with ether gave a pale yellow solid, m.p. 127 - 129°C. Orricrystallization from a mixture of ether and petroleum ether gave colorless rods, m.p. 127 - 129°C..

Example H

2-amino-9-chloro-7-(2-chlorophenyl)-5H-pyrimidc>r5,4- d]\2 1-benzazepine

In two equal portions, 14.4 g (80 mmol) of guanidine carbonate were obtained

and 20 ml (82 mmol) of 4.12 M methanol solution of sodium methoxide added over 90 min. to a solution of 3.6 g

(10 mmol) 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one in 100 ml of methanol. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oil. Krysta Hising the oil with methylene chloride gave a white solid, m.p. 240 - 241°C. Recrystallization from a mixture of ether and methylene chloride gave colorless needles,

m.p. 2 40 - 241°c.

Example 12

7-(2-Chlorophenyl)-2-methyl-5H-pyrimido[5,4-d]\2lbenzazepine-methanesulfonate

In 4 equal portions, 7.2 g (76 mmol) of acetamidine hydrochloride were

rid and 18 ml (80 mmol) of a 4.46 M methanolic solution of sodium methoxide added over a 3 hour period to a solution of 4.5 g (14 mmol) of 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. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an amber oil. The amber oil was dissolved in a mixture of 15 ml isopropanol and 1.3 g (14 mmol) methanesulfonic acid, and the isopropanol was removed under redu-

hard pressure. The residue was crystallized from a mixture of ether and methylene chloride giving a pale yellow solid, m.p.

147 - 151°C. Recrystallization from a mixture of ether and methylene chloride gave yellow prisms as the semi-hydrate, m.p.

159 - 160°C.

Example 13

2- methyl- 7- phenyl- 5H- pyrimido[ 5, 4- d] f21benzazepine dihydrochloride

In 5 equal portions, 9.0 g (95 mmol) of acetamidine hydrochloride and 22.5 ml (0.1 mol) of a 4.46 M methanol solution of sodium methoxide were added over 3 hours to a solution of 4, 5 g (15 mmol) of 1-phenyl-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one in 180 ml of methanol and 180 ml of methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oil. The oil was dissolved in an excess of 6% methanolic hydrogen chloride and the solvent was removed under reduced pressure to dryness. The residue was crystallized from a mixture of ether and methylene chloride which gives a white solid, m.p. 211 - 221°C. Recrystallization from a. mixture of methanol and ether gave white flakes, m.p.

217 - 227°C.

Example 14

9- chloro- 7-( 2- chlorophenyl)- 2- methyl- 5H- pvirimidor5, 4- d ][ 2 ] benzazepine- 6- oxide

A solution of 2.0 g (5.6 mmol) of 9-chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido[5,4-d][2]benzazepine and 2.2 g (10.8 mmol) of 85% meta-chloroperbenzoic acid in 100 ml of methylene chloride was stirred at room temperature for 21 hours. The methylene chloride solution was washed with cold dilute aqueous sodium hydroxide,

dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. Purification by trickle filtration (silica gel, 25 g, eluent 1000 ml 1:1 ether methylene chloride) gave a colorless solid, m.p. 215 - 216°C.

Example 1. 5

9- chloro- 7-( 2- chlorophenyl)- 2- methyl- 5H- pvrimidor5, 4- d][ 2] benzazepine- 3, 6- dioxide

A solution of 3.8 g (10.7 mmol) of 9-chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido[5, 4-d] [2 jbenzazepine and 9.6 g ( 47 mmol) 85% metachloroperbenzoic acid in 400 ml methylene chloride was stirred at room temperature for 55 hours. The methylene chloride solution was washed with cold dilute aqueous sodium hydroxide, dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. Purification by drop filtration (silica gel, 25 g, eluents 400 ml 1:1 ether, methylene chloride followed by 200 ml 9:1 methylene chloride, methanol) gave a colorless solid, m.p. 241 - 243°C.

Example 16

9- chloro- 7-( 2- chlorophenyl)- 6, 7- dihydro- 2- methyl- 5H- pvirimidor5, 4- dl-[ 2Ibenzazepine dihydrochloride

A mixture of 3.7 g (10.5 mmol) of 9-chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido[5,4-d][2Jbenzazepine, 1.3 g of zinc dust, and 40 ml of acetic acid in 90 ml of methylene chloride was stirred at -15°C

to -20°C for 30 min. The mixture was filtered through Hy.flo and the filtrate basified with cold dilute aqueous sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oil. The yellow oil was crystallized from an excess of 6% methanolic hydrogen chloride to give the title compound as a white solid, m.p. 272 - 274°C. Recrystallization from methanol gave colorless rods, m.p. 272 - 274°C.

A sample of the above material was partitioned between dilute aqueous sodium hydroxide and methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue was crystallized from ether, which gives the free base as cream-colored prisms, m.p. 176 - 177°C.

If the reaction is carried out in acetic acid using hydrogen

over a pre-hydrogenated platinum oxide catalyst, two equivalents of hydrogen are consumed which, when worked up, give the tetrahydro compound described in example 29. These tetrahydro derivatives also contain useful CNS properties.

Intermediate 9

8- chloro- 1-(2- chlorophenyl)- 3, 4- dihydro- 4-[(dimethylamino) methylene]-5H- 2- benzazepin- 5- one

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 was slowly heated (about 50° ) for 12 hours. The mixture was concentrated under reduced pressure to dryness. The residue was crystallized from a mixture of ether and methylene chloride giving the final product. as a yellow solid, m.p. 170 - 171°C. Recrystallization from ether gave yellow prisms, m.p.

170 - 171°C.

Intermediate 10

1- ( 2- chlorophenyl)- 3, 4- dihydro- 4-[( dimethylamino) methylene]- 5H-2- benzazepin- 5- one

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 dimethyl acetal was refluxed for 2 hours. The mixture was concentrated under reduced pressure and the resulting solid was triturated with ether to give a light brown solid, m.p.

155 - 157°C. Recrystallization from a mixture of methylene chloride and ether gave yellow prisms, m.p. 158 - 159°C.

Intermediate 11

3, 4- dihydro- l- phenyl- 4-[(dimethylamino) methylene]- 5H- 2- benzazepin- 5- one

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 was refluxed for 4 hours. The mixture was concentrated under reduced pressure to dryness. The residue was crystallized with ether which gave a yellow solid, m.p. 131 - 133°C. Recrystallization from ether gave yellow prisms, m.p. 131 - 132°C.

Example 17

9-chloro-7-(2-chlorophenyl)-2-(methylthio)-5H-pyrimido[5,4-dl\. 2 1-benzazepine

A mixture of 1.1 g (3.0 mmol) 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-2-thiol, 1.0 ml (10 mmol) of dimethyl sulfate, 20 ml of 1N sodium hydroxide and 10 ml of ethanol were stirred at room temperature for 15 min. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil. Crystallization from ether gave colorless prisms, m.p. 187 - 188°C.

Example 18

9- chloro- 7-( 2- chlorophenyl)- 2-( methylthio)- 5H- pyrimidor5, 4- dlf21 — benzazepine methanesulfonate

The methanesulfonate salt of 9-chloro-7-(2-chlorophenyl)-2-(methylthio)-5H-pyrimido[5,4-dl[2]benzazepine was prepared by adding equimolar amounts of the above compound and the methanesulfonic acid to methanol and by precipitation of the resulting salt with the addition of ether. Recrystallization from ethanol gave cream needles, m.p.

165 - 166°C.

Example 19

9- chloro- 7-( 2- chlorophenyl)- 5H- pyrimido[ 5, 4- dl[ 2lbenzazepine- 2- thiol

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, and 8.0 ml (32 mmol) of a 4.0 M methanolic solution of sodium methoxide in 80 ml of methanol were stirred at room temperature for 18 hours. The mixture was diluted with water and extracted with ether. That aqueous layer was neutralized with acetic acid and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow solid, m.p. 238 - 239°C. Recrystallization from tetrahydrofuran gave yellow crystals, m.p. 232 - 234°C.

Example 20

Preparation of 9-chloro-7-(2-fluorophenyl)-5H-pyrimidof5,4-d]-\2lbenzazepin-2-ol

A solution of 1.2 g (0.00354 mol) of 9-chloro-7-(2-fluorophenyl)-2-amino-5H-pyrimido[5,4-d][2jbenzazepine in 20 ml of concentrated sulfuric acid and 20 ml of water was refluxed for 12 hours,

and then cooled. After addition of ice, the reaction mixture was made basic with ammonium hydroxide and extracted with 100 ml of dichloromethane. The solids were collected by filtration and recrystallized from dichloromethane/methanol giving the final product as white prisms, m.p. 297 - 299° Dec. The dichloromethane extract was dried, evaporated and the residue crystallized from dichloromethane/methanol giving additional product.

Example 21

Preparation of 2,9-dichloro-7-(2-fluorophenyl)-5H-pvrimido-\5 . 4-d][2]benzazepine

A solution of 1.0 g (0.00294 mol) of 9-chloro-7-(2-fluoro-phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-ol in 5 ml of phosphorus oxychloride was heated over the steam bath for 4 hours,

and evaporated to dryness. The solid was crystallized from dichloromethane/ether, and the precipitate was partitioned between 50 ml of dichloromethane and 40 ml of saturated sodium bicarbonate solution. The organic layer was dried, evaporated and crystallized from ether. Recrystallization from dichloromethane/ether gave the final product as grey-white prisms, m.p.

157 - 160°.

Example 22

Preparation of 9-chloro-N-methyl-7-(2-fluorophenyl)-5H-pyrimidol5,4-d][2]benzazepine-2-amine

A solution of 1 g (0.00279 mol) of 2,9-dichloro-7-(2-fluoro-phenyl)-5H-pyrimido[5,4-d][2]benzazepine in 4 ml of N,N-dimethylformamide was cooled in an ice bath and saturated with methylamine. After 64 hours at room temperature, 50 mL of ice water was added and the reaction was filtered. The precipitate was partitioned between 50 ml of dichloromethane and 50 ml of water, and the organic layer was washed with 25 ml of brine, dried and evaporated to dryness. The oil was crystallized from ether and then recrystallized from dichloromethane/ether and then from methanol giving the final product as white prisms, m.p. 172 - 179°.

Example 23

Preparation of 9-chloro-N,N-dimethyl-7-(2-fluorophenyl)-5H-pyrimidor5,4-dl[2]benzazepine-2-amine

A solution of 4.0 g (0.0112 mol) of 2,9-dichloro-7-(2-fluoro-phenyl)-5H-pyrimido[5,4-d][2]benzazepine in 15 ml of N,N- dimethylformamide was cooled in an ice bath and saturated with dimethylamine. After 18 hours at room temperature, 80 ml of ice water was added and the precipitate was collected by filtration and recrystallized twice from methanol giving the final product as

o

white staves, m.p..175 - 179 .

Example 24

Preparation of 9-chloro-7-(2-fluorophenyl)-N-(3-N,N-dimethylaminopropyl)-5H-pyrimido[5,4-d]\2lbenzazepine-2-amine

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 N,N-dimethylformamide was added 2 .7 ml (0.0215 mol) of 3-dimethylaminopropylamine while the reaction was cooled in an ice bath. After 66 hours at room temperature, 50 ml of ice water was added and the reaction was filtered. The precipitate" was dissolved in 50 ml of dichloromethane, washed with 40 ml of water and evaporated. The oil was dissolved in dilute hydrochloric acid and brought to pH 2 with ammonium hydroxide. The acidic solution was extracted

quenched with dichloromethane (2x50 ml), and the acidic layer was then basified with ammonium hydroxide and extracted with 75 ml of dichloromethane, which was dried and evaporated. The residue was crystallized and recrystallized from ether/petroleum ether giving white needles, m.p. 90 - 101°„

Example 25

Preparation of 9-chloro-2-methoxy-7-(2-fluorophenyl)-5H-pvrimidofS, 4-d][2jbenzazepine

To 25 ml of methanol was added 1.0 g (0.00279 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2Jbenzazepine and 0.18 g (0, 00335 mol) of sodium methoxide. The reaction was stirred for 18 hours and evaporated to dryness. The solid was dissolved in 50 ml of dichloromethane and washed with 40 ml of water, dried and evaporated to dryness. The oil was crystallized and recrystallized from ether/petroleum ether and then from ether giving the final product as white prisms, m.p. 137 - 141°.

Example 2 6

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

A mixture of 34.2 g (0.1 mol) of 8-chloro-3,4-dihydro-1-(2-fluorophenyl)-4-[(dimethylamino)methylene]-5H-2-benzazepine-5-

on, 62.4 g (0.6 mol) formamidine acetate and 35 g (0.63 mol) sodium methoxide in 700 ml methanol were stirred at room temperature for 3 hours, while nitrogen was bubbled through the solution. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a red oil. The oil was suspended in boiling hexane and the hexane solution decanted. After cooling, the final product was collected by filtration. Recrystallization from cyclohexane gave grey-white crystals, m.p. 123 - 125°C.

Example 27

9- chloro- 7-( 2- fluorophenyl)- 5H- pyrimido[ 5, 4- d][ 2 ]- benzazepine-6- oxide

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 85% m-chloroperbenzoic acid in 100 ml of methylene chloride was stirred at room temperature for 4 hours. The reaction mixture was washed with an excess of ice-cold dilute sodium hydroxide, dried over anhydrous sodium sulfate and filtered over Hyflo. The filtrate was concentrated under reduced pressure to dryness. The residue was crystallized from a mixture of methylene chloride and ether to give the crude product, m.p. 185 - 186°C. Recrystallization from a mixture of methylene chloride and ether gave the pure product, m.p. 187 - 188°C.

Example 28

9- chloro- 7-( 2- fluorophenyl)- 5H- pyrimidor5, 4- d][ 2lbenzazepin-5- oleacetate

A mixture of 2.5 g (7.4 mmol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-6-oxide and 50 ml of acetic anhydride was heated over a steam bath for 24 hours. The reaction mixture was concentrated under reduced pressure to dryness and the residue was crystallized from a mixture of methylene chloride and ether to give the crude product, m.p. 197 - 198°C. Recrystallization from a mixture of methylene chloride and ether

gave the pure product as cream colored prisms, m.p. 200 - 201°C.

Example 29

9- chloro- 7-( 2- chlorophenyl)- 4, 5, 6, 7- tetrahydro- 2- methyl- 1H- pyrimidoTS, 4- d][ 2 Ibenzazepine, hydrochloride salt

A solution of 3.8 g (10.7 mmol) of 9-chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido[5,4-d][2]benzazepine in 50 ml of acetic acid was hydrogenated at room temperature and atmospheric pressure in the presence of 0.5 g of prehydrogenated platinum oxide. After 3 hours approx. 500 ml (- about 2 equivalents) of hydrogen absorbed and the catalyst was separated by filtration. The filtrate was concentrated under reduced pressure to dryness. The residue was dissolved in methylene chloride, washed with an excess of dilute ice-cold sodium hydroxide and dried over anhydrous sodium sulfate. The methylene chloride solution was diluted with an excess of methanolic hydrogen chloride and concentrated under reduced pressure. The residue was triturated with isopropanol and the crude product was collected by filtration.

Recrystallization from methanol gave the pure product, m.p.

275 - 276°C.

Example 30

2-- amino- 9- chloro- 7- ( 2- fluorf enyl)- 5H- pyrimido [ 5, 4- dl [ 2 1benzazepine- 6- oxide

In two equal portions, 28 g (150 mmol) of guanidine carbonate were obtained

and 38 mL (150 mmol) of a 4.09 M methanolic solution of sodium methoxide added over a period of 2 hours to a solution of 7.0 g (20 mmol) of 8-chloro-1-(2-fluorophenyl)-3 ,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one-2-oxide in 210 ml of methanol. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a red solid. Recrystallization from a mixture of methanol and ethyl acetate gave the product as fine yellow needles, m.p. 320 - 323°C.

Example 31

9- chloro- 7-( 2- chlorophenyl)- 6, 7- dihydro- 2, 6- dimethyl- 5H- pyrimido-[ 5, 4- dl[ 2Ibenzazepine

A mixture of 4 g (11 mmol) 9-chloro-7-(2-chlorophenyl)-6,7-dihydro-2-methyl-5H-pyrimido[5,4-d][2Jbenzazepine 2 ml 88% formic acid and 2 ml of 37.5% formaldehyde solution was heated over a steam bath for 3 hours. The reaction mixture was poured into an excess of dilute ice-cold sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue was crystallized from ether to give the crude product, m.p. 155 - 156°C. Recrystallization from ether gave the pure product as colorless prisms, m.p. 156 - 157°C.

Intermediate 12

8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one

Method A. A mixture of 7.2 g (25 mmol) 8-chloro-1-(2-fluoro-phenyl)-3,4-dihydro-5H-2-benzazepin-5-one and 50 ml of dimethylformamide dimethyl acetal was refluxed in 1 hour. The mixture was concentrated under reduced pressure to give light brown crystals. Recrystallization from ether gave yellow prisms, m.p. 228 - 233°C.

Method B. A mixture of 10 g (35 mmol) of crude 8-chloro-3,4-dihydro-1-(2-fluorophenyl)-5H-2-ben^;a zepin-5-one and 10 g ( 84 mmol) of dimethylformamide-dimethylformamide in 10 ml of dimethylformamide was stirred at room temperature for 12 hours. The resulting precipitate was collected by filtration and washed successively with ethanol and ether to give light brown crystals identical in every respect to an authentic sample.

Intermediate 13

8-chloro-1-phenyl-3,4-dihydro-4-[(dimethylamino)methylene-5H-2-benzazepin-5-one.

The preparation of 8-chloro-1-phenyl-3,4-dihydro-4-[(dimethylamino) methylene]-5H-2-benzazepin-5-one was carried out in the same manner as the preparation of 8-chloro-1-(2 -fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one (Method A) which gives yellow prisms, m.p. 180 - 183°C.

Intermediate 14

8-chloro-1-(2-fluorophenyl)-3,4-dihydro-5H-2-benzazepine-5-one-2-oxide

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 was stirred at room temperature for 2 hours. The methylene chloride solution was washed with saturated aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oil. The oil was crystallized from a mixture of ether and petroleum ether which gives grey-white prisms, m.p. 166 - 168°C. Recrystallization from a mixture of ether and methylene chloride gave colorless prisms, m.p. 168 - 170°C.

Intermediate 15

8-chloro-1-(2-chlorophenyl)-3,4-dihydro-5H-2-benzazepine-5-one-2-oxide

The preparation of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one-2-oxide was carried out in the same manner as the preparation of 8-chloro-1-(2- fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one-2-oxide which gives yellow prisms, m.p.

184 - 187°C.

Intermediate 16

8- chlorine-. l-(2-fluorophenyl)-3,4-dihydro-4-f(dimethylamino)methylene l-5H-2-benzazepine-5-one-2-oxide

A mixture of 3.4 g (11 mmol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one-2-oxide and 26 ml of dimethylformamide dimethyl acetal was stirred at room temperature for 12 hours. The mixture was diluted with ether and the precipitate collected to give a yellow solid, m.p. 175 - 178°C. Recrystallization from a mixture of ether and ethyl acetate gave yellow needles, mp 193 - 194°C.

Intermediate 17

8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepine-5-one-2-oxide

The preparation of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one-2-oxide was prepared in the same way as the preparation of 8-Chloro-1-(2-fluorophenyl)-.3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one-2-oxide which gives yellow prisms, m.p.

196 - 198°C.

Example 32

9- chloro- 7-( 2- chlorophenyl)- 2- methyl- 5H- pyrimido[ 5/ 4- d][ 2]- benzazepine- 6- oxide

A mixture of 1 g (2.8 mmol) of 8-chloro-1-(2-chlorophenyl)-4-[(dimethylamino)methylene]-3,4-dihydro-5H-2-benzazep.in-5-one- 2-oxide, 1.0 g (11 mmol) of acetamidine hydrochloride and 2.0 ml (9.9 mmol) of a 4.46 M methanolic solution of sodium methoxide in a mixture of 20 ml of methanol and 20 ml of methylene chloride were stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Recrystallization of the residue from a mixture of ether and methylene chloride gave a colorless solid, m.p. 215 - 216°C.

Example 33

9- chloro- 7-( 2- fluorophenyl)- 5H- pyrimidor5, 4- d][ 2] benzazepin-5-ol

A solution of 3.7 g (9.7 mmol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-5-ol acetate in a mixture of 25 ml tetrahydrofuran, 50 ml methanol and 2 ml 3N sodium hydroxide was stirred at room temperature for 0.5 hour. The reaction mixture was poured into ice water and extracted with methylene chloride. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue crystallized from a mixture of methylene chloride and ether giving a crude product melting at 186-188°C. Recrystallization from a mixture of ether and methylene chloride gave the product as cream-colored prisms, m.p. 196 - 198°C.

Example 34

9- chloro- 7- ( 2- chlorophenyl)- 5H- pyrimidc>r5, 4- dlf 2 lbenzazepine- 6-oxide

A solution of 6.8 g (20 mmol) 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2jbenzazepine, 6 g (30 mmol) 85% m-chloroperbenzoic acid in 200 ml methylene chloride was stirred at room temperature for 4 hours. The mixture was washed with an excess of ice-cold dilute sodium hydroxide, dried over anhydrous sodium sulfate and filtered over Hyflo. The filtrate was concentrated under reduced pressure to dryness. The residue was crystallized from a mixture of methylene chloride and ether giving a crude product, m.p. 228 - 229°C. Recrystallization from a mixture of methylene chloride and ether gave the product, m.p. 216 - 217°C.

Example 35

9- chloro- 7-( 2- chlorophenyl)- 5H- pyrimido[ 5, 4- d][ 2Ibenzazepin-5-ol- acetate

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 was heated over a steam bath in 22 hours. The reaction mixture was concentrated under reduced pressure to dryness and the residue was crystallized from a mixture of methylene chloride and ether to give a product of m.p. 211 - 212°C. Recrystallization from a mixture of methylene-

chloride and ether gave the pure product as colorless prisms, m.p. 211 - 212°C.

Example 36

9- chloro- 7-( 2- chlorophenyl)- 5H- pyrimido[ 5, 4- dl\ 2 Ibenzazepine-

5- etc

A solution of 4.8 g (12 mmol) of 6-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-5-ol-acetate in a mixture of 50 ml of tetrahydrofuran , 50 ml of methanol and 4 ml of 3N sodium hydroxide were stirred at room temperature for 30 min. The reaction mixture was poured into ice water and extracted with ethylene chloride. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue was crystallized from a mixture of methylene chloride and ether which gives a product with m.p. 105 - 117°C. Recrystallization from a mixture of methylene chloride and acetone gave the pure product as colorless prisms, m.p.

174 - 175°C.

Example 37

9- chloro- 7-( 2- fluorophenyl)- 2-( 4- methyl- 1-piperazinyl)- 5H-pyrimido[ 5, 4- d][ 2] benzazepine hydrochloride

To a solution of 3.0 g (0.00838 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine in 8 ml of N,N-dimethylformamide 2 g (0.02 mol) of N-methylpiperazine was added. After 20 hours, ice water (40-ml) was added to the reaction which was then filtered. The solid was distributed between 50 ml dichloromethane <p>g 50 ml 1N hydrochloric acid, and.

The pH was adjusted to 1-2 with ammonium hydroxide. The resulting precipitate was filtered and recrystallized twice from methanol to give white prisms, m.p. 187 -194°C. The acidic layer was made basic with ammonium hydroxide

syd, and extracted with 100 ml of dichloromethane which was dried and evaporated. The oil was acidified with IN hydrochloric acid, in-

adjusted to pH 1-2 with ammonium hydroxide, cooled and filtered. The precipitate was recrystallized from methanol, which gives a further yield of product.

Example 38

9-kl or-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-2-acetic acid ethyl ester

1.9 g (16.8 mmol) of potassium tertiary butoxide was added to 20 ml of diethyl malonate with stirring and nitrogen and after 15 min. 2.0 g (5.59 mmol) of 2,9-dichloro-7-(2-fluoro-phenyl)-5H-pyrimido[5,4-d][2]benzazepine was added. The reaction was held at 110°C for 2 hours and 140°C for 4 hours. Ice was added to the reaction mixture which was then acidified with concentrated hydrochloric acid and extracted with 100 ml of ether. The ether layer was extracted with 25 ml of 3N hydrochloric acid, and the combined acid layers were made basic with ammonium hydroxide and extracted with ether (2 x 100 ml). The solution was dried, activated charcoal filtered and concentrated to a small volume. Petroleum ether was added and the product was filtered and recrystallized from the same solvents giving white rods, m.p. 98 - 103°C.

Example 39

9- chloro- 7-( 2- fluorophenyl)- 5H- pyrimido[ 5, 4- d][ 2] benzazepine-2- acetic acid

A solution of 4.0 g (9.76 mmol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-2-acetic acid ethyl ester in 30 ml of ethanol and 2 5 ml of 1N sodium hydroxide was heated on the steam bath for 3 hours. The mixture was partitioned between 75 ml of water and 75 ml of ether. The basic layer was acidified with acetic acid and extracted with dichloromethane (2 x 100 mL), which was dried and evaporated. The resulting oil was crystallized from methanol and recrystallized from dichloromethane/ether/petroleum ether to give grey-white prisms, m.p. 138 - 140°C.

Example 4Q

9- chloro- 7-( 2- fluorophenyl)- N- methyl- 5H- pyrimido[5, 4- d][ 2] benzazepine- 2- acetamide

Methylamine was bubbled into a solution of 2.6 g (6.3 4 nmol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-2-acetic acid ethyl ester in 60 ml ethanol for 10 min. After standing for 18 hours, the reaction mixture was evaporated and the residue was partitioned between 75 ml of dichloromethane and 50 ml of water.

The organic layer was dried and evaporated. The residue was crystallized and then recrystallized from dichloromethane/ether giving white rods, m.p. 175 - 177°C.

Example 41

9- chloro- 7-( 2- chlorophenyl)- 5H- pyrimido-[ 5, 4- d][ 2] benzazepine

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) formamidine acetate and 1.0 L of formamide were heated over a steam bath for 16 hours. The mixture was cooled to 0° and the resulting precipitate collected by filtration. The precipitate was washed with water and dried to constant weight, yielding grey-white crystals, m.p.

120 - 121°C.

Example 4 2

9- chloro- 7-( 2- fluorophenyl)- 5H- pyrimido[ 5, 4- d] f2Ibenzazepine-6- oxide

A mixture of 0.4 g (1.1 mmol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one- 2-oxide, 1.0 g (9.6 mmol) formamidine acetate and 20 ml formamide were heated over a steam bath for 6 hours. The mixture was poured over ice and extracted with methylene chloride. The mstylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue crystallized with the addition of a mixture of ether and methylene chloride which gives gray-white crystals, m.p.

186 - 188°C.

Example 43

9-chloro-7-(2-chlorophenyl)-5H-pyrimidor5,4-dl[2"lbenzazepine-6-oxide

A mixture of 0.4 g (1.1 mmol) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene-1-5H-2-benzazepin-5-one-2 -oxide and 1.0 g (9.6 mmol) formamidine acetate in 20 ml formamide were heated over a steam bath for 7 hours. The mixture was poured over ice and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with ether which gives a grey-white solid, m.p. 215 - 217°C.

E xample 4 4

9- chloro- 7-( 2- chlorophenyl)- 5H- pyrimidor5, 4- dl[ 21- benzazepine

A mixture of 0.5 g (1.3 mmol) of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-dl[2]benzazepine-6-oxide and 1/0 ml (10 mmol ) phosphorous trichloride in 20 ml of methylene chloride was refluxed for 3 hours. The mixture was cooled, poured over ice, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure» The residue crystallized after the addition of ether giving colorless prisms, m.p.

121 - 123°C.

Example 4 5

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

A mixture of 0.5 g (1.5 mmol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-6-oxide and 1.0 ml (10 mmol) of phosphorus-containing trichloride in 20 ml of methylene chloride was heated

on return for 2 hours. The mixture was poured over ice,

made basic with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue was crystallized from ether which gives gray-white crystals, m.p. 122 - 124°C.

Example 46

9- chloro— 7-( 2- fluorophenyl)- 5H- pyrimidor5, 4- d]\ 2 lbenzazepine- 2- thiol- 6- oxide

A mixture of 1.5 g (4 mmol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one-2- oxide, 1.5 g (20 mmol) of thiourea and 5 ml of a 4 M methanolic solution of sodium methoxide in 30 ml of methanol were stirred at room temperature for 5 hours. The mixture was poured into water and extracted with ether. The aqueous solution was acidified with acetic acid and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with methylene chloride which gives an orange solid. Recrystallization from methylene chloride gave the product as orange crystals, m.p. 323 - 325°C. (dec.).

Example 47

9- chloro- 7-( 2- chlorophenyl)- 6, 7- dihydro- 5H- pyrimido[ 5, 4- d][ 2]-benzazepine

A mixture of 68 g (0.2 mol) 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine, 27 g zinc dust and 250 ml . acetic acid in 600 ml of methylene chloride was stirred at -30°C for 2 hours. The mixture was filtered over Hyflo in a stirred mixture of 600 ml of concentrated ammonium hydroxide. and 500 ml of ice. The methylene chloride solution was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue crystallized from a mixture of methylene chloride and ether, giving the product as a colorless solid. Recrystallization from a mixture of ether and methylene chloride gave the product as colorless needles, m.p. 169 - 170°C.

Intermediate product 18

9- chloro-7-( 2- chlorophenyl)- 6, 7- dihydro- 6-[( 4- methylphenyl) sulfonyl]-SH- pyrimidoCS, 4- dl[ 2lbenzazepine

A solution of 14.5 g (42 mmol) of 9-chloro-7-(2-chlorophenyl)-6,7-dihydro-5H-pyrimido[5,4-d] [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 were stirred at room temperature for 24 hours. The mixture was washed with an excess of dilute ice-cold hydrochloric acid and dilute aqueous sodium hydroxide. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue crystallized from a mixture of methylene chloride and ether to give the product as a white solid, m.p. 200 - 201°C. Recrystallization from a mixture of ether and methylene chloride gave the pure product as colorless prisms, m.p. 200 - 201°C.

Intermediate 19

9- chloro- 7-( 2- chlorophenyl)- 6, 7- dihydro- 6-( trifluoroacetyl)- 5H- pvirimido[ 5, 4- d][ 2] benzazepine

5.0 ml (35 mmol) of trifluoroacetic anhydride was added dropwise to 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 10 ml (12.8 mmol) pyridine in 75 ml methylene chloride which was cooled to 0°C. After stirring for 1 hour, the mixture was poured into ice-cold dilute hydrochloric acid. The methylene chloride solution was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from ether giving the product as pink crystals, m.p. 178 - 179°C. Recrystallization from ether gave the product as grey-white crystals, m.p. 179 -

180°C.

Intermediate 20

9- chloro- 7-( 2- chlorophenyl)- 6, 7- dihydro- 6-[( 4- methylphenyl) sulfonyl]- 5H- pyrimido[ 5, 4- d][ 2] benzazepine- 3- oxide

A solution of 7.6 g (15 mmol) of 9-chloro-7-(2-chlorophenyl)-5,7-dihydro-6-[(4-methylphenyl)sulfonyl]-5H-pyrimido[5,4-d] -[2]benzazepine and 4.0 g (20 mmol) of m-chloroperbenzoic acid in 300 ml of methylene chloride were stirred at room temperature for 48 hours. The mixture was washed with cold dilute sodium hydroxide and saturated aqueous sodium chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue (8.2 g) was purified by column chromatography (silica gel, 20 g, eluents, methylene chloride then ethyl acetate) the methylene chloride eluent gave 2.0 g of the starting material as a colorless solid. The ethyl acetate eluent gave 2.1 g of the product as an off-white solid, m.p. 242 - 243°C. Recrystallization from a mixture of ether and methylene chloride gave the product as colorless crystals, m.p. 243 - 244°c.

Example 48 9-chloro-7-(2-chlorophenyl)-5H-pyrimidof 5,4-d][2]benzazepine-3-oxide

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]bsnzazepine-3-oxide and 8 ml of a 4M methanol solution of sodium methoxide in a mixture of 130 ml of tetrahydrofuran and 180 ml of methanol were stirred at room temperature for 19 hours. The mixture was whole in an ice-cold sodium chloride solution and extracted with methylene chloride. The methylene chloride solution was washed with aqueous sodium chloride, dried over aqueous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography in (silica gel, 20 g, eluents 20% ether in methylene chloride then 10% methanol in methylene chloride) giving the product in 10% methanol in methylene chloride eluent as a white solid. Recrystallization from a mixture of methylene chloride and ether gave the product as long colorless prisms, m.p. 189 - 190°C.

Method B. A mixture of 1.5 g (4.3 mmol) of 9-chloro-7-(2-chlorophenyl)-6,7-dihydro-5H-pyrimido[5,4-d][2]benzazepine-3 -oxide,

and 6 ml of a 5% methylene chloride solution of bromine in 600 ml methylene chloride was stirred at room temperature for 30 min. The mixture was made basic by the addition of 4.5 ml (32 mmol) triethylamine and stirred for 10 min. The mixture was washed with saturated aqueous sodium chloride, dried over aqueous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 50 g, eluents methylene chloride then ethyl acetate then 30% tetrahydrofuran in methylene chloride). The ethyl acetate eluent contained a colorless solid, m.p. 242 - 244°C which was identified as an isomeric compound with the product of the isomeric bond. The 30% tetrahydrofuran in the methylene chloride eluent contained the product as colorless prisms, m.p. 189 - 190°C.

Intermediate product 21

9- chloro- 7-( 2- chlorophenyl)- 6, 7- dihydro- 6-( trifluoroacetyl)- 5H-pyrimido[ 5, 4- d][ 2] benzazepine- 3- oxide

The preparation of 9-chloro-7-(2-chlorophenyl)-6,7-dihydro-6-(trifluoroacetyl)-5H-pyrimido[5,4-d][2]benzazepine-3-oxide was carried out in the same manner 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 which gives the product as colorless crystals, mp 209 - 211°C.

Intermediate 2 2

9-chloro-7-(2-chlorophenyl)-6,7-dihydro-5H-pvrimido[5. 4- d] benza zepine- 3- oxide

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 aqueous sodium hydroxide, 100 ml of ethanol and 100 ml of tetrahydrofuran were stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure to a small volume. The resulting precipitate was isolated by filtration to give a colorless solid,

m.p. 259 - 260°C. Recrystallization from tetrahydrofuran gave the product as colorless crystals, m.p. 263 - 264°C.

Claims (2)

1. Analogue procedure in the production of therapeutic activity ve pyrimido-2-benzazepines of the general formula where A is one of the groups R<1> is hydrogen, chlorine, bromine, lower alkyl, the group NR4R5, the group -CH2-CO-R<7>, the group -NH(CH2)mNR<8>R<9>, hydroxy, lower alkoxy, mercapto or lower alkyl mercapto, R 3 is hydrogen, lower acyloxy or hydroxy, X is hydrogen or halogen, Y is hydroaene or halogen, 4 5 R and R are each hydrogen or lower alkyl or together with the common nitrogen atom form 4-methyl-l-piperazinyl, 7 8 9 R is hydroxy, lower alkoxy or NR R , 8 9 R and R are each hydrogen or lower alkyl, n is 0 or 1 and m is 1 - 7, with the proviso that (i) when R 3 is lower acyloxy or hydroxy, A is group (a), and if R-<*-> is the group -NH(CH2)mNR<8>R<9>, R8 and R<9> are each lower alkyl; (ii) when A is group (d) and R 1 is the group -NH(CH 2 )mNR 8 R 9 , R<8> and R<9> are each lower alkyl; and (iii) when n is 1, R is hydrogen, lower alkyl, lower alkoxy, chlorine or bromine or the group -CH 2 -CO-R 7 (where R 7 is as indicated above) and A is. the group (a) or (b) ; and pharmaceutically acceptable acid addition salts thereof, characterized in that one (a) cyclizes a compound of the general formula where X and Y are as above and R is hydrogen, 8 9 8 9 lower alkyl or NR R •where R and R are as above, or (b) dehydrogenates a compound of the general formula wherein X, Y and R are as above, or (c) reacts a compound of the general formula formula where X and Y are as above, p is 0 or 1 21 and R ar di-lower alkylarnino, with cyanamide, or (d) reacts a compound of general formula IV" as above with a compound of general formula 12 where R is hydrogen, mercapto, lower 8 9 alkyl mercapto, lower alkyl or NR R 8 9 where R and R are as above, or (e) reduces a connection with the general formula wherein X, Y and P?~ are as above, or (f) lower-alkylates a compound therewith general formula where X, Y and R1 are as above, or (g) oxidizes a compound of the general formula 13 where X, and Y are as indicated above and R is hydrogen, lower alkyl, hydroxy, lower alkoxy, NR<41>R<51> (wherein R<41> and R <51> each is hydrogen or lower alkyl ), chlorine, bromine or the group -CK2-CO-R<7> (wherein R<7> is as above), or (h) lower-alkylates a compound of the general formula wherein X, Y and p are as above and 14 R is mercapto or hydroxy, or (i) transfers a compound of the general formula where X, Y and p are as above, in the corresponding 2-hydroxy compound, or (k) transfers a compound with the general formula where X and Y are as above, in a corresponding 2-chloro or bromo compound, or (1) treats a compound with the general formula in which X, Y and p are as above indicated and R is chlorine or bromine, with hydrogen sulphide, with a lower alkyl mercaptan, with a lower alkanol, with a compound of the formula HNR 4 R 5 in which R and R 5 are as indicated above, with a compound of the formula H2N-(CH2)mNR<8>R<9> wherein R<8>, R<9> and m are as above or with the carbanion of a compound of formula wherein R <71> is lower alkoxy and R <21> is as above, and saponifies and decarboxylates the thus obtained intermediate, or (m) transfers a compound of the general formula 71 where R , X, Y and p are as above, in the corresponding free acid or in a corresponding amide, lower alkylamide or di-lower- alkylamide, or (n) transacts a connection with the general formula 16 in which x and Y are as indicated above, R is hydrogen, chlorine, bromine, lower alkyl, 4 5 7 the group NR R , the group -CH_-CO-R , the group;. 81 91 '-NH(CH2)mNR R-, hydroxy, -lower alkoxy, mercapto or lower alkyl mercapto, R and R<91> are liver lower alkyl 4 5 7 and R , R , and R are as above, with a lower acylating agent, or (o) hydrolyzes a compound with the general formula 16 in which X , Y and R are as indicated above 31 and R is lower acyloxy, or (p) deoxygenates a compound of the general formula in which x °g Y is as indicated above, R"*"7 4 5 is hydrogen, lower alkyl, the group NR R , the group -CH2-CO-R<7>, the group -NH(CH2) mNR8R9, hydroxy, lower alkoxy, mercapto or 4 5 7 8 9 lower alkyl mercapto and R , R , R , R and R are as indicated above, or (q) removes elements of H-Z from a compound of - dan general formula in which X and Y are as above an<g>itt, R is hydrogen, lower alkyl, lower alkoxy, kR l7orer , bsorm om oveelnlefr or graunpgppiten t) -CoHg „Z -COe-r R h7yd(hrovgorenia or an easily cleavable acyl group, and optionally transferring a compound of formula I prepared above into a pharmaceutically acceptable acid addition salt. 2. Method according to claim 1 in the production of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido [5;, 4-d] [2]benzazepine, characterized in that correspondingly substituted starting materials are used.