US3622565A

US3622565A - Dibenzazepine derivatives and their preparation

Info

Publication number: US3622565A
Application number: US698436A
Authority: US
Inventors: Jean Clement Louis Fouche; Claude Georges Alexandre
Original assignee: Rhone Poulenc SA
Current assignee: Rhone Poulenc SA
Priority date: 1967-01-18
Filing date: 1968-01-17
Publication date: 1971-11-23
Anticipated expiration: 1988-11-23
Also published as: OA03401A; DE1695666A1; AT279631B; SU406354A3; AT279619B; FI48927C; GB1180165A; FR94320E; IE31926B1; YU12168A; IL29340A; ES354500A1; SE338995B; ES349459A1; YU33110B; AT281842B; AT279630B; NL6800363A; SU464112A3; YU269272A

Abstract

The invention provides new 10-amino-10,11-dihydrodibenzo(b, f)azepine derivatives and their salts which are useful as antidepressants, analgesics, anticonvulsants and tranquillizers.

Description

United States Patent [72] Inventors [21] Appl. No.

[22] Filed [45] Patented [73] Assignee [32] Priorities Jean Clement Louis Fouche Hauts-de-Seine; Claude Georges Alexandre Gueremy, Valde-Marne, both of France Jan. 17,1968

Nov. 23, 1971 Rhone-Poulenc S.A.

Paris, France Jan. 18, 1967 France Nov. 9, 1967, France, No. 127,611

[54] DIBENZAZEPINE DERIVATIVES AND THEIR PREPARATION 1 1 Claims, No Drawings 8/1968 Switzerland Primary Examiner-Alton D. Rollins Attorney-Stevens, Davis, Miller & Mosher ABSTRACT: The invention provides new IO-amino-IOJ ldihydrodibenzolb,flazepine derivatives and their salts which are useful as anti-depressants, analgesics. anticonvuisants and tranquilizers.

DIBENZAZEPINE DERIVATIVES AND THEIR dihydrodibenzo[b,f]e-azepine derivatives of the formula:

and their acid addition salts and quaternary ammonium derivatives, in which R and R are the same or different'and represent hydrogen, alkyl of one to five carbon atoms, hydroxyalkyl of one to five carbon atoms, hydroxyalkoxyalkyl of one to five carbon atoms in each alkyl residue, phenylalkyl of one to five carbon atoms in the alkyl residue, orphenylalkyl of one to five carbon atoms in the alkyl residue in which the phenyl nucleus is substituted by one or more of halogen, alkyl of one to five carbon atoms, alkoxy of one to five carbon atoms, nitro, amino, or trifluoromethyl, and R, is hydrogen, alkyl of one to five carbon atoms, phenylalkyl of one to five carbon atoms in the alkyl residue, or phenylalkyl of one to five carbon atoms in the alkyl residue in which the phenyl nucleus is substituted by one or more of halogen, alkyl of one to five carbon atoms, alkoxy of one to five carbon atoms, or trifluoromethyl.

In accordance with the invention, the compounds of formula 1 are prepared by one of the following methods: I. The compounds of formula 1 in which R and R are both hydrogen may be prepared by reducing a compound of the general formula:

in which R, is as hereinbefore defined, preferably by the action of sodium in a saturated primary aliphatic alcohol of two to six carbon atoms, for example butanol, or by the action of sodium amalgam.

2. The compounds of formula I in which is of the formula N in which R is hydrogen, alkyl of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, hydroxyalkoxyalkyl of one to four carbon atoms in each alkyl residue, phenyl, phenylalkyl of one to four carbon atoms in the alkyl residue, or phenylalkyl of one to four carbon atoms in the alkyl residue in which the phenyl nucleus is substituted by one or more of halogen, alkyl of one to five carbon atoms, alkoxy of one to five carbon atoms, amino, or trifluoromethyl, and R is hydrogen, alkyl of one to five carbon atoms, phenylalkyl of one to five carbon atoms in the alkyl residue, or phenylalkyl of one to five carbon atoms in the alkyl residue in which the phenyl nucleus is substituted by one or more of halogen. alkyl of one to five carbon atoms, or trifluoromethyl, may be prepared by reducing a compound of the formula:

in which R,, R, and R are as hereinbefore defined, by any method suitable for reducing a carbonamide group to a methyleneamino group. As reducing agent it is advantageous to employ lithium aluminum hydride'and to carry out the operation in when organic solvent such as an ether, for example diethyl ether or tetr ahydrofuran.

3. The compounds of formula I in which represents the group -N Clin -R,

in which R, is aspreviously defined and R is hydrogen, alkyl of one to fivecarbon atoms, hydroxyalkyl of one to five carbon atoms, hydroxyalkoxyalkyl of one to five carbon atoms in each alkyl residue, phenylalkyl of one to five carbon atoms in the alkyl residue, or phenylalkyl of one to five carbon atoms in the alkyl residue in which the phenyl nucleus is substituted by one or more of halogen, alkyl of one to five carbon atoms, alkoxy of one to five carbon atoms, amino, trifiuoromethyl, may be prepared by reacting a compound of the formula:

Rr-CHO IV 2 which R, is as previously defined, and hydrogen in the presence of ahydrogenation catalyst, on a compound of the formula:

in which R, and R are as hereinbefore defined.

When this process is applied to compounds of formula V in which R, is a hydrogen atom, and two molecular proportions or more of the aldehyde of formula IV and hydrogen are employed, compounds of formula I are obtained, in which is ofthe formula -N(CH,-R

In all cases, it is advantageous to operate in a saturated lower primary aliphatic alcohol such as ethanol and to employ ,Raney nickel or Adams platinum as hydrogenation catalyst.

In some cases, when it is desired to produce a compound in which'R, is hydrogen, it may be advantageous to react the al-,

dehyde of formula IV and the hydrogen with a compound of the formula:

R -NH V1:

in which Ac represents an acyl radical which may be readily eliminated by acid hydrolysis and R is as previously defined. and then to eliminate the Ac radical by hydrolysis.

N is of the formula N in which R is as hereinbefore defined, and R is alkyl of one to five carbon atoms, hydroxyalkyl of one to five carbon atoms, hydroxyalkoxyalkyl of one to five carbon atoms in each alkyl residue, phenylalkyl of one to five carbon atoms in the alkyl residue, or phenylalkyl of one to five carbon atoms in the alkyl residue in which the phenyl nucleus is substituted by one or more of halogen, alkyl of one to five carbon atoms, alkoxy of one to five carbon atoms, nitro, amino, or trifiuoromethyl, may be prepared by reacting a compound of the formula:

R,-x VI in which R is as hereinbefore defined and X represents a reactive ester residue such as a halogen atom or a sulphuric or sulphonic ester residue (for example a methanesulphonyloxy or toluene-p-sulphonyloxy residue) with a compound of the formula:

is of the formula: -N( R,,),.

It is advantageous to operate in an inert organic solvent such as dimethylformamide-and in the presence of sodium bicarbonate, preferably at the boiling temperature of the solvent.

5. The compounds of formula I in which is of the formula NHR in which R, is as hereinbefore defined, may be prepared by replacing,

in a compound of the formula:

iii N RsNY VII! in which R, and R, are as hereinbefore defined and Y is cyano. alkoxy, carbonyl, alkanoyl, alkanesulphonyl or arylsulphonyl radical. the radical Y by a hydrogen atom. The replacement of the radical Y by hydrogen may be carried out by the usual methods specific to each of the meanings of Y.

6. The compounds of formula I in which is of the formlua N in which R,, is hydrogen or alkyl of one to live carbon atoms. may be prepared by reducing a compound of the formula:

by any method known per se for the preparation of oximes from ketones.

The compounds of formula X in which R, is other than hydrogen, may be prepared in accordance with German Pat. No. 1,142,870. This method consists in alkylating a compound of the formula:

CH: XI

with a compound of the formula:

R,X X" in which R, is the same as R,, but not hydrogen, and X is as hereinbefore defined, followed by hydrolyzing the intermediate for the formula:

thus obtained.

The compounds of fonnula III in which R, and R are as hereinbefore defined may be prepared from compounds of the formula:

XIII

XIV

in which R, and R are as hereinbefore defined, by any method of acylation known per se.

it appears particularly advantageous to employ a chloride or anhydride of an acid of formula:

R COOH (where R is as hereinbefore defined) and to operate in an inert organic solvent such as benzene or toluene, with reflux of the solvent and in the presence or absence of a base such as a tertiary amine, for example pyridine.

When R, in formula III is hydrogen, it is particularly advantageous to carry out the acylation with ethyl formate and to operate in an autoclave at a temperature between 50 and 150 C.

The compounds of formula lX, in which R and R, are as hereinbefore defined may be prepared by any method known per se for the preparation of urethanes from compounds of the formula:

in which R is as hereinbefore defined.

The compounds of formulae V, VI] and XIV, in which R, R and R, are as hereinbefore defined, but are not hydrogen, may be prepared by successive application of one or more of the methods l to 6 described herein to compounds of the formula:

NH: XVI

s- VIIIa in which R, and R are as hereinbefore defined. b. By alkylation of a compound of the formula:

in which R, and Y are as hereinbefore defined, with a reactive ester of the formula VI in the presence of an alkaline condensation agent.

The compounds of formula Vlllb may be obtained from compounds of the formula:

NE: V 1110 in which R, is as hereinbefore defined, by the action of cyanogen bromide, an alkyl chloroformate, an acid halide or an aliphatic or aromatic sulphonyl chloride.

The compounds of formula I may optionally be purified by physical methods (such as distillation, crystallization or chromatography) or by chemical methods (such as formation of salts, crystallization of the latter and decomposition in alkaline medium). in these operations, the nature of the anion of the salt is immaterial, the only condition being that the salt should be well-defined and readily crystallizable.

The compounds of formula I may be converted into acid addition salts and quaternary ammonium derivatives. The acid addition salts may be obtained by the action of the bases on acids in appropriate solvents. The organic solvents employed may be, for example, alcohols, ethers, ketones or chlorinated solvents. The salt formed precipitates after optional concentration of its solution and is separated by filtration or decantation. The quaternary ammonium derivatives may be obtained by the action of the bases on esters, optionally in an organic solvent, at ambient temperature or more rapidly with moderate heating.

The compounds of formula I and their acid addition salts and quaternary ammonium derivatives have interesting pharmacodynamic properties. They are very active on the central nervous system as antidepressants and analgesics. They also have good activity as anticonvulsants and tranquillizers. They have given good results in physiological tests on animals in doses of 5 to 50 mg. per kg. of animal weight. The most interesting compounds are those of formula I in which R,, R and R, which are identical or different, represent hydrogen atom or alkyl of one to five carbon atoms. especially S-methyl-lO- methylaminol O, l l-dihydrodibenzo[ bflazepine.

For medicinal use, the new compounds may be employed either as bases or as pharmaceutically acceptable acid addition salts or quaternary ammonium derivatives, i.e. salts and derivatives which are nontoxic in the doses in which they are employed. As examples of pharmaceutically acceptable acid addition salts, there may be mentioned salts of mineral acids (such as hydrochlorides, sulphates, nitrates and phosphates) and salts of organic acids (such as acetates, propionates, succinates, benzoates. fumarates. maleates, tartrates, theophyllineacetates, salicylates, phenolphthalinates and methylenebis-B-hydroxynaphthoates) or substitution derivatives of these acids. As examples of pharmaceutically acceptable quaternary ammonium derivatives there may be mentioned derivatives of mineral or organic esters such as the methochlorides, methobromides, methiodides, ethochlorides, ethobromides. ethiodides, allylchlorides, allylbromides, allyliodides, benzyl chlorides," benzyl-bromides, benzyliodides, the methyland ethyl-sulphates, the benzene-sulphonates and substitution derivatives of these compounds.

The following Examples illustrate the invention.

EXAMPLEI To a solution of l9 g. of S-methyl-l0-hydroximino-l0,l l-

dihydrodibenzo[b,f]eazepine in 200 cm. of hutnnnl at C,

13 g. of sodium are added in portions in 90 minutes. The reaction mixture is then heated under reflux of the butanol for 20 minutes until the sodium has completely disappeared. After cooling, 160 cm. of distilled water are added and one-half of the solvents is evaporated under reduced pressure (20 mm.Hg). cm. of distilled water are added and the residual butanol is evaporated under normal pressure. The aqueous suspension obtained is diluted with 700 cm. of distilled water and extracted with 150 cm. of diethyl ether. The separated aqueous solution is then twice washed with a total of 200 cm. of diethyl ether. The combined ethereal solutions are extracted six times with a total of 300 cm. of aqueous 2N methane sulfonic acid solution. The combined aqueous acid solutions are made alkaline with 100 cm. of 10 N sodium hydroxide solution and extracted three times with a total of 350 cm. of diethyl ether. The combined ethereal solutions are washed 3 times to neutrality with a total of 300 cm. of distilled water, dried over anhydrous sodium sulphate and evaporated. The residue (16.5 g.) is dissolved in 20 cm. of boiling diisopropyl ether. After cooling at 3 C. for 4 hours, the crystals which have appeared are separated, twice washed with a total of 20 cm. ice-cold diisopropyl ether and dried under reduced pressure (20 mm.Hg). 1 1.5 g. of 5-methyl-10- amino- 10,1 l--dihydrodibenzo[b,f]azepine, m.p. 93 C., are ob tained. The pure product (m.p. 96 C.) may be obtained by preparing the hydrochloride in ethanol and then converting it into the base and recrystallizing the latter from acetonitrile.

The starting S-methyl-l-hydroximino-10,1 1- dihydrodibenzo-[b,f]azepine may be prepared as follows. Methyl-l0-oxo-10,l 1-dihydrodibenzo[b,f]azepine (m.p. 104 C.) is prepared by the method of German Pat. No. 1,142,870. The reaction of an excess of hydroxylamine on 60 g. of 5- methyl--oxo-10,1 1-dihydrodibenzo[b,f]azepine in aqueous ethanolic medium under reflux gives 53.3 g. of 5-methyl-l0- hydroximino-10,1l-dihydrodibenzo[b,f]azepine (m.p. 196 C.).

EXAMPLE II A solution of 6.7 g. of 5-methyl-10-amino-10,11-

dihydrodibenzo[b,flazepine in 360 cm. of ethanol and 40 g.:.

of 30 percent (by weight) aqueous formaldehyde is hydrogenated in the presence of 18 g. of Raney nickel at normal temperature under a hydrogen pressure of 50 bars for 7 hours. After the catalyst has been filtered off and washed with ethanol, the clear filtrate is evaporated under reduced pressure (l4mm.Hg). The residue is treated with 150 cm. of diethyl ether. The insoluble matter which appears is filtered off and washed with diethyl ether. The ethereal solution obtained is extracted four times with a total of 200 cm. of an icecold 2 N aqueous methanesulphonic acid solution, and the combined acid solutions are made alkaline in the cold with 45 cm. of 10N sodium hydroxide solution. The oil which separates out is extracted three times with a total of 300 cm. of diethyl ether. The combined ethereal solutions are twice washed with a total of 200 cm. of distilled water, dried over anhydrous potassium carbonate, and evaporated. The residue (6.3 g.) is dissolved at boiling point in 14 cm. of ethanol and 3 cm. of distilled water. On cooling to about 50 C. and seeding, crystals appear. The crystallization is continued at 3 C. for 2 hours.,The crystals are separated, washed with 1 1 cm. of icecold 80 percent aqueous ethanol and dried under reduced pressure (14 mm.1-1g). 5 g. of S-methyl-10'dimethylamino- 10,1 1-dihydrodibenzo[b,f]azepine, m.p. 65 C., are obtained.

EXAMPLE 111 2.2 g. of S-methyl-10-forrnamido-10,1 1-

dihydrodibenz0[b f]azepine are added in small portions in 2 1 minutes to a suspension of 1 1 of lithium aluminum hydride in 180 cm. of anhydrous diethyl ether, and the mixture is refluxed for 5 hours. The suspension, cooled to 5 C., is hydrolyzed in minutes by adding successively 1.3 cm. of distilled water, 0.95 cm. of 5 N sodium hydroxide solution and 4.3 cm. of distilled water. After stirring for 1 hour at ambient temperature, the precipitate formed is separated and washed three times with a total of 120 cm. of boiling methylene chloride The filtrate is evaporated and the residue dissolved in 250 cm. of diethyl ether. The ethereal solution obtained is extracted three times with a total of 150 cm. of aqueous 2 N methanesulphonic acid solution. The combined acid solutions are made alkaline in the cold with 40 cm. of 10N sodium hydroxide solution. The oil which separates out is extracted three times with a total of 300 cm? of diethyl ether.

The combined ethereal solutions are twice washed with a total of 200 cm. of distilled water, dried over anhydrous sodium sulfate and evaporated. To the residue (2 g.) in solution in 10 cm. of isopropanol are added 2 cm. of an anhydrous solution of hydrogen chloride in diethyl ether (containing 4 mol of acid per liter of solution). After cooling for 1 hour at 3 C., the crystals formed are separated, washed with an ice-cold mixture of 4 cm. of isopropanol and 3 cm. of anhydrous diethyl ether and dried under reduced pressure 1 1 mm.l-lg). 1.9 g. of 5-methyl-l0-methy1amino-10,l 1-dihydrodibenzo[b,f]azepine hydrochloride, m.p. 238240 C., are obtained.

The starting S-methyl- 10-formamido-10, 1 ldihydrodibenzo-[b,f]a;epine is prepared as follows. 2 g. of 5- methyl-10-formarnido-l0, 1 1-dihydrodibenzo[ b,f]azepine (m.p. 142 C.) are obtained by heating 2.25 g. of 5-methy1-l0- amino-10,11dihydrodibenzo[b,f]azepine and 14.8 g. of ethyl formate in an autoclave at C. for 2 hours.

EXAMPLE IV 205 g. of sodium amalgam containing 2.5 percent of sodium and 6.1 g. of l0-hydroximino-10,1 1-dihydrodibenzo[ b,f]azepine are brought into contact at a temperature between 30 and 40 C. in 76 cm. of percent ethanol until the sodium of the amalgam is completely consumed. in the course of this operation, the pH of the reaction medium is maintained in the neighborhood of 6 by the addition of a total of 18 cm." of acetic acid. The reaction mixture is diluted with 760 cm. of distilled water. The mercury regenerated in the course of the reaction is eliminated by decantation. The aqueous phase is made alkaline with 25 cm. of 5N sodium hydroxide and extracted three times with a total of 750 cm. of diethyl ether. The combined ethereal solutions are twice extracted with a total of 200 cm. of aqueous 2 N methanesulphonic acid solution. The combined aqueous acid solutions are washed with 40 cm. of diethyl ether and then made alkaline with 45 cm. of 10 N sodium hydroxide solution. The oil which separates out is extracted three times with a total of 750 cm. of diethyl ether. The ethereal extracts are washed five times with a total of 450 cm. of distilled water, dried over potassium carbonate and evaporated. The product obtained (4.7 g., m.p. 122 C.) is chromatographed on 42 g. of alumina eluting with a mixture of benzene and ethyl acetate. The chromatographed product (2.5 g.) is dissolved in 30 cm. of a boiling mixture of cyclohexane and benzene (7:3 by volume). After cooling for 1 hour at 20 C. the crystals which have appeared are separated, washed twice with a total of 8 cm. of a mixture of cyclohexane and benzene (7:3 by volume) and dried under reduced pressure (20 mm.Hg). To a boiling solution of 2.4 g. of purified product (m.p. 123 C.) in 8 cm. of acetone is addeda boiling solution of 1.1 g. of anhydrous oxalic acid in 2.5 cm. of acetone. After cooling for half an hour at 3 C., the crystals which have appeared are separated, washed twice with a total of 10 cm. of acetone, and then with 8 cm of anhydrous diethyl ether, and dried under reduced pressure (20 mm. Hg.). 2.8 g. of 10amino-10,1 1-dihydrodibenzo[b,f]azepine oxalate, m.p. 194 C., are obtained.

The starting 10-hydroximino-10,1 l-dihydrodibenzo[ b,f]azepine may be prepared as follows. IO-Methoxydibenzo[b,f]azepine (m.p. 125 C.) is prepared by the method of Swiss Pat. No. 375,721. The action of dilute hydrochloric acid on 14.0 g. of l0-methoxydibenzo[b,f] azepine, gives 8.1 g. of 10-oxo-10,1 1-dihydrodibenzo-[ b,f]azepine (m.p. 141 C.). The action of an excess of hydroxylamine on 8 g. of 10-oxo-10,1 1-dihydrodibenzo[b,f]azepine, in aqueous ethanolic medium under reflux gives 6.1 g. of 10- hydroximino-10,1 1-dihydrodibenzo[b,f]azepine (m.p. 1 68 C.).

EXAMPLE V dihydroflibenzow,f]azepine are brought into contact at 70 C.

in 320 cm. of 95 percent ethanol until the sodium of the amalgam has been completely consumed. 1n the course of this operation, the pH of the reaction medium is maintained in the neighborhood of 6 by the addition of a total of 30 cm. of acetic acid. When the reaction has ended, the regenerated mercury is eliminated by decantation. The aqueous ethanol phase is concentrated under reduced pressure (20 mm.l-lg) to a volume of about 50 cm. and then diluted with 500 cm. of distilled water and made alkaline with aqueous sodium carbonate solution. The oil in suspension is extracted three times with a total of 300 cm. of diethyl ether and the combined ethereal solutions are extracted five times with 500 cm. of aqueous 2 N methanesulphonic acid solution. The aqueous acid solutions are made alkaline with 100 cm. of 10 N sodium hydroxide solution, and the oil which separates out is extracted three times with a total of 450 cm. of diethyl ether. The ethereal extracts are twice washed with a total of 200 cm. of distilled water, dried over anhydrous sodium sulfate, and evaporated. The residue obtained (7.5 g.) is dissolved in 20 cm. of boiling heptane. After cooling for 24 hours at 3 C., the crystals which have appeared are separated, washed with 10 cm. of heptane and dried under reduced pressure (20 mm.Hg). The product obtained (6.7 g., m.p. 89 C.) is purified by conversion into the fumarate which is recrystallized from ethanol (8.2 g., m.p. 200 C.) and reconverted into the base, which is then crystallized from heptane. 4.6 g. of -ethyl-l0- amino-10,11-dihydrodibenzo[b,f]-azepine, m.p. 90 C., are obtained.

The starting 5-ethy1- 1 O-hydroximinol 0,1 1- dihydrodibenzo-[b,f]azepine may be prepared as follows. Methoxydibenzo[b,f]azepine is prepared as indicated in example IV. The reaction of sodamide and the n of ethyl iodide H in hexamethylphosphotriamide on g. of 20-methoxydibenzo[b,f]azepine give 15.4 g. of 5-ethyl-lO-methoxydibenzo[b,f]azepine (m.p. 180 C.). The action of dilute hydrochloric acid on 12.7 g. of 5-ethyl-l0-methoxydibenzo[ b,f]azepine gives 10.7 g. of 5-ethyl-l0-oxo-l0,l1- dihydrodibenzolbflazepine (m.p. 120 C.). The atlion of an excess of hydroxylamine on 10.5 g. of 5-ethyl-10-oxo-10,l ldihydrodibenzo[b,f]azepine gives 10.8 g. of 5 ethyll0- hydroximino- 1 0:1 l d i hydrodiben2o[b,f]azepine (m.p. 207 C.

EXAMPLE V1 327 g. of sodium amalgam containing 2.5 percent of sodium and 1 1.6 g. of S-benzyl-lO-hydroximino-10,1 ldihydrodibenz0[b,f]azepine are brought intp ontacttug/31g in 320 cm. of 95perze iitqlianol until the sodium of the amalgam has been completely consumed. In the course of this operation, the pH of the reaction medium is maintained in the neighborhood of 6 by the addition of a total of 25 cm. of acetic acid. The mercury regenerated in the course of the reaction is eliminated by decantation. The aqueous ethanol phase is concentrated under reduced pressure (20 mm.Hg) to a volume of about 100 cm. and then diluted with 600 cm. of distilled water and made alkaline with aqueous sodium carbonate solution. The oil in suspension is extracted three times with a total of 600 cm. of diethyl ether. The combined ethereal solutions are extracted four times with a total of 400 cm. of an aqueous 2 N methanesulphonic acid solution. The aqueous acid solutions are made alkaline with 85 cm. of 10 N sodium hydroxide solution, and the oil which separates out is extracted three times with a total of 450 cm. of diethyl ether. The ethereal extracts are twice washed with a total of 200 cm. of distilled water, dried over anhydrous sodium sulphate, and evaporated. The residue obtained 10.1 g.) is dissolved in 28 cm. of anhydrous ethanol and the solution is filtered and treated at 3 C. with 16.8 cm. ofa 1.95 N methanesulphonic acid solution in ethanol. After cooling for 1 hour at 3 C., the crystals which have appeared are separated, washed with 10 cm. of ice-cold anhydrous ethanol and then with 10 cm. of anhydrous diethyl ether and dried under reduced pressure (20 benzyl-10-oxo-10,11-dihydrodibenzo-[b,f]azepine gives 12.0 1

g. of S-benzyl-10hydroximino-10,1 l-dihydrodibenzo[ b,f] azepine (m.p. 202 C.).

EXAMPLE V" 14.9 g. of S-methyl-10-acetylamino-10,1 l-dihydrodibenzo- [b,f]azepine are added in small portions in 2 minutes to a suspension of 6.35 g. of lithium aluminum hydride in 700 cm. of anhydrous diethyl ether. The mixture is heated under reflux for 5 hours and the suspension is then cooled to 5 C. and hydrolyzed by the addition of 7.3 cm. of distilled water, followed by 5.45 cm. of 5 N sodium hydroxide, and finally 25 cm. of distilled water. After stirring for 1 hour at 20 C.. the precipitate formed is separated and twice washed with a total of 100 cm. of boiling methylene chloride. The filtrate is thrice extracted with a total of cm. of aqueous 2 N methanesulphonic acid solution. The aqueous acid solutions are washed with 40 cm. of diethyl ether and then made alkaline with 18 cm. of 10 N sodium hydroxide solution. The oil which separates out is twice extracted with a total of cm.- of diethyl ether and the ethereal extracts are washed three times with a total of cm. of distilled water, dried over potassium carbonate and evaporated. The residue obtained 12.4 g.) is purified by conversion into the fumarate which is crystallized from ethanol (14 g., m.p. -138 C.) and reconversion into the base. The purified product (7.9 g.) is dissolved in 30 cm of anhydrous diethyl ether and the solution is treated at 3 C. with 16.1 cm. of a 1.94 N methanesulphonic acid solution in ethanol. After cooling for 2 hours at 3 C., the crystals which have appeared are separated, twice washed with a total of 20 cm. of anhydrous diethyl ether, and dried under reduced pressure (20 mm.Hg). 10.2 g. of S-methyll O-ethylamino- 1 0,1 l-dihydrodibenzo- [b,f]azepine methanesulphonic, m.p. 196 C., are obtained.

The starting S-methyl- 1 O-acetylamino- 1 0,1 1- dihydrodibenzo-[b,f]azepine may be prepared as follows. 5- Methy1-10-amin0-10,l 1dihydrodibenzo[b,f]azepine (m.p. 96 C.) is prepared as described in Example 1.

The action of acetic anhydride in pyridine on 36 g. of 5- methyl- 1 O-aminol 0,1 1-dihydrodibenzo[b,f]azepine gives 41.4 of S-methyl-l0-acetylamino-10,l 1- dihydrodibenzo[b,f]eazepine (m.p. 187 C.).

EXAMPLE Vlll A solution of 8.9 g. of 5methyl-10-( N-acetyl-N- ethylamino)-l0,1l-dihydrodibenzo[b,f]azepine in 40 cm. of anhydrous diethyl ether is added in 7 minutes to a suspension of 3.4 g. of lithium aluminum hydride in cm. of anhydrous diethyl ether at 20 C. After heating under reflux for 5 hours, the suspension is cooled to 5 C. and hydrolyzed by the addition of 3.9 cm? of distilled water, followed by 2.9 cm. of 5 N sodium hydroxide, and finally 13.2 cm. of distilled water. After stirring for 1 hour at ambient temperature, the precipitate formed is separated and twice washed with a total of 70 cm. of boiling methylene chloride. The filtrate is evaporated under reduced pressure (20 mm.Hg). The residue (8.5 g.) is dissolved in 30 cm. of diethyl ether and the ethereal solution obtained is twice extracted with a total of 70 cm. of ice-cold aqueous 2 N methanesulphonic acid solution. The combined aqueous acid solutions are made alkaline at 3 C. with 18 cm of 10 N sodium hydroxide solution and the oil which separates out is extracted three times with a total of 1 30 cm. of diethyl ether. The extracts are twice washed with a total of 200 cm. of distilled water, dried over anhydrous magdihydrodibenzo[b,f]azepine may be prepared as follows. 5-

Methyl-1o-ethylamino-l lfil-dihydrodibenakfi bfiaiepirie is prepared as described in example VII. The action of acetic anhydride in pyridine on 8.4 g. of 5-methyl-l0-ethylamino-l0,l l -dihydrodibenzo[b,f]azepine gives 8.9 g. of 5-methyl-l0(N- acetyl-N-ethylamino l 0,1 l-dihydrodibenzo[ b,f] azepine (as a crude oily product).

EXAMPLE 1X A solution of 10 g. of 5-methyl-l0-( N-formyl-N- ethylamino)-l0,l l-dihydrodibenzo[b,f]azepine in 200 cm. of anhydrous diethyl ether is added in 10 minutes to a suspension of 4.1 g. of lithium aluminum hydride in 200 cm. of anhydrous diethyl ether at 20 C. After heating under reflux for 4 hours, the suspension is cooled to 5 C. and hydrolyzed by the addition of 4.8 cm. of distilled water, followed by 3.5 cm. 3 of 5 N sodium hydroxide, and finally 15.8 cm. of distilled water. After stirring for 15 minutes at 5 C., the precipitate formed is separated and twice washed with a total of 200 cm. of boiling methylene chloride. The filtrate is twice extracted with a total of 200 cm. of aqueous 2 N methanesulphonic acid solution and three times with a total of 150 cm. of distilled water. The combined aqueous acid solutions are made alkaline with 70 cm. of 5 N sodium hydroxide and the oil which separates out is extracted with 100 cm. of diethyl ether. The aqueous alkaline phase is saturated with sodium chloride and then again twice extracted with a total of 200 cm. of diethyl ether. The combined ethereal solutions are dried over potassium carbonate and evaporated. The residue obtained (8.0 g.) is dissolved in 4 cm. of boiling ethyl acetate and the solution obtained is treated with a boiling solution of 3.5 g. of maleic acid in 25 cm. of ethyl acetate. After cooling at 3 C. for 2 hours, the crystals which have appeared are separated, twice washed with a total of 10 cm. of ethyl acetate and then twice with a total of 20 cm. of anhydrous diethyl ether and dried under reduced pressure (20 mm.l-lg). 10.5 g. of S-methyl-lO- methylethylamino-10,l ldihydrodibenzo-[b,f]azepine maleate, m.p. 135C., are obtained.

The starting S-methyll N-formyl-N-ethylamino )-N 10,11-dihydrodibenzo[b,f]azepine may be prepared as follows. 5 -Methyl-l0-ethylamino-10,1 l-dihydrodibenzo [b,f]azepine is prepared as described in example VII. The action of an excess of formylacetic anhydride at ambient temperature on 9.1 g. of S-methyl-l0-ethylamino-l0,l ldihydrodibenzo[b,f]azepine gives g. of S-methyl-lO-(N- formyl-N-ethylamino)-10,1 1 dihydrodibenzo[b,f] azepine (as a crude oily product).

EXAMPLE X To a solution of 3.5 g. of S-methyl-lO-methylamino-10,1 ldihydrodibenzo[b,f]azepine in 10 cm. of anhydrous dimethylformamide containin g lfl g. of sodium bicarbonate a solution of 1.39 g. of dimethylsulphate in 5 amid? anhydrous dimethylformamide is added in the course of 4 minutes. The suspension obtained is agitated at ambient temperature for 3 hours. 150 cm. of ice-cold distilled water and 10 cm. of 10 N sodium hydroxide solution are added, and the mixture is extracted three times with a total of 180 cm. of diethyl ether. The united ethereal solutions are extracted twice with a total of 60 cm. of aqueous N methanesulphonic acid. The aqueous acid solutions are united and made alkaline with 10 cm. of 10 N sodium hydroxide solution, and the alkaline mixture is extracted three 3 times with a total of 120 cm. of diethyl ether. The etherealsolutions are united, dried over potassium carbonate, and evaporated. The residue 1.6 g.) is converted into the hydrochloride in ethanol, and then reconverted into the base which is recrystallized from aqueous ethanol to give 0.9 g. of S-methyl-l0-dimethylamino-10,l l-dihydrodibenzo[ b,f] azepine, m.p. 65-66 C.

EXAMPLE X1 A solution of 0.53 g. of S-methyl-lO-(N-cyano-N- methylamino)- l 0,1 l-dihydrodibenzo[ b,f]azepine (m.p. -87 C.) in 10 cm. of n-butanol is heated under reflux for 8 hours in the presence of 0.66 g. of potassium hydroxide. After cooling, cm. of distilled water are added, and the mixture is extracted twice with a total of 100 cm. of diethyl ether. The united ethereal extracts are washed with 25 cm of distilled water, and then extracted twice with a total of 100 cm. of ice-cold aqueous N methanesulphonic acid. The united aqueous acid solutions are made alkaline with 25 cm. of 10 N sodium hydroxide solution and extracted three times with a total of cm. of diethyl ether. The united ethereal extracts are washed with 20 cm." of distilled water, dried over anhydrous magnesium sulphate and evaporated. The residue obtained (0.40 g.) is converted in isopropanol into the hydrochloride of S-methyll O-methylaminol 0,1 ldihydrodibenzo[b,f]eazepine (0.42 g.) m.p. 237-240 C.

EXAMPLE Xll A solution of 1.0 g. of 5-methyl-10(N-ethoxycarbonyl-N- methylamino)-10,l l-dihydrodibenzo[b,f]azepine (b.p. l72l75 C./0.l mm.Hg) in 5 cm. of n-butanol is heated under reflux for 4 hours in the presence of 1.0 g. of potassium hydroxide. After cooling, 100 cm. of distilled water are added, and the mixture is extracted twice with a total of 120 cm. of diethyl ether. The united ethereal extracts are washed with 25 cm. of distilled water and then extracted twice with a total of 100 cm. of ice-cold aqueous N methanesulphonic acid solution. The aqueous acid solutions are combined and made alkaline with 25 cm. of 10 N sodium hydroxide solution, and extracted twice with a total of 120 cm. of diethyl ether. The united ethereal extracts are washed with 20 cm. of distilled water, dried over anhydrous sodium sulfate, and evaporated. The residue (0.31 g.) is converted in isopropanol into the hydrochloride of S-methyl-l0-methylamino-l0,l dihydrodibenzo[b,f]e-azepine (0.27 g.), m.p. 238-240C.

EXAMPLE Xlll A solution of 0.53 g. of 5-methyl-l0-(N-formyl-N- methylamino)-l0,ll-dihydrodibenzo(b,f]azepine in 10 cm. of n-butanol is heated under reflux for 8 hours in the presence of 0.66 g. of potassium hydroxide. After cooling, 100 cm. of distilled water are added, and the mixture is extracted twice with a total of 100 cm. of diethyl ether. The united ethereal extracts are washed with 25 cm. of distilled water, and then extracted twice with a total of 100 cm. of ice-cold aqueous N methanesulphonic acid solution. The united aqueous acid solutions are made alkaline with 25 cm. of 10 N sodium hydroxide solution, and extracted three times with a total of 120 cm. of diethyl ether. The united ethereal extracts are washed with 30 cm. of distilled water, dried over anhydrous magnesium sulphate, and evaporated. The residue obtained (0.39 g.) is converted in isopropanol into the hydrochloride of 5-methyll O-methylamino- 1 0,1 l-dihydrodibenzo[b,f]azepine (0.39 g.), m.p. 237-240C.

The S-methyl- 1 0-(N-formyl-N-methylamino)- l 0,1 ldihydrodibenzo-[b.flazepine used as starting material can be prepared as follows. S-Methyll O-formamidol 0,1 1- dihydrodibenz0[b,f]azepine is prepared the manner des'cibedin'examplelll. By the action of sodium hydride, followed by dimethyl sulphate, at ambient temperature in anhydrous tetrahydrofuran, on 2.5 g. of 5-methyl-l0-formamido-l0,1 l-dihydrodibenzo-[b,f]azepine, 1.8 g. of 5- methyl-10-(N-formyl-N-methylamino)-10, l ldihydrodibenzo[b,f]azepine, m.p. 95 C., are obtained.

EXAMPLE XIV 0.58 g. of sodium is added in portions over 8 minutes to a suspension of 0.98 of 5-methyl-l0-(N-methyl-N- tosylamino)-l0,l l-dihydrodibenzo[b,f]azepine in 15 cm. of n-butanol at 100 C. The reaction mixture is then heated under reflux for 30 minutes until the sodium has completely disappeared. After cooling, 100 cm. of distilled water are added, and the mixture is extracted twice with a total of 100 cm. of diethyl ether. The united ethereal extracts are extracted twice with a total of 80 cm. of ice-cold aqueous N methanesulphonic acid solution. The united aqueous acid solutions are made alkaline with 20 cm. of 10 N sodium hydroxide solution, and extracted twice with a total of 120 cm. of diethyl ether. The united ethereal extracts are dried over potassium carbonate and evaporated. The reside (0.56 g.) is dissolved in a mixture of 3 cm. of isopropanol and 3 cm. of diethyl ether. 0.6 cm. of a 4 N anhydrous solution of hydrogen chloride in diethyl ether is added, and after cooling for 1 hour at 3 C., the crystals formed are separated, washed with 2 cm. of a mixture of isopropanol and diethyl ether (1:1), then twice with a total of 4 cm. of diethyl ether, and finally dried under reduced pressure (20 mm.l-lg). 0.6 g. ofthe hydrochloride of 5-methyll methylamino-l0,l ly zol tflazsain l,m-i 37?2 0i9 ar sm The -methyl- (N -methyl-N -tosylamino) -F), 1 l dihydrodibenzo[b,flazepine used as starting material can be prepared as enews? 5 lVlethyl lUamiho lfill dihydrodibenzo[b,flazepine (m.p. 96 C.) is prepared by the method of example ll Thereact ioh o f 1.0 ETBTp tolEEnest JTfo nyl chloride on 2.24 g. of 5-methyl-l0-amino-l0,l ldihydrodibenzo[b,flazepine in pyridine at ambient temperature gives 2 v g. of 5351514 (YuEylammjl dihydrodibenzo[b,f1azepine m.p. 158 C. The reaction of 0.75 g. of dimethylsulphate on 0.95 g. of S -meth yFl (Y tosylamino-10,1l-dihydrodibenzo[b,f]azepine in ethanol in the presence of an acid-binding agent gives 0.74 g. of 5- EXAMPLE XV A solution of 4.9 g. of S-methyl-lO-(N-ethoxycarbonyl-N- methylamino)-l0,l l-dihydrodibenzo[b,f]azepine in 75 cm. of anhydrous diethyl ether is added in 25 minutes to a suspension of 1.25 g. of lithium aluminum hydride in 75 cm. of anhydrous diethyl ether. The mixture is refluxed for 3 hours. The suspension is then cooled to 5 C. and hydrolyzed in 1 hour by the successive addition of 1.45 cm. of distilled water, 1.1 cm. of 5 N sodium hydroxide solution, and 4.9 cm. of distilled water. The precipitate formed is filtered off and washed four times with a total of 200 cm. of diethyl ether. The filtrate is extracted twice with a total of 100 cm. of ice-cold aqueous 2 N methanesulphonic acid, and then with 50 cm? of distilled water. The united aqueous acid solutions are made alkaline with cm. of 10 N sodium hydroxide solution and then extracted three times with a total of 240 cm. of diethyl ether. The ethereal solutions are united and washed with cm. of distilled water, dried over anhydrous magnesium sulphate, and evaporated. The residue obtained (3.8 g.) is dissolved in 7 cm. of lukewarm ethanol, 1.7 cm. of distilled water are added, and crystallization begins. After 16 hours cooling at 3 C., the crystals which have appeared are separated, washed with 1.5 cm. ofa mixture of ethanol and distilled water (4:1 and dried under reduced pressure (20 mm.l-lg). 3.6 g. of 5- methyl- 1 O-dimethylaminol 0,1 l-dihydrodibenzo[b,f]azepine, m.p. 6566 C. are obtained.

The S-methyl-10-(N-ethoxycarbonyl-N-methylamino)- l0,l l-dihydrodibenzo[b,f]azepine used as starting material can be prepared as follows: S-Methyl-10-methy1amino-l0,l ldihydrodibenzo[b,f]azepine is prepared by the method of ex-z ample Ill. The action of ethyl chlorofiarmatein benzene in the presence of triethylamine on 13.9 g. of S-methyl-lO- methyIamino-l0,l l-dihydrodibenzo[b,f]azepine, gives 10.1 g. of 5 -methyl-l0-(N-ethoxycarbonyl-N-ethylamino)-10,1 ldihydrodibenzo[b,f]azepine, b.p. l72-l75 C./0.l mmllg.

The invention includes within its scope pharmaceutical compositions comprising, in association with a pharmaceutically acceptable carrier or coating, at least one 10,1 1- dihydrodibenzo[b,f]eazepine derivative of formula 1 or a nontoxic acid addition salt or quaternary ammonium derivative thereof. These compositions may be in a form suitable for oral, parenteral, or rectal administration.

Solid compositions for oral administration include tablets, pills, powders, or granules. In such solid compositions, the active compound is mixed with one or more inert diluents such as sucrose, lactose or starch. These compositions may also comprise, as is normal practice, substances other than diluents, e.g. lubricants such as magnesium stearate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixers containing inert diluents such as water or paraffin oil. These compositions may also comprise substances other than diluents, for example wetting agents, sweetening agents, perfumes and preservatives.

The compositions according to the invention for parenteral administration may be aqueous or nonaqueous sterile solutions, suspensions or emulsions. As solvent or vehicle, there may be employed propylene glycol, polyethylene glycol, vegetable oils, more particularly olive oil, and injectable organic esters, for example ethyl oleate. These compositions may also contain adjuvants, more particularly wetting agents, emulsifiers and dispersing agents. The sterilization may be effected in various ways, for example with the aid of a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. The compositions may also be prepared in the fonn of sterile solid compositions which may be dissolved at the time of use in sterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories which contain, in addition to the active compound, excipients such as cacao butter or suppository wax.

The dose employed depends upon the desired therapeutic effect, the route of administration and the duration of treatment. When orally administered, generally between 10 and 250 mg. per day of active product is administered to an adult.

The following examples illustrate pharmaceutical compositions according to the invention:

EXAMPLE A Tablets having the following composition are prepared by the usual technique:

S-methyl-lO-amino-IOJ l-dihydrodihenzo[b.1'lazepine 10mg. starch mg.

colloidal silica 32 mg. magnesium stcurute 3 mg.

EXAMPLE B Tablets having the following composition are prepared by the usual technique:

S-methyl-lO-rnethylamino-10,1 l-dihydrodibenzo[b,f]-

azepine hydrochloride 28.9 mg. starch 86.1 mg. colloidal silica 32 mg. magnesium stearate 3 mg.

We claim: 1. A 10,11-dihydrodibenzo[b,f]azepine derivative of the formula:

and its pharmaceutically acceptable acid addition salts, in which R and R are the same or different and each represent hydrogen or alkyl of one to five carbon atoms, and R, is hydrogen, alkyl of one to five carbon atoms, or benzyl.

2. A 10,! l-dihydrodibenzo[b,f]azepine derivative as claimed in claim 1 and its acid addition salts and quaternary ammonium derivatives to which R and R are each hydrogen or alkyl of one to five carbon atoms and R, is hydrogen or alkyl of one to five carbon atoms.

6. A derivative as claimed in claim I, which is lO-aminol0,l l-dihydrodibenzo[b,f]azepine or a pharrnaceutically acceptable acid addition salt.

7. A derivative as claimed in claim I, which is S-ethyl-lO- amino-10,1l-dihydrodibenzo[b,f]azepine or 'a pharmaceutically acceptable acid addition salt.

8. A derivative as claimed in claim 1, which is S-benzyl-lO- amino-10,1l-dihydrodibenzo[b,f]azepine or a pharmaceutically acceptable acid addition salt.

9. A derivative as claimed in claim 1, which is 5-methyl-l0- ethylamino-lO,l l-dihydrodibenzo[b,f]azepine or a pharrnaceutically acceptable acid addition salt.

10. A derivative as claimed in claim 1, which is S-methyl- IO-diethylamino- 10,1 l-dihydrodibenzo[b,f]azepine or a pharrnaceutically acceptable acid addition salt.

11. A derivative as claimed in claim I, which is S-methyll0-methylethylamino-l0,l l-dihydrodibenzo[b,f]azepine or a pharrnaceutically acceptable acid addition salt.

Claims

2. A 10,11-dihydrodibenzo(b,f)azepine derivative as claimed in claim 1 and its acid addition salts and quaternary ammonium derivatives in which R and R'' are each hydrogen or alkyl of one to five carbon atoms and R1 is hydrogen or alkyl of one to five carbon atoms.
3. A derivative as claimed in claim 1, which is 5-methyl-10-methylamino-10,11-dihydrodibenzo(b,f)azepine or a pharmaceutically acceptable acid addition salt.
4. A derivative as claimed in claim 1, which is 5-methyl-10-amino-10,11-dihydrodibenzo(b,f)azepine or a pharmaceutically acceptable acid addition salt.
5. A derivative as claimed in claim 1, which is 5-methyl-10-dimethylamino-10,11-dihydrodibenzo(b,f)azepine or a pharmaceutically acceptable acid addition salt.
6. A derivative as claimed in claim 1, which is 10-amino-10,11-dihydrodibenzo(b,f)azepine or a pharmaceutically acceptable acid addition salt.
7. A derivative as claimed in claim 1, which is 5-ethyl-10-amino-10,11-dihydrodibenzo(b,f)azepine or a pharmaceutically acceptable acid addition salt.
8. A derivative as claimed in claim 1, which is 5-benzyl-10-amino-10,11-dihydrodibenzo(b,f)azepine or a pharmaceutically acceptable acid addition salt.
9. A derivative as claimed in claim 1, which is 5-methyl-10-ethylamino-10,11-dihydrodibenzo(b,f)azepine or a pharmaceutically acceptable acid addition salt.
10. A derivative as claimed in claim 1, which is 5-methyl-10-diethylamino-10,11-dihydrodibenzo(b,f)azepine or a pharmaceutically acceptable acid addition salt.
11. A derivative as claimed in claim 1, which is 5-methyl-10-methylethylamino-10,11-dihydrodibenzo(b,f)azepine or a pharmaceutically acceptable acid addition salt.