IE51286B1 - 3h-2-benzazepines,intermediate products and processes for their preparation,and medicaments containing them - Google Patents

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 3H-2-Benzazepines of the general formula see diagramm : EP0041627,P28,F2 wherein X signifies hydrogen, chlorine or bromine, Y signifies hydrogen, fluorine or chlorine, the dotted line signifies an optional bond, n signifies the number 0 or 1, R1 signifies hydrogen, bromine, chlorine, iodine or a residue of the formula see diagramm : EP0041627,P28,F3 or see diagramm : EP0041627,P28,F4 and R2 signifies hydrogen, (C1 -C7 )-alkyl, hydroxy, amino, (C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino and R3 signifies hydroxy or amino, with the proviso that X and Y do not both signify hydrogen, and that the dotted line signifies an additional bond when R1 does not signify hydrogen, and pharmaceutically acceptable salts thereof. 1. Claims for the Contracting State : AT A process for the manufacture of 3H-2-benzazepines of the general formula see diagramm : EP0041627,P32,F1 wherein X signifies hydrogen, chlorine or bromine, Y signifies hydrogen, fluorine or chlorine, the dotted line signifies an optional bond, n signifies the number 0 or 1, R1 signifies hydrogen, bromine, chlorine, iodine or a residue of the formula see diagramm : EP0041627,P32,F2 or see diagramm : EP0041627,P32,F3 and R2 signifies hydrogen, (C1 -C7 )-alkyl, hydroxy, amino, mono-(C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino and R3 signifies hydroxy or amino, with the proviso that X and Y do not both signify hydrogen, and that the dotted line signifies an additional bond when R1 does not signify hydrogen, and of pharmaceutically acceptable salts thereof, characterized by a) cyclizing a compound of the general formula see diagramm : EP0041627,P32,F4 wherein X and Y have the above significance and the dotted line signifies an optional bond, or b) oxidizing a compound of the general formula see diagramm : EP0041627,P32,F5 wherein X and Y have the above significance, R11 signifies hydrogen, bromine, chlorine or iodine and the dotted line signifies an optional bond, with the proviso that the dotted line signifies an additional bond when R11 does not signify hydrogen, or c) dehydrohalogenating a compound of the general formula see diagramm : EP0041627,P33,F1 wherein X and Y have the above significance and R12 signifies chlorine, bromine or iodine, or d) reacting a compound of the general formula see diagramm : EP0041627,P33,F2 wherein X, Y, n and R12 have the above significance, with a compound of the general formula HC -= C-CH2 -R21 wherein R21 signifies hydrogen, (C1 -C7 )-alkyl, hydroxy, mono-(C1 -C7 )-alkylamino or di-(C1 -C7 )-alkylamino, in the presence of a palladium salt, copper (I) iodide, an organophosphine and a secondary or tertiary amine, or e) cleaving off the phthaloyl group(s) in a compound of the general formula see diagramm : EP0041627,P33,F3 or see diagramm : EP0041627,P33,F4 wherein X, Y and n have the above significance and Phth signifies phthalimido, and, if desired, f) converting a compound of general formula I obtained into a pharmaceutically acceptable salt.

Description

This invention relates to 3H-2-benzazepines, intermediate products and processes for their preparation, and medicaments containing them. 3H-2-Benzazepines, but wherein R^, Y and X in the fonnula I below are hydrogen, have been disclosed in the prior art, see Tetrahedron Letters, No. 1, pp 33-36, 1974, Pergamon Press. These compounds in testing, however, have proven to be inactive. The compounds of the present invention, however, exhibit good psychotropic activity although related in structure to the inactive substance.

The present invention provides 3H-2-benzazepines of wherein X is hydrogen, chlorine or bromine, Y is hydrogen, fluorine or chlorine, the broken line denotes an optional bond, n is zero or 1 and R^ is hydrogen, bromine, chlorine, iodine or a radical of the formula or 5128 6 wherein R2 is hydrogen, (C^-C7>-alkyl, hydroxy, amino, mono-(C^-C^)-alkylamino or di-fC^-C?)alkylamino and Rg is hydroxy or amino, with the proviso that X and Y cannot both be hydrogen and that the broken line denotes an additional bond when R^ is other than hydrogen, and pharmaceutically acceptable salts thereof.

In accordance with the present invention, the compounds of formula I and pharmaceutically acceptable salts thereof can be prepared by a) cyclizing a compound of the general formula wherein X and X have the significance given above and the broken line denotes an optimal bond. or b) oxidizing a compound of the general formula Ia X 51386 wherein X and Y have the significance given above, is hydrogen, bromine, chlorine or iodine and the broken line denotes an optional bond with the proviso that the broken line denotes an additional bond when is other than hydrogen, c, dehydrohalogenating a compound of the general formula III wherein X and Y have the significance given above and R^2 is chlorine, bromine or iodine, d) reacting a compound of the general formula Ib wherein X, Y, and n have the significance given above, with a compound of the general formula HC = C-CH2-R21 IV wherein R^is hydrogen, (C^-C7) -alkyl, hydroxy, mono5 (C^-Cy)-alkylamino or di-(C^-Cy)-alkylamino, in the presence of a palladium salt, cuprous iodide, an organophosphine and a secondary or tertiary amine, or e) raioziig ttE phthaloyl group(s) from a compound of the V or VI wherein X, Y and n have the significance given above and Phth is phthalimido, and, if desired, f) converting a compound of formula I into a pharmaceutically acceptable salt.

The above process embodiments for the preparation of the compounds of formula I and the preparation of starting materials therefor are illustrated by the following Reaction Schemes wherein X, Y, Rj2' n and phth have the significance given above and R22 is hydrogen, phthalimido, (Cy-C^)-alkyl, hydroxy, amino, mono-(C^-Cy)-alkylamino or di-fCj^-Cy)alkylamino, is hydroxy, phthalimido or amino and R^ is (C^-Cy)-alkoxy: 51386 Reaction Scheme I Beaetion Scheme II Reaction Scheme III The compounds of formulae III, V and VI also form part of the present invention. ihe corpounds of general fonnula VII may generally be prepared by diazotizing the corresponding known aminobenzophenone using sodium nitrite in sulfuric acid and isolating the salts by precipitating the respective tetrafluoroborate salts which are thereafter slurried in water and treated with aqueous potassium iodide to give the iodobenzophenone. These reactions are carried out utilizing methods known in the art. Thereafter the iodobenzophenone is treated with propargylphthalimide in the presence of a mixture of palladium chloride, an organophosphine, cuprous iodide and a secondary amine in a suitable solvent to produce the phthalimidopropyne of formula VII.

VII-» VIII A conpound of general fonnula VH is hydrogenated utilizing a 51386 transition metal catalyst, such as Raney nickel or platinum oxide at from atmospheric pressure to 3.45 bar, with atmospheric pressure preferred. Solvents which may be utilized include to Cg alcohols, tetrahydrofuran, dioxan and toluene.

VIII and IX>Ia The ccnpounds of general formulae VIXI and IX can be reacted with an aqueous solution of a lower alkyl amine, e.g., methyl amine. A Cj to alcohol can be utilized as the solvent with ethanol preferred. The reaction is most preferably carried out at room temperature. The first formed open amine is not isolated but undergoes spontaneous ring closure to the compound of formula la' ad la, irfpecLuely.

An alternative method for producing the conpounds of general formulae la' and Ia consists of the reaction of the ccnpounds of general fonrailae VIII and IX with hydrazine in an inert solvent, such as, ethanol, tetrahydrofuran, aqueous ethanol or a mixture of ethanol' and chloroform. The reaction temperature may vary from room temperature to 100°C with reflux temperature of the selected solvent preferred. The product is extracted with dilute mineral acid and thereafter recovered and neutralized.

A third method which may be utilized to produce the compounds of formulae la' and la consists of a base followed by an acid hydrolysis of the compounds of formulae VIII and IX. For the base part of the hydrolysis an alkali metal hydroxide, such as, potassium or sodium hydroxide is utilized. For t 286 the acid part of the hydrolysis, a 10% solution of a mineral acid, such as, hydrochloric, hydrobromic, sulfuric or phosphoric acid may be utilized. The hydrolyses are run at room temperature to reflux temperatures with reflux temperatures preferred. Organic solvents, such as, to alcohols or tetrahydrofuran may be utilized to solubilize the ingredients.

A compound of general formula VII is hydrogenated using a Lindlar catalyst (prehydrogenated 10% palladium on barium sulfate) at about atmospheric pressure and about room temperature. Solvents suitable for the reaction include to Οθ alcohols, tetrahydrofuran, dioxan or toluene.

A compound of general formula VII can be reacted with a primary lower alkyl amine, e.g., methyl or ethylamine, or with hydrazine in a water miscible solvent, such as, to C, alcohols, ethers or dimethylformamide. The reaction tempera0 ture may range from O°C to 6O°C with room temperature preferred.

Another method which may be utilized to produoe a oaipound of general formula X consists of a base followsd by an acid hydrolysis of the conpound of general formula VH. For the base part of the hydrolysis, an alkali metal hydroxide, such as, potas25 sium or sodium hydroxide is utilized. For the acid part of the hydrolysis, a 10% solution of a mineral acid, such as, hydrochloric, hydrobromic, sulfuric or phosphoric acid may be uti11 lized. The hydrolyses are run at room temperature to reflux temperatures with reflux temperatures preferred. Organic solvents, such as, to alcohols or tetrahydrofuran may be utilized to solubilize the ingredients.

X — Ia A cctrpound of general fonnula X can be converted into a oorpotnd of general formula Ia by utilizing the reactants and reaction parameters used in the carvers icn of a compound of general formula VII to a caipound of general formula IX. The first formed open amine is not isolated but undergoes spontaneous ring closure to the catpound of general formula Ia. x—»ia1 A oarpourd of general formula X can be hydrogenated using Raney nickel as a catalyst at frcm atmospheric pressure to 3.45 bar, with atmospheric pressure preferred. The reaction is run at about room temperature. Solvents suitable for the reaction include to Cg alcohols, tetrahydrofuran, dioxan and toluene. The first formed open amine is not isolated but undergoes spontaneous ring closure to the compound of general formula la'.

Ia' > Ic and la —» Id and Ib'-» Ib11 Tbe ccnpounds of general formulae Ia', Ia and Ib' can be reacted with a suitable oxidizing agent such as metachloroperbenzoic acid in an inert organic solvent such as methylene chloride. The reaction may be run at between 0°C and the reflux temperature of the solvent with room temperature preferred.

Ia-» III A conpound of general formula Ia can be halogenated utilizing a halogenating agent, such as, elemental chlorine, bromine or iodine in a halogenated hydrocarbon, such as, methylene chloride or chloroform. The reaction is carried out at from 0°C to room temperature with about room temperature preferred.

Ill-» lb' A compound of the general fonnula III can be dehydrohalogenated utilizing an alkali metal-, e.g., potassium or sodium, hydroxide, carbonate or alkoxide. Suitable solvents include to Cg alco10 hols, tetrahydrofuran, dioxan and dimethylformamide. When a C, to C, alcohol is used as a solvent in the above reaction an 1 o end product mixture of compounds of the general formulae lb' and XI is produced. The reaction temperature may vary from O’C to reflux temperature of the chosen solvent with room 15 temperature preferred.

Ib—» XII or XIII A compound of general formula Ib can be reacted with a nonosubstituted acetylene of the formula, HC^C-CHy-Ryy wherein Rjj is hydrogen, phthalimide, (C^-Cy)-alkyl, hydroxy, mono20 (Cy-Cy)-alkylamino or di-(C^-Cy)-alkylamino. Examples of the above include propargyl alcohol, propargylphthalimide, Kmethylpropargylamine, propyne or N,N-dimethylpropargylamine.

The reaction is carried out in the presence of palladium chloride, cuprous iodide, triphenylphosphine and a di- or trialkylamine, such as, di- or triethylamine. Suitable solvents include halogenated hydrocarbons, e.g., methylene chloride or chloroform and dimethylformamide. The reaction temperature may vary from O°C to reflux temperature with room taiperature preferred.

It was found that shorter reaction times and the use of mono- or di-tC^-C?) -alkyl amino substituted aoetylenes tended to produce ccnpoixids of general formula XIX whereas longer reaction times and the use of hydroxy and phthalimido substituted acetylenes tended to form conpounds of general formula XIII.

To obtain the carpovnds wherein or is amino, cne can remove the phthaloyl group fran the corresponding conpound wherein R^ or R^ is phthalimido by an acid or base hydrolysis or by reaction with an aqueous monoalkyl amine or hydrazine as in step vii x.

As used herein the term lower alkyl or alkyl shall mean a to C7 with to as preferred, straight or branched chain hydrocarbon e.g., methyl, ethyl or prcpyl.

A suitable pharmaceutical dosage unit can contain from i to 500 mg of the benzazepine end products with a dosage range of from 1 mg to 100 mg being the preferred oral administration and a dosage range of from 1 mg to 50 mg being preferred for parenteral administration. However, for any particular subject, the specific dosage regimen should be adjusted according to individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compounds. It is to be understood that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of this invention. 51386 The term dosage unit as employed throughout this Specification refers to pharmaceutically discrete units suitable as unitary dosages for mammalian subject each containing a predetermined quantity of active material calculated to pro5 duce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle.

The 3H-2-benzazepines of general formula I are useful as pharmaceuticals especially as sedative and anxiolytic agents. These compounds can be used in the form of conventional pharmaceutical preparations; for example, the aforesaid compounds can be mixed with conventional organic or inorganic, inert pharmaceutical carriers suitable for parenteral or enteral administration such as, for example, water(gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gums, polyalkylene glycols Or vaseline.

They can be administered in conventional pharmaceutical forms, e.g., solid forms, for examples, tablets, dragees, capsules or suppositories, or in liquid forms, for example, solutions, suspensions or emulsions. Moreover, the pharmaceutical compositions containing compounds of this invention can be subjected to conventional pharmaceutical expedients such as sterilization, and can contain conventional pharmaceutical excipients such as preservatives, stabilizing agents, wetting agents, emulsifying agents, salts for the adjustment of osmotic pressure, or buffers. The compositions can also contain other therapeutically active materials.

An example of the activities possessed by the compounds of the present invention is illustrated by the results of the metrazol test of several species of the present invention.

Periodically a metrazol standardization test precedes the assay to ascertain the quantity of metrazol, administered to control mice, sufficient to induce convulsive seizures in all animals. This is usually 125 mg/kg. In the antimetrazol test, a compound is administered orally to groups of four mice at various dose levels. One hour later, metrazol (at a dose level previously determined in the standardization test) is administered subcutaneously and the animals are observed for protection from convulsive seizures. Results are recorded as the number of animals protected against convulsions. The dose at which 50% of the animals are protected from convulsive seizures is expressed as the EDjq. On active compounds, 8 animals see employed per dose group. The EDjq is calculated by the Miller-Tainter method (Proc. Soc. Exp. Med. and Bio., 57, 261, 1944). 8-Qlloro-5-(l-amino-2-propyn-3-yl)-l-phenyl-3H-2-benzazepine dihydrochloride Metrazol EDjfl » 32 mg/kg p.o.

Toxicity a 500 mg/kg p.o. (24 hr. IOjq) 8-Chloro-5-(l-amino-2-propyn-3-yl)-1-(2-fluorophenylJ-3H-2benzazepine dihydrochloride Metrazol Εϋ,-θ » 3 mg/kg p.o.

Toxicity » 500 mg/kg p.o. (24 hr. LDjjq) 8-Chloro-l-phenyl-3H-2-benzazepine-2-oxide Metrazol EDg0 « 5.2 mg/kg p.o.

Toxicity » 1000 mg/kg p.o. (24 hr. LC^) 8-Chloro-5-(1-dimethylamino-2-propyn-3-yl)-1-(2-fluorophenyl )-3H-2-benzazepine dihydrochloride Metrazol ED5Q = 19 mg/kg p.O.

Toxicity = 1000 mg/kg p.o. (24 hr. 1¾)) The compounds of the present invention wherein R^ is hydrogen, bromine, chlorine and iodine are also intemediates in the production of other active benzazepines, for exanple, pyrimidobenzazepines.

Preferred are compounds of the general formula Ie wherein X' is chlorine, Y' is hydrogen, fluorine or chlorine and R^g is a radical of the formula '32 V32 wherein R23 is amino, mono-(Cj-Cy)-alkylamino or di(Cg-C^)-alkylamino and Rgg is amino.

Especially preferred are compounds of the above formula Ie wherein is a radical of the formula '23 51386 wherein Rj^ is amino, mono-fC^-C.?)-alkylamino or di-iC^-C?)-alkylamino.

Especially preferred compounds of the above general formula Ie are: 8-chloro-5-(l-amino-2-propyn-3-yl)-l-phenyl-3H-2benzazepine; and 8-chloro-5-(l-amino-2-propyn-3-yl)-1-(2-fluorophenyl)3H-2-benzazepine.

The above ccnpounds of general formula Ie exhibit anti1O depressant activity as illustrated in the imipramine binding test as outlined below.

Male rats (180 g) are decapitated and the brains immediately placed on ice. The cortex is dissected and homogenized in 8 volumes of 0.25 M sucrose. The homogenate is centrifuged at 2900 rpm (1000 x g). The supernatant is decanted and polytronized for 60 seconds. Dilutions of imipramine hydrochloride are made in ethanol (1:5). Each assay sample contains: 1.8 ml of Krebs Ringer Buffer, 20 μΐ of imipramine or other drugs and 20 μΐ of 3H-imipramine (0.1 mM). imipramine (10-3 M) is used to define nonspecific binding.

Incubation is for 15 minutes at room temperature. Samples are then put in an ice bath for 5 minutes. Each sample is filtered. The filter papers are placed in 13 ml of aquasol and shaken for 2 hours, then the radioactivity trapped on the filter is determined by liquid scintillation spectrometry. 11) Compound 3H-Imipramine Binding IC50 (μΜ) Imipramine 7.1 8-Chloro-5-(l-amino-2-propyn-3-yl)-l5 phenyl-3H-2-benzazepine dihydrochloride 11.0 8-Chloro-5-(l-amino-2-propyn-3~yl)-l(2-fluorophenyl)-3H-2-benzazepine dihydrochloride 20.0 The expression pharmaceutically acceptable salts is used to include salts with both inorganic and organic pharmaceutically acceptable acids, such as, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid and paratoluenesulfonic acid. Such salts can be formed quite readily by those skilled in the art, with the prior art and the nature of the compound to he plaasdin salt form, in view.

The following Exanples are illustrative, but not limi20 tative of this invention. All temperatures given are in degrees centigrade, unless indicated otherwise. 51386 EXAMPLE 1 1-/4 -Chloro-2-benzoylphenyl7~3-phthalimidopropane A mixture of 2 g (5 mmole) of l-/4-chloro-2-benzoylphenyl7~3-phthalimidopropyne and 1/2 teaspoonful of Raney 5 nickel in 25 ml of tetrahydrofuran was hydrogenated at room temperature and atmospheric pressure. When 240 ml of hydrogen was absorbed, the catalyst was separated by filtration and the filtrate concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of ether and petroleum to give the crude product as a tan solid, mp 94-97°C. Recrystallization from ether gave pale yellow prisms, mp 98-99°C.

EXAMPLE 2 l-/?-Chloro-2-(2-fluorobenzoyl)phenyl7~3-phthallmldopropane A mixture of 9.6 g (23 mmole) of l-/4-chloro-2-(2f luorobenzoyl) phenyl7-3'-phthalimidopropyne and 1 teaspoonful of Raney nickel in 70 ml of tetrahydrofuran was hydrogenated at room temperature and atmospheric pressure. When 1.05 L of hydrogen was absorbed the catalyst was separated by filtration and the filtrate was concentrated at reduced pressure to dryness. The residue crystallized from a mixture of ether and petroleum ether to give the product as a tan solid, mp 98-99°C.

EXAMPLE 3 8-Chloro-4,5-dihydro-l-phenyl-3H-2-benzazepine hydrochloride A solution of 5.1 g (12.6 mmole) of l-/5’-chloro-2286 benzoylphenyl.7-3-phthalimidopropane in 100 ml of ethanol and 20 ml of 3N sodium hydroxide was refluxed for 2 hr.

The solution was diluted with 60 ml of 3N hydrochloric acid and refluxed for 12 hr. The mixture was diluted with water and extracted with ether. The aqueous layer was separated, made alkaline with dilute sodium hydroxide, and extracted with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was purified by plug filtration (silica gel, 10 g; eluant, methylene chloride) and the eluant was acidified with methanolic hydrogen chloride. The solution was concentrated at reduced pressure to dryness and the residue was crystallized from a mixture of isopropanol and ether to give a colorless solid, mp 234-235°C. Recrystallization from a mixture of methylene chloride and ether gave colorless needles, mp 234-235°C dec.

EXAMPLE 4 8-Chloro-4,5-dlhydro-l-(2-fluorophenyl)-3H-2-benzazepine hydrochloride Method A. A mixture of 2.9 g (10 mmole) of 3-aminol-/4-chloro-2-(2-fluorobenzoyl)phenyl7propyne and 1/4 teaspoonful of Raney nickel in 50 ml of tetrahydrofuran was hydrogenated at room temperature and atmospheric pressure. When 430 ml of hydrogen was absorbed the catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to dryness. A solution of the residue in an excess of methanolic hydrogen chloride was diluted with ether and end product, mp 176-177°C dec was collected by filtration. Recrystallization from a mixture of methanol and ether gave pale yellow plates, mp 209-215°C dec.

Method B. A solution of 5.9 g (14 mmole) of 1-/4chloro-2-(2-fluorobenzoyl)pheny1-3-phthalimidopropane in a mixture of 100 ml of ethanol and 20 ml of 3N sodium hydroxide was refluxed for 2 hr, diluted with 60 ml of 3N hydrochloric acid and refluxed for 12 hr. The reaction mixture was poured into water and extracted with ether. The aqueous acid layer was separated, made alkaline with dilute sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification by plug filtration (allumina Woelm I, 50 g; eluant, methylene chloride) gave an oil which was diluted with an excess of methanolic hydrogen chloride and concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of methanol and ether to give product which was identical in every respect to an authentic sample.

EXAMPLE 5 l-/?-Chloro-2-benzoylphenyl7~3-phthalimidopropene A mixture of 2.0 g (5 mmole) of l-/4-chloro-2-benzoylphenyl7-3-phthalimidopropyne and 0.1 g of prehydrogenated 10% palladium on barium sulfate in 50 ml of tetrahydrofuran was hydrogenated at room temperature and atmospheric pressure until 85 ml of hydrogen was absorbed. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to dryness. The residue was crystallized from ether to give a white solid, mp 7O-72°C. Recrys5 tallization from ether gave colorless prisms, mp 7O-72°C.

EXAMPLE 6 l-/4-Chloro-2-(2-fluorobenzoyl)pheny17-3-phthalimidopropene The preparation of l-/^-chloro-2-(2-fluorobenzoyl)phenyl7-3-phthalimidopropene was conducted in the same manner as the preparation of l-/4-chloro-2-benzoylphenyj-7-3phthalimidopropene to give colorless needles, mp 117°C.

EXAMPLE 7 8-Chloro-l-phenyl-3H-2-benzazepine hydrochloride Method A. A mixture of 0.1 g of prehydrogenated 10% palladium on barium sulfate and 27 g (0.1 mole) of 3-amino1- /7-benzoyl-4-chloropheny)-7propyne in 100 ml of tetrahydrofuran was hydrogenated at room temperature and atmospheric pressure until 2.4 L (ca 0.1 mole) of hydrogen was absorbed. The catalyst was removed by filtration. The filtrate was diluted with an excess of methanolic hydrogen chloride and 100 ml of isopropanol and concentrated at reduced pressure to a crystalline residue. Trituration with a mixture of ether and methanol gave a tan solid, mp 224-226°C dec. Recrystallization from a mixture of methanol and ether gave cream colored prisms, mp 227-228°C dec.

Method B. A mixture of 6 g (15 mmole) of l-/4-chloro2- benzoylphenyl7-3-phthalimidopropene, 0.9 g (18 mmole) of 85% hydrazine hydrate and 70 ml of 95% ethanol was refluxed for 2.5 hr. The insoluble precipitate formed was separated by filtration. The filtrate was acidified with ice cold dilute hydrochloric acid and extracted with ether. The aqueous layer was separated, made alkaline with dilute sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate, acidified with methanolic hydrogen chloride, diluted with isopropanol and concentrated at reduced pressure to a small volume. The crude product was collected by filtration to give tan prisms, mp 223-225°C dec which was identical in every respect to an authentic sample.

EXAMPLE 8 8-Chloro-l-(2-fluorophenyl)-3H-2-benzazepine hydrochloride The preparation of 8-chloro-l-(2-fluorophenyl)-3H-2benzazepine hydrochloride was conducted in the same manner as the preparation of 8-chloro-l-phenyl-3H-2-benzazepine hydrochloride to give product (Method A) and (Method B) as off-white prisms, mp 21O-212°C dec, EXAMPLE 9 8-Chloro-l-(2-chlorophenyl)-3H-2-benzazepine A mixture of 4.6 g (15 mmole) of 3-amino-l-/2-(2-chlorobenzoyl)-4-chlorophenyl7propyne and 0.1 g of prehydrogenated palladium on barium sulfate in 30 ml of tetrahydrofuran was hydrogenated at room temperature and atmospheric pressure until 355 ml of hydrogen was absorbed. The catalyst was removed by filtration and the filtrate concentrated at reduced pressure. The residue was crystallized frcm ether to give a cream colored solid, mp 113-115°C. recrystallization frcm ether gave cream colored prisms, up 117-118°C.

The methanesulfonate salt of 8-chloro-l-(2-chlorophenyl)-3H-2-benzazepine was 5 prepared by the addition of an excess of a IM methanol solution of methanesulfonic acid to a methanol solution of the above compound and isolated by precipitating the salt with the addition of ether. Recrystallization from a mixture of methanol and ether gave the methanesulfonate salt as colorless plates, mp 201-202° C.

Example 10 l-(2-Chlorophenyl)-3 H-2-benzazepine hydrochloride The preparation of l-(2-chlorophenyl)-3H-2-benzazepine hydrochloride was conducted in the same manner (Method A) as the preparation of 8-chloro-l-phenyl-3H-2benzazepine hydrochloride to give tan needles, mp 201-202° C dee.

Example 11 8-Chloro-4,5-dihydro-l-phenyl-3H-2-benzazepine-2-oxide A solution of 1.4 g (5.5 mmole) of 8-chloro-4,5-dihydro-l-phenyl-3H-2-benzazepine and L4 g (7 mmole) of 85% m-chloroperbenzoie aeid in 50 ml of methylene chloride was stirred at room temperature for 18 hr. The reaction mixture was washed with dilute aqueous sodium hydroxide and the organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vaeuo to dryness. The residue was crystallized from ether to give a colorless solid, mp 120-125° C. Recrystallization from ether gave colorless prisms, mp 142-143° C. 31286 Example 12 8-Chloro-i-phenyl-3H-2-benzazepine-2-oxide A mixture of 10.7 g (42 mmole) of 8-ehloro-l-phenyl-3H-2-benzazepine, 10.7 g (53 mmole) of 85% metachloroperbenzoic acid and 100 ml of methylene chloride was stirred at room temperature or 16 hr. The mixture was washed with cold dilute aqueous sodium hydroxide and brine. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized with ether to give crude product, mp 130-131’ C. Recrystallization from ether gave tan prisms, mp 122-123’ C.

Example 13 8-Chloro-l-i2-fluorophenyl]-3H-2-benzazepine-2-oxide The preparation of 8-ehloro-l-(2-fluorophenyD~3H-2-benzazepine-2-oxide was conducted in the same manner as the preparation of 8-chloro-l-phenyl-3H-2-benzazepinc-2~ oxide to give colorless prisms, mp 138-139’ C.

Example 14 8-Chloro-l-(2-chlorophenyl)-3H-2-benzazepine-2-oxide The preparation of 8-chloro-l-(2-ehlorophenyD-3H-2-benzazepine-2-oxide was conducted in the same manner as the preparation of 8-chloro-l-phenyl-3H-2-benzazepine-2oxide to give cream colored prisms, mp 196-197’ C.

Example 15 H2-Chlorophenyl)-3H-2-benzazepine-2-oxide The preparation of l-(2-chlorophenyl)-3H-2-benzazepine-2-oxide was conducted in the same manner as the preparation ot 8-chloro-l-phenyl-3H-2-benzazepine-2-oxide to give cream colored rods, mp 115-116’ C.

Example 16 8-Chloro-4,5-dibromo-4,5-dihydro-I-phenyl-3H-2-benzazepine Dropwise 200 ml (0.18 mole) of a 5% bromine solution in methylene chloride was added to 26.5 g (0.1 mole) of 8-chloro-l-phenyl-3H-2-benzazepine in 300 ml of methylene chloride. The mixture was stirred at room temperature for 1 hr, diluted with an excess of saturated aqueous sodium carbonate and stirred at room temperature for 15 min. The methylene chloride solution was separated, dried over anhydrous sodium sulfate, and diluted with an excess of methanolic hydrogen chloride. The acid solution was concentrated to a small volume at reduced pressure and the salt was precipitated by the addition of ether to give the salt as a colorless solid, mp 164-165“ C. Eecrystallization from methylene chloride gave colorless crystals, mp 164-165“ C dee. The compound has been found to have a second melting point of 172-173’ C dee.

A methanol solution of the salt was neutralized with dilute aqueous sodium hydroxide and the resulting crystals collected by filtration. Eeerystallization from methanol gave the end product as colorless prisms, mp 113-Π5’ C. 81889 Example 17 8-Chloro-4,5-dibromp-4,5-dihydro-l-(2-fluorophcnyl)-3H-2-benzazepine The preparation of 8-cWoro-4,5-dibromo-4,5-dihydro-I-(2-fluorophenyl)-3H-2-benzazepine was conducted in the same manner as the preparation of 8-chioro~4,5-dibromo5 4,5-dihydro-l-phenyl-3H-2-benzazepine to give the hydrochloride salt as a colorless solid, mp 158-159’ C dee. and the end product as colorless prisms, mp 102-103’C.

Example 18 8-Chloro-4,5-dibromo-4,5-dihydro-l-(2-chlorophenyl)-3H-2-beiizazepine The preparation of 8-chloro-4,5-dibromo-4,5-dihydro-l-{2-chlorophenyl)-3H-2-ben10 zazepine was conducted in the same manner as the preparation of 8-chloro-4,5-dibromo4,5-dihydro-l-phenyl-3H-2-l>enzazepine to give pale yellow prisms, mp 139’ C dec.

Example 19 8-Chloro-5-bromo-l-phenyl-3H-2-benzazepine hydrochloride and 8-Chloro-3-methoxy-l-phenyl-3H-2-benzazepine methanesulfoiiate A solution of 24 g (53 mmole) of 8-chloro-4,5-dibromo-4,5-dihydro-l-phenyl-3H-2benzazepine hydrochloride in I L of methanol and 180 ml of 10% aqueous sodium hydroxide was stirred at room temperature for 45 hr. The mixture was concentrated in vacuo to a small volume and the residue was extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate, diluted with an excess of methanolic hydrogen chloride and concentrated in vacuo to dryness. The residue crystallized from a mixture of isopropanol and ether to give an off-white solid, mp 229230’C. Recrystallization from methylene chloride gave the hydrochloride of the bromo compound as colorless prisms, mp 230-235’C dec. 5128S The crude mother liquors were basified with dilute aqueous sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated in vacuo.

Purification by column chromatography (silica gel; eluants methylene chloride, then ether) gave after concentration of the ether fractions a colorless oil. The oil was dissolved in a methanol solution of methanesulfonic acid and the salt was precipitated by the addition of ether.

Recrystallization from a mixture of methanol and ether gave off-white prisms, mp 139-14O°C.

EXAMPLE 20 8-Chloro-5-bronP-l-(2-fluorophenyl) -3H-2-benzazepine hydrochloride A mixture of 21 g (45 mmole) of 8-chloro-4,5-dibromo4,5-dihydro-l-(2-fluorophenyl)-3H-2-benzazepine hydrochloride, 40 ml of dioxan, 360 ml of methanol and 40 ml of 10% aqueous sodium hydroxide was stirred at room temperature for 5 hr and then concentrated at reduced pressure to a small volume.

The concentrate was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate, diluted with isopropanol and an excess of methanolic hydrogen chloride. The mixture was concentrated at reduced pressure to a small volume to give the hydrochloride salt as a colorless solid, mp 231-232°C. Recrystallization from a mixture of methylene chloride and ether gave the salt as colorless crystals, mp 233-234°C dec. The methanesulfonate salt of the by-product (8-chloro-3-methoxy-l-(2-fluoropheny1)30 3H-2-benzazepine) was not isolated in this case.

Example 21 8-Chloro-5-bromo-l-(2-chlorophenyl)-3 H-2-benzazeplne and 8-Chloro-3-mettioxy-l-(2-chlorophenyI)-3H-2-benza2eplne A solution of 60.0 g (0.134 mole) of 8-ehloro-4,5-dibromo-4,5-dihydro-l-(25 chlorophenyl)-3H~2-benzazepine and 75 ml of 40% aqueous sodium hydroxide in a mixture of 300 ml of dioxan and 900 ml of methanol was stirred at room temperature for 4 hr. The mixture was concentrated in vacuo to a small volume and the residue was extracted with methylene chloride. The methylene chloride solution was (fried over anhydrous sodium sulfate, diluted with an excess of methanolic hydrogen chloride and isopropanol and concentrated in vacuo to dryness. The residue crystallized from a mixture of isoprophnol and ether to give a white solid. The white solid was partitioned between methylene chloride and aqueous sodium bicarbonate. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give an amber oil. Purification by column chromatography (silica gel, 250 g; eluant, methylene chloride) gave the bromo compound as colorless prisms, mp 125-127° C.

The crude mother liquors were partitioned between methylene chloride and aqueous ammonium hydroxide. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure. Trituration with a mixture of ether and petroleum ether gave the methoxy compound as a tan solid. Recrystailization from a mixture of ether and pertroleum ether gave cream colored prisms, mp 83-85° C. 81386 Example 22 8-Chloro-5-bromo-l-phenyl-3H-2-benzazepine-2-oxide A solution of 6.9 g (20.7 mmole) of 8-chloro-5-bromo-l-phenyl-3H-2-benzazepine and 6 g (29 mmole) of 85% m-chloroperbenzoie acid in 100 ml of methylene chloride was 5 stirrred at room temperature for 1 hr. The mixture was washed with cold dilute sodium hdyroxide, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from ether to give a white solid, mp 184-185’C.

Recrystallization from ether gave colorless prisms, mp 185-186° C dee.

Example 23 8-Chloro-5-(l-dimethylamino-2-propyn-3-yl)-l-phenyl-3H-2-faenzazepine dihydrochloride 1/4 molar hydrate A mixture of 120 ml of 98% diethylamine, 88.6 mg (0.5 mmole) of palladium chloride, 262.4 mg (1 mmole) of triphenylphosphine, 95.2 mg (0.5 mmole) of cuprous iodide, 8.7 g (26 mmole) of 8-chloro-5-bromo-l-phenyl-3H-2-benzazepine and 25 g (0.3 mole) of 115 dimethylamino-2-propyne was stirred under argon for 24 hr. The mixture was concentrated at reduced pressure to dryness. The residue was dissolved in methylene chloride and washed with water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification by column chromatography (silica gel, 50 g; eluant, methylene chloride then ether) gave an oil. The oil was dissolved in ethanol and diluted with an excess of ethanolic hydrogen chloride to give the dihydroehloride salt as a colorless solid, mp 193-195’C dec. Recrystallization from methylene chloride gave the salt as colorless crystals, mp 198199° C dec. 51386 Example 24 8-CMoro-5-(l-dimethylamino-2-propyn-3-yl)-l-(2-fluorophenyl)-3H-2-benzazepine dihydrochloride A mixture of 40 ml of 98% diethylamine, 44.3 mg (0.25 mmole) palladium chloride, 131.2 mg (0.5 mmole) of triphenylphosphine, 47.6 mg (0.25 mmole) of cuprous iodide, 3.5 g (9.4 mmole) of 8-ehloro-5-bromo-l-(2-fluorophenyl)-3H-2-benzazepine and 16 ml of 1dimethylamino-2-propyne was stirred under nitrogen at room temperature for 23 hr. The mixture was concentrated at reduced pressure to dryness. The residue was dissolved in methylene chloride, washed with water and dried over anhydrous sodium sulfate. The methylene chloride solution was diluted with an excess of methanolic hydrogen chloride and concentrated in vacuo to dryness. The residue crystallized from a mixture of ethanol and isopropanol to give the dihydrochloride as a yellow solid, mp 155-156° C. Recrystallization from a mixture of ethanol and ether gave the salt as pale yellow rods, mp 194195° C dec.

Example 25 8-Chloro-5-fl-dimethylamino-2-propyn-3-yD-I-phenyl-3H-2-benzazepine-2-oxide A mixture of 3.5 g (10 mmole) of 8~ehloro-5-bromo-l-phenyl-3H-2-benzazepine-2oxide, 40 ml of 98% diethylamine, 40 ml of dimethylformamide, 44.3 mg (0.25 mmole) of palladium chloride, 131.2 mg (0.5 mmole) of triphenylphosphine, 47.6 mg (0.25 mmole) of cuprous iodide and 16 ml of l-dimethylamino-2-propyne was stirred at room temperature under nitrogen for 24 hr. The mixture was concentrated at reduced pressure to dryness. An ether solution of the residue containing petroleum ether was washed with water followed by dilute cold hydrochloric acid. The aqueous solution was separated, made alkaline with dilute cold sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue crystallized from a mixture of ether and petroleum ether to give a tan solid, mp 121-123° C. Eeerystallization from ether gave tan prisms, mp 124-125° C.

Example 26 8-Chloro-5-(l-hydroxy-2-propyn-3-yl)-l-phenyl-3H-2-benzazepine hydrochloride ή mixture of 40 ml of 98% diethylamine, 44.3 mg (0.25 mmole) of palladium chloride, 131.2 mg (0.5 mmole) of triphenylphosphine, 47.6 mg (0.25 mmole) of cuprous 5 iodide, 3.5 g (10.5 mmole) of 8-chloro-5-bromo-l-phenyl-3H-2-benzazepine and 5 ml of propargyl alcohol was stirred at room temperature under nitrogen for 7 hr. The mixture was concentrated at reduced pressure to dryness. The residue was dissolved in methylene chloride, and washed with water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification by column chromatography (silica gel, 20 g; eluant 20% ether in methylene chloride) gave a colorless oil- The oil was dissolved in an excess of methanolic hydrogen chloride and concentrated at reduced pressure to dryness. The residue crystallized from a mixture of methanol and ether to give a tan solid, mp 228-229° C dee.

Example 27 8-Chloro-5-(l,6-dihydroxy-2-hexen-4-yn-3-yl)-l-phenyl-3H-2-benzazepine A mixture of 40 ml of 98% diethylamine, 44.3 mg (0.25 mmole) of palladium chloride, 131 mg (0.5 mmole) of triphenyl phosphine, 47.6 mg (0.25 mmole) of cuprous iodide, 3.5 g (10.5 mmole) of 8-chloro-5-bromo-l-phenyl-3H-2-benzazepine and 5 ml of propargyl alcohol was stirred at room temperature under nitrogen for 24 hr. The mixture was concentrated at reduced pressure to dryness. The residue was dissolved in methylene chloride, and washed with water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification by column chromatography (20 g silica gel; eluant, 20% ether in methylene chloride) gave an oil which crystallized from a mixture of tetrahydrofuran and ether to give tan prism, mp 210-212° C dec. 51386 The hydrochloride salt was prepared by dissolving the end product in an excess of methanolic hydrogen chloride and isolated by precipitating the salt by the addition of ether. Recrystallization from a mixture of methanol and ether gave the hydrochloride salt as cream colored plates, mp 290’C.

Example 28 8-Chloro-5-(l-propynyl)-l-phenyI-3H-2-benzazepine hydrochloride A stirred mixture of 180 ml of 98% diethylamine (degassed with nitrogen), 7.2 g (21.6 mmole) of 8-ehloro-5-bromo-l-phenyl-3H-2-benzazepine, 0.4 g (0.6 mmole) of dichlorobis(triphenylphosphine)palladium (Π), 0.1 g (0.5 mmole) of cuprous iodide was saturated with propyne and stirred under an atmosphere of propyne for 23 hr. The mixture was concentrated at reduced pressure to dryness. The residue was dissolved in methylene chloride and washed successively with dilute sodium carbonate and water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness to give an oil. A methylene chloride solution of the oil was diluted with an excess ethanolic hydrogen chloride, concentrated at reduced pressure and crystallized from a mixture of ethanol and isopropanol to give the hydrochloride salt as a yellow solid, mp 206-207° C dec. Recrystallization from a mixture of ethanol and ether gave the salt as pale yellow prisms, mp 210-211° C dec.

Example 29 8-Chloro-5-(l-phthalimido-2-propyn-3-yl)-l-phenyl-3H-2-benzazepine and 8-Chioro-5-(l,6-diphthalimido-2-hexen-4-yn-3-yl)-l-phenyl-3H-2-benzazepine A mixture of 600 ml of 98% diethylamine, 600 ml of methylene chloride, 24 g (65 mmole) of 8-chloro-5~bromo-l-phenyl-3H-2-benzazepine hydrochloride, 7.2 g (10 mmole) of dichlorobis(triphenylphosphine)palladium (Π), 1.8 g (9.5 mmole) of cuprous iodide and 20 g (0.11 mole) of propargyl phthalimide was stirred at room temperature under nitrogen for .5 hr. The mixture was concentrated at reduced pressure to dryness and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification by column chromatography (silica gel, 450 g; eluant, methylene chloride gradient to 10% ether in methylene chloride) gave as the first product band the propynoyl compound as a tan solid, mp 177-178° C. Reerystallization from a mixture of methylene chloride and ether gave tan prisms, mp 185-186° C.

A second product band gave the hexen-4-yn-3-yl compound as an off-white solid, mp 185-190° C. Reerystallization from acetonitrile gave gray needles, mp 196-198° C.

Example 30 8-Chloro-l-(2-fluorophenyl)-5-(l-phthalimido-2-propyn-3-yl)-3H-2-benzazepine A mixture of 40 ml of 9895 diethylamine, 50 ml of methylene chloride, 0.6 g (0.9 mmole) dichlorobis(triphenylphosphine)palladium (II), 0.1S g (0.8 mmole) cuprous iodide, 3.8 g (10.8 mmole) of 8-chloro-5-bromo-l-(2-fluorophenyl)-3H-2-benzazepine and 3 g (16 mmole) of propargyl phthalimide was stirred under nitrogen at room temperature for 24 hr. The mixture was concentrated at reduced pressure to dryness. The residue was dissolved in methylene chloride and washed with water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification of the residue by column chromatography (silica gel, 50 g; eluant, methylene chloride gradient to 595 ether in methylene chloride) gave as the major fraction a colorless solid. Recrystallization from ether gave colorless needles, mp 164-165° C.

Example 31 8-Chloro-5-(N-methyl-l-amino-2-propyn-3-yl)-I-phenyl-3H-2-benzazepine dihydrochloride A mixture of 3.7 g (10 mmole) of 8-chloro-5-bromo-l-phenyl-3H-2-benzazepine hydrochloride, 0.4 g (0.6 mmole) of dichlorobis(triphenylphosphine)palladium (Π), 0.2 g (1 mmole) cuprous iodide and 2 ml (excess) of 9795 N-methylpropargylamine in 50 ml of 9895 diethylamine and 100 ml of methylene chloride was stirred at room temperature under nitrogen for 24 hr. The reaction was concentrated at reduced pressure to dryness. The residue was dissolved in methylene chloride and extracted with dilute ice cold hydrochloric acid. The acid extract was made alkaline with dilute ice cold sodium carbonate and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification of the residue bycolumn chromatography (silica gel, 20 g; eluant, 2095 ether in methylene chloride followed by 10% methanol in methylene chloride) gave from the latter eluant an amber oil. The oil was dissolved in an excess of methanolic hydrogen chloride and concentrated at reduced pressure to dryness. The residue crystallized from isopropanol to give end product which when reerystallized from isopropanol gave tan crystals, mp 169-175° C dec.

Example 32 8-Chloro-5-(i-amino-2-propyn-3-yl)-l-phenyl-3H-2-benzazepine dihydrochloride A mixture of 5 g (U.4 mmole) of 8-ehloro-5-{l-phthalimido-2-propyn-3-yl)-l-phenyl3H-2-benzazepine, 100 ml of ethanol and 20 ml of 40% aqueous methylamine was stirred at 5 room temperature for 1 hr, poured into ice water and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was dissolved in an excess of methanolic hydrogen chloride and concentrated at reduced pressure to dryness. The residue crystallized from a mixture of ethanol and isopropanol to give a tan solid, mp 247-248° C. Recrystallization from a mixture of ethanol and ether gave tan prisms, mp 247-248° C.

Example .33 8-Chloro-5-(l-amino-2-propvn-3-yl)-l-(2-fluorophenyl)-3H-2-benzazepine dihydroohloride A mixture of L3 g (2.9 mmoles) of 8-chloro-5-0-phthaIimido-2-propyn-3-yl)-I-(2fluorophenyl)-3H-2-benzazepine, 50 ml of ethanol and 10 ml of 40% aqueous methylamine was stirred at room temperature for 1 hr. The mixture was poured into ice water and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was dissolved in an excess of ethanolic hydrogen chloride and the resulting salt precipitated by the addition of ether to give an off-white solid, mp 211-216° C. RecrystaHization from a mixture of methanol and ether gave gray needles, mp 216-218° C dee.

EXAMPLE 34 -Chloro-2-lodobenzophenone A mixture of 76 g (1.1 mole) of sodium nitrate and 450 ml of sulfuric acid was heated on a steam bath to ca 5 80° until complete solution was achieved. The solution was cooled to 30° and 232 g (1.0 mole) of 2-amino-5-chlorobenzophenone was added in portions keeping the temperature between 30° and 40°. The mixture was stirred for 1 hr and then slowly poured into 3 L of an ice and water mixture.

The solution was filtered through Hy-Flo and to the stirred filtrate was added slowly a solution of 200 g (1.83 mole) of sodium fluoborate in 800 ml of water. The resulting precipitate was collected by filtration and washed with water (2x100 ml) to give a moist white solid.

The moist 2-benzoyl-4-chloro^enzenediazonium fluoroborate was slurried in 3L of water, and a solution of 332 g (2 moles) of potassium iodide in 1 L of water was added dropwise. The mixture was stirred at room temperature for 4 hr and the resulting precipitate was collected by filtration. The crude product was added to 1 L of boiling ether, filtered, and dried with anhydrous sodium sulfate. The ether solution was concentrated to 500 ml and the addition of 100 ml of petroleum ether gave end product.

A small amount of end product was recrystallized from a mixture of ether and petroleum ether to give light yellow prisms, mp 80-82°. 51386 EXAMPLE 35 -Chloro-2 1-fluoro-2-iodobenzophenone The preparation of 5-chloro-2'-fluoro-2-iodobenzophenone was conducted in the same manner as the preparation of 55 chloro-2-iodobenzophenone to give the end product as light yellow prisms, mp 78-81°.

EXAMPLE 36 21,5-Dichloro-2-iodobenzophenone The preparation of 2'-5-dichloro-2-iodobenzophenone was conducted in the same manner as the preparation of 5chloro-2-iodobenzophenone to give the end product as light yellow prisms, mp 64-66°.

EXAMPLE 37 21-Chloro-2-iodobenzophenone The preparation of 2'-chloro-2-iodobenzophenone was conducted in the same manner as 5-chloro-2-iodobenzophenone to give the end product as pale yellow prisms, mp 62-64°.

EXAMPLE 38 l-/4~-Chloro-2-benzoylphenyl7-3-phthalimidopropyne A mixture of 0.71 g (4.0 mmole) of palladium chloride, 2.1 g (8.0 mmole) of triphenylphosphine, 0.80 g (4.2 mmole) of cuprous iodide, 68.8 g (0.20 mmole) of 5-chloro-2-iodobenzophenone, 200 ml of diethylamine, and 400 ml of methylene chloride was stirred at room temperature under argon until complete solution was obtained. In one portion, 51386 40.0 g (0.22 mole) of N-propargyl-phthalimide was added to the solution and the resulting mixture stirred for 20 hr. The volatiles were removed at reduced pressure and the residue was triturated with 200 ml of isopropanol. The resulting precipitate was collected by filtration to give crude end product. Recrystailization from acetone gave cream colored prisms, mp 148-150°C.

EXAMPLE 39 l-/T-Chloro-2-(2-fluorobenzoyl)phenyl7-3-phthallmldopropyne The preparation of l-/?-chloro-2-(2-fluorobenzoyl)phenyl7-3-phthalimidopyropyne was conducted in a similar manner as the preparation of l-/4’-chloro-2-benzoylphenyl73-phthalimidopropyne to give cream colored prisms, mp 158161°C.

EXAMPLE 40 l-/4-Chloro-2-(2-chlorobenzoyl)phenyl7-3-phthalimidopropyne The preparation of l-/4-chloro-2-(2-chlorobenzoyl)~ phenyl7-3-phthalimidopropyne was conducted in the same manner as the preparation of l-/¥-chloro-2-benzoylphenyl7-3-phthali20 midopropyne to give cream colored prisms, mp 144-145°C.

EXAMPLE 41 1-/2-(2-chlorobenzoy1)pheny1/-3-phthalimidopropyne The preparation of l-/2’-(2-chlorobenzoyl)phenyl7_3phthalimidopropyne was conducted in the same manner as the preparation of l-/?-chloro-2-benzoylphenyl7“3-phthalimido51236 propyne to give cream colored prisms, mp 149-15O°C.

EXAMPLE 42 3-Amino-l-/2-benzoy1-4-chlorophenyl7propyne Method A, A mixture of 72 g (0.18 mole) of 1-/4-chloro 2-benzoylphenyl/-3-phthalimidopropyne, 90 ml of 40% agueous methylamine, and 300 ml of ethanol was stirred at room temperature for 90 min. The mixture was diluted with 300 ml of ether, and the precipitate was removed by filtration.

The filtrate was further diluted with 300 ml of ether, washed with water and dried over anhydrous sodium sulfate.

Concentration of the ether solution at reduced pressure gave a brown oil, which when triturated with ether gave a yellow solid. Reerystallization from ether gave pale yellow prisms mp 68-69°C.

Method B. A mixture of 4 g (10 mmole) of l-/4-chloro2-benzoylphenyl7-3-phthalimidopropyne and 0.6 g (16 mmole) of 85% hydrazine hydrate in 150 ml of 95% ethanol was refluxed for 5.5 hr. The mixture was cooled and the insoluble precipitate removed by filtration. The filtrate was diluted with water, acidified with hydrochloric acid and extracted with ether. The aqueous solution was basified with dilute sodium carbonate and extracted with methylene chloride.

The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of ether and petroleum ether to give a pale yellow solid, 51386 mp 68-69°C which was identical in every respect to an authentic sample.

The hydrochloride salt of 3-amino-l-ZT-chloro^benzoylphenyl7propyne was prepared by the addition of an excess of 6% methanolic hydrogen chloride to a methanol solution of the product and isolated by precipitating the salt with the addition of ether. Recrystallization from a mixture of methanol and ether gave the hydrochloride as white needles, mp 173-174°C.

EXAMPLE 43 3-Amino-l-/¥-chloro-2-(2-fluorobenzoyl)phenyl7propyne Method A. The preparation of 3-amino-l-/?-chloro-2(2-fluorobenzoyl)phenyl7propyne was conducted in the same manner (Method A) as the preparation of 3-amino-l-/4-chloro15 2-benzoylphenyl7propyne to give yellow prisms, mp 89-91°C.

Method B. A mixture of 50 g of l-/7-chloro2-(2-fluorobenzoyl)phenyl7-3-phthalimidopropyne, 50 ml of 40% aqueous methylamine and 150 ml of dimethylformamide was stirred at room temperature for 25 min. Dropwise 500 ml of water was added, and the resulting precipitate was collected by filtration. The precipitate was dissolved in methylene chloride, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a pale yellow solid. Recrystallization from ether gave pale yellow prisms, mp 89-91°C which was identical in every respect to an authentic sample.

Method C. A mixture of 400 g (0.96 mole) of 1-/4chloro-2-(2-fluorobenzoyl)pheny 3./-3-phthalimidopropyne, 1.3L of ethanol and 300 ml of 40% aqueous methylamine was stirred at room temperature for 2 hr. Dropwise 2.8 1 of water was added, and the resulting precipitate was collected by filtration to give a pale yellow solid, rap 79-80°C. Recrystallization from ether gave pale yellow prisms, mp 89-91°C which was identical in every respect to an authentic sample .

EXAMPLE 44 3-Amino-l-/l-chloro-2-(2-chlorobenzoyl)phenyl^propyne The preparation of 3-amino-l-/T-chloro-2-(2-chlorobenzoyl) phenyl7propyne was conducted in the same manner as the preparation of 3-amino-l-/4-chloro-2-benzoylphenyl/15 propyne /Method A/ to give pale yellow prisms, mp 81-82°c. EXAMPLE 45 S-Amino-l-/?-(2-chlorobenzoyl)phenyl/ptopyne The preparation of 3-amino-l-/7-(2-chlorobenzoyl)phenyl7 propyne was conducted in the same manner as the preparation of 3-amino-l-/4-chloro-2-benzoylphenyl/propyne /Method A/ to give an amber oil.

The hydrochloride salt of 3-amino-l-/2-(2-chlorobenzoyl) pheny 1/propyne was prepared by the addition of an excess of 6% methanolic hydrogen chloride to a methanol solution of the product and isolated by precipitating the salt by the addition of ether. Recrystallization from a mixture of methanol and ether gave the salt as white needles, mp 160162°C.

Example 46 TABLET FORMULATION (Wet granulation) Item Ingredients mg/tablet mg/tablet mg/tablet mg/tablet 5 1. 8-chloro- l-phenyi-3H- 2- benzazepine-2-oxide or 3- 5-chloro- l-(2-fiuorophenyl)-3H-2-benzazepin5-yl/-2-propyn-l-amine 1 5 10 50 2. Lactose 195 230 264 263 10 3. Modified Starch 12.5 15 17.5 20 4. Pregelatinized Starch 12.5 15 17.5 20 5. Cornstarch 25 30 35 40 6. Magnesium Stearate 4 5 6 7 7. Distilled Water qj. *· — — 15 Weight of tablet 250 mg 300 mg 350 mg 400 mg Procedure: 1. Mix items 1-5 in a suitable mixer. 2. Granulate with sufficient distilled water to proper consistency. Mill. 3. Ory in a suitable oven. 4. Mill and mix with magnesium stearate, . Compress on a suitable press equipped with appropriate punches.

Example 47 TABLET FORMULATION (Direct compression) Item Ingredients mg/tablet mg/tablet mg/tablet mg/tablet 5 1. S-chloro- l-phenyl-3H2-benzazepine-2-oxide or i 5 10 50 3-/3-chloro- l-(2-fluoro- phenyl)-3H-2-benzazepin- S-yff-2-propyn-I-amine 2. Lactose 127 155.5 182 206 10 3. Microcrystalline Cellulose 40 50 60 80 4. Direct Compression Starch 10 12 15 20 5. Cornstarch 20 25 30 40 6. Magnesium Stearate 2 25 3 4 V/eight of tablet 200 mg 250 mg 300 mg 400 mg Procedure: 1. Mix items 1-5 in a suitable mixer for 1 to 15 minutes. 2. Add magnesium stearate and mix for 5 minutes. 3. Compress on a suitable press equipped with appropriate punches.

Example 48 CAPSULE FORMULATION Item Ingredients mg/tablet mg/tablet mg/tablet mg/tablet 1. 8-chloro-l-phenyl-3H- 1 5 10 50 2-benzazepine-2-oxide or 3-ZS-chloro- l-(2-f!uorophenvD-3H-2-benzazepin5-yj/-2-propyn-I-amine 2. Lactose 149 132.5 215 250 10 3. Cornstarch 40 50 60 30 4. Talc 8 10 12 16 5. Magnesium Stearate 2 2.5 3 4 Capsule fill weight 200 mg 250 mg 300 mg 400 mg Procedure» 1. Mill items 1, 2 and 3 in a suitable mixer. Mill. 2. Add 4 and 5 and mix well. 3. Encapsulate on suitable equipment.

Claims (22)

CLAIMS :

1. A 3H-2-henzazepine of the general formula wherein X is hydrogen, chlorine or branine, Y is hydrogen,

2. A ccnpound according to claim 1 of the general formula wherein X' is chlorine, Y* is hydrogen, fluorine or wherein i- s amino, nono-(C^-C^)-alkylnmino or di(C^-Cy) -alkylamino and is amino.

3. A ocnpound according to claim 2, wherein Rj^ is a 10 radical of the formula and R 23 is as defined in claim 2.

4. 8-chloro-5-(l-amino-2-propyn-3-yl)-1-(2-fluorophenyl )-3H-2-benzazepine.

5. Defined in claim 9, substantially as hereinbefore described and exemplified. 5 and Y cannot both be hydrogen, and n is zero or 1 and Phth is phthalimido. 5 fluorine or chlorine, the broken line denotes an optional bond, n is zero or 1 and is hydrogen, bromine, chlorine, iodine or a radical of the formula

6. 8-Chloro-5-(l-dimethylamino-2-propyn-3-yl)-1-(2fluorophenyl)-3H-2-benzazepine.

7. 8-Chloro-l-phenyl-3H-2-benzazepine-2-oxide.

8. A compound of the general formula wherein X is hydrogen, chlorine or bromine and Y is hydrogen, fluorine or chlorine with the proviso that X and Y cannot both be hydrogen and R 12 is chlorine, bromine or iodine.

9. A compound of the general formula wherein X is hydrogen, chlorine or bromine and Y is hydroqen, fluorine or chlorine with the proviso that X 10. Compound according to any one of claims 1 to 7, in association with a pharmaceutically acceptable carrier or diluent therefor.

10. A ccnpotnd according to any cne of claims 1 to 7 as a pharmaceutically active substance . 10 wherein Rg is hydrogen, (C^-C?)-alkyl, hydroxy, amino, mono-(C^-C 7 )-alkylamino or di-(C^-C?)-alkylamino and Rg is hydroxy or amino, with the proviso that X and Y cannot both be hydrogen, and that the broken line denotes an additional bond when

11. A compound according to any cne of claims 1 to 7 as a 10 sedative and anxiolytic.

12. A corpound according to any one of claims 2 to 6 as an antidepressant.

13. A process for the preparation of a conpound according to any one of claims 1 to 7 which comprises a) cyclizing a compound of the general formula II wherein X and Y have the significance given j, n claim 1 and the broken line denotes an optional bond. b) oxidizing a compound of the general formula Ia wherein X and Y have the significance given in claim 1 is hydrogen, bromine, chlorine or iodine and the broken line denotes an optional bond, with the proviso that the 10 broken line denotes an additional bond when R^ is other than hydrogen, or c) dehydrohalogenating a compound of the general formula III wherein X and Y have the significance given in claim 1 and Rjj is chlorine, brcmine or iodine. or d) reacting a compound of the general formula wherein X, Y and n have the significance given in claim 1 and R 12 has the significance given above, with a compound of the general formula HC = C-CH 2 -R 21 IV wherein R 21 is hydrogen, (C^-C?)-alkyl, hydroxy, nono(C-^-C^)-alkylamino or di-tC^-C?)-alkylamino. in the presence of a palladium salt, cuprous iodide, an organophosphine and a secondary or tertiary amine, or e) rarowigthe phthaloyl group(s) from a compound of the general formula or V wherein X, Y and n have the significance given in claim 1 and Phth is phthalimido, and, if desired, f) converting a compound of general formula I into a pharma 5 ceutically acceptable salt.

14. A medicament containing a compound according to any one of claims 1 to 7, in association with a pharmaceutically acceptable carrier or diluent therefor. 15. A pharmaceutically acceptable carrier or diluent therefor.

15. A sedative and anxiolytic medicament containing a 15 5. 8-Chloro-5-(l-amino-2-propyn-3-yl)-l-phenyl-3H-2benzazepine. S1286 15 is other than hydrogen, or a pharmaceutically acceptable salt thereof.

16. An antidepressant medicament containing a compound according to any one of claims 2 to 6, in association with

17. A compound according to any one of claims 1 to 7 whenever prepared by the process according to claim 13 or by an obvious chemical equivalent thereof.

18. A compound of the general formula I given and defined 20 in claim 1 or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified.

19. A compound of the general formula III given and defined in claim 8, substantially as hereinbefore described and exemplified.

20. A compound of the general formula V or VI given and

21. A process for the preparation of a compound of the general formula I given and defined in claim 1 or a pharmacuetically acceptable salt thereof, substantially as herein10 before described and exemplified.

22. A medicament according to any one of claims 14-16, substantially as hereinbefore described with particular reference to Examples 46-48 of the accompanying Examples.