NZ197103A - 3h-2-benzazepines - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 97103 Priority Dats{s): ^ b. .H ... Compiote Specification Filed: '.V."V.V. Class: . Co-70.2,2^ - _i £31 / 55" Publication Date: .. J&1, jWL J9B4. P.O. Jwirnri Wo: .. l^?9 NEW ZEALAND PATENTS ACT, 1953 \ v* COMPLETE SPECIFICATION BENZODIAZEPINE DERIVATIVES No.: Date: ¥/We, F- HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss company, hereby declare the invention for which X / we pray that a patent may be granted to iSS/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by la) The present invention relates to 3H-2-benzazepines of the general formula wherein X is hydrogen, chloro or bromo, Y is hydrogen, fluoro or chloro, the broken line denotes an optional bond, n is zero or 1 and is hydrogen, bromo, chloro, iodo, a radical of the formula R- or a radical of the formula R, wherein R2 is hydrogen, lower alkyl, hydroxy, amino, monoalkylamino or dialkylamino and is hydroxy or amino with the proviso that (i) X and Y cannot both be hydrogen, and (ii) where is other than hydrogen then the bond denoted by the broken line must be present, Bt/1LG.'1.01 - la i 97!03 and to pharmaceutically acceptable salts thereof. 3H-2-Benzazepines but wherein R^=Y=X=H have been disclosed in the prior art, see Tetrahedron Letters, No. 1, pp 33-36, 1974, Pergamon Press. These compounds in testing, 5 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.

In accordance with the present invention, the compounds 10 of formula I and pharmaceutically acceptable salts thereof can be prepared by a) for preparing a ccrrpound of the general formula I wherein R^ is hydrogen and n is zero, cyclising a compound of the general formula and the broken line denotes an optional bond, or b) for preparing a ccttpound of the general fomula (I) 1 wherein R is hydrogen, bromo, chloro or iodo and n is 1, oxidising a carrpound of the general formula 7 10 7 I / / I l J or c) wherein X and Y have the significance given above, is hydrogen, bromo, chloro or iodo and the broken line denotes an optional bond with the proviso that when R^ is other than hydrogen, then the bond denoted by the broken line must be present, for preparing a compound of the general formula (I) wherein R^ is hydrogen and the bond denoted by the broken line is present, dehydrohalogenating a compound of the general formula ^12 - /l2 III or d) wherein X and Y have the significance given above and chloro, bromo or iodo, for preparing a compound of the general formula I wherein is a radical of the formula / or a radical of the formula R.

R. wherein R2 is hydrogen, lower alkyl, hydroxy, mono-loweralkylamino or diloweralkylamino and R3 is hydroxy, reacting a compound of the general formula lb wherein X, Y, R12 and n have the significance given above, ■j Q7 1 n \ S i i with a compound of the general fonttula HC C-CH2-R21 IV wherein R,,^ is hydrogen, lower alkyl, hydroxy, mono-lower alkylamino or di-lower alkylamino, in the presence of a palladium salt, cuprous iodide, an organophosphine and a secondary or tertiary amine, or e) for preparing a compound of the general formula I wherein R^ is a radical of the formula y or a radical of the formula R.

R, wherein each of R2 and R^ is amino, removing the phthaloyl group (s) from a ccitpound of the general formula V or VI wherein X, Y and n have the significance given above and Phth is phthalimido, or N.Z. PATENT OFFICE 2 5 AUG 1983 •; Q "7 i I /' l i -J 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 15 materials therefor are illustrated by the following Reaction Schemes wherein X, Y, R^' n anc^ Phth have the significance given above and R^2 is hydrogen, phthalimido, lower alkyl, hydroxy, amino, mono alkyl amino or dialkylamino, is hydroxy, phthalimido or amino and R4 is to Cg alkoxy.

Reaction Scheme I Reaction Scheme II Q 7 1 / i n~; »—J Reaction Scheme III The compounds of formulae II, III, V, VI, VIII and IX also form part of the present invention.

The compounds of formulas VII and X do not form part of the present invention but such ccsrpounds are described and claimed in our New Zealand Patent Specification No. 192775. Exairples 34 to 45 of the present specification set forth methods for preparing these compounds.

The compound of formula 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 The compound of formula VII is hydrogenated utilizing a 197:03 transition metal catalyst, such as, Raney nickel or platinum oxide at from about atmospheric pressure to 50 pounds/square inch with atmospheric pressure preferred. Solvents which may be utilized include C. to Cr alcohols, tetrahydrofuran, 1 D dioxane and toluene.

VIII > la' and IX-" ->Ia" The compounds of formulas VIII and IX can be reacted with an aqueous solution of a lower alkyl amine, e.g., methyl amine. A to alcohol can be utilized as the 10 solvent with ethanol as preferred. The reaction is most preferably carried out at about room temperature. The first formed open amine is not isolated but undergoes spontaneous ring closure to the compound of formula la1 aid la", respectively.

An alternate method to produce the compounds of formulas 15 la' and la" consists of the reaction of the compounds of formulas 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 about room temperature to about 100°C with reflux tempera-20 ture of the selected solvent as 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 formulas la' and la1 ' consists of a base hydrolysis followed by an acid hydrolysis of the canpounds of formulas VIII and IX. For the base part of the hydrolysis an alkali metal hydroxide, such as, potassium or sodium hydroxide is utilized. For Z. PATENT OFFICE 2 5 AUG 1983 7 1H'1 / i V 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 or about room temperature to reflux temperatures with reflux 5 temperatures preferred. Organic solvents, such as, to alcohols or tetrahydrofuran may be utilized to solubilize the ingredients.

VII - >IX The compound of formula VII is hydrogenated using a 10 Lindlar catalyst (prehydrogenated 10% palladium on barium sul fate) at about atmospheric pressure and about room temperature. Solvents suitable for the reaction include to Cg alcohols, tetrahydrofuran, dioxane or toluene.

VII > X The compound of 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 alcohols, ethers or dimethylformamide. The reaction tempera- o ture may range from about 0°C to 60°C with about room tempera-20 ture as preferred.

Another method which may be utilized to produce the compound of formula X consists of a base hydrolysis followed by an acid hydrolysis of the compound of formula VII. For the base part of the hydrolysis, an alkali metal hydroxide, such as, potassium or sodium hydroxide is utilized. For the acid part of the hydrolysis, a 10% solution of a mineral acid, such as, hydrochloric, hydrobrcmic, sulfuric or phosphoric acid may be uti- lized. The hydrolyses are run at or about room temperature to reflux temperatures with reflux temperatures preferred. Organic solvents, such as, to alcohols or tetrahydro-furan may be utilized to solubilize the ingredients.

X >la" The compound of formula X can be converted into a compound of formula la" by utilizing the reactants and reaction parameters of step VII ■> IX. The first formed open amine is not isolated but undergoes spontaneous ring closure to the 10 compound of formula la".

X ■■> la' The compound of formula X can be hydrogenated using Raney nickel as a catalyst at from atmospheric pressure to 50 pounds/square inch with atmospheric pressure as preferred. The reaction is run at about room temperature. Solvents suitable for the reaction include C, to C, alcohols, tetrahydrofuran, 1 b dioxane and toluene. The first formed open amine is not isolated but undergoes spontaneous ring closure to the compound of formula la'. la' ^ Ic and la" > Id and lb' } lb" The compounds of formulas la' and la" and lb' can be reacted with a suitable oxidizing agent such as metachloro-perbenzoic acid in an inert organic solvent such as methylene chloride. The reaction may be run at between 0°C to the reflux 25 temperature of the solvent with room temperature preferred.

Ia". » III The compound of 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 about 0°C to about room temperature with about room temperature as 5 preferred.

Ill » lb' The compound of the formula III can be dehydrohalogenated utilizing an alkali metal, e.g., potassium or sodium, hydroxide, carbonate or alkoxide. Suitable solvents include C, to Cr alco- 1 o hols, tetrahydrofuran, dioxane and dimethylformamide. When a C. to Cc alcohol is used as a solvent in the above reaction an 1 b end product mixture of compounds of the formulas lb' and XI is produced. The reaction temperature may vary from 0°C to reflux temperature of the chosen solvent with about room 15 temperature as preferred.

Ib » - XII or XIII The compounds of formulas Ib can be reacted with a mono-substituted acetylene of the formula, HC=C-CH2~R22 wherein R22 is hydrogen, phthalimido, lower alkyl, hydroxy, mono-20 lower alkylamino or di-lower alkylamino. Examples of the above include propargyl alcohol, propargylphthalimide, N-methylpropargylamine, propyne or N,N-dimethylpropargylamine. The reaction is carried out in the presence of palladium chloride, cuprous iodide, triphenylphosphine and a di- or 25 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 about 0°C to reflux temperature with room temperature as preferred.

It was found that shorter reaction times and the use of mono- or di-alkyl amino substituted acetylenes tended to produce compounds of formula XII whereas longer reaction times 5 and the use of hydroxy and phthalimido substituted acetylenes tended to form compounds of formula XIII.

To arrive at or as amino, one can remove the phthaloyl substituent at ^22 or R31 ^ an ac;'-<^ or base hydrolysis cr by reaction with an aqueous monoalkyl amine or 10 hydrazine as in step VII ^ X.

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

A suitable pharmaceutical dosage unit can contain from 15 about 1 to about 500 mg of the benzazepine end products with a dosage range of from about 1 mg to about 100 mg being the preferred oral administration and a dosage range of from about 1 mg to about 50 mg being preferred for parenteral administration. However, for any particular subject, the specific dosa-20 ge 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 25 scope or practice of this invention.

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 pro-5 duce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle.

The 3H-2-benzazepines of formula I are useful as pharmaceuticals and are characterized by activity especially as sedative and anxiolytic agents. These compounds can be used 10 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, 15 vegetable oil, gums, polyalkylene glycols, Vaseline or the like. They can be administered in conventional pharmaceutical forms, e.g., solid forms, for examples, tablets, dragees, capsules, suppositories or the like, or in liquid forms, for example, solutions, suspensions or emulsions. Moreover, the 20 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 25 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 5 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 10 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 ED^q. On active compounds, 8 animals ace employed per dose group. The ED^q is calculated by the 15 Miller-Tainter method (Proc. Soc. Exp. Med. and Bio., 57, 261, 1944). 8-chloro-5-(l-amino-2-propyn-3-yl)-l-phenyl-3H-2-benzazepine dihydrochloride Metrazol ED^q = 3 2 mg/kg (PO) Toxicity = 50 0 mg/kg (24 hr. LD^) (PO) 8-chloro-5-(l-amino-2-propyn-3-yl)-1-(2-fluorophenyl)-3H-2-benzazepine dihydrochloride Metrazol ED,-q = 3 mg/kg (PO) Toxicity = 500 mg/kg (24 hr. LDjq) (PO) 8-chloro-l-phenyl-3H-2-benzazepine-2-oxide Metrazol ED^q = 5.2 mg/kg (PO) Toxicity = ^ 1000 mg/kg (24 hr. LDjq) (po) CI V 8-chloro-5-(1-dimethylamino-2-propyn-3-yl)-1-(2-fluorb-phenyl)-3H-2-benzazepine dihydrochloride Metrazol ED 50 Toxicity = 19 mg/kg (PO) = ^ 1000 mg/kg (24 hr. LDj-q) (PO) The compounds of the present invention wherein R^ is hydrogen, bromo, chloro and iodo are also intermediates in the production of other active benzazepines, for example, pyri-midobenzazepines.

As preferred are compounds of the formula Sl3 Ie wherein X' is chloro, Y' is hydrogen, fluoro or chloro and R13 is a radical of the formula /R23 or a radical or the formula ,32 wherein ^23 amino> monoalkylamino or dialkylamino and R^2 is amino.

N.Z. PATENT OFFICE Especially preferred are compounds of the above formula ti-R- Ie wherein R^^ i-s a radical of the formula 2 5 AUG 3983 23 - wherein R^2 i-s amino, monoalkylamino or di alkyl amino.

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

The above compounds of formula Ie exhibit antidepressant 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 ul of imi- 3 pramine or other drugs and 20 ul of H-imipramine (0.1 mM). _3 Imipramine (10 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. ■i o ~7 ! n -» \ S t < v/ Compound H-Imipramine Binding IC50 (uM) Imipramine 7.1 8-Chloro-5-(l-amino-2-propyn-3-yl)-l-5 phenyl-3H-2-benzazepine dihydrochloride 11.0 8-Chloro-5-(l-amino-2-propyn-3-yl)-1-(2-fluorophenyl)-3H-2-benzazepine dihydrochloride 20.0 The expression "pharmaceutically acceptable salts" 10 prefers to i salts with both inorganic and organic pharmaceutically acceptable acids, such as, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, para-15 toluenesulfonic acid and the like. Such salts can be formed quite readily by those skilled in the art, with the prior art and the nature of the compound to be placed in salt form, in view.

The following examples are illustrative, but not limitative of this invention. All temperatures given are in degrees centigrade, unless indicated otherwise. 1 2 3 4 6 7 8 9 11 12 13 14 16 17 •IS 19 21 22 23 24 :25 '26 127 Example 1 l-f4-Chloro-2-bcnzovlphcnyn -3-ohthnlimidopropnne A mixture of 2 g (5 mmolc) of l-[4-chloro-2-bcnzoylphenyl] -3-phthalimidopropyne and 1/2 teaspoonful of Raney nickel in 25 ml of tetrahydrofuran was hydrogenated at room I 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 I dryness. The residue was crystallized from a mixture of ether and petroleum to give crude product as a tan solid, mp 94-97°C. Recrystallization from ether gave pale yellow prisms, mp 98-99° C.

Example 2 l-[4-Chloro-2-(2-fluorobenzoyl)phenyl] -3-phthalimidoDropane A mixture of 9.6 g (23 mmole) of l-[4-chloro-2-(2-fluorobenzoyl)phenyl] -3-phthal- : imidopropyne 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 ' i was absorbed the catalyst was separated bv filtration and the filtrate was concentrated at I 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-3I-I-2-benzazepine hydrochloride A solution of 5.1 g (12.6 mmole) of l-[4-chIoro-2-benzoylphenyl] -3-phthalimido- 1 i propane in 100 ml of ethanol and 20 ml of 3N sodium hydroxide was '•efluxed for 2 hr. The ; solution was diluted with 60 ml of 3N hydrochloric acid and refluxed for 12 hr. The ' I mixture was diluted with water and extracted with ether. The aqueous layer was • I separated, made alkaline with dilute sodium hydroxide, and extracted with methylene . i j cliloride. The methylene chloride extract was dried over anhydrous sodium sulfate and 1 2 3 tf 6 7 S 9 11 12 13 14 16 17 IS 19 '20 21 22 23 24 26 27 28 •; o i n i , i w J conccntraled at reduccd pressure to dryness. The residue was purified by plug filtration (silica gel, 10 g; clucnt, methylene chloride) and the eluent 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. Rccrystallization from a mixture of methylene chloride and ether gave colorless needles, mp 234-235° C dec.

• " Example 4 8-Chloro-4.5-dihydro-l-(2-fluorophenyl)-3H-2-benzazepine hydrochloride Method A. A mixture of 2.9 g (10 mmole) of 3-amino-l-[4-chloro-2-(2- ! fluorobenzoyl)phenyl]propyne and 1/4 teaspoonful of Raney nickel in 50 ml of tetrahydro- ^ furan wos_hydrogenated at room temperature, and atmospheric pressure. When 430 ml of • !' hydrogen was absorbed the catalyst was removed by filtration and the filtrate was : i concentrated at reduced pressure to dryness. A solution of the residue in an excess of . i niethanolic hydrogen chloride was diluted with ether and end product, mp 176-177° C dec j w-as collected by filtration. Reerystallization 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 l-[4-chlor~o-2-(2-fluorobenzoy]) phenyl] ■ 3-phthalimidopropane in a mixture of 100 ml of ethanol and 20 ml of 3N sodium hydroxide i was refluxed for 2 hr, diluted with 60 ml.of. 3N hydrochloric acid and refluxed for 12 hr. ' f i 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 i methylene chloride. The methylene chloride solution was dried ever anhydrous sodium : ! sulfate and concentrated at reduced pressure to dryness. Purification by plug filtration ■ (alumina Woelm I, 50 g; eluent, methylene chloride) gave an oil which was diluted with an exccss of methanolic hydrogen chloride and concentrated at reduced pressure to dryness.

! The residue was crystallised from a mixture of methanol and ether to give product which was identical in every respect to an authentic sample. 1 2 3 4 6 7 S 9 11 12 13 14 16 17 IS 19 21 22 23 24 26 27 Example 5 H-l-Chloro-S-bcnzovlplionvll -3-phthnlimidopropcnc A mixture of 2.0 [j (5 mmole) of H4-chloro-2-benzoylphcnyl] -3-phthalimidopropvnc: I 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 eoncentratedj at reduced pressure to dryness. The residue was crystallized from ether to give a white solid, mp 70-72° C. Reerystallization from ether gave colorless prisms, mp 70-72° C.

Example 6 H4-Chloro-2-(2-fluorobenzoyl)phenvl] -3-phthalimidopropene The preparation of l-[4-ehloro-2-(2-fluorobenzoyl)phenyl] -3-phthalimidopropene was conducted in the same manner as the preparation of l-[4-chloro-2-benzoylphenyl] -3-phthalimidopropene to give colorless needles, mp 117° C. - : Example 7 8-Chloro-l-phenvl-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-amino-l-[2-benzoyl-4-chlorophenyl] propyne 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. Thej filtrate was diluted with an excess of methanolic hydrogen chloride and 100 ml ofj isopropanol and concentrated at reduced pressure to a crystallint residue. Trituration with a mixture of ether and methanol gave a tan solid, mp 224-226°C dec. Reerystallization from a mixture of methanol and ether gave cream colored prisms, mp 227-228° C doc. ) .2 3 4 6 7 8 9 11 12 13 14 16 17 .18 19 21 22 23 24 26 27 Method B. A mixture of 6 g (15 mmole) of l-[I-chloro-2-bcnzoylphenyl] -3-phthalimidopropene, 0.9 g (18 mmole) of 85% hydrazine hydrate and 70 ml of 95% ethanol wasj refluxed for 2. 5 hr. The insoluble precipitate formed was separated by filtration. Thej I filtrate was acidificd with ice cold dilute hydrochloric acid and extracted with ether. The! I aqueous layer was separated, made alkaline with dilute sodium hydroxide and extracted: with methylene chloride. The methylene chloride solution was dried over anhydrousj sodium sulfate, acidified with methanolic hydrogen chloride, diluted with isopropanol andj 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-fluorophenyI)-3H-2-benzazepine hydrochloride The preparation of 8-chloro-l-(2-fluorophenyl)-3H-2-benzazepine hydrochloride was conducted in the same manner as the preparation of 8-chloro-l-phenyl-3H-2-benzazepinej hydrochloride to give product (Method A) and (Method B) as off-white prisms, mp 210— 212° C dec.

Example 9 8-Chloro-I-(2-chlorophenyl)-3H-2-benzazepine A mixture of 4.6 g (15 mmole) of 3-amino-l-[2-(2-chlorobenzoyl)-4-ch!oro-phenyl] propyne 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 from ether to give a cream colored solid, mp 113-115° C. Reerystallization from ether gave cream colored prisms, mp 117-118° C. 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 • 0 « • • • • • • I* •••» The methanesulfonate salt of 8-chloro-l-(2-chlorophenyl)-3H-2-benzazepine was prepared by the addition of an excess of a 1M methanol solution of methanesulfonic acid to a methanol solution of the above compound and isolated by precipitating the salt with the addition of ether. Reerystallization 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-2- benzazepine hydrochloride to give tan needles, mp 201-202° C dec.

* Example 11 8-Chloro-4)5-dihydro-l-phenyl-3H-2-benzazepine-2-oxide A solution of L4 g (5.5 mmole) of 8-chloro-4,5-dihydro-l-phenyl-3H-2-benzazepine and 1.4 g (7 mmole) of 85% m-chloroperbenzoic acid 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 vacuo to dryness. The residue was crystallized from ether to give a colorless solid, mp 120-125° C. Reerystallization from ether gave colorless prisms, mp 142-143° C. 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 197103 Example 12 8-Chloro-l-phenyl-3H-2-benzazepine-2-oxide A mixture of 10.7 g (42 mmole) of 8-chloro-l-phenyl-3H-2-benzazepine, 10.7 g (53 mmole) of 85% metachloroperbenzoic acid and 100 ml of methylene chloride was stirred at son temperature for '.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..' j dryness. . The, residue was, crystallized with ether .to give crude product,1 mp 130-131°C. Reerystallization frcm ether gave tan prisms, np 122-123°C.

Example 13 8-Chloro-l-f2-fluorophenyl] -3H-2-benzazepine-2-oxide The preparation of 8-chloro-l-(2-fluorophenyl)-3H-2-benzazepine-2-oxide was conducted in the same manner as the preparation of 8-chloro-l-phenyl-3H-2-benzazepine-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-chlorophenyl)-3H-2-benzazepine-2-oxide was conducted in the same manner as the preparation of 8-chloro-l-phenyl-3H-2-benzazepine-2-oxide to give cream colored prisms, mp 196-197° C.

Example 15 l-(2-Chlorophenvl)-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 of 8-chloro-l-phenyl-3H-2-benzazepine-2-oxide to give cream colored rods, mp 115-116° C. office. 1 2 3 4 6 7 S 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 Example 16 8-Chloro-4,5-dibromo-4,5-dihydro-l-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. Reerystallization from methylene chloride gave colorless crystals, mp 164-165° C dec. The compound has been found to have a second melting point of 172-173° C dec.

A methanol solution of the salt was neutralized with dilute aqueous sodium hydroxide and the resulting crystals collected by filtration. Reerystallization from methanol gave the end product as colorless prisms, mp 113-115° C. 1 2 3 4 6 7 8 9 11 12 13 14 16 17 IS 19 21 22 23 24 26 27 Example 17 8-Chloro-4,5-dibromo-4>5-dihydro-l-(2-fluorophenyl)-3H-2-benzazepine The preparation of 8-chloro-4,5-dibromo-4,5-dihydro-l-(2-fluorophenyl)-3H-2-ben-zazepine was conducted in the same manner as the preparation of 8-chloro-4,5-dibromo-4,5-dihydro-l-phenyl-3H-2-benzazepine to give the hydrochloride salt as a colorless solid, mp 158-159° C dec. 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-benzazepine The preparation of 8-chloro-4,5-dibromo-4,5-dihydro-M2-chlorophenyl)-3H-2-ben-zazepine was conducted in the same manner as the preparation of 8-chloro-4,5-dibromo-4,5-dihydro-l-phenyl-3H-2-benzazepine 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 methanesulfonate A solution of 24 g (53 mmole) of 8-chloro-4,5-dibromo-4,5-dihydro-l-phenyl-3H-2-benzazepine hydrochloride in 1 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 229-230° C. Reerystallization from methylene chloride gave the hydrochloride of the bromo compound as colorless prisms, mp 230-235° C dec. 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 « • •• • » » • • • The crude mother liquors were basified with dilute aqueous sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried ovcri anhydrous sodium sulfate and concentrated in vacuo. Purification by column chromato-j grcphy (silica gel; eluents methylene chloride, then ether) gave after concentration of the: ether fractions a colorless oil. The oil was dissolved in a methanol solution of! I methanesulfonic acid and the salt was precipitated by the addition of ether. Recrystal-j lization from a mixture of methanol and ether gave off-white prisms, mp 139-140° C.

Example 20 8-ChIoro-5-bromo-I-(2'-nuorophcnyl)-3H-2-benzazepine hydrochloride A mixture of 21 g (45 mmole) of 8-chloro-4,5-dibromo-4,5-dihydro-H2-fluoro-phenyl)-3H-2-benzazepine hydrochloride, 40 ml of dioxane, 360 ml of methanol and 40 mlj of 10% aqueous sodium hydroxide was stirred at room temperature for 5 hr and thenj concentrated at reduced pressure to a small volume. The concentrate was diluted withj 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. Reerystallization 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-fluorophenyl)-JH-2-benzazepine) was not isolated. 1 2 3 4 6 7 S 9 11 12 13 14 16 17 18 19 21 22 23 2<f 26 27 Example --21 8-Chloro-5-bromo-l-(2-chlorophenyl)-3 H-2-benzazepine and 8-ChIoro-3-methoxy-l-(2-chIorophenyl)-3H-2-benzazepine A solution of 60.0 g (0.134 mole) of 8-chloro-4,5-dibromo-4,5-dihydro-l-(2-chlorophenyl)-3H-2-benzazepine and 75 ml of 40% aqueous sodium hydroxide in a mixture of 300 ml of dioxane 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 dried 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 isoprop'anol 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 ar amber oil. Purification by column chromatography (silica gel, 250 g; eluent, 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 anc petroleum ether gave the methoxy compound as a tan solid. Reerystallization from a mixture of ether and pertroleum ether gave cream colored prisms, mp 83-85° C. —-7-7 - 1 2 3 4 6 7 S 9 io 11 12 13 14 16 17 18 19 21 22 23 24 26 27 Example 2 2 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-chloroperbenzoic acid in 100 ml of methylene chloride was 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. Reerystallization from ether gave colorless prisms, mp 185-186° C dec.

Example 2 3 8-Chloro-5-(l-dimethylamino-2-propyn-3-yl)-l-phenyl-3H-2-benzazepine 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 1-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; eluent, 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 dihydrochloride salt as a colorless solid, mp 193-195° C dec. Reerystallization from methylene chloride gave the salt as colorless crystals, mp 198-199° C dec. 1 2 3 4 6 7 s 9 11 12 13 14 16 17 is 19 21 22 23 24 26 27 28 29 Example 24 8-Chloro-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-chloro-5-bromo-l-(2-fluorophenyl)-3H-2-benzazepine and 16 ml of 1-dimethylamino-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. Reerystallization from a mixture of ethanol and ether gave the salt as pale yellow rods, mp 194-195 °C dec.

Example 25 8-Chloro-5-(l-dimethylamino-2-propyn-3-yl)-l-phenyl-3H-2-benzazepine-2-oxide A mixture of 3.5 g (10 mmole) of 8-chloro-5-bromo-l-phenyl-3H-2-benzazepine-2-oxide, 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. Reerystallization from ether gave tan prisms, mp 124-125° C. 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 Example 26 8-Chloro-5-fl-hvdroxy-2-propyn-3-yl)-l-phenyI-3H-2-benzazepine hydrochloride A 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 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; eluent 20% ether in methylene chloride) gave a colorfess 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 dec.

Example 2 7 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; eluent, 20% ether in methylene chloride) gave an oil which crystallized from a mixture of tetrahydrofuran and ether to give tan prism, mp 210-211° C dec. 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 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. Reerystallization 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-phenyl-3H-2-benzazepine hydrochloride A stirred mixture of 180 ml of 98% diethylamine (degassed with nitrogen), 7.2 g (2L8 mmole) of 8-chloro-5-bromo-l-phenyl-3H-2-benzazepine, 0.4 g (0.6 mmole) of dichlorobis(triphenylphosphine)palladium (n), 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 J 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. Reerystallization from a mixture of ethanol and ether gave the salt as pale yellow prisms, mp 210-211° C dec. 1 2 3 4 6 7 s 9 11 12 13 14 16 17 is 19 21 22 23 24 26 27 Example 29 8-Chloro-5-(l-phthalimido-2-propyn-3-yI)-l-phenyl-3H-2-benzazepine and 8-Chloro-5-(l,6-diphthalimido-2-hexen-4-yn-3-yl)-l-phenvl-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 (ED, 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 5.5 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; eluent, methylene chloride gradient to 10% ether in methylene chloride) gave as the first product band the propyn-3-yl 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. 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 Example 3 0 8-Chloro-l-(2-fluorophenyl)-5-(l-phthalimido-2-propyn-3-yl)-3H-2-benzazepine A mixture of 40 ml of 98% diethylamine, 50 ml of methylene chloride, 0.6 g (0.9 mmole) dichlorobis(triphenylphosphine)palladium (II), 0.15 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; eluent, methylene chloride gradient to 5% ether in methylene chloride) gave as the major fraction a colorless solid. Reerystallization from ether gave colorless needles, mp 164-165° C.

Example 31 8-Chloro-5-(N-methyl-l-amino-2-propyn-3-yl)-l-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 (n), 0.2 g (1 mmole) cuprous iodide and 2 ml (excess) of 97% N-methylpropargylamine in 50 ml of 98% 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 by column chromatography (silica gel, 20 g; eluent, 20% ether in methylene chloride followed by 10% methanol in methylene chloride) gave from the latter eluent 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 recrystallized from isopropanol gave tan crystals, mp 169-175° C dec. 1 2 3 4 6 7 S 9 11 12 13 14 16 17 IS 19 21 22 23 24 26 27 Example 32 8-Chloro-5-(I-amino-2-propyn-3-vl)-l-phenvl-3H-2-benzazepine dihydrochloride A mixture of 5 g (11-4 mmole) of 8-chloro-5-(l-phthalimido-2-propyn-3-yl)-l-phenyl-3H-2-benzazepine, 100 ml of ethanol and 20 ml of 40% aqueous methylamine was stirred at 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. Reerystallization from a mixture of ethanol and ether gave tan prisms, mp 247-248° C.

$ Example 3 3 8-Chloro-5-(l-amino-2-propyn-3-yl)-l-(2-fluorophenyl)-3H-2-benzazepine dihydrochloride A mixture of 1.3 g (2.9 mmoles) of 8-chloro-5-(l-phthalimido-2-propyn-3-yl)-l-(2-fluorophenyl)-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. Reerystallization from a mixture of methanol and ether gave gray needles, mp 216-218° C dec. 1 2 3 k 6 7 8 9 11 12 13 Ik 16 17 18 19 21 22 23 2h 26 27 •; n '? -1 .*"> I ; ; ^ Example 34 -Chloro-2-iodoben7.ophenone A mixture of 76 g (1.1 mole) of sodium nitrite and 450 ml I of sulfuric acid was heated on a steam bath to ca 80° until complete solution was achieved. The-solution was cooled to 30° and 232 g j !• (1.0 mole) of 2-amino-5-chlorobenzophenone was added in portions j keeping the temperature between 30° and 4 0°. 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 • I was collected by filtration and washed with water (2x100 ml) to give a moist white solid.

The -moist 2-benzoyl-4-chlorobenzenediazonium fluoLorate ,vas slurried in 3 L of water, and a solution of 332 g (2 moles) 3f potassium iodide in 1 L of water'was added dropwise. "The nixture 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 50 0 ml and :he addition of 100 ml of petroleum ether gave end product. A ;mall amount of end product was recrystallized from a mixture of jther and petroleum ether to give -light yellow prisms, mp 80-82°.

MZ. PATENT OFFICE 25AWG3W 1 2 3 6 7 S 9 11 12 13 14 16 17 IS 19 21 22 23 21 26 27 c 7 Example 35 -Chloro-2' -f luoro-2-iodobenzophenone The preparation of 5-chloro—2 ' -f luoro-2-iodobenzophenone was conducted in the same manner as. the preparation of 5-chloro-2 iodobenzophenone to give the end product as light yellow prisms, mp 78-81°.

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

Example ,37 2' -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°.

N.Z. PATENT OFFICE 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 • • • • • Example 3 8 1-{4-Chloro-2-benzoylphcny1)-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 mole) 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 jbtained. In one portion, 40.0 g (0.22 mole) of N-propargyl-jhthalimide was added to -the solution and the resulting mixture stirred for 20 hr. The volatiles were removed at reduced pressure ind tire residue was triturated with 200 ml of iospropanol. The esulting percipitate was collected by filtration to give crude j I nd product. Reerystallization from acetone gave cream colored prisms, mp 148-150° C. - • • Example ,39 1-14-Chloro-2-(2-fluorobenzoy1)phenyl]-3-phthalimidopropyne The preparation of 1— [4—chloro-2— (2—fluorobenzovl)phenyl] 3-phthalimidopyropyne was conducted in a similar manner as the preparation of 1-[4—chloro—2-benzoylphenyl] -3-phthalimidopropyne to give cream colored prisms, mp 158-161° C. 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 Example 40 1-(4-Chloro-2-(2-chlorobenzoyl)phenyl 1 - 3-phthalimidopropyne * The preparation of l-[4-chloro-2- (2-chlorobenzoyl) phenyl] -3-phthalimidopropyne was conducted in the same manner as the preparation of 1- [4-chloro-2-benzoylphenyl] -3-phthalimidopropyne to give cream colored prisms, mp 144-145° C.

Example A1 1-[2-(2-chlorobenzoyl)phenyl]-3-phthalimidopropyne The preparation of l-[2- (2-chlorobenzoyl) phenyl] -3-phthal-imidopropyne was conducted in the same manner as the preparation of l-[4-chloro-2-benzoylphenyl]-3-phthaliraidopropyne to give cree colored prisms, mp 149-150° C. 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 i Example -42 3-Amino-l-[2-bcw.oyl-4-chlorophenyU propyne Method A. A mixture of 72 g (0.1S mole) of M4-chloro-2-behzoylphcnyl] -3-phthalimidopropync, 90 ml of 40% aqueous 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-chloro-2-benzoylphenyll -3-phthalimidoprcpyne and 0.G 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'meihylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residua was crystallized from a mixture of ether and petroleum ether to give a pale yellow solid, mp 08-69° C which was identical in every respect to an authentic sample.

The hydrochloride salt of 3-amino-H4-chloro-2-benzoylphcnyl] propyne was prepared by the addition of an excess of 6% methanolic hydrogen chloridc to a methanol solution of the product and isolated by precipitating the salt with the addition of ether. Reerystallization from a mixture of methanol and ether gave the hydrochloride as white needles, mp 17 3-17 4° C. ... 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 Example - 43 3-Ami*no-]-ri-oh)oro-2-(2-fli!orohc'n7,ovl)nl:pnv11 proovne Method A. The preparation of 3-nmino-H4-chloro-2-(2-fluorcbenzoyl)phenyl] -propyne was conducted in the same manner (Method A) as the preparation of 3-amino-l-{4-ch]oro-2-benzoylphenyl] propyne to give yellow prisms, mp 89-91° C.

Method D. A mixture of 50 g of l-[4-chloro-2-(2-fluorobenzoyl)phenyl] -3-phthalimiuoprcpyne, 50 r.*l of cquccuc methylamine and 150 ml of dimethylformamide ;vas 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. Reerystallization 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 l-[4-chloro-2-(2-fluorobenzoyl)-phenyl]-3-phthalimidopropyne, 1.3L of ethanol and 300 ml of 4096 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, mp 79-80° C. Iiecrystallization from ether gave pale yellow prisms, mp 89-91° C which was identical in every respect to an authentic sample. 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 2i 2f 27 •• •••• • • • ••* < • • • • • • • • • • • • • • • • • • • • • < • • • • • • « • • • • • • • • •• Example ,44 -Amino-!-? l-ch1orp-7.-(?.-<'IUorotK>n,/pv,0r»hc,nvl? rronvMQ The preparation of 3-amino-l-U-chloro-2-(2-chlorobcnzoyj)phenyl) propyne was onductcd in the same manner as the preparation of 3-amino-W4-chloro-2-benzoyl-licnyl] propyne [Method A] to give pale yellow prisms, mp 81-82° C.

Example 45 3-Amino-H2-(2-chIoroben7,oyi)phenvll proovne The preparation of 3-aniino-H2-(2-chlorobenzoyl)phor.yn propyne was conducted in the same manner as the preparation of 3-amino-l-[4-chloro-2-benzoy!phenyI] propyne [Methad A] to give an amber oil.

The hydrochloride salt of 3-amino-l-[2-(2-chlorob'2nzoyl)phenyl] propyne was prepared by the addition of an excess of G% methanolic hydrogen chloride to a methanol solution of tne product and isoJated by precipitating the salt py the acainon of ether. Reerystallization from a mixture of methanol and ether gave the salt as white needles, npl60-lG2°C. 1 2 3 4 6 7 S 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 •• •••• • • • • • • < Example 46 TABLET FORMULATION (Wet granulation) Item Ingredients mg/tablet 1. 8-chloro-l-phenyl-3H- 2-benzazepine-2-oxide or 3-ZS&-chloro-l-(2-fluoro~ phenyl)-3H-2-benzazepin-5-yi7-2-propyn- 1-amine 2. Lactose 3. Modified Starch 4. Pregelatinized Starch . Cornstarch * 6. Magnesium Stearate 7. Distilled Water q.s.

Weight of tablet 1 195 12.5 12.5 25 4 mg/tablet 5 230 15 15 30 5 mg/tablet mg/tablet 10 50 264 17.5 17.5 35 6 263 20 20 40 7 250 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. Dry in a suitable oven. 4. Mill and mix with magnesium stearate.

. Compress on a suitable press equipped with appropriate punches. 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 19 i "** J V Example 47 TABLET FORMULATION (Direct compression) Item Ingredients mg/tablet mg/tablet mg/tablet mg/tablet 1. 8-chloro- l-phenyl-3H- 2-benzazepine-2-oxide or 3-Zl-chloro- l-(2-fluoro-phenyD-3H-2-benzazepin-5-yi7-2-propyn- 1-amine 1 50 2.

Lactose 127 155:5 | 182 206 3.

Microcrystalline Cellulose 40 50 60 80 4.

Direct Compression Starch 12 .

Cornstarch 4 40 6.

Magnesium Stearate 2 2.5 3 4 Weight 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.

Claims (18)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 •j Q 7 1 n l ^ < 1 ^ Example .48 CAPSULE FORMULATION Item Ingredients mg/capsule mg/caosule mg/capsu3.e mg/capsule L

1. 8-chloro-l-phenyl-3H- 2-benzazepine-2-oxide or 1 5 10 50 3-ZB-chloro- l-(2-fluoro-phenyl)-3H-2-benzazepin-5-yl/-2-propyn- 1-amine

2. Lactose 149 182.5 215 250

3. Cornstarch 40 50 60 80

4. Talc 8 10 12 16

5. Magnesium Stearate 2 2.5 3 4 Capsule fill weight 200 mg 250 mg 300 mg 400 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: WHAT CLA-.M rS: BS '10-08/315 1. 3H-2-Benzazepines of the general formula wherein X is hydrogen, chloro or bromo, Y is hydrogen, fluoro or chloro, the broken line denotes an optional bond, n is zero or 1 and R^ is hydrogen, bromo, chloro, iodo, a radical of the formula r- J 10 or a radical of the formula r- wherein is hydrogen, lower alkyl, hydroxy, amino, monoalkylamino or dialkylamino and is hydroxy or amino with the proviso that (i) X and Y cannot both be hydrogen, and (ii) where R^ is other than hydrogen then the bond denoted 15 by the broken line must be present, and pharmaceutically acceptable salts thereof. 2. Compounds according to claim 1 of the general formula - 45 - X' B5—4I1^87ieir5 Ie wherein X' is chloro, Y' is hydrogen, fluoro or chloro and is a radical of the formula k23 or a radical of the formula r32 wherein R23 Is amino, monoalkylamino or dialkylamino and R^2 Is amino. 3. Compounds according to claim 2 wherein R^ is a radi-10 cal of the formula and R22 is as defined in claim 2. 4. 8-Chloro-5-(l-amino-2-propyn-3-yl)-1-(2-fluoro-phenyl)-3H-2-benzazepine. 15 5. 8-Chloro-5-(l-amino-2-propyn-3-yl)-l-phenyl-3H-2- benzazepine. - 46 - 197103

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

7. 8-Chloro-l-phenyl-3H-2-benzazepine-2-oxide. S-. Compounds of the formula

III wherein X is hydrogen, chloro or bromo and Y is hydrogen, fluoro or chloro with the proviso that X and Y cannot both be hydrogen and is chloro, bromo or iodo. it

Compounds of the formulae Phth n

I V or VI wherein X is hydrogen, chloro or bromo and Y is hydrogen, fluoro or chloro with the proviso that X and Y cannot both be hydrogen, n is zero or 1 and Phth is phthalimido. lOi. Compounds according to any one of claims 1 to 7 in a form suitable for use as pharmaceutically active substances. - 47 - 197103

11. Compounds according to any one of claims 1 to 7 in a form suitable for use as sedatives and anxiolytics.

12. Compounds according to any one of claims 2 to 6 in a form suitable for use as antidepressants.

13. A process for the preparation of compounds according to any one of claims 1 to 7 which comprises a) for preparing a compound of the general formula I wherein is hydrogen and n is zero, cyclizing a compound of the general formula wherein X and Y have the significance given in claim 1 and the broken line denotes an optional bond, or b) for preparing a compound of the general formula I x NH 2 II wherein is hydrogen, brcrno, chloro or iodo and n is 1, oxidising a ccrrpound of the general formula Ia wherein X and Y have the significance given in claim 1, R^ is hydrogen, bromo, chloro or iodo and the broken line denotes an optional bond with the proviso that when R^ is other than hydrogen, then the bond denoted by the broken line must be present, or - 48 - V c) or for preparing a compound of the general formula I wherein is hydrogen and the bond denoted by the broken line is present, dehydrohalogenating a compound of the general formula 197:03 hi wherein X and Y have the significance given in claim 1 and is chloro, brono or iodo, d) for preparing a compound of the general formula I wherein is a radical of the formula R, or a radical of the formula R„ wherein R^ is hydrogen, lower alkyl, hydroxy, mono-loweralkylamino or diloweralkylamino and is hydroxy, reacting a compound of the general formula R12 Ib wherein X, Y and n have the significance given in claim 1 and R^2 has the significance given above, with a compound of the general formula N.Z. F " IBAUC" hc—c-ch2-r21 IV wherein R2^ is hydrogen, lower alkyl, hydroxy, mono-lower alkylamino or di-lower alkylamino, - 49 - in the presence of a palladium salt, cuprous iodide, an organophosphine and a secondary or tertiary amine, or e) for preparing a compound of the general formula I or a radical of the formula wherein each of and is amino, removing the phthaloyl group (s) frcm a conpound of the general formula wherein X, Y and n have the significance given in claim 1 and Phth is phthalimido, or f) converting a ccropound of formula I into a pharmaceutically acceptable salt. •I

14. A medicament containing a compound according to any one of claims 1 to 7. - 50 - 197103

15. A sedative and anxiolytic medicament containing a compound according to any one of claims 1 to 7.

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

17. A process for the preparation of compounds of the general formula (I) defined in claim 1, substantially as hereinbefore described with particular reference to any one of the foregoing Examples 3, 4, 7 to 15, 19 to 28 and 30 to 33.

18. Compounds according to any one of claims 1 to 7 whenever prepared by the process according to claim 13 or claim 17. DATED THIS IUCL DAY OF A 10 ^ A. J. PARK & SON PER JJ S. J\Q£KTS FOR THE APPLICAN. »