NZ204242A - 8-halo-6-phenyl-2,3-dihydro-1h,4h-pyrrolo(3,4-d)(2)benzazepine-(1-or 3-ones or 1,3-diones) - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £04242 Pnority Date(s): ■ ' /C • S~- Complete Specification Filed: aass: f.?3 7,.. A# .

P.O. Journal, No: 204242 new zealand patents act, 1953 No.: Date: complete specification BENZAZEPINE DERIVATIVES XI/We, F. HOFFMANN-LA ROCHE & CO. AKTIENGESLLESCHAFT, 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss company, hereby declare the invention for which XK/ we pray that a patent may be granted to roe/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by la) - la - 204242 The present invention relates to pyrrolo[3,4—d][2] benzazepine derivatives of the general formula wherein Rn and are hydrogen, lower alkyl, hydroxy, lower alkoxy or acyloxy (as hereinafter defined) and and R^ are hydrogen or R^ and R^ and/or R^ and R^ taken together are oxo groups with the proviso that at least one oxo group is present; R is hydrogen, lower alkyl, to C^ carboxylic acid or an ester or amide thereof, amino to alkyl or hydroxy C2 to alkyl, mono- or di-lower alkyl amino C^ to C7 alkyl; R^ is halogen having an atomic number not greater than 35 or hydrogen; and R^ is halogen having an atomic number not greater than 35 with the proviso that when R^ or R^ is hydroxy, lower alkoxy or acyloxy, then R is lower alkyl or hydrogen and the N-oxides and the pharmaceutically acceptable acid addition salts thereof.

The compounds exhibit activity as sedative and anxiolytic agents. t N -9 MAY 1986 2,04242 By the term "halogen having an atomic number not greater than 35" is meant bromo, chloro or fluoro except as limited herein.

By the term "lower alkyl" is meant both straight and branched chain to C7 hydrocarbon groups, preferably to carbon-hydrogen radicals, such as methyl, ethyl, propyl, isopropyl and the like.

By the term "acyloxy" is meant a radical derived from an organic carboxylic acid by the removal of the hydrogen atom i.e., radicals of the formula -O-C-R wherein R is C-, to Cr alkyl, lf 1 6 0 phenyl or hydrogen, e.g., acetyl, propionyl, butyryl, 15 benzoyl, etc.

Bv the terra "C2 to C^ carboxylic acid or an ester or amide thereof" is meant radicals of the formula -C^ to Cg alkyl- COR2^ where &21 hydroxy, lower alkoxy, amino or amino which is mono- or di-substituted by lower alkyl.

The expression "pharmaceutically acceptable acid addition salts" is used to mean salts with both inorganic and organic pharmaceutically acceptable acids, such as sulfuric acid, 25 hydrochloric acid, nitric acid, methansulfonic acid and p-toluenesulfonic acid. Such salts can be formed quite readily by those skilled in the art with the prior art and the nature of the compounds to be placed in salt form in view.

Preferred compounds within the scope of the present invention are those of the formula.I, i.e., the Schiff bases.

Further preferred compounds are those of the formula I wherein R^ and R4 taken together are an oxo group. Still further preferred compounds are those of formula I wherein R2 is hydrogen, R^ is preferably hydrogen or lower alkyl, more preferably hydrogen or methyl. The preferred meaning-" O' of R is hydrogen or lower alkyl, more preferably hydrogen \-z \ - V, 204252 or methyl. R5 is preferably halogen having an atomic number not greater than 35.

From the above it follows that an especially preferred 5 group of compounds within the scope of the present invention are those of formula I, wherein R and R^ are hydrogen or lower alkyl, preferably methyl, hydrogen, and R^ taken together are an oxo group and R,. is halogen having an atomic number not greater than 35.

Preferred compounds are: 8-chloro-6-(2-fluorophenyl)-3,4-dihydropyrrolo[3,4-d]-[2]benzazepin-l(2H)-one, 15 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d]- [2]benzazepin-l(2H)-one, 8-chloro-3,4-dihydro-6-phenylpyrrolo[3,4-d][2]benzaze-pin-1(2H)-one, 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-2-methyl-20 pyrrolo[3,4-d][2]benzazepin-l(2H)-one, 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l-hvdroxy-pyrroloC 3,4-d][2]benzaz epin-3(2H)-one, 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-3-hydroxy-pyrrolot 3,4-d][2]benzazepin-l(2H)-one, 25 8-chloro-6-(2-chlorophenyl)pyrrolo[3,4-d][2]benzazepin- 1,3-(2H,4H)-dione, 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-d]-[2]benzazepin-3(2H)-one-5-oxide, 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d]-30 [2]benzazepin-l(2H)-one-5-oxide, 8-chloro-6-(2-chlorophenyl)-1-ethyl-1,4-dihydropyrrolo-[3,4-d][2]benzazepin-3(2H)-one, 8-chloro-6- ( 2-chlorophenyl) -1, 2 , 3 , 4-tetrahvdro-l-methyl-3-oxo-pyrrolo[3,4-d][2]benzazepine-2-acetic acid methyl 35 ester and 8-chloro-6- ( 2-chlorophenyl!) -1,2,3, 4-tetrahydro-l-methyl-3 - oxo - pyrrolo[3,4-d][2]benzazepine-2-acetamide. 2 042 4 2 Especially preferred compounds are: 8-chloro-6-(2-fluorophenyl)-1,4-dihydropyrrolo[3,4-d]-[2]benzazepin-3(2H)-one, pin-3(2H)-one, 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l,2-dimethyl-pyrroloC 3,4-d][2]benzazepin-3(2H)-one and 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-(2-hydroxy-10 ethyl)-1-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one.

The most preferred compounds are: 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-d]- [2]benzazepin-3(2H)-one, 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l-methyl-pyrrolo[3,4-d][2]benzazepin-3(2H)-one and 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-methyl-pyrroloE 3,4-d][2]benzazepin-3(2H)-one.

The compounds of formula I, the N-oxides and the pharmaceutically acceptable salts thereof can be prepared in accordance with the invention a) for preparing compounds of the formula I above wherein or is hydrogen or lower alkyl and the remaining sub-stituents are as above and the N-oxides thereof, by oxidizing a compound of the formula 8-chloro-l,4-dihydro-6-phenylpyrrolo[3,4-d][2]benzaze- R II 204242 wherein one of ^ and R^ is hydrogen and the other -is hydrogen or lower alkyl and R, R,- and Rg are as above with a peracid, or b) for preparing compounds of the formula I above wherein R^ or is hydroxy and the remaining substituents are as above or R^ and R2 and R^ and R^ , respectively, are, when taken together, oxo groups and the remaining symbols are as above, by oxidizing a compound of formula I wherein R^ or R^ is hydrogen and the remaining substituents are as above, or a compound of the formula II above wherein R^ and R^^ are hydrogen, with a lead (IV) carboxylate in the presence of a strong acid, or c) for preparing compounds of the formula I above wherein R-^ or R^ is acetoxy and the remaining substituents- are as above, by treating a compound of the formula I wherein R^ or R3 is hydrogen and the remaining substituents are as above, or a compound of the formula II above wherein R^ and R^^ are hydrogen, with lead tetraacetate in acetic acid, or d) for preparing compounds of the formula I above wherein 25 R^ or R^ is acyloxy and the remaining substituents are as above, by treating a compound of formula I wherein R^ or R^ is hydroxy and the remaining substituents are as above, with an appropriate organic carboxylic acid anhydride in the presence of a base, or e) for preparing compounds of the formula I above wherein R^ or R^ is lower alkoxy and the remaining substituents are as above, by treating a compound of formula I wherein R^ or R^ is acyloxy or hydroxy and the remaining substituents are as above, or a compound of the formula o 204242 III wherein is acetoxy and R, and Rg are as above with a to alkanol in the presence of a strong acid, or -|5 f) for preparing compounds of the formula I above wherein R^ or R^ is hydrogen or lower alkyl and the remaining substi- by desoxygenating an N-oxide of the R tuents are as above, formula IA wherein R^ or R^ is hydrogen or lower alkyl and R, R^, R„, R and R^ are as above and, if desired, 4' 5 6 g) by converting a compound of formula I into a pharmaceutically acceptable acid addition salt or converting a pharmaceutically acceptable acid addition salt of a compound of formula I into another pharmaceutically acceptable acid addition salt.

The oxidation of a compound of formula II with a peracid according to process embodiment a) of the present "" ft n\s Xyf C c l ^ ' 20424? process is performed in a manner known per se. Suitable peracids for this oxidation step are peracids such as m-chloroperbenzoic acid, pertrifluoroacetic acid and the like. Depending on the reaction conditions used, one will 5 obtain either the corresponding compounds of formula I or the N-oxides thereof. For obtaining the compounds of formula I, the reaction is expeditiously performed in a C^ to carboxylic acid such as acetic acid, trifluoroacetic acid, propionic acid and the like or in a mixture of such a car-10 boxylic acid with a suitable inert solvent such as a chlorinated hydrocarbon, e.g., methylene chloride, an aromatic hydrocarbon, e.g., benzene, toluene, and the like, in the presence of a strong mineral acid such as sulfuric acid and the like. In case a corresponding N-oxide is desi-15 red, the reaction is conveniently performed in a suitable inert solvent such as a chlorinated hydrocarbon, e.g., methylene chloride, or an aromatic hydrocarbon, e.g., benzene, toluene and the like, in the absence of a strong mineral acid. The oxidation of a compound of formula II is 20 preferably performed at a temperature between about 0°C and about room temperature. It should be noted that a mixture of the 1-oxo and 3-oxo compounds will be obtained when in the starting material of formula II both and R^ are hydrogen. In case the oxidation is performed under strong 25 acidic conditions, the 3-oxo compound will predominate whereas the 1-oxo compound will be the predominant product when the reaction is performed in the absence of a strong mineral acid. The mixture obtained can be separated according to standard methods such as fractional crystallization 30 and chromatography. b) of the present process is also performed according to methods known per se. In this oxidation, lead (IV) carboxy-35 lates such as lead tetraacetate or lead (IV) trifluoroace-tate in an inert solvent such as chlorinated hydrocarbons such as methylene chloride or chloroform, and the like in' the presence of a strong acid such as trifluoroacetic acid The oxidation in accordance with process embodiment - .4 20424C and the like can suitably be used. The reaction is preferably performed in a temperature range of from about 0°C to about room temperature. In the case of a compound of formula II wherein and are hydrogen, a mixture of the 5 l-hydroxy-3-oxo, the 3-hydroxy-l-oxo and 1,3-dioxo compounds is obtained. The mixture thus obtained can be separated by standard chromatographic procedures. ment c) of the present process is performed according to known methods. Thus, the starting material can be reacted with lead tetraacetate in acetic acid, preferably at about room temperature. In case a compound of formula II wherein R^^ and R^ are hydrogen is used as starting material, a 15 mixture of the l-acetpxy-3-oxo and 3-acetoxy-l-oxo compounds and of a 1,3-bis-acetoxy compound of formula III will be obtained. The mixture obtained can be separated by standard chromatographic procedures.

The reaction of a compound of formula I wherein R-^ or R^ is hydroxy with a carboxylic acid anhydride in accordance with process embodiment d) of the present process is also performed in a manner known per se, preferably in the presence of a base such as pyridine, 4-dimethylaminopyridine, 25 N-methylpiperidine and the like. Inert solvents which can be used in this reaction are chlorinated hydrocarbons such as methylene chloride, ethers such as tetrahydrofuran, and the like. The reaction is conveniently performed at a temperature in the range of about 0°C to about room tempe-30 rature.

The etherification in accordance with process embodiment e) of the present process is performed in a manner known per se, expediently by reacting a compound of formu-35 la I wherein R^ or R^ is acyloxy, preferably acetoxy, or a compound of formula III, with an excess of a to alkanol containing a catalytic amount of a strong acid such as., 7 methane sulfonic acid and the like. This reaction ; Also, the reaction in accordance with process embodi- 20424 ferably performed at a temperature between about 0°C and about room temperature.

The desoxygenation in accordance with process embodi-5 ment f) of the present process is also performed according to known methods, conveniently by treating a compound of the formula IA with a desoxygenating agent such as phosphorous trichloride or triphenylphosphine in an inert solvent such as chlorinated hydrocarbons, e.g., methylene *10 chloride, aromatic hydrocarbons, e.g., toluene, ethers, e.g., tetrahydrofuran, and the like at a temperature between about room temperature and the reflux temperature of the solvent.

The starting materials of formula II are known or can be prepared in an analogous manner to the preparation of the known compounds. The following reaction schemes illustrate the preparation of these formula II compounds. 20424 Scheme I wherein Is hydrogen or lower alkyl and Rj. and Rc are as above. b 204242 III —^ IV The compound of formula III can be reacted with an a-tosyl alkylisocyanide in the presence of a base such as sodium hydride using a mixture of dimethylsulfoxide and 5 an ether, such as diethylether, dioxane or tetrahydrofuran as solvent. The reaction temperatures may range from about 0°C to about 40°C with about room temperature being preferred. The a-tosyl alkylisocyanides mentioned above may be prepared following the teaching of van Leusen et al. , 10 Tetrahedron Letters, 3487 (1975).

IV > Ila The compound of formula IV can be reacted with hydrogen at pressures ranging from about atmospheric pressure to 15 five atmospheres in the presence of a transition metal catalyst, such as Raney nickel using glacial acetic acid as solvent. The reaction temperature is suitably about room temperature.

The first formed ring open amine is not isolated but cyclizes spontaneously to product Ila.

IV > V The compound of formula IV can be reacted with a metal 25 hydride reducing agent, such as lithium aluminum hydride in an etherial solvent such as tetrahydrofuran. The reaction temperature may range from about -20°C to about room temperature, with about 0°C being preferred.

V > Ila The compound of formula V can be reacted with manganese dioxide in an ether solvent, such as tetrahydrofuran or another suitable solvent, such as toluene. The resulting amine thus formed cyclizes spontaneously to product Ila. 35 The reaction temperature may range from about room temperature to the boiling point of the solvent, with about 40°C being preferred. 204242 Scheme II Ila' Ha" lib wherein R.. and R_„ are lower alkyl and Rc and R 14 32 2 5 6 are as above. 20424 Ila' > Ila" + lib The compound of formula Ila' can be reacted with one equivalent of a strong base such as lithium diisopropyl-amide at between about -80°C to about 0°C, with about -20°C 5 being preferred. The resulting anion is treated with the desired alkylating agent, such as a lower alkyl halide or sulfonate. A mixture of formula Ila" and lib isomers results which can be separated by standard column chroamtography procedures. 204242 Scheme III wherein R" is lower alkyl, R^ is lower alkyl, Rg and Rg are hydrogen or lower alkyl and n is an integer from 1 to 6 and R]_l» **31/ R5 and R^ are as above. 2 042 Xjc vnh m A compound of the formula lie can be reacted with a halo ester such as ethyl bromoacetate or ethyl 3-bromopro-pionate in the presence of a base such as an alkali metal 5 alkoxide in a polar solvent such as dimethyl sulfoxide or dimethylformamide. The reaction temperature may range from about -20°C to about room temperature, with about 0°C being preferred. If desired, the product of formula Ilh thus obtained may be treated with an alkali metal carbonate or 10 hydroxide in an aqueous ethereal solvent, such as tetra-hydrofuran. Subsequent addition of a strong mineral acid thus yields the corresponding carboxylic acid of formula Ilj Ilh » Ilf -|5 A compound of the formula Ilh can be reacted with ammonia or a mono- or di-lower alkyl amine and a catalytic amount of its hydrochloride salt with a to C4 alcohol solvent. The reaction is usually conducted at about 100°C using a pressure apparatus to contain the volatile reactants Ilh » Hi A compound of the formula Ilh can be reacted with a metal hydride such as lithium aluminum hydride in an etheral solvent such as tetrahydrofuran or dioxane. The reaction 25 temperature may range from about -80°C to about room temperature, with about 0°C being preferred. lie * Ilq A compound of the formula lie can be reacted with a 30 compound of the formula wherein X is halide or sulfonate and Rg, Rg and n are as above in the presence of a base such as an alkali metal alkoxide X- ( CH VI 20424 in a polar solvent such as dimethylsulfoxide or dimethyl-formamide. The reaction temperature may range from about -20 °C to about room temperature with about room temperature being preferred. lie > lie A compound of the formula lie can be reacted with a base such as an alkali metal alkoxide, e.g., potassium or sodium methoxide, followed by an alkylating agent, such as 10 a lower alkyl halide or sulfonate in a polar aprotic solvent such as dimethylformamide or dimethyl sulfoxide. The reaction temperature may range from about 0°C to about room temperature, with about 0"C being preferred.

Ilf » Ilq or Ilh > Ili A compound of the formula Ilf or Ilh is reacted with a metal hydride reducing agent, such as lithium aluminum hydride in an ether solvent, such as tetrahydrofuran. The reaction temperature may range from about -20°C to about 20 room temperature, with about 0°C being preferred. lie ^ Ili A compound of formula lie can be reacted in the presence of a base such as an alkali metal alkoxide, and 25 dimethylformamide or dimethyl sulfoxide with a compound of the formula X- (CH2) n+ioz VI1 wherein Z is a hydroxy protecting group and X and n are as above.

Suitable hydroxy protecting groups include the tetra-hydropyranyl ether group. Subsequent treatment with aqueous 35 acid yields the desired end product. 2 042 4 lie » Ilf A compound of formula lie can be reacted with a compound of the formula Rg "*>N-C0-(CHo) -X VIII yr i n R9 wherein X is as above and Rg, Rg and n are as above 10 in the presence of a base such as an alkali metal alkoxide, and dimethylformamide or dimethylsulfoxide.

The compounds of the invention are useful as pharmaceuticals and are characterized by activity as sedatives 15 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, 20 for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gums, polyalkylene glycols, Vaseline or the like. They can be administered in conventional pharmaceutical forms, e.g., solid forms, for example, tablets, dragees, capsules, suppositories or the like, or 25 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 30 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.

A suitable pharmaceutical dosage unit can contain from about 0.1 to about 500 mg of the compounds of the invention with a dosage range of from about 0.1 mg to about 100 mg being preferred for oral administration and a dosage range 2042 4 of from about 0.1 mg to about 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 5 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.

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 calls culated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle.

The following data is indicative of the pharmacological 20 activities of the compounds of the invention utilizing pharmacological tests well-known in the art.

Rat brain cortical fragments are prepared and the binding procedures performed as described by Mohler and Okada (Life Sciences, 2_0, 2101, 1977) except that Tris 30 buffer is substituted for Krebs buffer. Drugs are assayed in triplicate. Radioactivity is measured by liquid scin-* filiation counting. The results are expressed as IC5g (nM), i.e. the concentrations required to inhibit the bindung by 5 0%.

Activity of Standard Drugs: IC5Q (nm) 3 H-Diazepam Binding Assay The Assay acts as a screen for antianxiety drugs.

Diazepam Flunitrazepam Flurazepam . 0 1.8 15.6 204242 Results obtained with compounds of the invention: ^C5Q ^n^ 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-5 methylpyrroloC 3,4-d][2]benzazepin-3(2h)-one [LD^q - 800 mg/kg (po)(mice)] 0-006 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one 10 Cld5q - greater than 1000 mg/kg (po)(mice)] 1.0 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo-[3,4-d][2 Jbenzazepin-3(2H)-one 0.25 molar hydrate micronized -15 [LD5q - greater than 1000 mg/kg (po)(mice)] 0.003 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo-[3,4-d][2]benzazepin-3(2H)-one [LD50 - 300 mg/kg (po)(mice)] 0.002 Intravenous Antimetrazol-Test The test evaluates anticonvulsant agents and is considered to be predictive of anxiolytic activites.

Male mice, 45-54 days old, housed in facilities for one week an food-deprived for about 24 hours, are used in this test. The test compound, dispersed in 5% acacia, is administered orally to mice, 3 animals being used per dose 30 level. One hour later, metrazol is administered intravenously at 70 mg/kg (convulsant dose 100 mg/kg) and the animals are observed 30 seconds for protection against convulsions. The number of animals protected from convulsions is determined. The dose at which 50% of the animals are protected 35 from convulsive seizures is expressed as the ED^q. The approximate ED^q is calculated by the method of Miller and Tainter (Proc. Soc. Exp. Biol. Med. 57:261, 1944).

C-9MAYW86 20424C Activity of Standard Drugs: ED^^ mg/kq po Chlordiazepoxide 3.9 Diazepam 1.0 Sodium Phenobarbital 19 Results obtained with compounds of the invention: ED^^ mg/kg po 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one 0.08 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-15 l-methylpyrrolo[3,4-d][2]benzazepin- 3(2H)-one 0.08 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo C 3,4-d][2]benzazepin-3(2H)-one 20 0.25 molar hydrate micronized 0.07 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo [ 3,4-d][2]benzazepin-3(2H)-one 0.03 The following examples are illustrative of the inven tion but are not meant to limit such invention. 2 042 4 Example 1 a) To a solution of 5.0 g of cupric sulfate in 3 liters of concentrated ammonium hydroxide solution were added 300 g (4.6 mol) of activated zinc dust and 100 g (0.42 mol) of 2-benzoyl-4-chlorobenzoic acid. The mixture was refluxed for 3 days, during which the volume was maintained by the addition of concentrated ammonium hydroxide solution. The mixture was cooled, and the excess zinc was removed by 10 filtration. The filtrate was acidified by the addition of concentrated hydrochloric acid to a pH of 3. The resulting precipitate was collected by filtration and dried to constant weight to give 2-benzyl-4-chlorobenzoic acid as a white solid, mp 142-144°C. b) To a solution of 28.4 g (0.75 mol) of lithium aluminum hydride in 800 ml of ether, which was cooled to 0°C, were addeddropwise 85.1 g (0.345 mmol) of 2-benzyl-4-chloro-benzoic acid in 250 ml of ether. The mixture was allowed to warm to room temperature and was stirred for 2 hours. The excess lithium aluminum hydride was discharged by the addition of 28.5 ml of water, 28.5 ml of 10% aqueous sodium hydroxide solution, and 85.5 ml of water. The precipitate was removed by filtration, and the filtrate was dried over 25 sodium sulfate. Removal of the ether at reduced pressure gave 2-benzyl-4-chlorobenzyl alcohol as a colorless oil which crystallized upon standing, mp 46.5-49°C. c) To a suspension of 238 g (1.1 mol) of pyridinium chloro-30 chromate and 300 ml of methylene chloride were added 79.3 g (0.34 mol) of 2-benzyl-4-chlorobenzyl alcohol. The mixture was stirred at room temperature for 2 hours. The chromium salts were precipitated by the addition of 2.4 liters of a 1:1 mixture of ether and petroleum ether, and the preci-35 pitate was removed by filtration through Celite. The solvent was removed at reduced pressure to give 2-benzyl-4-chloro-benzaldehyde as a yellow oil, which was used without further purification. 204242 d) To a suspension of 10.5 g (0.437 mol) of mineral oil free sodium hydride in 1.2 liters of tetrahydrofuran were added dropwise 58.4 g (0.328 mol) of diethylcyanomethyl phosphonate. After the hydrogen evolution had ceased (ca 60 min.), 69.4 g (0.3 mol) of 2-benzyl-4-chlorobenzaldehyde, in 75 ml of tetrahydrofuran, were added dropwise. The mixture was stirred overnight at room temperature. The tetra-hydrofuran solution was decanted and concentrated at room temperature. The residue was partitioned between 2 liters 10 of water and 1.5 liters of ether. The ether solution was separated, washed with water, and dried over sodium sulfate. The ether was removed at reduced pressure to give 3 — [2 — benzyl-4-chlorophenyl]-2-propenenitrile as a yellow oil which was used without further purification. e) A mixture of 28.8 g (0.14 mol) of 3-[2-benzyl-4-chloro-phenyl]—2-propenenitrile, 50 g (0.5 mol) of chromium trioxide, 100 ml of methylene chloride, and 300 ml of acetic acid was stirred at room temperature overnight. The excess chromium trioxide was discharged by the slow addition of 30 ml of ethanol. The mixture was diluted with 800 ml of water and extracted with 500 ml of ether. The ether solution was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The ether solution 25 was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give 3-(2-benzoyl-4-chlorophenyl)-2-propenenitrile as a yellow oil.

A sample of the product was purified by preparative 30 layer chromatography (silica gel, 2 mm; 1:1 mixture of methylene chloride and pentane) to give a white solid, mp 8 7-89 °C. 3-(2-Benzoyl-4-chlorophenyl)-2-propenenitrile was also 35 prepared as follows: f) A solution of 92.7 g (0.4 mol) of 2-amino-5-chloro-benzenephenone in 250 ml of acetonitrile was added to a 2 0424 mixture of 70 g (0.52 mol) of cupric chloride, 65 g (0.63 mole) of t-butylnitrite, 500 ml of acrylonitrile and 500 ml of acetonitrile. When the addition was complete, stirring at room temperature was continued for 2 hours. The mixture 5 was diluted with 80 ml of 6N hydrochloric acid and 1500 ml of water, extracted with ether and dried over anhydrous sodium sulfate. The ether solution was concentrated at reduced pressure to give a brown oil, which contained the end product, a,4-dichloro-2-(benzoyl)benzenepropanenitrile, 10 and 2,5-dichlorobenzophenone. Trituration of the oil with a mixture of ether and petroleum ether gave the. end product as a tan solid. Recrystallization of a small portion of the end product from a mixture of ether and petroleum ether gave pale yellow needles, mp 69-71°C. g) A mixture of 50.9 g (0.168 mol) of a., 4-dichloro-2-(benzoyl)benzenepropanenitrile, 17 g (0.14 mol) of potassium carbonate, 50.9 g (0.5 mol) of potassium bicarbonate and 510 ml of dimethyl sulfoxide was stirred at room tempera-20 ture for 48 hours. The mixture was diluted with 1.5 liters of water, and the resulting precipitate was collected by filtration. Recrystallization from a mixture of methylene chloride and ether gave 3-(2-benzoyl-4-chlorophenyl)-2-propenenitrile as off-white prisms, mp 89-91°C. * * * h) A mixture of 10.7 g (40 mmol) of 3-(2-benzoyl-4-chloro- phenyl)-2-propenenitrile, 5.3 g (38 mmol) of tosylmethyl isocyanide, 75 ml of dimethyl sulfoxide and 150 ml of ether were added dropwise to a suspension of 3.7 g (77 mmol) of 30 50% sodium hydride in mineral oil and 170 ml of ether. When the addition was complete, stirring was continued for 2 hours. The mixture was diluted with water, and the ether layer was separated. The aqueous solution was extracted with ether. The combined ether extracts were washed with 35 water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a dark green oil. Purification by column chromatography (800 g silica gel; eluent, 5% ether in methylene chloride) gave 4-C2-benzoyl-4-chloro- 2042 phenyl]-lH-pyrrole-3-carbonitrile as off-white prisms, mp 175-177°C. i) A mixture of 4.0 g (13 mmol) of 4-[2-benzoyl-4-chloro-5 phenyl]-lH-pyrrole-3-carbonitrile, 4 g of Raney nickel, and 300 ml of acetic acid were hydrogenated on a Parr apparatus for 4 hours. The Raney nickel was removed by filtration and the filtrate was diluted with 400 ml of ice water. The acetic acid was neutralized with sodium bicarbonate, and 10 the resulting solution extracted with methylene chloride. The methylene chloride solution was washed with water and dried over sodium sulfate. Concentration of the methylene chloride solution gave a yellow solid. Recrystallization from methylene chloride/ether gave 8-chloro-6-phenyl-2H,4H-15 pyrrolo[3,4-d][2]benzazepine as white solid, mp 203-206°C. j) In one portion, 4.0 g (13.6 mmol) of 8-chloro-6-phenyl 2H,4H-pyrrolo[3,4-d][2]benzazepine were added to a mixture of 3.4 g (15.7 mmol) of m-chloroperbenzoic acid in 100 ml 20 of 2% concentrated sulfuric acid in acetic acid and the resulting mixture was stirred for 1 hour. The excess per-acid was discharged by the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between 25 methylene chloride and water and neutralized with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a dark residue. Purification of the residue by column chromato-30 graphy (silica gel, 100 g; eluent 5% methanol in methylene chloride) gave after crystallization from ethyl acetate 8-chloro-l,4-dihydro-6-phenylpyrrolo[3,4-d][2]benzazepin-3(2H)-one as pale yellow prisms, mp 205-208°C.

Thin layer chromatography of the crystallization fil trates indicated the presence of the isomeric 8-chloro-3,4-dihydro-6-phenylpyrrolo[3,4-d][2]benzazepin-l(2H)-one. ^0424 Example 2 a) The preparation of a,4-dichloro-2-(2-fluorobenzoyl)-benzenepropanenitrile was conducted in the same manner as the preparation of a,4-dichloro-2-(benzoyl)benzenepropane-nitrile described in Example If) to give pale yellow prisms, mp 94-95 °C. b) The preparation of 3-C2-(2-fluorobenzoyl)-4-chloro-10 phenyl]-2-propenenitrile was conducted in the same manner as the preparation of 3-(2-benzoyl-4-chlorophenyl)-2-pro-penenitrile described in Example lg) to give off-white prisms, mp 137-139°C. 3 — C 2 —(2-Fluorobenzoyl)-4-chloropheny1]-2-propenenitrile was also prepared as follows: c) A solution of 5.0 g (14 mmol) of 5-chloro-2'-fluoro-2-iodobenzophenone, 2 ml (14.3 mmol) of triethylamine, 2 ml (30 mmol) of acrylonitrile and 35 mg (1.5 mmol) of palladium acetate was refluxed under an atmosphere of argon for 16 hours. The mixture was diluted with 100 ml of IN hydrochloric acid and the resulting precipitate was collected by filtration. The precipitate was washed with ether and 25 air dried to give 3-E2-(2-fluorobenzoyl)-4-chlorophenyl]- 2-propenenitrile as an off-white solid,mp 130-133°C. * * * d) The preparation of 4-C2-(2-fluorobenzoyl)-4-chlorophenyl ]-lH-pyrrole-3-carbonitrile was conducted in the same manner as the preparation of 4-C2-benzoyl-4-chlorophenyl]-lH-pyrrole-3-carbonitrile described in Example lh) to give off-white prisms, mp 177-179°C. e) A mixture of 3.0 g (9 mmol) of 4-C2-(2-fluorobenzoyl)-35 4-chlorophenyl]-lH-pyrrole-3-carbonitrile, ca 3 g of Raney nickel and 150 ml of glacial acetic acid was hydrogenated on a Parr aparatus at 50 psi for 6 hours. The Raney nickel was removed by filtration, and the acetic acid was removed 20424 at reduced pressure to give a yellow oil. The yellow oil was poured on to ice, basified with ammonium hydroxide solution and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium 5 sulfate and concentrated at reduced pressure to give tan crystals. Recrystallization from a mixture of ether and methylene chloride gave 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrroloC3,4-d][2]benzazepine as cream-colored prisms, mp 197-199°C. f) In one portion, 5.0 ml (42.1 mmol) of 30% hydrogen peroxide solution was added to 100 ml of a 1% solution of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 5.0 g (16.0 mmol) of 8-chloro-6-(2-fluoro-^5. phenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the resulting mixture was stirred for 4 hours. The excess peracid was discharged by the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between 20 methylene chloride and water and basified with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give 5.0 g of a residue. Purification by HPLC (silica gel; eluent, 3% 25 methanol in methylene chloride) gave in the first product band after crystallization from ethyl acetate 8-chloro-6-(2-fluorophenyl) -3, 4-dihydropyrrolo [3, 4-d] [2 ]benzazepin-l(2H) -one as pale yellow prisms, mp 223-225°C.

Further elution gave in the second product band after crystalli zation from ethyl acetate 8-chloro-6-(2-fluorophenyl)-1,4-dihydropyrro-lo[3,4-d][2]benzazepin-3(2H)-one as colorless prisms, mp 217-218°C.

Example 3 a) The preparation of a,4-dichloro-2-(2-chlorobenzoyl)-benzenepropanenitrile was conducted in the same manner as the preparation of a,4-dichloro-2-(benzoyl)benzenepropane- 204242 nitrile described in Example If) to give off-white prisms, mp 102-103°C. b) The preparation of 3-[2-(2-chlorobenzoyl)-4-chloro- phenyl]-2-propenenitrile was conducted in the same manner as the preparation of 3-(2-benzoyl-4-chlorophenyl)-2-pro-penenitrile described in Example lg) to give off-white prisms, mp 140-141°C. c) The preparation of 4-[2-(2-chlorobenzoyl)-4-chlorophenyl ]-lH-pyrrole-3-carbonitrile was conducted in the same manner as the preparation of 4-[2-benzoyl-4-chlorophenyl]-lH-pyrrole-3-carbonitrile described in Example lh) to give off-white prisms, mp 182-184°C. d) The preparation of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was conducted in the same manner as the preparation of 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine described in Example 2e) to give cream-colored prisms, mp 204-206°C. e) In one portion, 10.0 g (30.5 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine were added to a mixture of 7.6 g (35.2 mmol) of 80% m-chloroperbenzoic acid in 225 ml of 2% concentrated sulfuric acid in acetic acid and stirred at room temperature for 1 hour. The excess peracid was discharged with saturated aqueous sodium bisulfite solution, and the mixture was concerrtrated at reduced pressure. The residue was partitioned between methylene chloride and water and basified with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give 10.0 g of a yellow residue. Crystallization from methylene chloride gave 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-d][2]-benzazepin-3(2H)-one as pale yellow prisms, mp 243-244°C. Crystallization of the mother liquor from ethyl acetate gave 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d][2]- 20424 benzazepin-l(2H)-one as pale yellow prisms, mp 195-197°C.

Example 4 In one portion, 9.8 ml of 30% hydrogen peroxide solu tion were added to 195 ml of a 1% solution of concentrated sulfuric acid in acetic acid. The mixture was stirred at room temperature for 1 hour. In one portion, 9.8 g (30 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d]-10 [2]benzazepine were added to the mixture and stirred at room temperature for 2.5 hours. The excess peracid was discharged by the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between 15 methylene chloride and water and basified with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give 10.0 g of a yellow residue. Purification of the residue by column 20 chromatography (silica gel, 200 g; eluent, 5% methanol in methylene chloride) gave in the first product band after crystallization from ethyl acetate 8-chloro-6-(2-chloro-phenyl)-3,4-dihydropyrrolo[3,4-d][2]benzazepin-l(2H)-one as pale yellow prisms, mp 195-197°C. Further elution gave in 25 the second product band after crystallization from methylene chloride 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-pyrrolo[3,4-d][2]benzazepin-3(2H)-one as colorless prisms, mp 243-244°C.

Example 5 In one portion, 15.0 g (69.5 mmol) of 80% m-chloro-perbenzoic acid were added to a solution of 10.0 g (30.5 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d]-35 [2]benzazepine in 350 ml of methylene chloride which was cooled to 0°C. The reaction mixture was stirred at 0°C for 2.5 hours and then neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloride solution 20424 was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to yield 11.0 g of a yellow residue. Purification of the residue by column chroma tography (silica gel, 150 g; 5% methanol in methylene chlo-5 ride) gave a mixture of two products. Further purification of the mixture by chromatography (alumina, 15 0 g; eluent, 5% methanol in methylene chloride) gave in the first product .band after crystallization from a mixture of ethyl acetate and methanol 8-chloro-6-(2-chlorophenyl)-3,4-10 dihydropyrrolo[3,4-d][2]benzazepin-l(2H)-one-5-oxide as pale yellow prisms, mp 243-244°C.

Further elution gave in the second product band after crystallization from a mixture of ethyl acetate and metha-15 nol 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrroloC3,4-d]-[2]benzazepin-3(2H)-one-5-oxide as pale yellow prisms solvated with 0.5 mole of methanol, mp 234-236°C.

Example 6 a) A mixture of 33.9 g (0.11 mol) of 3-[2-(2-chloro-benzoyl)-4-chlorophenyl]-2-propenenitrile, 20 g (0.96 mol) of 1-tosylethyl isocyanide in 150 ml of dimethylsulfoxide and 100 ml of ether was added dropwise to a suspension of 25 4.6 g (0.1 mol) of a 50% mineral oil dispension of sodium hydride in 100 ml of ether which was immersed in a room temperature water bath. Stirring at room temperature was continued for 2 hours. The mixture was diluted with 1.2 liters of water and 40 ml of IN hydrochloric acid and 30 extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a dark green oil. Crystallization from a mixture of ether and petroleum ether gave 4-[4-chloro-2-(2-chlorobenzoyl)phenyl]-35 5-methyl-lH-pyrrole-3-carbonitrile, mp 206-208°C, as tan crystals. Recrystallization from ether gave the desired product as colorless crystals, mp 210-2ll°C. 2 042 42 A second crop of crystals consisting of 6-chloro-8-(2-chlorophenyl)-1,8-dihydro-8-hydroxy-2-methylindeno-[2,l-b]pyrrole-3-carbonitrile, mp 221-225°C, was obtained from ether. Recrystallization from ether gave pale yellow 5 prisms, melting at 232-237°C. b) A mixture of.8.5 g (24 mmol) of 4-C4-chloro-2-(2-chlorobenzoyl)phenyl]-5-methyl-lH-pyrrole-3-carbonitrile, 1 spoonful of Raney nickel and 250 ml of glacial acetic "10 acid was hydrogenated on a Parr apparatus at 55 psi overnight. The catalyst was removed by filtration, and the acetic acid was removed at reduced pressure. The residue was diluted with water, basified with concentrated ammonium hydroxide solution, and the resulting precipitate was collec-15 ted by filtration. The precipitate was dissolved in tetra-hydrofuran, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was crystallized from a mixture of ether and petroleum ether to give off-white crystals, mp 219-222°C. Recrystallization from a 20 mixture of ether and methylene chloride gave 8-chloro-6- (2-chlorophenyl)-1-methyl-2H,4H-pyrroloC 3,4-d]C 2]benzazepine as colorless crystals, mp 221-225°C. c) In one portion, 1 ml of 30% hydrogen peroxide was 25 added to 40 ml of a 1% solution of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 2.0 g (5.8 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrroloC3,4-d]C2]benzazepine were added, and the resulting mixture was stirred at room temperature for 30 minutes. The 30 mixture was diluted with methylene chloride and neutralized with concentrated ammonium hydroxide solution. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to a dark residue. Crystallization from ethyl acetate gave 8-chloro-35 6-( 2-chlorophenyl)-1,4-dihydro-l-methylpyrroloC3,4-d]C 2]-benzazepin-3(2H)-one as pale yellow prisms, mp 239-241°C. 2 0424 Example 7 a) In one portion, 0.7 g (2.2 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.3 g (2.6 mmol) of potassium t-butoxide in 30 ml of dry dimethylformamide which was cooled to 0°C, After stirring for 15 minutes, 1.0 ml (16 mmol) of methyl iodide was added, and the mixture was allowed to warm to room temperature. Water was added, and the mixture was 10 extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a yellow oil. Purification by column chromatography (silica gel, 20 g; eluent, 5% ether in methylene chloride) and 15 recrystallization from a mixture of ether and petroleum ether gave 8-chloro-6-(2-chlorophenyl)-2-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine as colorless prisms, mp 167-168 ° C. ■20 The methanesulfonate salt of 8-chloro-6-(2-chloro- phenyl)-2-methyl-2H,4H-pyrrolo[3,4-d][2Ibenzazepine was prepared by adding equimolar amounts of the base compound and methanesulfonic acid to methanol and isolated by precipitating the salt with the addition of ether. Re-25 crystallization from a mixture of methanol and ether gave the methanesulfonate salt as orange prisms, mp 200-203°C. b) In one portion, 1.4 ml of 30% hydrogen peroxide were added to 56 ml of a 1% solution of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 2.8 g (8.2 mmole) of 8-chloro-6-(2-chlorophenyl)-2-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated at reduced pressure and the residue 35 was partitioned between methylene chloride and water. The methylene chloride solution was neutralized with concentrated ammonium hydroxide solution, washed with brine, dried over anhydrous sodium sulfate and concentrated at reduced 204242 pressure to a yellow residue. Purification of the residue by column chromatography (silica gel, 100 g; eluent, 5% methanol in methylene chloride) gave in the first product band after crystallization from ether 8-chloro-6-(2-chloro-5 phenyl)-3,4-dihydro-2-methylpyrrolo[3,4-d][2Ibenzazepin-l(2H)-one as yellow prisms, mp 177-178°C.

Further elution gave in the second product band after crystallization from ether 8-chloro-6-(2-chlorophenyl)-1,4-10 dihydro-2-methylpyrrolo[3,4-d]C2]benzazepin-3(2H)-one as pale yellow prisms, mp 173-175°C.

Example 8 a) A solution of 30.0 g (99.3 mmol) of 3-C2-(2-chloro-benzoyl)-4-chlorophenyl]-2-propenenitrile and 23.0 g (103 mmol) of 1-tosylpropyl isocyanide in a mixture of 200 ml of ether and 200 ml of dimethyl sulfoxide was added drop-wise over a 20 minute period to an ice-cooled suspension of 20 6.7 g (140 mmol) of a 50% mineral oil dispersion of sodium hydride in 145 ml of ether. After stirring for 1.5 hours, 500 ml >of water were added dropwise, followed by 50 ml of IN aqueous hydrochloric acid. The aqueous solution was extracted with 3 x 500 ml of ether. The ether solutions were 25 combined and washed with 6 x 800 ml of water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give 35.0 g of dark residue. Purification by column chromatography (silica gel, 500 g; eluent, 50% ether in petroleum ether) gave in the first product band 30 after crystallization from a mixture of ether and methylene chloride 4-C4-chloro-2-(2-chlorophenyl)phenyl]-5-ethyl-lH-pyrrole-3-carbonitrile as off-white prisms, mp 163-164°C.

Further elution gave in the second product band after 35 crystallization from ether 6-chloro-8-(2-chlorophenyl)-2-ethy1-1,8-dihydro-8-hydroxyindeno C 2,l-b]pyrrole-3-carbo-nitrile a's colorless prisms, mp 172-174°C. 204242 b) A mixture of 3.3 g (8.9 mmol) of 4-[2-(2-chlorobenzoyl ) -4-chlorophenyl]-5-ethyl-lH-pyrrole-3-carbonitrile, 0.5 teaspoon of Raney nickel, and 100 ml of acetic acid was hydrogenated on a Parr apparatus at 50 psi for 16 hours. 5 The Raney nickel was removed by filtration through a pad of Celite, and the filtrate was concentrated at reduced pressure to a dark residue. The residue was partitioned between ice water and ether and basified with concentrated ammonium hydroxide solution. The ether was removed at 10 reduced pressure, and the aqueous residue was stirred for 1 hour. The resulting precipitate was collected by filtration and dissolved in tetrahydrofuran. The tetrahydrofuran solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to a residue which crystalli-15 zed from ether to give 8-chloro-6-(2-chlorophenyl)-1-ethyl-2H,4H-pyrrolo[3,4-d][2]benzazepine as yellow prisms, mp 251-253°C. Recrystallization from a mixture of ether and methylene chloride gave off-white prisms, mp 254-255°C. c) In one portion, 0.9 ml (7.9 mmol) of 30% hydrogen peroxide was added to 40 ml of a 1% solution of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 2.0 g (5.6 mmol) of 8-chloro-6-(2-chlorophenyl)-1-ethyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the 25 resulting mixture was stirred for 20 minutes. The excess peracid was discharged by the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between methylene chloride and water and neutralized with concen-30 trated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure. The resulting oil was crystallized from ether to give 8-chloro-6-(2-chlorophenyl)-1-ethyl-1,4-dihydropyrrolo[3,4-d][2]benza-35 zepin-3(2H)-one as yellow prisms, mp 233-235°C. Recrystallization from a mixture of ethyl acetate and methanol gave colorless prisms, mp 236-237°C. 2042 4 Example 9 a) In one portion, 2.0 g (5.8 mmol) of 8-chloro-6-(2-chlorophenyl)-l-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to an ice-cooled solution of 0.8 g (7.1 mmol) of potassium t-butoxide in 20 ml of dry dimethylformamide. After stirring at 0°C for 10 minutes, 0.8 ml (12.8 mmol) of methyl iodide was added and the resulting solution was stirred for 20 minutes. The mixture was diluted with water, 10 and the resulting precipitate was collected by filtration. The solid was dissolved in methylene chloride, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give 8-chloro-6-(2-chlorophenyl)-1,2-dimethyl-2H,4H-pyrrolo[3,4-d][2jbenzazepine as orange prisms, mp 15 200-202°C. A sample was recrystallized from a mixture of ether and methylene chloride to give pale yellow prisms, mp 203-204 °C. b) In one portion, 0.7 ml (5.9 mmol) of a 30% hydrogen 20 peroxide solution was added to 33 ml of a 1% solution of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 1.8 g (5.0 mmol) of 8-chloro-6-(2-chlorophenyl)-1,2-dimethyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the resulting solution was stirred for 20 minutes. The 25 excess peracid was discharged by the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between methylene chloride and water and basififed with concentrated ammonium hydroxide solution. The methylene 30 chloride solution was washed with brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a yellow residue. Crystallization from ethyl acetate gave 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l,2-dimethylpyrrolo-[3,4-d][2]benzazepin-3(2H)-one as pale yellow prisms, 35 mp 207-208 °C. £-04232 Example 10 a) In one portion, 2.0 g (5.8 mmol) of 8-chloro-6-(2-chlorophenyl)-l-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine 5 were added to an ice-cooled solution of 0.8 g (7.1 mmol) of potassium t-butoxide in 30 ml of dry dimethylformamide. After stirring at 0°C for 15 minutes, 0.65 ml (7.7 mmol) of methyl bromoacetate was added, and the resulting solution was stirred for 5 minutes. ,;,The mixture was diluted 10 with water and extracted with ether. The ether solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to an oily residue. Purification of the residue by column chromatography (silica gel, 40 g; eluent, 5% ether in methylene chloride) 15 gave after crystallization from a mixture of ether and petroleum ether 8-chl.oro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolot3,4-d][2]benzazepine-2-acetic acid methyl ester as off-white prisms, mp 174-176°C. b) In one portion, 0.8 ml (7.0 mmol) of a 30% hydrogen peroxide solution was added to a solution of 35 ml of 1% concentrated sulfuric acid in acetic acid. After stirring the solution for 1 hour, 2.0 g (4.8 mmol) of 8-chloro-6-(2-chlorophenyl) - 2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic 25 acid methyl ester were added, and the resulting solution was stirred for 30 minutes. The excess peracid was discharged with the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between methy-30 lene chloride and water and neutralized with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to a residue which crystallized in ethyl acetate to give 8-chloro-6-(2-§5§^hlorophenyl ) —1,2,3,4- tetrahydro-l-methyl-3-oxo-pyrrolo[3,4-d]-rfijt 2]benzazepine-2-acetic acid methyl ester as pale yellow ^ prisms, mp 221-223°C. Recrystallization from ethyl acetate # .gave colorless prisms, mp 223-224°C. \ ' Example 11 a) In one portion, 4.0 g (11.7 mmol) of 8-chloro-6-(2-chlorophenyl)-l-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine 5 were added to an ice-cooled solution of 1.6 g (14.2 mmol) of potassium t-butoxide in 60 ml of dry dimethylformamide. After stirring at 0°C for 15 minutes, 1.4 g (15.0 mmol) of 2-chloroacetamide were added, and the resulting solution was stirred for 5 minutes. The mixture was diluted with 10 water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a red residue. Purification of the residue by column chromatography (silica gel, 100 g; eluent, 50% ether in 15 tetrahydrofuran) gave 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetamide as a yellow solid. Recrystallization from ethyl acetate gave colorless needles, mp 142-145°C. b) In one portion, 0.7 ml (6.2 mmol) of 30% hydrogen peroxide was added to a 1% solution of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 1.7 g (4.2 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H- . pyrrolo[3,4-d][2]benzazepine-2-acetamide were added, and the 25 resulting solution was stirred for 30 minutes. The excess peracid was discharged by the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between methylene chloride and water and neutralized with concen-30 trated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure. The residue was crystallized from ethyl acetate to give 8-chloro-6-(2-chlorophenyl )-l,2,3,4-tetrahydro-l-methyl-3-oxo-pyrrolo[3,.4-d]- 204242 Example 12 a) A solution of 4.0 g (9.6 mmol) of 8-chloro-6-(2-chlorophenyl )-l-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic 5 acid methyl ester in 40 ml of tetrahydrofuran was added dropwise to a solution of 0.8 g (21.0 mmol) of lithium aluminum hydride in 50 ml of tetrahydrofuran which was cooled to -78°C. When the addition was complete, the reaction mixture was allowed to warm to 0°C and stirred for 30 minutes. 10 The mixture was treated with 1 ml of water, 1 ml of a 3N solution of aqueous sodium hydroxide and 3 ml of water. The resulting precipitate was removed by filtration, and the filtrate was concentrated at reduced pressure. The residue crystallized from ether to yield 8-chloro-6-(2-chloro-15 phenyl)-l-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepin-2-ethanol as pale yellow prisms, mp 149-152°C. Recrystallization from a mixture of ether and methylene chloride gave white prisms, mp 151-153°C. b) In one portion, 0.58 ml (5.1 mmol) of 30% hydrogen peroxide was added to a 1% solution of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 1.3 g (3.3 mmol) of 8-chloro-6-(2-chlorophenyl)-l-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepin-2-ethanol were added, and the 25 resulting solution was stirred for 30 minutes. The excess peracid was discharged with the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between methylene chloride and water and neutrali-30 zed with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to a yellow residue. Purification by column chromatography (silica gel, 30 g; eluent, 3% methanol in methylene 35 chloride) gave in the first product band after crystallization from a mixture of ether and methylene chloride 2 — [2 — (acetoxy)ethyl]-8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one as colorless 20424 prisms, mp 152-154°C.

Further elution gave in the second product band after crystallization from a mixture of ethyl acetate and ether 5 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-(2-hydroxyethyl)-1-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one as colorless prisms, mp 164-165°C.

Example 13 In one portion, 0.7 g (2 mmol) of 8-chloro-6-(2-chloro-phenyl)-3,4-dihydropyrrolo[3,4-d][2]benzazepin-l(2H)-one was added to an ice-cooled solution of 2.6 g (15.8 mmol) of trichloroacetic acid and 2.0 g (4.4 mmol) of lead tetra-■|5 acetate in 30 ml of methylene chloride. After stirring for 1 hour, the mixture was neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a yellow residue. 20 Purification of the residue by column chromatography (silica gel, 10 g; eluent, 5% methanol in methylene chloride) followed by crystallization from ether gave 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-3-hydroxypyrrolo[3,4-d][2]benza-zepin-1(2H)-one as pale yellow prisms, mp 221-222°C.

Example 14 In one portion, 0.35 g (1 mmol) of 8-chloro-6-(2-chloro-phenyl)-1,4-dihydropyrrolo[3,4-d][2]benzazepin-3(2H)-one 30 was added to an ice-cooled solution of 1.3 g (7.9 mmol) of trichloroacetic acid and 1.0 g (2.2 mmol) of lead tetraacetate in 15 ml of methylene chloride. After stirring for 4 hours, the mixture was neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloride solu-35 tion was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a yellow residue. Purification of the residue by column chromatography (silica gel, 10 g; eluent, 5% methanol in methylene 20424 chloride) followed by crystallization from ether gave 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-hydroxypyrrolots , 4-d] [ 2 ]benzazepin-3 ( 2H) -one as pale yellow prisms, mp 247-249°C.

Example 15 In one portion, 5.0 g (15.2 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine were added 10 to a cooled solution of 20.0 g (120 mmol) of trichloroacetic acid and 14.0 g (31.6 mmol) of lead tetraacetate in 50 ml of methylene chloride. The mixture was stirred at room temperature for 4 hours and then diluted with methylene chloride and water. The methylene chloride solution 15 was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a green residue. Purification of the residue by column chromatography (silica gel, 100 g; eluent, 5% methanol in methylene chloride) gave in the first pro-20 duct band after crystallization from ether 8-chloro-6-(2-chlorophenyl)pyrrolo[3,4-d][2]benzazepin-l,3(2H,4H)-dione as yellow prisms, mp 224-225°C.

Further elution gave in the second product band after 25 crystallization from ether 8-chloro-6-(2-chlorophenyl)- 3,4-dihydro-3-hydroxypyrrolo[3,4-d]C 2]benzazepin-l(2H)-one as pale yellow prisms, mp 222-223°C.

Still further elution gave in the third product band 30 after crystallization from ether 8-chloro-6-(2-chloro-phenyl)-1,4-dihydro-l-hydroxypyrrolo[3,4-d][2]benzazepin-3(2H)-one as pale yellow prisms, mp 247-249°C.

Example 16 Portionwise, 12.0 g (27 mmol) of lead tetraacetate were added over 2 hours to a solution of 6.0 g (12.2 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benza- 204252 zepine in 120 ml of acetic acid. After stirring for an additional 2 hours, hydrogen sulfide gas was bubbled into the solution. The resulting precipitate was removed by filtration over Celite. The filtrate was neutralized by 5 the addition of saturated aqueous sodium carbonate solution and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a brown oil. Purification by column chromatography (silica 10 gel, 100 g; eluent, 100% methylene chloride to 20% ether in methylene chloride gradient) gave in the first product band an off-white solid. Recrystallization from a mixture of methylene chloride, ether, and petroleum ether gave 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d]benzazepine-l,3-15 diol diacetate as colorless needles, mp 189-190°C.

Further elution gave 1.95 g of a foam which crystallized from a mixture of ether and petroleum ether to give 8-chloro-6-(2-chlorophenyl)-3-acetoxy-3,4-dihydropyrrolo-20 C3,4-d][2]benzazepin-l(2H)-one as colorless prisms, mp 172-174 °C.

Continued elution gave fine needles. Recrystallization from a mixture of ether and methylene chloride gave 8-25 chloro-6-(2-chlorophenyl)-l-acetoxy-l,4-dihydropyrrolo-[3,4-d][2]benzazepin-3(2H)-one, mp 219-221°C.

Example 17 A solution of 0.3 g (0.9 mmol) of 8-chloro-6-(2- chlorophenyl)-3-hydroxy-3,4-dihydropyrrolo[3,4-d][2]benza-zepin-1(2H)-one, 0.3 g (1.3 mmol) of benzoic acid anhydride, and 0.3 g (2.5 mmol) of 4-dimethylaminopyridine in a mixture of 30 ml of methylene chloride and 10 ml of tetrahydrofuran , . v~-35 was stirred at 0°C for 1 hour. The mixture was diluted with oT" ' • '• water, washed successively with cold, dilute hydrochloric ^acid, saturated aqueous sodium bicarbonate solution, and brine and dried over anhydrous sodium sulfate. The methy- 2 04242 lene chloride solution was concentrated at reduced pressure The residue was purified by column chromatography (silica gel, 10 g; eluent, 5% ether in methylene chloride) to give 8-chloro-6-(2-chlorophenyl)-3-(benzoyloxy)-3,4-dihydro-pyrroloC3,4-d][2]benzazepin-l(2H)-one as colorless crystals Recrystallization from ether gave colorless crystals, mp 140-142°C.

Example 18 A solution of 0.6 g of 8-chloro-6-(2-chlorophenyl)-3-acetoxy-3,4-dihydropyrrolo[3,4-d][2]benzazepin-l(2H)-one and 3 ml of a lM methanolic solution of methanesulfonic acid in 10 ml of methanol was stirred at room temperature 15 for 30 minutes. The solution was concentrated at reduced pressure to half the volume, diluted with ether, and the resulting precipitate was collected by filtration to give orange crystals. Recrystallization from a mixture of methanol and ether gave 8-chloro-6-(2-chlorophenyl)-3,4-20 dihydro-3-methoxypyrrolo[3,4-d][2]benzazepin-l(2H)-one methanesulfonate as off-white prisms, mp. 157-160°C.

Example 19 A solution of 0.1 g (0.25 mmol) of 8-chloro-6-(2- chlorophenyl)-1-acetoxy-1,4-dihydropyrrolo[3,4-d][2]benza-zepin-3(2H)-one and 1 ml of a lM methanolic solution of methanesulfonic acid was allowed to stand at room temperature for 36 hours. The mixture was diluted with ether, 30 and the resulting precipitate was collected by filtration to give 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l-methoxy-pyrrolot 3,4-d][2]benzazepin-3(2H)-one methanesulfonate. Recrystallization from a mixture of ether and methanol gave fine needles, mp 185-187°C. 2,04242 Example 2 0 A solution of 1.5 g (3.4 mmol) of 8-chloro-6~- (2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepin-l,3-diol 5 diacetate in 25 ml of a lM methanol solution of methane-sulfonic acid was refluxed for 6 h. The reaction was cooled, made basic by the addition of saturated aqueous sodium bicarbonate and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous 10 sodium sulfate and concentrated at reduced pressure. The residue was dissolved in 4 ml of a lM methanol solution of methanesulfonic acid, diluted with ether until turbid and filtered. The filtrate was made basic with saturated aqueous sodium bicarbonate.- The ether solution was dried 15 over anhydrous sodium sulfate and concentrated at reduced pressure to give 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-3-methoxypyrrolo[3,4-d][2]benzazepin-l(2H)-one as off white crystals, mp 192-194°C. The presence of the isomeric 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l-methoxypyrrolo-20 [3,4-d][2]benzazepin-3(2H)-one was noted by the thin layer chromatography but was not isolated.

The methanesulfonate salt of 8-chloro-6-(2-chlorophenyl )-1,4-dihydro-3-methoxypyrrolo[3,4-d][2]benzazepin-25 l(2H)-one was prepared by dissolving the free base in an excess of methanolic methanesulfonic acid and isolated by precipitating the salt with the addition of ether. Recrystallization from a mixture of methanol and ether gave the salt as colorless crystals, mp 157-160°C.

In one portion, 1.8 ml (20 mmol) of phosphorus trichloride were added to a solution of 0.9 g (2.5 mmol) of 35 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-d][2]- benzazepin-3(2H)-one-5-oxide in 180 ml of methylene chloride. The mixture was refluxed for 1 hour and then concentrated at reduced pressure. The residue was dissolved in methylene Example 21 \ 204242 chloride and neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give 8-chloro-6-(2-chlorophenyl)-1,4-5 dihydropyrrolo[3,4-d][2]benzazepin-3(2H)-one as an orange solid. Recrystallization from ethyl acetate gave pale yellow prisms of a 0.25 mole hydrate, mp 255-256°C.

Example 22 In one portion, 2 ml (2.3 mmol) of phosphorus trichloride were added to a solution of 1.0 g (2.7 mmol) of 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d][2]-benzazepine-1(2H)-one-5-oxide in 200 ml of methylene chlo-15 ride and refluxed for 1 hour. The mixture was concentrated at reduced pressure. The residue was dissolved in methylene chloride and neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at 20 reduced pressure to give a dark red residue. Purification of the residue by column chromatography (silica gel, 20 g; eluent, 5% methanol in methylene chloride) followed by crystallization from ethyl acetate gave 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d][2]benzazepin-l(2H)-25 one as pale yellow prisms solvated with 0.5 mole ethyl acetate, mp 195-197°C. 2042 4 Example A Tablet Formulation (Direct compression) Item Ingredients mg/tablet 1. 8-chloro-6-(2-chlorophenyl)- 1, 4-dihydropyr.roloC 3 , 4-d]- [2]benzazepin-3(2H)-one 1 5 10 25 or 8-chloro-6-(2-chlorophenyl)- 1,4-dihydro-l-methylpyrrolo-[3,4-d][2]benzazepin-3(2H)-one 2.

Lactose 221 217 212 181 3.

Avicel 45 45 45 55 4.

Direct Compression Starch .

Magnesium Stearate 3 3 3 4 Weight of tablet 300 300 300 300 Procedure: 1.

Mix Item 1 with an equal amount of lactose.

Mix well 2. Mix with Items 3 and 4 and the remaining amount of Item 2. Mix well. 3. Add magnesium stearate and mix for 3 minutes. 4. Compress on a suitable press equipped with appropriate punches. 2 0424 Example B Tablet Formulation (Wet granulation) Item Ingredients mg/tablet 1. 8-chloro-6-(2-chlorophenyl)- 1,4-dihydropyrrolo[3,4-d]- [2]benzazepin-3(2H)-one 1 5 10 25 or 8-chloro-6-(2-chlorophenyl)- 1,4-dihydro-l-methylpyrrolo-[3,4-d][2]benzazepin-3(2H)-one 2.

Lactose 202 232 261 280 3.

Modified Starch 45 55 4.

Pregelatinized Starch .

Distilled Water q.s. - - - - 6.

Magnesium Stearate 2 3 4 Weight of tablet 250 300 350 400 Procedure: 1. Mix Items 1-4 in a suitable mixer. 2. Granulate with sufficient distilled water to proper 25 consistency. Mill. 3. Dry in a suitable oven. 4. Mill and mix with magnesium stearate for 3 minutes.

. Compress on a suitable press equipped with appropriate punches. 204242 Example C Capsule Formulation I tern Ingredients mg/capsule 1. 8-chloro-6-(2-chlorophenyl)- 1,4-dihydropyrrolo[3,4-d]- [2]benzazepin-3(2H)-one 1 5 10 25 or 8-chloro-6-(2-chlorophenyl)- 1,4-dihydro-l-methylpyrrolo-[3,4-d][2]benzazepin-3(2H)-one 2.

Lactose 203 193. 328 372. 3.

Starch 40 4.

Talc .

Aerosol OT 1 1. 2 2.

Capsule fill weight 250 250 400 450 Procedure: 1. Mill Items 1, 2, 3, and 5 in a suitable mixer 2. Add talc and mix well. 3. Encapsulate on suitable equipment. 986 204242

Claims (25)

WHAT WE CLAIM IS:

1. Pyrrolo[3,4-d][2]benzazepine derivatives of the general formula wherein and R^ are hydrogen, lower alkyl, hydroxy, lower alkoxy or acyloxy (as hereinbefore defined) and R2 and R4 are hydrogen or R1 and R2 and/or R3 and R4 taken together are oxo groups with the proviso that at least one oxo group is present; R is hydrogen, lower alkyl, C^ to C^ carboxylic acid or an ester or amide thereof, hydroxy C2 to C^ alkyl, amino C2 to C7 alkyl or mono- or di-lower alkyl amino C2 to C? alkyl; R5 is halogen having an atomic number not greater than 35 or hydrogen; and R^ is halogen having an atomic number not greater than 35 with the proviso that when R^ or R^ is hydroxy, lower alkoxy or acyloxy, then R is lower alkyl or hydrogen the N-oxides and the pharmaceutically acceptable acid addition salts thereof.

2. Compounds of the general formula I as defined in claim 1 and pharmaceutically acceptable acid addition salts thereof.

3. Compounds as claimed in claim 1 or claim 2 wherein® R^ and R4 taken together are an oxo group. R I ^1986 204242

4. Compounds as claimed in any one of claims 1 to 3 wherein R2 is hydrogen.

5. Compounds as claimed in any one of claims 1 to 4 5 wherein is hydrogen or lower alkyl.

6. Compounds as claimed in claim 5, wherein R^ is hydrogen or methyl. 10

7. Compounds as claimed in any one of claims 1 to 6 wherein R is hydrogen or lower alkyl.

8. Compounds as claimed in claim 7 wherein R is hydrogen or methyl. 15

9. Compounds as claimed in any one of claims 1 to 8 wherein R^ is halogen having an atomic number not greater than 35. 20

10. 8-Chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo- [3,4-d][2]benzazepin-3(2H)-one.

11. 8-Chloro-6-(2-chlorophenyl)-1,4-dihydro-l-methyl-pyrrolo[3,4-d][2]benzazepin-3(2H)-one. 25

12. 8-Chior0-6-(2-chlorophenyl)-1,4-dihydro-2-methy1-pyrrolo[3,4-d][2]benzazepin-3(2H)-one.

13. 8-Chior0-6-(2-fluorophenyl)-1,4-dihydropyrrolo- 30 [3,4-d][2]benzazepin-3(2H)-one.

14. 8-Chloro-l,4-dihydro-6-phenylpyrrolo[3,4-d][2]-benzazepin-3(2H)-one. 35

15. 8-Chloro-6-(2-chlorophenyl)-1,4-dihydro-l,2- dimethylpyrrolo[ 3 , 4-d] [ 2 ] benz az epin-3 ( 2.H) -one . - 49 - 204252

16. 8-Chloro-6-(2-chlorophenyl)-1,4-dihydro-2-(2-hydroxyethyl)-l-methylpyrrolo[3,4-d][2Ibenzazepin-3(2H)-one.

17. A compound selected from the group consisting of 5 8-chloro-6-(2-fluorophenyl) -3 ,4-dihydropyrrolo[3,4-d]- [2]benzazepin-l(2H)-one, 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d]-[2]benzazepin-l(2H)-one, 8-chloro-3,4-dihydro-6-phenylpyrrolo[3,4-d][2]benza-10 zepin-1(2H)-one, 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-2-methyl-pyrroloC3,4-d][2]benzazepin-l(2H)-one, 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l-hydroxy-pyrroloC 3,4-d][2]benzazepin-3(2H)-one, 15 8-chioro-6-(2-chlorophenyl)-3,4-dihydro-3-hydroxy- pyrrolo[3,4-d][2]benzazepin-l(2H)-one, 8-chloro-6-(2-chlorophenyl)pyrroloC 3,4-d][2]benzazepin-1,3-(2H,4H)-dione, 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-d]-20 C 2]benzazepin-3(2H)-one-5-oxide, 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d]-[2]benzazepin-1(2H)-one-5-oxide, 8-chloro-6-(2-chlorophenyl)-l-ethyl-l,4-dihydropyrrolo-[3,4-d][2]benzazepin-3(2H)-one, 25 8-chloro-6-(2-chlorophenyl)-1,2,3,4-tetrahydro-l-methyl- 3 - oxo-pyrroloC3,4-d][2]benzazepin-2-acetic acid methyl ester and 8-chloro-6-(2-chlorophenyl.)-l/2,3,4-tetrahydro-l-methyl-3 - oxo —pyrroloC 3,4-d]C 2]benzazepine-2-acetamide. 30 * 'A;

18. Compounds as claimed in any one of claims 1 to 17 suitable for use as pharmaceutically active substances.;

19. Compounds as claimed in any one of claims 1 to 17 suitable for use as sedatives and anxiolytics.;

20. A process for preparing compounds as claimed in;JJany o;Iany one of claims 1 to 17 which comprises;><v 2;2042;a) for preparing compounds of the formula I given in claim 1 wherein or R^ is hydrogen or lower alkyl and the remaining substituents are as defined in claim 1 and the N-oxides thereof, oxidizing a compound of the formula;10;15;II;wherein one of R^ and R^ is hydrogen and the other is hydrogen or lower alkyl and R, Rj. and Rg are as defined in claim 1 20 with a peracid, or b) for preparing compounds of the formula I given in claim 1 wherein R^ or R^ is hydroxy and the remaining substituents are as defined in claim 1 or R^ and R^ and R^ 25 and R^, respectively, are, when taken together, oxo groups and the remaining symbols are as defined in claim 1, oxidizing a compound of formula I given in claim 1 wherein R^ or R ^ is hydrogen and the remaining substituents are as defined in claim 1, or a compound of the formula II above 30 wherein R^ and R^ are hydrogen, with a lead (IV) car-boxylate in the presence of a strong acid, or c) for preparing compounds of the formula I given in claim 1 wherein R^ or R^ is acetoxy and the remaining 35 substituents are as defined in claim 1, treating a compound of the formula I given in claim 1 wherein R^ or R^ is hydrogen and the remaining substituents are as defined in claim 1, or a compound of the formula II above wherein;- 51 -;204242;R.j^ and R^ are hydrogen, with lead tetraacetate in acetic acid,., or d) for preparing compounds of the formula I given in 5 claim 1 wherein R^ or R^ is acyloxy and the remaining substituents are as defined in claim 1, treating a compound of formula I given in claim 1 wherein R^ or R^ is hydroxy and the remaining substituents are as defined in claim 1, with an appropriate organic carboxylic acid anhydride 10 in the presence of a base, or e) for preparing compounds of the formula I given in claim 1 wherein R^ or R^ is lower alkoxy and the remaining substituents are as defined in claim 1, treating a 15 compound of formula I given in claim 1 wherein R^ or R^ is acyloxy or hydroxy and the remaining substituents are as defined in claim 1, or a compound of.the formula;20;25;III;30 wherein R^ i-s acetoxy and R, R^ and Rg are as defined in claim 1;with a to alkanol in the presence of a' strong acid, or f) for preparing compounds of the formula I given in 35 claim 1 wherein R1 or R3 is hydrogen or lower alkyl and the remaining substituents are as defined in claim 1, desoxy-"'^ genating an N-oxide of the formula;■y ! a;- 52 -;204242;R;wherein or R^ is hydrogen or lower alkyl and R,;R„ , R. , Rr and R,_ are as defined in claim 1 2 4 5 6;and, if desired g) converting a compound of formula I into a pharmaceutically acceptable acid addition salt or converting a pharmaceutically acceptable acid addition salt of a compound of formula I into another pharmaceutically acceptable acid addition salt.;O.;- 53 -;204242;

21. A medicament containing a compound as claimed in any one of claims 1 to 17.;

22. A sedative and anxiolytic medicament containing a compound as claimed in any one of claims 1 to 17.;

23. A process for preparing compounds as claimed in any one of claims 1 to 17, substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 22.;

24. Compounds as claimed in any one of claims 1 to 17, whenever prepared by the process as claimed in claim 20 or claim 23.;

25. A medicament containing a compound as claimed in any one of claims 1 to 17, substantially as hereinbefore described with particular reference to any one of the foregoing Examples A to C.;HATED THIS! DAY OF 1^-*^ A. Jo PARK r sow f. . ! A>_LN73 APPLICANTS Reference has been directed,in pursuance of Section 16(1) of the Patents Act 1953, to Patent No. 197920. H. BURTON Assistant Commissioner of Patents