IE55134B1 - Pyrrolo(3,4-d)(2)benzazepine derivatives - Google Patents

Abstract

1. Claims (for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE) Pyrrolo[3,4-d][2]benzazepine derivatives of the general formula see diagramm : EP0094668,P27,F1 wherein R1 and R3 signify hydrogen, (C1 -C7 )-alkyl, hydroxy, (C1 -C7 )-alkoxy or the group -OCOR', R' signifies hydrogen (C1 -C6 )-alkyl or phenyl and R2 and R4 signify hydrogen or R1 and R2 and/or R3 and R4 together signify oxo groups, with the proviso that at least one oxo group is present, R signifies hydrogen, (C1 -C7 )-alkyl, hydroxy-(C2 -C7 )-alkyl, amino-(C2 -C7 )-alkyl, mono- or di-(C1 -C7 )-alkylamino-(C2 -C7 )-alkyl or the group -(C1 -C6 )-alkyl-COR**21 , R**21 signifies hydroxy, (C1 -C7 )-alkoxy, amino or mono- or di-(C1 -C7 )-alkylamino, R5 signifies halogen with an atomic number not exceeding 35 or hydrogen and R6 signifies halogen with an atomic number not exceeding 35, with the proviso that R signifies (C1 -C7 )-alkyl or hydrogen when R1 or R3 signifies hydroxy, (C1 -C7 )-alkoxy or -OCOR', the N-oxides and the pharmaceutically acceptable salts thereof. 1. Claims (for the Contracting State AT) A process for the manufacture of pyrrolo[3,4-d][2]benzazepine derivatives of the general formula see diagramm : EP0094668,P29,F2 wherein R1 and R3 signify hydrogen, (C1 -C7 )-alkyl, hydroxy, (C1 -C7 )-alkoxy or the group -OCOR', R' signifies hydrogen, (C1 -C6 )-alkyl or phenyl and R2 and R4 signify hydrogen or R1 and R2 and/or R3 and R4 together signify oxo groups, with the proviso that at least one oxo group is present, R signifies hydrogen, (C1 -C7 )-alkyl, hydroxy-(C2 -C7 )-alkyl, amino-(C2 -C7 )-alkyl, mono- or di-(C1 -C7 )-alkylamino-(C2 -C7 )-alkyl or the group -(C1 -C6 )-alkyl-COR**21 , R**21 signifies hydroxy, (C1 -C7 )-alkoxy, amino or mono- or di-(C1 -C7 )-alkylamino, R5 signifies halogen with an atomic number not exceeding 35 or hydrogen and R6 signifies halogen with an atomic number not exceeding 35, with the proviso that R signifies (C1 -C7 )-alkyl or hydrogen when R1 or R3 signifies hydroxy, (C1 -C7 )-alkoxy or -OCOR', of N-oxides and of pharmaceutically acceptable salts thereof, characterized by a) for the manufacture of compounds of formula I above in which R1 or R3 signifies hydrogen or (C1 -C7 )-alkyl and the remaining symbols have the above significance and of N-oxides thereof, oxidizing a compound of the general formula see diagramm : EP0094668,P30,F1 wherein one of R11 and R31 signifies hydrogen and the other signifies hydrogen or (C1 -C7 )-alkyl and R, R5 and R6 have the above significance, with a peracid, or b) for the manufacture of compounds of formula I above in which R1 or R3 signifies hydroxy and the remaining substituents have the above significance or R1 and R3 and R4 in each case together signify oxo groups and the remaining symbols have the above significance, oxidizing a compound of formula I in which R1 or R3 signifies hydrogen and the remaining substituents have the above significance or a compound of formula II above in which R11 and R31 signify hydrogen with a lead (IV) carboxylate in the presence of a strong acid, or c) for the manufacture of compounds of formula I above in which R1 or R3 signifies acetoxy and the remaining substituents have the above significance, treating a compound of formula I in which R1 or R3 signifies hydrogen and the remaining substituents have the above significance or a compound of formula II above in which R11 and R31 signify hydrogen with lead tetraacetate in acetic acid, or d) for the manufacture of compounds of formula I above in which R1 or R3 signifies -OCOR' and the remaining substituents have the above significance, treating a compound of formula I in which R1 or R3 signifies hydroxy and the remaining substituents have the above significance with a carboxylic acid anhydride in the presence of a base, or e) for the manufacture of compounds of formula I above in which R1 or R3 signifies (C1 -C7 )-alkoxy and the remaining substituents have the above significance, treating a compound of formula I in which R1 or R3 signifies -OCOR' or hydroxy and the remaining substituents have the above significance or a compound of the formula see diagramm : EP0094668,P30,F2 wherein R12 signifies acetoxy and R, R5 and R6 have the above significance, with a (C1 -C7 )-alkanol in the presence of a strong acid, or f) for the manufacture of compounds of formula I above in which R1 or R3 signifies hydrogen or (C1 -C7 )-alkyl and the remaining substituents have the above significance, desoxidizing an N-oxide of the general formula see diagramm : EP0094668,P31,F1 wherein R, R1 , R2 , R3 , R4 , R5 and R6 have the above significance, and, if desired, g) converting a compound of formula I into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable salt of a compound of formula I into another pharmaceutically acceptable salt. [EP0094668A2]

Description

55134 Z The present invention relates to pyrrolo[3,4-d][2]-benzazepine derivatives of the general formula R wherein and R3 are each hydrogen, (C^—C7)-alkyl, 5 hydroxy, (C1-C7)-alkoxy or a group -QCOR , where r' is hydrogen, (0χ-06)-alkyl or phenyl and R2 and R4 are each hydrogen or Rx and R2 and/or Rj and R4 taken together are oxo groups, with the proviso that at least one oxo group is present; R is hydrogen, (C^-C,^-alkyl, 10 hydroxy-(C2~C7)-alkyl, amino-(C2~C7)-alkyl, mono- or di-(C1-C7)alkylamino-(C2-c7)alkyl or a group -(C^-Cg)-alkyl - COR21, where R2 is hydroxy, (C^-C^J-alkoxy, amino or mono- or di-(C1-C7)-alkylamino; R5 is halogen having an atomic number not greater than 35 or 15 hydrogen; and Rg is halogen having an atomic number not greater than 35 with the.proviso that when R. or R, is I * * hydroxy, (C^-c^-alkoxy or -OCOR , then R is (C1-C7)-alkyl or hydrogen; and the N-oxides and the pharmaceutically acceptable 20 salts thereof.

The compounds exhibit activity as sedative and anxiolytic agents.

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 "alkyl" is meant both straight and branched chain hydrocarbon groups, preferably Cj to carbon-hydrogen radicals, such as methyl, ethyl, propyl and isopropyl.

Radicals of the formula -OCOR1 are, e.g., acetyl, propionyl, butyryl or benzoyl.

The expression "pharmaceutically acceptable salts" is used to include salts with both inorganic and organic pharmaceutically acceptable acids, such as sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic 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 R^ taken together are an oxo group. Still further preferred compounds are those of formula I wherein R2 is hydrogen, R^ is preferably hydrogen or (C^—e-y)-alkyl, more preferably hydrogen or methyl. The preferred meaning of R is hydrogen or (C^-Cy)-alkyl, more preferably hydrogen 4 or methyl. Rg is preferably halogen having an atomic number not greater than 35.

From the above it follows that an especially preferred group of compounds within the scope of the present invention are those of formula X, wherein R and R^ are hydrogen or (CyOyJ-alkyl, preferably methyl, is hydrogen, Rg and R^ taken together are an oxo group and Rg 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, 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrroloC 3,4-dl-[2]benzazepin-l(2H)-one, 8-chloro-3,4-dihydro-6-pheiiylpyrrolo[3,4-d][2]benzaze-pin-l(2H)-one, 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-2-methyl-pyrrolo[3,4-d][2]benzazepin-l(2H)-one, 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l-hydroxy-pyrrolo[3,4-d][2]benzazepin-3(2H)-one, 8-chloro-6-(2-chlorophenyl.)-3,4-dihydro-3-hydroxy- . pyrrolo[3,4-d][2]benzazepin-l(2H)-one, 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]-[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)-1,4-dihydro~l-methyl-3-oxo-2H-pyrrolo[3,4-d]C2]benzazepine-2-acetic acid methyl ester and 8-chloro-6~(2-chlorophenyl)-1,4-dihydro~l-methyl-3-oxo-2H-pyrrolo[3,4-d][2]benzazepine-2-acetamide. 55134 Especially preferred compounds are: 8-chloro-6-(2-fluorophenyl)-1,4-dihydropyrrolo[3,4-d]-[2]benzazepin-3(2H)-one, 8-chloro-l,4-dihydro-6-phenylpyrrolo[3,4-d][2]benzaze-5 pin-3(2H)-one, 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l,2-dimethyl-pyrrolo[3,4-d][2]benzazepin-3(2H)-one and 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-(2-hydroxy-ethyl )-1-methylpyrroloC 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 15 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-methyl- pyrrolo[3,4-d][2]benzazepin-3(2H)-one.

The compounds of formula X, the N-oxides and the pharmaceutically acceptable salts thereof can be prepared in accordance with the invention 20 a) for preparing compounds of the formula I above wherein R^ or R^ is hydrogen or (C^-C-y)-alkyl and the remaining substituents are as above and the N-oxides thereof, by oxidizing a compound of the formula R 6 - 55134 wherein one of R^ and R^ is hydrogen and the other is hydrogen or alkyl and R, Rg and Rg are as above with a peracid, or 5 b) for preparing compounds of the formula I above wherein R^ or Rg is hydroxy and the remaining substituents are as above or R^ and Rg and Rg 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^ 10 or Rg is hydrogen and the remaining substituents are as above, or a compound of the formula XI above wherein R^ and R31 are each hydrogen, with a lead (XV) carboxylate in the presence of a strong acid, or c) for preparing compounds of the formula I above wherein 15 R^ or Rg is acetoxy and the remaining substituents are as above, by treating a compound of the formula I wherein R^ or Rg is hydrogen and the remaining substituents are as above, or a compound of the formula II above wherein R^ and are each hydrogen, with , lead tetraacetate in acetic acid, 20 or d) for preparing compounds of the formula I above wherein R^ or Rg is -OCOR1 and the remaining substituents are as above, by treating a compound of formula I wherein R^ or Rg is hydroxy and the remaining substituents are as above, 25 with a carboxylic anhydride in the presence of a base, or e) for preparing compounds of the formula I above wherein R^ or R3 is (C1-C7)-alkoxy and the remaining substituents are as above, by treating a compound of formula I wherein R^ or Rg is -OCOR1 or hydroxy and the remaining substituents 30 are as above, or a compound of the formula R wherein R^2 is acetoxy and R, R5 and Rg are as above with a (Ci-C7)-alkanol in the presence of a strong acid, or f) for preparing compounds of the formula I above wherein 5 or R3 is hydrogen or (Cy-Cy)-alkyl and the remaining substituents are as above, by desoxygenating an N-oxide of the formula R wherein R, R^, R2, R3, R4, Rg and Rg are as above and, if desired, g) by converting a compound of formula X into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable salt of a compound of formula X into another pharmaceutically acceptable salt.

The oxidation of a compound of formula II with a peracid according to process embodiment a) of the present 15 55134 β 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 lower 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 -: λ 0°C and v. 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 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.

The oxidation in accordance with process embodiment b) of the present process is also performed according to methods known per se. In this oxidation, lead (IV) carboxy-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 35 9 and the like can suitably be used. The reaction is preferably performed in a temperature range of from - 0°C to room temperature. In the case of a compound of formula II wherein R^ and R^ are hydrogen, a mixture of the 1-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.

Also, the reaction in accordance with process embodiment 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 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, dimethylaminopyridine, N-methylplperidine 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 0"C to room tempe 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 formula I wherein R^ or R^ is -0C0R1 preferably acetoxy, or a compound of formula III, with an excess of a lower alkanol containing a catalytic amount of a strong acid such as methane sulfonic acid and the like. This reaction is pre- 55134 1 Ο ferably performed at a temperature between 0°C and room temperature.

The desoxygenation in accordance with process embodiment f) of the present process is also performed according 5 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 chloride, aromatic hydrocarbons, e.g., toluene, ethers, 10 e-g·, tetrahydrofuran, and the like at a temperature between room temperature and the reflux temperature of the solvent.

The starting materials of formula IX are known or can be prepared in an analogous manner to the preparation of 15 the known compounds. The following reaction schemes illus trate the preparation of these formula IX compounds.

J 1 Scheme I 55134 f Da wherein is hydrogen or (C^CyJ-alkyl and and R,. are as above, b 13 55134 III -p IV The compound of formula III can be reacted with an α-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 ,. 0°C to 40°C with about room temperature being pre ferred. The α-tosyl alkylisocyanides mentioned above may be prepared following the teaching of van Leusen et al., 10 Tetrahedron Letters, 3487 (1975).

IV -» IXa The compound of formula IV can be reacted with hydrogen at pressures ranging from atmospheric pressure to five atmospheres in the presence of a transition metal 15 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 hydride reducing agent, such as lithium aluminum hydride in an etherial solvent such as tetrahydrofuran. The reaction temperature may range from -· -20°C to * : room tempe- 25 rature, 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 30 amine thus formed cyclizes spontaneously to product Ila.

The reaction temperature may range-from - room temperature to the boiling point of the solvent, with about 40°C being preferred. 13 Scheme IX IXa' SS134 wherein R^4 and R.^ are (¢^-07)-alkyl and Rg and Rg are as above. 14 145 513 4 Ila* -» Ila" + IXb The compound of formula Ila' can be reacted with one equivalent of a strong base such as lithium diisopropyl-amide at between . -80°C to '**.,,· o°c, with about -20°C 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 chromatography procedures.

SS134 1 a Scheme III wherein R" is (Cj-C^-alkyl, R? is (Cj-C^-alkyl, Rg and Rg are hydrogen or (Cj-Cy)-alkyl and n is an integer from 1 to 6 and R-q , R^, R^ and Rg are as above. 513 4 IB He -» IXh -» Ilj 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 -20°C to 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 -9 Ilf A compound of the formula Ilh can be reacted with 15 ammonia or a mono- or di- (C j-C~) -alkyl amine and a catalytic amount of its hydrochloride salt with a to-alcohol solvent. The reaction is usually conducted at about 100"C using a pressure apparatus to contain the volatile reactants.

Ilh —7-» Ili 20 A compound of the formula ilh can be reacted with a metal hydride such as lithium aluminum hydride in an ethereal solvent such as tetrahydrofuran or dioxane. The reaction temperature may range from -- ->·- -80®C to .- - room temperature, with about 0°C being preferred. lie -£ Ilq A compound of the formula lie can be reacted with a compound of the formula VI x-(ch2Wn\ wherein X is halide or sulfonate and RD, R_ and n o y are as above in the presence of a base such as an alkali metal alkoxide 30 17 1755134 in a polar solvent such as dimethylsulfoxide or dimethylformamide. The reaction temperature may range from -20*C to -··- room temperature with about room temperature being preferred.

He -» 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 a (c -C )-alkyl halide or sulfonate in a polar aprotic solvent such as dimethylformamide or dimethyl sulfoxide. The reaction temperature may range from · 0°C to room temperature, with about 0“C being preferred.

Ilf -* Ilg or Ilh -» Hi 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 -20°C to .·· room temperature, with about 0°C being preferred. lie -> Hi A compound of formula lie can be reacted in the presence of a base such as an alkali metal alkoxide, and dimethylformamide or dimethyl sulfoxide with a compound of the formula X‘(lCH2)n+!0Z 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 acid yields the desired end product. 18 55134 He -» Ilf A compound of formula lie can be reacted with a compound of the formula N-CO-(CH~) -X VIII 2 n 5 wherein X is as above and Rg, Rg and n are as above 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 10 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, 15 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 20 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 25 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 0.1 to 500 mg of the compounds of the invention with a dosage range of from 0.1 mg to 100 mg being preferred for oral administration and a dosage range 30 19 1955134 of from 0.1 mg to 50 mg being preferred for parenteral administration. However, for any particular subject, the specific dosage regimen should be adjusted according to individual need and the professional judgment of 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. ΙΟ 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 produce the desired therapeutic effect in asso-15 ciation with the required pharmaceutical diluent, carrier or vehicle.

The following data is indicative of the pharmacological activities of the compounds of the invention utilizing pharmacological tests well-known in the art. 3 20 Η-Diazepam Binding Assay The Assay acts as a screen for antianxiety drugs.

Rat brain cortical fragments are prepared and the binding procedures performed as described by Mohler and Okada (Life Sciences, 20_, 2101, 1977) except that Tris 25 buffer is substituted for Krebs buffer. Drugs are assayed in triplicate. Radioactivity is measured by liquid scintillation counting. The results are expressed as IC,-q (nM), i.e. the concentrations required to inhibit the bindung by 50¾.

Activity of Standard Drugs: IC-,, Diazepam 5.0 Flunitrazepam 1.8 Flurazepam 15.6 20 55134 Results obtained with compounds of the. invention: IC^g (nM) 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one 5 ^LD50 ” 800 mg/kg (poHmice)] 0.006 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l- methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one [LD5q - greater than 1000 mg/kg (poHmice)] 1.0 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo-10 [3,4-d][2]benzazepin-3(2H)-one 0.25 molar hydrate micronized [LD5q - greater than 1000 mg/kg (poHmice)] 0.003 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo-[3,4-d][2lbenzazepin-3(2H)-one 15 ^LD50 “ 808 mg/kg (po)(mice)] 0.002 Intravenous ftntimetrazol-Test The test evaluates anticonvulsant agents and is considered to be predictive of anxiolytic activates.

Male mice, 45-54 days old, housed in facilities for 20 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 level, one hour later, metrazol is administered intravenously at 70 mg/kg (convulsant dose 100 mg/kg) and the animals are 25 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 from convulsive seizures is expressed as the ED^g. The approximate ED,-q is calculated by the method of Miller and 30 Tamter (Proc. Soc. Exp. Biol. Med. 57:261, 1944). 21 5 10 15 Activity of Standard Drugs: Chlordiazepoxide Diazepam Sodium Phenobarbital EDgQ mq/kq po 3.91.0 19 Results obtained with compounds of the invention: ΕΡ,-q mq/kcr 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- l-methylpyrrolo[3,4-d][2 jbenzazepin- 3(2H)-one 0.08 8-chloro-6-(2-chlorophenyl)-1,4-dihydro- pyrrolo[3,4-d][2]benzazepin-3(2H)-one 0.25 molar hydrate micronized 0.07 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-pyrrolo[3,4-d][2]benzazepin-3(2H)-one 0.03 The following examples are illustrative of the invention but are not meant to limit such invention. 55134 55134 2 2 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 (4.5 mol) of activated zinc dust and 100 g (0.42 mol) 5 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 filtration. The filtrate was acidified by the addition of 10 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 alu- 15 minum hydride in 800 ml of ether, which was cooled to 0°C, were added dropwise 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 addi-20 tion 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 sodium sulfate. Removal of the ether at reduced pressure gave 2-benzyl-4-chlorobenzyl alcohol as a colorless oil 25 which crystallized upon standing, mp 46»5-49°C. c) To a suspension of 238 g (1.1 mol) of pyridinium chloro-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 30 salts were precipitated by the addition of 2.4 liters of a 1:1 mixture of ether and petroleum ether, and the precipitate 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 35 purification. 23 23S 51 3 4 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 tetrahydrofuran solution was decanted and concentrated at room temperature. The residue was partitioned between 2 liters 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—C 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 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 layer chromatography (silica gel, 2 mm; 1:1 mixture of methylene chloride and pentane) to give a white solid, mp 87-89°C. 3-(2-Benzoyl-4-chlorophenyl)-2-propenenitrile was also prepared as follows: f) A solution of 92.7 g (0.4 mol) of 2-amino-5-chloro-benzophenone in 250 ml of acetonitrile was added to a 24 55134 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-(benzoylIbenzenepropanenihrile, 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- (benzoylibenzenepropanenitrile, 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 temperature for 48 hours. The mixture was diluted with 1.5 liters 20 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-25 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 50¾ sodium hydride in mineral oil and 170 ml of ether. When the addition was complete, stirring was continued for 30 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 water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a dark green Oil. Purification 35 by column chromatography (800 g silica gel; eluent, 5% ether in methylene chloride) gave 4-[2-benzoyl-4-chloro- 25 255 513 4 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-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 aaid was neutralized with sodium bicarbonate, and 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-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]C2]benzazepine were added to a mixture of 3.4 g (15.7 mmol) of m-chloroperbenzoic acid in 100 ml 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 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 chromatography (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 filtrates indicated the presence of the isomeric 8-chloro-3,4-dihydro-6-phenylpyrrolo[3,4-d][2]benzazepin-l(2H)-one. 26 5 5 13 4 Example 2 a) The preparation of a,4-dlchloro-2-(2-fluorobenzoyl)-benzenepropanenitrile was conducted in the same manner as the preparation of a,4-dichloro-2-(benzoyl)benzenepropane- 5 nitrile described in Example If) to give pale yellow prisms, mp 94-95°C. b) The preparation of 3-[2-(2-fluorobenzoyl)-4-chloro-phenyl]-2-propenenitrile was conducted in the same manner as the preparation of 3-(2-benzoyl-4-chlorophenyl)-2-pro- 10 penenitrile described in Example lg) to give off-white prisms, mp 137-139^0. 3-[2-(2-Fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile was also prepared as follows: c) A solution of 5.0 g (14 mmol) of 5-chloro-2'-fluoro-2- 15 iodobenzophenone, 2 ml C14.3 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 15 hours. The mixture was diluted with 100 ml of IN hydrochloric acid and the resulting precipitate was collected 20 by filtration. The precipitate was washed with ether and air dried to give 3—C2-(2-fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile as an off-white solid,mp 130-133°C. * * * d) The preparation of 4-t2-(2-fluorobenzoyl)-4-chlorophenyl ]-lH-pyrrole-3-carbonitrile was conducted in the same 25 manner as the preparation of 4-C2-benzoyl-4-chlorophenyll- 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-[2-(2-fluorobenzoyl)-4-chlorophenyl]-lH-pyrrole-3-carbonitrile, ca 3 g of Raney 30 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 55134 Zl 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 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-pyrrolo[3,4-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 (15.0 mmol) of 8-chloro-6-(2-fluoro-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 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% methanol in methylene chloride) gave in the first product band after crystallization from ethyl acetate 8-chloro-6-(2-fluoro-Fhenyl)-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 crystallization 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- 28 55134 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 5 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-chloro-phenyll-lH-pyrrole-3-carbonitrile was conducted in the same 10 manner as the preparation of 4-[2-benzoyl-4-chlorophenyl]- lH-pyrrole-3-carbonitrile described in Example Ih) to give off-white prisms, mp 182-184°C. d) The preparation of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrroloE 3,4-d] [2]benzazepi'ne was conducted in the same 15 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 20 to a mixture of 7.6 g (35.2 mmol) of 80¾ m-chloroperbenzoic acid in 225 ml of 2¾ 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 concentrated at reduced 25 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 30 residue. Crystallization from methylene chloride gave 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo E3,4-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-dihydropyrroloE3,4-d]E2]- 29 2955134 benzazepin-l(2H)-one as pale yellow prisms, mp 195-197°C.

Example 4 In one portion, 9.8 ml of 30¾ hydrogen peroxide solution were added to 195 ml of a 1¾ 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]-[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 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 chromatography (silica gel, 200 g; eluent, 5¾ 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 the second product band after crystallization from methylene chloride 8-chloro-6-(2-chlorophenyl)-l,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 80¾ 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]-[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 30 5 513 4 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 chromatography (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, 150 g; eluent, 5¾ methanol in methylene chloride) gave in the first product band after crystallization from a mixture of ethyl acetate and methanol 8-chlor0-6-(2-chlorophenyl)-3,4-10 dihydropyrrolo[3,4-d][2]benzazepin-l(2H)-one-5-oxide as pale yellow prisms, mp 243-244°0.

Further elution gave in the second product band after crystallization from a mixture of ethyl acetate and methanol 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-d]-15 [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) 20 of 1-tosylethyl isocyanide in 150 ml of dimethylsulfoxide and 100 ml of ether was added dropwise to a suspension of 4.6 g (0.1 mol) of a 5050 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 25 continued for 2 hours. The mixture was diluted with 1.2 liters of water and 40 ml of IN hydrochloric acid 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 dark 30 green oil. Crystallization from a mixture of ether and petroleum ether gave 4-[4-chloro-2-(2-chlorobenzovl)phenyl]-5-methyl-lH-pyrrole-3-carbonitrile, mp 206-208°c, as tan crystals. Recrystallization from ether gave the desired product as colorless crystals, mp 210-211^0. 31 55134 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 221-225^0, was obtained from ether. Recrystallization from ether gave pale yellow prisms, melting at 232-237°C. b) A mixture of 8.5· g (24 mmol) of 4-[4-chloro-2-(2-chlorobenzoyl) phenyl]-5-methyl-lH-pyrrole-3-carbonitrile, 1 spoonful of Raney nickel and 250 ml of glacial acetic 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 collected 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 219-222^0. Recrystallization from a mixture of ether and methylene chloride gave 8-chloro-6- (2-chlorophenyl)-l-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine as colorless crystals, mp 221-225°C. c) In one portion, 1 ml 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 (5.8 mmol) of 8-chloro-6-(2-chlorophenyl)-l-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the resulting mixture was stirred at room temperature for 30 minutes. The 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-6-(2-chlorophenyl)-1,4-dihydro-l-methylpyrrolo[3,4-d][2]-benzazepin-3(2H)-one as pale yellow prisms, mp 239-241°C. 32 326 513 4 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 5 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 extracted with methylene chloride. The methylene chloride 10 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 recrystallization from a mixture of ether and petroleum 15 ether gave 8-chloro-6-(2-chlorophenyl)-2-methyl-2H,4H- pyrroloC3,4-d][2]benzazepine as colorless prisms, mp 167— 168 °C.

The methanesulfonate salt of 8-chloro-6-(2-chloro-phenyl)-2-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine was 20 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. Recrystallization 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-chloto-6-(2-chlorophenyl)-2-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the resulting 30 mixture was stirred at room temperature for 16 hours. The mixture was concentrated at reduced pressure and the residue was partitioned between methylene chloride and water. The methylene chloride solution was neutralized with concentrated ammonium hydroxide solution, washed with brine, dried 35 over anhydrous sodium sulfate and concentrated at reduced 33 3355134 pressure to a yellow residue. Purification of the residue by column chromatography (silica gel, 100 g; eluent, 5¾ 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][2]benzazepin- 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-dihydro-2-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one as 10 pale yellow prisms, mp 173-175^(3.

Example 8 a) A solution of 30.0 g (99.3 mmol) of 3-[2-(2-chloro-benzoyl)-4-chlorophenyl]-2-propenenitrile and 23.0 g (103 mmol) of 1-tosylpropyl isocyanide in a mixture of 200 ml 15 of ether and 200 ml of dimethyl sulfoxide was added drop- wise over a 20 minute period to an ice-cooled suspension of 6.7 g (140 mmol) of a 50¾- 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 20 IN aqueous hydrochloric acid. The aqueous solution was extracted with 3 x 500 ml of ether. The ether solutions were . 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 25 column chromatography (silica gel, 500 g; eluent, 50¾ ether in petroleum ether) gave in the first product band after crystallization from a mixture of ether and methylene chloride 4-[4-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 crystallization from ether 6-chloro-8-(2-chlorophenyl)-2-ethyl-1,8-dihydro-8-hydroxyindenoC 2,1-b]pyrrole-3-carbo-nitrile as colorless prisms, mp 172-174°C. 34 345 513 4 fa) A mixture of 3.3 g (8.9 mmol) of 4-[2-(2-chloro-benzoyl)-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.

The Raney nickel was removed fay 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 fay- 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-chIoro-6-(2-chlorophenyl)-1-ethyl-2H,4H-pyrroloC3,4-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 30¾ hydrogen 20 peroxide was added to 40 ml of a 1¾ 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)-l-ethyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the resulting mixture was stirred for 20 minutes. The excess 25 peracid was discharged fay 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 concentrated ammonium hydroxide solution. The methylene chloride 30 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-chIoro-6-(2-chlorophenyl)-1-ethyl-1,4-dihydropyrrolo[3,4-d][2]benza-zepin-3(2H)-one as yellow prisms, mp 233-235°C. Recrystalli 35 zation from a mixture of ethyl acetate and methanol gave colorless prisms, mp 236-237°C. 55134 Example 9 a) In one portion, 2.0 g (5.8 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to an ice-cooled solution of 0.8 g (7.1 mmol) 5 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, 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)-l,2-dimethyl-2H,4H-pyrrolo[3,4-d][2]benzazepine as orange prisms, mp 200-202°C. A sample was recrystallized from a mixture of 15 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 peroxide solution was added to 33 ml of a 1% solution of concentrated sulfuric acid in acetic acid. After stirring 20 for 1 hour, 1.8 g (5.0 mmol) of 8-chloro-6-(2-chlorophenyl)-l,2-dimethyl-2H,4H-pyrrolo[3,4-d][2]ben2azepine were added, and the resulting solution was stirred for 20 minutes. The excess peracid was discharged by the addition of saturated aqueous sodium bisulfite solution, and the mixture was con-25 centrated 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 a 30 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, mp 207-208°C. 55134 3 δ: 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 were added to an ice-cooled solution of 0,8 g (7.1 mmol) 5 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 with water and extracted with ether. The ether solution 10 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) gave after crystallization from a mixture of ether and 15 petroleum ether 8-chl.oro-6-(2-chlorophenyl)-l-methyl-2H,4H-pyrrolo[3,4-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 30¾ hydrogen peroxide solution was added to a solution of 35 ml of 1% 20 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]L2]benzazepine-2-acetic acid methyl ester were added, and the resulting solution was stirred for 30 minutes. The excess peracid was dis-25 charged 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 neutralized with concentrated ammonium hydroxide solution. The methylene chloride solu-30 tion 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-chlorophenyl)-1,4-dihydro-l-methyl-3-oxo-2H-pyrrolo[3,4-d]-[2]benzazepine-2-acetic acid methyl ester as pale yellow 35 prisms, mp 221-223°C. Recrystallization from ethyl acetate gave colorless prisms, mp 223-224eC. 37 3755134 Example 11 a) In one portion, 4.0 g (11.7 mmol) o£ 8-chloro-G-(2-chlorophenyl)-l-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine 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 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, 50¾ ether in 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 30¾ hydrogen peroxide was added to a 1¾ 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)-l-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetamide were added, and the 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 concentrated 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)-1,4-dihydro-l-methyl-3-oxo-2H-pyrrolo[3,4-d]- [2]benzazepine-2-acetamide as colorless prisms, mp 221-222°C. 55134 3 8 Example 12 a) A solution of 4.0 g (9.6 mmol) of 8-chloro-6-(2-chloro-phenyl)-l-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic acid methyl ester in 40 ml of tetrahydrofuran was added 5 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. The mixture was treated with 1 ml of water, 1 ml of a 3N 10 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-phenyl)-l-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepin-2-ethanol 15 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 30¾ hydrogen peroxide was added to a 1% solution of concentrated sul-20 furic 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-ethan°l were added, and the resulting solution was stirred for 30 minutes. The excess peracid was discharged with the addition of saturated 25 aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between methylene chloride and water and neutralized with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried 30 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 chloride) gave in the first product band after crystallization from a mixture of ether and methylene chloride 2—[2— 35 (acetoxy) ethyl]-8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l- methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one as colorless 39 55134 prisms, mp 152-154°C.

Further elution gave in the second product band after crystallization from a mixture of ethyl acetate and ether 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-(2-hydroxyethyl) -l-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 tetraacetate 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. 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-chlorophenyl )-1,4-dihydropyrrolo[3,4-d][2]benzazepin-3(2H)-one 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 solution 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 chloride) followed by crystallization from ether gave 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l-hydroxypyrrolo-[3,4-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 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 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 product band after crystallization from ether 8-chloro-6-(2-chlorophenyl)pyrrolot 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 crystallization from ether 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-3-hydroxypyrrolo[3,4-d][2]benzazepin-l(2H)-one as pale yellow prisms, mp 222-223“C.

Still further elution gave in the third product band after crystallization from ether 8-chloro-6-(2-chloro-phenyl)-l,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- 41 55134 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][2]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-[3,4-d][2]benzazepin-l(2H)-one as colorless prisms, mp 20 172-174°C.

Continued elution gave fine needles. Recrystallization from a mixture of ether and methylene chloride gave 8-chloro-6-(2-chlorophenyl)-1-acetoxy-l,4-dihydropyrrolo-[3,4-d]C2]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 dimethylaminopyridine in a mixture 30 of 30 ml of methylene chloride and 10 ml of tetrahydrofuran was stirred at 0°C for 1 hour. The mixture was diluted with water, washed successively with cold, dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine and dried over anhydrous sodium sulfate. The methy- 42 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-5 pyrrolo[3,4-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)-10 3-acetoxy-3,4-dihydropyrrolo[3,4-d][2]benzazepin-l(2H)-one and 3 ml of a 1M methanolic solution of methanesulfohic acid in 10 ml of methanol was stirred at room temperature for 30 minutes. The solution was concentrated at reduced pressure to half the volume, diluted with ether, and the 15 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-dihydro-3-methoxypyrrolo[3,4-d][2]benzazepin-l(2H)-one methanesulfonate as off-white prisms, mp 157-160^0.

Example 19 A solution of 0.1 g (0.25 mmol) of 8-chloro-6~(2-chlorophenyl)-1-acetoxy-l,4-dihydropyrrolo[3,4-d][2]benza-zepin-3(2H)-one and 1 ml of a 1M methanolic solution of methanesulfonic acid was allowed to stand at room tempe-25 rature for 3G hours. The mixture was diluted with ether, and the resulting precipitate was collected by filtration to give 8-chloro-6-(2-chlorophenyl)-l,4-dihydro-l-methoxy‘-pyrrolo[3,4-d][2]benzazepin-3(2H)-one methanesulfonate. Recrystallization from a mixture of ether and methanol gave 30 fine needles, mp 185-187°C. 43 4355134 Example 20 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 diacetate in 25 ml of a 1M 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 sodium sulfate and concentrated at reduced pressure. The residue was dissolved in 4 ml of a 1M 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 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-5-(2-chlorophenyl)-1,4-dihydro-l-methoxypyrrolo-[3,4-d][2]benzazepin-3(2H)-one was noted Toy 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-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.

Example 21 In one portion, 1.8 ml (20 mmol) of phosphorous trichloride were added to a solution of 0.9 g (2.5 mmol) of 8-chlor0-6-(2-chlorophenyl)-1,4-dihydropyrroloC 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 44 55134 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-chlor0phenyl)-l,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 phosphorous tri-10 chloride were added to a solution of 1.0 g (2.7 mmol) of 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrroloC 3,4-d][ 2 ]-benzazeplne-l(2H)-one-5-oxide in 200 ml of methylene chloride and refluxed for 1 hour. The mixture was concentrated at reduced pressure. The residue was dissolved in methylene 15 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 a dark red residue. Purification of the residue by column chromatography (silica gel, 20 g; 20 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-l12H) -one as pale yellow prisms solvated with 0.5 mole ethyl acetate, mp 195-197°C. 43 5 513 4 Example A Tablet Formulation (Direct compression) 5 10 15 Item Ingredients mg/tablet 1. 8-chloro-6-(2-chlorophenyl) - 1,4-dihydropyrrolo[3,4-d]- C 2]benzazepin-3(2H)-one 1 5 10 25 or 8-chloro-6-(2-chlorophenyl) - 1,4-dihydro-l-methylpyrrolo - [3,4 —d 3 C2]benzazepin-3(2H) - one 2. Lactose 221 217 212 181 3. Avicel 45 45 45 55 4. Direct Compression Starch 30 30 30 35 5. 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 .

Example B Tablet Formulation (Wet granulation) Item Ingredients mq/tablet 1. 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrroloC3,4-d]- [2]benzazepin-3(2Ή)-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 25 35 45 55 4. Pregelatinized Starch 20 25 30 . 35 5. Distilled Water q.s. - - - 6. Magnesium Stearate _2 _3 4 _5 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 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. . 4755134 Example C Capsule Formulation Item Ingredients mg/capsule 1. 8-chloro-6-(2-chlorophenyl)- 5 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- 10 [3,4-d][2]benzazepin-3(2H)-one 15 2. Lactose 203 193.5 328 372.5 3. Starch 30 35 40 30 4. Talc 15 15 20 20 5. Aerosol OT 1 1.5 _2 2.5 Capsule fill weight 250 350 400 450 Procedure: 1. Mill Items 1, 2, 3, and 5 in a suitable mixer. Mill. 2. Add talc and mix well. 3. Encapsulate on suitable equipment.

Claims (28)

48 S5134 CLAIMSi

1. A pyrrolo[3,4-d]t2]benaaaepine privative of the general formula R I

2. A compound of the general formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof.

3. A compound as claimed in claim 1 or claim 2 wherein R3 and R^ taken together are an oxo group. 25 49 4955134

4. A compound as claimed in any one of claims 1 to 3 wherein is hydrogen. 5. Examples 1-22 of the accompanying Examples.

5. A compound as claimed in any one of claims 1 to 4 wherein R^ is hydrogen or (Cj-Gy)-alkyl. 5 10 15 20 wherein R^ and R3 are each hydrogen, (C^-C.^}-alkyl, hydroxy, (C1~C7)-alkoxy or a group -0C0R , where R is hydrogen, (C^Cg)-alkyl or phenyl and R2 and R^ are each hydrogen or R^ and R2 and/or R3 and R^ taken together are oxo groups, with the proviso that at least one oxo group is present; R is hydrogen, (Cj-C7)-alkyl, hydroxy-(C2-C7)-alkyl, amino-(C2-C7)-alkyl, mono- or di-(C1-c7)-alkylamino-(C2-C7) alkyl or a group -(C^-Cg) -alkyl-COR21, where R21 is hydroxy, (C1~C7)-alkoxy, amino or mono- or di-(C1-C7)-alkylamino; Rs is halogen having an atomic number not greater than 35 or hydrogen; and Rg is halogen having an atomic number not greater than 35 with the proviso that when R^ or R3 is hydroxy, (C^-C^-alkoxy or -0C0R , then R is (C^—C7) — alkyl or hydrogen; or an N-oxide thereof or a pharmaceutically acceptable salt thereof.

6. A compound as claimed in claim 5, wherein R^ is hydrogen or methyl.

7. A compound as claimed in any one of claims 1 to 6 wherein R is hydrogen or(C1-C7)-alkyl.

8. A compound as claimed in claim 7 wherein R is hydrogen or methyl.

9. A compound as claimed in any one of claims 1 to 8 wherein R5 is halogen having an atomic number not greater than 35.

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

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

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

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

15. 8-Chloro-6-(2-chlorophenyl)-1,4-dihydro-l,2-dimethylpyrroloE 3,4-d][2]benzazepin-3(2H)-one.

16. 8-Chloro-6-(2-chlorophenyl)-1,4-dihydro-2-(2-hydroxyethyl)-l-methylpyrrolo[3,4-d]t2]benzazepin-3(2H)-one.

17. 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-zepin-1(2H)-one, 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-2-methyl-pyrrolo[3,4-d][2]benzazepin-l(2H)-one, 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l-hydroxy-pyrroloC3,4-d][2]benzazepin-3(2H)-one, 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-3-hydroxy-pyrrolo[3,4-d][2]benzazepin-l(2H)-one, 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]-[2]benzazepin-l(2H)-one-5-oxide, 8-chloro-6-(2-chlorophenyl)-1-ethvl-1,4-dihydropyrrolo-[3,4-d][2]benzazepin-3(2H)-one, 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-l-methyl-3-oxo-2H-pyrrolo[3,4-d][2]benzazepin-2-acetic acid methyl ester or 8-chloro-6-(2-chlorophenyl)-l,4-dihydro-l-methyl-3-oxo-2H-pyrrolo[3,4-d][2]benzazepine-2-acetamide.

18. A compound as claimed in any one of claims 1 to 17 for use as a pharmaceutically active substance.

19. A ccmpound as claimed in-any one of claims 1 to 17 for use as a sedative or anxiolytic agent.

20. A process for preparing a canpound as claimed in any one of claims 1 to 17 which comprises a) for preparing a compound of the formula I given in claim 1 wherein R^ or R3 is hydrogen or (C^Cy)-alkyl and the remaining substituents are as defined in claim 1 or an N-oxide thereof, oxidizing a compound of the formula R V II wherein one of R^ and R33 is hydrogen and the other is hydrogen or (C^-C^)-alkyl and R, Rg and Rg are as defined in claim 1 with a peracid, or b) for preparing a compound of the formula I given in claim 1 wherein or R3 is hydroxy and the remaining substituents are as defined in claim 1 or R^ and Rj and R3 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 R3 or R3 is hydrogen and the remaining substituents are as defined in claim 1, or a compound of the formula II above wherein R^^ and R^ are each hydrogen, with a lead (IV) car— boxylate in the presence of a strong acid, or c) for preparing a compound of the formula I given in claim 1 wherein R^ or R3 is acetoxy and the remaining substituents are as defined in claim 1, treating a compound of the formula I given in claim 1 wherein R^ or R3 is hydrogen and the remaining substituents are as defined in claim 1, or a compound of the formula II above wherein R11 and 1*3·^ are each hydrogen, with lead tetraacetate in acetic acid, or d) for preparing a compound of the formula I given in claim 1 wherein R^ or R^ is -OCOR1 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 a carboxylic anhydride in the presence of a base, or e) for preparing a compound of the formula I given in claim 1 wherein R^ or R3 is (C^Cy)-alkoxy and the remaining' substituents are as defined in claim 1, treating a compound of formula I given in claim 1 wherein R^ or R3 is -OGOR1 or hydroxy and the remaining substituents are as defined in claim 1, or a compound of the formula R wherein R^2 is acetoxy and R, Rg and Rg are as defined in claim 1 with a (Cj-Cy) -alkanol in the presence of a strong acid, or f) for preparing a compound of the formula I given in claim 1 wherein R^ or R, is hydrogen or -alkyl and the - remaining substituents are as defined" in claim 1, desoxy-genating an N-oxide of the formula are as defined wherein R, , R2» R3. R^/ Rg and Rg in claim 1 and, if desired, 5 g) converting a compound of formula I into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable salt of a compound of formula I into another pharmaceutically acceptable salt.

21. A medicament containing·a compound as claimed in 10 any one of claims 1 to 17 and a therapeutically inert excipient.

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

23. The use of a compound as claimed in any one of claims 1 to 17 for the preparation of a medicament for the control or prevention of excitation and anxiety.

24. A compound as claimed in any one of claims 1 to 17, whenever prepared by the process as claimed in claim 20. 20

25. A pyrrolo[3, 4-d][2]benzazepine derivative of the general formula I given and defined in claim 1 or an N--oxide thereof or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with part-25 icular reference to Examples 1-22 of the accompanying Examples. 54 5 513 4

26. A process for preparing a pyrrolo[3, 4-dl [2]ben2iizopine derivative of the general formula I given and defined in claim 1. or an N-oxide thereof or a pharmaceutically acceptable salt thereof·, substantially as hereinbefore described with particular reference to

27. A pyrrolo[3, 4-d][2]benzazepine derivative of the general formula I given and defined in claim 1 or an N-oxide thereof or a pharmaceutically acceptable salt thereof, whenever prepared by a process claimed in claim 26. 10

28. A medicament according to claim 21, substantially as hereinbefore described with particular reference to Examples A-C of the accompanying Examples. F. R. KELLY & CO. , AGENTS FOR THE APPLICANTS.