CA1202970A - Benzazepine derivatives - Google Patents

Abstract

ABSTRACT

Compounds of the formula I

wherein R1 and R3 are hydrogen, lower alkyl, hydroxy, lower alkoxy or acyloxy 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, C2 to C7 carboxylic acids and the esters and amides thereof, hydroxy C2 to C7 alkyl, amino C2 to C7 alkyl or mono- or di-lower alkyl amino C2 to C7 alkyl; R5 is halogen having an atomic number not greater than 35 or hydrogen; and R6 is halogen having an atomic number not greater than 35 with the proviso that when R1 or R3 is hydroxy, lower alkoxy or acyloxy, then R
is lower alkyl or hydrogen and the N-oxides and the pharmaceutically acceptable salts thereof exhibit activity as sedative and anxiolytic agents.

Description

`` 12~Z~7Q

The present invention relates to pyrrolo[3,4-d][2]-benzazepine derivatives of the general formula R
I

~ 4 --N

~ R5 IJ
wherein Rl and R3 are hydrogen, lower alkyl, hydroxy, lower alkoxy or acyloxy and R2 and R4 are hydrogen or Rl 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, C2 to C7 : carboxylic acids and the esters and amides thereo~, hydroxy C2 to C7 alkyl, amino C2 to C7 alkyl or mono- or di-lower alkyl amino C2 to C7 alkyl; R5 is halogen having an atomic number not greater than 35 or hydrogen; and R6 is halogen having an akomic number not greater than 35 with the proviso that when Rl or R3 is hydroxy, lower alkoxy or acyloxy, then R
is lower alkyl or hydrogen and the N-oxides and the pharmaceutically acceptable salts th`~ereof.

The compounds exhibit activity as sedative and anxio-35 lytic agents.

Bt/25.3.83 .~

V~970 By the term "halogen having an atomlc number not greater than 35" is meant bromo, chloro or fluoro except as limited herein.

6 By the term "lower alkyl" is meant bobh straight and branched chaln Cl to C7 hydrocarbon groups, preferably Cl to C4 carbon-hydrogen radicals, such as methyl, ethyl, propyl, isopropyl and the like.

By the term "acyloxy" is meant a radical derived from an organic acid by the removal of the hydrogen atom i.e., radicals of the formula -O-I~R wherein R is Cl to C6 alkyl, phenyl or hydrogen, eOg., acetyl, propionyl, butyryl, 15 benzoyl, etc.

By the term "C2 to C7 carboxylic acids and the esters and amides thereof" is meant radicals of the formula -Cl to C6 alkyl COR2l where R2l is hydroxy, lower alkoxy, amino or 20 amino which is mono- or di-substituted by lower alkyl.

The expression "pharmaceutically acceptable salts" is used to include 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 R3 and R4 taken together are an oxo group. Still further preferred compounds are those of formula I wherein R2 is hydrogen, Rl is preferably hydrogen or lower alkyl, more preferably hydrogen or methyl. The preferred meaning of R is hydrogen or lower alkyl, more prefera~ly hydrogen or methyl. R5 is pre~erably 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 inven-tion are those of formula I, wherein R and R1 are hydrogen or lower alkyl, preferably methyl, R2 is hydrogen, R3 and R4 taken together are an oxo ~roup and R5 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-1~2H)-one, 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d]-[2]benzazepin-1(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-Z0 pyrrolo[3,4-d][2]benzazepin-1(2H)-one, 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-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-1(2H)-one, 8-chloro-6-(2-chlorophenyl)pyrroloC3,4-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-1(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-1-me~hyl-3-oxo-2H-pyrrolo~3,4-d][2]benzazepine-2-acetic acid methyl 35 ester and 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methyl-3-oxo-2H-pyrrolo[3,4-d][2]benzazepine-2-acetamide.

~2~2~3~0 ~specially preferred compounds are: .

8-chloro-6-(2~fluorophenyl)-l,4-dihydropyrrolo~3,4-d]-~2]benzazepin-3(2H)-one, 8-chloro-l,4-dihydro-6-phenylpyrrolo[3,4-d][2]benzaze-pin-3(2H)-one, 8-chloro-6-(2-chlorophenyl)-l,4-dihydro-l,2-dimethyl-pyrrolo~3,4-d]~2]benzazepin-3(2H)-one and 8-chloro-6-(2-chlorophenyl)-l,4-dihydro-2-(2-hydroxy-10 ethyl)-l-methylpyrrolo~3~4-d][2]benzazepin-3(2H)-one~

The most preferred compounds are:

8-chloro-6-(2-chlorophenyl)-l,4-dihydropyrrolo[3,4-d]-15 [2]benzazepin-3(2H)-one, 8-chloro-6-(2-chlorophenyl)-l,4-dihydro-l-methyl-pyrrolo[3,4-d][2]benzazepin-3(2H)-one and 8-chloro-6-(2-chlorophenyl)-l,4-dihydro-2-methyl-pyrrolo[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 25 a) for preparing compounds of the formula I above wherein Rl or R3 is hydrogen or lower alkyl and the remaining sub-stituents are as above and the N-oxides thereof, by oxi-dizing a compound of the formula N
R~ t R31 ~ ~ II
35 R6 ~ N
~ R5 ~Z(~2970 wherein one of Rll and R3l is hydrogen and the other is hydrogen or lower alkyl and R, R5 and R6 are as above with a peracid, or b) for preparing compounds of the formula I above wherein Rl or R3 is hydroxy and the remaining substituents are as above or Rl and R2 and R3 and R4, respectively, are, when taken together, oxo groups and the remaining symbols are 10 as above, by oxidizing a compound of formula I wherein R
or R3 is hydrogen and the remaining substituents are as above, or a compound of the formula II above wherein Rll and R3l are hydrogen, with a lead (IV) carboxylate in the presence of a strong acid, or c) for preparing compounds of the formula I abo~e wherein Rl or R3 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 20 above, or a compound of the formula II above wherein Rll : and R3l are hydrogen, with lead tetraacetate in acetic acid, or d) for preparing compounds of the formula I above wherein 25 Rl or R3 is acyloxy and the remaining substituents are as : above, by treating a compound of formula I wherein Rl or R3 is hydroxy and the remaining substituents are as above, with a carboxylic anhydride in the presence of a base, or~

30 e) for preparing compounds of the formula I above wherein Rl or R3 is lower alkoxy and the remaining substituents are as above, by treating a compound of formula I wherein Rl or R3 is acyloxy or hydroxy and the remaining substituents are as above, or a compound of the formula .

~12 ~ ~ R12 III
~ =
~T--R5 `~

wherein R12 is acetoxy and R, R5 and R6 are as above with a lower alkanol in the presence of a strong acid, or 1~ f) for preparing compounds of the formula I above wherein Rl or R3 is hydrogen or alXyl and the remaining substi-tuents are as above, by desoxygenating an N-oxide of the formula R~ ~ R3 R2 ~ - / R4 6 ?
R ~ ~ ~
~5 ...
l~ R2, R3, R4, R5 and R~ are as above 30 and, if desired, g) by converting a compound of formula I into a pharma-cautically acceptable salt or converting a pharmaceutically acceptable salt of a compound of formula I into another 35 pharmaceutically acceptable sal~.

The oxidation of a compound of formula II with a peracid according to process embodiment a) of the present ~;J

~2~ 70 process is performed in a manner known per se. Suitable peracids for this oxidation step are peracids such as m-chloroperben20ic acid, pertrifluoroacetic acid and the like. Depending on the reaction conditions used, one will obtain elther the corresponding compounds of formula I or the N-oxides thereof. For obtaining the compounds of formu-la 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 achlorinated hydrocarbon, e.g., methylene chloride, an aro-matic 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 suitableinert 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 0C and about room temperature. It should be noted that a mixture of the l-oxo and 3-oxo compounds will be obtained when in the starting material of formula II both Rll and R3l are hydrogen. In case the oxidation is performed under strong 25 acidic conditions, the 3-oxo compound will predominate whereas the l-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 accor-ding 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-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 stron~ acid such as trifluoroacetic acid lZ~Z97~

and the like can suitably be used. The reaction is prefera-bly performed in a temperature range of from about 0C to about room temperature. In the case of a compound of formu-la II wherein Rll and R3l are hydrogen, a mixture of the l-hydroxy-3-oxo, the 3-hydroxy-l-oxo and l,3~dioxo com-pounds is obtained. The mixture thus obtained can be separa-ted by standard chromatographic procedures.

Also, the reaction in accordance with process embodi-10 ment c) of the present process is performed according toknown 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 Rll and R3l are hydrogen is used as starting material, a 15 mixture of the l-acet~xy-3-oxo and 3-acetoxy l-oxo com-pounds and of a l,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 Rl or R3 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, 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 0C to about room tempe-30 rature.

The etherification in accordance with process embodi-ment e) of the present process is performed in a manner known per se, expediently by reacting a compound of formu-35 la I wherein Rl or R3 is acyloxy, preferably acetoxy, or acompound 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-~2970 g ferably performed at a temperature between about 0C andabout room temperature.

The desoxygenation in accordance with process embodi-ment f) of the present process is also performed according to known methods, conveniently by treatlng a compound of the ~ormula IA with a desoxygenating agent such as phos~
phorous trichloride or triphenylphosphine in an inert sol-vent such as chlorinated hydrocarbons, e.g., methylene 10 chloride, aromatic hydrocarbons, e.g., toluene, ethars, e.g., tetrahydrofuran, and the like at a temperature bet-ween about room temperature and the reflux temperature of the solvent.

The startlng 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 illus-trate the preparation of these formula II compounds.

l~Z97~

Scheme I

R6 _ CHCN ~ CN

S ~ R5 ~1 / N

I V H

R ~ R ~ 0~ NH2 ~ R5 ~ R5 IIa V

wherein R13 is hydrogen or lower alkyl and R5 and R6 are as above.

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 an ether, such as diethylether, dloxane or tetrahydrofuran as solvent. The reaction temperatures may range from about 0C to about 40C with about room temperature being pre-ferred. The a--tosyl alkylisocyanides mentioned above may be prepared following the teaching of van Leusen et al., 10 Tetrahedron Letters, 3487 (l975).

IV --~ IIa The compound of formula IV can be reacted with hydro-gen 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 IIa.

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 -20C to about room tempe-rature, with about 0C being preferred.

30 V ~ IIa 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 IIa.
35 The reaction temperature may range from about room tempera-ture to the boiling point of the solvent, with about 40C
being preferred.

~LZ~;~970 Scheme II
H

R6~
~R5 IIa' ////// I ~\\' [~3 R5 ~ R5 IIa" IIb wherein R14 and R32 are lower alkyl and R5 and R6 are as above.

IIa' --~ IIa" + IIb The compound of formula IIa' can be reacted with one equivalent of a strong base such as lithium diisopropyl-amide at between about -80C to about 0C, with about -20C
being preferred. The resulting anion is treated with the desired alkylating agent, such as a lower alkyl halide or sulfonate. A mixture of formula IIa" and IIb isomers results which can be separated by standard column chromatography procedures.

97~) Scheme III
Rn ~6 - ~ ~3 R5 \

V ~ ~c,~ ,cocr~
tCH2)n+lN \ I 2n ~ ~ N~

R

~g ~ ~

(C~2~nCOoH ~ 32~n.~.lH

R J~ R6J~

wherein R" is lower alkyl, R7 is lower alkyl, R8 and Rg are hydrogen or lower alkyl and n is an lnteger from 1 to 6 and R11, R31, R5 and R6 are as above.

:~LZ~2!3 7~

IIc ~ IIh --~ IIj A compound of the formula IIc 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 alkoxide in a polar solvent such as dimethyl sulfoxide or dimethylformamlde. The reaction temperature may range from about -20C to about room temperature, with about 0C being preferred. If desired, the product of formula IIh 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 IIj.

IIh ~ IIf A compound of the formula IIh can be xeacted with ammonia or a mono- or di-lower alkyl amine and a catalytic amount of its hydrochloride saLt with a Cl to C4 alcohol solvent. The reaction is usually conducted at about 100C
using a pressure apparatus to contain the volatile reactants.
IIh A compound of the formula IIh 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 -80C to about room tempe-rature, with about 0C being preferred.

IIc --~ IIg A compound of the formula IIc can be reacted with a 30 compound of the formula X-(CH2)n+l-N \ VI
Rg wherein X is halide or sulfonate and R8, Rg and n are as above in the presence of a base such as an alkali metal alkoxide ."

~2~70 in a polar solvent such as dlmethylsulfoxide or dimethyl-formamide. The reaction temperature may range from about -20C to about room temperature with about room temperature being preferred.
IIc ~ IIe A compound of the formula IIc 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 sol-vent such as dimethylformamide or dimethyl sulfoxide. The reaction temperature may range from about 0C to about room temperature, with about 0C being preferred.

1~ IIf --~ IIg or IIh --~ IIi A compound of the formula IIf or IIh 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 -20C to about 20 room temperature, with about 0C being preferred.

IIc ~
A compound of formula IIc 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 ( 2)n+1 VII

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.

~Z~ 70 IIc -~ IIf A compound of formula IIc can be reacted with a com-pound of the formula ~; R8 ~ N-C0-(CH2)n-X VIII

wherein X, R8, 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 pharma-ceuticals and are characterized by activity a- sedatives 1~ and anxiolytic agents. These compounds can be used in the form of conventional pharmaceutical preparations; for example, the aforesaid compounds can be mixed with conven-tional organic or inorganic, inert pharmaceutical carriers suitable for parenteral or enteral administration such as, 20 for example, water, gelatin, lactose, starch, magnesium stearate, talc, vagetable oil, gums, polyalkylene glycols, Vaseline or the like. They can be administered in conven-tional 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 con-taining compounds of this invention can be subjected to conventional pharmaceutical expedients such as steriliza-tion, 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 administratisn and a dosage range 312029~0 - 18 ~

of from about 0.1 mg to about 50 mg being preferred for parenteral adminlstration. However, for any particular sub-ject, the specific dosage regimen should be adjusted accor-ding to individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compounds. It is to be understood that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of this invention.

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 cal-16 culated to produce the desired therapeutic effect in asso-ciation 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.

H-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 30 buffer is substituted for Krebs buffer. Drugs are assayed in triplicate. Radioactivity is measured by liquid scin~-tillation counting. The results are expressed as IC50 (nM), i.e. the concentrations required to inhibit the bindung by 50%.

3~ Activity of Standard Drugs: IC50 (nm) Diazepam 5.0 Flunitrazepam1.8 Flurazepam 15.6 ~Z{~Z~3170 -- 19 _ Results obtained with compounds of the invention: IC5~ (nM) 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-5 methylpyrxolo~3,4-d]~2]benzazepin-3(2H)-one ~LD50 ~ 800 mg/kg (po)(mice)] 0.006 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methylpyrrolo~3,4-d]~2]benzazepin-3(2H)-one 10 ~LD50 ~ greater than lQ00 mg/kg (po)(mice)] 1.0 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo-[3,4-d]~2]benzazepin-3(2H)-one 0.25 molar hydrate micronized 15 [LD50 ~ 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 consi-dered 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 protectlon against convulsions.
The number of animals protected from convulsions is deter-mined. The dose at which 50% of the animals are protected 35 from convulsive seizures is expressed as the ED50. The approximate ED50 is calculated by the method of Miller and Tainter (Proc. Soc. Exp. Biol. Med. 57:261, 1944).
,.~,,1 ~LZC~Z~7~

Activity of Standard Drugs:ED50 mg/kq po Chlordiazepoxide 3.9 Diazepam 1.0 5 Sodium Phenobarbital 19 Results obtained with compounds of the invention: ED50 m~//kq po 10 8-chloro-6-~2-chlorophenyl)-l~4-dihydr 2-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one 0.08 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-15 1-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one 0.08 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-pyrrolo~3,4-d]~2]benzazepin-3(2H)-one 20 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 inven-tion but are not meant to limit such invention.

,t~

1` ~2~2~0 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 hydrochioric acid to a pH of 3. The resulting precipitate was collected by filtration and dried to con-stant weight to give 2-benzyl-4-chlorobenzoic acid as a white solid, mp 142-144C.

b) To a solution of 28.4 g (0.75 mol) of lithium alu-minum hydride in 800 ml of ether, which was cooled to 0C, were addeddropwise 85.1 g (O.345 mmol) of 2-benzyl-4-chloro-benzoic a~id in 250 ml of ether. The mixture was allowed to 2~ warm to room temperature and was stirred for 2 hours. The excess lithium aluminum hy~ride was discharged by the addi-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 26 sodium sulfate. Removal of the ether at reduced pressure gave 2-benzyl-4-chlorobenzyl alcohol as a colorless oil which crystallized upon standing, mp 46.5-49C.

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 solventwas removed at reduced pressure to give 2-benzyl-4 chloro-benzaldehyde as a yellow oil, which was used without further purification.
*Trademark r~

i ~z~70 _ 22 -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 mix-ture 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 2~.8 g (0.14 mol) of 3-[2-benzyl-4-chloro-phenyl] -2-propenenitrile, 50 g (0.5 mol) of chromlum trioxide, 100 ml of methylene chloride, and 300 ml of acetic acid was stirred at room temperature overnight. The excess 20 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 S00 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 87-89C.

3-(2-~enzoyl-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-benzophenone in 250 ml of acetonitrile was added to a . . ,~.1 ~Z~Z~7~

mixture of 70 g (0.52 mol) of cupric chloride, 65 g (0.63 mole) o~ 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 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 69-71C.

g) A mixture of 50.9 g (0.168 mol) of a,4-dichloro-2-(benzoyl)benzenepropanenitrile, 17 g tO.14 mol) of potassium carbonate, SO.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 litersof 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 89-91C.
* * *
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 dim~thyl 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-~2-benzoyl-4-chloro-"

2~7~) phenyl~-lH-pyrrole-3-carbonitrile as off-white prisms, mp 175-177C.

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 appara-tus 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 203-206C.

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 concen-trated 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 methylenechloride) gave after crystallization from ethyl acetate 8-chloro-1,4-dihydro-6-phenylpyrrolo[3,4-d][2]benzazepin-3(2H)-one as pale yellow prisms, mp 205-208C.

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-1(2H)-one.

~2~Z97~

Example 2 a) ~he preparation of a,4-dichloro-2-(2-fluorobenzoyl)-benzenepropanenitrile was conducted in the same manner as S the preparation of a,4-dichloro-2-(benzoyl)benzenepropane-nitrile described in Example lf) to give pale yellow prisms, mp 94-95C.

b) The preparation of 3-[2-(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 137-139C.

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-iodobenzophenone, 2 ml (14.3 mmol) of triethylamine, 2 ml 20 (30 mmol) of acrylonitrile and 35 mg (1.5 mmol) of palla-dium acetate was refluxed under an atmosphere of argon for 16 hours. The mixture was diluted with 100 ml of lN hydro-chloric acid and the resulting precipitate was collected by filtration. The precipitate was washed with ether and ?5 air dried to give 3-[2-(2-fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile as an off-white solid,mp 130-133C.
* * *
d) The preparation of 4-~2-(2-fluorobenzoyl)-4-chloro-phenyl]-lH-pyrrole-3-carbonitrile was conducted in the same 30 manner as the preparation of 4-[2-benzoyl-4-chlorophenyl]-lH-pyrrole-3-carbonitrile described in Example lh) to give off-white prisms, mp 177-179C.

e) A mixture of 3.0 g (9 mmol) of 4-~2-(2-fluorobenzoyl)-3S 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 filtra-tion, and the acetic acid was removed :~2~;Z970 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 methy-lene chloride solution was drled 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 197-199C.
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, S.0 g (15.0 mmol) of 8-chloro-6-(2-fluoro-15 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. Purificaticn 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-fluoro-phenyl)-3,4-dihydropyrrolo[3,4-d][2]benzazepin-1(2H)-one as pale yellow prisms, mp 223-225C.

F~rther elution gave in the second product band after crystalli-zation from ethyl acetate 8-chloro~6-(2-fluorophenyl)-1,4-dihydropyrro-10[3,4-d][2]benzazepin-3(2H)-one as colorless prisms, mp 217-218C.

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-lZ~7~

nitrile described in Example lf) to give off-white prisms, mp 102-103C.

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 o~f-white prisms, mp 140-141~C.

10 c) The preparation of 4-[2-(2-chlorobenzoyl)-4~chloro-phenyl]-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 182-184C.
1~
d) The preparation of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d~[2]benzazep~ne was conducted in the same manner as the preparation of 8-chloro-6-t2-fluorophenyl)-2H,4H-pyrrolo[3,4-d]~2]benzazepine described in Example 2e) to give cream-colored prisms, mp 204-206C.

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 25 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 bisul-- fite solution, and the mixture was concentrated at reduced pressure. The-residue was partitioned between methylene 30 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 35 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-d][2]-benzazepin-3(2H)-one as pale yellow prisms, mp 243-244C.
Crystallization of the mother liquor from ethyl acetate gave 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d][2]-97~
~ 28 -benzazepin-1(2H)-one as pale yellow prisms, mp 195-197C.

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 ln 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,4~-pyrroloC3,4-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 o 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 solu-tion 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-dihydropyrroloC3,4-d][2]benzazepin-1(2H)-one as pale yellow prisms, mp 195-197C. Further elution ga~e in 25 the second product band after crystallization from methy' lene chloride 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-pyrrolo~3,4-d][2]benzazepin-3(2H)-one as colorless prisms, mp 243-244C.

Example S

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 C2]benzazepine in 350 ml of methylene chloride which wascooled to 0C. The reaction mixture was stirred at 0C
for 2.5 hours and then neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloride solution ~LZV2~7~

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-ride) gave a mixture of two products. Further purification of the mixture by chromatography (alumina, 150 g; eluent, 5% methanol in methylene chloride) gave in the first pro-duct 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-1(2H)-one-S-oxide as pale yellow prisms, mp 243-244C.

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

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 Qil 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 lN 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 206-208C, as tan crystals. Recrystallization from ether gave the desired product as colorless crystals, mp 210-211C.

12~ 9~

A second crop of crystals consisting of 6-chloro-8-(2-chlorophenyl)-1,8-dihydro-8-hydroxy-2-methylindeno-[2,1-b]pyrrole-3-carbonitrile, mp 221-225C, was obtained from ether. Recrystallization from ether gave pale yellow prisms, melting at 232-237C.

b) A mixture of 8.5 g (24 mmol) of 4-[4-chloro-2-(2 chlorobenzoyl)phenyl]-S-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 over-night. 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 concen-trated at reduced pressure. The residue was crystallized from a mixture of ether and petroleum ether to give off-~hite crystals, mp 219 222C. Recrystallization from a 20 mixture of ether and methylene chloride gave 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine as colorless crystals, mp 221-225C.

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-pyrrolo[3,4-d][2]benzazepine were added, and the resulting mixture was stirred at room temperature for 30 minutes. The 30 mixture was diluted with methylene chloride and neutrali-zed 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-1-methylpyrrolo[3,4-d][2]-benzazepin-3(2H)-one as pale yellow prisms, mp 239-241C.

25~'7~1 Example 7 a) In one portion, 0.7 g (2.2 mmol) of 8-chloro-6-~2-chlorophenyl)-2H,4H-pyrroloC3,4-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 0C.
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 167-168C.

The methanesulfonate salt of 8-chloro-6-(2-chloro-phenyl)-2-methyl-2H,4H-pyrrolo~3,4-d]~2]benzazepine 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-26 cr~stallization from a mixture of methanol and ether gave the methanesulfonate salt as orange prisms, mp 200-203C.

b) In one portion, 1.4 ml of 30% hydrogen peroxide were added to 56 ml of a 1% solu-tion of concentrated sulfuric 30 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 concentra-ted ammonium hydroxide solution, washed with brine, dried over anhydrous sodium sulfate and concentrated at reduced ` ~2~Z97~31 ' 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 crystalliza~ion from ether 8-chloro-6-~2-chloro-phenyl)-3,4-dihydro-2-methylpyrrolo~3,4-d]~2]benzazepin-1(2H)-one as yellow prisms, mp 177-178C.

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]~2]benzazepin-3(2H)-one as pale yellow prisms, mp 173-175C.

Example 8 15 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 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. Afte~ stirring for 1.5 hours, 500 ml of water were added dropwise, followed by 50 ml of lN 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-[-2-(2-chlorobenzoyl)-4-chlorophenyl]-5-ethyl-lH-pyrrole-3-carbonitrile as off-white prisms, mp 163-164C.

Further elution gave in the second product ban~ after crystallization from ether 6-chloro-8-(2-chlorophenyl)-2-ethyl-1,8-dihydro-8-hydroxyindeno[2,1-b]pyrrole-3-carbo-nitrile a`s colorless prisms, mp 172-174C.
,~:

lZ~2g7~

b) A mixture of 3.3 g (8.9 mmol) of 4-[2-(2-chloro-benzoyl)-4-chlorophenyl]-5-ethyl-lH-pyrrole-3-carbonitrile, O.S 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 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 wlth 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 filtra-tion and dissolved in tetrahydrofuran. The tetrahydrofuran solution was dried over anhydrous sodium sulfate and con-centrated 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 251-253C. Recrystallization from a mixture of ether and methylene chloride gave off-white prisms, mp 254-255C.

20 c) In one portion, 0.9 ml ~7.9 mmol) of 30% hydrogen peroxide was added to 40 ml of a 1% solution of concentra-ted 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 chloridesolution was washed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure. The resul-ting oil was crystallized from ether to give 3-chloro-6-(2-chlorophenyl)-1-ethyl-1,4-dihydropyrrolo[3,4-d][2]benza-35 zepin-3(2H)-one as yellow prisms, mp 233-235C. Recrystalli-zation from a mixture of ethyl acetate and methanol gave colorless prisms, mp 236-237C.

~ ~ . 3 ~Z(?Z97~

Example 9 a) In one portion, 2.0 g (5.8 mmol) of ~-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) of potassium t-butoxide in 20 ml of dry dimethylformamide.
After stirring at 0C 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 resultlng 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~[2]benzazepine as orange prisms, mp 200-202C. A sample was recrystallized from a mixture of ether and methylene chloride to give pale yellow prisms, mp 203-204C.

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% solutlon 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 con-centrated at reduced pressure. The residue was partitioned between methylene chloride and water and basified 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-1,2-dimethylpyrrolo-~3,4-d][2~benzazepin-3(2H)-one as pale yellow prisms, 3S mp 207-208Oc.

~,J~

:~Z~Z970 Example 10 a) In one portion, 2.0 g (5.8 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d]C2]benzazepine were added to an ice-cooled solution o~ 0.8 g (7.1 mmol) of potassium t-butoxide in 30 ml of dry dimethylfoxmamide.
After stirring at 0C for 15 minutes, 0.65 ml (7.7 mmol) of methyl bromoacetate was added, and the resulting solu-tion was stirred for 5 minutes.iThe 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-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic acid methyl ester as off-white prisms, mp 174-176C.

20 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 dis-charged with the addition of saturated aqueous sodium bi-sulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between methy-30 lene chloride and water and neutralized with concentratedammonium hydroxide solution. The methylene chloride solu-tiOII 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-(2-35 chlorophenyl)-1,4-dihydro-1-methyl-3-oxo-2H-pyrrolo[3,4-d]-[2]benzazepine-2-acetic acid methyl ester as pale yellow prisms, mp 221-223C. Recrystallization from ethyl acetate gave colorless prisms, mp 223-224C.

~2~970 a) In one portion, 4.0 g (11.7 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo~3,4-d]~2]benzazeplne 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 0C for lS minutes, 1.4 g (15.0 mmol) of 2-chloroacetamide were added, and the resulting solution was stirred for S ~ninutes. The mixture was diluted with 10 water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhy-drous 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 142-145C.

~0 b) In one portion, 0.7 ml (6.2 mmol) of 30/O hydrogen peroxide was added to a 1% solution of concentrated sul-furic 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-pyrroloC3,4-d]~2]benzazepine-2-acetamide were ~dded, 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)-1,4-dihydro-1-methyl-3-oxo-2H-pyrrolo~3,4-d]-35 ~2]benzazepine-2-acetamide as colorless prisms, mp 221-222C.

3L2~2~70 Example 12 a) A solution of 4.0 g (9.6 mmol) of 8-chloro-6-~2-chloro-phenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic acid methyl ester in 40 ml of tetrahydrofuran was added dropwise to a solution of 0.8 g (21.0 mmol) of lithium alu-minum hydride in 50 ml of tetrahydrofuran which was cooled to -78C. When the addition was complete, the reaction mix-ture was allowed to warm to 0C 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)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepin-2-ethanol as pale yellow prisms, mp 149-152C. Recrystallization from a mixture of ether and methylene chloride gave white prisms, mp 151-153~C.

20 b) In one portion, 0.58 ml (5.1 mmol) of 30% hydrogen peroxide was added to a 1% solution of concentrated sul-furic acid in acetic acid. After stirring for 1 hour, 1.3 g (3.3 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4 d][2]benzazepin-2-ethanol were added, and the 25 resulting solution was stirred ~or 30 minutes. The excess ~eracid was discharged with the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was parti-tioned between methylene chloride and water and neutrali-30 zed with concentrated ammonium hydroxide solution. Themethylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to a yellow residue. Purifica-tion by column chroma-tography (silica gel, 30 g; eluent, 3% methanol in methylene 35 chloride) gave in the first product band after crystalliza-tion from a mixture of ether and methylene chloride 2-[2-(acetoxy)ethyl]-8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one as colorless ~ZQ~970 prisms, mp 152-154C.

Further elution gave ln 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)-on~ as colorless prisms, mp 164-165C.

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-1(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-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.
Purification of the residue by column chromatography (silica gel, 10 g; eluent, 5% methanol in methylene chloxide) followed by crystallization from ether gave 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-3-hydroxypyrrolo[3,4-d][2]benza-zepin-1(2H)-cne as pale yellow prisms, mp 221-222C.

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 tetra-ace-tate 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 sodiumsulfate and concentrated at reduced pressure to a yellow residue. Purification of the residue by column chromato-graphy (silica gel, 10 g; eluent, 5% methanol in methylene o chloride) followed by crystallization from ether yave 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-hydroxypyrrolo-[3,4-d][2]benzazepin-3(2H)-one as pale yellow prisms, mp 247-249C.

Example 15 In one portion, 5.0 g (15.2 mmol) of 3-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 trichloro-acetic acid and 14.0 g (31.6 mmol) of lead ~etraacetate in 50 ml of methylene chloride. The mixture was stirred at room temperature for 4 hours and then diluted with methy-lene chloride and water. The methylene chloride solution 15 was washed with saturated aqueous sodium bicarbonate solu-tion, 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 ~3-chloro-6-(2-chlorophenyl)pyrrolo~3,4-d][2]benzazepin-1,3(2H,4H)-dione as yellow prisms, mp 224-225C.

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][2]benzazepin-1(2H)-one as pale yellow prisms, mp 222-223C.

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

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-I

l~a~

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 the addition of saturated aqueous sodium carbonate solution and extracted with methylene chloride. The methylene chlo-ride 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-pyrroloZ3,4-d][2]benzazepine-1,3-diol diacetate as colorless needles, mp 189-190C.

Further elution gave 1.95 g of a foam which crystalli-zed from a mixture of ether and petroleum ether to give 8-chloro-6-(2-chlorophenyl)-3-acetoxy-3,4-dihydropyrrolo-20 t3,4-d][2]benzazepin-1(2H)-one as colorless prisms, mp 172-174C.

Continued elution gave fine needles. Recrystallization from a mixture of ether and methylene chloride gave 8-25 chloro-6-(2-chlorophenyl)-1-acetoxy-1,4-dihydropyrrolo-[3,4-d][2]benzazepin-3(2H)-one, mp 219-221C.

Example 17 A solution of 0.3 g (O.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 of 30 ml of methylene chloride and 10 ml of tetrahydrofuran 35 was stirred at 0C 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-~2~ 0 - 41 ~

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-~benæoyloxy)-3,4-dihydro-pyrrolo[3,4-d]~2]benzazepin-1(2H)-one as colorless crystals.
Recrystallization from ether gave colorless crystals, mp 140-142C.

Example 18 A solution of 0.6 g of 8-chloro-6-(2-chlorophenyl)-3-acetoxy-3,4-dihydropyrrolo[3,4-d][2]benzazepin-1(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 157-160C.

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 tempe-rature 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-1-methoxy-pyrrolo[3,4-d][2]benzazepin-3(2H)-one methanesulfonate.
Recrystallization from a mixture of ether and methanol gave fine needles, mp 185-187C.

~L2~2970 Example 20 ~ solution of 1.5 g (3.4 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepin-1,3-diol 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 resid~e 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-1(2H)-one as off white crystals, mp 192-194~C. The presence of the isomeric 8-chloro-6-(2-chloropAenyl)-1,4-dihydro-1-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-chloro-phenyl)-1,4-dihydro-3-methoxypyrrolo[3,4-d][2~benzazepin-25 1(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. Re-crystallization from a mixture of methanol and ether gave the salt as colorless crystals, mp 157-160C.
Example 21 In one portion, 1.8 ml (20 mmol) of phosphorous tri-chloride 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 ., ~2~297~

chloride and neutralized with saturated a~ueous 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-dihydropyrrolo[3,4-d]C2]benzazepin-3(2~)-one as an orange solid. Recrystallization from ethyl acetate gave pale yellow prisms of a 0.25 mole hydrate, mp 255-256C.

Example 22 In one portion, 2 ml (2.3 mmol) of phosphorous tri-chloride 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 reflu~ed for 1 hour. The mixture was concentratedat 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-1(2H)-25 one as pale yellow prisms solvated with 0.5 mole ethylacetate, mp 195-197C.

~Z~;~970 Example A

Tablet Formulation (Direct compression) 5 Item Ingredients mg/tablet 1. 8~chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-d]-[2]benzazepin-3(~H)-one 1 5 10 25 or 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methylpyrrolo-[3,4-d][2]benzazepin-3~2H)-one 2. Lactose 221 217 212 181 3. Avicel 45 45 45 55 15 4. Direct Compression Starch 30 30 30 35 5. Magnesium Stearate _ 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.

* Trademark ~Z~2~0 - 45 _ Example B

Tablet Formulation (Wet granulation) 5 Item Ingredients mg/tablet 1. 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrroloC3,4-d]-[2]benzazepin-3(2H)-one1 5 10 25 or 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methylpyrrolo-~3,4-d]~2]benzazepin-3(2H)-one 2. Lactose 202 232 261 280 3. Modified Starch 25 35 45 55 15 4- Pregelatinized Starch20 25 30 35 5. Distilled Water q.s.
6. Magnesium Stearate 2 3 4 5 Weight of tablet 250 300 350 400 20 Procedure:

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.
5. Compress on a suitable press equipped with appropriate punches.

Example C

Capsule Formulation 5 Item Ingredients mg/capsule 1. 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo~3,4-d]-~2]benzazepin-3(2H)-one1 510 25 or 8-chloxo-6-(2-chlorophenyl)-1,4-dihydro-1-methylpyrrolo-~3,4-d]~2]benzazepin-3~2H)-one 2. Lactose 203 193.5 328 372.5 3. Starch 30 3540 30 15 4- Talc * 15 1520 20 5. Aerosol OT 1 1.5 2 2.5 Capsule fill weight250 350400 450 Procedure:

1. Mill Items 1, 2, 3, and 5 in a suitable mixer. ~ill.

2. Add talc and mix well.

25 3. Encapsulate on suitable equipment.

* Trademark P~

Claims (33)

1. A process for preparing pyrrolo[3,4-d][2]benzaze-pine derivatives of the general formula I

wherein R1 and R3 are hydrogen, lower alkyl, hydroxy, lower alkoxy or acyloxy 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, C2 to C7 carboxylic acids and the esters and amides thereof, hydroxy C2 to C7 alkyl, amino C2 to C7 alkyl or mono- or di-lower alkyl amino C2 to C7 alkyl; R5 is halogen having an atomic number not greater than 35 or hydrogen; and R6 is halogen having an atomic number not greater than 35 with the proviso that when R1 or R3 is hydroxy, lower alkoxy or acyloxy, then R
is lower alkyl or hydrogen the N-oxides and the pharmaceutically acceptable salts thereof which comprises a) for preparing compounds of the formula I above wherein R1 or R3 is hydrogen or lower alkyl and the remaining sub-stituents are as above and the N-oxides thereof, oxi-dizing a compound of the formula II

wherein one of R11 and R31 is hydrogen and the other is hydrogen or lower alkyl and R, R5 and R6 are as above with a peracid, or b) for preparing compounds of the formula I above wherein R1 or R3 is hydroxy and the remaining substituents are as above or R1 and R2 and R3 and R4, respectively, are, when taken together, oxo groups and the remaining symbols are as above, oxidizing a compound of formula I wherein R1 or R3 is hydrogen and the remaining substituents are as above, or a compound of the formula II above wherein R11 and R31 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 R1 or R3 is acetoxy and the remaining substituents are as above, treating a compound of the formula I wherein R1 or R3 is hydrogen and the remaining substituents are as above, or a compound of the formula II above wherein R11 and R31 are hydrogen, with lead tetraacetate in acetic acid, or d) for preparing compounds of the formula I above wherein R1 or R3 is acyloxy and the remaining substituents are as above, treating a compound of formula I wherein R1 or R3 is hydroxy and the remaining substituents are as above, with a carboxylic anhydride in the presence of a base, or e) for preparing compounds of the formula I above wherein R1 or R3 is lower alkoxy and the remaining substituents are as above, treating a compound of formula I wherein R1 or R3 is acyloxy or hydroxy and the remaining substituents are as above, or a compound of the formula III

wherein R12 is acetoxy and R, R5 and R6 are as above with a lower alkanol in the presence of a strong acid, or f) for preparing compounds of the formula I above wherein R1 or R3 is hydrogen or alkyl and the remaining substi-tuents are as above, desoxygenating an N-oxide of the formula IA

wherein R, R1, R2, R3, R4, R5 and R6 are as above and, if desired, g) converting a compound of formula I into a pharmaceuti-cally acceptable salt or converting a pharmaceutically acceptable salt of a compound of formula I into another pharmaceutically acceptable salt.

2. A process as claimed in claim 1 wherein there are prepared compounds of formula I as defined in claim 1 or pharmaceutically acceptable acid addition salts thereof.

3. A process as claimed in claim 1 wherein R3 and R4 taken together are an oxo group.

4. A process as claimed in any one of claim 1 wherein R2 is hydrogen.

5. A process as claimed in any one of claim 1 wherein R1 is hydrogen or lower alkyl.

6. A process as claimed in claim 5 wherein R1 is hydrogen or methyl.

7. A process as claimed in any one of claim 1 wherein R is hydrogen or lower alkyl.

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

9. A process as claimed in any one of claim wherein R5 is halogen having an atomic number not greater than 35.

10. A process as claimed in claim 1 wherein 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-d][2]benzazepin-3(2H)-one is prepared by oxidizing 8-chloro-6-(2-chloro-phenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine with a peracid.

11. A process as claimed in claim 1 wherein 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methylpyrrolo[3,4-d][2]-benzazepin-3(2H)-one is prepared by oxidizing 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo-[3,4-d][2]benzazepine with a peracid.

12. A process as claimed in claim 1 wherein 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-methylpyrrolo[3,4-d][2]-benzazepin-3(2H)-one is prepared by oxidizing 8-chloro-6-(2-chlorophenyl)-2-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine with a peracid.

13. A process as claimed in claim 1 wherein 8-chloro-6-(2-fluorophenyl)-1,4-dihydropyrrolo[3,4 d][2]benzazepin-3(2H)-one is prepared by oxidizing 8-chloro-6-(2-f1uoro-phenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine with a peracid.

14. A process as claimed in claim 1 wherein 8-chloro-1,4-dihydro-6-phenylpyrrolo[3,4-d][2]benzazepin-3(2H)-one is prepared by oxidizing 8-chloro-6-phenyl-2H,4H-pyrrolo [3,4-d][2]benzazepine with a peracid.

15. A process as claimed in claim 1 wherein 8-chloro-6-(2-chlorophenyl)-I,4-dihydro-1,2-dimethylpyrrolo[3,4-d][2]
benzazepin-3(2H)-one is prepared by oxidizing 8-chloro-6-(2-chlorophenyl)-1,2-dimethyl-2H,4H-pyrrolo[3,4-d][2]
benzazepine with a peracid.

16. A process as claimed in claim 1 wherein 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-(2-hydroxyethyl)-1-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one is prepared by oxidizing 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepin-2-ethanol with a peracid.

17. Pyrrolo[3,4-d][2]benzazepine derivatives of the general formula I

wherein R1 and R3 are hydrogen, lower alkyl, hydroxy, lower alkoxy or acyloxy 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, C2 to C7 carboxylic acids and the esters and amides thereof, hydroxy C2 to C7 alkyl, amino C2 to C7 alkyl or mono- or di-lower alkyl amino C2 to C7 alkyl; R5 is halogen having an atomic number not greater than 35 or hydrogen; and R6 is halogen having an atomic number not greater than 35 with the proviso that when R1 or R3 is hydroxy, lower alkoxy or acyloxy, then R
is lower alkyl or hydrogen the N-oxides and the pharmaceutically acceptable salts thereof, whenever prepared according to the process claimed in claim 1 or by an obvious chemical equivalent thereof.

18. Compounds of the general formula I as defined in claim 17 and pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 2 or by an obvious chemical equivalent thereof.

19. Compounds as claimed in claim 17 wherein R3 and R4 taken together are an oxo group, whenever prepared according to the process claimed in claim 3 or by an obvious chemical equivalent thereof.

20. Compounds as claimed in claim 17 wherein R2 is hydrogen, whenever prepared according to the process claimed in claim 4 or by an obvious chemical equi-valent thereof.

21. Compounds as claimed in claim 17 wherein R1 is hydrogen or lower alkyl, whenever prepared according to the process claimed in claim 5 or by an obvious chemical equivalent thereof.

22. Compounds as claimed in claim 17, wherein R1 is hydrogen or methyl, whenever prepared according to the process claimed in claim 6 or by an obvious chemical equivalent thereof.

23. Compounds as claimed in claim 17 wherein R is hydrogen or lower alkyl, whenever prepared according to the process claimed in claim 7 or by an obvious chemical equivalent thereof.

24. Compounds as claimed in claim 17 wherein R is hydrogen or methyl, whenever prepared according to the process claimed in claim 8 or by an obvious chemical equivalent thereof.

25. Compounds as claimed in claim 17 wherein R5 halogen having an atomic number not greater than 35, whenever prepared according to the process claimed in claim 9 or by an obvious chemical equivalent thereof.

26. 8-Chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo-[3,4-d][2]benzazepin-3(2H)-one, whenever prepared according to the process claimed in claim 10 or by an obvious chemical equivalent thereof.

27. 8-Chloro-6-(2-chlorophenyl)-1,4-dihydro-l-methyl-pyrrolo[3,4-d][2]benzazepin-3(2H)-one, whenever prepared according to the process claimed in claim 11 or by an obvious chemical equivalent thereof.

28. 8-Chloro-6-(2-chlorophenyl)-1,4-dihydro-2-methyl-pyrrolo[3,4-d][2]benzazepin-3(2H)-one, whenever prepared according to the process claimed in claim 12 or by an obvious chemical equivalent thereof.

29. 8-Chloro-6-(2-fluorophenyl)-1,4-dihydropyrrolo-[3,4-d][2]benzazepin-3(2H)-one, whenever prepared according to the process claimed in claim 13 or by an obvious chemical equivalent thereof.

30. 8-Chloro-1,4-dihydro-6-phenylpyrrolo[3,4-d][2]-benzazepin-3(2H)-one, whenever prepared according to the process claimed in claim 14 or by an obvious chemical equivalent thereof.

31. 8-Chloro-6-(2-chlorophenyl)-1,4-dihydro-1,2-dimethylpyrrolo[3,4-d][2]benzazepin-3(2H)-one, whenever prepared according to the process claimed in claim 15 or by an obvious chemical equivalent thereof.

32. 8-Chloro-6-(2-chlorophenyl)-1,4-dihydro-2-(2-hydroxyethyl)-1-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one, whenever prepared according to the process claimed in claim 16 or by an obvious chemical equivalent thereof.

33. A process as claimed in claim 2 wherein R3 and R4 taken together are an oxo group.