AU558354B2 - Pyrrolo(3,4-d)(2)benzazepines - Google Patents

Description

U

IHVVKa 1331 NOIUflOS3d )AdO0CrnIvq

97-1w; Bj rzm MalI111

is pr~sc,-' R is hydrogen, lower alkyl, C2 to C 7 carbt, xyl ;ds and the esters and amides thereof, hydr,v tc alkvl, amino C, to alkvl or

TACT 1953

GCONVE PTAW3 ~17 AY9B LdI S.0 PATENT OF~CE Full nams) of -VWe F.Hoffmann-La Roche Applicant(s). Co.

of 124-184 Grenzache~rstrasse, Basle,. k itZeriand Addres(es) of Applican*) Ful naxme(s) of Applicaitt(s). hereby apply for the grant of as candard potent for an invention entitled

Title of lmvendlti- "Benzazepine derivatives" ONSHNRED

4.

which is described in the accompanying complete specification. Basic ountry(ies). DETAILS OF BASIC APPLICATION(S) a Number(s) of Basic Application(s) Priority. Date(s) 379,400 and 393,142 Basic Applicant(s) bo t Narne(-94 of Convention Country(4es- in which Basic Application(s) wftswere tiled US. A. 4 0 .PI!'Ifnw.ne(s) and addreas(es) of inwtnAor(s) C 4S4S 4* Date(s) of Basic Application(s) *4C

M@ 1 18, 1982 and June 28, 1982 (respectively)

M,4Our address for service is: SPRUSON FERGUSON Set out-'how Applicant(s) PATENT ATTORNEYS derive title-from actual inventor(s)'e.g. The CBA CENTRE, 60 MARGARET ST. .Applicant(s) is/are the asignee(s) 6f the SYDNEY. NEW SOUTH WALES. Invention'from the inventor(s) LODGED AT SU1-OF~iKL AUSTRALIA. Dated this 8th day of April 1983

Sydeney

Je an-Jac cluxis IHolder of' procu

To: The Cbmmissionei of Patents

<A MWtALTH toF AUST.RALIA

P~.N~ACT 1952 qJ .s~j Q

CMPLETE SECIFICATION (OR IG INAL) ILIA

~(~NE~jIN 2~ ATP7 A PATENT* rinupr o4 "Cox v ti,6hApp .pa etjofr ap 'n'er.benild -Titbofitvent~onW JjBe"1h az bp'ir0 14"r1,tiveE

I/e oaridBor r7 'FiuW' is)and 4iddz~s(4i) -of (of 'Stockacker~tr.sse 10, -,einach Switzerlalid

do solemnly and sincerely declare as follows:- Miliname(s) of Applicajit(s). (or, in the case of an-application by a bogty corporate) jam/! W~ Uthorised by F.Hoffmaxi-Ia Roche Co. Aktienigesellschaft the applicant(&) for the patent to make this declaration on its/+1*4 behalf. 2. The basic application(s) as defined by Section 141 of the Act was/ywere made

Bas'lcZountry(ies). in USA Priority. Date(s) onl Nay 18, 1982 and June 28, 1982 Basic Applicant(s) both by Rodney Ian'Fryer, Eugene J. Trybuiski and Armin Walser

3. ~mmnhia~ .Pt'lf~atne(s) and addrems(es) of iintor(s) (or where a person other than the in ilentor is the applicant)

3. 1) Rodney Ian-Fryer 2) Eugene J. Trybulski 3) Armin Walser Eton Drive, North Caldwell, USA Of 2) 13 Homer Street, Parsippany, USA 3) 19 Crane Avenue, West Caldwell, USA (respectively) -Wsare the actual inventor(s) of the -invention and the facts upon .I' which the applicant(s4 is/.are entitled to make the application are 4.44

as follows: Hof fmann-La Roche Inc. Nutley, N.J. USA is the Set out how Applicant(s) derive tide-from actual assignee of said Rodney Ian Fryer, Eugene J. Trybulski and inventor(s)e.g. The Afrmin Walser, and F.Hloffmann-iLa Roche Co. Aktiengesell- .olats)is/are the assignee(s) of the schaft, Basle, Switzerland, is the assignee of said invention'troni die Hoffmann-ia Roche Inc. invelntor(s)

The basic. application(s) referred to in paragr'aph 2 of this Declaration woe/were the first applivation(s) made in a Convention country in respect -of the invention the subject of the applicatio.i.

Deeared at -Basle this 8th day of April 19 83

4 4

*44.

SFP4 Signature of Decplarant(s) 1/81.

(12) AUSTRALIAN PATENT ABRIDGMENT (19) AU AU-B--14605f83

(54) PYRROLO [344 CZJBENZAZEPINES (71) F. HOFFMANN-.LA ROCHE CO. PKTIENGESELLSCHAFT (21) 14605/83 558354 (22) 17. 5.83 (24) 18.5 .82 (31 379400 (32) 18.5.82 (33) us 393142 28.6 .82 us

(43) 24. 11 .83 (44) 29. 1.87 C07D 487/04 A61K 31/55 (72) RODNEY IAN FRYER, EUGENE J. TRYBULSKI AND ARM1IN WAL SER (74) SF (56) 7382 5/8 1 545298 C07D 487/04

Sedative and anxiolytic agents

1. Pyrrolo[3,4-d1[2]benzazepine derivatives of the general formul.a R

wherein R 1 and R 3 are hydrogen, lower alkyl, hydroxy, lower alkoxy or acyloxy and R 2and R 4are hydrogen ori ad R2 ad/or R 3 andi R4 taken together are oxo groups with the proviso that at least one oxo group -/2

2 2

116==45/8 is prS6e R is hydrogen, lower alkyl, C2 to C 7 carbxyVl .ds and the esters and amides thereof, hydr,-Ky to C 7 alkyl, amino C 2 to C 7 alkyl or mono- or :-lower alkyl amino C 2 to C 7 alkyl; R5 is halogen having )n atomic number not greater than or hydrogen; and R 6 is halogen having an atomic number not greater than .5 with the proviso that when R or R is hydroxy, lower alkoxy or acyloxy, then R is lower alkyl or hydrogen the N-oxi.des and the pharmaceutically acceptable salts thereof.

116==45/9

r t: 4 it x A tip Holde of pc~agion Holder Of procuration

To: ThetiCommisionerof Patent

CO0mmOV4W AuLT" VF AiUST RA LIA

COMPrLETE SPECIFICATION (ORIGINAL)

FOR OFFICE USE

Class Int. Class Application Number Lodged

Complete Specification Lodged Accepted Published T dduxluet C-Ontains

Priority

Related Art

Name of Applicarnfts) F .HOFFMANN-LA ROCHE CO. AKTIENGESELLSCHAFT

Address of Applicant(+) 124-184 Grenzacherstrasse, Basle, Switzerland

Actual Inventor (s) RODNEY IAN FRYER, EUGENE J. TRYBULSKI and ARMIN WALSER

Address for bervice Spruson Ferguson, Patent Attorneys, OBA Centre Margaret Street, Sydney, New South Wales. 2000 Australia

Complete Specification for the invention entitled

"BEN?,AZEPINE DERIVATIVES"t

,Th~f~low~g~statelnent is a full description of this invenvion, including the best method of performing 'I kowo /us

Roeland-. Bor-er- Signature of Declaran.t(s)

cv>.

0: RAN 4008/329

ABSTRACT

Compounds of the formula

wherein R 1 and R 3 are hydrogen, lower alkyl, hydroxy, lower alkoxy or acyloxy and R 2 and R 4 are hydrogen or R 1 and R 2 and/or R 3 and R 4 taken together are oxo groups with the proviso that at least one oxo group is present; R is hydrogen, lower alkyl, C 2 to C 7 carboxylic acids and the esters and amides thereof, hydroxy C 2 to C 7 alkyl, amino C 2 to C 7 alkyl or mono- or di-lower alkyl amino C 2 to C 7 alkyl; R 5 is halogen having an atomic number not greater than or hydrogen; and R 6 is halogen having an atomic number not greater than 35 with the proviso that when R or R 3 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.

,*B

RAN 4008/329

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

rr

r *rn r

wherein R 1 and Ri are hydrogen, lower alkyl, hydroxy, lower alkoxy or acyloxy and R 2 and R 4 are hydrogen oit 9 (D C, 20 or R 1 and R 2 and/or R 3 and R 4 taken together are cxo groups with the proviso that at least one oxo group r

is present; R is hydrogen, lower alkyl, C 2 to C 7

J carboxylic acids and the esters and amides thereof, 1~ hydroxy C 2 to C 7 alkyl, amino C 2 to C 7 alkyl or mono- or d2-lower alkyl amino C 2 to C 7 alkyl; R 5 is halogen having an atomic number not greater than C1 or hydrogen; and R 6 is halogen having an atomic ~lb~~

number not greater than 35 with the proviso that when R 1 or R 3 is hydroxy, lower alkoxy or acyloxy, then R is lower alkyl or hydrogen and the N-oxides and the pharmaceutically acceptable salts thereof.

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

t t~ Bt/25.3.83

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

By the term "lower alkyl" is meant both straight and branched chain C 1 to C 7 hydrocarbon groups, preferably C 1 to C 4 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-C-R wherein R is C 1 to C 6 alkyl, 0 phenyl or hydrogen, acetyl, propionyl, butyryl, 15 benzoyl, etc.

By the term "C 2 to C 7 carboxylic acids and the esters and amides thereof" is r.meant radicals of the formula -C 1 to C 6 alkyl- COR21 where R21 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, hydrochloric acid, nitric acid, methansulfonic acid and p-toluenesulf-nic 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, the Schiff bases. Further preferred compounds are those of the formula I wherein R 3 and R 4 taken together are an oxo group. Still further preferred compounds are those of formula I vherein R 2 is hydrogen. R 1 is preferably hydrogen or lower alKyi, more preferably hydrogen or methyl. The preferred meaning of R is hydrogen or lower alkyl, more preferably hydrogen

I I I I' -3

or methyl. R 5. is preferably halogen having an atomic number 1 0 :ept not-greater than

From the above it follows that an especially preferred t and 5group of compounds within the scope of the present inven- [2]be Ly tion are those of formula I, wherein R and R 1 are hydrogen thyl, or lower alkyl, preferably methyl, R 2 is hydrogen, R 3 and pin-3 Rtaken together are an oxo group and R5 is halogen having an atomic number not greater than 35. pyrrc Ifrom L. e., Preferred compounds are: 10 ethyl alkyl, 8-chloro-6-(C2-fluorophenyl 4-dihydropyrrolo[ 3, 4-d]

[2]Ibenzazepin-1 C2H) -one, 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d]-

[2]benzazepin-1(2H) -one, 15 [21be esters 8-chloro-3 ,4-di.hydro-6-phenylpyrrolo[ 3,4-dl[2 ]benzaze- -C1 to pin-i1 )-one, pyrrco imino or 8-chloro--6-( 2-chlorophenyl)-3, 4-dihydro--2-methyl- pyrrolo[3,4-d][2]bv~nzazepin-1(2H)-one, pyrrol 8-ch'Loro--6-( 2-chlorophenyl 4-dihydro-l-hydroxy- is pyrrolo[ 3, 4-d] [2jbenzazepin-3(C2H) -one, 8-chloro-6-(C2-chiorophenyl 4-dihydro-3-hydroxy- ph arn pyrrolo[ 3, 4-dJ [2 ]benzazepin-1(2H) -one, in al tnd 25 8--chloro-6-(2-chlorophenylipyrrolo[3,4-dl[2]benzazepin- 1,3- (2H, 4H)-dione, 25 a) t and 8-chloro-6-( 2-chlorophenyl 4-dihydropyrroloL 3,4-dI R 1or iin *40.

[2 ]benzazepin-3(C2H) -one-S-oxide, sti tu 8-chloro-6-(C2-chiorophenvl) 4-dihvdropyrroloi3, 4-d I- d.1 z in,

[2]benzazepin-1( 28)-one-S-oxide, ent 8-chloro-6-r.2-chlorophenvl)-l-ethvl-1 ,4-dihydropyrrolo- f bases. 4-d] [2 Jbenzazepin-3 C2H) -one, 8-chloro-6-( 2-chlorophenyl 4-dihydro-l-methyl-3- oxo-2H-pyrrolo[3,4-d][2]b~enzazepine-2-acetic acid methyl er e in 35 ester and KVi 8-chloro-6-( 2-chlorophenyl 4-dihydro-1-methyl-3- n ng oxo-2H-pyrrolo[ 3,4-dJ [2 ]benzazepine-2--acetamide. ogen

17 r~ 0

Especially preferred compounds are:

8-chloro-6-(2-fluoropheny2l)-l ,4-dihydropyrrolo[3,4-dI-

[2 Jbenzazepin-3 (2H) -one, 8-chloro-1,4-dihydro-6-phenylpyrrolo[3,4-d][2]benzaze- pin-3 (2H) -one, 8-chloro-6-( 2-chlorophenyl 4-dihydro-1 ,2-dimethyl-

pyrrolo[3,4-d][2]benzazepin-3(2H)-one and 8-chloro-6- (2-chlorophenyl ,4-dihydro-2- (2-hydroxy-

ethyl) rethylpyrrolo[3, 4-d][2]benzazepin-3 (2H) -one.

The most preferred compounds are:

8-chloro-6-(2-chlorophenyl)-l ,4-dihydropyrrolo[3,4-d]-

[2]benzazepin-.3(2H)-one, 8-chloro-6- (2-chloropheriyl) 4-dihydro-1 -methyl pyrrolo[3,4-dl[2]bEtnzazepin.-3(2H)-one and 8-chloro-6-( 2-chiorophenyl) 4-dihydro-2-methyl- pyrrolo[3,4-d][2]benzazepin-3(2H) -one.

The compounds of formula I, the N-oxides and the pharmaceut--cally acceptable salts thereof can be prepared in accordance with the invention

a) for preparing compounds of the formula I above wherein R 1or R 3is 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 R N

R1 a31

I i wherein one of RI and R31 is hydrogen and the other is hydrogen or lower alkyl and R, R and R 6 are as above Swith a peracid, or

b) for preparing compounds of the formula I above wherein R or R 3 is hydroxy and the remaining substituents are as 31 Sabove or R and R 2 and R 3 and R 4 respectively, are, when taken together, oxo groups and the remaining symbols are 10 as above, by oxidizing a compound of formula I wherein R 1 or R is hydrogen and the remaining substituents are as *1 above, or a compound of the formula II above wherein Ri and R 3 are hydrogen, with a lead (IVl carboxylate in the presence of a strong acid, or 1 f 15 R1 c) for preparing compounds of the formula I above wherein tue R 1 or R is acetoxy and the remaining substituents are as 1 3 for" above, by treating a compound of the formula I wherein 9, or R 3 is hydrogen and the remaining substituents are as above, or a compound of the formula II above wherein R11 and R are hydrogen, with lead tetraacetate in acetic acid, or

d) for preparing compounds of ':he formula I above wherein R 1 or R 3 is acyloxy and the remaining substituents are as Sabove, by treating a compound of formula I wherein R 1 or R is hydroxy and the remaining substituercs are as above, 3 with a carboxylic anhydride in the precence of a base, or

30 and, 9 30 e) for preparing compounds of the formula I above wherein R1 or R 3 is lower alkoxy and the remaining substituents are as above, by treating a compound of form'ila I wh.r-in R 1 ceu 5' iceut or R is .icyloxy or hydroxy and the remaining substituents 3 acce are as above, or a compound of the formula 35 pharl

.pera(

1, I

"P

ea~~-r i -6

III

rein as en e

m wherel .n R12 is acetoxy and R, R5 and R6 are as above i with a lowe r alkanol in the presence of a strong acid,. or a

naring compounds of the formula I above whbrein 15 r f) for j i R1 or R3 1 .ydrogen or alkyl and the remaining substi- m rein tuents are as above, by desoxygenating an N-oxide of the ;1 b as formula R m P RR a R 2 R4 0 acid, t IA

,rein 25 a n w as R w r ma ve, di or o~

r o wherea n R, R11 R-41 4j, R, and R, are as above 30 ar rors 30 and, if desired, O rein ar e g) by converting a compound of formula I into a pharma- b) ceutically acceptable salt or converting a pharmaceutically acceptable salt of a compound of formula I into another pharmaceutically acceptable salt.

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

;P ,t 1;

0' -7

known per se. Suitable an process is performed in a manner peracids.for this oxidation step are peracids such as bl

m-chloroperbenzoic acid, pertrifluoroacetic acid and the ab

like. Depending on the reaction conditions used, one will 1a

obtain either the corresponding compounds of formula I or 5 1- the N-oxides thereof. For obtaining the compounds of formu- po la I, the reaction is expeditiously performed in a lower te

carboxylic acid such as acetic acid, trifluoroacetic acid, propionic acid and the like or in a mixture of such a car- boxylic acid with a suitable inert solvent such as a 10 me chlorinated hydrocarbon, methylene chloride, an aro- kn

matic hydrocarbon, benzene, toluene, and the like, wi ove in the presence of a strong mineral acid such as sulfuric ro or acid and the like. In case a corresponding N-oxide is desi- R

15 red, the reaction is conveniently performed in a suitable 15 mi (rein po inert solvent such as a chlorinated hydrocarbon, e.g., be he methylene chloride, or an aromatic hydrocarbon, e.g., st benzene, toluene and the like, in the absence of a strong r rri mineral acid. The oxidation of a compound of formula II is 0 preferably performed at a temperature between about 0 C and about room temperature. It should be noted that a mixture R3 of the 1-oxo and 3-oxo compounds will be obtained when in wit per the starting material of formula II both R1 1 and R 3 1 are pre hydrogen. In case the oxidation is performed under strong r

acidic conditions, the 3-oxo compound will predominate 25 N- whereas the 1-oxo compound will be the predominant product t: be

when the reaction is performed in the absence of a strong as

mineral acid. The mixture obtained can be separated accor- the sr ding to standard methods such as fractional crystallization tem 30 rat r r 30 and crhromatography. r r

The oxidation in accordance with process embodiment ~iz b) of the present process is also performed according to men

known per se. In this oxidation, lead (IV) carboxy- kno methods lates such as lead tetraacetate or lead (IV) trifluoroace- 35 la ii tate in an inert solvent such as chlorinated hydrocarbons corr r such as methylene chloride or chloroform, and the like in con t:; met r the presence of a strong acid such as trifluoroacetic acid

4:i

t

21 0l ia S

8

ble and the like can suitably be used. The reaction is prefera- fe abc sbly performed in a temperature range of from about 0°C to the about room temperature. In the case of a compound of formu- will la II wherein R11 and R31 are hydrogen, a mixture of the 5 l-hydroxy-3-oxo, the 3-hydroxy-l-oxo and 1,3-dioxo com- 5 men I or formu- pounds is obtained. The mixture thus obtained can be separa- to the )wer ted by standard chromatographic procedures. th acid, pho a car- Also, the reaction in accordance with process embodi-en ment c) o-f the present process is performed according to 10 chl

aro- known methods. Thus, the starting material can be reacted e.g

ke, with lead tetraace.tate in acetic acid, preferably at about wee tb uric room temperature. Ir case a compound of formula II wherein Sdesi- R1 and R3 are hydrogen is used as starting material, a :able 15 mixture of the l-acetoxy-3-oxo and 3-acetoxy-l-oxo com- 15 be h pounds and of a 1,3-bis-acetoxy compound of formula III will the be obtained. The mixture obtained can be separated by standard chromatographic procedures. trat :rong II is iC and 20 The reaction of a compound of formula I wherein R 1 or :ture R 3 is hydroxy with a carboxylic acid anhydride in accordance n in with process embodiment d) of the present process is also are performed in a manner known per se, preferably in the rong presence of a base such as pyridine, dimethylaminopyridine, e 25 N-methylpiperidine and the like. Inert solvents which can oduct be used in this reaction are chlorinated hydrocarbons such'" rong as methylene chloride, ethers such as tetrahydrofuran, and ccor- the like. The reaction is conveniently performed at a zation temperature in the range of about 0°C to about room tempe- 30 rature.

nt The etherification in accordance with process embodi- to ment e) of the present process is performed in a manner :boxy- known per se, expediently by reacting a compound of formu- )ace- 35 la I wherein R 1 or R 3 is acyloxy, preferably acetoxy, or a )ons compound of formula III, with an excess of a lower alkanol in containing a catalytic amount of a strong acid such as acid methane sulfonic acid an,' the like. This reaction is pre-

,II '4, i~ri4

i w p22- i rZ.ili ;I fer'ably performed At a temperature between abo,,t 00 C and 'era :about r.oom temperature. to )rmu- The desoxygenation in accordance with process embodi- ie ment f) of the present process is also performed according to known methods, conveniently by treating a compound of apara- the formula IA with a desoxygenating agent such as phos- phorous trichioride or triphenyiphosphine in an inert sol- R 6 vent such as chlorinated hydrocarbons, methylene odi- chloride, aromatic hydrocarbons, toluene, ethers, to tetrahydrofuran, and the like at a temperature bet- ted ween about room temperature and the reflux temperature of bout tbn solvent. rein i a The starting materials of formula IT are known or can be prepared in an analogous manner to the preparation of r I will ror the known compounds. The following reaction schemes illus- sr i ar trate the preparation of these formula II compounds. iii or rdance Iso dine, can such a.

and

r

rpe- c

odi- Ha r Lrmu- or a anol

C _:Z

Scheme I

odi ding of CH-CN

Sol,-

can

US

4

H

4

wherein R1 is hydrogen or lower alkyl and R5 and R6 are as above.

24

I

/2

ND 2 2

116==45/8

11

IlI IV The compo'nd 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, dioxane or tetrahydrofuran as solvent. The reaction temperatures may range from about D0C to about 40"C with about room temperature being pre- ferred. The a-tosyl alkylisocyanides mentioned above may be prepared following the teaching of van Leusen et al., Tetrahedron Letters, 3487 (19751.

IV Ila The cc;npound of formula IV can be reacted with hydro- gen at pressures ranging from about atmospheric pressure to five atmosphere:. 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 spontaneo'sly to prDduct IIa.

IV V The compound of formula TV can be reacted with a metal hydride reducing agent, such as lithium aluminu. hydride in an therla. solvent such as tetrahydrofuran. The reaction temperature may range from about -20°C to about room tempe- Tature, with about 3"C being preferred.

V :a The compound of formula V can be reacted with manganese dioxide in an ether 3olvent, such as tetrahydrofuran or another suitable solvent, such as toluene. The resulting amine thus formed cyclizes spontaneously to product IIa. The reaction temperature may range from about room tempera- ture to the boiling point of the solvent, with about 400 C being pi -'erred.

1)

Scheme II H

Ila'

IIa" wherein R 14and R 32are lower alkyl and R 5and R6 are as above.

10/82

13

IIa' IIa" IIb The compound of formula IIa' can be reacted with one equivalent of a strong base such as lithium diisopropyl- amido at between about -80 C to about 0°C, with about 1 5 being preferred. The resulting anion is. treated with the desired alkylating agent, such as a lower alkyl halide or sulfonate. A mixture of formula IIa" and IIb isomers results which can be separated by standard c,.umnhroamtgrph procedures.

~4

I

.4*

'V

7Th Scheme III

H I -I-

wherein R" is lower alkyl, R 7is lower alkyl, R and 8 R9 are hydrogen or lower alkyl and n is an integer from 1 to 6 and Rl1 R3 1 R 5 and R 6 are as'above.

IIc IIh IIj A compound of the formula IIc can be reacted with a halo -ester such as ethyl bromoacetate or ethyl 3-bromopro- 1 pionate in the presence of a base such as an alkali metal alkoxide in a polar solvent such as dimethyl sulfoxide or dimethylformamide. The reaction temperature may range from Sabout -20*C to about room temperature, with about 0°C being preferred. If desired, the product of formula IIh thus obtained may be treated with an alkali metal carbonate or 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 reacted with ammonia or a mono- or di-lower alkyl amine and a catalytic amount of its hydrochloride salt with a C 1 to C 4 alcohol solvent. The reaction is usually conducted at about 100°C using a pressure apparatus to contain the volatile reactants.

IIh IIi 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 temperature may range from about -80°C to about room tempe- rature, with about 0°C being preferred.

IIc IIg A compound of the formula IIc can be reacted with a compound of the formula

R8 X-(CH 2 2 n+1 -Nn+l V R 99

wherein X is halide or sulfonate and R 8 R 9 and n 81 9 are as above in the presence of a base such as an alkali metal alkoxide

I

R 2 is hydrogen. R 1 is preferably hydrogen or lower alKyi, more preferably hydrogen or methyl. The preferred meaning of R is hydrogen or lower alkyl, more preferably hydrogen

16-

in a polar solvent such as dimethylsulfoxide or dimethyl- formamide. The reaction temperature may range from about -200C 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, potassium or sodium methoxide, followed by an alkylating agent, such as

i~ 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 0°C to about room temperature, with about 0 C being preferred.

ft ft

IIf IIg or IIh IIi A." A compound of the formula IIf or IIh is reacted with k *4. a metal hydride reducing agent, such as lithium aluminum hydride in an ether solvent, such as tetrahydrofuran. The ,t t f reaction temperature may range from about -20*C to about 20 room temperature, with about 0°C being preferred.

L IIc IIi 3:is 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

f4, X-(CH2)n+1OZ VII 2 n+1

wherein Z is a hydroxy protecting group and X and n '4ai are as above.

*v1FI: Suitable hydroxy protecting groups include the tetra- hydropyranyl ether group. Subsequent treatment with aqueous acid yields the desired end product.

IIc IIf A compound of formula IIc can be reacted with a com- pound of the formula

R8 VIII -N-CO-(CH 2 n-X R

wherein X i- as abov" and R8 R 9 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 pharma- ceuticals and are characterized by activity as sedatives 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, for example, water, gelatin, lactose, starch, magnesium stearate, vegetable oil, gums, polyalkylene glycols, talc, Vaseline or the like. They can be administered in conven- tional pharmaceutical forms, solid forms, for example, tablets, dragees, capsules, suppositories or the like, or In liquid forms, for example, solutions, suspensions or emulsions. Moreover, the pharmaceutical compositions con- taining compounds of this invention can be subjected to S* conventional pharmaceutical expedients such as steriliza- tion, and can contain conventional pharmaceutical excipients such as preservatives, stabilizing agents, wetting agents, emulsifying agents, salts for the adjustment of osmotic pressure, or buffers. The compositions can also contain other therapeutically active materials.

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 ahout 0.1 mg to about 100 mg being preferred for oral administration and a dosage range of from about 0.1 mg to about 50 mg being preferred for I parenteral administration. 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 it" as employed throughout this specification refsrs pharmaceutically discrete units suitable as unitary do-;ges for mammalian subject each containing a predetermined quantity of active material cal- culated to produce the desired therapeutic effect in asso- ciation with the required pharmaceutical diluent, carrier or vehicle.

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

3 H-Diazepam Binding Assay

The 4ssay 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 buffer is substituted for Krebs buffer. Drugs are assayed 6 in triplicate. Radioactivity is measured by liquid scin- tillation counting. The results are expressed as IC 5 0 i.e. the concentrations required to inhibit the bindung by Activity of Standard Drugs: IC50 -50 (nm) Diazepam Flunitrazepam 1.8 Flurazepam 15.6

Result's obtained with compounds of the invention: IC 5 0 (nM)

8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2- methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one

[LD 50 800 mg/kg (po)(mice)] 0.006

8-chloro-6-(2-chloroplienyl) 4-dihydro-l- methylpyrrolo[3,4-d][2]benzazepin-3(2Hl-one

[LD50 greater than 1000 mg/kg (po)(mice)]

8-chloro-6-(2-chlorophenyl)-1,4-dlhydropyrrolo-

[3,4-d][2]benzazepin-3(2H)-one 0.25 molar hydrate micronized

[LD 50 greater th.an 1000 mg/kg (po)(mice)] 0.003

1. 8-chloro-6-(2-chlorophenyl)-1,4-dhydropyrrolo--

[3,4-d][2Jbenzazepin-3(2H)-one 300 mg/kg (po)(mice)] 0.002

Otan trnitr Tes In travenous/ Atna~fRetr-a-a -Testt

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 f r 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 observed 30 seconds for protection against convulsions. The number of animals protected from convulsions is deter- mined. The dose at which 50% of the animals are protected from convulsive seizures is expressed as the ED 5 0 The approximate ED50 is calculated by the method of Miller and Tainter (Proc. Soc. Exp. Biol. Med. 57:261, 1944).

8'J' "A

Activity of Standard Drugs.: ED p

Chiordiazepoxide 3.9 Diazepam Sodium Phenobarbital 19

Results obtained with compounds of the invention: ED 50m~gp0

8-chloro-6-(C2-chlorophenyl ,4-dihvdro- 2-methylpyrrolo[ 3, 4-dI [2 Jbenzazepin- 3( 2H) -one 0.08

8-chloro>-6-( 2-chiLorophenyl )-1,4-dihydro- 1-methylpyrrolo[3,4-dM[2lbenzazepin- 3(2H) -one 0.08

8-chloro-6-( 2-chiorophenyl -1,4-dihydro- pyrrolo[3,4-dl[2lbenzazepin-3(2H)-one 0.25 molar hydrate micronized 0.07

B-chloro-6- (2-chiorophenyl ,4-dihydro- pyrroloE3,4-dM[2]benzazepi-n-3(2H)-one 0.03

The following examples are illustrative of the inve n- tion but are not meant to limit such invention.

Example 1

a) To a solution of 5.0 g of cupric sulfate in 3 liters of concentrated ammonium xide 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 filtration. The filtrate was acidified by the addition of concentrated hydrochloric acid to a pH of 3. The resulting precipitate was collected by filtration and dried to con- stant weight to give 2-benzyl-4-chlorobenzoic acid as a white solid, mp 142-144 0 C.

b) To a solution of 28.4 q (0.75 mol) of lithium alu- minum hydride in 800 ml of ether, which was cooled to 0°C, were addeddropwise 85.1 g (0.345 mmol) of 2-benzyl-4-chloro- benzoic acid in 250 ml of ether. The mixture was allowed to S 20 warm to room temperature and was stirred for 2 hours. The excess lithium aluminum hydride 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 sodium sulfate. Removal of the ether at reduced pressure gave 2-benzyl-4-chlorobenzyl alcohol as a colorless oil which crystallized upon standing, mp 46.5-49 0 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 salts were precipitated by the addition of 2.4 liters of a 1:1 mixture of ether and petroleum ether, and the preci- pitate was removed by filtration through Celite. The solvent was removed at reduced pressure to give 2-benzyl-4-chloro- benzaldehyde as a yellow oil, which was used without further purification.

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 of water and 1.5 liters of ether. The ether solution was separated, washed with water, and dried over sodium sulfate. The ether was removed at reduced pressure to give 3-[2- benzyl-4-chlorophenyl]-2-propenenitrile as a yellow oil which was used without further purification.

e) A mixture of 28.8 g (0.14 mol) of 3-[2-benzyl-4-chloro- phenyl]-2-propenenitrile, 50 g (0.5 mol) of chromium trioxide, 100 ml of methylene chloride, and 300 ml of acetic A 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 I methylene chloride and pentane) to give a white solid, 4 mp 87-89"C. a(

3-( 2 -Benzoyl-4-chlorophenyl)-2-propenenitrile was also prepared as follows:

f) A solution of 92.7 g (0.4 mol) of en n 250 ml of acetonitrle was added to a bonaoriphznonc in 250 ml of acetonitrile was added to a 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 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)benze-eproparenitrile, 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- S(benzoyl)benzenepropanenitrile, 17 g (0.14 mol) of potassium carbonate, 50.9 g (0.5 mol) of potassium'bicarbonate and 510 ml of dimethyl sulfoxide was stirred at room tempera- 20 ture for 48 hours. The mixture was diluted with 1.5 liters of water, and the resulting precipitate was collected by filtration. Recrystallization from a mixture of methylene chloride and ether gave 3-(2-benzoyl-4-chlorophenyl)-2- propenenitrile as off-white prisms, mp 89-91°C. S. S 25 25 h) A mixture of 10.7 g (40 mmol) of 3-(2-benzoyl-4-chloro- phenyl)-2-propenenitrile, 5.3 g (38 mmol) of tosylmethyl isocyanide, 75 ml of dimethyl sulfoxide and 150 ml of ether were added dropwise to a suspension of 3.7 g (77 mmol) of 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 S' 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 by column chromatography (800 g silica gel; eluent, ether in methylene culoride) gave 4-[2-benzoyl-4-chloro-

i

:7

wherein R13 is hydrogen or lower alkyl and R 5 and R 6 are as above. 6

24

24

63 0 ml phenyl]-lH-pyrrole-3-carbonitrile as off-white prisms, ng mp 175-177C. ure ml i) A mixture of 4.0 g (13 mmol) of 4-[2-benzoyl-4-chloro- phenyl]-1H-pyrrole-3-carbonitrile, 4 g of Raney nickel, and 300 ml of acetic acid were hydrogenated on a Parr appara- he tus for 4 hours. The Raney nickel was removed by filtration, le, and the filtrate was diluted with 400 ml of ice water. The th a acetic acid was neutralized with sod'-.m bicarbonate, and t 10 the resulting solutior racted with methylene chloride. the The methylene chloride on was washed with water and dried over sodium sulfa Concentration of the methylene chloride solution gave a yellow solid. Recrystallization from methylene chloride/ether gave 8-chloro-6-phenyl-2H,4H- 0 pyrrolo[3,4-d][2]benzazepine as white solid, mp 203-206 C. Ssium j) In one portion, 4.0 g (13.6 mmol' of 3-chloro-6-phenyl- 2H,4H-pyrrolo[3,4-d][2]benzazepine were added to a mixture .rs. of 3.4 g (15.7 mmol) of m-chloroperbenzoi: acid in 100 ml of 2% concentrated sulfuric acid in acetic acid and the e 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 oro- 25 methylene chloride and water and neutralized with concen- trated ammonium hydroxiac solution. The methylene chloride her solution was washed with brine, dried over anhydrous sodium Ssulfate and concentrated at reduced pressure to a dark f hen residue. Purification of thp residue by column cnromato- 30 graphy (silica gel, 100 g; eluent 5% methanol in methyiene chloride) gave after crystallization from ethyl acetate 8-chloro-1,4-dihydro-6-phenylpyrrolo[3,4-d ][2benzazepin- 3(2H)-one as pale yellow -risms, mp 205-208°C. ted on 35 Thin layer chromatography of the crystallization fil- trates indicated th presence of the isomeric 8-chloro- 3,4-dihydro-6-phenylpyrrolo[ 3, 4-d [C2 ]benzazepin-1 (2H) -one.

M 1

At AA*.

A o A h i38 amine thi's formed cyclizes spontaneously to product ha. The reaction temperature may range from about room tempera- ture to the boiling point of the solvent, with about being pit-erred.

Example 2.

a) The preparation of QL,4-dichloro-2-(2-fluorobenzoyl)- benzenepropa,,,enitrile was conducted in the same manner as1 the preparat-on of a,4-dichloro-2-(bEnzoyl)benzenepropane- 5 s nitrile desc:ibed in Examale 1f) to give pale yellow c*is C mp 94-05*C. rr

b) The oreparation of 3-[2/--(2-fluorobenzovi)-4-ch'loro- IT

inenv.-L---propenenitrile was conducted in the same manner as the preparation of 3-(2-benzovl-4-chlorophenyl)-2-pro- f oeren:trile described in Example lcg) to give off-white prisms, nip 13"-139*C. C

2-.2-FLuroenzoyl;.4-chlor-.?henyl>'J2-.propenenitrile 15 F was a'so prepared as follows: t

A sc_,:tion of 5.0 g (14 mmol)" of -ho2flro-S :idonenzooPhe-ncne, 2 ml (14.3 mmol) if trien..lamine, 2 mla 3t) mint> of acrvLm)ritr1ie and 35 mq (1.5 minol) )f palla- 20 m Jium ace*tate 'as refluxeu under -in atmosphere if argon for a lo nours. The mixture was diluted w.,h >0m! of IN hydro-W cni.of~ acd anu the resulting precipitat was collected a by;%,f *.rition. The precipitate was washed with ether and r air driedi'e 3-[L2-'2-fluorobenzoyi)-4-cnlDropnenyli]- t7, 2-oropenenitr,.le as an rff-white scl_-i,mp I36_-133 0 C.

1 Te ore~arati~n if 4-K2-'2-f'4icr')benrzovi'-4-ch.Loro- cr 15-yrle--abrIt lwa~s :zrnduc ted in the same JC 'mar.ni-~r as -eoreparatir -iff 4K12-roerzoyi -4-c-hi-)rr phenvl :Hr~~rl-3cabnir~edescribed in' Example 1h to give z :rr-wn:-e orisms, mp 177-.79*00.1

"ix t.ir e -of 3.3 m'imo 1) of 4K- 2 f .o robe n zov1 4 r-ohe ny I 1-1 H-py rri e- 3-c ar or)nitrle ca 3 i R aney 3 i_-K l and 150 ml o f -4pac-a 1 ai: e ti- ac id ias hyaroaen ateia a Parr aparatus at 5C psi for 6 hours. The Raney n:ICe. was removed by filtration, and the acetic acil was removed t

L 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 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 (16.0 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 acueous sodiur- bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between methylene chloride and water and basified with concentrated ammonium hvyroxide 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- phenyl) 4-dihydropyrrolo[ 3, 4-d] [2]benzazepin-1 (2H) -one as pale yellow prisms, mp 223-225"C.

Further elution gave in the second product band after crystalll- zation from ethyl acetate 8-cihloro-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-chlorobenzoy-'- bensenepropanenitrile was conducted in the same manner as the preparation of a, 4 -dichloro-2-(benzoyl)benzenepropane-

Itrile described in Example if) to give off-white prisms, mp 102-103"C.

b) The preparation of 3-[2-(2-chlorobenzoyl)-4-chloro- phenylj-2-propenenitrile was conducted in the same manner as the preparation of 3-(2-benzoyl-4-chlorophenyl)-2-pro- penenitrile described in Example Ig) to give off-white prisms, mp 140-141 0 C.

c) The preparation of 4-[2-(2-chlorobenzoyl)-4-chloro- phenyl]-1H-pyrrole-3-carbonitrile was conducted in the same manner as the preparation of 4-L2-benzoyl-4-ch'orophenyll- 1H-pyrrole-3-carbonitrile described in Example lh) to give off-white prisms, mp 182-184'C.

d) The preparation of 8-chloro-6-(2-chlorophenyl)-2H,4H- pyrrolo[3,4-d][2]benzazepine was conducted in the same manner as the preparation of 8-chloro-6-(2-fluorophenyl)- 2H,4H-pyrrolol3,4-d][2]benzazepine descrioed in Example 2e) to giv2 cream-colored prisms, mp 204-206"C.

e) In one portion, 10.0 g (30.5 mmcl) of 8-chloro-6-(2- chlorophenyl)-2H,4H-pyrrolo[3,4-d][23benzazepine were added to a mixture of 7.6 g (35.2 mmol) of 80% m-chloroperbenzoic acid in 225 ml of 2% concentrated sulfuric acid in acetic acid and stirred at room temperature for 1 hour. The excess peracid was discharged with saturated aqueous 3odium bisul- fite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between rethylene chloride and :.ater and basified with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give 10.0 g of a yellow residue. Crystallization from methylene chloride gave 8-chloro-6-(2-chlorophenyl)-1,4-d ydropyrrolot3,4-d][2]- benzazepin-3(2H)-one as pale yellow prisms, mp 243-244o. Crystallization of the mother liquor from ethyl acetate gave 8-chloro-6-(2-chlorophenyl)-3,4-dinydropyrrolo[3,4-d[2-

Iii

wherein R" is lower alkyl, R 7 is lower alkyl, R 8 and R 9 in are hydrogen or lower alkyl and n is an integer from 1 to 6 and R1 R R 5 and R are as above. 31' 5 6

28

i was s, benzazepin-1(2H)-one as pale yellow prisms, mp 195-197°C. was and yel Example 4 y tog

r 5 In one portion, 9.8 ml of 30% hydrogen peroxide solu- o of tion were added to 195 ml of a 1% solution of concentrated sulfuric acid in acetic acid. The mixture was stirred at duc room temperature for 1 hour. In one portion, 9.8 g ac mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d]- dih

[2]b nzazepine were added to the mixture and stirred at p pal same room temperature for 2.5 hours. The excess peracid was 1- discharged by the addition of saturated aqueous sodium ve bisulfite solution, and the mixture was concentrated at cr reduced pressure. The residue was partitioned between no methylene chloride and water and basified with concentrated C2 4H- ammonium hydroxide solution. The methylene chloride solu- so tion was washed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give 10.0 g 2e) of a yellow residue. Purification of the residue by column chromatography (silica gel, 200 g; eluent, 5% methanol in a) methylene chloride) gave in the first product band after be be 2- crystallization from ethyl acetate 8-chloro-6-(2-chloro- of dded phenyl)-3,4-dihydropyrrolo[3,4-d][2]benzazepin-l(2H)-one as S* an( zoic pale yellow prisms, mp 195-197°C. Further elution gave in 4. 4. ic 25 the second product band after crystallization from methv- hy cess lene chloride 8-chloro-6-(2-chlorophenyl)-1,4-dihydro- t te sul. pyrrolo[3,4-d][2]benzazepin-3(2H)-one as colorless prosms, co Ced mp 243-244 0 C.

e ium 30 Example 5 so su and In one portion, 15.0 g (69.5 mmol) of 80% m-chloro- low perbenzoic acid were added to a solution of 10.0 g (30.5 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d]- 35 [2]benzazepine in 350 ml of methylene chloride which was c cooled to 0°C. The reaction mixture was stirred at 0 C p gave for 2.5 hours and then neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloride solution

irir- 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, 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- dihydropyrrolo[3,4-d][2]benzazepin-l(2H)-one-5-oxide as pale yellow prisms, mp 243-244 0 C.

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-oxide as pale yellow prisms solvated with 0.5 mole of methanol, mp 234-236°C.

Example 6

a) A mixture of 33.9 g (0.11 mol) of 3-[2-(2-chloro- benzoyl)-4-chlorophenyl]-2-propenenitrile, 20 g (0.96 mol) of 1-tosylethyl isocyanide in 150 ml cf dimethylsulfoxide and 100 ml of ether was added dropwise to a suspension of 4.6 g (0.1 mol) of a 50% mineral oil dispension of sodium hydride in 100 ml of ether which was immersed in a room temperature water bath. Stirring at room temperature was continued for 2 hours. The mixture was diluted with 1.2 C qd

t liters of water and 40 ml of 1N 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 green oil. Crystallization from a mixture of ether and petroleum ether gave 4-[4-chloro-2-(2-chlorobenzoyl)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°C.

i '4 I. 'tr.

iyuxiupyLjdny euner group. Subsequent treatment with aqueous acid yields the desired end product.

30

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 221-225°C, 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]-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 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- ted by filtration. The precipitate was dissolved in tetra- hydrofuran, dr J 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- white crystals, mp 219-222°C. Recrystallization from a 20 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.

S" 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 chlcride 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] benzazepin-3(2H)-one as pale yellow prisms, mp 239-241'C.

"I

Example 7

a) In one portion, 0.7 g (2.2 mmol) of 8-chloro-6-(2- chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.3 g (2.6 mmol) of potassium t-butoxide in 30 ml of dry dinethylformamide 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 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 ether gave 8-chlorc-6-(2-chlorophenyl)-2-methyl-2H,4H- pyrrolo[3,4-d][2]benzazepine as colorless prisms, mp 167- 1680C.

The methanesulfonate salt of 8-ch.oro-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- crystallization from a mixture of methanol and ether gave the methanesulfonate salt as orange prisms, mp 2C0-203°C.

b) In one portion, 1.4 ml of 30% hydrogen peroxide were added to 56 ml of a 1% solution of concentrated sulfuric 3C 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 w7.s concentrated at reduced pressure and the residue 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 pressure to a yellow residue. Purification of the residue by column chromatography (silica gel, 100 g; eluent, methanol in methylene chloride) gave in the first product band after crystallization from ether 8-chloro-6-(2-chloro- phenyl)-3,4-dihydro-2-methylpyrrolo[3,4-d][2benzazepin- l(2H)-one as yellow prisms, mp 177-178°C.

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

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 l-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 6.7 g (140 mmol) of a 50% mineral oil dispersion of sodium hydride in 145 ml of ether. After stirring for 1.5 hours, 500 ml of water were added dropwise, followed by 50 ml of IN aqueous hydrochloric acid. The aqueous solution was extracted with 3 x 500 ml of ether. The ether solutions were 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 colimn chromatography (silica gel, 500 g; eluent, ether in petroleum ether) gave in the first product band after crystallization from a mixture of e'her and methylene chloride 4-[4-chloro-2-(2-chlorophenyl)phenyl]-5-ethyl-1- 0 pyrrole-3-carbonitrile as off-white prisms, mp 163-164 C.

Further elution gave in the second product band after 3; 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 172-174*C.

b) A mixture of 3.3 g (8.9 mmol) of 4-[2-(2-chloro- benzoyl)-4-chlorophenyl]-5-ethyl-1H-pyrrole-3-carbonitrile, 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 with concentrated ammoni im hydroxide solution. The ether was removed at 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- zed from ether to give 8-chloro-6-(2-chlorophenyl)-l-ethyl- 2H,4H-pyrrolo[3,4-d][2]benzazepine as yellow prisms, mp 251-253"C. Recrystallization from a mixture of ether and methylene chloride gave off-white prisms, mp 254-255°C.

c) In one portion, 0.9 ml (7.9 mmol) of 30% hydrogen peroxide was added to 40 ml of a 1% solution of concentra- ted sulfuric acid in acetic acid. After stirring for 1 hour, g (5.6 mmol) of 8-chloro-6-(2-chlorophenyl)-1-ethyl- 2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the 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- trated ammonium hydroxide solution. The methylene chloride solution was v.ashed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure. The resul- ting-oil was crysta.llized from ether ou give S-chloro-6- (2-chlorophenyl -1-ethyl-1,4-dihydropyrrolo[3,4-d][2]benza- zepin-3(2H1-one as yellow prisms, mp 233-235"C. Recrystalli- zation from a mixture of ethyl acetate and methanol gave colorless prisms, mp 236-237C.

Example 9

a) In one portion, 2.0 g (5.8 mmol) of 8-chloro-6-(2- chlorophenyl)-l-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to an ice-cooled solution of 0.8 g (7.1 mmol) of potassium t-butoxide in 20 ml of dry dimethylformamide. After stirring at 0°C for 10 minutes, 0.8 ml (12.8 mmol) of methyl iodide was added and the resulting solution was stirred for 20 minutes. The mixture was diluted with water, and the resulting precipitate was collected by filtration. The solid was dissolved in methylene chloride, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give 8-chloro-6-(2-chlorophenyl)-1,2-dimethyl- 2H.,4H-pyrrolo[3,4-d][2]benzazepine as orange prisms, mp 200-202°C. A sample was recrystallized from a mixture of ether and methylene chloride to give pale yellow prisms, mp 203-204'C.

b) In one portion, 0.7 ml (5.9 mmol) of a 30% hydrogen peroxide solution was added to 33 ml of a 1% solution of concentrated sulfuric acid in acetic acid. Aftel 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 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 bas.&a-i 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-dlhydro-1,2-dimethylpyrrc'o-

[3,4-d][2]benzazepin-3\2H)-one as pale yellow prisms, mp 207-208*C.

Example

a) In one portion, 2.0 g (5.8 mmol) of 8-chloro-6-(2- chlorophenyl)-l-methyl-2H,4H-pyrroloC3,4-d][2]benzazepine 5 were added to an ice-cooled solution of 0.8 g (7.1 mmol) of potassium t-butoxide in 30 ml of dry dimethylformamide. After stirring at 0°C for 15 minutes, 0.65 ml (7.7 mmol) of methyl bromoacetate was added, and the resulting solu- tion was stirred for 5 minutes. The mixture was diluted 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) 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 174-176°C.

b) In one portion, 0.8 ml (7.0 mmol) of a 30% hydrogen peroxide solution was added to a solizon 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 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- S 30 lene chloride and water and neutralized 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 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 prisms, mp 221-223*C. Recrystallization from ethyl acetate Sgave colorless prisms, mp 223-224*C.

3-.(2-Benzoyl-4-chlorophenyl)-2-propenenitrile was also prepared as follows:

f) A solution of 92.7 g (0.4 mol) of b:enzoricphone in 250 ml of acetonitrile was added to a

36

Example 11

a) In one portion, 4.0 g (11.7 mmol) of 8-chloro-6-(2- chlorophenyl)-l-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine 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 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 tetrahydrofuran) gave 8-chloro-6-(2-chlorophenyl)-l-methyl- 2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetamide as a yellow solid. Recrystallization from ethyl acetate gave colorless needles, mp 142-145°C.

b) -In one portion, 0.7 ml (6.2 mmol) of 30% hydrogen ~peroxide was added to a 1% solution of concentrated sul- furic 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 mJxture was concentrated at reduced pressure. The residue was partitioned between 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. 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.

Example 12

Sa) 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 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 -78°C. When the addition was complete, the reaction mix- ture was allowed to wa.m to 0°C and stirred for 30 minutes. 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- phenyl )-l-;nethyl-2H,4H-pyrrolo[3,4-d][ 2 ]benzazepin-2-ethanol as pale yellow prisms, mp 149-152°C. Recrystallization from a mixture of ether and methylene chloride gave white prisms, mp 151-153 0 C.

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)-l-methyl-2H,4H- pyrrolo[3,4-d][2]benzazepin-2-ethanol were added, and the resulting solution was stirred for 30 minutes. The excess peracid was discharged with the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was parti- tioned between methylene chloride and water and neutrali- zed with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to a yellow residue. Purification by column chroma- tography (silica gel, 30 g; eluent, 3% methanol in methylene 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-l- methylpyrrolo(3,4-d][2]benzazepin-3(2H)-one as colorless prisms, mp 152-154'C

Further elution gave in the second product band after crystallization from a mixture -of ethiyl acetate and ether 8-hoo6(-hoohnl,'.4dhdo.-2hdo,,tv) 1-methyloyrrolo[3,4-d]E2]benzazepin-3(2H)-one as colorless prisms, mp 164-165'C.

Examrple 13

In one portion, 0.7 g (2 .nmol) of 8-chloro-f5-(2-chloro- phenyl) 4-dihydropyrrolo[3, 4-di [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- 1acetat§e in 30 ml of methylene chloride. After stirrinq for 1 hour, the mixture was neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloridle 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) 4-dihydro-3-hydrox,'pyrrolo[ 3, 4-dI [2 ]benza- zepin-1(2H)-one as pale yellow prisms, mp 221-222'-C.

Example 14

in one portion, 0.35 g 'mol Df 3-chloro-6-(2-ch1DrD- phenyl)-l,4-dihydropyrrolo)[3,4 d!L27benzOazepin-3(2H)-one was added to an ice-cooled solution o 1.3 g (7.9 mrmoll of 0 *00 trichloroacetic acid ancd 1.0 g (2.2 rnmol) lead tetra- 0 acetate in 15 ml of methylene chloride. After stirring t:r 4 hours, the mixture was neutralized with saturate,!~uzu sodium bicarbonal-e solution. The met-hylere chlor:_oe s was washed with water, dried ovier annJr.irus so--".z-m sulfate and concentrated at reduced pressure i'el" residue. Purification of the res.-iue ov :ol~mn :hr:ma~- graphy (silica gel, 10 q; eluent, 5% metr.ano. ,n n~.l

I.

e) A mixture of 3.0 g (9 mmoi) of 4-A2-(2-fluorobenzov1)- 4-noohnl-Hprrl--abntie ca 3 g of Raney niCKel and 15.0 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

39

chloride) followed by crystallization from ether gave 8-chloro-6- (2-chlorophenyl 4-dihyd ro-l-hydroxypvrrolo- E3,4-dl[2!benzazepin-3(2H)-one as pale yellow prisms, mp 247-249aC.

Example

:n One Portion, 5.V g (15.2 mmol) o! 8-chicro-6-(2- :hlorcphenvl)-2H,4H-orrolocj3,4-d>72]benzazepine were added tca zoo-.ed sclticon of 2j.: 4 !125 mmal) of trichluro- acet-: nc ana 14.2 *g !31.6 mmcl! of lead tetraanetate in 71m=ln ~sie The mixture was stirred at =7 e- t r !r 4 ours and !her di luted with methy- lnnvnlr-n anu xa"r The mennyleo :hloride solution i3 "a with saturao aqueous sodium bicarbonate solu- tL-noAsSOver 3rr''-"s sodo um sul.fane and :uncentrate3 0i~~ -ez ressure oc a 4reen residue. ?irf:vaon of the resid~ z% s.imn chomatocraony (siia lei, q; eluent, 7ec an in met~y~a' :rlrie' vae i.n one fr. pro-

nav' rancd afte:

-r n f r V ln

as nrrims M

'3 L> r r 2-7 !Or

Jr xj r A bn zZA

1010its ovo7 2 mr on 4 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 net-i:ralized 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 reduQed pressure to give a brown oil. Purification by column chromatography (silica gel 100 g; eluent, 1000%1 methylene chloride to 20% ether in methylene chloride gradient) gave in the first product band an off-white solid. Recryistallization from a mixture of methylene chloride, ether, and petroleum ether gave B-chloro- 6-C 2-chlorophenyl) -2H, 4H-pyrrolo[ 3,4-dlfbenzazepine-1, 3- diol diacetate as colorless needles, mp 189-190'C.

Further elution gave 1.95 :g of a foam which crvstalli- zed from a mixture of: ether and petroleum ether to lo ve 8-chloro-6-(2-chlorophenyl)-3-acetoxy-3,4-dihyd,-ropvrrolo-

[L3,4-dli2]benzazepin-1.(2H)-one as colorless prisms, mp 17 2-17 4 C

Continued elition gave fine needles. Recrstallization from a mix-ture :f eth~er and me thviene chlor ~ie gave 8- c 2-c lrpey I-c oy 14- hd o y r71o- l~r

[3,4-dMJ 2'Jbenizazeponi-3(2H4-onre, mo 219-221*C.

Ak solut.,Dn of '2.3 C mmol') of 3clr--2 chnoropheny.-3-hydroxv-3,4-di.hy/dr-opvrr-,,lo[3,4-dj[2beza- zepin-!.2H)-one, D.3 g imol1 of benzoic acidj anhydride, and 3 gj (2.5 mmol) of n a mixture )-nrvar~o''rdn of 30 m'l of methylene chl-.,ride and ml of t-?trahydrofuiran w~i- stirred at ~0for I hozur. m'.xrur- %vas diLluted with water, washed success.,velv wi': ILoLite yrcnrc acid, saturated aoue-.1-i soriom cicarbn.-e sz'lution, -and brine ana iroed over annyirous sn-iium suifate. rhe 9neth,_- 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-(benzovloxy) 4-dihydro- pyrrolo[3,4-dlll2]benzazepin-l(2H)-one as colorless crystals. Recrystallization from ether gave colorless crystals, mp 140-142 0 C.

Example 18

A solut~on of 0.6 g of 8-chloro-6-(2-chlorophenyl)- 3-acetoxy-3, 4-dihydropyrrolo[ 3, 4-dI [2]benzazepin- 2H) -one and 3 ml of a IM methanolic solution of methanesulfonic acid in 10 ml of methanol was stirred at i-oom temperature for 30 minutes. The solution was concentrated at reduced pressure to half the volume, diluted :Ihethier, 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-chloropheny'L)-3,4- dihydro-3-methoxypyrrolo[3,4-d][2]benzazepi.n-lV-H)-one methanesulfonate as off-white prisms, mp 157-160'C.

F-impLe 19

A solation of _1.1 q (0.25 mmol) of 8-chloro-6-(2- clhlorophenvl)-l-acetoxy-l ,4-dihydropyrrolo[3,4-dl[2lbenza- zepin-3(2H)-one and 1 ml of a IM methanolic solution of metnanesulfonic acid was allowed to stand at room tempe- rature for 36 hours The mixture was I'uted with ether and the resulting precipitate was collected by filtration to give 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-I-methoxy- pyrrolo[3,4-dl[2]benzazepin-3(2H)-one methanesulfoDnate. Recr-stallization from a mixture of ether and methanol 4iave 87 fine needles, mp l83-l *C.

Example

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-1(2H)-one as off white crystals, 0 mp 192-194 C. The presence of the isomeric 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methoxypyrrolo-

[3,4-d][2]Denzazepin-,(2)-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- 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 157-160°C.

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 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 green oi±. -LyL. L-L--i petroleum ether gave 4-[4-chloro-2-(2-chlorobenzoyl)phenyl]- 0 mp 206-208 C, as tan 5-methyl-lH-pyrrole-3-carbonitrile, ether gave the desired crystals. Recrystallization from 0 mp 210-211 C. product as colorless crystals,

43

chloride and neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give 8-chloro-6-(2-chlorophenyl)-1,4- 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 0 C.

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- ride and refluxed for 1 hour. The mixture was concentrated at reduced pressure. The residue was dissolved in methylene chloride and neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a dark red residue. Purification of the residue by column chromatography (silica gel, 20 g; eluent, 5% methanol in methylene cnloride) followed by crystallization from ethyl acetate gave 8-chloro-6-(2- chlorophenyl)-3,4-dihydropyrrolo[3,4-d][2]benzazepin-l(2H- one as pale yellow prisms solvated with 0.5 mole ethyl acetate, mp 195-197°C.

Ex,77ple A

Tablet Formulation (Direct compression)

Item Ingredients mg/tablet 8-chloro-6-( 2-chiorophenyl) 1, 4-dihydro-oyrrolo[3 ,4-

[2 jbenzazepin-3 (2H) -one 1 5 10 or 8-chloro-6-(C2-chlorophenyl) 1 ,4-lihydro-1-methylpyrrolo- 4-dI [2lbenzazepin-3( 2H) one 2. Lactose 2 21 217 212 181 3. Av ice 1 45 45 45 4- Direct Compression bstarch 30 30 3 (C Magnesium Stearate 3 3 3 4 Weight of tablet 3 00 300 300 300

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 minutces.

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

Example B

Tablet Formulation (Wet granulation)

Item Ingredients mg/tablet 1. B-chloro-6- C2-chlorophenyl) 1, 4-dihydropyrroloL 3, 4-dI-

[21benzazepin-3(2H)-one 1 5 10 or 8-chloro-6-( 2-chlorophenyl) 1,4-dihyd' 1-methylpyrrolo- E3,4 -djl2]benzazepin-3(2H)-one Lactose 202 232 261 280 Modified Starch 25 35 45 4. Pregelatinized Starch 20 25 30 Distilled Water q.s. 6. Magnesium Stearate 2 3 4 Weight of tablet 250 300 350 400

Procedure:

1. Mix Items 1-4 in a suitable mixer.

2. Granulate with sufficient distilled water to proper 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 C, punches.

zk ~4~

Example C

Capsule Formulation

Item Ingredients mg/capsule 8-ch2'oro-kC-( 2-chlorophenyl) 1, 4-dihydropyrrolo[ 3,4-di]-

[2 lbenzazepin-3 (2H) -one 1 5 10 or 8-chloro-6-( 2-chiorophenyl) 1 4-dihydro-1-.nethylpyrrolo- 4-dl[2 lbenzazepin-3( 2H) -one 2. Lactiose 2 03 193 .5 328 372. 3. Starch 30 35 40 4. Talc 15 15 20 Aer-osol OT 1 1.5 2 2. Capsule fill weight 2 50 350 400 450

Procedure:

1. Mill Items 1, 2, 3, and 5 in a suitable mixer. M.11.

2. Add talc and mix well.

3. Encapsulate o n suitable equipment.

ring-oii was crystaizea rrom etner 7o give d-cnioro-u- (2-chlorophenyl)-1-ethyl-i, 4-dihydropyrroloL 3,4-d] [2]ibenza- 36 zepin-3(2H)-onea a yellow prisms, mp 233-235 0 C. Recrvstalli- 35 i

zation'from a mixtuire of ethyl acetate and! methanol gave colorless prisms, mp 236-237'C.

genm

372.5

2. 450

i T Mill. w

the ther

clal. .ther

R a

I I I -u J LJ..LLU-I LILY -LP-L IHYL I

E3,4-d3[2 2benzazepin-3(2-)-one as pale yellow prisms, mp 207-208*C.

kq,"~

47 FS 4008/329

4;A44G- ThG claims defining the invention are as follows:

1. Pvrrolo[3,4-d][2]benzazepine derivatives of the general formula

wherein R1 and R 3 are hydrogen, lower alkyl, hydroxv, 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, 02 to 07 carboxylic acids and the esters and amides thereof,

hydroxy 02 to C-7 alkyl, amino 02 to 07 alkyl or mono- or di-lower alkyl amino 02 to 07 alkyl; R5 is halogen having an atomic number not greater than

or hydrogen; and R6 is halogen having an atomic number not greater than 35 with the proviso that when

R 11 or R3 is hydroxy, lower alkoxy or acyloxy, then R 'is lower alkyl or hydrogen the N-oxides and the pharmaceutically acceptable salts thereof.

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

3. Compounds as claimed in claim 1 or claim 2 wherein R 3 .and R4 taken together are an oxo group. V

N

-48 ES 4008/329

4. Compounds as claimed in any one of claims 1 to 3 wherein R2is hydrogen.

as claimed in any one of claimns 1 to 4 wherein R1is hydrogen or lower alkyl.

6. Compounds as claimed in claim 5, wherein R 1is hydrogen or methyl.

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

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

9. Compounds as claimed in any one of claims 1 to 8 wherein Ris halogen having an atomic number not greater than

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

11. 8-Chloro-6-(2-chlorophenyl)-,4-Oaihydrolmethyl- pyrrolo[ 3,4-dI [2 lbenzazepin-3 (2H) -one.

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

13. S-Chloro-6-(2-fluorophenyl)-..dhviroyrrolo.

[3,4-d3[21benzazepin-3(2H)-on..

4. 8 -Chloro-1,4-dlhydro-6-phenlpyrroo[34d[2..

benzazepin-3(2H)-one.

15. 8-Chloro-6-(2-chiorophenyi)-,4-dhydro-1,2-. dimethylpyrrolo[ 3,4-a] [2 lbenzazepin-3 2i)-one.

chlorophenyl) -1 4 -dihydro-1l-me thy].-3-0x0.2H-pyrrolIo[ 3,4-d]

[2]benzazepine-2-acetamide as colorless prisms, mp 221-222 0 c.

49 -ES 4008/329

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

17. A compound selected from the group consisting. of 8-chloro-6-C2-fluorophenvl)-3,4-dihydropyrrolo[3,4-d]-

[21benzazepin-I(2H)-one, B-chl~oro-6-( 2-chlorophenyl) 4-dihydropyrroloL 3, 4-dI-

[2]benzazepin- 2H) -one, 8-chloro-3, 4-dihydro-6-phenylpyrrolo[ 3, 4-dI [2 lbenza- zepin-l(2H)-one, 8-chloro-6-(C2-chiorophenyl) 4-dihydro-2-methyl- pyrroloL 3, 4-dI [2]benzazepin-l 2H) -one, 8-chloro-6-C( 2-chiorophenyl 4-dihvdro-1 -hydroxy- pyrrolo[ 3, 4-dI [2]benzazepin-3(C2H) -one, 8-chloro-6-( 2-chiorophenyl 4-dihydro-3-hydroxy- pyrrolo[3,4-d][2]benzazepin-1C2H) -one, 8-chloro-6-(2-chlorophenyl)pyrrolo[3,4-dJ[2]benzazepin- l.,3-(2H,4H)-dione, 8-chloro-6-(2-chlorophenyl)-,4-dihydroprrolo[3,4-dJ-

[2ibenzazepin-3(2H)-one-5-oxide, 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-dj-

[2 ]benzazepin-l C2H) -one-S-oxide, 8-chloro-6-( 2-chiorophenyl )-l-ethyi-i, 4-dlhydropyrroI-o- 4-di [2 benzazepin-3(C2H) -one, 8-chloro-6-( 2-chlorophenyl )-1,4-dihydro-l-methvl-3- oxo.-2H-pyrrolo[3,4-d][2]benzazepin-2-acetic acid methyl ester and 8-chloro-6-C 2-chlorophenyl )-14 4-raihydro-1..-methyl-3- oxo-2H-pyrroloC3,4-d[2]benzazepine-2-acetamiie,

'7 as 10. c"Peounela fa~clemz inla4:zf~ me I te 17 apharmaceutically active s ances.

19. ounds as claimed >.any one o f cIa ims 1 to 17 cc.a-IFe C and IQ4 !y;Q

A process for preparing compounds as claimed in A. any one of claims 1 to 17 which comprises

I-

50 ES 4008/329

a) for preparing compounds of the formula I given in claim 1 wherein R or R 3 is hydrogen or lower alkyl and the remaining substituents are as defined in claim 1 and the N-oxides thereof, oxidizing a compound of the formula

,is R I

R N

1 Sclai wherein one of R and R3 is hydrogen and the other

20 with a peracid, or Ssutis hydrogen or lower alkyl and R, R 5 and R 6 are as b) b) preparing compounds of the formula II given in for preparing d tdefned r ni in claim.1 ml a claim 1 wherein R 1 or R 3 is hydroxy and the remaining

1 2 3 and R 4 respectively, are, when taken together, oxo groups and the remaining symbols are as defined in claim 1, substtuents defined are as claim a compound inor of 1 the formula R a R 2 abovnd R 3

boxylate in the presence of a strong acid, or

c) for preparing compounds of the formula I given in claim 1 wherein R 1 or R 3 is acetoxy and the remaining substituents are as defined in claim 1, treating a compoundg of a the formula I given in claim 1 wherein h r nR

is hydrogen and the remaining substituents are as lefined in claim 1, or a compound of the formula II above wh in SI3

IfI*

.4

51 :S 4008/320

RI and R31 are hydrogen, with lead tetraacetate in acetic acid, or

d) for preparing compounds of the formula I given in claim 1 wherein R1 or R 3 is acyloxy and the remaining substituents are as defined in claim 1, treating a compound of formula I given in claim 1 wherein R 1 or R3 is hydroxy and the remaining substituents are as defined in claim 1. with a carboxylic anhydride in the presence of a base, or

I e) for preparing compounds of the formula I given in claim 1 wherein R 1 or R 3 is lower alkoxy and the remaining substituents are as defined in claim 1, treating a compound of formula I given in claim 1 wherein R1 or R3 is acyloxy or hydroxy and the remaining substituents are as S defined in claim 1, or a compound of the formula

rR

20 N A 20 R12 R1 N 2 III

6

o" r

wherein R 1 2 is acetoxy and R, R5 and P6 are as defined In claim 1 S' with a lower alkanol in the presence of a strong acid, or

f) for preparing compounds :f the formula Igiven in Si! 35 claim 1 wherein R, or R is hydrogen or alkyv and the remaining substituents are as defined in claim 1, desoxy- genating an -N-oxide of the formula AA

tA>. ~AA..g a MI I--e

(2 T roL; >ad t -:ra e ta ce Aeeaddead ovter 2 7?_u tz nt o s~ur 6. 12.2 mmro i Df 2- c" loor -chenvI 2-noo.- 4-7 3- benz a

52 ES 4008/329

iA

R RP -anj R, ar- -as ciefined

"r a )rno.;'~nd f f %rm,_1a into a -:harma ae-1 or aa 7 a:rc c e u-:L

a nt a1,ot- and 0.3 g (2.5 mmol) of dimethvlam-,notpvridine in a mixture of m ofmetylee 0 cIoride and 10 ml of tetrahydrofuran was stirred at COC for 1 hour. The mixture was diluted with water, washed successively with coldJ, dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine and dried over anhydrous sodium sulfate. The methy-

-53- ES 4008/329

SA medicament containing a compound as claimed in any one of claims 1 to 17. -LC' ,2r. A sedative and anxiolytic medicament containing a compouind as claimed in any one of claims 1. to 17.

Recrystallization from a mixture of ether and methanol gave fine needles, mp 185-187'C.

54 ES 4008/329

-23. T he us f compo"Ads -a claime ~-o ad ;LC IQ' nn claims 1. to 17 in the control or vention of illnesses.

24. The use compounds as claimed in any one of 17 in the control or prevention of excitation

Q

0

I

'4 I Pi

55 ES 4008/329

Compounds as claimed in any one of claims 1 to 17, Whenever prepared by the process as cl'aimed in claim or by an obvious chemical equivalent thereof.

*5ft S ft ft. ft

S

S 44

''4

Claims (1)

1. 22. Pyrrolo 13,4 d] benzazepine derivatives of Formula I according to Claim 1, substantially as hereinbefore described with reference to any one of Examples 1-22. 23. A process for preparing a compound of Formula I according to Claim 1, substantially as hereinbefore described with reference to any one of Examples 1-22. 24, A pharmaceutical preparation comprising a compound of. Formula I according to Claim 1 and a pharmaceutically acceptable excipient, diluent or carrier, substantially as hereinbefore described with reference to any one of .amples A-C.

   st'",

   JMC81 .$r

   L 0 57" ES 4008/329

   A method of treating excitation and anxiety which comprises administering to a host in neece of such treatment an effective amiount of a compo-ind as claimed in any one of claims 1 to 17.

   DATED this FIFTH day of MiAY, 1983

   F.HOB'FMANN-LA ROCHE CO. AKTIENGESELLSCHAFT

   Patent Attorneys' for the Applicant SPRUSON FERGUSON

   4 w~ punches.

   rwhich eatment one