PH27152A - Fused benzazepines and its method of use - Google Patents

Description

A | 298

This invention relates to fused derivatives of compounds having a fused nucleus which imecludes a 2,3,4,5-tetrahydre-1H.3-benzazepine system, to methods for their preparation, to intermediates useful 4n their preparaticn, and to pharmaceutical composi~- tions containing them, The compounds have waluable, pharmaceutical properties in the treatment of psychosmea, dopression, pain and hypertension.

Supstituted 1-phenyl-2,3,k4,5-te trahydro-18-3~ venrazepines have been desoribed in the art. For exam- ple, see U.S. Patents 3,393,192, 3,609,138, 4,011,319, 4,284,555 and 4,477,378 se well ss British Patent 1,118, 688. The activities discussed for the compounds die- closed in these patents inelude anti-bacterial effects gantral nervous system affects and hypotonsive sffects.

This invention relates to trans isomers of com- pounds according to the structural formula I, and phar- maceutiocally acceptable salte thereof, x - x

Wo

Ad J-R 1 A) ype 12 “ox a iv. R vherein:

R is hydrogen, alkyl, -CH CH=CH, or CH=" | ; : RY, ri! and rl? may be the same or differemt and each is hydrogen or alkylj

X is hydrogen, halo, elkyl, alkylthie, alkyl- sulfinyl, alkylsulfonyl, hydroxy, alkoxy or trifBuoro- methyls 0 ”"

Y is hydrogen, hydroxy, alkoxy, -0CNR2R, 0 0 " 0 " 1 7" -0c-RY, -NpY/2+ -NHCR or -0P (OH)OR! uhere at is as defined above;

W is hydrogen, hydroxy or alkoxyj ring t | represents a fused thipphene or fused bensene ring, said fused benzene ring optionally being substituted with a substituent 7 as defined pelowy

R? and R> are independently hydrogen (provided that both are not hydrogen), alkyl, aralkyl, eycloalkyl, aryl, hydroxyalkyl, or alkoxyalkyljy

In addition, when one of rR? and rR is as defined above, the other may be -"npr® fwherein at is alkane- diryl, R° is hydrogen or alkyl and gS is alkyl, or Yt and and RS together with the nitrogen atom foem a l-apetidi- nyl, 1-pyrrolidinyl, l-piperidinyl, 1-(b-,lky1piperaeinyl),

W-morpholinyl or l-(hexahydroarepinyl) group}

in further addition, r° and R> together with the nitrogen atom may a l~-aszetidinyl, 1- pyrrolidinyl, 1l- piperidinyl, 4-morpholinyl, 1-(bealkylpiperasinyl), 1- (4-alkoxyalkylpiperazinyl), 1-(4-hydroxyalkylpiperasinyl), 1-(3-hydroxyacetidinyl), 1-(3-alkexyagetidinyl), 1-(3~ nydroxypyrrolidinyl),1-(3-alyoxypyrrolidinyl), 1-(3- or 4-hydroxypiperidinyl), 1-(3- or h-alkoxypiperidinyl), l= (4=oxopiperidinyl) or 1-(3-pxopyrrolidinyl) rings in still further addition, when r® is hydrogen, > may be ~cnr7co,88, wherein R? and B® are independently hydrogen, alkyl or aralkyl;

R° 1s alkyl, aralkyl, aryl, alkoxyalkyl, aryloxy- alkyl, aralkoxyalkyl, ayoloslkylalkyl, alkoxycarbonylalkyl, cycloalkyl, l-adamantyl, cycloalkoxyalkyl, alkoxy, aral- : 1% koxy, cycloalkoxy, arylexy or -aRR7NRRS { wherein R’ and r8 are as defined above} 3 and 7 is X as defined above, amino, alkylamine or 0 i . ”" -ncr2® 5 whedein R10 is hydrogen, alkyl or aryl} .

A preferred subgenus is repfesented by structural formula I above, where nll of the substituents are as defined above but with the provision that when X is OCHy,

Y 1s Of, 2 and R* are both H, R cannot to CH.

Another preferred subgenus is ropresented by struect- ural formula Ia below: i Ca xX. . at i .

Bp K-R

H TE ae

LY

0 Se ot . , Lo :

J ’ 2 Ia wherein R, rt, pH, RZ, X, Y, and Z, are as defined above.

A third preferred subgenus of formula I is herein Y is -O-CRRZR> (wherein RZ and R> are both alkyl ] or one of R? and R> is hydrogen and the other 1s alkyl), 0 " -NHRY (wherein rt iz hydrogen or methyl), -NHCRY (where- in 0. ’ 1 " 9

R* in hydrogen or methyl), -OCR’ (yherein RY is as defined above) amino or hydroxy, W is preferably Ko. X is hydre- gen, alkyl, halogen or alkoxyy while Z j8 hydrogen, halogea alkyl, hydroxy or alkoxy. R is methyl and rt is hydrogen or methyl. Ring t represents a fused benzene ring op- tionally substituted with halo, alkyl, or ort.

A third preferred subgenus of compounds is those ef formula Ia above wherein R is methyl rR, pit and r}2 are hydrogen X is hydrogen, methyl, ,ethoxy, chloro or promej

Y is cette EE — EEE et 2162 0 " ~0CN (CHy) 5 or -NHCH,3 and 2 is hydrogen, halo, alkyl or -or? {wherein Rl is hydrogen or alkyl) or a pharmaceutically acceptable salt of such a compound. preferred compounds 8f formula I inoluda (1) trans=5,5,7 +7048 12b-hexahydro-2-hydroxy-3- chloro-7-methyl-benz(d) indeno-/7,1-b/nzepine or a pharmaceutically acceptnble malts ther-of} (2) (+)=trans-5,6,7,78,8,12b-hexahydro-2-hydroxy-3- chloro-7-me thyl-benz/ d_7@indeno/Z,1-b_/ arepine : +10 or a pharmaceutically acceptable salt thereof} (3) (=)-trans-5,6,7,7a,12b-hexahydro-2-hydroxy-3= chloro-7-me thyl-benz/ & 7-indeno/Z,1-b/ azepine or a pharmaceutically acceptable salt thereof} (4) trans-5,6.7,72,8,12b-hexahydro-2-hydroxy-3- 1% me thoxy-7-ge thyl-benz/ d_/-indeno [Z1-0/nzepine or a pharmaceutically acceptable Balt thereof} (5) trans=-5,6,7,78,12p-hexahydro-2-amino-3- ohloro-7-me thyl-bens/d/-indeno/Z,1-p/ asmepine or a pharmaceutically acceptable oalt thereof (6) trans-5,6,7,7a,12h-Jexahydro-2-hydroxy-7- methyl-benz/ difdeno/Z,1-7 arepine or a phermaceutically acoaptable salt thereef} - 6 = BAD ORIGINAL Tu

(7) trans-5,6,7,7a,12b-hexahydro-3,7- dimethyl,2-hydroxy-bens / d/-indene/Z,1-b/ axepine or a pharmaceutically acceptable salt thereof} (8) trenn-5,6,7,7a,12b-hayahydro-3~chloro=7- cycle-propylme thyl-2-hydroxy-bene/ a_/ indeno/2,1~b/ agzepine or a pharmaceutically acceptable salt thereof (9) trans-5,6,7,7a,12b-hexahydro-7pallyle3- chloro-2-hyiroxy-benz/ d/ indeno/Z,1-b/asepine or a pharmaceutically acceptable salt thereof) (10) trans-5,6,7,7a,12b-hexahydro~-3-chloro-2- hydroxy-7,8,8-trimethyl_-benr/ 47 indeno/Z,1-b/ arepine or a phermaceutically acceptable salt thereof; and (11) trans-3.chloro-5,6,7,7a,11b~hexahydre-7- me thyl-thieno/2',3'14,5/ oyalopenta/T,2-a7 /3 7 benzazepine-2-0l op a pharmaceutically aocept- able salt thereof,

Farticularly preferred aompounds ares (1) trane-5,6,7,78,8,12b-hexahydro.2-hydroxy=3- chloro-7-methyl-bens-/d 7 indeno/Z,1~b/asepine or a pharmaceutically acceptable salt thereof}

tet ————————— EE — mere Ce

A152 (2) (+)=trans-5,6,7,7a,8,12b-hexahydro-2-pydroxy 3-chloro-7-methyl -benzfd /-indeno/Z,1-b/ - azapine or a pharmaceutically acceptable salt thereof (3) (=) trans-5,6,7,7a,8,12-b~hexahydro-2-hydroxy- 3-chloro-7-msthyl-bens/d /-indeno/Z,1-b/ - azepine or a pharmaceutically acceptable salt \ thereof u) trann=5,6,7,78,8,12b-hexahydro-2-hydroxy-3% methoxy -7-methyl.benz [b_7-indeno/Z,1-%/ azepine or a pharmaceutically acceptable salt thereof} (5) trans- 5,6,7,78,8,12b-hexahydro-2-amino~3- chloro-7-methyl.bang/ d_7/-indeno/Z-1-b/azepine or a pharmaceutically acceptable salt thereof (6) trans=5,6,7,78,8,12b-hexahydro-2-hydroxy-3- methyl-benz/ d/pindenc /[Z,1-b/azepine or a pharmaceutically soceptable salt thereofy (7 trans~5,6,7478,8,12b-hexahydro-3,7-dimethyl- 1,2-hydroxy-benz/ d 7 -indens/Z,1-b/asepine or a pharmaceutically acceptable salt thereof} and (8) trans=5,6,7,78,8,12b-hexahydro-2-hydroxy-3- chloro-7,8,8-tri-methyl-bana/ 4 Jindeno/Z,1-b/ agopine .

2JH52 “nother aspect of the invention is the use of a compound of formula I for the preparation of a pharmacsutical composition useful in the treatment of psychoses, pain and/or depression.

Yet another aspect of the invention comprises a method of meking a pharmaceutical composition com- prising mixing a compound of formula T with a pharma- ceutizally acceptable carrior,

Still another aspect of the invention comprises intermediate compounds having she formulae IX, XI, XIII and XIV

Y -. JR? . Lm

X~ 7 A xo \

Ji a yr |! ~~ JF

Tr ~ OF A Y eel — xX \ i? :* A 22

LA CT a ~ at oy R

Vb '

II XI cH(oRY), X_N” x -~ 9 - ~ -m I] ya abo \ NR TY 7’ ~_ Me

B wh, W i 12 / xr] R

VA

Lt It ’

XIII XIv aap ORIGINA-

Lo ot useful in the preparation of compounds of formula I whereint

R is nydrogen, alkyl, -CICil=CH, or -CH, = : rt, ptt and rl? are the same or different and ench is hydrogen or alkyl

X is hydrogen, halo, alkyl, alkylthio, alkyl=- sulfiny), alkylsulfonyl, hydroxy, alkoxy or trifluoromethylj

Y is hydrogen, hydroxy, alkoxy, 0 0 " 2 3 " 9 3 On 1 A i -0cNR?R>, -0c-R%, -Na'2, -BHCR! or -OR(OH)ORM!

W 48 hydrogen, hydroxy or alkoxy; ring it) reprenents a fused thiphene or fused benzene ring, said fused benzene ring optionally being substituted with a substituent Z as defined belows p? and R> are independently hydrogen (provided) 1s that both ere not hydrogen), alkyl, aralkyl, cyole- alkyl, aryl, hydroxyalkyl, or alkoxyalkyl; in addition, when one of RZ and R? is as defined above, the other may be -R"nrR® {wherein RY is alkene- diyl, rR’ ig hydrogen or alkyl and r® is alkyl, or Rr’ and r® together with the nitrogen atom form a l- azetidinyl, l-pyrrolidinyl, l-piperidinyl,l-(4-alkylpiperazinyl) b= morpholinyl or l-hexahydroazepinyl group),

JH6 in further addition, R and R> together with the nitrogen atom may form a l-azatidinyl, 1-pyrrolidinyl, l-piperidinyl, L-morpholinyl, 1~(4-alkylpiperazinyl), 1-( h-alkoxyalkylpiperazinyl), 1-(4- hydroxyalkylpipera- 2inyl)-1-(3-hydroxyazetidinyl), 1-(3-alkoxyaze tidinyl), 1-( 3-hydroxypyrrolidinyl), 1(3-alkoxyazstidinyl), 1-(3~ hydroxypyrrolidinyl), 1e( 3 plkoxypyrrolidinyl) 1-(3-or h-pydrexypiperazinyl), 1-(z-or h-alkoxypiperazinyl), 1-(b-oxopiperidinyl) or 1-(3-oxopyrrolidinyl) ring; in still further addition, when rR? is hydrogen,

BR may be _ona’e) 28, wherein rR’ and rd ars independently nydrogen, alkyl or aranlkyly

Rr’ 15 alkyl, aralkyl aryl, nlkoxynlkyl, aryloxy= alkyl, aralkoxyalkyl, cycloalkylalkyl alkoxycarbonyl- alkyl, cycloalkyl, 1-adamentyl, cjcloalkexyalkyl, alkoxy, aralkoxy, cycloalkoxy, aryloxy or ~CHRTHARS (wherein R’ and 28 are as defined above); * 3 - .

RY in a Cy Cs alkyl; and " 2 4s X as defined above, amino, alkylamino or 0 -NRCRYC, {wherein RO te hydrogen, alkyl or aryl).

Another aspect of the invention is a process for producing a compound paving the structural formula I ee EEE sr EE

J7)52

Ww i rR x . \

N-R ro / mH 12

H™ . RB I ! aN lL pil ( % wherein n is hydrogen, alkyl, -CR, CH=CH, or ~CR,= Cs r, pil and p17 are the same or different and each jn hydrogen or alkyly

Y is hydrogen, halo, alkyl, alkylthio, alkylsul- finyl, alkylsulfonyl, hydroxy, alkoxy or trifluoromethyl

Y in hvdrogen, hydroxy, alkoxy, 0 0 0 noo 3 f 9 1" 1 " -OCNR°R’, -0C-R? , _NR1/2, -NHCR® or -OP(OR))R};

W is hydrogen, hydroxy or alkoxyj - rine ¢ | represents a fused thiphene or fused benzene ring said fusad benvene ring optionally being substituted with a substituent 7 as defined belows 2 3 . rR? and R’ are independently hydrogen (provided that both are not hydrogan) , alkyl aralkyl, cyoloalkyl, . aryl, hydroxyalkyl, or nllkoryalkylj : be 4 in additicm, whan ore of 2 snd rR’ is sa defined h, 5.6 y : above, the other may he =R Mp’R° (wherein R’ is alkane- diyl, n’ is hydrogen or alkyl and 6 io mlkyl, or Rr’

CTT ae - 12 = . BAD ORIGIMA! 3 :

27 152 and p® together with the nitrogen atom form a 1- azetidinyl, l-pyrrolidinyl, l-piperidinyl,l-(h- alkylpiperazinyl)-b-morpholinyl or l-hexahydro- azephinyl group), in further addition, RZ and R> together with the nitrogen atom may form a l-azetidinyl, l-pyrroli- dinyl, lepiperazinyl, 4-morrholinyl, l-(b=mlkylpipera- ginyl) ,1-(h-alkoxyalkylpiperazinyl) ,1-(k-hydroxyalkylpi- perazinyl),1-(3-hydroxyazetidinyl),1-(3-alkoxypyrroli- dinyl),1-(3-or 4-pydroxypiperidinyl),l-(3-or b-alkoxy- piperitingl),1-(4-oxopiperidinyl) or 1-{ 3-oxopyrrolidinyl) ring; in still further addition , when RZ is hydrogen,

R my be ~cr?co 1, wherein RY and g" are independently hydrogen, alkyl or aralkyl; :

J is alkyl, -ralkyl, aryl, alkoxyalkyl, aryloxy- alkyl, aralkoxyalkyl, cycloalkylalkyl, alkoxycarbonyl- alkyl, cycloolkyl, l-adanantyl, aycloalkp¥yalkyl, alikox¥. aralkoxy, cycloalkoxy, aryloxy or CHR HAR ( herein r’ : and 28 are ap defined above); and 7 ie X as defined above, amino, alkylamino or tL 0 | \ - -nuer® (wherein 810 44 nydrogen, alkyl or aryl), oo vo characterized by: | 3

IN

- 13 - ORIGINAL A N

Loe ee —————— meee ER 24152 (A) intramolecular condensation of a compound of the formula v 1 ~ Le, , R

X- pr we Ee “ Te {

Fe a ! i \ RL? / “ nd ' pit

P 9 (11)

Vompounds according to formula I may he pre- pared by intramuscular condensation of a compound having the structural formula II in the presence of a dehydration catalyst. Effective dehydration cata- lysts include sulfuric acid, methanesulfonic acid, triflvoromecthanesulfonic acid, phosphoric acid and anhydrous hydrofluoric acid. ’ The intramuscular condensation deacridbed above may be performed at various temperatures and pressures, @eey betwoen 0° and 100% and at reduced, atmosphario or elevated pressure. An inert solvant may be employed or the reaction may be run in the absence of solvent)

The time raquired for obtaining the deaired product va- rious somewhat with the temperature, pressure and patch size but the reaction is generally complete within 2b hrs. i. Compounds of formula &T may be obtained by \ wt BC ; ’ i - 1b = BAD ORIGHRA- I» oe

’ : A152 reacting nn amine of formula V with a compound ef formula VI \ Ww o

CX al J

IY (he

TIX NHR ft ~~ gd v VI - to produce a corpound of formula VI w

X 1

Nor 3 17 J } - ot © VIX followed by reduction of the oarbvenyl group in the pro- duct of formule VII to hydrexy. The symbol L represents a readily displaceable moiety commonly known as a "leav- ing group". Buitadble leaving groups used by those akill- od in the art jpolude but are not tinited to the halides, e.g+, chlorine, brouine or iodine, and 0S0,R wherein R may by hydrogen, alkyl, perfluoroalkyl arylalkyl, or aryl (for example para-teluenesulfonyl). Preferred reducing agents for the reduction step include NaBH, , LinAlH, Bly, and NeAlH, (OCH.CH,0CH,),. Catalysts reductions using

NE od 1152 catalyst such as palladium on carbon or Raney mickel and hydrogen gas at 1 to 10 atmospheres pressure are also effective, 11. Compcunds of formula II may also be ob- tained by reacting an amine of formula VIIX with a compound of formula IX under the conditions desoribed 4a the precedding paragraph but without the reduction step:

EE | :

NER . y > CY : CN - lo Y gt

VIII 1x ’

The amine of formula VIII may be made by methods known by those skilled in the art including J. Org, Chem. 52, 1649 (1987). §14{ Oompoupds of formula II can be prepared by reacting an aldehyde (Ra H) or ketone (Rls alkyl) of 1% _ gopmula X with an amino alechol ef formula VIII in the presence of an appropriate reducing agent such as sediun ‘* oysanoborohydride at pH h-7.

CR NHR rr J 1. | + | ~~ 1X . ~~ + , Wd !

Y ~~ + { . }

X VIII ive Compounds of formula II may also be prepared by reaction of compounds of formule VIII with aldehydes or ketones of formulse X with prior removal of water of . 5 condensation followed by reduction of the resulting in- termediate condensation product with reducing agents such as NaBH, or NaCNBH,, by catalytic reduction using catalysts such as pallidium on carbdon or Raney nickel un- der a hydrogen atmosphere at 1-10 atmospheres pressure, (B) OCoumpsunds of formula I also may be prepared by feacting a compound of the formula a Ny “)

A. PR »

Y oN R 12 - R 0 } [TT le” Bt : XI

: A752 vith a suitable reducing agent to produce the com- pound of formula I. Preferred reducing agents comprise hydrogen and a catalyst with Pt0, being a particularly preferred catalyst, and NaCNEH, at pHbL-7, preferably in

S the presence of acetic acid.

The compound of formula XI may be prepared, for example, by reacting a oompound of formula XII same as ¥XI with a l-hale-2,2~dialkoxyethane in the presence of a suitable solvent such as dimeshylformamide and a cate- lysts such as an alkali metal fedide, preferably potassium iedide, to produce a compound of formula XIII, where R' 18 a C04 alkyl

Yo | | Tz OH(0R"), te : Jl nz : H J \ RY \ / "HER LJ 7 / BroH_OR(OR'), k/ t/ DMF, K1 " :

X11 XIIX

The compound of formula XIII gay be reacted with a strong : acid such as trifluoromethane sulfonic aoid, nethanesulge-~ nie acid, or sulfuric acid at a temperature ranging between about ©-23°C to produce the compound of formula XI and in addition compounds of formula I wherein W is ON or OR,

C. Compounds of formula I also may be prepared by

Af reacting a compound of formula XIv

Tr ~~ - nf 6 ‘ A ri [v/

XIV

Co with a reducing agent such as LiAlR, or BHy, prefer- ably BHys at & temperature ranging between avout 0°C ; and about 720% to produce the compound of formula I.

One methed for preparing the compound of formula

XIV is set forth below. This method is particularly ap- plicable where Y is OH or alkexy. where Y is one of the ” other stbstituents defined, additional process steps known in the art may be necessary in addition to those - described below. Oompounds XIV may be prepared by first “reacting a compound of formula XV with & compound ef pal 0 / ld

A FN

> pil +

A » : Mjhal

Xv | XVa to produce a gompound of the formula XVI ! . - 19 - i

SFI52 ‘ ~_--OR

J

\

Xv : which may be dehydrated to a compound of formula Xvi using acidic catalysts such as toluene sulfonic acid : or phosphorus oxychloride/pyridine at a temperature ) 5 ranging betwsen about 20°C and about 120°C with oconti- nuous removal of water. € ) . 12 ( Ca t/ R

Xvi

The compound of formula XVII may be oxidized to preduce a compound of formula XVIII below using m-chloreperveaseio acid at a temperature ranging between aboud 0° and about oo 20°C, followed by contact with an alkali metal hydroxide such as sodium hydroxide, followed by contact with a strong mineral solid.

FNL

I~ a

NT

2 , foi

XVILI

The compound of formula XVIII may in turn be reacted with an alkyl amine with conténuous removal of water : to produce a compound of formula XIX

Ig 3 L THR ™\ 12 / [7 at xXx which then may be reduced im the presence of & cata- : lyst such as sinc dust and scetio acid or RaONBH, at } pH 4-7, preferably in the presence of acetic acid or sodium cyanoborohydride in the presence of acetic acid to produce a compound of formula XX

*71a92 , x . Y - iQ

J n R12

CR

/ A bY 2

Xx which may then be treated with a strong base in dime-~ thylsulfoxide (DMSO) or a mixed solvent comprising

DMSO plus a polar aprotic solvent, e.g.s dimethylfor- mamide (DMF) to produce a compound of foraula XXI.

Sgrong bases utilised are preferably potassium tert butexide or sodiue hydride.

YZ

Lo! Vl ~N 0

BR" - NER ‘ { + wt?

A vd 11

XXX

Alternatively the compound of formule XVII may be reacted with BH,-methyl sulfide complex in a halo~- sarbon solvent (e.g. CH,C1,) at temperature of 20°-65°, and the resultimg rection mixture treated with hydroxyl- . amino -O-sulfonic acid at temperature of 80-120° in a mix- ed solvent gystem such as diglyme/CH, C1, to furnish oom- pounds of formula XX1 with ReH,

BE | 152

The compound of formula XXI may be contacted with a haloacetyl halide to produce a compound of formula

XXI1 : Ts Ny 0H,01 , = co ¢ © N=R / 12 / vo ph ts

XXIX which may be exposed to light to produce the compound oo formula XIV

TT 5

N-R

INS “

A

" > . rt? ha t R

XIV which may them be reduced to the compound of formula I.

In the above processes A=C, it is sometimes de- sirable and/or necessary to protect certain R, rl, mlle 212, Wy, X, Y and % groups during the reactions.

Conventional protecting groups are operable. For exam~ ple, the groups listed in column 1 of the following ¢a- ble may be protected as indicated in column 2 of the table.

Freon ee ee ——————————————————————— EE — EE ———————————— r= FT —

IE

7162 : 1 v i 1. Group to be Protacted 2. Protected Group -COOE -CO0alkyl, -COObanzyl, -COOphenyl

Mum oN N \ _ _N-COjalkyl, _.N-COpbenzyl, P N-CO,CH CCl, 0 0 : / . \ yar JN

J ou —o oem - - 0 .

Co 0 : -NHqy A . : ) s ’ oo Of course, other protecting groups well known in the art may be used. After the reaction or reactions, the ; protecting groups may be removed by standard procedures.

Also, R, rl, ril, R12, W, X, Y and Z groups in - formula I may be varied by appropriate selection of

Tee starting materials from which the compounds are

Y ’ . i synthesized or by reacting a compound of formula I with a suitable reagent to effect the desired conversion of the substituent to another R, rl, R11, R12, W, X, Y and 2 : 1 group. The latter procedure is particularly applicable ! ] for changing the substituents X. For example, a chlorine substituent may be added in place of hydrogen by reaction : : . . , . : with a chlorinating agent such as sulfuryl chloride in a non-reactive solvent. A hydroxymethyl substituent in the : - ab - . ;

‘ IFiod

X position may be added in place of hydrogen by react- jon with formaldehyde in a suitable solvent system, e.g. . in a mixed solvent system consisting of fimethyoxyethane : and aqueous potascium hydroxide, preferably at an elevated 8 temperature. Such a hydroxymethyl substituent may be re- duced to a methyl group by reaction with a catalyst such as palladium hydroxide in a hydrogen atmosphere under pre- assure. Methoxy substituents may be converted to hydroxy, ®.8ey by refluxing in a mixture of sodium hydride, DMT amd ethanethiol, or by reaction with concentrated hydrodbromio acid. Othar substitutions may be assemplished using stand- : , ard techniques.

When utilized herein and in the appended claims, the following terms, unless otherwise specified, have the : 1% following scope: . halo = reprecents fluoro, shlorec., brome or iddoy alkyl (including, for example, the alkyl portions of alkylthio, alkoxy, eralkyl, alkoxyslkoxy, eto) -repre- sents straight or branched carbon chains having 1 to 6 carbon atomsy cycloalkyl groups (including the cyoloalkyl pro- tion in oycloalkoxy groups) - represents saturated oar- becyclic rings having 3 to 7 oarbon atoms)

Alkanediyl - represents a divalent, straight or branched hydrocarbon ehain having frem 1 to 6 carbon atoms, the two available pond being from the same or different carbon atoms thersef, e.g., methylene, ethyl- ene, sthylidene, ~CH,0R, CH -y ~cH,CHCH, =CHOH,CH,, _ eto aryl (including, for example, the aryl moiety . in aralkyl or aralkexy groups)-raeprasents unsubstituted . phenyl and phenyl mone substituted by alkyl, hydroxy, al- kexy, hale or trifluoropethyl.

The compounds of formula I pousess analgesic, _ anticholinergic, antiaggressive and general tranquilis- ing properties. The invention therefore includes phar- mpaceutical gompositions comprising a compound ef formula

Iin combination with a pharmaceutically acceptable car- rier and methods for treating mental disorders including puychoges, schizophrenia or depragsion ia a mammal, or for the control of pair er anxiety in a mammal py edwinie- ” tering an effective amount of a compound of formula I to the affected mammals. The compounds of formula I provide © 20 a long duration of astivity.

Certain compounds of formula I wherein X and Y¥ are hydroxy and R is hydrogen are alse active as renal vaso~- dilators. These compounds can thus be used ia pharmasgeu- tical compositions in combination with a pharmaceutioally 2% acceptable carrier and in nethods for comtrolling hyper

Tra tension by administering to a mammal a renal vasedilat- ing effective amount of such a compound. while the present invention is directed at trans ig isomers of formula I, racemic mixtures alse would be Co

S useful. Therefore, it 4s not believed necessary te separate the trans compounds fo formula I from the race- mio mixture. All such jsomeric forms and mixtures there- } pf are within the scope of the present invention. Upless . otherwise indicated, the methods of preparation discloned Lv herein result in product distributions which include all ; possible structural {somers, although it is understoed nN that physiolegical response may vary according te stereo- \ chemical structure. The ismers may be separated by con- 5 ventional means such as fractional crystalisation et EFLO. \ 1% : Ring &/ nay represents a fused thiophene ping.

Co the sulfur atom in such fused thipphene rimg may be in any of the nonfused positions of said ring.

Compounds of formulae T and Ia can exist in ua- solved as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharsageu- : tically acceptable solvents such as water, ethanol and . the like, are equivalent to the unsolved forms for pur- poses of this invention.

The compounds of formas I and Ia may form phar- maceutically acceptable ealts vith organic and inorganic

I7152 \ acids. Examples of suitable molds for salt formation are hydrochloric, sulfuric, phosphoric, acetio ottrte, malonio, salicylic, malic, fumaric, succinic, ascorbig, maleic, methanesulfonic and other mineral and carbooylie seids well known to thope in the art. The malts are oro pared by contacting the free base form with a suttiotont \ amount of the desired acid te produce & salt in the con- " ventional mannar, The free pase gorms may be regenarated \ by treating the selt with a suitable dilute aqueous base " solution 4ucn 2s dilute aqueous sodium hydroxide, potas- Co : sium carbopate, ammonia and sodium bicarbonate. The free B base forms differ from their respective sally forma mome- what in certain physical properties, such as solubility in polar solvents, but the eslts are otherwise equivalent % to their respective free base forms for purposes of the : invention,

The compounds of formula I display pharmacological activity in teat procedures designed to indicate anti- . psychotic and anti-depressive agtivity. The compounds ) 20 are non-toxic at pparmaceutiecally therapeutio doses. : COMPETITIVE INBIBITION ASSAY

Many compounds capable of effecting reproducible physiological changes in neural tissues are believed to operate by binding at ome or more receptor sites, Cem- pounds which interact strongly with thess receptor gites - 28 - . ap ORIGINAL DJ G in in vitro teats, using homogenates of the tamget organ or structure are expected to exhibit similar properties when administered in vive and are, there- fore, candidates for continued study as potential therapeutic and/or diagnostic agents.

Binding of a compownd to a receptor site, in yitro, is demonstrated by the specifically of binding and the saturability of the avmilable sites. A metho- dology for characterisation of D-1 and D-2 receptor binding and an interpretattion of the date are des- cribed by Billard et al., Life Sciences 33, 1985 (1984)

Co in which the binding of the bensasepine (R) ~(+)-8- chloro=2,3,4,6~tetrabydre-3-uethyl.5-phenyl-1i-3~benge- sepin-7-01 hemiraleate (8CH 23390) to the depomanin D-l receptor is charncterised. A selectivity for D-1 recept- or binding as compared to D-2 recepter binding is believed to confor the thaerapsutic advantage of avoiding trouble- some and potentially irrevocable neurological side effeots associated with D-2 receptor occupandy.

Materinls and Methods

Tritiated SCH 23390 and tritiated spiperone (a po- tent D-2 receptor ligand) were obtained as dascribed in the Bgllard, et al, reference supra and gorially diluted in 0.05 M Tris buffer, pH 7.4, es required. Oompounds of ‘ 25 this invention were syntheaised as disclosed herein and diluted in 0.05 M Tris buffer, PE §.4, as required.

Tissue Pyeparation : Male Sprague-Dawley rats (200 to 250 g) from gharles River Breeding Lyboratories, Mase. were used te obtain brain tissue. The rats were humanely e@cC~ rificed and their brains removed and placed on ice. striatal tissue was excised, pooled, and homogenized (Bpinkman Folytrom, 10 see) ip 100 volumes (w/v) of ice 001 50 mM Tris buffer, pE 7.4 (at 28%). The homogenate eentrifuged at 20,000 xg for 10 min. The resultant pel-

Jet was rehomogenized in Tris buffer and centrifuged again.

The final pellet was resuspended in 50 mM Tris buffer pH 7.h containing 120 mM NaCl o 3 mH KCL, 2 mi Cally, and 1 nM MgCl eo 13 Ageay -

Felypropylene {noubstion tubes received 100 al of the individual test compounds at various concentrations dissolved or suspended in 0.0% M Tis, pH 7.4 containing k mg/ml methylcellulose, 100 ul of a solution of 3n_scH 23390 in Trie buffer (final reaction mixture goncentra~ tion = 0.3 mM) or 100 ul of a solution of 38- spiperone in Tris buffer (final concentration =0.2 nM) and 800 wl of tissue suspension (cae 3 mg/assay). Tubes were incu- bated at 37°C for 15 minutes and rapidly vacuug filtered through Whatman GF/B filters and rinsed Ut times with & ml

J7102 : ’ : - of ice oold 50 mM Tris buffer, pH 7.4. The filtere wera transferred to scintillation vials, equilibated with 10 ml of scintillant (Scintosol, Isolab, Inas) for 16 hours at 23°C and the radioactivity determinod in n-1iquid pcintillation counter. Ky values were determined as described by Billard et ale, ueing the 3 ratisnahip Ky=1Cgo/T1 + 71.7 /R)0) wherein 10," con~- eontration of test drug necessary to displace 50% of specifically ysed in the aasay, and K,=dissociation cons~ tant, . '

Results ] : The inhibition cenetante (K,) determined from the ‘+ assays for a series of compounda of the invention are as shown in Table I below.

! c :

Oo] © oo af © ® gl S wn oN — = — hn aed - » \

A

ND , ml ~~ . ™ ~ , . “ : v

BN * 4 i — i] om jo} T i } $ i ’ ™ 0 | i — wl B = 0B ) — ta ~ :

T

0 5) T x i » : : ° . x = = i

Z| T= = wm :

T x =“ 5 & oO i 1! — 8 xl vO ( i : \ 1 ; 3 . . } i i ) - 32 - bY } } \

A

+ .

I

The comparatively amall K, values of these compounds in the competitive binding assay with SCH 23390 indicate that the compounds of formuja I bind strongly to the D-1 receptor site. The relatively high K, values for the D-2 site, for which gpiperone is highly selective, indicate that the compounds are rot epicifically bound to thet receptor site.

For prepnring pharmaceutical comporitions from the compounds of formula I, inert, pharmaceutically acceptable carrisrs are admixed with the active com- pounds. The pharmaceutically acceptable carriers may - be either solid or liquid. So1id form preparations in- olyde powdars, tablets, dispersible granules, capsules, oachets and suppositories. A solid garrier can be one or more rubgstenceas which may also act sn diluents, flav- ering agents, solubilizers, lubricants, suspending agents, binders or tablets disintegrating agents 4% nay also be . an encepsulating materiel.

Lyquid from preparations include solutions, sus- panded and emulsions. Af an example mey be mehtioned water or wnter-propylone glycol solutirns for parenteral injection.

Aleo included are solid form preparations which are intended to be converted, shortly bh foro use, to liquid form preparations for eithor oral or parventaral = 3 BAD ORIGINAL £5; o

A152 administration. Such liquid forms include solutions, suspensione and ehudeions. Ty ese particular solid form ; : preparations are most conveniently provided in unit dose form and ss such are used to provide a single 1li- quid dosage unit.

Tho {invention 2lnc contemplates alternative deli very syrteme drclnding, but not necessarily limited to, ‘ trenederrel delivery. The tranadermal compositions can taka the form of creams, lotions and/or emulsions and can be included in a transdermal patoh of the matrix or re- pervolr type as are conventional ia the art for this pur- pose.

Freferably, the pharmaceutical preparation is in unit dosage form. In snch form, the preparation §s eub- 19 divided into unit doses containing sppropriate quantities of the active components. Tne unit donsge form oan be a packaged preparation, tha package containing discrete qunati- ties of preparation guch as packeted tablets, capsules and powders in vials or smpules, The unit dosage form oan aleo be a capsule, cachet or tablat itself, or it may be the ap- propriate number of any of these in a packaged form.

The quantity of active compound in a unit dome pre= paration pay be varied or adjuated from 1 mg to 100 mg ao-~ acording to the particular application nnd the potency of the 2% active ingrodiant and the intended treatment. - 3 - | = 3

BAD ORIGINAL Si

L ‘

! : IN] , "ITER

This would correspond to a dose of about 0.02 te about 2.0 mg/kg which may be dividad over 1 to 3 administrations per day. The composition may, if desirod, also contain other therapeutic agents.

The dosages may be varied depending on the requirement of the patient, the peverity of the con- dition being treating and the particular compound be- ing employed. Determination of the proper dosage for a particular situation is vithin the skill of those in the medical art. For convenience, the total daily dosage may be divided and adnipistered in pertions throughout the day er by means providing continuous delivery.

The invention disclosed herein {eo exemplified 1% by the following preparative oxamples whieh should pot be construed to limit the scope of the disclosure. Al- tornative mechanistie pathvays and spalogous structures may be apparent to those skilled in the art. ryanu=6-Hg thyl-5,6,7,7a,12b-hexahydro-2-hydroxy=J-ohlere” ~bens/ d 7 {ndeno~/ 2, 1-b/ aseping

Ao 1-(3-Methoxy-li=ohlorophenyl)=1-indope

PHE2 i oo

Cl / Noms = — . J ms

I

~~ : : | XXIII ‘I,to a 500 mL three-neck flesk fitted with a reflux condepacr snd addition funnel was placed k.6 go (189 mmol) magnesium ribbon and ome erystal of iodine.

The flask wos flushed with dry nitrogen while heating © briefly with a flame. After cooling, 25 ml of a solu tion of 38.0 gm (0.172 mmol) 2~chloro-5-bromoanigele in : 200 mL dry ether was added from the eddition funnel, and ‘the flask vas varmed briefly to initiate reaction. There- after, the solution was added over the sou, ase of one hour ag 8 rate which maintained a gentle reflux. Vhen the addi- . tion wae complete, the reaction vas heried to reflux for an additional three hours. The flask was cooled in en 1ce- . salt bath to O degrees, and s solutien of l-indanone in 100 ul dry ether was added ever 90 minutes vhile gainteining the the reaotion temperature at loss than 10 degrees. There~ after, the reaction was stirred at room temperature overnight, then quenched with 1M aqueous HCl until pH?. The aqueous la- yor was separated and extracted twice with 200 ml, ether. The : 20 combined ether layers were dried (ngso,,) and evaporated to an - 36 - lwo orci a

, oil. This eas purified by HPLC, eluting with %¥ ethyl acetate in baxane to give 23.4 prams of desired pro- duot, 200 kHs NMR (oneL,) 4 3,51 (d,2Hy J=2Hx), 3.95 (83H) 4 6459(tr.1R,Jn2Hs), 6.85-7.58 (m,7H)

B. trans ~1-(3~Mothoxy-k-chlorephenyl)-2-indanamine cl 5

OME

N— ~ Ne 8 xxv ve

A solution of 17.9 grams (69.7nmmol) of the com- pound from step A dissolved in 70 sl. dry diglyme was treated with 11.6 al of 2M horane-methyl sulfide oon- plex in marthylene chloride, and the mixture was stirred at 65° for 2% hours. A solution fo 8.13 grams (71.8 mmol) : hydroxylamine O-sulfonic acid in %0 nl dry diglyme was aqded, and stirring was continued at 100° for 6 hpurs . 18 After cooling to room temperature, the reaction was quench- od with Ii HC) until acidic, then stirred for twe hours.

The resotion was diluted with 300 sl water and extracted three times with 200 ml ethyl acetate. The agquecus layer - ‘ was made basic with solid potassium hydroxide and extracted three times with 300 ml ethyl acetate. The organic layer vas dried (Mgs0y,) and evaporated. The rréstdue vas filtered : -® ao ORIGINAL »

S192 - through a silica gel column, eluting first yith pexane and then with 10¥ methanol-methylene chloride to give - 5.47 grams (28%) desired amine. 200 Ms NNR (CDCl) 4 2.76 (dd, 1R,J=9.16 Ha), s 3.2 (ad, 1H, J=8,16Hs), 3.86 (4a, 1H, J = 8s), 6.70 6.90 (m, 3H) 7-10-7.30 (m 6 bH)

CoN=(2,2-diethoxyethyl)-trans-1=( 3-Methoxy~Y4-chlore~ phenyl)~2~4indaamine

Cl 7 \

OME

/ LL ee R Me xxv ’ — \_— ” Sort

A mixture of 1.0 grms (3.65 mmol) eof the mice from step B. 0.55 mL (3.65 mmol) 2-bromoasetaldehyde diethyl acetatl, and 1,0 grams (7.3 mmol) anhydrous po- : taseium carbonate in 35 mL dry DMF was stirred at 1%0° for 4 hours. After cooling to room temperature, the mixture was poured ingo 300 mL ether, washed with three 8 80 M1 portions of water, dried (1g80,) and evaporated.

The residue was purified by flash chromatography, eluting with 111 héxane-ethyl acetate to give 1.1 grams (77%) of the desired product as an oil.

”r SR me —— et ST rm mn em yt Luh SET . ra 162 200 MHs NMR CDC1,) d 1.15 (tr, 6H, J=7Hs), 2470 290 (m, IH), 3.20-3.70( ms 6K), k.09 (de 1H,J=8Hg) , oo 4.55 (tr. 1H, J=5Hs), 6.70 (m, 3H), 7.10-7,30 (m 4H)

Dp, trans-7,78, 8, 12b~tetrahydro-2-nethoxy-3-chloro bene / 4 / indeno ~[Z,1-p/ azepine } . X AN TT,

Yr

UN 5 | XXVI

KE

Cd , A solution of the acetal from step C dissolved in 100 mL methylene chloride at 0° was treated with 100 al trifluoromethanssulfonie acid added in = slov ateady stream over 10 minutes. The mixture was stirred for five

Hours while coming to room temperature « The uixture was - C again cooled to 0° and cautiosly quenched with saturated aqueous with three 100 ul portions of methylebe chloride. - The organic layer vas dried (Mgs0y,) and evaporated to give 1% 0.57 grams of the enamine as & dark oil. 200 MHz NMR (CDCl) d 2.79 (dd,1H,J =BHn} 15Hs) = 3.50-3.59 (m ,2H) 3.78 (a8 3H) 3.27(4, 1H, Jublig) 45.21 (4, 1H,J=10Hs), 6.23 (ad, 1H, J=10Hs), 6.99 (s, 1H), , 7.18 (8,10), 7420-755 (m, hH) -» -

E. trans $,6,7,7a,8,12b=hexahydro-2-methoxy~3-chloro- bens [1 7 indene-/Z,1-v7 azspine : Cl "ON TT

RE mo 7 NL

RE

Ca co

I. I XXVIII ~> pd

The crude enamine from step D was dissolved in 20 nl, absolute ethanol and treated with 0.12 grams {1.91 mmol) sodium oyanoborehydride. To this was added 0.108 pl. glacial acetic scid, and the mixture was stirred at room temperature for 3 hours, The reaction was quenched with 10 ml HCl and stirred for 30 minutes, The react- ion was made basie with 20% NaOH snd extrsgtsed inte 250 ml ethyl! acetate, The organic layer was dried (MgSO) : and evaporated to give 350 ng (53% of the product gs an ] oll, } 200 MHz NMR (60814) d 3,60.2,85 (m, *H), 3.10 1% 3,40 (mei) 2.71 (a, 38), 4.Sh (d, 1H, J=8Bs), 7.07 (8,10) 7416 (5,10), 7.20-7.40 (m,bH)) ’ : F, trens-6-Mgthyl-5,6,7,78,8,12b-hexahydro-2-methoxy- ~2-ghloro-bens / 4 / indeno - /2, 1-b/ amepine - ho - ot ORIGINAL A) ‘ GH

: | _ J9i5

EE a

JI oo

MeO x \

AA XXVIIX

~~.

A solution of 300 mg (1,000 mmol) of the ootpound from gtep E was dissolved 20 ml acetonitrile and 0.40 al (5.3 mmol) 37% aqueous formaldehyde was added followed by 3.10 grams (1.539 mmol) sodium oyanoborohydrade. Atter 30 minutes, the solution was brought to pH 7 by dropwise ~ addition of glacial acetic acid then stirred an addition 1 hour and 45 minutes. Ty solvent was removed under res reduced pressure, and the residue was taken up into 125 ul, ethyl acetate. This was washed with 50 nl 10% sodive vicarbonate, dried (MgBO,) and ovaporated to give en ot, which was purified by flash chromatography ever si1ton gol, \ eluting with ethyl acetate to give 150 mg product as an oil. ON

ON

200 MHz NMR (CDC1,) 4 2.17 (ad, 1R\J=12, 120s) ne CN (a,3)y 2.37 (ay 30), 2.90-3.0 (my UE), 3.77(m,30), 0067 | A (d, 1H,J =9Hz), 7.03 (sy 1H), 7.17 (ay 1H), 7.20-7.35(n, i \ )

LE) | CN

G. trans-6- Methyl-3,67-,7a, 12b-hexahydro-2-hydrexy-3- i \ chloro-bens / d 7indeno-/ 3,1-7aanspine Eydroxysnide so

CN

: 3 hn

AN8

TY gn

BO / ’ I~.

HO NF

7 \o== xxix

A solution of 147 mg (0.47 mmol) of the present from step F in 10 ml, methylene chloride at -78° was treated with 90 ul, (microliters) borom tribromide, and the mixture was stirred for 4 hours while coming to room temperature. The reaction was quenched with 10 mL dry methanol and stirred for 10 .inntes. The solvent was eva- porated under reduced pressure, and the residue was treat- ed with a second 10 ml portion of methanol. After 10 mi- " nutes, the solvent was evaporated at 10 mm Hg and 50° for 5 minutes to give 180 mg (100%) -of tho orude hydrobro- mide, 200 Hg NMR (d6-DMSO) d 2.97 (ms, 3H), 2.90-3.90 (nm, 7H), 5.02 (d, 1H, J = BHs), 6.99 (8, 1R), 7.36 (wm, SH) 13 A portion was recrystallised from methanol ether

Calculated C 36,79 RH 5.03 N 3.68

Found © 56.40 H 4.92 N 3,58

By application of the above-described techniques and related procedures known to these skilled in the art, the compounds liated in Table II below may mlso be synthe- sired, For the combination of substituents shown in Table - U2 a

II, VW, gH and re are all hydrogen, (t) may be either : benzene or thiophene fused in either the 2,3 er 3,2 po- sition.

TABEE 11 1

X x 2 R R =e -t 3 a—— 9 : OCH, OH H BR Oly to C1 OH H H OH,

OCH, OH H B CHy

R OH R R CHy ca, OR H = Clg c1 on BH H H

E NH, R H Cly

CH, NH, R H CBy 1 NH, H H CHy crf * H R CH, * GC

CH,0 H R Hy

Note: * = -0CON(0H,) - 3 B

Claims (1)

1. ’ ! 2 Cl : i WE CLAIM 9 7 1 5

   1. A compound having the trans isomer structural . formulated I, and pharmaceutically acceptable salts thereof, v \ L_ ’ I gu . 3 Y J Ln 12 . / << R nS gil Pt wherein: R is hydrogen, alkyl, -CH,CH=CH, or ci] $s RY, pil and rt? are the same or different and sach im hydrogen or alkyljy % ie hydrogen, hale, alkyl, alkylthio, elkylsul- finyl, alkylsulfonyl, hydroxy, alkoxy er trifluorome-~ thyls 1 is hydrogen, hydroxy, alkeXY, g 0 0 0 —olr?a3, -od-r%, -nal/2 , nacht or ~oflcomonty where 2 is as defined above} W is hydrogen, hydroxy or alkoxys - Af -

   Co I752 ring Q represents a fused thiophene or fused benzene ring said fused benzehe ring optionally being substituted with a substituent 7 as defined below; R® and R3 are independently hydrogen (provided. that both are not hydrogen), alkyl, eralkyl, cycloalkyl, aryl, hydroxyalkyl, or alkoxyalkyl; In addition, when one of R® pnd R> is as defined above, the other may ba. 2 NRORG (wherein £ 1s alkenediyl R? is hydrogen or alkyl and 8 4s alkyl, | : In still further addition, when r2 is hydrogen, rR’ may ba=CHR700,R®, wherein Rr’ and 2° are independently * hydrogen, alkyl er aralkyl} J Rr is alkyl, aralkyl, aryl, alkoxyalkyl, aryloxy- ’ alkyl, aralkoxyalkyl, cycloalkylalkyl, alkoxyearbonyl- . alkyl, oyoloalk 1, l-adamantyl, oyoloalkoxyalkyl, alkoxy, © aralkoxy, laasi aryloxy or -oRR'NRRS( wherein rR’ and 8 are as defined above)y and 7 is X as defined above, 6 amine, : 0 "510 10 alkylamino or ~NHCR (wherein R~ 4s hydrogen, alkyl or : aryl) where | oH ’ hale represents fluoro, chloro, bromo or iodo; alkyl, including the alkyl portions of alkylthio

   Bh Co © AL alkoxy, aralkyl, alkoxyslkoxy, represents straight or branched carbon ohains having 1 to 6 carbon atoms , + cycloalkyl, including the oyocloalkyl portion in cycloalkoxy groups reprosents saturated carbocyclic rings having 3 to 7? carbon atoms; Alkanediyl represents a divalent, straight or ’ branched hydrocarbon chain having from 1 to 6 carbon Co _ atome, the twe available bonds being from the game or : different carbon atoms thereof} . ‘ aryl, including the aryl moiety in aralkyl or HL aralkoxy groups represents unsubstituted phenyl and Ho : ) pbehyl mono substituted by alkyl, hydroxy, alkoxy, \ hala or ‘rifluoromethyl. 20 A compound wherein the substituents are as defined in olaim 1 with the provise that vhen X is OCHy, Y ie : ( OH, 2 and Rt are both H, R cannot be CHye aN

   3. A compound as defined in elaim 1 wherein W, and i R 12 are. all hydrogen. he A compovad as defined in claim 3 above wherein Y is hydroxy; -0-CNRZR? where RZ and > are both alkyl or one of rR? and R? 44 hydrogen and the other is alkyl, -naRt

   . " where rR ie hydrogen or methylj NHCR® wherein R* is hy- bE

   - | Co 152

   0 . ” drogen or methyls or -OCR vherein r’ ie as defined : : in claim 1 : X 4s hydrogen, alkyl, halogen or alkoxy 7 is hydrogem, halogen, alkyl, hydroxy or S$ alkoxyy R 4s methyl; ang, al is hydrogen or methyl. 8, A compound as defined in claim 3 above wherein 0 0 Y' &a hydroxy, amino, 0dr, obn(en,), or ~NHCH, wherein RB’ is as defined in claim 1; ring t] ie a fused benzene ring; % is hydrogen, halo, alkyl or -OR} where rt is hydrogen or alkyls } ¥ is hydrogen, methyl , methoxy, chloro or bromo} R {is methyl; and R™ 4s hydrogen,

   : 6. A cotpound as defined in claim 1 which in trans 5,6,

   7.78, 8, 12b haxahydre~2-hydroxy-3shlore-7-sethyl-bens [4 Jindeno /Z,1-/ asepine or a pharmaceutically mocept- able salt thereof.

   7. A compound as defined in claim 1 whieh is (+)= trans 5,647,78,8,12b hexahydro-2-hydrexy-3-chloro-7-methyl- bens / d_/-indeno [Z,1-bfarepine or a pharmaceutically - 44 -

   - oo 2752 acceptable salt thereof. :

   8. A compound ee defined in claim 1 which fa (-3- trans 5,5,7.78,8, 12b-hpxahydre-2-hydroxy-3-chlore-? asthyl-beng [ad /-indens [Z2n-Y/ szepine or a pharse-~ : ceutically acceptable salt thereof.

   9. A compound as defined {n olaim 1 whieh is trans- $,6,7,73,8,12b=hexahydro-2-hydroxy-3-me thoxy-7-methyl : ~Wenz/~d #-indeno /2,1-l/ azepine or a pharmaceutically aocaptablo anlt thereof.

   10. A oompound as defined in claim 1 which is trans, $,67,7a, 8,12b-hexahydre-2-anino-chlore-7-yethyl-bena Za7/ ~-indeno [21-0] azepine or a pharmaceutically : : agceptable salt thereof,

   11. A compound as defined in claim 1 whioh is trans 5,6,7,7a,8,12b-pexahydro-2-hydroxy-7-methyl-bens/ d_7/ oo -indeno 72,1-bJarspine or a pharmaceutically sccapt- able salt thereof.

   12. A compound as defined in claim 1 which is trans- , 5,674 78,8 s12b-hoxahydre-3,7-dinethyl,2-hydfoxy-bens yx v4 indeno-/Z,1-b/ arepine or a pharmadeutically scceptable salt thereof. : 13. A compound as defined in claim 1 whieh 48 trans 5,6,7,78,8,12b=hexahydro-3-ehlore-7-cyclopropyles thyl-

   Co Toe 27152 © w=2-hydroxy-bens / d_/-indeno /Z,1-b/agepine, or a pharmaceutically acceptable salt thereof. lle A compound as defined in claim 1 which is trans. §,6,7478,8,12b-haxahydro-7-allyl-3-chloro-2-hydroxy-~ Ss bene/ 4 / ~indeno [Z,1-b/asepine, or a pharmaceutical- ly acosptable salt thereof. : i

   15. A compound as dafined in claim 1 which 4s trans- 5¢647477,8,12b-hexahydro-3-chlore~2-hydroxy-7,8,8-tri- . Ct : i me thyl-penz/"d_/oindeno [Z\1-b/azepine, or a pharmaceu- 1 \ - tically acceptable nalt thersof. i in .

   16. RA compound an defined in olaim 1 which is trane- ~ ~3-chloro-5,6,7,78,8,11b-hexahydro-7-methyl-thieno )

   Vo . [2 3 1k, 57cyclopehta/T,2-a7 [3 7 /benzarepine-2-ol,

   + . or a pharmaceutically acoeptable salt thereof. . 17, A compound of claim 1 which is trans«5,6,7,78,8,12b~ Co hexahydro-2-hydroxy-3-chloro-7,8y8.trimethyl-benn/ d_/ indeno [241-37 azepine,

   18. A pharmaceutical composition which comprises a compound as defined in claim 1 in combinstion with a vharmageutically acceptable carrier,

   19. A method of treatment of peychoses comprising administering to a mammal in peed of such treatment an effective amount of a compound of olaim 1 $n com~ =

   B TT - SHEL . : oe 2 R715 bination with a pharmaceutically acceptable earrier, JOEL GILBERT BERGER WEI KONG CHANG : ELIJAR HERMAR GOLD and JOHN WELCH CLADER Inventors

   ~~. 1 . b : Po

   7. ! L ’ SEE \ IT 4 LN TT oo \ - - i850 -

   [-. }