CA1119603A - Substituted benzhydrindanes, process for preparing same and pharmaceutical compositions containing said compounds - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Novel antiinflammatory antipyratic and analgesic agents based on substituted benzhydrindanes are de-veloped which can be used in anyconventional form in small doses. The compounds are prepared by series of reactions producing several intermediates which are isolable. The reactions start from benzhy-drindane and proceeding to the preparation of various substituted derivatives, the benzhydrindane itself being obtained from suitable cyclopentanone.

Description

6~3 This invel-ltion rel~.~te~ -to novel subsli-tl.lted benzhydrindan2s, -,process for preparing same and compositlons con-~a:ining said com~)o~dsO
This invention rnore particulirly relates to novel substi-tuted benzhy~rina~nes o~ the ~eneral ~o~lula I~ of the accompanying drawin.~s wherein R
is hydro~en~ al'iyl, alkoxy, hyiroxy, halosen or halogenoallsyl7 ~ stands for alk~ yàroxy, halogen, cyano, car~oxyl, inor3anic salts of car~oxyl, carbalkoxy, or CON~4R5 ~/herein .R4 and R5 are hydrogen~ alkyl, optionally substi-tuted aryl, op-tionaly substituted het-rocycle o.r (CH2~n R ~erein n stands ~or 1 - 7 and R stands for c~rboxyl7 inor3anic sal-ts o:~ carboxyl, carbalkoYy or CON~sO
R2 s-tands fol~ hydrogen or alkyl, m is the numeral zero or.one, and ~ stands for an atom of oxygenor hydro~en with the oroviso -that m is zero~tihen R3:is o~ygen atom and m is one when R~ is hydrogen atomO
This invention alsorelates to a process for preparinC said compoun.s o~ ~ormula IX and phar~a -ceutical compo;3itions containing same.
It has been ~ound by us -that -the compounds of the invention possess anti-inflammatory, ant.ipyre-tic '~ ' ' ~, ,,' .
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and analrestlc properties~ I-t is -t'lUS L~ossible to ~re~are ~harm~Lcell-tical com~o~i-tions usin~ the com~o~mds of this inventioll ith convention ~hlrmc,ceutioally acce?ted carl iers.
~ ccorllin~ .o this inv~ntion -there is provided com~ouncis of the e~eral iormula IX wherein ~ is hydro~?~en, alkyl, alkoxy, hy~roxy, halogen or halo<-enoalkyl, R1 stands for alkyl, hy~roxy~ halogen, cyano, carboxyl, norganic salts oi carbalkoxy, or COI~R4R5 .~herein R4 and R5 are hydrogen, alkyl, optionally substi-tuted aryl, optionally suDs-tituted heterocycle or (CH2)n R wh--rein n s-tands for 1-5 and R stands :Eor carboxyl, inorg~nic sal-ts of carboxyl, carbalkoxy or CONRL~R~.
R2 st-Ln~s ~or hydrogen or alkyl7 m is the numeral ~ero or one, and R s-t-ands îor an atom of oxygen or hydrogen with -the proviso tha-t m is ~ero ~hen R3 is oxygen-atom and m is one when ~3 is hydrogen atom.
There is also provided a process for preparing comooun~s of -the general ~ormula IX wherain R stands for hydrogen or alkyl, ~or example, me-thyl, ethyl, n-propyl, isopropyl or alkoxy, for example methoxy, ethoxy, n- propoxy7 isopropoxy or hydroxy or halogen, .or example fluoro, chloro, bromo or halogenoal~yl , ~or ex~mple trifluoromethylO

;:-,' ~ 1 stands for alkyl, ~or e~ample methyl, e-thyl, n -propyl or hydroxy or halo?;en, :for example chloro, bromo, or cyano or carboxyl or inorganic salts of carbo~yl such ~s sodium salt, calcil~ salt or car`oalkoxy, for example carbetho~y or COINR4R5 w:-lerein R~ and ~ are hydrogen or alkyl, ~or e~ample methyl, ethyl, n- ~ropyl or op-tionally substi-tu-ted aryl, `or example phenyl, p-chlorophenyl or o~tionally sub -stituted heterocycle, for example, pyridy~ uinolyl or (CH2)n ~, rherein n stands for 1-5 and ~6 s-t;-inds ~or carooxyl or inorg~lic salts oi carboxyl such as soiium salt, calcium salt or carbalkoxy, for example carbethoxy or CONR4R5~
R2 stands ~`or hydro~en or alkyl7 ~or example methyl, e-thyl, n- propyl, isopropyl, m s-tands ~or a numeral O or 1 and R~ s-tands for a hydro~en atom or an oxygena-tion wi-th the proviso that m is zero when is oxygen and m is 1 when RS is hydro~en which comprises subjectin~ the com-~ound of forrnula I
to alkylation with a ~henylethylhalide which may have a substi-tution 'R' wherein l~l is as defined before to g1ve a compound of formula IIwnere R is as define~ before, followed by subjecting t~e obtained com~ound of fo~lula II to reduc-tion in presence of re.~ucing agents -to give compound of the general formula III ~lere ~ is as deflnecl before, followecl by cyclization of the same to ~ive com~)ound of formula IV where R
is as defined be~ore , wher2af-ter the~compound of formula IV is -treated with an acid chlorile or acid anhydride ' ~

iO3 in the presence o~ ~el~fis acid like alumini-lm chlori(ie to give a coml?ound oî -formula VIIa or VII c, res.?ec-tively ~ollowed by trea ting the compoundci o:E '`ormula VII a, .~ii th an oxi~izing a,oent such as a hypohalite -to give COrnpo~m1 OI Iormul-~ VII b, -the com~ound o~ orrnula VII b being reduced using relucing agents likelithium aluminium hyclri:le to give a comoounci of formula VIIIa, -the compo-md of ormula VIII a being brominated with a bromina ting agent to ~=ive com?ound o:~' formula VIII b, the compound of formula VIII b being subjected to re~ction ~Ari-th acyaniding agent like alkali c;ranide in presence o~E solvent like dir.lethyl sulfo~ide o give ~ compound OI formula VII-I c, the compound of Iormula VIII c being alkyla-ted using alkylation a;,ents like alkyl hali~es in presence o:~ a base and solven-t like dimethyl sul:~oxi~le to give a compound of formùla VIII g~ hen desired, converting -the compound o~ Iormula VII a, by reaction i4Jith sul~hur and morpholine followed by alkaline hydrolysis to give compo~uld of formula VIII d, the compound of :fo.rmula VIII d being esterified using esterifyin,g agents like alcohol in the presence o:~ sulfuric acid to give com.pound -of :Eormula VXII i s which on alkylation usine alkyla-tion agents like alkyl halide in presence of a base and solvent like dimethyl .
suIfoxide is conver-ted to give compound of :Eormula VIII j and when desired, conver t'ing compound of f ormula VII a by treatmen-t with a re~cing agent to gi~e cornoound of formula VIII
the compound of formula VIII e being -then converted by tl~eatment with a chlorina-tinO agen-t such as thionyl chloride to give the compound of formula VIII f g the compound of ' for~ula VI~I f be.;.ng treated with a cyani~ing agerl-t like alkali cyanicle in presence of solven-t like dimethyl sulfoxide ::

, -~o giv2 a corl~ound of :~orr.lula VIII ~9 the comoouncl o~` i`o~llula~ VIII g or VIII j belng subjected -to acid or alkaline ~lydrolysis -to give co~ ound o~` ~ormula VII h, clnd .hen lesir?d converting the compound of formula IV ~/here ~ is as ~e:L:ined before by treatmen-t th ethyl o~alyl chloriie in the prese~.ceo~ Lewis acid like~lumini~n chloride to give compound of f ormula VII d whiGh on all:;aline hydrolysis gage com~ound o~
~or~ula VII e, the compound of forinula VII e being trea-ted with alkyl ma~nesium halide followed by treatment with a mineral acid an~ reduction to give compoun~ o-, formula VIII h, i~ desired -the compounds of formulae VII b and VII c and also compounds of ~ormulae VIII d and VIII h are converted to the corresponding acid chlori~ies by treatment with thionyl chloride in presence of ben~ene, theob-tained acid chlori~esbeing reac-ted wi-th ammonia or an amine like~lkylamine, op-tionally substituted arylarnine or heterocyclic amine to give compound OI ~ormulae VII f, VII g, VIII k or VIII 1 respectively wi-th the proviso that each of the above compounds of forcnula IV, VIIa, VIIb, VII o, VIId, VII e, 1 -VIIf, VIIg, VIIIa, VIIIb;. VIIIc, VIIId, VIIIe, VIII~
VIIIg, VIIIh, VIII i, ~/rIII j, VIII k a~d VIII 1 is isolable ancl-the reactions can be te~ninated or contined at the production o~ any ¢ompound as desired and as indicated ebo~e.

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~ 1~196~3 'rne reaction involviIl ~; al~ I a tion o:E cornpoun~l of -.o~nula I i;, pr- el ably c--l rrled out un ier r e ~'lux usinLr dioxane to give com,)ound OI ormula II ~hich on re(;luction ucing me-tal hydrides like sodiuM boroh~dri~ie ~,ave coinpound of ~or~llula IIIo However, ~e have also bee:~l able to cyclize the com~o~m~i of formula II usin~; ~?olyphosGhorlc acid and this 3ro~uced a mixture of cornr~ounds of lormulae IV and V. It is possible to convert compound o:. J~ormula V -to a compound of forrnula IV by a sim~le ca-.alytic ^educ-tion using hy;~rogen as reducing aoentO The catalysts can be ~latinum oxi le or palladium on carbon.
,~ ter preparin;, compound of l ormula IV, we have prepared theo ther ;ierivatives in -the order ~iven above.
Thus from com~,~o~md of ~orrnula IV, the following are prepared as shown below and these compounds con~orm to formula I~.

1~ Com~ound IV- VII c.

2. Compound IV - VI~ a - VII b - VIII a -VIII b -VIII c VIII g- VIII h.

3. Compound IV- VII a - VIII e- VIII f- VIII g- VIII ho

4. Compound IV ~ VII d- VIII d- VIII i VIII j- VIII ho

5. Compound IV - VII d- VI I e- VIII h Each of -the above compound can be i sol a-ted or the compound taken for -the next conversion as desiredO

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'/ . , ,, ' ," - ' ' In t.le conversion ol com(?o~m~ ol :c`ormula IV to coln-~ound of forinllla VII a or VI]: c~ ~re have usecl ha-tic acid cnloriae .and ali.)hatic decarboxylic acid a~hyiricle re-,~ec-tively.
So~iiun~ hy,~o~ li-te has been ~referred as oxidizing ~_ent co obtain compound of .eornl;lla VII b from VII a.
~hos?horous -tribroinide has been the ~referred brominating agent to convert com~ound oE .ormula VIII a to VIII b.
.i ~reI'erred base in convercing com?o-md o:E :Eormula -C
to VIII g or VIII i to VIII j is sodium hydrideO
We'h~..ve em~loyed as reducing agen-t, met~ hydride like so~um borohydricle or hydro~gen in presence of sui-table c-~.alyst -to conver-t coim~ound of Eormula VII a -to ~III eO
We have also ~ound that the compound ormulae VII b, - VII c, VIII d and VIII h can be conver-ted to -the res~ec-tive acid chlori;les using thionyl chloride in the presence o~
benzene. It is still ~urther ~ossible to conver-t these acid chlorides to -the amino derivatives o~ Eormula VII ~ :
VII g, VIII k anà VIII 1 res?ectively using suitable`
agents like ammonia or an amine like alkllamine, arylamine or heierocyclic amineO
It is -to be remembered -that thevarious conversions : :. are described with reference to preEerred agen-ts only : ~;
and theconversions are no-t lilnited to such agents only.
.~ny ch~mical e.~uiv.-llent ca~able o.E giv:ing the desired conversion is ~-~lso l.~ithin the ~urview o~ our conversions~

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~ '''' -~ll -r.he com)oun`,s re,~ortQd in -this s~)eci~ication ~re ne-.w. i~le ..~ e~l-t',ae pro?)lti~es oL s*veral com-poun~s -!n 1 l'O~ rl them -to ,?os,,ess the desired ~,?rope~rties.
r~le - 2 re.~or-t belo.l the proper~ties ~ie-t ils o~ one S;`Cil COI.I~OUrld.
4- ~ Benz ~ 3_7 hyclrirrdan~7~yl)~
oxobutyric acid has e,dlibit3d the following activi~ies:

(a) ~ ~y ~50 : 50 r.1g/kg/P.O. (;~at p`,1,~/ Oedema model) L~o : ~f500 m~,/kg!PO oo nti~v~ r~tic The efi'ect lasts for 5 hours or more a-t 50 and 100 mg/kg p.o. in rats.
~c, ~ ~a~
It exhibits 68 ~`~ o~ the activity of aspirin at 200 mg/kg P.O. in miceO
Tne proper-ties were d,etermined by usual s-tandards.
The-invention is illustrated but not limited by the follo~ring examples:

f~S
2-(2-~he,nvlethyl,) cyclo~tanone ~
To a solution o~ pyrrolidine enamine of` cyclo~?en-tan~ne ( 40 gi in dry dio:~ane ( 200 ml) was added phenylethyl bromide ~ 80 ~ der ni-trogen a-tm.~sphere and -the mixture -./as refluxed ~or 2Q hours. This was then cooled, water ~ 200 ml) was ;l~d~d to it ~nd -the refluxing continued for ~no-ther ~ ~lours. The solvent was removed ~m~ler redllced ~ressure, the residue extract*d .~li-th , ~ :

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ether (3 x lO0 ml~ and the e~tract ~a~hed with water, sodium bicarb~nate solution (10%) and wat~r, The extract as dried over anhydrous sodium sulp~ate, concentratad and the residue distilled under reduced pres~ure to a~ford II; yield 22 g~ bpo.s 130 32 ;
Ben~ ~ e ~ hydrindane (IV~

To a cooled solution o~ 2~ phenylethyl) cyclopen-tanone (II) ~25) g~ in methanol (~00 ml) was added sodium boro-hydride (lO g) and the mixture was stirr~d at room temperatore ~or 4 hours. ~thanol ~as removed under vacuo~
water ~as added and the product e~tracted with etherO The ethereal extract ~as washed with water, dilute hydrochlorio acid and water. It ~vas dxied over anhydrous ~odium sulphate and concentrated to aiford 2(~-phenylethyl)cyclopentanol ~III),D
This was cooled in icebath and sulphuric acid ~g~%; 25 mlj ~as added porti~nwise with ~igorous stirring and the stirring was then continued ior 30 minutes~ The mixture as cooled9 ~ater ~as added and the product ~tracted ~ith ether~ The ethereal extract was ~a~hed with water, sodium bicarbonata solu$ion (10%) a~d wa$er~ It wa~ dried over anhydrou3 sodium sulp~ate, concentrated and distilled under reduced pressure to a~ord IV; yield: 19 g; .
~p~ 12~.

(~_Acetyl-ben~ ~ e ~ hydrindane (~IIa) ) __ _ _ _ A guspension o~ anhydrous aluminium cblorids (12 g) in dry dichloromethane (150 ml) was cooled to 0G and to thi~ ~as added a mixture of benz ~, e_7 hydrindaile (IV~(10.4 g) and ~i ' .

L960~

~oetyl cbloride (5.16g) dropwise, It was then allowed to stir at room tempera-ture for 4 hours. It was cooled~ the complex was decompo~ed with water anal the product extracted with ether. The extract ~as washed with water, diluted hydro-chloric acid and waterO It was dried over anhydrous ~odium sulphate, concentrated and distillecl unde~ reduoed pre~sure to furnish YII a; yield: 12.5 g; bp 1 0 146-48.
(Benz ~ e ~hydrindane -7-carboxylic acid (VIIb)) Sodium hypo~romite r~as prepared by adding bromine ~8 ml) to ice--cold solution o~ sodium hydroxide (17.7 g) in water t70 ml).
To a ~olution o~ 7-a~etyl-benz ~e ~ hydrindane (VIIa~ t4g) in dio~ane (5 ml) ~as added sodium hypobromite ~olution slowly at ~-10 ~ and the mixture was ~tirred ~or one hour. The temperature was slowly raised to 40C and kept at th~
te~perature ~Qr 2 hours. The excess o~ sodium hypobromite was decomposed by adding aqu~ous sodium bi~ulpbite solution (5io) It ~as then acidified with concentrated hydroohloric acid and the ~roduct extracted ~ith ether. ~ha extraot ~as ~ssh~d with ~ater, dried over anhydrous sodium sulphate a~d concentrated to~give a residue wbich crystallised ~rom alcohol to a~ford yIIb; yield: 206 g, mp 216-20.

To a suspension of lithium aluminium hydride (6 g) i~ dry ether (100 ml~ was added a 501ution of benz / e ~ ~ydrindane -7-carbo~ylio acid (VIIb) (IQ g) in dry ether (lOO ml) and the mi~ture wa~ stirred overnight. It was then decomposed .

~3 g~O3 : 12 ~itb aqueous sodium hydro~ide solution (lOi) and the ethereal layer ~Yas decanted. The organic layer was ~vashed ~-iith diluted hydrochloric acid and ~vater~ dried over anhydrous sodium sulphate, concentrated and the residue distilled under reduced pressure to give VIIIa;
Yield: 8 g. bp1 0 l84-86 .

(~-Cyanome~hyl-~enz ~ e ~ hydrindane (~IIIc)3 , To an ice-cold solution o~ 7-hydroxy~ethyl-ben~ r e bydrindane (VIII a) (9g) in ~nhydrous benzene was added phosphorus tribromide ~4 ml) dropwise over a period o~ 30 minutes. The mixture ~as allowed to ~tir evern ~ht;
water ~Ya~ added t~ it and benze~e layer was separat.ed. Tbe organio layer was tvashed with water, sodium bioarbonate solution (10%) and water. It was dried oyer anhydrous sodium sulphate and concentrated in vacuo to give (7-bro mome thyl-benz ~o.~hydrindane (VIIIb)~. This wa~ the~ t~ken up in anhydrous diu~tbylsulphoxide (50 mlj and ~ded dropwi~e to a su~pension of sodium ~yanide (3. 6 g~ ln an~ydrous dimetbylsul~o~ide (100 ml) under stirring over a period o~ 30 minutes. The mixture waæ then allo~yed to ~tir oYernight~ It ~as diluted ~itb nater and extraoted with etber. The estract ~as washed witb water~ dried over anhydrou~ s~dium sulphate~ oonoentrated and the residue distilled under reduoed pressure to give ~IIIC; yield:

6.7 g, bp Z.0 164-66.

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-~2-(Ben~ ~ e _7 hydrindan -7-yl)propionitrile (VIII g)) (a) To a ~uspension of sodium hydr:ide (1.75 g; 50% ) in anhydrous dimethylsulfoxide (20 ml) was added a solution of 7-cyanomethyl-ben~ r e ~ hydrindane (VIIIc) ~6.30 g) in anhydrous dimethylsulfoxide (20 ml) under stirring. The rea¢tion mixture was allowed to stir for 4 hours~ cooled in ice-bath and methyl iodide (B ml) was added to it.
Another portion of methyl iodide (5 ml) was added arter stirring ~or 2 hours and the stirring was continued overnight.
Water was added to t~e reaction mixture and the product was e~tracted ~ith ether. The e~tract was wa~hed with water~
dried over anhydrous sodium sulphate~ concentrated and purified through a column o~ silica gel (S0 g) u~ing ben~ene as eluant. YIII g was obtained as a vi~cous oil a~ter distillation under reduced pressure; yield; 4.5 g;
bpl S 1?2-74 (b) 1. To a ~olution o~ 7~acetyl-benz ~ eJ hydrindane (VIIa) (5 g) in methanol (100 ml) was added sodium borohydride ~2.g~ in two portion and tbe mi~ture stirred for 6 hours. Solvent was relmoved under vacuo~ the complex was decomposed by adding water and the produot extracted ~itb ether. The e~tract was wasbed with water~ dried over ~anhydrous sodium a~alpbate, concentrated and the res~due distilled under reduced pre~ure to g~ve l-(benz ~ e hydrindan -7-yl) ethanol l-(VIIIe)~ yield: ~,2 g; bpl 0 142-44 "

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ii. To a cooled solu-tion o:f VIIIe (4 g) in anhydrous benzene ~50 ml) lvas added thionyl chloride (2 ml) and the mixture allo~7ed to stir overnight. Excess of thionyl chloride was decomposed by water and benzene layer was separated~ The organic layer was washed with water, dried over aDhydrous sodium sulphate and concentrated to yield l-(benz ~ e ~ bydrindan-7--yl) ethyl chlorids (VIII ~3. This ~as taken up in anhydlrous dimethyl sulfoxide (20 ml~ and added dropwise to a ~uspen~ion o~ sodium cy~nide (2g) in anhyd~ouæ dimethylsul~oxide (2S ml~
and it ~Jas then stirred overnight. Water was added to the reaction mixture and the product e~tracted with ether.
The extract was washed w ith ~vater ~ dr ied over aDhydrous sodium sulphate and concentrated to yield VIII g as a vis cous o il .
Ben~ r e ~ hydrinda~e -7-acetio acid (VIII d~

A mixture oi 7-acetyl-benz ~ e ~ hydri~dane (VII a) ~6g~
~ulphur (1 g~ and morpholing (3 ml) ~vere heated at- 140C
~or 12 hours. It was then deoomposad with ~ater and extracted with ether, The extraet was washed ~ith watex~ dried over anhydrous sodium sulphate and concentrated to ~ive a vi.scou~ liquid. This ~as tha~ obroma$ographed on ~:olumr~
of 3ilica gel (100 g) llSiDg benzene as eluant to give an intermediate compound which was re~luxed ~or 15 hour~
witb ethanolic pota,ssium hydro~lde (75 ml: 10%~ Ethanol wa~ removed uncler vacuo~ the residue ~as taken up in ~Jater, the aqueou~ 'layer was washed wi th ether to remo~e g603 unreacLed st~lrting m;lt~rials ancl then acidified. The prod.lct ias e~tracte~ ~vith etber, tbe extract s~ashed with ater, drie~ over anhydrolls so~ium ~lulphate and concentrated.
Ihe residue thus obtained ~ias chro~atographed on a colu of $ilica gel (60 g) ~Ising benzene as eluant to give a viscous oil ~hich r~as distilled ~ der reduced pressure to yield VIII d; yield: 3.~ g) bp 1 o 1.5~_60, ~enz r e ~ hy~lrindane-7-acetic acid ethylester (VIII i~

mi~ture of benz ~ e ~ hydrindane 7- acetic acid (~III d) ~4,2 g), absolate ethanol (7 cc), dichloroethane (lQ0 ml) and sulphuric ~cid (0,5 ml) were refluxed for 4 hours. Tbis ~as then poured into ~ater~ the organic layer was ssparated9 the aqueous layer extracted with ether and the combined or~anic layer wa9 Wa9hed ~gith water~ sodium bicarbonate solution (10%) and water, It was dried over anhydrous sodium sulphate~ concentrated a~d the residue distilled under reduced pressure to giYe VIII i; Yield : 4,2 g: bpo 5135--40.
2-Benz ~ e ~ hydrindan -7-yl) pro~ionic acid ethyl ester (V~

To a suspengion of sodium hydride (300 ~g~ 50% SllSpen9 ion) in ~ -anbydrous dimethylsul~oxide (3 ml) ~as added benz ~e~ hydrindane~

7-acetic acid ethyl e~ter ~YIII 1) (1 g) a~d the m~ture was stirred for 6 bour~ The reaction mixture ~as cooled in icebath, methyl iodide (1 ml~ was added to it and the 9 tirring was continoed for another 4 hour~. It was the~ decomposed with ~ater and the product extraoted with etherO The ethereal cxtract wa~ lashed with water, dried o~er anhydroas ~odium ~, ' 6~3 s~lFhate ~ncl concentrated. The residue thus obtained was chrom~to~,raphed on a colullm of silica gel (lS g) U~
hexarle-benzene (90:10) a~ elunnt. VIII j was obtained as a viscous liquid; yield: 800 mg.

2-Benz ~e _7 ~ydrindan-7-yl) propionic acid (VIII h) ~) A m~ture o~ 2-~benz ~ e _7 hydrindan-7-y~) propionic as3id ethyl est~r (VIII j) (500 mg) and etbanollc potas~ium hydroa~ide (30%, 10 ml~ was refluxed for 3 hour~. Ethanol was then removed under reduced pressure, water ~vas added to it, the residue acidified and e2~tracted ~l~ith e ther. The e tbereal e~traot ~as washed with water, dried over anhydrou~
sod~um 3ulphate, concentrated and pu~i~ied t~rough a column of silica gel (20 g) using ben~ene as eluant. VIII h was obtained as a viscous liquid which on cooling in defreezer over ~everal days gave a low melting solid; yield 300 mg.
b~ A mi~ture of 2_benz ~ e _7 hydrindan-7-yl)propionitrile (YIII g) (2 g) and a 901utio~ o~ potass~um by~ro~ide (2 g) in ethylene glycol (20 ml) was re~luxed for 20 boars~ This was then dilated with ~vater, washed with etber to remove unreaoted materisl and the alkaline 301utioll acidified with conoentrated hydrochloric acid,.
The product ~sas extracted with ether, the e~tract washed ~ith watex, dried ol~er anhydrouq sodium ~ulphate and concentrated.~ The residue thus obtained was purified through a oolumn of silica gel (1~ g~ using benzene as eluallt. Vlll h wss obtsined a9 a Vi~G~ Iiquid wbiob ,/

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~ 17:
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on cooling i~ deireezer oversev~al dayl3 gave a lo~
melti~g ~olid; yield; 1.6 gO ~ -

Claims (29)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing compounds of the general formula IX
wherein R is hydrogen, alkyl, alkoxy, hydroxy, halogen or halogenoalkyl, R1 stands for alkyl, hydroxy, halogen, cyano, carboxyl, inorganic salts of carboxyl, carbalkoxy, or CON R4 R5 wherein R4 and R5 are hydrogen, alkyl, optionally substituted aryl, optionally substituted heterocycle or (CH2)n R6 wherein n stands for 1-5 and R6 stands for carboxyl, inorganic salts of carboxyl, carbalkoxy or CONR4R5, R2 stands for hydrogen or alkyl, m is the numeral zero or one, and R3 stands for an atom of oxygen or hydrogen with the proviso that m is zero when R3 is oxygen atom and m is one when R3 is hydrogen atom, which process comprises:
(a) to produce a compound of formula VIIa or VIIc, reacting a compound of formula IV wherein R is as defined above, with an acid chloride or acid anhydride, respectively, in the presence of a Lewis acid;
(b) to produce a compound of formula VIIb, oxidizing a compound of formula VIIa with an oxidizing agent;
(c) to produce a compound of formula VIIIa, reducing a compound of formula VIIb;
(d) to produce a compound of formula VIIIb, brominating a compound of formula VIIIa;
(e) to produce a compound of formula VIIIc, reacting a compound of formula VIIIb with a cyanating agent;
(f) to produce a compound of formula VIIIg, alkylating a compound of formula VIIIc;
(g) to produce a compound of formula VIIId, reacting a compound of formula VIIa with sulphur and morpholine, followed by alkaline hydrolysis;
(h) to produce a compound of formula VIIIi, esterifying a compound of formula VIIId;
(i) to produce a compound of formula VIIIj, alkylating a compound of formula VIIIi;
(j) to produce a compound of formula VIIIe, reducing a compound of formula VIIa;

(k) to produce a compound of formula VIIIf, reacting a compound of formula VIIIe with a chlorinating agent;
(l) to produce a compound of formula VIIIg, cyanating a compound of formula VIIIf;
(m) to produce a compound of formula VIIIh, subjecting a compound of formula VIIIg or VIIIj to acid or alkaline hydrolysis;
(n) to produce a compound of formula VIId, subjecting a compound of formula IV wherein R is as defined above to reaction with ethyl oxalyl chloride in the presence of a Lewis acid;
(o) to produce a compound of formula VIIe, subjecting a compound of formula VIId to alkaline hydrolysis;
(p) to produce a compound of formula VIIIh, reacting a compound of formula VIIe with alkyl magnesium halide followed by treatment with mineral acid and reduction;
(q) to produce a compound of formula VIIf, VIIg, VIIIk or VIIII, converting a respective compound of formula VIIb, VIIc, VIIId or VIIIh to the corresponding acid chloride, followed by reaction with an amine of formula R4 R5 NH, wherein R4 and R5 are as defined above.

2. A process according to claim 1 for preparing a compound of formula VIIa or VIIc which comprises reacting a compound of formula IV with an acid chloride or an acid anhydride in the presence of aluminium chloride.

3. A process according to claim 1 for preparing a compound of formula VIIb which comprises reacting a compound of formula IV with an acid chloride or an acid anhydride in the presence of aluminium chloride and oxidizing the obtained compound of formula VIIa with a hypohalite oxidizing agent.

4. A process according to claim 1 for preparing a compound of formula VIIIa which comprises reacting a compound of formula IV with an acid chloride or an acid anhydride in the presence of aluminium chloride, oxidizing the obtained compound of formula VIIa with a hypohalite oxidizing agent and reducing the obtained compound of formula VIIb with lithium aluminium hydride.

5. A process according to claim 1 for preparing a compound of formula VIIIb which comprises reacting a compound of formula IV with an acid chloride or an acid anhydride in the presence of aluminium chloride, oxidizing the obtained compound of formula VII with a hypohalite oxidizing agent, reducing the obtained compound of formula VIIb with lithium aluminium hydride and brominating the obtained compound of formula VIIIa.

6. A process according to claim 5 which comprises the step of cyanat-ing the obtained compound of formula VIIIb by reaction with an alkali metal cyanide in dimethyl sulfoxide to obtain a compound of formula VIIIc.

7. A process according to claim 6 which comprises the further step of alkylating the compound of formula VIIIc by reaction with an alkyl halide in the presence of a base and in dimethyl sulfoxide to obtain a compound of formula VIIIg.

8. A process according to claim 1 for preparing a compound of formula VIIId which comprises reacting a compound of formula IV with an acid chloride in the presence of aluminium chloride and reacting the obtained compound of formula VIIa with sulphur and morpholine followed by alkaline hydrolysis.

9. A process according to claim 8 which comprises the further step of esterifying the compound of formula VIIId by reaction with an alcohol in the presence of sulphuric acid to obtain a compound of formula VIIIi.

10. A process according to claim 9 which comprises the further step of alkylating the compound of formula VIIIi by reaction with an alkyl halide in the presence of a base and in dimethyl sulfoxide to obtain a compound of formula VIIIj.

11. A process according to claim 1 for preparing a compound of formula VIIIe which comprises reacting a compound of formula IV with an acid chloride in the presence of aluminium chloride and reducing the obtained compound of formula VIIa.

12. A process according to claim 11 which comprises the further step of reacting the obtained compound of formula VIIIe with thionyl chloride to obtain a compound of formula VIIIf.

13. A process according to claim 12 which comprises the further step of reacting the obtained compound of formula VIIIf with an alkali metal cyanide in dimethyl sulfoxide to obtain a compound of formula VIIIg.

14. A process according to claim 13 which comprises the further step of subjecting the obtained compound of formula VIIIg to acid or alkaline hydrolysis to obtain a compound of formula VIIIh.

15. A process according to claim 10 which comprises the further step of subjecting the obtained compound of formula VIIIj to acid or alkaline hydrolysis to obtain a compound of formula VIIIh.

16. A process according to claim 1 for preparing a compound of formula VIId which comprises reacting a compound of formula IV with ethyl oxalyl chloride in the presence of aluminium chloride.

17. A process according to claim 16 which comprises the further step of subjecting the obtained compound of formula VIId to alkaline hydrolysis to obtain a compound of formula VIIe.

18. A process according to claim 17 which comprises the further step of reacting the obtained compound of formula VIIe with an alkyl magnesium halide followed by treatment with mineral acid and reduction to obtain a compound of formula VIIIh.

19. A process according to claim 18 wherein the reduction is carried out by hydrogenation in the presence of a platinum oxide or palladium on charcoal catalyst.

20. A process according to claim 2, 3 or 8 which comprises the further step of subjecting the obtained compound of formula VIIc, VIIb or VIIId to reaction with thionyl chloride to obtain the corresponding acid chloride, followed by reaction with an amine of formula to obtain a compound of formula VIIg, VIIf or VIIIk, respectively.

21. A process according to claim 14 or 15 which comprises the further step of subjecting the obtained compound of formula VIIIh to reaction with thionyl chloride to obtain the corresponding acid chloride, followed by reaction with an amine of formula to obtain a compound of formula VIIII.

22. A process according to claim 1 wherein R stands for hydrogen or a methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy group, a fluorine, chlorine or bromine atom or a trifluoromethyl group.

23. A process according to claim 1 wherein R stands for a methyl, ethyl, n-propyl or hydroxy group, a chlorine or bromine atom, a cyano group, a carboxyl group or the sodium or potassium salt of a carboxyl group, or a carbethoxy group.

24. A process according to claim 1 wherein R4 and R5 are hydrogen or methyl, ethyl, n-propyl, phenyl, chlorophenyl, pyridyl or quinolyl groups or groups of formula (CH2)n R6 wherein n is an integer from 1 to 6 and R6 stands for a carboxyl group, a sodium or calcium salt of a carboxyl group or a carbethoxy group or a group of formula CONR4R5.

25. A process according to claim 1, 23 or 24 wherein R2 stands for hydrogen or a methyl, ethyl, n-propyl or isopropyl group.

26. A process according to claim 1 wherein the compound of formula IV
is obtained, in admixture with a compound of formula V, by cyclization of a compound of formula II with polyphosphoric acid and wherein the compound of formula V is converted to a compound of formula IV by catalytic hydrogenation.

27. A process according to claim 25 wherein the hydrogenation catalyst is platinum oxide or palladium on carbon.

28. A process according to claim 1 wherein R and R2 are hydrogen and R1 is a methyl, hydroxy or cyano group or a chlorine atom.

29. A compound of formula IX as defined in claim 1 or a pharmaceutical-ly acceptable salt thereof when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.