PH25981A - (Benzosulphonamido alkyl)-cycloalkyl (1,2-b) indoles - Google Patents

Description

A

This application is a divisional application of applioation Berial No, 34883 {led on February 19, 1987.

The invention relstes to new aysloallane/T,9-h/- indole-sulphonsmides, to process for their Preparation 3 and to their use in medicaments, /Bensenesulphonamido- alkyl/oyoloaliano/T, 2-b/indoles, which are likewise new, osu be used as intermediates for the reparation of the new compounds,

New cycloalkans/I,2-h/indole~sulphonamides of the general formula (1) (CH) _=NH=SO_=R° 2'y 2 1 = —

R .

Om (1),

COOH in which rt represents hydregen, halogen, triflveromethyl, carboxyl or alkoxycarbonyl, represents a group 13 of the fermla ~3(0) 2’, in which

R’ denotes alkyl or aryl, smd n denotes one of the mmbers 0, 1 or 2, represents

BAD ORIGINAL /

i 25981 a group of the formula rt a < 5 in which nt ent B® are 14ention) or different ent represemt hydregen, alkyl, aryl, aralkyl er acetyl, re- presents a group of the formula oe, in which

B® denotes hydregen, alkyl, eryl, sralkyl, alkyl- 80,9 ary1-~80,- aralkyl-50,- or trifluere- methyl, er represents alkyl, alkemyl or aycle- alkyl, each of which is optionally substituted by carboxyl, alkexycarbonyl, hslogen, hydrexyl, alkoxy, slkylthie er cyano,

R? represents aryl which is optionally substitubed 1s up to 5 times Wy halogen, cysne, triflucre- nethyl, triflueremethoxy, triflusromethylthie, alkyl, corboxyalkyl, alkoxyosrborylalkyl, al- koxy, alkylthio, hydroxyl, earboxyl, alkexycer- bonyl, phenyl, phemoxy, benmyloxy, bensylthie or by a group of the formula

BAD ORIGINAL J ys 25981 rt -N /

N\ 5 in whieh

R* ant B® have the abovementioned meaning, x represents the mwmber 1, 2 or 3, and y represents the mmber 0 or 1, where appropriate in sn isomeric fomm, or their salts, have been found,

The aycloalksne/1,2-3/indole—sulshonanides according $0 the invention have several asymmetrie cer bon atoms end can thus exist in various stereochemical forms, The invention relates both to the individual isomers and to the mixtures thereof, : The following isomeric forms of the eyclealksmo- [3y2-3/ind01e-sulphonamides ney be mentioned by way of exemple a) Gyolealkeno/l,2-~p/indole-eulphonemides (CH,) ~NNeSO,-R> (II)

COOH r

BAD

. ORIGINAL 9)

SA

2 a (Cl) y~NH=80,~R (111)

COOH

. rR:

CH) =NH=50,~R? (IV)

COOH dT "(CH,) =NH-50,~R> (v)

Goon (GH,)y=NH-50,-R rt Ty (v1) (CH.,) =NHeS0.=R° coon £2 2 a CT (VII)

COOH

2 (CH, )y=NH=50_«R oad 2 2 (VIII)

COOH

Clip) ~NH=50,~K" (1x)

TI

BAD ORIGINAL na ¢ ¥) Cyoloalkeno/1,2-3/4ihydroindole-sulphonamides 2

H (CH) ~NH=SO,~R 1 ~~ -

R - (ci,) (x) \ pd x n

COOH

2

H (CH) -NH-S0,~R ) >X

R +1 AH) (XI) :

COOH rl, ®, x and y having the abovementioned meaning,

The oycloalksno/1,2-3/1ndole-sulphonemides sooor- ding to the invention can also be in the form of their salts, In general, the salts which may be mentioned in thie context are those with organic or inorganic bases,

Physiologically acceptable salts are preferred within the scope of the present invemtion, TFhysiological- 1y soceptable malts of the eyolealksmo/1,2-b/indele-eul- phonamides oan be metal or ammonium malts of the sube- y BAD ORIGfiv~.. bm =

UO oF 25981 tances according to the invention which have a fires oaxrboxyl group, Examples of those which are pmrtioule- 1y preferred mre sodium, petassiim, magnesium or caloiwm salts, as wll as mmmonivm salts which are derived from

S mmorda or organic amines such as, for exemple, ethyl- amine, di= or triethylamine, di- er triethanolamine, di eyolohexylamine, dimethylmincethanol, srgimine or ethylensdismine.

The substances according to the invention surpris- ingly exhibit an action inhibiting platelet sggregation and oan bo ured for the thermpsutic treatment of humems and animals,

Alkyl gererally represents a straight-chain or branched hydrocarbon radical having 1 to 12 carben atoms,

Tower alkyl having 1 $0, say, 6 carbon stows is preferred,

Examples which may be mentioned are methyl, ethyl, pwo- pyly isopropyl, Wwutyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, ischepiyl, octyl and imooctyl.

Alkenyl generally represents a straight-chain er brenched hydrocarbon radieal having 2 to 12 carbon atoms and ons or more, preferably having one ox two, double bonds, The lower alkyl radical heaving 2 to, say, 6 cur bon atoms and ons double bond is preferred, An alkenyl rodioal having 2 to 4 emrbon atoms end one double bord 28 is particularly preferred, Examples which may be men+ : BAD ORIGINAL 9

Le tioned are vinyl, allyl, propenyl, isopropenyl, Wrbenyl, isobutenyl, penmtenyl, isopentenyl, hexenyl, imshexenyl, heptenyl, ischepienyl, cctenyl and isooctenyl.

Ovoloalkyl generally represents a oyelie hydre- cerbon radical having 3 to 8 carbon atoms, The ayelo- pentane end the cyclohexene ring is preferred, Exmmples which may be mentioned are oyelepronyl, cyclopentyl, cyclohexyl, cyeloheptyl and ecyclooetyl.

Alkpxy generally represents a straight-chain or branched hydrocarbon radical which has 1 to 12 cerbon atoms and 4s bonded vie mn oxygen stom, lower alkoxy having 1 40, say 6 corbon atoms is preferred, Mn alkoxy redical heaving 1 to 4 earden atoms 48 particularly pre- ferred, Examples which may be mentioned are methoxy, 13 ethoxy, propoxy, isoprepaxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, ischexexy, hepboxy, ischeptoxy, ootoxy or imsoootoxy.

Alkvlthio generally represents a straight-chain or branched hydrocarbon radicel which has 1 $0 12 cerbon atoms and is bonded via a sulphur atom, Iower alkylthie having 1 to, say, 6 carbon atoms is preferred, An sl- kylthio radical having 1 to 4 carbon atoms is partioular- preferred, Examples which may be mentioned are methyl- thio, ethylthio, propylthio, isopropylthio, bukylthio, 23 isobutylthio, pentylthio, isopentylthio, hexylthio, ieo~

FF ee

BAD ORICA) A)

Co

0 © 25981 hexylthio, heptylthie, ischeptylthio, cotylthic emd isoootyltio,

Aryl generally represents en aromatic radicel having 6 to, say, 12 carbon atoms, Preferred aryl radi- cals ave phenyl, nephthyl and diphenyl,

Aralky]l generally represents en aryl radieal which has 7 to 14 carbon atoms end is bonded via an al- kylene ehain, /ralkyl radicals having 1 to 6 earbon atoms in the aliphatic part and € $0 12 searbon atoms in the sromatic part ere preferred, Examples which may be mentioned are the following aralkyl radicals: demsyl, naphthylmethyl, phenethyl and phenylproryl.

Alkoxvearbonyl cen be represented by, for example, ‘the formila «CO-alkyl 0

In this, alkyl represents a straight-chain or branched hydrocarbon radical having 1 to 8 carbon atoms, Tower alkoxycarbonyl having 1 to, may, 6 carbon atoms in the alkyl part is preferred, An alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl part is particularly pre- ferred, Exsmples which may be mentioned are the follow ing alkoxycarbonyl radicals: methoxycarbonyl, ethoxy~ carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy- carbonyl end isobutoxyearboryls AD ORIGINAL 2) he

N

A

25981

Sxrboxyalkyl generally represents a straight chedn or branched hydrocarbon radical which has 1 to 12 carbon atoms and is substituted ly a oarboxyl groups

Carboxy~lower-alkyl having 1 to, ssy, 6 esmxrbon atoms ism

S preferred. Exmuples which may be mentioned are: earbaxy- methyl, l-carboxyethyl, l-carboxypropyl, l-ocarbexybutyl, l-carboxypentyl, l-carboxyhexyl, 2-carboxyethyl, 2-oar- boxypropyly 2-carboxybutyly 3-sarboxypropyly, 3-esrboxy- butyl, 4~csrboxybutyl, 2-carboxy-l-promyl snd l-esrdoxye l-propyl,

Alkoxyoexbonylalkyl generally represents a stradght- chain or dranched hydrocarbon radical which hes 1 to 12 carbon atoms and is substituted by en alkoxycarbonyl group, alkoxycarbonyl having the abovementioned méaning, Iower alkoxycerbonyl-lower-alkyl having 1 to, say, § carbon atoms in each alkyl part is preferred, Examples which may be mentioned are: methoxyoarbonylmethyl, ethoxyoer- bonylmethyly propoxycarbonylmethyl, buboxycerbonylmethyl, isopropoxysarbonylimethyl, isobutoxycaxborylmethyl, 1- methoxyoarbonylethyl, l-ethoxyoarbonylethyl, l-propoxyca= bonylethyl, l-butoxycerbonylethyl, 1-isorropaxyesrbonyl~ ethyl, l-isobutoxycarbonylethyl, 2-methoxysaxrbonylethyl, 2-sthoxycaxrbonylethyl, 2-propoxycarbomylethyl, 2-butosy- oarbonylethyl, 2-isopropoxycarbonylethyl, 2-imobutoxy- 23 carbonylethyl, 2-methoxyocsrbomyl-2-propyl, 2-ethoxyear— -10 - pre

BAD ORIaIM At ~)

al 25981 bonyl-2-propyl, 2-propoxycarboryl-2-propyl, 2-butoxy- carbonyl-2-propyl, 2-imopropoxycarbonyl-2-propyl, 2-iscbu- toxyscarbonyl~2-propyl, 2-methoxyocarbonyl-2-propyl, }~ ethoxyeexrbonyl-2-propyl, 2-propomeyearbonyl-2-pronyl, le

S butoxycarbonyl-2-propyl, l-isopropoxyssrbonyl-2-propyl, 1-isobutoxycarbonyl-2-propyl, 3-methoxysarbonylpropyl, 3~ethoxyosrbonylpronyl, 3-feopropoxycarbonylronyl sd s=-izobutoxysarbonylpronyl,

Halogen generally represents fluorine, chlorine, bromine or iodine, preferebly fluorine, chlorine or bro- mine, Halogen particularly preferably represents fluorine or chlorine,

The compounds of the general formila (I) which sre preferred are those in which 1s rl represents hydrogen, fluorine, chlorine, bro- mine, trifluoromethyl, carbaxyl or lower alkoxy- ocerbonyl, represents a group of the formula -s(0) ¥ in which rR denotes lower alkyl or phenyl, amd n denotes a mmbexr 0 or 2, represents a group of the formula rt / -N

N p$ 2 BAD ORIGINAL 9d

A

25981 in which

R* and B® are 1dentical or 41fferent end denote hydrogen, lower alkyl, phenyl, benzyl or acetyl, or represents a group of the formula crf, in which gS denotes hydrogen, lower slkyl, phenyl, phenyl- 80,~me thy1-80,~, ethyl-80,~ or trifluoromethyl, or represents lower alkyl, lower slkenyl, ayelo- pentyl, or cyclohexyl, each of which is optional~ ly substituted hy carboxyl, nethoxycarbonyl, ethaxyoexbonyl, fluorine, chlorine, bromine, hydroxyl, lower alkyloxy or cyemo, ® represents rhenyl which is optionally substi tuted up to three times by fluorine, chlorine, ] bromine, cyemo, trifivoromethyl, trifluoramethedy, triflnoromethylthio, lower alkyl, ecsrboxymethyl, carboxyethyl, methoxymethyl, ethoxymethyl, methoxy - ethyl, ethoxyethyl, lower alkoxy, lower alkylihie, oe hydroxyl, carboxyl, lower alkoxycarbonyl, phemyl, rhenaxy, benzyloxy, benzylthio or by the group ot - r> in which

P———— -12 - BAD pga: >,

£ 25981

R* and R> have the meeming alresdy indicated, x represents the mmber 1, 2 or 3, od y represents the mmber O or 1, where sprropriste in an isomeric form, or their salts, 3 Te compounds of the general formule (I) which are particularly preferred are those in whish ® represents hydrogen, fluorine, chlorine, bre- ming, trifluoromethyl, meihylthio, ethylthio, methylsulphonyl, phemylthio, rhenylsulphonyl, amino, dimethylemino, diethylamino or acetyl- amino, or represents a group of the formule -®8, in which né denotes hydrogen, 0, ~C,-alkyl, phenyl or den- 13 Byl, or represents C,~0 oliyl,

R? represents phenyl which is substituted up to three times, identically or differently, hy fluorine, chlorine, bromine, oyemo, trifluorc- methyl, trifluoromethoxy, 0,=0,-slkyl, 0,~C ~ alkoxy, methylthio, hydroxyl, methaxysarbonyl, sthoxyecarbonyl, dimethylemino, atetylsmino, or diethylmmino, -13 ~

BAD ORIGINAL 2

Xx represents the mmber 1 or 2, end ¥ repressnts the mumber O or 1, where apmropriate in an isomeric form, or their salts,

The compounds of ths general farmls (I) which are very particularly preferred are those in which rl represents hydrogen, fluorine, methyl, methoxy, bensyloxy or hydroxyl,

B® represents phemyl which is wubstitried hy fluo- rine, chlorine, trifluoromethyl, methyl, ethyl, propyl, isopropyl or methoxy, x represents the mmber 1 or 2, md y represents the mmber O or 1. where appropriate in an isomeric form, or their salts.

Particularly preferred ere (4)- or (-)-dsamerie ay- 18 eloalkena/Y, 2-h/indole~eulphonsmides of the fermile . 2 (CH,) =NH=50,-R ~ | | .

COOH in which 0 GAR | ga SN ~U- BAD ORI “a ~N

YN

4 25981 rt represents hydrogen, fluorine, methyl, methoxy, bensyloxy or hydroxyl,

R2 represents phenyl which is substituted hy fluo- rine, chlorine, trifluoramethyl, methyl, pro- pyl, isopropyl or methaxy, end y represents the mmber O or 1, or their salts.

The following cycloalkemno/1,2-p/indole-sulphonamides may be mentio ed by way of exemple: 1~(bensenesulphonami dome thyl )=4-(2~carboxyethyl )oyoclo- peprteana/T, o-b/indole 4~(2~corboxyethyl)-1~(4~fluorophenylsulphonamdanetiyl )- oyelopentsno/E, 2-b/indole 4~(2-carboxyethyl )-1-(4~chlorophenylsulphonamidomethyl = 1% cyolopemtano/1, 2-b/indole 1-(bensenssulphonani domethyl )-4-(2~carboxyethyl )-T-nethaxy- cyolopent mo/1, 2-b/1nd ole 4=(2-carboxyethyl )-1-(4-fluorophenylsul phononidomethyl )-

T-methoxyeyclopentano/1, 2-b/indole 4=(2-carhoxyethyl )-1-(4~chlorophenyleul phonemidomethyl )-T= nethoxyeyclopenteno/1, 2-b/indole 1-(benzenesulphonami do )=4~(2-oarboxyethyl Jeyelopentano- 2-1 1ndole 4-(2-carbaxyethyl )~1-(4-fluorophenylsul phonemido )ayolo~ 4 petano/1,2-h/indole

BAD ORIGINAL .

0 £ A 25981 4=(2-0nrboxyethyl )=1«~(4<chlorophanylsulyhonmeidoe Yeyelo- ponbana/T,2-2/intole 1-(bensenesul phonsmi 40 }-4~(2-curbaxys thy )-T-me thoxy- oyolopentano/i, 2-3/indole s 4-(2-0srbaxyethyl )=1=(4=fluoropheryl sulphonamide }-T- methoxyeyolopentans/1,2-a/indele 4=(2-carhoxyetiyl)=1-(4~chlorophanyleul thonaeide)-7- netharyayolopemtans/1,2-/indole 1-(bensenemil phonseidometiyl )=4~(2~carboxysihyl)-T-nethyl- oyclopenteno/T, 2-a/indole 4~(2~0sxbaxyethyl )=1-(4=finorophenyl sulphone dome ttyl )- 7-methyloyelopentano/l, 2-h/indole 4=(2-0arboxyetiyl )-1=(4=ohlorophenylsulphonmed deme thyl )-

T-methyloyelopentana/1,2-2/indole 18 1~(vensenssulphonami do )=4~(2-carboxyeityl }-T-nethyloyelo- pentena/l2-2/indole 4~(2-0arboxyeihyl }e1=(4=f1uerophenyleul honsnd do )=T-methyl=~ eyolopenteno/1,2-R/indole 4=(2-0arboxyeihyl)-1=(4-chlorophenyleal phonamido JT-methyl~ oyclopentena/i, 2-3/indo1e 4-(2=carboxy ethyl )-1-(4=4olylmulphonant dome ttyl }-cycle- pentmna/l, 2-2/indole 4=-(2-ssrboxyethyl }=1~(4-dolylsulphonsmido) —oyelopentanc- [5,240 indole 28 3(bensenesulphonami de )=9=(2-carboxyetiyl }=1y 2) 3p 4y 48s Sa hexshydrocarbasole

Ce EN freee -16- BAD orien)

3=(bensenesulphonami do )-9-(2~carboxyethyl )-1,2,3, 4, 4a, 9a=hexahydrooarbasole 3~r~(benzenesul phonami 10 )-9-(2~carboxye thyl )~6-metheoy~ 142, 3y 4, 4a=t, Ya~t-hexahydroomrbasole 3=r-—(bensenesul phonamido )=9-(3-carboxyethyl )~§-methoxy- 1,2, 3,4) 42-0) 9a~o-hexahydroonrbasole

S-r=(bensenssulphonsed deme thyl )-9-(2-cuxboxyethyl 1,2, 5, ~ 4y 42%, a-t-hexahydroesrbanole 3-r=(bensenesulrhonani domethyl }-9-(2-carboxystiyl )= 1,2, 3,44 48-0) Sa~e~hexshydrocarbasole 3-r-(bonsenesil phonsmidoneiinyl J=9-(2-0arboxyeinyl )=g- methoxy=l,2,3,4,4a~t,9a~t-hexahydrocarbasole 3-2 (bensensmil phonamd dame thy }=9«(2-0arboxyethyl J=f- methaxy-l, 2, 3,4) 4a=c, 9a~o-hexahydrooarbasole 9~(2-0arboxyethyl )=3-r=(4-ehlorophenylsul phonmmide )- 1423) 4 4%, 9o~t-hexshydroearbasole 9~(2-0arboxyethyl }=3-r-(4~chlorophenylsulrhonamide = 1,2 3,4) 480, 9a~c-hexahydrocarbasole 9=(2~0arboxyethyl }=3-t(4~fluorophenylsulphonmmido )- 1,2, 3,44 42-4) Ya~t-hixahydrosarbasole 9-(2-carboxyethyl }=3-r=(4~flucrophenylsul phonmmido )- 192,34, 48-0, 9awo-hexalydrocarbasole, 9=(2-oarboxy ethyl )=3-r=(4-40lyimilrhonamide )=1,2, 3,4, et, 9a~t-hexahydrooarbasole 9-(2-oarboxyetiyyl)-3-r-(4-4olyleturhonamido )=1,2, 3,4, 4a, 0, 9a~o-hexahydrooarbasole

BAD ORIGINAL 9

Co -17-

va 25981 9=(2-carboxyetiyl }=3-r=(4~flucropheny sul phonand do )=6- methoxy=1,2, 3y 4, 4a~%, Ja~t-hexalydrooarbasole 9-(2-0arboxyethyl )=3-r=(4=fluorophenylaulphonamido )=6= methaxy-1,2, 3, 4) 4 a~0~Ja=o-hexalyirosarbam le (4)=3~(4-cnloropheny sulphonamide }=9~(2-earboxysihyl )- 1,2, 3y4-ketrehydrocardasole (4)=3-(4-f1uorophenyl aul phonemido }-§~(2-carbexyethyl )- 1525 3y4~tetrahydrocarbasole (= )}~3~(4-chlorophenylsulphonemd do J-0-(2-carboxyethyl )- 152, 3,4-tetrahydrocart esse (=)=3-(4-flucrophenyl sul phonsmido )-9-(2-carboxyethyl = 1,2, 3y4~tetrahydroearbasole (4 )=3~(4=chlorophenyleulphonmmido )-9-(2-oarboxyethyl = 192, 3, 4-tetrahydrocarbasole (4)=3~(4~f1uoropheny sul phonamido )=9~(2-carbaxyethyl = 1,2, 3) 4=tetrahydrooarbascles

Particularly preferred sret ($)=3=(4~fluorophenylisenl phonsmi do )-9~(2-carbaxy ethyl )- 1,2, 3,4~tetrahydrocarbascle end (=)=3=(4~f1u0ropheny1-mil rhonsmt do )-9-(2-carborylethyl )- 1y2, 3y4-4etrahydrooarbasole,

Furthermore, a process for the preparation of the oyoloalkamo/i, 2-h/indole-sulthonamides according to the in- vention, amd of their salts, has been found, which is oo -18 - pre

BAD ORs, N

AA

A> 25981 characterized in that /bensenesulphonsmidoalky]/syolo- alkeno/1,2-b/indoles of the general formila (IT) 2 (CH) =NH=50,-R 1 (XI11)

R Cit,

Ny N-

H in which rt represents hydrogen, halogen, trifluoromethyl, carboxyl or alkoxycarbonyl, represents a group of the formila -5(0)R%, in which

YY denotes alkyl or aryl, and n denotes one of the mmbers 0, 1 or 2, represents : a group of the formile rt -/ -N \ 3 in which at and BR are identical or different end represent hydrogen, #lkyl, aryl, eralkyl or asetyl, re- presents a group of the formula oe, in which

BAD ORIGINAL 9

A

25981

B® denotes hydrogen, sliyl, aryl, ereldyl, slkyl- 80y~y exyl-80,-, aralkyl-50,~ or trifluero- methyl, or represents alkyl, alkemyl or cyelo- alkyl, each of which is optionally substituted by eerbaxylf alkoxycarbonyl, halogen, hydroxyl, alkoxy, alkylthio or cyemo, ar? represents aryl which is optionally subetitubed up $0 5 times by halogen, cymmo, trifinoromethyl, trifinoromethoxy, trifluoromethylihio, alkyl gar baxyalkyl, alkoxycarbonylalkyl, alkoxy, alkyl- thio, hydroxyl, carboxyl, slkoxyosrbomyl, phenyl, phentxy, bensyloxy, bensylthio or by a group eof the formula ng *

Ng 13 in which 2* end 2% have the sbovementionst meaning, : X represents the mmber 1, 2 or 3, md

J represents the mmber O or 1, are reacted with acrylonitrile in the presence of ma inert solvent, where appropriate in the [resence of a base, then the X,'~biscyenoethyl compounds ere hydrolysed, them, in the case where the cycloalkuno/T,2-3/dihydroindole-sul~ phonmides are being prepared the aycloalkeno/T,2-p/indole-

CL -20 = frre

BAD Opi~n... N\

& sulphonzmides are hydrogenated, where appropriate in the presence of sn inert solvent, in the presence of mm acid and of a reducing agent, where appropriste the isomers sre separated in a customery mamer, end then, where sprropriate, in the case where the salts are being pre- ; pared reaction with an appropriate dase is cerried out. \

The process ascording to the invention cam de illustrated hy the diagrem which follows!

N/A z ee NH so. —F ——m

J

A 2 N,C=CH-CN

Zz wo _H-

CT Q _ ~

CN hydrolysis

CN meso Nr . 7 ee : —

ZC oT J N= 2 ’ ~

I reduction f A , -2] - BAD ORIGINAL :

4° 25981

H H

. ss Or = ) so dr + ~

H H

COOH COOH

The cycloalkano/T,2-p/dihydroindole~sulphonams dos within the scope of the formula (I) correspond to the formula (Ia) (CH,)_«NH=SO -R% : 1 . . R 5 CH,)

COOH in which rY, R%, x and y have the abovementioned meaning,

Then the process according to the invention is carried out, in general the intermediates produced csm be isolated, Thus, it is possible to carry out the pro- 0688 according to the invention in several prooess stages,

T | -22 ~ Fr —

BAD origi «, D oT Sa”

0 25981

However, 4% may also be possible $0 eombine various pro- cess steps.

Possible solvents for the process according to the invention are water and orgamic solvents which &o not change under the reaction conditions. These prefer- ably inslude alochols such as methanol, ethamol, propsmol or isopropanol, ethers such as diethyl ether, detrshy- drcfuren, dioxans, glycol monmethyl or Mnethyl ether, hydrocarbons sich as bensens, toluene, xylene, cyclo- hexane, hexane or petroleum fractions, dimethyl sul~- phaxide, dime thylformemide, hexemethylphosphorie tri- snide, ethyl acetate, acetonitrile or pyridine, It is equally possible to use mixtures of the madd solvents.

Possible bases for the process according to the invention are custamery basic compounds. These preferably 4nolude alkali metal end alkaline earth metal hydroxides, puch as lithium hydroxide, sodium hydroxide, potassium hy- araxide or barium hydroxide, alkall metal hydrides such a8 sodium hydride, alkali metal or alkaline earth metal carbonates such as sodium cerbonate, potassium carbonate, or alkeli metal alcoholates such as, for example, sodium methemolsate or ethanolate, potassium mathanolate or etheno- late, or potassium tert.-butylate, or amides such es soda mide or lithium diieopropylamide, or organic smines such as bensylirimethylemondium hydroxide, tetrabutylsmonim "Bs BAD ORIGINAL 9 \

& 25981 hydroxide, pyridine, triethylmmine or N-methylpi peri dine.

The process according to the invention is general- 1y carried out in a temperature range from 0%0, to 150°C, preferably fram 20°C. to 100°0.

The process according to the invention is gene~ rally carried out under atmospherie pressure, However, it 4s also possible to curry out the process under ve duced pressure or elevated rressure (for exemple in o renge from 0,5 to 5 bar),

In general, 1 to 20 mol, preferably 1 tc 10 mol, of sarylonitrile is used for each mol of /Hensenesulphon- emidoalky)/cycloalkano/T, 2h indole’

The N,N'-bis-oyanoethyl compounds sre hydrolysed in a mammer known per ss in the presence of bases such as alkali metal or alkaline earth metal hydroxides or al= kenolates, in inert solvents such as water or aloocholw.

The preferred bases which are used sre sodium, potassimm or barium hydroxide, sodium methmolate, potassiies me- thenolate, sodium ethenclate or potassium ethenolate, preferably in water or methemol, ethanol, propmmol er isopropanol, or in mixtures of these solvents.

In general 1 to 100 mol, preferably 2 to 50 mol, of base i8 used for each mol of N,N!~bimoyanoethyl come pound, 2% The hydrolysis is oarried out in a temperature range

LL rom) - 04 - BAD QI iar }

from 0°0, to 100°C, preferably from 20°c. to 80°C,

The hydrogenation is carried out in a memmer known per se, It is possible for the noid which is umed te be employed ss solvents for this, 8 Suitable solvents for the hydrogensiion are inert organie solvents which de not chenge under the resstion conditions, These preferably imelude others sugh as &i- ethyl ether, dioxane or Setrshydrofursm, or glacial ssetie acid, trifluoroacetic aoid, methanesulphonie acid er iri- flunoronethenesulphoniec acid,

Acids which can be used for all the proeess steps socording to the invention sre organie acids. These pre~ ferably include carboxylie acids much as, for exmmple, soetie acid) rropionie acid, shloreacetie acid, diehloro~ 13 soetic acid or triflucrossetic acid, all swifonie aside sush ss) for example, methemesulrhorde acid, ethamemil~ phonde acid, toluenesulphonic aiid or bensenesulphonie aoid oF trifiucromethemsimulphenic seid.

Sui¥sble reducing agents for the hydrogenation ageording 40 the invention are the customary reducing agents, These preferably include hydrides such as, for eoxsmple, sodium borehydride, sedium cysmodorohydride, te tratutylamonivn borohydride, tetrabutylamonium eysmebore~ hydride, tridutyltin hydride, triesthylsilane, dimethyl 2% pherylailane or trirhenylsilsne, -28 BAD ORIGINAL dD

AN

1

The hydrogenation is generally carried out in a temperature ronge from -40%0. $0 Ja0°c, rreferably from ~20%, to 460°0,

The Lbenzenesul phonami doaliyleyeloalicano1 J, Delf indoles of the general formula XIII which are used are new. A process for the preparstion of the Lensenemi~ phonanddoalkyl/~aycloalkano/T, 2-1/indoles has likewise been found, which is characteriwed in thet phenylhydre— sines of the general formula (XIV) 1

R ££) (xxv), ~ M-H, in which

R' hos the abovemantionsd meaning, are reacted with cyecloalksnonesulphonamides of the general formule (XV) (CH,)_~NH=SO_-R° (xv)

TC

. sr (CH) 0 in which a LE or - 26 ] ' RAN ~~~... .. N\

- 1e - ~axpApIses ‘euuxorp ‘Tape TARP ‘erdwexe Joy ‘es yore sey ‘Tool? pus Towsdoxd-08F ‘Towsdoxd-u éTounuye ¢pousygen ‘erduni® Jo 8% yons sTOUEITE epnrout Aq -JoZaxd eel; ‘AUOTIFPUOS UOTIVEBAI Og} Jepun FIO Jou

Op UOTUM SIUAATOS OTWSHIO0 JIMUT 908 OXY UOTHUSAUT SY} ot 0g uFprooos ese0oxd oy JOF SUGATOS SYqQTAROAI

H i Ag

A \ (pos / 4° CHN-HN_ X 0 d « 2 ogeny’

IBMOTTOF OPM WBaRUEp oyy £4 PIBIISULLT oq

Wo UOTRUAAUT us 0f BuFpIoooe seToput/-g tL/ousireorodo $ =/Tireoppsuoyd Tesuesueq/ 843 Jo uogysaedexd ayy *qeiregEo B Jo eoussexd a3 uj ‘agutadoxdde exeyu ‘pus @ImeATO@ 4IeUF Jo edussexd oyy UT ‘PUTUEOW PIUOTIUSWAAOGR OU] SABY £ pus X ‘Su

I RAC f

BAD ORIGINA 9 or a furan, glycol monomethyl or dimethyl ether, halogenated hydrocarbons such as di-, tri- or tetrachlorometheme, dichloroethylene end trichloroethylene, ethyl acetate, toluene, acetonitrile, glacial acetic acid, hexemethyl- phosphoric triamide, pyridine and acetone, Of course, it is possible to use mixtures of the solvents,

Suitable catalysts for the process according to . the invention are the customary acids or Iewis acids,

These preferably include inorgmnic acids such as hydro- chloric acid, hydrobromie acid or sulpmndo acid, or or- garde acids, much ss carboxylic acids or sulphonic acids, for example acetic acid, methimesulphonic acid amd $o- luenesulphonie acid, or Lewis acids such as, for exemple, sino chloride, sinc tromide or boron trifluoride ether ate.

The process according to the invention is general- 1y carried out in a temperature remnge fram 0°. to 200%, preferably from 20°C. to 150°C,

The process according to the invention 4s genersl- ly. carried out under atmdspherio pressures It is equal- ly possible to carry it out under elevated or reduced : pressure (for exmmple from 0.5 to 5 bar),

In general, the hydrazine is used in en mount of 1 to 3 mol, preferably 1 to 15 mol, relative to the 2% kotons, -28 - - N

I 0 ORIGINAL b a 25981

Examples of hydrasines which are used for the process acooxding to the invention are: phenylhydrazine, 4-methoxyrhenylhydrazine, 4-chlorophenylhydrasins, 4- fluorophenylhydrasine md 4-methylphenylhydrasine,

Excuples of ketones which are used according te the invention ere: 3~(bensenesulphonamidopethyl Joyolopentanone 3-(bensenesulphonemidonethyl Joyclohexenone 4-(venvenesul phonami domethyl Jeyolohexanone ’ 4-(bensenesulrhonamidomethyl )eyolohexanone 3-( benzenesulphonami do Joyolopent none 3—( benzene phonami do Jeyolohaxemone 4-(benzenesulphonsmi do Joyolohexeanons 3~(4=chlorophenylsulphonsmidomethy Joyolopentanons 3=(4~flnorophenylsulphonsm dome thyl Jeyelopentanone 3=-(4-methylphenylsulphonamd domethyl Joyclopernrtenons 3- (4~chlorophenylsulphonsmidomethyl Jeyelohexanone 3=(4-f1uorophenylsulphonsmi deme thyl Jeyclohexenons 3=(4-methylphenylsulphonamidomethyl Jeyolohexenons 4-(4=chlorophenylsulphonami domethyl Jayclohexenone 4 ~(4~fIuorophenylsulphonsmidomethyl )eyolohexanons 4~(methylrhenylsulphonamidomethyl Joyolohexsmone 3=(4~chlorophenylsulphonami do Jeyelopentmone 3-(4~flnarophenylsulphonsmi do Joyelopentsnone o% 3-(4-methylphenyloulphonami do Joyclopentanone

BAD ORIGINAL 9 -99 = - Co

3~(4~chlorophenyleulphonemido Joyclohexanons 3«(4~f1luorophenylsulphonamido Jeyclohexanone 3 (4-methylphenylmilphonanddo Jeyclohexeanone 4~(4~chlorophenylsulphonamido Jeyelohexanone 4~(4~fInorophenyleulphonamido Jeyolohexsnone 4=(4-methylphenyleulphonemi do Jeyelohexanone

The hydrasines XIV which are used as starting materials are known or can be prepared by know methods (compere Houben-Veyl, "Methoden der organischen Chemie" (Methods of QGrganic Chemistry), X/2, page 1, 123, (693),

Some of the ayolohexsnonssulphonamides of the genaral formula (XVga) 2 (on, )yH-S0,R $ (xv a), of in which y and x have the abovementioned meaning, vhich ere used as starting materials are mow, end they

Sen be prepared by methods nom per se (compare Houbene

Weyl "Methoden der organischen Chemie", IX, 608; A.

Hooradian et al., J. Med. Chem, 20 (4), 487 (1977)).

The cyclopentanonesulphonmmides of the general formula (XVh) a BAD opig \ . - !

Co “30 - Nac AY)

(CH, )_~NH-SO -R° . hor. 0 in vhich

Xy ¥y and RZ have the abovementioned meening, which are used as starting materials are likewise new.

A process for the preparation of the new cyclo- alkanonesulphonamides has nlso been found, which is characterized in that cycloalkanols of the general fore mila (XVI)

HO

Ton, (xvI), ( Hy) in vhich x and y have the abovementioned meaning, are reacted with sulphonyl halides of the goneral foymlas (xvi1)

Ha1-50,-8% (xv11), in which r

BAD ORIGINAL 9 - 31 - be

A? has the abovementioned meeming snd

Hal represents fluorine, chlorine, bromine or iodine, preferably chlorine or branine, in inert organic solvents and, where appropriate, in the presence of bases, and then oxidation in inert solvents is carried out,

The cyoloalkanols cen be prepared by reacting oycloalkenones (XVIII) 0 i

A h (xviI1), (cH,) — with nitromethane in inert argenic solvents, where epprorriate in the presence of bases, and then reducing the compounds (XIX) 0 0 (XIX), (cH,) ~~ Pa (oA 92, 89 849 and CA 87, 22 191).

The sulrhonyl halides cen be prepared hy methods know per se (Houben-Wayl's "Methoden der orgemischen

Chemie" IX, 564),

Prvo—— -32 - BAD ORjaimia, NW

£8

The preparation of the eyoloalksna/1, 2¢h/indole- sulphomamides according to the invention cam be illus trated ty the following reaction diagram: 0

JT] geno \ No, 0o= ——2 Jd y SE )

H,) step a 2'x step b 2’x p

HO

NON »

Halsop (chy) step o

HO

YT NT wesoper? step d —(CH,) 0 2

NN H-50,-R ete ~ aiep eo —(CH,) -33 - r

BAD ORIGINAL 9

Na 25981

According to this, in the first step a) oyolo- alkenonss are reacted with mitre compounds such as nd tro- methane, in inert molvents such as alochols, for example methanol, ethanol or propanol, or ethers, for exemple 3 diethyl ether, tetrahydrofuran or dicxans, or chlorinated hydrocarbons, for example methylene chloride, chlorofomm or carbon tetrachloride, in the presence of bases such o8y for example, sodium hydride, sodium or potassium me- thenolate, sodium or potassivm ethanolute, potassium terti-tutanolate, 1,5-diasabiaycle/d.3.0/non-S-ene, 1,%- a4asabioyolo/5.4.GAmlec-S-ene, pyridine or 4riethylamine, st temperatures in the range fram 0°0. to 100%, to give miro eampomds,

In step b) the nitro compounds are yedused in inert 13 solvents mich as ethers, for example tetrahydrofurm, ai- oxens or dethyl ether, in the presence of a reducing agent such a8 hydrides, for exemple INH, Na/A (00H, CH, 00H, )H, 7 or ai-1so-tutyl-aluninivmehydrid, ab tempera tures in the renge fram -20%0, ¥0 460°0 40 give ayolosl- kanols,

In step 0) the ayoloalkenols are converted with sulphonyl halides in iners solvents sich as ethers, for example dioxens, tetrshydrofirsn or diethyl ether, er chlorinated hydrocarbons such as methylene chloride, a chloroform ox carbon tetrachloride, or ethyl asetats ox

BAD ORIGINAL

Te ~ a 25981 pyridine, where appropriate in the presence of bases such as 1,5-di~ana~bioyolo(4.3.0 )non-5-en, 1,5-44~ana~bi- 6y010(5.4.0), pyridine or triethylamine, at temperatures from -20°C 40 060°0, into sulphonamides

In step 4), the sulphonanides sre oxidimed in inexrs solvents such as water, glacial acetic acid, ace~ tone, ryridine or mixtures thereof, with oxidising agents such oe ohromivm(VI) compounds, fer exsmple Orgy K,Or,0y or NagOr Oy ot temperature from «20°0 40 4100%0, to give oyoloalkmnonssulrhonsxides:

In step ¢) aycloalksnonemulphonamides (XVh) end hy- drasines XIV are reacted as described above $0 give the corresponding Jbensenseulphoneamidoalkyl/cyoloalkanc- /1,2-2/ind01en of the formals XIII _ (Cll) ~NH-50,-R° a Te (XIII), 18 A 2x

H in which

Bl, 22, x end y have the abovementioned mesning:

The enmtiomerically pure Jbensenssulphonsmido/- oyclohexano/1,2-b/indoles of the general formila (XIIlg) . oo sso BAD ORIGINAL 9

0 25981 2

NH=50,R 1 red

R . (XIIla), ~

H in which 2% and 12 have the indicated mening, sre ike wise new, 8 A process for the preparation of the enmntiomericsl-~ 1y pure /bensenesulphonaddg/ayslohexena/l, 2-4 indoles has been found, which is characterised in that enmtio- merically pure oyclohexeno/l,2-h/indolmines of the gene- ral formula (XX) 1, boo

H in which ' hos the indlcsted meaning, sre reacted with sul- phonyl halides of the general formula (XVII )

Ha1-50, 2" (xvi1), 13 in which

Coo x ro . 36 BAD ORIGINA; 2

W

+ 25981 2? hes the indicated mesming, end

Hal represents fluorine, chlorine, bromine or fodine, preferably chlorine or bromine, in the presence of inert solvents end, vhere appropriate, in the presence of a base, , Suitable solvents for the process are the custo- nary organic solvents which deo not change under the re- sotion conditions. Thess preferably include ethers such a8 diethyl ether, dioxane, tetralydrofuran or glycol 4i- nethyl ether, or hydrocarbons, such as bensens, toluene, xylens, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloramethene, tri- chloromsthane, $etrachloromethens, dichlorcethylons, tri- ehlorosthylens or chlorobensens, or ethyl mcetate; tri- 13 ethylanine, pyridine, dimethyl sulrhoxide, dimethylforme amide, hexamethylphosphorie trimmide, scetonitrile, moeténe or nitromethane, It is equally possible to use mixtures of the said solvents,

Beges for the process can be customary basic oom pounds, Thess preferably include alkald metal er alkaline sarth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide or bariim hydroxide, or alknld metal hydrides such as sodium hydride, or alkali netal or alkaline earth metal osrbonates such as sodiwm 23 carbonate, sodium bicarbonate, potassium serbonste or eal-

BAD ORIGINAL 9 (VE -3T =

& ’ 25981 olum carbonate, or alkali mstal alocholates mich as, for example, sodium methenolate, sodium ethanol ete, potassium methenolate, potassium ethemolate or potessimm tert.~butylate, or alkali metal amides such as 14thiwm diisopropylanide or sodamide, or organic saines such a8 ethylddisopropylemine, bensyltrimethylsmoniun hydroxide, tetrabutylamoniun hydraxide, pyridine, dimethylemine- pyridine, triethylamine, N-methylpiperidine, 1,%5-diasa~ bioyola/fi3.0/non-3-eme or 1,5-diesabicycle/5:4.0Amlesd

S-ene. : The process according to the invention iw gemeral- ly carried cut 4n a temperatures renge of from -30° C; to $150°0, preferably from 20% to 480°;

The process scoording to the invention 4s generally 13 carried out under atmospheric pressure. It is equally possible $0 carry 1% out under reduwed pressure or under elevated rwessure (for example in a range from 0.5 $0 200 bar), :

The enantiomerically pure ayolchexeno/l,2-h/- indolamines of the general formila (XX) asoording to the invention are new and oan be prepared by the following syn- thetie principles A, B or CO. r -

BAD ORIGINAL + “38 = bee =

A

Smibetis wrineinie A

HO— \ — NH=C=CH Stel , HO — —_ NH-C~CH, \ Y " 2 "” — 0 0

XX1 XXII

SNA, step 2 1 —otep 3, " £0. '

NHNH

. 2 XXIII

XIV separation individual

NH-R* 1 — an diastereomers

R ! ———)

H

XXIV diastereomer mixture } NH 2 step 4 rt =~

Ee -

R

. XX rt has the indicated meaning, and

R* represents an enmiiomerically pure Dey or I~ amino acid residue, preferably the 28-(chlore-

BAD ORIGINAL 9 -% bore acetani do )=3~phenylpropionyl radical

Smthetic nrinsicls B [ J 0 atep 2 step 1 rE — —2 smo AC

H

- 0 .

XXV XXVI th

EO t :

H CH

XXVII XXVIII : - NH ‘ == ACCT

H t. xX

Hl poy the inddoated meaning)

Synthetic mrinatols A

According to this, in mtep 1 parhcetemol (XII) 4s

BA

D ORIG, ~)

fA

AA

25981 hydrogenated on Renesy niolel to give a ¢is/trane mixture of 4-acetemidocyolohexenol (XXII) as described by Rill- men, J, Hey Rthler, J. Ay in J. An. Chem, Soe. T5, 1343 (1953), In step 2 4-scetemidogyclohexsnol (XXII) 418 mubjected in a one-pot process to a Fischer indole synthesis with oxidising agents such as phenylhydrasines (XIV), end then the acetyl group is removed by acid hy- drolywis,

This process step is carried out in solvents such a8 water, scetio acid and/or propionic acid, at tempers tures fram 0° to $150°0, preferably fram 0°0 to 110°C;

The racemi¢ 3-mmino-l,2,3,4-tetrahydrocarbasoles (XXIII) vhich are readily accessible in this way are gonverted in step 3 by coupling mith enenticerically pure mmino acids, 135 where appropriate in their activated form, into the cer- responding diastereomer mixtures which oan be separated into the individual dimsteromers ty ocustomexry methods such as crystallisation or colum chromatography.

Enantiomerically pure amino acid derivatives which 20 wre suitable and preferred are acetylphenylpherylalenine,

F=-tert-utoxyoardonylphenylalmine, chloroacetylphenyl- alenine, oarbo-bensoxyphemylelmine, methoxy-rhenylacetie 20id or acetoxy-phenylacetic acid, preferably N-ghloro- asetyl-N-rhenyl-alsmine,

The activating agents vhich are generally used

BAD ORIGINAL ¢; -4- Cn =

. \ ¢ 25981 are the customary peptide-ocoupling resgents, Thes pre- ferably include carbodiimides mich es, fur exsmple, di4sopropyloarbodiimide, 4iqyclohexyloarbodiimide or

N= (3-dimethyleminoi sopropy] }-' ~sthyloarbodi imi de hyaro- chloride, or sarbonyl compoumds such as csrbonylddimi- dagole, or 1,2-oxasolium compounds mich as 2-gthyl-S- phenyl=1,2-oxagolium 3-sulphomate, or propsmsphosphonie ahydride, or isobutyl chloroformate, or bensotriasolyl- oxy~tris(dinethylamino Jphosphonium hexefluarophosphabe, or methemesilphonyl chloride, where eprropriate in the presence of bases such es triethylanine or Neethylmorpho- lire or Nmethylpiperidine, or dicyoclohexyloarbolds mide end N-hydroxysucoinimide,

The coupling is generslly cexried out in inert organic solvents, preferably in shlorinated hydrocsrbons such as methylens chloride or chloroform, or hydrocarbons such as hensens, toluene, xylens or petroleum frastions, or in ethers much a8 dioxane, tetrahydrofuran or diethyl ether, or in ethyl acetate, dimethylformamide, dimethyl sulphoxide or acetons, scetonitrile or nitromethms, wb

Semperatures from ~80°0 to 45070, preferably from -40°C; to 430%;

After separation of the diamtereomer mixtures (XXIV); in stop 4 the individual Aiestereomers are subjected to acid hydrolysis to give the enmtiomerically pure smines coe BAD ORIGIN A

+ 25981 (x3,

The hydrolysis is generally ogrried out with in- organic or organic acids such es hydrochloric acid, hy- drobromic noid, sulphuric acid, phosphoric mold, formio

S acid, acetio acid, propionic acid, methanesiilphonie a0id or trifluoroacetic acid, or mixtures of the sald acide,

The solvents which mre generally used for this ere water or the squeous solution of the corresponding a0id or mixture of acids which is used,

The hydrolysis is generally carried out in a teme perature range from +20° 0 to 4150°0, preferably from 20% to 4120°%0,

The process according to the invention is generally 1s carried out under atmospherio pressure, It i» equally possible to carry it out under reduced or under elevated pressure, for example in m mtoclave or pressure tube,

It has proved advantageous in this to add thioeglycolie a0id to the reaction mixture es oxidation inhibitor,

Syathakie xrincinle 2

According to this, 1,4-cyclohexansdione monoethylene ketel (XXIV) 18 reacted with phemylhydramines (XIV) dn a

Piecher indols synthesis to give ketals (XXVI) as des- eribed ty A, Britten end OG. lookwood in J. Chem. So0e., 23 Perkin Trans, 1, 1974, 1824-1827, r

BAD ORIGIN.

Hydrolysis of the ketals (XXVI) in step 2 gives the ketones (XXVII) which, in step 3, are converted by reductive amination with S-phensthylemine into the dias toreomer mixtures (XXVIII),

The reductive amination is generally carried ous with reducing agents such as hydrogen, where appropriate in the presence of palladium, platinm, or pallsdimm on animal charcoal as oatalyst, or complex hydrides, prefer— ably sodium borohydride, potessium borohydride, lithium borohydride, sino borohydride, lithium sludniun borehy- dride, aluminium hydrides ai-4so~tutyl-alimi rdun-hydride, lithivm triethylhydridbborate, soddwm eymotrihydriddborate, tetrabutylamonium aysnotrihydridoborate, tetrabutylsmmonius hydridoborate, lithium eluminmium hydride, sodium bin/2- 18 methoxysthaxy/aihydridosluminate or }4thium hydrido—tris-

J-metiyipropyl/borate dn inert solvents mich as hydvo- cerbons, mreferably bensens, toluans or xylens, er chlo- rinated hydrocarbons such as methylene chloride or ghloro- form, or ethers such as diethyl ether, tetrahydrofirram, dioxene or 1,2-dimethoxymethene, or ecetonitrile, dime thylfomeamide, dimethylsulphoxide or alechols such ss methamoly ethenol, propensl or isopropanol, in a tempera- ture range from -80°C to 4100°0, preferably -80°C te 450%,

The dinstereomer mixture (XXVIII) 4s seperated -44 - BAD ORIn™ =: ®

& 25981 into the individual diastereomers hy customary methods such a8 chromatography or erystallisation, preferably by orytalligation, where appropriate in the form of suit- able acid addition products.

Suitable acid addition products in this context are addition products of the ensmtiomers sscording to the invention with inorgemio or orgmmie acids, Thepe pre- ferably include hydrochloric acid, sulphurie acid, phos- phorie acid or methanssulphorioc acid, benzenemilphonie acid, naphthalenedisulphorio acid or acetic acid, maleic mid, fumeric ncid, citric acid or lasctic acid,

The removal of the phenylethyl groups in the separated diastereomers (XXVIII) 48 carried out in step 4 by catalytic transfer hydrogenation to give the enen- 18 tiomerically pure amines (XX)

Step 4 ie generally carried out with reducing agents ouch as hydrogen, where appropriate in the presence of palladium, palladium on smimal chercosl, or platimm, or ammonium formate, in inert solvents such ae alochols, for example methanol, ethmol, propmmol or isopropemol, or dimethylformemide or dimethyl sulphoxide, in a tem- perature range fram 0°¢ to 400°, preferably from 420%, $150°C (I.E. Overman and S, Suge, J. Orgs Chem. 50, 4154-4155 (1985).

0 25981

Synthetic Principle C

According to this, racemats resolution of the compounds (XXIII) is carried out by salt formation with opticelly active acids and crystallization of

S thase salts, once or several times, from suitable solvents, Tha enantiomerically pure compounds (XXIII) are libarated, by treatment with bases, from the salts which have thus bean obtained.

Suitable optically active acids are: (+)=camphorsulphonic acid, (=)-camphorsulphonic acid, (4)=-camphor-3-garboxylic acid, (~)-cemphore3-gare boxylic acid, (+)-camphoric acid, (=)-camphoric acid, (=)=malic acid, (+)emandslic acid, (=)-mandelic acid, (+)=lsctic sold, (=)=lsctic mcid, (=)=2-/Tphanyle amino)carbonyloxy/proplanic acid, (=)-g~methoxyphenyle acetic sold, (=)~di-O-benzoylterteric acid, (-)edi-O- betoluoyltartaric acid, (=)-methoxyecetic scid, (-)- 1,1'«binaphthyle2,2'-diyl hydrogen phosphate.

Suitable solvents for the crystallization are solvents such as water, alcohols such as methenol, sthanol, isopropesnol, nepropanol, n-butanol, ssc- butanol or tert-butsnol, ethsrs such as disthyl ether, tetrehydrofui ai, dioxane or glycol dimethyl sther, ketones such as scetons, methyl sthyl ketone or mathyl isobutyl ketone, hydrocarbons such as ben

Pr —— - 46 - BAD Orpen

A

46 25981 zene, toluens, xylene, hexene or cyclohexans, chlorinated: hydrocerbons such as dichloromethane or chloroform, or sthyl scetate, scetonitrile, nitromethans, dimethyl sulphoxids, dimethylformamide or sulpholane., It is equelly possible to uss mix tures of the said solvents,

Possible bases for the process ars the cuse tomery basic compounds. Thess preferably include alkali metal or alkalines earth metml hydroxides such as lithium hydroxide, sodium hydroxide, potas- sium hydroxide or barium hydroxide, or alkali mstal hydrides such ss sodium hydridej or alkall metal or alkaline sarth metel carbonates such as sodium car- bonata, sodium bicarbonate, potmassium carbonats or csloium carbonate, or alkali metal slcbholates such as, for example, sodium methenolats, sodium ethenolate, potessium methanolates, potessium stha- nolate or potassium tert.-butylate.

The new cycloalkano/Y,2-p/indole=-sulphonee- mides and their salts can be used as motive compounds in medicements. Ths sctiva compounds exhibit an action inhibiting platelst sggragation snd antegonize ing thromboxans Rye They oan praferably be ussd for the treatment of thrombosss, thrombo-smbolisms, 23 ischeamias, and ew antissthmatics and ms anti.

SL - 47 -

A

25981 gllergics. Ths new potive mmpounds can be cone verted in s known manner {nto the customary Pormule- tions, such as tablets, capsules, coatasd tablets, pills, granules, aerosols, syrups, smilslons, sus pensions and solutions, using inert, non-toxic, pharmacsuticelly guitsble vehicles or solvents, The therapeutically active compound should in ssch cass bs present in a concentration of about 0.5 to 90% by weight, preferably 5 to 70% by weight, which suffices to schiave ths dosage range indicated.

The formulations ars prsparad, for sxsme ple, by extending the active pompounds with sole vents and/or vehicles, optionally with the use of gmulsifiesrs and/or dispersing agents, and, far sxam- ple, when using uater ms a dilusnt, orgenic solvents gen optionally be used as suxiliery solvanta.

Examples of auxiliariss which may be men= tioned ars: watar, non-toxic solvents, such as paraffins (for example petroleum rections), vegst- able oils (for example groundnut oil/sssame 0il), alcohols (for example athyl aleohol end glycerol) and glycols (for example propylene glycol and poly- sGhylens glycol), solid vehicles, such as, for exam- pls, natural rock powders (for example keolins, alu minas, talc and chalk), synthetic rock powders (for oa 25981 example highly disperse silica and silicates) and sugars (for example sucrose, lactose and glucose), emuleifiers (for sxample polyoxyathylens fatty soid esters, polyoxyethylene fatty slcohol ethers, alkylsulphonates and arylsulphonates), dispersing agenta (for exemple lignin, sulphite waste liquors, methylcellulose, starch and polyvinylpyrrolidonas) and lubricants (for sxempls magnesium stearate, talc, stearic mcid end sodium leuryl sulphate).

Administration can be effectsd in tha custo mary manner, praferably orally or parenterally, in particular parlingually or intravenously. In the cess of oral administration, the tablets can, of course, sleo contmin, in addition to the vehicles mentioned, additives such as sodium citrate, calcium carbonate and dicalecium phosphate, together with various edditionsl substances, such ss starch, pre farably potato starch, gslatine and the like. Fure thermore, lubricants such as magnesium etearats, so- dium lesuryl sulphats and talc cen also be ussd when making tablets, In the cmse of aquscue suspsnsions and/or elixirs which are intended for oral uss, the active compounds can he mixed with various flavour- improving agents or colorants in addition to the above mentionad auxiliaries.

Na 25981

In the cess of parenteral administration, so- lutions of the active compounds, employing suitsble liquid vehicles, can be used.

In general, it has proved advantageous, in the case of intravenous edministration, to administer amounts of sbout 0,001 to 1 mg/kg, prefersbly about 0.01 to 0.5 mg/kg, body weight to schieve affective results, and in the casa of oral edministration, the dosage is generally shout 0.01 to 20 mg/kg, prefer- sbly 0.1 to 10 mg/kg, of body weight.

Neverthaless, it cen mt times be mdventageous to daviate from tha smounts mentioned, snd in parti. cular to do so as a function of the body weight or of the nature of ths administration method, but also as a function of individual behaviour towards the madi. cemant, or tha nature of the formulation of the medi camant end the time or interval over which ths ad- ministration tekes place, Thus it can suffice in some cases to manage with less than the abovsmantioned minimum amount, whilst in other ocasss the upper limit mentionad mist be exceeded, Where relatively large amounts are administered, it can be advisable to di- vide thess into several individual administrations over the course of the day.

The oycloalksno/I,2-b/indols-sulphonamides sccording to the invention cen be used both in human medicines and in veterinary medicine,

Exapacration exampleg

Example 1 3-(Nitromathyl)cyclopentanons 0

J

[1 100 g of 2-cyclopentenone ars dissolved toge- ther with 666 ml of nitromethane end 5 g of 1,5-diaze- bicyclo=/k.3.0/non-5-sne (DBN) in 1.1 L of iscpro- psnol, and ths solution is left to stand et room temperature for 5 he The isopropanol is then subse tentislly distilled in vacuo, and the residus is dis- solved in athyl ecetate and the solution is washed twice with 0.5 1 of dilute sulphuric scid seach time,

The organic phase is dried with sodium sulphate end evaporated. In this way 154 g (88% of theory) of 3- (nitromethyl)cyclopantenone ere obtained sufficient- ly pure for the next resection.

Rf = 0.52 CH C1, CHyOH = 9911

KAS

25981

Example 2 3-(Aminomathyl)cyclopentanol

BO Np

Ta 57.2 g (D4 mol) of 3-(nitromethyl)eoyolopsn- tanone ara dissolvad, under nitrogen, in 573 ml of absolute tetrahydrofuran. At 0%, 800 ml of a one molar solution of lithium aluminium hydride in tetree hydrofuran are added dropwise to this solution. After the dropwise addition is complete, the mixturs is stirred at 09°C. for 1 h. The cooling bath is then re- moved, whersupon the temperatura of the reaction soe lution rises to 40°C. After the temperatures has fallsn to 20°C, the mixtura is stirred at this temperatures : for 1 he The resction mixture is cooled to 0°C and then 100 ml of 45% atrength sodium hydroxide solution are cautiously added dropuiss. After the dropwise addition is complates, the resction mixtures ie wtirred at room temperature for 1 h, filtered through kissel~ guhr, and the kieselguhr is weshed with 1,5 1 of te trahydrofuran, The combined filtrates are thoroughly

0 25981 evaporated in vacuo. In this way 22.5 g (49% of theory) of viscous oily product are obtained.

Rf = 0.01 CHCl, 1 CH4O0H = 911

Example 3 3. (Banzenesulphonanidomethyl)oyclopentenol

HO ~~ ”

AN hi TN R-40, ~)

Pe oh H —_— 9 g (0.078 mol) of 3. (aminomethyl)oyclopantenal are dissolved together with 13.8 g = 10 mL (0.078 mol) of tristhylamine in 200 ml of tetrshydrofurane Than, at 0-8°C, 7.9g= 10.8 ml (0.078 mol) of benzenasulphonyl chloride are edded dropwise. After the dropwise eddie tion is compkte, the mixtures is stirred at of for 1 he Tha raaction mixture is than diluted with 200 ml of mathylens chloride, and washed twice with 150 wml 1% of dilute sulphuric acid ssche The organic phass is then extracted twice with 150 ml of 2 N sodium hy droxids solution gach tims, the combined extrests ars poidified with consentrated hydroghloric acid and ex=- traoted twice with 150 ml of mathylene chloride seach “33a

©

I, 25981 time. The combined maethylena chloride phasss ers dried with sodium sulphate and sveporated in vacuo.

In this way S.1 g (39% of theory) of viscous oily isomar mixture ara obtained sas the product,

Re = 9,51 end 0.45 CHCl, ! CH4OH = 95:8

Example & 3-(Banzenasulphonamidomathyl)cyclopentanong & (tm, 0) =/ 7.5 g (0.0294 mol) of 3-(banzenesulphonemidoe= mathyl)-cyclopentanol are dissolved in 60 ml of glacial ascetic acid, At 0 - 58°C. 2.79 g (0.0279 mol) of chroe mium trioxide dissolved in 2 ml, of watsr end 8,8 ml of glecial scetic scid ere added dropwise, and than the temperature of the reection mixture is sllowed to rigs to room temperature. After the resction mixture hes been stirred st room temperature for 1 hour it is diluted with 200 ml of ether end weshed twica with 150 ml of water each time, Tha organic phases is then extrected twice with 200 wl of 2N sodium hydroxide solution esch time, and tha combined sodium hydroxide phases are acidified with concentrated hydrochloric scid and extracted twice with 200 ml of methylene chloride sech time. The combined methylene chloride phases are dried with sodium sulphate and evaporated 3 in vecuo. In this way 4.4 g (59% of theory) of vise cous polly product ars obtained.

Re = 0451 CHCL, ! CHy0H = 9535

Examples 5 1- (Benzene. sulphonsmidomethyl)eyclopentano/I, 2-b/indoly -_ ~N a re

N

H

21 g (0.0826 mol) of 3=-(banzenssulphonamidome- thyl)oyclopantanons are dissolved together with 9 g (0.0826 mol) af phenylhydrazine in 200 ml of glacial escetic acid, and the solution is heated under reflux for 4 hy, The reaction solution is than diluted with 1.3 1 of ether, and 500 ml of water sre added, While cooling and stirring, the mixturs is made alkaline with 45% strength sodium hydroxide solution, and than w 55 =

03 : the organic phase is separated off, The aqueous phase is extrected once more with 500 ml of eather, and the combined organic phases are dried with sodium sulphate and eveporsted. Tha residue which is thus obtainad is chromatographed on 2 kg of silica gel (Merck 0.04 « 0.063 mm) with a mixture of tolusnm and sthyl acetate in the ratio 85 to 15. In this way » fraction which after evaporation, provides 1,9 g (7% of theory) of cryastelline product is obtained, melting point: 161-164°C,

Re = 0,92 CHCl, ! CHLOH n 95:5

Examplg 6 1-/N- (Benzenesulphonyl) «N= (2-cyanoathyl) aminomathyl/- h=(2-cyanoethyl)cyclopentano/1, 2-b/indole on ~~

I J

~N ema —

CN

1.9 g (0.0058 mol) of le(benzenasulphonamido= mathyl)cyclopentano/T,2-p/indole are stirred together

A

25981 with 1.83 g = 2.3 ml (0.0346 mol) of ecrylonitrile and 0.24 g (0.00038 mol) of a 40% strength solution of benzyltrimethylammonium hydroxide in methanol in 60 ml of dioxens at 60 - 70°C for 2 h. Then the re- action mixturs is evaporated in vacuo, and the resi- dus is taken up in methylens ghloride and the solution is axtrected twice with dilute sulphuric scide. The organic phasa is washad with saturated bicarbonate solution, dried with sodium sulphete end avaporated.

In this way 2.4 g (95% of theory) of product are obe tained as a solid foam,

Rp = 0.L5 GHoClg $ CHO0H = 9911

Exemple 7 1 (Benzenesulphonamidomathyl)-b-(2-oerboxyathyl)eyelo- pantano/T ~-b7/indol _ FiL80, 3

Pa oN > ee oH 2.4 g (0.0055 mol) of 1=/N= (banzanssulphonyl)=-

ra (2-cyanoethyl)aminomathyl/=be-(2-cyanoethyl)cyclopan- teno-/I,2-b71indole are dissolved in 35 ml of isopro- panol, end 55 ml of a 10% strength potassium hydroxide solution are added. The resction mixtura is stirred at 70°C for 4 h, than diluted with 100 ml of water end extracted with 100 ml of methylene chloride. The aqueous phase is acidified with dilute sulphuric acid and extracted 3 times with 100 ml of methylene chlo- ride each time, The combined organic phases are dried with sodium sulphate and evaporated. Ths oily residus (1.9 g) is dissolved in methanol, and0,26 g. of sodium methylate is added. Eveporation of this solution pro- vides 2.0 g (69.2% of theory) of the product es a microcrystalline sodium salt.

Re = 0,37 CHCl, 3 CHyOH = 9515

Exampls 8 3=(b4=Fluorophenylsulphonamidomsthyl)cyelopantanol

Wo _

OY ys 4)

H —

In anelogy to the procedure for Example 3 19.8 g (0.172 mol) of 3-~(aminomathyl)cyclopentanol are re-

sO acted with 28.3 g (0.172 mol) of 4=~fluarophenylsul- phonamide, Thie rasults in 17.3 g (36% of thasory) of viscous oily isomer mixture being obtained as the pro- duct.

Ry = 0,53 and 0.46 CHCl, 1 CH;0H=9515

Exampla 9 3-(4=F luorophenylsulphonamidomathyl)cyclopentancne ° SN

Y A NE=-SO, F

In analogy to the procedura for Example 4 17.3 g (0.0638 mol) of 3-(4-fluorophenylsulphonamidomathyl)= cyclopentanol were oxidizeds This results in 14,3 g. (83% of theory) of viscous oily product being obtained.

Re = 0,76 CH CL, ! CH40H = 911

Example 10 18 1 (4~F luorophenylsulphonamidomethyl)oyclopentano/I, 2-b/- indole

Zz —

GE

H

- 59 o

14,3 g (0.0527 mol) of 3=(4=~fluorophanylsule phonamidomathyl)cyclopentanone ware reacted with phe- nylhydrezing in analogy to Example S. In this way, after chromatography on silica gal, 0.67 g (3.7% of theory) of microcrystalline product is obtained.

Ry nu D.47 LH, Cl, L CH4OH = 99:1

Example 11 be (2-Cysnosthyl)ele/N= (hf luorophenylsulphonyl)eN=(2= cyenoathyl)eminamethyl/cyelopantano/1, 2-b7 indole

CR a0 vd | i Dh

X~ a 0.67 g (0.00195 mol) of le(4=~fluoropheanylasulphone amidomathyl)eyclopentano/T,2-p/indole were reacted in analogy to Example 6, In this way 0.83 g (95% of the theory) of product is obteined as a solid foam.

Rp = 0.39 toluene : athyl scetate = 8:2

Examples 12 b= (2-Barboxysthyl)=l=(b=Fluorophenylsulphgnamidpmethyl)- gyclopentano/T,2-b/Indole ow 60 =»

« 25981 7” emia

R : ~

COOH

0.83 g (0.00184 mol) of L-(2-cyenocethyl)-le /F-(4-fluorophenylsulphonyl)=N=~(2~cyanocethyl)amino= methyl/cyclopentano/T,2=b/indole is hydrolysed in analogy to Example 7. In this way 0.67 g (87% of theory) of crystalline product is obtained as the sodium salt, melting point: 150-160°C.

R, = 0,59 CH,C1, 1 CH50H = 9:1

Example 13 3-(4-Chlorophenylsulphonamidomethyl)cyclopentanol

HO H

16.8 g (0.146 mol) of 3-(aminomethyl)cyclopen= tanol are reacted with L-chlorophenylsulphonyl chloride in analogy to Example 3. In this way 16.6 g. (39% “w 6) = of theory) of viscous oily product are obtained as sn isomar mixturs.

Re = DJ46 andO.bb CHCl, = CH4OH = 95:8

Example 1h 3. (4-Chlorophenylsulphonanidomathyl Joyclopsntenons 8 B 16.6 g (0.0573 mol) of 3. (4=-ohlorophenylsulphone- amidomethyl)cyclopentanol are oxidized in analogy to : Exompdd © Ne In this way 13.8 @ (83.7% of theory) of viscous oily product are pbtainad.

Ry = 07 CH,C1 1: CH4O0H = 955

Example 13 1 (4=Chlarophenylsulphonanidomathyl)oyolopenteno= i { 1 3 g=b/is do ig wre 7 YT oO aN

H

- B2 »

13.8 g (0.048 mol) of 3-(4=chlorophenylsulphone amidomathyl)cyclopentanone ere reacted with phenyle hydrazine in analogy to Exemple 5. In this way, after chromatography on silica gel, 1,65 g (9.5% of theory) of product are obtained as a solid foem,

Rp = DoU6 EH,C1, t CHyOH = 9911

Example 16 1-/Ne(2-Chloraphenylsulphonyl)=Ne(2-cyanoathyl)amino- mathyl/=be (2-cyanoethyl)cyclopentano/1, 2-b7/ indoles

OR

LO

7 N——— x

CK

1,65 g (D.0046 mol) of 1l=(4echlorophenylsulphon- emidomathyl)cyclopantano/T, 2-b/4indole ere reacted in analogy to Examplas 6. In this way 1.8 g (B4L% of theory) of product are obtained as a solid foam,

Ry = 0.38 toluans: ethyl acetate = 832 o 63 =»

#0

Exmpla 17

A=(2-Caxbaxvethy) =) (4=ghlororhenylsmlrhonsmd damethy) )- ayalopmteno/1,2-b/indole 0

Coo 149 g (0.0038 m01) 0f 1e/Fe(4~chlorephenyleulpho- 1yl }=N-(2-oyancethyl Jami done thy /~4~(2-cyancethyl Joyolo- penteno-/1, 2-h/indole are hydrolysed in analogy to Fxem- ple 7. In this way 1.33 g (81.9% of theory) of products are obtained as the orystalline modiwm sal, melting point: 160°C,

Ry ® 0,59 OH, 01, $ OH, 01 = 911

BRxaapla 18 4=(Banssnomirhonamnido ovyolohaxanol

HO

TL, “a~( 3

DN

BAD ORIGINAL o oo - 64 - a

2x14 69 g (0.6 mol) of 4~-mminocyolchexanol are re- aoted with 107 g (0.6 mol) of bensenesulphomyl chloride in enalogy to Example 3. In this way T2.8 g (47% of theory) of crystalline product sre obtained, melting points 106-1080,

Ry = 0,38 CH,0L, 1 CH, OH - 9518

Exsanla 19 )

OL wo, 72.8 g (04285 mol) of 4~(bensenesulphonamido Jay- olohexanol are oxidized in analogy 40 Rxemple 4. After orystallization from petroleun ether, 57.5 g (80% of theory) of product are obtained, melting point: 80-82%,

R, ® 0.66 0H,01, 1 OF OF = 9515 13 Exmapla 20 ) pon, (2)

Jy

XS»

H i TU ERR SR [ ™ - 65 ~ BAD ORIGINAL £7 [YR a 57:5 & (0.227 mol) of 4~(benwenssulphon=mido Jeyolo~ hexenone are reacted with phemylhydrasine in smalogy to Example 5, In this way 41.3 g (56% of theory) of product orystallised from isopropanol are obiained, melt- ing peint: 158%,

Rg ® 0,82 CHCl, + OH,CH = 9515

Bxsnola 21 2fhvl Joly 2, 3pd=tatrahydrooarhanole 7 ees —_ 2

ON

10 g (0.0306 mol) of 3«(bensenssulrhonsmido )- 192,34 4~tetrahydroocarbasole are ressted in snalogy to

Bxsmple 6. In this way 10 g (75% of theory) of product crystallised from ether are obtained, melting peimtt 180-190°C, 1s Ry «= 0,29 toluene : ethyl acetate = 8:2 - CL - $6 = -

Crd BAD ’

ya

Rxannla 22 3-(Bansenepulvhonsmido J=-8=(2-aarhaxyetiyl J=1,2,3,4~tatra- hrdronaxrbasale ~ —

Og

NN

Ccooll g (0.0263 mol) of 3/M-(bensenesulphoryl)-N-(2- eyenoethyl )aming/-9-(2-ayanoetiyl )=1, 2, 3, 4-tetrahydro- caxbasole are hydrolysed in analogy to Fxemple 7, In this way 7.57 g (687 of theory) of crystalline product 10 are obtained as the sodium salt, melting point: 160-165°c.

Ry, = 0.44 CH,01,,1 OH, oH - 95%

In emalogy to Example 18 the following compounds 14s%ed in Table 1 were prepered: o—( 1 )- NHS0, {4 )- x - - 61 ~ BAD ORIGINAL _ homeo ~

A

Zabla 1

Example X Yield R, ( 23 0 Li 0,37 OHO, + OH,OH = 93:5 28 F To Op4 CH,0L, 1 CH,OH = 9513 33 OH, 48, % 0,5 CHCl, + CligOH = 9513

In snalogy $0 Exemple 19 the following compounds listed in Table 2 were prepared:

Zable 2

Exsmaple X Yield R, Melting

Xo, poing: eet etter ee ree et eet een eee eh ea 24 01 ee 0,77 CHO), : CH OH = 9:1 103-4% from petro- 18 leum ether 29 Post 07 OHO, OH,Hegn 104-4% from petrolem ether 34 OR, 90, TF 0,87 CH, 0, t CH, OH ® 9515

Ff .

Co PTR BAD ORIGINAL d ce

In analogy to Example 20 the following eompoundw listed dn Tadle 3 wezre prepared! _eD

R abla ld

Example X Yield Ry Melting

No, point 2 OL T5,4% 0,52 toluensiethyl 163°C from ether acetate 8:2 30 ® T3% 039 CHOLCHGiw 146-0% from ether 9911 39 OH, 55% Opd2 OH 01,1 0H OH w 1%6-8°C from 812 isopropanol

In analogy to Exsaple 21 the following compounds listed in Table 4 were prepared: “ 0, = (J

CN

CR

- f i" BAD ORIGINAL - 89 = i mm

A fehle 4

Exeanple X Yield Ry Melting

Ho, Point: et er mt etre etree rte Assets ms APR, 26 OL 4T% 0.355 toluenerethyl 204-6°C from 8 soetate 8:12 ether/isopropanol 31 ¥ 53% 0,29 toluensiethyl 206-8°C from acetate 8:2 sther/isopropsnol 36 OH, @5% 0,37 toluenerettyl 180-90°C from acetate 8:2 other

In enalogy to Example 22 the following eonpounds listed in Table 5 were prepared! wi i

COOH

= TO »

Ca ae co ) : - oo RAD Arima... =

“ A

Zabla 8

Exemple X Yield Re Melting

Ho. eee eee eee ieee reemrnene SADR 27 01 89,5% 0,61 OHOL,CHOE=911 150° Na

S salt ” FP 98,3% 0,57 OHOL HOH =g:1 160¢70%

Na seals 3 OB 95% 0,3 ORCL OH OHwg) 150-60

Na mals » Examples 38 and 39 3=r—(4-Flucrophenylsul phonamido )=9=(2-carboxyethyl )=1,2, 3p 4y= 4a-%,9a~t-hexshydfooarbasole (isomer A) and S-a--(4-fluoro- phenyleulphonamido )-9-(2-carboxyethyl )=1,2,3, 44 4 a0, 90-0 hexahydrocarbasole (isomer B)

H

SN

13 / H Isomer A

COOH

3 : “Tl = >,

BAD ORIGINAL G5 t . .

A

25981

Sud NHS0, { _H- r Isomer B

COOH gs (0.0114 mol) of 3-(4-fluororhenylsulphon— amido )-g=(2=carboxyethyl )=1, 2, 3,A~tetrahydrooarbascle so- dium salt are dissolved in 50 ml of triflucroasetic scid 5 and, at 0°¢, 5.01 g (0.08 mol) of modiwm cy=moboreiy— dride are added in portions. The reaction mixture 4s allowed to reach room temperature, &iluted with water : end extracted with 200 ml of ethyl acetate. The wilyl acetate phase is extracted twice with each 100 ml of 2 N soddum hydroxide solution, the combined sodivm hydroxide phases are adjusted to pH 5, md extracted tihnree times with each 150 ml of methylene shloride, dried with sodium sulphate and thoroughly evaporated in vacuo, The residue 45 chromatographed on 500 g of silica gel (Merck, 0,040 = 13 0.083 rm) with a 100 to 1 mixture of methylene chloride and glsoial acetic acid, Two fractions are obtained in thie way end, after evaporation, provide 2,87 g (60.2 of theory) of isomer (A) and 0,7 g (14.9% of theory) of 1somer (B) respectively as a solid fomm;

I -T2 - rr p——

BAD ominmia A

0

R, of isomer (A) + 0.24

OH,01, t CH, 0oCH = 100192

Ry, of isomer (3): 0,14

Examples 40 snd 4) 3 wr (Bermenssulphonamido J-8«(2-carboxysthyl )=1,2, 3,4, 4a~ ty 9a~t-hexnhydrocarbasole (isomer A) and 3-1 (bensenssul phonemi 46 )-9~(2~carbexyethyl )-1y2, 3, 4, a= 8) 9a~c~hexshydrooarbasole (isomer B)

Lm,

JVHSO

2 (1womer 2)

H

: COCH 0 and

H / ( (Isomer 3)

H

COCH

41 a - Fm ? BAD ORIGINAL

: 3 of 25981 1.18 g (0.0028 mol) of 3-(benmenesulphonamido )-9- (2-carboxymethyl )=1,2, 3, 4=tetrahydrocarbascle moddum salt are reduced in enalogy to Exemple 38, Chromatoe graphy results in two fractions which, after evapora~ s tion, provide 0,45 g (40% of theory) of isomer A ad 0.9 g (18% of theory) of isomer ® as a 80114 foam,

Ry of isomer At O.4

OH, 01,1 OH, COOH ® J0014

Ry of isamer Bi 0,22

Exmnle 42 snd Rxomple 4% 3~r(4~Methylpheny oul phonemi do )9-(2~carboxyethyl )=1,2, 3- 4)4a~t,9a~t-hexshydrocarbasocle (isomer A) ~~ H

Isomer A - n

CcocH end 13 3wr—(4-me thylphenyleulphonanido )=§(2-carboxyethyl )- 1,2,3,4,4a-c,9a-c-hexshydrooarbasole (isomer B) -T4 = poe

SE BAD ORIGINAL A) ar a

H 4 ~/ ))

NHSO, _ —CHy

H

Igomer »

COOH

18,06 g of 3-(4-methylphenylsulphonamido )=9=(2- cerboxyethyl )=1, 2, 3, 4=tetrahydrocarbascle sodivm sald are reduced in smnlogy to Example 38, Chronetogrephy re- sults in two fractions which, after evaporation, provide 3.65 g (20% of theory) of Ssomer A 88 a orywballine re~ sidue, melting point: 156-6220, end 1.11 g (8% of theory) of isomer B as 0 s0lid fom,

R, of isomer Av 0,39

Ry, of isomer Bi 0,20

Bxanle 44 3=(4-Chlorophenylsulphonam do }=6-21uoro=1, 2, 5, 4-tetra~ hydrocarbasole

FP ~ HEa 80, ~ Han

SW

H

18 | 3 = BAD ORIGINAL Ei yo 25 981 26.5 g of 4 (h-chlorophenylsulphonamido)cyclo= nexanone are reacted with L-flurophenylhydrasine in analogy to Example Je. This results in 35.4 g (100% of theory) of product being obtained as a solid foam.

Ry = 0.53 toluenesethyl acetate = 8:2.

Example hs 3—/f-(hoohlorophanyl aul phony] )-N=(2-cyancethyl)aming/= 9-(2-0yanoethyl)-6-fluoro-1,2,3, otetrahydrocarbasole ’ ~ H- r «S0 Cl “0 : ~

CN

3.4b g of 4-(h-chlorophenylsulphonanido)=-6- f1uoro=1,2,3,li=tetranydrocarbasole are reacted in ana- logy to Example 7. In this vay 25.6 & (100% of theory) of crystalline product are obtained, melting point: : o 118-«130 Ce Ry = 0.52 CH,Cl, 3 CH 4OH= 9:1. - 76 - | Saas C——

BA

WA

Example 46 5- (h-Chlor ophenylsul phononido) -9=(2-carbexy ethyl) =6- f1uoro-1,2,3, i=tetrahydrocarbasole

COOH . 27.6 g of 3-/f-( chlor ophenylsulphonyl)=N-(2- oyanosthyl) aming/-9-(2-cyanoethyl)-6-fluora=de2.Jul- tetrahydrocarbasole are hydrolysed in analogy to

Example 7. In this way 25.6 8 (100% of theory) of crystalline product are obtained, melting point: 118- ’ 0 130 Ce. Ry = 0.52 CHCl, t CH, OH = 9:1

Example 47 3-(Nitromethyl) cyclohexanone

Je

NO

( of yd 21.9 g. of cyclohexanone are left to stand to- gehter with 175 ml of nitromethane and 2.1 g of 5=- diazabicyclo/F.3.0/-non=5-ene (DBN) in 250 ml of imo propanol at room temperature for 2 days. The working up is carried out in analogy to the procedure for Exam- ple 1 and provides 37.2 g& (100% of theory) of 3=(nitro=- methyl)cyclohexanone which is pure enough for the next reaction.

R, = 0.62 CH,C1, 3 CH, OH = 99:1

Example 48 3-(Aminomethyl)cyclohexanol ( ~~ 7

A

HO

37.2 g of 3-(nitromsthyl)cyclohexanone are re= duced with lithium aluminium hydride in analogy to the procedure for Example 2. In this way 7.5 g (24.5% of theory) of viscous oily 3_(aminomethyl)cyclohexanol are obtained.

Ry = 0,04 CH,C1, 2 CH, Of = 91

Example U9 3-(4-Fluorophenylsulphonamidomethyl)cyclohexanol sn

J

J

In analogy to the procedure for Example 3 7.3 § of 3-(aminomethyl)cyclohexanrol are reactod with 11.3 § of L-fluorophenylsulphonamide. This results in 11.05 g (66% of theory) of viscoun oily isomer mixture being obtained as the product.

Ry = 0.41 and 0,33 CH,C1, t CH OR = 95:9

Example 30 3«(h-Fluarophenylaulphonanidonethyl)oyclohexanone eso, er

Jf N\=/ 4 t 25981

In analogy to procedure for Example 4 11 g of 3-(4-fluorophenylsulphonamidomethyl)cyclohexanole are oxidized with chromium trioxide. This results in 9.3 g (86% of theory) of product being obtained as n solid foam.

Ry = 0.86 CH,Cl,: CH OH = 93)

Example 51 h-(h=Fluorophenylsulphonamidomethyl).l1,2,3,4=tetrahy- drosarbszole ; mao _H- r — rd > ~n~

XN

In analogy to the procedure for Example 5 9 g of 3-(4-fluorophenylsulphonamidomethyl)cyclohexanone are reacted with phenylhydrazine, This results in 9 g of crude product which is chromatographed on 1 kg. of silica gel (Merck 0.04 = 0,063 mm) in a mixture of to- luene and ethyl acetate in the ratio 8 to 2. One fraction from this results, after evaporation, in 0.8 ge (7.2% of theory) of product as a solid foam.

Ry? O.4k toluene: ethyl acetate = 8:2

Example 52 - 1 9-(2-Cynanoethyl)-k=/f-(4-fluorophenylsulphonyl)-N- (2-cyanoethyl)aminomethyl7-1,2,3,h-tetrahydrocarbazole : CN - F ( oil _)r ~ | 1

C oN

In analogy to the procedure for Example 6 0.8 g of 4-(4-f1lgorophenylsulphonamidomethyl)-1,2,3,4=te= trahydrocarbazole is reacted with acrylonitrile.

This results in 0.91 g (88% of theory) of product bes ing obtained as an oil,

R, = 0.37 toluene:ethyl acetate = 8:2

Example 53 9-(2-Carboxyethyl)=-(4-fluorophenyleulphonanidonethyl)= 1,2,3,l4~tetrahydrocarbazols

NH=S0 —F of A) owl lL Se ~ (

COOH

0.91 g of 9=(2-cyanocethyl)=be/N=(lt=fluorophenyle- sulphonyl)=Ne(2-cyanoethyl)aminomethyl/=1,2,3,kate= trahydrocarbazole is hydrolysed in analogy to Example 7. In this way 0.77 g (89% of theory) of crystalline product is obtained as the sodium salt,

Melting point: 160°¢

R, = 0.57 CH,Cl, t CH, OH = 9:1

Example 5h heN-Acetamidocyclohexanol ‘ HOw \ _ Naecec / "n 3 0 300 g of paracetamol in 750 ml of ethanol are hydrogenated on 30 g of Raney nickel at 180°¢ and under 100 bar, After uptake of hydrogen is complete, ] the catalyst is removed by filtration and, after eo 81

0 2590 1

OL addition of 30 g of Raney nickel, hydrogenation is repeated at 180°C and under 100 bar of excess pres- sure. Lhe catalyst is then removed by filtration, the filtrate is evaporated in vacuo, and 200 ml. of acetone are added to the still moist residue and stirred. After the crystals have been filtered off with suction, the mother liquor is concentrated fur-~ ther, the crystals which have separated out are once more filtered off with suction, and themther liquor is again concentrated. The total obtained together with this 3rd batch is 342.4 g (80.8% of theory) of the product.

Melting point: 100 - 103°0

Example 55 3-Amino=1,2,3,4-tetrahydrocarbazole (racemate)

NH,

Ana tL . N :

N

50 g (0.318 mol) of h-N-acetamidocyclokexanol are dissolved in 400 ml of glacial acetic acid and, while stirring at room temperature, a solution of 31.8 g (0.318 mol) of chromium trioxide in a mixture of

¢\ of 25981 26 ml. of water and 105 ml of glacial acetic acid is added.

This resulted in the temperature of the reaction solution rising to 60°c.

The reaction mixe ture was stirred for 3 hours, and then 45.7 g (0.423 mol) of phenylhydrazine were added.

This results in heating of the reaction solution to 80°C. and initial evolution of nitrogen.

The reaction mixture is then heated under reflux for 2.5 hours.

After the reaction mixture has been cooled, 500 ml. of concentrated hye drochloric acid and 59 ml of thioglycolic acid are added and the mixture is heated under reflux, under nitrogen, for 16 hours.

After cooling the mixture it is diluted with 500 ml of ethyl acetate and, while cooling, it is made alkaline with 45% strength sodium hydroxide solution.

The precipitated chromium hy= droxide is removed by filtration with suction through a layer of kieselguhr and is washed with a mixture of methylene chloride/methanol in the ratio 9:1. The or- ganic phase is separated off from the filtrate, and the aqueous phase is extracted 3 more times with ethyl acetates, The combined organic phases are washed twice with 2 N sodium hydroxide solution, and then extracted twice with 1 L of 2 N sulphuric acid each time.

The acidic aqueous phase is made alkaline with 45% strength sodium hydroxide solution and extracted 3 times with 1 L

@\

WO

25981 of methylene chloride each time. The combined me-~ thylene chloride phases are dried with sodium phose phate and evaporated. 300 ml of ether and 50 ml. of isopropanol are added to the residue, and the mix- ture is stirred. The precipitated product is filtered off with suction, washed with ether and dried in vacuo. 28.6 g (48.3% of theory) of product are obtained.

Melting point: 174 - 176°C.

Example 56 3-/28-(Chloroacetamido)-3-phenylpropionamido/-1,2,3,4= tetrahydrocarbazole (dastereomer mixture) 0) =

Ni h jl

Lo MN — © NH=C~CH_ CL

H : 0 43 g (0.231 mol) of I-amino-1,2,3,4-tetrahydro= carbazole and 55,87 g (0.231 mol) of N-chloroacetyl-

L-phenylalanine are suspended in 1,5 L of methylene chloride under nitrogen and, at 0°C. 115.2 ml (0.832 mol) of triethylamine ere added. Then, at -20%c, 150 ml (0.231 mol) of a 50% strength solution of propane-

A

2) . 5981 phosphonic anhydride in methylene chloride are added dropwise to the reaction mixture, It is stirred at -20°C for 30 minutes and then stirred at 0°c for 1.5 hours. For working up, the reaction mixture is washed with 1 I, of 2 N sulphuric acid, with 1 LL of water and twice with 1 L of saturated bicarbqnate solution each time. After drying with sodium sulphate and evapora- tion, 100 g of molid residue are obtained,

Examples 57 and Example 58 3-/25-(Chloroacetamido)~-3-phenylpropionamido/-1,2,3, 4= tetrahydrocarbazole (diastereomer A and diaatereomer

B) a) Diastereomer separation by column chromatography 100 g of crude product from Example 56 are €hro=- matographed on 2.5 kg of silica gel (0.063 to 0.2 mm,

Merck) with a mixture of toluens/ethyl acetate in the ratio 6:4 as mobile phase. In this way 2 fractions are . obtained, of which the first provides, after evapora- tion, 34 g (35.9% of theory) of diastereomer A (Exame ple 57).

Melting point: 217-220°¢.

The second fraction provides, after evapora=- tion, 24.3 g (25.7% of theory) of the other diastereo=- mer B (Example 58),

Melting point: 193 - 195°C

Rotation of diasteresmer A: /Q 7 20. 32.59° (CH 40H) (Example 57)

Rotation of diastereomer B: [A 7%° = 5.09° (CH OH) (Example 58) b) Diastereomer separation by orystallization 11.5 g of crude product from Example 56 are stirred in a mixture of ether and isopropanol. The crystals were filtered off with suction and heated under reflux in 40 ml of acetone for 3 hours. After cooling and leaving to stand overnight, the product was filtered off with suction and washed with acetone.

In this way 1.2 g (5.5% of theory) of pure diastereo- mer A (Example 57) are obtained.

Example 59 3-Amino-1,2,3,4=tetrahydrocarbazole (enantiomer A)

NH

: 2

ZN . lo!

H

24.1 g (0.059 mol) of diastereomer 57 are dis- solved in 460 ml of glacial acetic acid. 460 ml. of concentrated hydrochloric acid and 24 ml. of thiogly=-

0 . 25981 colic acid are added and heated under reflux, under nitrogen, for 3 days. The reaction mixture is then diluted with 200 ml of water and, while cooling, is adjusted to pH 5 with 45% strength sodium hydroxide solution. It is then extracted twice with 1.5 L bf ethyl acetate each time, and the aqueous phase is then made alkaline with 45% strength sodium hydroxide solution and extracted 3 times with 1.5 L of ethyl acetate sach time, The ethyl acetate extracts are combined, dried with sodium sulphate and evaporated.

The residue is stirred in 150 ml of ether. The pre-~ cipitated product is filtered off with suction and dried in vacuo. 7.8 g (71.3% of theory) of enantiomer

A are obtained. Melting point: 160 = 166°¢C

Rotation RA 7° = 78.38° (DMSO + 10% water)

Example 60 3-Amino-1,2,3,4=tetrahydrocarbazole (enantiomer B) i MH, 7 if @

NL Nw

H

Enantiomer B is prepared by hydrolysis of 58 in analogy to the procedure for 59 from 57.

A

25981

Melting point: 162 =- 167° ¢

Rotation /Q 77° = =78.11° (DMSO + 10% H,0)

Example 61 3,3~Ethylenedioxy-1,2,3,-tetrahydrocarbazole = A 0 7

LU

“XN IN

R

77.2 g (0.5 mol) of 1l,h-cyclohexanedione mono=- ethylene ketal are dissolved together with 48.4 ml (0.5 mol) of phenylhydrazine in 2 L of methylene chlo- ride, and 300 g of magnesium sulphate are added, and the mixture is stirred for 30 min. The magnesium sule phate is then filtered off with suction, washed with methylene chloride, and the filtrate is evaporated.

The residue is taken up in 1.5 L of benzene, and 62.1 g (0.46 mol) of anhydrous zinc chloride are added and the mixture is heated under reflux with a water sepa- rator for 3 h. The reaction solution is then concen= trated, 2N sodium hydroxide solution is added, and the mixture is extracted 3 times with ethyl acetate. The combined ethyl acetate phases are dried with sodium sulphate and evaporated. The residue crystallizes from a little ether. In this way 3.5 g (72.9% of theory) of the product are obtained.

re

Melting point: 145 - 16°C

Example 62 1,2,4,9~Tetrahydrocarbazol-3-one . . 0 =z hE - i

N Lo ! UN -

N

R

165 g (0,72 mol) of 3,3-ethylenedioxy=l,2,3,le tetrahydrocarbazole are dissolved in 2 L. of acetone, and 3 g of p=-toluenesulphonic acid are added, After the reaction solution has been heated under reflux for 4 h it is concentrated, 2 L of ethyl acetate are added, and the mixture is extracted 3 times with 1 L of saturated bicarbonate solution each time. The ore ganic phase is dried with sodium sulphate and eva- porated. The residue crystallizes from ether. In : this way 118.7 g (87.1% of theory) of the product 13 are obtained. Melting point: 145 - 148°C,

Example 63 3-(1S~Phenylethylamino)=1,2,3,4=tetrahydrocarbazole

\

AS

25981

Ws =

I~. 1) _ NH=CH=(\ /

CLL

H

11.06 g (0.0595 mol) of 1,2,4,9-tetrahydro- carbazol-3-one are heated together with 7.78 g (0.065 mol) of 1S-phenylethylamine in 300 ml of benzene under reflux with a water separator for 1 h, After removal of the benzene by evaporation, the residue is dissolved in 50 ml of methylene chloride, and the solution is added dropwise to a solution of 15.3 g (0.0595 mol) of tetrabutylammonium borohydride in 120 ml of me~ thylene chloride at -50°¢. The reaction mixture is allowed to return to room temperature within 1 h, 6 ml of methanol are added, and 120 ml of 2 N sulphuric acid are added cautiously (evolution of hydrogen).

After stirring at room temperature for 1 h, the crys- tals which have separated out are filtered off with suction and washed twice with water and once with me- thylene chloride. After drying under high vacuum, 0.16 g (39.7%) of theory) of the product is obtained as hy=- drogen sulphate.

Melting point: 160 - 170°C.

Rotation: /&7°0 = 26.36° (CH,O0H/H,0 = 80:20)

( oA 75981

Example 64 3-Amino=-1,2,3,4~tetrahydroéarbazole (enantiomer A) ~~ AM

Sue

NNN

H

[Example 64, prepared by process B, is identical to

Example 597 g of the hydrogen sulphate obtained from

Example 53 are, for conversion into the hydrochloride, suspended in 50 ml of methanol, and 30 ml of 2 N mso- dium hydroxide solution are added, and the mixture is 10 extracted with ethyl acetate. The organic phase is evaporated, and the residue is dissolved in 50 ml of methanol, and 20 ml of concentrated hydrochloric acid are added. The hydrochloride precipitates out on con- centration in vacuo. After filtration with suction, washing with water and drying in vacuo, 7.6 g of hye drochloride are obtained. These 7.6 g (0.023 mol) of hye drochloride are heated together with 7.17 g (0.115 mol) of ammonium formate and 7.2 g of 10% palladium on active charcoal in 80 ml of dry dimethylformamide under ree flux (under nitrogen) for 20 min. After cooling, the mixture is diluted with water, and the catalyst is fil- tered off with suction and washed with water. The combined filtrates are acidified with 2 N sulfurie

@\

Of 25981 acid and extracted twice with ethyl acetate, The aqueous phase is made alkaline with 2N sodium hy- droxide solution and extracted three times with ethyl acetate. The organic phases are dried with sodium sulphate and evaporated. Tha residue is fure ther evaporated under high vacuum to remove dimethyl- formamide. 3 g. (70% of theory) of crystalline enan- tiomer A are obtained from ether,

Melting point: 160 =~ 166°C

Rotation: R7° = 78,38° (DMSO + 10% water)

Example 65 3-(4=Fluorophenylsulphonamido)=-1,2,3,4=tetrahydro= carbazole (enantiomer A) i es »

Onl S , NH S0, A / r

Ci =~

B ] 3,72 g (0,02 mol) of Example 59 are suspended together with 3 ml (0,022 mol) of triethylamine in 30 ml of methylene chloride and, while cooling, 3.9 ge. (0.02 mol) of 4-fluorobenzenesulphonyl chloride are added. The reaction mixture is dissolved at room temperature for 1 h and then stirred with 200 ml of

AN

& 25981 ethyl acetate and extracted twice with 2 N sulphuric acid and twice with 2 N sodium hydroxide solution,

The organic phase is dried with sodium sulphate and evaporated. Ether is added to the solid residue which is crystallized. 5.8 g (84% of theory) of the product are obtained.

Melting point: 150 - 152°C.

Rotation: /@7%° = 50.43% (cHCl,)

Example 66 3-(4~Fluorophenylsulphonamido)=~1,2,3,4=~tetrahydrocar= bazole (enantiomer B) _ pro pr 1] x

RH

Enantiomer B is prepared from Example 60 in analogy to the preparation of Example 65 from Example 59.

Melting point: 150 « 152°C.

Rotation: /R7 2° = -48.99° (cre)

Example 67 3-/N-(4=-Fluorophenylsulphonyl)aming/-9=(2-cyancethyl)- 1,2,3,b=tetrahydrocarbazole (enantiomer A)

N=-50, — — F 2 4 2 oud H N__ hi vd

CN

5.16 g (0.015 mol) of Example 65 are dissolved in 200 ml of dry dimethylformamide under nitrogen, and 0.5 g (0.0165 mol) of sodium hydride with 20% spindle oil is added in portions. Once evolution of hydrogen is complete, 2 ml (0.03 mol) of acrylonitrile are added to the reaction mixture, After stirring at room temperature for 1 h, 0.5 ml of acrylonitrile is once more added, and the mixture is stirred at room temperature for 1 he It is diluted with 1 L of ethyl acetate and extracted three times with water. The ethyl acetate phase is dried with sodium sulphate and evaporated, In this way 7.8 g of crude product is obtained and is chromatographed on 150 g of silica gel (0.063 to 0.2 mm, Merck) with a mixture of toluene/

TA

~~ $ ’ 25981 ethyl acetate in the ratio 1:1. A fraction which, after evaporation, provides 5.8 g (86% of theory) of product as a solid foam is obtained,

The bis-cyanoethyl adduct (3-/N-(4-fluoro- phenylsulphonyl)-N-(2~-cyanoethyl)amino/-9-(2-cyano=~ ethyl)-1,2,3,4=-tetrahydrocarbazole) is produced under the conditions indicated in Example 6.

Example 68 3-/N=(4=-Fluorophenylsulphonyl)-N-(2-cyanoethyl)amido/= 9~(2-cyanoethyl)-1,2,3,betetrahydrocarbazole (enane tiomer B)

CN d

N=SO_ =f —F <r 2 /

AN !

XN Th

CN

Example 68 is prepared from Example 66 in ana= logy to the preparation of Example 67 from Example 65.

Example 69 (+)=3-(4-Fluorophenylsulphonamido)=9-(2-carboxyethyl)- ! 1,2,3,4=tetrahydrocarbazole

NH=S0 — ~~ =~ ) F a N—— ne

COOH

5.8 g (0,0128 mol) of Example 67 are dissolved in 60 ml of isopropanol, 130 ml of 10% strength potase sium hydroxide solution are added and, after heating under reflux for 16 h, the mixture is cooled, diluted with water and extracted with ethyl acetate. The aqueous phase im concentrated in vecuo and then acidie fied dropwise with concentrated hydrochloric acid while stirring vigorously. ‘he acid which precipitates out during this is filtered off with suction, washed with water and thoroughly dried in vacuo. Uk. g (86.6% of theory) of the product are obtained.

Melting point: 85 - 95°C

Rotation RA T7%° a b42.55° (cHCL,)

- A

Example 70 2 5 98 1 (=)=3=-(4=Fluorophenylsulphonamido)=9-(2-carboxyethyl)e 1,2,3,4=tetrahydrocarbazole

NH=SO J —F ~. 2 °\ /

Z - i” . / \ i ~ ~~ ~ #

COOH

Example 70 is prepared from Example 63 in ana- logy to the preparation of Example 69 from Example 67.

Melting point: 85 = 95°¢.

Rotation: /R7 20 = -37.83° (coy)

Example 71 (+)=3-Aminc=l,2,3,k=tetrahydrocarbazole = Nr Na

H

18.6g(0.1 mol) of racemic 3-amino=1,2,3,Ue tetrahydrocarbazole are heated together with 15.2 Eg. -97 a

& of 25981 (Oel mol) of (+)-mandelic acid in 100 ml of tetra=- o hydrofuran under reflux. Once a clear solution has been obtained, it is allowed to cool and a spatula tip of the (+)-mandelic acid salt of (+)-3-amino= 1,2,3,4-tetrahydrocarbazole (enantiomer A, Example 59) is added as seed crystals. The mixture is stirred overnight, and the crystals which have separated out are filtered off with suction. In this way 6.05 g. of enantiomerically enriched material are obtained. be? go of these crystals are dissolved in 330 ml. of boil- ing methyl isobutyl ketone and, after cooling slightly, the solution is sesded and stirred as cooling is con- tinued, After filtration with suction and washing with methyl isobutyl ketone, 3.4 g of (+)=3-amino- 1,2,3,4=tetrahydrocarbazole are obtained as the (+)= mandelic acid salt.

Example 72

For determination of the action inhibiting - platelet aggregation use was made of blood from healthy subjects of both sexes. One part of 3.8% strength aqueous sodium citrate solution was mixed as anti- coagulant with 9 parts of blood. Platelet-rich citrated plasma (PRP) is obtained from this blood by centrifugation (Jurgens/Beller, Klinische Msthoden der Blutgerinnungsanalyse (Chemical Methods of Blood

0 nf 25981

Coagulation Analysis); published by Thieme, Stutt- gart, 1959).

For these investigations, 0.8 ml of PRP and

O.1 ml of the active compound solution were prein- cubated in a waterbath at 37%. Subsequently the platelet aggregation was determined by the turbidome- tric method in an aggregometer at 37% (Born, G.V.R.,

Jo Physiol. (London), 162,1962 and Therapeutische

Berichte 47, 80-86, 1975). For this purpose, O.l ml of collagen, an aggregation-initiating agent, was added to the preincubated sample. The change in the optical density of the sample of PRP was recorded dur- ing a period of 6 minutes, and the deflection after 6 minutes was determined. For this purpose, the per- centage inhibition compared with the control is cale culated.

io 25981

Cycloalkano/I,2-b/indolesulphon- Limiting concentration amide of Example No. for inhibition (mg/kg) 6 10 - 3 12 0.03 =~ 0,01 17 0.03 =~ 0,01 22 3 - 1 27 0.1 - 0,03 32 0.1 =~ 0.03 38 1.0 =~ 0,3 39 0.3 =~ 0.1 40 1.0 « 0.3 1 0.3 «= 0,1 hé 0.1 =~ 0.01 52 0.3 = 0.1

Claims (2)

A CLAIMS:

1. /Benzenesulphonamidoalkyl/cycloalkyl=

[I.2-b/indoles of the formula (CH,)_~NH-S0,~R° 2°y 2 1 ~~ ~~ - x QE I | cH) . so 2x YT ed H in which rt represents hydrogen and halogen, R° represent phenyl which is optionally substie tuted up to 5 times by lower alkyl or haloe gen, X is 1 or 2, and Y is O or 1.

2. Frocess for the preparation of /benzenesul- phonamidoalkyl/cycloalkano/T,2-b/indoles of the for- mula a

{ . 2 (CH,) ~NH-50,-R 1 ~~ —— R gu CH,) “a No N in which rt represents hydrogen and halogen, RZ represent phenyl which is optionally substie tuted up to 5 times by lower alkyl or halo- gen, X is 1 or 2, and Y i8 O or 1l. HORST BOSHAGEN ULRICH ROSENTRETER FOLKER LIEB HERMANN OEDIGER : FRIEDEL SEUTER ELISABETH PERZBORN Inventors - 102 = oy