CA2142721A1

CA2142721A1 - Condensed indole derivatives as 5ht and 5ht antagonists

Info

Publication number: CA2142721A1
Application number: CA002142721A
Authority: CA
Inventors: Ian T. Forbes; Roger T. Martin; Peter Ham; Thomas P. Blackburn
Original assignee: Individual
Current assignee: SmithKline Beecham Ltd
Priority date: 1992-08-20
Filing date: 1993-07-29
Publication date: 1994-03-03
Also published as: EP0656003A1; TW248557B; CN1086819A; MA22955A1; JPH08500580A; AP9300560A0; WO1994004533A1; AU4704693A; SI9300438A; NZ254785A; MX9305037A; IL106737A0

Abstract

Compounds of formula (I) or a salt thereof wherein: P represents a quinoline or isoquinoline residue, or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur; R1 is hydrogen or C1-6 alkyl; R2, R3, R10 and R11 are independently hydrogen or C1-6 alkyl, or R10 and R11 together form a bond, or R2 and R10 or R3 and R11 together form a C2-6 alkylene chain; R4 is hydrogen, C1-6 alkyl, halogen, NR8R9 or OR12, where R8, R9 and R12 are independently hydrogen or C1-6 alkyl;
R5 is hydrogen or C1-6 alkyl; R7 is hydrogen, C1-6 alkyl, OR12 or halogen, where R12 is hydrogen or C1-6 alkyl; n is 2 or 3; and the groups R13 and R14 are independently hydrogen or C1-6 alkyl, are 5HT2C/5HT2B receptor antagonists and are of potential use in the treatment of CNS disorders such as anxiety.

Description

WO 94/04533 214 2 7 21 PCr~'EP93/02Q31 Condensed ~ndote der~vat~Yes as 5HT2o and SH~2E~, antagonists ,, ~
'~ This invention relates to cornpounds having pharrnacological activity, to a process S for their preparatioll, to compositions con~aining them and to their use in the treatment of mammals.
P. Fludz~nski et. al., J. Med. Chem. 1986 29 2415-2418 describes N-(1,2-dirnethyl-3-ethyl-lH-indol-5-yl)-N- (3-trifluoromethyiphenyl)urea which shows selectivity for the rat stomach fundus serotonin receptor.
WO 92/05170 descnbes certain urea denvatives which are described as possessing 5HT1C receptor antagonist activity. The 5HT1C receptor has recently been recla~sified as the 5HT2C receptor ~P. Hartig et al., Trends in Pharmacological Scienccs (IIPS) 1993].
A structurally distinct class of compounds has now ~een ~discovered, which 15 compounds have been found to have 5HT2C receptor antagonist activlty. Certaincompounds of the invention also show 5HT2B receptor antagonist activity, the 5HT2B
receptor being previously known as the fundus receptor [P.HarLig et~al., Trends in Pharrnac~logical Sciences (I~S) 1993]. 5HT2C /5HT2g ~receptor antagonists arc ~elieved to be of potential use in the treatment of CNS dlsorders such as anxiety 20 depression, obsessive compulsive disorders, migraine, anore~ia, Alzheimers diseasc, slccp disorders, bu~ia. panic attacks, withdrawal from drug abuse such as cocaine, eLhanol, nico~ine and benzodiazepines, schizophrenia, and also disorders associated with ~spln`~
trauma andlor head injury such as~ hydrocephalus.
Accordingly, in a first aspect, Ihe presem invenuon provides a compound of ; ;
25 ~ formula~T)ora saltthereof~

R ~ R
wherein~
;P represents a quinoline or IsoquinoLine residue, or~a 5- or 6-membered aromatie ; 30 heterocyclic nng containing up to tl~ree heteroatoms;selec~ed frosn ni~ogen, o~ygen or sulphur;
RI~ is hydro~en~ or CI 6 allcyl;

21~27~
WO 94/04533 ~d PCr~EP93/02031 R2, R3, R 10 ~nd R 11 are independently hydrogen or C 1-6 allcyl, or R10 and Rl 1 together form a bond, or R2 and R 10 or R3 and R l l together forrn a C2 6 aLkylene chain;
R4 is hydrogen, C1 6 alkyl, halogen, NR8R9 or OR12 where R8, R9 and R12 are independenLly hydrogen or C 1-6 alkyl;
R5 is hydrogen orCl 6alkyl; `
R7ishydrogen,C1 6alkyl,0R12orhalogen,whereR12ishydrogenorC1 6alkyl; and ~ :
nis20r3;and the groups R13 and R14 are independently hydrogen or C1 6 a~yl.
Cl 6 aLkyl moieties;can be straight chain or branched and are preferably C 1 3 aL~cyl, such as methyl, ethyl, n- and is~ propyl. ~
Suitable R4 and R7 halogens include chloro and bromo.
Suitably RI is hydrogen or C 1-6 alkyl such;~as methyl, ethyi or propyl. Preferably Rl is methyl or ethyl.
Suitably R2, R3, R10 and Rl 1 are independen~ly ;hy`drogen~or C1 6 alkyl, or R10 ~;
and Rl 1 together form a bond, or R2 and R10 or R3 and Rl l together form a C2 6 alkylene chain. Preferably R2 is hydrogen or methyl. Preferably R3 is hydrogen.
In an indoline structure, R10 and Rl 1 are preferably hydrogen. Most p~eferably R1O and R l l form a bond so as to give an indole structure. ~
Suitably R4 is hydrogen, C, 1~;6 alkylt halogen, NR8R9 ~or oR~2, where Rg, ~9 2 0 and R12 are independently hydrogen ~or Cl 6 aL~cyl. Preferably R4 is hyd~rogen or methyl.
Suitably R5 is hydrogen or C1 6 alkyL Preferably R5 is hydro~en.
Suitably R7 is hydrogen, C1-6 alkyl, OR~2 or halogen, where R12 is hydrogen or C1~6 allcyL The group R7 ;ca~n be attached to any vacant posidon in the phenyl pa~t of th:e indole or indoline rings, tha~ is ~to say, the 4-, 6- or 7-posiuons of the indole or indoline , r~ngs. Preferably R7 ~s hydrogen. ~
Suitably P represents a quinoline or isoquinoline~;residue, or a 5- or 6-membered aromatic heterocyclic ring containing up~to three heteroatoms selected from nitrog`en, oxygen or~sulphur- ~ Sui~bl~`mole~és when ~e ~g p is~ a~5-mem~red aromat heterocyclic ring include, for example,~isothia201yl,~iso~xazolyl, thladiazoiyl and ~riazolyl.
Suitable moieties when the ring P is~a 6-memberèd~aromatic he~erocyc1ic ring include, for ~ , ~
example, pyridyl, pyrirni~or`p~a~yl. When P~Is~aqu~oline oris~u~o~e residue' ~ ;!ftlf ~e ~ea~moie~c~ be;at~ched~at any~posiuon~of ~e r~g, preferably ta ~e ~posit on.
~eferably P~is a ~quinoline or~3-py~d~ g~oup. ~ t ~e ~ea moiety c~ attàched to~a c~bon`~or;any ~av~able~n~ogen atom of ~e~
35` ~ ng~P,~p~fe`ablyitis~att chedt ~a~c~bo atom.
Sui~ably ~e group -(CR13R14)n-` fo~s~e~ylene or propylene group each Qf w}~ich~ca~ ~ substitutéd ~ 6alkyl. ~e ~oup -(CR13R14)n- can ~ at~ched~to ~e 4 or:~-posidon of ~e ~dole~or indol~e~ng,::p~ferably i~ls::a~hed to ~e 3 2I ~ 1 pcr/Ep93/o2o3l .` 1`
6-position. Preferably the group -(CR13R14)n- is e~ylene.
P~icularly preferred compounds of formula (I) include:
S-Methyl- 1 -(3-pyridylcarbarnoyl)-2,3-dihydropyrrolo[2,3-f~indole 6-Methyl-3-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo[3,2-e]indole s 5,7-Dimethyl- 1-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo~2,3-f~indole 1-(3-Pyridylcarbamoyl)-2,3-dihydropyrrolo[2,3-flindole 6-Methyl-3-(4-pyridylcarbamoyl)-2,3-dihydropyrrolo[3,2-elindole 6-Me~hyl-3-(2-pyridylcarbarnoyl)-2,3-dihydropyrrolo[3 ,2-e]indo}e 5-Methyl- 1 -(2-pyridylcarbamoyl)-2,3-dihydropyrrolo~2,3-flindole 5-Methyl-1-(4-pyridylcarbamoyl)-2,3-dihydropyrrolo~2,3-flindole 5-Methyl-1-(3-pyridylcarbamoyl)-2,3,6,7-tetrahydropyrrolo~2,3-flindole 5-Ethyl- 1 -(3-pyr~dylcarbamoyl)-2,3-dihydropyrrolo~2,3-f~indole 5-n-Propyl- 1 -(3-pyridylcarbamoyl)-2,3-dihydropyrrolo~2,3-f~indole 5,6-Dimethyl- 1-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo[2,3-f~indole 6,7-Dimethyl-3-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo[3,2-e]Lndole l-Methyl-N-(3-pyridyl)-5,6,7,8-tetrahydro- lH-pyrrolo[2,3-g]qu~noline-S~arboxamide 3-Methyl-N-(3-pyridyl)-6,7 ,8 ~9-tetrahydro-3H-pyrrolo[3~2-flqu~noline-6~arbo~camide 6-Methyl-3-(2-methyl-4-quinolinylcarbamoyl)-2,3-dihydropyrrolo[3,2-e~indole, 6-Methyl-3-(5-quinolinylcarbas~oyl)-2,3-dihydro-pyIrslo~3,2-e]indole, ~0 6-Methyl-3-t3-~quinolinylcarbamoyl)-2,3-dihydropyrrolo [3,2-elindole, 5-Methyl-1-(2-methyl-~qu~nolis~ylcarbamoyl)-2,3-dihydropyrrolo~2,3-f~indole, ` 6,8-Dimethyl-3-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo~3,2-elindole, : 6-Methyl-3-(3-pyridylcarbamoyl)-2,3,7,8-tetrahydropy~rolo[3,2-e]-indole, S-Methyl- 1 -(2-pyrazinylcarbamoyl)-2,3-dihydropyrrolo[2,3-f]indole, 2,3-Dihydro-S-methyl-1-(3-methyl-S-iso~iazolylcarbamoyl)-lH-pyIrolo[3,2-e~indole, 2,3-Dihydro-S-methyl-1 -(3-methyl-S-isothiazolylcarbamoyl)- lH-pyrrolo~2~3-f~indole,: -: 2,3-Dihydro-S-meth~l-l-(S~uinolylcarbamoyl)-lH-pyrrolo~2,3-f~indole, 2,3-Dihydro-S-methyl-1-(3-methyl-5-iso~azolylcarbamoyl)-lH-pyrrolo[2,3-f]indole,N-(S-Isoquinolyl)-S-methyl-2,3-dihydropy~olo~2~3-f~ indole-1-carboxamide, N-(6-Quinolyl)-S-methyl-2,3-d~hydro-pyJrolo [2,3-flindole-l~arbo~amide;
or pharrnaceu~cally acceptable salts thereof. : ~ I
The compounds of the fonuula (I) can fonn acid addidon salts with acids, such asconventional pharmaceutically acceptable acids, for e~cample maleic,~hydrochloAc, hyd~obromic, phosphoAc. acetic, fumaric, salicylic, citric, lactic, mandelic, ~aric and rnethanesulphonic~ : D;
Compounds of formula (I) may also form N-o~ides or solvates such as hydrates, and the invendon also ex~ends to these fonns~ When refe~red to herein, i~ is urlde~stood - thal the ~erm 'compound of formula ~I)' also includes these forms.

3- :

4~33 21 PCT/EP93/02031 When Rl ~in an indole) and/or R5 are hydrogen or when R4 is hydroxy or NR8R9 and at least one of R8 and ~R9 are hydrogen the compounds of formula (I) may `' exist tautomericaliy in more than one form. The invention extends to these and any other tautomeric forms and mixtures thereof. ;
Certain compounds of formula (Ij are capable of exis~in,~ in stereoisomeric forrns including enantiomers and the invention extends to each of these stereoisomeric forms and ` ~'' to mix~ures thereof including racemates. The different sLereoisomer~c forms may be separated one from the other by the usual methods, or any glven isomer may be ob~ained by stereospecific or asymmetric synthesis.
The present invenuon also provides a process for the preparation of a compound ' of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises (a) tbe coupling of a compound of formula (11)~
,:
4' R ~ p . A (Il) 1 5 ~ ~
with a compoundof formula (m);

(CR R )n R R

R6~ /N~J~R
¦, :1 '':
~; ~ , ~ N
R ~ R

wherelll A and R6 con~ain the~appropnate funcuonal group(s) necessary to form the ~ -~
molety, -NR5 CO when~coupled, wherein R5' is~RS as defned in formùla (I) or a group conve~tible theoeto,~n is às defined in formula~ and the~variables Rl, R2, ~3, R~l, ' R1 1' R13', R14', R4', R5' and R7' are Rl, R2, R3,~R;10, Rl 1, R13, R14,~R4 a~d R7 25 respectively, as defned in1formula (I), or grou'ps conver~ible the~re~, and thereafter opdonally and as necessary and in any appropriate' order, converting~any Rl, R2, R3, R10,~R1~1, R13, R14, R'4 ,~RS and R7 when other~than~RI, R2, R3, R10, R11,~R13, Rl4i~ R4~ R5~ and R7 respeGdvèly~to Rl~ R2~ R3~Rlo~ Rl l~ Rl3~ Rl4 R4i R5 a~nd R7 interconve~ng RI, R2, R3,~RIO, RI l,~Rl3, R14,~ R5~and R7, and fonning a 30 pharmaceudcally acceptable salt~thereo~

2I~l272l 1~

or (b) cyclising a cornpourld of fonnula (IV):

~ ~13' 14 R5 (CR R )n ~N ~N~D

7' wherein R4, RS, R7, R1 3, and R 14 are as defined in forrnulae (Il) and~ (III), n is as defined in formula (I), and C and D contain the appropnate functional group~s) necessary to fo~n the indole or indoline nng substituted by R 1, R2, R3, R l 0 and R 1 1 a~. defined in formula (m)~ and thereafter optionally and as necessary in any appropriate order, convcmng any R1, R2, ~3, R10, Rl 1, Rl3, R14, R4, R5 and R7 when other than R1, R2 R3~RlotRll~Rl3~Rl4~R4~RsandR7~toRl~R2~R3~Rlo7Rll~Rl31Rl4t~4~R
and R7, interconver~ng Rl, R2, R3, Rl0, ~l l, R13, R14, R4, R5 and R7, and fom~ing a pha~aceu~cally acceptable salt.
Suitable examples of groups A and R~ include:
(i) A is -N=C=O and R6 is -H, lS (h~ A is -NR5 COL and R6 is -H, (iii) A is ~N~5 and R6 is COL, or : ~
(iv) A is halogen and R6 is -CONffR5, wherein R5 is as de~lned above and L ls a leaving group Examples of suitable leaving groups 1. include imidazole, halogen such as chloro or bromo or phenoxy or phenyithio optionally substituted for example with halogen. ~
Whcn A is -N=C=O and R6 is H the reaction ~is suitably ca~ied out in an inert solvent ~or exarnple dichloMrnethane or ~oluene at ambient temperature. ~ ~ i When A is -NR5 COL and R6 is H or when A is -NHR5 and R6 is COL, the ~ ~ 7 reacdon is suitably camed out in an inert solvent such as ~ichloromethane at ambient 2S temperat~re op~ionally in the presence of a base, such as tnethylamine or in ; ~ ~ dimethylfon~amide at ambient or~elevated temperature.
When A is halo en and R6 is CoNHR5, ~hc~reaction is suitably caIried out ~n an ~inert solv~nt such as toluene at elevated temperature, op~ionally in the~presence of a~ base.
The cyclisation of thc~ compound of forrnula~(JV) to~ prepare indoles (R l~and R I 1 are a bond)~ may be cffected using stand~rd melhodology such as described in ; 5 : . : :

WO '~4/04533 2 ~ 4 2 ~ æ l PCI /EP93/02031 Comprehensive Heterocyclic Chemistry 19844, 313 et. s~q. or J. Het. Chem. 1988 25 p.l et seq.
Examples of the more important routes include the Leimgruber synthesis, the Fischer synthesis, ~he Japp-Klingernann variation. the Madelung synthesis and the~
S Nordlander synthesis.
Examples of the groups C and D in the preparaLion of indoles include:
(v) C is N02 and D is CH=CH-NZ2 where each ~ is independently C 1-6 alkyl or togelher represent C2 7 alkylene;
(vi) C is NRl -N-C(R2 )-CH2R3 and D is H;
10 (vii) C is NH-N~C(Co2X)-CH~R3 and D is H where ~ is C l-6 alkyl;
(viii) C is NRl COR2 and D is CH2R3 .
(ix) C is NHCH2CR3 (OR)2 and D is H where~R is à Cl 6alkyl group.
lndolines may also be prepared by reduction. e.g. with NaC~BH3, of indoles produced by variants (vi) to (ix) above.
In reaction variant (v) (Leimgruber synthesis) the compound of formula (IV) is prepared from the 2-methylnitrophenyl urea by treatment with a dialkylacetal of the dialkylforrnamide OHCNZ2 with heating and the product of formula (IV~ cyclised by hydrogenadon over a suitable catalyst such as pall~dium and charcoal optionally under pressure to yield the compound of f~ula (I) where Rl=R2_R3=H.
In reacdon variant (vi) (Fischer synthesis) the compound of ~ormula (IV) is prepared from the hydrazinophenyl urea by dehydradon, ~referably by healing, with the appropAate ketone R2 CoCH2R3 and the product ~of formula (IV) cyclised by heating ~ ;
with an acid ca~lyst such as hydrochloAc 0 sulphuric acid.
In reaction vadant (vii)~(Japp-Klingemann synthesis) the compc)und of formula (1~) is prepared from the aminophenyl urea by dia~otisatiQn followed by ~eatment for example with CH3COCH(C 02X)~H2R3 wheoe X is C1.6 ~l under basic conditions in aqueous alcohol as solYeni.
llle product of formula (IV) may then be cyclised as in ~e Fischer synthesis above. s In reaction varian~ ~viii)~(~ladelung synthesis) the compound of fonnula (IV) iscyclised with base in an iner~ solvent op~ionally with ~heafing.
~; ~ In reaction variant (ix)~ ~Norol der synthesis), the compound of fo~ula (IV) is ~ s cyclîsed by heating in a mL~rure of ~trifluoroacetic anhy~ide/acid.
It will be appreciated ~at when D is hydrogen~ either or both indole isome~s may~
be formed duIing th~ cychsauon pr~ess.
, WO 94/04533 21 ~1 2 7 2 1 pcr/Eps3/o2o3l ~
.. i I
Suitable examples of groups R2 ~ R3 . R4, and R7 which are convertible to R2, ' `
R3, R4, ~d R7 alky! groups respec~ively, include acyl groups which are introduced conventionally and may be converted to the corresponding aLkyl group by comventional reduction, such as using sodium borohydride in an inert solvent followed by 5 hydrogenolysis in an inert solvent. Hydrogen substi~uents may be obtained fromalkoxycarbonyl groups which may be converted to hydrogen by hydrolysis and . ~, decarboxylation. When R4 is hydro~y it iS ~preferably protected in the compoun~l of forrnula (II) as, for example, benzyl which is removed by hydrogenation.
Suitable examples of a group Rl which is convertible to Rl, include typical 10 N-protecdng groups such as aLkoxycarbonyl, in par~icular t-butyloxycarbonyl, acetyl, trifluoroacetyl, benzyl and para-methoxy~enzyl which are converted to Rl hydrogen using conventional conditions.
Suitable examples of a group R5 which is convertible to R5 include alkoxycarbonyl and benzyl or para-metho~ybenzyl which are converted to R5 is 15 hydrogen using conventional condidons.
~ nterconversions of Rl, R2, R3, R10, Rll, R13, R14, R4, R5 and R7 are carried out by conventional procedures.
; For exarnple, in the case wherein Rl, R2 and R3 are C1 6 alkyl and R5 is hydrogen it is possible to introduce a C l -6 alkyl group at *e R5 position by conventional 20 `alkylation using 1 molar equivalent of a C 1-6 alkyl halide and 1 molar equivalent of a suitable base in an inert soh~ent. R 1 C 1-6 all~yl groups may also be inuoduced by conventional alkylation, for example using a Cl.6 aLkyl halide and base such as sodium hydride, or by reduction of C 1-6 acyl.
R4 halo and R7 halo may be introduced by selective halogenalion of the ring P or25 indole~indoline r~ng respectively using convendonal condiuons.
It should be appreciated that it may b: necessary to protec~ any Rl to R12 hydrogen variables w}lich are not required to be interconverted.
Protection, especially of a Rl hydrogen9 may also be necess~y during coupling reaction (a) and ring-forming reaction (b) above. ~ `
Suitable pro~ecting groups and methods for their attachment and removal are conven~ional in thè art of or~anic chemis~ry, sueh as those described~in Greene T.Wi.
'Protective groups in organic synthesis! New York, Wiley (1981~).
It is preferable, however, to irltroduce and interconvert ~he groups Rl to R12 before couphng compounds of formulae (Il) and (~m3 together,~ or cyclising the compound of formula (IV).
Compounds of formula (I) which are substi~ted~ indoles. and theLr appropna~e deAvatives, can be converted to the cor~esponding indolines, and vice versa, by : :

7 ~ :

2 ~ 42~ ~ t ~``; . `
WO 94/04533 pcr/Eps3~o2o3 conventional me~hods, e.~. reduction with NaCNBH3 in aCeLiC acid and oxidation usin~
MnO2 in an inert solvent~
Compounds of forrnula (II~ in which A is NHR5 are known compounds or can be prepared analogously to known compounds~ see, for example, WO 92105170.
Compounds of forrnula (Il) in which A is -N=C=O may be prepared by trea~ing a cornpound of formula ~11) in which:
i) A is amino, with phosgene or a phosgene equivalent, in the presence of excessbase in an inert solvent.
ii) A is acylazide (i.e. CON3), via the nitrene, by thermal rea~rian~ement usingconventional conditions ,'ref L.S. Trifonov et al, Helv. Chim. Acta 1987 70 262). ~`
iii) A is CONH2, via the nitrene intermediate using conventional conditions.
Compounds of formula (II) in which A is -NR5 COL may be~ prepared by reacting a compound of formula (1:1) in which A is -NHR5 with phosgene or a phosgene equivalent, in an inert solv`ent, at low temperat,-ure, if necessary in the presence of one equivalent of a base such as triethylam~ne.
Compounds of formula (m) may be prepared:
(a) by cyclisalion of compounds of formula (V), followed by reduction to the amine if neeessary ~ ~ 13~ 14' Pr R )m R1 l R3~

HR6 ~R ' R7 Rl' 2û wherein Q is CR13R14L, CR130 or C02R where L is a~leaving group and~R13 and Ri4 are as defined in formula ~I), m is l or 2, Rl', R2', R3', R7', R 10', Rl 1', R 13' a~d R 14'~ are as defined in formula ~) above, R6 is a group R6`æ defined in formula~ and R is an aryl or Cl 6alkyl group, 25, I - f or ,'b) cyclisation of compounds of formula (Vl) ~; ~ R ~ ~V) :: :

I

WO94/04533 2I'12721 pcr/Ep93/o2o3~
, !
wherein, R6, R7, R13, R14 ~nd n ar~ as defilned in formula (V) and C and D are as defined in formula (IV) above.
The cyclisaLioll of a compound of formula (V) may be suitably carried Out in an incrt solvent at ambient or ele~vated temperatures, optionally in the presence of a base. ', 5 Reduc~ion may be carr;ed OUt using conventional reduction techniques. The cyclisation of a compound of formula (VI) may be suitably carried out using the procedures outlined for lhe cyclisa~ion of a compound of formula (IV), above~
Compounds of forrnula (II) in which A is halogen and R4 is hydrogen are commercially available.
Novel intermediates of formulae (III) and (IV) also form part of the inven~ion.
Pharrnaceutically acceptable salts may be prepared conventionally by reacuon with the appropriate acid or aeid derivative.
N-oxides may be formed conventionally by reaction w1th hydrogen peroxide or percarboxylic acids.
Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT~,C receptor antagonist activity, and certain compounds show 5HT2B antagonist !
activity. Compounds of formula (I) are therefore believed to be of potential use in the treatment or prophylaxis of ~ety; depression, migraine, anore~ia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from 20 drug abuse, schizophrenia, and also disorders associated with spinal trauma and/or head injury sùch as hydrocephalus.
Thus the invendon also provides a compound of forrnula (I) or a pha~naceuticallyaceeptable salt thereof, for use as a therapeutic substance, in particular in the treatment or ~ ~ prophylaxis of the above disorders.
: ~ 25 The invention further provides a method of treatment or prophyla~ of the above disorders, which comprises administering to the sufferer a therapeutically effective amount of a compound of forrnula (i) or a phaDaceutically acceptable salt ~ereof.
In another aspect, the invention provides the use of a compound of formula ~1) or a pharmaceutically acceptable salt thèreof in the manufacture of a medicament for the 30 treatmerlt or prophylaxis the above disorders. ~, I Ihe present invention also provides a pharmaceutical cornposition, which comprises a compound of formula a) or a phannaceudcally acceptable salt thereof, and a pha~maceutically acceptable carrier~
~ pharmaceutical composition of ~he invention, which may be prepared by ~`
35 admixn~re, suitably at ambient temperature and atmospheric pressure, is usu~lly adapted `~, for oral,~ parenteral or rec~al administration and, as such, may be in the ~orm of tablets, capsules, oral liquld preparations, powders, granules. Iozenges, recons~tutable powders, ; ~ 9 - ~

`

WO 94/04533 æ pcr/Ep93/o2o3 injectable or infusable solu~ions or suspensions or suppositories. Orally administrable ComposiLions are generally pre~erred. 1 Tablets and capsules for oral administra~ion may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers. ~bletting lubncants, s disinte~rants and acceptable wet~ing agents. The tablets may be coa~ed according to methods well known in normal pharmaceutical pracdce.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the forrn of a dry product for reconstitution with waser or other suitable vehicle before use. Such liquid preparasions 10 may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which rrlay include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sserile vehicle. The compound, depending on the vehicle and concentration used, can be either ` `^
suspended or dissolved in the vehicle. In preparing solutions, the compound can be ~
dissolved for injection and filter sterilised before filling inso a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, p~eservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling mto the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, e~cept that the cornpound is suspended in the Yehicle instead of being dissolved, and sterilizadon cannot be accomplished by fLltration. The compound can be sterilised by e~posure to ethylene o~ide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilita~e unifonn distnbudon of ~e compound.
The composition may cQntain from 0~l% to 99~o by weight, preferably from l0 to 60% by weight, of ~he active material, depending on the method of administration.
The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the welght of the sufferer, and o~her similar factors. However, as a general guide suitable unit doæs may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for e~ample 0.2 to S mg, and such unit doses may be administered more than once a day, for examp!e two or three a day, so that ~e total daily dosage is in the range of about 0.01 to l00 mg; and such therapy may extend for , ;-! -a number of weeks or months.
When administered in accordance with the ~nven~ion, no unacceptable toxicological effects are expec~ed with the compounds of the invention.
.

:

~WO 94/04533 2 l~ 7~ l Pcr/EPg3/o2o3l ~`
l~e following Examples illustrate ~he preparation of pharmacologically acuve compounds of ~he inven~ion. The followin~g Descrip~ions illustrate the preparation of !
intermediat~s to compounds of the present invenUon. ~: ¦

~. :

`

`

: :

2~
~VO 94/(~453~ P~T/EP93/02031 Description 1 1~Acet~1-5-aminoindoline (Dl) I-Acetyl-S-nitroindoline ( 12~77g, 62 mmol), cyclohexene (62 ml, 610 mmol), and 5%
palladi~ on charcoal (2.34g) were stirred at refiux under nitrogen for 18h. A further s portion of catalyst (0.5g) wa~s then added, and reflux was condnued for a filr~her 3h. The l"
mixturc was cooled, ~lltered throu~h Kieselguhr, and evaporated tO give ~he titl~
compound (9.33g, 85%) as an orange-yellow solid.

NMR (D6-DMSO) ~: 2.05 (3H, s), 3.0 (2H, t, J 8), 3.97 (2H, t, J 8), 4.97 (2H, bs), 6.33(1H,dd.J7,1),6~46(1H,d,J 1),7.72(1H,d,J7).

Descr~p~on 2 N~ Acetyl-5~indolinyl)-2,~diethoxyethylamine (D2) I-Acetyl-5-aminoindoline (Dl) (9.33g, 53 mmol), bromoacetaldehyde diethyl acetal (6.0 ml, 40 mmo}) and sodium hydrogen carbonate (4.58g, 54 mmol) was sdrred at reflw;under nitrogen for 64h. Purther acetal (2.0 ml, 13 mmol) was then added, and reflux was continued for a further 24h. The mixture was cooled, filtered, and evaporated to near-dryness. Chromatography on silica gel using ethyl acetate/petroleum ether (b.p. 60-80C) (50-100% ethyl acetate~ gave the title compound (6.59g) as a yellow-brown solid, in addition to recovered starting amine (3.09g). The yield of product was 63%, based on consumed starting material.

NMR (CDC13) ~: 1.25 (6H, t, J 7), 2.2 (3H, s)l 3.13 (2H, t, J 8), 3.22 (2H, d, J 5), 3.5-3.65 (2H, m), 3.65-3.8 (2H, mj, 4.01 (2H, t, J 8), 4.68 (lH, ~ J 5), 6.5 (2H, m), 8.03 (lH, d, J 7).

Alternative Procedure 1-Acetyl-S-aminoindoline (Dl) was reducdvely alkylated wi~h glyoxal monoMethyl acetal in ethanol at 45C using 10% palladium on charcoal an,d hydrogen at 50~ p.s.i. Removal of the ca~lyst by filtration followed by evaporation of thè solvent a~forded the corresponding dime~hyl acetal which was used directly in Descripuon~3 instead of-the die~hyl ace~al. ~ ;
: !

.~

~`~

W O 94/04533 2 1 '~ 2 7 2 1 PCr/EP93/0~031 1 Description 3 , t 1-Acetyl-~-t~inuoroacetyl-2,~dihydropyrrolo~2,3 tlindole (D3) ', N~ cetyl-5-indolinyl)-2,2-diethoxyethylamine (D2) (6.51g, 22 mmol) was added to an ~ ;
ice-cold, stirred m~xture of tlifluoroacetic acid ~25 ml) and ~rifluoroaceuc anhydride~(25 S ml). The mixture was stirred at 0C under nitrogen for O~5h. after which time further trifluoroacetic acid (40 ml) was adùed~ The mixture w~c then heated at reflux for 64h, cooled, and evaporated to dryness~ Chroma~ography on silica gel using ethyl acetate/chlorofo~n (0-60% ethyl acetate) then gave the title compound (6.28, 89%) as a light cream solid which darkened sligh~ly on standing.

NMR (CDC13) ~: 2~33 (3H, s), 3~37 (2Hj t, J 8), 4.17 (2H, t, J 7), 6~76 (lH, d, J
3). 7-45 tlH. m). 8.27 tlH, s), 8.44 tlH.~s)~

I)escription 4 1-Aeetyl-2,3-dihydropyrrolo[2,3-f~indole tD4) ~ ~ ~
l-Acetyl-5-~ifluoroacetyl-2,3-dihydropyrrolo~2,3-f]indole (D3) t2.80g, 9~4 mmol) was suspended with sti~Ting in methanol (100 ml), and anhydrous potassium carbonate (1~96g, 14.2 mmol) was added. The mixn~re was~sti~ed for 0.5h, evaporated to near-dryness, and ` ~ partitionèd between ethyl acetate and water. After separadon, the aqueous portion was 20 e~tracted~ with 5% methanol/chloroform, and the combined organics were dried tNa2S04), filtered and evaporated, giving the title compound tl.53g, 80%) as a cream solid~

; ~ NMR (D6-DMS0) ~: 2.15 t3H. s), 3.18 (2H, t, J 8), 4.08~t2H, t, J 8), 6.33 tlH, bs), 7.2 (2H, m), 8.22 tlH, s), lO.9 tlH, bs).

Acet~l~S-methyl-2~dih~'drPYrr1~2~fl~ndle (D5)~
Sodium hyd~ide t80%, 0.25g, 8.3 mmol) was stirred under;nitrogen in dry N,N~
dimethylformamide (DMF) ~t5 ml), as 1-acetyl-2,3-dihydropyrrolo[2,3 Iflindole tD4) 30 tl.52g,~7.6 mmol) was added~in~DMF t20 ml),~with;effervescence. 111e mhture was~
n~ ~ sti~Ted for 0.5h, and ~iodomethane tO.52 ~ml, 8.3~mmol)~was then added:~in DMF (S ml)~
After stir~ing for a further lhf excess~so&ium hyd~ide~was quenched by~ addition of wa~r tl ml), and the mi~cture was partitioned;htween~ethyl aceta~ and wate~, and separated.
The~organic portion~ was washed~wi~h water and~ brine,~ied ~N~S04)~and evaporated~
35~; Chromatogràphy~onsilica~gelusing~ethylacetate/chloroform~0-50%ethylacetate);~en ga~ve~ ~e ~d~e compound tO.80g, 49%)~as a ~e ye~ow ~d.~

````: `
W 0 94/04533 ~ Z S P{~r/EP93/02031 ~-N~vIR ((~DCI3) ca.5:1 mixture of rotamers ~:
2.26 (major, 3H. s), 2.51 ~minor, 3H, s), 3.16 (minor, 2H. t, ~ 8), 3.3 (major, ~H, t, J 8~, 3.74 (rnajor, 3H, s), 3.77 ~minor, 3H, s), 4.1 (major, 2H, t, J 8), 4.19 (minor, 2H, t, J 8), 6.44 tboth, lH, d, J ~), S.98 tmajor, lH, d, J 2), 7.0 (minor, m), 7.09 (major, lH, s), 7.18 (minor, lH, s), 7.3l (minor, IH, s), 8.48 (major, IH, s). I ;
.:
Descrip~on 6 S-Methyl~2,~dihydropyrroIo[2,3-f3indoIe (D6) ~.
1 Acetyl-S-methyl-2,3-dihydropyrrolo~2,3-f3indo}e (D5) (0.70g, 3.3 mmol) was s~ined at retlux under nitrogen in 10% sodium hydro~cide solution (~0 ml) for 4h. The mix~ure was cooled, diluted with ~uater (200 rnl), and ex~racted with ethyl ace~te. The extract was dried (Na2S04) and evaporated to giYe the title;compound (0~58g) as a light brown gum, still containing ca 20% of the star~ing amide (NMR)~ This material was used in the next step without purification.

NMR (CDC13) ~: 3~12 (2H, t, J 9), 3.33 (lH, bs), 356 (2H, t, ~ 9), 3~7 (3H, s), 6.27 (lH,d,J3),6.85(1H,s),6.9(1H,d,J3),?.08~1H,s).

Description 7 ~1.Methyl~5~ o~indolyl)aceto~utrile (D7); ~ ~
Me~yl-S-nitroindole (0~77g, 4~4 mmol) and ~chloropheno~y)acetonitrile (0.88g, 5.2 mmol) were sti~red in dry DMF (10 ml) at 0C, and potassium t-buto~cide (1.47g, 13~1 mmol) was added in d~y DMF (lO ml)~ The mi~ture was ~ ed at 0C for 15 min, pou~d into lM hydrochloric acid (2~0 ml), and stirred until the precipitate coagulated. The solid was thèn filtered off and dried.~ ~Chromatography Qn silica gel us~ng chlorofonn then gave the~title compound (0.48g, 51%) as ayellow solid.
.
CDC13~ , 3.9 (3H, s), 4~37 (2H, s), 6~78 (1~, d, J 3), 7.31 (IH, d, ~ 3), 7~38~1H,d,J8),8.12(1H,d,J8)~

~; Descrip~on8 (1Methyl-5-ni*o 4~indolylk~ ol~
l-Methyl-5-nitr~indoIyl~acetonitrile (D7) (3.36g, 15:6 mmol)~ was stirred in drytetrahydro~ran ~F) (l~O ml) under nitrogen, as diisobut~rlaluminium hydride (l.~M in tolùene,~21 ml, 31.5 mmoO wa~ added. Tbe mi~cture was stiIred for 6h, and methanol (25 ~1~2~. ~
~W0 94/04533 pcr/Ep93/o2o3l ~;
ml~ was added. After a furLher S min, it was diluted with water (500 ml)t acidified with SM hydrochloric acid, and extracted with chloroform. The extract was dried (Na~S04), evaporated to a blackish gum, and suspended in ethanol (100 ml). Sodium borohydride t (0.88~" 23.1 mmol) was added, and the mixture was stirred for 0.5h, when a second similar S por~ion of sodium borohydride was added. After a further O.Sh, the mi~nlre was diluted with water (S00 ml~, acidified with 5M hydrochloric aeid, and extracted with chloroform. ~"
The extract was washed with brine, dried (~a~S04) and evaporated to a brown gum.Chromatography on silica gel using ethyl ace~telpetroleum ether (b.p. 60-8~C) (20-60%
ethyl acetate) gave the title compound (O.SOg, 15%) as a brown oil.
: .
NMR (CX13) ~: 3.47 (2H, t, J 7), 3.78 (3H, s), 4.02 t2H, t, J 7), 6.73 (lH, d. J
3), 7.2 (2H, m), 7.89 (l~I, d, J 8).

Descr~p~on 9 2~ Methyl-5-1~itro~indolyl)ethyl methanesulphonate (D9) 2~ lvlethyl-S-nitro-~indolyl)ethanol (D8) ~O.SOg, 2.3 mmol) and trie~hylam~ne (0.38 mh 2.7 mmol) were stirred in dichloromethane (10 ml), and methanesulphonyl chloride (0.21 ml, 2.7 mmol) was added. The mixture was sti~red for 10 min, when water (10 ml) was added, and then stirred vigorously for a flLrther 10 min. Mer acidificadon with SM
hydrochloric acid, the layers were separated, and the organic portion was dried (Na2~S04) and eYaporated to give a dark oil. Chromatography on silica gel using chloroformfollowed by dichloromethane gave the title compound (0.54g, 7~%) as an orange solid.

(CDC13) ~: 2.44 (3H, si, 3.6~ (2H, t, J 7), 3.85 (3H, s?, 4.63 (2EI, ~, ~ 7), 6.81(lH,d,J3),7.25(lH,d,J3),7.3(lH,d,J8),8.0(lH,d,J8).

; ~ . .
Descr~ption 10 6~Methyl-2,3~dihydropyrrolo[3,2~e]indole (D10) 2~ fethyl-S-nitro~-indolyl)ethyl methanesulphonate (D9) (0.38g, 1.3 mmol) was hydrogenated over 5% pa~ladium on charcoal (0.23gj in dry D~F t20 ml) ~t 80 p.s.i. H2 for 2h, diluted with ethanol (80 ml), filtered through Kieselguhr, and evaporated to a brown gum. The title compound can be pu~ified by preparation of the~HCI salt to glve 6 ` ~ Methyl-2,3-dihydropyrrolo[3,2-e~indolehydrochlodde.

2~
WO 94/n4533 PCr/EP93/0203 1 :
Description 1 1 N~ Ace~i~-5-indQIinyl~chloroallylan~ne~(D11) l-Acetyl-S-arninoindoline (Dl) (4~36g, 24 8 mmol), anhydrous potassium carbonate (S.lg, 37 mmol) and 2,3-dichloro-l-propene ~4.5 ml, 48.9 mmol) were s~i~red in dry DMF~(50 s ml) at 70C for 16 h. The rnixture was then diluted wilh water (SOO ml), and s~rred for 10 min. Filtration and air drying then gave the title compound (5.71g, 92%) as a dark olive solid.

NMR (CDCl3) ~ 2.19 (3H, s), 3.13 (2H, t, J 8), 3.9-4.2 (SH, m), 5.32 (lH, m), 5.41 (lH, m), 6.4-6.6 t2H, m), 8.05 (lH, d, J 9) Descrip~on 12 N~ Acetyl.S-;ndolinyl)~chloro-N-trifluoroacetylallylamine (D12) N-tl-Acetyl-5-indolinyl)-2-chloroallylamine ~D11) tS.71g, 24.8 mmoll and triethylamine t3.8 ml, 27.3 mmol) were stirred in chloroforrn tlOO ml), and trifluoroacetic anhydride (3.8 ml, 27.3 mmol) was added dropwise over 1 min. The mixture was ~stirred for 1 h, when water (lOO ml) was added. This mixture was stirred vigorously for 20 min, acidified with ~ M hydrochloric acid, and sepàrated. The organic portion was dried ~Na2S04) and evaporated to give the title compound as a dark oil (7.49 g, 95%), which solidified on standing.
I
NMR (CDC13) ~: 2.25 (31H, s), 3.24 (2H, t, J 8), 4.16 (2H, t, J 8), 4.52 (2H, s), 5.~3 (lH, s), 5.36 (lH, s), 7.1 (2Ht m), 8.23 (lH, d, 3 8) Descrip~don 13 ~ ;
l Acetyl 7-methyl-5-trinu~roacetyl-2,3 dihydropyrrolo[2,3~f]indole (D13~ :
N-(l-Acetyl-S-indolinyl)-2-chloro-N-t~luoroacetylallylamine (D12) (7.S3 g, 22 mmol) was stkred in polyphosphoric acid (38 g) at 140 C for l.Sh. The mi~cture was cooled, ` ~ I dispersed 'in water (200 ml) and ex~acted with ethyl ace~ate. The extract was filter~d through E~ieselguhr, d~ied (Na2S04) and evaporated to give a dark~gum (ca. 3g).
Chromatography on silica gel, eluung with 0-20% e~hyl`~acetate in chloroform gave the 3r~
~itle compound (0.49g, 7%~ as~a light yellow solid.

I)C13) ~: ~ 2.28 (3H, s), 2.33 (3H, s), 3.36 (2H, t, J 8), 4.18 (2H, a, J 8), 7.19 (1H, s), 8.24 (1H, s), 8.36 (1H, s).

16-~

214~721 WO 94/1)4533 PCr/EP93/0203l :;
Descnp~on 14 `
l-~cetyl-r~,-methyl-2,~dihydropy~rolo[2,3-f]indole ~DI4) This was prepared from l-acetyl-7-methyl-5-trifluoroacetyl-2,3-dihydropyrrolo~2,3-f]indole (D13) (0.49g, 1.58 mmol) follow~ng the procedure of Description 4, but ~orking s up by dilution with water. The title compound (0.31gi 91%) was then isolated by filtration and drying, as a yellow solid.

NMR ~D~-DMSO) ~: ~.15 (3H, s), 2.18 (3H, s), 3.17 ~2H, t, J 8), 4.09 (2H, t, J 8), 7.00 (1H, s), 7.14 (lH, s), 8.16 (lH, s)j lO.55 (1H, b s) Description 15 1Acetyl-5~7-dimethyl-2,3~dihydropyrrolo[2,3-f]indole (I)15) This was prepared from 1-acetyl-7-methy~-2,3-dihydropyrrolo[2,3-f}indole (D14) (C.31g, 1.46 mmol) following the procedulre of Des~nption 5, but working up by di~ution with water. The title compound (0.26g, 79%) was then isolated by filtration and drying, as an orange-yellow solid.

NM~ (CDC13) ca 5:1 m~nlre of rotamers, ~: -2.27 & 2.30 (major, 3H,~s ~ both, 3H, s), 2.53 (minor, 3H, s), 3.15 (minor, 2H, t, J 8), 3.30 (major, 2H, t, J 8), 3.68 (major, 3H, s), 3.70 (minor, 3H, s), 4.10 (major~ 2H, t, J 8), 4.20 (minor, 2H, t, J 8), 6.76 (major, }H, s), 6.80 (minor, lH, s), 7.05 (maJor~ lH, s), 7.13 (minor, lH, s), 7.19 (rninor, IH, s), 8.42 (major, lH, s).

Descr~ption 16 ~5 5,7~Dimethyl 2,3~dihydropyrrolo~2,3~f]1ndole(D16) is was prepared from 1-acetyl-5,7-dimethyl-2,3-dihydropyrrolo[2,3-flindole (D15)(0.44g, 1.93 mmol) following; the procedure of Descnption S, using 5:1 10% sodiwn ~ :
hydroxide solut~on/ethanol as solvenL NMR aRer 7h reaction time showed ca 60%
reac~ibn,;but~this material (0.30g) was used in the ne~t step without sep~ion of the starting material.

Descriv~on l7 ~ S
Aoeql~S-ethyl-2,3-dsbydropyrrolo[~ fpndole (D17)~
Ihe~ dtle compound was~prepared from l~acetyl~2,3-dihy~pyrrolo[2,3-f~indole (D4), ~;~
35~ ~ sodium hydride~and ethyl~iodide in 90% yield using; a procedure simiIar to that for D5.

wo 94/oqs33 7,~ 4~ pcr/Ep93/o2o31 NMR (C~)C13) (mixture of ro~Lmers) ~ major signals:
1.44 (3H, t, J 8), 2.23 (3H, s). 3.29 (2H, t, J 10), 4.0-4.25 (4H, m), 6.43 (lH, d, J 3), 7.03 (lH,d,J3),7.10(}H,s),8.48(1H,s) ~ ;

De~crip~on 18 5-Ethyl-2,3^dihydropyrrolo[273-f~indole (D1B) The title compound was prepared from l-acetyl-S-ethyl-2.3-dihydropyrrolo~2,3-flindole (D17) In 100% yield using a prc~?cedure similar to that for D6.

NMR (CDC13) ~ 1.41 (3H, t, J 8)? 3.12 (2H, t, J 10), 3.58 (2H, t, J 10), :
4.08(2~1,q,J8),6.26(1H,d,J3),6.84(1H,s),6.97~(1H,d,J3),7.12(1H,s) - .
~es?~p~on 19 1~Acetyl-5-n-propyl~2,3~dihydropyrrolo[2,3-f3indole (Dl9) Prepared as in Descrip~ion S using sodium hy~iride (80%, 0.08g, 2.8 mmol), 1-ace~yl-2,3-dihydropyrrolo[2,3-f~indole (D4) (0.4g, 2 mmol~ and l-iodopropane (0.27 ml, 2.8 mmol~.
The mixture wæ partitioned between e~er/H~O. The organic portion was separalcd. dricd and èvaporated to afford the ti~le compound (0.48 g, 99%)~as a yellow solid.
NMR (CD~13} ca 4:1 mi~t~re of rotamers, ~
0.92 (t, 3H, J=8.4Hz), 1.84 (m, 2H, Ja8,4Hz), 2.25 (major, s, 3H), 2.50 (m~nor, s, 3HI), 3. l4 (minor, t, 2H, J=8.4Hz), 3.29 (major, t, 2H, J-8.4Hz), ~.02 (t, 2H, J=8.4Hz), 4.()9 : (major, t, 2H, J=8.4Hz), 4.19: ~m~nor, t, 2H, J=8.4Hz), 6.44 (d, lH, J=SHz~, 7~02 ~d, IH.
J-SHz), 7.10 (s, 1~1), 8.46 (s,: lH).

:Description20 :~
~-n-Propyl-2~dihydropyrrolo[2,3-~indole ~(D20) p~lred as in Descripdon` 6 using~1-ace~ 5-propyl-2,I3-dihydropy~Tolo[2,3-f~indole 30 (Dl~) (0.48g, 1.9 mmol) in ethanol (30 ml) and lO~aOH solution~ ~S ml).~
Chromatography over silica gel eluting wIth 3% MeOH/~H2CI2 afforded the htle compound (0.23g, 60%). ~

:~ ~ N~ (CDC13) ~: ~ 0.93 (t, 3~1, J=8.4Hz~, ~1.86 (m, 2H. J-8.4Hz), 3.1~ (t, 2H, J-8.4Hz), 3.56: (t, 2H, J=8.4Hz), 4.01~ (t, 2H, J=8.4Hz~
6.27 (d, lH, J-5Hz), 6.87 (s, lH), 6.97 (d, lH, J=5Hz), 7.02 (s, lH). ~ :

:

: ` `

WO 94/04S33 21~4 ~ 7 2 1 PCr/EP93/02031 Descrip~on 21 N~ Acety1-5-indolinyl)~2-chlor~N-methylallylan~ine ~1~21) Formaldehyde (40% aq. solution, 2.8 ml, 36 mmol) and 3M sulphuric acid (Sml, lS mmol) s were stirred in ice. TQ this was added po:rtionwise a suspension of sodium~ borohydride (1.66g, 44 mmol) and N~ acetyl-S-indolinyl)-2-chloroallyIamine (D11) (3.08g, 12.2 mmol) in tetrahydrofuran (60 ml), maintaining temperature~ below 20 C. The mi~ture was then s~ ed at arnbient temperature for 0.25 h, and basified with e~cess solid sodium hydroxide. The supernatant was decanted, and ~he solid residue was dissolved in water (150 ml) and extracted wi~h ethyl acetate. 7he combined organics were dried (Na2S04) and evaporated to a brown tar, which was dissolved in thloroform, re-dried (Na )S04), filtered and evaporated to give ihe title compound (3.80g,~100%) as a brown solid. This was used without purification.
: ~ ~: . : : ~ .
NMR (CDC13) ~: 2.20 t3H, s), 3.00 (3H, s), 3.16 (2H, t, J 7), 3.95-4.20 (4H, m),5.22 (lH, m), 5.30 (lH, m), 6.56 (2H, m), 8.08 (lH, d, J 8) Description22 Acebl~S,6~dimethyl-2,3-dihydropyr~olol2,3-flindoleànd l-aceb1~6,7 dimethy1-2,3-20 dihydropyr~lo[3,2-e]indole (D22) ~
N-(l-~cetyl~S-indolinyl) 2-chloro-N methylallylamine;(D21)~ ~(2~Ig, 7.9 mmol) was stirred in po!yphospho~c acid (44g) at l40 C for 24h, cooled, dispe~sed în water (200 ml), and extracted with ethyl acetate. ~Ihe extract was washed~with brine, dried (Na2SO4) and evaporated to give a pin~ solid. Chromatography on silica gel, élu~g with 0-20%
2$ ;ethyl acetatè in dichloromethane, gave~
1) ;faster~luting matenal, the iinear [2,3-f~indole~(0.21g, 11.6%) æ~a w~te solid.
NMR showed a mka~re of rotamers. in appro~imatc ra~do 5~

NMR (CDC~l3) ~: 2.25 (3H, major, s), 2.39 ~3H, major, s), 2.41 (3H, minor, s), 2.50 (3H, mmor, s), 3. lS (~I, minor, t, J 7), 3.2~ (2H, maJor, t, J i), 3.62~ (3H, maJor, s),~ "
3 ~64 (3H, minor, s). 4.10 (2H,;~m~ajor, t, J 7), 4.19 (2H, m00r, ~, ~ 7), 6.22 ~lH,~both, s), 7.03~(1Hi major,~s), 7.11 (IH, minor, s), 7.ZI (lH, mino~ s),~8.38 (IH, major, s).~

2)`~ ~ ~ slower~lu~g ma~, ~e~guiar ~3,2-e3~doie (O.lOg, 5.5%) æ a wh~te;so~d.
35~ showed à mi~e~of~ro~ers, ~appro~à~ ra~o 8~

2 ~
WO 94/04533 pcr/Ep93/o2o3l :
NMR (CDC13) ~: 2.25 (3H. major, s), 2.4-2.5 (3H, minor, + 3EI. both:m), 3.1 t2H. minor, t, J 8), 3.33 (2H, major, t, J 8), 3.56 (3H, both, s), 4.15 (2H, major, t, J 8), . 4.26 (2H, minor, t, J 8), 6.1 (lEl. both, m), 7.0-7.15 (lH. both. + lH, minor: m), 8.20 (111, major,d,J8).

Descrip~on 23 S,6-Dimethyl-2,3 dihydropyrrolo~2,~flindole (D23) This was prepared from l-acetyl-5,6-dimethyl-2,3-dihydropyrrolol2,3-flindole ~D22) (0.42g, 1.84 mmol), following the procedure of D6. This gave the title compound (0.30g) lO as a brown gum. NMR indicated ca. 60% convers~on to the desired material. Thls was used without purification.
:
NMR (CDCI3) 8: 2.36 (3H,~s), 3.12 (2H, t,:~ 7),~3.56 (2H, t, J 7), 3.58 (3H, s), 6.06(1H,s),6.78(1H,s),7.03(1H,s).
lS
Description 24 ~ ~ ~
6,7~Dimethyl 2,3-dihydropyrrolo[3,2-e]indole (D24) This was prepared from l-acetyl 6,7-dimethyl-2,3-dihydropyrrolo[3,2-e~indole (D22) (0.156g, 0.68 mmol), follwing the procedure of D6. This ga~e the title compound 20 (0.124g, ~7%) as a dar~; oil. ~
~ .
:~ NMR (CDC13) ~: 2.38 (3H, s), 3.16 (2H, t, J 7), 3.6 (5H[, mj, 6.04 (LH, s3, 6.63 :~ (lH,d,J8),6.95(1H,d.J8) 25 Description 25 ~: : N~ Quinolyl)trifluoroacetamide (D25) 6~Aminoquinoline (5.75g, 40 mmol) and triethylamine (6.7 ml, 48 mmol) were stirred~
chloroform (100 ml), and trifluoroacetic ianhydride (6.7 ml, 48 mmolj was~added` over 2 ,:
m~. The m~xture was~stirred for 1 h., when~water (1:00 ml) was~ added. iAfter stilringl for 5 min, the gummy prec~pitate was filtered off, washed with chloroform and water, and - ', :~ ~ dried in v~cuo at 50 C:. Ihis `gave: the dtle compound (7.68g, 80%) as a straw-colo~d ~ ~ .
semi-solid, containing residual triethyLamine (N~).
~ ~ :
NMR (ClX13) ~: ~ 7.57~:(lH,~dd, J 9, 4), 7.97 (IH, dd, J 9, 2), 8.08 ~lH, d, J 9), 8.4 (2H, m), 8.90 (1H, dd, J ~, 2),~11.63 ~1H, s).

20- ::
:

~" ~
t~`' .
WO 94/04533 2 ~ ~1 7? 7 t,~ 1 PCr/EP93/0203 ~ 7 l I `
Description 26 N-(1,2,3,4-Tetrahydro-~quinolyl)trifluoroacetan~ide (D26) N-~6-Quinolyl)~ifluoroace amide (D25) ~6.84g, 28.5 mmol) and nickel chloride hexahydrate (1.36g, 5.71 mmol) were stirred in methanol (100 ml), arld sodium S borohydride (4.3g, 113 mmol) was added por~onwise over O.Sh. After stirring for a further O.Sh, another portion of sodium borohydride ~l.Og, 26 mmol) was added. After another 0.5 h, the mixture was evapora7ted to dryness, partitioned betu,een 5M
hydrochloric acid (25 ml) and e7~hyl; acetate ( lOO ml), and ~stirred until clear. This mixture '~
was neutralised with excess sodium ~hydrogen ca~rbona~e, and sepat~ted. Ihe a~ueous 10 portion was e~trac7~ed wi7~h further e7~hyl`àcetate, and~the combined organics were washed with brine, dried (Na2SO4) ànd'evaporated. Chrbmatography~on silica gel, eluting with 0-30% e~hyl acetate/chloroform, gave the title comp~und (5.07g,'73~O~as a~pale greenish soDd. ~

NMR (CDC13) 7~: 1.44 (2H, m), 2.75 (2H, t, J 6), 3.3~1 (2H, t, J 6), 3.92 ~lH, b s), 6.45~(1H, d, J 9), 7.09 (1H,~dd, J 9, 2), 7.16 (1H, d, J 2~, 7.65 (1H, b s).

Description 27 N-~t~Acetyl-1~2,3,4tetralhydro-6-quiodyl)trifluoroaoeta~ide (D27) 2O ~ N~ ,2,3,4-Te~r~hydro-6-ql~inolyl)t~ifluoroacetamide (D26) (5.64g, 23~.1 mmol) and ace~
:: :: : chlonde: (2:.0 ml, 28 mmol) were sti~re,d:in dichloromethane~'100 ml~ as pyridine: (2.25 ml, 28~mmol) was added.~ The mL~ was sti~re~d~for ff.5h, when~water (l00 ml) was added.
`Ater vigorous stirrulg for 0.25 h, it~was~acidified~with~5M~hydrochloric acid, and separà~d.~ or~a~c po~on~was washed~wl~bdne,~;~ed ~a~S~), ~d evaporated, 25 ~ ~giving ~e ~e com~und (S~g, 79~) a ~a cr i s ;` ~(C~13) ~8 ~ 199' H,-m (3H, s),~2.57 (2H, ' J 6), 3.78 (2H, ~ J 6), ` 7.3~(b), 7.52 (1H, b s), 8.08 (1'H, b s).

A~I-~ 'no l~n`linë~(D~) N-~I'~cetyl-1,2,3,~t~6-qu~oiyl)~uoroace~d ~27)(1.8 g,6.5~mmol)~
w~s~d~è~anol ~15~ml)','~d`~ium~dè (~52g.~ 3.0 m~o~) w~ ~ded~
wa~r~ ~em' ur ~ ~d`at b` t~ 0.5~h,~ d~enhe to~
35~ `reflùx `vèr~0.25~h -~r;O. h~ ' fl' ~ ' ,;a - ~d wi~M
odcàcid,b~ed~wi~sodium~ d '~wa~ (100~ ~d~

W094/04S33 2,~ pcr/Eps3/o2o3 extracted wiLh chloroform. The extract was dried (Na,S04~ and evaporated tO give the ti~le comFround (1~38g, ~I00%) as a brown oil con~aining residual chloroform (NMR).
..
NMR (CDCl3) ~ 92 (2H, rn), 2~27 (3H? S), 2~60 (2H, m), 3.67 (2H, b s), 3~79 s (2H,bm),6~5(2H,m),6~87(1H,bd,J6).

l~cscripfion 29 1~Acetyl~(2,~diethoxyethyl3an~Jn~1,2,3,~tetra}lydroql~inoline (D29) l-Acetyl-6-amino-1,2,3,4-tetrahydroquinoline (I~2g) (2.3~g, 12.4 mmol) and N,N-dusopropylethylamine (2.7 ml, 15.5 mmol) were st~rred in 1,2-dichloroethane (50 ml) under Ar. 2,2-Dietho~yethyl trifluoromethanesulphonate (3.78g, :ca. 90% purity, ca 13 mmol) was added dropwise in 1,2-dichloroethane (lO ml)`over ~ min~ The mL~ture was then stirred at reflux for 0.5 h, cooled, ivashed with water, driéd (Na2S04) and evaporated to give a black oil. This material was combined with that obtained by ~n identical procedure using 1~40g of the aminoquinoline reagen~, and chromatographed on silica gel ~ .
using 0-100% e~yl acetate/chloroform~ This gave the dtle compound (3.72g, 61%) as an .
amber oil, contaminated with a little :dialkylated material (N~)~

NMR (CDC13) ~: 1.25 (6H, t, J 7), 1.92 (2H, m), 2.20 (3H, s3, 2.63 (2H, b m), 3.25 (2H, tt J S)t 3.5-3.9 (7H, m)t 4.69 (lHt tt J 6:), 6.45 (2H, m), 6.8~ (lH, b d, J 6)~

Description 30 S Acetyl-l trinuoroacetyl-5,6,7,8-te~rahydro~lH~pyrrolo[2,3~g]quinoUne(D30) ~.
l~Acetyl-6-(2,2-diethoxyethyl)amino-1,2,3,~tetrahydroquino~e (I:)29) (3.72g, 12.2 mmol) was stirred at 0~ C under Ar in: a mLl~ture of trifluoroacetic acld (20 ml) and ~ :
tri~luoroaceùc anhydride (20 ml): for 0.5 h. Further trifluoroacetic acid (30 ml) was added, ~ :
and the soludon was then stirred at~reflu~ for 90 h, cooled, and evapo~rated to give a black gum. Chromatography on silica gel,:eluting with 0-60% ethyl acetate/chloroform, ga~e~
the,title compound (2.77g, 73%) as an amber oil.
:
DCl3/D6-I:)MS~) ~: 2.03 (2H, m), 2.25 (3H, s), 2.87 ~2H, t, J 6), 3.80 (2H, t, J 7), 6.83 (1H, d,:J 4), 7.51: (2H, m), 8.2~(1H,~s) : ~: : :

2L~2721 1~
WO 94/04533 pcr/ Ep93/o2o3 Descrip~on 31 5-Acetyl~,6,7,8-tetrahydr~1H-pyrrolo~2~g~q ~inoline (D31~ ~ -5-Acetyl- 1 -trifluoroacetyl-5,6,7 ,8-tetrahydro- 1 H-pyrrolo~2,3-g]quinohne (D30) (2.76g, ~`

8.9 mmol) and anhydrous potassium carbonate (3.7g, 27 mrnol) were stirred in methanol 5 (S0 ml) for 1 h. The mixture was ~hen concentrated in Y~C~O, diluted with water (lOû ml), and extracted with chloroform. The extract was dried (Na2S04) and evaporated, giving ~he title compound ( 1.40g, 73%) as an orange-brown solid. NMR showed a mi~nlre of rotamers in approximate ratio 9~

lo NMR (CDC13) ~: 1.97 (2H, major, m), 2.07 (2H, minor, m), 2.22 (3H. both, s), 2.73 (2H, major, t, J 6j, 3.01 (2~, minor, t, J 6), 3.86~ ~2H, both, t, J 7), 6.52 (lH, both, m), 7.20 (2H, both, m), 7.34 (IH, major~,~s), 8.33 (lH, both, b).

Descr~p~on 32 ~ ~ ~
S-Acetyl-1-methyl-5,6,7,&tetrahydro~1H-pyrrolo[2,3-g]quinoline (D32) -~ S-Acctyl-5,6,7,8-tetrahydro-lH-pyrroloi2,3-g]quino~e~(D31) (1.39g, 6.5 mmol) in dry i d~methylformarnide (DMF) (20ml) was added, with stirring under Ar, to a suspension of ~ `
sodium~hydride (80% in mineral oll, 0.25g, 8.3 mmol)~in DMF (5ml). After s~ning for 20 mi~, iodomethane (0.61 ml, 9.8~mmol) was~added. ~e~resulti~g suspension was stirred ~; 20 for lh,~ diluted with water (lOO ml), and e~tracted wi~ ethy!~ acetate. The e~act was~
wa~hed with water and bnne, dried ~a2S04) and~ evapora~ed ~o give a gum.
Chromatography on silica gel,~eluting with 0-100% e:,~yl acetate/chloroform, gave the title compound (0.97g, 65%) as ~a~pale, straw coloured oil~which~solidif1ed on `standing. NMR
showed a mixture of rotamers in appro3~imate rauo 6 1. ~

(CDC13) ~ 1.97;~aH, both, m3, 2.20~(3El,~both, s), 2.75 (2H, ma)or,~t, J 6), 2.~8 ~2H, minor, t, J 6),~3.78 (3H,~both, s), 3.84~(2H,~both,~t, J 7), 6.45 (IH, both,;d, J 3), 7.0~ (1H, both, d, J 3),~ 7.12; (1H, both,~s), 7.31 ~IH. both, s).~

}-Me~1-5,6,7,~te~ydr~1H-p~o[2~glqr'nolinè ~D33) i`l`'~J`~ ; ' 5-Acetyl-l-mè~ yl-5.6,7,8-~y~o-~lH-p~o~2,~] ' ~ ~e;(D32) (0,96g,4.2 mmol)~wa di~olved~ 1(10mlb~d2.5~M~so~ ml)~w~added~
~ mi ~ re ~w~ s~d at reflux~under`~for~23h" cooléd, d~ut with w~r ( OO~ml),~
35 :~dex ac~dwi~e~yl~ace~ta~. ~eext ctw~d~ )~d~evap r ~dto ' e~
e ti~ê~compound~(O.~g,~1%)~ a~ght brown gum.

Wo 94/04533 2,~ pcr/Ep93/o2o31 NM~ (CDC13) ~: 2.00 (2H, m), 2.95 (2H, 1, J 6), 3.0 (lH, b), 3.30 (2H, ~, J S.S), 3.68(3H,s),6.20(1H,d,J3),6.72(1H,s),6.87(1H,d,J3),6.92(1H,s).

I)escriptior~ 34 3-(1-M~thyl-S-nitro 4-indolyl)propionitrile tD34) 2~ Methyl-S-nitro~-indolyl)ethane methanesulphonate (D9) (1.60g, 5.4 mmol) and sodium cyanide (0.53g, 10.8 mmol) were stirred in dry dimethyl sulphoxide (15 ml) a~
100 C under Ar for Sh. After cooling, the mi~nlre was diluted with ethyl acetate (lS0 10 ml), washed with water, dried (Na2S04) and evaporated to give the title compound (1.16g, 94%) a~ a brown solid.

NMR (CDCl3) ~: 2.93 (2H, t, J 7), 3.60 (2H, t, J 7), 3.87 (3H, s), 6.80 (lH, d, J
3),7.3(2H,m),8.05(1H,d,J8).
Descrip'don 35 3~ Mlethyl~S~nitro~4.indolyl)propanoicacid ~D3~) 3~ Met~yl-S-nitro-~indolyl)propionitrile (D34) (1.16g, S.l mmol) was s~irred at reflu~
in concentrated hydrochloric acld (150 ml) for 7.5 h, Ater cooling, the dark mi~ture was:
20 extracted with ethyl acetate; the extract was dried (Na2504) and evapora~ed ~o give the dtle compound (0.74 g, 59%) as a brown solid.
:
(CDC13)~: 2.88(2H,I,J7),3.55~2H,~J73,3.84(3H,s),6.76(1H,d,J
3),7.21 (lH,d,J3),7.25(IH,d,J8),7;98(lH,d,J8).
~5 ~cription 36 .
Methyl~ (1.m~thyl-5-nitr~4~indolyl)propanoate (D36) ~ ~ ;
3-(1-Methyl-5-nitro-4~indolyl)propanoic acid (D35) ~0.94g, 3.8 mmol) was~s~irred in me~anol (10 ml) as thionyl chloridé (l ml) was added dropwise.~ ~The milcture was then, ~
30 stirred at reflux for 2h, and evaporated to a dark oi}. Chromatography on silica gel, eluting with d chloromethane, gave the~ title ~ompound (0.58g, 58%) as a pale yellow solid.

NMR (CE)C13) ~: ~ 2.81 (2H, t, J 7), 3.55 (2H,~t, J 7),~3.70 ~3H,~s), 3.84 (3H, s), 6.73(1H,dtJ3),7.20(1H,d,J~3),7.24(1H,d.J8),7.97(1H,d,J~8).

- 24~-~: `
WO 94/0~4533 21 ~ 2 721 pcr/Eps3/o2o3l ~ ~
Des,crip~,on 37 3~ Met~,~yl 5-nitro-~indolyl)-l~propanol (D37~
Methyl 3-(1-methyl-5-nitro-4-indolyl)propanoate (D36) (0.46g, 1.~ mmol) was stirred under ~r in t~tr~h,ydrofuran (25 ml) as li~hium aluminium hydr~de (O.lOg, 2.6 mmôl3 was added por~ionwise. After 3h. water (O.S ml), 2.5M sodium hydroxide solution (0.75 ml) j`
and water ( l.S ml) were successively added. The mixture was ~hen dried (Na2S04) and evaporated to a brown oil. Chromatography on silica gel, eluting with 0-20% ethyl acetate in dichloromethane, then gave the title compound (0.39g, 95%) as an orange solid.

NMR (CDC13) ~: 2.0~ (2H, m), 3.34 (2H, t, J 7), 3.78 (2H, q, J 6), 3.85 (4H, m),6.77(1H,d,J3),7.18(1H,d,J3),7.22(1H,~d,J8),7.96(1H,d,J8) Description 38 3~(1-Methyl~ni~o-4indolyl~1-propyl methanesulphonate (D38) This was prepared from 3~ methyl-S-nitro-4-indolyl)-1-propan,ol (D37) (0~39gr 1.7 mmol), following ~,e procedure of Description 8. This gave the title compound (0.54g, ~100%) as a brown oil, which was used withoul purificadon.

- NMR (CDC13) ~: 2.25, (2H, m), 3.05 (3H, s),~3.36 (2H, t, J 7), 3.84 (3H, s), 4.37 (2EItt,J7),6.73~1H,d,J3),7.21 (1H,diJ3),7.25(1H,d,J~,7.98(1H,d,J8).
, ~
rip~on 39 ` ~ ` ~Metl~yl 6,7,8~9~tetrabydro-3H-pyrrolo~3,2-f~quinol-ne(D39) This was prepared from 3~ methyl-5-niuo~indolyl)-I-propyl methanesulphonate (D38) ~0.54g, 1.7 mmol), following the procedure of Descripuon lO.~ Neutralisation with sodium hydrogen carbonate solution ~gave ~the title compound (0~21g, 65%), as a brown oil.

NMR (CDC13) ~: 2.05 (2H, m), 2~95 (2H, t, J 63. 332 (2H, t, J 6), 3~63 (1H, b), 3-73t3H.s).6.70i(1H,d.J3~.6.86(1H.d.J8).6.g6(1H,d.J3;),7.00~1H,d,J8) l~escription 40 ~ 3 Methyl 8-(N,~-dîmethylaminomethyl)-3~ pyridyl-carbamoyl)-2,3 dihydropyrrolo~3~e]indob 6~Methyl-3-(3-pyndylcarbamoyl)-2,3-dihydropyrrolo ~3,2-elindole lE2) (0.65g, ~ 0~0022moles) suspended in l,4-dioxan (lOmi) was~added to a mixture of 37% a~ueous ' ;25- ~ ~

:: :

W0~)4/0453~,~ 42~' pcr/Ep93/o2o3l -formaldehyde (0.2ml) and 33~ dimethylamine in ethanol (0.46ml) in a mixture of 1,4-dioxan (~Sml) and glacial ace~ic acid (3.5ml) a~ 5C with stiITing. The mixture was s~irred at ambient ~emperature for 20hrs ~hen diluted with wat~r (~Oml) and basified with 10% aqueous sodium hydroxide. FiltrnLion gave ~he title compound (D40) (0.66g, 85Yo) ns an off white solid.

NMR (I~6^DMSO) ~: 2.17 ~6H,s), 3.41 (2H, s), 3.50 (2H, t, J-8Hz), 3.71 (3H, s), 4.19 (2H, t, J-8Hz). 7.11-7.17 (lH, m), 7.26-7.34 (lH, m), 7.88 ~lH, d, J=8Hz), 7.9S-8.01 (lH, m), 8.16~8.22 tlH, m), 8.58 (lH, s), 8.74 (lH, d, J=4Hz) I)escrip~oll 41 2,3~Dihydro~ imidazolylcarbollyl)-S-methyl-lH-pyrrolo[2,3-t'lindole (D41) To a solution of carbonyldimidazole (0.71g, 4.4mmol) in;DMF (25ml) was added dihydropyrroloindole (D6) (0.69g, 4mmol) in DMF ~Sml). The mixture was stirred for lh at 110-140C7 ~hen cooled and poured into water. After allowing the precipi~ate t'o fo~m, solid material was filtered off, washed wi~h water and dried. Crude product was recrystallised from dichloromethane/petrol to give the dtle compound (0.45g, 42%), m.p.
178- 1 80C.

20 NMR (D6-DMSO) ~: 3.22 (2H, t, J=8), 3.77 (3H~ s), 4.24 (3H, a, J~8), 6.40 ( l~I, d, J=4), 7.08 (lH, s), 7.28 (lH, d, J=4), 7.38 (lH, s), ~7.69 (lH, s), 7.83 (lH, broad s), 8.24 (IH, s).

Descrip~on 42 ~ ;
25 1~Acetyl~2~methyl indoline (D42) : ~
2-methyL;ndoline (S.Og, 0.037 mol? in aceuc anhydnde (40 ml) and py~dine (2 ml) was hested under argon at reflux for A h. The mkture was;cooled, poured into wa~er (100 ml), allowed to stand for 30 mins, extracted (EtOAc 2x 250 ~1), the combined organic solution washed (K2C03 soludon),l and dned ~Na2S04). I h$; soludon was f~tered, evapora~ed lo 30 dryness under reduced pressure and purified by column chromatography ~SiO2, Et~O) to afford the product as a yellow oll (6.57 g, 96%) which crystalliæd on standing.

NMR (CDCl3) ~: i.30 (3H, d), 2.30 (3H, s?,~2.68 (lH, d), 3.41 (lH, dd), 4.49 (lH, m), 7.04 (lH, t), 7.~4 (2H, m), 8.18 (lH, d).

.

I .

W094/04533 1 ~ 721 pcr/Eps3/o2 De~scrip~on 43 1-Acetyl-2-m~thyl-S~I~itroindolirle (D43) l-Acetyl-2-methylindoline (D42) (6.57g, 37.5 mrnol) was dissolved in AcOH (56 ml) and a mixture of conc. HNO3 (16 ml) and AcOH (8 ml) was added. The blue solution was5 heated to 50 C under Ar, whereupon the solution was red/brown and began to ernit brown fumes. After stimng for 2h at 50 C, the solution was poured ihto water (500 ml), extracted with E~OAc (300 ml), washed with sa~ aq. K2C03 solution (200 ml), dried (Na~O4), evaporated under reduced pressure to give an orange oil. This was purified by column chromatography (SiO2) to afford an orange oil (7.82g~ 95%) which solidified on 10 standing.

NMR (CDC13) ~
1.3 (3H, d), 2.30 (3H, s), 2.72 (lH, d), 3.41 (lH, dd), 4.58 (lH, m), 8.10 (3H, rn).

15 Description 44 l-Acetyl-S-an~ino-~methyiindoline ~
l-Acetyl-2-methyl-S-nitroindoline (D43), (16g, 0.073 mol) was dissolved in EtOH (180 ml), 10% Pd-C (0.3g) added and the suspension hydrogenated at 50 C and 50 psi on a Parr rocker hydrogena~or for 6 h. The mi~cture was filtered through ce~te and evaporated 20 to dryness to afford the produc~ (D44) (14.0g, 100%) as a ~ed oil.

~CDC13) ~: 1.30 (3H, d), 2.24 (3H, s), 2.58 (lH, d), 3.38 (lH, dd), 4.41 ~lH, m), 6.58 (2~, m), 7.98 (lH, d). ~ ; `
~ ' :: :
25 Descrtption 45 l-Acetgl-5-[(2,2~dimethoxyethyl).amino].2~me~hylindoline; (D45) l-Aceyl-S-amino-2-methylindoline (D44), (5.0g, 0.027 mol)~was dissolved in EtOH (100 ml), 10% Pd-C (0.5g) added followed by glycolaldehyde dimethyl acetal (5.53g~ of a 60%
! ~ ~ .i soludon~ water, 1.i2 çquiv.) l~e mLsture was hyd~ogenated at rtp with sti~Ting ~ven~ight, 30 filtered through celite, evapora~ed to near dsyness, taken up in EtOAc (200 ml), washed (H~O, brine), dried (Na2SQ4), and evaporated to ~ess under reduced pressure to afford the produc~ (D45) as a brown oil (7.69g, 95%).
: ~:
N~ (CDC13~ ~: 1.30 (3H, d), 2.24 (3H, s), 2058 (lHi d), 3.23 ~2H, d), 3.33 (lH, 3S dd), 3.41 (6H, s), 4.41 (lH, m), 4.58 ~1H, t3, 6.51 (2H, m), 7.98 (IH, d).

27 - ~

~: :: ~ :

W0 94/04s33 ~ PCr/EP93/0203 l~escI~p~on 4fi 1-~c~ 2-1nethyl-~3-dihydropyrroI~[2,~-indole (D~K) l-Acetyl-5-[(2,2-dimethoxyethyl)amino~-2-methylindoline (D45) (7.5g, 0.027 mol) was dissolved in TFA (32 ml) and cooled to 0 C ùnder Ar. TFAA (30 ml) was added~and the brown solution s~i~red at 0 C for 30 mlns. l~A (50 mlj was added and the mixture I~
heated at reflux for 6 days, evapora~ed to dryness and purified by column chromatography (SiO2, CH2C12/MeOH 0.5-0.75%) to afford the product as a pale pink solid (4.84 g, 58%). 2.84 g, (9.2 mmol) was dissolved in MeOH (70 ml) and anhydrous K2C03 (1.90 g, 1.5 equiv.~ added. The mL~ture was stirred vigorously for lh, heated briefly to 40 C, cooled, evaporated to dryness and partitioned between water and CH(~13. The organic layer was dried (Na2S04) and evaporated to dryiless under reduced pressure to afford the product (D46) (1.89g, 96%) as a pale brown solid. ~ ~
:
NMR (CDC13) ~: ` 0.72 (3H, d), 2.17 (lH, d), 2.52 (3H, s), 2.91 (lH. m), 3.98 (lH, m), 5.80 (lH, s), 6.58 (lH, sj, 6.68 ~IH, s), 7.70 (lH, s), 9.95 (lH, s, N-H) Descr~p~on 47 2~Methyl.2,3-dihydropyrrolo~2,3~flindole (D47) l-Acet~ -methyl-2,3-dihydropyrrolo [2,3-fl indole (D46) (2.55g, 0.0119 mol) in EtOH
(30 ml) and 10% NaOH (120 ml) was heated at reflux under Ar overl~igh~ Ihe mi~cnlre was extracted with EIOAc (2 x 200 ml) the organic solution dried (Na2S04), evaporated to dryness and purified by column chromatography (SiO2, Et20/MeOH 1 %) to afford the product (D47) (1.4g, 68%). ~ ~
`: ~. ' : ;
N~ (CDC13) ~: 1.32 (3H, d), 2.71 ~lH, dd), 3.19 (lH, dd), 3.98 (lH, m), 6.38 (lH, s), 6.83 ~lH, s), 7.07 (iH, s), 7.12 tlH, s), 7.92 (lH, bs, NH) .
Description A~eql-2~s~dimethyl-2~3~hydro~pyrrolo[2,3~ ndole ~
3 0 As for Description 5 using; 1-acetyl-2-methyl-2,3-dihydropyrrolo~2,3-f3indole (D46) ( 1.35g, 6.3 mmol) in ~ D~IF (10 ml), NaH (265 ;mg of 80% suspension~ oD) in DMF(10 ml) and MeI (0.55 ~ml, 1.4 equiv.). After tho reaction was complete, ~e mLlcture was i, evaporated to dryness,~par~idoned be~ween sat a~ K2C03 (1GO ml) and CH2Cl2 (3 ~ 100 ` ml),` the organic solutions dried, combined and evaporated to ~ess with subs~quen~
3~ pu~ificadon by column chromatography (SiQ2, Et20/MeOH 2-20%) to afford the pro~uct ` ~ ~ (D48) as a pale yellow sol~d (1.16g, 81%).

WO 94/04~33 2 1 ~1 2 7 2 1 pcr/Ep93/o2o31 N~/fR tCDC13) ~: 1.30 (3H, d), 2.32 (3H, s), 2~40 (lH, d), 2~75 (lH, dd), 3.76 (3H, s, NMe)`, 4.50 (lH, m), 6~47 (lH, s), 7~00 (lH, s), 7.12 (lH, s), 8.4l (lH, s)~

s Descrip~on 49 2,5 Dimethyl-2~dihydropyrrolo~2,3-flindole (D49) l-Acetyl-2,~-dimethyl-2,3-dihydropyrrolo[2,3-flindole (D48) (l.lg, 4.82 mmol) in EtOH
(40 ml) and 10% NaOH (3.45 ml, 1.8 eq) with solid NaOH tl.93, 10 eq) ~was heated at reflux under an Ar atrnosphere (Firestone valve) for 6 h, partitloned bet~,veen H ~O and CH2C12, the orgar~ic solutions dned (Na2S04), evaporated to dryness and purified by column chromatography (SiO2, CHCl3/MeOH 10%) to a~ord the product as an oil ~370mg, 37%).

N~ (CDC13) ~: 1.30 (3H, d), 2.72 (lH, dd), 3.22 (lH, dd), 3.7g (3H, s, NMe), 4.00 (IH, m), 6.28 (lH, d), 6.89 (lH, d), 6.80 (lH, s), 7.08; (IH, s).

Example l `~ 5~Me~yl~ 3~pyridylcarbamoyl)-2,3~dihydropyrrolo[2,3~ ndole (El) ; ~ i Nicotinoyl azide (0.5Sg, 3.8 mmol) was stirred at reflux under nitrogen in dry toluenc (20 ml) for 0.75h, and cooled to ambient temperature. 5-Methyl-2,3-dihydropyrrolo[2.3-f~indole (I36) (0.59g, nominally 3.4 mmol) was added in dichloromethane (20 ml) was stirr~g, with immediate precipitation. The suspension;was stirred for Z.Sh, and ~hc solid was then filtered off, washed with 1:1 dichloromethane/toiuene, and ~horoughly dricd.
Ihis gave the dtle compound (0.60g,~60%) as a light grey powder.

NMR (D6-DMSO) ~: 3.28 (2H, t, J 8), 3.73 (3H, s), 4.17 (2H, t, J 8), ; 6.81 (1H, d, J 3), 7.1-7.35 (3H, m), 8.0 (1H, m), 8.03 (lH, s), 8.21 (lH, m), 8.63 (lH, s), 8.7fi (lH, d, J 2).
j:
.
Found: C, 70.1; H, 5.6; N,~ 18.8%
C17H16N4~ requlles C, 69.8; H, 5.5; N, 19.2%
Found: M~ 292, Cl7H16N40 requires ~92 :

2g- ~ ~

WO 94/04533 ~ 'r~ pcr/Ep93/o2o3 Example 2 6~Methyl-3-(3-pyridylcarbamoyl~2.3-dihydrop~rolo~3,2~]indole (E2) 2-(1-Me~hyl-5-nitro~-indolyl)ethyl methanesulphonate (D9) (0.38g, 1.3 mmol) was hydrogenated over 5% palladium on charcoal (0.23g) in dry DMF (20 ml) at 80 p.s~i. H2 S for 2h, diluted with ethanol (80 ml), filtered through Kieselguhr, and evaporated to a brown gum. This was dissolved in dichloromethane (10 ml~, and reacted with 3-pyridyl isocyanate, formed from pyrolysis of nico~noyl azide (0.20g, 2.35 mmol) as described in Example 1, but adding ~riethylamine (0.18g, 1.3 mmol) to the isocyanate before addition of the crude mesylate salt. After a reaction time of 16h, filtration, wa~hing, and drying as before, gave the title compound (0.16g, 44%) as a light green powder.

NMR (D6-DMSO) ~: 3.33 (2H, t, J 8), 3.77 (3H, s), 4.Z2 (2H, t, J 8), 6.28 (lH, d, J
3),7.23(1H,d,J8),7.3(2H,m),7.89(1H,d,J8),8.0~1H,d,J8),8.2(1H,d,JS),8.61 (lH,s),8.75(1H,d,J2).
..
Found: C, 66.1; H, 5.4; N, 17.8%
C17H16N40. H20 requires C, 65.8; H, 5.8; N, 18.0%
Found: M+ 292, C17H16N40 requires~292 Example 3 ~ ~
5,7~1:)imethyl 1~ pyridylcarbamoyl)~ dihydropyrrolo[2,3-~ind~le(E3) This was prepared from 5,7-dimethyl-2,3-dihydropy~olo~2,3-f~indole (D16) (0.30g,nominally 1.6 mmol) foUo~nng the procedure of E~xample 1. This gave the title compound (0.19g, 42% from (D15)) as a whi~e solid, sti}l containing traces of toluene (NMR).
N~ ~D6-DMSO) ~: 2.19 (3H, s), 3.27 (2H, t, J ~), 3.67 (3H, s), A.18 (2H, t, J 8), 6.96 (lH, s), 7.21 (1H, s), 7.32 (lH, dd, J 7, 4), 8.00 (lH, s), 8.02 (lH, dd, J 7, 2), 8.22 (lEI, dd, J 4, 2), 8.62 (lH, s), 8.77 tlH, s).

30 Found C, 70.6, H, 6.0~a, C IgH 1 8N4 requlres C, 70.6; H, 5.9%
Pound: M~ 306, Cl~HIgN4O requires 306 1~
Exsmple ~
~-(3-Pyridylcarbamoyl)-2~dihydrop~olo~2~flindole (E4) j `
35 This mat~rial was isolated by ch~omatography on silica gel, eluting with 0-S% me~hanol in chloro~onn,~ as an impu}ity in~ a sample of 5-methyl-1-(3-pyr~dylcarbamoyl)-2,3-:

j~.....

WO 94/04533 2 1 ~1 2 7 ~ 1 - PCTtEP93/02031 ``
dihydropyrrolo~2,3-~indole (El~. Recrystallisa~on from ethtanol/petroleum eLher ~b.p. 60-80 C) ga~e the cornpound as fine grey needles, m.p. 207-8 C (dec.), slill con~ining e~hanol of crystallisa~ion. 1~ can also be prepared by hydrolysing D4 and then coupling t with 3-pyridylisocyanate. ` ~ ~.
NMR (D6-DMSO) ~: l.lS (L, J 7; ELOH),3.34 (2Hi t, J 8~, 3.55 (4uintet, J 7; EtOH), 4.26 (2H, t, J 8),4.48 (t, J 6; EtOH), 6.42 (lH, s), 7.31 (2H, s), 7.42 (lH, dd, J 7, 4), 8.05-8.2 (2H, m), 8.31 (lH, d, J 4), B.72 (lH, s) 8.86 (IH, s), 10.95 (lH, s) 0 Found: C, 67.2; H, 6.1; N, 17.6%
C16H14N4- 0.75(C2H60) re~uires C, 67.2; H, 6.0; N, 17.9%
Found: M+278, Cl6,~14N4Orequires~2,78 Example S
6-MethyI-3-(4pyridylcarbamtoyl)~2,3-dihydrop~rolo[3,~e~indole (E5) The title compound was prepared from 4-aminopyridine, l,l'-carbonyldiis~ida~ole,6-methy~-~2,3-dihydropyrralo[3,2-e]indole) hydrochloride (D10) and triethylamine in methylene chloride/dimethylformamide. The ~eaction mi~c:ture was poured onta water to afford the title compound in 98~o yield, m.p >230 C.
NMR (D6-DMSO) 8: 3.30 (2H, ~, J 7), 3.75 ~3H, s), 4.25 (2H, t, J 7),6.30 (lH, d, J
4),7.21 tlH, d, J 10), 7.30 (lH, d, J 4),7.58 t}H, s),7.62 ~lH, s),7.90 (IH, d, J 10)7 8.31 (lH,s),&.36tlH,s),8.75(1H,s).

2s Pound: C,69.5;H,5.6;N, 19.1%i C17H16N40requ~resC,69.8;H,5.5;N, 19.1%
Pound M~ 292, C17H16N40 ~equires 292.

ExampIe 6 6-Methyl~3-(~pyridylcarb~noyl)-2,3-dihydropyrrolo[3,2-elindole (E6 30 The title compound was prepared ~rom 2-aminopyridine, 1,1'-ca~fonyffldiimidazole, 6-me~hyl-(2,3-dihydropy~olo~3,2-e]indole) hydrochlodde (D10) and triethylamine using a procedure similar to that described for Example S, in 39% yield, m.p 143-4 C.

N~ (D6-DMSO) ~: 3.35 (2H, t, J 7}, 3.85 (3H, s), 4.38~(2H, t, J 7), 6.40 (lH, d, J ~`
35 ~ 4), 7.08-7.1~ (lH, m), 7.33 (lH, d, J 7),7.41 (IH, d, J 4),7.79-7.89 (lH, m), 7.95-8.0S
(2H,m),8.39(1H,d,J4),9.00(1H,s). ~ ~ -WO 94/04~33 ~ L pcr/E

Found: C, 69 6; H, 5.6; N, 19.1%, C17E~16N40 requires C, 69.8, H, 5.5; N, 19.2%
Found M+ 292, C17H~6N40 requires 292 5 Example 7 5~Methyl~ 2-pyridylcarbamoyl~2,3-dihydropyrrolo~2,3-f~indole(E7) The ti~le compound was prepared from 2-aminopyr~dine, 1,1'-carbonyldiimidazole and S-methyl-(2,3-dihydropyrrolo~2,3-~indole) (D7) using a procedure simllar to that described ior Example 5, in 75% yield, m.p 137-8 C.
: : :
NMR (D6-DMSO) ~: 3.25 (2H, t, J 7), 3.75 (3H, s), 4.21 (2H, t, J 7), 6.31 (lH, d. J4), 7.03(1H,t,J4),7.20(1H,s),7.30(1H,s),7.75(1H,~J7),7.95(1H,d,J7),8.04(1H, s), 8.30 (lH, d, J 4), 8.95 (IH. s).

15 Found: C, 66.0; H, 5.6; N, 18.0%, C17H16N40. H20 requ~res C,65.8; H,5.8; N,18.0 Found: M~ 292, C17H16N40 requires 292 Example 8 ~ `
S-Methyl~1-(4-pyridylca~bamoyl) 2,3-dihydropyrrolol2,3-f~indole ~
The-title compound was prepared from 4-aminopyridine, 1,1'-carbonyldiimidazo~ and 5-~: methyl (2,3-dihydropyrrolo[2,3-f~indole) (D7) using~ a proceduse similar to tha~ dcscnbcd for E~xample S, in 84% yield, m.p 251-3 C. : ~ ~ :

N~ (D6-DMSO) ~: 3.25 (2H, t, J 7), 3.72:~(3H, s), 4.18 (2~, t, J 7), 6.32 ( 1 H. d. I
25 4), 7.18 (lH, d, J 4), 7.27 (IH, s),~ 7.62 (2H, d, J 7),~ &.05 (IH, s), 8.35 (2H, d, J 7), 8.85 (lH~ s). : ` ; :
~:: . : : : :
: , : , ,, ~ ;
~ound: C, 69.2; H, 5.7; N, 19.0%, C~17H16N4O requires C, 69.8; H, S.~; N, 19.2% : :: :
~Foulnd: M~292. jC17H16N4reqUlreS29 3~ ~

S~Methyl-l-(~pyridyicarb~noyl}2,3,6,7-tetrahydr~pyrrolo[2,3~qindoJe (E9): ~ ¦
S-Me~hyl~ 3-pyridylcar~amoyl~2,3-dihydropyIIolo~2,3-flîndole (El3 (0.8g, 2.7:mmol) : ~
was treated with sodium cyanoborohydride (0.86g, 13.7:~mmol) in glacial ace~ic acid (20 ~ j 35 mlj at room temperature for 4h. Wa~er (lOO~ml) was added and the mi~nlre b~sified with 10% aqueous sodi~m hydroxide. Extlaction wi~h~dichloromethane followed by drying ~

: : , :: : ~ -~`;
~; `'.
WO 94/04533 21 4 2 721 pcr/Ep93/û~o3l (Na2S04) and evaporation to dryne~s ~ave a solid. Recrystallisa~on from methanoV60-80 1`
petrol gaY~ ~he ti~le compound (E9) (0~43g,53%) as a whi~e crys~lline solid, m.p. 153-155 C. i:

NMR~D6-DMSO~: 2.62(3H,s),2.80(2H,t,J8),3.05(2H,t,J8),3.17(2H,t,J8), 4.10(2H,t,J8),6.40(1H,s),7.30(1H,q,J4),7.65(1H,s),7.91-7.98(1H,m),8.I9~lH, d,J4),8.55 (lH,s),8.72(1H,d,J4) Found: C, 68.7; H,6.2; N, 18.9%, C17HlgN4O requires C, 69.4; H, 6;2; N, 19.0%
Found: M+ 294, C17HlgN4O requL~es 294 Example 10 S-Ethyl~ pyridylcarbamoyl)-2,~dihydropyrrolo~2,3~flindole ~10) The title compound was prepared from 5~thyl-2,3-dihydropyIrolo~2,3-f~indole (D18) and 3-pyndylisocyana~ (prepared in situ from n~co~inoyl azide) in 58% yield using a procedure s~rs~ilar to that for El, m.p. 202-203 C.

NMR (D61:)MSC)) ~: 1.33 (3H, t, J 8), 3.28 (2H, t, J 10), 4.16 (4H, m), 6.31 (lH, d, J
3),7.24 (lH, d, J 3),7.30 (lH, s), 7.32 (lH, m), 8.00 (lH, m), 8.03 (lH, s), 8.22 (lH, m), 8.65 (lH, s), 8.77 (IH, s).

Found~ , 70.70; H, 6.01; N, 18.46~o, ClgHlgN4O requires C,70.57; H, 5.92;
N, 18.29~o `
Found: M~ 306, ClgHlgN4O requires 306 ` l~x~unple 11 5 n Propyl~l ~pyr~dylcarbamo~ 2,3-dihydropyrrolo~2,3~qindole (Ell) Prepared as in Example 1 using nlcotinoyl azide (0.19g, 1.4 mmol) and 5-propyl-2,3~
dihyd~op~rrolo~2~3-f~indole (0.23g, 1.2 mol). Ch~omatography over silica gel elutislg with t 5% MeOH/C~2CI~ ~fforded t~e ti~le compound (0.27g, 70%) as a pale green powder. ~r ~ , ;~ NMR (CDC13) 8: 0.93 (t, 3H, J=8.4Hzj, 1.87 (m, 2H, J=8.4H~),3.31 (t~ 2H, J3g.4~1Z), 4.0~ (t, 2H, J=8.4Hz), 4.28 (t,: 2H, J=8.4Hz), 6.45 (d, llH, J=2.8Hz), 6.77 (br~s, lH), 7.06 (d, lH9 J=2.8Hzj, 7.18 (s~ lH), 7.29 (m, 1~, ), 7.92 (s, lHj,7.85 (m, lH), 8.30 ~;-(dd, lH, J=2.8Hz), 8.~1 (s, IH) -t !~
W O 94/04533 2~ P ~ /EP93/02031 Found: C;70.54 H;6.34 N;17.39 Cl9H20N40-'~6H20 requires C; 70.58, H; 6.39, N; 17.33 Found: M+ = 320, C 1 gH20N4Q requu~- 320 5 Ex~unp1e 12 5,6-Dimethyl-1-~3-pyr~dylcarbamoyl~.2,3-dihydropysTolo[2,3-f~indole (E12) This was prepared from ~,6-dime-hyl-2.3-dihydropyrrolo~2,3-flindole (D23) (0.30g, nom ~ally 1.61 :m mol),fo~owing ~he procedure of Example 1. This gave ~e ~e compound(0.219g, 39% from D22), as a buff powder, containing residual CH2C1 ~N M R),and which decomposed atca 225 C.

N M R (D6-D M SO)S: ~2.36 (3H, s)~, 3.26 (2H, t,~J 8j, 3.60 (3Ht s), A.17 (2H, t, J 8), 6.11 (lH, s), 7.21 (lH, s), ;7.32 (IH, dd, J 7, 4), 7.93 (lH, s), 8.00 ~(1H, d, J 7), 8.21 (lH, d,J4),8.63(1H,s),8.75(1H,d,J2).
15 `
. Found: C,69.2;H,S.9;N, 17.6%
C18H18N4-(-8 CH2C12) requires C, 69.3; H, 5.8; Ni 17.9~o:
Found: M+306, ClgHIgN40requires306 20 Example l3 6~7-Dimethyl~ pJrridylcarbamoyl)-2,3-dihydropyrrolo[3,~e3indole (E13) This was prepared from 6,7-dime~hyl-2,3-dihydropy~rolo[3,2-e]lndole (D24~ (0.124g, 0.67 mmmol), following the procedu~; of ~Example 1. Tl~is gave ~he title compound (0.128g, 62%), as a light brown powder, containing residual CH2C12~(NMR), m.p. 216-8 C
25 (decomp).

N~ (D6-DM$O~ 2 .45 (3H, s), 3.33 (2H, t. J 8), 3~70 (3H, s), 4.28 (2H, t, J 8), 6.15 (lH, s), 7.21 (1H, d, J 9), 7.37 ~(1H, dd, J 8, Sj, 7.86 (1H, d, J 9), 8.06 (lH, dm, J 9), 8,26 !(lH, d,~J 5), 8.67 (IH,!s), 8.81 (lU, d, J 2).

Found: C, 69.4; H, 5.9;~N, 17.7%
c~8~l8N4o (o-~8 cH~l2) reqL~i~es c~ 69.3; H~s~8;;N~ l7~9%
Found: M+306, CigHIgN40requires306 ~

~`'.
WO 94/04S33 2~ ~12 721 PCr/EP93/02031 Example 14 /I`
1-Methyl~N, (~pyndyl)-5,6,7.~tetrahydr~ lH pyrrolo[2,~g~ql~inolin~
carboxamjde (E14) This material was prepared from l-me~hyl-5,6,7,8-tetrahydro-lH-pyrrolo[2,3-g~quinoline }
(D33) (0.64g, 3.4 mmol). following the procedure of Example 1. This ga~re a pale orange s solid, 0.64g (60%)~ Recryst~llisation from e~hanol/petroleum ether (b.p. 6Q-80 C) gave lustrous pale orange flakes (0.56g), m.p. 154.5-155.5 C.

NMR (D6-DMSO) o: 1.93 (2H, m), 2.80 (2H, t, J 7)i 3.72 (2H, t, J 7), 3.77 (3H, s), ~.34(1H,d,J3),7.25(3H,m),7.49(1H,s),7.89(1H.dt.J8.2).8.15(1H?dd.J4.2), 8.65 (2H, m).

Found: C, 70.2; H, 5.4; N, 18.0%, ClgHlgN4O re4uires C, 70.6; H, 5.9; N, 18.3%
Found: M+ 306, C 1 8H 1 gN4O requ~es 306 Example 15 3~Methyl-N (3 pyridyl)-6~7~8~9-tetrahydro-3H-pyrrolo[3~f~ql~inoline-6-carboxan~ide (E15) This was prepared from 3-methyl-6,7,8,9-te~rahydro-3H-pyrrolo[3,2-~quinoline (I:)39) (0.21 g, 1 . 1 mmol), following the procedure o~ E~cample 1 . The reac~ion was worked up by evaporation to give a brown oil, which was chromatographed on si~ica gel, eluting with 0-10% methanoil/dichlo~omethane. Finally, recrystallisadon from ethanol/petroleum ether (b.p. 60~80C) gave the title compound (0.26g, 75%) as a cream solid, m.p. 17~5 C, containing ~sidual ethanol (NMR) N~ (D6-DMSO) 8: 1.98 (2H,~ m), 2.94 (2H, t, J 7), 3.75 (SH, m), 6.41 (lH, d, J 3), 7,13 (1H, d, J 8), 7.23 (1H, d, J 8)i 7.25-7.30 (2H, m), 7.89 (lH, m), 8.1S (lH, d, J 3 8.64 (lH, m) 8.77 (lH. s) s Found: C, 70~2; H, 6.i; N, 17.8%
C18H18N4- (0-14 C2H6~ requires C, 70.2; H, 6.1; N,~17.9% Jj Found: M~ 306, ClgHlgN40 requires 306.
~ ~ }
T , ' :

~ - - 35 - ~
, :

W0 94/04533 ~2 ~L 4~ L pcr/Ep93/o2o3l -Exarnple 16 6-Methyl-3-(~me~yl~ql~inoliny~carbamoyl)-23-dihydr~pyrrolo~3,2-e]~ndole (E16) The ti~e compound was prepared from 2-methyl-4-aminoquinoline, 1,1 -car~onyl dumida~ole, 6-methyl-(2,3-dihydropyrrolo-[3,2-e~indole)hydrochlor~de (D10) and triethylamine, in 76% yield, m.p. ~ 230 C. 1;

NMR (D6-DMSO)~: 2.60 (3H, s), 3.34 (2H, ti J 7~, 3.75 (3H, s), 4.42 (2H, t, J 7), 6.31 (lH,d,J3),7.25(1H,d,J8),7.35(1H,d,J3),7.52(1H,t,J7),7.70(1H,t,J7),7.80 (lH, s), 7.88 (lH, s), 7.92 (IH, s), 8.17 (lH, d, J 7), 8.70 (lH, s) Found: C, 73.3; H, 5.8; N, lS.S
C22 H20 N40.114 H20 requires C, 73.3; H, 5.7; N, lS.S
Found: M~ 356, C22H20N40 requires 356 Example 17 ~ ~ ~
6-Me*yl~3-t5~quinolinylcarbamoyl)-2,3 dihydro~pyrrolo[3,~elinàole (E17) The t}tle compound was prepared from S-aminoquino~e, 1,1 ~arbonyl~imidazole, 6-~: ~ methyl-~2,3-dihydropyrrolo-[3,2-e]indole)hydrochloride (D10) and triethylamine, in 42%
yield, m.p. >240 C. ~ ~

N~(D6-DMS0)~: 3.35 (2H, t, J 7), 3.75 (3H, sj, 4.38 (2H, t, J 7), 6.30 (lH, d, J;
4), 7.19 (lH, d, J 8), 7.30 (1EI, d, J 4), 7.50-7.58 (lH, m), 7.62 (1H, d, J 7), 7.75 (lH, t, J
^ 7), 7.83-7.93 (2H, m), 8.45: (IH, d, J 7), 8.70 ~lH, s), 8.92 (~IH, d, J 4). : :
::
Found: C, 73,6; H, S~S0; N, 16.3 C21E~I gN40 requires C, 73.7; H,: 5.3; N, 16.4 Found:M+342, C~lHIgN40requ~es342 "
30 Example l8 6-Methyl~ ql~inoliJIyIcarbamoyl)-2,3~dihydropyrrolo [3~elindole (E18) The dtle compound was prepared ~om 3-amin~quinoline, 1~,1 ~arbonyl diimidazole,: 6 methyl-(2,3-dihydrop~olo-t3,2-e~-indole hydro~hloride~ (DlO) and triethylamine~ in 53%
;yield,m.p.222-4 C.

WO ~4~04~33 21 ~ 2 7 ,~ 1 PCr/EP93/02031 NMR(D6-DMSO)~: 3.35 (2H, d, J 7). 3.78 (3H, s), 4.32 (2H, d, J 7), 6.30 (lH, d, J ~`
4), 7.25 (lH. d, J 8), 7.32 (lH, d, J 4), 7.50-7.68 (2H, m), 7.83-8.00 ~3H, m), 8.54 (lH, d, J 4), 8.82 (lH, s), 9.05 (lH, s) Found:C, 72.9; H, S.S; N, 16.2, C21Hl8N40 "4 H20 requires C, 72.7; H, 5.3; N, 16.2 Found: M+ 342, C21HlgN40 requires 342 Example 19 S-Methyl~ 2-methyl-4 quinolinylcarbamoyl)-2,3 dihydropyrr~lo[2,3 flindole(E19) The title compound was prepa~ed ~rom 2-me~hyl-4-aminoquinol~ne, 1,1 ~arbonyl diirnidazo}e and S-methyl-~2,3-dihydropyrrolo[2,3-f~indole) ~D6), in 57% yield, m.p.~,240 C.

NMR (D6-DMSO)~: 2.64 (3H, s), 3.30 (2H, t, J 7), 3.72 (3H, s), 4.38 (2H, t,iJ 7), 6.3 (lH,d,J4),7.20(1H,d,J4),7.30(1H,s),7.53(1EI,t,J7~,7.70~1H,t~J7),7.78(1H,s), 7.90 (IH, d, J 7), 8.08 (lH, s), 8.15 (IH, d, J 7), 8.73 (IH,s) Example 20 6,8-Dimethyl-~(3-pyridylcarbamoyl)-2,3-dihydropyrroio~3~ejindole (E20) 6-Methyl-8-(N,N-dimethylaminomethyl)-3-(3-py~idylcarbamoyl)-2,3-dihydropylrolo [3,2-e] indole (D40) (O.Sg, 0.0014 moles) was hydrogenated at STP in ethanol (SOml) over 10% palladium on charcoal catalyst (O.Sg) for 24hrs tben a~ SOp.s.i. for 4hrs. Filtradon through kieselguhr followed by evaporadon to dryness gave the crude produc~ Flash 25 chromatography on silica gel e!uting with 0-5% methanoWichloromethane followed by recrystallisadon from ethyl acetate/methanol give the otle compound (E20)~(0. 174g, 40 as white crystals. m.p. 228-230C.i ~ ;, NMR~ (1:)6-DMSO) ~: ; 2.32 ~3H, s), 3.55 (2H, t7 J=8Hz)r 3~65 (3H, s), 4.21 (2H, t, J=8Hz), 7.00 (lH, s), 7.10 (lH, d, J=8Hz), 7.24 7.33 (lH, m), 7.83 (lH7 d, J-8Hz), 7.9 8.03 (lH, m), 8.19 (lH, d, J=4H~), 8.57 (lH, s), 8.73 ~lH, d, J=3~).
. ~
Found: C, 69.77; H, 6~00; N, 18.08~Yo ~ ~
C18H18N4 l/5~20 re~uiles: (:, 69.77, H, 5.94; N,~ 18.09%~ ;
E~ound: M~ 306, ClgHl~gN40 requires 306 : ~
~: ;

WO 94/04533 ~ pcr/Eps3/o2o3 Example 21 ~Methyl-3-(3-pyridylcarbamoyl)-2,3,7,~te~ahydropyrrolo[3,~e]-indole (E21~
6-Methyl-3-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo [3,2-e]indole (E2) ( 1 .Og, ~0.0034 moles) was dissolved in glacial acetic acid (25ml) and treated with sodium 1 -cyanoborohydride (l.Ogt 0.016 moles) at ambient temperature. The mLlcture was stirred for 4 hrs then diluted with water (lOOml). The mixture was basified with 10% aqueous sodium hydroxide and the product extracted into dlchloromethane, drying wi~ sodium sulphate. Evaporation of the solvent followed by llash chromatography on silica gel eludng with 0-5% methanol/dichloromethane gave a white~solid residue. Recrystallisation rom ethyl aceta~l60-80 petrol gave thè title compound ~ (E21) as white crystals (0.68g, 67%) m.p. 201-203C. ~ ~ ~

NMR (D6-DMSO) ~: 2.75 (3H, s), 2.89 (2H, ~, J=8Hz), 3.15 (2H, t, J=8Hz)~ 3.31 (2H, t, J=8Hz), 4.22 (2H, t, J=8H~), 6.40 (lH, d, J=7Hz), 7.33- 7.45 (lH, m), 7.70 (lH, d, J=7Hz), 8.03-81~2 ~lH, mj, 8.30 (lH, d, J=4Hz), 8.65 (lH, s), 8.85 ~lH, d, J=4Hzj.
`:
Pound: C, 69.07; H, 6.?9 N, 18.90%, C}7HlgN40 requires C, 69.37; H, 6.16; N, 19.03%
Found: M+ 294, C17HlgN40 re~uires 294 Example22 S~Methyl-1-(2-pyra~:inylcarbamoyl)-2,3-dihydropyrrolo[2,3~ dole ~E22) The title compousld was prepared from 2-am~opyra~ne anion (prepared using sodium;
hydride), l,l' carbonyldiimidazole, and 5-methyl-2,3-~dihydropyrrolo~ 2,3-f~indole in dimethylformamide using a procedure similar tQ that described for Example 5, in 75%
.
yield,m.p. l9~198C.

NMR (D6DMSO) ~: 3.26 (2H, t, J=10), 3.76 (3H, s), 4.25 (2H, t, J=10), 6.33 (lH, d, , I J, l3), 7.20 (lH, d, J-3), 7.28 (lH, s), 8.07 (lH, s), 8.28 (IH, d, J=2), 8.37 (IH, d, 3=2), 9.19 (lH, m), 9.38 (lH, s).

Found: C, 6S55; H, 5.3~; N, 23.54%, C16H1sNsO requires C, 65.52; H, 5.15; N, 23.88~;
Found:M+293, ~CI6HlsNsOrequires293 7 2 1 1~
wO 94/0453~ pcr/Ep93/o2 Example 23 ~, 2~3-Dillyd~o-S-methyl-l-(~methyl-S-isothiazolylcarbamoyl)-lH-pyrrolo~32-e]indole ~' (E23) To an ice-cooled solution of carbonyldiimidazole (CDI) (0~445g, 2~75 mmol) in s dichloromethane (lSml) was added a solution of S-amino-3-methylisothiazole hydrochloride (0~38g, 2~5mmol) and triethylamine (0~35ml, 2~5 mmol) in dichloromethane (lSml). The mixture was s~Ted for lh at 0C, ~hen evaporated to dryness~ The residue was dissolved in dimethyl ~ormamide (DMF) (lSml) and to this sollltion was addeddihydropyrroloindole hydrochloride (DlO) (0.~2g,2.5mmol) and triethylarnine (0.35ml) in 10 DMF (2.5ml). The mixture was heated at approx. 130C, with sti~ing, for lh, then cooled and poured into water. Solid product was filtered off, washed ~with water and dAed, ~hen triturated with dichloromethane/methanoL Tnturation liquor was concentrated, wi~h addition of petrol, to give a precipitate which was filtered off and combined with the tnturation residue. Drying in:vacuo gave the title compound, (0~42g, 54%) m~p. >250~
IS ~ i ~ (D6-DMSO) ~: 2.29 (3H, s), 3.33 (2H, t, J=7), 3.75 (3H, s), 4.20 t2H. t, J=7), 6.29 (lH, d, J=4), 6.74 (lH, s), 7.25 (~1H, d, J=9), 7.32 (IH, di J-4), 7.90 (1H, d, J=9), 10.41 (IH, s).

20 Found: C, 61.13; H, 5.16; N, 17.84%, C16H16N4OS regui~es C, fil.52; H. 5.16; N, 17.93% ~ ~

~pl~
2,3 Dihydro~S-me~yl~ methyl-~-isothiazolylcarbamoyl)-lH~pyrrolo~2,3~f~indole The title compound was prepared by the method of E23, using ~-amino-3-` ~ methylisothia~ole hydrochlonde~(0.60g, 4~mmol),~CDl (0.71g, 4.4 mmol), t~iethylarnine (0.56ml, 4 mmol~ and dihydropyrroloindole (D6) (0.69g, 4 mmol). Tnethylarnine was add~d,~only;~vith the isothiazole hydrochloAde.
30 After pouring the final mi~sture into water and ~lltering~ off the produc~, the crude mateAal was recrystallised from dichloromethane/methanol/petrol to give :the title compound (0.76g,61%),m.p.254255C.

N~R (D6-DMSO) ~: Z.30 (3H,~s), 3.30 (2H, t, J~ 3.74 (3H, s), 4.14:(2H,~t, J-7), 6.35 tlH, d,;J-~), 6.76 (lH, s), 7.20 (IH,;d, J=4), 7.29~ 1H, s), ~8.08 (lH, s), 10.48 (lH,~5).

;
39- ~ ~

w094/04533 2,~L4~ L pcr/Ep93/o2 Found: C, 61.31; H, 5.24; N, 17.74%~ C16H16N40S requires: C, 61.52. H, 5.15; N, 17.93%

Exarrlple 2~
2,3-Dihydro-5-methyl-1.(5-q~nolylc~bamoyl~-1H-pyrrolo[2,3~ dole (E2S) The title compound wa~s prepared by the method of E23, using 5-aminoquinolin~ (0.58g, 4 mmol), CDI (0.7 lg, 4.4 mmol), and dihydropyrroloindole (D6) (0.69g, 4 mmol). NoL~iethylamine was used, and the initial reaction mLltture was stilred for Ih at 0C and 0.5h at room temperature.
10 After pou~ing the final mi~ re into water and filtering off the produc~ the crude material wa~s recrystallised from dichloromethane/methan~petrol to glve the title~compound (0.48g, 35%), m.p. 240-243C.

N~ (D6-DMSO) ~: 3.43 (2H, L, J~8), 3.84 (3H, s). 4.42 (2H, t, J=8), 6.37 (lH, d,J=4), 7.27 (IH, d, J=4), 7.38 (lH, s), 7.63 (lH, dd, J-8.5), 7.72 ~lH. d, J=8), 7~87 ~1H,`t, J_8), 7.99 (lH, d, J=8), 8.08 (IH, s), 8.55 (lH, d, J=8), 8.84 (lH, s), 9.00 (lH. d, J=5).
: ~ :
Found: C, 72.85; ~I, 5.45; N, 16.36%, C21HlgN4O requ~res C, 73.67; H, 5.30; N, 16.36%
:
Example 26 :~
~: 2,3~ ihydro~S~n~thyl~ methyl~5-isoxa~olylcarbamoyl)-1H~pyrrolo~2,3-t~indole To a suspension of sodiwn hydride (80% in oil, 40mg, ~1.33 mmol) in dry DMF (lOml) was added S~amino-3-methylisoxazole 10.12g, 1.24 mmol),~and the mL~ture was stirred for ~0 m~n at 0C. Imida~olylcarbamoyl pyIToloindole (D41) (0.32g, 1~2a mmol) was ~nadded and the mi~ was s~irred for 1.5h~at lûO-130C, then cooled and poured into: water. The precipitate was f~red~off, washed with water arld dried to~give the title :
eompound (0.17g, 48%), m.p. 212-215C.

N~ (D6-DMSO) ~: 2.19 (3H, s), 3.24 (2H, t, J-7), 3.13 (3H, s), 4.14 (2H, t, J=7), 6.07 (lH, s,), 6.33 (IH, d, Ji~), ?.20 (iH~ d~ 1=4), 7.28 (IH,~ s). 8.05 llH, s), lQ20 Found: C? 64.83; H, ~.51; N, 18.83%, C16H16N402 requires: C, 64.85; H~, 5.44; N, :~
18.91~o 2l~2~2l ~`
WO 94/0453~ pcr/Ep93/o2o3l ~r`7``
t Example 27 ! `
N~(5-Isoq uinolyl~-methyl-2,3 dihydropyrrolo~2,3-fl indole-1-carboxamide (E27~ 1 The title compound was prepared from 5-aminoisoquinoline, carbonyl diimidazole and 1 amino-5-methyl- 2,3-dihydropyrrolo [2,3-f~indole, using a procedure similar tO that s described for Example 25, in 15% yield, m.p. 245-250C.
`,"~
NMR (D6 DMSO) ~: 3.48 (2H, L, J=6), 3.86 (3H, s), 4.42 (2H, t, J=6), 6.38 (lH, d, `~
J=2), 7.28 (lH, d, Ja2), 7.40 (lH, s), 7.80, (lH, t, d=6), 7.91 (lH, d, Ja6), 7.99 (lH, d, .
Ja6), 8.08 (2H, d, J=6), 8.60 ~IH, d, Ja6), 8.79 (lH, s), 9.42 ~lH, s). , ~ ~;
Found:M+342.40, C21H1gN4Orequires342.40 Example 28 N~ 2uinolyl)~5-methyl~2~dihydr~pyrrolo ~ indole-1-carboxamide (E28) l~he title compound was prepared ~rom 6-aminoql~inQline, carbonyl diimiida~ole, and 1-amino-5-methyl-2,3-dihydro-pyITiolo ~2,3-fl indole using a procedure simllar to ihat `
described for Exarnple 25, in 12% yield, m.p. 217-220C.
, i ~: tD6 DMSO~ ~: 3.30 (ZH, t, J=6), 3.74 (3H, s), 4.23 (2H, ~, J=6), 6.32 (lH, d, i.``?
~=2), 7.20 (lH, d, J=2), 7.29 (lH, s), 7.42-7.49 (lH, m), 7.94 (2H, s),8.09 (lH, s), 8.27 `
(2H, m), ~8,74-8.79 (2H, m).
j.
Found: M+ 342~0, C2lHlgN40 nequires 342.40 : ~
. : : 1,, 25 Example 29 2~Me*yl 1~ pyridylcar~amoyl)~2,3-dihy~pyrrolo[2,3~ dolea~29) : ,`
Nicotinoyl az~de (0.142g, 0.96 mmol) was stirred at reflu~ under Ar in dry toluene (40 ml) for lh, allowed ~o cool and 2-methyl-2,3-dihydropyrrolo~2,3-f~indole (D47~ (0.1~g, Q.87 ``~
mmol~ in dry ~oluene (10 ml) was added. The solution wa~ stirIed for 1 h, the resulti~g precipitate fil~ered off, washed with~a small quanti~ of Et20 and dried thoroughly:to ~ ' .
; ~ affor~ ~he title compound (E29) (70 mg, 28%).

NMR (D6-DMSO) ~: 1.25 (3H, d),~2.75 (lH, d), 3.46 (lH, dd), 4.82 (lH, m), 6.32 (lH, s), 7.20 (lEI, s), 7.33 ~lH,;dd),:8.01 (lH, m), 8.01 ~lH, s),~ 8.21 :~1H, d),:~8.68 ~lH, s) . ;;
~: 3S 8.78 ~lH, d~, 10.83 (1H, bs, NH).
:: ~
' i !
: : 41 ~ : ~
.
. .

WO 9~/û4~ 42~ pcr/Ep93/o2 Found: C, 69.69; H, 5.71; N, 19.16%
C17H16N40 reqùires C, 69.85; H, 5.52; N, 19.16%
Found: M~ 292 C17H16N40 requires 292 5 Example30 :
2,5-Dimethyl~ pyridylcarbamoyl)-2,3~dihydropyrrolo[~,3-f~-indole (E30) Nicotinoyl azide (28.7 mg, 1.1 e~.) was stirred at reflw~ under Ar in dry toluene (40 ml) for lh, allowed to cool and 2,5-dimethyl-2,3-dihydropy~olo~2,3-flindole (D49) (0.37g, 1.76 mmol) in dry toluene (10 ml) added. The solution was stirred for lh, the solution 10 evaporated to dryness, and purified by column chromatography (SiO2, CH~13/MeOH 9:1) to afford the product as a pale yellow oil which was triturated wi~h Et20 to give a pale yellow solid (17û mg).

N~ (CDC13) ~: 1.33 (3H. d), 2.89 (lH, d), 3.62 (lH, dd), 3.84 (3H, s, NMe),IS 4.96 (lH, m), 6.42 (lH, d), 7.30 (lH, d), 7.39 (lH, s), 7.42 (lH, dd), 8.08 (lH, s)~,8.13 (lH, s), 8.32 (lH, d), 8.80 (lH, s),:8.85 (lH, s, NH).

Found: C, 69.98; H~ 6.11; N, 17.72%
C18H18N40 IK EI20 requires C, 69.90; H, 6.04; N, 18.10%
20 Found: M~306, ClgHlgN40requ~res306. ~:

Example 31 ~Ethyl~1~(3~pyridylcarbsmoyl) 2,3,6,7~te~ydropyrrolo~2,3-~Jindole (E31):
5-l~ yl~ 3-pyridylcarbamoyl)-2,3-dihydropyrrolo-12,3-flindole (E 10) (0.7g, 0.0023 25 moles) was dissolved in glacial ace~c acid tl5 ml) and treated with sodi~n cyanoborohydride (0.72g, 0.0114 moles) a~ ambient temperature wit}~ StiITi~g. The ~ ~ mLx~e was stirred for l h then diluted with water (lûû ml), basi~led:with 10% aqueous ;: sodium hydroxide and extracted with dichloromethane (2x~100 ml). The organic solution w jas dried (Na2SO4), f~tereld and eYaporated to ~ess. Flash chromato~aphy on silica 30 gel eluting with 2-5% methanol/dichloromethane followed by recrystallisà~ion of!the sol~d obtained from ethyl ace~l40-60 petrol gave~ the tltle compound ~E31) a~ a white ~ ¦
crystalline solid (û~45 g, 64%) m.p. 151-153 C.

NMR (D6-DMSO) ~: : 1.10 ~3H, t, J 7), 2.81: (2H, t, J 7),~ .9B-3.11 (4H~ m), 3.21 (~H, 35 t, J 7), 4.07 (2H, t, J ~), 6.41 (IH~, s~, 7.29 (lH, q, J 5), 7.62 (IH, s), 7.93-7.96 (1H, m~,:
8.19 (1H, d,~J 2), 8.51 (IH, s), 8.70 (IH, s).

~: ~ :: - :
~ ~ - 42 -. . . .

W094/04533 2I'127,~1 pcr/Ep93/o2o3 Found: a, 69.56, H, 6.50; N, 18.W%
C18H20N4~ I20 requires: C, 69.58; H, 6.57; N, 18.03%
Found: M~308, C1gH2oN4Orequ~res308 ~ I, S ~i~
Example 32 '~
~-Methyl-l-(~meUlyl-4-ql~inolinylcarbamoyl)~ ,7-tRtrahydropyrrolo~2,3 f~i~ole ~ `
(E32) 5-Methyl-1-(2-methyl-4~uinolinylcarbamoyl)-2,3-dihydropyrro1O~2,3-f~indQle (E 19) (0.7 `-`
g, 0.002 moles) in glacial acetic acid (15 ml) was treated with sodium cyanoborohydride (0.58 g, 0.009 moles) as in the method of Example 9 to give the title compound (E32) as pale yellow crystals (0.44g, 63%) m.p. 242-244 C.

N~R (D6 DMSO) ~: 2.61 (3H, s), 2.69 (3H, s), 2.80 (2H, t, J 7),3~10-3.22 (4H, m~, -4.29 (2H, t, J 7), 6.45 (lH, s), 7.45-7.53 (lH, m). 7.6~7.77 (3H, m), 7.88 (lH, d, J 8). ~:
8.12(1H,d,J8),8.54~1H,s) Folmd: C, 72.69; H, 6.37; N, 15.36%
C22H22N4O 1/4 H2O lequires: C. 72.83; H, 6.21; N, 15.4~%
Found: M~358, C22H22N4Orequ~res358 Exs nple33 S Methyl l~t~methyl-4pyridylcarbamoyl)~2,3~ihydrop~:olo[2~f]~ndole (E33~
The title co~npound was prepared from 2-methyl-~am~nopyIidine anion (prepared usin~: ;
~odium hydrîde) 1,1 ~a~bonyldiimidazole. and ~-methyl-2,3-dihydropyrrolo~2,3-f]indolc : ~ i:
; in dimethylformamide using a pro~edure similar to that descr~bed ~or E~ample 5, in 45%
yield.
~ '.
(D6 DMSO) ~: 2~40 (3H, s), 3.27 (2H. t. J 7?~ 3.72 (3H, s), 4.18 (2H, t, J 7), ~ :
6.32 (lH, d, J 3), 7.19 (lH, d, J 3), 7.26 (lH, s), 7.43 ( jH, d, J g), 7.50 (lH, s), 8.05 (lH, ~ ;
s), 8.22 (1H, d, J 8), 8.74 (1H. s).
ound: M+306, C1gHlgN40requires306 : : . ~
...
~.

: - 43 -W0 94/04533?, J~ 4 ~ pcr/Er93/o2o3 Examp1e 34 Pharmaceutical compositions for oral administration may be prepared by combining the following:

s 1 ) Solid Dosage Formula~on ~0 w/w Compound of formula 1 10%
Magnesium stearate 0.5%
Starch 2.0%
HPM cellulose 1.0%
Microcrystalline cellulose ` 86.5%
The m~xture may be compressed to tablets, or filled into hard gelatin capsules.
The tablet may be coated by applying a suspension of film; former (e.g. HPM cellulose), pigment (e.g. ti~nium dioxide) and plasticiser ~e.g. diethyl phthalate) and drying the film by evaporation of the solvent. The film coat can compr~se 2.0%~to 6.0% of the tablet ~ ~
weigh~, preferably about 3.0%. `

2) Capsule ; ~
%wlw : ~'' Compound of fonnula 1 20%
Polyethylene glycol 80%
The medicinal compound is dispersed or dissolved in the liq~id camer, with a thicl~ening agent added, if required. The formulation is then enclosed in a soft gelatin capsule by suitable technology. ~ i;
, ~
2S ` ~
,.
unple 35 A pharmaceutical composition for parenteral admiois~abon rnay be prepared by combir~ing the following~
Preferred Le~el 30 1 I Compound of ~formula 1 1.0%;
Saline ~9.0%
The solution is ste~ilised and sealed ~n s~rile containers.

: : : . ~ : , ; ~, :

. .
. .

2 1 1 ~
WO 94/04~33 PCr~EP93/02031 1:

Pharmacological Data ', ~3H~-mesulergine binding to rat or human S-HT2C clones expressed in 2g3 cells invitro ~```
Evidence f~m the literature suggests that 5-Hl'2C an~gonists may have a number of therapeutic indications including the treatrnent of anxiety, migraine, depression, feeding disorders and obsessive compulsion disorders. (Curzon and Kennett, 199Q; Fo~d and Gray, 1989) and Alzheimer's Disease (Lawlor, 1989, J. Arch. Gen. Psychiat. Vol. 46 p.S42).
The affinity of test drugs for the 5-HT2C binding site can be detennined by 0 assessing their ability to displace [3H]-mesulergine from 5-Hl'2C clones expressed in 293 cells (Julius e~ al., 1988). The method employed was sin~ilar to that of Pazos et al, 1984. `~
The cells suspension (400ml) was incubated with [3Hl-mesulerg~ne (0.5nM) in Tris HCl buffer (pH 7.4) at 37C for 30 minutes. Non-specific binding was measure~d in the presence of rnianserin (10-6M). Ten concentrations of test dmg (3 x 10-9 to 10-4M ~`
final concentration) were added in a volume of SOml. The total assay volume was S~ml.
Incuba~on was stopped by rapid fil~ation using a Brandel cell harvester and radioac~vity mcasured by scindllation counting. The ICso values were detem~ined using a four parameter logistic program (DelA~ 1978) and the PKi (the negative logarithm of the inhibition constant) calculated *om the Cheng ~sof~ equanon where:
Ki- IC50 , l+ C . '' Kd l' Ki = inhibition constant.
C = concenuation of [3H~-mesulergine Kd = Af~nity of mesulergine for S-HT2C binding sites.
Curzon, G.A. and Kennett~ G.A. (1990). TIPS, Vol. 11, I81-182. i~
Fozard, J.R. and Gray, J.A. (1989). TlPS, Vol. 10, 307-309. ~ ' Pazos. A. et al. (1984)~ Eur. J. Pharmacol., 106, 531-538.
Julius et al. (1988) Science 241, 5S8-564 DeLean A, Munson R.J., Rodbaud D (1978) Am. J. Physiol 235, E97- ~ ;
E102.

Results: The compound of examples 1 to 11 have pK; values of 6.04 to 9.29.

-~.

~: :
- 45 - ;~
' .

W094/0493~ pcr/Ep93/o2p3 I~eYersal of MCPP-induced Hypolocomo~ion Ad~ninistration of m-(chlorophenyl)piperazine ~mCPP) to rats induces hypolocomotion (Kennett and Curzon 1988, Luckie e~ al. 1989) as seen with the related drug l-(m-trifluoromethylphenyl)piperazine (I FMPP) (Lucki and Frr lg82, Kennett s and Curzon 1988). This effect was blocked by the non specific 5-HT2C/5-HT2A receptor , - -antagonists mianserm, cyproheptadme and metP.rgoline and perhaps by mesulergine. ~t was not blocked by the S-HT2A receptor antagonists ketanselin and ritanserin at relevant doses (KeMett and Curzon 1991) nor by antagonists of 5~ A, 5-HT~g, 5-HT3, C~2 adrenoceptors or dopamine D2 receptors. The effect of mCPP is therefore considered to be mediated by 5-HT2C~ receptors (KeMett and Cu~zon 1988) as confinned by subsequent studies (Lucki et al., 1989). Since mCPP ~causes hypolocomotion when infused into the cerebral ventricles this effect is probably centrally mediated ~Kennett and ~unon I988).
mCPP-induced hypolocomodon was measured in automated locomo~ion cages of dimensions 56 cm long ~c 16l/2 cm wide x 25 cm high and made of black perspex. Two }5 photobeams traversed the width of the cages at either end a~ ground level. Se~uential breaking of these beams allowed the measurement of cage transits.
Male Sp~ague Dawiey rats (200-250g) (Charles River) were housed in groups of six. They were given drugs orally lh pretest and 40 mins later mCPP (7 mglkg i.p.).
After a further 20 min they were placed in individual automated cages in groups oî four under red light in an adjacent room. After 10 min the test wax terminated. Reversa~ of mCPP-induced hypolocomotion was considered as evidence of ~n vivo central S-HT2c~eceptor antagonist praperdes.
Kennett, G.A., Curzon, G., (1991). Brit. J.~Pharmacol. 103, 201~2020.
Lucki, I., Prazer, A., (1982). Am. Soc. Neurosci. 8 (abstr), 101.
2S Lucki, I., Ward, H.R., Frazer, A.. (1989). J. PharmacoL Exp. Therap. 249, IS5-1 64. . : ~

Resul~ e compounds of e:campies l, 2 and 4 had IDso's of 5.5 to 22.3mg/kg p.o.

!~ 1 30 SociallnteractionT~
Potendal anxiolytic properdes have hen evaluated us~ng the social interacdon test based on that described by File (1980~J.Neurosci.Meth., 2, 2I9). Active social in~era~tion t~ .
between male rats is usually quantitated by counting~ractive behaviours such as following, grooming, sniffing, climbing over or under, biting~moun~ng~and boxing. This !
35 behaviour is supressed when the rats encounter each other~ an envirom~e~t which is novel and brightly 11L Under these ci~cumstances an~iolytic dlugs will~enhance ~he level of social - int~raction.

: ~ ~ ' : ..

i~.
WO 94/04533 2 1 ~ ~ 7 2 1 pcr/Ep93/o2o31 1` `

Rats were housed in groups of 8 in a holding room adjacent to the e~perimental chamber for ~ days. They were then housed singly in the same room for 3 days prior to the experimental day. On the e~perimental day rats were injected p.o. lh pretest with vehicle or drùg in pairs at 15 rnin intervals ~egirming at 10.00 arn. 60 Mins later they were placed s with a weight matched pair mate ~encountered for the fL~e time) in the social interac~on box in a separate room. I~e bo~ was made of white perspe~ 54 ~ 37 ~ 26 cm with no lid.
The floor was divided into 24 equal squares and the cage was brightly lit. Active social interaction was scored blind over the next 15 min by remote video monitoring to give total interaction scores. The number of squares crossed by each rat was also scored and lo summed. At the end of each test the box was carefully wiped wi~h a damp clolh. IJnlike an~iolytic drugs, treatments that enhance social interaction by s~mulant action will also increase locomotion. Trea~nents that are sedative reduce l~omotion.

The compound of E~arnple 2 showed a significant increase in social interac~on at doses of 10 mg~kg.
.:, Geller-Sei~r Prooedure Potential an~iolytic pr~perties are evaluated using the Geller-Seifter procedurebased on that originally described by Geller and Seifter, (l960) Psychophannacologia, 1, 482-492. This procedure has been shown to be selecdve for drugs with anxiolytic properties (Cook and Sepinwall, (1975) '~echanism of Acdon of Ben~odiazepines" eL
Costa, E. and Greengard, P., Raven Press, New York, pp. 1-28).
Rats are trained on a variable interval 30 sec schedule (VI30) to press a lever in o~der to obtain food reward. The S misl sessions of the VI30 schedule alternate ~n~h 2-5 ~5 m~n of a schedule (F~5) in which every 5th lever press is followed by presenea~on of a food pellet pa~red with a 0.5 sec mild foot~shock. The total study lasts approximately 30 mins.
Rats typically respond with high rates of lever p~essing under the VI30 schedule and low response rates under the PRS 'conflict' session. An~cioly~c drugs hcrease the suppressed response rates of rats in a 'conflict' session.
I:)lugs ar~ administe~d intraperitoneally or o~ally to groups~o~ 3-8;ra~ 30 min;before tesdng. The results are expressed as the percentage inc~ase ~ the s~uare roo~ of the total ~wnber of lever presses in the FR5 'co~ct' session. ~Square root t~ansformadon is necess~oy to nonnalise the data ~or sta~s~ical analysis using parame~ic me~hods.The compound of Example 2 sbowed a sig~ificant increase in Iesponding in ~he ~ `~
'conflict' session at dose leveLs in Ihe ~ange 5 mg~kg p~o.

Claims

1. A compound of formula (I) or a salt thereof:

(I) wherein:
P represents a qumoline or isoquinoline residue, or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur;
Rl is hydrogen or C1-6 alkyl;
R2,R3,R10 and R11 are independently hydrogen or C1-6 alkyl, or R10 and R11 together form a bond, or R2 and R10 or R3 and R11 together form a C2-6 alkylene chain;
R4 is hydrogen, C1-6 alkyl, halogen, NR8R9 or OR12 where R8, R9 and R12 are independently hydrogen or C1-6 alkyl;
R5 is hydrogen or C1-6 alkyl;
R7. is hydrogen, C1-6 alkyl, OR12 or halogen, where R12 is hydrogen or C1-6 alkyl;
n is 2 or 3; and the groups R13 and R14 are independently hydrogen or C1-6 alkyl.

2. A compound according to claim 1 in which R1 is methyl or ethyl.

3. A compound according to claim 2 in which R2 and R3 are hydrogen and R10 and R11 together form a bond.

4. A compound according to claim 3 in which R4 is hydrogen or methyl.

5. A compound according to claim 4 in which R5 and R7 are hydrogen.

6. A compound according to claim 5 in which (CHR13)n is an ethylene group.

7. A compound according to claim 1 which is selected from:

5-Methyl-1-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo[2,3-f]indole 6-Methyl-3-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo[3,2-e]indole 5,7-Dimethyl-1-(3-pyridylcarbamoyl3-2,3-dihydropyrrolo[2,3-f]indole 1-(3-Pyridylcarbamoyl)-2,3-dihydropyrrolo[2,3-f]indole 6-Methyl-3-(4-pyridylcarbamoyl)-2,3-dihydropyrrolo[3,2-e]indole 6-Methyl-3-(2-pyridylcarbamoyl)-2,3-dihydropyrrolo[3,2-e]indole 5-Methyl-1-(2-pyridylcarbamoyl)-2,3-dihydropyrrolo[2,3-f]indole 5-Methyl-1-(4-pyridylcarbamoyl)-2,3-dihydropyrrolo[2,3-f]indole 5-Methyl-1-(3-pyridylcarbamoyl)-2,3,6,7-tetrahydropyrrolo[2,3-f]indole 5-Ethyl-1-(3-pyridylcarbamoyl)-2,3-dihydropylrrolo[2,3-f]indole 5-n-Propyl-1-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo[2,3-f]indole 5,6-Dimethyl-1-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo[2,3-f]indole 6,7-Dimethyl-3-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo[3,2-e]indole 1-Methyl-N-(3-pyridyl)-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-g]quinoline-5-carboxamide 3-Methyl-N-(3-pyridyl)-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]quinoline-6-carboxamide 6-Methyl-3-(2-methyl-4-quinolinylcarbamoyl)-2,3-dihydropyrrolo[3,2-e]indole, 6-Methyl-3-(5-quinolinylcarbamoyl)-2,3-dihydro-pyrrolo[3,2-e]indole, 6-Methyl-3-(3-quinolinylcarbamoyl3-2,3-dihydropyrrolo [3,2-e]indole, 5-Methyl-1-(2-methyl-4-quinolinylcarbamoyl)-2,3-dihyropyrrolo[2,3-f]indole, 6,8-Dimethyl-3-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo[3,2-e]indole, 6-Methyl-3-(3-pyridylcarbamoyl)-2,3,7,8-tetrahydropyrrolo[3,2-e]-indole, 5-Methyl-1-(2-pyrazinylcarbamoyl)-2,3-dihydropyrrolo[2,3-f]indole, 2,3-Dihydro-5-methyl-1-(3-methyl-5-isothiazolylcarbamoyl)-1H-pyrrolo[2,3-e]indole, 2,3-Dihydro-5-methyl-1-(3-methyl-5-isothiazolylcarbamoyl)-1H-pyrrolo[2,3-f]indole, 2,3-Dihydro-5-methyl-1-(5-quinolylcarbamoyl)-1H-pyrrolo[2,3-f]indole, 2,3-Dihydro-5-methyl-1-(3-methyl-5-isoxazolylcarbamoyl)-1H-pyrrolo[2,3-f]indole,N-(5-Isoquinolyl)-5-methyl-2,3-dihydropyrrolo[2,3-f]indole-1-carboxamide, N-(6-Quinolyl)-5-methyl-2,3-dihydro-pyrrolo[2,3-indole-1-carboxamide;
or a pharmaceutically acceptable salt thereof.

8. A compound according to any one of claims 1 to 7 for use in therapy.

9. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier or excipient.

10. A process for the preparation of a compound of formula (I) or a salt thereof, which process comprises:

(a) the coupling of a compound of formula (II);

(II) with a compound of formula (III);

(III) wherein A and R6 contain the appropriate funcuonal group(s) necessary to form the moiety, -NR5'CO when coupled, wherein R5' is R5 as defined in formula (I) or a group convertible thereto, n is as defined in formula (I), and the vanables R1', R2', R3', R10', R11'. R13', R14', R4', R5' and R7' are R1, R2, R3, R10, R11, R13, R14, R4 and R7respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as, necessary and in any appropriate order, converting any R1', R2', R3', R10', R11', R13', R14', R4', R5', and R7' when other than R1, R2, R3, R10, R11, R13, R14, R4, R5, and R7 respcctively to Rl, R2, R3, R10, R11, R13, R14, R4, R5 and R7, interconverting R1, R2, R3, R10, R11, R13, R14, R4, R5 and R7, and forming a pharmaceutically acceptable salt thereof;
or (b) cyclising a compound of formula (IV):

(IV) wherein R4', R5', R7', R13' and R14' are as defined in formulae (II) and (III), n is as defined in formula (I), and C and D contain the appropriate functional group(s) necessary to form the indole or indoline ring substituted by R1', R2', R3', R10' and R11' as defined in (III), and thereafter aptionally and as necessary in any appropriate order, converting any R1', R2', R3', R10', R11', R13', R14', R4', R5' and R7' when other than R1, R2, R3, R10, R11, R13, R14, R4, R5 and R7, to R1, R2, R3, R10, R11, R13, R14, R4, R5 and R7, interconverting R1, R2, R3, R10, R11, R13, R14, R4, R5 and R7, and forming a pharmaceutically acceptable salt.