CA2236832A1 - Substituted piperidine derivatives as selective agonists of 5-ht receptors - Google Patents

Abstract

A compound of formula (I), or a salt or prodrug thereof, wherein G is attached at position 3 or 4 of the piperidine ring and represents halogen or C1-6 alkoxy; R1 represents C3-6 alkenyl, C3-6 alkynyl, aryl(C1-6)alkyl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted; processes for its preparation and its use in therapy, particularly in the treatment of migraine.

Description

CA 02236832 l998-05-06 SUB~ 'U-lI~;L) PIPERIDINE DERIVATIVES AS SELECTIVE
AGONISTS OF ~-HT REC:~:PTORS

The present invention relates to a class of substituted piperidine derivatives which act on 5-hyd~ y~ t~min~. (6-HT) receptors, being selective agonists of so-called "5-HTl-like" receptors. They are therefore usefill in the treatment of ~lini~l con~itiorl.q for which a selective agonist of these receptors is inrli~ted.
It has been known for some time that 6-HTI-like receptor agonists which ~hihit selective vasoconstrictor activity are of use in the treatment of migraine (see, for example, A. Doenicke et al, The Lancet, 1988, Vol. 1, 1309-11; and W. Feniuk and P.P.A. Humphrey, Drug Deuelopment Research, 1992, 26, 235-240).
The human 5-HTl-like or 5-HTlD receptor has recently been shown by rnolecular cloning te~.hniques to exist in two distinct subtypes. These subtypes have been termed 5-HI'1D~,~ (or 5-HTlD l) and 5-HTlD~3 (or 5-HTlD 2), and their amino acid sequences are disclosed and claimed in WO-A-91/17174.
The ~-HTlD~ receptor subtype in humans is believed to reside on sensory termin~l~ in the dura mater. Stimulation of the 5-HTlD~ subtype inhibits the release of infl~mm~tory neuropeptides which are thought to contribute to the headache pain of migraine. The human 6-HTlD~ receptor subtype, meanwhile, is located pre~1omin~nt.ly on the blood vessels and in the brain, and hence may plav a part in mediating constriction of cerebral and coronary arteries, as well as CNS effects.
A~-lmini.~tration of the prototypical 5-HTlD agonist sumatriptan (GR43175) to humans is known to give rise at therapeutic doses to certain adverse cardiovascular events (see, for example, F. Willett et al., Br. Med.
C J., 1992, 304, 1415; J.P. Ottervanger et al., The Lancet, 1993,341,861-2;
and D.N. Bateman, The Lancet, 1993,341,221-4~. Since sumatriptan barely discriminates between the human 5-HTID~ and 6-HTlD~ eceptor subtypes (cf. WO-A-91/17174, Table 1), and since it is the blood vessels with which the 5-HTlD~, subtype is most closely associated, it is believed that the cardiovascular side-effects observed with Sllm~triI~tan can be attributed to stimulation of the ~-HTlD~ receptor subtype. It is accordingly considered (c~ G.W. Rebeck et a~., Proc. NatZ. Acad. Sci. USA, 1994, 91, 3666-9) that compounds which can interact selectively with the 5-HTlDa receptor subtype, whilst having a less pronounced action at the ~-HTlD~
subtype, might be free from, or at any rate less prone to, the llnr~sjrable cardiovascular and other side-ef~ects associated with non-subtype-selective 5-HTlD receptor agonists, whilst at the same time mainf~ininF a beneficial level of anti-migraine activity.
The compounds of the present invention, being selective 5-HTl-like receptor agonists, are accordingly of ~enefit in the treatment of migraine and associated conditions, e.g. cluster he~ he, chronic paroxysmal hemicrania, hes~ h~ associated with vascular disorders, tension he~ che and paediatric migraine. In particular, the compounds according to this invention are potent agonists of the human 5-HTlDa receptor subtype. Moreover, the compounds in accordance with this invention have been found to possess at least a 10-fold selective affinity for the 5-HTlDa receptor subtype relative to the 5-HTlD~ subtype. and they can therefore be expected to manifest fewer side-effects than those associated with non-subtype-selective 5-HTlD receptor agonists.
Several distinct classes of substituted ~lve-membered heteroaromatic compounds are described in published European patent applications 0438230. 0494774 and 0497612, and published International patent applications 93/18029, 94/02477 and 94/03446. The compounds described therein are stated to be agonists of 5-HT~-like receptors, and accordingly to be of particular use in the treatment of migraine and associated conditions. None of these publications, however, discloses nor even suggests the piperidine derivatives provided by the present invention.

In EP-A-0~48813 is described a series of alklJ~y~yr;din-4-yl and alkoxypyrimi-~in-4-yl derivatives of indol-3-ylalkylpiperazines which are alleged to provide tre~t.ment of v~ul~r or vRRc~ r-related he~ch~s, inclu(ling mig~aine. There is, however, no disclosure nor any suggestion in EP-A-0548813 of replacing the substituted piperazine moiety with a differently substituted piperidine moiety.
WO-A-91/18897 describes a class of trypt~mine derivatives substituted by various five-membered rings, which are stated to be specific to a particular type of''5~HTI-like'' receptor and thus to be effective agents for the treatment of rlinif ~l cor-rlitions, particularly migraine, requiring this activity. A further class of tryptamine derivatives with alleged anti-migraine activity is disclosed in WO-A-94/02460. However, neither WO-A-91/18897 nor W0-A-94102460 discloses or suggests the piperidine derivatives provided by the present invention.
Moreover, nowhere in the prior art mentitlned above is there any disclosure of a subtype-selective 5-HTlD receptor agonist having a 5-HTlD~
receptor binding affinity (ICso) below 50 nM and at least a 10-fold selective affinity for the 5-HTlD~ receptor subtype relative to the 5-HTlD~ subtype.
The compounds accolding to the present invention are subtype-selective 5-HTlD receptor agonists having a human 5-HTlD~ receptor binding affinity (IC~o) below 50 nM, typically below 1() nM and preferably below 1 nM; and at least a 10-fold selective afEnity, typically at least a 50-fold selective aff;nity and preferably at least a 100-fold selective affinity, for the human 5-HTlD,~ receptor subtype relative to the 5-HTlD~ subtype.
Moreover, the compounds in accordance with this invention possess interesting properties in terms of their efficacy and/or bioavailability.
The present invention provides a compound of formula I, or a salt or prodrug thereof:

Q - N ~ R
~-E ~
T V' wherein ~ represents hydrogen, halogen, cyano, nitro, triiluoromethyl, -OR5, -OCOR5, -OCONR5R6, -OCH2CN, -OCHaCONR5R6, -SR5, -SOR5, -SO2R5, -SO2NR~R6 -NR5R6, -NR5COR6, -NR5CO2R6, -NR5SO2R6, -COR5, -CO2R~, -CONR5R6, or a group of formula (Za), (Zb), (Zc) or (Zd):

N X ~ ~4 - N ~ R~ o~ NY

(Za) (Zb) (Zc) (Zd) in which the asterisk * denotes a chiral centre; or Z represents an optionally substituted five-membered heteroaromatic ring selected from furan, thiophene, pyrrole, oxazole, t.hi~7.01e, isoxazole, isot.hi~7.0l~, irni~1~7.ole, pyrazole, oxadiazole, thiadiazole, triazole and tetrazole;
X represents oxygen, sulphur, -NH- or methylene;
Y represents oxygen or sulphur;
E represents a chemical bond or a straight or branched alkylene chain cont~ining from 1 to 4 carbon atoms;
Q represents a straight or branched alkylene chain conts3ining fiom 1 to 6 carbon atoms, optionally substituted in any position by one or more substituents selected from fluoro and hydroxy;

CA 02236832 l998-05-06 W O 97/18202 PCT~GB96/027~5 T represents nitrogen or CH;
U represents nitrogen or C-R2;
- V represents oxygen, sulphur or N-R3;
G is ~tt~rh~d at position 3 or 4 of the piperidine ring and represents 5 halogen or Cl 6 alkoxy;
Rl rep~esents C3 6 alkenyl, C3-6 alkynyl, aryl(Cl 6)alkyl or heteroaryl(Cl 6)alkyl, any of which groups may be optional~y substituted;
R2, R3 and R4 indepe~ ntly represent hydrogen or Cl 6 alkyl; and R5 and R6 independently represent hydrogen, Cl.6 alkyl, 10 tri~Luoromethyl, phenyl, methylphenyl, or an optionally substituted aryl(Cl 6)alkyl or heteroaryl(Cl 6)alkyl group; or R5 and R6, when linked through a nitrogen atom, together represent the residue of an optionally substituted azetidine, pyrrolidine, piperidine, morpholine or piperazine ring.
VVhere Z in the compounds of formula I above represents a five-membered heteroaromatic ring, this ring may be optionally substituted by one or, where possible, two substituents. As will be appreciated, where Z
represents an o~ 7.01e, thiadiazole or tetrazole ring, only one substituent will be possible; otherwise, one or two optional substituents 20 may be accommodated around the five-membered heteroaromatic ring Z.
F,~rzlmples of suitable substituents on the five-membered heteroaromatic ring Z include C1_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.7 cycloalkyl, aryl, arY1(C1 6)a1kY1~ C3.7 heterocycloalkyl, heteroaryl, heteroaryl(Cl 6)alkyl, C1-G
alkoxy, C1 6 alkylthio, amino, C1 G alkyl~mino, di(Cl 6)alkyl~mino, halogen, 25 cyano and tri~uoromethyl.
The group R1 may be optionally substituted by one or more substituents, as also may the groups R5 or R6 where these represent aryl(Cl G)alkyl or heteroaryl(Cl 6)alkyl. Rl may be unsubstituted. R1 may be substituted Where Rl, R~ or R6 represents aryl(C~.6)alkyl or ~0 heteroaryl(Cl 6)alkyl, any optional substitution will suitably be on the arylor heteroaryl moiety thereof, although substitution on the alkyl moiety thereof is an alternative po.c.~ihilit.y ~.~r~mples of optional substituents thereon include halogen, cyano, tri~luoromethyl, triazolyl, tetrazolyl, Cl 6 alkyl-tetrazolyl, hy~ y, Cl 6 alkoxy, Cl 6 alkylthio, C2 6 alkoxycarbonyl, Ca 6 alkylcarbonyl, Cl.6 alkylsulphonyl, arylsulphonyl, ami~lo, Cl.6 alkyl~mino, di(Cl.6)alkyl~min.~, di(Cl.6)alkylaminomethyl, Ca.6 alkylcarbonyl~mino, arylcarbonylamino, C2.6 alkoxycarbonyl~minr, N-(Cl.6)al:kyl-N-(C2.6)alkoxycarbonylamino, Cl.6 alkylsulphonyl~minn, arylsulphonyl~mino, Cl 6 alkylsulphonyl~min(.methyl, aminocarbonyl~min-), Cl.6 alkyl~minoc~rbonylamino, di(Cl.6)alkylaminocarbonyl~n~in~, mono- or diaryl~minncarbonylamino, pyrrolidinylcarbonyl~mino, piperidinylcarbonyl~mino, aminocarbonyl, Cl.6 alkyl~minncarbonyl, di(Cl.6)alkylaminocarbonyl, ~mino~ulphonyl, C1.G
alkylaminosulphonyl, di(Cl.6)alkyl~minosulphonyl, aminosulphonylmethyl, Cl-6 alkylaminosulphonylmethyl and di(Cl.6)alkyl~minosulphonylmethyl.
When R5 and R6, when linked through a nitrogen atom, together represent the residue of an azetidine, pyrrolidine, piperidine, morpholiIle or piperazine ring, this ring may be unsubstituted or substituted by one or more substituents. ~.~mples of suitable substituents include Cl.6 alkyl, aryl(Cl.6)alkyl, C1-6 alkoxy, C2 6 alkoxycarbonyl and C1 G
all~yl~rninocarbonyl. Typical substituents include methyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and methylz~minocarbonyl. In particular, where R~ and R6 together represent the residue of a piperazine ring, this ring is preferably substituted on the distal nitrogen atom by a 2~ C2 6 alkoxycarbonyl moiety such as methoxycarbonyl or ethoxycarbonyl.
As used herein, the expression "Cl 6 alkyl" includes methyl and ethyl groups, and straight-chained or branched propyl, butyl, pentyl and hexyl groups Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as "ClG alkoxy", "C1-G
30 alkylthio" and "Cl 6 alkylamino" are to be construed accordingly.

CA 02236832 1998-0=.-06 W O 97/18202 PCT/~5''~2765 The expression ''C26 alkenyl" as used herein refers to straight-chained and branched alkenyl groups cont~ininF from 2 to 6 carbon atoms.
Ibpical examples include vinyl, allyl, dimethylallyl and butenyl groups.
The expression "C2 6 a~kynyl" as used herein refers to straight-chained and branched alkynyl groups col t~ining from 2 to 6 carbon atoms.
Typical examples include ethynyl and propargyl groups.
Typical C3-7 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Typical aryl groups include phenyl and naphthyl.
The expression "aryl(Cl 6)alkyl" as used herein includes benzyl, phenylethyl, phenylpropyl and naphthylmethyl. As rn~nt,ione~d above the alkyl group may be straight or branched.
Suitable heterocycloalkyl groups include azetidinyl, pyrrolidyl, piperidyl, piperazinyl and morpholinyl groups.
16 ~llit.~hle heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyrirlf~7~inyl~ pyrimi-1inyl, pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imitl~7.01yl, ben7imitl~zolyl, o~ 7.olyl, thiadiazolyl, triazolyl and tetrazolyl groups.
The expression "heteroaryl(Cl 6)alkyl" as used herein includes furylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl, oxazolylethyl, thiazolylmethyl, thiazolylethyl, imit~7.olylmethyl, imi~ 701ylethyl, o~ 7nlylmethyl, oxadiazolylethyl, thi~ 701ylmethyl, t.hi~ 7olylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridylmethyl, pyridylethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolylmethyl and isoquinolylmethyl.
The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine.
For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts m~ay, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the co~npounds of this invention include acid addition salts which may, for example, be formed by mi~ring a solution of the compound according to the invention with a solution of a ph~r~ceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, f~m~ric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; ~lkslline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic lig~n~.~, e.g. quaternary ammonium salts.
The present invention includes within its scope prodrugs of the compounds of formula I above. In general, such prodrugs will be 1~ functional derivatives of the compounds of formula I which are readily convertible in viuo into the re~uired compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H.
Bundgaard, Elsevier, 1985.
Where the compounds according to the invention have at least one asymmetric centre, they may accordi~gly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. For example, the compounds of formula I above wherein Z represents a group of formula 2~ (Zb) or (Zc) have a chiral centre denoted by the asterisk *, which may accordingly be in the (R) or (S) configuration. lt is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
Where E and Q, which may be the same or different, 1epresent 30 straight or branched alkylene chains, these mav be, for example, methylene~ ethylene, 1-methylethylene, propylene, 2-methylpropylene or g butylene. In ~(1(1it.i~, the alkylene chain Q may be substituted in any position by one or more substituents selected from fluoro and Ly~llo~y giving rise, for example, to a 2-hy(li~u~y~ropylene, 2-hydroxymethyl-propylene, 2-fluoropropylene or 2-~1uoromethyl-propylene chain Q.
- 5 Moreover, E may represent a f~hemic~l bond such that the moiety Z is ~tt~hed directly to the central fused bicyclic heteroaromatic ring system cont~ininF the variables T, U and V.
Suitably, E represents a chemical bond or a methylene ~inkage.
Representative alkylene chains for Q in~ Ae propylene, butylene, 2-hydrokyl~ropylene, 2-hydroxymethyl-propylene, 2-iluoropropylene and 2-fluoromethyl-propylene, especially propylene.
The compound of formula I in accordance with the present invention is suitably an indole, benzofuran or benzthiophene derivative of formula IA, an in~l~7.o~ derivative of formula IB, or a pyrrolo~2,3-clpyridine derivative of formula IC:

Q--Z E~ G (IA) Q - N ~ Rl Z E~ " ~ _ ~ G (IB) N
~R3 Q - N ~ Rl 'N' G (IC) W O 97/18202 PCT/G~9610276', wherein Z, E, Q, V, G, Rl, R2 and R3 are as defined above. Pre~erably, the compounds according to the invention are indole or pyrrolo~2,3-c]pyridine derivatives of formula ID: -~ - N ~ R
Z-E ~ 2 G

wherein Z, E, Q, T, G, R1, R2 and R3 are as defined above, in particular wherein R2 and R3 are both hydrogen.
Suitable values for the substituent Rl include allyl, dimethylallyl, 10 butenyl, propargyl, benzyl, phenylethyl, phenylpropyl, furylmethyl, thienylmethyl, furylethyl, thienylethyl, imirl~7.01ylmethyl and pyridylmethyl; alternatively allyl, dimethylallyl, butenyl, propargyl, benzyl, phenylethyl, phenylpropyl, furylmethyl, thienylmethyl, imi~ olylmethyl and pyridylmethyl, any of which groups may be 15 optionally substituted by one or more substituents selected typically i~rom halogen, cyano, trifluoromethyl, triazolyl, tetrazolyl, Cl.6 alkyl-tetrazolyl, C1.G alkoxy, amino, di(Cl.6)alkylamino, di(Cl.6)alkylaminomethyl, C2-G
alkylcarbonylarnino, C2.6 alkoxycarbonyl~mino, N-(Cl.G)alkyl-N-(C2.6)alkoxycarbonylamino, C1.6 alkylsulphonylamino, ~!0 aminocarbonylamino, aminocarbonyl, Cl 6 alkylaminocarbonyl, di(C1.G)alkyl~minocarbonyl, aminosulphonyl, di(Cl G)alkylaminosulphonyl and C~1-G alkylaminosulphonylmethyl.
Particular values of Rl include allyl, dimethylallyl, butenyl, propargyl, benzyl, fluorobenzyl, di~uorobenzyl, cyanobenzyl, tetrazolyl-25 benzyl, methyltetrazolyl-benzyl, methoxybenzyl, aminobenzyl, dimethylaminomethyl-benzyl, acetylamino-benzyl, aminocarbonyl-benzyl, methylaminocarbonyl-benzyl, dimethyl"minocarbonyl-benzyL
aminosulphonyl-benzyl, dimethylaminosulphonyl-benzyl, trifluoromethyl-CA 02236832 1998-0~-06 W O 97/18202 PCTIGB96/~276 benzyl, phenylethyl, fluoro-phenylethyl, difluoro-phenylethyl, trifluoromethyl-phenylethyl, cyano-phenylethyl, methoxy-phenylethyl, triazolyl-phenylethyl, amino-phenylethyl, dimethyl~mino-phenylethyl~
acetyl~rnino-phenylethyl, methoxycarbonylamino-phenylethyl, (N-methyl-N-methoxycarbonyVamino-phenylethyl, aminocarbony~mino-phenylethyl~
fluoro(phenyl)propyl, phenylpropyl, furylmethyl, thienylmethyl, furylethyl, thienylethyl, imirl:q7.01ylmethyl, pyridylmethyl and amino-pyridylmethyl;
other values are allyl, dimethylallyl, butenyl, propargyl, benzyl, ~luorobenzyl, di~1uorobenzyl, cyanobenzyl, tetrazolyl-benzyl, 10 methyltetrazolyl-benzyl, methoxybenzyl, aminobenzyl, dimethyl ~ m i n nmethyl-benzyl, acetylamino-benzyl, aminocarbonyl-benzyl, methyl~ninocarbonyl-benzyl, dimethylaminocarbonyl-benzyl, aminosulphonyl-benzyl, dimethylaminosulphonyl-benzyl, phenylethyl, fluoro-phenylethyl, difluoro-phenylethyl, trifluoromethyl-phenylethyl, 15 cyano-phenylethyl, triazolyl-phenylethyl, amino-phenylethyl, dimethyl~mino-phenylethyl, acetylamino-phenylethyl, methoxycarbonyl~mino-phenylethyl, (N-methyl-N-methoxycarbonyl)amino-phenylethyl, aminocarbonylamino-phenylethyl, phenylpropyl, furylmethyl, thienylmethyl, i m i .1 Zl ~.olylmethyl, 20 pyridylmethyl and amino-pyridylmethyl.
Suitably, R2 and R3 independently represent hydrogen or methyl, especially hydrogen.
Suitably, R4 represents hydrogen or methyl, especially hydrogen.
~ uitably, R5 and R6 are independently selected from hydrogen, 2O methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, trifluoromethyl, phenyl, methylphenyl (especially 4-methylphenyl), benzyl and phenethyl.
In the compounds of formula I above, the substituent G suitably represents fluoro or methoxy.
~ uitably, the substituent Z represents hydrogen, fluoro, cyano, 30 hydroxy, methoxy, ethoxy, benzyloxy, methylamino-carbonyloxy, cyano-methoxy, aminocarbonyl-methoxy, methylsulphonyl, aminosulphonyl, N-methyl~mino-sulphonyl, N,N-dimethylamino-sulphonyl, amino, formyl~mino, acetylamino, tri~1uoromethyl-carbonyl~minr., benzyloxy-carbonylamino, methyl-sulphonyl~minr~ ethyl-sulphonyl~mino, methylphenyl-sulphonyl~min~ N-methyl-(N-methylsulphonyl)-amino, N-methyl-(N-ethylsulphonyl)-amino, N-methyl-(N-tri~Luoromethylsulphonyl)-amino, N-ethyl-(N-methylsulphonyl)-amino, N-benzyl-(N-methylsulphonyl)-amino, N-benzyl-(N-ethylsulphonyl)-amino, acetyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methyl~minncarbonyl, ethylaminocarbonyl, propyl~minQcarbonyl, 10 butylaminocarbonyl, benzyl~minocarbonyl or phenethyl-aminocarbonyl; or a group of formula (Za), (Zb), (~c) or (Zd) as defined above; or an optionally substituted ~ve-membered heteroaromatic ring as specified above.
In a particular embodiment, Z represents -S02NR5R6 in which R5 and R6 are as defined above. In a subset of this embodiment, R5 and R6 15 independently represent hydrogen or Cl 6 alkyl, especially hydrogen or methyl. Particular values of Z in this context include aminosulphonyl, N-methyl~min(l-sulphonyl and N,N-dimethylamino-sulphonyl, especially N-methyl ~ m i n o-sulphonyl.
In another embodiment, Z represents a group of formula (Zb) in 20 which R4 is hydrogen or methyl. In a subset of this embodiment, ~i and Y
both represent oxygen. In a particular aspect of this subset, the chiral centre denoted by the asterisk * is in the (S) configuration.
When the group Z represents an optionally substituted five-membered heteroaromatic ring, this is suitably a 1,3-oxazole, 1,3-thiazole, 25 imi~3~70le, 1,2,4-oxadiazole, 1,3,4-ox~ 701e, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole or tetrazole ring. Preferably, the ring is a 1,3-oxazole, 1,3-thi~ol.o, 1,2,4-oxadiazole, 1,2,4-thiadiazole or 1,2,4-triazole ring, in particular a 1,2,4-triazol-1-yl or 1,2,4-triazol-4-yl moiety.

=== -W O 97/18202 PCT/GB96~a~765 Suitably, the five-membered heteroaromatic ring Z is unsubstituted.
~ m~les of optional substituents which may typically be attached to the - moiety Z include methyl, ethyl, benzyl and amino.
A particular sub-clas6 of compounds accoldillg to the invention is 5 represented by the compounds of formula IIA, and salts and prodrugs thereof:

N--(CH2)m ~_~ ~< (CH2)p T N
H

(IIA) ~0 wherein m is zero, 1, 2 or 3, preferably zero or 1;

p is zero, 1 or 2;

Ql represents a straight or branched alkylene chain cont~3ining fiom 2 to 5 carbon atoms, optionally substituted in any position bv one or more ~5 substituents selected from fluoro and hydroxy;

T represents nitrogen or CH;

Gl represents fluoro or methoxy;

A represents nitrogen or CH;

B represents nitrogen or C-R8;

2() ~7 and R8 independently represent hydrogen, C1-G alkyl, C~ G

alkenyl, C3.7 cycloalkyl, aryl, aryl(Cl 6)alkyl, C3., heterocycloalkyl, heteroaryl, heteroaryl(Cl-G)alkyl, Cl.6 alkoxy, C1-G alkylthio, amino, C1.

alkylamino, di(Cl 6)alkylamino, halogen, cyano or trifluorometh~rl;

W represents a group of formula (Wa), (Wb) or (Vi'c):

R~ ~ R9 W' W2 H
~a) ~Wb) ~c) in which Wl represents CH or nitrogen;
VV2 represents oxygen, sulphur, NH or N-methyl;
R9 represents hydrogen, halogen, cyano, trifluoromethyl, triazolyl, tetrazolyl, C1.6 alkyl-tetrazolyl, C1 6 alkoxy, C2.6 alkylcarbonyl, amino, C,.6 alkylamino, di(Cl ~)alkylz.mino, di(Cl 6~aL~cylaminomethyl, C2 G
alkylcarbonylz~mino, Cl 6 alkylsulphonylamino, aminocarbonylamino, C1 G
alkyl~n inocarbonyl, aminosulphonyl, di(Cl 6)alkyl~minosulphonyl or Cl 6 alkylaminosulphonylmethyl; and R10 represents hydrogen or C13 aLkyl optionally substituted by halogen.
Suitably, Q' represents a straight or branched 3 or 4 carbon alkylene chain, optionally substituted in any position by one or more substituents selected from fluoro and hydroxy. Particular alkylene chains for Ql include propylene, butylene, 2-hydlo~y~ropylene, 2-(hydroxymethyl)-propylene, 2-fluoropropylene and 2-(fluoromethyl)-propylene, especially propylene.
Particular values of R7 and R8 include hydrogen, methyl, ethyl, benzyl and amino, especially hydrogen.
Particular values of R9 include hydrogen, fluoro, cyano~ triazolyl, tetrazolyl, methyl-tetrazolyl, methoxy, amino, dimethyl~minnmethyl, acetvls~minn, aminocarbonylamino, methylaminocarbonyl, aminosulphonyl and dimethylaminosulphonyl, especially hydrogen or fluoro.
Particular values of Rl~ include hydrogen and Cl-3 alkyl, for example hydrogen and methyl.
-Another sub-class of compounds according to the invention is represented hy the compounds of formula IIB, and salts and prodrugs thereof:

o~\\ \~ N~<(~H~)p--<

~IB) wherein m, p, Ql, T, Gl, W and Rl~ are as defined with reference to formula IIA above; and R5 and R6 are as defined with reference to formula I above.
Particular values of R5 and R6 in relation to formula IIB above include hydrogen and Cl 6 alkyl, especially hydrogen or methyl. Suitably, one of Rs and R~ represents hydrogen and the other represents hydrogen or methyl.
A further sub-class of compounds according to the invention is represented by the compounds of formula IIC, and salts and prodrugs thereof:

y~ ~ 3 (CH~

(IIC) wherein the asterisk * denotes a chiral centre;

W O 97~1820~ PCT/GB96/0276 m, p, Ql, T, Gl, W and Rl~ are as defined with reference to formula ITA above; and R4 and Y are as defined with re~erence to formula I above.
Particular values of R4 in rel~ion to formula II~ include hydrogen 5 and methyl.
Preferably, Y in formula IIC is oxygen.
Preferably, the chiral centre denoted by the asterisk * in formula IIC is in the (S) configuration.
Specific compounds within the scope of the present invention 10 include:
4-benzyl-4-~luoro-1-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-YVpropyl~piperidine;
4-fluoro-4-r2-(3-fluorophenyl)ethyl]-1-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-YVpropyl]pipf~r~ ne;
4-fluoro-4-(3-fluorobenzyV-1-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]piperidine;
4-~luoro-4-(2-fluorobenzyl)-1-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl~piperidine;
4-benzyl-4-methoxy-1-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyllpiperidine;
4-benzyl-4-methoxy-1-[3-(5-(1,2,4-triazol-1-ylmethyl~-lH-indol-3-yl)propyl3piperidine;
4-(2-fluorobenzyl)-4-methoxy-1-[3-(~-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]piperidine;
4-(3-fluorobenzyl)-4-methoxy-1-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl~piperidine;
4-(4-fluorobenzyl)-4-methoxy-1-[3-(5-(1,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]piperidine;
4-fluoro-4-[2-(trifluoromethyl)benzyl] -1-{3-~ 5-(1,2,4-triazol-4-yl)- lH-indol-3-yl]propyl}piperidine;

4-~Luoro-4-~2-(N,N-dimethyl~minosulfonyl)benzyl]-1-~3-[5-(1,2,4-triazol-4-yl)-lH-indol-3-yl~propyl}piperidine;
4-fluoro-4-(2-phenylpropyV-1-{3-~5-(1,2,4-triazol-4-yl)-lH-indol-3-yl]propyl}piperifline;
4-fluoro-4-~3-fluoro-(2-phenyl)propyl~ 3-[5-(1,2,4-triazol-4-yl)-lH-indol-3-yl~propyl}piperidine;
4-fluoro-4-[2-(4-~1uorophenyl)ethyl]-1-{3-[~-~1,2,4-triazol-4-yl)-lH-indol-3-yl3~lv~yl~piper~ ne;
4-~luoro-4-(2-phenylethyl)-1-{3-[5-(1,2,4-triazol-4-yV-lH-indol-3-yl]propyl}piperidine;
4-fluoro-4-~2-(2-fluorophenyl~ethyl]-1-~3-~5-(1,2,4-triazol-4-yl)-lH-indol-3-yl]propyl}piperidine;
4-fluoro-4-~2-(2-methoxyphenyl)ethyl]- 1-{3-15-(1,2,4-triazol-4-yl)-lH-indol-3-yl~propyl}piperi~lin~;
1~ 4-fluoro-4-~2-(2-thienyl)ethyl]-1-{3-[5-(1,2,4-triazol-4-yl)-lH-indol-3-yl~propyl}piperidine;
4-[2-(2-cyanophenyl~ethyl3-4-fluoro-1-~3-[5-(1,2,4-triazol-4-yl)-lH-indol-3-yl]propyl}piperidine;
4-fluoro-4-r2-(3-methoxyphenyl)ethyl~-1-{3-~5-(1,2,4-triazol-4-yl)-lH-indol-3-yllpropyl}piperidine;
4-fluoro-4-~2-(3-thienyl)ethyl~-1-{3-~5-(1,~,4-triazol-4-yl)-lH-indol-3-yl3propyl}piperidine;
and salts and prodrugs thereo~
The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intr~nf~.c~l, subli~gual or rectal ~flmini.ctration, or for administration by inhalation or insufflation. For preparing solid , CA 02236832 1998-0=.-06 W O 97/18202 PCT/~5~2765 compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. convenfit n~l tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other ph~rm~eutical diluents, e.g. water, to form a solid preformulation composition con~ining a homogeneous mixture of a compound of the present invePtion, or a pharmaceutically acceptable salt thereof. When ref~rring to these preformulation compositions as homogeneous, it is meant that the ac~ive ingredient is dispersed evenly throughout the composition so that the lO composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above cont~ining from 0.1 to about 600 mg of the active ingredient of the present invention. 'I'ypical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the 20 former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric 25 acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably fLavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed 30 oil, sesame oil, coconut oil or peanut oil, as well as elixirs and .~imil~r pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tr~c~nt:h, ac~ alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of migraine, a suitable dosage level is about 0.01 to - 5 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 6 mg/kg per day. The compounds may be ~-lmini.~tered on a regimen of 1 to 4 times per day.
The compounds acco~ Ll.g to the invention wherein T represents CH, U represents C-R2 and V represents N-R3, corresponding to the indole derivatives of formula ID as defined above wherein T represents CH, may be prepared by a process which comprises re~tin~ a compound of formula III:
Z~

(III) wherein Z and E are as defined above; with a compound of formula I~, or a carbonyl-protected form thereof:

2 J~ ~ N~ ~, (IV) wherein Q, G, Rl and R2 are as defined above; followed, where requlred, bv N-alkylation by standard methods to introduce the moiety R3.
The reaction between compounds III and IV, which is an example of the well-known Fischer indole synthesis, is suitably carried out by heating the reagents together under mildly acidic COntlitioIls~ e.g. 4% sulphuric acid at reflux.
Suitable carbonyl-protected forms of the compounds of formula IV
include the dimethyl acetal or ketal derivatives. VVhere the alkylene chain 5 Q contains a hydl'o~y group, this group may coT~ e with the carbo~yl moiety in compound IV, whereby the carbonyl moiety is protected in the form of a cyclic hemiacetal.
The Fischer reaction between compounds III and I~ may be carried out in a single step, or may proceed via an initial non-cyclising step at a 10 lower temperature to give an intermediate of formula V:

Z--E ~ I ~ R' wherein Z, E, Q, G, Rl and R2 are as defined above; followed by cyt~ tion 15 using a suitable reagent, e.g. a polyphosphate ester.
The intermediates of formula IV, or carbonyl-protected forms thereof, may be prepared by reacting a compound of formula VI, or a carbonyl-protected form thereof, with a compound of formula ~ Q - Ll H - N ~ R' wherein Q, G, Rl and R2 are as defined above, and Ll represents a suitable leavmg group.
The leaving group Ll is suitably a halogen atom, e.g. chlorine or 25 bromine.

CA 02236832 1998-0=,-06 Where Ll represents a halogen atom, the reaction between compounds VI and VII is conveniently effected by stirring the reactaIlts under basic conditions in a suitable solvent, for example potassium carbonate in N,N-dimethylf~rm~mi~ , or triethyl~mine in tetrahydrofuran 6 or acetonitrile.
In an alternative procedure, the compounds according to the invention may be prepared by a process which comprises re~c~inE~ a compound of formula VII as defined above with a compound of formula VIII:

z--E ~,QIJ L2 (VIII) wherein Z, E, Q, T, U and V are as defined above, and L2 represents a suitable leaving group.
The leaving group L2 is suitably an alkylsulphonyloxy or arylsulphonyloxy group, e.g. methanesulphonyloxy (mesyloxy) or p-toluenesulphonyloxy (tosyloxy).
VVhere L2 represents an alkylsulphonyloxy or arylsulphonyloxy group, the reaction between compounds VII and VIII is conveniently 20 carried out in a suitable solvent such as 1,2-dimethoxyethane or isopropyl alcohol, typically in the presence of a base such as sodium carbonate or potassium carbonate, optionally with the addition of sodium iodide.
In one representative approach, the compounds of formula VIII
wherein T and U both represent CH, V represents NH and L2 represents a 25 mesyloxy or tosyloxy group may be prepared by the sequence of steps illustrated in the following reaction scheme (cf. Larock and Yum, J. Am.
Chem. Soc., 1991,113, 6689):

Z- E ~ Z-E ~ (2) NH2 N~2 ~) ~ I~ " z E ~ ~ ~

~ H

wherein Z, E and Q are as defined above, L3 represents mesyloxy or 5 tosyloxy, and TES is an abbreviation for triethylsilyl.
In Step ~ of the reaction scheme, the aniline derivative IX is treated with iodine monochloride, typically in methanol or acetonitrile, in order to introduce an iodine atom ortho to the amine moiety. Step 2 involves a palladium-mediated coupling reaction with the protected acetylene 10 derivative TES-C-C-Q-OTES, typically using palladium acetate and triphenylphosphine in the presence of lithium chloride and sodium carbonate, suitably in N,N-dimethylform~mi-~e at an elevated temperature. This is followed in Step 3 by removal of the TES moiety, typically by treatment with hydrochloric acid; followed in turn by 15 mesylation or tosylation, suitably by using mesyl chloride or tosyl chloride respectively in the presence of a base such as triethyl~m~n~ or pyridine, typically in dichloromethane/acetonitrile.
In another representative approach, the compounds of formula VIII
wherein T and U both represent CH, V represents NH, Q represents a 20 propylene chain and L2 represents a mesyloxy or tosyloxy group may be prepared by reacting 3,4-dihydro-2H-pyran with a compound of formula III
as defined above or a salt thereof, under a variant of the Fischer reaction conditions as described above for the reaction between compounds III and I~; followed by mesylation or tosylation of the 3-hydroxypropyl-indole derivative thereby obtained, typically by treatment with mesyl ~hlori~e or tosyl chloride under standard conditions.
The Fischer reaction with 3,4-dihydro-2H-pyran is suitably brought about by stirring the pyran derivative with an acid addition salt of the 5 hydrazine derivative III, typically the hydrochloride salt, in an inert solvent such as aqueous ethanol. The resulting hydrazide derivative can then be cyclised by treatment with a Lewis acid such as zinc chloride, in a solvent such as 1,2-dimethoxyethane, suitably at the reflux temperature of the solvent.
In a further procedure, the compounds according to the invention wherein U represents nitrogen and V represents N-R3, corresponding to the indazole derivatives of formula IB as defined above, may be prepared by a process which comprises cyclising a compound of formula X:
E

Q - N ~ Ri NH2 N -D' (X) wherein Z, ~, Q, G and 3:~l are as defined above, and Dl represents a readily displaceable group; followed, where required, by N-alkylation by standard methods to introduce the moiety R3.
The cyclisation of compound X is conveniently achieved in a suitable organic solvent at an elevated temperature, for example in a mixture of m-xylene and 2,6-lutidine at a temperature in the region of 140~C.
The readilv displaceable group Dl in the compounds of formula X
suitably represents a Cl4 alkanoyloxy group, preferably acetoxy. Where Dl represents acetoxy, the desired compound of formula X may be - conveniently prepared by treating a carbonyl compound of formula XI: ~5 'E

Q - N ~ R~

(XI) wherein Z, E, Q, G and Rl are as defined above; or a protected derivative thereof, preferably the N-formyl protected derivative; with hydlu~yl~min~
5 hydrochloride, advantageously in pyridine at the reflux temperature of the solvent; followed by acetylation with acetic anhydride, advantageously in the presence of a catalytic quantity of 4-dimethyl~minopyridine, in dichloromethane at room temperature.
The N-forrayl protected derivatives of the intermediates of formula 10 XI may conveniently be prepared by ozonolysis of the corresponding indole derivative of formula XII:

Q - N ~ R' Z-E ~ G

N

H

wherein Z, E, Q, G and Rl are as defined above; followed by a reductive 15 work-up, advantageously using dimethylsulphide.
The indole derivatives of formula XII may be prepared by methods analogous to those described in the accompanying Examples, or by procedures well known from the art.
In a still further procedure, the compounds according to the 20 invention wherein T represents CH, U represents C-R2 and V represents oxygen or sulphur. corresponding to the benzofuran or benzthiophene derivatives of formula LA wherein V is oxygen or sulphur respectively, may be prepared by a process which comprises cyclising a compound of formula XIII:

Z--E~'V R

~XIII) wherein Z, E, Q, G, Rl and R2 are as defined above, and Vl represents oxygen or sulphur.
The cyclisation of compound XIII is conveniently effected by using 10 polyphosphoric acid or a polyphosphate ester, advantageously at an elevated temperature.
The compounds of formula XIII may be prepared by reacting a compound of formula XIV with a compound of formula XV:

Z--E ~3~Vl--H ~~Q--N~ ~ ' Hal R

~ ~ (XV~

wherein Z, E, Q, G, Rl, R2 and Vl are as defined above, and Hal represents a halogen atom.
The reaction is conveniently effected in the presence of a base such 20 as sodium hydroxide.
The hydroxy and mercapto derivatives of formula XIV may be prepared by a variety of methods which will be readily apparent to those skilled in the art. One such method is described in EP-A-0497~12.

In a yet further procedure, the compounds accor~ g to the invention may be prepared by a process which comprises reducing a compound of formula XVI: -Q2 b~ ~ Rl Z-E ~ U G
T

5~gVI) wherein Z, E, T, U, V, G and R' are as defined above, and -Q2-CH2-corresponds to the moiety Q as def~ned above.
The reduction of compound XVI is conveniently ef~ected by treating the appropriate compound with a reducing agent such as lithium 10 aluminium hydride in an appropriate solvent, e.g. diethyl ether or tetrahydrofuran, or mixtures thereo~
The compounds of formula ~VI above may suitably be prepared by reacting the appropriate compound of formula VII as defined above with a compound of formula XVII:

Q--J

O,,~
T

~VII) wherein Z, E, T, U, V and Q2 are as defined above. and J represents a reactive carboxylate moiety.
Suitable values for the reactive carboxylate moiety J include esters, for example Cl 4 aLkyl esters; acid anhydrides, ~or example mixed W O 97/18202 PCT/GB9~02765 anhydrides with C~ lk~noi~ acids; acid h~ s~ for example acid chlorides; and acylimifl~olP~
By way of example, the intermediates of formula ~VII above whereiIl J is an acid rhlori~e moiety may be prepared by treating the 5 corresponding carboxylic acid derivative with thionyl ~hlnrifle in toluene.
~imil~rly, the intermediates of formula XVII wherein J is an acylimi~
moiety may be prepared by treating the corresponding carboxylic acid derivative with Ll~-carbony~ mitl~7~ Alternatively, the reactive carboxylate moiety J may be obtained by treating the corresponding 10 compound wherein J is carboxy with 1-(3-dimethyl~min-~propyl)-3-ethylcarbo~liimi(1~ hydrochloride and 1-hydroxybenzotri~ hydrate, optionally in the presence of triethyl~mina; the resulting activated carboxylate intermediate may then suitably be reacted irl situ with the required compound of formula VII.
1~ The hydrazine derivatives of formula III above may be prepared by methods analogous to those described in EP-A-0438230, EP-A-0497512, EP-A-0548813 and WO-A-91/18897, as also may the aniline derivatives of formula IX.
Where they are not commercially available, the starting materials 20 of formula VI, VII, XV and XVII may be prepared by methods analogous to those described in the accompanying F,~ mples, or by standard procedures well known from the art.
It will be understood that any compound of formula I init.i~lly obtained from any of the above processes may, where appropriate, 25 subsequently be elaborated into a further compound of formula I by techniques known from the art. For example, a compound of formula I
initiz~lly obtained wherein the Rl moiety is substituted by nitro or cyano may be converted by catalytic hydrogenation to the corresponding amino-or aminomethyl-substituted compound respectivel~. Additionally, a 30 compound of formula I wherein the Ri moiety is substituted by hydroxy, possibly obtained by lithium aluminium hydride reduction of a precursor CA 02236832 l998-0~-06 PCT/GB~6/02765 alkoxycarbonyl derivative, may be mesylated under standard conditions, and the mesyl group subsequently displaced by an amino moiety by treatment with the desired amine in a sealed tube at an elevated temperature. The amine derivative resulting from any of these procedures 5 may then, for example, be N-acylated using the appropriate acyl halide, e.g. acetyl ~hl~ritle; or aminocarbonylated, using potassium isocyanate, to the corresponding urea derivative; or converted to a 1,2,4-triazol-~yl derivative using N,N-dimethylform~mi~l~ azine; or reductively alkyla~ed by treatment with the appropriate aldehyde or ketone in the presence of 10 sodium cyanoborohydride. If desired, the amine derivative may also l~e carbamoylated by treatment with the requisite alkyl chlo- of u~ ate.
compound of formula I initi5~lly obtained wherein the Rl moiety is substituted by cyano may be converted, by treatment with sodium azide, to the corresponding tetrazole derivative, which in turn may be alkylated 15 on the tetrazole ring by treatment with an alkyl halide under standard con(lit.ion.~. By way of a~ ional illustration, a compound of formula I
ini~is3lly obtained wherein the Rl moiety is substituted by an alkoxycarbonyl moiety may be saponified, by treatment with an alkali metal hydroxide, to the corresponding carboxy-substituted compound, 20 which in turn may be converted to an amide derivative by treatment with the appropriate amine, advantageously in the presence of 1-(3-dimethyl~minopropyl)-3-ethylcarbodiimide hydror~hloriA~ and 1-hydroxybenzotriazole. Moreover, a compound of formula I wherein R3 is hydrogen initially obtained may be converted into a compound of formula I
2~ wherein R3 represents C1 G alkyl by standard alkylation techniques, for example by treatment with an alkyl iodide, e.g. methyl iodide, typically under basic conditions, e.g. sodium hydride in N,N-dimethylformz~mi~e.
Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of 30 stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The novel compounds may be , prepared in racemic form, or individual enantiomers may be prepared either hy enantiospecific synthe.~iq or by resolution. The novel compounds may, for example, be resolved into their component en~nti()merS by st~n-l~rd techniques such as preparative HPLC, or the ~ormz~tion Of 5 diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+~-di-p-toluoyl-l-tartaric acid, ~ollowed by fractional crystallization and regeneration of the free base.
The novel compo~ands may also be resolved by form~t.ion of diastereomeric esters or amides, ~ollowed by chromatographic separation and removal of 10 the chiral auxiliary.
During any of the above synthetic sequences it may be necessary andlor desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protectiue Groups ~n Organic l~i Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &
P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The following l~ mI)les illustrate the preparation of compounds 20 according to the invention.
The compounds in accordance with the present invention potently and selectively bind to the ~-HT1D~, receptor subtype, inhibit forskolin-stimulated adenylyl cyclase activity, and stimulate [35S~-GTP~S binding to membranes from clonal cell lines expressing human cloned receptors.
5-HT,D~/5-HTlD~ Radioligand Binding Chinese hamster ovary (CHO) clonal cell lines expressing the human 5-HTlD,~ and 5-HTlD~ receptors were harvested in PBS and 30 homogenised in ice cold ~0 mM Tris-HCl (pEI 7.7 at room temperature) with a ~inem~tica polytron and centrifuged at 48,000g at 4~C for 11 min.

PCT/GB96tO2765 The pellet was then resuspended in 50 mM Tris-HCl followed by a 10 min incubation at 37~C. Finally the tissue was recentrifuged at 48,000g, 4~C
for 11 min and the pellet resuspended, in assay buffer (composition in mM:
Tris-~ICl 50, pargyline 0.01, C~aCl2 4; ascorbate 0.1%; pH 7.7 at room temperature) to give the required volume immediately prior to use (0.2 mg protein/ml). Incubations were carried out for 30 min at 37~C in the presence of 0.02-150 nM [3HI-5-HT for saturation studies or 2-5 nM [3Hl-5-HT for displacement studies. The final assay volume was 1 ml. 5-HT (10 ~M) was used to define non-specific hinr~inE~. The reaction was initiated by 10 the addition of membrane and was termin~ted by rapid filtration through What.rn~n GFIB filters (presoaked in 0.3% PEI/ 0.5% Triton X) followed by 2 x 4 ml w~hing.~ with 50 mM Tris-HCl. The radioactive filters were then counted on a LKB beta or a Wallac beta plate counter. Binding parameters were determined by non-linear, least squares regres~ion 15 analysis using an iterative curve fittillg routine, from which ICso (the molar concentration of compound necessary to inhibit binding by 50%) values could be calculated for each test compound. The ICso values for binding to the 5-HTlD~ receptor subtype obtained for the compounds of the accompanying F.~r~m~les were below 50 nM in each case. Furthermore, 20 the compounds of the accompanying F,~mples were all found to possess a selective affinity for the 5-HTlD~ receptor subtype of at least 10-fold relative to the ~-HTIDIl subtype.

5-HTlDa/5-HTlD,3 Adenylyl Cyclase Assay Studies were performed essentially as described in J. Pharmacol.
Exp. Ther., 1986, 238, 248. CHO clonal cell lines expressing the human cloned 5-HTlDa and 5-HTlD~ receptors were harvested in PBS and homogenised, using a motor driven teflon/glass homogeniser, in ice cold Tris HCl-EGTA buffer ~composition in mM: Tris HCl 10, EGTA 1, pH 8.0 at room temperature) and incubated on ice for 30-60 min. The tissue was W O 97/18202 PCTlGB96~02765 then ~entrifuged at 20,000g for 20 min at 4~C, the supernatant discarded and the pellet resuspended in Tris HCl-EDTA buffer (composition in mM:
Tris HCl 50, EDTA 5, pH 7.6 at room temperature) just prior to assay.
The adenylyl cyclase activity was determined by measuring the conversion of a-[33P]-ATP to [33P3-cyclic AMP. A 10 ~Ll aliquot of the membr~ne suspension was incubated, for 10-15 min, in a final volume of 50 Ill, at 30~C, with or without forskolin (10 ,uM3, in the presence or absence of test compound. The incubation bufEer consisted of 50 mM Tris HCl ~pH 7.6 at room temperature), 100 mM NaCl, 30 ,uM GTP, 50 ,uM cyclic AMP, 1 mM
dithiothreitol, 1 mM ATP, 5 mM MgCl2, 1 mM l~:GTA, 1 mM 3-isobutyl-~-methyLxanthine, 3.5 mM cre~tinin~s phosphate, 0.2 mg~ml creatine phosphokins~.qe, 0.5-1 IlCi o~-[33P~-ATP and 1 nCi [3H~-cyclic AMP. The incubation was init.i~ted by the addition of membrane, following a 5 min preincubation at 30~C, and was terminated by the addition of 100 !ll SDS
(composition in mM: sodium lauryl sulphate 2%, ATP 45, cyclic AMP 1.3, pH 7.5 at room temperature). The ATP and cyclic AMP were separated on a double column chromatography system (Anal. Biochem., 1974, 58, 541).
Functional parameters were determined using a least squares curve fitting programme ALLFIT (Am. J. Physiol., 1978, 235, E97) from which Emax (m~im~l effect) and E C50 (the molar concentration of compound necessary to inhibit the m~rim~l effect by 50%) values were obtained for each test compound. Of those compounds which were tested in this assa~r, the F~C50 values for the 5-HTlD,~ receptor obtained for the compounds of the accompanying ~ mples were below 500 nM in each case. Moreover, the compounds of the accompanying F.~m}lles which were tested were all found to possess at least a 10-fold selectivity for the 5-HTlD,~ receptor subtype relative to the 5-HTlDa subtype.

, CA 02236832 1998-0=,-06 5-HTlDa/5-HTlDI,, GTPyS Binding Studies were performed essentially as described in Br. J.
Pharmacol., 1993, 109, 1120. CHO clonal cell lines expressing the human 5 cloned 5-HTlDa and 5-HTlD~ receptors were harvested in P~3S and homogenised using a Rinem~tica polytron in ice cold 20 mM HEPES
cont~inin~ 10 mM EDT~, pH 7.4 at room temperature. The membranes were then centrifuged at 40,000g, 4~C for 15 min. The pellet was then resuspended in ice cold 20 mM HEPES cont~inin~ 0.1 mM EDTA, pEI 7.4 at room temperature and recentrifuged at 40,000g, 4~C for 15-25 minutes.
The membranes were then resuspended in assay buffer ~composition in mM: HEPES 20, NaCl 100, MgCl2 10, pargyline 0.01; ascorbate 0.1%; pH
7.4 at room temperature) at a concentration of 40 ~lg protein/ml for the 5-HTlD~ receptor transfected cells and 40-50 ~Lg protein/ml for the 6-HTlD~
15 receptor transfected cells. The membrane suspension was then incubated, in a volume of 1 ml, with GDP (100 ~lM for ~-HTlDa receptor transfected cells, 30 ~lM for the 5-HTlD~ receptor transfected cells) and test compound at 30~C for 20 min and then transferred to ice for a further 15 min.
[35S]-GTP~S was then added at a final concentration of 100 pM and the 20 samples incubated for 30 min at 30~C. The reaction was initiated bv the addition of membrane and was terminated by rapid filtration through Whatman GF/B filters and washed with 5 ml water. The radioactive filters were then counted on a LKB beta counter. Functional parameters were determined by a non-linear, least squares regression analysis using 25 an iterative curve fitting routine, from which Emax (rn~imal effect) and ECso (the molar concentration of compound necessary to inhibit the m~im~l effect by 50%) values were obtained for each test compound. Of those compounds which were tested in this assay, the ECoO values for the 5-HTlD~ receptor obtained for the compounds of the accompanying 30 Examples were below 500 nM in each case. Moreover, the compounds of the accompanying Examples which were tested were all found to possess at least a 10-fold selectivity for the 5-HTlDa receptor ~ubtype relative to the 5-HTlD~ subtype.

INTl~,RMF.nIATE 1 ~ 5 3-~5-(1.2~4-1~iazol-4-vn-1E~-indol-3-vllpro~an-1-o 1. 4-Aminoacet~nili-l~
A solution o~4-nitroacet~nili-l~ (5.0g, 27.8mmol) in EtOH/EtOAc (160ml, 1:1), HzO (15ml) and 5N HCl (5.6ml, 28.0mmol) was hydrogenated over 10% Pd-C (O.~Og) at 50 psi for 0.2~h. The catalyst was removed by filtration through celite and the solvents removed under vacuum. The free base was generated by dissolving the product in H20, basifying with 2N
NaOH and extracting into EtOAc. The combined extracts were dried (M gSO4) and evaporated to give the title-aniline (3.75g, 90%); ~H (250MHz, CDCl3/d4-MeOH) 2.10 (3H, s, Me), 6.68 (2H, d, J=8.8Hz, Ar-H), ~.27 (2H, d, J=8.8Hz, Ar-H).

2. 4-(1~2.4-Triazol-4-Yl)acet~nili~
A mixture of the preceding aniline (3.52g, 23.4mmol), N,N-dimethylform~mi-l~ azine (3.33g, 23.4mmol; J. Chem. Soc. (C), ~Z 1664) andp-toluenesulphonic acid monohydrate (0.223g, 1.17mmol), in anhydrous toluene (lOOml) was heated at rei~ux for 17h. The beige coloured precipitate was filtered o~~, washed with toluene and CH2Cl2, and dried under vacuum to give the desired triazole (4.29g, 91%), ~ H (250MHz, d4-MeOH/d~-DMSO) 2.14 (3EI, s, CH3), 7.60 (2H, d, J=8.8Hz, Ar-H), 7.78 (2H, d, J=8.8Hz, Ar-H), 8.96 (2H, s, Ar-H).

3. 4~ 2,4-Triazol-4-vl)aniline A solution of the preceding acetanilide (4.91g, 24.3mmol) in 5N HCl (lOOml) was heated at 125~C for 1.5h. The mixture was cooled to 0~(~, basified with concentrated a~ueous NaOH solution and extracted with CH2Cl2 (x5). The combined extracts were dried (~ gSO4) and evaporated and the residue chromatographed on silica gel, eluting with CH2Cla/MeOH/NH3 (8~):8:1), to give the title-aniline (2.94g, 76%);
âH (250MHz, CDCls) 3.80 (2H, s, N H2), 6.71 (2H, d, ~=8.8Hz, Ar-H), 7.08 (2H, d, J=8.8Hz, Ar-H), 8.36 (2H, s, Ar-H).

4. 4-~1.2.4-Triazol-~-vl~Phenvlhvdrazine To a solution of the preceding ~niline (1.60g, 9.99mmoV in concen~rated HCl/EI2O (23ml and 3ml, respectively) was added, at -21~C, a solution of NaNO2 (0.69g, 9.99mmol) in HaO (8ml), at such a rate as to maintain the temperature below -10~C. The mixture was stirred for 0.3h and then filtered rapidly through a sinter, under vacuum. The filtrate was added to a cooled (-20~C) solution of SnCl2 ~20 (9.02g, 40.0mmol~ in concentrated HCl (17ml). The mixture was stirred at -20~C for 0.25h and 16 then at room temperature for 1.25h. The resulting solid was filtered of~, washed with Et20 and dried under vacuum. The crude product was dissolved in H20, basified with concentrated aqueous NaOH and extracted with EtOAc (x5). The combined extracts were dried (M gSO4) and evaporated to afford the t~tle-product (0.95g, 54%); ~H (250MHz, CDCl3/d4-MeOH) 3.98 (3H, br s, NH and NE2), 6.97 (2H, d, J=12.0Hz, Ar-H), 7.25 (2H, d, .,T=12.0Hz, Ar-H), 8.48 (2H, s, Ar-H~.

5. 3-r5-(1~2.4-Triazol-4-Yl)-1H-indol-3-vllPropan-l-ol A solution of 4-(1,2,4-triazol-4-yl)phenylhydrazine (26g, 143mmol) in dioxan (250ml) was treated with dihydropyran (24g, 286mmol) followed by lM hydrochloric acid (150ml) and heated at reflux for 18h. The reaction mixture was evaporated, treated with toluene the re-evaporated.
Inorganic solids were removed by treating the residue with a mixture of methanol and acetonitrile. The mother liquors were purifîed by column chromatography on silica using dichloromethanelmethanol (9:1~4:1) as the eluant. The compound was recrystallised from acetonitrile to afford the title compound as a colourle~s solid (10.24g, 30%); mp 205-207~C.
(Foam d: C, 64.37; H, 5.76; N, 22.83. Cl3Hl4N40 requires: C, 64.45;
H, 5,.82; N, 23.13%.) ~H (360MHz, DMSO-d6) 1.81 (2H, q, ~-7Hz, CH2), 2.75 (2H, t, J=8Hz, CH2), 3.46 (2H, dt, ~Jl=6, J2=5Hz, CH2), 4.43 (lH, t, J=6Hz, OH), 7.26 (l H, d, J=2 H z, Ar-H), 7.29 (lH, dd, Jl=9, J2=2Hz, Ar-H), 7.47 (lH, d, J=9Hz, Ar-H), 7.77 (lH, d, J=2Hz, Ar-H), 9.01 (2H, s, triazole-H), 11.0~, (lH, br s, indole NH~; m/z (CI) 243 (M+~1) INTh~RM~,l ll[ATE 2 6-Aza-6-tert-butvloxvcarbonvl-1-oxasPiror2.~octane Dimethyl sulphoxide (lOOml) was added dropwise to a stirred, cooled (10~C) mi~ture of sodium hydride ~3.70g of a 55% oil dispersion, 0.0846mol) and trimethylsulphoxonium iodide (18.6g, 0.0846mol) under a nitrogen atmosphere. After addition the cooling bath was removed and the mixture stirred at room temperature for 30 minutes, then cooled to ~,~C
and was treated with a solution of N-tert-butyloxycarbonyl-4-piperidone (16.86g, 0.0846mol) in dimethylsulphoxide (50ml). The cooling bath was removed and the reaction mixtùre stirred at room temperature for 15 minutes, then at 50~C for 1 hour. The mixture was stirred whilst cooling to room temperature then quenched with water (40ml) and stirred for a further 10 minutes. The reaction mixture was poured into water (600ml) and extracted with toluene (4 x 300ml). The combined organics were washed with water (300ml), dried (sodium sulphate), then evaporated to give an oil which was eluted through a short silica column using ethyl acetateln-hexane (1:1~ to give a colourless solid (10.Og, 55%), mp 49-51~C
(Found: C, 61.88; H, 9.05; N, 6.42. CllHlsNO3 requires C, 61.95; H, 8.98;
N, 6.57%). ~E~ (360MHz, DMSO-dG) 1.35-1.40 (2H, m, CH2), 1.41 (9H, s, C(C~13)3), 1.60-1.67 (2H, m, CH2), 2.65 (2H, s, CH20), 3.33-3.41 (2X, m, CH2), 3.46-3.54 (2H, m, CH2); m/z (ES) 214 (M+ +1).

I~rrF.R M F.n ~ TE 3 3-r~-(1.2.4-Triazol-l-vlmethvl)-lH-indol-3-vll~ropan-1-ol The title compound was obtained from 2-iodo-4-(1,2,4-triazol-1-ylmethyl)~niline and O,1-bis-triethylsilyl-1-pentyn-5-ol using the method described in Tet. Letts. 1994, 35, 6981-6984. mp 110~-112~C,~H (360MHz, DMSO-d6) 1.79 (2H, qn, J=7Hz, CH2CH2CH2), 2.70 (2H, t, J=7Hz, indole-CH2), 3.47 (2H, q, J=7Hz, CH20H), 4.44 (1~I, t, J=7Hz, OH), 6.44 (2H, s, CH2-triazole), 7.04 (1H, dd, ~=8 and lHz, Ar-H), 7.12 (lH, d, ~=2Hz, Ar-H), 7.30 (lH, d, J=8Hz, Ar-H), 7.52 (lH, s, Ar-H), 7.94 (lH, s, triazole-H), 8.62 (lH, s, tri~ole-H)~ 10.80 (lE, s, indole-NH).

INI'F,R,lv~,r)IATE 4 l-tert-ButyloxvcarbonYl-4-ethvnvl-4-fluoropiperidine 1. 1-tert-ButYloXVCarbOnYl-4-hvdlo~Y-4-(~-trimethVlSilVlethYn~l)-.
pl~erldme To a cooled (-40~C) soluti~n of trimethylsilylacetylene (34 ml, 241 mmol) in anhydrous tetrahydrofuran (400 ml) under an atmosphere of nitrogen was added slowly n-butyl lithium (96 ml of a 2.5M solution in hexs~nes, 241 mmol). After addition the mixture was stirred at -40~C for 1 hour then cooled to -78~C. To this mixture was added via a cannula a solution of 1-tert-butyloxycarbonyl-4-piperidone (40 g, 201 mmol) in anhydrous tetrahydrofuran (250 ml). After addition the mixture was stirred at -78~C for ~ hour, the cooling bath removed and the mixture stirred at room temperature for 72 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (300 ml), stirred for a further 10 minutes and poured into water (500 ml) and extracted with ethyl acetate (3 x 300 ml). The combined organic solutions ~vere washed with water (500 ml), brine (300 ml), dried (M gSO4) and evapor~ted to afford the title compound (55 g, 92%); mp 75~C; ~H (250MHz. CDCl3) 0.19 _ -W O 97/18202 PCT/GB9~02765 (9H, s), 1.48 (9H, s), 1.63-1.74 (2H, m), 1.80-1.92 (2H, m), 3.18-3.28 (2H, m), 3.71-3.84 (2H, m); m/z OES) 298 (M++l).

2. 1-tert-Butvloxvcarbonvl-4-Lv(l-~Y-4-(2-trimethvlsilvlethvnvl)-pi~eridine-cobalt h~ c~rbonvl To a solution of the product from the preceding step (55 g, 185 mmol) in diethyl ether (1000 ml) was added in a portionwise m~nn~3r cobalt octacarbonyl (70 g, 203 mmol). After ~(lditin~ the mixture was stirred at room temperature for 4.5 hours then evaporated. The residue was purified by column chromatography ~silica gel, h~n~ then diethyl ether-hexane 1:4) to give a red solid (80 g, 74%);8H (250MHz, CDCl3) 0.32 (9H, s), 1.48 (9H, s), 1.75 (4H, m), 3.14 (2H, m), 4.03 (2H, m~.

3. 1-tert-ButvloxYcarbonvl-4-ethvnvl-4-fluoroT)iPeridine 1~ To a cooled (-78~C) and stirred solution of diethylaminosulfur tri~luoride (18.1 ml, 137 mmol) in anhydrous dichloromethane (2~0 ml) was added via a cannula a solution of the product from the preceding step (80 g, 137 mmol) in anhydrous dichloromethane (400 ml) over 20 minutes, under nitrogen. After a further 1 hour at -78~C, the mixture was warmed to room temperature and stirred for a further 2 hours. Diethyl ether (1000 ml) was added and the organic solution was washed with a mixture of water (600 ml) and saturated aqueous potassium carbonate (300 ml), followed by brine (1 x 300 ml), dried (M gSO4) and concentrated. The residue was dissolved in acetone (750 ml) and ceric ammonium nitrate (226 g, 412 mmol) added in 5 g portions over 1 hour. After addition the mixture was stirred at room temperature for a further 3 hours then evaporated. The residue was treated with water (~00 ml) and the products extracted with dichloromethane (3 x 300 ml). The combined organic solutions were washed with water (1 x 400 ml), brine (1 x 200 ml), dried (MgS043 and concentrated. The residue was dissolved in anhydrous tetrahydrofuran (200 ml) cooled at 0~C and tetrabutylammonium fluoride _ (137 ml of a l.lM solution in THF, 151 mmoV added. After ~ fion the m~xture was stirred at 0~C for 1 hour, then poured into water ~500 ml) and products extracted with ethyl acetate (3 x 200 ml). The combined organic solutions were washed with water (1 x 400 ml), brine (1 x 200 ml), dried 5 (M gSO4) and concentrated. Flash chromatography of the residue (silica gel, diethyl ether-he~r~ne 20:80) afforded 20 g (~3%) of the required title compound, mp 46~C; ~;H (360MHz, CDCl3) 1.46 (9H, s), 1.93-2.00 (4H, m), 2.70 (lH, d, J=5.0Hz), 3.45-3.60 (4H, m).

E~MPLE 1 4-Benzyl-4-fluoro-1-~3-r5-(1,2~4-triazol-4-vl)-lH-indol-3-vllPropvl~l)iPeridine. 2.1 Hvdro~en Oxalate. 0.4 Hvdrate a) 1-tert-Butvloxvcarbonvl-4-benzvl-4-h~,dIv~v~ eridine A solution of 4-benzyl-4-hydroxypiperidine (14.5g, 75.8mmol) in dichloromethane (150ml) was treated portionwise with di-tert-butyl dicarbonate (16.55g, 75.8mmol) then stirred at ambient temperature for 4 hours. The solution was washed with 10% aqueous citric acid (50ml), dried (sodium sulphate), then evaporated to a~Eord a gum (23.8g) which was purified by column chromatography on silica using ethyl acetate/petroleum ether (60-80) (1:1). The product was obtained (19.3g, 87%) as a pale yellow solid, mp 87-88~C; ~H (360MHz, DMSO-d6) 1.32-1.37 (13H, m, (CH~)3C and 2xCH2), 2.67 (2H, s, CH2Ph), 2.98-3.05 (2H, m, 2xCH), 3.63 (2H, d, J=12Hz, 2xCH), 4.37 (lH, s, OH), 7.15-7.27 (5H, m, C6H5); m/z (ES) 292 (M++1).

b) 1-tert-Butvloxvcarbonvl-4-benzvl-4-fluoropi~eridine To a cooled (-71~C) and stirred solution of diethylaminosulfur trifluoride (634~L1, 4.80mmol) in anhydrous dichloromethane (15ml) was 30 added dropwise, v~a cannula, a solution of 1-tert-butyloxycarbonyl-4-benzyl-4-hydroxypiperidine (700mg, 2.40mmol~ in anhydrous CA 02236832 1998-0=,-06 dichloromethane (15ml) over 20 minutes, under nitrogen. After a further 60 minutes at -75~C, the mixture was warmed to -10~C and stirred for a further 2 hours. Water (20ml~ and saturated aqueous potassium carbonate (7ml) were added and products were extracted with diethyl ~ 5 ether (lx70ml). The organic solution was washed with brine (lx25ml), dried (M gSO4) and co~en~.rated. Flash chromatography of the residue (silica gel, he~ne-diethyl ether, 86:14) gave 190mg of 1-tert-butyloxycarbonyl-3,4-dehydro-4-benzylpiperidine and 360mg (51%) of the title compound as pale yellow oils; OH (360MHz, CDCl3) 1.44 (9H, s), 1.46-1.78 (4H, m), ~.90 (2H, d, J=22Hz), 2.98-3.08 t2H, m), 3.86-3.94 (2H, m), 7.16-7.34 (5H, m); m/z (ES3 294 (M++1).

c) 4-Benzvl-4-fluoroviperidine A solution of the product from the preceding step (360mg) in a mixture of trifluoroacetic acid and dichloromethane (1;2; 12ml) was allowed to stand at room temperature for 1 hour. Solvents were removed under vacuum and the residue was azeotroped with methanol (2x26ml).
Water (10ml), 4N sodium hydroxide (5ml) and brine (15ml) were added and the product was extracted with ethyl acetate ~2x50ml). The combined organic solutions were dried (Na2SO4) and concentrated to give 235mg (99%) of the title compound as a pale yellow oil which was used in the next step without further purification; ~H (360MHz, CDCl3) 1.50-1.78 (4H, m), 2.84-2.96 (6~I, m), 7.16-7.32 (5H, m); m/z (~:S) 194 (M+ +1).

2fi d) 4-Benzvl-4-fluoro-1-~3-r5-(1.2.4-triazol-4-vl)-1H-indol-3-YllT~ropyl~iperidine. 2.1 Hvdro~en Oxalate. 0.4 Hvdrate To a stirred suspension of Intermediate 1 (206mg, 0.85mmol) in anhydrous tetrahydrofuran (35ml) was added anhydrous triethylamine (237ml, 1.70mmol) followed by methanesulphonyl chloride (135~
1.70mmol) at room temperature, under nitrogen. After 1.5 hours of stirring, the mixture was diluted with ethyl acetate (100ml), washed with brine (2x30ml), dried (M gSO4) and concentrated (bath temperature 35~C).
The rem~ining residue was dissolved in isopropanol (60ml), potassium carbonate (164mg, 1.19mmoV and a solution of 4-benzyl-4-~uoropiperidine (230mg, 1.19mmol) in isopropanol (10mV were added, and the resulting mixture was re~uxed for 18 hours, under nitrogen. The solvent was removed under vacuum, the residue was dissolved in water (50ml) and saturated aqueous potassium carbonate (4mV, and products were extracted with ethyl acetate (2x80ml). The combined extracts were washed with brine (lx35ml), dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel, dichloromethane-methanol-ammonia, 95:5:0.5) gave 164mg (46%) of the title compound free base as a white foam. The oxalate salt was prepared from ethanol-diethyl ether, mp 79-85~C. (Found: C, 57.15; H, 5.42; N, 11.24. C2sH2sFNs x 2.1(C2H204) x 0.4H20 requires: C, 57.14; H, 5.42; N, 11.41%). ~H (360MHz, DMSO-d6) 1.84-2.10 (6H, m), 2.76 (2H, t, J=7.2~Iz), 2.96-3.14 (6H, m), 3.32-3.4~ (2H, m), 7.20-7.36 (7H, m), 7.51 (l~I, d, J=8.5Hz), 7.80 (lH, d, J-2.0Hz), 9.01 (2H, s), 11.18 (lH, s); m/z (ES) 418 (M++l).

E~AMPLE 2 4-Fluoro-4-r2-(3-fluoroPhenvl~ethvll-1-~3-~5-(1.2.4-triazol-4-vl)-1H-indol-3-yll~ro~yl~piperidine. 2.0 Hvdro~en Oxalate a) 1 -tert-Butvloxvcarbonvl-4- ~2- (3-fluoroPhenvl)ethvll -4-hvdroxvpil~eridine To magnesium turnings (494mg), covered with anhydrous diethyl ether (3ml), was added one crystal of iodine followed by a small amount (10%) of a solution of 3-fluorobenzyl bromide (4.12g, 21.8mmol) in anhydrous diethyl ether (8ml). The mixture was warmed with a water bath (35~C) to initiate Grignard formation, then the rem~inin~ solution of 3-fluorobenzyl bromide was added dropwise over 30 minutes at the same temperature. Steady refluxing was observed, which ceased after 30 minutes. The resulting mixture was cooled to -30~C and a solution of Tntermediate 2 (3.0g, 14.07mmol) in anhydrous diethyl ether ~8ml~ was added dropwise over 20 minutes. A large amount of gelatinous precipitate was formed m~kin~ stirring diffiicult. The mixture was stirred at -10~C for a further 4 hours 15 minutes, then ~llanf hed with saturated ammonium ~hl. ~ (lOOml) and produc~s were extracted with ethyl acetate (2x125ml). The combined organic solutions were washed with brine (~OmV, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel, he~ne-diethyl ether, 50:50 to 30:70) afforded 935mg (20.5%) of the required title compound; OH (250MHz, CDCl3) 1.47 (9H, s), 1.54-1.64 (4H, m), 1.72-1.8Z (2H, m), 2.66-2.78 (2H, m~, 3.12-3.26 (2H, m), 3.78-3.90 (2H, m~, 6.82-7.00 (3H, m), 7.1~-7.30 (lH, m); m/z (ES) 324 (M+
+1).

b) 1-tert-Butvloxvcarbonvl-4-fluoro-4-r2-(3-fluoroPhenYl)-ethvnPiperidine To a cooled (-72~C) and stirred solution of diethylaminosulfur trifluoride (760,u1, 5.75mmol) in anhydrous dichloromethane (lOml~ was added dropwise, uia cannula. a solution of the preceding alcohol (930mg, 2.87mmol) in anhydrous dichloromethane (15ml) over 40 minutes, under nitrogen. After a further 50 minutes at -75~C, the mixture was warmed to -~~C and stirred for 2 hours. Diethyl ether (lOOml) was added and the organic solution was washed with water-saturated aqueous potassium carbonate (2:1, 30ml~, brine (35ml), dried (MgSO4) and concentrated.
Flash chromatography of the residue (silica gel, hexane-diethyl ether, 86:14) gave 500mg of the title compound, impurified with l-tert-butyloxycarbonyl-3,4-dehydro-4- ~2-(3-fluorophenyl)ethyl]piperidine (ca 3:1). This was dissolved in dichloromethane (25ml), m-chloroperoxy-benzoic acid (80-85%; 400mg) was added, and the mixture was allowed to stand at room temperature for 12 hours. Diethyl ether (150ml) was added and the solution was washed with 2N sodium hydroxide (25ml), 2N

, sodium hydroxide - 10% aqueous sodium thiosulphite (1:1, 30ml), dried (M gSO4) and concentrated. Flash chromatography of the residue (silica gel, he~ne-diethyl ether, 86:14) afforded 305mg (33%) of the title compound as a colourless thick oil which solidified on st~n~inF; ~iH
~250MHz, CDCl3) 1.47 (9H, s), 1.50-2.00 (6H, m), 2.68-2.78 (2H, m), 3.02-3.16 (2H, m), 3.90-4.00 (2H, m), 6.84-7.00 (3H, m), 7.18-7.30 (lH, m); m/z (ES) 326 (M+ +1).

c) 4-Fluoro-4-r2-(3-fluoro~henvl~ethvll~iPeridine The title compound was prepared from the product of the preceding step following a .simil~r method to that described for F.~r~mple 1, step c.
~H (250MHz, CDC13-CD30D) 1.50-1.78 (2H, m), 1.82-2.00 (4H, m), 2.66-2.80 (2H, m), 2.88-3.00 (4H, m), 6.82-7.02 (3H, m), 7.18-7.30 (lH, m); mlz (ES) 226 (M+ +1).
d) 4-Fluoro-4-r2-(3-fluoro~henvl)ethvl~ 3-r5-(1.2.4-triazol-4-vl)-1H-indol-3-yll~ropvl~piPeridine. 2.0 Hvdro~en Oxalate The title compound free base was prepared from Intermediate 1 and the product from the preceding step following a Rilim~r method to that described for F.~mple 1, step d. The oxalate salt was prepared from ethanol-diethyl ether, mp 70-80~C. (Found: C, 57.06; H, 5.29; N, 11.17.
C26H2sF2N~ x 2.0C2H204 requires: C, 57.23; H, 5.28; N, 11.12%). SH
(360MHz, DMSO-d6) 1.86-2.14 (8H, m), 2.65-2.82 (4H, m), 3.00-3.20 (4H, m), 3.30-3.46 (2H, m), 6.96-7.12 (3H, m), 7.26-7.36 (3H, m), 7.50 (lH, d, J=8.6Hz), 7.81 ~lH, s), 9.02 ~2H, s), 11.18 (lH, s); m/z (ES) 450 (M++1).

Examples 3 and 4 were prepared from 1-tert-butyloxycarbonyl-4-(3-fluorobenzyl)-4-hydroxypiperidine and 1-tert-butyloxycarbonyl-4-(2-fluorobenzyl)-4-hydroxypiperidine (see F.~3mple 7, step a) following a 30 .simil~r procedure to that described for F,~mple 1 (steps b, c and d).

~AMPLl~ 3 4-Fluoro-4-(3-fluorobenzvl)-1-~3-r5-(1.2,4-triazol-4-vl)-lH-indol-3-YllProPvnpiperidine~ 1.5 HYdro~en Oxalate. 0.5 Etherate The oxalate salt was prepared from ethanol-diethyl ether, mp 80-83~C. (Found: C, 52.22; H, 5.00; N, 9.30. C2sH27F2Ns x 1.6C2H204 x 0.5C~HloO requires: C, 52.03; H, 5.03; N, 9.19%). ~iH (360MHz, 9:1 CDCl3-DMSO-d6~ 1.86-1.97 (2H, m), 2.04-2.56 (4H, m), 2.87-2.98 (6H, m), 3.02-3.0~ (2H, m), 3.40-3.50 (2H, m), 6.89-7.00 ~3H, m), 7.13 (lH, dd, J-8 and 2 Hz), 7.22-7.33 (2H, m), 7.60 (lH, d, J=8Hz), 7.65 (~H, d, ~=2Hz), 8.56 (2H, s) and 10.30 (lH, s); m/z (ES) 436 (M++l).

E~AMP~E 4 4-Fluoro-4-~2-fluorobenzvl~ 3-~5-(1.2,4-triazol-4-yl)-lH-indol-3-YnproPvl~piperidine. 1.0 Hvdro~en Oxalate. 0.6 Hvdrate The oxalate salt was prepared from ethanol-diethyl ether, mp 84-89~C. (Found: C, 65.75; H, 5.47; N, 11.22. C2sH27F2N~ x 1.0C2H204 x 0.6H2O requires: C, 55.61; H, 5.18; N, 11.18%). ~H (360MHz, 9:1 CDCl3-DMSO-d6+CF3CO2H) 1.92-2.00 (2H, m), 2.25-2.56 (4H, m), 2.84-3.12 (8H, m), 3.40-3.50 (2H, m), 7.04-7.30 (6H, m), 7.51 (1H, d, J-8Hz), 7.66 (lH, s) and 8.80 (2H, s); mlz (ES) 436 (M+ +1).

4-Benzvl-4-methoxv-1-~3-r5-(1.2~4-triazol-4-vl)-lH-indol-3-vllProl~vl~PiPeridine. Hvdro~en Oxalate.
a) l-tert-Butvloxvcarbonvl-4-benzvl-4-methox~rpiPeridine 1-tert-Butyloxycarbonyl-4-benzyl-4-hydroxypiperidine (Fx~mple 1, step a) (2.0g, 6.87mmol) was added to a stirred mixture of finely powdered potassium hydroxide (1.54g, 27.5mmol) in dimethyl sulphoxide (20ml).
30 After addition, the mixture was treated with iodomethane (0.85ml, 13.7mmol) then stirred at ambient temperature for 1 hour, poured into water (lOOml) and extracted with ethyl acetate (2x30ml). The combined organics were washed with water (2x30ml), dried (sodium sulphate) then evaporated to afford a gum (2.22g) wbich was puri~ed by column chromatography on silica using ethyl acetate/n-h~n~ 1). The title 5 compound was obtained as a viscous colourless gum (1.23g, 59%); OH
(250MHz, CDCl3) 1.36-1.50 (2H, m, 2xCH), 1.43 (9H, s, (CH3)3C), 1.62-1.77 (2H, m, 2xCH), 2.77 ~2H, s, CH2Ph), 2.95-3.06 (2H, m, 2xCH), 3.34 (31:I, s, OCH3), 3.70-3.90 (2H, m, 2xCH), 7.11-7.32 (5H, m, C6Hs); m/z (ES) 306 (M+
+1).
b) 4-Benzvl-4-methox~ eridine The product from the preceding step (1.22g, 4.0mmol) and trifluoroacetic acid (3.1ml, 40mmol) in dichloromethane (20ml) were stirred at ambient temperature for 24 hours. The solvent was evaporated 15 and the residue partitioned between dichloromethane (30ml) and saturated aqueous potassium carbonate solution (30ml). The organic layer was separated then the aqueous re-extracted with dichloromethane (30ml). The combined organics were dried (potassium carbonate) then evaporated to give a yellow gum (0.9Og) which was purified by column 20 chromatography on silica using dichloromethane/methanol/ammonia (9:1:0.1). The titZe compound was obtained as a colourless viscous gum (0.80g, 98%); ~H (250MHz, CDCl3) 1.43-1.51 (2H, m, 2xC H), 1.68 (2H, d, ~=12Hz, 2xCH), 2.77 (2H, s, CH2Ph), 2.78-2.92 (4H, m, 2xCH2), 3.33 (3H, s, OCH3~, 7.14-7.30 (5H, m, C6H6); m/z (ES) 206 (M~+l).
c) 4-Benzvl-4-methoxv~ 3-r5-(1,2,4-triazol-4-vl)-lH-indol-3-vll~roPYl~iperidine. H~dro~en Oxalate The title compound free base (135mg, 29%) was obtained from the mesylate of 3-[5-(1,2,4-triazol-4-yl)-lH-indol-3-yl]propan-1-ol and 4-benzyl-30 4-methoxypiperidine as described previously (Example 1, step d~. The hydrogen oxalate salt had mp 110~-115~C. (Found: C, 61.9~; H, 6.49; N, -12.09. C26H31N50 x 1.47C2H204 reqwres; C, 61.86; H, 6.09; N, 12.46%).~H
(360MHz, DMSO-d6) 1.65-1.74 (2H, m, 2xCH), 1.82 (2H, d, 3-12Hz, 2xCH, 1.98-2.06 (lH, m, CH2CHaCE2), 2.76 (2H, t, J=7Hz, indole-CH2), 2.82 (2H, s, CH2Ph), 2.82-3.00 (2H, m, 2xCH), 3.02-3.10 (~H,m, CH2N), 3.20-3.32 (2H, m, 2xCH), 3.27 (3H, s, OCH3), 7.18-7.34 (7H, m, indole-H, C6Hs, Ar-H), 7.50 (lH, d, ~=8Hz, Ar-H), 7.79 (lH, d, J=2Hz, Ar-H), 9.01 (2H, s, ~:ri~7~1,?-H), 11.18 (lH, s, indole-NH), m/z (ES) 430 (M++l).

E~AMPLlE 6 4-Benzvl-4-methoxv-1-(3-~5-(1.2.4-triazol-1-Ylmethvl)-lH-indol-3-vllPropvl)pi~eridine Hvdro~en Oxalate A stirred, cooled (-5~C) solution of 3-(5-[1,2,4-triazol-1-yln-ethyl)-lH-indol-3-yVpropan-1-ol (260mg, lmmol) in anhydrous tetrahydrofuran (20ml), under a nitrogen atmosphere, was treated with triethylamine 1~ (0.17ml, 1 ~mmol) and methanesulphonyl chloride (O.lOml, 1 ~mmol).
After 45 minutes the reaction mixture was filtered, then washed through the filter pad with tetrahydrofuran (lOml). The resulting mesylate solution was treated with potssium carbonate (263mg, l.9mmol), sodium iodide (285mg, l.9mmol~ and a solution of 4-benzyl-4-methoxypiperidine (400mg, l.9mmol) in tetrahydrofuran (lOml). The reaction mixture was stirred whilst heating at 50~C for 24 hours. The solvent was evaporated, the residue partitioned between dichloromethane (40ml) and water (20ml).
The organic layer was separated and the aqueous re-extracted with dichloromethane (40ml). The combined organics were extracted with aqueous citric acid (lg in 20ml), the aqueous was basified to p~=12 with 40% aqueous soldium hydroxide then extracted with dichloromethane (3x30ml). The organic extracts were combined, dried (potassium carbonate) then evaporated. The residue was purified by column chromatography on silica using dichloromethanefmethanolfammonia (9:1:0.1) to afford the title compound free Joase as a glass (332mg, 75%).
The hvdrogen oxalate salt has mp 84~-87~C. (Found: C, 60.81; H~ 6.34: N~

CA 02236832 l998-05-06 WO 97/18202 PCT/(iL,'i ~,~2765 ~1.68. C27H33NsO. 1.75C2H204 requires C, 60.94; H, 6.12; N, 11.65%). ~H
(360MHz, DMSO-d6) 1.65-1.78 (2H, m, 2xCH), 1.82 (2H, d, J=12Hz, 2xCH), 1.94-2.04 (2H, m, CH2CH2CH2), 2.71 (2H, t, 3=7Hz, indole-CH2), 2.82 (2H, s, CH2Ph), 2.82-3.00 (2H, m, 2xCH), 3.02-3.12 (2H, m, CHzN), 3.22-3.32 (2H, m, 2xCH), 3.28 (3H, s, OCH3), 5.43 (2H, s, CH2-triazole), 7.()5 (1H, d, ~=7Hz, Ar-H), 7.18-7.34 (7H, m, C6Hs, indole-H, Ar-H), 7.52 (lH, s, Ar-H), 7.94 (lH, s, triazole-H), 8.60 (lH, s, triazole-H), 10.92 (lH, s, indole-NEI);
m/z (ES) 444 (M+ +1).

E~MPLE 7 4-(2-:~luorobenzvl)-4-methoxv-1-(3-r5-(1.2.4-triazol-4-Yl)-lH-indol-3-YllProPvl~iperidine Hvdro~en Oxalate a) 1-tert-Butvloxvcarbonvl-4-(2-fluorobenzvl)-4-hvdroxvPi~eridine 1~ 1-Benzyl-4-piperidone (lOg, 53mmoV in diethyl ether (80ml) was added dlo~wise to a cooled (-4~C), stilTed mixture of 2-fluorobenzyl m~Fne.sium bromide (prepared from magnesium and 2-fluorobenzyl bromide (9.56ml, 80mmol) in diethyl ether (65ml)) under an atmosphere of nitrogen. The reaction mixture was stirred whilst warming to room temperature (30 minutes) then at room temperature for 20 minutes. The reaction mixture was ql~en~hed with 2M hydrochloric acid (lOOml). The aqueous was separated and washed with diethyl ether (lOOml). The aqueous was basified with 2M sodium hydroxide solution then exhaustively extracted with dichloromethane. The combined organics were dried ~sodium sulphate) then evaporated to give crude 1-benzyl-4-(2-fluorobenzyl)-4-hydroxypiperidine as a gum (9.Og). This crude product in methanol (lOOml) was treated with formic acid (6ml), ammonium formate (9.5g, 0.15mol) and 10% palladium on carbon (9OOmg). The mixture was stirred whilst heating at reflux for 4 hours, cooled, filtered then evaporated to afford 4-(2-fluorobenzyl)-4-hydrox.vpiperidine as a gum (3.4g); m/z (ES) 210 (M++1). This amine (3.35g, 16mmol) in dichloromethane (75mV was treated with di-t-butyldicarbonate (3.5g, 16mmol) and stirred at ambient temperature for 18 hours, washed with aqueous lQ% citric acid, dried (potassium carbonate), evaporated to give a gum which was puri~;ed by column chromatography on silica using ethyl acetate/n-h~ne (1:1) to al~ord the title compound as a colourless, viscous gum (3.62g, 73%). ~H (360MHz, CDC13) 1.46 (9H, s, (CH3)sC), 1.48 (2H, d, .J=13Hz, 2xCH), 1.63 (2H, ddd, Jl=5, J2=13. Js=17Hz. 2xCH), 2.82 (2H, d, J=lHz, CH2Ph), 3.11 (2H, ddd, Jl=3, J2=J3=13Hz, 2xCH~, 3.84 (2H, d, J=13Hz, 2xCH), 7.02-7.27 (4H, m, C6H4); m/z (ES) 310 (M+ +1).
b~ 1-tert-Butvloxvcarbonvl-4-(2-~uorobenzvl)-4-methox~ eridine The title compound was obtained (320mg, 31%) from the product of the preceding step as described for ~ m~}le 5 (step a); ~H (360MHz, DMSO-d6) 1.30-1.34 (2H, m, 2xCH), 1.36 (9H, s), (CH3)3C), 1.60-1.64 (2H, m, 2xCH), 2.80 (2H, s, CH2Ph), 2.82-2.98 (2H, m, 2xCH), 3.25 (3H, s, OCH3), 3.65-3.68 (2H, m, 2xCH), 7.10-7.28 (4H, m, C6H4); m/z ~ES) 324 (M+
+1).

c) 4-(2-Fluorobenzvl)-4-methoxYPi,~eridine The title compou7~d was obtained tl8lmg~ 82%) fiom the product of the preceding step as described for ~.~r~m~le 5 ~step b); ~H (260MHz, DMSO-d6) 1.37-1.49 (2H, m, 2xCH), 1.64-1.68 (2H, m, 2x(~H), 2.65-2.75 (4H, m, 2xCH2), 2.87 (2H, s, CH2Ph), 3.34 (3H, s, OCH3), 7.21-7.43 (4H, m, C6H~); m/z (ES) 224 (M++1).
d) 4-(2-Fluorobenzvl)-4-methoxv-1-~3-r5-(1,2,4-triazol-4-vl)-lH-indol-3-vllpropYn~ eridine Hvdro~en Oxalate The title compound free base was obtained (105mg, 33%) from the mesylate of 3-[5-(1,2,4-triazol-4-yl)-lH-indol-3-yl~propan-1-ol and 4-(2-fluorobenzyl)-4-methoxypiperidine as described previously. The hydrogen oxalate salt had mp 110~-115~C. (Found: C, 56.94; H, 5.80; N, 11.04.

W O ~7/~8202 Cz6H30FN5O. 2.1C2H204 requires: C, 56.98; H, 5.42; N, 11.00%). ~H
(360MEIz, DMSO-d6) 1.64-1.78 (2H, m, 2xCH), 1.80-188 (2H, m, 2xCH), 1.96-2.04 (2H, m, CH2CHaCH2), 2.70-2.78 (2H, m, indole-CHa), 2.84 t2H, s, C~lPh), 2.90-2.98 (2H, m, 2xCH), 3.02-3.10 (2H, m, CH2N), 3.26 (3H, s, OCH3), 3.25-3.32 (~H, m, 2xCH3, 7.13-7.33 (6H, m, C6H4, Ar-H, indole-H), 7.49 (lE, d, J=8Hz, Ar-H), 7.89 (lH, s, Ar-H), 9.00 (2H, s, 2 x triazole-H), 11.18 (lH, s, indole-NH); mtz (ES) 448 (M++l).

~5rAMPLE 8 4-(3-Fluorobenzvl)-4-methoxv- 1-~3-r5-(1.2.4-triazol-4-vl)- lH-indol-3-vll~roPvl~Piperidine Hvdro~en Oxalate The title compound free base was obtained (8amg, 44%) from the mesylate of 3-[5-(1,2,4-triazol-4-yl)-lH-indol-3-yl]propan-l-ol and 4-(3-fluorobenzyl)-4-methoxypiperi~;ne as described previously. The hydrogen oxalate salt had mp ~ 105~C. (Found: C, 57.81; H, 5.95; N, 11.05%.
Cz6H30FNsO. 1.85C2H204 requires: C, 58.09; H, 5.53; N, 11.40%); mlz (ES) 448 (M++1).

4-(4-Fluorobenzyl)-4-methoxv- 1-~3-[5-(1,2.4-triazol-4-vl)- lH-indol-3-vllT)ro~vl~l~iperidine HvdroFen Oxalate The t~tle compound free base was obtained (50mg, 20%) from the mesylate of 3-~5-(1,2,4-triazol-4-yl)-lH-indol-3-yl]propan-1-ol and 4-(4-fluorobenzyl)-4-metho~ypiperidine as described previously. The hydrogen oxalate salt had mp > 95~C ~dec.). (Found: C, 58.77; H, 5.89; N, 11.53.
C26H30FN5O. 1.75C2H204 requires: C, 58.55; H, a.58; N, 11.57%); m/z (ES) 448 (M++l).

_ ~9 EXAMPLI~ 10 4-Fluoro-4-r2-(trifluoromethvl~benzvn~ 3-r5-~1.2,4-triazol-4-vl)-lH-indol-3-vllPro~vl}PiPeridine. 2.0 Hvdro~en Oxalate. 0.4 l~therate. 0.25 Hvdrate.

5 a) 1-tert-Butvloxvcarbonvl-4-r2-(trifluoromethvl3benzvll-4-hv~l~v~Ly ~ eridine 2-Bromobenzotrifluoride (0.70 ml, 5.1 mmol) was added dropwise at -78~C to a stirred solution of tert-butyllithium (1.7 M in pentane, 6.0 ml) in anhydrous diethyl ether (25 ml) under nitrogen. After 30 minutes, a solution of Intermediate 2 (1.0 g, 4.69 mmol) was added. The white suspension was stirred at -78~C for 1.5 hours, then warmed slowly to room temperature and stirred for a further 18 hours. The mixture was diluted with saturated aqueous ammonium chloride (100 ml) and extracted with diethyl ether (2 x 50 ml). The extracts were dried (MgSO4), filtered and concentrated. Flash columIl chromatography on silica, eluting with 30%
then 50% ethyl acetate-he~r~ne, gave the product (1.44 g, 86%) as a pale yellow glass; ~H (360 MHz, CDCl3) 1.45 (9 H, s), 1.49 (2 H, dd, J=13 and 2), 1.65 (2 H, ddd, J=13, 13 and 6), 2.99 (2 H, s), 3.05 (2 H, ddd, J=13, 13 and 3), 3.90 (2 H, broad d, J=13), 7.35 (1 H, dd, J=7 and 7), 7.47-7.55 (2 H, m) and 7.67 (1 H, d, ~=8); Iz (ES) 360 (M++1).

b) 1-tert-Butvloxvcarbonvl-4-r2-~trifluoromethvl~benzvll-4-fluoroPi~eridine The title compound (0.70 g, 49%) was prepared from the product of the preceding step (1.43 g, 3.98 mmol) following a .~imil~lr method to that described for ~:xample 2, step b. ~H (360 MH~, CDCl3) 1.46 (9 H, s), 1.55-1.68 (4 H, m), 2.92-3.03 (2 H, m), 3.13 (2 H, d, J=24), 3.88-4.04 (2 H, m), 7.35 (1 H, dd, J=8 and 8), 7.49 (1 H, d, J=8 and 8), 7.57 (1 H, d, J=8) and 7.65 (1 H, d, J=8); m/z (ES) 384 ~M+~23 (Na~.

c) 4-r2-(TrifluoromethYl)benzvll-4-fluoro~iPeridine The title compound (0.454 g, 92%) was prepared from the product of the preceding step (0.687 g, 1.90 mmol) following a ~imilflr method to that described for ~"~mple 1, step c. ~H (250 MHz, CDCl3) 1.50-1.75 (4 E~, m)2.81-2.94 (4 H, m), 3.13 (2 H, d, ~-24), 7.34 (1 H, dd, J=8 and 8), 7.49 (1 H, dd, J=8 and 8), 7.58 (1 H, d, J=8) and 7.6~ (1 H, d, J=8); m/z (ES) 262 (M~+l)-d) 4-Fluoro-4-r2-(trifLuoromethvl)benzYn-1-~3-r5-(1.2.4-triazol-4-vl)-1H-indol- 3-vllProPvnPiPeridine. 2.0 Hvdro~en Oxalate. 0.4 Etherate. 0.2~i H~drate.
The title compound free base (0.133 g, 29%) was prepared from Intermediate 1 and the product of the preceding step following a .~imil~r method to that described for F'.~mrle1, step d. The o~ te salt was prepared from ethanol-diethyl ether, m.p. 88-91 ~C. (Found: C, 54.24; H, 4.90; N, 9.76. C26H27NsF4 x 2.0C2H204 x 0.4C4HloO x 0.25H20 requires C, 54.24; H, 5.11; N, 10.01%.) ~iH (360 MHz, 9:1 CDCl3+d6-DMSO) 1.~8-1.66 (2 H, m), 1.90-2.10 (4 H, m~, 2.~4-2.60 (2 H, m), 2.65-2.78 (Z H, m), 2.80-2.87 (2 H, m), 2.91 (2 H, d, ~=24), 3.18-3.24 (2 H, m), 6.86 (1 H, dd. J=9 and 1), 6.92 (1 H, s), 7.13 (1 H, dd, ~T=8 and 8), 7.21-7.27 (4 H, m), 7.38 (1 H, d, J=8), 8.30 (2 H, s) and 10.25 (1 H, s); m/z (ES) 486 (M++1).

li'.~MPLE 11 4-Fluoro-4-r2-(N~ N-dimethYlaminosulfonvl~benzvll-1-,3-r5-(1.2.4-triazol-4-vl)-1H-indol-3-vll~ro~Yl~PiPeridine 2.0 Hvdro~en Oxalate. 0.2 Etherate.
0.5 Hvdrate.
Example 11 was prepared from N,N-dimethylbenzenesulfon~3mi~e following a .~imil:~r procedure to that described for ~ mple 10 (steps a, b, c and d).
The oxalate salt was prepared from ethanol-diethyl ether, m.p. 94-98 ~C. (Found: C, 52.49; H, 5.41; N, 11.48. C27H33NGSO2F x 2.0CzH2O4 x W 097/18202 PCT/GB96~0276 0.2 G HloO x 0.5H2O requires C, 52.43; H, 5.53; N, 11.54%.~ ~H (360 MHz, d6-DMSO) 1.76-1.86 (2 E, m), 1.90-2.15 (4 H, m), 2.68 (6 H, s), 2.72-2.80 (2 H, m), 2.92-3.05 {2 H, m), 3.06-3.14 (2 H, m), 3.36-3.44 (2 H, m), 3.46 (2 H, d, J=2~), 7.31-7.33 (2 H, m), 7.49-7.56(3 ~1, m),7.67(1 H, dd, J=7), 7.79-7.81 (2 H, m), 9.00 (2 H, s) and 11.18 (1 H, s);m/z (ES) 525 (M+~1).

E~AMPLE 12 4-Fluoro-4-~2-~henvlPropyl)-1-~3-r5-(1,2,4-triazol-4-Yl)-lH-indol-3-vllProPvl}Piperidine. 2.0 Hvdro~en Oxalate. 0.15 Etherate. 0.06 HYdrate.

a) 1-tert-Butvloxvcarbonvl-4-r(2-~henvl~allvll-4-hYdro~vuiPeridine A solution of tert-butyllithium in pentane (1.7 M, 11 ml) was added dropwise at -78 ~C to a stirred solution of a-bromostyrene (2.3 ml, 17.7 mmol) in anhydrous THF (80 ml) under nitrogen. A~er 20 minutes, a 16 solution of lntermediate 2 (2.0 g, 9.38 mmol) in anhydrous THF (6 ml) was added. The black solution was warmed slowly to room temperature over 7 hours. The mixture was diluted with saturated aqueous ammonium chloride (200 ml) and extracted with ethyl acetate (100 ml). The extract was washed with brine (60 ml), dried (MgS04), filtered and concentrated.
Flash column chromatography on silica, eluting with 20% then 60% ethyl acetate-hexane, gave the title compound (1.67 g, 56%) as a yellow oil. ~H
(360 MHz, CDCl3) 1.39-1.47 (13 H, m), 1.57 tl H, s), 2.74 (2 H, s), 2.98-3.10 (2 H, m), 3.70-4.02 (2 H, m) and 7.Z6-7.42 (5 E, m); m/z (ES) 318 (M++l).

b) 1-tert-Butyloxvcarbonvl-4-(2-phenylpro~vl)-4-hvdrox~i~eridine ~ solution of 1-tert-butyloxvcarbonyl-4-[(2-phenyl)allyl~-4-hydroxypiperidine (1.67 g, 5.26 mmol) in ethyl acetate (25 ml) was hydrogenated over 1% palladium on activated carbon (0.8 g) at room temperature and 1 atm pressure of hydrogen for 1.5 hours. The mi~ture was filtered and the filtrate was concentrated to yield the title cornpourld (1.47 g, 87%) as a pale yellow glass. ~ (250 MHz. CDC13) 1.27 (3 H, d, _ J=7), 1.36-1.60 (13 H, m), 1.73 (1 H, dd, J=15 and 4), 2.01 (1 H, dd, J=15 and 10), 2.98-3.06 (3 H, m), 3.60-3.88 (2 H, m) and 7.16-7.36 (5 H, n~, m/z (ES) 320 (M++l).

c) 1-tert-Butvloxvcarbonvl-4-(2-Phen~ropvl)-4-fluoro~ eridiIle The title compound (0.651 g, 44%) was prepared from the product of the preceding step (1.47 g, 4.60 mmol) following a .sin~ r method to that described for h'.~mple 2, step b. ~H (250 MHz, CDCl3) 1.28 (3 H, d, J='7), 1.43 (9 H, s), 1.47-2.11 (6 H, m), 2.93-3.07 (3 H, m), 3.76-3.86 (2 H, m) and 7.15-7.33 (5 H, m); m/z (ES) 322 (M++l).

d) 4-(2-Phenvlpro~vl)-4-fluoro~iPeridine The title compound (0.374 g, 85%) was prepared from the product of the preceding step (0.640 g, 1.99 mmol) following a Rimil~r method to that described for Example 1, step c. ~H (360 MHz, CDCls) 1.28 (3 H, d, J=7), 1.35-1.60 (2 H, m), 1.70-1.79 (2 H, m), 1.83-2.09 (2 H, m), 2.79-2.93 (4 H, m), 3.03 (1 H, qt, J=7 and 7), 7.15-7.22 (3 H, m) and 7.26-7.31 (2 H, m); mlz (ES) 222 (M++l).

e) 4-Fluoro-4-(2-PhenYlPropv~ 3-r5-(l.2~4-triazol-4-yl)-lH-indol-3-v~l~ropvl~piperidine. 2.0 Hvdro~en Oxalate. 0.15 Etherate. 0.05 Hvdrate.
The t~tle compound free base (0.119 g, 32%) was prepared from Intermediate 1 and the product of the preceding step following a ~imil~r method to that described for F'~m~3lel, step d. The oxalate salt was prepared from ethanol-diethyl ether, m.p. 87-91 ~C. (Found: C, 59.24; H, 5.95; N, 11.28. Cz7H32NsF x 2.0C2H204 x 0.15C4HloO x 0.05H20 requires C, 59.52; H, 5.94; N, 10.98%.) ~H (360 MHz, d6-DMSO) 1.21 (3 H, d, J=7), 1.60-2.10 (10 H~ m), 2.75 ( 2 H, t, J=8), 2.90-3.12 (4 H, m), 3.26-3.28 (1 H, m), 7.16-7.20 (1 H, m), 7.24-7.35 (6 H, m), 7.50 (1 H, d, J=9), 7.79 (1 H, s), 9.01 (2 H, s) and 11.17 (1 H, s); m/z (~S) 446 (M++l).

3B~XAMPL1~ 13 4-Fluoro-4-r3-fluoro-(2-uhenvl~Propvl~ 3-r5-(1.2.4-triazol-4-vl)-lH-indol-3-vlll)lv~vl~piperidine.

a) 3-(1-tert-ButvloxvcarbonYl-4-h~d~ vuilJeridin-4-vl)-2-1~henvl-proPionic acid methvl ester A solllt.ir n of lithium h~ methyldisilylamide (1 M, 22 ml3 in T~F
was diluted with dry THF (40 mV and stirred at -70 ~C under nitrogen.
Methyl 2-phenylacetate (3.00 ml, 20.9 mmmol) was added dropwise and the orange sol~ltinn was stirred for 30 miIlutes. A solution of Intermediate 2 (4.26 g, 20 mmoV in dry THF (12 ml) was added, followed by dropwise addition of boron tri~1uoride etherate (2.5 ml, 20.3 mmol). The mixture was stirred at -70 ~C for 1.5 hours, then warmed slowly to room temperature and stirred for a further 17 hours. The yellow solution was diluted with saturated aclueous ammonium chloride (100 ml) and extracted with ethyl acetate (3 x 50 ml). The extracts were washed with brine (50 ml), dried (MgSO4), filtered and concentrated. Flash column chromatography on silica, eluting with 40% ethl acetate-hexane, gave the title compound (4.64 g, 64%~ as a viscous, colourless oil. OH (360 MEz, ~DC13) 1.45 (9 H, s),1.47-1.69 (4 H, m), 1.78 (2 H, dd, ~=15 and 4), 2.53 (~ H, dd, J=1~ and 10), 3.06-3.18 (2 H, m), 3.66 (3 H, s),3.72-3.85 (2 H, m), 3.86 (2 H, dd, J=10 and 4) and 7.24-7.34 (5 H, m); m/z (ES) 364 ~+tl).

b) 1-tert-Butvloxvcarbonvl-4-hvdroxv-4-r3-hvdroxv-(2-25 Phenvl)propvll~iPeridine.
A solution of the product of the previous step (3.50 g,9.63 mmol) in dry THF (50 ml) was added dropwise via cannula to a stirred solution of lithium aluminium hydride (1 M in THF, 20 ml) in dry THF ~30 ml) at under nitrogen, cooling the mixture in an ice-bath as necessary to control 30 the mild exotherm. After stirring for 1.5 hours at room temperature the soultion was cooled to 0~C and aqueous sodium hydroxide ~1 M, ~ ml) was , PCT/(,;Lr. !1,2765 wO 97/18202 added dropwise. The resulting gel was diluted with water (50 mlO and ~ci~ifi~d to pH 3-4 with aqueous citric acid (1 M, 50 ml), then extracted with ethyl acetate (3 x 100 ml). The extracts were washed with brine ~50 ml), dried (MgSO4), filtered and concentrated. Dry flash chromatography, 5 eluting with g;O% then 66% ethyl acetate-h~ne, then ethyl acetate, gave the title compound ~2.77 g, 86%) as a colourless glass. ~iH (360 MHz, CDC13) 1.44(9H,s), 1.45-1.69(4H,m), 1.96(2H,d,~~9),3.06-3.21(3H,m), 3.66-3.81 (4 H, m~ and 7.19-7.37 (5 H, m); m/z (ES) 336 (M++l).

10 c) l-tert-Butvloxvcarbonvl-4-hv~o2cY-4-~3-tosvloxv-(2-phenvl)propvllpiperidine .
A solution of the product of the previous step (1.67 g, 4.98 mmol) in dry p~ridine (40 ml) under nitrogen was stirred at 0~C and tosyl chloride (2.37 g, 12.5 mmol) was added in one portion. After stirring for 19 hours at 15 0~C the yellow soulti~n was poured onto crushed ice (150 ml), ~ fied to pE 5 with aqueous citric acid (1 M, 250 ml) and extracted with diethy-l ether (4 x 100 ml). The extracts were washed with water (100 ml), ~ri]le (100 ml), dried (MgSO4), filtered and concentrated. The resulting solid was washed with 5% ethyl acetate-h~ ne (100 ml) and dried in uacuo to yield the title compound (1.86 g, 76%) as very pale pinLc granules. ~H (360 MHz, CDC13) 1.25-1.5~) (4 H, m), 1.43 (9 H, s), 1.50-1.60 1 H, m), 1.91 (2 H, d, J=6), 2.43 ~3 H, s), 2.96-3.16 (2 H, m), 3.21-3.28 (1 H, m) 3.60-3.82 (2 H, m), 4.02-4.11 (2 H, m), 7.14 (2 H, d, J=8), 7.23-7.29 (5 H, m) and 7.65 (2 H, d, J=8); mJz (ES) 490 (M++1).
d) 1-tert-Butvloxvcarbonvl-4-fluoro-4-r3-tosY~oxv-(2-phenvl)~ropvllpiperidine The title compo~nd (1.08 g, 43%) was prepared from the product of the preceding step (2.51 g, 5.13 mmol) following a ~imil~r method to that described for ~ mple 2, step b. ~H (250 MHz, CDC13) 1.17-1.80 (13 H, m) 1.86-2.0~ (2 H, m), 2.43 (3 H, s), 2.87-3.04 (2 H, m), 3.16-3.28 (1 H, m), -CA 02236832 1998-0~-06 W o 97/18202 -5~-3.72-3.92 (2 H, m), 4.01 (1 H, dd, J=10 and 7), 4.11~1 H, dd, J=10 and 7), 7.08-7.12 (2 H, m), 7.22-7.30 (~ H, m) and 7.61-7.6~ (2 H, m); mlz (ES) 492 ~++1).

e) 4-Fluoro-4-r3-fluoro-12-Phenvl~ropvllPiPeridine A solution of the product of the previous step (1.00 g, 2.03 mmoV
and tetrabutyl~mmonium (triphenylsilyl)difluorosili~te (5.49 g, 10.2 mmoV in dry acetQrlitril~ (30 ml) was refluxed under nitrogen for 64 hours.
The mixture was cooled and solvent was removed by evaporation. The 10 residues were triturated with 60~~ ethyl acetate-he~c~ne and the mixture was filtered. The filtrate was concentrated and partly purif ied by ~ash column chromatography on silica, eluting with 15% ethyl acetate-hexane, to give crude 1-tert-butyloxycarbonyl-4-fluoro-4-[3-fluoro-(2-phenyl)propyllpiperidine. The material was dissolved in dichloromethane (4 ml) and trifluoroacetic acid (2 ml) was added. After st~n~ing at room temperature for 1.5 hours, solvent and excess acid were removed by evaporation. The residue was dissolved in aqueous sodium hydroxide (1 M, 15 ml) and extracted with dichloromethane (4 x 10 ml). The extracts were washed with brine (10 ml), dried (MgS04), filtered and concentrated.
20 Preparative thin layer chromatography on silica, eluting with 90:9:1 dichloromethane-methanol-ammonia, gave the title compound (0.0421 g, 9%) as a colourless oil. ~iH (250 MHz, CDCl3) 1.23-1.85 (4 H, m), ~.97-2.22 (2 E~, m), 2.76-2.92 (4 H, m), 3.22-3.34 (1 H, m), 4.52 (2 H, dd, J=47 and 6) and 7.21-7.46 (5 H, m); m/z (ES) 240 (M++1~.

f~ 4-~luoro-4-r3-fluoro-(2-Phenvl)~roPY~ 3-~5-(l~2~4-triazol-4 indol-3-vllProPvnPiperidine.
The title compound free base (0.024 g, 29%) was prepared ~rom Intermediate 1 and the product of the preceding step following a .simil~r 30 method to that described for ~ mple1, step d. Analytically pure material (2 mg~ was isolated by preparative high performance lic~uid ~6-chromatography. oH (360 MHz, CDCl3) 1.25-2.38 (10 H, m), 2.40-2.50 (2 H, m), 2.60-2.76 (2 H, m), 2.77 (2 H, t, J=5), 3.12-3.26 (1 H, m), 4.45 (2 H, dd, J=47 and 6), 7.14 (2 H, dd, J=8 and 2), 7.22-7.26 (3 H, m), 7.30-7.34 (2 H, m), 7.46 (1 H, d, J=9), 7.53 (1 H, d, ~=2), 8.30 (1 H, s) and 8.45 (2 H, s); m/z(ES) 464 (M++1).

l~AMPLE 14 4-Fluoro-4-r2-(4-fluoro~henvl)ethvn-1-~3-r5-(1.2.4-triazol-4-vl)-lH-indol-3-~llPropynpiperidine. Hvdro~en Oxalate.
a) l-tert-ButoxvcarbonYl-4-fluoro-r2-(4-fluoroPhenYl)ethvnYl1~ eridine A mixture of l-tert-butoxycarbonyl-4-ethynyl-4-fluoropiperidine (1 g, 4.4 mmol) and 4-fluoroiodobenzene (610 ~11, 5.3 mmol) in N,N-diethyl:~mine (20 ml) was flushed with nitrogen for 15 mins, then pa~adium bis(triphenylphosphine)-hlnri~ (150 mg, 0.2 mmol) and copper (I) iodide (42 mg, 0.2 mmol) added. The mixture was stirred at room temperature under an atmosphere of nitrogen for 2 hours, then evaporated. The residue was treated with water (50 ml) and extracted with diethyl ether (3 x 25 ml). The combined organic solutions were washed with water (1 x 50 ml), brine (1 x 20 ml), dried (M gSO4) and concentrated. Flash chromatography of the residue (silica gel, ethyl acetate-hexane 1:9) gave 1.3 g (80%) of the title compound: ~H (360MHz, CDCl3) 1.47 (9H, s), 2.01-2.08 (4H, m), 3.51-3.64 (4H, m)~ 7.00-7.05 (2H, m), 7.4~-7.46 (2H, m).

b) 1-tert-Butoxvcarbonvl-4-fluoro-4-r2-(4-fluoro~henvl~ethv~ eridine A solution of l-tert-butoxycarbonyl-4-fluoro-4-[2-(4-fluorophenyl)ethynyl3piperidine in methanol (20 ml) and glacial acid (1 ml) was hydrogenated over 10% Pd-C (0.5 g) at 50 psi for 5 hours. The catalyst was removed by filtration and the solvents removed under vacuum. The residue was dissolved in diethyl ether (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (2 x 15 ml)~ dried (M gSO4) and concentrated to give the title product (430 mg, 43~/O~ which was used in the next step without further pl-rif ~f.ion; OH (360MHz, CDCl3~ 1.46 (9H, s), 1.48-1.67 (2H, m), 1.82-1.93 (4H, m), 2.68-2.73 (2H, m), 3.05-3.20 (2H, m), 3.90-3.99 (2H, m), 6.94-6.99 (2H, m), 7.11-7.15 (2H, ~ ~ m): m/z (ES) 326 (M'+1).

c) 4-Fluoro-4- r2-(4-flu~roPhenvl)ethvll~iperidine A solution of the product from the preceding step (430 mg, 1.3 mmoV in a mixture of trifluoroacetic acid and dichloromethane (1:2, 9 ml) was allowed to stand at room temperature for 2 hours. Solvents were removed under vacuum, and the residue treated with saturated a~ueous sodium hydrogen carbonate (20 mV and the product was extracted with dichloromethane (3 x 15 ml). The combined organic solutions were dried (MgS04) and concentrated to give 290 mg (97%) of the title compound, which was used in the next step without further purification. ~H (360MHz, CDCl3) 1.52-1.71 (~2H, m), 1.82-1.92 (4H, m), 2.68-2.73 (2H, m), 2.93-3.00 (4H, m), 6.94-6.99 (2H, m), 7.12-7.16 (2H, m); m/z (ES) 226 (M++1).

d) 4-Fluoro-4-r2-(4-~luoro~henvl)ethvll-1-~3-~5~ 2.4-triazol-4-vl)-lH-indol-3-YllPro~vl~l)iPeridine. Hvdro~en Oxalate The title compound free base was prepared from Intermediate 1 and the product from the preceding step following a ~imil~r method to that les~rihed for h'.~m~le 1, step d. The oxalate salt was prepared from ethanol-diethyl ether, mp 205~C. (Found: C, 62.38; H, 5.80; N, 12.66.
C26H29F2Ns x 1.0C2H204 requires: C, 62.33; H, 5.79; N, 12.98%) OH
(360MHz, DMSO-d~) 1.82-2.14 (8H, m), 2.64-2.69 (2H, m), 2.77 (2H, t, J=7.3Hz), 2.92-3.16 (4H, m), 3.28-3.40 (2H, m), 7.09 (2H, t, J=8.8Hz), 7.25-7.34 (4H, m), 7.50 (lH, d, J=8.6Hz), 7.81 (lH, d, e7=1.8Hz)~ 9.()3 (2H, s), 11.20 (lH, bs); m/z (ES) 460 (M++1).

, m~les 16-21 were prepared from Intermediate 4 and the appropriate aryl-iodide following a ,~imilzlr procedure to that described for ~ le 14 (steps a, b, c and d).

4-Fluoro-4-(2-phenvlethvl)-1-~3-r5-(1.2,4-triazol-4-vl3-lH-indol-3-vllProPvl~PiPeridine~ 1.0 Hvdro~en Oxalate The oxalate salt was prepared from ethanol-diethyl ether, mp 212~C. (Found: C, 64.05; H, 6.13; N, 13.32. C26H30FNs x 1.0C2H204 requires: C, 64.48; H, 6.18; N, 13.43%). ~H (360MHz, DMSO-d6) 1.84-2.14 (8H, m), 2.64-2.69 (2H, m), 2.77 (2H, t, J=7.4Hz), 2.94-3.12 (4H, m), 3.28-3.40 (2H, m), 7.16-7.34 (7H, m), 7.50 (lH, d, J=8.6Hz), 7.81 (lH, d, J=1.9Hz), 9.03 (2H, s), 11.20 (lH, bs); m/z (ES) 432 (M++1).

9 -Fluoro-4- r2-(2-fluorophenYl)ethvl3 - 1-~3- r5-(1.2.4-triazol-4-vl~- lH-indol-3-vllproPYl~PiPeridine. 1.7 Hvdro~en Oxalate The oxalate salt was prepared from ethanol-diethyl ether. mp 144~C. (Found: C, 58.72; H, 5.66; N, 11.33. C26H2sF2Ns x 1.7C2H204 requires: C, 58.60; H, 5.42; N, 11.62%). ~H (360MHz, DMSO-dG) 1.84-2.14 (8H, m), 2.69-2.73 (2H, m), 2.7~-2.79 (2H, t, J=7.4Hz), 3.00-.310 (4H, rn), 3.36-3.44 (2H, m), 7.11-7.16 (2H, m), 7.23-7.29 (lH, m), 7.30-7.38 (4H, m), 7.50 (lH, d, J=8.6Hz), 7.81 (lH, d, J=1.9Hz), 9.03 (2H, s), 11.20 (lH, bs);
m/z (ES) 450 (M++l).

4-Fluoro-4-r2-(2-methoxvnhenYl)ethYn-1-~3-r5-(1.2.4-triazol-4-vl~-lH-indol-3-yllpropvl~piperidine. 1.3 Hvdro~en Oxalate The oxalate salt was prepared from ethanol-diethyl ether, mp. 98~C.
(Found: C, 61.21; H, 5.87; N, 12.38. C27H32FNsO x 1.3C2H201 requires: C, 61.44; H, 6.03; N, 12.10%). ~iH (360MHz, I)MSO-dG) 1.78-2.15 (8H, m), 2.60-, _ 2.65 (2H, m), 2.78 (2H, t, J=7.2Hz), 3.00-3.18 (4H, m), 3.34-3.44 (2H, m), 3.77 (3H, s), 6.86 (lH, t, J=7.4Hz), 6.94 (lH, d, J=7.8Hz), 7.14-7.20 (2H, m), 7.31-7.35 (2H, m), 7.50 (lH, d, J=8.6Hz), 7.81 (lH, d, J=1.9Hz), 9.02 (2H, s), 11.20 (lH, bs); m/z (ES) 462 (M++l).
h~MPLE 18 4-Fluoro-4-r2-(2-thienYl)ethvn~ 3-r5-(1.2.4-triazol-4-vl)-lH-indol-3-vll~roPvl~Pi~eridine 1.S Hvdro~en Oxalate The oxalate salt was prepared from etha~ol-diethyl ether, mp 211~C. (Found: C, 56.44; H, 5.60; N, 12.46. C24H2sFN~S x 1.5C2H204 re(luires: C, 56.63; H, 5.46; N, 12.23%). ~H (360MHz, DMSO-d6) 1.88-2.16 (8H, m), 2.74-2.79 (2H, m), 2.87-2.93 (2H, m), 2.95-3.12 (4H, m), 3.26-3.40 (2H, m), 6.90-6.9~ (2H, m), 7.31-7.34 (3H, m), 7.50 (lH, d, J=8.6Hz), 7.81 (lH, s), 9.03 (2H, s), 11.20 (lH, bs); m/z (ES) 438 (M++1).

~X~,MPLE 19 4-r2-(2-Cyanophenvl)ethvll-4-fluoro-1-~3-r5-(1,2.4-triazol-4-vl)-lH-indol-3-yllpropvUpiperidine 1.4 EIvdro~en Oxalate The oxalate salt was prepared from ethanol-diethyl ether, mp 98~C.
(Found: C, 61.42; H, 5.66; N, 14.32. C27H2~FN6 x 1.4C2H204 requires: C, 61.43; H, 5.50; N, 14.42%). ~H (360MHz, DMSO-dG) 1.88-2.20 (8H, m), 2.72-2.84 (2H, m~, 2.84-2.96 (2H, m), 3.00-3.20 (4H, m), 3.34-3.47 (2H, m), 7.32-7.35 (2H, m), 7.42 (lH, t, J=7.5Hz), 7.49-7.55 (2H, m), 7.65 (lH, t, ~7=7.3Hz), 7.78-7.82 (2H, m), 9.03 (2H, s), 11.21 (lH, bs3; mlz (ES) 457 (M~+1).

4-Fluoro-4-r2-(3-methoxv,PhenYl)ethYn-l-~3-r5-(l~2~4-triazol-4-v~ H-ind 3-vllpropyl}piperidine 1.5 Hvdro,~en Oxalate The oxalate salt was prepared from ethanol-diethyl ether, mp 164~C. (Found: (~, 60.77; H, 5.96; N, 11.65. C27H32FN~jO x l.oC2H2O4 requires: C, 60.39; H, 5.91; N, 11.74%).8H (360MHz, DMSO-d6) 1.86-2.18 (8H, m), 2.61-2.67 (2H, m), 2.78 (2H, t, J=7.3Hz), 3.00-3.18 (4H, m), 3.26-3.48 (2H, m), 3.73 (3H, s), 6.75 (lH, d, J=8.4Hz), 6.80 (2H,m), 7.19 (lH, t, J=8.2 and 8.0Hz), 7.31-7.35 (2H, m), 7.50 (lH, d, J-8.6Hz), 7.81 (lH, d, J=1.9Hz), 9.03 (2H, s), 11.21 (lH, bs); m/z (ES) 462 (~ f+l).

EX~![PLE 21 4-Fluoro-4-r2-~3-thienvl)ethvl~ 3-~5-(1~2~4-triazol-4-vl)-lH-indol-3-Yllpropvl~Piperidine 1.1 Hvdro~en Oxalate The oxalate salt was prepared from ethanol-diethyl ethert mp 208~C. (Found: C, 58.89; H, 5.81; N, 12.92. C24H2sFNsS x l.lC2HzO4 requires: C, 58.64; H, 5.67; N, 13.05%). ~H (360MHz, DMSO-d6) 1.98-2.18 (8EI, m), 2.66-2.71 (2H, m), 2.77 (2H, t, J=7.4Ez), 2.94-3.16 (4H, m~, 3.28-3.41 (2H, m), 7.02 (lH, d, J=4.9Hz), 7.20 (lH, s), 7.30-7.34 (2H, m), 7.44 (lH, dd, J=4.9 and 2.9Hz), 7.50 (lH, d, J=8.6Hz), 7.81 (lH, d, J=1.7Hz), 9.03 (2H, s), 11.22 (lH, bs); m/z (ES) 438 (M++l).

Claims (10)

CLAIMS:

1. A compound of formula I, or a salt or prodrug thereof:

wherein Z represents hydrogen, halogen, cyano, nitro, trifluoromethyl, -OR5, -OCOR5, -OCONR5R6, -OCH2CN, -OCH2CONR5R6, -SR5, -SOR5, -SO2R6, -SO2NR5R6, -NR5R6, -NR5COR6, -NR5CO2R6, -NR5SO2R6,-COR5,-CO2R5, -CONR5R6, or a group of formula (Za), (Zb), (Zc) or (Zd):

in which the asterisk * denotes a chiral centre; or Z represents an optionally substituted five-membered heteroaromatic ring selected from furan, thiophene, pyrrole, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole and tetrazole;
X represents oxygen, sulphur, -NH- or methylene;
Y represents oxygen or sulphur;
E represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms;

Q represents a straight or branched alkylene chain containing from 1 to 6 carbon atoms, optionally substituted in any position by one or more substituents selected from fluoro and hydroxy;
T represents nitrogen or CH;
U represents nitrogen or C-R2;
V represents oxygen, sulphur or N-R3;
G is attached at position 3 or 4 of the piperidine ring and represents halogen or C1-6 alkoxy;
R1 represents C3-6 alkenyl, C3-6 alkynyl, aryl(C1-6)alkyl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted;
R2, R3 and R4 independently represent hydrogen or C1-6 alkyl; and R5 and R6 independently represent hydrogen, C1-6 alkyl, trifluoromethyl, phenyl, methylphenyl, or an optionally substituted aryl(C1-6)alkyl or heteroaryl(C1-6)alkyl group; or R5 and R6, when linked through a nitrogen atom, together represent the residue of an optionally substituted azetidine, pyrrolidine, piperidine, morpholine or piperazine ring.

2. A compound according to claim 1 of formula IA, IB or IC:

wherein Z, E, Q, V, G, R1, R2 and R5 are as defined in claim 1.

3. A compound according to claim 1 of formula ID:

wherein Z, E, Q, T, G, R1, R2 and R3 are as defined in claim 1.

4 4-Benzyl-4-fluoro-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;
4-fluoro-4-[2-(3-fluorophenyl)ethyl]-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;
4-fluoro-4-(3-fluorobenzyl)-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;
4-fluoro-4-(2-fluorobenzyl)-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;
4-benzyl-4-methoxy-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;
4-benzyl-4-methoxy-1-[3-(5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl)propyl]piperidine;
4-(2-fluorobenzyl)-4-methoxy-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;

4-(3-fluorobenzyl)-4-methoxy-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;
4-(4-fluorobenzyl)-4-methoxy-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidine;
4-fluoro-4-[2-(trifluoromethyl)benzyl]-1-{3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidine;
4-fluoro-4-[2-(N,N-dimethylaminosulfonyl)benzyl]-1-{3-[5-(1,2,4-triazol-4 yl)-1H-indol-3-yl]propyl}piperidine;
4-fluoro-4-(2-phenylpropyl)-1-{3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidine;
4-fluoro-4-[3-fluoro-(2-phenyl)propyl]-1-{3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidine;
4-fluoro-4-[2-(4-fluorophenyl)ethyl]-1-{3-[5-(1,2,4-triazol-4-yl)-1H-indol-3 yl]propyl}piperidine;
4-fluoro-4-(2-phenylethyl)-1-{3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidine;
4-fluoro-4-[2-(2-fluorophenyl)ethyl]-1-{3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidine;
4-fluoro-4-[2-(2-methoxyphenyl)ethyl]-{3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidine;
4-fluoro-4-[2-(2-thienyl)ethyl]-1-{3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidine;
4-[2-(2-cyanophenyl)ethyl]-4-fluoro-1-{3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidine;
4-fluoro-4-[2-(3-methoxyphenyl)ethyl]-1-{3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidine;

4-fluoro-4-[2-(3-thienyl)ethyl]-1-{3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl}piperidine;
and salts and prodrugs thereof.

5. A process for producing a compound according to claim 1 which comprises:

A) when T represents CH, U represents C-R2 and V represents N-R3 in the compound of formula I, reacting a compound of formula III:

wherein Z and E are as defined in claim 1, with a compound of formula IV, or a carbonyl-protected form thereof:

wherein Q, G, R1 and R2 are as defined in claim 1; followed, where required, by N-alkylation by standard methods to introduce the moiety R3;

(B) reacting a compound of formula VII

wherein Q, G, R1 and R2 are as defined in claim 1, with a compound of formula VIII:

wherein Z, E, Q, T, U and V are as defined in claim 1, and L2 represents a suitable leaving group;

(C) when U represents nitrogen and V represents N-R3 in the compound of formula I, cyclising a compound of formula X:

wherein Z, E, Q, G and R1 are as defined in claim 1, and D1 represents a readily displaceable group; followed, where required, by N-alkylation by standard methods to introduce the moiety R3;

(D) when T represents CH, U represents C-R2 and V represents oxygen or sulphur in the compound of formula I, cyclising a compound of formula XIII:

wherein Z, E, Q, G, R1 and R2 are as defined in claim 1, and V1 represents oxygen or sulphur;

(E) reducing a compound of formula XVI:

wherein Z, E, T, U, V, G and R1 are as defined in claim 1, and -Q2-CH2- corresponds to the moiety Q as defined in claim 1; or (F) elaborating a compound of formula I into a further compound of formula I.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable carrier.

7. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof, for use in a method of treatment of the human or animal body.

8. A compound according to claim 7 for use in the treatment of migraine.

9. The use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof, in the manufacture of a medicament for the treatment of a clinical condition for which a selective agonist of 5-HT1Da receptors is indicated.

10. A method of treatment of a subject suffering from a clinical condition for which a selective agonist of 5-HT1Da receptors is indicated, which comprises administering to that subject a therapeutically effective amount of a compound according to any one of claims 1 to 4 or a therapeutically acceptable salt or therapeutically acceptable prodrug thereof.