CA2195759C - Tetrahydropyridinylmethyl derivatives of pyrrolo[2,3-b]pyridine - Google Patents

Abstract

A class of pyrrolo[2,3-b]pyridine derivatives of formula (I), wherein Q represents a moiety of formula Qa or Qb, are ligands for dopamine receptor subtypes within the body, in particular the dopamine D4 receptor subtype and are therefore useful in the treatment and/or prevention of disorders of the dopamine system, including schizophrenia.</SD OAB>

Description

~ 2195759 TETItAHYDROPYRIDINYLMETHYL DERNATIVES OF
PYRROLO12,3-b1 PYRIDINE

This invention relates to a particular class of heteroaromatic compounds. More particularly, the invention is concerned with certain substituted tetrahydropyridinylmethyl derivatives of pyrrolo[2,3-b]-pyridine. These compounds are ligands for dopamine receptor subtypes within the body, in particular the dopamine D4 receptor subtype. They are therefore of use in the treatment and/or prevention of disorders of the dopamine system, including schizophrenia, depression, anxiety, nausea, Parkinson's disease, tardive dyskinesias and extrapyramidal side-effects associated with treatment by conventional neuroleptic agents, neuroleptic malignant syndrome, disorders of hypothalamic-pituitary function such as hyperprolactinaemia and amenorrhoea, and delusional disorders (cf.
1s Catalano et al., Biol. Psychiatry, 1993, 34, 459).
Upper gastrointestinal tract motility is believed to be under the control of the dopamine system. The compounds according to the present invention may thus be of use in the prevention and/or treatment of gastrointestinal disorders, and the facilitation of gastric emptying.
Dependence-inducing agents such as cocaine and amphetamine have been shown to interact with the dopamine system.
Compounds capable of counteracting this effect, including the compounds in accordance with the present invention, may accordingly be of value in the prevention or reduction of dependence on a dependence-inducing agent.
Dopamine is known to be a peripheral vasodilator; for example, it has been shown to exert a dilatory effect on the renal vascular bed. This implies that the compounds of the present invention may be beneficial in controlling vascular blood flow.
The localisation of dopamine receptor mRNA in rat heart and large vessels has been noted. This suggests a role for dopamine receptor 2155759 ~

ligands in controlling cardiovascular function, either by affecting cardiac and smooth muscle contractility or by modulating the secretion of vasoactive substances. The compounds according to the present invention may therefore be of assistance in the prevention andlor treatment of such conditions as Ilypertension and congestive heart failure.
By virtue of their activity as ligands for dopamine receptor subtypes within the body, the compounds in accordance with the present invention may also be of benefit in enhancing cognitive function, and in treating andlor preventing cognitive disorders induding presenile and senile dementia (also known as Alzheimer's disease and senile dementia of the Alzheimer type respectively).
Molecular biological techniques have revealed the existence of several subtypes of the dopamine receptor. The dopamine D, receptor subtype has been shown to occur in at least two discrete forms. Two forms of the D2 receptor subtype, and at least one form of the D3 receptor subtype, have also been discovered. More recently, the D4 (Van Tol et al., Nature (London), 1991, 350, 6 10) and Ds (Sunahara et al., Nature (Londora,), 1991, 350, 614) receptor subtypes have been described.
The compounds in accordance with the present invention, being ligands for dopanmine receptor subtypes within the body, in particular the D4 receptor subtype, are accordingly of use in the treatment andlor prevention of disorders of the dopamine system, induding schizophrenia.
The present invention provides a compound of formula I, or a salt or prodrug thereof:

Cfiz -Q
N x k H
ll) WO 96/05200 PCTIcB95101820 _g.
wherein Q represents a moiety of formula Qa or Qb:

-N
R' -N_ ir---A

(Qa) (Qb) wherein Ri represents hydrogen, fluoro, cyano, trifluoromethyl,. Ci.s alkyl, Ci.s alkoxy or di(Ci.c)alkylamino; and R2 represents hydrogen, halogen, cyano, trifluoromethyl, Ci.6 alkyl or di(Ci-s)alkylamino; or Rl and R2 together represent methylenedioxy;
provided that Ri and R2 are not both simultaneously hydrogen; and A represents a group of formula (i), (ii) or (iii):

R R"

Ra V

0) (h) (W) in which V represents oxygen, sulphur or N-R5;
R3 represents halogen, cyano, trifluoromethyl, Ci-s alkyl or Ci.s alkoxy;
R¾ represents hydrogen, halogen, cyano, trifluoromethyl, C,.s alkyl or Ci.s alkoxy; and R$ represents hydrogen or Ci.s alkyl.

2195?5 ~

WO 96/05200 PCT/t'>B95l0]820 The compounds in accordance with the present invention are encompassed within the generic scope of co-pending International Patent Applfcation No. PCT1GB94f00384 (published on 15 September 1994 as WO
94/20459). There is, however, no specific disclosure therein of compounds corresponding to those of formula I above wherein Q is as defined above.
For use in medicine, the salts of the compounds of formula I
will be pharmaceutically acceptable salts. Other salts may, 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 compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, ci.tric 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 potassicun salts; alkaline earth metal salts, e.g. calrium or magnesium salts; and salts formed with suitable organic ligands, e.g.
quaternary ammonium salts.
As used herein, the expression Ci.6 alkyl" relates to methyl and ethyl groups, and straight-chained or branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as "C1.6 alkoxy" and "di(Ci.s)alkylamino" are to be construed accordingly.
The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine and chlorine.
The present invention includes within its scope prodrugs of the compounds of formula I above. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I. Conventional 2'95759 =

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 accordingly exist as enantiomers.
It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
Where the compounds of formula I above contain a moiety of formula Qa, the group Rl suitably represents fluoro, cyano, trifluoromethyl, methyl, methoxy or dimethylamino. Particular values of R' include fluoro, cyano, trifluoromethyl, methyl and methoxy.
Suitably, R2 represents fluoro, chloro, cyano, trifluoromethyl, methyl or dimethylamino, in particular fluoro or chloro, and especially chloro.
Moreover, one of R' and R2 may represent hydrogen when the other of Rl and R2 is other than hydrogen. Preferably, one of RI and R2 represents hydrogen and the other of R1 and R2 is other than hydrogen.
Where the compounds of formula I above contain a moiety of formula Qb, the integer V suitably represents sulphur.
Suitably, R3 represents fluoro, chloro, cyano, trifluoromethyl, methyl or methoxy. Particular values of R3 include fluoro, chloro, trifluoromethyl, methyl and niethoxy.
Suitably, R4 represents hydrogen, fluoro, chloro, cyano, trifluoromethyl, methyl or niethoxy, especially hydrogen.
Suitably, R5 represents hydrogen or methyl, especially methyl.
Particular values for the substituent A include fluorophenyl, chlorophenyl, cyanophenyl, trifluoromethylphenyl, methylphenyl, methoxyphenyl, pyridinyl and thienyl.

2 '9J159 WO 96/05200 PC TdGB95i01820 A particular sub-class of compounds according to the present invention is represented by the compounds of formula IIA, and salts and prodrugs thereof:

ii ~ R

Nr N
H
(IL4) wherein Rll represents fluoro, cyano, trifluoromethyl, Cr.s alkyl, Ci.s alkoxy or di(Ca.e)alkylamino.
Suitably, R" represents fluoro, cyano, trifluoromethyl, methyl, methoxy or dimethylamino.
Particular values of R" include fluoro, cyano, trifluoromethyl, methyl and methoxy.
Another sub-class of compounds according to the present invention is represented by the compounds of formula IIB, and salts and -5 prodrugs thereof:

N
N N R3a H
(IIB) wherein R12 represents halogen, cyano, trifluoromethyl, CI.e alkyl or di(Ci.s)alk,ylamino.
Suitably, R12 represents fluoro, chloro, cyano, trifluoromethyl, methyl or dimethylamino.

= 2?95759 Particular values of R12 include fluoro and chloro, especially chloro.
A further sub-class of compounds accordin.g to the present invention is represented by the compounds of formula IIC, and salts and s prodrugs thereof:

R
/
~
~ \ Rss N
H
(TIC) wherein R" is as defined with reference to formula IIA above; and R22 represents fluoro, chloro, trifluoromethyl or Cis alkyl.
Suitably, R22 represents fluoro, chloro, trifluoromethyl or methyl.
Suitably, Rli and R22 both represent fluoro.
A still further sub-class of compounds according to the present invention is represented by the compounds of formula IID, and salts and prodrugs thereof:

N_ ~}--_ ~

N \
H
' (IID) wherein R3 is as defined with reference to forniula I above.

2'9~:i759 A yet further sub-dass of compounds according to the present invention is represented by the compounds of formula I as defined above, and salts and prodrugs thereof, wherein Q represents a moiety of formula Qb in which A represents a pyridin-3-yl, thien-2-yl or thien-3-yl group.
Specific compounds within the scope of the present invention include:

3-[4-(4-trifluoromethylphenyl)ethynyl-1,2,3,6-tetrahydropyridin-l-yl]methyl-lH-pyrro.lo [2 , 3-b]pyridine;
3-[4-(pyridin-3-yl)ethynyl-1,2,3,6-tetrahydropyridin-1-yl] methyl-lH-1o pyrrolo[2,3-b]pyridine;
3-[4-(4-methoxyphenyl)ethynyl-1,2,3,6-tetrahydropyridin-1-yl] methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(4-methylphenyl)ethynyl-1,2,3,6-tetrahydrop yridin-l-yl]meth.yl-1H-pyrrolo [2, 3-b]pyrid.ine;
3-[4-(4-fluorophenyl)ethynyl-1,2,3,6-tetrahydropyridin-1-yl]methyl-lH-pyrrolo[2,3-b}pyridine;
3-[4-(4-chlorophenyl)ethynyl-1,2,3,6-tetrahydropyridin-1-yl}methyl-lH-pyrrolo[2,3-b]pyricline;
3-[4-(t,hien-3-yl)ethynyl-1,2,3,6-tetrahydropyridin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(thien-2-yl)etihynyl-1,2,3,6-tetrahydropyridin-l-yl]methyl-lH-py'rrolo[2,3-b]pyridine;
(E)-3-[4-(2-(4-trifluoromethylphenyl)ethenyI)-1,2, 3,6-tetrahydropyridin-l-yl] methyl-lH-pyrrolo[2,3-b]pyridine;
(E)-3-[4-(2-(4-methoxyphenyl)ethenyl)-1,2,3,6-tetrahydropyridin-l-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
(E)-3-[4-(2-(4-methylphenyl)ethenyl)- 1,2,3,6-tetrahydropyridin-1-yl] methyl-lH-pyrrolo[2, 3-b]pyridine;
(E)-3-[4-(2-(4-cyanophenyl)ethenyl)-1,2,3,6-tetrahydropyridin-l-yl]methyl-1H-pyrrol0[2,3-bjpyridine;

= 2 195759 (E)-3-[4-(2-(4-fluorophenyl)ethenyl)-1,2,3,6-tetrahydropyridin-l-yl]methyl-1H-pyrrolo[2 ,3-b]pyridine;
(E')-3-[4-(2-(3-chlorophenyl)ethenyl)-1,2,3,6-tetrahydropyridin-l-yl] methyl-lH-pyrrolo[2,3 -b]pyridine;
and salts and prodrugs thereof.
Additional specific compounds within the scope of the present invention also include:
(E)-3-[4-(2 -(3-fluorop henyl)ethenyl)-1,2,3,6-tetrahydropyridin-l-yl]methyl-1H-pyrrolo [2,3-b]pyridine;
(E)-3-[4-(2-(3,4-methylenedioxyphenyl)ethenyl)-1,2,3,6-tetrahydropyrid.in-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
()T)-3-[4-(2-(3-methylphenyl)ethenyl)-1,2,3,6-tetrahydropyridin-l-yl]methyl-lH-pyrrolo [2,3-b]pyridine;
(E)-3 -[4-(2-(3-cyanophenyl)ethenyl) -1,2,3,6-tetrahydropyridin-l-yl]methyl-1H-pyrrolo [2,3-bjpyridine;
(E)-3-[4-(2-(3,4-difluorophenyl)ethenyl)- 1,2,3,6-tetrahydropyridin- 1-yl]methyl -1H-pyrrolo [2, 3-b]pyridine;
and salts and prodrugs thereof.
Further specific compounds within the scope of the present invention include:
(E)-3-[4-(2-(3-fluoro-4-methoxyphenyl)ethenyl)-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
and salts and prodrugs thereof.
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, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the 2'957a9 =
WO 96/05200 PCTlGB9.5101820 -i0-compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. An erodible polymer containing the active ingredient may be envisaged. For preparing so.lid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a soiid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the 1s 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 containing from 0.1 to about 500 mg of the active ingredient of the present invention. Favoured 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 fornier. 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. A variety of materials can be used for such enteric layers or coatings, sucll materials including a number of polymeric acids and mixtures of polymeric 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 s cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of schizophrenia, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of I to 4 times per day.
In order to alleviate the symptoms of schizophrenia without causing sedation or extrapyramidal side-effects, it is believed that the dosage level of the active ingredient should be selected such that the dose administered is effective in substantially completely blocking the dopamine D., receptor subtype in human brain whilst displaying no or negligible dopamine D2 receptor subtype occupancy. A suitable dosage level in this regard is about 0.001 to 5.0 mg/kg per day, more particularly about 0.005 to 1.0 mg/kg per day, and especially about 0.01 to 0.5 mg/kg per day.
If desired, the compounds in accordance with this invention may be co-administered with another medicament, for example a known anti-schizophrenic agent which produces its effects via dopamine D2 and/or 5-HT2 receptor blockade. Such co-administration may be desirable where a patient is already on an established treatment regime, for example one involving conventional anti-schizophrenic medicaments such as haloperidol or chlorpromazine.

2195759 WO 96/05200 PCTlG$95/01820 The compounds in accordance with the present invention may be prepared by a process which comprises reacting a compound of formula III with a compound of formula IV:

i ~ i H-N' R

(TIl) (IV) wherein Q1 represents the residue of a moiety of formula Qa or Qb as defined above, and RF represents a hydrogen atom or a suitable protecting group; in the presence of a substantially equimolar amount of formaldehyde; followed, where required, by removal of the prote.ctinng group R.P.
The reaction is conveniently carried out by stirrin.g the reactants in aqueous acetic acid, ideally in the presence of a buffer such as sodium acetate tri.hydrate, suitably at room temperature.
The formaldehyde may be utilised in the form of parafornlaldehyde; or as a solution of formaldehyde in an inert solvent, e.g. 37% aqueous formaldehyde.
The protecting group Rr, when present, is suitably an acyl moiety such as acetyl, which can conveniently be removed as necessary by treatment under strongly basic conditions, e.g. sodium methoxide in methanol. Alternatively, the protecting group RP may be a carbamoyl moiety such as t-butoxycarbonyl (BOC), which can conveniently be removed as necessary by treatment under mildly acidic conditions.
In an alternative procedure, the compounds according to the present invention may be prepared by a process which comprises reacting a compound of formula IV as defined above with a compound of formula V:

= 2195759 CH~

I 6~ N
N
R
(V) wherein Rp is as defined above, and L represents a suitable leaving group;
followed, where required, by removal of the protecting group W.
The leaving group L is suitably a halogen atom, e.g. chlorine or bromine; or a dialkylami.no group, e.g. dimethylamino.
When L represents a halogen atom, the reaction between compounds IV and V is conveniently carried out by stirring the reactants under basic conditions in a suitable solvent, for example potassium carbonate in N,N-dimethylformamide, or triethylamine in tetrahydrofuran or acetonitrile. Where L represents a dialkylamino group, the reaction is conveniently effected by heating the reactants in an inert solvent such as toluene, typically at the reflux temperature of the solvent.
Where they are not commercially available, the starting materials of formula III, IV and V may be prepared by procedures analogous to those described in the accompanying Examples, or by standard methods well known from the art.
Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their coniponent enantiomers by standard techniques such as preparative HPLC, or the formation of 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, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
During any of the above synthetic sequences it may be necessary and/or 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 Protective Groups in Organic 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, 199 1. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The following Examples illustrate the preparation of t5 compounds according to the invention.
The compounds useful in this invention potently inhibit [gH]-spiperone binding to human dopamine D4 receptor subtypes expressed in clonal ce.ll lines.

2o [3H]-Spiperone Binding Studies Clonal cell lines expressing the human dopamine D4 receptor subtype were harvested in PBS and then lysed in 10 mM Tris-HCl pH 7.4 buffer containing 5 mlY1 MgSO4 for 20 min on ice. Membranes were 25 centrifuged at 50,000g for 15 min at 4 C and the resulting pellets resuspended in assay buffer (50 mM Tris-HCl pH 7.4 containing 5 mM
EDTA, 1.5 mM CaClz, 5 mM MgCl2, 5 mM KCI, 120 mM NaCl, and 0.1%
ascorbic acid) at 20 mglml wet weight. Incubations were carried out for 60 min at room temperature (22 C) in the presence of 0.05-2 nM [9H]-3e spiperone or 0.2 p.M for displacement studies and were initiated by addition of 20-100 g protein in a final assay volume of 0.5 ml. The ~ 2?95759 incubation was terminated by rapid filtration over GFB filters presoaked in 0.3% PEI and washed with 10 ml ice-cold 50 mM Tris-HC1, pH 7.4.
Specific binding was determined by 10 gM apomorphine and radioactivity determined by counting in a LKB beta counter. Binding parameters were determined by non-linear least squares regression analysis, from which the inhibition constant K could be calculated for each test compound.
The compounds of the accompanying Examples were tested in the above assay, and all were found to possess a K; value for displacement of [3H]-spiperone from the human dopamine D4 receptor subtype of below 1.5 M.

$-[4-(4-Tri.fluoromethvl)phenvlethvnyl-1 2 3 6-tetrahvdronvridin-l-y1]methvl-1H-12.3-binyridine Step 1: 1-tert-Butoxycarbonv1-4-oineridone Triethylamine (92ml, 0.66mo1) was added dropwise to a cold (0 C) suspension of 4-piperidone monohydrate hydrochloride (100g, 0.65mo1) and di-tert-butyl dicarbonate (142g, 0,65mo1) in dichloromethane (400m1) under a nitrogen atmosphere. The cooling bath was removed when about a quarter of the triethylamine had been added.
After 2 hours stirring at room temperature the vigorous bubbling had ceased, the mixture was diluted with water (500m1), the phases were separated and the aqueous was extracted with dichloromethane (3 x 250ni1). The combined organics were washed with brine (250m1), dried (MgSOa) and evaporated irt vacuo to give a light brown solid. The solid was dissolved in ethyl acetate (11) and treated with silica gel (150g). Filtration and evaporation gave the title compound as a white waxy solid (111.7g, 86%); SH (CDCIs) 1.49 (9H, s, OC(CH3)3), 2.44 2195759 WO 96/05200 PC1'1GB95/01820 (4FI, t, J 6.1Hz, 2 x piperidone CH2CO) and 3.72 (4H, t, J 6.1Hz, 2 x piperidone CH2-N).

Step 2: 1-tert-Butoxvcarbonvl-4-trimethvlsilylethvnvl-1.2.3.6-tetrahvdronyridine n-Butyl lithium (2.5M in hexanes, I lOml, 276mmol) was cannulated into a solution of trimethylsilylacetylene (40m1, 276mmo1) in tetrahydrofuran (500m1) at -70 C, under a nitrogen atmosphere, at such a rate that the temperature did not exceed -60 C. Once the addition was complete the solution was stirred at -70 C for one hour. The cooling bath was removed and the solution was cannulated into a solution of 1-tert-butoxycarbonyl-4-piperidone in THF (500m1) at -70 C under a nitrogen atmosphere at such a rate that the temperature did not exceed -65 C.
Once the addition was complete the mixture was stirred at -70 C for 10 minutes before warming to room temperature. Following a one hour stir at room temperature the mixture was cooled to 0 C and saturated ammonium chloride (500m1) was added. The solvent was removed itt vacuo and the residue extracted with dichloromethane (3 x 500m1). The organics were dried (MgSO4) and evaporated in vucuo to give an orange residue (89g). The residue was dissolved in diehloromethane (11) under a nitrogen atmosphere, triethylamine (52.5m1, 375mmo1) was added and the mixture was cooled to -10 C. Mesyl chloride was then added at such a rate that the temperature did not exceed 0 C. Once the addition was complete the mixture was stirred at 0'C for 10 minutes, allowed to warm to room temperature and stirred for 20 hours.
The solution was treated with sodium bicarbonate (sat., 400ml), the phases were separated and the aqueous extracted with dichloromethane (2 x 250m1). The combined organics were washed with brine (250ml), dried (MgSO4) and evaporated in vacuo to give a pale oil which was purified by column chromatography on silica, eluting with ethyl acetate/petroleum ether 60/80 (1:1), to give the title compound (51g, 72%) as a pale straw coloured oil; Sx (CDCla) 1.46 (9H, s, OC(CHs)a), 2.24 (2H, br s, tetrahydropyridinyl CH2), 3.47 (2H, t, J 5.6Hz, tetrahydropyridinyl CH2), 4.12 (2H, d, J 7.1Hz, tetrahydropyridinyl CH2) and 6.06 (1H, br s, tetrahydropyridinyl CH).
Step 3: 1-tert-Butoxvcarbonvl-4-ethynvl-1.2.3.6-tetrahvdronyridine Potassium carbonate (1.0g, 7.2mmol) was added to a solution of 1-tert-butoxycarbonyl-4-trimethylsilylethynyl-1,2,3,6-tetrahydropyridine (44.9g, 161mmo1) in methanol (250m1) under a nitrogen atmosphere and the mixture was stirred at room temperature for 3 hours. The solution was evaporated in vacuo without heating. The residue was dissolved in ether (250m1), washed with sodium carbonate (sat., 100m1), water (50m1) and brine (50m1) before drying (MgSO4) and evaporation in vacuo to give the title compound as a white waxy solid (30.0g, 90%); 5x (CDC13) 1.46 (9H, s, OC(CHa)s), 2.24-2.26 (2H, m, tetrahydropyridinyl CH2), 2.89 (1H, s, ethynyl CH), 3.49 (2H, t, J 5.7Hz, tetrahydropyridinyl CH2), 3.95-3.97 (2H, m, tetrahydropyridinyl CH2) and 6.10 (1H, s, tetrahydropyridinyl CH).
Step 4: 1-tert-Butoxycarbony1-4-1(4-trifluoromethyl)-phenvl ethvnvll-1.2.3.6-tetrahvdropvridine Bis(triphenylphosphine)palladium(II) chloride (61mg, 0.09mmo1) and copper(I) iodide (17mg, 0.09mmo1) were added to a solution of 1-tert-butoxycarbonyl-4-ethynyl-1,2,3,6-tetrahydropyridine (2.0g, 9.6mmol) and 4-iodobenzotrifluoride (3.15g, 11.6mmol) in diethylamine under a nitrogem atmosphere. The mixture was stirred at room temperature for 18 hours before evaporation in vacuo. The residue was diluted with dichloromethane (50m1) and washed with water (50m1). The aqueous was extracted with dichloromethane (2 x 50m1) and the combined organics were washed with brine (50m1), dried (NIgSO4) and evaporated in uacuo to give a red brown oil which solidified on standing. Purification by column chromatography on silica eluting with ethyl acetatelpetrnl (60-80 ) (1:9) gave the title compound as a beige solid (2.58g, 76%); Sa (CDCIs) 2.24-2.30 (2H, m, tetrahydropyridinyl CHa), 3.01 (2H, t, J 5.7Hz, tetraliydropyridinyl CH2), 6.23-6.26 (1H, m, tetrahydropyridinyl CH) and 7.49-7.58 (4H, m, ArH).

Step 5: 4-(4-Trifluoromethvl)nhen ~ Ilethynvl-1.2.3.6-tetrahydropvridine Trifluoroacetic acid (lOml) was added to a solution of 1-terG-butoxycarbonyl-4-[(4-trifluoromethyl)phenylethynyl] -1,2,3,6-tetrahydropyridine (2.40g, 6.83mmol) in dichloromethane (15m1) under a nitrogen atmosphere and the solution was stirred at room temperature for 30 minutes. The mixture was evaporated in vacuo and the residue diluted with dichloromethane (40m1) and washed with sodium hydroxide solution (1N, 40m1). The aqueous was extracted wth dichloromethane (2 x 40m1) and the combined organics were washed with brine (40m1), dried (KaCOs) and evaporated ira vacuo to give the title compouind as a yellow brown solid (1.69g, 99%); SFi (CDCIa) 2.24-2.30 (2H, m, tetrahydropyridinyl CHz), 3.01 (2H, t, J 5.7Hi, tetrahydropyridinyl CH2), 3.46-3.50 (2H, m, tetrahydropyridinyl CH2), 6.24-6.26 (1H, m, tetrahydropyri(iinyI CH) and 7.49-7.58 (411, m, ArI-1).

Step 6: 3-f(4-Trifluoromethyl)phenyletbvnvI-1.2.3.6-tetrahvcixonyri.din-I-vllmethyl-IH-nvrrolo12.3-binvizdine.
A mixture of 4-(4-trifluoromethyl)phenylethynyl-1,2,3,6-tetrahydropyridine (800mg, 3.2mmol) and 3-di.methylaminomethyl-IH-pyrrolo[2,3-b]pyridine (613mg, 3.5mmol) in dry toluene (30m1) under a nitrogen atmosphere was heated at reflux for 20 hours. The mixture was cooled to room temperature and the solid precipitate collected by filtration, washed krith toluene and dried in vacuo. The solid was recrystallised ~ 2'9575g from toluene to give the title compound as a white solid (615mg, 51%), m.p. 191-193 C (toluene); (found: C, 69.54; H, 4.65; N, 10.98. CzzHiaFaNs requires C, 69.28; H, 4.76; N, 11.02%); 611 (DMSO-d6) 2.27-2.30 (2H, m, tetrahydropyridinyl CHz), 2.58 (2H, t, J 5.6Hz, tetrahydropyridinyl CH2), 3.05 (211, m, tetrahydropyridinyl CH2), 3.73 (211, s, NCHzAr), 6.24 (1H, m, tetrahydropyridinyl CH), 7.04 (1H, dd, J 7.8 & 4.6Hz, 5-H), 7.38 (1H, d, J
2.3Hz, 2-H), 7.62 (2H, d, J 811z, ArH), 7.72 (2H, d, J 8Hz, ArH), 8.02 (1H, dd, J 7.8 & 1.4Hz, 4-H), 8.20 (1H, dd, J 4.6 & 1.5Hz, 7-H) and 11.48 (111, br s, NH); m/z (ES') 382 (M+1)4.

3-[4-(4-Methoxy)phenvlethynyl-12 3 6-tetrahvdronvridin 1 vl]methvl-IH
p ynolo(2.3-b2nvridine M.p. 207-209 C (toluene); (found: C, 76.65; H, 6.08; N, 12.08.
C22H2iN30 requires C, 76.94; H, 6.16; N, 12.24%); Sx (DMSO-ds) 2.23 (2H, br s, tetrahydropyridinyl CHz), 2.56 (2H, t, J 5.5Hz, tetrahydropyridinyl CHz), 3.02 (2H, d, J 2.9Hz, tetxahydropyridinyl CH2), 3.72 (2H, s, NCH2Ar), 3.76 (3H, s, OCHa), 6.08 (1H, m, tetrahydropyridinyl CH), 6.90-6.93 (2H, m, ArH), 7.03 (111, dd, J 7.8 & 4.6Hz, 5-H), 7.33-7.38 (3H, m, ArH), 8.02 (1H, dd, J 7.8 & 1.3Hz, 4-H), 8.19 (IH, dd, J 4.6 & 1.5Hz, 6-H) and 11.47 (1H, br s, NFi); m/z (ES*) 344 (M+1)'.

3-(4'-(3-Pvridinvl)ethynyl-1.2.3.6-tetrahvdropvridin-1-y llmethvl-lH-pyrrolo [2.3-blpyridin e The title compound was synthesised from 3-iodopyridine (prepared using the procedure of L.O. Shnaidmann et al., Tr. Inst.

ti WO 95l05200 Eksperim. Klinisch. Med. Akad. Nauk Latu. SSR, 1962, 27, 1-14) using chemistry analogous to Example 1.
M.p. 170-172 C (toluene); (found: C, 76.28; H, 5.69; N, 17.34.
CaoHrsN4Ø025 (C7Hs) requires C, 76.52; H, 5.79; N, 17.69%); 5x (DMSO-de) 2.26-2.29 (2H, m, tetrahydropyridinyl CHz), 2.58 (2H, t, J 5.6Hz, tetra:hydropyridinyl CHa), 3.05 (2H, d, J 3.2Hz, tetrahydropyridinyl CHa), 3.73 (2H, s, NCHaAr), 6.21 (1H, br s, tetrahydropyridinyl CH), 7.04 (1H, dd, J 7.8 & 4.7Hz, 5-H), 7.38-7.41 (2H, m, ArH), 7.81-7.84 (1H, m, ArH), 8.02 (111, dd, J 7.8 & 1.3Hz, 4-H), 8.19 (1H, dd, J 4.6 & 1.5Hz, 6-H), 8.52 (1H, dd, J 4.8 & 1.6Hz, ArH), 8.61 (iH, dd, J 2.1 & 0.6Hz, ArH) and 11.48 (1H, br s, NIi); m/z (ES+) 315 (M+1)'.

8-f 4-(3-Thienvl)ethynvl-1.2.3.6-tetrah ydrov vridin-1-vl]methyl-lH-pvrrolo (2.3-b1 pvri dine M.p. 203-205`C (methanol); (found: C, 70.45; H, 5.23; N, 12.83. Ci9Hi7N3SØ25 (HaO) requires C, 70.45; H, 5.45; N, 12.97%); 611 (I)MSO-dc) 2.28 (2H, br s, tetrahydropyridinyl CHa), 2.56 (2H, t, J 5.6Hz, tetrahydropyridinyl CHa), 3.02-3.03 (2H, m, tetrahydropyridinyl CH2), 3.72 (2H, s, NCHaAr), 6.10 (1H, br s, tetrahydropyridinyl CH), 7.03 (1H, dd, J 7.8 & 4.6Hz, 5-H), 7.12 (1H, dd, J 5.0 & 1.1Hz, ArH), 7.37 (1H, s, 2-H), 7.58 (1H, dd, J 5.0 & 2.9Hz, ArH), 7.72 (1H, dd, J 2.9 & 1.0Hz, ArH), 8.02 (1H, dd, J 7.8 & 1.4Hz, 4-H), 8.19 (1H, dd, J 4.6 & 1.5Hz, 6-H) and 11.47 (111, br s, NH); m/z (ES+) 320 (N,1+1)`.

~ 2195759 WO 96/05200 PCT/cs95/01820 3-f4-(4-Chloro)nhenyle hvnvl-1.2.3.6-tetrahydropyridin-l-yllmethyl-lH-nyrro1o f 2, 3-b1 oyridine M.p. 114-116 C (methanol); (found: C, 72.19; H, 5.29; N, 11.85. CaiHiaNsC1 requires C, 72.51; H, 5.22; N, 12.08%); Sx (DMSO-ds) 2.24 (2H, br s, tetrahydropyridinyl CHz), 2.57 (2H, t, J 5.5Hz, tetrahydropyridinyl CHz), 3.03 (2H, d, J 3.2Hz, tetrahydropyridinyl CH2), 3.72 (2H, s, NCH2Ar), 6.16 (1H, m, tetrahydropyridinyl CH), 7.03 (1H, dd, J 7.8 & 4.6Hz, 5-H), 7.37 (1H, d, J 2.3Hz, 2-H), 7.42 (4H, s, ArH), 8.02 (1H, dd, J 7.9 & 1.4Hz, 4-H), 8.19 (1H, dd, J 4.7 & 1.6Hz, 6-H) and 11.47 (1H, br s, NH); m/z (ES*) 348 (M+1)*.

1s EXAMPLE 6 3-f4-(4-Methvl)aheanvlethynyl-1,2,3,6-tetrahydronyridin-l-vllmethyl-lH-pvrrolof 2.3-blpvridine M.p. 219-221 C (methanol); (found: C, 79.80; H, 6.39; N, 12.64. C22H2N3Ø2 (H20) requires C, 79.82; H, 6.52; N, 12.69%); Sx (DMSO-ds) 2.23 (2H, br s, tetrahydropyridinyl CHa), 2.30 (3H, s, ArCHs), 2.56 (2H, t, J 5.6Hz, tetrahydropyridinyl CH2), 3.02 (2H, d, J 3.2Hz, tetrahydropyridinyl CHs), 3.72 (2H, s, NCHzAr), 6.10 (1H, m, tetrahydropyridinyl CH), 7.03 (1H, dd, J 7.8 & 4.7Hz, 5-H), 7.17 (2H, m, ArH), 7.29 (2H, m, ArH), 7.37 (111, d, J 2.3Hz, 2-H), 8.02 (1H, dd, J 7.8 &
1.4Hz, 4-H), 8.18 (1H, dd, J 4.7 & 1.5Hz, 6-H) and 11.47 (1H, br s, NH);
m/z (ES*) 328 (M+1)*.

EkAMPLE 7 344-(4-F1 uoro)oh envlethvnvl-1.2.3.6-tetrahvdron vridin -1-vll methyl-1H-Dvrrolof2.3-blovridine M.p. 191-192 C (methanol); (found: C, 75.98; H, 5.37; N, 12.54. CztHisFNa requires C, 76.11; H, 5.48; N, 12.68%); Sfi (DMSO-ds) 2.24 (2H, m, tetrahydropyridinyl CH2), 2.57 (2H, t, J 5.5Hz, tetrahydropyridinyl CH2), 3.03 (2H, d, J 3.0Hz, tetrahydropyridi:nyl CH2), 3.72 (2H, s, NCH2Ar), 6.14 (1H, br s, tetrahydropyridinyl CH), 7.04 (1H, dd, J 7.8 & 4.6Hz, 5-.H), 7.18-7.23 (2H, m, ArH), 7.38 (1H, s, 2-H), 7.44-7.48 (2H, m, ArH), 8.02 (IH, dd, J 7.8 & 1.5Hz, 4-H), 8.19 (1H, dd, J 4.7 &
1.5Hz, 6-H) and 11.47 (111, br s, NH); m/z (ES`) 332 (M+1)*.

344-(2-Thienvl)ethynvl 12 3 G tetrahydropvridin-l-yllmethyl-iH-Pyrrolof2.3-blpvridine Step 1: 4-(2-Thieny)ethynvl-1.2,3,6-tetrahydropyridine A solution of 1-tert-butoxycarbonyl-4-(2-thienyl)ethynyl-1,2,3,6-tetrahydropyridine (530mg, 1.8mmol) (prepared in a manner analogous to Example 1) in diethyl ether (10m1) at room temperature under a nitrogen atmosphere was treated with excess ethereal hydrogen chloride. Following a 3 hour stir at room temperature the dark mixture was diluted with water and extracted with diethyl ether (2 x 30ml). The aqueous phase was made basic with potassium carbonate solution (sat.) and extracted with diethyl ether (3 x 50ml). The extracts were dried (IisCQs) and evaporated in vacuo to give the title compound as a brown oil (267mg, 77%); 5a (CDCls) 2.24-2.29 (211, m, tetrahydropyridinyl CH2), 3.00 (2H, J 5.7Hz, tetrahydropyridinyl CH2), 3.45-3.47 (2H, m, WO 96/05200 PCTPGB9S/01$20 tetrahydropyridinyl CH2), 6.17-6.19 (1H, m, tetrahydropyridinyl CH), 6.94-6.97 (1H, m, ArH), 7.16-7.17 (1H, m, ArH) and 7.22-7.26 (1H, m, ArH).

Step 2: 3-f4-(2-Thieyl)ethynyl-1 2 3 6-tetrahvdropyridin-l-yllmethvl-lHQyrrolol2,3-binvridine The title compound was prepared from 4-(2-thienyl)ethynyl-1,2,3,6-tetrahydropyridine using chemistry analogous to Example 1.
M.p. 191-193 C (methanol); (found: C, 71.38; H, 5.24; N, 13.01. Ci9HI7N3S requires C, 71.44; H, 5.36; N, 13.16%); Sx (DMSO-ds) 2.36 (2H, br s, tetrahydropyridinyl CHz), 2.56 (2H, t, J 5-6Hz, tetrahydropyridinyl CH2), 3.03 (2H, d, J 3.1Hz, tetrahydropyriclinyl CHs), 3.72 (2H, s, NCHaAr), 6.15 (1H, br s, tetrahydropyridinyl CH), 7.02-7.07 (2H, m, ArH), 7.26 (1H, dd, J 3.6 & 1.2Hz, ArH), 7.37 (1H, d, J 2.3Hz, 2-H), 7.58 (IH, dd, J 5.1 & 1.0Hz, ArH), 8.02 (1H, dd, J 7.8Hz, 4-H), 8.19 (1H, dd, J 4.6 & 1.5Hz, 6-H) and 11.47 (1H, br s, NH); m/z (ES*) 320 (M+1)+-2o EXAMPLE 9 (E)-3-f4-f2-(4-Fluoron henvl)ethenyll-1 2 3 6-tetrahvdropyridin-1 yllmethvlnvrrolo f 2, 3-bi n vri dine Step 1: (E)-4-f2-(4-Fluorophenvl)ethenvllnyridine A mixture of 4-picoline (15.6m1, 161mmo1) and 4-fluorobenzaldehyde (20g, 161mmo1) in acetic anhydride (125m1) was = heated at reflux overnight. The reaction was cooled and the solvent evaporated. Water (100m1) was added to the residue, and the mixture stirred at room temperature for 30 minutes. Saturated sodium carbonate solution (100m1) and ethyl acetate (150m1) were then added, and stirring - - -- -WO 96/05200 PCTlGB95101820 continued for a further 30 minutes. The two phases were separated, and the aqueous phase extracted with ethyl acetate (3 x 200m1). The combined organic phases were dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting with 50% ethyl acetate/petrol (60-80 ). The appropriate fractions were combined and concentrated to yield (E)-4-[2-(4-fluorophenyl)ethenyl]pyridine (19g, 60%) as a beige solid.
Sx (CDCb) 6.93 (1H, d, J 16.3Hz, ArCHCH), 7.05-7.13 (2H, m, ArH), 7.26 (1H, d, J 16.3Hz, ArCHCID, 7.34-7.36 (2H, m, ArH), 7.48-7.54 (2H, m, ArH) and 8.56-8.60 (2H, m, ArH).
Step 2: (E)-1-Benzvl-4-f2-(4-fluorophenvl)ethenvll-I ?.3.6-tetrahvdropyridine To a solution of (E)-4-[2-(4-fluorophenyl)ethenyljpyridine (18.75g, 94.2mmo1) in dimethylformamide (30m1) at 900C was added is benzyl bromide (11.9m1, 100mmo1) and the reaction stirred at 90 C for 1 hour. The reaction was cooled to room temperature, diluted with ethanol (400m1) and sodium borohydride (4g, 105mmol) added in portions. The reaction was stirred at room temperature for 2 hours, after which time the solvent was evaporated to a slurry. Methanol was added, and the resultant solid filtered and dried to yield (E)-1-benzyl-4-[2-(4-fluorophenyl)ethenyi]-1,2,3,6-tetrahydropyridine (12g, 44%) as a white solid. Sx (CDCIa) 2.41 (2H, br s, tetrahydropyridinyl CH2), 2.68 (2H, t, J
5.8Hz, tetrahydropyridinyl CH2), 3.14 (2H, br s, tetrahydropyridinyl CHa), 3.63 (2H, s, NCHzEIr), 5.80 (1H, br s, tetrahydropyridinyl 5-CH), 6.40 (1H, d, J 16.2Hz, ArCHCHC), 6.69 (2H, d, J 16.2Hz, ArCHCHC), 6.96-7.02 (211, m, ArH) and 7.25-7.39 (711, m, ArH).

Step 3: (E)-4-[2-(4-Fluorophenyl)ethenyl]-1,2.3.6-tetrahvdrouyridine hvdrochloride To a.solution of (E)-1-benzyl-4-[2-(4-fluorophenyl)ethenyl]-1,2,3,6-tetrahydropyridine (I1.6g, 37.5mmol) in dichloromethane (500m1) ?195759 at 0 C was added 1-chloroethyl chloroformate (4.85m1, 45mmol). The reaction was stirred initially at 0 C, and allowing it to warm to room temperature over 2 hours. The solvent was evaporated and methanol (500m1) added. The mixture was heated at reflux for 1 hour, cooled to room temperature, and the solvent evaporated to a slurry. Diethyl ether was added and the resultant precipitate filtered and dried to yield (E)-4-[2-(4-fluorophenyl)ethenyl]-1,2,3,6-tetrahydrapyridine hydrochloride (6.2g, 69%) as a white solid. ba (DMSO-ds) 2.49-2.53 (2H, m, tetrahydropyridinyl CHz), 3.23 (2H, t, J 6.1Hz, tetrahydropyridinyl CH2), to 3.69 (2H, br s, tetrahydropyridinyl CH2), 5.90 (1H, br s, tetrahydropyridinyl5-CH), 6.61 (1H, d, J 16.3Hz, ArCHCHC), 6.92 (1H, d, J 16.3Hz, ArCHCHC), 7.15-7.20 (2H, m, ArH), 7.55-7.59 (7H, m, ArH) and 9.45 (1H, br s, NH).

Step 4: -3- 4- 2-(4-Fluorophenvl)ethenvll-1.2.3.6-tetrahyclronyridin-l-vl]methylnyrrolof 2.3-blpyridine A mixture of 3-dimethylaminomethyl-lH-pyrrolo[2,3-b]pyridine (1.57g, 9mmol) and (E)-4-[2-(4-fluorophenyl)ethenyl]-1,2,3,6-tetrahydropyridine (2g, 9mmo1) in toluene (50m1) was refluxed overnight.
The hot solution was filtered, and the product crystallised from toluene to give (E)-3-[4-[2-(4-fluorophenyl)ethenyl]-1,2,3,6-tetrahydropyridin-i-yl]methylpyrrolo[2,3-b]pyridine (1.2g, 40%). M.p. 211-213 C
(isopropanol). (Found: C, 75.05; H, 5.99; N,12.27; CziHzoFNa, 0.15H20 requires C, 75.04; H, 6.09; N, 12.50%); Sa (DMSO-dr) 2.29 (2H, br s, tetrahydropyridinyl CHz), 2.61 (211, t, J 5.GHz tetrahydropryridinyl CH2), 3.06 (2H, br s, tetrahydropyridinyl CH2), 3.73 (2H, s, NCHzAr), 5.87 (1H, br s, tetrahydropyridinvl5-CH), 6.45 (1H, d, J 16.3Hz, ArCHCHC), 6.83 (1H, d, J 1G.3Hz, ArCHCHC), 7.01-7.04 (1H, m, ArH), 7.14 (2H, t, J 8.9Hz, ArH), 7.38 (1H, s, ArH), 7.47-7.51 (2H, m, ArH), 8.02 (1H, d, J 7.9Hz, ArH), 8.18-8.20 (111, m, ArH) and 11.45 (1H, br s, NH); m/z (CI*, NHs), 334 (M+1)'.

(E)-3-f4-(2-(3-Chloronhenyl)ethenyll-12 3 6-tetrahvd.ronvridin-l-yllmethyln.yrroloL2.3-binyridine M.P. 208-210 C (isopropanol). (Found: C, 71.86; H, 5.74; N, 11.66; Ca,HsoCINa requires C, 72.09; H, 5.76; N, 12.01%). 511(DMSO-ds) 2.28 (2H, br s, tetrahydropyridinyl CHz), 2.61 (211, t, J 5.5Hz tetrahydropyridinyl CH2), 3.07 (2H, br s, tetrahydropyridinyl CHa), 3.73 (2H, s, NCHzAr), 5.93 (1H, br s, tetrahydropyridinyl 5-CH), 6.44 (1H, d, J
16.3Hz, ArCHCHC), 6.95-7.05 (2H, m, ArCHCHC, ArH), 7.24 (1H, d, J
8.1Hz, ArH), 7.30-7.43 (3H, m, ArH), 7.54 (1H, s, ArH), 8.02 (1H, d, J
7.8Hz, t1rH), 8.19 (1H, d, J 4.6Hz, ArH) and 11.45 (1H, br s, NH); m/z (CI,, NH3) 350 (M+1)*.

EXAMPLE 1 i (E}-3-f4-[2-(4-Cvanophenyl)ethenvll-1.2.3.6-tetrahydropyridin-i-2o y-ljmethvlp MoloL.3-blpvridine M.P. 213-215 C (toluene). (Found: C, 76.62;1I, 5.76; N, 16.05; C22H2oN4, 0.25H20 requires C, 76.61; H, 5.99; N, 16.24%). SF3 (DMSO-de) 2.31 (2H., br s, tetrahydropyridinyl C112), 2.62 (211, t, J 5.6Hz, tetrahydropryridinyl CH2), 3.09 (2H, br s, tetrahydropyridinyl CHz), 3.74 (2H, s, NCHzAr), 6.01(1H, br s, tetrahydropyridinyl5-CH), 6.52 (1H, d, J
16.2Hz, ArCHCHC), 7.01-7.06 (2H, m, ArCHCHC, ArH), 7.38 (1H, d, J
2.3Hz, ArH), 7.64 (2I1, d, J 8.4Hz, ArH), 7.75 (2H, d, J 8.4Hz, ArH), 8.03 (1H, d, J 7.8Hz, ArH), 8.18-8.20 (1H, m, ArH) and 11:46 (1H, br s, NH);
m/z ((;I', NHs) 341 (M+1)*.

=_ `' WO 96/05200 PC"T1GB95/01820 (E)-3-14-[2-(4-Methvlnhenvl)ethenvll-1 2 3 6-tetrahvdronyri ~n-1-r~l methvlnyrrolof2.3-binvridine M.p. 209-212 C (xylene). (Found: C, 80.18; H, 7.13; N, 12.57;
C23H23Ns requires C, 80.21; H, 7.04; N, 12.76%). Sa (DNISO-ds) 2.27-2.29 (5H, m, tetrahydropyridinyl CH2, ArCHs), 2.61 (2H, t, J 5.7Hz, tetrahydropyridinyl CH2), 3.06 (2H, br s, tetrahydropyridinyl CH2), 3.73 (2H, s, NCH2Ar), 5.84 (1H, br s, tetrahydropyridinyl5-CH), 6.41 (IH, d, J
16.3Hz, ArCHCHC), 6.82 (1H, d, J 16.2Hz, ArCHCHC), 7.01-7.04 (1H, m, ArH), 7.12 (2H, d, J 8.0Hz, ArH), 7.32-7.38 (3H, m, ArH), 8.03 (1H, d, J
8.0Hz, ArH), 8.18-8.20 (1H, m, ArH) and 11.46 (1H, br s, NH); mlz (CIt, NHa) 330 (M+1)*

(E)-3-f4-f2-(4-Methoxvnhenvl)ethenyll-1 2.3 6-tetrahydropyridin-l-y-IlmethYlnvrrolof2 3-bjpvridine M.p. 201-204 C (xylene). (Found: C, 76.20; H, 6.62; N, 12.12;
C22H23NsO requires C, 76.49; 11, 6.71; N, 12.16%). Slx (DMSO-ds) 2.25 (2H, br s, tetrahydropyridinyl CH2), 2.60 (2H, t, J 5.7Hz, tetrahydropyridinyl CH2), 3.05 (2H, br s, tetrahydropyridinyl CH2), 3.72 (2H, s, NCH2Ar), 3.74 (3H, s, OCH3), 5.81. (1H, br s, tetrahydropyridinyl 5-CH), 6.40 (1H, d, J
16.3Hz, ArCHCHC), 6.73 (1H, d, J 16.3Hz, ArCHCHC), 6.88 (2H, d, J
8.8Hz, ArH), 7.01-7.05 (1H, m, ArH), 7.37 (1H, s, ArH), 7.38 (2H, d, J
8.8Hz, ArH), 8.02 (1H, dd, J 7.8, 1.4Hz, ArH), 8.19 (1H, dd, J 4.6, 1.5Hz, ArH) and 11.45 (1H, br s, NH); m/z (ES*) 346 (M+1)'.

;.; 2195759 WO 96/05200 PCT/GB95/01821) E%AMPLE 14 (E)-3-I4-f2-(4-TrifluoromethvlnhenyI)ethenyll-1.2.3.6-tetrahvdropvidin-1-xl] methylp vrrolof 2.3-bl u vridine s M.p. 203-205 C (xyiene). (Found: C, 68.70; H, 5.28; N, 10.98;
Cz3H2aFsNs requires C, 68.92; H, 5.25; N, 10.96%). Sa (DMSO-ds) 2.32 (2H, br s, tetrahydropyridinyl CH2), 2.62 (2H, t, J 7.9Hz, tetrahydropyridinyl CH2), 3.09 (2H, br s, tetrahydropyridinyl CH2), 3.74 (2H, s, NCHsAr), 5.99 (1H, br s, tetrahydropyridinyl 5-CH), 6.54 (1H, d, J 16.2Hz, ArCHCHC), 7.01-7.09 (2H, in, ArCHCHC, ArH), 7.39 (1H, d, J 3.4Hz, ArH), 7.66 (4H, s, 2'-H, 3'-H, 5'-H, 6'-H), 8.03 (1H, dd, J 10.4, 2Hz, ArH), 8.19 (1H, dd, J
6.7, 2.3Hz, ArH) and 11.49 (1H, br s, NH); mCz (ES*) 384 (M+1)*.

M-3-14-f2-(3-FluoronhenvInyl_1-1,2,3,G-tetrLhydrgRyridin-l-YIlrr1&4h.YlpXTr1f2,3 b1PYridine Ivl.p. 199-201 C (propan-2-ol); (Found:, C, 75.42; H, 5.95; N, 12.86. C21ffioFN3 requires C, 75.65; H, 6.05; N, 12.60%); 5H '(Db'ISO-de) 2.29 (2H, m, tetrahydropyridinyl CH2), 2.61(2H, t, J 5.5Hz, tetrahydropyridinyl CH2), 3.07 (2H, br s, tetrahydropyridinyl CHs), 3.72 (2H, s, ArCH2N), 5.93 (1H, br s, tetrahydropyridinyl 5-CH), 6.45 (1H, d, J
16.2Hz, ArCHCHC), 6.93-7.05 (3H, m, ArCHCHC, ArH), 7.26-7.39 (4H, m, ArH), 8.02 (1H, d, J 7.8Hz, ArH), 8.19 (1H, dd, J 4.6, 1.5Hz, ArH) and 11.48 (1H, br s, NH); mlz (ES+) 334 (M+1)*.

= -M-3 f4-f2-(3.4-Methylenediox shenvllethen~l 1.2.3.6-tetrahydropyridin-1-vllmethylnyrrolo f 2.3-bjpyridine M.p. 206-208 C (propan-2-ol); (Found: C, 72.39; H, 5.80; N, 11.22. C22H2iN302 requires C, 72.61; H, 5.95; N, 11.54%); Sa (DMSO-d6) 2.65 (2H, br s, tetrahydropyridinyl CH2), 2.60 (2H, t, J 5.7Hz, tetrahydropyridinyl CH2), 3.05 (2H, br s, tetrahydropyridinyl CH2), 3.72 (2H, s, ArCH2N), 5.81 (1H, br s, tetrahydropvridinyl5-CH), 5.99 (2H, s, OCH2O), 6.37 (1H, d, J 16.2Hz, ArCHCHC), 6.74 (113, d, J 16.2Hz, ArCHCHC), 6.82-6.89 (2H, m, ArH), 7.01-7.04 (1H, m, ArH), 7.11 (1H, s, ArH), 7.37 (1H, s, ArH), 8.02 (1H, d, J 8.7Hz, ArH), 8.19 (1H, d, J 4.7Hz, ArH) and 11.45 (1H, br s, NH); m/z (ES') 360 (M+1)*.

(E)-3-f4-f2-(3-Methylphenvl)ethenyll-1 2 3 6-tetrahvdrqpvridin-l-yllmethylnvrrolo f 2,3-1ipvridine M.p. 210-212 C (propan-2-ol); (Found: C, 80.37; H, 6.89; N, 12.64. C22H23N3 requires C, 80.21; H, 7.04; N, 12.76%); Sa (DMSO-ds) 2.28 (2H, br s, tetrahydropyridinyl CH2), 2.61 (2H, t, J 5.6Hz, tetrahydropyridinyl CH2), 3.07 (2H, br s, tetrahydropyridinyl CH2), 3.73 (2H, s, ArCH2N), 5.87 (1H, br s, tetrahydropyridinyl 5-CH), 6.41 (1.H, d, J
16.3Hz, ArCHCHC), 6.86 (1H, d, J 16.4Hz, ArCHCHC), 7.01-7.04 (2H, m, ArH), 7.16-7.27 (3H, m, ArH), 7.38 (1H, s, ArH), 8.03 (1H, d, J 7.7Hz, ArH), 8.19 (1H, d, J 4.7Hz, ArH) and 11.46 (1H, br s, NH); m/z (ES') 330 (1\'1+1)`=

EX"PLE 18 (F')-3-f4-f2-(3-Cyanonhenvl)ethenyll-12 3 6-tetrahvdropyridin-i-vllmethylnyrrolo[2.3-binvridine M.p. 213-215 C (propan-2-ol); (Found: C, 77.39; H, 5.77; N, 16.25. C22H2oNa requires C, 77.62; H, 5.92; N, 16.46%); Sa (DMSO-de) 2.29 (2H, br s, tetrahydropyridinyl CH2), 2.62 (2H, t, J 5.7Hz, tetrahydropyridinyl CH2), 3.08 (2H, br s, tetrahydropyridinyl CH2), 3.73 (2H, s, ArCH2N), 5.96 (1H, br s, tetrahydropyridinyl 5-CH), 6.49 (1H, d, J
16.3Hz, ArCHCHC), 7.02-7.08 (2H, m, ArCHCHC, ArH), 7.38 (1H, d, J
2.4Hz, ArH), 7.51 (1H, t, J 7.8Hz, ArH), 7.64 (1H, d, J 7_711z, ArH), 7.79 (1H, (1, J 8.OHz, ArH), 7.94 (1H, br s, ArH), 8.03 (1H, d, J 29Hz, ArH), 8.19 (1H, d, J 4.6Hz, ArH) and 11.46 (1H, br s, NH); m/z (HS') 341 (M+1)+.
F.XAMPLE 19 (L+1-3-f 4-f 2 -(3.4-DifTuoronhenvl)ethenyll-1.2.3.6-tetrahvdrop,yridin-l-vllmethvlnvrroiof 2.3-blrrvridine M.p. 208-210 C (propan-2-ol); (Found: C, 71.60; H, 5.36; N, 12.17. C21Hi9F2N3 requires C, 71.78; H, 5.45; N, 11.96 .6); Sa (D14i$O-d6) 2.28 (2H, br s, tetrahydropyridinyl CH2), 2.61 (2H, t, J 5.7Hz, tetrahydropyridinyl. CH2), 3.07 (2H, br s, tetrahydropyridinyl CH2), 3.73 (2H, s, ArCHzM, 5.91 (1H, br s, tetrahydropyridinyl5-CIl), 6.43 (1H, d, J
16.2Hz, ArCHCHC), 6.90 (1H, d, J 16.2Hz, ArCHCHC), 7.01-7.04 (1H, m, ArH), 7.28-7.39 (3H, m, ArH), 7.54-7.60 (1H, m, ArH), 8.02 (1H, d, J
8.2Hz, ArH), 8.19 (1H, dd, J 4.3, 1.6Hz, ArH) and 11.46 (1H, br s, NH);
m/z (ES') 352 (M+1)+.

(E)-3-f4-f2-(3-Fluoro-4-methoxpphenvl)ethenyl1 -1 2 3 6-tetrahydropylidin-1-vll m ethvhayrrol o f 2. 3-bl a yri di n e M.p. 199.5-201.5 C (MeOH); (found: C, 73.12; H, 6.03; N, 11.53. C22I-i22FN30 requires C, 72.71; H, 6.10; N, 11.56%); Sx (DMSO-ds) 2.28 (2H, br s, tetrahy(iropyridinyl CH2), 2.61 (2H, t, J 5.7Hz, tetrahydropyridinyl CH2), 3.07 (2H, br s, tetrahydropyridinyl CHz), 3.73 (2H, s, NCH2Ar), 3.83 (3H, s, ArOCHs), 5.85 (1H, m, tetrahy(iropyridinyl 5-CH), 6.39 (1H, d, J 16.2Hz, CH=CHAr), 6.80 (1H, d, J 16.2Hz, CH=CHAr), 7.04 (1H, dd, J 7.8, 4.6Hz, 5-H), 7.10 (1H, t, J 8.7Hz, 5'-H), 7.21 (1H, m, 6'-H), 7.35-7.39 (211, m, 2-H, 2'-H), 8.03 (IH, dd, J 7.8, 1.4Hz, 4-H), 8.20 (1H, dd, J 4.6, 1.4Hz, 6-H), and 11.46 (1H, br s, NH); m/z (ES') 364 (M+1)*.

Claims (15)

CLAIMS:

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

wherein Q represents a moiety of formula Qa or Qb:

wherein R1 represents hydrogen, fluoro, cyano, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or di(C1-6)alkylamino; and R2 represents hydrogen, halogen, cyano, trifluoromethyl, C1-6 alkyl or di(C1-6)alkylamino; or R1 and R2 together represent methylenedioxy;

provided that R1 and R2 are not both simultaneously hydrogen; and A represents a group of formula (i), (ii) or (iii):

in which V represents oxygen, sulphur or N-R5;

R3 represents halogen, cyano, trifluoromethyl, C1-6 alkyl or C1-6 alkoxy;

R4 represents hydrogen, halogen, cyano, trifluoromethyl, C 1-6 alkyl or C1-6 alkoxy;
and R5 represents hydrogen or C1-6 alkyl.

2. A compound as claimed in claim 1 represented by formula IIA, or a salt thereof:

wherein R11 represents fluoro, cyano, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or di(C1-3)alkylamino.

3. A compound as claimed in claim 1 represented by formula IIB, or a salt thereof:

wherein R12 represents halogen, cyano, trifluoromethyl, C1-6 alkyl or di(C1-6) alkylamino.

4. A compound as claimed in claim 1 represented by formula IIC, or a salt thereof:

wherein R11 represents fluoro, cyano, trifluoromethyl, C1-6alkyl, C1-6 alkoxy or di(C1-3)alkylamino; and R22 represents fluoro, chloro, trifluoromethyl or C1-6 alkyl.

5. A compound as claimed in claim 1 represented by formula IID, or salt thereof:

wherein R3 is as defined in claim 1.

6. A compound as claimed in claim 1, or a salt thereof, wherein Q represents a moiety of formula Qb in which A represents a pyridin-3-yl, thien-2-yl or thien-3-yl group.

7. A compound selected from:

3-[4-(4-trifluoromethylphenyl)ethynyl-1,2,3,6-tetrahydropyridin-1-yl]methyl-pyrrolo[2,3-b]pyridine;

3-[4-(pyridin-3-yl]ethynyl-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;

3-[4-(4-methoxyphenyl)ethynyl-1,2,3,6-tetrahydropyridin-l-yl]methyl-1H-pyrrolo[2,3-b]pyridine;

3-[4-(4-methylphenyl)ethynyl-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;

3-[4-(4-fluorophenyl)ethynyl-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;

3-[4-(4-chlorophenyl)ethynyl-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;

3-[4-(thien-3-yl)ethynyl-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;

3-[4-(thien-2-yl)ethynyl-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
(E)-3-[4-(2-(4-trifluoromethylphenyl)ethenyl)-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
(E)-3-[4-(2-(4-methoxyphenyl)ethenyl)-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
(E)-3-[4-(2-(4-methylphenyl)ethenyl)-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
(E)-3-[4-(2-(4-cyanophenyl)ethenyl)-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
(E)-3-[4-(2-(4-fluorophenyl)ethenyl)-1,2,3, 6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
(E)-3-[4-(2-(3-chlorophenyl)ethenyl)-1,2,3,6-tetrahydropyridin-1-yl] methyl-1H-pyrrolo[2,3-b]pyridine; and salts thereof.

8. A compound selected from:
(E)-3-[4-(2-(3-fluorophenyl)ethenyl)-1,2,3,6-tetrahydropryridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
(E)-3-[4-(2-(3,4-methylenedioxyphenyl)ethenyl)-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
(E)-3-[4-(2-(3-methylphenyl)ethenyl)-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
(E)-3-[4-(2-(3-cyanophenyl)ethenyl)-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
(E)-3-[4-(2-(3,4-difluorophenyl)ethenyl)-1,2,3,6-tetrahydropyridin-1-yl]methyl-pyrrolo[2,3-b]pyridine; and salts thereof.

9. A compound selected from:
(E)-3-[4-(2-(3-fluoro-4-methoxyphenyl)ethenyl)-1,2,3,6-tetrahydropyridin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine; and salts thereof.

10. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

11. A composition as claimed in claim 10 further comprising a known anti-schizophrenic medicament which produces its effects via at least one of dopamine D2 and 5-HT2 receptor blockade.

12. A compound as claimed in any one of claims 1 to 9 for use in treating a disorder associated with the dopamine D4 receptor subtype.

13. The use of a compound as claimed in any one of claims 1 to 9 for the manufacture of a medicament for the treatment and or prevention of disorders of the dopamine D4 receptor subtype system.

14. A process for the preparation of a compound as claimed in claim 1 which comprises:

(A) reacting a compound of formula III with a compound of formula IV:

wherein Q1 represents the residue of a moiety of formula Qa or Qb as defined in claim 1, and R p represents a hydrogen atom or a protecting group; in the presence of a substantially equimolar amount of formaldehyde; followed, where required, by removal of the protecting group R p; or (B) reacting a compound of formula IV as defined above with a compound of formula V:

wherein R p is as defined above, and L represents a leaving-group; followed, where required, by removal of the protecting group R p.

15. A pharmaceutical composition for the treatment or prevention of disorders of the dopamine D4 receptor subtype system which comprises an effective amount of a compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.