CA2087710A1 - Therapeutic agents - Google Patents

Abstract

Platelet activating factor antagonists of formula (I), where X is -CH=CH- or S, R1 is a cyano, carboxy, carboxylic ester or optionally substituted carbamoyl or amido group and R2 is H, halogen or C1-C4 alkyl.

Description

20~771~
. `V092/034~ PCT/EP91/01491 THERAPEUTIC AGENTS

This invention relates to indane and cyclopentanothiophene derivatives which are potent, orally active antagonists of platelet activating factor and as such have clinical utility for treating allergic and inflammatory conditions such as asthma and arthritis respectively.
Platelet activating factor ~PAF, l-O-al~yl-2-acetyl-sn-gl~cQryl-~-phospho-ylcholinQ) is an ether phospholipid whose structure was first elucidated in 1979. It is produced by, released from and interacts with many pro-inflammatory cells, platelets and the kidney. In addition to potent platelet aggregating activity, PAF exhibits a wide spectrum of biological activities elicited either directly or via the release of other powerful mediators such as thromboxane A2 or the leukotrienes. In vitro, PAF stimulates the . movement and aggregation of neutrophils and the release therefrom of tissue-damaging enzymes and oxygen radicals. These activities contribute to actions of PAF i~ YiVo consistent with it playing a significant role in inflammatory and allergic responses. Thus, intradermal PAF has been shown to induce an inflammatory response, with associated pain, accumulation of inflammatory cells and increased ' .
... . . . .

W092/034~ ~0~ ~ 71 ~ PCT/EP91/01491 vascular permeability, comparable with the allergic skin reaction following exposure to allergen.
Similarly, both the acute broncho-constriction and chronic inflammatory reactions elicited by allergens in asthma can be mimicked by intratracheal administration of PAF. Accordingly agents which antagonise the actions of PAF and, consequently also prevent mediator release by PAF, will have clinical utility in the treatment OL a variety o^ allergic and infla~matory conditions such as asthma and arthritis, respectively.
In addition to the above, PAF has been implicated as being involved in a number of other medical conditions. Thus in circulatory shock, which is characterised by systemic hypotension, pulmonary hypertension and increased lung vascular permeability, the symptoms can be mimicked by infusion of PAF. This coupled with evidence showing that circulating PAF
levels are increased by endotoxin infusion indicate that PAF is a prime mediator in certain forms of shock.
Intravenous infusion of PAF at doses of 20-200 pmol kg min into rats results in the formation of extensive haemorrhagic erosions in the gastric mucosa and thus PAF is the most potent gastric ulcerogen yet described whose endogenous release may underlie or contribute to certain forms of gastric ulceration.
Psoriasis is an inflammatory and proliferative disease ~092/034~ ~ ~ 7 ~ A u PCT/EPgl/01491 characterised by skin lesions. PAF is pro-inflammatory and has been isolated from lesioned scale of psoriatic patients indicating PAF has a role in the disease of psoriasis. And finally, increasing evidence supports a potential pathophysiological role for PAF in cardiovascular disease. Thus recent studies in angina patients show PAF is rel2ased during atrial pacing and, in pigs, intracoronary injection of PAF induces a prolonged decr~ase in coronary riow wnile in guinea pig hearts it induces regional shunting an~ ischaemia. PAF
has also been shown to initiate thrombus formation in a i mesenteric artery preparation both when administered exogenously and when released endogenously. More recently PAF has been shown to play a role in brain ischaemia induced in animal models of stroke.
Thus compounds of the invention, by virtue of their ability to antagonise the actions of PAF, could well be of value in the treatment of any of the above conditions.
According to the invention there are provided compounds of formula (I):

R~

W092/0~ ~ ~ J ~3 PCT/EP91/01491 wherein X is -CH-CH- or S;
Rl is -CooR3~ -CN, -CoNR4R5 or -NR6CoR3 where R3 is H, Cl-C6 alkyl, C3-C7 cycloalkyl, or Cl-C4 alkyl substituted by phenyl;
:~ R4 and R5 are each independently H, Cl-c6 alkyl which may optionally be substituted by a hydroxyl or Cl-C~ alkoxy group, C3-C7 cycloalkyl, phenyl or pyridyl/ said phenyl : and pyridyl groups being optionally substituted by up to three groups independently selected from halo, hydroxy, -CF3, Cl-C4 alkyl and Cl-C4 alkoxy, or R4 and R5 together with the nitrogen atom to which they are attached represent a pyrrolidine, piperidine or morpholine ring; R6 is H or Cl-C4 alkyl;
and R2 is H, halo, or Cl-C4 alkyl;
and their pharmaceutically acceptable salts.
In the definitions given herein the term halo means fluoro, chloro, bromo or iodo. Alkyl and alkoxy groups of 3 or more carbon atoms may be straight or branched-chain.
R5, when present, is preferably H and Rl is preferably at the 2-position of the indane nucleus (when X is -CH=CH-) or the 5 position of the cyclopentanothiophene nucleus (when X is -S-).

;,' ' ~092/0~34 2 ~3 8 ~ f 1 v~ PCT/EP91/01491 Examples of Rl groups are cyano, carboxy, ethoxycarbonyl, t-butylcarbonylamino and group -CoNR4R5 where R4 and R5 together form a piperidino or morpholino group or R4 and R5 are independently selected from H, t-butyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, pyridyl and pyridyl substituted by a methyl group. A particularly preferred compound is 2-(2-met~.ylimid2-o[~,5-c]pyrid-l-yl)-5-(N-pyrid-2-yl-carbamoyl)-cyclopentano[b]-thiophene. Other particula ly preferred c_mpounds ar2:

2-(N,N-dipropylcarbamoyl)-5-(2-methylimidazo-[4,5-c]pyrid-l-yl)indane and 2-(N,N-dicyclopentyl-carbamoyl)-5-(2-methylimidazo[4,5-c]pyrid-l-yl)indane.
The compounds of formula (I) contain at least one asymmetric centre and will therefore exist as one or more pairs of enantiomers, and such pairs of individual isomers may be separable by physical methods, e.g. by fractional crystallisation or chromatography of the parent compounds or of a suitable salt or derivative thereof. Alternatively, particular isomers may be prepared using the corresponding optical isomers of the precursors used in preparation of compounds of the invention. The invention includes all the enantiomers of the compounds of formula (I) whether separated or not.
The pharmaceutically acceptable acid addition sa1ts of the compounds of formu1a (I) are those formed '' ' W092/0~ ~ 2 ~ PCT/EP91/01491 from acids which form non-toxic acid addition salts, for example the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, ~` citrate, fumarate, gluconate, lactate, maleate, succinatP, tartrate, methanesulphonate, benzenesulphonate and p~toluenesulphonate.
~ hen ~ is -C~=CH- and Rl is CN, the compound of formula (I) may oe o~talned by cyclising the corresponding compo-~nd of formula (I~), for example by treating i~ h ac2_i- arhydrid2 in the presence of acetic acid:

~ (CH~CO)20 ~ CH3 R2 ~ NH2 ~ R2 (II) This reaction may be carried out by heating the compound (II) with acetic anhydride and glacial acetic acid, followed by separation of t~e product by conventional methods.

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`~092/0~ ~ ~ PCT/EPg1/01491 : The corresponding compound (III) may be obtained by hydrolysing compound (I) in which Rl is CN and X i5 -CH=CH-, generally in the presence of an alkali, followed by acidification:

C ~ C ~R

( II I ) Compound (III) may be esterified by conventional .. methods to produce corresponding compounds in which R3 : is Cl-C6 alkyl, C3-C7 cycloalkyl or Cl-C4 alkyl substituted by phenyl.
:, When Rl is CoNR4R5 and X is -CH=CH- the compound of formula (I) may be prepared from the acid (III) by converting the latter to the corresponding carbonyl chloride, for-example by treatment with oxalyl chloride, and treating the product with the appropriate amine, or sodium salt of the amine:

' "

:' :

WO 92/03434 2 ~ ~ 1 7 i ~ PCr/EP9l/0l491 3 ~ /~N
CO2H ~R COCl ~,~

NHP~4?~5 or ~a NR R
(III) ~ ~)\ N N
R~ R
~
~N~

When R1 is NR6CoR3 the acid (III) may first be converted to a corresponding compound (IV~ in which is NH2, for example by treatment with diphenylphosphorylazide:

` ' ,: , .

2~3~
V092/0~ ~ PCT/EP91/01491 ~ ~
(III) (Ph) 2P (o)h3 : .

~ ~ 3 ~ N

(IV) .~ The amine (IV) may then be converted to the ~, carbonylamino compound (V) in which R6 is H by reaction : `
with the appropria~e carbonyl chloride: ~

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: ., WO 92~03434 2 ~ ~ 7 7 ~L ~ PCr/EPgl/0l491 (I~l) }o/~

"3COCl /--~1 R -- C--N N
O )--J~ R
~)~
N

Compounds in which R6 is alkyl may be made by alkylating compounds of formula (V) in known manner.
The novel intermediates (IV) constitute a further aspect of the present invention.
The compounds of formula (II) may be prepared from the corresponding cyanoindanes by the synthesis shown in Scheme 1. This synthesis entails nitration of the cyanoindane, for example with fuming nitric acid in acetic anhydride, followed by reduction of the nitro group, suitably with hydrogen in the presence of a .
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;, ' '"' " ' ' "' '" ~ ' '' :.

2 ~ ~3 r~
:-~092/034~ PCTtEP91/Ot491 palladium/carbon catalyst. The amine so formed may then be reacted with the appropriate chloro-nitropyridine derivative and the nitro group in the compound produced is reduced catalytically to give the compound of formula (II).

Scheme l ~ r~ ~ 1 HNO3 ~ NO H2 Pd/C
CN

NH2 ~, CN 2 ~`'`~2 ~ ï
R ~J R ~0 ' ` `;

(Tl) ;~11 ;i~ C~ 2 ~ , .

~g~7~ ~
W092/0~ ~ PCT/EP91/01491 When X is -S- and Rl is -CooR3 the cyclopentano [b]thiophenes of formula (I) may be made firstly by reacting a 3-cyclopentanone carboxylic ester with sulphur and a cyanoacetate to form a cyclopentano[b]
thiophene substituted by amino and carboxylate groups of formula (VI):

R 02C ~ O + S + NC5H"CO,,R

~ ~ C02R

R302C~ S ~

In the above formulae group R7 is an optionally substituted alkyl group such as ethyl or t-butyl. The reaction may be conducted by heating the reagents together in the presence of a solvent such as dimethylformamide and a base such as triethylamine.
The compound of formula tVI) may then be reacted with 4-chloro-3-nitropyridine in the presence of a base such as sodium bicarbonate, followed by reduction with hydrogen and a palladium catalvst to form a compound of formula (VII) below, ring closure with acetic anhydride and removal of the carboxylate group on the thiophene ring for example if R7 = t-butvl b~ treatment with a .. ~

~V092/034~ ~ PCT/EP91/01491 strong acid such as trifluoroacetic acid followed by heating with copper in the presence of quinoline.
These process steps are illustrated by Scheme 2 below:
Scheme 2 R 02C ~ ' Z ~ / 2, (vI) ~ C02R C02R

R302C Y li2, Pd/CR 02C ~ SN ~ N
~ No2 (VII) ~ / Nii2 (Cll CO) o 3 COOI~
~ 7 R302C ~ ~ ~
.: ,)~ ,/' /

_ N

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~ . .

2~87'f ~ ~

4 PCI'/EP91/01491 C0211 ~R o2c~ 3 N 1~ Cu t quin~ c \-J

- : ' , ., ,. ~ , . ,' . , :

~092/034~ ~ 3 i 7 ~ J PCT/EPgl/014gl The corresponding compounds of formula (I) in which R3 is H may be obtained by hydrolysing the ester produced by the synthesis o~ Scheme 2 by conventional methods. The compounds of formula (I) in which X is -S- and Rl is CoNR4R5 or NR6CoR3 may be prepared from those in which R1 is C02H by methods analogous to those described above for compounds in which X is -CH=CH-.
The acid in which Rl is C02H and X is S may be converted to the corresponding nitrile by conventional methods.
In the above synthesis of compound (VI) the Co2R3 group may be attached to the cyclopentane ring of compound (VI) at either the 4- or the 5-position of the cyclopentano~b]thiophene and in practice a mixture of both isomers is produced. These isomers may be separated by conventional methods, alternatively the further synthetic steps for obtaining compounds of formula (I) may be carried out on the mixture and the mixture of end products separated.
The activity of the compounds of the invention is shown by their ability to inhibit the platelet aggregating activity of PAF ~n vitro. Testing is performed as follows:
Blood samples are taken from either rabbit or man into 0.1 vol disodium ethylenediamine tetraacetic acid buffer and the samples centrifuged for 15 minutes to "
. :" ' :, ............................................................ ' 20~7'Y:~
W092/03434 PcT/Ep9l/ol49 obtain platelet rich plasma. The plasma is ~urther centrifuged to give a platelet pellet which i9 washed with a buffer solution (4mM KH2P04, 6mM Na2HP04, 100 mM
NaC1, 0.1% glucose and 0.1% bovine serum albumin, pH
7.25) and finally resuspended in buf~er solution to a concentration of 2 x 1o8 platelets/ml. A sample (0.5 ml) is pre-incubat~d fcr two minut2s at 37C in a Paton aggregometer with stirring, eithe_ with v~hlc~e alone, or with vehicle containing the particular compound under test. PAF is add~d at a su~^ ci~n~ ~oncen-rGtion to give a maximum aggregating response in the absence of test compound (lo 8 to 10 9 molar), and the platelet aggregation is measured by following the increase in light transmission of the solution. The experiment is repeated in the presence of test compound at a range of - concentrations and the concentration of compound required to reduce the response to 50% of its maxiumum value is recorded as the IC50 value.
The activity of the compounds of formula (I) is also demonstrated in v'vo by their ability to protect mice from the lethal effect of an injection of PAF. A
mixture of PAF (50 ~g~kg) and DL-propranolol (5 mg/kg) in 0.9% w/v sodium chloride is injected tO.2 ml) via a tail vein immediately prior to the PAF/propranolol injection or administered orally by gavage two hours earlier. The compounds are tested at several doses in groups of 5 mice and the dose which reduc2s mortality to 50% is recorded as the PD50 value.

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~092~03434 2 ~3 3 7 ~ PCT/EP91/01491 For therapeutic use the compounds of the formula (I) will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the~ may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone CL in admi~t~ ith excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. The~ may be injec.eà
parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral j administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
For administration to man in the curative ar ` prophylactic treatment of allergic bronchial conditions and arthritis, oral dosage of the compounds will generally be in the range of from 2-lO00 mg daily for an average adult patient (70 kg). Thus for a typical adult patient, individual tablets or capsules contain from l to 500 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier.
Dosages for intravenous administration would typically be within the range l to lO mg per single dose as required. For the -reatment of a ergic and bronchial ,.. . .

,,,, ,j W092/0~ ~ 2 0 ~ ~ 7 ~ ~ PCT/EP91/01491 hyper-reactive conditions, inhalation via a nebuliser or aerosol may be the preferred route of drug administration. Dose levels by this route would be within the range O.l to 50 mg per single dose as required. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, o. course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
Thus in a further aspect the invention provides a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
The invention also includes a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for use in medicine, in particular in the treatment of allergic and inflammatory conditions in a human being.
The preparation of the compounds of the invention is ~urther illustrated by the following Examples.

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~ ~ ~ 7 7 ~ ~ PCr/EP91/01491 -ExamPle 1 2-cyano-5-~2-methylimidazo[4!5--c]pyri-d-l-yl~L~3 ~(~> ~0 N~> I'd/C J~/
1~2N

Cl `;~i . H2N~'~ ~ C~

E~OH N ' N~ CN

Ac 2 0 \tJ~, ~ N J
(a) Fuming nitric acid (40 ml, 1.5 g/ml) was added dropwise with stirring to acetic anhydride (80 ml) keeping the temperature of the ~ixture at 0C. After the addition was complete 2-cyanoindane (11.33 g, 79.5 mmol, J. Chem. Soc. (B), (1969), 1197) was added dropwise with stirring over 30 minutes maintaining the reaction temperature between -5 and 0C. The mixture was stirred for a further 15 minutes then poured onto ice. The mixture was extracted with dichloromethane (4 x 150 ml~ and the extracts were washed with saturated aqueous sodium bicarbonate t3 x 150 ml), dried (MgS04) and concentrated under reduced pressure. The residue was recrystallised from ethanol to give 2-cyano-S-nitro-indane (12.09 g, 81%) as a yellow solid, m.p. 80-82C.

W092/03434 2 ~ 3 ~ 7 ~ ~ PCT/EP91/01491 H NMR (300 MHz, CDC13) ~ = 3.32-3.53 (5H, complex), 7.43 (lH,d, J =9Hz), 8.15 (lH,s), 8.17 (lH,d,J = 9Hz) P.p.m.
(b) A solution of 2-cyano-5-nitro-indane (11.90 g, 63.3 mmol) in methanol/dichlorometnane = 1:1 (200 ml) was hydrogenated over 10% palladium on charcoal (1.2 g) at 30 p.s.i. and 20C for 5 hours. Tne ca~al ~st was filtered off and the filtrate was concentrated under reduced pressure to gi ve 5-amlno-2-cyano-ind2ne (10.4 g, ca quantitativ~) which was used ~ r~tly ^sr t~o next reaction. A portion, recrystallised from ethanol, formed pinkish needles, m.p. 73-76C.

H NMR (300 MHz, CDC13) ~ = 3.11-3.30 (SH, complex), 3.65 (2H, br s), 6.58 tlH,d,J=8Hz), 6.61 (lH,s), 7.03 (lH,d,J=8Hz~ p.p.m.

(c) 4-Chloro-3-nitropyridine (11.46 g, 72.3 mmol) was added to a suspension of 5-amino-2-cyano-indane (10.4 g, 65.7 mmol) in ethanol (150 ml) at room temperature. The mixture was stirred overnight at room temperature and then poured into excess ice-cold aqueous ammonia. The yellow solid was filtered off, partially digested in hot ethanol (150 ml), cooled, and re-filtered to give 2-cyano-5-(3-nitropyrid-4-ylamino)-indane (13.61 g, 74%).

~ , , , .:, :
'', ' ~09~/0~ ~ ~ PC~/EP91/01491 H NMR (300 MHz, CDC13) ~ = 3.31-3.48 (5H, complex), 6.92 (lH,d,J=5Hz), 7.15(1H,d,J=6Hz), 7.19(1H,s), 7.37(1H,d,J=6Hz), 8.28(1H,d,H=5Hz), 9.31(1H,s), 9.64(lH, br s) p.p.m.

- (d) 2-Cyano-5-(3-nitropyrid-4-ylamino)indane (12.46 gm, 44.5 mmol) was suspended in methanol/
dichloromethane = 1:1 (750 ml) and hydrogenated at 20C
and 30 p.s.i. over 10% palladiu~ on charc~al (1.25 g) for 2 hours. The catalys~ W25 filto-od CfC and the filtrate was concentrated under reduced pressure to give 5-(3-aminopyrid-4-ylamino)-2-cyano-indane (12.28 g, ca quantitative) as a yellow solid, m.p. 98-100C.

H NMR (300 MHz, dmso-d6) ~ = 3.03-3.35(4H,m), 3.54 (lH,p,J=7Hz), 4.10(1H, br s), 4.64(2H, br s), 6.84(1H,d,J=5Hz), 6.92(1H,dd,J=7 and 2Hz), 7.00(1H,d,J=2Hz), 7.18(1H,d,J=7Hz), 7.60(2H,d,J=5Hz), 7.84(lH,s)p.p.m.

-(e) A mixture of 5-(3-aminopyrid-4-ylamino)-2-cyano-indane (12.28 g, ca 44.5 mmol from step (d) above), acetic acid (70 ml) and acetic anhydride (70 ml) was heated at reflux under nitrogen for 1.75 hours, cooled, and concentrated under reduced pressure. The residual brown gum was dissol~ed in 2N hydrochloric 2 ~ r! ~ ~ ' W092/0~ ~ PCT/EPg1/01491 acid (40 ml) and washed with ethyl acetate (50 ml).
The aqueous layer was rendered basic by the addition of 2N aqueous sodium hydroxide, and the product was extracted into dichloromethane (4 x 50 ml). The combined extracts were washed with water (50 ml), dried (MgS04) and concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel, 60-200~), eluting with ethyl acetate/
methanol=7:1. Fractions containing product were combined and concentrated to give a brown sum, which was recrystallised from ethyl acetate/methanol, to give the title compound as an off-white powder (9.674 g, 79%), ~.p. 174-176C.
Analysis %:-Found; C,74.40; H,5.17; N,20.72.
C17H14N4 requires C,74.43; H,5.14; N,20.42.

' Example 2 S-f2-Methylimidazo~4.5-clpyrid-1-yl)indan-2-carboxylic acid ' ~ ô,l~ ~, NaOII ~ 11()2C~ ) I 3 - . ~
.~ .

~V092/0~ ~ 2 ~ ~ 7 7 1 ~ PCT/EP91/01491 A mixture of 2-cyano-5-(2-methylimidazo-[4,5-c]pyrid-l-yl)-indane (Example 1, 739 mg, 2.70 mmol), 50% aqueous sodium hydroxide (l ml) and methanol (6 ml) was heated at reflux under nitrogen for 9 hours, cooled, poured onto ice, and the pH of the solution was adjusted to pH5 by the addition of dilute hydrochloric acid. The product precipitated as a white solid, (426mg, 54%) which was filtered off and dried in vacuo to sive the title compound, m.p. 264-267C.

Analysis %:-Found: C,68.91; H,5.08; N,14.08.
Cl7H15N302.l/5 H20 requires C,68.76; H,5.23; N,14.15.

Example 3 Ethyl 5-~2-Methylimidazo[4.5-c~pyrid-1-yl)indane-2-carboxylate :, C~3 EtO2C ~ N N

2 ~
WO 92/03434 PCT/EP91/0]491 Oxalyl chloride (1.3ml, 14.9mmol) was added dropwise over 5 min to a stirred suspension of 5-(2-methylimidazo[4,5-c]pyrid-1-yl)indane-2-carboxylic acid (Example 2, 1.46g, 5.0 mmol) in dry dichloromethane (20 ml) under nitrogen at room temperature. AftPr being stirred for lh, the resulting solution was concentra.od unde- rPduced pressure, redissolved in drv dichlorome~h2ne (~0 ml) ~n~ 2 mixture of ethanol (0.352 ml, 6.0 ~.ol) and triethylamine ~0.69~ ml, 5.0 ~Lm_l) ~2S a~ec' at rsom temperature. After a further lh, the solution was washed with saturated aqueous sodium bicarbonate (30 ml), dried (MgS04), and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with ethyl acetate:methanol =4:1 to give the title compound as a colourless gum, 1.4g (88%). The fumarate salt had m.p. 193-194C
(methanol).
:,, Ar~alysis g~:-Found: C,63.17; H,5.38; N,9.47 C1gH19N302.C4H402 requires; C,63.15; H,5.30; N,9.61 ,: . :

.:
. - . . ' , ' , . :,, ~092/0~ ~ ~ ~ 7 ~ } !3 PCT/EP91/01491 Exam~le 4 2-(N-tert-Butvlcarbamoyl)-5- r 2-methylimida~o-r4 5-clpyrid-1-yllindane li O~C ~) CH~ ~ Ch ~ \ N)~' C ~

5-~2-Nethylimidazo[4,5-c]pyrid-1-yl]indan-2-carboxylic acid (Example 2, 587 mg, 2 mmoles) was suspended in dry dichloromethane (15 ml). Oxalyl chloride (760 mg, 6 mmoles) was added followed by N,N-dimethylformamide (lO ~l). The mixture was stirred at room temperature for 1 hour to give a pale yellow : solution. The solvent was removed under reduced ;:.l pressure and the resulting 5-~2-methylimidazo~4,5-c]-pyrid-l-yl]indan-2-carbonyl chloride was redissolved in dichloromethane (15 ml). tert-Butylamine (438 mg, 6 mmoles) in dichloromethane (3 ml) was added over 5 minutes and the reaction mixture was stirred at room temperature for l hour.

, .` . :

~ .. , ,. : , . . -2 ~ 8 1 ~ ~ ~
W092/0~ ~ PCT/EP91tO1491 Saturated sodium bicarbonate (20 ml) was added and the mixture stirred at room temperature for 1 hour.
The dichloromethane layer was separated, dried over magnesium sulphate and the solvent removed under pressure. The residual foam was chromatographed over silica gel (40-63 ~), eluting with 15% methanol in ethyl acetate. Fractions containing product were evaporated to give a foam (500 mgJ which was dissolved in ether/ethyl acetate = 3:1 (20 ml), filtered and allowed to crystallise. The precipitated solid was filtered and dried in vacuo yielding the title compound as a white solid (345 mg, 50%), m.p. lS2-154C.
Analysis %:
Found: C,71.99: H,7.07; N,15.82.
C21H24N40 requires C,72.39; H,6.94; N,16.08.
` .
ExamDles 5-14 The compounds of Table 1 were made by the method of Example 3 using the appropriate nucleophile, and the acid chloride derived from the acid described in Example 2.

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V092/0~34 PCT/EP91/01491 Exam~le 15 (2R,2's~ and (2s.2's) N-(2-Hydroxy~ y~pentyl) -5-t2-methvlimidazo~4.5-c]pyrid-1-yl)indane-2-carboxamide ~ 0~_ C

A solution of 5-(2-methylimidazo[4,5-c]pyrid-l-yl)indane-2-carbonyl chloride (Example 4, 0.93g, 3.0 mmol) in dry dichloromethane (20 ml) was prepared. A
mixture of triethylamine (0.42 ml, 3.0 mmol) and S-l-amino-2-hydroxy-4-methylpentane (350 mg, 3.0 mmol) was added with stirring at room temperature. After 13h, the mixture was treated with saturated aqueous sodium bicarbonate (30 ml) and the products were extracted into dichloromethane (3 x 30 ml). The combined extracts were dried (MgS04), concentrated under reduced pressure and purified by flash chromatography (gradient elution with ethyl acetate/methanol/diethylamine) to afford two main product fractions.

:.

, .
.
.,- , w092/o3434 ~3~7 ~ '3 PCr/EP91/01491 ~

The faster running diast~ aomer (Rf = 0.25, EtOAc/MeOH = 3:1) was a light brown foam, 360 mg (31%), ; m.p. 67C.
H NMR (300 ~Hz, CDC13) ~ = 0.87 (3H,d,J=6Hz), 0.91 (3H,d,J-6Hz), 1.22 (lH,m), 1.39 (lH,m), 1.71 (lH,m~, 2.48 (3H,s), 3.10 (lH,m), 3.26 (5H,m), 3.53 (lH,m), 3.80 (lH,m), 6.11 (l-X, br s), 7.02 (lH,d,J=2~Z), 7.06 (lH,d,J=8Hz), 7.10 (lH,s), 7.35 (lH,d,J=3Hz), 8.30 (lH,d,J=5Hz), 8.97 ~ln~s~ p.p.m.
Th~ slower runnin~ diastereomer (~f = 0.06, EtOAc/MeOH = 3:1) was repurified by flash chromatography tgradient elution with dichloromethane/
methanol) to give a brown solid (324mg, 28%), m.p.
102-C.
H NMR (300 MHz, CDC13) ~ = 0.86 (3H,d,J=6Hz), 0.90 (3H,d,J=6Hz), 1.22 (lH,m), 1.66 (2H,m), 2.47 (3H,s), 3.06-3.48 (7H, complex), 3.79 tlH,m), 7.06 (3H,m), 7.35 (lH,d,J=8Hz), 8.30 (lH,d,J=5Hz), 8;97 (lH,s), p.p.m.

~' : ': . : -"

-W092/0~ ~ ~ ~ 7 r ~ ~ PCT/EP91/01491 Example 16 N-CYclohexyl-N-(2-propYl~-5-(2-methylimidazo[4 5-c]
~vrid-1-Yl)indane-2-carboxamide A mixture of cyclohexylisopropylamine (0.56g, 4.0 mmol) and sodium hydride (163mg, 60% dispersion in oil, 4.0 mmol) in 8ml dry tetrahydrofuran was stirred at room temperature under nitrogen for 15 mins. A
suspension of 5-(2-methylimidazo[4,5-c]pyrid-1-yl) indane-2-carbonyl chloride ~Example 4, 0.64g, 2.0 mmol) in dry tetrahydrofuran (8ml) was added, and the mixture was stirred at room temperature for 2h. The solvent was removed under reduced pressure, and the residue partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated, dried ~MgS04), and concentrated under reduced pressure. The residue was purified by flash .. . .
.: .
.
,~ .
' ~
.

W092/034~ ~ 3 ~ PCT/EP91/01491 chromatography (gradient elution with dichloromethane/
methanol) followed by chromatography on silica gel (20-40~), eluting with ethyl acetate: methanol:conc.
aqueous ammonia = 94:5:1, to give the title compound, 35 mg (4~). m.p. (fumarate salt) 100C.
H NMR (300 MHz, dmso-d6) ~ = 0.95-1.39 (4H,m), 1.13 (3H,d,J=6Hz), 1.23 (3H,d,J=6Hz), 1.45-1.70 (6H,m), 2.39 (3H,s), 3.02-3.4S (5H,m), 3.63 (2H,m), 6.52 (2H,s), 7.09 (lH,d,J=5Hz), 7.23 (lH,d,J=8Hz), 7.31 (lH,s), 7.37 (lH,d,J=8Hz), 8.20 (lH,d,J=5Hz), 8.81 (lH,s) p.p.m.
Analysis % -Found: C, 64.78; H, 6.48; N, 8.80 C27H32N40.3/4 fumarate C, 64.80; H, 6.42; N, 9.16%
H20 requires:
Example 17 N.N-Dicyclopentyl-5-(2-methylimidazo r 4.5-c~pyrid-1-yl)-indane-2-carboxamide , , .

, ':

Y092/034~ 2 ~ !~ 7 7 ~ ~ PCT/EP91/01491 A mixture of dicyclopentylamine (306 mg, 2.0 mmol) and sodium hydride (80 mg, 60% dispersion in oil, 2.0 mmol) in 8 ml of dry tetrahydrofuran was stirred under nitrogen at room temperature for lS minutes. A
suspension of 5-(2-methylimidazo[4,5-c]pyrid-l-yl)indane-2-carbonyl chloride (Example 4, 312 mg, l.0 mmol) in dry tetrahydrofuran (4 ml) was added and the mixture was stirred for 18 hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane (50 ml) and washed with saturated aqueous sodium bicarbonate (30 ml). The organic solution was dried (MgS04) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with ethyl acetate/methanol = 4:l) followed by preparative h.p.l.c. (Cl8 silanised silica, eluting with methanol/water = 9:l). The product was isolated as its fumarate salt, a white solid (38 mg, 9%) m.p. 133C.
Analysis %:-Found: C,64.78; H,6.48; N,8.80;

; C27H32N40.3~2 C4H404.l/2 H20: C,64 80; H,6.42; N,9.16.

~,, .~ .

~: .
' ' `

.

wo g2/03434 ; ~ 3 I r~ PCI/EP91/014gl Example 18 (a) 2-Amino-5-(2-methylimidaZo[4~5-c~pyrid-l-ylLiDaan~
;

N a > 1(,~ ~J ~

C~ N
~O~

5- [ 2-Methvlimi dazo~4,5-c]~r~_d-l~yl~indan-2-carboxylic acid (Example 2, 1.17 g, 4 mmoles) was suspended in toluene (8 ml). Triethylamine (444 mg, 4.4 mmoles) and diphenylphosphoryl azide (1.21 g, 4.4 mmoles) were added and the mixture was heated at 100C
for 20 minutes. The reaction mixture was cooled and treated with lM sodium hydroxide (30 ml). The aqueous phase was separated and washed with toluene (30 ml), neutralised (pH7) with 2M hydrochloric acid and extracted with dichloromethane (10 x 60 ml). The extracts were combined and dried (MgS04) and the solvent removed 'n vacuo. The product was chromatographed over silica gel t40-63~) eluting with diethylamine:methanol:ethyl acetate = 5:10:85.

Fractions containing product were evaporate~, yielding the title compound as an off-white foam, (870 mg, 82%).

.

''," '' '' ' ''' ''`' ' ', " ' , ' ~ ~ ~ 7 rl 1~
` V092/034~ PCT/EPg1/01491 lH NMR (300 MHz), CDC13), ~ = 2.00(2H,br), 2.54(3H,s), 2.82(2H,m), 3.21(2H,m), 3.96(lH,m), 7.05-7.21(3H,m), 7.39(1H,d,J=6Hæ), 8.36(1H,d,J-4Hz), 9.06(lH,s), p.p.m.

,...
(b) 2-ftert-Butvlcar~onvlamino)-5-(2-methylimidazo-r 4 5-clpvrid-1-yl)indane 'tC~,_ N ~--~--) ca3 ~ N ~) 2-Amino-5-(2-methylimidazo[4,5-c]pyrid-1-yl]indane (264 mg, 1 mmole) was dissolved in dichloromethane (5 ml) and pivaloyl chloride (132 mg, 1.1 mmole) and triethylamine (111 mg, 1.1 mmole) were added. The reaction was stirred at room temperature for 2 hours.
The dichloromethane solution was washed with saturated sodium ~icarbonate tl ml), dried (MgS04), and the solvent removed In vacuo. The crude product was chromatographed over silica gel (~0-63 ~) eluting with diethylamine:methanol:ethyl acetate = 3:3:94, and the fractions containing product were evaporated.

20~771~

The foam obtained (210 mg) was dissolved in methanol (5 ml), fumaric acid (70 mg) added and the solvent removed in vacuo. The resulting white foam was then sonicated in a mixture of ethyl acetate/ether =
1:3 (10 ml). The white solid was filtered off and dried, yielding the title compound as the fumarate salt (92 mg, 20~), m.p. 110-120C.
Analvsis %:-Found C,64.32; H,6.42; N,11.71;
C21H24N40.C4H404 re~uires C,64.64; H,6.08; N,12.06.

. .
~;
. ~ ~

.
, 2~ i'7~
:'092/034~. PCr/EP91/01491 Example 19 5-Ethoxvcarbonyl-2-(2-methvlimidazor4,5-cl~Yrid-1-Yl) -cvclopentanorblthiophene and 6-ethoxvcarbonY1-2-(2-methylimidazo-r4,5-cl~vrid-1-yl)cYclo~entano!bl thiophene ~ ~ ' EtO2C ~ CH3 CO2~CH3 ~NH 3 ,, 2Et Cl ~,~2 CH3 ~CH3 '. 2) H," Pd/C ~( C02Et 3) HOAc Ac2O
1~

.

''~

W092/034~ ~ PCT/EPgl/01491 ` 40 (a) Ethyl 3-cyclopentanonecarboxylate (10 g, 65 mmol), t-butyl cyanoacetate (9.4 g, 65 mmol), sulphur ~2.15 g, 65 mmol) and triethylamine (6.58 g, 65 mmol) were heated togeiher in dimethyl-formamide at 100C for 4 ; hours. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (50 ml), washed with watPr (~ x 20 ml), drieà (MgS04) and concentrated under reduced pressure. The residue was purified by flash chromatograph~ ~gr2di~nt ~lution with hexane/ethvl acetat~ ~o give a ~.ixtu~e of 2-amino-3-t-butoxycarbonyl-5-ethoxycarbonyl-cyclopentano[b]-thiophene and 2-amino-3-t-butoxycarbonyl-6-ethoxy-carbonylcyclopentano~b~thiophene (5.0 g, 25%).
''' lH NMR (300 MHz, CDC13) ~ = 1.15(3H,t,J = 7Hz), 1.5(9H,s), 2.6-3.4 (5H,m), 4.2(2H,q,J = 7Hz) p.p.m.
, : .
` (b) The aminothiophenes (5.0 g, 16 mmol) from (a) above, 4-chloro-3-nitropyridine (2.55 g, 16 mmol) and :,, sodium bicarbonate (1.35 g, 16 mmol) were stirred together in ethanol (50 ml) under nitrogen for 48 hours. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic phase was separated, dried (MgS04) and concentrated under reduced pressure to give a residue which was purified by flash chromatography ,..... ~

2 OJ 7 i i ~

` 41 (gradient elution with dichloromethane/methanol) to give a mixture of 3-t-butoxycarbonyl-5-ethoxycarbonyl-2-(3-nitropyrid-4-ylamino)cyclopentano~b]thiophene and 3-t-butoxy-carbonyl-6-ethoxycarbonyl-2-(3-nitropyrid-4-ylamino)cyclopentano~b]thiophene (2.6 g, 37%).

H N~R (300 ~Hz, CDC13) 5 isomer: ~ = 1.3(3H,t,J=7~7), 1.6(9H,s), 3.4(4H,m), 3.7(1H,m), 4.25(2X,q,J = 7X-), 7.6(1~,d,J = 5Hz), 8.5(1H,d,J = 5~ ), 9.~ ,s)p.p.m.

~, 4 isomer: ~ = 1.3(3H,t,J = 7Hz), 1.6(9H,s), 2.7(2H,q), 3.0(2H,m), 4.1(1H,t,J = 5Hz), 7.6(1H,d,J = 5Hz), 8.5(1H,d,J = 5Hz), 9.4(1H,s) p.p.m.

(c) The aminonitropyridines (2.5 g, 5.8 mmol) (from (b) above) were dissolved in ethanol (50 ml) and hydrogenated at 50 p.s.i. and 20C over 10% palladium on carbon (250 mg) for 3 hours. The catalyst was filtered off and the filtrate concentrated under reduced pressure to give a mixture of 2-(3-aminopyrid-4-ylamino)-3-t-butoxycarbonyl-5-ethoxy-carbonylcyclo-pentano~b]thiophene and 2-(3-aminopyrid-4-ylamino)-3-t-butoxycarbonyl-6-ethoxycarbonyl-cyclopentano-~b~thiophene (2.1 g, 90%).

. .
.. . .

.. . .

~ 17~i W092/034~ PCT/EP91/01491 H NMR (300 MHz, CDC13).
5-isomer: ~ = 1.3(3H,t,J = 7Hz), 1.6(9H,s), 1.8(2H,br s), 3.1-3.4(4~,m), 3.65(1H,m), 4.2(2H,q), 7.4~1H,d,J =
5Hz), 8.1(1H,d,J = 5Hz), 8.13(1H,s), 10.06(1H, br s) P-p.m.

4-isomer: ~ = 1.3(3H,t,J = 7Hz), 1.60(9H,s), 2.70(2H,m), 3.00(2H,m), 3.56(2H,br s), 4.05(1H,m), 4.20(2H,q J = 7Hz), 7.42(1H,d,J = 5Hz), 8.12(1H,d, J =
5HZ), 8.13(lH,s), 10.12(1H, br s~.

(d) The diaminopyridines (2.1 g, 5.2 mmol) (from (c) above), were heated in a mixture of acetic acid (S0 ml) and acetic anhydride (50 ml) at reflux for 1 hour. The ~; excess of reagents was removed under reduced pressure and the residue was dissolved in ethyl acetate (50 ml) amd washed with saturated aqueous sodium bicarbonate (2 ~ x 30 ml). The organic layer was separated, dried i (MgS04~, and concentrated under reduced pressure and :;
the residue was purified by flash chromatography ~3 (gradient elution with dichloromethane/methanol) to give a mixture of 3-t-butoxycarbonyl-5-ethoxycarbonyl-- 2-(2-methylimidazo[4,5-c]pyrid-1-yl)cyclopentano-~b~thiophene and 3-t-butoxycarbonyl-6-ethoxycarbonyl-2-(2-methyl-imidazo~4,5-c]pyrid-1-yl)cyclopentano~b]
thiophene (1.5 g, 68%).

2~r~ 7 ~
V092/034~ PCT/EP91/01491 lH NMR (300 MHz, CDC13).
5 isomer: ~ = l.OO(9H,s~, 1.28(3H,t,J = 7Hz), 2.48(3H,s), 3.40(5H,m), 4.2(2H,q,J = 7Hz), 7.05(1H,d,J
= 5Hz), 8.32(1H,d,J = 5Hz), 8.95(1H,s)p.p.m.

4 isomer: ~ = l.OO(9H,s), 1.28(3H,t,J = 7Hz), 2.45(3H,s), 2.7-3.2(4H,m), 4.2(2H,q,J = 7Hz, and lH,m), 7.00(1H,d,J = SHz), 8.35(1H,d,J = SHz), 8.95(1H,s)p.p.m.

; (e) The t-butylesters (1.5 g, 3.5 mmol) (from (d) above) were dissolved in trifluoroacetic acid and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase was washed with ethyl acetate and acidified with acetic acid, and extracted with ethyl acetate. The combined extracts were dried (MgS04) and concentrated under reduced pressure to give a mixture of 5-ethoxycarbonyl-2 (2-methylimidazo~4,5-c]pyrid-l-yl)cyclopentano~b]
thiophene-3-carboxylic acid and 6-ethoxycarbonyl-2-(2-methylimidazo[4~5-c]pyrid-l-yl)cyclopentano~b]

thiophene-3-carboxylic acid (1.1 g, 84~).

.. . . .

, .. . .

~ & ~ 7 '~
W092/034~ PCT/EPgl/01491 H N~R (300 MHz, CDC13).
5 isomer: ~ = 1.3(3H,t,J = 7Hz), 2.62(3H,s), 3.40(4H,m), 3.75(1H,m), 7.41(1H,d), 8.40(1~,d), 8.82(lH,s) p.p.m.

4 isomer: ~ = 1.3(3H,t,J = 7Hz), 2.60(3H,s), 2.80(2H,m), 3.2(7H,m), ~.2(2;~,q,J = 7~z and lH,m), 7.43(1H,d), 8.40(1X,d!, 8.82(1H,s~ p.p.m.

(f) The carbcxylic 2s~ds (lOO mg, 0.~? m~ol) (from (e) above), were dissolved in quinoline (1 ml) and copper powder (50 mg) was added. The mixture was heated under reflux for 1 hour, cooled, poured into water (10 ml) and extracted with ethyl acetate (3 x 15 ml). The combined extracts were washed with concentrated aqueous ammonia (20 ml) and water (20 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with dichloromethane/methanol) to give a mixture of 5-ethoxycarbonyl-2-(2-methylimidazo[4,5-c]pyrid-1-yl)-cyclopentano[d]thiophene and 6-ethoxycarbonyl-2-(2-methyl-imidazo~4,5-c]pyrid-1-yl)cyclopentano~b]
thiophene (40 mg, 45%).

The hydrochloride salt had m.p. 210-220C.

~'~092/0~ ~ ~1 3 7 7 ~ ~ PCT/EP9ltO1491 Analysis %:
Found: C,55.28; H,5.19; N,11.24.
C17H17N302S.HCl.1/4 H20 requires C,55.43; H,5.02;
N,11.41%.

lH NMR (DMSO-d~) 5-isomer; ~ = 1.3(3X,t), 2.5t3H,s), 3.2(4H,m), `~ 3.8(1H,m), 4.15(4H,q~, 7.8(1H,d!, 8.6!1H,d), 9.4(1H,s) P-p-m-4-isomer: ~ = 1.3(3H,t), 2.6(3H,s), 3.0(2H,m), 2.8(2H,m), 4.15(4H,q), 4.40(1H,t), 7.8(1H,d), 8.6(1H,d), 9.4(1H,s) p.p.m.
`, ' Example 20 2- r 2-Methylimidazo(4 5-c)pyrid-1-vll cvclo~entano~blthio~hene 5 and 6-car~oxvlic acids CH CH OC ~ ~
3 2 SN N NaOH ~ CH3 aq ethanol N ~ N

N

+ ~ 3 'r: ` ~ C ~

wo 92/03434 ~ 7 ~ ~ PCT~EP91/01491 A mixture of 5-ethoxycarbonyl-2-(2-methylimidazo-[4,5-c]-pyrid-1-yl)cyclopentano[b]thiophene and 6-ethoxycarbonyl-2-(2-methylimidazo[4,5-c]pyrid-1-yl)-cyclopentano[b]thiophene (Example 18, 3S0 mg, 1.07 mmoles) was dissolved in a mixture of ethanol (3 ml) and sodium hydroxide (80 mg, 2.0 mmole) in water (2 ml) was added. The mixture was stirred for 3 hours at room temperature then evaporated to low volume ln vacuo and acidified to pH 4.5 with acetic acid. Continuous extraction with CH2C12 gave the product (300 mg, 93%), m.p. 320C.
Analysis %:-Found: C,60.58: H,4.21: N,ll.01.
C15H13N302S requires C,60.20: H,4.35: N,10.70.

Example 21 2-(2-Methylimidazo r 4.5-clpyrid-1-yl)-5-t4-morpholino-carbonvl)cyclo~entanorb~thiophene and 2-~2-methylimidazor4.5-clpyrid-1-yl)-6-(4-mor~holino carbonyl)cyclopentano~b]thiophene A mixture of 2-~2-methylimidazo[4,5-c]pyrid-1-yl)-cyclopentano~b]thiophene-5-carboxylic acid and 2-(2-methylimidazo[4,5-c]pyrid-1-yl)cyclopentano[b]
thiophene-4-carboxylic acid (100 mg, 0.33 mmol) was stirred together with a solution of oxalyl chloride (50 ~1, 0.57 mmol) and dimethyl formamide (1 drop) in dry dichloromethane (5 ml) at room temperature for 1 hour.

~ ~ 3 ;~ r~
V092/034~ PCT/EP9l/01491 The solution was concentrated under reduced pressure and the residue dried in vacuo. The acid chloride thus formed was redissolved in dry dichloromethane ~3 ml) and added to a solution of morpholine (300 mg, 3.45 mmol) in dry dichloromethane (5 ml) at 0C. The mixture was allowed to warm to room temperature and was stirred for a further 1 hour. The mixture was poured into water (20 ml), and the aqueous phase was extracted with dichloromethane (3 x 10 ml). The combined extracts were dried (MgS04), concentrated under reduced pressure, and the residue was purified by flash chromatography (gradient elution with dichloromethane/methanol) to give the title compounds (45 mg, 37~)-Analvsis %:- (as fumarate salt, m.p. 232-240C).
Found: C,56.96: H,5.13; N,11.45.
C1gH2oN402S.C4H404 requires C,57.02; H,4.96; N,ll.S7.

Exam~les 22 and 23 The compounds of Table 2 were made by the method of Example 21 using diethylamine and 2-aminopyridine instead of morpholine.

WO 92/03434 2 ~ 3 ~ ri ~ ' PCI'/EP91/01491 4~

il ~ r ~ ~l ~n .

Claims (24)

1. A compound of formula (I):

(I) wherein X is -CH=CH- or s;
R1 is -COOR3, -CN, -CONR4R5 or -NR6COR3 where R3 is H, C1-C6 alkyl, C3-C7 cycloalkyl, or C1-C4 alkyl substituted by phenyl;
R4 and R5 are each independently H, C1-C6 alkyl which may optionally be substituted by a hydroxyl or C1-C4 alkoxy group, C3-C7 cycloalkyl, phenyl or pyridyl, said phenyl and pyridyl groups being optionally substituted by up to three groups independently selected from halo, hydroxy, -CF3, C1-C4 alkyl and C1-C4 alkoxy, or R4 and R5 together with the nitrogen atom to which they are attached represent a pyrrolidine, piperidine or morpholine ring;
R6 is H or C1-C4 alkyl;
and R2 is H, halo, or C1-C4 alkyl;
or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, in which R1 is at the 2-position of the indane nucleus when X is -CH=CH-or at the 5-position of the cyclopentanothiophene nucleus when X is -S-.

3. A compound according to claim 1 or 2, in which is a cyano, carboxy or ethoxycarbonyl group.

4. A compound according to claim 1 or 2, in which is a-CONR4R5 group where R4 and R5 together form a piperidino or morpholino group.

5. A compound according to claim 1 or 2, in which is a-CONR4R5 group and R4 and R are independently selected from H, t-butyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, pyridyl and pyridyl substituted by a methyl group.

6. A compound according to claim 5, in which R5 is H.

7. 2-(2-methylimidazo[4,5-c]pyrid-1-yl)-5-(N-pyrid-2-yl-carbamoyl)-cyclopentano[b]-thiophene.

8. 2-(N,N-dipropylcarbamoyl)-5-(2-methylimidazo-[4,5-c]pyrid-1-yl)indane.

9. 2-(N,N-dicyclopentylcarbamoyl)-5-(2-methylimidazo [4,5-c]pyrid-1-yl)indane.

10. A composition comprising a compound according to any preceding claim or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier or excipient.

11. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for use in medicine.

12. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for making a medicament for antagonising platelet activating factor.

13. A compound of formula (IV):

(IV) wherein R2 is as defined in claim 1.

14. A method of making a compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I) wherein X is -CH=CH-;
R1 is -COOR3, -CN, -CONR4R5 or -NR6COR3 where R3 is H, C1-C6 alkyl, C3-C7 cycloalkyl, or C1-C4 alkyl substituted by phenyl;
R4 and R5 are each independently H, C1-C6 alkyl which may optionally be substituted by a hydroxyl or C1-C4 alkoxy group, C3-C7 cycloalkyl, phenyl or pyridyl, said phenyl and pyridyl groups being optionally substituted by up to three groups independently selected from halo, hydroxy, -CF3, C1-C4 alkyl and C1-C4 alkoxy, or R4 and R5 together with the nitrogen atom to which they are attached represent a pyrrolidine, piperidine or morpholine ring;
R6 is H or C1-C4 alkyl;
and R2 is H, halo, or C1-C4 alkyl;
or a pharmaceutically acceptable salt thereof;
which comprises cyclising a compound of formula (II):

(II) wherein R2 is as defined above, and if necessary:

i) hydrolysing the compound of formula (I) produced to give a compound of formula (III):

(III) ii) esterifying the compound of formula (III) to produce a compound of formula (I) in which R3 is C1-C6 alkyl, C3-C7 cycloalkyl or C1-C4 alkyl substituted by phenyl, iii) converting the compound of formula (III) to its carbonyl halide and treating the carbonyl halide with an amine of formula HNR4R5 or a salt thereof to produce a compound of formula (I) in which R1 is -CONR4R5, iv) converting the compound of formula (III) to an amine of formula (IV) by treatment with an azide followed by hydrolysis of the product and treating the amine with a carbonyl halide of formula R3COY where Y
is a halogen to produce a compound of formula (I) in which R1 is -CHCOR3, (IV) v) treating the compound from (iv) with an alkyl halide to produce a compound of formula (I) in which is -NR6COR3 where R6 is alkyl, and (vi), forming a salt of the compound produced.

15. A method of making a compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I

wherein X is -S-;
R1 is -COOR3, -CN, -CONR4R5 or -NR6COR3 where R3 is H, C1-C6 alkyl, C3-C7 cycloalkyl, or C1-C4 alkyl substituted by phenyl;
R4 and R5 are each independently H, C1-C6 alkyl which may optionally be substituted by a hydroxyl or C1-C4 alkoxy group, C3-C7 cycloalkyl, phenyl or pyridyl, said phenyl and pyridyl groups being optionally substituted by up to three groups independently selected from halo, hydroxy, -CF3, C1-C4 alkyl and C1-C4 alkoxy, or R4 and R5 together with the nitrogen atom to which they are attached represent a pyrrolidine, piperidine or morpholine ring;
R6 is H or C1-C4 alkyl;
and R6 is H, halo, or C1-C4 alkyl;
or a pharmaceutically acceptable salt thereof, which comprises cyclising a compound of formula (VII) wherein R3 is C1-C6 alkyl, C3-C7 cycloalkyl or C1-C4 alkyl substituted by phenyl, and R7 is an optionally substituted alkyl group VII
and replacing the -CO2R7 group by H; and if necessary i) hydrolysing the compound of formula (I) produced to give a compound of formula (I) in which R3 is H, ii) converting the compound obtained from i) to its carbonyl halide and treating the product with an amine of formula HNR4R5 or a salt thereof to produce a compound of formula (I) in which R1 is -CONR4R5, iii) converting the compound from (i) to an amine by treatment with an azide followed by hydrolysis of the product, and treating the amine with a carbonyl halide of formula R3COY when Y is a halogen to produce a compound of formula (I) in which R1 is -NHCOR3, iv) treating the compound from iii) with an alkyl halide to produce a compound of formula (T) in which R1 is -NR6COR3 where R6 is alkyl, v) converting the compound of formula (I) in which is -COOH or -COOR3 to the corresponding nitrile, and vi) forming a salt of the compound produced.

16. A method according to claim 14 or 15, in which the compound of formula (II) or (VII) is cyclised by heating with acetic anhydride and acetic acid.

17. A method according to claim 14, 15 or 16, in which R1 is at the 2-position of the indane nucleus when X is -CH=CH- or at the 5-position of the cyclopentano thiophene nucleus when X is -S-.

18. A method according to any one of claims 14 to 17, in which R1 is a cyano, carboxy or ethoxycarbonyl group in the compound obtained.

19. A method according to any one of claims 14 to 17, in which R1 is a-CONR4R5 group where R4 and R5 together form a piperidino or morpholino group in the compound obtained.

20. A method according to any one of claims 14 to 17, in which R1 is a-CONR4R5 group and R4 and R5 are independently selected from H, t-butyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, pyridyl and pyridyl substituted by a methyl group in the compound obtained.

21. A method according to claim 20, in which R5 is H.

22. A method according to claim 15, in which the compound is 2-(2-methylimidazo[4,5-c]pyrid-1-yl)-5-(N-pyrid-2-yl-carbamoyl)-cyclopentano[b]-thiophene.

23. A method according to claim 14, in which ihe compound is 2-(N,N-dipropylcarbamoyl)-5-(2-methylimidazo-[4,5-c]pyrid-1-yl)indane.

24. A method according to claim 14, in which the compound is 2-(N,N-dicyclopentylcarbamoyl)-5-(2-methylimidazo[4,5-c]pyrid-1-yl)indane.