NZ188693A - 1-arylalkylimidazoles and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 88693 t 8 86 9 3 Priority Dats{s): (£(; iC. 77.i. i%. ; 7.X .

I ■ 2% * ^ Complete Specification Filed: XA \X% Ciass: A k K^U Publication Date: . 24. A0u.Utfj4-..

P.O. Journal, Wo: .... 13-ksl No.: Date: NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION "IMIDAZOLE DERIVATIVES ASD THEIR SALTS" XD?We, THE WELLCOME FOUNDATION LIMITED of 133-193 Euston Road, London, N.W.I., England, a company incorporated in England, hereby declare the invention for whichjjljj/ we pray that a patent may be granted to 32$g{/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (followed by pagela ) 1 8 86 Imidazole derivatives and salts thereof, their synthesis, and Intermediates, and pharmaceutical formulations.

The present invention relates to imidazole derivatives and salts thereof, to their synthesis and intermediates therefor, tc pharmaceutical formulations containing such compounds and to the use of these compounds in medicine.

Thromboxane (TXA2), a potent stimulator of blood platelet aggregation, is produced, in platelets, from the prostaglandin endoperoxides PGG2 and PGH^. Prostacyclin (PGI2), which has potent anti-aggregatory activity, is also produced (in blood vessel walls) from PGG2 an<^ *>®H2 an^ ^as *~aen suggested that a balance between the production of TXA2 and PGI2 is the controlling factor in thrombus formation. It would, in consequence, be desirable in the treatment and prophylaxis of thrombo-embolic disorders to be able to selectively inhibit TXA2 synthetase, thereby favouring the production of the anti-aggregatory agnet PGI^.

Imidazole and 1-methylimidazole are known to provide some degree of inhibition of the enzymic conversion of the endoperoxides (PGG^ and PGH2) to thromboxane by platelet microsomes (Moncada et al., Prostaglandins, 13/4, 611-618, 1977). Certain 1-rv-alkylimidazoles, especially 1-ri-dodecylimidazole and its higher 1 P O S I QUO 2 homologues have been described as being capable of lowering serum cholesterol levels (.U.K. Patent No. 1 364 312; Biochem. Pharmacol. 24, 1902-1903, 1975).

We have now discovered that TXA2 synthetase may be inhibited by 1-aryj.alkylimidazoles of formula (I) and acid addition salts thereof. The compounds of formula (I) and their salts are hereinafter referred to as the "active compounds".

The compounds of.formula (I) are novel and of formula: in which A is a straight or branched alkylene group of from 1 to 3 carbon atoms, or a straight or branched alkenylene or alkynylene group of from 2 or 3 carbon atoms, n is an integer which is at least 1, and the or each R substituent, which when n is greater than 1 may be the same of different, is a saturated alkyl group of from 1 to 4 rcirbcn atoms, or an unsaturated alkyl group of from 2 to 4 carbon atoms with the provisos that (a) when A is a methylene or ethylidene group, n is at least 2 when each R is saturated alkyl, (b) when A is a branched propylene, or straight propylidene group, n is at least 3 when each R is saturated alkyl, and (I) 188693 (c) when A is unsaturated R may also be selected from alkoxy of from 1 to 4 carbon atoms; when n is at least 2, alkylenedioxy of from 1 to 4 carbon atoms; halo; trihalomethyl; hydroxy; carboxy1; a salt of such a carboxy1 group; carboalkoxy; alkyl of from 1 to 4 carbon a terns; with the further proviso that when n is 1, R is not a saturated alkyl group; or an acid addition salt of such a 1-arylalkylimidazole.

The term "branched alkylene group" includes the straight or branched alkylidene groups ethylidene, propylidene and isopropyl-idene.

In formula (I) examples of the group A are:- -CI^-CH^CH-, (cis or trans or isomeric mixture therof).

A valuable class of compounds of formula (I) are those in which the aromatic ring is substituted by at least two saturated or unsaturated alkyl radicals, especially if one substituent is in the 4-position in the benzene ring and A is either methylene (-CH2~) or, in the orientation of formula (I), -CH2""CH=CH- (cis or trans or a cis/trans mixture-cinnamyl compounds). When A is unsaturated, preferred compounds are those in which the aromatic ring contains alkyl, chloro or methoxy substituents. 6 7 6 7 carboaxy loxy; carboarylalkyloxy; -NR R or -CDNR R in which 6 7 R and R may be the same or different and are hydrogen or methylene, propylene, and in the orientation of formula (I); 1 8 - 4 Compounds of formula CD may also be used as acid addition salts thereof, especially as pharmaceutically acceptable ones.

Especially preferred compounds include:-1-C3,4-dimethylbenzyl)imidazole 1-(2,4-dichlorocinnamyl)imidazole i.e. 1-[3—(2,4-dichloropheny L) 1- |^3- (2,6-dichlorophenyl)prop-2-enylj imidazole, and acid addition salts thereof.

Other preferred compounds include 1-(2,4,6-trimethylbenzyl)imidazole 1- jj3- (3,4,5-trimethoxypheny 1) prop-2-enylj imidazole 1- ^3- (3,4-dimethoxyphenyl) prop-2-enyl| imidazole 1-03- (2-hydroxyphenyl) prop-2-enylJ imidazole 1-03- (3-bromophtnyl) prop-2-enyl")imidazole 1- 05- (4-chlorophenyl) prop-2-onyfJ imidazole 1- 03- (3.4-dimethylphenvl) prop-2-enylJimidazole 1- 03- (2-methoxyphenyl)prop-2-enylj imidazole^and acid addition salts thereof. ossein contrast to imidazole and 1-methylimidazole, the compounds of formula CI) are more potent inhibitors of TXA2 synthetase. Many of the compounds Cfor example in formula (I) R is 3,4-dimethyl and A is or in the orientation of formula CI), -CH^CH^CH-) are also more selective in their action in not inhibiting other anti-aggregatory prostaglandi.i--gonerating enzymes. The compounds of formula (I) also do not produce the side-effects found with imidazole upon in_ vivo administration. The compounds of formula CI) are further capable of inhibiting platelet aggregation ill vivo and also are capable of disaggregating platelet clumps, the compounds l-(3, 4-dimethylbenzyl) imidazole, 1-(2,4-dichlorocinnamyl)imidazole and 1-(2,6-dichlorocinnamyl) unidazole, and their salts especially displaying these properties.

Imidazoles of formula CI) and acid addition salts thereof may be made by any method known in the art for the synthesis of compounds of analogous structure. In general these methods comprise linking the imidazole ring to the remainder of the molecule; converting a precursor molecule by elimination of a functional group; and formetion of the desired compound from a corresponding pyrazole, imidazoline or other unsaturated analogue.

A most convenient method of synthesis involves the reaction of imidazole (formula CH) or a salt thereof with an arylalkyl-ating agent of formula (III): 188693 6 - \ Z-A (R) n NH N CII) (III) wherein R, n, and A are as defined in formula (I) and Z is a leaving group. This reaction is well established in the literature, and the leaving group may be chosen from a variety of substituents but especially halo, preferably chloro or bromo, or from p-toluenesulphonyloxy but other aryl-sulphonyloxy, alkanesulphonyloxy or arylalkylsulphonyloxy radicals may be used. The reaction is preferably performed in the presence of an acid acceptor, for example an alkali metal alkoxide, such as sodium methoxide or potassium tertiary butoxide, in the presence of an alkanol. The leaving group Z may itself be formed in situ from the corresponding alkanol (Z = OH) by reaction with a hydrohalogenic acid (e.g. hydrochloric acid or a Lewis acid, such as aluminium chloride) and the resulting agent j of formula (III) reacted directly with imidazole without prior isolation. Alternatively an alkanol (Z = OH) or a derivative thereof (e.g. Z A-0"")may be reacted directly with 183693 imidazole CH) by heating in the presence of a dehydrating agent, such as phosphoric acid, or a phosphate, sulphuric acid or sulphates.

Among precursor molecules which may be converted to a compound of formula (I) or an acid addition salt thereof, are substituted imidazole derivatives of formula (IV) or addition salts thereof 1 2 3 wherein A, n and R are as defined in formula (I), and Q , Q , Q 4 and Q are the same or different, at least one being a radical capable.of removal by, for example reduction or oxidation, the remaining radical or radicals being selected from hydrogen or a radical capable of removal in the same or another manner (e.g. a carboxyl grcup -see formula (VI)-removed by decarboxylation)f y is Q oj: an integer with the proviso that y and ii together do not 12 3 4 exceed 5. Q , Q , Q and Q may be selected for example' from thio (-SH), alkylthio (-S-alkyl, wherein alkyl has from 1 to 4 carbon atoms) or halo preferably chloro or bromo. The reaction conditions are chosen according to the nature of the radicals 12 3 4 Q t Q r Q and Q . Desulphurisation may be performed by oxidative or reductive procedures using for example nitric acid or Raney 188693 nickel; and reductive dehalogenation by the use of zinc and acetic acid or Raney nickel or other reagents known in the art or described^in the literature.

Another class of examples include carboxyimidazoles or derivatives thereof of formula (VI); (VI) wherein A, n, and R are as defined in formula (I), at least 12 4 one of R , R and R is carboxyl or a derivative thereof (for example an ester such as an alkyl ester, an acid halide such as the chloride, or the nitrile) 0th3r Qr others of R^". 2 4. ' - R and R is or are hydrogen or carboxy]/or a derivative as described. The conpounds of formula (VI) may be converted into I the imidazoles of formula (I) by any suitable decarboxylation conditions which may simply conprise heating the compounds with or without a catalyst, such as copper.

The imidazoles of formula (I) may also be made from a compound of formula (VII); / - > 1 3 . N-A -R * / (VII) J wherein N is 1-imidazoline, 1-imidazole or 1-pyrazole, A is straight or branched saturated or unsaturated acyclic i 88693 9 hydrocarbon radical which contains no more than 3 1 3 carbon atoms and which may include a keto-group, and R (R) , ' . is n wherein R and n are as defined in formula (I) and when A is unsaturated R may also be nitro provided that at least one of N, A"*" and is other than 1- R) imidazole, a saturated acyclic hydrocarbon group and n as defined in formula (I). Thus an imidazoline (VIII): \ (R) n N-A- n (VIII) (H) wherein one of represents an extra bond, and A, n and R are as defined in formula (I),may be dehydrogenated to the corresponding imidazole in the presence of a catalyst, for nickel or platimun under pressure, or by heating with a dehy- drogenating agent, such as selenium or copper oxide. 1-Pyra- zole compounds (VII) may be treated with ultra-violet irradiation, optionally under an inert atmosphere (e.g. argon) in for example 1,2-dimethoxyethane at room or elevated temperatures (see for example "Ring Transformations of Heterocycles" edited van der Plas, Academic Press, 1973 at page 261). The unsaturated imidazoles of formula (I) (in formula' (VII) , A^" and/or R (within 3 R ) are unsaturated) may be reduced to corresponding less saturated or completely saturated compounds(but not reducing the aromatic nucleus) with a noble metal catalyst for example platinum example by heating to 250°C in the presence of palladium, or palladium in an alkanol. If R is amino in'the final product then its precusor may be a nitrogen-containing group reducible to amino e.g. nitro. A compound for example of formula w / N-CH2~C (IX) where R and n are as for formula (I), may be reduced at the keto group to a group for example by a Clemmensen reduction.

Where one or more of the R groups is a saturated or unsaturated alkyl group it may be introduce'! into the phenyl ring by a Friedel Crafts or similar Lewis-acid catalysed reaction of the type.

N-A N. n-x xRZ CX) N- \ N-A- (I) wherein A, R and n are as defined for formula (I), x is an integer less than or equal to n and Z* is a leaving group, e.g. halo, suitable fcr use ir this type of alkylation.

Compounds of formula (I) may also be prepared by cyclising preferably in the presence of an acid acceptor, a compound of formula 188693 - li - (xi: 2 wherein A, R and n are as defined for formula (I) and X is a leaving group.

Compounds of formula (I) may also be prepared by reacting a compound of formula (XII) wherein A, R and n are as defined for formulc. (I) , with a compound of formula: ••3 ,x4 CH—CB <XIII) 3 3 wherein either of X and Y is a leaving group such as halo or 3 3 hydroxy and the other is hydrogen/ or X and Y are both halo or together form a keto group or an acetal derivative Lhereof 3 3 4 4 e.g. both X and Y. are alkoxy, and X and Y are as defined 3 3 for X and Y , although they may be the same as or different from X3 and Y3.

An inline salt of for example formula 1 8 8693 IXIIIa) (wherein R and n are as for formula I, X is an anion, 2 A is a chemical bond or a straight or branching saturated or unsaturated acyclic hydrocarbon radical, which nuty include a 3 koto group, A is hydrogen or a saturated or unsaturated acyclic hydrocarbon radical, which may include 2 3 a keto group, with the proviso that A and A together contain no more tnan 2 carbon atoms) may be reduced to the ' corresponding compound of formula (I) , by e.g. zinc and ra"-mineral acid, e.g; hydrochloric acid.

The intermediates for use in the above described reactions may also be made by conventional methods known in the art. Thus •• the 1-pyrazole and 1-imidazoline intermediates (formula (VII) may be prepared by alkylation of pyrar.ole and imidazoline in an analogous manner to that described above for pre]: ar^tion of the 15 corresponding imidazoles. The intermediates of formula.(Ill) may be made in known manner preferably by halogenation of the corresponding alcohols (formula (III), Z = -OH) where A is unsaturated in such compounds the alcohol is conveniently prepared from paraformaldehyde- andra- precursor . / ' molecule with an unsaturated A group containing two ■A&53 carbon atoms (.cf Bull. Chem.^Soc. Japan, 46/8, 2512-5, 1973). The substituted imidazole intermediates of formula (IV) may be made in known manner, for example see "Imidazole and its derivatives" Part i, Ed. K. Hofmann, Interscience Publishers Inc. New York, 1973. For example the 2-thioimidazoles of formula (IV) may be made by cyclisation of an acetal of formula CCIV) : R50 \ CH-CH2.NH.—A j/ v—' <XI« with thiocyanate, wherein R^ is alkyl, aryl or arylalkyl.

The pharmaceutically acceptable addition salts of the 10 compounds of formula (I) may be prepared by any method known in the art. In particular they may be prepared by treating the parent imidazole with the appropriate acid.

Examples of the addition salts of the compounds of formula (I) include those salts derived from the following 15 acids: oxalic, hydrochloric, hydrobromic, suxphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic^lactic, salicyclic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthe.lene-2-sulphonic and benzenosulphonic.

The imidazoles of formula (I) may be used in conjunction with a phosphodiesterase inhibitor, which provides a further I o ® & « f U W •->:/ synergistic increase in effect, as it acts against platelet aggregation by a different pathway.

Suitable phosphodiesterase inhibitors for use in potentiating the anti-aggregatory effects of the active compounds include as such or as pharmaceutically acceptable salts (a) Xanthine derivatives such as:- Theophylline(3,7-dihydro-l, 3-dimethyl-ltI- purine-2,6-dione) , ai:d salts thereof. 3-Isobutyl-l-methyl-xanthine; Caffeine(3,7-dihydro-l,3,7-trimethyl-lH-purine- 2.6-dione) and salts thereof; and Aminophylline (adduct of Theophylline and 1,2-ethanediamine (2:1)) (b) Isoquinoline derivatives, for example:- Papaverine 1- {(3,4-dimethoxyphenyl)methyl]- 6.7-dimethoxyisoquinoline) and salts thereof; and 6,7-Diethoxy-l-(4,5-diethoxybenzyl)isoquinoline or its salts e.g. its hydrochloride; (c) Derivatives of pyrimido(5,4-d- pyrimidine, for example Dipyridamole (2,2' , 2" ' - (4,8-dipiperidino-::>yrimido [5,4-d] pyrimidin-2,6-diyldinitrilo) -tetraethanol) and its salts; 2,2' ,2" '-[C 4-(l-piperidinyl)pyrimido[5,4-dl pyrimidin-2,6-diyl] dinitrilojtetrakisethanol -and its salts; and 2,4,6-tri-4-morpholiny Ipyrimido [[5 , 4-dJ pyrimidine and its salts. (d) Derivatives of thieno [3,2-dJpyrimidine, for example:- N- [4- (4-morpholinyl) thieno ,2-d^jpyrimidin-2-ylJ-1,2-ethanediamine. 1 8 8693 _ 15 - fc*53 (e) Derivatives of pyrazolo (3' ,4':2,33pyrido [4,5-bJ £l,5 3 benzodiazepin-6-(3H)-one, for example:- 3-Ethyl-7,12-dihydro-7 ,12-dimethylpyrazolo- [4',3':5,6]]pyrido [4,3-b^]- 1,5 benzodiazepin-6 (3H) -one; -Chloro-3-ethyl-7,12-dimethyl-7,12-dihydrc-pyrazolo [4',31:5,6]pyrido(4,3-b^ Q-/5]benzodiazepin-6- (3H) -one. (f) Derivatives of 1H- or 2H-pyrazolo [3,4-b]-pyridine, for example:- 4- (Butylamino) -1-ethyl-lH-pyrazolo [3,4—Id] -pyridine-5-carboxylic ac:d ethyl ester, 4-(Butylamino)-lH-pyrazolo [3,4-b2pyridine-6-carboxylic acid ethyl ester; 4-Chloro-l-ethyl-3-methyl-lIJ-pyrazolo [3,4-b]| -pyridine-5-acetonitrilc; 1-Ethyl-4-(isopropylidenehydrazino)-3-methyl-lH-pyrazolo(3,4-b)pyridine-5-carboxylic acid ethyl ester or its salts such as its hydrochloride hemihydrate; and 2-Methyl-6-phenyl-4-(1-piperidinyl)-2H-pyrazolo-(j3,4-bJ pyridine or its salts e.g. its hydrochloride. (g) Derivatives of 5H-furo-[^3,4-eJpyrazolo-^3,4-bj pyridine-5-one, for example:- 4- (Butylamino) -1-ethyl-l, 7-dr.hydro-7-hydroxy-5H-furo- {3,4-eJpyrazolo£3,4-b]pyridine-5-one; and (h) Derivatives of 1 (2H)--naphthalenone, for example:- 2 |(Dimethylamino)methyl]-3,4-dihydro-7-methoxy-1(2H)-naphthalenone or its salts e.g. its 1:1 hydrochloride.

The active compounds are particularly useful in the treatment and/or prophylaxis of thrombo-embolic disorders in mammals, including man. It is to be understood that the term "thromboembolic disorders" includes those disorders whose etiology is associated with platelet aggregation. 1 8 8 _ 16 - ,£653" The active compounds are useful wherever it is desired to inhibit platelet aggregation and/or to reduce the adhesive character of'platelets, and consequently to treat or prevent the formation of thrombi in mammals, including man. For example, the compounds are useful in the treatment and prevention of myocardial infarcts, cerebro-vascular thrombosis and ischaemic peripheral vascular disease? to treat and prevent post-operative throiiix>sis; and to promote patency of vascular grafts following surgery.

The active compounds are also useful as an addition to blood, blood products, blood substitutes, and other fluids which are used in artificial extra-corporeal circulation and perfusion of isolated body jortions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant,,or attached to a new body. It may also be used in laboratory animals, e.g. cats, dogs, rabbits, monkeys and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.

The active compounds also exhibit some vasodilatory action on blood vessels and therefore have a utility as antihypertensives for the treatment of high blood pressure in mammals including man.

The amount of active compound required for therapeutic or prophylactic effect will vary with the route of administration, 1 8 and the nature of the condition under treatment. In general a suitable dose for a mammal, including man, of active compound will lie in the range of 0.1 to 300 mg per kg body weight, particularly from 0.5 to 10 mg per kg body weight, for example 2 mg per kg. A suitable single oral dose for an adult human lies within the range of 50 to 600 mg, for example 150 mg given say three times a day.

While it is possible for tlie active compounds to be administered as the raw chemical it is preferable to present them as a pharmaceutical formulation. The formulations, both for veterinary and for human medical use, of the present invention comprise an active compound as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be 'acceptable' in the sehce of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Unit doses of a formulation may contain between 60 mg and 1.5 g of an active compound.

The formulations include those suitable for oral, rectal, vaginal or parenteral (including subcutaneous, intramuscular and intravenous) administration. Preferred formulations include tablets, capsules and injectable suspensions or solutions.

The formulations may conveniently be presented in unit dosage from and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of 1 88693 bringing into association the active compound (in the form of the base or a pharmaceutically acceptable acid addition salt) with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

It will be appreciated from the foregoing that the present invention provides the following features (a) Novel 1-arylalkylimidazoles of formula (I), and acid addition salt thereof. (b) Methods of preparing imidazoles of formula (I) and acid addition salts thereof. (c) Pharmaceutical formulations containing the imidazoles of formula (I) or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. (d) Method of preparing the pharmaceutical formulations containing the imidazoles of formula (I) or a pharmaceutically acceptable acid addition salt thereof. (e) A method for the treatment of prophylaxis of a thromboembolic disorder in a mammal or mammalian tissue, excluding man or human tissue, comprising administering an active compound.

N.Z. PATENT OFFICE 1-1 JAN 1984 receive:' The following Examples are provided by way of an illustration of the present invention and should in no way be construed as constituting a limitation thereof. All temperatures are given in degrees Celsius. 18 8693 EXAMPLE 1 Preparation of 1-(3,4-Dimethylbenzyl)imidazole l-Chloromethyl-3/4-dimethylbenzene (34.76 g, 0.225 mol) was added to a. mixture of imidazole (13.6 g, 0.2 mol) and sodium 5 bicarbonate (16.8 g, 0.2 mol) in dry nethanol (100 ml).

Following the addition, the reaction mixture was stirred and heated under reflux for 3 h.

After cooling, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to afford a 10 yellow oil. The residue was extracted with chloroform (3 x 100 ml), and the combined extracts ^ere washed with saturated brine (lOO ml). The chloroform solution was dried over magnesium sulphate, and then concentrated under reduced pressu.ve. The resulting oil was purified using a silica gel column and ethyl 15 acetate/methanol (9:1) as eluent. The product fractions were poolea, concentrated, and the resulting oil was dis'.illed to afford 1-(3,4-dimethylbenzyl)imidazole b.p. 128-130°/0.3mm Hg.

EXAMPLE 2 - Salts of. 1-(3,4-Dimethylbenzyl) imidazole A. Hydrogen Fumarate 2o A solution of fumaric acid (0.29 g, 0.0025 mol) in hot ethanol (10 ml) was added to a stirred solution of 1-(3,4-dimethylbenzyl) imidazole (0.46 g, 0.0025 mol) in hot ethanol (10 ml). After boiling for 0.25 h, the solution was evaporated to afford a white solid. Recrystallisation of the solid from 1 8 86 ethyl acetate afforded 1-(3,4-dimethylbenzyl) imidazole hydrogen fumarate 1/6 hydratre as—a white solid m.p.. 138-140 °.

B. Hydrogen Succinate A hot solution of succinic acid (0.295 g, 0.0025 mol) in hot ethanol (20 ml) was added to a stirred, hot solution of 1-(3,4-dimethylbenzyl)inidazole (0.46 g, 0.0025 mol) in hot ethanol (10 ml) . After boiling for 0.25 h, the solution war. evaporated under reduced pressure to afford a white solid.

Recrystallisation of the solid from ethyl acetate/petroleum ether (b.p. 40-60°) afforded 1-(3,4-dimethylbenzyl)imidazole o hydrogen succinate as white crystals, m.p. 134-135 .

C. Hydrogen Oxalate A hot solution of oxalic acid (0.225 g, 0.0025 mol) in dry ethanol (10 ml> was added to a solution of 1-(3,4-dimethylbenzyl) imidazole (0.46 g, 0.0025 mol) in hot ethanol (20 ml). After boiling for 0.25 h, the solution was evaporated to afford a white solid. Recrystallisation of the solid from ethanol/ petroleum ether (b.p. 40-60°) afforded 1-(3,4-dimethylbenzyl) o imidazole hydrogen oxalate as a white solid, m.p. 92-93 .

EXAMPLE 3 Preparation of 1- [3-(2,4-Dichlorophenyl)prop-2-enyl]imidazole l-Chloro-3-(2,4-dichlorophenyl)prop-2-ene (11.1 g, 0.05 mol) was added dropwise to a stirred solution of imidazole (3,4 g, 0.05 mol) and potassium tert-butoxide (5.6 g, 0.05 mol) in 1 8 22 - butan-l-ol C100 ml). Following the addition, the reaction mixture was stirred and heated under reflux for 3.5 h.

After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Hydrochloric acid (150 ml, 2M) was then added to the residue and the aqueuos mixture was washed with ether CI x 60 ml). The acidic solution was then basified with sodium hydroxide solution (1CM) and the resulting oil was extracted with chloroform. The chloroform extracts were combined and dried over magnesium sulphate. Evaporation of the chloroform under reduced pressure afforded a pale yellow oil which was purified using a silica gel column and by elution with ethyl acetate/methanol (9:1). The product fractions wtre pooled and concentrated to afford an oil which was distilled, to afford l-[3-(2,4-dichlorophenyl) prop-2-enylJimidazole, b.p. 144-148°/0.007 mmHg.

EXAMPLE 4 Preparation of 1- Ij-C2,6-Dichlorophenyl)prop-2-enyJ imidazole l-Chloro-3-C2,6-Dichlorophenyl)prop-2-ene (11.1 g, 0.05 mol) was added dropwise to a stirred solution of imidazole (3.4 g, 0.05 mol) and potassium tert-butoxide (5.6 g, 0.05 mol) in butan-l-ol (100 ml). Following the addition, the reaction mixture was stirred and heated under reflux for 3.5 h.

After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Hydrochloric 1 8 8^9 acid (150 ml, 2M) was then added to the residue, and the aqueous mixture was washed with ether (1 x 60 ml). The acidic solution was then basified with sodium hydroxide solution (10M), and the resulting oil was extracted with chloroform. The chloroform 5 extracts were combined and dried over magnesium sulphate.

Evaporation of the chloroform under reduced pressure afforded a pale yellow oil which was purified using a silica gel column and by elution with ethyl acetate/methanol (9:1). The product fractions were pooled and concentrated to afford an 10 oil which was distilled, to afford 1-03-(2,6-dichlorophenyl)- prop-2-enylJ imidazole, b.p. 156-158°/0.02 mmHg.

EXAMPLE 5 Biological Results Horse platelets were prepared from whole horse blood by 15 differential centrifug:-,tion. Approximately 10^ platelets were homogenised in 1 ml 100 mM Tris buffer pH 7.4. Various concentrations of active compound were added and the reaction-sets incubated for 5 minutes at ambient temperature. To each tube was added 20 nM of arachidonic acid containing 10 20 disintegrations per minute (DPM) of labelled arachidonic acid and the tubes incubated for 3 minutes at 37°C in a shaking water bath. After incubation the radioactive products were extracted from the acidified aqueous phase with ethyl acetate and after concentration resolved by thin layer chromotography 25 on silica gel with chloroform/methanol/acetic acid/water I 8 86 O-g (90; 8; l;-0. 0) as a developing solvent. The amount of thromboxane produced was measured by scraping the radioactive zone corresponding to thromboxane and estimating the radioactivity in a liquid scintillation counter.

The concentration of active compound to reduce the enzyme, activity by 50% (ED^) was established. The results are shown in Table A.

The selectivi-cy of the active compounds was measured in a similar manner to that described above and the amount of PGE PGF and PGD produced was determined. The greater the selectivity, the more of the anti-aggregating prostaglandins are produced.

The ED5o and Selectivity results are shown in Toble A in which O indicates no selectivity; + low selectivity; ++ medium selectivity; +++ high selectivity, and ++++ exceptionally high selectivity TABLE A ED_ Compound oO (Reference Compound) ug/ml Selectivity (Imidazole) ^ 500 O to + (1-Methylimidazole) J^200 ++ 1-(3,4-dimethylbenzyl)imidazole 6 ++ 1- [3-(2,4-dichlorophenyl)prop-2- enyl3 imidazole 4.1 " + 1-[3-(2,6-dichlorophenyl) prop-2-enyl) imidazole 1 + 1 8 •; <• v\ v < • - 25 - £5&3 EXAMPLE 6 Tablet formulation 1-(3,4-dimethylbenzyl)imidazole (as a salt) 150 mg Starch 25 mg Polyvinylpyrrolidone 2 mg Magnesium stearate 3 mg The imidazole salt is ground to a fine powder, blended with the starch and then the mixture granulated with an aqueous solution of the polyvinylpyrrolidone. The granules 10 are sieved 1000 p., dried, sieved again and the magnesium stearate added. The mixture is then compressed into tablets.

In the same manner, tablets of 1-(3-(2,4-dichlorophenyl)-prop-2-enyl3imidazole and 1- [3-(2,6-dichlorophenyl)p-:op-2-enyi] imidazole are prepared.

EXAMPLE 7 Tablet formulation Tablets (150 mg) of the imidazoles described in the preceding example £ are prepared in the same manner from the following ingredients 2o The Imidazole Compound (as a salt) 150 mg Lactose 100 mg Starch 30 mg Polyvinylpyrrolidone 2 mg Magnesium stearate 3 mg 1 8 S*>9 -26- 4s®5 In the preparation, t".ie lactose is blended with the starch.

EXAMPLE 8 Tablet formulation 5 Tablets (.100 mg) of the imidazoles of Example 6 are prepared in the same manner from the following ingredients: The Imidazole Compound (r-.s a salt) 100 mg Sodium starch glycollate 10 mg Polyvinylpyrrolidone 2 mg Magnesium stearate 3 mg EXAMPLE 9 Tablet formulation Tablets (150 mg) of the imidazoles of Example 6 are prepared in the same manner from the following ingredients, 15 except that the starch, pregelled starch and imidazole compound are all b3.onded together prior to granulation The Imidazole Compound (as a salt) 150 mg Starch. 25 mg Pregelled starch 5 mg 2o Magnesium stearate 3 mg 1 8 0 A553 EXAMPLE 10 Injectable formulation Imidazole compound of formula (I) 15.0 g Lactic Acid B.P. q.s. to pH 3.0 Water for Injections B.P. to 100.O ml Suspend the compound in 3/4 of the available quantity of water. Add sufficient lactic acid to dissolve the compound and to reduce the pH to 3.0. Dilute to volume with Water for Injections.

Sterilise the solution by passage through a membrane filter, pore size 0.22 jim.

Distribute the solution using aseptic precautions into sterilised ampoules, 1 .^.1 per ampoule. Seal by fusion of the glass.

Each 1 ml ampoule supplies 150 mg of the imidazole compound: 1-(3,4-dimeihylbenzyl)imidazole hydrogen fumarate.

EXAMPLE 11 Injectable formulation Imidazole compound of formula (I) 15.O g Citric Acid B.P. q.s. to pH 3.0 Chlorocresol O.l g Water for Injections to lOO.O ml Suspend the compound in h the final volume of Water for Injections. Add sufficient citric acid as a 10% solution in 18 ©6 - 28 - ■*SSS Water for Injections to dissolve the compound and reduce the pH to 3.O. Dilute to volume with Water for Injections.

Sterilise the solution by passage through a membrane filter, pore size 0,22 ;um.

Distribute the solution with aseptic precautions into sterilised vials, 25 ml per vial. Stopper with sterile rubber closures and seal with an aluminium cap.

Each 1 ml of solution provides 150 mg of the compound: 1-(3,4-dimethylbenzyl)imidazole hydrogen fumarate.

EXAMPLE 12 Injectable formulation In the manner described in the preceding two Extoiples, injectable formulations of 1-(3-(2,4-dichlorophenyl)prop-2-enylj imidazole and 1- [~3- (2,6-dichlorophenyl)prop-2-eny£] imidazole salts were prepared.

EXAMPLE 13 By the method described in Example 1 above the following compounds were prepared:- (a) l-(2,4,6-trimethylbenzyl)imidazole (b) 1-03-(3,4,5-trimethoxyphenyl)prop-2-enyl]imidazole (c) 1-03~(3,4-dimethoxyphenyl)prop-2-enyl] imidazole (d) 1-03-(2-hydroxyphenyl)prop-2-enyljimidazole

Claims (18)

1 'Kb£> ■ft5S3- - 29 - (e) 1-[3-(3-bromophenyl)p^op-2-enyl]imidazole (f) 1- [j3- (4-chlorophenyl) prop-2-enyl[] imidazole (g) 1~ [?~(3/4-dimethylphenyl)prop-2-enyl] imidazole (h) 1-[3-(2-methoxyphenyl)prop-2-enyll imidazole - io- £^5-3-jBTT} What we claim is:-

1. A 1-arylalkylimidazole characterised in that said compound has the formula: \ R) n N-A- CI) N / in which A is a straight or branched alkylene group of from 1 to 3 carbon atoms, or a straight or branched alkenylene or alkynylene group of 2 or 3 carbon atoms, n is an integer which is at least 1, and the or each R substituent, which when n is greater than 1 may be the same or different, is a saturated alkyl group of from 1 to 4 carbon atoms or an unsaturated alkyl group of from 2 to 4 carbon atoms, with the proviso that (a) when A is a methylene or ethylidene group, n is at least 2 when each R is saturated alkyl; I 88693 - 31 - (b) when A is a branched propylene or straight propylidene group, n is at least 3 when each R is saturated alkyl; and (c) when A is unsaturated,R may also be 5 selected from alkoxy of from 1 to 4 carbon atoms5 when n is at least 2(alkylenedioxy of from 1 to 4 carbon atoms; halo; trihalomethyl; hydroxy; carboxyl; a salt of such a carboxyl group; carbo- 6 7 alkoxy; carboaryloxy; carboarylalkyloxy; -NR R 10 or -CONR^R^, in which R^ and R^ may be the same or different and are hydrogen or alkyl of from 1 to 4 carbon atoms, with the further proviso that when n is 1, R is not a saturated alkyl group; or an acid addition salt of such a 15 1-arylalkylimidazole.

2. A 1-arylalkylimidazole as defined in claim 1 characterised in that A is -CI^- or, in the orientation of formula (I), -CH2~CH=CH-.

3. A 1-arylalkylimidazole as defined in 20 claim 2 characterised in that R and n together are 3,4-dimethyl substituents in the benzene ling. 18.8693 -32- j

4. A 1-arylalkylimidazole characterised in that it is selected from 1-(3,4-dimethylbenzyl) imidazole, 1-(2,4-dichlorocinnamyl)imidazole, 1-(2 ,6-dichlorocinnc.myl) imidazole and acid addition salts thereof.

5. 1-(3,4-dimethylbenzyl)imidazole or an acid addition salt thereof.

6. 1-(3,4-dimethylbenzyl)imidazole. 10 15

7. A method of preparing a 1-arylalkylimidazole of the formula defined in any one of claims 1 to 6 or an acid addition ,calt thereof characterised in that one (a) reacts imidazole or a salt thereof with an alkylating agent of the formula Z wherein A, n and R are defined in claim 1 and Z is a leaving group; (b) converts a substituted imidazole of the formula: 0^ N -v u cv T \ ' and Q v E O wherein A, n and R are defined in formula (I) 2 3 4 Q , Q and Q are the same or different, at 1 86693 - 33 - least one being a radical capable of removal by reduction or oxidation, the remaining radical or radicals being selected from a radical having the same or other removable function or hydrogen, y is 0 or an integer, with the proviso that y and n together do not exceed 5; (c) decarboxylates a carboxyimidazole derivative of the formula: wherein A, n and R are defined in formula (I), 12 4 at least one of R , R and R is carboxyl or a 1 2 derivative thereof, and the other or others of R , R 4 and R is or are hydrogen, carboxyl or a derivative . thereof; (d) converts a precursor of the formula: r N-A1-R3 \ — ' wherein ( ^ is l-imidazoline, l-imidazole or ^ 1-pyrazole, A1 is a straight or branched saturated or f unsaturated acyclic hydrocarbon radical which contains no more than 3 carbon atoms and which may include a keto 3 . group and R is wherein R and n are as defined in formula (I), or 1 8 86 A£53 D(i) R may include nitro when A is unsaturated provided '~x 1 3 that at least one of < A and R is other than l-imidazole, a saturated acyclic hydrocarbon group an d -/©V^^n as defined in formula (I) ; (e) alkylates a compound of formula (X): % N-A J (R) ^ 3 n-x (X) 10 wherein A, R and n are as defined for formula (I) and x is an integer less than or equal to n with a compound of formula RZ"^ wherein R is an alkyl group as defined for formula (I) and Z is a leaving group; (£) cyclises a compound of formula (XI): % NH-A- \ 2 CHX (XI) wherein A, R and n are as defined for 2 formula (I) and X is a leaving group; (g) reacts a compound of formula (XII): HN = CH NH-A (XII) 1 8 -3f- A553 B(ifr wherein A, R and n are as defined for formula (I) with a compound of formula (XIII): X.5 Jt4 ^ch-<C (XIII) 3 3 wherein either of X and Y is a leaving 3 3 group and the other is hydrcgen or X and Y are both halo or together form a keto group or an acetal derivative thereof, and X4 and Y4 are as 3 3 defined for X and Y , being the same as or different from X^ and Y^• or (h) reduces an imino salt of formula (Xllla) Y J N=C-A (X") (Xllla) 10 wherein R and n are as for formula (I), 2 X is an ai>ion, A is a chemical bond or a straight or branching, saturated or unsaturated acyclic hydrocarbon radical, which may include a keto group, 3 A is hydrogen or a saturated. 15 or unsaturated acyclic hydrocarbon radical, which may include a keto group, with the proviso that \ 8 86 3*3;- -7- - ftS-D5 D(i>;3;and A together contain no more than 2 carbon atoms.;

8. A pharmaceutical formulation comprising a 1-arylalkylimidazole or a pharmaceutically;5 acceptable addition salt thereof as defined in any one of claims 1 to 6 in association with a pharmaceutically acceptable carrier therefor.;

9. A pharmaceutical formulation as claimed in claim 8 which is orally injestible.;10

10. A formulation as claimed in claim 9 in the form of a tablet or capsule.;

11. A formulation as claimed in claim 8 in the form of a parenterally acceptable injectable solution or suspension.;15

12. A tablet of 1-(3,4-dimethylbenzyl)imidazole or a pharmaceutically acceptable acid addition salt thereof.;\ 8;37';-JS - Afr53 B ( i);

13. A capsule of 1-(3,4-dimethylbenzyl) imidazole or a pharmaceutically acceptable acid addition salt thereof.;

14. A formulation as claimed in either of;5 claims 12 or 13 wherein the imidazole is present in an amount of from 50 to 600 mg.;

15. A method of preparing a pharmaceutical formulation as defined in claim 8 comprising the admixture of the imidazole or its salt with the;10 pharmaceutically acceptable carrier.;-33-;

16. A method for the treatment, or prophylaxis of a thrombo-embolic disorder in a mammal or mammalian tissue, excluding man or human tissue, comprising the administration to the mammal or the tissue of a 1-arylalkylimidazole 5 as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof.;

17. A method as claimcd in claim 16 wherein the compound is administered orally.;

18. A method as claimed in claim 16 wherein 10 the disorder is myocardial infarction.;"9. A method as claimed in claim 16 wherein the disorder is a thrombus.;20. A method as claimed in claim 16 wherein the disorder is ischaemic peripheral vascular 15 disease.;21. A method as claimed in claim 16 wherein the disorder is cerebro-vascular thrombosis.;■ o ^ .''0 7;; boo; j;- 39 -;/;22. A method as claimed in any Qne of claims 16;to 21 wherein the 1-arylalkylimidazole is l-(3,4-dimethylbenzyl)imidazole or a pharmaceutically acceptable acid addition salt thereof.;5 23. A 1-arylalkylimidazole or an acid addition salt thereof substantially as.hereinbefore described in any one of Examples 1 to 4 and 13.;24. A method of preparing a 1-arylalkylimidazole as defined in claim 1 substantially as hereinbefore;10 described in any one of Examples 1 to ,4 and 13.;25. * A pharmaceutical formulation of a 1-arylalkylimidazole substantially as hereinbefore described in anY one °f Examples 6 to 12. DATED Tl.TSttrK DAY A. J. F r; K f; coM AC|m3 fCii 7A:-?L!Cs\l-i7S