IE47650B1 - Pharmaceutical formulations comprising imidazole derivatives and salts - Google Patents

Description

The present invention relates to pharmaceutical formulations comprising imidazole derivatives and salts thereof, and to the use of these formulations In medicine.

Thromboxane A2 (TXA2), a potent stimulator of blood platelet aggregation, is produced in platelets, from the prostaglandin endoperoxides PGG^ and PGH.,. Prostacyclin (PGI2), which has potent anti-aggregatory activity, is also produced (in blood vessel walls) from PGG2 and PGH2 and it has been suggested that a balance hetween the production of TXA2 and PGI2 is the controlling factor in thrombus formation. It would, in consequence, be desirable in the treatment or prophylaxis of thrombo-embolic disorders to be able to selectively inhibit TAX2 synthetase, thereby facouring the · production of the anti-aggregatory agent PGI2· Imidazole and 1-methylimidazole are known to provide some degree of inhibition of the enzymic conversion of the endoperoxides (PGG2 and PGH2) to thromboxane A2 by platelet microsomes (Moncada et al., Prostaglandins. 13/4, 611-618, 1977). Certain 1-n-alkylimidazoles, especially 1-n20 dodecylimidazole and its higher homologues have heen 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-substituted imidazoles of formula (IA), and acid addition salts thereof. The compounds of formula (IA) and 5 their salts are hereinafter referred to as the active compounds.

Accordingly the present invention provides a pharmaceutical formulation which comprises an imidazole of formula (IA) (IA) wherein (I) A is a straight or branched alkylene or alkynylene group having 1,2,3 or 4 carbon atoms, and R is a naphythyl, tetrahydronaphthyl, heterocyclyl (preferably with the proviso that the hetero15 eyelyl group is not formed by a methylenedioxy group attached to adjacent positions on a benzene ring attached to the group A), arylthio, arylalkylthio, aryloxy, arylalky loxy, arylalkylcarbonyl, alkyloxy, alkylthio group or a cycloalkyl or cycloalkenyl group of from 4 to 9 carbon atoms substituted by a group other than a hydrocarbon group, (II) A is an -S02- group, and R is an aryl or heterocyclyl group, (iii) A is a chemical bond and R is a heterocyclyl or 2, 3-dimethyIphenyl group, or (iv) A is a straight or branched alkylene group having 1, or 3 carbon atoms and R is halo-substituted phenyl group providing that:a) where A is- a methylene group, R does not represent a mono- or dichloro-phenyl group or the 4-fluorophenyl group, and b) where A is an ethylene (-(CH2)2-) group, R does not 10 represent a 2- or 4-chlorophenyl or 2, 4- or 3, 4-dichlorophenyl group; or a pharmaceutically acceptable acid addition salt of such an imidazole, and a pharmaceutically acceptable carrier for the imidazole or salt thereof.

Preferably in the compounds of formula (IA) the group A is 15 methylene (-CH2-1.

In the compounds of formula (IA) the various groups R are preferably substituted by one or more hydroxy, alkloxy, halo or alkyl group(si, preferably hy one or more hydroxy, methoxy, chloro, bromo or methyl group(s).

Particularly preferred compounds for use in the pharmaceutical formulations are: 1-(1-naphthyImethyl)imidazole and its salts, 1-(2,3-dimethylphenyllimidazole and Its salts, l-(2-hromobenzyl)imidazole and its salts, l-(3-bromobenzyl)Imidazole and its salts, and 1-f3-(2,4-dichlorophenyl)propyimidazole and its salts. 47680 - 5 Of the compounds of formula (IA) those of formula (1) are novel: (1) wherein (1) A is a straight or branched alkylene or alkenylene group having 1,2,3 or 4 carbon atoms, and R is selected from: (a) a naphthyl group of formula wherein the two n's together are 0 or an integer of from 1 10 to 3, and the or each B, which, when the two n's together are greater than 1, may be the same or different, is halo, or alkyl or alkoxy of from 1 to 3 carbon atoms (b) a tetrahydronaphythyl group, (c) a heterocyclyl group, with the proviso that when the 15 heterocyclyl group is 2-pyridyl, 1-methylbenzimidazole-2yl, 2- or 3-indolyl, 1-piperindinyl or 1-morphonlinyl, the group A has 3 or 4 carbon atoms and, preferably, with a second proviso that the heterocyclyl group is not formed by a methylenedioxy group attached to adjacent positions on a benzene ring attached to the group A; (d) an arylalkylcarbonyl group; (e) an ethoxy group (when A is a straight alkylene group), (f) an alkylthio group; or (g) a cycloalkyl or cycloalkenyl group of from 4 to 9 carhon 5 atoms substituted by a group other than a hydrocarbon group; or (ii) A is an -S02- group, and R is an aryl or heterocyclyl group, (iii) A is a straight or branched alkylene group having 1, 2 or 3 carbon atoms and R is a halophenyl group providing that:a) when A is a methylene group, R does not represent a mono- or di-chloro-phenyl group; b) when A is an ethylene group, R does not represent a 2- or 4-chlorophenyl or 2, 4- or 3, 4-dichlorophenyl group; and c) when A is a branched propylene group, R does not represent a 2, 4-dichlorophenyl group or an acid addition salts of such an imidazole.

In these compounds of formula Cl) the group A is preferably methylene.

Preferably the group R in the compounds of formula Cl) is, where possible, substituted by one or more hydroxy, alkyloxy, halo or alkyl group(s), preferably by one or more hydroxy, methoxy, chloro or hrora, or methyl group(s). - 7 Preferred compounds of formula (1] are: 1-(1-naphthylmethyl]imidazole and its salts, 1-(2-bromobenzyl]imidazole and its salts, l-(3-bromobenzyl)imidazole and its salts, and 1-/3-(2,4-dichlorophenyl]propy_l7 imidazole and its salts.

The compounds of formula (1) are described and claimed in our copending Application No. 177/79.

Known compounds of formula (IA) that may be used in the pharmaceutical formulation include 1-skatolylimidazole, 1-(2-pyridyl)imidazole, 1-(3-pyridyl)imidazole, 1-(4-pyridyl)imidazole, 1- (4-(2-hydroxymethyl)pyridyl)Imidazole, 1-(2-(3-cyano)pyrimidylimidazole, 2- (imidazol-l-yl)-1-methylbenzimidazole, 1- (2-hydroxy naph.tE-1-ylmethyl) imidazole, 1-(2-pyridylmethyl)imidazole, 1-/2- (2-pyridyl) ethyl7i™i 1-/2-(4-methyl-2-pyrIdyl]ethyl7imidazole, 1-/7-(4,6-dimethyl-2-pyridy1)ethy l/imidazole, 1-/7-(6-methyl-2-pyridyl)ethyl/imidazole, 1-(l-methylindon-2-yImethyl]imidazole, 1-(1-piperindinylmethyl)imidazole, 1-(1-morpholinylmethyl]imidazole, 1-/7- (l-morphonlinyl)ethylj/imidazole, and their pharmaceutically acceptable acid addition salts. . 47650 - 8 The skatolyland 2 - hydroxynaphthalene derivatives may be made by the method described By G. Decodts and M. Waksekman in Compt. Rend. C 266 (15J 1168-70 (1968). The 2-pyridylethyl compounds may he made by the method of E. Profft and W. Georgi, Ann. 643, 136-44, (1961). The 2-pyridylmethyl compound may be made By the method of R. J. Sundberg et al, J. Heterocycl. Chem. 14(7), 1279-81 (1977). The benzimidazolyl compound may Be prepared by the method of Kolodyazhaya, S.N. et al, Khim. Geterotsiki. Soedin. 1970(2) 238-44.

The peiperidinyl compound may be prepared by the method of Fred. B. Stocker et al. J. Org. Chem. 1970, 35(4), 883-7) the 1-morpholinylmethyl compound may also be made by the same method. The 1-morpholinylethyl compound is known from French Patent Specification No. 1486817.

In contrast to imidazole and 1-methy1-imidazole the compounds of formulae (1) and (IA) are more potent inhibitors of TXAj synthetase. Many of the compounds are also more selective in their action in not inhibiting other antiaggregatory prostaglandin-generating enzymes. The compounds of formulae (1) and (IA) also do not produce the side effects found with Imidazole upon in vivo administration. The compounds of formulae (1) and (IA) are further capable of inhibiting platelet aggregation in vivo and also are capable of disaggregating platelet clumps.

Imidazoles of formulae (1) and (1A1 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 - 9 these methods preferably comprise (a) linking the imidazole ring to the remainder of the molecule; (b) converting a precursor molecule by elimination of a functional group from the imidazole or aromatic ring; pr (c) formation of the desired compound from a corresponding pyrazole, imidazoline, or other unsaturated analogue.

Processes for the preparation of compounds of formula (1) are described in our copending Application No. 177/79.

The imidazoles of formula (1) or tlAl may be used in conjunction with a phosphodiesterase inhibitor, which provides a further, synergistic increase in effect, as it acts against platelet aggregation by a different pathway.

Suitable phosphodiesterase inhibitors for use in - 5//15 furo - /3,4-7 pyrazolo /3,4-b7 pyridine - 5 - one; active compounds include as such or a pharmaceutically acceptable salts :(a) Xanthine derivatives such as:Theophylline (3,7-dihydro-l, 3-dimethyl-lH-purine-2, 6-dioneJ, Caffeine (3,7-dihydro-l, 3, 7-trimethyl- IH purine 2, 6-dione): and Aminophyline (adduct of Theophylline and 1, 2-ethanediamine (2:1)).

Isoquinoline derivatives, for example:papaverine (1-/C3,4-dimethoxyphenyl)methyl/ -6,7dimethoxylsoqulnoline), (bl Derivatives of pyrimido (5,4-d) - pyrimidine, for 5 example:Dipyridamole (2,3', 2 , 2 ’ - (.4,8-dipiperidinopyrimido /5,4-d7 pyrimidin - 2, 6-diyldinitrilo)-tetraethanol)and its salts, (cl Derivatives of thieno /3,2-/7 pyridimine, for example; N-/4-(4-morpholinyl)thieno/3,2-/7 pyrimidin-2-y_l7-l, 2-ethanediamine. (d) Derivatives of pyrazolo /3' ,4' :2, /7 pyri'do- /4,5-/7 - /1,/7 benzodiazepin -6-(3 //) one, for example:3- Ethyl-7, 12-dihydro-7, 12-dimethylpyrazolo'-/4',3^:5,6/ purido /4,3-57-/1,5/ benzodiazepin-6-(3 //) - one, (e) Derivatives of 1 // - or 2 // - pyrazolo' /3,4-57 pyridine, for example:_ 4- (Butylamino) - 1 - ethyl- 1//- pyrazolo /3,4-57 pyridine-5-carboxylic acid ethyl ester, and 2- methyl6-phenyl-4-(L-piperidinyll-2 // - pyrazolo - /3,4-57 pyridine. (fl Derivatives of 5 // - furo /J,4-e7 pyrazolo - /3,4-/7 pyridine - 5 - one, for example:_ 4-(Butylamino)-1-ethy1-1, 7-dihydro-7-hydroxy-5 // - furo /3,4-3/ pyrazolo /3,4-/7 pyridine - 5 - one, and (g) Derivatives of 1-(2 // ) - naphthalenone, for example :2-(dimethylamino)methyl-3, 4-dihydro-7-methoxy-lC2 //) naphthalenone or its salts e.g. its 1:1 hydrochloride.

The active compounds are particularly useful in the treatment and/or prophylaxis of thromboembolic disorders in mammals, including man. It is to be understood that the term thrombo-embolic disorders includes those disorders whose etiology is associated with platelet aggregation.

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 thrombosis; 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 portions, 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. - 12 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, and the nature of the condition under treatment. m 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 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. preferably 100 to 300 mg for example 150 mg given say three times a day.

While it is possible for the 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 therefore and optionally other therapeutic ingredients.

The carrier(s) must be acceptable in the sense 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 he presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound (in the form of the base or a pharmaceutically acceptable acid addition salts) with the carrier which constitutes one or more accessary 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) Pharmaceutical formulations containing the imidazoles of formula 1(A) or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.

I I ί (b) Method of preparing the pharmaceutical formulations j containing the imidazoles of formula 1(A) or a pharmac- j I eutically acceptable acid addition salt thereof, ί i ί - 14 (c) Pharmaceutical formulations comprising a 1-substituted imidazole of formula (IA) for use in the treatment or prophylaxis of a thrombo-embolic disorder in a mammal.

The following Examples are provided by way of an illustration 5 of the present invention and should in no way he construed as constituting a limitation thereof. All temperatures are given in degrees Celsius. The preparation of novel imidazoles of formula (1) is described in our said copending Application.

FORMULATION EXAMPLES' Example A - Tablet Formulation Imidazole of formula CD as a solid or 150 mg a solid salt thereof Starch 25 mg Polyvinylpyrrolidone 2 mg Magnesium stearate 3 mg The imidazole or 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 are sieved 1000 μ, dried, sieved again and the magnesium stearate added. The mixture is then compressed into tablets.

In this manner, tablets of 1—(1-naphthyImethyl) imidazole (as a salt) were prepared. - 15 Example Β - Tablet Formulation Tablets (150 mg) of the imidazoles or salts described in the preceding Example are prepared as in the same manner from the following ingredients: The Imidazole Compound (as such or as a salt, 150 mg Lactose 100 mg Starch 30 mg Polyvinylpyrrolidone 2 mg Magnesium stearate 3 mg In the preparation, the lactose is blended with the starch.

Example C - Tablet Formulation Tablets (100 mg) of the imidazoles or salts of Example A are prepared in the same manner from the following ingredients : The Imidazole Compound (as such or as a salt) 100 mg Sodium Starch Glycollate 10 mg Polyvinylpyrrolidone 2 mg Magnesium stearate 3 mg Example D - Tablet Formulation Tablets (150 mg) of the imidazoles or salts of Example A are prepared in the same manner from the following ingredients, except that the starch, pregelled starch and imidazole compound are all blended together prior to granulation: 656 The Imidazole Compound (as such or as a salt) 150 mg Starch 25 mg Pregelled starch 5 mg 5 Magnesium stearate 3 mg Example E - Injectable Formulation Imidazole Compound (or salt of formula (1)) 15.0 g Lactic Acid B.P. q.s. to pH 3.0 Water for Injections B;.P. to 100.0 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 pm.

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

Each 1 ml ampoule supplies 150 mg of the imidazole compound e.g. 1-(1-naphthylmethyl) imidazole.

Example F - Injectable Formulation Imidazole Compound or salt of formula (1) 15.0 g Citric Acid B.P. q.s. to pH 3.0 Chlorocresol 0.1 g Water for Injections to 100.0 ml Suspend the compound in % the final volume of Water for Injections. Add sufficient citric acid as a 10% solution in Water for Injections to dissolve the compound and 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 jun.

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 ml of the compound e.g. 1-(1-naphthylmethyl)imidazole.

Biological Results Example 1 Horse platelets were prepared from whole horse blood hy differential centrifugation. Approximately 106 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 mM of arachidonic acid containing 106 disintegrations per minute (DPMJ 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 chroanotography on silica gel with, chloroform/methanol/acetic acid/water (90:8:1:0.81 as a developing solvent. The amount of thromboxane produced was measured by scraping the radioactive zone corresponding to thromboxane B2 and estimating the radioactivity in a liquid scintillation counter.

The concentration of active compound to reduce the enzyme activity by 50% (ED50J. was established. The results are shown in Table A.

The selectivity 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 Table A in which 0 indicates no selectively; + low selectivity; ++ medium selectivity; +++ high selectivity; ++++ exceptionally high selectivity; ND not determined. - 19 TABLE A Compound (Reference Compound) (Imidazole) (1-Methylimidazole) 1-/2-(1-Naphthyl) ethylj'iinidazole 1-(1-NaphthyImethyl)imidazole 1- (2-tetrahydrofuranyImethyl) imidazole 1-(1,4 benzodioxan-2-yImethyl) imidazole 1-(2-hydroxy-2-phenylethyl) imidazole 1-(2-Ethylthioethyl)imidazole 1-(2,3-dimethyIphenyl) imidazole 1-(3,4-dibromocyclohexyImethyl) imidazole 1-(phenylthiomethyl!imidazole 1-(3-pyridyImethyl)imidazole 1-(5-chloro-2-thienyl) imidazole 1-(2-chloro-4,5-methylenedioxybenzyl)imidazole 1(Quinolin-2-yImethyl)imidazole pg/ml > 500 >200 /-v* 5 2*5 > 100 -7 //10 /-10 ~7 Selectivity to + ++ ++ ++(+).

+++ + ND ND ++ +++ ++ +++ ++ ++ (+) +(+) „ 476S0 - 2Q - CompoundED50 (Reference Compound) pg/ml Selectivity 1-(2-chlorobenzy1) imidazole 0.5 ++ 1-(2,4-dichlorobenzyl] imidazole 2-8 ++(+) 1- (2-bromobenzyl) imidazole 2.4,0.5 +++(+1 1-(4-bromobenzyl)Imidazole 4.6,15 (+1 1- (3-bromobenzyl) imidazole 14.5,17 +++ 1-(3-(2,4-dichloroph.enyl) propyl)imidazole 0.5 ++

Claims (22)

1. A pharmaceutical formulation which comprises an imidazole of formula (IA) wherein (i) (ii) (iii) R-A-N (IA) A is a straight or branched alkylene or alkenylene group having 1,2,3 or 4 carbon atoms, and R is a naphthyl, tetrahydronuphthyl, heterocyclyl, arylthio arylalkyIthio, aryloxy, arylalkyloxy, arylalkylcarbonyl, alkyloxy, alkylthio group or a cycloaikyl or cycloalkenyl group of from 4 to 9 carbon atoms substituted by a group other than a hydrocarbon group, A is an -S0 2 ~ group, and R is an aryl or a heterocyclyl group, A is a chemical bond and R is a heterocyclyl or 2, 3-dimethyl-phenyl group, or (iv) A is a straight or branched alkylene group having 1,

2. Or 3 carbon atoms and R is a halo-substituted phenyl group providing that:20 476S0 - 22 (a) where A is a methylene group, R does not represent a mono- or di-chloro-phenyl group or the 4-fluorophenyl group, and (£>) where A is an ethylene C-CCHjlj-) group, R does not 5 represent a 2- or 4-chlorophenyl or 2, 4- or 3, 4-dichlorophenyl group or a pharmaceutically acceptable acid addition salt of such an imidazole, and a pharmaceutically acceptable carrier for the imidazole or salt thereof. 10 2. A formulation according to claim 1 wherein, in the imidazole of salt thereof, the group R is substituted by one or more hydroxy, alkyloxy, halo or alkyl groups,

3. A formulation according to claim 2, wherein, In the imidazole or salt thereof, the group R is substituted by 15 one or more hydroxy, methoxy, chloro, bromo or methyl groups.

4. A formulation according to any one of claims 1 to 3 in which A in formula (IA) Is methylene.

5. A formulation according to claim 1 wherein the 20 imidazole is 1-Cl-naphthylmethyliImidazole or an acid addition salt thereof. - 23

6. A formulation according to claim 1 wherein the imidazole is l-(2,3-diroethylphenyl) imidazole or an acid addition salt thereof.

7. A formulation according to claim 1 wherein the 5 imidazole is 1-(2-bramobenzyl)imidazole or an acid addition salt thereof.

8. A formulation according to claim 1 wherein the imidazole is 1-(3-bromobenzyl)imidazole or an acid addition salt thereof.

9. A formulation according to claim 1 wherein the imidazole is a compound of formula - (1) wherein (i) A is a straight or branched 2, 3 or 4 carbon atoms, and R is selected from:(a) a naphthyl group of formula alkylene group having 1, (B) CB) 47 6 5 0 - 24 wherein the two n's together are 0 or an integer of from 1 to 3, and the or each H, which, when the two n's together are greater than 1, may he the same or different, is halo, or alkyl or alkoxy of from 1 to 3 carhon atoms, 5 (hl A tetrahydronaphthyl group, (c) A heterocyclyl group, with the proviso that when the heterocyclyl group is 2-pyridyl, 1-methyl-benzimidazol—2— yl, 2-or 3-indolyl, 1-piperidinyl, or 1-morpholinyl, the group A has 3 or 4 carhon atoms;

10. (d) an arylalkylcarbonyl group; (e) an ethoxy group Cwhen A is a straight alkylene groupl, (fl an alkylthio group, or (gl a cycloalkyl or cycloalkenyl group of from 4 to 9 carbon atoms substituted hy a group other than a hydrocarbon 15 group; or (ii) A is an -S0 2 ~ group, and R is an aryl or heterocyclyl group, (iii) A is a straight or branched alkylene group having 1, 2o 2 or 3 carbon atoms and R is a halophenyl group providing that;— a) when A is a methylene group, R does not represent a mono- or di-chloro-phenyl group, b) when A is an ethylene (—(CH 2 ) 2 -) group, R does not 25 represent a 2- or 4-chlorophenyl or 2, 4- or 3, 4dichlorophenyl group, and c) when A is a branched propylene group, R does not represent a 2, 4-dichlorophenyl group or an acid addition salts of such an imidazole. - 25 10. A pharmaceutical formulation comprising 1-/3-(2, 4-dichlorophenyl!propyX/imidazole or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier for the imidazole or salt thereof. 5

11. A formulation according to any one of claims 1 to 10 which is orally ingestable.

12. A formulation according to claim 11 in the form of a tablet or capsule.

13. A formulation according to any one of claims 1 to 10 10 in the form of a parenterally acceptable injectable solution or suspension.

14. A formulation according to claim 12 wherein the imidazole is present in an amount of from 50 to 600 mg.

15. A method of preparing a pharmaceutical formulation 15 according to any one of claims 1 to 14 which comprises admixing the imidazole or Its salts with the pharmaceutically acceptable carrier.

16. Pharmaceutical formulations according to any of claims 1 to 14 for use in the treatment or prophylaxis of 20 thrombo-embolic conditions in a mammal.

17. Formulations according to claim 16 for use In the treatment or prophylaxis of myocardial infarctions, - 26 cerebro-vascular thrombosis, ischaemic peripheral vascular disease or post-operative thrombosis in a mammal.

18. Formulations according to claim 10 for use in the treatment or prophylaxis of thrombo-embolic conditions in 5 a mammal.

19. A method of treatment or prophylaxis of a mammal, excluding man, which comprises the step of administering an effective amount of a formulation as claimed in any of claims 1 to 14. 10

20. A formulation according to any one of claims 1 to 14 prepared by a method according to claim 15.

21. A formulation substantially as hereinbefore described in any one of the formulation Examples A to F.

22. A method of treatment or prophylaxis substantially 15 as hereinbefore described.