CA1137481A - N-benzyl-imidazoles as selective inhibitors or the thromboxane synthetase enzyme, pharmaceutical compositions thereof and process for their preparation - Google Patents

Abstract

ABSTRACT
N-Benzyl-imidazoles of the formula:
---(I) wherein R1 is hydrogen, C1-C4 lower alkyl, C1-C4 lower alkoxy or halogen, Y is (CH2)n where n is an integer of from 1 to 4, or a group of the formula:

Description

113~481 This i~vention relates to certain i~idazole derivatives and in particular to a series of N-benzyl-~midaæoles being sub-stituted in the phenyl ring with acidic and polar groupings.
Such compounds are able to selectively inhibit he action of the thromboxane synthetase enzyme without significantly inhibiting the action of the prostacyclin synthetase or cyclo-oxygenase enzymes.
The compounds may thus be useful in, for ex mple, the treatment of thrombosis, ischaemic heart disease, stroke, transient ischaemic attack, migraine and the vascular complications of diabetes.
_ ~ __ 10 _ ____ According to the invention ',here are provided compounds of the general formula: Rl ~ - C~2 ~ ~~- (I) O--Y--Z
wherein R is hydrogen, Cl-C4 lower alkyl, Cl-C4 lower alkoxy or halogen, Y is (C~2)n where n is an integer of from 1 to 4,or a group of tne formula:

--C~ ' Z is C02R , CON~R , CON(R )2' CN or tetrazolyl, R is hydrogen or Cl-C4 lower alkyl, R is hydrogen, Cl-C4 lower alkyl or C2-C4 lower alkanoyl, each R is Cl-Ca lower alkyl or two groups R together with the nitrogen atom to which they are attached form ~ pyrrolidino or piperidlno group, -' 1137~8~

and the pharmaceutica'ly acceptable acid addition salts thereo' and bioprecursors therefor.
The invention zlso proviaes a method of inhibitinq the action of the thromboxane synthetase enzyme in an animal, including a human being, without significantly inhibiting the action of the prostacyclin synthetase or cyclo-oxygenase enzymes, which comprises administering to the animal an effective amount or a comFound of the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt together with a pharmaceutically acceptable diluent or carrier.
The invention further provides a compound o. the formula (I), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising such a compound or~sal~t together with a phzrmaceutically acceptab ~ iluent or carrier, for use in reating an animal, including a human being, to inhibit the action of the thromboxane synthetase enzyme without signi~icantly inhibiting the action of the prostacyclin synthetase or cyclo-oxysen2se enzymes.
The invention also includes 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 pharmaceutically acceptable bioprecursors of compounds of the formula (I). For the purpose of this specification the term "pharmaceutically acceptable bio-precursor" of a compound of the formula (I) means a compour.d havinga structural formula different from the compounds of the formula (T) but which nonetheless, upon administration to an animal or human being, is converted in the patient's body to a compound of the formula (I).

il37~1 Pharmaceutically acceptable acid addition salts oî the compounds of the invention are salts with acids containing pharma-ceutically acceptable anions, e.g. the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate and _-toluene sulphonate salts.
In this specification "halogen" indicates fluorine, chlorine, bromine or iodine. Aikyl and alkoxy groups having 3 or more carbon atoms and alkanoyl groups having 4 carbon atoms may be straight or branched chain.
Preferred compounds of the invention are those in which R is hydrogen or methyl, and Z is a group CO2H or C~N~2. In one preferred group of compounds Y is a C1-C3 alkylene chain particul2rly a methylene group. In a further preferred group of compounds Y is a benzyl sroup, particularly a 4-substituted benzyl g~oup.
Particularly preferred compounds include:

2-(1-Imidazolylmethyl)-4-methyl-pnenoxyacetic acid 4-~2-(1-Imidazolylmethyl)-4-methyl-phenoxy3butyramide 4- ~2-(1-Imidazolylmethyl)-4-methyl-phenoxymethy~ benzoic acid 4-(1-Imidazolylmethyl)phenoxyacetic acid 4-(1-Imidazolylmethyl)phenoxyacet2mide and

3-(1-Imidazolylmethyl)phenoxyacetic acid.
The compounds of the invention may be prepared by a number of different routes. In one process according to the invention the compounds of the formula (I) may be prepared from a phenol of the formula:

~137481 ~ - CR2 ~ Rol --- (II) where R is as previously defined, by first reacting with an al~ali metal hydride and then reacting with a halide of the formula:
Hal-Y-Z --- (III) where Y and z are as previously de~ined and ~al means chlorine, bromine or iodine.
The reaction is conveniently performed by adding one equivalent of the alkali metal hydride, e.g. sodium hydride to a solution of the phenol (II) in a dry inert organic solvent, e.g.
N,N-dimethylformamide. The hydride is conveniently used ~n the form of a dispersion in a mineral oil The reaction mixture is stirred at room temperature and the initial reaction is generally complete within one or two hours. If the reaction is slow, however, the reaction mixture may be heated, e.g. at 100 C for a further period of 30 - 60 minutes, to ensure that all the sodium -hydride has reacted and evolution of hydrogen has ceased.
The solution is cooled and the halide (III) is added, preferably in an amount of 1 equivalent or a slight (e.g. 10 ~) excess. The reaction may be allowed to proceed to completion at room temperature but it is sometimes advantageous to heat the reaction mi~ture, e.g. at 100 C to accelerate the reaction.
The time ta~en for the reaction to go substantially to completion will naturally depend on the precise conditions and temperature used and on the nature of the reactants.

~.37~81 we have found, however, that even with the less reactive compounds a period of 9 hours at 100 C is generally sufficient to ensure that the reaction is substantially complete. The reaction product is worked-up in a conventional manner, e.g. by removal of the S solvent under vacuum or by pouring the reaction mixture into water to precipitate the product. The crude product is purified by solvent extraction and washins and may be further purified, if desired, by crystallisation or chromatography.
Naturally certain of the groups Z may be obtained by chemical transformation reactions and these possibilities will be well known to those skilled in the art. Thus for example the compounds of the formula (I) where Z is a carboxyl group may be obtained via hydrolysis of the corresponding esters where Z is a sroup C02R anc R is a lower alkyl group. Alternatively reat-ment of the esters with ammonia gives the amides where Z is CON~2.The amides may alternatively be prepar æ via hydrolysis of the compound of formula (I) wherein Z is a cyano group usins concen-trated hydrochloric acid or, in the case of aromatic ~itriles, alkaline hydrogen peroxide. Acid hydrolysis of the nitriles can also be used to yield the corresponding acids where Z is a carboxyl group. The acids may be further converted to a varie.y of deri-vatives by conventional methods, thus formation of _he acid chloride e.g. by reaction with thionylchloride followed by reaction with ammonia or a Cl-C4 lower alkylamine gives compounds where Z is CON~R and R is hydrogen or lower alkyl respectively, or alternatively reaction of the acid chloride with a di-lower alkylamine or with pyrrolidine or piperidine gives compounds where z is CON(R )2 ~137'481 ~gain the acid may be reacted with N,N-carbor.yldiimidazole and the adduct reacted with a lower alXylamine or amide to give N-substituted amido products.
Compound where Z is tetrazolyl ar~ prepared from the S cyano derivative by reaction with sodium azide and ammonium chloride. All these reactions are quite conventional and conditions for their performance will be well ~nown to those skilled in the art.
The starting materials of formula (II) are generaily known compounds obtainable by conventional techniques. Thus they may prepared from a phenol of the formula:

. --- - - ~/ \) ~ R

where ~1 is as previously defined and Q is a leaving group, e.q. a dimethylamino group or a halogen atom, by reaction with imidazole or, in the case of the meta-hydroxy-benzylimidazoles, by reaction with the sodium salt prepared by reaction of imidazole with sodium hydride.
The compounds o' formula (I) have been found to selectively inhibit the action of the thromboxane synthetase enzyme without significantly affecting the action of the prostacyclin synthetase or cyclo-oxygenase enzymes.

1~3~48~

Thus the comEounds are of value in the treatment of a variety of clinical conditions which ~re cnaracterised by an inbalance of prostacyclinJthromboxane A2. For the reasons given below these conditions may include thrombosis, ischaemic heart disease, stroke, transient ischaemic attack,migraineand.nevascularo~mplic2tionsofciabetes.
Research work has established that in most tissues the major product of the arachidonic acid metabolism is either of two unstable substances, thromboxane A2 (TxA2) or prostacyclin (PGI2).
(Proc. Nat. Acad. Sci. U.S.A., 1975, 72, 2994, Nature, 1976, 263, 663, Prostaglandins, 1976, 12, 897). In most cases the prosta-glandins P OE 2' PGF2 and PGD2 are comparatively minor by-products in this bio-synthetic pathway. The discovery of thromboxane A2 and prostacyclin has sisnificantly increased our understanding o. vascular homeostasis, prostacyclin for instance is a powe-ful vasodilator and inhibitor of platelet aggregation, and in ,nis last respect is the most potent endogenous substance so far dis-covered. The prostacyclin synthetase enzvme is located in the endothelial layer of the vasculature, and is fed by endope-oxides released by blood platelets coming into contact with the vessel wall. The prostacyclin thus produced is important for prevention of platelet deposition on vessel walls. (Prostaglandins, 1976, 12, 685, Science, 1976, 17, Nature, 1978, 273, 765).
Thromboxane A2 is synthetised by the thromboxane SyD-thetase enzyme which is located in, for example, the blood plate-lets. Thromboxane A2 is a powerful vasoconstrictor and pro-aggregatory substance.

~137481 g As such its actions are in direct opposition to those of prosta-cyclin. If, for any reason, prostacyclin formation by the vas-culature is impaired, then the endoperoxides produced by platelets coming into contact with the vessel wall are converted into 'hrom-boxane, but are not converted effectively into prostacyclin (Lancet,1977, 18, Prostaglandins, 1978, 13, 3). Alteration of the prosta-cyclin/thromboxane balance in favour of the latter substance could result in platelet aggregation, vasospasm (Lancet, 1977, 479, Science, 1976, 1135, Amer. J. Cardiology, 1978, 41, 787) and an increased susceptibility to atherothrombosis (Lancet (i) 1977, 1216).
It is also known that in experimental atherosclerosis prostacyclin generation is suppressed and thromboxane A2 production is enhanced (Prostaglandins, 1977, 14, 1025 and 1035). Thus thromboxane A2 has been implicated as the causitive agent in variant angina, ~yocardial infarction, sudden carciac death and stroke (Thromb. ~aemostasis, 1977, 38, 132). Studies in rabbits have shown tha. ~CG changes typical of these conditions were produced when freshly pre~ared thromboxane A2 was injected directly into the animal's hea-t (Biochem. aspects of Prostaglandins and Thromboxanes, ~ditors, N. Kharasch and J. Fried, Academic Press 19?7 page 189). This technique is considered to represent a unique animal model of the heart attacks of coronary patients and has been used to show that administration of a compouDd believed to antagonise the effects of thromboxane A2 protects the rabbits from the adverse conse-quences of thromboxane A2 injection.
Another area where a PGI2/TxA2 imbalance is considered to be a contributory factor is that of migraine.

~3~9L~

The migraine headache is associ~ted with changes in intra and extra-cerebral blood flow, in particular a pre-headache reduction of cerebral blood flow followed by clilatation in both vascular areas during the headache phase.
Prior to the development of the headache, blood levels of S-hydroxytryptamine are elevated, and this suggests the occurrence of ln vivo aggregation and release of the amine from the platelet stores. It is known that the blood platelets of migraine patients are more prone to aggregate than are those of normal individuals (J. Clin. Pathol., 1971, 24, 250, J. ~eadache, 1977, 17, 101). Furthermore, it has now been postulated that not __ _ only is an abnormality of platelet function a major factor in the pathogenesis of migraine attacks but it is in fact their prime cause (Lancet (i), 1978, 501). Thus a drug that selectively modifies platelet function to inhibit thromboxane A2 formation could be of considerable benefit in migraine therapy.
Abnormalities of platelet behaviour have been reported in patients with diabetes mellitus (Metabolism, 1979, 28, i94, Lancet, 1978 (i) 235). Diabetic patients are known to be particularly sus-ceptible to microvascular complications, atherosclerosis and throm-bosis and platelet hyper-reactivity has been suggested as the cause of such angiopathy. Diabetic platelets produce elevated amounts of TxB2 and malondialdehyde (Symposium "Diabetes and Thrombosis -Implications for Therapy", ~eeds U.K., April 1979). Also it has been shown that in rats with experimental diabetes vascular prostacyclin production is impaired and TxA2 synthesis from the platelets is elevated (IV International Prostaglandin Confere~ce, Washington, D.C.
May 1979~.

1~37~

Thus the imbalance between prostacyclin and TxA2 is considered to be responsible for the microvascular complications of diaoetes.
A TxA2-syntehtase inhibitor could therefore find clinical utility in preventing these vascular complications.
Aspirin and oost other non-steroidal anti-inflammatory drugs inhibit the cyclo-oxygenase enzyme. The sffect of this is to shut down the production of the PGG2J~2 endoperoxides and by so doing to reduce both the prostacyclin and thromboxane A2 levels.
Aspirin and aspirin-like drugs have been evaluated clinically for prevention of stroke and heart attack ~New England and J. Med. 1978, 299, 53, B.M.J., 1978, 1188, Stroke, 1977, 8 301).
Although some encouraging results have been obtained with these drugs, a compound which specifically inhibits thromboxane A2 formation leaving the biosynthesis of prostacyclin u?impaired would be more valuable in these clinical conditions (Lzncet, (ii), 1978, 780~.

1~3~ 8J.
1 ~ -- .
The effect of the compounds of the formula (I) on the thromboxane synthetase enzyme, and the prostacyclin synthetase and cyclo-oxygenase enzymes has been measured by the following in vitro enzyme assays:-_ _ .
1. Cyclo-oxygenase Ram seminal vesicle microsomes (Biochemistry, 1971, 10, 2372) are incubated with arachidonic acid (100 ~M: 1 min.: 22) to produce PG~2 and aliquots of the reaction mixture injected into a stream of Krebs-bicarbonate at 37 C (containing a mixture of antagonists~~~Nrature, 19/8, ~8~-~135t and indomethacin (Brit. J.
Pharmacol., 1972, 45, 451) which is superfusing a spirally-cut rabbit aorta strip (Nature, 1969, 223, 29). The ability of a com-pound to inhibit the enzyme is measured by comparing the increases in isometric tension produced by PG~2 in the absence of the test compound, and following pre-incubation of the enzyme with the test compound for 5 minutes.
2. Prostacyclin (PGI2) Synthetase Pig aorta microsomes (Nature, 1976, 263, 663) are incubated (30 sec.: 22 C) with PGH2 produced as in 1) and aliquots bio-assayed as in 1. PGI2 production is assessed indirectly by measuring the decrease in PG~2-induced tension (PGI2 itsel does not contract the aorta). This decrease can be prevented completely by pre-incubation of the enzyme with the selecti-~e PGI2 synthetase inhibitor, 15-hydroperoxy-arachidonic acid (Prostaglandins, 1976, 12, 715). The test compound is then pre-incubated with the enzyme for 5 minutes, and its ability to prevent tAe decrease in tension is measured.

3. Thromboxane A2 (TxA2) Synthetase Indomethacin pre-treated human platelet microsomes (Science 1976, 193, 163) are incubated (2 min.: O C) with PGH2 (produced 2S in 1) and aliquots of the reaction mixture super-fused over two rabbit aorta spirals which are separated by a delay coil t2 min.). The latter is required to allow the selec-tive decay of the more unstable thromboxane A2 (Proc. Nat. Acad.
Sci., 1975, 72, 2994) thereby enabling the separate measuremene of increased isometric tension due to the TxA2 formed and the PG~2 remaining. The test compound is pre-incubated with the enzyme for 5 minutes, and its ability to inhibit the thromboxane synthetase enzyme is measured as its reduction of the TxA2 com-ponent of the isometric tension.

1~371~81 ~ ompounds of the invention tested in this way have been shown to be capable of selectively inhibiting the thromboxane synthetase enzyme. The results of these tests are shown in the following Table, which gives the molar concentration of each S compound which caused a 50~ change in the effect of the relevant enzyme on isometric tension, i.e. caused a 50~ inhibition of the action of that enzyme.

Example Molar concentration causing 50% inhibitlon of (1) th~o=b~n=__ (2) cyclo- (3) prostacyclin 10 synthetase oxygenase synthetase 2 8.2 x 10-9 >10-4 ~10-4

4 2.4 x 10-9 ~10-4 4.7 x 10-8 ~10-4 _ .
7 1.0 x lo-ll 8 g.6 x 10-8 ~10-4 24 4.5 x 10-9 1~3~48~l ;~, The results given in the Table show that all of the compouncs tested caused a 50~ inhibition of the thromboxane syn-thetase enzyme at a molar concentration of 1.0 x 10 or less, and several caused S0~ inhibition at concentrations of 10 or less.
S Of the compounds tested for inhibition of the cyclo-oxygenase en~yme, none caused 50% inhibition at a m~Lar concentra-tion of 10 or less, their ability to inhibit that enzyme being at least 2,100 times less, than their ability to inhibit the thronkoxane synthetase enzyne.
Of the compounds tested for inhibition of the prosta-cyclin synthetase enzyme, none caused S0~ inhibition at a molar concentration less than 2,000 times greater than that at which they caused S0~ inhibition of the thromboxane synthetase enzyme, i.e.
they were all at least 2,000 times more potent as inhibitors o-'S thronboxane synthetase than of prostacyclin synthetase. _ _ It is expected that all the compounds of the invention when tested in this way will give results within the range of those already tested.
In addition to the above an in vitro assay for neasuring the inhibition of human blood platelet aggregation has been described and this may be predictive of anti-thrombotic efficacy clinically (Lancet (ii), 1974, 1223, J. Exp. Med., 1967, 126, 171). Both clinically effective agents aspirin and sulphinpyrazone show inhibitory activity ln vitro against a variety of aggresating agents in this test.
A numbe_ of in vivo tests in aninals have also been des-cribed for evaluating potential anti-thrombotic drugs.

~13~4~

In~ravenous injection of arachidonic acid causes ~eath in rabbits by causing platelet clumping and em~ollsation in the lungs. Again both the clinically effective aspirin (Agents and Actions, 1977, 1, 481) and sulphinpyrazone (Pharmacology, 1976, 14, 522) protect the rabbit from the lethal effect of the injection. Sulphinpyrazone has also been shown to prevent the aggregation of ?lat21ets in an extra corporeal loop of the abdominal aorta of rats ln vivo (Thromb.
Diathes. Haem., 1973, 30, 138).
The compounds mzy be administer æ orally in the for~ of 10 -- tablets or capsules containing a unit dose of thë comrour.d together with such excipients as maize s',2rch, calcium carbonate, ~ic21cium phosphate, alginic acid, lactose, magnesium stearate, "Primogel"
(Trace ~arX~ or tzlc. The æblets are ty?iczlly ?rep2r æ by granu-12ting the ingredients togethe_ &~d compressing the--~es~ ing mixture to tablets of the desired s ze. Capsules are ty?icaIl~y~~re~2red~by srznulating the ing-edients tosetner anc filling them ir.t- h2rd gelatine c2psules of the a~pro?ri2te si7e to con~æin the inc,reiients.
The compounds m2y also be administered ?arenter211y, or example by int~amuscular, intrzver.ous or subcutaneous injection.

For parenteral administration, they 2_e bes. used in the form of a st rile acueous solution which may con~ain ather solutes such as tonic and p~ adjusters. The compounds may be addec to-cist lled water anc the p~ aajusted to 3 - 6 using an acid such 2s ci~ic, lactic o-hydrochloric acid. Sufficient solutes such as dextrose or s21ine m2y be added to render the solution isotonic. The resulting solutionmay then be sterilise and filled ir.to sterile gl~ss vials of an appropriate size to contain the desired volume of ~olution.

1~37~

The compounds of the invention may also be administered by the infusion of a parenteral formulation as described above into a vein.
For oral administration to human patients, it is expected that the daily dosage level of a compound of the invention will be from 0.1 to 20 mg/kg per day for a typical adult patient (70 kg).
For parenteral administration, it is expected that the daily dosage level of a compound of the formula (I) will be from 0.01 -0.5 mg/kg per day, for a typical adult patient. Thus tablets or capsules can generally bë expected to contain from 5 to 150 mg of the active compound for administration orally up to 3 times a day.
Dosage units for parenteral administration can be expected to contain from 0.5 - 35 mg of the active compound. A typical vial could be a 10 ml vial containing 5 mg of the active compound in 6 - 10 ml of solution. _ _ It should of course be appreciated that .he physician in any event will determine the actual dosage which will be most suitable for the individual and it will vary with the age, weight and response of the patient. The above dosages are exemplary of the average patient, there may of course be individual cases where higher or lower dosage ranges are merited.
The preparation of the novel compounds of the invention is illustrated by the following Examples:-l~7~m (A~ 1-(2-8ydroxy-5-methyl)benzylimidazole A solution of 2-dimethylaminoethyl-4-methylphenol (4.95 g) and imidazole (2.04 g) in xylene (30 ml) wzs heated under reflux for 3 hours and then allowed to cool. The solid was filtered off and crystallised from ethyl acetate to give 1-(2-hydroxy-5-methyl)benzyl-imidazole (4.36 g), m.p. 166 - 167 C. Found: C, 70.19, ~, 6.50, N, 14-94. CllH12N20 requires: C, 70.19, H, 6.43, N, 14.89%.
(B) 2-(1-I~idazolylmethyl)-4-methyl-phenoxyacetic acid ethyl ester (2-Hydroxy-5-methyl)benzylimidazole (5.64 g) was dissolved in dry N,N-dimethylformamide (50 ml) and sodium hydride (1.50 g, 50%
dispersion in mineral oil) was added. The mixture was stirred at room temperature for 1 hour and then ethyl bromoacetate (5.04 g) was_ added over 10 minutes. The mixture was stirred at room temperature for 2 hours and then allowed to stand overnight before being poured - into water.-- The~resuIting mixture was extracted with chloroform (2 x 150 ml) and the co~bined chloroform extracts were washed well with water and dri æ (Na2SO4). The solvent was evaporated and the mixture was triturated with petrol (b.p. 60 - 80 C) to give a solid ~5.3 g) whieh was crystallised twice from ethyl acetate/petrol (b.p.
60 - 80 C) to give 2-(1-imidazolylmethyl)-4-methyl-phenoxyacetic acid ethyl ester, m.p. 86 - 88 C. Found: C, 65.36, H, 6.63, N~ 10-15- C15H13N2O3 requires: C, 65.67, ~, 6-61, N, 10-21~-1~3 ~

-- lq EXA~PLE 22-(1-Imidazolylmethyl)-4-mzthyl-~henoxvacetic acid hydrochloride hemihydrate A mixture of 2-(1-imidazolylmethyl)-q-methyl-phenoxyacetic S acid ethyl ester (1.0 g) and 10 ml of 2.5N sodium hydroxide solution was stirred at room temperature overnight. The solution was acidified with dilute hydrochloric acid and evaporated. The residue was extrac-ted with boiling ethanol (2 x 50 ml) and the extracts were evaporated to give a solid which was crystallised from ethanol/ether to give , . _ .. _ . .. ... . . .
2-(1-imidazoly~methyl)-4-methyl-phenoxyacetic acid hycroc~loride hemihydrate (0.50 g), m.p. 198 - 201C. Found: C, 53.69, H, 5.26, N, 9.45. C13H14N203.HCl.~H20 requires: C, 53.52, H, 5.53, N, 9.60%.

4-C2-(l-Imicazolylmethyl)-4-methyl-~henoxy~butyric acid .
-- -----15 _ ethyl ester hvdrochloride This compound was prepared as described in Example 1~
using ethyl 4-bromobutyrate instead of bromoacetate and a cataiytic quantity of potassium iodide. The hydrochloride salt had an m.p.
101 - 103 C (from ethyl acetate). Found: C, 59.87, ~, 6.84, N, 8-17- C17H22N203.HCl requires: C, 60.35, H, 6.79, N, 8.27~.

4-~2-(1-Imidazolylmethyl)-4-methyl-Dhenoxy~butyramide A mixture of 4-~2-(1-imidazolylmethyl~-4-methyl-phenoxy~
butyric acid ethyl ester (1.0 g) and o.sao ammonia solution was stirred for 6 hours and allowed to stand for a furthe_ 36 hours.

il379~81 The solid was filtered off and crystallised from water to give 4 {2-t1-imidazolylmethyl)-4-methyl-phenoxy~butyramide (0.30 g), m.p. 114 - 116 C. Found: C, 65.31, ~, 7.23, N, 15.13.
C15HlgN3O2 requires: C, 65.91, H, 7.01, N, 15.37~.
S EXAMPLE S
4-[2-(1-Imidazolylmethyl)-4-methyl-phenoxymethy~ ben~oic acid Treatment of (2-hydroxy-5-methyl)benzylimidazole with ethyl (4-bromomethyl)benzoate by the method of Example lB gave 4-~2-(1-imidazolylmethyl)-4-phenoxy)benozic~acid ethyl ester. A
solution of the ester (4.17 g) in ethanol (40 ml) was treated with a solution of sodium hydroxide (2.0 g) in water (80 ml). The solution was heated under reflux for 1 hour and then allowed to stand at room temperature for 18 hours. The solution W25 evaporated ~OD-api~roximately half volume and just acidified ~ 2cetic acid.
- -- 15 The precipitate was filtered off, washed with water and crystallised from ethanol to give 4-C2-(1-imidazolylmethyl)-4-methyl-phenoxymethy~
benzoic acid (2.33 g), m.p. 220 - 221 C. Found: C, 70.34, ~, 5.57, N, 8.59. C1gH18N203 requires: C, 70.78, H, 5.63, N, 8.69%~
EXAMæ~F 6 4-(1-Imidazolylmethyl)phenoxyacetic acid ethyl ester fumarate Sodium hydride (3.17 g of 50~ suspension in mineral oil) was added in portions to a stirred mixture of 1-(4-hydroxybenzyl) imidazole (11.50 g) in dry N,N-dimethyl-formamide (100 ml) at room temperature. The mixture was stirred at room temperature for 10 minutes and then heated to 100 C for 30 minutes. It was then cooled and ethyl bromoacetate (11.04 g) was added dropwise with stirring.

~137~8~
- 2~ -The resulting mixture was heated on a steam bath for 9 hours and then poured into water. The mixture was extracted with chloroform and the combined chloroform extracts were washed well with w~ter and dried (Na2SO4). Evaporation of the solvent gave an oil which S was chromatographed on silica gel. Elution with chloroform gave first some impurity and mineral oil followed by pure product.
The product containing fractions were combined and evaporated to give an oil (13.90 g). A portion was dissolved in ether and the solution was treated with an excess of an ethereal solution of fumaric acid. The solid was filtered off and crystallised from ethyl acetate to give 4-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester fumarate m.p. 99 - 101 C. Foun,d,,_ C, 57.16, ~, 5.29, , .
N2O3.C4~4O4 requires: C, 57.44, ~, 5;36 N 7 44 EXAMpt,~ 7 '- 15 4-(1-Imidazolvlmethyl)phenoxyacetic acid h,vdrochloride A solution of 4-(1-imidazolylmethyl)pheno~acetic acid ethyl ester (6.0 g) in concentrated hydrochloric acid (10 ml) was heated at 100 C for 8 hours and then evaporated to give an oil which solidi.ied on trituration with ethyl acetate. The solid was crystallised twice from aqueous acetonitrile to give 4-(1-imidazolyl-methyl)phenoxyacetic acid hydrochloride (4.84 g), m.p. 107 - 110C.
Found: C 50 24, ~, 5.31, N, 9.83. C12H12N2O3.~Cl. 2 q C, 50.28, ~, 5.23, N, 9.77~.

113748~
- 2~ -4-(1-Imidazolvlmethyl)phenoxyacetamide A solution of 4-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester (2.0 g) in ethanol (10 ml) and concentrated aqueous ammonia (SG 0.880) were heated under reflux for 2 hours and then evaporated. The residue was crystallised from a mixture of methanol and 2-butanone to give 4-~1-imidazolylmethyl)phe xyacetamide (1.31 g) m.p. 173 - 174 C. Found: C, 62.42, H, 5.76, N, 17.40. C12H13N3O2 requires: C, 62.32, H, 5.67, N, 18.17%.
EXAMPTT g N-Methyl-4-(1-Imidazolylmethyl)phenoxyacetamide A solution of 4-(1-imidazolylmethyl)phenoxyacetic acid .. ..
ethyl ester (1.02 g) in 33% ethanolic methylamine was allowed to stand for ~ ~hour. The solution was evaporated and the residue was crystallised from ethyl acetate/petrol to give N-methyl-4-(1-imidazolylmethyl)phenoxyacetamide (0.61 g), m.p. 124 - 125C.
Found C, 63.44, H, 6.21, N, 17-25- C13H15N302 requires:
C, 63.66, H, 6.16, N, 17.13%.

1-~4-(Tetrazol-5-ylmethoxy)benzy~ imidazole A. Sodium hydride (1.92 g of 50% dispersion in mineral oil was added portionwise to a stirred solution of 1-(4-hydroxybenzyl) imidazole (7.08 g) in dry N,N-dimethylformamide (100 ml) at 0 C
and the resulting mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0C and chloroacetonitrile (2.96 g) was added over 2 mir.utes with stirring.

i~3~481 - 2~ -The mixture was allowed to stand overnight and then evaporated.
The residue was dissolved in chloroform and the mixture was filtered. The filtrate was evaporated and the residue was chro-matographed on silica gel. Elution with chloroform save initially mineral oil and impurity followed by pure product. Further pure product was obtained on changing the eluant to chloroform/methanol (9:1). The product-containing fractions were evaporated to give 4~ imidazolylmethyl)phenoxyacetonitrile !5.2 g) as an oil.
B. The nitrile (2.13 g), sodium azide (3.25 g) and a~monium chloride (2.67 g) were heated on a steam bath for 4 hours in N,N-dimethylformamide. The solution was then evaporated to dryness and a few ml. of water were adde~ to the residue. The solid was collected by 'iltration and crystallised from ethanol to sive 1-~4-~ (tetrazol-5-ylmethoxy)~enzy~ imidazole (0.88 g), m.p. 189 - 191C.
Found: C, 56.04, ~, 4.73, N, 33.05. C12H12N6O requires: C, 56-24, ~, 4.72, N, 32.80~.
EXAM~LE 11 . 1-(4-eycroxy-3-methoxy)benzylimidazole A mixture o~ imidazole (20.4 g) and 4-hydroxy-3-methoxybenzyl alcohol (46.25 g) was heated at 160 C for 2 hours.
The resulting mixture was cooled and the product was crys allised twice from ethanol/petrol to give 1-(4-hydroxy-3-methoxy)benzyl-imidazole (48.7 g), m.p. 159 - 160 C. Found: C, 64.73, ~, 5.98, N, 13.70. C11H12N2O2 requires: C, 64.69, ~, 5.90, N, 13-67~-~3~E~l B. 4-(1-Imldazolylmethyl)-2-methoxyphenoxyacetic acid ethyl ester Sodium hydride (3.8 g of 50~ dispersion in mineral oil) was added portionwise to a stirred solution of 1-(4-hydroxy-3-methoxy)benzylLmidazole (14.3 g) in dry N,N-dimethylformamide (150 ml) at 0 C. The mixture was stirred at room temperature for 1 hour and then cooled to 0 C Ethyl bromoacetate (11.69 g) was added over 5 minutes with stirring and the mlxture was stirred for 4 hours at room temperature. A few mls. of water was added to decompose excess sodium hydride and the mixture was evaporated.
The residue was chromatographed on silica gel. Elution with chloro-form gave mineral oil and some im?urity. Elution with chloroform/
~ ethanol (20:1) gave a solid which was crystallised fro~ ethyl acetate~
petrol to give 4-(1-imidazolylmethyl)-2-methoxy?henoxyacetic acid ethyl ester (9.02 g), m.?. 9I C. Found: C, 61.94, H, 6.26, N, 9.69.
C15H18N2O4 requires: C, 62.05, ~, 6.25, N, 9.55~.

4-(1-Imidazolyl~ethyl)-2-methoxy?henoxyacetamide Treatment of 4-(1-imidazolylmethyl)-2-methoxypnenoxy-acetic acid ethyl ester with ammonia as described in Example 8 gave4-(1-imidazolylmethyl)-2-methoxvphenoxyacetamide, m.p. 124 - 125 C
(from chloroform/pe rol). Found: C, 59.39, ~, 5.83, N, 16.07.
C13H15N3O3 requires: C, 59.75, H, 5.78, N, 16.08~.

2-(1-Imidazolylmethyl)phenoxyacetic acid ethyl ester Treatment of 2-(1-imidazolylmethyl)phenol with sodium hydride in dry N,N-dimethylformamide followed by ethyl bromo2cetate as described in Example ilB gave 2-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester as an oil which was used without further characteri-sation.

11374~31 2-(1-ImiZazol lmeth 1)DhenoYyacetic ac~d Y Y
2-(1-Imidazolylmethyl)phenoxyacetic acid ethyl ester (1 g) was heated on a steam bath for 30 minutes in a solution of potassium hydroxide (0.5 q) in water (10 ml) and the solution was allowed to stand at room temperature for 18 hours. The solution was then evaporated to small volume and acidified to pH 5 with acetic acid. The solid was collected by filtration and crystallised from water to give 2~ imidazolylmethyl)phenoxyacetic acid (0.26 g), m.p. 213 - 214 C. Found: C, 61.83, H, 5.24, N, 12.34.
C12H12N2O3 requires: C, 62.05, 8, 5.21, N, 12.06%.
EXAMæLE 15 A. 1-(5-Chloro-2-hvdroxy)benzvlimidazole .
A solution of 4-chlo-o-2-dimethylaminomethylphenol (30.0 g) and imidazole (11.75 g) in xylene (200 ml) was heated under reflux for 3.5 hours. The solution was evaporated and the residue was triturated with a little ethyl acetate to induce crystallisation.
The product was crystallised from ethyl acetate/petrol to give 1-(5-chloro-2-hydroxy)benzylimidazole (15.91 g), m.p. 142 - 144C.
Found: C, 57.33, 8, 4.36, N, 13.45. C1o89ClN2O requires:
C, 57.56, 8, 4.35, N, 13.43~.
B. 4-Chloro-2-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester Treatment of 1-(5-chloro-2-hydroxy)benzylimidazole with sodium hydride in dry N,N-dimethylformamide followed by ethyl bromoacetate as described in Example 1lB gave 4-chloro-2-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester, m.p. 108 - 110 C
(from ethyl acetate/petrol). Found: C, 56.80, X, 4.83, N, 9.16.
C14H15ClN2O3 requires: C, 57.06, H, 5.06, N, 9.51%.

1~l374t31 4-Chloro-2-(1-imidazolylmethyl)phenoxyacetic acid ~ydrolysis of 4-chloro-2-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester by the method of Example 14 gave 4-chloro-2-(1-imidazolylmethyl)phenoxyacetic acid, m.p. 222 - 224 C (from water).
Pound: C, 53.95, H, 4.10, N, 10.52. C12H11ClN2O3 requires:
C, 54.04, ~, 4.16, N, 10.50~.

4-Chloro-2-(1-imidazoLylmethyl)phenoxyacetamide Treatment of 4-chloro-2-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester with ammonia as described in ~xample 8 gzve-4-chloro-2-(1-imidazolylmethyl)phenoxyacetamide, m.?. 162 - 164 C
(from isopropanol/petrol). ~ound: C, 53.91, ~, 4.51, N, 15.79.
C12~12ClN3O2 cequires: C, 54.23, ~, 4.57, N, 15.81%.
EXAMæLE 18 4-C2-(l-Imidazolylmethyl)phenoxy~butyric acid ethyl ester Treatment Oc 1-(2-hydroxybenzyl)imidazoie with sodium hydride followed by ethyl 4-bromobutyrate as described in ExamDle 3 gave 4- 2-(1-imidazolylmethyl)phenoxy buty-ic acic ethyl ester as an oil.
A portion of the product was dissolved in a small volume of ethanol and the solution was treated with an excess of a saturated diethyl ether solution of oxalic acid. The solid was filtered off and crystallised from ethyl acetate/petrol to give 4- 2-(1-imidazolylmethyl)phenoxy butyric zcid ethvl ester oxalate, m.p. 76 - 81 C. Found: C, 56.76, ~, 5.88, N, ?.43. C16~20N203 requires: C, 57.13, ~, 5.86, N, 7.41~.

4-~2-(1-Imidazolylmethyl)phenoxy~butyric acid Hydrolysis of 4-~2-(1-imidazolylmethyl)phenoxy~ butyric acid ethyl ester by the method of Example 14 gave 4-~2-(1-imidazolylmethyl)phenoxy~butyric acid, m.p. 150 - 152 C tfrom water). Found: C, 64.27, ~, 6.29, N, 10.71- C14H16N203 requires:
C, 64.59, H, 6.19, N, 10.76%.

4-c2-(l-Imidazolylmethyl)phenoxymethy~ benzonitrile Treatment of 2-(1-imidazolylmethyl)phenol with sodium hydride and 4-bromomethylbenzonitrile in dry N,N-dimethylformamide by the method of Example 1B gave 4-t2-(1-imidazolylmethyl)phenoxy-methyl~ benzonitrile, m.p. 116 - 118 C (from ethyl acetate/petrol).
Found: C, 74.64, H, 5.16, N, 14.65. C18Y.15N30 requires: C, 74.68, H, 5.22, N, 14.52%.

4-~2-(1-Imidazolylmethyl)phenoxymethy~ benzamide 4-~ -(1-Imidazolylmethyl)phenoxymethyl~ benzonitrile (1.0 g) was dissolved in ethanol (10 ml) and 30% hydrogen peroxide (5 ml) was added followed by 6N sodium hydroxide solution (5 ml).
The mixture was heated at 50 C for 1 3/4 hours and then evaporated to small volume. The solid was filtered off and crystallised from ethanol/petrol to give 4- 2-(1-imidazolylmethyl)phenoxyethyl benzamide (0.60 g), m.p. 209 - 211C. Found: C, 69.97, ~, 5.70, N, 13.28. C18H17N3O2 requires: C, 70.34, H, 5.57, N, 13-67%-ExAMæLE 22

5-c4-(2-Imidazo~ ylmethyl)phenoxymethyllphenyl-tetrazole Treatment of 4-~2-(1-imidazolylmethyl)phenoxymethy~
benzonitrile with sodium azide and a~monium chloride as described in Example 10 gave 5-~4-(2-imidazol-1-ylmethyl)phenoxymethy~
phenyltetrazole, m.p. 232 - 234 C (from methanol/ethyl acetate.
Found: C, 64.74, H, 4.84, N, 25.69. C18H16N6O requires: C, 65.06, H, 4.82, N, 25.30~.

A~ 2-~ydroxybenzyl)imidazole hydrobromide A solution of 1-(3-methoxybenzyl)Lmidazole (18.1 g) in 48 % hydrochloric acid (150 ml) was heated under reflux for 2 hours and then evaporated to give a thick oil. Trituration with~
ether gave a solid which W25 c_ystallised from isopropanol to give 1-(3-hydroxybenzyl)imidazole hydrobromide (19.25 g), m.~. 126 -128 C. Found C, 46.46, H, 4.27, N, 11.17. Clo~lON2o~ 3 r requires:
C, 47.07, H, 4.35, N, 10.98~.
B. 3-(1-Imidazolylmethyl)phenoxyacetic acid ethyl ester fumarate Sodium hydride (3.2 g of 50~ dispersion in mineral oil) was added portionwise to a stirred solution of 1-(3-hydroxybenzyl) imidazole hydrobromide (8.0 g) in dry N,N-dimethylformamide zt 0C.
When the addition was complete the mixture was warmed briefly to 100C and cooled to room temperature. Ethyl bromoacetate (5.50 g) was added over 2 minutes with stirring and the resulting mixture was heated to 100 C for 1.5 hours and then evaporated. The residue was partitioned between water and chloro~orm and the aqueous layer was separated.

- ~l3748~
-- 2q --The chloroform layer was dried (Na2S04) and evaporated to give an oil which was chromatographed on silica gel. Elution with chloro-form gave initially mineral oil and some impurity followed by pure product. Evaporation of the product containing fractions gave an 5 oil (5.80 g).
A portion of the oil was dissolved in a little ethanol and an excess of a diethyl ether solution of fumaric acid was added.
The solid was filtered off and crystallised from ethyl acetate to give 3-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester fumarate m.p. 85 - 86 C. Found: C, 57.50, H, 5.35, N, 7.39. C14H16N203.
C4~4O~, requires: C, 57.44, E~, 5.36, N, 7.44%.

3-(1-Imidazolylmethyl)phenoxyacetic acid hydrochloride Hydrolysis of 3-(1-imidazolylmethyl)phenoxyacetic acid 15 ethyl ester free base with concentrated hydrochloric acid according to the method of E~xample 7 gave 3-(1-imidazolyln~ethyl)phenoxyacetic acid hydrochloride, m.p. 179 - 181 C (from aqueous acetonitrile).
Found: C, 53.23, H, 4.84, N, 10.65. C12H12N2O3.HCl requires:
C, 53.64, ~i! 4.88, N, 10.43%.

113'~4~1 4-(1-Imidazolylmethyl)phenoxyacetic acid hydrochloride (1 g) was added to distilled water (900 ml) and the p~ adjusted to 5 with hydrochloric acid. Sodium chloride (18 g) was added S and the solution made up to 2 litres. The final solution was sterilised by filtration throush a bacteria-proof filter under aseptic conditions into 10 ml glass vials so as to comply with the test for sterility of Appendix 121 British Pharmacopea 1973.

Capsules are compounded from the following ingredients:
- ~ mg/capsule-~-4-(1-Imidazolylmethyl)phenoxyacetic acid HCl 20 Lactose 250 Maize starch 75 Magnesium stearate S

The ingredients are thoroughly blended, granulated and then filled into hard gelatine capsules of the desired size.

Claims (18)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the general formula:

--- (I) wherein R1 is hydrogen, C1-C4 lower alkyl, C1-C4 lower alkoxy or halogen;
Y is (CH2)n where n is an integer of from 1 to 4, or a group of the formula Z is CO2R2, CONHR3, CON(R4)2, CN or tetrazolyl, wherein R2 is hydrogen or C1-C4 lower alkyl;
R3 is hydrogen, C1-C4 lower alkyl or C2-C4 lower alkanoyl;
each R4 is C1-C4 lower alkyl or two groups R4 together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino group;
and the pharmaceutically acceptable acid addition salts thereof, which comprises reacting a phenol of the formula:

--- (II) where R1 is as previously defined with an alkali metal hydride and adding a halide of the formula:
Hal-Y-Z

where Y and Z are as previously defined and Hal means chlorine, bromine or iodine, and where required effecting one or more of the following steps: (a) converting any compound of formula (I) into a pharmaceutically acceptable salt thereof; (b) transforming any compound so formed of formula (I) where Z is CO2R or CN into a compound of formula (I) where Z is CO2H, CONHR (where R
is hydrogen, C1-C4 lower alkyl or C2-C4 lower alkanoyl), CON(R4)2 (where R4 is C1-C4 lower alkyl or two groups R4 together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino group) or tetrazolyl.

2. A process as claimed in claim 1 wherein said alkali metal hydride is sodium hydride.

3. A process as claimed in claim 2 wherein Hal is bromo.

4. A process as claimed in claim 1, 2 or 3 wherein R1 is hydrogen or methyl.

5. A process as claimed in claim 1, 2 or 3 wherein Y is methylene.

6. A process as claimed in claim 1, 2 or 3 wherein Y is a substituted benzyl group.

7. A process as claimed in claim 1, 2 or 3 wherein Z is CO2H or CONH2.

8. A process as claimed in claim 1, 2 or 3 wherein R1 is hydrogen or methyl, Y is methylene and Z is CO2H or CONH2.

9. A process as claimed in claim 1, 2 or 3 wherein R1 is hydrogen or methyl, Y is a 4-substituted benzyl group and Z is CO2H or CONH2.

10. A process as claimed in claim 1, 2 or 3 wherein R1 is hydrogen or methyl, Y is methylene and Z is CO2H.

11. A process as claimed in claim 1, 2 or 3 wherein R1 is hydrogen or methyl, Y is methylene and Z is CONH2.

12. A process as claimed in claim 1, 2 or 3 wherein R1 is hydrogen or methyl, and -Y-Z is .

13. A process as claimed in claim 1, 2 or 3 wherein R1 is hydrogen or methyl, and -Y-Z is .

14. A process which comprises reacting 1-(4-hydroxybenzyl)imidazole with sodium hydride, adding ethyl bromoacetate and hydrolysing the formed product to give 4-(1-imidazolylmethyl)phenoxyacetic acid.

15. A process which comprises reacting 1-(4-hydroxybenzyl)imidazole with sodium hydride, adding ethyl bromoacetate, and converting the latter into its hydrochloride.

16. A compound of formula (I) defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

17. 4-(1-Imidazolylmethyl)phenoxyacetic acid, when prepared by the pro-cess of claim 14 or by an obvious chemical equivalent thereof.

18. 4-(1-Imidazolylmethyl)phenoxyacetic acid hydrochloride, when prepar-ed by the process of claim 15 or by an obvious chemical equivalent thereof.