GB2067993A - Imidazole hydrazone derivatives - Google Patents

Abstract

Compounds corresponding to the following general formula: <IMAGE> wherein Ar and Ar<1>, which may be the same or different, each represents an aromatic (including heteroaromatic) radical which may be substituted one or more times by halogen and/or nitro and/or lower alkyl and/or trihalomethyl and/or cyano and/or lower alkoxy and/or di-lower alkyl-amino, the alkyl groups optionally completing a ring optionally incorporating a further heteroatom, and/or lower alkyl sulphonyl; Alk<1> and Alk<2>, which may be the same or different, each represents an alkylene group containing from one to eight carbon atoms which may be substituted one or more times by aryl and/or cycloalkyl and/or lower alkyl and if two such alkyl groups are present, they may complete a ring optionally containing a heteroatom and in which the imidazole ring may be further substituted; and m represents 0 or 1; provided that not both Ar and Ar<1> represent phenyl; and acid addition salts thereof. Such compounds are prepared by reaction of a compound corresponding to the following general formula: <IMAGE> with a compound of the formula: Ar<1>-NH-NH2. The compounds have an antifungal activity as well as an antianaerobe and anti-thrombotic activity.

Description

SPECIFICATION Imidazole hydrazone derivatives This invention relates to imidazole hydrazone derivatives.

The present invention provides compounds corresponding to the following general formula I:

wherein Ar and Ar1, which may be the same or different, each represents an aromatic radical which may be substituted one or more times by halogen and/or nitro and/or lower alkyl and/or trihalomethyl and/or cyano and/or lower alkoxy and/or di-lower alkyl-amino, the alkyl group optionally completing a ring optionally incorporating a further heteroatom, and/or lower alkyl sulphonyl;Alk1 and Alk2, which may be the same or different, each represents an alkylene group containing from one to eight carbon atoms which may be substituted one or more times by aryl and/or cycloalkyl and/or lower alkyl, and if two such alkyl groups are present, they may complete a ring optionally containing a heteroatom; and in which the imidazole ring may be further substituted in particular by one or more lower alkyl groups and m represents 0 or 1; provided that not both Ar and Ar1 represent phenyl; and acid addition salts thereof.

The wavy line between the C=N and NHAr' groups indicates the possibility of the isomerism. The compounds may be isolated in the form of a mixture of isomers or as the isomers themselves in particular the E and Z isomers and the invention extends to such mixtures and such isomers.

For the present purposes, the term 'lower' as used in referring to alkyl or alkoxy groups means those groups having from 1 to 7 carbon atoms.

The alkylene group represented by Alk' and Alk2 preferably contains 1 to 3 carbon atoms. The imidazole group may be unsubstituted or substituted.

Certain preferred compounds according to the present invention are those wherein Ar and Ar', which may be the same or different, each represents optionally substituted phenyl, thienyl or pyridyl.

(The substituents being as described above). Preferred substituents in this context include halogen and/or trihalomethyl and/or cyano.

In one preferred case, Alk2 represents -CH2- and m represents 0.

Examples of specific groups falling within the above definition of Ar and Ar1 include: phenyl, 2-; 3or 4-chlorophenyl; 2,3-; 2,4-; 2,5-; 2,6-; 3,4-; or 3,5- dichlorophenyl; 2,4,6-trichlorophenyl; 2-; 3- or 4bromophenyl; 2- or 4-fluorophenyl; 2- or 4-methylphenyl; 2- or 4-methoxyphenyl; 3-trifluoromethylphenyl, 4-cyanophenyl; 4-dimethylaminophenyl; 4-methylsulphonylphenyl; 2-thienyl; 5-chloro-2thienyl; 2-pyridyl and 2-; 3- or 4-nitrophenyl.

Particularly preferred compounds include those wherein: Ar represents 4-chlorophenyl and Arl represents 2,4-dichlorophenyl; Ar represents 4-chlorophenyl and Arl represents 2,6-dichlorophenyl; Ar represents 2-chlorophenyl and Ar1 represents 2,4-dichlorophenyl; Ar represents 4-chlorophenyl and Ar' represents 2,3,4,5,6-pentafluorophenyl; Ar represents 2,4-dichlorophenyl and Arl represents 2,4,6-trichlorophenyl; Ar represents 4-chlorophenyl and Arl represents 2-chlorophenyl; Ar represents 5-chlorothien-2-yl and Ar' represents 2,6-dichlorophenyl; and Ar represents phenyl and Arl represents 2,4-dichlorophenyl.

Specific preferred compounds according to the invention include the following: (E)-1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride.

(Z)-1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,6-dichlornphenylhydrnzone, hydrochloride.

(E)-1 -(5-chlorothienyl-2-yl)-2-( 1 H-imidazol- 1 -yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride.

(Z)-1 -(4-chlorophenyl)-1 -(1 H-imidazol-1 -yl)ethanone, 2-chlorophenylhydrazone, hydrochloride.

1 -(2,4-dichlorophenyl)-2-( 1 H-imidazol- 1 -yl)ethanone, 2,4,6-trichlorophenylhydrazone, hydrochloride.

(Z)- 1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,3,4,5,6-pentafluorophenylhydrazone, hydrochloride.

The compounds according to the present invention may be prepared by reacting a compound corresponding to the following general formula II:

wherein Ar, Alk1, Alk2 and m are as defined above; with a compound corresponding to the following general formula: Ar1-NH-NH2 wherein Ar' is as defined above; the product if desired being isolated in the form of an acid addition salt, or subsequently converted from one salt to another salt.

The process is preferably carried out at an elevated temperature particularly in the presence of a solvent and an acidic catalyst. Either or both of the reactants may be used in the reaction in the form of acid addition salts.

Preferred reaction temperatures are from 20 to 1000C, advantageously from 78 to 800C.

The nature of the solvent is not critical. Preferred solvents include methanol and ethanol.

As acid catalyst, sulphuric acid or hydrochloric acid may be used.

After reaction, the mixture may be neutralised by the addition of alkali and the product solventextracted and isolated by removal of the solvent. Acid addition salts of the resulting compound may be cbtained if desired, by dissolving the product in a non-aqueous solvent, for example chloroform, and reacting it with a non-aqueous solution of a suitable acid.

Compounds of formula II in which m = o, a number of which have been reported in the literature, may be prepared according to the reaction scheme set out below, in which X is bromo or chloro, using methods analogous to those described in the literature, e.g. for the preparat;on of 1 -(4-chlorophenyl)-2 (1 H-2-ethylimidazol-1 -yl)ethanone (U.K. Patent Specification 1,244,530), and for the preparation of 1 (4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone (P. A. J. Janssen et al, J. Med.Chem., 1969, 12, 781).

Novel compounds of formula 11, (m = 0), which we have prepared are identified in the table below: (A) Compounds in which the imidazole group is unsubstftuted Ar Alk mp( C) 2-Br Phenyl CH2 191-192.5 (HCl) 3-Br Phenyl CH2 123-124.5 2-F Phenyl CH2 159-160 (HNO3) 2,5-Cl2 Phenyl CH2 1 64-1 68 (HNO3) 2,6-Cl2 Phenyl CH2 245-247 (HCl) 3,4-Cl2 Phenyl CH2 132-134 (HNO3) 2-CF3 Phenyl CH2 > 250 decomp (HCl) 3-CF3 Phenyl CH2 101-102 4-CF3 Phenyl CH2 139-140 4-CN Phenyl CH2 214-216(HNO3) 3-MeO Phenyl CH2 105-107 2-NO2 Phenyl CH2 171-172(HNO3) 3-NO2 Phenyl CH2 146-149 (HNO3) 4-NO2 Phenyl CH2 237-238 3-MeOOC-4-MeO Phenyl CH2 160-161 2-Pyridyl CH2 115-116 2-Naphthyl CH2 228-230 (HCl) 2-Benzofuranyl CH2 150-152 Thien-3-yl CH2 143-144 (HCl) 5-Br Thien-2-yl CH2 168-169 4,5-Br2-Thien-2-yl CH2 185-186 2,5-Cl2 Thien-3-yl CH2 134-135 5-Me Thien-2-yl CH2 126-127 4-Cl Phenyl CHCH3 189-190 (HCl) 4-F Phenyl CHCH3 266-268 (HCl) 4-CF3 Phenyl CHCH3 240-242 (HCl) 3,4-Br2 Thien-2-yl CHCH3 236-238 (HCl) 4,5-Br2 Thien-2-yl CHCH3 136-138 5-Cl-Thien-2-yl CHCH3 96-97 Phenyl CH Phenyl Gum 4-Me2N Phenyl CH Phenyl 125-127 (HCl) Ar Alk2 mp( C) 4-Me2N Phenyl CH(4-Cl Phenyl Gum 4-CI Phenyl CHCH2(2,4-Ci2 220-222 (HCI) Phenyl 4-CI Phenyl CHCH2CH20COCH3 101-102 4-CI Phenyl CH2CH2 1 65-1 66 (HCI) {B} Compounds in which the imidazole group is substituted as indicated Ar Imidazole Group Alk2 mp 4-Br Phenyl 2-methylimidazole CH2 228.5-231.5 (HCI) 4-CI Phenyl 4-methylimidazole CH2 164-166 4-Cl Phenyl 2-ethyl-4-methyl- CH2 141-142 imidazole 4-Cl Phenyl 2-methylimidazole CHCH3 263-265 (HCI) Compounds of formula V in which m is 1 can be prepared by methods analogous to that described by N. Yoshida et al, Sanky Kenkyusho Nempo, 1970, 22, 89, for the preparation of 1 -chloro-3-(4- chlorophenyl) propan-2-one. These compounds may then be converted to compounds of formula Il as described above.By this method 1 -(4-chlorophenyl)-3-(1 H-imidazol-1 -yl)propan-2-one was prepared, in the form of colourless needles m.p. 104--1050C.

The compounds according to the invention have an antifungal activity. They are also active against anaerobic bacteria. They also have an antithrombotic activity.

The anti-fungal activity of the compounds is very pronounced against a wide range of pathogenic fungi, such as those of the Trichophyton species and of the Candida species and against Epidermophyton floccosum and Microsporum canis. Compared with known antifungal agents such as miconazole, econazole and clotrimazole they have the considerable and unexpected advantage of high activity when administered by the oral route. The compounds according to the invention have a toxicity which is comparable to that of the prior anti-fungal agents mentioned above but because they are more active their therapeutic index is better. Also compared with the prior known antifungal agents they are active when given by the oral route, which simplifies their administration.

The activity of the compounds against anaerobic bacteria has been demonstrated against a number of important pathogenic anaerobic bacteria such as Clostridium species, Bacteroides species and Trichomonas vaginalis. Like metronidazole, which is widely used at present, they are of high activity and have the advantage that they appear to be non-mutagenic in both bacterial Ames tests and mammalian cell transformation assays (Ames et al, Mutation Res., (1975), 31,347 and McCann et al, Proc. Nat. Acad. Sci. USA, (1975), 75,5135) whereas metronidazole is reported to be mutagenic and teratogenic.Compared with another known antianaerobic agent namely Cl inda mycin (trans--methyl- 7-chloro-6,7,8-trideoxy-6-( 1 -methyl-4-propyl)-L-(2-pyrrolidineca rboxamido)- 1 -thio-L-threo-D-ga lactooctopyranoside) they have the advantage of having a low toxicity. They also exhibit activity against nonpathogenic anaerobic bacteria such as Desulfovibrio desulfuricans which is an anaerobe present in oil wells. The use of the compounds of the invention to kill or effectively control such anaerobes is part of the present invention.

The anti-thrombotic activity of the compounds of the invention has been determined by their ability to inhibit production of thromboxane A2 (TxA2) by blood platelets the synthesis of which is considered to be an important factor in the aggregation of platelets and the initiation of thrombosis (R.

J. Gryglewski, CRC Crit. Rev. Biochem., 1980, 7(4), 291).

Thus, there is evidence that thrombosis is determined by the balance of products derived from prostaglandin cyclic endoperoxides between the thrombogenic TxA2 released on platelet aggregation and the thrombolytic prostacyclin (PGl2) formed in the vessel walls. Blocking or reducing the production of TxA2 is expected to be useful in the treatment and prophylaxis of thrombosis.

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 thrombosis in mammals, including man. For example, the compounds may be useful in the treatment and prevention of myocardial infarcts, cerebro-vascu la r thrombosis, ischaemic peripheral vascular disease and thrombo-embolic microangiopathy; to treat and prevent post-operative thrombosis; and to promote patency of vascular grafts following surgery.

The compounds in which the activity as an antifungal is best demonstrated are those wherein Ar' is dichlorophenyl, in particular 2,6-dichlorophenyl. The activity of the compounds as antianaerobes is best demonstrated with those compounds in Ar1 is di- or tri-chloro, in particular 2,4-dichloro and 2,4,6trichloro, also in those compounds in which Alk2 has more than one carbon atom.

The compounds according to the invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the treatment intended.

Accordingly the invention provides a pharmaceutical composition comprising one or more compounds according to the invention in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The composition may for example be applied topically, orally or by injection. For topical administration, the composition may be formulated as, for example, a cream gel or ointment. Such a composition could, for example, be applied topically twice daily for a suitable period, such as two or three weeks. A suitable concentration of active ingredient in the composition could be from 1 to 5% w/w. For vaginal use, the active ingredient may be incorporated in a pessary, or a cream may be used with an applicator, or an impregnated tampon may be utilized.

For oral administration, the pharmaceutical composition may take the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit contained in a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. These may with advantage contain an amount of active ingredient from 5 to 250 mg preferably 25 to 1 50 mg. A suitable daily dose for a mammal may vary widely depending on the condition of the patient and other factors. However, a dose of from 0.1 to 300 mg/kg body weight particularly 0.5 to 10 mg/kg body weight preferably 5 mg to 10 mg/kg body weight may be appropriate.

The active ingredient may also be administerd by injection as a composition wherein, for example, saline, dextrose or water for injection may be used as a suitable carrier. When used as an antithrombotic the preferred routes of administration are the oral route or by injection.

As indicated the dose administered and the treatment regimen will be dependent, for example, on the infection, the severity thereof, on the patient being treated and his response to treatment and therefore may be widely varied.

The pharmaceutical compositions may be prepared by techniques well known in the art and described, inter alia, in Remington's Pharmaceutical Science, Mach Publishing Co., Easton, Penn., 1965.

The present invention is further illustrated by the following Examples.

EXAMPLE 1 E- 1 -(4-chlorophenyl)-2-( 1 H-imidazol- 1 -yl)ethanone,2,4-dichlorophenylhydrazone, hydrochloride A mixture of 1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone (133.5 g), 2,4- dichlorophenylhydrazine, hydrochloride (154.0 g), and hydrochloric acid (0.5 ml of 12M) in ethanol (615 ml) was heated under reflux, with stirring, for 5 hours.On cooling the product was filtered off and recrystallised from ethanol/ethyi acetate to give (E)- 1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride, m.p. 1 87--1 88 OC. (Analysis found: C, 49.14; H, 3.32; Cl, 33.84; N, 13.36. C,7H,4CI4N4 requires: C,49.06; H, 3.39; Cl, 34.07; N, 13.46%).

NMR (da-DMSO)G 5.68 (2H, singlet), 7.2--7.9 (10H, multiplet,) 8.36 (1H, singlet), 9.29 (1H, singlet).

The E-stereochemistry was confirmed by X-ray crystrallographic analysis.

EXAMPLE 2 Z- 1 -r4-chlorophenyl)-2-f 1 H-imidazol- 1 -yl)ethanone,2,4-dichlorophenylh ydrazone, hydrochloride A mixture of 1-(4-chlorophenyl)-2-(1 H-imidazol-1-yl)ethanone (6.6 g) and 2,4 dichlorophenylhydrazine, hydrochloride (7.5 g) were dissolved, with stirring in ethanol (70 ml). The resulting solution was heated at 350C for 30 minutes and then left to cool at OOC for 2 hours to give (Z)- 1 -(4-chlorophenyl)-2-( 1 H-imidazol- 1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride, m.p.

186-1 880C.

NMR (d6-DMSO) S 5.98 (2H, singlet). 7.1--8.0 OH, multiplet), 9.51 (1H singlet), 9.63 (1H singlet).

EXAMPLE 3 Z- 1 -(4-Chlorophenyl)-2-( 1 H-imidazol- 1 -yl)ethanone, 2, 6-dichlorophenylhydrazone, hydrochloride To a stirred solution of 1 -(4-chlorophenyl)-2-(1 H-imidazol-1 -yl)ethanone (33.08 g) in ethanol (400 ml) at 70dC was added a solution of 2,6-dichlorophenylhydrazine, hydrochloride (34.16 g) in ethanol (400 ml). The mixture was heated under reflux for 6 hours, concentrated (to 250 ml) and allowed to cool. The product was filtered off and recrystallised from ethanol to give (Z)-1 -(4 chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2.6-dichlorophenylhydrazone, hydrochloride, m.p.

210-211 OC. (Analysis found: C, 49.03; H, 3.37; CI, 33.92; N, 13.45. Ca7H,4CI4N4 requires: C, 49.06; H, 3.39; Cl, 34.08; N, 13.46%).

NMR (d6-DMSO) S 5.80 (2H, singlet), 7.13-7.84(1 OH, multiplet), 9.22 (1H singlet), 9.65 (1H singlet).

The Z-stereochemistry was confirmed by X-ray crystallographic analysis.

EXAMPLE 4 E-1-(4-Chlorophenyl)-2-(1H-imidazol-1-yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride A mixture of 1-(4-Chlorophenyl)-2-(1H-imidazol-1-yl)ethanone, (2.61 g) and 2,6dichlorophenylhydrazine, hydrochloride (2.77 g) in ethanol (500 ml) was heated under reflux for 120 hours. The solution was concentrated (to 30 ml) and filtered. The filtrate was further concentrated (to 5 ml) and treated dropwise with ether (200 ml). The precipitated product was filtered off and washed with ether to give (E)-1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride, as an unstable solid, m.p. 208-9 C (decomp).

NMR (d6-DMSO) S 5.41 (2H, singlet), 6.7-7.8 (1 OH, multiplet), 7.99 (1 H singlet), 9.18 (1 H singlet).

EXAMPLE 5 E-1-(5-Chlorophenyl)-2-(1H-imidazol-1-yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride 1 -(5-Chlorothien-2-yl)-2-( 1 H-imidazol-1 -yl)ethanone (4.73 g) and 2,6-dichlorophenylhydrazine, hydrochloride (4.70 g) were dissolved in ethanol (160 ml) and heated under reflux for 18 hours. Toluene (160 ml) was added and the solution was concentrated (to 100 ml) and on cooling afforded (E)-1-(5 chlorothien-2-yl)-2-( 1 H-imidazol-l -yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride, m.p.

186-1 880C. (Analysis found: C, 42.72; H, 2.83; N, 13.15. C,5H,2Cí4N4S requires: C, 42.68; H, 2.87; N, 13.27%).

NMR (d6-DMSO) S 5.77 (2H, singlet), 7.7-8.4 (8H, multiplet), 9.30 (1 H, singlet), 9.75 (1 H, singlet).

The E-stereochemistry was confirmed by X-ray crystallographic analysis.

EXAMPLE 6 Z- 1 -(5-Chlorothien-2-yl)-2-( 1H-imidazol- 1 -yl)ethanone, 2, 6-dichlorophenylhydrazone, hydrochloride (E)-1 -(5-Chlorothien-2-yl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride (2.0 g) was dissolved in methanol (30 ml) and heated under reflux for 10 minutes. 1,2- Dichlorethane (500 ml) was then added and the solution was heated under reflux for 5 hours. On cooling the solution was filtered and the filtrate was evaporated to dryness at 400C under reduced pressure.The residue was washed with 1 2-dichloroethane and dried at 300C in vacuo to give (Z)-1 (5-chlorothien-2-yl )-2-(1 H-imidazol- 1 -yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride, as an unstable solid, m.p. 1470C (decomp).

NMR (d5-DMSO) S 5.53 (2H, singlet), 7.0-7.9 (8H, multiplet), 8.40 (1 H, singlet), 9.29 (1 H, singlet).

EXAMPLE 7 E-AndZ-1-(4-Chlorophenyl)-2-(1H-imidazol-1-yl)ethanone, 2,3,4,5,6-pentafluorophenylhydroazone, hydrochloride 1 -(4-Chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone (22.0 g) and 2,3,4,5,6pentafluorophenylhydrazine (20.0 g) were dissolved in ethanol (300 ml) containing an excess of ethereal hydrogen chloride (ca 5 ml) and heated under reflux for 1 5 hours. The solution was evaporated to dryness under reduced pressure and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (1000 ml) and extracted with dichloromethane (3 x 250 ml). The combined extracts were dried over anhydrous sodium carbonate and the solvent was evaporated off under reduced pressure to give a residue which was chromatographed on silica.Elution with 5% ethanol-chloroform gave two hydrazone free-bases, each of which were dissolved in chloroform (60 ml) and acidified with ethereal hydrogen chloride. On standing the solution derived from the less polar freebase afforded (E)-1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,3,4,5,6pentafluorophenylhydrazone, hydrochloride, m.p. 1 60-1 620C. (Analysis found: C, 46.42; H, 2.58; N, 12.60. C17H11Cl2F5N4 requires: C, 46.70; H, 2.54; N, 12.82%).

NMR (d5-DMSO) S 5.40 (2H, singlet), 7.4-7.8 (7H, multiplet), 8.80 (1 H, singlet), 9.1 5 (1 H, singlet).

Similarly, the more polar free-base afforded (Z)-1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,3,4,5,6-pentafluorophenylhydrazone, hydrochloride, m.p. 170-172 C. (Analysis found: C, 46.43; H, 2.60; N. 12.74 C17H11Cl2F2N4 requires: C, 46.70; H, 2.54; N, 12.82%).

NMR (d5-DMSO) S 5.91 (2H doublet), 7.3-7.9 (7H, multiplet), 9.28 (1 H, singlet), 10.42 (1 H, singlet).

EXAMPLE 8 E- 1 -(4-Chlorophenyl)-2-( 1 H-imidazol- 1 -yl)ethanone, 2-chlorophenylhydrazone, hydrochloride 1 -(4-Chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone (22 g) and 2-chlorophenylhydrazine, hydrochloride (19 g) were dissolved in ethanol (300 ml) and heated under reflux for 48 hours. The solution was evaporated to dryness and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (1000 ml) and extracted with dichloromethan (3 x 250 ml). The combined extracts were dried over anhydrous sodium carbonate and the solvent was evaporated off under reduced pressure to give a residue which was chromatographed on silica. Elution with 5% ethanolchloroform gave the hydrazone free-base which was dissolved in chloroform (100 ml) at 600C and acidified with ethereal hydrogen chloride.On cooling the solution afforded (E)-1 -(4-chlorophenyl)-2- (1 H-imidazol- 1 -yl)ethanone, 2-chlorophenylhydrazone, hydrochloride, m.p. 1 79-1 800 C. (Analysis found: C, 53.37; H, 4.05; N, 14.86. C17H15CI3N4 requires: C, 53.49; H, 3.96; N, 14.68%).

NMR (d6-DMSO) 5.50 (2H, singlet), 7.1-7.9 (1 OH, multiplet), 8.22 (1 H, singlet), 9.23 (1 H, singlet).

EXAMPLE 9 Z- 1 -(4-Chlorophen yl)-2-( 1 H-imidazol- 1 -yl)ethanone, 2-chlorophen ylhydrazone, hydrochloride (E)-1 -(4-Chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2-chlorophenylhydrazone, hydrochloride (20 g) was suspended in 1,2-dichloroethane (250 ml) and heated under reflux for 60 hours. On cooling the product was filtered off and recrystallised from cold ethanol-ether to give (Z)-1 -(4-chlorophenyl)-2 (1H-imidazol-l -yl)ethanone, 2-chlorophenylhydrazone, hydrochloride, m.p. 190-192 C. (Analysis found: C, 53.47; H, 3.95; Cl, 27.83; N, 14.83. C17H15Cl2N4 requires: C, 53.49; H, 3.93; CI, 27.90; N, 14.68%).

NMR (d6-DMSO) a 5.85 (2H, singlet), 6.75-7.05 (1 H, multiplet), 7.10-7.90 (9H, multiplet), 9.25 (1 H, singlet), 9.40 (1 H, singlet).

EXAMPLE 10 I -12,4-Dichlorophenyl)-2-l I H-imidazol- I-yllethanone, 2,4-dichlorophenylhydrazone, hydrochloride 1 -(2,4-Dichlorophenyl)-2-( 1 H-imidazol-l -yl)ethanone (4.9 g) and 2,4-dichlorophenylhydrazine, hydrochloride (4.7 g) were dissolved in ethanol (100 ml) and heated under reflux for 18 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in chloroform (50 ml) and acidified with ethereal hydrogen chloride. The precipitated product was filtered off and recrystallized from ethanol to give 1 -(2,4-dichlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,4- dichlorophenylhydrazone, hydrochloride, m.p. 1 92-1 940 C.

EXAMPLE 11 I -/4-Chlorophenyll-2-( 1 H-imidazol- I-yllethanone, phenyihydrazone, hydrochloride 1 -(4-Chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone (4.41 g) and phenylhydrazine, hydrochloride (3.20 g) were dissolved in ethanol (100 ml) and heated under reflux for 2 hours. The solvent was evaporated off under reduced pressure and the residue was recrystallised from aqueous ethanol to give 1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, phenylhydrazone, hydrochloride, m.p. 207-208 C.

EXAMPLE 12 (a) 1 -(4-Fluorophenyl)-2-( 1 H-imidazol- 1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride A mixture of 1-(4-fluorophenyl)-2-(1H-imidazol 1 yl)ethanone (4.08 g) and 2,4 dichlorophenylhydrazine, hydrochloride (4.7 g) in ethanol (100 ml) was heated under reflux for 16 hours. The solution was evaporated to dryness under reduced pressure and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (3 x 50 ml). The combined extracts were dried over anhydrous sodium carbonate and the solvent was evaporated off under reduced pressure to give a residue which was chromatographed on silica. Elution with 2 1/2% ethanol-chloroform gave the hydrazone free-base which was dissolved in ether (50 ml)and acidified with ethereal hydrogen chloride.The precipitated product was filtered off and recrystallised from ethanol/ethyl acetate to give 1-(4-fluorophenyl)-2-(1 H-imidazol-1 -yl)ethanone, 2,4dichlorophenylhydrazone, hydrochloride, m.p. 1 59-600C.

The following were prepared in an analogous manner: (b) 1-(4-methylphenyl)-2-(1H-imdazol-1-yl)ethanone. 2,4-dichlorophenylhydrazone.

hydrochloride, m.p. 1 82-30C.

(c) 1 -{2-chlorophenyl}-2-(1 H-imidazol-1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride. m.p. 110-2 C.

(d) 1 -(3,4-dichlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride, m.p. 196-70C.

(e) 1-(4-nitrophenyl)-2-(1H-imidazol-1-yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride m.p. 137-1390C.

EXAMPLE 13 1-(4-Methoxyphenyl)-2-(1H-imidazol-1-yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride 1 -(4-Methoxyphenyl)-2-( 1 H-imidazol-1 -yl)ethanone (4.32 g) and 2,4-dichlorophenylhydrazine, hydrochloride (4.70 g) were dissolved in ethanol (50 ml) and heated under reflux for 16 hours. The solution was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate solution, diluted with water (200 ml) and extracted with dichloromethane (3 x 100 ml). The combined extracts were dried over anhydrous sodium sulphate and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in ether (50 ml) and acidified with ethereal hydrogen chloride.The precipitated product was filtered off and recrystallised from ethanol/ether acetate to give 1 -(4 methoxyphenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride, m.p.

208209 C.

EXAMPLE 14 (a) 1-(4-Methylphenyl)-2-(1H-imidazol-1-yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride A solution of 1-(4-methylphenyl)-2-(1H-imidazol-1-yl)ethanone, (4.0 g) in ethanol (50 ml) at 700C was added to a solution of 2,4-dinitrophenylhydrazine (4.0 g) in methanolic sulfuric acid [50 ml of a 95% methanol5% sulfuric acid (18M) mixture] and heated under reflux for 16 hours. The solution was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate solution, diluted with water (200 ml) and extracted with dichloromethane (3 x 100 ml). The combined extracts were dried over anhydrous sodium sulphate, treated with acetone (5 ml) and allowed to stand at ambient temperature for 10 minutes. The solvent was evaporated off under reduced pressure and the residue was extracted with ether (2 x 50 ml).The combined extracts were filtered acidified with ethereal hydrogen chloride and the precipitated product was filtered off and recrystallised from ethanol/ethyl acetate to give 1 -(4methylphenyl)-2-(1H-imidazol-1-yl)ethanone, 2,4-dinitrophenylhydrazone, hydrochloride, m.p.

195--196"C.

The following compounds were prepared in an analogous manner: (b) 1-phenyl-2-(1H-imidazol-1-yl)ethanone, 2,4-dinitrophenylhydrazone, hydrochloride, m.p.

237-90C.

(c) 1-(4-chlorophenyl)-2-(1 H-imidazol-1 -yl)ethanone, 2,4-dinitrophenylhydrzone, hydrochloride, m.p. 219-21 0C.

(d) 1 -(4-bromophenyl)-2-( 1 H-imidazol- 1 -yl)ethanone, 2,4-dinitrophenylhydrazone, hydrochloride, m.p. 235-60C.

(e) 1-(4-fluorophenyl)-2-(1 H-imidazol-l -yl)ethanone, 2,4-dinitrophenylhydrazone, hydrochloride, m.p. 218-20 C.

(f) 1 -(4-methoxyphenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,4-dinitrophenylhydrzone, hydrochloride, m.p. 223-50C.

(g) 1 -(2-chlorophenyl)-2-(1 H-imidazol- 1 -yl)ethanone, 2,4-dinitrophenylhydrazone, hydrochloride m.p. 227-90C.

(h) 2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone. 2,4-dinitrophenylhydrazone, hydrochloride, m.p. 21 1-30C.

(i) 1 -(3,4-dichlorophenyl)-2-( 1 H-imidazol- 1 -yl)ethanone, 2,4-dinitrophenylhydrazone, hydrochloride, m.p. 286-80C.

(j) 1 -(4-nitrophenyi)-2-(1 H-imidazol-1 -yl)ethanone, 2,4-dinitrophenylhydrazone, hydrochloride, m.p. 235-80C.

EXAMPLE 15 (a) 1 -(4-Chlorophenyl)-2-( 1H-imidazol- 1 -yl)ethanone, 4-chlorophenylhydrazone, hydrochloride 1 (4-Chlorophenyl)-2-(1 H-imidazol-1 -yl)ethanone (4.41 g) and 4-chlorophenylhydrazine, hydrochloride (4.0 g) were dissolved in ethanol (100 ml) and heated under reflux for 16 hours. The solution was evaporated to dryness under reduced pressure and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with chloroform (3 x 50 ml). The combined extracts were dried over anhydrous sodium sulphate and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in ether (50 ml) filtered and acidified with ethereal hydrogen chloride.The precipitated product was filtered off and recrystallised from ethanol ethyl acetate to give 1 -(4-chlorophenyl)-2-(1 H-imidazol-1 -yl)ethanone, 4-chlorophenylhydrazone, hydrochloride, m.p. 200-201 C The following were prepared in an analogous manner: (b) 1-(4-chlorophenyl)-1-(1 H-imidazol-1 -yl)ethanone, 2-chlorophenylhydrazone, hydrochloride, m.p. 185-60C.

(c) 1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 3-chlorophenylhydrazone, hydrochloride, m.p. 209-21 OOC.

(d) 1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yI)ethanone, 2,3-dichlorophenylhydrazone, hydrochloride, m.p. 200-201 OC.

(e) 1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,5-dichlorophenylhydrazone, hydrochloride, m.p. 1 98-90C.

EXAMPLE 16 (a) 1 -(4-Chlorophenyl)-2-( 1 H-imidazol- 1 -ylVethanone, 3,4-dichlorophenylhydrazone 1 -(4-Chlorophenyl)-2-( 1 H-imidazol-1-yl)ethanone (4.41 g) and 3,4-dichlorophenylhydrazine, hydrochloride (4.80 g) were dissolved in ethanol (50 ml) and heated under reflux for 1 6 hours. The solution was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate solution and diluted with water (200 ml). The precipitated product was filtered off and recrystallised from aqueous ethanol to give 1 -(4-ch lorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone. 3,4-dichlorophenylhydrazone m.p.

207-80C.

The following was prepared in an analogous manner: (b) 1 -(4-ch lorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 3,5-dichlorophenylhydrazone, m.p.

207-80C.

EXAMPLE 1 7 1 -(2-chlorophenyl)-2-( 1 H-imidazol-l -yl)ethanone (0.22 g) and 2 ,6-dichlorophenylhydrazine, hydrochloride (0.22 g) were dissolved in ethanol (50 ml) and heated under reflux for 18 hours. The solution was evaporated to dryness under reduced pressure and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (3 x 50 ml). The combined extracts were dried over anhydrous sodium carbonate and the solvent was evaporated off under reduced pressure to give a residue which was chromatographed on silica.Elution with chloroform gave the hydrazone free-base which was dissolved in chloroform (25 ml) and treated with ethereal hydrogen chloride to give 1-(2-chlorophenyl)-2-(1 H-imidazol-1-yl)ethanone, 2,6- dichlorophenylhydrazone, hydrochloride m.p. 1 79-1 800 C.

EXAMPLE 18 1 -Phenyl-2-( 1 H-imidazol-1 -yl)ethanone (0.1 9 g) and 2,6-dichlorophenylhydrazine, hydrochloride (0.22 g) were dissolved in ethanol (50 ml) and heated under reflux for 1 5 hours. Toluene (50 ml) was added and the solution was concentrated to half-volume. On cooling the solution afforded a colourless crystalline solid which was filtered off and recrystallised from ethanol/toluene to give 1-phenyl-2-(1 H-imidazol-1 -yl(ethanone, 2,6-dichlorophenylhydrazone, hydrochloride, m.p.

189-1 9O0C.

EXAMPLE 19 1 -(2,4-Dichlorophenyl)-2-( 1 H-imidazol-l -yl)ethanone (0.30 g) and 2,6-dichlorophenylhydrazone, hydrochloride (0.22 g) were dissolved in ethanol (50 ml) and heated under reflux for 1 8 hours. The solution was evaporated to dryness under reduced pressure and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (3 x 50 ml). The combined extracts were dried over anhydrous sodium carbonate and the solvent was evaporated off under reduced pressure to give a residue which was chromatographed on silica. Elution with chloroform gave the hydrazone free-base which was dissolved in chloroform (25 ml), acidified with ethereal hydrogen chloride, heated to 600C and treated with dry toluene until turbid.On cooling the solution afforded 1 -(2,4-dichlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,6-dich lorophenylhyd razone, hydrochloride m.p. 209-2100C.

EXAMPLE 20 1 -(3-Nitrophenyl)-2-( 1 H-imidazol-1 -yl)ethanone (0.54 g) and 2,6-dichlorophenylhydrazine, hydrochloride (0.43 g) were dissolved in ethanol (50 ml) and heated under reflux for 6 hours. Toluene (50 ml) was added and the solution was concentrated to half-volume. On cooling the solution afforded a pale yellow crystalline solid which was filtered off and recrystallised from ethanol)toluene to give 1 -(3 nitrophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride m.p.

178-1 800C.

EXAMPLE 21 1 -(4-Cyanophenyl)-2-( 1 H-imidazol-1 -yl)ethanone (2.33 g) and 2,6-dichlorophenylhydrazone, hydrochloride (2.14 g) were dissolved in ethanol (100 ml) and heated under reflux for 1 5 hours. The solution was concentrated to half-volume and on cooling afforded 1 -(4-cyanophenyl)-2-(1 H-imidazol-1 yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride m.p. 217-21 90C.

EXAMPLE 22 1 -(2-Fluorophenyl)-2-( 1 H-imidazol-1 -yI)ethanone (2.0 g) and 2,4-dichlorophenylhydrazine, hydrochloride (2.2 g) were dissolved in ethanol (100 ml) and heated under reflux for 1 5 hours. The solvent was evaporated off under reduced pressure and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (200 ml) and extracted with dichloromethane (3 x 100 ml). the combined extracts were dried over anhydrous sodium carbonate and the solvent was evaporated off under reduced pressure to give a residue which was chromatographed on silica. Elution with chloroform gave the hydrazone free-base which was dissolved in dichloromethane (100 ml) and acidified with ethereal hydrogen chloride.The solvent was evaporated off under reduced pressure and the residue was recrystallised from dichloromethane/benzene to give 1 -(2-flurophenyl)-2-( 1 H-imidazol-l -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride, m.p. 1 66-1 680C.

EXAMPLE 23 1 -(4-Chlorophenyl)-2-( 1 H-imidazol-l -yl)ethanone (2.20 g) and 2-bromophenylhydrazine, hydrochloride (2.23 g) were dissolved in ethanol (100 ml) and heated under reflux for 12 hours. The solution was evaporated to dryness under reduced pressure and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (3 x 50 ml). The combined extracts were dried over an hydros sodium carbonate and the solvent was evaporated off under reduced pressure to give a residue which was chromatographed on silica. Elution with chloroform gave the hydrazone free-base as an oil which was dissolved in chloroform (25 ml). The solution was acidified with ethereal hydrogen chloride heated to 600C and treated with dry benzene until turbid.On cooling the solution afforded colourless needles of 1 -(4-chlorophenyl)-2-(1 H-imidazol 1 -yl)ethanone,2-bromophenylhydrazone, hydrochloride, m.p. 180-181 0C.

EXAMPLE 24 (a) 1-(4-bromophenyl)-2-(1H-imidazol-1-yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride 1-(4-Bromophenyl)-2-(1 H-imidazol-1-yl)ethanone (0.53 g) and 2,4-dichlorophenyl hydrazine, hydrochloride (0.43 g) were dissolved in ethanol (50 ml) and heated at reflux for 12 hours. The solution was evaporated to dryness under reduced pressure and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (3 x 50 ml). The combined extracts were dried over anhydrous sodium carbonate and the solvent was evaporated off under reduced pressure to give a residue which was chromatographed on silica. Elution with 5% ethanol/chloroform gave the hydrazone free-base as an oil which was dissolved in chloroform (25 ml).

The solution was acidified with ethereal hydrogen chloride and on starting afforded colourless crystals of 1 -(4-bromophenyl)-2-( 1 H-imidazol-l -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride m.p.

169-1720C.

The following compounds were prepared in an analogous manner: (b) 1-Phenyl-2-(1 H-imidazol-1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride m.p.

180--182"C.

(c) 1 -(2-nitrophenyl)-2-( 1 H-imidazol- 1 -yl)ethanone, 2,4-dichlorophenylhydrazone. hydrochloride, m.p. 200-201 OC.

(d) 1 -(2,4-dichlorophenyl)-2-(1 H-imidazol-1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride, m.p. 192-1 940 C.

(e) 1 -(5-chlorothien-2-yl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride, m.p. 183-1 850C.

(f) 1 (4-chlorophenyl)-2-(1 H-imidazol-1 -yl)propanone, 2,4-dichlorophenylhydrazone, hydrochloride, m.p. 114-11 60C.

(g) 1 -(2,5-dichlorophenyl)-2-(1 H-imidazol-1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride, m.p. 205-2080C.

(h) 1-(2-methoxyphenyl)-2-(1H-imidazol-1-yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride, m.p. 167-1 680C.

(i) 1-(4-chlorophenyl)-2-(1H-2-methylimidazol-1-yl)ethanone, 2,4-dichlorphenylhydrazone, hydrochloride, m.p. 204-2050C (j) 1-(4-chlorophenyl)-2-(1 H-2-ethyl-4-methylimidazol-1 -yl)ethanone, 2,4 dichlorophenylhydrazone, hydrochloride, m.p.1 90-1 920C (k) 1 -(4-chlorophenyl)-2-(1 H-2-methylimidazol-1 yl)propan-1-one, 2,4-dichlorophenyl- hydrazone, hydrochloride, m.p. 188-1 900 C.

(1)1 -(5-chlorothien-2-yl)-2-( 1 H-2-methylimidazol-1 -yl)propan-1 -one, 2,4 dichlorophenylhydrazone, hydrochloride, m.p. 180-1 820C.

(m) 1-(4-chlorophenyl)-2-(1H-2-ethylimidazol-1-yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride, m.p. 202-204 C.

(n) 1-(4-Chlorophenyl)-2-(1 H-3-methylimidazol-1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride, m.p. 189-191 0C.

EXAMPLE 25 (a) 1-(5-bromothien-2-yl)-2-(1H-imidazol-1-yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride 1 -(5-Bromothien-2-yl)-2-( 1 H-imidazol-1 -yl)ethanone (2.71 g) and 2,6-dichlorophenylhydrazine, hydrochloride (2.13 g) were dissolved in ethanol (100 ml) and heated under reflux for 24 hours. Toluene (100 ml) was added and the solution was concentrated to half-volume and then heated under reflux for a further 24 hours. The solution was evaporated to dryness under reduced pressure and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (3 x 50 ml). The combined extracts were dried over anhydrous sodium carbonate and the solvent was evaporated off under reduced pressure to give a residue which was chromatographed on silica.Elution with chloroform gave the hydrazone free-base which was dissolved in chloroform (25 ml) and acidified with ethereal hydrogen chloride. On standing the solution afforded pale-yellow crystals of 1 -(5-bromothien-2-yl)-2-(1H-imidazol-1 -yl)ethanone, 2 ,5-dichlorophenylhydrazone, hydrochloride m.p. 191-1950C The following compounds were prepared in an analogous manner: (b)l -(2,5-dichlorothien-2-yl)-2-( 1 H-imidazol-l -yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride, m.p. 194-195 C.

(c) 1-(4-bromophenyl)-2-(1H-imidazol-1-yl)ethanone. 2,6-dichlorophenylhydrazone hydrochloride, m.p. 209-2100C.

(d) 1 -(2-fluorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride m.p. 177-1780C.

(e) 1 -(4-methoxyphenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride, m.p. 192-1 940 C.

(f) 1-(4-chlorophenyl)-2-(1 H-imidazol-1 -yl)propanone, 2,6-dichlorophenylhydrazone, hydrochloride, m.p. 138-1400C.

(g) 1 -(3-carbomethoxy-4-methoxy)-2-( 1H-imidazol-1 -yl)ethanone, 2,6-dichlorophenylhydrarone, hydrochloride, m.p. 170-172 C (h) 1-(2-methylphenyl)-2-(1H-imidazol-1-yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride, m.p. 190 C.

(i) 1-(4-methylphenyl)-2-(1H-imidazol-1-yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride m.p. 184-1950C.

(j) 1 -(2-nitrophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride m.p. 192-194 C.

(k) 1-(2-trifluoromethylphenyl)-2-(1H-imidazol-1-yl)-ethanone, 2,6-dichlorophenylhydrazone, hydrochloride, m.p. 206-210 C.

(l) 1-(4-trifluoromethylphenyl)-2-(1H-imidazol-1-yl)-ethanone, 2,6-dichlorophenylhydrazone, hydrochloride, m.p. 177-178 C.

(m) 1-(3-trifluoromethylphenyl)-2-(1H-imidazol-1-yl)-ethanone, 2,6-dichlorophenylhydrazone, hydrochloride m.p. 1 98-2000C.

(n) 1-(4-chlorophenyl)-4-(1H-imidazol-1-yl)propan-2-one, 2,6-dichlorophenylhydrazone, hydrochloride m.p. 150-152 C.

EXAMPLE 26 (a) 1-r4-methoxyphenyl)-2-{lH-imidazol-1-yl)ethanone, 2,5-dichlorophenylhydrazone, hydrochloride 1 -(4-Methoxyphenyl)-2-( 1 H-imidazol- 1 -yl)ethanone (2.16 g) and 2,5-dichlorophenylhydrazone, hydrochloride (2.14 g) were dissolved in ethanol (50 ml) and heated at reflux for 18 hours. The solution was evaporated to dryness under reduced pressure and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (3 x 50 ml). The combined extracts were dried over anhydrous sodium carbonate and the solvent was evaporated off under reduced pressure. The residue was dissolved in dichloromethane (20 ml) and acidified with ethereal hydrogen chloride.The solvent was evaporated off under reduced pressure and the residue was recrystallized from ethanol/ ether to give 1 -(4-methoxyphenyl)-2-(1 H-imidazol-1 -yl)ethanone, 2,5dichlorophenylhydrazone, hydrochloride, m.p. 181-183 C.

The following compounds were prepared in an analogous manner: (b) 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethanone 2,5-dichlorophenylhydrazone, hydrochloride, m.p. 196-197 C.

(b) 1-(4-cyanophenyl)-2-(1H-imidazol-1-yl)ethanone 2,5-dichlorophenylhydrazone, hydrochloride, m.p. 195-1970C.

(d) 1-(2-fluorophenyl)-2-(1H-imidazol-1-yl)ethanone 2,5-dichlorophenylhydrazone, hydrochloride, m.p. 131-1330C.

(e) 1-(4-fluorophenyl)-2-(1- H-imidazol-1 -yl)ethanone, 2,5-dichlorophenylhydrazone, hydrochloride, m.p. 1 72-1 740C.

(f) 1 -(2-methylphenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,5-dichlorophenylhydrazone, hydrochloride, m.p. 220-221 OC.

EXAMPLE 27 (a) 1 -phenyl-2-( 1 H4midazol- 1 -yl)ethanone, 3,4-dichlorophenylhydrazone, hydrochloride 1 -Phenyl-2-(1 H-imidazol-1 -yl)ethanone (2.14 g) and 3,4-dichlorophenylhydrazone, hydrochloride (1.86 g) were dissolved in ethanol (50 ml) and heated under reflux for 16 hours. The solution was evaporated to dryness under reduced pressure and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (3 x 50 ml). The combined extracts were dried over anhydrous sodium carbonate and the solvent was evaporated off under reduced pressure. The residue was dissolved in dichloromethane (50 ml) and acidified with ethereal hydrogen chloride.The solvent was evaporated off under reduced pressure and the residue was recrystallized from ethanol/ ether to give 1 -phenyl-2-(1 H-imidazol-1 -yl)ethanone, 3,4- dichlorophenylhydrazone. hydrochloride m.p. 193-1 940 C.

The following compounds were prepared in an analogous manner: (b) 1-(4-bromophenyl)-2-(1H-imidazol-1-yl)ethanone 3,4-dichlorophenylhydrazone, hydrochloride, m.p. 195-1 960C.

(c) 1 -(4-cyanophenyl)-2-(1 H-imidazol-1 -yl)ethanone, 3,4-dichlorophenylhydrazone, hydrochloride, m.p. 2120C.

(d) 1 -(44luorophenyl)-2-(1 H-imidazol-1 -yl)ethanone, 3,4-dichlorophenylhydrazone, hydrochloride, m.p. 200-2020C.

EXAMPLE 28 (a) 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone 2,4,6-trichlorophenylhydrazone, hydrochloride 1 -(2.4-Dichlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone (2.55 g) and 2,4,6-trichlorophenylhydrazine (2.20 g) were dissolved in ethanol (100 ml) containing saturated ethereal hydrogen chloride (1 ml) and heated under reflux for 8 hours. Toluene (100 ml) was added and the solution was concentrated to halfvolume and then heated under reflux for a further 8 hours The solution was evaporated to dryness under reduced pressure and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (3 x 50 ml). the combined extracts were dried over anhydrous sodium carbonate and the solvent was evaporated off under reduced pressure to give a residue which was chromatographed on silica.Elution with chloroform gave the hydrazone free-base which was dissolved in chloroform (25 ml), and acidified with ethereal hydrogen chloride, heated to 600C and treated with dry benzene until turbid. On cooling the solution afforded 1 (2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone 2,4,6-trichlorophenylhydrazone, hydrochloride, m.p. 206-207 C.

The following were prepared in an analogous manner: (b) 1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,4,6-trichlorophenylhydrazone, hydrochloride, m.p. 156-157 C.

(c) 1-(2-chlorophenyl)-2-(1H-imidazol-1-yl)ethanone 2,4,6-trichlorophenylhydrazone, hydrochloride, m.p. 196-1 980C.

(d)1-(4-trifluoromethylphenyl)-2-(1H-imidazol-1-yl)ethanone 2,4,6-trichlorophenylhydrazone, hydrochloride, m.p. 104-106 C.

(e) 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethanone 2,4,6-trichlorophenylhydrazone, hdrochloride, m.p. 169-171 0C.

(f) 1 -(5-chlorothien-2-yl)-2-(1 H-imidazol-1 -yl)ethanone, 2,4,6-trichlorophenylhydrazone, hydrochloride, m.p. 129-1300C.

(g) 1-phenyl-2-(1H-methylimidazol-1-yl)ethanone, 2,4,6-trichlorophenylhydrazone, hydrochloride, m.p. 142-1450C.

EXAMPLE 29 1 (4-chlorophenyl)-3-(2,4-dichlorophen yl)-2 -(1 H-imidazol- 1 -yl)propanone, 4-chlorophenylhydrazone, hydrochloride 1-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-2-(1 H-imidazol-1 -yl)propanone, hydrochloride (2.08 g) and 4-chlorophenylhydrazine, hydrochloride (1.07 g) were dissolved in ethanol (50 ml) and heated under reflux for 15 hours. The solution was evaporated to dryness under reduced pressure and the residue was recrystallised from ethanol to give 1 -(4-chlorophenyl)-3-(2,4-dichlorophenyl)-2-( 1 H imidazol-1-yl)propanone, 4-chlorophenylhydrazone, hydrochloride m.p. 154-1 550C.

EXAMPLE 30 2-(4-chlorophenyl)- 1 -(4-dimethylaminophenyl)-2-( 1 H-imidazol- 1 -yl)ethanone, 2,4 dichlorophenylhydrazone, hydrochloride 2-(4-Chlorophenyl)-1 -(4-dimethylaminophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, hydrochloride (0.20 g) and 2,4-dichlorophenylhydrazine, hydrochloride (0.11 g) were dissolved in ethanol (50 ml) and heated at reflux for 1 5 hours. The solution was evaporated to dryness under reduced pressure and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with ethyl acetate (3 x 50 ml).- The combined extracts were dried over anhydrous sodium carbonate and the solvent was evaporated off under reduced pressure to give a residue which was chromatographed on silica.Elution with chloroform gave the hydrazone free-base as an oil which was dissolved in dry ether and treated with ethereal hydrogen chloride to precipitae 2-(4-chlorophenyl)-1 - (4-dimethylaminophenyl)-2-(1 H-imidazol-l -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride, m.p. 155-1570C.

EXAMPLE 31 1 -(2-fluorophen yl)-2-( 1 H-imidazol- 1 -yl)ethanone 2,3dichlorophenylhydrazine, hydrochloride 1 -(2-fluorophenyl)-2-( 1 H-imidazol- 1 -yl)ethanone (2.67 g) and 2,3-dichlorophenylhydrazine, hydrochloride (2.14 g) were dissolved in ethanol (50 ml) and heated under reflux four 16 hours. The solution was evaporated to dryness under reduced pressure and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (3 x 50 ml). The combined extracts were dried over anhydrous sodium carbonate and the solvent was evaporated off under reduced pressure. The residue was dissolved in dichloromethane (50 ml) and acidified with ethereal hydrogen chloride. The solvent was evaporated off under reduced pressure and the residue was recrystallised from ethanol to give 1 -(2-fluorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,3-dichlorophenylhydrazone, hydrochloride, m.p. 197-1 980 C.

Other compounds which have been prepared by methods analogous to those described above are identified in the table below: TABLE I

Alk Alk m Ar Ar1 m.p.

( C) - CH2 0 4-cl phenyl 4-Br phenyl 199-200 - CH2 O 4-Cl phenyl 4-CN phenyl (HCl) (HCI) - CH2 O 4-NO2 phenyl 2,6-C2 phenyl 180-2 (HCl) - CH2 O 4-F phenyl 2,6-Cl2 phenyl 181-3 (HCl) - CH2 O 4-Cl phenyl Pyrid-2-yl 235-7 (2HCl) - CH2 O 4-CN phenyl 2,4-Cl2 phenyl 190-191 (HCl) - CH (phenyl) O 4-Me2N phenyl 2,4-Cl2 phenyl 124 (HCl) - CH2 O 5-Cl Thien-2-yl 3,4-Cl2 phenyl 180-1 (HCl) - CH2 O 4-Methyl 2,4,6-Cl3 172-4 phenyl phenyl (HCl) - CH2 O 4-CN phenyl 2,4,6-Cl3 183-5 phenyl (HCl) - CH2 O 4-F phenyl 2,4,8-Cl3 165-7 phenyl (HC I) - CH2 O 4-Cl phenyl 2,3,5,6-F4 210-12 phenyl (HCl) - CH2 O 4-NO2 phenyl 2-Cl phenyl 202-5 (HCl) - CH2 O 4-NO2 phenyl 2,3,5,6-F4 196-8 phenyl (HCI) - CH2 O 4-NO2 phenyl 2,8,4,5,6-F, 179-180 phenyl (HCI) - CH2 O 4-MeO phenyl 2,4,6-Cl3 191-3 phenyl (HCI) - CH2 O 3,4-Cl2 phenyl 2,4,6-Cl3 186-8 phenyl (HCl) - CH2 O 3-MeO phenyl 2,4-Cl2 180-2 phenyl (HCI) - CH2 O 2,4-Cl2 phenyl 2-Cl phenyl 178-9 (HCl) - CH2 O 4-F phenyl 2-Cl2 phenyl 179-181 (HCl) TABLE I (Continued)

m.p.

Alk Alk m Ar Ar ( C) - CH2 O 4-NO2 phenyl 2,4,6-Cl3 185-B phenyl (HCl) - CH2 O 4-MeO phenyl 2,6-Cl2 186-8 phenyl (HCl) - CH2 O 2,4-Cl2 phenyl 2,3,4,5,6-F, 178-9 phenyl (HCl) - CH2 O 4-Cl phenyl 2,6-Me2 168-170 phenyl (HCI) - CH2 O 2,4-Cl2 phenyl 3,4-Cl2 242-3 phenyl (HCI) - CH2 O 4-F phenyl 2,3-Cl2 185-7 phenyl (HCl) - CH2 O 2,5-Cl2 phenyl 2,6-Cl2 205-8 phenyl (HCI) - CH2 O 5-Me Thien-2- 2,6-cl2 181-2 yl phenyl (HC I) - CH2 O Thien-2-yl 2,6-Cl2 179-180 phenyl (HCl) - CH2 O 2,4-Cl2 phenyl 3-CF3 phenyl 170-2 (HCl) - CH2 O 4-CN phenyl 2-Cl phenyl 176-8 (HCl) - CH2 O Phenyl 2-Cl phenyl 200-3 (HCl) - CH2 O 4-CF3 pheny 2,4-Cl2 169-171 phenyl (HCI) - CH2 O 2,6-Cl2 phenyl 2,4-Cl2 202-4 phenyl (HCl) - CH2 O Pyrid-2-yl 2,6-Cl2 212-4 phenyl (HCl) - CH2 O 5-Br-Thien- 2,4,6-Cl3 155-8 2-yl phenyl (HCl) - CH2 (phenyl) O Phenyl 2,4-Cl2 GUM phenyl - CH2 O 3-Br phenyl 2,6-Cl2 179-182 phenyl (HCl) - CH2 O 4-Cl phenyl 3-CF3 phenyl 194-6 (HCl) TABLE 1 (Continued)

m.p.

Alk Alk m Ar Ar ( C) - CH2 O 2-F phenyl 2,4-6-Cl3 197-9 phenyl (HCl) - CH2 O Thien-3-yl 2,6-Cl2 183-5 phenyl (HCl) - CH2 O Naphth-2-yl 2,4-Cl2 183-5 phenyl (HCl) - CH(CH3) O Phenyl 2,6-Cl2 160-1 phenyl [(HOOC)2] - CH(CH3) O 4-F phenyl 2,4-C2 186 phenyl (HCI) - CH2 O 4,5-Br2 Thien- 2,4-Cl2 198-9 2-yl phenyl (HC I) CH(CH2CH2CH3) O Phenyl 2,4,6-Cl3 130-2 phenyl [(COOH)2] - CH[CH2(2,4-Cl2 phenyl)] O 4-Cl phenyl 2,6-Cl2 152-3 phenyl - CH2 O 3-Br phenyl 2,4-Cl2 159-161 phenyl (HCl) - CH(CH3) O 4-F3C phenyl 2,6-Cl2 120-2 phenyl [(HOOC)2] - CH(CH3) O 4-F3C phenyl 2,4-Cl2 143-6 phenyl [(HOOC)2] - CH(CH2CH2CH3) O Phenyl 2,6-Cl2 158-160 phenyl [(HOOC)2] - CH(CH2CH2CH3) O Phenyl 2,4-Cl2 79-81 phenyl [(HOOC)2] - CH(CH3) O 5-Cl Thien- 2,4-Cl2 136-8 2-yl phenyl (HCl) - CH(CH3) O 4-F3C phenyl 2,4,6-Cl3 114-116 phenyl [(HOOC)2] - CH(CH3) O Phenyl 2,4-Cl2 113-115 phenyl - CH2 O Benzofuran- 2,4-Cl2 199-201 2-yl phenyl (HC I) - CH2 O 2-Pyridyl 2,4-Cl2 222-4 phenyl (HCl) - CH2 O 4-Cl phenyl 3-MeO phenyl 209-11 (HCl) TABLE 1 (Continued)

Alk Alk m Ar Ar ( C) - CH2 O 2-Pyridyl 2,4,6-Cl3 215-6 phenyl (HCl) - CH(CH2CH3) O Phenyl 2,4,6-Cl3 127-9 phenyl - C(CH3)2 O 4-Cl phenyl 2 4-Cl 146-7 phenyl (HCI) - CH(CH3) O 3A-Br2 Thien 2,4Cl2 160-1 2-yl phenyl (HCl) - CH2 O 5-Br Thien- 2,4-Cl2 194-5 2-yl phenyl (HC I) - CH[CH2(2,4-Cl2 phenyl)] 0 4-Cl phenyl 2 4-Cl2 130-132 phenyl - CH(CH3) O Phenyl 2,4,6-Cl3 131-3 phenyl [(COOH)2] CH2 CH2 1 4-Cl phenyl 2,4-Cl2 151-3 phenyl (HCl) - CH(CH2CH3) O Phenyl 2,4-Cl2 128 phenyl [(COOH)2] - CH(CH2CH2CH2CH3) O 4,5-Br-thien- 2,4-Cl2 148-150 2-yl phenyl (HCl) For purposes of exemplification, certain compounds according to the present invention were tested to demonstrate the anti-fungal activity thereof by oral, topical and intravenous administration to test animals and in vitro, as compared to the activity of known anti-fungal agents. Several of the present compounds proved to possess outstanding efficacy against both Candida and dermatophyte infection by either oral, intravenous or topical administration.

The number preceding the name of the compound tested is the reference number used by us, and is retained as a matter of convenience.

HC274-(E)-1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride.

HC278--1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,4-dichlorophenylhydrazone, nitrate.

HC3 1 6-1 -(2-Chlorophenyl-2-(1 H-imidazol-1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride HC344-(Z)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride HC390-(E)-1-(5-chlorophenyl)-2-(1H-imidazol-1-yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride HC415-(Z)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethanone, 2,3,4,5,6-pentafluorophenylhydrazone, hydrochloride Miconazole 1-[2-(2,4-Dichlorophenyl)-2-[2,4-dichlorophenyl)methoxy]ethyl]-1H-imidazole.

Tioconazole 1-[2-(2-Chloro-3-thienyl)methoxy-2-(2,4-dichlorophenyl)ethyl-1H-imidazole.

Ketoconazole cis- 1 -Acetyl-4-[4-[(2-(2,4-dichlorophenyl)-2-( 1 H-imidazol-1 -yl-methyl)-1 ,3-dioxolan -4-yl) methoxy]piperazine.

Clo trimazole 1 -(2-Chlorophenyl)diphenylmethyl-1 H-imidazole Effect ofHC274, Miconazole and Tioconazole on the recovery of viable candida cells from the kidneys of infected mice.

Mice receive 25 x 104 cells of C. albicans i.v. Treatments (25 mg/kg) administered in PEG/Dextrose 1 h and 24h after infection. Animals sacrificed 48 h after injection and kidneys excised, weighed, homogenized and decimal dilutions spread on glucose-peptone agar.

Treatment No. ofCFU/g kidney at 48 h p.o. i.v.

Control 2.4 x 105 2.4 x 105 HC 274 3.3 x 10 9 x 10 Miconazole 1.4 x 103 9 x 102 Tioconazole 2.2 x 103 1.2 x 103 CFU = colony forming units.

Effect of intravenous administration ofHC274 and Tioconazole at 25 mg/ml on the recovery of viable candida cells from the kidneys of infected mice.

Treatment CFU/g kidney % of control HC274 7.7 x 103 52 Tioconazole 8.1 = 103 55 Control 14.7 =103 100 Effect of oral treatment with HC274, HC3 16, HC390, HC4 15 andKetoconazole on the recovery of viable candida albicans from the kidneys of infected mice.

Recovery of C. albicans (as percentage of control) Dose 20 mg/kg 5 mglkg HC274 47.8 84.2 HC390 41.1 57.3 HC316 46.5 56.2 HC415 17.2 14.0 Ketoconazole 11.7 51.0 Effect of oral or topical administration of HC2 74 and ketoconazole on vaginal candida infection in rats.

Clearance of C. albicans from rat vagina following oral or topical treatment (as percentage of control).

Topical: HC274 95.5 Ketoconazole 99.9 Clotrimazole 100 Oral: HC274 20 mg/kg HC274 10 mg/kg Ketoconazole 10 mg/kg 91.3 94.3 99.9 Topical treatment: 1% solution in polyethylene glycol administered twice daily for 3 days.

Oral treatment: Once daily for 3 days.

Effect of oral or topical administration ofHC274, HC344, Clotrimazole, and Ketoconazole on experimental Trichophyton mentagrophytes infection in guinea pigs.

Disease rating * Days after infection 5 10 Control 100 68.0 Clotrimazole (t) 100 51.9 HC274 (40 mg/kg p.o.) 100 46.9 HC274 (t) 100 35.4 HC344 (t) 100 24.6 Ketoconazole (20 mg/kg p. o.) 100 63.7 Ketoconazole (t) 100 56.4 * Based on degree of hair loss, erythema, desquamation, Max. = 100 Treatments administered in Carbopol (!) gel, once daily days 5-10.

All drugs at 1% w/w.

(t) = topical adminstration; (p.o.) = oral administration.

The antibacterial activity of the compound HC274 according to the present invention was also compared with the activity of known anti-bacterial agents with the following results: Anti-bacterial activity ofHC274 Organism Zone diameter (MM) given by 50,ug of drug HC2 74 AMP NA PM Staphyloccoccus aureus 8 21 9 7 Streptococcus pyrogenes 9 25 0 0 Nocardia brasiliensis 12 38 7 Nocardia asteroides 11 38 0 11 Pseudomonas aeruginosa 0 0 7 10 Proteus vulgaris 0 28 25 12 Klebsiella pheumoniac 0 11 21 10 Escherichia coli 0 17 18 10 AMP = Ampicillin NA = nalidixic Acid PM = Polymyxin Furthermore, the toxicity of compound HC274 according to the present invention was measured and compared with values obtained for known anti-fungal agents.The results, obtained by conventional procedures, were as follows: 7 day acute toxicity in male mice Comparison of oral and i.v. toxicity of HC274, HC344, HC390 and known anti-fungal agents Compound LD50(mg/kg) LD12.5(mg/kg) i.v. p.o.

HC274 85 440 Miconazole 80 > 500 Tiooconazole 188 > 500 Amphotericin B 4 280 Clotrimazole 10 500 5-Fluorocytosine 500 500 HC344 780 (i.p.) > 1500 HC390 610(i.p.) > 1500 The activity of HC274 against anaerobic bacteria is shown in tests against the following strains of anaerobic bacteria (ATCC-American type culture collection; AP'-American petroleum institute):- Clostridium sporogenes ATCC 19404 Bacteroides fragills ATOC 23745 Bacteroides uniformis ATCC 8492 Desulfovibrio desulfuricans API- CORE Desulfovibrio desulfuricans API - BREWER Desulfovibrio desulfuricans API- SW2 The first three organisms are representative of species that are pathogenic in man. The D.

desulfuricans strains represent a type of microorganism that causes series problems in the recovery of oil and gas.

The tests were conducted by mixing a series of decreasing amounts of HC274 with a liquid nutrient medium that had been inoculated with one of the test organisms. These preparations were incubated for 24 hours at 37 C and were then examined for the presence of growth as indicated by turbidity in the liquid medium. Results were recorded as the lowest concentrations, in mg/@) of HC274 that prevented growth of the test organisms (minimal inhibitory concentrations). Each test was run three times. The results are tabulated below.

Minimal Inhibitory Concentrations of 74 (mg/i) Organism Test HC2 74 Metronidazole 1 2 3 1 2 3 C. sporogenes ATCC 19404 2.5 2.5 7.5 0.5 0.25 0.75 B. fragilis ATCC 23745 2.5 5.0 7.5 0.75 0.75 0.5 B. uniformis ATOC 8492 2.5 2.5 5.0 0.5 0.25 0.25 D. desulfuricans API-CORE 0.75 1.0 1.0 0.5 0.25 0.25 D. desulfuricans API-BREWER 0.75 1.0 0.5 0.5 0.5 0.5 D. desulfuricans API-SW2 1.0 1.0 1.0 0.25 0.25 0.25 The activity of the compounds identified in the Table II below was tested for antianaerobic activity against one strain of Bacteroides fragilis, one strain of Bacteroides uniformis, one strain of Clostridium sporogenes and one strain of Trichomonas vaginalis as the test organism. The methods used involved determining the minimum inhibitory concentration by the standard broth dilution method. The values for metronidazole (2-methyl-5-nitro-1 H-imidazole-1-ethanol) are given above for reference purposes. For convenience the compounds are referred to by an internal reference number (an HC number) and this is correlated with the number of the Example wherein its production is described.The results obtained show that the compounds of the invention have high activity.

The compounds are also active against Clostridium perfringens as demonstrated in similar tests to those conducted for HC274. The results for HC3 1 6 and HC390 are shown below: Minimal inhibitory Concentrations ofHC31 6 and HC390 {mg/lJ against C. perfringens KATCC 13124) HC316 HC390 Metronidazole MlC(mg/1) 0.8 3.1 0.3 TABLE IT

Compound Test Minimal Inhibitory Concentration (MIC mg/l) Ref. No.

# C. C. sporogenes B. fragilis B. uniformis T. vaginalis Ex. No. ATCC 19404 ATCC 23745 ATCC 8492 ATCC 30001 HC-274 1 2.5 2.5 2.5 5 2 2.5 5 2.5 7.5 (1) 3 7.5 7.5 .5 > 10 HC-306 1 10 10 10 50 2 2.5 2.5 2.5 50 (24(b)) 3 2.5 2.5 2.5 25 HC-316 1 1 2.5 2.5 50 2 2.5 2.5 2.5 50 (12(n)) 3 2.5 2.5 2.5 50 HC-363 1 2.5 1 2.5 50 2 2.5 2.5 2.5 50 (24(e)) 3 7.5 2.5 2.5 50 HC-364 1 10 10 10 50 2 5 2.5 2.5 50 (25(c)) 3 25 5 2.5 50 HC-378 1 50 10 10 > 50 2- 25 2.5 2.5 > 50 (24(a)) 3 25 2.5 5 50 HC-380 1 10 10 10 50 2 2.5 2.5 2.5 25 (24(d)) 3 2.5 2.5 2.5 25 HC-390 1 2.5 5 2.5 > 50 2 5 2.5 2.5 > 50 (5) 3 7.5 2.5 2.5 > 50 HC-403 1 1 5 2.5 < 50 2 7.5 2.5 2.5 7.5 (25(f)) 3 50 5 2.5 < 50 HC-420 1 10 10 10 50 2 2.5 2,5 1 50 (28(a)) 3 2.5 2.5 2.5 50 HC-433 1 1 1 0.5 75 2 2.5 2.5 5 50 (24(f)) 3 # 2.5 2.5 2.5 50 TABLE II (Continued)

Compound Test Minimal Inhibitory Concentration (MIC mg/l) Ref. No. C. sporogenes B. fragilis B. uniforms T. vaginalis Ex. No. ATCC 19404 ATCC 23745 ATCC 8492 ATCC 30001 HC-438 1 2.5 5 5 25 2 7.5 7.5 5 50 (25(1)) 3 2.5 5 5 75 HC-442 1 5 2.5 2.5 50 3 2.5 5 5 75 (27(a)) 3 2.5 5 5 100 HC-464 1 2.5 2.5 2.5 10 2 5 5 2.5 50 (26(a)) 3 2,5 5 2.5 50 HC-466 1 5 1 1 50 2 5 5 5 50 (25(a)) 3 5 5 5 50 HC-469 1 2.5 5 5 50 2 7.5 5 1 75 {26(b)) 3 1 10 2,5 100 HC-474 1 7.5 7.5 5 10 2 5 7,5 5 50 (25(m)) 3 5 7,5 7.5 50 HC-482 1 5 5 2.5 25 2 5 5 2.5 25 (28(d) ) 3 5 5 2.5 25 HC-486 1 2.5 5 2,5 50 2 5 5 2.5 50 (23) 3 5 5 5 75 HC-506 1 > 50 5 5 (27(d)) 2 > 50 5 2.5 HC-507 1 2.5 2.5 5 (31) 2 2.5 5 2.5 HC-523 1 2.5 7.5 5 50 2 2.5 5 2.5 50 (28(c)) 3 5 7.5 5 50 HC-525 1 2.5 2,5 2.5 50 2 2.5 2,5 2.5 50 (24(g)) 3 2.5 2.5 2.5 50 HC-561 1 1 1 5 > 100 2 1 2,5 7.5 > 100 (28(e)) 3 1 5 7.5 > 100 The compounds used according to the invention as anti-thrombotics were tested by the following method for their ability to inhibit platelet thromboxane generation.

Platelet rich plasma preparation Human venous blood was collected from healthy male donors, who had denied any medication in the previous 14 days. Nine volumes of blood were mixed with one volume of 3.24% trisodium citrate.

The citrated blood was centrifuged at 1 60 g for 10 mins. at 220C to obtain platelet rich plasma (PRP).

The platelets were then counted on a Coulter counter, and the platelet count was adjusted to 200,000 peril with plasma.

Thromboxane Generation The PRP was then dispensed as aliquots into micro-Eppendorf tubes, maintained at 370C in a dry bath. The compounds dissolved either in saline, ethanol, or DMSO were added in duplicate to the PRP aliquots to produce final concentrations of 0.3, 3 and 30 Mg/ml. When ethanol and DMSO were used as the vehicle, triplicate controls containing the same percentage of vehicle as the test compounds were made. The final concentration or organic solvent was never more than 0.1%, which in previous experiments had no effect on TxB2 generation.

Following a 10 min. incubation with test compounds or vehicle, collagen was added to produce a final concentration of 8 ssg/ml. The tubes were then whirly-mixed for 1 5 seconds and replaced in the dry bath for a further 10 minutes, controls received saline instead of collagen. The reaction was then stopped by rapid centrifugation, 1 500 g for 3 mins. The plasma was removed and frozen art 2900 until assayed.

Assay of Thromboxane B2 Briefly, 100 Fl aliquots, in tricine buffered saline + 0.8% gelatin (pH 8.0) of the following were incubated together for 1 hour at 37 CC: thromboxane Tx B2 (plasma extract, spiked plasma extract or standards 20 to 20,000 pg/ml), 3H-TxB2 (approximately 1 5,000 dpm) and anti-TxB2 antiserum (0.5 g/1 00 yI). The free and protein bound 3H-TxB2 were separated by ammonium sulphate precipitation followed by centrifugation. 300 yl of the supernatant was added to an aqueous scintillation fluid, and the radioactivity present was counted in a liquid scintillation counter. The binding of 3H-TxB2 in the absence of added TxB2 was approximately 55%.The least amount of TxB2 to be detected accurately in the plasma was 0.08 ng/ml. Cross reactivity with other prostaglandins is less than .005% except PGD2 which is 1%.

Thus plasma samples were assayed to give a rough approximation of TxB2 content. The plasma was then appropriately diluted and assayed in duplicate to give accurate values.

Analysis of Results The amount of TxB2 generated by the collagen was calculated by substracting mean values obtained for the saline stimulated platelets from the mean values obtained from the collagen stimulated platelets. Then the amount of TxB2 generated in the presence of each concentration of compound was expressed as a % control and dose responsive curves were then constructed to determine the concentration of compound which produced a 50% inhibition. These values known as the 1050 obtained for various compounds tested are given in table Ill below.

TABLE III

Compound Activity Ref. No. Ex, No. # C5 HC 274 1 15.9 HC 290 11 4.9 HC 336 14(9) 0.9 HC 346 16(b) 2.7 HC 365 17 3.6 HC 368 18 0.8 HC 377 19 2J HC 402 20 OJ HC 416 21 13.8 HC 418 25(k) 20.9 HC 426 22 5.5 HC 500 8 > 80 HC 501 9 < 0.78 HC 501 has also been evaluated for platelet aggregation 3 hrs. after oral administration in the retired male breeder rat model (R. N. Saunders et al, Lab. Anim. Sci., 1977, 27, 757).

ED50 (3 hr. post oral Compound administration) HC 501 0.003 mg/kg Aspiin 7.7 mg/kg Dipyridamide 6.8 mg/kg Sulfinpyrazone 4.1 mg/kg Aspirin : 2-(Acetyloxy)benzoic acid, Dipyridamide : 2,2', 2", 2"'-[(4,8-Di-1-piperidinylpyrimido [5,4-d]pyrimidine-2,6-diyl)dinitri@o]tetrakis- ethanol Sulfinpyrazone : 1 ,2-D iphenyl-4;[2-(phenylsu Ifiny l)ethy113,5- pyrazolidinedione.

EXAMPLE 32 Pharmaceutical Compositions (a) Tablets. The active imidazole compound (e.g. HC274) is ground to a fine powder, blended with starch and lactose, and moistened with water before granulation. The granule mass is then milled, blended with magnesium stearate and compressed into tablets. The amount of active ingredient used was such as to provide 50 mg of active ingredient per tablet.

(b)-Creams. Creams may be prepared by dissolving an appropriate amount of the active ingredient (e.g.

HC344) in Polyethylene Glycol 400 and then blending with Polyethylene Glycol 4000 in a 60:40 ratio.

A suitable concentration of active ingredient in the cream is from 1 to 5%.

(c) Suppositories. A suppository may be made by dispensing the active ingredient (e.g. HC344) in a suitable molten base in an appropriate amount and allowing the mass to solidify in a mould.

Claims (35)

CLAIMS:

1. Compounds of the general formula:

wherein Ar and Ar1, which may be the same or different, each represents an aromatic radical which may be substituted one or more times by halogen and/or nitro and/or lower alkyl and/or trihalomethyl and/or cyano and/or lower alkoxy and/or di-lower alkyl-amino, the alkyl group optionally completing a ring optionally incorporating a further heteroatom, and/or lower alkyl sulphonyl; Alk1 and Alk2, which may be the same or different, each represents an alkylene group containing from one to eight carbon atoms which may be substituted one or more times by aryl and/or cycloalkyl and/or lower alkyl, and if two such alkyl groups are present, they may complete a ring optionally containing a heteroatom; and in which the imidazole ring may be further substituted and m represents 0 or 1; provided that not both Ar and Ar1 represent phenyl; and acid addition salts thereof.

2. Compounds as claimed in claim 1 wherein the alkylene group represented by Alk1 or Alk2 contains 1 to 3 carbon atoms.

3. Compounds as claimed in claim 1 or claim 2 wherein the imidazole ring is unsbstituted.

4. Compounds as claimed in any of claims 1 to 3 wherein Ar and Ar1, which may be the same or different, each represents optionally substituted phenyl, thienyl or pyridyl.

5. Compounds as claimed in claim 4 wherein Ar and/or Ar1 is/are substituted at least once by halogen and/or trihalomethyl and/or cyano.

6. Compounds as claimed in any of claims 1 to 5 wherein Ar and Ar1, which may be the same or different, each represents phenyl; 2-; 3- or 4-chlorophenyl; 2,3-; 2,4-; 2,5-; 2,6-; 3,4- or 3,5dichlorophenyl; 2,4,6-trichlorophenyl; 2-; 3- or 4-bromophenyl; 2- or 4-fluorophenyl; 2- or 4methylphenyl; 2- or 4-methoxyphenyl; 3-trifluoromethylphenyl; 4-cyanophenyl; 4dimethylaminophenyl; 4-methylsulphonylphenyl; 2-thienyl; 5-chloro-2-thienyl; 2-pyridyl, or 2-; 3- or 4nitrophenyl.

7. Compounds as claimed in any of claims 1 to 6 wherein Alk2 represents -OH2-; and m represents 0.

8. Compounds as claimed in claim 1 wherein Ar represents 4-chlorophenyl; and Ar1 represents 2,4-dichlorophenyl.

9. Compounds as claimed in claim 1 wherein Ar represents 4-chlorophenyl; and Ar1 represents 2,6-dichlorophenyl.

10. Compounds as claimed in claim 1 wherein Ar represents 2-chlorophenyl; and Ar1 represents 2,4-dichlorophenyl.

11. Compounds as claimed in claim 1 wherein Ar represents 4-chlorophenyl; and Ar1 represents 2,3,4,5,6-pentafluorophenyl.

12. Compounds as claimed in claim 1 wherein Ar represents 2,4-dichlorophenyl; and Ar represents 2,4,6-trichlorophenyl.

13. Compounds as claimed in claim 1 wherein Ar represents 4-chlorophenyl; and Ar1 represents 2-chlorophenyl.

14. Compounds as claimed in claim 1 wherein Ar represents 5-chlorothien-2-yl and Ar1 represents 2,6/dichlorophenyl.

1 5. Compounds as claimed in claim 1 wherein Ar represents phenyl; and Ar1 represents 2,4dichlorophenyl.

16 (E)-1 -(4-chlorophenyl)-2-( 1 K-imidazol-1 -yl)ethanone, 2,4-dichlorophenylhydrazone, hydrochloride.

1 7. (Z)- 1 -(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)ethanone, 2,6-dichlorophenylhydrazone, hydrochloride.

18. (E)-1 -(5-chlorothienyl-2-yl)-2-( 1 H-imidazol-1 -yl)ethanone. 2,6-dichlorophenylhydrazone, hydrochloride.

1 9.(Z)-1 -(4-chlorophenyl)-1 -(1 H-imidazol-1 -yl)ethanone, 2-chlorophenylhydrazone, hydrochloride.

20. 1 -(2,4-dichlorophenyl)-2-(1 H-imidazol-1 -yl)ethanone, 2,4,6-trichlorophenylhydrazone, hydrochloride.

21. (Z)-1 -(4-chlorophenyl)-2-( 1 H-imidazol- 1 -yl)ethanone, 2,3,4,5,6-pentafluorophenylhydrazone, hydrochloride.

22. Compounds as claimed in claim 1 substantially as herein described.

23. Compounds as claimed in claim 1 substantially as herein described with reference to the Examples.

24. A process for the preparation of a compound as claimed in claim 1 which comprises reacting a compound corresponding to the following general formula II:

wherein Ar, Alk1, Alk2 and m are as defined in Claim 1; with a compound corresponding to the following general formula: Ar1-NH-NH2 wherein Ar1 is as defined in claim 1; the reactants optionally being used in the form of acid addition salts and the product optionally being isolated as, or converted into, an acid addition salt and optionally converting the resulting compound into an acid addition salt thereof.

25. A process as claimed in claim 24 in which-the reaction is effected at an elevated temperature and in the presence of a solvent and an acidic catalyst.

26. A process as claimed in claim 24 substantially as herein described.

27. A process as claimed in claim 25 substantially as herein described with reference to the Examples.

28. Compounds as claimed in claim 1 when prepared by a process as claimed in any of claims 24 to 27.

29. A pharmaceutical composition which comprises a compound as claimed in any of claims 1 to 23 or 28 and a pharmaceutically acceptable carrier and/or diluent.

30. A composition as claimed in claim 29 substantially as herein described.

31. A composition as claimed in claim 29 substantially as herein described with reference to the Examples.

32. A process for the preparation of a composition as claimed in claim 29 substantially as herein described.

33. A process for the preparation of a composition as claimed in claim 29 substantially as herein described with reference to the Examples.

34. A composition as claimed in claim 29 when prepared by a process as claimed in claim 32 or claim 33.

35. The pharmaceutical use of a compound as claimed in any of claims 1 to 23 or 28 or a composition as claimed in any of claims 29 to 31 or 34.