ARYLIMIDAZOLES, THEIR SYNTHESIS AND PHARMACEUTICAL OR VETERINARY PREPARATIONS CONTAINING THEM

Abstract: Fluorosubstituted benzaldehydes are condensed with anisil and ammonium acetate to yield the corresponding 2-(fluorosubstituted phenyl)-4,5-bis(p-methoxyphenyl)-imidazoles. Alternatively fluorosubstituted benzaldehydes are condensed with anisil monoxime and ammonium acetate to yield the corresponding 2-(fluorosubstituted phenyl)-4,5-bis (p-methoxyphenyl)-imidazole-3-oxides which can subsequently be reduced to yield the corresponding 2-(fluorosubstituted phenyl)-4,5-bis(p-methoxyphenyl)-imidazoles. These imidazoles have interesting pharmacological properties.

Description: The present invention relates to novel imidazole derivatives and to processes for their preparation, The novel compounds possess intercsting physiological properties, Certain substituted imidazoles have been described in the literature and these have been prepared in a number of different ways and for varoius purposes. In Davidson, Weiss and Jelling: J. Org. Chem 2, 319 (1937); Brederech and Theilig: Chem. Ber. 86, 88 (1953); Bederech, Gompper and Hayer: Chem. Ber. 92, 338 (1959); lihit-e and Sonnenberg: J. Org. Chem, 29, 1926 (1964); Ogata, Kawasaki and Sugiura: J. Org. Chem. 34, 3981 (1969); 1. Lettau: Z Chem. 11, 10 (1971) and Wegner and Schunack: Arch. Pharmaz, 307, 492 (1974) various imidazoles are prepared without any indication as to their utility. Radziszewski: Chem. Ber. 10, 70 (1877), Cook and Jones: J. Chem Soc. 278 (1941) and others have found that a number of arylimidazoles exhibit chemiluminescence under certain conditions. This property can be utilized in certain copying techniques (e.g. xerography) and forms the basis of German Patent No. 1,106,599, Belgian Patent No. 585,555 and French Patent No. 1,351,818. Certain 2,4,5-triarylimidazoles have been tested as anti-fertility agents by Bhaduri and Khanna: Indian J Chem. 4, 419 (1966). Certain 2-alkyl-4,5-diarylimidazoles are describedin German Offenlegungsschrift No. 2,064,520 as possessing analgesic, antiinflammatory and antipyretic activity. One of the preferred compounds of this series, 2-isopropyl 4,5-bis(2methoxyphenyl) imidazole, has been included'in the pharmacological tests described hereinafter, from which it can be seen that this preferred compound possesses a much weaker analgesic activity than the compounds of the present invention. Certain 2,4,5-trisubstituted imidazoles containing a trifluoromethyl group in one of these positions and in some cases also substituted in the l-position have been described in German Offenlegungsschrift No. 2,155,558 (cf. Lombardino and Wieseman: J Med. Chem. 17, 1182 (1974)). The preferred compound of this series, 2-trifluoromethyl- 4,5-bis (p-metho,ryphenyl) imidazole, has been included in the pharmacological data hereinafter described from which it will be seen that tests indicate this preferred compound to possess a weaker analgesic activity, but a higher toxicity than the compounds of the present invention Our British Patent No. 1,469,532 describes and clays certain imidazoles substituted in the l-position by an acetic acid or propionic acid group or ester thereof. Our investigations on animal models conventionally employed in pharmacology using such compounds show that in general, arylimidazoles substituted in the l-position by a propionic acid group are more active than the corresponding imidazole unsubstituted in the 1-position. The present invention is based on the discovery of certain 2-(fluoro-substituted phenyl)-4,5-bis (±-methoxy phenyl)-imidazoles unsubstituted in the l-position which possess substantially improved properties over the compounds disclosed in German Offenlegungsschrift Nos. 2,064,520 and 2,155,558 and more particularly show improved activity over l-(2-carhoxyethyl)-2-(±-fluorophenyl)-4,5-bis(±-methoxy phenyl)- imidazole, a corresponding imidazole substituted in the l-position by a propionic acid group. Thus according to the present invention there are provided compounds of the formula: EMI4.1 wherein one or two of the substituients R2, R , R4, R5 und R6 represent a fluorine atom while the remaining substituents are hydrogen atoms. Examples of compounds according to the present invention are: 2-(2-Fluorphenyl)-4,5-bis(p-methoxyphenyl)imidazole 2-(3-Fluorphenyl)-4,5-bis(p-methoxyphenyl)imidazole 2-(4-Fluorphenyl)-4,5-bis(p-methoxyphenyl)imidazole 2-(2,3-Difluorphenyl)-4,5-bis(p-rr,ethcxyphenyl)imidazole 2-(2,4-Difluorphenyl)-4,5-bis-(p-methoxyphenyl)-imidazole 2-(2,4-Difluorphenyl)-4,5-bis-(p-methoxyphenyl)-imidazole 2-(2,6-Difluorphenyl)-4,5-bis(p-methoxyphenyl)imidazole 2-(3,4-Difluorphenyl > -4,5-bis(p-methoxyphenyl)imi.dazOie 2-(3,5-Difluoxphenyl)-4,5-bis(p-methoxyphenyl)iMidazole Tests which we have conducted show the compounds of the invention are potent prostaglandin synthesis inhibitors both in vjtro and in vivo and possess interesting pharmacological properties. In particular the compounds of the invention exhibit good analgesic, antlinflanimatory and antipyretic activity whilst possessing low ulcerogenicity and toxicity The potency of the compounds of formula I is of the same order of magnitude. The compounds of the present invention were submittcd to a pharmacological screening programme comprising the following tests: Tests or analgesic activity 1. Writhing test in mice. (SPF females of the strain NMRI/BOM, weighing 20-25 g). The test substance was administered by gavage 1/2 hour prior to an intraperitoneal injection of acetic acid. The number of writhing movements in 20 minutes was counted. 2. Randall-Selitto test in rats. (SPF males of the strain Sprague-Dawley, weighing 90-100 g). The test was performed on the whole as described by Randall and Selitto: Arch. Int. Phanmacodyn. Ther. 111, 409 (1957). An analgesia-meter of the make Ugo Basile was used and the test substance was adininistered by gavage 2 hours after injection of a suspension of brewer S yeast into the rat paw. Test for antiinflammatory activity in rats SPF inales of the strain Sprague-Dawley, weighing rv 1.50 g were used. The test was performed according to Winter et al.: Proc. Soc. Exp. Biol. Med. 111, 544 (1962). The test substance was given by gavage 1 hour prior to injection of a carrageenin-suspension into the rat paw. Test for acute toxicity (LD50) in mice The test substance was administered by gavage. Observation period: 168 hours Ulcerogenic activity in rats SPF males of the strain Sprague-Dawley weighing 180-250 g were used. 5 hours after administration by gavage of the test substance the rats were kiiled by an overdose of ether. The stomachs were removed and opened along the greater curvature The number of ulcers was assessed and compared to control rats. Prostaglandin-svnthetase inhibition test Performed on the whole according to Vane: Nature New Biol. 231, 232 (1972). Platelet aggregation inhibition test The ability of the test substance to inhibit arachidonic acid induced aggregation of human platelet rich plasma was tested in a HU aggregometer (from H. Upchurch & BR< Co. ttd.). Table 1 comprises the results of the phqrmacological screening of the following fifteen compounds: Compound No. 1. 1- (2-Carboxyethyl) -2- (p-fluorphenyl) -4,5-his (p-mct1-1oxy- phenyl)imidazole. 2. 2-(o-Fluorphenyl)-4,5-bis-(p-methoxyphenyl)imidazole 3. 2- (m-Fluorphenyl) -4 ,5-bis (p-methoxyphenyl) imidazole . 4. 2-(p-Fluorphenyl)-4,5-bis(p-methoxyphenyl)imidazole. 5. 2-(2,3-Difluorphenyl)-4,5-bis-(p-methoxyphenyl)imidazole 6.. 2-(2,4-Difluorphenyl)-4,5-bis(p-methoxyphenyl)imidazole. 7. 2-(2,5-Difluorphenyl)-4,5-bis-(p-methoxyphenyl)imidazole. 8. 2-(2,6-Difluorphenyl)-4,5-bis-(p-methoxyphenyl)imidazole 9. 2-(3,4-Difluorphenyl)-4,5-bis-(p-methoxyphenyl)imidazole 10. 2-(3,5-Difluorphenyl)-4,5-bis-(p-methoxyphenyl)imidazole 11. 2-Trifluormethyl-4,5-bis-(p-metoxyphenyl)imidazole. 12. 2-Isopropyl-4,5-bis-(p-methoxyphenyl)imidazole. 13. Indomethacin. 14. Naproxen 15. Acetyl salicylic acid. TABLE 1 The doses stated for ED50 and LD50 are mg/kg Analgesic ED50 Inhibition of Compound Antiinflam- Acute Ulcerogenic Inhibition of platelet No. Writhing Analgesia- matory test toxicity activity PG-synthetase aggregation test meter ED50 LD50 ED50 IC50 IC100 g/10 g AA+ g/190 g AA+ 1 > 200 > 2000 2 15 0,3 130 > 2000 590 3 3,2 0,25 38 > 2000 870 4 5 0,3 14 1900 360 0,18 0,048 5 4,6 0,55 120 > 2000 800 0,21 0,024 6 4 0,8 47 > 2000 > 300 0,27 0,12 7 16 0,55 110 > 2000 1000 1,71 0,024 8 6,8 0,55 300 > 2000 > 300 0,13 0,012 9 1,9 0,062 15 > 2000 0,006 10 10 0,45 150 780 11 75 25 > 2000 450 0,06 12 200 > 2000 13 8 0,36 28 21 9,7 0,65 1,19 14 33 1,6 10 1340 19,5 0,49 4,76 15 100 350 1700 340 7,61 2,38 AA+ = Arachidonic acid The compounds of the present invention may be prepared by the following processes: : a) the reaction of anisil and ammonium acetate with a compound of the formula: EMI9.1 where one or two of the substituents R2, R3, R4, R5 and R6 represent a fluorine atbm, while the remaining substituents represent hydrogen atoms, whereby a compound of formula I as hereinbefore defined is obtained. The reaction may, for example, be effected in a manner analogous to the method of white and Sonnenberg: J. Org. Chem. 29, 1926 (1964). Thus anisil, ammonium acetate and the appropriate aldehyde are reacted together conveniently in the presence of a protic solvent, preferably acetic acid. It is convenient to use the anisil and aldehyde in equimolar quantities in which case it is advantageous to use about five times the equimolar amount of ammonium acetate. It is convenient to use about 2 litres of solvent e.g. acetic acid per mole of anisil The reaction is conveniently effected at the reflux temperature of the reaction mixturc, but lower 4temperatures will also lead to the desired product. The precise proportion between the reactants, the concentration of each reactant and the reaction temperature is not of vital impcrtance. b) the reduction of a compound of the formula: EMI10.1 where R2, R3, R4, R5 and R6 are as hereinbefore defined, whereby a compound of formula I as hereinbefore defined is obtained. The reduction is advantageously effected in the presence of zinc, preferably in powder form,and is conveniently effected at the reflux temperature of the reaction mixture. The compound of formula III is preferably first prepared by reacting anisil monoxime with-ammoniurn acetate and a compound of formula II as hereinbefore defined. The reaction and reduction may, for example, be effected in a manner analogous to the method of,ll Lettnu: Z hem. 11, 10 (1971). Thus anisil monoxime, ammonium acetate and the appropriate aldehyde are reacted together advantageously in the presence of a lower alkanoic acid, e.g. acetic acid, and the 3-oxide thus obtained is reduced, preferably in situ i.e. without isolation, conveniently by the addition of zine preferably in the form of a powder. It is convenient to use the anisil monoxime and aldehyde in equimoiar quantities in which case it is advantageous to use about ive times the equimolar amount of ammonium acetate. The amount of solvent used is conveniently 2 litres per mole of anisil monoxime The reaction is preferably effected at the reflux temperature of the reaction mixture. According to a still further feature of the present invent ion there are provided pharmaceutical or veterinary for the treatment of human patents or domestic mammals compositions/comprising as active ingredient at least one compound of formula I as hereinbefore defined in association with a pharmaceutical or veterinary carrier or excipient. The compositions may be presented in a form suitable for oral, topical, rectal or parenteral administration or in a form for inhalation. Thus, for example, the compositions may be solid or liquid and may take the fonn of granules, tablets, coated tablets, capsules, syrups, suppositories, ointments, creams, emulsions; suspensions, drops or injectable solutions, such compositions comprising carriers or excipients conventionally used in the pharmaceutical and veterinany art. Advantageously, the compositions may be formulated as dosage units, each unit being adapted to-supply a fixed dose of active ingredient. Tablets, coated tablets and capsules are examples of suitable dosage unit forms. Each dosage unit preferably contains 10 to 500 mg of active - ingredient, the total daily dosage is 2-5 mg/kg body weight. The present invention also includes as a feature thereof the compounds of the general formula: EMI13.1 where R2, R , R4, R5 and R6 are as hereinbefore defined. The following Examples illustrate the preparation of compounds according to the invention: Example 1 2-(p-Fluorphenyl)-4,5-bis (p-methoxyphenyl)imidazole 800 ml of acetic acid, 310 g (4.0 mole) of ammonium acetate, 108 g (0.4 mole) of anisil and 50 g (0.4 mole) of p-fluorobenzaldehyde are refluxed together for one hour. Boiling water is then added to the clear solution until a slight turbidity persists and the heating is stopped. After cooling the white precipitate formed is filtered 'off, washed with 2N ammonia and then with water, dried and recrystallised from 2-propanol. Yield of recrystallised product: 119.7 g (80%). The product is homogenous by TLC and shows a melting point of 207.5 - 210.5 C. EMI14.1 <tb> <SEP> C <SEP> H <SEP> N <tb> C23H19FN2O2 <SEP> Calc. <SEP> 74.28 <SEP> 5.15 <SEP> 7.53 <tb> (374.40) <SEP> Found <SEP> 73.95 <SEP> 4.91 <SEP> 7,51 <SEP> <tb> The mass spectrum shows a molecular ion at m = 374 C (base peak), m/e = 359 (M-15), metastable mx/e = 345 (correspond ing to the fragmentation M+ # (M-15)+). The IR-spectrum shows the following characteristics: 3450 cm-Ú (broad) NH; 3100-2900 cm-Ú NH and CH (aromatic); 2840 cm-Ú CH(OCH3) 1620, 1525, 1505 cm-Ú aromatic ring 2840 cm CH COCH3, 1620, 1525, 1505 cm aromatic ring -1 aryl-OCH: 835 cm-1 system; 1250, 1035 cn aryl-OCIJ3; 835 cm 1,4-substituted benzene rings. The NMR-spectrum shows the following characteristics: 6(ppm) = 3.87, singlet (6H) (CH30) x 2 7,0: /.6, AB quartet (8H) (C6H4OCH3) x 2 7.1, triplet (2H) 7.9, doublet of doublets (2H) (C6H4F) ¯10.5, broad singlet (1H) (NH) Example 2 2-(2 ,4 -Difluorophenyl)-4 5-bis(n methoxyphehyl) imidazole 210 ml of acetic acid, .84 g (1.09 mole) of amnonium acetate, 28.4 g (0.105 mole) of anisil and 14.95 g (0.105 mole) of 2,4-difluorobenzaldehyde are refluxed together for one hour. The heating is stopped and boiling water is added to the clear solution until a slight turbidity persists After cooling the white precipitate formed is filtered off, washed with 2N ammonia and then with water, dried and recrystallised from 2-propanol. Yield of recrystallised product: 34.9 g (85%). The product is homogenous by TLC and shows a melting point of 137 - 80 C. EMI16.1 <tb> <SEP> C <SEP> H <SEP> N <tb> C23H18F2N2O2 <SEP> Calc. <SEP> 70.38 <SEP> 4.62 <SEP> 7.18 <tb> (392.39) <SEP> Found <SEP> 70.45 <SEP> 4.50 <SEP> 7.11 <tb> The mass spectrum shows a molecular ion at m/e = 392 (base peak),m/e = 377 (M-15), metastable mx/e = 363 (corresponding to the fragmentation M+ - > (M-15)+).. The IR-spectrum shows the following characteristics: 3470 cm-1 (sharp) NH; 3500-3400 cm-1 (broad) NH; 31003000 cm 1 CH (aromatic); 2845 cm CH (OCH3); 1620, 1525, 1500 cm-1 aromatic ring system: 1250, 1035 cm-1 aryl-O-CH3; 855, 845,, 835 cm-1 1,4-substituted benzene rings. The NMR-spectrum shows the following characteristics: 6(ppm) - 3.82, singlet (6H? (CH30) x 2 6.9; 7.5, AB quartlet (8H) (C6H4OCH3) x 2 6.9, multiples (2H) ) (C6H3F2) 8.4, multiplet (1H) ) 9.. 5, broad singlet (1H) (NH) 2,4-Difluorobenzaldehyde can be prepared from 2,4difluorotoluene according to Gunther Lock: Montash. 90 680 (1959). Example 3 2-(p -Pluorophenyl)-4,5-bisb -methoxyphenyl)imidazole '28.5 g (0.1 mole) of anisil monoxime, 20 g (0.26 mole) of ammonium acetate, 12.4 g (0.1 mole) of p-fluorobenzaldehyde and 200 ml of acetic acid are refluxed together. After 2 hours, 20 g of zinc powder are added to the reaction mixture in small portions, and the refluxing is continued for a further 4 hours After cooling, the precipitate of zinc acetate and unreacted zinc powder is filtered off and discarded. The filtrate is added dropwise to one litre of water with vigorous stirring. The precipitate formed is filtered off, washed by suspension first in 2N ammonia and then in water, dried and finally recrystallised from 2propanol Yield of recrystallised product: 29 g (74%) Melting point: 208 - 2100C IR spectrum identical with the IR-spectrum of the product from Example 1. Example 4 2-(2 ,4 -Difluorphenyl)-4,5-bis (p -methoxyphenvl)imidazole 28.5 g (0.1 mole) of anisil monoxime, 20 g (0.26 mole) of ammonium acetate, 14.2 g (0.1 mole) of 2,4-difluoro- benzaldehyde and 200 ml of acetic acid are refluxed together After 2 hours, 20 g of zinc powder are added to the reaction mixture in small portions, and the refluxing is continued for a further 4 hours0 After cocling the preCipifate of zinc acetate and unreacted zinc powder is filtered off and discarded, The filtrate is added dropwise to one litre of water under vigorous stirring. The precipitate formed is filtered off, washed by suspension first' in 2N ammonia and then in water, dried and finally recrystallised from 2-propanol. Yield of recrystallised product: 32.3 g (82%). Melting point: 137-80C IR-spectrum identical with the IR-spectrum of the product from Example 2. Example 5 2-(m-fluorophenyl)-4,5-bis(p-methoxyphenyl)imidazole 380 ml of acetic acid, 151 g (1.96 mole) of ammonium acetate, 51 g (0.19 mole) of anisil and 23.5 g (0.189 mole) of m-fluorobenzaldehyde are refluxed together for one hour. Boiling water is then added to the clear solution until a slight turbidity persists and the heating is stopped. After cooling the white precipitate formed is filtered off, washed with 2N ammonia and then with water, dried and recrystallised from 2-propanol. Yield of recrystallised product: 40.5 g (57t). The product is homogenous by TLC and shows a felting point of 221.7-223.7 C. The IR-spectrum (KBr) shows the following characteristics: 3440 cm (broad) NH; 3100-2900 cm NH and CH (aromatic) ; 2840 cm 1 CH (OCH3) ; 1620, 1525 and 1495 cm 1 aromatic ring system; 1250 and 1035 cm 1 aryl-OCH3; 835 cm 1 1,4-substituted benzene rings. The 60 Hz 1H NMR-spectrum of a 10% solution in DMSO-d6 shows the following characteristics: #(ppm) = 3.85 singlet (3H) (CH3) 3.90 singlet (3H) (CH30) 7.1; 7.7 AB quartet (8H) (C6H4OCH3) x 2 EMI19.1 <tb> -7.3 <SEP> (pattern <SEP> not <SEP> resolved) <SEP> (1H) <tb> 8.1 <SEP> multiplet <SEP> (2H) <tb> 13.1 broad singlet (1H) (NH) Example 6 2-(o-fluorphenyl)-4,5-bis-(p-methoxyphenyl)imidazole 380 ml of acetic acid, 151 g (1.96 mole) of ammonium acetate, 51 g (0.19 mole) of anisil and 23.5 g (0.189 mole) of o-fluorobenzaldehyde are refluxed together for one hour. Boiling water is then added to the clear solution until a slight turbidity persists and the heating is stopped. After cooling the white precipitate formed is filtered off, washed with 2N ammonia and then with water, dried and recrystallised from 2-propanol. Yield of recrystallised product: 46.0 g (65%). The product is homogenous by TLC and shows a melting point of 97.2-104.4 C. The IR-spectrum shows the following characteristics: 3460 cm 1 (broad) NH; 3100-29D0 cm NH and CH (aromatic); 2845 cm 1 CH (OCH3,; 1620, 1525 and 1500 cm 1 aromatic ring system; 1250 cm-1 and 1035 cm 1 aryl-OCH3; 840 cm-1 1,4-substituted benzene rings. The 60 Mflz 1H NMR-spectrum of a 10% solution in DMSO-d6 shows the following characteristics: # (ppm) = 3.80 singlet (3H) (CH30) 3.85 singlet (3H) (CH3O) 7.1; 7.6 AB quartet (8H) (C6H4OCH3) x 2 EMI20.1 <tb> -7.3 <SEP> (pattern <SEP> not <SEP> resolved) <SEP> (2H)1 <SEP> <tb> -7.5 <SEP> (pattern <SEP> not <SEP> resolved) <SEP> (1H) <SEP> (C6H4F) <SEP> <tb> <SEP> 8.2 <SEP> doublet <SEP> of <SEP> doublets <SEP> (1H) <SEP> <tb> 12.8 broad singlet (1H) (NH) Example 7 2-(2,5-difluorphenyl)-4,5-bis-(p-methoxyphenyl)imidazole 200 ml of acetic acid, 77 g (1.0 mole) of ammonium acetate, 27 g (0.1 mole) of anisil and 14.95 g (0.105 mole) of 2,5-difluorobenzaldehyde are refluxed together for one hour. Boiling water is then added to the clear solution until a slight turbidity persists and the heating is stopped. After cooling the white precipitate formed is filtered off, washed with 2N ammonia and then with water, dried and recrystallised from 2-propanol. Yield of recrystallised product: 28.2 g (69%). The product is homogenous by TLC and shows a melting point of 140.1-141.6 C. The IR-spectrum (KBr) shows the following characteristics: 3460 cm 1 (broad) NH; 3100-2900 cm-1 NH and CH (aromatic) ; 2850 cm 1 CH (OCH3) ; 1622, 1525 and 1500 cm 1 aromatic ring systems; 1250 cm 1 (assym.) and 1035 cm (sym.) C-O-C; 838 cm 1,4-disubstituted benzene rings. The 60 VlHz H NMR-spectrum of a 10% solution in DMSO-d6 shows the following characteristics: 6(ppm) = 3.90 singlet (6H) (CLi3O) x 2 7.3; 7.9 AB quartet (8H) (C6H40CH3) x 2 EMI21.1 7.6 <SEP> multiplet <SEP> (2H) <tb> (C6H3F2) <tb> 8.2 <SEP> multiplet <SEP> (1H) <tb> 13.1 broad singlet (1H) (NH) The 2,5-difluorobenzaldehyde used as a starting compound can be prepared from 1,4-difluorobenzene in the same way as described for 2,6-difluorobenzaldehyde by A.M. Roe et al.: J. Med. Chem. 11 (1968) 814. b15 = 54-56 C. Example 8 2-(2,6-difluorophenyl)-4,5-bis(p-methoxyphenyl)imidazole 200 ml of acetic acid, 77 g (1.0 mole) of ammonium acetate, 27 g (0.1 mole) of anisil and 14.95 g (0.105 mole) of 2,6-difluorohenzaldehyde are refluxed together for one hour. Boiling water is then added to the clear solution until a slight turbidity persists and the heating is stopped. After cooling the white precipitate formed is filtered off, washed with 2N ammonia and then with water, dried and recrystallised from 2-propanol/diisopropylether (1/1). Yield of recrystallised product: 16.7 g (42t). The product is homogenous by TLC and shows a melting point of 156.4-157.4 C. The IR-spectrum (KBr) shows the following characteristics: 3460 cmll (broad) NH; 3140-2900 cm CH (aromatic); 2845 cm-1 CH (OCH3); 1620, 1525 and 1500 cm aromatic ring systems; 1250 cm-1 (assym.) and 1035 cm-1 (sym.) C-O-C; 850 and 840 cm 1 1,4-disubstituted benzene rings. The 60 EWz 1H NMR-spectrum of a 10% solution in DMSO-d6 shows the following characteristics: #(ppm) = 3.83 single.t (3H) (CH30) 3.80 singlet (3H) (CH3O) 7.0; i7.5 AB quartet (4H) (CgH4OCH3) 7.1; 7.6 AB quartet (4H) (C6H4OCH3) -7.2 hidden signal (1H) (C6H3F2) 7.45 triplet (2H) (C6H3F2) 12.9 ppm broad singlet (1H) (NH) The 2,6-difluorobenzaldehyde used as a starting compound can be prepared as described by A.M. Roe et al.: J.Med. Chem. 11 (1968) 814. b21 = 88-900C. Example 9 2-(2,3-difluorophenyl)-4,5-bis(p-methoxyphenyl)imidazole 200 ml of acetic acid, 77 g (1.0 mole) of ammonium acetate, 27 g (0.1 mole of anisil and 14.95 g (0.105 mole) of 2,3-difluorobenzaldehyde are refluxed together for one hour. Boiling water is then added to the clear solution until a slight turbidity persists and the heating is stopped. After cooling the white precipitate formed is filtered off, washed with 2N ammonia and then with water, dried and recrystallised from 2-propanol. Yield of recrystallised product: 29.3 g (75t). The product is hontogenous by TLC and shows a melting The IR-spectrum (KBr) shows the following characteristics: 3460 cm (broad) NH; 3140-2900 cm CH (aromatic); 2850 cm 1 CH (OCH3); 1625, 1525 and 1495 cm 1 aromatic ring systems; 1240 cm 1 (assym.) and 1040 cm 1 (sym.) C-O-C; 840 cm 1 1,4-disubstituted benzene rings. The 60 AtEz 1H NMR-spectrum of a 10% solution in DMSO-d6 shows the following characteristics: #(ppm) = 3.80 singlet (6H) (CH3O) x 2 7.0; 7.5 AB quartet (8H) (C6H4OCH3) x 2 EMI23.1 <tb> -7.3 <SEP> multiplet <SEP> (2H) <tb> <SEP> (C6H3F2) <SEP> <tb> <SEP> 7.8 <SEP> multiplet <SEP> (1H) <tb> 12.6 broad singlet (1H) (NH) The 2,3-difluorobenzaldehyde used as a starting compound can be prepared from 1,2-difluorobenzene in the same way as described for 2,6-difluorobenzaldehyde by A.M. Roe et al.: J.Med. Chem. 11 (1968) 814. b15 = 60-610C. Example 10 2-(3,4-difluorophenyl)-4,5-bistp-methoxyphenyl)intidazole 200 ml of acetic acid, 77 g (1.0 mole) of ammonium acetate, 27 g (0.1 mole) of anisil and 14.95 g (0.105 mole) of 3,4-difluorobenzaldehyde are refluxed together for one hour. Boiling water is then added to the clear solution until a slight turbidity persists and the heating is stopped. After cooling the white precipitate formed is filtered off, washed with 2N ammonia and then with water, dried and recrystallised from 2-propanol. Yield of recrystallised product: 29.7 g (76%). The product is homogenous by TLC and shows a melting point of 188-191.1 C. The IR-spectrum (KBr) shows the following characteristics: 3450 cm 1 (broad) NH; 3100-2900 cm 1 CII (aromatic); 2350 cm 1 CH (6CH3); 1620, 1530 and 1510 cm-1 aromatic ring systems; 1255 cm-1 (assym.) and 1040 cm-1 (sym.) C-O-C; 840 cm-1 1,4-disubstituted benzene rings. 'The 60 MHz 1H NMR-spectrum of a 10% solution in DMSO-d6 shows the following characteristics: #(ppm) = 3.93 singlet (6H) (CH30) x 2 7.7; 7.1 AB quartet (8H) (C6H4OCH3) x 2 EMI24.1 <tb> 7.3 <SEP> multiplet <SEP> (2H) <SEP> # <SEP> (C6H3F2) <SEP> <tb> 7.9-8.7 <SEP> multiplet <SEP> (1H) <SEP> # <SEP> <tb> 13.1 broad singlet (1H) (NH) The 3,4-difluorobenzaldehyde used as a starting compound can be prepared as follows: 1,2-difluorobenzene is brominated by a method analogous to the one described in Organic Synthesis Coll. Vol. I p. 123. From the resulting 3,4-difluorobromobenzene, 3,4-difluorophenylmagnesiumbromide is prepared in diethylether, and this Grignard reagent is added dropwise t6 a solution of N-methylformanilide in tetrahydrofuran. From the reaction mixture, 3,4-difluorobenzalde- hyde is obtained. b17 = 80-820C. Example 11 2-(3,5-difluormethyl)-4,5-bis-(p-methoxyphenyl)imidazole 200 ml-of acetic acid, 77 g (1.0 mole) of ammonium acetate, 27 g (0.1 mole) of anise and 14.95 g (0.105 mole) of 3,5-difluorobenzaldehyde are refluxed together for one hour. Boiling water is then added to the clear solution until a slight turbidity persists ad the heating is stopped. After cooling the white precipitate formed is filtered off, washed with 2N ammonia and then with water, dried and recrystallised fox 2-propanol. Yield of recrystallised product: 22 g (56%). The product is homogenous by TLC and shows a melting point of 234-2370C. The IR-spectrum (KBr) shows the following characteristics: 3450 cm-1 (broad) NH: 314-2900 cm-1 CH (aromatic) 2850 cm 1 CH (OCH3); 1635, 1530, 1500 and 1460 cm 1 aromatic ring systems; 1255 cm-1 (assym.) and 1040 cm-1 (sym.) C-O-C; 840 cm-1 1,4-disubstituted benzene rings. The 60 NHz 1H NMR-spectrum of a 10% solution in DMSO-d6 shows the following characteristics: 6(ppm) = 3.85 singlet (6H) (CH3O) x 2 7.1; 7.6 AB quartet (8H) (C6H40CH3) x 2 EMI25.1 <tb> 7.3 <SEP> multiplet <SEP> (lH) <SEP> <tb> 7.9 <SEP> multiplet <SEP> (2H) <SEP> (C6H3F2) <SEP> <tb> 13 broad tinglet (1h) (NH) The 3,5-difluorobenzaldehyde used as a starting compound can be prepared as follows: 3,5-difluorophenylmagnesiumbromide can be prepared as described by A. Roe and W.F. Little: J.Org.Chem. 20 (1955) 1577. A solution of 3,5-difluorophenylmagnesiumbromide in diethylether is added dropwise to a solution of N-methylformanilide in tetrahydrofuran. By working up this reaction mixture, 3,5-difluorobenzaldehyde is obtained. b55 = 8688cL.

Claims: Patent Claims 1. Novel imidazole derivative of the formula: EMI26.1 wherein one or two of the substituents R2, R3, Rk, R5 and R6 represent a fluorine atom while the remaining substituents are hydrogen atoms. 2. Imidazole derivative as per claim 1, viz. 2-(2-fluorophenyl)-4,5-bis(p-methoxyphenyl)imidazole. 3. Imidazole derivative as per claim 1, viz. 2-(3-fluorophenyl)-4,5-bis(p-methoxyphenyl)imidazole. 4. Imidazole derivative as per claim 1, viz. 2-(4-Eluorophenyl).-4,S-bis(p-methoxyphenyl)imidazole. 5. Imidazole derivative as per claim 1, viz. 2-(2,3-difluorophenyl)-4,5-bis(p-methoxyphenyl)imidazole. 6. Imidazole derivative as per claim 1, viz. 2-(2,4-difluorophenyl)-4,5-bis(p-methoxyphenyl)imidazole. 7. Imidazole derivative as per claim 1, viz. 2-(2,5-difluorophenyl)-4,5-bis(p-methoxyphenyllimidazole. 8. Imidazole derivative as per claim 1, viz. 2-(2,6-dif luorophenyl) -4,5-bis (p-methoxyphcnyl) imidazole. 9. Imidazole derivative as per claim 1, viz. 2-(3,4-difluorophenyl)-4,5-bis(p-methoxyphenyl)imidazole. 10. Imidazole derivative as per claim 1, viz. 2- (3, 5-difluorophenyl) -4 ,5-bis (p-methoxyphenyl) imidazole. 11 Process for the preparation of an imidazolo derivative as per claim 1 consisting 1) of a reaction of anisil with a compound of the formula: EMI27.1 where one or two of the substituents Rê, R , R4, R5 and R6 represent a fluorine atom, while the remaining substituents represent hydrogen atoms, and ammonium acetate, or 2) of a reduction of a compound of the formula: EMI27.2 12. Process according to claim 11, where the reaction of anisil with a compound of formula II and ammonium acetate is performed in the presence of a protic solvent. 13. Process according to claim 11, where in reacting anisil with a compound of forrula II and ammonium acetate, a quantity of five times the equimolar amount of ammonium acetate is used. 14. Process according to claim 12, where approximately two litres of solvent per mole of anisil is used. 15. Process according to claim 12, where the reaction is performed at the reflux temperature of the reaction mixture. 16. Process according to claim 11 where the reduction of the compound of formula III is performed in the presence of zinc. 17. Process according to claim 16, where zine powder is used. 18. Process according to claim 11, where a compound of formula III is prepared by reaction of anisil monoxime with ammonium acetate and an appropriate aldehyde in the presence of a lower alkanoic acid and the reduction is preformed without isolation of the resulting compound. 19. A pharmaceutical or veterinary preparation containing as an active ingredient at least a compound of formula I. 20. Novel imidazole derivative of the formula EMI28.1 where R2, R3, R41 R5 and R6 each represent a fluorine atom or a hydrogen atom.

Inventors: DYRSTING H, JOERGENSEN D, DYRSTING, HJARNE, JORGENSEN, DAN
Applicants: DUMEX LTD AS, A/S DUMEX (DUMEX LTD.)
Application year: 1979
Main classification: C07D233
IPC codes: C07D233, C07C45