IL34516A - Phenyl-imidazolyl-alkanoic acid derivatives,their production and pharmaceutical compositions containing them - Google Patents

Phenyl-imidazolyl-alkanoic acid derivatives,their production and pharmaceutical compositions containing them

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IL34516A
IL34516A IL34516A IL3451670A IL34516A IL 34516 A IL34516 A IL 34516A IL 34516 A IL34516 A IL 34516A IL 3451670 A IL3451670 A IL 3451670A IL 34516 A IL34516 A IL 34516A
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acid
acid methyl
imidazolyl
acetic acid
compounds according
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IL34516A
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Bayer Ag
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34516/3 niK c son ninpn 'Twain jii." Phenyl-imidazolyl-alkanoic acid derivatives, their production and pharmaceutical compositions containin«£them BAYER AKTIENGESBLLSCHAFT The invention relates to certain new phenyl-imidazolyl-alkanoic acid derivatives and salts thereof, to a process for their production and to their use as chemotherapeutical agents.
The phenyl-imidazolyl-alkanoic acid derivatives according to the invention have the formula in which: 1 2 3 R , R , R may be the same or different and are each hydrogen or lower alkyl; X is a carboxy, carbalkox , carbobenzyloxy, cyano, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, the alkyl radicals of the monoalkyl or dialkyl-carbamoyl groups together optionally being constituents of a 6-membered ring system which may contain a further oxygen or nitrogen hetero-atom and may optionally be substituted by an alkyl group with 1-4 carbon atoms in the ^-position; 4 R is hydrogen, alkyl, alkoxy, alkylthio, halogen, nitro or trifluoromethylj is phenyl optionally substituted by the radicals mentioned 4 for R j or an alkyl radical? n i3 0, 1 or 2; m is 0, 1 or 2; and salts thereof. 1 2 3 When any of R , R or R are alkyl they preferably contain 1 to 4 carbon atoms.
When R 4 is alkyl it c1ontains 1 to 4 c'arbon at'*om"s but preferably R^" is methyl. V.¾en R^ is alkoxy or alkylthio it preferably contains 1 to.4 carbon atoms. The term alkyl or lower alkyl as used in this context includes straight-chain as well as branched alkyl.
If X is an estor group, it is a carbalkoxy group whose alkyl moiety may be straight-chain or branched and may contain 1-18, preferably 1-12, carbon atoms or a carbobenzyloxy group. If X is a carbamoyl group, it may be a free carbamoyl group, a monoalkyl carbamoylgroup or a dialkyl-carbamoyl group*. The. alkyl radicals of the mono- or dialkyl-carbamoylgroups together may be constituents of a saturated 6-membered ring system which may contain a further oxygen or nitrogen hotoro atom, and which » may be substituted 'by a .1 owcr alkyl c oup with preferably 1 - 4 carbon atoms in the ^-position.
When the compounds are to be used as chemotherapeutical .agents, and, if they are in salt form, the salt should be a physiologically compatible salt derived- from a physiologically compatible acid. Examples of such acids are the hydrohalic acids, phosphoric acids, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, for example acetic, maleic, succinic, fumaric, tartaric, citric, salicylic, sorbic, lactic and 1,5-naphthalene- · disulphonic acid.
The invention also provides a process for the production of compounds of formula I and of salts thereof in which (a) a halogen derivative of the formula in which X, R , S » n and m have the same meaning as above and Hal is halogen, preferably chlorine, is reacted with an optionally alkyl-substituted imidazole in the presence of an acid-binding base or an excess of imidazole, expediently in an inert polar solvent (such as acetonitrile , toluene, xylene, chlorobenzene , cyclohexane, acetone, diethyl ketone, dimethyl formamide or dimethyl sulphoxlde), at a temperature of about to about 180°C, especially from 50 to 100°C; or (b) a halogen derivative of the formula II is reacted with an alkali metal or silver salt of an optionally alkyl-substituted imidazole in an inert solvent (such as benzene, toluene, xylene or cyclohexane) at a temperature of about 20 to about 200°C, preferably 50 to 120°C$ or (c) a hydroxy compound of the formula OH A ς in which X, R , R , n and m have the same meaning as above, is reacted with an optionally alkyl-substituted imidazole with the elimination of water.
These reactions ca be carried out by the usual methods, for example in the mel or with the aid of the azeotropic elimination of water in the presence of higher-boiling solvents, such as xylene, chlorobenzene etc., at the boiling point of the solvent concerned. In addition, it may sometimes be expedient to facilitate the elimination of water by the addition of dehydrating agents, such as alkaline earth metal oxides (MgO, BaO, CaO) or AlgO^.
Some imidazolyl derivatives which are particularly preferred, are given in the following Table 1 by way of example: Table 1 (1) diphenyl-j.midazolyl-acetic acid methyl ester (2) diphenyl-imidazolyl-acetic acid (3) diphenyl-imidazolyl-acetic acid ethyl ester (4) diphenyl-imidazolyl-acetic acid n-propyl ester (5) diphenyl-imidazolyl-acetic acid isobutyl ester (6) diphenyl-imidazolyl-acetic acid n-octyl ester (7) diphenyl-imidazolyl-acetic acid n-decyl ester (8) diphenyl-imidazolyl-acetic acid benzyl ester (9) diphenyl-imidazolyl-acetic acid nitrile (10) phenyl-4-methylphenyl-imidazolyl-acetic acid methyl ester (13) hydrochloride of Example (1) (14) phehyl-4-chlorophenyl-imidazolyl-acetic acid ethyl ester (15) phenyl-4-chlorophenyl-imidazolyl-acetic acid methyl ester (16) phenyl-2-chlorophenyl-imidazolyl-acetic acid methyl ester (17) phenyl-isopropyl-imidazolyl-acetic acid ethyl ester (18) diphenyl-imidazolyl-acetic acid amide (19) diphenyl-imidazolyl-acetic acid methylamide (20) diphenyl-imidazolyl-acetic acid dimethylamide (21) diphenyl-imidazolyl-acetic acid morpholide (22) diphenyl-imidazolyl-acetic acid piperidide (23) bis-(4-chlorophenyl)-imidazolyl-acetic acid methyl ester (24) bis-(4-tolyl)-imidazolyi-acetic acid methyl ester.
A preferred group of compounds (and salts thereof) are characterized by formula (I) in whic 1 R and R"^ are both hydrogen 2 R is hydrogen or methyl; X is the carboxyl group, or is the -COOR^- group(in which R6 is straight-chain or branched alkyl with 1 to 10 carbon atoms or benzyl) or is a group of the formula (in which R' and R , which may be the same or different, are hydrogen or methyl, or R' and R together with the amide nitrogen form a morpholino ring or a piperidino ring), or is a cyano group; R^" is hydrogen, methyl, methoxy, nitro, fluorine, chlorine, or bromine; by fluorine, chlorine, bromine, methyl, methoxy or nitro, or straight-chain or Some further given in the following Table 2 by way of example: T«A>\e (25) bis-(4-bromophenyl)-imidazolyl-acetic acid methyl ester (26) bis-(4-fluorophenyl)-imidazolyl-acetic acid methyl ester (27) bis-(4-methoxy-phenyl)-imidazolyl-acetic acid methyl ester (28) bis-(4-nitro-phenyl)-imidazolyl-acetic acid ethyl ester hydrochloride (29) phenyl-isopropyl-in&dazolyl-propionic acid ethyl ester (30) phenyl-isopentyl-imidazolyl-propionic acid ethyl ester (31) phenyl-eth l-imidazolyl-isobutyric acid methyl ester (32) diphenyl-2-methyl-imidazolyl-acetic acid methyl ester (33) phenyl-tert.-butyl-imidazolyl-acetic acid methyl ester (34) diphenyl-imidazolyl-acetic acid methyl ester-tartrate (35) diphenyl-imidazolyl-acetic acid methyl ester-succinate (36) diphenyl-imidazolyl-acetic acid methyl ester sulphate (37) diphenyl-imidazolyl-acetic acid methyl ester-methane- sulphonate (38) diphenyl-imidazolyl-acetic acid methyl ester-naphthalene- 1, -disulphonate.
As particularly preferred compounds , diphenyl-imidazolyl-acetic acid methyl ester and its hydrochloride are mentioned.
The starting compounds required for the preparation of the new compounds are known or are obtainable according to known processes.
The invention is further illustrated by the following Examples.
Example 1 13 g er (b.p. 140°C/ acid chlorid heated with temperature for 18 hours. After distillin off the solvent in a vacuum, 50 ml of water are added and the mixture is extracted with methylene chloride. After drying over sodium sulphate, the solvent is distilled off in a vacuum and the residue recrystallised from a little ethyl acetate. The diphenyl-imidazolyl-acetic acid methyl ester is thus ohtained in the form of colourless crystals of m.p. 155°C (with decomposition) .
Example 2 The corresponding carboxylic acid is obtained by hydrolysis of the diphenyl-imidazolyl-acetic acid methyl ester obtained in Example 1, with an alcoholic potassium hydroxide solution.
Examples 3-8 < The compounds of these Examples were obtained by a procedure completely analogous to that of Example 1.
Prom 13.7 g diphenyl-chloroacetic acid ethyl ester (0.05 mo3e) (Ber. 22, 1537): the diphenyl-imidazolyl-acetic acid ethyl ester of m.p. 104°C.
From 14.4 g diphenyl-chloro-acetic acid propyl ester (b.p. 155°C/0.3 mm Hg): the diphenyl-imidazolyl-acetic acid ° (b.p. 150°C/0.2 mm Hg): the diphenyl-imidazolyl-acetic acid isobutyl ester as oil.
Prom 16.0 g diphenyl-chloro-acetic acid octyl ester (b.p. 195°C/0.3 mm Hg) : the diphenyl-imidazolyl-acetic acid n-octyl ester as oil.
From 19.3 g diphenyl-chloroacetic acid decyl ester: the diphenyl-imidazolyl-acetic acid decyl ester of m.p. 48°C.
Prom 16.8 g diphenyl-chloroacetic acid benzyl ester: the diphenyl-imidazolyl-acetic acid benzyl ester as oil.
The second reaction component in all these Examples was imidazole. from diphenyl-chloroacetamide, Ber. £1, 3593 by heatin in phosphorus oxychloride; b.p. 130°C/0.4 mm Hg) are heated, with g imidazole in 50 ml acetonitrile at boiling: temperature for 18 hours. After treating with 20 ml of water, the mixture is extracted with methylene chloride. The solvent is distilled off after drying in a vacuum. The solid residue is re- crystallised from ethyl acetate/petroleum ether. Diphenyl- imidazolyl-acetonitrile of m.p. 98°c is thus obtained.
Example 10 13.7 g phenyl-£-tolyl-chloroacetic acid methyl ester (prepared from j3-toluyl-magnesium bromide and berizoyl-formic acid methyl ester and treatment with Cl^; (b.p.150°C/0.3 mm Hg)are heated with 10 g imidazole in 100 ml acetonitrile at boiling temperature for 16 hours. The acetonitrile is distilled off in a vacuum. The residue is treated with 50 ml of water and then extracted with methylene chloride. The methylene chloride solution is distilled off in a vacuum and the residue recrystallised from a little ethyl acetate. The phenyl-p-tolyl-imidazolyl-acetic acid methyl ester of m.p. 146°G is thus obtained.
Example 11 The phenyl-o-toly(yl-imidazolyl-acetic acid methyl ester (m.p. 148°C) is obtained in a analogous way from phenyl-o-toljdyl-chloroacetic acid methyl ester (b.p. 160°C/0.4 mm Hg) . Example 12 14.4 g (0.05 mole) β-οη1θΓθ-β ,β-rdiphenyl-propionic acid ethyl ester (prepared from £-hydroxy-^ ,β-diphenyl-propionic acid ethyl ester, Ber. 0, 4538, by treatment with phosphorus pentachloride) are heated in 100 ml acetonitrile with 10 g imidazole at boiling temperature for 16 hours. The solvent is distilled off in a vacuum, the residue treated with 50 ml of water and extracted with methylene chloride. After drying, the solvent is distilled off in a vacuum. The β-άπϋ^ζοΐνΐ-β ,β- diphenyl-propionic acid ethyl ester is thus obtained in the form of crystals of Pp 75° C.
Example 15 g of the diphenyl-imidazolyl-acetic acid methyl ester of Example 1 are dissolved in carbon tetrachloride and hydrogen chloride is introduced with cooling. The carbon tetrachloride is decanted off from the precipitated oily salt and the salt is reprecipitated from acetone/ether. The hydrochloride pf the above base is thus obtained; m.p. 131°C (decomp.).
Example 14 .45 g (0.05 mo¾ phenyl-p^chlorophenyl-chloroacetic acid ethyl ester (prepared from £-chlorophenyl-magnesium bromide with thionyl chloride; b.p. l60°C/0.2 mm Hg) are boiled with 10 g imidazole in 100 ml acetonitrile for 16 hours. After distilling off the solvent, 50 ml of water are added, and the mixture is extracted with methylene chloride.- After drying, the solvent is distilled off in a vacuum and the phenyl-jg-chlorophenyl-imidazolyl-acetic acid ethyl ester is obtained in the form of an oil which solidifies after a fairly long time.
Example 15 The phenyl-j^chlorophenyl-imidazolyl-acetic acid methyl ester of melting point 135°0 (ethyl acetate) is obtained in an analogous way.
Example 16 The phenyl-o-chlorophenyl-imidazolyl-acetic acid methyl ester of melting point 138°C (ethyl acetate) is obtained by the method described in Example 14, Example 1 12 g (0.05 molf^ phenyl-isopropyl-chloroacetic acid ethyl ester (b.p. 95°C/0.3 mm Hg) are heated with 10 g imidazole and 100 ml acetonitrile at boiling temperature for 18 hours. After distilling off the solvent in a vacuum, 50 ml of water are added and the mixture is extracted by shaking with methylene chloride. The methylene chloride is dried and distilled off in a vacuum. The phenyl-isopropyl-imidazolyl acetic acid ethyl ester is thus obtained in the form of an oil.
Example 18 12.27 g (0.05 mol^ diphenyl-chloroacetic acid amide (Ber.4i,3593) are heated with 11.8 g imidazole in 100 ml acetonitrile at boiling temperature for 18 hours. After cooling the crystals are suspended in water and rinsed. After recrys- amide of m.p. 218°C is obtained.
Example 19 13 g (0.05 mo]e) diphenyl-chloroacetic acid methylamide (prepared from diphenyl-chloroacetic acid chloride and methyls . amine in analogy with Ber.41, 3593; m.p. 108°C) are heated with 11.5 g imidazole in 100 mi acetonitrile at boiling temperature for 18 hours. After cooling, the crystals are filtered off with suction, digested with water and rinsed.
After recrystallisation from methanol, diphenyl-imidazolyl-acetic acid methylamide of b.p. 237°C is obtained.
Example 20 18.I diphenyl-chloroacetic acid dimeth lamlde (m.p. 128°C, prepared in analogy with Example 19) are heated with 15.6 g imidazole in 120 ml acetonitrile at boiling temperature for 18 hours. The solvent is distilled off in a vacuum. After the addition of 70 ml of water, the mixture is extracted with methylene chloride. After drying, the solvent is distilled off in a vacuum and the solid residue is recrystallised from methanol. The diphenyl-imidazolyl-acetic acid dimethyl amide of m.p. 202°C is thus obtained in the form of colourless crystals.
Example 21 The diphenyl-imidazolyl-acetic acid morpholide is obtained from 15·5 g diphenyl-chloroacetic acid morpholide (m.p. 113°C) and 11 g imidazole in 100 ml acetonitrile on analogy with Example 20.
The hydrochloride of diphenyl-imidazolyl-acetic acid morpholide of m.p. 118°C is obtained by adding ethereal hydrochloric acid to a solution of diphenyl-imidazolyl-acetic acid morpholide in ethyl acetate.
Example 22 The di hen l-im dazo - cet a i e d d f m . (m.p. 82°C) and 10 g imidazole in 100 ml acetonitrile in analogy with Example 20.
Example 23 162.6 g (0.434 mole) of 4,4 '-dichlorodiphenylbromoacetic acid methyl ester (prepared from 4,4'-dichlorobenzilic acid methyl ester) and phosphorus pentabromide (b.p. 190°/0.5 mm Hg) are heated to the boil for 14 hours, with stirring, with 90 (1.32 moles) of imidazole in 1 litre of acetonitrile. The acetonitrile is distilled off in a vacuum. For the removal of imidazole, the residue is twice shaken with, in each case, 1.3 litres of water, then taken up in 950 ml of methylene chloride and again extracted with 1.8 litres of water. After drying with sodium sulphate, the methylene chloride is distilled in a vacuum. The residue is boiled out four times with, in each case, 250 ml of ether; the ethereal solution, after clarification with charcoal, is precipitated with ethereal hydrochloric acid. The precipitate is digested with absolute ether and taken up in methylene chloride; after filtration, ethyl acetate is added. When the methylene chloride is evaporated on a water-bath, the hydrochloride of bis-(4-chloro-phenyl)-imidazolyl-acetic acid methyl ester of the melting point 150°C (with decomposition) crystallises out in colourless crystals.
When the hydrochloride is shaken with methylene chloride and solution of sodium carbonate, a solution of the base is obtained. After this has been dried, distillation in a vacuum is effected' and the residue is recrystallised from dry ether. There are so obtained the colourless crystals of bis-(4-chloro-phenyl)-imidazolyl-acetic acid methyl ester of the melting point 132°C.
Example 24 in 100 ml acetonitrile the hydrochloride of bis-(4-tolyl)-imidazolyl-acetic acid methyl ester of the melting point 140°C (with decomposition) in colourless crystals.
Example 25 19.4 g 4,4'-dibromodiphenylbromoacetic acid methyl ester (prepared from 4,4*-dibromodiphenylacetic acid methyl ester and bromosuccinimide) are heated to the boil for 15 hours with 8.4 g imidazole in 8.5 ml acetonitrile. The acetonitrile is distilled off in a vacuum. The residue is shaken twice with, in each instance, 110 ml of water and decanted. The residue is then taken up in about 100 ml of methylene chloride and again extracted with 80 ml of water. After drying of the methylene chloride, the latter is distilled off in a vacuum. The residue is boiled out four times with, in each case, 100 ml of absolute ether. The ether is clarified with charcoal and precipitation is effected with ethereal hydrochloric acid. The hydrochloride precipitating in lumps is digested twice with absolute ether, then taken up in methylene chloride. After filtration, ethyl acetate is added, and the methylene chloride is evaporated on a water-bath. After cooling, the hydrochloride of bis-(4-bromophenyl)-imidazolyl-acetic acid methyl ester of the melting point 140°C crystallises out in colourless crystals.
The hydrochloride is shaken with methylene chloride and solution of sodium carbonate. The solution of the base in methylene chloride is dried and distilled off in a vacuum. The residue is recrystallised from a little absolute ether. There are so obtained the colourless crystals of bis-(4-bromophenyl)-imidazolyl-acetic acid methyl ester of the melting point 135°C. Example 26 In the same manner as in Example 23, there is obtained from 40.1 g 4,4'-difluorodiphenylbromoacetic acid methyl ester ° acid methyl ester and N-bromosuccinimide) and 23.6 g imidazole in 236 ml acetonitrile the hydrochloride of bis-(4-fluorophenyl)-imidazolyl-acetic acid methyl ester of the melting point 147°C. From this there is obtained, with solution of sodium carbonate in methylene chloride, the free base of the melting point 128°C. Example 27 In the same manner as in Example 23, there is obtained from 4,4,-dimethoxybenzilic acid methyl ester (m.p. 110°C) with phosphorus pentachloride via 4,4,-dimethoxyphenyl-a-chloroacetic acid methyl ester with imidazole i acetonitrile the bis-(4-methoxyphenyl)-imidazolyl-acetic acid methyl ester of the melting point 131°C Example 28 In the same manner as in Example 23 , with analogous working up, there is obtained from 10.25 g 4,4,-dinitrodiphenylbromo-acetic acid ethyl ester (m.p. 130°, prepared from 4,4'-dinitro-diphenylacetic acid ethyl ester and N-bromosuccinimide) and ,5 g imidazole in 70 ml acetonitrile the hydrochloride of bis-(4-nitrophenyl)-imidazolyl-acetic acid ethyl ester of the melting point 130°C (with decomposition) in colourless crystals.
Example 29 Analogously with Example 12,. phenylisopropylimidazolyl-propionic acid ethyl ester is obtained as oil, and from this there is obtained, with ethereal hydrochloric acid , the hydrochloride of the melting point 194°C Example 30 Analogously with Example 12, phenylisopentylimidazolyl-propionic acid ethyl ester is obtained as oil.
Example 31 Analogously with Example 12, phenylethylimidazolyl-iso-butyric acid ethyl ester is obtained as oil.
Example 3 ' ' ■ . : .Other compounds of formula I prepared by one of the processes according to the invention are those listed below: 34.516/2 Example 3f From the diphen limidazolyl-acetic acid methyl ester obtainable according to Example 1 and the appropriate acids, the following salts of diphenylimidazolyl-acetic acid methyl ester are obtained ■ Acid tartrate melting poin 135° C; (decomp) Acid succinate It - 107° C (decon-μ) Sulphate n 145° C (decomp) Hethane-sulphonate t» 154° c (decomp) Acid naphthalene-l,5-disulphonate ·· -229° c (decon-μ) As already mentioned, the ompounds according to the invention, and their salts, possess an excellent anti-mycotic effectiveness, as can be seen from the following in -vivo and in-vitro experiments.
The excellent anti-mycotic in-vitro effectiveness of the new compounds can be seen from Tables 3 and 4.
The type of activity of the compounds in vitro is primarily fungistatic Fungicidal effects with a reduction of the inoculum by 9 $ in 24 hours can be achieved with the two- to three-fold minimum inhibition concentrations. » The determination of the minimum inhibition concentrations stated in Tables 3 and 4 in γ/ml of nutrient solution was effected! (a) in the case of dermatophytes and mould fungi, in Sabouraud's milieu d 'epreuve. (b) in the case of yeasts, in dextrose/meat broth bouillon.
The incubation temperature was 28°C and the duration of incubation was 48 to 96 hours.
Table 3 Minimum inhibition concentration in γ/ml test medium i Compound Trichophyl ;on ment. Candida εilbicans Pen. from without with without with comune Example Serum Serum Serum Serum 1 ^4 4 4 100 4 3 <4 ^4 10 40 ^4 4 ^4 ^4 4 20 ^4 ^4 ^4 4 ^100 10 6 <4 40 20 ^100 7IOO 7 10 10 -7IOO 9 ^4 Z4 20 100 4 10 10 10 11 10 10 10 14 ^4 4 4 7-100 17 4 10 - 18 7100 ^100 r'100 19 100 100 ^ioo 7100 20 20 7IOO .7100 For the following compounds, the excellent in-vivo effectiveness was shown by way of example: diphenyl-imidazolyl-acetic acid methyl ester (Example 1) diphenyl-imidazolyl-acetic acid ethyl ester (Example 3) diphenyl-imidazolyl-acetic acid n-propyl ester (Example 4) diphenyl-imidazolyl-acetic acid iso-butyl ester (Example 5) phenyl-2-methylphenyl-imidazolyl-acetic acid methyl esteii-j-samplell diphenyl-imidazolyl-acetic acid methyl ester hydrochloride (Example 13) diphenyl-imidazolyl-acetic acid morpholide hydrochloride^xample 21 bis-(4-chlorophenyl)-imidazolyl-acetic acid methyl ester(ExaiipiLe 23 bis-(4-chlorophenyl)-imidazolyl-acetic acid methyl ester hydrochloride (Example 23) bis-(4-bromophenyl)-imidazolyl^acetic acid methyl ester (base) (Example 25) bis-(4-bromophenyl)-imidazolyl-aoetic acid methyl ester hydrochloride (Example 25) bis-(4-fluorophenyl-imidazolyl-acetic acid methyl ester hydrochloride (Bxample 26) bis-(4-methoxyphenyl)-imidazolyl-acetic acid methyl ester (base) (Example 27) bis-(4-nitrophenyl)-imidazolyl-acetic acid ethyl ester hydrochloride (Example 28) A. Oral treatment of experimental candidiasis of the white mouse with the compounds of Examples 1,3,4, ,11,13,21,23,25»26, 27 and 28. cornice of the strain CP1 - SPF of 20-22 g weight were infected intravenously with 2-5 x 10^ Candida albicans cells per mouse. With this experimental arrangement, untreated animals died of the infection within 6 days.
When 30-60 mg of the said compounds per kilogram body after infection. In the case of treatment with the compound from Example 13, even 19-20 animals survived. The optimum dosage for compounds from Examples 1 , 3,5,13, 23 and 28 was 2 x 50 mg per kilogram daily; for the compounds from Examples 4,11, 21 , 25,26 and 27 , 2 x 60 mg per kilogram daily.
For oral application, the preparations were suspended in 0.2 76-strength glucose-agar and administered with the oesophageal sound.
B. Parenteral treatment of experimental candidiasis and histoplasmosis of the mouse with the compound from Example 13· In the case of a parenteral administration of the compound from Example 13 in a dosage of 2 x 25 mg per kilogram and day, 18 of 20 animals survive 6 days after the infection.
C. Local treatment Of experimental guinea-pig trichophytosis with the compound from Example 13.
Infection of the animals was effected by Trichophyton mentagrophytes. From the 3rd day after infection, the infection point was treated once daily by application of 0.5 ml of a l#-strength solution of the active compound in polyethylene-glycol 400. This treatment was continued up to the 14th day after infection. Within the therapy period, the dermatosis healed up. In the case of untreated infected control animals, bleeding ulcerations of the infection point as well as loss of hair occurred up to about 30 days after infection.
The compounds of the formula (I) which, as was shown, possess, in surprising manner, an excellent anti-mycotic effectiveness and thus represent an enlargement of the store of medicaments, can be used in the following diseases: (a) in human medicine: 1. Dermatomycoses caused by fungi of the species Trichophytes, Microsporium, Epidermophytes, Aspergillus, Candida albicans and other easts 2. Organ mycoses caused by yeasts, mould fungi and Dermatophytes, (b) in veterinary medicine: Dermatomycoses and organ mycoses by yeasts, mould fungi and Dermatophytes.
The new compounds of the general formula (I) and their salts can be applied orally, parenterally or locally.
In general, it has proved advantageous to apply amounts of about 20 mg to about 50 mg per kilogram body weight per day in order to achieve satisfactory results. However, it may be necessary to deviate from the aforesaid amounts, dependent upon the body weight of the test animal or the method of application, but also on account of the animal species and its individual reaction to the medicament or the kind of formulation of the latter, and the moment in time or the interval at which it is administered. It may be sufficient in some cases to use less than the aforesaid minimum amount, whereas in other cases the upper limit mentioned above will have to be exceeded. If larger amounts are administered, it may be advisable to distribute them in several individual doses over the day. The same range of dosage is envisaged for application in veterinary and/or human medicine. All other explanations given above apply accordingly.
The chemotherapeutical agents can be used as such or in combination with pharmaceutically acceptable carriers. Suitable forms of application, in combination with various inert carriers are the following: tablets, capsules, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers comprise solid diluents or fillers, a sterile aqueous medium as well as non-toxic organic solvents and the like. Tablets and the like intended for oral application may, substances. In the aforesaid case the therapeutically active compound should be present at a concentration of about 0*5 to 90 per cent by weight of the total mixture, i.e. in quantities which are sufficient to achieve the range of dosage mentioned above.
In the case of oral application, the tablets can obviously also contain additives , such as sodium citrate , calcium carbonate and dicalcium phosphate together with various other additives, such as starch, preferably potato starch, and the like, and binding agents, such ae polyvinyl-pyrrolidone , gelatin and the like. Lubricants, such as magnesium stearate, sodium lauryl sulphate and talc may also be added for the production of tablets. In the case of aqueous suspensions and/or elixirs which are intended for oral application, the active substances may be used with various flavouring agen1¾ colouring substances , emulsifiers and/or together with diluents, such as water, ethanol, propylene glycol, glycerol and similar compounds or combinations of this type.
In the case of parenteral application, solutions of the active substances in sesame or peanut oil, or in aqueous propylene glycol or Ν,Ν-dimethyl formamide can be used as can sterile aqueous solutions in the case of water-soluble compounds. Aqueous solutions of this kind should be buffered in usual manner if necessary; furthermore, the liquid diluent should previously be rendered isotonic by the additon of the necessary amount of salt or glucose. Such aqueous solutions are particularly suitable for intravenous, intramuscular, intraperitoneal and subcutaneous injections. Sterile aqueous media of this kind are prepared in known manner.
The compounds according to the invention can of course be administered in the form of the free bases as well as in the Local application is effected in the form of 0.5 - 5Ϊ-, preferably 1?S, solutions (for example in dimethyl formaciide, glycerol, water; alcohol, such as ethanol and isopropanol and buffer solutions), but also as emulsions, suspensions, powders and tablets.
The compounds of the formula (I) may be contained in capsules, tablets, pastilles, dragees, ampoules, etc.
The compounds may be got up alone or in a pharmaceutic, composition in dosage unit form, each dosage unit form being so adapted that it provides a single dose of the active constituent or, possibly, a plurality or fraction of such dose, especially two, three or four doses or a half, quarter or third of a dose.
The hitherto known anti-mycotics are, as already mentioned, effective only against yeasts, such as amphotericin B, or only against dermatophytes, such as griseofulvin.
As against this, the substances according to the invention, even in the case of oral application, act against yeasts as well as against dermatophytes.
It is particularly to be emphasised that the compounds according to the invention are substantially more non-toxic then amphotericin B, and in their effectiveness they exceed considerably that of griseofulvin.
Besides the anti-mycotic activity, the compounds according to the invention also possess an activity against pathogenic protozoa, such as trypanosomes, trichomonades, Entamoeba histolytica, causative organisms of malaria, as well as an activity against gram-positive cocci, such as staphylococci, and against gram-negative bacteria, such as E.coli.
Prom the general discussion above i is evident that the present invention also provides a pharmaceutical composition comprising as active ingredient one of the new active compounds in admixture with a pharmaceutically acceptable solid or liquid diluent or carrier; and that the invention further provides a medicament in dosage unit form comprising one of the new active compounds either alone or in admixture with a solid or liquid diluent or carrier. The medicament ma include a protective envelope containing the active compound and, if used, the diluent or carrier.
The term "medicament in dosage unit form" as used in the present specification means a medicament as defined above in the form of discrete portions each containing a unit dose, or a multiple or sub-multiple of a unit dose of the active compound or compounds. Such portions may, for example, be in monolithic coherent form, such as tablets, suppositories, pills or dragees; in wrapped or concealed form, such as wrapped powders, cachets, sachets, or capsules; in ampoules , either free or as a sterile aolution suitable for parenteral injection; or in any other form known to the art.

Claims (1)

  1. acid derivatives the in 1 2 R R R may toe the same or different and are each hydrogen or lower X is a the alkyl radicals of the monoalkyl or groups together optionally toeing constituents of ring system which may contain a oxygen or nitrogen and optionally be substituted to an alkyl group with carbon atoms in the is nitro or trifluoromethylj phenyl optionally substituted by the radicals 4 mentioned for R or an alkyl n is 1 or is 1 or salts 1 2 Compounds according to Claim 1 in which R and are hydrogen or alkyl containing 1 4 carbon atomsf is alkoxy or alkylthio containing 1 to 4 carbon is an optionally substituted benzene ϊ ring which may carry as the groups mentioned A 5 as possibly being R or is an l radical with 1 to 8 carbon Compounds according to Claim 2 in which R is methyl or chlorine is an alkyl radical 1 to carbon Compounds according to any of Claims in which X is a carboxyl cyano carbalkoxy group whose alkyl moiety may be straight or branched and have carbon oxy or a radical or X is a or acid methyl acid ethyl acid acid isobutyl acid acid benzyl acid acid methyl acid methyl propionic acid ethyl acid ethyl acid methyl ic acid ethyl acid acid acid acid acid ic acid methyl acid methyl Compounds according to any of Claims which in the form of physiologically compatible Compounds according to Claim 28 which are salts of phosphoric or bifunctional carboxylic acids or acid methyl ester acid derivatives of the formula given in Claim 1 in which 1 and are both hydrogenj is hydrogen or 6 X is the carboxyl or is the group 6 which is branched alkyl with 1 to 10 carbon atoms or or is a group of the ormula which and which may the same or hydrogen or or 1 and R8 together with the amide nitrogen form a ring or a piperidino or is a is or ia phenyl substituted in by Or or or branched with 1 to 5 carbon n is and is or acid methyl acid methyl acid methyl acid ethyl ester acid ethyl acid ethyl acid acid methyl ic acid methyl acid methyl ie acid methyl ester acid methyl acid methyl Compounds according to any Claims which are in the form of physiologically acceptable Compounds according to Claim 46 which are salts of hydrohallc phosphoric or blfunctional carboxylic acids or hydrox A process for the production of compounds according to any of Claims in which a halogen derivative of the in which R R and have the same meaning as in Claim 1 and Hal is is reacted with an optionally imidazole in the presence of an base or an excess of at a temperature of about 20 to about or a halogen derivative o formula II reacted with an alkali metal or silver salt of an optionally substituted imidazole in an inert solvent at a temperature of about 20 to about and a hydroxy compound of the 4 5 in which R R n and have the same meaning as in Claim reacted with an optionally Imidazole with the elimination of process according to Claim 48 in which Hal is A process according to Claim or 49 which the reaction is carried out in an inert polar process according to Claim 48 49 Or 50 in which the reaction is carried out at 50 to A process according to Claim 48 in which the reaction is carried out at to A process for the production of compounds according Claim substantially as hereinbefore described in any of Examples Compounds according to Claim 1 whenever prepared by a process according to any of Claims Pharmaceutical compositions containing as active ingredient a compound according to any of Claims 1 to 47 or 54 in admixture with a pharmaceutically acceptable solid or liquid diluent or A in dosage unit form hereinbefore comprising a compound according to an of Claims 1 to 47 or 54 either alone or in admixture with a solid or diluen or insufficientOCRQuality
IL34516A 1969-05-21 1970-05-13 Phenyl-imidazolyl-alkanoic acid derivatives,their production and pharmaceutical compositions containing them IL34516A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19691925994 DE1925994C3 (en) 1969-05-21 Phenyl imidazolyl fatty acid derivatives

Publications (2)

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IL34516A0 IL34516A0 (en) 1970-07-19
IL34516A true IL34516A (en) 1973-01-30

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ES (1) ES379870A1 (en)
IE (1) IE34289B1 (en)
IL (1) IL34516A (en)
NO (1) NO128571B (en)
PH (1) PH12184A (en)
PL (1) PL80851B1 (en)
RO (1) RO56292A (en)

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IL34516A0 (en) 1970-07-19
PH12184A (en) 1978-11-21
PL80851B1 (en) 1975-08-30
IE34289B1 (en) 1975-04-02
IE34289L (en) 1970-11-21
NO128571B (en) 1973-12-10
RO56292A (en) 1974-08-01
ES379870A1 (en) 1972-09-16

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