US3657442A - N-trityl-imidazoles for treating fungal infections - Google Patents

N-trityl-imidazoles for treating fungal infections Download PDF

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US3657442A
US3657442A US36394A US3657442DA US3657442A US 3657442 A US3657442 A US 3657442A US 36394 A US36394 A US 36394A US 3657442D A US3657442D A US 3657442DA US 3657442 A US3657442 A US 3657442A
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methyl
imidazole
diphenyl
trityl
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Karl H Buchel
Erik Regel
Manfred Plempel
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2

Definitions

  • Hal Xu' wherein the substituents are as above defined and Hal is halogen. These compounds are useful as antimycotics.
  • the present invention is concerned with N-tritylimidazoles and salts thereof and the production of such compounds. More particularly, the present invention is con- 3,657,442 Patented Apr. 18, 1972 cered with N-trityl-imidazoles and salts thereof of the formula:
  • R, R and R are hydrogen, lower alkyl or phenyl, or R and R together form an annulated benzene ring,
  • X, X and X" are alkyl of 1 to 12 carbon atoms or an electro-negative moiety
  • n, n and n" are an integer from O to 2
  • R, R or R are alkyl moieties, those having 1 to 4 carbon atoms are preferred.
  • X, X or X" is an alkyl moiety, it is prefered that such have '1 to 12 carbon atoms and such moieties having 1 to 4 carbon atoms are especially preferred.
  • Electro-negative substituents which are particularly preferred are the halogens, i.e., fluorine, chlorine, bromine and iodine, N0 CF CN, as Well as S-lower alkyl and O-lower alkyl; it is preferred that the alkyl moieties have 1 to 4 carbon atoms.
  • alkyl and lower alkyl comprises straight chain as well as branched chain alkyl moieties and also include those containing a double bond.
  • the salts of the N-trityl-imidazoles (I) are the pharmaceutically acceptable non-toxic acid salts.
  • suitable acids are the hydrohalic acids (hydrochloric being particularly preferred), phosphoric acid, monoand bifunctional carboxylic acids, such as acetic acid, propionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid and 1,5- naphthalene-disulphonic acid.
  • the hydrohalides, especially the hydrochlorides, lactates and salicylates are of particular 'value.
  • N-trityl-imidazoles have the formula:
  • XGw (11) (Ha) wherein X, X' and X" are alkyl of 1 to 12 carbon atoms or electro-negative substituents and n, n and n" are 1 or 2.
  • substituent values are those Where X" is fluorine, chlorine, bromine, iodine, N0 CF CN, SCH OCH and n" is l.
  • the compounds of the present invention can be prepared according to techniques per se known, such as 'by reacting silver salts or alkali metal salts, in particular the potassium salts of imidazoles of the Formula III with trityl halides of the Formula IV:
  • the compounds of the present invention can also be prepared according to techniques per se known by reacting irnidazole derivatives of the Formula -III with tritylcarbinols (cf. the reaction of the carbinol corresponding to the halide IV with secondary amines).
  • the irnidazole is generally used in an excess of up to about 100%. If the process is carried out under pressure, molar amounts may be used.
  • dehydrating agents such as e.g. alkaline earth metal oxides (MgO, BaO, CaO) and of A1 approximately molar amounts being generally used, but possibly also an excess of up to about 2-3 moles.
  • dehydrating agents such as e.g. alkaline earth metal oxides (MgO, BaO, CaO) and of A1 approximately molar amounts being generally used, but possibly also an excess of up to about 2-3 moles.
  • the same compound can also be obtained, when finely powdered silver salt of irnidazole is suspended with the equimolar amount of p-chlorophenyl-diphenyl-methyl chloride in absolute benzene, the mixture is heated with stirring and with the exclusion of light at boiling temperature for about 3 hours, the precipitated silver chloride is subsequently filtered off and the residue remaining after removal of the solvent is recrystallised from benzene/ light petrol.
  • l-(tris-phenyl-methyl)-imidazole is produced from 1-tris-phenyl-methyl-carbinol and imidazole and 1-(p-tolyl-diphenyl)-irnidazole is produced from 1-p-tolyl-diphenyl-methyl-carbinol and irnidazole.
  • the other compounds (I, II) can also be obtained according to the above processes.
  • the conversion of the free compounds into the salts is likewise carried out in known manner.
  • um-salicylate oil 1-(n1-chlorophenyl-diphenyl-methyl) imidazolium hydrochloride 153 1-(o-chlorophenyl-diphenyl-methyl) imidazolium-chloride 159 l-(p-fluorophenyl-diphenyl-methyl) imidazolium-chloride 1 l0 l-(p-fluorophenyl-diphenyl-methyl) imidazolium-lactate 95 1-(o-fiuorophenyl-diphenyl-methyl) imidazoliurn-lactate 1 1-(m-fiuorophenyl-diphenyl-methyl) imidazolium-lactate 120 1-(p-fiuorophenyl-diphenyl-methyl) imidazolium-salicylate 80 1-(p-cyanophenyl-diphenyl-methyl) imidazolium-chloride 147 1-(o-cyanophen
  • the compounds (I, II) and their salts are effective against hyphomycetes as well as against yeast, even in the case of oral administration. It is another advantage that the compounds according to the invention are well tolerated by warm-blooded animals.
  • the compounds can be used as antimycotics, inter alia, in the form of an aqueous emulsion, suspension or solution which can be administered per os. It is also possible to use aqueous solutions of the new salts of the said compounds (I).
  • Trich. asteroides Trich. crateriforme (3) T1ich.equinum (NL) Trich. equinum, woolly (Hoechst) Trich. equt'num, gran. (Hoechst) Trich. tonsurans Trich. verrucosum. Trich. granulosttm. Trich. interdigitale.
  • Microsp. gallz'nae (19) Microsp. felineum (20) Aspergz'llus m'ger (21) Fen. c0mune (22) Mucor muceda. (23) Blakesleatrispora- (24) Cami. albicans 1 40-1 1 Fungistase.
  • Equally eflective results are produced when other compounds within the scope of (I) or salts of compounds within the scope of (I) and specifically salts of compounds (a), '(e), (f), (g), (i) and (p) are used.
  • Compounds which are unsubstituted in the imidazole ring may be substituted in one phenyl group by a halogen atom, preferably chlorine or fluorine in the 0-, mor p-position; such compounds and their salts with hydrochloric acid, lactic acid or salicylic acid are particularly uesful.
  • the following usages and dosage ranges are used for the compounds of the present invention.
  • dermatomycoses caused by fungi of the species Trichophytes, ,Microsporium, Epidermophytes, Aspergillus, Candida albicans and other yeasts;
  • the compounds of the present invention are administered orally or parenterally as well as locally in the form of solutions, e.g., alcohol, preferably ethanol and isopropanol, buffer solutions, powders, tablets.
  • solutions e.g., alcohol, preferably ethanol and isopropanol, buffer solutions, powders, tablets.
  • the dosage range for humans is in the range of from about 20 to about 100 mg./kg. and preferably from about 40 to about 60 mg./ kg. Administration is generally recommended at intervals of about 12 hours and such administration should be continued for from about 10 to about '60 days.
  • the compounds of the present invention can be used either as such or in combination with pharmaceutically acceptable carriers.
  • suitable forms for administration in combination with various inert carriers are tablets, capsules, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups and the like.
  • Carriers of this type comprise solid extenders or fillers, a sterile aqueous medium as well as various non-toxic organic solvents and the like.
  • the tablets and the like suitable for oral administration can be provided with an addition of saccharin or a similar additive.
  • the therapeutically active compound should be present in the total mixture at a concentration of about 0.5 to percent by weight, i.e., in quantities which suffice to attain the range of dosage mentioned above.
  • tablets may also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch and the like, and binders such as polyvinyl-pyrrolidone, gelatin and the like. It is further possible to add lubricants such as magnesium stearate, sodium lauryl-sulphate and talc for producing tablets.
  • the active ingredient may be used together with various agents for improving the flavor, dyestuffs, emulsifiers and/or diluents, such as water, ethanol, propylene-glycol, glycerol and other compounds or combi nations of this type.
  • aqueous solutions of the active ingredients in sesame or peanut oil or in aqueous propylene-glycol or N,N-dimethyl formamide, as well as sterile aqueous solutions if the compounds are water-soluble.
  • aqueous solution should be bufiered in tL: usual manner; if required, and the liquid diluent should previously be rendered isotonic by the addition of the necessary amount of salt or glucose.
  • tL usual manner; if required, and the liquid diluent should previously be rendered isotonic by the addition of the necessary amount of salt or glucose.
  • a dosage of 40 mg./ kg. administered at intervals of 12 hours result in a blood level of between and 11 7/ ml.
  • the half-life period in human serum in vivo amounts to 6 hours on the average.
  • Up to 30 to 40% of the administered amount of the substance are excreted with the urine in active form.
  • the resorption quota amounts to more than 70% in the case of oral administration.
  • mice, rats, rabbits, dogs and cats lies between about 600 and 2200 mg. of the stated compounds/ kg. body weight in the case of oral administration.
  • the present invention also includes pharmaceutical compositions comprising at least one of the N-trityl-imidazoles or salts thereof in admixture with a solid or liquid diluent or carrier which may be any of the conventional diluents or carriers used in pharmaceutical compositions.
  • the present invention also includes unit dosage forms of medication which comprise at least one of the compounds of the present invention either alone or in admixture with a solid or liquid diluent or carrier.
  • the compounds of the present application may include a protective envelope or cover containing the active compound within.
  • Unit dosage form means that the composition is in the form of discrete portions, each containing a unit dose or a multiple or sub-multiple of the unit dose of the active ingredient which is the compound of the present invention.
  • 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 8 powders, cachets, sachets or capsules, in ampules such as in sterile solution; or in other forms known to the art.
  • An antifungal composition useful for administration to humans and animals which comprises a therapeutically effective amount of a compound of the formula:
  • X" is S-lower alkyl, or a pharmaceutically acceptable non-toxic salt thereof.

Abstract

N-TRITYL-IMIDAZOLES AND SALTS THEREOF OF THE FORMULA:
WHEREIN R, R1 AND R2 ARE HYDROGEN, LOWER ALKYL OR PHENYL, OR R1 AND R2 TOGETHER FORM AN ANNULATED BENZENE RING, X,X'' AND X" ARE ALKYL OF 1 TO 12 CARBON ATOMS OR AN ELECTRO-NEGATIVE MOIETY, AND N, N'' ARE AN INTEGER FROM 0 TO 2, OR PHARMACEUTICALLY ACCEPTABLE A ACID SALTS THEREOF MAY BE PRODUCED BY REACTING A SILVER SALT OR ALKALI METAL SALT OF AN IMIDAZOLE OF THE FORMULA:

2-R,4-R'',5-R2-IMIDAZOLE

WITH A TRITYL HALIDE OF THE FORMULA:

(X)N,(((X'')N-PHENYL)-C(-HAL)(-(PHENYLENE)-(X")N")-)BENZENE

WHEREIN THE SUBSTITUENTS ARE AS ABOVE DEFINED AND HAL IS HALOGEN. THESE COMPOUNDS ARE USEFUL AS ANTIMYCOTICS.

1-(((X)N-PHENYL)-C(-(PHENYLENE)-(X")N")(-(PHENYLENE)-

(X'')N'')-),2-R,4-R1,5-R2-IMIDAZOLE

Description

United States Patent Office 3,657,442 N-TRITYL-IMIDAZOLES FOR TREATING FUN GAL INFECTIONS Karl H. Buchel, Leverkusen, and Erik Regel and Manfred Plempel, Wuppertal-Elberfeld, Germany, assignors to Farbenfabriken Bayer Aktiengesellschaft, Leverkusen, Germany No Drawing. Original application Sept. 9, 1968, Ser. No. 758,594. Divided and this application May 11, 1970, Ser. No. 36,394 Claims priority, application Germany, Sept. 15, 1967, F 53,504 Int. Cl. A61k 27/00 US. Cl. 424-273 4 Claims ABSTRACT OF THE DISCLOSURE N-trityl-imidazoles and salts thereof of the formula:
or pharmaceutically acceptable acid salts thereof may be produced by reacting a silver salt or alkali metal salt of an imidazole of the formula:
with a trityl halide of the formula:
Hal Xu' wherein the substituents are as above defined and Hal is halogen. These compounds are useful as antimycotics.
This application is a division of our co-pending application Ser. No. 758,594, filled Sept. 9, 1968.
The present invention is concerned with N-tritylimidazoles and salts thereof and the production of such compounds. More particularly, the present invention is con- 3,657,442 Patented Apr. 18, 1972 cered with N-trityl-imidazoles and salts thereof of the formula:
wherein R, R and R are hydrogen, lower alkyl or phenyl, or R and R together form an annulated benzene ring,
X, X and X" are alkyl of 1 to 12 carbon atoms or an electro-negative moiety, and
n, n and n" are an integer from O to 2,
or pharmaceutically acceptable acid salts thereof. When R, R or R are alkyl moieties, those having 1 to 4 carbon atoms are preferred. When X, X or X" is an alkyl moiety, it is prefered that such have '1 to 12 carbon atoms and such moieties having 1 to 4 carbon atoms are especially preferred. Electro-negative substituents which are particularly preferred are the halogens, i.e., fluorine, chlorine, bromine and iodine, N0 CF CN, as Well as S-lower alkyl and O-lower alkyl; it is preferred that the alkyl moieties have 1 to 4 carbon atoms. The term alkyl and lower alkyl comprises straight chain as well as branched chain alkyl moieties and also include those containing a double bond.
The salts of the N-trityl-imidazoles (I) are the pharmaceutically acceptable non-toxic acid salts. Examples of suitable acids are the hydrohalic acids (hydrochloric being particularly preferred), phosphoric acid, monoand bifunctional carboxylic acids, such as acetic acid, propionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid and 1,5- naphthalene-disulphonic acid. The hydrohalides, especially the hydrochlorides, lactates and salicylates are of particular 'value.
In a particularly preferred embodiment of the present invention, the N-trityl-imidazoles have the formula:
XGw (11) (Ha) wherein X, X' and X" are alkyl of 1 to 12 carbon atoms or electro-negative substituents and n, n and n" are 1 or 2.
. Wtih regard to Formula Ila, particularly preferred substituent values are those Where X" is fluorine, chlorine, bromine, iodine, N0 CF CN, SCH OCH and n" is l.
The compounds of the present invention can be prepared according to techniques per se known, such as 'by reacting silver salts or alkali metal salts, in particular the potassium salts of imidazoles of the Formula III with trityl halides of the Formula IV:
(III) X4" wherein R, R and R X, X and X" and n, n and n" have the above meanings and Hal is chlorine, bromine or iodine, in an inert solvent such as benzene, toluene, hexane, cyclohexane or diethyl ether, at a temperature of from about 20 C. to about 100 C. [cf. Chem. Ber. 92, 92 (1959); 93, 570 (1960)].
The compounds of the present invention can also be prepared according to techniques per se known by reacting irnidazole derivatives of the Formula -III with tritylcarbinols (cf. the reaction of the carbinol corresponding to the halide IV with secondary amines). In this case, the irnidazole is generally used in an excess of up to about 100%. If the process is carried out under pressure, molar amounts may be used. Furthermore, it may be expedient to carry out the elimination of water azeotropically in the presence of a high boiling inert organic solvent, such as xylene, chlorobenzenes and the like, at the boiling point of the solvent used. In the absence of solvents, the process is carried out at a temperature range of from about 140 C. to about 230 C. and preferably from about 170 C. to about 190 C.
It may further be expedient to facilitate the elimination of water by working in the presence of dehydrating agents, such as e.g. alkaline earth metal oxides (MgO, BaO, CaO) and of A1 approximately molar amounts being generally used, but possibly also an excess of up to about 2-3 moles.
The following table gives the constants of some N-tritylimidazoles (I, II) by way of example:
M.P., C. (a) l-(trisphenyl-methyl)-imidazole 226-227 (b) l-(trisphenyl-methyl)-2-methyl-irnidazole 225 (c) 1-(trisphenyl-methyl)-2,4-dimethyl-imidazole 232 (d) l-(trisphenyl-methyl)-4,5-diphenylirnidazole 228-230 (e) 1-(p-chlorophenyl-diphenyl-methyl)-imidazole 140 (f) 1-(p-fluorophenyl-diphenyl-methyl)-imidazole 145 (g) 1-(tolyl-diphenyl-methyl)-imidazole 128 (h) l-(trisphenyl-methyl)-benzimidazole 180-181 (i) 1-(o-chlorophenyl-diphenyl-methyl)- irnidazole 147-149 (j) 1-(m-chlorophenyl-diphenyl-methyl)-imidazole 114 (k) 1-(p-bromophenyl-diphenyl-methyl)-imidazole 152 (l) 1-(o-fiuorophenyl-diphenyl-methyl)-imidazole 185 (m) 1-(m-fiuorophenyl-diphenyl-methyl)-imidazole 174 (n) 1-(p-nitrophenyl-diphenyl-methyl)- irnidazole 160-170 (0) 1-(m-trifluoromethylphenyl-diphenylmethyl) -imidazole 6 (p) 1-(p-cyanophenyl-diphenyl-methyl)-imidazole 164 (q) 1-(o-methoxyphenyl-diphenyl-methyl)- methyl)-imidazole (x) 1-(m-cyanophenyl-diphenyl-methyl)-imidazole 119 (y) 1-(o-cyanophenyl-diphenyl-methyl) irnidazole EXAMPLE OF PREPARATION 1- [p-chlorophenyl-diphenyl-methyl] -imadazole (e) 1 mole p-chlorophenyl diphenyl methyl carbinol is mixed with about 2 moles imidazole and the mixture is heated, without a solvent, at about 180 C. for 5 hours. After cooling, the reaction product is reprecipitated from xylene in order to remove the excess irnidazole. After another reprecipitation from benzene light petrol, the pure l-[p-chlorophenyl diphenyl methyl] irnidazole is obtained.
M.P. 140-143 C.; yield 53% of theory.
The same compound can also be obtained, when finely powdered silver salt of irnidazole is suspended with the equimolar amount of p-chlorophenyl-diphenyl-methyl chloride in absolute benzene, the mixture is heated with stirring and with the exclusion of light at boiling temperature for about 3 hours, the precipitated silver chloride is subsequently filtered off and the residue remaining after removal of the solvent is recrystallised from benzene/ light petrol.
By analogous procedure, l-(tris-phenyl-methyl)-imidazole is produced from 1-tris-phenyl-methyl-carbinol and imidazole and 1-(p-tolyl-diphenyl)-irnidazole is produced from 1-p-tolyl-diphenyl-methyl-carbinol and irnidazole.
The other compounds (I, II) can also be obtained according to the above processes. The conversion of the free compounds into the salts is likewise carried out in known manner.
SALTS OF TRITYL-IMIDAZOLES N-triphenyl-methyl-imidazolium lactate 31 g. N-trityl-imidazole are dissolved by heating in acetonitrile and 10 g. (0.11 mole) d,l-lactic acid are subsequently added. The residue remaining after distilling off the solvent is caused to crystallise by covering it with ether, the crystallisation product is washed with ether and dried. Yield 40 g. of a colourless crystalline powder of M.P. 170-180 C.
N-triphenyl-methyl-imidazolium chloride 31 g. N-trityl-imidazole are dissolved in 400 ml. carbon tetrachloride, and hydrogen chloride is subsequently passed into the solution at room temperature. The hydrochloride is precipitated after some time and filtered off with suction. Colourless crystals of M.P. C. after recrystallisation from acetone/ether 1:1. Yield 33 g.
The following salts are obtained in an analogous manner:
1- (p-chlorophen 1551213251:
um-salicylate oil 1-(n1-chlorophenyl-diphenyl-methyl) imidazolium hydrochloride 153 1-(o-chlorophenyl-diphenyl-methyl) imidazolium-chloride 159 l-(p-fluorophenyl-diphenyl-methyl) imidazolium-chloride 1 l0 l-(p-fluorophenyl-diphenyl-methyl) imidazolium-lactate 95 1-(o-fiuorophenyl-diphenyl-methyl) imidazoliurn-lactate 1 1-(m-fiuorophenyl-diphenyl-methyl) imidazolium-lactate 120 1-(p-fiuorophenyl-diphenyl-methyl) imidazolium-salicylate 80 1-(p-cyanophenyl-diphenyl-methyl) imidazolium-chloride 147 1-(o-cyanophenyl-diphenyl-methyl) imidazoliurn-chloride 131 1-(p-cyanophenyl-dipheny1-methyl) imidazoliurn-lactate 90 The previously known antimycotics are effective either only against yeasts, such as e.g. Amphotericin B, or only against hyphomycetes, such as eg Griseofulvin.
In contrast thereto and surprisingly, the compounds (I, II) and their salts are effective against hyphomycetes as well as against yeast, even in the case of oral administration. It is another advantage that the compounds according to the invention are well tolerated by warm-blooded animals.
The compounds can be used as antimycotics, inter alia, in the form of an aqueous emulsion, suspension or solution which can be administered per os. It is also possible to use aqueous solutions of the new salts of the said compounds (I).
THERAPEUTIC EFFECT (1) In vitro-effect against human-pathogenic fungi Fungistatic Minimum inhibiting concentration as 'y/rnl.
Without serum With serum (1) Trich. asteroides (2) Trich. crateriforme (3) T1ich.equinum (NL) Trich. equinum, woolly (Hoechst) Trich. equt'num, gran. (Hoechst) Trich. tonsurans Trich. verrucosum. Trich. granulosttm. Trich. interdigitale.
95 opl- HHHHHHHHr-HHHHHHHHHHH (l8) Microsp. gallz'nae (19) Microsp. felineum (20) Aspergz'llus m'ger (21) Fen. c0mune (22) Mucor muceda. (23) Blakesleatrispora- (24) Cami. albicans 1 40-1 1 Fungistase.
(2) Effect in vivo (a) Experimental candidosis in white mice: In the case of oral administration, curative effects can be achieved with daily doses of 2-3 times 0.5-1 mg./mouse/ day.
(b) Experimental trichophytia in mice caused by Trich. quinckeanum: Development of the infection is prevented by daily doses of 1-2 times 1-2 mg./mouse orally.
(0) Experimental trichophytia in guinea pigs caused by T rich. ment. When 15-30 mg. are administered twice Trich. quinokeanum: Development of the infection isbizi per os to guinea pigs Weighing 40 grams, a reproducible effect on the course of the infection and rapid healing of the mycotic lesions is found.
Equally eflective results are produced when other compounds within the scope of (I) or salts of compounds within the scope of (I) and specifically salts of compounds (a), '(e), (f), (g), (i) and (p) are used. Compounds which are unsubstituted in the imidazole ring may be substituted in one phenyl group by a halogen atom, preferably chlorine or fluorine in the 0-, mor p-position; such compounds and their salts with hydrochloric acid, lactic acid or salicylic acid are particularly uesful. The following usages and dosage ranges are used for the compounds of the present invention.
(a) For use with humans:
(1) dermatomycoses, caused by fungi of the species Trichophytes, ,Microsporium, Epidermophytes, Aspergillus, Candida albicans and other yeasts;
(2) organomycoses caused by yeasts, mould fungi and dermatophytes;
(b) For veterinary use:
Dermatomycoses and organomycoses caused by yeasts,
mould fungi and dermatophytes.
The compounds of the present invention are administered orally or parenterally as well as locally in the form of solutions, e.g., alcohol, preferably ethanol and isopropanol, buffer solutions, powders, tablets.
The dosage range for humans is in the range of from about 20 to about 100 mg./kg. and preferably from about 40 to about 60 mg./ kg. Administration is generally recommended at intervals of about 12 hours and such administration should be continued for from about 10 to about '60 days.
Nevertheless it may sometimes be necessary to digress from the aforesaid amounts, dependent on the method of administration or also on account of individual reactions to the medicine or on the type of its formulation and the moment in time or the intervals at which it is administered. In some cases, it may be sufficient to use less than the minimum amount stated above, whereas in other cases it may be necessary to go beyond the stated upper limit. If larger amounts are applied, it may be advisable to distribute these over a day in several individual doses.
The compounds of the present invention can be used either as such or in combination with pharmaceutically acceptable carriers. Suitable forms for administration in combination with various inert carriers are tablets, capsules, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Carriers of this type comprise solid extenders or fillers, a sterile aqueous medium as well as various non-toxic organic solvents and the like. Obviously, the tablets and the like suitable for oral administration can be provided with an addition of saccharin or a similar additive. In the aforesaid case, the therapeutically active compound should be present in the total mixture at a concentration of about 0.5 to percent by weight, i.e., in quantities which suffice to attain the range of dosage mentioned above.
In the case of oral administration, obviously, tablets may also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch and the like, and binders such as polyvinyl-pyrrolidone, gelatin and the like. It is further possible to add lubricants such as magnesium stearate, sodium lauryl-sulphate and talc for producing tablets. In the case of aqueous suspensions and/or elixirs which are intended for oral administration, the active ingredient may be used together with various agents for improving the flavor, dyestuffs, emulsifiers and/or diluents, such as water, ethanol, propylene-glycol, glycerol and other compounds or combi nations of this type.
In the case of parenteral administration, there may be used solutions of the active ingredients in sesame or peanut oil or in aqueous propylene-glycol or N,N-dimethyl formamide, as well as sterile aqueous solutions if the compounds are water-soluble. Such aqueous solution should be bufiered in tL: usual manner; if required, and the liquid diluent should previously be rendered isotonic by the addition of the necessary amount of salt or glucose. These aqueous solutions are particularly suitable for intravenous, intramuscular and intraperitoneal injections.
In humans, a dosage of 40 mg./ kg. administered at intervals of 12 hours result in a blood level of between and 11 7/ ml. The half-life period in human serum in vivo amounts to 6 hours on the average. Up to 30 to 40% of the administered amount of the substance are excreted with the urine in active form. The resorption quota amounts to more than 70% in the case of oral administration.
The LD for mice, rats, rabbits, dogs and cats lies between about 600 and 2200 mg. of the stated compounds/ kg. body weight in the case of oral administration.
The present invention also includes pharmaceutical compositions comprising at least one of the N-trityl-imidazoles or salts thereof in admixture with a solid or liquid diluent or carrier which may be any of the conventional diluents or carriers used in pharmaceutical compositions.
The present invention also includes unit dosage forms of medication which comprise at least one of the compounds of the present invention either alone or in admixture with a solid or liquid diluent or carrier. The compounds of the present application may include a protective envelope or cover containing the active compound within. Unit dosage form means that the composition is in the form of discrete portions, each containing a unit dose or a multiple or sub-multiple of the unit dose of the active ingredient which is the compound of the present invention. 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 8 powders, cachets, sachets or capsules, in ampules such as in sterile solution; or in other forms known to the art.
What is claimed is: 1. An antifungal composition useful for administration to humans and animals, which comprises a therapeutically effective amount of a compound of the formula:
wherein X" is S-lower alkyl, or a pharmaceutically acceptable non-toxic salt thereof.
4. A method according to claim 3, wherein the compound is 1 (p-thiomethylphenyl-diphenyl-methyl)-imidazole.
References Cited UNITED STATES PATENTS 3,321,366 5/1967 Mussell et a1 424273 JEROME D. GOLDBERG, Primary Examiner
US36394A 1967-09-15 1970-05-11 N-trityl-imidazoles for treating fungal infections Expired - Lifetime US3657442A (en)

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US13797A Expired - Lifetime US3705172A (en) 1967-09-15 1970-02-24 N-trityl-imidazoles
US36395A Expired - Lifetime US3657445A (en) 1967-09-15 1970-05-11 N-trityl-imidazoles for treating fungal infections
US36396A Expired - Lifetime US3660576A (en) 1967-09-15 1970-05-11 N-trityl-imidazoles for treating fungal infections
US36425A Expired - Lifetime US3655899A (en) 1967-09-15 1970-05-11 N-trityl-imidazoles for treating fungal infections
US36426A Expired - Lifetime US3655900A (en) 1967-09-15 1970-05-11 N-trityl-imidazoles for treating fungal infections
US36424A Expired - Lifetime US3658956A (en) 1967-09-15 1970-05-11 N-trityl-imidazoles for treating fungal infections
US36394A Expired - Lifetime US3657442A (en) 1967-09-15 1970-05-11 N-trityl-imidazoles for treating fungal infections
US00126277A Expired - Lifetime US3720770A (en) 1967-09-15 1971-03-19 1-(p-chloro-m-nitrophenyl-diphenylmethyl)-imidazole as an antifungal agent
US00161274A Expired - Lifetime US3839573A (en) 1967-09-15 1971-07-09 Antifungal compositions and methods of treatment employing n-trityl imidazoles
US00218521A Expired - Lifetime US3711498A (en) 1967-09-15 1972-01-17 N-trityl-imidazoles
US00218524A Expired - Lifetime US3717657A (en) 1967-09-15 1972-01-17 N-trityl-imidazoles
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US00218519A Expired - Lifetime US3767668A (en) 1967-09-15 1972-01-17 Process for the production of n-trityl-imidazoles
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US36395A Expired - Lifetime US3657445A (en) 1967-09-15 1970-05-11 N-trityl-imidazoles for treating fungal infections
US36396A Expired - Lifetime US3660576A (en) 1967-09-15 1970-05-11 N-trityl-imidazoles for treating fungal infections
US36425A Expired - Lifetime US3655899A (en) 1967-09-15 1970-05-11 N-trityl-imidazoles for treating fungal infections
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US00161274A Expired - Lifetime US3839573A (en) 1967-09-15 1971-07-09 Antifungal compositions and methods of treatment employing n-trityl imidazoles
US00218521A Expired - Lifetime US3711498A (en) 1967-09-15 1972-01-17 N-trityl-imidazoles
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US3720770A (en) 1973-03-13
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US3717657A (en) 1973-02-20
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US3655900A (en) 1972-04-11
US3660576A (en) 1972-05-02
US3711498A (en) 1973-01-16
US3711499A (en) 1973-01-16
US3660577A (en) 1972-05-02
US3658956A (en) 1972-04-25
LU57488A1 (en) 1969-03-13
US3767668A (en) 1973-10-23
US3705172A (en) 1972-12-05
US3655899A (en) 1972-04-11

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