US3658956A - N-trityl-imidazoles for treating fungal infections - Google Patents

N-trityl-imidazoles for treating fungal infections Download PDF

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US3658956A
US3658956A US36424A US3658956DA US3658956A US 3658956 A US3658956 A US 3658956A US 36424 A US36424 A US 36424A US 3658956D A US3658956D A US 3658956DA US 3658956 A US3658956 A US 3658956A
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imidazole
trityl
methyl
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salts
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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

  • R, R and R are hydrogen, lower alkyl or phenyl, or R and R together form an anellated benzene ring
  • X, X and X" are alkyl of 1 to 12 carbon atoms or an electro-negative moiety
  • n, n and n" are integers from to 2
  • Hal X Xrr wherein the substituents are as above defined and Hal is halogen. These compounds are useful as antimycotics.
  • the present invention is concerned with N-trityl-imidazoles and salts thereof and the production of such compounds. More particularly, the present invention is concerned with N-trityl-imidazoles and salts thereof of the formula:
  • X, X and X are alkyl of 1 to 12 carbon atoms or an electro-negative moiety
  • n, n' and n" are integers from 0 to 2
  • R, R and R are alkyl moieties, those having 1 to 4 carbon atoms are preferred.
  • X, X or X is an alkyl moiety, it is preferred 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, succinicyacid, fumaric acid, tartaric acid, citric acid, saliylic acid, sorbic acid, lactic acid and 1,S-naphthalene-disulphonic acid.
  • the hydrohalides, especially the hydrochlorides, lactates and salicylates are of particular value.
  • N-trityl-imidazoles have the formula:
  • 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 1.
  • 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 imidazole derivatives of the Formula III with trityl-carbinols (cf. the reaction of the carbinol corresponding to the halide IV with secondary amines).
  • the imidazole 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, C210) 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 imidazole 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 011 and the residue remaining after removal of the solvent is recrystallised from benzene/ light petrol.
  • 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.
  • N-tritylimidazole 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 crystallize by covering it with ether, the crystallisation product is washed with ether and dried.
  • 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. 155 C. after recrystallisation from acetone/ether 1:1.
  • the previously known antimycotics are effective either only against yeasts, such as e.g. Amph t ricin B, or only against hyphomycetes, such as e.g. Griseofulvin.
  • the compounds (I, 'II) and their salts are effective against hyphomycetes as well as against yeasts, even in the case of oral administration. It is another advantage that the compounds according to the invention are well tolerated by warmblooded animals.
  • the compound can be used as antimycotics, inter aha, 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).
  • Microsp. cam's (NL) (15) Microsp. cam's (our isolation) (16) Microsp. duboisii-.. (17) Microsp. fulvum- (18) .Microsp. galliruze (19) Microsp. felimum (20) Aspergillus niger (21) Pen. prepared o KHHD- HHHHHHHHHHHHHwHD- (22) Mucor mucedo 10 (23) Blakeslea trisporm 10 10 (24) Cami. albica'ns 1 40-1 40*1 1 Fungistase.
  • 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, and tablets.
  • solutions e.g., alcohol, preferably ethanol and isopropanol, buffer solutions, powders, and 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 suflice to attain the range of dosage mentioned above.
  • tablets may also contain additives such as sodium citrate, calicum 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 tale 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 combinations of this type.
  • aqueous solutions of the active ingredients in sesame or peanut oil or in aqueous propylene-glycol of N,N-dimethyl formamide, as well as sterile aqueous solutions if the compounds are water-soluble.
  • aqueous solution should be buffered in the usual manner, if required, and the liquid diluent should previously be rendered isotonic by the addition of the necessary amount of salt or glucose.
  • aqueous solutions are particularly suitable for intravenous, intramuscular and intraperitoneal injections.
  • a dosage of 40 mg./kg. administered at intervals of 12 hours result in a blood level of between and 11 y/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 cotnpounds/kg. body weight in the case of oral administration.
  • the present invention also includes pharmaceutial 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 comprises 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 drages; in wrapped or concealed form, such as wrapped powders, cachets, sachets or capsules,
  • 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'NO or a pharmace-utically acceptable nontoxic salt thereof.

Abstract

N-TRITYL-IMIDAZOLES AND SALTS THEREOF OF THE FORMULA:

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

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

WHEREIN

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

2-R,4-R1,5-R2-IMIDAZOLE

WITH A TRITYL HALIDE OF THE FORMULA:

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

BENZENE

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

Description

United States Patent ()fice Int. Cl. A61k 27/00 US. Cl. 424-273 4 Claims ABSTRACT OF THE DISCLOSURE N-trityl-imidazoles and salts thereof of the formula:
X" wherein R, R and R are hydrogen, lower alkyl or phenyl, or R and R together form an anellated 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 integers from to 2,
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 X Xrr 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 filed Sept. 9, 1968.
The present invention is concerned with N-trityl-imidazoles and salts thereof and the production of such compounds. More particularly, the present invention is concerned with N-trityl-imidazoles and salts thereof of the formula:
3,658,956 Patented Apr. 25, 1972 wherein R, R and R are hydrogen, lower alkyl or phenyl, or R and R together form an anellated 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 integers from 0 to 2,
or pharmaceutically acceptable acid salts thereof. When R, R and R are alkyl moieties, those having 1 to 4 carbon atoms are preferred. When X, X or X is an alkyl moiety, it is preferred 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, succinicyacid, fumaric acid, tartaric acid, citric acid, saliylic acid, sorbic acid, lactic acid and 1,S-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:
X,," (II) (Ila) 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. With regard to Formula IIa, particularly preferred substituent values are those where X is fluorine, chlorine, bromine, iodine, N0 CF CN, SCH OCH and n is 1.
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:
R1'N Xn 13,1 x, mi 1.. N H
(III) XQw 1v 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 110 C. [cf. Chem. Ber. 92, 92- (1959); 93, 570
The compounds of the present invention can also be prepared according to techniques per se known by reacting imidazole derivatives of the Formula III with trityl-carbinols (cf. the reaction of the carbinol corresponding to the halide IV with secondary amines). In this case, the imidazole 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 elemination 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, C210) 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- trityl-imidazoles (I, II) by way of example:
' M.P.: C. (a) 1-(trisphenyl-methyl)-i midazole 226-227 b) l-(trisphenyl-methyl)-2-methyl-imidazole 225 (c) l-(trisphenyl-methyl) 2,4 dimethyl-iinidazole 232 (d) l-(trisphenylmethyl) 4,5 diphenyl-imidazole 228-230 (e) l-(p-chlorophenyl diphenyl methyD-imidazole 140 (f) l-(p-fluorophcnyl diphenyl methyD-imidazole 145 (g) I-(p-tolyl diphenyl methyl) imidazole 128 (h) 1 (trisphenyl-methyl)-benzimidazole 180-181 (i) l-(o-chlorophenyl diphenyl methyl)-imidazole 147-149 (j) l-(m-chlorophenyl diphenyl methyl) -imidazole 114 (k) 'l-(p-bromophenyl diphenyl methyl) -imidazole 152 (l) l-(o-fluorophenyl diphenyl methyD-imidazole I 1 85 (m) l-(m-fluorophenyl diphenyl methyl)- imidazole 174 (n) l-(p-nitrophenyl diphenyl methyl)-imidazole 160-170 (0) 1-(m trifluoromethylphenyl diphenylmethyl) imidazole 156 (p) I-(p-cyanophenyl diphenyl methyD-imidazole 164 (q) 1-(o-methoxyphenyl diphenyl methyl)- imidazole 130 (r) l-(p methylthiophenyl-diphenyl-methyl)- imidazole 142 (s) l-(p-fiuorophenyl diphenyl methyl)-2- methyl imidazole 199 (t) l-(p-fluorophenyl p chlorophenyl-phenyl-methyl)-imidazole 144 (u) l-(p-chlorophenyl m fluorophenyl-phenyl methyl) imidazole 116 (v) l-(p chloro m nitrophenyl diphenylmethyl) imidazole 150 (w) 1-( p-bromophenyl p chlorophenyl-phen- 'yl methyl) e imidazole '140 (x) l-(m-cyanophenyl diphenyl methyl)-imidazole 119 (y) l-(o cyanophenyl diphenyl methyl)- imidazole 149151 Example of preparation 1- [p-chlorophenyl-diphenyl-methyl]-imidazole (e) U com-d 1 mole p-chlorophenyl diphe nyl methyl carbinol is mixed with about 2 moles imidazole and thernixture 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'i-midazole. After another reprecipitation from benzene light petrol, the pure 1 [p chlorophenyl diphenyl-methyl1- imidazole is obtained.
M.P. 143 C.; yield 53% of theory.
The same compound can also be obtained, when finely powdered silver salt of imidazole 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 011 and the residue remaining after removal of the solvent is recrystallised from benzene/ light petrol.
By analogous procedure, "-l-(tris phenyl methyl)- irnidazole is produced from 1 tris phenyl methylcarbinol and imidazole and l-(p-tolyl diphenyD-imidazole is produced from 1 p tolyl diphenyl methylcarbinol and imidazole.
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-tritylimidazole 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 crystallize by covering it with ether, the crystallisation product is washed with ether and dried.
Yield 40 g. of a colourless crystalline powder of MP. -l80 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. 155 C. after recrystallisation from acetone/ether 1:1.
Yield 33 g.
The following salts are obtained in an analogous manner:
M.P.: C.
N-triphenylmethyl-irnidazoliurn maleate 106-117 N-triphenylmethyl-imidazolium tartrate -180 N-triphenylmethyl-imidazolium citrate 138-145 N-triphenylmethyl-imidazolium acetate 231 N-triphenylmethyl-imidazolium salicylate 145-168 N-triphenylmethyl-imidazolium sorbate 148-160 N-triphenylmethyl-imidazolium succinate 188-189 N-triphenylmethyl-imidazolium fumarate 200-206 1-(p-chlorophenyl-diphenyl methyl) imidazolium-chloride 128-30 1-(p-chlorophenyl-diphenyl methyl) imidazolium-lactate 90 1-(p-chlorophenyl-diphenyl methyl) imidazoliurn-salicylate (1) 1-(m-chlorophenyl-diphenyl methyl)-imidazolium hydrochloride 153 M.P.: C. 1-(o-chlorophenyl-diphenyl methyl)-imidazolium-chloride 159 1-(p-fluorophenyl-diphenyl methyl)-imidazohum-chloride 1 l0 1-(p-fiuorophenyl-diphenyl methyl)-imidazoloum-lactate 95 1-(o-fiuorophenyl-diphenyl methyl)-imidazo lium-lactate 100 1(m-fluorophenyl-diphenyl methyl)-imidazolium-lactate 120 1-(p-fluorophenyl-diphenyl methyD-imidazolium-salicylate 80 1-(p-cyanophenyl-diphenyl methyl)-imidazohum-chloride 147 1-(o-cyanophenyl-diphenyl methyl)-imidazolium-chloride 13 l 1-(p-cyanophenyl-diphenyl methyl)-imidazolium-lactate 90 1 Oil.
The previously known antimycotics are effective either only against yeasts, such as e.g. Amph t ricin B, or only against hyphomycetes, such as e.g. Griseofulvin.
In contrast thereto and surprisingly, the compounds (I, 'II) and their salts are effective against hyphomycetes as well as against yeasts, even in the case of oral administration. It is another advantage that the compounds according to the invention are well tolerated by warmblooded animals.
The compound can be used as antimycotics, inter aha, 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 (a) Candida albicans:
compound (a) 40 'y/ml compound (e) 4 'y/ml compound (f) 4 'y/Inl. compound (g) 4 /ml. compound (i) 4'y/ml compound (p) 4 'y/ml.
(b) Trichophyton mentagr 'phytesz 4-10 'y fungistatic MiCrOSp. fel. 4 'y. The test meditun was Milieu dpreuve according to Sabouraud.
The spectrum of activity and the intensity of activity (compound i) (in vitro) can be seen from the following table:
fungistatic (14) Microsp. cam's (NL) (15) Microsp. cam's (our isolation) (16) Microsp. duboisii-.. (17) Microsp. fulvum- (18) .Microsp. galliruze (19) Microsp. felimum (20) Aspergillus niger (21) Pen. comune o KHHD- HHHHHHHHHHHHHHHwHD- (22) Mucor mucedo 10 (23) Blakeslea trisporm 10 10 (24) Cami. albica'ns 1 40-1 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 0.51 mg./mouse/day.
(b) Experimental trychophytia in mice caused by Trich. quinckeanum: Development of the infection is prevented by daily doses of 1-2 times 1-2 mg./mouse orally.
(c) Experimental trichophytia in guinea pigs caused by Trich. me'nl: When 15-30 mg. are administered twice per os to guinea pigs weighing 400 grams, a reproducible effect on the course of the infection and rapid healing of the mycotic lesions is found.
Equally effective 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 useful. The following usages and dosage ranges are used for the compounds of the present invention:
(a) for use with humans:
(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, and 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 suflice to attain the range of dosage mentioned above.
In the case of oral administration, obviously, tablets may also contain additives such as sodium citrate, calicum 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 tale 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 combinations 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 of N,N-dimethyl formamide, as well as sterile aqueous solutions if the compounds are water-soluble. Such aqueous solution should be buffered in the 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 y/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 cotnpounds/kg. body weight in the case of oral administration.
The present invention also includes pharmaceutial 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 comprises 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 drages; in wrapped or concealed form, such as wrapped 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'NO or a pharmace-utically acceptable nontoxic salt thereof.
4. A method according to claim 3, wherein the compound is 1- (p-nitrophenyl-diphenyl-methyl)-imidazole.
References Cited UNITED STATES PATENTS 3,321,366 5/1967 Mussell et al. 424273 JEROME D. GOLDBERG, Primary Examiner
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US36425A Expired - Lifetime US3655899A (en) 1967-09-15 1970-05-11 N-trityl-imidazoles for treating fungal infections
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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
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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
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US3657445A (en) 1972-04-18
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US3660576A (en) 1972-05-02
US3711498A (en) 1973-01-16
US3711499A (en) 1973-01-16
US3660577A (en) 1972-05-02
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US3705172A (en) 1972-12-05
US3655899A (en) 1972-04-11

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