US3711501A - N-trityl-imidazoles - Google Patents

N-trityl-imidazoles Download PDF

Info

Publication number
US3711501A
US3711501A US00218526A US3711501DA US3711501A US 3711501 A US3711501 A US 3711501A US 00218526 A US00218526 A US 00218526A US 3711501D A US3711501D A US 3711501DA US 3711501 A US3711501 A US 3711501A
Authority
US
United States
Prior art keywords
methyl
phenyl
imidazole
diphenyl
imidazolium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US00218526A
Inventor
K Buchel
E Regel
M Plempel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Application granted granted Critical
Publication of US3711501A publication Critical patent/US3711501A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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 an integer from 0 to 2
  • nharmaceutically acceptable acid salt thereof may be produced by reacting a silver salt or alkali metal salt of an imidazole of the formula:
  • Hal X I 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:
  • R, R and R are hydrogen, lower alkyl or phenyl, or
  • X, X and X" are alkyl of 1 to 12 carbon atom or an electro-negative moiety
  • n, n and n" are an integer from 0 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 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 0- 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,
  • the N-trityl-imidazoles ha ve the formula: to about 2-3 moles.
  • n, n and n" are 1 or 2.
  • particularly preferred sub- M P stituent values are those Where X" is fluorine, chlorine, 6 'f bromine, iodine, N0 CF CN, SCH OC-H and n" is 1.
  • M P C molar amounts may be used. Furthermore, it may be expedient to carry out the elimination of water azeotropi- Yleld 53% of theory cally in the presence of a high boiling inert organic sol- 70
  • the same compound can also be obtained, when finely vent, such as xylene, chlorobenzeues and the like, at the powdered silver salt of imidazole is suspended with the boiling point of the solvent used.
  • finely vent such as xylene, chlorobenzeues and the like
  • the process is carried out at a temperature range chloride in absolute benzene, the mixture is heated with of from about 140 C. to about 230 C.
  • 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)-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.
  • 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.
  • N-triphenylmethyl-imidazolium malcate 106-117 N-triphenylmethyl-imidazolium tartrate 175-180 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)-imidazolium-salicylate (1) 1 (m-chlorophenyl-dip
  • antimicotics are effective either only against yeasts, such as e.g. Amphotericin B, or only against hyphomycetes, such as e.g. Griseofulvin.
  • T richophyton mentagrophytes 4l0'y fungistatic microsp. fel. 4
  • test medium was Milieu dpreuve according to Sabouraud.
  • Trich. asteroides 1 Trish. crateriforme 1 (3) Trich. equinum (NL) 1 (4) Trich. equinum, wooly (Hoechst 1 (5) Trich. equirzum, gran. (Hoechst) 1 (6) Trish. tori-swans 1 7) Trich. verrucosum 1 (8) Trich. granulosttmn 1 Trr'ch. interdigitale 1 (l0) Trich.rnegninii 0.1 (11) Trick. mentagr0phytes 01 (12) Trz'ch. rubrum i 1 (13) Mt'crosp. audouinii 1 (14) Microsp. cam's (NL) 0.
  • MiCTOSp.ca7LiS our lsolat 1
  • Mi'crosp. duboisii 1 (17)
  • Microspjulvum 1 (18)
  • Microsp. gaZlinae 1 (l9)
  • Microsp. felirzeum 1 (20) Asperigz'llus mger 1 4
  • Pen. comma.-- 1 (22)..- Mucor mucedo 4 10
  • Blakesleatrz'spora 10 10 (24)
  • dermatomycoses caused by fungi of the species Trychophytes, 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., dimethyl sulphoxide/glycerol/water 222:6, alcohol, preferably ethanol and isopropanol, buffer solutions, powders, tablets.
  • solutions e.g., dimethyl sulphoxide/glycerol/water 222:6, alcohol, preferably ethanol and isopropanol, buffer solutions, powders, tablets.
  • the dosage range from 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 or 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 90 percent by weight, i.e., in quantities which sufiice 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 tale for producing tablets.
  • the active ingredient may be used together with various agents for improving the flavor, dyestuifs, emulsifiers and/or diluents, such as water, ethanol, propylene-glycol 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 buttered 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 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 half-life period in human serum in vivo 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 or 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 powders, cachets, sachets or capsules, in ampules such as in sterile solution; or in other forms known to the art.
  • a salt according to claim 1 selected from the group consisting of hydrochloride, phosphate, acetate, propionate, maleate succinate, fumarate, tartrate, citrate, salicylate, sorbate, lactate or 1,S-naphthalene-disulphonate.

Abstract

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

1-(((X)N-PHENYL-)((X'')N''-PHENYL-)((X")N"-PHENYL-)C-),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 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 AN INTEGER FROM 0 TO 2, OR PHARMACEUTICALLY ACCEPTABLE ACID SALT 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-),((X'')N-PHENYL-)((X")N"-PHENYL-)C-HAL

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

Description

United States Patent Int. Cl. c07d 49/36 U.S. Cl. 260309 8 Claims ABSTRACT OF THE DISCLOSURE 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 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 an integer from 0 to 2,
or nharmaceutically acceptable acid salt thereof may be produced by reacting a silver salt or alkali metal salt of an imidazole of the formula:
N 9-21 R2 H with a trityl halide of the formula:
ice
Hal X I wherein the substituents are as above defined and Hal is halogen. These compounds are useful as antimycotics.
This is a divisional application of Ser. No. 13,797, filed Feb. 24, 1970 which is a divisional of Ser. No. 758,594, filed Sept. 9, 1968, now U.S. Pat. 3,660,577.
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:
N R a 3 :2".
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 atom or an electro-negative moiety, and
n, n and n" are an integer from 0 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 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 0- 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 It may further be expedient to'facilitate the eliminaacid and 1,5-naphthalene-disulphonic acid. The hydrotion of water by working in the presence of dehydrating halides, especially the hydrochlorides, lactates and saliagents, such as e.g. alkaline earth metal oxides (MgO, cylates are of particular value. BaO CaO) and of A1 approximately molar amounts In a particularly preferred embodiment of the present 5 being generally used, but possibly also an excess of up invention, the N-trityl-imidazoles ha ve the formula: to about 2-3 moles.
N N (,2 n I X,
The following table gives the constants of some N-tritylwherein X, X and X are alkyl of 1 to 12 carbon atoms imidazoles (I, y y of example:
or electro-uegative substituents an n, n and n" are 1 or 2. With regard to Formula Ila, particularly preferred sub- M P stituent values are those Where X" is fluorine, chlorine, 6 'f bromine, iodine, N0 CF CN, SCH OC-H and n" is 1.
(a) l-(tris hen l-meth l)-imidazole 226-227 The compqunds of Pmsent Invention can be P (b) 1-(trisghengl-methgl)-2 methyllmldazole 221s pared according to techniques per se known, such as by (c) l-(tnsp y y ,di et y da 23 reacting silver salts or alkali metal salts, in particular the 38 potassium salts of imidazoles of the Formula III with $0 i-gi 5 g e y i p y g g hg )ggidaz l ig OY eny 1% y "11111 az trltyl hahdes of the Formula 'IV" (1%) l-(trispheny f-methyl)-benzimidazole 180-181 (1) 1-(o-chl0rophenyl-diphenyl-methy1)dmtdazole.-. 147-149 (j) 1-(m-ch1orophenyl-diphenyl-methyl)-lmidazole 114 (k) 1-(p-bromophenyl-diphenyl-methyl) -lmidazole 152 (l) l-(o-fluorophenyl-diphenylmethyl)-i midaz01e (m) 1-(m-fluorophenyl-dlphenyl-methyl)-lmldazo1e (n) 1-(p-nitrophenyl-dlphenyl-methyl)-imidazole. 1 H31 (0) 1-(m-Erifluoromethylpheuyl-dlphenyl-methyl)-imid- 156 820 6. R (p) 1-(p-cyanophenyl-dlphenyl-methyl)-1midazole 164 x X (q)--- 1-(0-methoxyphenyl-diphenyl-methyl)-imidazo1e 130 a (r) 1-(p-methylthiophenyl-diphonyl-methyl)-irnidaz0le 142 (s) 1-(p-fiuorophenyl-diphenyl-methyl)-2-methyl- 199 C 40 lmidazole.
(t) 1-(p-fluorophenyl-p-chlorophenyl-phenyl-methyl)- 144 2 N R lmldazolo. R E (u) 1-gggglortiphenyl-m-fluorophenyl-phenyl-methyl)- 116 I(1Z0 8' (v) 1-( i-c111oro-m-nltrophenyl dlphenyl-methyl) -imidaz- 150 O 8. (III) (w). 1-(p-bromophenyl-p-chlorophenyl-phenyl-methyl)- 140 imldazole.
(x) 1-(mcyanophenyl-diphenyl-methyl)-lmidazole 119 (17) (y) 1-(o-cyanophenyl-dlphenylmethyl)imidazole 149-151 EXAMPLE OF PREPARATION 1- [p-chlorophenyl-diphenyl-methyl] -imidazole (e) N wherein I 1 R, R and R X, X and X" and n, n and n" have the N above meanings and (E Hal is chlorine, bromine or iodine, in an inert solvent such as benzene, toluene, hexane, cyclohexene or di- I ethyl ether, at a temperature of from about 20 C. to
about 1 (1960) 0 C [of Chem Ber 92 (1959) 570 1 mole p-chlorophenyl-d1phenyl-methyl-carbinol 1s 0 mixed with about 2 moles imidazole and the mixture is The compounds of the present invention can also be heated, without a solvent, at about 180 C. for 5 hours. Prepared accordlllg techmques P 8e known y t- After cooling, the reaction product is reprecipitated from ing lmidazole derivatives of the Formula III with tritylylene in order to remove the excess imidazole. After carbmols cf. the reaction of the carbinol corresponding another reprecipitation from benzene light petrol, the to the halide I V with secondary ammes). In this. case, pure 1-[p-chlorophenyl-diphenyl-methyl]-imidazole is obthe imidazole is generally used in an excess of up to r in d.
about If! the process is carried out under pressure, M P C molar amounts may be used. Furthermore, it may be expedient to carry out the elimination of water azeotropi- Yleld 53% of theory cally in the presence of a high boiling inert organic sol- 70 The same compound can also be obtained, when finely vent, such as xylene, chlorobenzeues and the like, at the powdered silver salt of imidazole is suspended with the boiling point of the solvent used. In the absence of solequimolar amount of p-chlorophenyl-diphenyl-methyl vents, the process is carried out at a temperature range chloride in absolute benzene, the mixture is heated with of from about 140 C. to about 230 C. and preferably stirring and with the exclusion of light at boiling temperfrom about C. to about C. 75 ature 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)-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-trityl-imidazole are dissolved by heating in acetonitrile and 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.
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-imidazolium malcate 106-117 N-triphenylmethyl-imidazolium tartrate 175-180 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)-imidazolium-salicylate (1) 1 (m-chlorophenyl-diphenyl-methyl)-imidazolium-chloride 153 1 (o chlorophenyl-diphenyl-methyl)-imidazolium-chloride 159 l (p fluorophenyl-diphenyl-methyl)-imidazolium-chloride 1 l0 1 (p fluorophenyl-diphenyl-methyl)-imidazolium-lactate 95 1 (o fluorophenyl-diphenyl-methyl)-imidazolium-lactate 110 1 (m-fiuorophenyl-diphenyl-methyl)-imidazo- Hum-lactate 120 1 (p fluorophenyl-diphenyl-methyl)-imidazoliurn-salicylate 80 1 (p cyanophenyl-diphenyl-methyl)-imidazolium-chloride 147 1 (0 cyanophenyl-cliphenyl-methyl)-imidazolium-chloride 13 1 1 (p cyanophenyl-diphenyl-methyl)-imidazolium-lactate 90 1 Oil.
The previously known antimicotics are effective either only against yeasts, such as e.g. Amphotericin B, or only against hyphomycetes, such as e.g. Griseofulvin.
THERAPEUTIC EFFECT (1) in vitroeffect against human-pathogenic fungi (a) Candida albicans (fungistatic):
compound (a) 40 'y/ml.
compound (e) 4 'y/ml.
compound (f) 4 'y/ml.
compound (g) 4 'y/ml.
compound (i) 4 'y/ml.
compound (p) 4 'y/ml.
T richophyton mentagrophytes: 4l0'y fungistatic microsp. fel. 4
The test medium 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:
MINIMUM INHIBIIING CONCENTRATION AS S/ML.
Without With serum serum (1) Trich. asteroides 1 (2) Trish. crateriforme 1 (3) Trich. equinum (NL) 1 (4) Trich. equinum, wooly (Hoechst 1 (5) Trich. equirzum, gran. (Hoechst) 1 (6) Trish. tori-swans 1 7) Trich. verrucosum 1 (8) Trich. granulosttmn 1 Trr'ch. interdigitale 1 (l0) Trich.rnegninii 0.1 (11) Trick. mentagr0phytes 01 (12) Trz'ch. rubrum i 1 (13) Mt'crosp. audouinii 1 (14) Microsp. cam's (NL) 0. 1 (15) MiCTOSp.ca7LiS (our lsolat 1 (16). Mi'crosp. duboisii 1 (17)..." Microspjulvum 1 (18) Microsp. gaZlinae 1 (l9) Microsp. felirzeum 1 (20) Asperigz'llus mger 1 4 (21) Pen. comma.-- 1 (22)..- Mucor mucedo 4 10 (23) Blakesleatrz'spora 10 10 (24)..." C'and. albiclms 40-1 40-1 1 Fungistase.
(2) Effect in vivo (21) Experimental candidosis in white mice: In the case of oral administration, curvative effects can be achieved with daily doses of 2-3 times 0.5-1 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 Tich. ment: When 15-30 mg. are administered twice per as 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 o-,mor p-position; such compounds and their salts with hydrochloric acid, lactic acid or salicyclic acid are particularly useful. 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 Trychophytes, 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., dimethyl sulphoxide/glycerol/water 222:6, alcohol, preferably ethanol and isopropanol, buffer solutions, powders, tablets.
The dosage range from 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 or 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 sufiicient 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 90 percent by weight, i.e., in quantities which sufiice 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 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, dyestuifs, emulsifiers and/or diluents, such as water, ethanol, propylene-glycol 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 buttered 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 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 and 11 'y/ml. The half-life period in human serum in vivo 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 or 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 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. A compound of the formula:
wherein X" is (IN, or a pharmaceutically acceptable nontoxic salt thereof.
2. A salt according to claim 1 selected from the group consisting of hydrochloride, phosphate, acetate, propionate, maleate succinate, fumarate, tartrate, citrate, salicylate, sorbate, lactate or 1,S-naphthalene-disulphonate.
3. The compound according to claim 1 which is l-(pcyanophenyl-diphenyl-methyl)-imidazole.
4. The compound according to claim 1 which is l-(mcyanophenyl-diphenyl-methyl -imidazole.
5. The compound according to claim 1 which is l-(ocyanophenyl-diphenyl-methyl -imidazole.
6. The compound according to claim 1 which is l-(ocyanophenyl-diphenyl-methyl)imidazolium chloride.
7. The compound according to claim 1 which is 'l-(pcyanophenyl-diphenyl-methyl)-imidazolium lactate.
8. The compound according to claim 1 which is l-(pcyanophenyl-diphenyl-methyl)-imidazolium chloride.
References Cited UNITED STATES PATENTS 3,321,366 5/1967 Mussell et a1. 260-309 NATALIE TROUSOF, Primary Examiner US. Cl. X.R.
US00218526A 1967-09-15 1972-01-17 N-trityl-imidazoles Expired - Lifetime US3711501A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DEF0053504 1967-09-15
LU57488 1968-12-06
US21852472A 1972-01-17 1972-01-17

Publications (1)

Publication Number Publication Date
US3711501A true US3711501A (en) 1973-01-16

Family

ID=27210542

Family Applications (16)

Application Number Title Priority Date Filing Date
US758594A Expired - Lifetime US3660577A (en) 1967-09-15 1968-09-09 N-trityl-imidazoles as antifungal agents
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
US00218525A Expired - Lifetime US3711500A (en) 1967-09-15 1972-01-17 N-trityl-imidazoles
US00218526A Expired - Lifetime US3711501A (en) 1967-09-15 1972-01-17 N-trityl-imidazoles
US00218519A Expired - Lifetime US3767668A (en) 1967-09-15 1972-01-17 Process for the production of n-trityl-imidazoles
US00218523A Expired - Lifetime US3711499A (en) 1967-09-15 1972-01-17 N-trityl-imidazoles

Family Applications Before (13)

Application Number Title Priority Date Filing Date
US758594A Expired - Lifetime US3660577A (en) 1967-09-15 1968-09-09 N-trityl-imidazoles as antifungal agents
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
US00218525A Expired - Lifetime US3711500A (en) 1967-09-15 1972-01-17 N-trityl-imidazoles

Family Applications After (2)

Application Number Title Priority Date Filing Date
US00218519A Expired - Lifetime US3767668A (en) 1967-09-15 1972-01-17 Process for the production of n-trityl-imidazoles
US00218523A Expired - Lifetime US3711499A (en) 1967-09-15 1972-01-17 N-trityl-imidazoles

Country Status (5)

Country Link
US (16) US3660577A (en)
BE (1) BE720801A (en)
FR (2) FR1597530A (en)
GB (1) GB1170188A (en)
LU (1) LU57488A1 (en)

Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH513893A (en) * 1968-07-20 1971-10-15 Bayer Ag Process for the preparation of N-diaryl-pyridylmethyl-imidazoles and their salts
CH531518A (en) * 1968-11-29 1972-12-15 Bayer Ag Process for the preparation of N-substituted imidazoles and their salts
DE2009020C3 (en) * 1970-02-26 1979-09-13 Bayer Ag, 5090 Leverkusen Process for the preparation of N- (l, l, l-trisubstituted) -methylazoles
US3980780A (en) * 1970-03-23 1976-09-14 Bayer Aktiengesellschaft N-Methyl-imidazole derivatives for treating mycotic infections
US3764609A (en) * 1970-06-22 1973-10-09 Koninklijke Pharma Fab Nv 1 (dibenzo {8 4,d{9 {0 cyclohepten-5-yl), 1-(dibenzo {8 a,d{9 {0 cycloheptan-5-yl) and 1-(dibenzo {8 a,d{9 {0 cyclooctanyl)imidazoles
DE2037610A1 (en) * 1970-07-29 1972-02-03 Bayer Ag New alpha-substituted benzyl-azoles, processes for their production and their use as pharmaceuticals
US4117142A (en) * 1972-03-22 1978-09-26 Bayer Aktiengesellschaft Disubstituted triphenylmethylmidazoles for treating mycotic infections
DE2213863C3 (en) * 1972-03-22 1982-05-13 Bayer Ag, 5090 Leverkusen Disubstituted triphenylmethylimidazoles, processes for their preparation and pharmaceuticals containing them
DE2314985A1 (en) * 1973-03-26 1974-10-17 Hoechst Ag 1- (IMIDAZOL-1-YL) -ISOCHINOLINES AND THE PROCESS FOR THEIR MANUFACTURE
JPS6048486B2 (en) * 1976-01-01 1985-10-28 木場 常義 antirheumatic agent
FR2387658A1 (en) * 1977-03-25 1978-11-17 Ciba Geigy Ag PROCEDURE FOR FIGHTING MICROORGANISMS
US4267169A (en) * 1978-07-22 1981-05-12 Toko Yakuhin Kogyo Kabushiki Kaisha Novel preparation of clotrimazole
US4216333A (en) * 1978-10-30 1980-08-05 Sumitomo Chemical Company, Limited Process for preparing N-tritylimidazole compounds
US4439441A (en) * 1979-01-11 1984-03-27 Syntex (U.S.A.) Inc. Contraceptive compositions and methods employing 1-substituted imidazole derivatives
JPS5692887A (en) * 1979-12-05 1981-07-27 Sumitomo Chem Co Ltd N-substituted imidazole derivative
JPS58150566A (en) * 1982-03-03 1983-09-07 Yoshitomi Pharmaceut Ind Ltd Novel imidazole derivative
US4755526A (en) * 1984-06-18 1988-07-05 Eli Lilly And Company Method of inhibiting aromatase
US4775678A (en) * 1984-10-01 1988-10-04 Schering Corporation Clotrimazole cream
US4978672A (en) * 1986-03-07 1990-12-18 Ciba-Geigy Corporation Alpha-heterocyclc substituted tolunitriles
US4749713A (en) * 1986-03-07 1988-06-07 Ciba-Geigy Corporation Alpha-heterocycle substituted tolunitriles
US4937250A (en) * 1988-03-07 1990-06-26 Ciba-Geigy Corporation Alpha-heterocycle substituted tolunitriles
EP0352352B1 (en) * 1988-07-28 1991-10-16 J. URIACH & CIA. S.A. 1-[(2-Fluorophenyl)(4-fluorophenyl)phenylmethyl]-1H-imidazole
US5177099A (en) * 1989-04-10 1993-01-05 Sociedad Espanola De Especialidades Farmaco-Terapeuticas S.A. Dichloro-substituted imidazole derivatives as antifungal agents
CA2035758C (en) * 1990-03-06 2002-04-02 Yataka Murata Antimycotic external imidazole preparations
ZA934007B (en) * 1992-06-08 1994-03-09 Schering Plough Healthcare Stable imidazole anti-fungal powder compositions
US6177427B1 (en) * 1994-06-28 2001-01-23 Alcon Laboratories, Inc. Treatment of glaucoma and ocular hypertension
EP1052990A2 (en) * 1997-11-14 2000-11-22 Neurosearch A/S Chemical compounds having ion channel blocking activity for the treatment of immune dysfunction
US6103733A (en) * 1998-09-09 2000-08-15 Bachmann; Kenneth A. Method for increasing HDL cholesterol levels using heteroaromatic phenylmethanes
US6080744A (en) * 1999-02-10 2000-06-27 Ayon-Covarrubias; Blas Topical antifungal treatment
US6450515B1 (en) * 2000-10-10 2002-09-17 James F. Guth Clip-on wheels for pallets or other structures with runners
US20060211632A1 (en) * 2005-03-17 2006-09-21 Bachmann Kenneth A PXR agonists for cardiovascular disease
EP1958613A1 (en) * 2007-02-15 2008-08-20 Polichem S.A. Dermal film-forming liquid formulations for drug release to skin
CL2008003553A1 (en) * 2007-12-05 2009-11-27 Grindeks Jsc Process to prepare atipamezole or 5- (2-ethyl-2,3-dihydro-1h-inden-2-yl) -1h-imidazole hydrochloride: and the intermediate compounds considered in the process
BRPI0904249B1 (en) 2009-08-28 2018-03-06 Biolab Sanus Farmacêutica Ltda. BENZYL ARALQUIL ETHER COMPOUNDS, PREPARATION PROCESS FOR THEM, USE OF SUCH COMPOUNDS, PHARMACEUTICAL COMPOSITION
AU2010300550B2 (en) 2009-10-01 2014-10-30 Adare Pharmaceuticals, Inc. Orally administered corticosteroid compositions
WO2015034678A2 (en) 2013-09-06 2015-03-12 Aptalis Pharmatech, Inc. Corticosteroid containing orally disintegrating tablet compositions for eosinophilic esophagitis
JP6723698B2 (en) * 2015-07-23 2020-07-15 東京応化工業株式会社 Fine particle-containing composition
US20170112824A1 (en) * 2015-10-23 2017-04-27 Wright State University Combination therapies for the treatment of fungal infections
TWI728172B (en) 2016-08-18 2021-05-21 美商愛戴爾製藥股份有限公司 Methods of treating eosinophilic esophagitis
EP3558304A2 (en) 2016-12-23 2019-10-30 Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Inhibitors of cytochrome p450 family 7 subfamily b member 1 (cyp7b1) for use in treating diseases

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3321366A (en) * 1965-11-15 1967-05-23 Dow Chemical Co Fungicidal methods and compositions

Also Published As

Publication number Publication date
US3839573A (en) 1974-10-01
US3720770A (en) 1973-03-13
GB1170188A (en) 1969-11-12
DE1617481B2 (en) 1975-07-24
US3711500A (en) 1973-01-16
FR1597530A (en) 1970-06-29
DE1617481A1 (en) 1971-04-08
BE720801A (en) 1969-03-13
US3717657A (en) 1973-02-20
FR8112M (en) 1970-07-27
US3657442A (en) 1972-04-18
US3657445A (en) 1972-04-18
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

Similar Documents

Publication Publication Date Title
US3711501A (en) N-trityl-imidazoles
US3755349A (en) Alpha-substituted benzyl-imidazoles
IL33918A (en) Substituted n-benzylimidazoles,their production and pharmaceutical compositions containing them
US4171365A (en) Antiviral aryloxyalkylpyrazoles
GB2092569A (en) Substituted imidazole derivatives and their preparation and use
DK147682B (en) ANALOGY PROCEDURE FOR PREPARING 1-ARYL-2- (1-IMIDAZOLYL) ALKYLETHERS OR THIOETHERS
US3881014A (en) N-tritylimidazoles for treating fungal infections
US3821394A (en) Antimycotic composition and method employing a substituted benzyl-azoles
US3836540A (en) 1-(dimesitylmethyl)imidazole
US5411982A (en) Cycloalkylene azoles, and their use as aromatase inhibitors
US3872095A (en) N-trityl-imidazoles and their production
US3778447A (en) N-(substituted)fluorene-,dibenzocycloheptane-and dibenzocycloheptene-imidazoles
US3872117A (en) Phenyl-imidazolyl acetic acid amino alkanol esters and amides
US3787415A (en) N-methyl-imidazole derivatives and their production
CA1258461A (en) 2-azolylmethyl-3-difluorobenzyloxy-2,3- dihydrofluorobenzo¬b|thiophene antifungal compounds and method of using same
US3928348A (en) N-methyl-imidazole derivatives and their production
US4052409A (en) Disubstituted triphenylmethylimidazoles
US3978069A (en) Phenyl-imidazolyl-fatty acid derivatives
JPH01258671A (en) 5-(1h-imidazol-1-yl)-3(2h)-pyridazinone derivative
US3629273A (en) N-diaryl-pyridyl-methyl-imidazoles salts thereof
US3826837A (en) 9-azolyl-(1)-fluorene-9-carboxylic acid derivatives as an anti-mycotic agent
US3737531A (en) N-diaryl-pyridyl-methyl-imidazoles,salts thereof as antifungal agents
US4117142A (en) Disubstituted triphenylmethylmidazoles for treating mycotic infections
US3836663A (en) N-tritylimidazoles as antifungal agents
US3842175A (en) N-tritylimidazoles as antifungal agents