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US3711498A - N-trityl-imidazoles - Google Patents

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US3711498A
US3711498A US00218521A US3711498DA US3711498A US 3711498 A US3711498 A US 3711498A US 00218521 A US00218521 A US 00218521A US 3711498D A US3711498D A US 3711498DA US 3711498 A US3711498 A US 3711498A
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imidazole
phenyl
methyl
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salts
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K Buchel
E Regel
M Plempel
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Bayer AG
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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

  • 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 to 2
  • the present invention is concerned with N-trityl imidazoles and salts thereof and the production of such compounds. More particularly, the present invention is Patented Jan. 16, 1973 concerned with N-trityl-imidazoles and salts thereof of the formula:
  • R TN Bl Xn N X' 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
  • 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 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, mono-and 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:
  • Gig M 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 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 imidiazoles of the Formula III with trityl halides of the Formula IV:
  • 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 [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 imidazole derivatives of the Formula III with tritylcarbinols (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 outunder pressure, molar amounts may be used. Furthermore, it may be expedient to carry out the elimination of water azeotropicallyvin 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.
  • dehydrating agents such as e.g. alkaline earth metal oxide (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 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 oil and the residue remaining after removal of the solvent is recrystallised from benzene/light petrol.
  • 1-(tris-phenyl-methyl)-imidazole is produced from 1-tris-phenyl-methyl-carbinol and imidazole and l-(p-tolyl-diphenyl)-imidazole is produced from 1-p-tolyl-diphenyl-methyl-carbinol 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-tritylimidazole Salts of trityl-imidazoles N-triphenyl-methyl-imidazolium lactate.31 g. N-tritylimidazole are dissolved by heating in acetonitrile and 10 g. (0.11 mile) d,1-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 30-31 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.
  • antimycotics are effective either only against yeasts, such as e.g. Amphotericin 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 administra tion. 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 08. It is also possible to use aqueous solutions of the new salts of the said compounds (I).
  • test medium was Milieu dpreuve according to Sabouraud.
  • Trish. asteroides 1
  • Trish. srateriforme 1O
  • Trish. equimim NL
  • Trish. equinum Wooly
  • Trish. equinum gran.
  • Trish. t0nsurans. 2 Trish. verrusosum 4 Trish. granulosurrr..- 2 Trish. interdigitale 4 Trish. msgninii 0 1 Trish. mentagrophyte 0. 1 Trish. rubrum 2 Misrosp. audouiniin (l4). Misrosp. semis (NL)... (15)..-" Microsp.
  • 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 2:226, alcohol, preferably ethanol and isopropanol, buffer solutions, powders, tablets.
  • solutions e.g., dimethyl sulphoxide/glycerol/water 2:226, alcohol, preferably ethanol and isopropanol, buffer solutions, powders, tablets.
  • the dosage range for humans is in the range of from about 20 to about 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 90'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 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, it 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 ,5 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 compounds/ kg. body weightvin 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 multpile 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 l,S-naphthalene-disulphonate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

N-TRITYL-IMIDAZOLES 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 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-),((X'')N-PHENYL-)((X")N"-PHENYL-)C-HAL

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

Description

United States Patent 6) rm. (:1. 061a 49/36 US. Cl. 260-309 3 Claims ABSTRACT OF THE DISCLOSURE N-trityl-imidazoles and salts thereof of the formula:
x. U- @tQ xn 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 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:
Xn Hal wherein the substituents are as above defined and Hal is halogen. These compounds are useful an 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 US. 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 Patented Jan. 16, 1973 concerned with N-trityl-imidazoles and salts thereof of the formula:
R TN Bl Xn N X' 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 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 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, mono-and 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:
Gig M 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 imidiazoles of the Formula III with trityl halides of the Formula IV:
21). QiQ
(III) 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 [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 imidazole 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 imidazole is generally used in an excess of up to about 100%. If the process is carried outunder pressure, molar amounts may be used. Furthermore, it may be expedient to carry out the elimination of water azeotropicallyvin 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 oxide (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) 1-(trispheny1-methyl-2-methyl-imidazole 225 (c) 1 (trisphenyl methyl) 2,4 dimethylimidazole 232 (d) 1 (trisphenyl methyl) 4,5 diphenylimidazole 228-230 (e) 1 (p chlorophenyl diphenyl methyl)- imidazole 140 (f) 1 (p fluorophenyl diphenyl methyl)- imidazole 145 (g) 1-(p-tolyl-diphenyl-methyl)-imidazole 128 (h) l-(trisphenyl-methyl)-benzimidazole 180-181 (i) 1 (o chlorophenyl diphenyl methyl)- imidazole 147-149 (j) 1 (m chlorophenyl diphenyl methyl) imidazole 114 (k) '1 (p bromophenyl diphenyl methyl)- imidazole 152 (l) 1 (o fluorophenyl diphenyl methyl) imidazole 185 (m) 1 (m fluorophenyl diphenyl methyl)- imidazole 174 (n) 1 (p nitrophenyl diphenyl methyl)- imidazole 160-170 (0) 1 (m trifluoromethylphenyl diphenylmethy1)-imidazole -2"--- 156 (p) 1 (p cyanophenyl diphenyl methyl)- imidazole 164 (q) 1 (o methoxyphenyl diphenyl methylimidazole (r) 1 (p methylthiophenyl-diphenyl-methyl)- imidazole 142 (s) 1 (p fluorophenyl diphenyl methyl)-2- methyl-imidazole 199 (t) 1 (p fluorophenyl p-chlorophenyl-phenyl-methyl)-imidazole 144 (u) 1 (p chlorophenyl m fluorophenylphenyl-methyl)-imidazole 1 16 (v) 1 (p chloro m nitrophenyl diphenylmethyl)-imidazole (w) l (p bromophenyl p chlorophenylphenyl-methyD-imidazole 140 (x) 1 (m cyanophenyl diphenyl methyl)- imidazole 119 (y) 1 (o cyanophenyl-diphenyl methyl)-imidazole 149-151 EXAMPLE OF PREPARATION l-[p-chlorophenyl-diphenyl-methyl]-imidazole (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 xyle'ne in order to remove the excess imidazole. After another reprecipitation from benzene light petrol, the pure 1-[p-chlorophenyl-diphenyl-methyl]-imidazole is obtained. M. P.:140-143 (1.; 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 oil and the residue remaining after removal of the solvent is recrystallised from benzene/light petrol.
By analogous procedure, 1-(tris-phenyl-methyl)-imidazole is produced from 1-tris-phenyl-methyl-carbinol and imidazole and l-(p-tolyl-diphenyl)-imidazole is produced from 1-p-tolyl-diphenyl-methyl-carbinol 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 mile) d,1-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-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 1-(p-fluorophenyl-diphenyl methyl) imidazolium-chloride 1 1-(p-fluorophenyl-diphenyl methyl) 5 imidazolium-lactate 95 1-(o-fiuorophenyl-diphenyl methyl) imidazolium-lactate 1 10 1-(m-fiuorophenyl-diphenyl methyl) imidazolium-lactate 120 1- (p-fluorophenyl-diphenyl methyl) imidazolium-salicylate 80 1-(p-cyanophenyl-diphenyl methyl) imidazolium-chloride 147 1- (o-cyanophenyl-diphenyl methyl) imidazolium-chloride 13 1 1-(p-cyanophenyl-diphenyl methyl) imidazolium-lactate 90 1 Oil.
The previously known antimycotics are effective either only against yeasts, such as e.g. Amphotericin 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 administra tion. 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 08. It is also possible to use aqueous solutions of the new salts of the said compounds (I).
THERAPEUTIC EFFECT (1) in vitro-eifect against humanpathogenic 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 7/ ml.
compound (p) 4 'y/ml. (b) Trichophyton mentagrophytes: 4-l07 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 inhibiting concentration as 'y/mI.
Without With serum serum (1) Trish. asteroides 1 (2) Trish. srateriforme 1O (3) Trish. equimim (NL) 10 (4) Trish. equinum, Wooly (Hoechst) 10 (5) Trish. equinum, gran. (Hoechst) 10 Trish. t0nsurans. 2 Trish. verrusosum 4 Trish. granulosurrr..- 2 Trish. interdigitale 4 Trish. msgninii 0 1 Trish. mentagrophyte 0. 1 Trish. rubrum 2 Misrosp. audouiniin (l4). Misrosp. semis (NL)... (15)..-" Microsp. sanis (our isolation) (16) Misrosp. dubisii Micrasp. fuivum- (21) Pen. commie (22) Mucor muced0 (2 i) Blakeslea trisgpora.-- (24)-.." Cami. aibistms 1 Fnngistase.
(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 trychophytia in mice caused by Trish. quinckenum.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 Trish. ment.-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 o-, 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:
(1) dermatomycoses, caused by fungi of the species Trychophytes, Microsporium, Epidermophytes, Aspergillus, Candida albicans and other yeasts;
(2) organomycoses caused by yeast, mould fungi and dermatophytes;
(b) For veterinary use.Dermat-omycoses 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 2:226, alcohol, preferably ethanol and isopropanol, buffer solutions, powders, tablets.
The dosage range for humans is in the range of from about 20 to about 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 suflicient 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 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 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, it 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 ,5 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 compounds/ kg. body weightvin 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 multpile 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:
XII
wherein X is N0 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 l,S-naphthalene-disulphonate.
3. The compound according to claim 1 which is l-(pnitrophenyl-diphenyl-methy1) -imidazole.
References Cited UNITED STATES PATENTS 3,321,366 5/1967 Mussell et al. 260-309 NATALIE TRO USO F, Primary Examiner US. Cl. X.R.
US00218521A 1967-09-15 1972-01-17 N-trityl-imidazoles Expired - Lifetime US3711498A (en)

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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
US36396A Expired - Lifetime US3660576A (en) 1967-09-15 1970-05-11 N-trityl-imidazoles for treating fungal infections
US36395A Expired - Lifetime US3657445A (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
US36425A Expired - Lifetime US3655899A (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
US36426A Expired - Lifetime US3655900A (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
US00218523A Expired - Lifetime US3711499A (en) 1967-09-15 1972-01-17 N-trityl-imidazoles
US00218526A Expired - Lifetime US3711501A (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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US36396A Expired - Lifetime US3660576A (en) 1967-09-15 1970-05-11 N-trityl-imidazoles for treating fungal infections
US36395A Expired - Lifetime US3657445A (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
US36425A Expired - Lifetime US3655899A (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
US36426A Expired - Lifetime US3655900A (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
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US4117142A (en) * 1972-03-22 1978-09-26 Bayer Aktiengesellschaft Disubstituted triphenylmethylmidazoles for treating mycotic infections
US6103733A (en) * 1998-09-09 2000-08-15 Bachmann; Kenneth A. Method for increasing HDL cholesterol levels using heteroaromatic phenylmethanes
US20060211632A1 (en) * 2005-03-17 2006-09-21 Bachmann Kenneth A PXR agonists for cardiovascular disease

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US3660576A (en) 1972-05-02
US3717657A (en) 1973-02-20

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