US 3705172 A
Description (OCR text may contain errors)
United States Patent 3,705,172 N-TRITYL-IMIDAZOLES Karl-Heinz Buchel, Leverkusen, Erik K. Regel, Wuppertal- Kronenberg, and Manfred Plempel, Wuppertal-Elberfeld, Germany, assignors to Farbenfabriken Bayer Aktiengesellschaft, Leverkusen, Germany No Drawing. Original application Sept. 9, 1968, Ser. No. 758,594. Divided and this application Feb. 24, 1970, Ser. No. 13,797 Claims priority, application Germany, Sept. 15, 1967, F 53 504 US. Cl. 260-309 20 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 pharmaceutically acceptable acid salts thereof may be produced by reacting a silver salt or alkali metal salt of an imidazole of the formula:
R; N all with a trityl halide of the formula:
X. inn X'n Q XI/nII wherein the substituents are as above defined and Hal is halogen. These compounds are useful as antimycotics.
This is a division of our copending US. 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 con- 3,705,172 Patented Dec. 5, 1972 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 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 wellas S-lower alkyl and O-lower alkyl; it is preferred that the alkyl moieties have 1 to 4 carbon atoms. The term alkyl and lower alkyl comprises straight chain as well as branched chain alkyl moieties and also include those containing a double bond.
The salts of the N-trityl-imidazoles (I) are the pharmaceutically acceptable non-toxic acid salts. Examples of suitable acids are the hydrohalic acids (hydrochloric being particularly preferred), phosphoric acid, monoand bifunctional carboxylic acids, such as acetic acid, propionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid and 1,S-naphthalene-disphonic acid. The hydrohalides, especially the hydrochlorides, lactates and salicylates are of particular value.
In a particularly preferred embodiment of the present 0 invention, the N-trityl-imidazoles have the formula:
XHnII wherein X, X and X" are alkyl of 1 to 12 carbon atoms or electro-negative substituents and n, n and n" are 1 to 2. With regard to Formula IIa, particularly preferred substituent values are those where X" is fluorine, chlorine,
- bromine, iodine, N CF CN, SCH OCH and n" is 1.
( n" (IV) 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 (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 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 elimination of water azeotropically in the presence of a high boiling inert organic solvent, such as xylene, chlorobenzenes and the like, at the boiling point of the solvent used. In the absence of solvents, the process is carried out at a temperature range of from about 140 C. to about 230 C. and preferably from about 170 C. to about 190 C.
It may further be expedient to facilitate the elimination of water by working in the presence of dehydrating agents, such as e.g. alkaline earth metal oxides (MgO, BaO, CaO) and of A1 0 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:
(a) l-trisphenyl-methyl)-imidazole 226-227 (b) 1 (trisphenyl 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 (1) 1 (o fluorophenyl diphenyl methyl)- imidazole 135 (m) 1 (m fluorophenyl diphenyl methyl)- imidazole 174 (n) 1 p nitropheny ldiphenyl methyl)- imidazole 160-170 (0) 1 (m trifluoromethylphenyl diphenylmethyl) -imidaz0le 156 M.P., C. (p) 1 (p cyanophenyl diphenyl methyl) imidazole 164 (q) 1 (o methoxyphenyl diphenyl methyl)- imidazole (r) 1 (p methylthiophenyl diphenyl methyl -imidazole 142 (s) 1 (p fluorophenyl diphenyl methyl)- Z-methyl-imidazole 199 (t) l (p fluorophenyl p chlorophenylphenyl-methyl) -irnidazole 144 (u) 1 (p chlorophenyl m fluorophenylphenyl-methyl) -imidazole 1 16 (v) 1 (p chloro m nitrophenyl diphenylmethy1)-imidazo1e 150 (w) 1 (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 1- [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 xylene in order to remove the excess imidazole. After another reprecipitation from benzene light patrol, the pure 1 [p chlorophenyl diphenyl methyl] imidazole is obtained.
M.P. 140-143-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 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-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 1actate.-31 g. N-trityl-imidazole are dissolved by heating in acetonitrile and 10 g. (0.11 mole) d,l-lactic acid are subsequently added. The residue remaining after distilling off the solvent is caused to crystallise by covering it with ether, the crystallisation product is washed with ether and dried.
Yield 40 g. of a colourless crystalline powder of M.P.
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 01f with suction, Colourless crystals of MP. 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 maleate 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-oil 1 (m chlorophenyl diphenyl methyl)- imidazolium-chloride 153 l (o chlorophenyl diphenyl methyl)- imidazolium-chloride 159 1 (p fluorophenyl diphenyl methyl)- imidazolium-chloride 110 1 (p fluorophenyl diphenyl methyl)- imidazolium-lactate 95 1 (o fluorophenyl diphenyl methyl)- imid azolium-lactate 1 l 1 (m fluorophenyl diphenyl methyl)- imidazolium-lactate 120 1 (p fluorophenyl diphenyl methyl)- imidazolium-salicylate 80 l (p cyanophenyl diphenyl methyl)- imidazolium-chloride 147 1 (o cyanophenyl diphenyl 4 methyl)- imidazolium-chloride 131 1 (p cyanophenyl diphenyl methyl)- imidazolium-lactate 90 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 administration. It is another advantage that the compounds according to the invention are well tolerated by warmblooded animals.
The compounds can be used as antimycotics, inter alia, in the form of an aqueous emulsion, suspension or solution which can be administered per os. It is also possible to use aqueous solutions of the new salts of the said compounds (I).
THERAPEUTIC EFFECT (1) In vitro-efiect against human-pathogenic fungi (a) Candida albz'cans:
(b) Trichophyton mentagrophytes: 4-10'y fungistatic microsp. fel. 4'y
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/ml.
Without serum Trich. asteroz'dcs Trich. crateriforme Trich. equinum (N L) Trtch. equinum, woolly (Hoeehs Tnch. equmum, gran. (Hoechst) Trich. tonsura'ns Trich. verrucosum Trich. granulosum- Trzjch. interdz'gitale (1 (13) Microsp. audouinii (14) Microsp. cam's (N L) (15) Microsp. cunts (our isolation) (16) Microsp. duboisii (17) Microspjulvum (18) Microsp. gallinae (l9) Microsp. felineum-- 0) Aspergillus 'm'qer (21) Pen. comune 1 (22) Mucor TIL'LLCBdO--- 4 (23) Blakeslea trispora- 10 (24) Cami. albicans 1 40-1 1 Fungistase.
(2) EFFECT IN VIVO (a) Experimental candidosis in white mice In the case of oral administration, curative effects can be achieved with daily doses of 2-3 times 0.5-1 mg./mouse/day.
(b) Experimental 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.
(0) Experimental trichophytia in guinea pigs caused by Trich.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.
(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 organomy coses caused by yeasts, mould fungi and dermatophytes.
The compounds of the present invention are administered orally or parenteraly as well as locally in the form of solutions, e.g., dimethyl sulphopride/ glycerol/ water 2:2:6, 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 suificient 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 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, 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, dyestufis, 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 aqeuous solutions are particularly suitable for intravenous, intramuscular and intraperitoneal injections.
In humans, a dosage of 40 mg./kg. administered at intervals of 12 hours result in a blood level of between and 11 7/ ml. The half-life period in human serum in vivo amounts to 6 hours on the average. Up to 30 to 40% of the administered amount of the substance are excreted with the urine in active form. The resorption quota amounts to more than 70% in the case of oral administration.
The LD for mice, rats, rabbits, dogs and cats lies between about 600 and 2200 mg. of the stated compounds/ kg. body weight in the case or oral administration.
The present invention also includes pharmaceutical compositions comprising at least one of the N-tritylimidazoles 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 halogen or a pharmaceutically acceptable non-toxic acid salt thereof.
2. A salt according to claim 1 selected from the group consisting of the hydrochloride, phosphate, acetate, propionate, maleanate, succinate, fumarate, tartrate, citrate, salicylate, sorbate, lactate or l,S-naphthalene-di'sulphomate.
3. The compound according to claim 1 which is l-(pchlorophenyl-diphenyl-methyl) -imidazole.
4. A compound according to claim 1 wherein X" is chlorine.
5. The compound according to claim 1 which is l-(pfluorophenyl-diphenyl-methyl)-imidazole.
6. The compound according to claim 1 which is 1-(0- chlorophenyl-diphenyl-methyl -imidaz0le.
7. The compound according to claim 1 which is l-(mchlorophenyl-diphenyl-methyl -imidazole.
8. The compound according to claim 1 which is l-(pbromophenyl-diphenyl-methyl) -imidazole.
9. The compound according to claim 1 which is l-(orfluorophenyl-diphenyl-methyl) -imidazole.
10. The compound according to claim 1 which is l-(mfluorophenyl-diphenyl-methyl)-imidazole.
11. The compound according to claim 1 which is l-(pchlorophenyl-diphenyl-methyl)-imidazolium chloride.
12. The compound according to claim 1 which is l-(pchlorophenyl-diphenyl-methyl)-imidazolium lactate.
13. The compound accordingto claim 1 which is l-(pchlorophenyl-diphenyl-methyl)-imidazolium salicylate.
14. The compound according to claim 1 which is l-(mchlorophenyl-diphenyl-methyl)-imidazolium chloride.
15. The compound according to claim 1 which is l-(ochlorophenyl-diphenyl-methyl)-imidazolium chloride.
16. The compound according to claim 1 which is l-(pfluorophenyl-diphenyl-methyl)-imidazolium chloride.
17. The compound according to claim 1 which is l-(p- :fluorophenyl-diphenyl-methyl)-imidazolium lactate.
18. The compound according to claim 1 which is l-(ofluorophenyl-diphenyl-methyl)-imidazolium lactate.
19. The compound according to claim 1 which is l-(mfluorophenyl-diphenyl-methyl)-imidazolium lactate.
20. The compound according to claim 1 which is l-(pfluorophenyl-diphenyl-methyl)-imidazolium salicylate.
(References on following page) References Cited Giesemann et al., Chem. Abstr., v01. 53, columns UNITED STATES PATENTS 101904 (1959)- G' l. h 3,299,090 1/1967 Hoff 260309 ggf gjg flggf c m Benchte Pp 92 8 3321366 5/1967 Mussenet a1 260-309 5 Giesemann et a1., Chem. Abstn, v01. 54, columns 3,322,783 Dunn 5 9 Q 3,323,990 6/1967 Budde et a1 260-309 1 I I 3,418,318 12/1968 Lambie 6161. 260-3092 50933 3 9 Chem Bemhte 570 6 OTHER REFERENCES Tolkmith et al., Science, vol. 158, pp. 1462-3 (1967).
Fournari et al., Bul. Soc. Chim., France, 1968, pp. 10 Q1534 2438-46 (June 1968). QD1.S4.