US3767668A - Process for the production of n-trityl-imidazoles - Google Patents
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- US3767668A US3767668A US00218519A US3767668DA US3767668A US 3767668 A US3767668 A US 3767668A US 00218519 A US00218519 A US 00218519A US 3767668D A US3767668D A US 3767668DA US 3767668 A US3767668 A US 3767668A
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- imidazole
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- trityl
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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
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- 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
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- 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
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- 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
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- 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
- 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 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 O to 2
- R, R or R are alkyl moieties, those having 1 to 4 carbon atoms are preferred.
- X, X or X" is an alkyl moiety, it is preferred that such have 1 to 12 carbon atoms and such moieties having 1 to 4 carbon atoms are especially preferred.
- Electro-negative substituents which are particularly preferred are the halogens, i.e., fluorine, chlorine, bromine and iodine, N0 CF CN, as well as S-lower alkyl and O-lower alkyl; it is preferred that the alkyl moieties have 1 to 4 carbon atoms.
- alkyl and lower alkyl comprises straight chain as well as branched chain alkyl moieties and also include those containing a double bond.
- the salts of the N-trityl-imidazoles (I) are the pharmaceutically acceptable non-toxic acid salts.
- suitable acids are the hydrohalic acids (hydrochloric being particularly preferred), phosphoric acid, monoand bifunctional carboxylic acids, such as acetic acid, pro pionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbc 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:
- X, X and X" are alkyl of 1 to 12 carbon atoms or electro-negative substituents and n, n and n" are 1 or 2.
- substituent values are those where X" is fluorine, chlorine, bromine, iodine, N0 CF ,CN, SCH OCH and n" is 1.
- the compounds of the present invention can be prepared according to techniques per se known such as by reacting silver salts or alkali metal salts, in particular the potassium salts of imidazoles of the Formula III with trityl halides of the Formula IV:
- R N X lilal X u 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, cyclohrexane 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).
- the imidazole is generally used in an excess of up to about 100%. If the process is carried out unde pressure, molar amounts may be used.
- dehydrating agents such as e.g. alkaline earth metal oxides (MgO, BaO, CaO) and of A1 approximately molar amounts being generally used, but possibly also an excess of up to about 23 moles.
- dehydrating agents such as e.g. alkaline earth metal oxides (MgO, BaO, CaO) and of A1 approximately molar amounts being generally used, but possibly also an excess of up to about 23 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 off and the residue remaining after removal of the solvent is recrystallised from benzene/ light petrol.
- l-(tris-phenyl-methyl)-imidazole is produced from 1tris-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 freecompounds into the salts is likewise carried out in known manner.
- N-triphenylmethyl-imidazolium maleate 106-117 N-triphenylmethyl-imidazolium tartrate 175-1 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-imidazoliurn succinate 188-189 N-triphenylmethyl-imidazolium fumarate 200-206 1-( p-chlorophenyl diphenyl methyD-imidazohum-chloride 128-30 1-( p-chlorophenyl diphenyl methyU-imidazohum-lactate 1-( p-chlorophenyl diphenyl methyl)-imidazoliurn-salicylate (1) l-(
- antimycotics are effective either only against yeasts, such as e.g. Amphotericin B, or only against hyphomycetes, such as eg Griseofulvin.
- the compounds (I, II) and their salts are effective against hyphomycetes as well as against yeasts, even in the case of oral administration. It is another advantage that the compounds according to the invention are Well tolerated by warmblooded animals.
- the compounds can be used as antimycotics, inter alia, in the form of an aqueous emulsion, suspension or solution which can be administered per 05. It is also possible to use aqueous solutions of the new salts of the said compounds (I).
- Trichophyton mentagrophytes 4-l0 fungistatic microsp. fel. 4'y.
- quinckeanum Development of the infection is prevented by daily doses of 1-2 times l-2 rug/mouse orally.
- 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 2:2:6, alcohol, preferably ethanol and isopropanol, buffer solutions, powders, tablets.
- solutions e.g., dimethyl sulphoxide/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 100 mg/kg. and preferably from about 40 to about 60 mg./kg. Administration is generally recommended at intervals of about 12 hours and such adminstration should be continued for from about 10 to about 60 days.
- the compounds of the present invention can be used either as such as in combination with pharmaceutically acceptable carriers.
- suitable forms for administration in combination with various inert carriers are tablets, capsules, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups and the like.
- Carriers of this type comprise solid extenders or fillers, a sterile aqueous medium as well as various non-toxic organic solvents and the like.
- the tablets and the like suitable for oral administration can be provided with an addition of saccharin or a similar additive.
- the therapeutically active compound should be present in the total mixture at a concentration of about 0.5 to percent by weight, i.e., in quantities which suflice to attain the range of dosage mentioned above.
- tablets may also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch and the like, and binders such as polyvinyl-pyrrolidoue, gelatin and the like. It is further possible to add lubricants such as magnesium stearate, sodium lauryl-sulphate and talc for producing tablets.
- 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-pyrrolidoue, gelatin and the like.
- binders such as polyvinyl-pyrrolidoue, 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, propyleneglycol, 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-di methyl formamide, as well as sterile aqueous solutions if the compounds are water-soluble.
- aqueous solution should be buffered in the usual manner, if required, and the liquid diluent should previously be rendered isotonic by the addition of the necessary amount of salt or glucose.
- aqueous solutions are particularly suitable for intravenous, intramuscular and intraperitoneal injections.
- a dosage of 40 mg./ kg. administered at intervals of 12 hours result in a blood level of between and ll 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 resoption quota amounts to more than 70% in the case of oral administration.
- mice, rats, rabbits, dogs and cats lies between about 600 and 2200 mg. of the stated compounds/ kg. body Weight in the case or oral administration.
- the present invention also includes pharmaceutial compositions comprising at least one of the N-trityl-irnidazoles 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 process for the production of a compound of the W Q Q XII wherein X" is methyl, halogen, N0 CF CN, S-lower alkyl or O-lower alkyl or a pharmaceutically acceptable non-toxic acid salt thereof which comprises reacting imidazole with N-triyl-carbinol substituted in 1 phenyl moiety by methyl, halogen, NO ,CF, CN, S-lower alkyl or O-lower alkyl and recovering the compound produced.
- a process for the production of l-(p-chlorophenyldiphenyl methyl)-imidazole which comprises reacting imidazole with p-chlorophenyl-diphenyl-methyl carbinol and recovering the compound produced.
- a process for the production of l-(trisphenyl-methyl)-imidazole, or a pharmaceutically acceptable non-toxic acid salt thereof which comprises reacting imidazole with l-(trisphenyl-methyl)carbinol and recovering the compound produced.
Abstract
N-TRITYL-IMIDAZOLES AND SALTS THEREOF OF THE FORMULA:
(2-R,4-R1,5-R2-IMIDAZOL-1-YL)-C(-C6H4-(X)N)(-C6H4-(X'')N'')-
C6H4-(X")N"
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 SLAT OR ALKALI METAL SALT OF AN IMIDAZOLE OF THE FORMULA:
2-R,4-R1,5-R2-IMIDAZOLE
WITH A TRITYL HALIDE OF THE FORMULA:
HAL-C(-C6H4-(X)N)(-C6H4-(X'')N'')-C6H4-(X")N"
WHEREIN THE SUBSTIUENTS ARE AS ABOVE DEFINED AND HAL IS HALOGEN. THESE COMPOUNDS ARE USEFUL AS ANTMYCOTICS.
(2-R,4-R1,5-R2-IMIDAZOL-1-YL)-C(-C6H4-(X)N)(-C6H4-(X'')N'')-
C6H4-(X")N"
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 SLAT OR ALKALI METAL SALT OF AN IMIDAZOLE OF THE FORMULA:
2-R,4-R1,5-R2-IMIDAZOLE
WITH A TRITYL HALIDE OF THE FORMULA:
HAL-C(-C6H4-(X)N)(-C6H4-(X'')N'')-C6H4-(X")N"
WHEREIN THE SUBSTIUENTS ARE AS ABOVE DEFINED AND HAL IS HALOGEN. THESE COMPOUNDS ARE USEFUL AS ANTMYCOTICS.
Description
United States Patent US. Cl. 260-309 3 Claims ABSTRACT OF THE DISCLOSURE N-trityl-imidazoles and salts thereof of the formula:
XIIn
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:
R14\N R l! R with a trityl halide of the formula:
Xu ital XIIn 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 now US. Pat. No. 3,705,172 which is a divisional of Ser. No. 758,594 filed Sept. 9, 1968 now U.S. Pat. No. 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;
TW R2- E -R XI,
X'fiw 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 O to 2,
or pharmaceutically acceptable acid salts thereof. When R, R or R are alkyl moieties, those having 1 to 4 carbon atoms are preferred. When X, X or X" is an alkyl moiety, it is preferred that such have 1 to 12 carbon atoms and such moieties having 1 to 4 carbon atoms are especially preferred. Electro-negative substituents which are particularly preferred are the halogens, i.e., fluorine, chlorine, bromine and iodine, N0 CF CN, as well as S-lower alkyl and O-lower alkyl; it is preferred that the alkyl moieties have 1 to 4 carbon atoms. The term alkyl and lower alkyl comprises straight chain as well as branched chain alkyl moieties and also include those containing a double bond.
The salts of the N-trityl-imidazoles (I) are the pharmaceutically acceptable non-toxic acid salts. Examples of suitable acids are the hydrohalic acids (hydrochloric being particularly preferred), phosphoric acid, monoand bifunctional carboxylic acids, such as acetic acid, pro pionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbc 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:
wherein X, X and X" are alkyl of 1 to 12 carbon atoms or electro-negative substituents and n, n and n" are 1 or 2. With regard to Formula IIa, particularly preferred substituent values are those where X" is fluorine, chlorine, bromine, iodine, N0 CF ,CN, SCH OCH and n" is 1.
The compounds of the present invention can be prepared according to techniques per se known such as by reacting silver salts or alkali metal salts, in particular the potassium salts of imidazoles of the Formula III with trityl halides of the Formula IV:
R N X lilal X u 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, cyclohrexane 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 unde pressure, molar amounts may be used. Furthermore, it may be expedient to carry out the elimination of water azeotropically in the presence of a high boiling inert organic solvent, such as Xylene, chlorobenzenes and the like, at the boiling point of the solvent used. In the absence of solvents, the process is carried out at a temperature range of from about 140 C. to about 230 C. and preferably from about 170 C. to about 190 C.
It may further be expedient to facilitate the elimination of Water by working in the presence of dehydrating agents, such as e.g. alkaline earth metal oxides (MgO, BaO, CaO) and of A1 approximately molar amounts being generally used, but possibly also an excess of up to about 23 moles.
The following table gives the constants of some N- trityl-imidazoles (I, II) by Way of example:
(a), 1 (trisphenyl-methyD-imidazole -1 226-227 (b) 1-(tzisphe-nyl-methyl)-2-methyl-imidazole. 225 (0)0 1-(trisphenyl-methyl)2,4-dimethyl-imidaz0l 232 (d).-. l-(trisphenyl-methyl)4,5-diphanyl-imidaz0le. 228-230 (e) 1-(p-chlorophenyl-diphenyl-methyl)-irnidazole 140 (f) l-(p-fluorophenyl-diphenyl-metliyll-irnidazole 145 (g) l-(p-tolyl-diphenyl-methyl)-irnidazole 128 (h) l-(trisphenylqnethyl)-benzimidazole 180-181 (i) 1-(0-ehlorophenyl-diphenyhmethyU-irnidazole 147-149 {1) l-(m-chlorophenyl-dip henyl-me thyD-imidazol 114 (k) 1-(p-brornophenyl-diphenyl-methyD-lrnidazole 152 (l). 1-(o-flourophenyl-diphenyl-methyl)1midazole 185 (m) l-(mdlourophenyldiphenyl-methyl)imidazole 174 (n). 1 (p-nitrophenyl-diphenyl-methyD-imidazole 160470 (o) l-(m-trifluorornethylphenyl-diphenyl-methyl)- imidazole 156 (p) 1-(pcyanophenyl-diphenyl-methyl)-imidazole 164 (q)... 1-(o-rnethoxyphenyl-diphenyl-methyD-irnidazole 130 (r) 1-(p-methylthiophenyldiphenyl-methyll-imidazole 142 (s) 1-(p-fluorophenyl-diphenyl-methyl 2-rnethylimidazole 199 (t) 1-(pfluorophenylpchlor0phe imidazole 144. (u) 1-(p-chlorophenyl-m-fluorophenyl-phenyl-methyl)- imidazole 116 (v) 1- 1(pchlo10-rn-nitrophenyl-diphe nyl-meth yl)inu'dazo1e 150 (W) l-(p-brornophenyl-p-chlorophenyl-phenyl-methyl)- irnidazole 140 (x). l-(m-cyanophenyl-diphenylmethyl)-imi lazole 119 (y) l-(o-eyanophenyl-diphenyl-methyl)imidazole 1494.51
EXAMPLE OF PREPARATION 1- [p-chlorophenyl-diphenyl-methyl1 -1mrdazole (e) CH AJ Cl 1 mole of 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 petrol, the
4 pure 1-[p-chlorophenyl-diphenyl-methyl]-imidazole is obtained. M.P. 140143 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 1tris-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 freecompounds 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 in heating in acetonitrile and 10 g. (0.11 mole) d,l-lactic acid are subse quently added. The residue remaining after distilling 01f 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. l70-180 C.
N-triphenyl-methyl-imidazolium chloride 31 g. N-trityl-imidazole are dissolve din 400 ml. carbon tetrachloride, and hydrogen chloride is subsequently passed into the solution at room temperature. The bydrochloride 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 maleate 106-117 N-triphenylmethyl-imidazolium tartrate 175-1 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-imidazoliurn succinate 188-189 N-triphenylmethyl-imidazolium fumarate 200-206 1-( p-chlorophenyl diphenyl methyD-imidazohum-chloride 128-30 1-( p-chlorophenyl diphenyl methyU-imidazohum-lactate 1-( p-chlorophenyl diphenyl methyl)-imidazoliurn-salicylate (1) l-(m-chlorophenyl diphenyl methyDimidazohum-chloride 153 l-(o-chlorophenyl diphenyl methyl)-imidazolium-chloride 159 l-(p-fluorophenyl diphenyl methyD-imidazohum-chloride 1 10 1-(p-fluoropheny1 diphenyl methyl)-imidazohum-lactate l-(o-fiuorophenyl diphenyl methyU-imidazolium-lactate 1 10 1-( m-fluorophenyl diphenyl methyD-imidazolium-lactate 1-(p-fluorophenyl diphenyl methyl)-imidazolium-salicylate 80 l-(p-cyanophenyl diphenyl methyl)-imidazohum-chloride 147 1-(o-cyanophenyl diphenyl methyU-imidazolium-chloride 13 1 l-(p-cyanophenyl diphenyl methyD-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 eg 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 05. It is also possible to use aqueous solutions of the new salts of the said compounds (I).
THERAPEUTIC EFFECT (1) In vitroetfect against human-pathogenic fungi:
(a) Candida albicans:
Compound (a) 40 'y/ml. Compound (e) 4 'y/m1. Compound (f) 4 -y/ml. Compound (g) 4 'y/ml. Compound (i) 4 /ml. Compound (P) 4 y/ml.
Fungistatic.
(b) Trichophyton mentagrophytes: 4-l0 fungistatic microsp. fel. 4'y.
Minimum inhibiting concentration as 'y/ml.
Without With serum serum 1 1 1 1O 1 10 1 l0 1 10 1 2 1 4 1 2 1 4 0. 1 1 0. 1 1 1 2 13) Microsp. audouinii... 1 14) Microsp. canis (NL) 0. 1 15) Microsp. cam's (our isolation) 1 16) lvlicrosp. duboisiL 1 (17) Microsp. fulvum- 1 (18) Microsp. galli'nae 1 (19) Microsp. felineum 1 (20) Aspergillus niger 1 4 21) Pen. comune 1 (22) Mucor mucedo 4 10 (23) Blakeslea trispom 10 10 $24) Cami. albicans 1 40-1 40-1 1 Fungistase.
(2) Effect in v1v0:
(a) Experimental candidosis in white mice: In the case of oral administration, curative eifects 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 l-2 rug/mouse orally.
(c) Experimental trichophytia in guinea pigs caused by T rich. 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 compoundn (a), (e), (f), (g), (i) and (P) are used. Compounds which are unsubstituted in the imidazole ring may be substituted in one phenyl group by a halogen atom, preferably chlorine or fluorine in the 0-, mor pposition; 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 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 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 100 mg/kg. and preferably from about 40 to about 60 mg./kg. Administration is generally recommended at intervals of about 12 hours and such adminstration should be continued for from about 10 to about 60 days.
Nevertheless it may sometimes be necessary to digress from the aforesaid amounts, dependent on the method of administration or also on account of individual reactions to the medicine or on the type of its formulation and the moment in time or the intervals at which it is administered. In some cases, it may be sufficient to use less than the minimum amount stated above, whereas in other cases it may be necessary to go beyond the state 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 as in combination with pharmaceutically acceptable carriers. Suitable forms for administration in combination with various inert carriers are tablets, capsules, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Carriers of this type comprise solid extenders or fillers, a sterile aqueous medium as well as various non-toxic organic solvents and the like. Obviously, the tablets and the like suitable for oral administration can be provided with an addition of saccharin or a similar additive. In the aforesaid case, the therapeutically active compound should be present in the total mixture at a concentration of about 0.5 to percent by weight, i.e., in quantities which suflice to attain the range of dosage mentioned above.
In the case of oral administration, obviously, tablets may also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch and the like, and binders such as polyvinyl-pyrrolidoue, 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, propyleneglycol, 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-di methyl formamide, as well as sterile aqueous solutions if the compounds are water-soluble. Such aqueous solution should be buffered in the usual manner, if required, and the liquid diluent should previously be rendered isotonic by the addition of the necessary amount of salt or glucose. These aqueous solutions are particularly suitable for intravenous, intramuscular and intraperitoneal injections.
In humans, a dosage of 40 mg./ kg. administered at intervals of 12 hours result in a blood level of between and ll 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 resoption 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 pharmaceutial compositions comprising at least one of the N-trityl-irnidazoles 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.
8 What is claimed is: 1. A process for the production of a compound of the W Q Q XII wherein X" is methyl, halogen, N0 CF CN, S-lower alkyl or O-lower alkyl or a pharmaceutically acceptable non-toxic acid salt thereof which comprises reacting imidazole with N-triyl-carbinol substituted in 1 phenyl moiety by methyl, halogen, NO ,CF, CN, S-lower alkyl or O-lower alkyl and recovering the compound produced.
2. A process for the production of l-(p-chlorophenyldiphenyl methyl)-imidazole which comprises reacting imidazole with p-chlorophenyl-diphenyl-methyl carbinol and recovering the compound produced.
3. A process for the production of l-(trisphenyl-methyl)-imidazole, or a pharmaceutically acceptable non-toxic acid salt thereof which comprises reacting imidazole with l-(trisphenyl-methyl)carbinol and recovering the compound produced.
No references cited.
HENRY R. JILES, Primary Examiner M. A. M. CROW'DER, Assistant Examiner U.S. Cl X.R. 424273
Applications Claiming Priority (3)
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DEF0053504 | 1967-09-15 | ||
LU57488 | 1968-12-06 | ||
US21852472A | 1972-01-17 | 1972-01-17 |
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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 |
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 |
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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 |
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 |
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US00218523A Expired - Lifetime US3711499A (en) | 1967-09-15 | 1972-01-17 | N-trityl-imidazoles |
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BE (1) | BE720801A (en) |
FR (2) | FR1597530A (en) |
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US3914236A (en) * | 1973-03-26 | 1975-10-21 | Hoechst Ag | 1-(Imidazole-1-yl)-isoquinolines and process for preparing them |
US4216333A (en) * | 1978-10-30 | 1980-08-05 | Sumitomo Chemical Company, Limited | Process for preparing N-tritylimidazole compounds |
US20110028733A1 (en) * | 2007-12-05 | 2011-02-03 | Viesturs Lusis | Process for the preparation of 5-(2-ethyl-dihydro-1h-inden-2-yl)-1h-imidazole and salts thereof |
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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 |
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 |
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 |
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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 |
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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 |
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US3321366A (en) * | 1965-11-15 | 1967-05-23 | Dow Chemical Co | Fungicidal methods and compositions |
-
1968
- 1968-09-03 GB GB41773/68A patent/GB1170188A/en not_active Expired
- 1968-09-09 US US758594A patent/US3660577A/en not_active Expired - Lifetime
- 1968-09-13 FR FR1597530D patent/FR1597530A/fr not_active Expired
- 1968-09-13 BE BE720801D patent/BE720801A/xx not_active IP Right Cessation
- 1968-12-06 LU LU57488D patent/LU57488A1/xx unknown
- 1968-12-12 FR FR177895A patent/FR8112M/fr not_active Expired
-
1970
- 1970-02-24 US US13797A patent/US3705172A/en not_active Expired - Lifetime
- 1970-05-11 US US36395A patent/US3657445A/en not_active Expired - Lifetime
- 1970-05-11 US US36396A patent/US3660576A/en not_active Expired - Lifetime
- 1970-05-11 US US36425A patent/US3655899A/en not_active Expired - Lifetime
- 1970-05-11 US US36426A patent/US3655900A/en not_active Expired - Lifetime
- 1970-05-11 US US36424A patent/US3658956A/en not_active Expired - Lifetime
- 1970-05-11 US US36394A patent/US3657442A/en not_active Expired - Lifetime
-
1971
- 1971-03-19 US US00126277A patent/US3720770A/en not_active Expired - Lifetime
- 1971-07-09 US US00161274A patent/US3839573A/en not_active Expired - Lifetime
-
1972
- 1972-01-17 US US00218521A patent/US3711498A/en not_active Expired - Lifetime
- 1972-01-17 US US00218524A patent/US3717657A/en not_active Expired - Lifetime
- 1972-01-17 US US00218525A patent/US3711500A/en not_active Expired - Lifetime
- 1972-01-17 US US00218526A patent/US3711501A/en not_active Expired - Lifetime
- 1972-01-17 US US00218519A patent/US3767668A/en not_active Expired - Lifetime
- 1972-01-17 US US00218523A patent/US3711499A/en not_active Expired - Lifetime
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3914236A (en) * | 1973-03-26 | 1975-10-21 | Hoechst Ag | 1-(Imidazole-1-yl)-isoquinolines and process for preparing them |
US4216333A (en) * | 1978-10-30 | 1980-08-05 | Sumitomo Chemical Company, Limited | Process for preparing N-tritylimidazole compounds |
US20110028733A1 (en) * | 2007-12-05 | 2011-02-03 | Viesturs Lusis | Process for the preparation of 5-(2-ethyl-dihydro-1h-inden-2-yl)-1h-imidazole and salts thereof |
US8431717B2 (en) * | 2007-12-05 | 2013-04-30 | Jsc Grindeks | Process for the preparation of 5-(2-ethyl-dihydro-1H-inden-2-yl)-1H-imidazole and salts thereof |
Also Published As
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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 |
US3711501A (en) | 1973-01-16 |
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 |
US3705172A (en) | 1972-12-05 |
US3655899A (en) | 1972-04-11 |
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