US3691178A - Substituted imidazoles - Google Patents

Substituted imidazoles Download PDF

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US3691178A
US3691178A US20126A US3691178DA US3691178A US 3691178 A US3691178 A US 3691178A US 20126 A US20126 A US 20126A US 3691178D A US3691178D A US 3691178DA US 3691178 A US3691178 A US 3691178A
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imidazole
substituted
chlorophenyl
acid
pyridyl
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John J Baldwin
Frederick C Novello
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Merck and Co Inc
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Merck and Co Inc
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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
    • C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • 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
    • C07D233/66—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • ABSTRACT Imidazoies substituted at the 2 and 4(5) positions having an optional substituent in the 1 position are provided. Methods of preparing the novel substituted imidazoles are described.
  • the substituted imidazoles are useful as anti-gout and anti-hyperuricemic agents.
  • Compositions useful in the treatment of gout and hyperuricemia containing a substituted imidazole as the active ingredient are provided.
  • Gout is a condition affecting humans and lower animals, particularly birds and reptiles, which is characterized by perversion of the purine metabolism resulting in an excess of uric acid in the blood,by attacks of acute arthritis, and by formation of chalky deposits in the cartilages of the joints. These deposits are made up chiefly of urates, or uric acid.
  • Hyperuricemia is a condition characterized by an excess of uric acid in the blood.
  • Uric acid serves no biochemical function in the body and is merely an end product of purine metabolism. It is well known in the art that the purine bases adenine and guanine, which play key roles in a wide variety of chemical processes, both give rise to uric acid in the body. Adenylic acid and guanylic acid are converted to the free purine bases by destructive metabolic enzymes. A portion'of the free purine bases is converted to purine ribonucleotides and the remainder is degraded to the free bases xanthine and hypoxanthine. A single enzyme, xanthine oxidase, converts both xanthine and hypoxanthine to uric acid for excretion.
  • Allopurinol acts as a specific inhibitor of the enzyme xanthine oxidase, which is responsible for the conversion of both hypoxanthine and xanthine to uric acid.
  • xanthine oxidase As a direct result of the administration of this compound to patients afflicted with gout, part of the uric acid which would normally end up in the urine is replaced instead by the oxypurines, hypoxanthine and xanthine, thus greatly reducing the content of uric acid in serum and urine.
  • Azathioprine has also been employed in patients afflicted by gout to inhibit the excessive purine synthesis, which tends to produce abnormal amounts of uric acid.
  • substituted imidazoles which are the subject of this invention have been found to be effective anti-gout and anti-hyperuricemic agents in that they will inhibit the action of the enzyme xanthine oxidase and thus reduce the content of uric acid in serum and urine.
  • R is hydrogen or loweralkyl wherein the alkyl group contains from one to five carbons, such as methyl, ethyl, butyl and thelike, R is naphthyl or heteroaryl such as quinolyl or cinnolyl, or a 5 or 6 membered heteroaryl ring system containing 1-3 hetero atoms wherein the hetero atom is selected from the group oxygen, nitrogen, and sulfur, such as a pyrazinyl, thienyl, thiazolyl, or pyridiyl ring,
  • alkoxy group contains from one to five carbons, such as methoxy, ethoxy, butoxy and the like, loweralkanoylamino wherein the alkyl group contains from two to five carbons such as butyl- 3 acetylamino, propionylamino, butyrylamino, and the like, nitro, amino, lowermonoalkylamino and lowerdialkylamino wherein the alkyl group contains from one to five carbons, such as methylamino, diethylamino, dibutylamino, and
  • a fused loweralkylene bridge containing from three to six carbons such as a propylene, butylene, or pentylene bridge, and
  • alkoxycarbonyl wherein the alkoxy group contains one to five carbons, such as methoxycarbonyl, ethoxycarbonyl, or butoxycarbonyl,
  • alkanoyl group contains from one to five carbons, such as acetyl, propionyl, butyryl, and the like, or
  • R is carboxy, R is not pnitrophenyl or m-nitrophenyl.
  • the phenyl ring may contain from 1-3 substituents.
  • the substituent on the phenyl ring is a loweralkylene bridge
  • the bridge is joined to the phenyl ring on adjacent carbons such as, for example, a 3,4-propylene bridge.
  • R is a naphthyl group
  • the naphthyl group is joined to the imidazole ring at the l or 2 position of the naphthyl group.
  • the substituent on the phenyl ring is a methylenedioxy group
  • the oxygen atoms are joined to the phenyl ring on adjacent carbons such as, for exam ple, a 3,4-methylenedioxy substituent.
  • non-toxic pharmaceuticallly acceptable quaternary salts such as the methiodides and ethiodides where the heterocyclic group in the 2-position contains a nitrogen atom, alkali metal and alkaline earth metal salts, such as the sodium, potassium, and calcium salts, and those mineral acid salts such as the hydrochloride salts, wherein the substituent in the 2-position is a heterocyclic ring containing at least one nitrogen atom, such as a pyridine ring.
  • disalts which are formed in those cases where R is carboxy.
  • R in Formula I is hydrogen, R 'is pyridyl or halophenyl, and R is carboxy, loweralkoxycarbonyl, carbamoyl, cyano, loweralk'anoyl or benzoyl represent a preferred sub-class of compounds falling within the scope of the present invention.
  • the l-unsubstituted imidazoles discussed herein are compounds in which the R substituent is at either the 4or 5 position on the imidazole ring.
  • the hydrogen atom on a nitrogen in the imidazole ring is in a state of tautomeric equilibrium, with the result that the 4 and 5 positions are equivalent.
  • Typical of the compounds falling within the definition of Formula I are: ethyl 2-( p-chlorophenyl)imidazole-4( 5 )-carboxylate methyl 2-( 4-pyridyl )imidazole-4( 5 )-carboxylate 4( 5 )-acetyl-2-( p-bromophenyl )-imidazole 2-( p-bromophenyl )imidazole-4( 5 )-carboxylic acid methyl 2-(p-nitrophenyl)imidazole-4( 5 )-carboxylate 2-( p-bromophenyl)imidazole-4-( 5 )-carboxamide 2-( 4-pyridyl )imidazole-4( 5 )-carboxamide 2-( p-chlorophenyl)imidazole-4( 5 )-carboxylic acid methyl 2-(6-quinolyl)imidazole-4(5 )-carboxylate 2-
  • the compounds of the present invention having the structural formula N R5 I wherein R, is hydrogen or loweralkyl, R is naphthyl, substituted phenyl, heteroaryl, substituted heteroaryl, and R is carboxy, loweralkoxycarbonyl, carbamoyl, cyano, or loweralkanoyl, can be prepared by a series of reactions from a substituted imidazole compound such as a 4(5)-trifluoromethylimidazole compound.
  • those compounds where the substituent at the 4(5)-position is carboxy can be prepared by treating a substituted 4(5 )-trifluoromethylimidazole with excess aqueous alkali, such as sodium hydroxide or potassium hydroxide.
  • aqueous alkali such as sodium hydroxide or potassium hydroxide.
  • the substituted trifluoromethylimidazole compound is suspended in the alkali solution and the reaction mixture is maintained at room temperature for about l-5 hours. it is preferred, however, to carry out the reaction at about 8( )l20 C.
  • the resulting carboxy-2-substituted imidazole is then obtained by acidifying the alkaline solution with a mineral acid such as, for example, hydrochloric acid, and is purified by recrystallization or other techniques known in the art.
  • Those compounds of Formula I wherein R is alkoxycarbonyl are prepared by converting the compounds where R is carboxy to the desired ester by reaction with the appropriate alcohol in the presence of a mineral acid such as hydrochloric acid or sulfuric acid.
  • a mineral acid such as hydrochloric acid or sulfuric acid.
  • the ester is prepared by heating the 4(5)-carboxyimidazole in methanol in the presence of dry hydrogen chloride or concentrated sulfuric acid.
  • Loweralkanols having l-6 carbons may be employed as the alcohol.
  • the reaction may be carried out at room temperature or at the reflux temperature of the solvent. Generally, temperatures between room temperature and 160 C. may be employed.
  • the alcohol reactant may also be employed as the solvent, although hydrocarbons such as benzene and toluene may also be employed as solvents.
  • the 4(5)-alkoxycarbonylimidazole is then obtained by concentrating the reaction mixture.
  • the residual acid is neutralized by the addition of base, such as sodium hydroxide, and the alkoxycarbonylimidazole is purified by recrystallization from a suitable solvent, such as acetonitrile, or alcohol, or by other techniques known in the art.
  • Those compounds of Formula I wherein R is carbamoyl or substituted carbamoyl are prepared by reacting a 4(5)-loweralkoxycarbonylimidazole with an amine, such as methylamine orethylamine, or ammonia, in a suitable solvent.
  • an amine such as methylamine orethylamine, or ammonia
  • the starting 4(5 )-carboxylate is reacted with an excess of the amine in a closed reaction system at a temperature from about 80-l 50 C. for from about -25 hours.
  • Solvents such as methanol or ethanol may be employed.
  • the 4(5)- carbamoylimidazole is obtained from the reaction mixture by techniques known in the art. For example, the solvent is removed in vacuo and the residue is crystallized from a suitable solvent, such as methanol in water.
  • the imidazole 4(5)-carboxamides can be prepared by reacting an imidazole-4(5)-carboxylic acid with a halogenating agent such as thionyl chloride or phosphorous oxychloride to form the corresponding acid halide, and the acid halide formed is then reacted with an excess of a primary or secondary amine or ammonia in a suitable solvent, such as benzene or toluene.
  • a suitable solvent such as benzene or toluene.
  • the reaction with the halogenating agent is generally carried out at a temperature between about 050 C. Where the halogenating agent is employed as the solvent, a convenient temperature for the reaction is the reflux temperature of the solvent.
  • Hydrocarbons such as benzene, toluene and ether may also be employed as solvents.
  • the amine reactant is ammonia
  • aqueous solutions of ammonia may be employed.
  • the reaction with the amine is carried out at atemperature between 050 C.
  • the excess amine is neutralized with dilute mineral acid such as dilute hydrochloric acid, and the product is collected and purified by techniques known in the art.
  • the imidazole 4(5 )-carboxamide can be collected by filtration and purified by recrystallization.
  • Those compounds of Formula I wherein R is cyano can be prepared by reacting an imidazole 4(5)-carboxamide with an excess of a dehydrating agent, such as phosphorous oxychloride.
  • a dehydrating agent such as phosphorous oxychloride.
  • the reaction is generally carried outat a temperature between 75-l50 C. for about l-5 hours.
  • the excess phosphorous oxychloride is removed by conventional means, for example, under reduced pressure, and the residue is neutralized with dilute alkali, such as sodium bicarbonate.
  • the 4(5)- cyanoimidazole compound is collected by filtration, and purified by techniques known in the art.
  • Those compounds of Formula I wherein R is loweralkanoyl can be prepared by reacting a 4(5)- cyanoimidazole with about a 2-4 molar excess of a loweralkyl metal halide such as, for example, methyl magnesium iodide, in a suitable solvent, such as ether or tetrahydrofuran.
  • a suitable solvent such as ether or tetrahydrofuran.
  • the reaction mixture is then heated, generally at the reflux temperature of the solvent, for about l-5 hours, after which it is heated at about room temperature for about 20 hours.
  • the reaction mixture is then poured into dilute acid, such as dilute hydrochloric acid or aqueous ammonium chloride, and the mixture is extracted with a suitable solvent such as, for example, ether.
  • the loweralkanoylimidazole is obtained by concentration of the extract.
  • an aryl metal halide such as phenyl magnesium halide, is employed.
  • Those compounds wherein the substituent in the 2- position is nitrophenyl are not prepared in this manner.
  • the 2-phenyl-4(5)-alkanoylimidazole compound is prepared first and is then nitrated to form the corresponding 2-nitrophenyl compounds.
  • the nitrophenyl compounds can also be reduced by known techniques to the corresponding amino compound; the alkanoylamino compounds can be prepared from the amino compounds by well known methods used to acylate amines.
  • the trifluoromethylimidazole compounds can be prepared by first reacting l,l-dibromo-3,3,3- trifluoroacetone with mild base, such as sodium acetate or potassium carbonate, at a temperature between room temperature and C., and then reacting the mixture with the appropriate carboxaldehyde and ammonia at room temperature.
  • mild base such as sodium acetate or potassium carbonate
  • the carboxaldehyde may be a substituted arylcarboxaldehyde, such as ochlorobenzenecarboxaldehyde, p-nitrobenzenecarboxaldehyde, p-sulfamoylbenzenecarboxaldehyde, and pmethoxybenzenecarboxaldehyde, or a heteroarylcarboxaldehyde, such as pyridinecarboxaldehyde, quinolinecarboxaldehyde, thiazolecarboxaldehyde, thiophenecarboxaldehyde, or cinnolinecarboxaldehyde.
  • a substituted arylcarboxaldehyde such as ochlorobenzenecarboxaldehyde, p-nitrobenzenecarboxaldehyde, p-sulfamoylbenzenecarboxaldehyde, and pmethoxybenzenecarboxaldeh
  • the starting materials used to prepare those compounds of Formula I wherein R is loweralkyl can be prepared by reacting a 4(5)-trifluoromethylimidazole such as, for example, 2-(p-fluorophenyl)-4(5)- trifluoromethylimidazole, with an alkylating agent such as diazomethane in ether or with a loweralkylsulfate such as dimethylsulfate in a suitable solvent.
  • Dimethylsulfate itself may be employed as the solvent; loweralkanoic acids such as formic acid and acetic acid may also be employed as the solvent.
  • the alkylation may be carried out at room temperature, but in the case of dimethylsulfate, it is preferred to carry out the reaction at elevated temperatures from about 50-l50 C. for from about l-3 hours.
  • the reflux temperature of the solvent is a convenient temperature for the alkylation step.
  • the alkylated trifluoromethylimidazole compound is then isolated by techniques known in the art. One isolation method, for example, is to remove the solvent and triturate the residue with dilute alkali, such as ammonium hydroxide, and take up the product in a suitable solvent, such as hexane. The alkylated trifluoromethylimidazole compound is then obtained upon removal of the solvent.
  • the metal salts of the 2-substituted-4(5)-substituted imidazoles can be prepared by methods known in the art.
  • the sodium or potassium salt can be prepared by addition of an equivalent amount of sodium or potassium hydroxide to a solution of the substituted imidazole compound. The salt is then obtained by concentrating the reaction mixture.
  • the acid addition salts of the substituted imidazoles having in the 2- position a heterocyclic ring containing at least one nitrogen atom can be prepared by any of the known methods for preparing acid addition salts of amines.
  • substituted imidazoles which are the subject of this invention inhibit the action of the enzyme xanthine oxidase resulting in a significant decrease in the concentration of uric acid in the blood and urine and are, therefore, capable of aborting attacks of gout.
  • xanthine oxidase obtained from milk may be employed to demonstrate the ability of the 2-substituted-4(5)-substituted imidazoles to inhibit the enzyme.
  • the general procedure is to employ a 5-10 unit suspension of the enzyme per milliliter of 60 percent saturated ammonium sulfate of the enzyme; 1 unit of such a suspension converts 1;]. mole of xanthine to uricacid per minute.
  • about 0.05 ml. of enzyme is diluted with about 3 ml. of buffer.
  • tris buffer (0.05 mole) pH 7.4 maybe employed.
  • the inhibitor to be tested is dissolved in buffer or a suitable solvent, such as dimethylsulfoxid'e; the same solvent is used to dilute the solution.
  • the buffer, hypoxanthine and solvent are placed in a cell, and the resulting solution is shaken to absorb air.
  • the diluted enzyme solution is then added, and the rate of increase in absorbance at 290mg. is noted with a recording spectrophotometer.
  • sufficient enzyme is employed to give about 0.1 absorbance units change per minute, and sufficient inhibitor is used to give 30-70 percent inhibition.
  • the p.M concentration of inhibitor necessary for 50 percent inhibition (V /V 2) is determined by plotting V l V against 1, where V velocity withoutinhibitor, V, velocity with inhibitor, and l inhibitor concentration.
  • the therapeutically active substituted imidazoles can be administered as the active ingredient in association with a pharmaceutically acceptable carrier in the form of tablets, elixirs, capsules, and the like.
  • a pharmaceutically acceptable carrier in the form of tablets, elixirs, capsules, and the like.
  • These preparations may be made by any of the known pharmaceutical methods.
  • they are compounded with an inert pharmaceutical carrier which may contain a suitable binder such as, for example, gums, starches, and sugars. They may also be incorporated into a gelatin capsule or formulated into elixirs which have the advantage of being susceptible to manipulations in flavor by the addition of standard natural or synthetic flavoring materials.
  • the compound is generally administered in compositions which are so proportioned as to afford a unitdosage of about 30 mg. to 1.5 gm. per day.
  • the preferred dosage level is about 100-800 mg. per day.
  • Formulation l Compressed Tablet Comprising 0.5 gm. of Active Ingredient
  • the methyl 2-( p-chlorophenyl)imidazole-4(5)-carboxylate is granulated with the starch paste and while moist passed through a No. 14 screen, dried at 45 C. for 20 hours, and then passed 3 times through a No. 14 screen.
  • the starch is then passed through a No. bolting cloth onto the granulation, and all ingredients are blended thoroughly
  • the magnesium stearate is passed through a No.
  • Formulation ll Encapsulationfor 250 mg. Capsule Ingredient Amt-Mg.
  • EXAMPLE 6 2-(4-PYRIDYL)IMIDAZOLE-4( 5 )-CARBOXAMIDE and 2-(p-rnethoxcyanoimidazole 11
  • EXAMPLE 7 2-(p-CHLOROPHENYL)lMIDAZOLE-4( 5 CARBOXAMIDE
  • Z-(p-Chlorophenyl)imidazole-4(5)-carboxylic acid (Zgrams) is dissolved in thionyl chloride (40 ml.), and the resulting solution is heated at reflux for 30 minutes. The thionyl chloride is removed under reduced pressure, and the solid residue is added with cooling to concentrated aqueous ammonia (40 ml.).
  • Sodium acetate trihydrate (l 1.6 grams, 0.084 mole) is dissolved in 40 ml. of water, and l,l-dibromo-3,3,3- trifluoroacetone (11.6 grams, 0.042 mole) is added to the resulting aqueous solution.
  • the solution is heated for 30 minutes at 100 C. and is then cooled in an ice bath.
  • the cooled solution is added to a solution of 4- pyridinecarboxaldehyde (4.7 grams, 0.044 mole) in methanol (200 ml.).
  • Concentrated aqueous ammonia (50 ml.) is added to the alcoholic solution, and the reaction mixture is allowed to stand for 5 hours at room temperature.
  • PREPARATION B I Z-(p-ELUOROPHENYU-l-METl-lYL-4(AND s TRIFLUOROMETHYLIMIDAZOLE hydroxide, water, and then with hexane.
  • the hexane extract is concentrated to a solid residue and is sublimed to yield 200 mg. of product.
  • 2-(p-fluorophenyl)-l-methyl-4 (and 5)-trifiuoromethylimidazole are obtained, m.p. 81-84.5 C.
  • Thin layer chromatography and VPC indicate the presence of two isomeric components.
  • R is hydrogen or lower alkyl
  • R is naphthyl, pyridyl, quinolyl, cinnolyl, indanyl
  • R is hydrogen or lower alkyl
  • R2 is naphthyl, halophenyl, dihalophenyl
  • R is carboxy, carbamoyl, lower alkylcarbamoyl,
  • R is loweralkanoyl
  • a compound of claim 1, which compound is 2- (3,4-dichlorophenyl )imidazole-4( 5 )-carboxylic acid.
  • R is pyridyl or halophenyl and R is carboxy, carbamoyl, cyano, lower alkanoyl or benzoyl.

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3835142A (en) * 1970-01-28 1974-09-10 Warner Lambert Co 1-(2-imidazolin-2-yl)-2-(1,2,3,4-tetrahydro-2-isoquinolyl)-2-imidazolines
US3852292A (en) * 1972-05-05 1974-12-03 Merck & Co Inc 2-(pyridyl)-imidazole-4,5-dicarboxylic acid and derivatives
USB383852I5 (enrdf_load_html_response) * 1972-05-05 1975-01-28
US4035390A (en) * 1971-06-19 1977-07-12 Lilly Industries, Ltd. Thiazole derivatives
US4058614A (en) * 1973-12-04 1977-11-15 Merck & Co., Inc. Substituted imidazole compounds and therapeutic compositions therewith
US4125530A (en) * 1969-12-15 1978-11-14 Merck & Co., Inc. Trifluoromethylimidazoles and a method for their preparation
US4139708A (en) * 1977-05-24 1979-02-13 Sk&F Lab Co. Intermediates and processes useful for preparing medicinal agents imidazolemethylphosphonium salts
US4179512A (en) * 1977-03-01 1979-12-18 Merck & Co., Inc. 4-Substituted-2-arylimidazoles
US4281005A (en) * 1979-03-05 1981-07-28 Merck & Co., Inc. Novel 2-pyridylimidazole compounds
US4314844A (en) * 1979-01-11 1982-02-09 Rohm And Haas Company Herbicidal substituted imidazoles
US4851424A (en) * 1986-06-06 1989-07-25 Ciba-Geigy Corporation 1-Phenyl-lower alkyl-imidazole 4- or 5-carboxamide compounds which are useful in the treatment of epilepsy
US5872136A (en) * 1996-04-03 1999-02-16 Merck & Co., Inc. Arylheteroaryl inhibitors of farnesyl-protein transferase
WO2009137742A1 (en) * 2008-05-08 2009-11-12 Ampac Fine Chemicals Llc Process for the preparation of cyano-substituted-nitrogen-containing heteroaryl compounds
CN101805294A (zh) * 2010-01-12 2010-08-18 北京华禧联合科技发展有限公司 盐酸右美托咪定关键中间体的制备
CN101921234B (zh) * 2009-06-12 2012-05-30 中国中化股份有限公司 一种制备美托咪啶的方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3147270A (en) * 1961-11-03 1964-09-01 Warner Lambert Pharmaceutical Substituted 2-imidazolines
FR1487345A (fr) * 1965-04-16 1967-07-07 Merck & Co Inc Nouveau procédé de préparation d'alkyl-imidazoles hydroxylés ou hydroxyalkylés en position 1

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4125530A (en) * 1969-12-15 1978-11-14 Merck & Co., Inc. Trifluoromethylimidazoles and a method for their preparation
US3835142A (en) * 1970-01-28 1974-09-10 Warner Lambert Co 1-(2-imidazolin-2-yl)-2-(1,2,3,4-tetrahydro-2-isoquinolyl)-2-imidazolines
US4035390A (en) * 1971-06-19 1977-07-12 Lilly Industries, Ltd. Thiazole derivatives
US3852292A (en) * 1972-05-05 1974-12-03 Merck & Co Inc 2-(pyridyl)-imidazole-4,5-dicarboxylic acid and derivatives
USB383852I5 (enrdf_load_html_response) * 1972-05-05 1975-01-28
US3914246A (en) * 1972-05-05 1975-10-21 Merck & Co Inc Tri-substituted imidazoles
US4058614A (en) * 1973-12-04 1977-11-15 Merck & Co., Inc. Substituted imidazole compounds and therapeutic compositions therewith
US4179512A (en) * 1977-03-01 1979-12-18 Merck & Co., Inc. 4-Substituted-2-arylimidazoles
US4139708A (en) * 1977-05-24 1979-02-13 Sk&F Lab Co. Intermediates and processes useful for preparing medicinal agents imidazolemethylphosphonium salts
US4314844A (en) * 1979-01-11 1982-02-09 Rohm And Haas Company Herbicidal substituted imidazoles
US4281005A (en) * 1979-03-05 1981-07-28 Merck & Co., Inc. Novel 2-pyridylimidazole compounds
US4336257A (en) * 1979-03-05 1982-06-22 Merck & Co., Inc. Novel 2-pyridylbenzimidazole compounds
US4851424A (en) * 1986-06-06 1989-07-25 Ciba-Geigy Corporation 1-Phenyl-lower alkyl-imidazole 4- or 5-carboxamide compounds which are useful in the treatment of epilepsy
US5872136A (en) * 1996-04-03 1999-02-16 Merck & Co., Inc. Arylheteroaryl inhibitors of farnesyl-protein transferase
WO2009137742A1 (en) * 2008-05-08 2009-11-12 Ampac Fine Chemicals Llc Process for the preparation of cyano-substituted-nitrogen-containing heteroaryl compounds
US20090292122A1 (en) * 2008-05-08 2009-11-26 Ampac Fine Chemicals Llc Process for the preparation of cyano-substituted-nitrogen-containing heteroaryl compounds
US8198461B2 (en) 2008-05-08 2012-06-12 Ampac Fine Chemicals Llc. Process for the preparation of 3-cyano-1,2,4-triazoles
CN101921234B (zh) * 2009-06-12 2012-05-30 中国中化股份有限公司 一种制备美托咪啶的方法
CN101805294A (zh) * 2010-01-12 2010-08-18 北京华禧联合科技发展有限公司 盐酸右美托咪定关键中间体的制备
CN101805294B (zh) * 2010-01-12 2015-06-10 北京华禧联合科技发展有限公司 盐酸右美托咪定关键中间体的制备

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GB1319026A (en) 1973-05-31
DE2112349A1 (de) 1971-10-14
NL7102531A (enrdf_load_html_response) 1971-09-20
FR2085714B1 (enrdf_load_html_response) 1974-08-02
JPS5425028B1 (enrdf_load_html_response) 1979-08-24
CA958709A (en) 1974-12-03
CH565157A5 (enrdf_load_html_response) 1975-08-15

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