US3691178A - Substituted imidazoles - Google Patents
Substituted imidazoles Download PDFInfo
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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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- 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
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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
- C07D233/66—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.
Abstract
Imidazoles 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 antihyperuricemic agents. Compositions useful in the treatment of gout and hyperuricemia containing a substituted imidazole as the active ingredient are provided.
Description
United States Patent Baldwin et al.
[451 Sept. 12, 1972 SUBSTITUTED IMIDAZOLES Inventors: John J. Baldwin, Lansdale, Pa. 19446; Frederick C. Novello, Berwyn, Pa. 19312 Assignec: Merck & (10., Inc., Rahway, NJ.
Filed: March 16, 1970 Appl. No.: 20,126
References Cited OTHER PUBLICATIONS Lawson, J. Chem. Soc. 1957, 4,225- 8.
Primary Examiner-Henry R. Jiles Assistant Examiner-G. Thomas Todd Attorney-J. Jerome Behan and 1. Louis Wolk [57] 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.
11 Claims, No Drawings SUBSTITUTED IMIDAZOLES BACKGROUND OF THE INVENTION 2 position are aryl or heteroaryl groups, while the substituents in the 4(5) positions are carboxy or carbamoyl groups, or a group derived therefrom.
2. Description of the Prior Art The herein-described substituted imidazoles have utility as anti-gout and anti-hyperuricemic agents.
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.
Although human purine biosynthesis can be inhibited at the stage of formyl glycinimide ribotide by the glutamine antagonists azaserine and 6-diazo-5-oxol-norleucine, a high incidence of undesirable side effects precludes their being used clinically for this purpose. In recent years, substantial progress has been made in attempting to control the excessive levels of uric acid in patients afflicted with gout through the use of pharmaceutical agents. Uric acid synthesis has been effectively blocked by the use of allopurinol, 4-hydroxypyrazolo-[3,4d]-pyrimidine, a compound which is a structural isomer of hypoxanthine. 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. 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. Other compounds, such as acetylsalicylic acid, thiophenylpyrazolidine, and phenylbutazone have been employed in the treatment of gout. Many of the existing compounds used in the treatment of gout, however, relieve the inflammation and other symptoms connected therewith but have no effect on the conditions which give rise to gouty arthritis or hyperuricemia. Thus, there is still a need for compounds which can be employed in the prophylactic treatment of gout as well as for the treatment of other abnormal conditions associated with hyperuricemia.
The 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.
SUMMARY OF THE INVENTION DESCRIPTION OF THE PREFERRED EMBODIMENTS The novel imidazoles which are the subject of the present invention can be structurally depicted as follows:
N R l wherein 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,
substituted heteroaryl containing l 3 substituents wherein the substituent is loweralkyl or a loweralkoxy group wherein the alkyl and alkoxy groups contain one to five carbons, substituted phenyl wherein the substituent is halogen, such as fluorine, bromine, chlorine or iodine, loweralkyl wherein the alkyl group is a straight or branched chain group containing one to five carbons, such as methyl, ethyl, propyl, butyl, isopropyl, and pentyl, sulfamoyl, loweralkylsulfamoyl wherein the alkyl group contains from one to five carbons, such as dimethylsulfamoyl, ethylsulfamoyl,
sulfamoyl, and the like, loweralkoxy wherein the 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
the like,
methylenedioxy, I
or a fused loweralkylene bridge containing from three to six carbons such as a propylene, butylene, or pentylene bridge, and
R is
carboxy,
loweralkoxycarbonyl wherein the alkoxy group contains one to five carbons, such as methoxycarbonyl, ethoxycarbonyl, or butoxycarbonyl,
carbamoyl,
substituted carbamoyl wherein the substituent is loweralkyl having one to three carbons,
cyano,
loweralkanoyl wherein the alkanoyl group contains from one to five carbons, such as acetyl, propionyl, butyryl, and the like, or
benzoyl,
provided that where R is carboxy, R is not pnitrophenyl or m-nitrophenyl.
Where the substituent on the imidazole ring is a substituted phenyl group, the phenyl ring may contain from 1-3 substituents. Where 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. Where R is a naphthyl group, the naphthyl group is joined to the imidazole ring at the l or 2 position of the naphthyl group. Where 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.
Also within the scope of the present invention are the 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. Also included are the disalts, which are formed in those cases where R is carboxy.
Those compounds wherein 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.
It should be understood that 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-( paminophenyl )imidazole--46 )-carboxylic acid 4( 5 )-propionyl-2-( 4-pyridyl )imidazole A l-ethyl-4-acetyl-2-( p-chlorophenyl)imidazole 2-( p-chlorophenyl)-4( 5 )-cyanoimidazole l-methyl-2-( Z-thienyl )imidazole-4-carboxylate l -butyl-2-( p-chlorophenyl )-4-cyanoimidazole 2-( l-naphthyl)imidazole-4(5 )-carboxylic acid methyl Z-(p-chlorophenyl)imidazole-4(S-carboxylate 4( 5 )-acetyl-2-( p-chlorophenyl )imidazole 2-(p-chlorophenyl)-imidazole-4(5)-carboxamide, and 2-( 4-pyridyl )-4( 5 )-cyanoimidazole.
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. For example, those compounds where the substituent at the 4(5)-position is carboxy, i.e., compounds having the formula N H000 I where R, and R are as defined above, can be prepared by treating a substituted 4(5 )-trifluoromethylimidazole with excess aqueous alkali, such as sodium hydroxide or potassium hydroxide. Generally, 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. For example, where the alkoxy carbonyl group is methoxycarbonyl, 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. Generally, 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.
Alternatively, 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. 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. Where 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. For example, 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. 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. 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. To obtain those compounds where R, is benzoyl, 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. 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.
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, that is, those compounds where R in F ormula I is hydrogen, can be prepared by methods known in the art. For example, 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.
The 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.
For testing purposes, 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. Generally, for a l-day assay, about 0.05 ml. of enzyme is diluted with about 3 ml. of buffer. As the buffer, tris buffer (0.05 mole) pH 7.4 maybe employed. The inhibitor to be tested is dissolved in buffer ora 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. Generally, 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. These preparations may be made by any of the known pharmaceutical methods. For example, in tablet form, 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, however, is about 100-800 mg. per day.
The following examples serve to illustrate typical tablet, capsule, and elixir formulations incorporating the therapeutically active 2-substituted-4(5)-sub- "stituted imidazoles of this invention:
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. 90 bolting cloth onto the granulation, and these ingredients are blended, after which the granulation is compressed into tablets using a fourteen thirty-seconds of an inch flat, bevelled, scored punch having a thickness of 0.205: 0.005 inch yielding 1,000 tablets each weighing 0.543 grams.
Formulation ll: Encapsulationfor 250 mg. Capsule Ingredient Amt-Mg.
2-( 3,4-dichlorophcnyl )imiduzole- 4( 5 )-carboxylic acid 250 Lactose 9 3 Talc 7 Blend lactose, talc and the 2-(3,4-dichlorophenyl)imidazole-4(5)-carboxylic acid in suitable blending equipment, and encapsulate into a No. 2 capsule at a target weight of 350 mg.
Formulation 11!: Liquid Suspension Formula Ingredient Amt.g./l.
Veegum H.V. 3.0 Water 150.0 Methyl paraben 1.0 2-( 4-pyridyl )-4( 5 )-cyanoimidazole 50.0 Kaolin 10.0 Flavor 1.0
Glycerin, 9.5 to 1 liter EXAMPLE 1 METHYL 2-( p-CHLOROPI-IENYL)IMIDAZOLE-4(5 )-CARBOXYLATE I Dry hydrogen chloride is introduced into a solution of 2-(p-chlorophenyl)imidazole-4(5)-carboxylic acid (3.5 grams) in methanol ml.) at reflux for one hour. The reaction mixture is then allowed to cool to room temperature and is concentrated under reduced pressure to a solid residue. Upon recrystallization from acetonitrile-water, 3 grams of methyl-Z-(p-chlorophenylimidazole-4(5 )-carboxylate, mp. 23 7-238 C., is obtained.
When in the above procedure 2-(p-bromophenyl)- imidazole-4( )-carboxylic acid, 2-( lnaphthyl)imidazole-4-(5)-carboxylic acid and 2(2- thienyl)imidazole-4(5)-carboxylic acid are employed in place of 2-(p-chlorophenyl)imidazole-4(5)-carboxylic acid, there are obtained-methyl 2-(bromophenyl)imidazole-4(5)-carboxylate, methyl 2-( l-naphthyl)- imidazole-4(5)-carboxylate and methyl 2-(2-thienyl)imidazole-4(5 )-carboxylate, respectively.
EXAMPLE 2 METHYL 2-(4-PYRlDYL)lMlDAZOLE-4(5 CARBOXYLATE Dry hydrogen chloride is introduced into a solution of 2-(4pyridyl)imidazole-4(5)-carboxylic acid (3.5 grams) in methanol (150 ml.) at reflux for one hour. The reaction mixture is then cooled to room temperature and is concentrated under reduced pressure until a solid residue is obtained.'Upon recrystallization from acetonitrile-water, methyl 2-(4-pyridyl)-imidazole-4 (5 )-carboxylate, m.p. 2 l 8.5220 C. is obtained.
EXAMPLE 3 4(5 )-ACETYL-2(p-CHLOROPHENYL)IMIDAZOLE 2-(p-Chlorophenyl)-4(5)-cyanoimidazole (2 grams, 0.01 mole) is dissolved in tetrahydrofuran (100 ml.), and the resulting solution is added dropwise to methyl magnesium iodide (0.03 mole) in ether (30 ml.). The reaction mixture is refluxed for 3 hours, after which it is cooled to room temperature and maintained at this temperature for hours. The reaction mixture is then concentrated to 30 ml. and poured with cooling onto dilute hydrochloric acid (about 100 ml.). The mixture is then extracted with ether, and the ether extract is dried over sodium sulfate. The ether extract is then concentrated until a solid residue is obtained. Upon recrystallization of the solid residue from acetonitrile, 4(5) -acetyl-2( p-chlorophenyl )imidazole, m.p. 244.5-246.5 C. is obtained.
When in the above procedure ethyl magnesium iodide and phenyl magnesium iodide are employed in place of methyl magnesium iodide, there are obtained 4( 5 )-propionyl-2-( p-chlorophenyl)imidazole and 4( 5 benzoyl-2-(p-chloro-phenyl)imidazole, respectively.
EXAMPLE 4 2-(p-CHLOROPHENYL)lMlDAZOLE-4(5 CARBOXYLIC ACID A suspension of 2-(p-chlorophenyl-)-4(5)- trifluoromethylimidazole (17 grams) in l N aqueous sodium hydroxide (1 liter) is heated at 100 C. for 1- /z hours. The resulting solution is filtered, and the filtrate is acidified with hydrochloric acid. A solid separates from the acid solution and is collected by filtration. Upon recrystallization of the solid product from acetonitrile-water, 2-(p-chlorophenyl)imidazole-4( 5 carboxylic acid, m.p. 26 1 C., is obtained.
When in the above procedure 2-(4-pyridyl)-4(5)- trifluoromethylim-idazole is employed in place of 2-(pchlorophenyl )-4( 5 )-trifluoromethylimidazole, 2-( 4- pyridyl)-imidazole-4(5)-carboxylic acid, m.p. 300 C., is obtained.
When in the above procedure 2-(3,4-dichlorophenyl)-4(5)-trifluoromethylimidazole is employed in place of a (p-chlorophenyl)-4(5)-trifluoromethylimidazole, 2-( 3 ,4-dichlorophenyl)imidazole-4( 5 )-carboxylic acid, m.p. 249250 C., is obtained.
When in the above procedure 2-(4-thiazolyl)-4(5)- trifluoromethylimidazole is employed in place of 2-(pchlorophenyl)-4( 5 )-trifluoromethylimidazole, there is obtained 2-(4-thiazobyl )-imidazole-4(5 )-carboxylic acid.
EXAMPLE 5 Z-(P-CHLOROPHENYL)lMIDAZOLE-4( 5 CARBOXAMIDE Methyl 2-(p-chlorophenyl)-imidazole-4(5 )-carboxylate (2.36 grams, 0.01 mole) is reacted with ammonia (9 grams) in methanol (50 ml.) at C. for 18 hours. The reaction mixture is then concentrated until a solid residue is obtained. Upon recrystallization of the residue from methanol-water, 2-(p-chlorophenyl)imidazole-4(5)-carboxamide, m.p. 272274 C., is obtained.
When in the above procedure methyl 2-(2-quinolyl)- imidazole-4( 5 )-carboxylate, ethyl 2-( 3-cinnolyl)imidazole-4(5)-carboxylate and methyl 2-(psulfamoylphenyl)imidazole-4(5)-carboxylate are employed in place of methyl 2-(p-chlorophenyl)imidazole-4(5)-carboxylate, there are obtained 2- (2-q uinolyl )imidazole-4( 5 )-carboxamide, 2-( 3-cinnolyl )imidazole-4( 5 )-carboxamide and 2-( psulfamoylphenyl)imidazole-4(5)-carboxamide, respectively.
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.). The reaction mixture is then stirred for 45 minutes at room temperature, diluted with water (40 ml.), and concentrated under reduced pressure to 40 ml. The concentrated solution is neutralized with dilute hydrochloric acid and the solid which precipitates is collected by filtration. Upon recrystallization of the solid from methanolwater, I 2-(p-chlorophenyl)imidazole-4(5)-carboxamide, m.p. 272.5-275 C., is obtained.
EXAMPLE 8 Z-(p-CHLOROPHENYL -4( 5 )-CYANOIMIDAZOLE ane, 2-(-p-chlorophenyl)-4(5)-cyanoimidazole, m.p.
2 l -2 1 3 C., is obtained.
When in the above procedure 2-(2-quinolyl )imidazole-4(5 )-carboxamide and 2-( 2- naphthyl)imidazole-4(5 )-carboxamide are employed in place of 2-(p-chlorophenyl)imidazole-4(5)-carboxamide there are obtained 2-( 2-q uinolyl)-4( 5 cyanoimidazole and 2-( 2-naphthyl)-4(5 cyanoimidazole.
EXAMPLE 9 2-( 4-PYRIDYL )-4(5 )-CYANOIMIDAZOLE A suspension of 2-(4-pyridyl)imidazole-4(5 )-carboxamide (1 gram) in phosphorous oxychloride (10 ml.) is heated at 100 C. for 3- hours. The phosphorous oxychloride is removed under a stream of air until a solid residue is obtained. Dilute sodium bicarbonate solution is added to neutralize the residual acid, and the solid precipitate is collected by filtration. Upon recrystallization from benzene-hexane, 2-(4-pyridyl)-4(5)- cyanoimidazole, m.p. 295-297 C., is obtained.
When in the above procedure 2-(3,4-dichlorophenyl)imidazole-4(5 )-carboxamide and 2-( S-indanyl)imidazole-4(5)-carboxamide are employed in place of 2-(4-pyridyl)imidazole-4(5)-carboxamide, there are obtained 2-(3,4-dichlorophenyl)-4(5)- and 2-(5-indanyl)-4(5)- cyanoimidazole, respectively.
PREPARATION A 2-( 4-PYRIDYL )-4( 5 TRIFLUOROMETHYLIMIDAZOLE The trifluoromethylimidazoles used as the starting materials are prepared as follows:
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. The mixture is then concentrated to about ml., and the product separates from the solution as an oil which solidifies on standing. Upon recrystallization from water, there is obtained 2-(4- pyridyl)-4( 5 )-trifluoromethylimidazole, m.p. 156- 1 5 When in the above procedure 3-pyridinecarboxaldehyde is employed in place of 4- pyridinecarboxaldehyde, there is obtained 2-(3-pyridyl)-4(5)- trifluoromethylimidazole, m.p. 228228.5 C.
When in the above procedure Z-pyridinecarboxaldehyde is employed in place of 4-pyridinecarbox'aldehyde, there is obtained 2-(2-pyridyl)-4(5)- trifluoromethylimidazole, m.p. l56-l 57.5 C.
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. Upon recrystallization from hexane, 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.
When in the above procedure diethylsulfate is employed in place of dimethylsulfate, 2-(p-fluorophenyl)- i1 l-ethyl-4(and 5)-trifluoromethylimidazole are obtained.
It should be understood that although this invention has been described with reference to particular embodiments thereof, changes and modifications may be made which are within its intended scope, and it should be limited only by the language of the appended claims.
What is claimed is:
1. A compound of the formula and non-toxic salts thereof, wherein R, is hydrogen or lower alkyl; R is naphthyl, pyridyl, quinolyl, cinnolyl, indanyl,
thienyl or thiazolyl, substituted phenyl wherein the substituent is halogen,
and non-toxic salts thereof, wherein R is hydrogen or lower alkyl; R2 is naphthyl, halophenyl, dihalophenyl,
pyridyl, quinolyl, cinnolyl, thienyl or thiazolyl, and
R is carboxy, carbamoyl, lower alkylcarbamoyl,
cyano, v benzoyl, and
lower alkanoyl. 3. A compound of claim 1 wherein R is hydrogen, R
is halophenyl and R is carboxy.
4. A compound of claim 1 wherein R is hydrogen, R
is halophenyl and R is loweralkanoyl.
5. A compound of claim 1, which compound is 2- (3,4-dichlorophenyl )imidazole-4( 5 )-carboxylic acid.
6. A compound of the formula:
and the non-toxic salts thereof, wherein R is pyridyl or halophenyl and R is carboxy, carbamoyl, cyano, lower alkanoyl or benzoyl.
7. Z-(Pyridyl)imidazole-4(5)-carboxylic acid. 8. 2-(Halophenyl)imidazole-4( 5 )-carboxamide. 9. Z-(Pyridyl)imidazole-4(5)-carboxamide.
l0. 2-(Halophenyl)-4(5 )-cyanoimidazole.
ll. 2-( 4-Pyridyl)-4(5 )-cyanoimidazole.
Claims (10)
- 2. A compound of the formula
- 3. A compound of claim 1 wherein R1 is hydrogen, R2 is halophenyl and R5 is carboxy.
- 4. A compound of claim 1 wherein R1 is hydrogen, R2 is halophenyl and R5 is loweralkanoyl.
- 5. A compound of claim 1, which compound is 2-(3,4-dichlorophenyl)imidazole-4(5)-carboxylic acid.
- 6. A compound of the formula:
- 7. 2-(Pyridyl)imidazole-4(5)-carboxylic acid.
- 8. 2-(Halophenyl)imidazole-4(5)-carboxamide.
- 9. 2-(Pyridyl)imidazole-4(5)-carboxamide.
- 10. 2-(Halophenyl)-4(5)-cyanoimidazole.
- 11. 2-(4-Pyridyl)-4(5)-cyanoimidazole.
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JP (1) | JPS5425028B1 (en) |
CA (1) | CA958709A (en) |
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DE (1) | DE2112349A1 (en) |
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Cited By (15)
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 (en) * | 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 (en) * | 2010-01-12 | 2010-08-18 | 北京华禧联合科技发展有限公司 | Preparation of dexmedetomidine hydrochloride key intermediate |
CN101921234B (en) * | 2009-06-12 | 2012-05-30 | 中国中化股份有限公司 | Method for preparing dexmedetomidine |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3147270A (en) * | 1961-11-03 | 1964-09-01 | Warner Lambert Pharmaceutical | Substituted 2-imidazolines |
FR1487345A (en) * | 1965-04-16 | 1967-07-07 | Merck & Co Inc | New process for the preparation of hydroxylated or hydroxyalkylated alkyl-imidazoles in position 1 |
-
1970
- 1970-03-16 US US20126A patent/US3691178A/en not_active Expired - Lifetime
-
1971
- 1971-02-25 NL NL7102531A patent/NL7102531A/xx not_active Application Discontinuation
- 1971-03-01 CA CA106,578A patent/CA958709A/en not_active Expired
- 1971-03-10 JP JP1254771A patent/JPS5425028B1/ja active Pending
- 1971-03-15 FR FR7108947A patent/FR2085714B1/fr not_active Expired
- 1971-03-15 DE DE19712112349 patent/DE2112349A1/en active Pending
- 1971-03-15 CH CH371871A patent/CH565157A5/xx not_active IP Right Cessation
- 1971-04-19 GB GB2340471*A patent/GB1319026A/en not_active Expired
Cited By (20)
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 (en) * | 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 (en) * | 2009-06-12 | 2012-05-30 | 中国中化股份有限公司 | Method for preparing dexmedetomidine |
CN101805294A (en) * | 2010-01-12 | 2010-08-18 | 北京华禧联合科技发展有限公司 | Preparation of dexmedetomidine hydrochloride key intermediate |
CN101805294B (en) * | 2010-01-12 | 2015-06-10 | 北京华禧联合科技发展有限公司 | Preparation of dexmedetomidine hydrochloride key intermediate |
Also Published As
Publication number | Publication date |
---|---|
DE2112349A1 (en) | 1971-10-14 |
NL7102531A (en) | 1971-09-20 |
FR2085714A1 (en) | 1971-12-31 |
CH565157A5 (en) | 1975-08-15 |
CA958709A (en) | 1974-12-03 |
GB1319026A (en) | 1973-05-31 |
JPS5425028B1 (en) | 1979-08-24 |
FR2085714B1 (en) | 1974-08-02 |
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