Claims
- 1. A process for preparing a compound of the formula: ##STR9## wherein R.sub.2 is hydrogen,
- methyl,
- C.sub.3 -c.sub.5 alkyl,
- 2-dimethylaminoethyl,
- 1-dimethylamino-2-methyl-2-propyl,
- pyridyl,
- pyridyl-N-oxide,
- monomethylpyridyl,
- dimethylpyridyl,
- 6-quinolyl,
- 2-quinolyl,
- 3-quinolyl,
- 4-quinolyl,
- pyrazinyl,
- methoxypyrazinyl,
- 4-chlorophenyl-4-pyrazolyl,
- 4-thiazolyl,
- phenyl,
- o-cyanophenyl,
- p-ethylphenyl,
- p-sulfamoylphenyl,
- p-N-methylsulfamoylphenyl,
- p-methoxyphenyl,
- 3-furyl,
- 2-thienyl,
- o-methoxyphenyl,
- p-acetylaminophenyl,
- p-cyanophenyl,
- p-dimethylaminophenyl,
- 5-indanyl,
- 1-indanyl,
- 3,4-dichlorophenyl,
- p-carboxyphenyl,
- 2-indanyl,
- 2-naphthyl,
- 1-naphthyl,
- monohalophenyl,
- p-methylsulfonamidophenyl,
- p-diethylaminoethoxyphenyl,
- diphenylmethyl,
- 1-methyl-4-pyrazolyl,
- p-nitrophenyl,
- 2-aminophenyl,
- 2-furyl,
- 2,4-dichlorophenyl,
- p-carboxyphenyl,
- monomethylphenyl,
- 3. 4-methylenedioxyphenyl,
- p-isopropylphenyl,
- 3,4-dimethoxyphenyl,
- p-N,N-dimethylsulfamoylphenyl,
- p-methylaminophenyl,
- 2,6-dimethyl-4-pyridyl,
- 4,6-dimethyl-2-pyridyl,
- pyrazinyl,
- m-methoxymethoxyphenyl,
- p-diethylaminoethoxyphenyl,
- 1-benzyl-4-pyrazolyl,
- 1-phenyl-4-pyrazolyl,
- 1-methyl-4-pyrazolyl, and
- 1-piperidino-2-methyl-2-propyl
- which comprises the steps of
- (a) treating 1,1-dihalo-3,3,3-trifluroacetone with a base and then
- (b) treating the resulting mixture with ammonia and the appropriate carboxaldehyde.
- 2. The process of claim 1 wherein the product thus obtained is treated with 1,2-epoxyethane or 1,3-epoxypropane in the presence of a Lewis acid to afford the corresponding 1-hydroxyalkyl-4(5)-trifluoromethylimidazole.
- 3. The process according to claim 1 wherein R.sub.2 is said naphthyl, alkyl, quinolyl, thiazolyl, furyl, thienyl, pyrazinyl or substituted phenyl group.
- 4. The process of claim 1 wherein 1,1-dibromo-3,3,3-trifluoroacetone is treated with sodium acetate trihydrate at 80.degree.-100.degree. C., and the resulting mixture is treated with 2,3,4-or 6- quinolinecarboxaldehyde and ammonia to afford the corresponding 2-(quinolyl)-4(5)-trifluoromethylimidazole.
- 5. The process of claim 1 wherein 1,1-dibromo-3,3,3-trifluoroacetone is treated with sodium acetate trihydrate at 80.degree.-100.degree. C., and the resulting mixture is treated with p-chlorobenzenecarboxaldehyde and ammonia to afford 2-(p-chlorophenyl)-4(5)-trifluoromethylimidazole.
- 6. The process of claim 1 wherein 1,1-dibromo-3,3,3-trifluoroacetone is treated with sodium acetate trihydrate at 80.degree.-100.degree. C, and the resulting mixture is treated with 4-thiazolecarboxaldehyde and ammonia to afford 2-(4-thiazolyl)-4(5)-trifluoromethylimidazole.
BACKGROUND OF THE INVENTION
This is a continuation of Ser. No. 610,903, filed Sept. 5, 1975, now abandoned, which in turn is a continuation-in-part of application Ser. No. 455,709, filed Mar. 28, 1974, now abandoned which in turn is a division of application Ser. No. 265,016, filed June 21, 1972 now U.S. Pat. No. 3,818,014, which in turn is a continuation-in-part of application Ser. No. 885,362 filed Dec. 15, 1969, now abandoned.
This invention relates to a class of chemical compounds which may be described as 4(5)-trifluoromethylimidazoles. These novel trifluoromethylimidazoles may be substituted in the 3 position by an alkyl group, an aryl group, or a heteroaryl group and in the 1 position by an alkyl group or an hydroxyalkyl group.
The herein-described 4(5)-trifluoromethylimidazoles 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 enxyme, 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-oxo-1-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-[3,4-d]-pyrimidine, a compound which is a structural isomer of hypoxanthine. Allopurinol acts as a specific inhibitor of the enxyme 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 the 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.
An object of this invention is to provide novel 4(5)-trifluoromethylimidazoles which are useful in the treatment of gout and hyperuricemia. A second object of this invention is to describe products which have utility as hypotensive agents and products which are useful in the treatment of bronchoconstriction.
Still another object of this invention is to describe a method for preparing the herein disclosed products as, for example, by reacting a 1,1-dihalo-3,3,3-trifluoroacetone with an appropriate carboxaldehyde and ammonia.
Also, included within this invention are the nontoxic pharmaceutically acceptable quaternary salts and alkali metal and alkaline earth metal salts of the 4(5)-trifluoromethylimidazoles, and those acid salts wherein the substituent in the 2 position is a heterocyclic ring containing at least one nitrogen atom.
US Referenced Citations (4)
| Number |
Name |
Date |
Kind |
|
3652579 |
Hofber et al. |
Mar 1972 |
|
|
3691178 |
Baldwin et al. |
Sep 1972 |
|
|
3786061 |
Novello et al. |
Jan 1974 |
|
|
3818014 |
Baldwin et al. |
Jun 1974 |
|
Divisions (1)
|
Number |
Date |
Country |
| Parent |
265016 |
Jun 1972 |
|
Continuations (1)
|
Number |
Date |
Country |
| Parent |
610903 |
Sep 1975 |
|
Continuation in Parts (1)
|
Number |
Date |
Country |
| Parent |
885362 |
Dec 1969 |
|
Patent Grant
4125530
