Claims
- 1. A process for reducing blood lipid levels in warm blooded animals which comprises administering an amount of a compound of the formula: ##STR9## wherein R is lower alkyl; R.sub.2 is hydrogen, hydroxy, lower alkoxy, or amino; R.sub.3 and R.sub.4 individually are lower alkyl, aryl, aralkyl or hydrogen; or a pharmaceutically acceptable salt thereof, in an amount effective for reducing blood lipid levels.
- 2. The process of claim 1 wherein said compound is: ##STR10## or a pharmaceutically acceptable salt thereof.
- 3. A method for reducing body fat in warm-blooded animals comprising administering a compound of the formula: ##STR11## wherein R is lower alkyl; R.sub.2 is hydrogen, hydroxy, lower alkoxy, or amino; R.sub.3 and R.sub.4, which may be the same or different, are lower alkyl, aryl, aralkyl, acyl and hydrogen; or a pharmaceutically acceptable salt thereof, in an amount which is effective as an antiobesity agent.
- 4. The method of claim 3 wherein the compound is ##STR12## or a pharmaceutically acceptable salt thereof.
- 5. The process of claim 2 wherein the compound is 4-amino-5-ethyl-3-thiophene carboxylic acid methyl ester.
- 6. The process of claim 2 wherein the pharmaceutically acceptable salt is 4-amino-5-ethyl-3-thiophene carboxylic acid methyl ester hydrochloride.
- 7. The process of claim 1 wherein the compound is 4-amino-5-ethyl-3-thiophene carboxylic acid.
- 8. The method of claim 4 wherein the compound is 4-amino-5-ethyl-3-thiophene carboxylic acid methyl ester.
- 9. The method of claim 4 wherein the pharmaceutically acceptable salt is 4-amino-5-ethyl-3-thiophene carboxylic acid methyl ester hydrochloride.
- 10. The method of claim 3 wherein the compound is 4-amino-5-ethyl-3-thiophene carboxylic acid.
CROSS REFERENCE TO RELATED APPLICATIONS
This is a divisional of application Ser. No. 318,779, filed Nov. 6, 1981, now abandoned, which in turn is a divisional of Ser. No. 111,637, filed Jan. 14, 1980, now U.S. Pat. No. 4,317,915, which in turn is a continuation-in-part application of Ser. No. 889,459, filed Mar. 23, 1978, now abandoned, which in turn is a continuation-in-part application of Ser. No. 820,521, filed Aug. 1, 1977, now abandoned, which in turn is a continuation-in-part application of Ser. No. 716,853, filed Aug. 23, 1976, now abandoned.
This invention is directed to compounds of the formula: ##STR1## wherein R is lower alkyl; R.sub.2 is hydrogen, hydroxy, lower alkoxy, or amino; R.sub.3 and R.sub.4, which may be the same or different, are lower alkyl, aryl, aralkyl, acyl and hydrogen; or a pharmaceutically acceptable salt thereof.
The compounds are useful as blood lipid lowering agents and as antiobesity agents.
Usage of the compounds within the scope of formula I has resulted in significant lowering of lipid levels and reduction in body weight of warm-blooded animals.
Atherosclerosis, a form of arteriosclerosis, is characterized by internal thickening of the major blood vessels due to localized accumulation of lipids, of which cholesterol and triglycerides, comprise the major constituents. Furthermore, it has been found that those suffering from the disease exhibit abnormally high blood cholesterol levels. While the etiology of the disease is not fully understood, it is believed that cholesterol plays an important role. A high level of blood triglycerides is also a risk factor for atherosclerosis. (The Heritable Hypoliproteinemias and Atherosclerosis, C. J. Glueck and R. W. Fallat, Lipids, Lipoproteins and Drugs, pp. 169-183 and 305-316, Plenum Press, 1975.
In the advanced stages of the disease, plaques, comprising cholesterol and other .beta.-lipoproteins, accumuate in the aorta coronary, cerebral, and peripheral arteries of the lower extremities. As these plaques increase in size the danger of fibrin deposition, possibly resulting in thrombosis and occlusion, is enhanced.
While no sure method has been found for preventing the disease, it has been recommended that dietary habits be observed that will insure low .beta.-lipoprotein levels. Besides stringent dietary management, various therapeutic agents such as estrogens, thyroxine analogs and sitosterol preparations have been used to lower the cholesterol levels of those afflicted with the condition.
It has now been found that various thiophene derivatives are effective hypolipemic agents because of their ability to lower the blood lipid level of warm blooded animals. Consequently, these compounds can be expected to be useful in the treatment of atherosclerosis and related cardiovascular diseases which are associated with elevated blood lipid levels.
Obesity represents a state of increased body fat which may decrease longevity, aggravate the onset and progression of other diseases, (e.g., heart disease, diabetes, gallstones) and impact on one's social or economic status. (The Obese Patient, G. A. Bray, Vol. IX in the series "Major Problems in Internal Medicine", W. B. Saunders Co., 1976.)
It has also been found that the thiophene compounds of the invention selectively reduce body fat by suppressing its biosynthesis and thus are useful in the treatment of obesity.
As used throughout this application, the term "lower alkyl" denotes straight and branched chain, saturated aliphatic alkyl groups having from 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl and the like. The term "lower alkoxy" denotes saturated straight or branched chain alkoxy groups having from 1 to 8 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy and the like. The term "halogen" includes all four halogens, i.e., chlorine, bromine, iodine, and fluorine. The term "acyl" refers to acyl groups having attached thereto lower alkyl, aryl, aralkyl and alkoxy moieties. Typical acyl groups include benzoyl, acetyl, propionyl, carbomethoxy and the like. The term "aryl" denotes mono-nuclear aryl groups such as unsubstituted or substituted phenyl, said substitutions being in one or more positions and selected from lower alkyl, trihalomethyl, such as trifluoro and trichloro methyl, aralkyl, halogen, lower alkoxy, amino, nitro, mono and di-lower alkylamino. The term "amino" as used herein includes unsubstituted and substituted amino groups wherein said substituents may be lower alkyl, acyl, aryl or aralkyl. The term "alkali metal" denotes metals such as sodium, potassium, lithium and the like. The term "alkanol" as used herein, denotes straight or branched chain alcohols having 1-20 carbon atoms. The term "lower alkanols" denotes alkanols having 1-6 carbon atoms. The term "alkoxide" as used herein, refers to metal salts, preferably alkali and alkaline earth metal salts of alkanols. The term "alkaline earth metal" refers to calcium, barium, magnesium and the like. The term "aralkyl" connotes groups wherein aryl and lower alkyl are as described above.
In accordance with this invention, the thiophene of formula I is obtained by initially reacting a compound of the formula: ##STR2## with a compound of the formula: ##STR3## to form a compound of the formula: ##STR4## wherein R is as previously defined, R.sub.1 is lower alkyl, R'.sub.2 is lower alkoxy and R.sub.8 is halogen, mesyloxy and tosyloxy.
The foregoing reaction is carried out in the presence of a lower alkanol and an alkali metal alkoxide, preferably methanol and sodium methoxide. Although temperature and pressure are not critical, this reaction is generally carried out at atmospheric pressure and temperature of from about 15.degree. C. to about 60.degree. C., preferably 25.degree. C.
Compound IV is then treated with an alkali metal alkoxide, preferably sodium methoxide in the presence of an aromatic hydrocarbon, preferably benzene to form a compound of the formula: ##STR5## wherein R and R'.sub.2 are as defined above. Although temperatures and pressures are not critical, this reaction is generally carried out at atmospheric pressure and a temperature of from about 15.degree. C. to about 60.degree. C., preferably 25.degree. C.
Compound V is then transformed to an oxime of the formula: ##STR6## wherein R and R'.sub.2 are as defined above. Any conventional method of preparing an oxime from a keto compound can be used to convert the 4,5-dihydrothiophene of formula V to the oxime of formula VI. Preferably, the 4,5-dihydrothiophene of formula V is treated with a hydroxylamine hydrohalide, preferably hydroxylamine hydrochloride, in a nitrogen-containing base. In carrying out this reaction, any conventional nitrogen-containing base can be utilized. The preferred nitrogen-containing bases are the amines. Among the amines which can be utilized are the primary amines, such as the loweralkylamines, particularly methylamine, ethylamine, and aniline; the secondary amines, such as the diloweralkylamines, particularly dimethylamine and diethylamine, and pyrrole; and the tertiary amines, such as the triloweralkylamines, particularly trimethylamine and triethylamine, pyridine and picoline. Also, in carrying out this reaction with a hydroxylamine hydrohalide, temperature and pressure are not critical, and the reaction can be suitably carried out at from room temperature to reflux and at atmospheric pressure. Preferably, this reaction is carried out at room temperature (about 22.degree. C.). Further, this reaction can be carried out in an inert organic solvent. In this reaction any conventional inert organic solvent can be utilized, such as the aliphatic or aromatic hydrocarbons, as for example n-hexane or benzene. Preferably, this reaction is carried out in an excess of the nitrogen-containing base, which serves as the solvent medium.
The oxime of formula VI is converted to an amine of the formula: ##STR7## wherein R and R'.sub.2 are as above, R.sub.3 and R.sub.4 are hydrogen. This reaction is suitably carried out by treating the oxime of formula VI with an acid, preferably a hydrohalide, in an inert, organic solvent under substantially anhydrous conditions. This reaction can be carried out preferably by treating the oxime of formula VI with hydrogen chloride. In carrying out this reaction, any conventional inert organic solvent can be utilized. The preferred inert organic solvents are the ethers, particularly the dilower alkyl ethers, such as diethyl ether, and the cyclic ethers, such as tetrahydrofuran and dioxane. In carrying out this reaction, temperature and pressure are not critical, and this reaction can be suitably carried out at from 0.degree. C. to about 70.degree. C. and at atmospheric pressure. Preferably, this reaction is carried out at room temperature. Where it is desired that R.sub.3 and/or R.sub.4 be lower alkyl or lower acyl, these moieties may be introduced by conventional procedures for converting an aromatic primary amine to N-alkyl and N-acyl derivatives. For example, treatment of compound VII with a carboxylic acid anhydride or halide in the presence of base affords the corresponding N-acyl derivatives of compound VII. The N-acyl derivatives then may be reduced preferably with a hydride reducing agent such as diborane and an inert solvent such as ether (e.g., tetrahydrofuran). Such reductions afford the N-alkyl derivatives of compound VII.
Typical carboxylic acid anhydrides and halides are acidic anhydride, acetyl chloride and benzoyl chloride. Suitable bases illustratively include organic tertiary amines such as pyridine and triethylamine.
Compound VII, where R'.sub.2 is lower alkoxy, may then be converted to a compound of the formula: ##STR8## wherein R, R.sub.3 and R.sub.4 are as previously defined. In carrying out this reaction, any conventional method of basic hydrolysis can be utilized. This hydrolysis can be suitably carried out in a conventional inert organic solvent. The preferred solvents are the lower alkanols, particularly methanol and ethanol, and the aqueous ether solvents, preferably the aqueous dilower alkyl ethers, particularly diethyl ether, and the aqueous cyclic ethers, particularly tetrahydrofuran and dioxane. In this reaction, any conventional base can be utilized. Among the preferred bases are the alkali metal hydroxides, such as sodium, potassium and lithium hydroxide, and the alkaline earth metal hydroxides, such as barium, calcium and magnesium hydroxide, especially the alkali metal hydroxides. In this hydrolysis, temperature and pressure are not critical, and this reaction can be suitably carried out at from about 0.degree. C. to about 100.degree. C. and at atmospheric pressure. Preferably, this reaction is carried out at reflux, especially at about 70.degree. C.
Compound VII and/or compound VIII may be transformed to its corresponding aldehydes, amides or esters by conventional methods for converting esters or acids to the aforementioned compounds.
For example, treatment of compound VIII with a lower alkanol (e.g., methanol, ethanol and isopropyl) or arylalkanol (e.g., benzyl alcohol) in the presence of an acid catalyst (Fisher esterification) affords corresponding lower alkyl or arylalkyl esters of formula VII.
Suitable acid catalyst include hydrogen halides, preferably hydrogen chloride. The above reaction may occur within an approximate temperature range of 60.degree. to 150.degree. C. but is preferably carried out at the boiling point of the alcohol which is utilized.
As previously mentioned, the herein described thiophene derivatives as well as their pharmaceutically acceptable salts, lower alkyl esters and amides, are effective hypolipidemic agents, i.e., they lower the blood lipid level of mammals. This property has been dramatically demonstrated in rats, groups, each comprising animals, of normal female Charles River rats weighing from 150-180 g. are first fed a corn oil-glucose mixture for several days and then dosed with typical compounds disclosed herein in gum arabic or water either orally or parenterally. The mechanism by which the thiophene derivatives lower body weight (antiobesity activity) and blood lipids (hypolipidemic activity) appears to be through inhibition of lipid synthesis. Potent inhibition by the compounds disclosed herein of fatty acid and cholesterol synthesis was demonstrated in rat hepatocytes in vitro and in rat liver in vivo (see below, Tables I, II, IV, V and VI). Lowered blood lipid levels were the result of decreased biosynthesis. Blood cholesterol (Table VII) and triglyceride levels (Table III and Table VII) were reduced significantly by the oral or parenteral of these compounds.
The compounds described herein can be administered parenterally as well as orally. For purposes of parenteral administration, solutions and suspensions of the herein described compounds in water or gum arabic can be employed. Of particular suitability are sterile aqueous solutions of the corresponding water-soluble salts previously described. These dosage forms are especially suitable for peritoneal injection purposes. The aqueous solutions, including those of the salts dissolved in pure distilled water, are additionally useful for intravenous injection purposes provided that their pH be properly adjusted beforehand. Such solutions should also be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. In this connection, the sterile aqueous media employed are readily obtained by standard techniques well known to those in the art. For instance, distilled water is ordinarily used as the liquid diluent.
The dosage required to lower the blood lipid level will be determined by the nature and the extent of the symptoms. Generally, small dosages will be administered initially with a gradual increase in dosage until the optimum leel is determined. It will generally be found that when the composition is administered orally, larger quantities of the active ingredient will be required to produce the same level as produced by a smaller quantity administered parenterally. In general, from about 0.1 to 200 mg. of active ingredient per kilogram of body weight administered in single or multiple dosage units significantly lowers the blood lipid level or body fat level.
As previously mentioned, the compounds disclosed and claimed herein are also useful as antiobesity agents. This property has been dramatically demonstrated in high fat fed Charles River rats. Groups of 10 rats were fed ad libitum a 10% corn oil, 60% glucose diet in accordance with the methodology described in Sullivan et al., Am. J. Clin. Nutr. 30:767-776 (1977). The effect of 4-amino-5-ethyl-3-thiophene carboxylic acid methyl ester hydrochloride on body weight, total body fat and protein was determined. The results are tabulated in Example 35 (Table VIII and Table IX) of the specification.
Table VIII demonstrates that the above compound significantly reduces body weight gain in high fat fed rats. Table IX illustrates that the decreased weight gain resulting from the compound is caused by selective reductions in carcass fat of the high fat fed rats. The data illustrates the dramatic antiobesity activity of the inventive thiophenes.
The dosage required for antiobesity activity is determined by the nature and the extent of obesity. Generally, small dosages will be administered initially with a gradual increase in dosage until the optimum level is determined. In general, from about 0.1 to 200 mg. of active ingredient per kilogram of body weight administered in single or multiple dosage units significantly lowers body weight. The preferred daily dose of active ingredient is 0.1 to 20 mg. per kilogram of body weight administered in single or multiple dose units.
The following non-limiting examples further illustrate this invention. All temperatures are in degrees Centigrade and the ether used is diethyl ether.
US Referenced Citations (15)
Foreign Referenced Citations (5)
| Number |
Date |
Country |
| 574279 |
Dec 1945 |
GBX |
| 608969 |
Sep 1948 |
GBX |
| 837086 |
Jun 1960 |
GBX |
| 1133850 |
Nov 1965 |
GBX |
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GBX |
Non-Patent Literature Citations (2)
| Entry |
| Baker et al., Jour. Org. Chem., vol. 18, pp. 138-152 (1953) Particularly pp. 138-139 and 145 (Compounds IV and VII). |
| Arzneim. Forsch., vol. 22, pp. 2146-2147 (1972) (English Language Summary at p. 2147, bottom of column). |
Divisions (2)
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Number |
Date |
Country |
| Parent |
318779 |
Nov 1981 |
|
| Parent |
111637 |
Jan 1980 |
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Continuation in Parts (3)
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Number |
Date |
Country |
| Parent |
889459 |
Mar 1978 |
|
| Parent |
820521 |
Aug 1977 |
|
| Parent |
716853 |
Aug 1976 |
|
Patent Grant
4428963
