CA1111855A - Substituted thiophenes - Google Patents

Abstract

ABSTRACT

The invention relates to compounds of the formula I

wherein R1 is lower alkyl; R2 is hydroxy or lower alkoxy; R3 and R4, which may be the same or different, are lower alkyl or hydrogen; and the pharma-ceutically acceptable salts thereof, as well as to a process for the prepar-ation thereof. These compounds and salts have plasma lipid level lowering properties.

Description

1~18S5 This invention is directed to a process for preparing novel com-pounds of the formula: R3 O ~ \ R4 S Rl wherein Rl is lower alkyl; R2 is hydroxy or lower alkoxy; R3 and R4, which may be the same or different, are lower alkyl or hydrogen; and the pharma-ceutically acceptable salts thereof.
The invention also relates to a process for the production of compounds of Formula I as defined above which compri.ses treating a compound of the formula:

~ ~ VI
S \Rl wherein Rl is as above and R2 is lower alkoxy, with an acid and, if desired, reacting the amino group contained in the obtained product with an alkylating agent, and, if desired, hydrolyzing an obtained ester in the presence of a base and converting an obtained compound into a pharmaceutically acceptable salt.
Usage of the compounds within the scope of Formula I has resulted in si.gnificant lowering of lipid levels in the blood of warm-blooded animals.
Background of the Invention Atherosclerosis, a form of arteriosclerosis, is characterized by internal thickening of the major blood vessels due to localized accumulati.on of lipids, of which cholesterol and other ~-lipoproteins, such as triglycer-ides, comprise the major constituents. Furthermore, it has been ~.ound that those suffering from the disease exhibit abnorma]ly high blood cholesterol -1- ~
~.

levels, While the etiology of the disease is not fully understood, it is believed that ~-lipoproteins, in particular cholesterol, play an important role.
In the advanced stages of the disease, plaques, comprising chc-lesterol and other ~-lipoproteins, accumulate in the aorta, coronary, cere-bral, and peripheral arteries of the lower extremities. As these plaques increase in size the danger of fibrin deposition, possibly resulting in throm-bosis 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 ensure low ~-lipoprotein levels. Besides stringent dietary management, various thera-peutic 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 ef-fective 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.
Detailed ~escription of the In~ention As used throughout this application, the term "lower alkyl" de-notes 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, pro-poxy, isopropoxy and the like. The term "halogen" includes all four halogens, i.e., chlorine, bromine, iodine, and fluorine. The term "alkali metal" de-notes sodium, potassium and lithium. The term "alkoxide" as used herein, re-fers to metal salts, preferably alkali and alkaline earth metal salts of al-kanols. The term "alkaline earth metal" refers to calcium, barium and mag-nesium.
The thiophene of Formula I can be obtained by reacting a compound of the formula:
~0 \ R' with a compound of the formula: 2 ~ C - CH - Rl III

to form a compound of the formula:
COR'2 fO2R

~ S ~ Rl IV

wherein Rl is as previously defined, R is lower alkyl, R'2 is lower alkoxy and R8 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 meth-oxide. Although temperature and pressure are not critical, this reaction is generally carried out at atmospheric pressure and temperature of from about 15C. to about 60 C., preferably 25 C.
Compound IV is then treated with an alkali metal alkoxide, pre-ferably sodium methoxide in the presence of an aromatic hydrocarbon, prefer-ably benzene to form a compound of the formula:

R'20C O
\~ V
S--Rl wherein Rl and R'2 are as defined above. Although temperatures and pressures are not critical, this reaction is generally carried out at atmospheric pres-sure and a temperature of from about 15C. to about 60C., preferably 25C.
Compound V is then transformed to an oxime of the formula:

R'20C NOH

¦ 1 VI

~ S/'\ Rl wherein Rl and R'2 are as defined above. Any conventional method of prepar-ing an oxime from a keto compound can be used to convert the 4,5-dihydrothio-phene of Formula V to the oxime of Formula VI. Preferably, the 4,5-dihydro-thiophene of Formula V is treated with a hydroxylamine hydrohalide, prefer-ably 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 low¢raIkyamines, 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 triloweralkyalamines, particu-larly trimethylamine and triethylamine, pyridine and picoline. Also, in car-rying 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 22C.). Further, this re-action can be carried out in an inert organic solvent. In this reaction any conventional inert organic solvent can be utilizcd, 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 solven~ medium.
The oxime of ~ormula VI is converted to an amine of the formula:

~.

~111855 R'20C N
\ / \
~ ~ \ R4 VII

S Rl wherein Rl and R'2 are as above, R3 and R4 are hydrogen. This rçaction is suitably carried out by treating the oxime of Formula VI with an acid, pre-ferably a hydrohalide, in an inert, organic solvent under substantially an-hydrous conditions. This reaction can be carried out preferably by treating the oxime of Formula VI with hydrogen chloride. In carrying out this reac-tion, 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 ~his reaction can be suitably carried out at from 0C. to about 70C. and at atmospheric pressure. Preferably, this reaction is carried out at room temperature. Where it is desired that R3 and/or R4 be lower alkyl, this moiety may be introduced by conventional procedures for converting an aromatic primary amine to the N-alkyl derivative. Compound VII may be trans-formed to the corresponding acid or other esters by conventional methods for converting esters to the aforementioned compounds.
Compound VII, where R2 is lower alkoxy, may then be converted to a compound of the formula:

2 ~ N

~ ~ R4 VIII

S \ Rl wherein Rl, R3 and R4 are as previously defined. In carrying out this reac-tion, any conventional method of basic hydrolysis can be utilized. This hy-drolysis can be suitably carried out in a conventional inert organic solvent.

. -5-~111855 The preferred solvents are the lower alkanols, particularly methanol and eth-anol, and the aqueous ether solvents, preferably the aqueous dilower alkyl ethers, particularly diethy] ether, and the aqueous cyclic ethers, particular-ly 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 hy-droxides, such as barium, calcium and magnesium hydroxides, especially the alkali metal hydroxides. In this hydrolysis, temperature and pressure are not critical, and this reaction can be suitab]y carried out at from about 0C. to about 100C. and at atmospheric pressure. Preferably, this reaction is carried out at reflux, especially at about 70C.
As previously mentioned, the herein described thiophene deriva-tives as well as their pharmaceutically acceptable salts, lower alkyl esters and amides, are effective hypolipedemic agents, i.e., they lower the blood lipid level of mammals. This property has been demonstrated in female Charles River rats weighing from lS0-1~0 g. The animals are first fed a corn oil-glucose mixture for several days and then dosed with typical compounds dis-closed herein in dimethylsulfoxide (DMS0) either orally or parenterally. The activity of typical compounds disclosed herein on fatty acid and cholesterol synthesis on isolated rat hepatocytes were also determined.
Comparison of the blood triglyceride levels of rats receiving the test compounds shows a significant reduction as compared to the triglyceride levels of untreated animals. Similar resu]ts were obtained in the case of the rat hep atocytes.
The compounds described herein can be administered parenterally as well as orally. ~or purposes of parenteral administration, solutions and suspensions of the herein described compounds in DMS0, water or gum arabic can be employed. Of particular suitability are sterile a~ueous solutions of the corresponding water-soluble salts previously described. These dosage forms are especially suitable for peritoneal injection purposes. The a-~ueous solutions, including those of the salts dissolved in pure distilled water, are additionally useful for intravenous injection purposes provided that -6a-F~

their pH be properly adjusted beforehand. Such solutions should also be suitable 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 level 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 1.2 mg. of active ingredient per kilogram of body weight administered in single or multiple dosage units significantly lowers the blood lipid level.
The compounds disclosed and claimed herein are also potentially useful as antiobesity agents.
The following non-limiting examples further illustrate this invention. All temperatures are in degrees Centigrade and the ether used is diethyl ether.
Example 1 A solution of 116.S5 g (.971 mole) of methyl-3-mereaptopropionate in 220 ml of dry methanol at -20 was treated with 52.46 g (.971 mole) of sodium methoxide. After 20 minutes, a solution of 203.0 g (.971 mole) of ethyl-2-bromovalerate in 150 g of dry methanol was added dropwise. The reaction was allowed to warm to room temperature and stirred overnight.
The methanol was evaporated and the residue was partitioned between ether/
water. The organic phase was washed with 10% bicarbonate solution and water.
After drying over magnesium sulfate, theether was evaporated to yield 130 g 8S~

( 524 mole, 54%) of methyl-4-thia-5-carbomethoxyoctanoate as a colorless oil.
Example 2 To a suspension of 54.0 g (1.0 mole) of sodium methoxide in 500 ml of anhydrous benzene was added dropwise at 25, 130 g (.524 mole) of methyl-4-thia-5-carbomethoxyoctanoate. The mixture was stirred over-night and poured into ice-water. The aqueous phase was extracted with benzene/ether, 1:1, and then acidified to pH 1 with 6N HCl. The product, which partially separates from the water at this point, is taken up in methylene chloride. The aqueous layer is further extracted with methylene chloride. The combined organic phases are dried and evaporated to yield 94.0 g (.466 mole, 89%) of pure 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene as a colorless oil.
Example 3 A solution of 94.0 g (.465 mole) of 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene in 250 ml of dry pyridine was treated with 40.0 (.576 mole) of hydroxylamine hydrochloride at 25. The reaction was stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between lN HCl and methylene chloride. The organic phase was dried over sodium sulfate and evaporated to afford 100 g (.461 mole, 99%) of pure 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene oxime as a colorless oil.
Example 4 Gaseous hydrogen chloride was bubbled into one liter of anhydrous ether in which 100.0 g (.461 mole) of 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene oxime had been dissolved. lhis process was carried out at 0 for one hour. The reaction flask was stoppered with a drying tube and allowed to stir at room temperature overnight. The solvent was evaporated until the product crystallized. The white solid was collected by filtration and washed well with ether to afford 60.0 g .~

(.255 mole, 55%~ of 3-amino-4-carbomethoxy-2-N-propylthiophene hydrochloride, m.p. 178-180. The product was recrystallized from methanol/ether to yield 50.0 g (.212 mole, 46%) of pure 3-amino-4-carbomethoxy-2-n-propylthiophene hydrochloride, m.p. 180-181.
Example 5 Fatty Acid and Cholesterol Synthesis in Isolated Hepatocytes Female Charles River rats are fasted 48 hours, then meal-fed a 1% corn oil, 70% glucose diet for 7 to 14 days from 8-11 a.m. The isolated rat hepatocytes are prepared by perfusing the liver in situ.
The hepatocytes are incubated in an oscillating water bath at 37C. for 60 minutes. Each flask contains a total of 2.1 ml volume, consisting of 1 ml isolated rat hepatocytes (10-20 mg dry weight cells), 1 ml Krebs-Henseleit bicarbonate buffer pH 7.4, 16.5 mM glucose, 1 ~mole L-alanine, 1 ~Ci rU-14C]alanine 1 mCi H20, and 2 mM inhibitor in H20 or DMS0 at pH 7.4 (unless otherwise specified). All incubations are done in triplicate and all experiments are repeated at least twice. C02 is collected in each flask following the 60 minutes incubation by adding 0.3 ml ethanolamine:
2-methoxy-ethanol (1:2) to the center well, 0.4 ml of 62.5% citric acid to the cell media, and incubating for 45 minutes. The contents of the center well are transferred to scintillation counting fluid and 14C02 content is determined. The media is saponified, acidified (only for determining the rate of lipogenesis) and extracted with hexane. At this stage the lipids are either counted (to determine the rate of lipogenesis~ or precipitated with digitonin, washed, and counted (to determine the rate of cholestero-genesis). The conversion of 3H20 and L14C]alanine into fatty acids or sterols is determined in a PDS/3, Mar~ II liquid scintillation counting system. Data are expressed as nmoles 3H20 and [14C]alanine converted into fatty acids or cholesterol, and nmoles [14CIalanine oxidized to C02 per mg dry weight cells per 60 minutes. The results are set forth in Table I.

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1~11855 Example 6 Fatty Acid and Cholesterol Synthesis In Vivo Rats are prepared by fasting 48 hours and refeeding a 1% corn oil 70% glucose diet for several days (5-15). On the experimental day, rats are dosed 30 or 60 minutes before the 3 hour meal by oral intubation, or 60 minutes after the end of the 3 hour meal by intraperitoneal injection. ~The dose concentrated is in mmoles/kg/5-10 ml ~2 or 1% gum arabic depending on the solubility of the compound). Rats are sacrificed by decapitation after a 30 minute pulse consisting of: 1 mCi 3H20, 5 ~Ci [U-14C]alanine, 12.3 mg alanine, and 30.6 mg ~-ketoglutaric acid in 0.25 ml saline, given at the end of the 3 hour meal by i.v. injection into the tail vein. The livers are quickly excised, saponified, and acidified (only for determining the rate of lipogenesis~ and extracted with hexane. At this stage the lipids are either counted (to determine the rate of lipogenesis) or precipitated with digitonin, washed, and counted (to determine the rate of cholesterogenesis).
The conversion of 3H20 and [14C]alanine into fatty acids or sterols is determined in a PDS/3, Mark II liquid scintillation countin~ system. Data are expressed as ~moles 3H20 nmoles converted into fatty acids and cholesterol per g liver per 30 minutes. The results are set forth in Tables II-IV.

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Example 7 ~ ~
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A solution of 66.29 g. (.552 mole) methyl-3-mercapto~
propionate in 50 ml. anhydrous methanol was cooled to 0 and treated with 120 ml. of a 25% solution of sodium methoxide in methanol. To this ~- ~
solution was added dropwise 100 g. (.552 mole~ of ethyl-2-bromopropionate ;
in 100 ml. anhydrous methanol. The reaction was allowed to proceed at 25 overnight. The solvent was evaporated, and the residue was partitioned between ether and 10% sodium bicarbonate. The aqueous phase was further extracted with ether. The combined organic extracts were dried over magnesium sulfate and evaporated to yield 121.40 g. (100%) of 2-methyl-3-thia-1,6-hexanedionic acid-1-ethyl-6-methyl ester as a pale yellow oil. -.~ . .
Similarly, 61.4 g. (.Sl mole) of methyl-3-mercaptopropionate was 1 combined with 106.8 g. (.51 mole) of ethyl-2-bromovalerate to yield 120.91 g.
f. (96%) of 2-isopropyl-3-thia-1,6-hexanedionic acid-1-ethyl-6-methyl ester.
Example 8 A solution of 121.4 g. (.552 mole) of 2-methyl-3-thia-1,6-hexanedioic acid-l-ethyl-6-methyl ester in 90 ml. dry benzene uas added ,., 'i dropwise to a suspension of 30 g. anhydrous sodium methoxide in 200 ml. dry s~ benzene. The reaction was allowed to proceed overnight. The mixture was partitioned between water/ether. The aqueous phase was further extracted r. with benzene. The aqueous phase was then acidified to pH 1 with 6N HCl and extracted three times with methylene chloride. The methylene chloride extracts were combined, dried over sodium sulfate, and evaporated to afford 79.17 g. (82%) of pure4-carbomethoxy~3-keto-2-methyltetrahydrothiophene as a colorless oil.
Similarly, 120.91 g. of 2-isopropyl-3-thia-1,6-hexanedionic acid-l-ethyl-6-methyl ester was converted to 91.0 g. (93%) of 4-carbomethoxy-2-isopropyl-3-keto-tetrahydrothiophene.
Example 9 A solution of 37.26 g. (.214 mole) of 4-carbomethoxy-3-keto-~111855 2-methyltetrahydrothiophene in 100 ml. anhydrous pyridine was treated with 18.0 g. (0.261 mole) hydroxylamine hydrochloride. The Mixture was stirred 24 hours at 25. The reaction was concentrated and partitioned between lN
hydrochloric acid/methylene chloride. The aqueous phase was extracted two times with methylene chloride. The combined organic extracts were dried and evaporated to yield 40.1 g (99%) of pure 4-carbomethoxy-3-keto-2-methyl-tetrahydrothiophene oxime as a colorless oil.
Similarly, 52.8 g. (0.26 mole) of 4-carbomethoxy-2-isopropyl-

3-keto-tetrahydrothiophene was converted to 49.0 g. (.226 mole) (87%) of

4-carbomethoxy-2-isopropyl-3-keto-tetrahydrothiophene oxime.
Example 10 A solution of 41.1 g. (.217 mole) of 4-carbomethoxy-3-keto-2-methltetrahydrothiophene oxime in 600 ml. anhydrous ether, previously saturated with gaseous hydrogen chloride at 0, was allowed to stir at 25 overnight. The separated solid was collected, washed well with ether, and dried to afford 33.2 g. Evaporation of the filtrated yielded after recrystallization of the residue an additional 4.2 g. to afford a total yield of pure 3-amino-4-carbomethoxy-2-methylthiophene hydrochloride of 37.4 g. (84%). The compound melts 191-192.
Similarly, 49.12 g. (.226 mole) of 4-carbomethoxy-2-isopropyl-3-keto-tetrahydrothiophene was converted to 18.49 g. (35%) of 3-amino-4-carbomethoxy-2-isopropylthiphene hydrochloride, m.p. 185 Idec.) Example 11 A solution of 2.07 g (.010 mole) of 3-amino-4-carbomethoxy-2-methylthiophene hydrochloride in 35 ml. methanol was treated with 23 ml.
lN sodium hydroxide. The mixture was heated under reflux 0.5 hour, cooled, and poured into brine. The pH was adjusted to 5 and extracted seven times with methylene chloride/methanol, 4:1. The organic extracts were combined, dried, and evaporated to yield 1.23 g. (78%) of pure 3-amino-4-carboxy-2-methylthiophene, m.p. 162-164. The compound was recrystallized from ethyl ~1~18SS

acetate/pentane to afford an analytical sample, m.p. 163-164 .
Similarly, 5.0 g.(9.021 mole) of 3-amino-4-carbomethoxy-2-isopro-pylthiophene hydrochloride was converted into 3.3 g. (84%) of 3-amino-4-car-boxy-2-isopropylthiophene, m.p. 117-118.
Similarly, 1.41 g. (.00708 mole) 3-amino-4-carbomethoxy-2-propyl-thiophene hydrochloride was converted into 0.625 g. (48%) of 3-amino-4-car-boxy-2-propylthiophene, m.p. 144-145.
~xample 12 Preparation of 4-amino-5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride.
To a solution of 125 g of methyl-3-mercapto-propionate in 75 ml of dry methanol was added dropwise at 0 249 ml of 25% sodium methoxide/meth-anol. The resulting mixture was treated dropwise at 0 with 200 g of ethyl-2-bromobutyrate in 75 ml of dry methanol. The cooling bath was removed and the reaction stirred overnight at 25. The mixture was concentrated and part-itioned between water and methylene chloride. The organic extracts were dried and evaporated to yield 229 g of diester as a colorless oil.
To a suspension of 63.5 g of sodium methoxide in 300 ml of dry benzene was added dropwise at 25 229 g of said diester in 200 ml of dry ben-zene. After stirring overnight at room temperature, the reaction was pouredinto 800 ml of water and the benzene layer was further extracted with ~111855 200 ml of water. The aqueous phases were combined, carefully acidified with 6N HCl and extracted three times with methylene chloride/methanol,

5:1. The organic extracts were dried and evaporated to afford 149.7 g of pure ketone as a colorless oil.
To a solution of 276.1 g of said ketone in 500 ml of anhydrous pyridine was added in several portions 121.6 g of hydroxylamine hydrochloride.
The reaction was allowed to proceed for 20 hours at 25, concentrated and partitioned between methylene chloride/3N HCl. The aqueous phase was backwashed two times with methylene chloride/methanol 5:1. The organic phaseswere dried and evaporated to afford 253 g (82%) of pure oxime as a pale yellow oil.
A solution of 253 g of said oxime in 2 1 of anhydrous ether was treated at 25 with a stream of gaseous hydrogen chloride for one hour. The reaction was seeded with 0.5 g of authentic product and stirred overnight at 25. The crude product was filtered, washed with anhydrous ether and recrystallized from methanol/ether to afford 173 g of pure amino thiophene hydrochloride, m.p. 161 .
The following examples illustrated pharmaceutical compositions containing 3-amino-4-carbomethoxy-2-n-propylthiophene hydrochloride (active compound~.
Example 13 Capsule Formulation Per Capsule Active compound 10 mg Lactose, U.S.P. 165 mg Carn Starch, U.S.P. 30 mg Talc, U.S.P. 5 mg Total Weight 210 mg 11111~55 Procedure 1. Active compound, lactose and corn starch were mixed in a suitable mixer.
2. The mixture was further blended by passing through a Fitzpatrick Comminuting ~achine with a lA screen with knives forward.
3. The blended powder was returned to the mixer, the talc added and blended thoroughly.
4. The mixture was filled into 4 hard shell gelatin capsules on a Parke Davis capsulating machine. (Any similar type capsulating machine may be used).
Example 14 Capsule Formulation Per Capsule Active compound 50 mg Lactose, U.S.P. 125 mg Corn Starch, U.S.P. 30 mg Talc, U.S.P. 5 mg Total Weight 210 mg Procedure 201. Active compound was mixed with lactose and corn starch in a suitable mixer.
2. The mixture was further blended by passing through a Fitzpatrick Comminuting Machine with a lA screen with knives forward.
3. The blended powder was returned to the mixer, the talc added and blended thoroughly.
4. The m~xture was filled into 4 hard shell gelatin capsules on a Parke Davis capsulating machine.

~' Example 15 Tablet Formulation Per Tablet Active compound 25.00 mg Dicalcium Phosphate Dihydrate, Unmilled 175.00 mg Corn Starch 24.00 mg Magnesium Stearate 1.00 mg Total Weight 225.00 mg Procedure 1. Active compound and corn starch were mixed together and passed through an 00 screen in Model "J" Fitzmill with hammers forward.
2. This premix was then mixed with dicalcium phosphate and one-half of the magnesium stearate, passed through a lA screen in Model "J" Fitzmill and knives forward, and slugged.
3. The slugs were passed through a 2A plate in a Model "D"
Fitzmill at slow speed with knives forward, and the remaining magnesium stearate was added.
4. The mixture was mixed and compressed.
Example 16 Tablet Formulation Per Tablet Active compound 100 mg Lactose, U.S.P. 202 mg Corn Starch, ll.S.P. 80 mg Amijel B011* 20 mg Calcium Stearate 8 mg Total Weight 410 mg A prehydrolyzed food grade corn starch. Any similar prehydrolyzed corn starch may be used.

Procedure 1. Active compound, lactose, corn starch, and Amijel B011 were blended in a suitable mixer.
2. The mixture was granulated to a heavy paste with water and the moist mass was passed through a 12 screen. It was then dried overnight at 110F.
3. The dried granules were passed through a 16 screen and transferred to a suitable mixer. The calcium stearate was added and mixed until uniform.
4. The mixture was compressed at a tablet weight of 410 mg, using tablet punches having a diameter of approximately three-eight inch.
(Tablets may be either flat or biconvex and may be scored if desired).

Claims (16)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the formula:

I

wherein R1 is lower alkyl; R2 is hydroxy or lower alkoxy; R3 and R4, which may be the same or different, are lower alkyl or hydrogen; and the pharmaceutically acceptable salts thereof, which comprises treating a com-pound of the formula:

VI

wherein R1 is as above and R2 is lower alkoxy, with an acid and, if desired, reacting the amino group contained in the obtained product with an alkylating agent, and, if desired, hydrolyzing an obtained ester in the presence of a base and converting an obtained compound into a pharmaceutically acceptable salt.

2. A process as in claim 1, wherein 4-amino-5-ethyl-3-thiophene-carboxylic acid methyl ester hydrochloride is prepared from 4-carbomethoxy-3-keto-2-ethyltetrahydrothiophene oxime.

3. A process as in claim 1, wherein 4-amino-5-ethyl-3-thiophene-carboxylic acid is prepared by hydrolyzing 4-amino-5-ethyl-3-thiophene-carboxylic acid methyl ester hydrochloride.

4. A process as in claim 1, wherein 4-amino-5-propy1-3-thiophene-carkoxylic acid methyl ester hydrochloride is prepared from 4-carbomethoxy-3-keto-2-propyltetrahydrothiophene oxime.

5. A process as in claim 1, wherein 4-amino-5-methyl-3-thiophenecarboxylic acid is prepared by hydrolyzing 4-amino-5-methyl-3-thiophenecarboxylic acid methyl ester hydrochloride.

6. A process as in claim 1, wherein 4-amino-5-methyl-3-thiophenecarboxylic acid methyl ester hydrochloride is prepared from 4-carbomethoxy-3-keto-2-methyltetrahydrothiophene oxime.

7. A process as in claim 1, wherein 4-amino-5-isopropyl-3-thiophenecarboxylic acid is prepared by hydrolyzing 4-amino-5-isopropyl-3-thiophenecarboxylic acid methyl ester hydrochlo-ride.

8. A process as in claim 1, wherein 4-amino-5-isopropyl-3-thiophenecarboxylic acid methyl ester hydrochloride is prepared from 4-carbomethoxy-3-keto-2-isopropyltetrahydrothiophene oxime.

9. A compound of the formula:

I
wherein R1 is lower alkyl; R2 is hydroxy or lower alkoxy; R3 and R4, which may be the same or different, are lower alkyl or hydrogen;
and the pharmaceutically acceptable salts thereof, whenever prepared by the process as claimed in claim 1 or by an obvious chemical equi-valent thereof.

10. 4-Amino-5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride, whenever prepared by the process as claimed in claim 2 or by an obvious chemical equivalent thereof.

11. 4-Amino-5-ethyl-3-thiophenecarboxylic acid, whenever prepared by the process as claimed in claim 3 or by an obvious chemical equivalent there-of.

12. 4-Amino-5-propyl-3-thiophenecarboxylic acid methyl ester hydro-chloride, whenever prepared by the process as claimed in claim 4 or by an obvious chemical equivalent thereof.

13. 4-Amino-5-methyl-3-thiophenecarboxylic acid, whenever prepared by the process as claimed in claim 5 or by an obvious chemical equivalent there-of.

14. 4-Amino-5-methyl-3-thiophenecarboxylic acid methyl ester hydro-chloride, whenever prepared by the process as claimed in claim 6 or by an obvious chemical equivalent thereof.

15. 4-Amino-5-isopropyl-3-thiophenecarboxylic acid, whenever prepared by the process as claimed in claim 7 or by an obvious chemical equivalent thereof.

16. 4-Amino-5-isopropyl-3-thiophenecarboxylic acid methyl ester hy-drochloride, whenever prepared by the process as claimed in claim 8 or by an obvious chemical equivalent thereof.