JPS6121235B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula [In the formula, R ₁ is lower alkyl, aryl, aralkyl, -(CH ₂ ) _o -R ₅ or

[Formula], where R ₅ is hydroxy or

[Formula], R ₆ is hydrogen, lower alkoxy or amino, R ₇ is lower alkyl, n is an integer from 1 to 6; R ₂ is hydrogen, hydroxy, lower alkoxy or amino; _R3
and R ₄ may be the same or different and are lower alkyl, aralkyl, acyl and hydrogen, and salts thereof. The compound of formula and its salts are used as antiobesity agents and blood lipid lowering agents.
It is useful as a lipid lowering agent. Furthermore, they are associated with high blood lipid levels, such as atherosclerosis and related cardiovascular disease.
It can also be expected to be useful in the treatment of. As used throughout this specification, the term "lower alkyl", either by itself or in combination e.g. "lower alkoxy" or "aralkyl", refers to straight and branched chains having from 1 to 8 carbon atoms. Saturated aliphatic alkyl groups, such as methyl, ethyl,
Propyl and isopropyl are shown. "halogen"
The term includes all four halogens: chlorine, bromine, iodine and fluorine. The word "acyl" includes lower alkyl, aryl, aralkyl,
Indicates a carbonyl group bound to an alkoxy or amino residue. Representative acyl groups include benzoyl, acetyl, propionyl, carbomethoxy and carbamoyl. Aroyl, lower alkanoyl and carbamoyl residues are preferred. The term "aryl" refers to a mononuclear aryl group such as phenyl or substituted phenyl, which substituents may be present in one or more positions, and which includes lower alkyl,
Trihalomethyl, for example selected from trifluoro and trichloromethyl, aralkyl, halogen, lower alkoxy, amino, nitro, mono- and di-lower alkylamino. The term "alkali metal" refers to sodium, potassium or lithium.
The term "lower alkanol" means 1 to 6 carbon atoms.
Indicates the number of alkanols. The term "alkoxide" relates to metal salts of alkanols, preferably alkali metal salts and alkaline earth metal salts. The term "alkaline earth metal" means calcium, barium or magnesium. The term "lower alkanoic acid" refers to alkanoic acids containing 1 to 8 carbon atoms. Preferred compounds of the formula include R ₁ lower alkyl;
or aryl, especially lower alkyl; _R2 is lower alkoxy or hydroxy, especially lower alkoxy; and -N( _R3 , _R4 ) is amino, lower alkanoylamino or ureido, especially amino. According to the invention, compounds of formula and salts thereof are:
formula [In the formula, R ₂ ' is lower alkoxy, and R ₁
is as above] is treated with acid to form the formula [wherein R ₂ ' and R ₁ are as above] and optionally converting the lower carbalkoxy group to a carboxy, formyl or carbamoyl group and/or converting the amino group to a lower alkyl group. and, if desired, converting the compound of the formula into a salt. Compounds of formula a can be prepared by reacting an oxime of formula with an acid,
Preferably, it is obtained by treatment with hydrogen halide, most preferably with hydrogen chloride. The temperature and pressure of this reaction are not critical. The reaction can suitably be carried out at about 0-70°C, preferably at room temperature, and at normal pressure. Compound a can be converted into the corresponding aldehyde,
It may be converted into acids, amides or other esters of the formula or salts thereof. That is, the lower carbalkoxy group contained in compound a can be dissolved in a conventional inert organic solvent, preferably a lower alkanol, especially methanol or ethanol, an aqueous ether solvent, preferably an aqueous di-lower alkyl ether, especially diethyl ether, or an aqueous cyclic solvent. It can be converted to carboxy by basic hydrolysis in an ether, especially tetrahydrofuran or dioxane. Suitable bases are alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and alkaline earth metal hydroxides, such as barium hydroxide, calcium hydroxide and magnesium hydroxide, especially alkali metal hydroxides. It is an oxide. In this hydrolysis temperature and pressure are not critical. The reaction is suitably carried out under atmospheric pressure at about 0-100°C, preferably at reflux temperature, especially at about
It can be carried out at 70°C. Treatment of ester a with a reducing agent e.g. LiAlH ₄ gives the corresponding primary alcohol, which is subsequently treated with e.g. MnO ₂
can be oxidized to the corresponding aldehyde of formula. Treatment of ester a with ammonia provides the corresponding amide of formula where R ₂ is amino. If R ₃ and/or R ₄ are desired to be lower alkyl, aralkyl or acyl, these groups are introduced by conventional methods for converting aromatic primary amines into their N-substituted derivatives. be able to. That is, primary amine a
is a lower alkylating agent such as a lower alkyl halide, an aralkylating agent such as an aralkyl halide,
Alternatively, it can be reacted with an acylating agent such as a lower alkanoic anhydride such as acetic anhydride, or an alkali metal cyanate such as potassium cyanide. A compound with the formula Formula the compound of By reacting with a compound of formula It can be produced by producing a compound of However, in these formulas, R ₁ and R ₂ ' are as described above, R is lower alkyl, and R ₈ is halogen, mesyloxy or tosyloxy. This reaction can be 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, the reaction is generally conducted under normal pressure and at a temperature of about 15 to about 60°C, preferably 25°C. Compound V is then treated with an alkali metal alkoxide in the presence of an aromatic hydrocarbon, preferably benzene.
Preferably treated with sodium methoxide to form A compound of the formula [wherein R ₁ and R ₂ ' are as described above] is produced. Although temperature and pressure are not critical, the reaction is generally conducted under normal pressure and at a temperature of about 15 to about 60°C, preferably 25°C. The compound is then converted to the oxime of the formula by using conventional methods for converting ketones to oximes. The ketone is treated with a hydroxylamine halide, preferably hydroxylamine hydrochloride, preferably in a nitrogenous base.
In this case, the customary nitrogen-containing bases, preferably amines, can be used. Amines that can be used are primary amines, such as lower alkyl amines, especially methylamine, ethylamine or aniline; secondary amines,
For example di-lower alkylamines, especially dimethylamine or diethylamine, or pyrrole; and tertiary amines, such as tri-lower alkylamines, especially trimethylamine and triethylamine, pyridine and picoline. Temperature and pressure are not critical. The reaction may be carried out in a suitably inert organic solvent, for example an aliphatic or aromatic hydrocarbon such as n-hexane or benzene, under normal pressure and at room temperature to reflux temperature, preferably about 22°C.
Preferably, the reaction is carried out in an excess of nitrogenous base, which serves as a solvent medium. R ₁ is aryl, aralkyl, -(CH ₂ ) _o -R ₅ or -CHR ₇ -COOH, where R ₅ is hydroxy or

[Formula], R ₆ is H or NH ₂ , R ₇ is lower alkyl, and n is an integer from 1 to 6, and intermediates thereof, and R ₁ is aryl, aralkyl, -(CH ₂ ) _o −R ₅ or −CHR ₇ −COOH,
where R ₅ is hydroxy or

Intermediates of the formula, in which R ₆ is H, lower alkoxy or NH ₂ , R ₇ is lower alkyl, and n is an integer from 1 to 6, are novel and as such are of the invention. It constitutes part 1. As mentioned above, thiophene derivatives of the formula and pharmaceutically acceptable salts thereof are effective hypolipemic agents, ie, lower blood lipid levels in mammals. These properties are demonstrated using a group of normal female Charles River rats weighing 150-180 g. Rats are first fed a corn oil-glucose mixture for several days, and then the test compound in dimethyl sulfoxide (DMSO) is administered orally or parenterally. A comparison of blood triglyceride, fatty acid and cholesterol levels in rats receiving the test compound shows a significant reduction compared to the corresponding levels in untreated animals. Similar results were obtained with rat hepatocytes. Synthesis of fatty acids and cholesterol in isolated hepatocytes Female Charles River rats were fasted for 48 hours and then fed a diet of 1% corn oil, 70% glucose from 8 a.m. to 11 a.m. for 7 to 14 days. Gave. Isolated rat hepatocytes are prepared by dissecting the liver in situ. This liver cell is 37
Incubate in a shaking water bath for 60 min at °C. Each flask contains 1 isolated rat hepatocyte.
ml [dry water cell]
cell) 10-20 mg], Krebs-Henseleit bicarbonate buffer (PH7.4) 1
ml, 16.5 mM glucose, 1 μmol L-alanine, 1 μCi [ ¹⁴ C]alanine, 1 mCi ³ H ₂ O and 2 mM inhibitor, containing a total of 2.1 ml of a solution in H ₂ O or DMSO at pH 7.4 (not specified). under these conditions). All incubations are performed three times and all experiments are repeated at least twice. Ethanolamine: 2-methoxy-ethanol (1:
2) Pour 0.3ml into the center well
Add 0.4 ml of 62.5% citric acid to cell medium (cell
Following a 60 minute incubation by adding the media) and incubating for 45 minutes.
_CO2 is collected in each flask. Transfer the contents of the center well to scintillation counting fluid;
¹⁴ Determine the CO ₂ content. The medium was saponified, acidified (only for determining the rate of lipo-genesis) and extracted with hexane. At this stage lipids were counted (to determine the rate of lipogenesis) or precipitated with digitonin, washed and counted [cholesterol formation (cholesterol formation)].
[to determine the genesis)]. Conversion of ³ H ₂ O and [ ¹⁴ C]alanine to fatty acids or sterols was determined with a liquid scintillation counting system. Data converted to fatty acids or cholesterol
Expressed as n moles of ³ H ₂ O and [ ¹⁴ C]alanine and n moles of [ ¹⁴ C]alanine oxidized to ¹⁴ CO ₂ per mg dry weight of cells in 60 minutes. The results are shown in Table 1.

[Table] Fatty acid and cholesterol synthesis in vivo 48 hours fasting and 1% corn oil, 70
Rats are prepared by refeeding % glucose diet for 5-15 days. On the day of the experiment, the rats were given 3
It was administered by oral intubation 30 minutes before a 3-hour meal or by intraperitoneal injection 30 minutes after the end of a 3-hour meal. in 0.25 ml of saline given by intravenous injection into the tail vein at the end of a 3-hour meal.
³ H ₂ O1 mCi, [ ¹⁴ C] alanine 5 μCi, alanine
Consisting of 12.3 mg and 30.6 mg of α-ketoglucose acid.
Rats were killed by dissection after a 30 minute pulse. The liver was quickly dissected, saponified, acidified (only to determine the rate of adipogenesis), and extracted with hexane. Lipids are counted at this stage (to determine the rate of lipogenesis) or precipitated with digitonin, washed and counted (to determine cholesterol formation). Conversion of ³ H ₂ O and [ ¹⁴ C]alanine to fatty acids or sterols was determined with a liquid scintillation counting system. The results are shown in Tables.

【table】

【table】

【table】

[Table] Furthermore, the inhibitory activities of fatty acid synthesis (IFAS) and cholesterol synthesis (ICS) of representative compounds of the present invention were
Propylthiophene (R ₁ = n-propyl, R ₂ =
The table below shows the percentage of the activity of methoxy. In addition, the acute toxicity data (LD ₅₀
values) are also shown.

Table: Compounds of formula and pharmaceutically acceptable salts thereof can be administered parenterally as well as orally. For purposes of parenteral administration, the compound
Solutions and suspensions in DMSO, water or gum arabic may be used. Particularly suitable are sterile aqueous solutions of the corresponding water-soluble salts. These dosage forms are particularly suitable for intraperitoneal injection. Aqueous solutions in pure distilled water, including solutions of salts, are also useful for intravenous injection purposes, provided the PH is suitably adjusted beforehand. Such solutions should be suitably buffered, if necessary, and should be liquid dilutions initially made isotonic with sufficient saline or glucose. The sterile aqueous media used in this connection are readily obtained by standard methods well known to those skilled in the art. For example, distilled water is commonly used as a liquid diluent. The dosage required to lower blood lipid levels will be determined by the nature and severity of the disease symptoms. Generally, small doses will be administered initially with increasing doses until the optimal amount is determined. It has been found that when the compositions are administered orally, larger amounts of the active ingredient are generally required to achieve the same amount of effect as would be obtained by administering smaller amounts parenterally. . In general, about 0.1 to 1.2 mg of active ingredient per kilogram of body weight when administered in single or multiple doses significantly lowers blood lipid levels. The invention is further illustrated by the following examples. All temperatures are expressed in degrees Celsius and the ether used is diethyl ether. Example 1 Gaseous hydrogen chloride was bubbled into anhydrous ether 1 in which 100.0 g of 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene oxime was dissolved. This step was carried out for 1 hour at 0°C. The reaction flask was capped with a drying tube and stirred at room temperature overnight. The solvent was evaporated until the product crystallized. Separate the white solid and wash thoroughly with ether to obtain 3-amino-4-carbomethoxy-2-n-propylthiophene hydrochloride having a melting point of 178-180°60.0
I got g. The product was recrystallized from methanol/ether to give 50.0 g of pure 3-amino-4-carbomethoxy-2-n-propylthiophene hydrochloride, melting point 180-181°. The starting material can be prepared as follows: a A solution of 116.55 g of methyl-3-mercapto-propionate in 220 ml of absolute methanol at -20 DEG C. is treated with 52.46 g of sodium methoxide. After 20 minutes, a solution of 203.3 g of ethyl-2-promvalerate in 150 g of absolute methanol was added dropwise. The reaction mixture 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, the ether was evaporated to give 130 g of methyl-4-thia-5-carbomethoxyoctaate as a colorless oil. b To a suspension of 54.0 g of sodium methoxide in 500 ml of anhydrous benzene, methyl-4-thia-5-
130 g of carbomethoxyoctanoate were added dropwise at 25°C. The mixture was stirred overnight and poured into ice water. The aqueous phase was extracted with benzene/ether (1:1) and then acidified to PH1 with 6NHCl. The product, which at this point partially separated from the water, was trapped in methylene chloride. The aqueous phase was further extracted with methylene chloride. The combined organic phases were dried and evaporated to give pure 4-carbomethoxy-
94.0 g of 3-keto-2-propyl-tetrahydrothiophene were obtained as a colorless oil. c A solution of 94.0 g of 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene in 250 mg of anhydrous pyridine was treated with 40.0 g of hydroxylamine hydrochloride at 25°. The reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between 1NHCl and methylene chloride. The organic phase was dried over sodium sulfate and evaporated to give 100 g of pure 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene oxime.
was obtained as a colorless oil. Example 2 4-Carbomethoxy- in 600 ml of anhydrous ether presaturated with gaseous hydrogen chloride at 0°C
A solution of 41.1 g of 3-keto-2-methyl-tetrahydrothiophene oxime was stirred at 25°C overnight.
The separated solid was collected, thoroughly washed with ether, and dried to obtain 33.2 g. Evaporation of the liquid gave an additional 4.2 g after recrystallization of the residue. This corresponded to a total yield of 37.4 g of pure 3-amino-4-carbomethoxy-2-methylthiophene hydrochloride.
This compound melted at 191-192°. Similarly, 49.12 g of 4-carbomethoxy-2-isopropyl-3-keto-tetrahydrothiophene oxime has a melting point of 185° (decomposition).
18.49 g of 4-carbomethoxy-2-isopropylthiophene hydrochloride was successfully converted. The starting material can be prepared as follows: a A solution of 66.29 g of methyl-3-mercapto-propionate in 50 ml of absolute methanol is cooled to 0° C. and treated with 120 ml of a 25% methanol solution of sodium methoxide. . To this solution was added dropwise 100 g of ethyl-2-bromopropionate in 100 ml of absolute methanol. Reaction at 25℃
I let it run through the night. 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 with magnesium sulfate and
Evaporation gave 121.40 g of 2-methyl-3-thia-1,6-hexanedioic acid-1-ethyl-6-methyl ester as a pale yellow oil. Similarly, 61.4 g of methyl-3-mercaptopropionate was combined with 106.8 g of ethyl-2-bromovalerate to produce 2-isopropyl-3
120.91 g of -thia-1,6-hexanedioic acid-1-ethyl-6-methyl ester was obtained. b 1-ethyl-6 2-methyl-3-thia-1,6-hexanesionate in 90 ml of anhydrous benzene.
- A solution of 121.4 g of methyl ester in 30 g of anhydrous sodium methoxide in 200 ml of anhydrous benzene.
was added dropwise to the suspension. The reaction was allowed to proceed overnight at room temperature. The mixture was partitioned between water/ether. The aqueous phase was further extracted with benzene. The aqueous phase was then acidified to PH1 with 6NHCl and extracted three times with methylene chloride. The methylene chloride extracts were combined, dried over sodium sulfate and evaporated to give 79.19 g of pure 4-carbomethoxy-3-keto-2-methyltetrahydrothiophene as a colorless oil. Similarly, 2-isopropyl-3-thia-
1-ethyl-6-1,6-hexanedioate
120.91 g of methyl ester was converted to 91.0 g of 4-carbomethoxy-2-isopropyl-3-keto-tetrahydrothiophene. c A solution of 37.26 g of 4-carbomethoxy-3-keto-2-methyl-tetrahydrothiophene in 100 ml of anhydrous pyridine was treated with 18.0 g of hydroxylamine hydrochloride. The mixture was stirred at 25° for 24 hours. The reaction was concentrated and partitioned between 1N hydrochloric acid/methylene chloride. The aqueous phase was extracted twice with methylene chloride. The combined organic extracts were dried and evaporated to yield 40.1 g of pure 4-carbomethoxy-3-keto-2-methyltetrahydrothiophene oxime as a colorless oil. Similarly, 4-carbomethoxy-2-isopropyl-3-keto-tetrahydrothiophene
52.8 g were converted to 49.0 g of 4-carbomethoxy-2-isopropyl-3-keto-tetrahydrothiophene oxime. Example 3 A solution of 2.07 g of 3-amino-4-carbomethoxy-2-methylthiophene hydrochloride in 35 ml of methanol was treated with 23 ml of 1N sodium hydroxide. The mixture was heated under reflux for 0.5 h, cooled and poured into brine. The pH was adjusted to 5 and extracted 7 times with methylene chloride/methanol (4:1). The organic extracts were combined, dried and evaporated to yield 1.23 g of pure 3-amino-4-carboxy-2-methylthiophene, melting point 162-164°. This compound was mixed with ethyl acetate/
An analytical sample with a melting point of 163-164° was obtained by recrystallization from pentane. Similarly, 3-amino-4-carbomethoxy-
5.0 g of 2-isopropyl-thiophene hydrochloride was mixed with 3-amino-4-carboxy-2 having a melting point of 117-118°.
- Converted to 3.3 g of isopropylthiophene. Similarly, 3-amino-4-carbomethoxy-
Melting point 144 of 2-propylthiophene hydrochloride 1.41g
Converted to 0.625 g of 3-amino-4-carboxy-2-propylthiophene of ~145°. Example 4 3-amino-4-carbomethoxy- in 30 ml of water
Add a solution of 1.03 g of 2-methylthiophene hydrochloride to 10 g of water.
Treated with a solution of 0.45 g of potassium cyanide in ml. A white solid separated. The mixture was extracted three times with methylene chloride. The organic extracts were combined, dried and evaporated to yield 0.82 g of pure 4-[(amino-carbonyl)-amino]-5-methyl-3-thiophenecarboxylic acid methyl ester. Recrystallization of this compound from ethyl acetate gave a white solid with a melting point of 194-195°. Example 5 4-Carbomethoxy in 600 ml of anhydrous ether
Gaseous hydrogen chloride was added to a solution of 80.0 g of 3-keto-2-phenyltetrahydrothiophene oxime at 0°C.
I let it bubble for 1 hour. This suspension was treated with 300 ml of methanol and stirred at 25° overnight. The product was separated, washed with ether and 4-amino-
70.0 g of 5-phenylthiophene-3-carboxylic acid methyl ester hydrochloride was obtained as a pale yellow solid with a melting point of 181-182°. This compound could be recrystallized from methanol. The starting material can be prepared as follows: a A solution of 104.95 g of methyl-3-mercaptopropionate in 200 ml of methanol is cooled to 0° and treated with 207.5 g of a 25% methanol solution of sodium methoxide. did. To the resulting homogeneous solution was added 200.0 g of methyl-α-bromo-phenylacetate in 200 ml of methanol under argon. The reaction was stirred at 25° overnight. The solvent was removed by evaporation and the residue was partitioned between water and methylene chloride to give 2-phenyl-3-thia-
234.0 g of adipic acid dimethyl ester was obtained as a colorless oil. b 2-phenyl-3- in 300 ml of anhydrous benzene
A solution of 234.0 g of thia-adipate dimethyl ester was added dropwise to 54.05 g of sodium methoxide at 25°. The reaction was stirred overnight and poured into water. The solids were separated and the liquid was extracted twice with ether. the solid is then added to the aqueous phase;
The mixture was made acidic to pH 1 with 6NHCl. The mixture was extracted three times with methylene chloride. The organic extracts were dried over sodium sulfate and evaporated to give 145.24 g of 4-carbomethoxy-3-keto-2-phenyl-tetrahydrothiophene as a pale yellow oil. c A solution of 82.24 g of 4-carbomethoxy-3-keto-2-phenyl-tetrahydrothiophene in 120 ml of anhydrous pyridine was treated with 28.85 g of hydroxylamine hydrochloride. The solution was stirred at 25° for 2 days and the solvent was evaporated under vacuum. residue
Partitioned between 1NHCl and methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, and evaporated to yield 90.0 g of 4-carbomethoxy-3-keto-2-phenyltetrahydrothiophene as a colorless oil. Example 6 A solution of 10.0 g of 4-amino-5-phenylthiophene-3-carboxylic acid methyl ester hydrochloride in 80 ml of methanol was treated with 82 ml of 1N sodium hydroxide. The reaction was heated under reflux for 30 minutes and cooled to room temperature. After adjusting the pH to 5 and separating the separated product, drying and recrystallizing from ethyl acetate/pentane, pure 4-amino-5-phenylthiophene-3-carboxylic acid with a melting point of 201-202° is obtained. acid
8.2g was obtained. Example 7 A solution of 13.3 g of 4-amino-5-phenylthiophene-3-carboxylic acid methyl ester hydrochloride in 70 ml of anhydrous pyridine was treated with 5.93 ml of acetic anhydride to give 40
It was heated to 50° for an hour. At this point, an additional 5 ml of acetic anhydride was added and the solution was heated to 50° for an additional 16.0 hours. The reaction was cooled and the solvent was evaporated. residue
Partitioned between 1NHCl and methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, and evaporated to give pure 4-acetamido-5-phenylthiophene-3.
-13.7 g of carboxylic acid methyl ester were obtained. Recrystallization of the compound from ethyl acetate/pentane gave 117-118° white needles with a melting point of 117-118°. Example 8 A solution of 8.6 g of 4-acetamido-5-phenylthiophene-3-carboxylic acid methyl ester in 30 ml of methanol was treated with 34.4 ml of 1N NaOH and heated under reflux for 1.5 hours. The reaction was cooled, acidified with 1NHCl and diluted with methylene chloride/methanol (8:2).
Extracted with. The organic extracts were collected, dried over sodium sulfate, evaporated and then recrystallized from ethyl acetate to give pure 4-acetamido-5-phenylthiophene-3-carboxylic acid, melting point 182-183°.
7.2g was obtained. Example 9 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 absolute methanol was added dropwise at 0 DEG C. 249 ml of 25% sodium methoxide/methanol. The resulting mixture was dissolved in ethyl-2-frombutyrate in 75 ml of absolute methanol at 0°.
200 g was treated dropwise. The cooling bath was removed and the reaction was stirred at 25° overnight. Concentrate the mixture;
Partitioned between water and methylene chloride. The organic extracts were dried and evaporated to give 229 g of the diester as a colorless oil. Sodium methoxide in 300ml of anhydrous benzene
229 g of the diester in 200 ml of anhydrous benzene were added dropwise at 25° to a suspension of 63.5 g. After stirring overnight at room temperature, the reaction was poured into 800 ml of water and
The benzene phase was further extracted with 200 ml of water. The aqueous phases were combined, carefully acidified with 6NHCl and extracted three times with methylene chloride/methanol (5:1). The organic extracts were dried and evaporated to give 149.7 g of the pure ketone.
was obtained as a colorless oil. To a solution of 276.1 g of the ketone in 500 ml of anhydrous pyridine was added 121.6 g of hydroxylamine hydrochloride in portions. The reaction was allowed to proceed for 20 hours at 25°, and the reaction was concentrated and partitioned between methylene chloride/3NHCl. The aqueous phase was divided into methylene chloride/methanol (5:
1) was backwashed twice. The organic phase was dried and evaporated to give 253 g (82%) of pure oxime as a pale yellow oil. A solution of 253 g of the oxime in anhydrous ether 2 was treated with a stream of gaseous hydrogen chloride at 25° for 1 hour. The reaction was seeded with 0.5 g of standard product and stirred at 25° overnight. Filtration of the crude product, washing with anhydrous ether and recrystallization from methanol/ether gave 173 g of pure aminothiophene hydrochloride, melting point 161°. The following Examples 10 and 11 demonstrate pharmaceutical compositions containing 3-amino-4-carbomethoxy-2-n-propylthiophene hydrochloride as the active compound. Example 10 Capsule formulation Active compound per capsule 10 mg 50 mg Lactose 165 mg 125 mg Corn starch 80 mg 30 mg Talc 5 mg 5 mg Total weight 210 mg 210 mg Example 11 Tablet formulation Active compound per tablet 25.00 mg Dicalcium phosphate dihydrate (mil (untreated) 175.00mg Corn starch 24.00mg Magnesium stearate 1.00mg Total weight 225.00mg

Claims (1)

[Claims] 1 formula A compound and a salt thereof, wherein R ₁ is lower alkyl or aryl, and R ₂ is hydroxy or lower alkoxy. 2. A compound of the formula according to claim ₁ , wherein R 1 is lower alkyl and R ₂ is lower alkoxy. 3. A salt of a compound of the formula according to claim 1 which is 4-amino-5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride. 4 3-amino-4-carbomethoxy-2-n-
A salt of a compound of formula according to claim 1 which is propylthiophene hydrochloride. 5. A compound of the formula according to claim 1 which is 3-amino-4-carboxy-2-methylthiophene. 6 3-Amino-4-carbomethoxy-2-methylthiophene hydrochloride. A salt of a compound of formula according to claim 1, which is 3-amino-4-carbomethoxy-2-methylthiophene hydrochloride. 7. A compound of the formula according to claim 1 which is 3-amino-4-carboxy-2-isopropylthiophene. 8. A salt of a compound of the formula according to claim 1 which is 3-amino-4-carbomethoxy-2-isopropylthiophene hydrochloride. 9 4-amino-5-phenylthiophene-3-
A salt of a compound of formula according to claim 1 which is carboxylic acid methyl ester hydrochloride. 10 4-amino-5-phenylthiophene-3
- A compound of the formula according to claim 1 which is a carboxylic acid. 11 formula wherein R ₁ is lower alkyl or aryl and R ₂ is lower alkoxy, is reacted with an acid, and optionally,
Formulas characterized by converting the resulting compound into a salt In the formula, R ₁ and R ₂ are as described above. A method for producing a compound and a salt thereof. 12. A process according to claim 11 for preparing a compound of formula a, wherein R ₁ is lower alkyl and R ₂ is lower alkoxy. 13. The method according to claim 11 for producing 4-amino-5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride. 14 3-amino-4-carbomethoxy-2-n
- The method according to claim 11 for producing propylthiophene hydrochloride. 15 formula wherein R ₁ is lower alkyl or aryl and R ₂ is lower alkoxy, the compound of the formula is hydrolyzed and, if necessary, the resulting compound is converted into a salt. In the formula, R ₁ is as described above. A method for producing a compound and a salt thereof. 16 formula An anti-obesity or blood lipid-lowering agent characterized by containing a compound or a salt thereof as an active ingredient, wherein R ₁ is lower alkyl or aryl, and R ₂ is hydroxy or lower alkoxy.