MC1156A1 - CYCLIC COMPOUNDS - Google Patents

Description

The present invention relates to new cyclic compounds of the formula aralcoyl, -(CB^^-R^ or -CKR^-COOII, where R^ is a hydroxyl group

II

or -C~R6, Rg being hydrogen or a lower alkoxy group 15 or amino; Rr, is a lower alkyl group, n is an integer from 1 to 6, R2 is hydrogen, a hydroxy group,

lower alkoxy or amino; R^ and R^s which may be identical or different, are lower alkyl', aryl, alkyl, acyl or hydrogen groups;

20 and their salts.

The compounds of formula I and their salts are useful as anti-obesity agents and agents for lowering blood lipid levels. They may also be expected to be useful in the treatment of atherosclerosis and related cardiovascular disorders that are associated with high blood lipid levels.

As used here, the term "lower alkyl," alone or in combination, such as "lower alkoxy" or "aralcoyl," refers to saturated aliphatic alkyl groups, straight-chain or branched, having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, and isopropyl groups. The term "halogen" encompasses the four halogens: chlorine, bromine, iodine, and fluorine. The term "acyl" refers to carbonyl groups to which lower alkyl, aryl, aralcoyl, alkoxy, or amino portions are attached. Typical examples of acyl groups include benzoyl, acetyl, propionyl, carbomethoxy, and carbamoyl. Aroyl, lower aloanoyl, and por- groups

■2~

Carbamoyl groups are preferred. The term "aryl" refers to monocyclic aryl groups such as phenyl or substituted phenyl, these substitutions being in one or more positions and being chosen from lower alkyl groups, 5-trihalogenethyl groups such as trifluoro and trichloromethyl,

alkali metal, halogen atoms, lower alkoxy, amino, nitro, mono- and di-lower alkali-amino groups. The term "alkali metal" refers to sodium, potassium, or lithium. The term "lower alkanols" refers to alkanols having 1 to 6 carbon atoms. The term "alkoxide," as used here, refers to metal salts, preferably alkali and alkaline earth metal salts, of alkanols. The term "alkaline earth metal" refers to calcium, barium, or magnesium. The term "lower alkanoic acids" refers to alkanoic acids having 1 to 8 carbon atoms.

Preferred compounds of formula I are those in which R^ is a lower alkyl or aryl group, especially lower alkyl, R2 is a lower alkoxy or hydroxy group, especially lower alkoxy; and -N(R1,R^) is an amino, lower alkanoylamino or ureido group, especially amino.

According to the invention, compounds of formula I and their salts can be obtained by a process in which a compound of formula is treated

25 • '

in which RJ> is a lower alkoxy group and R^ is such as above,

35 with an acid to obtain a compound of the formula

-3-

\

,nh2

in which ±U> and are such as above 5 - and, if desired, the lower carbalcoxy group is transformed into a carboxy, formyl or carbamoyl group and/or the amino group is reacted with a lower alkoxylation, alkoxylation or acylation agent and, if desired further, a compound of formula I is transformed into a salt.

The compound of formula 1a can be obtained by treating the oxime of formula II with an acid, preferably a hydrogen-ligandic acid, in particular hydrochloric acid, in an inert organic solvent, for example an ether, in particular a lower alkyl oxide, such as ethyl oxide; a cyclic ether, such as tetrahydrofuran or dioxane; a lower alkanol; or water. The temperature and pressure of the reaction are not critically important. The reaction can be conveniently carried out at temperatures between about 0°C and about 70°C, preferably at room temperature and atmospheric pressure.

23. The compound can be transformed into the aldehyde,

the acid, the corresponding amides, or other esters of formula I or their salts by conventional processes to transform the esters into the compounds mentioned above. Thus, the lower carbalcoxy group contained in compound la can 30 be transformed into a carboxy group by basic hydrolysis in a conventional inert organic solvent, preferably a lower alkanool, in particular methanol or ethanol, an aqueous ether solvent, preferably an aqueous lower alkyl oxide, in particular ethyl oxide, or an aqueous cyclic ether, 35 in particular tetrahydrofuran or dioxane. Among the

"Preferred bases include alkali metal hydroxides, such as sodium, potassium, and lithium hydroxides, and alkaline earth metal hydroxides, such as hydroxides

"Barium, calcium, and magnesium, especially alkali metal hydroxides, are used in this hydrolysis. In this reaction, temperature and pressure are not critically important. The reaction can be conveniently carried out between approximately 0°C and 100°C, preferably under reflux, especially at approximately 70°C, under atmospheric pressure. Treating an ester with a reducing agent, for example, LiAlCl, yields the corresponding primary alcohol, which can then be oxidized, for example, with MnOgI, to give the corresponding aldehyde of formula I. Treating an ester with ammonia yields the corresponding amide of formula I, where R is an amino group. When it is desired that R and/or R be lower alkyl, alkali, or acyl groups, these portions can be introduced

by classical processes to transform a primary aromatic amine into its N-substituted derivatives. Thus, a primary amine can be reacted with a lower alkylating agent, for example, a lower alkyl halide.

^ agen-t--dJ-a:ey-l-a: ti-on:Tgxempie--un-hral-ogenide--daryie-j- an aralkylating agent, for example an aralkyl halide, or an

20 acylation agent, for example a lower alkanoic acid anhydride, such as acetic anhydride, or an alkali metal cyanate, such as potassium cyanate.

Compounds of formula II can be obtained by reacting a compound of formula

25 ~ '

R-2^ ^ ^sh ni

30

with a compound of the formula

35

IV

-5-

to form a compound of the formula r

where and E2 are such as above, R is a lower 10 alkyl group and Rg is a halogen or a mesyloxy or tosyl-oxy group.

This reaction can be carried out in the presence of a lower alkanool and an alkali metal alkoxide, preferably methanol and sodium methylate. Although temperature and pressure are not critically important, the reaction is usually carried out at atmospheric pressure and at a temperature between approximately 1°C and approximately 60°C, preferably at 25°C.

Compound V is then treated with an alkali metal hydroxide, preferably sodium methoxide, in the presence of an aromatic hydrocarbon, preferably benzene, to form a compound of the formula

25

VI

30

35

in which R^ and are such as above.

Although temperatures and pressures are not critically important, this reaction is usually conducted at atmospheric pressure and at a temperature between about 15°C and about 60°C, preferably at 25°G.

• Compound VI is then transformed into an oxime of formula II, using any conventional method for transforming a ketone into an oxime. Preferably, the

-6-

Ketone VI is treated with a hydroxylanine hydrohalogen, preferably hydroxylamine hydrochloride, in a nitrogen-containing base. Any conventional nitrogenous base may be used, preferably a smine. Among the 5 amines that may be used are primary amines, such as (lower alkyl)amines, especially methylamine, ethylamine, or aniline; secondary amines, such as di(lower alkyl)amines, especially dimethylamine or diethylamine, or pyrrole; and tertiary amines, such as tri(lower alkyl)amines, especially trimethylamine and triethylamine, pyridine, and picoline. Temperature and pressure are not critically important. The reaction can be carried out between room temperature and reflux temperature, preferably around 22°C-15°F, and under atmospheric pressure, in an inert organic solvent, such as an aliphatic or aromatic hydrocarbon, for example n-hexane or benzene. Preferably, this reaction is carried out in an excess of the nitrogenous base, which serves as the solvent medium.

20 The intermediate products of formulas V and VI in which R^ is an aryl, aralcoyl, -(CH^^-R^ or -Cïlïï^-COOH group, where is a hydroxy group or

~C , Rg being H or es_fc an inferior alkyl group-

25 XE6

rieur and n is an integer from 1 to 6, as well as the intermediate products of formula II, where R^ is an aryl, aralcoyl, -(CEL^-R^ or -CHRr,-COOH group, where R^ is a hydroxyl or

50 -0 , R^ being H, a lower alkoxy group or Rr; is

Xes is a lower alkyl group and n is an integer from 1 to 6, are new and as such are also part of the invention.

As previously mentioned, thiophene 55 derivatives of formula I and their pharmaceutically acceptable salts are effective hypolipidemic agents, meaning they decrease the amount of lipids in the blood of mammals. This property has been demonstrated in groups of Charles River rats.

-7~

normal females weighing 150 to 180 g. They are first fed a corn oil-glucose mixture for several days and then the tested compounds are administered in dimethyl tallow oxide (DMSO) orally or parenterally.

5. A comparison of the amounts of triglycerides, fatty acids, and cholesterol in the blood of rats receiving the tested compounds shows a significant reduction compared to the corresponding amounts in the blood of untreated animals. Similar results were obtained in the case of rat hepatocytes.

Synthesis of fatty acids and cholesterol in isolated hepatocytes.

Female Charles River rats are fasted for 48 hours, then fed a meal containing 15% corn oil and 70% glucose for 7 to 14 days between 8 and 11 a.m. Hepatocytes isolated from the rats are prepared by in situ liver perfusion. The hepatocytes are incubated in a 37°C oscillating water bath for 60 minutes. Each flask contains a total of 2.1 cm³, consisting of 1 cm³ of isolated rat hepatocytes (10–20 mg of cells).

•y

dry cells), 1 cm of Zrebs-Henseleit bicarbonate buffer at pH 7.4-, 16.5 mM glucose, 1 pmole of L-alanine, 1 jiCi of

(^C)alanine » ^ saOi of ^^0 and 2 mM inhibitor in H^O or

DMSO at pH 754 (unless otherwise specified). All incu-

25 batches are carried out in triplicate and all experiments are repeated at least twice. CO₂ is collected in each flask after 60 minutes of incubation by adding 0.3 cm³ of ethanolamine:2-methoxyethanol (1:2) to the central well.

0.4 cm of 62.5% citric acid in the cellular medium and in

.30 incubating for 45 minutes. The contents of the central well are transferred to a scintillation counting fluid

14 ~

and the CO2O content is determined. The medium is saponified, acidified (only to determine the rate of lipogenesis), and treated by hexane extraction. At this stage, the lipids are counted (to determine the rate of lipogenesis) or precipitated with digitonin, washed, and counted (to determine the rate of cholesterogenesis). The conversion of μEUO and μC)alanine into fatty acids and ste-

kings is determined in a liquid counting system within-

, . , ~A

tillations. The results are expressed in nmoles of jEIo0 and

1/f.

of (C)alanine transformed into fatty acids or cholesterol and of nmoles of (C)alanine oxidized to CO2 per mg of cells by dry weight per 60 minutes. The results are presented in Table I.

TABLE I

Effect of 3-amino-4-carbomethoxy-2-n-propylthiophene hydrochloride on lipid synthesis and CQ production in isolated rat hepatocytes

Treatment Dose Fatty acid synthesis Cholesterol synthesis Production of

" - —2

nM ^2° [^Cjalanine JHpO ^ ["^Cjalanine [^Cjalanine transformed transformed transformed

As a percentage compared to the control

Control (DMSO) -- 100 100 100 100 100 3-amino- hydrochloride

4-carbomethox^--2-n- 0.05 17* 9* 28* 19* 49*

propyl—thiophene 0.25 21* 10* 29* 21* 50*

0.10 18* 10* , 35* 23* 53*

0.05 18* 11* 33* 26* ' , 34*

0.01 30* 19*- 49* • 31* 73*-

Each vial contains 13.7 mg of cells by dry weight and 25pX of DMSO. Each value is the average of 2 to 14 determinations.

Statistically different from the control value.

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In vivo synthesis of fatty acids and cholesterol

Rats are prepared by fasting them for 48 hours and then feeding them a diet containing 1% corn oil and 70% glucose for 5 to 15 days. On day 5 of the experiment, the compound to be tested is administered to the rats 30 minutes before the 3-hour feeding by oral intubation or after the end of the 3-hour feeding by intraperitoneal injection. The rats are sacrificed by decapitation after an im-

7.

30-minute pulse consisting of; 1 mCi of Ho0, 5 uCi of

Ali.

10 (C)alanine, 12.3 mg of alanine and 30.6 mg of alpha-keto-

Glutaric acid in 0.25 ml of saline solution was administered at the end of the meal, 3 hours later, by intravenous injection into the tail vein. The livers were rapidly excised, saponified, and acidified (only to determine the rate of lipogenesis).

15 and treated by hexane extraction. At this stage, the pips are counted (to determine the rate of lipogenesis) or precipitated with digitonin, washed, and counted (to determine the rate of cholesterogenesis). The *5 *14*

The conversion of H^O and ( "C)alanine into fatty acids or 20 of the sterols is determined in a liquid scintillation counting system.' The results are presented in Tables ' II to V.

TABLE II

Effect of intraperitoneal administration of 3-amino-4-carbomethoxy-2-n~propyl-thiophene hydrochloride on lipogenesis and cholesterol production in vivo.

Dose mmol/kg

Synthesis of reras acids^ Synthesis of cholesterol8, nmoles [^C]alanine ^umoles^IL^O nmoles [^Cjala-

transformed/g/30 min. transformed- Unformed/g/

mees/g/30min. ,n . &/

Control (1% gum arabic)

c 3-amino-M-carbome thoxy-2-n-propylthiophene hydrochloride

0.1

614 - 66

251 - 36*

1.36 to 0.07 35.7 - 3.2

0.85 - 0.06** 17.6 - 1.9

a The results are expressed in yumoles of ^H^O ï11110!63 of (^C)alanine transformed into fatty acids or cholesterol per gram of liver per 30 minutes.

5 * P > 0.01

** p > 0.001

TABLE III

Effect of 3-amino-4-carbomethoxy-2-n-propylthiophene hydrochloride on serum lipids.

Route of administration - Dose - Triglycerides - Cholesterol - Ingestion - moles - Ag mg%

Control (%) gum arabic i.p. 67 ~ 4- 116-7

3-amino-4-carbomethoxy-2-n-■ hydrochloride

propylthiophene i.p. 0.1

51 t 3*

105 ~ 11

* p > 0.01

TABLE IV

Effect of oral administration of 3-amino-4-carbomethoxy~2~n~propylthiophene hydrochloride on the in vivo synthesis of fatty acids.

Dose • Fatty acid synthesis a

simoles/kg, umoles. HgO % of nmoles [Cjalanine % of transformed/ control transformed/g/ control g/30 min. 30 min0

Control (1% gum arabic) 19.6 t 2.4 100 473 ± 76 100

j\o 3-amino- i hydrochloride

_HAS

4-carbomethoxy-2-n- . Y?

propylthiophene 1.2 7.1 - 1.7* 36 162 i 60* ' 34

■y if

The results are expressed in yumoles of HLjO and in nmoles of (C)alanino transformed into fatty acids per g of liver per 30 minutes.

as * p y 0.01

TABLE V

Effect of oral administration of 3-amino-4-carbomethoxy-2-n-propylthiophene hydrochloride on cholesterogenesis.

Pose AHnoles ^Ho0a % of nmolesjj'^Cjalanine8' % of

^oTp./v,, transformed s/ transformed control es/g/30min. . • nmoles/kg g/50 min_ „emoxn

Control (1% gum arabic)

3-Amino-4-Carh ometh oxy-2-n-propylthiophene hydrochloride

+

1.35 - 0.04

1.2

0.4

0.88 t 0.16* 0.96 t 0.05***

100

33.0 t 3.1

100

65 71

15.2 - 3.2** 17.4 t 0.9***

46 53

a The results are expressed in nmoles of ^E^O and in nmoles of ('lZi"C)alanine transformed into cholesterol per g of liver per 30 minutes.

* p >0.05 ** P >0.01 *** p >0.001

The compound of formula I and its pharmaceutically acceptable salts can be administered parenterally as well as orally. For parenteral administration, solutions or suspensions of these compounds in DMSO, water, or acacia gum may be used. Sterile aqueous solutions of the corresponding water-soluble salts are particularly suitable. These dosage forms are especially appropriate for peritoneal injection.

Aqueous solutions, including those of salts, dissolved in 10 parts pure distilled water, are also useful for intravenous injection provided their pH is correctly adjusted beforehand. These solutions should also be appropriately buffered, if necessary, and the liquid diluent should first be made isotonic with a sufficient quantity of saline or glucose solution. In this regard, the sterile aqueous media used are easily prepared by standard techniques well known to those skilled in the art. For example, distilled water is commonly used as a liquid diluent.

The dose required to lower the amount of lipids in the blood will be determined by the nature and severity of the symptoms. Generally, low doses will be administered initially, with a gradual increase in dosage until the optimal level is determined. It is generally found that when the composition is administered orally, larger quantities of the active ingredient are required to produce the same effect as that produced by a smaller quantity administered parenterally. In general, amounts of approximately 0.1 to 1.2 mg of the active ingredient per kilogram of body weight administered in single or multiple dose units noticeably decrease the amount of lipids in the blood.

The following non-limiting examples further illustrate the invention. All temperatures are in degrees Celsius and the ether used is diethyl ether.

35 Example 1

Gaseous hydrochloric acid is bubbled through 1 liter of anhydrous ether in which 100.0 g of 4-carbomethoxy-3-keto-2-propyltetrahydrothiophene oxime has been dissolved. This

-16-

The operation is conducted at 0°C for one hour. The reaction flask is stoppered with a desiccant tube and shaken at room temperature overnight. The solvent is evaporated until the product crystallizes. The white solid matter is collected by filtration and thoroughly washed with ether to give 60.0 g of 3-amino-4-carbomethoxy-2-n-propylthiophene hydrochloride, melting point 178-180°C. The product recrystallizes.

i lise from methanol/ether to give 50.0 g of pure 3~amino~4-carbomethoxy-2~n-propylthiophene hydrochloride, melting point 10 180-181°.

The starting material can be prepared as follows: a) A 116.55 6 solution of 3-mercaptopropionate

3 s of niethyl in 220 cm³ of anhydrous methanol at -20°C is treated with 52.46 g of sodium methoxide. After 20 minutes, a solution of 203.0 g of ethyl 2-bromovalerate in 150 g of anhydrous methanol is added dropwise. The reaction mixture is allowed to warm to room temperature and stirred overnight. The methanol is evaporated, and the residue is divided between ether and water. The organic phase is washed with a 10% sodium bicarbonate solution and water. After drying over magnesium tallow, the ether is evaporated to give 130 g of methyl 4-thia-5-carbomethoxyoctanoate as a colorless oil.

" - b) To a suspension of 54.0 g of sodium methoxide y?

25. In 500 cm³ of anhydrous benzene, 130 g of methyl 4-thia-5-carbomethoxyoctanoate is added dropwise at 25°C. The mixture is stirred overnight and poured into ice water. The aqueous phase is treated by extraction with a benzene/ether mixture (1:1) and then acidified to pH 1 with 6N HCl. The product, which partially separates from the water at this point, is reconstituted in methylene chloride. The aqueous layer is further treated by extraction with methylene chloride. The combined organic phases are dried and evaporated to give 94.0 g of 4-carbomethoxy-3-keto-2-propyltetrahydrothiophene as a colorless oil.

c) A solution of 94.0 g of 4-carbomethoxy-3-keto-2-propyltetrahydrothiophene in 250 cm³ of anhydrous pyridine is treated with 40.0 g of hydroxylamine hydrochloride at 25°C.

-17-

The reaction mixture is stirred overnight at room temperature. The solvent is evaporated and the residue is divided between C1N and methylene chloride. The organic phase is dried over sodium sulfate and evaporated to give 100 g of 4-carbomethoxy-5-keto-2-propyl-tetrahydrothiophene oxime in the form of a colorless oil.

Example 2

A solution of 41.1 g of 4-carbomethoxy-3-keto-2-methyltetrahydrothiophene oxime in 600 mL of anhydrous ether, previously saturated with anhydrous hydrochloric acid gas at 0°, is stirred at 25° overnight. The separated solid matter is collected, thoroughly washed with ether, and dried to yield 33.2 g. Evaporation of the filtrate, after recrystallization of the residue, gives an additional 4.2 g, resulting in a total production of 3-amino-4-carbomethoxy-2-methylthiophene hydrochloride of 37 g. The compound melts at 191-192°.

In a similar way, 49.12 g of 4-carbomethoxy-2-isopropyl-3-keto~tetrahydrothiophene oxime is transformed into 18.49 g of 3-amino-4-carbomethoxy-2-isopropyl-20 thiophene hydrochloride, melting point 185° (dec.).

The starting material can be prepared as follows:

a) A 66.29 g solution of 3-mercaptopropicnate

3 ^

of methyl in 50 cm of anhydrous methanol is cooled to 0°

—t and treated with 120 cm³ of a 25% solution of sodium 25 methoxide in methanol. To this solution, drop by drop, is added

Drop 100 g of ethyl 2-bromopropionate into 100 g of anhydrous methanol. The reaction is allowed to proceed at 25°C overnight. The solvent is evaporated, and the residue is divided between ether and a 10% sodium bicarbonate solution. The aqueous phase is further treated by ether extraction. The combined organic extracts are dried over magnesium sulfate and evaporated to give 121.40 g of 1-ethyl-6-methyl 2-3-thia-1,6-hexanedioate as a pale yellow oil.

35 In a similar way, 61.4 g of 3- are combined

methyl mercaptopropionate with 106.8 g of ethyl 2-bromovalerate to obtain 120.91 g of 1-ethyl-6-methyl 2-isopropyl-3-thia-1,6-hexane-dioate.

-*18™

b) A solution of 121.4 g of 2-methylthia-1,6-

7)

1-ethyl-6-methyl hexanedioate in 90 cm³ of anhydrous benzene is added dropwise to a 30 g suspension of methylate

-£

d© anhydrous sodium in 200 cm of anhydrous benzene. We leave the

\

The reaction continues at room temperature overnight. The mixture is divided between water and ether. The aqueous phase is further treated by benzene extraction. The aqueous phase is then acidified to pH 1 with HCl 62ST and treated by three extractions with methylene chloride. The methylene chloride extracts are combined, dried over sodium sulfate, and evaporated to give 79.17 g of pure 4-carbomethoxy-3-keto-2-methyltetrahydrothiophene as a colorless oil.

In a similar way, 120.91 g of 15' 2-isopropyl-3-thia-1,6-hexane-dioate of 1-ethyl-6-methyl is transformed into

91.0 g of 4-carbomethoxy-2-isopropyl-3-keto-tetrahydrothiophene*

c) A solution of 37.26 g of 4-carbomethoxy-3-keto-2-

18.0 g of methyltetrahydrothiophene in 100 mL of anhydrous pyridine is treated with 18.0 g of hyaroxylamine hydrochloride. The mixture is stirred for 24 hours at 25°C. The reaction mixture is concentrated and divided between hydrochloric acid and methylene chloride. The aqueous phase is treated by double extraction with methylene chloride. The combined organic extracts are dried and evaporated to give 40.1 g of pure 4-carbomethoxy-3-keto-2-methyltetrahydrothiophene oxime as a colorless oil.

Similarly, 52.8 g of 4-carbomethoxy-2-isopropyl-3-keto-tetrahydrothiophene is transformed into 49.0 g of 4-carbomethoxy-2-isopropyl-3-keto-tetrahydrothiophene oxime. Example 3

A solution of 2.7 g of 3-amino-4-carbomethoxy-2-methylthiophene hydrochloride in 35 mL of methanol is treated with 23 mL of 1 N sodium hydroxide. The mixture is heated under reflux for 0.5 h, cooled, and poured into 35 mL of brine. The pH is adjusted to 5, and the mixture is treated by extraction several times with a 4:1 methylene chloride/methanol mixture. The organic extracts are combined, dried, and evaporated to give 1.23 g of 3-amino-4-carbomethoxy-2-methyl-

-19-

Pure thiophene, melting point 162-164°. The compound is recrystallized from ethyl acetate/pentane to give a pure sample for analysis, melting point 163-164°.

In a similar way, 50 g of chlor-5 hydrate of 3-amino-4-carbomethoxy-2-isopropylthiophene is transformed into 3.3 g of 3-3inino-4-carboxy-2-isopropylthiophene, melting point 117-118°.

In a similar manner, 1.41 g of 3-amino-4-carbomethoxy-2-propylthiophene hydrochloride is transformed into 0.625 g of 3-amino-4-carboxy-2-propylthiophene, melting point 144-145°C - Example 4

A solution of 1.03 g of 3-amino-4-carbomethoxy-2-methylthiophene hydrochloride in 30 cm³ of water is treated

5

15 with a solution of 0.45 g of potassium cyanide in 10 cm³ of water. A white solid separates. The mixture is treated by triple extraction with methylene chloride. The organic extracts are combined, dried, and evaporated to give 0.82 g of pure 4-[(amino-carbonyl)-aniino]-5-niethyl-3-thiophene 20 methyl carboxylate. The compound can be recrystallized from ethyl acetate to give a white solid with a melting point of 194–195°C.

Example 5

In a solution of 80.0 g of 4-carbomethoxy-25-3-keto-2-phenyltetrahydrothiophene oxime in 600 mL of anhydrous ether, gaseous hydrochloric acid at 0°C is bubbled through the mixture for one hour. The suspension is treated with 300 mL of methanol and stirred at 25°C overnight. The product is collected by filtration and washed with ether to give 70.0 g of methyl 4-amino-5-phenylthiophene-3-carboxylate hydrochloride as a pale yellow solid, melting point 181-182°C. The compound can be recrystallized from methanol.

The starting material can be prepared as follows:

a) A 104.95 g solution of 3-mercaptopropionate

■5 * •

35 g of methyl in 200 cm³ of methanol is cooled to 0°C and treated with 207.5 g of a 25% sodium methoxide solution in methanol. To the resulting homogeneous solution, 200.0 g of methyl-alpha-bromo-phenolyl is added dropwise under argon.

-20-

•2

acetate in 200 cm³ of methanol. The reaction mixture is stirred at 25°C overnight. The solvent is removed by evaporation and the residue is partitioned between water and methylene chloride to give 234.0 g of di-3-methyl 2-phenyl-3-thia-adipate in the form of a colorless oil.

b) A solution of 234.0 g of dimethyl 2-phenyl-3-thia-adipate in 300 mL of anhydrous benzene is added dropwise at 25°C to 54.05 g of sodium methoxide. The

• The reaction mixture is left overnight and then poured into water. 10 The solid material is isolated by filtration, and the filtrate is treated twice by ether extraction. The solid material is then added to an aqueous phase, which is subsequently acidified to pH 1 with 6 N HCl. The mixture is treated three times by methylene chloride extraction. The organic extracts are 15 dried over sodium sulfate and evaporated to give 145.24 g of 4-carbomethoxy-3-keto-2-phenyltetrahydrothiophene as a pale yellow oil.

c) A solution of 82.24 g of 4-carbomethoxy-3-keto-2-phenyltetrahydrothiophene in 120 cm³ of anhydrous pyridine is

20. The solution was treated with 28.85 g of hydroxylamine hydrochloride. It was stirred at 25°C for two days, and the solvent was evaporated under vacuum. The residue was divided between 1 N HCl and methylene chloride. The aqueous phase was further treated by methylene chloride extraction. The organic extracts were combined, dried over sodium sulfate, and evaporated to give 90.0 g of 4-carbmethoxy-3-keto-2-phenyltetrahydrothiophene oxime as a colorless oil.

Example 6 ••

A 10.0 g solution of 4-amino-5- hydrochloride

3

30 methyl phenylthiophene-3-carboxylate in 80 cm³ of methanol is treated with 82 cm³ of 1 N sodium hydroxide. The reactants are heated under reflux for 30.0 minutes and cooled to room temperature. The fold is set to 5 and the separating product is isolated by filtration and dried for 35 minutes to give 8.2 g of pure 4-amino-5-phenylthiophene-3-carboxylic acid, melting point 201-202° after recrystallization from ethyl acetate/pentane.

~21 —

Example 7

A 13>3 S solution of 4-amino-5- hydrochloride

' ~ 3

• Methyl phenylthiophene-3-carboxylate in 70 cm³ of anhydrous pyridine is treated with 5593 cm³ of acetic anhydride and heated at 50°C for 4.0 hours. At this point, an additional 5 cm³ of acetic anhydride is added and the solution is heated at 50°C for a further 16.0 hours. The reaction mixture is cooled and the solvent is evaporated. The residue is divided between 1 N HCl and methylene chloride. The aqueous phase is further treated by methylene chloride extraction. The organic extracts are combined, dried over sodium sulfate, and evaporated to give 13.7 g of pure methyl 4-acetamido-5-phenylthiophene-3-carboxylate. The compound is recrystallized from ethyl acetate/pentane to give white ai~ 15 guilles, melting point 117-118°.

Example 8

An 8.6 g solution of 4-acetamido-5-phenylthiophene

3-methyl carboxylate in 30 cm³ of methanol is treated

7:

with 34.4 cm³ of 1 N TaOH and heated under reflux for 1.5 hours. The reaction mixture is cooled, acidified with 1 N HCl, and treated by extraction with a methylene chloride/methanol mixture (8:2). The organic extracts are combined, dried over sodium sulfate, and evaporated to give 7.2 g of pure 4-acetamido-5-phenylthiophene-3-carboxylic acid, melting point 182-183°C, after recrystallization from ethyl acetate. Example 9

Preparation of methyl 4-amino-5-ethyl-thiophen-3-carboxylate hydrochloride.

To a solution of 125 g of 30% methyl 3-mercaptopropionate in 75 mL of anhydrous methanol, a 25% solution of sodium methoxide in methanol is added dropwise at 0°C. To this mixture, 200 g of ethyl 2-bromobutyrate in 75 mL of anhydrous methanol is added dropwise at 0°C. The mixture is stirred overnight at 25°C, then concentrated and divided between water and methylene chloride. The organic phase is dried and concentrated, yielding 229 g of diester in the form of a colorless oil.

-22-

To a suspension of 63.5 g of sodium methoxide in 300 cm³ of anhydrous benzene, 229 g of the diester obtained in 200 cm³ of anhydrous benzene are added dropwise at 25°C. The mixture is stirred overnight at room temperature.

-HAS

5. Then poured into 800 cm³ of water, and the benzene layer is extracted with 200 cm³ of water. The aqueous phases are combined, carefully acidified with 6N HCl, and extracted three times with a 5:1 methylene chloride/methanol mixture. The organic extracts are dried and evaporated, yielding 14–9.7 g of pure 10-ketone as a colorless oil.

To a solution of 276.1 g of this ketone in 500 mL of anhydrous pyridine, 121.6 g of hydroxylamine hydrochloride is added per portion. The mixture is left to stand for 20 hours at 25°C, then concentrated and divided between methylene chloride and 3N HCl. The aqueous phase is washed twice with a 5:1 methylene chloride/methanol mixture. The organic phases are dried and evaporated, yielding 253 g of pure oxime in the form of a yellowish oil.

In a solution of 253 g of the oxime obtained in 20.2 liters of anhydrous ether, gaseous hydrochloric acid is introduced at 25°C for one hour. The mixture is seeded with 0.5 g of the solid product and stirred overnight at 25°C. The crude product is filtered, washed with anhydrous ether, and recrystallized from a methanol/ether mixture, yielding 25,173 g of aminothiophene hydrochloride with a melting point of 161°C.

Examples 10 and 11 below illustrate pharmaceutical compositions containing 3-amino-4-carbomethoxy-2-n-propylthiophene hydrochloride as the active compound.

Example 10 30 Capsule Composition

Per capsule

Active ingredient 10 mg 50 mg

Lactose 165 mg 125 mg

Corn starch 30 mg 30 mg

35 Talc ■ . 5 mg 5 mg

Total weight 210 mg 210 mg

-23-

Example 11

Composition in tablet form

Per tablet

Active compound 25.00 mg 5 Dicalcium phosphate dihydrate,

Unground. 17500 mg

Corn starch 24.00 mg

Magnesium stearate 1.00 mg

Total weight 225500 mg

Claims (1)

"24-- formula - CLAIMS -1 - A process for preparing a compound of the 10 in which R,j is a lower alkyl, aryl group, V ^0 aralcoyl, -(CH,)^^ or -CHR^-C^ ^ " _ 2yn 5 7 ^OH 5 5 e a SrouPs ^0 15 hydroxy or -C, R,- being hydrogen, an alkoxy group ^E6 6 lower or amino; R^ is a lower alkyl group, n is an integer from 1 to 6; R2 is hydrogen, a hydroxy group, 5 ^lower alkoxy or amino; R^ and R^, which may be identical or different, are lower alkyl groups, acyl or hydrogen; and salts of such a compound, a process by which a compound of the formula is reacted 25 N-OH II 30 35 in which RJ> is a lower alkoxy group and R^ is such as above, with an acid to obtain a compound of the formula 0 .nh2 there -25- in which Ri> and R^ are such as above, and5 if desired, the lower carbalcoxy group is transformed into a carboxy, formyl or carbamoyl group and/or the amino group is reacted with a lower alkoxide, -ary- y, -alcohol or acylant agent and, if desired, the compound of formula I is transformed into a seà.. 2 - A process according to claim 1 for the preparation of a compound of formula I, characterized in that R^ is a lower alkyl or aryl group, in particular an in-alkyl group 10 lower, R2 is a lower alkoxy or hydroxy group, in particular lower alkoxy; and -N(R^,R^) is an amino, (lower alkanoyl)amino or ureido group, in particular amino. 3 - A method according to claim 1, characterized in that we prepare 3-amino-4-carbomethoxy- hydrochloride / 15 2-n-propylthiophene. 4 - A process according to claim 1, characterized in that methyl 4-amino-5-ethyl-thiophene 3-carboxylate hydrochloride is prepared. 5 - A process for preparing compositions 20 having anti-obesity and quantity-reducing properties of lipids in the blood, characterized in that a compound of formula I given in claim 1 or a pharmaceutically acceptable salt of such a compound is mixed, as an active substance, with inert, non-toxic, therapeutically compatible solid or liquid vehicles commonly used in such preparations, and/or excipients.