KR810000630B1 - Process for preparing cyclic compounds - Google Patents

Abstract

Title compds. [I; R1 = low alkyl, aryl, aralkyl; R2= H, hydroxy, low alkoxy, amino; R3, R4 = low alkyl, aralkyl, H and their salts, with antiobese and hypolipemic effect, were prepd. Thus. compd.II(R2 = low alkoxy) was reacted with acid to give compd. [Ia , and if necessary, low carbalkoxy group is converted o carboxy, formyl or carbamoyl group, and/or amino group is alkylated with low alkylating agent or aralkylating agent.

Description

Method for preparing cyclic compound

The present invention relates to a process for preparing a cyclic compound having the following structure (I) and a salt thereof, which is effective as a lipid lowering agent.

In the above structural formula

R ₁ is lower alkyl, aryl, aralkyl

R ₂ is hydrogen, hydroxy, lower alkoxy or amino

R ₃ and R ₄ may be the same or different and are lower alkyl, aralkyl, or hydrogen.

Structural formula (I) compounds and salts thereof are useful as agents for the treatment of obesity and for lowering lipid levels in the blood. These compounds are also useful in the treatment of circulatory disorders associated with atherosclerosis and elevated blood lipid levels. Structural formula (I) of the present invention, unlike the novel 3-amino-thiophene-4-carboxylic acid derivatives, the compounds described in US Pat. No. 3,076,817 are 3-amino-thiophene-2-carboxylic acid derivatives. Furthermore, compounds of formula (I) are used as effective anti-obesity and blood lipid lowering agents, as described below, whereas the compounds of the US patent are used only as intermediates for preparing dyes and pharmaceutical products. Mixed forms such as "lower alkyl" alone or "lower alkoxy" or "aralkyl" in this specification are straight or branched saturated aliphatic alkyls having 1 to 8 carbon atoms, such as methyl, ethyl, propyl or isopropyl. . Halogens contain four elements: chlorine, bromine, iodine and fluorine. “Aryl” is a mononuclear aryl group, such as phenyl or substituted phenyl, substituted at one or more of the trihalomethyl, aralkyl, halogen, lower halk, such as lower alkyl, trifluoro or trichloromethyl C, amino, nitro, mono or di-lower alkylamino. "Alkali metal" means sodium, potassium or lithium. "Lower alkanol" means an alkanol having 1 to 6 carbon atoms. In the present specification, “alkoxide” refers to a metal salt, and alkali and alkaline earth metal salts of alkanols are preferable. Alkaline-to-metal means calcium, barium or magnesium. "Lower alkanophosphate" refers to alkanophosphate having 1 to 8 carbon atoms.

Preferred compounds of formula (I) are those in which R ₁ is lower alkyl or aryl, in particular lower alkyl, R ₂ is lower alkoxy or hydroxy, in particular lower alkoxy and -N (R ₃₁ R ₄ ) is amino.

According to the present invention, the compound of formula (I) and salts thereof are treated with an acid to produce a compound of formula (IIa) and optionally a lower carboalkoxy group with a carboxy, formyl or carbamoyl group. And / or the amino group is reacted with a lower alkylating agent or an aralkylating agent and, if necessary, converted into the salt of structural formula (I).

In the above structural formula

R ' ₂ is lower alkoxy

R ₁ is as described above.

Compounds of formula (Ia) are oximes of formula (II) with acids, preferably halogens and hydrogen acids, most preferably with hydrochloric acid, ethers, in particular di (lower alkyl) ethers, ie diethyl ether, tetrahydrofuran or dioxin It can be obtained by treatment in an inert organic solvent such as cyclic ether, lower alkanol or water. The temperature and pressure conditions of this reaction are not critical. The reaction can be suitably carried out at atmospheric pressure between 0 ° C. and 70 ° C., preferably at room temperature.

Structural formula (Ia) compounds can be converted to the cast (I) aldehyde acids, amides or other esters or salts thereof according to conventional methods of converting the corresponding esters to the abovementioned compounds. The lower carboalkoxy groups contained in the compounds of formula (Ia) are therefore preferably used in conventional inert organic solvents, preferably lower alkanols, in particular methanol or ethanol, water soluble ether solvents, preferably water soluble dilower alkyl ethers, in particular diethyl. Te may be converted to the carboxy group by basic hydrolysis in water or in water-soluble cyclic ethers, in particular tetrahydrofuran or dioxane. Preferred bases include alkali metal hydroxides such as sodium hydroxide, potassium and lithium, and alkali earth hydroxides such as barium hydroxide, calcium and magnesium, and are particularly suitable for alkali metal paper at 100 ° C. and reflux conditions are preferred. In particular, 70 ℃ is good. The ester of structure (Ia) can be treated with a reducing agent such as LiAlH ₄ to obtain the corresponding primary alcohol which can then be oxidized to manganese dioxide or the like to oxidize the corresponding aldehyde of structure (I). The ester of formula (Ia) is treated with ammonia to obtain the corresponding amide of formula (I) wherein R ₂ is amino. When R ₃ and / or R ₄ is lower alkyl or aralkyl, it is preferred to introduce this group according to conventional methods of converting aromatic primary amines to their N-substituted derivatives. Thus, the primary amine of formula (Ia) can be reacted with an aralkylating agent such as a lower alkylating agent aralkyl halide such as lower alkyl halide.

The compound of formula (II) may be obtained by reacting a compound of formula (III) with a compound of formula (IV) to produce a compound of formula (IV).

In the above structural formula

R ₁ and R ' ₂ are as described above

R is lower alkyl

R ₈ is a halogen, mesyloxy or tosyloxy group.

The reaction can proceed in the presence of alkoxides of lower alkanols and alkali metals, preferably methanol and sodium methoxide. Although temperature and pressure conditions are not critical, the reaction generally proceeds at a temperature of 15 to 60 ° C., preferably 25 ° C., at atmospheric pressure.

The compound of formula V is then treated with an alkoxide of an alkali metal, preferably sodium methoxide, in the presence of an aromatic hydrocarbon, preferably benzene, to give the compound of formula VI.

In the above structural formula

R ₁ and R ′ ₂ are as described above.

Although temperature and pressure conditions are not critical, the reaction is generally run at 15 ° to 60 ° C., preferably 25 ° C., at atmospheric pressure.

The compound of formula (VI) is then converted to the oxime of structure (II) using conventional methods of converting ketones to oximes. It is preferable to treat the ketone of the formula (VI) in a base containing nitrogen with a hydroxy amine hydrohalide, preferably hydroxyamine hydrochloride. All conventional nitrogen containing bases, preferably amines, can be used.

The amines that may be used include lower alkylamines, in particular methylamines, or primary amines such as aniline, lower alkylamines, in particular secondary amines such as dimethylamine or diethylamine or pyrrole and trilower alkylamines, in particular trimethylamine or tri Ethylamine, or tertiary amines such as pyridine and picoline. Temperature and pressure conditions are not critical. The reaction is suitably carried out at room temperature to reflux at atmospheric pressure, preferably in an inert organic solvent such as aliphatic or aromatic hydrocarbons such as n-hexane or benzene at 22 ° C. This reaction is preferably carried out in a base containing excess nitrogen used as the solvent.

Intermediates of formula (II) wherein R ₁ is aryl, aralkyl are all novel and are also contained in the present invention.

The process for preparing an amine of formula (I) from the corresponding ketone of formula (VI) via an oxime of formula (II) is analogous to the process described in US Pat. No. 3,978,084, ie, the oxime of formula (II) This can be done by converting the ketone of formula (I) to the amine of formula (III).

As mentioned above, thiophene derivatives of the formula (I) and their pharmaceutically harmless salts are effective lipid lowering agents, for example, having a function of lowering the lipid concentration in mammals. This action was demonstrated by animal experiments on a group of Charles River rats, 150-180 g normal. They are initially fed with a corn oil-glucose mixture for several days and then the test compound is mixed orally or parenterally with dimethyl sulfoxide (DMSO).

The concentrations of triglycerides, fatty acids and cholesterol in the blood of rats treated with the test compound resulted in a significant decrease compared to the concentrations of the corresponding substances in the control group without administration. Similar results were obtained for rat hepatocytes.

Synthesis of Fatty Acids and Cholesterol in Isolated Hepatocytes

The Charles River rat is starved for 48 hours and then fed with 1% corn oil and 70% glucose for 7-14 days between 11 AM. Isolated mouse liver cells are prepared from intact livers. Hepatocytes are incubated in a vibrating water bath at 37 ° C. for 60 minutes. Each flask contains 1 ml of isolated rat hepatocytes (10 to 20 mg of dry cells), 1 ml of pH 7.4 Crebbs-Henslide bicarbonate buffer, 16.5 mmol glucose, 1 micromol L-alanine, 1 μCi [ ¹⁴ C] it can contain alanine, 1μ Ci ³ H ₂ O and pH7.4 (otherwise technology also) for a total of 2.1ml containing an inhibitor of 2 mmol of H ₂ O or DMSO. All cultures should be three per condition and all experiments should be repeated at least twice. 0.3 ml of ethanolamine / 2-methoxy-ethanol (1: 2) of carbon dioxide was added to the center well, and 0.4 ml of 62.5% citric acid was added to the cell medium and incubated for 45 minutes to incubate for 60 minutes. Collect. Transfer the material from the center wells to the scintillator counting solution and quantify the amount of ¹⁴ CO ₂ . The medium is saponified and acidified (only to measure the lipidation rate) and hexane is extracted. At this stage, the lipids can be calculated (to determine the rate of lipidation) or precipitated with digitonin and washed and then calculated (to determine the rate of cholesterol). The conversion of ³ H ₂ O [ ¹⁴ C] alanine to either sucrose or sterols is measured by a liquid scintillator counter. The data are also expressed in millimoles of [ ¹⁴ C] alanine of ³ H ₂ O converted to cholesterol and nmoles of [ ¹⁴ C] alanine oxidized to ¹⁴ CO ₂ per mg dry cell per 60 minutes. The results are the same in Table (I).

TABLE 1

a) Each flask contains 13.7 mg of dry cells and 25 mM of DMSO. Each value is the average of 2 to 15 measurements.

Statistically different from the control value.

Fatty acid and cholesterol synthesis in vivo

Rats starve for 48 hours and again feed 1% corn oil and 70% glucose for 5-15 days. On the day of the experiment, rats are administered orally by tube 30 minutes before 3 hours of meal or by intraperitoneal injection after 3 hours of meal. Mice were treated with 1m Ci ³ H ₂ O, 5μCi [ ¹⁴ C] alanine, 12.3mg alanine, and 30.mg α-ketoglutaric acid in 0.25ml physiological saline for 30 minutes, and then the vein in the tail vein. Kill the throat after the injection. Liver is quickly removed, saponified and acidified (just to measure the rate of lipidation). Extract with hexane. At this stage, lipids can be counted (to measure the lipidation rate) or precipitated with digitonin, washed and counted (to measure the cholesterol rate). The conversion of ³ H ₂ O [ ¹⁴ C] alanine to fatty acids or sterols is measured by a liquid scintillator counter. The results are shown in Tables (II)-(V) below.

TABLE 2

Data are expressed in μmole [ ¹⁴ C] alanine in n mole for 30 min, ³ H ₂ O converted to fatty acids or cholesterol per g liver.

* P ＞ 0.01 ** P ＞ 0.001

TABLE 3

* P ＞ 0.01

TABLE 4

Claims (1)

Reacting a compound of formula (II) with an acid to produce a compound of formula (Ia), converting the lower carbalkoxy group to a carboxy, formyl or carbamoyl group and / or an amino group as a lower alkoxylating agent, Or reacting with an aralkylating agent and, if necessary, activating the compound of formula (I) with a salt thereof.

Wherein R ₁ is lower alkyl, aryl, aralkyl, R ₂ is hydrogen, hydroxy, lower alkoxy or amino and R ₃ and R ₄ are the same or can be handled and are lower alkyl, aralkyl, or hydrogen and R ' ₂ is lower alkoxy.