SE446734B - PROCEDURE FOR PREPARING 4- (2-TIENYLMETHYLAMINO) -BENZOIC ACID DERIVATIVES - Google Patents

Description

Wherein R is hydrogen or C 1-3 alkyl and X, Y and Z are independently hydrogen, chlorine or bromine, with the proviso that at least one of X, Y and Z is chlorine or bromine.

Pharmaceutically acceptable salts of the p-aminobenzoic acids, i.e. when R is hydrogen, is also within the scope of the invention. Pharmaceutically acceptable salts refer to acid addition salts of the bases which form a salt with a carboxylic acid and which do not cause any harmful physiological effect when administered to an animal at a dosage which gives good pharmacological activity. Thus suitable bases include, for example, alkali metal and alkaline earth metal hydroxides, carbonates and bicarbonates such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium bicarbonate or magnesium carbonate; ammonia, primary, secondary and tertiary amines. Aluminum salts can also be obtained by treating the corresponding sodium salt with a suitable aluminum complex, such as aluminum chloride hexahydrate.

The compounds of the invention have been shown to have hypolipidemic activity in animals, especially in mammals. Hypolipidemic activity herein refers to the ability to lower blood lipid levels and in particular serum cholesterol and triglyceride levels. The compounds are therefore suitable for the treatment of serum hyperlipidemia in mammals and are particularly useful for the treatment of hypercholesterolemia and hypertriglyceridemia, i.e. abnormally high levels of lipids, cholesterol and serum triglycerides. The compounds may be administered orally or parenterally by subcutaneous, intravenous or intraperitoneal injection or by implantation, but oral administration is most suitable.

The effective hypolipidemic amount of the p-aminobenzoic acid compounds intended to be administered to an animal, i.e. the amount that effectively and significantly lowers the serum lipid level may vary with respect to such factors as the animal treated, the compound specifically used, the intended lipid level, whether or not the animal is hyperlipidemic, the period of administration and the mode of administration.

In general, an effective daily dose ranges from about 1 mg / kg body weight to 200 mg / kg body weight, especially a daily dose of about 10-100 mg / kg body weight.

For oral administration, pharmaceutical preparations can be prepared using the following conventional techniques. These methods include granulation and pressing, when required, or mixing of various kinds and dissolving or suspending the components to achieve the desired purpose. A variety of pharmaceutical forms can be used to support the compounds. Thus, for example, the pure compound may be used or it may be mixed with a solid carrier. 446 734 3 In general, inorganic pharmaceutical carriers are particularly suitable, especially solid inorganic carriers. One reason for this is the large number of inorganic materials which are known to be pharmaceutically safe and acceptable as well as being very suitable in the manufacture of compositions. The compositions may be prepared in the form of tablets, linguettes, powders, capsules, dilutions, trocets or lozenges and such compositions may be prepared according to standard pharmaceutical techniques.

Tablet compositions may be coated or uncoated and may be formulated as effervescent tablets. Conventional excipients for tablet formulation years can be used. Thus, for example, inert diluents such as magnesium carbonate or lactose, disintegrants such as corn starch or alginic acid, and lubricants such as magnesium stearate may be used.

If a liquid carrier is used, the preparation may be prepared in the form of a soft gelatin capsule, syrup, liquid solution or suspension.

The hydrocarbon solubility of most compounds of the invention is high enough to allow the use of pharmaceutically acceptable oils and carriers. Thus, for example, vegetable or animal oils can be used, such as sunflower oil, safflower oil, corn oil or cod liver oil. You can also use glycerol. The latter solvent can be added with 2-30% water. When only water is used as carrier or when the solubility of the compound in oil is low, the preparations can be administered in the form of a slurry.

Emulsion compositions can be prepared using emulsifiers such as sorbitan trioleate, polyoxyethylene sorbitan monooleate, lecithin, acacia or tragacanth. Aqueous suspensions may be prepared by means of wetting agents, such as polyethylene oxide condensation products of alkylphenols, fatty alcohols or fatty acids with suspending agents, such as a hydrophilic colloid, for example polyvinylpyrrolidone. The emulsions and suspensions may contain conventional excipients, such as sweeteners, colorants or preservatives.

The compounds can also be incorporated into a nutritious food, such as butter, margarine, edible oils, casein or carbohydrates. Such nutritional compositions are suitable for administration as a partial or total diet or as additives to the diet. Such compositions preferably contain about 0.02 to 2.0% of active ingredient when administered as the total diet. The compositions may contain higher concentrations of the active component when administered as an additive. For parenteral use, the compounds may be formulated with sterile components, mixed and packaged aseptically. They can be administered intravenously or intramuscularly. Common solvents for such compositions are polyhydric aliphatic alcohols and mixtures thereof. Particularly satisfactory are the pharmaceutically acceptable glycols, such as propylene glycol, and mixtures thereof. Glycerol is especially suitable. Up to 25-30% by volume of water can be incorporated into the vehicle, if desired. An 80% propylene glycol solution in water is a particularly suitable solvent system. A pH of approximately 7.4 and isotonicity compatible with body isotonicity are desirable.

The basicity can be controlled by adding a base as needed and a particularly suitable base is monoethanolamine. It is often desirable to incorporate a local anesthetic and these are generally known to those skilled in the art.

The content of compound to be used in the pharmaceutical carrier can be varied. It is necessary that the compound be of such a proportion that a suitable dosage be obtained and it is especially convenient to use pharmaceutical compositions containing at least 10% by weight of the compound. The activity increases with the concentration of the agent in the carrier, but those compositions which contain a significant amount of carrier, such as at least 1% and preferably at least 5%, are most suitable. as they allow for easier administration of the compound.

The active compounds of the invention are prepared according to known procedures. In general, the compounds are prepared by reacting p-aminobenzoic acid or an ester thereof in an inert solvent with a halogen-substituted 2-thiophenecarboxaldehyde. The resulting Schiff base is reduced to give the corresponding p-aminobenzoic acid derivative. A suitable method of carrying out the latter procedure involves mixing the Schiff's base with an excess of ethanol and water. Diluted sodium hydroxide solution in water may optionally be added to the mixture. Sodium borohydride is added at room temperature and the mixture is stirred until complete dissolution. The mixture is then heated, poured onto ice and acidified. The product can be filtered off in the form of a precipitate and further purified according to known methods.

Several of the halogenated aldehydes were not readily available and were prepared from methods well known in the literature. Thus, for example, 4-chloro-2-thiophenecarboxaldehyde was prepared by chlorination of 2-thiophenecarboxaldehyde using a large excess of aluminum chloride catalyst. See J. Org. Chem., Gl, 381 (1956) and J. Heter. Chem., 393 (1976). Using the same method, 4,5-dichloro--2-thiophenecarboxaldehyde was also prepared from 5-chloro-2-thiophenecarboxaldehyde. See C.A. 57; The invention is further illustrated by the following examples, in which the temperatures indicated refer to degrees Celsius.

Example Gel 1- 4- (3,5-Dichloro-2-thienylmethylamino) -benzoic acid A 50% oil dispersion (5.8 g, 0.12 mol) of sodium hydride was washed with hexane under nitrogen. The mixture was added with 200 ml of dry dimethylformamide and 29.5 g (0.113 mol) of solid ethyl N-trifluoroacetyl-4-aminobenzoate. The reaction mass showed a weak exothermic reaction.

The mixture was cooled to 20 ° and stirred for 15 minutes. Then 27.7 g of 3,5-dichloro-2-bromomethylthiophene were added. The reaction mass was heated for 18 hours at 850. The mixture was then poured into 1 liter of cold water and extracted with methylene chloride. The product was dried over anhydrous sodium sulfate and the dried solution was concentrated to a brown oil. This was refluxed for two hours together with 50 ml of ethanol and 200 ml of SN sodium hydroxide solution. The cooled, brown solution was diluted with water and acidified with acetic acid. The crude 4- (3,5-dichloro-2-thienylmethylamino) -benzoic acid was obtained as a brown sticky product and recrystallization from propylene glycol methyl ether gave 17 g of brown crystals, m.p.

Calculated: C 47.71 H 3.00 N 4.63 Found: C 47.8 H 3.06 N 4.74 Example gel 2. 4- (5-chloro-2-thienylmethylamino) -benzoic acid A mixture containing 46.6 g (0.34 mol) of p-aminobenzoic acid, 50 g (0.4 mol) of 5-chloro-2-thiophenecarboxaldehyde and 400 ml of toluene were refluxed for 3.5 hours. The water formed was collected in a Dean-Stark trap. The reaction mass was then cooled and the Schiff's base was recovered as a tan solid. A mixture of the Schiff's intermediate base and 1.2 liters of glacial acetic acid was added with 21.2 g (0.35 mol) of dimethylaminoborane. The reaction mass was heated for about 30 minutes at 400 and poured into 2 liters of ice water. The white precipitate of 4- (5-chloro-2-thienylmethylamino) -benzoic acid was washed in water, dried and recrystallized from toluene. Yield 60 g (70%), melting point 177-17 °.

Example 3. 4- (4,5-Dichloro-2-thienylmethylamino) -benzoic acid Step 1: Synthesis of 4,5-dichloro-2-thiophenecarboxaldehyde A mechanically stirred solution of 31.8 g (0.217 mol) of 5-chloro -2-Thiophenecarboxaldehyde in 150 ml of methylene chloride was added with 659 (0.487 mol) of anhydrous aluminum chloride in small portions. The mixture showed a 446,734 exothermic reaction and turned purple. This mixture was added dropwise with 20.6 g (0.29 mol) of chlorine in 250 ml of carbon tetrachloride. The reaction mass was refluxed for about 15 hours and an additional 15 g (0.2 mol) of chlorine in 200 ml of carbon tetrachloride was added. The mixture was refluxed for an additional 7 hours. The reaction was quenched by the addition of over one liter of ice water. The aqueous layer was extracted with chloroform.

The chloroform solution was washed with water and sodium bicarbonate solution.

After drying over anhydrous sodium sulfate and concentration in vacuo, a tan oil was obtained. The crude 4,5-dichloro-2-thiophenecarbozaldehyde crystallized on storage and was recrystallized from hexane.

Step 2: The product 4- (4,5-dichloro-2-thienylmethylamino) -benzoic acid, m.p. 225-2270, was prepared from the 4,5-dichloro-2-thiophenecarboxaldehyde intermediate in substantially the same manner as described in Example 2; yield 88%.

Calculated: C 47.71 H 3.00 N 4.63 Found: C 47.6 H 3.09 N 4.80 In addition to the compounds described in the previous examples, other compounds were prepared using essentially the same technique.

These compounds are summarized in Examples 4, 5 and 6.

Example 4. 4- (5-Chloro-2-thienylmethylamino) -benzoic acid ethyl ester, m.p. 108-1099, was prepared from ethyl p-aminobenzoate and 5-chloro-2-thiophenecarbosaldehyde. Yield 87%.

Calculated: C 56.86 H 4.77 N 4.73 Found: C 56.7 H 4.87 N 4.85 Example 5. 4- (5-bromo-2-thienylmethylamino) -benzoic acid, m.p. 188-197 ° C, yield 61 %.

Calculated: C 46.18 H 3.23 N 4.49 Found: C 46.1 H 3.29 N 4.65 Example 6. 4- (4-chloro-2-thienylmethylamino) -benzoic acid, m.p. 165-1680, yield 96%.

Calculated: C 53.85 H 3.77 N 5.23 Found: C 53.6 H 3.80 N 5.38 7 446 734 Example gel 7.

The hypolipidemic effect of the compounds of the invention was illustrated in rats. In this experiment, a compound was dissolved in acetone, taken up on silica gel and mixed with normal ground feed to give a concentration of 0.125% of the compound in the animal feed. The treated feed was administered to male rats weighing 150-160 g for 14 days. After the feeding period, the rats were sacrificed and blood samples were taken. The liver was removed, weighed and frozen for future analysis.

The relative levels of serum cholesterol in the blood samples were determined according to the Henly method. A.A. Henly, Analyst, 82, 286 (1957). Liver cholesterol was determined according to the Sperry-Webb method. Journal of Biological Chemistry, 187, 97 (1950). The relative levels of triglycerides in the blood and liver samples were determined by the method according to Von Handel and Zilversmit.

J. Lab. Clin. With. 50, 152 (1957) and Clin, Chem, 7, 249 (1961). By taking the mean levels of the control rats as standard, the mean results of the treated groups were obtained.

Table I summarizes the results obtained from these studies. .cmmmsuma fl onpcox wwš mm fl wumwim fifl cmuswu mnm fi ncmswn mm Hmm mcmuHm>> m cwms fl uwcw m flfi msu fl muoum: mm umumucwmwumwu mumø mm flfi uñmm 446 734 ^ X ON + W: H: + ON: + m: w 1 w + Hm: Nwx v HH + N: am: m: wm: mv: m æ + m: vd: ß + wm: vn: N w fl + ON + m: mv: Am: H umø fl uwuæ fl m fi uu Houwpmw fl oä xnww fl uwoæ fl m fl N fi oumumw fi ox .us Hwmëmxm xux fl> uw> øA xux fl> wmm0HM X: nw> øQ X | Hw> wA lësnww: ënuwm wc flfi muwm H H fl wnmë 446 734 9 of serum cholesterol and serum triglycerides, while only minimal changes in liver weight and total body weight are achieved. The compounds 4- (4,5-dichloro-2-thienylmethylamino) -benzoic acid (Example 3) and 4- (5-chloro-2-thienylmethylamino) -benzoic acid ethyl ester (Example 4) were found to be particularly valuable for lowering cholesterol levels in mammals. Similarly, the compounds 4- (5-chloro-2-thienylmethylamino) -benzoic acid ethyl ester (Example 4) and 4- (4-chloro-2-thienylmethylamino) -benzoic acid (Example 6) were found to be particularly effective in lowering serum triglycerides. .

Claims (7)

446 734 CLAIMS 1. An analogous process for the preparation of a 4- (2-thienylmethylamino) -benzoic acid compound of the formula / \\\ '1'; \ / \. Wherein R represents hydrogen or C1-3-alkyl and X, Y and Z are independently hydrogen, chlorine or bromine, with the proviso that at least one of X, Y and Z is chlorine or bromine, and pharmaceutically acceptable salts thereof, characterized by reacting a 4-aminobenzoic acid compound corresponding to / \ NH 2 N a X “S CHO wherein R, X, Y and Z have the meaning given above, and reduce the Schiff base formed. An analogous process according to claim 1, characterized in that 4- (3,5-dichloro-2-thienyl-methylamino) -benzoic acid is prepared. 3. An analogous process according to claim 1 which comprises preparing 4- (5-chloro-2-thienylmethylamino) -benzoic acid. 4. An analogous process according to claim 1, wherein the preparation is prepared from 4- (4,5-dichloro-2-446,734,11-thienylmethylamino) -benzoic acid. 5. An analogous process according to claim 1 characterized in that 4- (5-bromo-2-thienyl-methylamino) -benzoic acid is prepared. An analogous process according to claim 1, characterized in that 4- (4-chloro-2-thienylmethylamino) benzoic acid is prepared. An analogous process according to claim 1, characterized in that 4- (5-chloro-2-thienylmethylamino) -benzoic acid ethyl ester is prepared.