DE1911539C3 - Sulfur-containing substituted benzoic acids and agents containing them - Google Patents

Description

COOH

S (O) _n - A

10

(Y = COOH)

COOH

in which R is a chlorine atom, η = zero and A is the 4-chlorobenzyl, 2-chlorobenzyl, 3-bromobenzyl or 2-methoxybenzyl group or R is the trifluoromethyl, M = Zero and AdieBenzyKu-methylbenzyl, 4-chlorobenzyl or 3,4-dimethoxybenzyl group or R is a hydrogen atom, η = 1 and A is the benzyl group and their pharmaceutically acceptable salts with inorganic bases.

2. 2- (4-ChlorbencyIt hio) -5-chlorobenzoic acid.

3. 2- {u- Methylbenzylthio) -5-trifluoromethylbenzoic acid.

4. Means for reducing the lipid level in the blood, characterized by a content of a compound according to claim 1.

30th

hydrolysis

S-A

oxidation

COOH
J -SO A

35

The invention relates to the subjects described in the claims.

The new compounds lower the level of lipids in the blood of humans and mammals.

Patients suffering from atheroscopic eyelet show one abnormally high levels of cholesterol in the blood. Atherosclerosis. a form of arteriosclerosis through an internal thickening of the main blood vessels on Gruni '. a local gathering from lipids, which consist mainly of cholesterol and other / <- lipoproteins such as triglycerides. In the advanced stages of the disease, cholesterol and other lipoproteins accumulate containing platelets in the aorta, coronary, cerebral and peripheral arteries of the lower extremities at. If these particles become larger, the risk of fibrin deposition increases Thrombosis and occlusion can result. In addition to a special diet, various Therapeutics like estrogens, thyroxine analogs and Sitosterol supplements have been used with varying degrees of success for lowering cholesterol.

The compounds of the invention can be prepared by various methods. In which The process shown in Reaction Scheme I is an appropriately substituted benzylmereaptane (HS-A) either with a halobenzonitrile or a halobenzoic acid in the presence of alkali, usually potassium or sodium hydroxide. In some cases the addition is recommended a small amount of a copper catalyst.

In the above scheme, Y represents a cyano or carboxyl group, while R and A represent those in the claim 1 have the same meaning (where n = 1 for the compound obtained by oxidation, in the case of the unoxidized compounds, however, «= O).

If a chlorobenzonitrile is used as the starting material, the benzyl mercaptide is usually produced by treating the benzyl mercaptan with an alkali metal alkoxide in a lower one Alkanol, /. B. with sodium ethylate in ethanol. The alkali metal benzyl mercapid is isolated and dissolved in anhydrous dimethylformamide. This solution then becomes the correspondingly substituted one Chlorobenzonitrile added (scheme I). After the reaction mixture to complete the reaction was stirred at room temperature, it is poured into water, and the crude, substituted Benzylthiobenzonitrile is extracted with a suitable solvent, generally ether. That Solvent is then evaporated and the crude product is refluxed with a aqueous sodium hydroxide solution containing little ethanol, hydrolyzed. After the ethanol has evaporated the remaining oil is extracted with ether. When the ether evaporates, an oil is obtained is suspended in water. The aqueous suspension is acidified, and the substituted benzylthiobenzoic acid, which is deposited in the process is isolated.

As can be seen from Scheme 1, substituted chlorobenzoic acid can also be used in place of chlorobenzonitriles use as raw materials. In this case, the chlorobenzoic acid is heated several times Hours with a benzyl mercaptan and a strong base, e.g. B. potassium or sodium hydroxide, and usually a small amount of copper powder. The reaction mixture is then cooled, filtered and diluted with mineral acid, then the substituted benzylthiobeizoic acid is isolated.

The benzylbenzoic acid sulfoxides are produced by oxidation of the corresponding benzylthiobenzoic acids This oxidation can be done with common oxidizing agents such as nitric acid, potassium permanganate or chromium trioxide can be carried out; however, hydrogen peroxide in glacial acetic acid is particularly recommended or in formic acid.

Another synthesis of the compounds according to the invention is shown in Reaction Scheme II:

Reaction scheme II
Cf) OH

+ Shark -A

IO

20th

COOH

oxidation

COOH

R-

SO-A

35

40

In the above scheme, Hai denotes a chlorine, bromine or iodine atom in group A which, like R, has the meaning given in claim 1 (where = 1 for the compound obtained by oxidation, but = 1 for the unoxidized compounds η = O).

According to Reaction Scheme II, a substituted one Mercaptobenzoic acid with a substituted egg or optionally unsubstituted benzyl halide (Hal.-A) in an alkaline mixture implemented a lower alkanol and water. In general, sodium carbonate is preferred as the alkali. After brief heating, most of the solvent is evaporated off and the residue is diluted with water. When acidifying with dilute mineral acid, the desired one separates substituted benzylthiobenzoic acid from: while the benzyl-benzoic acid sulfoxide, as previously described, obtained by oxidation of 2-benylthio-benzoic acid will.

Most of the starting materials used to make the compounds of the invention are known from the literature; so the benzyl halides are expediently from the corresponding Substituted toluene prepared, for example the chlorides and bromides! Easily by reaction of the appropriately substituted toluene with chlorine or bromine, preferably under UV irradiation. The production is also possible by reacting the compounds mentioned with sulfuryl chloride ia Presence of a peroxide possible.

The Benzylrnercaptans (see. Reaction scheme I) are expediently from the corresponding halides produced, which is first heated with thiourea in absolute ethanol, whereupon under Aqueous sodium hydroxide solution is added to further heating. The bulk of the ethanol will be evaporated at reduced pressure, and the remaining aqueous solution is acidified, the mercaptan is extracted with ether and in itself cleaned in a known manner.

To prepare the 2-halo-5-substit.-benzoic acids (see Reaction scheme I), the reactive Halogen in position 2 in the phenyl ring by diazotizing the amino group accordingly substituted aminobenzoic acid and treating the resulting diazbüium salt with an inorganic ash Halide are formed.

The 2-mercaptobeozoic acids used according to reaction scheme II are also made from the corresponding aryldiazonium salts. One can these diazonium salts either with sodium sulfide react with the formation of an aryl disulfide, which when reduced with zinc dust-acetic acid the desired 2-mercaptobenzoic acid results, or with potassium ethylxanthate, which results in a phenyldithiocarbonate leads, which also provides the desired product after decomposition in an alkaline solution.

The pharmaceutically acceptable salts of the above described compounds according to the invention are also effective agents for reducing the Lipid levels in the blood of mammals. Although the pharmacological effect of the molecule from the anion it is necessary to use a salt with a pharmaceutically acceptable cation, usually one works with cations like ammonium, sodium. Potassium, calcium and magnesium ions. The salts of the compounds described above are prepared in a manner known per se, for example by adding the acid to an aqueous solution containing an equivalent amount of a pharmaceutical Contains allowable base, d. H. a base containing one of the above cations, and then Concentration of the resulting mixture “Suitable bases are hydroxides, carbonates and bicarbonates. Salts with pharmaceutically unacceptable bases can be used to purify the above compounds and also use for the production of pharmaceutically acceptable salts

For example, a raw acid can be purified, by dissolving them in an aqueous solution of a pharmaceutically unacceptable base and the resulting solution extracted with a suitable organic solvent to remove the non-acidic impurities to remove. By acidifying the remaining solution, the pure acid is separated out, which can be filtered. In the manner described above, this acid can then be converted into a pharmaceutically acceptable salt are transferred.

example 1

12.4 g (0.1 M mol) of benzyl mercaptan are added to 100 ml of ethanol given. While passing nitrogen through the solution, 100 mls of 1 molar are added Sodium ethylate solution in ethanol too. The solvent is then evaporated, and the crude, solid

Sodium mercaptide is made with JOO dal anhydrous dimethylformamide offset. The resulting solution is then 21 g (0.10 mol) of 4-CbJor-3-cyanobenzotrifluoride admitted. The reaction mixture is s under nitrogen at room temperature for half an hour long and then poured into about 800 ml of ice water. After stirring this mixture for 5 minutes is extracted 4 times with 200 ml of ether each time.

The extracts are combined, dried over anhydrous sodium sulfate and evaporated, whereby after drying under high vacuum. a pale yellow Ui which turns to a solid on standing crystallized. In this way, 27.4 g (94%) of 2-benzylthio.5-trifluoromethylbenzonitrile are obtained.

In about 15 ml of ethanol, 17.5 g (0.06 mol) of the above raw compound are added, then become 200 ml of 20% sodium hydroxide solution were added.

This reaction mixture is refluxed for about 27 hours. After removing the main set Ethanol at reduced pressure is the Ul present in the aqueous phase in three portions extracted from each 200 ml of ether. The ether extracts are combined and evaporated, the remaining oil is suspended in about 500 ml of water. This suspension is made with 6N hydrochloric acid acidified, and the white solid which separates out is filtered off. 15.7 g (84%) of 2-benzylthio-5-trifluoromethylbenzoic acid are obtained from melting point 169 to 174 ° C. After recrystallization from benzene the melting point is 180 to 181 C.

Neutralization Equivalents 315

Theoretical value 312

Analysis for C ₁₅ H ₁₁ F ₁ O ₂ S:

Calculated ... C 57.68. H 3.55%;
found .... C 57.46, H 3.64%.

Using the appropriate starting parameters, the following procedures are made according to the above Compounds made: 2- (4'-chlorobenzylthio) -5-trifluoromethyl-benzoic acid. F. 183 to 184.5 C.

Analysis:

Calculated ... C 51.95. H 2.91%;
found .... C 52.24, H 2.91%.

2- (u-Methylbenzylthio) -5-trifluoromethyl-benzocic acid, F. 140 to 142 C.

Analysis:

Calculated ... C 58.89. H 4.01%;

found .... C 58.61. H 4.07%.

Example 2

To a solution of 4.15 g (0.030 mol) of potassium carbonate in 50 ml of water are successively 100 ml of ethanol, 0.030 mol of 5-chloro-2-mercapto-benzoic acid and 2.030 moles of 2-methoxybenzyl chloride. As soon as the carbon dioxide development subsides, the mixture is refluxed on a steam bath for 1 hour. Then it cools down, and the majority of the solvent is evaporated off under reduced pressure. The cloudy, white one liquid residue is diluted with water to a volume of about 600 ml. This mixture will then filtered, cooled and acidified with 6N hydrochloric acid. The separating white precipitate

35 is filtered off and rubbed with about 400 ml of water. After filtering and drying in a high vacuum, 2 · (2'-Methoxybenz7lthio) -5-chlorobenzoic acid: mp 178 to 179 C.

Example 3

Treating 1 mol of 2-benzylthio benzoic acid with 1 mol of hydrogen peroxide (as a 30% solution) in Glacial acetic acid or formic acid. In general, it is heated to about 100 C (steam bath) until all of the hydrogen peroxide is present is used up (the presence of hydrogen peroxide is determined with starch-iodide paper). Then the reaction mixture is diluted with water and the benzylbenzoic acid sulfoxide becomes isolated and crystallized from a solvent: F. 161 to 162 C.

Analysis:

Calculated ... C 64.59, H 4.65%:
found .... C 64.67. H 4.79%.

Example 4

0.10 mol of 2-benzylthio-5-trifluoromelhylbenzoic acid are added with stirring to 500 ml of an aqueous solution of 0.10 mol of sodium hydroxide. Once everything is resolved. the resulting solution is concentrated, 0.10 mol of the sodium salt being added the starting acid receives.

Using equivalent amounts of the appropriate The following salts are obtained from the above process for bases. Potassium, ammonium. Calcium and magnesium salt of 2-benzylthio-5-trifluoromethylbenzoic acid.

According to the above procedure, the pharmaceutically acceptable sodium, potassium, ammonium, Calcium and magnesium salts are formed from the compounds of the previous examples.

Example 5

0.10 mol of crude 2-benzylthio-5-trifluoromethylbenzoic acid, prepared according to procedure I, are added in 1 liter of an aqueous solution of 0.05 mol of Ba (OH) ₂ .8 H ₂ O with stirring. The solution is extracted with ether and concentrated, 0.05 mol of the barium salt of the starting acid being obtained.

The barium salt is then added to water, the resulting solution is acidified, and the Purified 2-benzylthio-5-trinuormethy! -benzoic acid, which separates out in the process, is isolated. The pharmaceutical Allowable salts of this acid can be prepared according to the procedure of the previous example will.

The following compounds according to the invention were also produced:

2- (3 ', 4'-Dimethoxy-benzylthio) -5-chloro-benzoe-

acid, m.p. 219 to 222 ° C,
2- (2'-chloro-benzylthio) -5-chloro-benzoic acid,

F. 195 to 196.5 ° C,
2- (4'-chloro-benzylthio) -5-chloro-benzoic acid,

F. 165 to 170 "C,
2- (3'-bromo-benzylthio) -5-chloro-benzoic acid,

F. 166 to 167.5 ° C.

Claims (1)

Reaction scheme I. Patent claims: I. Sulfur-containing substituted benzoic acids of the formula + HS-A (Y = CN)