CH517068A - Aryloxy and arylthio-acetic acid derivs - Google Patents

Abstract

Aryloxy- and arylthio-acetic acid derivs. Cpds. (I), useful as hypolipaemic and anti-inflammatory agents: (where R1 is 1-10C alkyl or benzyl; R2 is H or Me; R3 is H or alkyl; X is O or S) are prepd. by standard methods from the 20ols or 2-thiols through the dicarboxylic acids or nitriles or amides which cpds. also form part of the invention. Prefd. cpds. are the 2-heptanoic acids.

Description

  

  
 



  Process for the preparation of new aryloxy and arylthioacetic acid derivatives
The present invention relates to a process for the preparation of new aryloxy and arylthioacetic acid derivatives.



   Compounds of the general formula I
EMI1.1
 in which Rr is an alkyl group with a maximum of 10 carbon atoms or the benzyl group, R2 is hydrogen or the methyl group, R5 is a lower alkyl group and X is oxygen or sulfur, have not yet become known.



   As has now been found, these compounds and the alkali and alkaline earth metal salts of the free carboxylic acids corresponding to the esters of the general formula I, which can be administered orally or rectally, have interesting pharmacological properties and a high therapeutic index. In particular, they show hypolipemic efficacy, which z. B.



  in the lowering of cholesterol and triglyceride levels in the blood and liver after repeated oral administration to male rats according to standard methods. The total cholesterol is determined according to R. Richterich and K. Lauber [cf. Clin. Wochenschr.



  40, 1252-1256 (1962)] directly in the serum.



  Furthermore, according to J. Folch et al. [see. J. Biol. Chem.



  226, 497 (1957)] serum and liver lipids extracted and triglycerides and total cholesterol with the autoanalyzer according to G. Kessler and H. Lederer [cf. Automation in der analytischen Chemie (1965), Technicon GmbH, Frankfurt / M, pages 863-872, or W. D. Block et al., Ibid. Pages 970-971].



   In the compounds of the general formula I, R1 as an alkyl group having a maximum of 10 carbon atoms is z. B. the methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, 2,2-dimethyl-propyl, hexyl, isohexyl, 3,3-dimethyl-butyl, heptyl , Octyl, nonyl or decyl group. As a lower alkyl group, R3 denotes e.g. B. the methyl, ethyl, propyl or isopropyl group.



   According to the process according to the invention, carboxylic acid esters of the general formula I are prepared by adding a nitrile of the general formula II
EMI1.2
 in which X, R1 and Re have the meaning given under formula I, reacts with a lower alkanol in the presence of water and mineral acid. Several variants are possible for carrying out the method according to the invention. For example, the nitrile of the general formula II can be refluxed in the presence of an equimolar amount of sulfuric acid and water with an excess of lower alkanol. The end product is isolated by diluting the reaction mixture with water, the ester of general formula I, which is sparingly soluble in this medium, separating out as a crude product.



   In a further embodiment of the process according to the invention, the nitrile of the general formula II can first be converted into the imidoester hydrochloride by reaction with a lower alkanol in the presence of a mineral acid, for example hydrogen chloride, and this can then be hydrolyzed to an ester of the general formula I.



  The conversion of the nitrile into the imidoester hydrochloride is advantageously carried out in a solvent. As such, e.g. B. serve excess alkanol, ether or chloroform. The reaction temperature is between 0 and 100. The subsequent hydrolysis of the salt of the imidoalkyl ester can be carried out in water or optionally in a mixture of water and a lower alkanol corresponding to the imidoalkyl ester at a reaction temperature of about 20-50.



   Finally, water can also initially be added to a nitrile of the general formula VII and the amide obtained can be subjected to alcoholysis in the presence of a mineral acid. The addition of water to the nitrile is advantageously carried out in 80-95% strength sulfuric acid and an excess of alkanol is added to the resulting solution of the amide in sulfuric acid and the mixture is refluxed. The easiest way to isolate the end product is to dilute the reaction mixture with water, the desired ester separating out as the crude product.



   Examples of starting materials of the general formula VII are those nitriles, the radicals X, R1 and R2 of which correspond to the groups which were listed after formula I. These nitriles can e.g. B.



  obtained when starting from 4b, 5,6,7,8,8a-hexahydro-fluoren-2-ol- or -2-thiol, these compounds are converted into the sodium derivatives by means of sodium ethylate in methanol and the sodium derivatives with 2 haloalkane -nitriles or α-halohydrocinnamonitriles.



   The 4b, 5,6,7,8,8a - hexahydro - fluoren - 2 - ol is z. B. prepared as follows: You start from 2- (m-methoxybenzylidene) cyclohexanone [cf. R. Baltzli et al., J. Am.



  Chem. Soc. 77, 624 (1955)], which is reduced catalytically in the presence of Raney nickel to 2- (m-methoxybenzyl) -cyclohexanone; the reduction product cleaves in the presence of conc. Sulfuric acid intramolecularly from 1 mol of water and goes over with ring closure in the 2-methoxy-5,6,7,8-tetrahydro-fluorene, which catalytically in the presence of palladium carbon to 2-methoxy-4b, 5,6,7,8, 8a-hexahydro-fluorene is hydrogenated; the ether obtained is split by means of hydroiodic acid. For the preparation of 4b, 5,6,7,8,8a hexahydro-fluorene-2-thiol one goes from 1,2,3,4,4a, 9a hexahydro-fluorene [cf. W. Treibs and E. Heyner,
Chem. Ber. 90, 2285 (1957)]. Conc.

  Sulfuric acid and acetic anhydride convert this compound into crude 4b, 5,6,7,8,8a-hexahydro-fluorene-2-sulfonic acid, which converts phosphorus oxychloride into 4b, 5,6,7,8,8a-hexahydro-fluorene- 2-sulfonyl chloride converts. The sulfonyl chloride is reduced to the thiol with the aid of lithium aluminum hydride.



   As mentioned above, the compounds of the general formula I are administered orally or rectally. The daily doses range between 0.5-10 mg / kg for warm-blooded animals. Suitable dosage unit forms, such as dragees, tablets, suppositories and capsules, preferably contain 10-250 mg, e.g. B. 50 or 100 mg, of a compound of the general formula I.



   Unit dosage forms for oral use contain as active ingredient preferably between 10 and 90 million of a compound of general formula I. To prepare them, the active ingredient is combined, for. B.



  with solid, powdery carriers such as lactose, sucrose, sorbitol, mannitol; Starches, such as potato starch, corn starch or amylopectin, also laminaria powder or citrus pulp powder; Cellulose derivatives or gelatin, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols, to tablets or to dragee cores. The dragee cores are coated, for example, with concentrated sugar solutions, which z. B. can also contain gum arabic, talc and / or titanium dioxide, or with a varnish that is dissolved in volatile organic solvents or solvent mixtures. Dyes can be added to these coatings, e.g. B. to identify different drug doses.



   Push-fit capsules made of gelatin and soft, closed capsules made of gelatin and a plasticizer, such as glycerine, are suitable as further oral unit forms. The push-fit capsules contain the active ingredient preferably as granules, e.g. B. in a mixture with fillers such as corn starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers such as sodium metabisulfite (Na2SgO) or ascorbic acid. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as liquid poly ethylene glycols.



   As unit dosage forms for rectal use, for. B. suppositories into consideration, which consist of a combination of an active ingredient with a suppository base material. As a suppository base are z. B. natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkanols. Gelatin rectal capsules, which consist of a combination of the active ingredient and a base material, are also suitable. As a base material are such. B. liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.



   The following examples explain the preparation of the compounds of general formula I and salts thereof in more detail, but are not intended to restrict the scope of the invention in any way. The temperatures are given in degrees Celsius.



   Examples
1.485 g (5 mmol) of 2- (4b, 5,6,7,8,8a-hexahydrofluoro-2-yloxy) -heptanoic acid nitrile are dissolved in 50 ml of chloroform and 5 ml of abs. Dissolved ethanol and treated with a stream of dry hydrochloric acid at 0-5. The solution saturated with hydrogen chloride is left to stand overnight at room temperature and the blue-green colored reaction solution is then evaporated in vacuo at 30-35. The residue is taken up in 10 ml of dioxane and 2 ml of water and stirred at 40 for 5 hours. After the dioxane has been evaporated off in vacuo and the water is removed azeotropically by repeated distillation with benzene, the crude product is taken up in benzene and the ammonium chloride which has precipitated out is filtered off.

  The filtrate is evaporated on a rotary evaporator and the crude ester is purified by chromatography on silica gel (Merck; 0.05-0.2 mm; eluent: benzene). 1.34 g, 77.9% of theory, result in ethyl 2- (4b, 5,6,7,8,8a-hexahydrofluoren-2-yloxy) -heptanoate in the form of a colorless oil, n 2D: 1.5112.



   The starting compound, 2- (4b, 5,6,7,8,8a-hexahydrofluoren-2-yloxy) -heptanoic acid nitrile, can be obtained as follows: a) A solution of 33.5 g (0.155 mol) 2- ( m methoxybenzylidene) cyclohexanone [cf. R. Baltzli et al., J. Am. Chem. Soc. 77, 624 (1955)] is in 350 ml of abs. Ethanol is hydrogenated with hydrogen in the presence of 3 g of Raney nickel at room temperature and normal pressure. After 1 mol of hydrogen has been taken up, the reaction solution is filtered off from the catalyst and the solvent is evaporated in vacuo. The residue, 2- (m-methoxybenzyl) -cyclohexanone, is in the form of an oil (nr) ': 1.5374), which is processed further directly.



   b) A solution of 9.7 g (0.0444 mol) of the compound obtained according to a) is cooled in an ice bath. Then it is added dropwise with stirring at 0-5 117 ml (2.1 mol) of conc. Sulfuric acid is added, the mixture is stirred for a further hour and the orange-colored reaction mixture is poured onto ice. Then the mixture is extracted with ether, the ether solution is washed with 2N sodium carbonate solution and water, dried over sodium sulfate and evaporated. The residue, which crystallizes, is recrystallized several times from ethanol. 6.5 g of pure 2-methoxy-5,6,7,8tetrahydrofluorene with a melting point of 590 are obtained, which is unstable at room temperature (yield 73%).



   c) 13.5 g (0.067 mol) of the compound obtained according to b) are dissolved in 200 ml of abs. Dissolved ethanol and added an ethanolic slurry of 1.5 g (5%) palladium on carbon to the solution. The solution is hydrogenated at room temperature and atmospheric pressure until 1 mol of hydrogen has been taken up, then the catalyst is filtered off and the solvent is evaporated in vacuo. 12.8 g of a colorless oil are obtained which solidify in crystalline form on standing in the cold. Recrystallization from ethanol gives 11.7 g of pure 2-methoxy4b, 5,6,7,8,8a-hexahydrofluorene with a melting point of 290 (yield 85.8% of theory).



   d) A solution of 10.9 g (0.054 mol) of the compound obtained in c) in 50 ml of glacial acetic acid and 50 ml of 57% aqueous hydriodic acid (d: 1.70) is refluxed for one hour. The reaction mixture is then poured onto ice and extracted with ether. The organic phase is washed with 2N sodium carbonate solution and water, dried over sodium sulfate and evaporated. The residue is recrystallized from gasoline, 7.5 g (73.9% of theory) of 4b, 5,6,7,8,8a-hexahydro-fluoren-2-ol having a melting point of.



     92-940 received.



   e) 1.68 g (35 mmol) of a 50% sodium hydride dispersion are dissolved in 140 ml of abs. Dimethylformamide entered. Then 6.59 g (35 mmol) of 4b, 5,6,7,8,8a-hexahydrofluoren-2-ol are added and the reaction mixture is heated to 350. The solution of the sodium hexahydrofluorene then becomes the solution while stirring and passing in nitrogen 7.6 g (40 mmol) of 2-bromo-heptane aurenitrile were added dropwise to -2-olats. After 3 hours of heating to 600, stirring is continued for 1 hour at 700 and then the solvent is evaporated off in vacuo. The oily residue is distributed between ether and water, the ether phase is washed with 1N sodium hydroxide solution and then with water, dried over sodium sulfate and the solvent is evaporated off on a rotary evaporator.

  The crude product is purified by column chromatography (silica gel Merck; 0.05-0.2 mm; eluent: benzene). This gives 6.22 g, 59.8% of theory, 2- (4b, 5,6,7,8,8a-hexahydrofluoren-2-yloxy) -heptanoic acid nitrile in the form of a colorless oil, n 2D0: 1.5239 .



   2.2 g of 4b, 5,6,7, 8,8a-hexahydrofluoren-2-ol are recovered by elution with benzene: ethyl acetate (9: 1).

 

Claims (1)

PATENT CLAIM Process for the preparation of new aryloxy and arylthioacetic acid derivatives of the general formula I, EMI3.1 in which R1 is an alkyl group with a maximum of 10 carbon atoms or the benzyl group, R2 is hydrogen or the methyl group, R3 is a lower alkyl group and X is oxygen or sulfur, characterized in that a nitrile of the general formula II, EMI3.2 in which X, R1 and R2 have the meaning given in claim 1 under formula I, reacted with a lower alkanol in the presence of water and mineral acid.