DE2632114A1 - CARBONIC ACID COMPOUNDS, PROCESS FOR THEIR MANUFACTURING AND MEANS CONTAINING THESE COMPOUNDS - Google Patents

Description

KRAUS & WEISERT 26321 U

PATENT LAWYERS

DR. WALTER KRAUS DIPLOMA CHEMIST DR.-ING. ANNEKÄTE WEISERT DIPL.-ING. SPECIALIZATION CHEMISTRY IRMGARDSTRASSE 15 D-8OOO MÜNCHEN 71 TELEPHONE 089 / 797077-797078 TELEX O5-212156 kpatd

TELEGRAM KRAUS PATENT

1276 WK / rm

Societe Civile de Recherches et d'Etudes Nouvelles

S.C.R.E.E.N., Paris / France

Carboxylic acid compounds, process for their preparation and agents containing these compounds

In the German patent specification .. .. «^ * ······ (P 25 01 834.2, DT-OS 2 501 834) are carboxylic acid derivatives and a process for their preparation and containing these compounds Medicines described.

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As already stated in DT-OS 2 501 834, these acids have therapeutic properties of great interest and they are used as active ingredients especially for appetite suppressant drugs.

A group of compounds from this family has now been found which have a particularly high appetite suppressant effect Owns activity.

The compounds of the invention are alkoxybenzoylcyclopentanecarboxylic acids of the general formula I:

(I)

in the

and

denotes a methyl or ethyl group and R ″ denotes a hydrogen atom or in which R ^ denotes a hydrogen atom and R ₂ denotes a methyl or ethyl group, and in which

R ^ is a lower alkyl group and / or a hydrogen atom mean.

The invention also relates to Gemsiche of compounds of the formula I as well as means which such compounds or Contain mixtures thereof.

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Preferred agents or compositions contain positional isomers, ie at the same time products in which R ^ is a methyl or ethyl group, while R _{2 is} a hydrogen atom, and products in which FL is a hydrogen atom, while R ^ is a methyl or ethyl group. In one group of compounds according to the invention, the isomers of the second type predominate and they are present in amounts in particular approximately from 51 to 70% by weight, based on the mixture.

The invention also relates to racend compounds and active isomers as well as the derivatives, in particular the esters and their physiologically acceptable salts.

A preferred group of compounds according to the invention corresponds to the general formula II:

COOK

(IX)

in which the substituents R ^ to R ^ have the meanings given above to have.

The compounds _t according to the invention in which R ·, and R ^ are both lower alkyl groups are particularly preferred.

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When the substituents R ₁ , R ₂ , R, and R ^ are an alkyl group, then it is particularly preferred that the latter be a methyl group.

The compounds according to the invention are produced by a Friedel-Crafts condensation manufactured.

To do this, it is used in an organic solvent and in the presence of a catalyst, e.g. aluminum chloride, aluminum bromide or zinc oxide, a metadisubstituted benzene derivative of the general formula III:

(III)

with an anhydride of camphoric acid of formula IV:

(IV)

in which the substituents R ^ to R ^ are those given above Have meanings to.

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This condensation stage is carried out in a solvent in which the starting materials are soluble. Advantageously, by operating at a temperature of -5 to +5 ⁰ C, preferably around ⁰ ° C.

The compounds of the invention can be extracted from the mixture with ether and this is then distilled removed"

According to the invention it is possible to use either one or the other of the positional isomer compounds or a mixture of isomers in various desired proportions depending on the polarity of the solvent used to obtain.

Thus, using a solvent of strong polarity, the isomers in which R _{1 is} methyl or ethyl are obtained.

If you have solvents with increasingly weaker polarity is used, then the mixture becomes richer in the isomers in which R £ is a methyl or ethyl group.

Among the solvents with strong polarity, solvents such as nitromethane are particularly preferred. Under the Solvents with weak polarity are, if one strives for a mixture of isomers, the predominantly those of the the second type contains solvents such as carbon disulfide and 1,2-dichloroethane, particularly well suited.

The positional isomers can each be obtained from the mixture according to classical separation methods, for example through crystalline

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sation or distillation. One can also treat the acid mixture with an alcohol to form the corresponding esters and, for example, fractionate them Subject to crystallizations. The esters separated in this way then become the corresponding acids saponified.

The following examples explain the process according to the invention for the preparation of acids of the formula I.

example 1

Production of a mixture of left-handed 3- (2 *, 4 · - Dimethoxybenzoyl) -2,2,3-trimethylcyclopentanecarboxylic acid and levorotatory 3- (2 ', 4'-dimethoxybenzoyl) -1,2,2-trimethylcyclopentanecarboxylic acid of formulas V and VI:

VX

2.5 g of D (+) - camphor anhydride are mixed with 2.7 g of 1,3-dimethoxybenzene in 30 ml of 1,2-dichloroethane. 3.8 g of aluminum chloride are added in portions at ^{0 ° C. with stirring}

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added. After the reaction mixture has reached ambient temperature has returned, stirring is continued for 2 hours. The reaction mixture is poured onto ice and it becomes extracted with ether after addition of hydrochloric acid.

After washing the ethereal solution and distilling off the ether, 3.0 g of an oil are obtained which slowly crystallizes. This represents a mixture of 47.5% 3- (2 ', 4 »-dimethoxybenzoyl) -1,2,2-trimethylcyclopentanecarboxylic acid and 52,59 ^ 3- (2', 4 * -dimethoxybenzoyl) -2, ^ - trimethylcyclopentanecarboxylic acid represent.

Example 2

Production of levorotatory 3- (2 ^r , 4 * -dimethoxybenzoyl) -2,2,3-trimethylcyclopentaricarboxylic acid of the above formula ^:

To 16 g of an acid mixture according to Example 1, 500 ml of anhydrous methyl alcohol, which is saturated with dry hydrogen chloride gas, are added and the mixture is then refluxed for 4 minutes. After distilling off the alcohol, 11 g of a mixture of the methyl esters of the acids mentioned are obtained. Recrystallization of the Estergemisches in petroleum ether to 4.6 g Methylester of 3- (2 x, 4 x -Dimethoxybenzoyl) -2,2,3-trimethylcyclopentanecarboxylic acid with a mp. Of 108 ⁰ C obtained.

By saponifying 2 g of this ester with 30% alcoholic potassium and under reflux for 2 hours, 5 »5 g of 3- (2 ^f , 4'-dimethoxybenzoyl) -2,2,5-trimethylcyclopentanecarboxylic acid with a melting point of 134 ° C received. .

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Analysis of this acid gives the following results:

Microanalysis C% E%

theoretical 67.5 7.5 found 67.39 7.56

Optical rotation = [a] _D 20 ⁰ C «-14.1 (1 = 1, · e = 2.5 in CHCl ₃ ) Example 3

Preparation of the racemic 3- (2 ', 4'-dirnethoxybenzoyl) -2,2,3-trimethylcyclopentanecarboxylic acid:

The procedure is as in Examples 1 and 2, but the levorotatory camphoric anhydride is replaced by the corresponding racemic derivative. In this manner, 4.6 g of the Methylesters with a mp. Of 82 ⁰ C and 5.5 g of racemic acid with a mp. Of 158 ° C obtained.

Example 4

Preparation of the levorotatory 3- (2 ', 4 ^f -dimethoxybenzoyl) -1,2,2-trimethylcyclopentanecarboxylic acid of the formula VI given above:

2.5 g levorotatory camphor anhydride are mixed with 2.7 g 1,3-dimethoxybenzene in 30 ml nitromethane. At ⁰ ° C., 3.8 g of aluminum chloride are added in portions and with stirring. When the reaction mixture has returned to ambient temperature, stirring is continued for 2 hours. The reaction mixture is then poured onto ice. Towards-

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hydrochloric acid is extracted with ether.

After washing the ethereal solution and distilling off the ether, a residue is obtained which crystallizes in an ethanol / water or in an ether / petroleum ether mixture. In this manner, 1.7 g of 3- (2 _'t 4'-dimethoxybenzoyl) -1,2,2-trimethylcyclopentanecarboxylic acid obtained with a mp. Of 145 ° C.

The analysis of this acid gives the following results:

Microanalysis C % H %

theoretically 67.5 7.5

found 67.35 7.55

Optical rotation = [a] _D 22 ° C = - 51.4 ° (c = 2.5; 1 = 1 in CHCl ₃ ) Example 5

Preparation of the racemic 3- (2 *, 4 * -dimethoxybenzoyl) -1,2,2-trimethylcyclopentanecarboxylic acid of the formula VI given above:

The procedure is as in Example 4, but using the racemic anhydride of camphoric acid. In this way, 1.7 g of the acid with a melting point of 182 ^° C. are obtained.

The new compounds according to the invention have therapeutically useful properties and, in particular, particularly

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remarkable appetite suppressant effects as it is gives the results of pharmacological tests given below.

As part of these investigations, the effect of 3- (2 *, 4 ^f -dimethoxybenzoyl) -1 ^^ - trimethylcyclopentanecarboxylic acid and 3- (2 ^f ^ '- dimethoxybenzoyl) ^^, 3-trimethylcyclopentanecarboxylic acid and a mixture of these acids according to Example 1 determined on the amount of feed consumed by rats.

Male Wistar strain rats with an average body weight of 150 g were used in groups of 10 animals. Each animal was placed in a single cage. Weighing was carried out for 2 days prior to the examinations determined the amount of feed that had been consumed by the animals during 24 hours. Then it became the same for 5 days Treatment carried out, which included:

At 9 a.m.: weighing the animals

at 9.30 a.m .: oral administration of 5 mg / kg body weight the rat of a 1% solution of the substances according to the invention. to the rats, in the case of the comparison animals only administration of the equal volume of distilled water

at 10 a.m.: Calculation of the amount of feed consumed in 24 hours by weighing the remaining feed.

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On the first day of treatment, there was a decrease in the amount of the ingested feed was observed in the treated rats. The body weight decreased on the second Treatment day.

At the end of the fifth day the reduction in ingested was Feed amount 52%, $ 48 and 53% based on that Comparison animals. The reduction in body weight was 15% »12% and 16%, based on the comparison animals.

The results obtained prove the importance of the appetite suppressing effect of the substances according to the invention and in particular that effect caused by the mixture Caused by positional isomers according to Example 1 will. In contrast, it is about a reduction in body weight in the order of magnitude as they evoke by administering the compounds of the invention in Quantities of 5 mg / kg achieved, required 100 mg / kg of 3- (p-methoxybenzoyl) -1,2,2-trimethylcyclopentanecarboxylic acid to be used according to the main patent.

The compounds according to the invention have practically no toxicity. They have a particularly remarkable harmlessness. The DLc ₀ was determined in mice by oral administration of the substances in the form of an aqueous suspension. The results obtained for 3- (2 ^l , 4 ^l -dimethoxybenzoyl) -1,2,2-trimethylcyclopentanecarboxylic acid and for 3- (2 ¹ ^ * -dimethoxybenzoyl) -2,2,3-trimethylcyclopentanecarboxylic acid are 1.50 g / kg or more than 5 g / kg.

Because of their valuable properties, the present invention Compounds valuable active ingredients, especially

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for the treatment of all types of obesity and overweight.

The unit dose is about 20 to 100 mg, preferably about 40 to 75 mg. The daily dose is approximately 100 to 300 mg and preferably about 50 mg to 200 mg.

The medicaments according to the invention can preferably be peroral in the form of tablets, capsules, coated tablets or Solutions are administered in ampoules »

The compounds according to the invention can also be administered rectally or parenterally. In all cases, the Compounds together with inert carriers or diluents that are customary for pharmaceutical products, be used.

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Claims (13)

P a t e η t a η s p r ü c he 1. Carboxylic acids g e k e η η ζ ei c h η e t through the general formula I: - in which R ^ denotes a methyl or ethyl group and Rg denotes a hydrogen atom or in which Rx denotes a hydrogen atom and R2 denotes a methyl or ethyl group, and in which R., and Rr denote a lower alkyl group and / or a hydrogen atom. 2. Carboxylic acids according to claim 1, g e k e η η characterized by the general formula Ils > CN y c H CH cook ■ 6Ü3Ü85 / 1 1 8 6 in which R ^, Rg, R * and R ^ are given in claim 1 Have meanings. 3. Carboxylic acids according to claim 1 or 2, characterized in that both substituents R, and R ^ are lower alkyl groups. 4. Optical isomers and racemates of the compounds according to Claim 1 or 2. 5. Derivatives, especially esters and addition salts with physiologically acceptable acids, the compounds according to any one of claims 1 to 4. 6. Mixture, characterized in that there are compounds of the formula I in which R * is a methyl or ethyl group and R «is a hydrogen atom, and compounds of the formula I in which R«. represents a hydrogen atom and ^R _{2 represents} ^a methyl or ethyl group, or contains esters of these compounds or their corresponding salts. 7. Mixture according to claim 6, characterized in that it predominantly, in particular in an amount of about 51 to 70 wt .-% of the mixture, contains compounds in which R, j is a hydrogen atom and R _{2 is} a methyl or ethyl group. 8. Racemic or levorotatory carboxylic acids, namely 3- (2 ', 4 * -Dirnethoxybenzoyl) -2,2,3-trimethylcyclopentanecar- -15- 609885/1 1 86 bonsäure, 3- (2 *, A'-dimethoxybenzoylO-i, 2,2-trimethylcyclopentanecarboxylic acid or a mixture thereof, in particular in the respective approximate proportions of 52.5 and 47.5 parts by weight. 9. methyl esters of acids according to claim 8. 10. Process for the preparation of carboxylic acids of the formula I according to claim 1, characterized in that that one in a Friedel-Crafts condensation reaction in the presence of a catalyst such as aluminum chloride, aluminum bromide or zinc oxide, and in an organic one Solvent in which the starting materials are soluble, a benzene derivative of the formula III: a). with an anhydride of the combat acid of the formula IVj . (IV) 6 098 857 1186 wherein R ^ to R ^ have the meanings given in claim 1 have implemented. 11. The method according to claim 10, characterized in that in order to predominantly obtain compounds of the formula I ₉ in which R ^ is a methyl or ethyl group and R _{2 is} a hydrogen atom, a solvent with strong polarity, such as nitromethane, or that, in order to obtain predominantly compounds in which R _{1 is} a hydrogen atom and Rg is a methyl or ethyl group ₉ , a solvent with a weak polarity _s such as 1 _ΰ 2-dichloroethane or carbon disulfide is used. 12o drug characterized ₉ g © _g denotes that it contains as active ingredient mindesttas © © ine compound according INEM of claims 1 to 9. 13. Medicaments, in particular appetite suppressants, according to claim 12s, characterized in that it is present or administered in unit doses of 20 to 100 mg and in daily doses of 100 to 300 mg. 609885/1 186