DE2632114C3 - Cyclopentanecarboxylic acid compounds, processes for their preparation and compositions containing these compounds - Google Patents

Description

CH, CH ₃

in which Ri is a methyl or ethyl group and Rj stands for a hydrogen atom, or in the Ri denotes a hydrogen atom and R2 denotes a methyl or ethyl group, and in which R3 and R4 is a lower alkyl group or a hydrogen atom mean their optical isomers, esters, especially methyl esters, and physiologically acceptable ones Salts.

2. Racemic or levorotatory 3- (2 ', 4'-DimethoxybenzoyO ^^ S-trimethylcyclopentanecarboxylic acid or 3- (2 ', 4'-dimethoxybenzoyl) -l, 2,2-trimethylcyclopentanecarboxylic acid or their mixtures with an approximate proportion of the first mentioned 51-70 wt% compound.

3. Process for the preparation of the compounds according to claim 1, characterized in that one in a manner known per se in a Friedel-Crafts reaction in the presence of a known catalyst, such as aluminum chloride, aluminum bromide or zinc oxide, and in an organic solvent, in which the starting materials are soluble, a benzene derivative of the formula III

R ₄ O

CH ₁
CH,

(IV)

Il ο

in which Ri to R4 have the meanings given in claim I, and the acid _{b0 obtained is} optionally separated into the optical isomers by methods known per se, esterified or converted into physiologically acceptable salts.

4. The method according to claim 3, characterized in that in order to obtain predominantly compounds b ^r > of the formula II, in which Ri is a methyl or ethyl group and R _{2 is} a hydrogen atom, a solvent with a strong subject of DE -OS 25 01 834 are drugs that contain at least one carboxylic acid of the general formula

(UI)

with an anhydride of camphoric acid of the formula IV

(R3OL

R ₄ O

-CO-

in the Ri-R4 have the following meaning and n = 0 or 1 denotes, in addition to customary carriers or diluents.

As already stated there, these acids have great therapeutic properties Interest and are used in particular as active ingredients for appetite suppressant drugs.

A group of connections in this family has now been found that are very special has high appetite suppressing activity.

The compounds of the invention are alkoxybenzoylcyclopentanecarboxylic acids of the general formula 1

OR,

R ₄ O

CH.,

in the

50

55 denotes a methyl or ethyl group and R2 denotes a hydrogen atom or in which Ri denotes a hydrogen atom and R2 denotes a methyl or ethyl group, and in which

and R4 is a lower alkyl group or a hydrogen mean torn whose optical isomers, Esters, especially methyl ester, and physiologically acceptable salts.

Mixtures of 51-70% by weight of 3- (2 ', 4'-Dimeihoxybcnzoyl) -2,2,3-trimethylcyclopentanecarboxylic acid are particularly advantageous and 3- (2 ', 4'-dimethylbenzoyl) -1 ^ -trimethylcyclopentanecarboxylic acid.

The compounds according to the invention in which Ri and R4 are both lower alkyl groups become special preferred.

When the substituents Ri, R2, Rj and R4 are an alkyl group it is particularly preferred that the latter be a methyl group.

The compounds according to the invention are in an

known way by a Friedel-Crafts reaction of a benzene derivative of the general formula III

(III)

Example 1

Mixture of levorotatory 3- (2 ', 4'-dimethoxybenzoyl ^ ÄS-trimethylcyclopentanecarboxylic acid (V) and levorotatory 3- (2 ', 4'-dimethoxybenzoyl) -1, 2,2-trimethylcyclopentanecarboxylic acid (VI)

OCH ₃

10

with an anhydride of the martial acid of the formula IV O

(IV)

15th

20th

ΌΟΗ (VI)

CH ₃ O

CHX COOH (V)
CH, CH,

25th

in which the substituents Ri to R4 have the meanings given above, in an organic solvent in which the starting materials are soluble, in the presence of a known catalyst, such as aluminum chloride, aluminum bromide or zinc oxide, jo produced. It is advantageous to work at a temperature of -5 to +5 "C., preferably in the region of ⁰ ° C.

If appropriate, the acid obtained can be converted into the optical isomers by methods known per se separated, esterified or converted into a physiologically acceptable salt.

The compounds according to the invention can be extracted from the mixture with ether, and this is then removed by distillation.

According to the invention it is possible to use either one or the other of the positional isomers or a Mixture of isomers with different proportions depending on the polarity of the solvent used to echo.

So if you use a solvent with strong polarity, you get the isomers in which Ri is a methyl or ethyl group.

If one uses a solvent with progressively weaker polarity, the mixture of isomers is richer, where R2 is a methyl or ethyl groupc is.

Among the solvents with strong polarity, solvents such as nitrocellulose are particularly preferred. Among the solvents with weak polarity, if one strives for a mixture of isomers, the contains predominantly those of the current type. solvent such as carbon disulfide and 1,2-dichloroethane are particularly suitable.

The positional isomers can each be derived from the Ge ω mixed by classical separation methods, for example by crystallization or distillation, isolated. The acid mixture can also be treated with an alcohol to form the corresponding ester, and these, for example, fractional crystallizations b5 subject. The esters separated in this way are then saponified to give the corresponding acids. Optical

The following examples illustrate the invention. CHCI3).

2.5 g of D (+) camphoric anhydride are mixed with 2.7 g of 1,3-dimethoxybenzene in 30 ml of 1,2-dichloroethane. With stirring, 3.8 g of aluminum chloride are added in ^{portions at 0 ° C.} After the reaction mixture has reached ambient temperature, stirring is continued for an additional 2 hours. The reaction mixture is poured onto ice and, after addition of hydrochloric acid, it is extracted with ether.

After washing the ethereal solution and distilling off the ether, 3.0 g of an oil are obtained which slowly crystallized. This represents a mixture of 47.5% 3- (2-; 4'-dimethoxybenzoyl) -1,2,2-trimethyl-

cyclopentanecarboxylic acid and 52.5% 3- (2 ', 4'-dimethoxybenzoyl ^^ - trimethylcyclopentanecarboxylic acid represent.

Example 2

Left-handed 3- (2 ', 4'-dimethoxybenzoyl) -2,2,3-trimethylcyclopentanecarboxylic acid (V)

500 ml of anhydrous methyl alcohol, which is saturated with dry hydrogen chloride gas, are added to 16 g of the acid mixture obtained in Example 1, and the mixture is then refluxed for 4 minutes. After the alcohol has been distilled off, 11 g of a mixture of the methyl esters of the acids mentioned are obtained. By Umkristallisalion of F.stergemisches in Pelroläther 4.6 g Methylester be (, 4'-Dimelhoxybenzoyl 2 ') -2,2,3-lrimethylcyclopentan-carboxylic acid with a mp. Of 108 ⁰ C the obtained 3-.

By the usual saponification of 2 g of this ester with 30% alcoholic potassium and less than 2 hours 5.5 g of 3- (2 ', 4'-dimethoxybenzoyl) -2,2,3-trimethylcyclopentanecarboxylic acid are refluxed obtained with a melting point of 134 ° C.

Analysis of this acid gives the following results:

Microanalysis:

Theoretical C 67.5, H 7.5%;
found C 67.39, H 7.56%.

Rotation = ^ ⁰ "] = -14.1 (1 = 1; c = 2.5

Optical rotation
CHCI3).

: [*] "'= - 51.4 ° (C = 2.5: 1 = 1

Example 5

Racemic 3- (2 ', 4'-dimethoxybenzoyl) -1,2,2-trimethylcyclopentanecarboxylic acid (VI)

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 of the invention have therapeutically useful properties and in particular remarkable appetite suppressant effects, as can be seen from the results given below by pharmacological tests results.

In the course of these investigations, the effect of 3- (2 ', 4'-dimethoxybenzoyl) -1,2,2-trimethylcyclopentanecarboxylic acid (VI) and the 3- (2 ', 4'-di-

methoxybenzoyl) -2,2,3-trimethylcyclopentanecarboxylic acid (V) and a mixture of these acids according to Example 1 is determined on the amount of feed consumed by rats.

Male rats of the Wistar strain with a mean body of 150 g were grouped used by ten animals. Each animal was placed in a single cage. 2 days before the examinations the amount of feed consumed by the animals within 24 hours was determined by weighing had been. dfinn was carried out the same treatment within 5 days, the following steps included:

15th

Example 3

Racemic 3- (2 ', 4'-dimethocybenzoyl) -2,2,3-trimethylcyclopentanecarboxylic acid

The procedure is as in Examples 1 and 2, but the levorotatory combat epic anhydride is replaced by the corresponding racemic derivative. In this manner, 4.6 g of the Methylesters with a mp. Of 82 ^C C and 5.5 g of racemic acid with a mp. Of 185 ° C obtained.

Example 4

Left-handed 3- (2 \ 4'-DimethoxybenzoyI) -l, 2,2-trimethylcyclopentanecarboxylic acid (VI)

2.5 g of levorotatory camphoric anhydride are mixed with 2.7 g of 1,3-dimethoxybenzoI in 30 ml of nitromethane. At 0 ⁰ C 3.8 g of aluminum chloride are added portionwise and under stirring. When the reaction mixture has returned to ambient temperature, stirring is continued for 2 hours. The reaction mixture is then poured onto ice. After adding hydrochloric acid, the mixture is extracted with ether.

After washing the ethereal solution and distilling off the ether, a residue is obtained which is in an ethanol / water or an ether / petroleum ether mixture crystallized. In this way, 1.7 g of 3- (2 ', 4'-dimethoxybenzoyl) -1,2,2-trimethylcyclopentanecarboxylic acid are obtained obtained with a melting point of 145 ° C.

Analysis of this acid gives the following results nits:

Microanalysis:

Theoretical C 67.5, H 7.5%;
found C, 67.35. H 7.55%.

50

35

faO

b5 At 9.00 a.m .: weighing the animals.

At 9:00 am: oral administration of 5 mg / kg body weight of the rat of a 1% strength Solution of the substances according to the invention to the rats, in the case of the comparison animals just one administration of the same volume of distilled water.

At 10.00 a.m .: Calculate the amount of feed consumed in 24 hours by weighing the remaining feed.

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

At the end of the fifth day the reduction in the amount of feed consumed was 52%, 48% and 53%, based on the comparison animals. The reduction in body weight was 15%. 12% and 16% based on the comparison animals.

In the case of a known remedy with the same effect, namely diethylaminopropiophenone, when administered in an amount of 50 mg / kg (i.e. 10 times the dosage as described above in connection with the compounds according to the invention) a reduction in the amount of feed consumed by 31.6% and a reduction in the Body weight of 8% was found.

The results obtained show the advantageous appetite suppressing effect of the substances according to the invention.

It is also necessary to add 100 mg / kg of the 3- (p-Methoxybenzoy I) -1 ^ -trimethoxycyclopentanecarboxylic acid according to the patent 25 01 834 to use a reduction in body weight of the order of magnitude cause, as by administration of the compounds according to the invention in amounts of 5 mg / kg is achieved.

The compounds according to the invention have practically no toxicity. They are particularly well tolerated. The DL50 was tested in mice by oral administration of the substances in the form of an aqueous suspension certainly. The results obtained in the

3- (2 ', 4'-Dimethoxybenzoyl) -1, 2,2-trimethylcyclopentanecarboxylic acid and in the case of 3- (2 ', 4'-dimethoxybenzyol) -2,2,3-trimethylcyclopentanecarboxylic acid are 1.50 g / kg or more than 5 g / kg.

Due to their valuable properties, the compounds according to the invention are valuable active ingredients, especially 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 about 100 to 300 mg, and preferably about 50 to 200 mg.

The medicaments according to the invention can preferably be perorally in the form of tablets, Capsules, coated tablets or solutions in ampoules are administered.

The compounds according to the invention can also be administered rectally or parenterally. In all In cases, the compounds can be used together with inert carriers or diluents for galenicals Products are common to be used.

So far, the preferred appetite suppressant has been 2-diethylaminopropiophenone or the ß-cyclohexylisopropylamine described in DE-PS 9 70 480

turns. In contrast to those according to the invention, these contain Compounds nitrogen and also differ from the compounds according to the invention by C6H4-C-cycloalkylene (with 5 or 6 C-atoms J-COOH linkages. Since these structural features if the compounds according to the invention are absent, they also do not have the known undesirable ones Side effects of amphetamine appetite suppressants such as sympathomimetic effects, such as Agitation, insomnia, tachycardia, behavioral disorders or hypertension, as well as neoanaleptic Effects associated with an action on the central nervous system and for various psychomotor phenomena are responsible.

Claims (5)

Patent claims: ! .Cyclopentanecarboxylic acids of the general formula II IO polarity, such as nitrpmethane, is used, or that a solvent with weak polarity, such as 1,2-dichloroethane or carbon disulfide, is used to obtain predominantly compounds in which Ri is a hydrogen atom and R2 is a methyl or ethyl group , used 5. Medicament, characterized by a content of at least one compound according to claim 1 to 2, as an active ingredient.