FR2573653A1 - Antiandrogen pharmaceutical compositions based on fatty acids - Google Patents

Abstract

The invention relates to pharmaceutical compositions having antiandrogen, and especially antiprostatic, activity, based on a fatty acid containing a saturated linear C9 to C13 hydrocarbon fragment. The compositions according to the invention correspond to the general formula I: R-(CH2)n-COOH in which: R represents a -CH3 radical or alternatively a radical -CH=CH-R', where R' denotes a hydrogen atom or a saturated or unsaturated C6 to C10 hydrocarbon radical, and 7 </= n </= 11. t

Description

 The present invention relates to pharmaceutical compositions with antiandrogenic and in particular antiprostatic activity, based on fatty acids comprising a linear hydrocarbon fragment saturated with Cg to C13.

The invention relates more particularly to a pharmaceutical composition with antiandrogenic activity, in particular antiprostatic, characterized in that, in combination with a pharmaceutically acceptable carrier, it contains as active substance at least one fatty acid comprising a linear saturated hydrocarbon fragment in Cg to C13 and corresponding to the general formula
R - (CH2) n - COOH (I) in which
R represents a radical -CH3 or else -CH = CH-R '
where R 'denotes a hydrogen atom or a
saturated or unsaturated hydrocarbon radical in
C6 to C10, and 7 n 11.

According to an additional characteristic of the
present invention the fatty acids used as
active substance correspond to the general formula I, in
which the omega carbon of the hydrocarbon fragment
linear saturated with Cg to C11 carries a cis-ethylenic bond.

According to another characteristic of the present
invention, said fatty acids correspond to general formula I
in which the radical R 'contains one or two bonds
ethylenic.

 In the known prior art, compounds derived from acetic acid, but different from those of the present invention, are known as ketoglutaric aminobutyric transaminase inhibitors, antianoxics and anticonvulsants (FR-A- 75 18499), and omega acids Dialkylakanoics in the form of salts are presented as useful in the treatment of central neurological disorders (EP-A-0 005 422).

Using a 3-binding test
HR 1881 "on prostate cells, described in detail in the experimental part, the applicant discovered the astonishing activity of lauric acid, an activity all the more specific and specific than myristic acid, stearic and palmitic acid are inactive, as are caprylic and arachidonic acids.

 On the other hand, an activity analogous to that of lauric acid is found with unsaturated C18 acids such as oleic and linolenic acids and isomyristic and antisomyristic acids (FR-A- 84 00586).

 During the various experiments carried out, it was demonstrated that the antiandrogenic activity of the fatty acids previously mentioned was closely linked to the presence in their molecule of a linear hydrocarbon fragment saturated with Cg to C13. In the case of higher homologs of tridecanolic acid, the linear hydrocarbon fragment is too long and in the case of lower homologs of nonanolque acid, this fragment is too short to confer any activity on the molecule.

 On the other hand, in the case of oleic or linoleic acids, the presence of the cis-ethylenic bond leads to a saturated linear chain containing 9 carbon atoms.

By way of example of fatty acids corresponding to general formula I, exhibiting antiandrogenic activity, and in particular antiprostatic activity, mention should be made of the following acids caproleic acid or 9 décénolqúe CH CH2 = CH- (CH2) 7-COOH acid 9 dodecanolque CH3-CH2-CH = CH- (CH2) 7-COOH acid 9 tetradecenolque CH3 (CH2) 3-CH = CH- (CH2) 7-COOH palmitoleic or physetoleic acid :: 9 hexadecenoeto CH3- (CH2) 5- CH = CH- (CH) 7-COOH oleic acid 9 octadecenolque CH3 (CH2) 7-CH = CH- (CH2) 7-COOH acid 11 octadecenorque CH3 (CH2) 5-CH = CH- (CH2) 9-C00H acid 12 octadecenoic CH3- (CH2) 4-CH = CH- (CH 2 10-C0OH 11 eicosenoic acid CH3- (CH2) 6-CH = CH- (CH tCH2) 9 .CQOH ketolelic acid (11 docosenolic) CH3- (CH2 ) 9-CH = CH- (CH2) 9-C0OH erucic acid (13 docenoseno) CH3- (CH2) 7-CH = CH- (CH2) 11-C00H linoleic acid 9-12 octadecadienol
CH3- {CH2) 4-CH = CH-CH2-CH- = CH- (CH2)? - COOH linolenic acid 9-12-15 octadecatrienorque
CH3-CH2-CH = CH-CH2-CH = CH-CH2-CH = CH- (CH2) 7-COOH eleostearic acid 9-11-13 octadecatrienol CH3-CH2-CH = CH-CH = CH-CH = CH- (CH2) 7-COOH.

 It will be observed in this connection that the inactivity of certain fatty acids, such as arachidonic acid for example, is explained precisely by the absence of this saturated C 8 -C 13 hydrocarbon chain.

Experimental part
Male rats (Charles River, 300g) are neutered at 18 hours before the sacrifice.

 The ventral prostate is removed and homogenized in 3 volumes of TED-Glycerol buffer [10mM Tris-HCI, 1.5 mM EDTA, 1mM dithiothreitol, 10% (W / V) glycerol, pH 7.4 to 20 Cg using an Ultra Turrax (2 passages for each tube 15 seconds and 10 seconds).

 The cytosol is obtained after ultracentrifugation of this homogenate at 100,000 g for 1 hour. 3H-methyltrienolone ([3H] R-1881) (90 Ci / mmol, NEN) is used as radioactive ligand at the final dose of 5 mM. This synthetic androgen is incubated for 2 hours at 40C with 100 l of cytosol. 3 H-R 1881 and the radioactive ligands are dissolved in a toluene / ethanol mixture (9/1, V / V).

 The tubes are brought to dryness under a nitrogen ramp before the addition of the cytosol. At the end of the incubation, 400 μl of dextran charcoal are added to each tube. This incubation lasts 10 minutes at OOC. The soluble ligand / receptor complex is then separated from the free ligands by filtration through Watman Gf / B liters, the free ligands being absorbed on carbon. The filtrate is mixed with scintillating liquid and the radioactivity is counted. Nonspecific binding is estimated in the presence of an excess of unlabeled R-1881 (luM).

 Proteins are determined according to the method of Lowry et al. (J, Biol. Chem. 193,265-275, (1951).

Protein measurement with folin phenol reagent).

 The following results are obtained, expressing the I.C.

50 in g / ml.

 Caprylic acid (C8>> 1000; lauric acid (C12):: 250; myristic acid (C14):> 1000; isomyristic acid (C14): 310; antisomyristic acid (C14> 220 stearic acid (C18):>: 1000; oleic acid (C18 :: 1) 230; linoleic acid (C18: 2): 150; arachidonic acid (C20: 4):> 1000.

 In accordance with a particular embodiment of the subject of the present invention, the pharmaceutical compositions can advantageously be presented in a unit dosage form containing from approximately 5 to approximately 500 mg of active substance. These pharmaceutical compositions can in particular be in the form of coated tablets.

 As an illustration of a pharmaceutical composition according to the invention, an example of a particular formulation of coated tablet will be mentioned below.

Excipient: magnesium carbonate, colloidal silica, heavy kaolin, wheat starch, methylated casein, polyvidone excipient, magnesium stearate, q.s. for a nucleus of 0.5009; hydroxypropyl methyl cellulose, titanium oxide, indigotin blue lacquer, yellow lacquer and quinoline, glycerol q.s.

for a film-coated tablet of 0.4259.

Active substance: lauric acid 0.1009.

Claims (5)

 1. Pharmaceutical composition with antiandrogenic activity, in particular antiprostatic, characterized in that, in combination with a pharmaceutically acceptable carrier, it contains, as active substance, at least one fatty acid comprising a linear hydrocarbon fragment saturated with Cg to C13 and corresponding to general formula 1:  R - (CH2) n - COOH (I) in which  R represents a radical -CH3 or else -CH = CH-R '  where R 'denotes a hydrogen atom or a  saturated or unsaturated hydrocarbon radical in  C6 to C10, and 7 # n # 11.  2. Pharmaceutical composition according to claim 1, characterized in that the omega carbon atom of said linear hydrocarbon fragment saturated with Cg to C13 carries a cis-ethylenic bond.  3. Pharmaceutical composition according to claim 1 or 2, characterized in that, in the general formula I, the radical R 'contains one or two ethylenic bonds.  4. Pharmaceutical composition according to one of claims 1 to 3, characterized in that it is in a unit dosage form containing from about 5 to about 500 mg of active substance.  5. Pharmaceutical composition according to one of claims 1 to 4, characterized in that it is in the form of coated tablets.