FR2565823A1 - PHARMACEUTICAL AND COSMETOLOGICAL PREPARATIONS CONTAINING VITAMIN A DERIVATIVES - Google Patents

Abstract

PHARMACEUTICAL OR COSMETIC COMPOSITIONS CONTAINING, AS ACTIVE SUBSTANCES, THE ACID OF 4-OXO- OR 4-HYDROXY-13-CIS-VITAMIN A, MAY BE USED FOR THE TREATMENT OF ACNE OR SEBORRHEA.

Description

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  The invention relates to pharmaceutical compositions.

  Ceuticals or cosmetics which are characterized in that they contain 4-oxo- or 4-hydroxy-13-cis-vitamin A acid. 4-oxo- and 4-hydroxy acids -13- cis- vitamin A (in systematic classification: acid

  (Z, E, E, E) -3,7-dimethyl-9- (2,6,6-trimethyl-3-oxo-1-cyclo-

  hexene-1-yl) -2,4,6,8-nonatetraenoic and acid (Z, E, E, E)

  -3,7-dimethyl-9- (2,6,6-trimethyl-3-hydroxy-11-cyclohexene-

  1-yl) -2,4,6,8-nonatetraenoic respectively) are

  13-cis-vitamin A acid metabolites [J. Biol.

Chem. 255, 8057 (1980)].

  We have now found that the acids of 4-

  oxo- and 4-hydroxy-13-cis-vitamin A had therapeutic activity. In particular, these compounds can be used for the treatment of acne and

seborrhea.

  The compositions according to the invention can

  sister in compositions for systemic administration or for topical application. We prefer the compositions

  for oral administration, for example capsules.

  The compositions may contain, with the active substances, usual pharmaceutical auxiliary products

  such as binders, fillers or anti

  oxidants. A dosing unit, for example a capsule,

  may contain from about 10 to 100 mg of active substance.

  For the treatment of acne and seborrhea, the active substances can be administered to humans

  at daily dosages of 0.5 to 5 mg / kg, pre-

  ference of 1 to 2 mg / kg orally.

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  For topical application, the compounds may

  can be put in the form of solutions or lotions or be introduced into hair washing products (shampoos). Solutions, lotions and shampoos can contain about 0.01 to 2%, preferably 0.1 to 0.5% of active substance and can be applied to the skin one or more times a day or used (shampoos) once a day or once or twice a week for

washing the hair.

  The following examples illustrate more

completely the invention.

Example 1

  Preparation of the active substances A 56.2 g of [5- (3-oxo-2,6,6 trimethyl) bromide

  -1-cyclohexene-1-yl) -3-methyl-2,4-pentadienyl] -triphenyl-

  phosphonium and 11.4 g of 4-hydroxy-3-methyl-2-butenolide in 250 ml of isopropanol, 94.3 ml of 2.12N KOH in isopropanol (0.2 mol) are added at 0-5 C. ). The reaction mixture is left to stand for 1 hour at 510 ° C. and then brought back to room temperature. 30 minutes later, the reaction mixture is poured into 5% brine, acidified with sulfuric acid and extracted with ethyl acetate. The organic extract is washed with brine, dried and evaporated; a crude product is obtained from which the crystallization in the mixture

  hexane / ethyl acetate gives the acid (E, E, Z, Z) -3,7-di-

  methyl-9- (2,6,6-trimethyl-3-oxo-1-cyclohexene-1-yl) -2.4,

  6,8-pure nonatetraenoic melting at 159-160 C.

  13.4 g of this acid are treated in 600 ml of methanol at 0 ° C. with an excess of diazomethane. The reaction mixture is allowed to return to ambient temperature and after 30 min, it is concentrated; (E, E, Z, Z) -3,7-dimethyl-9- (2,6,6-trimethyl-3-oxo-1-cyclohexene -l-yl) -2,4,6,8 are obtained -methyl nonatetraenoate in the form of a crude product. 14.2 g of the crude product are isomerized into

  acetonitrile with 1.48 g of dichloro-bis-benzonitrile-

  Pd (II) and 2.5 ml of triethylamine. Purification by chromatography gives (Z, E, E, E) -3,7-dimethyl-9- (2,6,

  6-trimethyl-3-oxo-1-cyclohexene-1-yl) -2,4,6,8-nonatetraa-

  methyl noate. 13.3 g of this ester are hydrolyzed by

  heating for 30 minutes with a hydro- potassium wash

  ethanolic (13.8 g of KOH, 300 ml of ethanol). We cool

  says the reaction mixture, we run in ice water,

  acidified with acetic acid and extracted with acetic

  ethyl tate. The extract is washed with brine, dried and evaporated; the crude product is crystallized from a hexane / ethyl acetate mixture. Recrystallization from ethyl acetate / hexane gives the acid

  (Z, E, E, E) -3,7-dimethyl-9- (2,6,6-trimethyl-3-oxo-1l-cyclo-

  hexene-l-yl) -2,4,6,8-pure nonatetraenoic melting at 164-

166 C.

  0.314 g of acid (Z, E, E, E) -3,7-dimethyl are treated

  -9- (2,6,6-trimethyl-3-oxo-1-cyclohexene-1-yl) -2,4,6,8-

  nonatetraenoic for 5 min with sodium borohydride

  dium in the methanol / water mixture. The reaction mixture is acidified with acetic acid and extracted with methylene chloride. The extract is washed with brine, dried, evaporated and crystallized from the ethyl acetate / hexane mixture. We get the acid (Z,

  E, E, E) -3,7-dimethyl-9- (2,6,6-trimethyl-3-oxo-1-cyclohe-

  xene-1-yl) -2,4,6,8-pure nonatetraenoic.

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Example 2

  Preparation of a capsule for oral administration An aqueous suspension of 27% by weight of gelatin (Bloom 30), 41% by weight of maltodextrin MD 05, 7% by weight of sodium ascorbate and 25% by weight are ground

  acid (Z, E, E, E) -3,7-dimethyl-9- (2,6,6-trimethyl-3-oxo-

  l-cyclohexene-l-yl) -2,4,6,8-nonatetraenoic at one di-

  average particle size of 0.5 micron and atomized.

  25 mg of the powder thus obtained are mixed in each case.

  held, 20 mg of Avicel PH 102, (microcrystalline cellulose),

  34 mg lactose and 6 mg Polyplasdone (polyvinylpyrro-

  crosslinked lidone; Crosspovidon) and we introduce in

gelatin capsules.

Example 3

Preparation of a lotion

acid (Z, E, E, E) -3,7-dimethyl-9-

  (2,6,6-trimethyl-3-oxo-1-cyclohexene-

  l-yl) -2,4,6,8-nonatetraenoic 0.01 to 2.0 g - ethyl alcohol 10.0 to 52.0 g propylene glycol to 50.0 g polyethylene glycol 0 to 50.0 g dimethyl sulfoxide 0 to 50.0 g The active substance is dissolved in the mixture

solvents.

Claims (4)

  1. Pharmaceutical or cosmetic composition charac-   terized in that it contains the acid of 4-oxo- or 4-hydroxy-13cis-vitamin A. 2. Composition according to claim 1, in the form of capsules containing 10 to 100 mg of active substance.   3. The acids of 4-oxo- and 4-hydroxy-13-   cis-vitamin A for use as substances   therapeutic or cosmetic active ingredients.   4. The acids of 4-oxo- and 4-hydroxy-13-   cis-vitamin A for use as substances   active against acne and seborrhea.