FR2529201A1 - POLYETHYLENE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THEIR THERAPEUTIC USES, IN PARTICULAR AS ANTITUMING AGENTS - Google Patents

Abstract

POLYETHYLENIC COMPOUNDS, THEIR PREPARATION AND THEIR THERAPEUTIC USES. THESE COMPOUNDS RESPOND TO THE FORMULA: (CF DRAWING IN BOPI) IN WHICH R REPRESENTS A REMAINING FORMULA: (CF DRAWING IN BOPI) R REPRESENTS A HYDROXY, ALCOXY INFERIEUR, AMINO, MONO- OR DI-ALKYL INFERIEUR) -AMINO, R REPRESENTS A LOWER ALKYL GROUP OR A HALOGEN; R REPRESENTS A LOWER ALKYL GROUP; R REPRESENTS A LOWER ALCOXY GROUP; R REPRESENTS HYDROGEN OR A LOWER ALKYL GROUP; AND R REPRESENTS A LOWER ALKYL GROUP OR A HALOGEN. THESE COMPOUNDS HAVE PHARMACOLOGICAL PROPERTIES ENABLING THEIR USE IN PARTICULAR IN THE TREATMENT OF NEOPLASIA, PRE-MALIGNANT LESIONS, ACNE, PSORIASIS OR RHEUMATISMAL DISEASES OF INFLAMMATORY OR DEGENERATIVE ORIGIN.

Description

1 - The present invention relates to new

  polyethylene compounds, a process for their preparation

  ration and their therapeutic uses, in particular

as anti-tumor agents.

  The compounds according to the invention correspond to the general formula: CH 3

R 1 C = CH CH =

R -C = CH CH =

CH 3

C CH = CH COR 2

  in which R 1 represents a residue of formula: H 3 C H 3 C H 3 C

CH = CH-

  CH 3 or b R 4 R 5 R 6 R 7 c R 2 represents a hydroxy, lower alkoxy, amino, mono- or di-lower alkylamino group, R represents a lower alkyl group or a halogen; R 4 represents a lower alkyl group; R is lower alkoxy; R 6 is hydrogen or lower alkyl and R 7 is lower alkyl or halogen. The preferred (c) residues are those in which

3 4 7

  R, R and R represent lower alkyl groups,

  R is lower alkoxy and R 6 is hydrogen.

  The alkyl groups and the alkyl portions of the alkoxyamino and alkylamino groups preferably contain up to 6 carbon atoms. They can be straight or branched and they are, for example, methyl, ethyl, isopropyl or 2-methylpropyl groups, preferably 'a

methyl group.

  Examples of alkylamino or dialkyl groups

  amino, there will be mentioned methylamino groups, ethylamino and diethylamino. The compounds of formula I according to the invention can be obtained by reacting a compound of general formula R A with a compound of general formula: CH 3

B CH = C CH = CH COR 2 II

  R and R having the meanings indicated above and

  or A is 1- (triphenylphosphonium) -

  ethyl of formula H 3 C-CH-PlXl 3 + Y in which X represents

  is a phenyl group and Y is the anion of an organic or inorganic acid, and B is a formyl group; or A represents an acetyl group and B represents a dialkoxyphosphinylmethyl group of formula -CH 2 -PPZl 2 in which Z represents a lower alkoxy group, and if desired converting a carboxylic acid ester obtained into a carboxylic acid

  or a carboxylic acid amide.

  3 - Among the anions of mineral acids Y, the chlorine, bromine and hydrosulphate ions are preferred, and

  among the anions of organic acids, the toluene ion

  sulfonyloxy. The reaction of a formyl compound of formula II with a phosphorane is carried out in a manner known per se in the presence of an acid-fixing agent, for example in the presence of a strong base such as butyllithium,

  sodium hydride or the sodium salt of dimethyl-

  sulfoxide, optionally in a solvent, for example

  in an ether such as ethyl ether or tetrahydro-

  furan, or in an aromatic hydrocarbon such as benzene, in a temperature range from room temperature to the boiling point of

reaction mixture.

  The reaction of a phosphonate of formula II with a compound R COCH 3 is also carried out in a manner known per se in the presence of a base and preferably in the presence of an inert organic solvent, for example in the presence of the hydride of sodium in the

  benzene, toluene, dimethylformamide, tetrahydro-

  furan, dioxane or a 1,2-dimethoxyalkane, or in the presence of a sodium alkoxide in an alkanol, for example sodium methoxide in methanol, in a temperature range from 00 C to

  boiling point of the reaction mixture.

  The reactions mentioned above can also be carried out in situ, that is to say without isolating the phosphonium salt or the phosphonate

artwork.

  A carboxylic acid ester of formula I can be hydrolysed in a manner known per se, by

  example by treatment with an alkali, in particular

  particularly by treatment with sodium hydroxide solution or aqueous alcoholic potassium hydroxide, in a temperature range from room temperature up to the boiling point of the reaction mixture, and then converted into a halogenide. acid or even directly amide

as described below.

  A carboxylic acid of formula I may be converted in a manner known per se into the acid chloride, for example by treatment with thionyl chloride, preferably in pyridine, or with the aid of phosphorus trichloride in toluene; the acid chloride can itself be converted into esters by reaction with alcohols and amides by reaction

with the appropriate amines.

  A carboxylic acid ester of formula I may be converted directly to the corresponding amide, for example by treatment with lithium amide. Lithium amide is reacted with

  the ester advantageously at room temperature.

  A carboxylic acid of formula I forms with bases, in particular with alkali metal hydroxides, preferably sodium or potassium hydroxide, salts which are also an object of the invention.

cis and trans.

  The compounds of formula I can be obtained in the form of cis / trans mixtures which can be separated, if desired, in a manner known per se into the cis and trans compounds or isomerized into the compounds which are entirely trans.

  prefers fully trans (fully-E) compounds.

  The compounds of formula I constitute

  They may be used for the treatment of

  topical and systemic treatment of benign and malignant neoplasia, premalignant lesions and also

  systemic and topical prophylaxis of these conditions.

  They can also be used for

  topical and systemic treatment of acne, psoriasis and - other dermatoses accompanied by keratinisation

  strengthened or pathological and also of

  In addition, the compounds of formula I may be used for the treatment of mucosal diseases accompanied by inflammatory or degenerative or metaplastic changes, as well as for the oral treatment of rheumatic diseases, in particular of the nature of the disease.

  inflammatory and degenerative, affecting the joints

  tions, muscles, tendons and other parts of the mobile device. Examples of such diseases are chronic polyarthritis, Spondylarthritis

  ankylopoetica Bechterew and Arthropathia psoriatica.

  The inhibitory effect of the products according to the

  Tumors on the tumors are significant. In the papilloma test (Europ J Cancer 10, 731-737 (1974)) a regression of induced tumors is observed.

  by dimethylbenzanthracene and croton oil.

  In the course of two weeks, the diameter of the papillae

  lomes decreased by approximately 49% in administration

  intraperitoneal 50 mg of (fully-E) -4-

  methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-

  naphthyl) -2,4,6-octatrienoate ethyl.

  The compounds of formula I can be used as medicaments, for example in the form of pharmaceutical compositions. The compositions for systemic administration can be prepared, for example, by adding to a compound of formula I, the active ingredient, solid or liquid non-carriers. inert toxicants customary in this type of composition The compositions can be administered enterally or parenterally The products suitable for enteral administration are for example in the form of tablets, capsules, dragees, syrups, suspensions, solutions or of suppositories For parenteral administration, products will be used

  in the form of solutions for infusions or for injection

tions.

  The dosages administered to the products

  of the invention may vary according to the mode of administration and the route of administration and according to

the needs of patients.

  The products of the invention may be administered in a daily amount of about 0.01 to 5 mg in one or more doses. A preferred mode of administration is in capsules at a level of about 0.1 mg to 1.0 mg.

mg of active substance.

  The compositions may contain inert additives or also additives possessing a pharmacodynamic activity. The tablets or granules may contain, for example, numerous binders, fillers, carriers or diluents. The liquid compositions may be, for example, in the form of sterile miscible solutions. In addition to the active ingredient, the capsules may contain a filler or a thickening agent. In addition, the compositions may contain taste-improving additives and products usually used as preservatives, stabilizers, humectants and agents. emulsifiers, or salts to modify the

  osmotic pressure, buffers and other additives.

  The vehicles and diluents mentioned above may consist of organic or inorganic materials, for example water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and similar substances. Of course, all the auxiliary products used in preparation of compositions

  must be free from toxicity.

  For topical application, the products according to the invention will advantageously be used in the form of ointments, dyes, creams, solutions, lotions, aerosols, suspensions and in similar forms. Ointments and creams and also solutions These compositions intended for topical application can be prepared by mixing the products according to the invention, active constituents, with inert non-toxic solid or liquid vehicles suitable for topical application.

  and usual in this type of composition.

  For topical application, solutions containing from about 0.01 to 0.3%, preferably from 0.02 to 0.1% of substance, will be advantageously used.

  active ingredient, or ointments or creams containing

  0.05 to 5%, preferably about 0.05 to 1% of

active substance.

  To these compositions may be added, where appropriate, an antioxidant, for example tocopherol, N-methyl-γ-tocopheramide or hydroxyanisole.

  butyl or butylated hydroxytoluene.

  The following examples illustrate the invention

  without, however, limiting its scope; in these examples, the indications of parts and percentages

  by weight unless otherwise indicated.

EXAMPLE 1

  To 23.4 g of l-bromide (5,6,7,8-tetrahydro-

  , 5,8,8-tetramethyl-2-naphthyl) -ethyl-triphenylphosphonium in 150 ml of dry tetrahydrofuran, 26.25 ml of a 1.6 M solution of butyllithium in hexane are slowly added with stirring at -15 C. minutes later, at the same temperature, 6.72 g (40 ml.

  mmol) of (fully-E) -5-formyl-4-methyl-2,4-

  ethyl pentadienoate in 30 ml of tetrahydrofuran

  then stir for a further 2 hours at temperature -

  After addition of ethyl acetate, the organic 8-phase is stirred with 0.1 N hydrochloric acid, washed with water until neutral, dried over sulfate.

  of magnesium and concentrated in the rotary evaporator.

  Two crystallizations of the residue in about 100 ml of ethanol give 3.47 g (24%) of (fully-E) -

  4-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-

  naphthyl) -2,4,6-octatrienoate, ethyl, 87.5 -

  89 C From the mother liquor, one can still

  obtain by chromatography 1.6 g of pure product.

  (Fully-E) -5-formyl-4-methyl-2,4-

  Ethyl pentadienoate may be prepared as follows: a) 43.23 g of triethylphosphonoacetate are added to 4.63 g of sodium hydride in 100 ml of dry tetrahydrofuran. 0-50 is then added dropwise. C 25.0 g (0.18 mole) of aldehyde-γ-acetoxytiglic in 50 ml of tetrahydrofuran The reaction mixture is stirred for 20 hours at room temperature, diluted with 200 ml of ethyl acetate and washed. with saturated brine and dried over sodium sulfate Concentration and distillation at 103 ° C / 0.35 mm Hg

  give 28.6 g (76%) of 6-acetoxy-4-methyl-2,4-hexa

ethyl dienoate.

  (b) 27.5 g of ethyl 6-acetoxy-4-methyl-2,4-hexadienoate are refluxed for 3 hours; g of sodium carbonate and 2 ml of triethanolamine in 250 ml of ethanol After addition of ethyl acetate, the mixture is washed with saturated brine, dried over magnesium sulphate and concentrated at 110.degree. mm

  Hg gives 15.7 g (71%) of 6-hydroxy-4-methyl-2,4-hexa

ethyl dienoate.

  (c) 11.7 g of ethyl 6-hydroxy-4-methyl-2,4-hexadiencate in 200 ml of dichloromethane are stirred for 4 hours at room temperature with 30 g of manganese-IV oxide.

9 -

  The reaction mixture is concentrated and the residue is recrystallized from hexane / cyclohexane to give 9.1 g (78%) of ethyl 5-formyl-4-methyl-2,4-pentadienoate.

melting at 48-49 C.

EXAMPLE 2

  By operating as described in Example 1,

  obtained from 1-methyl-3- (2,6,6-trihydro

  methyl-1-cyclohexen-1-yl) -allyltriphenylphosphonium and ethyl 5-formyl-4-methyl-2,4-pentadienoate, the

  4,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl)

  2,4,6,8-ethyl nonatetraenoate melting at 65-66 ° C

  (after recrystallization from methanol).

EXAMPLE 3

  By operating as described in Example 1,

  obtained from 1-methyl-3- (2,3,6-trihydro-

  methyl-4-methoxyphenyl) -allyltriphenylphosphonium and ethyl -formyl-4-methyl-2,4-pentadienoate (all

  E) -9- (4-methoxy-2,3,6-trimethylphenyl) -4,7-dimethyl-

  2,4,6,8-ethyl nonatetraenoate.

EXAMPLE 4

  9 g of (all-E) -4-methyl-7 are dissolved

  (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2,4,6-

  ethyl octatrienoate in 200 ml of ethanol and a solution of 8.2 g of potassium hydroxide in 20 ml of water is added. After stirring for 18 hours at room temperature, the reaction mixture is poured into the reaction mixture. iced water, acidified with 2 N sulfuric acid and filtered the acid which precipitated after recrystallization from methanol,

  7.8 g of (fully-E) -4-methyl-7- (5,6-

  7,8-tetrahydro-5,8,8-tetramethyl-2-naphthyl) -2,4,6-octa-

  trienoic in the state of yellow crystals melting at 232-

234 C.

-

EXAMPLE 5

  4.5 g of (fully-E) acid are dissolved

  methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-

  naphthyl) -2,4,6-octatrienoic acid in 200 ml of tetra-

  hydrofuran and 2.6 g of 1,4-carbonyldiimidazole are added. After stirring for 3 hours at room temperature, the mixture is cooled to 5-10 ° C. and a stream of ethylamine is injected for 1 hour. The bath is removed.

  refrigerant and stir for another night at

  room temperature is then poured into the reaction mixture

  in ice water, acidified with 6N sulfuric acid and extracted with ethyl acetate. The organic phase is washed with 2N sodium carbonate solution and then with saturated brine, dried over sulfate. After purification of the crude product by chromatography on silica gel (eluent: methylene chloride / acetone = 95: 5) and recrystallization from toluene, 1.6 g of

  N-ethyl-4-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetrahydrate)

  methyl-2-naphthyl) -2,4,6-octatrienamide in the form of

  yellow crystals melting at 158-159 C.

EXAMPLE A

  Preparation of a filling mass of capsules with the following composition:

  - (fully-E) -4-methyl-7- (5,6,7,8-tetrahydro-

  Ethyl 5,8,8-tetramethyl-2-naphthyl) -2,4,6-octa-trienoate 0.1 mg mixture of waxes 50.5 mg vegetable oil 98.9 mg

  trisodium salt of ethylene

diaminotetraacetic 0.5 mg 11 -

Claims (7)

  1. Polyethylenic compounds having the general formula CH 3 CH 3 R C = CH CH = C CH = CH COR   in which R 1 represents a residue of formula: H 3 C H 3 C CH 3 CH = CH-   CH 3 or R 4 R 5 R 7 R 2 represents a hydroxy, lower alkoxy, amino, mono- or di-lower alkylamino group, R 3 represents a lower alkyl group or a halogen; R 4 represents a lower alkyl group; R 5 represents a lower alkoxy group; R 6 represents hydrogen or a lower alkyl group; and R represents a lower alkyl group or a halogen.   12 - 2. Compounds according to claim 1, characterized in that R represents a residue of   formula c) and R 3, R and R of the lower alkyl groups   R, a lower alkoxy group and R a hydrogen atom. 3. Compounds according to claim 1 taken from the group consisting of the following:   (fully-E) -4-methyl-7- (5,6,7,8-   tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2,4,6 ethyl octatrienoate;   4,7-dimethyl-9- (2,6,6-trimethyl-1-   cyclohexene-1-yl) -2,4,6,8-ethyl nonatetraenoate;   (fully-E) -9- (4-methoxy-2,3,6-   trimethylphenyl) -4,7-dimethyl-2,4,6,8-ethyl nonatetraenoate;   (fully-E) -4-methyl-7- (5,6,7,8-   tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2,4,6-octa- trienoic;   N-ethyl-4-methyl-7- (5,6,7,8-tetrahydro-   5,5,8,8-tetramethyl-2-naphthyl-2,4,6-octatriénamide;   (Fully-E) -5-formyl-4-methyl-2,4- pentadienoate tethyl.   4. Process for the preparation of the compounds according to claim 1, characterized in that a compound of general formula R 1 A is reacted with a compound of general formula: CH 3 B CH = C CH = CH COR II   R 1 and R 2 having the meanings indicated above and   or A is 1- (triphenylphosphonium) -   ethyl having the formula: wherein X is phenyl and Y is the anion of an organic or inorganic acid and B is formyl; or A is acetyl and B is dialkoxyphosphinylmethyl of the formula wherein Z is lower alkoxy; and if desired converting a carboxylic acid ester to a carboxylic acid or a carboxylic acid amide. 5. As new drugs, particularly useful for the treatment of neoplasia, premalignant lesions, acne, psoriasis or rheumatic diseases of inflammatory or degenerative nature,   the compounds of claim 1.   6. Pharmaceutical compositions containing as active substance at least one compound according to claim 1.   7. Forms of administration of the compositions   pharmaceutical preparations according to claim 6.