NL8302136A - POLYENE COMPOUNDS, METHOD FOR PREPARING THE SAME AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE POLYENE COMPOUNDS. - Google Patents

Description

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Sr \ N.0. 31,883 1

Polyene compounds, process for their preparation and pharmaceutical preparations containing these polyene compounds

The present invention relates to new polyene compounds, a process for their preparation and pharmaceutical preparations containing these polyene compounds.

The compounds according to the invention correspond to the general formula 1, in which R is a radical of the formula 2, 3 or 4 »2 B a hydroxyl, alkoxy, amino, mono- or dialkylamxno group, 3 4 5 R an alkyl group or a halogen atom, R an alkyl group, B a 6 7 alkoxy group, R a hydrogen atom or an alkyl group and R an alkyl group or a halogen atom.

Preferred radicals of the formula IV are those residues wherein R 1, R 1 and R 1 represent an alkyl group, R 1 represents an alkoxy group and R 1 hydrogen atom.

Alkyl groups and alkyl radicals in alkoxy and alkylamino groups preferably contain up to 6 carbon atoms. They can be straight or branched, such as, for example, the methyl, ethyl, isopropyl or 2-methylpropyl group, the methyl group being particularly preferred.

Examples of alkyl or dialkylamino groups are methyl amino, ethylamino and diethylamino groups.

The compounds of the formula I can be obtained according to the invention by reacting a compound of the general formula RA with a compound of the general formula 5, wherein R and R have the meanings indicated above and A has a 1 - (triphenylphosphonium) -ethyl group of the formula 6, wherein X represents a phenyl group and Y ~ the anion of an organic or inorganic acid, and B represents a formyl group; or A represents an acetyl group and B represents a dialkoxyphosphinylmethyl group of the formula 7 wherein Z represents an alkoxy radical; and, if desired, converting a carboxylic acid ester obtained into a carboxylic acid or a carboxylic acid amide.

Of the inorganic acid anions Y, the chlorine and bromine ion or the hydrogen sulfate ion is preferred, of the organic acid anions the tosyloxy ion is preferred.

The reaction of a formyl compound of the formula V with a phosphorane is made in a manner known per se in the presence of an acid-binding agent, for example in the presence of a strong base, such as, for example, butyl lithium, sodium hydride or 8302136 J i 2, the sodium salt of dimethyl sulfoxide, optionally in a solvent, for example in an ether such as diethyl ether or tetrahydrofuran, or in an aromatic hydrocarbon such as benzene at a temperature in the range between room temperature and the boiling point of the reaction mixture.

The reaction of a phosphonate of the formula 3 with a 1. . bond R COCH 2 also becomes 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 sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or 1,2- dimethoxyethane, or in the presence of a sodium alcoholate in an alkanol, for example sodium methanolate in methanol, at a temperature in the range between 0 ° C and the boiling point of the reaction mixture.

The above reactions can also be carried out in situ, ie without isolating the respective phosphonium salt or phosphonate, respectively.

A carboxylic acid ester of the formula 1 can be used in a manner known per se, for example by treatment with bases, in particular by treatment with sodium hydroxide or potassium hydroxide containing water-alcohol at a temperature in the range between room temperature and the boiling point of the reaction mixture hydrolyzed and immediately amidated via an acid halide or, as described below.

A carboxylic acid of the formula I can be converted into the acid chloride in a manner known per se, for example by treatment with thionyl chloride, preferably in pyridine, or phosphorus trichloride in toluene, which is converted by conversion with alcohols into esters and with amines in the corresponding amide can be converted.

For example, a carboxylic acid ester of the formula 1 can be converted directly into the corresponding amide by treatment with lithium amide. The lithium amide is advantageously reacted with the respective ester at room temperature.

1 ...

A carboxylic acid of the formula forms salts with bases, especially with the alkali metal hydroxides, preferably with sodium or potassium hydroxide, which are also subject of the invention. Formula 1 includes cis and trans forms.

The compounds of the formula I can be obtained as cis / trans mixtures, which, if desired, can be separated in known manner into the cis and trans components, or 8302136 3 * t * to the all-trans compounds can be isomerized. The all-trans (all-E) compounds are preferred.

The compounds of formula 1 form drugs. They can be used for the local and systemic therapy of benign 5 and malignant neoplasms, of premalignant lesions, as well as for the systemic and local prophylaxis of the mentioned disorders.

They are furthermore suitable for the topical and systemic therapy of acne, psoriasis and other dermatoses associated with enhanced or pathologically altered cornification, as well as inflammatory skin diseases and allergic dermatological conditions. The compounds of the formula I can furthermore also be used for the control of mucosal diseases with inflammatory or degenerative or metaplastic changes, respectively, as well as for the oral treatment of rheumatic diseases, in particular such diseases of an inflammatory and degenerative nature, which affect joints, muscles , affect tendons and other parts of the musculoskeletal system. Examples of such disorders are the primary chronic polyarthritis, ankylosing spondylarthritis Bechterew and arthropathia psoriatica.

The tumor inhibitory effect of the products according to the invention is significant. * A regression of the tumors induced with dimethylbenzantracene and croton oil was observed in the papule test (Europ. J. Cancer 10, 731-737 [1974]. of papillomas took over 2 weeks with intraperitoneal administration of 30 mg all-E-4-methyl-7- (5,6,7 »8-tetrahydro-5,5» 8,8-tetramethyl-2-naphthyl) -2 , if, 6-octatric acid ethyl ester about 49%.

The compounds of the formula I can be used as medicaments, for example in the form of pharmaceutical preparations. The preparations for systemic use can be prepared, for example, by adding non-toxic, inert solid or liquid carriers which are themselves conventional in such preparations to a compound of the formula I as active ingredient. The agents can be administered enterally or parenterally. For the enteral administration, agents in the form of tablets, capsules, dragées, syrups, suspensions, solutions and suppositories are suitable. For parenteral administration, agents in the form of infusion or injection 8302136 solutions are suitable.

The dosages in which the products of the invention may be administered may vary depending on the mode of administration and route of administration as well as the needs of the patient.

The products of the invention may be administered in one or more dosages in amounts of from about 0.01 to about 5 mg daily. A preferred dosage form is capsules containing from about 0.1 mg to about 1.0 mg of active ingredient.

The preparations may contain inert or also pharmacodynamically active additives. For example, tablets or granules can contain a range of binders, fillers, carriers or diluents. Liquid preparations can, for example, be in the form of a sterile water-miscible solution.

In addition to the active ingredient, capsules can also contain a filler or thickener. Furthermore, flavor enhancing additives, as well as the substances commonly used as preservative, stabilizing, emulsifying and moisturizing agents, further also salts for altering osmotic pressure, buffers and other additives may be present.

The above-mentioned carriers and diluents may consist of organic or inorganic substances, for example water, gelatin, milk sugar, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. The condition is that all auxiliary substances used in the preparation of the preparations are non-toxic.

For the topical application, the products according to the invention are preferably used in the form of ointments, tinctures, creams, solutions, lotions, sprays, suspensions and the like. Preferred are ointments and creams as well as solutions. These preparations intended for topical application can be prepared by mixing the products according to the invention as active ingredient with non-toxic, inert, topical treatment suitable per se solid or liquid carriers which are usual in such preparations.

For topical application, from about 0.01 to about 0.3 weight percent, preferably from 0.02 to 0.1 weight percent solutions, and from about 0.05 to about 40 weight percent, are expedient. percents, preferably about 0.05 to about 8302136 5% by weight 1% ointments or creams are suitable.

The compositions may optionally be mixed with an antioxidant, for example tocopherol, N-methyl - / - tocopherin, as well as butylated hydroxyanisole or butylated hydroxytoluene.

Example I

To 23> 4 g of [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -ethyl] -triphenylphosphonium bromide in 150 ml dry tetrahydrofuran were added at - 2 °, 25 ml of 1.6 molar butyl lithium (in hexane) are added slowly with stirring at 15 ° C. After 30 minutes at the same temperature, 6.72 g (40 mmol) of all-E-5-formyl-4-methyl-2,4-penta-dienoic acid ethyl ester in 30 ml of tetrahydrofuran was added dropwise and then an additional 2 hours at stirred at room temperature.

After addition of ethyl acetate, the organic phase was shaken with 0.1 N hydrochloric acid, washed with water until the washing liquid reacted neutral, dried over magnesium sulfate and concentrated with a rotary evaporator. Crystallizing the residue twice from about 100 ml of ethanol gave 3.47 g (24%) (all-E) -4-methyl-7- (5,6,7 »8-tetrahydro-5» 5 * 8,8-) tetramethyl-2-naphthyl) -2,4,6-octatric acid ethyl ester, mp 87.5 -20 89 ° C. A further 1.6 g of pure product could be obtained from the mother liquor by chromatography.

The all-E-5-formyl-4-methyl-2,4-pentadienoic acid ethyl ester can be prepared as follows: a) 43.23 g of phosphonoacetic acid triethyl ester were added to 4.63 g of sodium hydride in 100 ml of dry tetrahydrofuran. Then 25.0 g (0.18 mol) / -acetoxy-tigline-aldehyde in 50 ml of tetrahydrofuran were added dropwise at 0-5 ° C. The reaction mixture was stirred at room temperature for 20 hours, diluted with 200 ml of ethyl acetate, washed with saturated saline and dried over magnesium sulfate. Concentration and distillation at 103 ° C / 0.35 mm Hg gave 28.6 g (76%) of 6-acetoxy-4-methyl-2,4-hexadienoic acid ethyl ester.

b) 27.5 g of 6-acetoxy-4-methyl-2,4-hexadienoic acid ethyl ester, 20 g of sodium carbonate and 2 ml of triethanolamine were refluxed in 250 ml of ethanol for 3 hours. After addition of ethyl acetate, it was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Distillation at 110 ° C / 0.4 mm Hg gave 15.7 g (71%) of 6-hydroxy-4-methyl-2,4-hexa-dienoic acid ethyl ester.

C) 11.7 g of 6-hydroxy-4-methyl-2,4-hexadienoic acid ethyl ester were stirred 8302136 * * 6 in 200 ml of dichloromethane with 30 g of manganese (IV) oxide at room temperature for hours. The reaction solution was filtered, concentrated and the residue recrystallized from hexane / cyclohexane. 9.1 g (78%) of 5-formyl-if-methyl-2, if-pen-5-adienic acid ethyl ester with a melting point of if8-if9 ° C are obtained.

Example II

Analogous to Example I, 1-methyl-3- (2,6,6-trimethyl-1-cyclohexen-1-yl) allyl-triphenylphosphonium chloride and 5-formyl-if-methyl-2, if-pentadienoic ethyl ester gave the if, 7-dimethyl-10 9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2, if, 6,8-nonatetraenoic acid ethyl ester, mp 65-66 ° C (from methanol).

Example III

Analogous to Example I, 1-methyl-3- (2,3,6-trimethyl-if-methoxyphenyl) allyl-triphenylphosphonium chloride and 5-formyl-if-methyl-2, if-pentadienoic acid ethyl ester were obtained (all E ) -9- (if-methoxy-2,3,6-trimethylphenyl) -if, 7-dimethyl-2, if, 6,8-nonat etraic acid ethyl ester.

Example IV

9 g (all-E) -if-methyl-7- (5,6,7 »8-tetrahydro-5» 5 »8,8-tetra-20 methyl-2-naphthyl-2, if, 6-octatric acid- ethyl ester was dissolved in 200 ml of ethanol and a solution of 8.2 g of potassium hydroxide in 20 ml of water was added After stirring at room temperature for 18 hours, the reaction mixture was poured onto ice water, acidified with 2 N sulfuric acid and filtered the resulting acid 25. After recrystallization from methanol, 7.8 g of (all-E) -if-methyl-7- (5 * 6,7,8-tetrahydric o-5,5 * 8,8-te) were obtained. tramethyl-2-naphthyl) -2, if, 6-octatrienecarboxylic acid as yellow crystals, mp 232-234 ° C.

Example V

30 if, 5 g (all-E) -if-methyl-7- (5,6,7,8-tetrahydro-5,5 »8,8-tetra-methyl-2-naphthyl) -2, if, 6 Octatrienecarboxylic acid was dissolved in 200 ml of tetrahydrofuran and 2.6 g of 1,1-carbonyldiimidazole were added. After stirring at room temperature for 3 hours, the mixture was cooled to 5-10 ° C and an ethyl amine stream was introduced for 1 hour. After removing the cooling bath, it was stirred overnight at room temperature. The reaction mixture was then poured onto ice water, acidified with 6 N sulfuric acid and extracted with ethyl acetate. The organic phase was washed with 2N soda solution and saturated sodium chloride solution, dried over sodium sulfate and evaporated. After further purification of the crude product 8302136 * 7 by chromatography on silica gel (dichloromethane / acetone solvent = 95: 5) and recrystallization from toluene, 1.6 g of N-ethyl-4-methyl-7- (5f6.7) were obtained. 8-tetrahydro-5 * 5 * 8,8-tetramethyl-2-naphthyl) -2,4,6-octatrioic acid amide as yellow crystals, mp -155-159 ° C.

Example VI

Preparation of a mass for filling capsules of the following composition: all-E-4-methyl-7- (5 »6,7 * 8-tetrahydro-10 5 * 5,8,8-t etramethyl-2-naphthyl -2,4,6-octatric acid ethyl ester 0.1 mg wax mixture 50.5 mg plant oil 98 * 9 mg trisodium salt of ethylenediamine tetra-15 acetic acid 0.5 mg 8302136

Claims (5)

1. Compounds of the formula 1, wherein R is a radical of the formula 2, 3 or ^ R a hydroxyl, alkoxy, amino, mono or dialkylamino group, R ^ an alkyl group or a halogen atom, R ^ a 5 8 5 alkyl group, R represents an alkoxy group, R represents a hydrogen atom or an alkyl group, and R represents an alkyl group or a halogen atom. Compounds according to claim 1, wherein R represents a radical of the formula b and R 1, R 1 and R 1 alkyl groups, R 1 represents an alkoxy group and R 1 represents a hydrogen atom. 10 3 · (all-E-if-Methyl-7- (5,6,7,8-t etrahydro-5,5,8,8-1 etramethyl-2-naphthyl) -2, if, 6-octatrienoic acid- ethyl ester. 4if, 7-Dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2, if, 6,8-nonatetraenoic acid ethyl ester, (all-E) -9- (if-methoxy-2,3,6-trimethylphenyl) -if, 7-dimethyl-2, if, 6,8-nonatetraenoic acid ethyl ester, 13 (all-E) -if-methyl-7- (5.6, 7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2, if, 6-octatrienecarboxylic acid and N-ethyl-if-methyl-7- (5,6,7,8-t etrahydr o-5,5,8,8-t etramethyl-2-naphthyl-2, if, 6-oc tatric acid amide. 5 · all-E-5-Formyl-if-methyl-2, if-pentadienoic acid ethyl ester · 6. Compounds according to claims 1-5 in the treatment of neoplasms, premalignant lesions, acne, psoriasis or rheumatic diseases of an inflammatory or degenerative nature. Pharmaceutical preparations based on a compound according to claims 1 - 5 « 8. Process for the preparation of compounds of formula 1 or according to claims 1-5, characterized in that a compound of the general formula RA is reacted with a compound of the general formula 5, wherein R and R has the meanings indicated in claim 1 and A represents a 1- (triphenylphosphonium) -ethyl group of the formula 6 wherein X represents a phenyl-30 group and Y represents the anion of an organic or inorganic acid and B represents formyl, or A represents acetyl and B represents a dialkoxyphosphinylmethyl group of the formula VII wherein Z represents an alkoxy radical and, if desired, converting a carboxylic acid ester obtained into a carboxylic acid or a carboxylic acid amide. 8302136 - *> · «► i CH, Cjj 1 1 3/3 R - C = CH - CH = C - CH = CH - COR2 i 1 h3c \ ^ CH3 h3c \ ^ - CH3 h3 ^ CH3 J k r3 R \ ^ \ ^ CH = CH_ “1 CH3 R3 R? I B - CH = C - CH a CH - COR2 R6 I L 1 n2c ^ HKl2 - y - -CH -? Cz'ÏT '"^ 2 o \ 8302136