SE454984B - POLYENIC SOCIETIES, PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE - Google Patents

Description

15 454 984 CH i 3 2 B-Ci-1 = C-CH = CH-COR II wherein R 1 and R 2 have the meanings given above and either A represents a 1- (triphenylphosphonium) -ethyl group of the formula H 3 C-Cl 1P (X] 3 + Y-, wherein X represents phenyl and Y 'the anion of an organic or inorganic acid, and B is formyl; or A is acetyl and B represents a dialkoxyphosphinylmethyl group of the formula -Cl-1z-ï (212, wherein Z represents a lower alkoxy residue, and if desired, the resulting carboxylic acid ester is converted to a carboxylic acid or a carboxylic acid amide.

Of the inorganic acid anions Y, the chlorine and bromine ions or hydrosulfate ion are preferred, and of the organic acid anions, the tosyloxy ion is preferred.

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 some acid-binding agent, e.g. in the presence of a strong base, such as butyllithium, sodium hydride or the sodium salt of dimethyl sulphoxide, optionally in a solvent, e.g. in an ether, such as diethyl ether or tetrahydrofuran, or in an aromatic hydrocarbon, such as benzene, in a temperature range between room temperature and the boiling point of the reaction mixture.

The reaction of a phosphonate of Formula II with a compound RICOCHB is also carried out in a manner known per se in the presence of a base and preferably in the presence of some inert organic solvent, e.g. in the presence of sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or LZ-dimethoxyethane, or in the presence of a sodium alcoholate in an alkanol, e.g. sodium methylate in methanol, in a temperature range between 0 ° and the boiling point of the reaction mixture.

The above reactions can also be performed in situ, i.e. without isolating the phosphonium salt resp. the phosphonate in question.

A carbonic acid ester of Formula I can be hydrolyzed in a manner known per se, e.g. by treatment with alkalis, in particular by treatment with aqueous alcoholic soda or potassium hydroxide solution in a temperature range between room temperature and the boiling point of the reaction mixture and amidated, either via an acid halide or, as described below, directly.

A carboxylic acid of formula 1 can in a manner known per se, e.g. by treatment with thionyl chloride, preferably in pyridine, or phosphorus trichloride in toluene is converted to the acid chloride, which by reaction with alcohols can be converted to ester, and with amines to the corresponding amide. "4-p, 3,454,984 A carbonic acid ester of Formula 1 can be converted, for example, by treatment with lithium amide directly to the corresponding amide. The lithium amide is preferably reacted with the ester in question at room temperature.

A carboxylic acid of the formula I forms salts with bases, in particular with alkali metal hydroxides, preferably with sodium or potassium hydroxide, which are also the subject of the invention. Formula 1 shall include cis- and transformers.

The compounds of Formula I may be formed as cis / trans mixtures, which if desired. per se known manner can be divided into the cis and trans components or isomerized to the all-trans compounds. The all-trans (all-D) compounds are preferred.

The compounds of formula I constitute drugs. They can be used for topical and systemic therapy of benign and malignant neoplasms, of premalignant lesions, as well as for systemic and topical prophylaxis of the indicated affection. They are further suitable for topical and systemic therapy of acne, psoriasis and other dermatoses which progress with an intensified or pathologically altered keratinization, as well as of inflammatory and allergic dermatological affections. The compounds of the formula I can furthermore also be used for the control of mucosal diseases with inflammatory or degenerative resp. metaplastic changes as well as for oral treatment of rheumatic diseases, especially those of an inflammatory and degenerative nature, which affect joints, muscles, tendons and other parts of the musculoskeletal system. Examples of such diseases are primary chronic polyarthritis, Spondylarthritis ankylopoetica Bechterew and Arthropathia psoriatica.

The tumor inhibitory effect of the procedure products is significant.

Papilloma tests (Europ. J. Cancer 10, 731-737 (1974)) observe a regression of tumors induced by dimethylbenzanthracene and croton oil.

Papilloma diameters were reduced within 4 weeks by 4996 by intraperitoneal application of 50 mg of all-E-β-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ) -2,14,6-octatrienoic acid ethyl ester.

The compounds of formula I may find use as medicaments, e.g. in the form of pharmaceutical preparations. The preparations that serve for systemic use can e.g. can be prepared by adding a compound of Formula I as an active ingredient to non-toxic, inert, solid or liquid carriers which are per se customary in such preparations. The agents can be administered enterally or parenterally. For enteral application, e.g. agents in the form of tablets, capsules, dragees, syrups, suspensions, solutions and suppositories. 454 984 For parenteral administration, infusion or injection solutions are suitable.

The dosages in which the method products are administered may vary depending on the type of use and the route of use as well as the needs of the patients.

The process products may be administered in amounts of about 0.01 to about 5 mg per day in one or more doses. A preferred dosage form is capsules having a content of about 0.1 mg to about 1.0 mg of active substance.

The preparations may contain inert or also pharmacodynamically active additives. Tablets or granules can e.g. contain a range of binders, fillers, carriers or diluents. Liquid preparations may, for example, be in the form of a sterile, water-miscible solution. Capsules may, in addition to the active substance, also contain a filler or thickener. In addition, taste-enhancing additives, as well as substances commonly used as preservatives, stabilizers, moisturizers and emulsifiers, as well as salts for altering the osmotic pressure, buffer substances and other additives may be included.

The above-mentioned carrier substances and diluents may consist of organic or inorganic substances, e.g. of water, gelatin, milk sugar, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. A prerequisite is that all excipients used in the preparation of the preparations are non-toxic.

For topical use, the process product is suitably used in the form of ointments, tinctures, creams, solutions, lotions, sprays, suspensions and the like. Ointments and creams as well as solutions are preferred. These preparations intended for topical use can be prepared by mixing the process products as active ingredient with non-toxic, inert, solid or liquid carriers which are suitable for topical treatment and are per se customary in such preparations.

For topical use, it is suitably about 0.01 to about 0.396, preferably 0.02 to 0.696 solutions, as well as about 0.05 to about 596, preferably about 0.05 to about 966. , ointments or creams suitable.

In the preparations, an antioxidant, e.g. tocopherol, N-methyl-γ-tocopheramine as well as butylated hydroxyanisole or butylated hydroxytoluene are mixed.

The invention is further illustrated in the following, non-limiting embodiments. 15, 454 984 Example 1 23.0 g of 1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylethyl] triphenylphosphonium bromide in 150 μl of dry tetrahydrofuran were added at -15 Slowly stirring with 26.25 ml of 1.6 molar-butyllithium (in hexane) After 30 minutes, 6.72 g (40 mmol) of all-ES-formyl-β-methyl-2,4 were added dropwise at the same temperature. -pentadienoic acid ethyl ester in 30 ml of tetrahydrofuran and then continued stirring for 2 hours at room temperature After the addition of ethyl acetate, the organic phase was shaken with 0.1 N hydrochloric acid, washed neutral with water, dried over magnesium sulfate and concentrated on a rotary evaporator.

Crystallization 2 times of the residue from about 100 ml of ethanol gave 3.47 g (2096) (all-E) -1 + -methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthyl) -2,14,6-octatrienoic acid ethyl ester with m.p. 87.5-89 ° C. An additional 1.6 g of pure product could be obtained from the mother liquors by means of chromatography. all-E-Formyl-1β-methyl-2,1-pentadienoic acid ethyl ester can be prepared as follows: a) 43.23 g of phosphonoacetic acid triethyl ester are added to 4.63 g of sodium hydride in 100 ml of dry tetrahydrofuran. Then, at 0-5 ° C, 25.0 g (0.18 mol) of γ-acetoxy-tiglinaldehyde in 50 ml of tetrahydrofuran are added dropwise. The reaction mixture is stirred for 20 hours at room temperature, diluted with 200 ml of ethyl acetate, washed with saturated brine and dried over magnesium sulfate. Concentration and distillation at 103 ° / 0.35 mmHg give 28.6 g (7696) of G-acetoxy-β-methyl-Zβ-hexadienoic acid ethyl ester. b) 27.5 g of α-acetoxy-11-methyl-Zβ-hexadienoic acid ethyl ester, 20 g of sodium carbonate and 2 ml of triethanolamine are heated to reflux in 250 ml of ethanol for 3 hours. After addition of ethyl acetate, wash with saturated brine, dry over magnesium sulfate and concentrate. Distillation at 110 ° / 0.1 + mmHg gives 15.7 g of (7196) 6-hydroxy-β-methyl-2β-hexadienoic acid ethyl ester. c) 11.7 g of δ-hydroxy-β-methyl-Zβ1-hexadienoic acid ethyl ester in 200 ml of dichloromethane are stirred for 1 hour with 30 g of manganese (IV) oxide at room temperature. The reaction solution is filtered, concentrated and the residue is recrystallized from hexane / cyclohexane. 9.1 g (78%) of 5-formyl-11-methyl-21β-pentadienoic acid ethyl ester are obtained, m.p. ua-49 ° c.

Example 2 In analogy to Example 1, the compound 1-methyl-3- (2,6,6-trimethyl-1-cyclohexen-1-yl) allyitriphenylphosphonium chloride and 5-formyl-1-methyl-Zβ-pentadienoic acid ethyl ester are obtained. 2,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,1 +, 6,8-nonatetraenoic acid ethyl ester, m.p. 65-66 ° C (from methanol). 454 984 Example Gel 3 In analogy to Example 1, 1-methyl-3- (2,3-trimethyl-k-methoxyphenyl) allyl trienylphosphonium chloride and S-formyl-1-methyl-Zβ-pentadienoic acid ethyl (all-E1-9 - (4-methoxy-2,3,6-trimethylphenyl) -4,7-dimethyl-2,1 +, 6,8-nonatetraenoic acid ethyl ester. The ester compound Exemgel 4 9 g (2111-E) -4-methyl-7- ( 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) - 2,4,6-octatrienoic acid ethyl ester is dissolved in 200 ml of ethanol and added with a solution of 8.2 g of potassium hydroxide in 20 ml. After stirring for 18 hours at room temperature, the reaction mixture is poured onto ice water, acidified with 2N sulfuric acid and the acid formed is filtered off. After recrystallization from methanol, 7.8 g of (all-E) -1 + -methyl-7- ( 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -l10-octatrienecarboxylic acid in yellow crystals, mp 232-23 ° C.

Example 5 14.5 g of (all-E) -1-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -Z-octo-triethenecarboxylic acid are dissolved in 200 ml of tetrahydrofuran and add 2.6 g of LP-carbonyldiimidazole. After stirring for 3 hours at room temperature, the mixture is cooled to 5 DEG-10 DEG C. and a stream of ethylamine is introduced for 1 hour. After removing the cold bath, stir overnight at room temperature. The reaction mixture is then poured onto ice water, acidified with 6N sulfuric acid and extracted with ethyl acetate. The organic phase is washed with 2N soda solution and with saturated brine, dried over sodium sulfate and evaporated. After further 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-β-methyl-7- (5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthyl) -2,4,6-octatrienoic acid amide in yellow crystals, m.p. 15s-159 ° C.

Example gel AF framing a capsule-filled mass having the following composition: all-E-4-methyl-7- (Z6,7,8-tetrahydro-5,5,8,8-tetramethyl-Z-naphthyl) -2,4ß- octatrienoic acid ethyl ester 0.1 mg Wax mixture 50.5 mg Vegetable oil 98.9 mg Trisodium salt of ethylenediaminetetraacetic acid 0.5 mg

Claims (1)

454 984 7 PATENT REQUIREMENTS 1. Compounds of the formula CH CH 1-33 2 R- = CH-CH = C-CH = CH-COR where R 1 is a group of the formula H 3 C C H 3 H 3 C H 3 cH = cH- C H 3 H 3 H3 ab or R3 H4 c HmH- R5 '7 H6 C Rz is hydroxy, lower alkoxy, amino, mono- or di- (lower alkylamino; Ra is lower alkyl or halogen; Rq is lower alkyl; Rj is lower alkoxy R 10 is hydrogen or lower alkyl, and R 2 is lower alkyl or halogen. Compounds according to claim 1, characterized in that R 1 is group (c) and R 3, R 3 and R 7 are lower alkyl, R 5 is lower anxy and R 5 is a Compound according to Claim 1, characterized in that it is (all-E) -1 + -methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 -Nethyl) -2,4,6-octatrienoic acid ethyl ester 4. A compound according to claim 1, characterized in that it is 11β-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) 2,1 +, 6,8-nonatetraenoic acid ethyl ester, (all-E) -9- (1 + -methoxy-2,3,6-trimethylphenyl-4,7-dimethyl-2,4,6ß-nonatetraenoic acid ethyl ester, (all-E ) -1 + -methyl-7- (5,6,7,8-tetrahydride oS, 5,8,8-tetramethyl-Z-naethyl) -2, #, 6-octatrienecarboxylic acid or N-ethyl-1-methyl-7- (5,6,7,8-tetrahydro-5,5, 8,8-tetramethyl-Z-naphthyl) -2,11,6-octatrienoic acid amide. 454 984 8 5. Compounds of formula I C113 C53 R "C = CH-CH = C_CH = CH_COR2 where RI is a group of the formula HCH H3C H3 3 3 CH = CH- C H3 H30 C H3 ab or H3 H4 c H- _-cH- Rs 0 7 _ Re C RZ is hydroxy, lower alkoxy, amino, mono- or di- (lower alkylamino; RB is lower alkyl or halogen; R "is lower alkyl; R5 is lower alkoxy; 126 is hydrogen or lower alkyl, and R 2 is lower alkyl or halogen, for use in the treatment of neoplasms, premalignant lesions, acne, psoriasis or rheumatic diseases of an inflammatory or degenerative nature 6. Pharmaceutical preparations based on a compound of the formula CH CH 3 1a a1-å = c fl- cu = c-cn = cn-conz 10 where R 1 is a group of the formula 5 454 984 9 _ H3C H3 H3C H3 C HïCH-- CH H30 c H3 3 ab or R3 H4 cH = cH- RS H7 RB R is hydroxyl, lower alkoxy, amino, mono- or di- (lower alkylamino; RB is lower alkyl or h7810 gene; R is lower alkyl; Rs is lower alkoxy; R0 is hydrogen or lower alkyl; and R is lower alkyl or halogen 7. Process for the preparation of compounds of the formula CH 3 CH 1 (1: 1 3 2 R- = CH-Cl-1 = C-CH = CH..CQR where R 1 is a group of the formula H 30 CH 3 H 30 cH CH 2 H - HC CH CH 3 3 ab or F 45 cH = cH - - R 2 is hydroxy, lower alkoxy, amino, mono- or di- (lower alkylamino; RB is lower alkyl or halogen; Ru is lower alkyl; R 5 is lower alkoxy; R 5 is hydrogen or lower alkyl; and R 7 is lower alkyl or halogen, characterized in that a compound of the general formula R 1A is reacted with a compound of the general formula CHB 1 2 B-CH = C-CH = CH-COR II wherein R 1 and R 2 have the the meanings given above and either A denotes a 1. - (triphenylphosphonium octyl group of the formula H3C-CH-P (X] 3 + Y_, wherein X represents phenyl and Y 'represents the anion of an organic or inorganic acid, and B is formyl; or A is acetyl and B represents a dialkoxyphosphinylmethyl group of the formula -CH 2 -l [Z] 2, wherein Z represents a lower alkoxy group, and that, if desired, a resulting carboxylic acid ester is converted to a carboxylic acid or a carboxylic acid amide.