CH651007A5 - POLYEN CONNECTIONS. - Google Patents

Description

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 have the general formula ch3 ch3

I I

R> -C = CH-CH = C-CH = CH-COR2 wherein R1 is a radical of the formulas

3rd

651 007

H3C CH3

H3C. XH3

C H — CH-

or

CH = CH-

R2 is hydroxy, lower alkoxy, amino, mono- or di- (lower alkyl) amino, R3 is lower alkyl or halogen; R4 lower * alkyl; R5 lower alkoxy; R6 is hydrogen or lower alkyl; and R7 is lower alkyl or halogen.

Preferred radicals (c) are those in which R3, R4 and R7 are lower alkyl, R5 is lower alkoxy and R6 is hydrogen.

Alkyl groups and the alkyl radicals in alkoxy and alkyl amino groups preferably contain up to 6 carbon atoms. They can be branched or unbranched, such as the methyl, ethyl, isopropyl or 2-methyl-propyl group, with methyl being particularly preferred.

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

The compounds of the formula I can be obtained according to the invention by reacting a compound of the general formula R1 A with a compound of the general formula

CH3 I

B-CH = C-CH = CH-COR2

II

implemented, where R1 and R2 have the meanings given above and either A represents an 1- (triphenylphosphonium) ethyl group of the formula H3C-CH-P [X] 3 + Y ~, where X is phenyl and Y ~ the anion of an organic or inorganic Denotes acid and B is formyl; or A is acetyl and B represents a dialkoxyphosphinylmethyl group of the formula -CH2-P [Z] 2, in which Z is a lower alkoxy radical

i

O

draws. A carboxylic acid ester obtained can be converted into a carboxylic acid or a carboxylic acid amide.

Of the inorganic acid anions Y, the chlorine and bromine ion or hydrosulfate ion is preferred, 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 an acid-binding agent, for. B. in the presence of a strong base, e.g. Butyllithium, sodium hydride or the sodium salt of dimethyl sulfoxide, optionally in a solvent, e.g. B. in an ether, such as diethyl ether or tetrahydrofuran, or in an aromatic hydrocarbon, such as benzene in a between

25 room temperature and the boiling point of the reaction mixture lying temperature range.

The reaction of a phosphonate of formula II with a compound R ^ OCH- 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, e.g. 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, e.g. Sodium methylate in methanol, a temperature range between 0 ° and the boiling point of the reaction mixture.

The above reactions can also be carried out in situ, i.e. without isolating the relevant phosphonium salt or phosphonate. 40 A carboxylic acid ester of formula I can be prepared in a manner known per se, e.g. hydrolysed by treatment with alkalis, in particular by treatment with aqueous alcoholic sodium or potassium hydroxide in a temperature range between room temperature and the boiling point of the reaction mixture and either amidated via an acid rehalide or, as described below, directly.

A carboxylic acid of the formula I can be prepared in a manner known per se, e.g. B. by treatment with thionychloride, preferably in pyridine, or phosphorus trichloride in toluene can be converted into the acid chloride, which can be converted into the corresponding amide by reaction with alcohols in esters with amines.

A carboxylic acid ester of formula I can e.g. B, by Be-55 trading with lithium amide can be converted directly into the corresponding amide. The lithium amide is advantageously reacted with the ester in question at room temperature.

A carboxylic acid of the formula I forms salts with bases, in particular with the alkali metal hydroxides, preferably with sodium or potassium hydroxide, which are also an object of the invention. Formula I is intended to include ice and trans forms.

65 The compounds of the formula I can be obtained as cis / trans mixtures which, if desired, are separated into the ice and trans components or isomerized to the all-trans compounds, if desired

651 007

that can. The all-trans (all-E) compounds are preferred.

The compounds of the formula f represent steep remedies. They can be used for the topical and systemic therapy of benign and malignant neoplasms, of pre-malignant lesions, and also for the systemic and topical prophylaxis of the affection mentioned.

They are also suitable for topical and systemic therapy of acne, psoriasis and other dermatoses associated with increased or pathologically altered cornification, as well as for inflammatory and allergic dermatological affections. The compounds of the formula I can also be used to combat mucosal diseases with inflammatory or degenerative or metaplastic changes and for oral treatment of rheumatic diseases, in particular those of an inflammatory and degenerative nature which affect joints, muscles, tendons and other parts of the musculoskeletal system. Examples of such diseases are primarily chronic polyarthritis, spondylarthritis ankylopoetica Bechterew and Arthro-pathia psoriatica.

The tumor-inhibiting effect of the process products is significant. A regression of the tumors induced with dimethylbenzanthracene and croton oil was observed in the papilloma test (Europ. J. Cancer 10,731-737 [1974]). The diameters of the papillomas increased over 2 weeks with the intraperitoneal application of 50 mg of all-E-4-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naph -thyl) -2,4,6-octatriensäureäthylester by 49%.

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

The dosages in which the process products are administered can vary depending on the type of application and route of use and on the needs of the patients.

The process products can be administered in amounts of approximately 0.01 to approximately 5 mg daily in one or more doses. A preferred dosage form are capsules with a content of about 0.1 mg to about 1.0 mg of active ingredient.

The preparations can contain inert or pharmacodynamically active additives. Tablets or granules e.g. can contain a number 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, taste-improving additives, as well as the substances usually used as preservatives, stabilizers, humectants and emulsifiers, as well as salts for changing the osmotic pressure, buffers and other additives can also be present.

The above-mentioned carriers and diluents can be made from organic or inorganic substances, e.g. B. from water, gelatin, milk sugar, starch, magnesium stearate, talc, gum arabic, polyalky

lenglycols and the like. The prerequisite is that all auxiliary substances used in the manufacture of the preparations are non-toxic.

For topical use, the process products are expediently used in the form of ointments, tinctures, creams, solutions, lotions, sprays, suspensions and the like. Ointments and creams and solutions are preferred. These preparations intended for topical use can be prepared by admixing the process products as an effective component of non-toxic, inert, solid or liquid carriers which are customary in such preparations and are suitable for topical treatment.

For topical use, approximately 0.01 to approximately 0.3%, preferably 0.02 to 0.1%, and approximately 0.05 to approximately 5%, preferably approximately 0, are suitable. 05 to approx. 1%, ointments or creams suitable.

An antioxidant, e.g. Tocopherol, N-methyl-y-tocopheramine and butylated hydroxyanisole or butylated hydroxyto-luol can be added.

example 1

23.4 g of [l- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide in 150 ml of dry tetrahydrofuran were at -15 ° C slowly mixed with 26.25 ml of 1.6 molar butyllithium (in hexane). After 30 minutes, 6.72 g (40 mmol) of all-E-5-formyl-4-methyl-2,4-pentadienoic acid ethyl ester in 30 ml of tetrahydrofuran was added dropwise at the same temperature and then stirring was continued for 2 hours at room temperature . After adding ethyl acetate, the organic phase was shaken with 0.1N hydrochloric acid, washed neutral with water, dried over magnesium sulfate and concentrated on a rotary evaporator. Twice crystallization of the residue 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-octatriensäureäthylester of melting point 87.5-89 ° C. A further 1.6 g of pure product could be obtained from the mother liquors 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 triethyl phosphonoacetate are added to 4.63 g of sodium hydride in 100 ml of dry tetrahydrofuran. 25.0 g (0.18 mol) of y-acetoxy-tiglinaldehyde in 50 ml of tetrahydrofuran are then added dropwise at 0-5 ° C. The reaction mixture is stirred at room temperature for 20 hours, diluted with 200 ml of ethyl acetate, washed with saturated sodium chloride solution and dried over magnesium sulfate. Concentration and distillation at 103 ° /

0.35 mmHg gives 28.6 g (76%) of 6-acetoxy-4-methyl-2,4-hexadienoic acid ethyl ester.

b) 27.5 g of ethyl 6-acetoxy-4-methyl-2,4-hexadienoate, 20 g of sodium carbonate and 2 ml of triethanolamine are refluxed in 250 ml of ethanol for 3 hours. After adding ethyl acetate, the mixture is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Distillation at 110 ° / 0.4 mmHg gives 15.7 g (71%) of 6-hydroxy-4-methyl-2,4-hexadienoic acid ethyl ester.

c) 11.7 g of 6-hydroxy-4-methyl-2,4-hexadienoic acid ethyl ester are stirred in 200 ml of dichloromethane with 30 g of manganese (IV) oxide at room temperature for 4 hours. The reaction solution is filtered, concentrated and the residue is recrystallized from hexane / cyclohexane. 9.1 g (78%) of 5-formyl-4-methyl-2,4-pentadienoic acid ethyl ester of melting point 48-49 ° C. are obtained.

4th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

651 007

Example 2

Analogously to Example 1, l-methyl-3- (2,6,6-trimethyl-l-cyclohexen-l-yl) allyl-triphenylphosphonium chloride and 5-formyl-4-methyl-2,4-pentadienoic acid are obtained ethyl ester 4,7-dimethyl-9- (2,6,6-trimethyl-l-cyclohexen-1-yl) -2,4,6,8-nonatetraenoic acid ethyl ester, melting point 65-66 ° C (from methanol).

Example 3

Analogously to Example 1, 1-methyl-3- (2,3,6-trimethyl-4-methoxyphenyl) allyl-triphenylphosphonium chloride and 5-formyl-4-methyl-2,4-pentadienoic acid ethyl ester are obtained (all-E) -9- (4-methoxy-2,3,6-trimethylphenyl) -4,7-dimethyl-2,4,6,8-nonatetraenoic acid, ethyl ester.

Example 4

9 g (all-E) -4-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl-2,4,6-octatrienoic acid ethyl ester are dissolved 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 onto ice water, acidified with 2N sulfuric acid and the acid obtained is filtered off Recrystallization from methanol gives 7.8 g of (all-E) -4-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2.4 , 6-octatrienecarboxylic acid in yellow crystals, melting point 232-234 ° C.

Example 5

4.5 g (all-E) -4-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl) -2,4,6- octatrienecarboxylic acid are dissolved in 200 ml of tetrahydrofuran and mixed with 2.6 gl, l'-carbonyldiimidazole. After stirring for 3 hours at room temperature, the mixture is cooled to 5-10 ° C. and an ethylamine stream is passed in for 1 hour. After removing the cooling bath, the mixture is stirred 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 sodium carbonate solution and with saturated sodium chloride solution, 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-4-methyl-7- (5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthyl) -2,4,6-octatrienamide in yellow crystals, melting point 158-159 ° C.

Example A

Production of a capsule filling compound with the following composition:

all-E-4-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2,4,6-octatrienoic acid ethyl ester 0.1 mg

Wax mix 50.5 mg

Vegetable oil '98.9 mg

Trisodium salt of ethylenediamine tetraacetic acid 0.5 mg

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

Claims (6)

651 007 1. Compounds of the formula wherein R1 a rest of the formulas claims ch3 ch3 I I rj-c = ch-ch = c-ch = ch-cor2 H3C \ ^ ch3 h3c ch3 H3c \ ^ CH3 > <^ / c h — ch— or CH = CH— R2 is hydroxy, lower alkoxy, amino, mono- or di- (lower alkyl) amino, R3 is lower alkyl or halogen; R4 lower alkyl; R5 lower alkoxy; R6 is hydrogen or lower alkyl; and R7 is lower alkyl or halogen. 2. Compounds according to claim 1, wherein R1 is a radical (c) and R3, R4 and R7 lower alkyl, R5 lower alkoxy and R6 is hydrogen. 3. (all-E) -4-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2,4,6-octatrienoic acid- ethyl ester, as a compound according to claim 1. 4,4,7-dimethyl-9- (2,6,6-trimethyl-l-cyclohexen-l-yl) -2,4, 6,8-nonatetraenoic acid ethyl ester, (all E) -9- (4-methoxy-2, 3,6-trimethylphenyl) -4,7-dimethyl-2,4,6,8-nonatetraenoic acid re-ethyl ester, (all-E) -4-methyl-7- (5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-naphthyl) -2,4,6-octatriene-carboxylic acid and N-ethyl-4-methyl-7- (5,6,7,8-tetrahydro-5,5, 8,8-tetramethyl-2-naphthyl-2,4,6-octatrienamide, as compounds according to claim 1. 5. Compounds according to claim 1 as agents for the treatment of neoplasia, pre-malignant lesions, acne, psoriasis, or rheumatic diseases of inflammatory or degenerative nature. 6. Pharmaceutical preparations containing a compound according to claim 1. 7. A process for the preparation of compounds according to claim 35, characterized in that a compound of the general formula R1 A with a compound of the general formula 40 CH3 I. B-CH = C-CH = CH-COR2 II implemented, wherein R1 and R2 have the meanings given above-45 gene and either A represents an 1- (triphenylphosphonium) ethyl group of the formula H3C-CH-P [X] 3 + Y ~, where X is phenyl and Y ~ is the anion of a denotes organic or inorganic acid, and B is formyl; or A is acetyl and B represents a dialkoxyphosphinylmethyl group of the formula so -CH2-P [Z] 2, in which Z is a lower alkoxy radical I. O draws. 55 8. all-E-5-formyl-4-methyl-2,4-pentadienoic acid ethyl ester, as starting material for the process according to claim 7.