DK159392B - ANALOGY PROCEDURE FOR THE PREPARATION OF POLYENE COMPOUNDS - Google Patents

Description

DK 159392 B

The present invention relates to an analogous process for the preparation of novel polyene compounds with which compounds can be prepared pharmaceutical compositions.

The compounds of the invention have the general formula I

CH3 ch3

R1 - C = CH - CH = C - CH = CH - COR2 I

wherein R1 represents a group of formula a, b or c h3c «v X H3 H3C ^ X H3> OcH = CH-

Ϊ J M

H 3 C ch 3 a 3 b or R 3 xo R 2 represents hydroxy, lower alkoxy, amino or mono- or di (lower alkyl) amino; R3 represents lower alkyl or halogen; R4 represents lower alkyl; R5 represents lower alkoxy; R6 represents hydrogen or lower alkyl; and R7 represents lower alkyl or halogen.

Preferred groups c) are those wherein R 3, R 4 and R 7 represent lower alkyl, R 5 represents lower alkoxy, and R 6 represents hydrogen.

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The alkyl groups and the alkyls in the alkoxy and alkylamino groups preferably contain no more than 6 carbon atoms. They may be branched or unbranched, for example methyl, ethyl, isopropyl or 2-methylpropyl, preferably methyl.

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

From DK publication no. 155043, DK no. 155730 and DE publication no.

2 102 586 are known polyene compounds; the compounds of the present invention differ from these known polyene compounds in that the methyl groups in the polyene side chain are closer together. Compared to the known compounds, the compounds of the invention are substantially less toxic than the known isomers, as evidenced by the lower vitamin A activity listed below.

The process of the invention for the preparation of the compounds of formula I is characterized by reacting a compound of the general formula R - * - A with a compound of the general formula II

20 CH3

B - CH = C - CH = CH - COR2 II

wherein R1 and R2 have the meaning given above and either A

represents an 1- (triphenylphosphonium) ethyl group of the formula H3C-CH-P [X] 3 + Y ", where X represents phenyl 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 -CH 2 -P [Z] 2, 4-

ISLAND

Wherein Z represents a lower alkoxy group; and, if desired, converting a won carboxylic acid ester to a carboxylic acid or a carboxylic acid amide.

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

The reaction between a formyl compound of formula II and 5 a phosphorane is carried out in a manner known per se in the presence of an acid-binding agent, for example in the presence of a strong base, for example, butyl lithium, sodium hydride or the sodium salt of dimethylsulfoxide, optionally in a solvent, e.g. an ether such as diethyl ether or tetrahydrofuran 10 or in an aromatic hydrocarbon, for example benzene, in a temperature range which is between room temperature and the boiling temperature of the reaction mixture.

The reaction between a phosphonate of formula II and a compound of formula R RCOCI CO 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 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 20 sodium methylate in methanol, in a temperature range between 0 ° C and the boiling temperature of the reaction mixture.

The above reactions can also be carried out in situ, i.e. without isolating the phosphonium salt or phosphonate in question.

A carboxylic acid ester of formula I can be hydrolyzed and amidated in a manner known per se, for example, by treatment with bases, in particular by treatment with aqueous, alcoholic sodium or potassium hydroxide solution, in a temperature range between room temperature and the reaction temperature of the reaction mixture. either via an acid halide or, as described below, directly.

A carboxylic acid of formula I may be known per se, for example, by treatment with thionyl chloride, preferably in

DK 159392 B

4 pyridine, or phosphorus trichloride in toluene is converted to the acid chloride, which upon reaction with alcohols can be converted to esters, with amines to the corresponding amide.

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

A carboxylic acid of formula I forms with bases, especially with the alkali metal hydroxides, preferably with sodium or potassium hydroxide, salts which are also included in the invention. Formula I should include cis and trans forms.

The compounds of formula I may exist as cis / trans mixtures which, in a manner known per se, can be digested into the cis and trans components or isomerized to the all-trans compounds. The all-trans (all-E) compounds are preferred.

The compounds of formula I are drugs. They can be used for topical and systemic therapy of benign and malignant neoplasms, premalignant lesions, and for systemic and topical prophylaxis of the aforementioned disorders.

They can also be used for topical and systemic therapy of acne, psoriasis, and other associated with enhanced or pathologically altered dermatosis, as well as for inflammatory and allergic dermatological disorders. Furthermore, the compounds of formula I can also be used to combat mucosal diseases with inflammatory or degenerative or metaplastic changes, respectively, and for oral treatment of rheumatic diseases, especially inflammatory and degenerative diseases which attack the joints, muscles, tendons and other parts of the movement apparatus. Examples of such diseases are primary chronic polyarthritis, spondylarthritis ankylopoetica Bechterew and arthropathia psoriatica.

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The tumor inhibitory effect of the compounds of this invention is significant. In the papilloma test (Europ. J. Cancer 10, 731-737 [1974], regression of dimethylbenz-anthracene and croton oil-induced tumors was observed. The diameters of the 5 papillomas decreased within 2 weeks after intraperitoneal application of 50 mg all-E. 4-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2,4,6-octatrienoic acid ethyl ester with 49%.

As mentioned initially, the compounds of the invention are substantially less toxic than the known isomers, as shown by their lower vitamin A activity. A-hypervitaminosis manifests itself in changes in skin and mucous membranes and causes symptoms such as dryness of mouth, lips and eyes. Comparative experiments have been performed between the 4,7-dimethyl retinoids IA, II-A, III-A, IV-A of the present invention and the 3,7-dimethyl retinoids I (known from DK 123708), II (known from DK 155043) , III (known from DK 155730) and IV (known from DK 155730).

Compound I (DK 123708) 20 v CO

Compound I-A

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6

Compound II (DK 155043) CO 2 Et

Compound II-A 5 CO 2 Et

Compound III (DK 155730) yj

Compound III-A

ζΟι1

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7

Compound IV (DK 155730)

Compound IV-A 5 C ° 2Et

These compounds were tested for their A-hypervitaminosis and anti-papilloma activity as follows:

TESTS

10 1 ^. A-Hypervitaminosis A-hypervitaminosis symptoms suggestive of toxicity of retinoids manifest as weight loss, redness and peel of the skin, hair loss, changes in foot and nose mucus obstructions, and bone fractures. A-hypervitaminosis can be produced in mice over a short period of time by using high doses of vitamin A, vitamin A acid or analogs thereof. The α-hypervitaminosis test was performed on mice weighing 25-27 g, which over a 14-day period received 10 i.p. injections of the test substance suspended in peanut oil.

The following symptoms were evaluated using a scale of 0-4:

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8 0 12 3 4 Weight loss <1 g 1-3 g 4-6 g 7-9 g> 10 g

Skin peeling no rings moderately severe very 5 severe Hair loss no rings moderate severe very severe

Bone fractures in extremities 0123 4 or> 4 10 (number, macroscopic observation)

The lowest daily dose of each of the test compounds, which causes A-hypervitaminosis in the 14-day study, was determined. A-hypervitaminosis was defined as being the condition of the animals in which the addition of all symptom scores yielded at least 3. This lowest daily dose is given in mg / kg / day in the following test results table.

2. Paoilloma Effect 20 Induction of skin oaoilloma 7,12-Dimethylbenz (a) anthracene (DMBA) was applied twice to the dorsal skin of bald albino mice at a 14-day interval.

150 mcg of DMBA dissolved in 0.2 ml of acetone was painted on each mouse at a skin area of approximately 5 cm2. After 3 weeks, croton oil-25 treatment was started. 0.5 mg of croton oil dissolved in 0.2 ml of acetone was applied to the skin of the animals twice a week for 3-8 months. During this time, most of the animals had developed several papillomas, mostly in a number of 4-10.

The therapeutic study was started after 30 papillomas had reached an average diameter of 3 mm.

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Hudpapilloma therapy

A number of mice (5 times a week) with papilloma were treated i.p. Once a week or daily (5 times a week) with one-fifth of the weekly dose with a peanut oil suspension of the retinoid over a 2-week period.

Evaluation

The sum of the papilloma diameters was determined for each mouse and the average value was determined for each group. These measurements were performed at the beginning of therapy (day 0) as well as 10 2 weeks (day 14) after the first administration of the drug part. The increase or decrease in the average of the papilloma diameters per animal has been expressed as a percentage of the initial value (day 0). This figure is expressed in the table below as percent regression: From the above data, the minimum for papilloma within 2 weeks was determined. This ED50 is listed in the table below.

RESULTS

TABLE

PORBINDESE HYPEkVlTAMINOSE ΑΝΤΤΡΆΡΤΤ.Τ ΩΜΆ 20 Lowest daily dose ED50% regression (mg / kg / day) (mg / kg / week) (%) I 50 400 -47 I- A> 400 400 -37 25 II 50 25 -48 II - A> 400 400 -7 III 3 3 -11 III- A 25 25 +2 IV 1.5 1.5 -31 30 IV-A 50 50 -49

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From the above results, it is seen that the 4,7-dimethyl retinoids of the present invention, as measured by the A-hypervitaminosis test, are at least 8 times (8 x) less toxic than the corresponding known 3,7-dimethyl retinoids.

The compounds of formula I may be used as drugs, for example in the form of pharmaceutical preparations. For example, compositions used for systemic therapy may be prepared by adding as an active ingredient a compound of Formula I to non-toxic, inert, per se, in such compositions, 10 usual solid or liquid carriers. The agents may be administered enterally or parenterally. For enteral application, the agents may be used, for example, in the form of tablets, capsules, dragees, syrups, suspensions, solutions and suppositories. For parenteral application, the agents 15 may be used in the form of infusion or injection solutions.

The dosages in which the products are administered can be varied depending on the method and method of application and according to the patient's needs.

The present compounds can be administered in amounts of 20 0.01 to approx. 5 mg daily in one or more doses. A preferred form of administration is capsules having a content of approx. 0.1 mg - approx. 1.0 mg of active substance.

The compositions may contain inert or pharmacodynamically active additives. For example, tablets or granules may contain a variety of binders, fillers, carriers or diluents. For example, liquid preparations may be in the form of a sterile water-miscible solution. In addition to the active ingredient, the capsules may also contain a filler or thickener. In addition, 30 flavor enhancing additives as well as the substances used as preservatives, stabilizers, humectants and emulsifiers, as well as salts for altering the osmotic pressure, buffers and other additives may be present.

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The aforementioned carriers and diluents may also consist of organic or inorganic substances, e.g., water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic or polyalkylene glycols. It is a prerequisite that all the adjuvants used in the preparation of the compositions are non-toxic.

For topical use, the compounds are suitably in the form of ointments, tinctures, creams, solutions, lotions, sprays or suspensions. 10 ointments and creams and solutions are preferred. The compositions intended for topical application can be prepared by mixing the products prepared by the process of the invention as active ingredient with non-toxic, inert, topical treatment suitable, per se, in such compositions as usual solid or liquid carriers.

For topical use, approx. 0.01 - approx.

0.3%, preferably 0.02-0.1%, solutions and approx.

0.05 - approx. 5%, preferably approx. 0.05 - approx. 1% s, ointments or creams suitable.

Optionally, an antioxidant may be added to the compositions, for example tocopherol, N-methyl-7-tocopheramine and butylated hydroxyanisole or butylated hydroxytoluene.

The process according to the invention is illustrated in more detail by the following examples: EXAMPLE 1

To 23.4 g of [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] triphenylphosphonium bromide in 150 ml of dry tetrahydrofuran was added slowly at -15 ° C with stirring. 26.25 ml 1.6M butyllithium in hexane. After 30 minutes, 6.72 g (40 g) were added dropwise at the same temperature

DK 159392B

12 millimoles) of all-E-5-formyl-4-methyl-2,4-pentadienoic acid ethyl ester in 30 ml of tetrahydrofuran and then stirred for 2 hours at room temperature. After addition of ethyl acetate, the organic phase was shaken with 0.1 N hydrochloric acid, washed neutral with water, dried over magnesium sulfate and evaporated on a rotary evaporator. Twice crystallization of the residue of ca. 100 ml of ethanol gave 3.47 g (24%) of (all-E) -4-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl) ) -2,4,6-octatric acid ethyl ester, mp 87.5-89 ° C. An additional 1.6 g of pure product could be obtained from the mother liquor by chromatography.

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 is added to 4.63 g of sodium hydride in 100 ml of dry tetrahydrofuran. Then 25.0 g (0.18 mol) of 7-acetoxy-tiglinaldehyde in 50 ml of tetrahydrofuran are subsequently dropped at 0-5 ° C. 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. Evaporation and distillation at 103 ° C / 0.35 mm Hg yields 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 are heated for reflux in 250 ml of ethanol. After addition of ethyl acetate, wash with saturated brine, dry over magnesium sulfate and evaporate. Distillation at 110 ° C / 0.4 mm Hg 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 in 200 ml of dichloromethane are stirred at room temperature for 4 hours with 30 g of manganese (IV) oxide. The reaction solution is filtered and evaporated and the residue is recrystallized from hexane / cyclo

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13 hexane. 9.1 g (78%) of 5-formyl-4-methyl-2,4-pentadiene acid ethyl ester is obtained, mp 48-49 ° C.

Example 2 In analogy to Example 1, is obtained from 1-methyl-3- (2,6,6-5 trimethyl-1-cyclohexen-1-yl) allyl-triphenylphosphonium chloride and 5-formyl-4-methyl-2, 4-pentadienoic acid ethyl ester 4,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraenoic acid ethyl ester, m.p. 65-66 ° C (of methanol).

EXAMPLE 3 In analogy 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 ( all-E) - 9- (4-methoxy-2,3,6-trimethylphenyl) -4,7-dimethyl-2,4,6,8-15 nonatetraenoic acid ethyl ester, m.p. 117-118 ° C.

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-octatric acid) Ethyl ester is dissolved in 200 ml of ethanol and a solution of 8.2 g of potassium-20 hydroxide in 20 ml of water is added. After recrystallization from methanol, 7.8 g (all-E) - 4-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) - are obtained. 2,4,6-octatricene carboxylic acid in the form of yellow crystals, mp 232-234 ° C.

14

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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, Dissolve 6-octatrienecarboxylic acid in 200 ml of tetrahydrofuran and add 2.6 g of 1,1'-carbonyl diimidazole. After 3 hours of stirring at room temperature, cool to 5-10 ° C and for 1 hour an ethylamine stream is added.

After removing the cooling bath, stir at room temperature overnight. Then, the reaction mixture is poured into 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 in the ratio 95: 5) and recrystallization of 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-octatric acid amide in the form of yellow crystals, mp 158-159 ° C.

EXAMPLE A

Preparation of capsule filler with the following composition: all-E-4-Methyl-7- (5,6,7,8-tetrahydro-5.5.8.8-tetramethyl-2-naphthyl) -2,4,6-octatric acid ethyl ester 0 , 1 mg

Wax mixture 50.5 mg Vegetable oil 98.9 mg

Trisodium salt of ethylene diamine tetraacetic acid 0.5 mg »

Claims (3)

1. Analogous Process for Preparing Polyene Compounds of General Formula I CH3 ch3 R 1 - C = CH - CH = C - CH = CH - COR2 In which R1 represents a group of the formula a, b or c H3XX / H3 "X ^ ch = ch- OCX OCh or R3 H = CH- R6 C R2 represents hydroxy, lower alkoxy, amino or mono- or di (lower alkyl) amino; R3 represents lower alkyl or halogen; R4 represents lower alkyl; R5 represents lower alkoxy; R6 represents hydrogen or lower alkyl; and R7 represents lower alkyl or halogen , characterized in that a compound 15 of the general formula R 1 -A is reacted with a compound of the general formula II CH 3 B - CH = C - CH = CH - COR 2 II DK 159392B wherein R 1 and R 2 have the meaning given above. and either A represents an 1- (triphenylphosphonium) ethyl group of the formula H3C-CH-P [X] 3 " or A represents acetyl and B represents a dialkoxyphosphinylmethyl group of the formula -CH 2 -P [Z] 2, -Ι Ο where Z represents a lower alkoxy group; m desired 10 converts a won carboxylic acid ester into a carboxylic acid or a carboxylic acid amide. Process according to claim 1, characterized in that compounds of formula I are prepared, wherein R 1 represents a group c) and R 3, R 1 and R 2 represent lower alkyl, R 3 represents alkoxy and R 4 represents hydrogen. Process according to claim 1, characterized in that (all-E) -4-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalamide) is prepared. Ethyl (2,4,6-octatric acid) ethyl ester. Process according to claim 1,2 E) -4-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2,4,6-octatrienecarboxylic acid or N -ethyl-4-methyl-7- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2,4,6-octatric acid amide. 3 characterized in that 4,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraacetic acid ethyl ester is prepared, -E) -9- (4-methoxy-2,3,6-trimethylphenyl) -4,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester,