CS265240B2 - Process for preparing tetrahydrotetramethylnaphthylpropenylphenoles - Google Patents

Abstract

Tetramethyl- tetrahydronaphthyl propenylphenol cpds. of formula (I) are new. where R1= o-, m- or p-hydroxyphenyl; 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl; or 2,3,4-, 2,3,5-, 2,4,5-, 2,4,6-, 3,4,5- or 2,3,6-trihydroxyphenyl. Pref. the olefinic double bond has the trans-configuration.

Description

The invention relates to a process for the preparation of tetrahydrotetramethylnaphthylpropenylphenols of the formula I

^H 3 ^C CH ₃ 9H3 -C-CH-R ¹ H ₃ c CH ₃

(I) wherein R ¹ is o-, m- or p-hydroxyphenyl.

The compounds of formula I may exist as trans- or cis-isomers or an isomeric cis / trans mixture. Generally, trans compounds of formula I are preferred, wherein o-, m- or p-hydroxyphenyl, especially p-hydroxyphenyl, is preferred.

The compounds of formula I may be used in the treatment and prophylaxis of neoplasia and dermatosis in the form of pharmaceutical preparations.

A process for the preparation of compounds of the formula I is characterized in that from protected tetrahydrotetrunethylnaphthylpropenylphenol of the formula II

where R ¹¹ is the radical R ¹ in which the hydroxy is protected, cleaves the protecting group.

Preferably the starting compound is a compound of formula II in which the olefinic double bond has a trans-configuration and R ¹¹ represents a phenyl 2-residue having a hydroxy-protected p-position.

Suitable protecting groups are all conventional hydroxy protecting groups. Examples of such protecting groups are ethers, especially 2-tetrahydxopyranyl ether and silyl ether such as trimethylsilyl ether; alkyl ethers such as methyl ether; and esters such as a low alkanoic acid ester such as acetate and carbonate. The deprotection can be carried out in a known manner by reaction with acids, bases or reducing agents. Ether protecting groups such as tetrahydropyranyl and trimethylsilyl can be cleaved by reaction with acids such as p-toluenesulfonic acid or Lewis acids such as BF 4 or BBr 4. Ester protecting groups such as acetate or carbonate are removed by treatment with bases, for example an alcoholic or aqueous-alkali metal hydroxide solution.

Compounds of formula (II) can be obtained by reacting a compound of formula (III)

(III)

H ₃ c CH ₃ with a compound of formula IV

BR ¹¹ (IV) where

A denotes the radical -CH / CH3 / P ⁺ / Q / ^ Y or -CH / CH3 / P / O / OAlk / ^ and V denotes formyl, n, Lk,

A denotes acetyl and represents the radical -CH ₂ P ⁺ / Q / ₃ Y or -СН ^ Р / О // ОА1к / ₂ and

Q is aryl, especially phenyl,

Y is an anion of an organic or inorganic acid, for example

Br and Alk are low alkyl, for example methyl, and

R ¹¹ is as defined above.

The reaction of the compound of formula III and IV can be carried out according to a known method of Wittig or Horner reaction.

In the Wittig reaction, i.e. when using a compound of formula III with A = -CB / CH3 / P ⁺ / Q / Y- or + -3 of formula IV with V = -CH ₂ P / Q / Y Y, the components are left react at a temperature between room temperature and the boiling point of the reaction mixture in the presence of an acid-binding agent, for example in the presence of a strong base such as butyllithium, sodium hydride or dimethylsulfoxide sodium, especially in the presence of ethylene oxide optionally substituted by low alkyl such as 1,2- butylene oxide, optionally in a solvent such as an ether such as diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon such as benzene.

Of the inorganic anions of acid Y, a chlorine and bromine ion or hydrogen sulphate ion is preferred, of the organic acid anions, a tosyloxy ion is preferred. The aryl radical Q is preferably a phenyl radical or a substituted phenyl radical such as p-tolyl.

In the Horner reaction, i.e. using a compound of formula III with A or formula IV with V = -СН ₂ Р / О // ОА1к / ₂ boiling point of the reaction mixture using a base and = -СН / СНу-Р / О // ОА1к / ₂ , the components are condensed at a temperature in the range of 0 [deg.] C. and preferably in the presence of an inert organic solvent, for example with sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; sodium in methanol.

Alkoxy radicals OAlk are especially low alkoxy radicals having one to six carbon atoms, such as methoxy or ethoxy.

The compounds of formula I may be in trans- or cis-form. They are mostly produced in trans form. The cis moieties, if any, can optionally be separated in a known manner.

The starting compounds of the formulas III and IV can be prepared analogously to known or described processes, if their preparation is not known or described in the following.

The compounds of formula I are therapeutically active. They have particularly antiseborrhoic, antikeratinising, antineoplastic and antiallergic (antiinflammatory effect, which can be demonstrated in subsequent experiments.

AND

A) The effect of preventing chemically induced breast tumors can be determined by the following procedure. Spraque-Dawley female rats are maintained under controlled temperature and light conditions, with free access to drinking water and food. At 50 days of age, 15 mg of dimethylbenzantraceae dissolved in peanut oil was administered to each rat via a gastric tube. Treatment with test compounds begins one day after administration of the carcinogenic agent. The body weight of the test animals is recorded and the tumor is palpated weekly and measured with a caliper. The volume is calculated according to the formula D ² , where D represents a larger and smaller diameter of the tumor ellipsoid. The experiment is terminated after 11 weeks and evaluated. In this experiment, in addition to the 30 control animals receiving exclusively normal food, the following two groups of test animals were used:

1. 33 rats given daily 30 mg / kg of test compound mixed with food

2. 36 rats given daily 90 mg / kg of test compound mixed with food.

B) The effect on tumors can be further determined on transplanted chondrosarcoma of rats according to the following method. The solid tumor of the animal donor is finely divided and suspended in a phosphate buffer / saline solution. 0.5 ml of 30% tumor slurry is implanted subcutaneously in white rats. The transplanted rats are divided into treatment groups of eight animals. Test compounds are suspended in peanut oil and administered orally five times a week via pharynx within 24 days. Tumors are excised and weighed on day 24. The results are expressed in quotient C / T, which is calculated as follows:

_C / _{T =} Average tumor weight of the control_______

Mean tumor weight of treated animals

C) The antimetaplastic effect can also be determined in rats according to the following method. Holtzman female rats weighing about 100 g are subjected to ovariectomy after 8 days of habituation under thiogenic anesthesia and an experiment is performed for a further 14 days. Two animals with free access to a diet containing approximately 2,000 IU of analytically determined vitamin A are placed in the cage. Prior to oral administration of the test compound, one µg of estradiol benzoate and 250 µg of testosterone propionate dissolved in 0.1 are administered subcutaneously daily for 6 consecutive days. ml of sesame oil. Parenteral hormonal administration leads to the formation of a pure cylindrical stage in the vaginal region, i.e. scaly metaplasia. Two days after the oral administration of the test substance, the result of the reaction on the vaginal epithelium is again determined. The blanket method of Behrens and Karber is used to calculate the average effective doses.

The results of experiments A to C with the compound of formula I, p- (R) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl phenol, are shown in the following: Tables I-III.

Table I

A) Prophylaxis of chemically induced breast tumor

Dose of rats (mg / kg) dor (%)

after.

Average number of tumors per rat (% of control)

Mean tumor volume per rat in min (% of control)

52.4

14.1

72.6

3.9

Table II

В) Effect on rat transplanted chondrosarcoma Dose C / T tumor weight quotient of untreated (mg / kg) control and treated animals

p.o animals

120 · 3.8 • bulka III C) Antimetaplastic effect in rat Compound 1 Relative effect trans retinoid acid 1 Compound I 0.91

The compounds of formula (I) may be used for the topical and systemic therapy of benign and malignant neoplasias, premalignant lesions, and also for the systemic and local prophylaxis of said effects.

Furthermore, they are suitable for the local and systemic therapy of acne, psoriasis and other dermatoses associated with enhanced or pathologically altered cornealization, as well as inflammatory and allergic dermatological effects. The products of formula I can furthermore also be used for the treatment of mucosal diseases with inflammatory or degenerative or metaplastic changes. The compounds of formula I exhibit particularly low toxicity or better tolerability compared to known retinoids.

The formulations may be administered in galenic forms of use enterally, parenterally or topically. For enteral use, for example, tablets, capsules, dragees, syrups, suspensions, solutions and suppositories are suitable. Formulations in the form of infusions or injectable solutions are suitable for parenteral administration.

The dosages at which the preparations are administered may vary according to the type and manner of use and the need of the patient. In general, daily doses of 0.1 to 50 mg / kg, preferably 1 to 15 mg / kg, are suitable.

The compositions may be administered in single or multiple doses. A preferred form of administration is a capsule containing about 5 to 200 mg of active ingredient.

The formulations may contain inert or pharmacologically active ingredients. Tablets or granules may contain, for example, a variety of binders, fillers, carriers or diluents. For example, the liquid preparations may be in the form of a sterile, water-miscible solution. The capsules may contain, in addition to the active ingredient, a filler or a thickening agent. In addition, flavor enhancers and substances commonly used as preservatives, stabilizers, desiccants and emulsifiers, as well as salts for varying the osmotic pressure, buffers, and other additives may be present.

The foregoing carriers and diluents may consist of organic or inorganic substances such as water, gelatin, milk sugar, starch, magnesium stearate, talc, arabic cu, i /, polyalkylene glycols and the like. All excipients used in the formulation are non-toxic. .

For topical use, the active compounds are preferably used in the form of ointments, elixirs, creams, solutions, lotions, sprays, suspensions and the like. Ointments and creams and solutions are preferred. These topical formulations may be prepared by admixing the products of the invention as an active ingredient with the nontoxic, inert, topical, solid or liquid carriers customary in such formulations.

For topical use, preferably about 0.1 to 5%, preferably about 0.3 to 2% solutions and about 0.1 to 5%, preferably about 0.3 to 2% ointments or creams are suitable.

The preparations may optionally be mixed with an antioxidant, for example tocopherol, N-methyl-gamma-tocopheramine and butylated hydroxyanisole or butylated hydroxytoluene.

The following examples further illustrate the invention. The temperature is given in degrees Celsius. Example 1

82.3 g of p- [2- / 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl / propenyl] phenylacetate are suspended in two liters of ethanol and a solution of 130 g of hydroxide is added. of potassium in 600 ml of water. After stirring at room temperature for 1 hour, it was acidified with dilute hydrochloric acid under ice-cooling and extracted several times with acetate. The organic phase is washed four times with water, dried over sodium sulphate and evaporated. The crystalline residue was recrystallized from hexane / acetate to give 66 g of p - [(E) -2- / 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl] propenyl]. m.p. 140-142 ° C.

The starting material can be prepared as follows:

360 g of η 1 - / 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl / ethyl] triphenylphosphonium bromide are suspended in 500 ml of tetrahydrofuran and 410 ml of n- butyllithium (1.6 molar in hexane). After stirring at 0 ° C for one hour, a solution of 94.5 g of 4-acetoxybenzaldehyde in 300 ml of tetrahydrofuran was added dropwise and stirred for another 2 hours at room temperature. The reaction mixture was then poured into 2 L of methanol / water (6: 4) and extracted several times with hexane. The organic phase is washed 3 times with water and, after drying with sodium sulfate, evaporated. Filtration of the residue through silica gel (hexane / acetate = 9: 1) and crystallization from hexane yielded 83 g of β-β- / 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 114 DEG-116 DEG C. 2-naphthyl / propenyl] phenylacetate in colorless crystals.

Example 2

Analogously to Example 1, it was prepared by hydrolyzing m- (2- (5,6,7,8-tetrahydro-5,5,8,8-tetisamethyl-2-naphthyl) propenyl) phenylate m- (E) -E. (-2-) 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl / propenylphenol, m.p. 91-93 ° C.

Example 3

Analogously to Example 1, it was prepared by hydrolyzing o- (E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenylacetate. (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenol, m.p. 97-99 ° C.

The preparation of the forms of use of the compounds of formula I can be carried out in a conventional manner, for example according to the following examples.

Example A

Hard gelatin capsules can be prepared as follows:

Ingredient mg / capsule

1. A spray-dried powder containing Compound I

200

2. Sodium dioctylsulfosuccinate 0.2

3. Sodium carboxymethylcellulose4,8

4. Microcrystalline cellulose86.0

5. Talc .8,0

6. Magnesium stearate1,0

Total 300

A spray-dried powder consisting of the active ingredient, gelatin and microcrystalline cellulose and having an average active ingredient grain size of 1 µm (measured by autocorrelation spectroscopy) is moistened with an aqueous solution of sodium carboxymethylcellulose and sodium dioctylsulfosuccinate and kneaded. The resulting mass is granulated, dried and sieved and the obtained granulate is mixed with microcrystalline cellulose, talc □ magnesium stearate. The powder is filled into size 0 capsules.

Example В

Tablets may be prepared as follows:

Component mg / tablet 1. Compound I as a finely divided powder 500 2. Powdered milk sugar 100 ALIGN! 3. White corn starch 60 4. Povidon K30 8 5. Corn starch white 112 6. Talc 16 7. Magnesium stearate 4

Total 800 mg / capsule

450

Total 500

The finely ground substance is mixed with milk sugar and a portion of corn starch. The mixture is moistened with an aqueous solution of povidone K30 and kneaded, and the resulting mass is granulated, dried, and sieved. The granulate is mixed with the remaining corn starch, talc and magnesium stearate and compressed into tablets of a suitable size.

Example C

Soft gelatin capsules can be prepared as follows:

Component

Compound I

2. The triglyceride g of compound I is dissolved in 90 g of medium chain triglyceride under stirring, under inert gas and in the absence of light. This solution is formulated as a filler into soft gelatin capsules containing 50 mg of active ingredient.

Example D

The lotion can be prepared as follows:

Component

1. Compound I, finely ground

2. Carbopol 934

3. Sodium hydroxide

4. Ethanol, 94%

5. demineralized water

3,0 g

0.6 g arbitrarily to pH 6 50.0 g to 100.0 g

The active ingredient is formulated with 94% ethanol / water in the absence of light. Carbopol 934 is mixed until complete gelling and the pH is adjusted with sodium hydroxide.

Claims (3)

SUBJECT OF THE INVENTION 1. A process for preparing tetrahydrotetramethylnaftylpropenylfenolů of formula I wherein R ^{@ 1} is o-, m- or p-hydroxyphenyl _t wherein the protected tetrahydrotetramethylnaftylpropenylfenolu of formula II H ₃ C CH 3 where r H represents a radical in which the hydroxy group is protected, cleaves the protecting group. 2. Method according to claim 1, characterized in that the starting substance used is a compound of formula II in which the olefinic double bond of trans configuration and R ¹¹ is as defined above. 3. The method according to claim 1, characterized in that as starting compound used is a compound of formula II wherein R ¹¹ is a phenyl group having at the p-position protected hydroxy.