MC1817A1 - TETRAHYDRONAPHTALENE DERIVATIVES - Google Patents

Description

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The present invention relates to novel tetrahydronaphthalene derivatives of general formula:

in which R^" is the 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.

Compounds of formula I can be in the form of trans- or cis isomers or mixtures of cis/trans isomers. In general, trans compounds of formula I are preferred, especially those in which R"*" is o-, 10 m- or p-hydroxyphenyl, particularly p-hydroxyphenyl.

The invention further relates to a method for preparing formula I compounds, pharmaceutical preparations based on formula I compounds, formula I compounds for the treatment and prophylaxis of neoplasms and dermatoses, as well as the use of formula I compounds in the manufacture of pharmaceutical preparations for the

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treatment and prophylaxis of such diseases.

Compounds of formula I can be prepared according to the invention by removing the protecting group from a compound of general formula:

CH-

CH- R

11

II

H_C CH,

5 in which R"^ is a remainder R"*", in which the hydrjoxy group(s) is or are protected.

As protecting groups, all conventional protecting groups are taken into account. Examples of such protecting groups are ethers, in particular 2-tetrahydropyranyl ether and silyl ether, such as trimethylsilyl ether; also alkyl ethers such as methyl ether and esters, for example the ester of lower saturated carboxylic acids such as acetates and carbonates. The removal of protecting groups can be re-

I

15. Eliminated in a manner already known by treatment with acids, bases or reducing agents. Ether protecting groups such as tetrahydropyranyl or trimethylsilyl are removed by treatment with acids, such as p-toluenesulfonic acid or Lewis acids such as BF-j or BBr-j. 20. Ester protecting groups such as acetate or carbonate are removed by treatment with bases. Example of an alcoholic or hydro-alcoholic alkali hydroxide solution.

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Compounds of general formula II can be obtained by condensing a compound of general formula

H-,0 CH, y \/ 3

in

H,C CH, J J

with a compound of general formula

B - R

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5 in which either

A is one of the remainders -CH(CH^) P + (Q)^Y= or -CH ( CH^ ) P ( 0 ) ( Q A1 '< ) and B is the formyl, i.e

A is acetyl and B is one of the residues -Cf^P^CO-jY or -CH2P(oaik)2.

10Q is an aryl, specifically phenyl

Y is the anion of an organic or mineral acid, for example Br₂ and Akl is a lower alkyl group, for example methyl and

R

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the same meaning as above

The condensation of compounds of formulas III and IV can be carried out according to the known methods of Wittig or Horner.

In the Wittig reaction, that is, using a compound of formula III with A = -CH(CH^)P + (Q)Y or of formula IV with B = -CH2P+(Q)^Y, the components are condensed in the presence of an acid-fixing medium, for example in the presence of a strong base, such as butyl-

lithium, sodium hydride or sodium salt of dimethyl sulfoxide, but especially in the presence of ethylene oxide substituted by a lower alkyl such as butylene-1,2 oxide if appropriate, in a solvent, for example 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.

Among the acidic anions Y, the chloride, bromide, or hydrosulfate ions are preferred; among the acidic ions, the tosyloxy ion is preferred. The aryl residue Q is preferably a phenyl group or a substituted phenyl group such as p-tolyl.

In the Horner reaction, that is, using a compound of formula III with A = -CH(CH₂)-P(0)(OAlk) or of formula IV with B = -CH₃-PCOHOAlk, the components are condensed using a base and preferably in the presence of an inert organic solvent, for example, using sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane, or 1,2-dimethoxyethane, or also using a sodium alkoxide in an alkanol, for example, sodium methoxide in methanol, within a temperature range

O

between 0 and the boiling point of the reaction mixture.

Al.coxy remains are primarily lower 1-coxy remains with 1-6 carbon atoms, such as methoxy or ethoxy.

Compounds of formula I can be in trans- or cis- form.

During preparation, they are mostly in trans form. Any cis content that may be formed can be separated in the known manner, if desired.

Starting compounds of formula III and IV, insofar as their preparation is not known or described below, may be prepared by analogy to processes known or described below.

Formula I compounds are therapeutically effective. In particular, they possess anti-seborrheic, anti-keratinizing, anti-neoplastic, and anti-allergic anti-inflammatory efficacy, which can be demonstrated using the test procedures described below.

A - The prophylactic action against chemically induced mammary tumors can be determined according to the following procedure. Female Sprague-Dawley rats are kept under controlled light and temperature conditions, with free access to drinking water and food. At 50 days of age, each rat is administered, via a gastric tube, 15 mg of dimethylbenz(a)anthracene dissolved in peanut oil. Treatment with the test compounds begins 1 day after administration of the carcinogen. The weights of the test animals are recorded, and the tumors are palpated weekly and measured with calipers. Volumes are calculated according to the 2

formula D . d , in which D is the largest diameter and 2

d is the smallest diameter of the tumor ellipsoid. The trial is stopped after 11 weeks and evaluated. In this trial, in addition to the 30 control animals, which receive only normal food, the following two groups of test animals are used:

1-33 rats, to which are administered daily, mixed with food, 30 mg/kg of the test compound.

2-36 rats, to which are administered daily, mixed with food, 90 mg/kg of the test compound.

B. The action on tumors can also be determined on transplantable splenic chondrosarcomas, according to the procedure

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Next. The solid tumor of a sacrificed animal is finely ground and suspended in a phosphate/sodium chloride buffer solution. 0.5 ml of the 30% tumor paste is implanted subcutaneously into albino rats.

5. The transplanted rats are divided into test groups of 8 animals each. The test compounds are suspended in peanut oil and administered orally for 24 days, five times a week, using a pharyngeal tube. Tumors are excised on day 24 and weighed. The results are expressed by the C/T ratio, which is calculated as follows:

r/t - Average weight of the controls

Average weights of the treated

C- The antimetaplastic effect can also be determined using the following method. Female Holtzmann rats weighing approximately 100 g are ovariectomized under anesthesia with thiogenal after an 8-day acclimation period and are introduced into the test after 14 days. Two animals are placed per cage with free access to food, which contains approximately 2,000 IU of vitamin A as measured by analysis.

20. Before oral administration of the tested compound,

The animals are treated subcutaneously daily for 6 consecutive days with 1 µg of estradiol benzoate and 250 µg of testosterone propionate dissolved in 0.1 ml of sesame oil. Parenteral administration of the hormone leads to the formation of a pure stage of desquamation in the vaginal area, i.e., squamous metaplasia. Two days after oral administration of the tested substance, the result of the reaction on the vaginal epithelium is examined again. To calculate the dose

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30 average effective we use the surface method according to Behrens and Karber.

The results of the AC tests with the compound of formula I p-/XE)-2-(5,6,7,8-1etrahydro-5,5,8,8-1etramethy1-2-

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naphtyl)propeny 1/phenol are presented in the following tables I — 111.

Table I

A) Prophylaxis of chemically induced breast tumors

Dose mg/kg rates with

Average number of

Average volume of ^

p.o.

tumors tumors per spleen tumor per spleen in mm

(%)

(?o of witnesses)

(?o of witnesses)

30

68

52.4

72.6

90

35

14.1

3.9

Table 11

B) Action on transplantable rat chondrosarcoma

Dose mg/kg p.o.

C/T ratio of tumor weight in untreated control animals and treated animals

120

CD

Table III

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C) Antimetaplastic action on the rat

Compound

Related activity

All-trans retinic acid

1

Compound 1

0.91

Formula I compounds can be used in topical and systemic therapy of benign and malignant neoplasms, premalignant lesions, as well as in systemic and topical prophylaxis of the aforementioned condition.

They are also suitable for topical and systemic therapy of acne, psoriasis and other deep dermatoses with increased keratinization in pathologically modified 10 as well as inflammatory dermatological conditions and c.

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allergic. Formula <J products can also be used to combat diseases of the mucous membranes with inflamed or degenerative or metaplastic alterations. Formula I compounds are characterized in particular by reduced toxicity or better compatibility compared to known retinoids.

The products can be administered via enteral, parenteral, or topical dosage forms. For enteral administration, suitable options include products in the form of pills, capsules, coated tablets, syrups, suspensions, solutions, and suppositories.

Products in the form of a solution for infusion or injection are suitable for parenteral application.

The dosages at which the preparations are administered may vary depending on the method of use and route of administration, as well as the needs of the patients.

Generally, daily doses of approximately 0.1-50 mg/kg, preferably 1-15 mg/kg, are taken into account for adults.

The preparations can be administered in one or more doses. A preferred dosage form is the capsule with a content of approximately 5-200 mg of active ingredient.

The preparations may contain inert or pharmacodynamically active additives. Tablets or granules may contain a range of binders, fillers, carriers, or diluents. Liquid preparations may, for example, be presented as a sterile, water-miscible solution. Capsules may contain, in addition to the active ingredient, a filler or a thickener. Furthermore, there may be flavoring additives, as well as products commonly used as

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preservatives, stabilizers, humidifiers and emulsifiers, as well as salts to modify osmotic pressure, buffering capacity, and other additives.

The vehicles and diluents mentioned above (5) may be organic or mineral products, for example, water, gelatin, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols, or similar substances. The requirement is that all additives used in the manufacture of the preparations (10) must be non-toxic.

For topical application, the active ingredients are appropriately used in the form of balms, tinctures, creams, solutions, lotions, sprays, suspensions, and similar preparations. Balms and creams, as well as solutions, are preferred. These preparations for topical application can be produced by adding, as an active component, solid or liquid vehicles commonly used in such non-toxic, inert preparations suitable for topical treatment to the products of the process.

20 For topical use are suitable solutions of about 0.1-5%, preferably about 0.3-2%, as well as balms and creams of about 0.1-5%, preferably about 0.3-2%.

An antioxidant agent, such as tocopherol, N-methyl-V-tocopheramine, butylated hydroxyanisole, or butylated hydroxytoluene, can also be added to the preparations.

The following examples describe the invention more broadly. Temperatures are given in degrees Celsius.

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EXAMPLE 1

82.3 g of p-/2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl 1,2-naphthyl 1) acetate is suspended in 2 L of ethanol, and a solution of 5130 g of potassium hydroxide in 600 mL of water is added. After 1 hour of stirring at room temperature, the mixture is acidified while ice-cooled with dilute hydrochloric acid and extracted several times with the acetic ester. The organic phase is washed four times with water, dried over sodium sulfate, and evaporated. The crystalline remainder is recrystallized in the hexane/acetic ester mixture and gives 66 g of p-Z~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-2-naphthyl)propenyl7phenol, melting point 140-142°C.

The starting product can be prepared from 15 in the following way:

360 g of Z~1 bromide - (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl-7-triphenylphosphonium is suspended in 500 mL of tetrahydrofuran, and 410 mL of n-butyllithium (1.6 molar in 20 L hexane) is added at 0°C. After 1 hour of stirring at 0°C, a solution of 94.5 g of 4-acetoxybenzaldehyde in 300 mL of tetrahydrofuran is added dropwise, and the mixture is stirred for another 2 hours at room temperature. The reaction mixture is 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 over sodium sulfate, is evaporated. After filtering the remainder through silica gel (eluting agent hexane/acetic ester = 9:1) and crystallization in hexane, 83 g of p-/2-(5,6,7,8-tetrahydro-5,5,8,8-30 tetramethyl1-2-naphthy1)propenylphenyl acetate is obtained in the form of colorless crystals, melting point 114-116°C.

I

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EXAMPLE 2

In analogy with example 1, m-/2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl-7phenyl/lle m-/*(E)-2-(5,6,5,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl-7phenol, melting point 91-93°C, was prepared by hydrolysis of the acetate.

EXAMPLE 3

In analogy with example 1, o-2-(5,6,7,8-tetrahydro-5,5,108,8-tetramethyl-1-2-naphthyl)propenyl-17phenol was prepared by hydrolysis of the acetate o-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenylphenol, melting point 97-99°C.

The preparation of usable forms of compounds of formula I can be carried out in the usual way, 15 for example using the examples below.

EXAMPLE A

Hard gelatin capsules can be prepared as follows:

MQ/capsule components

20 1. Spray-dried powder containing 75 µg of compound I 200

2. sodium dioctylsulfosuccinate 0.2

3. sodium carboxymethylcellulose 4.8

4. Microcrystalline cellulose 86.0 255. Talc 8.0

6. Magnesium stearate 1.0

Total 300

<-=-^

j

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The spray-dried powder, composed of the active ingredient, gelatin, and microcrystalline cellulose, and with an average particle size of less than 1 µm (measured by autocorrelation spectroscopy), is moistened with an aqueous solution of sodium carboxymethylcellulose and sodium dioctyl sulfosuccinate and kneaded. The resulting mass is granulated, dried, and sieved, and the granules are mixed with microcrystalline cellulose, talc, and magnesium stearate. The powder is packaged in size 0 capsules.

EXAMPLE B

Pills can be prepared in the following way:

Components mq/pill

1. Compound I in the form of finely ground powder 500

2. Lactose powder 100

3. White corn starch 60

4. Povidone K30 8

5. White corn starch 112

6. Talc 16

7. Magnesium stearate 4

Total 800

The finely ground substance is mixed with lactose and some of the corn starch. The mixture is moistened with an aqueous solution of Pivodone K30 and kneaded. The resulting mass is granulated, dried, and sieved. The granules are mixed with the remaining corn starch, talc, and magnesium stearate, and compressed into appropriately sized pills.

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EXAMPLE C

Capsules prepared as follows:

Components

5 1. compound I

2. Soft gelatin triglyceride can be mq/capsule

50,450

Total 500

10 g of compound I are dissolved under stirring, inert gas sweep, and protected from light in a medium-chain triglyceride. This solution is then converted into a capsule filling mass, using a soft gelatin capsule containing 50 mg of the active ingredient.

EXAMPLE D

A lotion can be prepared as follows:

Components

15 1. compound I, finely ground

2. Carbopol 934

3. sodium hydroxide

4. Ethanol, 94%

5. demineralized water

3.0 g 0.6 g q.s. for pH 6

50.0 g up to 100 g

20 The active ingredient is incorporated, protected from light, into the ethanol 94%/water mixture. Carbopol 934 is added and stirred until complete gelation, and the pH is adjusted using sodium hydroxide.

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Claims (2)

DEMANDS 1. Manufacturing process for compounds with general formula: H70 CH, 3 \ r 3 CH. — C CH—RJ H,C CH, 3 3 in which R is the 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 characterized in that the protecting group(s) of a compound of general formula are eliminated: H,C CH, 3 \ r 3 CH- ■ 0' CH- R 11 II H^O CH^ in which R^* is a remainder R"*" in which the hydroxy group(s) is or are protected. 10 2. A process according to claim 1, characterized in that compounds are prepared in which the olefinic double bond has the trans configuration. 3. Process according to claim 1 characterized in that p-ZT( E )-2-( 5 , 6 , 7 , 8-tetrahydro-15 5,5,8,8-tetramethyl-2-naphthyl)propenyl7phenol is prepared. 15 4. Process according to claim 1, characterized in that m-/~(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramet.hyl-2-naphthyl)propenyl/phenol is prepared. 5. Method according to claim 1 character- 5 terized in that we prepare o-Z"(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl7phenol. pharmaceuticals which contain as an active ingredient a compound of general formula I, characterized in that a compound of general formula I is put into a galenic form for use. 6. Manufacturing process for preparations 26 b', Princess Charlotte Blvd. MONTE CARLO »*-i'ayé îsuî C U R A U up^eti eo Industrial property