CH668962A5 - New hydroxy:phenyl:propenyl substd. naphthalene cpds. - 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

       

  
 



   DESCRIPTION



   The present invention relates to new tetrahydronaphthyls
EMI1.3


<tb> propenyl-phenols <SEP> of the <SEP> general <SEP> formula <SEP> j
<tb> <SEP> m
<tb> <SEP> c <SEP> cii
<tb> <SEP> ¸c <SEP> I <SEP> Cll3
<tb> <SEP> H3C <SEP> cfi
<tb> <SEP> 3
<tb> wherein Rl is hydroxy and m is an integer from 1-5.



   The compounds of the formulas can be present as trans or cis isomers or cis / trans isomer mixtures. In general, the trans compounds of formula I are preferred, furthermore those in which m = 1.



   The invention further relates to a process for the preparation of the compounds of the formula I, pharmaceutical preparations based on the compounds of the formula I and the use of the compounds of the formula I in the production of pharmaceutical preparations for the treatment and prophylaxis of neoplasias and dermatoses.



   According to the invention, the compounds of the formulas can be prepared by using a compound of
EMI1.4


<tb> general <SEP> formula
<tb> <SEP>) I-G <SEP> CI3 <SEP> CH <SEP> = <SEP> CH <SEP> II
<tb> <SEP> H3C <SEP> CH
<tb> wherein R1l is a protected hydroxy group and m is the same as above, splitting off the protecting group.



   All conventional hydroxy protective groups can be considered as protective groups. Examples of such protective groups are ethers, in particular 2-tetrahydropyranyl ether and silyl ether, such as trimethylsilyl ether; furthermore alkyl ethers, such as the methyl ether; and esters, e.g. B. lower alkane carboxylic acid esters such as acetates and carbonates. The protecting groups can be split off in a manner known per se by treatment with acids, bases or reducing agents. Ether protecting groups such as tetrahydropyranyl and trimethylsilyl can be split off by treatment with acids such as p-toluenesulfonic acid or Lewis acids such as BF3 or BBr3. Ester protecting groups such as acetates or carbonates are treated with bases, e.g. B. alcoholic or aqueous-alcoholic alkali hydroxide solution removed.



   The compounds of general formula II can be obtained by using a compound of general formula
EMI1.5
 with a compound of the general formula
EMI1.6
 implements, either
A represents one of the radicals -CH (CH3) P + (Q) 3Y- or -CH (CH3P (O) (OAlk) 2 and B formyl, or
A represents acetyl and B represents -CH2P + (Q) 3Y- or -CH2P (O) (OAlk) 2; and
Q aryl, especially phenyl,
Y- the anion of an organic or inorganic acid, e.g. B. Br and alk lower alkyl, e.g. B. methyl and R11 and m mean the same as above.



   The compounds of the formulas III and IV can be reacted by the known methods of the Wittig or Horner reaction.



   In the Wittig reaction, i. H. when using a compound of formula III with A = -CH (CH3) P + (Q) 3Y- or of formula IV with B = -CH2P + (Q) 3Y-, the components in the presence of an acid-binding agent, e.g. B. in the presence of a strong base, such as. B. butyllithium, sodium hydride or the sodium salt of dimethyl sulfoxide, but primarily in the presence of an optionally substituted by lower alkyl ethylene oxide such as 1, 2-butylene oxide, optionally in a solvent, for. B. 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.



   Of the inorganic acid anions Y-, the chlorine and bromine ion or the hydrosulfate ion is preferred, of the organic acid anions the 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. H. when using a compound of formula III with A = -CH (CH3) -P (O) (OAlk) 2 or of formula IV with B = -CHrP (O) (OAlk) 2, the components with a base and preferably in the presence of an inert organic solvent, e.g. B. with the help of sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or 1, 2-dimethoxyalkane, or with the aid of a sodium alcoholate in an alkanol, for. B. sodium methylate in methanol, condensed in a temperature range between 0 and the boiling point of the reaction mixture.



   The alkoxy radicals OAlk are primarily lower alkoxy radicals with 14 carbon atoms, such as methoxy or ethoxy.



   The compounds of the formulas can be in trans or cis form. Most of them are produced in the trans form during production. If necessary, cis fractions can be separated off in a manner known per se, if desired.



   Unless their preparation is known or described below, the starting compounds of the formulas III and IV can be prepared analogously to known methods or the methods described below.



   The compounds of the formulas are therapeutically active.



  They have in particular anti-seborrheic, anti-keratinizing, anti-neoplastic and anti-allergic / anti-inflammatory activity, which can be demonstrated with the experimental arrangements described below:
A) The effect in preventing chemically induced breast tumors can be determined according to the following procedure. Female Sprague-Dawley rats are kept under temperature and light controlled conditions, with free access to drinking water and feed. At the age of 50 days, 15 mg dimethylbenz (a) anthracene dissolved in arachis oil were administered to each rate using a gastric tube. Treatment with the test compounds begins 1 day after the carcinogen administration. The body weights of the test animals are recorded and the tumors palpated weekly and measured using a caliper.

  The volumes are according to the formula. d2
2 calculated, where D is the larger and d the smaller diameter of the tumor ellipsoid. The trial is ended and evaluated after 11 weeks. In this experiment, the following two groups of experimental animals are used in addition to the 30 control animals, which receive only normal food:
1. 33 rats to which 30 mg / kg of test compound are administered mixed with the feed daily.



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



   B) The effect on tumors can also be determined on the transplantable chondrosarcoma of the rat using the following method. The solid tumor of a donor animal is finely divided and suspended in phosphate buffer / saline.



  0.5 ml of the 30% tumor pulp is implanted subcutaneously in albino rats.



     The transplanted rats are divided into test groups of 8 animals each. The test compounds are suspended in arachis oil and administered orally by gavage five times a week for 24 days. The tumors are excised and weighed on day 24. The results are expressed in the quotient C / T, which is calculated as follows: C / T = mean tumor weight of the control mean tumor weight of the treated
C) The antimetaplastic effect can also be determined in rats using the following method. Female Holtzmann rats weighing approx. 100 g are ovariectomized after an acclimatization period of 8 days under thiogenal anesthesia and put to the test after a further 14 days.

  Two animals each are housed in a cage with free access to feed containing approximately 2000 IU of analytically determined vitamin A. Before the oral administration of the test compound, the animals are subcutaneously treated with 1 pg of oestradiol benzoate and 250 g of testosterone propionate, dissolved in 0.1 ml of sesame oil, for 6 consecutive days. The parenteral hormone application leads to the formation of a pure plaice stage in the vaginal area, i.e. H. a squamous metaplasia. 2 days after the oral administration of the test substance, the reaction result is again read on the vaginal epithelium. The area method according to Behrens and Kärber is used to calculate the mean effective doses.

 

   The results of the experiments AC with the compound of the formula I, p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenol are shown in listed in Tables I-III below.



   Table I
A) Prophylaxis of the Chemically Induced Breast Tumor Dose Rats with Average Average [mg / kg] Tumors Number of Tumor Tumor Volume per p.o. [%] ren per rat rat in mm3 of controls] [% of controls] 30 68 52.4 72.6 90 35 14.1 3.9
Table II
B) Effect on the transplantable chondrosarcoma of the rat dose quotient C / T of tumor weight of the untreated [mg / kg] th control animals and the treated animals p.o.



  120 3.8
Table III
Table III
C) Anti-metaplastic effect on the rat compound relative activity all-trans retinoic acid 1 compound I 0.91
The compounds of the formula I can be used for topical and systemic therapy of benign and malignant neoplasms, of pre-malignant lesions and also for 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 process products of formula I can also be used to combat mucosal diseases with inflammatory or degenerative or metaplastic changes. The compounds of the formula I are notable in particular for low toxicity or better tolerance in comparison with known retinoids.



   The agents can be administered enterally, parenterally or topically. For enteral application z. B.



  Preparations in the form of tablets, capsules, dragees, syrups, suspensions, solutions and suppositories. Agents in the form of infusion or injection solutions are suitable for parenteral administration.



   The dosages in which the preparations are administered can vary depending on the type of application and route of use, as well as on the needs of the patients. Daily doses of about 0.1-50 mg / kg, preferably 1-15 mg / kg, are generally suitable for adults.



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



   The preparations can contain inert or pharmacodynamically active additives. Tablets or granules. B. 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, flavor-enhancing additives and those which are usually used as preservatives, stabilizers and moisturizers.



  substances and emulsifiers, salts for changing the osmotic pressure, buffers and other additives are also 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, polyalkylene glycols and the like. The prerequisite is that all auxiliary substances used in the manufacture of the preparations are non-toxic.



   For topical use, the active ingredients 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.



   Approximately approx.



     0.1-5%, preferably 0.3-2% solutions and approx.



     0.1-5%, preferably about 0.3-2% ointments or creams are suitable.



   The preparations can optionally contain an antioxidant, e.g. B. tocopherol, N-methyl-y-tocopheraminsowiebutylieres hydroxyanisole or butylated hydroxytoluene.



   The following examples further illustrate the invention.



  The temperatures are given in degrees Celsius.



   example 1
82.3 gp- [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenylacetate are suspended in 21% ethanol and a solution of 130 g potassium hydroxide added in 600 ml of water. After stirring for 1 hour at room temperature, the mixture is acidified with dilute hydrochloric acid while cooling with ice and extracted several times with ethyl acetate. The organic phase is washed four times with water, dried over sodium sulfate and evaporated. The crystalline residue can be recrystallized from hexane / ethyl acetate and gives 66 g of p - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenol Melting point 140-142 C.



   The starting material can be prepared as follows: -360 g [1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethyl] -triphenylphosphonium bromide are dissolved in 500 ml of tetrahydrofuran suspended and mixed with 410 ml of n-butyllithium (1.6 molar in hexane) at 0 ° C. After stirring for 1 hour at 0 ° C., a solution of 94.5 g of 4-acetoxy-benzaldehyde in 300 ml of tetrahydrofuran is added dropwise and stirred for a further 2 hours at room temperature. The reaction mixture is then poured into 1 methanol / water (6: 4) and extracted several times with hexane. The organic phase is washed three times with water and, after drying, evaporated with sodium sulfate.

  After filtration of the residue over silica gel (eluent hexane / ethyl acetate = and crystallization from hexane), 83 g of p- [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl) -2 are obtained -naphthyl) propenyl] phenylacetate in colorless crystals, melting point 11S116 C.



   Example 2
In analogy to Example 1, by hydrolysis of m- [2 (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenylacetate, the m - [(E) - 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenol, melting point 91-93 C.

 

   Example 3
In analogy to Example 1, the o - [(E) - was obtained by hydrolysis of o- [2 (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenyl acetate. 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthyl) propenyl] phenol. Melting point 97-99 C.



   The preparation of use forms of the compounds of the formulas can be carried out in a conventional manner, e.g. B. using the examples below.



   Example A
Hard gelatin capsules can be produced as follows: Components mg / capsule 1. containing spray-dried powder
75% compound I 200 2. sodium dioctylsulfosuccinate 0.2 3. sodium carboxymethyl cellulose 4.8 4. microcrystalline cellulose 86.0 5. talc 8.0 6. magnesium stearate 1.0
Total 300
The spray-dried powder, which is based on the active ingredient, gelatin and microcrystalline cellulose and has an average grain size of the active ingredient of <1 y (measured by autocorrelation spectroscopy), is moistened and kneaded with an aqueous solution of sodium carboxymethyl cellulose and sodium dioctylsulfosuccinate. The resulting mass is granulated, dried and sieved, and the granules obtained are mixed with microcrystalline cellulose, talc and magnesium stearate.

  The powder is filled into size 0 capsules.



   Example B
Tablets can be produced as follows: Ingredients mg / tablet 1. Compound I as finely ground powder 500 2. Milk sugar powder 100 3. Maize starch white 60 4. PovidoneK30 8 5. Maize starch white 112 6. Talc 16 7. Magnesium stearate 4
Total 800
The finely ground substance is mixed with milk sugar and part of the 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 granules are mixed with the remaining corn starch, talc and magnesium stearate and pressed into tablets of a suitable size.

 

   Example C
Soft gelatin capsules can be produced as follows: Components mg / capsule 1. Compound 1 50 2. Triglyceride 450
Total 500
10 g of compound I are dissolved in 90 g of medium-chain triglyceride with stirring, inert gassing and light protection. This solution is processed as a capsule filling compound into soft gelatin capsules containing 50 mg of active ingredient.



   Example D
A lotion can be made as follows:
Components
1. Compound 1, finely ground 3.0 g
2. Carbopol 934 0.6g
3. Sodium hydroxide q.s. adpH
4. ethanol, 94% 6
5. demineralized water ad 50.0g
100.0g
The active ingredient is incorporated under light protection into the 94% ethanol / water mixture. Carbopol 934 is stirred in until complete gelation and the pH is adjusted with sodium hydroxide.


    

Claims (9)

 PATENT CLAIMS 1. Compounds of general formula I EMI1.1  wherein R 'is hydroxy and m is an integer from 1-5.  2. Compounds according to claim 1, in which the olefinic double bond has a trans configuration.  3. Compounds according to claims 1 or 2, in which m = list.  4. p - [(E) -2- (5,6,7,8-tetrahydro-5, 5,8,8-tetramethyl-2-naphthyl) propenyl] phenol, as a compound according to claim 1.  5. m - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenol, as a compound according to claim 1 6. o - [(E) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl] phenol, as a compound according to claim 1 7. Pharmaceutical preparations containing 5-200 mg of a compound of the general formulas according to claim 1 per dose unit.    8. Use of a compound of general formula I according to claim 1 for the manufacture of pharmaceutical preparations, suitable for the treatment of neoplasias and dermatoses.  9. A process for the preparation of compounds of general formula I according to claim 1, characterized in that from a compound of general formula EMI1.2  where R11 is a protected hydroxyl group and m is an integer from 1-5 which cleaves the protecting group.