MXPA01002376A - 5,6-dihydronaphthalenyl derivatives having retinoid-like activity - Google Patents

Abstract

The 5,6-dihydronaphthalenyl derivatives of the formulae (I) and (II) possess potent retinoid-like activity against dermatological diseases with a substantially reduced irritancy profile when administered topically.

Description

DERIVATIVES OF 5, 6-DIHIDRONAFTALENILO THAT HAVE AN ACTIVITY SIMILAR TO THAT OF THE RETINOID.

Field of Invention The present invention provides a series of 5,6-dihydronaphthalenyl derivatives which exhibit unexpectedly good therapeutic indices in the treatment of skin disorders such as, but not limited to, acne and age-related damage or irradiation and inflammatory skin diseases. Chronicles such as psoriasis and atopic dermatitis. The compounds are also useful as antitumor agents for the treatment of, but not limited to, breast, skin, prostate, cervical, uterine, colon, vesicle, esophagus, stomach, lung, larynx, and blood and lymphatic systems.

Background of the Invention Compounds that have activity similar to that of the retinoid are well known in the art and are described in numerous patents and scientific publications. Generally accepted Ref: 127232 that pharmaceutical compositions having a retinoid-like compound are useful for the treatment and / or prevention of skin-related diseases such as, but not limited to, acne, actinic seratosis, psoriasis, eczema and atopic dermatitis. It is also known that these are useful for reversing or treating the effects of age and photographic damage to the skin and for preventing and / or treating carcinogenic or pre-cancerous conditions.

One of the major significant disadvantages associated with the use of retinoids, especially in the topical treatment of dermatological diseases, is local irritation. Retinoids or compounds that have an activity similar to that of retinoids that combine good topical efficacy and skin sensitivity are not very common. Recently, the new adapalene drug ("Diferin", CIRD Galderma) is reported to offer these favorable characteristics and to be launched in several countries as a water-based gel formulation.

Adapalene The U.S. patent No. 5,648,514 discloses a series of substituted derivatives of (5,6) -dihydronaphthalene having a biological activity similar to that of the retinoid of the formula where Ri is hydrogen or alkyl of 1 to 10 carbons R2 and R3 are hydrogen, or alkyl of 1 to 6 carbons, and the substituted ethenyl group occupies either the 2 or 3 position of the dihydronaphthalene nuclei; m is an integer that has the value of 0-3 or is an integer that has the value of 0-3; Y is a phenyl, or heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyrid, sinyl, pyridinyl, pyrazinyl, thiazolyl, oxaxolyl, and imidesolyl, said groups being optionally substituted with 1 or 2 R2 groups; A is (CH) n < where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple links; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, CH2OH, CH2ORn, CH2OCORn, CHO, CH (ORi2) 2, CH0R? 30, COR7, CR7 (OR? 2) 2, CHOR130, COR7, CR7 (OR? 2) 2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing from 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons otr imet i 1 si li 1 alkyl wherein the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, Rn is lower alkyl, phenyl or lower alkylphenyl, Ri2 is lower alkyl, Ri3 is a divalent alkyl radical of 2-5 carbons; v R22 is hydrogen, alkyl of 1 to 10 carbons, alkyl substituted with fluorine of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having from two to 10 carbons and 1 to 3 bonds triple, carbocyclic aryl selected from the group consisting of phenyl, Ci-C10 alkylphenyl. naphthyl, C1-C10 alkylamide, phenyl, C1-C10 alkyl, C1-C10 alkyl-naphthyl, C1-C10 alkenyl 1 having 1 to 3 double bonds, C 1 -C 1 alkynylphenyl having from 1 to 3 bonds triples, C1-C10 alkenylphenyl having 2 to 3 double bonds, C1-C10 alkynylphenyl having 1 to 3 triple bonds, hydroxyalkyl of 1 to 10 carbons, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 bonds triples, acyloxyalkyl of 1 to 10 carbons or acyloxyalkyipid of 2 to 10 carbons and of 1 to 3 triple bonds, where the asyl group is represented by CORi4, CN, C0N (Rx) 2, (CH2) PC02R8 where p is an integer between 0 to 10, or R22 is aminoalkyl or thioalkyl of 1 to 10 carbons, or a 5- or 6-membered heteroaryl group optionally substituted with a Ci to Cio alkyl group and having 1 to 3 heteroatoms, said heteroatoms being selected from the group consists of O, S, and N, or R22 is represented by (CH2) pXR? or by (CH2) pNR? R2; where X is O or S, the group Ri4 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 bonds triples, the ilocarbocyclic selected from the group consisting of phenyl, Ci-Cio alkylphenyl, naphthyl, at least C 1 -C 0 alkyl, C 1 -C 0 alkylphenyl, or C 1 -C 0 alkylnaphthyl.

The description is specifically limited to the ethinyl linker. The two compounds described in the present invention have the ethenyl linker.

The substituent at position 8 (R22) is defined as being, among others, an alkenyl group of 2 to 10 carbons and having 1 to 3 double bonds or an alkynyl group having 2 to 10 carbons and 1 to 3 triple links. This general definition does not specify the direct link to the dihydronaphthalene nucleus at position 8.

The published PCT patent application WO 97/48672 describes a series of derivatives of 5,6-dihydronaphthalene which have activity similar to the retinoid antagonist and / or the retinoid of the formula where X? is [C (R?) 2] n where R x is independently H or alkyl of 1 to 6 carbons, and n is an integer of between 0 and 2; Z is -N = N-, -N (0) = N-, -N = N (0) -, -N = CR? -, -CR? = N, -CR? = CR?) N '"where n 'is an integer having the value of 0 to 5, -CO-NR-, -CS-NRi-, -NRi-CO-, -NRi-CS-, -COO-, -OCO-, -CSO-, -OCS-, -CO-CR? = CR? -; R2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, 1, CF3, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is hydrogen, lower alkyl of 1 to 6 carbons or F; m is an integer that has the value of 0 to 3; or is an integer that has the value of 0 to 3; R3 is hydrogen, lower alkyl of 1 to carbons or F; m is an integer that has the value of 0-3 is an integer that has the value of 0-3 Y is a phenyl or naphthyl, or heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridasinyl, pyrimidyl, pyrazinyl, thiazolyl, oxasolyl, imidesolyl and pyraziloyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups , or when Z is - (CR? = CR?) n'- and n 'is 3.4 or 5, then Y represents a direct balance between said group (CR2 = CR2) n' and B; A is (CH2) q wherein q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl which it has 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, CH2OH, CH2ORn, CH2OCORn, CHO, CH (OR? 2) 2, CHOR130, -COR, CR7 (OR? 2) 2, CR7OR? 30 or If (C C_6 alkyl) 3, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl) alkyl wherein the alkyl group has from 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, Rg and Rio independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, Ri2 is lower alkyl, and Ri3 is a divalent alkyl radical of 2-5 carbons; Y R14 is alkyl substituted with (R15) r of 1 to 6 carbons, alkenyl substituted with (R15) r of 1 to 6 carbons and of 1 or 2 double bonds, substituted alkynyl (R15A of 1-6 carbons and 1 or 2 triple bonds) , phenyl (R? s) r.naphthyl (R? s) r or heteroaryl (R? s) r wherein the heteroaryl group has from 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is a whole which has the values of 0-5, and R? 5 is independently H, F, Cl, Br, 1, N02, N (R8) 2, N (R8) COR8, NR8CON (R8) 2, OH, OCORg, OR8, CN, COOH, COOR8 and an alkyl group having from 1 to 10 carbons, a fluorinated substituted alkyl group having from 1 to 10 carbons, and an alkenyl group having from 1 to 10 carbons and from 1 to 3 bonds doubles, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a group (trialkyl) silyl or (trialkyl) silyloxy group where the alkyl groups independently have from 1 to 6 carbons.

Two of the agents included within the scope of WO 97/48672 are the compounds having the structural formula I and II These compounds show a very potent activity against dermatological diseases.

Unexpectedly, the present inventors have discovered that these compounds also show a substantially reduced irritability profile. Although WO 97/48672 generally describes these compounds as having an activity similar to that of retinoid as agents for the treatment of skin-related diseases, it does not have a specific description of compounds I and II or their unexpected low irritability profiles. , which are the subject of the present invention.

In another aspect, the present inventors have also found that compounds 1 and 2 are effective agents that inhibit the tumor, and thus are useful in veterinary and human medicine. WO 97/48672 generally describes these compounds having activity similar to that of the retinoid and as agents for preventing or treating carcinogenic and pre-cancerigenic conditions. The evaluation supporting this statement is a measure of the inhibition of the induction of 12-O-tet radecanoi 1 phorbol-13-acetate (TPA) of ornithine decarboxylase (ODC) in the epidermis of the mouse by certain compounds described in application. The ODC activity that induces TPA is known to occur in pre-ill ignited stages. Although the correlation of this evaluation with cell antiproliferation is well established, there is no evidence in the patent application WO 97/48672 of the in vivo inhibition of tumor growth completely established by the described compounds. The present inventors have found that the anti-proliferation activity of the compounds of this invention results in a potent inhibition of established tumor growth, equivalent to more potent antitumor agents such as doxorubicin.

Brief Description of the Invention The present invention provides (5,6) -dihydronaphthalenyl compounds having an activity similar to that of the retinoid and the structural formula i p or pharmaceutically acceptable non-toxic salts, physiologically hydrolysable esters or solvates thereof. These have unexpected low irritability profiles and are useful in the treatment of skin diseases such as, but not limited to, acne and damage by age or irradiation and chronic inflammatory skin diseases such as psoriasis and atopic dermatitis or as agents antitumor for the treatment of cancers of the breast, skin, prostate, cervix, uterine, colon, vesicle, esophagus, stomach, lung, larynx, blood and lymphatic systems.

Detailed Description of the Figures Figure 1 shows the dose response in the ratio between Compound I and tRA in the mouse mouse trial. The compounds are applied topically in an ethanol vehicle daily for 5 days. Skin samples are taken on day 7 and processed for image analysis. The values represented mean ± SD of 7 animals. Twenty determinations are made for the animal. The ED30 value is the dose that reduces the diameter of the utricle by 30%, which is equivalent to the ED50, because the maximum achievable response is around 60% in this model.

Figure 2 shows the study of irritability of rabbit skin. Compound I and tRA are applied topically to the skin of the rabbit for 14 days. Irritation is assessed by the degree of erythema, edema, and scales. The sum of all the results is defined as the result of global irritation, which is used to derive the AUC values for each compound.

Figure 3 is a graph of growth inhibition in the tumor when compound I is administered.

Detailed description of the invention The present invention relates to formula compounds 1 p or pharmaceutically acceptable non-toxic salts, esters or physiologically hydrolysable solvates thereof.

Definitions..

The compounds of formula I and II can form pharmaceutically acceptable metals and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the compound. These salts are part of the present invention. Suitable metal salts include sodium salts, potassium, calcium, barium, zinc and aluminum. Sodium or potassium salts are preferred. Amines that are capable of forming stable salts include trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl 1-β-phenet and lamina, 1-efenamine, N, N'-dibenzylethylene diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine. , dicycloexylamine, or the like.

The compounds of formula I and II can also form physiologically hydrolysable esters which serve as pro-drugs to be hydrolyzed in the body to provide compounds of formula I or II by themselves. These are preferably administered orally since hydrolysis in many instances occurs mainly under the influence of digestive enzymes. Parenteral administration can be used where the ester is active by itself, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolysable esters of the compounds of formula I include C 1 -C 6 alkylbenzyl, 4-methoxybenzyl, indanyl, ethalyl, methoxymethyl, C 1 -C 6 alkanoyloxy-C 6 alkyl, eg acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl, C6-6 alkoxycarbonyloxyC6-6alkyl, for example, methoxycarbonylloxymethyl or ethoxycarbonyloxymethyl, glycimyloxymethyl, phenoliglyloxylmethyl, (5-methyl-2-oxo-1,3-dioxolen-4) -yl) -methyl, and other well-known physiologically hydrolysable esters used, for example, in the penicillin and cephalosporin techniques. Such esters are prepared by conventional techniques known in the art.

Administration modes The compounds of formula I and II above can be used topically or systemically, as anti-cancer agents in the treatment, alleviation or prevention of skin disorders. In this regard, they can be used for the therapy in mammals, including animals, of pre-malignant epithelial cell lesions, such as prophylaxis against tumor cell promotion in epithelial cells and treatment for dermatoses such as ichthyosa, follicular disorders, epithelial disorders. benign and other skin proliferative diseases such as psoriasis, eczema, atopic dermatitis, non-specific dermatosis and the like. These can also be used to reverse and prevent the effects of radiation damage on the skin. When used for the above purposes, these will usually be formulated with a liquid, semi-solid, or pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier is a material that is non-toxic and is generally inert, and does not adversely affect the functionality of the active ingredients. Such materials are well known and include those materials sometimes referred to as diluents or carriers (excipients) in the pharmaceutical formulating art. The carriers can be of organic or inorganic nature. Examples of pharmaceutically acceptable carriers that can be used to formulate a compound of formula I or II are water, gelatin, lactose, starch, mineral oil, cocoa butter, dextrose, sucrose, orbital, mannitol, acacia gum, alginates, cellulose , talc, magnesium stearate, polyoxyethylene sorbitan monolaurate, and other commonly used pharmaceutical carriers. In addition to the compound of formula I or II and the carrier, the formulation may contain minor amounts of additives such as flavoring agents, coloring agents, thickening or gelling agents, emulsifiers, wetting agents, buffers, stabilizers, and preservatives such as antioxidants.

The doses and the dose regimen in which the compounds of formula I and II are administered, vary in accordance with the dosage form, mode of administration, the condition to be treated and the particulars of the patient to be treated. Consequently, the optimal therapeutic concentrations will be better determined at the time and place during the experimentation routine.

In treating dermatoses, it is generally preferred to administer the drug topically, although in some cases oral administration may be used. If the compounds according to the invention are used topically, it is found that they exhibit good activity over a very wide range of dilution; in particular the concentrations of compound or active compounds in the range from 0.0005% to 2% by weight can generally be used. Of course it is possible to use higher concentrations if these become necessary for a particular application; however, the preferred concentration of the active ingredient will be from 0.002% to 1% by weight.

For topical administration, the compounds of formula I and II are conveniently provided in the form of ointments, gels, creams, ointments, powders, painting compositions, solutions, suspensions, emulsions, lotions, sprays, adhesive patches and impregnated wipes. The compounds according to the invention can be mixed with suitable bases for non-toxic inert topical treatment, generally liquid or in paste. The preparation of such topical formulations is well described in the art of pharmaceutical formulations as exemplified, for example, by Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvama. Other medications can be added to such a formulation for secondary purposes such as the treatment of dry skin, pro-polar protection against light; other medications for the treatment of dermatoses, prevent infection, reduce irritation, inflammation and the like.

The compounds according to the invention can also be used inter alia. Orally, the compounds according to the invention are administered appropriately at a ratio of 100 mg to 100 mg per day per kg of body weight. The required dose can be administered in one or more portions. For oral administration, suitable forms are, for example, tablets, pills, dragees, syrups, suspensions, emulsions, solutions, powders and granules; A preferred method of administration is to use pills containing from 1 mg to 1000 mg of active substance.

The U.S. patent No. 4,876,381 published October 24, 1989 to Lang et al. Provides examples of formulations consisting of gel, ointment, powder, cream, and the like. The U.S. Patent The aforesaid can be used as a guide for formulating a compound of formula I and II and is therefore incorporated for full reference.

Isotretinoin ("Acutana") and etretinata ("Tegison") are used clinically to treat severe recalcitrant cystic acne and severe recalcitrant psoriasis, including the erroneous generalized pustular and pustular types, respectively. Its mode of use is amply illustrated in the Physician's Desk Reference, Edition 47 (1993), published by Medical Economics Data. The compounds of formula I and II can also be used for the treatment of severe recalcitrant psoriasis. In some way, the compounds of the present invention can be used in a manner similar to estrotetinoin and etretinata; in this way, the relevant sections in isotretinoin and the etretinata in Physi cian's Des Reference will serve as a convenient guide that obviously will not need any undue experimentation.

The compounds according to the invention can also be administered parenterally in the form of solutions or suspensions for infusions or intravenous or intramuscular injections. In this case, the compounds according to the invention are generally administered in the ratio of about 10 mg to 10 mg per day per kg of body weight; A preferred method of administration is to use solutions or suspensions containing about 0.01 mg to 1 mg of active substance per ml.

Several retinoids have been found to possess anti-tumor properties. Roberts, A.B., and Goodman, D.S., eds., 2, pages 209-286 (1984), Academic Press, New York; Lippman, S.M., Kessler, J.F., and Meyskens, F.L., Cancer Treat. Rep., 71, page 391 (1987); ibid., page 493. As used herein, the term "anti-tumor" includes both the use chemoprevent i vo (prophylactic or inhibition of tumor promotion) and therapeutic (curative). For example, all transretinoic acids can be used to treat acute promyelocytic leukemia. Huang, M. et al., Blood, 72, page 567 (1988). Iso-retinoin has been shown to be useful in the prevention of second primary tumors in squamous cell carcinoma of the head and neck. Hong, W.K. and collaborators, N. Engl. J. Med., 323, page 795 (1990).

The compounds of formula I and II can be used in a manner substantially similar to retinoids for the treatment (both chemopreventive and therapeutically) of various tumors. For the compounds of this invention, the anti-tumor dose to be administered, as a single dose, multiple dose, or daily dose, will, of course, vary with the particular compound employed due to the variation in potency of the compound, the route of administration chosen, the size of the container, the type of tumor, and the nature of the patient's condition. The dose to be administered is not subject to defined bonds, but usually it can be an effective amount, or equivalent in a molar basis, of the pharmacologically active free form produced from a dose formulation during the metabolic release of the active drug to be performed desiring pharmacological effects and physiological A skilled oncologist skilled in the art of cancer treatment will be able to guess, without undue experimentation, the appropriate protocols for the effective administration of the compounds of the present invention, such as with reference to previously published studies on retinoids found They have anti-tumor properties. For example, for the prevention of second primary tumors with a compound of formula I and II in squamous cell carcinoma of the head and neck, an oncologist may refer to the study by Hong, W.K. and collaborators in N. Engl. J. Med., 323, page 795 (1990). For the treatment of acute pr omelocytic leukemia, the oncologist may refer to the studies made by Huang, M. and collaborators in Blood, 72, page 567 (1988).

Biological Activity The activity similar to that of the retinoid and the efficacy of these compounds has been confirmed by the retinoid transactivation assays described in Skin Pharmacology, 8, pages 292-299 (1995). HeLa cells are co-transfected with DNA encoding RARa, β or β, and a CAT reporter gene with RAR response. The efficacy of the retinoid is measured by the concentration of the CAT gene product induced as determined by the ELISA assay. The compounds of the present invention show activity as agonists or partial agonists in at least one of the three receptor subtypes (a, β, β). The apparent K d to bind these compounds to the three RAR receptors has also been evaluated by an assay described in Skin Pharmacology, 8, pages 292-299 (1995) and Mode of Action of Drugs on Cells, Arnold Publishers, London (1993) and Table 1 shows the data of compounds I and II.

Table 1 'Completely t rans-ret inoxic acid The comedolytic activity of the compounds of the present invention is evaluated by the mouse mouse assay model. The compounds are administered daily to the mouse topically in ethanol at various concentrations for 5 days. Signs of skin irritation are evaluated at day 5 by a visual inspection of the mouse skin and the degree of edema, erythema (flushing) and de-scaling (leaflet lameness) with scales of 1-5 and 1-4, respectively. The skin samples are taken on day 7 and processed for imaging analysis to measure the size of the utricle.

Table 2 provides the percent inhibition at two different concentrations of the compounds I and II of the present invention as well as some other compounds generically described by the patent application WO 97/48672.

Table 2 COjH * Completely acidic rans-ret inóico ** Not tested No irritation is observed for compound 1 at concentrations up to 10 mM. The positive control drug, completely trans-retinoic acid (tRA), causes a degree of erythema of 4.8 and a degree of de-escalation of 2.5 to 1 mM. The pharmacological activity to reduce the size of utricles is shown in Figure 1. The potency of the compounds is determined by ED30 values, which are the doses at which a 30% reduction in the size of the utricles is made. This is equivalent to ED50 in other studies since the maximum reduction of utricles achievable in this model is ~ 60%. Compound 1 has an ED30 value of 0.055 mM as compared to the tRA with an ED30 value of 0.028 mM in this study.

The irritation study of the retinoid compounds of this invention is also carried out with a more sensitive animal model, that is, the skin irritation model of the rabbit. In this model, the compounds are applied topically daily to the mouse skin for 14 days in an ethanol vehicle. The animals are graduated daily for signs of irritation, that is, edema, erythema and scaling, which are the typical retinoid effects on the skin. The result of total irritation during the period of 14 days is used to obtain the area under the curve (AUC).

Table 3 shows the erythema result of compounds I and II of the present invention, as well as the erythema result of some other compounds generically described in patent application WO 97/48672. It can be reported that for compounds I and II, the irritation and inflammation usually observed with topically administered retinoids is not observed. It is noteworthy that many other compounds of the patent application WO 97/48672 are found to be irritant. This demonstrates that the compounds of the present invention are unexpectedly devoid of skin irritation which is not a common feature of the compounds having an activity similar to that of the retinoid and is not predicted for such compounds.

Table 3 COjH Fully t rans acid - retinoic acid The result of the total irritation during the 14-day period was used to obtain the area under the curve (AUC) for compound I, and the ART at different doses as shown in Figure 2. Clearly, AR causes significant irritation. to rabbit skin at concentrations above 0.1 mM, while compound I does not cause any irritation at 1 mM. Even at higher doses (5 mM), the compound does not cause any sign of irritation to rabbit skin.

The compounds of the present invention have also been tested as inhibitors of cell proliferation (3 H-thymidine absorption). The cells are placed in 96-well trays at a predetermined density so that 80% of the cell confluence is reached on day 7. 24 hours after placing, the culture medium is changed and the cells are treated with the appropriate drug or vehicle (day 0). The culture medium is changed on days 3 and 6. Cell proliferation is measured on day 7 by quantifying the amount of titrated trinidine ([3 H] -TdR) incorporated in the cellular DNA (Odham, KG (1977) in: Radiotracer Techniques and Applications, edited by EA Evans and M. Murawatsu, M. Dekker Inc. New York; 2, 823).

Table 4 shows the ED30 values of topical activity as well as a measure of the concentration necessary to perform an irritation result of 3 (IS3) for compounds I and II of the present invention and the compounds generically described in the patent application. WO 97/48672. Compound I, which shows no irritation signal at 5 mM, has a highly superior therapeutic index for TRA and for most of the closely related analogues described in WO 97/48672. The compound I of the present invention, unlike its closely related analogues, is unexpectedly unique in this respect.

Table 4 Table 5 provides the IC 50 values of some representative compounds in various carcinoma cell lines. The compounds of the present invention show potent anti-proliferative activity.

Table 5 * completely t rans-ret inoxic acid This potent anti-proliferative activity also results in subcutaneous carcinomas of breast carcinoma (ER +) presenting H3396 in athymic mouse i n vi vo (P. A. Trail, et al., Cancer Research, 52, pages 5693-5700 (1992)). The athymic mouse is implanted with 0.72 mg estradiol pellets (60 days release) (Innovative Research of America, Toledo, OH) one day before the implantation of H3396 tumors. H3396 tumors are measured in two perpendicular directions at weekly and bi weekly intervals., using gauge compass. The tumor volume is calculated according to the equation: V = 1 x w2 / 2, where V is equal to volume (mm3), 1 equals measurement of the longest angle (mm), and w equals the measurement of the perpendicular axis a 1. In general, they were 8-10 mice in each of the controls or treatment groups. The data are presented as an average tumor size for the control or treated groups. Anti-tumor activity is expressed in terms of measured TVDD values, where TVDD = T -C / TVDT; CT is defined as the average time (days) to treat tumors up to 500 mm3 in size minus the average time to control tumors to reach 500 mm3 in size, and TVDT is the time (days) to control tumors up to twice of the volume (250-500 mm3).

Compound I, when administered intraperitonally every 2 days for 10 days, is potent as doxorubicin in the model that inhibits tumor growth as shown in Figure 3 and Table 5. In this experiment, tumor growth was postpone to an equivalent of 1.2 log cell deletions at 30 mg / kg.

Description of the Specific Modalities.

The synthesis of the compounds of the present invention can be carried out by a wide variety of methods using conventional starting materials and processes. The synthetic descriptions and specific examples that follow are only intended for purposes of illustration, and are not constructed as limiting in any way in the preparation of the compounds of the present invention by other methods.

The preparation of the compounds of the present invention as well as their related analogs is described in Schemes 1 and 2. The tetralone III described in US Pat. No. 5,648,385 (scheme 1) is converted to the corresponding vinyl triflate V as described in US Pat. WO 97/48672. This triflate is then treated with various acetylenes or tin derivatives under Heck or Stille conditions to provide 8-substituted dihydrona ft to IVb, d or e. The reduction of the acetylenes IVb and Ivd respectively gives the cis IVc and Ivf olefins. The tetralone III also reacts with isopropylthiol in the presence of titanium chloride to produce the vinyl fluoride.

To prepare the 7-methyl analogue A, tetralone VI (Scheme 2) described in U.S. Pat. No. 5,648,385 is alkylated using methyl triflate and then coupled to the methyl p-vinylbenzoate under Heck conditions to give the 7-methylated tetralone VIII. The conversion of the acetone to the corresponding vinyl triflate is then continued by the usual coupling Heck with a t-butylacetylene and the 8-substituted dihydronaphthalene derivative IVg is produced.

The 8,6-substituted 6,6-dihydronaphthalene compounds IVa to g are then saponified under the usual conditions to provide the compounds of the present invention I and II and analogs A, 3, C and D.

SCHEME 1 SCHEME 2 IVfl IX IVa-9 I R'-H, R «- tBu II R'tH, R? c; »- CH» CH-C (CH J) JOH A R '«M #, R» - tBu B R' > H, R »c /» - CH = Cr.-C (Et)? CHj C R '- H, R - C / «- CH > CH-tBu D R '- H, R - SIPr Description of the Specific Examples Analytical grade solvents are used for reactions and chromatographies. The flash column chromatographies are run on Merck 60 silica gel (230-400 mesh) and Merck 60 F254 0.5 mm silica gel trays are used. All melting points are determined in a Gallenkamp melting point apparatus and are not correct. The 1H NMR spectrum is measured on Bruker AMX400 instruments (400 MHz). Chemical changes are reported in units d using the solvent as an internal standard. The signals are described as s (singlet), d (doublet), t (triplet), qa (quartet), qi (quintet), m (multiplet) and br (broad). The infrared spectra are recorded on a Perkin-Elmer 781 and the optical rotations are measured on a Perkin-Elmer 241 apparatus.

EXAMPLE 1. 4 - [(E) - (5,6-Dihydro-5,5-dimethyl-8- (3,3-dime-il-1-bu tin-l-yl) -2-naphthalenyl) ethenyl] benzoic acid 4 - [(E) - [5,6-dihydro-5, 5-dimethyl-8-t -difluoromet anosul-fonyloxy-2-naphthalenyl] ethenyl] -benzoic acid methyl ester A solution of 4 - [[(E) - (5 , 6, 7, 8-1 and methyl rahydro-5, 5-dimethyl-8-oxo) -2-naphthalenyl] inyl] benzoate (US Pat. No. 5,618,839 and EP 661, Al 259) (10.02 g, 30 mmol) in Tetrahydrofuran (200 mL) at -78 ° C, was treated dropwise with a solution of lithium bis (trimethylsilyl) amide (1.0M in tetrahydrofuu, 42 mL, 42 mmol). The solution was stirred for 30 minutes and then treated with a solution of 2- [N, N-bis (trifluoromet ilsulfonyl) amino] pyridine (14 g, 39 mmol) in tetrahydrofuran (100 mL). The mixture was stirred overnight and allowed to reach room temperature. The mixture was cooled to 0-5 ° C, was diluted with water (200 mL) and ethyl acetate (200 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine and dried over anhydrous magnesium sulfate, filtering and concentrating. The residue was purified by chromatography on silica gel (toluene to toluene / ethyl acetate 8: 2) and triturated in hexanes to give the title material (10.5 g, 75%) as a white solid. 2 H NMR 400 MHz (CDC13) d (ppm): 1.34 (6H, s, 2x-CH3), 2.45 (2H, d, J = 4.8 Hz, H-6 '), 3.94 (3H, s, -OCH3), 6.02 (HH, t, J = 4.8 Hz, H-7 '), 7.13 (HH, d, J = 16.3 Hz, vinyl' H), 7.22 (HH, d, J = 16.3 Hz, vinyl H), 7.34 ( HH, d, J = 8.0 Hz, H-4 '), 7.51 (HH, dd, J = 8.0 and 1.6 Hz, H-3'), 7.54 (HH, br,, H-l '), 7.59 (2H , d, J = 8.3 Hz, H-3 and H-5), 8.05 (2H, d, J = 8.4 Hz, H-2 and H-6). 4 - [(E) - (methyl 5,6-dihydro-5,5-dimethyl-8- (3,3-dimethyl-l-butin-1-yl) -2-naphthalenyl] benzoate To a cold solution (5 ° C) of 4 - [(E) - [5,6-dihydro-5,5-dimethyl-8-trifluoromethanesulfonyloxy-2-naphthalenyl]] ethenyl] benzoate (13.73 g, 29.46 mmol) in tetrahydrofuran (200 mL) was added, in order, dimet i lbut ino (6.05 g, 73.65 mmol, 9.07 mL), bist ri fenilfos finpaladium (II) chloride (250 mg), copper iodide (1.4 g, 7.37 mmol) ) and diisopropylamine (30 mL). The reaction mixture was stirred at 5 ° C for 2 hours, then diluted with ethyl ether and washed with water, IN hydrochloric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. A brown solid was obtained which was triturated in ethyl ether / hexane and gave the title compound (5.9 g, 50%). The filtrate was concentrated and the residue was purified by chromatography on silica gel (0-10% ethyl acetate / hexane) to give an additional amount of the title compound (4.37 g, 37%). Some impure material was discharged (> lg).

IR (KBr)? Max (ciri): 2985, 1715 (C = 0), 1605 XH NMR 400 MHz (CDC13) d (ppm): 1.30 (6H, s, 2 x -CH3), 1.42 (9H, s, -tBu), 2.32 (2H, d, J = 4.8 Hz, H-6 ') , 3.94 (3H, s, -OCH3), 6.33 (HH, t, J = 4.8 HZ, H-7 '), 7.13 ((ÍH, d, J = 16.3 Hz, vinyl H), 7.23 (HH, d, J = 16.3 Hz, vinyl H), 7.30 (HH, d, J = 7.9 Hz, H-4 '), 7.39 (HH, dd, J = 7.9 and 1.7 Hz, H-3'), 7.56 (2H, d , H-3 and H-5), 7.85 (ÍH, d, J = 1.6 Hz, H-1 '), 8.04 (2H, d, J = 8.3 Hz, H-2 and H-6).

Analysis calculated for C28H30O2: C84.38; H7.59. Found: C83.95; H 7.69. 4- [(E) - (5,6-Dihydro-5,5-dimethyl-l 3, 3-dimet i 1-1 -butin-1-yl) -2-naphthalenyl) ethenyl] benzoic acid A solution of 4 - [(E) - (5, 6-dihydro-5, 5-dimethyl-8- (3, 3-dimet i 1-1 -butin-1-yl) -2-naphthaleni 1) ethenyl] benzoate methyl (3.0 g, 7.53 mmol) in a mixture of tet rahydrofuran / et anol (1: 1, 60 mL) was treated with 4N sodium hydroxide (9.4 mL, 32.64 mmol) and stirred at room temperature for 20 hours. The reaction mixture was then diluted with water (100 mL) and acidified to a pH of 1 with concentrated hydrochloric acid. The precipitate was extracted with ethyl acetate and the extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated. The resulting solid was dissolved in dichloromethane / ethanol (150 mL / 100 mL) and the solution was filtered through a sintered glass and the filtrate was concentrated. During the concentration, the title compound was crystallized and collected and dried to give 2.62 g (90%) of the title material as a white solid.

UR (KBr? "(Cm" 3650-2000 (br) 2825 1670 (C = 0), 1600. XH NMR 400 MHz (DMSO-d6) d (ppm): 1.22 (6H, s, 2 x -CH3), 1.37 (9H, s, -tBu), 2.28 (2H, d, J = 4.8 Hz, H-6 '), 6.31 (ÍH, t, J = 4.8 Hz, H-7'), 7.20 81H , d, J = 16.4 Hz, vinyl H), 7.36 (ΔI, d, J = 8.0 Hz, H-4 '), 7.41 (ΔI, d, J = 16.4 Hz, vinyl H), 7.55 (1H, dd, J = 8.0 and 1.7 Hz, H-3 '), 7.71 (2H, d, J = 8.3 Hz, H-3 and H-5), 7.72 (ÍH, br s, H-l'), 7.94 (2H, d, J = 8.3 Hz, H-2 and H-6).

Analysis calculated for C27H2802: C84.34; H7.34. Found: C84.22; H 7.23.

EXAMPLE 2 4 - [(E) - (5,6-Dihydro-5,5-dimethyl-8- ((Z) -3-methyl-3-hydroxy-1-bu en-1-yl) -2-naphthalenyl acid) ethenyl] benzoic 4- [(E) - (5,6-dihydro-5,5-dimethyl-8- (3-met i 1-3-hydroxyl-1-butin-1-yl) -2-na phthaleni 1) et eni 1] methyl benzoate A solution of methyl 4 - [(E) - [5,6-dihydro-5,5-dimethyl-8-tri fluoromethanesulfonyl-2-ylphthalenyl] ethenyl] benzoate (0.350 g, 0.75 mmol ) was reacted as described in Example 1 using 3-met il-3-hydroxyl-1-but ino (0.158 g, 1.88 mmol, 0.18 mL) and tet rachistri phenylphosphoria (0) and gave the title material ( 0.295 g, 98%) which was crystallized from ethyl ether at -20 ° C.

IR (CH2CL-? R cm): 1716 (C = 0 1604 X H NMR 400 MHz (CDC13) d (ppm): 8.04 (2 H, d, J = 8.3 Hz, H-2 and H-6), 7.76 (H H, br s, H-l '), 7.57 (2 H, d , J = 8.3 Hz, H-3 and H-5), 7.43 (1H, br d, J = 8.0 Hz, H-3 '), 7.32 (H, d, J = 8.0 Hz, H-4'), 7.23 and 7.12 (2 x ÍH, 2 d, J = 16.3 Hz, vinyl H), 6.42 (ÍH, t, J = 4.8 Hz, H-7 '), 3.94 (3H, s, -0CH3), 2.34 (2H , d, J = 4.8 Hz, H-6 '), 2.05 (HH, br S, -OH), 1.71 (6H, s, 2 x -CH3), 1.30 (6H, s, 2 x -CH3). 4- [(E) - (5,6-dihydro-5, 5 -dimet i 1-8- ((Z) -3-methyl-3-hydroxy-1-oxen-1-yl) -2-naphthalenyl) methyl etheno] benzoate A mixture of 4 - [(E) - (5,6-dihydro-5,5-dimet i 1-8- (3-methyl-3-hydroxy-1-butin-1-yl) - Methyl 2-naphthalenyl) ethenyl] benzoate (0.228 g, 0.57 mmol) and 10% Pd / BaSO4 (75 mg) in pyridine (5 mL), was hydrogenated (rubber ball) for 60 minutes at room temperature. The reaction mixture was then filtered through celite and the pad washed with ethyl ether. The filtrate was washed with water, IN hydrochloric acid and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane / acetonitrile) to give the title material (135 mg, 59%) as a white solid. 1 W NMR 400 MHz (CDC13) d (ppm): 8.03 (2H, d, J = 8.3 Hz, H-2 and H-6), 7.58 (2H, d, J = 8.3 Hz, H-3 and H- 5), 7.43 (ÍH, dd, J = 8.0 and 1.8 Hz, H-3 '), 7.39 (ÍH, d, J = 1.6 Hz, H-l'), 7.35 (ÍH, d, J = 7.9 Hz, H-4 '), 7.21 and 7.08 (2 x H, 2 d, J = 16.3 Hz, vinyl H), 6.15 (H, dq, J = 12.4 and 2.1 Hz, -CH = CH (CH3) 2OH), 5.98 (ÍH, m, H-7 '), 5.91 (ÍH, d, J = 12.4 Hz, CH = CH (CH3) 20H), 3.94 (3H, s, -OCH3), 2.33 (2H, dd, J = 4.4 and 2.6 Hz, H-6 '), 1.41 and 1.31 (2 x 6H, 2s, 4 x -CH3). 4- [(E) - (5,6-Dihydro-5,5-dimethyl-Z) -3'-methyl-3-hydroxy-1-1-buten-1-yl) -2-naphthalenyl) ethenyl] benzoic acid 4 - [(E) - (5,6-Dihydro-5,5-dimethyl-8- ((Z) -3-met il-3-hydroxy-1-buten-1-yl) -2 was saponified methylnaphthalenyl) ethenyl] benzoate as described in Example 1 and gave the title material (0.083 g, 64%) as a white soft solid.

IR (nujol)? Max (crn-1): 2924, 2855, 1681 (C = 0), 1604.

* H NMR 400 MHz (DMSO-d6) d (ppm): 7.92 (2H, d, J = 8.1 Hz, H-2 and H-6), 7.72 (2H, d, J = 8.2 Hz, H-3 and H-5), 7.52 (1H, br d, J = 8.0 Hz, H-3 '), 7.40-7.36 (3H, m, vinyl H, H-l 'and H-4'), 7.21 (ÍH, d, J = 16. 4 Hz, vinyl H), 6.03 (HH, br d, J = 12.5 Hz, - CH = CH (CH3) 2OH), 5.89 (HH, br s, H-7 '), 5.87 (HH, d, J = 12.5 Hz, -CH = CH (CH3) 2OH), 2.25 (2H, br s, H-6 '), 1.25 (12H, s, 4 x -CH3).

Analysis calculated for C26H2803: C80.38; H7.27. Found: C80.47; H6.96 EXAMPLE 3 (Reference Compound A) 4- [(E) - (5,6-Dihydro-5,5-dimethyl-7-methyl-8- (3,3-dimethyl-1-bu in-1-yl) -2-naphthalenyl) ethenyl acid ] benzoic 1, 2, 3, -tetrahydro-4,4-dimethyl-2-methyl-l-oxo-7-brorno-naphthalene.

To a suspension of potassium hydride (35% in oil, 4.6, 40 mmol) in ethyl ether (50 mL) was added dropwise a solution of 1,2,3,4-tet rahydro-4, 4-dimethyl. -l-oxo-7-bromo-naphthalene (US Patent 5,618,839 and EP 661,259 Al) (5.06 g, 20 mmol) in ether (10 mL). The mixture was stirred at room temperature for 2 hours, then cooled down to -30 ° C. Methyl triflate (3.4 mL, 30 mmol) was added and the mixture was stirred at -30 ° C for 1 hour and 30 minutes at room temperature. The mixture was cooled to 0 ° C and INN hydrochloric acid was slowly added. The organic phase was separated and the aqueous phase was extracted with ethyl ether. The combined organic phases were washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate anhydride, filtered and concentrated. The residue was purified by chromatography on silica gel (4.5 x 15 cm, 30 to 100% hexane / toluene) and titrated in hexane (3.9 g, 73%) as a white solid.

IR (KBr)? Raax (cm "1): 2960, 2915, 2860, 1685 (C = 0). XH NMR 400 MHz (CDC13) d (ppm): 8.12 (H, d, J = 2.2 Hz, H- 8), 7.62 (ÍH, dd, J = 8.4 and 2.2 Hz, H-6), 7.30 (ÍH, d, J = 8.4 Hz, H-5), 2.87-2.78 (ÍH, m, H-2), 1.92-1.86 (2H, m, H-3), 1.42 and 1.38 (2 x 3H, 2s, 4-CH3), 1.26 (3H, d, J = 6.6 Hz, 2-CH3).

Analysis calculated for C? 3H? 5BrO: C58.44; H5.66. Found: C58.59; H5.62. 4- [[(E) - (5,6,7,8-tetrahydro-5,5-dimethyl-7-methyl-oxo) -2-naphthalenyl] vinyl] methyl benzoate.

A solution of 1, 2,3,4-tetrahydro-4,4-dimethyl-2-methyl-l-oxo-7-bromo-naphthalene (0.267 g, 1.0 mmol), methyl 4-vinylbenzoate ( 0.245 g, 1.5 mmol), palladium (II) acetate (12 mg), tetrabutylammonium chloride monohydrate (0.292 g, 1.05 mmol) and sodium bicarbonate (0.210 g, 2.5 mmol) was degassed and then heated to 70 °. C for 6 hours and stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed with water (2 x 20 mL), saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (3 x 15 cm, dichloromethane) and triturated in hexane to give the title material (0.270 g, 78%) as a white solid. p.f .: 157 ° C.

IR (KBr)? Max (cm "2960 2930 1710 1685 C = 0) 1600. 1 H NMR 400 MHz (CDC13) d (ppm): 8.17 (H, d, J = 2. 0Hz, hl '), 8.04 (2H, d, J = 8.4Hz, H-2 and H-6), 7.69 (ÍH, dd, J = 8.2 and 2.0 Hz, H-3'), 7.58 (2H, d , J = 8.4Hz, H-3 and H-5), 7.44 (HH, d, J = 8.2 Hz, H-4 '), 7.24 (HH, d, JAB = 16.4 Hz, vinyl H), 7.20 (HH) , d, JAB = 16.4 Hz, vinyl H), 3.94 (3H, s, -OCH3), 2.91-2.81 (1H,, H-7 '), 1.94 (2H, d, J = 9.0 Hz, H-6' ), 1.45 and 1.41 (2 x 3H, 2 s, 5'-CH3), 1.29 (3H, d, J = 6.6 Hz, 7'-CH3).

Analysis calculated for C23H2403: C79.28; H6.94. Found: C78.99; H6.92. 4- [(E) - [5,6-dihydro-5,5-dimethyl-7-methyl-1-trifluoromethanesulfonyloxy-2-naphthalenyl] ethenyl] enzoate methyl.

A solution of methyl 4 - [[(E) - (5, 6, 7, 8 -ethyl rahydro-5, 5-dimethyl-7-met i 1-8 -oxo) -2-naphthalenyl] vinyl] benzoate ( 0.245 g, 0.7 mmol) in tetrahydrofuran (6 mL) was treated with a solution of lithium bis (t rimet ilsyl i 1) amide (1.0 M in tetrahydrofuran, 1.04 mL, 1.04 mmol) at -78 ° C and the resulting mixture it was stirred for 50 minutes. A solution of 2- [N, N-bis (trifluoromet-ilsulfonyl) amino] pyridine (327 mg, 0.91 mmol) in tetrahydrofuran (3.5 mL) was added dropwise and the mixture was allowed to reach room temperature overnight. The mixture was then cooled to 0 ° C and water was added followed by ethyl acetate. The organic phase was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (2 x 15 cm, toluene) and triturated in hexanes at 0 ° C to give the title material (0.245 g, 85%) as a white solid.

IR (KBr)? Max (cm "1): 2980, 2960, 1720, (C = 0), 1610. 1ti NMR 400 MHz (CDC13) d (ppm): 8.04 (2H, d, J = 8.3 Hz, H-2 and H-6), 7.58 (2H, d, J = 8.3 Hz, H-3 and H-5 ), 7.52 (ÍH, br s, H-l '), 7.44 (ÍH, br d, J = 8.0 Hz, H-3'), 7.30 (ÍH, d, J = 8.0 Hz, H-4 '), 7.20 (HH, d, J = 16.3 Hz, vinyl H), 7.11 (HH, d, J = 16.3 Hz, vinyl H), 3.94 (3H, s, -0CH3), 2.35 (2H, s, H-6 ' ), 2.02 (3H, s, -CH3-7 '), 1.33 (6H, s, Analysis calculated for C24H23F305S: C59.99; H4.83. Found: C60.15; H4.80. 4- [(E) - [5,6-dihydro-5,5-dimet i 1 -7-methyl-8 - (3,3-dimethyl-l-butin-1-yl) -2-naphthalenyl) ethenyl ] methyl benzoate Reacted methyl 4 - [(E) - [5,6-dihydro-5,5-di and il-7-methyl-8 -trif luoromet anosul-fonyloxy-2-naphthalenyl] ethenyl] benzoate (0.220 g, 0.458 mmol) and 3, 3-dimet i 1- 1 -but ino (2 x 0.141 mL, 2 x 1.15 mmol) as described in Example 1, and gave the title material (0.148 g, 78%) as a solid white.

IR (KBr)? Max (cm "1): 2980, 2910, 2870, 1718 (C = 0), 1610. XH NMR 400 MHz (CDC13) d (ppm): 8.03 (2H, d, J = 8.4Hz, H-2 and H-6), 7.84 (ÍH, d, J = 1.7 Hz, H-l '), 7.56 (2H, d, J = 8.4 Hz, H-3 and H-5), 7.34 (ÍH, dd, J = 7.8 and 1.7 Hz, H-3 '), 7.27 (IH, d, J = 7.8 Hz, H-4'), 7.23 (1H, d, J = 16.3 Hz, vinyl H), 7.12 (IH , d, J = 16.3 Hz, vinyl H), 3.94 (3H, s, -OCH3), 2.25 (2H, s, H-6 '), 2.14 (3H, s, -CH3-7'), 1.43 (9H , s, -tBu), 1.26 (6H, s, 2 x -CH3).

Analysis calculated for C29H3202: C84.42; H7.82. Found: C84.05; H7.91. 4- [(E) - (5,6-Dihydro-5,5-dimethyl-7-methyl-8- (3, 3 -dimet-il-1-buten-1-yl) -2-naphthalenyl) ethenyl] acid benzoic.

Saponify 4 - [(E) - [5,6-dihydro-5,5-dimethyl-7-met-8- (3, 3-dimet-il-1 -but in- 1 -i 1) -2 methylnaphthalenyl) ethenyl] benzoate (0.130 g, 0.315 mmol) as described in Example 1, and gives the title material (0.125 g, 100%) as a white soft solid.

IR (KBr)? Max (cm "1): 2975, 2960, 1670 (C = 0), 1605. XH NMR 400 MHz (DMS0-d6) d (ppm): 12.90 (H, s, -C02H), 7.94 (2H, d, J = 7.9Hz, H-2 and H-6), 7.71 (2H, d, J = 7.9 Hz, H-3 and H-5), 7.71 (ÍH, br s, H-1 '), 7.49 (HI, d, J = 8.0 Hz, H-3'), 7.40 (ÍH, d, J = 16.4 Hz, vinyl H), 7.32 (ÍH, d, J = 8.0 Hz, H-4 '), 7.19 (ÍH, d, J - 16.4 Hz, vinyl H), 2.24 (2H, s, H-6'), 2.09 (3H, s, -CH3-7 '), 1.39 (9H, s, -tBu), 1.20 (6H, s, 2 x -CH3).

Analysis calculated for C28H3o02: C83.63; H7.62. Found: C83.52; H7.50 EXAMPLE 4 (Reference Compound C) 4- [(E) - (5,6-Dihydro-5,5-dimethyl-8- ((Z) -3,3-dimethyl-l-bu ten-l-yl) -2-naphthalenyl) ethenyl] acid benzoic. 4- [(E) - [5,6-d? H? Dro-5,5-d? Met? L-8- ((Z) -3, 3-d? Met? L-1-buten-A l) -2-naphthalenyl) eteml] methyl benzoate A solution of 4 - [(E) - (5,6-d? Hydro? 5, 5-d? Met? L-8- (3, 3-d? Met? Ll-butm-l-? L ) -2-naphthalene? L) ethenyl] benzoate prepared in Example 1 (4.39 g, L1.02 mmol) in pyridine (40 mL) was stirred under an atmosphere of hydrogen (rubber balloon) in the presence of 5% of Pd / BaS04 (2.0 g) for 16 hours. Then more catalyst (1.0 g) was added and the hydrogenation was resumed for another 8 hours. The reaction mixture was diluted with ethyl ether and filtered through celite. The filtrate was washed with water, IN hydrochloric acid and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was triturated in hexane and collected to give the title material (3.0 g, 68%).

IR (CH2Cl2)? Ma (cm "1): 2950, 1705 (C = 0), 1595.

H NMR 400 MHz (CDC13) d (ppm): 8.03 (2H, d, J = 8.4 Hz, H-2 and H-6), 7.58 (2H, d, J = 8.4 Hz, H-3 and H- 5), 7.41 (2H,, Hl 'and H-3' or H-4 '), 7.34 (ÍH, m, H - 3' or H - 4 '), 7.22 (ÍH, d, J = 16.3 Hz, vinyl H), 7.08 (HH, d, J = 16.3 Hz, vinyl H), 6.00 (HH, dq, J = 12.4 and 2.2 Hz), -CH = CH-tBu), 5.84 (HH, td, J = 4.4 and 1.8 Hz, H-7 '), 5.73 (HI, d, J = 12.4 Hz, -CH = CH- tBu), 3.94 (3H, s, -OCH3), 2.30 (2H, dd, J = 4.4 and 2.7 Hz, H-6 '), 1.31 (6H, s, 2 x -CH3), 1.11 (9H, s, tBu). 4- [(E) - (5,6-Dihydro-5,5-dimethyl-8- ((Z) -3,3-dimet i 1-1 -but en-l-yl) -2-naphthalenyl) acid etenil] benzoic.

A solution of 4 - [(E) - [5,6-dihydro-5,5-dimethyl-8- ((Z) -3,3-dimet i 1-1 -but en-1-yl) -2 -naphthalenyl) methyl ethenylbenzoate (3.0 g, 7.49 mmol) in tetrahydrofuran (60 mL) and ethanol (30 mL) was treated with 4N sodium hydroxide (9.36 mL, 37.6 mmol) and stirred for 30 hours. The reaction mixture was diluted with water and acidified to a pH of 2 with concentrated hydrochloric acid. The precipitated acid was extracted into ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude residue was dissolved in dichloromethane (75 mL) and ethanol (50 mL), filtered through a sintered glass and the filtrate was concentrated. The title material was precipitated and collected and dried to give a white solid (2.455 g, 85%).

IR (nujol)? Max (cm "1): 2915, 2845, 1680 (C = 0), 1595. XH NMR 400 MHz (DMSO-d6) d (ppm): 7.91 (2H, d, J = 8.2 Hz, H-2 and H-6), 7.72 (2H, d, J = 8.2 Hz, H-3 and H-5), 7.54 (1H, br d, J = 8.0 Hz, H-3 '), 7.42-7.34 (3H, m, vinyl H, Hl 'and H-4'), 7.19 (ÍH, d, J = 16.4 Hz, vinyl H), 6.01 (ÍH, br d, J = 12.4 Hz, -CH = CH-tBu ), 5.81 (ΔI, br s, H-7 '), 5.70 (ΔI, d, J = 12.4 Hz, -CH = CH-tBu), 2.26 (2H, br s, H-6'), 1.25 (6H , s, 2 x -CH3), 1.07 (9H, s, -tBu).

Analysis calculated for C27H30O2: C83.90; H7.82. Found: C83.27; H7.73 EXAMPLE 5 (Reference Compound B). 4- [(E) - (5,6-Dihydro-5,5-dimethyl-8- ((Z) -3-methyl-3-ethyl-1 -penten-1-yl) -2-naphthalenyl) ethenyl acid ] benzoic Iodide of (Iodomet il) t r i phenyl fosium A solution of triphenylphosphine (6.56 g, 25 mmol) and diiodomethane (8.7 g, 32.5 mmol) in benzene (25 mL) was heated at 60 ° C for 20 hours. The mixture was cooled to room temperature and the precipitated salt was collected, washed with benzene and dried to give the title material (7.38 g, 56%).

(Z) -3-ethyl-3-methyl-l-iodo-l-pentene.

A suspension of (iodomethyl) triphenylphosphonium iodide (0.530 g, 1 mmol) in tetrahydrofuran (3 mL) was treated dropwise at room temperature with sodium bis (t-rimethylsilyl) amide (1 mL, IM solution in THF, 1 mL). mmol) for 2-3 minutes. The solution was then cooled to -78 ° C and a solution of 2 -et i 1 -2 -met-il-butanal (0.100 g, 0.88 mmol) in tetrahydrofuran was added dropwise. The cooling bath was removed and stirring continued at room temperature for 1 hour. The reaction mixture was diluted with hexane, filtered and evaporated. The crude compound was purified by chromatography on silica gel (hexane) and gave the title compound (0.130 g, 62%).

XH NMR 400 MHz (CDC13) d (ppm): 0.84 (6H, t, J = 7.5 Hz, 2 x -CH2CH3), 1.15 (3H, s, -CH3), 1.47 and 1. 65 (2 x 2H, 2m, 2 x -CH2-CH3), 6.20 (IH, d, J = 8. 5 Hz, -CH = CH1), 6.36 (ÍH, d, J = 8.5 Hz, = CH1).

(Z) -3-ethyl-3-methyl-1- (tributyltin) -1-pentene A solution of (Z) -3-yl-3-met il-1-iodo-1-pentene (0.660 g, 2.78 mmol) and bi s (tributyl t-year) (3.22 g, 5.55 mmol) in dioxane was heated at 85 ° C for 16 hours in the presence of tetrakis (triphenylphosphine) palladium (0) (50 mg). The solvent was evaporated and the residue was purified by chromatography on silica gel (hexane) to give the title compound (0.440 g, 40%) contaminated with 11% of the trans isomer.

XH NMR 400 MHz (CDC13) d (ppm): 075-097 and 1.27-1.53 (40H, 4 sets of m, 3 x - (CH2) 3CH3, 2 x -CH2CH3 and -CH3), 5.71 (1H, d, J = 14.2 Hz, -CH =), 6.45 (ÍH, d, J = 14.2 Hz, = CH-Sn). 4- [(E) - (5,6-dihydro-5,5-dimethyl-8- ((Z) -3-met il-3-ethyl-1-penten-l-yl) -2-naphthalenyl) ethenyl ] methyl benzoate.

A solution of methyl 4 - [(E) - [5,6-dihydro-5,5-dimethyl-8-tr: '- fluoromethanesulfonyloxy-2-naphthalenyl] ethenyl] benzoate (0.320 g, 0.685 mmol) and (Z ) -3-ethyl-3-methyl-1- (tributylstannyl) -1-pentene (0.440 g, 1.1 mmol), lithium chloride (87 mg, 2.06 mmol) and tet rachis (trifeni 1 fos) palladium (0) (30 mg) in dioxane, was heated at 95 ° C for 20 hours. The solvent was evaporated and the crude residue was purified by chromatography on silica gel (5% ethyl acetate / hexane) to give the title material (0.525 g, 86%) as a colorless foam. Crystallization from hexane at -15 ° C gave the pure cis isomer (0.040 g) free of the trans isomer, but contaminated with 10% of the unsubstituted analogue 8. 1ti NMR 400 MHz (CDC13) d (ppm): 0.89 (6H, t, J = 7.4 Hz, 2 x -CH2CH3), 0.97 (3H, s, -CH3), 1.31 (6H, s, 2 x -CH3) , 1.26-1.50 (4H, m, 2 x -CH2CH3), 2.29 (2H, dd, J = 4.4 and 2.7 Hz, H-6 '), 3.93 (3H, s, -OCH3), 5.53 (ÍH, d, J = 12.7 Hz, = CH-C (Et) 2CH3), 5.83 (IH, dd, J = 4.5 and 1.9 Hz, H-7 '), 6.14 (IH, dq, J = 12.7 and 2.3 Hz, -CH = CH- (Et) 2CH3), 7.08 and 7.20 (2 x 1 H, 2 d, J = 16.3 Hz, vinyl H), 7.33 (H, d, J = 7.9 Hz, H-4 '), 7.38 (1H, dd, J = 7.8 and 1.8 Hz, H-3 '), 7.47 (ÍH, d, J = 1.5 Hz, Hl'), 7.56 (2H, d, J = 8.3 Hz, H-3 and H-5), 8.02 (2H, d, J = 8.4 Hz, H - 2 and H - 6).

Acid 4-; (E) - (5,6-Dihydro-5,5-dimethyl-8- ((Z) -3-methyl-3-ethyl-l-penten-1-yl) -2-naphthalenyl) ethenyl] benzoic acid Saponified 4 - [(E) - (5,6-dihydro-5,5-dimet i 1 - 8 - ((Z) -3-methyl-3-ethyl-1-penten-1-yl) -2- methyl naphthalenyl) enyl] benzoate (0.042 g, 0.1 mmol) as described in Example 1, and gave the title compound (0.018 g, 43%).

IR (nujol)? Max (cm "1): 2924, 2855, 1687 (C = 0). XH NMR 400 MHz (DMSO-d6) d (ppm): 7.92 (2H, d, J = 8. 2 Hz, H-2 and H-6), 7.70 (2H, d, J = 8.2 Hz, H-3 and H-5), 7.50 (H, d, J = 7.9 Hz, H-3 '), 7.41 (ÍH, br s, H-l '), 7.37 (ÍH, d, vinyl H), 7.36 (ÍH, d, H-4'), 7.17 (1H, d, J = 16.4 Hz, vinyl H), 6.17 (ÍH, br dq, J = 12.7 and 2.0 Hz, -CH = CH- C (Et) 2CH3), 5.79 (ÍH, br q, J = 1.4 Hz, H-7 '), 5.50 (ÍH, d, J = 12.7 Hz, = CH-C (Et) 2CH3), 2.26 (2H, br d, J = 2.9 Hz, H-6 '), 1.38 (4H, m, 2 x -CH2CH3), 1.25 (6H, s, 2 x -CH3), 0.91 (3H, s, -CH3), 0.82 (6H, t, J = 7.3 Hz, 2 x -CH2CH3).

MS: 413.2 (MH) A EXAMPLE 6 (Reference Compound D). 4- [(E) - (5,6-Dihydro-5,5-dimethyl-8- (1-methyl-1-ethano-thio) -2-naphthalenyl) ethenyl] benzoic acid. 4- [(E) - (methyl, 5,6-dihydro-5,5-dimethyl-8- (l-methyl-l-ethano-thio) -2 -naphthalenyl) ethenyl] benzoate To a stirred solution of methyl 4 - [[(E) - (5,6,7,8-tetrahydro-5,5-dimethyl-8-oxo) -2 -naphthalenyl] vinyl] benzoate (US Patent 5,618,839 and EP 661.259 Al) (1.0 g, 3 mmol) in tetrahydrofuu (30 mL) was added dropwise titanium chloride (IM in dichloromethane, 3 mL, 3 mmol). The resulting dark solution was stirred for 5 minutes and a solution of sodium thiol (420 μL, 0.343 g, 4.5 mmol) and trientylamine (0.607 g, 0.84 mL, 6 mmol) in tetrahydrofuu (2 mL) was added again. . The reaction mixture was stirred at room temperature for 20 hours. Then mercury trifluoroacetate (1.3 g, 3 mmol) and lithium carbonate (1.3 g, 18 mmol) were added at the same time and the mixture was stirred for 5 minutes. Silica gel (20 mL) was added and the mixture was subsequently filtered for 2 minutes. The solid was washed with dichloromethane (100 mL) and the filtrate was concentrated. The residue was purified on silica gel chromatography (dichloromethane) and gave the title compound which was recrystallized from ethanol (0.956 g, 88%).

XH NMR 400 MHz (CDC13) d (ppm): 8.04 (2H, d, J = 8.4 Hz, H-2 and H-6), 7.98 (H, d, J = 1.8 Hz, H1 '), 7.60 (2H , d, J = 8.3 Hz, H-3 and H-5), 7.43 (ΔH, dd, J = 8.0 and 1.8 Hz, H-3 '), 7.35 (ΔH, d, J = 7.9 Hz, H-4 '), 7.26 and 7.14 (2 x H, 2 d, J = 16.3 Hz, vinyl H), 6.39 (H, t, J = 4.7 Hz, H-7'), 3.94 (3H, s, -Ome), 3.20 (ÍH, m, J = 6.7 Hz, -CH (CH3) 2), 2. 34 (2H, d, J = 4.7 Hz, H-6 '), 1.31 (6H, s, 2 x -CH3), 1.31 (6H, d, J = 6.6 Hz, -CH (CH3) 2. 4 - [(E) - (5,6-Dihydro-5,5-dimethyl-8- (1-meth i 1-1-ethano-thio) -2-naphthalenyl) ethenylbenzoic acid.

It was saponified methyl 4- ((E) - (5,6-dihydro-5,5-dimethyl-8- (1-methyl-l-ethano-thio) -2-naphthalenyl) ethenyl] benzoate (0.729 g, 1.857 mmol) as described in Example 1 and gave the title material (0.675 g, 96%) as a white solid.

IR (KBr)? Max (cm "1): 3435, 2957, 1682 (C = 0), 1603.? H NMR 400 MHz (DMSO-d6) d (ppm): 7.93 (2H, d, J = 8.4 Hz , H-2 and H-6), 7.84 (H, d, J = 1.6 Hz, H-1 '), 7.73 (2 H, d, J = 8.4 Hz, H-3 and H-5), 7.59 (H , dd, J = 8.0 and 1.6 Hz, H-3 '), 7.47 (HH, d, J = 16.4 Hz, vinyl H), 7.38 (HH, d, J = 8.0 Hz, H-4'), 7.25 ( 1H, d, J = 16.4 Hz, vinyl H), 6.34 (IH, t, J = 4.7 Hz, H-7 '), 3.21 (IH, m, J = 6.6 Hz, -CH (Me) 2), 2.30 (2H, d, J = 4.7 Hz, H-6 '), 1.25 (6H, s, 2 x -CH3), 1.24 (6H, d, J = 6.5 Hz, -CH (CH3) 2) MS: 377.07 (MH) ".

Analysis calculated for C24H26? 2S: C76.15; H6.92. Found: C75.89; H6.50.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (6)

Claims
1. A retinoid compound of formula I or a pharmaceutically acceptable non-toxic salt, physiologically hydrolysable ester or solvate of the same
2. A retinoid compound of formula II II or a pharmaceutically acceptable non-toxic salt, physiologically hydrolysable ester or solvate of the same
3. 3. A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of the retinoid compound of claim 1, and a pharmaceutically acceptable carrier or excipient.
4. 4. The pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of the retinoid compound of claim 2, and a pharmaceutically acceptable carrier or excipient.
5. 5. A method for inhibiting the growth of a tumor in a host mammal, characterized in that it comprises administering to said host an inhibitory amount of tumor growth of the compound of claim 1.
6. 6. A method for inhibiting the growth of a tumor in a host mammal, characterized in that it comprises administering to said host an inhibitory amount of tumor growth of the compound of claim 2.