MXPA99000418A - Adamantile derivatives that induce apoptosis and its use as anti-can agents - Google Patents

Abstract

The present invention relates to retinoid compounds that contain adamantyl group derivatives or specific adamantyls induce apoptosis of cancer cells. These adamantyl derivatives are used for the treatment of many types of cancer and solid tumors, especially androgen-independent prostate cancer, skin cancer, pancreatic carcinomas, colon cancer, melanoma, ovarian cancer, liver cancer, lung carcinoma of small cells, non-small cell lung carcinoma, cervical carcinoma, brain cancer, bladder cancer, breast cancer, neuroblastoma / glioblastoma, and leukemia. Also, the invention relates to novel compounds derived from the adamathyl group or novel adamantyls which are used as active agents for the treatment or prevention of alteration of queritization and other dermatological conditions, and other conditions.

Description

ADAMANTILE DERIVATIVES THAT INDUCE APOPTOSIS AND ITS USE AS ANTI-CANCER AGENTS • FIELD OF THE INVENTION The invention relates to the discovery that the specific adamantyl or adamantyl group derivative That contains compounds related to retinoid induces apoptosis of cancer cells and by. therefore, it can be used for the treatment of cancer, including advanced cancers. Also, the present invention relates to novel antilhas or derivatives of adamantyl group containing compounds related to the retinoid and its use for the treatment and / or prevention of cancer, keratinization disorders, dermatological conditions and other therapies.

BACKGROUND OF THE INVENTION Solid tumors are the cause that lead to death attributable to global cancers. Methods conventional cancer treatments include REF .: 29277 surgical treatments, the administration of chemotherapeutic agents, and recently immune-based treatments which typically involve the administration of an antibody or antibody fragment which can be conjugated to a therapeutic moiety such as a radionuclide. However, to date, such treatments have been of limited results. Surgical treatments are generally successful only if the cancer is detected in an early state, that is, before the cancer infiltrates larger organisms and surgery is not feasible. The chemotherapeutic treatments available today are also of limited utility due to their toxicity of their and / or non-selective death of most cell types. Also, many tumor cells eventually become resistant against the chemotherapeutic agent, in addition, making treatment of solid tumors and other non-feasible tumors. For example, people treated with cisplatin often develop tumors which are resistant to cisplatin. Immune-based treatments are also subject to numerous problems including difficulty in targeting antibodies to desired sites, eg, solid tumors, and immune responses to the host to the antibody administered, attributable to the fact that to date, most of the Therapeutic antibodies have been of murine origin. The use of retinoids for the prevention of cancer has also been reported. In contrast, for the majority of the chemotherapeutic agents, the retinoid function via specific transduction signal pathway, activates the defined receptors in the cell nuclei. The receptors, RARs, and RXRs link to specific DNA sequences, retinoic acid response elements, or RAREs. In addition, retinoids interact with other transcription factors, particularly the activator of protein-1 (AP-1). It is believed that the selective action of certain synthetic retinoids is based on the ability of these molecules to selectively activate subclasses of RARs and / or RXRs in the context of specific DNA sequences and / or proteins. Due to this specificity, not all retinoids have the same activities. In fact, thousands of different retinoids have been synthesized for the purpose of identifying retinoids that have optimal therapeutic activity. To date, most retinoids have been found to inhibit tumor progression or cell proliferation of certain cancers, but they do not directly kill cancer cells. Consequently, retinoids have been predominantly considered for cancer prevention but not for direct treatment. A special class of retinoids or compounds related to retinoids comprise adamantyl retinoid derivatives. These compounds are heterocyclic aromatic retinoids which contain an adamantyl group or an adamantyl group derivative. In contrast to normal retinoids such as retinoic acid (all -trans, 9-cis, or 13-cis) and their synthetic analogs and derivatives, the adamantyl retinoid derivatives exhibit increased activity against both specific tumor cells in vi tro or in vivo. Retinoids also comprise the known use in the treatment of keratinization alteration and other dermatological conditions. For example, the use of retinoic acid, vitamin D or analogs thereof for the topical treatment of various dermatological conditions and in the cosmetic field is well known. However, the large number of retinoids which have been reported is not supported, the identification of retinoids or compounds related to retinoids having increased properties, in particular the increased therapeutic activity, constitutes a significant need in the art.

BRIEF DESCRIPTION AND OBJECTS OF THE INVENTION It is an object of the invention to identify specific retinoids or compounds related to retinoids that have increased properties, in particular anti-cancer activity. It is a more specific object of the invention to identify specific classes of adamantyl or compounds related to retinoids containing adamantyl derivatives having anti-cancer activity, preferably characterized by the ability to induce apoptosis of cancer cells. It is an even more specific object of the invention to use compounds related to adamantyl retinoids of the following formulas for the treatment of cancer: with the provision that such a compound is not a specific receptor agonist ligand RAR-? (defined infra) and, in which W is independently -CH2-, -O-, -S-, -SO- or -S02-, X is a radical selected from the following formulas (i) - (iii) ): where Y is a radical -CO-V-, -CH = CH-, -CH3C = CH- - ' V is an oxygen atom (-0), an aza radical (-NH-), a radical -CH = CH- or -C = C-; Z is a radical -CH- and Z 'is an oxygen atom, or Z is a nitrogen atom (N) and Z' is an aza radical (-NH-); Ri is a hydrogen atom, a halogen, or a lower alkyl radical; R'i is a hydrogen atom, a halogen, or a lower alkyl radical; R2 is a hydroxyl radical, a halogen, an alkyl radical, optionally substituted by one or more hydroxyl or acyl groups, an alkoxyl radical, optionally substituted by one or more hydroxyls, alkoxy or aminocarbonyl groups, and / or optionally interrupted by one or more oxygen atoms, an acyl radical, an aminocarbonyl radical or a halogen; R3 is a hydrogen atom, a halogen, a hydroxyl radical, an alkenyl radical, or an alkoxy radical; R2 and 3 can together form a radical -0-CH2-0-; R 4 is a hydrogen atom, an alkyl radical, an alkoxy radical or a halogen; R5 is a radical -CO-R10, an alkyl radical, optionally substituted by one or more hydroxyl groups, or a halogen; R6 is a hydrogen atom, a halogen atom, an alkoxy radical or a hydroxyl group; R7 is a hydrogen atom or a halogen; R8 is a hydrogen atom, a halogen atom or an alkyl radical; R9 is a hydrogen atom, a hydroxyl radical or a halogen atom; Rio is a hydroxyl radical, an alkoxy radical, a radical of formula -Nr'r ", wherein rr and r" represent a hydrogen atom, an optionally substituted aminoalguyl radical, a mono or polyhydroxyalogyl radical, an optionally substituted aryl radical or a amino acid or sugar residue or alternatively, taken together, they form a heterocycle; or a compound having the following generic formula (III): wherein R'i, Ri, R2, R3 / / s Re and W are as defined for the compounds of formula (I); or a compound that has the generic formula: wherein R'i, Ri, R2, R3 / R / s / T, R7 and W are as defined for the compounds of formula (I). For compounds having the formula IV, R6 is preferably not hydrogen. It is a further object of the invention to provide novel classes of adamantyl and retinoids containing adamantyl derivatives having desirable cosmetic and / or pharmacological properties. It is a more specific object of the invention to provide novel classes of adamantyl and retinoids containing adamantyl derivatives having desirable cosmetic and / or pharmacological properties, having the formula set forth below: wherein independently is -CH2-, -0-, -S-, -SO- or -S02-, X is a radical selected from those of the following formulas (i) - (iii) where Y is a radical -CO-V-, -CH = CH-, -CH3C = CH- V is an oxygen atom (-0), an aza radical (-NH-), a radical -CH = CH- or -C = C-; Z is a radical -CH- and Z 'is an oxygen atom, or Z is a nitrogen atom (N) and Z' is an aza radical (-NH-); Ri is a hydrogen atom, a halogen, or a lower alkenyl radical; R 'i is a hydrogen atom, a halogen, or a lower alkenyl radical; R2 is a hydroxyl radical, a halogen atom, an alkenyl radical, optionally substituted by one or more hydroxyl or acyl groups, an alkoxyl radical, optionally substituted by one or more hydroxyl, alkoxy or groups. aminocarbonyl, and / or optionally interrupted by one or more oxygen atoms, an acyl radical, an aminocarbonyl radical .. or a halogen; R3 is a hydrogen atom, a halogen, a hydroxyl radical, an alkyl radical, or an alkoxy radical; R2 and R can together form a radical -0-CH2-0-; R 4 is a hydrogen atom, an alkyl radical, an alkoxy radical or a halogen; R5 is a radical -CO-Ro, an alkyl radical, optionally substituted by one or more hydroxyl groups, or a halogen; R6 is a hydrogen atom, a halogen atom, an alkoxy radical or a hydroxyl group; R7 is a hydrogen atom or a halogen; R8 is "a hydrogen atom, a halogen atom or an alkyl radical, Rg is a hydrogen atom, a hydroxyl radical or a halogen atom, Rio is a hydroxyl radical, an alkoxy radical, a radical of formula -Nr ' r ", wherein r 'and r" represent a hydrogen atom, an optionally substituted aminoalkyl radical, a mono or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid or sugar residue or alternatively, taken together, form a heterocycle, its pharmaceutically acceptable salts, their optical and / or geometric isomers thereof, with the proviso that at least two of R2, R3 and R4 can not be hydrogen and the additional provision that R2 and R3 can not together form -0-CH2- 0- or is a compound of the general formula (I); where V, W, Ri ', Ri, R2, R3, R4, R5 / e, R ?, R8. Rg, Rio, XY, Z ', Z are as defined above, with the proviso that at least one of _ is -0-, -S-, -SO-, or -S02-, and / or at least one of Ri and Ri 'is halogen or a lower alkyl radical, and more preferably at least one W is -O- and / or Ri is a lower alkyl radical and / or Ri' is a lower alkyl radical; or is a compound of the generic formula (I); where V, W, Ri ', Ri, R2, R3, R4, R5, Re R ?, Rß / Rg / Rio, XY, Z', and Z are as defined above, with the proviso that R5 is - CO-Rio and Rio is a radical of formula -Nr'r ", wherein one of r 'and r" is hydrogen, and the other is an optionally substituted aminoalkyl radical or alternatively r' and r ", together, form a heterocycle, preferably a piperazine or a homologue thereof, wherein preferably X has the formula (ii) and / or R8 is preferably hydrogen and / or Rg is preferably hydrogen, or is a compound of the formula (III): wherein R'i, Ri, R2, R3 / RRs / Rd and W are as defined for the compounds of formula (I). It is another object of the invention to provide therapeutic and / or cosmetic compositions containing such novel retinoid compounds. It is a further object of the invention to provide therapeutic / prophylactic / cosmetic methods involving the administration of a new adamantyl compound or adamantyl derivative according to the invention. Such methods will include known uses of retinoid compounds, in particular, use for the treatment / prophylaxis of keratolytic associated disorders associated with differentiation and / or proliferation and other skin-related disorders.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 compares the activity of adamantyl retinoids selected according to the invention and all-trans-retinoic acid against human cancer cell lines. Figure 2 compares the activity of adamantyl retinoids selected according to the invention and all trans retinoic acid against a non-small cell line of human lung carcinoma. Figure 3 compares the activity of adamantyl retinoids selected according to the invention and all trans retinoic acid against in prostate adenocarcinoma, human metastatic prostate adenocarcinoma and human prostate carcinoma cell lines. Figure 4 compares the activity of adamantyl retinoids selected according to the invention and all trans retinoic acid against a human liver cell line. Figure 5 shows the effect of 6- [3-1 (1-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid in a human pancreatic cancer BxP-3 animal model.

DETAILED DESCRIPTION OF THE INVENTION Until the end, totally surprising, it has been discovered that the derivatives of specific adamantyl retinoids induce the apoptosis of cancer cells. This is highly unexpected in contrast to most conventional chemotherapeutic agents, the retinoids and also the adamantyl retinoids mostly known, work via a path of specific transduction signal, activating the defined receptors in the cell nuclei. In contrast, it has been unexpectedly discovered that specific adamantyl retinoid derivatives which are described infra induce apoptosis of cancer cells and therefore can be used to eradicate cancer cells. Consequently, these retinoids can be used for the direct treatment of cancers, including advanced cancers.

More specifically, the present invention relates to the use of adamantyl retinoid derivatives having the following formula (I) to induce apoptosis: wherein W is independently -CH2, -O-, -S-, -SO-, or -S02-, X is a radical selected from those of the following formulas (i) - (iii) • where Y is a radical -CO-V-, -CH = CH-, -CH3C = CH-, V is an oxygen atom (-0), an aza radical (-NH-), a radical -CH = CH- or -C = C-; Z is a radical -CH- and Z 'is an oxygen atom, or Z is a nitrogen atom (N) and Z' is an aza radical (-NH-); Ri is a hydrogen atom, a halogen atom, or a lower alkyl radical; R 'i is a hydrogen atom, a halogen, or a lower alkyl radical; R2 is a hydroxyl radical, a halogen atom, an alkyl radical, optionally substituted by one or more hydroxyl or acyl groups, an alkoxyl radical, optionally substituted by one or more hydroxyls, alkoxyl or aminocarbonyl groups, and / or optionally interrupted by one or more oxygen atoms, an acyl radical, an aminocarbonyl radical or a halogen; • R3 is a hydrogen atom, a halogen, a hydroxyl radical, an alkyl radical, or an alkoxy radical; R2 and R3 can together form a radical -O-CH2-O-; R 4 is a hydrogen atom, a halogen atom, an alkyl radical, or an alkoxy radical; R5 is a radical -CO-R10, an alkyl radical, optionally substituted by one or more hydroxyl groups; R6 is a hydrogen atom, a halogen atom, preferably fluorine, an alkoxyl radical or a hydroxyl group; R7 is a hydrogen atom or a halogen atom, preferably a fluorine atom; Rs is a hydrogen atom, a halogen atom or an alkyl radical; Rg is a hydrogen atom, a halogen atom or a hydroxyl radical; Rio is a hydroxyl radical, an alkoxy radical, a radical of formula -Nr'r ", wherein r 'and r" represent a hydrogen atom, an optionally substituted aminoalkyl radical, a mono or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid or residue of sugars or alternatively, taken together, form a heterocycle, its pharmaceutically acceptable salts, or its optical and / or geometric isomers thereof, with the proviso that such compounds do not include the agonist ligands of the specific receptor RAR-? . For agonist ligands of the specific receptor RAR-? In the subject application, ligands are tried which have a dissociation constant for ligands of the type RAR-to which are at least 10 times larger than the dissociation constant of these ligands for RAR-? Type receptors and wherein such ligands further induce the differentiation of F9 cells. All trans-retinoic acid and certain analogs thereof are known to be capable of inducing the differentiation of F9 cells from tetracarcinic to embryonic cultured in the presence of agonists of the RAR receptors. Also, the secretion of the plasminogen activator is known to accompany this differentiation and is an indicator of the biological response of these cells to retinoids (see Skin Pharmacol., 3: 256-267 (1994)). Methods for measuring these dissociation constants are known in the art. For example, suitable methods are described in the following references which are incorporated by reference. "Selective Synthetic Ligands for Nucleic Retinal Acid Receptor Subtypes", in Retinoids, Progress in Research and Clinical Applications, Chapter 19 (pages 261-267), Marcer Dekker Inc., edited by María A. Livrea and Lester Packer; "Synthetic Retinoids: Receptor Selectivity and Biological Activiy", in Pharmacol. Skin, Basal, Karger, 1993, Vol. 5: 117-127; "Selective Synthetic Ligands for huan Nuclear Retinoic Acid Receptors", in Skin Pharmacol., Vol. 5: 57-65 (1992); "Identification of Synthetic Retinoids with Selectivity for Human Nuclear Retinoic Acid Receptor-?", In Biochemical and Biophysical Research Communications, Vol. 186, No. 2, July 1992, pages 977-983; and "Selective High Affinity RAR-a or RAR-ß Retinoic Acid Receptor Ligands", in Molecular Pharmacology, Vol. 40: 556-562. See also WO 97/13505, which describes methods for the identification of RAR-? Agonist ligands. More preferably, the apoptosis-inducing derivatives of formula (I) will have the formula (II): wherein W, X, Ri, R'i, R2, Rs and R4 are defined above, and wherein such compounds do not include RAR-? ligands agonists of the specific receptor. In a preferred embodiment, at least two of the radicals W are -CH2-. Even more preferably all. radicals W are -CH2-.

In other preferred embodiments, at least one of Ri and Ri 'is a hydrogen atom. Still, more preferably, Ri and R2, are both hydrogen atoms. According to the invention, the lower alkyl radicals refer to a radical having from 1 to 6 carbon atoms, especially the methyl, ethyl, pr, isopr, butyl, tert-butyl and hexyl radicals. Alkyl radicals refer to a radical having from 1 to 20 carbon atoms, straight or branched chain, especially the methyl, ethyl, pr, isopr, butyl, tert-butyl, hexyl, 2-ethylhexyl, octyl radicals, Dodecyl, hexadecyl and octadecyl. Acyl radicals refer to a radical having from 1 to 20 carbon atoms, straight or straight chain or branched, containing a group CO, such as acetyl or benzoyl. Alkoxy radicals refer to a radical having from 1 to 20 carbon atoms, straight or straight chain or branched, containing an alkoxy group. The sugar residue refers to a residue derived in particular from glucose, galactose or mannose or alternatively from glucuronic acid. The monohydroxyalkyl radical refers to a radical having from 1 to 6 carbon atoms, especially a hydroxymethyl, 2-hydroxyethyl, 2-hydroxypr, 3-hydroxypr, 4-hydroxybutyl, 5-hydroxypentyl or 6-hydroxyhexyl radical. The polyhydroxyalkyl radical refers to a radical having from 3 to 6 carbon atoms and 2 to 5 hydroxyl groups, especially a 2,3-dihydroxypr, 2,3,4-trihydroxybutyl or 2,3,4,5- radical. tetrahydroxypentyl or the pentaerythritol residue The aryl radical refers to a phenyl radical optionally substituted by at least one halogen, a hydroxyl or a nitro functional group The optionally substituted aminoalkyl radical refers to an alkyl radical substituted by an amino residue, the residue Amino can also be substituted by at least one alkyl radical, such as an aminoethyl, methylaminoethyl or dimethylaminoethyl radical The amino acid residue refers to a residue derived from any amino acid, such as lysine, glycine or aspartic acid. refers to a piperidino, morpholino, pyrrolidino, piperazino or homologues thereof, optionally substituted in the 4-position by an alkyl radical of 1 to 6 a carbon atoms or a mono or polyhydroxyalkyl radical as defined above. Some compounds have the above generic formulas and their preparation has been described in the following patents and patent applications incorporated herein in their entirety for reference: U.S. 4,740,519; U.S. 4,920,140; U.S. 5,059,621; U.S. 5,260,295 U.S. 5,428,052; US 4,717,720; U.S. 4,940,696; U.S. 5,183,889; U.S. 5,212,303; U.S. Re 34440; U.S. 4,927,928 U.S. 5,200,550; U.S. 5,332,856; U.S.: 5,468,897; U.S Patent No. 5,547,983; 1992; U. S. 5, 476, 860; U.S. 5,015,758; U.S. 5,183,889; FR 91 05394; French Patent Application No. 95 14260, filed on December 1, 1995; and French patent application No. 95 14261, filed on December 1, 1995. Also, the present invention provides new specific classes of adamantyl retinoid derivatives having the generic formulas set forth below, or their pharmaceutically acceptable salts, or optical and / or geometric isomers thereof, which can induce apoptosis and / or which also comprises other desirable pharmacological properties: wherein R'i, Ri, R 2, R 3, R / X and W are as defined supra, with the proviso that at least two of R 2, R 3 and R 4 are other than hydrogen; and with the additional provision that R2 and R3 can not together form -0-CH2-0-, or generic compounds of formula I, set out below: where W, X, R4, R5, R6, R7, V are as defined above, except with the proviso that at least one of W is -O-, -S-, -SO- or -S02 and / or at least one of Ri and R? F is halogen or a lower alkyl radical, preferably, wherein at least one of W is -O- and / or Ri is a lower alkyl radical and / or Ri 'is a lower alkyl radical, and / or also preferably wherein X comprises formula (ii), and / or R8 is or preferably hydrogen and R5 is -CO-R10; or generic compounds of formula I, set out below: < D where W, X, RX, R1, R2, R3, R4, R5 / Re, R ?, Re, Rg, Rio, Y, V are as defined above, except with the proviso that R5 is -CO-Rio / and Rio is a radical of formula Nr'r ", wherein at least one of r'y r" is hydrogen and the other is an optionally substituted aminoalkyl radical or alternatively r 'and r ", taken together, form a heterocycle, preferably a piperazine or a homologue thereof, preferably wherein X comprises the formula (ii) and / or more preferably Rs is hydrogen and / or Rg is hydrogen .. Also, preferred are the compounds of formula (I) wherein R2 is a radical alkoxy or a hydroxyl group and / or R3 is hydrogen and / or R4 is hydrogen and / or R2 and R3 together form -0-CH2-0-, or compounds of formula (III): where R'i, Ri, R2 R3, R. / R5 and Re and W are as defined supra; A more specific subclass of compounds of the formula (I) comprises compounds of the formula (II) below: wherein R'i, Ri, R2, R3, R4, X and W are as defined above and at least two of R2, R3 and R are not hydrogen, and wherein R2 and R3 can not together form -0-CH2 -0; or compounds of the formula (II) wherein R5 is -CO-R10, Rio is a radical of the formula -Nr'r ", wherein one of r 'and r" is hydrogen and the other is an optionally substituted aminoalkyl radical, or alternatively r 'and r "taken together form a heterocycle, preferably piperazine or a homologue thereof, and wherein preferably Rs is hydrogen and / or Rg is hydrogen, or compounds of formula (II) wherein at least one of Ri and Ri is halogen or a lower alkyl radical, wherein X preferably has the formula (ii), and more preferably R8 is hydrogen and / or Rg is preferably hydrogen and / or R5 is -CO-Rio. Also preferred are compounds of the formula (II) wherein R 2 is an alkoxy radical or a hydroxyl group and / or R 3 is hydrogen and / or R 4 is hydrogen and / or R 2 and R 3 together form -0-CH 2 0. Still further specific subclasses of new compounds related to the retinoids of formula (I) comprise compounds related to adamantyl retinoids which they have the generic formula exposed below. where R2, R3, R4, Rs, R6, Ri, R8, Rg and W are as defined above, with the proviso that at least two of R2, R3 and R4 are other than hydrogen, and with the additional provision of that R2 and R3 can not together form -0-CH2-0-. Preferred compounds of the formula (V) comprise compounds related to the retinoids wherein R5 is a hydroxycarbonyl radical, preferably -CO-R10 and / or compounds wherein R2 is a hydroxyl radical, an alkoxyl radical, and / or R8 is hydrogen , and / or Rg is hydrogen and / or R3 is a hydroxyl radical or an alkoxyl radical, and / or R4 is hydrogen or an alkyl radical. Other preferred compounds of the formula (V) include compounds wherein at least one of W is -0-, -S-, -SO- 0 -S02- and / or at least one of Ri and R '1 is halogen or a lower alkyl radical. The novel retinoid derivatives of the present invention can be synthesized by known methods for the synthesis of retinoids such as those described in the patents and applications incorporated herein by reference. In addition, the specific methods for the synthesis of the retinoids of the formula (V) are described below.

SCHEME I In accordance with Synthetic Scheme I, a halobenzene derivative (1) (see the schematic of Scheme I below) is coupled to a naphthyl halide or to 2-naphthyl trifluoromethanesulfonate (2) to form (3), for example, through the treatment of (1) in dry THF with butyl lithium at -78 ° C followed by zinc chloride, followed by (2) in the presence of nickel dichloride bis (diphenylphosphino) ethane. A tertiary ester or a halide derived from an oxaadamantyl, adamantyl, thiaadamantyl or related molecule of the formula (4) is then reacted with (3) in the presence of 0.1 to 1.3 molar equivalents of an appropriate acid (eg, sulfuric acid) or trifluoromethylsulfonic acid if X 3 is acetoxy or mesyloxy) in a mixed solvent, preferably containing cyclohexane and any heptane, dichloromethane, or 1,2-dichloroethane at a temperature between 25 ° C and 90 ° C. The esters obtained in accordance with the above methods wherein R5 is an ester group can be converted, in accordance with known procedures, into several analogues which are the objects of the meanings for the radical R5. For example, such esters include saponified acids which can be transformed into acid chlorides which are easily converted into amides. Alternatively, such amides can be obtained as described above. However, the reduction of the esters, aldehydes or amides by an appropriate reducing agent (for example lithium aluminohydride) also allows the production of the corresponding alcohols and amines. The synthetic method subjected is especially preferred if R2 is an alkoxy or hydroxy group and R5, R8 and Rg are not strongly electron donating groups such as alkoxy, hydroxy or alkanoy, and all functionalities are preferably R'i, Ri, and W are compatible with butyl lithium or can be used in a protective form that is compatible with butyl lithium.

SCHEME I SCHEME II A second method (Scheme II) for synthesizing the new adamantyl retinoids of formula (V) is shown in Scheme II. This method comprises reacting a tertiary ester or a halide derived from an oxaadamantyl, adamantyl, thiaadamantyl or related molecule of formula (3) with a halobenzene derivative (1) in the presence of 0.1 to 1.3 molar equivalents of an appropriate acid (acid). sulfuric or trifluoromethylsulfonic acid if X3 is acetoxy, hxy or mesyloxy) in a mixed solvent containing cyclohexane and any heptane, dichloromethane, or 1,2-dichloroethane at a temperature between 25 and 90 ° C. The resulting adduct (6) is then coupled to the 2-naphthyl halide or the 2-naphthyl trifluoromethanesulfonate (2) to form (5) for example, through the treatment of (6) in dry THF with butyl lithium a - 78 ° C followed by zinc chloride, followed by (2) in the presence of bis (diphenylphosphino) ethane nickel dichloride. Esters obtained in accordance with the methods described above wherein R5 is an ester group can be converted, in accordance with known procedures, into various analogs, which are provided to be based on the definition of the radical R5 in the generic formula (I) . For example, such esters include saponified acids which can be transformed into acid chlorides which in turn are easily converted into amides. Alternatively, such amides can be obtained by the direct action of amines in esters obtained readily. The reduction of the esters, andehydes or amines by an appropriate reducing agent (eg, lithium aluminohde) also allows the production of the corresponding alcohols and amines. This synthetic scheme is preferred if R5, R8 and / or Rg are strongly electron donor groups such as alkoxy, hxy or alkanoy, and all functionalities are compatible with butyl lithium or can be used in a protective form that is compatible with butyl lithium .

SCHEME II The adamantyl retinoid derivatives subjects identified above which induce apoptosis can be used for the treatment of different types of cancer. Specific examples of cancers treatable with the subject retinoid derivatives include, by way of example, bladder cancer, brain cancer, neck and head cancer, kidney cancer, lung cancers such as small cell lung cancer and lung cancer. non-small cells, myeloma, neuroblastoma / gioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, colon cancer, cervical carcinoma, breast cancer, and leukemias. However, due to its activity that induces apoptosis, the retinoid derivatives of adamantyl subjects are especially well suited for the treatment of solid tumors and advanced cancers which can not be treated by most conventional cancer therapies. In the treatment of cancer, the adamantyl or adamantyl-derived compounds of the present invention can be administered by any pharmaceutically acceptable means eg, systemically, enterally, parenterally or locally. An effective therapeutic dosage will comprise a dosage sufficient to induce apoptosis of cancer cells. This dosage will vary depending on factors such as the condition of the patient to be treated, the specific compound, whether they are used alone or in combination with other therapies, among other factors. In general, an effective dosage will vary from 0.01 mg / kg to 100 mg / kg of body weight, and more preferably 1 mg to 50 mg of body weight, typically administered in the ratio of 1 to 3 dosages per diem. As discussed, the adamantyl retinoid derivatives according to the invention which induce apoptosis are used for the treatment of many different types of cancers. The specific adamantyl retinoid compounds according to the invention which have been demonstrated to exhibit such activities are discussed below. The specific types of cancers in which these compounds have been shown to be active against these are also identified.

LIST OF ACTIVE COMPOUNDS Name of the compound Types of cancers against the active 6- [3- (1-adamantyl) -4- acid Brain, cervical, methoxyphenyl] -2-naphthoic head and neck, leukemia, lymphoma, prostate, skin Carboxylic acid 2- [3- (l- Brain, colon, adamantyl) -4-methoxyphenyl] -5 leukemia, lung, benzimidazole lymphoma, myeloma, ovary, pancreatic, prostate, skin, liver Acid 6- [3- (1- adamantyl) -4- Bladder, brain, hydroxymethyl-phenyl] -2- breast, cervical, naphthenic colon, head and neck, leukemia, kidney, lung, myeloma, ovary, pancreatic, prostate, skin, liver Acid 6- [3- (l-adamantyl) -4- Brain, breast, - \ hydroxy-5-methoxyphenyl] -2- kidney, lung, naphthoic leukemia, lymphoma, myeloma, ovary, pancreatic, prostate, skin, liver Acid 6- [3- ( l-adamantyl) -4- Head and neck, acetoxymethyl-phenyl] -2- leukemia, lung, naphthenic lymphoma, myeloma, pancreatic, skin Acid 6- [3- (1-adamantyl) - Brain, chest, 4, 5-methylenedioxyphenyl] -2- head and neck, naphthenic kidney, leukemia, lung, lymphoma, myeloma, ovary, prostate, skin, liver N-. { 6- [3- (l-adamantyl) -4- Brain, chest, ethoxy-phenyl] -2- head and neck, naphthalenecarboxyl} - myeloma, prostate, piperizide skin 8 Acid 4-. { 3-oxo-3- [3- (l- Brain, breast, adamantyl) -4-methoxyphenyl] -1- leukemia, lung, propinyl Jbenzoic lymphoma, skin, liver 9 Acid 4- [N- (3- (1- adamantyl) - Head and neck, 4-methoxybenzoyl) amido] 2- kidney, ovary, methoxybenzoic skin 10 2- [3- (l-adamantyl) -4- Leukemia, lymphoma, methoxyphenyl] -5- myeloma methylbenzimidazole 11 Acid 6- [3- (1-adamantyl) -4- Brain, chest, (1,2-dihydroxy-ethyl) phenyl] -leukemia, pancreatic 2-naphthoic, skin 12 Acid 6- [3- (1-adamantyl) -4- Head and neck, hydroxy-6-methylphenyl] -2- leukemia, naphthenic pancreatic 13 Acid 6- [3- (1-adamantyl) -4- Brain, head and methoxy-6-methylphenyl] -2- neck, leukemia, naphthenic pancreatic, 14 6- [3- (l-adamantyl) -4- Bladder, kidney, hydroxyphenyl] -2- skin, hydroxymethylnaphthalene 15 Acid 4- [3- (l-adamantyl) -4- Chest, leukemia, methoxybenzyl-oxo] benzoic prostate 16 Acid 2- [3- (l-adamantyl) -4- Brain, breast, methoxyphenyl] -5- prostate, benzofurancarboxylic 17 Methyl ester Acid 6 - Leukemia 3 [- (1-adamantyl) -4-hydroxyphenyl] -2-naphthoic acid 1-methyl ester 1-Lymphoma, liver, methyl-4-hydroxy-6- [3- (1-adamantyl) -4 -methoxyphenyl] -2- naphthoic 19 N-. { 4- [N- (3- (l-adamantyl) -4- Kidney, myeloma, methoxy prostate, benzoyl skin) amido] benzoyl} morpholide 20 4- [3- (1-adamantyl) -4- Lymphoma, methoxybenzoyl-oxo] -2-fluorobenzoic acid 21 Ester of 4-hydroxycarbonyl- Leukemia, 2-fluorophenyl of 3- (1-adamantyl) -4 -methoxy-benzoic acid 22 6- [3- (1-adamantyl) -4- breast, leukemia, ethylphenyl] -2-naphtho myeloma 23 6- [3- (1-adamantyl) -4- breast, leukemia, (3-hydroxy-propoxy) phenyl] -2- lymphoma, naphthoic acid 24-6- [3- (1-adamantyl) -4- Leukemia, aminocarbonyl-phenyl] -2- naphtholic acid 25 N- (4-carboxyphenyl) - 3- (1- lymphoma, adamantyl) -3-oxopropionamide 26 2-hydroxy-4- acid. { 2- [3- (1- Lymphoma, adamantyl) -4-methoxyphenyl] -2- hydroxyethoxy} benzoic Acid (S) -6- [3- (1-Leukemia, adamantyl) -4- (2S, 3-dihydroxypropoxy) phenyl] -2-naphthoic acid 28 (E) of 4. { 3-oxo-3- [3- Leukemia methoxy-4- (1-adamantyl) phenyl] prop-1-enyl} benzoic acid 29 (E) of 4-. { 3-oxo-3- [4- Brain, leukemia, (2-methoxyethoxy-methoxy) -3- (1- lung, lymphoma, adamantyl) phenyl] prop-l-prostate enyl (benzoic acid (E) 4- { 2- [4- (6- Lymphoma, myeloma aminocarbonylpentyl-oxy) -3- (1-adamantyl) phenyl] ethenyl.}. - benzoic acid 31 3- (1-adamantyl) -4-methoxy-N- Leukemia (4-carboxyphenyl) benzamidine 32 Ester 4"-Eryromycin A of Leukemia, 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid lymphoma 33 Leukemia 4-carboxyphenyl ester, 3- (l-adamantyl) acid skin -4- (2, 3- dihydroxyproxy) Benzoic acid 34- [3- (1-adamantyl) -4- Leukemia, skin (2,3-dihydroxypropoxy) phenyl] -2-naphthoic acid 35 N-4-carboxyphenyl of 3- (1-Leukemia), lymphoma, adamantyl) -4- myeloma (methoxycarbonyl) benzamide 36 Acid 6- [3- (l-adamantyl) - Brain, head and 4,5-dihydroxy-phenyl] -2- neck, leukemia, naphthenic lymphoma, myeloma, pancreatic 37 Acid 6- [3- (3-methyl-l- Kidney, leukemia, adamantyl) -4, 5- lung, lymphoma, methylenedioxyphenyl] -2- naphthic skin 38 Acid 6- [3- (2-oxa-l - Leukemia, adamantyl skin) -4,5-methylenedioxyphenyl] -2- naphthoic acid 39- [3- (2-oxa-1-Kidney, lymphoma, adamantyl) -4-methoxy-phenyl] - skin, liver, 2 -naphtolic 40 Acid 6- [3- (2-oxa-3-methyl-l- Bladder, breast, adamantyl) -4-methoxyphenyl] -2- kidney, leukemia, naphthenic lung, lymphoma, ovary, prostate, skin 41 Acid 6- [3- (3-methyl-l Adamantyl skin) -4-methoxyphenyl] -2- naphthoic 42 6- [3- (3,5-dimethyl-l- adamantyl) -4-methoxyphenyl] -2- acid naphthenic 43 Acid 6- [3- (3, 5-dimethyl-l- Prostate, breast, ada antil) -4, 5- neuroblastoma, methylenedioxyphenyl] -2- naphthoic 44 N-. { 6- [3- (l-adamantyl) -4- Bladder, kidney, methoxy-phenyl] -2- epidermal, naphthalenecarboxyl} homoleukemia, lung, piperazide beuroblastoma, hepatoma, cervico, skin. 45 N- (2-aminoethyl) -. { 6- [3- (1- Liver, kidney, adamantyl) -4-methoxyphenyl] -2- prostate, naphthalene-carboxamide] leukemia, chest, lung, neuroblastoma, hepatoma, pancreas, cervix, skin 46 N-. { 6- [3- (l-adamantyl) -4,5- Prostate, methylenedioxy] -2- neuroblastoma, naphthalenecarboxyl} piperazide hepatoma 47 N { 6- [3- (l-adamantyl) -4,5- Bladder, methylenedioxy] -2- neuroblastoma, naphthalenecarboxoyl} homo-cervix, piperazide skin 48 N- (2-aminoethyl) -6. { - [3- (l- Chest, hepatoma, adamantyl) -4, 5- methylenedioxypheni] -2- naphthalenecarboxamide skin} 49 Acid 6- [3- (3-methyl-l- Chest, adamantyl) -4-hydroxyphenyl] - neuroblastoma, 2-naphthalenecarboxylic leukemia As can be seen above, subject adamantyl retinoids exhibit a broad range of activity against numerous different types of cancers. However, the present invention also relates to the use of the specific novel classes of adamantyl retinoid compounds identified above for other therapeutics as well as cosmetic uses. Depending on the nature of the radicals used, the adamantyl subject or adamantyl derivative containing retinoid compounds should exhibit any agonist activity in the assays for the differentiation of embryonic teratocarcinoma cells (F9) in mice (Cancer Research, 43, p.5268 ( 1983) and / or in the assay for the inhibition of ornithine decarboxylase after induction by TPA in mice (Cancer Research, 38., pp. 793-801 (1978)) or, in contrast, an antagonistic activity with respect to to the expression of one or more biological markers in the assay for the differentiation of embryonic teratocarcinoma cells (F9) in mice (Skin Pharmacol., 3, pp. 256-267 (1990)) and / or for the in vitro differentiation of human keratinocytes (Anal. Biochem., 192, pp. 232-236 (1991).) Based on these properties, the new adamantyl or adamantyl derivative containing retinoid compounds according to the invention are well suited in the following entities fields of therapy: (1) for the treatment of dermatological conditions associated with an alteration of keratinization related to differentiation and proliferation, in particular for the treatment of acne vulgaris, comedonic or polymorphic acne, acne rosacea, nodulocístico acne, acne conglobata , senile acne and secondary acnes such as solar, medication or occupational acne. (2) For the treatment of other types of keratinisation disorders, in particular ichthyosis, ichthyosis conditions, Darier's disease, palmoplantar keratoderma, leukoplakia and conditions of leukoplakia or cutaneous lichen or mucosal (oral) forms. (3) For the treatment of other dermatological conditions associated with alterations of keratinization by manifesting an inflammatory and / or immunoallergic component, and in particular, all forms of psoriasis, whether cutaneous, mucous or ungual, and even psoriatic rheumatism, or alternatively skin or atopy of the skin, such as eczema, or respiratory atopy or alternatively gingival hypertropia; the compounds can be used in certain inflammatory conditions exhibiting no alterations of the keratinization; (4) For treatment of all dermal or epidemic proliferations, whether malignant or benign, whether or not of vaginal origin, such as common warts, flat warts and epidermodisplasia verruciformis, oral papillomatous florida and proliferations which can be induced by ultraviolet radiation, in particular in the case of basal cells and epithelioma of needle-shaped cells; (5) For the treatment of other dermatological alterations such as dermatosis bolosa and collagen diseases; (6) For the treatment of certain ophthalmological alterations in particular corneopathies; (7) For the restoration or control of skin aging, either photo-induced or chronological, or for the reduction of actinic geratosis or pigmentation, or any pathology associated with chronological or actinic aging; (8) to prevent or treat the stigma of epidermal and / or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy; (9) to prevent or treat alterations of health, or for the prevention or for the restoration of extended marks; (10) to control alterations of sebaceous function, such as acne hyperseborrhea or simple seborrhea; (11) for the prevention of carcinogenic or precancerous conditions; (12) for the treatment of inflammatory conditions such as arthritis; (13) for the treatment of any condition of viral origin at the cutaneous or general level; (14) for the prevention or treatment of alopecia; (15) for the treatment of dermatological or general conditions that include an immunological component; (16) for the treatment of foods of the cardiovascular system, such as arteriosclerosis, and myocardial infarction; and (17) for the treatment or prevention of osteoporosis. For the therapeutic or pharmaceutical applications mentioned above, the novel compounds according to the invention can be advantageously used in combination with other compounds that exude a retinoid-like activity, with vitamins D or derivatives thereof, with corticosteroids, with compounds with free radicals of control, α-hydroxy or α-keto acids or derivatives thereof, or alternatively with channel-blocking ions. By "vitamins D or derivatives thereof" one tries, for example, vitamin D2 or D3 derivatives and in particular 1,25-dihydroxyvitamin D3. By "compounds with free radicals of control" one tries, for example, α-tocopherol, dismutase superoxide, ubiquinol or certain metal chelating agents. By "a-hydroxy acids or α-keto or derivatives thereof", there is tried, for example, lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acids or salts, amides or esters thereof. By "channel blocking ions" is tried, for example Minoxidil (2-4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof.

The present invention also features characteristic medical compositions containing at least one of the novel adamantyl retinoid compounds identified above, one of its helical or geometric isomers, or one of its pharmaceutically acceptable salts, or other derivatives thereof. The pharmaceutical / therapeutic compositions of the present invention, especially intended for the treatment of the disease conditions mentioned above, comprise a pharmaceutically acceptable carrier, a carrier or diluent which is compatible with the mode or administration regime selected for the given composition and at least one novel adamantyl compound according to the invention or one of its helical or geometric isomers, or a pharmaceutically acceptable salt thereof. The administration of the compounds according to the invention can be carried out by any suitable means of administration, for example, systemically, enterally, parenterally, topically or ocularly. For enteral administration, the pharmaceutical / medicinal compositions may be in the form of tablets, hard gelatin capsules, dragees, syrups, suspensions, solutions, elixirs, powders, granules, emulsions or lipid or polymer microspheres or nanospheres or vehicles which allow a controlled release. For parenteral administration, the compositions may be in the form of solutions or suspensions for perfusion or injection. Effective dosages of a novel retinoid compound according to the invention in the therapies identified above can be determined by well-known methods. In general, the compounds according to the invention are administered at a daily dosage of about 0.01 mg / kg to 100 mg / kg of body weight, and at a ratio or regimen of 1 to 3 doses per diem. For topical administration, pharmaceutical compositions based on novel compounds according to the invention are more particularly intended to treat the skin and mucous membranes and can then be provided in the form of ointments, creams, milks, balms, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be provided in the form of polymeric vehicles or lipids or nanospheres or microspheres or polymeric patches and hydrogels which allow for controlled release. These compositions for topical administration may, however, be provided in either anhydride or in an aqueous form, in accordance with clinical indications For ocular administration, they are mainly ocular washes.These compositions for topical or ocular application contain at least one novel adamantyl retinoid according to the invention, or one of its optical isomers or or, alternatively one of their salts, at a concentration preferably in the range of 0.001% to 5% by weight relative to the total weight of the composition.As discussed, the novel adamantyl compounds according to the invention also find application in the cosmetic field, in particular for the care and hygiene of the cu hair and hair, and especially for the treatment of skin that tend to develop acne, for the rebirth of the hair and combat the loss thereof, to combat the appearance of skin or hair grease, for protection against the effects deleterious to sunlight or in the treatment of physiologically dry skin, and to prevent and / or to control photoinduced or chronological aging.

For cosmetic applications, the novel compounds according to the invention can, however, be advantageously used in combination with other compounds which exhibit a retinoid-like activity, with vitamin D or derivatives thereof, with corticosteroids, with compounds in which the radicals are free of control, with α-hydroxy or α-keto acids or derivatives thereof, or alternatively with channel-blocking ions, all of these various active agents are as defined above. The invention therefore also features characteristic cosmetic compositions comprising a cosmetically acceptable vehicle, a carrier or a diluent which is suitable for topical application, at least one of the novel adamantyl retinoid compounds identified above or one of its geometric or helical isomers , or one of its salts, etc. Such cosmetic compositions are advantageously in the form of a cream, milk, lotion, ointment, gel, polymeric carriers or lipids or nanospheres or microspheres, soaps or shampoos. The concentration of the retinoid compound in the cosmetic compositions according to the invention is advantageously in the ranges of 0.001% and 3% by weight relative to the total weight of the composition.

The cosmetic and medicinal compositions according to the invention can, in addition, contain inert or even pharmacodynamically or cosmetically active additives or combinations of these additives, and especially: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; moisturizing or wetting agents such as glycerol, PEG 400, thiamorpholinone and its derivatives or alternatively urea; anti-seborrhoeic or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, its salts or derivatives thereof, or bezoyl peroxide; antibiotics such as erythromycin and esters thereof, neomycin, clindamycin and esters thereof, or tetracyclines; anti-fungal agent, such as ketoconazole or 4,5-polymethylene-3-isothiazolidones; Hair renaissance promoting agents, such as Minoxidil (2, 4-diamino-6-piperidino-pyrimidino-3-oxide) and derivatives thereof, Diazoxide (1,1-chloro-3-methyl-1,2,4-benzothiadiazine) and phenytoin (5,5-diphenylimidazolidine-2,4-dione); non-steroidal anti-inflammatory agents; carotenoids and especially β-carotene; anti-psoriatic agents such as anthralin and its derivatives; and finally, eicosa-5, 8, 11, 14-tetranoic and eicosa-5, 8, 11, triinoic acids, and esters and amides thereof.

The compositions according to the invention may also contain preservative-enhancing agents such as para-hydroxybenzoic acid esters, stabilizing agents, moisture regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifying agents, UV-A and UV-B protective agents and antioxidant agents such as α-tocopherol, butylated hydroxyanisole or butylated hydroxytoluene. In order to further illustrate the present invention and the advantages thereof, the following specific examples are given, it being understood that they are intended only as illustrative and not in a limiting manner.

EXAMPLES The following examples relate to the synthesis of compounds related to specific adamantyl retinoids. All initiator materials were obtained from Aldrich Chemical Company, except for 6- (4-methoxyphenyl) -naphthalic acid methyl ester (which was synthesized in accordance with U.S. Patent 5,015,758) and 3-methyl-2-oxa -l-adamantol (which was synthesized in accordance with Stetter, Chemische Berichte, 99, p.1435 (1966)).

"EXAMPLE 1 Synthesis of 2-oxa-l-adamantol 386. 6 mg (2.54 moles) of bicyclo [3.3.1] nonane-3,7-dione were dissolved in 5 ml of methanol and treated with sodium borohydride (100 mg, 2.64 mmol) at 0 ° C for 2 hours. The solution was treated with 5 mL of saturated aqueous sodium bicarbonate for 1 hour at 25 ° C and extracted with 3 x 10 mL portions of chloroform. The combined chloroform extracts were combined, dried over sodium sulfate, removed from the solvent in vacuo, and purified by column chromatography (silica, eluent = 50% hexanes, 50% ethyl acetate) yield 343 mg (88%). %) of the desired product. 1HI_MN (CDC13, 500 Mhz): d 1,563 (d, 2H), 1.70-1.76 (m, ÍH), 1,788 (d, 2H, J = ll.l Hz), 1,839 (d, 2H, J = 13.1 Hz) , 1,925 (d, 2H, J = 13.0 Hz), 2,310 (s, 2H), 2,690 (s, ÍH), 4,283 (s, ÍH).

EXAMPLE 2 Synthesis of 3-methyl-l-adamantyl acetate 121 mg (0.728 mmol) of 3-methyl-1-adamantol are dissolved in 0.2 mL of n-heptane and 0.2 mL of cyclohexane. A mixture of 0.2 mL (2.55 moles) of acetic anhydride and 2 microliters (0.036 mmol) of concentrated sulfuric acid is added, and the mixture is stirred at room temperature for 20.5 hours. The solution is dissolved in 10 L of the ether and extracted with 10 L of water. The aqueous layer is extracted with 10 mL of ester. The ether layers are combined, extracted with 2 x mL of water followed by 40 L of aqueous sodium bicarbonate (10 g / liter), dried over magnesium sulfate, and separated from the solvent in vacuo. The product is a colorless oil with Rf 0.55 (silica: 75% eluent hexane, 25% ethyl acetate).

EXAMPLE 3 Synthesis of 3,5-dimethyl-l-adamantyl acetate 2.486 (10.2 mmoles) of 3,5-dimethyl-1-bromoadantane is refluxed for 16 hours with 2.034 g (20.7 mmoles) of potassium acetate in 10 L of acetic acid. The solution is poured on 100 grams of ice, allowing to mix it and extract it with 3 x 10 mL of diethyl ether. The combined ether extracts are washed with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride, then dried over sodium sulfate. The solvent is removed under vacuum, obtaining 1,521 (67%) of the desired product, a colorless oil. TLC: Rf = 0-68 (silica plate: eluent 90% hexanes, 10% ethyl acetate). 1HNMR (CDC13, 500 Mhz): 0.858 (s, 6H), 1115 (d, 2H, J = 12.4 Hz), 1177 (d, 2H, J = 12.4 Hz), 1260 (d, 2H, J = 12.3 Hz), 1367 (d, 2H, J = 12.3 Hz), 1.714 (d, 2H, J = 11.6 Hz), 1766 (d, 2H, J = 11.6 Hz), 1.939 (s, 2H), 1976 (s, 3H), 2,191 (m, ÍH).

EXAMPLE 4 Synthesis of 2-oxa-l-adamantyl mesylate 340 mg (2.21 mmol) of 2-oza-1-adamantol (see Example 1) and 20 mg (0.163 mmol) of 4-dimethylamino-pyridine are dissolved in 5 mL of dry pyridine under argon at -40 ° C. A suspension of 565 mg (3.25 mmol) of methanesulfonic anhydride in 8 mL of dry pyridine are added at -40 ° C. The rest of the methanesulfonic anhydride was added to the reaction flask. The mixture is stirred at 0 ° C, and allowed to warm to 25 ° C for 18 hours. After removing the solvent in vacuo, the residue was dissolved in 20 mL of dichloromethane, washed with 10 mL of water and dried to obtain 512 mg (100%) of the desired product. Rf = .50 (50% ethyl acetate in hexanes). 1HNRM (CDC13, 500 Mhz): d 1594 (d, 2H, J = 13.0 Hz), 1.76-1.86 (m, 2H), 2.010 (d, 4H, J = 12.5 Hz), 2.330 (d, 2H, J = 11.9 Hz), 2.380 (s, 2H), 3148 (s, 3H), 4.439 (s, ÍH).

EXAMPLE 5 Synthesis of 3-methyl-2-oxa-l-adamantyl mesylate A mixture of 230 mg (1.37 mmol) of 3-methyl-2-oxa-1-adamantol, 20 mg (0.163 mmol) of 4-dimethyl-aminopyridine, and 350 mg (2.0 mmol) of methanesulfonic anhydride is treated with 10 mL of pyridine under argon at -40 ° C. The reaction mixture is warmed to 0 ° C and left to gradually warm to 25 ° C for 13 hours. The solvent is removed in vacuo, and the residue is dissolved in 20 mL of dichloromethane, washed with 10 mL of water, dried over sodium sulfate, and removed from the solvent in vacuo, obtaining 341 mg of crude product (approximately 95%). % pure). TLC: Rf = 0.75 (Silica: 50% hexanes, 50% ethyl acetate).

EXAMPLE 6 Synthesis of 6- (3,4-methylenedioxyphenyl) -2-naphthoic acid methyl ester.

Magnesium returns (1.48 g, 61 mmol) were placed in a 250 mL three neck flask attached to a reflux condenser. The flask was evacuated under vacuum with a heat gun. Argon and dry THF (100 mL) are introduced. 5-Bromo-l, 3-benzodioxole (6.0 L, 10.0 g, -49.8 mmol) is added and the mixture is heated to 80 ° C in an oil bath, a few minutes after the reaction is started and the mixture is subjected to reflux for 3 hours. A portion of such Grignard solution (50 mL, 24.9 mmol) is added in a solution of anhydrous zinc chloride (3.46 g, 24.9 mmol) in dry THF (40 mL) and the resulting mixture is stirred for 30 minutes at room temperature. .

The zinc organ solution is transferred into a flask containing dichloronickel (II) of 1-bis (diphenylphosphono) ethane (400 mg) and methyl 6-bromo-2-naphthoate (5.23 g, 19.9 mmol) in dry THF (40 mL). The reaction solution is stirred at room temperature for 18 hours. Water is added (150 ml) and the whole is extracted with ethyl acetate (200 ml). After drying over anhydrous sodium sulfate, concentration and recrystallization (heptane and dichloromethane) gave the desired product (3.25 g, 53%). P.F. 147-149 ° C.

EXAMPLE 7 Synthesis of 6- [3- (3,5-dimethyl-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid methyl ester 121 mg (0.54 moles) of the ester obtained in the Example 3 and 147.5 mg (0.505 mmol) of 6- (4-methoxyphenyl) naphthoic acid methyl ester were dissolved in a mixture of 0.4 mL of cyclohexane and 1 mL of 1, 2-dichloroethane. While stirring vigorously, concentrated sulfuric acid (15 microliters, 0.27 mmol) was added. The mixture was heated at 75 ° C for 5 hours while stirring and stirred at 25 ° C for 28 days. The solvent was removed in vacuo, and the material was purified by column chromatography on silica using toluene as an eluent, obtaining 157 mg (68%) of the desired product. P.F. = 143-147 ° C.

EXAMPLE 8 Synthesis of 6- [3- (3-methyl-1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid methyl ester. 36. 4 mg (0.175 mmol) of the ester obtained in the Example 2 and 51 mg (0.175 mmol) of 6- (4-methoxyphenyl) naphthoic acid methyl ester were dissolved in a mixture of 0.14 L of cyclohexane and 0.35 mL of 1,2-dichloroethane. While stirring vigorously, concentrated sulfuric acid (5 microliters, 0.09 mmol) was added. The mixture is stirred at 90 ° C for 14 hours and at 25 ° C for 24 hours. The solvent is removed in vacuo, and the material is purified by column chromatography on silica using toluene as the eluent, obtaining 15.8 mg (20.5%) of the desired product. P.F. = 146-147 ° C.

EXAMPLE 9 Synthesis of 6- [3- (2-oxa-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid methyl ester 142 mg (0.61 moles) of 2-oxa-l-adamantyl mesylate (from Example 4) and 137.5 mg (0.47 mmoles) of the 6- (4-methoxyphenyl) naphthoic acid methyl ester are dissolved in 2 mL of dichloromethane and 0.2 mL of cyclohexane. 80 microliters (0.9 moles) of concentrated trifluorosulfonic acid are added. The mixture is stirred for 90 hours, dissolved in 25 L of dichloromethane, filtered and adsorbed on 2 grams of silica. The compound is purified by column chromatography on silica using toluene as the eluent, obtaining 32.3 mg (16%) of the desired product. TLC: Rf = 0.12 (silica plate: eluent = toluene). 1HNMR CDC13, 500 MHz): 1.709 d, 2H J = 12.3 Hz) 1.'817 d, 2H J = 12.3 Hz) 1.92652 (d, ÍH J = 12.7 Hz) 1.996 d, ÍH, J = 12._ 5 Hz ) 2.099 d, 2H v J = 12. .2 Hz) 2,217 S / 2H) 2,706 d, 2H t J = 12. .7 Hz) 3,886 s, 3H) 3,986 s, 3h) 4,379 s, ÍH) 6,988 d, ÍH, J = 8. .4 Hz) 7,577 dd, ÍH. , Jl = -8, .4 Hz, J2 = 2.2 Hz) 7.849 d, ÍH, J = 7. .8 Hz) 7.919 d, ÍH, J = 8. .7 Hz) 7.971 d, ÍH, J = 8. .7 Hz) 8,954 dd,. ÍH. , Jl = = 11.1 Hz, J2 = l. 6 Hz) 8.076 s, ÍH) 8.079 s, ÍH) 8,600 s, ÍH) EXAMPLE 10 Synthesis of 6- [3- (2-oxa-3-methyl-1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid methyl ester 76. 2 mg (0.26 mmol) of the 6- (4-methoxyphenyl) naphthoic acid methyl ester and 61.3 mg (0.25 mmol) of the mesylate obtained in Example 5 are suspended in a mixture of 0.85 L of 1,2-dichloroethane and 80 microliters. of cilcohexane. 30 microliters of the concentrated trifluorosulfonic acid (0.339 mmol) are added, and the suspension is stirred at 25 ° C for 5 days. The product is purified using preparative TLC on silica plates with toluene as the eluent, obtaining 4.5 mg (4%) of the desired product. TLC: Rf = 0.38 (silica plate: eluent = toluene). 1HNMR (DMSO-d6, 500 Mhz) 1,763 (s, 4H9, 2,074 (s, 3H), 2,140 (s, 5H), 2,539 (s, 3H), 3,872 (s, 3h), 3,924 (s, 3H), 7,128 (d, 1H, J = 3.5 Hz), 7,584 (d, ÍH, J = 1.8 Hz), 7,664 (dd, ÍH, Jl = 1.7 Hz), J2 = 8.7 Hz), 7,914 (dd, ÍH, Jl = 1.5 Hz, J2 = 7.3 Hz), 7.988 (d, ÍH, J = 9.1Hz), 8.108 (d, ÍH, J = 9.1 Hz), 8.185 (d, ÍH, J = 3.6 Hz), 3.238 (s, ÍH ), 8.637 (s, ÍH). MS 454 (M +).

EXAMPLE 11 Synthesis of 6- [3- (3,5-dimethyl-l-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid methyl ester To a mixture of 6- (3,4-methylenedioxyphenyl) -2-naphthoisole methyl ester (see Example 6, 70 mg, 0. 23 mmole), 3, 5-dimethyl-l-adamantyl acetate (see Example 3, 63.4 mg, 0.285 mmole) in dichloroethane (1.2 mL) are added two drops of cyclohexane followed by the addition of trifluoromethanesulfonic acid (0.030 mL, 0.34 mmole). The reaction mixture is stirred at room temperature for four days. Purification with preparative TLC (10% ethyl acetate in hexanes) gave the desired product (44 mg, 40%): Rf: 0.24 (10% ethyl acetate / hexane) XHNMR (CDC13, 500 Mhz) 0.899 (s) , 6H), 1233 (s, 2H), 1395 (d, 2H, J = 13.3 Hz), 1463 (d, 2h, J = 12.2 Hz), 1681 (d, 2H, J = 12.2 Hz), 1741 ( d, 2H, J = 12.1 Hz), 1929 (d, 2H, J = 1.4 Hz), 2.18-2.20 (m, ÍH), 3.990 (s, 3H), 6.012 (s, .2h9, 7.078 (d, ÍH , J = 1.7 Hz), 7,099 (s, lh), 7,743 (dd, ÍH, Jl = 1.7 Hz, J2 = 3.5 Hz), 7,919 (d, ÍH, J = 8.7 Hz), 7,974 (s, ÍH), 7.983 (d, ÍH, J = 9.2 Hz), 8.072 8d, ÍH, J = 7.8 Hz), 8.610 (s, ÍH), MS 468 (M +).

EXAMPLE 12 Synthesis of 6- [3- (3-methyl-1-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid methyl ester To a mixture of 6- (3, -methylenedioxyphenyl) -2-naphthoic acid methyl ester (see Example 6, 48.9 mg, 0.16 mmole), 3-methyl-1-adamantyl acetate (see Example 2, 40.2 mg, 0.193 mmole) in dichloromethane (1.2 L) were added two drops of cyclohexane followed by the addition of trilofluoromethanesulfonic acid (0.020 ml, 0.227 mmole). The reaction mixture was stirred at room temperature for four days. Purification with preparative TLC (10% ethyl acetate in hexanes) gave the desired product (35 mg, 48%), Rf = 0.27 (10% ethyl acetate in hexanes). * HNRM (CDC13, 500 Mhz), 0.87 (s 3H), 1,520 (s, 4H), 1,661 (d, ÍH, -J = 12.5 Hz), 1,737 (d, 1H, J = 12.4 Hz), 1,787 ( s, 2H), 1,984 (d, 2H, J = 11.7 Hz), 2,049 (d, 2H J = 12.2 Hz), 2,154 (s, 2H), 3,990 (s, 3H), 6,012 (s, 2H), 7,084 (s, ÍH), 7.105 (s, ÍH), 7.745 (d, ÍH, J = 8.3 Hz), 7.94 (d, ÍH, J = 8.6 Hz), 7.974 (s, ÍH), 7.982 (d, ÍH, J = 8.4 Hz), 8.071 (d, ÍH, J = 3.6 Hz), 8.610 (s, ÍH). MS 454 (M +).

EXAMPLE 13 Synthesis of 6- [3- [(2-oxa-1-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid methyl ester To a mixture of the 6- (3,4-methylenedioxyphenyl) -2-naphthoic acid methyl ester (see Example 6, 22.6 mg, 0.074 mmole), 2-oxa-l-adamantyl mesylate (see Example 4, 50 mg, 0.22 mmole) in dichloromethane (1.2 mL) were added two drops of cyclohexane followed by the addition of trifluoromethanesulfonic acid (0.020 mL, 0.227 mmole). The reaction mixture was stirred at room temperature for two days. Purification with preparative TLC (10% ethyl acetate in hexanes) gave the desired product (5 mg, 15%). Rf = 0.15 (silica 10% ethyl acetate, 90% hexanes MS: 443 (M + H +).

EXAMPLE 14 Synthesis of 6- [3- (3-methyl-l-adamantyl) -4-methoxyphenyl] -2- naphthoic mg (0.0226 mmol) of the ester of Example 8 were dissolved in 0.5 mL of n-butanol and treated with 0.1 mL of 1 molar potassium hydroxide in n-BuOH (0.1 mmol of potassium hydroxide). The solution was heated to 105 ° C for 110 minutes and cooled to 25 ° C. The reaction mixture is treated with 2.5 mL of water and 0.5 mL of acetic acid, and the volatiles are removed under vacuum. They were washed with water to remove the potassium acetate and dried under vacuum obtaining 6.6 mg (68.5%) of the desired product. - "" HNMR (DMSO-d6, 500 Mhz) 0.873 (s, 3H), 1203 (s, 2H), 1363 (d, 2H, J = 11.9 Hz), 1434 (d, 2H, J = 11.3 Hz), 1723 (d, 2H, J = 12.0 Hz), 1783 (d, 2H, J = 11.9 Hz), 1.968 (s, 2H), 2.154 (s, 2H), 3,862 (s, 3H), 7,124 (d, ÍH, J = 3.7 Hz), 7,566 (d, ÍH, J = 2.2 Hz), 7,653 (dd, ÍH, Jl = l .8 Hz, J2 = 8.0 Hz), 7.88 (d, 1H, Jl = 1.4 Hz, H2 = 8.7 Hz), 7.987 (dd, ÍH, Jl = 1.5 Hz, J2 = 8.8 Hz), 8.078 (d, ÍH, J = 8.6 Hz), 8.162 (d , ÍH, 1 = 8.6 Hz), 8,199 (s, ÍH), 8,599 (s, ÍH).

EXAMPLE 15 Synthesis of 6- [3- (3,5-dimethyl-l-adamantyl) -4-methoxy-phenyl] -2-naphthoic acid The ester of Example 7 is hydrolyzed as described in Example 14, obtaining 35% of the desired product. P.F. 258-263 ° C.

EXAMPLE 16 Synthesis of 6- [3- (2-oxa-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid The ester of Example 9 is hydrolyzed as described in Example 14, obtaining 70% of the desired product. XHNMR (DMSO-d6, 500 MHz), 1632 (s, 2H), 1696 (s, 2H, J = 11.8 Hz), 1910 (s, 2H). 1969 (d, 2H, J = 11.6 Hz), 2,167 (s, 2H), 2,686 (s, 2H), 3,856 (s, 3H), 4,330 (s, ÍH), 7,130 (d, ÍH, J = 8.6 Hz ), 7,678 (dd, ÍH, Jl = 7.3 Hz, J2 = 2.0 Hz), 7,827 (d, 1H, J = 8.7 Hz), 7,975 (d, ÍH, J = 2.4 Hz), 7,984 (s, ÍH), 8.0686 (d, lh, J = 8.5 Hz), 8.138 (d, 1H, J = 8.7 Hz), 8.147 (s, 1H), 8.562 (s, 1H).

EXAMPLE 17 Synthesis of 6- [3- (2-oxa-3-methyl-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid The ester of Example 10 is hydrolyzed as described in Example 14, obtaining the desired product. 2HNMR (DMSO-d6, 500 MHz), 1763 (s, 4H), 2.073 (s, 3H), 2.141 (s, 5H), 2.539 (s, 3H), 3.871 (s, 3H), 7.126 (d, ÍH) , J = 7.6 Hz), 7,580 (d, ÍH, J = l .8 Hz), 7,659 (dd, ÍH, Jl = 8.1 Hz, J2 = 1.7 Hz), 7,895 (d, ÍH, J = 9.3 Hz), 7.974 (dd, ÍH, Jl = 8.8, J2 = 1.4), 8.077 (d, 1H, J = 8.7 Hz), 3.156 (d, ÍH, J = 8.6 Hz), 8.223 (s, 1H), 8.587 (s, ÍH).

EXAMPLE 18 Synthesis of 6- [3- (3,5-dimethyl-l-adamantyl) -4,5-methyl-enodioxyphenyl] -2-naphthoic acid The ester of Example 11 is hydrolyzed as described in Example 14, obtaining 78% of the desired product. Rf: 0.23 (50% ethyl acetate in hexanes). - "? NMR (DMSO-d6, 500 Mhz), 0.875 (s, 6H), 1,208 (s, 2H), 1368 (d, 2H, J = 11.5 Hz), 1432 (d, 2H, J = 12.0 Hz) , 1674 (d, 2H, J = 12.0 Hz), 1717 (d, 2H, J = 12.0 Hz), 1905 (s, 2H), 2.16-2.18 (m, 1H), 6.063 (s, 2H), 7.143 ( s, ÍH), 7,284 (s, ÍH), 7,843 (d, ÍH, J = 8.5 Hz), 7,990 (d, ÍH, J = 9.0 Hz), 8,024 (d, 1H, J = 9.0 Hz), 8,120 ( d, HH, J = 8.5 Hz), 8.186 (s, HH), 8.561 (s, HH), MS 454 (M +).

EXAMPLE 19 Synthesis of 6- [3- (3-methyl-l-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid The ester of Example 12 is hydrolyzed as described in Example 14, obtaining 59% of the product wanted. Rf: 0-22 (50% ethyl acetate in hexanes). 1HNR (DMSO-d6, 500Mhz): 0.861 (s, 3H), 1485 (s, 4H), 1.622 (d, ÍH, J = 12.4 Hz), 1692 (d, 1H, J = 12.3 Hz), 1766 (s, 2H), 1,962 (d, 2H, J = 11.5 Hz), 2,009 (d, 2H, J = 12.3 Hz), 2,117 (s, 2H), 6,065 (s, 2H), 7,156 (s, ÍH) , 7,297 (s, ÍH), 7,877 (d, ÍH, J = 8.3 Hz), 7,981 (d, ÍH, J = 8.2 Hz), 8.060 (d, 1H, J = 8.6 Hz), 8.147 (d, ÍH, J = 3.6 Hz), 8.221 (s, ÍH), 8.601 (s, ÍH). MS: 440 (M +). • EXAMPLE 20 Synthesis of 6- [3- [(2-oza-l-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid The ester of Example 13 is hydrolyzed as described in Example 14, obtaining 65% of the desired product. Rf: 0.16 (50% ethyl acetate in hexanes). twenty EXAMPLE 21 Synthesis of 6- [3- (3-methyl-1-adamantyl) -4-hydroxyphenyl] -2-naphthalenecarboxylic acid methyl ester To a solution of the ester obtained in Example 8 (129 mg, 0.29 mmol) in methylene chloride anhydride (5 mL) was added a solution of 2M boron tribromide (2.1 mL, 2.1 mmol) slowly under argon at 0 ° C. The solution was stirred at 0 ° C for 90 minutes before adding methanol (20 mL). After 16 hours, the reaction solution was poured into an aqueous solution of sodium hydrogen sulfate (0.48 g) and potassium carbonate (0.8 g). The mixture was extracted with ether (2 x 100 mL). The ether layer was dried over sodium sulfate and evaporated. Column chromatography with silica gel gave the desired product (83 mg, 65.6%), XNMR (CDC13 500 MHz); 0.891 (s, 3H), 1.528 (s, 4H), 1.665 (d, 1H, J = 12.4), 1754 (d, ÍH, J = 12.0), 1892 (s, 2H), 2.087 (d, 2H, J = 11.2 Hz), 2.155 d, 2H, J = ll.l Hz), 2.167 (s, 2H), 3.99 (s, 3H), 6.780 (d, ÍH, J = 8.2), 7.430 (dd, ÍH, J = 2.0, 8.2), 7.585 (d, IH, J = 2.0), 7.774 (dd, 1H, J = 1.4, 8.4), 7.918 (d, IH J = 8.6), 7.988 (d, IH, J = 8.2) , 7,996 (s, ÍH), 8,069 (dd, ÍH, J = 1.6, 8.4), 8.612 (s, 1H).

EXAMPLE 22 Preparation of 6- [3- (3-methy1-1-adamantyl) -4-hydroxy-phenyl] -2-naphthalenecarboxylic acid A solution of the ester of Example 24 (75 mg, 0.172 mmol) in 0.25 M potassium hydroxide in n-butanol (10 L) was refluxed under argon for 4 hours. A slight excess of acetic acid was added and the whole was extracted with methylene chloride. The organic layer was washed with saline, dried over magnesium sulfate and evaporated. Column chromatography with silica gel (1:15 methanol / methylene chloride) gave the desired product in the quantitative preparation. 1NMR (DMSO-d6, 500 MHz): .843 (s, 3H), 1,464 (s, 4H), 1.6109 (d, III), 1,668 (d, ÍH), 1,844 (s, 2H), 2.96 (m, 6H), 6.91 (d, ÍH, T = 8.0 Hz), 7.49 (dd, ÍH, J = 2.5, 10.4), 7.85 (dd, ÍH, J = 1.5, 8.8), 7.96 (dd, ÍH, J = 0.6 -7.6), 8.05 (d, ÍH, J = 8.7), 8,124 (d, ÍH, J = 8.7), 8,147 (s, ÍH), 8,571 (s, ÍH).

EXAMPLE 23 Preparation of N- (2-aminoethyl) -. { 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthalenecarboxamide} .

To a suspension of 6- [3- (1-adamantyl) -4-methoxy-phenyl] -2-naphthalenecarboxylic acid (3 g, 7.27 mmol) in dry toluene (20 mL) was added thionyl chloride (0.6 mL, 8.22 mmoles) and DMF (0.04 mL) under argon. The reaction mixture was heated at 100 ° C for ten minutes and another 0.04 mL of DMF was added. After 30 minutes, more thionyl chloride (0.1 mL, 1.37 mmol) was added and the reaction mixture was heated at 110 ° C for 60 minutes. The solvent and excess thionyl chloride were removed in vacuo. The resulting solid was stirred with 100 L dry methylene chloride under argon. This was added to a mixture of ethylenediamine (5.25 mL, 70 mmol) in dry methylene chloride under argon at 0 ° C while stirring rapidly. The solution is left to warm to room temperature while stirring rapidly for one hour. The reaction mixture is carefully poured into 350 mL of IN aqueous HCl while stirring, and the methylene chloride is removed in vacuo. The resulting precipitate (hydrochloride salt of the product) is washed with IN HCl, water, THF, and methylene chloride. Yield of the hydrochloride salt: 2.76 g, 77%. The free base is generated by neutralization with aqueous sodium bicarbonate and the product is extracted into tetrahydrofuran, the organic layer is dried over sodium sulfate, and the solvent is removed. MS 455 (M + H +).

EXAMPLE 24 Preparation of N-. { 6- [3- (1-adamantyl) -4-methoxyphenyl] -2- naphthalenecarboxoyl} homopiperazide This amide is prepared from 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthalenecarboxylic acid and homopiperazine using a procedure analogous to one in Example 24. MS: 495 (M + H +).

EXAMPLE 25 Preparation of N-. { 6- [3- (1-adamantyl) -4,5-methylenedioxy] -2- naphthalenecarboxoyl} piperazide.

This amide is prepared from 6- [3- (l-adamantyl) -4,5-methylenedioxy] -2-naphthalenecarboxylic acid and piperazine using a procedure analogous to one in Example 24. Ms: 495 (M + H +) .

EXAMPLE 26 N-. { 6- [3- (1-adamantyl) -4,5-methylenedioxy] -2-naphthalenecarboxyl} homopiperazide This amide is prepared from 6- [3- (l-adamantyl) -4,5-methylenedioxy] -2-naphthalenecarboxylic acid and homopiperazine using a procedure analogous to one in Example 24: MS: 509 (M + H +) .

EXAMPLE 27 N- (2-aminoethyl) -. { 6- [3- (1-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthalenecarbozamide} .

This amide was prepared from 6- [3- (1-adamantyl) -4,5-methylenedioxy] -2-naphthalenecarboxylic acid and ethylenediamine using a procedure analogous to one in Example 24: MS 469 (M + H +).

EXAMPLE 28 N- (2-dimethylaminoethyl) -. { 6- [3- (1-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthalenecarboxamide} .

This amide was prepared from 6- [3- (l-adamantyl) -4,5-methylenedioxy] -2-naphthalenecarboxylic acid and 2-dimethylaminoethylamine using a procedure analogous to one in Example 24. MS: 495 (MH ") .

EXAMPLE 29 The anti-cancer activity of various adamantyl retinoid compounds according to the invention were compared to all trans-retinoic acid using protective assays based on high performance cells. Specifically, the following compounds are evaluated in such assays: all-trans-retinoic acid, 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid, 2- [3- (l-adamantyl) -4 -methoxyphenyl] -5-benzimidazole carboxylic acid, 6- [3- (1-adamantyl) -4-acetoxymethylphenyl] -2-naphthoic acid and 6- [3- (1-adamantyl) -4,5-methylenedioxyphenyl] -2 acid -naftoic These compounds were titrated against a panel of tumor cell lines which have a variety of tissue origins, and have distinctive tumor characteristics. The tumor cell cultures were exposed to the above compounds for specific furation. After such exposure, the percentage of surviving cells was then measured using standard assays or assays. These results were then compared for the different compounds, with an active compound being defined as one which results in a survival percentage of less than 80. These results are contemplated in Figure 1. Based on these results, it can be seen that The compounds according to the invention are active against a different number of cancers in humans. By contrast, all-retinoic acid did not give comparable results.

EXAMPLE 30 Based on the previous results, several active compounds according to the invention, in particular 2-3 [- (α-adamantyl) -4-methoxyphenyl] -5-benzimidazole carboxylic acid, 6- [3- (1 -damyl) -4-hydroxymethylphenyl] -2-naphthoic; 6- [3- (l-adamantyl) -4,5-methyl-enodioxyphenyl] -2-naphthoic acid, as well as all-trans-retinoic acid, were tested with various human cancer cell lines at concentrations of retinoids of the range from 10 ~ 9M to 10_5M. . These results are contained in Figures 2-4, and show that the adamantyl compounds according to the invention exhibit significant anti-carcinogenic activity. By contrast, all-trans-retinoic acid exhibits no similar activity. EXAMPLE 31 The anti-cancer activity of a compound according to the invention, 6- [3- (1-adamantyl) -4,5-methylenedioxy-phenyl] -2-naphthoic acid was also evaluated in a mouse animal model xenográfto that contains pancreatic cancer BxPC-3 tumor cells. Twenty-eight initiated after the inoculation of the tumor cells, said mice containing xenografto were administered the retinoid compound intraperitoneally at a dosage of 80 mg / kg per body weight. Also a control group of said mice were inoculated under similar conditions with the pharmaceutical vehicle used for the formulation (but lacking the retinoid compound). These results are contained in Figure 5 and show that the retinoid compound according to the invention, 6- [3- (1-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid resulted in a substantial reduction in size of the tumor compared to the control group in which this retinoid compound was not administered. Therefore, based on these results, it is apparent that the anti-carcinogenic activity of the adamantyl compounds according to the invention, which is apparently attributable to the activity that induces apoptosis is observed in both in vi tro and in vivo .

STRUCTURE OF ACTIVE COMPOUNDS fifteen It is noted that, in relation to this date, the best method known by the Applicant to carry out said invention is that which is clear from the present description of the invention. Having described the inference as above, property is claimed as contained in the following.

Claims (94)

1. A method for treating cancer in a subject in need of such treatment which comprises the induction of apoptosis of cancer cells which comprises administering a therapeutically effective amount of a compound related to the adamantyl retinoid having one of the following generic formulas exposed to then a pharmaceutically acceptable salt, and optical and / or geometric isomers thereof; a compound of the generic formula (I): with the provision that said retinoid of Formula (I) is not a specific receptor agonist ligand RAR- ?, and wherein W is independently -CH2, -0-, -S-, -SO-, or -S02-, X is a radical selected from those of the following formulas (i) - (iii) -14- where Y is a radical -CO-V-, -CH = CH-, -CH3C = CH-, V is an oxygen atom (-0), an aza radical (-NH-), a radical -CH = CH- or -C = C-; Z is a radical -CH- and Z 'is an oxygen atom, or Z is a nitrogen atom (N) and Z' is an aza radical (-NH-); Ri is a hydrogen atom, a halogen atom, or a lower alkyl radical; R 'i is a hydrogen atom, a halogen, or a lower alkyl radical; R2 is a hydroxyl radical, a halogen atom, an alkyl radical, optionally substituted by one or more hydroxyl or acyl groups, an alkoxyl radical, optionally substituted by one or more hydroxyls, alkoxyl or aminocarbonyl groups, and / or optionally interrupted by one or more oxygen atoms, an acyl radical, an aminocarbonyl radical or a halogen; R3 is a hydrogen atom, a halogen, a hydroxyl radical, an alkenyl radical, or an alkoxy radical; R2 and R3 can together form a radical -0-CH2-0-; R 4 is a hydrogen atom, a halogen atom, an alkyl radical, or an alkoxy radical; R5 is a radical -CO-Rio, an alkyl radical, optionally substituted by one or more hydroxyl groups; R6 is a hydrogen atom, a halogen atom, preferably fluorine, an alkoxyl radical or a hydroxyl group; R7 is a hydrogen atom or a halogen atom, preferably a fluorine atom; R8 is a hydrogen atom, a halogen atom or an alkyl radical; R9 is a hydrogen atom, a halogen atom or a hydroxyl radical; Rio is a hydroxyl radical, an alkoxy radical, a radical of formula -Nr'r ", wherein r 'and r" represent a hydrogen atom, an optionally substituted aminoalkyl radical, a mono or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid or residue of sugars; or a compound having the generic formula (III): wherein R'i, Ri, R2, R3, R, R5 and Re and are as defined for the compounds of formula (I) or is a compound of formula (IV) wherein R'i, R, R2, R3, R4, X and W are as defined above for the compounds of formula (I).

2. The method according to claim 1, characterized in that the adamantyl retinoid compound has the formula set out below: wherein W, X, Ri, R'i, R2, R3 and R are as defined in claim 1, or comprise a pharmaceutically acceptable salt, or optical or geometric isomers thereof, and with the proviso that said compound it is not a specific receptor agonist ligand RAR- ?.

3. The method according to claim 1, characterized in that the adamantyl retinoid compound is of the formula (I) and at least two of R2, R3 and R4 are not hydrogen.

4. The method according to claim 2, characterized in that at least two of R2, R3 and R4 are not hydrogen.

5, The method according to claim 1, characterized in that at least two of the radicals are -CH2-.

6. The method according to claim 5, characterized in that all three of the radicals are -CH2-.

7. The method according to claim 1, characterized in that R'i, and Ri, are both hydrogen.

8. The method according to claim 1, characterized in that the adamantyl compound is of the formula (IV).

9. The method according to claim 1, characterized in that the adamantyl compound is of the formula (IV).

10. The method according to claim 1, characterized in that the treated cancer is selected from the group consisting of prostate cancer, skin cancer, pancreatic carcinoma, colon cancer, melanoma, ovarian cancer, liver cancer, lung carcinoma. of small cells, non-small cell lung carcinoma, cervical cancer, breast cancer, bladder cancer, brain cancer, neuroblastoma / glioblastoma, leukemia, head and neck cancer, neuroblastoma / gioblastoma, leukemia, head and neck cancer , kidney cancer, lymphoma, myeloma and ovarian cancer.

11. The method according to claim 1, characterized in that said method comprises the administration of a compound selected from the group consisting of 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid; Carboxylic acid 2- [3- (l-adamantyl) -4-methoxyphenyl] -5-benzimidazole; 6- [3- (l-adamantyl) -4-hydroxymethyl-phenyl] -2-naphthoic acid; 6- [3- (1-Adamantyl) -4-hydroxy-5-methoxyphenyl] -2-naphthoic acid; 6- [3- (1-Adamantyl) -4-acetoxymethyl-phenyl] -2-naphthoic acid; 6- [3- (1-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid; N-. { 6- [3- (1-adamantyl) -4-methoxy-phenyl] -2-naphthalenecarboxyl} -piperizide; 4- Acid. { 3-oxo-3- [3- (1-adamantyl) -4-methoxyphenyl] -l-propynyl} benzoic; 4- [N- (3- (l-adamantyl) -4-methoxybenzoyl) amido] 2-methoxybenzoic acid; 2- [3- (1-adamantyl) -4-methoxyphenyl] -5-methylbenzimidazole; 6- [3- (1-Adamantyl) -4- (1, 2-dihydroxy-ethyl) phenyl] -2-naphthoic acid; 6- [3- (1-adamantyl) -4-hydroxy-6-methylphenyl] -2-naphthoic acid; 6- [3- (1-adamantyl) -4-methoxy-6-methylphenyl] -2-naphthoic acid; 6- [3- (1-adamantyl) -4-hydroxyphenyl] -2-hydroxymethylnaphthalene; 4- [3- (l-adamantyl) -4-methoxybenzyl-oxo] benzoic acid; 2- [3- (1-adamantyl) -4-methoxyphenyl] -5-benzofurancarboxylic acid; 6-3 [- (1-Adamantyl) -4-hydroxyphenyl] -2-naphthoic acid methyl ester; Methyl ester of l-methyl-4-hydroxy-6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid; N-. { 4- [N- (3- (1-adamantyl) -4-methoxy-benzoyl) amido] benzoyl} morpholide; 4- [3- (l-adamantyl) -4-methoxybenzoyl-oxo] -2-fluorobenzoic acid; 4-hydroxycarbonyl-2-fluorophenyl ester of 3- (l-adamantyl) -4-methoxy-benzoic acid; 6- [3- (1-Adamantyl) -4-ethylphenyl] -2-naphthoic acid; 6- [3- (1-Adamantyl) -4- (3-hydroxy-propoxy) phenyl] -2-naphthoic acid; 6- [3- (l-adamantyl) -4-aminocarbonyl-phenyl] -2-naphthoic acid; N- (4-carboxyphenyl) -3- (1-adamantyl) -3-oxopropionamide; 2-hydroxy-4- acid. { 2- [3- (1-adamantyl) -4-methoxyphenyl] -2-hydroxyethoxy} benzoic; (S) -6- [3- (1-Adamantyl) -4- (2S, 3-dihydroxypropoxy) phenyl] -2-naphthoic acid; Acid (E) of 4-. { 3-oxo-3- [3-methoxy-4- (1-adamantyl) phenyl] prop-1-enyl} benzoic; Acid (E) of 4-. { 3-Oxo-3- [4- (2-methoxyethoxy-ethoxy) -3- (1-adamantyl) phenyl] prop-1-enyl} benzoic; Acid (E) of 4-. { 2- [4- (6-aminocarbonylpentyl-oxy) -3- (1-adamantyl) phenyl] ethenyl} -benzoic 3- (1-adamantyl) -4-methoxy-N- (4-carboxyphenyl) benzamidine; Ester 4"6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid erythromycin A; 4-carboxyphenyl ester of 3- (l-adamantyl) -4- (2, 3-) acid dihydroxypropoxy) Benzoic; 6- [3- (1-adamantyl) -4- (2,3-dihydroxy-propoxy) phenyl] -2-naphthoic acid; N-4-carboxyphenyl of 3- (1-adamantyl) -4- (methoxycarbonyl) benzamide; 6- [3- (l-adamantyl) -4,5-dihydroxy-phenyl] -2-naphthoic acid; 6- [3- (3-methyl-l-adamantyl) -4,5- methylenedioxyphenyl] -2-naphthoic; 6- [3- (2-oxa-l-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid; 6- [3- (2-Oxa-l-adamantyl) -4-methoxy-phenyl] -2-naphthoic acid; 6- [3- (2-Oxa-3-methyl-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid; 6- [3- (3-Methyl-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid; 6- [3- (3, 5-Dimethyl-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid; 6- [3- (3,5-dimethyl-l-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid; N-. { 6- [3- (1-adamantyl) -4-methoxy-phenyl] -'2-naphthalenecarboxyl} homo-piperazide; N- (2-aminoethyl) -. { 6- [3- (l-adamantyl) -4-methoxyphenyl] -2-naphthalene-carboxamide] N-. { 6- [3- (1-adamantyl) -4,5-methylenedioxy] -2-naphthalenecarboxyl} piperazide; N { 6- [3- (1-adamantyl) -4,5-methylenedioxy] -2-naphthalenecarboxoyl} homo-piperazide N- (2-aminoethyl) -6. { - [3- (1-adamantyl) -4,5-methylenedioxypheni] -2-naphthalenecarboxamide}; 6- [3- (3-Methyl-1-adamantyl) -4-hydroxyphenyl] -2-naphthalenecarboxylic acid

12. The method according to claim 1, characterized in that said method comprises the administration of a compound selected from the group consisting of 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid; 2- [3- (1-adamantyl) -4-methoxyphenyl] -5-benzimidazole carboxylic acid; 6- [3- (l-adamantyl) -4-hydroxymethylphenyl] -2-naphthoic acid; 6- [3- (l-adamantyl) -4-hydroxy-5-methoxyphenyl] -2-naphthoic acid; 6- [3- (1-adamantyl) -4-acetoxymethylphenyl] -2-naphthoic acid; and 6- [3- (l-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid.

13. The method according to claim 1, characterized in that the compound is of formula (V) exposed to below Or it comprises a pharmaceutically acceptable salt, or geometric and / or optical isomers thereof, with the proviso that said compound is not an agonist ligand of the specific RAR-α receptor.

14. The method according to claim 13, characterized by the compound of formula (V), R5 is a hydroxycarbonyl radical and / or R2 is a hydroxyl radical, an alkoxyl radical or R2 and R3 together form a radical -0-CH2-0 .

15. The method according to claim 1, characterized in that the retinoid compound is administered systemically, enterally, parenterally, topically or ocularly.

16. The method according to claim 15, characterized in that the therapeutic dosages are in the range of 0.01 mg / kg to 100 mg / kg of body weight.

17. An adamantyl retinoid compound which comprises one of the following generic formulas or a pharmaceutically acceptable salt, geometric and / or optical isomers thereof; a compound of the generic formula (I): wherein W is independently -CH2 ', -O-, -S-, -SO-, or -S02-, X is a radical selected from those of the following formulas (i) - (iii) where Y is a radical -CO-V-, -CH = CH-, -CH3C = CH-, V is an oxygen atom (-0), an aza radical (-NH-), a radical -CH = CH- or -C = C-; Z is a radical -CH- and Z 'is an oxygen atom, or Z is a nitrogen atom (N) and Z' is an aza radical (-NH-); 1 Ri is a hydrogen atom, a halogen atom, or a lower alkyl radical; R'i is a hydrogen atom, a halogen, or a lower alkyl radical; R2 is a hydroxyl radical, a halogen atom, an alkyl radical, optionally substituted by one or more hydroxyl or acyl groups, an alkoxyl radical, optionally substituted by one or more hydroxyls, alkoxyl or aminocarbonyl groups, and / or optionally interrupted by one or more oxygen atoms, an acyl radical, an aminocarbonyl radical or a halogen; R is a hydrogen atom, a halogen, a hydroxyl radical, an alkyl radical, or an alkoxy radical; R2 and R3 can together form a radical -0-CH2-0-; R 4 is a hydrogen atom, a halogen atom, an alkyl radical, or an alkoxy radical; R5 is a radical -CO-R10, an alkyl radical, optionally substituted by one or more hydroxyl groups; R6 is a hydrogen atom, a halogen atom, preferably fluorine, an alkoxyl radical or a hydroxyl group; R 7 is a hydrogen atom 0 a halogen atom, preferably a fluorine atom; Rs is a hydrogen atom, a halogen atom or an alkyl radical; Rg is a hydrogen atom, a halogen atom or a hydroxyl radical; Rio is a hydroxyl radical, an alkoxy radical, a radical of formula -Nr'r ", wherein r 'and r" represent a hydrogen atom, an optionally substituted aminoalkyl radical, a mono or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid or residue of sugars, or alternatively, r and r "together, form a heterocycle, with the proviso that at least two of R2, R3 and R4 can not be hydrogen, and the additional provision that R2 and R3 can not together form - 0-CH2-0-, or is a compound of the generic formula (III): wherein R'i, Ri, R2, R3, R, 5 and Rβ and W are as defined for the compounds of formula (I), or a compound of the generic formula (I): where, X, R? ', Ri, R2, Rs, R, R5, e, R?, Rs, Rg, Rio, Y, V are as defined supra, except with the provision that at least one of W is -O-, -S-, -SO- or -S02 and / or at least one of Ri and Ri 'is halogen or an alkenyl radical; or is a compound of the generic formula (I): where W, X, Rx ', R1 R2, R3, R4, R5, R6, R7, R8, Rg, Rio, Y, V are as defined above, except with the proviso that R5 is -CO-R10 , and Rio is a radical of formula Nr'r ", wherein at least one of r'y r" is hydrogen and the other is an optionally substituted aminoalguyl radical or alternatively r 'and r ", taken together, form a heterocycle.

18. The adamantyl retinoid compound according to claim 17, characterized in that it is of the formula (I), wherein at least two of R2, R3 and R4 can not be hydrogen and R2 and R3 can not together form -0-CH2-0 -, or a pharmaceutically acceptable salt or a geometrical and / or optical isomer thereof.

19. The adamantyl retinoid compound according to claim 17, characterized in that it is of formula (III), or a pharmaceutically acceptable salt or a geometrical and / or optical isomer thereof.

20. An adamantyl retinoid compound of formula (I), according to claim 17, characterized in that R5 is -CO-R10 and RIO is a radical of formula -Nr'r ", wherein one of r 'and r" is hydrogen and the another is an optionally substituted aminoalkyl radical, or alternatively r 'and r "together form a heterocycle.

21. The compound according to claim 20, characterized in that r 'and r "together form a piperazino group, or a homologue thereof.

22. The compound according to claim 20, which is selected from the group consisting of: N- (2-dimethylaminoethyl) -. { 6- [3- (1-adamantyl) -4,5-methylenedioxypinyl] -2-naphthalenecarboxamide}; N-. { 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthalenecarboxoyl} homopiperazide; N- (2-aminoethyl) -. { 6- [3- (l-adamantyl) -4-methoxyphenyl] -2-naphthalenecarboxamide]; N-. { 6- [3- (1-adamantyl) -4,5-methylenedioxyl] -2-naphthalenecarboxoyl} piperazide; N-. { 6- [3- (1-adamathyl) -4,5-methylenedioxyl] -2-naphthalenecarboxoyl} homopiperazide; N- (2-aminoethyl) -. { 6- [3- (1-adamantyl) -4,5-methyl-enodioxyphenyl] -2-naphthalenecarboxamide} .

23. An adamantyl retinoid compound of formula (I) according to claim 17, characterized in that at least one of es - = -, -S-, -SO- or -S02, and / or at least one of Rl and Rl 'is halogen or a lower alkyl radical.

24. An adamantyl retinoid compound according to claim 23, characterized in that it is selected from the group consisting of 6- [3- (3-methyl-1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid methyl ester; 6- [3- (2-oxa-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid methyl ester; 6- [3- (2-oxa-3-methyl-1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid methyl ester; 6- [3- (3,5-dimethyl-l-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid methyl ester; 6- [3- (3-methyl-l-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid methyl ester; 6- [3- [(2-oxa-l-adamantyl) -4,5-methyl-enioxyphenyl] -2-naphthoic acid methyl ester; 6- [3- (3-methyl-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid; 6- [3- (3, 5-dimethyl-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid; 6- [3- (2-oxa-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid; 6- [3- (2-oxa-3-methyl-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid; 6- [3- (3,5-dimethyl-1-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid; 6- [3- (3-methyl-l-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid; 6- "3- [(2-oxa-l-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid; 6- [3- (3- (3-methyl-1-adamantyl) -4,5- methylenedioxyphenyl] -2-naphthoic acid 6- [3- (2-oxa-l-adamantyl) -4,5-methylenedioxyphenyl] -2-naphthoic acid 6- [3- (2-oxa-3-methyl-1 -damn) -4-methoxyphenyl] -2-naphthoic acid 6- "3- (2-oxa-3-methyl-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid 6- [3- (3 -methyl-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid, 6-3- (3-methyl-l-adamantyl) -4-methoxyphenyl] -2-naphthoic acid, 6- [3- (3, 5-dimethyl-1-adamanyl) -4-methoxyphenyl] -2-naphthoic acid 6- [3- (3,5-dimethyl-l-adamantyl) -4,5-methylenedioxy-phenyl] -2-naphthoic acid; 6- [3- (3-methyl-l-adamantyl) -4-hydroxyphenyl] -2-naphthalenecarboxylic acid.

25. A retinoid-adamantyl compound according to claim 23, characterized in that at least one of W is -0- and / or R1 is a lower alkyl radical and / or R1 is a lower alkyl radical.

26. A compound according to claim 25, characterized in that X comprises the formula (ii).

27. A compound according to claim 25, characterized in that R8 is hydrogen and / or R9 is hydrogen, and / or R5 is -COR10.

28. An adamantyl retinoid compound of formula (I) according to claim 17, characterized in that R2 is an alkoxy radical or a hydroxyl group and / or R3 is hydrogen and / or R4 is hydrogen and / or R2 and R3 together form -O-CH2-O-.

29. An adamantyl compound according to claim 19, characterized in that said compound is 2- [3- (1-adamantyl) -4-methoxy-phenyl} -5-benzofurancarboxylic.

30. The adamantyl retinoid compound according to claim 17, characterized in that it has the generic formula: where W, X, RX ', Ri, R2, Rs, R4, Rs, Re, 7, R8, Rg, Rio, Y, V are as defined above, except with the proviso that at least two of R2 and R3 are not hydrogen, and R2 and R3 can not together form -0-CH2-0-; or a compound of formula (II) where, X, RX, Ri, R2, R3, R4, Rs, Re, R ?, Rs, Rg, Rio, Y, are as defined above, except with the provision that at least one of W is -O-, -S-, -SO- or -S02, and / or at least one of R1 and R1 'is halogen or a lower alkyl radical; or is a compound of formula (II) wherein R5 is -CO-R10, RIO is a radical of formula Nr'r ", wherein at least one of r 'and r" is hydrogen, and the other is an aminoalkyl radical optionally substituted, or alternatively r 'and r "together form a heterocycle or a famaceutically acetable salt or optical and / or geometric isomers thereof.

31. An adamantyl retinoid compound according to claim 30, characterized in that at least one of is -O-, -S-, -SO- or -S02, and / or at least one of R1 and R1 is a halogen or a radical lower alkyl.

32. The compound according to claim 31, characterized in that at least one of W is -O- and / or R 1 is a lower alkyl radical and / or R 1 'is a lower alkyl radical.

33. An adamantyl retinoid compound according to claim 30, characterized in that it comprises the formula (ii).

34. The compound according to claim 33, characterized in that R8 is hydrogen and / or R9 is hydrogen and / or R5 is -CO-R10.

35. An adamantyl compound according to claim 30, characterized by R5 is -CO-R10 and RIO is a radical of formula -Nr'r ", wherein one of r 'and r" is hydrogen and the other is an optionally substituted aminoalkyl radical or alternatively r 'and r "together forms a heterocycle.

36. A compound according to claim 35, characterized in that r 'and r "together form a piperazino group, or a homologue thereof.

37. An adamantyl compound of generic formula (II) according to claim 35, characterized in that R2 is an alkoxy radical or a hydroxyl group and / or R3 is hydrogen and / or R4 is hydrogen, and / or R2 and R3 together form -0-CH2-0.

38. A compound according to claim 30, characterized in that it is selected from the group consisting of 6- [3- (1-adamantyl) -4-hydroxy-5-methoxyphenyl] -2-naphthoic acid; 6- [3- (l-adamantyl) -4-hydroxy-6-methylphenyl] -2-naphthoic acid; 6- [3- (1- (adamantyl) -4-methoxy-6-methylphenyl] -2-naphthoic acid; 6- [3- (1-adamantyl) -4,5-dihydroxyphenyl] -2-naphthoic acid.

39. An adamantyl retinoid compound according to claim 30, characterized in that the compound comprises the generic formula set out below: wherein W, R'l, and Rl to R9 are as defined above, with the proviso that at least two of R2, R3 and R4 are not hydrogen, and R2 and R3 can not together form -0-CH2-0 -, and / or a pharmaceutically acceptable salt or an optical and / or geometric isomer thereof.

40. The compound according to claim 39, characterized in that at least two of the portions W are -CH2-.

41. The compound according to claim 40, characterized in that R1 ', and R1 are both hydrogen.

42. A compound according to claim 39, characterized in that at least one of W is -O-, -S-, -SO- or S02, and / or at least one of Rl and Rl 'is halogen or a lower alkyl radical

43. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 17.

44. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 18.

45. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 19.

46. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 20.

47. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 21.

48. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 22.

49. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to the claim 23.

50. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to the claim 24.

51. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 25.

52. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 26.

53. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 27.

54. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 28.

55. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 29.

56. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 30.

57. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 31.

58. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 32.

59. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 33.

60. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 34.

61. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 35.

62. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 36.

63. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 37.

64. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 38.

65. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 39.

66. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 40.

67. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 41.

68. A pharmaceutical or cosmetic composition of the subject, characterized in that it comprises a therapeutically or cosmetically effective amount of an adamantyl retinoid compound according to claim 42.

69. A pharmaceutical or cosmetic composition of claim 43, which is adapted by topical, systemic, enteral, parenteral or ocular administration.

70. A pharmaceutical or cosmetic composition of claim 43, comprising a tablet, a capsule, a syrup, a lozenge, a suspension, microsphere, nanosphere, lipid vesicle, polymeric vesicles, or an injectable.

71. The pharmaceutical or cosmetic composition according to claim 43, characterized in that it comprises an ointment, a cream, a milk or emulsion, a balsam, an impregnated pad, an atomizer or a lotion.

72. The pharmaceutical or cosmetic composition according to claim 43, characterized in that it further comprises another retinoid compound, a vitamin D or a derivative thereof, a corticosteroid, an anti-free radical agent, an α-hydroxy acid or α-keto or a derivative thereof, or a combination thereof.

73. A method of treating or preventing a dermatological condition associated with an alteration of the related keratinization. differentiation and / or proliferation, characterized in that it comprises administering a therapeutically or prophylactically effective amount of a retmoid compound according to claim 17.

74. The method according to claim 17, characterized in that said alteration is selected from the group consisting of common acne, comedonic acne or polymorphic acne, acne rosary, nodulocystic acne, acne conglobolata, senile acne and secondary acnes.

75. The method according to claim 73, characterized in that the alteration of keratinization includes inctiosis, ichthyosiform conditions, Darier's disease, plaque keratoderma plaque, leukoplakia, leukoplakus conditions, cutaneous or mucosal lichens (oral).

76. The method in accordance with the claim 73, characterized in that the alterations of keratinization have an anti-inflammatory and / or immunoallergic component.

77. The method in accordance with the claim 76, characterized in that said alteration of keratinization includes all forms of psoriasis, cutaneous atopy or skin, and gingival hypertrophy.

78. A method of treating or preventing dermal or epidermal proliferations, which may be malignant or benign, and optionally of viral origin, characterized in that it comprises administering a therapeutically or prophylactically effective amount of a retinoid compound according to claim 17. 79. The method according to claim 78, characterized in that said dermal or epidermal proliferations include common warts, flat warts, epidermodisplasia verruciformis,. Incarnated oral papillomatous, and proliferation induced by ultraviolet radiation. 80. A method of treating dermatosis bullous and / or a collagen condition comprising administering a therapeutically or prophylactically effective amount of a retionoid compound according to claim 17. 81. A method for treating a condition selected from the group consisting of repairers or controllers of skin aging, whether the actinic keratosis and pigmentation is photoinduced or chronological, and other pathologies associated with chronological or actinic aging, characterized in that it comprises administering a therapeutically or prophylactically effective amount of a retinoid compound according to claim 17. 82. A method for preventing or treating the stigmata of epidermal and / or dermal atrophy induced by systemic or local corticosteroids, or other forms of cutaneous atrophies, characterized in that it comprises administering a therapeutically or prophylactically effective amount of a retinoid compound according to claim 17 . 83. A method for preventing and / or treating alterations of health or preventing and / or repairing marked wrinkles, characterized in that it comprises administering a therapeutically or prophylactically effective amount of a retinoid compound according to claim 17. 84. A method for controlling alterations of sebaceous function, characterized in that it comprises administering an effective amount of a retinoid compound according to claim 17. 85. A method for the prevention of cancerous or pre-cancerous conditions, characterized in that it comprises administering a prophylactically effective amount of a retinoid compound according to claim 17. 86. A method for the treatment of a condition associated with an inflammation, characterized in that it comprises administering a therapeutically effective amount of a retinoid compound according to claim 17. 87. The method according to claim 86, characterized in that the inflammatory condition is arthritis. 88. A method for the treatment of an associated viral condition, characterized in that it comprises administering a therapeutically effective amount of a retinoid compound according to claim 17. 89. A method for the prevention or treatment of alopecia, characterized in that it comprises administering a prophylactically or therapeutically effective amount of a retinoid compound according to claim 17. 90. A method for the treatment of dermatological or general conditions that include an immunological component, characterized in that it comprises administering a therapeutically effective amount of a retinoid compound according to claim 17. 91. A method for the treatment of a disease associated with the cardiovascular system, characterized in that it comprises administering a therapeutically effective amount of a retinoid compound according to claim 17. 92. The method in accordance with the claim 91, characterized in that the disease is arteriosclerosis or myocardial infarction. 93. A method for the treatment or prevention of osteoporosis, characterized in that it comprises administering a therapeutically or prophylactically effective amount of a retinoid compound according to claim 17. 94. The method in accordance with the claim 1, characterized in that it is used for the treatment of a cancer not related to the skin. SUMMARY OF THE INVENTION The present invention relates to retinoid compounds that "contain adamantyl group derivatives or specific adamantyls induce apoptosis of cancer cells.These adamantyl derivatives are used for the treatment of many types of cancer and solid tumors, especially prostate cancer independent of the androgen, skin cancer, pancreatic carcinomas, colon cancer, melanoma, ovarian cancer, liver cancer, small cell lung carcinoma, non-small cell lung carcinoma, cervical carcinoma, brain cancer, bladder cancer, cancer chest, neuroblastoma / gioblastoma, and leukemia Also, the invention relates to novel compounds derived from the adamantyl group or novel adamantyls which are used as active agents for the treatment or prevention of the alteration of gueratinization and other dermatological conditions, and other ailments

79. The method according to claim 78, characterized in that said dermal or epidermal proliferations include common warts, flat warts, epidermodysplasia verruciformis, oral papillomatous incarnation, and proliferations induced by ultraviolet radiation.

80. A method of treating dermatosis bullous and / or a collagen condition comprising administering a therapeutically or prophylactically effective amount of a retionoid compound according to claim 17.

81. A method for treating a condition selected from the group consisting of repairers or controllers of skin aging, whether the actinic keratosis and pigmentation is photoinduced or chronological, and other pathologies associated with chronological or actinic aging, characterized by comprising administering a therapeutically or prophylactically effective amount of a retinoid compound according to claim 17.

82. A method for preventing or treating the stigmata of epidermal and / or dermal atrophy induced by systemic or local corticosteroids, or other forms of cutaneous atrophies, characterized in that it comprises administering a therapeutically or prophylactically effective amount of a retinoid compound according to claim 17 .

83. A method for preventing and / or treating alterations of health or preventing and / or repairing marked wrinkles, characterized in that it comprises administering a therapeutically or prophylactically effective amount of a retinoid compound according to claim 17.

84. A method for controlling alterations of sebaceous function, characterized in that it comprises administering an effective amount of a retinoid compound according to claim 17.

85. A method for the prevention of cancerous or precancerous conditions, characterized in that it comprises administering a prophylactically effective amount of a retinoid compound according to claim 17.

86. A method for the treatment of a condition associated with an inflammation, characterized in that it comprises administering a therapeutically effective amount of a retinoid compound according to claim 17.

87. The method according to claim 86, characterized in that the inflammatory condition is arthritis.

88. A method for the treatment of an associated viral condition, characterized in that it comprises administering a therapeutically effective amount of a retinoid compound according to claim 17.

89. A method for the prevention or treatment of alopecia, characterized in that it comprises administering a prophylactically or therapeutically effective amount of a retinoid compound according to claim 17.

90. A method for the treatment of dermatological or general conditions that include an immunological component, characterized in that it comprises administering a therapeutically effective amount of a retinoid compound according to claim 17.

91. A method for the treatment of a disease associated with the cardiovascular system, characterized in that it comprises administering a therapeutically effective amount of a retinoid compound according to claim 17.

92. The method in accordance with the claim 91, characterized in that the disease is atherosclerosis or myocardial infarction.

93. A method for the treatment or prevention of osteoporosis, characterized in that it comprises administering a therapeutically or prophylactically effective amount of a retinoid compound according to claim 17.

94. The method of compliance- with the claim 1, characterized in that it is used for the treatment of a cancer not related to the skin.