MXPA97004733A - Monographers of ciclohesan-1-ona 4,4-dissolved and related compounds - Google Patents

Abstract

This invention relates to 4,4- (disubstituted) cyclohexan-1-ones derivatives and related compounds, which are useful for treating allergic or inflammatory diseases.

Description

MONOGRAPHERS OF CICLOHEXAN-1-ONA 4,4-DISSTITUTES AND RELATED COMPOUNDS COHPQ OF THE INVENTION r > The present invention relates to 4,4- (disust tuted) c-clohexan-l -ones and related compounds; to compositions containing these compounds and to their use in the treatment of allergic or inflammatory diseases, and for G to inhibit the production of Turnoral Necrosis Factor (TNF).

BACKGROUND OF THE INVENTION Bronchial astin is a complex multisystem disease, characterized by the reversible rejection of the respiratory tract and the respiratory sensitivity to exogenous stimuli. The identification of novel therapeutic agents for asthma is made difficult by the fact that multiple mediators are responsible for the development of the disease, therefore, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on the three components. of chronic asthma. An alternative to the "mediator approach" is to regulate the activity of the cells that are responsible for the pathophysiology of the disease. One such way is to raise the levels of cMFfi (3 ', 5' - cyclic adenosine monophosphate). It has been demonstrated that the cyclic MFA is a second messenger that mediates the biological responses in a great variety of hormones, neuretransmitters and drugs; CKrebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 1.7-29, 1973]. When the appropriate agonist binds to specific cell surface receptors, the adenylate cyclase which converts Mg + 2 ~ TFA to cMFA is activated at an accelerated rate. Cyclic MFfi modulates the activity of most, if not all, cells that contribute to the physiology of extrinsic (allergic) asthma. As such, an elevation of the cMFñ would produce beneficial effects that would include: (1) relaxation of the smooth muscle of the respiratory tract; (2) inhibition of mastoidal cell mediator release; (3) suppression of neutrophil granulation, - (4) inhibition of basophil granulation; and (5) inhibition of the activation of rnonocitos and rnacrofagos. Accordingly, compounds that activate adenylate cyclase or inhibit phosphodiesterase would be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The main cellular mechanism for the activation of cMFfi is the hydrolysis of the 3'-phosphodiester bound by one or more of the family of isozymes known as cyclic nucleotide foefodiesterases (FDE). It has been shown that a distinct cyclic nucleotide phosphodiesterase (FDE), the isozi to FDE IV is responsible for the decomposition of cMFO in the smooth muscle of the respiratory tract and in the inflammatory cells [Torphy "Phosphodiesterase Isozymes: Potential Targets for Novel Anti --asthnatic ñgents "in New Drugs for Asthrna, Barnes, ed. IBC Technical Services Ltd., 1989]. Research indicates that the inhibition of this enzyme not only results in relaxation of the smooth muscle of the respiratory tract, but also suppresses the granulation of the mastoidal.es cells, the basophils and the neutrophils, together with the inhibition of the activation of rhonocytes and neutrophils. In addition, the beneficial effects of FDE IV inhibitors are markedly enhanced when the adenylate cyclase activity of the target cells is elevated, by appropriate hormones or autocoids, as the case may be, in vivo. Thus, inhibitors of FDE IV would be effective in the asthmatic lung, where the levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are high. These compounds would offer a similar approach to the pharmacotherapy of bronchial asthma and possible important therapeutic advantages with respect to the agents currently existing in the market. The compounds of this invention also inhibit the production of Tumor Necrosis Factor. (FNT), a serum glycoprotein. Excessive production of TNF, or unregulated production thereof, has been implicated in the mediation or exacerbation of numerous diseases, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis or other arthritic conditions.; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, respiratory distress syndrome in adults, cerebral malaria, inflammatory disease of chronic inflamed lung, silicosis, pulmonary sarcoidosis, bone reabsorption diseases, reperfusion damage, reactions of the graft against the recipient, allograft rejections, fever and myalgia due to infection, such as influenza, cachexia secondary to infection or malignant disease, cachexia secondary to acquired human immunodeficiency syndrome (AIDS), AIDS, CRS (AIDS-related complex) , keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis or pireeis, in addition to numerous other autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosus (SLE). AIDS is the result of the infection of T lymphocytes with the Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, namely HIV-1, HIV-2 and HIV-3. As a result of HIV infection, T cell-mediated immunity is damaged and infected individuals manifest severe opportunistic infections and / or unusual neoplasms. The entry of HIV into the T lymphocyte requires the activation of the T lymphocyte. Viruses such as HIV-1 or HIV-2 infect the T lymphocytes after the activation of the T cell, and said expression of the virus protein and / or reproduction it is mediated or maintained by said T-cell activation. Once the activated T lymphocyte is infected with HIV, it must continue to remain in an activated state the T lymphocyte to allow the expression of the HIV gene and / or the reproduction of HIV . Cytokines, specifically in FNT, are involved in the expression of the activated T cell-mediated HIV protein and / or the reproduction of the virus, by playing a role in the maintenance of the T lymphocyte. Therefore, interference with the Cytokine activity, such as, for example, by inhibiting cytokine production, notably from TNF in an HIV-infected mdLviduo, helps to limit the maintenance of T cell activation, thereby reducing the progress of the mfectivity with HIV to previously uninfected cells, which results in a decrease or elimination in the advancement of immune dysfunction caused by HIV infection. Onsocits, macrophages, and related cells, such as kupffer and glial cells, have also been implicated in the maintenance of HIV infection. These cells, like T cells, are targets for viral reproduction, and the level of viral reproduction depends on the state of activation of the cells. See Rosenberg and co-authors, The Irnmunopathogenesis of HIV Infection, Advances m Imm? Nology, Volume 57, 1989]. Renal diseases, such as FNT, have been shown to activate the reproduction of HIV in monocytes and / or macroagles [See Poli et al., Proc. Nati Acad. Sci., 87: 782-784, 1990], therefore, the inhibition of monoquin production or its activity helps to limit the progression of HIV, as previously indicated for T cells. The TNF has also been involved in various roles in other viral infections, such as citornegalovirus (CMV), influenza virus, adenovirus and herpes virus, for reasons similar to those noted. FNT is also associated with yeast and fungal infections. Specifically, it has been shown that Candida albicans induces the production of FNT i vitro in human monocytes and in natural killer cells. CVirse Riipi and coauthors, Infection and Im unity, 58 (9): 2750-54, 1990; and Dafari and co-authors, Journal of Infectious Diseases, 164: 389-95, 1991. See also laan and co-authors, Antimicrobial Agents and Chernotherapy, 35 (10): 2046-48, 1991; and Lu e and co-authors, Journal of Infectious Diseases, 152: 211-214, 1990]. The ability to control the adverse effects of TNF is increased by the use of compounds that inhibit TNF in mammals in need of such use. There remains a need for compounds that are useful for treating morbid states mediated by TNF, which are exacerbated or caused by the excessive and / or unregulated production of TNF.

BRIEF DESCRIPTION OF THE INVENTION The novel compounds of this invention are represented by the formula (I): where: Rl is - (CR4R5) nC (0) 0 (CR4R5) mR6, - (CR «R5) n C (0) NR« (CR4R5) «? 6, - (CR4R5) nO (CR.; R5) m Re or - (CR-R) RS wherein the alkyl portions may be unsubstituted or substituted with one or more fl ow atoms; m is 0 to 2; n is 0 a 4, r is 0 to 6, R4 and s are independently hydrogen or alkyl of 1 to 2 carbon atoms, Re is hydrogen, methyl, hydroxyl, aryl, aryl substituted with halogen, aryloxy-C1-3 alkyl, aryloxy-alkyl of C1-3 substituted with halogen, indanyl, indenyl, polycycloalkyl of 7 to 11 carbon atoms, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 4 to 6 carbon atoms containing one or two unsaturated ligatures; wherein the cycloalkyl or heterocyclic portion may be unsubstituted or substituted with 1 to 3 methyl groups, an ethyl group or a hydroxyl group; provided that: (a) when Rβ is hydroxy. lo, then m ee 2; or (b) when Rβ is hydroxyl, then r is 2 to 6; or (c) when Rβ is 2-tetrahydropyranyl, 2-tetra-hydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then it is 1 or 2; or (d) when Rβ is 2-tetrahydropyranyl, 2-tetra-hydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then r is 1 to 6; (e) when n is 1 and m is 0, then Rβ is different from H in - (CR * Rβ) n0 (CR «R5) mRβ; X is YR2, fluorine, NR4R5 or formi sheet; Y is 0 OR S (0) m '; rn 'is 0, 1 or 2; X3 is hydrogen or X; R2 is -CH3 or -CH2CH3 unsubstituted or substituted by one or more fluorine atoms; s is 0 to 4; R3 is COOR14, C (0) R4? "Or R7; Ul is alkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 6 carbon atoms; Z os 0, NR7, NCR4RSC2-6 alkenyl, NOR14, NOR15, NOOR4R5C2-6 alkene, NNR4R14, NNR4R15, NCN, NNRßC (0) NRβ R14, NNR8C (S) NR8R? -4 or - ~ Z is 2- (1, 3-d? T? An), 2- (1, 3-d? T? Olano), < J? Rnet? L? Ocetal, diethylthioaceta, 2- (1,3-d? Oxolane), 2- (1,3-dioxane), 2- (l, 3-oxat tolane), dinethyl ketal or diethyl ketal; F? 7 is - (CR4R5) qR12 or alkyl of 6 carbon atoms, wherein the group R12 or alkyl of 1 to 6 carbon atoms is unsubstituted or substituted one or more times with methyl or ethyl, unsubstituted or substituted with one or three fluorine atoms, -F, -Br, -Cl, -NO2, -NR10R11, -C (0) Rβ, -CO2 Rβ, -0 (CH2) 2-4? R8, -0 (CH2) qRβ, ~ CN, -C (0) NR? O Rl 1, -0 (CH2) qC (0) NRioRll, -0 (CH2) qC (0) R9 / -NR10 C (0) NR? O Rl 1, -NR10 C (0) Ri 1, -NR10 C (0) 0R9, -NR? OC (0) Ri3 , -C (NR? O) NR? O Rl 1, -C (NCN) NR? O Rl 1, - C (NCN) SR9, NR? OC (NCN) SR9, -NR10 C (NCN) NR? O Rl 1, -NR10 S (0) 2 R9, -S (0) m'R9, -NR10 C (0) C (0) NR? O Rl 1, ~ NR? Or C (0) C (0) Rio or R13; q e s, 1 or 2; R12 is R13, cycloalkyl of 3 to 7 carbon atoms (2-, 3- or 4-pyridyl), pyridyl, pyrazolyl, (1- or 2-ynidazolyl), pyrrolyl, piperazinyl, piperidi nyl, rnorfol milo, furamlo, (2- or 3-tLen? Lo), quinolmyl, naphthyl or femlo; Rβ is hydrogen or R9; R9 is alkyl of 1 to 4 carbon atoms, unsubstituted or substituted by one to three fluorine atoms; R11 is hydrogen or alkyl of 1 to 4 carbon atoms, unsubstituted or substituted by one to three fluorine atoms; or when Rio and Rn are like NR10 11 then, together with nitrogen, they can form a 5- to 7-membered ring consisting solely of carbon atoms or carbon atoms and at least one heteroatom selected from 0, N or S; R 13 is a substituted or unsubstituted heteroaryl group, selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl and thiadiazolyl; and wherein R13 is substituted on R12 or R13 the rings are connected by means of a carbon atom and every second ring R13 may be unsubstituted or substituted with one or two alkyl groups of 1 to 2 carbon atoms, unsubstituted or substituted in methyl, with 1 to 3 fluorine atoms; RIA is hydrogen or R7; or when Rß and Ru are like NRßRi4, can form, together with nitrogen, a ring of 5 to 7 members consisting solely of carbon atoms or of carbon atoms and at least one heteroatom selected from 0, N or;; provided that: (f) R7 is not alkyl of 1 to 4 carbon atoms, unsubstituted or substituted with 1 to 3 fluorine atoms; or their pharmaceutically acceptable salts. Another series of compounds of this invention are represented by the formula (II): wherein: Rl is - (CR «R5) nC (0) 0 (CR« Rs) mRβ - (CR «R5) n C (0) NR« - (CRAR5) n0 (CR4Re) mRβ or - (CR < R5) RR6 wherein the alkyl portions may be unsubstituted or substituted with one or more fluorine atoms; rn ee 0 to 2; n is 0 a; r is 0 to 6; RA and Rs are independently selected from hydrogen or alkyl of 1 to 2 carbon atoms; Rβ is hydrogen, methyl, hydroxyl, aryl, aryl substituted by halogen, aryloxy-C1-3 alkyl, aryloxy-C1-3 alkyl substituted with halogen, indanyl, indenyl, polycycloalkyl of 7 to 11 carbon atoms, tetrahydro-furanyl , furanyl, tetrahydropyranyl, pyranyl, tetrahydro-thienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 4 to 6 carbon atoms containing one or two unsaturated ligatures; wherein the cycloalkyl and heterocyclic portions may be unsubstituted or substituted with 1 to 3 methyl groups, an ethyl group or a hydroxyl group; provided that: (a) when Rβ is hydroxyl, then rn ee 2; or (b) when Rβ is hydroxyl, then r is 2 to 6; or (c) when Rβ is 2-tetrahydropyranyl, 2-tetra-hydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then rn is 1 or 2; or (d) when Rβ is 2-tetrahydropyranyl, 2-tetra-hydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then r is 1 to 6; (e) when n is 1 and m is 0, then Rβ is different from H in - (CR «Re) nO (CR« Rs) m ß; X is YR, fluorine, NRs Rs or forrn lamina; Y is 0 or S (0) m '; rn 'is 0, 1 or 2; X3 is hydrogen or X; R2 is independently selected from -CH3 or -CH2CH3, unsubstituted or substituted by one or more fluorine atoms; s is 0 to 4; R3 is COOR14, C (0) NRARIA OR R7; U is alkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; Z is C (Y ') RIA, C (0) 0Ru, C (Y') NR? Or Rl4, C (NR? O) NR? ORl4, CN, C (N0R8) Ri-i, C (0) NR? NR8C (0) R?, C (0) NR? NR? ORl4, C (N0Ri4) R?, C (NR8) N? or l4, C (NRi4) NR8 RβC (NCN) NR? oRl4, CINCNSRg), (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-) triazole? loCl, 2, 3]), (3- or 5-triazo.li.loCl, 2, 4]), (5-tetrazo.lilo), (2-, 4- or 5-oxazolyl), (3 -, 4- or 5-isoxazolyl), (3- or 5-oxadia.zolylCl, 2,4]), (2-oxadiazolylCl, 3,4.]), (2-thiadiazolyl.oCl, 3,)), (2-, 4- or 5-thiazolyl), (2-, 4- or 5-oxazo.idinyl), (2-, 4- or 5-thiazolidinyl) or (2, -, 4- or 5-imidazolidinyl); wherein all the heterocyclic ring systems may be optionally substituted one or more times with R14; Y 'is 0 or S; R? is - (CR4R5) qR12 or alkyl of 6 carbon atoms, wherein the group R12 or alkyl of 1 to 6 carbon atoms is unsubstituted or substituted one or more times with methyl or ethyl, unsubstituted or substituted by one or three fluorine atoms, -F, -Br, -Cl, -NO2, -NR10R11, ~ C (0) R8, -CO2R8, ~ 0 (CH2) 2-4? Rβ, -0 (CH2) qRβ, - CN, -C (0) NR? O Rl 1, --0 (CH2) q C (0) NRioRll, -0 (CH2) qC (0) R9, -NR? OC (0) NR? Or RI 1, -NR? OC (O) Ri 1, -NR10 C (0) 0R9, -NR? OC (0 ) Ri3, -C (NR10) NR? OlI, -C (NCN) NR? O 11, -C (NCN) SR9, NR? OC (NCN) SR9, -NR? 0C (NCN) NR? Or Rll, - NR10 S (0) 2 R9, - S (0) m'R9, -NR? OC (0) C (0) NR? ORll, -NR10 C (0) C (0) Rio O R13; q is 0, 1 or 2; R12 is R13, cycloalkyl of 3 to 7 carbon atoms or an unsubstituted or substituted aryl or heteroaryl group, selected from the group consisting of (2-, 3- or 4-? Iridi.lo), pyrirnidyl, pyrazolyl, (1 - or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, orpholinyl, furanyl, (2- or 3-thienyl), quinoxylin, naphthyl and phenyl; R8 is independently selected from hydrogen or R; R is alkyl of 1 to 4 carbon atoms, unsubstituted or substituted by one to three fluorine atoms; Rio © s 0R8 or Rn; R11 is hydrogen or alkyl of 1 to 4 carbon atoms, unsubstituted or substituted by one to three fluorine atoms; or when Rio and R11 are as NR10R11, together with nitrogen, they can form a 5- to 7-membered ring consisting solely of carbon atoms or carbon atoms and at least one heteroatom selected from 0, N or S; R13 is a substituted or unsubstituted heteroaryl group, selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, irnidazolyl, irnidazolidinyl, tlazol.idinyl, isoxazolyl, oxadiazolyl and thiadiazolyl; and when R13 is substituted on R12 or R13 the rings are connected by means of a carbon atom and every second ring R13 can be unsubstituted or substituted by one or two alkyl groups of 1 to 2 carbon atoms, unsubstituted or substituted on methyl, with 1 to 3 fluorine atoms; R14 is hydrogen or R7; or when Rß and R14 are as NRßRi-n, they can form, together with the nitrogen, a ring of 5 to 7 members consisting solely of carbon atoms or of carbon atoms and at least one heteroatom selected from 0, N O S; provided that: (f) R7 is not alkyl of 1 to 4 carbon atoms, unsubstituted or substituted with 1 to 3 fluorine atoms; or their pharmaceutically acceptable salts. This invention also relates to pharmaceutical compositions comprising a compound of the formula (I) and (II) and a pharmaceutically acceptable carrier or diluent. The invention also relates to a method of measuring the enzymatic activity (or catalytic activity) of FDE IV in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of the formula (I). ) and (II), as shown later. The invention further provides a method for treating allergic or inflammatory diseases, comprising administering to a mammal, including humans in need thereof, an effective amount of a compound of formula (I) and (II). The invention also provides a method for treating the. asthma, which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of the formula (I) and (II). This invention also relates to a method for inhibiting the production of TNF in a mammal, including humans, which method comprises administering to a mammal in need of said treatment an effective, TNF-inhibiting amount of a compound of the formula (I). ) and (II). This method can be used for the prophylactic treatment or prevention of certain disease states mediated by TNF, which are susceptible to it. This invention also relates to a method of treating a human afflicted with a human deficiency virus (HIV), which comprises administering to said human an effective, TNF-inhibiting, amount of a compound of the formula (I) and ( II). The compounds of the formula (I) and (II) are useful in the treatment of additional viral infections, wherein said viruses are sensitive to up-regulation, by * FNT, or which will unleash the in vivo production of TNF. In addition, the compounds of the formula (I) and (II) are also useful for treating yeast and / or fungal infections, wherein said yeasts and said fungi are sensitive to up-regulation by means of TNF, or will unleash the production of FNT in vivo.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to a method for mediating or inhibiting the enzymatic activity (or catalytic activity) of FDE IV in a mammal in need thereof, or to inhibit the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula (I) and (II). Inhibitors of phosphodiesterase IV are useful in < A variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, sopasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, damage by reperfusion of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and respiratory distress syndrome in adults. In addition, inhibitors of FDE IV are useful in the treatment of diabetes mellitus and alterations in the central nervous system, such as depression and dementia due to multiple infarcts. The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those that are sensitive to inhibition, for example, by decreased reproduction, directly or indirectly, by the TNF inhibitors of the formula (I) and (II). Such viruses include, but are not limited to: VTH-1, HIV-2 and HIV-3, cytomogalovirus (CMV), influenza, adenovirus and herpes group virus, such as, but not limited to, Herpes zoster and Herpes simplex. This invention relates more specifically to a method of treating a mammal afflicted by a human immunodeficiency virus (HIV) comprising administering to said mammal an effective, TNF-inhibiting, amount of a compound of the formula (I) and ( II). The compounds of this invention may also be used in association with the veterinary treatment of animals, which are not human, and which require the inhibition of TNF production. The diseases mediated by TNF to be treated, therapeutically or prophylactically, in animals, include disease states, such as those noted above, but in particular viral infections. Examples of such viruses include, but are not limited to, feline immunodeficiency virus (FIV) and other retroviral infections, such as equine infectious anemia virus, goat arthritis virus, visna virus, virus. maedi and other lentiviruses. Also useful are the compounds of this invention for treating yeast and fungal infections, wherein said yeasts and said fungi are sensitive to upregulation by TNF or will unleash the production of TNF in vivo. A preferred disease state to be treated is fungal meningitis. Additionally, the compounds of formula (I) and (II) can be administered in conjunction with other screening agents for systemic infections by yeast and fungi. The selection drugs for fungal infections include, but are not limited to, the class of compounds called poly-toxins, such as Polyrnicma B; the class of compounds called the midazoles, such as clotrimazole, econazole, miconazole and ketoconazole; the class of compound called the tnazoles, such as fluconazole and itranazole; and the class of compounds called amphotems, in particular Amphotericin B and Amphotericin B liposornica. The compounds of the formula (I) and (II) can also be used to inhibit and / or reduce the toxicity of an anti fungal, antibacterial or antiviral agent by administering an effective amount of a compound of the formula (I) and (II) ) to a mammal in need of such treatment. Preferably, a compound of the formula (I) and (II) is administered to inhibit or reduce the toxicity of the class of amphoteric compounds, in particular Anfo epycine B. The term "alkyl groups of 1 to 3 carbon atoms" , "C 1-4 alkyl", "C 1-6 alkyl" or "alkyl" is used herein to include both straight chain or branched chain radicals of 10 carbon atoms, unless the chain length is specifically limited, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butiio, secondary butyl, isobutyl, tertiary butyl, and the like. "Alkenyl" means straight chain and branched chain radicals of 1 to 6 carbon atoms, unless the length of the chain is specifically limited, including, but not limited to: vi n lo, 1-propen? Lo , 2-propemlo or 3-met? L-2-propemlo. The term "cycloalkyl" or "cycloalkylalkyl" means groups of at 7 carbon atoms, such as cyclopropyl, cyclopropyl and ilo, cyclopentyl or cyclohexyl. Where specified otherwise, "aplo" or "aralkyl" means a ring or system of aromatic rings, of 6 to 10 carbon atoms, such as phenyl, benzyl, phenethiio or naphthyl. Preferably it is rnonocicyclic, ie, phenyl. It is meant that the alkyl chain includes both straight or branched chain radicals, of 1 to 4 carbon atoms. "Hetero p lo" means an aromatic ring system that contains one or more heteroatoms. "Halogen" means all halogens, i.e., chlorine, fluorine, bromine or iodine. "Inhibit the production of IL-1" or "inhibit the production of TNF" means: (a) a decrease in excessive levels of IL-1 or FNT in vivo, respectively, in a human, at normal levels or below from normal levels, they measured the inhibition of the live release of IL-1 by all cells including, but not limited to, monocytes or RNAs; (b) down-regulation, at the translational or trans-national level, of excessive in vivo levels of IL-1 or TNF, respectively, in a human, at normal levels or below normal levels; or (c) a down-regulation, by inhibiting the direct synthesis of the levels of II. ~ 1 or FNT, as a post-translational event. The phrase "illness or disease states mediated by FNT" means any and all disease or morbid states in which the TNF plays a role, either by the production of the TNF itself or because the TNF causes another cytokine to be released. , such as, but not limited to, IL-1 or IL-6. A disease state in which IL-1, for example, is a major component, and whose production or action is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF. As FNT-fí (also known as lymphotoxin) has a close structural homology with FNT-o (also known as caq? Ectin), and since each of them induces similar biological responses and binds to the same cellular receptor, both TNF-a and TNF ~ (3 are inhibited by the compounds of the present invention and, thus, will be referred to collectively herein as "FNT", unless specifically delineated in another manner. FNT- "Cytokines" is inhibited means any secreted polypeptide that affects the functions of cells and is a molecule that modulates the interactions between cells in immune responses, inflammatory or hematopoietic. A cytokine includes, but is not limited to, monokines and lymphocytes, regardless of which cell produces them. The cytokine inhibited by the present invention for use in the treatment of a human infected with HIV must be a cytokine that is involved in: (a) the initiation and / or maintenance of T cell activation and / or expression and / or reproduction of the HIV gene, mediated by activated T cell, and / or (b) any problem associated with a cytokine-mediated disease, such as cachexia or muscle degeneration. Preferably this cytokine is FNT-OI. All compounds of the formula (I) and (II) are useful for inhibiting the production of TNF, preferably by rnacrophages, monocytes or macrophages and rhonocytes, in a mammal including humans in need thereof. All the compounds of the formula (T) and (II) are useful for inhibiting or mediating the enzymatic or catalytic activity of FDE IV and in the treatment of the disease states mediated by them. Preferred compounds are the following: When i for the compounds of the formula (I) and (II) is an alkyl substituted with 1 or more halogens, preferably the halogens are fluorine and chlorine, better still, an alkyl of 1 to 4 carbon atoms substituted with one or more fluorine atoms. The length of the preferred halogen-substituted alkyl chain is 1 or 2 carbon atoms and, most preferably, are the portions -CF3, -CH2F, -CHF2, CF2CHF2, CH2CF3 and -CH2CHF2. The preferred Ri substituents for the compounds of the formula (I) and (II) are CH2-cyclopropyl, CH2-cycloalkyl of 5 to 6 carbon atoms, cycloalkyl of 4 to 6 carbon atoms unsubstituted or substituted by OH, polycycloalkyl of 7 to 11 carbon atoms, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or alkyl of 1 to 2 carbon atoms unsubstituted or substituted by one or more fluorine atoms, - (CH2) -3C (0) (CH2)? -2CH3, - (CH2) l -3? (CH2)? -2CH3 V- (CH2) 2-4? H. When the term Ri is (CR4R5), the terms R4 and Rs are independently hydrogen or alkyl. This allows the branching of the individual methylene units as (CR4R5) n or (CR «Rs) m; each repeating methylene unit is independent of the others, for example, (CR4Rs) n where n is 2 can be -CH2CHI -CH3) -, for example. The individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon may be unsubstituted or substituted with fluorine, independently from each other to produce, for example, the preferred Ri substitutions, which were noted above. When Ri is a polycycloalkyl of 7 to 11 carbon atoms, examples are bicycloC2.2.1] heptyl, bicyclo-C2.2.2] octyl, bicycloC3.2.1] octyl, tricycloCS .2.1.02. ß] -decile, etc. additional examples of which are described in Saccamano and co-inventors, UO 87/06576, published on November 5, 1987, the description of which is incorporated herein by reference in its totality. Preferred Z terms are 0, NCN, NR7, NOR14, NOR15, NNR4R14, NNR4R15, 2- (1, 3-dithiane), dimethylthioketal. , 2- (1,3-dioxolane) or dimethyl ketal. More preferred is 0, NR, NOR14, NOR15 and 2 - (., 3-dioxolane). Preferred X groups of formula (I) and (II) are those in which X is YR2 and Y is oxygen. The preferred group X2 for formula (I) and (II) is that in which X2 is oxygen. The preferred group X3 for formula (I) and (II) is that in which X3 is hydrogen. Preferred R2 groups, when applicable, are an alkyl of 1 to 2 carbon atoms unsubstituted or substituted with one or more halogens. The halogen atoms are preferably fluorine and chlorine, better still, fluorine. The most preferred R2 groups are those in which R2 is methyl or alkyl substituted with fluorine, specifically an alkyl of 1 to 2 carbon atoms, such as a portion -CF3, -CHF2 or -CH2CHF2. Most preferred are the portions -CHF2 and -CH3-Lae portions R7 include R13, - (CH2) or-2 (2-, 3- or 4-pyridyl) unsubstituted or substituted, (CH2)? -2- (2-imidazolyl) ), (CH 2) 2 (4-morpholinyl), (CH 2) 2 (4-piperazinyl), (CH 2)? -2- (2-thienyl), (CH 2)? -2- (4-thiazolyl), unsubstituted pyrimidinyl or substituted and (CH2) o-2 substituted or unsubstituted phenyl. Preferred rings, when Rio and R11 in the -NR10R11 portion together with the nitrogen to which they are attached, form a 5- to 7-membered ring, consisting solely of carbon or carbon atoms and at least one het round selected from 0, N or S, include, but is not limited to, a 1-α-dazolyl ring, 2- (Rβ) -1-? rn? dazolyl, 1-pyrazolyl, 3 ~ ( R8) -l- ??? razol lio, 1-t riazolilo, 2-tpazol i lo, 5- (R8) -l-triazolyl, 5- (R?) -2-tr? Azol? 5 ~ (Rβ) -l-tetrazolyl, 5- (R8) -2-tetrazol lyo, 1- tet razo ll lo, 2- et razol i lo, rnorfol ímlo, piperazmilo, 4- (R8) - l- piperazinyl or r-rol? lo. Preferred rings, when R8 and R? In the -NRßRi-i portion, together with the nitrogen to which they are attached, can form a 5- to 7-membered ring, consisting solely of carbon atoms and at least one heteroatom , selected from 0, N or S include, but are not limited to: 1-ylidazolyl, 1-??? razol ?, 1-tpazolyl, 2-riazolyl, 1-tetrazolyl, 2-1-etrazolyl, rnorfolinyl, piperazimide and pyrrolyl. . The respective rings may be additionally substituted, where applicable, at a nitrogen or carbon atom available, with the R7 portion which was described herein for formula (I) and (TI). Illustrations of such substitutions at the carbon atom include, but are not limited to, 2- (R7) -l-nidazolyl, 4 ~ (R7) -l-? Rn? Dazol 1I0, 5 ~ (R7) -l- irnidazolyl, 3- (R7) ~ l - ?? razol? lo, 4- (R7) - 1 -pi razol 1 lo, 5- (R7) -lp? azol lyo, 4- (R7) -2-tpazol lyo, 5- (R7) -2-tr? a ol lio, 4- (R7) -l-tpazol?, 5- (R) 1 -triazolyl, - (R7) -1-tetrazole? Lo and 5- (R7) -2-tetrazole? Lo. The substitution applicable to nitrogen, with R7 include, but is not limited to: l- (R7) -2- tet razol i lo, 2- (R7) -1- tet razol i lo, 4- (R7) -. l-piperazinyl.

When applicable, the ring may be substituted one or more times with R? . Preferred groups for NR8Ri4 containing a heterocyclic ring, are 5- (R ") -l-tetrazolyl, 2- (R?") - l-imidazolyl, 5- (Ri4) -2-tetrazolyl, 4- (R? ") -1-piperazinyl or 4- (Riß) -1-? Iperazinyl. Preferred rings for R13 include (2-, 4- or 5-irnidazolyl), (3-, 4- or 5-urazolyl), (4- or 5-triazolylCl, 2,3]), (3- or 5-yl) -triazolylCl, 2, 4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolylCl, 2,4 ]), (2-oxadiazolylC.l, 3, 4]), (2-thiadiazolylCl, 3,4]), (2-, 4- or 5-thiazolyl), (2-, 4- or 5-oxazolidinyl) , (2-, 4- or 5-thiazolidinyl) or (2-, 4- or 5-irnidazolidinyl). When the group R7 is unsubstituted or substituted with a heterocyclic ring, such as imidazolyl, pyrazolyl, pyrirnidinyl, triazolyl, tetrazolyl or thiazolyl, the heterocyclic ring itself may be unsubstituted or substituted with Rβ, either at a nitrogen or a nitrogen atom. available carbon, such as 1- (R8) -2-imidazolyl, 1 ~ (R8) -4-imidazolyl, 1- (R8) -5-irnidazolyl, 1 ~ (R8) -3-pyrazolyl, 1- (R8) -4- pi razoli.Lo, 1- (Rβ) -5-? Ir * azoli.lo, 1- (Rβ) -4-triazolyl or 1- (R8) ~ 5-triazolyl. When applicable, the ring may be substituted one or more times with Rβ-U preferably it is alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, where when it is alkenyl or alkynyl, one or two double or triple bonds may be present. . What is most preferred is that W is ethinyl or 1,3-butadiinyl. Preferred are those compounds of the formula (I) and (II) in which R is -CH2-cyclopropyl, -CH2-cycloalkyl of 5 to 6 carbon atoms, cycloalkyl of 4 to 6 carbon atoms unsubstituted or substituted with OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or alkyl of 1 to 2 carbon atoms unsubstituted or substituted by one or more fluorine atoms, and - (CH2) 2-4 [beta] H; R2 is methyl or alkyl substituted with fluorine; R3 is R7, wherein R7 is an unsubstituted or substituted aryl or heteroaryl ring; X is YR2 and Z is 0, NR7. Z 'preferably is COOR14. More preferred are those compounds in which R ee-CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; And it's oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl, W is ethynyl or 1,3-butadiinyl, R3 is a substituted or unsubstituted pyrirnidinyl ring, and Z is 0, NR7. The pharmaceutically acceptable salts of the compounds of the present invention, when they can be prepared, are also intended to be covered by this invention. Those salts will be those that are acceptable in their application for pharmaceutical use. By this is meant that the salt retains the biological activity of the original compound and that the salt has no undesirable or detrimental effect on its application or its use in treating the diseases. The pharmaceutically acceptable salts are prepared in a common and current manner. The original compound, dissolved in a suitable solvent, is treated with an excess of an organic or inorganic acid, in the case of the acid addition salts of a base, or an excess of organic or inorganic base, when the molecule contains a COOH, for example. The pharmaceutical compositions of the present invention comprise a pharmaceutical carrier or diluent and a certain amount of a compound of the formula (I) and (II). The compound may be present in an amount that effects a physiological response, or may be present in a minor amount, so that the user needs to take two or more units of the composition to effect the intended treatment. These compositions can be constituted as a solid, a liquid or in gaseous form. Or one of these three forms can be transformed into another at the moment of being admixed, for example, when a solid is supplied by means of an aerosol, or when a liquid is supplied as a spray or an aerosol. The nature of the composition and the pharmaceutical carrier or diluent, of course, will depend on the intended route of administration, for example, parenteral, topical, oral or by inhalation. For topical administration, the pharmaceutical composition is in the form of a cream, an ointment, a liniment, a lotion, pastes, aerosols and drops suitable for administration to the skin, eyes, ears or nails. For parenteral administration, the pharmaceutical composition will be in the form of a sterile injectable liquid, such as an ampule or an aqueous or non-aqueous liquid suspension. For oral administration, the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, troche, caramel, syrup, liquid or emulsion. When the pharmaceutical composition is used in the form of a solution or a suspension, examples of suitable pharmaceutical carriers or diluents include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid paraffins and mixtures thereof, with water; for solid systems, lactose, kaolin and mamtol; and for aerosol systems dichlorodifluoromethane, chlorotropfluoroethane and compressed carbon dioxide. Also in addition to the pharmaceutical carrier or diluent, other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like can be included in the compositions herein, provided that said additional ingredients do not have detrimental effects on the therapeutic option of the compositions herein. In such a manner, the pharmaceutical preparations described are prepared following the conventional techniques of pharmaceutical chemistry, when appropriate, for the desired final product. In those compositions, the amount of carrier or diluent will vary, but preferably it will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid, it may be present in amounts less than, equal to or greater than that of the solid active ingredient. Usually a compound of the formula (D) is administered to a subject in a composition comprising a non-toxic amount sufficient to produce an inhibition of the symptoms of a disease in which the leukotrienes are a factor.The topical formulations will contain between 0.01 and 5.0% by weight, approximately, of the active ingredient and will be applied as required as a preventive or curative agent to the affected area When used as an oral regimen or other ingested or injected regimen, the dosage of the composition of the scale of 50 mg to 1000 mg of active ingredient for each administration For convenience, equal doses will be administered from one to five times a day, with the daily administration regimen being selected from around 50 ng to around 5000 rng. some of the compounds of the formula (I) and (TI) can exist in racernic and optically active forms. n different diastereomeric forms that have different physical and biological properties. All of those compounds are considered to be within the scope of the present invention. The compounds of the formula (I) wherein Z is 0 or (II) can exist in a tautome form, for example, as the enol form. This can be represented by »0, which is exocyclic with respect to the cyclohexane ring (or in contrast to the endocyclic portion or portion -C (-0H) ~ C (-R) -, wherein the cyclohexane ring is now unsaturated at position 1-2, ie, cyclohex-l-ene, or and R is Z in the formula (II). It will also be recognized that the position 2 of the ring in the exocyclic form may be substituted (R), such as in the compounds of the formula (I) or (II). The following examples are given to further illustrate the present invention. These examples are only intended to illustrate the invention and should not be read as limiting the invention in any way. The claims are referred to for what is reserved for the inventors according to the present invention. No unacceptable toxicological effects are expected when these compounds are administered according to the present invention.

METHODS OF PREPARATION SCHEME (S) OF SYNTHESIS WITH TEXTUAL DESCRIPTION The compounds of the formula (I) can be prepared by the processes described herein which comprise reacting a terminal acetylene, such as, for example, the compound 1-Scheme 1, with an aryl halide, such as phenyl iodide, in the presence of a suitable catalyst, such as a copper halide (I) and a bivalent or zero valent palladium compound, in the presence, for example, of tri-phenylene phosphine, in a suitable solvent such as an amine, as in the process from Brandsma and co-authors, (Syn.Comm., 1990, 20, 1889), followed by hydrolysis of the ketal protecting group, under common and current conditions, which gives a compound of the formula 1-Scheme 1. The compounds of the Formula 1-Scheme 1 can be prepared by procedures analogous to those described in previously filed US Patent Applications, 07 / 862,083; 07 / 968,753 and PCT / US93 / 0.1990, which designates the United States, and filed on March 5, 1993 (UIPO Publication No. UO 93/19748) or the application of TCP PCT / US93 / 02325, published as UO 93/19750.

SCHEME 1 (a) Pd (PPh3) -v, PPh3, Cul, CßHsI, piperidine; b) p-pyridinium toluensul fonate (H3O2CO / H2O) Alternatively, the compounds of the formula (I) can be prepared by reacting a terminal acetylene such as, for example, compound I-Scheme 2 with appropriate halide, R3X , where R3 represents R3, as defined by '. "> to the formula (I), or a group convertible to R3, in the presence of a suitable catalyst, such as a copper halide (I) or a bivalent or zero valent palladium compound, in the presence, for example , of tri-phenyl phosphine, in a suitable solvent such as an amine, in the procedure of Brandsrna and co-authors, (Syn. Comm., 1990, 20, 1889), to give a compound of the formula 2-Scheme 2, - said compounds of the formula (I) can then be converted to other compounds of the formula (I) by common manipulation of the functional groups in the portion R. The compounds of the formula 1-Scheme 2 can be prepared by analogous procedures. to those described in the pending United States patent applications, previously filed, 07 / 862,083; 07 / 968,753 and PCT / US93 / 01990, which designates' the United States, and filed on March 5, 1993 (UIPO publication No. UO 93/19748) or the TCP request PCT / US93 / 02325, published gives as UO 93/19750.

SCHEME 2 of (a) Pd (PPh3, PPh3, C? l, R3X, piperidine Alternatively, the oxidation cartilage of a terminal acetylene, for example, as compound 1-Scheme 3, using an appropriate metal salt, such as a copper salt, with a catalytic amount of a palladium salt, in the presence of a suitable base, such as an acid trap, for example, sodium acetate in a suitable alcohol, such as methanol, as in the Tsuji method and coauthors, (Tet., Lett., 1980, 21, 849), followed by hydrolysis of the methyl ester under common and current conditions, then provides the compound of the formula (I) (2-Esq? ema 3), said compounds of the formula (I) can then be converted to other compounds of the formula (I) by normal manipulation of the carboxylic ester moiety.

SCHEME 3 COOCH (a) PdCl2, C? Cl2, Na? 2 CCH3, CO, CH3 OH.

The compounds of the formula (II) can be prepared by methods analogous to those of schemes 1, 2 and 3 above, as illustrated in scheme 4 hereof. Depending on the exact nature of the Z 'groups of the compounds of the formula (II), the group = 0 may require protection during the coupling steps described herein, for example, as a compound of the formula (II) in wherein -0 is a dimethylketal or 2- (1, 3-dioxolane), followed by deprotection, and then reaction by the synthesis procedures described in the copending US patent applications, previously filed 07 / 862,083; 07 / 968,753 and PCT / US93 / 01990, which designates the United States, and filed on March 5, 1993 (UIPO publication No. UO 93 / 1.9748) or the application of TCP PCT / US93 / 02325, published as UO 93 / 19750, to provide the compound of the formula (II); likewise, the group Z 'may require protection during the coupling steps, followed by deprotection to give * the compound of the formula (II) and said protecting groups are well known to those skilled in the art. (See: Greene, T. and Uuts, P.G.M. Protecting Groups in Organic Synthesis, second edition, John Uiley and Sons, New York, 1991).

SCHEME 4 (a) Pd (PPh3) «, PPh3, Cul, R3X, piperidine. The preparation of the remaining compounds of the formulas (I) and (II) can be achieved by procedures analogous to those described above and in the examples that follow. It will be recognized that the compounds of the formula (I) and (II) can exist in different diastereomeric forms that have different physical and biological properties; said isomers can be separated by common and current chromatographic methods. The following examples are given to further illustrate the present invention. These examples are intended only to illustrate the invention and are not read as limitations on the invention in any way. Reference is made to the claims for what is reserved to the inventors, according to the present.

EXAMPLES OF SYNTHESIS EXAMPLE 1 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXIFENID-1, 1- (ETHYLENDIOXI) -4- (2-PYRIDILETINYL) CICLOHEXANE (la) 4-CYANO-4- (3-CICLOPENTILOXI-4-METOXYPENYL) -1, 1- (ETHYLEN-DIOXDCICLOHEXAN) A solution of 1.0 g, 3.19 mmoles, of 4 ~ cyano-4 ~ (3-cyclopentiioxy) was treated. 4- ethoxy phenyl) cyclohexan-1-one, (prepared by the methods described in the applications of TCP PCT / US93 / 01990 (publication UIPO No. UO 93/19748) and PCT / US93 / 02325, published as UIPO number UO 93 / 19750), in 25 ml of benzene, with 5 mg of p-toluenesulfonic acid and 0.18 rnl, 3.19 mmoles, of ethylene glycol, and heated to reflux under an argon atmosphere, the water was removed from the mixture by means of a Dean trap. Starch: After 1.5 hours, 200 ml of ether was added, the solution was washed with 5% aqueous sodium bicarbonate, dried over potassium carbonate and evaporated to provide clear colorless oil.1 H NMR (250 MHz CDCl 3) d 7.0 (m, 2H), 6.85 (d, J = 7 Hz, 1H), 4.8 (rn, 1H), 4.0 (m, 4H), 3.85 (s, 3H), 1.58-2.20 (m, 16H ). (lb) 4- (3-CICLOPENTILQXI-4-METOXIFENIL) -1, 1- (ETILENDIOXI) -4-FORMILCICLOHEXANO 1.0 mmol of isobutylaluminum hydride in 8.13 ml, 8.13 mmol, of toluene was added dropwise to a solution of 1.16 g, 3.19 mmoles, of 4-cyano-4- (3-cyclopentyloxy-A-phenyl-phenyl) -1, 1 - (ethylenedioxy) cyclohexane, dissolved in 20 ml of toluene, under an argon atmosphere. After 18 hours at room temperature, 100 ml of saturated aqueous sodium bisulfite was added and the mixture was extracted three times with dichloromethane. The combined organic extract was washed with brine, dried over potassium carbonate and evaporated. Purification by flash chromatography, hexane / ethyl acetate 4: 1 yields a clear colorless oil. NMR with * H (400 MHz CDCl 3) 6 9.35 (s, 1H), 6.88 (broad s, 2H), 6.80 (s, 1H), 4.73 (, 1H), 3.95 (rn, 4H), 3.85 (s, 3H) ), 2.33 (m, 2H), 2.10 (m, 2H), 1.57-1.99 (rn, 1.2H). (le) 4- (3-CICL0PENTILQXI-4-MET0XIFENIL) -1, 1- (ETILENDIOXI) -4-ETINILCICLOHEXANO A solution of 0.516 g, 3.44 rnrnoleSj (diazornetil) dimethyl phosphonate, prepared as in Seyferth, was added, D .; Marrnor, R.S .; Hilbert, P.J. Org Chem. 1971, 36 (10), 1379-1386), dissolved in 10 ml of dry tetrahydrofuran, by caning, to a solution of 0.386 g, 3.4 mrnoles, of potassium tert-butoxide, dissolved in 10 ml. Dry rahydrofuran, at -78 ° C, under an argon atmosphere. A solution of 0.62 g, 1.72 mol, of 4- (3-cyclopentyloxy-4-rethoxyphenyl) -l, 1- (ethylenedioxy) -4-phenyl-cyclohexane in 10 mmol of tetrahydrofuran was added quickly to this. After 2 hours the reaction was warmed to room temperature, water was added and the mixture was extracted three times with ethyl acetate. The combined organic extract was washed with brine, dried over magnesium sulfate and evaporated. Purification by flash evaporation chromatography, eluting with 3: 1 hexanes / ethyl acetate, yielded a white solid, mp 53.5-55 ° C.

(Id) 4- (3-CICLOPENTILOXI-4-METOXIFENIL) -1, 1- (ETHYLENDIOXI) -4- (2-PYRIDILETINYL) CYCLOHEXANE To a solution of 0.15 g, 0.42 mmol, of 4 ~ (3-c? Clopentine ? iox? -4-methox? phen?) -l, l- (et? lend? ox?) - 4-et? nilc? clo-hexane and 0.040 ml, 0.42 mmoles of 2-brornopyridine in 2 rnl of piperidma, under an argon atmosphere, 0.02 g, 4%, of tetrak? s (tpphenylphosphine) palladium, 0.005 g, was added % copper iodide (I) and a small crystal of tpfem lfosf ina, and the mixture was heated at 80 ° C for 0.5 hours. Water was added and the mixture was extracted three times with dichloromethane, the extract was dried over magnesium sulfate and evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate: hexanes, yielded 4- (3-c? Clo? Ent? Lox? -4-? Netox? Phen?) -l, 1 - (ethylenedioxy) -4- (2-pyridyl-1-ene-1) c-clohexane, as a white foam, mp 41-42 ° C. NMR with 1H (400 MHz CDCI3) 6 8.58 (d, J = 4.6 H, 1H), 7.65 (t, 3-7.7 Hz), 7.43 (d, J = 8.0 Hz, 1H), 7.21 (m, 2H), 7.17 (d, J = 8.5 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 4.81 (rn, 1H), 3.99 (s, 4H), 3.84 (s, 3H), 2.25 (m, 2H), 2.15 (m, 4H), 1.8-2.0 (m, 8H), 1.59 (rn, 2H) EXAMPLE 2 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -l, 1- (ETHYLENDIOXY) -4- (FENILETINYL) CICLOHEXAN-1-ONA A sample of 0.1.5 g, 0.42 mrnoles, 1,1- (ethylenedioxy) -4- (3-cyclopentiioxy-4-rethoxyphenyl) -4-ethynylcyclohexane with oligomeric amounts of tri-enylphosphine, tetrakis (triphenylphosphine) was treated. )? aladium (0) and copper iodide (I). Then 0.47 ml, 4.2 moles, of iodobenzene and 2 ml of piperidine were added, and the mixture was heated under an argon atmosphere. After 3 hours the mixture was diluted with 50 ml of ethyl acetate, washed once with dilute aqueous HCl, dried over magnesium sulfate and evaporated. Purification by flash evaporation chromatography (4: 1 hexanes / ethyl acetate) yielded a clear, colorless oil. NMR with H (400 MHz CDC13) d 7.44 (m, 2H), 7.3 (rn, 3H), 7.23 (d, J = 2 Hz, 1H), 7.12 (dd, J = 2 and 8, 1H), 6.81 ( d, J = 8 Hz, 1H), 4.8 (, 1H), 4.0 (s, 4H), 3.85 (s, 3H), 2.25 (rn, 2H), 2.10 (rn, 2H), 1.78-2.03 (rn, 10H), 1.6 (m, 2H).

EXAMPLE 3 PREPARATION OF 4- (3-CICLQPENTIL0XI-4-MET0XIFENIL) -4- (FENILETINIL) CICLOHEXAN-1-ONA To a solution of 0.18 g, 0.42 rnmoles, of 4- (3-cyclopenti lox? -4- ethox? Phen? L) -1, 1- (ethylenedioxy) -4- (phenylethynyl) c? Clohexan-1 -one, dissolved in 4: 1 acetone / water (5 rnl), 5 rng of p-toluensul ponate fonate was added. The mixture was heated to reflux or argon atmosphere. After 6 hours 15 mL of water was added and the mixture was extracted three times with ethyl acetate. The combined organic extract was dried over magnesium sulfate and evaporated. It was purified by trituration in ether / hexanes to give a white solid, mp 99-100 ° C.

EXAMPLE 4 PREPARATION OF 4- (3-CYCLOOPENTILOXY-4-METOXYPENYL) -4- (2-PYRIDYLENIDYCL0HEXAN-1-0NA A mixture of 0.17 g, 0.309 rnmoles, of 4- (3-c? Clopent? Lox? -4-methoxyphenyl) -l, l- (et? lend? ox?) - 4- (2-p? r? d? let? n? l) c? Clohexane and 0.10 g, 0.39 mrnols, of p-toluensul ponate fonate in 4 ml of acetone and 1 ml of water was left at reflux for 3 hours, and then evaporated. Water was added, the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and evaporated. Purification by flash evaporation chromatography, eluting with 25:75 ethyl acetate: hexanes, yielded 4- (3-cyclopentyloxy-4-methoxyphenyl) -1, 1- (ethylenedioxy-4- (2-? Iridylethynyl) cyclohexan- l-one, as a cer-a. NMR with * H (400 MHz CDCI3) 5 8.61 (d, 3 = 4.8 Hz, 1H), 7.68 (dt, 3 = 7.8, 1.8 HZ, 1H), 7.47 (d, 3 = 7.8 Hz, 1H), 7.27 (m, 1H), 7.20 (d, 3 = 2.3 Hz, 1H), 7.15 (dd, 3 = 8.5, 2.4 Hz) 1H), 6.87 (d, 3 = 8.5 Hz, 1H), 4.81 (m, 1H), 3.85 (s, 3H), 3.07 (dt, 3 = 1.4.4, 5.8 Hz, 2H), 2.49 (d, 3 = 14.8 Hz, 2H), 2.41 (m, 2H) ), 2.27 (dt, 3 = 13.4, 3.9 Hz, 2H), 1.8-2.0 (rn, 6H), 1.61 (m, 2H), Analysis (C2SH27NO3"0.65 H2O) calculated: C, 74.84; H, 7.11; N, 3.49; found: C, 75.00; H, 6.83; N, 3.52.

EXAMPLE 5 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -l, 1- (ETHYLENDIOXY) -4- (4-NITRQFENILETINYL) CICLOHEXANE To a solution of 0.15 g, 0.42 mrnoles, of 4- (3-cyclopentyloxy-4-methoxy phenyl) -1,1- (ethylenedioxy) -4-ethynylcyclohexane and 0.11 g, 0.42 mmol.es, of 4-iodonitrophenol in 2 ml of piperidine, under an argon atmosphere, 0.02 g, 4% of tetrakis (triphenylphosphine) palladium (0), 0.005 g, 6% copper iodide (I) and a small crystal of tri phenylphosphine were added. After heating at 80 ° C for 0.5 hour, water and IN hydrochloric acid were added. The mixture was extracted three times with dichloromethane, the extract was dried over magnesium sulfate and evaporated. Purification by flash chromatography, eluting with 2: 8 ethyl acetate: hexanes yielded 4 ~ (3-cyclo-opentyloxy-4-methoxyphenyl) -1, 1- (ethylenedioxy) -4- (4-nitrophenylenetin .il) cyclohexane, co or a red-orange wax mp 58-59 ° C. NMR with * H (400 MHz CDC13) d 8.18 (d, 3 = 6.7 Hz, 2H), 7.58 (d, 3 = 8.7 Hz, 2H), 7.16 (d, 3 = 2.5 Hz, 1H), 7.1.2 ( dd, 3 = 8.4, 2.5 Hz, 1H), 6.86 (d, 3 = 8.4 Hz, 1H), 4.80 (rn, 1.H), 4.01 (s, 4H), 3.85 (s, 3H), 1.8-2.3 (rn, 14H), 1.6 (rn, 2H).

EXAMPLE 6 PREPARATION OF 4- (3-CICLQPENTILOXI-4-METOXYPENYL) -4- (4-AMINOPHENILETINYL) CICLOHEXAN-1-ONA At 0.19 g, 0.40 mmol, of 4- (3-cyclopentyloxy-4-methoxy-phenyl) -1, 1- (ethylenedioxy) -4- (4-nitrophenylethynyl) cyclohexane in 1 mL of methanol, 1.2 ml of acetic acid and 1.2 ml of water, under an argon atmosphere, 0.3 g, 2 mmole, of titanium trichloride was added. After stirring for 1.5 hours at room temperature, 1.2 ml of water and 2.5 ml of ammonium hydroxide were added. After stirring for another hour, 17.5 ml of methanol, 1.7.5 ml of 5% sodium carbonate and 35 nr of dichloromethane were added, and stirring was continued for 3 days. The suspension was filtered through Celite®, washed well with dichloromethane and evaporated. Water was added, the mixture was extracted three times with dichloromethane, the extract was dried over magnesium sulfate and evaporated. Purification by flash chromatography, eluting with 3: 7 ethyl acetate: hexanes, yielded 4- (3-c? Clopent? Lox? -4-rethoxyphenyl) -4- (-arn? Nofen? LetmiD cyclohexan -l-one, as a colorless oil, NMR with 1H (400 MHz CDCI3) 6 7.28 (d, 3-8.4 H, 2H), 7.24 (cj, 3 = 2.1 Hz, 1H), 7.12 (d, 3 = 8.5 Hz, 1H), 6.85 (d, 3 = 8.5 Hz, 1H), 6.64 (d, 3 = 8.1 Hz, 2H), 4.80 (rn, 1H), 3.85 (s, 3H), 3.05 (dt, 3 = 14.3, 4.1 Hz,? H), 2.45 (broad d, 3 = 14.6 Hz, 2H), 2.29 (n, 4H), 1.8-2.0 (m, 6H), 1.6 (m, 2H).

EXAMPLE 7 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METQXIFENIL) -4- (4-ACETAMIDOPHENILETINIL) CICLOHEXAN-1-ONA At 0.12 g, 0.29 rnmoles, of 4- (3-c-clopenoxy-4-rnetoxifeni 1) -4- (4-aminofemletiml) c-clohexan-l-one on 3 rnl of dichloromethane, under an argon atmosphere, added 5 drops of pyridy to 0.081 mL, 0.86 mmol, of acetic anhydride and the reaction was stirred at room temperature for 2 hours. IN hydrochloric acid was added, the mixture was extracted three times with dichloromethane, the extract was dried over magnesium sulfate and evaporated. Purification by flash evaporation chromatography, eluting with L: 1 ethyl acetate: hexanes, yielded 4- (3-c? Clopen 1 lox? -4-methox? Feml) -4 ~ (4 -aceta? N? Dofemlet ml) c-clohexan-1-one, as a white solid, mp 79-80 ° C; Analysis (C28H3iN0; - 0.5 H20) calculated: C, 73.98; H, 7.10; N, 3.08; found: C, 74.11; H, 7.24; N, 3.03.

EXAMPLE 8 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -l, 1- (ETHYLENDIOXY) -4- (3-NITROPHENILETINYL) CICLOHEXANQ To a solution of 0.14 g, 0.38 rnmoles, of 4- (3-c? Clopen? Lox? -4-rnetox? Phenyl) -l, l- (et? Lend? Ox?) - 4-etm? Lc? Clo -hexane and 0.10 g, 0.38 rnmoles, of 3-iodine? t phenol in 2 rnl of piperidine, under argon atmosphere, 0.02 g, 4%, of tet rak? s (tpfen? lfosf? na)? aladio (0), 0.005 g, 6% copper iodide ( I) and a small crystal of tp phenylphosphma. After heating to 70 ° C for 0.33 hours, the mixture was diluted with dichloromethane, washed with 1N hydrochloric acid, dried over magnesium sulfate and evaporated. Purification by flash evaporation chromatography eluting with 2: 8 ethyl acetate: hexanes yielded 1,1- (ethylenediox i) -4 ~ (3-c? Clopen? Lox? -4-methox? Phen?) - 4- (3-M-phenylene-ethynyl) -cyclohexane, like an orange wax. NMR with iH (400 MHz CDCI3) d 8.29 (S, IH), 8.16 (d, 3 = 9.0 Hz, 1H), 7.75 (d, 3 = 7.9 Hz, 1H), 7.50 (t, 3 = 8.0 Hz, IH ), 7.26 (d, 3 = 2 Hz, IH), 7.14 (dd, 3 = 8.3, 2 Hz, 1H), 6.86 (d, 3 = 8.3 Hz, 1H), 4.82 (rn, 1H), 4.01 (s) , 4H), 3. 85 (s, 3H), 2.18 (m, 4H), 2.07 (m, 2H), 1.93 (m, 4H), 1.85 (m, 4H), 1.6 (rn, 2H).

EXAMPLE 9 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (3-AMINOPHENILETINIDCICLOHEXAN-1-ONA At 0.17 g, 0.35 immoles, of 4- (3-cyclopenti.loxy-4-nithoxyphenyl) -l, 1- (ethylenedioxy) -4- (3-nitrophenylethynyl-Cyclohexane in 1 ml of methanol, 1.2 ml of acetic acid and 1.2 rnl of water, under an argon atmosphere, 0.3 g, 2 mmole of titanium trichloride was added, after stirring for 1.5 hours at room temperature, 0.3 g, 2 rnrnoles, titanium trichloride and 1.2 ml of water were added. and the mixture was stirred for 0.5 hours at room temperature and for 0.5 hours at 45-50 ° C, then cooled to room temperature, 1.2 rnl of water and 2.5 rnl of aluminum hydroxide were added, after stirring for another At the same time, 17.5 ml of methanol, 17.5 ml of 5% sodium carbonate and 35 ml of dichloromethane were added and stirring was continued for 2 hours.The suspension was filtered through Celite®, washed well with dichloromethane and the extract was evaporated. The residue was diluted with dichloromethane, the organic layer was washed with 5:95 ammonium hydroxide: ag? A, s dried over potassium carbonate and evaporated. Purification by flash chromatography, eluting with 3: 7 ethyl acetate: hexanes, yielded a mixture of 4- (3-cyclo-entyloxy-4-rethoxyphenyl) -4- (3-arninophenylethynyl) cyclohexan-1-one. and 4- (3-cyclopentiioxy-4-rethoxyphenyl) -l, 1- (ethylenedioxy) -4- (3-amino-phenylethynyl) cyclohexane (0.07 g). The mixture and a spatula tip of p-tolueneul were allowed to reflux for 3 days. pyridinium fonate in 4 ml of acetone and 1 ml of water and then evaporated. Water was added and the mixture was extracted three times with dichloromethane, the extract was dried over magnesium sulfate and evaporated. Purification by flash evaporation chromatography eluting with 35:65 ethyl acetate: hexanes yielded 4- (3-cyclo-entyloxy-4-methoxypheni.l) -4- (3-arninophenylethynyl) cyclohexan-1-one. a colorless oil. NMR with 1H (400 MHz CDC13) d 7.22 (d, 3 = 2.2 Hz, 1H), 7.14 (rn, 2H), 6.87 (rn, 2H), 6.82 (d, 3 = 2.8 Hz, 1H), 6.66 (dd) , 3 = 9.0, 2.4 H, IH), 4.81 (m, 1H), 3.85 (s, 3H), 3.7 (broad, 2H), 3.04 (dt, 3 = 14.3, 6.0 Hz, 2H), 2.47 (broad d, 3 = 14.6 Hz, 2H) , 2.2 - 2.3 (rn, 4H), 1.8-2.0 (, 6H), 1.61 (, 2H).

EXAMPLE 10 PREPARATION OF 4-l3-CICLOPENTILOXY-4-METOXYPENYL) -4- (3-ACETAMIDOPHENILETINIL) CICLOHEXAN-1-ONA To 0.07 g, 0.18 mmol, of 4- (3-cyclopentyloxy-4-rnetoxifeniD-4- (3-aminophenylethynyl) cyclohexan-1-one in 2 ml of dichloromethane, under argon atmosphere, 3 drops of pyridine and 0.05 were added. mi, 0.53 mmol, of acetic anhydride and the reaction mixture was stirred at room temperature for 2 hours, IN hydrochloric acid was added, the mixture was extracted three times with dichloromethane, the extract was dried over magnesium sulfate and evaporated. Purification by flash evaporation chromatography, eluting with 45:55 ethyl acetate, hexanes, yielded 4- (3-c? Clopent? Iox? - -rneto? Feml) -4- (3-acetamide idofem letinil) ) c-clohexan-l -one, as a white solid, mp 63-64 ° C; Analysis (C2ßH3iN0 / -. - 1.5 H 2 O) calculated: C, 70.49; H, 7.29; N, 2.94; found: C 70.09; H, 6.94; N, 2.83.

EXAMPLE 11 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -1, 1- (ETHYLENDIOXY) -4- (3-CARBQMETOXIFENILETINIL) CICLOHEXANE A mixture of 0.150 g, 0.421 mrnoles, of 4- (3-c? Clopentj lox? -4-rneto? Phen?) -l, 1 - (ethylendioxy) -4-et mil-cyclohexane and 0.110 g was treated, 0.421 mrnoles, of methyl 3-iodobenzoate in 2.1 rnl of dry pipepdine, under argon atmosphere, with a mixture of 0.020 g, 0.017 rnrols, tetra? S (trifemlfosfine) palladium (O), 0.010 g, 0.053 rnrnoles, cuprous iodide and a glass of tnfemlfosfma, and the mixture was heated at 80 ° C for 40 minutes. The reaction mixture was cooled to 0 ° C, poured into ice water, acidified with 3N hydrochloric acid and extracted five times with rnetylene chloride. The organic phase was washed with dilute hydrochloric acid, with water, with saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was preadsorbed and cronogenated on silica gel, eluting with to 20% ethyl acetate in hexanes to give a pale yellow oil. NMR with lH (400 MHz CDCI3) 6 8.11 (t, 3 = 1.4 Hz, 1H), 7.97 (dd, 3 = 1.3 Hz, 3 = 7.9 Hz, 1H), 7.63 (dd, 3 = 7.8 Hz, 3 = 1.3 Hz, 1H), 7.39 (t, 3 = 7.8 H, 1H), 7.23 (d, 3 = 2.2, IH), 7.15 (dd, 3 = 8.4 Hz, 3 = 2.3 Hz, 1H), 6.89 (d, 3 = 8.4 Hz, 1H), 4.80 (rn, 1H), 4.00 (s broad, 4H), 3.92 (s, 3H), 3.84 (s, 3H), 2.4 to 1.75 (m, 18H).

EXAMPLE 12 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (3-CARBOMETOXIFENILETINIL) CICLOHEXAN-1-ONA A solution of 0.060 g, 0.12 mmol, of 4- (3-cyclopentyloxy-4-methoxy phenyl) -1, 1- (ethylenedioxy) -4- (3-carbomethoxy phenylethynyl) was heated at 55-60 ° C for 2 hours. cyclohexane in 5 ml of tetrahydrofuran containing 0.60 ml of 3N hydrochloric acid, under an argon atmosphere. The cooled reaction mixture was partitioned between dilute aqueous sodium carbonate solution, cooled with ice, and ethyl acetate. The organic phase was washed with water, with saturated brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 15% ethyl acetate / hexanes to give a resin. Analysis (C2ßH3oOs - 1/4 H2O) calculated: C, 74.56; H, 6.82; found: C, 74.43; H, 6.80. NMR with 1H (400 MHz CDCI3) d 8.15 (s, 1H), 8.00 (dd, 3 = 1.5 Hz, J = 6.6 Hz, 1H), 7.65 (dd, 3 = 1.3 HZ, 3 = 7.7 Hz, 1H), 7.43 (t, 3 = 7.7 Hz, 1H), 7.21 (d, 3 = 2.1, 1H), 7.12 (dd, 3 = 2.0 Hz, 3 = 8.5 Hz, 1H), 6.87 (d, 3 = 8.5 Hz, 1H ), 4.81 (m, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.04 (dt, 3-6.0 Hz, 3 = 14.2 Hz, 2H), 2.50 (broad d, 3 = 14.8, 2H) ), 2.4 - 2.2 (, 4H), 2.0 - 1.5 (rn).

EXAMPLE 13 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -1, 1- (ETHYLENDIOXY) -4- (3-CARBQXIFENILETINYL) CICLOHEXANE A solution of 0.12 g, 0.245 mmol, of 4- (3 ~ c? Clopent? Iox? -4-rnetox? Phen?) -l, 1- (et? Iend? Ox?) - 4- (3 -carbo-rnetoxifeniletmiD cyclohexane in 5 ml of methanol, with 0.3 rnl, 0. 374 mmolee, of 10% aqueous sodium hydroxide, under an argon atmosphere, and heated at 55 ~ 60 ° C for 2.5 hours.

The cooled reaction mixture was concentrated in a stream of argon and the residue was partitioned between cold water acidified with dilute hydrochloric acid and rnetylene chloride. The aqueous phase was extracted another two times with rnetylene chloride and the combined organic phase was dried over magnesium sulfate to give the title compound, as an oil. NMR with * H (400 MHz CDC13) d 8.18 (s, 1H), 8.02 (d, 3 = 7.9 Hz, 1H), 7.68 (d, 3 = 7.8 Hz, 1H), 7.42 (t, 3 = 7.8 Hz, 1H), 7.23 (d, 3 = 2.2, IH), 7.14 (dd, 3 = 8.4 Hz, 3 = 2.3 Hz, 1H), 6.85 (d, 3 = 8.4 Hz, 1H), 4.82 (p, 1H), 4.01 (t, 4.2H), 3.85 (s, 3.2H), 2.4 to 1.5 (m, 17H).

EXAMPLE 14 PREPARATION OF 4- (3-CYCLOOPENTILOXY-4-METOXYPENYL) -4- (3-CARBOXYPHENYLLINYNCYCLE-1-ONO) It was heated under argon atmosphere at 55-70 ° C, during 2 hours, a solution of 0.11 g, 0.23 mmol, of 4- (3-cyclopethyl) -4-methox-phenyl) -1, 1- (et? Lend? Ox?) - 4- (3- carboxy-phenylethylcyclohexane in 6 ml of tetrahydrofuran containing 0.7 ml of 3N hydrochloric acid The cooled reaction mixture was concentrated in vacuo and the residue was partitioned between water and methylene chloride, the organic phase was washed with saturated The brine was dried over magnesium sulphate and evaporated, the residue was chromatographed on silica, eluting with methylene chloride / methanol / ag? a (90/5 / 0.25 to 90/10 / 0.5) and concentrated in vacuo. dissolved the residue in methanol and vacuum-poured to give a white fractured glass Analysis (C2 H2S0s - 1/4 H2O-I / 4 CH3OH) calculated: C, 73.55; H, 6.68; found: C, 73.51; H, 6.66., NMR with 1H (400 MHz CDCI3) d 8.22 (t, 3 = 1.5 Hz, 1H), 8.09 (dd, J = 1.3 Hz, 3 = 7.9 Hz, 1H), 7.72 (dd, 3 = 1.3 Hz; 3 = 7.8 Hz, 1H), 7. 47 (t, 3 = 7.8 H, 1H), 7.22 (d, 3 = 2.2, IH), 7.13 (dd, 3 = 2.3 Hz, 3 = 8.4 Hz, IH), 6.88 (d, 3 = 8.5 Hz, 1H ), 4.82 (p, 1H), 3.86 (s, 3H), 3.25 (d, 3 = 20 Hz, CH3OH, 0.55H), 3.04 (dt, 3 = 5.8 Hz, 3 = 14.5 Hz, 1.7H), 2.50 (broad d, 3 = 14.8, 1.8H), 2.4 - 2.2 (n, 4H), 2.0 - 1.5 (m).

EXAMPLE 15 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (4-PYRIDILETINYL) CICLQHEXAN-1-ONA (15a) 4- (3-CICLOPENTILQXI-4-METOXIFENIL) -4- (-PIRIDIL-ETINIL) -1, 1- (ETHYLENDIOXI) CYCLOHEXANE To a solution of 0.10 g, 0.28 rnmoles, of 4- (3-c? clopent? lox-4-rnetox? fen? l) -4-et mi 1-1, l- (et? lend? ox?) cyclohexane and 0.54 g, 2.8 mmoles, of -brornopyridma in 1.5 ml of pipepdina , under argon atmosphere, 0.13 g, 4%, of tet rak? s (tpfemlfosf? na)? alad? o (O), 0.004 g, 6%, of copper iodide (I) and a small crystal of copper were added. tpfeml phosphine, and the mixture 4a was heated at 80-85 ° C for 0.5 hour. Water was added and the mixture was extracted three times with dichloromethane, dried over magnesium sulfate and evaporated. Purification by flash evaporation chromatography, eluting with 35:65 ethyl acetate: hexanes, yielded 4- (3-cyclopent y lox i -4-rnetox? Phen? L) -4- (4-p? R? D ? let? n? l) -l, l- (et? lend? ox?) c? clohexane, as a pale yellow oil (0.11 g, 93%). NMR with * H (400 MHZ CDCl 3) d 8.56 (d, 3 = 5.3 Hz, 2H), 7.33 (d, 3 = 5.3 Hz, 2H), 7. 16 (d, 3 = 2.2 Hz, 1H), 7.09 ("Id, 3 = 8.4, 2.2 Hz, 1H), 6.85 (d, 3 = 8.5 Hz, 1H), 4.80 (rn, 1H), 4.00 (rn, 4H), 3.85 (s, 3H), 2.0-2.2 (rn, 6H), 1.8-2.0 (m, 8H), 1.59 (m, 2H) (15b) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4 - (4-PIRIDYL-ETINIDCICL0HEXAN-1-QNA) A mixture of 0.10 g, 0.24 mmol, of 4- (3-c? Clo? Ent? Lox? -4-methoxyphen?) -4 was left at reflux for 20 hours. - (4 -? Pd? Let? Ni 1) -1, l- (et? Lend? Ox?) C? Clohexane and 0.06 g, 0.24 mmol, of p-tol? Ensulphonate pyridinium in 4 ml of acetone Water was added, the mixture was extracted twice with dichloromethane, dried over magnesium sulfate and evaporated, purification by flash evaporation chromatography, eluting with 35:65 of ethyl acetate, and then evaporating. Hexanes, produced 0.08 g, 91%, of 4- (3-c? clopentyloxy-4-rnetox? phen? l) -4- (4? ?? pd? let? n? l) c? clohexan -l-one, mp 148-149 ° C. Analysis (C25H27NO3 -0.5 H2O) calculated: C, 75.29; H, 7.08; N, 3.51; found: C, 75.51; H, 6.95; N, 3.42.

EXAMPLE 16 4- (3-CICLOPENTILOXI-4-METQXIFENIL) -4- (3-PYRIDILETINYL) CICLOHEXAN-1-ONA To a solution of 0.22 g, 0.70 mmol, of 4- (3-c? Clo? Ent? Lox? -4-methox? Phenyl) -4-et? Mlc? Clohexan-l-one and 0.70 rnl, 7.0 mmol, of 3- indium brine in 2 ml of piperidine, under an argon atmosphere, 0.034 g, 4% of tetrakisftphenyl-phosphine) was added (0), 0.009 g, 6%, of copper iodide (?) and a small triphenyl phosphine crystal, and the mixture was heated to 80-85 ° C for 0.5 hours. Ammonium chloride was added, the mixture was extracted again with dichloromethane, dried over magnesium sulfate and evaporated. Purification by flash evaporation chromatography, eluting with 35:65 ethyl acetate: hexanes, yielded 0.22 g, 80%, of 4- (3-cyclopentiioxy-4-methox? Fen D-4-Í4 -pyridi le mil) c? clohexan-l -one, like a solid white mate. The product was further triturated in ether-hexanes mp 88-89 ° C. Analysis (C2SH27NO3 -0.375 H2O) calculated: C, 75.78; H, 7.03; N, 3.53; found: C, 75.77; H, 6.89; N, 3.40.

EXAMPLE 17 4- (2-CARBOMETQXITIEN-5-ILETINIL) -4- (3-CICLOPENTILOXI-4- METOXIFENIL) CICLOHEXAN-1-ONA (17a) 2-BROMO-5-CARBOXIMETILTIOFENO 2-Bromo-5-carbox? Met? Lt? Ofeno was prepared by ordinary chemistry, well known to those skilled in the art and was solid white, mp 59-60 ° C. (17b) 4- (2-CARB0MET0XITIEN-5-ILETINIL) -4- (3-CICLOPENTILOXI-4-METOXYPENYL) CYCLOHEXAN-1-ONA To a solution of 0.21 g, 0.7 rnmoles, of 4- (3-c? Clopentine ? lox? -4-methox? phen?) -4-et? mlc? clohexan-1-one and 0.18 g, 1.2 mmoles, of 2-bromo-5-carbox? met? lt? ofeno in 2 rnl of tetylamine, under argon atmosphere, 0.031 g, 4% tetrak? s were added (tpfen? lfosf? na) palladium (0) and 0.008 g, 6%, of copper iodide (I), and the mixture was heated at 80-85 ° C for 4.5 hours. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, dried over magnesium sulfate and evaporated. Purification by rapid evaporation chromatography, eluting with 2: 8 ethyl acetate: hexanes, yielded 4- (2-carbomethoxythien-5-ylethynyl) -4- (3-cyclo-entyloxy-4-methoxy-phenyl) -cyclohexan-1-one, as an oil yellow (0.25 g, 82%). NMR with 1H (400 MH CDC13) d 7.67 (d, 3 = 4.0 Hz, 1H), 7.16 (d, 3 = 4.0 Hz, 1H), 7.15 (d, 3 = 2.2 Hz, 1H), 7.07 (dd, 3 = 8.4, 2.2 Hz, 1H), 6.87 (d, 3 = 8.4 H, 1H), 4.80 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.95 (dt, 3 = 14.5, 5.9 Hz, 2H), 2.49 (broad d, 3 = 14.5 Hz, 2H), 2.36 (rn, 2H), 2.26 (dt, 3 = 13.4, 4.0 Hz, 2H), 1.8 - 2.0 (rn, 6H), 1.6 (m, 2H) ppm. Analysis (C26H2ßOsS-0.25 H2O) calculated: C, 68.32; H, 6.28; found: C, 68.25; H, 6.12.

EXAMPLE 18 SODIUM SALON OF 4- (2-CARBOXITIEN-5-ILETINIL) -4- (3-CICLOPENTILOXI-4-METOXIFENIDCICLOHEXAN-1-ONA A solution of 0.13 g, 0.30 mmol, of 4- (2-carbomethoxythien-5-ylethynyl) -4- (3-cyclopentyloxy-4-rhetoxy phenyl) was stirred at room temperature under argon for 24 hours. cyclohexan-1-one, and 0.025 g, 0.45 mmoles, of coarse ground potassium hydroxide in 5 i of tetrahydrofuran, 5 nl of methane! and 2 ml of water. The reaction was acidified with 10% HCl, extracted three times with 5:95 methane! dichloromethane, dried over magnesium sulfate and evaporated. The crude product was treated with .10% sodium hydroxide to form the salt. Reverse phase chromatography, eluting with 1: 1 methanol: ag? A yielded the sodium salt of 4- (2-carboxytien-5-ylethynyl) -4- (3-cyclopentiyoxy-4-methoxy phenyl) cyclohexan-1 -one, as a white solid (0.070 g, 55%), mp 194-195 ° C. Analysis (C25H25O5 SNa- 1.25 H2O) calculated: C, 62.16; H, 5.74; found: C, 61.90; H, 5.49.

EXAMPLE 19 4- (CIANOTIEN-5-ILETINIL) -4- (3-CICLOPENTILOXI-4-METOXYPENYL) CICLOHEXAN-1-ONA (19a) 2-BROMINE-5-CYANOTIOFEN 2-Bromo-5-cyanothiophene was prepared by ordinary chemistry well known to those skilled in the art, and was a colorless oil. NMR with * H (400 MHz, CDCl 3): d 7.40 (d, 3 = 4 Hz, 1H), 7.10 (d, 3 = 4 Hz, 1H) pprn. (19b) 4- (2-CIANQTIEN-5-ILETINIL) -4-y3-CICLOPENTILOXI-4-METQXIFENIL) CYCLOHEXAN-l-ONA To a solution of 0.22 g, 0.7 mmol, of 4- (3-cyclopentyloxy-4-) methoxyphenyl) -4-ethynyl-cyclohexan-l-one and 0.13 g, 0.7 mol of 2-bromo-5-cyanothiophene in 5 rnl of triethylamine, 0.034 g, 4% of tetrakis (triphenylphosphine) palladium were added under argon atmosphere ( 0) and 0.007 g, 6% copper iodide (I), and the mixture was heated at 85-90 ° C for 2 hours. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, dried over magnesium sulfate and evaporated. Purification by flash evaporation chromatography, eluting with 2: 8 ethyl acetate: hexanes afforded 0.06 g, 18%, of 4- (2-cyanothien-5-yl.etinyl-4- (3-cyclopentyloxy-4-methoxy) phenyl) cyclohexan-1 -one This was combined with 0.0.17 g of product obtained in a second similar reaction, and triturated in dichloromethane-hexanes to give a white solid, mp.106-107o C. Analysis (C2SH2SNO3 S-0.5 H20) calculated: C, 70.07; H, 6.1.1; N, 3.27; found: C, 70.15; H, 5.84; N, 3.32.

EXAMPLE 20 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4-C5- (5-METHYL-Cl, 2J43QXADIAZOL-2-IL) TIEN-2-ILETINIL3CICLOHEXAN-1-ONA (20a) 2-BROMO-5- (5-METHYL- [1,2,43 QXADIAZOL-2-IL) THIOPHENE 2-Bromo-5- (5-methyl- [1,2,4-oxadiazole-2-2- il) thiophene by ordinary chemistry, well known to those skilled in the art, and was a white solid, mp 48-49 ° C. (20b) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4-C5- (5-METHYL-Cl, 2,4] OXADIAZOL-2-IL) TIEN-2-ILETINIL3CICLOHEXAN-l-ONA To a solution of 0.17 g, 0.88 mmol, of 4 ~ (3 ~ cyclopentyloxy-4-methoxyphenyl) -4-ethynyl-cyclohexan-1-one and 0.18 g, 1.2 mmol of 2-bromo-5- (5-rnet? l-Cl, 2 , 4] oxadiazole-2? L) t? Ofeno in 5 rnl of triethylamine, under argon atmosphere, 0.037 g, 4%, of tetrak? S (tnphenylphosphma) palladium 0) and 0.010 g, 6% of iodide were added. of copper (T), and the mixture was heated at 85-90 ° C for 2 h. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, dried over magnesium sulfate and evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate-hexanes, yielded 0.17 g, 45%, of 4 ~ (3-cyclopentyl lox? -4-rnetoxifeni 1) -4- 5- ( 5 ~ met? L ~ C l, 2, 4 Joxadiazol -2-? L)? En-2-ylethynyl-3-cyclohexan-1-one, as a white wax, mp 94-95 ° C. Analysis (C27H2ß 2? Ü S) calculated: C, 68.04; H, 5.92; N, 5.88; found: C, 67.83; H, 5.89; N, 5.92.

EXAMPLE 21 4- (2-CARBOMETOXITIEN-4-ILETINIL) -4- (3-CICLOPENTILOXI-4- METOXIFENIL) CICLOHEXAN-1-ONA 21 (a) 4-BROMINE-2-CARBOXIMETILTIOFENO 4-Bromo-2-carboxymethyl-ofenne was prepared by ordinary chemistry, well known to those skilled in the art, and was a brown oil. NMR with 1H (400 MHz, CDCl 3) d 7.69 (d, 3 = 1.5 Hz, 1H), 7.45 (d, 3 = 1.5 H, 1H), 3.90 (s, 3H) pprn. 21 () 4- (2-CARBQMETOXITIEN-4-ILETINIL) -4- (3-CICLOPENTILOXI-4-METOXIFENIL) CYCLOHEXAN-1-ONA To a solution of 0.25 g, 0.8 mrnoles, of 4- (3-cyclopentyl) loxi-4-methoxyphenyl) -4-ethi nil-ci clohexan-1 -one and 0.27 g, 1.2 mmol of 4-bromo-2-carbox? met? lthiophene in 3.5 ml of tettiiamine, under argon atmosphere, 0.038 was added g, 4%, of tetrakie (tr? phen? loffin)? aladium (0) and 0.010 g, 6% copper iodide (I), and the mixture was heated at 80-85 ° C for 0.5 hours. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, dried over magnesium sulfate and evaporated. Purification by flash chromatography, eluting with 2: 8 ethyl acetate or hexanes, yielded 0.15 g, 42%, of 4- (2-carbomethoxy? T? En-4-yletin? L) -4- ( 3-cyclopen? Lox-4-rethoxyphenyl) -cyclohexan-1-one, as a yellow glass. NMR with iH (400 MHz, CDC13) d 7.81 (d, 3 = 1.3 Hz, 1H), 7. 60 (d, 3 = 1.3 Hz, 1H), 7.16 (d, 3 = 2.2 H, 1H), 7.10 (dd, 3 = 8.5, 2.2 Hz, 1H), 6.86 (d, 3 = 8.5 Hz, 1H), 4.80 (m, 1H), 3.90 (s, 3H), 3.84 (e, 3H), 2.98 (dt, 3 = 14.8, 5.7 Hz, 2H), 2.48 (broad d, 3 = 14.8 Hz, 2H), 3.33 ( m, 2H), 2.26 (dt, 3 = 13.6, 4 H, 2H), 1.9-2.0 (m, 6H), 1.6 (m, 2H) ppra. Analysis (C26H28O5) calculated: C, 69.00; H, 6.24; found: C, 68.82; H, 6.04.

EXAMPLE 22 4- (2-CARBOXITIEN-4-ILETINIL) -4- (3-CICLOPENTILQXI-4-METOXIFENIDCICLOHEXAN-1-ONA A solution of 0.19 g, 0.43 mmol, of 4 - (2-carbomethoxy? T-en-4-? Let? N) was stirred at room temperature, under argon atmosphere, for 24 hours. - 4 - (3-cyclopentyl lox? -4-rnet oxypheni 1) c? Clohexan-1-one, and 0.036 g, 0.64 mmoles, of coarse ground potassium hydroxide in 2 ml of tetrahydrofuran, 2 ml of rnetanol and 0.4 ml of Water. The reaction was acidified with HCl at 10%, extracted three times with 5:95 of methanol: di chloromethane, dried over magnesium sulfate and evaporated. The crude product was treated with 10% sodium hydroxide to form the salt. Reverse phase chromatography, eluting with 0.1: 3: 97 acetic acid: methanol: dichlorornetane yielded the sodium salt of 4- (2-carboxyt en-4-? Letm? L) -4 ~ (3 ~ cyclopent i lox? -4-rnetox? feml) c? clohexan-1-one, as a white solid ate (0.18 g, 95%), mp 80 ~ 82 ° C. Analysis (C2SH26O5 - 0.25 H2O) calculated: C, 67.78; H, 6.03; found: C, 67.72; H, 6.02.

EXAMPLE 23 4- (2-CIANOTIEN-4-ILETINIL) -4- (3-CICLOPENTILOXI-4-METOXIFENI) CICLOHEXAN-1-ONA (23a) 4-BROMO-2-CYANOTIOFEN 4-Brorno-2-cyanothiophene was prepared by ordinary chemistry, well known to those skilled in the art, and was a pinkish solid, mp 43-44 ° C. (23b) 4- (2-CIANOTIEN-4-ILETINIL) -4- (3-CYCLOOPENTILOXY-4-METOXYPENYL) CYCLOHEXAN-1-ONA To a solution of 0.25 g, 0.8 mmol, of 4- (3-cyclopenti iox? ~ 4-methox? Feml) -4-et? N? Lc? Clohexan-l-one and 0.15 g, 0.8 mmoles of 4-bromo-2-c? Anot? Ofeno in 5 ml of traeti lamina, under argon atmosphere , 0.038 g, 4%, tetrakisitpfem lfosf? na) paladin (O) and 0.008 g, 6% copper iodide (I) was added, and the mixture was heated at 85-90 ° C for? 4 hours . Ammonium chloride was added and the mixture was extracted three times with di-chloromethane, dried over magnesium sulfate and evaporated. Purification by flash evaporation chromatography, eluting with 2: 8 ethyl acetate: hexanes, yielded 0.08 g, 24%, of 4- (2-c? Anot? En-4? Let il) -4- (3 -c? clopen 11 ox i -4-rnetox? phen? Dc? clohexan-l-one, which was further triturated in dichloromethane-hexanes, as a white solid, mp 112-113? C Analysis (C25H25N03S- 0.375 H2O) calculated: C, 70.44; H, 6.09; N, 3.29; found: C, 70.38; H, 5.94; N, 3.20.

EXAMPLE 24 4- (3-CICLOPENTILOXI-4-METOXIFENI) -4- 2 - (5-METHYL- [1, 2,430XADIAZ0L-2-IL) TIEN-4-ILETINIL3CICL0HEXAN-1-QNA (24a) 4-BROMINE-2- (5-METHYL-Cl, 2,43 QXADIAZOL-2-IL) THIOPHENE 4-Bromo-2 ~ (5-met? L-ri, 2, 43 -oxad-azol -2- was prepared i1) thiophene by ordinary chemistry well known to those skilled in the art, and is a white solid, mp 66-67 ° C. (24b) CIS-C4- (3-CICLOPENTILOXI-4-METOXIFENIL) -4-C2- (5-METHYL- [l, 2,430XADIAZ0L-2-IL) TIEN-4-ILETINIL3CICL0HEXAN-l-0L To a solution of 0.25 g, 0.8 mmole, of trane-T 4 - (-c? Clopentylox? -4-methox? Phenyl) -4- iletmilciclohexan-l-ol] (prepared as described in the pending patent application, identified as P50287, and filed on the same date as the present one) and 0.20 g, 0.8 mmol, of 4-brorno- 2- (5- met? i- [i, 2,43-oxad-azole-2-? l) t-iofen in 5 ml of tetylamine, under an argon atmosphere, 0.038 g, 4%, of tetrakisipphenyl phosphine)? aladium (O), 0.009 was added g, 6% copper iodide (I) and a small crystal of triphenyl phosphine, and the mixture was heated at 70 ~ 75 ° C for 0.5 hours. 5% hydrochloric acid was added and the mixture was extracted three times with dichloromethane, dried over magnesium sulfate and evaporated. Purification by flash evaporation chromatography, eluting with 1: 1 ethyl acetate: hexanes, yielded 0.20 g, 53%, of cis-4- (3-cyclopentyl? I-4-methoxy) -4-C2- ( 5-methyl-Cl, 2,43-oxadiazol-2-yl) thien-4-ylethynyl-3-cyclohexan-1-ol 3, which was further triturated in dichloromethane-hexanes, to give a white solid, mp 142-143 ° C. Analysis (C27H3? 2? «S) calculated: C, 67.76; H, 6.32; N, 5.85; found: C, 67.85; H, 6.42; N, 5.54. (24c) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4-C2- (5-METHYL- [l, 2,43 QXADIAZOL-2-IL) TIEN-4-ILETINIL3CICLOHEXAN-l-ONA To a suspension of 0.04 g 0.020 mmol. Of pyridinium chlorocrornate in 1 ml of dichloromethane at room temperature, under an argon atmosphere, a solution of 0.06 g, 0.13 mmoles, of c_is-4- (3-cyclopentyloxy-4-methoxyfen) was added rapidly. il) - -t2- (5-methyl-L "1,2,43-oxadiazol-2-iDtien-4-ylethynyl-3-cyclohexan-1-ol3 in 2 ml of dichloromethane, and the mixture was stirred for 1 hour. The mixture was filtered through Celite® and evaporated, purification by flash evaporation chromatography eluting with 25:75 ethyl acetate: hexanes yielded 4- (3-cyclopentyloxy). methoxy phenyl) -4-L "2- (5-methyl-E1,2,43-oxadiazol-2-yl) thien-4-yl-ethynyl-3-cyclohexan-1-one, as a colorless oil. Recrystallization from dichloromethane-hexanes yielded 0.33. g, 53%, of solid white, mp 94-95 ° C. sis (C27H2β2? «S-1.0 H2O) calculated: C, 65.75; H, 6.11; N, 5.66; found: C, 65.46; H, 5.74; N, 5.60.

EXAMPLE 25 4- (4-CARBOMETOXITIEN-2-ILETINIL) -4- (3-CICLOPENTILOXI-4-METOXYPENYL) CICLOHEXAN-1-ONA (a) 2-BROMINE-4-CARBOXIMETILTIOFENO 2-Brorno-4-carboxymethylthiophene was prepared by ordinary chemistry, well known to those skilled in the art, and is a brown oil. NMR with * H (400 MHz, CDCl 3) d 7.99 (s, 1 H), 7.47 (s, 1 H), 3.86 (s, 3 H) pprn. (b) 4- (4-CARBOMETOXITIEN-2-ILETINIL) -4- (3-CICLOPENTILOXI-4-METOXIFENIL) CICLQHEXAN-1-ONA To a solution of 0.35 g, 1.12 rnmoles, of 4- (3-cyclo? enti.loxi-4-methoxypheniD-4-ethynylcyclohexan-l-one and 0.25 g, 1.13 mmol, of 2-bromo-4-carboxymethiitiofen in 5 ml of triethylanine, under argon atmosphere, 0.044 g, 4% of tetrakis (triphenylphosphine) palladium (0), 0.011 g, 6% copper iodide (I) and a small crystal of tr.ife.il fos fines, and the mixture was heated at 80-85 ° C for 0.5 hours. water and 10% hydrochloric acid were added and the mixture was extracted three times with dichloromethane, dried over magnesium sulfate and evaporated.

Purification by flash chromatography, eluting with 2: 8 ethyl acetate: hexanes, yielded 0.29 g, 58%, of 4- (4-carbornetoxythien-2-ylethynyl) -4 ~ (3-cyclopentyl. 4 ~ rnetoxifeni.Dciclohexan-1-one, as a yellow gum, 1 H NMR (400 MHz, CDCl 3) d 7.61 (d, 3 = 1.1 H?, 1H), 7.16 (d, 3 = 2.2 Hz, 1H), 7.07 (dd, 3 = 8.4, 2.2 Hz, 1H), 6.87 (d, 3 = 8.4 Hz, 1H), 4.81 (, IH), 3.88 (s, 3H), 3.86 (e, 3H), 2.97 (dt, 3--14.5, 5.7 Hz, 2H), 2.49 (broad d, 3 = 13.5 Hz, 2H), 2.35 (m, 2H), 2.29 (m, 2H), 1.9 - 2.0 (m, 6H), 1.6 (rn , 2H) pprn Analysis (C2sH280s) calculated: C, 69.00; H, 6.24; found: C, 68.76; H, 6.46.

EXAMPLE 26 4- (4-CARBOXITIEN-2-ILETINIL) -4- (3-CICLOPENTILQXI-4-METOXIFENIL) CICLOHEXAN-1-ONA A solution of 0.12 g, 0.427 mmol, of 4- (4-carbornetox? T? En-2-ylethynyl) -4- (3-c? Clopent) was stirred at room temperature under argon atmosphere for three days. -? lox? -4 ~ rnetoxifem l) c? clohexan-1-one, and 0.045 g, 0.81 mmoles, of coarse ground potassium hydroxide in 2.5 ml of tetrahydrofuran, 2.5 ml of methanol and 0.5 ml of water. The reaction was acidified with 10% HCl, extracted three times with 5:95 of rnetanol: di chloronetane, dried over magnesium sulfate and evaporated. Purification by flash chromatography, eluting with 0.25: 2.5: 97.5 acetic acid: rnetanol: di chloro-methane, yielded 0.11 g, 94%, of 4 ~ (4 ~ carbox? T? En-2-y-ethyl ester). ) -4- (3-c? Clopentyloxy-4-methox? Phenyl) c? Clohexan-1-one, as a white matt foam, mp 75-76 ° C. Analysis (C25H26O5 S> 0.25 H2O) calculated: C, 67.78; H, 6.03; found: C, 67.73; H, 5.80.

EXAMPLE 27 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4-C4- (5-METHYL-Cl, 2,43 XADIAZOL-2-IL) TIEN-2-ILETINIL3CICLOHEXAN-1-ONA (27a) 2-BROMO-4- (5-METHYL-Cl, 2,4] QXñDIAZOL-2-IL) THIOPHENE 2-Brorno ~ 4- (5-rnet? Lp, 2,43-oxad-azol -2- was prepared i1) iofen by common chemistry well known to those skilled in the art, and is a white solid, mp 72-73 ° C. (27) CIS4- (3-CICLOPENTILOXI-4-METOXIFENIL) -4-C4- (5-METHYL- [l, 2,430XADIAZ0L-2-IL) TIEN-2-ILETINIL3CICL0HEXAN-l-0L To a solution of 0.25 g, 0.8 rnmoles, of trans- [4- (3-c? clo? ent? iox? -4-methox? phen?) -4-ile? ilc? clohexan-l-ol (prepared as described in the pending patent application, filed by the same inventors, identified as P50287, and filed on the same date as this) and 0.20 g, 0.8 mmoles, 2-bromo-4- (5-met? I- [1, 2, 43oxad? Azole-2-yl) thiophene in 5 ml of tetylamine, under an argon atmosphere, 0.038 g, 4% tetrakistrifex phosphine was added ) palladium (0), 0.009 g, 6% copper iodide (T) and a small crystal of rife ilphosphine, and the mixture was heated at 70-75 ° C for 0.5 hours. 5% hydrochloric acid was added and the mixture was extracted three times with dichloromethane, dried over magnesium sulfate and evaporated. Purification by flash evaporation chromatography, eluting with 1: 1 ethyl acetate: hexanes, yielded cis -3- (3-cyclo-entlyo-4-methoxyphenyl) -4-C4- (5-methyl- [I] , 2,43-oxadiazol-2-yl) thien-2-yl-1-ethyl-3-cyclohexan-1-ol, which was further triturated in dichloromethane-hexanes, to give 0.20 g, 53%, of a white solid, mp 142-143 ° C. Analysis (C27H30N2O4 S-0.75 H20) calculated: C, 65.90; H, 6.45; N, 5.69; Found: C, 66.06; H, 6.42; N, 5.50. (27c) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4-C4- (5-METHYL-Cl, 2,43? XADIAZOL-2-IL) TIEN-2-ILETINIL3CICLOHEXAN-l-ONA To a suspension of 0.07 g, 0.031 mmoles of pyridinium chlorochromate in 1 ml of dichloromethane at room temperature, under argon atmosphere, a solution of 0.10 g, 0.21 mmole, of cis-4- (3-cyclopenti loxi-4-methoxyphenyl) was added rapidly -4-C- (5- ethyl -Ti, 2,3,4-oxadiazol-2-yl) thien-2-ylethynyl-3-cyclohexan-1-ol 3 in 2 ml of dichloromethane, and the mixture was stirred for 0.5 hour. 20 mL of ether was added and stirring was continued for 0.5 hour. The mixture was filtered through Celite® and evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate: hexanes yielded 4- (3-cyclopentyloxy-4-netoxyphenyl J-4-C4- (5-metii-Ci, 2,43-oxadiazole-2-yl. ) thien-2-yl-ethynyl-3-cyclohexan-1-one, as a colorless solid, mp 90-91 ° C Analysis (C27H2eN2O - .SO.25 H2O) calculated: C, 67.41; H, 5.g7; N, 5.82; found: C, 67.43; H, 5.87; N, 5.80.

EXAMPLE 28 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2-METHYLSULFONYL PYYRIMIDIN-4-ILETINIDCICLOHEXAN-1-ONA (28a) 4-IODO-2-TIOMETHYPYRIMIDINE 4-iodo-2-thiomethylpipmidma was prepared following the procedure of the literature (A.3, Majeed, F. Antonsen, T. Benneche, K. Undhei, Tetrahedron 1898, 45, 993 -1006). (28b) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2-METHYLTHYL-PIRIMIDIN-4-ILETINIDCICLOHEXAN-l-ONA) To a solution of 0.35 g, 1.12 mol, of 4- (3-cyclopentyl lox? -4-methox? Phen?) -4-et? Mlc? Clohexan-l-one and 0.56 g, 2.4 mmoles, of 4-iodo-2-t? Omet? Lp? R? M? Dma (as a mixture of 4-iodo-2-t? ornet? lp? pm? d? na and 4-chloro-2-t? omet? lp? pm? dina) in 5 ml of triethylamine, under an argon atmosphere, was added 0. 051 g, 4%, of tet rak? S (tr? Phen? Lfosf? Na) palad? O (0) and 0.014 g, 6% copper iodide (I) and the mixture was heated at 85-90 ° C for 0.5 hours. Ammonium chloride was added and the mixture was extracted three times with di chloro-methane, dried over magnesium sulfate and evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate: hexanes, yielded 4- (3 ~ c? Clopent? Iox? -4-methox? Phen?) -4- (2-methyt? op? r? rn? d? n-4-? let? n?) c? clohexan-l-one, as a res to yellow (0.35 g, 72%). NMR with * H (400 MHz, CDC13) d 8.50 (d, 3 = 5.3 Hz, 1H), 7.17 (d, 3 = 2.3 Hz, 1H), 7.08 (dd, 3 = 8.5, 2.3 Hz, 1H), 7.03 (d, 3 = 5.3 Hz, 1H), 6.87 (d, 3 = 8.5 H, 1 H), 4.81 (rn, 1H), 3.86 (S, 3H), 2.99 (dt, 3 = 14.7, 8.7 Hz, 2H), 2.58 (s, 1H), 2.46 (broad d, 3 = 18.7 Hz, 2H), 2.40 (, 2H), 2.29 (rn, 2H), 1.8 - 2.0 (m, 6H), 1.6 (m, 2H) ppm. (28c) 4- (3-CICLOPENTILOXI-4-METOXIFENIL) -4- (2-METILSULFONIL) PIRIMIDIN-4-ILETINIDCICLOHEXAN-1-ONA To a solution of 0.35 g, 0.81 mrnol, of 4 ~ (3-c? Clopent? Lox? -4-methox? Phen?) -4- (2-met? Lt? Op? Pm? Dm-4-? L-eti nil) c Clohexan-1 -one, in 5 ml of chloroform, at -10 ° C, under an argon atmosphere, a solution of 0.31 g, 1.78 rnmoles, of 3-chloroperox-benzo? acid was added dropwise over 20 minutes. co in chloroform. The reaction was stirred for 1 hour at -10 ° C, then for 1 hour at room temperature, then treated with 5% sodium carbonate, extracted three times with dichloromethane, dried over potassium carbonate and dried. evaporated Purification by flash chromatography, eluting with 1:99 methanol: d? Chloromethane, yielded 0.27 g, 72% of 4 - (3-c? Clopent? Lox? -4-rnetox? Phen? 1) - 4 - (2-methyl-sulphonyl-pyridine-4-? Let? N) cyclohexan-1 -one, as a white foam, mp 60-64 ° C. A second charge was produced by oxidation of the sulfoxide as a white foam, mp 71-73 ° C. Analysis (C2SH28N2O5S-O .25 H2O) calculated: C, 63.47; H, 6.07; N, 5.92; Found: C, 63.43; H, 6.07; N, 5.58.

EXAMPLE 29 4- (2-AMINOPYRIMIDIN-4-ILETINIL) -4- (3-CICLOPENTILOXI-4-METOXYPENYL) CICLOHEXAN-1-ONA 4 mL of liquid ammonia was condensed in a solution of 0.26 g, 0.56 mmol, of 4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (2-methylisulfonylpyrirnidin-4-ylethynyl) cyclohexan-1-one in 4 ml of methanol, the pressure tube was sealed and the reaction was stirred at room temperature for 2.5 hours. After cooling evaporated the solvents. Purification required two chromatographies, eluting first with 2:98 methanol: dichloromethane and secondly with 4: 6 ethyl acetate: hexanes, to give 0.18 g, 73%, of 4- (2-amino-irimidin- 4-ylethynyl) -4- (3-cyclopentyloxy-4-rethoxyphenyl) cyclohexan-1-one, as a white solid, mp 58-70 ° C. Analysis (C 24 H 27 N 3 O 3 -0.2 H 2 O) calculated: C, 70.46; H, 6.75; N, 10.27; Found: C, 70.73; H, 6.79; N, 9.87.

EXAMPLE 30 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (1-METHYLIMIDAZOL-2-ILETINIL) CYCLOHEXAN-1-ONA (a) l-METHYL-2-YODYIMIDAZOLE 1-Methyl-2-iodoirnidazole was prepared by ordinary chemistry, well known to those skilled in the art, and was a white solid. (b) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (l-METHYLIMIDPHLZOL-2-ILETINIDCICLOHEXAN-1-ONA To a solution of 0.50 g, 1.6 mmol, of 4- (3-cyclopentylox? -4 -rnetoxyphenyl) -4-ethynylcyclohexan-l-one and 0.35 g, 1.6 mmol, of l-methyl-2-iodoirnidazole in 50 ml of triethylamine, under argon atmosphere, 0.074 g, 4%, of tetrakis (triphenylphosphine) was added. palladium (0), 0.018 g, 6% copper iodide (I) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85 ° C for 1 hour, water was added and the mixture was extracted three times. with dichloromethane, dried over magnesium sulfate and evaporated, purification by flash evaporation chromatography, eluting with 3: 1 ethyl acetate: hexanoe, yielded 0.16 g, 26%, of 4- (4-carbomethoxyethyl). 2-ylethynyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) c-clohexan-1-one impure, which was combined with the product of a second reaction (0.16 g, 43%) and purified by Rapid evaporation chromatography, the? going with 1:99 of r methanol: dichloromethane, followed by recrystallization from dichloromethane-hexanes to give 4- (3-cyclopentiioxy-methoxy phenyl) -4- (1-methylimidazol-2-ylenynyl) cyclohexan-1 -one (0.12 g) pure, as a matt white solid, mp 137-138 ° C. Analysis (C2-iH2β2? 3 -0.2 H2O) calculated: C, 72.77; H, 7.23; N, 7.0 ?; found: C, 72.82; H, 7.99; N, 6.97.

EXAMPLE 31 SALT 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (IMIDAZOL-2-ILETINIL) CICLOHEXAN-1-ONA CHLORHYDRATE 31 (a) l-TER-BUTLICARBQNIL-2-YODOIMIDAZOL Was prepared 1-ter-util carbon? l -2-yodoim? dazol med i before common and current chemistry, well known by experts in the field, and was only bl anco, p f 77 - 78 ° C. 31 (b) 4- (3-CICLOPENTILOXI-4-METOXIFENIL) -4- (1-TER-BUTOXICARBOXI-IMIDAZOL-2-ILETINIL) CICLQHEXAN-l-ONA To a solution of 0.28 g, 0.9 mmol, of 4- ( 3-C-clopentyloxy-4-methoxyphenyl) -4-ethynylcyclohexan-l-one and 0.29 g, 0.97 mmol, of 1-tert-butylcarbonyl-2-iodoirn-dazole in 5 ml of triethylamine, under an argon atmosphere, was added 0.042 g, 4%, of tetrakis (triphenylphosphine) palladium (0), 0.005 g, 6% copper iodide (I) and a small crystal of tri phenyl phosphine, and the mixture was heated at 80-85 ° C for 1 hour. hour. Water was added and the mixture was extracted three times with dichloromethane, dried over magnesium sulfate and evaporated. Purification by flash evaporation chromatography, eluting with 3: 7 ethyl acetate: hexanes, yielded 0.18 g, 4%, of 4- (4-carboethoxytien-2-ylethynyl) -4- (1-ter- butylcarbonylimidazole-2-i iml) cyclohexan-1-one as a colorless oil. NMR with 1H (400 MHz CDC13) d 7.36 (s, 1H), 7.20 (d, 3 = 2.1 Hz, 1H), 7.17 (dd, 3 = 8.5, 2.1 Hz, 1H), 7.01 (s, 1H), 6.85 (d, 3 = 8.5 Hz, 1H), 4.85 (m, 1H), 3.84 ís, 3H), 3.18 (m, 2H), 2.44 (m, 4H), 2.22 (m, 2H), 1.8-2.0 (rn , 6H), 1.6 (rn, 11H) ppn. (31c) SALT 4- (3-CICLOPENTILOXI-4-METOXIFENID-4- (IMIDAZOL-2-ILETINIL) CICLOHEXAN-1-ONA HYDROCHLORIDE Agitated under argon atmosphere, at room temperature, for 24 hours, a solution of 0.18 g, 0.37 nm, of 4- (4-car * bomethoxythien-2-ylethyl) -4- (l-tert-buty-i-carbomlimidazole-2-ylethynyl) ) cyclohexan-1-one and 40 drops of ethyl acetate saturated with hydrogen chloride in 10 ml of ethyl acetate. The suspension was cooled to 0 ° C and filtered to give 0.12 g, 76%, of hydrochloride salt of 4 ~ (3-cyclopentyloxy-4-methoxy phenyl) -4- (imidazol-2-ylethynyl) cyclohexan-1 -one, co or a white solid, mp 183-184. Analysis (C23H26N2O3 -HC1-0.25 H2O) calculated: C, 65.70; H, 6.83; N, 6.66; found: C, 65.46; H, 6.65; N, 6.44.

EXAMPLE 32 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2-C4-f2-HYDROXYETAN-1-OXY) PHENYL3ETINYL) CICLQHEXAN-1-ONA (32a) 4- (2-HYDROXYETOXY) YELLOW PHENYL A 6.5 g molten bath, 74 rnmoles, of ethylene carbonate was treated in a small flask, under argon, with 0.400 g, 1.82 rnmolee, 4-iodophenol, and 1.26 g, 9.1 mmol, powdered potassium carbonate, and stirred at 90 ° C for 3 hours. The mixture was treated with cold diluted hydrochloric acid to decompose the excess potassium carbonate and an excess of aqueous sodium hydroxide solution was added slowly, and the mixture was stirred overnight. The suspension was extracted with methylene chloride, washed with water and with brine, dried over sodium sulfate and separated to give a white solid, which was purified by flash chromatography on 20 ml of silica gel, with chloride of methylene to give 0.128 g, 27%) of the title intermediate, as a white solid, mp 76-77, 5 ° C. (32) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2-C4- (2-HYDROXY-ETAN-1-OXY) PHENYL3ETINYL) -1, 1- (ETHYLENDIOXY) CICLOHEXAN A solution of 0.059 was treated g, 0.22 mmol, of 4 ~ (2-hydroxethoxy?) phenyl iodide and 0.080 g, 0.22 mmol, of 4- (3-c? Clo? Entox? -4-methox? Phen 1) -1, 1- (et? Lend? Ox?) -4-ethm? L-cyclohexane in 1 ml of dry piperidine, with a mixture of 0.013 g, 0.11 mmoles, of tetrak? s (triphenylphosphine) palladium, 0.0025 g, 0. 0013 m ioles of iodide c? Proso and a triphenylphophine crystal, as described above in example 11. Purification of the crude product by chromatography (silica gel, 2% methanol in methylene chloride), followed by pumping to the vacuum produced the intermediate of the title, like? n viscous oil. NMR with * H (400 MHz, CDCl 3) d 7.39 (d, 3 = 9.0 Hz, 2H), 7.24 (d, 3 = 2.1 Hz, 1H), 7.13 (d-d, 3 = 8.3 Hz, 3 = 2.1 Hz, 1H), 6.85 (d, 3 = 8.7, 2H), 6.84 (d, 3 = 8.3 HZ, 1H), 4.81 (p, 3 = 2.0 Hz, 1H), 4.09 ( t, 3 = 4.4 Hz, 2H), 4.00 (s, 4H), 3.97 (t, 3 = 4.4 Hz, 2H), 3.84 (s, 3H), 2.3 to 1.5 (rn, 12H with H2O). (32c) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4-y2-C4- (2-HYDROXYETAN-1-OXY) PHENYL3ETINYL) CYCLOHEXAN-1-ONA A solution of 0.090 g, 0.18 rnmoles, of 4 was treated. - (3-cyclopentoxy-4-methoxyphenyl) -4- (2-C4- (2-hydroxyethan-1-oxy) phenyl-3-ethyl) -l, 1- (etnedioxy) cyclohexane in 8 ml of tetrahydrofuran, with 0.9 ml of hydrochloric acid 3N, as in example 12. Purification by chromatography (silica gel, 40 to 50% ethyl acetate in hexanes), gave al. Dry under vacuum at 60 ° C the title compound, like a glass. Analysis (C28H32O5"1/4 H2O) calculated: C, 74.23; H, 7.23; found: C, 74.31; H, 7.24, C NMR cori * H (400 MHz, CDCI3) 6 7.41 (d, 3 = 8.9 HZ, 2H ), 7.23 (d, 3 = 2.3 Hz, 1.H), 7.13 (dd, 3 = 8.5 Hz, 3 = 2.3 Hz, 1H), 6.89 (d, 3 = 8.7, 2H), 6.86 (d, 3 = 8.3 Hz, 1H), 4.80 (p, 1H), 4.11 (t, 3 = 4.5 Hz, 2H), 3.98 (t, 3 = 4.4 Hz, 2H), 3.85 (s, 3H), 3.04 (dt, 3 = 14.1 Hz, 3 = 6.1 Hz, 2H), 2.47 (broad d, 3 = 13.0 Hz, 2H), 2.4 to 1.5 (m, 19H with H20).

EXAMPLE 33 PREPARATION OF 4- (4-CARBOMETOXIFENILETINIL) -4- (3-CICLOPENTILOXI-4-METOXIFENIL) CICLOHEXAN-1-ONA (33a) 4- (4-CARBQMETOXIFENILETINIL) -4- (3-CICLQPENTILQXI-4-METOXIFEHIL) -!,! - (ETILENDIOXI) CICLOHEXAN A stirred mixture of 0.200 g, 0.56 mmol, of 4- (4-cycle) was treated. β-methoxyphenyl) -l, l- (et? iend? oxi) -4-ethynyl cyclohexane and 0.147 g, 0.56 mrnol, of methyl 4-iodobenzoate in 2.5 ml of dry triethylamine, with a mixture of 0.032 g, 0.028 rnmoles, of tetrakis (tpfen? lfosfina) palladium and 0.0064 g, 0.034 mrnoles, of cuprous iodide and a crystal of tpfenilfosfina, by the procedure of the Example Id. The reaction mixture was extracted and chromatographed as described in the Id example and it was stripped under vacuum to produce 0.25 g, 91%, of a light yellow oil. NMR with iH (400 MHz, CDCI3) d 7.98 (d, 9.4 Hz, 2H), 7.50 (d, 3 = 9.4 Hz, 2H), 7.20 (d.3 = 1.9 Hz, 1H), 7.12 (dd, 3 = 1.9 Hz, 3 = 8.6 Hz, 1H), 6.84 (d, 3 = 8.6, 1H), 4.80 (p, 3 = 3.8 Hz, 1H), 4.00 (broad s, 4H), 3.92 (s, 3H), 3.85 (s, 3H), 2.3 to 1.5 (rn, 17H with H20). (33b) 4- (4-CARBOMETOXIFENILETINIL) -4- (3-CICLOPENTILOXI-4-METOXYPENYL) CYCLOHEXANE A stirred solution of 0.150 g, 0.12 rnmoles, of 4- (4-carbomethoxyphenylethyl) -4- (3 -c? clo? entiioxi-4 ~ rnetox i phenyl) -1, 1- (et? lendiox?) cyclohexane in 7 ml of tetrahydro urane, with 0.70 ml of 3N hydrochloric acid, as described in example 14 above. The crude product was purified by chromatography (silica, 20% ethyl acetate / hexanes) and the solvent removed in vacuo to give the title compound as a resin (0.063 g, 46%). Analysis (C28H3? Os-L / 10 H2O) calculated: C, 75.01; H, 6.79; found: C, 74.97; H, 6.87. 1 H NMR (400 MHz, CDCl 3) & 8.01 (d, 3 = 8.5 Hz, 2H), 7.53 (d, 3 = 8.5 Hz, 2H), 7.20 (d, 3 = 2.4 Hz, 1H), 7.11 (dd, 3 = 8.5 Hz, 3 = 2.4 Hz, 1H), 6.87 (d, 3 = 8.5, 1H), 4.80 (p, iH), 3.93 is, 3H), 3.86 (s, 3H), 3.04 (dt, 3 = 6.2 Hz, 3 = 14.4 Hz, 2H) , 2.50 (broad d, 3 = 14.9 Hz, 2H), 2.42 - 2.32 (m, 2H), 2.26 (dt, 3 = 2.8 Hz, 3 = 14.4 Hz, 2H), 2.00 - 1.5 (m, 11H with H20) .

EXAMPLE 34 PREPARATION OF 4- (4-CARBQXIFENILETINIL) -4- (3-CICLOPENTILOXI-4-METOXYPENYL) CYCLOHEXAN-1-ONA A stirred solution of 0.146 g, 0.326 mrnoles, of 4- (4-carbomethoxyphenethyl) -4- (3-c-clopentiioxy-4-methoxy em 1) c-clohexane in 5 ml of methanol was treated with 0.46 ml. , 1.15 mmol, of a 10% aqueous solution of sodium hydroxide, under an argon atmosphere, as described in example 13. The crude acid was purified by chromatography (silica, ethyl acetate / methylene chloride / formic acid , 10: 90: 1), the product fractions were washed three times with water, separated in vacuo, crystallized with ether and dried under vacuum to yield the title compound, as a white solid (0.077 g, 55% ), mp 170-171 ° C. Analysis (C27H280s) calculated: C, 74.98; H, 6.53; found: C, 74.78; H, 6.54.

EXAMPLE 35 PREPARATION OF 4- (3-CYCLOOPENTILOXY-4-METOXYPENYL) -4- (2-C4- (1-PIPERIDINOCARBONYLMETOXY) PHENYL3ETINYL) CYCLOHEXAN-1-ONfl (35a) METHYL ESTER OF 4-YODOPHENOXYACETIC ACID It was sealed and heated at 70 ° C for 4 hours, a stirred mixture of 0.50 g, 2.27 mmol, of 4-iodophenol, 0.382 g, 2.50 mmol, of 2-bruno cetato methyl and 0.314 g, 2.27 mmoles, powdered potassium carbonate, in dry acetone, under argon. The cooled mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by chromatography (silica, 40 to 50% methylene chloride in cyclohexane) and the solvent was removed in vacuo to give 0.41 g, 62%, of the intermediate. title, as? n white powder, mp 69-70 ° C. (35b) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -1, 1- (ETHYLENDIOXY) -4- (2- (1-PIPERIDINOCARBONYLMETOXY) FENYL3ETINYL) CYCLOHEXANE A stirred mixture of 0.150 g, 0.42 mmol, was treated. 4- (3-cyclopentyloxy-4-rethoxyphenyl) -l, 1- (ethylenedioxy) -4-ethynylcyclohexane and 0.123 g, 0.42 mmol, of 4-iodophenoxyacetic acid methyl ester in 2 ml of piperidine, at 80 ° C, during 1.5 hours, by the procedure of Example 11, with a mixture of 0.027 g, 0.0023 mmole, tetrakisitophenylphosphine) α-aladium, 0.0048 g, 0.0025 mmole, cuprous iodide, and triphenylphosphine crystal. The crude product was chromatographed (silica 50 to 75% ethyl acetate in petroleum ether) and removed in vacuo to give the title intermediate, as a viscous yellow oil (0.232 g, 96%). NMR with 1H (400 MHz, CDCI3) d 7.38 (d, 3 = 8.7 Hz, 2H), 7.24 (d, 3 = 2.3 Hz, 1H), 7.13 (d-d, 3 = 8.4 Hz, 3 = 2.3 Hz, IH), 6.89 (d, 3 = 8.9, 1H), 6.84 (d, 3 = 8.4, 1H), 4.81 (p, IH), 4.69 (s, 2H), 4.00 (s, 4H), 3.84 (s, 3H), 3.56 (t, 3 = 5.5 H, 2H), 3.49 (t, 3 = 5.5 Hz, 2H), 2.3 to 1.5 (, 32H with H20). (35c) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2-C4- (1- PIPERIDINOCARBONYLMETOXY) PHENYL3ETINYL) CICLQHEXAN-1-ONA A stirred solution of 0.232 g, 0.40 mrnoles, of 4- ( 3-cyclopentyloxy-4-methoxyphenyl) -1, 1- (et? Le-dioxy) -4- (2-C4- (1-piper? Dinocarbonylmethoxy) phenyl 3-ethynyl) -cyclohexane in 9 ml of tetrahydrofuran, with 0.90 ml of 3N hydrochloric acid, as described in example 12 above. The crude product was purified by chromatography (silica, 50% ethyl acetate / hexanes) and the solvent removed in vacuo to give 0.127 g, 59%, of the title compound, as a resin. Analysis (C2ßH3oOs -1/10 H2O) calculated: C, 75.01; H, 6.79; found: C, 74.97; H, 6.87.

NMR with 1H (400 MHz, CDCl 3) 7.41 (d, 3 = 9.1 Hz, 2H), 7.22 (d, 3-2.3 Hz, 1H), 7.11 (dd, 3 = 8.4 Hz, 3 = 2.3 Hz, IH), 6.92 (d, 3 = 8.6, 1H), 6.86 (d, 3 = 8.5, 1H), 4.80 (p, 1H), 4.70 (s, 2H), 4.00 (s, 4H), 3.85 (s, 3H), 3.56 (t, 3 = 5.5 Hz, 2H), 3.48 (t, 3 = 5.5 Hz, 2H), 3.03 (dt, 3 = 6.1 Hz, 14.3, 2H), 2.47 (broad d, 3 = 1.49, 2H), 2.4 - 2.2 (m, 4H), 2.0 to 1.5 (, 25H with H20).

EXAMPLE 36 PREPARATION OF 4- (2-C4-CARBQXIMETILOXIFENIL3ETINID-4- (3-CICLOPENTILOXI-4-METQXIFENIDCICLOHEXAN-1-ONA 36 (a) 4- (2-C4-CARBOXIMETILOXIFENYL3ETINYL) -4- (3-CICLO-PENTILOXI-4-METOXYPENYL) -lJl- (ETHYLENDIOXI) CYCLOHEXANE A stirred mixture of 0.075 g, 0.21 mrnol, of 4- ( 3- cyclopentyloxy-4-methoxy-fe-1) -1, 1- (ethylenedioxy) -4- and cyclohexane and 0.60 g, 0.21 mmoles methyl ester of 4-iodophene-acetic acid, prepared as described in example (35a), in 2 ml of triet 1 dry sheet, at 80 ° C for 1.5 hours, by the procedure of example 11, with a mixture of 0.018 g, 0.016 rnmoles, of tetrak? s (tr? phenyl-? Phosphine)? 0. 004 g, 0.021 mmoles, of cuprous iodide and? N crystal of tnphenilfoefi na. The crude product was chromatographed on silica, with 40 to 50% ethyl acetate in hexanes, and removed in vacuo to yield the title intermediate, as a dark or red oil (0.080 g, 73%). NMR with * H (400 MHz, CDCI3) d 7.98 (d, 9.4 Hz, 2H), 7.50 (d, 3 = 9.4 H, 2H), 7.20 (d, 02 Jl.9 H, 1H), 7.12 (7.12 (dd, 3 = 1.9 Hz, 3 = 8.6 Hz, 1H), 6.84 (d, 3 = 8.6, IH), 4.80 (p, 3 = 3.8 Hz, IH), 4.00 (s broad, 4H), 3.92 (s, 3H), 3.85 (s, 3H), 2.3 to 1.5 (rn, 17H with H2O). (36b) 4- (2-C4-CARBOXIMETILOXIFENYL3ETINYL) -4- (3-CYCLE-PENTILOXY-4-METOXYPENYL) CYCLOHEXAN-1-ONA A stirred solution of 0.232 g, 0.40 mrnol, of 4- (2-C4) was treated. -carbometox? met? loxifeniDeti mi) -3- (3-ci clopent? lox? - -rnetox? phen? l) -l, 1 - (etiiendioxy) c? clohex or in 9 ml of tetrahydrofuran, with 0.90 rnl of hydrochloric acid *? co 3N, as described in example 12 above. The crude product was purified by chromatography (silica, 50% ethyl acetate / hexanes) and the solvent removed in vacuo to give 0.127 g, 59%, of the title compound, as a resin. Analysis (C2ßH3? Os -1/10 H2O), calculated; C 75.01, H 6.79, found; C 74.97, H 6.87. NMR with * H (400 MHz, CDCl 3) d 8.01 (d, 8.5 Hz, 2H), 7.53 (d, 3 = 8.5 H, 2H), 7.20 (d, 3 = 2.4 H, 1H), 7.11 (dd, 3 = 8.5 HZ, 3 = 2.4 Hz, IH), 6.87 (d, 3 = 8.5, 1H), 4.80 (p, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.04 (dt, 3 = 6.2 Hz, 3 = 14.4, 2H), 2.50 (wide d, 3 = 14.9, 2H), 2.42 - 2.32 (rn, 2H), 2. 26 (d-t, 3 = 2.8 Hz, 3 = 14.4 Hz, 2H), 2.00-1.5 (rn, 11H with H2O).

EXAMPLE 37 PREPARATION OF 4- (2-C4-CARBOMETOXIMETILOXIFENYL3ETINYL) -4- (3-CICLOPENTILOXI-4-METOXYPENYL) CYCLOHEXAN-1-ONA A stirred mixture of 0.075 g, 0.24 mmol, of 4- (3-cyclopentyloxy) was treated. -4-rethoxyphenyl) -4-ethynylcyclohexan-l-one 7 0.070 g, 0.24 mmoles, of 4-iodophenoxyacetic acid methyl ester, prepared as described in the example (35a), in 1.2 ml of dry triethylamine, at 75 ° C for 1 hour, with a mixture of 0.012 g, 0.010 mmol, of tetrakis (tri-phenyl-phosphine) palladium and 0.0024 g, 0.0.13 mmol, of cuprous iodide and a small crystal of triphenylphosphine, under argon. The reaction mixture was concentrated in vacuo and the residue was treated with cold hydrochloric acid, then extracted twice with ethyl acetate and the organic phase was washed with water, brine and dried with anhydrous sodium sulfate. The crude product was chromatographed (silica, 25 to 30% ethyl acetate in hexanes) and removed in vacuo to give 0.097 g, 85%, of the title intermediate, as an amber resin. Analysis (C29H32O6), calculated; C 73.09, H 6.77, found; C 72.91, H 6.78. NMR with 1H (400 MHz, CDCI3) d 7.41 (d, 8.9 Hz, 2H), 7.21 (d, 3 = 2.2 Hz, 1H), 7.11 (dd, 3 = 1.9 Hz, 3 = 8.4 Hz, 1H), 6.87 (d, 3 = 8.9, 2H), 6.85 (d, 3 = 8.4, 1H), 4.80 (p, 3 = 4.4 Hz, 1H), 4.65 (s, 2H), 3.84 (s, 3H), 3.81 (s) , 3H), 3.02 (dt, 3 = 6.2 Hz, 3 = 1.4.2, 2H), 2.46 (broad d, 3 = 14.8, 2H), 2.4 - 1.5 (, 16H with H2O).

EXAMPLE 38 PREPARATION OF 4- (2-CARBOMETOXIFENILETINIL) -4- (3-CICLOPENTILOXI-4-METOXIFENIL) CICLOHEXAN-1-QNA A mixture of 0.150 g, 0.48 mmol, of 4- (4-cyclo-entyloxy-4-methoxy phenyl) -4-ethynylcyclohexan-1-one and 0.126 g, 0.48 mmol, of methyl 2-iodobenzoate in 2.4 ml was treated. of dry triethylamine, with a mixture of 0.024 g, 0.021 mmol, of tetrakis (triphenylphosphine) palladium (0), 0.0048 g, 0.026 mmol, of cuprous iodide, and? 3 phenylphosphine crystal, under an argon atmosphere and stirred at 80 ° C for 7 hours. The reaction mixture was concentrated in vacuo and the residue was treated as described in Example 20, chromatographed twice (silica, 20% ethyl acetate in hexanoe, and 2% ethyl acetate in methylene chloride), it was crystallized from ether: hexanes and dried at 60 ° C under vacuum to give 0.051 g, 24%, of a white powder, mp 88.5-90 ° C. Analysis (C2ßH3? Os), calculated; C 75.31, H 6.77, found; C 75.11, H 6.78.

EXAMPLE 39 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2-C3, 5- DICARBOMETOXIFENYL3ETINYL) CYCLOHEXAN-1-ONA A mixture of 0.075 g, 0.24 mmol, of 4- (4-cyclopentyloxy-4-rethoxyphenyl) -4-ethynylcyclohexan-1-one and 0.107 g, 0.33 mmol, of dimethyl 5-iodoisophthalate (Trans Uorld Chemicals) was treated, in 1.9 ml of dry triethylamine, with a mixture of 0.12 g, 0.010 rnmol.es, of tetrakisí tri phenylephine) palladium, 0.0025 g, 0.013 mmoles, of cuprous iodide and a small crystal of triphenylphosphine, under an argon atmosphere, and stirred at 80 ° C for 1 hour. The reaction mixture was concentrated in vacuo and the residue was chromatographed (silica, 1 to 2% ethyl acetate in ethylene chloride) and dried at 50 ° C in vacuo to give a tan powder (0.100 g, 83%). ), mp 133.5-135 ° C. Analysis (C30H33O7), calculated; C 71.41, H 6.39, found; C 71.19, H 6.41.

EXAMPLE 40 PREPARATION OF 4- (2-C4-CHLOROPHENYL-3-ETINYL) -4- (3-CICLOPENTILOXY- -METOXYPENYL) CICLONEXAN-1-ONA A mixture of 0.075 g, 0.24 mmol, of 4- (4-cyclopentyloxy-4-methoxypheniD-4-ethynylcyclohexan-1-one and 0.057 g, 0.24 mmol, of 4-chloro-1-iodobenzene in 1.7 mL of trietüamine was treated. dry, with a mixture of 0.012 g, 0.010 mmole, of tetrakis (triphenylphosphine), palladium, 0.0025 g, 0.013 rn olee, of iodide or cuprous and a small crystal of triphenylphosphine, under an argon atmosphere and stirred at 80 ° C for 2 hours The reaction mixture was concentrated in vacuo and the residue was treated with dilute hydrochloric acid, extracted three times with ethyl acetate and the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed (silica, 0.05 to 1% ethyl acetate in 3: 1 rnetienene / hexanes chloride) and the title compound is dried at 25 ° C under vacuum, to give 0.051 g, 50% of a white powder, mp 104-105 ° C Analysis (C26H27CIO3), calculated C 73.83, H 6.43, found, C 73.69, H 6.41.

EXAMPLE 41 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2-C3- (5-METHYL-ClJ2J430X0DIAZ0L-3-IL) PHENYL3ETINYL) CICL0NEXAN-1-0NA (41a) 3- (3-YODOFENYL) -5-METHYL-Cl, 2,43 QXADIAZOL 3- (3-iodophene-1) -5-methyl-Cl, 2,3,4-oxadiazole was prepared by ordinary chemistry, well known by those skilled in the art, and it is a white solid, mp 90-91.5 ° C. (41b) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2-C3- (5-METHYL-Cl, 2J43? XODIAZOL-3-IL) PHENYL3ETINYL) CICLONEXAN-1-ONA A stirred solution of 0.200 g, 0.64 mmole, of 4- (3-c? Clopentylox? -4-methox? Phen?) -4-et? N? Lc? Clohexan-1-one and 0.200 g, 0.70 mrnoles, of 3- ( 3-iodophene? D-5-rnet? Lp, 2,43-oxadol-azole, in 4.6 ml of dry tetylamine, with a mixture of 0.032 g, 0.028 mrnoles, of tet rak? S (tpfen? L phosphma) -palladium, 0.0067 g, 0.035 mmole, of cuprous iodide and a small crystal of triphenylphosphine, at 75 ° C for 1 hour 20 minutes, under argon, the reaction mixture was concentrated in vacuo and the residue was treated with cold diluted hydrochloric acid, extracted two With methylene chloride, the organic phase was washed with water, brine and dried over anhydrous sodium sulfate, and the crude product was chromatographed (silica, 3 to 6% ethyl acetate, methylene chloride / hexanes 4: 1) and the fractions were combined, concentrated in vacuo, crystallized from ethyl ether and dried at 60 ° C under vacuum to give 0.235 g, 78%, of the title compound, as a white solid, mp 122.5-123.5 ° C. Analysis (C29H30N2O.; ), calculated; C 74.02, H 6.43, N 5.95; found; C 73.94, H 6.37, N 5.96. EXAMPLE 42 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2-C3- (3-METHYL-Cl, 2,430XADIAZ0L-5-IL) PHENYL3ETINYL) CICL0NEXAN-1-0NA JS (42a) 5- (3-Y0D0FENIL) -3-METHYL-ClJ2,430XADIAZ0L 5- (3-Iodophenyl) -3-rnethyl-Cl, 2,43-oxadiazole was prepared by common chemistry well known to those skilled in the art. material and was a white solid, mp 102-103 ° C. (42b) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2-C3- (3-METHYL-Cl, 2,43 QXADIAZOL-5-IL) PHENYL3ETINYL) CICLONEXAN-1-ONA A stirred mixture was treated of 0.200 g, 0.64 mmole, of 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-ethynylcyclohexan-1-one and 0.201 g, 0.70 mmole, of 5- (3-iodophenyl) -3-methy.l-25 Cl, 2,43-oxadiazole, in 4.6 nl of dry triethylamine, under argon, with a mixture of 0.032 g, 0.028 mmol, of tetrakis (triphenylphosphine) palladium, 0.0067 g, 0.035 mmol, of cuprous iodide and a small crystal of tri phenyl. phosphine, at 75 ° C for 1 hour and at 25 ° C for 15 hours. The reaction mixture was concentrated in vacuo and a solution of the residue was dissolved in rnnilene chloride, treated with cold dilute hydrochloric acid, and dried over anhydrous sodium sulfate. The crude product was chromatographed (silica, 5 to 10% ethyl acetate, methylene chloride / hexanes 1: 1) and the pure fractions were combined, concentrated in vacuo, crystallized from ethyl ether and dried at 60 ° C. under vacuum to give 0.235 g, 78%, of the title compound, as a white matte powder, mp 88-91 ° C. Analysis (C29H30N2O;), calculated; C 74.02, H 6.43, N 5.95; found; C 73.77, H 6.53, N 5.78.

EXAMPLE 43 PREPARATION OF 4- (2-C3-CYANOPHENYLETHYL) -4- (3-CICLOPENTILOXY-4-METOXYPENYL) CYCLOHEXAN-1-ONA A mixture of 0.100 g, 0.32 mmol, of 4- (4-cyclopentyloxy-4-methoxyphenyl) -4-ethynylcyclohexan-1-one and 0.088 g, 0.38 mmol, of 3-iodobenzonitrile in 2.5 ml of dry triethylamine was treated, with a mixture of 0.016 g, 0.013 mmol, of tetrakis (triphenylphosphine) palladium, 0.0033 g, 0.017 mmol, of cuprous iodide and a small crystal of triphenylphosphine, under an argon atmosphere, and stirred at 75 ° C for 1 hour 15 minutes, followed by the room temperature for 15 hours.

The reaction mixture was concentrated in vacuo and a solution of the residue was dissolved in methylene chloride, washed with dilute hydrochloric acid, with water, with brine and dried over sodium sulfate. The crude product was chromatographed (silica, 3% ethyl acetate in 4: 1 ruthenium chloride / hexanoe) and the title compound was dried at 60 ° C under vacuum to yield 0.075 g, 47%, of a solid. white, mp 1.23.5-125.5 ° C. Analysis (C27H27NO3), calculated; C 78.42, H 6.58, N 3.39; found; C 78.13, H 5.67, N 3.40.

EXAMPLE 44 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) 4- (2-C3, 5- DICI NOFENYL3ETINYL) -CICLOHEXAN-1-ONA (44a) 3,5-DICIANOPENYL YODIDE 3,5-Dicyanophenium iodide was prepared by ordinary chemistry well known to those skilled in the art and was a white solid, mp 145.5-146.5 ° C. (4b) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) 4- (2-3,5-DICIAN-PHENYL3ETINID-CICL0HEXAN-1-ONA A mixture of 0.150 g, 0.48 mrnol, of 4- (4 -cyclopentyloxy-4-methoxy phenyl) -4-ethynylcyclohexan-l-one and 0.17.1 g, 0.67 mmoles, of 3,5-dicyanophenyl iodide in 7.5 ml of dry triethylamine, with a mixture of 0.024 g, 0.021 rnmolee, of tetrakis (triphenylphosphine) palladium, 0.005 g, 0.026 mmol, of cuprous iodide and a small crystal of fine phosphorus, or argon, and stirred at 80 ° C for 0.5 hour and at 25 ° C for 15 hours. The reaction mixture was concentrated in vacuo and a solution of the residue was dissolved in rncliene chloride, washed with dilute hydrochloric acid, with water, with brine, and dried over sodium sulfate. The residue was chromatographed (silica, 2 a). 3% ethyl acetate in hexane chloride / hexanes, 9: 1) and dried in vacuo to yield 0.177 g, 84%, of a white powder, mp 147.5- 147.5 ° C. Analysis (C28H26N2O3), calculated, C 76. 69, H 5.98, N 6.39, found; C 76. 41, H 5.92, N 6.39.

EXAMPLE 45 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) 4- (2-C4-HYDROXYPENYL3-TINYL) -CICLOHEXAN-1-ONA A mixture of 0.090 g was treated, 0.29 rnrnoles, of 4- (4-c? Clopen? Loxi-4-methox? Feml) -4-et? N? Lc? Clohexan-l -one and 0.076 g, 0.35 immoles, of 4-iodophenol in 3 rnl of dry triethylamine, with a mixture of 0.013 g, 0.012 rnrnoles, of tetrak? s (tpfen? lfosfina) palad? o, 0.003 g, 0.016 mmolee, of iodide c? proso and? n small crystal of trifeml fosfina, under the atmosphere of argon, and stirred at 75 ° C for 40 minutes. The reaction mixture was concentrated in vacuo and a solution of the residue was dissolved in methylene chloride, washed with dilute hydrochloric acid, with water, with brine and dried over pH 9.1.

Sodium sulfate and concentrated in vacuo. The residue was chromatographed (silica, 4 to 7% ethyl acetate in 4: 1 rnetylene chloride / hexanes) and the title compound was recrystallized from netanol to yield 0.035 g, 30%, of a white powder, mp 144- 146 ° C. Analysis (C26H280¿- 1/5 H2?), Calculated; C 76.52, H 7.01; found; C 76.57, H 6.97. NMR with 1H (400 MHz, CDCI3) d 7.36 (d, 8.5 Hz, 2H), 7.23 (d, 3 = 2.2 Hz, 1H), 7.12 (dd, 3 = 2.2 Hz, 3 = 8.5 Hz, 1H), 6.86 (d, 3 = 8.5, 1H), 6.80 (d, 3 = 8.5, 2H), 5.22 (e, 1H), 4.80 (d, 3 = 3.8 Hz, 1H), 3.85 (s, 3H), 3.04 (dt) , 3 = 6.0 Hz, 3 = 1.4.2, 2H), 2.47 (broad d, 3 = 14.8, 2H), 2.4 -2.1 (m, 4 H, 2.0 to 1.5 (m, 12H with H20).

EXAMPLE 46 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2-C3- (5-METHYL-Cl, 3,43-T-DIAZOL-2-IL) PHENYL3ETINYL) CYCLOHEXAN-1-ONA (46a) 2- (3-YODOPHENYL) -5-METHYL- 1, 3, -TIADIAZOL 2- (3-Iodophenyl) -5-rnettyl, 3,43-thiadiazole was prepared by common chemistry and well-known chemistry. the experts in the field. (6b) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -C2-C3, 5-DICIAN-PHENYL3ETINID-CICL0HEXAN-1-0NA A stirred mixture of 0.100 g, 0.32 rnmoles, of 4- (3-cyclopentyloxy) was treated. 4-methoxyphenyl) -4-ethynylcyclohexan-1-one and 0.0.97 g, 0.32 mmol, of 2- (3-iodophenyl) -5-methyl-Cl, 3,3,4-thiadiazole in 2.5 ml of dry triethylamine, under argon, with a mixture of 0.016 g, 0.0.1.3 mmole, of tetrakistriphenyl-foefine)? aladium, 0.0033 g, 0.017 mmole, of cuprous iodide and a small crystal of triphenylphosphine, and at 70 ° C for 1 hour and at 25 ° C during 15 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between methylene chloride and cold diluted hydrochloric acid. The organic phase was chromatogenated (silica, 10 to 202 ethyl acetate in methylene chloride) and the pure fractions were combined, concentrated in vacuo and dried at 50 ° C, under vacuum, and the brittle resin was milled to give 0.028 g, 79%, of the title compound, as a yellow powder. Analysis (C29H30N2O3S-H2O), calculated; C 69.02, H 6.39, N 5.55; found; C 68.91, H 6.21, N 5.35. NMR with * H (400 MHz, CDCl 3) d 8.06 (t, 3 = 1.6 Hz, 1H), 7.88 (dt, 3 = 1.4 Hz, 3 = 8.1 H, 1H), 7.58 (dd, 3 = 1.2 Hz, 3 = 9.0 H, 1H), 7.45 (t, 3 = 7.8 Hz), 7.21 (d, 3 = 2.2 Hz, 1H), 7.14 (dd, 3 = 8.4 Hz, 3 = 2.1 Hz, 1H), 6.88 (d, 3 = 8.5, 1H), 4.82 (p, 3 = 4.1 Hz, 1H), 3.86 (s, 3H), 3.04 (dt, 3 = 6.1 Hz, 3 = 14.2, 2H), 2.84 (s, 3H), 2.50 (broad d, 3 = 14.9, 2H), 2.42 - 2.32 (m, 2H), 2.27 (dt, 3 = 2.8 Hz, 3 = 14.2 Hz, 2H), 2.00 - 1.5 (rn, 4 H), 2.0 to 1.5 (rn, 12H with H2O).

EXAMPLE 47 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2-C3- (5-METHYL-Cl, 3,430XADIAZ0L-2-IL) PHENYL3ETINYL) CICL0HEXAN-1-0NA (47a) 2- (3-YODQFENIL) -5-METILC1,3, 43QXADIAZOL 2- (3-iodophenyl) -5-rnet? I-f1,3,43-oxadiazole was prepared by common chemistry well known to the experts in the art and it was a white solid, mp 112.5-113.5 ° C. (47b) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2-C3- (5-METHYL-Cl, 3,430XADIAZOL-2-IL) PHENYL3ETINYL) CYCLOHEXAN-1-ONA A stirred mixture of 0.100 was treated g, 0.32 mrnol, of 4- (3-c? clopenyloxy-4-methox? phen?) -4-et? n? lc? clohexan-1-one and 0.0915 g, 0.32 mmol, of 5- (3-iodophen? L) -2-met? L-Cl, 3, 43oxadiazol in 3.5 ml of dry triethiiarnine, under argon, with a mixture of 0.016 g, 0.013 rnmoles, of tet rak is (t rifenil-fosf? Na ) palladium, 0.0033 g, 0.017 mmoles, of cuprous iodide and a small crystal of fine phenyl phos, at 75 ° C for 1 hour. The reaction mixture was concentrated in vacuo, the residue was extracted into methylene chloride and the organic phase was washed with cold dilute hydrochloric acid, with water, with brine, and dried over sodium sulfate. Purification by chromatography (silica, 10 to 20% ethyl acetate in rnetylene chloride) and then drying at 50 ° C, under vacuum, yielded 0.068 g, 45% of the title compound, as a white powder, mp 139- 141 ° C.

Analysis (C29H30N2OA "1/3 H2O), calculated: C 73.09, H 6.49, N 5.88, found, C 73.07, H 6.35, N 5.79. NMR with * H (400 MHz, CDCI3) d 8.15 (t, 3 = 1.6 Hz, 1H), 8.01 (dt, 3 = 1.4 Hz, 3 = 7.9 Hz, 1H), 7.62 (dd, 3 = 1.5 Hz, 3 = 7.8 Hz, IH), 7.49 (t, 3 = 7.9 Hz), 7.21 (d, 3 = 2.3 Hz, 1H), 7.14 (dd, 3 = 8.5 Hz, 3 = 2.4 Hz, 1.H), 6.88 (d, 3 = 8.5, 1H), 4.82 (p, 3 = 4.2 Hz, 1.H), 3.86 (s, 3H), 3.04 (dt, 3 = 6.1 Hz, 3 = 14.2, 2H), 2.64 (s, 3H), 2.5.1 (broad d, 3 = 15.0, 2H), 2.42 - 2.32 (, 2H), 2.27 (dt, 3 = 2.8 Hz, 3 = 14.2 Hz, 2H), 2.00-1.5 (m, 9H with H20).

EXAMPLE 48 PREPARATION OF 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2CE3- (3-CI NOFENYL) ETENYL) CICLOHEXAN-1-ONADDzGP + D (48a) 3-CYANOBENCILPHOSPHONIC ACID ESTER DIETILICO A stirred mixture of 0.500 g, 2.95 mmol, of triethyl phosphite and 0.609 g, 2.95 mmol, of 3-cyanobenzyl bromide, was brought to reflux, at 140 ° C, under argon, for 2 hours and the resulting volatiles were removed at room temperature, under vacuum, to give 0.62 g, 84% of the title intermediate, as a colorless oil. NMR with iH (400 MHz, CDCI3) d 7.7 - 7.5 (rn, 3H), 7.44 (t, 3 = 7.8 Hz, 1H), 4.06 (d, 3 = 7.6 Hz, 4H), 3.17 (d, 3 = 21.8 Hz, 2H), 1.27 (t, 3 = 7.1 Hz, 6H). (48b) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2CE3- (3-CI NOFENYL) ETENYL) -!,! - (ETHYLENDIOXY) CICLQHEXAN A solution of 0.54 g, 2.13 mmol, of the ester was added * diethyl ester of the 3-c? anobenzyl phosphonic ester, dissolved in 7 ml of dry tetrahydrofuran, by means of cannula, to a solution of 0.237 g, 2.11 mmoles, of potassium tei-butoxide dissolved in 15 ml of tetrahydrofuran dry, both solutions under argon, and cooled to 0 ° C. While stirring for 45 minutes, a solution of 0.38 g, 1.06 rnmoles, of 4-4- (3-c? Clopent? Iox? - 4-rnetox? Phen? L) -l, l- (et. lend? ox?) -4-forrnilcyclohexane in 5 ml of tetrahydrofuran. The reaction mixture was allowed to warm to room temperature. After 15 hours the mixture was quenched with an aqueous solution of ammonium chloride, concentrated in vacuo, partitioned between ethylene chloride / aqueous solution of ammonium chloride and the organic extract was washed with water, brine, dried over Sodium sulfate and concentrated in vacuo to give a mixture containing the desired title product and excess phosphonate ester as a crude resin. NMR with * H (400 MHz, CDCl 3) d 7.62-7.4 (, 4H), 7.36 (t, 3 = 7.8 Hz, 1H), 6.90 (syd, 2H), 6.83 (d, 3 = 8.7 Hz, 1H), 6.30 (d, 3 = 16.4 Hz, 1H), 6.16 (d, 3 = 16.3 Hz, 1H), 4.75 (p, 3 = 4.4 Hz, 1H), 4.06 (p, 3 = 7.6 Hz, 1H), 3.96 ( c, 3 = 3.3 Hz, 4H), 3.84 (s, 3H), 3.17 (d, 3 = 21.8 Hz, 0.3 H), 2.35 - 1.5 (m, 20H with H20), 1.27 (t, 3 = 7.1 Hz, 1.3 H). (48c) 4- (3-CICLOPENTILOXI-4-METOXYPENYL) -4- (2CE3- (3-CI NOFENYL) ETENYL) CYCLOHEXAN-1-QNA A solution of 0.58 g, 1.06 mmol, of 4- (3- c? clopentyl? -4-methox? phen?) -4- (2CE3- (3-c? anophen? l) ethen?) -1, 1 - (ethylenedioxy) c? clohexane crude in 20 nl of Rahydro-furan, with 2.3 ml of 3N aqueous hydrochloric acid, under argon, and heated at 75-80 ° C for 1 hour. Then 13 rnl more hydrochloric acid was added, and the mixture was heated at 75 ° C for another 15 minutes. The reaction mixture was concentrated in vacuo, extracted into rnetylene chloride and the organic extract was washed with water, with dilute sodium bicarbonate solution, with brine, and dried over sodium sulfate. Purification by chromatography (silica, 1 to 2% ethyl acetate in rnetylene chloride) and crystallization from ethyl ether gave 0.329 g, 74%, of the title compound, as a white solid, mp 116-117 ° C . Analysis (C27H29NO3 - 1/6 H2O), calculated; C 77.48, H 7.06, N 3.35; found; C 77.63, H 6.94, N 3.33. NMR with * H (400 MHz, CDCI3) d 7.60 (e, 1H), 7.55-7.45 (, 2H), 7.39 (t, 3 = 7.7 Hz, IH), 6.97 (dd, 3 = 2.4 Hz, J = 8.5 Hz, 1H), 6.89 (d, 3 = 8.4 Hz, 1H), 6.37 (d, 3 = 16.1 Hz, 1H), 6.22 (d, 3 = 16.2 HZ, 1H), 4.77 (p, 3 = 4.5 Hz, 1H), 3.86 (s, 3H), 2.6-1.5 (m, 18H with H2O).

EXAMPLE 49 PREPARATION OF 4- (2-ACETAMIDOPIRIMIDIN-5-ILETINIL) -4- (3-CICLOPENTILOXY-4-METOXYPENYL) CICLOHEXAN-1-ONA, SB 240712 To a stirred suspension of 0.288 g, 1.34 rnmoles, of pyridinium chlorochromate in 4 ml of dry methylene chloride, under argon, was added via a cannula a solution of 0.20 g, 0.445 mmoles, of cs- C4- (2-acetamidop? R? Midin-5-ylethynyl) -4- (3-cyclopentyloxy-4-rnetoxy? Phenyl) cyclohexan-l-ol3, prepared as described in the pending US patent application, identified as P50287 (filed on the same date as this), in 5 ml in total of methylene chloride. After 2 hours at 25 ° C, about 10 ml of ethyl acetate was added, the reaction was filtered and the precipitate was washed with another 10 ml of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel, with 1: 9 ethyl acetate: dichloromethane, eluting the product with 20:80 to 30:70 ethyl acetate: dichloromethane, to produce 0.033 g, 5.5%, of 4- (2-acetamidopyrirni din-5-yl-ethynyl) -4- (3-cyclopentyloxy-4-methox-enyl) cyclohexan-1-one, as a white solid, mp 170-171 ° C. NMR with * H (400 MHz, CDC13) d 8.65 (S, 2H), 8.47 (s, 1H), 7.14 (d, 3 = 2.1 Hz, 1H), 7.09 (dd, 3 = 8.4, 2.3 Hz, 1H) , 6.87 (d, 3 = 8.5 Hz, 1H), 4.80 (p, 3 = 4.7, 1H), 3.86 (s, 3H), 2.94 (dt, 3 = 23, 8.8 Hz, 2H), 2.50 (s superimposed on 2.6-22 m, 9H), 2.0-1.5 (m, superimposed on water) ppm.

EXAMPLE 50 By proceeding in the manner set forth in any or all of the preceding examples, the following compounds can be prepared: 4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (2-C3- (5-t) fluoromet? lCi, 2,43-oxad? azole ~ 3-? l) phenyl et.ini l) c-clohexan-L-one; 4- (3-c? Clo? Ent? Lox? -4-methox? Phen?) ~ 4- (2-C ~ (3-tr *? -fluoromet ll, 2,43-oxad-azole-5? ) phenol3etm? dc? clohexan-1-one; 4- (3- c? clo? ent? lox? -4-methox? phen?) -4- (2 ~ C3- (5-t p-fluorometii 1,3,43-oxad-azole-2- (1) phen-3-methyl) c-clohexan-1-one; 4- (3-c? Clo? Ent? -iox? -4-rnetox? Phen?) - 4- (2-3- (5-tn-fluoromethylCl, 3,43tr? D? Azol-2-? 1) feml3et.mil) c? Clohexan-1-one; and 4- (3-c? Clopent? Lox) ? -4-rnetox? Fen? D-4- (2 ~ C2-acetam? Dopyrim? D? N-5-? L etm? L) cyclohexan-l-one.

EXAMPLES OF UTILITY EXAMPLE A INHIBITOR EXAMPLE OF FORMULA (I) AND (II) ON THE PRODUCTION OF FNT IN VITRO BY HUMAN MQNOCITS The inhibitory effect of the compounds of the formula (I) and (II) on the production of TNF in vitro by human monocytes can be determined by the protocol described in Badger and co-inventors, published by EPO 0 411 754 A2, February 5, 1991, and in Hanna, UO 90/15534, December 27, 1990.

EXAMPLE B Two models of endotoxic shock have been used to determine TNF activity in vivo for the compounds of formula (I) and (II). The protocol used for these models is described in Badger and co-inventors, patent application published by EPO 0 411 754 A2, of February 6, 1991, and in Hanna, UO 90/15534, December 27, 1990. The compound of the example 1 of this, demonstrated a positive response in vivo by reducing TNF levels in the serum, induced by the injection of endotoxin.

EXAMPLE C ISOLATION OF ISOZIMAS OF FDE The phosphodiesterase inhibitory activity and the selectivity of the compounds of the formula (I) and (II) can be determined using a battery of five isozyms other than FDE. The tissues used as sources of the different isozymes are the following: (1) FDE Ib, porcine aorta; (2) FDE him, heart of whose; (3) FDE III, heart of which; (4) FDE IV, human monocyte; and (5) FDE V (also called "the"), canine trachea. FDE la, Ib, le and III are partially purified using common chromatographic techniques CTorphy and Cieslinski, Mol Pharrnacol., 37: 206-214, 19903. FDE IV is purified to kinetic homogeneity by sequential use of exchange resin of anions, followed by chromatography with heparin-Sepharose CTorphy and co-authors, Biol. Chem. 267: 1798-1804, 19923. The phosphodiesterase activity is analyzed as described in the protocol of Torphy and Cieslinski, Mol.

Pharrnacol., 37: 206-214, 1990. It has been shown that the positive CIso is on the nanomolar to micrornolar scale for the working examples described herein, for the formulas (I) and (II).

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula (I) where: R is - (CRR) CIO) OR (CRR) R, - (CRR) C (0) NR (CRR) R, ~ (CRR) 0 (CRR) R o - (CRR) R where the portions alkyl may be unsubstituted or substituted with one or more fluorine atoms; m is 0 to 2; n is 0 to 4; r is 0 to 6; R and R are independently hydrogen or alkyl of 1 to 2 carbon atoms; R ee hydrogen, methyl, hydroxyl, aryl, halogen-substituted aryl, aryloxy-C-alkyl, aryloxy-alkyl, substituted with halogen, indanyl, indenyl, polycycloalkyl of 7 to 11 carbon atoms, tetrahydrofuranyl, furanyl, tetrahydropyranyl , pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, cycloalkyl of 3 to 6 carbon atoms or cycloalkyl of 4 to 6 carbon atoms containing one or two unsaturated ligatures; wherein the cycloalkyl or heterocylic portion may be unsubstituted or substituted with 1 to 3 methyl groups, an ethyl group or a hydroxyl group; provided that: (a) when R is hydroxyl, then n is 2; or (b) when R is hydroxyl, then r is 2 to 6; or (c) when R is 2-tetrahydropyranyl, 2-tetrahydrothioanthyl, 2-tetrahydrofuranyl or 2-tetrahydro-thienyl, then it is 1 or 2; or (d) when Re is 2-tetrahydropyranyl, 2-tetra-hydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then r is 1 to 6; (e) when n is 1 and rn is 0, then Rs is different from H in - (CR «Rs) n0- (CR« Rs) m Re; is YR2, fluorine, NR «Rs or formylamine; Y is 0 or S (0) m '; m 'is 0, 1 or 2; X2 is O or NR8; X3 is hydrogen or X; R2 is -CH3 or -CH2CH3 unsubstituted or substituted by one or more fluorine atoms; s is 0 a; R3 is COORnv, C (0) R4R? «Or R7; U is alkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; Z is 0, NR, NCR _-. RsC2-s alkenyl, NOR14, NOR15, N0CR «RsC2-6 alkenyl, NNR4R14, NNR4R15, NCN, NNR8C (0) NRβRl4, NNRβC (S) NR8 R14 or = Z is 2 ~ ( 1,3-dithiane), 2- (1,3-dithiolane), dimethylthioketal, diethylthioketal, 2- (1,3-dioxolane), 2- (1,3-dioxane), 2- (1,3-oxathiolane) , dimethyl ketal or diethyl ketal; R7 is - (CRARS) qR12 or alkyl of 1 to 6 carbon atoms, wherein the group R12 or alkyl of 1 to 6 carbon atoms is unsubstituted or substituted one or more times with methyl or ethyl, unsubstituted or substituted with one or three fluorine atoms, -F, -Br, -Cl, -NO2, -NR10R11, -C (0) R8, - CO2R8, -0 (CH2) 2-4? R8, -0 (CH2) qRβ , -CN, -C (0) NR? O Rl 1, - 0 (CH2) qC (0) NRioRll, -0 (CH2) q CIO) R9, -NR? 0C (0) NR? O Rll, - NR ? oC (0) Rn, -NR10 C (0) 0R9, -NR10 C (0) R13, -C (NR10) NR? or Rll, -C (NCN) NR? oRll, -C (NCN) SR9, - NR10 CINC) SR9, -NR? OC (NCN) NR? O Rll, -NR? OS (0) 2R9, -S (0) m'R9, -NR10 C (0) C (O) NR? O Rl 1 , -NR? 0C (0) C (0) Rio or R13; d is 0, 1 or 2; R12 is R13, cycloalkyl of 3 to 7 carbon atoms (2-, 3- or 4-p? Pd? Lo), pipmidyl, pyrazolyl, (1- or 2-? M? Dazol?), Pyrrolyl, piporazmyl, pipepdimlo, rnorfolmilo, furanyl, (2- or 3-t? in? l), q? inolinyl, naphthyl or phenyl; R8 is hydrogen or R9; R9 is alkyl of 1 to 4 carbon atoms, unsaturated or substituted with one to three fluorine atoms; Rio is OR8 or R11; R n is hydrogen or alkyl of 1 to 4 carbon atoms, unsubstituted or substituted by one to three fluorine atoms; or when Rio and R11 are like NR10R11 then, together with the nitrogen, they can form a 5- to 7-membered ring consisting solely of carbon atoms or of carbon atoms and at least one heteroatom selected from 0, N or S; R 13 is a substituted or unsubstituted heteroaryl group, selected from the group consisting of oxazolidimide, oxazolyl, thiazolyl, pyrazolyl, triazoyl, tetrazolyl, imidazolyl, isoxyzolidimide, tlazol 1 di, isoxazolyl, oxadiazolyl and thiadiazolyl; and wherein R13 is substituted at R12 or R13 the rings are connected by means of a carbon atom and every second ring R13 may be unsubstituted or substituted with one or two alkyl groups of 1 to 2 carbon atoms, unsubstituted or substituted in methyl, with 1 to 3 fluorine atoms; R "is hydrogen or R7; or when R8 and RIA are as NRßRi *, they can form, together with nitrogen, a 5- to 7-membered ring consisting solely of carbon atoms or of carbon atoms and at least n heteroatom selected from 0, N or S; provided that: (f) R 7 is not alkyl of 1 to 4 carbon atoms, unsubstituted or substituted with 1 to 3 fluorine atoms; or their pharmaceutically acceptable salts.

2. A compound in accordance with the claim 1, further characterized in that Ri is -CH2-cyclopropyl, -cyclopentyl, -3-hydroxycyclopentiio, methyl or CF2H; X is YR2; And it's oxygen; X2 is oxygen; X3 is hydrogen; R2 is CF2H or methyl, U is ethynyl or 1,3-butadiinyl, R3 is a substituted or unsubstituted pyrirnidinyl ring, X is YR2 and Z is 0, NR7.

3. A compound in accordance with the claim 2, further characterized in that it is: 4- (3-cyclopentyloxy-4-methoxyphenyl) ~ 4 ~ (2-rnethylsulfonylp.yrirnidin-4-ylethynyl) cyclohexan-1-one; 4- (2-aminopyrimidin-4-ylethynyl) -4- (3-cyclopentyloxy-methoxyphenyl) cyclohexan-1-one; 4- (2-aminopyrimidin-5-ylethyndiD-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one 4.- A compound according to claim 1, further characterized in that Ri is -CH2-cyclopropyl, -cyclopentyl, -3-hydroxycyclopentyl, methyl or CF2H, X is YR2; And it's oxygen; X2 is oxygen; X3 is hydrogen; R2 is CF2H or methyl; U is ethynyl or 1,3-butadiinyl; R3 is R7, wherein R7 is an aryl or heteroaryl ring, unsubstituted or suetitides; X is YR2 and Z is 0. 5. A compound according to the claim 4, further characterized in that it is: 4- (3-cyclopentyloxy-4-rnetoxy phenyl) -4- (4-arni not f eni.L.etinyl) cyclohexan-l-one; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (4-acetamidophenylethynyl) -cyclohexane-1-one; 4- (3-cyclo-entyloxy-4-methyl group) -4- (3-acetarnide-phenylethynyl) cyclohexan-1-one; 4- (3-cyclo-entyloxy-4-r-methoxy-phenyl) -4- (3-carbomethoxyphenylethynyl) -cyclohexan-1-one; 4- (3-cyclo-entyloxy-4-ribethoxyphenyl) -4- (3-carboxyphenylethynyl) -cyclohexane-1-one; 4- (3-cyclopentyloxy-4-rethoxyphenyl) -4- (3-arnino-phenylethynyl) -cyclohexan-1-one; 4- (3-cyclopenti.loxy-4-methoxyphenyl) -4- (4-pyridylethynyl) -cyclohexan-1-one; 4- (3 ~ cyclopentyl-oxy-4-methoxyphenyl) -4-. { 4- (2-hydroxyethan-1-oxy) phenyl-3-ethynyl} -cyclohexan-1-one; 4- (3-cyclopentyloxy-4-rnetoxyphenyl) -4- (3-pyridylethynyl) -cyclohexan-1-one; 4- (3-cyclo? Entiioxy-4-rneto i-fe il) -4- (2- 4- (2-hydroxyethan-1-oxy) phen.hillethynyl) cyclohexan-1-one; 4- (4-carbometho ifeniletinyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -cyclohexan-1-one; 4- (4-carboxyphenylethynyl) -4- (3-cyclo-pentiioxy-4-rethoxyphenyl) -cyclohexan-1-one, 4- (3-cyclopentiyoxy-4-methoxy phenyl) -4- (2-4- (l-piperidinocarbonylmethoxy) phenyl-3-yl) cyclohexan-1-one; 4- (2-C4-Carboxymethyloxy-phenyl3-ethyl) -4- (3-cyclopentiioxy-4-methoxy-phenyl) -cyclohexan-1-one 4- (2-C4-carbomethoxy-ethyloxy-phenyl-3-ethyl) -4- (3-cyclopentyloxy) 4-methoxymethyl) -cyclohexan-1-one; 4- (2-Carbornetoxyphenylethyl) -4- (3-cycloopentyloxy-4-rnetoxy enyl) -cyclohexan-1-one; 4- (3-cyclopentyl-4-methoxyphenyl) -4- (2- C3,5-dicarbomethoxy-phenyl-3-nitinoi) -cyclohexan-1-one; 4- (2-C4-chlorophenyl-3-ynyl) -4- (3-cyclo-pentiyoxy-4-methoxyphenyl) -cyclohexan-1-one; 4- (2-carbomethoxythien-5-ylethynyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one; 4- (2-3-cyano-phenyl-3-ynyl) -4- (3-cyclopentyloxy-4-methoxy-en-D-cyclohexan-1-one; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (2-4-hydroxyphenyl-ethynyl) cyclohexan-1-one; 4- (3-cyclo-entyloxy-4-nitroxyphenyl) -4- (2CE - (3-cyano-phenyl) -ethenyl) -cyclohexan-1-one; 4- (3-cyclopentyloxy-4-methoxy-phen) .il) -4- (2- C3, 5-dicyanophen.-3-ethynyl) cyclohexan-1-one; sodium eal of 4- (2-carboxytien-5-ylethynyl) -4 ~ (3-cydopentyloxy-4) -methoxyphenyl) cyclohexan-1-one; 4- (2-cyanothien-5-ylethynyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -cyclohexan-1-one; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-C5- (5-methyl-l, 2,43-oxadiazol-2-yl) thien-2-ylethynyl-3-cyclohexan-1-one; 4- (3-cyclopentyloxy-4-rethoxyphenyl) 4- (2-3 (5 -rnethyl-Cl, 2,3,4-oxadiazol-3-yl) phenyl-3-ynyl) -cyclohexan-1-one; 4- (3-cyclopentyl-oxy-methoxyphenyl) -4- (2-3 (3-methyl-1, 2,4-oxadiazole-5-yl) -phenyl-3-ynyl) -cyclohexan-1-one; 4- (3-cyclopentiyoxy-4-rnetoxy-phenyl) -4-C4- (5-methyl-l, 2,43-oxadiazole-2- il) thien-2-ylethynyl-3-cyclohexan-1-one; 4- (3-cyclopentyloxy-4-methox) ifenyl) -4- (2-C3- (5-R-ethyl-1,3,4-oxadiazol-2-yl) -phenyl-3-ynyl) -cyclohexan-1-one; 4- (2-carbomethoxythien-4-ylethynyl) -4- (3-cyclopentyloxy-4-methoxy-phenyl) cyclohexan-1-one, SB; 4- (2-carboxytien-4-ylethynyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one, S; 4- (2-cyanothien-4-ylethynyl) -4 ~ (3-cyclopentyloxy-4-methoxyphenyl) -cyclohexan-1-one; 4- (3-cyclopentyloxy-4-rethoxyphenyl) -4- (2-3- (3-rnenyl, 2,43-oxadiazol-5-yl) enyl-3-ynyl) -cyclohexan-1-one, SB; 4- (3-cyclopentyloxy-4-rethoxyphenyl) -4- 2- (5-methyl-Cl, 2,4-oxadiazol-2-yl) thien-4-ylethynyl-3-cyclohexan-1-one; 4- (4-carbo-rnetoxythien-2-ylethynyl) -4- (3-cyclopentyloxy-4-methoxyphenyl) -cyclone an-1-one; 4- (4-carboxytien-2-ynyl) -4- (3-cyclopentyl-4-methoxyphenyl) cyclohexan-1-one; 4- (3-cyclopentyl-4-? -neurox? Phen?) -4- (2-3 (5-met? I-Cl, 3,43t? Ad? Azole-2-? L) phenyl-e iml) c? clohe n-1 -one; 4- (3-C? Clopent? Lox? - 4-rnetox? Pheni) -4- (l-rnet? L? M? Dazol-2-? Letm? L) c? Clohexan-1 -one; 4- (3-cyclopentyloxy-4-methox? phen?) -4- (irnide-2-let?? dc? clohexan-1-one hydrochloride salt; 4- (2-acetarn? dop? pm? d? n-5? let? n? l) -4- (3-c? clopent? lox? ~ 4-methox? phen?) c? clohexan-l-one; 4- (3-c? clopent iox? ~ 4-rnetox i faith ni 1) -4- (2-C3- (5-rnet? ll, 3, 43oxad? azol ~ 2 ~ ll) phen? 3etm? l) c? clohexan-l-one or 4- (3-c? clopent? lox? -4-rnetox? phen? l) -4- (2- C3- (5-rnet ilTl, 3, 43 t? ad? azol-2-? l) feml -et thousand) c-clohexan-l -one 6.- A compound of the formula (II): where: Ri is - (CR <4 Rs) n C (0) 0 (CRÜ Rs) m Re / - (CR¿ Rs) nC (0) NR «(CRARS) mRs, - (CR4R5) nO (CR "R5) mR6 or - (CR.v Rs) r Rs wherein the alkyl portions may be unsubstituted or substituted with one or more fluorine atoms; rn is 0 to 2; n is 0 to 4; r is 0 to 6; R1, and Rs are independently selected from hydrogen or alkyl of 1 to 2 carbon atoms; Rβ is hydrogen, methyl, hydroxyl, aryl, substituted halogen, aploxyC1-3 alkyl, aryloxyC1-3 alkyl substituted with hal, mdanyl, mdenyl, polycycloalkyl of 7 to 11 carbon atoms, tetrahydro-furanyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydro-thienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, cycloalkyl of 3 to 6 carbon atoms or a cycloalkyl of 4 to 6 carbon atoms which contains one or two unsaturated ligatures; wherein the cycloalkyl and heterocyclic portions may be unsubstituted or substituted with 1 to 3 methyl groups, an ethyl group or a hydroxyl group; provided that: (a) when Rs is hydroxyl, then it is 2; or (b) when Re is hydroxyl, then r is 2 to 6; or (c) when R & is 2-tetrahydropranyl, 2-tetra-hydrothiopyran, 2-tet-rahydrofranyl or 2-tetrahydrothienyl, then it is 1 or 2; or (d) when Re is 2-tetrah? dropiranyl, 2-tetrahydrothiopyram, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then r is 1 to 6; (e) when n is 1 and m is 0, then Rs is different from H in - (CR * Rs) n0 (CR4Rs) mRs; X is YR2, fluorine, NR ^ Rs or formylamine; Y is 0 or S (0) m '; m 'is 0, 1 or 2; X2 is 0 or NRβ; X3 is hydrogen or X; R2 is independently selected from -CH3 or -CH2CH3, unsubstituted or substituted by one or more fluorine atoms; s is 0 to 4; R3 is COOR14, C (0) NR «R A OR R7; U is alkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; Z is C (Y ') R? «, C (0) 0R?«, C (Y') NR? ORl4, CINTER) NR? OR? «, CN, C (NOR8) R14, C (0) NRβNR8C (0) R8, C (0) NR8NR? Or RI4, C (N0Ri4) R8, C (NR8) NR? Or RI4 C (NR? «) NR8R? C (NCN) NR? or Rl4, C (NCNSR9), (2-, 4- or 5-irnidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolylCl, 2.33), (3- or 5-) triazolylCl, 2, 43), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolylCl, 2, 43), (2-oxadiazolylCl, 3, 43), (2-thiadiazolylCl, 3.43), (2-, 4- or 5-thiazolyl), (2-, 4- or 5-oxazolidinyl), (2-, 4- or 5-thiazolidinyl) or (2, -, 4- or 5-imidazolidinyl); wherein all the heterocyclic ring systems may be optionally substituted one or more times with R14; Y 'is 0 or S; R7 is - (CR4Rs) qRi2 or alkyl of 1 to 6 carbon atoms, wherein the group R12 or alkyl of 1 to 6 carbon atoms is unsubstituted or substituted one or more times with methyl or ethyl, unsubstituted or substituted with one or three fluorine atoms, -F, -Br, -Cl, -NO2, -NR10R11, -C (0) Rβ, -C02Rβ, -0ÍCH2) 2-4? Rβ, -0 (CH2) qRβ, -CN , -C (0) NR? O Rl 1, -0 (CH2) qC (0) NRioRll, -0 (CH2) qC (0) R9, -NRi0C (0) NR? O Rl 1, -NR? OC ( 0) Rn, -NR10 C (0) 0R9, ~ NR? OC (0) R? 3, -C (NR? O) NR? Or Rll, -C (NCN) NR? ORll, -C (NCN) SR9 , NR? OC (NCN) SR9, ~ NR? OC (NCN) NR? O Rll, -NR? OS (0) 2R9, -S (0) ro'R9, -NR10 C (0) C (0) NR ? or Rl 1, -NR10 C (0) C (0) Rio or R13; q is 0, 1 or 2; R12 is R13, cycloalkyl of 3 to 7 carbon atoms or an unsubstituted or substituted aryl or heteroaryl group, selected from the group consisting of (2-, 3- or 4-pyridyl), pyrirnidyl, pyrazolyl, (1- or 2-pyridinyl) imidazolyl), pyrrolyl, piperazinyl, piperidinyl, rnorpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl and phenyl; Rβ is independently selected from hydrogen or R; R9 is alkyl of 1 to 4 carbon atoms, unsubstituted or substituted by one to three fluorine atoms; Rio is 0R8 or R11; R n is hydrogen or alkyl of 1 to 4 carbon atoms, unsubstituted or substituted by one to three fluorine atoms; or when Rio and R11 are like NR10R11, together with nitrogen, they can form a 5- to 7-membered ring consisting solely of carbon atoms or carbon atoms and at least one heteroatom selected from 0, N or S; R 13 is a substituted or unsubstituted heteroaryl group, selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl and thiadiazolyl; and when R13 is substituted on R12 or R13 the rings are connected by means of a carbon atom and each second ring R13 may be unsubstituted or substituted with one or two alkyl groups of 1 to 2 carbon atoms, unsubstituted or substituted in methyl, with 1 to 3 fluorine atoms; R14 is hydrogen or R7; or when Rβ and R14 are as NRβR?, they can form, together with the nitrogen, a 5- to 7-membered ring consisting solely of carbon atoms or of carbon atoms and at least one heteroatom selected from 0, or; provided that: (f) R 7 is not alkyl of 1 to 4 carbon atoms, unsubstituted or substituted with 1 to 3 fluorine atoms; or their pharmaceutically acceptable salts. 7. A compound according to claim 6, further characterized in that Ri is -CH2-cyclopropyl, -cyclopentyl, -3-hydroxycyclopentyl; methyl or CF2H; X is YR2; And it's oxygen; X2 is oxygen; X3 is hydrogen; R2 is CF2H or methyl; U is ethynyl or 1,3-butadiinyl; R3 is R7, wherein R7 is an aryl or heteroaryl ring, unsubstituted or substituted; X is YR2; Z is 0 and Z 'is COOR1

4. 8. A composition according to claim 7, further characterized in that U is 1,3-butadiinyl and R3 is? Irimidin-5-i.lo unsubstituted or substituted. 9. A pharmaceutical composition, characterized in that it comprises a compound according to any of claims 1 to 5, and a pharmaceutically acceptable excipient. 10. The use of an effective amount of compound according to any of claims 1 to 5, in the preparation of compositions for treatment of asthma, in a mammal, including a human in need thereof.