MXPA97004739A - Monomeros de 3,3- (disustitude) ciclohexan-1-ona and components related - Google Patents

Abstract

This invention relates to monomer derivatives of 3,3- (disubstituted) cyclohexan-1-one and to related compounds which are useful for treating allergic and inflammatory diseases.

Description

MONOMEROS DE 3, 3- (DISUSED) CICLQHEXflN ^ l-ONfl AND RELATED COMPOUNDS FIELD OF THE INVENTION The present invention relates to rnonóroe of 3,3- (dietitudo) cyclohexan-l-ones and related compounds; to pharmaceutical compositions containing these compounds and their use in the treatment of allergic and inflammatory diseases, and to inhibit the production of Tumor Necrosis Factor (FNT).

BACKGROUND OF THE INVENTION Bronchial asthma is a multifactorial, complex disease characterized by the reversible narrowing of the respiratory tract and the hyper-reactivity of the respiratory tract to external stimuli. The identification of novel therapeutic agents for asthma is complicated by the fact that multiple mediators are responsible for the development of the disease. Thus, 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 cMFA (3 ', 5'-cyclic adenosine rnonophosphate). It has been shown that the cyclic UFA is a second messenger that mediates biological responses to a wide variety of hormones, neurotransmitters and drugs; CKrebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, .19733. When the appropriate agonist binds to specific receptors on the cell surface, the adenylate cyclase that converts Mg + 2-TFA to ctIFP is activated at an accelerated rate.; The cyclic MFA modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of the extrinsic (allergic) aerian. In such a way, an elevation of the cMFA would produce beneficial effects that would include: (1) relaxation of the smooth muscle of the respiratory tract; (2) 5 inhibition of the release of the rnastoid cell mediator; (3) suppression of neutrophil degranulation; (4) inhibition of basophilic granulation; and (5) inhibition of - ^ activation of monocytes and macrophages. Therefore, compounds that activate adenylate cyclase or that inhibit foefodieeterase must be effective in suppressing inappropriate activation of smooth muscle of the respiratory tract and a wide variety of inflammatory cells. The main cellular mechanism for the inactivation of cMFA is the hydrolysis of the 3'-foefodiéeter bound by one or more of a family of isozymes known as the cyclic nucleotide phosphodiesterase (FDE).

It has been shown that a distinct cyclic nucleotide isozyme phosphodiesterase (FDE), FDE IV is responsible for the decomposition of cMFA in the smooth muscle of the respiratory tract and in the inflammatory cells CTorphy 5"Phosphodieeteraee Isozyrnes: Potential Targete for Novel Anti- aethrnatic Agents "in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 19893. Research indicates that the inhibition of this enzyme does not only cause relaxation of the airway muscle, but also suppresses I "the degranulation of rnastoidalee cells, basophils and neutrophils, together with the inhibition of monocyte and neutrophil activation.In addition, the beneficial effects of FDE IV inhibitors are greatly enhanced when adenylate cyclase activity is elevated of the cells of destination, using appropriate hormones or autocoids, as it would happen, in vivo. Thus, inhibitors of FDE IV would be effective in the asthmatic lung, where the level of -proetaglandin E2 and pro-cyclin (adenylate-cyclase activator) are elevated. These compounds would offer a similar approach towards a pharmacotherapy of bronchial asthma and possible 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. The excessive production of FNT, or the unregulated production of it, has been implicated in the mediation or in the exacerbation of numerous diseases, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, respiratory distress syndrome in adults, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidoeis, bone resorption diseases, reperfusion injury, reactions of the graft against the receiver, «• • allograft rejections, fever and allergies due to infection, such as influenza, cachexia secondary to infection or malignant disease, cachexia secondary to human immunodeficiency acquired immunodeficiency (AIDS), AIDS, CRS (AIDS-related complex) , keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis or pyresis, in addition to numerous other autoimmune diseases, talee like multiple sclerosis, autoinological diabetes and lupus erythematosus (SLE). AIDS is the result of the infection of the 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 consequence of HIV infection, T cell-mediated immunity is damaged and infected individuals manifest opportunistic opportunistic infections and / or neoplaemae infection. 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 lymphocyte after the activation of the T cell, and said expression and / or reproduction of virus protein is mediated or maintained by said T cell activation. Once the T lymphocyte is infected activated, with HIV, the T lymphocyte must continue to be maintained in an activated state to allow the expression of the HIV gene and / or the reproduction of HIV. Cytokines, specifically FNT, are involved in the expression of HIV protein and / or the reproduction of • f virus, mediated by activated T cell, by playing a role in the maintenance of T lymphocyte. Therefore, interference with cytokine activity, such as, for example, by inhibiting cytokine production, notably of TNF, in an individual infected with HIV, helps limit the maintenance of T cell activation, thereby reducing the progress of HIV infectivity to previously infected cells, which results in a decrease or elimination in the advancement of immune dysfunction caused by infection with HIV It has also been involved in monocytes, macrophages and related cells, such as upffer and glial cells, 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 Roeenberg and coautoree, The Immunopathogenesis of HIV Infection, Advances in Immunology, Lathe 57, 19893. Monokines, such as FNT, have been shown to activate the reproduction of HIV in rnonocitoe and / or macrophages [See Poli et al., Proc. Nati Acad. Sci., 87: 782-764, 19903, therefore, the inhibition of monoquinone production or its activity helps to limit the progression of HIV, as noted above for T cells. The TNF has also been implicated in various papers and other viral infections, such as 1; cytomegalovirus (CMV), influenza virus, adenovirus and herpes virus, for reasons similar to those noted above. FNT is also associated with yeast and fungal infections. Specifically, it has been shown that 15 Candida albicans induces the production of TNF in vitro in human monocytes and in natural aseein cells. [See 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 Uasan and coauthors, Antimicrobial Agents and 20 Chemotherapy, 35 (10): 2046-48, 1991; and Luke and coauthors, Journal of Infectious Dieeaees, 162: 211-214, 19903. The cap > to control the adverse effects of the FNT is increased by the use of compounds that inhibit FNT in mammals that need such use. There continues to be a need for comptables that are useful for treating morbid states mediated by FNT, which are exacerbated or caused by excessive and / or unregulated production of TNF.

BRIEF DESCRIPTION OF THE INVENTION In a first aspect, this invention relates to cornpueetoe of the formula (I): where: Rl ee - (CR4R5) nC (0) 0 (CR4Rs) m 6, - (CR4R5) nC (0) NRi (CR < Rs) m 6, - (CR4R5 nO (CR4R5) m ß o - (CRjRsir ß where the alkyl portions may be unsubstituted or substituted with one or more fluorine atoms; rn is 0 to 2; is 0 to 4, r is 0 to 6, R "and R5 are independently hydrogen or alkyl of 1 to 2 carbon atoms, Re ee hydrogen, methyl, hydroxyl, aryl, aryl substituted with halogen, aryloxy-alkyl of 1 to 3 carbon atom, aryloxy-alkyl of 1 to 3 carbon atoms, substituted with halogen, indanyl, indenyl, polycycloalkyl of 7 to 11 carbon atoms, tetrahydrofuranyl, furanyl, tetra- hydropyranyl, 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 group, an ethyl group or a hydroxyl group; provided that: (a) when R & is hydroxyl, then rn is 2; or '. * (b) when Re is hydroxyl, then r is from 2 to 6; or (c) when Re is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then m is 1 or 2; or (d) when Re ee 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then R ee 1 to 6; (e) when n is 1 and m is 0, then Re is different from H in -ÍCR * Rs) n0 (CR4 Rs) m Re; X is YR2, fluorine, NR Rs or formyl ina; And ee 0 or YES) », '; rn 'is 0, 1 or 2; X3 is hydrogen or X; R2 is independently selected from -CH3 or -CH2CH3 unsubstituted or substituted with one or more fluorine atoms; s is O to 4; R3 is COORi / i, C (0) R4R? < 4 or R7; W is alkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; Z ee 0, NR7, NCR4R5 -alkenyl of 2 to 6 carbon atoms, NOR14, NOR15, NOCR ^ Rs-alkenyl of 2 to 6 carbon atoms, NNR4R14, NNR ^ Ris, NCN, NNR8C (0) NR8Ri4, NNR8C ( S) NR8RIA; or -Z is 2- (1,3-dithiane), 2- (1,3-dithiolane), dirnethylthioketal, diethylthioketal, 2- (1,3-dioxolane), 2- (1,3-dioxane), 2- (1, 3-oxathiolane), dimethyl ketal or diethyl ketal; R7 is - (CR 'Rs) qRi2 or alkyl of 6 carbon atoms, wherein R12 or the alkyl group of 1 to 6 carbon atoms is unsubstituted or substituted one or more times with 5 methyl or ethyl, unsubstituted or substituted with one or three fluorine atoms, -F, -Br, -Cl, -NO2, -NR10R11, -C (0) Rβ, -CO2R8, -0 (CH2) 2-4? R8, -0 (CH2) QR8, -CN, -C (0) NR? ORll, ~ 0 (CH2) qC (0) NR10R11, -0 (CH2) qC (0) R9, -NR? OC (0) NR? O Rll, -NR? OC (O) Rn, -NR10 C (0) 0R9, -NR? OC (0) Ri3, -C (NR? O) NR? ORll, -C (NCN) NR? O RI 1, -0 C (NCN) SR9, NR? OC (NCN) ) SR9, -NR? OC (NCN) NR? Or Rll, -NR10 S (0) 2 R9, - SfOm'Rg, -NR? OC (0) C (0) NR? ORll, -NR10 C (0) C (0) R? Oo R13; q ee 0, 1 or 2; R12 ee R13, cycloalkyl of 3 to 7 carbon atoms (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, orpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl or phenyl; R8 is hydrogen or R9; R9 is alkyl of 1 to 4 carbon atoms, unsubstituted or substituted by one to three fluorine atoms; 5 Rio is 0R8 or R11; R11 is hydrogen or alkyl of 1 to 4 carbon atoms, non-substituted or substituted with one to three fluorine atoms; or when Rio and R11 are as NR10R11 then, together with the nitrogen, they can form a 5- to 7-membered ring which optionally contains at least one additional heteroatte 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, iiolzolyl, i idazoLidinyl, thiazolidinyl, isooxazolyl, oxadiazolyl and thiadiazolyl; and when R13 is substituted in R12 or R13, the rings are connected by means of "one carbon atom, and each second ring R13 may be non-substituted or substituted by one or two alkyl groups of 1 to 2 carbon atoms, non-substituted or substituted in methyl, with 1 to 3 fluorine atoms; R14 is hydrogen or R7; or when Re and R14 are like NR8R? ", they can form, together with the nitrogen, a ring of 5 to 7 members, optionally containing one or more additional heteroatoms 5, selected from 0, N or S; RlS is C (0) R? «, C (0) R4R?«, S (0) 2R7 S (0) 2NR; R14; 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 is represented by the formula (II): where: Rl is -IC ARS) nC (0) 0 (CR <iRs Rß, - (CR «Rs) R C (0) NR« 15 (CRüRs m 6, wherein the alkyl portions may be unsubstituted or substituted with one or more fluorine atoms;;; - is 0 to 2 n is 0 to 4 0 r ee 0 to 6. R4 and Rs are independently hydrogen or alkyl of 1 to 2 carbon atoms; Re is hydrogen, methyl, hydroxyl, aryl, aryl substituted by halogen, aryloxy-alkyl of 1 to 3 carbon atoms, aryloxy-alkyl of 1 to 3 carbon atoms substituted by halogen, indanyl, indenyl, polycycloalkyl from 7 to 11 carbon atoms, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, cycloalkyl of 3 to 6 carbon atoms or a 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 the 3 methyl groups, an ethyl group or a hydroxyl group; provided that: '*' (a) when Re is hydroxyl, then m is 2; or (b) when Re ee hydroxyl, then r is 2 to 6; or (c) when Re is 2-tetrahydropyranyl, 2-tetra-hydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, entoncee ee 1 or 2; or 5 (d) when Re is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then r is 1 to 6; (e) when n is 1 and m is 0, then Re is different from H in - (CR4 Rs)? »0 (CR« Rs) »R6; 0 X is YR2, fluorine, NR Rs or formyl ina; And ee 0 O S (0) m '; m 'is 0, 1 or 2; X2 is 0 or NRβ; X3 is hydrogen or X; R 2 is independently selected from -CH 3 or -CH 2 CH 3, unsubstituted or substituted by one or more fluorine; s ee 0 a k • R3 is COORIA, C (0) NR4Ri-v 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 ') Ri4, C (0) OR? «, C (Y') NR? Or Rl4, CINRIO) NR? ORl «, CN, C (N0R8) RI ?, C (0) NR8NR8C (0) R8, C (0) NR8NR? ORl4, C (N0R? «) Rß, C (NR8) NR? Or Rl4, CINN) NR8 R8? * C (NCN) NR? ORl4, CINCNSR), (2-, 4- or 5-imidazolyl), (3-, 4- or -pyrazolyl), (4- or 5-triazolylCl, 2, 3), (3- or 5- triazolylotl, 2, 43), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), ( 3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl [1, 2,), (2-oxadiazolyl [1, 3.43), (2-thiadiazolyl [1, 3,), (2 -, 4- or 5-15-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 substituted; ... optionally one or more times with R14; And 'ee 0 or S; R7 ee - (CR Rs) qRi2 or alkyl of 1 to 6 carbon atoms, wherein R12 is phenyl or an alkyl group of 1 to 6 carbon atoms is unsubstituted or substituted one or more alkyl with 1 to 2 alkyl Carbon atom, unsubstituted or substituted with one to three fluorine atoms; -F, -Br, -Cl, -NO2, 5 -Yi (R;) 3, -NR10R11, -C (0) Rβ, -0 (CH2 , -CO2 R8, -0R8, -CN, -C (0) NR? ORll, -OC (0) NR? ORll, -OC (0) R?, -NR? OC (0) NR? ORll - NR? OC (0) Rn, -NR? OC (0) OR9, -NR? OC (O) R13, -CINRIO) NR? O Rll, - C (NCN) NR oRll, -C (NCN) SR9, - NR? OC (NCN) SR9, -NR? OC (NCN) NR? ORll, -NR? OS (0) 2R9, -S (0) m'R9, -NR? OC (0) C (O) NR? or 1, NR? oC (0) C (0) R? o, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, 5-triazolyl or tetrazolyl; q ee 0, 1 or 2; R12 is Ri3, cycloalkyl of 3 to 7 carbon atoms, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-irnidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, *. the piperidinyl, rnorpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, (4- or 5-thiazolyl), quinolinyl, naphthyl or phenyl; R8 is independently selected from hydrogen or R9; R9 is alkyl of 1 to 4 carbon atoms, not substituted or substituted by one to three fluorine atoms; Rio is 0R8 or R11; R11 is hydrogen or alkyl of 1 to 4 carbon atoms. carbon, not replaced or substituted with one to three fluorine atoms; or when Rio and R11 are as NR10R11, together with the nitrogen, they can form a 5- to 7-membered ring optionally containing at least one additional heteroatom selected from O, N or S; R13 is a substituted or unsubstituted heteroaryl group, selected from the group consisting of 5-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 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 R8 and RIA are co or N ßRi ?, they can form, together with the nitrogen, a 5-7 membered ring optionally containing one or more additional heteroatoms, selected from 0, or S; provided that: i f) R7 is not alkyl of 1 to 4 carbon atoms, unsubstituted or substituted by 1 to 3 fluorine atoms; or their pharmaceutically acceptable salts. The 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 mediating or inhibiting 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 and inflammatory diseases, which comprises administering to a mammal, including humans that they need an effective amount of a compound of the formula (I) and (II). The invention also provides a method for treating asthma, which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of formula (I) and (II). This invention also relates to a method for inhibiting the production of TNF in a mammal, including humans; method comprising administering to a mammal that l. * in need of said treatment, an effective, inhibitory amount of TNF, of a compound of the formula (I) and (II). This method can be used for the prophylactic treatment or the prevention of certain cases of disease mediated by FNT, which are susceptible to it. This invention also relates to a method for treating a human afflicted with a human immunodeficiency virus (HIV), which comprises administering to said human an effective inhibitory amount of TNF of a compound of the formula (I). ) and (II) 20 The compounds of the formula (I) and (II) are useful in the treatment of additional viral infections, where said viruses are sensitive to up-regulation, by TNF, or which will unleash the production in vivo. In addition, the compounds of the formula (I) and (II) are also useful for treating yeast and / or fungal infections, wherein said yeasts and fungi are sensitive to upregulation by TNF, or will unleash the production of TNF in vivo.

DETAILED DESCRIPTION OF THE INVENTION This invention also relates to a method for mediating or inhibiting the enzymatic activity (or catalytic activity) of FDE IV in a human in need thereof, or for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of the formula (I) and (II). The inhibitors of phosphodiesteraea IV are useful in the treatment of a variety of allergic and inflammatory diseases that include: aema, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, soriae, reurnatoid arthritis, shock septic, ulcerative colitis, Crohn's disease, damage by reperfusion of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and edema and respiratory distress in adults.

In addition, FDE IV inhibitors are useful in the treatment of diabetes insipidue and alterations in the central nervous system, such as depression and dementia due to multiple infarction. Viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those that are sensitive to inhibition, by example, by means of decreased reproduction, directly or indirectly, by the TNF inhibitors of the formula (I) and (II). Such viruses include, but are not limited to: HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza virus, adenovirue and the herpes group virus, such as but not limited to them , Herpes zoster and Herpee ei plex. This invention relates more specifically to a method for 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 can also be used in association with the veterinary treatment of animals, which are not human, and which need the inhibition of TNF production. Lae 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) or other retroviral infections, such as equine infectious anemia virus, caprine arthritis virus, vienna virus, virue 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 regulation. ascending by TNF or unleashing TNF production in vivo. A preferred disease state to be treated is fungal meningitis. Additionally, the compounds of the formula (I) and (II) can be administered together with other selection drugs for eietérnicae infections by yeast and fungi. Selection drugs for fungal infections include, but are not limited to, the class of compound called polymyxins, such as Polymycin B; the claee de compueetoe called the imidazoles, tai 'ta' as clotrimazole, econazole, miconazole and ketoconazole, the class of compounds called the triazoles, talee as fluconazole and itranazole, and the class of compounds called amphotericins, in particular Amphotericin B and Amphotericin B Lipoeoric 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 injected to inhibit or reduce the toxicity of the class of amphotericin compounds, in particular the Amphotericin B. The term "alkyl of 1 to 3 carbon atoms", "alkyl of 1 to 4 carbon atoms", "alkyl of 1 to 6 carbon atom" or "alkyl" is used herein to include radicals both straight chain c omo chain branched from 1 to 10 carbon atoms, unless the chain length is specifically limited, including, but not limited to, the methyl, ethyl, n-propyl, ieopropyl, n-butyl, secondary butyl, isobutyl, butyl groups 5 tertiary and similar. "Alkenyl" means straight chain and branched chain radicals of 1 to 6 carbon atoms in length, unless the length of the chain is specifically limited, including, but not limited to: vinyl, 1- l .. - ~ propenyl, 2-propenyl or 3-methyl-2-pro? enyl. The term "cycloalkyl" or "cycloalkylalkyl" means groups of 3 to 7 carbon atoms, such as cyclopropyl, cyclopropyl ethyl, cyclopentyl or cyclohexyl. Unless otherwise specified, "arilo" or "Aralkyl" means a ring or system of aromatic rings, of 6 to 10 carbon atoms, such as phenyl, benzyl, phenethyl or naphthyl. Preferably aryl is '., rnonocíclico, that is to say, phenyl. It is meant that the alkyl chain includes both straight chain radicals or branched, from 1 to 4 carbon atoms. "Heteroaryl" means a seventh aromatic ring containing one or more heteroatoms. "Halogen" means all halogens, ie, chlorine, fluorine, bromine or iodine. 25"Inhibit the production of IL-1" or "inhibit the production of TNF" means: (a) a decrease in excessive levels of IL-1 or TNF in vivo, respectively, in a human, at normal levels or at levels below normal, by inhibiting the in vivo release of IL-1 by all the cells including, but not limited to, monocytes or RNAs; (b) a down-regulation, at the translational or tranecriptional level, of excessive in vivo levels of I.L-1 or FNT, respectively, in a human at levels Itr normal or below normal levels; or (c) a downward regulation, by inhibiting the direct sinteeie, of the level of IL-1 or FNT, as a poetranelational event. The fraee "disease or disease states mediated by FNT "means any and all disease 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, therefore, would be considered a disease state mediated by TNF. Co or FNT-ß (also known as lymphotoxin) has a close structural homology with TNF-a (also known as cachectin), and 5 since each induces similar biological responses and binds to the same cellular receptor, both the TNF-a and ? ? TNF-β are inhibited by the compounds of the present invention and, thus, will be referred to collectively herein as "FNT", unless specifically delineated in another way. Preferably, 5 TNF-a is inhibited. "Cytokines" means any secreted polypeptide that affects the functions of cells and is a molecule that modulates the interaction between cells in immune, inflammatory or hematopoietic responses. A cytokine includes, but is not limited to, lae rnonoquinae and lae lymphokinase, regardless of which cell they produce 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 the maintenance of T cell activation and / or expiation and / or reproduction of the HIV gene, mediated by activated T cell, and / or (b) any problems associated with a "Cytokine-mediated disease, such as cachexia or muscle degeneration, preferably this cytokine is FNT-a. All the compounds of the formula (I) and (II) are useful in the method for inhibiting TNF production, preferably by macrophages, monocytes or acrophages and monocytes, in a mammal including humans that need it All of the compounds of the formula (I) and (II) are useful in the method to inhibit or mediate the enzymatic or catalytic activity of FDE IV and in the treatment of disease states mediated by him. The preferred compounds are as follows: When Ri for the compounds of the formula (I) and (II) is an alkyl substituted with 1 or more halogens, the halogens are preferably fluorine and chlorine, better still, an alkyl of 1 to 4. carbon atoms substituted with one or more fluorine atoms. The preferred halogen-substituted alkyl chain length is 1 or 2 carbon atoms and, most preferably, the portions -CF3, ~ CH2F, ~ CHF2, -CF2CHF2, , 3; ^ - "" CH2CF3 and -CH2CHF2- The preferred substituents Ri for the compounds of the formula (I) and (II) eon 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 4-5-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or unsubstituted 1 or 2-carbon alkyl or substituted with one or more fluorine atoms, - (CH2)? - 3C (0) (CH2) or-2CH3, - (CH2) l-3? (CH2 Í0-2CH3 and "(CH2) 2-4? H When the term Ri is (CR4R5), the terms R1 and R5 are independently hydrogen or alkyl, this allows the branching of the individual methylene units as (CRiRs) no (CR /; R5) 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 5 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 alcohols, which were noted above. When Ri is a polycycloalkyl of 7 to 11 carbon atoms, the examples are bicyc.Lo [2.2.l3heptyl, bicyclo- [2.2.23octyl, bicyclo [3.2.l3octiio, tricyclo [5.2.1.02.6] _ decyl, etc. additional examples of the eetán cualee described in Saccamano and co-inventors, UO 87/06576, published on November 5, 1987, whose incorporation is incorporated here as ^ rTr reference in its entirety. Preferred Z terms are O, NCN, NR7, NORm, NORis, NRARIÜ, NNR4R15, C (CN) 2, C (-CN) 0C (0) R9, C (-CN) 0R9, CRi4C (0) 0R8, CR C (0) Ri3Ri4, 2- (1, 3- dithiane), dirnethylthioketal, 2- (1, 3-dioxolane) or dimethyl ketal. Most preferred is 0, NR7, NORIÜ, NOR15 and 2- (1, 3-di? Xolane). The preferred group X for formula (I) and (II) are those in which X ee YR2 and Y is oxygen. The group X2 * preferred for formula (I) and (II) is that in which X2 is oxygen. The preferred group X3 for formula (I) and (II) is the one 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 halogen atoms. The halogen atoms are preferably fluorine and chlorine, better still, fluorine. The most preferred R2 group are those in the R3 is methyl or the alkyl substituted with fluorine, specifically an alkyl of 1 to 2 carbon atoms, such as > a portion -CF3, -CHF2 or -CH2CHF2. Very preferred are the portions -CHF2 and -CH3. U preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, and when it is alkenyl or alkynyl, one or two double or triple bonds can be present. Z 'preferably is COOR14. Preferred R7 portions include R13, - (CH2) or-2 (2-, 3- or 4-pyridyl) unsubstituted or substituted, (CH2H-2I2-irnidazolyl), (CH2) 2 (4-morpholinyl), (CH2) ) 2 (-piperazinyl), 1 '- (CH 2)? -2- (2-thienyl), (CH 2)? -2- (4-thiazolyl), unsubstituted or substituted pyridinyl and (CH 2) or-2 substituted phenyl or not replaced. 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, optionally containing at least one additional heteroatom selected from 0, N or S, include, but are not limited to, a ring of 1- irnidazolyl, 2- (R8) -l-irnidazolyl, 1-pyrazolyl, 3- (R8) -l-pyrazolyl, 1-triazolyl, 2-triazolyl, 5- ( R8) -1-triazolyl, 5-20 (R8) -2-triazolyl, 5- (R8) -1-tetrazolyl, 5- (R8) -2-tetrazolyl, 1-tetrazolyl, 2-tetrazolyl, orpholinyl, piperazinyl, 4- (R8) -1-piperazinyl or a pyrrolyl ring.The preferred ring, when R8 and R? "In the portion -NR8Ri4, together with the nitrogen to which they are attached, can forming a ring of 5 to 7 members, optionally containing at least one additional heteroatom selected from 0, N or S include, but are not limited to: 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazoloyl, 2-tetrazolyl, rnorpholinyl, piperazinyl and pyrrolyl. The respective rings may be substituted additionally, when applicable, at a nitrogen or carbon atom available, with the portion R7 which was described herein for formula (I) and (II). The illustrations of said substitutions in the carbon include, but are not limited to, 2- (R7) -l-irnidazolyl, 4- (R7) -l-imidazolyl, 5- (R7) -1-ii azolyl, 3- ( R7) -1-pyrazolyl, fe b'- 4- (R7) -l-pyrazolyl, 5- (R7) -1-? Irazolyl, 4- (R7) -2-triazolyl, 5- (R7) -2- triazolyl, 4- (R7) -1-triazolyl, 5- (R7) -1-triazolyl, 5- (R7) -1-tetrazolyl and 5- (R7) -2-tetrazolyl. The applicable substitution on nitrogen, with R7 includes, but is not limited to: 1- (R) -2-tetrazolyl, 2- (R7) -1-tetrazolyl, 4- (R7) -l-5-piperazinyl. When applicable, the ring may be substituted one or more times with R7. The preferred group for NR8Rm containing a »Heterocyclic ring, eon 5- (Ri4) -l-tetrazolyl, 2- (Rn;) - l-imidazolyl, 5- (Rm) -2-tetrazolyl, 4- (Rn;) -l-piperazinyl or 4- 0 (Ris) -l-piperazinyl. Preferred rings for R13 include (2-, 4- or 5- irnidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5- triazolyl [1, 2.33), (3- or 5 -triazolyl [1, 2, 43), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), 5 (3- or 5-oxadiazolyl] , 2.43), (2-oxadiazolyl [1, 3.43), (2-thiadiazolyl [1, 3.43), (2-, 4- or 5-thiazolyl), (2-, 4- or 5 - oxazolidinyl), (2-, 4- or 5-thiazolidinyl) or (2-, 4- or 5-irnidazolidinyl). When the R7 group is unsubstituted or substituted with a heterocyclic ring, such as imidazolyl, pyrazolyl, triazolyl, tetrazolyl or thiazolyl, the heterocyclic ring itself may be unsubstituted or substituted with R8, either at a nitrogen or carbon atom available, such as 1- (R8) -2-irnidazolyl, 1- (R8) -4-imidazolyl, 1- (R8) -5-irnidazolyl, 1- (R8) -3-? irazoiyl, 1- (R8) -4-pi.razolyl, 1- (R8) - "> 5-? Izololyl, 1- (R8) -4-triazole or 1- (R8) -5-triazolyl. When applicable, the ring can be replaced one or more times with R8. U preferably is alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, and when it is alkenyl or alkynyl, "One or doe double or triple ligadurae is preeent." What is most preferred is that U is ethynyl or 1,3-butadiinyl, Those compounds of the formula (I) and (II) in which Ri ee -CH2 are preferred. -cyclopropyl, -CH2-cycloalkyl of 5 to 6 carbon atoms unsubstituted or substituted with OH, 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, not replaced or substituted with one or more fluorine atoms, and - (CH2) 2-4? H; R2 is methyl or alkyl substituted with fluorine; R3 ee R7, wherein R7 is an aryl or heteroaryl ring not substituted or substituted; X is YR2 and Z is 0, NR7.

Most preferred are those compounds in which R 1 is -CH 2 -cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF 2 H; X is YR2; And it's oxygen; X2 is oxygen; X3 is hydrogen; R2 is CF2H or methyl; U ethylenyl or 1,3-butadiinyl; R3 is a substituted or unsubstituted pyrirnidinoyl ring; and Z is 0, NR7. The pharmaceutically acceptable salts of the constituents of the present invention, when they can be prepared, are also intended to be protected by this invention. Those? - 'salee 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. Pharmaceutically acceptable lae ealee are prepared in a common and current manner. Treat the original compound, dissolved in a suitable solvent, with an excess of an acid ? organic or inorganic, in the case of the acid addition salts of a baee, or with 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 some amount of a compound of the formula (I) and (II). The composition may be present in an amount that performs a physiological response, or may be present in a smaller amount, so that the user needs to take two or more units of the composition to carry out the intended treatment. Eeae conpoeitions can be constituted as a solid, liquid or gaseous form. Either one of these forms can be transformed into another at the time of being administered, 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 route of The intended administration, for example, parenteral, topical, oral or by inhalation. For topical administration, the pharmaceutical composition will be in the form of a cream, an ointment, a liniment, a lotion, pads, aerosols and drops suitable for '15 administration to the skin, eyes, ears or nose. 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, a capsule, a powder, a pellet, a troche, a caramel, a syrup, a liquid or an emulsion. When the pharmaceutical composition is used in the form of a solution or a suspension, the examples of Suitable pharmaceutical carriers or diluents include: for sisternae acuoeoe, water; for non-aqueous products, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid paraffins and mixtures thereof, with water; for sieternae eolidoe, lactose, kaolin and mannitol; and for aerosol dichlorodifluorornetane, chlorotrifluoroethane and compressed carbon dioxide. Also in addition to the pharmaceutical carrier or diluent, it can be included in the compositions of the ? ? Other ingredients such as stabilizers, antioxidants, preservatives, lubricants, sweetening agents, viscoeity modifiers and hair extensions are provided, provided that said additional ingredients do not have detrimental effects on the therapeutic option of lae. compositions of the present. The prescribed pharmaceutical preparations are prepared following the conventional techniques of chemistry 'Pharmaceutical, when appropriate, for the desired final product. In those compositions, the amount of carrier or diluent will vary, but will preferably be the largest proportion of a solution 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 active ingredient solid. A compound of the formula is administered (D) a substance in a composition comprising a nontoxic 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 to 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 employed as an oral regimen or other ingested or injected regimen, the dosage of the composition of the scale from 50 rng to 1000 g is selected. -r of active ingredient for each administration For convenience, equal doses of one to five times a day will be administered, with the daily administration regimen being selected from about 50 mg to about 5000 mg.

Formula (I) and (II) can exist in racemic and optically active forms. Some may also exist in different diaetereomeric forms, which have different properties I: -. physical and biological All of which are compotetoe ee coneidera that are within the scope of the present invention. 20 The compueetos of the formula (I) where Z is 0 or (II) can exist in a tautomeric form, for example, as the enolic form. This can be represented by = 0, which is exocyclic with a cyclohexane ring (or in contrast to the endocyclic portion or portion -C (-OH) = C (-R) ~, wherein the cyclohexane ring is now unsaturated in the 1-2 position, i.e., cyclohexyl-ene, or and R ee Z in formula (I). It will also be recognized that the ring 2 in the exocyclic form can be substituted (R), as in the compotetoe of the formula (I). 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. Reference is made to the claims for what is reserved for the inventors according to the present. There are no unacceptable toxicological effects when these compounds are administered according to the present invention.

METHODS OF PREPARATION SYNTHETIC SCHEME (S) 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 palladium or bivalent or zerovalent compound, in the presence, for example, of tri-phenyl phosphine, in a suitable solvent such as an amine, as in the procedure of Brandsma and co-authors, (Syn. Co m., 1990, 20, 1889), followed by hydrolysis of the ketal protective group, under common conditions, giving a compound of the formula 2-Scheme 1. The compounds of the formula I-Scheme 1 ee can be prepared by analogous proceeding to that described in the pending US patent application, 08 / 130,215 filed on October 10, 1993 and its progeny, presented as follows by means of the TCP.

ESOUEMA 1 (a) Pd (PPh3) 4, PPh3, Cul, CßHel, piperidine; b) pyridinium p-toluene sulfonate (H3O2CO / H2O) Alternatively, it is possible to prepare the compounds of the formula (I) by reacting a terminal acetylene, such as, for example, compound 1-Scheme 2, with an appropriate halide, R3X, in where R3 represents R3, as defined in relation to 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, preemption, for example, of triphenylphosphine, in a suitable solvent such as an amine, as in the Brands and co-authors procedure, (Syn. Comm., 1990, 20, 1889), to give a compound of the formula 2-Scheme 2 so that the compounds of the formula (I) can 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 I-Scheme can be prepared. 2 by means of procedures analogous to those described in the pending United States patent application, number 08 / 130,215, filed on October 10, 1993 and its progeny, presented subsequently by means of the TCP.

ESOUEMA 2 fifteen • - "i (a) Pd (PPh3U, PPh3, Cul, R3X, piperidine 20 Alternatively, the oxidizing carbonylation of a terminal acetylene, for example, as compound I-Scheme 3, using an appropriate metal eal, such as an eal of copper, with a catalytic amount of a palladium eal, in the presence of a suitable base, such as a trap FOR acid, For example, sodium acetate in a suitable alcohol, such as methanol, as in the method of Tsu i and co-authors, (Tet. Lett. 1980, 21, 849), followed by hydrolysis of the methyl ester under ordinary conditions, then provides the compound of the formula (I) (2-Scheme 3); said compounds of the formula (I) can then be converted to other components of the formula (I) by common and ordinary manipulation of the carboxylic ether moiety.

ESOUEMA 3 COOCH 'fifteen '• (a) PdCl2, C? Cl2, Na02CCH3, CO, CH3OH. The compounds of the formula (II) can be prepared by methods analogous to those of the foregoing items 1, 2 and 3, as illustrated in scheme 4 of the present invention. Depending on the exact nature of the groups Z 'of the compounds of the formula (II), the group = 0 may require protection during the coupling steps described herein, for example, when a compound of the formula (II) wherein = 0 is a dimethylketal or 2- (1,3-dioxolane), followed by deprotection and then reaction by the synthesizing procedures described in the co-pending US patent application number 08 / 130,215, filed on October 10, 1993, and its progeny, presented as follows by means of the TCPrn, to give the compound of the formula ( II); likewise, the group Z 'may require protection during the coupling steps, followed by protection to give the compound of the formula (II); and said protecting groups are well known to those skilled in the art. (See: Greene, J lif T. and luts, P.G.M. Protecting Groups in Organic Synthesis, second edition, John Uiley and Sons, New York, 1991).

ESOUEMA 4 0 (a) Pd (PPh3, PPh3, Cul, R3X, piperidine.5 The preparation of the remaining compounds of the formulas II) and (II) ee can be achieved by analogous to those previously mentioned and in the examples that follow. It will be recognized that the components of formulas (I) and (II) can exist in different diastereomeric forms that possess different physical and biological properties; Said isomer can be prepared by standard chromatographic methods.

EXPERIMENTS, v '' EXAMPLE 1 PREPARATION OF 3- (CARBOMETOXYETINYL) -3- (3-CICLOPENTILOXI-4-METOXYPENYL) CYCLOHEXAN-1-ONA (la) 3- (3-CICL0PENTILQXI-4-MET0XIFENIL) -3-TRIMETILSILILETINIL CICL0HEXAN-1-0NA 2.45 M n-butyllithium in 5.7 ml was added dropwise, < » 13.96 rnols of hexanes, for 5 minutes, to a solution of 1.97 ml, 13.96 mmoles, of tri-ethylsilylacetylene, dissolved in 30 ml of ether, at -45 ° C, under argon. After After 20 hours, this solution was cannulated into a 1.0 M solution of dimethylaluminum chloride in 13.96 ml of hexanoe, 13.96 mrnolee. Deep ée of 3.5 hours at room temperature, the mixture was filtered through Celite ** under an argon atmosphere. In a separate flask was added dropwise 1.0 M of hydride diisobutylaluminum, in 1.4 ml, 1.4 mmol of toluene, to a stirred mixture of 360 mg, 1.4 mmol, of acetylacetonate of Nickel in 25 rnl of dry ether, at 0 ° C, under an argon atmosphere. After 10 minutes, the mixture was further cooled to -10 ° C and the aluminum acetinide solution was added by cannulation for 15 minutes. 2.0 g, 6.98 min., Of 3- (3-cyclopentyloxy-4-ribethoxyphenyl) cyclohex-2-en-l-one (prepared as described in US Pat. No. 5,362,915), dissolved was added dropwise over 20 minutes. in 70 ml of dry ether. After 18 hours at room temperature, the mixture was poured into a saturated aqueous solution of 100 rnl of phosphate *. of potassium (monobasic) at 0 ° C, 100 ml of a 3N aqueous solution of HCl was added and the aqueous layer was extracted two times with ether. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated. Purification by flash chromatography, eluting with 2: 1 -15 hexane / ether, followed by trituration in ether / hexane, then by purification of the mother liquor by flash chromatography, eluting with 4: 1 hexanes / ethyl acetate. ethyl, followed by trituration in ether / hexanes, yielded white solid, mp 102-103 ° C. 20 (Ib) 3- (3-CICL0PENTIL0XI-4-MET0XIFENIL) -3-ETINILCICL0HEXAN-l- ONA A mixture of 900 mg, 15.6 mmol, of potassium fluoride and 0.3 g, 0.68 mmol, of 3- (3 - 25-cyclopentyloxy-4-methoxyphenyl) -3-trimethylsilylethynyl-cyclohexan-1-one in 3 ral of dry N, N-dimethylformamide, under an argon. After 18 hours, the solvent was removed in vacuo, the residue was partitioned between water and ethyl acetate, the aqueous layer was extracted with ethyl acetate, the combined extract was dried over magnesium and evaporated. . Purification by flash evaporation chromatography, eluting with 4: 1 hexanes / ethyl acetate gave a clear colorless oil. Analisis (C20H24O3 - 1/10 H2O) calculated: C 76.45, H 7.76; found: C 76.32, H 7.60. (3- (CARBOMETQXYETINYL) -3- (3-CICLOPENTILOXY- -METOXYPENYL) CYCLOHEXflN-1-ONfl 0.30 g, 0.98 mmol, of 3- (3-cyclo-entyloxy-4-methoxyphenyl) -3-ethynylcyclohexan- was dissolved. The mixture was dissolved in 20 ml of dry methanol and bubbled in the 5-carbon rnonoxide solution for 10 minutes, and a mixture of 0.264 g, 1.96 mmole of copper (II) chloride and 0.267 g, 1.96 mmole of trihydrate was added. of sodium acetate, then an amount was added :: oligonucleic palladium chloride (II). After 2.5 hours at room temperature, water was added and the methanol evaporated. 0 The residue was extracted three times with etherThe combined extract was washed with brine, dried over magnesium sulfate and evaporated. Purification by flash evaporation chromatography, eluting with 2: 1 hexanes / ethyl acetate, gave a pale yellow oil. NMR with -H (400 MHz, CDCl 3) d 7.0 5 (d, J = 2.3 Hz, 1H), 6.95 (dd, J = 8.4, 2.3 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 4.78 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 2.82 (d, 4. 1.

J = 25 Hz, 1H), 2.78 (d, J = 25 H, 1H), 2.5 - 2.1 (m, 5H), 2.0 - 1.8 (rn, 7H), 1.61 (rn, 2H).

EXAMPLE 2 PREPARATION OF 3- (CARBQXYETINYL) -3- (3-CICLOPENTILOXI-4-METOXYPENYL) CYCLOHEXAN-1-QNA 0.14 g, 0.38 milliliters of 3-β (carbornetoxyethynyl) -3- (3-cyclopentyloxy-4-rnetoxy phenyl) -cyclohexan-1-one were dissolved in 5: 5: 2 tetrahydrofuran / methanol / water and treated with 0.046 g, 1114 mole of powdered eodium hydroxide. After 2 hours at room temperature, the mixture was concentrated in vacuo, diluted with 5 ml of water, acidified with aqueous 3N HCl and extracted five times with dichloromethane. The combined extract was dried and evaporated. Purification by flash chromatography, eluting with 88: 10: 2 chloroform / methanol / acetic acid, produced an oil, which was redissolved and evaporated tree vecee with toluene and doe vecee with chloroform, to give a colorless eolide , pf 71-72.5 ° C.

EXAMPLE 3 RESOLUTION OF (»/ -) - 3- (3-CICLOPENTILOXI-4-METOXYPENYL) -3-ETINYL-CYCLOHEXAN-1-ONA The compound of Example Ib was solved in the following manner to give enantiomeric oils: HPLC Rt = 15.5 rninutoe (enantiomer 1 = El), 23.2 minutes (enantiomer 2 = E2) (Diacel Chiralpak AS, 21.2 x 250 nm, hexane: isopropanol, 4: 1, 10 ml / minute, UV detection at 295 nm). EXAMPLE 4 PREPARATION OF (+/-) 3- (3-CICLOPENTILOXI-4-METOXYPENYL) -3- FENILETINYL-CICLOHEXAN-1-ONA To a solution of 0.125 g, 0.4 mmol, of the compound of Example Ib and 0.4 mL, 2.0 mmol, of iodobenzene in 6 mL of piperidine, under an argon atmosphere, traces of tetrakistriphenylphenol) palladium (O), copper iodide were added. (I) and triphenylphosphine. The mixture was refluxed for 5 hours, then concentrated in vacuo. The residue was diluted with 100 ml of ethyl acetate, washed with brine, dried over MgSO and evaporated. Purification by flash evaporation chromatography, eluting with 2: 1 hexanes / ethyl acetate, and then trituration in ether / hexanes, afforded 0.09 g, 58%, of the title compound, as a white solid, m.p. 90-91 ° C.

EXAMPLE 5 PREPARATION OF i * / -) 3- (3-CICLOPENTILOXI-4-METOXYPENYL) -3- (3-CARBOMETOXYPENYL) ETINYL-CYCLOHEXAN-1-ONflDDzGP + D (5a) 3-IODINE METHYL ENZOATE Methyl 3-iodobenzoate was prepared by ordinary chemistry, well known to those skilled in the art, and is a white solid, m.p. 40-41 ° C. 10 (5b) (+/-) 3- (3-CICLOPENTILOXI-4-METOXYPENYL) -3- (3-CARBOMETOXY-PHENYL) ETINYL-CYCLOHEXAN- 1 -ONE To a solution of 0.30 g, 0.96 rn oles, of the compote of example Ib and 0.30 g, 1.15 mmoles, of 3-iodobenzoate of methyl in 10 nl of triethylamine, under argon atmosphere, traces of tetrakis (triphenylphophine) palladium (0), iodide were added '* of copper (I) and tri-phenyl phosphine. The mixture was refluxed for 0.5 hour and then concentrated in vacuo. The residue was partitioned between water and ethyl acetate .. The organic phase was dried on Na2SO0 «and then evaporated. Purification by flash evaporation chromatography, eluting with 2: 1 hexanes / ethyl acetate, afforded the title compound, as a pale yellow oil (0.35 g, 80%). Analisis (C2SH30OS • 1.0 H2O) calculated: C 72.39, H 6.94; found: C 72.47, H 6.80.

EXAMPLE 6 PREPARATION OF (- * • / -) 3- (3-CflRBQXIFENILETINIL) -3- (3- CYCLOPENTILQXI-4-METOXYPENYL) CICLOHEXAN-1-ONA To a solution of the compound of Example 5 (b) in .1.0 ml of 5: 5: 2 THF / methanol / water, under an argon atmosphere, 0.60 g, 1.5 mmol, of sodium hydroxide was added. The mixture was heated at 60 ° C for 2 h and then concentrated in vacuo. The residue was extracted into 3N HCl with ethyl acetate, washed with brine, dried over MgSO 4 and evaporated. Purification by flash chromatography, eluting with 98: 2: 0.3 chloroform / methanol / acetic acid, yielded white solid, m.p. 71-73 ° C.

EXAMPLE 7 PREPARATION OF 3- (3-CICLOPENTILOXI-4-METOXYPENYL) -3- [3- (5-METHYL-RI, 3-J43-TIFL-DIAZOL-2-IL) FENILETINYL-3-CHLORHEXAN-1-ONLY (7a) l-IODO-3- (5-METHYL-Cl, 3 J43TIflDIflZOL-2-IL) BENZENE L-iodo-3- (5-methyl- [l, 3,43-thiadiazol-2-yl) benzene was prepared by common chemistry well known to the expert in the field and ee a white solid, mp 86-89 ° C. (7b) 3- (3-CICLOPENTILOXI-4-METOXYPENYL) -3- [3- (5-METHYL- [l, 3,4 TIADIflZOL-2-IL) FENILETINYL] CYCLOHEXAN-l-ONA To a solution of 0.10 g , 0.32 mmole of the composition of Example 3 (El) and 0.10 g, 0.32 mmol, of l-iodo-3- (5-methyl- [1,3, 43-diazodiazol-2-yl) benzene in 5 mL of triethylamine, under nitrogen) Argon cone, tetrakie (triphenylphophine) palladium (0), copper iodide (I) and tri-phenyl phosphine were added. The mixture was refluxed for 0.20 hours, allowed to cool to room temperature and concentrated in vacuo. The residue was divided between ethyl acetate and water.

The organic product was washed with water, dried over MgSO4 and evaporated. Purification by flash evaporation chromatography, eluting with 1: 1 hexane / ethyl acetate afforded the title compound, as a white solid (0.135 g, 87%), m.p. 97-99 ° C. The enantiomer was prepared in a similar manner, from the composition of Example 3 (E2), as a white solid, m.p. 97-99 ° C.

EXAMPLE 8 PREPARATION OF 3- (3-CICLOPENTILOXI-4-METOXYPENYL) -3-C3- (5- METHYL-Cl.3,4] QXflDIflZOL-2-IL) FENILETINYL3CICLOHEXAN-1-ONA (Ba? L-IODO-3- (5-METHYL-, 3, 30XADIAZOL-2-IL) BENZENE L-iodo-3- (5-methyl- [l, 3,43-oxadiazol-2-yl) benzene was prepared by well-known common chemistry and current par-a loe skilled in the art and is a white solid, m.p. 104-105 ° C. (8b) 3- (3-CICLOPENTILOXI-4-METOXYPENYL) -3-C3- (5-METHYL-5 Cl, 3,430XADIAZOL-2-IL) FENILETINIL3CICLOHEXAN-l-ONA To a solution of 0.125 g, 0.4 mmol of the compound of example 3 (El) and 0.09 g, 0.32 mmolee, of l-iodo-3- (5-methyl- [1,3, 3-oxadiazol-2-yl) benzene in 3 rnl of triethylamine, under an argon atmosphere, was added traces of tetra tetraisphenylphosphine) palladium (O), copper iodide (I) and triphenylphosphine. The mixture was heated at 80 ° C for 0.2 hours, cooled to room temperature and concentrated in vacuo. The residue was divided between ethyl acetate and water. The organic fae was washed with brine, dried over MgSO / i and evaporated. Purification by flash evaporation chromatography, eluting with 2: 1 ethyl acetate / hexanes, and then by recrystallization from ethyl acetate / hexanes, afforded the title compound, as a white solid (0.11 g, 61%), pf 117-1190C. 0 The enantiomer was prepared in an exemplary manner, starting from the composition of Example 3 (E2), as a white solid, m.p. 117-119 ° C.

EXAMPLE 9 PREPARATION OF 3- (3-CICLOPENTILOXI-4-METOXYPENYL) -3- [3- (3-METHYL- [lJ2,43 QXADIAZOL-5-IL) FENILETINYL3CICLQHEXAN-1-ONA (9a) l-IODO-3- (3-METHYL-RI, 2,43 QXADIAZOL-5-IL) BENZENE L-iodo-3- (3-rneti- [1,2- 43-oxadiazol-5-yl) -enol was prepared by ordinary chemistry well known to those skilled in the art and is a white solid, mp 101.5-103 ° C. 10 (9b) 3- (3-CICL0PENTIL0XI-4-MET0XIFENIL) -3- [3- (3-METHYL- [1,2,4-OXADIAZOL-5-IDFENILETINIL3CICLOHEXAN-1-ONA To a 0.125 g solution, 0.4 rnrnolee of the composition of example 3 (El) and 0.09 g, 0.32 mmol, of l-iodo-3- (3-methyl-15 [1, 2,43 oxadiazol-5-yl) benzene in 3 ml of triethylamine, under the argon, traces of ».. tetrakis (triphenylphophine)? aladioï?), copper iodide (I) and triphenylphophene were added. The mixture was heated at 80 ° C for 0.2 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO .; and ee evaporated. Purification by flash evaporation chromatography, eluting with 2: 1 hexane / ethyl acetate, followed by trituration in hexane / ethyl acetate, afforded the title compound, as a white solid, m.p. 122-123 ° C. The enantiomer was prepared in an eimilar manner, starting from of the compound of Example 3 (F2), as a white solid, m.p. 122-123 ° C.

EXAMPLE 10 PREPARATION OF 3- (3-CICLOPENTILOXY-4-METOXYPENYL) -3- [3- (5-METHYL-p, 2, 430XADIflZ0L-3-IL) FENIt-ETINYL3CICL0HEXAN-1-0NA (10a) l-IODO-3- (5-METHYL- [1, 2,4? XADIAZOL-3-IL) BENZENE -j L-iodo-3- (5-rnethyl- [l, 2,43-oxadiazole ~ 3- lo il) benzene by ordinary chemistry well known to those skilled in the art and is a white solid, mp. 86-87 ° C. (10b) 3- (3-CICLOPENTILOXI-4-METOXYPENYL) -3-C3- (5-METHYL-15 Cl ^ lOXADIAZOL-S-lDFENILETINILICCICLOHEXAN-l-ONA To a solution of 0.125 g, 0.4 mrnol of compound J of the example 3 (El) and 0.09 g, 0.32 mmol, of l-iodo-3- (5-? Nitril- [1, 2, 43-oxadiazol-3-yl) benzene in 3 ml of triethylamine, under argon atmosphere, traces were added from tetrakisftrnylphosphine) palladium (O), copper (I) iodide and fine tiffany. The mixture was heated at 80 ° C for 0.2 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO < and it evaporated. The Purification by flash evaporation chromatography, eluting with 2: 1 hexanes / ethyl acetate, followed by Trituration in hexanes / ethyl acetate yielded the title compound as colorless crystals (0.12 g, 67%), m.p. 116- 118 ° C. The enantiomer was prepared in a similar manner, starting from the compound of Example 3 (E2), as colorless crystals, m.p. 116-118 ° C.

EXAMPLE 11 PREPARATION OF 3- (3-CYCLOOPENTILOXY-4-METOXYPENYL) -3- (3-l 'CYANOPHENILETINYL3CICLOHEXAN-1-ONA To a solution of 0.125 g, 0.4 mmole of the compound of example 3 (El) and 0.09 g, 0.4 mmole, of 3-iodobenzonitrile (Traneworld) in 3 ml of triethylamine, under an argon atmosphere, traces of tetrakis (trnylphophine) palladium (0), copper iodide (I) and trnylphosphine were added. The mixture was heated at 80 ° C for 0.2 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSD /; and it evaporated. The residue was purified by flash chromatography, eluting with 2: 1 hexane / ethyl acetate, to give the title compound, as a light yellow glass (0.12 g, 73%), MS (EI) m / e 414 [M + H3 + 5 The enantiomer was prepared in a similar manner, from the compound of example 3 (E2), as a yellow glass Clear.

EXAMPLE 12 PREPARATION OF 3- (3-CICLOPENTILOXY-4-METOXYPENYL) -3- (3-NITROPHENILETINYL3CICLOHEXAN-1-ONA At an eolution of 0.2 g, 0.64 mmoles of the compound of Example 3 (El) and 0.16 g, 0.64 mmoles, of 3-iodonitrobenzene (Aldrich) in 4 rnl of triethylamine, under argon atmosphere, traces of tetrakisítri fenil foefina were added) palladium (O), copper iodide (I) and tri-phenyl phosphine. The mixture was heated at 80 ° C for 0.2 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO; and it evaporated. The residue was purified by flash chromatography, eluting with 3: 1 hexanes / ethyl acetate, to give the title compound, as a light yellow glass (0.25 g, 90%), m.p. 46-48 ° C. The enantiomer was prepared in a similar manner, from the compound of Example 3 (E2), as a light yellow glass, m.p. 46-48 ° C.

EXAMPLE 13 PREPARATION OF 3- (3-CICLOPENTILOXI-4-METOXIFENID-3- (2-HYDROXYETOXYPHENILETINYL3CICLOHEXAN-1-QNADDzGP + D (13) 2-HYDROXYETOXY-1-YODOBENZENE 2-Hydroxyethoxy-1-iodobenzene was prepared by common chemistry well known to those skilled in the art and a colorless oil. NMR with * H (400 MHz, CDCl 3) d 7.77 (dd, J = 7.9, .1.3 H, 1H), 7.3 (t, J = 7H, 1H), 6.84 (d, .1 = 7.9 Gz, 1H), 6.74 (t, J = 7.9 Hz, 1H), 4.13 (t, J = 4.3 Hz, 2H), 3.99 (t, J = 4.3 Hz, 2H), 2.2 (wide e, 1H). (13b) 3- (3-CICLQPENTILOXI-4-METOXYPENYL) -3- (2-HYDROXYETOXIFENILETINIL3CICLOHEXflN-l-ONflDDzG3fD At a 0.25 g solution, 0.8 mrnolee of the composition of example 3 (El) and 0.21 g, 0.8 mmoles, of 2-hydroxyethoxy-l-iodobenzene in 5 ml of triethylamine, under argon atmosphere, was added traces of tetrakis (triphenylphophine) palladium (0), copper (I) iodide and triphenylphophine. The mixture was heated at 80 ° C for 1 hour, cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO. and ee evaporated. Purification by flash evaporation chromatography, eluting with 1: 1 hexanes / ethyl acetate, afforded the title compound, co or a white solid (0.05 g, 14%), m.p. 93-94 ° C.

R? EXAMPLE 14 PREPARATION OF 3- (3-ACETAMID-PENILETINYL) -3- (3-CICLOPENTILOXY-4-METOXYPENYL) CYCLOHEXAN-1-ONA (14a) 3-ACETAMIDO-l-YODOBENCENO 3-acetamido-l-iodobenzene was prepared by ordinary chemistry well known to those skilled in the art and a colorless oil, m.p. 1.17 ~ 118 ° C (14b) 3- (3-ACETAMIDOFENILETINIL) -3- (3-CICL0PENTIL0XI-4- METOXIFENIL) CICLOHEXAN-1-ONA To a solution of 0.2 g, 0.64 mmolee of the cornpueeto of Example 3 (El) and 0.17 g, 0.64 mmolee , of 3-acetamido-l-iodobenzene in 5 ml of triethylamine, under argon, added traces of tetrakietriphenylphenol) palladium (O), copper iodide (I) and triphenylphophene. The mixture was heated to 80 ° C for 0.3 hour, cooled to room temperature and concentrated in vacuo. The residue was purified by flash evaporation chromatography, eluting with 1: 1 hexanes / ethyl acetate, to give the title compound. title, as a tan solid (0.17 g, 60%), m.p. 58-60 ° C.

EXAMPLE 15 PREPARATION OF 3- (3-CYCLOOPENTILOXY-4-METOXYPENYL) -3- (3-METANSULFONAMIDOFENILETINIL3CICLOHEXAN-1-ONA (15a) l-IODO-3-METANSULFONAMIDOBENZENE L-iodo-3-rnetane-sulfonanenidobenzene was prepared by ordinary chemistry well known to those skilled in the art and is a colorless oil, m.p. 102-103 ° C * LO (15b) 3- (3-CICLOPENTILOXY-4-METOXYPENYL) -3- (3-METANSULFON-AMIDOPHENILETINIL3CICLOHEXAN-1-ONA To a solution of 0.2 g, 0.64 mmole of the compound of Example 3 ( ) and 0.19 g, 0.64 mmole, of l-iodo-3-ethanesulfonamidobenzene in 5 ml of triethylamine, under an atmosphere of argon, traces of tetrakis (triphenylphenylene) palladium (O), copper iodide (I) and triphenylphosphine were added. HE - heated the mixture at 80 ° C for 0.3 hour, cooled to the I room temperature and concentrated in vacuo. The residue was purified by flash chromatography, eluting 20 with 1: 1 hexanes / ethyl acetate, to give the title compound, as a tan solid (0.18 g, 58%), m.p. 59-62 ° C.

EXAMPLE 16 PREPARATION OF 3-Q-AMINOPHENILETINIL 3- (3-CICLOPENTILOXI-4- METOXIFENIL) CICLOHEXAN-1-ONA (16a) 1-IODO-3-TRIFLUORACETAMIDOBENZENE 1-Iodo-3-trifluoroacetamidobenzene was prepared by ordinary chemistry well known to those skilled in the art and is a colorless oil, m.p. 120-121 ° C (16b) 3- (3-CICLOPENTILOXI-4-METOXIFENIL) -3- (3-TRIFLUOROACET) AMIDOPHENILETINIDCICLOHEXAN-I-ONA To a solution of 0.5 g, 1.6 rnrnoles of the composition of example 3 (El) and 0.5 g, 1.6 mmolee, of l-iodo-3-trifluoroacetarnidobenzene in 10 rnl of triethylamine, under At the argon atom, a small amount of tetrakis (triphenyl-phosphine) palladium (O), copper iodide (I) and --4 triphenylphosphine. The mixture was heated at 80 ° C for 0.2 hour, The mixture was cooled to room temperature and concentrated in vacuo.The residue was purified by flash evaporation chromatography eluting with 3: 1 hexane / ethyl acetate to give the title compound as a tan solid. (0.62 g, 78%), mp 63-65 ° C. (16c) 3- (3-AMINOPHENILETINYL) -3- (3-CICLOPENTILOXI-4- 5 METOXYPENYL) CYCLOHEXflN-1-ONfl At a 0.62 g, 1.24 mmole, of 3- (3- cyclopentyloxy-4-methoxy phenyl) -3- (3-trifluoroacetamidophenyl-ethynyl) cyclohexan-1-one in 10 ml of 95: 5 rnetanol / water, under an argon atmosphere, 0.86 g, 6.2 mmoles, of carbonate potassium. The mixture was refluxed for 6 hours and stirred for 18 hours at room temperature. The precipitated solid was collected and purified by trituration in ethyl acetate / hexanes to give 0.39 g, 77%, of the title compound as a white solid, m.p. 100-102 ° C.

EXAMPLE 17 Using the methods and procedures set forth in the above examples, the following compounds can also be prepared: 3- (3-cyclopentyloxy-4-methoxyphenyl) -3- (2- [3- (5-trifluoromethyl) [1,2] , 4-oxadiazol-3-yl) phenyl3-ethynyl) -cyclohexan-1-one; 3- (3-cyclopentyloxy-4-methoxyphenyl) -3- (2- [3- (3-tri-fluoromethyl [l, 2,43-oxadiazol-5-yl) phenyl-3-ynyl) -cyclohexan-1-one; 3- (3-Cyclopentyloxy.i-4-methoxy phenyl) -3- (2- [3- (5-tri-fluoromethyl [1,3,4-3-oxadiazol-2-yl) -phenyl-3-ethyl) -cyclohexan-1-one; or 3- (3-cyclopentyloxy-4-rethoxyphenyl) -3- (2- [3- (5-trifluoromethyl [1,3,43-diazodiazol-2-yl) -phenol-1-yl) -cyclohexan-1-one; EXAMPLE 18 PREPARATION OF (+/-) - 3- (4-CARBOXYPHENILETINYL) -3- (3-CICLOPENTILOXY-4-METOXYPENYL) CICLOHEXAN-1-ONA (18a) 4-METHYLODODYBENZOATE Methyl 4-iodobenzoate was prepared by ordinary chemistry well known to those skilled in the art and is a colorless oil, m.p. 103-105 ° C , K 0 (18b) (»/ -) -3- (-CARBOMETOXIFENILETINIL) -3- (3-CICLOPENTIL-OXI-4-METOXIFENIL) CYCLOHEXAN-l-ONA To a solution of 0.2 g, 0.64 rnmoles of the compound of the example Ib and 0.17 g, 0.64 mmol, of methyl 4-iodobenzoate in 5 ml of triethylamine, under an argon atmosphere, tetrakie (triphenyl-foefine) palladium (0), copper (I) and tri-phenyl iodide were added. foefina. The mixture was allowed to reflux for 0.25 hour, cooled to room temperature and concentrated in vacuo. The residue was purified by flash evaporation chromatography, eluting with 3: 1 hexanes / ethyl acetate, to give the title compound, as a clear, colorless oil (0.25 g, 87%). (18c) (* / -) -3- (4-CflRBOXIFENILETINIL) -3- (3-CICLOPENTILOXI-4-METOXYPENYL) CYCLOHEXflN-1-ONfl 5 To a solution of 0.25 g, 0.55 mmoles, of the compound 17b in 5 ml of 5: 5: 2 tetrahydrofuran / methanol / water, low Argon atmosphere, 1.1 mmole, 0.04 g, of eodium hydroxide was added. The mixture was heated at 60 ° C for 2 hours, cooled to room temperature and acidified with 3N hydrochloric acid. The aqueous phase was extracted three times with chloroform, dried over magnesium sulfate and evaporated. The residue was recrystallized from hexane / ethyl acetate to give the title compound as a white solid (0.18 g, 78%), m.p. 102-104 ° C.

EXAMPLE 19 PREPARATION OF 3- (3-CICLOPENTILOXY-4-METOXYPENYL) -3- [3- (5- TRIFLUOROMETHYL [1, 2, 4 0XADIAZOL-3-IL) PHENYL3ETINYL) CICL0HEXAN-1-ONA (19a) 3- (3-YODOFENYL) -5-TRIFLUOROMETHYL) TI, 2, 0XADIAZOL 3- (3-Iodophenyl) -5-tri fluorometyl [1,2,4,4-oxadiazole was prepared by ordinary chemistry and well known to those skilled in the art and is a colorless oil, mp 36-37 ° C (19b) 3- (3-CICL0PENTIL0XI-4-MET0XIFENIL) -3-C3- (5-TRIFLUORQ METHYL [l, 2,430XADIflZ0L-3-IL) FENYL3ETINYL) CICL0HEXAN-l-0NA A stirred mixture of 0.200 g was treated, 0.64 mmoles of the composition of example 3 (El) and 0.220 g, 0.64 mmolee, of 3- (3-iodophenyl) -5-trifluoromethyl [l, 2,43-oxadiazole in 5 ml of triethylamine, under argon atmosphere, with trace from tetrakis (triphenyl-fos ina) palladium?) and copper iodide (I). The mixture was allowed to reflux for 0.2 hour, cooled to room temperature and evaporated. The residue was adsorbed on eilice gel and purified by flash evaporation chromatography eluting with 3: 1 hexanes / ethyl acetate, and recrystallization from cold hexanes afforded the title compound, as a white solid (0.27 g, 83% ), pf 99-100 ° C. Analysis (C 29 H 27 F 3 N 2 O 4), calculated: C 66.40, H 5.19, N 5.304; found: C 66.46, H 5.35, N 5.15.

EXAMPLE 20 PREPARATION OF l *) AND (-) 3- (3-CICLOPENTILOXI-4-METQXYPENYL) -3- PHENYLENETHYCYCLOHEXAN-1-ONA A stirred mixture of 0.13 g, 0.40 mmol, of the compound of Example 3 (El) and 0.40 g, 2.0 mmol of iodobenzene in 6 mL of dry piperidine was treated under a • argon, with tetrakietriphenylphenol veetigioe) palladium (O) and copper iodide (I). The mixture was allowed to reflux hours, the mixture was cooled to room temperature and evaporated. The residue was dissolved in 100 ml of ethyl acetate and washed twice with brine, dried twice over magnesium sulfate and evaporated. Purification by flash evaporation chromatography eluting with 2: 1 hexane / ether, and Trituration from ether / hexanes afforded the title compound as a white solid (0.03 g, 19%), m.p. 90-91 ° C.

The enantiomer was prepared in an energetic manner, starting from the composition of Example 3 (E2), as a white solid (0.09 g, 58%), p. f. 90-91 ° C.

EXAMPLE 21 PREPARATION OF 3- [3-N- (4-BROMOBENCIL) BENZAMID-O-METHYL-3- (3- CYL-PENTIL-0XI-4-METHODYLENE) CICL0HEXAN-1-0NA (21a) 3-METHYL MEODOBENZOATE? Methyl 3-iodobenzoate was prepared by ordinary chemistry well known to those skilled in the art and a colorless oil, m.p. 40-41 ° C (21b) 3- (3-CICLOPENTILOXI-4-METOXYPENYL) -3- (3-CARBOMETOXY-15 PHENYL) ETINYL-CYCLOHEXAN-1-ONA The title compound was prepared in a manner r? similar to the compound of example 5b, from 0.30 g, 0.96 nm, of the compound of Example 3 (El), as a light yellow oil (0.43 g, 100%). NMR with 1H (400 MHz, CDC13) d 8.07 (s, 1H), 7.96 (dd, J = 7.8, 1.5 Hz, 1H), 7.58 (dd, J = 7.8, 1. 5 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 2.2 Hz, 1H), 7. 06 (dd, J = 8.43, 2.2 Hz, 1H), 6.86 (d, J = 8.43 Hz, 1H), 4.B0 (m, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 2.82 (dd, J = 26, 13.6 Hz, 2H), 2.50 (m, 1H), 2.42-2.15 (rn, 4H), 2.05 (rn, 1H), 1.90 (m, 6H), 1.62 (m, 3H). (20c) 3- (3-CICLOPENTILOXI-4-METOXIFENIL) -3- (3-CARBOXIFENI) Cyclohexane-1-Onya Cyclohexane The title compound was prepared in a manner similar to that of Example 6, starting with 0.43 g, 0.96 mg, of Example 20c, as a white powder (0.36 g, 87%), m.p. 82-84 ° C. (21d) 3- [3-N- (4-BROMOBENCIL) BENZAMIDQ3ETINYL-3- (3-CYCLO- • - • * PENTIL0XI-4-MET0XYPENYL) CICL0HEXAN-l-0NA '"V. 10 To a stirred mixture of 0.36 g, 0.83 mg, of the composition of Example 20c, 0.13 g, 0.91 mmolee, of 1-hydroxybenzoatriazole hydrate (Aldrich), 0.19 rnl, 1.7 rnmolee, of 4-rnetiimorpholine (Aldrich) and 0.20 g, 0.91 rnnol, of hydrochloride of 4-brornobenzylamine (Aldrich) in 5 mmol dichloromethane, low After argon at 0 ° C, 0.18 g, 0.91 mmol, of l- (3-dimethiaminopropyl) -3-ethylcarbodiirnide hydrochloride (Aldrich) was added. After stirring for 24 hours at the temperature, water was added. The mixture was acidified with 3N hydrochloric acid, extracted three times with dichloromethane, washed once With water, it was washed once with 10% sodium hydroxide, dried over magnesium sulfate and evaporated. Purification by flash chromatography, eluting with 2: 1 ethyl acetate / hexanes, followed by trituration in ether / hexanes, gave the title compound as a white solid. (0.25 g, 50%), m.p. 98-100 ° C.

EXAMPLES OF UTILITY EXAMPLE TO THE INHIBITOR EFFECT OF THE COMPOUNDS OF FORMULA (I) AND (II) ON THE PRODUCTION OF IN VITRO FNT BY HUMAN MONOCYTES 5 The inhibitory effect of the compotetoe of the formulas (I) and (II) can be determined on the production of TNF in vitro by human rnonocitos, through the protocol that was - -% described in Badger and co-inventors, patent application published by EPO 0 411 754 A2 and in Hanna, UO 90/15534, December 27, 1990.

EXAMPLE B Doe models of encotóxico shock have been used to determine the activity of TNF in vivo for the cornp? Estoe of ' the formula (I) and (II). The model protocol is described in Badger and co-inventors, patent application published by EPO 0 411 754 A2 and in Hanna, UO 90/15534, 27 December 20, 1990. The compound of example i herein demonstrated a positive response in vivo by reducing serum TNF levels induced by endotoxin injection.

EXAMPLE C ISOLATION OF ISOZIMAS OF FDE The inhibitory activity of foefodieeteraea and the electivity of the compound of the formula (I) and (II) ueando a battery of five ieozirnas of different FDE. The tissues that are the source of the different samples are the following: (1) FDE Ib, porcine aorta; (2) FDE him, heart of whose; (3) FDE III heart of whose; (4) FDE IV, human immunocytocyte; and (5) FDE V (also called "the"), canine trachea. The FDE la, Ib, le and III were partially purified using common chromatographic techniques [Torphy and Cieslineki, Mol. Pharmacol., 37: 206-214, 19903. FDE IV haeta kinetic homogeneity is purified by the sequential use of Anion exchange followed by heparin-sepharose chromatography [Torphy and co-authors, J. Biol. Chem., 267: 1798-1804, 19923. The activity of foefodiesterase as described in the protocol of Torphy and Cieslineki, Mol. .

Pharmacol., 37: 206-214, 1990. Positive CIs on the nanorollar to micromolar scale, for the compounds of the working examples described herein for formula (I) and (II), have been demoetradae.

Claims (3)

53 NOVELTY OF THE INVENTION CLAIMS

1 . - A compound of formula (I): lü where: Ri is - (CR * Rs) n C (0) 0 (CR4Rs) Re, - (CR4 Rs) nC (0) NR; - (CR4R5) m 6, - (CR4R5) n0 (CR /; R5) m Rs or - (CR * Rs) rR6 wherein the alkyl portions may be unsubstituted or substituted with one or more fluorine atoms; ee 0 to 2; n ee 0 to 4; r ee 0 to 6; R-i and Rs are independently hydrogen or alkyl of 1 to 2 15 carbon atoms; Re is hydrogen, methyl, hydroxyl, aryl, aryl substituted with halogen, aryloxy-alkyl of 1 to 3 carbon atoms, aryloxy-alkyl of 1 to 3 carbon atoms, * - * 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 25 substituted with 1 to 3 methyl group, an ethyl group or a hydroxyl group; provided that: (a) when Re is hydroxyl, entoncee is 2; or (b) when Re is hydroxyl, then r is 2 6; or (c) when Rs is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then it is 1 or 2; or (d) when R ee 2-tet rahidropi rani lo, 2 -tet ra-hi drotiopi rani lo, 2 -tet rahi. dro-furanyl or 2-tetrahydrothienyl, then r ee 1 to 6; (e) when n ee 1 and is 0, then Re ee different from H in - (CR * Rs) n0 (CR /; R5) mR6; X ee YR2, fluorine, NR .; Rs or formila ina; And ee 0 or S (0) m '; rn 'ee 0, 1 or 2; X2 ee 0 or NRβ; X3 and 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? * Or R7; W is alkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; Z ee O, NR7, NCR * Rs -alkenyl of 2 to 6 carbon atoms, NORi *, NOR15, NOCR ^ Rs -alkenyl of 2 to 6 carbon atoms, NNR4R1 *, NNR4R15, NCN, NNR8C (0) NR8 R14 , NNR8C (S) NR8R? -4; 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 - (CR "R5) qRi2 or alkyl of 1 to 6 carbon atoms, wherein R12 or the alkyl group of 1 to 6 carbon atoms is unsubstituted or substituted one or more times with methyl or ethyl, not substituted or is substituted with one or more fluorine atoms, -F, -Br, -Cl, -N02, -NRioRll, -C (0) R8, -C02R8, -0 (CH2) 2-4? R8, -0 (CH2) qRß, -CN, -C (0) NR? oRll, -0 (CH2) q C (0) NR? o Rll, -0 (CH2) q C (0) R9, -NR? OC (0) NR? ORll, -NRIQC (O) Rn, -NR10 C (0) 0R9, NR? OC (0) Ri3, -CNRioRii, -CN (NCN) NR? Oll, -C (NCN) SR9, - NR? OC (NCN) SR9, -NR? OC (NCN) NR? ORll, -NRio S (0) 2 F? 9, -S (0) ra'R9, -NR? OC (0) C (0) NR? ORll, -NR? OC (0) C (0) R? Oo R13; q is, l or 2; R12 ee R13, cycloalkyl of 3 to 7 carbon atoms (2-, 3- or 4- pyridyl), pyrimidyl, pyrazolyl, (1- or 2-irnidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2 - or 3-thienyl), quinolinyl, naphthyl or phenyl; R8 is hydrogen or R; R9 is alkyl of 1 to 4 carbon atoms, unsubstituted or substituted by one to three fluorine atoms; Rio ee X 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 then, together with the nitrogen, they can form a 5- to 7-membered ring optionally containing at least one additional heteroatom 5 selected from 0, or S; R 13 is a heteroaryl 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 0 or substituted in R12 or R13, the ring is 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; Ri * ee hydrogen or R ?; or when R8 and 5 Ri * eethan as NR8R? «, they can form, together with the nitrogen, a ring of 5 to 7 members, optionally containing one or more additional heteroatoms, selected from 0, N or S; R15 is C (0) R? *, C (0) NR * R? *, S (0) 2R7 or S (0) 2 NR * Ri *; provided that: (f) R7 is not alkyl of 1 to 4 carbon atoms, is not substituted or is substituted with 1 to 3 fluorine atoms; or their pharmaceutically acceptable salts.

2. A compound according to claim 1, further characterized in that Ri is -CH2-cyclopropyl, -cyclopentyl, -3-hydroxycyclohetyl, methyl or CF2H; X is YR2; And oxygen is; X2 is oxygen; X3 is hydrogen; R2 is CF2H or methyl i; U is ethynyl or 1,3-butadiinyl; R3 is a pyrirnidinyl ring substituted or not substituted, X ee YR2 and Z ee 0, NR7.

3. A compoteto in accordance with the claim 1, further characterized in that R is -CH2-cyclopropyl, - "15-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 unsubstituted or substituted aryl or heteroaryl ring, excluding pyridinyl; X is YR2 and Z ee 0. 20 4.- A compound in accordance with the claim 4, further characterized in that it is: (+/-) 3- (3-cyclopentiyoxy-4-methoxy phenyl) -3-phenylethynylcyclohexan-1-one; (+/-) 3- (3-Cyclo-pentyndiioxy-4-methoxyphenyl) -3- (3-carbomethoxyphenyl) ethynyl cyclohexane-1-one; (+/-) 3- (3-carboxyphenylethynyl) -3- (3-cyclopentyl-1-oxo-4-rnetoxy-phenyl) -cyclohexan-1-one; 3- (3-cyclo-entyloxy-4-methoxyphenyl) -3- [3- (5-methyl [l, 3,4-thiadiazol-2-yl) phenylethynyl- cyclohex n-1-one; 3- (Cyclo-entyloxy-4-methoxy-phenyl) -3- [3- (5-rnethyl [l, 3,43-oxadiazol-2-yl) -phenyl-ethenyl-3-cyclohexan-1-one; 3- (3-cyclopentyloxy-4-r-methoxy-enyl) -3- [3- (3-methyl- [1,2- 43-oxadiazol-5-yl) -phenylethynyl-3-cyclohexan-1-one; 3- (3-cyclopentyloxy-4-methoxy-3-phenyl) -3- [3- (5-rnenyl [1,2,44-oxadiazol-3-yl] -phenyl-3-cyclohexan-1-one]; 3- (3-cyclopentyloxy-4-methoxy phenyl) -3- (cyanophenyl-yl) cyclohexan-1-one; 3- (3-cyclopentyloxy-4-rnetoxy phenyl) -3- (3-nitropheni letini.1) cyclohexan-1-one; 3- (3-cyclopentyloxy-4-methoxy-phenyl) -3- (2-hydroxyethoxy.pheni.leti nor 1) cycloexitan-1-one; 3- -o (acetam-dophenylethynyl) -3- (3-c? Clopentyloxy-4-methoxyphenyl) -cyclohexane-1-one; 3- (3-cyclopentyloxy-4-methoxyphenyl) -3- (3- rnetazulfone idiophenylethynyl) cyclohexan-1-one; 3- (3-am.i nofeni.1-ethynyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -cyclohexan-1-one; (+/-) -3- (4-carboxyphenylethynyl) -3- (3-cyclopentiyoxy-4-methoxy-5-phenyl) -cyclohexan-1-one; 3- (3-cyclopentyloxy-4-methoxy phenyl) -3- [3- (5-trifluoromethyl [1,2, 43-oxadiazol-3-yl) -phenylethydiD-cyclohexan-1-one; (+) and (-) 3- (3-cyclopentyloxy-4-methoxyphenyl) -3-phenylethynylcyclohexan-1-one; or 3- [3-N- (4-bromobenzyl) benz-arnido ethynyl-3- (3-cyclopentyloxy-4-methoxy phenyl) cyclohexan-1-one. 5. A pharmaceutically acceptable composition characterized in that it comprises a compound according to formula (I) of claim 1, and a pharmaceutically acceptable excipient. 6. The use of a compound of the formula (I) according to claim 1, in the preparation of a composition to treat asthma in a mammal that needs it. 7. A compound of the formula (II): iu * where: Ri is - (CR * Rs) nC (0) 0 (CR * Rs) «Re, - (CR * Rs) nC (0) NR * (CR * Rs) n» R6, - (CR * R5) n0 (CR * R5) mRs or ~ (CR * Rs) rR6 wherein the alkyl portion may be unsubstituted or substituted with one or more fluorine atoms; m is 0 to 2; n ee 0 to 4; r ee 0 to 6; R * and Rs are independently hydrogen or alkyl of 1 to 2 15 Carbon atornoe; Re is hydrogen, methyl, hydroxyl, aryl, aryl substituted with halogen, aryloxy-alkyl of 1 to 3 carbon atoms, aryloxy-alkyl of 1 to 3 carbon atoms substituted with halogen, indanyl, indenyl, polycycloalkyl of 7 to 11 atom. carbon, tetrahydrofuranyl, furanyl, Tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, cycloalkyl of 3 to 6 carbon atoms or a 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 the 3 methyl groups, an ethyl group or a hydroxyl group; provided that: (a.) when Re is hydroxyl, entoncee m ee 2; or (b) when R & ee hydroxyl, then r ee 2 to 6; or (c) when Re is 2-tetrahydropyranyl, 2-tetrahydrothio? Iranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then m is 1 or 2; or (d) when Re is 5-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 Re is different from H in - (CR * Rs) n0 (CR * Rs) mR6; X is YR2, fluorine, NR * Rs or formylamine; And it is 0 or S (0) m '; m 'ee 0, 1 or 2; 2 ee 0 or NR8; 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 ee COORi *, C (0) NR * R? * Or R7; 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? *, 15 C (Y 'ÍNRioRl *, CÍNRio) NR? ORl *, CN, C (MORß) R? *, C (0) NR8NR8C (0) R8, C (0) NR8NR? ORl *, C (N0R? *) R8, C (NR8) NRi0 Rl *, C (NR? *) NRßR8 C (NCN) NR? ORl4, C (NCNSR9), (2-, 4- or 5-imidazolyl), (3-, 4- or '5-pyrazolyl), (4- or 5-triazolylCl, 2,33), (3- or 5-triazolyl, 2,43), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), 20 (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl [1,2,43), (2-oxadiazolyl [1, 3.43), (2-thiadiazolyl [1, 3.43] ), (2-, 4- or 5-thiazolyl), (2-, 4- or 5-oxazolidinyl), (2-, 4- or 5-thiazolidinyl) or (2, -, 4- or 5-imidazolidinyl); where everything that is eietemae an? laree heterocyclic can be suetituidos 25 optionally one or more times with Ri *; Y 'is 0 or S; R7 is - (CR * Rs) - | Ri2 or alkyl of 1 to 6 carbon atoms, wherein R12 is phenyl or an alkyl group of 1 to 5 carbon atoms is unsubstituted or substituted by one or more alkyl with 1 to 2 carbon atoms, unsubstituted or substituted by one to three fluorine atoms; -F, -Br, -Cl, -NO2, -Si (R *) 3, -NR10R11, - 5 C (0) R8, -0 (CH2) 2- * 0R8, -C? 2Rβ, -0R8, - CN, -C (0) NR or Rl 1, - 0C (0) NRa0R? L, -0C (O) R8, -NR? OC (0) NR? ORll, -NR? OC (O) Ri 1, - NR? OC (0) OR9, -NR? OC (0) Ri3, -C (NR? O) NRi0 RI 1, -C (NCN) NR? O RI 1, - C (NCN) SR9, -NR? OC (NCN) SR9, -NR? OC (NCN) NR? Or Rll, -NR10 S (0) 2 R9, - S (0) «'R9, -NR? OC (0) C (0) NR? OR? ?, -NR10 C (O) C (0) Rio, thiazolyl, > * imidazolyl, oxazolyl, pyrazolyl, triazolyl or tetrazolyl; q is 0, 1 or 2; R12 is R13, cycloalkyl of 3 to 7 carbon atoms, (2-, 3- or 4-? Iridyl), pyrimidyl, pyrazolyl, (1- or 2-irnidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl , furanyl, (2- or 3-thienyl), quinolinyl, (4- or 5-thiazolyl), quinolinyl, naphthyl or phenyl; R8 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 ee 0R8 or Rn; R e is hydrogen or alkyl of 1 to 4 carbon atoms, unsubstituted or 0 substituted with one to three fluorine atoms; or when Rio and R11 are as NR10R11, together with the nitrogen, they can form a ring of 5 to 7 members which optionally contains, at least one additional heteroatom selected from 0, N or S; R 13 is a substituted or unsubstituted heteroaryl group, selected from the group of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, irnidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl and thiadiazolyl; and when R13 is substituted at R12 or R13 the rings are connected by means of a carbon atom and every second ring R13 can be non-substituted or substituted with one or two alkyl groups of 1 to 2 carbon atoms, unsubstituted or substituted in methyl, with 3 fluorine atoms; Ri * is hydrogen or R7; or when R8 and R * eethan as NR8R? *, can form, together with the nitrogen, a 5-7 membered ring optionally containing one or more additional iS heteroatoms, selected from 0, N or S; provided that: (f) R7 is not alkyl of 1 to 4 carbon atoms, unsubstituted or substituted by 1 to 3 fluorine atoms; or pharmaceutically acceptable salts. 8. A compoteto in accordance with the claim 15 8, characterized in that Ri is -CH2-cyclopropyl, -cyclopentyl, -3-hydroxycyclohetyl, methyl or CF2H; X is YR2; And it's oxygen; X2 is oxygen; X3 is hydrogen; R2 is CF2H or methyl, Ue e ethynyl or 1,3-butadiinyl, R3 is a substituted or unsubstituted pyridinyl ring, X is YR2 and Z is 0, NR7. 9. A pharmaceutically acceptable composition, characterized in that it comprises a composition according to formula (I) of claim 8 and a pharmaceutically acceptable excipient.