COMPOUNDS

"Compounds Useful for Treating Allergic and Inflammatory Diseases* Field of Invention The present invention relates to novel compounds, pharmaceutical compositions containing these compounds, and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).

Background of the Invention Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli.

Identification of novel therapeutic agents for asthma is made difficult 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 all three components of chronic asthma. An alternative to the "mediator approach" is to regulate the activity of the cells responsible for the pathophysiology of the disease.

One such way is by elevating levels of cAMP (adenosine cyclic 3',5'monophosphate). Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg+2-ATP to cAMP at an accelerated rate.

Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Antiasthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo.

Thus PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.

The compounds of this invention also inhibit the production of Tumor Necrosis Factor (TNF), a serum glycoprotein. Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions;

sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.

AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, T-celI-mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T lymphocyte requires T lymphocyte activation. Viruses such as HIV- 1 or HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication.

Cytokines, specifically TNF, are implicated in activated T-cell-mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation.

Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection. Monocytes, macrophages, and reIated cells, such as kupffer and glial cells, have also been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the Ievel of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57, 1989].

Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages [See Poli et al., Proc. Natl. Acad.

Sci., 87:782-784, 1990], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T cells.

TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.

TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al., Infection and Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal of Infectious Diseases, 164:389-95, 1991. See also Wasan et al., Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Luke et al., Journal of Infectious Diseases, 162:211-214,1990].

The ability to control the adverse effects of TNF is furthered by the use of the compounds which inhibit TNF in mammals who are in need of such use. There remains a need for compounds which are useful in treating TNF-mediated disease states which are exacerbated or caused by the excessive and/or unregulated production of TNF.

Summarv of the Invention This invention relates to the novel compounds of Formula (I), as shown below, useful in the mediation or inhibition of the enzymatic activity (or catalytic activity) of phosphodiesterase IV (PDE IV). The novel compounds of Formula (I) also have Tumor Necrosis Factor (TNF) inhibitory activity.

This invention also relates to the pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.

The invention also relates to a method of mediation or inhibition of the enzymatic activity (or catalytic activity) of PDE IV in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I), as shown below.

The invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I).

The invention also provides a method for the treatment of asthma which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I).

This invention also relates to a method of inhibiting TNF production in a mammal, including humans, which method comprises administering to a mammal in need of such treatment, an effective TNF inhibiting amount of a compound of Formula (I). This method may be used for the prophylactic treatment or prevention of certain TNF mediated disease states amenable thereto.

This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HIV), which comprises administering to such human an effective TNF inhibiting amount of a compound of Formula (I).

The compounds of Formula a) are also useful in the treatment of additional viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo.

The compounds of Formula (I) are also useful in the treatment of yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.

The compounds of this invention are represented by Formula (I): EMI4.1

wherein: R1 is -(CR4Rs)nC(O)O(CR4Rs)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4Rs)nO(CR4Rs)mR6, or -(CR4Rs)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens; m is O to 2; nis 1 to4; ris 1 to 6; R4 and Rs are independently selected from hydrogen or C1-2 alkyl;

; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCI 3 alkyl, halo substituted aryloxyC1-3 alkyl, indanyl, indenyl, C7 11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2;

or d) when R6 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 R6 is other than H in -(CR4Rs)nO(CR4Rs)mR6; X is YR2, halogen, nitro, NR4R5, or formyl amine; Y is O or S(O)m'; m' is 0, 1, or 2 ; X2 is O or NR8 ; X3 is hydrogen or X; R2 is independently selected from -CM3 or -CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4;

; R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, -CH=CR8'R8', cyclopropyl optionally substituted by R8W, CN, ORg, CH2OR8, NR8RI0,CH2NR8R10, C(Z')H, C(O)ORg, C(O)NR8R10, or Z' is O, NR9, NOR8, NCN, C(-CN)2, CR8CN, CR8NO2,CR8C(O)OR8,CR8C(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NR8R8;

; Z is CR8R8OR14, CRgRgOR15, CR8R8SR14, CR8R8SR15, CR8R8S(O)m'R7, CR8R8NR10R14, CR8R8NR10S(O)2NR10R14, CR8R8NR10S(O)2R7, CR8R8NR10C(Y')R14, CR8R8NR10C(O)OR7, CR8R8NR10C(Y')NR10R14, CR8R8NR10C(NCN)NR10R14, CR8R8NR10C(CR4NO2)NR10R14, CR8R8NR10C(NCN)SR9, CR8R8NR10C(CR4NO2)SR9, CR8R8C(O)OR14, CR8R8C(Y')NR10R14, CR8R8C(NR10)NR10R14, CR8R8CN, CR8R8(tetrazolyl), CR8R8(imidazolyl), CR8R8(imidazolidinyl), CR8R8(pyrazolyl), CR8R8(thiazolyl), CR8R8(thiazolidinyl), CR8R8(oxazolyl), CR8R8(oxazolidinyl), CR8R8(triazolyl), CR8R8 (isoxazolyl),CR8R8(oxadiazolyl), CR8R8(thiadiazolyl), CRgRg(morpholinyl), CR8R8(piperidinyl), CR8R8(piperazinyl), CR8R8(pyrrolyl), CR8R8C(NOR8)R14, CR8R8C(NOR 14)R8, CR8R8NR1OC(NR1O)SR9, CR8R8NR 10C(NR10)NR10R14, CR8R8NR10C(O)C(O)NR10R14,

or CR8R8NR10C(O)C(O)OR14 ; X5 is H, Rg, OR8, CN, C(O)Rg, C(O)ORg, C(O)NRgRg, or NR8R8; or Z and X5 together is -CRgRgO-; Y' is O or S; R7 is -(CR4Rs)qR12 or C1-6 alkyl wherein the R12 or C1-6 alkyl group is optionally substituted one or more times by C1-2 alkyl optionally substituted by one to three fluorines, -F, -Br, - Cl, -NO2, -NR10R11, -C(O)R8, -C(O)OR8, -OR8, -CN, -C(O)NR10R11, -OC(O)NR10R11, -OC(O)R8, -NR10C(O)NR10R11, -NR10C(O)R11, -NR10C(O)OR9, -NR10C(O)R13, -C(NR10)NR10R11, -C(NCN)NR10R11, -C(NCN)SR9, -NR10C(NCN)SR9, -NR10C(NCN)NR10R11, -NR10S(O)2R9, -S(O)m'R9, -NR10C(O)C(O)NR10R11, -NR10C(O)C(O)R10, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; q is 0, 1, or 2 ;

; R12 is C3-7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2or 3-thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl; R8 is independently selected from hydrogen or Rg; Rsl is R8 or fluorine; R9 is C14 alkyl optionally substituted by one to three fluorines; R10 is OR8 orRil; R11 is hydrogen, or C1 4 alkyl optionally substituted by one to three fluorines;

or when R10 and R1 l are as NR1oRl l they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from 0, N,or S; R13 is oxazolidinyI, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C1 2 alkyl groups; R14 is hydrogen or R7;

or when R10 and RI4 are as NR1OR14 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from 0, N,or S; R15 is C(O)R14, C(O)NR8R14, S(O)2NR8R14,S( )2R7; provided that: f) when R12 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, Npiperidinyl, or N-morpholinyl, then q is not 1; g) when X2R1 is OCF2H or OCF3, X is F, OCF2H or OCF3, X3 is H, s is zero, Xs is H, Z is CH2OR14, and R14 is C1:7 unsubstituted alkyl, then R3 is other than H; or a pharmaceutically acceptable salt thereof.

Detailed Description of the Invention This invention relates to the novel compounds of Formula (I), and to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent. This invention also relates to a method of mediating or inhibiting the enzymatic activity (or catalytic activity) of PDE IV in a mammal in need thereof and to inhibiting 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).

Phosphodiesterase IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome. In addition, PDE IV inhibitors are useful in the treatment of diabetes insipidus, [Kidney Int., 37:362, 1990; Kidney Int., 35:494, 1989] and central nervous system disorders such as depression and multi-infarct dementia.

The compounds of Formula (I) are also useful in the treatment of viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo. The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (1). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.

This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I).

The compounds of Formula (I) may also be used in association with the veterinary treatment of animals, other than in humans, in need of inhibition of TNF production. TNF mediated diseases for treatment, 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 infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.

The compounds of Formula (I) are also useful in the treatment of yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo. A preferred disease state for treatment is fungal meningitis.

Additionally, the compounds of Formula (I) may be administered in conjunction with other drugs of choice for systemic yeast and fungal infections. Drugs of choice for fungal infections, include but are not limited to the class of compounds called the polymixins, such as Polymycin B, the class of compounds called the imidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; the class of compounds called the triazoles, such as fluconazole, and itranazole, and the class of compound called the Amphotericins, in particular Amphotericin B and liposomal Amphotericin B.

The co-administration of the anti-fungal agent with a compound of Formula (I) may be in any preferred composition for that compound such as is well known to those skilled in the art, for instance the various Amphotericin B formulations. Co-administration of an antifungal agent with a compound of Formula (I) may mean simultaneous administration or in practice, separate administration of the agents to the mammal but in a consecutive manner.

In particular, the compounds of Formula (I) may be co-administered with a formulation of Amphotericin B, notably for systemic fungal infections. The preferred organism for treatment is the Candida organism. The compounds of Formula (I) may be co-administered in a similar manner with anti-viral or anti-bacterial agents.

The compounds of Formula (I) may also be used for inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti-viral agent by administering an effective amount of a compound of Formula (I) to a mammal in need of such treatment. Preferably, a compound of Formula (I) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.

Preferred compounds are as follows: When R1 for the compounds of Formula (I) is an alkyl substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably a C1-4 alkyl substituted by 1 or more fluorines. The preferred halo-substituted alkyl chain length is one or two carbons, and most preferred are the moieties -CF3, -CH2F, -CHF2, -CF2CHF2, -CH2CF3, and -CH2CHF2. Preferred R1 substitutents for the compounds of Formula (I) are CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, C7-11 polycycloalkyl, (3- or 4cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C1-2 alkyl optionally substituted by 1 or more fluorines, -(CH2) 1.3C(O)O(CH2)0-2CH3,-(CH2) 1-3 O(CH2)0-2CH3, and -(CH2)2-40H.

When the R1 term contains the moiety (CR4R5), the R4 and Rg terms are independently hydrogen or alkyl. This allows for branching of the individual methylene units as (CR4R5)n or (CR4R5)m; each repeating methylene unit is independent of the other, e.g., (CR4R5)n wherein n is 2 can be -CH2CH(-CH3)-, for instance. The individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon can optionally be substituted by fluorine independent of each other to yield, for instance, the preferred R1 substitutions, as noted above.

When R1 is a C7-11 polycycloalkyl, examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.02,6]decyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987, whose disclosure is incorporated herein by reference in its entirety.

Z is preferably CRgRgOR14, CR8R8OR15, CR8R8SR14, CR8R8SR15, CR8R8S(O)m'R7, CR8R8NR10R14, CR8R8NS(O)2NR10R14, CR8R8NS(O)2R7, CR8R8NR10C(O)R14, CR8R8NR10C(O)OR7, CR8R8NR10C(O)NR10R14, CR8R8NR10C(NCN)NR10R14, CR8R8NR10C(CR4NO2)NR10R14, CR8R8NR10C(NCN)SR9, CR8R8NR10C(CR4NO2)SR9, CR8R8C(O)OR14, CR8R8C(O)NR10R14, CR8R8C(NR10)NR10R14, CR8R8CN, CR8R8C(NOR8)R14, CR8R8C(NOR14)R8, CR8R8NR10C(NR10)SR9,CR8R8NR1 0C(NR10)NR10R14, CR8R8NR1oC(o)C(o)NRloRl4 or CR8R8NR1OC(O)C(O)OR14; most preferred are those compounds wherein the R8 group of Z is H and the R14 group of Z is R4.

Preferred X5 groups are H, OH, OCH3, CN, C(O)Rg, C(O)OH, C(O)OCH3, C(O)NH2, CON(CH3)2, NH2, or N(CH3)2. The most preferred groups are H, OH, CN, C(O)OH, C(O)NH2 or NH2.

The preferred group wherein Z and X5 together is -CRgRgCO- is -CH2CO-.

Preferred X groups for Formula (I) are those wherein X is YR2 and Y is oxygen. The preferred X2 group for Formula (I) is that wherein X2 is oxygen. The preferred X3 group for Formula (I) is that wherein X3 is hydrogen. Preferred R2 groups, where applicable, is a C1 alkyl optionally substituted by 1 or more halogens. The halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R2 groups are those wherein R2 is methyl, or the fluoro-substituted alkyls, specifically a C1-2 alkyl, such as a -CF3, -CHF2, or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.

Preferred R3 moieties are C(O)NH2, C=-CR8, CH2NHC(O)C(O)NH2, CN, C(Z')H, CH20H, CH2F, CF2H, and CF3. More preferred are CBCH and CN. Z' is preferably 0 or NOR8.

Preferred R7 moieties include optionally substituted -(CH2) 1-2(cyclopropyl), -(CH2)0-2(cyclobutyl), -(CH2)0-2(cyclopenty1), - (CH2)0.2(cyclohexyl), -(CH2)0-2(2-, 3- or 4-pyridyl), (CH2)1 2(2-imidazolyl), (CH2)2(4-morpholinyl), (CH2)2(4-piperazinyl), (CH2)1-2(2-thienyl), (CH2) 1 2(4-thiazolyl), and (CH2)0-2phenyl;

; Preferred rings when R10 and R11 in the moiety -NR10R11 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 1imidazolyl, 2-(R8)-1-imidazolyl, 1 -pyrazolyl, 3-(Rg)-1-pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R8)-1-triazolyl, 5-(Rg)-2-triazolyl, 5-(Rg)-1-tetrazolyl,5-(R8)-2-tetrazolyl, 1 -tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(Rg)-1-piperazinyl, or pyrrolyl ring.

Preferred rings when R1o and R14 in the moiety -NR1oRl4 together with the nitrogen to which they are attached may 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 1imidazolyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, and pyrrolyl. The respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I).

Illustrations of such carbon substitutions includes, but are not limited to, 2-(R7)- 1 -imidazolyl,4-(R7)- 1 -imidazolyl,5-(R7)- 1 -imidazolyl, 3-(R7)-1-pyrazolyl, 4-(R7)- 1 -pyrazolyl, 5-(R7)-1-pyrazolyl, 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.

Applicable nitrogen substitution by R7 includes, but is not limited to, 1-(R7)-2-tetrazolyl, 2-(R7)-1-tetrazolyl, 4-(R7)-1-piperazinyl. Where applicable, the ring may be substituted one or more times by R7.

Preferred groups for NR10R14 which contain a heterocyclic ring are 5-(R14)-1tetrazolyl, 2-(R 14)- 1 -imidazolyl,5-(R14)-2-tetrazolyl,or 4-(R 14)-l-piperazinyl.

Preferred rings for R13 include (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5isoxazolyl), (3- or 5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[ 1,3,4]),(2-thiadiazolyl[ 1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).

When the R7 group is optionally substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, the heterocyclic ring itself may be optionally substituted by R8 either on an available nitrogen or carbon atom, such as 1-(R8)-2-imidazolyl, 1-(R8)-4-imidazolyl, 1-(R8)-5-imidazolyl, 1-(R8)-3-pyrazolyl, 1-(R8)-4-pyrazolyl, 1-(R8)-5-pyrazolyl, 1-(R8)-4-triazolyl, or 1-(R8)-5-triazolyl. Where applicable, the ring may be substituted one or more times by R8.

Preferred are those compounds of Formula (I) wherein R1 is -CH2-cyclopropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -C1-2 alkyl optionally substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluoro-substituted alkyl, R3 is CN or CiCR8; and X is YR2.

Most preferred are those compounds wherein R1 is -CH2-cyclopropyl, cyclopentyl, methyl or CF2H; R3 is CN or CCH; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl.

A preferred subgenus of the compounds of Formula (I) is the compounds of Formula (Ia) EMI10.1

wherein: R1 is CH2-cyclopropyl, CH2-C5.6 cycloalkyl, C4-6 cycloalkyl, C7-1 1 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C1-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)1-3C(O)O(CH2)0-2CH3, -(CH2)1-3O(CH2)0-2CH3, and -(CH2)2-4OH ; X is YR2, halogen, nitro, NR4R5, or formyl amine; Y is O or S(O)m' ; m' is 0, 1, or 2 ; R2 is -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; R3 is hydrogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, CN, CH2ORg, C(Z')H, C(O)OR8, C(O)NR8RlO, or C=-CR8;

; Z' is O or NOR8 ; Z is CR8R8OR14,CR8R8OR15,CR8R8SR14,CR8R8SR15, CR8R8S(O)m'R7, CR8R8NR10R14, CR8R8NS(O)2NR10R14, CR8R8NS(O)2R7, CR8R8NR10C(Y')R14, CR8R8NR10C(O)OR7, CR8R8NR10C(Y')NR10R14, CR8R8NR10C(NCN)NR10R14, CR8R8NR10C(CR4NO2)NR10R14, CR8R8NR10C(NCN)SR9, CR8R8NR10C(CR4NO2)SR9, CR8R8C(Y')OR14, CR8R8C(Y')NR10R14, CR8R8C(NR10)NRIoR14,CR8R8CN, CR8R8C(NOR8)R14, CR8R8C(NOR14)R8, CR8R8NR10C(NR10)SR9, CR8R8NR10C(NR10)NR10R14, CR8R8NR10C(O)C(o)NR10R14, or CR8R8NR10C(O)C(O)OR14 ; X5 is H, OR8, CN, C(O)ORg or NR8R8;

or Z and X5 together is -CRgRgCO-; Y'isOorS; R7 is -(CR4R5)qR12 or C1-6 alkyl wherein the R12 or C16 alkyl group is optionally substituted one or more times by methyl or ethyl substituted by 1-3 fluorines, -F, -Br, -Cl, -NO2, -NR10R11, -C(O)R8,-C(O)OR8, -OR8, -CN, -C(O)NR10R11, -OC(O)NRloR 11, -OC(O)R8, -NR10C(O)NR10R11, -NR10C(O)R11, -NR10C(O)OR9, -NR10C(O)R13, -C(NR10)NR10R11, -C(NCN)NR10R11, -C(NCN)SR9, -NR10C(NCN)SR9, -NR10C(NCN)NR10R11, -NR10S(O)2R9, -S(O)m'R9, -NR10C(O)C(O)NR10R11, -NR10C(O)C(O)R10, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; q is 0, 1, or 2 ; R12 is C3-C7 cycloalkyl, (2-, 3- or 4-pyridyl), (1- or 2-imidazolyl), piperazinyl, morpholinyl, (2- or 3-thienyl), (4- or 5-thiazolyl), or phenyl;

; R8 is independently selected from hydrogen or R9; Rg is C1-4 alkyl optionally substituted by one to three fluorines; 1 R10 is OR8 or R11 ; R11 is hydrogen or C1-4 alkyl optionally substituted by one to three fluorines; or when R10 and Ri 1 are as NR10R11 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from 0, N,or S; R13 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C1-2 alkyl groups; R14 is hydrogen or R7;

or when Rio and R14 are as NRl0Rl4 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from 0, N,or S; R15 is C(O)R14, C(O)NR8R14, S(0)2NR8R14, S(0)2R7; provided that: a) when R12 is N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, or Nmorpholinyl, then q is not 1; b) when R1 is CF2H or CF3, X is F, OCF2H or OCF3, X5 is H, Z is CH2OR14, and R14 is C1-7 unsubstituted alkyl, then R3 is other than H; or the pharmaceutically acceptable salts thereof.

Preferred compounds of Formula (I) are: methyl 2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -yl]acetate ; cis- [4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan 1 -yl] methanol; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan- 1 - yl]methylamine; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan- 1,1 diyl]oxirane; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexan-1yl]methanol; trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan- 1,1 diyl]oxirane;

and trans- [4-cyano-4- (3.cyclopropylmethoxy.4-methoxyphenyl) - 1 -hydroxycyclohexan 1 -yl]methanol Some of the compounds of Formula (I) may exist in both racemic and optically active forms; some may also exist in distinct diastereomeric forms. All of these compounds are considered to be within the scope of the present invention. Therefore another aspect of the present invention is the administration of either a racemate, a single enantiomeric form, a single diastereomeric form, or mixtures thereof.

Definitions The terms "C1.3alkyl","C1.4 alkyl", "C1.6 alkyl" or "alkyl" include both straight or branched chain radicals of 1 to 10, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like. "AIkenyl" includes both straight or branched chain radicals of I to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl, 1-propenyl, 2propenyl, 2-propynyl, or 3-methyl-2-propenyl. "Cycloalkyl" or "cycloalkyl alkyl" includes radicals of 3-7 carbon atoms, such as cyclopropyI, cyclopropylmethyl, cyclopentyl, or cyclohexyI.

"Aryl" or "aralkyl", unless specified otherwise, means an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl, or naphthyl. Preferably the aryl is monocyclic, i.e, phenyl. The alkyl chain is meant to include both straight or branched chain radicals of 1 to 4 carbon atoms. "Heteroaryl" means an aromatic ring system containing one or more heteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl. "Halo" means chloro, fluoro, bromo, or iodo.

By the phrase "inhibiting the production of IL-1" or "inhibiting the production of TNF" means: a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels by inhibition of the in vivo release of IL-1 by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the translational or transcriptional level, of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels; or c) a down regulation, by inhibition of the direct synthesis of IL-1 or TNF levels as a postranslational event.

By the term "TNF mediated disease or disease states" is meant any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6. A disease state in which IL-1, for instance is a major component, and whose production or action, is exacerbated or secretes in response to TNF, would therefore be considered a disease state mediated by TNF.

As TNF-B (also known as lymphotoxin) has close structural homology with TNF-a (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-a and TNF-ss are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF" unless specifically delineated otherwise. Preferably TNF-a is inhibited.

"Cytokine" means any secreted polypeptide that affects the functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses. A cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce them. For instance, a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte, but many other cells produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes, and B-lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells.

Examples of cytokines for the present invention include, but are not limited to, Interleukin-l (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-a) and Tumor Necrosis Factor-beta (TNF-ss).

The cytokine inhibited by the present invention for use in the treatment of a HIVinfected human must be a cytokine which is implicated in (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HIV gene expression and/or replication, and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration. Preferrably, his cytokine is TNF-a.

The cytokine inhibited by the present invention for use in the treatment of a HIVinfected human must be a cytokine which is implicated in (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HIV gene expression and/or replication, and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration. Preferrably, his cytokine is TNF-o:.

All of the compounds of Formula (I) are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal, including humans, in need thereof. All of the compounds of Formula (I) are useful in the method of inhibiting or mediating the enzymatic or catalytic activity of PDE IV and in treatment of disease states mediated thereby.

METHODS OF PREPARATION: Preparing compounds of Formula (I) can be accomplished by one of skill in the art according to the procedures outlined in the Examples, infra. The preparation of any remaining compounds of Formula (I) not described therein may be prepared by the analogous processes disclosed herein which comprise:

: a) for compounds of Formula (I) wherein R3 is other than C(=Z')H and wherein Z is CH2COOCH3, reacting a compound of Formula (2) EMI14.1 where R1 represents R1 as defined in relation to Formula (I) or a group convertable to R and X and X3 represent X and X3 as defined in relation to Formula (I) or a group convertable to X or X3 and R3 represents R3 as defined in relation to Formula (I) or a group convertable to R3, with a stabilized acetate anion, such as sodium trimethylphosphonoacetate or lithium ethyl (trimethylsilyl)acetate, in a suitable non-reacting solvent, such as 1,2dimethoxyethane or tetrahydrofuran, followed by reduction of the resulting ethylidene intermediate with, e.g., hydrogen and a suitable catalyst, to provide compounds of Formula (I) wherein R3 is other than C(=Z')H and wherein Z is CH2COOCH3;

preparation of such compounds of Formula (I) wherein R3 is C(=Z')H proceed in an analogous fashion from the compound of Formula (2) wherein =Z is an aldehyde protecting group, such as a dimethylacetal or a dioxolane, followed by deprotection to the aldehyde and subsequent elaboration by standard procedures known to those of skill in the art to the remaining compounds of Formula (I) wherein Z' is other than 0.

Saponification of the ester moiety of compounds of Formula (I) wherein R3 is other than COORg and wherein Z is CH2COOCH3 with, e.g., potassium hydroxide in methanol, provides compounds of Formula (I) wherein R3 is other than COORg and wherein Z is CH2COOH; preparation of such compounds of Formula (I) wherein R3 is COORg proceed in an analogous fashion from the compound of Formula (2) wherein =Z' is an aldehyde protecting group, such as a dimethylacetal or a dioxolane, followed by deprotection to the aldehyde and subsequent elaboration by standard procedures known to those of skill in the art to the remaining compounds of Formula a) wherein R3 is COORg.

Compounds of Formula (I) wherein R3 is other than C(=Z')H and wherein Z is CH2OH may be prepared in a wide variety of ways. For example, with appropriate manipulation of certain chemically sensitive functional groups, conversion of the ketone of the compounds of Formula (2) wherein R1 represents R1 as defined in relation to Formula (I) or a group convertable to R1 and X and X3 represents X and X3 as defined in relation to Formula (I) or a group convertable to X or X3 and R3 represents R3 as defined in relation to Formula (I) or a group convertable to R3 and wherein R3 is other than C(=Z')H, to the corresponding olefin by Wittig, Peterson or other olefination reactions followed by, e.g., hydroboration-oxidation;

preparation of such compounds of Formula Q wherein R3 is C(=Z')H proceed in an analogous fashion from the compound of Formula (2) wherein =Z' is an aldehyde protecting group, such as a dimethylacetal or a dioxolane, followed by deprotection to the aldehyde and subsequent elaboration by standard procedures known to those of skill in the art to the remaining compounds of Formula (I) wherein Z' is other than 0.

Alternatively, compounds of Formula (I) may be obtained by homologation of the ketone of appropriate compounds of Formula (2) by, e.g., ketene thioacetal formation, subsequent hydrolosis to the aldehyde and reduction. Reductive amination with, e.g., ammonium formate and sodium cyanoborohydride in an alcoholic solvent, rather than reduction of such homologated aldehyde intermediates, provides the compounds of Formula (I) wherein R3 is other than C(=Z')H and Z is CH2NH2;

preparation of such compounds of Formula (I) wherein R3 is C(=Z')H proceed in an analogous fashion from the homologated aldehyde intermediates wherein =Z' is an aldehyde protecting group, such as a dimethylacetal or a dioxolane, followed by deprotection to the R3 aldehyde and subsequent elaboration by standard procedures known to those of skill in the art to the remaining compounds of Formula (I) wherein Z' is other than 0.

It will be recognized that compounds of Formula (I) may exist in two distinct diastereomeric forms possessing distinct physical and biological properties; such isomers may be separated by standard chromatographic methods. Such isomers may be independently converted to other compounds of Formula (I) wherein Z is, e.g., CR8R8oRl47CR8RSOR 15,CR8RSNR13R14,CRgRgNS(O)2NR13R14,CR8R8NS(O)2R7, or CR8R8NR13C(Y')R14,by any of the wide variety of 0 and N alkylation or acylation procedures known to those of skill in the art.

For example, with proper manipulation of any chemically sensitive functional groups, compounds of Formula (1) wherein NR13R14 represent a ring, such as a 1- or 2-tetrazole, may be derived from reaction of an appropriate compound of Formula (I) wherein Z possesses a leaving group,L, as in CRgRgL, and L is a mesylate, tosylate, chloride or bromide, with the appropriate metal salt of HNR13Rl4, e.g., 5-(R14)-tetrazole; the appropriate compound of Formula (I) wherein Z is mesylate, tosylate, Br or Cl, derived in turn from the appropriate compound of Formula (1) wherein Z is CRgRgOH. Using similar procedures but with the appropriate metal salt of SR14 or SR15, compounds of Formula (I) wherein Z is CR8R8SR14 or CR8R8SR1 may be prepared.

Compounds of Formula (2) may be prepared in turn by the processes described in copending application USSN 07/862,083 filed 2 April 1992.

The following examples are provided to illustrate how to make and use this invention.

These examples are not intended to and should not be viewed as limiting the scope or practice of this invention in any way.

SYNTHETIC EXAMPLES EXAMPLE 1 4-Cvano4-(3-cvcloDentvloxv-4-methoxvDhen i-one (Intermediate of the Formula 2) la [3-Cyclopentyloxy-4-methoxyphenyl)acetonitrile To a solution of 3-cyclopentyloxy4-methoxybenzaldehyde (20 g, 90.8 mmol) in acetonitrile (100 mL) was added lithium bromide (15 g, 173 mmol) followed by the dropwise addition of trimethylsilyichloride (17.4 mL, 137 mmol). After 15 min, the reaction mixture was cooled to OOC, 1,1,3,3tetramethyldisiloxane (26.7 mL, 151 mmol) was added dropwise and the resulting mixture was allowed to warm to room temperature. After stirring for 3h, the mixture was separated into two layers. The lower layer was removed, diluted with methylene chloride and filtered through Celite.

The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and refiltered. The solvent was removed in vacuo to provide a light tan oil. To a solution of this crude a-bromo-3-cyclopentyloxy-4-methoxytoluene in dimethylformarnide (160 mL) under an argon atmosphere was added sodium cyanide (10.1 g, 206 mmol) and the resulting mixture was stirred at room temperature for 18h, then poured into cold water (600 mL) and extracted three times with ether. The organic extract was washed three times with water, once with brine and was dried (potassium carbonate).

The solvent was removed in vaciw and the residue was purified by flash chromatography, eluting with 10% ethyl acetate/hexanes, to provide an off-white solid (17.7 g, 84%): m.p. 32-340C; an additional quantity (1.3 g) of slightly impure material also was isolated.

1b. Dimethyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate To a solution of (3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (7 g, 30.3 mmol) in acetonitrile (200 mL) under an argon atmosphere was added a 40% solution of Triton-B in methanol (1.4 mL, 3.03 mmol) and the mixture was heated to reflux. Methyl acrylate (27 mL, 303 mmol) was added carefully, the reaction mixture was maintained at reflux for 5h and then cooled. The mixture was diluted with ether, was washed once with IN hydrochloric acid and once with brine, was dried (magnesium sulfate) and the solvent was removed in vacuo. The solid residue was triturated with 5% ethanol/hexane to provide a white solid (9 g, 74%): m.p. 81-820C; and additional 1.1 g (9%) was also obtained from the filtrate.

Analysis Calc. for C22H29NO6: C 65.49, H 7.25, N 3.47; found: C 65.47, H 7.11, N 3.49.

1c. 2-Carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one To a solution of dimethyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate (5.9 g, 14.6 mmol) in dry 1,2-dimethoxyethane (120 mL) under an argon atmosphere was added sodium hydride (80% suspension in mineral oil, 1.05 g, 43.8 mmol). The mixture was heated to reflux for 4.5h, then was cooled to room temperature and was stirred for 16h. Water was added and the reaction mixture was partitioned between ether and acidic water The organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, to provide a white foam (4.9 g, 93%).

Analysis Calc. for C1gH23No3-lI4H2o: C 67.09, H 6.84, N 3.72; found: C 66.92, H 6.61, N 3.74.

id.4Cvano-4(3-cvdopentvloxv-4methoxvphenvlcvclohexan- 1-one A mixture of 2 carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- i-one (0.80 g, 2.15 mmol), dimethyl sulfoxide (16 mL), water (1 mL) and sodium chloride (0.8 g) under an argon atmosphere was heated at 140-1450C for 5h. The reaction mixture was cooled and concentrated. The residue was purified by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, to provide a yellow solid. Trituration with hexanes/ethyl acetate yielded a white solid (0.52 g, 77%): m.p. 111-1120C.

Analysis Calc. for C1gH23NO3: C 72.82, H 7.40, N 4.47; found: C 72.72, H 7.39, N 4.48.

EXAMPLE 2 Methyl 2-[4-cyano-4-(3-cyclpropylmethoxy-4-methoxyphenyl)cyclohexan-1-yl]acetate 3a. Methyl 4-cyano-4-(3-cyclpropylmethoxy-4-methoxyphenyl)cyclohexan-1-ylidene acetate A solution of methydiethylphosphonate (1.2 mL, 6.68 mmol) in ethylene glycol dimethyl ether (10 mL) was treated with solid sodium hydride (0.22 g, 7.3 mmol, 80% dispersion in mineral oil) at room temperature under an argon atmosphere. After stirring for 1.5h, a solution of 4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexanone (1.0 g, 3.34 mmol) was added and the mixture was allowed to stir for an additional 3h. The reaction mixture was partitioned between methylene chloride and water, was extracted twice, was dried (potassium carbonate) and was evaporated to an oil.

Purification by flash column chromatography, eluting with 2:1 hexanes/ethyl acetate, provided an oil (0.48 g, 40%).

Analysis Calc. for C21H25NO41/8 H2O: C 70.51, H 7.12, N 3.92; found: C 70.36, H 7.01, N 3.89.

3 b. Methvl 2-l4cvano-4 (3-cvdpropvlmethoxvmethoxvphenvl)cvclohexan- 1- vllacetate A solution of methyl 4-cyano-4-(3-cyclpropylmethoxy4-methoxyphenyl)cyclohexan-1-ylidine acetate (0.19 g, 0.52 mmol) in methanol (10 mL) was hydrogenated with 10% palladium on carbon at 50 psi for 3h. The reaction mixture was filtered through Celite, was washed with methylene chloride and was evaporated.

Purification by flash column chromatography, eluting with 3:1 hexanes/ethyl acetate, provided an oil (0.16 g, 86%).

Analysis Calc. for C21H27No4: C 70.56, H 7.61, N 3.92; found: C 70.49, H 7.65, N 3.88.

EXAMPLE 3 cis- f4-Cvano-4- (3-cvclopropv1methoxv4-methoxvphenvlcvclohexan- 1 -vll meth anol A suspension of methyl 2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyi)cyclohexan- l-yl]acetate (0.18 g, 0.52 mmol) in ether (2.0 mL) with methanol (0.025 mL) and lithium borohydride (0.02 g, 0.78 mmol) was stirred overnight at room temperature under an argon atmosphere. The reaction mixture was partitioned between methylene chloride and acidic water, was extracted three times, was dried (magnesium sulfate) and was evaporated. Purification by flash column chromatography, eluting with 1:1 hexanes/ethyl acetate, provided a white solid (0.1 g, 58.5%): m.p. 119-1200C.

Analysis Calc. for C1gH2sNO3: C 72.35, H 7.99, N 4.44; found: C 71.96, H 7.90, N 4.33.

EXAMPLE 4 cis-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-yl]methylamine A solution of cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan- 1-yl]methanol (0.05 g, 0.16 mmol) in tetrahydrofuran (1.2 mL) under an argon atmosphere was treated with triphenylphosphine (0.04 g, 0.16 mmol), phthalimide (0.02 g, 0.16 mmol) and then diethylazodicarboxylate (0.03 mL, 0.16 mmol) was added dropwise. The reaction flask was covered with foil and the mixture was stirred at room temperature for 30h. The solvent was evaporated and the residue was purified by flash column chromatography, eluting with 2:1 hexanes/ethyl acetate, to provide the phthalimide (0.06 g, 89.7%), which was dissolved in ethanol (0.5 mL) under an argon atmosphere and refluxed with hydrazine hydrate (0.08 mL, 0.15 mmol) for 3h.

The reaction was cooled, the precipitate was removed by filtration, the filtrate was applied to a silica column and the product was eluted with 95:5 chloroform/methanol to provide an oil (0.3 g, 60%).

Analysis Calc. for C1gH26N2o3 1/4 H2O: C 71.55, H 8.37, N 8.78; found: C 71.47, H 8.21, N 8.67.

EXAMPLE 5 cis- & vano-4-(3-cyclopropvlmethoxv-4-methoxyphenvl)cvClohexan- 1 -vllmethvleneoxide To a mixture of 80% sodium hydride in mineral oil (0.06 g, 2.00 mmol) and trimethylsulfonium iodide (0.41g, 2.00 mmol) at room temperature under an argon atmosphere was added dropwise dimethylsulfoxide (4 mL) and the reaction mixture was stirred for 0.5h. A solution of 4-cyano-4-(3-cyclopropylmethoxy-4methoxyphenyl)cyclohexan-1-one (0.50 g, 1.67 mmol) in dimethylsulfoxide (2 mL) was added and stirring was continued for 45 min. The reaction mixture was quenched with saturated ammonium chloride, was partitioned between ethyl acetate and water, was dried (magnesium sulfate) and the solvent was removed in vacuo.

The residue was purified by flash chromatography, eluting with 3:7 ethyl acetate/hexanes, to provide a white solid (0.28 g, 53%): m.p. 90-910C.

Analysis Calc. for ClgH23NO3 1/4 H2O: C 71.79, H 7.45, N 4A1; found: C 71.97, H 7.33, N4.36.

A small amount of the trans-isomer (0.09 g, 17%) was also isolated.

EXAMPLE 6 cis- r4-Cvano-4-(3-cvclopropvlmethoxv-4-methoxvphenvl)- 1 -hvdroxvcvclohexan- 1 vllmethanol A mixture of cis- [4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan- 1 - yl]methyleneoxide (0.14 g, 0.45 mmol) and potassium hydroxide (0.02 g, 0.36 mmol) in 85:15 dimethylsulfoxide/water (14 mL) under an argon atmosphere was heated at 100-110oC for 1.5h, was cooled, was diluted with water and was extracted three times with ethyl acetate.

The organic extract was washed four times with water, once with brine, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2% methanoUdichloromethane, provided the cis-isomer as a white solid (0.09 g, 60%): m.p.

48-500C.

Analysis Calc. for C1gH2NO4-l/8 H2O: C 68.39, H 7.63, N 4.20; found: C 68.23, H 7.59, N 4.13.

EXAMPLE 7 trans-r4-Cvano-4-(3-cvclopropvlmethoxv-4-methoxvphenvl)- 1 -cvclohexan- lr vllmethvleneoxide To a mixture of 80% sodium hydride in mineral oil (0.33 g, 11 mmol) and trimethylsulfoxonium iodide (1.69 g, 7.67 mmol) at room temperature under an argon atmosphere was added dropwise dimethylsulfoxide (12 mL) and the reaction mixture was stirred for 30 min. A solution of 4-cyano-4- (3-cyclopropylmethoxy-3-methoxyphenyl) -cyclohexan-1-one (2.00 g, 6.68 mmol) in dimethylsulfoxide (5 mL) was added and stirring was continued for 30 min. The reaction mixture was quenched with saturated ammonium chloride, was partitioned between ethyl acetate and water, was dried (magnesium sulfate) and the solvent was removed in vacuo.

The residue was purified by flash chromatography, eluting with 1:3 ethyl acetate/hexanes, to provide a colorless oil (1.42 g, 68%).

Analysis Calc. for C19H23NO3-H20: C 68.86, H 7.30, N 4.23; found: C 69.22, H 7.11, N 4.17. Starting material was also recovered (0.6 g, 30%).

EXAMPLE 8 trans-r4-Cvano-4-(3-cvclopropvlmethoxv-4-methoxvphenvl)- 1 -hvdroxvcvclohexan- 1? vllmethanol A mixture of trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl) -cyclohexan-l-yl]methyleneoxide (1.31 g, 4.18 mmol) and potassium hydroxide (0.14 g, 2.5 mmol) in 85:15 dimethylsulfoxide/water (140 mL) under an argon atmosphere was heated at 100-1 100C for lh, was cooled, was diluted with water and was extracted three times with ethyl acetate. The organic extract was washed five times with water, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3.5:96.5 methanoudichloromethane, provided the trans-isomer as a sticky white solid: m.p. 38420C (0.96 g, 69%).

Analysis Calc. for ClgH25N04: C 68.86, H 7.60, N 4.23; found: C 68.96, H 7.62, N 4.03.

METHODS OF TREATMENT In order to use a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be used neat though a preferred technique is to present them with a carrier/diluent accordance with standard pharmaceutical practice. Any formulation compatible with the chosen method of delivery and the stafility of the compound may be used. One skilled in the art will be able to select and prepare an acceptable formulation in accordance with standard practices in the field of the formulary arts.

The compounds of Formula Q or may be administered orally (when active by this route), oral, intravenous, intraperitoneal, and intramuscular administration, topically, parenterally, or by inhalation in conventional dosage forms prepared by combining such agent with standard pharmaceutical carriers according to conventionaI procedures in an amount sufficient to produce the desired therapeutic activity.

The amount of a compound of Formula (I) required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the condition and the animal undergoing treatment, and is ultimately at the discretion of the physician.

The daily dosage regimen for oral administration is suitably about .001 mg/kg to 100mg/kg, preferably 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit activity.

UTILITY EXAMPLES EXAMPLE A Inhibitorv effect of compounds of Formula (I) on in vitro TNF production bv human monocvtes The inhibitory effect of compounds of Formula (I) on in vitro TNF production by human monocytes may be determined by the protocol as described in Badger et al., EPO published Application 0 411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990.

EXAMPLE B Two models of endotoxic shock have been utilized to determine in vivo TNF activity for the compounds of Formula (I). The protocol used in these models is described in Badger et al., EPO published Application 0 411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December27, 1990.

The exemplified compounds herein demonstrated a positive in vivo response in reducing serum levels of TNF induced by the injection of endotoxin.

EXAMPLE C Isolation of PDE Isozymes The phosphodiesterase inhibitory activity and selectivity of the compounds of Formula (I) can be determined using a battery of five distinct PDE isozymes. The tissues used as sources of the different isozymes are as follows: 1) PDE Ib, porcine aorta; 2) PDE Ic, guinea-pig heart; 3) PDE III, guinea-pig heart; 4) PDE IV, human monocyte; and 5) PDE V (also called "Ia"), canine trachealis. PDEs Ia, Ib, Ic and III are partially purified using standard chromatographic techniques [Torphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE IV is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-Sepharose chromatography [Torphy et al., J. Biol. Chem., 267:17981804, 1992].

Phosphodiesterase activity is assayed as described in the protocol of Torphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Positive IC50's in the nanomolar to CLM range for compounds of the workings examples described herein for Formula (I) have been demonstrated.

EXAMPLE D The ability of selected PDE IV inhibitors to increase cAMP accumulation in intact tissues is assessed using U-937 cells, a human monocyte cell line that has been shown to contain a large amount of PDE IV. To assess the activity of PDE IV inhibition in intact cells, nondifferentiated U-937 cells (approximately 105 cells/reaction tube) were incubated with various concentrations (0.01-1000 RM) of PDE inhibitors for one minute and 1M prostaglandin E2 for an additional four minutes. Five minutes after initiating the reaction, cells were lysed by the addition of 17.5% perchloric acid, the pH was neutralized by the addition of 1M potassium carbonate and cAMP content was assessed by RIA. A general protocol for this assay is described in Brooker et al., Radioimmunassay of cyclic AMP and cyclic GMP., Adv.

Cyclic Nucleotide Res., 10:1-33, 1979. The compounds of the working examples as described herein for Formula (I) have demonstrated a positive ECsos in the RM range in the above assay.

No toxic effects are expected when these compounds are administered in accordance with the present invention.