Related Compounds

Field of Invention

The present invention relates to novel 4,4-(disubstituted)cyclohexan-l-ylidine acetate monomers and related 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 c AMP 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 Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. HBC 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.

ADDS 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-cell- 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 related 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 level 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, 162:21 1-214,1990].

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. Summary of the Invention

The novel compounds of this invention are represented by Formula (I):

wherein:

R! is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5) _m R6, or -(CR4R5) _r R6 wherein the alkyl moieties unsubstituted or substituted with one or more halogens;

m is 0 to 2; n is 0 to 4; r is 0 to 6;

R4 and R5 are independently selected hydrogen or -2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC 1-3 alkyl, halo substituted aryloxyC 1.3 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 or heterocyclic moiety is unsubstituted or substituted by 1 to 3 methyl groups, one ethyl group, or an hydroxyl 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 R 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 Rό is other than H in -(CR4R5)nO(CR4R5)mR6;

X is YR2, fluorine, NR4R5, or formyl amine; Y is O or S(O)nϊ; m' is O, l, or 2; X2 is O or NRδ; X3 is hydrogen or X;

X4 is H, R9, OR8, CN, C(O)R8, C(O)ORg, C(O)NRgR8, or NRgRδ; R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4; W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;

R ₃ is COOR14, C(O)NR4Ri4 or R7;

Z is C(-CN)2, CR14CN, CRi4C(O)OR8, CRi4C(O)NRsRl4, C(-CN)NO2, C(-CN)C(O)OR9, C(-CN)OC(O)R9, C(-CN)OR9, or C(-CN)C(O)NRsRl4; Y' is O or S;

R7 is -(CR4R5)qRi2 or C\. alkyl wherein the R12 or C .^ alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, -F, -Br, -Cl, -NO2, -NRjo l 1» -C(O)Rs, -CO2R8,

-O(CH ₂ ) _q R8. -CN, -C(O)NRiθRl 1, -O(CH ₂ ) _q C(O)NRiθRl 1, -O(CH ₂ ) _q C(O)R9, -NRiθC(O)NRιoRl l, -NRιoC(O)Rn, -NRιoC(O)OR9, -NRioC(O)Ri3, -C(NRio)NRiθRl 1, -C(NCN)NRιoRl 1, -C(NCN)SR9, -NRιoC(NCN)SR9 , -NRioC(NCN)NRioRl l, -NRιoS(O)2R9, -S(O) _m 'R9, -NRιoC(O)C(O)NRιoRl l, - NRιoC(O)C(O)Rio, or R ₁₃ ; q is O, 1, or 2;

Rl2 is R _j 3, C3-C7 cycloalkyl, or an unsubstituted or substituted aryl or heteroaryl group selected from the group consisting of (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, and phenyl;

Rg is independently selected from hydrogen or R9; R9 is Cj_4 alkyl optionally substituted by one to three fluorines; RiO is ORδ or Rn ;

R\ 1 is hydrogen, or C 1.4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Ri 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S;

R 13 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and where Ro is substituted on R _i2 or R ₎₃ the rings are connected through a carbon atom and each second R| ₃ ring may be unsubstituted or substituted by one or two Cι_2 alkyl groups unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms;

Rl4 is hydrogen or R7; or when Rβ and R 14 are as NR8R14 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S; provided that:

(f) R7 is not Cj_4 alkyl unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof. 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).

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

Detailed Description of the Invention

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 and central nervous system disorders such as depression and multi-infarct dementia.

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 (I). 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 this invention 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 this invention are also useful in treating 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 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.

The term "Cj.3 alkyl", "Cι_ ₄ alkyl", "Cj.6 alkyl" or "alkyl" groups as used herein is meant to 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.

"Alkenyl" means both straight or branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl, 1- propenyl, 2-propenyl, 2-propynyl, or 3-methyl-2-propenyl. The term "cycloalkyl" or "cycloalkyl alkyl" means groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl.

"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 all halogens, i.e., chloro, fluoro, bromo, or iodo.

"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.

The phrase "TNF mediated disease or disease states" means 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 secreted in response to TNF, would therefore be considered a disease state mediated by TNF. As TNF-β (also known as lymphotoxin) has close structural homology with TNF-oc (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-α and TNF-β are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF" unless specifically delineated otherwise. Preferably TNF-α 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.

The cytokine inhibited by the present invention for use in the treatment of a HIV-infected 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-α.

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.

Preferred compounds are as follows: When R 1 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 Ci-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 Ri substitutents for the compounds of Formula (I) are CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, C7.11 polycycloalkyl, 3- or 4-cyclopentenyl, 3-hydroxycyclopentyl, phenyl, tetrahydrofuran-3-yl, benzyl or Ci-2 alkyl unsubstituted or substituted by 1 or more fluorines, -(CH2)1-3C(O)O(CH2)0-2CH3, -(CH2)l-3θ(CH2)0-2CH3, and -(CH2)2-4OH. When the Ri term is (CR4R5), the R4 and R5 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 unsubstituted or be substituted by fluorine independent of each other to yield, for instance, the preferred Ri substitutions, as noted above.

When Ri is a C7-1 1 polycycloalkyl, examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0 ' 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.

Preferred Z terms are C(-CN)2, CRi4C(O)OR8, CRi4C(O)NR8Rl4, C(-CN)C(O)OR9, C(-CN)OC(O)R9, C(-CN)OR9, or C(-CN)C(O)NRδRl4 _;

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 Ci-2 alkyl unsubstituted or 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 -2 alkyl, such as a -CF3, -CHF2, or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.

Preferred R7 moieties include unsubstituted or substituted -(CH2)0-2(2-, 3- or 4-pyridyl), (CH2)l-2(2-imid___olyl), (CH2)2(4-morpholinyl), (CH2)2(4-piρerazinyl),

(CH2)l-2(2-thienyl), (CH2)l-2(4-thiazolyl), unsubstituted or substituted pyrimidinyl, and substituted or unsubstituted (CH2)0-2phenyl.

Preferred rings when Rio and Rl 1 in the moiety -NRioRl 1 together with the nitrogen to which they are attached form a 5 to 7 membered ring unsubstituted or containing at least one additional heteroatom selected from O, N, or S include, but are not limited to 1 -imidazolyl, 2-(Rs)-l -imidazolyl, 1 -pyrazolyl, 3-(R8)- 1 -pyrazolyl, 1- triazolyl, 2-triazolyl, 5-(R8)-l-triazolyl, 5-(R8)-2-triazolyl, 5-(R8)-l-tetrazolyl, 5-(R8)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, mo holinyl, piperazinyl, 4-(R8)-l- piperazinyl, or pyrrolyl ring. Preferred rings when Rs and R14 in the moiety -NR8R14 together with the nitrogen to which they are attached may form a 5 to 7 membered ring unsubstituted or containing at least one additional heteroatom selected from O, N, or S include, but are not limited to 1 -imidazolyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, moφholinyl, 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 is not limited to, 2-(R7)-l -imidazolyl, 4-(R7)-l -imidazolyl, 5-(R7)-l -imidazolyl, 3-(R7)-l -pyrazolyl, 4-(R7)-l -pyrazolyl, 5-(R7)-l -pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-l-triazolyl, 5-(R7)-l-triazolyl, 5-(R7)-l-tetrazolyl, and 5-(R7)-2-tetrazolyl. Applicable nitrogen substitution by R7 includes, but is not limited to, l-(R7)-2-tetrazolyl, 2-(R7)-l-tetrazolyl, 4-(R7)-l- piperazinyl. Where applicable, the ring may be substituted one or more times by R7.

Preferred groups for NRsRl4 which contain a heterocyclic ring are 5-(Ri4)-l- tetrazolyl, 2-(Rι 4)- 1 -imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(Ri 4)- 1 -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 5-isoxazolyl), (3- or 5-oxadiazolyl[ 1,2,4]), (2-oxadiazolyl[ 1,3,4]), (2-thiadiazolyl[l,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 unsubstituted or substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, the heterocyclic ring itself may be unsubstituted or substituted by Rs either on an available nitrogen or carbon atom, such as l-(R8)-2-imidazolyl, 1 -(R8)-4-imidazolyl, l-(R8)-5-imidazolyl, l-(R8)-3-pyrazolyl, l-(R8)-4-pyrazolyl, l-(R8)-5-pyrazolyl, l-(R8)-4-triazolyl, or l-(R8)-5-triazolyl. Where applicable, the ring may be substituted one or more times by

R8-

Preferred are those compounds of Formula (I) wherein R\ is -CH2- cyclopropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl unsubstituted or substituted by

OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -Ci-2 alkyl unsubstituted or substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluoro- substituted alkyl, W is ethynyl or 1,3-butadiynyl; R ₃ is R ₇ where R ₇ is an unsubstituted or substituted aryl or heteroaryl ring, X is YR2, and Z is CRi4C(O)OR8- Most preferred are those compounds wherein Ri is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl, W is ethynyl or 1,3-butadiynyl, and R3 is a substituted or unsubstituted pyrimidinyl ring.

Pharmaceutically acceptable salts of the instant compounds, where they can be prepared, are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases. Pharmaceutically acceptable salts are prepared in a standard manner.

The parent compound, dissolved in a suitable solvent, is treated with an excess of an organic or inorganic acid, in the case of acid addition salts of a base, or an excess of organic or inorganic base where the molecule contains a COOH for example. Pharmaceutical compositions of the present invention comprise a pharmaceutical carrier or diluent and some amount of a compound of the formula (I). The compound may be present in an amount to effect a physiological response, or it may be present in a lesser amount such that the user will need to take two or more units of the composition to effect the treatment intended. These compositions may be made up as a solid, liquid or in a gaseous form. Or one of these three forms may be transformed to another at the time of being administered such as when a solid is delivered by aerosol means, or when a liquid is delivered as a spray or aerosol.

The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.

For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, aerosols, and drops suitable for administration to the skin, eye, ear, 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, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.

When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or diluent, the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.

The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product. In these compositions, the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient.

Usually a compound of formula I is administered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor. Topical formulations will contain between about 0.01 to 5.0% by weight of the active ingredient and will be applied as required as a preventative or curative agent to the affected area. When employed as an oral, or other ingested or injected regimen, the dosage of the composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration. For convenience, equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 50 mg to about 5000 mg.

No unacceptable toxicological effects are expected when these compounds are administered in accordance with the present invention. Methods Of Preparation Synthetic Schemes

Compounds of Formula (I) may be prepared by the processes disclosed herein which comprise reacting a terminal acetylene, wherein Z represents Z as defined in relation to Formula (I) or a group convertible to Z, as, e.g., compound 1 -Scheme 1. with an appropriate halide, R3X, wherein 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(I) halide and a bivalent or zerovalent palladium compound in the presence of, e.g., triphenylphosphine, in a suitable solvent, such as an amine, as in the procedure of

Brandsma et al. (Syn. Comm., 1990, 20, 1889), provides a compound of the Formula 2-Scheme 1. Compounds of the Formula 1 -Scheme 1 may be prepared by procedures analogous to those described in prior filed co-pending U.S. applications 07/862,083, 07/968,753 and PCT/US93/01990 designating the United States and filed 05 March 1993 (WIPO publication No. WO 93/19748) or PCT application PCT/US93/02325 published as WO 93/19750.

Scheme 1

a) Pd(PhP3)4, PPh3, Cul, R3X, piperidine

Alternatively, compounds of the Formula (I), wherein Zand R3 represent Zand R3 as defined in relation to Formula (I) or a group convertible to Z or R3, may be prepared from the corresponding ketones as, e.g., compound 1 -Scheme 2. by the synthetic procedures described in above referenced PCT application PCT/US93/01990; syntheses of such ketone starting materials are described in that same application.

Scheme 2

Alternatively, oxidative carbonylation of a terminal acetylene as, e.g., compound 1 -Scheme 3. using an appropriate metal salt, such as a copper salt with a catalytic amount of a palladium salt, in the presence of a suitable base as an acid trap, such as sodium acetate, in a suitable alcohol, such as methanol, as in the method of Tsuji et al. (Tet. Lett., 1980, 21, 849), then provides the compound of the Formula 2- Scheme 3: such compounds may then be converted to compounds of the Formula (I)

by manipulation of the ketone as described above and by independent manipulation of the carboxylic ester moiety using standard transesterification or amidation conditions.

Scheme 3

a.b

rrxϊ. C ^' rOOCH ₃

J_

a) PdCI ₂ , CuCI ₂ , NaO ₂ CCH ₃ , CO, CH ₃ OH; as inScheme 2

Preparation of the remaining compounds of the Formula (I) may be accomplished by procedures analogous to those described above and in the Examples, infra.

It will be recognized that some compounds of the Formula (I) may exist in distinct diastereomeric forms possessing distinct physical and biological properties; such isomers may be separated by standard chromatographic methods.

The following examples are given to further illustrate the described invention. These examples are intented solely for illustrating the invention and should not be read to limit the invention in any manner. Reference is made to the claims for what is reserved to the inventors hereunder.

Examples

Example 1 Preparation of [4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- pyridylethynyDcyclohexan- 1 -ylidinelmalononitrile

A mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- pyridylethynyl)cyclohexan-l-one (0.125 g, 0.32 mmol, prepared by the procedures described in a co-pending U.S. patent application filed on even date herewith and identified as P50283) and malononitrile (0.042 g, 0.64 mmol) is heated to 110°C. To this melt is added water (2 mL) containing a trace of β-alanine and heating is continued for an additional 3 h. The mixture is cooled, is partitioned between water and ethyl acetate, is extracted twice with ethyl acetate, the organic extract is dried (potassium

carbonate) and the solvent is removed in vacuo. Purification by flash chromatography provides the title compound.

Example 2 Preparation of methyl .4-f 3-cyclopentyloxy-4-methoxyphenyl)-4-(4- pyridylethynyl .cyclohexan- 1 -ylidinelacetate A solution of methy diethylphosphonoacetate (1.2 mL, 6.68 mmol) in ethylene glycol dimethyl ether (10 mL) is 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-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4- pyridylethynyl)cyclohexan-l-one (1.3 g, 3.34 mmol) is added and the mixture is allowed to stir for an additional 3 h. The reaction mixture is partitioned between methylene chloride and water, is extracted twice, is dried (potassium carbonate) and is evaporated. Purification by flash column chromatography provides the title compound.

Similarly the other compounds of Formula I can be prepared by proceeding in a similar manner as described above by simply substituting for the intermediates named in Examples 1 and 2, the other appropriate intermediates needed to make the other compounds of Formula I.

UTILITY EXAMPLES

EXAMPLE A Inhibitory effect of compounds of Formula (I) on in vitro TNF production by human monocytes 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 041 1 754 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 0411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990.

The compound of Example 1 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 lb, 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 "la"), canine trachealis. PDEs la, lb, Ic and III are partially purified using standard chromatographic techniques [Toφhy 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 [Toφhy et al, J. Biol. Chem., 267: 1798-1804, 1992]. Phosphodiesterase activity is assayed as described in the protocol of Toφhy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Positive ICso's in the nanomolar to μM range for compounds of the workings examples described herein for Formula (I) have been demonstrated.