EP0796092A1

EP0796092A1 - 3,3-(disubstituted)cyclohexan-1-one dimers and related compounds

Info

Publication number: EP0796092A1
Application number: EP95943940A
Authority: EP
Inventors: Siegfried B. Christensen, Iv; Joseph M. Karpinski
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 1994-12-23
Filing date: 1995-12-21
Publication date: 1997-09-24
Also published as: JPH10511657A; EP0796092A4; WO1996019980A1

Abstract

This invention relates to certain dimers of phenylcyclohexan-3-ones which are useful for treating allergic and inflammatory diseases, among other diseases.

Description

3 -(Disubstituted)cyclohexan-l-one Dimers and Related Compounds

Field of Invention

The present invention relates to novel dimers of certain 3,3- (disubstituted)cyclohexan-l-ones 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 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 Anti-asthmatic 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, HTV-2 and HTV-3. As a consequence of HTV 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 HTV, the T lymphocyte must continue to be maintained in an activated state to permit HTV gene expression and or HTV replication.

Cytokines, specifically TNF, are implicated in activated T-cell-mediated HTV 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 HTV 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 HTV Infection, Advances in Immunology, Vol. 57, 1989]. Monokines, such as TNF, have been shown to activate HTV replication in monocytes and/or macrophages [See Poli et al, Proc. Nad. Acad. Sci., 87:782-784, 1990], therefore, inhibition of monokine production or activity aids in limiting HTV 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 die excessive and/or unregulated production of TNF.

Summary of the Invention Certain novel compounds of this invention are represented by Formula (I):

CI7US95/16708

wherein:

Rl is independendy -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4RR4R5)mR6, or -(CR4R5)rR6 wherein the alkyl moieties may be unsubstituted or substituted with one or more fluorines; m is 0 to 2; n is 0 to 4; r is 0 to 6;

R4 and R5 are independently selected hydrogen or C 1-2 alkyl; R6 is independendy hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCl-3 alkyl, halo substituted aryloxyCl-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 may be unsubstituted or substituted by 1 to 3 methyl groups, an ethyl group, or an hydroxyl group; provided tiiat: a) when R6 is hydroxyl, U en 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-tetrahydropyτanyl, 2-tetrahydrotiιiopyranyl, 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 -(CR4R5)_nO(CR4R5)mR6; W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;

X is independendy YR2, fluorine, NR4R5, or formyl amine;

Y is independendy O or S(O)m'; m' is 0, 1, or 2;

X2 is independendy O or NR8;

X3 is independendy hydrogen or X;

R2 is independendy selected from -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more fluorines; s is 0 to 4;

Z is independendy O, NR7, NCR4R5C2-6 alkenyl, NOR 14, NOR 15, NOCR4R5C2-6 alkenyl, NNR4R14, NNR4R15, NCN, NNRsC(O)NR8Rl4, NNR8C(S)NR8Rl4, C(-CN)2, CR14CN, CRl4C(O)OR8, CRi4C(O)NRsRl4, C(-CN)NO2, C(-CN)C(O)OR9, C(-CN)OC(O)R9, C(-CN)OR9, C(-CN)C(O)NRsRl4, or =Z is 2-( 1 ,3-dithiane), 2-( 1 ,3-dithiolane), dimediyldiio ketal, diethylduo ketal, 2-( 1 ,3- dioxolane), 2(l,3-dioxane), 2-(l,3-oxathiolane), dimethyl ketal or diethyl ketal;

R7 is independendy -(CR4R5)qRl2 or C 1. alkyl wherein the R 12 or C ι_g 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, -NRJQRI 1, -C(O)R8, -CO2R8, -O(CH₂)_qR8, -CN, -C(O)NRi()Rl 1. -O(CH₂)_qC(O)NRιoRl 1, -O(CH₂)_qC(O)R9, -NRiθC(0)NRiθRn, -NRiθC(O)Rπ, -NRlθC(O)OR9, -NRi0C(O)Ri3, -C(NRlO)NRioRl 1, -C(NCN)NRιoRl 1, -C(NCN)SR9, -NRi()C(NCN)SR9 , -NRiθC(NCN)NRιoRl l, -NRιoS(O)2R9, -S(O)_m'R9, -NRiθC(O)C(O)NRι₀Rl l, - NRiθC(O)C(O)Rlθ, or R₁₃; q is 0, 1, or 2;

Rl2 is independendy R13, C3-C7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, mo holinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl;

R is independendy selected from hydrogen or R9; R9 is independendy Cj_4 alkyl unsubstituted or substituted by one to tiiree fluorines;

RjO is independendy OR8 or Ri 1;

R\ 1 is independently hydrogen, or C 1.4 alkyl unsubstituted or substituted by one to tiiree fluorines; or when Rio and Ri 1 are as NR10R11 they may together with the nitrogen form a 5 to 7 membered ring unsubstituted comprised of carbon or carbon and at least one heteroatom selected from O, N, or S; Rl3 is independendy oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or diiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two Cι_2 alkyl groups;

Rj4 is independendy hydrogen or R7; or when Re 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 at least one heteroatoms selected from O, N, or S;

Rl5 is independendy C(O)Ri4, C(O)NR4Rl4, S(O)2R7, or S(O)2NR4Rl4; or the pharmaceutically acceptable salts thereof.

Another set of compounds of this invention are represented by Formula (II):

wherein:

Rl is independendy -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)mR6, or -(CR4R5)r 6 wherein the alkyl moieties may be unsubstituted or substituted with one or more fluorines; m is 0 to 2; n is 0 to 4; r is 0 to 6; R4 and R5 are independendy selected hydrogen or C 1-2 alkyl;

R6 is independendy hydrogen, mediyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCl-3 alkyl, indanyl, indenyl, C7-H polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloallcyl containing one or two unsaturated bonds, wherein die cycloalkyl and heterocyclic moieties may be 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 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, tiien R6 is odier than H in -(CR4R5)nO(CR4R5)mR6;

X is independendy YR2, fluorine, NR4R5, or formyl amine; Y is independendy O or S(O)m'; m' is O, l, or 2;

X2 is independently O or NR8; X3 is independendy hydrogen or X;

W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;

Z' is independendy COOR14, C(O)ORi4, C(Y^*)NRιoRl4, C(NRιo)NRi()Rl4, CN, C(NOR8)Rl4, C(O)NRsNR8C(O)R8, C(O)NRsNRιoRl4, C(NORi4)R8, C(NR8)NRioRl4, C(NRi4)NRδR8 C(NCN)NRιoRl4, C(NCN)SR9, (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[l,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); wherein all of the heterocylic ring systems may be unsubstituted or substituted one or more times by R7; Y' is O or S; R7 is independendy -(CR4R5)_qR 12 or C 1 _g alkyl wherein the R 12 or C .5 alkyl group is unsubstituted or substituted one or more times by C 1-2 alkyl unsubstituted or substituted by one to three fluorines, -F, -Br, -Cl, -NO2, -Si(R4)3, -NRIQRI J, -C(O)R8, - CO2R8, -OR8, -CN, -C(O)NRiθRl 1, -OC(O)NRιoRl 1, -OC(O)Rs, -NRlθC(O)NRlθRl l, -NRlθC(O)Rπ, -NRiθC(O)OR9, -NRlθC(O)Ri3, -C(NRiθ)NRioRl 1, -C(NCN)NRiQRl 1, -C(NCN)SR9, -NRiθC(NCN)SR9 , -NRiθC(NCN)NRioRl l, -NRlθS(O)2R9, -S(0)ιrfR9. -NRιoC(O)C(O)NRiθRl l, -

NRiθC⁽O⁾C⁽O⁾RlO, Rl3; q is 0, 1, or 2;

Rl2 is independendy C3-7 cycloall yl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, moφholinyl, furanyl, (2- or 3-thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl; Rg is independendy selected from hydrogen or R9; R9 is independendy C .4 alkyl unsubstituted or substituted by one to three fluorines; R o is independendy OR8 or Ri 1;

Rl 1 is independendy hydrogen, or C 1-4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Rl 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from O, N, or S; R 13 is independendy 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 Cι_2 alkyl groups;

Rl4 is independendy hydrogen or R7; or when R8 and R14 are as NR8R14 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatoms selected from O, N, or S; 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 die enzymatic activity (or catalytic activity) of PDE TV 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 Q). 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 (HTV), 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 die enzymatic activity (or catalytic activity) of PDE IV in a mammal in need thereof and to inhibiting die 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 d e 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 indirecdy, by the TNF inhibitors of Formula (I). Such viruses include, but are not limited to HTV-1, HTV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and die Heφes 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 (HTV), 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 widi 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 (FTV) 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, d e 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 die 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 Ri 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), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-2 alkyl unsubstituted or substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2)0-2CH3, -(CH2) l-3θ(CH2)0-2CH3, and -(CH2)2-4OH.

When the Rl term is (CR4R5), the R4 and R5 terms are independendy 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 die 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 C7-11 polycycloalkyl, examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2. l]octyl, tricyclo[5.2.1.θ2.6]_cι_eCy _{t 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 O, NCN, NR7, NOR14, NOR15, NNR4R14, NNR4Rl5,C(CN)2, C(-CN)OC(O)R9, C(-CN)OR9, CRi4C(O)OR8, CR9C(O)NRi3Ri4, 2-(l,3-dithiane), dimediylthio ketal, 2-(l,3-dioxolane), or dimethyl ketal. More preferred are O, NR7, NORi4, NORi5, and 2-(l,3-dioxolane).

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

W is preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, and where it is alkenyl or alkynyl, that one or two double or triple bonds be present It is most preferred that W be 1,3-butadiynyl.

Z' is preferably O or NOR8-

Preferred R7 moieties include R13, unsubstituted or substituted -(CH2)l- 2(cyclσpropyl), -(CH2)0-2(cyclobutyl), -(CH2)0-2(cyclopentyl), -(CH2)0-2(cyclohexyl), -(CH2)0-2(2-, 3- or 4-pyridyl), (CH2) l-2(2-imidazolyl), (CH2)2(4-mσφholinyl),

(CH2)2(4-piperazinyl), (CH2)l-2(2-tlιienyl), (CH2)l-2(4-thiazolyl), and (CH2)0-2phenyl; aPreferred rings when Rio and Ri 1 in the moiety -NR10R11 together witii the nitrogen to which they are attached form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 2-(R8)-l-imidazolyl, 1-pyrazolyl, 3-(R8)-l -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, moφholinyl, piperazinyl, 4-(R8)-l -piperazinyl, or pyrrolyl ring. aPreferred rings when R8 and R14 in the moiety -NR8R14 together with the nitrogen to which they are attached may form a 5 to 7 membered ring comprised of carbon or carbon and at least one 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, cm 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)- 1 -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 NR8R 14 which contain a heterocyclic ring are 5-(R 14)- 1 - tetrazolyl, 2-(Ri4)-l-imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(Ri4)-l-piperazinyl, or

4-(R 15)- 1 -piperazinyl.

Preferred rings for R 13 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[l,3,4]),

(2-dύadiazolyl[ 1,3,4]), (2-, 4-, or 5-tiιiazolyl), (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 R8 either on an available nitrogen or carbon atom, such as l-(R8)-2-imidazolyl, l-(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) and (II) wherein Ri is -CH2- cyclopropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl unsubstituted or substituted with

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 metiiyl or fluoro-substituted alkyl and X is YR2.

Most preferred are those compounds wherein Ri is -CH2-cyclopropyl, -CH2-3- hydroxycyclopropyl, -CH2-3-hydroxycyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; W is 1,3- butadiynyl, and R2 is CF2H or methyl, and R3 is COOR14 or R7.

The compound specifically illustrated herein is l,4-bis-{ [3-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one]-3-yl}buta-l,3-diyne.It will be recognized tiiat some of the compounds of Formula (I) or (II) may exist in both racemic and optically active forms; some may also exist in distinct diastereomeric forms possessing distinct physical and biological properties. All of these compounds are considered to be within the scope of the present invention.

Compounds of Formula (I) where Z is O and Formula (II) may exist in a tautomeric form, such as the enol form. This may be represented by die =O being

or -

C(-OH =C(-R)- moiety wherein the cyclohexane ring is now unsaturated in the

recognized that the 2-position of die ring in the exocyclic form can be substituted (R) such as in the compounds of Formula (II). The term "C1.3 alkyl", "C1.4 alkyl", "Cι_6 alkyl" or "alkyl" groups as used herein is meant to include both straight or branched chain radicals of 1 to 10, unless die chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl, rerr-butyl, and the like.

"Alkenyl" means both straight or branched chain radicals of 1 to 6 carbon lengths, unless die 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 diienyl.

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

"Inhibiting die production of IL-1" or "inhibiting die 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, eidier 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-α (also known as cachectin), and since each induces similar biologic responses and binds to die same cellular receptor, bodi 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 HTV- 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 HTV 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 die 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 die enzymatic or catalytic activity of PDE IV and in treatment of disease states mediated thereby.

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 wdl retain the biological activity of d e 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 d e composition and the pharmaceutical carrier or diluent will, of course, depend upon die intended route of administration, for example parenterally, topically, orally or by inhalation.

For topical administration the pharmaceutical composition wdl 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 parafϊns 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 die pharmaceutical carrier or diluent die 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 die 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 die active ingredient. When the dduent 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 die symptoms of a disease in which leukotrienes are a factor. Topical formulations will contain between about 0.01 to 5.0% by weight of die active ingredient and will be applied as required as a preventative or curative agent to die affected area. When employed as an oral, or other ingested or injected regimen, the dosage of the composition is selected from die 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 Scheme(s) With Textual Description

Compounds of Formula (I), wherein W is a 1,3-butadiyne and wherein A and B represent Z as defined in relation to Formula (I) or a group convertible to Z, may be prepared by the processes disclosed herein which comprise, for example, coupling of a molecule of die Formula 1- Scheme 1 with a molecule of die Formula 2-Scheme 1 using an appropriate metal salt, such as cupric acetate, in a suitable solvent, such as DMF or pyridine, or a combination, such as pyridine/metiianol/water, as in the method of Eglington and Galbraith (J. Chem. Soα, 1959, 889), to provide a compound of die Formula __ Scheme 1. Intermediates of formulas 1- Scheme- 1 and 2-Scheme-2 are prepared as described in copending U.S. patent application 08/130215 filed 1 October 1993 .and incoφporated herein by reference and as also described in U.S. patent application identified 08/130213 filed 01 October 1993 and its progeny USSN 08/209039 filed 09 March 1994 and PCT application PCT/US94/10816 filed 23 September 1994 and a co¬ pending U.S. application denomiinated P50284 filed on even date herewith both of which have been assigned to a common assignee. Sch m 1

a) Cu(OAc )₂ ^«H₂0, DMF or C ₅H₅N

Reduction of a compound of the Formula (I), wherein W is a 1,3-butadiyne and wherein Z represents Z as defined in relation to Formula (I) or a group convertible to Z to a compound of die Formula (I) wherein W is a fully saturated hydrocarbon chain (i.e., n- butyl) may be accomplished using, e.g., palladium metal according to the method of Tedeschi (J. Org. Chem., 1962, 27, 2398), or, e.g., platinum oxide according to the metiiod of Jutz (Bex., 1958, 91, 1867) or that of Suzuki and Kurosawa (Chem. Lett., 1980, 1177). Reduction of a compound of die Formula (I), wherein W is a 1,3-butadiyne and wherein Z represents Z as defined in relation to Formula (I) or a group convertible to Z, to provide a compound of die Formula (I) wherein W is a 1,3-butadiene may be accomplished using, e.g., the hydroboration-protonolysis procedure of Zweifel and Polston (J. Am. Chem. Soc., 1970, 92, 4068), or, e.g., the hydroalumination-protonolysis procedure of Zweifel et al. (Synthesis, 1977, 52).

Depending upon die exact nature of the Z groups of the compounds of the Formula (I), the Z groups may require protection during the coupling and/or reductive steps described herein as, e.g., a compound of the Formula (I) wherein =Z is a dimethyl ketal or 2-(l,3-dioxolane), followed by deprotection and then reaction by the synthetic procedures described in in U.S. patent application identified 08/130213 filed 01 October 1993 and its progeny USSN 08/209039 filed 09 March 1994 and PCT application PCT/US94/10816 filed 23 September 1994 , to provide the Formula (I) compound; such protective groups are well known to those skilled in the art (See: Greene, T. and Wuts, P.G.M., Protecting Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons, New York, 1991.)

Compounds of Formula (II), wherein W is a 1,3-butadiyne and wherein Z' represents Z' as defined in relation to Formula (IT) or a group convertible to Z\ may be prepared by the processes disclosed herein which comprise, for example, coupling of a molecule of the Formula 1-Scheme 2 with a molecule of d e Formula 2-Scheme 2 using an appropriate metal salt, such as cupric acetate, in a suitable solvent, such as DMF or pyridine, or a combination, such as pyridine/methanol/water, as in the method of Eglington and Galbraith (J. Chem. Soc., 1959, 889), to provide a compound of die Formula __ Scheme 2. Compounds of formula l-Scheme-2 and 2-Scheme-2 are prepared by the methods recited in co-pending U.S. application 08/130,213 filed 1 October 1993 and a continuation of that case filed March 1994 and having USSN 08/209,039.

Schema 2

a) Cu(OAc )_*H₂0, DMF or C ₅H₅N Reduction of a compound of die Formula (II), wherein W is a 1,3-butadiyne to a compound of the Formula (II) wherein W is a fully saturated hydrocarbon chain (i.e., n- butyl) may be accomplished using, e.g., palladium metal according to the method of Tedeschi (J. Org. Chem., 1962, 27, 2398), or, e.g., platinum oxide according to die method of Jutz (Ber., 1958, 91, 1867) or that of Suzuki and Kurosawa (Chem. Lett., 1980, 1177). Reduction of a compound of die Formula (II), wherein W is a 1 ,3- butadiyne, to provide a compound of die Formula (II) wherein W is a 1,3-butadiene may be accomplished using, e.g., the hydroboration-protonolysis procedure of Zweifel and Polston (J. Am. Chem. Soc., 1970, 92, 4068), or, e.g., the hydroalumination-protonolysis procedure of Zweifel et al. (Synthesis, 1977, 52).

Depending upon die exact nature of the Z' groups of the compounds of the Formula (II), die =O group may require protection during die coupling and/or reductive steps described herein as, e.g., a compound of the Formula (II) wherein =O is a dimethyl ketal or 2-(l,3-dioxolane), followed by deprotection and then reaction by die synthetic procedures described in United States patent application 08/130213 filed 01 October 1993 and its progeny USSN 08/209039 filed 09 March 1994 to provide the Formula (II) compound; likewise, the Z' group may require protection during the coupling and/or reductive steps, followed by deprotection to provide the Formula (II) compound and such protective groups are well known to those skilled in die art (See: Greene, T. and Wuts, P.G.M., Protecting Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons, New York, 1991.)

Alternatively, compounds of die Formula (II), wherein W and Z' represent W and Z' as defined in relation to Formula (II) or a group convertible to W or Z', may be prepared from the corresponding ketones of the Formula (I) as, e.g., compound 1-Scheme 2, by the synthetic procedures described in United States patent application 08/130213 filed 01 October 1993 and its progeny USSN 08209039 filed 09 March 1994.

Scheme 3

Preparation of the remaining compounds of the Formulas (I) and (II) may be accomplished by procedures analogous to those described above and in the Examples, infra. It will be recognized that compounds of die Formulas (I) and (II) 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 set out to illustrate how to make the compounds of this invention and methods for determining associated therapeutic activity. These examples are not intended to limit the invention in any manner, their purpose is illustrative rather than limiting.

Specific Embodiments

Example 1

Preparation of 1.4-to-f r3-(3-cvclopentvloxv-4-methoxvphenvl^cvclohexan-l-on1-3- yl)buta-l,3-djyne la) 3-(3-cyclopentyloxy-4-memoxyphenyl)-3-(trimethylsilylethynyl)cyclohexan-l--one n-Butyllithium (2.45 M in hexanes, 5.7 mL, 13.96 mmol) was added dropwise over 5 min to a solution of trimethylsdylacetylene ( 1.97 mL, 13.96 mmol) dissolved in dry etiier (30 mL) at -45°C under an argon atmosphere. After 1.5 h, this solution was cannulated into a solution of dimethylaluminum chloride (1.0 M in hexanes, 13.96 mL, 13.96 mmol). After 3.5 h at room temperature, the mixture was filtered through Celite® under an argon atmosphere. In a separate flask, diisobutylaluminum hydride (1.0 in toluene, 1.4 mL, 1.4 mmol) was added dropwise to a stirred mixture of nickel acetylacetonate (360 mg, 1.4 mmol) in dry edier (25 mL) at 0°C under an argon atmosphere. After 10 min, the mixture was cooled to -10°C and the solution of die aluminum acetylide was added via cannula over 15 min. A sample of 3-(3-cyclopentyloxy- 4-methoxyphenyl)cyclohex-2-en-l-one (2.0 g, 6.98 mmol, prepared by the procedures described in U.S. patent 5362915 which are incorporated herein by reference ) dissolved in dry ether (70 mL) was added dropwise over 20 min. After 18 h at room temperature, the mixture was poured into a 100 mL saturated aqueous solution of potassium phosphate (monobasic) at 0°C, lOOmL of aqueous 3H HC1 solution was added and the aqueous layer was extracted twice with ether. The combined extract was washed with brine, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting witii 2:1 hexanes/ether, followed by trituration from ether/hexanes, then furthur purification of the mother liquor by flash chromatography, eluting witii 4:1 hexanes/ethyl acetate, followed by trituration from edier hexanes, provided a white solid, mp 102- 103°C. lb) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclohexan-l-one

A mixture of potassium fluoride (900 mg, 15.6 mmol) and 3-(3-cyclopentyloxy-4- methoxyphenyl)-3-(trimethylsilylethynyl)cyclohexan-l-one (0.3 g, 0.78 mmol) was stirred in dry N,N-dimethylformamide (3 mL) under an argon atmosphere. After 18 h, the solvent was removed in vacua, the residue was partitioned between water and ethyl acetate, the aqueous layer was extracted twice with ethyl acetate, the combined extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 4:1 hexanes/ethyl acetate, provided a clear colorless oil. .Anal. (C20H24O3 I/IO H2O) calcd: C 76.45, H 7.76; found: C 76.32, H 7.60.

lc) l,4-b«-{[3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-on]-3-yl}buta-l,3- diyne

Copper (II) acetate monohydrate (0.40g, 2.02 mmol) was added to a solution of 3- (3-cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclohexan-l-one (0.30g, 0.96mmol) dissolved in 1:1:4 pyridine/methanol/ether (75 mL). The mixture was refluxed under an argon atmosphere. After 30 h, the solvents were evaporated and the residue was partitioned between dichloromed ane and aqueous 31 HC1. The aqueous layer was extracted twice with dichloromethane, the combined extract was washed with brine, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 99: 1 chloroform/methanol, followed by trituration from ether/hexanes, provided a white solid, mp 173-174.5°C.

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 0411 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 Isozvmes

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 die different isozymes are as follows: 1 ) PDE lb, porcine aorta; 2) PDE

Ic, guinea-pig heart; 3) PDE HI, guinea-pig heart; 4) PDE TV, human monocyte; and 5)

PDE V (also called "la"), canine trachealis. PDEs la, lb, Ic and m 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.

Claims

What is claimed is:

1. A compound of Formula I

wherein:

Rl is independendy -(CR4R5)_nC(O)O(CR4R5)mR6> -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4RR4R5)mR6, or -(CR4R5)rR wherein the alkyl moieties may be unsubstituted or substituted with one or more fluorines; m is 0 to 2; n is 0 to 4; r is 0 to 6;

R4 and R5 are independendy selected hydrogen or C 1-2 alkyl;

R6 is independendy hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloall yl containing one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic moiety may be unsubstituted or substituted by 1 to 3 methyl groups, an ethyl group, or an hydroxyl group; provided that: a) when R(_ 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-tctrahydrσpyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrodιienyl, then r is 1 to 6; e) when n is 1 and m is 0, men R6 is otiier than H in -(CR4R5)_nO(CR4R5)mR6; W is allcyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;

X2 is independendy O or NR8; X3 is independendy hydrogen or X;

Z is independendy O, NR7, NCR4R5C2-6 alkenyl, NOR14, NOR15, NOCR4R5C2-6 alkenyl, NNR4R14, NNR4R15, NCN, NNR8C(O)NR8Rl4, NNR8C(S)NR8Rl4, C(-CN)2, CR14CN, CRl4C(O)OR8, CRi4C(O)NRsRl4, C(-CN)NO2, C(-CN)C(O)OR9, C(-CN)OC(O)R9, C(-CN)OR9, C(-CN)C(O)NRsRl4, or =Z is 2-(l,3-dithiane), 2-(l,3-didιiolane), dimediylthio ketal, diethylduo ketal, 2-(l,3- dioxolane), 2(l,3-dioxane), 2-(l,3-oxathiolane), dimethyl ketal or diethyl ketal; R7 is independendy -(CR4Rs)qR 12 or C 1.5 alkyl wherein the R 12 or C 1.g 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, -NRIQRI 1, -C(O)R8, -CO2R8, -O(CH₂)_qR8, -CN, -C(O)NRιoRll, -O(CH₂)_qC(O)NRioRl l, -O(CH₂)_qC(O)R9, -NRiθC(O)NRiθRll, -NRl()C(O)Rll, -NRiθC(O)OR9, -NRiθC(O)Ri3, -C(NRlθ)NRlθRl 1, -C(NCN)NRioRl 1, -C(NCN)SR9, -NRlθC(NCN)SR9 ,

-NRιoC(NCN)NRιoRl l, -NRιoS(O)2R9, -S(O)m'R9, -NRιoC(O)C(O)NRiθRl l, - NRlθC(O)C(O)Riθ, or R\ , q is O, l, or 2;

Rl2 is independendy R 13, C3-C7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, moφholinyl, furanyl, (2- or 3-dιienyl), quinolinyl, naphthyl, or phenyl;

R8 is independendy selected from hydrogen or R9; R9 is independently C1.4 alkyl unsubstituted or substituted by one to d ree fluorines; Rio is independendy OR8 or Ri 1; Rl 1 is independendy hydrogen, or C 1.4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Rl 1 are as NRio l 1 they may together with the nitrogen form a 5 to 7 membered ring unsubstituted comprised of carbon or carbon and at least one heteroatom selected from O, N, or S; R 13 is independendy oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazohdinyl, 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;

Rl4 is independendy hydrogen or R7; or when R8 and Rl4 are as NR8R14 tiiey may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatoms selected from O, N, or S;

Rl5 is independendy C(O)Ri4, C(O)NR4Rl4, S(O)2R7, or S(O)2NR4R ; or the pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 wherein -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -C 1-2 alkyl unsubstituted or substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluoro-substituted alkyl, W is 1,3-butadiynyl, and X is YR2-

3. A compound of claim 2 which is 3,3'-(l,3-butadiyn- l,4-diyl)-b«-[3-(3- cyclopentyloxy-4-methoxyphenyl)-cyclohexan- 1 -one] . 4. A compound of Formula II

wherein: Rl is independendy -(CR4R5)nC(O)O(CR4R5)mR6. -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CaR4R5)nO(CR4R5)mR6, or -(CR4R5)rR6 wherein the alkyl moieties may be unsubstituted or substituted with one or more fluorines; m is 0 to 2; n is 0 to 4; r is 0 to 6;

R4 and R5 are independendy selected hydrogen or C 1-2 alkyl;

R6 is independendy hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alakyl, h-alo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tctrahydrothiopyranyl, thiσpyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be 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 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-tetrahydrotiιienyl, then r is 1 to 6; e) when n is 1 and m is 0, tiien R6 is otiier dian H in -(CR4R5)_nO(CR4R5)mR6; X is independendy YR2, fluorine, NR4R5, or formyl amine; Y is independendy O or S(O)nϊ; m" is 0, 1, or 2;

X2 is independently O or NR8; X3 is independendy hydrogen or X;

W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; R2 is independendy selected from -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more fluorines; s is 0 to 4;

Z' is independendy C(Y')Ri4, C(O)ORi4, C(Y')NRιoRl4, C(NRιo)NRιoRl4, CN, C(NOR8)Rl4, C(O)NR8NRsC(O)R8, C(O)NRsNRιoRl4, C(NORi4)R8. C(NR8) fRlθRl4, C(NRi4)NRδR8 C(NCN)NRiθRl4, C(NCN)SR9, (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-oxa.zolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[l,2,4]), (2-oxadiazolyl[ 1,3,4]), (2-thiadiazolyl[ 1,3,4]), (2-, 4-, or 5-tiύa-zolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl); wherein all of the heterocylic ring systems may be unsubstituted or substituted one or more times by R7; Y' is O σr S;

R7 is independendy -(CR4R5)qRi2 or Cι_6 alkyl wherein the R12 or Cι_6 alkyl group is unsubstituted or substituted one or more times by C 1-2 alkyl unsubstituted or substituted by one to three fluorines, -F, -Br, -G, -NO2, -Si(R4)3, -NRIQRI 1, -C(O)R8, - CO2R8, -OR8, -CN, -C(O)NRιoRn, -OC(O)NRιoRl l, -OC(O)Rs, -NRiθC(O)NRlθRl 1, -NRioC(O)Ri 1, -NRi()C(O)OR9, -NRlθC(O)Rl3, -C(NRiθ)NRioRl l, -C(NCN)NRιoRl l, -C(NCN)SR9, -NRlθC(NCN)SR9 , -NRiθC(NCN)NRιoRl l, -NRioS(O)2R9, -S(O)_m'R9, -NRioC(O)C(O)NRι₀Rl l, - NRlθC(O)C(O)Riθ, R13; q is O, l, or 2; Rl2 is independendy C3-7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl,

(1- or 2-imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, moφholinyl, furanyl, (2- or 3-thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl;

R% is independendy selected from hydrogen or R9;

R9 is independendy C1.4 alkyl unsubstituted or substituted by one to three fluorines;

RlO is independendy OR8 or Ri 1;

Rl 1 is independendy hydrogen, or C 1.

4 alkyl unsubstituted or substituted by one to diree 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 at least one heteroatom selected from O, N, or S;

Rl3 is independendy oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazobdinyl, 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 Cι_2 alkyl groups; R14 is independendy hydrogen or R7; or when R8 and R14 are as NR8R14 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatoms selected from O, N, or S; or the pharmaceutically acceptable salts thereof.

5. A compound of claim 4 wherein -CH2-C5-6 cycloallcyl, -C4-6 cycloall yl, 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 1,3-butadiynyl, X is YR2 and Z' is COOR14 or R₇.

6. A pharmaceutically acceptable composition comprising a compound of Formula I according to claim 1 and a pharmaceutically acceptable excipient

7. A method for treating allergic and inflammatory disease which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula I according to claim 1.