WO1996020153A1

WO1996020153A1 - 4,4-(disubstituted)cyclohexan-1-one dimers and related compounds

Info

Publication number: WO1996020153A1
Application number: PCT/US1995/016719
Authority: WO
Inventors: Siegfried B. Christensen, Iv; Joseph M. Karpinski
Original assignee: Smithkline Beecham Corporation
Priority date: 1994-12-23
Filing date: 1995-12-21
Publication date: 1996-07-04
Also published as: JPH10512552A; EP0799176A4; EP0799176A1

Abstract

This invention relates to compounds of Formula I or II which are useful in treating, among other things, allergic and inflammatory diseases wherein the various substituents are defined therein.

Description

4,4-φi_ubstituted)cyclohexan-l-one Dimers and Related Compounds Field of Invention

The present invention relates to novel 4.4-(disubstituted)cyclohexan-l-one dimers 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, miiltifactorial 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 c AMP 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 iiiflammatory 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 pyrosis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus ervthematosis.

AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HTV). At least three types or strains of HTV have been identified, i.e., HTV-1, HIV-2 and HIV-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 HTV-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 HTV protein expression and/or virus replication by playing a role in mamtaining T lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HTV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HTV 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 HTV 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 HTV replication in monocytes and/or macrophages [See Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T cells.

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

TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al., Infection and Immunity, 58(9) .2750-54, 1990; and Jafari et al., Journal of Infectious Diseases, 164:389-95, 1991. See also Wasan et al., Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Luke et al., Journal of Infectious Diseases, 162:211-214,1990]. The ability to control the adverse effects of TNF is furthered by the use of the compounds which inhibit TNF in mammals who are in need of such use. There remains a need for compounds which are useful in treating TNF-mediated disease states which are exacerbated or caused by the excessive and/or unregulated production of TNF. Summary of the Invention Certain novel compounds of this invention are represented by Formula (I):

CO wherein:

Rl is independently -(CR4R5)_nC(O)O(⁽_R4R5)mR6» -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R 4R5)mR , 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 Rs are independently selected hydrogen or C_-2 alkyl;

R6 is independently hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahy dropyranyl, 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 that: a) when R6 is hydroxyl, then m is 2; or b) when R is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahy dropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetτahydrothienyl, 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 independently YR2, fluorine, NR4R5, or formyl amine;

Y is independently O or S(O)m", m' is O, l, or 2;

__2 is independently O or NRg; X3 is independently hydrogen or X;

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

Z is independently O, NR7, NCR4R5C2-6 alkenyl, NOR14, NOR15, NOCR4R5C2-6 alkenyl, NNR4R14. NNR4R15, NCN, NNR8C(O)NR8Rl4, NNR8C(S)NR8Ri4, C(-CN)2, CR14CN, CRl4C(O)OR8, CRi4C(O)NR8Ri4, C(-CN)NO2, C(-CN)C(OX)R9, C(-CN)OC(O)R9, C(-CN)OR9, C(-CN)C(O)NR8Ri4, or =Z is 2-(l,3-dithiane), 2-(l,3-dithiolane), dimethylthio ketal, diethylthio ketal, 2-(l,3- dioxolane), 2(l,3-dioxane), 2-(l,3-oxathiolane), dimethyl ketal or diethyl ketal;

R7 is independently - CR4R5)qRl2 or Cj_6 alkyl wherein the R12 or Cj_6 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)NRiθRll, -O(CH2)_qC(O)NRlθRl 1, -O(CH2)qC(O)R9, -NRιoC(O)NRιoRιι, -NRιoC(O)Rn, -NRioC(O)OR9, -NRlθC(O)Rl3, -C(NRio)NRlθRll, -C(NCN)NRiθRn, -C(NCN)SR9, -NRioC(NCN)SR9 , -NRιoC(NCN)NRιoRl 1, -NRlθS(O)2R9, -S(O)_m'R9, -NRlθC(O)C(O)NRιoRl 1, - NRloC(O)C(O)Rιo, or R₁₃; q is O, l, or 2;

Rl2 is independently R1 , (CH2 q. C3-C7 cycloalkyl, (2-, 3- or4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl; Rg is independently selected from hydrogen or R9; R9 is independently Cj_4 alkyl unsubstituted or substituted by one to three fluorines;

RjO is independently OR8 or Ri 1; Rj 1 is independently hydrogen, or Cj_ alkyl unsubstituted or substituted by one to three 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 independently 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 Cj_2 alkyl groups;

Rj4 is independently 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;

Rl5 is independently 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 independently -(CT_4R5)_nC(O)O(αUR5)mR » -(Ol4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)mR , 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 Ci-2 alkyl; R is independently hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7.1i polycycloalkyl, tetrahy drofuranyl, furanyl, tetrahy dropyranyl, pyranyl, teπ^ydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be 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 R 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 R is 2-tetrahy dropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl,or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R6 is other than H in -(CR4 5)nO(CR4R5)mR ; X is independently YR2, fluorine, NR4R5, or fσrmyl amine;

Y is independently O or S(O)nϊ; m' is O, l, or2; X2 is independently O or NRβ; X3 is independently 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 independently selected from -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more fluorines; s is 0 to 4;

T is independently C(Y.Rl4. C(O)ORi4. COONR10R14, C(NRιo)NRιoRl4. CN, C(NOR8)Rl4, C(O)NR8NR8C(O)R8, C(O)NR8NRlθRl4. C(NORl4)R8. C(NR8)NRlθRl4, C(NRl4)NR8R8 C(NCN)NRlθRl4. C(NCN)SR9, (2-, 4- or

5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[l A3]), (3- or _-triazolyl[ 1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[l,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 independently -(C 4R5)qRl2 or Cι_6 alkyl wherein the R12 or Cι_6 alkyl group is unsubstituted or substituted one or more times by Ci-2 alkyl unsubstituted or substituted by one to three fluorines, -F, -Br, -Cl, -NO2, -Si(R4)3, -NRiøRl 1, -C(O)R8, - CO2R8, -OR8, -CN, -C(O)NRiθRl 1, -OC(O)NRιoRl 1, -OC(O)R8,

-NRiθC(O)NRιoRn, -NRiθC(O)Rn, -NRlθC(O)OR9, -NRiθC(O)Rl3, -C(NRiθ)NRlθRn, -C(NCN)NRlθRll, -C(NCN)SR9, -NRiθC(NCN)SR9 , -NRlθC(NCN)NRiθRl 1, -NRK)S(O)2R9. -S(O)_m'R9. -NRlθC(O)C(O)NRiθRι l , - NRl0C(O)C(O)Ri0, R13; q is 0, 1, or 2;

Rl2 is independently C3-7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, orphenyl; Rg is independently selected from hydrogen or R9; R9 is independently C\_4 alkyl unsubstituted or substituted by one to three fluorines;

RlO is independently OR8 or Ri 1;

R 1 is independently hydrogen, or Cj_4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Ri 1 are as NRloRl 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 independently 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; R14 is independently 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 (II) 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) and (-3) 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) and (II).

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) and (II).

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) and (II). 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) and (II).

Compounds of Formula (I) and (II) are also useful in d e 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) and (II) 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) and (H).

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) and (H). Such viruses include, but are not limited to HTV-1, HTV-2 and HTV-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 (HTV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I) and (II).

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 (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 f tngi 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) and (II) 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) and (II) may also be used for inhibiting and/or reducing the toxiciry of an anti-fungal, anti-bacterial or anti-viral agent by administering an effective amount of a compound of Formula (I) and (H) to a rriamrnal in need of such treatment Preferably, a compound of Formula (I) and (H) is administered for inhibiting or reducing the toxiciry of the Amphotericin class of compounds, in particular Amphotericin B. The term "C1.3 alkyl", "Cι_4 alkyl", "Cι_6 alkyl" or "alkyr 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, rerr-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, e, phenyl. The alkyl chain is meant to include both straight or branched chain radicals of 1 to 4 carbon atoms.

Ηeteroaryl" 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 hσmology with TNF-α (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) and (II) 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) and (II) 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 Ri for the compounds of Formula (I) and (II) is an alkyl substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably a Cl-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) and (II) are CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl with or without an hydroxyl group, 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 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., (CR4Rs)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, die preferred R 1 substitutions, as noted above.

When Ri is a C7-11 polycycloalkyl, examples are bicyclo[2.2.1]-heptyl, bicyclo[2___i]octyl, bicyclo[3.2,l]octyl, tricyclo[5.2.1.θ2»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 O, NCN, NR7, NOR14, NOR15, NNR4R14, NNR4Rl5.C(CN)2, C(-CN)OC(O)R9, C(-CN)OR^Q, CRi4C(O)OR8, CR9C(O)NRi3Ri4, 2-(l,3-dithiane), dimethylthio ketal, 2-(1 -dioxolane), or dimethyl ketal. More preferred are O, NR7, NOR14, NOR15, and 2-(l,3-dioxolane).

Preferred X groups for Formula (I) and (II) are those wherein X is YR2 and Y is oxygen. The preferred X2 group for Formula (I) and (II) is that wherein X2 is oxygen. The preferred X3 group for Formula (I) and (II) is that wherein X3 is hydrogen. Preferred R2 groups, where applicable, is a C 1-2 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 C(O)ORi4-

Preferred R7 moieties include unsubstituted or substituted -(CH2)l- 2(cyclopropyl), -(CH2)0-2(cyclobutyl), -(CH2)0-2(cyclopentyl), -(CH2)0-2(cyclohexyl), -(CH2)0-2(2-, 3- or 4-pyridyl), (CT2)l-2(2-irniά zolyl), (CH2)2(4-morpholinyl),

(CH2)2(4-piperazinyl), (CH2)l-2(2-thienyl), (CH2)l-2(4-thiazolyl), and (CH2)0-2phenyl;

Preferred rings when Rio and Ri 1 in the moiety -NRioRl 1 together with the nitrogen to which ti ey 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, l-pyrazolyl, 3-(Rδ)-l -pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R8H -triazolyl, 5-(R8)-2-triazolyl, 5-(R8)-l-tetrazolyl, 5-( 8)-2-tetrazolyl, 1 -tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(R8)-l-piperazinyl, or pyrrolyl ring.

Preferred rings when R$ and Rl4 in the moiety -NRsRl4 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, l-pyrazolyl, 1 -triazolyl, 2-triazolyl, 1 -tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, and pyrrolyL The respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I) and (II). Illustrations of such carbon substitutions includes, but is not limited to, 2-(R7)-l -imidazolyl, 4-(R7)-l -imidazolyl,

5-( 7)-l-inridazolyl, 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, 1 -(R7)-2-tetrazolyl, 2-(R7)- 1 -tetrazolyl, 4-(R7)- 1 - piperazinyl. Where applicable, the ring may be substituted one or more times by R7. Preferred groups for NR8R14 which contain a heterocyclic ring are 5-(Rl4)-l- tetrazolyl, 2-(R 14)- 1 -imidazolyl, 5-(Ri4)-2-tetrazolyl, 4- (Ri 4)- 1 -piperazinyl, or 4-(R 15)- 1 -piperazinyl.

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

When the R7 group is 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-(^8)-2-imidazolyl, l-(R8)-4-imidazolyl, l-(^8)-5-imidazolyl, l-(R8)-3-pyrazolyl, l-(R8)-4-pyrazolyl, l-(R8)-5-ρyrazolyl, l-(R8)-4-tτiazolyl, 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 (IT) wherein Ri is -CH2- cyclopropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl, 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 and X is YR2-

Most preferred are those compounds wherein Ri is -CH2-cyclopropyl, -CH2-3- hydroxycyclopropyl, cyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl. The compounds specifically illustrated herein are

1 ,4-bis - { [4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -one]-4-yl } buta- 1,3 diyne and

1 A-bis -(4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexan- l-on-4-yl)butane. It will be recognized that some of the compounds of Formula (I) and (II) may exis 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) or (II) may exist in a tautomeric form, such as the enol form. This may be represented by the =O being exocyclic to the cyclohexane ring

d R i Z i F l (I) I i l i d h d 2 iti f h ring in the exocyclic form can be substituted (R) such as in de compounds of Formula (I). 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) and (II). 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 die 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 die 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 the intended route of administration, for example parenterally, topically, orally or by inhalation. For topical administration die 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 die 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, com 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, dichlorcxiifluoromethane, 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 tiiat 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 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 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 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) ith Textual Description

Compounds of Formula (I) and (II), wherein W is a 13-butadiyne and wherein A and B represent Z as defined in relation to Formula (I) and (II) or a group convertible to Z, may be prepared by die processes disclosed herein which comprise, for example, coupling of a molecule of the Formula 1-Scheme 1 with a molecule of the 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/methanol water, as in the method of Eglington and Galbraith (J. Chem. Soc., 1959, 889), to provide a compound of the Formula 3-Scheme 1. Compounds of formula 1-Scheme-l and 2-Scheme-l can be made by the processes described in PCT applications PCT/US93 02325 or PCT/US93/01990 (respectively WO 93/19750 and WO 93/19748).

Schem 1

a) Cu(OAc ) ₂*l-l _jO, DMF or C ₅H₅N

Reduction of a compound of the Formula (I) and (II), 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 the 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 method of Jutz (Ber., 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 d e 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 hydroaluminaticHi-protonolysis procedure of Zweifel et al. (Synthesis, 1977, 52).

Depending upon the 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 deprotectionand then reaction by the synthetic procedures described in copending United States patent applications 07/862,083, 07,968,753, PCT/US93/01990, and PCT/US93/02325 and filed 05 March 1993 (WIPO publication No. WO 93/19748), to provide die Formula (I) compound; 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.)

Compounds of Formula (II), wherein W is a 1,3-butadiyne and wherein Z' represents Z' as defined in relation to Formula (H) or a group convertible to T, 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 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/methanol/water, as in the method of Eglington and Galbraith (J. Chem. Soc., 1959, 889), to provide a compound of the Formula 2_ Scheme 2. Here also the starting materials can be obtained by die methods refered to above in the following PCT applications: PCT/US93/02325 or PCT/US93/01990 (respectively WO 93/19750 and WO 93/19748).

S-h_m_ _

a) Cu(OAc JjMaO. DMF or C _δH_sN

Reduction of a compound of d e 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 d e mediod of Tedeschi (J. Org. Chem., 1962, 27, 2398), or, e.g., platinum oxide according to the mediod of Jutz (Ber., 1958, 91, 1867) or that of Suzuki and Kurosawa (Chem. Lett, 1980, 1177). Reduction of a compound of d e 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 hydroalunaination-protonolysis procedure of Zweifel et al. (Synthesis, 1977, 52).

Depending upon the exact nature of the Z' groups of the compounds of d e Formula (II), die =O group may require protection during the coupling and/or reductive steps described herein as, e.g., a compound of die Formula (II) wherein =O is a dimethyl ketal or 2-(l,3-dioxolane), followed by deprotection and then reaction by the synthetic procedures described in 07/862,083, 07,968,753, PCT/US93/01990, and PCT/US93/02325 and filed 05 March 1993 (WIPO publication No. WO 93/19748), 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 (H) compound and 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.)

Alternatively, compounds of the Formula (II), wherein W and Z' represent W and Z^* as defined in relation to Formula (LI) or a group convertible to W or Z¹, may be prepared from the corresponding ketones of the Formula (I) as, e.g., compound 1-Scheme 2, by the synthetic procedures described in PCT/US93/01990 and filed 05 March 1993 (WIPO publication No. WO 93/19748).

Sch m 3

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

It will be recognized that compounds of d e Formulas (I) and (II) may exist in distinct diastereomeric forms possessing distinα physical and biological properties; such isomers may be separated by standard chromatographic methods.

Experimentals

Example 1 Preparation of 1.4-bis- ( ϊ4-( 3-cyclopentv loxv-4-methox vphenvlV 1.1 -(ethvlenedioxy .- cv-lohexanl-4- vl ) buta- 1.3-divne la) 4-cyano-4-(3-cyclσpentyloxy-4-methoxyphenyl)-l, l-(ethylenedioxy)cyclohexane

A solution of cyancπl-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one (1.0 g, 3.19 mmol, prepared by the procedures described in PCT application PCT/US93/01990 and published as WO 93/19748) in benzene (25 mL) was treated with p-toluenesulfonic acid (5 mg) and ed ylene glycol (0.18 mL, 3.19 mmol) and was heated to reflux under an argon atmosphere; water was removed from the mixture via a Dean- Stark trap. After 1.5 h, ether (200 mL) was added, d e solution was washed with aqueous 5% sodium bicarbonate and brine, was dried (potassium carbonate) and was evaporated to provide a clear colorless oil. ^l NMR(250 MHz, CDCI3) δ 7.0 (m, 2H), 6.85 (d, J=7 Hz, IH), 4.8 (m, IH), 4.0 (m, 4H), 3.85 (s, 3H), 1.58-2.20 (m, 16H).

lb) 4-(3-<^clopentyloxy-4-me_ιoxyphenyl l,l-(eώylenemoxy)-4-formylcyclohexane Diisobutylaluminum hydride (1.0 M toluene, 8.13 mL, 8.13 mmol) was added dropwise to a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l- (ethylenedioxy)cyclohexane (1.16 g, 3.19 mmol) dissolved in toluene (20 mL) under an argon atmosphere. After 18 h at room temperature, saturated aqueous sodium bisulfite

(100 mL) was added and the mixture was extracted three times with dichloromethane.

The combined organic extract was washed with brine, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 4:1 hexanes/ethyl acetate, provided a clear colorless oil. H NMR(400 MHz, CDCI3) δ 9.35 (s, IH), 6.88

(br s, 2H), 6.80 (s, IH), 4.73 (m, IH), 3.95 (m, 4H), 3.85 (s, 3H), 2.33 (m, 2H), 2.10 (m,

2H), 1.57-1.99 (m, 12H).

lc) 4-(3-cyclopentyloxy-4-methoxyphenyl)- 1 , 1 -(ethylenedioxy)-4-ethynylcyclohexane A solution of dimethyl (diazomethyl)phosphonate (0.516 g, 3.44 mmole, prepared as in Seyferth, D.; Marmor, R. S.; Hilbert P. J. Org. Chem. 1971, 36(10), 1379-1386) dissolved in dry tetrah drofuran (10 mL) was added via cannulation to a solution of potassium t-butoxide (0.386 g, 3.4 mmol) dissolved in dry tetrahydrofuran (10 mL) at - 78°C under an argon atmosphere. To this was added rapidly a solution of 4-(3- cyclopentyloxy-4-methoxyphenyl)- 1 , 1 -(edιylenedioxy)-4-formylcyclohexane (0.62 g, 1.72 mmol) in dry tetrahydrofuran (10 mL). After 2 h, the reaction was warmed to room temperature, water was added and die mixture was extracted three times with ethyl acetate. The combined organic extract was washed wid brine, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate provided a white solid. mp 53.5-55°C.

Id) l,4-_t«-{[4-(3-cyclopentyloxy-4-medιoxyphenyl)-l,l-(ethylenedioxy)-cyclohexan]-4- yl}buta-l,3-diyne

4-(3-Cyclopentyloxy-4-methoxyphenyl)- 1 , l-(ethylenedioxy)-4-ethynylcyclohexane (0.20 g, 0.56 mmol) was treated with copper (Η) acetate (0.335 g, 1.68 mmol) and pyridine (50 mL) and the mixture was heated to 90°C under an argon atmosphere. After 1 h, die pyridine was evaporated and the residue was diluted with dichlσromethane and aqueous 3__ HQ. The aqueous phase was extracted twice with dichloromethane, the combined organic extract was washed with brine, was dried (magnesium sulfate) and was evaporated to an off-white solid. Purification by dissolving the solid in hot ethyl acetate, filtration, and trituration with hexanes provided a white solid, mp 173- 174°C.

Example 2 Preparation of 1. -_>__-f r4- 3- ^clcφentvloxv-4-methoxvphenvncvclohexan-l-on1-4- yl}buta-]l,3-diyng To a suspension of 1 -bis- [ [4-(3-cyclopentyloxy-4-medκ>xyphenyl)- 1,1-

(edιyleBedioxy)-cyclohexan]-4-yl}buta-l,3-diyne (0.17 g, 024 mmol) in 4:1 acetone/water (10 mL) was added pyridinium p-toluenesulfonate (0.06 g, 0.24 mmol) and d e mixture was heated to reflux under an argon atmosphere. After 100 h, the acetone was evaporated, water was added, and die aqueous phase was extracted three times with dichloromethane. The combined organic extract was dried (magnesium sulfate) and was evaporated to a solid. Purification by stirring in ether/hexanes provided a white solid, mp 154-155°C.

Example 3 Preparation of l.4-to-(r4-f3-cvclopentyloxy-4-methoxyphenyn-l.1-rethvlenedioxvV cyclohexan]-4-yl ) butane To a stirred suspension of palladium on carbon (10%, 30 mg) in dry tetrahydrofuran (5 mL) under an argon atmosphere was added a solution of l,4-bi_-{[4- (3-cyclopentyloxy-4-me_ιoxyphenyl)- 1 , 1 -(ethylenedioxy)-cyclohexan]-4-yl } buta- 1 ,3- diyne (75 mg, 0.106 mmol) in dry tetrahydrofuran (7 mL) under an argon atmosphere. The vessel was alternately evacuated and filled with hydrogen gas from a ballon three times and stirred for 22 h. The suspension was then purged with argon and was filtered tiirough Celite®. The resulting solution was stripped in vacua to afford die tided product as a colorless oil. -NMR (400 MHz, CDCI3) δ 6.76 (s, 3H), 4.82 (p, IH), 3.91 (d-d, J=4.8 H, J=16, 4H), 3.82 (s, 3H), 2.08 (d, br, 2H), 1.86 (s,br, 6H), 1.7-1.47 (m, +H2O, 12H), 1.32 (s, br, 2H), 0.78 (s, br, 2H). Example 4 Preparation of 1.4-fc_?-(r4-f3-cvclc^n oxy-4-methoxyphenyncvclohexan-l-on1-4- yl.butane. A solution of l,4-_>i_-{[4-(3-cydopentyloxy-4-_Qethoxyphenyl)-l,l- (ethylenedioxy)cyclohexan]-4-yl} butane (0.07 g, 98 μmol) in acetone (6 mL) was placed in a sealed glass tube with p-toluenesulfonic acid (0.07g, 368 μmol) under an argon atmosphere and was heated at 70 °C for 4 h. The solvent was removed in vacua and the residue was partitioned between cold aqueous sodium carbonate solution and methylene chloride. The organic phase was washed witii water, brine, was dried over anhydrous sodium sulfate and was evaporated. The residue was dissolved in ethyl acetate:methylene chloride (1%) and chromatographed on silica, eluting with ethyl acetatε:metiιylene chloride (4 to 8%), to provide an oil, which was crystallized from medianol to give the tided product as a white solid, mp 118-119.5 °C. AnaL (C40H54O6) calcd: C 76.16, H 8.63; found: C 75.83, H 8.62. UTILITY EXAMPLES

EXAMPLE A Inhibitory effect of compounds of Formula CD and OI) on in vitro TNF production bv human monocvtes

The inhibitory effect of compounds of Formula (I) and (U) on in vitro TNF production by human monocytes may be determined by d e 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 P Two models of endotoxic shock have been utilized to determine in vivo TNF activity for d e compounds of Formula (I) and (II)- 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 die injection of endotoxin.

EXAMPLE C Isolation of PDE Isozvmes

The phosphodiesterase inhibitory activity and selectivity of the compounds of

Formula (I) and (II) can be determined using a battery of five distinct PDE isozymes. The tissues used as sources of d e different isozymes are as follows: 1) PDE lb, porcine aorta;

2) PDE Ic, guinea-pig heart; 3) PDE IE, guinea-pig heart; 4) PDE IV, human monocyte; and 5) PDE V (also called "la"), canine trachealis. PDEs la, lb, Ic and IE are partially purified using standard chromatographic techniques [Torphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE IV is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-Sepharose chromatography [Torphy etal., J. Biol. Chem., 267:1798-1804, 1992]. Phosphodiesterase activity is assayed as described in d e protocol of Torphy and

Qeslinski, Mol. Pharmacol., 37:206-214, 1990. Positive IC5θ's in the nanomolar to uM range for compounds of die workings examples described herein for Formula (I) and (II) 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, -(CR4RR4 5)m 6, 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 Ci-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, diiopyranyl, 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 that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, dien r is 2 to 6; or c) when R is 2-tetrahydropyranyl, 2-tetrahydrodιiopyranyl, 2-tetrahy drofuranyl, or 2-tetrahydrothienyl, dien m is 1 or 2; or d) when R is 2-tetrahydropyranyl, 2-tetrahydrotiύopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrodιienyl, dien r is 1 to 6; e) when n is 1 and m is 0, then R6 is other than H in -(CR4R5)nO(CR4R5)m ; 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 arr-dne;

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

X2 is independendy O or NR8;

X3 is independendy hydrogen orX;

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, NCR4R5 2-6 alkenyl, NOR14, NOR15, NOCR4R5C2-6 alkenyl, NNR4R14, NNR4R15, NCN, NNR8C(O)NRsRl4, NNR8C(S)NR8Rl4. C(-CN)2, CR14CN, CRi4C(O)OR8, CRi4C(O)NR8Rl4, C(-CN)NO2, C(-CN)C(O)OR9, C(-CN)OC(O)R9, C(-CN)OR9, C(-CN)C(O)NR8Rl4, or =Z is 2-(l,3-didιiane), 2-(l,3-didιiolane), dimemylthio ketal, diethyldiio ketal, 2-(l,3- dioxolane), 2(l,3-dioxane), 2-(l,3-oxadιiolane), dimethyl ketal or diethyl ketal;

R7 is independendy -(CR4R5)qRl2 or Cι_6 alkyl wherein the R12 or Cι_6 alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, -F, -Br, -Cϊ, -NO2, -NRIQRI 1, -C(O)R8, -CO2R8, -O(CH2)_qR8, -CN, -C(O)NRιoRl 1, -O(CH2)_qC(O)NRιoRl 1, -O(CH2)_qC(O)R9, -NRlθC(O)NRιoRιι, -NRιoC(O)Rn, -NRιoC(O)OR9, -NRlθC(O)Rl3, -C(NRιo)NRlθRll. -C(NCN)NRιoRll, -C(NCN)SR9, -NRiθC(NCN)SR9 , -NRlθC(NCN)NRiθRii, -NRioS(O)2R9, -S(O)_m'R9, -NRiθC(O)C(O)NRlθRll, - NRιoC(O)C(O)Rιo, or R₁₃; q is 0, 1, or 2;

Rl2 is independendy R13, (CH2)q, C3-C7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrirrddyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl;

Rg is independendy selected from hydrogen or R9; R9 is independendy C1- alkyl unsubstituted or substituted by one to three fluorines;

Rj0 is independendy OR8 or Ri 1;

Rl 1 is independendy hydrogen, or C1- alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Rl l are as NRioRl 1 they may togemer 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 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;

Rj4 is independendy hydrogen or R7; or when R8 and R14 are as NR R14 diey 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)NR4Ri4, S(O)2R7. or S(O)2NR4Rl4; or die pharmaceutically acceptable salts thereof.

2. A compound of 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 die 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 Ci-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 cycloalkyl 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 diat: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, dien r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrodιiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, dien m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl,or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R6 is other than H in -(CR4R5)_nO(⁽_R4R5)_mR6. X is independendy YR2, fluorine, NR4R5, or formyl amine; Y is independendy O or S(O)_m'; m' is O, l, or2;

X2 is independendy O or NRδ; X3 is independendy hydrogen orX;

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 C(Y^")Rl4, C(O)ORi4, C(Y')NRιoRl4, C(NRiθ)NRioRl4. CN, C(NOR8)Rl4, C(O)NRsNR8C(O)R8, C(O)NR8NRlθRl4, C(NORi4)R8, C(NR8) RlθRl4, C(NRi4)NRsR8 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-dιiazolidinyl), or (2-, 4-, or 5-imidazoUdinyl); 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)qRi2 or C \. alkyl wherein the R_2 or Cι_6 alkyl group is unsubstituted or substituted one or more times by C 1-2 alkyl unsubstimted or substituted by one to three fluorines, -F, -Br, -Cl, -NO2- -Si(R4)3> - RloRl 1> -C(O)R8, - CO2R8, -OR8, -CN, -C(O)NRιoRll, -OC(O)NRιoRll, -OC(O)Rs, -NRlθC(O)NRιθRl l, -NRioC(O)Rn, -NRιoC(O)OR9, -NRιoC(O)Ri3, -C(NRlθ)NRlθRll, -C(NCN)NRiθRl 1, -C(NCN)SR9, -NRιoC(NCN)SR9 , -NRιoC(NCN)NRlθRl l, -NRιoS(O)2R9, -S(O)_m'R9, -NRιoC(O)C(O)NRιoRπ, - NRιoC(O)C(O)Rια R13; q is O, l, or 2; Rl2 is independendy C3-7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrirrddyl, pyrazolyl, (1- or 2- imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4- or 5-dιiazolyl), quinolinyl, naphthyl, or phenyl;

Rg is independendy selected from hydrogen or R9; R9 is independendy C1- alkyl unsubstimted or substimted by one to three fluorines;

RlO is independendy OR8 or Ri 1;

R 1 is independendy hydrogen, or C 1-4 alkyl unsubstimted or substimted 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;

Rl3 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 unsubstimted 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 d e 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.

3. A compound according to claim 1 wherein wherein Ri is

-CH2-cyclopropyl, -CH2-3-hydroxycyclopropyl, cyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or mediyL

4. A compound according to claim 3 which is

1 ,4-bis- [ [4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -one]-4-yl } buta- 1,3- diyne, or

1 ,4-_tw-(4-[3-cyclopentyloxy-4-medιoxyphenyl]cyclc_ιexan- 1 -on-4-yl)butane.

5. A pharmaceutically acceptable compostion comprising a compound Formula I according to claim 1 and a pharmaceutically acceptable carrier or diluent

6. 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 alone or in admixture with a pharmaceutically acceptable excipient