Compounds

Field of Invention

The present invention relates to novel 4,4-(disubstituted)cyclohexan-l- carboxylate 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, 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 degranulanon, 4) inhibition of basophil degranulaάon, 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 inacrivation of c AMP is hydrolysis of the 3'- phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs). It has now been shown that a distinct cyclic nucleotide phosphodiesterase

(PDE) isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Toiphy, "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 signi icant 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 erythe atosis. AIDS results from the infection of T lymphocytes with Human

Immunodeficiency Virus (HIV). At least three types or strains of HTV have been identified, i.e., HTV-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. HTV entry into the T lymphocyte requires T lymphocyte activation. Viruses such as HTV- 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 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 HTV 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 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. Natl. 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 cvtomegalovirus (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

The compounds of this invention are represented by Formulas (la) and (lb):

da) (lb) wherein:

Rj is independently selected from -(CR4R5)nC(O)O(CR4R5)mR6» -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)m 6, or -(CR4R5)r 6 wherein the alkyl moieties is unsubstituted or substituted with one or more fluorines; m is 0 to 2; n is 1 to 4; r is 0 to 6;

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

R6 is independently selected from hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCl-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 the cycloalkyl or heterocyclic moiety is unsubstituted or substituted by 1 to 3 methyl groups, one ethyl group, or an hydroxyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,

2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R6 is other than H in

-(CR4R5)nO(CR4R5)mR6;

X is independently selected from YR2, fluorine, NR4R5, or formyl amine; Y is independently selected from O or S(O)πϊ; m' is 0, 1, or 2;

X2 is independently selected from O or NR8; X3 is independently selected from hydrogen or X; X4 is independently selected from H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NR8R8, or NR8R8;

R2 is independently selected from the group consisting of -CH3 and -CH2CH3 optionally substituted by 1 or more fluorines; s is 0 to 4;

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

Z is independently selected from C(Y')Rl4. C(O)ORi4, C(Y ^* )NRιoRl4, C(NRιo)NRlθRl4, CN, C(NOR8)Rl4, C(O)NR8NRsC(O)R8, C(O)NR8NRlθRl4, C(NORl4)R8, C(NR8)NRlθRl4, 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[l,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (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-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl); wherein all of the heterocylic ring systems are unsubstituted or substituted one or more times by R 14;

Y ^* is independently selected from O or S;

R7 is -(C 4R5)qRi2 or C\__ alkyl wherein the R12 or C _ alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, -F, -Br, -Cl, -NO2, -NRl0 ^R l 1. -C(O)R8, -CO2R8, -O(CH ₂ ) _q R8, -CN, -C(O)NRlθRl 1, -O(CH ₂ ) _q C(O)NRιoRl 1, -O(CH ₂ ) _q C(O)R9, -NRιoC(O)NRιoRll, -NRlθC(O)Rn, -NRiθC(O)OR9, -NRlθC(O)Rl3, -C(NRιo)NRιoRll, -C(NCN)NRlθRl l. -C(NCN)SR9, -NRJOC(NCN)SR9 , -NRlθC(NCN)NRιoRll, -NRιoS(O)2R9. -S(O) _m 'R9, -NRlθC(O)C(O)NRιoRl l, - NRlθC(O)C(O)Rio, or R ₁₃ ; q is 0, 1, or 2;

Rl2 is independently selected from R13, C3-7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl; R is independently selected from hydrogen or R9; R9 is independently selected from Cj .4 alkyl optionally substituted by one to three fluorines;

RjO is independently selected from OR8 or Ri 1; R] 1 is independently selected from hydrogen, or Cj_4 alkyl optionally substituted by one to three fluorines; or when Rio and Ri ] 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 additional heteroatom selected from O, N, or S;

Rl3 is independently selected from 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 R14 is hydrogen or R7; or when Rs and R] 4 are as NRsRl4 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S; or the pharmaceutically acceptable salts thereof.

This invention also relates to the pharmaceutical compositions comprising a compound of Formula (la) or (lb) 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 (la) or (lb) 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 (la) or (lb).

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 (la) or (lb).

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 (la) or (lb). This method may be used for the prophylactic treatment or prevention of certain TNF mediated disease states amenable thereto.

This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HIV), which comprises administering to such human an effective TNF inhibiting amount of a Compound of Formula (la) or (lb). Compounds of Formulas (la) or (lb) 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 Formulas (la) or (lb) 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 TV in a mamma] 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 (la) or (lb).

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

The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (I). Such viruses include, but are not limited to HIV-1, HTV-2 and HIV-3, cytomegalovirus (CMV),

influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.

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

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 fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo. A preferred disease state for treatment is fungal meningitis. Additionally, the compounds of Formulas (la) or (lb) 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 Formulas (la) or (lb) may also be used for inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti- viral agent by administering an effective amount of a Compound of Formula (la) or (lb) to a mammal in need of such treatment. Preferably, a Compound of Formula (la) or (lb) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.

The term "Cj-3 alkyl", "C1.4 alkyl", "C\^ alkyl" or "alkyl" groups as used herein is meant to include both straight or branched chain radicals of 1 to 10, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, wt-butyl, and the like. "Alkenyl" means both straight or branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl, 1- propenyl, 2-propenyl, 2-propynyl, or 3-methyl-2-propenyl.

The term "cycloalkyl" or "cycloalkyl alkyl" means groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl.

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

'Ηalo" 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 D 1 or TNF levels as a postranslational event

The phrase 'TNF mediated disease or disease states" means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6. A disease state in which IL-1, for instance is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF. As TNF-β (also known as lymphotoxin) has close structural homology with TNF-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 afreets 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 HIV gene expression and/or replication, and/or (b) any cytolrine-mediated disease associated problem such as cachexia or muscle degeneration. Preferrably, this cytokine is TNF-α.

All of the compounds of Formulas (la) or (lb) 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 Formulas (la) or (lb) 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:

While the following preferred compounds are more or less described in terms of preferring a symetrical molecule, each substituent described herein above, and below, may be independently varied based on the definitions of each provided herein. For example R\ may be a cyclopentyl group and a CF3 group within the same molecule of a given embodiment of Formula (la), (lb) or (Ic). Similarly each and every one of the other groups may be independently selected, or may be the same, in any given embodiment of this invention. When Ri 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 are CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl with or without an OH group, C7.11 polycycloalkyl, (3- or 4- cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or Ci-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2)0-2CH3, -(CH2)1-3O(CH2)0-2CH3, and -(CH2)2-4OH.

When the Ri term contains the moiety (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 the other, e.g., (CR4R5) _n wherein n is 2 can be -CH2CH(-CH3)-, for instance. The individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon can optionally be substituted by fluorine independent of each other to yield, for instance, the preferred R] substitutions, as noted above.

When Ri is a C7-11 polycycloalkyl, examples are bicyclo[2.2J]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2J]octyl, etc. additional examples of which are described in Saccamano et al, WO 87/06576, published 5 November 1987. 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.

Z is preferably C(O)Ri4, C(O)ORi4, C(O)NRιoRl4, C(NRiθ)NRi()Rl4, CN, C(NOR8)R8. C(O)NRδNR8C(O)R8, C(NR8)NRiθRl4. C(NCN)NRιoR14, C(NCN)SR9, (1-, 4- or 5-[R8}-2-imidazolyl), (1-, 4- or 5-(R8)-3-pyrazolyl), (1-, 2-

or 5-{R8)-4-triazolyl[ ,3]), (1-, 2-, 4- or 5-{R8}-3-triazolyl[ 1,2,4]), (1- or 2- {R8}-5-tetrazolyI), (4- or 5-{R8)-2-oxazolyl), (3- or 4-{R8)-5-isoxazolyl), (3- {R8}-5-oxadiazolyl[l,2,4]), (5-{R8}-3-oxadiazolyl[l,2,4]), (5- {R8}-2-oxadiazolyl[l,3,4]), (5-{R8)-2-thiadiazolyl[l,3,4]), (4- or 5-{R8)-2-thiazolyl), (4- or 5-{R8)-2-oxazolidinyl), (4- or 5-{R8}-2-thiazolidinyl),(l-, 4- or

5-{R8)-2-imidazolidinyl); most preferred are those compounds wherein the R8 group of Z is R4. Z is preferably C(O)Ri4, C(O)ORl4, or C(O)NRιoRl4*

Preferred X groups are those wherein X is YR2 and Y is oxygen. The preferred X2 group is oxygen. The preferred X3 is hydrogen. Preferred R2 groups, where applicable, are Cl-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 Cl-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.

Preferred R7 moieties include optionally substituted -(CH2)l-2(cyclopropyl), -(CH2)0-2(cyclobutyl), -(CH2)0-2(cyclopentyl) with or without an OH group, -(CH2)0-2(cyclohexyl), -(CH2)0-2(2-, 3- or 4-pyridyl), -(CH2)l-2(2-imidazolyl), -(CH2)2(4-morpholinyl), -(CH2)2(4-piperazinyl), -(CH2) 1 -2(2-thienyl), -(CH2) 1 -2(4- thiazolyl), and -(CH2)0-2phenyl;

Preferred rings when Rio and Rl l in the moiety -NRioRl 1 together with the nitrogen to which they are attached form a 5 to 7 membered ring containing at least one additional heteroatom selected from O, N or S include, but are not limited to 1- imidazolyl, 2-(Rs)- 1 -imidazolyl, 1-pyrazolyl, 3-(R8)- 1 -pyrazolyl, 1 -triazolyl, 2- triazolyl, 5-(R8)-l-triazolyl, 5-(R8)-2-triazolyl, 5-(R8)-l-tetrazolyl, 5-(R8)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(Rβ)-l- piperazinyl, or pyrrolyl ring.

Preferred rings when Rio and R14 in the moiety -NR10R14 together with the nitrogen to which they are attached form a 5 to 7 membered ring containing at least one additional heteroatom selected from O, N or S include, but are not limited to 1- imidazolyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, and pyrrolyl. The respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I). Illustrations of such carbon substitutions includes, but are not limited to, 2-(R7)-l-imidazolyl, 4-(R7)-l -imidazolyl, 5-(R7)-l -imidazolyl, 3-(R7)-l-pyrazolyl, 4-(R7)-l -pyrazolyl, 5-(R7)-l -pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-l -triazolyl, 5-(R7)-l -triazolyl, 5-(R7)-lJetrazolyl, 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, tlie ring can be substituted one or more times by R7.

Preferred groups for NR10R1 which contain a heterocyclic ring are 5-(Rl4)- 1-tetrazolyl, 2-(Rι 4)- 1 -imidazolyl, 5-(Ri4)-2-tetrazolyl, or 4-(R ₁₄ )- 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[l,3,4]), (2-thiadiazolyl[l,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl). When the R7 group is optionally substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, the heterocyclic ring itself may be optionally substituted by R8 either on an available nitrogen or carbon atom, such as 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 Rs*

Preferred are those compounds of the Formula (I) wherein R is -CH2- cyclopropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl unsubstituted or substituted with an hydroxyl group, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -Cl-2 alkyl optionally substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluσro-substituted alkyl, and W is alkynyl of 2 to 4 carbon atoms.

Most preferred arc those compounds wherein Ri is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; X4 is hydrogen, R2 is CF2H or methyl and W is acetylene or 1,3-butadiyπyl, and Z is C(O)ORi4. Exemplified compounds are:

1 ,4-bis- 1 [c-4-(3-cyclopentyloxy-4-methoxyphenyl)-r- 1 -cyclohexancarboxylic acid]-4-yl } buta- 1 ,3-diyne, and 1 ,4-bis- [ [methyl c-4-(3-cyclopentyloxy-4- methoxyphenyl)-r-l-cyclohexancarboxylate]-4-yl] buta-l,3-diyne.The following examples are set forth to illustrate the invention. These examples are not intended to limit the scope of the invention in any manner or fashion. Reference is made to the claims for what is reserved to the inventor hereunder. Methods Of Preparation

Synthetic Scheme(s) With Textual Description

Compounds of Formula (la), wherein W is a 1,3-butadiynyl and wherein A and B represent Z as defined above 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 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-

Schema 1

a) Cu(OAc ) ₂ «H ₂ 0, DMF or C _S H ₅ N

likewise, compounds of Formula (lb), wherein W is a 1,3-butadiynyl and wherein A and B represent Z as defined above or a group convertible to Z and wherein X4 represents X4 as defined above or a group convertible to X4, 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 the 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 the Formula 3-Schcmc 2-

Schema 2

a) Cu(OAc ) ₂ "H ₂ 0, DMF or C ₅ H ₅ N

Reduction of a compound of the Formula (lb), wherein W is a 1,3-butadiynyl and wherein Z represents Z as defined above 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 the Formula (lb), wherein W is a 1,3- butadiynyl and wherein Z represents Z as defined above or a group convertible to Z, to provide a compound of the Formula (lb) 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).

Alternatively, compounds of the Formula (la), wherein W and Z represent W and Z as defined above or a group convertible to W or Z, may be prepared from the corresponding ketones as, e.g., compound 1 -Scheme 3. by the synthetic procedures described in co-pending U.S patent application number 07/862,030 filed 2 April 1992 and its progeny USSN 07/968,762 filed 30 October 1992 and PCT appliation number PCT/US93/01991 designating the United States as a continuing application and filed 05 March 1993; syntheses of such ketone starting materials are described in co- pending U.S application serial number 07/862,083 and 07/968,753 and PCT

application serial number PCT/US93/02045 filed 05 March 1993 (designating the U.S. as a continuation application) now published.

Scheme 3

Likewise, compounds of Formula (lb) wherein W, X4 and Z represent W, X4 and Z as defined in relation to Formula (lb) or a group convertible to W, X4 or Z, may be prepared from the corresponding ketones as, e.g., compound 1- Scheme 4. by the synthetic procedures described in United States patent application cited above, i.e., 07/862,030 filed 2 April 1992 ; syntheses of such ketone starting materials are described in the aforementioned co-pending application (s) USSN 07/862,083 and its noted progeny.

Schema 4

Depending upon die exact nature of the Z groups of the compounds of Formula (la) and die Z and X4 groups of the compounds of the Formula (lb), the Z and X4 groups may require protection during the coupling and/or reductive steps described herein, followed by deprotection, to provide the Formula (la) and (lb) compounds, as in processes described in a co-pending application U.S. assigned to the same owner and filed on even date herewith; 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.)

Preparation of the remaining compounds of the Formula (la) and (lb) may be acccmiplished by procedures analogous to those described in the co-pending patent applications noted above and in the Examples, infra.

It will be recognized diat compounds of die Formula (I) and (lb) may exist in distinct diastereomeric forms possessing distinct physical and biological properties; such isomers may be separated by standard chromatographic methods. The following examples are given to illustrate the invention and are not intended to limit it in any fashion. Reference is made to the claims for what is reserved to the inventor hereunder.

Synthetic Examples Example 1

Preparation of 1.4- τ-frmethvl c-4-π-cvclopentvloxv-4-methoxvphenvn-r-l- cyclphexane carbpχyiatel-4-yl ) buta- 1 ,3-diyne la) -r4-r3-cvclopentvloxv-4-methoxvphenvn-4-formvlcvclohexane- 1 -carhoxvlic acid! To a suspension of ctf-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyano cyclohexane-1-carboxylic acid] (1.002 g, 2.91 mraol, prepared as described in U.S patent application number 07/862,030 filed 2 April 1992 and its progeny USSN 07/968,762 filed 30 October 1992 and PCT appliation number PCT/US93/01991) in toluene (30 mL) at 0°C under an argon atmosphere was dropwise added over 15 min. a 1.0 M solution of diisobutylaluminum hydride in toluene (6.00 mL, 6.00 mL). The solution was stirred for 2 h at room temperature, then was quenched at 0°C with saturated ammonium chloride, was diluted with ethyl acetate and 10% hydrochloric acid (50 mL), and was extracted twice with ethyl acetate. The extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 5:95 methanol/dichloromediane provided c«-[4-(3-cyclopentyloxy-4- meώoxyphenyl 4-foιmylcyclohexane-l-carboxylic acid] as a white solid, m.p. 137- 139°C. -1H-NMR (400 MHz, CDCI3) δ 9.31 (s, 1H), 6.85 (m, 2H), 6.77 (m, 1H),

4.75 (m, IH), 3.83 (s, 3H), 2.58 (br d, J=12Hz, 2H), 2.35 (m, IH), 2.09 (m, 2H), 1.8 - 2.0 (m, 6H), 1.5 - 1.8 (m, 6H).

1 hi cfrJmethvl 4-f -cvclopentvloxv-4-methoxvphenvlV4-formvlcvclohexane- 1 - cartoxylaiel

To a suspension of 80% sodium hydride/mineral oil (0.029g, 0.96 mmol) in hexamethylphosphoramide (1 mL) at room temperature under an argon atmosphere was added dropwise a solution of cύ-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4- foπnylcyclohexane-1-carboxylic acid] (0.30g, 0.87 mmol) in hexamethylphosphoramide (1 mL). After 0.5 h, dimediyl sulfate (0.090 mL, 0.96 mmol) was added and stirring was continued for an additional hour. The reaction was quenched with saturated ammonium chloride and was extracted twice with ethyl acetate. The extract was washed tiiree times with water, once with brine, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate/hexanes, provided cw-[methyl 4-(3-cyclopentyloxy-4- methoxyphenyl)-4-formylcyclohexane-l -carboxylate] as a colorless oil. -1H-NMR (400 MHz, CDC13) δ 9.31 (s, IH), 6.84 (m, 2H), 6.76 (m, IH), 4.75 (m, IH), 3.97 (s, 3H), 3.68 (s, 3H), 2.56 (br d, J=12 5Hz, 2H), 2.30 (m, IH), 1.8 - 2.0 (m, 10H), 1.5 - 1.7 (m, 4H).

1 c traτu-\ et v\ 4-f 3-cvclopentvloxv-4-methoxvphenvn-4-ethvnvlcvclohexane- 1 - carhoxvlatel

A solution of dimethyl (diazomethyl)phosphonate (0.407 g, 2.71 mmole, prepared as in Seyferth, D.; Marmor, R.S.; Hilbert, P. J. Org. Chem. 1971, 36(10), 1379- 1386) dissolved in dry tetrahydrofuran (4 mL) at -78°C was added via cannulation to a solution of potassium t-butoxide (0.344 g, 3.06 mmol) dissolved in dry tetrahydrofuran (4 mL) at -78°C under an argon atmosphere. After 15 min, a solution of cis- [methyl 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexane-l- carboxylate] (0.552 g, 1.53 mmol) in dry tetrahydrofuran (4 mL) at -78°C was added rapidly. The reaction was allowed to warm gradually to room temperature over lh and was stirred for an additional hour. The reaction was quenched with saturated ammonium chloride, was extracted three times with dichloromed ane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 1:9 ethyl acetate/hexanes, provided frα/w-[methyl 4-(3-cyclopentyloxy-4- methoxyphenyl)-4-edιynylcyclohexane-l -carboxylate] as a colorless oil. -^H-NMR (400 MHz, CDCI3) δ 7.14 (d, J=2.1Hz, IH), 7.04 (dd, J=8.4, 2.1Hz, IH), 6.83 (d, J=8.4Hz, IH), 4.80 (m, IH), 3.84 (s, 3H), 3.71 (s, 3H), 2.45 (s, IH), 2.33 (m, IH), 1.8 - 2.1 (m, 12H), 1.70 (m, 2H), 1.56 (m, 2H).

Id) 1-4- τ-frmethvl r-4-n-cvclopentvloxv-4-methoxvphenvn-r-l-cvclohexane- carbpχylatel-4-yJ 1 buta- I .3-diync

A mixture of irfl/tr-[methyl 4-(3-cyclopentyloxy-4-methoxyphenyl)-4- ethynylcyclohexane-1 -carboxylate] (0.075 g, 0.21 mmol) and copper acetate monohydrate (0.126g, 0.63 mmol) in dimethylformamide (2 mL) was stirred at 65- 70°C under an argon atmosphere for lh, then was cooled. The reaction was diluted with water and was extracted twice with ethyl acetate. The extract was washed three times with water , once with brine, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate/hexanes, provided 1 ,4- to- ( [methyl c-4-(3-cyclopentyloxy-4-methoxyphenyl)-r- 1 -cyclohexane carboxylate]-4-yl } buta- 1 ,3-diyne as a white solid, mp.l 30- 131 °C. Anal calcd for C44H54O8 I.25 H2O: C, 72.06, H.7.76; found: C, 72.16, H, 7.50. -1H-NMR (400 MHz, CDCI3) δ 7.09 (d, J=2.2Hz, 2H), 7.01 (dd, J=8.4, 2.2Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 4.80 (m, 2H), 3.84 (s, 6H), 3.71 (s, 6H), 2.31 (m, 2H), 1.5 - 2.1 (m, 32H).

Example 2

Preparation of 1 A-hia- f f c- 4-f3-cvclσρentyloxy-4-methoxyphenvn-r-1-cvclohexane cartoxylic acidH-yl ) buta- 1.3-diyne

2a) trans-] 4-f 3-cvclopentv1oxv-4-methoxvphen vn-4-ethvnvlcvcIohexane- -carfeoxvlic acid!

A solution of dimethyl (diazomethyl)phosphonate (0.30 g, 2.0 mmole, prepared as in Seyferth, D.; Marmor, R.S.; Hilbert, P. J. Org. Chem. 1971, 36(10), 1379-1386) dissolved in dry tetrahydrofuran (2 mL) at -78°C was added via cannulation to a solution of potassium t-butoxide (0J69 g, 1.50 mmol) dissolved in dry tetrahydrofuran (2 mL) at -78°C under an argon atmosphere. After 15 min, a solution of cis-[ 4-(3- cyclopentyloxy- memoxyphenyl)-4-fσrmylcyclohexane-l-carboxylic acid] (0J73g, 0.5 mmol) in dry tetrahydrofuran (2 mL) at -78°C was added rapidly. The reaction was allowed to warm gradually to room temperature over 1 h and then was stirred for an additional hour. The reaction was quenched with saturated ammonium chloride, was acidified with 10 % hydrochloric acid, was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3.J ethyl acetate/hexanes, provided trans-[ 4-(3-cycIopentyloxy-4- methoxyphenyl)-4-ethynylcyclohexane-l-carboxylic acid] as a white solid, m.p. 152- 153°C. - -NMR (400 MHz, CDCI3) δ 7J5 (d, J=2.2Hz, IH), 7.04 (dd, J=8.5,

2.2Hz, IH), 6.83 (d, J=8.5Hz, IH), 4.80 (m, IH), 3.84 (s, 3H), 2.46 (s, IH), 2.37 (m, IH), 2.07 (m, 6H). 1.8 - 2.0 (m, 6H), 1.73 (m, 2H), 1.62 (m, 2H).

2M 1.4-bis- ( fc-4-f 3-cvclopentvloxv-4-methoxvphen vl Vr- 1 -cvclohexane caifaoxvlic acidl-4-vl 1 buta- 1.3-di vne

A mixture of ra/tr-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4- ethynylcyclohexane-1-carbox lic acid] (0J01 g, 0.29 mmol) and copper acetate monohydrate (0J76 g, 0.88 mmol) in dimethylformamide (2 mL) was stirred at 70- 75°C under an argon atmosphere for 3h. Additional copper acetate monohydrate (0J75g, .88 mmol) was added and stirring was continued for 16 h. The reaction was diluted with water and was extracted twice with ethyl acetate. The extract was washed three times with water , once with brine, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 0.5:5:95 acetic acid/medianol/dichloromemane, provided l,4-bis-{[c- 4-(3-cyclopentyloxy-4- methoxyphenyl)-r-l-cyclohexane carboxylic acid]-4-yl)buta-l,3-diyne as a white solid, mp >230°C. Anal calcd for C42H50O8 O.75 H2O: C, 72.44; H, 7.45; found: C, 72.17; H, 7.27. Utility Examples

EXAMPLE A Inhibitory effect of compounds of Formulas la or b) on in vitro TNF production bv human monocytes

The inhibitory effect of compounds of Formulas (la) or (lb) 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 Formulas (la) or (lb). The protocol used in these models is described in Badger et al, EPO published Application 0411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990.

The compound of Example 1 herein demonstrated a positive in vivo response in reducing serum levels of TNF induced by the injection of endotoxin.

EXAMPLE C Isolation of PDE Isozymes

The phosphodiesterase inhibitory activity and selectivity of the compounds of

Formulas (la) or (lb) can be determined using a battery of five distinct PDE isozymes. The tissues used as sources of the different isozymes are as follows: 1) PDE lb, porcine aorta; 2) PDE Ic, guinea-pig heart; 3) PDE HI, guinea-pig heart; 4) PDE IV, human monocyte; and 5) PDE V (also called "la"), canine trachealis. PDEs la, lb, Ic and m are partially purified using standard chromatographic techniques [Torphy and

Cieslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE IV is purified to kinetic

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