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Title:
3,3-(DISUBSTITUTED)CYCLOHEXAN-1-ONE MONOMERS AND RELATED COMPOUNDS
Document Type and Number:
WIPO Patent Application WO/1996/020158
Kind Code:
A1
Abstract:
This invention relates to derivatives of 3,3-(disubstituted)cyclohexan-1-one monomers and related compounds which are useful for treating allergic and inflammatory diseases.

Inventors:
Christensen IV, Siegfried B.
Karpinski, Joseph M.
Ryan, Dominic M.
Bender, Paul E.
Application Number:
PCT/US1995/016710
Publication Date:
July 04, 1996
Filing Date:
December 21, 1995
Export Citation:
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Assignee:
Smithkline
Beecham
CORPORATION
Christensen IV, Siegfried B.
Karpinski, Joseph M.
Ryan, Dominic M.
Bender, Paul E.
International Classes:
C07D271/06; A61K31/41; A61K31/4245; A61P11/00; C07B57/00; C07C45/67; C07C45/68; C07C45/78; C07C49/753; C07C59/90; C07C65/40; C07C69/738; C07C69/76; C07C205/45; C07C225/22; C07C233/33; C07C233/76; C07C255/56; C07C311/08; C07D271/10; C07D285/12; (IPC1-7): C07C69/76
Foreign References:
DE2748466A1
Other References:
See also references of EP 0799183A1
Download PDF:
Claims:
What is claimed is:
1. A compound of Formula (I) wherein: Rl is (CR4R5)nC(0)0(CR4R5)mR6, (O R5)n (0)NR4(CR4R5)m 6, (CR4R5)nO(CR4R5)ιrιR j or (CR4R5)rR6 wherein the alkyl moieties may be unsubstituted or substituted widi one or more fluorines; m is 0 to 2; n is 0 to 4; r is 0 to 6; R4 and R5 are independendy hydrogen or C 12 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi3 alky halo substituted aryloxyCi3 alkyl, indanyl, indenyL C711 polycycloalkyl, tetrahydrofiiranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, d iopyranyl, C36 cycloalkyl, or a C46 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic moiety may be unsubstituted or substituted by 1 to 3 methyl groups, one etiiyl group, or an hydroxyl group; provided that: a) when R6 is hydroxyl, dien m is 2; or b) when R6 is hydroxyl, tiien r is 2 to 6; or c) when R6 is 2tetrahydropyranyl, 2teijahydrothiopyranyl, 2tetrahydrofuranyl, or 2tetrahydrodienyl, dien m is 1 or 2; or d) when Rβ is 2tetrahydropyranyl, 2tetrahydrothiopyranyl, 2tetrahydrofuranyl,or 2tetrahydrodιienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R6 is odier than H in (CR4R5)nO(CR4R5)mR6; X is YR2, fluorine, NR4R5, or formyl amine; Y is O or S(O)m'; m' is O, l, or 2; X.
2. is O or NR8; X.
3. s hydrogen or X; R2 is independendy selected from CH3 or CH2CH3 unsubstituted or substituted by 1 or more fluorines; s is 0 to 4; R3 is COOR14, C(0)NR4Rl4 or R7; 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 O, NR7, NCR4R5C26 alkenyL NOR14, NOR15, NOCR4R5C26 alkenyl, NNR4R14, NNR4R15, NCN, NNR8C(0)NR8Rl4, NN 8C(S)NRgRi4, or =Z is 2(l,3dithiane), 2(13dithiolane), dimethylthio ketal, diethylthio ketal, 2(l,3 dioxolane), 2(l,3dioxane), 2(l,3oxathiolane), dimethyl ketal or diethyl ketal; R7 is (CR4R5)qRi2 or C g alkyl wherein the R12 or C g alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 13 fluorines, F, Br, Cl, NO2, NRioRn, C(0)R8, CO2R8, O(CH2)24θR8, 0(CH2)qR8, CN, C(O)NRι0Rl l, O(CH2)qC(O)NRιoRι ι, 0(CH2)qC(0)R9, NRioC(0)NRioRll, NRioC(0)Rn, NRιoC(O)OR9, NRi0C(O)Ri3, C(NRιo)NRιoRl l, C(NCN)NRιoRl l, C(NCN)SR9, NRioC(NCN)SR9 , NRlθC(NCN)NRιoRl l, NRioS(O)2R9, S^m^, NRlθC(O)C(O)NRιoRl 1, NRlθC(O)C(O)Rlθ, or R13; q is O, l, or 2; R12 is R13, C3C7 cycloalkyl, (2, 3 or 4pyridyl), pyrimidyl, pyrazolyl, (1 or 2imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2 or 3thienyl), quύκ>linyL naphthyl, or phenyl; Rg is hydrogen or R9; R9 is Cι_4 alkyl unsubstituted or substituted by one to three fluorines; Rio is ORδ or Rn; Rj 1 is hydrogen, or Cι_4 alkyl unsubstituted or substituted by one to tiiree fluorines; or when Rio and Rl l are as NRioRl 1 they may together with die nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S; R13 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and where Rι3 is substituted on Rι2 or Rπ the rings are connected drrough a carbon atom and each second Rι3 ring may be unsubstituted or substituted by one or two C 2 alkyl groups unsubstituted or substituted on die methyl with 1 to 3 fluoro atoms; Rj.
4. is hydrogen or R7; or when Rs and R 1.
5. are as NR8R1.
6. diey may togedier widi die nitrogen form a.
7. o 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S; Rl5 is C(0)Rl4, C(0)NR4Rl4, S(0)2R7, or S(0)2NR4Rl4; provided diat: (f) R7 is not C1.4 alkyl unsubstituted or substituted by one to diree fluorine or die pharmaceutically acceptable salts diereof.
8. 2 A compound according to claim 1 wherein Ri is CH2cyclopropyl, cyclopentyl, 3hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; R2 is CF2H or mediyl, W is ediynyl or 1,3butadiynyl, R3 i substituted or unsubstituted pyrimidinyl ring, X is YR2. and Z is O, NR7.
9. 3 _ A compound according to claims 1 wherein Ri is CH2cyclopropyl, cyclopentyl, 3hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; R2 is CF2H or mediyl, W is ethynyl or 1,3butadiynyl, R3 is R where R is an unsubstituted or substituted aryl or heteroaryl ring, excluding pyridiminyl, X is YR2, and Z is O.
10. 4 _ A compound according to claim 4 which is (+/) 3(3cyclopentyloxy4methoxyphenyl)3phenylethynylcyclohexanlo (+/) 3(3cyclopentyloxy4methoxyphenyl)3(3 carbomethoxyphenyl)ethynylcyclohexan 1 one, (+/) 3(3carboxyphenylethynyl)3(3cyclopentyloxy4 methoxypheny l)cyclohexan 1 one, 3(3cyclopentyloxy4methoxyphenyl)3[3(5methyl[ 1 ,3,4]thiadiazol2 yl)phenylethynyl]cyclohexan 1one, 3(3cyclopentyloxy4methoxyphenyl)3[3(5 methyl[ 1 ,3,4]oxadiazol2yl)phenylethynyl]cyclohexan 1 one, 3(3 cyclopentyloxy4methoxyphenyl)3[3(3methyl[ 1 ,2,4]oxadiazol5 yl)phenyledιynyl]cyclohexanlone, 3(3cyclopentyloxy4methoxyphenyl)3[3(5 methyl[ 1 ,2,4]oxadiazol3yl)phenylethynyl]cyclohexan 1 one, 3(3 cyclopentyloxy4methoxyphenyl)3(3cyanophenylethynyl)cyclohexanlone, 3(3cyclopentyloxy4methoxyphenyl)3(3nitrophenylethynyl)cyclohexanl one, 3(3cyclopentyloxy4methoxyphenyl)3(2 hydroxyethoxyphenylethynyl)cyclohexan 1 one, 3(3acet3midophenyledιynyl)3(3cyclopentyloxy4 methoxyphenyl)cyclohexan 1 one, 3(3cyclopentyloxy4methoxyphenyl)3(3 memanesulf onaιτudophenylethynyl)cyclohexan 1 one, 3(3 uτύnophenylethynyl)3(3cyclopentyloxy4methoxyphenyl)cyclohexan 1one, (+/)3(4carboxyphenylethynyl)3(3cyclopentyloxy4 methoxyphenyl)cyclohexan 1 one, 3(3cyclopentyloxy4methoxyphenyl)3[3(5 fluoromethyl [ 1 ,2,4]oxadiazol3yl)phenyledιynyl)cyclohexan 1 one, (+) and () 3(3cyclopentyloxy4medιoxyphenyl)3phenylethynylcyclohexan 1one, or 3[3N(4bromobenzyl)benzamido]ethynyl3(3cyclopentyloxy4 methoxyphenyl)cyclohexan 1 one. 5. A pharmaceutically acceptable composition comprising a compound according to eidier of Formula I according to claims 1 and a pharmaceutically acceptable excipient .
11. A method for treating asthma which comprises administering to a mammal in need tiiereof an effective amount of a compound of Formula (I) according to claim 1 alone or admixed widi a pharmaceutical excipient.
12. A compound of Formula π wherein: Ri is (CR4R5)nC(0)0(CR4R5)mR6, (CR4R5)nC(0)NR4(CR4R5)mR6, (CR4R5)nO(CR4R5)πR6, or (CR4R5)rR6 wherein the alkyl moieties may be unsubstituted or substituted with one or more fluorines; m is 0 to 2; n is 0 to 4; r is 0 to 6; R4 and R5 are independendy hydrogen or C 12 alkyl; R6 is hydrogen, mediyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi3 alkyl, halo substituted aryloxyCl3 alkyl, indanyl, indenyl, C711 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyL pyranyl, tetrahydrothienyL thienyl, tetrahydrothiopyranyl, thiopyranyl, C36 cycloalkyL or a C46 cycloalkyl containing one or two unsaturated bonds, wherein d e cycloalkyl or heterocyclic moiety is 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, then r is 2 to 6; or c) when R6 is 2tetrahydropyranyl, 2tetrahydrothiopyranyl, 2tetrahydrofuranyl, or 2tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2tetrahydropyranyl, 2tetrahydrothiopyranyl, 2tetrahydrofuranyl,or 2tetrahydrothienyl, 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 YR2, fluorine, NR4R5, or formyl amine; Y is O or S(0)m, m' is 0, 1, or 2; X2 is O orNR8J X3 is hydrogen or X; R2 is independendy selected from CH3 or CH2CH3 unsubstituted or substituted by 1 or more fluorines; s is 0 to 4; R3 is COOR14, C(O)NR4Rl4 or R7; W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 t carbon atoms; Z is C(Y')Rl4, C(O)ORi4, C(Y,)NRlθRl4, C(N io)NRio l4, CN, C(NOR8)Rl4, C(0)NRgNR8C(O)R8, C(O)NRsNRiθRl4, C(NORi4)R8, C(NR8)NRlθRl4, C(NRi4)NR8R.
13. C(NCN)NRiθRl4, C(NCN)SR9, (2, 4 or 5imidazolyl), (3, 4 or 5pyrazolyl), (4 or 5triazolyl[ 1,2,3]), (3 or 5triazolyl[ 1,2,4]), (5tetrazolyl), (2, 4 or 5oxazolyl), (3, 4 or 5isoxazolyl), (3 5oxadiazolyl[l,2,4]), (2oxadiazolyl[l,3,4]), (2thiadiazolyl[ 1,3,4]), (2, 4, or 5dιiazolyl), (2, 4, or 5oxazolidinyl), (2, 4, or 5thiazolidinyl), or (2, 4, or 5imidazolidinyl); wherein all of the heterocylic ring systems may be optionally substituted one or more times by R14; Y is O or S; R7 is (CR4R5)qRl2 or C\. alkyl wherein the R12 is phenyl or C\._ alkyl group is unsubstituted or substituted one or more times by C 12 alkyl unsubstituted substituted by one to tiiree fluorines, F, Br, Cl, NO2, Si(R4)3, NR QRI 1. C(O)R8, O(CH2)24θR8. CO2R8, OR8, CN, C(O)NRioRl l, OC(0)NRιoRll, OC(0)R8, NRiθC(O)NRiθRll, NRιoC(O)Rn, NRlθC(O)OR9, NRiθC(0)Ri3, C(NRlθ)NRiθRll, C(NCN)NRιoRl l, C(NCN)SR9, NRiθC(NCN)SR9 , NRioC(NCN)NRιoRll, NRlθS(O)2R9, S(0)m'R9, NRi0C(O)C(O)NRi0Rll, NRiθC(0)C(O)RlO, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; q is O, l, or 2; Rl2 is R13, C37 cycloalkyl, (2, 3 or 4pyridyl), pyrimidyl, pyrazolyl, (1 or 2imidazolyl), thiazolyl, triazolyl, pyrrolyL piperazinyl, piperidinyl, morpholinyl, furanyl, (2 or 3tiιienyl), (4 or 5thiazolyl), quinolinyl, naphthyl, or phenyl; R is independently selected from hydrogen or R9; R9 is Cι_4 alkyl unsubstituted or substituted by one to three fluorines; Rlθ is OR8 or Rn; Rl 1 is hydrogen, or C1.4 alkyl unsubstituted or substituted by one to diree fluorines; or when Rio and Rl 1 are as N ioRl 1 they may together widi die nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S; Rl3 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and where Rπ is substituted on Rι2 or Rι3 the rings are connected tiirough a carbon atom and each second Rι3 ring may be unsubstituted or substituted by one or two Cι_2 alkyl groups unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms; R 4 is hydrogen or R7; or when R8 and R14 are as NR8R14 they may together with die nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S; provided that: (f) R7 is not Cι_4 alkyl unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof.
14. 8 A compound according to claim 8 wherein Ri is CH2cyclopropyl, cyclopentyl, 3hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; R2 is CF2H or methyl, W is ethynyl or 1,3butadiynyl, R3 is a substituted or unsubstituted pyrimidinyl ring, X is YR2, and Z is O, NR7.
15. 9 A pharmaceutically acceptable composition comprising a compound according to either of Formula II according to claims 8 and a pharmaceutically acceptable excipient.
Description:
3 -Φisu stituted)cyclohexan-l-one Monomers and Related Compounds Field of Invention

The present invention relates to novel 3,3-(disubstituted)cyclohexan-l-one n-onomers 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 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 die 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 inflanirnatory 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 neutrσphils 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 Necrosi

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

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

Cytokines, specifically TNF, are implicated in activated T-cell-mediated HTV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV-infected individual aids in ---tniting the maintenance of T cell activation, thereby reducing the progression of HTV infect-vity 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 d e level of viral replication is dependent upon die 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 l-imiting 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 Rϋpi et al., j-nfection and fcnmunity, 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 In a first aspect, this invention relates to compounds of Formula (I):

wherein:

R λ is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, (CR4R5) n O(CR4R5) m R6, or -(CR4R5) r R6 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 hydrogen or Ci-2 alkyl;

R is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCl-3 alkyl halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7.11 polycycloalkyl tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrorhienyl, thienyl, tetrahydrot iopyranyl, 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, 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-tet-^ydrothiopyranyl, 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 YR2, fluorine, NR4R5, or formyl amine;

Y is O or S(O)nϊ; m' is 0, 1, or 2;

X2 is O or NR8;

X3 is hydrogen or X;

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

R3 is COOR14, C(O)NR4Rl4 or R7;

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 O, NR7, NCR4R5C2-6 alkenyl, NOR14, NOR15, NOCR4R5C2-6 alkenyl, NNR4R14, NNR4R15, NCN, NNR8C(0)NR8Rl4, NNRδC(S)NR8Rl4, or =Z is 2-(l,3-dithiane), 2-(l,3-didιiolane), dimethylthio ketal, diediyldiio ketal, 2-(l,3- dioxolane), 2(l,3-dioxane), 2-(l,3-oxadιiolane), dimethyl ketal ordiediyl ketal;

R7 is -(CR4R5)qRi2 or C\._ alkyl wherein the R12 or C\.(, alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, -F, -Br, -Cl, -NO2, -NRJORJ 1, -C(O)R8, -CO2R8, -O(CH 2 ) 2 -4θR8> -O(CH 2 ) q R8, -CN, -C(O)NRιoRll, -O(CH 2 ) q C(O)NRιoRll, - 0(CH 2 ) q C(0)R9, -NRlθC(O)NRiθRll, -NRioC(0)Rn, -NRiθC(O)OR9, -NRioC(O)Ri3, -C(NRiθ)NRiθRll, -C(NCN)NRiθRll, -C(NCN)SR9,

-NRιoC(NCN)SR9 , -NRioC(NCN)NRiθRιi, -NRioS(O)2R9, -S(O) m 'R9, -NRl0C(O)C(O)NRl0Rll, -NRiθC(O)C(O)Riθ, or R 13 ; q is 0, 1, or 2;

Rl2 is Rj3, C3-C7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, rnαroholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or pheny

Rg is hydrogen or R9;

R9 is Cj_4 alkyl unsubstituted or substituted by one to three fluorines;

RlO is ORδ orRn; Ri 1 is hydrogen, or Cj_4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Ri 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S;

Rl3 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyL isoxazolyl, oxadiazolyl, and tl iadiazolyl, and where Rι 3 is substituted on Rι 2 or R ]3 die rings are connected through a carbon atom and each second Rι 3 ring may be unsubstituted or substituted by one or two Cj_2 alkyl groups unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms; R14 is hydrogen or R7; or when R8 and R14 are as NR8R14 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S;

Rl5 is C(O)Ri4, C(0)NR4Rl4, S(0)2R7, or S(O)2NR4Rl4; provided that: (0 R7 is not Cι_4 alkyl unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof. Another set of compounds of mis invention are represented by Formula (U):

wherein:

Rl is -(CR4R5)nC(0)0(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, (CR4R5)nO(CR4R5)mR6, or -(CR4R5) r R6 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 independenUy hydrogen or Ci-2 alkyl;

R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alk halo substituted aτyloxyCi-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 or heterocyclic moiety is 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-tetrahydropyranyl, 2-teιτahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-teuahydrothienyl, 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, men R6 is other than H in

-(CR4R5)nO(CR4R5)mR6; X is YR2, fluorine, NR4R5, or formyl amine;

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

X2 is O or NRδ;

X3 is hydrogen or X; R2 is independendy selected from -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more fluorines; s is 0 to 4;

R3 is COOR14, C(0)NR4Rl4 or R7;

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

Z' is C(Y)Ri4, C(0)ORi4, C(Y')NRiθRl4, C(NRio)NRιoRl4, CN, C(NOR8)Rl4, C(O)NRgNR8C(O)R8, C(O)NR8NRιoRl4, C(NORl4)R8, C(NR8)NRlθRl4, C(NRi4)NRδR8 C(NCN)NRlθRl4, C(NCN)SR9, (2-, 4- or 5-ιmidazolyl), (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[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 may be optionally substituted one or more times by R14;

Y is O or S;

R7 is -(CR4R5)qRi2 or C\._ alkyl wherein me R12 is phenyl or C . 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, -NRIQRI J, -C(0)R8, -0(CH2)2^0R 8 , -CO2R8, -OR8, -CN, -C(0)NRιoRl 1, - OC(0)NRιoRn, -OC(0)R8, -NRioC(0)NRioRn, -NRιoC(0)Rn, -NRloC(0)OR9, -NRi0C(O)Rl3, -C(NRio)NRιoRn, -C(NCN)NRιoRn, - C(NCN)SR9, -NRιoC(NCN)SR9 , -NRiθC(NCN)NRιoRll, -NRlθS(0)2R9, -S(0) m 'R9. -NRιoC(0)C(0)NRιoRll, -NRlθC(0)C(0)Rio, thiazolyl, i---ώ-azolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; q is 0, 1, or 2;

Rl2 is R13, 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, or phenyl; Rg is independendy selected from hydrogen or R9;

R9 is Cι .4 alkyl unsubstituted or substituted by one to three fluorines; RlO is ORδ or Rn;

Ri is hydrogen, or C 1.4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Ri 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S;

Rl3 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and where Rι 3 is substituted on R t2 or R t3 the rings are connected through a carbon atom and each second Rj 3 ring may be unsubstituted or substituted by one or two C\.2 alkyl groups unsubstituted or substituted on d e methyl with 1 to 3 fluoro atoms;

Rj4 is hydrogen or R7; or when R8 and R14 are as NR8R14 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S; provided that:

(0 R7 is not Cj.4 alkyl unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof.

This invention also relates to the pharmaceutical compositions comprising a compound of Formula (I) and (II) and a phaπnaceutically acceptable carrier or diluent The invention also relates to a method of mediation or inhibition of the erizymatic activity (or catalytic activity) of PDE IN in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I) and (II) 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 adm-mstering 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 marrttnal, including humans, which method comrmses adimnistering 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 the treatment of additional viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo.

In addition, compounds of Formula (I) 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 admiiύstering to said mammal an effective amount of a compound of Formula (I) and (II).

Phosphodiesterase IV inhibitors are useful in the treatment of a variety of allergic and inllammatory diseases including: asthma, chronic bronchitis, atopic deπnatitis, 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 IN 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 TΝF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directiy or indirecdy, by the TΝF inhibitors of Formula (I) and (II). Such viruses include, but are not limited to HTV-1, HTV-2 and HTV-3, cytomegalovirus

(CMV), influenza, adeπovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.

This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV), which con-prises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I) and 0D>

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 (FIN) 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 TΝF or will elicit TΝF 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 irnidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; the class of compounds called the triazoles, such as fluconazole, and itranazole, and die class of compound called the Amphotericins, in particular Amphotericin B and liposomal Amphotericin B. The compounds of Formula (I) and (IT) may also be used for inhibiting and/or reducing die toxicity of an anti-fungal, anti-bacterial or anti-viral agent by administering an effective amount of a compound of Formula (I) and (II) to a mammal in need of such treatment Preferably, a compound of Formula (I) and (II) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.

The term "C1.3 alkyl", "Cι_4 alkyl", "Cι_6 alkyl" or "alkyl" groups as used herein is meant to include both straight or branched chain radicals of 1 to 10, unless die chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t -butyl, and the like. "Alkenyl" means both straight or branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited tiiereto, including but not hmited to vinyl, 1 - propenyl, 2-propenyl, 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 bot straight or branched chain radicals of 1 to 4 carbon atoms. "Heteroaryl" means an aromatic ring system containing one or more heteroatoms.

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

"-hlύbiting die production of IL- 1 " or "inhibiting the production of TNF' means: a) a decrease of excessive in vivo JL-1 or TNF levels, respectively, in a huma 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 vivo IL-1 or TNF levels, respectively, in a human to noπrial levels or below normal levels; or c) a down regulation, by inhibition of the direct synthesis of IL- 1 or TNF level as a postranslational event

The phrase 'TNF mediated disease or disease states" means any and all diseas 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 LL-1 or LL-6. A disease state in which LL-1, for instance is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF. As TNF-β (also known as lymphotoxin) has close structural homology with TNF-α (also known as cachectin), and since each induces similar biologic responses and binds to die same cellular receptor, both TNF- and TNF-β are inhibited by the compounds of the present invention and thus are herei referred to collectively as "TNF' unless specifically delineated odierwise. Preferably TNF-α is inhibited.

"Cytokine" means any secreted polypeptide diat 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 ly-rjphokines regardless of which cells produce diem. The cytokine inhibited by the present invention for use in the treatment of a HTV-infected human must be a cytokine which is implicated in (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HTV gene expression and/or replication, and or (b) any cyto-άne-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 rnammal, including humans, in need thereof. All of

the compounds of Formula (I) and (II) are useful in the method of inhibiting or mediating die enzymatic or catalytic activity of PDE IV and in treatment of disease states mediated thereby.

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 Ci-4 alkyl substituted by 1 or more fluorines. The preferred halo-substituted alkyl chain length is one or two carbons, and most preferred are the moieties -CF3, -CH2F, - CHF2, -CF2CHF2. -CH2CF3, and -CH2CHF2. Preferred Ri substitutents for the compounds of Formula (I) and (JJ) are CH2-cyclopropyl, CH2-C5-6 cycloalkyL C4-6 cycloalkyl unsubstituted or substituted widi OH, C7-11 polycycloalkyL (3- or 4- cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or Ci-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)2-4θH. When the Ri term is (CR4R5), the R4 and R5 terms are independendy hydrogen or alkyl. This allows for branching of the individual methylene units as (CR4R5)n or (CR4R5) m ; each repeating methylene unit is independent of 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 die branching hydrocarbon can unsubstituted or be substituted by fluorine independent of each other to yield, for instance, the preferred Ri substitutions, as noted above.

When Ri is a C7.11 polycycloalkyl, examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0 2 '°]deeyl, etc. additional examples of which are described in Saccamano et al, WO 87/06576, published 5 November 1987, whose disclosure is incorporated herein by reference in its entirety. Preferred Z terms are O, NCN, NR7, NOR14, NOR15, NNR4R14, NNR4Rl5,C(CN)2, C(-CN)OC(O)R9, C(-CN)OR9, CRi4C(0)OR8, CR9C(0)NRi3Ri4, 2-(l,3-dithiane), dimethylthio ketal, 2-(l,3-dioxolane), or dimethyl ketal. More preferred are O, NR7, NOR 14, NOR 15, 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 (JJ) is that wherein X3 is hydrogen. Preferred R2 groups, where applicable, is a Ci-2 alkyl unsubstituted or substituted by 1 or more halogens. The halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R2 groups are those wherein R2 is methyl, or the fluoro-substituted alkyls, specifically a Ci-2 alkyl, such as a -CF3, - CHF2, or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.

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

X is preferably COOR14.

Preferred R7 moieties include R13, unsubstituted or substituted -(CH2)0-2(2-, 3- or 4-pyridyl), ( -H2)l-2(2-imidazolyl), (OT2)2(4-πκ> ho]inyl), (CH2)2(4- piperazinyl), (CH2)l-2(2-thienyl), ( Η2)l-2(4-thiazolyl), unsubstituted or substituted pyrimidinyl, and substituted or unsubstituted (CH2)0-2phenyL

Preferred rings when Rio and Ri 1 in the moiety -NRioRl 1 together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containin at least one additional heteroatom selected from O, N, or S include, but are not limite to 1-imidazolyL 2-(R8)-l-imidazolyL 1-pyrazolyL 3-(R8)-l-p razolyl, 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-(R8)-l- piperazinyL or pyrrolyl ring.

Preferred rings when R8 and R14 in the moiety -NR8R14 together with the nitrogen to which they are attached may form a 5 to 7 membered ring optionally 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, rriorpholinyl, piperazinyl, and pyrrolyl. The respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by d e moiety R7 as described herein for Formula (I) and (IT). Illustrations of such carbon substitutions includes, but is not limited to, 2-(R7)-l--jnidazolyl, 4-(R7)-l-imidazolyL 5-(Tl7)-l-i idazolyl, 3-(R7)- 1 -pyrazolyl, 4-(R7)-l -pyrazolyl, 5-(R7H-pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-l-triazolyL 5-(R7)-l -triazolyl, 5-(R7)-l -tetrazolyl, and 5-(R7)-2-tetrazolyl. Applicable nitrogen substitution by R7 includes, but is not limited to, l-(R7)-2-tetrazolyl, 2-(R7)-l -tetrazolyl, 4-(R7)-l- piperazinyL Where applicable, the ring may be substituted one or more times by R7. Preferred groups for NR8R14 which contain a heterocyclic ring are 5-(Ri4)- 1- tetrazolyl, 2-(Ri4)-l-imidazo_yl, 5-(Ri4)-2-tetrazolyl, 4- (Ri 4)- 1 -piperazinyl, or 4-(Ri5)-l-piperazinyl.

Preferred rings for R 13 include (2-, 4- or 5-ixnidazolyl), (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[ 1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).

When the R7 group is unsubstituted or substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, the heterocyclic ring itself may be unsubstituted or substituted by R8 either on an available nitrogen or carbon atom, such as l-(R8)-2-imidazolyl, l-(R8)-4-imidazolyl, l-(R8)-5-imidazolyl, l-(R8)-3-pyrazolyl, l-(R8)-4-pyrazolyl, l-(R8)-5-pyrazo_yl, l-(R8)-4-mazolyl, or

l-(Rg)-5-triazolyL Where applicable, the ring may be substituted one or more times by R8.

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 is ethynyl or 1,3-butadiynyL

Preferred are those compounds of Formula (I) and (JJ) wherein Rj is -CH2- cyclopropyL -CH2-C5-6 cycloalkyl unsubstituted or substituted widi OH, -C4-6 cycloalkyl unsubstituted or substituted with OH, tetrahydrofuran-3-yL (3- or 4- cyclopentenyl), benzyl or -Ci-2 alkyl unsubstituted or substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluoro-substituted alkyl, R 3 is R where R 7 is an unsubstituted or substituted aryl or heteroaryl ring, X is YR2» and Z is O,

NR7.

Most preferred are those compounds wherein Ri is -CH2-cyclopropyl,

-cyclopentyl, -3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; R2 is C 2H or methyl, W is ethynyl or 1,3-butadiynyL R3 is a substituted or unsubstituted pyrimidinyl ring, and Z is O, NR7.

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

Pharmaceutically acceptable salts are prepared in a standard manner.

The parent compound, dissolved in a suitable solvent, is treated widi 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 (IT). The compound may be present in an amount to effect a physiological response, or it may be present in a lesser amount such that the user will need to take two or more units of the composition to effect the treatment intended. These compositions may be made up as a solid, liquid or in a gaseous form. Or one of these three forms may be transformed to another at the time of being administered such as when a solid is delivered by aerosol means, or when a liquid is delivered as a spray or aerosol.

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

For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, aerosols, and drops suitable for administration to die 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 de pharmaceutical composition will be in the form of 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, far non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water, for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dicMσrodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or diluent, the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on d e therapeutic action of the instant compositions. The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product

In these compositions, die amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. Whe 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 adπ inistered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor. Topical formulations will contain between about 0.01 to 5.0% by weight of the active ingredient and will be applied as required a a preventative or curative agent to the affected area. When employed as an oral, or other ingested or injected regimen, die 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.

It will be recognized that some of the compounds of Formula (I) and (IT) may exist in both racemic and optically active forms; some may also exist in distinct diastereomeric forms possessing distinct physical and biological properties. All of these compounds are considered to be wid in the scope of the present invention.

Compounds of Formula (I) where Z is O and (II) may exist in a tautomeric form, such as the enol form. This may be represented by the =0 being exocyclic to the

cyclohexane ring (or ) as contrasted to the endocyclic or -C(-OH)=C(-

R>- moiety wherein the cyclohexane ring is now unsaturated in the 1-2 position, i.e.

cyclohex- 1-ene , or is Z in Formula (I). It is also recognized that the 2-position of the ring in the exocyclic form can be substituted (R) such as in the compounds of Formula (I).

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

No unacceptable toxicological effects are expected when these compounds are administered in accordance with the present invention. Methods Of Preparation Synthetic Scheme(s) With Textual Description

Compounds of Formula (I) may be prepared by the processes disclosed herein which comprise reacting a terminal acetylene as, e.g., compound 1 -Scheme 1. widi an aryl halide, such as phenyl iodide, in die presence of a suitable catalyst such as a copper(T) halide and a bivalent or zerovalent palladium compound in the presence of, e.g., triphenylphosphine, in a suitable solvent such as an amine, as in the procedure of Brandsma et al. (Syn. Comm., 1990, 20, 1889), followed by hydrolysis of the ketal protecting group under standard conditions, provides a compound of the Formula 2_ Scheme 1. Compounds of the Formula 1 -Scheme 1 may be prepared by procedures analogous to those described in co-pending United States patent application 08/130,215 filed 10 October 1993 and its progeny filed as a continuation via the PCT.

Scheme 1

a) Pd(PPh 3)4, PPh 3 , Cul, C 6 H 5 I, pipβridinβ; b) pyridinium p-toluβπβsulfonatβ, (H 3 C) 2 COH 2

Alternatively, compounds of Formula (I) may be prepared by reacting a terminal acetylene as, e.g., compound 1- Scheme 2. wid an appropriate halide, R3X, wherein R3 represents R3 as defined in relation to Formula (I) or a group convertible to R3, in the presence of a suitable catalyst such as a copper (I) halide and a bivalent or zerovalent palladium compound in die presence of, e.g., triphenylphosphine, in a suitable solvent such as an amine, as in the procedure of Brandsma et al. (Syn. Comm., 1990, 20, 1889), to provide a compound of the Formula 2-Scheme 2: such compounds of die Formula (I) may then be converted to otiier compounds of the Formula (I) by standard manipulation of the functional groups on die R3 moiety. Compounds of the Formula 1-Scheme 2 may be prepared by procedures analogous to those described in co-pending United States patent application 08/130,215 filed 10 October 1993 and its progeny filed as a continuation via the PCT.

a) Pd(PPh 3 ) 4 , PPh 3 , Cul, R 3 X, piper.dine

Alternatively, oxidative carbonylation of a terminal acetylene as, e.g., compound 1-Scheme 3. using an appropriate metal salt, such as a copper salt with a

catalytic amount of a palladium salt, in the presence of a suitable base as an acid trap, such as sodium acetate, in a suitable alcohoL such as medianol, as in the method of Tsuji et al. (Tet Lett, 1980, 21, 849), followed by hydrolysis of the methyl ester under standard conditions, then provides the con-pound of die Formula (I) (2-Scheme 3); such compounds of die Formula (I) may men be converted to other compounds of die Formula (I) by standard manipulation of the carboxylic ester moiety.

Scheme 3

COOCH

i) PdCI 2 , CuCI 2 , NaO 2 CCH 3 , CO, CH 3 OH

Compounds of Formula (II) may be prepared by processes analogous to those in Schemes 1, 2 and3 above, as illustrated in Scheme 4 wherein. Depending upon die exact nature of the Z' groups of the compounds of ty require protection during the coupling steps described herein as, e.g., a compound of the Formula (II) wherein =O is a dimethyl ketal or 2-(l,3-dioxolane), followed by deprotection and then reaction by the synthetic procedures described in co-pending United States patent application

08/130,215 filed 10 October 1993 and its progeny filed as a continuation via the PCT, to provide the Formula (II) compound; likewise, the Z' group may require protection during the coupling steps, followed by deprotection to provide the Formula (JJ) 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.)

a) Pd(PPh 3)4, PPh 3 , Cul, R 3 X, pipβridine

Preparation of the rem--ining compounds of the Formulas (I) and (T) may be accomplished by procedures analogous to those described above and in die Examples infra.

It will be recognized that compounds of the Formulas (I) and (II) may exist in distinct diastereomeric forms possessing distinct physical and biological properties; such isomers may be separated by standard chromatographic methods. Experimental^ Example 1

Preparation of 3-(carbomethoxyethynyl)-3-(3-cyclopentyloxy-4-methoxyphenyl) - cyclQheχan-1-pne la) 3-(3-cyclopentyloxy-4-memoxyphenyl)-3-trjmethylsilylethynyl cyclohexan-1-one n-Butyllithium (2.45 M i hexanes, 5.7 mL, 13.96 mmol) was added dropwise over 5 min to a solution of trimethylsilylacetylene ( 1.97 mL, 13.96 mmol) dissolved i dry ether (30 mL) at -45°C under an argon atmosphere. After 1.5 h, tiiis solution was cannulated into a solution of dimethylaluminum chloride (1.0 M in hexanes, 13.96 mL 13.96 mmol). After 3.5 h at room temperature, the mixture was filtered through Celite® under an argon atmosphere. In a separate flask, dusobutylaluminum hydride (1.0 M in toluene, 1.4 mL, 1.4 mmol) was added dropwise to a stirred mixture of nickel acetylacetonate (360 mg, 1.4 mmol) in dry ether (25 mL) at 0°C under an argon atmosphere. After 10 min, the mixture was ftirther cooled to -10°C and the solution of aluminum acetylide was added via cannulation over 15 min. 3-(3- cyclopentyloxy-4-π_ethoxyphenyl)cyclohex-2-en-l-one (2.0 g, 6.98 mmol, prepared as described in U.S. patent 5362915) dissolved in dry ether (70 mL) was added dropwise over 20 rnin. After 18 h at room temperature, the mixture was poured into a 100 mL saturated aqueous solution of potassium phosphate (monobasic) at 0°C, lOOmL of aqueous 3N HC1 solution was added and the aqueous layer was extracted twice widi ether. The combined extract was washed with brine, was dried (magnesium sulfate)

and was evaporated. Purification by flash chromatography, eluting with 2: 1 hexanes/ether followed, by trituration from ether hexanes, then furdiur purificaticxi of the mother liquor by flash chromatography, eluting wid 4:1 hexanes/ethyl acetate followed by trituration from ether hexanes, provided a white solid, mp 102-103°C. lb) 3-(3-cyclopentyloxy* -medrøxyphenyl 3-ethynylcyclohexan-l-one A mixture of potassium fluoride (900 mg, 15.6 mmol) and 3-(3- cyclopentyloxy-4-medrøxyphenyl)-3-triιnethylsilylethynyl cyclohexan-1-one (0.3 g, 0.78 mmol) was stirred in dry N,N-dimethylfθ-T-----mide (3 mL) under an argon atmosphere. After 18 h, the solvent was removed in vacuo, the residue was partitioned between water and ethyl acetate, the aqueous layer was extracted twice with ethyl acetate, the combined extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 4:1 hexanes ethyl acetate provided a clear colorless oil . Anal. (C20H24O3 I/IO H2O) calcd: C 76.45, H 7.76; found: C 76.32, H 7.60. lc) 3-(carix memoxyedιynyl)-3-(3-cyclor*entyloxy-4-ιτ-ethoxyphenyl)cyc lohexan-l- one

3-(3-Cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclohexan- 1 -one (0.30 g, 0.98 mmol) was dissolved in dry methanol (20mL) and carbon monoxide was bubbled into the solution for 10 min. A mixture of copper (II) chloride (0.264 g, 1.96 mmol) and sodium acetate trihydrate (0.267 g, 1.96 mmol) was added, then trace palladium (JJ) chloride was added. After 2.5 h at room temperature, water was added and d e methanol was evaporated. The aqueous residue was extracted three times with ether, the combined extract was washed with brine, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, provided a pale yellow oil. NMR(400 MHz, CDC13) 57.0 (d, J= 2.3 Hz, 1H), 6.95 (dd, J= 8.4, 2.3 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.78 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 2.82 (d, J=25 Hz, 1H), 2.78 (d, J=25 Hz, 1H), 2.5-2.1 (m, 5H), 2.0- 1.8 (m, 7H), 1.61 (m, 2H).

Example ? Preparation of 3-(carboxyethynyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclo hexan-

1-one 3-(Carlx>meώoxyethynyl)-3-(3-cyclopentyloxy-4-methoxyphe nyl)cyclohexan- 1-one (0.14 g, 0.38 mmol) was dissolved in 5:5:2 teti^ydrorurari/methanol/water and treated with powdered sodium hydroxide (0.046 g, 1.114 mmol). After 2 h at room temperature, the mixure was concentrated in vacuo, was diluted widi water (5 mL), was acidified with aqueous 3N HC1 and was extracted five times with dichloromethane. The combined extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 88:10:2 chloroform/methanol acetic acid, provided an oil, which was redissolved and

evaporated three times with toluene and two times widi chloroform to provide a colorless solid. mp 71-72.5°C.

Example 3

Resolution of W-V3-(3-cyclopentyioxy-4-mctf τ QχyphCTyl V-3-ethyπyl- cvclohexan-1-one

The compound from Example lb was resolved in the following manner to give enantiomeric oils: HPLC Rt = 15.5 min (enantiomer 1 = El), 23.2 min (enantiomer 2 = E2) (Diacel Chiralpak AS ; 21.2 x 250 mm; hexaneasopropanol, 4:1; 10 ml-Vmin; UN detection at 295 nm). Example 4

Preparation of (+/-) 3-(3-cyclopentyloxy-4-methoxyphenylV3-phenylethynyl- cyclohexan-1-one To a solution of the compound of Example lb (0.125 g, 0.4 mmol) and iodobenzene (0.4 mL, 2.0 mmol) in piperidine (6 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was refluxed for 5 h, then concentrated in vacuo. The residue was diluted with ethyl acetate (100 mL), was washed widi brine, was drie (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 2: 1 hexanes/ethyl acetate, followed by trituration from ether/hexanes, provided die tide compound as white solid (0.09 g, 58%), m.p. 90-91°C.

Example 5 Preparation of (+/•) 3-f3-cyclopentyloxy-4-methoxvphenvn-3-(3- carbomethoxyphenyDethvnylcvclohexan- 1 -one 5a) methyl 3-iodobenzoate Methyl 3-iodobenzoate was prepared by standard chemistry well known to those versed in die art and is a white solid, m.p. 40-41°C. 5b) (+/-) 3-(3-cyclopentyloxy-4-memoxyphenyl)-3-(3-ca- * rximethoxyphenyl)ethynyl- cyclohexan-1-one

To a solution of die compound from Example lb (0.30 g, 0.96 mmol) and mediyl 3-iodobenzoate (0.30 g, 1.15 mmol) in triemylamine (10 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was refluxed for 0.5 h and was then concentrated in vacuo. The residue was partitioned between water and etiiyl acetate. The organic phase was dried (Νa2Sθ4) and was evaporated. Purification by flash chromatography, eluting with 2: 1 hexanes/ethyl acetate, provided the tide compound as a pale yellow oil (0.35 g, 80%). Anal (C28H30O5 O H2O) calcd: C, 72.39; H, 6.94; found: C, 72.47; H, 6.80.

Example 6

Preparation of (+/-) S-rS-carboxyphenvlethvnvn-S- -cvclopentvloxv^- methoxvphen vl icvclohexan- 1 -one To a solution of the compound from Example 5(b) in 5:5:2 THF/irethanol/water (10 mL) under an argon atmosphere was added sodium hydroxide (0.60 g, 1.5 mmol). The mixture was heated at 60°C for 2 h and was then concentrated in vacuo. The residue was extracted from 3U HC1 with ethyl acetate, was washed with brine, was dried (MgSθ4) and was evaporate Purification by flash chromatography, eluting with 98:2:0.3 cldoroform/methanol/acetic acid, provided a white solid, m.p.71-73°G Ex----αpl--JZ

Preparation of 3-r3-cvclopentvloxy-4-nιethoxvphenvlV3r3-f5-meΦvl-ri.3.41t hiadiazol-

2- vl iphenylethyn vllcvclohexan- 1 -one 7a) 1 -iodo-3-(5-medιyl- [ 1 ,3,4]dιiadiazol-2-yl)benzene l-Iodo-3-(5-medιyl-[l,3,4]thiadiazol-2-yl)benzene was prepared by standard chemistry well known to those versed in the art and is white solid, mp. 86-89°C. 7b) 3-(3-cyclopentyloxy-4-ιrιethoxyphenyl)-3-[3-(5-methyl-[l,3 ,4]dιiadiazol-2- yl)phenylethynyl]cyclohexan- 1 -one

To a solution of the compound from Example 3 (El) ( 0.10 g, 0.32 mmol) and l-iodo-3-(5-methyl-[l,3,4]dιiadiazol-2-yl)benzene (0.10 g, 0.32 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetralds(triphenylphosphine)palldium(0), copper(I) iodide and triphenylphosphine. The mixture was refluxed for 0.20 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed widi brine, was dried (MgS04) and was evaporated. Purification by flash chromatography, eluting with 1:1 hexanes/ediyl acetate provided the tide compound as a white solid (0.135 g, 87%), m.p. 97-99°C.

The enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a white solid, m.p. 97-99°C.

Example 8 Preparation of 3- -cyclopentyloxy-4-methoxyphenyl ' ι-3-r3-f5-medιyl-

[ 1.3.4]oxadiazol-2-yl iphenylethynyllcyclohexan- 1 -one 8a) l-iodo-3-(5-medιyl-[l,3,4]oxadizol-2-yl)benzene

1- Iodo-3-(5-medιyl-[l,3,4]oxadiazol-2-yl)benzene was prepared by standard chemistry well known to those versed in the art and is a white solid, m.p. 104-105°C. 8b) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(5-methyl-[ 1 ,3,4]oxadiazol-2- yl)phenylethynyl]cyclohexan- 1 -one

To a solution of die compound from Example 3 (El) (0.125 g, 0.4 mmol) and l-iodo-3-(5-methyl-[l,3,4]oxadiazol-2-yl)ben--ene (0.09 g, 0.32 mmol) in triethylamine (3 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)-

palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80°C for 0.2 h , was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed widi brine, was dried (MgSθ4) and was evaporated. Purification by flash chrorj-tatography, eluting with 2: 1 ethyl acetate/hexanes, followed by recrystallization from ethyl acetate hexanes, provided die tide compound as a white solid (0.11 g, 61%), m.p. 117-119°C.

The enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a white solid, πxp. 117-119°C. Example 9

Preparation of _-( -cvclopentvloxv-4-me-hoxvphenvlV3-r3-f3-medιvl- T 1.2.41oxadiazol-5-vl iphenvlethvnvllcvclohexan- 1 -one 9a) l-iodo-3-(3-meΛyl-[l,2,4]oxadiazol-5-yl)be_ιzene l-Ic>do-3-(3-memyl-[l,2,4]oxadiazol-5-yl)benzene was prepared by standard chemistry well known to those versed in the art and is a white solid, m.p. 101.5- 103°C.

9b) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(3-methyl-[ 1 -2,4]oxadiazol-5- yl)phenylethynyl]cyclohexan- 1 -one

To a solution of die compound from Example 3 (El) (0.125 g, 0.4 mmol) and l-iodo-3-(3-medιyl-[ 1 ,2,4]oxadiazol-5-yl)benzene (0.09 g, 0.32 mmol) in triemylamine (3mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)- palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80°C for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed widi brine, was dried (MgSθ4) and was evaporated. The residue was purified by flash chromatography, eluting widi 2:1 hexanes/ethyl acetate, followed by trituration from hexanes/ethyl acetate, to provide the tide compound as a white solid, m.p. 122 123°C.

The enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as awhite solid, m.p. 122-123°C.

Example 10 Preparation of 3-f 3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(5-methyl- [ 1.2.41oxadiazol-3-v phenylethynyl1cyclohexan- 1 -one 10a) 1 -iodo-3-(5-methyl-[ 1 ,2,4]oxadiazol-3-yl)benzene l-iodo-3-(5-methyl-[l ,2,4]oxadiazol-3-yl)benzene was prepared by standard chemistry well known to those versed in the art and is a white solid, m.p. 86-87°C. 10b) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(5-methyl-[l^,4]ox adiazol-3- yl)phenylethynyl]cyclohexan- 1 -one

To a solution of die compound from Example 3 (El) (0.125 g, 0.4 mmol) and l-iodo-3-(5-methyl-[l,2,4]oxadiazol-3-yl)benzene (0.09 g, 0.32 mmol) in triethylamine (3 mL) under an argon atmosphere was added trace tetralds(triphenylphosphine)- palladium(O), copper(I) iodide and triphenylphosphine. The mixture was heated at 80°C for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed widi brine, was dried (MgS04) and was evaporated. Purification by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, followed by trituration from hexanes/ethyl acetate, provided die tide compound as colorless crystals (0.12 g, 67%), m.p. 116-118°C

The enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as colorless crystals, m.p.l 16-118°C.

Example 11 Preparation of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3- cvanophen vleth vnvl icvclohexan- 1 -one

To a solution of the compound from Example 3 (El) (0.125 g, 0.4 mmol) and 3-iodobenzonitrile (Transworld, 0.09 g, 0.4 mmol) in triethylamine (3mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copperT) iodide and triphenylphosphine. The mixture was heated at 80°C for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed widi brine, was dried (MgSθ4) and was evaporated. The residue was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, to provide die tide compound as a clear yellow glass (0.12 g, 73%). MS(EI) rn/e 414 [M+H]+. The enantiomer was prepared in similar manner, starting with d e compound from Example 3 (E2), as a clear yellow glass.

Exam le 12 Preparation of 3-f3-cvcIopentyloxy-4-methoxyphenvlι-3-(3- nitrophenylethynyl yclohexan- 1 -one To a solution of the compound from Example 3 (El) (0.2 g, 0.64 mmol) and 3- iodonitrobenzene (Aldrich, 0.16 g, 0.64 mmol) in trieώylamine (4 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), coppeir ) iodide and triphenylphosphine. The mixture was heated at 80°C for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed widi brine, was dried (MgSθ4) and was evaporated. Purification by flash chromatography, eluting with 3: 1 hexanes/ethyl acetate, provided the tide compound as yellow solid (0.25 g, 90%), m.p. 46-48°C.

The enantiomer was prepared in a similar manner, starting widi the compound from Example 3 (E2), as a yellow solid. m.p. 46-48°C.

Example 13 Preparation of 3-(3-cyclopcntyloxy- --i-emoxyphenyiy3-(2- hydroxyethoxyphenyledιynyl)cyclohexan- 1 -one

13a) 2-hydroxyethoxy-l-iodobenzene

2-hydroxyethoxy-l-iodobenzene was prepared by standard chemistry well known to those versed in the art and is a colorless oil. *H NMR(400 MHz, CDCI3) δ 7.77 (dd, J=7.9, 1.3 Hz, 1H), 7.3 (t, J=7H, 1H), 6.84 (d, J=7.9 Hz, 1H), 6.74 (t, J=7.9 Hz, 1H), 4.13 (t, J=4.3 Hz, 2H), 3.99 (t, J=4.3 Hz, 2H), 2.2 (br s, 1H).

13b) 3-(3-cyclor«ntyloxy-4-me oxvphenyl 3-(2-hydroxyedioxyphenylethynyl)- cyclohexan- 1 -one

To a solution of the compound from Example 3 (El) (0.25 g, 0.8 mmol) and 2- hydroxyedιoxy-1-iodobenzene (0.21 g, 0.8 mmol) in triemylamine (5 mL) under an argon atmosphere was added trace tetralris(triphenylpho-φhine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80°C for 1 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSθ4) and was evaporated. Purification by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, provided die tide compound as a white solid (0.05 g, 14%), m.p. 93-94 0 C.

Example 14 Preparation of 3-(3-acetamidophenylethynylV3-(3-cyclopentyloxy-4- methoxyphenyl icyclohexan- 1 -one 14a) 3-acetarnido-l-iodobenzene

3-acetamido-l-iodobenzene was prepared by standard chemistry well known to those versed in die art and is a white solid, m.p. 117-118°C. 14b) 3-(3-acetamidophenyledιynyl)-3-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -one To a solution of the compound from Example 3 (El) (0.2 g, 0.64 mmol) and 3- acetamido-1-iodobenzene (0.17 g, 0.64 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetra!ds(triphenylphosphine)palladium(0), coppeiiT) iodide and triphenylphosphine. The mixture was heated at 80°C for 0.3 h, was cooled to room temperature and was concentrated in vacuo. The residue was purified by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, to provide the tide compound as tan solid (0.17 g, 60%), m.p. 58-60°C.

Example 15

Preparation of 3-(3-cyclopentyloxy-4-medιoxyphenyl)-3-(3- memanesι_--fonaιτridophenyleϋ.ynyl)cyclohexan- 1 -one

15a) l-iodo-3-me anesulfon--midobenzene l-iodo-3-med anesulfoιιamidobenzene was prepared by standard chemistry well known to those versed in the art and is light-pink solid, m.p. 102-103°C. 15b) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3- methanesul-fonamidophenylemynyl)cyclohexan-l-one

To a solution of the compound from Example 3 (El) (0.2 g, 0.64 mmol) and 1- iodo-3--τ-cthanesu-fonamidobenzene (0.19 g, 0.64 mmol) in triemylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladiiim(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80°C for 0.3 h, was cooled to room temperature and was concentrated in vacuo. The residue was purified by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, to provide the tide compound as a tan solid (0.18 g, 58%), m.p. 59-62°C.

Example 16 Preparation of 3-G-arrιinophenvlethvnvn-3-(3-cvclopentyloxv-4- methoxyphenyPcyclohexan- 1 -one

16a) l-iodo-3-trifluoroacetamidobenzene l-icdo-3-trifluoroacetamidobenzene was prepared by standard chemistry well known to those versed in die art and is a white solid, m.p. 120-121°C. 16b) 3-(3-cyclopentyloxy-4-me oxvphenyl)-3-(3-ι.rifluoroacetarm cyclohexan-1-one

To a solution of the compound from Example 3 (El) (0.5 g. 1.6 mmol) and 1- iodo-3-trifluoro-.cetamidobenzene (0.5 g, 1.6 mmol) in mediylamine (10 mL) under an argon atmosphere was added a small amount of totrakis(triphenylphospMne)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80°C for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was purified by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, to give the tide compound as a pale yellow solid (0.62 g, 78%), m.p. 63-65°C.

16c) 3-(3-aminophenyleώynyl)-3-(3-cyclopentyloxy-4-methoxyphenyl )cyclohexan- 1 - one

To a solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3- i--τfluOToacetamidophenyledιynyl)cyclohexan-l-one (0.62 g, 1.24 mmol) in 95:5 methanol water (10 mL) under an argon atmosphere was added potassium carbonate (0.86 g, 6.2 mmol). The mixture was refluxed for 6 h and was stirred for 18 h at room temperature. The solid precipitate was collected and purified by trituration from ethyl acetate/hexanes to provide die tide compound as a white solid (0.39 g, 77%), m.p. 100-102°C.

Example 17

Using the methods and processes set forth in the foregoing examples, the following compounds can also be made:

3-(3-cyclopentyloxy-4-medιoxyphenyl)-3-(2-[3-(5- trLfluoιx)methyl[l^,4]oxadia-tol-3-yl)phenyl]ethynyl)cycloh exan-l-one, 3-(3-cyclopentyloxy-4-medκ)xyphenyl)-3-(2-[3-(3- trifluon>methyl[l^,4]oxad-i---ol-5-yl)phenyl]ethynyl)cycl ohexan

3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(2-[3-(5- trifluorome yl[l,3,4]oxadiazol-2-yl)phenyl]emynyl)cyclohexan-l-o^

3-(3-cyclopentyloxy-4-medιoxyphenyl)-3-(2-[3-(5- trifluoromethyl[ 1 ,3,4]tlιiadiazol-2-yl)phenyl]edιynyl)cyclohexan- 1 -one.

Example 18 Preparation of (+/-)-3-(4-c---tx)xyphenylethynylV3-f3-cyclopentyloxy-4- methoxyphenyDcyclohexan- 1 -one

18(a) methyl 4-iodobεnzoate Methyl 4-iodobenzoate was prepared by standard chemistry well known to those versed in die art and is a cream-colored solid, m.p. 103-105°C. 18(b) (+/-) 3-(4-carbomedιoxyphenyledιynyl 3-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -one

To a solution of the compound from Example lb (0.2 g, 0.64 mmol), methyl 4-iodobenzoate (0.17 g, 0.64 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0) and copper(I) iodide . The mixture was refluxed for 0.25 h, was cooled to room temperature and was concentrated in vacuo. The residue was purified by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, to provide the tide compound as a clear, colorless oil (0.25 g, 87%).

18(c) (+/-) 3-(4-carboxyphenylethynyl)-3-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -one

To a solution of the compound from Example 17b ( 0.25 g, 0.55 mmol) in 5:5:2 tet-rahydrofiiran/methanol/water (5 mL) under an argon atmosphere was added sodium hydroxide (1.1 rnmol, 0.04 g). The mixture was heated at 60°C for 2 h, was cooled to room temperature and was acidified widi 3N hydrochloric acid. The aqueous phase was extracted three times with chloroform, was dried (magnesium sulfate) and was evaporated. The residue was recrystallized from hexanes/ethyl acetate to provide the tide compound as a white solid (0.18g, 78%), m.p. 102-104°C.

Example 19

Preparation of 3-r3-cvclopentyloxy-4-memoxyphenylV3-r3-f5-trifluoromethyl-

.1.2.41oxadiazol-3-ynphen vleth vn vl icvclohexan- 1 -one

19(a) 3-(3-iodophenyl)-5-trifluoromedιyl-[l^,4]oxadiazole 3-(3-Iodophenyl)-5-trifluoromethyl-[l ,2,4]oxadiazole was prepared by standard chemistry well known to those versed in the art and is a white solid, mp 36-

37°C.

19(b) 3-(3-cyclopentyloxy-4-memoxyphenyl 3-[3-(5-trifluoreιmethyl-

[l,2,4]oxadiazol-3-yl)phenyledιynyl)cyclohexan-l-one A stirred mixture of die compound from Example 3 (E 1, 0.200 g, 0.64 mmol) and 3-(3-iodophenyl)-5-trifluoromethyl-[l,2,4]oxadiazole (0.220 g, 0.64 mmol) in dry trie ylarnine (5 mL) was treated under an argon atmosphere with trace tetralris(triphenylphosphirιe)palladium and copper(I) iodide. The mixture was refluxed for 0.2 h, was cooled to room temperature and was evaporated.The residue was adsorbed onto silica gel and was purified by flash chromatography eluting with 3: 1 hexanes/ethyl acetate and recrystallization from cold hexanes provided die tide compound as a white solid (0.27 g, 83%), mp 99-100°G Anal. (C29H27F3N2O4) calcd: C 66.40, H 5.19, N 5.304 ;found: C 66.46, H 5.35 , N 5.15.

Example 20 Preparation of (+) and (-. 3-G-cyclopentyloxy-4-methoxyphenyl )-3- phenvlethvnvlcvclohexan- 1-one A stirred mixture of the compound from Example 3 (El, 0.13 g, 0.40 mmol) and iodobenzene (0.40 g, 2.0 mmol) in dry piperidine (6 mL) was treated under an argon atmosphere with trace tetralds(triphenylphosphine)palladium(0) and copper(I) iodide. The mixture was refluxed for 5 h, was cooled to room temperature and was evaporated. The residue was dissolved in etiiyl acetate (100 mL), was washed twice with brine, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography eluting with 2:1 hexanes/ether, and trituration from ether/hexanes provided the tide compound as a white solid (0.03 g, 19%), m.p. 90-91°C. The enantiomer was prepared in a similar, starting widi the compound from

Example 3 (E2), as a white solid (0.09 g, 58%), m.p. 90-91°C.

Example 21 Preparation of 3-[3-N-('4-bromobenzyl)benzan-ido1etfιynyl-3-t ' 3-cvclopentyloxy-4- methoxyphenyl icvclohexan- 1 -one

21(a) methyl 3-iodobenzoate

Methyl 3-iodobenzoate was prepared by standard chemistry well known to those versed in die art and is a white solid, m.p.40-41°C. 21 (Ob) 3-(3-cyclopentyloxy-4-memoxyphenyl)-3-(3-carix)memoxy^ cyclohexan-1-one

The tide compound was prepared in a similar manner to the compound of Example 5b, starting from the compound of Example 3 (El, 0.30 g, 0.96 mmol), as a clear yellow oil (0.43 g, 100%). l H NMR(400MHz, CDC1 3 ) δ 8.07 (s, IH), 7.96 (dd, J=7.8, 1.5 Hz, IH), 7.58 (dd, J=7.8, 1.5 Hz, IH), 7.38 (t, J=7.8 Hz, IH), 7.16 (d, J=2.2 Hz, IH), 7.06 (dd, J=8.43, 2.2 Hz, IH), 6.86 (d, J=8.43 Hz, IH), 4.80 (m, IH), 3.92 (s, 3H), 3.85 (s, 3H), 2.82 (dd, J=26, 13.6 Hz, 2H), 2.50 (m, IH), 2.42-2.15 (m, 4H), 2.05 (m, IH), 1.90 (m, 6H), 1.62, (m, 3H).

20c) 3-(3-cyclopentyloxy-4-memoxyphenyl)-3-(3-c--ri»xyphenyl)eth ynyl-cyclohexan- 1-one The tide compound was prepared in a similar manner to die compound from

Example 6, starting from the compound from Example 20c (0.43 g, 0.96 mmol), as a white solid (0.36 g, 87%), m.p. 82-84°C.

21 (d) 3-[3-N-(4-brorrκ)benzyl)benzamido]edιynyl-3-(3-cyclopentyl oxy-4- methoxyphenyl)cyclohexan- 1 -one To a stirred mixture of the compound from Example 20c (0.36 g, 0.83 mmol),

1-hydroxybenzotriazole hydrate (Aldrich, 0.13 g, 0.91 mmol), 4-methylmorpholine (Aldrich, 0.19mL, 1.7 mmol) and 4-fromobenzylamine hydrochloride (Aldrich, 0.20 g, 0.91 mmol) in dichloromethane (5 mL) under an argon atmosphere at 0°C was added l-(3-diiΩeΛylaπ.inorjrcφyl)-3^ hydrochloride (Aldrich, 0.18 g, 0.91 mmol). After stirring 24 h at room temperature, water was added. The mixture was acidified with 3N hydrochloric acid, was extracted three times with dichloromethane, was washed once widi water, was washed once with 10% aodium hydroxide, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:1 ethyl acetate/hexanes, followed by trituration from ether/hexanes provided die tide compound as a white solid (0.25 g, 50%), m.p.98-100°C.

UTILITY EXAMPLES

EXAMPLE A Inhibitory effect of compounds of Formula (D and (JJ) on in vitro TNF production by human monocytes The inhibitory effect of compounds of Formula (I) and (U) on in vitro TNF production by human monocytes may be determined by die 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 deterπiine in vivo TNF activity for the 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 die different isozymes are as follows: 1) PDE lb, porcine aorta; 2) PDE Ic, guinea-pig heart; 3) PDE DJ, guinea-pig heart; 4) PDE IN, human monocyte; and 5) PDE V (also called "la"), canine trachealis. PDEs la, lb, Ic and IJJ are partially purified using standard chromatographic techniques [Torphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE JN is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-Sepharose chromatography [Torphy et al., J. Biol. Chem., 267:1798-1804, 1992].

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