WO1993019720A2 - Compounds - Google Patents

Abstract

Novel compounds of Formulas (I) and (II) are described herein. These compounds inhibit the production of Tumor Necrosis Factor and are useful in the treatment of disease states mediated or exacerbated by TNF production; these compounds are also useful in the mediation or inhibition of enzymatic or catalytic activity of phosphodiesterase IV.

Description

COMPOUNDS Field of Invention

The present invention relates to novel 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).

Back-round 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 -- ATP to cAMP at an accelerated rate.

Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of c AMP is hydrolysis of the 3'- phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Anti- asthmatic Agents" in New Drugs for Asthma, Barnes, ed. 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 prostaglandinE2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market The compounds of this invention also inhibit the production of Tumor Necrosis Factor

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

AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HTV have been identified, i.e., HIV-1, HTV-2 aπdHIV-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 HIV 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 anHlN-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HTV infection. Monocytes, macrophages, and related cells, such as kupffer and glial cells, have also been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al., The Immunopathogenesis of HTV Infection,

Advances in Immunology, Vol. 57, 1989]. Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages [See Poli et al, Proc. Nad. Acad. Sci., 87:782-784, 1990], therefore, inhibition of monokine production or activity aids in limiting HTV progression as stated above for T cells. TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.

TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al., Infection and Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal of Infectious Diseases, 164:389-95, 1991. See also Wasan etal., Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Luke etal., 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

This invention relates to the novel compounds of Formulas (I) and (II) as shown below, useful in the mediation or inhibition of the enzymatic activity (or catalytic activity) of phosphodiesterase IV (PDE IV). These compounds also have Tumor Necrosis Factor (TNF) inhibitory activity. This invention also relates to the pharmaceutical compositions comprising a compound of Formulas (I) or (II) and a pharmaceutically acceptable carrier or diluent.

The invention also relates to a method of mediation or inhibition of the enzymatic activity (or catalytic activity) of PDE IV in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I) or (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) or (II).

The invention also provides a method for the treatment of asthma which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I) or (II).

This invention also relates to a method of inhibiting TNF production in a mammal, including humans, which method comprises administering to a mammal in need of such treatment, an effective TNF inhibiting amount of a compound of Formula (I) or (IT). This method may be used for the prophylactic treatment or prevention of certain TNF mediated disease states amenable thereto.

This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HIV), which comprises administering to such human an effective TNF inhibiting amount of a compound of Formula (I) or (J3). Compounds of Formula CD or (H) 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 (T) or (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.

The compounds of Formula (I) are represented by the following structure:

wherein:

R! is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(C 4R5)mR6₅ or-(CR4R5)_rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens; m is 0 to 2; n is 1 to 4; ris 1 to 6;

R4 and R5 are independently selected from hydrogen or a Ci-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCl-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl contaixiing one or two unsaturated bonds, wherein the cycloalkyl and eterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl 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 Rβ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is I 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, halogen, nitro, NR4R5, or formyl amine;

Yis O orS(O)n ; m' is 0, 1, or 2; X2is O orNR8;

X3 is hydrogen orX; R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4; R3 is hydrogen, halogen, C1-4 alkyl,CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, -CH=CR8'R8\ cyclopropyl optionally substituted by Rs¹, CN, OR8, CH2OR8, NRgRiO, CH2NR8R10, C(Z')H, C(O)OR8, C(O)NRsRl0- or G≡CRδ';

Z is S(O)πVR9, OS(O)2R9, OR9, OC(O)NR7R9, OC(O)(O)_qR7, O(CR4R5)nOR9, or NR9R9;

Z^* is O, NR8, NNR8R8, NOR8, NCN, C(-CN)2, CRδCN, CR8NO2, CR8C(O)OR8, CRsC(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NRδR8; q is 0 or 1;

R7 is independently hydrogen or R9;

R8 is independently selected from hydrogen or C \__\ alkyl optionally substituted by one to three fluorines, or when R8 and Rio are as -NRδRlO they may together with the nitrogen form a a 5 to 7 membered ring optionally containing one or more additional heteroatom selected from O, N, or S;

R8' is R8 or fluorine;

R9 is independendy Cl-lO alkyl, C2-10 alkenyl, C3-7cycloalkyl, C4-6 cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which may be optionally substituted by one or more fluorine atoms, or two R9 terms appearing as NR9R9 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;

Rlθ is OR8 orR8; provided that: f) when q is 1 in OC(O)(O)qR7 , then R7 is not hydrogen; g) when Z' is NRs , then R8 is not hydrogen; or the pharmaceutically acceptable salts thereof. The other set of compounds of this invmtion are represented by Formula (II):

wherein the several groups are the same as those of Formula (I) and: Z is also NHR14;

Z" is C(Y')Rl4, C(O)ORi4, C(Y')NRiθRl4, C(NRifj)NRioRl4, CN, C(NOR8)Rl4, C(NORi4)R8, C(NRg)NRiθRl4, C(NRi4)NRδR8 C(NCN)NRioRl4, C(NCN)SRl l, (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-oxadiazolyI[l,3,4]), (2-thiadiazolyl[l,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl); wherein all of the heterocylic ring systems may be optionally substituted one or more times by R14; T is O orS;

R-ll -*^s --1-4 ^a~^c ^ optionally substituted by one to three fluorines; Rl2 is C3-7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2- imϊdazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, mo holinyl, furanyl, (2- or 3-thϊenyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl; R13 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two Cj_2 alkyl groups;

Rl4 is hydrogen orRχ5; orwhen Rio and R14 are as NR 0R14 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from Q/N/or S;

Rj5 is -(CR4R-)_rRi2 or C β alkyl wherein the R12 or C g alkyl group is optionally substituted one or more times by Cι_2 alkyl optionally substituted by one to three fluorines, -F, -Br, -CI, -NO₂, -Si(R₄)₂, -NR₈RlO- -C(O)Rs, -C(O)ORs, -ORs, -CN, -C(O)NRgR₁₀, -OC(O)NR₈R₁₀, -OC(O)R8, -NRι₀C(O)NR₈R₁₀, -NRιoC(O)R₈, -NRiθC(O)OR₉, -NRιoC(O)Ri3, -C(NRιo)NR₈Rι₀₎ -C(NCN)NR₈Rι₀, -C(NCN)SRn, -NRioC(NCN)SRιι , -NRιoC(NCN)NRιoR8, -NRioS(O)2R9, -S(O)_m'Rn, -NRιoC(O)C(O)NR8Rιo, -NRιoC(O)C(O)Rιo, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; r is O, 1, or 2; provided that:. h) when R12 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N- piperidinyl, orN-morpholinyl, then q is not 1; or the pharmaceutically acceptable salts thereof.

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 aojninistering to said mammal an effective amount of a compound of Formula (I) or (LI).

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 aπhritis, 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 indirecdy, by the TNF inhibitors of Formula (I) or (LI). Such viruses include, but are not limited to HTV-1, HIV-2 and HTV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.

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

The compounds of this invention may also be used in association with the veterinary treatment of animals, other than in humans, in need of inhibition of TNF production. TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections. Examples of such viruses include, but are not limited to feline immunodeficiency virus (FIV) or other retroviral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.

The compounds of this invention are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo. A preferred disease state for treatment is fungal meningitis. Additionally, the compounds of Formula (I) or (II) may be administered in conjunction with other drugs of choice for systemic yeast and fungal infections. Drugs of choice for fungal infections, include but are not limited to the class of compounds called the polymixins, such as Polymycin B, the class of compounds called the imidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; d e class of compounds called the triazoles, such as fluconazole, and itranazole, and the class of compound called the Amphotericins, in particular Amphotericin B and liposomal Amphotericin B.

The compounds of Formula (I) or (II) may also be used for inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti- viral agent by administering an effective amount of a compound of Formula (I) or (II) to a mammal in need of such treatment. Preferably, a compound of Formula (I) or (II) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B. Preferred compounds are as follows: When Ri for the compounds of the Formula (I) is an alkyl substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably a Ci-4 alkyl substituted by 1 or more fluorines. The preferred halo-substituted alkyl chain length is one or two carbons, and most preferred are the moieties -CF3, -CH2F, -CHF2, -CF2CHF2, -CH2CF3, and -CH2CHF2. Preferred Ri substitutents for the compounds of the Formula (I) are CH2-cycIopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, C7-H polycycloalkyl, (3- or 4- cyclopentenyl), phenyl, tet-^~ώydrofiιran-3-yl, benzyl orCl-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2)θ-2CH3, -(CH2)l-3θ(CH2)0-2CH3, and -(CH2)2-4OH. When the Ri term contains the moiety (CR4R5), the R4 and R5 terms are independently hydrogen or alkyl. This allows for branching of the individual methylene units as (CR4R5)n or (CR4R5)m; each repeating methylene unit is independent of the other, e.g., (CR4R5)n wherein n is 2 can be -CH2CH(-CH3)-, for instance. The individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon can optionally be substituted by fluorine independent of each other to yield, for instance, the preferred Ri substitutions, as noted above.

When Ri is a C7-H polycycloalkyl, examples are bicyclo[2.2J]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2J]octyl, tricyclo[5.2.1.0-> ]decyl, etc. additional examples of which are described in Saccamano etal., WO 87/06576, published 5 November 1987, whose disclosure is incorporated herein by reference in its entirety.

Zis S(O)_m'R9, OS(O)2R9, OR9, OC(O)NR7R9, OC(O)(O)_qR7, 0(CR4R5)nOR9, or NR9R9 in compounds of the Formula (L) and also NHR14 in compounds of the Formula (H). Preferably, q is 0. Preferred Z terms are S(O)_m'R9, OS(O)2R9, OR9, OC(O)NR7R9, O(CR4R5)_nOR9, or NR9R9 in compounds of the Formula (I) and also NHR14 in compounds of the Formula (II).

Z" in Formula (LI) is preferably C(O)Rl4, C(O)ORi4, C(O)NRioRl4, C(NRio)NRlθRl4, CN, C(NORδ)Rl4, C(NR8)NRιoRl4, C(NCN)NR8Rl4, C(NCN)SRn, (1-, 4- or 5-{Ri4}-2-imidazolyl), (1-, 4- or 5-{Ri4}-3-pyrazolyl), (1-, 2- or 5-{Ri4}-4-triazolyl[l,2,3]), (1-, 2-, 4- or 5-{Rl4.-3-triazolyl[l,2,4]), (1- or 2-{Ri4}-5- tetrazolyl), (4- or 5-{Ri4}-2-oxazolyl), (3- or 4-{Ri4)-5-isoxazolyl), (3- {Rl4}-5-oxadiazolyl[l,2,4]), (5-{Ri4}-3-oxadiazolyl[l,2,4]), (5- [Rl4}-2-oxadiazolyl[l,3,4]), (5-{Rl4}-2-thiadiazolyl[l,3,4]), (4- or5-{Ri4)-2-thiazolyl), (4- or 5-{Ri4}-2-oxazolidinyl), (4- or 5-{Ri4}-2-thiazolidinyl),(l-, 4- or 5- {R14} -2-imidazolidinyl). Preferred X groups for Formulas (I) and (It) are those wherein X is YR2 and Y is oxygen. The preferred X2 group Formulas (I) and (II) is that wherein X2 is oxygen. The preferred X3 group is hydrogen. Preferred R2 groups, where applicable, are a Cι_2 alkyl optionally 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 arid -CH3 moieties.

Preferred R3 moieties are C(O)NH2, OCRs, CN, C(Z')H, CH2OH, CH2F, CF2H, and CF3: Z is preferably O or NOR8- More preferred are C≡CH and CN. Preferred R15 moieties include optionally substituted -(CH2)l-2(cyclopropyl), -(CH2)0-2(cyclobutyl), -(CH2)0-2(cyclopentyl), -(CH2)0-2(cyclohexyl), -(R4R5)0-2(2-, 3- or4-pyridyl), (R4R5)i-2(2-imidazolyl), (R4R5)2(4-morpholinyl), (R4R5)2(4-piperazinyl), (R4R5)l-2(2-thienyl), (R4R5)i-2(4-thiazolyl), and (R4R5)θ-2phenyl; Preferred rings when the two R9 terms in the moiety NR9R9 together with the nitrogen to which they are attached form a a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N or S include, but are not Umited to, the morpholinyl, piperazinyl, or pyrrolyl rings.

Preferred rings when R8 and Rio in the moiety -NRδRlO together with the nitrogen to which they are attached form a 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, 2-(R8)-l-imidazolyl, 1-pyrazolyl, 3-(R8)-l -pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R8)-l-triazolyl, 5-(Rs)-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 Rio and R 14 in the moiety -NR 1 OR 14 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, morpholinyl, piperazinyl, and pyrrolyl. The respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R15 as described herein for Formula (IT).

Illustrations of such carbon substitutions includes, but is not limited to, 2-(Ri5)-l-imidazolyl, 4-(Rl5)-l-imidazolyl, 5-(Rl5)-l-imidazolyl, 3-(Rl5)-l-pyrazolyl, 4-(Ri5)-l-pyrazolyl, 5-(Rl5)-l-pyrazolyl, 4-(Ri5)-2-triazolyl, 5-(Ri5)-2-triazolyl, 4-(Rι 5)- 1 -triazolyl, 5-(Rl 5)- 1 -triazolyl, 5-(Rl 5)- 1 -tetrazolyl, and 5-(Ri5)-2-tetrazolyl. Applicable nitrogen substitution by R15 includes, but is not limited to, l-(Ri5)-2-tetrazolyl, 2-(Ri5)-l-tetrazolyl, 4-(Rl5)-l-piperazinyl. Where applicable, the ring may be substituted one or more times by

Rl5-

Preferred groups for -NR10R14 which contain a heterocyclic ring are 5-(Ri4)-l- tetrazolyl, 2-(Rι 4)- 1 -imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(Rι 4)- 1 -piperazinyl, or 4-(Ri5)-l-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[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[l,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazohdinyl).

When the R15 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-(Rg)-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 R .

Preferred are those compounds of Formulas (I) and (II) wherein Ri is -CH2- cyclopropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl, 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 fluoro-substituted alkyl, R3 is CN or C≡CRδ; and X is YR2.

Most preferred are those compounds wherein Ri is -CH2-cyclopropyl, cyclopentyl, methyl or CF2H; R3 is CN or C≡CH; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl. A preferred subgenus of the compounds of the Formula (I) is the compounds of the

Formula Ota)

wherein: Ri is CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, C7- 11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or Cl-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2)θ-2CH3, -(CH2)1-3O(CH2)0-2CH3, and -(CH2)2-4OH;

X is YR2, halogen, nitro, NR4R5, or formyl amine; Yis O or S(O)nϊ; m' is 0, 1, or 2;

R2 is -CH3 or -CH2CH3 optionally substituted by 1 or more halogens;

R3 is hydrogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, CN, CH2OR8, C(Z^*)H, C(O)OR8, C(O)NR8Rl0, orC≡CRδ; Z is S(O)_m'R9, OS(O)2R9. OR9, OC(O)NR7R9, OC(O)(O)_qR7, 0(CR4R5)_nOR9, or

NR9R9;

Z' is O orNORs; qis O or l;

R7 is independendy hydrogen orR9; R8 is independendy selected from hydrogen or C _4 alkyl optionally substituted by one to ύiree fluorines;

Rg¹ is R8 or fluorine;

R9 is independendy Ci-io alkyl, C2-10 alkenyl, C3-7cycloalkyl, C4-6 cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which may be optionally substituted by one or more fluorine atoms, or two R9 terms appearing as NR9R9 may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O/N/orS;

Rlθis OR8 orR8; provided that: f) when q is 1 in OC(O)(O)qR7 , then R7 is not hydrogen; g) when Z' is NR8 then R8 is not hydrogen; or the pharmaceutically acceptable salts thereof.

Exemplified compounds of Formula (I) are:

4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex- 1 -en- 1 -yl trifluoromethylsulfonate;

4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)- 1 -methoxycyclohex- 1 -ene; and

4-cyano-4-(3-cyclopropylmemoxy-4-methoxyphenyl)cyclohex- 1 -en- 1 -yl trifluoromethylsulfonate.

Exemplified compounds of Formula (II) are: 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 -

(medιoxymeuιyloxy)cyclohex- 1 -ene;

2-carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - (methoxymethyloxy)cyclohex-l -ene;

2-aminocarbonyI-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - (methoxymethyloxy)cyclohex- 1 -ene;

1 -amino-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl])-2,4-dicyanocyclohex- 1 - ene;

2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-l- (methoxymethyloxy)cyclohex- 1-ene; 2-carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)- 1 -

(methoxymethyloxy)cyclohex- 1 -ene;

2-aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-d-fluoromethoxyphenyl)-l- (methox ymethyloxy)cyclohex- 1 -ene; l-amino-2-carbomethoxy- 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-l- ene; methyl 2-[S-(α)---bromophenethylamino]-5-cyano-5-(R and S)-(3-cyclopentyloxy-4- difluoromethoxyphenyl)cyclohex- 1 -en- 1 -yl carboxylate; methyl 2-amino-5-cyano-5-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)- cyclohex-1-en-l-yl carboxylate; methyl 2-ben^~ylamino-5-cyano-5-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohex-

1-en-l-yl carboxylate; and methyl 2-[S-(α)---nitrophenethylamino]-5-cyano-5-(R and S)-(3-cyclopentyloxy-4- difluoromethoxyphenyl)cyclohex- 1 -en- 1 -yl carboxylate. It will be recognized that some of the compounds of Formula (I) and (II) may exist in both racemic and optically active forms; some may also exist in distinct diastereomeric forms possessing distinct physical and biological properties. All of these compounds are considered to be widiin the scope of the present invention.

Compounds of Formula (U) may exist in a tautomeric form, such as the imine form. ylidine bond) being exocyclic to die cyclohexane ring

the endocyclic or -C(-ZH)=C(-R)- moiety wherein the cyclohexane ring is now unsaturatedin the Imposition, i.e. cyclohex-1-ene , or

(IT). 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 (LI). The term "C1.3 alkyl", "Cμ4 alkyl", "Cι_6 alkyl" or "alkyl" groups includes both straight or branched chain radicals of 1 to 10, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, rerr-butyl, and die like. "Alkenyl" means both straight or branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl, 1-propenyl, 2- propenyl, 2-propynyl, or 3-methyl-2-propenyl.

The term "cycloalkyl" or "cycloalkyl alkyl" means groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl. "Aryl" or "aralkyl", unless specified otherwise, means an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl, or naphthyl. Preferably the aryl is monocyclic, i.e, phenyl. The alkyl chain is meant to include both straight or branched chain radicals of 1 to 4 carbon atoms.

"Heteroaryl" means an aromatic ring system containing one or more heteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl. "Halo" means all halogens, i.e., chloro, fluoro, bromo, or iodo. Inhibiting the production of IL-1" or "inhibiting the production of TNF" means: a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels by inhibition of the in vivo release of LL-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 die direct synthesis of IL-1 or TNF levels as a postranslational event The phrase "TNF mediated disease or disease states" means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to LL-1 or LL-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 affects die functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses. A cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce them. The cytokine inhibited by the present invention for use in the treatment of a HTV- infected human must be a cytokine which is implicated in (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HTV gene expression and/or replication, and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration. Preferrably, his cytokine is TNF-α. All of the compounds of Formulas (I) and (II) are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal, including humans, in need thereof. All of the compounds of Formulas (I) and (II) are useful in the method of inhibiting or mediating me enzymatic or catalytic activity of PDE IV and in treatment of disease states mediated thereby.

METHODS OF PREPARATION: Preparation of the compounds of the Formula (I) can be carried out by one of skill in the art acccnrling to the procedures outiined in the Examples, infra. The preparation of any remaining compounds of the Formula (I) not described therein may be prepared by the analogous processes disclosed herein which comprise: a) reacting a compound of the Formula (2)

wherein Ri represents Ri as defined in relation to Formula (I) or a group convertable to Ri and X, X2 and X3 represent X, X2 and X3 as defined in relation to Formula (I) or a group convertable to X, X2 or X3 and R2 and R3 represent R2 and R3 as defined in relation to Formula © or a group convertable to R2 or R3, with a suitable base in a suitable non-reacting solvent followed by reaction with a suitable alkylating or acylating agent {LS(O)2R9, LR9- L(CR4R5)_nOR9, LC(O)(O)qR7, or LC(O)NR7Rα, wherein L is a leaving group] to provide compounds of the Formula (I) wherein Z is OS(O)2R9, OR9, 0(CR4R5)nOR9, OC(O)(O)qR7, or OC(O)NR7R7 and R3 is other than C(=Z')H; preparation of such compounds of Formula (I) wherein R3 is C(=Z')H proceeds in an analogous fashion from the compound of Formula (2) wherein =Z' is an aldehyde protecting group, such as a dimethylacetal or a dioxolane, followed by deprotection to die aldehyde and subsequent elaboration by standard procedures known to those of skill in the art to die remaining compounds of Formula (T) wherein 71 is od er than O. b) preparation of compounds of die Formula (I) wherein Z is NR9R9 or SR9 proceeds by reacting a compound of the Formula (2) widi an appropriate amine of the formula HNR9R9 or an appropriate thiol of the formula HSR9 in the presence of a suitable acidic or basic catalyst with scavenging or removal of water. Alternatively, such compounds may be obtained by treatment of an appropriate compound of the Formula (I) wherein Z is OS(O)2R9, OR9, or O(CR4R5)nOR9 and R3 is other than C(=Z')Hwith an appropriate amine of the formula HNR9R9 or an appropriate thiol of the formula HSR9 in an aptotic solvent; preparation of such compounds of Formula (I) wherein R3 is C(=Z')H proceeds in an analogous fashion from the compound of Formula (2) wherein =Z is an aldehyde protecting group, such as a dimethylacetal or a dioxolane, followed by deprotection to the aldehyde and subsequent elaboration by standard procedures known to tiiose of skill in the art to the remaining compounds of Formula (I) wherein Z' is other than O.

Compounds of the Formula (2) may be prepared in turn by the processes described in co-pending U.S. application serial number 07/862,083 filed 2 April 1992 and its corresponding continuation-in-part application USSN 968,753 filed 30 October 1992.

Some compounds of the Formula (H) may be prepared by processes analogous to those above by reacting the appropriate reagent with a compound of die Formula (3)

wherein Ri represents Ri as defined in relation to Formula (I) or a group convertable to Ri and X, X2 and X3 represent X, X2 and X3 as defined in relation to Formula (I) or a group convertable to X, X2 or X3 and R3 represents R3 as defined in relation to Formula (I) or a group convertable to R3 and Ri6 is an alkyl, phenyl or benzyl group. Compounds of the Formula (3) may be prepared in turn by the processes described in co-pending U.S. application serial number 07/862,083 filed 2 April 1992 and its corresponding continuation-in-part application filed on even date herewitfi.

In addition, some compounds of die Formula (LI) may be prepared by reacting a compound of the Formula (4)

Rl represents Ri as defined in relation to Formula (I) or a group convertable to Ri and X, X2 and X3 represent X, X2 and X3 as defined in relation to Formula (I) or a group convertable to X, X2 or X3 and R3 represents R3 as defined in relation to Formula (I) or a group convertable to R3, and X4 is CN with an excess of acrylonitrile in the presence of a base, such as excess metal hydride, or catalytic or excess quaternary amine base, such as benzyltrimethylammonium hydroxide, in a suitable non-reacting solvent, such as tetrahydrofuran or 1,2-dimethoxyethane when a metal hydride base is used or these sovents or acetonitrile when a quaternary amine base is used, to provide a compound of the Formula (5)

wherein X4 is CN; reaction of a compound of the Formula (5) with a base, such as excess metal hydride, in a suitable non-reacting solvent, such as tetrahydrofuran or 1,2- dimethoxyed ane, at an elevated temperature then provides a compound of the Formula (6)

wherein X4 is CN and X5 and X6 are bodi H; alternatively, a compound of the Formula (6) [a subset of die compounds of the Formula (II)] may be obtained direcdy from a compound of Formula (5) wherein X4 is as described above by reaction with an excess of optionally R2-substituted acrylonitrile, with excess base, such as a metal hydride, in a suitable non- reacting solvent, such as tetrahydrofuran or 1,2-dime oxyethane, at an elevated temperature. Treatment of a compound of the Formula (6) with an acid, e.g., 6N hydrochloric acid at ambient or elevated temperature, in a solvent, such as ethanol, with or without a co-solvent, such as chloroform, provides a compound of Formula (7), which may be converted to compounds of Formula (II) by processes analogous to those described above.

Compounds of Formula (8)

wherein X5 is H, are prepared by heating compounds of the Formula (7) in a solution of hydrazoic acid generated in situ by, e.g., adπiixture of an alkalai metal azide, such as sodium azide, with an ammonium halide, such as triethylamine hydrochloride, in a polar non-protic solvent such as N-meu ylpyrrolidinone such compounds may be converted to compound of Formula (LQ by processes analogous to those described above. Some compounds of Formula (II) may be prepared from other compounds of the

Formula (H) by, e.g., functional group manipulation of the Z" group either proceeding functional group manipulation of the Z group or, in some cases, widi appropriate protection and deprotection of chemically sensitive Z group functionality during functional group manipulation of the Z" group. Some such manipulations of die Z" group may be accomplished by die processes described in co-pending U.S . application serial number 862,030 filed 2 April 1992 and its corresponding continuation-in-part application USSN 968,762 filed 30 October 1992.

The following examples are set out to illustrate how to make the compounds of this invention and memods for determining associated therapeutic activity. These examples are not intended to limit me invention in any manner, their purpose is illustrative ratiier than limiting.

SYNTHETIC EXAMPLES

EXAMPLE 1

4-Cvano-4-(3-cvclopentyloxy-4-methoxyphenyl)cvclohex-l-en-l-yl trifluorometfιylsulfonate To a solution of άiisopropylamine (1.95 milliliters (hereinafter (mL), 13.9 millimoles

(hereinafter mmol)) in tetι^~hydrofuran (12 mL) at 0°C under an argon atmosphere was added n-butyllithium (5.8 mL of 2.5M solution, 14.15 mmol), the resulting solution was stirred for 25 minutes (hereinafter min) and then was cooled to -78°C. To tiiis was added a solution of 4- cyaπo-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one (2 grams (hereinafter g), 6.64 mmol) in tetrahydrofuran (9 mL). The resulting mixture was stirred at -78°C for 2 hours (hereinafter h), at which time N-phenyl-trifluoromediylsulfonimide (4.98 g, 13.9 mmol) was added. The mixture was allowed to warm slowly to room temperature and after 5h, the mixture was poured into water and extracted witii methylene chloride. The organic extract was dried (potassium carbonate) and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 4:1 hexanes/ethyl acetate, to afford an oil (1.09 g, 37%).

EXAMPLE 2 4-Cvano-4-(3-cvcloρentvloxv-4-methoxvphenvn-l-methoxvcvclohex-l-ene To a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one (0.3 g, 0.96 mmol) in dimemylformamide (3 mL) at 0°C under an argon atmosphere was added potassium t-butoxide (0J1 g, 0.96 mmol) and, 0.5h later, dimethyl sulfate (0.09 mL, 0.96 mmol). After 5 min, ammonium chloride was added, die mixture was extracted three times widi ether, the organic extract was washed three times witii water, once with brine, was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 9: 1 hexanes/ethyl acetate, provided a white solid (0.06 g, 19%): m.p. 123- 125°C.

Analysis Calc. for C20H25NO3-0.35 H2O: C 71.98, H 7.76, N 4.20; found: C 71.98, H 7.66, N 3.95

EXAMPLE 3 1 -Amino-4-(3-cyclopropylmethoxy-4-difluorome oxyphen yll)-2.4-dicyanocyclohex- 1 -ene 3a. 4-Cyano-4-(3-cyclopropylmedιoxy-4-difluoromethoxypheny pimelonitrile To a stirred solution of 3-cyclopropylmethoxy-4-difluoromethoxyphenylacetonitrile (1.0 g, 3.95 mmol) in dry acetonitrile (25 mL) under an argon atmosphere was added a 40% solution of Triton-B in methanol (0J86 mL, 0.40 mmol) followed by acrylonitrile (2.9 mL, 44 mmol). The solution was heated to reflux for 20 min, quenched by addtion of dilute aqueous hydrochloric acid and concentrated in vacuo. The residue was partitioned between ethyl acetate and water acidified with dilute hydrochloric acid, die organic phase was washed with brine, was dried (sodium sulfate) and the solvent was evaporated. The residue was purified by flash chromatography, eluting with 33% ethyl acetate/hexanes, and the oil was triturated with etiier to provide white crystals (0.56 g, 39%): m.p. 95-97°C.

Analysis Calc. for C19H19F2N3O2J/8 H2O: C 63.11, H 5.37, N 11.62; found: C 63.14, H 5.29, N 11.53.

3b. l-Amino-4-(3-cvclopropylmethoxy-4-difluoromethoxyphenyl -2.4-dicyanocvclohex-l- ene To a stirred suspension of sodium hydride (0.92 g, 3.07mmol) in dry 1,2- dimethoxyediane (8 mL) heated at 70°C under an argon atmosphere was added dropwise a solution of 4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)pimelonitrile (0.53 g, 1.48 mmol) in dry 1,2-dimethoxyethane (2.5 mL). After the addition, the mixture was heated to 85°C for 20 min and men quenched into ice water. The suspension was neutralized wid a few drops of acetic acid and was extracted three times with ether. The combined organic extract was washed with water, brine, was dried (sodium sulfate) and was evaporated. Half of tiiis residue was purified by flash chromatography, eluting widi 1% medianol/med ylene chloride and the residue was triturated with ether to provide a tan solid (0J02 g, 38%):m.p.

147-148.5°C Analysis Calc. for C19H19F2N3O2: C 63.50, H 5.33, N 11.69; found: C 63.26, H: 5.40, N

11.40.

EXAMPLE 4 l- Amino-2- carbomethoxy-4-cvano-4-(3-cyclopropylmethoxy-4-methoxyphenyl cyclohex-l- ene.

4a. 4-Cyano-4-f3-cyclopropyImethoxy-4-methoxyphenyl cvclohex-l-en-l-yl trifluoromethylsulfonate To a solution of 2,6-di-t-buryl-4-medιylpyridine (0.43 g, 2J mmol) in dichloromediane (8 mL) at room temperature under an argon atmosphere was rapidly added trifluoromedianesulfonic anhydride (0.30 mL, 1.78 mmol), followed immediately by the dropwise addition over 20 min of a solution of 2-carboxymetiιyl-4-cyano-4-(3- cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-l-one (0.50 g, 1.4 mmol) in dichloromediane (4 mL). The mixture was stirred for 24h, was quenched widi 1% hydrochloric acid, was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 25% ethyl acetate hexanes, provided a sticky white solid (0.60 g, 84 %): m.p. 73-74°C.

4b. l-Amino-2-carbome oxy-4-cvano-4-(3-cvcIopentyloxy-4-methoxyphenvD-l- cvclohex-1-ene A solution of 4-cyano-4-(3-cyclopropylmedιoxy-4-methoxyphenyl)-cyclohex- 1-en-l-yl trifluoromethylsulfonate (0J4 g, 0.28 mmol) in N,N-dimetiιyIfo^~mamide (2 mL) was saturated with ammonia gas and was stirred at room temperature under an argon atmosphere for 6h. The mixture was partitioned between water and ethyl acetate, the organic extract was washed three times widi water, once with brine, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting widi 35% ethyl acetate/hexanes, followed by trituration from dichloromediane/hexanes, provided a white solid (0.074 g, 74 %): m.p. 164-165°C. Analysis Calc. for C20H24N2O4J/2 H2O: C 65.74, H 6.90, N 7.67; found: C 65.72, H 6.69, N 7.58.

EXAMPLE 5 Memyl 2-rS-rα)-^~-bromophenethylaminol-5-cvano-5-(3-cvclopentyloxy-4- difluoromethoxyphenvDcyclohex- 1 -en-1 -yl carboxylate

A solution of 2-carboxymethyl-4-cyano-4-(3-cycIopropylmeihoxy-4- medιoxyphenyl)cyclohexan-l-one (1.00 g, 2.54 mmol) and S-(α)-bromophenetiιylamine (1 mL) in toluene (7.5 mL) was stirred at reflux with a Dean-Stark trap for 24h and was cooled. The mixture was diluted with ether, was washed with water and brine, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 10% ethyl acetate hexanes, provided two separate diastereomers distinguished by their NMR spectra and

TLC behavior

A: a white foamy solid (0.44 g, 30 %), further purified by trituration from methanol-water, to provide a white solid: m.p. 55-58°C; TLC Rf (20% ethyl acetate/hexanes): 0.33.

Analysis Calc. for C28H29BrF2N2θ4: C 58.44, H 5.08 N 4.87; found: C 58.45, H 5J0, N

4.73.

B: a white solid (0.51 g, 35 %), further purified by trituration from methanol-water, to provide a white solid: m.p. 55-58°C; TLC Rf (20% ethyl acetate/hexanes): 0.44. Analysis Calc. for C28H29BrF2N2θ4: C 58.44, H 5.08, N 4.87; found: C 58.32, H 5.02, N

4.75.

The following were also prepared by analogous mediods:

Methyl 2-amino-5-cvano-5-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl - cvclohex-1-en-l-yl carboxylate. a solid: m.p. 149-151°C. Analysis Calc. for C20H22F2N2O4J/4 H2O: C 60.52, H 5.71 , N 7.14; found: C 60.50, H

5.54, N 6.85.

Methyl 2-benzylamino-5-cyano-5-(3-cvclopropylmethoxy-4-methoxyphenyl cyclohex-

1-en-l-yl carboxylate. a solid: m.p. 119-120°C.

Analysis Calc. for C27H30N2O4J/4 H2O: C 71.90, H 6.82, N 6.21; found: C 71.80, H 6.74, N 6.24.

Methyl 2-rS-(α)-^~-nitrophenethyIaminol-5-cvano-5-(3-cvclopentyloxy-4- difluoromethoxyphenyl)cvclohex-l-en-l-yl carboxylate. as two separable diastereomers:

A: a solid: m.p. 121-122°C.

Analysis Calc. for C28H29F2N3O6: C 62.10, H 5.40, N 7.76; found: C 61.90, H 5.43, N 7.39.

B: a semi-solid.

METHODS OF TREATMENT In order to use a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

The compounds of Formula (I) or (LI), or a pharmaceutically acceptable salt tiiereof can be used in die manufacture of a medicament for the prophylatic or dierapeutic treatment of any disease state in a human or other mammal which is mediated by inhibition of PDE IV, such as but not limited to asthma, allergic, or inflammatory diseases. The compounds of Formula (I) or (U) are administered in an amount sufficient to treat such a disease in a human or other mammal.

For d e purposes herein all methods of treatment and dosage regimens apply equally to both the compounds of Formula (I) or (II). In order to use a compound of Formula OD or (LI), or a pharmaceutically acceptable salt tiiereof, for die treatment of humans and other mammals it is normally formulated in accordance widi standard pharmaceutical practice as a pharmaceutical composition.

The amount of a compound of Formula (I) or (II) required for tiierapeutic effect on topical administration will, of course, vary widi die compound chosen, die nature and severity of the condition and the animal undergoing treatment, and is ultimately at the discretion of the physician.

The daily dosage regimen for oral administration is suitably about .001 mg kg to lOOmg kg, preferably 0.01 mg Kg to 40 mg Kg, of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt tiiereof calculated as the free acid or base, which ever is appropriate. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit activity.

No unacceptable toxic effects are expected when tiiese compounds are administered in accordance widi me present invention.

UTILITY EXAMPLES EXAMPLE A Inhibitory effect of compounds of the compounds of this invention on in vitro TNF production bv human monocvtes The inhibitory effect of compounds of Formula (I) or (Et) on in vitro TNF production by human monocytes may be determined by die protocol as described in Badger er al., EPO published Application 0411754 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 die compounds of this invention. The protocol used in these models is described in

Badger et al., EPO published Application 0411 754 A2, February 6, 1991, and in Hanna, WO

90/15534, December 27, 1990. The compound of Example 1 herein demonstrated a positive in vivo response in reducing serum levels of TNF induced by the injection of endotoxin.

EXAMPLE C Isolation of PDE Isozvmes The phosphodiesterase inhibitory activity and selectivity of die compounds of of t is invention.s can be determined using a battery of five distinct PDE isozvmes. 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 III, guinea-pig heart; 4) PDE TV, human monocyte; and 5) PDE V (also called "la"), canine trachealis. PDEs la, lb, Ic and III are partially purified using standard chromatographic techniques [Torphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE IV is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-Sepharose chromatography [Torphy etal., J. Biol. Chem., 267:1798- 1804, 1992]. Phosphodiesterase activity is assayed as described in the protocol of Torphy and

Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Positive ICso's in die nanomolar to μM range for compounds of the workings examples described herein for compounds of this invention have been demonstrated.

EXAMPLE D

The ability of selected PDE IV inhibitors to increase cAMP accumulation in intact tissues is assessed using U-937 cells, a human monocyte cell line that has been shown to contain a large amount of PDE IV. To assess the activity of PDE IV inhibition in intact cells, nondifferentiated U-937 cells (approximately 10- cells/reaction tube) were incubated widi various concentrations (0.01-1000 μM) of PDE inhibitors for one minute and lμM prostaglandin E2 for an additional four minutes. Five minutes after initiating the reaction, cells were lysed by die addition of 17.5% perchloric acid, me pH was neutrahzed by the addition of IM potassium carbonate and cAMP content was assessed by RIA. A general protocol for this assay is described in Brooker et al, Radioimmunassay of cyclic AMP and cyclic GMP., Adv. Cyclic Nucleotide Res., 10:1-33, 1979. The compounds of the working examples as described herein for compounds of this invention have demonstrated a positive EC50S in the μM range in the above assay.

Claims

1. A compound of formula (I):

wherein:

Rl is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)_mR6, or -(CR4R5)r 6 wherein the alkyl moieties may be optionally substituted widi one or more halogens; m is 0 to 2; nis i to 4; r is I to 6;

R4 and R5 are independendy selected from hydrogen or a Cl-2 alkyl; R6 is hydrogen, mediyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-J1 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrodiienyl, thienyl, tetrahydrodiiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 mediyl groups or one ethyl group; provided that a) when R is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R is 2-tetrahydropyranyl, 2-tetrahydrothiopvranyl, 2-tetrahydrofuraπyI, or 2-tetrahydrotiιienyl, then m is 1 or 2; or d) when Rβ is 2-tetrahydropyranyl, 2-tetrahydrotiιiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, dien r is 1 to 6; e) when n is 1 and m is 0, dien R6 is otiier than H in -(CR4R5)nO(CR4R5)rrιR6; X is YR2, halogen, nitro, NR4R5, or formyl amine;

Yis O orS(O)m'; m' is 0, 1, or 2; X2 is O orNR8;

X3 is hydrogen or X;

R2 is independendy selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4; R3 is hydrogen, halogen, C1-4 alkyl,CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, -CH^*-CR8^,R8', cyclopropyl optionally substituted by R8', CN, OR8, CH2OR8, NR8R10, CH2NR8R10. C(Z')H, C(O)OR8, C(O)NRsRl0, or G≡CRδ';

Z is S(O)nVR9, OS(O)2R9, OR9, OC(O)NR7R9, OC(O)(O)_qR7, 0(CR4R5)nOR9, or NR9R9;

Z' is O, NR8, NNR8R8, NOR8, NCN, C(-CN)2, CRδCN, CR8NO2, CR8C(O)OR8, CR8C(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NR8Rδ; q is 0 or 1;

R7 is independendy hydrogen or R9; Rg is independendy selected from hydrogen or C 1.4 alkyl optionally substituted by one to tirree fluorines, or when R% and Rio are as -NRgRio they may togetiier with the nitrogen form a a 5 to 7 membered ring optionally containing one or more additional heteroatom selected from O, N, or S;

Rg* is Rg or fluorine; R9 is independendy Ci-Jo alkyl, C2-10 alkenyl, C3-7cycloalkyl, C4-6 cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which may be optionally substituted by one or more fluorine atoms, or two R9 terms appearing as NR9R9 may togetiier wid d e nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S; Rιois OR8 orR8; provided that: f) when q is 1 in OC(O)(O)qR7 , then R7 is not hydrogen; g) when Z' is NR8 , then R8 is not hydrogen; or the pharmaceutically acceptable salts thereof.

2. A compound of claim 1 which is

4-cyano-4-(3-cyclopentyloxy-4-medιoxyphenyl)cyclohex- 1 -en- 1 -yl trifluoromethylsulfonate;

4-cyano-4-(3-cyclopentyloxy-4-methoxypheny 1)- 1 -methoxycyclohex- 1 -ene; and 4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohex-l-en-l-yl trifluoromethylsulfonate.

3. A pharmaceutical composition comprising a compound of Formula (I) according to claim 1 and a pharmaceutically acceptable excipient

4. A method for treating an allergic or inflammatory state which method comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) according to claim 1 alone or in combination with a pharmaceutically acceptable excipient.

5. A compound of Formula (IT)

wherein:

R! is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR R5)_nO(CR4R5)πιR , or -(CR4R5)_rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens; m is 0 to 2; n is 1 to 4; ris l to 6;

R4 and R5 are independendy selected from hydrogen or a Cl-2 alkyl; Rβ is hydrogen, mediyl, hydroxyl, aryl, halo substituted aryl, aryloxyCι.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 and heterocyclic moieties may be optionally substituted by 1 to 3 mediyl groups or one ethyl group; provided that a) when Rβ is hydroxyl, then m is 2; or b) when R is hydroxyl, dien ris 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrodιienyl, then m is 1 or 2; or d) when Rβ is 2-tetrahydropyranyl, 2-tetrahydrodιiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrotirienyl, then r is 1 to 6; e) when n is 1 and m is 0, then Rβ is other than H in -(CR4R5)nO(CR4R5)_mR6; X is YR2, halogen, nitro, NR4R5, or formyl amine; Yis O orS(O)_m-; m' is 0, 1, or 2;

X2is O orNR8;

X3 is hydrogen or X;

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

R3 is hydrogen, halogen, -4 alkyl,CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, -GH^*-CR8^,Rg', cyclopropyl optionally substituted by Rδ', CN, OR8, CH2OR8, NRgRlO, CH2NRgRιo, C(Z')H, C(O)ORg, C(O)NRgRιo, or C≡CRg'; Z is S(O)m'R9, OS(O)2R9, OR9, OC(O)NR7R9, OC(O)(O)_qR7, O(CR4R5)nOR9, NR9R9 or NHR14

Z' is O, NRg, NNRgRg, NORg, NCN, C(-CN)2, CRgCN, CRgNO2, CRgC(O)ORg, CRgC(O)NRgRg, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NRgRg; q is O or l;

R7 is independendy hydrogen or R9;

Rg is independendy selected from hydrogen or C 1.4 alkyl optionally substituted by one to three fluorines, or when Rg and Rio are as -NRgRio they may together with the nitrogen form a a 5 to 7 membered ring optionally containing one or more additional heteroatom selected from O, N, or S;

Rg¹ is Rg or fluorine;

R9 is independendy Ci-io alkyl, C2-10 alkenyl, C3-7 cycloalkyl, C4-6 cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which may be optionally substituted by one or more fluorine atoms, or two R9 terms appearing as NR9R9 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;

RlO is ORg orRδ; provided that: f) when q is 1 in OC(O)(O)qR7 , then R7 is not hydrogen; g) when Z¹ is NR8 , then Rs is not hydrogen;

Z" is C(Y)Rl4, C(O)ORi4, C(Y)NRioRl4, C(NRiθ)NRiθRl4, CN, C(NOR8)Rl4, C(NORl4)R8, C(NR8)NRiθRl4, C(NRi4)NRδR8 C(NCN)NRiθRl4, C(NCN)SRχ 1, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[l,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[l,3,4]), (2-thiadiazolyl[ 1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-irnidazolidinyl); wherein all of the heterocylic ring systems may be optionally substituted one or more times by R14;

Y is O or S;

Rll I^s Cl-4 lkyl optionally substituted by one to tiiree fluorines; R12 is 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;

Rl3 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two Cι_2 alkyl groups;

Rl4 is hydrogen or R15; or when Rio and R14 are as NR10 14 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 - CR4R5)_rRi2 or C\_β alkyl wherein the R12 or C\_β alkyl group is optionally substituted one or more times by Cχ_2 alkyl optionally substimted by one to tiiree fluorines, -F, -Br, -CI, -NO₂, -Si(R₄)₂, -NRgRio, -C(O)R8, -C(O)OR8, -ORg, -CN, -C(O)NR₈R₁₀, -OC(O)NR₈Rio, -OC(O)R8, -NRlθC(O)NR₈Rιo, -NRιoC(O)R8, -NRlθC(O)OR9, -NRιoC(O)Ri3, -C(NRiθ)NR8RlO- -C(NCN)NR₈Rι₀, -C(NCN)SRi 1,

-NRιoC(NCN)SRn , -NRioC(NCN)NRιoR8, -NRιoS(O)2R9, -S(O)_m-Rn, -NRιoC(O)C(O)NR8Rιo, -NRioC(O)C(O)Rιo, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; ris O, 1, or 2; provided that h) when R12 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N- piperidinyl, or N-morpholinyl, dien q is not 1; or the pharmaceutically acceptable salts thereof.

6. A compound according to claim 5 which is 2-carbomedιoxy-4-cyano-4-(3-cyclopropylmethoxy-4-medιoxyphenyl)-l-

(methoxymethyloxy)cyclohex-l-ene;

2-carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-l- (medιoxymethyloxy)cyclohex- 1-ene;

2-aπ-inocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-l- (memoxymethyloxy)cyclohex-l-eπe; l-ammo-4-(3-cyclopropylmemoxy-4-difluoromethoxyphenyl])-2,4-dicyanocyclohex-l- ene;

2-^arbomethoxy-4-cyano-4-(3-cycIopropylmethoxy-4-difluoromethoxyphenyl)-l- (methoxymemyloxy)cyclohex-l-eneι 2-carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromedιoxyphenyl)-l-

(medιoxymethyloxy)cyclohex- 1-ene;

2-aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)- 1 - (methoxymethyloxy)cyclohex- 1-ene; l-amino-2-carbomethoxy-4-cyano-4-(3-cyclopenryloxy-4-medιoxyphenyl)cyclohex-l- ene; methyl 2-[S-(α)-^~-bromophenedιylamino]-5-cyano-5-(R and S)-(3-cycIopentyloxy-4- difluoromethoxyphenyI)cyclohex- 1-en-l-yl carboxylate; mediyl 2-amincH5-cyano-5-(3-cyclopropylmethoxy- -difluoromethoxyphenyl)- cyclohex-l-en-l-yl carboxylate; mediyl 2-benzylamino-5-cyano-5-(3-cyclopropylmethoxy-4-me±oxyphenyl)cyclohex—

1-en-l-yl carboxylate; or methyl 2-[S-(α)-p-nitrophenedιylamino]-5-cyano-5-(R and S)-(3-cyclopentyloxy-4- difluoromedιoxyphenyl)cyclohex-l-en- 1-yl carboxylate.

7. A pharmaceutical composition comprising a compound of Formula (II) according to claim 6 and a pharmaceutically acceptable excipient.

8. A method for treating an allergic or inflammatory state which method comprises administering to a subject in need tiiereof an effective amount of a compound of Formula (II) according to claim 6 alone or in combination widi a pharmaceutically acceptable excipient.