SI9300168A - 3,4-disubstituted phenylcyclohexan-1-on useful for treating pde iv related diseases - Google Patents

Abstract

New Cyclohexanes of Formulas (I) are described herein and (II): Sl 9300168 A They inhibit tumor necrosis factor formation and are useful in treating disease states that mediates aG accelerates TNF formation. These compounds are also useful in mediating or inhibiting enzymatic but the catalytic activities of phosphodiesterase IV.

Description

The present invention relates to novel compounds, to pharmaceutical compositions containing these compounds, and to their use in the treatment of allergic and inflammatory diseases and in the inhibition of tumor necrosis factor (TNF) production.

BACKGROUND OF THE INVENTION

Bronchial asthma is a complex, multifactorial disease characterized by reversible airway narrowing and hyperresponsiveness of the respiratory tract to external stimuli.

The identification of new therapeutic agents for asthma is complicated by the fact that many mediators are responsible for the development of the disease. Therefore, it seems unlikely that eliminating the effects of a single mediator will have a significant 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 increasing cAMP levels (cyclic adenosine 3 ', 5'-monophosphate). Cyclic AMP has been shown to be the second transmitter of information that mediates biological responses to a wide range of hormones, neurotransmitters and agents [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the appropriate agonist binds to specific receptors on the cell surface, adenylate cyclase is activated, which rapidly converts Mg ⁺² -ATP to cAMP.

Cyclic AMP modulates the activity of most, if not all, cells that contribute to the pathophysiology of asthma caused by external causes (allergic asthma). As such, an increase in cAMP would have beneficial effects, including: 1) relaxation of respiratory smooth muscle, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of activation of monocytes and macrophages. Therefore, compounds that activate adenylate cyclase or inhibit phosphodiesterase are effective in suppressing inappropriate activation of respiratory smooth muscle and a wide range of inflammatory cells. The main cellular mechanism for cAMP inactivation is the hydrolysis of the 3′-phosphodiester bond with one or more members of the isozyme family, termed cyclic nucleotide phosphodiesterase (PDE).

However, it has now been shown that a particular isocyme of cyclic nucleotide phosphodiesterase (PDE), PDE IV, is responsible for the disintegration of cAMP in respiratory smooth muscle and inflammatory cells. [Torphy, Phosphodiesterase Isozymes: Potential Targets for Novel Antiasthmatic Agents in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research shows that inhibition of this enzyme not only causes relaxation of the respiratory smooth muscle but also prevents degranulation of mast cells, basophils and neutrophils, while inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly potentiated when increased with the appropriate hormones or autocoids, as added in vivo, to the target cell cyclase adenate activity. Therefore, PDE IV inhibitors will be effective in asthmatic lungs where the levels of prostaglandin E ₂ and prostacyclin (adenylate cyclase activator) are elevated. Such compounds would offer a unique approach to the pharmacotherapy of bronchial asthma and would have significant therapeutic advantages over currently available commercially available agents.

The compounds of the invention also inhibit the production of tumor necrosis factor (TNF), which is a serum glycoprotein. Excessive or disorderly TNF formation is involved in the transmission or exacerbation of a variety of diseases, including rheumatic arthritis, rheumatic spondylitis, osteoarthritis, gout, and other arthritic conditions; sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcodiosis, bone resorption disease, reperfusion injury, transplant recipients, transplant recipients, transplant recipients, transplant recipients myalgia due to an infection such as influenza, cachexia after infection or malignancy, cachexia after acquired human immunodeficiency syndrome (AIDS), AIDS, ARC (AIDS-related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis or pyrosis in addition to a variety of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes, and systemic lupus erythematosus.

AIDS is caused by human immunodeficiency virus (HIV) infection of T lymphocytes. At least three types of HIV strains have been identified, namely HIV-1, HIV-2 and HIV-3. The consequence of HIV infection is that T cell-mediated immunity is impaired and that infected persons show serious opportunistic infections and / or unusual neoplasms. T lymphocyte invasion requires activation of T. lymphocytes. Viruses such as HIV-1 or HIV-2 infect T lymphocytes upon activation of T cells, and thus the expression and / or replication of the viral protein mediates or maintains such activation of T. cells. once activated HIV lymphocyte T, lymphocyte T must remain in the activated state to allow HIV gene expression and / or HIV replication.

Cytokines, especially TNFs, are involved in HIV protein expression and / or virus replication mediated by activated T cells, since cytokines play a role in maintaining T lymphocyte activation. Therefore, disruption of cytokine activity such as e.g. by inhibiting the production of cytokines, in particular TNF, in the HIV-infected person, will help to limit the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells, resulting in a slowdown or elimination progression of immune dysfunction caused by HIV infection. Monocytes, macrophages and related cells, such as Kuppfer cells and glial cells, are also involved in maintaining HIV infection. These cells are, like T cells, targets for viral replication and the level of viral replication depends on the state of cell activation [see Rosenberg et al., The Immunopathogenesis of HIV 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., Et al. Natl. Acad. Sci., 87: 782-784, 1990], therefore, inhibition of monokine formation or activity helps limit HIV progression, as noted above for T cells.

TNF has also been involved in various roles in other viral infections, such as cytomegalovirus (CMV), influenza virus, adenovirus, and herpes virus, for similar reasons as mentioned above.

TNF is also associated with yeast and fungal infections. Candido albicans, in particular, have been shown to induce TNF formation in vitro in human monocytes and natural killer cells [see Riipi et al., Infection and Immunity, 58 (9): 2750-54, 1990; and Jafari et al., Journal of Infectious Diseases, 164: 389-95, 1991. See also Wasan et al., Antimicrobial Agents and Chemotherapy, 35, (10): 2046: 48, 1991; and Luke et al., Journal of Infectious Diseases, 162: 211-214,1990].

The ability to control the adverse effects of TNF is supported by the use of TNF-inhibiting compounds in mammals in need of such use. There is a need for compounds useful in the treatment of TNF-mediated disease states that exacerbate or cause excessive and / or disorderly TNF production.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds of formulas (I) and (II), as shown below, which are useful in mediating the inhibition of the enzyme activity (or catalytic activity) of phosphodiesterase IV (PDE IV). These compounds also have an inhibitory effect on tumor necrosis factor (TNF).

The present invention also relates to pharmaceutical compositions comprising a compound of formulas (I) and (II) and a pharmaceutically acceptable carrier or diluent.

The invention also relates to a method for mediating or inhibiting the enzyme activity (or catalytic activity) of a PDE IV enzyme in mammals, including humans, comprising administering an effective amount of a compound of formula (I) or (II) as shown below to a mammal he needs it.

The invention further provides a method for treating an allergic and inflammatory disease comprising administering to an mammal, including humans, an effective amount of a compound of formula (I) or (II) as shown below.

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

The present invention also relates to a method for inhibiting the production of TNF in mammals, including humans, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula (I) or (II) that inhibits TNF. This procedure can be used to prophylactically treat or prevent certain TNF-mediated disease states to which they respond.

The present invention also relates to a method for treating a human being infected with a human immunodeficiency virus (HIV), comprising administering to a human being an effective amount of a compound of formula (I) or (II) that inhibits TNF.

The compounds of formulas (I) or (II) are also useful in the treatment of viral infections where the viruses are susceptible, sensitive to the positive effect of TNF on their development or will induce TNF production in vivo.

In addition, compounds of formulas (I) or (II) are also useful in the treatment of yeast and fungal infections, where yeasts and fungi are susceptible to the positive effect of TNF on their development or will induce TNF production in vivo.

Some novel compounds of the invention are represented by formula (I)

where it is

R _x - (CR ₄ R ₅ ) C (O) O (CR ₄ R ₅ ) _m R ₆ , - (CR ₄ R ₅ ) C (O) NR ₄ (CR ₄ R ₅ ) _m R ₆ ,

- (CR ₄ R ₅ ) _n O (CR ₄ R ₅ ) _m R ₆ or - (CR ₄ R ₅ ) _r R ₆ , wherein the alkyl moieties may optionally be substituted by one or more halogens; m is 0 to 2;

n is 1 to 4;

r is 1 to 6;

R and R are independently selected from hydrogen or C 1-6 alkyl;

R ₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC ₁₃ alkyl, halo substituted aryloxy ₃ alkyl, indanyl, indenyl, C ₇ _ polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, _C3 ^ cycloalkyl or C ₄ ^ cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group;

provided that,

a) when hydroxyl, then m 2; or

b) when R _{6 is} hydroxyl, then r is 2 to 6; or

c) when R _{6 is} 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or

2-tetrahydrothienyl, then m is 1 or 2; or

d) when R _{6 is} 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or

2-tetrahydrothienyl, then r is 1 to 6;

e) when n is 1 and mO, then R _{6 is} other than H in - (CR ₄ R ₅ ) _n O (CR ₄ R ₅ ) _m R ₆ ;

X is YR ₂ , halogen, nitro, NR ₄ R ₅ or formyl amine;

Y is O or S (O) _m> ;

m is 0.1 or 2;

X _{2 is} O or NR ₈ ;

X1 is hydrogen or X;

R ₂ is independently selected from -CH ₃ and -CH ₂ CH ₃ , which are optionally substituted by 1 or more halogens; s is 0 to 4;

R ₃ is hydrogen, halogen, C _p alkyl, halogen-substituted ₄ alkyl, CH ₂ NHC (O) C (O) NH _2, -CH = CR _8, R _g ,, cyclopropyl, which is optionally substituted by R _g 'CN, OR ₈ , CH ₂ OR ₈ , NR ₈ R ₁₀ , CH ₂ NR _g R ₁₀ , C (Z') H, C (O) OR _g , C (O) NR _g R ₁₀ or C = CR _g ,;

Z'is O, NR ₉ , NOR _g , NCN, C (-CN) ₂ , CR _g CN, CR _g NO ₂ , CR _g C (O) OR _g ,

CR _g C (O) NR _g R _g , C (-CN) NO ₂ , C (-CN) C (O) OR ₉ or C (-CN) C (O) NR _g R _g ;

Z is O, NR _? , NCR ₄ R ₅ C ₂ -alkenyl, NOR ₁₄ , NOR ₁₅ , NOCR ₄ R ₅ C ₂ -alkenyl,

NNR ₄ R ₁₄ , NNR ₄ R ₁₅ , NCN, NNR _g C (O) NR _g R ₁₄ , NNR ₈ C (S) NR _g R ₁₄ or = Z

2- (1,3-dithio), 2- (1,3-dithiolane), dimethylthio ketal, diethylthio ketal, 2- (1,3-dioxolane),

2- (1,3-dioxane), 1- (1,3-oxathiolane), dimethyl ketal or diethyl ketal;

R _? is - (CR ₄ R ₅ ) _q R ₁₂ or C ₁₄₅ alkyl, wherein R ₁₂ or C 1-4 alkyl is optionally one or more times substituted with C _{4 2} alkyl, which is optionally substituted by 1 to 3 fluors, -F, -Br, -Cl, -NO ₂ , -Si (R ₄ ) ₃ , -NR ₁₀ R _n , -C (O) R _g , -CO ₂ R _g , -OR _g , -CN, -C (O) NR ₁₀ R _n , -OC (O) NR ₁₀ R _n , -OC (O) R _g , -NR ₁ 'qO) NR ₁₀ R ₁₁ , -NR ₁₀ C (O) R _n , -NR ₁₀ C (O) OR ₉ , -NR ₁₀ C (O) R ₁₃ , -C (NR ₁₀ ) NR ₁₀ R ₁₁ , -C (NCN) NR ₁₀ R _n , -C (NCN) SR ₉ , -NR ₁₀ C (NCN) SR ₉ , -NR ₁₀ C (NCN) NR ₁₀ R _lp -NR ₁₀ S (O) ₂ R ₉ , -S (O) _m , R ₉ , -NR ₁₀ C (O) C (O) NR ₁₀ R _n , -NR ₁₀ C (O) C (O) R ₁₀ , thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl or tetrazolyl;

q is 0.1 or 2;

R ₁₂ is C _3-7 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;

R _g is independently selected from hydrogen or R ₉ ;

R 8 is R 8 or fluorine;

R ₉ is C ₁₄ alkyl which is optionally substituted by 1 to 3 fluorines;

^R io J ^{e OR} 8 ^{or R} ir

R _n is hydrogen or C _M alkyl, optionally substituted with 1 to 3 fluorines; or if R ₁₀ and R _{u are} NR ₁₀ R _n , together with nitrogen, may form a 5- to 7-membered ring containing optionally at least one additional heteroatom selected from O, N or S;

R ₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl or thiadiazolyl, and each of these heterocyclic rings is bonded via a carbon atom and 1 is optionally substituted by a carbon atom and ₁₂ alkyl groups;

R ₁₄ is hydrogen or R _? ; or if R _g and R _{14 are} NR _g R ₁₄ , together with nitrogen, they may form a 5 to 7 membered ring containing optionally one or more additional heteroatoms selected from O, N or S;

R ₁₅ is C (O) R ₁₄ , C (O) NR ₄ R ₁₄ , S (O) ₂ R ₇ or S (O) ₂ NR ₄ R ₁₄ ;

provided that (f) when ZO, X is XR ₂ , Y is oxygen, oxygen, X ₃ is hydrogen, s is 0, R ₂ is CH ₃ and R ₃ is CH ₃ , then R _{3 is} different from CN;

(g) when ZO is oxygen, X ₃ is hydrogen, s is 0 and X is YR ₂ , then R _{3 is} other than hydrogen;

(h) when Z is NO-CH ₂ CH = CH ₂ , X is YR ₂ , Y is oxygen, X is hydrogen, s is 0, R 1 is CH ₃ and R ₃ is CH ₃ , then R ₃ different from CN;

(i) when R _{12 is} N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N-piperidinyl or N-morpholinyl, then q is not 1; or (j) when ZO or Z is 2- (1,3-dioxolane) and R ₃ is CH ₃ , CH ₂ OH or CH ₂ OC is _M- alkyl, then R 4 is not C ₃ -alkoxy and X is not halogen , methoxy, ethoxy, methylthio or ethylthio;

or a pharmaceutically acceptable salt thereof.

Another group of compounds of the invention is represented by formula (II)

(Π) where

R _x - (CR ₄ R ₅ ) _n C (O) O (CR ₄ R ₅ ) _m R ₆ , - (CR ₄ R ₅ ) C (O) NR ₄ (CR ₄ R ₅ ) _m R ₆ ,

- (CR ₄ R ₅ ) _n O (CR ₄ R ₅ ) _m R ₆ or - (CR ₄ R ₅ ) _r R ₆ , wherein the alkyl moieties may optionally be substituted by one or more halogens; m is Odo 2;

n is 1 to 4;

r is 1 to 6;

R ₄ and R ₅ are independently selected from hydrogen or C ₁₂ alkyl;

R ₆ is hydrogen, methyl, hydroxyl, aryl, halogen substituted aryl, aryloxyC ₁₃ alkyl, halogen substituted aryloxyC ₃ alkyl, indanyl, indenyl, C _{7 n} polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thiron , thiopyranyl, C _34J cycloalkyl or C ₄₆ cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group;

provided that,

a) when R _{f is} hydroxyl then m 2; or

b) when R _{6 is} hydroxyl, then r is 2 to 6; or

c) when R _{6 is} 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then m is 1 or 2; or

d) when R _fi 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 R _{6 is} other than H in - (CR ₄ R ₅ ) _n O (CR ₄ R ₅ ) _m R ₆ ;

X is YR ₂ , halogen, nitro, NR ₄ R ₅ or formyl amine;

Y is O or S (O) _m> ;

m 'is 0.1 or 2;

X ₂ is O or NR _g ;

X ₃ is hydrogen or X;

R ₂ is independently selected from -CH ₃ and -CH ₂ CH ₃ , which are optionally substituted by 1 or more halogens;

s is 0 to 4;

R ₃ is hydrogen, halogen, C _M alkyl, CH ₂ NHC (O) C (O) NH ₂ , halogen substituted C _1-4 alkyl, -CH = CR _g , R _g 'cyclopropyl, optionally substituted by R _g> , CN, OR _g , CP ^ ORg, NR ₈ R ₁₀ , CP ^ NR _g R ^, C (Z ') H, C (O) OR _g , C (O) NR _g R ₁₀ or C = CR ₈ , ;

Z'is O, NR ₉ , NORg, NCN, C (-CN) ₂ , CR _g CN, CR _g NO ₂ , CR ₈ C (O) OR ₈ ,

CR _g C (O) NRgRg, C (-CN) NO ₂ , C (-CN) C (O) OR ₉ or C (-CN) C (O) NR ₈ R _g ;

Z is C (Y ') R ₁₄ , C (O) OR ₁₄ , C (Y') NR ₁₀ R ₁₄ , C (NR ₁₀ ) NR _w R ₁₄ , CN, C (NOR ₈ ) R ₁₄ , C (O ) NR ₈ NR ₈ C (O) Rg, C (O) NR _g NR ₁₀ R ₁₄ , C (NOR ₁₄ ) R ₈ , C (NR ₈ ) NR ₁₀ R ₁₄ , C (NR ₁₄ ) NR ₈ Rg, C (NCN) NR ₁₀ R ₁₄ , C (NCN) SR ₉ , (2-, 4- or 5-imidazolyl), (3-, 4- or

5- pyrazolyl), (4- or 5-triazolyl [1,2,3], (3- or 5-triazolyl [1,2,4]), (5-tetrazolyl), (2-, 4 or 5-oxazolyl) ), 3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl [1,2,4]), (2-oxadiazolyl [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 heterocyclic ring systems may optionally be substituted one or more times with R ₁₄ ;

Y 'is O or S;

residual substituents for compounds of formula (II), including R _? , q, R ₁₂ , R ₈ , R _g 'R ₉ , R ₁₀ , ^ 13' ^ 14 and R _1S have the same definitions as given with respect to formula (I), where appropriate;

provided that

f) when R _{12 is} N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N-piperidinyl or N-morpholinyl, then q is not 1; or

g) when ZC (O) is OR ₁₄ , where R _{14 is} lower alkyl and R ₃ is CN, then R 4 is not C ₁₃ alkoxy and X is not halogen, methoxy, ethoxy, methylthio or ethylthio;

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention also relates to a method for mediating or inhibiting the enzymatic activity (or catalytic activity) of PDE IV in a mammal in need thereof and inhibiting the production of TNF in a mammal in need thereof, comprising administering an effective amount of a compound with formula (I) or (II) to a mammal in need thereof.

Phosphodiesterase IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases, including asthma, chronic bronchitis, atypical dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, eosinophilic granuloma, psoriasis, arthritis, rheumatitis, rheumatitis, ulcer reperfusion injury to the myocardium and brain, chronic glomerulonephritis, endotoxic shock, and adult respiratory distress syndrome. In addition, PDE IV inhibitors are useful in the treatment of insipidus diabetes and central nervous system disorders such as depression and multi-infarct dementia.

The viruses discussed herein are those that produce TNF as a result of infection, or those that are susceptible to inhibition, as by directly or indirectly reducing replication, with TNF inhibitors of formula (I) or (II). Such viruses include, but are not limited to, HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza virus, adenovirus, and a group of herpes viruses such as, but not limited to, Herpes zoster and Herpes simplex.

The present invention more specifically relates to a method for treating a mammal infected with a human immunodeficiency virus (HIV) comprising administering to a mammal an effective amount of a compound of formula (I) or (II) that inhibits TNF.

The compounds of the invention may also be used in connection with the veterinary treatment of animals, ie not only humans in need of inhibition of TNF production. TNF-mediated diseases suitable for therapeutic or prophylactic treatment of animals include disease states such as those mentioned above, but in particular viral infections. Examples of such viruses include, but are not limited to, Feline Immune Deficiency Virus (FIV) and other retrovirus infections such as equine infectious virus virus, goat arthritis virus, visna virus, maedi virus and other lentiviruses.

The compounds of the invention are also useful in the treatment of yeast and fungal infections, where such yeasts and fungi are sensitive to the positive effect of TNF on their development or will induce TNF formation (formation) in vivo. The preferred disease state for treatment is fungal menigitis. In addition, compounds of formula (I) or (II) may be administered in combination with other selected systemic agents for yeast and fungal infections. Selected drugs for fungal infections include, but are not limited to, a class of compounds called polymyxins, such as polymyxin B, a class of compounds called imidazoles, such as clotrimazole, econazole, miconazole, and ghetoconazole; a class of compounds called triazoles, such as fluconazole and itranazole, and a class of compounds called amphotericins, in particular amphotericin B and liposomal amphotericin B.

Compounds of formula (I) or (II) may also be used to inhibit and / or reduce the toxicity of an antifungal, antibacterial or antiviral agent by administering an effective amount of a compound of formula (I) or (II) to a mammal in need of such treatment . A compound of formula (I) or (II) is preferably administered to inhibit or reduce the toxicity of amphotericin class compounds, in particular amphotericin B.

Preferred compounds are as follows:

If R in the compound of formula (I) or (II) alkyl, substituted with 1 or more halogen atoms, the halogen is preferably fluorine and chlorine, more preferably a C ₁₄ alkyl substituted by 1 or more fluorines. Preferred halogen substituted alkyl chain lengths are 1 or 2 carbons, and most preferred are -CF ₃ , -CH ₂ F, -CHF ₂ , -CF ₂ CHF ₂ , -CH ₂ CF ₃ and -CH ₂ CHF ₂ . Preferred substituents R for the compounds of formula (I) are CH ₂ -cyclopropyl, CH ₂ -C ₅ _ ₆ cycloalkyl, C _{4 6} cycloalkyl, C _{7 n} -policikloalkil, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran- 3-yl, benzyl or C ₂ -alkyl which is optionally substituted by 1 or more fluorines, - (01) ^ (0) 0 (0¾) ^ ¾ - (CH ₂₎ j. ₃ O (CH ₂ ) ₀ . ₂ CH ₃ and - (C ^ OH.

If the term Rj (CR ₄ R ₅ ), the terms R ₄ and R _{5 are} independently hydrogen or alkyl. This permits the branching of individual methylene units as (CR ₄ R ₅ ) _n or (CR ₄ R ₅ ) _m ; each repeating methylene unit is independent of the others; e.g. (CR ₄ R ₅ ) _n , where n 2 may be e.g. -CH ₂ CH (-CH ₃ ) -. The individual hydrogen atoms of a repeating methylene unit or a branched hydrocarbon may optionally be substituted independently of one another by fluorine to give e.g. preferred substitutions for R _p as mentioned above.

If Rj is C _? jj-polycycloalkyl are examples of bicyclo [2.2.1] -heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, tricyclo [5.2.1.0 ^2,6 ] decyl, for which further examples are described in Saccamano et al., W0 87/06576, published November 5, 1987, and the description of this publication is incorporated herein by reference in its entirety.

Preferred terms Z are O, NCN, NR ₇ , NOR ₁₄ , NOR ₁₅ , NNR ₄ R ₁₄ , NNR ₄ R ₁₅ , dimethyl ketal or dimethyl tio thio ketal. O or NOH are more preferred.

Preferred X groups of formula (I) are those wherein X is YR and Y is oxygen. The preferred group X for formula (I) is one where X is oxygen. The preferred group of formula (I) is one where X _{3 is} hydrogen. The preferred group R1, where appropriate, is C1-C6 alkyl optionally substituted by 1 or more halogens. Halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R ₂ groups are those wherein R 1 is methyl or fluoro substituted alkyl, especially C 1 -alkyl, as parts of -CF ₃ , -CHF, or -CH ₂ CHF ₂ . The most preferred parts are -CHF, and -0¾.

The preferred portions of R ₃ are C (O) NH ₂ , C = CR _g , CN, C (Z ') H, CH ₂ OH, CH ₂ F, CF ₂ H and CF _g . More preferred are C ^ CH and CN. Z 'is preferably O or NOR _g .

Advantages of R _? include optionally substituted - (CH ₂ ) ₁₂ (cyclopropyl), - (CH ₂ ) ₀ . ₂ (cyclobutyl), - (CH ₂ ) _{0 2} (cyclopentyl), - (CH ₂ ) _{0 2} (cyclohexyl), - (CH ₂ ) _{0 2} (2-, 3- or 4-pyridyl), - (CH ₂ ) ₁₂ (2- (imidazolyl), - (CH ₂ ) ₂ (4-morpholinyl), - (CH ₂ ) ₂ (4-piperazinyl), - (CH ₂ ) ₁₂ (2-thienyl), - (CH ₂ ) ₁₂ (4-thiazolyl) and - (CH ₂ ) _{O 2} phenyl.

If ^{R 10} and R 11 in the -NR 10 ^R n moiety together with the nitrogen to which they are attached form a 5- to 7-membered ring containing optionally at least one additional heteroatom selected from O, N or S, include, but non-limiting, 1-imidazolyl, 2- (R _g ) -limidazolyl, 1-pyrazolyl, 3- (R _g ) -1-pyrazolyl, 1-triazolyl, 2-triazolyl, 5- (R _g ) -1-triazolyl, 5- ( R _g ) -2-triazolyl, 5- (R _g ) -1-tetrazolyl, 5- (R _g ) -2-tetrazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, 4- (R _g ) -1 -piperazinyl or pyrrolyl ring.

If R _g and R ₁₄ in the -NR _g R ₁₄ moiety together with the nitrogen to which they are attached may form a 5- to 7-membered ring containing optionally at least one additional heteroatom selected from O, N or S include priority rings, but not limitless,

1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetarazolyl, 2-tetrazolyl, morpholinyl, piperazinyl and pyrrolyl. The corresponding rings may be further substituted, where appropriate, on the available nitrogen or carbon by part R _? , as described herein for formula (I). Examples of such carbon substitutions includes, but are not limited to, 2- _(R?) -L-imidazolyl, 4- _(R7) -l-imidazolyl, 5- _(R7) -l-imidazolyl, 3- (R ₇₎ -l-pyrazolyl, 4- _(R?) -1-pyrazolyl, 5- _(R7) -l-pyrazolyl, 4- _(R7) -2-triazolyl, 5- _(R7) -2-triazolyl, 4 - _(R7) -l-triazolyl, 5- _(R?) -L-triazolyl, 5- _(R7) -l-tetrazolyl, and 5- _(R7) -2-tetrazolyl. Suitable nitrogen substitution with R _? It includes, but is not limited to, l- _(R7) -2-tetrazolyl, 2- _(R7) -l-tetrazolyl, 4- (R ₇₎ -lpiperazinil. Where appropriate, the ring may be substituted one or more times with R _? .

Preferred groups for NR _g R _14, which contain a heterocyclic ring are 5- (R ₁₄₎ -ltetrazolil, 2- (R ₁₄₎ -l-imidazolyl, 5- _(R14) -2-tetrazolyl, 4- (R ₁₄ -l-piperazinyl or 4- (R ₁₅ ) -lpiperazinyl.

Preferred rings for R ₁₃ include (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4 or 5-triazolyl [1,2,3]), (3- or 5- triazolyl [1,2,4], (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl [1, 2,4]), (2-oxadiazolyl [1,3,4]), (2-thiadiazolyl [1,3,4j), (2-, 4- or 5-thiazolyl), (2-, 4- or 5-oxazolidinyl), (2-, 4- or 5-thiazolidinyl) or (2-, 4- or 5-imidazolidinyl).

If the group is R _? optionally substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, triazolyl, tetrazolyl or thiazolyl, the heterocyclic ring itself may be optionally substituted by R _g either on the available nitrogen or carbon atom, such as 1- (R _g ) -2- imidazolyl, 1- (R _g ) -4-imidazolyl, 1- (R _g ) -5-imidazolyl, 1- (R _g ) 3-pyrazolyl, 1- (R _g ) -4-pyrazolyl, 1- (R _g ) -5-pyrazolyl, 1- (R _g ) -4-triazolyl or 1- (R _g ) -5triazolyl. Where appropriate, the ring may be substituted one or more times with R _g .

Preferred are those compounds of formula (I) wherein R1 is -CH ₂ -cyclopropyl, -CH ₂ -C ₅ cycloalkyl, -C ₄₆ -cycloalkyl, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -C _{3 2} -alkyl, optionally substituted by 1 or more fluorines, and - (CH ₂ ) ₂₄ OH; R ₂ is methyl or fluoro substituted alkyl, R ₃ is CN or C = CR _g ; and X is XR ₂ .

Most preferred are those compounds wherein R _{x is} -CH ₂ -cyclopropyl, cyclopentyl, methyl or CF ₂ H; R ₃ is CN or C = CH; X is YR ₂ ; Y is oxygen; X ₂ is oxygen; X ₃ is hydrogen and R ₂ is CF ₂ H or methyl.

A preferred subtype of compounds of formula (I) are compounds of formula (Ia)

(Ia) where

R 1 is CH ₂ -cyclopropyl, CH ₂ -C ₅ -cycloalkyl, C ₄₆ -cycloalkyl, C _{? n-} polycycloalkyl, (3- or

4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C ₂ -alkyl which is optionally substituted by 1 or more fluorines, - (CH _{2) first 3} C (O) O (CH ₂ ) ₀ . ₂ CH ₃ , - (CH ^^ CH ^ CH., MCH ^ OH;

X is XR ₂ , halogen, nitro, NR ₄ R ₅ or formyl amine;

Y is O or S (O) _m> ;

m 'is 0.1 or 2;

R ₂ is -CH ₃ or -CH ₂ CH ₃ which is optionally substituted by 1 or more halogens;

R ₃ is hydrogen, C _1-4 alkyl, halogen substituted C _1-4 alkyl, CH ₂ C (O) C (O) N, CH ₂ NHC (O) C (O) NH ₂ , CN, CH ₂ OR ₈ , C (Z ') H, C (O) OR ₈ , C (O) NR ₈ R ₁₀ or C ^ CR _g ; Z 'is O or NOR _g ;

Z is O, NR ₇ , NOR ₁₄ , NOR ₁₅ , NNR ₄ R ₁₄ , NNR ₄ R ₁₅ , NCN or = Z is 2- (1,3-ditian), dimethylthio ketal, 2- (1,3-dioxolane) or dimethyl ketal;

R ₇ is - (CR ₄ R ₅ ) R, ₂ or C 1-6 alkyl, wherein R ₁₂ or C _1-4 alkyl group is optionally substituted one or more times with C ₁₂ alkyl which is optionally substituted by 1 up to 3 fluorines, -F, -Br, -Cl, -NO ₂ , -Si (R ₄ ) ₃ , -NR ₁₀ R _n , -C (O) R _g , -CO ₂ R _g , -OR _g ,

-CN, -C (O) NR ₁₀ R _u , -OqO) NR ₁₀ R _u , -OC (O) R _g , -NR ₁₀ C (O) NR ₁₀ R ₁₁ , -NR ₁₀ C (O) R _u , -NR ₁₀ C (O) OR ₉ , -NR ₁₀ C (O) R ₁₃ , -C (NR ₁₀ ) NR ₁₀ R _n ,

-C (NCN) NR ₁₀ R _n, -C (NCN) SR _9, -NR _{1 °} C (NCN) SR _9, -NR ₁₀ C (NCN) NR ₁₀ R _lp -NR ₁₀ S (O) ₂ R _9, -S (O) _m R _9, -NR ₁₀ C (O) C (O) NR ₁₀ R _lp -NR ₁₀ C (O) C (O) R _10, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl, ;

q is 0.1 or 2;

R ₁₂ is C _3-7 -cycloalkyl, (2-, 3- or 4-pyridyl), (1- or 2-imidazolyl), piperazinyl, morpholinyl, (2- or 3-thienyl), (4- or 5-thiazolyl ) or phenyl;

R _g is independently selected from hydrogen or R ₉ ;

R ₉ is C 1-6 alkyl optionally substituted by 1 to 3 fluorines;

^R and _O is OR ₈ or R _lp

R _n is hydrogen or C1-6-alkyl optionally substituted by 1 to 3 fluorines; or when R ₁₀ and RJJ as NR j R _{0 lp} can be taken together with the nitrogen form a 5- to 7-membered ring optionally containing at least one additional heteroatom selected from O, N or S;

R ₁₃ 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 with 1 or 2 Cl ₂ -alkyl groups;

R ₁₄ is hydrogen or R _? ; or if R _g and R _{14 are} NR _g R ₁₄ , together with nitrogen, they may form a 5 to 7 membered ring containing optionally one or more additional heteroatoms selected from O, N or S;

R ₁₅ is C (O) R ₁₄ , C (O) NR ₄ R ₁₄ , S (O) ₂ R _? or S (O) ₂ NR ₄ ^R 14;

provided that

a) when ZO, X is YR ₂ , Y is oxygen, R ₂ is CH ₃ and R 1 is CH ₃ , then R _{3 is} different from CN;

b) when R _{12 is} N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl or N-morpholinyl, then q is not 1;

or a pharmaceutically acceptable salt thereof.

In the examples shown, the preferred compounds of formula (I) are:

4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one;

4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexan-1-one;

4-cyano-4- (3-difluoromethoxy-4-methoxyphenyl) cyclohexan-1-one;

4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-one;

4-cyano-4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) cyclohexan-1-one;

4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one; 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one oxime; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-formylcyclohexan-1-one; 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one dimethyl ketal;

4- (3-cyclopentyloxy-4-methoxyphenyl) -4-formylcyclohexane-1-one dimethyl ketal; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (hydroxymethyl) cyclohexan-1-one; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (hydroxymethyl) cyclohexan-1-one dimethyl ketal: 4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (fluoromethyl) cyclohexan-1-one; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (fluoromethyl) cyclohexan-1-one dimethyl ketal; 4-Aminocarbonyl-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one; 4-Aminocarbonyl-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one dimethyl ketal; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-ethynylcyclohexan-1-one; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-ethynylcyclohex-1-one dimethyl ketal; 4- (3,4-bisdifluoromethoxyphenyl) -4-ethynylcyclohexan-1-one; 4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexan-1-one dimethyl ketal; 4- (3,4-bisdifluoromethoxyphenyl) -4-formylcyclohexan-1-one dimethyl ketal; 4- (3,4-bisdifluoromethoxy) -4-ethynylcyclohex-1-one dimethyl ketal; 4- (3,4-bisdifluoromethoxyphenyl) -4- (oxamidomethyl) cyclohexan-1-one; 4-Aminomethyl-4- (3,4-bisdifluoromethoxyphenyl) cyclohexan-1-one dimethyl ketal; 4- (3,4-bisdifluoromethoxyphenyl) -4- (oxamidomethyl) cyclohexan-1-one dimethyl ketal; 4-cyano-4- [3-cyclopentyloxy-4- (4-fluorobenzyloxy) phenyl] cyclohexan-1-one; 4-cyano-4- [3-cyclopentyloxy-4- (4-fluorobenzyloxy) phenyl] cyclohexan-1-one oxime; 4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -4-ethynylcyclohexan-1-one; 4-cyano-4- (3-cyclopropomethoxy-4-methoxyphenyl) cyclohexan-1-one oxime.

Preferred Z groups are for compounds of formula (II) C (O) R ₁₄ , C (O) OR ₁₄ ,

C (O) NR ₁₀ R ₁₄ , C (NR ₁₀ ) NR ₁₀ R ₁₄ , CN, C (NOR ₈ ) R ₁₄ , C (O) NR ₈ NR ₈ C (O) R ₈ ,

C (O) NR ₈ NR ₁₀ R ₁₄ , C (NOR ₁₄ ) R ₈ , C (NR ₈ ) NR ₁₀ R ₁₄ , C (NR ₁₄ ) NR ₈ R ₈ ,

C (NCN) NR ₁₀ R ₁₄ , C (NCN) SR ₉ , (1-, 4- or 5- {R ₁₄ } -2-imidazolyl), (1-, 4- or 5- {R ₁₄ } -316 pyrazolyl), (1-, 2- or 5- {R ₁₄ } -4-triazolyl [1,2,3]), (1-, 2-, 4- or 5- {R ₁₄ } -3-triazolyl [1, 2,4j), (1- or 2- {R ₁₄ } -5-tetrazolyl), (4- or 5- {R ₁₄ } -2-oxazolyl), (3- or 4- {R ₁₄ } -5- isoxazolyl), (3- {R ₁₄ } -5-oxadiazolyl [1,2,4j), (5- {R ₁₄ } -3-oxadiazolyl [1,2,4j), (5- {R ₁₄ } -2 -oxadiazolyl [1,3,4]), (5- {R ₁₄ } -2-thiadiazolyl [1,3,4]), (4- or 5- {R ₁₄ } -2-thiazolyl), (4- or 5- {R ₁₄ } -2-oxazolidinyl), (4- or 5- {R ₁₄ } -2-thiazolidinyl), (1-, 4- or 5- {R ₁₄ } -2-imidazolidinyl). The remaining preferred substituents for the compounds of formula (II) are the same as those indicated above for the compounds of formula (I), where appropriate.

In the examples shown, the preferred compounds of formula (II) are:

2-carbomethoxy-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one;

4- (3,4-bisdifluoromethoxyphenyl) -2-carbomethoxy-4-cyanocyclohexan-1-one;

2-carbomethoxy-4-cyano-4- (3-difluoromethoxy-4-methoxyphenyl) cyclohexan-1-one;

2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-one;

2-carbomethoxy-4-cyano-4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) cyclohexanyl-one;

2- carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexanyl-one;

2-Aminocarbonyl-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-one; 4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -2- [2- (trimethylsilyl) ethoxycarbonyl)] -cyclohexan-1-one;

2-carboxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one; 4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -2,4-dicyclocyclohexan-1-one and

2-Aminocarbonyl-4-cyano-4- (3-cyclopropylmethoxy) -4-difluoromethoxyphenyl) cyclohexan-1-one.

It is understood that some of the compounds of formula (I) and (II) may exist in both racemic and optically active forms; some may also exist as distinct diastereomeric forms having distinct physical and biological properties. All of these compounds are intended to be within the scope of the present invention.

Some compounds of formula (I) or (II) may exist in tautomeric form as enol. This can be represented by = 0 in the exocyclic position with respect to the cyclohexane ring (or

Η

Ο in contrast to the one-cyclic moiety or moiety -C (-OH) = C (R) -, where the cyclohexane ring is now unsaturated in position 1-2, i.e. cyclohex-l-en, or and R is H in formula (I ) or Z in formula (II). It is also understood that the 2 position in the ring in the endocyclic form may be substituted (R) as in the compounds of formula (II).

The terms C ₃ alkyl, C _{x 4} alkyl, C _x6 alkyl or alkyl, as used herein, include both radicals having straight or branched chain with 1 to 10 members, including, unless the chain length is not limited to them, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl and the like.

Alkenyl includes 1 to 6 straight or branched chain radicals, including, but not limited to, vinyl chain, but not limited to,

1-propenyl, 2-propenyl, 2-propynyl or 3-methyl-2-propenyl.

The term cycloalkyl or cycloalkyl alkyl includes groups of 3 to 7 carbon atoms such as cyclopropyl, cyclopropylmethyl, cyclopentyl or cyclohexyl.

Aryl or aralkyl means, unless otherwise stated, an aromatic ring or ring system of 6 to 10 carbon atoms, such as phenyl, benzyl, phenethyl or naphthyl. Preferably aryl is monocyclic, e.g. phenyl. The alkyl chain includes radicals with 1 to 4 carbon atoms, both straight and branched.

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.

The term inhibiting IL-1 formation or inhibiting TNF formation means:

a) reduction of excessive levels of IL-1 or. TNF in vivo in humans to normal or sub-normal levels by inhibiting IL-1 release in vivo in all cells, including, but not limited to, monocytes or macrophages;

b) down-regulation at translational or transcriptional levels of excessive levels of IL-1 or. TNF in vivo in humans to normal or below normal levels; or

c) down-regulation by inhibiting the direct synthesis of IL-1 or TNF levels as a posttranslational event.

TNF-mediated disease or disease states means any and all disease states in which TNF plays a role, either by the production of TNF itself or by the TNF causing the release of another cytokine such as, but not limited to, IL-1 or IL -6. A disease state in which IL-1 is e.g. a major component that is secreted in response to TNF or whose formation or function in response to TNF exacerbates this disease state will therefore be considered a TNF-mediated disease state. Because TNF- / 3 (also known as lymphotoxin) has a structurally close homology to TNF-α (also known as cachectin), and because each induces similar biological responses and binds to the same cellular receptor, they inhibit the compounds of the invention by TNF-α. -α as TNF-β, and we therefore refer to them collectively as TNF, unless specifically indicated otherwise. Preferably, they inhibit TNF-α.

A cytokine means any secreted polypeptide that affects cell function, and is a molecule that modulates cell-cell interactions in immune, inflammatory, or hematopoietic responses. Cytokines include, but are not limited to, monokines and lymphokines no matter what cells produce them.

The cytokine inhibited by the present invention for use in treating a human being infected with HIV must be a cytokine involved in (a) initiating and / or maintaining activation of T cells and / or expression and / or replication of the HIV gene by is mediated by an activated T cell, and / or (b) in any problem associated with a cytokine-mediated disease, such as cachexia or muscle degeneration. Preferably, this cytokine is TNF-α.

All of the compounds of formulas (I) and (II) are useful in a method of inhibiting TNF formation, preferably in macrophages, monocytes or macrophages and monocytes, in mammals, including humans, in need thereof. All of the compounds of formulas (I) and (II) are useful in a method of inhibiting or mediating the enzymatic or catalytic activity of PDE IV and in treating the conditions mediated therein.

Preparation procedures

The preparation of the compounds of formula (I) may be performed by one skilled in the art in accordance with the procedures described in the examples below. The preparation of any of the remaining compounds of formula (I) not described therein may be carried out by analogous methods described herein and comprising:

a) for compounds where X and Xj are other than Br, J, NO ₂ , amine, formylamine or S (O) m ', when m' is 1 or 2, the metabolism of the compound of formula (2)

where Rj is Rj as defined with respect to formula (I) or a group which can be converted to Rj and X is X as defined with respect to formula (I) ah a group that can be converted in X, and X ₃ means X _y as defined with respect to formula (I), or a group which can be converted to Xy and Xj is H, with lithium halide and silyl halide in a suitable solvent followed by reduction of s suitable reducing agents such as siloxane to give a compound of formula (3) wherein X _{4 is} halide. Alternatively, the reduction of a compound of formula (2) wherein X 1 is H, with a suitable reducing agent such as sodium borohydride, is a compound of formula (3) wherein X _{4 is} OH. The metabolism of such a compound of formula (3) with e.g. phosphorus trichloride, thionyl chloride, phosphorus tribromide, copper (n) bromide or carbon tetrabromide and triphenylphosphine also give a compound of formula (3) wherein X _{4 is a} halide;

the halidation of the cyanide yields a compound of formula (3) wherein X is ₄ CN. The metabolism of a compound of formula (3) wherein X _{4 is} CN with an excess of acrylate, such as methyl, ethyl, phenyl, benzyl or t-butyl acrylate, in the presence of a base, such as excess metal hydride, or catalysis or an excess of a quaternary amine base, such as benzyltrimethylammonium hydroxide, in a suitable non-reactive solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, using a metal hydride base, or in these solvents or acetonitrile, using a quaternary amine base, then a compound of formula (4) in which X _{4 is} CN and R _{16 is an} alkyl, phenyl or benzyl group.

Metabolism of a compound of formula (4) with a base such as excess metal hydride in a suitable non-reactive solvent such as tetrahydrofuran or 1,2-dimethoxyethane at an elevated temperature to then give a compound of formula (5) wherein X _{4 is} CN and R _{16 is an} alkyl, phenyl or benzyl group;

Alternatively, a compound of formula (5) [a subset of compounds of formula (II)] can be obtained directly from a compound of formula (3), wherein X ₄ and R ₁₆ are as described above with an excess of acrylate such as methyl. ethyl, phenyl, benzyl or t-butyl acrylate, with an excess of base, such as a metal hydride, in a suitable non-reactive solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, at elevated temperature.

Treatment of a compound of formula (5), e.g. with sodium chloride in aqueous dimethylsulfoxide at elevated temperature results in the saponification and decarboxylation of the ester moiety to give a compound of formula (I) wherein R _{3 is} CN and Z is O. Alternatively, a compound of formula (2) wherein Χ _χ H, converted to a homologous compound of formula (3), where X _{4 is} COOR _1? , by a number of methods known in the art, such as reaction with methyl methylsulfinylmethyl sulfide and a base, such as sodium hydroxide, followed by treatment with e.g. alcoholic (R _1? OH) acid. The metabolism of such a compound of formula (3) wherein X _{4 is} COOR ₁₇ , with an excess of acrylate, such as methyl, ethyl, phenyl, benzyl or t-butyl acrylate, and with an excess of base, such as a metal hydride, in a suitable non-reactive solvent , such as tetrahydrofuran or 1,2-dimethoxyethane, to give a compound of formula (4) wherein X _{4 is} COOR ₁₇ and R ₁₆ and R _{1 are?} independently an alkyl, phenyl or benzyl group. The metabolism of a compound of formula (4) wherein X _{4 is} COOR _1? and are R ₁₆ and R _J? independently an alkyl, phenyl or benzyl group, with a base, such as excess metal hydride, in a suitable non-reactive solvent such as tetrahydrofuran or 1,2-dimethoxyethane at elevated temperature to then give a compound of formula (5) wherein Χ _χ COOR ₁₇ and are R ₁₆ and R _1? independently an alkyl, phenyl or benzyl group. Treatment of such a compound of formula (5) with e.g. sodium chloride in aqueous dimethylsulfoxide at elevated temperature results in saponification and decarboxylation of the 3-ketoester to give the compound of formula (I) wherein R _{3 is} COOR _1? and is ZO, although under certain reaction conditions we will also obtain some compounds of formula (I) wherein R _{3 is} COOH and Z is O. The carboxyl group of such compound of formula (I) can then be converted into several esters in which R ₃ COOR _g , or amides in which R _{3 is} CONR _g R _g , using any of the very different variants of standard conversions known in the art. In some cases, keto carbonyl of such a compound of formula (I) may require protection, such as e.g. ketal, before the formation of an ester or amide, with the release of the protected ketone under suitable mild acidic conditions as a final step. A simple amide derivative, one in which R _{3 is} CONH ₂ and is ZO, can be treated with a dehydrating agent after appropriate protection of the ketone to give, after removal of the ketone protection, a compound of formula (I) in which R _{g is} CN and Z is O.

Compounds of formula (I) wherein R _{3 is} CHO and ZO can be prepared from a compound of formula (I) in which R _{3 is} CN and ZO, by suitable protecting the ketone such as e.g. ketal followed by reduction of CN part by e.g. diisobutylaluminium hydride, followed by appropriate recovery and deprotection of the ketone.

Compounds of formula (I) wherein R _{3 is} CH ₂ OH and ZO can be prepared by reduction of a compound of formula (I) wherein R _{3 is} CHO and = Z is a ketal protecting group, e.g. with sodium borohydride, followed by appropriate recovery and deprotection of the ketone.

Compounds of formula (I) wherein R _{3 is} CH ₂ NR _g R _g and ZO can be prepared by reduction of a compound of formula (I) in which R _{3 is} CN and = Z is a ketal protecting group, e.g. lithium aluminum hydride or hydrogen in the presence of a catalyst, followed by suitable processing, standard alkylation with R _g and then deprotection of the ketone.

Compounds of formula (I) wherein R _{3 is} OH and ZO can be prepared from a compound of formula (I) wherein R _{3 is} CHO and = Z is a ketal protecting group, e.g. Bayer-Villiger oxidation of the aldehyde and saponification of the ester to give a compound of formula (I) wherein R _{3 is} OH and = Z is a ketal protecting group followed by deprotection of the ketone.

Compounds of formula (I) wherein R _{3 is} halogen and ZO can be prepared from a compound of formula (I) wherein R _{3 is} OH and = Z is a ketal protecting group, e.g. by dehydration to olefin and the addition of hydrochloric acid to give a compound of formula (I) wherein R _{3 is} halogen and = Z is a ketal protecting group followed by deprotection of the ketone.

Compounds of formula (I) wherein R _{3 is} C = CR _g and ZO can be prepared from a compound of formula (I) wherein R _{3 is} CHO and = Z is a ketal protecting group, by reaction with a mixture of dimethyl ( diazomethyl) phosphonate and potassium t-butoxide or other suitable base, in an inert solvent such as tetrahydrofuran, at reduced temperature, followed by appropriate processing and deprotection of the ketone to give compounds of formula (I), where R ₃ C = CH; alternatively, it is obtained before deprotection of the ketone, by alkylation of acetylene under suitable conditions with a strong base and then an alkylating agent R _g L, where L is a leaving group and R _g is not H, followed by deprotection of the ketone, a compound of formula (I ), where R ₃ C = CR _g '

Compounds of formula (I) wherein R _{g is} CH ₂ F and ZO can be prepared from a compound of formula (I) wherein R _{3 is} CH ₂ OH and = Z is a ketal protecting group by treatment with diethylamine sulfur trifluoride (DAST ) followed by deprotection of the ketone.

Compounds of formula (I) wherein R _{3 is} CHO and ZO can be prepared from a compound of formula (I) wherein R _{3 is} CHF ₂ and = Z is a ketal protecting group by treatment with diethylamine sulfur trifluoride (DAST), which followed by deprotection from the ketone.

Compounds of formula (I) wherein R _{3 is} CF ₃ and ZO can be prepared from a compound of formula (3) wherein CF ₃ using the procedures described above for the preparation of compounds of formula (I) wherein R ₃ CN or COOR ₁₆ and ZO; a compound of formula (3) wherein CF is ₃ can be prepared according to its invention from a compound of formula (2) wherein Χ _{χ is} H or electrochemically by the method of Shono et al., J. Org. Chem., 56: 2-4, 1991, or by treating a compound of formula (6)

where X _{5 is} e.g. bromine, with a metallizing agent such as alkyllithium, in an inert solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, at -78 ° C, and then with trifluoroacetic acid or difluoroacetic acid according to the method of Nada et al., known, 71,1959: Chem. Abstr., 53, no. 14977 and 53, no. 17933, 1959, to give a compound of formula (2), wherein X 1 is CF ₃ , which is then thioketalized with e.g. 1,3-propanedithiol and then desulfurized with e.g. Raney nickel.

Compounds of formula (I) wherein R _{3 is} C _x alkyl and ZO can be prepared from a compound of formula (I) wherein R _{3 is} CH ₂ OH and = Z is a protected ketone by reductively removing alcohol with lithium in ammonia , with aluminum hydride, or by converting the alcohol to the corresponding thiocarbamate followed by reduction by e.g. tributyltin hydride or trialkylsilyl hydride and deprotection of the ketone; alternatively, compounds of formula (I) wherein R _{3 is} C _x alkyl and ZO can be prepared from a compound of formula (I) wherein R _{3 is} CHO and = Z is a protected ketone, by formation of a thioketal, desulfurization and deprotection by ketala.

Compounds of formula (I) wherein R _{3 is} C _2-4 alkyl or halogen substituted C _2-4 alkyl and is ZO can be prepared by analogous deoxygenation processes from the corresponding alcohol resulting from the metabolism of the compound of formula (I). wherein R _{3 is} CHO and = Z is a protected ketone, with a metalalkyl or halogen substituted C ₂₄ -methylalkyl reagent and the subsequent deprotection to release = Z ketone.

Compounds of formula (I) wherein R _{3 is} vinyl and ZO can be prepared e.g. by a Wittig or other olefinization reaction of a compound of formula (I) wherein R _{3 is} CHO and = Z is a protected ketone, followed by deprotection to release = Z a ketone.

Compounds of formula (I) wherein R _{3 is} cyclopropyl and ZO can be prepared from a compound of formula (I) wherein R _{3 is} vinyl and = Z is a protected ketone, by reaction with e.g. methylene iodide and a pair of zinc-copper, and this subsequent deprotection to release = Z ketone.

Alternatively, certain compounds of formula (I) wherein ZO and R _{3 are} COOR ₈ (or COOR ₁₆ ) can be prepared by reducing the double bond of cyclohexenone synthetic intermediates obtained by the method of Parkinson and Pinhey, J. Chem. Soc. Perkin Trans. I, 1053-7, 1991, which is incorporated herein by reference in its entirety. A similar reduction of the double bond of the corresponding synthetic intermediates, wherein R ₃ CN, performed by analogous procedures using 4-cyano-3-cyclohexen-1-one and / or 4-cyano-2-cyclohexen1-one, may give certain compounds of formula (I), where ZO and R _{3 are} CN.

Most of the compounds of formula (I) wherein Z is not O are prepared from the corresponding compounds of formula (I) wherein ZO is by conversion with the corresponding amine, alcohol or thiol, in the presence of a catalyst, or by removal of water if necessary, as described in the procedures described in the examples below. However, if R _{3 is} CHO, this R ₃ group may require protection during metabolism, e.g. like ketal, then removing the protection.

b) Compounds of formula (I) wherein X or X _{3 is} formyl amine and ZO can be prepared by formulating - as a last step - compounds where = Z is a protected ketone and X NH ₂ obtained by removing the protecting group from the amine functions; such protecting groups are well known to one skilled in the art, see Greene, T. and Wuts, PGM, Protecting Groups and Organic Synthesis, 2nd Ed., John Wiley and Sons, New York (1991).

c) Compounds of formula (I) wherein X or X is ₃ Br or J and ZO can be prepared from an amine from which the protection has been similarly removed by diazotizing the amine and replacing the diazonium via Sandmeyer reaction.

d) Compounds of formula (I) wherein X or X is NO ₂ and ZO can be prepared from an amine from which the protection has been similarly removed by oxidation of the amino group to the nitro group.

e) Compounds of formula (I) wherein YS (O) is m 'when m' is 1 or 2 and ZO can be prepared from compounds of formula (I) wherein YS is by oxidation of part SR ₂ at conditions well known to the person skilled in the art.

Compounds of formula (II) wherein R ₁₄ in C (O) OR _{14 of} group Z is other than an alkyl, phenyl or benzyl group are obtained from compounds of formula (5) or from other compounds of formula (II) by standard diversion procedures . Similarly, other compounds of formula (II) can be prepared, e.g. With amides, aldehydes, ketones, hydrazides, etc., from other compounds of formula (II), e.g. by standard manipulation of a functional group on group Z, either before or after manipulation of a functional group of group R ₃ . In some cases, during the manipulation of the functional groups of group Z, adequate protection of certain chemically sensitive groups R ₃ and / or keto (= O) may be performed with the formula (II) followed by deprotection to give the desired compound of the formula (II). Some such manipulations of Group Z can be performed according to the procedures described in US application no. 862 030, filed April 2, 1992, which is currently undergoing testing, and in its respective partial continuation application USSN 968,762, filed October 30, 1992. In other cases, some compounds of formula (II) may be converted to other compounds of formula ( II) by manipulation of the R ₃ group using the general techniques described above and, if necessary, using appropriate protection and deprotection of chemically sensitive functionalities, such as keto (= 0) moieties or chemically sensitive moieties of group Z. Some compounds of formula ( II) can also be prepared by metabolizing a suitable compound of formula (I) with a suitable base in suitable proportions under suitable conditions followed by metabolism with a haloformate, such as methyl or ethyl chloroformate, or by treating a suitable compound of formula (I) with methyl methoxymagnesium carbonate; such compounds of formula (II) can then be converted by more and the techniques described below into other compounds of formula (II).

In addition, some compounds of formula (II) can be prepared by metabolizing a compound of formula (3), wherein R _x is R _p as defined with respect to formula (I), or a group which can be converted to R _p and X , and X ₃ is X, X ₂ and as defined in connection with formula (I), or a group which can be converted or X _y and R ₃ is R ₃ as defined in connection with formula (I), or a group which can be converted to R ₃ and X _{4 is} CN, with an excess of acrylonitrile in the presence of a base, such as excess metal hydride, or a catalytic or excess quaternary amine base, such as benzyltrimethylammonium hydroxide, in a suitable non-reactive solvent, as tetrahydrofuran or 1,2dimethoxyethane using a metal hydride base or in these solvents or acetonitrile using a quaternary amine base to give a compound of formula ((

where X _{4 is} CN. Metabolism of a compound of formula (7) with a base such as excess metal hydride in a suitable non-reactive solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, at elevated temperature to then give a compound of formula (8)

where X _{4 is} CN and X ₅ and X ₆ are both H. Alternatively, a compound of formula (8) can be obtained directly from a compound of formula (7), wherein X ₄ is as described above with a excess excess given the case of R ₂ substituted acrylonitrile, with an excess of base, such as a metal hydride, in a suitable non-reactive solvent such as tetrahydrofuran or 1,2-dimethoxyethane at elevated temperature.

Treatment of a compound of formula (8) with an acid, e.g. 6N hydrochloric acid, at room or elevated temperature, in a solvent such as ethanol, with or without a co-solvent, as with chloro-

where X is ₅ H, is prepared by heating the compounds of formula (9) in a hydrazoic acid solution, prepared in situ, e.g. by mixing alkali metal azide, such as sodium azide, and ammonium halide, such as triethylamine hydrochloride, in a polar non-protic solvent such as N-methylpyrrolidinone.

Using the sequence of reactions described above, starting with the reaction of the corresponding compound of formula (3) but with 2- (R ₂ ) - or 3- (R ₂ ) -acrylate, the corresponding and sequentially 2,6- (R ₂ ) ₂ are obtained - but

3,5- (R2) _2- pimellates of formula (4), 2,6- (R ₂ ) ₂ - or 3,5- (R ₂ ) ₂ -2- (COOR ₁₆ ) -cyclohexanones of formula (5) and then 2,6- (R ₂ ) ₂ - or 3,5- (R ₂ ) ₂ -cyclohexanones of formula (I). Similarly, starting with the metabolism of a suitable compound of formula (3) but with 2,3- (R2) ₂ - or

3,3- (R ₂ ) _2- acrylate, respectively and sequentially, 2,3,5,6- (R ₂ ) ₄ - or 3,3,5,5- (R ₂ ) _4- pimellates of formula (4 ), 2,3,5,6- (R ₂ ) ₄ - or 3,3,5,5- (R ₂ ) ₄ -2- (COOR ₁₆ ) -cyclohexanones of formula (5) and then 2,3, 5,6- (R ₂ ) ₄ - or 3,3,5,5- (R ₂ ) _4- cyclohexanones of formula (I). Similarly, starting with the metabolism of a suitable compound of formula (3) but with a mixture of suitable acrylates, e.g. methyl acrylate and methyl 3- (R ₂ ) - ah 2,3- (R ₂ ) _2- acrylate, respectively and sequentially e.g. 3- (R ₂ ) - or 2,3- (R ₂ ) _2- pimellates of formula (4), 3- (R ₂ ) -, 5- (R ₂ ) -, 5,6- (R ₂ ) ₂ - or 2,3 (R ₂ ) ₂ -2- (COOR ₁₆ ) -cyclohexanones of formula (5) and then 3- (R ₂ ) - or 2,3- (R ₂ ) ₂ - (R ₂ ) ₄ 27 cyclohexanones of formula (I). Alternatively, metabolizing a suitable compound of formula (I) with a base in suitable proportions under suitable conditions, followed by a reaction with an alkyl agent R _? L, where L is a leaving group, 2- (R ₂ ) -, 2,2- (R ^ ₂ -, 2,6- (R ₂ ) ₂ and 2,2,6,6- (R ₂ ) ₄ - cyclohexanones of formula (I) A similar metabolism of a suitably alkylated compound of formula (I), e.g., 3,5- (R ₂ ) ₂ - or 2,6- (R 2) ₂ -cyclohexanone, e.g.

2,3,5- (R ₂ ) ₃ - or 2,2,6- (R ₂ ) _3- cyclohexanone of formula (I). Similarly, a similar metabolism of a compound of formula (5), e.g. 2- (R ₂ ) -, 2,6- (R ₂ ) ₂ - or 2,6,6- (R 2) ₃ -2- (COOR ₁₆ ) cyclohexanones of formula (5). Such compounds of formula (5) can then be converted to the corresponding compounds of formula (I) by ester saponification and decarboxylation as described above. Such compounds of formula (I) can then be converted to other compounds of formula (I) using the general techniques and, if necessary, appropriate protection and deprotection of the chemically sensitive functionalities described above. Similarly, such compounds of formula (II) can be converted to other compounds of formula (II) using the general techniques and, if necessary, appropriate protection and deprotection of the chemically sensitive functionalities described above.

The following examples are given to illustrate how to prepare the compounds of the invention and methods for determining the therapeutic activity associated with them. These examples are not intended to limit the invention in any way, their purpose is more illustrative than restrictive.

EXAMPLES

2-Carbomethoxy-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -cyclohexan-1-one. (3-Cyclopentyloxy-4-methoxyphenyl) acetonitrile. To a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (20 g, 90.8 mmol) in acetonitrile (100 ml) was added lithium bromide (15 g, 173 mmol) and then trimethylsilyl chloride (17.4 ml, 137 mmol) was added dropwise. After 15 min, the reaction mixture was cooled to 0 ° C, 1,1,3,3tetramethyldisiloxane (26.7 ml, 151 mmol) was added dropwise and the resulting mixture was allowed to warm to room temperature. After stirring for 3 h, the mixture was separated into two layers. The bottom layer was removed, diluted with methylene chloride and filtered through Celite. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and filtered again. The solvent was removed in vacuo to give a pale yellow oil. To a solution of this crude α-bromo-3-cyclopentyloxy-4-methoxytoluene in dimethylformamide (160 ml) was added sodium cyanide (10.1 g, 206 mmol) under argon atmosphere, the resulting mixture was stirred at room temperature for 18 h, then poured in cold water (600 ml) and extracted three times with ether. The organic extract was washed three times with water, once with brine and dried (potassium carbonate). The solvent was removed in vacuo and the residue purified by flash chromatography eluting with 10% ethyl acetate / hexanes to give a gray-white solid (17.7 g, 84%): mp. 32-34 ° C. An additional amount (1.3 g) of lightly contaminated material was also isolated.

lb. Dimethyl 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) pimelate. To a solution of (3cyclopentyloxy-4-methoxyphenyl) acetonitrile (7 g, 30.3 mmol) in acetonitrile (200 ml) was added a 40% solution of Triton-B in methanol (1.4 ml, 3.03 mmol) under an argon atmosphere. ) and the mixture heated to reflux. Methyl acrylate (27 ml, 303 mmol) was carefully added, the reaction mixture was maintained at reflux for 5 h and then cooled. The mixture was diluted with ether, washed once with 1 N hydrochloric acid and once with brine, dried (magnesium sulfate) and the solvent removed in vacuo. The solid residue was triturated with 5% ethanol / hexane to give a white solid (9 g, 74%): m.p. 81-82 ° C; an additional 1.1 g (9%) was also obtained from the filtrate.

Analysis: Calc. for C25 H28 NO4 C 65.49, H 7.25, N 3.47; found: C 65.47, H 7.11,

N, 3.49.

lc. 2-Carbomethoxy-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one.

To a solution of dimethyl 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) pimelate (5.9 g, 14.6 mmol) in dry 1,2-dimethoxyethane (120 ml) was added sodium hydride (80). % suspension in mineral oil, 1.05 g, 43.8 mmol). The mixture was heated to reflux for 4.5 h, then cooled to room temperature and stirred for 16 h. Water was added and the reaction mixture was partitioned between ether and acidified water. The organic extract was dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by flash chromatography eluting with 3: 1 hexanes / ethyl acetate to give a white foam (4.9 g, 93%).

Analysis: Calc. for C ₁₉ H ₂₃ NO ₃ .1 / 4H ₂ O: C 67.09, H 6.84, N 3.72; Found: C 66.92, H 6.61, N 3.74.

EXAMPLE 2

4- (3,4-bisdifluoromethoxyphenyl) -2-carbomethoxy-4-cyanocyclohexane-1-one

2a. 3,4-bisdifluoromethoxybenzaldehyde. During vigorous stirring, a mixture of 3,4-dihydroxybenzaldehyde (40 g, 290 mmol) and powdered potassium carbonate (120 g, 870 mmol) in dimethylformamide (500 ml) was heated under chlorodifluoromethane at 80 ° C for 7 h and then stirred at room temperature for 7 h. nights. The mixture was diluted with ether and filtered. The filtrate was concentrated under reduced pressure, the residue was partitioned between ether and aqueous potassium carbonate and extracted five times with ether. The organic extract was washed with aqueous potassium carbonate and dried (potassium carbonate). The solvent was removed in vacuo and the residue purified by flash chromatography eluting with 4: 1 hexanes / ether to give an oil (26.2 g, 38%).

2b. 3.4-bisdifluoromethoxybenzyl alcohol. 3,4-bisdifluoromethoxybenzaldehyde (26.2 g, 110 mmol) in absolute ethanol (150 ml) was treated under argon atmosphere for 0.5 h with sodium borohydride (8.32 g, 220 mmol). 10% sodium hydroxide (130 ml) was added, the ethanol removed in vacuo, the mixture partitioned between ether and water and extracted twice with ether. The organic extract was dried (magnesium sulfate) and evaporated to a pale yellow oil (26.4 g, 100%).

2c. 2- (3,4-bisdifluoromethoxyphenyl) acetonitrile. A solution of 3,4-bisdifluoromethoxybenzyl alcohol (26.4 g, 110 mmol) and pyridine (9.79 ml, 120 mmol) in chloroform (200 ml) was treated with thionyl chloride (9.62 ml, 130 mmol) under an argon atmosphere. and the mixture was heated at reflux for 1 h. The solvent was removed, ether was added and the precipitate was removed by filtration. The filtrate was concentrated to a scarlet oil. To a solution of this

3,4-bisdifluoromethoxybenzyl chloride in dimethylformamide (200 ml) was added sodium cyanide (11.86 g, 240 mmol) under an argon atmosphere. The resulting mixture was stirred and gently heated at 45 ° C for 3 h, cooled and concentrated. The mixture was partitioned between ether and 5% aqueous sodium carbonate and extracted five times with ether. The organic extract was washed once with brine, dried (sodium carbonate) and the solvent removed in vacuo to give an oil (27 g).

2d. Dimethyl 4-cyano-4- (3,4-bisdifluoromethoxyphenyl) -4-cyanopimelate. To the solution

2- (3,4-bisdifluoromethoxyphenyl) acetonitrile (27 g, 108 mmol) and 40% solution of Triton-B in methanol (5 ml, 11 mmol) in acetonitrile (450 ml) were added at room temperature under an argon atmosphere. acrylate (48.6 ml, 540 mmol). After 20 min, hydrochloric acid (3 N, 20 ml) was added and the mixture concentrated. The residue was partitioned between water and ether, extracted twice with ether, this layer dried (magnesium sulfate) and evaporated in vacuo to give a yellow oil (45.32 g, 99%).

2e. 4- (3,4-bisdifluoromethoxyphenyl) -2-carbomethoxy-4-cyanocyclohexan-1-one.

To a solution of dimethyl 4- (3,4-bisdifluoromethoxyphenyl) -4-cyanopimelate (45.32 g, 107 mmol) in dry 1,2-dimethoxyethane (450 ml) was added sodium hydride (80% dispersion in an argon atmosphere). mineral oil, 13 g, 432 mmol). The resulting mixture was refluxed for 1 h, cooled to room temperature, poured into water and concentrated. The mixture was partitioned between ether and acidified brine, extracted twice with ether, the organic layer dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by flash chromatography eluting with 3: 1 hexanes / ethyl acetate to give a pale orange oil (19.5 g, 46.6%).

Analysis: Calc. for C _1? H ₁₅ F ₄ NO ₅ : C 52.45, H 3.88, N 3.60; found: C 52.60, H 4.07, N 3.22.

EXAMPLE 3

2 "carbomethoxy-4-cyano-4- (3-difluoromethoxy-4-methoxyphenyl) cyclohexan-1-one

3a. 3-difluoromethoxy-4-methoxybenzaldehyde. During vigorous stirring, we are a mixture

Of 3-hydroxy-4-methoxybenzyladehyde (2.5 g, 16.4 mmol) and powdered cesium carbate bonate (5.6 g, 17.2 mmol) in dimethylformamide (50 ml) were heated under chlorodifluoromethane atmosphere at 80 ° C for 4 h . The mixture was allowed to cool, poured into water and extracted three times with ethyl acetate. The organic extract was dried (sodium sulfate) and the solvent removed in vacuo. Purification by flash chromatography eluting with 5% ethyl acetate / chloroform gave an oil (2 g, 60%).

3b. (3-Difluoromethoxy-4-methoxyphenyl) acetonitrile. Lithium bromide (1.7 g, 19.6 mmol) and acetonitrile (11 ml) were added to 3-difluoromethoxy-4-methoxybenzaldehyde (2 g, 9.8 mmol). After dissolution, the reaction mixture was cooled to 0 ° C. Trimethylsilyl chloride (1.86 ml, 14.7 mmol) was slowly added and the reaction was allowed to warm to room temperature and stirred for 15 min. The reaction mixture was again cooled to 0 ° C, 1,1,3,3-tetramethyldisiloxane (2.6 ml, 14.7 mmol) was added and the resulting mixture was allowed to warm to room temperature. After stirring for 3 h, the mixture was separated into two layers. The bottom layer was removed, diluted with methylene chloride and filtered. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and filtered again. The solvent was removed in vacuo to give an oil which was dissolved in dimethylformamide (10 ml) under an argon atmosphere and treated with sodium cyanide (1.08 g, 22 mmol). The resulting mixture was stirred at room temperature overnight, then poured into cold water (250 ml) and extracted three times with ethyl acetate. The organic extract was washed three times with water, once with brine and dried (potassium carbonate). The solvent was removed in vacuo to give a yellow oil (1.54 g, 74%), which was used without purification.

3c. Dimethyl 4-cyano-4 (3-difluoromethoxy-4-methoxyphenyl) pimelate. To a solution of (3difluoromethoxy-4-methoxyphenyl) acetonitrile (1.54 g, 7.2 mmol) in acetonitrile (78 ml) was added a 40% solution of Triton-B in methanol (0.33 ml, 0, under an argon atmosphere). 72 mmol). The resulting mixture was heated to reflux and methyl acrylate (13 ml, 144 mmol) was carefully added. After 3 h, the reaction mixture was cooled to room temperature, water was added and the mixture was concentrated. The residue was partitioned between aqueous hydrochloric acid and ethyl acetate, extracted twice with ethyl acetate, the organic layer was dried (magnesium sulfate) and evaporated. Purification by flash chromatography eluting with 2: 1 hexanes / ethyl acetate afforded foam (1.7 g, 61%).

3d. 2-Carbomethoxy-4-cyano-4- (3-difluoromethoxy-4-methoxyphenyl) cyclohexanone. To a suspension of sodium hydride (95%, 0.33 g, 13.2 mmol) in dry 1,2dimethoxyethane (70 ml) was added a solution of dimethyl 4-cyano4- (3-difluoromethoxy-4-methoxyphenyl) pimelate under an argon atmosphere. (1.7 g, 4.4 mmol) in dry 1,232 dimethoxyethane (70 ml). The resulting mixture was refluxed for 5 h, cooled to room temperature, stirred overnight and poured with water. The mixture was partitioned between ethyl acetate and acidified water, extracted three times with ethyl acetate, the organic layer was dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography eluting with 3: 1 hexanes / ethyl acetate gave an oil (0.51 g, 33%, 51% yield on the basis of the recovered starting material).

EXAMPLE 4

2-Carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-one.

4a. 3-cyclopropylmethoxy-4-methoxybenzaldehyde. During vigorous stirring, a mixture of 3-hydroxy-4-methoxybenzaldehyde (20 g, 131 mmol), chloromethylcyclopropane (18.2 ml, 197 mmol) and powdered potassium carbonate (27.3 g, 197 mmol) in dimethylformamide (400 ml) was heated. under an argon atmosphere at 80 ° C for 9 h. The mixture was allowed to cool and filtered through Celite. The filtrate was concentrated under reduced pressure, the residue was extracted twice with ethyl acetate, the organic extract was washed five times with saturated aqueous sodium carbonate and dried (sodium sulfate). The solvent was removed in vacuo to give a gray-white solid (21.2 g, 78%): m.p. 67-69 ° C.

4b. 3-cyclopropylmethoxy-4-methoxyphenyl) acetonitrile. To 3-cyclopropylmethoxy-4methoxybenzaldehyde (21.2 g, 103 mmol) was added lithium bromide (17.8 g, 206 mmol) and acetonitrile (110 ml). After dissolution, the reaction mixture was cooled to 0 ° C. Trimethylsilyl chloride (19.6 ml, 154 mmol) was slowly added, the reaction was allowed to warm to room temperature and stirred for 15 min. The reaction mixture was again cooled to 0 ° C, 1,1,3,3-tetramethyldisiloxane (27.2 ml, 154 mmol) was added and the resulting mixture was allowed to warm to room temperature. After stirring for 2 h, the mixture was separated into two layers. The bottom layer was removed, diluted with methylene chloride, filtered and the filtrate concentrated under reduced pressure. This procedure was repeated a total of three times. The resulting light yellow brown oil was dissolved in dimethylformamide (90 ml) under an argon atmosphere and treated with sodium cyanide (11.3 g, 232 mmol). The resulting mixture was stirred at room temperature for 2 h, then poured into cold water and extracted twice with ethyl acetate. The combined organic extract was washed three times with water and once with brine and dried (sodium sulfate). The solvent was removed in vacuo to give an oil (21.4 g, 96%), which was used without purification.

4c. Dimethyl-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) pimelate. To a solution of (3-cyclopropylmethoxy-4-methoxyphenyl) acetonitrile (21.4 g, 98.6 mmol) in acetonitrile (400 ml) was added a 40% solution of Triton-B in methanol (4.5 ml, under argon atmosphere). 9.9 mmol). The resulting mixture was heated to reflux and methyl acrylate (178 mL, 197 mmol) was carefully added. After 3 h, the reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between 10% aqueous hydrochloric acid and ethyl acetate, extracted three times with ethyl acetate, the organic layer was dried (potassium carbonate) and evaporated. Purification by flash chromatography eluting with 2: 1 hexanes / ethyl acetate gave an oil (27 g, 71%).

4d. 2-Carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexane-one. To a solution of dimethyl 4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) pimelate (10.4 g, 26.7 mmol) in dry 1,2-dimethoxyethane (500 ml) was added sodium hydride (80). % dispersion in mineral oil, 2.5 g, 31.2 mmol). The resulting mixture was refluxed for 4 h, cooled to room temperature and poured with water. The mixture was partitioned between ethyl acetate and acidified water, extracted three times, the organic layer dried (magnesium sulfate) and the solvent removed in vacuo. The product was purified by flash chromatography eluting with 2: 1 hexanes / ethyl acetate to give an oil (9 g, 95%).

Analysis: Calc. for C 22 H 26 NO 3 1 / S P 2 O: C 66.79, H 6.52, N 3.89; found: C 66.62,

H, 6.43; N, 3.92.

EXAMPLE 5

2- carbomethoxy-4-cyano-4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) cyclohexane-one

5a. 4-difluoromethoxy-3-hydroxybenzaldehyde. During vigorous stirring, we are a mixture

3,4-Dihydroxybenzaldehyde (50 g, 362 mmol) and powdered potassium carbonate (50 g, 362 mmol) in dimethylformamide (250 ml) were heated under an atmosphere of ldorodifluoromethane for 5.5 h at 100 ° C using a condenser at -78 ° C. An additional amount of potassium carbonate (10 g) was added and the reaction was continued for another 0.5 h. The mixture was allowed to cool, acidified with concentrated hydrochloric acid at pH 5-6, and concentrated under reduced pressure. The residue was partitioned between ether and 3 N aqueous hydrochloric acid and extracted five times with ether. The organic extract was dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by flash chromatography eluting with 2: 1 hexanes / ethyl acetate to give a yellow solid, which was triturated with ethyl acetate / hexanes to give a white solid in three yields (12.1 g, 18 %): m.p. 84-86 ° C.

5b. 3-Cyclopentyloxy-4-difluoromethoxybenzaldehyde. Bromocyclopentane (2.5 ml, 23 mmol) was added to a mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde (2.9 g, 15 mmol) and powdered potassium carbonate (3.2 g, 23 mmol) in dimethylformamide (15 ml). and the mixture was stirred and heated at 50 ° C for 1 h and at 80-85 ° C for 1.5 h. The mixture was allowed to cool and partitioned between ethyl acetate and water. The organic extract was washed three times with water, dried (sodium sulfate) and the solvent removed in vacuo. Purification by flash chromatography eluting with 20-30% ether / hexanes gave a yellow solid (3.5 g, 89%).

5c. (3-Cyclopentyloxy-4-difluoromethoxyphenyl) acetonitrile. To a solution of (3cyclopentyloxy-4-difluoromethoxyphenyl) benzaldehyde (3.4 g, 13.4 mmol) in absolute ethanol (33 ml) was added sodium borohydride (1.06 g, 28 mmol) under an argon atmosphere at room temperature. After 20 min, 10% aqueous sodium hydroxide (15 ml) was added, the ethanol removed in vacuo and the aqueous residue extracted three times with ether. The organic extract was washed twice with brine, dried (magnesium sulfate) and evaporated to a pale yellow oil (3.44 g). A solution of this alcohol (1.52 g, 5.89 mmol) and pyridine (0.48 ml, 6 mmol) in alumina-dried chloroform (15 ml) was treated with thionyl chloride (0.52 ml, 7) under an argon atmosphere. , 08 mmol) and the mixture was refluxed for 1 h. The solvent was removed, ether was added and the precipitate was removed by filtration. The filtrate was concentrated to a pale yellow oil, which was dissolved in dimethylformamide (10 ml) under an argon atmosphere and treated with sodium cyanide (0.58 g, 11.8 mmol). After stirring at room temperature for 72 h, the mixture was partitioned between 5% aqueous sodium carbonate and ether. The organic extract was washed four times with water, dried (potassium carbonate) and evaporated. Purification by flash chromatography eluting with 15-20% ethyl acetate / hexanes gave a light yellow solid (3.2 g, 90%): m.p. 39-41 ° C.

5d. Dimethyl 4-cyano-4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) pimelate. To a solution of (3-cyclopentyloxy-4-difluoromethoxyphenyl) acetonitrile (1.8 g, 6.7 mmol) in acetonitrile (35 ml) was added a 40% solution of Triton-B in methanol (0.31 ml, under argon). 0.67 mmol). The resulting mixture was heated to reflux and methyl acrylate (6.1 mL, 67.2 mmol) was carefully added. After a further 20 min, the reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between aqueous hydrochloric acid and ether, the organic layer was dried (magnesium sulfate) and evaporated to an oil (3.1 g, 100%).

5e. 2-Carbomethoxy-4-cyano-4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) cyclohexan-1-one. To a solution of dimethyl 4-cyano-4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) pimelate (3.1 g, 6.7 mmol) in dry 1,2-dimethoxyethane (50 ml) was added sodium hydride (80). % mineral oil dispersion, 0.81 g, 27 mmol). The resulting mixture was refluxed for 20 minutes, an additional 1,2 dimethoxyethane (50 ml) was added and the mixture was refluxed for another 70 min. The mixture was cooled to 0 ° C, acidified with dilute hydrochloric acid and concentrated. The mixture was partitioned between ether and dilute hydrochloric acid, the organic layer was dried (magnesium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography eluting with 85/15 hexanes / ethyl acetate to give a white solid (0.76 g, 37%); m.p. 109-110.5 ° C.

Analysis: Calc. for C 61.91, H 5.69, N 3.44; found: C 61.83, H 5.66,

N, 3.39.

EXAMPLE 6

2-Carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenylcyclohexane-1-one

6a. 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde. To a mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde (19.55 g, 104 mmol) and potassium carbonate (21.56 g, 156 mmol) in dimethylformamide (150 ml) was added bromomethylcyclopropane (15.13 ml) under argon at 60 ° C. 156 mmol) and the mixture was stirred and heated at 65 ° C. After 1.5 h, the mixture was allowed to cool and filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water and extracted four times with ethyl acetate. The organic extract was washed twice with water and dried (sodium sulfate). The solvent was removed in vacuo to give an oil (26.4 g).

6b. 3-cyclopropylmethoxy-4-difluoromethoxybenzyl alcohol. The crude 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (26.4 g) in absolute ethanol (200 ml) was treated with sodium borohydride (8.23 g, 217 mmol) at room temperature under argon at 0.33 h. 10% aqueous sodium hydroxide (150 ml) was added, the ethanol was removed in vacuo and the aqueous residue was extracted three times with ether. The organic extract was washed twice with brine, dried (sodium sulfate), filtered and evaporated to a pale yellow oil (24.4 g).

6c. 3-cyclopropylmethoxy-4-difluoromethoxybenzyl chloride. A solution of crude 3-cyclopropylmethoxy-4-difluoromethoxybenzyl alcohol (24.4 g) and pyridine (9.8 ml, 120 mmol) in chloroform (150 ml) was treated with thionyl chloride (8.0 ml, 110 mmol) under an argon atmosphere. and the mixture was heated at reflux for 1 h. The solvent was removed, ether was added and the precipitate was removed by filtration. The filtrate was concentrated to a pale yellow oil (26 g).

6d. (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) acetonitrile. Sodium cyanide (9.7 g, 198 mmol) was added to 3-cyclopropylmethoxy-4-difluoromethoxybenzyl chloride (26 g) in dimethylformamide (150 ml). The resulting mixture was stirred at room temperature and heated gently for 2 h, then cooled and concentrated. The mixture was partitioned between alkaline brine and ether and extracted twice. The organic extract was washed with brine and dried (sodium sulfate). The solvent was removed in vacuo to give an orange-brown oil (24 g), which was used without purification.

6e. Dimethyl 4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) pimelate. To a solution of crude (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) acetonitrile (24 g) in acetonitrile (500 ml) was added a 40% solution of Triton-B in methanol (4.3 ml, 9.5 mmol) under an argon atmosphere. The resulting mixture was heated to reflux and methyl acrylate (43 ml, 470 mmol) was carefully added. After 20 min, the reaction mixture was cooled to room temperature, water was added and dilute hydrochloric acid was added and the mixture was concentrated. The residue was partitioned between water and ether, the organic layer was dried (magnesium sulfate) and evaporated to an orange-brown oil (41 g).

6f. 2-Carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one. To a suspension of sodium hydride (80% mineral oil dispersion, 11.6 g, 388 mmol) in dry 1,2-dimethoxyethane (700 ml) was added a solution of crude dimethyl 4-cyano-4- (3- cyclopropylmethoxy-4-difluoromethoxyphenyl) pimelate (41 g) in dry 1,2-dimethoxyethane (700 ml). The resulting mixture was heated at 60 ° C for 1 h, cooled to room temperature, poured with dilute hydrochloric acid and concentrated. The residue was diluted with water, acidified to pH 3 and extracted twice with methylene chloride. The organic extract was washed with acidified water, dried (sodium sulfate) and the solvent removed in vacuo.

Purification by flash chromatography eluting with methylene chloride followed by trituration with cold ether gave a solid (17.7 g, 43% from 3-cyclopropylmethoxy4-difluoromethoxybenzaldehyde): m.p. 115-116 ° C.

Analysis: Calc. for C _2Q H ₂₁ F ₂ NO ₅ : C 61.06, H 5.38, N 3.56; found: C 61.16, H 5.40,

N, 3.52.

EXAMPLE 7

4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one

A mixture of 2-carbomethoxy-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one (0.80 g, 2.15 mmol), dimethyl sulfoxide (16 ml), water (1 ml) and of sodium chloride (0.8 g) was heated at 140-145 ° C for 5 h under an argon atmosphere. The reaction mixture was cooled and concentrated. The residue was purified by flash chromatography eluting with 3: 1 hexanes / ethyl acetate to give a yellow solid. Trituration with hexanes / ethyl acetate gave a white solid (0.52 g, 77%): m.p. 111-112 ° C.

Analysis: Calc. for C ₁₉ H ₂₃ NO ₃ : C 72.82, H 7.40, N 4.47; found: C 72.72, H 7.39,

N, 4.48.

EXAMPLE 8

4- (3,4-bisdifluoromethoxyphenyl) 4-cyanocyclohexan-1-one

A mixture of 2-carbomethoxy-4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexan-1-one (0.55 g, 1.4 mmol), dimethyl sulfoxide (8 ml), water (0.5 ml) and sodium of chloride (0.5 g) was heated at 140-145 ° C for 4 h under an argon atmosphere. The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between ether and water, the organic layer was dried (magnesium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography eluting with 1: 1 hexanes / ether. The residue was partitioned between water and ethyl acetate and the organic layer was evaporated to give a yellow solid. Trituration with a minimal amount of ethyl acetate / hexanes gave a solid (0.3 g, 63.6%): m.p. 64-66 ° C.

Analysis: Calc. for C ₁₅ H ₁₃ NO ₃ F ₄ : C 54.39, H 3.96, N 4.23; found: C 54.25, H 3.96,

N, 4.20.

EXAMPLE 9

4-cyano- (3-difluoromethoxy-4-methoxyphenyl) cyclohexan-1-one

A mixture of 2-carbomethoxy-4-cyano-4- (3-difluoromethoxy-4-methoxyphenyl) cyclohexanone (0.51 g, 1.44 mmol), dimethyl sulfoxide (11 ml), water (1 ml) and sodium chloride (0.53 g) was heated at 150 ° C for 5 h under argon. The reaction mixture was partitioned between ethyl acetate and water and extracted three times with ethyl acetate. The combined organic extract was washed twice with water and once with brine, dried (potassium carbonate) and the solvent removed in vacuo. The product was purified by flash chromatography eluting with 2: 1 hexanes / ethyl acetate to give an oil (0.36 g,

%).

Analysis: Calc. for C ₁₅ H ₁₅ NO ₃ F ₂ .1 / 8 H ₂ O: C 60.55, H 5.17, N 4.71; found: C 60.42, H 5.07, N 4.77.

EXAMPLE 10

4-cyano- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-one

A mixture of 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-one (1.7 g, 4.7 mmol), dimethyl sulfoxide (34 ml), water (3 ml) and sodium chloride (1.6 g) was heated at 150 ° C for 4 h under argon, stirred at room temperature overnight and concentrated. The residue was partitioned between ethyl acetate and water and extracted three times with ethyl acetate. The combined organic extract was washed twice with water and once with brine, dried (magnesium sulfate) and the solvent removed in vacuo. The product was purified by flash chromatography eluting with 2: 1 hexanes / ethyl acetate to give a solid (1.09 g, 77%): mp. 116-118 ° C.

Analysis: Calc. Calcd for C 16 NOj 1/8 H ₂ O: C 71.68, H 7.10, N 4.64; found: C 71.51, H 7.03, N 4.55.

EXAMPLE 11

4-cyano-4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) cyclohexan-1-one

Mixture of 2-carbomethoxy-4-cyano-4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) cyclohexan-1-one (0.98 g, 2.4 mmol), dimethyl sulfoxide (10 ml), water (0.62 ml) ) and sodium chloride (0.62 g) were heated at 145 ° C for 5 h under an argon atmosphere. The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between ether and water, the organic layer was washed with water, dried (magnesium sulfate) and the solvent removed in vacuo. The product was purified by flash chromatography eluting with 20 to 30% ethyl acetate / hexanes. The isolated residue was dissolved in ethyl acetate, the solution was washed twice with dilute sodium hydroxide, once with water and once with brine and then dried and evaporated to give a solid (0.2 g, 23.6%): m.p. 76-78.5 ° C.

Analysis: Calcd. For C ₁₉ H ₂₁ F ₂ NO ₃ .l / 6 Hfi: C 64.76, H 6.10, N 3.97; found: C 64.76, H 6.04, N 3.89.

EXAMPLE 12

4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one

A mixture of 2-carbomethoxy-4-cyano-4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) cyclohexan-1-one (0.5 g, 1.27 mmol), dimethyl sulfoxide (10 ml), water (1 ml) and of sodium chloride (0.5 g) was heated at 145-150 ° C for 4.5 h under an argon atmosphere. The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water, extracted twice with ethyl acetate, the organic layer was washed twice with water and once with brine, dried (sodium sulfate) and the solvent removed in vacuo. The product was purified by flash chromatography eluting with 20-25% ethyl acetate / hexanes and the resulting solid triturated with ether / hexane and then with cold ether to give a solid (0.22 g, 51.6%): m.p. . 85.5-86.5 ° C.

Analysis: Calc. for C _lg H ₁₉ F ₂ NO _3: C 64.47, H 5.71, N 4.18; found: C 64.28, H 5.63, N 4.20.

EXAMPLE 13

4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one oxime

To a solution of 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one (0.125 g,

0.4 mmol) in pyridine (2 ml) was added hydroxylamine hydrochloride (0.031 g, 0.44 mmol), the mixture was stirred at room temperature under an argon atmosphere for 4 h and the solvent was evaporated. The mixture was partitioned between water and ethyl acetate, extracted twice with ethyl acetate, the organic extract dried (potassium carbonate) and the solvent removed in vacuo. Purification by flash chromatography eluting with 25% ethyl acetate / hexanes followed by trituration of the product with ether / hexanes gave a white solid (0.125 g, 95%); m.p. 50-53 ° C.

Analysis: Calc. Calcd for C25H25N3O: C, 69.44; H, 7.37; N, 8.53; Found: C 69.35, H 7.47, N 8.28.

EXAMPLE 14

4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-formylcyclohexan-1-one

14a. 4-Cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one dimethyl ketal. A mixture of 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one (0.5 g, 1.6 mmol), trimethyl orthoformate (0.21 ml, 1.9 mmol) and catalytic amounts of p -toluenesulfonic acid in methanol (20 ml) was gently heated under an argon atmosphere for 2 h. The mixture was cooled, partitioned between aqueous sodium carbonate and ethyl acetate, extracted twice with ethyl acetate, the organic extract dried (potassium carbonate) and the solvent removed in vacuo to give an oil (0.57 g, 99%).

14b. 4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-formylcyclohexan-1-one dimethyl ketal. A solution of 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one dimethyl ketal (0.57 g, 1.6 mmol) in toluene (20 ml) was treated with argon at room temperature. diisobutylaluminum hydride (1.5 M in toluene, 2.7 ml, 4 mmol). After 2 h, a saturated aqueous sodium bisulfite solution was added and the mixture was extracted twice with ethyl acetate. The organic extract was washed with 5% aqueous sodium carbonate, dried (potassium carbonate) and the solvent removed in vacuo to give an oil (0.55 g, 96%).

14c. 4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-formylcyclohexan-1-one. 4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-formylcyclohexan-1-one dimethyl ketal (0.1 g, 0.28 mmol) in ethyl acetate (2 ml) was treated with 3 N hydrochloric acid (5 ml). and the mixture was stirred vigorously and heated gently for 10 min. The mixture was extracted twice with ethyl acetate, the combined organic extracts were washed with 5% aqueous sodium carbonate, dried (potassium carbonate) and the solvent removed in vacuo. This material, combined with the material obtained from the same metabolite, was purified by flash chromatography eluting with 2% ethyl acetate / chloroform to give a white solid (0.1 g, 57%): mp. 55-57 ° C.

Analysis: Calc. for C ₁₉ H ₂₄ O ₄ : C 72.13, H 7.65, found: C 72.09, H 7.57.

EXAMPLE 15

4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (hydroxymethyl) cyclohexan-1-one

15a. 4- (3-Cyclopentyloxy-4-methoxyphenyl) -4- (hydroxymethyl) cyclohexan-1-one dimethyl ketal. To a solution of 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-formylcyclohexan-1-one dimethyl ketal (0.24 g, 0.66 mmol) in 1,2-dimethoxy-ethane (5 ml) was placed under an argon atmosphere sodium borohydride (0.05 g, 1.3 mmol) was added and the mixture was stirred at room temperature for 0.75 h. Water was added, the mixture was partitioned between ether and water, extracted twice with ether, the organic extract was dried (potassium carbonate) and evaporated to an oil (0.19 g, 79%).

15b. 4- (3-Cyclopentyloxy-4-methoxyphenyl) -4- (hydroxymethyl) cyclohexan-1-one. 4- (3cyclopentyloxy-4-methoxyphenyl-4- (hydroxymethyl) cyclohexan-1-one dimethyl ketal (0.15 g, 0.41 mmol) in ether (2 ml) was treated with 1 N hydrochloric acid (2 ml) and The mixture was stirred vigorously and heated gently for 10 minutes The mixture was extracted with ether, the combined organic extracts were washed with 5% aqueous sodium carbonate, dried (potassium carbonate) and the solvent removed in vacuo. / chloroform gave wax (0.06 g, 56%).

Analysis: Calc. for C 71.67, H 8.23, found C 71.81, H 8.19.

EXAMPLE 16

4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (fluoromethyl) cyclohexan-1-one

16a. 4- (3-Cyclopentyloxy-4-methoxyphenyl) -4- (fluoromethyl) cyclohexan-1-one dimethyl ketal. A solution of 4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (hydroxymethyl) cyclohexane-1 dimethyl ketal (0.37 g, 1.02 mmol) in methylene chloride (5 ml) was added dropwise under an argon atmosphere to the solution. diethylamine sulfur trifluoride (0.14 ml,

1.02 mmol) at -78 ° C. The mixture was allowed to warm to room temperature and 5% aqueous sodium carbonate was added after 0.75 h. The mixture was extracted with chloroform, the organic extract was dried (magnesium sulfate) and the solvent removed in vacuo to give a yellow oil (0.3 g, 80%).

16b.4- (3-Cyclopentyloxy-4-methoxyphenyl) -4- (fluoromethyl) cyclohexan-1-one. 4- (3-Cyclopentyloxy-4-methoxyphenyl) -4- (fluoromethyl) cyclohexan-1-one dimethyl ketal (0.35 g, 0.95 mmol) in ethyl acetate (2 ml) was treated with 1 N hydrochloric acid ( 2 ml) and the mixture was stirred vigorously and heated gently for 10 min. The mixture was extracted with ethyl acetate, the organic extract was washed with 5% aqueous sodium carbonate, dried (magnesium sulfate) and the solvent removed in vacuo. Purification by flash chromatography eluting with 25% ethyl acetate / hexanes followed by trituration with ether / hexanes gave a white solid (0.075 g, 24%): mp. 72-74 ° C.

Analysis: Calc. for C ₁₉ H ₂₅ FO ₃ : C 71.23, H 7.87, found C 71.22, H 7.70.

EXAMPLE 17

4-Aminocarbonyl-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one

17a. 4-Aminocarbonyl-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one dimethyl ketal. A solution of 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one dimethyl ketal (0.34 g, 0.95 mmol) and powdered potassium carbonate (0.7 g, 5.1 mmol) in methanol (20 ml) and water (4 ml) were treated with hydrogen peroxide at 0 ° C (30% solution, 2.55 ml). The mixture was allowed to warm to room temperature and saline was added after 7 days and the mixture extracted with methylene chloride. The organic extract was washed twice with brine, dried (potassium carbonate) and the solvent removed in vacuo. Purification by flash chromatography afforded the amide (0.055 g, 15%) together with the recovered starting material (0.25 g).

17b. 4-Aminocarbonyl-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one. A mixture of 4-aminocarbonyl-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohex-1-one dimethyl ketal (0.055 g, 0.15 mmol) and p-toluenesulfonic acid (catalytic amount) in 20% aqueous acetone (5 ml) was stirred under an argon atmosphere at reflux for 8 h. The mixture was cooled, diluted with water and extracted with methylene chloride. The organic extract was dried (magnesium sulfate) and the solvent removed in vacuo to give a hygroscopic, amorphous material (0.035 g, 72%).

Analysis: Calc. for C ₁₉ H ₂₅ NO ₄ . 3/8 Κ, Ο: C 67.48, H 7.67, N 4.14; found: C 67.38, H

7.54, N 3.86.

EXAMPLE 18

4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-ethynylcyclohexan-1-one

18a. 4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-ethynylcyclohex-1-one dimethyl ketal.

To a solution of potassium t-butoxide (0.155 g, 1.38 mmol) in dry tetrahydrofuran (5 ml) was added a solution of dimethyl (diazomethyl) phosphonate (purity about 88%, 0.24 g, 1 under an argon atmosphere at -78 ° C). , 38 mmol). After 0.25 h, a solution of 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-formylcyclohexan-1-one dimethyl ketal (0.42 g, 1.15 mmol) in dry tetrahydrofuran (5 ml) was added dropwise. the mixture was stirred at -78 ° C under an argon atmosphere for 5 h. Aqueous acetic acid was added, the mixture was concentrated, partitioned between methylene chloride and water and extracted twice. The organic extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography eluting with 3: 1 hexanes / ethyl acetate gave an oil (0.13 g, 32%).

18b. 4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-ethynylcyclohexan-1-one. A mixture of 4- (3cyclopentyloxy-4-methoxyphenyl) -4-ethynylcyclohex-1-one dimethyl ketal (0.13 g, 0.36 mmol) and p-toluenesulfonic acid (catalytic amount) in acetone (5 ml) was stirred under atmosphere of argon at room temperature for 1.5 h. The mixture was concentrated, diluted with ethyl acetate and washed with water. The organic extract was dried (magnesium sulfate) and the solvent removed in vacuo to give an oil (0.11 g, 97%).

Analysis: Calc. for 1/2 H ₂ O: C 74.74, H 7.84; found: C 74.81, H 7.84.

EXAMPLE 19

4- (3,4-bisdifluoromethoxyphenyl) -4-ethynylcyclohexan-1-one

19a. 4- (3,4-Bisifluoromethoxyphenyl) -4-cyanocyclohexan-1-one dimethyl ketal. A mixture of 4-cyano-4- (3,4-bisdifluoromethoxyphenyl) cyclohexan-1-one (1.34 g, 4.05 mmol), trimethyl orthoformate (0.53 ml, 4.85 mmol) and p-toluenesulfone catalytic amounts the acids in methanol (40 ml) were warmed slightly under an argon atmosphere for 2 h. The mixture was cooled and then concentrated. The residue was partitioned between 5% aqueous sodium carbonate and ethyl acetate, extracted twice with ethyl acetate, the organic extract dried (potassium carbonate) and the solvent removed in vacuo to give an oil (1.5 g, 98%).

19b. 4- (3,4-Bisifluoromethoxyphenyl) -4-formylcyclohexan-1-one dimethyl ketal. A solution of 4-cyano-4- (3,4-bisdifluoromethoxyphenyl) cyclohexan-1-one dimethyl ketal (1.5 g, 3.98 mmol) in toluene (50 ml) was treated with diisobutylaluminum hydride at room temperature under argon. (1M in toluene, 10 ml, 10 mmol). After 4 h, a saturated aqueous sodium bisulfite solution was added and the mixture was extracted twice with ethyl acetate. The combined organic extract was dried (potassium carbonate) and the solvent removed in vacuo to give an oil (1.5 g, 99%).

19c. 4- (3,4-bisdifluoromethoxy) -4-ethynylcyclohex-1-one dimethyl ketal. A solution of dimethyl (diazomethyl) phosphonate (purity about 90%, 0.27 g) was added to a suspension of potassium t-butoxide (0.18 g, 1.6 mmol) in dry tetrahydrofuran (5 ml) under an argon atmosphere at -78 ° C. , 1.6 mmol) in tetrahydrofuran (5 ml). After 0.25 h, a solution of 4- (3,4-bisdifluoromethoxyphenyl) -4-formylcyclohexan-1-one dimethyl ketal (0.5 g, 1.3 mmol) in dry tetrahydrofuran (5 ml) was added dropwise and the mixture stirred under argon at -78 ° C for 10 min. Aqueous acetic acid was added, the mixture was concentrated and partitioned between methylene chloride and water. The organic extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography eluting with 3: 1 hexanes / ethyl acetate gave an oil (0.2 g, 41%).

19d. 4- (3,4-Bisifluoromethoxyphenyl) -4-ethynylcyclohexan-1-one. A mixture of 4- (3,4-bisdifluoromethoxyphenyl) -4-ethynylcyclohex-1-one dimethyl ketal (0.2 g, 0.53 mmol) and p-toluenesulfonic acid (catalytic amount) in acetone (10 ml) was stirred under atmosphere of argon at room temperature for 0.5 h. The mixture was concentrated, diluted with methylene chloride and washed with water. The organic extract was dried (magnesium sulfate) and the solvent removed in vacuo to give an oil (0.17 g, 98%).

Analysis: Calc. for C ₁₆ H ₁₄ F ₄ O ₃ : C 58.19, H 4.27; found: C 58.30, H 4.40.

EXAMPLE 20

4- (3,4-bisdifluoromethoxyphenyl) -4- (oxamidomethyl) cyclohexan-1-one

20a. 4-Aminomethyl-4- (3,4-bisdifluoromethoxyphenyl) cyclohexan-1-one dimethyl ketal. A solution of 4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexan-1-one dimethyl ketal (0.5 g, 1.33 mmol) in tetrahydrofuran (3 ml) was added at room temperature under atmospheric ferro argon to a suspension of lithium aluminum hydride (0.1 g, 2.66 mmol) in tetrahydrofuran (4.5 ml). After 6 h, ethyl acetate and saturated aqueous sodium potassium tartrate solution were added, followed by saturated aqueous sodium carbonate, and the mixture was extracted four times with ethyl acetate. The organic extract was dried (potassium carbonate) and the solvent removed in vacuo to give an oil (0.43 g, 85%).

20b. 4- (3,4-bisdifluoromethoxyphenyl) -4- (oxamidomethyl) cyclohexan-1-one. To a solution of 4-aminomethyl-4- (3,4-bisdifluoromethoxyphenyl) cyclohexan-1-one dimethyl ketal (0.43 g, 1.13 mmol) and triethylamine (0.16 ml, 1.13 mmol) in methylene chloride ( 7 ml) was added methyl oxalyl chloride (0.12 ml, 1.07 mmol) under an argon atmosphere at -78 ° C. After 5 min, water was added and the mixture was partitioned between methylene chloride and acidified water and extracted twice. The organic extract was dried (potassium carbonate) and evaporated to an oil (0.59 g). This methanol oil (about 2 ml) in the pressure tube was cooled to -78 ° C and the same volume of anhydrous ammonia was condensed into the tube. The tube was airtight, allowed to warm to room temperature, and stirred for 6 hours under pressure. The ammonia was evaporated, the mixture partitioned between chloroform and water and extracted three times. The organic extract was dried (potassium carbonate) and evaporated to ketal, oil (0.6 g). This oil was treated with 5% hydrochloric acid (7.6 ml) in tetrahydrofuran (13 ml) and the mixture was stirred under an argon atmosphere at room temperature for 20 h. The mixture was poured into acidified water, extracted three times with methylene chloride, the organic extract dried (potassium carbonate) and the solvent removed in vacuo. Purification by flash chromatography eluting with 5% ether / chloroform followed by trituration with ether / methylene chloride gave a white solid (0.21 g, 45%): m.p. Mp 164-165 ° C.

Analysis: Calc. for C ₁₇ H _lg F ₄ N ₂ O _5: C 50.25, H 4.47, N 6.89; found: C 50.04, H 4.45.

N, 6.64.

EXAMPLE 21

4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl-2-yl- (trimethylsilyl) ethoxycarbonyl) cyclohexan-1-one

A solution of 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) cyclohexan-1-one (0.18 g, 0.45 mmol) in 2- (trimethylsilyl) -ethanol (1.0 ml) was heated at 180 ° C under an argon atmosphere for 2.5 h. The mixture was cooled, concentrated and the product purified by flash chromatography eluting with 3: 1 hexanes / ether to give a colorless oil (0.2 g, 95%).

EXAMPLE 22

4-cyano-4- [3-cyclopentyloxy-4- (4-fluorobenzyloxy) phenylcyclohexan-1-one

A solution of 4-cyano-4- [3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one (0.75 g, 2.4 mmol) and concentrated hydrochloric acid (2 ml) in methanol (10 ml) was heated at reflux. under an argon atmosphere for 2 h. The mixture was cooled, diluted with water and extracted three times with methylene chloride. The organic extract was dried (magnesium sulfate) and evaporated to phenol (0.54 g, 92%). During vigorous stirring, a mixture of this phenol, 4-fluorobenzyl bromide (0.83 ml, 6.6 mmol) and potassium carbonate (0.92 g, 6.6 mmol) in dimethylformamide (12 ml) was heated under an argon atmosphere at 90 °. C 2 h. The mixture was allowed to cool, diluted with water and extracted three times with ether. The organic extract was dried (magnesium sulfate) and the solvent removed in vacuo. Purification by flash chromatography eluting with 30% ethyl acetate / hexanes gave a white solid (0.6 g, 78%): mp. 145-146 ° C.

5.59, N 3.99.

EXAMPLE 23

4-cyano-4- [3-cyclopentyloxy-4- (4-fluorobenzyloxy) phenyl] cyclohexane-1-onoxime

A solution of 4-cyano-4- [3-cyclopentyloxy-4- (4-fluorobenzyloxy) phenyl) cyclohexan-1-one (0.525 g, 1.49 mmol) and hydroxylamine hydrochloride (0.114 g, 1.63 mmol) in pyridine ( 5 ml) was stirred at room temperature under an argon atmosphere for 18 h. The mixture was partitioned between 1 N hydrochloric acid and methylene chloride, the organic extract dried (magnesium sulfate) and the solvent removed in vacuo. Purification by flash chromatography eluting with 35% ethyl acetate / hexanes gave a white solid (0.45 g, 82%): mp. 55-57 ° C.

EXAMPLE 24

4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -4-ethynylcyclohexan-1-one

The title compound, prepared essentially as described above for 4- (3,4-bis47 difluoromethoxyphenyl) -4-ethynylcyclohexan-1-one in Example 19, was isolated as a solid: m.p. 75-77 ° C.

Analysis: Calc. for C 68.25, H 6.03; found: C 67.93, H 6.10.

EXAMPLE 25

4-cyano-4- (3-cyclopropomethoxy-4-methoxyphenyl) cyclohexane-1-one oxime

The title compound, prepared essentially as described above for 4-cyano-4- (3cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-one oxime in Example 13, was isolated as a solid; m.p. 75-77 ° C.

Analysis: Calc. for CjgH ^ C ^. 1/4 H ₂ O: C 67.80, H 7.11, N 8.78; found: C 68.03, H 7.08, N 8.59.

EXAMPLE 26

2-Aminocarbonyl-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-one

26a. 2-Carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) -1- (methoxymethyloxy) cyclohex-1-ene. A solution of 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-one (1.0 g, 2.8 mmol) and sodium hydride (80% mineral oil dispersion, 0 , 09 g, 3.1 mmol) in dry hexamethylphosphoryl triamide (8 ml) was stirred under an argon atmosphere at room temperature for 0.5 h. Chloromethyl methyl ether (0.26 ml, 3.4 mmol) was added and stirring continued for 4.5 h. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, extracted three times, the organic layer dried (sodium sulfate) and the solvent removed in vacuo. The product was purified by flash chromatography eluting with 3: 1 hexanes / ethyl acetate to give a white solid (0.5 g, 44%): mp. 98-99 ° C.

26b. 2-carboxy-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) -1- (methoxymethyloxy) -cyclohex-1-ene. A solution of 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4methoxyphenyl) -1- (methoxymethyloxy) cyclohex-1-one (0.5 g, 1.25 mmol) and potassium hydroxide (0.21 g, 3 , 75 mmol) in methanol (13 ml), tetrahydrofuran (5 ml) and water (7.5 ml) were heated at 65 ° C for 3 h under argon. The mixture was partitioned between methylene chloride and acidified water, extracted twice, the organic layer dried (magnesium sulfate) and the solvent removed in vacuo. Purification by flash chromatography eluting with 5% methanol / chloroform gave an oil (0.26 g, 54%).

26c. 2-Aminocarbonyl-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) -1- (methoxymethyloxycyclohex-1-ene. A mixture of 2-carboxy-4-cyano-4- (3-cyclopropylmethoxy-4methoxyphenyl) -1- (methoxymethyloxy) cyclohex-1-ene (0.26 g, 0.67 mmol), N-methyl morpholine (0.09 ml, 0.8 mmol) and isobutyl chloroformate (0.1 ml, 0.77 mmol) in Dry 1,2-dimethoxyethane (7 ml) was stirred under an argon atmosphere at room temperature for 10 minutes Ammonium hydroxide (0.07 ml, 1.0 mmol) was added and stirring was continued for 0.5 h The mixture was partitioned between methylene chloride and 5% aqueous sodium carbonate were extracted three times, the organic layer was dried (potassium carbonate) and the solvent removed in vacuo to give a white solid (0.22 g, 85%): mp 120122 ° C.

26d. 2-Aminocarbonyl-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexanyl-one. A solution of 2-aminocarbonyl-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) -1 (methoxymethyloxy) cyclohex-1-one (0.22 g, 0.57 mmol) in 50% aqueous acetic acid ( 12 ml containing 9 drops of concentrated sulfuric acid per 30 ml) was heated at 75 ° C under an argon atmosphere for 2 h. The mixture was cooled, partitioned between methylene chloride and water, extracted twice, the organic layer was dried (potassium potassium) and the solvent was removed in vacuo. Purification by flash chromatography eluting with 5% methanol / chloroform followed by crystallization from ether / methylene chloride gave a white powder (0.07 g, 51%): mp. Mp 154-155 ° C.

Analysis: Calc. for C ^ N ^. 1/2 H ₂ O: C 64.94, H 6.60, N 7.97; found: C 64.93, H 6.56, N 7.61.

EXAMPLE 27

2- carboxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) cyclohexan-1-one

27a. 4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -2- [2- (trimethylsilyl) ethoxycarbonyl)] cyclohexan-1-one. A solution of 2-carbomethoxy-4-cyano-4- (3cyclopropylmethoxy-4-difluoromethoxy-phenyl) cyldohexan-1-one (0.18 g, 0.45 mmol) in 2- (trimethylsilyl) ethanol (1.0 ml) was obtained. heated at 180 ° C under an argon atmosphere for 2.5 h. The mixture was cooled, concentrated and the product purified by flash chromatography eluting with 3: 1 hexanes / ether to give a colorless oil (0.2 g, 95%).

27b. 2-carboxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -cyclohexan-1-one. Solution of 4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) 2- [2- (trimethylsilyl) ethoxycarbonyl)] cyclohexan-1-one (0.2 g, 0.42 mmol) and tetrabutylammonium fluoride (1 M solution in tetrahydrofuran (2 ml, 2 mmol) was stirred at room temperature under an argon atmosphere for 2.5 h. The mixture was poured into cold dilute aqueous hydrochloric acid, extracted twice with ether, the organic extract washed three times with ice water, dried (sodium sulfate) and the solvent removed in vacuo. Trituration of the residue gave a white powder (0.12 g, 77%): m.p. 110-112 ° C (decomposition).

Analysis: Calc. for C ₁₉ H ₁₉ F ₂ NO ₅ : C 60.16, H 5.05, N 3.69; found: C 60.25, H 5.07, N 3.57.

EXAMPLE 28

4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -2,4-dicyclocyclohexan-1-one

To a solution of 1-amino-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -2,4-dicyanocyclohex-1-ene (0.25 g, 0.696 mmol) in ethanol (2 ml) 6 N hydrochloric acid ( 0.6 ml) and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured into ice water, extracted three times with ether and the combined organic phase washed with water and brine and dried (sodium sulfate). The solvent was evaporated and the residue purified by flash chromatography eluting with 4% methanol / toluene and the residue triturated with ether to give a white powder (0.08 g, 32%): mp. 142143 ° C.

Analysis: Calc. for C ₁₉ H _lg F ₂ N ₂ O ₃ . 1/4 H ₂ O: C 62.55, H 5.11, N 7.68; found: C 62.69, 62.39, H 5.05.5.04, N 7.47.7.43.

EXAMPLE 29

2-Aminocarbonyl-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane

29a. 2-Carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) 1- (methoxymethyloxy) cyclohex-1-ene. The title compound, prepared essentially as described above for 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) -1- (methoxymethyloxy) cyclohex-1-ene in Example 26a, was triturated with ether to give white crystals (0.334 g, 77%): m.p. 81-82.5 ° C.

Analysis: Calc. for C ₂₂ H ₂₅ F ₂ NO ₆ : C 60.41, H 5.76, N 3.20; found: C 60.32, H 5.80, N 3.21.

29b. 2-carboxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -1 (methoxymethyloxy) cyclohex-1-ene. The title compound, prepared essentially as described above for 2-carboxy-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) -1 (methoxymethyloxy) cyclohex-1-ene in Example 26b, was isolated as an oil .

29c. 2-Aminocarbonyl-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -1 (methoxymethyloxy) cyclohex-1-ene. The title compound, prepared essentially as described above for 2-aminocarbonyl-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) 1- (methoxymethyloxy) cyclohex-1-ene in Example 26c, was isolated as an oil .

29d. 2-Aminocarbonyl-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one. The title compound, prepared essentially as described above for 2-aminocarbonyl-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-one in Example 26d, was isolated as a white powder (0.025 g, 24 %): m.p. Mp 157-159 ° C.

Analysis: Calc. for C ^ H ^ N ^. 1/2 H ₂ O: C 58.91, H 5.46, N 7.23; Found: C 58.86, H 5.32, N 6.95.

Treatment procedures

For the use of 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 preparation.

The compounds of formula (I) or (II), or a pharmaceutically acceptable salt thereof, can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease condition in a human or other mammal mediated by PDE IV inhibition, such as, but not limited to, asthma , allergic or inflammatory diseases.

The compounds of formula (I) or (II) are administered in an amount sufficient to treat such a disease in a human or other mammal.

The purposes herein apply to all treatment procedures and dosage regimens, equally for compounds of formula (I) and formula (II).

For the use of 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 preparation.

The amount of a compound of formula (I) or (II) required for therapeutic effect in topical administration will, of course, vary depending on the compound selected, the nature and severity of the condition and being treated, and is ultimately left to the discretion of the physician.

Suitable daily dosage regimens for oral administration are about 0.001 mg / kg to 100 mg / kg, preferably 0.01 mg / kg to 40 mg / kg, of a compound of formula (I), or a pharmaceutically acceptable salt thereof, calculated as the free base. The active ingredient may be administered 1 to 6 times daily in an amount sufficient to show effect.

When administered in accordance with the present invention, no toxic effects are expected.

APPLICABILITY EXAMPLES

EXAMPLE A

Inhibitory effect of compounds of formula (I) on the in vitro production (formation, production) of TNF in human monocytes.

The inhibitory effect of compounds of formula (I) on the in vitro formation (formation, production) of TNF in human monocytes can be determined by regulation as described by Badger et al., EPO Publication No. 0 411 754 A2, February 6, 1991, and Hanna, WO 90/15534, Dec 27 1990.

EXAMPLE B

Two endotoxic shock models were used to determine the in vivo activity of TNF for compounds of formula (I). The regulations we used in these models describe

Badger et al., EPO application 0 411 754 A2 published, February 6, 1991, and Hanna, WO

90/15534, Dec 27 1990.

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

EXAMPLE C

Isolation of PDE isozymes

The inhibitory effect of compounds of formula (I) or (II) on phosphodiesterase and their selectivity can be determined using a group of five different PDE isozymes. The tissues used as the source of the various isozymes are as follows: 1) PDE Ib, porcine aorta; 2) PDE Ic, bud heart; 3) PDE III, bud heart; 4) PDE IV, human monocyte; and 5) PDE V (also called la), a canine trachea. PDE 1a, Ib, Ic, and III are partially purified using standard chromatographic techniques [Torphy and Cieslinski, Mol. Pharmacol., 37: 206214, 1990]. PDE IV is purified to kinetic homogeneity by sequential use of anion exchange followed by heparin-Sepharosa chromatography [Torphy et al., J. Biol. Chem., 267: 1798-1804, 1992].

Phosphodiesterase activity is assayed as described in Torphy and Cieslinski, Mol. Pharmacol., 37: 206-214, 1990. Positive IC ₅₀ values in the nanomolam to µΜ range for the compounds of formula (I) or (II) from the embodiments described herein have been demonstrated.

EXAMPLE D

The ability of selected PDE IV inhibitors to increase cAMP accumulation in intact tissues was determined using U-937 cells, a human monocyte lineage that has been shown to contain a large amount of PDE IV. To determine PDE IV inhibition activity in intact cells, undifferentiated U-937 cells (approximately 10 ⁵ cells / tube) were incubated with different concentrations (0.01 to 1000 μΜ) of PDE inhibitors for one minute and 1 μΜ of prostaglandin E2 for another four minutes. Five minutes after initiation of the reaction, cells were lysed by the addition of 17.5% perchloric acid, pH 1 was neutralized by the addition of 1 M potassium carbonate, and the cAMP content was determined by RIA. The general regulation for this test is described in Brooker et al., Radioimmunas say of cyclic AMP and cyclic GMP. Adv. Cyclic Nucleotide Res., 10: 1-33, 1979. Compounds of embodiments as described herein for formula (I) or (II) showed positive EC ₅₀ values in the µΜ range in the above test.

Claims (11)

A compound of formula (I) (R ₂ ) _with (D substituted with one or more halogens; m is Odo 2; n is 1 to 4; r is 1 to 6; R ₄ and R ₅ are independently selected from hydrogen or C ₁₂ alkyl; R ₆ is hydrogen, methyl, hydroxyl, aryl, halogen substituted aryl, aryloxyC ₁₃ alkyl, halogen substituted aryloxyC ₁₃ alkyl, indanyl, indenyl, C _{7 n} polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, thienyl thiopyranyl, C _3-4 cycloalkyl or C _43-10 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may optionally be substituted by 1 to 3 methyl groups or one ethyl group; provided that, a) when R _{6 is} hydroxyl then m 2; or b) when R _{6 is} hydroxyl, then r is 2 to 6; or c) when R _{6 is} 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R _{6 is} 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and mO, then R _{6 is} other than H in - (CR ₄ R ₅ ) _n O (CR ₄ R ₅ ) _m R ₆ ; X is YR 2, halogen, nitro, NR ₄ R ₅ or formyl amine; Y is O or S (O) _{m <} ; m 'is 0.1 or 2; XJeOaliNR ₈ ; is hydrogen or X; R is independently selected from -CH ₃ and -CH ₂ CH ₃ , which are optionally substituted by 1 or more halogens; s is 0 to 4; R ₃ is hydrogen, halogen, C _1-4 alkyl, halogen substituted C _1-4 alkyl, CH ₂ NHC (O) C (O) NH ₂ , -CH = CR ₈ , R ₈ 'cyclopropyl, optionally substituted by R g, CN, OR ₈ , CH ₂ OR ₈ , NR _g R ₁₀ , CH ₂ NR _g R _{1 ()} , C (Z ') H, C (O) OR _g , C (O) NR _g R ₁₀ or C = CR _g> ; Z'is O, NR ₉ , NORg, NCN, C (-CN) ₂ , CR _g CN, CR _g NO ₂ , CR ₈ C (O) OR ₈ , CR _g C (O) NR ₈ R ₈ , C (-CN) NO ₂ , C (-CN) C (O) OR ₉ or C (-CN) C (O) NR ₈ R ₈ ; Z is O, NR _? , NCR ₄ R ₅ C ₂ -alkenyl, NOR ₁₄ , NOR ₁₅ , NOCR ₄ R ₅ C ₂ -alkenyl, NNR ₄ R ₁₄ , NNR ₄ R ₁₅ , NCN, NNRgC (O) NR ₈ R ₁₄ , NNR ₈ C (S) NR ₈ R ₁₄ or = Z 2- (1,3-ditian), 2- (l. 3-dithiolane), dimethylthio ketal, diethylthio ketal, 2- (1,3-dioxolane), 2- (1,3-dioxane), 1- (1,3-oxathiolane), dimethyl ketal or diethyl ketal; R _? is - (CR ₄ R ₅ ) _q R ₁₂ or C 1-6 alkyl, wherein R ₁₂ or C 1-6 alkyl is optionally one or more times substituted with C ₁₂ alkyl, which is optionally substituted by 1 to 3 fluorines, - F, -Br, -Cl, -NO ₂ , -Si (R ₄ ) ₃ , -NR ₁₀ R _n , -C (O) R _g , -CO ₂ R _g , -OR _g , -CN, -C ( O) NR ₁₀ R _n , -OC (O) NR ₁₀ R _n , -OC (O) R ₈ , -NR ₁₀ C (O) NR ₁₀ R _n , -NR ₁₀ C (O) R _n , -NR _w C (O) OR ₉ , -NR ₁₀ C (O) R ₁₃ , -C (NR ₁₀ ) NR ₁₀ R _n , -C (NCN) NR ₁₀ R _n , -C (NCN) SR ₉ , -NR ₁₀ C (NCN) SR ₉ , -NR ₁₀ C (NCN) NR ₁₀ R _u , -NR ₁₀ S (O) ₂ R ₉ , -S (O) _m , R ₉ , -NR ₁₀ C (O) C (O) NR ₁₀ R _n , -NR ₁₀ C (O) C (O) R ₁₀ , thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl or tetrazolyl; q is 0.1 or 2; R ₁₂ is C _3-7 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; R 8 is independently selected from hydrogen or R ₉ ; R8 is R8 or fluorine; R ₉ is C _1-10 alkyl which is optionally substituted by 1 to 3 fluorines; ^R 10 J ^{is 0 R} 8 ^{or R} 11 ' R _n is hydrogen or C _M alkyl, optionally substituted with 1 to 3 fluorines; or if R ₁₀ and R _{n are} NR ₁₀ R _n , together with nitrogen, may form a 5- to 7-membered ring containing optionally at least one additional heteroatom selected from O, N or S; R ₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl or thiadiazolyl, and each of these heterocyclic rings is bonded via a carbon atom and 1 is optionally substituted by a carbon atom and ₁₂ alkyl groups; R ₁₄ is hydrogen or R _? ; or if R _g and R _{14 are} NR _g R ₁₄ , together with nitrogen, they may form a 5 to 7 membered ring containing optionally one or more additional heteroatoms selected from O, N or S; R ₁₅ is C (O) R ₁₄ , C (O) NR ₄ R ₁₄ , S (O) ₂ R ₇ or S (O) ₂ NR ₄ R ₁₄ ; provided that (f) when ZO, X is XR ₂ , Y is oxygen, oxygen, X ₃ is hydrogen, s is 0, R ₂ is CH ₃ and R ₇ is CH ₃ , then R _{3 is} different from CN; (g) when ZO is oxygen, X ^ is hydrogen, s is 0 and X is ΥΙ ^, then R _{3 is} other than hydrogen; (h) when Z is NO-CH ₂ CH = CH ₂ , X is YR ₂ , Y is oxygen, X ₂ is oxygen, X ₃ is hydrogen, s is 0, R2 is CH ₃ and R ₇ is CH ₃ , then R _{3 is} other than CN; (i) when R _{12 is} N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N-piperidinyl or N-morpholinyl, then q is not 1; or (j) when ZO or Z is 2- (1,3-dioxolane) and R ₃ is CH ₃ , CH ₂ OH or CH ₂ OC ₁₄ -alkyl, then R 4 is not C _{7 3} -alkoxy and X is not halogen , methoxy, ethoxy, methylthio or ethylthio; or a pharmaceutically acceptable salt thereof. A compound according to claim 1 having the formula (Ia) da) where is R _x CH ₂ -cyclopropyl, CH ₂ -C ₅₄ -cycloalkyl, C ₄₄ -cycloalkyl, C _{7 n} -policycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C ₇ -alkyl , which is optionally substituted by 1 or more fluorines, - (CH ₂ ) ₁ . ₃ C (O) O (CH ₂ ) ₀ . ₂ CH ₃ , - (CH ₂ ) ₁ . ₃ O (CH ₂ ) ₀ . ₂ CH _{3 in -} ^ OH; X is XR ₂ , halogen, nitro, NR ₄ R ₅ or formyl amine; Y is O or S (O) _m ,; m 'is 0.1 or 2; R ₂ is -CH ₃ or -CH ₂ CH ₃ which is optionally substituted by 1 or more halogens; R ₃ is hydrogen, _4- alkyl, halogen substituted C ₁₄ -alkyl, CH ₂ C (O) C (O) N, CfH NHCfOjClOjNR, CN, CH ₂ OR _g , C (Z ') H, C ( O) OR _g , C (O) NR _g R ₁₀ or C = CR _g ; Z 'is O or NOR _g ; Z is O, NR _? , NOR ₁₄ , NOR ₁₅ , NNR ₄ R ₁₄ , NNR ₄ R ₁₅ , NCN or = Z is 2- (1,3-ditian), dimethylthio ketal, 2- (1,3-dioxolane) or dimethyl ketal; R ₇ is - (CR ₄ R ₅ ) _q R ₁₂ or C 1-6 alkyl, wherein R ₁₂ or C 1-4 alkyl is optionally substituted once or more by C ₁₂ alkyl which is optionally substituted by 1 up to 3 fluorines, -F, -Br, -Cl, -NO ₂ , -Si (R ₄ ) ₃ , -NR 2 ', -C (O) R _g , -CO ₂ R _g , -OR _g , -CN, -C (O) NR ₁₀ R _n , -OC (O) NR ₁₀ R _n , -OC (O) R _g , -NR ₁₀ C (O) NR ₁₀ R ₁₁ , -NR ₁₀ C (O) R _n , -NR ₁₀ C (O) OR ₉ , -NR ₁₀ C (O) R ₁₃ , -C (NR ₁₀ ) NR ₁₀ R _n , -C (NCN) NR ₁₀ R _n , -C (NCN) SR ₉ , -NR ₁₀ C (NCN) SR ₉ , -NR ^ ONCNjNRj ^ j, -NR ₁₀ S (O) ₂ R ₉ , -S (O _m , R ₉ , -NR ₁₀ C (O) C (O) NR ₁₀ R _n , -NR ₁₀ C (O) q O) R ₁₀ , thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl or tetrazolyl; q is O, 1 or 2; R ₁₂ is C _3-7 -cycloalkyl, (2-, 3- or 4-pyridyl), (1- or 2-imidazolyl), piperazinyl, morpholinyl, (2- or 3-thienyl), (4- or 5-thiazolyl ) or phenyl; R _g is independently selected from hydrogen or R ₉ ; R ₉ is C 1-6 alkyl optionally substituted by 1 to 3 fluorines; ^R 10 J ^{is OR} 8 ^{or R} 11 ' R _n is hydrogen or C 1-6 alkyl optionally substituted by 1 to 3 fluorines; or if R ₁₀ and R _{n are} NR ₁₀ R _n , together with nitrogen, may form a 5- to 7-membered ring containing optionally at least one additional heteroatom selected from O, N or S; R ₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl or thiadiazolyl, and each of these heterocyclic rings is bonded via carbon or 1 and may be substituted or unsubstituted by carbon ₁₂ -alkyl groups; R ₁₄ is hydrogen or R _? ; or if R _g and R _{14 are} NR _g R ₁₄ , together with nitrogen, they may form a 5 to 7 membered ring containing optionally one or more additional heteroatoms selected from O, N or S; R ₁₅ is C (O) R ₁₄ , C (O) NR ₄ R ₁₄ , 8 (O) ₂ or S (O) ₂ NR ₄ R ₁₄ ; provided that a) when ZO, X is YR ₂ , Y is oxygen, R ₂ is CH ₃ and R _x is CH ₃ , then R _{3 is} different from CN; b) when R _{12 is} N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl or N-morpholinyl, then q is not 1; or a pharmaceutically acceptable salt thereof. Compound according to claim 2, characterized in that R _{x is} -CF ₃ , -CH ₂ F, -CHF ₂ , -CF ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , CH, -cyclopropyl , CH ₂ -C _{5 6} -cycloalkyl, C ₄₆ cycloalkyl, C _{7 n} -policycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1 -alkyl which is unsubstituted or substituted by 1 or more fluorine, - (CH ₂ ) ₁ . ₃ C (O) O (CH ₂ ) ₀ . ₂ CH ₃ , or - (CHJ ^ OH; Z is O, NCN, NR _? , NOR ₁₄ , NOR ₁₅ , NNR ₄ R ₁₄ , NNR ₄ R ₁₅ , dimethyl ketal or dimethylthio ketal; X is YR, and Y is oxygen; X, is oxygen; Xg is hydrogen; R 1 is metU, -CF ₃ , -CHF, or -CH, CHF ,; R ₃ is C (O) NH 3, C 1 -C ₈ , CN, C (Z ') H, CH, OH, CH, F, CF, H or CF ₃ ; Z 'is O or NOR _g ; R _? is unsubstituted or substituted - (CH,) ₁₂ (cyclopropyl), - (CH ₂ ) ₀ _, (cadobutyl), - (CH ₂ ) _{0 2} (cyclopentyl), - (CH ₂ ) ₀ , (cyclohexyl), - ( O, N, (2-, 3- or 4-pyridyl), (0¾¾, (2-imidazoyl), (CH ₂ ) ₂ (4-morpholinyl), (CH,), (4-piperazinyl), (0¾¾ , (2-thienyl), (CH ₂ ) ₁₂ (4-thiazolyl) or (01¾¾, (phenyl); if R ₁₀ and R _n in the -NR ₁₀ R _n moiety together with the nitrogen to which they are attached form a 5- to 7-membered ring, it is 1-midazolyl, 2- (R _g ) -1-imidazoia, 1-pyrazolyl , 3- (R _g ) -1-pyrazolyl, 1- triazole, 2-triazolyl, 5- (R _g ) -1-triazole, 5- (R _g ) -2-triazoyl, 5- (R _g ) -1-tetrazoyl, 5- (R _g ) 2- tetrazolyl , 1-tetrazolyl, 2-tetrazolU, morpholinyl, piperazinyl, 4- (R _g) -l-piperazine or piroUl; if R _g and R ₁₄ in the -NR _g R ₁₄ moiety together with the nitrogen to which they are attached may form The 5- to 7-membered ring is 1-imidazoyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2- tetrazolyl, morpholinyl, piperazine and pyrrolyl; where each ring can be substituted on the available nitrogen or carbon by R _? Which is 2- _(R7) -l-imidazole, 4- _(R7) -l-imidazolyl, 3- _(R7) -l-imidazole, 3- _(R7) -l-pyrazolyl, 4- _(R?) -L-pyrazolyl, 5- _(R7) -l-pyrazolyl, 4- _(R?) -2triazolil, 5- _(R7) -2-triazolyl, 4- (R ₇₎ -L-triazolyl, 5- _(R7) -l-triazolyl, 5- _(R7) -l-tetrazolyl, and 5- ( R ₇₎ -2-tetrazolyl; R ₁₃ is (2-, 4- or 5-imidazoyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl [1,2,3]), (3- or 5-triazolyl) [1,2,4], (5-tetrazoyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl [1,2] , 4]), (2-oxadiazolyl [1,3,4]), (2-thiadiazoyl [1,3,4]), (2-, 4- or 5-thiazoyl), (2-, 4- ah 5-oxazolidinyl), (2-, 4- or 5-thiazolidinyl) or (2-, 4- or 5-imidazolidinyl). A compound according to claim 2, wherein R _{x is} -CH ₂ -cyclopropyl, cyclopentenyl, methyl or CF ₂ H; R ₃ is CN or C = CR _g , C (O) NH ₂ or C (Z ') H; X is YR ₂ ; Y is oxygen; is oxygen; X ^ is hydrogen and R ₂ is CF ₂ H or methyl. A compound according to claim 4, wherein 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one; 4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexan-1-one; 4-cyano-4- (3-difluoromethoxy-4-methoxyphenyl) cyclohexan-1-one; 4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-one; 4-cyano-4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) cyclohexan-1-one; 4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one; 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-onoxime; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-formylcyclohexan-1-one; 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one dimethyl ketal; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-formylcyclohexan-1-one dimethyl ketal; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (hydroxymethyl) cyclohexan-1-one; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (hydroxymethyl) cyclohexan-1-one dimethyl ketal; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (fluoromethyl) cyclohexan-1-one; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4- (fluoromethyl) cyclohexan-1-one dimethyl ketal; 4-Aminocarbonyl-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one; 4-Aminocarbonyl-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one dimethyl ketal; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-ethynylcyclohexan-1-one; 4- (3-cyclopentyloxy-4-methoxyphenyl) -4-ethynylcyclohex-1-one dimethyl ketal; 4- (3,4-bisdifluoromethoxyphenyl) -4-ethynylcyclohexan-1-one; 4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexan-1-one dimethyl ketal; 4- (3,4-bisdifluoromethoxyphenyl) -4-formylcyldohexan-1-one dimethyl ketal; 4- (3,4-bisdifluoromethoxy) -4-ethynylcyclohex-1-one dimethyl ketal; 4- (3,4-bisdifluoromethoxyphenyl) -4- (oxamidomethyl) cyclohexan-1-one; 4-Aminomethyl-4- (3,4-bisdifluoromethoxyphenyl) cyclohexan-1-one dimethyl ketal; 4- (3,4-bisdifluoromethoxyphenyl) -4- (oxamidomethyl) cyclohexan-1-one dimethyl ketal; 4-cyano-4- [3-cyclopentyloxy-4- (4-fluorobenzyloxy) phenyl] cyclohexan-1-one; 4-cyano-4- [3-cyclopentyloxy-4- (4-fluorobenzyloxy) phenyl] cyclohexan-1-one oxime; 4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -4-ethynylcyclohexan-1-one or 4-cyano-4- (3-cyclopropomethoxy-4-methoxyphenyl) cyclohexane-1-one oxime. A compound of formula (II) (Π), characterized in that R _x - (CR ₄ R ₅ ) _n C (O) O (CR ₄ R ₅ ) _m R ₆ , - (CR ₄ R ₅ ) C (O) NR ₄ (CR ₄ R ₅ ) _m R ₆ , - (CR ₄ R ₅ ) _n O (CR ₄ R ₅ ) _m R ₆ or - (CR ₄ R ₅ ) _r R ₆ , wherein the alkyl moieties may optionally be substituted by one or more halogens; meDo 2; n is 1 to 4; r is 1 to 6; R ₄ and R ₅ are independently selected from hydrogen or C ₁₂ alkyl; R ₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxy ₃ alkyl, halo substituted aryloxy ₃ alkyl, indanyl, indenyl, _{C? 41} polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, _C3 ^ cycloalkyl or C _{4 6} cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties are unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group; provided that, a) when R _{6 is} hydroxyl then m 2; or b) when R _{6 is} hydroxyl, then r is 2 to 6; or c) when R _fi is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R _{6 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 R _{6 is} other than H in - (CR ₄ R ₅ ) _n O (CR ₄ R ₅ ) _m R ₆ ; X is YR ₂ , halogen, nitro, NR ₄ R ₅ or formyl amine; Y is O or S (O) _m> ; m 'is 0.1 or 2; X _{2 is} O or NR _g ; X ^ is hydrogen or X; R ₂ is independently selected from -CH ₃ and -CH ₂ CH ₃ , which are optionally substituted by 1 or more halogens; s is 0 to 4; R ₃ is hydrogen, halogen, C 1 _M alkyl, CH ₂ NHC (O) C (O) NH ₂ , with halogen substituted C ₁₄ -alkyl, -CH = CR _g , R _{8 '} , cyclopropyl which is optionally substituted by R _gl , CN, ORg, CH ₂ OR ₈ , NR ₈ R ₁₀ , CH ^ NRgR ^, C (Z' ) H, C (O) OR _g , C (O) NR _g R ₁₀ or C = CR ₈ Z 'is O, NR ₉ , NOR ₈ , NCN, C (-CN) ₂ , CRgCN, CR ₈ NO ₂ , CR _g qO) OR ₈ , CR ₈ C (O) NR ₈ Rg, C (-CN) NO ₂ , q-CN) C (O) OR ₉ or C (-CN) qO) NR _g R ₈ ; Z is C (Y ') R ₁₄ , C (O) OR ₁₄ , C (Y') NR ₁₀ R ₁₄ , C (NR ₁₀ ) NR ₁₀ R ₁₄ , CN, C (NOR ₈ ) R ₁₄ , C (O ) NR ₈ NR ₈ C (O) Rg, C (O) NR ₈ NR ₁₀ R ₁₄ , C (NOR ₁₄ ) R ₈ , C (NR ₈ ) NR ₁₀ R ₁₄ , C (NR ₁₄ ) NR ₈ R ₈ , C (NCN) NR ₁₀ O R _W , C (NCN) SR ₉ , (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl [1,2,3]), (3- or 5-triazolyl [1,2,4]), (5-tetrazolyl), (2-, 4 or 5- oxazolyl), 3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl [1,2,4]), (2-oxadiazolyl [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 heterocyclic ring systems may optionally be substituted one or more times with R ₁₄ ; Y 'is O or S; R ₇ is - (CR ₄ R ₅ ) _q R ₁₂ or C 1-6 alkyl, wherein R ₁₂ or C ₁₆ alkyl is optionally substituted once or more with C ₁₂ alkyl which is optionally substituted by 1 up to 3 fluorines, -F, -Br, -Cl, -NO ₂ , -Si (R ₄ ) ₃ , -NR ₁₀ R _n , -C (O) R _g , -CO ₂ R _g , -OR _g , -CN, -C (O) NR ₁₀ R _n , -OC (O) NR ₁₀ R _n , -OC (O) R ₈ , -NR _lo qO) NR ₁₀ R _n , -NR ₁₀ C (O) R _n , -NR ^ OjOR ,, -NR _lo qO) R ₁₃ , -C (NR ₁₀ ) NR ₁₀ R _n , -C (NCN) NR R _{1O U} -qNCN) SR _9, -NR ₁₀ C (NCN) SR _9, -NR _lo qNCN) NR _lo R _n, -NR = O) R, -S (O) _m, R _9, -NR ₁₀ QO) QO) NR ₁₀ R _u, -NR _lo q O) q O) R _10, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; q is O, 1 or 2; R ₁₂ is C _3-7 -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; R 8 is independently selected from hydrogen or R ₉ ; Rg. R _g or fluorine; R ₉ is C 1-6 alkyl optionally substituted by 1 to 3 fluorines; ^R ioJ ^{e OR} 8 ^aliR ll ' R _n is hydrogen or C ₁ _ ₄ -alkyl which is optionally substituted with 1 to 3 fluorines; or if R ₁₀ and R _{n are} NR ₁₀ R _n , together with nitrogen, may form a 5- to 7-membered ring containing optionally at least one additional heteroatom selected from O, N or S; R ₁₃ 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 with 1 or 2 q ₂ -alkyl groups; R ₁₄ is hydrogen or R _? ; or if R _g and R _{14 are} NR _g R ₁₄ , together with nitrogen, they may form a 562 to 7 membered ring containing optionally one or more additional heteroatoms selected from O, N or S; R, _s is C (O) R ₁₄ , C (O) NR ₄ R ₁₄ > S (O) ₂ R, or S (O) ₂ NR ₄ R ₁₄ ; provided that f) when R _{12 is} N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, Npiperidinyl or N-morpholinyl, then q is not 1; or g) when ZC (O) is OR ₁₄ , where R _{14 is} lower alkyl and R _{3 is} CN, then X ₁ X ₂ is not C 1-4 alkoxy and X is not halogen, methoxy, ethoxy, methylthio or ethylthio; or a pharmaceutically acceptable salt thereof. A compound according to claim 6, wherein R 1 is -CF ₃ , -CH ₂ F, -CHF ₂ , -CF ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , CH ₂ -cyclopropyl, CH ₂ -C ₅ . ₆ -cycloalkyl, C ₄ . ₆ cycloalkyl, C _{7 n} -policikloalkil, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C ₂ -alkyl which is unsubstituted or substituted by 1 or more fluorines,. (^ 0) 0 (¾¾ - (CH ₂ ) _{1. 3} O (CH ₂ ) _{0. 2} CH ₃ or - (CH ^ OH; Z is O, NCN, NR _? , N0R ₁₄ , N0R ₁₅ , NNR ₄ R ₁₄ , NNR ₄ R ₁₅ , dimethyl ketal or dimethylthio ketal; X is YR ₂ and Y is oxygen; X ₂ is oxygen; is hydrogen; R ₂ is methyl, -CF ₃ , -CHF ₂ or -CH ₂ CHF ₂ ; R ₃ is QO) NH ₂ , C = CR _g , CN, C (Z ') H, CH ₂ O, CH ₂ F, CF ₂ H or CF ₃ ; Z 'is O or NOR _g ; R _? is unsubstituted or substituted - (CH _{2 -} (cyclopropyl), - (CH ₂ ) _{0 2} (cyclobutyl), - (CH ₂ ) _{0 2} (cyclopentyl), - (CH ₂ ) _{0 2} (cyclohexyl), - (CH ₂ ) ₀₂ (2-, 3- or 4-pyridyl), (CH ₂ ) ₁₂ (2-imidazolyl), (CH ₂ ) ₂ (4-morpholinyl), (CH ₂ ) ₂ (4-piperazinyl), (CH ₂ ) ₁₂ (2-thienyl), (CH ₂ ) ₁₂ (4-thiazolyl) or _2- phenyl; if R ₁₀ and R _n in the -NR ₁₀ R _n moiety together with the nitrogen to which they are attached form a 5- to 7-membered ring, is 1-imidazolyl, 2- (Rg) -1-imidazolyl, 1-pyrazolyl, 3- _(Rg) -l-pyrazolyl, 1- triazolyl, 2-triazolyl, 5- (R _g ) -1-triazolyl, 5- (R _g ) -2-triazolyl, 5- (R _g ) -1-tetrazolyl, 5- (R _g ) -2- tetrazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, 4- _(Rg) -l-piperazinyl, or pyrrolyl; if R _g and R ₁₄ in the -NR _g R ₁₄ moiety together with the nitrogen to which they are attached may form The 5- to 7-membered ring is 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2- tetrazolyl, morpholinyl, piperazinyl and pyrrolyl; where each ring can be substituted on the available nitrogen or carbon by R _? Which is 2- _(R7) -l-imidazolyl, 4- _(R7) -l-imidazolyl, 5- _(R7) -l-imidazolyl, 3- _(R7) -l-pyrazolyl, 4- _(R7) -l-pyrazolyl, 5- _(R7) -l-pyrazolyl, 4- (R ₇₎ -263 triazolyl, 5- _(R7) -2-triazolyl, 4- _(R7) -l- triazolyl, 5- _(R7) -l-triazolyl, 5- _(R7) -l-tetrazolyl, and 5- _(R7) -2-tetrazolyl; R ₁₃ is (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl [1,2,3]), (3- or 5-triazolyl) [1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), 3- or 5-oxadiazolyl [1,2, 4]), (2-oxadiazolyl [1,3,4]), (2-thiadiazolyl [1,3,4J), (2-, 4- or 5-thiazolyl), (2-, 4- or 5- oxazolidinyl), (2-, 4- or 5-thiazolidinyl) or (2-, 4- or 5-imidazolidinyl). A compound according to claim 7, characterized in that R _x -CH 1 -cyclopropyl, cyclopentyl, methyl or CF ₂ H; R ₃ is CN or C = CR _g , C (O) NH ₂ or C (Z ') H; X is YR 2; Y is oxygen; Χ2 is oxygen; is hydrogen; R is CF ₂ H or methyl; and Z is C (O) R ₁₄ , C (O) OR ₁₄ , C (O) NR ₁₀ R ₁₄ , C (NR ₁₀ ) NR ₁₀ R ₁₄ , CN, C (NOR ₈ ) R ₁₄ , C (O) NR ₈ NR ₈ C (O) R ₈ , C (O) NR ₈ NR ₁₀ R ₁₄ , C (NOR ₁₄ ) R ₈ , C (NR ₈ ) NR ₁₀ R ₁₄ , C (NR ₁₄ ) NR ₈ R ₈ , C (NCN ) NR ₁₀ R ₁₄ , C (NCN) SR ₉ , (1-, 4- or 5- {R ₁₄ } -2-imidazolyl), (1-, 4- or 5- {R ₁₄ } -3-pyrazolyl, (1-, 2- or 5- {R ₁₄ } -4-triazolyl [1,2,3]), (1-, 2-, 4- or 5- {R ₁₄ } -3-triazolyl [1,2] , 4]), (1- or 2- {R ₁₄ } -5-tetrazolyl), (4- or 5- {R ₁₄ } -2-oxazolyl), (3- or 4- {R ₁₄ } -5- isoxazolyl), (3- {R ₁₄ } -5-oxadiazolyl [1,2,4]), (5- {R ₁₄ } -3oxadiazolyl [1,2,4]), (5- {R ₁₄ } -2 -oxadiazolyl [l, 3,4j), (5- {R _14} -2tiadiazolil [l, 3,4]), (4- or 5- {R _14} -2-thiazolyl), (4- ah 5- {R ₁₄ } -2-Oxazolidinyl), (4- or 5- {R ₁₄ } -2-thiazolidinyl), (1-, 4- or 5- {R ₁₄ } -2-imidazolidinyl). A compound according to claim 8, wherein 2-carbomethoxy-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one; 4- (3,4-bisdifluoromethoxyphenyl) -2-carbomethoxy-4-cyanocyclohexan-1-one; 2-carbomethoxy-4-cyano-4- (3-difluoromethoxy-4-methoxyphenyl) cyclohexan-1-one; 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-one; 2-carbomethoxy-4-cyano-4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) cyclohexanyl-one; 2- carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexanyl-one; 2-Aminocarbonyl-4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-one; 4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -2- [2- (trimethylsilyl) ethoxycarbonyl)] -cyclohexan-1-one; 2-carboxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one; 4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -2,4-dicyclocyclohexan-1-one and 2-Aminocarbonyl-4-cyano-4- (3-cyclopropylmethoxy) -4-difluoromethoxyphenyl) cyclohexan-1-one. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable excipient. Use of a compound according to any one of claims 1 to 9 in the manufacture of a medicament for use in the treatment of allergic reactions.