HUT77003A - 3,3-(disubstituted)cyclohexan-1-one derivatives and pharmaceutical compositions contg. them - Google Patents

Description

The present invention relates to novel 3,3- (disubstituted) -1-cyclohexanone derivatives and related compounds, to pharmaceutical compositions containing these compounds, and to their use in the treatment of allergic and inflammatory diseases and in the inhibition of the formation of tumor necrosis factor (TNF). .

Asthma bornchiale is a complex, multifactorial disease characterized by reversible airway obstruction due to external stimuli and airway hyperactivity.

The identification of new therapeutic agents for asthma is complicated by the fact that several mediators are responsible for the development of the disease. It seems unlikely that eliminating the effects of a single mediator would have a significant effect on all three components of chronic asthma. An alternative to the mediator approach may be to regulate the activity of cells responsible for the pathophysiology of the disease.

One such option is to increase the levels of cAMP (cyclic adenosine 3 ', 5'-phosphate). Cyclic AMP has previously been shown to be a second messenger that mediates biological responses to a variety of hormones, neurotransmitters, and drugs (Krebs Endocrinology Proceedings of the 4th International Congress Experta Medica, 1973, 29-29). When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg-ATP to cAMP at an increased rate.

Cyclic AMP modifies the activity of most, but not all, of the cells contributing to extrinsic (allergic) asthma. Thus, increasing the amount of cAMP would result in the following beneficial effects: 1) relaxation of airway smooth muscle cells; 2) inhibition of mast cell mediator release; 3) suppressing neutrophil degranulation; 4) inhibition of basophilic degranulation; and 5) inhibition of monocyte and macrophage activation. Accordingly, compounds that activate adenylate cyclase or phosphodiesterase inhibitors should suppress improper activation of respiratory smooth muscle cells and various inflammatory cells. The cellular mechanism for the inactivation of cAMP is the hydrolysis of the 3'-phosphodiester bond by one or more members of the family of isozymes, namely cyclic nucleotide phosphodiesterases (PDEs).

Recently, it has also been pointed out that a different cyclic nucleotide phosphodiesterase (PDE) isozyme, called PDE IV, is responsible for the degradation of cAMP in respiratory smooth muscle and inflammatory cells. fór Asthma, Barnes, ed. IBC Technical Services Ltd. (1989)]. Studies indicate that inhibition of this enzyme not only results in smooth muscle cell relaxation but also suppresses degranulation of mast cells, basophils and neutrophils, in addition to inhibiting the activation of monocytes and neutrophils. In addition, the beneficial effects of PDE IV inhibitors can be greatly enhanced when the adenylate cyclase activity of target cells is enhanced by appropriate hormones or autacoids, as in vivo. PDE IV inhibitors would be effective in the asthmatic lung, where the concentration of prostaglandin E ₂ and prostacyclin higher (the prostaglandin E ₂ and prostacyclin activators of adenylate cyclase). Such compounds may provide a unique solution to the pharmacotherapy of asthma bornchiale and may have significant advantages over currently available active ingredients.

The compounds of the invention also inhibit the formation of tumor necrosis factor (TNF) (a tumor necrosis factor is a serum glycoprotein). Excessive or unregulated formation of tumor necrosis factor affects or exacerbates many diseases; such diseases include, but are not limited to, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, and other arthritic conditions; sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pneumonia, silicosis, pulmonary sarcoidosis, osteoporosis, reerfusion injury, reperfusion injury fever or myalgia such as influenza, secondary cachexia due to infection or malignancy, secondary cachexia due to human acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Chn diseases such as ulcerative colitis or pyrexia; as well as many autoimmune diseases such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.

AIDS arises from the infection of T lymphocytes with the Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified so far, such as HIV-1, HIV-2 and HIV-3. As a result of HIV infection, T cell-mediated immunity is compromised and the infected individuals develop severe opportunistic infections and / or abnormal neoplasms. Entering HIV into T lymphocytes requires activation of T lymphocytes. After T-cell activation, viruses such as HIV-1 or HIV-2 infect T-lymphocytes and such viral protein expression and / or replication is mediated or maintained by T-cell activation. When activated T-lymphocytes become infected with HIV, T-lymphocytes must remain continuously activated in order to allow HIV gene expression and / or HV replication.

Cytokines, more particularly tumor necrosis factor, as they play a role in T lymphocyte activation, are incorporated into the expression and / or viral replication of activated T cell-mediated HIV. In an HIV-infected individual, disruption of cytokine activity, such as inhibition of cytokine production, namely inhibition of tumor necrosis factor, contributes to limiting the survival of T-cell activation, thereby reducing the progression and progression of HIV infection in previously uninfected cells. the development of immune dysfunction caused by HIV infection is eliminated. Monocytes, macrophages and related cells such as Kuppfer cells and glial cells also play a role in the survival of HIV infection. These cells, such as T cells, serve as target cells for viral replication, and the intensity of viral replication depends on the activation status of these cells. See Rosenberg et al., The Immunopathogenesis of Hiv Infection, Advances in Immunology, Vol. 1989)]. Monokines, such as tumor necrosis factor, have previously been shown to activate HIV replication in monocytes and / or macrophages [see Poli et al., Proc. Natl. Acad. Sci., 87, 782784 (1990)], which implies that inhibition of monokine formation or activity contributes to limiting the development of HIV, as detailed above in relation to T cells.

The tumor necrosis factor also plays a role in other viral infections. Viruses that cause such infections include, but are not limited to, cytomegalovirus (CMV), influenza virus, adenovirus, and herpes virus.

Tumor necrosis factor is also involved in yeast and other fungal infections. Candida albicans has previously been shown to induce TNF formation in human monocytes and natural killer cells in vitro (see Riipi et al., 1990, 58 (9), 2750-2754;

Jafari et al., 1991, Journal of Infectious Diseases, 164, 389-395;

Wasan et al., 1991, Antimicrobial Agents and Chemotherapy, 35 (10), 204-62048; and Luké et al., Journal of Infectious Diseases,

162: 211-214 (1990).

A further possibility of controlling the adverse effects of tumor necrosis factor is the use of compounds that inhibit tumor necrosis factor in mammals in need thereof. There is a significant need for compounds that can be used to treat diseases mediated by tumor necrosis factor that are exacerbated or caused by overexpression of tumor necrosis factor.

One object of the present invention is the compounds of formula (I)

(I) - in which

R _T is - (CR4R5) _n C (0) 0 (CR4R5) _m R, - (CR4R5) _n 0 _{(CR4 R5) m R6,} - (CR4R5) _n C (0) _NR4 (CR4R5) _m R ₆ or - (CR ₄ R ₅ ) _r R _{6 in} which the alkyl groups are optionally substituted with one or more fluorine atoms;

is 0, 1 or 2;

is 0, 1, 2, 3 or 4;

r is 0, 1, 2, 3, 4, 5 or 6;

R ₄ and R ₅ are independently hydrogen or

C 1-2 alkyl;

Rg is hydrogen, methyl, hydroxy, optionally substituted aryl with halogen, aryloxy (C1-C3 alkyl) optionally substituted with halogen, indanyl, indenyl, polycycloalkyl (C7-C11), tetrahydrofuryl, furyl-. , tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6cycloalkyl and C4-6cycloalkyl having one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic groups are optionally substituted with one to three methyl groups; / or monosubstituted with ethyl or hydroxy;

with the proviso that

a) when Rg is hydroxy then m is 2;

obsession

b) when Rg is hydroxy then m is 2, 3,

4, 5 or 6; obsession

c) when Rg is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuryl or 2-tetrahydrothienyl, m is 1 or 2; obsession

d) when Rg is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuryl or 2-tetrahydrothienyl, then r is 1, 2, 3, 4, 5 or 6; obsession

e) when n is 1 and m is 0, in the group - (CR 4 R 5) _n O (CR ₄ R 5) _m R 8, R 8 is other than hydrogen;

X is YR 2, fluoro, NR ₄ R _5, or Formylamino-; group;

Y is O or S (O) _m i;

m 'is 0, 1 or 2;

X ₂ is O or NR ₈ ;

X ₃ is hydrogen or the same as X;

R ₂ is methyl or ethyl optionally substituted with one or more fluorine atoms;

s is 0, 1, 2, 3 or 4;

R ₃ is COOR ₁₄ , C (O) NR ₄ R ₁₄ or R ₇ ;

W is (C 2 -C 6) -alkyl, (C 2 -C 6) -alkenyl or (C 2 -C 6) -alkynyl; and

Z is O, NR ₇ , NCR ₄ R 5 (C 2 -C 6 alkenyl),

NOR ₃₄ NOR15, NOCR ₄ R 5 (2-6C) alkenyl, NNR ₄ R _14, NNR ₄ Ri5 group of the formula NCN, NNR _g C (0) NR ₈ R _14, NNRgC (S) NR ₈ R A group of formula ₁₄ ;

obsession

Z = 2- (1,3-dithianane), 2- (1,3-dithiolane), dimethylthiocetal, diethylthiocetal, 2- (1,3-dioxolane), 2- (1, 3-oxathiolane), dimethyl ketal or diethyl ketal;

R ₇ is - (CR ₄ R 5) _q R ₃₂ or C 1-6 alkyl, wherein - (CR ₄ R 5) _q R ₁₂ or C 1-6 alkyl is optionally mono- or polysubstituted Methyl or ethyl substituted with 1 to 3 fluorine atoms, fluorine, bromine, · ·

- 10 a chlorine atom, a nitro group, ^{- r} ii NRio <C (O) R, -CO ₂ R,

-0 _(CH2) 2-4OR8, -O (CH _{2) q} R c, cyano, -0 _(CH2) q C (0) _{R9, -NR10} C (O) OR _9,

-C (NCN) NR ₁₀ R _n ,

-C (0) NR ₁₀ R _n, -0 (CH _{2) q} C (0) NR ₁₀ R _n,

-NRiqC (0) NR ₁₀ R _n, -NR ₁₀ C (O) _R13,

-C (NCN) SR ₉ ,

-NR ₁₀ C (NCN) NR ₁₀ R ₁₁ , -NR ₁₀ S (O) ₂ R ₉ ,

-NR ₁₀ C (O) C (0) NR _n R _10, -NR ₁₀ C (0) C (0) _R10

-NR ₁₀ C (O) R _n ,

-C (NR ₁₀ ) NR ₁₀ R ₁₁ , -NR ₁₀ C (NCN) SR ₉ , -S (O) _m R ₉ , or R ₁₃ ;

q is 0, 1 or 2;

R ₁₂ is the same as R ₁₃ or C 3-7 cycloalkyl, 2-, 3- or 4-pyridyl, pyrimidyl, pyrazolyl, 1- or

2-imidazolyl, pyrrolyl, piperazinyl, piperidyl, morpholinyl, furyl, 2- or

3-thienyl, quinolyl, naphthyl or phenyl;

Rg is selected from hydrogen or R _9, respectively;

R ₉ is C 1-4 alkyl optionally substituted with 1 to 3 fluorine atoms;

_R10 is ORg or _R31 radical;

R ₃₁ is C 1-4 alkyl optionally substituted with 1 to 3 fluoro atoms; or when R ₁₀ and R _{1: l} are NR ₁₀ R ₁₃ , together with the nitrogen atom, a 5- to 7-membered group; A ring containing only carbon atoms or a 5-7 membered carbon atom and at least one of oxygen, nitrogen and / or may form a cyclic group containing a heteroatom selected from sulfur;

R ₁₃ is an optionally substituted heteroaryl group selected from:

oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl and thiadiazolyl; and wherein R ₁₃ R ₁₂ ~ n or R ₁₃ substituted on the rings is connected through a carbon atom and each second _R13 ring is optionally substituted by one or two C1-2 alkyl group include a methyl group optionally

Substituted with 1 to 3 fluorine atoms;

R ₁₄ is hydrogen or the same as R 7; or when R 8 and R ₁₄ are NR _g R ₁₄ , together with the nitrogen atom, a 5-7 membered ring containing only carbon atoms or a 5-7 membered carbon atom and at least one of oxygen, nitrogen and / or may form a cyclic group containing a heteroatom selected from sulfur;

R 15 is C (O) R ₁₄ , C (O) NR ₄ R ₁₄ , S (O) ₂ R 6; or · »· J ··» · · · · · · · ·

S (O) 2 NR4R14; with the proviso that (f) R _{7 is} not C 1-4 alkyl optionally substituted with 1 to 3 fluorine atoms - or a pharmaceutically acceptable salt thereof.

Another class of compounds of the invention are compounds of formula II

- of which

Rl is - (CR4R5) _n C (0) 0 (CR4R5) _m R, - (CR4R5) _n 0 (CR4R5) _m R, - (CR4R5) _n C (0) _NR4 (CR4R5) _{m R6,} or - ( CR ₄ R ₅ ) _r R ₆ wherein the alkyl groups are optionally substituted with one or more fluorine atoms;

m is 0, 1 or 2; n is 0, 1, 2, 3 or 4;

r is 0, 1, 2, 3, 4, 5 or 6;

_R4 and R5 are independently hydrogen or

C 1-2 alkyl;

R ₆ is hydrogen, methyl, hydroxy, aryl optionally substituted by halogen, aryloxy (C 1-3 alkyl) optionally substituted by halogen, indanyl, indenyl.

1 • ··· * * n ··· ♦ ·· «··« · «·« * · * · · · 11 t

- 13 powders, C7-C11 polycycloalkyl, tetrahydrofuryl, furyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-C6 cycloalkyl and C4-C6 cycloalkyl containing one or two unsaturated bonds wherein the cycloalkyl or heterocyclic groups are optionally substituted one to three times with methyl and / or mono- or ethyl or hydroxy;

with the proviso that

a) when Rg is hydroxy then m is 2;

obsession

b) when Rg is hydroxy then m is 2, 3,

4, 5 or 6; obsession

c) when Rg is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuryl or 2-tetrahydrothienyl, m is 1 or 2; obsession

d) when Rg is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuryl or 2-tetrahydrothienyl, then r is 1, 2, 3, 4, 5 or 6; obsession

e) If n is 1 and m is 0 then a

- in the group (CR4R5) _n O (CR4R5) _m Rg, Rg is other than hydrogen;

X is YR ₂ , fluoro, NR 4 R 5, or formylamino;

Y is O or S (O) _m . a group of the general formula;

• · «· ·» * ·

- 14 m 'is 0, 1 or 2;

X ₂ is oxygen or NRg;

X ₃ is hydrogen or the same as X;

R ₂ is methyl or ethyl optionally substituted with one or more fluorine atoms; s is 0, 1, 2, 3 or 4;

R ₃ is COOR ₁₄ , C (O) NR ₄ R ₁₄ or R 7;

W is (C 2 -C 6) -alkyl, (C 2 -C 6) -alkenyl or (C 2 -C 6) -alkynyl; and

Z 'is C (Y') R ₁₄ , C (O) OR ₁₄ , C (Y ') NR ₁₀ R ₁₄ , C (NR ₁₀ ) NR ₁₀ R ₁₄ , cyano, C (NOR ₈ ) R ₁₄ , C (0) NRgNRgC (0) _Rg, C (0) _{NR8 NR10 R14,} C _{(NOR14) R8,} C (NR) NR ₁₀ R _14, C _(NR14) NRgRg, C (NCN ) NR ₁₀ R ₁₄ , C (NCN) SR ₉ , 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-4 or -5-yl, 1,2,4-triazole; 3- or -5-yl, 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,4-oxadiazol-3 or -5-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolidinyl, 2- , 4- or 5-thiazolidinyl or 2-, 4- or 5-imidazolidinyl, wherein all heterocyclic groups are optionally substituted with one or more groups R ₁₄ ;

Y 'is oxygen or sulfur;

R ₇ is - (CR ₄ R ₅₎ q R ₁₂ or a group C 1-6 alkyl wherein the R ₁₂ report • • · · · · · · · · · · · • • ·· ······ Phenyl or C 1 -C 6 alkyl optionally mono- or polysubstituted with 1 to 3 fluorine atoms or methyl substituted with ethyl, fluorine, bromine, chlorine, nitro, -Si (R ₄ ) ₃ , "NR ^^ q R ^, -C (O) R _g ,

_-CO2 Ri -0 _{(CH2) 2} -4ORg, -0R _g group of the formula CN, C (0) NR ₁₀ R _{1 1,} -0C (0) _NR10 Rn, -OC (O) R _g ,

-NR ₁₀ C (O) _NR10 Rn, -NR ₁₀ C (0) R _n, -NR ₁₀ C (0) 0R _9,

-NR ₁₀ C (O) _R13, -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 ₁₁ ,

-NR ₁₀ S (O) ₂ R ₉ z -S (O) _m , R ₉ , -NR ₁₀ C (O) C (O) NR ₁₀ R 11,

-NR ₁₀ C (O) C (O) R ₁₀ , thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl or tetrazolyl;

q is 0, 1 or 2;

R ₁₂ is the same as R ₁₃ or C 3-7 cycloalkyl, 2-, 3- or 4-pyridyl, pyrimidinyl, pyrazolyl, 1- or 2-imidazolyl, thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidyl, , morpholinyl, furyl, 2- or 3-thienyl, 4 or 5-thiazolyl, quinolyl, naphthyl or phenyl;

R _g is hydrogen or the same as R ₉ ;

R ₉ is C 1-4 alkyl optionally substituted with 1 to 3 fluorine atoms;

• · · · · · · · · · · · · · · · · · · · · · · ···

- 16 R ₁₀ is ORg or R _1T ;

R _X1 is optionally substituted with 1-3 fluoro, C1-4 alkyl; or when R ₁₀ and R _n are NR ₁₀ Rh, together with the nitrogen atom a 5-7 membered ring containing only carbon atoms or a 5-7 membered carbon atom and at least one of oxygen, nitrogen and / or may form a cyclic group containing a heteroatom selected from sulfur;

R ₁₃ is an optionally substituted heteroaryl group selected from:

oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl and thiadiazolyl; and wherein R ₁₃ R 2 _X ⁿ or R ₁₃ substituted on the rings is connected through a carbon atom and each second _R13 ring is optionally substituted by one or two C1-2 alkyl group, wherein optionally a methyl group case

Substituted with 1 to 3 fluorine atoms;

R ₁₄ is hydrogen or the same as R ₇ ; or when R 9 and R ₁₄ are NR ₉ R ₁₄ , together with the nitrogen atom, a 5- to 7-membered ring containing only carbon atoms or a 5-membered ring; It may form a 7-membered ring containing atoms and at least one heteroatom selected from oxygen, nitrogen and / or sulfur;

with the proviso that (f) R _{7 is} not C 1-4 alkyl optionally substituted with 1 to 3 fluorine atoms - or a pharmaceutically acceptable salt thereof.

The invention also encompasses pharmaceutical compositions comprising a compound of formula (I) or (II) and a pharmaceutically acceptable carrier or diluent.

The invention further encompasses a method of modifying or inhibiting the enzymatic activity (or catalytic activity) of PDE IV in a mammal, including a human, comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) or (II).

The invention also provides a method of treating an allergic or inflammatory disease comprising administering to a mammal in need thereof, including a human, an effective amount of a compound of formula (I) or (II).

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

The invention further provides a method of inhibiting the formation of tumor necrosis factor in a mammal, including a human, comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) or (II) that inhibits tumor necrosis factor. The method can also be used for the prophylactic treatment or prevention of certain TNF-mediated diseases.

The present invention also provides a method of treating a human infected with the Human Immunodeficiency Virus (HIV) by administering to a patient an effective amount of a compound of formula (I) or (II) which inhibits tumor necrosis factor.

The compounds of formulas I and II may also be used in the treatment of other viral infections in which the viruses are sensitive to regulation by TNF or in which the viruses induce TNF formation in vivo.

In addition, the compounds of formulas I and II may be used in the treatment of yeast and other fungal infections in which yeast and other fungi are sensitive to regulation by TNF or in which yeast and other fungi induce TNF formation in vivo.

The invention thus provides a method for modifying or inhibiting the enzymatic activity (or catalytic activity) of PDE IV and inhibiting the formation of tumor necrosis factor in a mammal in need thereof, comprising administering to the mammal a compound of formula (I) or (II). effective amount.

Phosphodiesterase IV inhibitors are well-suited for use alone. · · ···························

- 19 types of allergic and inflammatory diseases such as asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, spring conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septicemia, disease, myocardium and brain reperfusion injury, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome. In addition, PDE IV inhibitors may also be useful in the treatment of diabetes insipidus and central nervous system disorders such as depression and mixed infarct dementia.

Viruses that can be treated by the method of the invention include those that produce tumor necrosis factor as a result of infection or those that are susceptible to inhibition by TNF inhibitors of Formulas I and II, directly or indirectly, such as replication by said inhibition. decrease. Such viruses include, but are not limited to, HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus, and the Herpes family of viruses, including Herpes zoster and Herpes simplex.

The present invention also provides a method of treating a human infected with the Human Immunodeficiency Virus (HIV) comprising administering to a patient an effective amount of a compound of formula (I) or (II) which inhibits tumor necrosis factor.

The compounds of the present invention may also be used in veterinary treatment of animals in need of inhibition of tumor necrosis factor formation. Therapeutic or prophylactic treatment in animals of diseases mediated by tumor necrosis factor include those mentioned above, among which are viral infections. Examples of viruses that cause such infections include, but are not limited to, Feline (cat) Immunodeficiency Virus (FIV) and other retroviruses such as equine anemia virus, goat arthritis virus, visna virus, maedi virus and other lentivirus.

In addition, the compounds of formulas I and II may be used in the treatment of yeast and other fungal infections in which yeast and other fungi are sensitive to regulation by TNF or in which yeast and other fungi induce TNF formation in vivo. Of particular importance to the process of the invention. fungal meningitis. The compounds of formula (I) and (II) may also be administered in combination with other active ingredients, for example, in case of systemic yeast or fungal infections. Other agents for treating fungal infections include, but are not limited to, the following: compounds of the so-called polymyxin class, such as Polymycyn B; imidazole class compounds such as clotrimazole, econazole, miconazole and ketoconazole; triazole class compounds such as fluconazole and itranazole; and compounds belonging to the class of so-called Amphotericins, in particular Amphotericin B and liposomal Amphotericin B.

• · · ·

The compounds of formula (I) and (II) may also be used to inhibit and / or reduce the toxicity of antifungal, antibacterial and antiviral agents, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula (I) or (II). The compounds of formula I and II are preferably used to inhibit and / or reduce the toxicity of compounds of the class Amphotericin, in particular Amphotericin B.

As used herein, "C 1-3 alkyl, C 1-4 alkyl, C 1-6 alkyl, or alkyl is straight or branched chain and, unless otherwise specified, is intended to include C 1-10 alkyl such as others. in addition to methyl, ethyl, η-propyl, isopropyl, η-butyl, sec-butyl, isobutyl, tert-butyl and the like.

The term alkenyl is straight or branched chain and, unless otherwise specified, is intended to include C2-C6 alkenyl groups such as, for example, vinyl, 1-propenyl, allyl and 2-butenyl.

The term cycloalkyl or cycloalkylalkyl refers to C3-C7 groups such as, for example, cyclopropyl, cyclopropylmethyl, cyclopentyl or cyclohexyl.

The term aryl or aralkyl, unless otherwise indicated, means a C 6 -C 10 group derived from an aromatic ring or ring system, such as, for example, phenyl, benzyl, phenethyl and naphthyl. The aryl group is preferably a monocyclic group such as phenyl. The alkyl chain in these cases denotes straight-chain or branched C 1 -C 4 groups.

The term heteroaryl refers to aromatic groups containing one or more heteroatoms.

The term halogen includes all halogens, i.e., chlorine, fluorine, bromine and iodine.

The term inhibition of IL-1 production, inhibition of IL-1 production, or inhibition of TNF formation or inhibition of TNF production refers to:

(a) reducing excessive levels of in vivo IL-1 or TNF to normal levels or below normal levels in humans by inhibiting in vivo release of IL-1 by cells, including monocytes and macrophages;

b) reducing excessive levels of in vivo IL-1 or TNF to normal levels or below normal levels in humans by regulation at the translational or transcriptional level;

c) regulation by post-translational inhibition of the direct synthesis of IL-1 or TNF.

The term TNF-mediated disease encompasses all diseases in which the tumor plays a role in necrosis factor, such as the formation of TNF itself, or the cytokine, including IL-1 or IL-6.

TNF-induced release. TNF-mediated be- 23 ······································································································ · Thus, we also consider diseases in which IL-1 is a major component and where the production or effect of IL-1 is enhanced in response to TNF. TNF-β (also known as lymphotoxin) has a close structural homology to TNF-α (also known as cachectin). Because they each induce similar biological responses and bind to the same cell receptor, and the compounds of the invention inhibit both TNF and TNF-β, TNF and TNF-β are collectively referred to as TNF or tumor necrosis factor, unless otherwise indicated in the particular case. Preferably, TNF-α is inhibited using the present invention.

The term cytokine includes any selected (secreted) polypeptide that affects cell function or any molecule that modifies cellular interactions in immune, inflammatory, or haemopoietic responses. Cytokines include, but are not limited to, monokines and lymphokines, regardless of the type of cells that produce them. The cytokine inhibited by the present invention for use in the treatment of HIV-infected subjects should be one that plays a role in (a) initiating and / or maintaining T-cell activation and / or expression and / or replication of the activated HIV-mediated HVV gene. ; and / or (b) problems associated with any cytokine-mediated disease, such as cachexia or muscle degeneration. Preferably, the cytokine is TNF-α.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Each of the compounds of Formulas I and II can be used to inhibit TNF production, preferably by macrophages, monocytes, or macrophages and monocytes, in mammals, including humans, in need thereof. Each of the compounds of formulas I and II can be used to inhibit or regulate the enzymatic or catalytic activity of PDE IV and to treat diseases mediated in this way.

Preferred compounds are as follows.

When R1 is alkyl substituted by one or more halogens in the compounds of formulas I and II, the halogen is preferably fluorine or chlorine, more preferably Rx is substituted by one or more fluorine atoms

C 1-4 alkyl. The halogen substituted alkyl group is preferably C 1-2 and most preferred is trifluoromethyl, fluoromethyl, difluoromethyl, 1,1,2,2-tetrafluoroethyl, 2,2,2-. trifluoroethyl; and 2,2-difluoroethyl. Preferred R 1 substituents for compounds of Formulas I and II include, but are not limited to, optionally hydroxy-substituted cyclopropylmethyl, (C 5 -C 6 cycloalkyl) methyl, C 4 -C 6 cycloalkyl. , C 7 -C 11 polycycloalkyl, 3 or 4-cyclopentenyl, phenyl, 3-tetrahydrofuryl, benzyl or C 1-2 alkyl optionally substituted with one or more fluorine atoms, - (CH ₂ ) 1-3 O (CH ₂ ) q-2 ^ch. 3 '- _(CH2) 1-3C (0) 0 _{(CH2) 2} O- and CH ₃ - (CH _{2) 2} _ ₄ OH radical.

• ·· · · * · «» »♦ ·» · · · · · · · · · · · · · · · · · · ·

When R _{x is} a substituent selected from the group consisting of CR ₄ R ₅ , R ₄ and R 5 are each independently hydrogen or alkyl. In the case of (CR ₄ R ₅ ) _n or (CR ₄ R ₅ ) _m , it is also possible to branch off the individual methylene group; the repetitive methylene groups are independent, for example, when n is 2 in the (CR 4 R 5) _n group, the formula may also be a -CH ₂ CH (CH ₃ ) - group. The hydrogen atoms of the repeating methylene group or of the branched hydrocarbon group may be optionally independently substituted with a fluorine atom, for example according to the preferred substitutions R1 described above.

When R 1 is C 7 -C 11 polycycloalkyl, examples of such substituents include, but are not limited to, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, tricyclo [5.2.1.0 ² ' ⁶ ] decyl, etc. (other such groups are described, for example, in International Patent Application Publication No. WO 87/06576).

Preferably, Z is O, NCN, NR ₇ , NOR ₁₄ , NO ₁₅ , N ₄ R ₁₄ , N ₄ R ₁₅ , C (CN) ₂ , C (-CN) OC (O) R ₉ , X (-CN). ) OR ₉ , CR ₁₄ C (O) OR ₉ , CR ₉ C (O) NR 43 R 44, 2- (1,3-dithiane), dimethylthiocetal, 2, (1,3-dioxolane) or dimethyl ketal . More preferably, Z is O, _NR7, NOR44, NOR ₃ 5 radical and 2- (1,3-dioxolane).

In the compounds of formulas I and II, preferably X is YR ₂ , in which Y is ·· «· · * ο *

- 26 oxygen atoms. In the compounds of formula (I) and (II) ', X ₂ is preferably oxygen. In the compounds of the formulas I and II, X ₃ is preferably hydrogen. Where applicable, R ₂ is preferably C 1-2 alkyl optionally substituted with one or more halogen atoms. Halogen is preferably fluorine or chlorine, more preferably fluorine. More preferably, R ₂ is methyl or fluoro-substituted alkyl, especially C 1 -C 2 alkyl, such as trifluoromethyl, difluoromethyl or 2,2-difluoroethyl. Most preferred are difluoromethyl and methyl.

W is preferably C 3 -C 5 alkyl, alkenyl or alkynyl. Alkenyl or alkynyl groups may have one or two double or triple bonds in the group.

Z 'is preferably COOR ₁₄ . Preferably _R7 is R13 or optionally substituted - _{(CH2) 0} _ ₂ (2-, 3- or 4-pyridyl);

- _(CH2) I_ ₂ (2-imidazolyl), - _{(CH2) 2} (4-morpholinyl), - _{(CH2) 2} (4-piperazinyl), - _(CH2) χ_ _2- (2-thienyl), - (CH ₂ ) _{2 -} (4-thiazolyl), optionally substituted pyrimidinyl, or optionally substituted phenyl, benzyl or phenethyl.

When, in the group NR ₁₀ R h, R ₁₀ and R _{T 1} together with the nitrogen atom to which they are attached form a 5-7 membered ring containing only carbon atoms or a 5-7 membered carbon atom and at least one of oxygen, nitrogen and / obsession • · · · • · ·· ·· · ··· • · · ······ · · • · ·· · · ···

- form a ring containing 27 heteroatoms selected from a sulfur atom, preferred examples of such groups include, - among others - the following: 1-imidazolyl, 2- (Rg) -1-imidazolyl, 3- _(Rg) -1-pyrazolyl - Ι-triazolyl, 2-triazolyl, 5- (Rg) -1-triazolyl, 5- (Rg) -2-triazolyl, 5- _(Rg) -l-tetrazolyl, 5- (R ) -2-tetrazolyl, Ι-tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, 4- (Rg) -1-piperazinyl or pyrrolyl.

When R ₈ and R ₄ in the group NR ₈ R ₁₄ together with the nitrogen atom to which they are attached form a 5-7 membered ring containing only carbon atoms or a 5-7 membered carbon atom and at least one of oxygen, nitrogen and / or heteroatoms selected from the group consisting of Ι-imidazolyl, 1-pyrazolyl, Ι-triazolyl, 2-triazolyl, Ι-tetrazolyl, and the like. , 2-tetrazolyl, morpholinyl, piperazinyl or pyrrolyl. Suitable ring groups may carry additional R ₇ substituents, where possible, on a suitable nitrogen or carbon atom, as described for compounds of formula (I) and (II). Such substituted carbon atom groups include, but are - among others - the following: 2- _(R7) -1-imidazolyl, 4- _(R7) -1-imidazolyl, 5- _(R7) -1-imidazolyl , 3- (R ₇ ) -1-pyrazolyl, 4- (R ₇ ) -1-pyrazolyl, 5- (R ₇ ) -1-pyrazolyl, 4- (R ₇ ) -2-triazolyl, 5- (R ₇ ) -2-triazolyl, 4- (R ₇ ) -1-triazolyl, 5- (R ₇ ) -Ι-triazolyl, 5- (R ₇ ) -1-tetrazolyl and 5- _(R7) -2-tetrazolyl. Such nitro · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · terms · · · · ·

Examples of groups substituted with R _{7 on} 28 gene atoms include, but are not limited to, 1- (R ₇ ) -2-tetrazolyl, 2- (R ₇ ) -1-tetrazolyl and 4- (R ₇ ) -1 piperazinyl. Where possible, the ring group may be substituted by one or more R ₇ groups.

Preferred examples of the groups of formula NR ₈ R ₃₄ containing a heterocyclic group include: 5- (R ₁₄ ) -1-tetrazolyl, 2- (R ₁₄ ) -1-imidazolyl, 5- (R ₁₄ ) -2 tetrazolyl, 4- (R ₁₄ ) -1-piperazinyl and 4- (R ₁₅ ) -1-piperazinyl.

Preferred examples of groups in the meaning of R ₁₃ include, but are not limited to:

2-, 4- or 5-imidazolyl; 3-, 4- or 5-pyrazolyl; 1,2,3-triazol-4- or -5-yl; 1,2,4-triazol-3 or -5-yl; 5-tetrazolyl; 2-, 4- or 5-oxazolyl; 3-, 4- or 5-isoxazolyl; 1,2,4-oxadiazol-3 or -5-yl; 1,3,4-oxadiazol-2-yl; 1,3,4-thiadiazol-2-yl; 2-, 4- or 5-thiazolyl; 2-, 3- or 5-oxazolidinyl; 2-, 4- or 5-thiazolidinyl; and 2-, 4- or 5-imidazolidinyl.

When R _{7 is} optionally substituted with a heterocyclic group such as imidazolyl, pyrazolyl, pyrimidinyl, triazolyl, tetrazolyl, or thiazolyl, the heterocyclic group itself may be optionally substituted with R _{8 on} a suitable nitrogen or carbon atom. For example the following groups: 1- _(R8) -2-imidazolyl; 1- _(R8) -4-imidazolyl group; 1- (R _g ) -5-imidazolyl;

• · ·

1- (Rg) -3-pyrazolyl group; 1- (R8) -4-pyrazolyl; 1- _(R8) - -5-pyrazolyl group; 1- _(R8) -4-triazolyl; or 1- (R8) -5-triazolyl. Where possible, the ring moiety may be substituted by one or more Rg groups.

W is preferably C 3 -C 5 alkyl, alkenyl or alkynyl. Alkenyl or alkynyl groups may have one or two double or triple bonds in the group. Most preferably, W is ethynyl or 1,3-butadynyl.

Preferred compounds of formula I and II are those in which

R 1 is cyclopropylmethyl, (C 5 -C 6 cycloalkyl) methyl, optionally substituted with hydroxy,

C4-6 cycloalkyl, 3- or 4-cyclopentenyl group, 3-tetrahydrofuryl, optionally substituted by one or more fluorine atoms, benzyl or C1-2 alkyl, and ~ _{(CH2) 2} _ ₄ OH radical;

R ₂ is methyl or fluoro-substituted alkyl;

R ₃ is a group R ₇ wherein

R ₇ is optionally substituted aryl or heteroaryl;

X is YR ₂ ; and

Z is O or NR ₇ .

Most preferred are the compounds in which

R 1 is cyclopropylmethyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or difluoromethyl;

- X represents YR ₂ ;

Y is O;

X ₂ is O;

X ₃ is hydrogen;

R ₂ is difluoromethyl or methyl;

W is ethynyl or 1,3-butadynyl;

R ₃ is optionally substituted pyrimidinyl;

and

Z is O or NR ₇ .

The invention also encompasses pharmaceutically acceptable salts of the compounds of the invention. Pharmaceutically acceptable salts include those suitable for pharmaceutical use. This means that the salts retain the biological activity of the parent compound and do not have any undesirable or deleterious effect when used or used in the treatment of diseases.

Pharmaceutically acceptable salts are prepared by standard methods. For example, the parent compound is dissolved in a suitable solvent and then reacted with an excess of an organic or inorganic acid to form an acid addition salt of a base, or, if the molecule contains, for example, a carboxyl group, with an excess of an organic or inorganic base.

The pharmaceutical compositions of the present invention comprise a pharmaceutically acceptable carrier or diluent and a defined amount of a compound of formula (I) or (II). The invention relates to pharmaceutical compositions.

The compound of claim 31 is present in an amount that elicits an adequate physiological response or, if less than the amount of the active ingredient is contained in the pharmaceutical composition, the user should employ two or more units of the composition to achieve the desired effect of the treatment. The compositions of the invention may be prepared in solid, liquid or gaseous form. These three forms may also be converted into each other prior to administration, for example, when a solid is aerosolized, or when a liquid is injected as a spray or aerosol into the body to be treated.

The nature of the composition or pharmaceutically acceptable carrier or diluent will, of course, be determined by the route of administration chosen, for example parenteral, topical, oral or inhalation administration.

For topical application, the pharmaceutical composition may be in the form of a cream, ointment, diluted ointment, lotion, paste, aerosol or droplet for application to the skin, eyes, ears or nose.

The pharmaceutical composition for parenteral administration may be in the form of a sterile injectable liquid or an aqueous or non-aqueous suspension.

The pharmaceutical composition for oral administration may be in the form of tablets, capsules, powders, pellets, wafers, lozenges, syrups, liquids or emulsions.

When used in the form of a solution or suspension, examples of suitable pharmaceutically acceptable carriers or diluents include, but are not limited to, the following: include: for water systems, water; for non-aqueous systems, ethanol, glycerol, propylene glycol, corn oil, cottonseed oil, hazelnut oil, sesame oil, liquid paraffin and mixtures thereof; for solid systems, lactose, kaolin and mannitol; and, in the case of aerosol systems, difluorodichloromethane, chlorotrifluoromethane and compressed carbon dioxide. In addition to pharmaceutically acceptable carriers and diluents, the pharmaceutical compositions of the present invention include ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers, and the like. provided that the added components do not diminish the therapeutic effect of the pharmaceutical compositions of the invention.

The pharmaceutical compositions of the present invention are prepared using conventional methods of pharmaceutical chemistry according to the nature of the desired end product.

The amounts of the carriers or diluents in the compositions will vary, but will preferably be in the form of a major part of the suspension or solution of the active ingredient. When the diluent is a solid, the diluent may be present in an amount of less than, greater than, or equal to the amount of solid active ingredient.

Typically, the compound of formula (I) is administered to the subject to be treated in a composition comprising the active ingredient in a non-toxic amount sufficient to suppress symptoms of a disease in which leukotrienes play a role. Formulations for topical administration contain from about 0.01% to about 5.0% by weight of the active ingredient, and are formulated in an amount sufficient to provide a preventive or curative effect. into the damaged area. In the case of oral or parenteral administration, the active ingredient is present in doses of from 50 mg to 1000 mg. For example, the composition may be administered 1 to 5 times daily, resulting in a total daily dose of from about 50 mg to about 5000 mg.

One of ordinary skill in the art will recognize that certain compounds of Formulas I and II may exist in racemic and optically active forms. Some of these may even be in the form of different diastereomers with different physical and biological properties. All compounds of this type are within the scope of the invention.

Compounds of formula (I) wherein Z is oxygen or compounds of formula (II) may exist in tautomeric forms, such as enol. This can be illustrated by the fact that in the case of the keto compound the = 0 substituent is exocyclic with respect to the cyclohexane ring.

as opposed to the enol form, in which an endocyclic -C (-OH) = C (-R) - moiety forms part of a molecule which has an unsaturated bond at the 1,2-position. · · · · · · · · · · · · · · · · · · · · ·

forms (^ 3) [a

The exocyclic form, such as the glaze, i.e. a 1-cyclohexenyl group of formula (II), is R 1]. of the formula (II) in formula (R) substituted compounds of formula (I) and (II).

The following examples serve to illustrate further details of the invention described above. It is to be understood that the examples are illustrative only and are not intended to limit the scope of the invention. The scope and scope of the invention are defined by the appended claims.

No unacceptable toxic effects are expected when the compounds of the present invention are administered.

Production procedures

(2) (1)

a) Pd (PPh ₃ ) ₄ , PPh ₃ , Cul, C 5 H 5 I, piperidine;

b) Pyridinium p-toluenesulfonate, (H ₃ C) ₂ CO / H ₂ O.

·································································································· ···

For example, the compounds of formula (I) may be prepared according to the procedure of Brandsma et al., Syn. Comm., 20, 1889 (1990)] may conveniently be prepared by reacting a terminal triple bond compound, such as an acetylene derivative of formula (1) in Scheme 1, in a suitable solvent such as an amine with a suitable catalyst such as copper. ) halide and a divalent or zero palladium compound, such as triphenylphosphine palladium, is reacted with an aryl halide, e.g. Further derivatives corresponding to the compound of formula (1) in Scheme 1 are described in Scheme 08 / 130,215. U.S. Pat.

Scheme 2

(1) (2) a) Pd (PPh ₃ ) ₄ , PPh ₃ , Cul, R ₃ X, piperidine.

Alternatively, the compounds of Formula I may be prepared according to the procedure of Brandsma et al., Syn. Comm., 20, 1889 (1990)] may conveniently be prepared by reacting a terminal triple bond compound such as an acetylene derivative of formula (1) in Scheme 2 in a suitable solvent such as an amine with a suitable catalyst such as copper (I). ) halide and a divalent or zero palladium compound, such as triphenylphosphine palladium, in the presence of a corresponding halide of formula R ₃ X wherein R ₃ is as defined above for formula (I) or is convertible to R ₃ , to give compound (2) in Scheme 2. The compounds of formula (I) thus prepared can be converted to other compounds of formula (I) by standard conversion of the functional groups on the R ₃ substituent. Further derivatives corresponding to the compound of formula (1) in Scheme 2 are described in Scheme 08 / 130,215. U.S. Pat.

Scheme 3

(2)

(1)

a) PdCl ₂ , CuCl ₂ , NaO ₂ CCH ₃ , CO, CH ₃ OH.

- 37 • · '· · * V - «ί · (» «1 • * ·» »• *> *« · ··· • · * * «·« · * · J · * »· · ··· *

Alternatively, for example, according to the Tsuji process (Tsuji et al., Tetrahedron Letters, 21, 849 (1980)), a compound having a terminal triple bond, such as an acetylene derivative of formula (1) in Scheme 2, may be used in alcohol. in methanol, for example, in the presence of a suitable base as an acid scavenger such as sodium acetate, oxidative carbonylation using a suitable metal salt such as a copper salt and a catalytic amount of palladium salt and then hydrolyzing the methyl ester under standard conditions. second Scheme II (Compound 2). The compounds of formula (I) thus prepared can be converted to other compounds of formula (I) by standard conversion of the ester group.

Scheme 4

Compounds of formula (II) may be prepared according to Scheme 4, Schemes 1, 2, and 3.

- 38 analogous methods. Depending on the nature of the Z 'groups of the compounds of formula II, the = O group must be protected during the coupling reaction, for example, the = 0 group is pre-converted to the corresponding dimethyl ketal or the corresponding 2- (1,3-dioxolane) - and then, after deprotection, proceed as described in 08 / 130,215. U.S. Pat. Similarly, other Z 'groups may require preliminary protection during the coupling steps, and then deprotected to provide the corresponding compounds of formula II. Suitable protecting groups are well known to those skilled in the art (see, e.g., Greene, T. and Wuts, P.G.M., Protecting Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons, New York, 1991).

Compounds of formula (I), not detailed above, may be prepared by methods analogous to those of the preceding teachings or to the preparation examples below.

The compounds of formulas I and II may exist in different diastereomers with different physical and biological properties. Such isomers may be separated by standard chromatographic techniques.

• · · · ·

MANUFACTURING EXAMPLES

Example 1

Preparation of 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [(methoxycarbonyl) ethynyl] -1-cyclohexanone la) 3- [3- (Cyclopentyloxy) -4- methoxy-phenyl] -3 - [(trimethylsilyl) ethynyl] -1-cyclohexanone

To a solution of (trimethylsilyl) acetylene (1.97 mL, 13.96 mmol) in anhydrous diethyl ether (30 mL) was added dropwise 5.7 mL (13.96 mmol) under argon, dropwise over 5 minutes at -45 ° C. Of 45 N n-butyllithium in hexane.

The reaction mixture was stirred for 1.5 hours and then added via tube to a solution of 13.96 mL (13.96 mmol) of 1.0 M dimethylaluminum chloride. The reaction mixture was stirred at room temperature for 3.5 hours and then filtered through celite under an argon atmosphere. In a separate flask, nickel acetylacetonate (360 mg, 1.4 mmol) was dissolved in dry diethyl ether (25 mL) under argon, and diisobutylaluminum hydride (1.4 mL, 1.4 mmol) was added dropwise with stirring. After 10 minutes, the mixture was cooled to -10 ° C and 2.0 g (6.98 mmol) of 3- [3- (cyclopentyloxy) -4-methoxyphenyl] was added dropwise over 15 minutes to the cooled mixture. A solution of -2-cyclohexen-1-one (U.S. Pat. No. 5,362,915) in 70 ml of anhydrous diethyl ether. The reaction mixture was stirred at room temperature for 18 hours, followed by 100 ml of saturated aqueous dipotassium hydrogen phosphate at 0 ° C.

Poured to 40, 100 ml of 3M hydrochloric acid was added to the resulting mixture and the aqueous layer was extracted twice with diethyl ether. The organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (2: 1 v / v hexane / diethyl ether) and the crude product was triturated with diethyl ether / hexane. The mother liquor was further purified by flash chromatography (4: 1 v / v hexane / ethyl acetate) and the crude product was triturated with diethyl ether / hexane. The title compound was obtained as a white solid.

102-103 ° C.

1b) 3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3-ethynyl-1-cyclohexanone

900 mg (15.6 mmol) of potassium fluoride, 0.3 g (0.78 mmol) of 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [(trimethylsilyl) - ethinyl] -1-cyclohexanone and 3 ml of anhydrous N, N-dimethylformamide was stirred under argon for 18 hours.

The solvent was removed in vacuo, the residue was partitioned between water and ethyl acetate, the aqueous phase was extracted twice with ethyl acetate, the organic solutions were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography eluting with 4: 1 v / v hexane.

41 xane / ethyl acetate was used. As a result, the title compound was obtained as a clear, colorless oil.

Elemental C20H24O3.0,10H ₂ O Calcd:

Calculated (%): C, 76.45; H, 7.76;

Found: C, 76.32; H, 7.60.

le) 3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - [(methoxycarbonyl) ethynyl] -1-cyclohexanone

3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3-ethynyl-1-cyclohexanone (0.30 g, 0.98 mmol) was dissolved in dry methanol (20 mL) and carbon monoxide was added to the solution for 10 minutes. bubbled. A mixture of copper (II) chloride (0.264 g, 1.96 mmol) and sodium acetate trihydrate (0.267 g, 1.96 mmol) was added, followed by trace amounts of palladium (II) chloride. The reaction mixture was stirred at room temperature for 2.5 hours, water was added and the methanol was evaporated. The aqueous residue was extracted three times with diethyl ether, the combined organic extracts washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using a 2: 1 by volume mixture of hexane and ethyl acetate as eluent. As a result, the title compound was obtained as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.0 (d, J = 2.3 Hz, 1H), 6.95 (dd, J = 8.4 Hz, J = 2.3 Hz, 1H ), 6.84 (d, J = 8.4 Hz, 1H), 4.78 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 2.82 (d) , J = 25 Hz, 1H), 2.78 (d, J = 25 Hz, 1H), 2.5-2.1 (m, 5H), 2.0-1.8 (m, 7H), • · · ·

- 42 1.61 (m, 2H).

Example 2

Preparation of 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-carboxyethynyl-1-cyclohexanone

3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - [(methoxycarbonyl) ethynyl] -1-cyclohexanone (0.14 g, 0.38 mmol) was dissolved.

5: 5: 2 (v / v) tetrahydrofuran / methanol / water and 0.046 g (1.114 mmol) of powdered sodium hydroxide was added to the solution. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was diluted with water (5 mL), acidified with 3M hydrochloric acid and extracted five times with dichloromethane. The organic solutions were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using a mixture of chloroform / methanol / acetic acid (88: 10: 2 by volume) as eluent. The oil thus obtained was re-evaporated three times with toluene and twice with chloroform. As a result, the title compound was obtained as a colorless solid.

Melting point: 71-72.5 'C.

Example 3

Resolution of (±) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-ethynyl-1-cyclohexanone

Example 1 The compound of Step 1b) is described below

Preparation of (±) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (methoxycarbonyl) phenyl] ethynyl} -1-cyclohexanone

5a) Methyl 3-iodobenzoate

Methyl 3-iodobenzoate was prepared by standard chemical procedures well known to those skilled in the art. The title compound was obtained as a white solid.

Melting point: 40-41 ° C.

5b) (±) -3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (methoxycarbonyl) phenyl] ethynyl} -1-cyclohexanone

To a solution of 0.30 g (0.96 mmol) of Example 1 (b) in Example 1 and methyl 3-iodobenzoate (0.30 g, 1.15 mmol) in triethylamine (10 mL) under trace amounts of tetrakis (triphenyl) under argon -phosphine) palladium (0), copper (I) iodide and triphenylphosphine were added and the mixture was refluxed for 30 minutes. The reaction mixture was then concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using a 2: 1 by volume mixture of hexane and ethyl acetate as eluent. This afforded the title compound as a pale yellow oil (0.35 g, 80%).

Elemental analysis for C ₂ gH ₃₀ O5.1, 0H ₂ O:

Calculated (%): C, 72.39; H, 6.94;

found (%):

C, 72.47; H, 6.80.

• · ·

Example 6

Preparation of (±) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [(3-carboxyphenyl) ethynyl] -1-cyclohexanone

Sodium hydroxide (0.60 g, 1.5 mmol) was added to a solution of the compound of Example 5 (5b) in 10 ml of a 5: 5: 2 mixture of tetrahydrofuran / methanol / water under argon. The reaction mixture was heated at 60 ° C for 2 hours and then concentrated in vacuo. To the residue was added 3M hydrochloric acid and the mixture was extracted with ethyl acetate. The organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using 98: 2: 0.3 v / v chloroform / methanol / acetic acid as eluent. As a result, the title compound was obtained as a white solid.

Melting point: 71-73 ° C.

Example 7

3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (5-methyl-1,3,4-thiadiazol-2-yl) phenyl] ethynyl} -1 - Preparation of cyclohexanone

7a) 2- (3-Iodo-phenyl) -5-methyl-1,3,4-thiadiazole

2- (3-Iodo-phenyl) -5-methyl-1,3,4-thiadiazole was prepared by standard chemical procedures well known to those skilled in the art. The title compound was obtained as a white solid.

Melting point: 86-89 ° C.

···· ·· · ....

. · ': ..:. ^: · • * ...

- 46 7b) 4- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (5-methyl-1,3,4-thiadiazol-2-yl) phenyl] ethynyl } -l-cyclohexanone

The (E1) enantiomer of Example 3 (0.10 g, 0.32 mmol) and 2- (3-iodo-phenyl) -5-methyl-1,3,4-thiadiazole (0.10 g, 0.32 mmol) To a solution of 5 mL of triethylamine was added trace amounts of tetrakis (triphenylphosphine) palladium (0) reagent, copper (I) iodide and triphenylphosphine under argon, and the mixture was refluxed for 12 minutes.

The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (hexane / ethyl acetate = 1: 1). This afforded the title compound as a white solid (0.135 g, 87%).

Melting point: 97-99 ° C.

The other enantiomer was similarly prepared from the (E2) enantiomer of Example 3 as a white solid.

Melting point: 97-99 ° C.

Example 8

3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] ethynyl} -1 - Preparation of cyclohexanone

8a) 2- (3-Iodophenyl) -5-methyl-1,3,4-oxadiazole.

Melting point: 117-119 ° C.

Example 9

3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] ethynyl} -1 - Preparation of cyclohexanone

9a) 5- (3-Iodophenyl) -3-methyl-1,2,4-oxadiazole

5- (3-Iodophenyl) -3-methyl-1,2,4-oxadiazole was prepared by standard chemical procedures well known to those skilled in the art. The title compound was obtained as a white solid.

Melting point: 101.5-103 ° C.

9b) 3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] ethynyl} - 1-cyclohexanone

Example 125 (0.125 g, 0.4 mmol) and 5- (3-iodophenyl) -3-methyl-1,2,4-oxadiazole (0.09 g, 0.32 mmol) in triethylamine (3 mL) To the solution of the reaction mixture was added trace amounts of tetrakis (triphenylphosphine) palladium (O) reagent, copper (I) iodide and triphenylphosphine under argon, and the mixture was heated at 80 ° C for 12 minutes and then cooled to room temperature. concentrated. The residue was partitioned between water and ethyl acetate.

The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using a 2: 1 by volume mixture of hexane and ethyl acetate as eluent. The resulting * · 9

- 50 »» ♦ opened. The residue was partitioned between water and ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using a 2: 1 by volume mixture of hexane and ethyl acetate as eluent. The crude product was triturated under ethyl acetate / hexane. This afforded the title compound as a white solid (0.12 g, 67%).

Melting point: 116-118 ° C.

The other enantiomer was similarly prepared from the (E2) enantiomer of Example 3 as a white solid.

Mp 116-118 ^e C.

Example 11

Preparation of 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [(3-cyanophenyl) ethynyl] -1-cyclohexanone

To a solution of the (E1) enantiomer of Example 3 (0.125 g, 0.4 mmol) and 3-iodobenzonitrile (0.09 g, 0.4 mmol) in triethylamine (3 mL) was added trace amounts of tetrakis (triphenylphosphine) under argon. Palladium (0) reagent, copper (I) iodide and triphenylphosphine were added and the mixture was heated at 80 ° C for 12 minutes, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using a 2: 1 by volume mixture of hexane and ethyl acetate as eluent. This afforded the title compound as a clear yellow glassy material (0.12 g, 73%).

MS (EI) m / e 414 [M + H] ⁺ .

The other enantiomer was similarly prepared from the enantiomer (E2) of Example 3 in the form of a clear yellow glassy material.

Example 12

Preparation of 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [(3-nitrophenyl) ethynyl] -1-cyclohexanone

To a solution of the (E1) enantiomer of Example 3 (0.2 g, 0.64 mmol) and 3-iodonitrobenzene (0.16 g, 0.64 mmol) in triethylamine (4 mL) was added traces of tetrakis (triphenyl) under argon atmosphere. -phosphine) palladium (0), copper (I) iodide and triphenylphosphine were added and the mixture was heated at 80 ° C for 12 minutes, cooled to room temperature and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography, eluting with 3: 1 hexane / ethyl acetate ·· * «* ¹ ··

V · · · · · - 52 solvent mixtures were used. This gave the title compound as a yellow solid (0.25 g, 90%).

Melting point: 46-48 ° C.

The other enantiomer was similarly prepared from the (E2) enantiomer of Example 3 as a yellow solid.

Melting point: 46-48 ° C.

Example 13

Preparation of 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - {[2- (2-hydroxyethoxy) phenyl] ethynyl} -1-cyclohexanone

13a) 2- (2-Hydroxyethoxy) phenyl iodide

2- (2-Hydroxyethoxy) phenyl iodide was prepared by standard chemical procedures well known to those skilled in the art. The title compound was obtained as a colorless oil.

¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.77 (Dd, J = 7.9 Hz, J = 1.3 Hz, 1H), 7.3 (t, J = 7Hz, 1H), 6.84 (D, J = 7.9 Hz, 1H), 6.74 (T, J = 7.9 Hz, 1H), 4.13 (t, J = 4.3 Hz, 2H), 3.99 (t, J = 4.3

Hz, 2H), 2.2 (bs, 1H).

13b) 3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - {[2- (2-hydroxyethoxy) phenyl] ethynyl} -1-cyclohexanone

0.25 g (0.8 mmol) of the (E1) enantiomer of Example 3 and

To a solution of 0.21 g (0.8 mmol) of 2- (2-hydroxyethoxy) -phenyl iodide in 5 ml of triethylamine in traces of tetrakis (triphenylphosphine) palladium (0) under argon atmosphere, ···· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · iodide and triphenylphosphine were added and the mixture was heated at 80 ° C for one hour, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (4: 1 v / v hexane / ethyl acetate). This afforded the title compound as a white solid (0.05 g, 14%).

Melting point: 93-94 ^° F.

Example 14

Preparation of 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (acetylamino) phenyl] ethynyl} -1-cyclohexanone

14a) 3- (Acetylamino) phenyl iodide

3-Acetylamino-phenyl iodide was prepared by standard chemical procedures well known to those skilled in the art. The title compound was obtained as a white solid.

Melting point: 117-118 ° C.

14b) 3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (acetylamino) phenyl] ethynyl} -1-cyclohexanone

0.2 g (0.64 mmol) of the (E1) enantiomer of Example 3 and

To a solution of 3-acetylamino-phenyl iodide (0.17 g, 0.64 mmol) in triethylamine (5 mL) was triturated under argon.

54 volumes of tetrakis (triphenylphosphine) palladium (O), copper (I) iodide and triphenylphosphine were added and the mixture was heated at 80 ° C for 18 minutes, then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (hexane / ethyl acetate = 1: 1). This afforded the title compound as a tan solid (0.17 g, 60%).

Melting point: 58-60 ° C.

Example 15

Preparation of 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [{3 - [(methylsulfonyl) amino] phenyl} ethynyl] -1-cyclohexanone

15a) 3 - [(Methylsulfonyl) amino] phenyl iodide

3 - [(Methylsulfonyl) amino] phenyl iodide was prepared by standard chemical procedures well known to those skilled in the art. The title compound was obtained as a pale pink solid.

102-103 ° C.

15b) 3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - [{3 - [(methylsulfonyl) amino] phenyl} ethynyl] -1-cyclohexanone

The (E1) enantiomer of Example 3 (0.2 g, 0.64 mmol) and 3 - [(methylsulfonyl) amino] phenyl iodide (0.19 g, 0.64 mmol) were prepared in 5 mL of triethylamine. to the solution were added trace amounts of tetrakis (triphenylphosphine) palladium (0) reagent, copper (I) iodide and triphenylphosphine under argon, followed by the

- 55 master batch for 18 minutes at 80 ^° C, then cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography (hexane / ethyl acetate = 1: 1). This afforded the title compound as a tan solid (0.18 g, 58%).

Melting point: 59-62 ° C.

Example 16

Preparation of 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [(3-aminophenyl) ethynyl] -1-cyclohexanone

16a) 3 - [(Trifluoroacetyl) amino] phenyl iodide

3 - [(Trifluoroacetyl) amino] phenyl iodide was prepared by standard chemical procedures well known to those skilled in the art. The title compound was obtained as a white solid.

Melting point: 120-121 ° C.

16b) 3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - [((3 - [(trifluoroacetyl) amino] phenyl} ethynyl] -1-cyclohexanone

0.5 g (1.6 mmol) of the (E1) enantiomer of Example 3 and 0.5 g (1.6 mmol) of 3 - [(trifluoroacetyl) amino] phenyl iodide were prepared in 10 ml of triethylamine. to the solution was added trace amounts of tetrakis (triphenylphosphine) palladium (O), copper (I) iodide, and triphenylphosphine under argon, and the mixture was heated at 80 ° C for 12 minutes, then cooled to room temperature and cooled to room temperature. breaking into · · · ·

- We opened it. The residue was purified by flash chromatography (3: 1 v / v hexane / ethyl acetate). This gave the title compound as a pale yellow solid (0.62 g, 78%).

M.p. 63-65 ° C.

16c) 3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - [(3-aminophenyl) ethynyl] -1-cyclohexanone

0.62 g (1.24 mmol) of 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [{(3 - [(trifluoroacetyl) amino] phenyl] ethynyl] - Potassium carbonate (0.86 g, 6.2 mmol) was added to a solution of 1-cyclohexanone (10 mL, 95: 5 in methanol / water) under argon and the mixture was heated at reflux for 6 hours and stirred at room temperature for 18 hours. The solid precipitate was filtered off and purified by trituration with ethyl acetate / hexane to give the title compound as a white solid (0.39 g, 77%).

Melting point: 100-102 ° C.

Example 17

Other compounds of the invention may be prepared in a similar manner by appropriate substitution of the starting compounds and intermediates described in the preceding Examples. The compounds of the present invention which can be prepared in this way include, but are not limited to:

3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - [{3- [5 • ··· ·· · ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 35 to 35 <♦ ···

- 57 - (trifluoromethyl) -1,2,4-oxadiazol-3-yl] phenyl} ethynyl] -1-cyclohexanone;

3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [{3- [3- (trifluoromethyl) -1,2,4-oxadiazol-5-yl] phenyl] ethynyl ] -1-cyclohexanone;

3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [{3- [5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl] phenyl} ethynyl ] -1-cyclohexanone; and

3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [{3- [5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] phenyl} ethynyl ] -1-cyclohexanone.

Example 18

Preparation of (±) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [(4-carboxyphenyl) ethynyl] -1-cyclohexanone

18a) Methyl 4-iodobenzoate

Methyl 4-iodobenzoate was prepared by standard chemical procedures well known to those skilled in the art. The title compound was obtained as a cream solid.

Melting point: 103-105 ° C.

18b) (R) -3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - {[4- (methoxycarbonyl) phenyl] ethynyl} -1-cyclohexanone

To a solution of 0.2 g (0.64 mmol) of Example 1 (b) in Example 1 and methyl 4-iodobenzoate (0.17 g, 0.64 mmol) in triethylamine (5 mL) under trace amounts of tetrakis (triphenyl) under argon -phosphine) -Palladium (0) reagent and copper (I) -jo * ·

- We gave 58 didot. The reaction mixture was refluxed for 15 minutes, then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (3: 1 v / v hexane / ethyl acetate). As a result, the title compound was obtained as a clear, colorless oil (0.25 g, 87%).

18c) (R) -3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - [(4-carboxyphenyl) ethynyl] -1-cyclohexanone

0.25 g (0.55 mmol) Example 17b. Sodium hydroxide (0.04 g, 1.1 mmol) was added to a solution of Step (5) (5 mL) in a 5: 5: 2 (v / v) mixture of tetrahydrofuran / methanol / water. The reaction mixture was stirred at 60 ° C for 2 hours and then acidified with 3M hydrochloric acid. The aqueous phase was extracted with chloroform (3x), the organic solutions were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was recrystallized from hexane / ethyl acetate. This afforded the title compound as a white solid (0.18 g, 78%).

Melting point: 102-104 ° C.

Example 19

3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - [{3- [5- (trifluoromethyl) -1,2,4-oxadiazol-3-yl] phenyl} - Preparation of ethynyl] -1-cyclohexanone

19a) 3- (3-Iodophenyl) -5- (trifluoromethyl) -1,2,4-oxadiazole

- 59 ····························································• ··

3- (3-Iodophenyl) -5- (trifluoromethyl) -1,2,4-oxadiazole was prepared by standard chemical procedures well known to those skilled in the art. The title compound was obtained as a white solid.

Melting point: 36-37 C ^Oh

19b) 3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - [{3- [5-

- (trifluoromethyl) -1,2,4-oxadiazol-3-yl] phenyl} ethynyl] -1-cyclohexanone

The (E1) enantiomer of Example 3 (0.200 g, 0.64 mmol) and 3- (3-iodo-phenyl) -5- (trifluoromethyl) -1,2,4 (0.22 g, 0.7 mmol) To a solution of oxadiazole in 5 ml of triethylamine was added trace amounts of tetrakis (triphenylphosphine) palladium (0) and copper (I) iodide under argon and the mixture was refluxed for 12 minutes. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was adsorbed onto silica gel and purified by flash chromatography (3: 1 v / v hexane / ethyl acetate). The product thus obtained was recrystallized from cold hexane. This gave the title compound as a white solid (0.27 g, 83%).

Melting point: 99-100 ° C.

Elemental analysis for C29H27F3N2O4:

Calculated (%): C 66, 40; H, 5.19; N, 5,304;

found (%):

C, 66.46; H, 5.35; N, 5.15.

- 60 • · ··· «···· • 4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 20

Preparation of (+) - and (-) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3- (phenylethynyl) -1-cyclohexanone

To a solution of the (E1) enantiomer of Example 3 (0.13 g, 0.40 mmol) and iodobenzene (0.4 mL, 2.0 mmol) in anhydrous piperidine (6 mL) under trace amounts of tetrakis (triphenylphosphine) palladium under argon Reagent (O) and copper (I) iodide were added and the mixture was refluxed for 5 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (100 mL), washed twice with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using a 2: 1 by volume mixture of hexane and ethyl acetate as eluent. The resulting product was triturated under diethyl ether / hexane to give the title compound as a white solid (0.03 g, 19%).

Melting point: 90-91 ° C.

The other enantiomer was similarly prepared from the (E2) enantiomer of Example 3 as a white solid (0.09 g, 58%).

Melting point: 90-91 ^° F.

; ··· »t ··· · · · · · · · · · · · ·

Example 21

3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - {[3 - {[(4-bromobenzyl) amino] carbonyl} phenyl] ethynyl] -1-cyclohexanone production

21a) Methyl 3-iodobenzoate

Methyl 3-iodobenzoate was prepared by standard chemical procedures well known to those skilled in the art. The title compound was obtained as a cream solid.

Melting point: 40-41 ° C.

21b) 3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (methoxycarbonyl) phenyl] ethynyl} -1-cyclohexanone

The title compound was prepared in a manner similar to that of Example 5, Step 5c except that 0.30 g (0.96 mmol) of the Example 3 (E1) enantiomer was used as starting material. The title compound was obtained as a clear yellow oil (0.43 g, 100%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.07 (s, 1H), 7.96 (dd, J =) : 7.8 Hz, J = 1.5 Hz, 1H), 7.58 (dd, J = 7.8 Hz, J = 1.5 Hz, 1H), 7, 38 (t, J = 7.8 Hz, 1H), 7, 16 (d, J = 2.2 Hz, 1H), 7.06 (Dd, J = 8.43 Hz, J = 2.2 Hz, 1H), 6.86 (d, J = 8.43 Hz, 1H), 4.80 (M, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 2.82 (dd, J = 26 Hz, J = 13.6 Hz, 2H), 2.50 (m, 1H), 2 42-2.15 (m, 4H), 2.05 (M, 1H), 1.90 (m, 6H), 1.62 (m, 3H).

20c) 3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - [(3-carboxyphenyl) ethynyl] -1-cyclohexanone

The title compound was prepared in a similar manner to Example 6 except that 0.43 g (0.96 mmol) of Example 20, Step 20c, was used as starting material. The title compound was obtained as a white solid (0.36 g, 87%).

M.p. 82-84 ° C.

20d) 3- [3- (Cyclopentyloxy) -4-methoxyphenyl] -3 - {[3 - {[(4-bromobenzyl) amino] carbonyl} phenyl] ethynyl} -1- cyclohexanone

Example 20 Compound Step 20c (0.36 g, 0.83 mmol), 1-hydroxybenzotriazole hydrate (Aldrich) (0.13 g, 0.91 mmol), 0.20 g (0.91 mmol) To a solution of 4-bromobenzylamine hydrochloride (Aldrich) and 5 mL of dichloromethane was added 0.18 g (0.91 mmol) 1- [3- (dimethylamino) under stirring at 0 ° C under argon. -propyl] -3-ethylcarbodiimide (Aldrich). The reaction mixture was stirred at room temperature for 24 hours and then water was added. The resulting mixture was acidified with 3M hydrochloric acid and extracted three times with dichloromethane. The organic solutions were combined, washed once with water and once with 10% aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (2: 1 ethyl acetate: hexane) to give a crude product which was triturated under diethyl ether / hexane. This gave 0.25 g (50%) of the title compound as a white solid.

- 63 churches.

Melting point: 98-100 ^e C.

APPLICATION EXAMPLES

Example A

Inhibitory effect of compounds of formulas I and II on TNF production by human monocytes in vitro

The inhibitory effect of the compounds of formula (I) and (II) on the production of human monocytes by TNF is described in European Patent Application 0 411 754 and WO 90/15534. International Patent Application Ser.

Example B.

Two endotoxic shock models were used to determine in vivo TNF activity for compounds of Formulas I and II. The protocol used in these models is described in European Patent Application 0 411 754 and WO 90/15534. International Patent Application Ser.

To reduce serum levels of TNF induced by endotoxin injection, the compound of Example 1 produced a positive in vivo response.

- 64 Example C

Isolation of PDE isozymes

The phosphodiesterase inhibitor activity and selectivity of the compounds of formulas I and II can be determined using a series of five different PDE isozymes. The tissues used as a source of various isozymes are: 1) PDE 1b, porcine aorta; 2) PDE Ic, guinea pig heart; 3) PDE III, guinea pig heart; 4) PDE IV human monocyte; and 5) PDE V (also known as PDE 1a), canine trachealis. PDE Ia, Ib, Ic and Ill by standard chromatographic methods [Torphy and Cieslinski, Mol. Pharmacol., 37, 206-214 (1990)]. PDE IV was subjected to sequential anion exchange followed by heparin-Sepharose chromatography [Torphy et al., J. Bxol. Chem., 267, 1798-1804 (1992)] until kinetic homogeneity is achieved.

The phosphodiesterase activity was determined according to the method of Torphy and Cieslinski, Torphy and Cieslinski, Mol. Pharmacol., 37, 206-214 (1990)]. Positive IC ₅₀ values in the nanomolar and micromolar ranges were obtained for the compounds of formulas I and II in the Preparation Examples.

Claims (9)

PATENT CLAIMS A compound of formula (I): wherein: R j is - (CR ₄ R ₅ ) _n C (O) 0 (CR ₄ R ₅ ) _m R ₆ , - (CR ₄ R ₅ ) _n O (CR ₄ R ₅ ) _m R ₆ , - (CR ₄ R ₅ ) _n C (O) NR ₄ (CR ₄ R ₅ ) _m R ₆ or - (CR ₄ R ₅ ) _r R ₆ , wherein the alkyl groups are optionally substituted with one or more fluorine atoms; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; r is 0, 1, 2, 3, 4, 5 or 6; R ₄ and R ₅ are independently hydrogen or C 1-2 alkyl; R ₆ is hydrogen, methyl, hydroxy, aryl optionally substituted by halogen, aryloxy (C 1-3 alkyl) optionally substituted by halogen, indanyl, indenyl, polycycloalkyl of 7-11 carbon atoms, tetrahydrofuryl, furyl -, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl C3-C6 cycloalkyl and C4-C6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic groups are optionally substituted one to three times with methyl and / or mono- or ethyl or hydroxy; with the proviso that a) when Rg is hydroxy then m is 2; obsession b) when Rg is hydroxy then m is 2, 3, 4, 5 or 6; obsession c) when Rg is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuryl or 2-tetrahydrothienyl, m is 1 or 2; obsession d) when Rg is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuryl or 2-tetrahydrothienyl, then r is 1, 2, 3, 4, 5 or 6; obsession e) when n is 1 and m is 0, in the group - (CR 4 R 5) _n O (CR ₄ R 5) _m R 8, R 8 is other than hydrogen; X is YR ₂ , fluoro, NR 4 R 5, or formylamino; Y is O or S (O) _m i; m 'is 0, 1 or 2; X ₂ is O or NR ₈ ; X ₃ is hydrogen or the same as X; R ₂ is optionally substituted with one or more fluorine atoms::: ··· - 67 ί, a substituted methyl or ethyl group; s is 0, 1, 2, 3 or 4; R ₃ is COOR ₁₄ , C (O) NR ₄ R ₁₄ or R ₇ ; W is (C 2 -C 6) -alkyl, (C 2 -C 6) -alkenyl or (C 2 -C 6) -alkynyl; and Z is O, NR ₇ , NCR ₄ R 5 (C 2 -C 6 alkenyl), NO R ₁₄ , NOR ₇₅ , NOCR ₄ R 5 (C 2 -C 6 alkenyl), NNR ₄ R ₁₄ , NNR ₄ R ₁₅ , NCN, NNRgC (0) _{NR8 R14,} NNRgC (S) NR ₈ R ₁₄ radical; obsession Z = 2- (1,3-dithianane), 2- (1,3-dithiolane), dimethylthiocetal, diethylthiocetal, 2- (1,3-dioxolane), 2- (1, 3-oxathiolane), dimethyl ketal or diethyl ketal; R ₇ is - (CR ₄ R 5) _q R ₁₂ or C 1-6 alkyl, wherein - (CR ₄ R 5) _q R ₁₂ or C 1-6 alkyl is optionally mono- or polysubstituted substituted with 1-3 fluoro, methyl or ethyl-substituted, fluorine, bromine, chlorine, nitro, ^- NRio II ^R 'C (O) R, -CO ₂ R, -0 _{(CH2) 2} _ ₄ ORg, CN, -O (CH ₂ ) _q C (O) R ₉ , O _{(CH2) q-R8,} -C (0) _{NR10 R11,} -0 _{(CH2) q} C (0) NR ₁₀ R _n, -NR ₁₀ C (O) NR ₁₀ R _{1: L,} -NR ₁₀ C (O) R _n, NR ₁₀ C (O) 0 R ₉ , C (NCN) NR ₁₀ R 11, NR ₁₀ C (NCN) NR ₁₀ R _11z -NR ₁₀ C (O) R ₁₃ , -C (NCN) SR ₉ , -NR ₃ qS (O) ₂ R ₉ , -C (NR ₁₀ ) NR ₁₀ R _n , -NR ₁₀ C (NCN) SRg, “S (0) _m iRg, *** xj ··· • · · • · · ·« -NR ₁₀ C (O) C (O) NR ₁₀ R ₁₁ , -NR ₁₀ C (O) C (O) R ₁₀ or R ₁₃ ; q is 0, 1 or 2; R ₁₂ is the same as R ₁₃ or C 3-7 cycloalkyl, 2-, 3- or 4-pyridyl, pyrimidyl, pyrazolyl, 1- or 2-imidazolyl, pyrrolyl, piperazinyl, piperidyl, morpholinyl, furyl, 2- or 3-thienyl, quinolyl, naphthyl or phenyl; _R8 is hydrogen or Rg; R ₉ is C 1-4 alkyl optionally substituted with 1 to 3 fluorine atoms; _R10 is ORg or R ₁₁ of the formula; R ₁ is C 1 -C 4 alkyl optionally substituted with 1 to 3 fluorine atoms; or when ^{R 10} and R 11 are NR 10 ^R n, together with the nitrogen atom, a 5-7 membered ring containing only carbon atoms or a 5-7 membered carbon atom and at least one of oxygen, nitrogen and / or sulfur atoms may form a cyclic group containing a selected heteroatom; R ₁₃ is an optionally substituted heteroaryl group selected from: ···· · *** f · · · · · · · · · · · · · · · · · · · · · · · · · · · ············· * , tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl and thiadiazolyl; and wherein substituted R ₁₃ R ₁₂ N or R ₁₃ at the rings is connected through a carbon atom and each second _R13 ring is optionally substituted by one or two C1-2 alkyl group include a methyl group optionally Substituted with 1 to 3 fluorine atoms; R ₁₄ is hydrogen or the same as R 7; or when R 8 and R ₁₄ are NR ₈ R ₁₄ , together with the nitrogen atom, a 5-7 membered ring containing only carbon atoms or a 5-7 membered carbon atom and at least one of oxygen, nitrogen and / or may form a cyclic group containing a heteroatom selected from sulfur; 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 ; with the proviso that (f) R _{7 is} not C 1-4 alkyl optionally substituted with 1 to 3 fluorine atoms - or pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein R1 is cyclopropylmethyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or difluoromethyl; X is YR2; Y is O; X ₂ is O; X ₃ is hydrogen; R ₂ is difluoromethyl or methyl; W is ethynyl or 1,3-butadynyl; R ₃ is optionally substituted pyrimidinyl; and Z is O or NR ₇ . A compound according to claim 1, wherein Rj is cyclopropylmethyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or difluoromethyl; X is YR ₂ ; Y is O; X ₂ is O; X ₃ is hydrogen; R ₂ is difluoromethyl or methyl; W is ethynyl or 1,3-butadynyl; R ₃ is a group of formula R ₇ wherein R ₇ is optionally substituted aryl or heteroaryl, except pyrimidinyl; and Z is oxygen. A compound according to claim 1 selected from: (±) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3- (phenyl71 ethynyl) -1-cyclohexanone; (±) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (methoxycarbonyl) phenyl] ethynyl} -1-cyclohexanone; (±) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [(3-carboxyphenyl) ethynyl] -l-cyclohexanone; 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (5-methyl-1,3,4-thiadiazol-2-yl) phenyl] ethynyl} -1-cyclohexanone; 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] ethynyl} -1-cyclohexanone; 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] ethynyl} -1-cyclohexanone; 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] ethynyl} -1-cyclohexanone; 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [(3-cyanophenyl) ethynyl] -1-cyclohexanone; 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [(3-nitrophenyl) ethynyl] -1-cyclohexanone; 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - {[2- (2-hydroxyethoxy) phenyl] ethynyl} -l-cyclohexanone; 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - {[3- (acetylamino) phenyl] ethynyl} -1-cyclohexanone; 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [{3 - [(methylsulfonyl) amino] phenyl} ethynyl] -1-cyclohexanone; 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [(3-aminophenyl) ethynyl] -1-cyclohexanone; (±) -3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [(4-carboxyphenyl) ethynyl] -l-cyclohexanone; > · Ι ι »» · · · * • «• ·· * 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - [{3- [5- (trifluoromethyl) -1,2,4-oxadiazol-3-yl] phenyl} ethynyl ] -1-cyclohexanone; (+) - and (-) - 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3- (phenylethynyl) -1-cyclohexanone; obsession 3- [3- (cyclopentyloxy) -4-methoxyphenyl] -3 - {[3 - {[(4-bromobenzyl) amino] carbonyl} phenyl] ethynyl} -l-cyclohexanone. 5. A pharmaceutical composition comprising a compound of formula I according to claim 1 and a pharmaceutically acceptable carrier. 6. A method of treating asthma, comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) according to claim 1. A compound of formula II: wherein Rl is - (CR4R5) _n C (0) 0 (CR4R5) _m R, - (CR4R5) _n 0 (CR4R5) ^ Rg, - (CR4R5) _n C (0) NR ₄ (CR ₄ R 5) _m R g, or - A group of formula (CR ₄ R ₅ ) _r R 8 in which the alkyl groups are optionally substituted with one or more fluorine atoms; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; , _r .. ··· ······················································································································································································································································ Adding value for value · · · · · · · · · · · · · · R ₄ and R 5 are each independently hydrogen or C 1-2 alkyl; _R6 is hydrogen, methyl, hydroxy, optionally halo-substituted aryl, halo substituted aryloxy (C1-3) alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6cycloalkyl, and C4-6cycloalkyl having one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic groups are optionally substituted with one to three methyl groups and or monosubstituted with ethyl or hydroxy; with the proviso that a) when Rg is hydroxy then m is 2; obsession b) when Rg is hydroxy then m is 2, 3, 4, 5 or 6; obsession c) when Rg is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuryl or 2-tetrahydrothienyl, m is 1 or 2; obsession d) when Rg is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuryl or 2-tetrahydrothienyl, then r is 1, 2, 3, 4, 5 or 6; or ••• J * ♦ · · *** t J * · · • · · · · · · · · · · · · · · · · · · · · · · · · · · - 74 e) If n is 1 and m is 0 then a - in the group (CR ₄ R ₅ ) _n O (CR ₄ R ₅ ) _m R _{6 -} R 8 is other than hydrogen; X is YR ₂ , fluoro, NR ₄ R _5, or formylamino; Y is O or S (O) _m . a group of the general formula; m 'is 0, 1 or 2; X ₂ is oxygen or NRg; X ₃ is hydrogen or the same as X; R ₂ is methyl or ethyl optionally substituted with one or more fluorine atoms; s is 0, 1, 2, 3 or 4; R ₃ is COOR ₁₄ , C (O) NR ₄ R ₁₄ or R ₇ ; W is (C 2 -C 6) -alkyl, (C 2 -C 6) -alkenyl or (C 2 -C 6) -alkynyl; and Z 'is C (Y') R _4, C (O) _OR14, C (Υ ') NR ₁₀ R _i4, C _{(NR10) NR10 R14,} cyano, C (NOR ₈₎ R ₁₄ , C (0) NRgNRgC (0) Rg, C (O) _{NR8 NR10 R14,} C _{(NOR14) R8,} C (NR) NR _1o R _14, C _{(NR14) NR8 R8,} C (NCN) NR ₁₀ R ₁₄ , C (NCN) SR ₉ , 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-4 or -5-yl, 1,2,4- triazol-3 or -5-yl, 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,4-oxadiazol-3 or -5-yl, 1,3,4-oxadiazol-2- yl, 1,3,4-thiadiazol-2-yl, 2-, 4- or 5-thiazolyl, 2-, 4- or 575 -oxazolidinyl, 2-, 4-, or 5-thiazolidinyl or 2-, 4-, or 5-imidazolidinyl, wherein each heterocyclic group is optionally substituted with one or more R ₁₄ groups; Y 'is oxygen or sulfur; R ₇ is - (CR ₄ R ₅ ) _q R ₁₂ or C 1-6 alkyl, wherein R ₁₂ is phenyl or C 1-6 alkyl optionally mono- or polysubstituted with 1 to 3 fluoro atoms or ethyl substituted, fluoro, bromo, chloro, nitro, -Si (R ₄ ) ₃ , ^-NR 10 ^R 11 ' ^- C (O) R 8, -CO 2 ^R 8, -O (CH 2) 2 ^- 4 ° 8' ^{- or} 8 a group of formula -CN, -C (0) NR 10 ^R nz -0C (0) NR 10 ^R n, -OC (O) R g, -NR 10 C (O) NR ₁₀ R _n, -NR ₁₀ C (O) R _11z -NR ₁₀ C (O) 0 R ₉ , -NR ₁₀ C (O) R ₁₃ , -C (NR ₁₀ ) NR ₁₀ ^R ₁₁ , -C (NCN) NR ₁₀ ^R ₁₁ , -C (NCN) SR _9, -NR ₁₀ C (NCN) SR _9, -NR ₁₀ C (NCN) NR ₁₀ R _n, -NR ₁₀ S (O) ₂ R ₉ , -S (O) _m R ₉ , -NR ₁₀ C (O) C (O) NR ₁₀ R ₉ , -NR ₁₀ C (O) C (O) R ₁₀ , thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl or tetrazolyl; q is 0, 1 or 2; ^r 12 has the same meaning as R ₄₃ or C 3-7 cycloalkyl, 2-, 3- or 4-pyridyl, pyrimidinyl, pyrazolyl, 1- or 2-imidazolyl, thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidyl; , morphol • ··· • · ··· * N-76, furyl, 2- or 3-thienyl, 4 or 5-thiazolyl, quinolyl, naphthyl or phenyl; Rg is hydrogen or the same as Rg; R ₉ is C 1-4 alkyl optionally substituted with 1 to 3 fluorine atoms; R 1 -q is ORg or R _n ; R _n is C 1-4 alkyl optionally substituted with 1-3 fluoro atoms; or when R ₁₀ and R _{X 1} are NR ₁₀ ^R 11 together with the nitrogen atom a 5-7 membered ring containing only carbon atoms or a 5-7 membered carbon atom and at least one of oxygen, nitrogen and / or may form a cyclic group containing a heteroatom selected from sulfur; R ₁₃ is an optionally substituted heteroaryl selected from oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl; and wherein R ₁₃ is R ₁₂ ^- n or R ₁₃ substituted on the rings is connected through a carbon atom and each second _R13 ring group optionally substituted by one or • ··· ·· *! substituted with two C 1-2 alkyl groups wherein the methyl group is optionally substituted Substituted with 1 to 3 fluorine atoms; R ₁₄ is hydrogen or the same as R ₇ ; or when R ₈ and R ₁₄ are NR ₈ R ₁₄ , together with the nitrogen atom, a 5-7 membered ring containing only carbon atoms or a 5-7 membered carbon atom and at least one of oxygen, nitrogen and / or may form a cyclic group containing a heteroatom selected from sulfur; with the proviso that (f) R _{7 is} not C 1-4 alkyl optionally substituted with 1 to 3 fluorine atoms - or pharmaceutically acceptable salts thereof. A compound according to claim 7, wherein R ₃ is cyclopropylmethyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or difluoromethyl; X is YR ₂ ; Y is O; X ₂ is O; X ₃ is hydrogen; R ₂ is difluoromethyl or methyl; W is ethynyl or 1,3-butadynyl; R ₃ is optionally substituted pyrimidinyl; and r - 78 Z is O or NR ₇ . 9. A pharmaceutical composition comprising a compound of formula II according to claim 7 and a pharmaceutically acceptable carrier.