CA2133439C - Compounds useful for treating allergic and inflammatory diseases - Google Patents
Compounds useful for treating allergic and inflammatory diseases Download PDFInfo
- Publication number
- CA2133439C CA2133439C CA002133439A CA2133439A CA2133439C CA 2133439 C CA2133439 C CA 2133439C CA 002133439 A CA002133439 A CA 002133439A CA 2133439 A CA2133439 A CA 2133439A CA 2133439 C CA2133439 C CA 2133439C
- Authority
- CA
- Canada
- Prior art keywords
- cyano
- methoxyphenyl
- cis
- cyclohexane
- cyclopropylmethoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 0 *c1ccc(*)c(*)c1 Chemical compound *c1ccc(*)c(*)c1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/08—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Abstract
Novel compounds of formula (I) are described herein. These compounds inhibit the production of Tumor Necrosis Factor and are useful in the treatment of disease states mediated or exacerbated by TNF production. The compounds of the present invention are also useful in the mediation or inhibition of enzymatic or catalytic activity of phosphodiesterase IV and are therefore useful in the treatment of disease states in need of mediation or inhibition thereof.
Description
'NVO 9~/197~1~ ~ ~ 9 P~'7f1US93/0~99~
"Compounds Useful for Tr~~ing Allergic and Inflammatory Diseases°' Field of Invention The present invention relates to novel compounds, pharmaceutical compositions containing these compounds, and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).
Background of the Invention Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli.
Identification of novel therapeutic agents for asthma is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all three components of chronic asthma. An alternative to the "mediator approach"
is to regulate ehe activity of the cells responsible for the pathophysiology of the disease.
1~ One such way is by elevating levels of cAMP (adenosine cyclic 3',S'-monophosphate). Cyclic AI~IP has been shown to be a second messenger mediating the biologic responses to a wide range of hoamones, neurotransmitters and drugs;
[Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-2g, 173].
When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg+2-ATP to CAMP .at an accelerated rate.
Cyclic AMP tnadulates the activity of most, if not all; of the cells that contribnt~ to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2)Vinhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation; and 5) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase hould be effective in suppressing the inappropriate activation of airway smooch muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred eo as cyclic nucleotide phosphodiesterases (PDEs).
It has now been Shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozytne; PDE I'~, is responsible for cAPvllP breakdown in airway smooth muscle and inflarnm~tory cells. [Torphy; "Phosphodiesterase Isozymes: Potential Targets for' Novel :Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Seavices i.td"
'1959]. Research indicates that itahibidon of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and netitrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly patentiated when adenylate cyclase activity of target cells is elevated bra appropriate hormones or autocoids, as would be the casein vivo.
~V() 93/197~i9 ~'~/U593J01991 Thus PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin Ez and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.
The compounds of this invention also inhibit the production of Tumor Necrosis Factor (TNF), a serum glycoprotein. Excessive or unregulated TI~a'F production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs.
host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, i.e., HIV-I, HIV-~
and HIV-3. As a consequence of HIV infection, T-cell-mediated immunity is impaired and infected individuals manifest severe opportunistic infections andlor unusual neoplasms. HIV
entry into the T lymphocyte requires T lymphocyte activation. Viruses such as HIV-1 or HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T
2S lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication.
Cytokines> specifically TNF, are implicated in activated T-cell-mediated HIV
protein expression and/or virus replication by playing a rode in maintaining T
lymphocyte activation.
, Therefore, interference with cytokine activity such as by inhibition of cytokine production, 30 notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection. Ivionocytes, macrophages; and related cells, such as kupffer and glial cells, have also been implicated in maintenance of the HIV infection. These cells, like T cells, are 35 targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al., The Immunopathogenesis of HIV
Infection, Advances in Immunology, Vol. 57, 1980. Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages [See Poli et al., Proc. Natl. Acad.
WO 93/ i 97~t9 ~ ~ ~ ~ p~i'/US93J0~ 993 Sci., 87:7$2-784, 1990], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T cells.
TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CIvIV), influenza virus, adenovirtts> and the herpes virus for similar reasons as those noted.
TNF is also associated with yeast and fungal infections. Specifically ~Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al., Infection and Immunity, 58(9):2750-54, 1990;
and Jafari et al., Journal of Infectious Diseases, 1b4:389-95> 1991. See also Wasan et al., Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Luke et al., Journal of Infectious Diseases, 162:211-214,1990J.
The ability to control the adverse effects of TNF is furthered by the use of the compounds which inhibit TNF in mammals who are in need of such use. There remains a need for compounds which are useful in treating TNF-mediated disease states which are exacerbated or caused by the excessive and/or unregulated production of TNF.
Summary of the Invention This invention relates to the novel compounds of the Formula (I), as shown below, useful in the mediation or inhibition of the enzymatic activity (or catalytic activity) of phosphodiesterase IV (PDE IV). The novel corrapounds of the Formula (I) also have Tumor Necrosis Factor (TNF) inhibitory activity.
This invention also relates to the pharmaceutical compositions comprising a compound of the Formula (I) and a pharmaceutically acceptable carrier or diluent.
The invention also relates to a method of mediation or inhibition of the enzymatic activity (or catalytic activity) of PDE IV in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of the Formula (I), as shown below.
The invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal, including humans, in b need'thereof, an effective amount of a compound of the Formula (I).
The invention also provides a method for the treatment of asthma which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of the Formula (I).
This invention also relates to a method of inhibiting TNF production in a marnmal>
including humans, which method comprises administering to a mammal in need of such treatment, an effective TNF inhibiting amount of a compound of the F~rmula (I). This method may be used for the prophylactic treatment or prevention of certain TNF
mediated disease states amenable thereto.
"Compounds Useful for Tr~~ing Allergic and Inflammatory Diseases°' Field of Invention The present invention relates to novel compounds, pharmaceutical compositions containing these compounds, and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).
Background of the Invention Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli.
Identification of novel therapeutic agents for asthma is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all three components of chronic asthma. An alternative to the "mediator approach"
is to regulate ehe activity of the cells responsible for the pathophysiology of the disease.
1~ One such way is by elevating levels of cAMP (adenosine cyclic 3',S'-monophosphate). Cyclic AI~IP has been shown to be a second messenger mediating the biologic responses to a wide range of hoamones, neurotransmitters and drugs;
[Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-2g, 173].
When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg+2-ATP to CAMP .at an accelerated rate.
Cyclic AMP tnadulates the activity of most, if not all; of the cells that contribnt~ to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2)Vinhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation; and 5) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase hould be effective in suppressing the inappropriate activation of airway smooch muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred eo as cyclic nucleotide phosphodiesterases (PDEs).
It has now been Shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozytne; PDE I'~, is responsible for cAPvllP breakdown in airway smooth muscle and inflarnm~tory cells. [Torphy; "Phosphodiesterase Isozymes: Potential Targets for' Novel :Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Seavices i.td"
'1959]. Research indicates that itahibidon of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and netitrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly patentiated when adenylate cyclase activity of target cells is elevated bra appropriate hormones or autocoids, as would be the casein vivo.
~V() 93/197~i9 ~'~/U593J01991 Thus PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin Ez and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.
The compounds of this invention also inhibit the production of Tumor Necrosis Factor (TNF), a serum glycoprotein. Excessive or unregulated TI~a'F production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs.
host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, i.e., HIV-I, HIV-~
and HIV-3. As a consequence of HIV infection, T-cell-mediated immunity is impaired and infected individuals manifest severe opportunistic infections andlor unusual neoplasms. HIV
entry into the T lymphocyte requires T lymphocyte activation. Viruses such as HIV-1 or HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T
2S lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication.
Cytokines> specifically TNF, are implicated in activated T-cell-mediated HIV
protein expression and/or virus replication by playing a rode in maintaining T
lymphocyte activation.
, Therefore, interference with cytokine activity such as by inhibition of cytokine production, 30 notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection. Ivionocytes, macrophages; and related cells, such as kupffer and glial cells, have also been implicated in maintenance of the HIV infection. These cells, like T cells, are 35 targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al., The Immunopathogenesis of HIV
Infection, Advances in Immunology, Vol. 57, 1980. Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages [See Poli et al., Proc. Natl. Acad.
WO 93/ i 97~t9 ~ ~ ~ ~ p~i'/US93J0~ 993 Sci., 87:7$2-784, 1990], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T cells.
TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CIvIV), influenza virus, adenovirtts> and the herpes virus for similar reasons as those noted.
TNF is also associated with yeast and fungal infections. Specifically ~Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al., Infection and Immunity, 58(9):2750-54, 1990;
and Jafari et al., Journal of Infectious Diseases, 1b4:389-95> 1991. See also Wasan et al., Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Luke et al., Journal of Infectious Diseases, 162:211-214,1990J.
The ability to control the adverse effects of TNF is furthered by the use of the compounds which inhibit TNF in mammals who are in need of such use. There remains a need for compounds which are useful in treating TNF-mediated disease states which are exacerbated or caused by the excessive and/or unregulated production of TNF.
Summary of the Invention This invention relates to the novel compounds of the Formula (I), as shown below, useful in the mediation or inhibition of the enzymatic activity (or catalytic activity) of phosphodiesterase IV (PDE IV). The novel corrapounds of the Formula (I) also have Tumor Necrosis Factor (TNF) inhibitory activity.
This invention also relates to the pharmaceutical compositions comprising a compound of the Formula (I) and a pharmaceutically acceptable carrier or diluent.
The invention also relates to a method of mediation or inhibition of the enzymatic activity (or catalytic activity) of PDE IV in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of the Formula (I), as shown below.
The invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal, including humans, in b need'thereof, an effective amount of a compound of the Formula (I).
The invention also provides a method for the treatment of asthma which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of the Formula (I).
This invention also relates to a method of inhibiting TNF production in a marnmal>
including humans, which method comprises administering to a mammal in need of such treatment, an effective TNF inhibiting amount of a compound of the F~rmula (I). This method may be used for the prophylactic treatment or prevention of certain TNF
mediated disease states amenable thereto.
'fVC) 93119TW ;~ ~ PCT/LJS~93/01~99 This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HIV), which comprises administering to such human an effective TNF inhibiting amount of a compound of the Formula (I).
The compounds of the Formula (I) are also useful in the treatment of additional viral infections, where such viruses are sensitive to upregulation by T1VF or will elicit TNF
production in vivo.
The compounds of the Formula (I) are also useful in the treatment of yeast and fungal infections, where such yeast and fungi are sensitive eo upregulation by TNF or will elicit TNF production in vivo.
The compounds of this invention are represented by Formula (I):
FttX2 /, Xa s~
X Xa (I) wherein:
R 1 is -(CR~RS)nC(~)C(C~RS)mR6, -(CR.4R5)nC(Q)NR4(CR4R5)mR6, -(CR~RS)n~(CR~RS)mR6, or -(CRq.RS)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens;
mis 4to2;
n is 1 to 4;
r is 1 to b;
2p R4 and R5 are indept~ndently selected froze hydrogen or a Cl_~ alkyl;
R~ is hydrogen; methyl, hydroxyl, aryl; halo substituted aryl, aryloxyCl_3 alkyl, halo substituted aryloxyCl~3 alkyl, ir~danyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyran~l, pyranyltetrahvdrothienyl, thienyl;
tetrahydrothiopyranyl, thiopyranyl, C3_~, cycloalkyl; or a Cq.-6 cycloalkyl containing one or two unsaturated bands, wherein the cycloaikyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or on~'ethyl group;
provided that:
a) when R6 is hydroxyl, then zn is 2; ax b) when Rb is hyd:raxyl, then r is 2 to 5; or 3d c) when R~ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or !2-tetrahydrothienyl, then m is 1 or 2; or d) when Rb is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrozhiertyl, then r is l to 6;
e) vrhen'n is l and m is 0, then Rg is other than I-I ir~ -(CR4R5)n0(CR~RS)mR~,;
~ is YR2, halQgert; nitro;1VR~RS; ar formyl amine;
Y' is 0 or ~a'(O)m;
m' is 0, l, or 2;
The compounds of the Formula (I) are also useful in the treatment of additional viral infections, where such viruses are sensitive to upregulation by T1VF or will elicit TNF
production in vivo.
The compounds of the Formula (I) are also useful in the treatment of yeast and fungal infections, where such yeast and fungi are sensitive eo upregulation by TNF or will elicit TNF production in vivo.
The compounds of this invention are represented by Formula (I):
FttX2 /, Xa s~
X Xa (I) wherein:
R 1 is -(CR~RS)nC(~)C(C~RS)mR6, -(CR.4R5)nC(Q)NR4(CR4R5)mR6, -(CR~RS)n~(CR~RS)mR6, or -(CRq.RS)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens;
mis 4to2;
n is 1 to 4;
r is 1 to b;
2p R4 and R5 are indept~ndently selected froze hydrogen or a Cl_~ alkyl;
R~ is hydrogen; methyl, hydroxyl, aryl; halo substituted aryl, aryloxyCl_3 alkyl, halo substituted aryloxyCl~3 alkyl, ir~danyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyran~l, pyranyltetrahvdrothienyl, thienyl;
tetrahydrothiopyranyl, thiopyranyl, C3_~, cycloalkyl; or a Cq.-6 cycloalkyl containing one or two unsaturated bands, wherein the cycloaikyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or on~'ethyl group;
provided that:
a) when R6 is hydroxyl, then zn is 2; ax b) when Rb is hyd:raxyl, then r is 2 to 5; or 3d c) when R~ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or !2-tetrahydrothienyl, then m is 1 or 2; or d) when Rb is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrozhiertyl, then r is l to 6;
e) vrhen'n is l and m is 0, then Rg is other than I-I ir~ -(CR4R5)n0(CR~RS)mR~,;
~ is YR2, halQgert; nitro;1VR~RS; ar formyl amine;
Y' is 0 or ~a'(O)m;
m' is 0, l, or 2;
ENO 93/1749 2 ~ ~ ~ ~, ~~e~s~~iom~a X2 is O or NRg;
X3 is hydrogen or X;
X4 is Z Z
~~z)s ~ ~ d~z)s ~3 Or R3 ;
(a) (b) X5 is H, R9~ ORg, CN, C(O)Rg, C(O)ORg, C(O)NRgRg~ or NRgRg;
R2 is independently selected from the group consisting of -CH3 and -CH2CH3 optionally substituted by 1 or more halagens;
sisOto4;
R3 is hydrogen, halogen, Cl-4 alkyl, CH2NHC(O)C(O)Nl-i2r halo-substituted Cl-~
alkyl, -CH=CRg°Rg°, cyclopropyt optionally substituted by Rg°, CN; ORg, CH20Rg;
NRgRIp, CH2NRgRlp, C(Z')H, C(O)ORg, C(O)NRgR~~, or C-CRg ;
Z' is O; NRg, NORg, NCN, C(-CN)2, CRgCN; CRgNO2; CRgC(O)ORg, CRgC(O)NR$Rg, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NRgR~
Z is C(X')R14, C(~)4R14~ C('Y')NR1pR14; C(NR1Q)N~lORl4> CN, G(NORg)R14>
C(O)NRgNRgC(~)Rg; C(~)NRgNRIpRl4. ~(NORIq.)Rg, C(NRg)NRlpRI4;
C(NR14)NRgRg, C(NCN)NR1pR14: C(NCN)SR9, (z-, 4- or 5-icnidazolyl), (3-; 4- or 5-pyrazolyl), (4- ox 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]), (5-tetrazolyl); (2-, 4- car 5-oxazolyl), (3'-; 4- or 5-isoxazolyl); (3- or 5-oacadiazolyl[1,2,4]), (2-ox~diazolyl[1,3,4x);
(2-thiadiazolyl[1;3;40, (2-, 4-; or S-thiazolyl), '2-, 4-, or 5-pxazolidinyl), (2-, 4-; or 5-thiazolidinyl); or (2-, 4-, or 5-imidazolidinyl)y wherein all of the heterocylic ring systems may be optionally substituted one or more dines by R14;
the dotted line in forniula (a) represents a single or double bond;
.y' ;s ,p or S;
' R7 is -(CR4R5)qRI2 nr C1~6 allcyl wherein the' R12 or CI( alkyl group is optionally stabstituted one or more times by C1_2 alkyl optionally 'substituted by one to three fluorines,' _~, -Br, -Cl, -NOZ> -NRlpRl I, ~Cr(O)Rg> °C(O)~Rg~ -ORg, ~CN, -C(O)NR,IOR11>
-OC(O)IoTR 1 pR l 1, -UC(O)Rg, -NR 1 pC(O)NR 1 ~R 1 I > -NR 1 pC(O)R 11 > -?sTR 1 ~C(O)Ol~~, -NRldC(D)R13; -C(NR10)NR10R11~ -C(NCN)NItlpRll> -C(NCN)SR9 -NR1~C(NCN)SR9 , -NRlpC(NCN)NRlORI l-NRlOS(O)2R9> -S(4)m'R9> , -NRlpC(~)C(O)NRIpRI l, -P~lRlpC(O)C(O)R10; thiazolyl, imidazolyloxazolyl>
pyrazolyl;
triazolyl; or tea-azolyl ~l is 0; l ~ or 2;
R12 is G3_' cycloalkyl(2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, ( 1- or 2-imidazolyl), thiazolyl;' triaxolyl, pyrrolyi; piperazinyl; piperldinyl, morpholinyl, fur~nyl, (2-or 3-thienvl), (4- or 5-thiazblyl), quinblinyl, naphthyl, tar phenyl;
Rg is independently selected from hydrogen or R9;
1'C1'/US93/0~ 99i Rg~ is Rg or fluorine;
R9 is CI_~ alkyl optionally substituted by one to three fluorines;
R10 is ORg or R11;
R I 1 is hydrogen, or C1 _4 alkyl optionally substituted by one to three fluorines; or when Rlp and R11 are as NR1pR11 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O/N/or S;
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 by one or twa Cl_2 alkyl gz~oups;
R 1 ~ is hydrogen or R~; or when R 1 p and R14 are as NR 1 OR 1 ~ they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S;
provided that:
f) when R12 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1; or g) when 7C2R1 is OCF2H or OCF3, X i~ F; OCF2I-I or OCF3, X3 is H, s is zero, ACS
is I-i, Z is C(O)OR14 and R14 is C1_7 unsubsti~tuted alkyl, then R3 is other than H;
or the phaa~maceutically acceptable salts thereof.
Degailed Descriptis~ryaf the Invention This invention relates to the novel compounds of Formula (I), and to pharmaceutical compositions comprising a cotxipouctd of Formula (I) and a pharmaceutically acceptable .
cazxier or diluent. This invention also relates to'a method of mediating or inhibiting the enzymatic activity (or catalytic activity) of PIKE IV in ~ mammal in need thereof and to inhibiting the production ofTNF in a mai~a~tnal in need thereof, which comprises administering to said tnamm~l an effective amodnt of a compound of the Formula (I).
Phosphodiesterase IV inhibitors are useful in the treatment of a variety of allet-gic and inflammatory diseases including: asthma, chranic bronchitis; atopic dermatitis; urticaria, allergic rhinitis; allergic conjuioctivitis; vernal coc~junctivitis, eosinaphilic granuloma, psoriasis; rhaut~atoid arehrltis, septic shock, ulcerative colitis, Crohn's disease9 reperfusion -injixry of the it~ttyacardittrn and brain; chranic glomerulanephritis, endotoxic shock and a~tiilt respiratory distress syndrome. In addition, PDE I'V inhibitors are useful in the treatment of diabetes insipidus, [Kidney Int.; 37:362; X990; Kidney Int.; 35:44, 1989] and central nervous system disorders such as depression and multi-infarct dementia.
The compounds of the Formula (I) axe also useful in the treatment of viral infections, where such viruses are sensitive to upregttlatian by TNF flr will elicit TNF
production irc vivo. The viruses contemplated for treatment herein are those that produce TNF
as a result of wo 33/ r o7ao ~. PCT/US93/01991 infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of the Formula (1). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytamegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes sdmpdex.
This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of the Formula (I).
The compounds of the Formula (I) may also be used in association with the veterinary treatment of animals, other than in humans, in need of inhibition of TrdF
production. TNF
mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
Irxamples of such viruses include, but are not limited to feline immunodeficiency virus (FIV) or other retraviral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
1 ~ The compounds of the Formula (I) are also useful in the treatment of yeast and fungal infections, where such yeast and fungi are sensitive to upregularion by TNF or will elicit TIVF production in viva. A prefeaxed c.':: ease state for treatment is fungal meningitis.
Additionally, the compounds of the Formula (I) may be administered in conjunction with other drugs of choice for systemic yeast and funl;al infections. Drugs of choice far fungal infections, include but are not limited to the class of compounds Balled the polymixins, such as Polymycin B, the class of compounds called the imidazoles, such as cl~trimazole, ecanazole, miconazole, and ketoconazale; the class of compounds called the triazoles, such as fluconazole, and itranazole, and the class of compound called the Amphotericins, in particular Amphotericin B and liposotnal Amphotericin B.
?5 The co-administration of the anti-fungal agent with a compound of the Formula (I) may be in any preferred composition fnr that compound such as is well known to those skilled in the art, for instance the various Amphotericin B formulations. Ca-administration of an anti-fungal agent with a compound of the Formula (I) may mean simultaneous administration or in practice, separate administration of the agents to the mammal but in a consecutive manner. In particular, the compounds of the Formula (I) may be co-administered with a formulation of Amphotericin B, notably for systemic fungal infections:
The preferred organism far treatment is the Candida organism. The compounds of the Formula (I) may be co-administered in a similar manner with anti-viral or anti-bacterial agents.
The compounds of the Farmul~ (I) may also be used far inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti-viral agent by administering an effective amount of a compound of the Fot~nula (I) to a mammal in need of such treatmetat, Preferably, a compound of the Formula (I) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.
4'VO 93/19749 PCT/US93/01991 When RI for the compounds of the Formula (I) is an alkyl substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably a C1-4 alkyl substituted by 1 or more fluorines. The preferred hula-substituted alkyl chain length is one or two carbons, and most preferred are the moieties -C'F3, -CH2F, -CHF2, -CF2CHF2, S -CH2CF3, and -CH2CHF2. Preferred R1 substitutents for the compounds of the Formula (I) are CH2-cyclopropyl, CH2-CS_b cycloalkyl, C4-6 cycloalkyl, C7_I 1 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrafuran-3-yl, benzyl or CI-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)1-3C(O)O(CH2)0-2CH3~ -(CH2)1-30(CH2)0-2CH3~ and -(CH2)2-40H.
When the R1 term contains the moiety (CR4R5), the R4 and RS terms are independently hydrogen or alkyl. This allows for branching of the individual methylene units as (CR4R5)n or (CR4R5)m; each repeating methylene unit is independent of the other, e.g., (CR4R5)" wherein n is 2 can be -CH2CH(-CH3)-, for instance. The individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon can optionally be substituted by fluorine independent of each other to yield. #or instance, the preferred R1 substitutions, as noted above.
When R~ is a C7-11 polycycloalkyl, examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicycio[3.2.1]octyl, tncyclo[5.2.1.02.6]decyl, etc.
additional examples of which are described in Saccamano et al.. WO 87/06576, published 5 November 1987 .
Z is preferably C(O)Rg, C(O)ORg, C(O)NRgRgy C:(NRg)NRgRg, CN, C(NORg)Rg, C(O)NRgNRgC(O)Rg, C(NRg)NRgRg, C(NCN)NRgRg, C(NCN)SR9, (1-, 4- or 5-(Rg}-2-imidazolyl), (1-, 4-ors-{Rg)-3-pyrazalyl), (1-, 2- or 5-{Rg}-4-tziazolyl[1,2,3]), (1-, 2-, 4- or 5-(Rg)-3-triazolyl[1,2,4)), (1- or 2-(Rg}-5-tetrazolyl), (4- or 5-(Rg}-2-oxazolyl), ?~ (3-or4-(Rg}-S-isoxazolyl), (3-{Rg}-5-oxadiazolyl[1,2,4]), (5-{Rg)-3-oxadiazolyl[1,2,4]), (~-{Rg)-2-oxadiazolyl[1,3,4)), (5-{Rg)-2-thiadiazolyl[1,3,4]), (4-ors-(Rg}-2-thiazolyl), (4-or 5-(Rg)-2-oxazolidinyl), (4- or 5-{Rg}-2-thiazolidinyl),(1-, 4- or 5-{ Rg }-2-imidazolidinyl); most preferred are those compounds wherein the Rg group of Z is R4.
XS is preferably hydrogen, Cl-2 alkyl optionally substituted by one to three fluorines, ORg, CN, C(O)Rg, C(O)ORg, C(O)NRgRg, or NRgRg.
Preferred X groups far Formula (I) are those wherein X is YR2 and Y is oxygen.
The preferred X2 group for Formula (I) is that wherein X2 is oxygen. The preferred X3 group for Formula (I) is that wherein X3 is hydrogen. Preferred R~a groups, where applicable, are C1-?
alkyl optionally substituted by I or more halogens. The halogen atoms are preferably fluorine and chlorine, mare preferably fluarine. More preferred R2 groups are those wherein R2 is methyl, ar the fluoro-substituted alkyls, specifically a C1-2 alkyl, such as a -CF3, -CHF2, or -CH2CHF2 moiety. Most preferred are the -C~HF~? and -CH3 moieties.
w~ gar ~ ~7a~ ~ :~ ~~ 3 4 ~ ~ , ~crri»~~r~' 9~~
Preferred R3 moieties are C(O)NH2, C---CRg, CN, C(Z')H, CH20H, CH2F, CF2H, and CF3. Mare preferred are CrCH and CN. Z' is preferably O ar NORg.
Preferred R7 moieties include optionally substituted -{CH2)1-2(cYclopropyl), -(CH2)0-2(cYclobutyl), -(CH2)0-2(cYclopentyl), -(CH2)p-2(cYclohexyl), -(CHZ)0-2(?-, 3- or 4-pyridyl), -(CH2)1_2(2-imidazolyl), -(CH2)2(4-morpholinyl), -(CH2)2(4-piperazinyl), -(CH2)1-2(2-thienyi), -(CH2)1_2(4-thiazolyl), and -(CH2)0-2Phenyl;
Preferred rings when R10 and R11 in the moiety -NR10R11 together with the nitrogen to which they are attached faun a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O/N/ ar S include, but are not limited to 1-imidazolyl, 2-(Rg)-1-itnidazolyl, 1-pyrazolyl, 3-(Rg)-1-pyrazolyl, 1-triazolyl, 2-triazolyl, 5-{Rg)-1-triazolyl, 5-{Rg)-2-triazolyl, 5-(Rg)-1-tetrazolyl, 5-(Rg)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazlayl, morpholinyl, piperazinyl, ~-(Rg}-1-piperazinyl, or pyrz°olyl ring: ..
Preferred rings when Rlp and R14 in the moiety -NRlpRl~ together with the nitrogen to which ehey are attached may form a 5 to 7 membered sing optionally containing at least one additional heteroatam selected from O, N, or S include, but are not limited to 1-imidazalyl, 1-pyrazolyl, 1-triazalyl; 2-triazolyl, 1-terrazolyl; 2-tetrazolyl, morpholinyl, piperazinyl, and pyrrolyl. The respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I). Illustrations of such carbon substitutions includes, but are not limited to, 2-(R~)-1-imidazolyl, 4-(R7)-1-imidazalyl, 5~(R~)-1-imidazolyl, 3-{R7)-1-pyrazolyl, 'I-(R7)-1°PYmzolyl, 5-(R~)-1-pyrazolyl, '4-(R7)-2-tt-~azolyi; 5-{R7)-2-triazolyl, 4-(R~)-l~triazolyl, 5-(R7)-1-triazolyl, 5-(R~7)-1-tetra;iolyl, and 5-{R7)-2-tet~azolyl.
Applicable nitrogen substitution by R7 includes, but is not limited ta, 1-(R~)-2-tetrazolyl;
2-(R'7);1-tetrazolyl, 4-{R~}-1-piperazinyl: there applicable, the ring tray be substituted one ~5 or more times by R7.
Preferred groups for NRlaRl4 which contain a heterocyclic ring are J-(R14)~1-tetraz~lyl; 2-(R14)-1-itnidazolyl; 5-(R1~)-2-tetrazolyl, or 4-(R14)-1-PiPerazinyl.
Preferred rings for Rl3 istclude (2-, 4- or 5-imidazoly~), (3-; 4- or 5-Pyrazolyl), (4- or 5-triazplyl[1,2;3]), (3- or 5-txiazolyl(1,24]), (S-tetrazolyl), ~2-, 4- or S-oxazolyl), (3-, 4- or 5 isoxaxolyl), (3- or 5-oxadiazolyl[1;2,4]); (2-oxadiaLOlyljl,3,4]}, (~~thiadiazolyl[1,3;4]), (2-, -; or 5-thiazolyl); (2-, 4-, or 5-oxazolidinyl); (2-, 4-, or 5-thiazolidiriyl), or (2-, 4-; or S~imidazc~lidinyl).
. . ' ' When the R~' group is' optionally ubstituted by a heterocyclic ring such as imidazolyl, gyrazolyl, triazolyl; tetrazolyl, or thiazolyl, the heterocyclic ring itself may be optionally substituted by Rg either on an available nitrogen ox' carbon atom, such as 1-(Rg)-2-imidazolyl, l-(Rgy-4-imid~zolyl; 1-(Rg)-5-irnidazolyl, 1-(Rg)-3-pyrazolyl;
1-(Rg)-4-pyrazolyl, 1-(Rg)-5-pyrazolyl, 1-(Rg)-4-triazolyl, or 1-(Rg)-S~triazolyl. Where applicable, the ring may be substituted one or more times by Rg.
WO 93/19749 l ~C'i'/LJ~93/t1~99i Preferred are those compounds of the Formula (I) whdrein R1 is -CH2-cyclc~propyi, -CI-12-C5_6 cyclaalkyl, -C4_6 cycloalkyl, tetrahydrofuran-3-yl, (3- ar 4-cyclopentenyl), benzyl or -Cl_2 alkyl optionally substituted by 1 or more fluarines, and -(CH2)2_4 QH; R2 is methyl ar fluoro-substituted alkyl, R3 is CN or C=CRg; and X is YR2.
Most preferred are those compounds wherein R 1 is -CH2-cyclopropyl, cyclopentyl, .
methyl or CF2H; R3 is CN or C=CH; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen;
and R2 is CF21-i or methyl.
A preferred subgenus of the compounds of the Formula (I) is the compounds of the Formula (la) ~1 , (Ia) wherein:
R1 is CH2-cyclopropyl, CH2-C5-~ cycloalkyl, C4_6 cycloalkyl, C7-1 I
palycycloalkyl, (3- or 4-cyclapentenyl), phenyl, tetxahydrofuran-3-yl, benzyl or C1_2 alkyl optionally substituted by 1 or more fluarines, -(CH2)1_3C(O)C~(CH2)0_2CH3, -(CH2)1-3~(CH2)0-2CH3, and -(CH2)2-4CH~
X is YR2, halogen, nitra, NR4R5, or formyl amine;
X4 is Z
xs or R3 ;
() () X5 is H, R9, C~Rg, CN, C(~)Rg; C(O)C)Rg, C(C)NRgRg, or NRgRg;
Y is O ar S(~)m ;
rrt' is 0, 1, or 2; .
R2 is -CH3 or -CI~2CH3 optionally substituted by T ar more halogens;
R~ is hydrogen, Cl-~ alkyl, CH2N~-IC(O)C(O)NH2; halo-substituted Cl-4 alkyl, ChT, CH2CJRg, C(Z')H, C(~)ORg, C(())NRgRlO, or C-CRg;
Z' is O or NQRg;
Z is C(O)R14, C(~)oRl4, C(ta)NR1OR14, C(NR10)NR10R14, CN, C(N~Rg)R14, , ~(p')NR~NRgC(O)Rg, ~(p)NRgNRIOR14, C(NOR14)Rg, C(NRg)NRIOR14, C(NR14)NRgRg, C(NCN)hlR1pR14; C(NCN)SR~, (1-, 4- or S-{R14]-2-imidazolyl), (1-; 4-or 5-{R14)-~-pyrazolyl), (1-, 2° or 5-{R14)-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-{R14)-5-isaxazolyl), (3-{R14)-5-oxadiazolyl[1,2;4]), (5-{R14)-3-oxadiazolyl[1,2,4]), (5-{R14)-2-axadiazolyl[1,3,4]), (5°{R14)-2-thiadiazolyl[1,3,4]), (4-ors-{R14)-2-thiazolyl), W(a ~3/ i ~7~1~
a , PCi'/LJ~93/01~191 (4- or S- ( R 1 q }-2-oxazolidinyl), (~- or 5- ( R 14 }-2-thiazolidinyl),( 1-, 4- or ~- ( R 14 }-2-imidazolidinyl);
R7 is -(CR~RS)qRl2 or C1_6 alkyl wherein the R12 or C1_b alkyl group is optionally substituted one or more times by C1_2 alkyl optionally substituted by one to three fluosines, S -F, -Br, -Cl, -N02, -NR10R11, -C(O)Rg, -C(O)ORg, -ORg, -CN, -C(O)NR10R11, -OC(O)NR10R1 l, -OC(O)R8, -NR10C(O)NR10R11, -NR10C(O)R11, -NR10C(O)OR9, -NR10C(O)R13, -C(NR10)NRI0R11, -C(NCN)NR10R11~ -C(NCN)SR9, -NR10C(NCN)SR9 , -NR10C(NCN)NR10R11, -NR10S(O)2R9, -S(O)m'R9, -NR 10C(O)C(O)NR 1 pR 11, -NR l OC(O)C(O)R 10, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl;
tl is 0, 1, or 2;
R 12 is C3-C~ cycloalkyl, (2-, 3- or 4-pyridyl), ( 1- or 2-imidazolyl), piperazinyl, morpholinyl, (2- or 3-thienyl), (4- or 5-thiazolyl), or phenyl;
the dotted line formula (a) represents a single or double bond:
Rg is independently selected from hydrogen or R9;
R9 is C1-4 alkyl optionally substituted by one to three fluorines;
R 10 is ORg or R 11;
R 11 is hydrogen or C 1-4 alkyl optionally substituted by one to three fluorines; or when R10 and R11 are as fdR10R11 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one aClditional heteroatom selected from O/N/or S;
R13 is oxazalidinyl; oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazalidinyl, thiazolidinyl, isoxazolyl, oxadiazalyl, or thiadiazolyl, and each of these h~terocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C 1 _2 alkyl groups;
R l4 is hydrogen ar R7; or when R l O and R l4 are as NR 10R 1.~ they may together with the nitrogen forma j to 7 membered ring optionally containing one or more additional heteroatoms selected from OlN/or S;
provided that:
a) when Rlz is N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, or N
rrtorphc~linyl, then tl is noz l; or b) when R1 is CF2H or CF3, X is F, OCF2H, or OCF~, ~s is H, Z is C(O)OR14 and Rl4 i5 C1_7 unsubstituted alkyl, then R3 is other than H;
or the pharmaceutically acceptable salts thereof.
3S Exemplified compounds of Formtala (I) are:
methyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyph~nyl)cyclohex-1-ene-1-carboxylate;
4-cyano-4-(3-cyclopentyloxy-~4-methoxyphenyl)cyclohex-1-ene-1-carboxylic acid;
WC) 9a/ 197~1~) IPC.'T/U~93/(D8991 4 i methyl cis-(4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyi)cyclohexane-1-carboxylate];
methyl traps-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate];
J methyl cis- [4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];
methyl traps-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];
cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid];
cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxyiate], tris(hydroxymethyl)ammonium methane salt;
cis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylic acid];
traps-j4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid];
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid];
1~ traps-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid];
methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate];
methyl traps-[4-eyano-4-(3-cyclopropylmetlwxy-4-methoxyphenyl)cyclohexane-1-carboxylate];
methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylate];
methyl traps-[4-cyano-4-(3-cyclopropylrnethoxy-4-difluorornethoxyphenyl)-cyclohexane-1-carboxylate];
2S cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylic acid];
traps-[.4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylic acid];
cis-[4-cy~no-4-(3-cyclopeetcyloxy-4-methoxyphenyl)cyclohex~ne-1-carboxamide];
cis-[4-cyano-4-(3,4-bisdifluoramethoxyphenyl)cycloh~xane-1-carboxamide];
traps-(4-cyano-4-(3,4-bissiifluc~rorraethoxyphenyl)cychhexane-1-c~rboxamide];
cis-[4-cyano-4~(3,4~bisdifluorr~methoxyphenyl)cyclohexane-1-carbohydrazideJ;
cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-I-(2- ;
acetylcarbohydrazide)];
cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane ) ;
cis- ( 4-(3,4-bisdif7uoromethoxyphenyl)-4-cyano-1-(2-methyl[ 1,3,4]o~cadiazol-yl)cyclohexane);
WC) 93/ 1 X749 ~i3~.~~~~3~
cis- ( 4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[ 1,3,4] thiadiaxol-yl)cyclohexane };
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-1-tris(methylthio)methylcyclohexane];
methyl cis-(4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-cyclohexane-1-carboxylate};
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylic acid};
cis-(4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxamide];
methyl cis-(4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxy-cyclohexane-1-carboxylate];
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylic acid];
cis-(4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide];
traps-(4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-cyclohexane-1-carboxaldehyde];
methyl mans-( 4-cyano-4-(3-cyclopropylmethoxy-4-triethoxyphenyl)-1-hydroxycyclohexane-1-carboxylate];
trar8s-(4-cyano-4-(3-cyclopropylmethoxy-4-~methoxyphenyl)-1-hydroxycyclohexane-1-carboxylic acid];
methyl prans-[4-cyano-4-{3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate];
traps-(4-cyano-4-(3-~ycl~propylmethoxy-4~rz3ethoxyphenyl)-l-methoxycyclohexane-1-carboxylic acid];
traps-[4-cyano-4-{3-cyclopropylnaethoxy-4-tnethoxyphenyl)-1-methaxycyclohexane-1-carboxamid~J;
cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexarte-1-carboxatnic 3~ acid];
N-methyl-cis-[4-cyanc~-4-(3-dyclopentyloxy=4-rnethoxyphenyl)cyclohexane- l -carboxamic acid];
cis-[4-cyanp-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-I~1-(2-cyanoethyl)carboxamide];
cis-[ 1-(2-cyanoethyl)-5- ( 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl ) tetrazole]; and cis-(4-cyano-4-(3-cycloperttyloxy-4-msthoxyphenyl)-1-(tetrazol-S-yl)cyclohexane].
Some compounds of Formula (I) tray exist in both raGemic and optically active forms; some txoay also exist in distinct diastereomeric fozms possessing distinct phwsical and Wt) 93/ I 9'749 , , .
1'CT/1JS93/01991 biological properties. All of these compounds are considered to be within the scope of the present invention. Therefore another aspect of the present invention is the administration of either a racemate, a single enantiomeric forpn, a single diastereomeric form, or mixtures thereof.
The terms cis and traps denote stereochemistry at the C-1 position of the cyclohexane ring relative to the 123 group at the C-4 position.
The terms"C1_3 alkyl", "C1_4 alkyl", "C1_b alkyl" or "alkyl" include both straight or branched chain radicals of 1 to 10, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like. "Alkenyl" includes both straight or branched chain radicals of 1 to b carbon lengths, unless the chain length is Limited thereto, including but not limited to vinyl, 1-propenyl, 2-propenyl, 2-propynyl, or 3-methyl-2-propenyl. "Cycloalkyl" or "cycloalkyl alkyl" includes groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl. "Aryl" ox "aralkyl", unless specified otherwise, means an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl, or naphthyl.
Preferably the aryl is monocyclic, i.e, phenyl. The alkyl chain includes both straight or branched chain radicals of 1 to 4 carbon atoms. "Heteroaryl" as used herein, is meant an aromatic ring system containing one or more heteroatoms, such as imidazolyl, triazolyl, oxazolyl; pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furany~, or thienyl. "Halo" as used herein is meant all halogens, i.e., chloro, fluoro, bromo, or ioda.
The phrase "inhibiting the production of IL-1" or "inhibiting the production of T1~F"
means:
a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels ~r below normal levels by inhibition of the an vivo release of IL-1 by all cells, incltading but not limited to monbcytes or macrophages;
b) a down regulation, ~t the translational or transcriptional level, of excessive in vivo IL-1 oir TrdF levels, respectively, in a human to nornnal Levels ~r below normal levels; or c) a down regulation, by inhibition of the direct synthesis of IL-1 or TNF
levels as ~
postranslational event.
"'I'NF mediated disease or disease states°' means any and all disease states in which TIVF plays a role, either by production of 'Y'1~1F itself, or by 'I'NF
Gatasing' another cytokinie to be released, such as but not limited to IL-1 or iL-~. A disease state in which IL-1, fox ins~anc~ is a mayor compor~~nt; and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF. As TN~~-!3 (also known as lymphotoxin) has close structural homology with TNF-a (also known as cachect~n), and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-a and TNF-(3 are inhibited by the compounds of the present invention and thus are herein refezred'to collectively as "TfolF" unless specifically delineated otherwise:
Preferably TNF-a is inhibited.
dvo ~3r~~~a9 lPCrrus93ro~9~' "Cytokine" means any secreted polypeptide that affects the functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses. A cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce them. For instance, a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte, but many other cells produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes, and B-lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cytokines for the present invention include, but are not limited to, Interleukin-1 (IL-1), Interleukin-6 (1L-6), Interleukin-8 (IL,-8), Tumor Necrosis Factor-alpha (TNF-ce) and Tumor Necrosis Factor-beta ( i'NF-Vii).
The cytokine inhibited by the present invention for use in the treatment of a HIV- , infected human must be a cytokine which is implicated in (a) the initiation and/or maintenance of '1:' cell activation and/or activated T cell-mediated HIV gene expression and/or replication, and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration. Preferrably this cytakine is TNF-cc.
All of the compounds of Formula (I) are useful in the method of inhibiting the production of TNF, preferably by macrophages, rnonocytes o~ macrophages and monocytes, in a mammal, including humans, in need thereof. All of the compounds of Forra~ula (I) are useful in the method of inhibiting or mediating the enzymatic or catalytic activity of PDE IV
and in treatment of disease states mediated thereby.
METHODS OF PREPARATION:
Preparing compounds of the Formula (I) can be carried out by one of skill in the art according to the procedures outlined in the Examples, infra. The preparation of any remaining compounds of the Formula (I) not described therein may be prepared by the analogous processes disclosed herein which comprise:
a) fox compotands of the Formula (I) wherein R3 is H, CN, OR9, C1_4 alkyl or C1_rl halosubstituted alkyl, wherein X or X~ is ether than Br, I, N02; amino, fozmyl amine or S(O)m' when rn' is 1 or 2, ~.vherein Z is CHO and the double bond is present, reacting a compound of the Formula (2) RIO
l R3 X (2) wherein R I represents R l as defined in relation to Formula (I) or a group convertible to R 1 and X and X3 represent X and X3 as defined in relation to Formula (I) or a group convertible ~5 to X or X3 and R~ represents R3 as defined in relation to Formula (I) or a group convertible to R3, with nitromethane in a suitable non-reacting solvent in the presence of a base (catalyst) ~''~"~" ~'~'~ 2 ~. 3 3 ~ ~ 9 v I'C~'/IJS93/019'9i to provide compounds of the Formula (I) wherein R3 is H, CN, ORc~~ C1_4 alkyl or C1_~
halosubstituted alkyl, wherein X and X3 are other than Br, I, NO2, amino, formyl amine or S(O)m' when m' is 1 or 2, wherein Z is CH2N0~ and the double bond is present;
treatment of such compounds with a base, such as sodium methoxide, in the presence of, e.g., buffered titanium trichloride, provides compounds of the Formula (I) wherein R3 is H, CN, OR9, C1-4 alkyl or C1_4 halosubstituted alkyl, wherein X or X3 are other than Br, I, N02, amino, formyl amine or S(O)m' when m' is 1 or 2 and wherein Z is CHO and the double band is present. Double bond reduction of such compounds of the Formula (I) provides the corresponding saturated ring Formula (I) compounds; oxidation of the aldehyde function of either these saturated or unsaturated compounds of the Formula (I) provides the corresponding Formula (I) carboxylates (Z = COOH), which may be converted by standard procedures with proper manipulation of any chemically sensitive functional groups to the , corresponding ester, amide, nitrite, oxazolidinone, etc., Z groups of the Formula (I).
Alternatively, reaction of a compound of the Formula (2) with, e.g., tosylmethyl isocyanide and potassium t-butoxide (followed by hydrolysis) or lithium methoxyphenylthiotrimethylsilylmethane (followed by hydrolysis) provides compounds of the Formula (I) wherein R3 is H, CN, OR9 , C1_4 alkyl or C1_4 halosubstituted alkyl, wherein X and X3 are other than Br, I, NO2, amino, formyl amine or S(O)m' when m' is 1 or 2, wherein Z is C07R l g, the double bond is present, and R 1 ~ is H or simple allcyl; these then may be converted by standard procedures with proper manipulation (protection/deprotection) of any chemically sensitive functional groups to the corresponding ester, amide, rritrile, oxazoliditzone, etc., Z groups of the Formula (I).
Alternatively, reaction ref a compotand of the Formula (2) with, e.g., triflic anhydride in the presence of an appropriate tez~tiary amine base, or with an alkyl lithium at a reduced temperature followed by treatment with N-phenyl trifluorosulfanimide, provides the corresponding snot triflat~, which is then reacted vith carbon monoxide in the presence of an alcs~hol ar amine and an appropriate palladium catalyst to provide compounds of the Formula (I) wherein R3 is I-I, CN, OR9 , C1_~ alkyl or Cl_4 hat~substituted alkyl, wherein X and X3 are other than Br, I, NOZ, amino, forenyl amine or S(O)m' when m' is 1 or ~, wherein Z is C02R 1$ car CONR 1 OR 14, he double bond xs present, and R 1 S is I-I or simple alkyl; these thenuxaay be converted by standard procedures with proper manipulation (protection/deprotection) of any chemically sensitive functional groups to the corresponding ester; amide, nitrite, oxazoiidinone, etc., Z groups of the Formula (I):
Alternatirrely, reaction of a compound of the Fornattla (2) with, e,g., lithium 3S tris(methylthio)methane at reduced temperature; followed by mercury salt hydrolysis and alcohol treatment provides campounds of the Formula (I) wherein R3 is H, CN, ()R~ ; C1_r~
alkyl or C1_~ halosubstituted alkyl, wherein X end X3 are otht;r than Br, I, NO2, amino, formyl amine ar S(O)m' when m' is 1 or 2, wherein Z is CO?R15 and X5 is OH, the double bond is absent, and R15 is I-I or simple alkyl. Sueh compounds may also be obtained by WO 93/1949 ~ ~ P~d'/~1593/Oi991 reaction of a compound of the Formula (2) with trimethylsulfoxonium iodide or trimethylsulfonium iodide and an appropriate base, such as sodium hydride, to provide the exo-epoxide followed by treatment with aqueous potassium hydroxide in, e.g., dimethylsulfoxide and oxidation of the resulting primary alcohol to the carboxyl provides compounds of the Formula (I) wherein R3 is H, CN, OR9 , C1_4 alkyl or C1_~
halosubstituted alkyl, wherein X and X3 are other than Br, I, NO2, amino, formyl amine or S(O)m' when m' is 1 or 2, wherein Z is C02R1~ and X~ is OH, the double bond is absent, and R15 is H or simple alkyl; the R~ hydroxyl may be alkylated and these compounds then may be converted by standard procedures with proper manipulation (protection/depratection) of any chemically sensitive functional groups to the corresponding ester, amide, nitrite, oxazolidinone, etc., Z groups of the Formula (I).
Alternatively, reaction of a compound of the Formula (2) with, e.g., 2-lithio-(trimethylsilyl)-1,3-dithiane followed by acidic hydrolysis with a mercury salt, such as mercury (II) chloride, or reaction of a compound of the Formula (2) with, e.g., sodio-[diethyl i 5 t-butoxy(cyano)methyl phosphonate~ followed by ~eatment with acetic anhydride and a zinc halide and then followed by treatment with an alkoxide provides compounds of the Formula (I) wherein R3 is H, CN, OR9 , C1_4 alkyl or Cl-4 halosubstituted alkyl, wherein X and X3 are other than Br, I, NOZ, amino, formyl amine or S(O)m' when in' is 1 or 2, wherein Z is C02R 15, the double bond is not present, and R 1$ is H or simple alkyl and R~
is H; these then may be converted by standard procedures with proper manipulation (protection/deprotection) of any chemically sensitivb functional groups to the corresponding ester, amide, nitrite, oxazolidinone; etc., Z groups of the Formula (I).
Preparation of such compounds ~f the Formula (I) wherein R3 is C(=Z')H proceed in an analogous fashion from the compound of the Formula (~) wherein =Z' is an aldehyde protecting group, such as a dimethylacetal or a dioxolane, followed by aldehyde deprotection and subsequent manipulation by standard procedures known to those of skill in the art to the remaining compounds of the Formula (I) wherein Z' is other than O or R3 is other than H;
CN; OR9 , C 1 _q. alkyl or C 1 _~, halosubstituted alkyl.
With proper manipulation (protection/deprotection) of any chemically sensitive functional groups:
a) Compounds of the Formula (I) wherein X or X3 are formyl amine may be formed at the last step, by formylating a compound wherein X or X3 is NH2, obtained by removal of a protecting group, from the amine functionality; such protective groups are well known to those skilled in the art, She Greens, T. and Wuts, P.G.M., Protecting Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons; New York (1991).
c) Compounds of the Formula (I) wherein X or X3 are Br or I may be prepared from a similarly deprotected amine by diazotization of the amine and diazonium displacement.
d) Compounds of the Formula (I) wherein X or X3 are NO2 may be prepared from a similarly deprotected amine by oxidation of the amine to the nitro group.
e) Compounds of the Formula (I) wherein Y is S(O)m' when m' is 1 or 2 may be prepared from the compounds of the Formula (I) wherein Y is S by oxidation of the SR2 moiety under conditions well known those skilled in the art Compounds of the Formula (2) may be prepared in turn by the processes described in U.S. Patent Number 5,449,686.
It will be recognized that compounds of the Formula (1) may exist in two distinct diastereomeric forms possessing distinct physical and biological properties;
such isomers rnay be separated by standard chromatographic methods.
The following examples and methods are provided to illustrate how the make and use the invention. These materials are not intended to limit the invention in any manner; please refer to the claims appended hereto for determining what has been reserved to the inventors hereunder.
S YNTHETI~EXAMPL~S
Methyl 4-cvano-4-(3-cXcIQpen,~vlQxt-4-methox~yphen~,l~cvclohex-1-ene-1-carbox~ate 4-Cygno-4-(3-cyclc~pentylaxv-4-methoxyphen lY )_I_cyclohexenyl trifluQromet>~ls~ fonate To a solution of diisopropylamine [ 1.95 milliliters (hereinafter mL), 13.9 millimvles (hereinafter mmol)] in tetrahydrofuran ( 12 mL) at Oo C under an argon atmosphere was added n-butyllithium (5.8 mL of 2.5M solution, 14.15 mmol), the resulting solution was stirred for 25 minutes (hereinafter min) and then was cooled to -78oC. To this was added a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one [2 grams (hereinafter g), 6.64 mmol] in tetrahydrofuran (9 mL). The resulting mixture was stirred at -78o C for 2 hours (hereinafter h), at which time N-phenyl-trifluoromethylsulfonimide (4.98 g, 13.9 mmol) was added. The mixture was allowed to warm slowly to room temperature and after 5h, the mixture was poured into water and extracted with methylene chloride. The organic extract was deed (potassium carbonate) and conccntrated under reduced pressure. The residue was purified by flash chromatography, eluting with 4:1 hexanes/ethyl acetate, to afford an oil (1.09 g, 37%).
Methyl 4-cvano-4-(3-c~pentylox~4-methoxvph~nyl)cvclohex-I-ene-1=
carboxylate To a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-cyclohexenyl trifluoromethylsulfonate (1.0 g, 2.24 mmol) in 1:1 methanol/N,N-dimethylformamide (8 mL) were added triethylamine (0.66 mL, 4.72 mmol) and tetrakis(triphenylphosphine)palladium (0.13 g, 0.11 mmol). The resulting mixture was stirred at room temperature in the dark under a carbon monoxide atmosphere for 3h. The mixture was partitioned between water and ethyl acetate, the organic extract was washed three times with water, once with brine, was dried (potassium carbonate) and was evaporated.
CA 02133439 2002-09-23"x", L v ..
'WO 93/197A9 PCT/US93/01991 Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, provided an off-white solid (0.64 g, 80%): m.p. 128-1290 C.
Analysis Calc. for C21H25N04~1/8 H20: C 70.52, H 7.12, N 3.92; found: C 70.45, H 6.93, N 3.87.
4-Cvano-4-(3-c~clopent~x-y,-4-methoxxphenxl)cyclohex-gene-1-carboxylic acid To a solution of methyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate (0.07 g, 0.18 mmol) in methanol (0.5 mL, containing just enough tetrahydrofuran to solubilize the ester) under an argon atmosphere was added a solution of potassium hydroxide (0.03 g, 0.55 mmol) in water (0.4 mL). The resulting mixture was stirred at room temperature for 4h, then poured into water and extracted with ethyl acetate.
The aqueous phase was acidified with 3N hydrochloric acid and extracted twice with ethyl acetate. The organic phase from the acid extraction was dried (sodium sulfate) and concentrated under reduced pressure to provide a viscous oil, which solidified upon standing.
The solid was recrystallized from hexanes/methylene chloride (0.05 g, 82%):
m.p. 161-163oC.
Analysis Calc. for C2pH23N04~ 1/2H20: C 68.55, H 6.90, N 4.00; found: C 68.65, H 6.55, N
3.82.
~XA MPLE 3 Meth n r - 4-c -4- 1 t x -4- th x h 1 c lohexan - _ carboxvlatel Procedure 3A:
To a solution of methyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate (0,26 g, 0.73 mmol) in methanol (12 mL) was added 10%
palladium on activated carbon (0.15 g) and the resulting mixture was hydrogenated at 50 psi for 5h. The mixture was filtered through a pad of Celite and concentrated under reduced pressure. The residue was partitioned between methylene chloride and water, the extract was dried (potassium carbonate) and evaporated to a solid which was primarily the cis-ester (0.14 g, 54%): m.p. 94-95oC.
Ang_lysis Calc. for C21H27N04~1/8 H20: C 70.32, H 7.38, N 3.90; found: C
70.33. H 7.59, N 3.81.
Procedure 3B:
2 f4 Cvano 4 (3 ctc_looentvloxy_4-methox~henx_1)cvclohexylidenel-1 3-dithiane To a solution of 2-trimethylsilyl-1,3-dithiane (9.25 mL, 48.7 mmol) in dry tetrahydrofuran (80 mL) at 0o C under an argon atmosphere was added rapidly n-butyllithium (2.5M
in hexanes, 19.2 mL, 48 mmol). After 10 min, the mixture was cooled to -78oC and a solution of 4-cyano-4-(3-cyclopentyioxv-4-methoxyphenyl)cyclohexan-1-one (7.53 g, 23 mmol) in * trade mark CA 02133439 2002-09-23 , tetrahydrofuran (40 mL) was added. After 10 min, aqueous sodium chloride was added, the mixture was allowed to warm to room temperature and was diluted with water.
This mixture was combined with the product of three substantially similar reactions conducted on ketone (3.04, 6.01 and 6.1 g, 48.3 mmol total), the combined mixture was extracted three times with S methylene chloride, the extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 10% ethyl acetate/hexanes, provided a white solid (26 g, 87%): m.p. 115-116oC.
M th 1 - 4-c -4- -c 1 x -4- x h n 1 c 1 h xan -I=
carboxvlatel Perchloric acid (70%, 13.$ mL, 160 mmol) and mercuric chloride (34.1 g, 126 mmol) were added to a solution of 2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexylidene]-1,3-dithiane (13 g, 31.3 mmol) in methanol (0.5 L) under an argon atmosphere and the mixture was heated at reflux for 2h and then was allowed to stir at room temperature for 42h. The mixture was diluted with methylene chloride, was filtered x through Celite and the filtrate was combined with that of a similar reaction conducted concun:ently on the same scale. The mixture was neutralized with aqueous sodium bicarbonate, was extracted three times with methylene chloride, the organic extract was washed three times with aqueous sodium sulfite, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 15% ethyl acetate/hexanes, provided the cis-ester as a white solid (12.4 g, 56%): m.p. 119-120oC, along with an additional quantity of slightly impure product (2.6 g, 12%).
M h I r - 4-c ano-4- -c 1 en 1 x -4- th x h n I c lohex ne-I=
carboxylatel The mans-ester was also isolated from this mixture as a solid (1.04 g, 5%): m.p.
SO-51 o C.
Analysis Calc. for C21H27N04~314 H20: C 67.99, H 7.74, N 3.?8; found: C 67.98, H ?.35, N 3.65.
Methyl cis- and trans-14-(3 4-bisdifluoromelh_oxYphen_,~ It ?-4-cyanocvclohexane-1_ carboxylate 1 Procedure 4A:
2-14-(3 4-BisdifluoromethoxyrLe_null-4-cvanocvc~e~lidene]-2-/ert-butvloxY
acetonitrile Sodium hydride ($0% dispersion, 0.35 g, 11.7 mmol) was washed three times with pentane, was suspended in tetrahydrofuran ( 15 mL) at room temperature under an argon atmosphere and diethyl tern-butyl(cyano)methylphosphonate (2.66 g, 10.7 mmol) was added.
After O.Sh, a solution of 4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexan-I-one (1.77 g, 5.34 mmol) in tetrahydrofuran (5 mL) was added and the mixture was heated at rellux for O.Sh. The mixture was cooled, aqueous sodium chloride and water were added, the mixture was extracted three times with ether, the extract was dried (magnesium sulfate) and * trac7e-mark ~ ~. ~ ~ 4 3 9 ~ ~'~TSVS93/01991 evaporat . Purification by flash chromatography, eluting with 20% ethyl acetate/hexanes, provided the title compound as a white solid ( 1.1$ g, 52%).
I_yIethyl cis- and tran~f4-(3 4-bisdifluoromethox~!Dhenvl)-4-c~yclohexane-I=
carboxylatel A mixture of 2-(4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexylidene]-2-tart-butyloxy acetonitrile (0.25 g, 0.59 mmol) and zinc chloride (0.1 g, 0.7 mmol) in acetic anhydride ( 1.5 mL) under an argon atmosphere was heated at reflux for 10 min, was cooled, was diluted with water and was extracted three times with ether. The organic extract was washed with water, dried (magnesium sulfate) and evaporated. A solution of this acetate in methanol (6 mL) was treated with a solution of sodium methoxide (25% in methanol, 0.17 mL, 0.71 mmol) and the mixture was stirred under an argon atmosphere for 2h.
The mixture was acidified with hydrochloric acid (1101), water was added and the mixture was extracted thxee times with methylene chloride. The organic extract was dried (magnesium sulfate) arDd evaporated. Purification by flash chromatography and eluting with 20% ethyl acetate/hexanes provided the traps-isomer as a colorless oil (0.07 g, 30%).
Analysis Calc. for C17H17F4NO4: C 54.40, H 4.57, N 3.73; found: C 54.57, H
4.51, N 3.58.
The cis-isomer was also isolated as a yellow ail (0.1 g, 47%).
Procedure 4B:
Meth l cis-L4-(3.4-bisdifluoromethox~nhen~yl)-4-cyanocvclohexane-1-carhoxylatel A
solution of cds-(4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-i-carboxylic acid (EXAMPLE 10, 0.07 g, 0.19 mrnol) and trimethylsilyl chloride (0.12 mL, 0:95 mmol) in methanol (5 mL) was stirred at roam temperature under an argon atmosphere for 24h. The solvent was evaporated and the residue was purified by flash chromatography, eluting with 15°lo ethyl acetate/hexanes, provided a colorless ail (0.05 g, 63%).
Analysis Calc. for C17H17F4N~4: C 54.40, H 4.57; N 3.73; found: C 54.45, H
4.49, IV 3.42.
- 4-C ono-4- 3-c cl ant lox -4-m thox he 1 c clohexane-1-carbox lic acid and cis-4- 4-bisdifluarom~tht~x hen 1 -4-c an clohexane-1-carbox lic acid Ta a solution of methyl cis~-(4-cyapo-4-(3-cyclopentyloxy-4-methaxyphenyl)cyclohexane-1-c~rboxylate] (0.12 g; 0:34 mr~ol) in methanol (0.9 rnL, cbntaining just enough tetrahydrafuran to salubilize the ester) under an argon atrnasphtrre was added a solution of potassium hydroxide (O.Ofi g, 0.9 mmol) in water (0.7 mL). The resuating mixture was stirred at roam temperature for l:Sh, then poured into r ater and extracted with ethyl acetate. The aqueous phase was acidified with 10%
hydrotrhloric acid and extracted twice with ethyl acetate. 'i"he organic phase from the acid extraction was dried (sodium sulfate) and concentrated under reduced pressure to provide a solid.
T'he solid was purified by flash chromatography, eluting with 4% methanol/chloroform, to provide a white solid (0.05 g, 44%): m.p. 157oC:
WO 9~l197A) ~crm~~3/omg~
Analysis Calc. for C2~H25N~04~1/8H20: C 68.75, H 7.40, N 4.01; found: C
68.74,~H 7.08, N
3.84.
In a similar manner there was prepared:
cis-[4-(3,4-Bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylic acid] as a solid: m.p. 143-144oC.
Analysis Calc. for C16H15~4N04: C 53.19, H 4.18, N 3.88; found: C 53.57, H
3.91, N 3.59.
- 4- n -4- 1 -4- x 1 1 h x n -1- x 1 tn~Lk~~'d~~~I~~'lla~9~t~ ane bane salt To a solution of cis-{4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-carboxylic acid] (0.17 g, 0.5 mznol) in methanol (2 mL) was added an aqueous solution of, tris(hydroxymethyl)aminomethane (1.OI~JI, 0.5 mL). After 10 min, the solvent was evaporated, toluene and xt~ethanol were added and the liquads were removed in vacuo.
Trituration with ether provided a white solid (0.18 g, 79%): m:p. 191-194oC:
Analysis Calc. for C24H36N2O7-2:5I-120: C 56.57, H 8.11; N 5.50; found: C
56:44, H 7.75, N 5.62.
E7C~MPLE 7 trc~ns~f4-Cvano-4-(:~cvClo~ e~nt,~ox~4-mP~hQx~tt~h~n_yl~.yelohexan~I-carb~xvlic ~,cidl To a solution of methyl mans-[4-cyano-4-(3-cyciop~ntyloxy-4-"rnethoxyphenyl)cyclohexane-f-carboxylate] (0.68 g; I:9 mtnol) in methanol (8 mL, containing just enough tetrahydrofur~n to solubili~:e the ester) under an argon atmosphere was added mvater (4 mL) and patassium hydroxide (0.32 ~, 5:7 mmol). The resulting mixture was stirred at room temperature for 24h, was acidified with 10% hydrochloric acid and was extracted three times with 10°lo methanol/methylene chlorides The org~ic extract was dried (i7nagnesium ~aalfate) and cancentrated axndez~ reduced pressure: Purification by flash chromatography, eluting with 4% methanol/methylene chloride; provided a white semi-solid (0.52 880°l0), which was triturated with ether to yield a white solid (0.43 g): rn,p. 157-lS8oC:
Analysis Calc. for C2pH2~NOq.. C 69:95,1 7.34; N 4.08; found: C 68:69, I-I
7.30, N 4.07:
~ ~XAM1'L;E 8 ':
r ~ 4_ _~, r x -4- x' n 1 cl h x n -1=-carboxvlic acidl 8A. 2- 4- -4- n l x -4.m h x ~ ~ 1 1 h ~ li 1 - -~~loxy acetonitrile This cotxipound; prepared substantially as described above for 2-[4-~3,4-9aisdifluoromethoxyphenyl)-4-cyanocyclo-hexyiidenej-2-tart-butyloxy acetoriitrile in Procedure A of EXAMPLE 4; was isolated as a white solid: m:p. 109-110°C.
~Vl~ 93/ 19749 ~ ~" ~ ~ d~. ~ y, , . : ~'(.'1"/ >! 1593/01991 8B. M~hvl cis- and trctns-f4-cyano-4-(3-hvdroxy,-4-methoxyphenvllcvclohexane~
1-carboxylatel These compounds, prepared substantially as described above for methyl cis-and rrans-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylateJ
in Procedure A of EXAMPLE 4, were isolated as solids [cis-isomer (0.35 g, 33%):
m.p. 105-106oC; craps-isomer (0.52g, 49%): m.p. 103-104oCJ.
8C. Methyl cis-f4-cyana-4-(3-cYclopropylmethoxv-4=
methoxvohenvl cvclohexane-1-carbox r~at~i~ A suspension of methyl cis-[4-cyano-4-(3-hydroxy-4-methoxyphenyl)cyclohexane-l~-carhoxylate] (0.35 g, 1.20 mmol), powdered potassium carbonate (0.5 g, 3.6 mmol) and bromomethyl cyclopropane (0.35 mL, 3.6 mmol) in dry dimethylformamide (15 mL) under an argon atmosphere was heated at 85oC
far 4h.
The mixture was cooled, was diluted with water and was extracted three times with ether.
The organic extract was washed four times with water, once with brine, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 20% s ethyl acetate/hexanes, provided an oil (0.34 g, 82%).
1~ 8~~ ~ -~.L~4-Cvano-4-(3-cXc~ rmethoxv-4-methoxyphenYlWcvclohexane-1=
c_arboxvlic acidl The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid] in EXAMPLE
7, was isolated as a solid: m.p. 165-167oC .
Analysis Calc. for C1gH23NC)4~1/5 H20: C 68.53, H 7.08, N 4.21; found: C
68.70, H 7.07, N 4.16.
8E. Methyl traps-f4-cvano-4-(3-cyclopropylrnethoxx4~
methoxvohenvl)cvclohexane-1-carboxvatel The title compound, prepared substantially as desGa°ib~d above for methyl cis-[4~cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxyateJ in EXAMPLE 8C was isolated as a solid:
m.p.
127.5-128oC .
Analysis Calc. for C20H25N04-3l8 y120: C 68.60, H 7.41, N 4.00; found: C
68.50, H 7.28, N 3.88.
BF. r n - 4-C ano-4- 3-c c16 ro Imethox -4-methox hen 1 c clohexane-1-carboxviic acidl The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-rnethoxyphenyl)cyclohexane-l-carboxylic acid] in EXA1~PLE
'/, was isolated as a solid: m.p. 148oC .
Analysis Calc. for C1gH23N~4: C 69.28;1-3 7.04; N 4.25; found: C 68.97, H
7.03, N 4.25.
i - and tr - 4-C ano-4- 3-c clo ro lmethox -4-difluoromethox henvl c clohexane-c~rboxylic acidl 9A. 2-(4-CYano-4-(3-c~clop.~p l~methoxy-4_ difluoromethox hen~c cY_lohexvlidene,]-1 3-dithiane This compound, prepared substantially as described above for 2-[4-cyano-4-(3-cyclopentyloxy-4-'i~V(D 9~~/19749 ~ ~, ~ ~ ~ ~ P(.'t'/US93/~1991 methoxyphenyl)cyclohexylidene]-1,3-dithiane in Procedure B of EXAMPLE 3, wad isolated as a solid: m.p. 84-85oC .
9B. Methyl ci,s- and trap -f4-cyano-4-(3-cyclopropylmethoxv-4-difluorometno~=
phenvlLyclohexane-1-carboxvlatel These compounds, prepared substantially as described above for methyl cis- and trans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate] in Procedure B of EXAMPLE 3, were isolated as oils.
9C. cis-[4-Cyano-4-(3-cvcloprppylrrtethoxy-4=
difluoromethoxypheny~cyclohexane-1-carboxylic acids This compound, prepared substantially as described above for cis-[4-cyano-4-(3-eyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid] in EXAMPLE 7, was isolated as a solid:
m.p. 134-135oC . .
r Analysis Calc. for C19H21F2N04: C 62.46, H 5.79, N 3.83; found: C 62.15, H
5.83, N 3.88.
917, t-raps-I4-Cvano-4-(3-c cal _lopropylmethoxy-4-difluoromethoxy;~henxl)~
cyclohexane-1-carboxylic acidl The title compound, prepared substantially as described above for cfs-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid] in EXAMPLE 7, was isolated as a solid: m.p. 128-129oC.
EXAMPLE; 1~
~-14-Cyano-4-(3-c~clopentyloxv-4-~thoxvphen~l)c c~lo_hexane-1-carboxamidel To a solution of methyl cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cycloh~xane-1-carboxylate] (0.22 g; 0.62 mmol) and formarnide (0.08 n~.L, 2.(38 mm01) at 100oC in dimethylformarlaide (2 rnL,) under an argon atmosphere was added p~rtionwise over 20 min sodium metlaoxide (25% solution in methanol, 0:1 mL, 0.43 mmol).
After an additional 1.25h at lUOoC, the mixture was cooled; was poured into isopropanol, was filtered and the filtrate evaporated. The residue was dissolved in ethyl acetate, the organic phase was washed three times with water, was dried (magnesium sulfate) and vsras concentrated under reduced pressure. Purification by flash chromatography;
eluting with 3%
methanol/methylene chloride; provided'a white foam (O.Ob g, 28%).
Analysis Calc. for C20I-126N2O3~3/8H20: C 68:79, H 7.72, N.8.02; found: C
68.86, H 7.49, N 7.93.
ExAMPL.E 11 i - 4- 3 4-Bisdifiuoromethox hen 1 -4-c: ano-1- 3-meth 1 1 2 4 oxadiazol-5-yl)cxclohexane j, cis-and traps-~4-(3,4-Bisdifluoromethox~pheti l~-c~ano~cyclohexane-1-carboxatrtidel These compounds, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide] in EXAMPLE 14, were isolated as a solid (Cis isomer: m:p. i09-1 lOoC ) and as an oil (traps isomer).
~vo ~a~l m7ao PCT/US93/Oi 99 i C!S_- L4-f 3.4-Bisdifluoromethoxy~henXl )-4-c~tana-1~3-methyl I~
1,2.41oxadiazol-5 xl)cyclohexane 1 A solution of cis-[4-(3,4-bisdifluaromethaxyphenyl)-4-cyanocyclohexane-1-carboxamide] (0.06 g, 0.17 mmol) in N,N-dimethylacetamide dimethyl acetal (0.5 mL) was heated at 110aC under an argon atmosphere for lh, was cooled and the solvent was evaporated. Dioxane (0.35 mL), acetic acid (0.35 mL), hydroxylamine hydrochloride (0.02 g, 0.29 mmol) and 10% aqueous sodium hydroxide (0.09 mL, 0.26 mmol) were added and the mixture was heated at 95oC under an argon atmosphere for 2.5h. The mixture was cooled, water was added, the mixture was extracted three times with methylene chloride, the organic extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 4% methanol/methylene chloride, provided a solid (0.03 g, 37%). This product was combined with that (0.04 g) from a sirniiar reaction sequence and was triturated with hexane to yield a tan solid: m.p. 83-84oC.
Analysis Calc. for C1gH17F4N3~03: C 54.14,-H 4.29; N 10.52; found: C 54.11, H
4.35, N
10.13.
cis- f 4-(3,4-Bisdifiuaromethaxv~henXl~ 4-~ano-1-(2-methyl[1,3.41oxadiazol-5~
yl~c clohexane 1 - 4- 4-Bis ifluoromethox hen 1 -4-c noc clohexane-l~carboh drazide A
solution of methyl cis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclahexane-1-carboxylate] ( 0.2 g, 0.53 moral) xnd hydrazine hydrate (0.28 txZL, 9.0 mmol) in ethanol (2.5 mL) was heated at reflux for 6h and then stirred at room temperature for 16h.
Water ores added, the mixture was extracted thr~~ times with nnethylene cla~oride, the extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 4%
methanol/metttytene chloride; provided a solid (0.12 g; SB%): ixi.p. 80-8loC.
4- 4.-Bisdifluoromethox hen 1 -4-c anoc clohexane-1- 2-~cet 1-carho-hxdrazidell A solution of ~rnethyl ciS-[4=(3,4-bisdifluarotnethaxyphenyl)~4-cv~nocyclahexane-1 ~earbohyrirazide] ( 0:11 g, 0.29 rnmol); triethylamine (0:09 mL, 0.65 txtmol) attd acetic anhydride (0.05 mL; 0.54 moral) in trthanol (7:S mL) was heated at reflex for lh, was cooled and the solvent rwas evaporated: VVat~r was added; the mixture was extracted three times with rnethylene chloride, the ex~atrt u~as dried (magnesitam sulfate) and evaporated to provide a'~rhate solid (0.11 g, 85%): m:~. 144-145aC.
~s- ( 4-~3 4 ~8i,~difluorarnethaxvtJhen~,li-4-c~ana-1-(3-tnethvl f l ,3.41oxadiazol-5e yl)~~clohexane i A smlution of cis-[4-(3,4-bisdifluaramethoxyphenyl)-4-eyanacycloheacane-1-(2-acetyl-carbohydrazide)] (0:1 g, 0.24 mmol) and phosphorpus oxychlaride (0.25 nnL, 2:6$ mri~al) in toluene (3 mL) was heated at reflex under an argon atmosphere for 1.5h. The mixture was cooled, water was added, the mixture was extracted three times with 5%
methanol/methylene chloride, the organic extract was dried (magnesium sulfate) and was V1~~ 93/ 19749 P(.°T/ U~9~/01991 evaporated. Purification by flash chromatography, eluting with 1:2 hexanes/ethyl acetate, provided an oil.
Analysis Calc. for C18H17F4N3C3~1.0 H20: C 51.80, H 4.59, N 10.07; found: C
52.00, H
4.25, N 9.76.
( 4-(3,4-Bisdifluoromethoxxphenyl)-4-cXano-1-(2-meth~I 1 3 4lthiadiazol-5=
xlZcvclohexane 1 A solution of ciS-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-(2-acetyl-carbohydrazide)] (0.1 g, 0.24 mmol) and Lawesson's Reagent (0.13 g, 0.32 mmol) in toluene (3 mL) was heated at reflux under an argon atmosphere for 0.5h. The mixture was cooled, saturated aqueous sodium bicarlaonate was added, the mixture was extracted three times wish methylene chloride, the organic extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with~l:l hexanes/ethyl acetate, provided a solid: m.p. 66-67oC. , Analysis Calc. for C18H 17F4N302 S: C 52.04, H 4.13, N 10.12; found: C 51.67, H 4.06> N
9.92.
~~-(4-C~ano-4-(3-cvclopropvlmethox~G-methoxyphen 1~-hh,ydroxy-1-tris(meth~lthio meth lcwclohexanel n-Bdtyllithium (1:9M in hexanes, 0.4 mL, 0.76 mtnol) was added dropvvise over xnin to a solution of tzis(methylthio)rnethane (0.11 mI:, 0.83 mmol) iri dry tetrahydrofuran (3 mL) at -78oC under an argon atmosphere: After ~ S min, a solution of 4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane (0:2 g; 0:67 mmol) in dry tetrahydrofuran (3 mL) was added drop~?vise over :10 rnin;. t~fter 0.5h;
aqueous aaxtmonium chloride was added and the' mixture was allowed to warm to room tempez°ature. The mixture was extracted three times with trtethylesie ~hioride; the organic extract was dried (magnesium sulfate) and evaporated. P~rifica ion by flash chromatography; eluting ~rith 25% ethyl acetate/hexanes; provided a white solid (0:25 g, 84%): m.p: 123-124oC:
Analysis Calc: for C2z1H31N~~53: C 58.21, H f:89; N 3:09; foa~nd: C 58.57, II
X3 is hydrogen or X;
X4 is Z Z
~~z)s ~ ~ d~z)s ~3 Or R3 ;
(a) (b) X5 is H, R9~ ORg, CN, C(O)Rg, C(O)ORg, C(O)NRgRg~ or NRgRg;
R2 is independently selected from the group consisting of -CH3 and -CH2CH3 optionally substituted by 1 or more halagens;
sisOto4;
R3 is hydrogen, halogen, Cl-4 alkyl, CH2NHC(O)C(O)Nl-i2r halo-substituted Cl-~
alkyl, -CH=CRg°Rg°, cyclopropyt optionally substituted by Rg°, CN; ORg, CH20Rg;
NRgRIp, CH2NRgRlp, C(Z')H, C(O)ORg, C(O)NRgR~~, or C-CRg ;
Z' is O; NRg, NORg, NCN, C(-CN)2, CRgCN; CRgNO2; CRgC(O)ORg, CRgC(O)NR$Rg, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NRgR~
Z is C(X')R14, C(~)4R14~ C('Y')NR1pR14; C(NR1Q)N~lORl4> CN, G(NORg)R14>
C(O)NRgNRgC(~)Rg; C(~)NRgNRIpRl4. ~(NORIq.)Rg, C(NRg)NRlpRI4;
C(NR14)NRgRg, C(NCN)NR1pR14: C(NCN)SR9, (z-, 4- or 5-icnidazolyl), (3-; 4- or 5-pyrazolyl), (4- ox 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]), (5-tetrazolyl); (2-, 4- car 5-oxazolyl), (3'-; 4- or 5-isoxazolyl); (3- or 5-oacadiazolyl[1,2,4]), (2-ox~diazolyl[1,3,4x);
(2-thiadiazolyl[1;3;40, (2-, 4-; or S-thiazolyl), '2-, 4-, or 5-pxazolidinyl), (2-, 4-; or 5-thiazolidinyl); or (2-, 4-, or 5-imidazolidinyl)y wherein all of the heterocylic ring systems may be optionally substituted one or more dines by R14;
the dotted line in forniula (a) represents a single or double bond;
.y' ;s ,p or S;
' R7 is -(CR4R5)qRI2 nr C1~6 allcyl wherein the' R12 or CI( alkyl group is optionally stabstituted one or more times by C1_2 alkyl optionally 'substituted by one to three fluorines,' _~, -Br, -Cl, -NOZ> -NRlpRl I, ~Cr(O)Rg> °C(O)~Rg~ -ORg, ~CN, -C(O)NR,IOR11>
-OC(O)IoTR 1 pR l 1, -UC(O)Rg, -NR 1 pC(O)NR 1 ~R 1 I > -NR 1 pC(O)R 11 > -?sTR 1 ~C(O)Ol~~, -NRldC(D)R13; -C(NR10)NR10R11~ -C(NCN)NItlpRll> -C(NCN)SR9 -NR1~C(NCN)SR9 , -NRlpC(NCN)NRlORI l-NRlOS(O)2R9> -S(4)m'R9> , -NRlpC(~)C(O)NRIpRI l, -P~lRlpC(O)C(O)R10; thiazolyl, imidazolyloxazolyl>
pyrazolyl;
triazolyl; or tea-azolyl ~l is 0; l ~ or 2;
R12 is G3_' cycloalkyl(2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, ( 1- or 2-imidazolyl), thiazolyl;' triaxolyl, pyrrolyi; piperazinyl; piperldinyl, morpholinyl, fur~nyl, (2-or 3-thienvl), (4- or 5-thiazblyl), quinblinyl, naphthyl, tar phenyl;
Rg is independently selected from hydrogen or R9;
1'C1'/US93/0~ 99i Rg~ is Rg or fluorine;
R9 is CI_~ alkyl optionally substituted by one to three fluorines;
R10 is ORg or R11;
R I 1 is hydrogen, or C1 _4 alkyl optionally substituted by one to three fluorines; or when Rlp and R11 are as NR1pR11 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O/N/or S;
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 by one or twa Cl_2 alkyl gz~oups;
R 1 ~ is hydrogen or R~; or when R 1 p and R14 are as NR 1 OR 1 ~ they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S;
provided that:
f) when R12 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1; or g) when 7C2R1 is OCF2H or OCF3, X i~ F; OCF2I-I or OCF3, X3 is H, s is zero, ACS
is I-i, Z is C(O)OR14 and R14 is C1_7 unsubsti~tuted alkyl, then R3 is other than H;
or the phaa~maceutically acceptable salts thereof.
Degailed Descriptis~ryaf the Invention This invention relates to the novel compounds of Formula (I), and to pharmaceutical compositions comprising a cotxipouctd of Formula (I) and a pharmaceutically acceptable .
cazxier or diluent. This invention also relates to'a method of mediating or inhibiting the enzymatic activity (or catalytic activity) of PIKE IV in ~ mammal in need thereof and to inhibiting the production ofTNF in a mai~a~tnal in need thereof, which comprises administering to said tnamm~l an effective amodnt of a compound of the Formula (I).
Phosphodiesterase IV inhibitors are useful in the treatment of a variety of allet-gic and inflammatory diseases including: asthma, chranic bronchitis; atopic dermatitis; urticaria, allergic rhinitis; allergic conjuioctivitis; vernal coc~junctivitis, eosinaphilic granuloma, psoriasis; rhaut~atoid arehrltis, septic shock, ulcerative colitis, Crohn's disease9 reperfusion -injixry of the it~ttyacardittrn and brain; chranic glomerulanephritis, endotoxic shock and a~tiilt respiratory distress syndrome. In addition, PDE I'V inhibitors are useful in the treatment of diabetes insipidus, [Kidney Int.; 37:362; X990; Kidney Int.; 35:44, 1989] and central nervous system disorders such as depression and multi-infarct dementia.
The compounds of the Formula (I) axe also useful in the treatment of viral infections, where such viruses are sensitive to upregttlatian by TNF flr will elicit TNF
production irc vivo. The viruses contemplated for treatment herein are those that produce TNF
as a result of wo 33/ r o7ao ~. PCT/US93/01991 infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of the Formula (1). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytamegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes sdmpdex.
This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of the Formula (I).
The compounds of the Formula (I) may also be used in association with the veterinary treatment of animals, other than in humans, in need of inhibition of TrdF
production. TNF
mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
Irxamples of such viruses include, but are not limited to feline immunodeficiency virus (FIV) or other retraviral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
1 ~ The compounds of the Formula (I) are also useful in the treatment of yeast and fungal infections, where such yeast and fungi are sensitive to upregularion by TNF or will elicit TIVF production in viva. A prefeaxed c.':: ease state for treatment is fungal meningitis.
Additionally, the compounds of the Formula (I) may be administered in conjunction with other drugs of choice for systemic yeast and funl;al infections. Drugs of choice far fungal infections, include but are not limited to the class of compounds Balled the polymixins, such as Polymycin B, the class of compounds called the imidazoles, such as cl~trimazole, ecanazole, miconazole, and ketoconazale; the class of compounds called the triazoles, such as fluconazole, and itranazole, and the class of compound called the Amphotericins, in particular Amphotericin B and liposotnal Amphotericin B.
?5 The co-administration of the anti-fungal agent with a compound of the Formula (I) may be in any preferred composition fnr that compound such as is well known to those skilled in the art, for instance the various Amphotericin B formulations. Ca-administration of an anti-fungal agent with a compound of the Formula (I) may mean simultaneous administration or in practice, separate administration of the agents to the mammal but in a consecutive manner. In particular, the compounds of the Formula (I) may be co-administered with a formulation of Amphotericin B, notably for systemic fungal infections:
The preferred organism far treatment is the Candida organism. The compounds of the Formula (I) may be co-administered in a similar manner with anti-viral or anti-bacterial agents.
The compounds of the Farmul~ (I) may also be used far inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti-viral agent by administering an effective amount of a compound of the Fot~nula (I) to a mammal in need of such treatmetat, Preferably, a compound of the Formula (I) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.
4'VO 93/19749 PCT/US93/01991 When RI for the compounds of the Formula (I) is an alkyl substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably a C1-4 alkyl substituted by 1 or more fluorines. The preferred hula-substituted alkyl chain length is one or two carbons, and most preferred are the moieties -C'F3, -CH2F, -CHF2, -CF2CHF2, S -CH2CF3, and -CH2CHF2. Preferred R1 substitutents for the compounds of the Formula (I) are CH2-cyclopropyl, CH2-CS_b cycloalkyl, C4-6 cycloalkyl, C7_I 1 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrafuran-3-yl, benzyl or CI-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)1-3C(O)O(CH2)0-2CH3~ -(CH2)1-30(CH2)0-2CH3~ and -(CH2)2-40H.
When the R1 term contains the moiety (CR4R5), the R4 and RS terms are independently hydrogen or alkyl. This allows for branching of the individual methylene units as (CR4R5)n or (CR4R5)m; each repeating methylene unit is independent of the other, e.g., (CR4R5)" wherein n is 2 can be -CH2CH(-CH3)-, for instance. The individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon can optionally be substituted by fluorine independent of each other to yield. #or instance, the preferred R1 substitutions, as noted above.
When R~ is a C7-11 polycycloalkyl, examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicycio[3.2.1]octyl, tncyclo[5.2.1.02.6]decyl, etc.
additional examples of which are described in Saccamano et al.. WO 87/06576, published 5 November 1987 .
Z is preferably C(O)Rg, C(O)ORg, C(O)NRgRgy C:(NRg)NRgRg, CN, C(NORg)Rg, C(O)NRgNRgC(O)Rg, C(NRg)NRgRg, C(NCN)NRgRg, C(NCN)SR9, (1-, 4- or 5-(Rg}-2-imidazolyl), (1-, 4-ors-{Rg)-3-pyrazalyl), (1-, 2- or 5-{Rg}-4-tziazolyl[1,2,3]), (1-, 2-, 4- or 5-(Rg)-3-triazolyl[1,2,4)), (1- or 2-(Rg}-5-tetrazolyl), (4- or 5-(Rg}-2-oxazolyl), ?~ (3-or4-(Rg}-S-isoxazolyl), (3-{Rg}-5-oxadiazolyl[1,2,4]), (5-{Rg)-3-oxadiazolyl[1,2,4]), (~-{Rg)-2-oxadiazolyl[1,3,4)), (5-{Rg)-2-thiadiazolyl[1,3,4]), (4-ors-(Rg}-2-thiazolyl), (4-or 5-(Rg)-2-oxazolidinyl), (4- or 5-{Rg}-2-thiazolidinyl),(1-, 4- or 5-{ Rg }-2-imidazolidinyl); most preferred are those compounds wherein the Rg group of Z is R4.
XS is preferably hydrogen, Cl-2 alkyl optionally substituted by one to three fluorines, ORg, CN, C(O)Rg, C(O)ORg, C(O)NRgRg, or NRgRg.
Preferred X groups far Formula (I) are those wherein X is YR2 and Y is oxygen.
The preferred X2 group for Formula (I) is that wherein X2 is oxygen. The preferred X3 group for Formula (I) is that wherein X3 is hydrogen. Preferred R~a groups, where applicable, are C1-?
alkyl optionally substituted by I or more halogens. The halogen atoms are preferably fluorine and chlorine, mare preferably fluarine. More preferred R2 groups are those wherein R2 is methyl, ar the fluoro-substituted alkyls, specifically a C1-2 alkyl, such as a -CF3, -CHF2, or -CH2CHF2 moiety. Most preferred are the -C~HF~? and -CH3 moieties.
w~ gar ~ ~7a~ ~ :~ ~~ 3 4 ~ ~ , ~crri»~~r~' 9~~
Preferred R3 moieties are C(O)NH2, C---CRg, CN, C(Z')H, CH20H, CH2F, CF2H, and CF3. Mare preferred are CrCH and CN. Z' is preferably O ar NORg.
Preferred R7 moieties include optionally substituted -{CH2)1-2(cYclopropyl), -(CH2)0-2(cYclobutyl), -(CH2)0-2(cYclopentyl), -(CH2)p-2(cYclohexyl), -(CHZ)0-2(?-, 3- or 4-pyridyl), -(CH2)1_2(2-imidazolyl), -(CH2)2(4-morpholinyl), -(CH2)2(4-piperazinyl), -(CH2)1-2(2-thienyi), -(CH2)1_2(4-thiazolyl), and -(CH2)0-2Phenyl;
Preferred rings when R10 and R11 in the moiety -NR10R11 together with the nitrogen to which they are attached faun a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O/N/ ar S include, but are not limited to 1-imidazolyl, 2-(Rg)-1-itnidazolyl, 1-pyrazolyl, 3-(Rg)-1-pyrazolyl, 1-triazolyl, 2-triazolyl, 5-{Rg)-1-triazolyl, 5-{Rg)-2-triazolyl, 5-(Rg)-1-tetrazolyl, 5-(Rg)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazlayl, morpholinyl, piperazinyl, ~-(Rg}-1-piperazinyl, or pyrz°olyl ring: ..
Preferred rings when Rlp and R14 in the moiety -NRlpRl~ together with the nitrogen to which ehey are attached may form a 5 to 7 membered sing optionally containing at least one additional heteroatam selected from O, N, or S include, but are not limited to 1-imidazalyl, 1-pyrazolyl, 1-triazalyl; 2-triazolyl, 1-terrazolyl; 2-tetrazolyl, morpholinyl, piperazinyl, and pyrrolyl. The respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I). Illustrations of such carbon substitutions includes, but are not limited to, 2-(R~)-1-imidazolyl, 4-(R7)-1-imidazalyl, 5~(R~)-1-imidazolyl, 3-{R7)-1-pyrazolyl, 'I-(R7)-1°PYmzolyl, 5-(R~)-1-pyrazolyl, '4-(R7)-2-tt-~azolyi; 5-{R7)-2-triazolyl, 4-(R~)-l~triazolyl, 5-(R7)-1-triazolyl, 5-(R~7)-1-tetra;iolyl, and 5-{R7)-2-tet~azolyl.
Applicable nitrogen substitution by R7 includes, but is not limited ta, 1-(R~)-2-tetrazolyl;
2-(R'7);1-tetrazolyl, 4-{R~}-1-piperazinyl: there applicable, the ring tray be substituted one ~5 or more times by R7.
Preferred groups for NRlaRl4 which contain a heterocyclic ring are J-(R14)~1-tetraz~lyl; 2-(R14)-1-itnidazolyl; 5-(R1~)-2-tetrazolyl, or 4-(R14)-1-PiPerazinyl.
Preferred rings for Rl3 istclude (2-, 4- or 5-imidazoly~), (3-; 4- or 5-Pyrazolyl), (4- or 5-triazplyl[1,2;3]), (3- or 5-txiazolyl(1,24]), (S-tetrazolyl), ~2-, 4- or S-oxazolyl), (3-, 4- or 5 isoxaxolyl), (3- or 5-oxadiazolyl[1;2,4]); (2-oxadiaLOlyljl,3,4]}, (~~thiadiazolyl[1,3;4]), (2-, -; or 5-thiazolyl); (2-, 4-, or 5-oxazolidinyl); (2-, 4-, or 5-thiazolidiriyl), or (2-, 4-; or S~imidazc~lidinyl).
. . ' ' When the R~' group is' optionally ubstituted by a heterocyclic ring such as imidazolyl, gyrazolyl, triazolyl; tetrazolyl, or thiazolyl, the heterocyclic ring itself may be optionally substituted by Rg either on an available nitrogen ox' carbon atom, such as 1-(Rg)-2-imidazolyl, l-(Rgy-4-imid~zolyl; 1-(Rg)-5-irnidazolyl, 1-(Rg)-3-pyrazolyl;
1-(Rg)-4-pyrazolyl, 1-(Rg)-5-pyrazolyl, 1-(Rg)-4-triazolyl, or 1-(Rg)-S~triazolyl. Where applicable, the ring may be substituted one or more times by Rg.
WO 93/19749 l ~C'i'/LJ~93/t1~99i Preferred are those compounds of the Formula (I) whdrein R1 is -CH2-cyclc~propyi, -CI-12-C5_6 cyclaalkyl, -C4_6 cycloalkyl, tetrahydrofuran-3-yl, (3- ar 4-cyclopentenyl), benzyl or -Cl_2 alkyl optionally substituted by 1 or more fluarines, and -(CH2)2_4 QH; R2 is methyl ar fluoro-substituted alkyl, R3 is CN or C=CRg; and X is YR2.
Most preferred are those compounds wherein R 1 is -CH2-cyclopropyl, cyclopentyl, .
methyl or CF2H; R3 is CN or C=CH; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen;
and R2 is CF21-i or methyl.
A preferred subgenus of the compounds of the Formula (I) is the compounds of the Formula (la) ~1 , (Ia) wherein:
R1 is CH2-cyclopropyl, CH2-C5-~ cycloalkyl, C4_6 cycloalkyl, C7-1 I
palycycloalkyl, (3- or 4-cyclapentenyl), phenyl, tetxahydrofuran-3-yl, benzyl or C1_2 alkyl optionally substituted by 1 or more fluarines, -(CH2)1_3C(O)C~(CH2)0_2CH3, -(CH2)1-3~(CH2)0-2CH3, and -(CH2)2-4CH~
X is YR2, halogen, nitra, NR4R5, or formyl amine;
X4 is Z
xs or R3 ;
() () X5 is H, R9, C~Rg, CN, C(~)Rg; C(O)C)Rg, C(C)NRgRg, or NRgRg;
Y is O ar S(~)m ;
rrt' is 0, 1, or 2; .
R2 is -CH3 or -CI~2CH3 optionally substituted by T ar more halogens;
R~ is hydrogen, Cl-~ alkyl, CH2N~-IC(O)C(O)NH2; halo-substituted Cl-4 alkyl, ChT, CH2CJRg, C(Z')H, C(~)ORg, C(())NRgRlO, or C-CRg;
Z' is O or NQRg;
Z is C(O)R14, C(~)oRl4, C(ta)NR1OR14, C(NR10)NR10R14, CN, C(N~Rg)R14, , ~(p')NR~NRgC(O)Rg, ~(p)NRgNRIOR14, C(NOR14)Rg, C(NRg)NRIOR14, C(NR14)NRgRg, C(NCN)hlR1pR14; C(NCN)SR~, (1-, 4- or S-{R14]-2-imidazolyl), (1-; 4-or 5-{R14)-~-pyrazolyl), (1-, 2° or 5-{R14)-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-{R14)-5-isaxazolyl), (3-{R14)-5-oxadiazolyl[1,2;4]), (5-{R14)-3-oxadiazolyl[1,2,4]), (5-{R14)-2-axadiazolyl[1,3,4]), (5°{R14)-2-thiadiazolyl[1,3,4]), (4-ors-{R14)-2-thiazolyl), W(a ~3/ i ~7~1~
a , PCi'/LJ~93/01~191 (4- or S- ( R 1 q }-2-oxazolidinyl), (~- or 5- ( R 14 }-2-thiazolidinyl),( 1-, 4- or ~- ( R 14 }-2-imidazolidinyl);
R7 is -(CR~RS)qRl2 or C1_6 alkyl wherein the R12 or C1_b alkyl group is optionally substituted one or more times by C1_2 alkyl optionally substituted by one to three fluosines, S -F, -Br, -Cl, -N02, -NR10R11, -C(O)Rg, -C(O)ORg, -ORg, -CN, -C(O)NR10R11, -OC(O)NR10R1 l, -OC(O)R8, -NR10C(O)NR10R11, -NR10C(O)R11, -NR10C(O)OR9, -NR10C(O)R13, -C(NR10)NRI0R11, -C(NCN)NR10R11~ -C(NCN)SR9, -NR10C(NCN)SR9 , -NR10C(NCN)NR10R11, -NR10S(O)2R9, -S(O)m'R9, -NR 10C(O)C(O)NR 1 pR 11, -NR l OC(O)C(O)R 10, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl;
tl is 0, 1, or 2;
R 12 is C3-C~ cycloalkyl, (2-, 3- or 4-pyridyl), ( 1- or 2-imidazolyl), piperazinyl, morpholinyl, (2- or 3-thienyl), (4- or 5-thiazolyl), or phenyl;
the dotted line formula (a) represents a single or double bond:
Rg is independently selected from hydrogen or R9;
R9 is C1-4 alkyl optionally substituted by one to three fluorines;
R 10 is ORg or R 11;
R 11 is hydrogen or C 1-4 alkyl optionally substituted by one to three fluorines; or when R10 and R11 are as fdR10R11 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one aClditional heteroatom selected from O/N/or S;
R13 is oxazalidinyl; oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazalidinyl, thiazolidinyl, isoxazolyl, oxadiazalyl, or thiadiazolyl, and each of these h~terocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C 1 _2 alkyl groups;
R l4 is hydrogen ar R7; or when R l O and R l4 are as NR 10R 1.~ they may together with the nitrogen forma j to 7 membered ring optionally containing one or more additional heteroatoms selected from OlN/or S;
provided that:
a) when Rlz is N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, or N
rrtorphc~linyl, then tl is noz l; or b) when R1 is CF2H or CF3, X is F, OCF2H, or OCF~, ~s is H, Z is C(O)OR14 and Rl4 i5 C1_7 unsubstituted alkyl, then R3 is other than H;
or the pharmaceutically acceptable salts thereof.
3S Exemplified compounds of Formtala (I) are:
methyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyph~nyl)cyclohex-1-ene-1-carboxylate;
4-cyano-4-(3-cyclopentyloxy-~4-methoxyphenyl)cyclohex-1-ene-1-carboxylic acid;
WC) 9a/ 197~1~) IPC.'T/U~93/(D8991 4 i methyl cis-(4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyi)cyclohexane-1-carboxylate];
methyl traps-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate];
J methyl cis- [4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];
methyl traps-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];
cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid];
cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxyiate], tris(hydroxymethyl)ammonium methane salt;
cis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylic acid];
traps-j4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid];
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid];
1~ traps-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid];
methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate];
methyl traps-[4-eyano-4-(3-cyclopropylmetlwxy-4-methoxyphenyl)cyclohexane-1-carboxylate];
methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylate];
methyl traps-[4-cyano-4-(3-cyclopropylrnethoxy-4-difluorornethoxyphenyl)-cyclohexane-1-carboxylate];
2S cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylic acid];
traps-[.4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylic acid];
cis-[4-cy~no-4-(3-cyclopeetcyloxy-4-methoxyphenyl)cyclohex~ne-1-carboxamide];
cis-[4-cyano-4-(3,4-bisdifluoramethoxyphenyl)cycloh~xane-1-carboxamide];
traps-(4-cyano-4-(3,4-bissiifluc~rorraethoxyphenyl)cychhexane-1-c~rboxamide];
cis-[4-cyano-4~(3,4~bisdifluorr~methoxyphenyl)cyclohexane-1-carbohydrazideJ;
cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-I-(2- ;
acetylcarbohydrazide)];
cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane ) ;
cis- ( 4-(3,4-bisdif7uoromethoxyphenyl)-4-cyano-1-(2-methyl[ 1,3,4]o~cadiazol-yl)cyclohexane);
WC) 93/ 1 X749 ~i3~.~~~~3~
cis- ( 4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[ 1,3,4] thiadiaxol-yl)cyclohexane };
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-1-tris(methylthio)methylcyclohexane];
methyl cis-(4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-cyclohexane-1-carboxylate};
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylic acid};
cis-(4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxamide];
methyl cis-(4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxy-cyclohexane-1-carboxylate];
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylic acid];
cis-(4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide];
traps-(4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-cyclohexane-1-carboxaldehyde];
methyl mans-( 4-cyano-4-(3-cyclopropylmethoxy-4-triethoxyphenyl)-1-hydroxycyclohexane-1-carboxylate];
trar8s-(4-cyano-4-(3-cyclopropylmethoxy-4-~methoxyphenyl)-1-hydroxycyclohexane-1-carboxylic acid];
methyl prans-[4-cyano-4-{3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate];
traps-(4-cyano-4-(3-~ycl~propylmethoxy-4~rz3ethoxyphenyl)-l-methoxycyclohexane-1-carboxylic acid];
traps-[4-cyano-4-{3-cyclopropylnaethoxy-4-tnethoxyphenyl)-1-methaxycyclohexane-1-carboxamid~J;
cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexarte-1-carboxatnic 3~ acid];
N-methyl-cis-[4-cyanc~-4-(3-dyclopentyloxy=4-rnethoxyphenyl)cyclohexane- l -carboxamic acid];
cis-[4-cyanp-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-I~1-(2-cyanoethyl)carboxamide];
cis-[ 1-(2-cyanoethyl)-5- ( 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl ) tetrazole]; and cis-(4-cyano-4-(3-cycloperttyloxy-4-msthoxyphenyl)-1-(tetrazol-S-yl)cyclohexane].
Some compounds of Formula (I) tray exist in both raGemic and optically active forms; some txoay also exist in distinct diastereomeric fozms possessing distinct phwsical and Wt) 93/ I 9'749 , , .
1'CT/1JS93/01991 biological properties. All of these compounds are considered to be within the scope of the present invention. Therefore another aspect of the present invention is the administration of either a racemate, a single enantiomeric forpn, a single diastereomeric form, or mixtures thereof.
The terms cis and traps denote stereochemistry at the C-1 position of the cyclohexane ring relative to the 123 group at the C-4 position.
The terms"C1_3 alkyl", "C1_4 alkyl", "C1_b alkyl" or "alkyl" include both straight or branched chain radicals of 1 to 10, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like. "Alkenyl" includes both straight or branched chain radicals of 1 to b carbon lengths, unless the chain length is Limited thereto, including but not limited to vinyl, 1-propenyl, 2-propenyl, 2-propynyl, or 3-methyl-2-propenyl. "Cycloalkyl" or "cycloalkyl alkyl" includes groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl. "Aryl" ox "aralkyl", unless specified otherwise, means an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl, or naphthyl.
Preferably the aryl is monocyclic, i.e, phenyl. The alkyl chain includes both straight or branched chain radicals of 1 to 4 carbon atoms. "Heteroaryl" as used herein, is meant an aromatic ring system containing one or more heteroatoms, such as imidazolyl, triazolyl, oxazolyl; pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furany~, or thienyl. "Halo" as used herein is meant all halogens, i.e., chloro, fluoro, bromo, or ioda.
The phrase "inhibiting the production of IL-1" or "inhibiting the production of T1~F"
means:
a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels ~r below normal levels by inhibition of the an vivo release of IL-1 by all cells, incltading but not limited to monbcytes or macrophages;
b) a down regulation, ~t the translational or transcriptional level, of excessive in vivo IL-1 oir TrdF levels, respectively, in a human to nornnal Levels ~r below normal levels; or c) a down regulation, by inhibition of the direct synthesis of IL-1 or TNF
levels as ~
postranslational event.
"'I'NF mediated disease or disease states°' means any and all disease states in which TIVF plays a role, either by production of 'Y'1~1F itself, or by 'I'NF
Gatasing' another cytokinie to be released, such as but not limited to IL-1 or iL-~. A disease state in which IL-1, fox ins~anc~ is a mayor compor~~nt; and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF. As TN~~-!3 (also known as lymphotoxin) has close structural homology with TNF-a (also known as cachect~n), and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-a and TNF-(3 are inhibited by the compounds of the present invention and thus are herein refezred'to collectively as "TfolF" unless specifically delineated otherwise:
Preferably TNF-a is inhibited.
dvo ~3r~~~a9 lPCrrus93ro~9~' "Cytokine" means any secreted polypeptide that affects the functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses. A cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce them. For instance, a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte, but many other cells produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes, and B-lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cytokines for the present invention include, but are not limited to, Interleukin-1 (IL-1), Interleukin-6 (1L-6), Interleukin-8 (IL,-8), Tumor Necrosis Factor-alpha (TNF-ce) and Tumor Necrosis Factor-beta ( i'NF-Vii).
The cytokine inhibited by the present invention for use in the treatment of a HIV- , infected human must be a cytokine which is implicated in (a) the initiation and/or maintenance of '1:' cell activation and/or activated T cell-mediated HIV gene expression and/or replication, and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration. Preferrably this cytakine is TNF-cc.
All of the compounds of Formula (I) are useful in the method of inhibiting the production of TNF, preferably by macrophages, rnonocytes o~ macrophages and monocytes, in a mammal, including humans, in need thereof. All of the compounds of Forra~ula (I) are useful in the method of inhibiting or mediating the enzymatic or catalytic activity of PDE IV
and in treatment of disease states mediated thereby.
METHODS OF PREPARATION:
Preparing compounds of the Formula (I) can be carried out by one of skill in the art according to the procedures outlined in the Examples, infra. The preparation of any remaining compounds of the Formula (I) not described therein may be prepared by the analogous processes disclosed herein which comprise:
a) fox compotands of the Formula (I) wherein R3 is H, CN, OR9, C1_4 alkyl or C1_rl halosubstituted alkyl, wherein X or X~ is ether than Br, I, N02; amino, fozmyl amine or S(O)m' when rn' is 1 or 2, ~.vherein Z is CHO and the double bond is present, reacting a compound of the Formula (2) RIO
l R3 X (2) wherein R I represents R l as defined in relation to Formula (I) or a group convertible to R 1 and X and X3 represent X and X3 as defined in relation to Formula (I) or a group convertible ~5 to X or X3 and R~ represents R3 as defined in relation to Formula (I) or a group convertible to R3, with nitromethane in a suitable non-reacting solvent in the presence of a base (catalyst) ~''~"~" ~'~'~ 2 ~. 3 3 ~ ~ 9 v I'C~'/IJS93/019'9i to provide compounds of the Formula (I) wherein R3 is H, CN, ORc~~ C1_4 alkyl or C1_~
halosubstituted alkyl, wherein X and X3 are other than Br, I, NO2, amino, formyl amine or S(O)m' when m' is 1 or 2, wherein Z is CH2N0~ and the double bond is present;
treatment of such compounds with a base, such as sodium methoxide, in the presence of, e.g., buffered titanium trichloride, provides compounds of the Formula (I) wherein R3 is H, CN, OR9, C1-4 alkyl or C1_4 halosubstituted alkyl, wherein X or X3 are other than Br, I, N02, amino, formyl amine or S(O)m' when m' is 1 or 2 and wherein Z is CHO and the double band is present. Double bond reduction of such compounds of the Formula (I) provides the corresponding saturated ring Formula (I) compounds; oxidation of the aldehyde function of either these saturated or unsaturated compounds of the Formula (I) provides the corresponding Formula (I) carboxylates (Z = COOH), which may be converted by standard procedures with proper manipulation of any chemically sensitive functional groups to the , corresponding ester, amide, nitrite, oxazolidinone, etc., Z groups of the Formula (I).
Alternatively, reaction of a compound of the Formula (2) with, e.g., tosylmethyl isocyanide and potassium t-butoxide (followed by hydrolysis) or lithium methoxyphenylthiotrimethylsilylmethane (followed by hydrolysis) provides compounds of the Formula (I) wherein R3 is H, CN, OR9 , C1_4 alkyl or C1_4 halosubstituted alkyl, wherein X and X3 are other than Br, I, NO2, amino, formyl amine or S(O)m' when m' is 1 or 2, wherein Z is C07R l g, the double bond is present, and R 1 ~ is H or simple allcyl; these then may be converted by standard procedures with proper manipulation (protection/deprotection) of any chemically sensitive functional groups to the corresponding ester, amide, rritrile, oxazoliditzone, etc., Z groups of the Formula (I).
Alternatively, reaction ref a compotand of the Formula (2) with, e.g., triflic anhydride in the presence of an appropriate tez~tiary amine base, or with an alkyl lithium at a reduced temperature followed by treatment with N-phenyl trifluorosulfanimide, provides the corresponding snot triflat~, which is then reacted vith carbon monoxide in the presence of an alcs~hol ar amine and an appropriate palladium catalyst to provide compounds of the Formula (I) wherein R3 is I-I, CN, OR9 , C1_~ alkyl or Cl_4 hat~substituted alkyl, wherein X and X3 are other than Br, I, NOZ, amino, forenyl amine or S(O)m' when m' is 1 or ~, wherein Z is C02R 1$ car CONR 1 OR 14, he double bond xs present, and R 1 S is I-I or simple alkyl; these thenuxaay be converted by standard procedures with proper manipulation (protection/deprotection) of any chemically sensitive functional groups to the corresponding ester; amide, nitrite, oxazoiidinone, etc., Z groups of the Formula (I):
Alternatirrely, reaction of a compound of the Fornattla (2) with, e,g., lithium 3S tris(methylthio)methane at reduced temperature; followed by mercury salt hydrolysis and alcohol treatment provides campounds of the Formula (I) wherein R3 is H, CN, ()R~ ; C1_r~
alkyl or C1_~ halosubstituted alkyl, wherein X end X3 are otht;r than Br, I, NO2, amino, formyl amine ar S(O)m' when m' is 1 or 2, wherein Z is CO?R15 and X5 is OH, the double bond is absent, and R15 is I-I or simple alkyl. Sueh compounds may also be obtained by WO 93/1949 ~ ~ P~d'/~1593/Oi991 reaction of a compound of the Formula (2) with trimethylsulfoxonium iodide or trimethylsulfonium iodide and an appropriate base, such as sodium hydride, to provide the exo-epoxide followed by treatment with aqueous potassium hydroxide in, e.g., dimethylsulfoxide and oxidation of the resulting primary alcohol to the carboxyl provides compounds of the Formula (I) wherein R3 is H, CN, OR9 , C1_4 alkyl or C1_~
halosubstituted alkyl, wherein X and X3 are other than Br, I, NO2, amino, formyl amine or S(O)m' when m' is 1 or 2, wherein Z is C02R1~ and X~ is OH, the double bond is absent, and R15 is H or simple alkyl; the R~ hydroxyl may be alkylated and these compounds then may be converted by standard procedures with proper manipulation (protection/depratection) of any chemically sensitive functional groups to the corresponding ester, amide, nitrite, oxazolidinone, etc., Z groups of the Formula (I).
Alternatively, reaction of a compound of the Formula (2) with, e.g., 2-lithio-(trimethylsilyl)-1,3-dithiane followed by acidic hydrolysis with a mercury salt, such as mercury (II) chloride, or reaction of a compound of the Formula (2) with, e.g., sodio-[diethyl i 5 t-butoxy(cyano)methyl phosphonate~ followed by ~eatment with acetic anhydride and a zinc halide and then followed by treatment with an alkoxide provides compounds of the Formula (I) wherein R3 is H, CN, OR9 , C1_4 alkyl or Cl-4 halosubstituted alkyl, wherein X and X3 are other than Br, I, NOZ, amino, formyl amine or S(O)m' when in' is 1 or 2, wherein Z is C02R 15, the double bond is not present, and R 1$ is H or simple alkyl and R~
is H; these then may be converted by standard procedures with proper manipulation (protection/deprotection) of any chemically sensitivb functional groups to the corresponding ester, amide, nitrite, oxazolidinone; etc., Z groups of the Formula (I).
Preparation of such compounds ~f the Formula (I) wherein R3 is C(=Z')H proceed in an analogous fashion from the compound of the Formula (~) wherein =Z' is an aldehyde protecting group, such as a dimethylacetal or a dioxolane, followed by aldehyde deprotection and subsequent manipulation by standard procedures known to those of skill in the art to the remaining compounds of the Formula (I) wherein Z' is other than O or R3 is other than H;
CN; OR9 , C 1 _q. alkyl or C 1 _~, halosubstituted alkyl.
With proper manipulation (protection/deprotection) of any chemically sensitive functional groups:
a) Compounds of the Formula (I) wherein X or X3 are formyl amine may be formed at the last step, by formylating a compound wherein X or X3 is NH2, obtained by removal of a protecting group, from the amine functionality; such protective groups are well known to those skilled in the art, She Greens, T. and Wuts, P.G.M., Protecting Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons; New York (1991).
c) Compounds of the Formula (I) wherein X or X3 are Br or I may be prepared from a similarly deprotected amine by diazotization of the amine and diazonium displacement.
d) Compounds of the Formula (I) wherein X or X3 are NO2 may be prepared from a similarly deprotected amine by oxidation of the amine to the nitro group.
e) Compounds of the Formula (I) wherein Y is S(O)m' when m' is 1 or 2 may be prepared from the compounds of the Formula (I) wherein Y is S by oxidation of the SR2 moiety under conditions well known those skilled in the art Compounds of the Formula (2) may be prepared in turn by the processes described in U.S. Patent Number 5,449,686.
It will be recognized that compounds of the Formula (1) may exist in two distinct diastereomeric forms possessing distinct physical and biological properties;
such isomers rnay be separated by standard chromatographic methods.
The following examples and methods are provided to illustrate how the make and use the invention. These materials are not intended to limit the invention in any manner; please refer to the claims appended hereto for determining what has been reserved to the inventors hereunder.
S YNTHETI~EXAMPL~S
Methyl 4-cvano-4-(3-cXcIQpen,~vlQxt-4-methox~yphen~,l~cvclohex-1-ene-1-carbox~ate 4-Cygno-4-(3-cyclc~pentylaxv-4-methoxyphen lY )_I_cyclohexenyl trifluQromet>~ls~ fonate To a solution of diisopropylamine [ 1.95 milliliters (hereinafter mL), 13.9 millimvles (hereinafter mmol)] in tetrahydrofuran ( 12 mL) at Oo C under an argon atmosphere was added n-butyllithium (5.8 mL of 2.5M solution, 14.15 mmol), the resulting solution was stirred for 25 minutes (hereinafter min) and then was cooled to -78oC. To this was added a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one [2 grams (hereinafter g), 6.64 mmol] in tetrahydrofuran (9 mL). The resulting mixture was stirred at -78o C for 2 hours (hereinafter h), at which time N-phenyl-trifluoromethylsulfonimide (4.98 g, 13.9 mmol) was added. The mixture was allowed to warm slowly to room temperature and after 5h, the mixture was poured into water and extracted with methylene chloride. The organic extract was deed (potassium carbonate) and conccntrated under reduced pressure. The residue was purified by flash chromatography, eluting with 4:1 hexanes/ethyl acetate, to afford an oil (1.09 g, 37%).
Methyl 4-cvano-4-(3-c~pentylox~4-methoxvph~nyl)cvclohex-I-ene-1=
carboxylate To a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-cyclohexenyl trifluoromethylsulfonate (1.0 g, 2.24 mmol) in 1:1 methanol/N,N-dimethylformamide (8 mL) were added triethylamine (0.66 mL, 4.72 mmol) and tetrakis(triphenylphosphine)palladium (0.13 g, 0.11 mmol). The resulting mixture was stirred at room temperature in the dark under a carbon monoxide atmosphere for 3h. The mixture was partitioned between water and ethyl acetate, the organic extract was washed three times with water, once with brine, was dried (potassium carbonate) and was evaporated.
CA 02133439 2002-09-23"x", L v ..
'WO 93/197A9 PCT/US93/01991 Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, provided an off-white solid (0.64 g, 80%): m.p. 128-1290 C.
Analysis Calc. for C21H25N04~1/8 H20: C 70.52, H 7.12, N 3.92; found: C 70.45, H 6.93, N 3.87.
4-Cvano-4-(3-c~clopent~x-y,-4-methoxxphenxl)cyclohex-gene-1-carboxylic acid To a solution of methyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate (0.07 g, 0.18 mmol) in methanol (0.5 mL, containing just enough tetrahydrofuran to solubilize the ester) under an argon atmosphere was added a solution of potassium hydroxide (0.03 g, 0.55 mmol) in water (0.4 mL). The resulting mixture was stirred at room temperature for 4h, then poured into water and extracted with ethyl acetate.
The aqueous phase was acidified with 3N hydrochloric acid and extracted twice with ethyl acetate. The organic phase from the acid extraction was dried (sodium sulfate) and concentrated under reduced pressure to provide a viscous oil, which solidified upon standing.
The solid was recrystallized from hexanes/methylene chloride (0.05 g, 82%):
m.p. 161-163oC.
Analysis Calc. for C2pH23N04~ 1/2H20: C 68.55, H 6.90, N 4.00; found: C 68.65, H 6.55, N
3.82.
~XA MPLE 3 Meth n r - 4-c -4- 1 t x -4- th x h 1 c lohexan - _ carboxvlatel Procedure 3A:
To a solution of methyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate (0,26 g, 0.73 mmol) in methanol (12 mL) was added 10%
palladium on activated carbon (0.15 g) and the resulting mixture was hydrogenated at 50 psi for 5h. The mixture was filtered through a pad of Celite and concentrated under reduced pressure. The residue was partitioned between methylene chloride and water, the extract was dried (potassium carbonate) and evaporated to a solid which was primarily the cis-ester (0.14 g, 54%): m.p. 94-95oC.
Ang_lysis Calc. for C21H27N04~1/8 H20: C 70.32, H 7.38, N 3.90; found: C
70.33. H 7.59, N 3.81.
Procedure 3B:
2 f4 Cvano 4 (3 ctc_looentvloxy_4-methox~henx_1)cvclohexylidenel-1 3-dithiane To a solution of 2-trimethylsilyl-1,3-dithiane (9.25 mL, 48.7 mmol) in dry tetrahydrofuran (80 mL) at 0o C under an argon atmosphere was added rapidly n-butyllithium (2.5M
in hexanes, 19.2 mL, 48 mmol). After 10 min, the mixture was cooled to -78oC and a solution of 4-cyano-4-(3-cyclopentyioxv-4-methoxyphenyl)cyclohexan-1-one (7.53 g, 23 mmol) in * trade mark CA 02133439 2002-09-23 , tetrahydrofuran (40 mL) was added. After 10 min, aqueous sodium chloride was added, the mixture was allowed to warm to room temperature and was diluted with water.
This mixture was combined with the product of three substantially similar reactions conducted on ketone (3.04, 6.01 and 6.1 g, 48.3 mmol total), the combined mixture was extracted three times with S methylene chloride, the extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 10% ethyl acetate/hexanes, provided a white solid (26 g, 87%): m.p. 115-116oC.
M th 1 - 4-c -4- -c 1 x -4- x h n 1 c 1 h xan -I=
carboxvlatel Perchloric acid (70%, 13.$ mL, 160 mmol) and mercuric chloride (34.1 g, 126 mmol) were added to a solution of 2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexylidene]-1,3-dithiane (13 g, 31.3 mmol) in methanol (0.5 L) under an argon atmosphere and the mixture was heated at reflux for 2h and then was allowed to stir at room temperature for 42h. The mixture was diluted with methylene chloride, was filtered x through Celite and the filtrate was combined with that of a similar reaction conducted concun:ently on the same scale. The mixture was neutralized with aqueous sodium bicarbonate, was extracted three times with methylene chloride, the organic extract was washed three times with aqueous sodium sulfite, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 15% ethyl acetate/hexanes, provided the cis-ester as a white solid (12.4 g, 56%): m.p. 119-120oC, along with an additional quantity of slightly impure product (2.6 g, 12%).
M h I r - 4-c ano-4- -c 1 en 1 x -4- th x h n I c lohex ne-I=
carboxylatel The mans-ester was also isolated from this mixture as a solid (1.04 g, 5%): m.p.
SO-51 o C.
Analysis Calc. for C21H27N04~314 H20: C 67.99, H 7.74, N 3.?8; found: C 67.98, H ?.35, N 3.65.
Methyl cis- and trans-14-(3 4-bisdifluoromelh_oxYphen_,~ It ?-4-cyanocvclohexane-1_ carboxylate 1 Procedure 4A:
2-14-(3 4-BisdifluoromethoxyrLe_null-4-cvanocvc~e~lidene]-2-/ert-butvloxY
acetonitrile Sodium hydride ($0% dispersion, 0.35 g, 11.7 mmol) was washed three times with pentane, was suspended in tetrahydrofuran ( 15 mL) at room temperature under an argon atmosphere and diethyl tern-butyl(cyano)methylphosphonate (2.66 g, 10.7 mmol) was added.
After O.Sh, a solution of 4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexan-I-one (1.77 g, 5.34 mmol) in tetrahydrofuran (5 mL) was added and the mixture was heated at rellux for O.Sh. The mixture was cooled, aqueous sodium chloride and water were added, the mixture was extracted three times with ether, the extract was dried (magnesium sulfate) and * trac7e-mark ~ ~. ~ ~ 4 3 9 ~ ~'~TSVS93/01991 evaporat . Purification by flash chromatography, eluting with 20% ethyl acetate/hexanes, provided the title compound as a white solid ( 1.1$ g, 52%).
I_yIethyl cis- and tran~f4-(3 4-bisdifluoromethox~!Dhenvl)-4-c~yclohexane-I=
carboxylatel A mixture of 2-(4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexylidene]-2-tart-butyloxy acetonitrile (0.25 g, 0.59 mmol) and zinc chloride (0.1 g, 0.7 mmol) in acetic anhydride ( 1.5 mL) under an argon atmosphere was heated at reflux for 10 min, was cooled, was diluted with water and was extracted three times with ether. The organic extract was washed with water, dried (magnesium sulfate) and evaporated. A solution of this acetate in methanol (6 mL) was treated with a solution of sodium methoxide (25% in methanol, 0.17 mL, 0.71 mmol) and the mixture was stirred under an argon atmosphere for 2h.
The mixture was acidified with hydrochloric acid (1101), water was added and the mixture was extracted thxee times with methylene chloride. The organic extract was dried (magnesium sulfate) arDd evaporated. Purification by flash chromatography and eluting with 20% ethyl acetate/hexanes provided the traps-isomer as a colorless oil (0.07 g, 30%).
Analysis Calc. for C17H17F4NO4: C 54.40, H 4.57, N 3.73; found: C 54.57, H
4.51, N 3.58.
The cis-isomer was also isolated as a yellow ail (0.1 g, 47%).
Procedure 4B:
Meth l cis-L4-(3.4-bisdifluoromethox~nhen~yl)-4-cyanocvclohexane-1-carhoxylatel A
solution of cds-(4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-i-carboxylic acid (EXAMPLE 10, 0.07 g, 0.19 mrnol) and trimethylsilyl chloride (0.12 mL, 0:95 mmol) in methanol (5 mL) was stirred at roam temperature under an argon atmosphere for 24h. The solvent was evaporated and the residue was purified by flash chromatography, eluting with 15°lo ethyl acetate/hexanes, provided a colorless ail (0.05 g, 63%).
Analysis Calc. for C17H17F4N~4: C 54.40, H 4.57; N 3.73; found: C 54.45, H
4.49, IV 3.42.
- 4-C ono-4- 3-c cl ant lox -4-m thox he 1 c clohexane-1-carbox lic acid and cis-4- 4-bisdifluarom~tht~x hen 1 -4-c an clohexane-1-carbox lic acid Ta a solution of methyl cis~-(4-cyapo-4-(3-cyclopentyloxy-4-methaxyphenyl)cyclohexane-1-c~rboxylate] (0.12 g; 0:34 mr~ol) in methanol (0.9 rnL, cbntaining just enough tetrahydrafuran to salubilize the ester) under an argon atrnasphtrre was added a solution of potassium hydroxide (O.Ofi g, 0.9 mmol) in water (0.7 mL). The resuating mixture was stirred at roam temperature for l:Sh, then poured into r ater and extracted with ethyl acetate. The aqueous phase was acidified with 10%
hydrotrhloric acid and extracted twice with ethyl acetate. 'i"he organic phase from the acid extraction was dried (sodium sulfate) and concentrated under reduced pressure to provide a solid.
T'he solid was purified by flash chromatography, eluting with 4% methanol/chloroform, to provide a white solid (0.05 g, 44%): m.p. 157oC:
WO 9~l197A) ~crm~~3/omg~
Analysis Calc. for C2~H25N~04~1/8H20: C 68.75, H 7.40, N 4.01; found: C
68.74,~H 7.08, N
3.84.
In a similar manner there was prepared:
cis-[4-(3,4-Bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylic acid] as a solid: m.p. 143-144oC.
Analysis Calc. for C16H15~4N04: C 53.19, H 4.18, N 3.88; found: C 53.57, H
3.91, N 3.59.
- 4- n -4- 1 -4- x 1 1 h x n -1- x 1 tn~Lk~~'d~~~I~~'lla~9~t~ ane bane salt To a solution of cis-{4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-carboxylic acid] (0.17 g, 0.5 mznol) in methanol (2 mL) was added an aqueous solution of, tris(hydroxymethyl)aminomethane (1.OI~JI, 0.5 mL). After 10 min, the solvent was evaporated, toluene and xt~ethanol were added and the liquads were removed in vacuo.
Trituration with ether provided a white solid (0.18 g, 79%): m:p. 191-194oC:
Analysis Calc. for C24H36N2O7-2:5I-120: C 56.57, H 8.11; N 5.50; found: C
56:44, H 7.75, N 5.62.
E7C~MPLE 7 trc~ns~f4-Cvano-4-(:~cvClo~ e~nt,~ox~4-mP~hQx~tt~h~n_yl~.yelohexan~I-carb~xvlic ~,cidl To a solution of methyl mans-[4-cyano-4-(3-cyciop~ntyloxy-4-"rnethoxyphenyl)cyclohexane-f-carboxylate] (0.68 g; I:9 mtnol) in methanol (8 mL, containing just enough tetrahydrofur~n to solubili~:e the ester) under an argon atmosphere was added mvater (4 mL) and patassium hydroxide (0.32 ~, 5:7 mmol). The resulting mixture was stirred at room temperature for 24h, was acidified with 10% hydrochloric acid and was extracted three times with 10°lo methanol/methylene chlorides The org~ic extract was dried (i7nagnesium ~aalfate) and cancentrated axndez~ reduced pressure: Purification by flash chromatography, eluting with 4% methanol/methylene chloride; provided a white semi-solid (0.52 880°l0), which was triturated with ether to yield a white solid (0.43 g): rn,p. 157-lS8oC:
Analysis Calc. for C2pH2~NOq.. C 69:95,1 7.34; N 4.08; found: C 68:69, I-I
7.30, N 4.07:
~ ~XAM1'L;E 8 ':
r ~ 4_ _~, r x -4- x' n 1 cl h x n -1=-carboxvlic acidl 8A. 2- 4- -4- n l x -4.m h x ~ ~ 1 1 h ~ li 1 - -~~loxy acetonitrile This cotxipound; prepared substantially as described above for 2-[4-~3,4-9aisdifluoromethoxyphenyl)-4-cyanocyclo-hexyiidenej-2-tart-butyloxy acetoriitrile in Procedure A of EXAMPLE 4; was isolated as a white solid: m:p. 109-110°C.
~Vl~ 93/ 19749 ~ ~" ~ ~ d~. ~ y, , . : ~'(.'1"/ >! 1593/01991 8B. M~hvl cis- and trctns-f4-cyano-4-(3-hvdroxy,-4-methoxyphenvllcvclohexane~
1-carboxylatel These compounds, prepared substantially as described above for methyl cis-and rrans-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylateJ
in Procedure A of EXAMPLE 4, were isolated as solids [cis-isomer (0.35 g, 33%):
m.p. 105-106oC; craps-isomer (0.52g, 49%): m.p. 103-104oCJ.
8C. Methyl cis-f4-cyana-4-(3-cYclopropylmethoxv-4=
methoxvohenvl cvclohexane-1-carbox r~at~i~ A suspension of methyl cis-[4-cyano-4-(3-hydroxy-4-methoxyphenyl)cyclohexane-l~-carhoxylate] (0.35 g, 1.20 mmol), powdered potassium carbonate (0.5 g, 3.6 mmol) and bromomethyl cyclopropane (0.35 mL, 3.6 mmol) in dry dimethylformamide (15 mL) under an argon atmosphere was heated at 85oC
far 4h.
The mixture was cooled, was diluted with water and was extracted three times with ether.
The organic extract was washed four times with water, once with brine, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 20% s ethyl acetate/hexanes, provided an oil (0.34 g, 82%).
1~ 8~~ ~ -~.L~4-Cvano-4-(3-cXc~ rmethoxv-4-methoxyphenYlWcvclohexane-1=
c_arboxvlic acidl The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid] in EXAMPLE
7, was isolated as a solid: m.p. 165-167oC .
Analysis Calc. for C1gH23NC)4~1/5 H20: C 68.53, H 7.08, N 4.21; found: C
68.70, H 7.07, N 4.16.
8E. Methyl traps-f4-cvano-4-(3-cyclopropylrnethoxx4~
methoxvohenvl)cvclohexane-1-carboxvatel The title compound, prepared substantially as desGa°ib~d above for methyl cis-[4~cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxyateJ in EXAMPLE 8C was isolated as a solid:
m.p.
127.5-128oC .
Analysis Calc. for C20H25N04-3l8 y120: C 68.60, H 7.41, N 4.00; found: C
68.50, H 7.28, N 3.88.
BF. r n - 4-C ano-4- 3-c c16 ro Imethox -4-methox hen 1 c clohexane-1-carboxviic acidl The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-rnethoxyphenyl)cyclohexane-l-carboxylic acid] in EXA1~PLE
'/, was isolated as a solid: m.p. 148oC .
Analysis Calc. for C1gH23N~4: C 69.28;1-3 7.04; N 4.25; found: C 68.97, H
7.03, N 4.25.
i - and tr - 4-C ano-4- 3-c clo ro lmethox -4-difluoromethox henvl c clohexane-c~rboxylic acidl 9A. 2-(4-CYano-4-(3-c~clop.~p l~methoxy-4_ difluoromethox hen~c cY_lohexvlidene,]-1 3-dithiane This compound, prepared substantially as described above for 2-[4-cyano-4-(3-cyclopentyloxy-4-'i~V(D 9~~/19749 ~ ~, ~ ~ ~ ~ P(.'t'/US93/~1991 methoxyphenyl)cyclohexylidene]-1,3-dithiane in Procedure B of EXAMPLE 3, wad isolated as a solid: m.p. 84-85oC .
9B. Methyl ci,s- and trap -f4-cyano-4-(3-cyclopropylmethoxv-4-difluorometno~=
phenvlLyclohexane-1-carboxvlatel These compounds, prepared substantially as described above for methyl cis- and trans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate] in Procedure B of EXAMPLE 3, were isolated as oils.
9C. cis-[4-Cyano-4-(3-cvcloprppylrrtethoxy-4=
difluoromethoxypheny~cyclohexane-1-carboxylic acids This compound, prepared substantially as described above for cis-[4-cyano-4-(3-eyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid] in EXAMPLE 7, was isolated as a solid:
m.p. 134-135oC . .
r Analysis Calc. for C19H21F2N04: C 62.46, H 5.79, N 3.83; found: C 62.15, H
5.83, N 3.88.
917, t-raps-I4-Cvano-4-(3-c cal _lopropylmethoxy-4-difluoromethoxy;~henxl)~
cyclohexane-1-carboxylic acidl The title compound, prepared substantially as described above for cfs-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid] in EXAMPLE 7, was isolated as a solid: m.p. 128-129oC.
EXAMPLE; 1~
~-14-Cyano-4-(3-c~clopentyloxv-4-~thoxvphen~l)c c~lo_hexane-1-carboxamidel To a solution of methyl cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cycloh~xane-1-carboxylate] (0.22 g; 0.62 mmol) and formarnide (0.08 n~.L, 2.(38 mm01) at 100oC in dimethylformarlaide (2 rnL,) under an argon atmosphere was added p~rtionwise over 20 min sodium metlaoxide (25% solution in methanol, 0:1 mL, 0.43 mmol).
After an additional 1.25h at lUOoC, the mixture was cooled; was poured into isopropanol, was filtered and the filtrate evaporated. The residue was dissolved in ethyl acetate, the organic phase was washed three times with water, was dried (magnesium sulfate) and vsras concentrated under reduced pressure. Purification by flash chromatography;
eluting with 3%
methanol/methylene chloride; provided'a white foam (O.Ob g, 28%).
Analysis Calc. for C20I-126N2O3~3/8H20: C 68:79, H 7.72, N.8.02; found: C
68.86, H 7.49, N 7.93.
ExAMPL.E 11 i - 4- 3 4-Bisdifiuoromethox hen 1 -4-c: ano-1- 3-meth 1 1 2 4 oxadiazol-5-yl)cxclohexane j, cis-and traps-~4-(3,4-Bisdifluoromethox~pheti l~-c~ano~cyclohexane-1-carboxatrtidel These compounds, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide] in EXAMPLE 14, were isolated as a solid (Cis isomer: m:p. i09-1 lOoC ) and as an oil (traps isomer).
~vo ~a~l m7ao PCT/US93/Oi 99 i C!S_- L4-f 3.4-Bisdifluoromethoxy~henXl )-4-c~tana-1~3-methyl I~
1,2.41oxadiazol-5 xl)cyclohexane 1 A solution of cis-[4-(3,4-bisdifluaromethaxyphenyl)-4-cyanocyclohexane-1-carboxamide] (0.06 g, 0.17 mmol) in N,N-dimethylacetamide dimethyl acetal (0.5 mL) was heated at 110aC under an argon atmosphere for lh, was cooled and the solvent was evaporated. Dioxane (0.35 mL), acetic acid (0.35 mL), hydroxylamine hydrochloride (0.02 g, 0.29 mmol) and 10% aqueous sodium hydroxide (0.09 mL, 0.26 mmol) were added and the mixture was heated at 95oC under an argon atmosphere for 2.5h. The mixture was cooled, water was added, the mixture was extracted three times with methylene chloride, the organic extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 4% methanol/methylene chloride, provided a solid (0.03 g, 37%). This product was combined with that (0.04 g) from a sirniiar reaction sequence and was triturated with hexane to yield a tan solid: m.p. 83-84oC.
Analysis Calc. for C1gH17F4N3~03: C 54.14,-H 4.29; N 10.52; found: C 54.11, H
4.35, N
10.13.
cis- f 4-(3,4-Bisdifiuaromethaxv~henXl~ 4-~ano-1-(2-methyl[1,3.41oxadiazol-5~
yl~c clohexane 1 - 4- 4-Bis ifluoromethox hen 1 -4-c noc clohexane-l~carboh drazide A
solution of methyl cis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclahexane-1-carboxylate] ( 0.2 g, 0.53 moral) xnd hydrazine hydrate (0.28 txZL, 9.0 mmol) in ethanol (2.5 mL) was heated at reflux for 6h and then stirred at room temperature for 16h.
Water ores added, the mixture was extracted thr~~ times with nnethylene cla~oride, the extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 4%
methanol/metttytene chloride; provided a solid (0.12 g; SB%): ixi.p. 80-8loC.
4- 4.-Bisdifluoromethox hen 1 -4-c anoc clohexane-1- 2-~cet 1-carho-hxdrazidell A solution of ~rnethyl ciS-[4=(3,4-bisdifluarotnethaxyphenyl)~4-cv~nocyclahexane-1 ~earbohyrirazide] ( 0:11 g, 0.29 rnmol); triethylamine (0:09 mL, 0.65 txtmol) attd acetic anhydride (0.05 mL; 0.54 moral) in trthanol (7:S mL) was heated at reflex for lh, was cooled and the solvent rwas evaporated: VVat~r was added; the mixture was extracted three times with rnethylene chloride, the ex~atrt u~as dried (magnesitam sulfate) and evaporated to provide a'~rhate solid (0.11 g, 85%): m:~. 144-145aC.
~s- ( 4-~3 4 ~8i,~difluorarnethaxvtJhen~,li-4-c~ana-1-(3-tnethvl f l ,3.41oxadiazol-5e yl)~~clohexane i A smlution of cis-[4-(3,4-bisdifluaramethoxyphenyl)-4-eyanacycloheacane-1-(2-acetyl-carbohydrazide)] (0:1 g, 0.24 mmol) and phosphorpus oxychlaride (0.25 nnL, 2:6$ mri~al) in toluene (3 mL) was heated at reflex under an argon atmosphere for 1.5h. The mixture was cooled, water was added, the mixture was extracted three times with 5%
methanol/methylene chloride, the organic extract was dried (magnesium sulfate) and was V1~~ 93/ 19749 P(.°T/ U~9~/01991 evaporated. Purification by flash chromatography, eluting with 1:2 hexanes/ethyl acetate, provided an oil.
Analysis Calc. for C18H17F4N3C3~1.0 H20: C 51.80, H 4.59, N 10.07; found: C
52.00, H
4.25, N 9.76.
( 4-(3,4-Bisdifluoromethoxxphenyl)-4-cXano-1-(2-meth~I 1 3 4lthiadiazol-5=
xlZcvclohexane 1 A solution of ciS-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-(2-acetyl-carbohydrazide)] (0.1 g, 0.24 mmol) and Lawesson's Reagent (0.13 g, 0.32 mmol) in toluene (3 mL) was heated at reflux under an argon atmosphere for 0.5h. The mixture was cooled, saturated aqueous sodium bicarlaonate was added, the mixture was extracted three times wish methylene chloride, the organic extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with~l:l hexanes/ethyl acetate, provided a solid: m.p. 66-67oC. , Analysis Calc. for C18H 17F4N302 S: C 52.04, H 4.13, N 10.12; found: C 51.67, H 4.06> N
9.92.
~~-(4-C~ano-4-(3-cvclopropvlmethox~G-methoxyphen 1~-hh,ydroxy-1-tris(meth~lthio meth lcwclohexanel n-Bdtyllithium (1:9M in hexanes, 0.4 mL, 0.76 mtnol) was added dropvvise over xnin to a solution of tzis(methylthio)rnethane (0.11 mI:, 0.83 mmol) iri dry tetrahydrofuran (3 mL) at -78oC under an argon atmosphere: After ~ S min, a solution of 4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane (0:2 g; 0:67 mmol) in dry tetrahydrofuran (3 mL) was added drop~?vise over :10 rnin;. t~fter 0.5h;
aqueous aaxtmonium chloride was added and the' mixture was allowed to warm to room tempez°ature. The mixture was extracted three times with trtethylesie ~hioride; the organic extract was dried (magnesium sulfate) and evaporated. P~rifica ion by flash chromatography; eluting ~rith 25% ethyl acetate/hexanes; provided a white solid (0:25 g, 84%): m.p: 123-124oC:
Analysis Calc: for C2z1H31N~~53: C 58.21, H f:89; N 3:09; foa~nd: C 58.57, II
6.81; N 2:92.
Methyl ads-L-cyano-4-(3-cvclopropylm~thoxy-4-methoxyphen l~~rdrox~c~clohexane-3$ carboxvlatel Mercuric chloride (0.2:3 g, 0.85 tnmol) an~3 mercuric oxide (0.08 g, 0.37 tz~mol) were added to a solution of cis-[4-c~rano-4-(3-cyclopropylrnethoxy-4-methoxyph~nyl)-1-hydroxy-1-Iris(meth~lthio)rnethylcyciohexane] (0.1 g, 0:22 mmol) in 12:1 anethanol/water (2 mL) under an argon atmosphere and the mixture was allowed to stir at room temperature for 4h.
L ~ ~..,..
The mixture was filtered through Celite, the filtrate was diluted with water and was extracted three times with methylene chloride, the organic extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35% ethyl acetate/hexanes, provided a sticky solid (0.67 g), which was mturated with ether/hexane to provide a solid (0.47 g, 59%). m.p. 102-103oC.
Analysis Calc. for C2pH25NO5~1/2 H20: C 65.20, H 7.11, N 3.80; found: C 65.31, H 6.83, N 3.54.
EXAMPLE 1~
- 4- n -4- -c cl r -4- n 1 -1- x c 1 xane-1=
carboxv~ acidl The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid] in EXAMPLE 5, was isolated as a solid: m.p. 168-169oC .
Analysis Calc. for C19H23N05~1/4 H20: C 65.22, H 6.77, N 4.00: found: C 64.94, H 6.62, N 3.80.
EXAMP~.E 17 - 4- ano-4- -c cl r lm th x -4- h x h n 1 -1-h rox c clohexan -1=
car~vxamidel A solution of cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxy-phenyl)-1-hydroxycyclohexane-1-carboxylic acid) (0.15 g, 0.42 mmol) and a trace of sodium cyanide in methanol ( 1.5 mL) contained in a pressure vessel was cooled to -78 and anhydrous ammonia (2 rnL) was condensed into the tube. The tube was sealed, was allowed to come to room temperature and the reaction was stirred for 2 days. The ammonia was allowed to evaporate and the reaction was partitioned between water and methvlene chloride. The organic extract was dried (magnesium sulfate) and the solvent was evaporated. Purification by flash chromatography, eluting with 3% methanol/chloroform, provided a solid (0.054 g, 38%):
m.p. 144-145oC.
Analysis Calc. for CI9H24N2~4~ 1/4 H2O: C 65.41, H 7.08. N 8.03; found: C
65.16, H 6.96, N 7.86.
Methyl cis-f4-cvano-4-(3-cYclovropvlmethox~t-4-methoxx~henyl)-1-methoxycvclohexane-1=
carbox~latel Silver (I) oxide (0.62 g, 2.7 mmol) was added to a solution of methyl cis-(4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate]
(0.62 g, 1.7 mmol) and iodomethane (5 mL) in acetonitrile (5 mL) under an argon atmosphere and the mixture was heated at reflux in the dark for 18h. The mixture was cooled, was filtered * trade-mark WU 93/ 19749 .& r ~'C°1'/U~93/01991 through Celite and the filtrate was evaporated. Pu:rifrcat.ion by flash chromatography, eluting with 20% ethyl acetate/hexanes, provided a solid (U.SS g, 86%): m.p. 75-76oC.
.
Analysis Calc. for C21H27N05: C 67.54, H 7.29, N 3.75; found: C 67.46, H 7.30, N 3.80.
His-f 4-Cyano-4-(3-cvclovrorwlmethoxy-4-methoxyphenvl)-1-methoxycvclohexane-1=
carboxylic acidl The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclahexane-1-carboxylic acid] in EXAMPLE 5, was isolated as a solid: m.p. 110-112oC .
Analysis Calc. for C20H25NU5: C 66.84, H 7.01, N 3.90; found: C 66.64, H 7.29, N 3.95.
ci~.~.14-C ono-4-~3-c~,cloprop~lrnethoxy-4-methoxyphenvl -1-methoxXcyclohex~ne-1=
carboxamidel A solution of cis-~4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylic acid] (0.13 g, 0.36 mmol) and N-methylmorpholine (0.05 mL, 0.45 mmol) in 1,2-dimethoxyethane (2.5 mL) at room temperature under an argon atmosphere r ~as treated with isobutyl chloroformate (0.05 mL, 0.39 mmol).
After 10 min, concentrated ammonium hydroxide (6 drops) was added and the mixture was stirred for an additional O.Sh. Water was added, the mixture was extracted three times with 5%
methanol/methylene chloride, the organic extract was dried (magnesium sulfate) and the solvent avas edaporated. Purification by flash chromatography, eluting with 3%
methanol/chloroform, provided a solid (0.13 g; 100%): m.p. 165-166oC.
' Analysis Calc: for CzOH26N?U4~3/8 H2U: C 65.78, H 7.35> N 7:67; found: C
65.65, H 7.23;
N 7.47.
Me h I r - 4-c ono-4- 3-c clo ro Iran ,thox -4-m th x hen 1 -1-h drox c clohexane-1-carboxvlatei ~ _ 4-C ana-4- -c cl rn Imethox -Q-meth x hen 1 -1-c cl hexane-1 1-divlloxiranel 'I'o a mixture of 80% sodium hydride in mineral oil (0:33 g, l l mmol) and tr-irrtethylsulfoxonium iodide (1.69 ~, 7.67 anmol) at roorm temperature under an argon atmosphere was added dropwise dimethylsulfoxide (12 mL) and the reaction mixture gas stirred for 30 min. A solution of 4-cyan'o-4-(3-cyclopropylmethaxy-3-methoxyphenyl) -cyclohexanone (2.00 g; 6:68 mmol) in dimethylsulfoxide (S mL) vvas added and stirring was continued for 30 min: The reaction mixture was quenched with saturated ammonium chloride, was partitioned between ethyl acetate and water; was dried (magnesium sulfite) and zs W~ 93/ y 97d9 ~ e7 PC~'/US93/01991 the solvent was removed in vactso . The residue was purified by flash chromatograj~hy, eluting with 1:3 ethyl acetate/hexanes, to provide a colorless oil (1.42 g, 6810).
Analysis Calc. for C19H23N~33'H2p: C 68.86, H 7.30, N 4.23; found: C 69.22, H
Methyl ads-L-cyano-4-(3-cvclopropylm~thoxy-4-methoxyphen l~~rdrox~c~clohexane-3$ carboxvlatel Mercuric chloride (0.2:3 g, 0.85 tnmol) an~3 mercuric oxide (0.08 g, 0.37 tz~mol) were added to a solution of cis-[4-c~rano-4-(3-cyclopropylrnethoxy-4-methoxyph~nyl)-1-hydroxy-1-Iris(meth~lthio)rnethylcyciohexane] (0.1 g, 0:22 mmol) in 12:1 anethanol/water (2 mL) under an argon atmosphere and the mixture was allowed to stir at room temperature for 4h.
L ~ ~..,..
The mixture was filtered through Celite, the filtrate was diluted with water and was extracted three times with methylene chloride, the organic extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35% ethyl acetate/hexanes, provided a sticky solid (0.67 g), which was mturated with ether/hexane to provide a solid (0.47 g, 59%). m.p. 102-103oC.
Analysis Calc. for C2pH25NO5~1/2 H20: C 65.20, H 7.11, N 3.80; found: C 65.31, H 6.83, N 3.54.
EXAMPLE 1~
- 4- n -4- -c cl r -4- n 1 -1- x c 1 xane-1=
carboxv~ acidl The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid] in EXAMPLE 5, was isolated as a solid: m.p. 168-169oC .
Analysis Calc. for C19H23N05~1/4 H20: C 65.22, H 6.77, N 4.00: found: C 64.94, H 6.62, N 3.80.
EXAMP~.E 17 - 4- ano-4- -c cl r lm th x -4- h x h n 1 -1-h rox c clohexan -1=
car~vxamidel A solution of cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxy-phenyl)-1-hydroxycyclohexane-1-carboxylic acid) (0.15 g, 0.42 mmol) and a trace of sodium cyanide in methanol ( 1.5 mL) contained in a pressure vessel was cooled to -78 and anhydrous ammonia (2 rnL) was condensed into the tube. The tube was sealed, was allowed to come to room temperature and the reaction was stirred for 2 days. The ammonia was allowed to evaporate and the reaction was partitioned between water and methvlene chloride. The organic extract was dried (magnesium sulfate) and the solvent was evaporated. Purification by flash chromatography, eluting with 3% methanol/chloroform, provided a solid (0.054 g, 38%):
m.p. 144-145oC.
Analysis Calc. for CI9H24N2~4~ 1/4 H2O: C 65.41, H 7.08. N 8.03; found: C
65.16, H 6.96, N 7.86.
Methyl cis-f4-cvano-4-(3-cYclovropvlmethox~t-4-methoxx~henyl)-1-methoxycvclohexane-1=
carbox~latel Silver (I) oxide (0.62 g, 2.7 mmol) was added to a solution of methyl cis-(4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate]
(0.62 g, 1.7 mmol) and iodomethane (5 mL) in acetonitrile (5 mL) under an argon atmosphere and the mixture was heated at reflux in the dark for 18h. The mixture was cooled, was filtered * trade-mark WU 93/ 19749 .& r ~'C°1'/U~93/01991 through Celite and the filtrate was evaporated. Pu:rifrcat.ion by flash chromatography, eluting with 20% ethyl acetate/hexanes, provided a solid (U.SS g, 86%): m.p. 75-76oC.
.
Analysis Calc. for C21H27N05: C 67.54, H 7.29, N 3.75; found: C 67.46, H 7.30, N 3.80.
His-f 4-Cyano-4-(3-cvclovrorwlmethoxy-4-methoxyphenvl)-1-methoxycvclohexane-1=
carboxylic acidl The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclahexane-1-carboxylic acid] in EXAMPLE 5, was isolated as a solid: m.p. 110-112oC .
Analysis Calc. for C20H25NU5: C 66.84, H 7.01, N 3.90; found: C 66.64, H 7.29, N 3.95.
ci~.~.14-C ono-4-~3-c~,cloprop~lrnethoxy-4-methoxyphenvl -1-methoxXcyclohex~ne-1=
carboxamidel A solution of cis-~4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylic acid] (0.13 g, 0.36 mmol) and N-methylmorpholine (0.05 mL, 0.45 mmol) in 1,2-dimethoxyethane (2.5 mL) at room temperature under an argon atmosphere r ~as treated with isobutyl chloroformate (0.05 mL, 0.39 mmol).
After 10 min, concentrated ammonium hydroxide (6 drops) was added and the mixture was stirred for an additional O.Sh. Water was added, the mixture was extracted three times with 5%
methanol/methylene chloride, the organic extract was dried (magnesium sulfate) and the solvent avas edaporated. Purification by flash chromatography, eluting with 3%
methanol/chloroform, provided a solid (0.13 g; 100%): m.p. 165-166oC.
' Analysis Calc: for CzOH26N?U4~3/8 H2U: C 65.78, H 7.35> N 7:67; found: C
65.65, H 7.23;
N 7.47.
Me h I r - 4-c ono-4- 3-c clo ro Iran ,thox -4-m th x hen 1 -1-h drox c clohexane-1-carboxvlatei ~ _ 4-C ana-4- -c cl rn Imethox -Q-meth x hen 1 -1-c cl hexane-1 1-divlloxiranel 'I'o a mixture of 80% sodium hydride in mineral oil (0:33 g, l l mmol) and tr-irrtethylsulfoxonium iodide (1.69 ~, 7.67 anmol) at roorm temperature under an argon atmosphere was added dropwise dimethylsulfoxide (12 mL) and the reaction mixture gas stirred for 30 min. A solution of 4-cyan'o-4-(3-cyclopropylmethaxy-3-methoxyphenyl) -cyclohexanone (2.00 g; 6:68 mmol) in dimethylsulfoxide (S mL) vvas added and stirring was continued for 30 min: The reaction mixture was quenched with saturated ammonium chloride, was partitioned between ethyl acetate and water; was dried (magnesium sulfite) and zs W~ 93/ y 97d9 ~ e7 PC~'/US93/01991 the solvent was removed in vactso . The residue was purified by flash chromatograj~hy, eluting with 1:3 ethyl acetate/hexanes, to provide a colorless oil (1.42 g, 6810).
Analysis Calc. for C19H23N~33'H2p: C 68.86, H 7.30, N 4.23; found: C 69.22, H
7.11, N
4.17. Starting material was also recovered (0.6 g, 30%).
Ir~4-C ano-4-(3-cvc~rowlmethoxX-4-methoxyvhen~)-1-hxdroxymethvl-1~
cvclohexanol A mixture of traps-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-cyclohexane-1-methyleneoxide (1.31 g, 4.18 mmol) and potassium hydroxide (0.14 g, 2.5 mmol) in 85:15 dimethylsulfaxide/water { 140 mL) under an argon atmosphere was heated at 100-I lOoC for Ih, was cooled, was diluted with water and was extracted three times with ethyl acetate. The organic extract was washed five times with water, was dried (magnesium stalfate) and was evaporated. Purification by flash chromatography, eluting with 3.5:96.5 methanol/dichloromethane, provided the rran~-isomer as a sticky white solid:
m.p. 38-42oC
(0.96 g, 69%).
Analysis Calc, for C19H25N~4: C 68.86, H 7.60, N 4.23; found: C 68.96, H 7.62, N 4.03.
. traps-j4-Cvano-4-(3-c~propvlmethoxy-4-rnethoxvphenvl) 1 hvdroxv-cvclohexane-1-carboxaldeh~ To a solution of oxalyl chloride (0.28 rte, 3.21 mmol) in dichloromethane (3.5 mL) at -78oC under an argon atmosphere was added dropwis~
a solution of dimethylsulfoxide (0.46 tnL., 6.48 mmol) in dichlorornethane (3.5 mL) such that the internal temperature did not exceed -6UoC. A solution of trams-4-cyano-4-(3-cyclopropylmethoxy-3-methoxyphenyl)-1-hydroxymethyl-1-cyclohexanol (0:89 g, 2.68 mmol) in dichloromethane (7 mL) was added dropwise and stirring was continued for 30 min. Triethylamine ( 1.80 mL, 12.9 mmol ) was added over 10 min, then 5 min later, the reaction mixture was allowed to warm to room temperature over 1 h. The reaction mixture was queb,ched with water and was extracted with three portions of dichloromethane. The combined organic layers were washed with I% hydrochloaic acid, 5% sodium carbonate and water, dried (magnesium sulfate) and the solvent was removed in vacuo to provide crude alciehyde (0:85 g, 9? %).
Meth 1 r - 4-c ano-4- -c cl ro lmethox -4-rnethox hen 1 -1-h drox cyclohexan~-1-carbox~,laiel To a solution of traps-[4-cyarao-4-(3-cyclopropylmethoxy-4-methbxyphenyl)-1-hydroxycyclohexane-l-carboxaldehyd~ (0.79 g, 2.4 mm01) in methannol (25 rnL) at 0aC under ati argon atmosphere was rapidly added a solution of potassium hydroxide (0.36 g, 6.43 mmol) in nnethanol (5 mL); followed by a solution of iodizie (0.80 g, 3.15 mmol) in metltanol (S mL). After I5 min the reaction was acidified with IN
hydrochloric acid and extracted with three portions of dichloromethane. The combined organic layers were washed :with ague~us sodium bisulfite until color was discharged, then with water, dried (magnesium sulfate), and the salvent was removed in vacuo..
Purification by flash chromatography, eluted with 35:65 ethyl acetate/hexanes , provided a white solid (0.82 g, 94 %): ri'r.p.148-149aC.
'WCD 93/ t 9749 ~'CT/LJS93/O1991 Analysis Calc, for C20H25NC5'1/4 H20: C 66.01, H 7.06, N 3.84; found: C 65.86:
H 6.92, N 3.85.
r -4- n - n I- -h x 1 x n -ar xylic a~dl The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid] in EXAMPLE 5, was isolated as a solid: m.p. 147-148oC.
Analysis Calc. for C1gH23N05: C 66.07, H 6.71, N 4.06; found: C 66.02, H 6.71, N 4.04.
EXAMPLE 23 , I~I~h, 1 r - 4- n -4- r 1 -4- ~ h x h n I -1-m h x I h n -1-warboxvlatel The title compound, prepared substantially as described above for methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- l-methoxycyclohexane-1-carboxylate]
in EXAMPLE 18, was isolated as a solid: m.p. 84-85oC.
Analysis Calc. for C21H27Nt75: C 67.54, H 7:29, N 3.75; found: C 67.34, H
7.25, N 3.77.
r - 4.- -4- -4- LYlwll-1°methox~ry~l exam-1=
~ r x lic act]
The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentylaxy-4-methoxyphenyl)cycloh~xan~-1-carboxylic acid] in EXAli~'LE S>
was isolated as a solid: m.p, 15$-159°C.
Apalysis Calc. for C2pH~5NC~5~1/4 ~T2C: C 66.01, I~ 7.06, N 3.85; fotynd: C
65.98; H 6.91, N 3:75.
~XA~.~IV1PLE 2~' r = 4- ~ n -4- r 1 x -4- h x h n 1 _ 1 _~ h X c ~ n -carboxamydel The title bampbund; prepaz~ed substantially as described above for cis-[4-cyano-4-(3-cyclopenty)axy-4-methoxyphenyl)-1-ra~etho;cycyclohexane-1-carboxarriide] in EXAMPLE'' 20; was isolated as a solid: m:p: 16$-169oC:
Analysis Calcfor C2pH2~N204v1/8 H20: C 6.60; H 7.34,1x17.70; found: C 66.60, H
7,30;
loI 7.74.
'1~0 93/ 19749 ~ ~. 3 ~ ~ 3 ~ ~c~-eus93eoa99~
~-f4-~ano-4-(,~cvclopentyloxv-4-methoxvvhenv~cyclohexane-1-carboxamic acidl The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide] in EXAMPLE
but using hydroxylamine instead of ammonia, was isolated as a solid: m.p. 100-102oC.
Analysis Calc. for C2pH26N2o4: C 67.02, H 7.31, N 7.82; found: C 66.75, H
7.58, N 7.42.
N-M~thyl-cis-t4-c~~ano-4-(3-c c~~,lopentvlox ~~-4-methoxxphen~~c clv ohe_xane-1-carboxamic acid The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide] in EXAMPLE
but using N-methylhydroxylamine instead of ammonia, was isolated as a solid:
rri.p. 75-76oC.
Analysis Calc. for C21H28N2O4~1/4 H20: C 66.91, H 7.62, N 7.43; found: C
66.95, H 7.54, N 7.35.
- 4-C ono-4- ~-c clo ent lox -4-metlaox hen I c clohexane-l-N- 2-c a~noeth, Iwcarboxamide To a solution of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-carboxylic acid] (0.55 g, 1.6 mmol), 1-hydroxybenzotriazole (0.24 g, 1.76 mmol) and 3-atninopropionitrile (0.11 g, l.6 mz~ol) in dichlorort3ethane ( 10 mL) at OaC
under an argon atmosphere was added l-(3-diethyi~minopropyl)-3-ethylcarbodiimide hydrochloride (0,34 g, ?5 1.76 mmol) and the mixture was allowed to warm to room temperature. After 6h, the mixt>are eeas diluted with dichloromethane; was gashed twice with 10% aqueous potassium ~~~~ate; twice with 10 % hydrochloric acid and was dried (znagnesiutn sulfate). The solvent was evaporated and the residue was crystallized from hexanes/ethyl acetate to provide a solid (0:54 g, 85%): tn.p: 146-147eC.
Analysis Calc: for C23H29Io13~3: C 69.85, H 7.39, N 10:62; found: C 69.491-17.41; N 10.46.
cis-f 1-(2-Cyanoethr~l -5-f 4-cva~~o-4-f3-cyclo~entvloxy-4 methox~phen~yclbhex~l tetxazole, 'To a solution of cas-[4-cyano-4-(3-cyclopentylaxy-4-methoxyphenyl)cyclohexane-N-(2-cyanoethyl)carboxatnide] (0.15 g, 0.37 mmol), triphenylphosphin~ (0.19 g, 0.73 mmol) and trimethylsilylazide (0.097 mL, 0.73 mmol) in dry tetrahydrofuran (2 mL) at ro~m temperature under an argon atmosphere was added dropwise diethyl azodiearboxylate (0.12 mL, 0.73 tnmol) and the mixture was stirred in the dark for 24h. Ceric ammonium nitrate ~Vtn 9:i/1974~1 ~ t~ ~ l~ PCT/US93J0~991 (0.81 g, 1.48 mrnol) in water (10 mL) was added at OeC, the mixture was extracted Three times with dichloromethane, the extract was dried (magnesium sulfate) and the solvent was evaporated. Purification by flash chromatography, eluting with 2:1 ethyl acetate/hexanes, followed by recrystallization from hexanes/ethyl acetate, provided a white solid (0.03 g, 19%): m.p. 149-1 SO~C.
Analysis Calc. for C23H28N602: C 65.69, H 6.71, N 19.99; found: C 65.45 H
6.72, '~t 19.91.
~XAIvIfLE 3~
- 4- an -4- 1 n 1 x -4-m h x h n 1 -1- z 1 1 c 1 h xan A mixture of cis-( i-(2-cyanoethyl)-5- { 4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl } tetrazole~ (0.098 g, 0.23 mrnol) and sodium hydroxide (0,018 g, 0.46 mmol) in 10:1 tetrahydrofuran/water (5 mlL) at room temperature under an argon atmosphere was stirred overnight. The mixture was acidified with 3N
hydrochloric acid, was extracted three times with ethyl acetate, the extract was dried (magnesium sulfate) and the solvent was evaporated. Purification by flash chromatography, eluting with 80:20:?
chloroform/methanol/water, followed by trituration .with hexanes/ethyl acetate, provided a white solid (0.038 g, 45%): m.p. 190-191nC.
Analysis Calc. for C20H25N5~2~ 1/2 I-I20: C 63.81, H 6.96, N 18.60; found: C
64.07 H 6.79, N 18.54.
TH~L~S CaF_'1R~ATNLENT
In order to use a compound of Formula (I) ~or a:pharmaceutically acceptable salt Thereof for the treatment of humans-and other mammals, it is normally formulated in accordance with standard pharmaceutical practice .as a pharmaceutical composition. The compounds of Formula (I) ar a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the praphylatic or therapeutic treatment of any disease state rn a human ~r other mammal dvhich is mediated by inhibition of PDP IV, such as but/not limieed to asthma; allergic, or inflammatory diseases. The cornp~urads of Foranula (I) are administered art an amount sufficient to treat rush a disease in a human or other mammal.
The method of treatment and monitoring for an I-IIV-infected human manifesting immu~~ dysfunction or cytokine-mediated disease associated problems is taught in Hanna, W0 90/15534; December 27; 1990. In general, an initial treatment regimen can be copied from that known to be effective in interfering with "fI~F activity fir other TNF mediated disease states by the compounds ~f Formula (I). Treated individuals wall be regularly checked for T cell numbers and T4/T8 ratios and/or measures of ~riremia~ such as levels of reverse transcriptase or viral proteans, and/or for progression of monokine-mediated disease associated problems such as cachexia or muscle degeneration: If no effect is seen following the normal treatment regimen, then the amount of the monokine activity interfering agent administered is increased, e.g., by fifty percent per week.
'WU 93/19749 ~ , .
~~Cl"/U~93/01991 The pharmaceutical composition of the present invention will comprise an effective, non-toxic amount of a compound of Formula (1) and a pharmaceutically acceptable carrier or diluent. The compounds of Formula (n are administered in conventional dosage forms prepared by combining a compound of Formula (17 in ari amount sufficient to produce TNF
production inhibiting activity, respectively, with standard pharmaceutical carriers according to conventional procedures. These procedures may involve mixing, granulating, and compressing or dissolving the ingredients as appropriate to the desired preparation.
'Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 gram. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension. Where the compositie~n is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates, ar oils and are incorporated in a soft gelatin capsule shell. A
'syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine, or water with a flavoring or coloring agent.
The daily dosage regimen for oral administration is suitably about .001 mg/kg to 100mg/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 rriay be administered from l to ~5 times a day, sufficient to exhibit activity.
While it is possible for an active ingredient to be administered neat; it is preferable to present it as a pharmaceutical formulation. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g., from l% to 2% by weight of formulation, although it may comprise ~s xntich as 10% w/w but preferably not in excess of 5% w/w and snore preferably from 0.1 % to l % w/w of Formulation:
__._ Formulations of the present invention comprise an active ingredient together with one or more acceptable carriers) thereof arid optionally any other therapeutic itagi~edient(s). The carriers) must be 'acceptable' in the sense of being compatible with the other ingredients of Formulation and not deleterious to the recipient thereof.
It will be recognized by one of skill in the art that the form and~character of the pharmaceutically acceptaole carrier or diluent is dictated by the amount of active ingredient with which it is'to be combined, the route of administration, and other well-known variables.
No ttsxic effects are expected when these compounds are administered in accordance with the present invention.
~vo 9m ~ 97a9 ~ ~. 3 ~ ~~ 3 ~ , PC1'/ IJS93/01991 J~TILIT'Y EXAMPLES
EXAMPLE A
Inhibitory effect of compounds of the Fortnula (I) on in vitro TNF production by human monocytes The inhibitory effect of compounds of the Formula (I) on zn vitro TIrTF
production by human monocytes may be determined by the protocol as described in Badger et al., EPO
published Application 0 411 754 A2, February 6, 1991, and in Hanna, WO
90/15534;
December 27, 1990.
EXAMPLE B
Two models of endotoxic shock have been utilized to determine in vivo TNF
activity for the compounds of the Formula (Ij. The protocol used in these models is described in ~ w Badger et al., EPO published Application 0 411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990.
The exemplified compounds herein demonstrated a positive tn vivo response in reducing serum levels of TNF induced by the injection of endotoxin.
EXAMPLF-C
Isolation of PDE I >oz~mes The phosphodiesteraSe inhibitory activity and selectivity of the compaunds of the 1~ormula (I) can be detetynined using a battery of five distinct PIaE
isozymes, The tissues used as sources of the different i5ozymes are as follaws: 1 ) PDE Ib, porcine aorta; 2) PI)E Ic, guinea-pig heart; 3) F'I7E III, guinea-pig heart; 4) PDE IV, human monocyte;
and 5) PDE '~l (also called "Ia"), canine tracheaolis. PDEs Ia> Ib; Ic and 1;II are partially purified using seandard ch;oaaaatographic techniques ~'orphy and ~iesl~nski; IVIoI.
Pharmacal., 37:206-214, 1990j. PDE IV is purified to kiqaetic homogeneity by the equential use of anion~exchange ' followed by heparin-Sepharose chromatography ~'Torphy et al; J. Biol. Chern:, 267:1798-1804; 1992):
~hosphodiesterase activity as nssaye~i as described in the protocol of Toaphy and Cieslinski, ~Ioi. Pharanacol:; 37:206-214; 1990: Positive ICSO's in the nanomolar to ltNf range for compounds of the workings ekample~ described herein for Formula (I) have been demonstrated.
$y EXAMPLE D
S
The ability of selected PDE IV inhibitors to increase cAIvIP acc~amulatian in intact °5sues is assessed using U-937 cells, a human monocyte cell line that his been shown to ontain a large amount of PDE IV. To assess the activity of PDE I~l inhibition in intact cells, 'nondzfferentiated U-937 cells (approxirn~tely 105 cells/reactiozt tube) were incubated with ;; 34 WO 93/ 1 ~D74~9 PC'T/U~93/01991 various concentrations (0.01-1000 ~.M) of PIKE inhibitors for one minute and l~liVI
prostaglandin E2 for an additional four minutes. Five minutes after initiating the reaction, cells were lysed by the addition of 17.5°Jo perchloric acid, the pPI
was neutralized by the addition of 11\~i potassium carbonate and cAMP content was assessed by RIA. A
general S protocol for this assay is described in Brooker et al., Radioimmunassay of cyclic AMP and cyclic GMP., Adv. Cyclic Nucleotide Res., 10:1-33, 1979. The compounds of the working examples as described herein for Formula (I) have demonstrated a positive ECSOs in the p.M
range in the above assay.
4.17. Starting material was also recovered (0.6 g, 30%).
Ir~4-C ano-4-(3-cvc~rowlmethoxX-4-methoxyvhen~)-1-hxdroxymethvl-1~
cvclohexanol A mixture of traps-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-cyclohexane-1-methyleneoxide (1.31 g, 4.18 mmol) and potassium hydroxide (0.14 g, 2.5 mmol) in 85:15 dimethylsulfaxide/water { 140 mL) under an argon atmosphere was heated at 100-I lOoC for Ih, was cooled, was diluted with water and was extracted three times with ethyl acetate. The organic extract was washed five times with water, was dried (magnesium stalfate) and was evaporated. Purification by flash chromatography, eluting with 3.5:96.5 methanol/dichloromethane, provided the rran~-isomer as a sticky white solid:
m.p. 38-42oC
(0.96 g, 69%).
Analysis Calc, for C19H25N~4: C 68.86, H 7.60, N 4.23; found: C 68.96, H 7.62, N 4.03.
. traps-j4-Cvano-4-(3-c~propvlmethoxy-4-rnethoxvphenvl) 1 hvdroxv-cvclohexane-1-carboxaldeh~ To a solution of oxalyl chloride (0.28 rte, 3.21 mmol) in dichloromethane (3.5 mL) at -78oC under an argon atmosphere was added dropwis~
a solution of dimethylsulfoxide (0.46 tnL., 6.48 mmol) in dichlorornethane (3.5 mL) such that the internal temperature did not exceed -6UoC. A solution of trams-4-cyano-4-(3-cyclopropylmethoxy-3-methoxyphenyl)-1-hydroxymethyl-1-cyclohexanol (0:89 g, 2.68 mmol) in dichloromethane (7 mL) was added dropwise and stirring was continued for 30 min. Triethylamine ( 1.80 mL, 12.9 mmol ) was added over 10 min, then 5 min later, the reaction mixture was allowed to warm to room temperature over 1 h. The reaction mixture was queb,ched with water and was extracted with three portions of dichloromethane. The combined organic layers were washed with I% hydrochloaic acid, 5% sodium carbonate and water, dried (magnesium sulfate) and the solvent was removed in vacuo to provide crude alciehyde (0:85 g, 9? %).
Meth 1 r - 4-c ano-4- -c cl ro lmethox -4-rnethox hen 1 -1-h drox cyclohexan~-1-carbox~,laiel To a solution of traps-[4-cyarao-4-(3-cyclopropylmethoxy-4-methbxyphenyl)-1-hydroxycyclohexane-l-carboxaldehyd~ (0.79 g, 2.4 mm01) in methannol (25 rnL) at 0aC under ati argon atmosphere was rapidly added a solution of potassium hydroxide (0.36 g, 6.43 mmol) in nnethanol (5 mL); followed by a solution of iodizie (0.80 g, 3.15 mmol) in metltanol (S mL). After I5 min the reaction was acidified with IN
hydrochloric acid and extracted with three portions of dichloromethane. The combined organic layers were washed :with ague~us sodium bisulfite until color was discharged, then with water, dried (magnesium sulfate), and the salvent was removed in vacuo..
Purification by flash chromatography, eluted with 35:65 ethyl acetate/hexanes , provided a white solid (0.82 g, 94 %): ri'r.p.148-149aC.
'WCD 93/ t 9749 ~'CT/LJS93/O1991 Analysis Calc, for C20H25NC5'1/4 H20: C 66.01, H 7.06, N 3.84; found: C 65.86:
H 6.92, N 3.85.
r -4- n - n I- -h x 1 x n -ar xylic a~dl The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid] in EXAMPLE 5, was isolated as a solid: m.p. 147-148oC.
Analysis Calc. for C1gH23N05: C 66.07, H 6.71, N 4.06; found: C 66.02, H 6.71, N 4.04.
EXAMPLE 23 , I~I~h, 1 r - 4- n -4- r 1 -4- ~ h x h n I -1-m h x I h n -1-warboxvlatel The title compound, prepared substantially as described above for methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- l-methoxycyclohexane-1-carboxylate]
in EXAMPLE 18, was isolated as a solid: m.p. 84-85oC.
Analysis Calc. for C21H27Nt75: C 67.54, H 7:29, N 3.75; found: C 67.34, H
7.25, N 3.77.
r - 4.- -4- -4- LYlwll-1°methox~ry~l exam-1=
~ r x lic act]
The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentylaxy-4-methoxyphenyl)cycloh~xan~-1-carboxylic acid] in EXAli~'LE S>
was isolated as a solid: m.p, 15$-159°C.
Apalysis Calc. for C2pH~5NC~5~1/4 ~T2C: C 66.01, I~ 7.06, N 3.85; fotynd: C
65.98; H 6.91, N 3:75.
~XA~.~IV1PLE 2~' r = 4- ~ n -4- r 1 x -4- h x h n 1 _ 1 _~ h X c ~ n -carboxamydel The title bampbund; prepaz~ed substantially as described above for cis-[4-cyano-4-(3-cyclopenty)axy-4-methoxyphenyl)-1-ra~etho;cycyclohexane-1-carboxarriide] in EXAMPLE'' 20; was isolated as a solid: m:p: 16$-169oC:
Analysis Calcfor C2pH2~N204v1/8 H20: C 6.60; H 7.34,1x17.70; found: C 66.60, H
7,30;
loI 7.74.
'1~0 93/ 19749 ~ ~. 3 ~ ~ 3 ~ ~c~-eus93eoa99~
~-f4-~ano-4-(,~cvclopentyloxv-4-methoxvvhenv~cyclohexane-1-carboxamic acidl The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide] in EXAMPLE
but using hydroxylamine instead of ammonia, was isolated as a solid: m.p. 100-102oC.
Analysis Calc. for C2pH26N2o4: C 67.02, H 7.31, N 7.82; found: C 66.75, H
7.58, N 7.42.
N-M~thyl-cis-t4-c~~ano-4-(3-c c~~,lopentvlox ~~-4-methoxxphen~~c clv ohe_xane-1-carboxamic acid The title compound, prepared substantially as described above for cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide] in EXAMPLE
but using N-methylhydroxylamine instead of ammonia, was isolated as a solid:
rri.p. 75-76oC.
Analysis Calc. for C21H28N2O4~1/4 H20: C 66.91, H 7.62, N 7.43; found: C
66.95, H 7.54, N 7.35.
- 4-C ono-4- ~-c clo ent lox -4-metlaox hen I c clohexane-l-N- 2-c a~noeth, Iwcarboxamide To a solution of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-carboxylic acid] (0.55 g, 1.6 mmol), 1-hydroxybenzotriazole (0.24 g, 1.76 mmol) and 3-atninopropionitrile (0.11 g, l.6 mz~ol) in dichlorort3ethane ( 10 mL) at OaC
under an argon atmosphere was added l-(3-diethyi~minopropyl)-3-ethylcarbodiimide hydrochloride (0,34 g, ?5 1.76 mmol) and the mixture was allowed to warm to room temperature. After 6h, the mixt>are eeas diluted with dichloromethane; was gashed twice with 10% aqueous potassium ~~~~ate; twice with 10 % hydrochloric acid and was dried (znagnesiutn sulfate). The solvent was evaporated and the residue was crystallized from hexanes/ethyl acetate to provide a solid (0:54 g, 85%): tn.p: 146-147eC.
Analysis Calc: for C23H29Io13~3: C 69.85, H 7.39, N 10:62; found: C 69.491-17.41; N 10.46.
cis-f 1-(2-Cyanoethr~l -5-f 4-cva~~o-4-f3-cyclo~entvloxy-4 methox~phen~yclbhex~l tetxazole, 'To a solution of cas-[4-cyano-4-(3-cyclopentylaxy-4-methoxyphenyl)cyclohexane-N-(2-cyanoethyl)carboxatnide] (0.15 g, 0.37 mmol), triphenylphosphin~ (0.19 g, 0.73 mmol) and trimethylsilylazide (0.097 mL, 0.73 mmol) in dry tetrahydrofuran (2 mL) at ro~m temperature under an argon atmosphere was added dropwise diethyl azodiearboxylate (0.12 mL, 0.73 tnmol) and the mixture was stirred in the dark for 24h. Ceric ammonium nitrate ~Vtn 9:i/1974~1 ~ t~ ~ l~ PCT/US93J0~991 (0.81 g, 1.48 mrnol) in water (10 mL) was added at OeC, the mixture was extracted Three times with dichloromethane, the extract was dried (magnesium sulfate) and the solvent was evaporated. Purification by flash chromatography, eluting with 2:1 ethyl acetate/hexanes, followed by recrystallization from hexanes/ethyl acetate, provided a white solid (0.03 g, 19%): m.p. 149-1 SO~C.
Analysis Calc. for C23H28N602: C 65.69, H 6.71, N 19.99; found: C 65.45 H
6.72, '~t 19.91.
~XAIvIfLE 3~
- 4- an -4- 1 n 1 x -4-m h x h n 1 -1- z 1 1 c 1 h xan A mixture of cis-( i-(2-cyanoethyl)-5- { 4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl } tetrazole~ (0.098 g, 0.23 mrnol) and sodium hydroxide (0,018 g, 0.46 mmol) in 10:1 tetrahydrofuran/water (5 mlL) at room temperature under an argon atmosphere was stirred overnight. The mixture was acidified with 3N
hydrochloric acid, was extracted three times with ethyl acetate, the extract was dried (magnesium sulfate) and the solvent was evaporated. Purification by flash chromatography, eluting with 80:20:?
chloroform/methanol/water, followed by trituration .with hexanes/ethyl acetate, provided a white solid (0.038 g, 45%): m.p. 190-191nC.
Analysis Calc. for C20H25N5~2~ 1/2 I-I20: C 63.81, H 6.96, N 18.60; found: C
64.07 H 6.79, N 18.54.
TH~L~S CaF_'1R~ATNLENT
In order to use a compound of Formula (I) ~or a:pharmaceutically acceptable salt Thereof for the treatment of humans-and other mammals, it is normally formulated in accordance with standard pharmaceutical practice .as a pharmaceutical composition. The compounds of Formula (I) ar a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the praphylatic or therapeutic treatment of any disease state rn a human ~r other mammal dvhich is mediated by inhibition of PDP IV, such as but/not limieed to asthma; allergic, or inflammatory diseases. The cornp~urads of Foranula (I) are administered art an amount sufficient to treat rush a disease in a human or other mammal.
The method of treatment and monitoring for an I-IIV-infected human manifesting immu~~ dysfunction or cytokine-mediated disease associated problems is taught in Hanna, W0 90/15534; December 27; 1990. In general, an initial treatment regimen can be copied from that known to be effective in interfering with "fI~F activity fir other TNF mediated disease states by the compounds ~f Formula (I). Treated individuals wall be regularly checked for T cell numbers and T4/T8 ratios and/or measures of ~riremia~ such as levels of reverse transcriptase or viral proteans, and/or for progression of monokine-mediated disease associated problems such as cachexia or muscle degeneration: If no effect is seen following the normal treatment regimen, then the amount of the monokine activity interfering agent administered is increased, e.g., by fifty percent per week.
'WU 93/19749 ~ , .
~~Cl"/U~93/01991 The pharmaceutical composition of the present invention will comprise an effective, non-toxic amount of a compound of Formula (1) and a pharmaceutically acceptable carrier or diluent. The compounds of Formula (n are administered in conventional dosage forms prepared by combining a compound of Formula (17 in ari amount sufficient to produce TNF
production inhibiting activity, respectively, with standard pharmaceutical carriers according to conventional procedures. These procedures may involve mixing, granulating, and compressing or dissolving the ingredients as appropriate to the desired preparation.
'Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 gram. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension. Where the compositie~n is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates, ar oils and are incorporated in a soft gelatin capsule shell. A
'syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine, or water with a flavoring or coloring agent.
The daily dosage regimen for oral administration is suitably about .001 mg/kg to 100mg/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 rriay be administered from l to ~5 times a day, sufficient to exhibit activity.
While it is possible for an active ingredient to be administered neat; it is preferable to present it as a pharmaceutical formulation. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g., from l% to 2% by weight of formulation, although it may comprise ~s xntich as 10% w/w but preferably not in excess of 5% w/w and snore preferably from 0.1 % to l % w/w of Formulation:
__._ Formulations of the present invention comprise an active ingredient together with one or more acceptable carriers) thereof arid optionally any other therapeutic itagi~edient(s). The carriers) must be 'acceptable' in the sense of being compatible with the other ingredients of Formulation and not deleterious to the recipient thereof.
It will be recognized by one of skill in the art that the form and~character of the pharmaceutically acceptaole carrier or diluent is dictated by the amount of active ingredient with which it is'to be combined, the route of administration, and other well-known variables.
No ttsxic effects are expected when these compounds are administered in accordance with the present invention.
~vo 9m ~ 97a9 ~ ~. 3 ~ ~~ 3 ~ , PC1'/ IJS93/01991 J~TILIT'Y EXAMPLES
EXAMPLE A
Inhibitory effect of compounds of the Fortnula (I) on in vitro TNF production by human monocytes The inhibitory effect of compounds of the Formula (I) on zn vitro TIrTF
production by human monocytes may be determined by the protocol as described in Badger et al., EPO
published Application 0 411 754 A2, February 6, 1991, and in Hanna, WO
90/15534;
December 27, 1990.
EXAMPLE B
Two models of endotoxic shock have been utilized to determine in vivo TNF
activity for the compounds of the Formula (Ij. The protocol used in these models is described in ~ w Badger et al., EPO published Application 0 411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990.
The exemplified compounds herein demonstrated a positive tn vivo response in reducing serum levels of TNF induced by the injection of endotoxin.
EXAMPLF-C
Isolation of PDE I >oz~mes The phosphodiesteraSe inhibitory activity and selectivity of the compaunds of the 1~ormula (I) can be detetynined using a battery of five distinct PIaE
isozymes, The tissues used as sources of the different i5ozymes are as follaws: 1 ) PDE Ib, porcine aorta; 2) PI)E Ic, guinea-pig heart; 3) F'I7E III, guinea-pig heart; 4) PDE IV, human monocyte;
and 5) PDE '~l (also called "Ia"), canine tracheaolis. PDEs Ia> Ib; Ic and 1;II are partially purified using seandard ch;oaaaatographic techniques ~'orphy and ~iesl~nski; IVIoI.
Pharmacal., 37:206-214, 1990j. PDE IV is purified to kiqaetic homogeneity by the equential use of anion~exchange ' followed by heparin-Sepharose chromatography ~'Torphy et al; J. Biol. Chern:, 267:1798-1804; 1992):
~hosphodiesterase activity as nssaye~i as described in the protocol of Toaphy and Cieslinski, ~Ioi. Pharanacol:; 37:206-214; 1990: Positive ICSO's in the nanomolar to ltNf range for compounds of the workings ekample~ described herein for Formula (I) have been demonstrated.
$y EXAMPLE D
S
The ability of selected PDE IV inhibitors to increase cAIvIP acc~amulatian in intact °5sues is assessed using U-937 cells, a human monocyte cell line that his been shown to ontain a large amount of PDE IV. To assess the activity of PDE I~l inhibition in intact cells, 'nondzfferentiated U-937 cells (approxirn~tely 105 cells/reactiozt tube) were incubated with ;; 34 WO 93/ 1 ~D74~9 PC'T/U~93/01991 various concentrations (0.01-1000 ~.M) of PIKE inhibitors for one minute and l~liVI
prostaglandin E2 for an additional four minutes. Five minutes after initiating the reaction, cells were lysed by the addition of 17.5°Jo perchloric acid, the pPI
was neutralized by the addition of 11\~i potassium carbonate and cAMP content was assessed by RIA. A
general S protocol for this assay is described in Brooker et al., Radioimmunassay of cyclic AMP and cyclic GMP., Adv. Cyclic Nucleotide Res., 10:1-33, 1979. The compounds of the working examples as described herein for Formula (I) have demonstrated a positive ECSOs in the p.M
range in the above assay.
Claims (7)
1. A compound of Formula (I):
wherein:
R1 is -(CR4R5)n C(O)O(CR4R5)m R6, -(CR4R5)n C(O)NR4(CR4R5)m R6, -(CR4R5)n O(CR4R5)m R6, or -(CR4R5)r R6 m is 0 to 2;
n is 1 to 4;
r is 1 to 6;
R4 and R5 are independently selected from hydrogen or a C1-2 alkyl;
R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC1-3 alkyl, halo substituted aryloxyC1-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; and wherein the alkyl moieties may be optionally substituted with one or more halogens;
provided that:
a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;
e) when n is 1 and m is 0, then R6 is other than H in -(CR4R5)n O(CR4R5)m R6:
X is YR2, halogen, nitro, NR4R5, or formyl amine;
Y is O or S(O)m';
m' is 0, 1, or 2;
X2 is O or NR8;
X3 is hydrogen or X;
X4 is X5 is H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NR8R8, or NR8R8;
R2 is independently selected from the group consisting of -CH3 and -CH2CH3 optionally substituted by 1 or more halogens;
s is 0 to 4;
R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, -CH=CR8'R8', cyclopropyl optionally substituted by R8', CN, OR8, CH2OR8, NR8R10, CH2NR8R10, C(Z')H, C(O)OR8, C(O)NR8R10, or C=CR8';
Z' is O, NR9, NOR8, NCN, C(-CN)2, CR8CN, CR8NO2, CR8C(O)OR8, CR8C(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NR8R8;
Z is C(Y')R14, C(O)OR14, C(Y')NR10R14, C(NR10)NR10R14, CN, C(NOR8)R14, C(O)NR8NR8C(O)R8, C(O)NR8NR10R14, C(NOR14)R8, C(NR8)NR10R14, C(NR14)NR8R8 C(NCN)NR10R14, C(NCN)SR9, (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 of the heterocylic ring systems may be optionally substituted one or more times by R14;
the dotted line in formula (a) represents a single or doubly bond;
Y'is O or S;
R7 is -(CR4R5)q R12 or C1-6 alkyl wherein the R12 or C1-6 alkyl group is optionally substituted one or more times by C1-2 alkyl optionally substituted by one to three fluorines, -F, -Br, -Cl, -NO2, -NR10R11, -C(O)R8, -C(O)OR8, -OR8, -CN, -C(O)NR10R11, -OC(O)NR10R11, -OC(O)R8, -NR10C(O)NR10R11, -NR10C(O)R11, -NR10C(O)OR9, -NR10C(O)R13, -C(NR10)NR10R11, -C(NCN)NR10R11, -C(NCN)SR9, -NR10C(NCN)SR9 , -NR10C(NCN)NR10R11, -NR10S(O)2R9, -S(O)m'R9, -NR10C(O)C(O)NR10R11, -NR10C(O)C(O)R10, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl;
q is 0, 1, or 2;
R12 is C3-C7-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;
R8 is independently selected from hydrogen or R9;
R8' is R8 or fluorine;
R9 is C1-4 alkyl optionally substituted by one to three fluorines;
R10 is OR8 or R11;
R11 is hydrogen, or C1-4 alkyl optionally substituted by one to three fluorines; or when R10 and R11 are as NR10R11 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N and S;
R13 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C1-2 alkyl groups;
R14 is hydrogen or R7; or when R10 and R14 are as NR10R14 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S;
provided that:
f) when R12 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1; or g) when X2R1 is OCF2H or OCF3, X is F, OCF2H or OCF3, X3 is H, s is zero, X5 is H, Z is C(O)OR14 and R14 is C1-7 unsubstituted alkyl, then R3 is other than H;
or pharmaceutically acceptable salts thereof.
wherein:
R1 is -(CR4R5)n C(O)O(CR4R5)m R6, -(CR4R5)n C(O)NR4(CR4R5)m R6, -(CR4R5)n O(CR4R5)m R6, or -(CR4R5)r R6 m is 0 to 2;
n is 1 to 4;
r is 1 to 6;
R4 and R5 are independently selected from hydrogen or a C1-2 alkyl;
R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC1-3 alkyl, halo substituted aryloxyC1-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; and wherein the alkyl moieties may be optionally substituted with one or more halogens;
provided that:
a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;
e) when n is 1 and m is 0, then R6 is other than H in -(CR4R5)n O(CR4R5)m R6:
X is YR2, halogen, nitro, NR4R5, or formyl amine;
Y is O or S(O)m';
m' is 0, 1, or 2;
X2 is O or NR8;
X3 is hydrogen or X;
X4 is X5 is H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NR8R8, or NR8R8;
R2 is independently selected from the group consisting of -CH3 and -CH2CH3 optionally substituted by 1 or more halogens;
s is 0 to 4;
R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, -CH=CR8'R8', cyclopropyl optionally substituted by R8', CN, OR8, CH2OR8, NR8R10, CH2NR8R10, C(Z')H, C(O)OR8, C(O)NR8R10, or C=CR8';
Z' is O, NR9, NOR8, NCN, C(-CN)2, CR8CN, CR8NO2, CR8C(O)OR8, CR8C(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NR8R8;
Z is C(Y')R14, C(O)OR14, C(Y')NR10R14, C(NR10)NR10R14, CN, C(NOR8)R14, C(O)NR8NR8C(O)R8, C(O)NR8NR10R14, C(NOR14)R8, C(NR8)NR10R14, C(NR14)NR8R8 C(NCN)NR10R14, C(NCN)SR9, (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 of the heterocylic ring systems may be optionally substituted one or more times by R14;
the dotted line in formula (a) represents a single or doubly bond;
Y'is O or S;
R7 is -(CR4R5)q R12 or C1-6 alkyl wherein the R12 or C1-6 alkyl group is optionally substituted one or more times by C1-2 alkyl optionally substituted by one to three fluorines, -F, -Br, -Cl, -NO2, -NR10R11, -C(O)R8, -C(O)OR8, -OR8, -CN, -C(O)NR10R11, -OC(O)NR10R11, -OC(O)R8, -NR10C(O)NR10R11, -NR10C(O)R11, -NR10C(O)OR9, -NR10C(O)R13, -C(NR10)NR10R11, -C(NCN)NR10R11, -C(NCN)SR9, -NR10C(NCN)SR9 , -NR10C(NCN)NR10R11, -NR10S(O)2R9, -S(O)m'R9, -NR10C(O)C(O)NR10R11, -NR10C(O)C(O)R10, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl;
q is 0, 1, or 2;
R12 is C3-C7-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;
R8 is independently selected from hydrogen or R9;
R8' is R8 or fluorine;
R9 is C1-4 alkyl optionally substituted by one to three fluorines;
R10 is OR8 or R11;
R11 is hydrogen, or C1-4 alkyl optionally substituted by one to three fluorines; or when R10 and R11 are as NR10R11 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N and S;
R13 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C1-2 alkyl groups;
R14 is hydrogen or R7; or when R10 and R14 are as NR10R14 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S;
provided that:
f) when R12 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1; or g) when X2R1 is OCF2H or OCF3, X is F, OCF2H or OCF3, X3 is H, s is zero, X5 is H, Z is C(O)OR14 and R14 is C1-7 unsubstituted alkyl, then R3 is other than H;
or pharmaceutically acceptable salts thereof.
2. A compound of claim 1 which is methyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;
4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylic acid;
methyl cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate];
methyl trans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate];
methyl cis- [4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];
methyl trans-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];
cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate], tris(hydroxymethyl)ammonium methane salt;
cis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylic acid];
trans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid];
cis-(4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid];
trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid];
methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate];
methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate];
methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylate];
methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-cyclohexane-1-carboxylate];
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylic acid];
trans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylic acid];
cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1-carboxamide];
cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide];
trans-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide];
cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carbohydrazide];
cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-(2-acetylcarbohydrazide)];
cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane};
cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]oxadiazol-5-yl)cyclohexane};
cis-(4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]thiadiazol-5-yl)cyclohexane};
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-1-tris(methylthio)methylcyclohexane];
methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-cyclohexane-1-carboxylate];
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylic acid];
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxamide];
methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxy-cyclohexane-1-carboxylate];
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-l-methoxycyclohexane-1-carboxylic acid];
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide];
trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-cyclohexane-1-carboxaldehyde];
methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate];
trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylic acid];
methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate];
trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylic acid];
trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide];
cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamic acid];
N-methyl-cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamic acid];
cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-N-(2-cyanoethyl)carboxamide];
cis-[1-(2-cyanoethyl)-5-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl]tetrazole]; or cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-(tetrazol-5-yl)cyclohexane].
4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylic acid;
methyl cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate];
methyl trans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate];
methyl cis- [4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];
methyl trans-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];
cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate], tris(hydroxymethyl)ammonium methane salt;
cis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylic acid];
trans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid];
cis-(4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid];
trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid];
methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate];
methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate];
methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylate];
methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-cyclohexane-1-carboxylate];
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylic acid];
trans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylic acid];
cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1-carboxamide];
cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide];
trans-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide];
cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carbohydrazide];
cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-(2-acetylcarbohydrazide)];
cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane};
cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]oxadiazol-5-yl)cyclohexane};
cis-(4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]thiadiazol-5-yl)cyclohexane};
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-1-tris(methylthio)methylcyclohexane];
methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-cyclohexane-1-carboxylate];
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylic acid];
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxamide];
methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxy-cyclohexane-1-carboxylate];
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-l-methoxycyclohexane-1-carboxylic acid];
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide];
trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-cyclohexane-1-carboxaldehyde];
methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate];
trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylic acid];
methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate];
trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylic acid];
trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide];
cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamic acid];
N-methyl-cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamic acid];
cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-N-(2-cyanoethyl)carboxamide];
cis-[1-(2-cyanoethyl)-5-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl]tetrazole]; or cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-(tetrazol-5-yl)cyclohexane].
3. A pharmaceutical composition comprising a compound of Formula (I) according to claim 1 and a pharmaceutically acceptable excipient.
4. Use of an effective amount of a compound of Formula (I) according to claim alone or in combination with a pharmaceutically acceptable excipient for treating an allergic or inflammatory state mediated by a phosphodiesterase IV inhibitor.
5. Use of an effective amount of a compound of Formula (I) according to claim alone or in combination with a pharmaceutically acceptable excipient in the manufacture of a medicament for treating an allergic or inflammatory state mediated by a phosphodiesterase IV inhibitor.
6. A compound according to claim 1 which is cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid, or pharmaceutically acceptable salts thereof.
7. A pharmaceutical composition comprising a compound according to claim 6 and a pharmaceutically acceptable excipient.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US86203092A | 1992-04-02 | 1992-04-02 | |
| US07/862,030 | 1992-04-02 | ||
| US96876292A | 1992-10-30 | 1992-10-30 | |
| US07/968,762 | 1992-10-30 | ||
| SG1996007903A SG47107A1 (en) | 1992-04-02 | 1993-03-05 | Compounds useful for treating allergic and inflammatory diseases |
| PCT/US1993/001991 WO1993019749A1 (en) | 1992-04-02 | 1993-03-05 | Compounds useful for treating allergic and inflammatory diseases |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2133439A1 CA2133439A1 (en) | 1993-10-14 |
| CA2133439C true CA2133439C (en) | 2005-07-26 |
Family
ID=27356137
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002133439A Expired - Lifetime CA2133439C (en) | 1992-04-02 | 1993-03-05 | Compounds useful for treating allergic and inflammatory diseases |
Country Status (18)
| Country | Link |
|---|---|
| US (4) | US5552438A (en) |
| EP (1) | EP0633776B1 (en) |
| CN (1) | CN1066436C (en) |
| AP (2) | AP519A (en) |
| AU (1) | AU677776B2 (en) |
| BG (1) | BG62235B1 (en) |
| CA (1) | CA2133439C (en) |
| CZ (1) | CZ283425B6 (en) |
| FI (1) | FI944549A (en) |
| GR (1) | GR3036347T3 (en) |
| HU (1) | HU225869B1 (en) |
| IL (1) | IL105221A (en) |
| MX (1) | MX9301943A (en) |
| NO (1) | NO303116B1 (en) |
| NZ (1) | NZ251092A (en) |
| SI (1) | SI9300169B (en) |
| SK (1) | SK279958B6 (en) |
| WO (1) | WO1993019749A1 (en) |
Families Citing this family (240)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2229221T3 (en) * | 1993-06-18 | 2005-04-16 | Smithkline Beecham Corporation | IDENTIFICATION PROCEDURE OF A PDE INHIBITOR IV. |
| GB9312853D0 (en) | 1993-06-22 | 1993-08-04 | Euro Celtique Sa | Chemical compounds |
| WO1995003794A1 (en) | 1993-07-30 | 1995-02-09 | Smithkline Beecham Corporation | 3-cyano-3-(3,4-disubstituted)phenylcyclohexyl-1-carboxylates |
| GB9404706D0 (en) * | 1994-03-11 | 1994-04-27 | Smithkline Beecham Corp | Compounds |
| US6013827A (en) * | 1994-03-11 | 2000-01-11 | Smithkline Beecham Corporation | Compounds |
| US5998428A (en) * | 1995-05-31 | 1999-12-07 | Smithkline Beecham Corporation | Compounds and methods for treating PDE IV-related diseases |
| US20060019963A1 (en) * | 1994-06-17 | 2006-01-26 | Smithkline Beecham Corporation | Compounds |
| US5591776A (en) * | 1994-06-24 | 1997-01-07 | Euro-Celtique, S.A. | Pheynl or benzyl-substituted rolipram-based compounds for and method of inhibiting phosphodiesterase IV |
| US5922751A (en) | 1994-06-24 | 1999-07-13 | Euro-Celtique, S.A. | Aryl pyrazole compound for inhibiting phosphodiesterase IV and methods of using same |
| EP0799182A4 (en) * | 1994-12-23 | 1998-03-25 | Smithkline Beecham Corp | 3,3-(disubstituted)cyclohexan-1-ol dimers and related compounds |
| WO1996020156A1 (en) * | 1994-12-23 | 1996-07-04 | Smithkline Beecham Corporation | 3,3-(disubstituted)cyclohexan-1-carboxylate dimers and related compounds |
| EP0799187A4 (en) * | 1994-12-23 | 1998-03-25 | Smithkline Beecham Corp | 4,4-(disubstituted)cyclohexan-1-carboxylate dimers and related compounds |
| US5863926A (en) * | 1994-12-23 | 1999-01-26 | Smithkline Beecham Corporation | 4,4-(disubstituted)cyclohexan-1-carboxylate monomers and related compounds |
| EP0796097A4 (en) * | 1994-12-23 | 1998-03-25 | Smithkline Beecham Corp | 3,3-(disubstituted)cyclohexan-1-carboxylate monomers and related compounds |
| DK0828727T3 (en) * | 1995-05-18 | 2003-04-22 | Altana Pharma Ag | Cyclohexyldihydrobenzofurans |
| EP0828728B1 (en) * | 1995-05-18 | 2003-01-22 | ALTANA Pharma AG | Phenyl dihydrobenzofuranes |
| US6166041A (en) | 1995-10-11 | 2000-12-26 | Euro-Celtique, S.A. | 2-heteroaryl and 2-heterocyclic benzoxazoles as PDE IV inhibitors for the treatment of asthma |
| US5891883A (en) * | 1995-12-21 | 1999-04-06 | Smithkline Beecham Corporation | 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds |
| US6075016A (en) | 1996-04-10 | 2000-06-13 | Euro-Celtique S.A. | 6,5-fused aromatic ring systems having enhanced phosphodiesterase IV inhibitory activity |
| AP1147A (en) * | 1996-05-03 | 2003-02-25 | Pfizer | Substituted indazole derivatives and related compounds. |
| AU3102697A (en) | 1996-06-19 | 1998-01-07 | Rhone-Poulenc Rorer Limited | Substituted azabicylic compounds and their use as inhibitors of the production of tnf and cyclic amp phosphodiesterase |
| SK176598A3 (en) * | 1996-06-25 | 2000-06-12 | Pfizer | Indazole derivatives, pharmaceutical composition on their base and methods of treatment |
| WO1998022453A1 (en) * | 1996-11-20 | 1998-05-28 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Substituted dihydrobenzofurans as pde inhibitors |
| DK1295869T3 (en) * | 1997-02-12 | 2005-11-21 | Smithkline Beecham Corp | Compounds and Processes for Preparing Substituted 4-Phenyl-4-Cyanocyclohexanoic Acids |
| UY24882A1 (en) | 1997-02-12 | 2001-08-27 | Smithkline Beecham Corp | SUBSTITUTED 4-PHENYL-4-CIANO-CYCLOHEXANOIC ACIDS |
| EP1524268B1 (en) * | 1997-02-12 | 2007-01-17 | Smithkline Beecham Corporation | Compounds and method for preparing sustituted 4-phenyl-4-cyanocyclohexanoic acids |
| UA67753C2 (en) * | 1997-10-10 | 2004-07-15 | Смітклайн Бічам Корпорейшн | Method for obtaining substituted of cyanocyclohexan acid |
| UY25338A1 (en) | 1998-01-07 | 2001-08-27 | Smithkline Beecham Corp | METHOD FOR TREATING COPD |
| JP2002500187A (en) * | 1998-01-07 | 2002-01-08 | スミスクライン・ビーチャム・コーポレイション | How to treat multiple sclerosis |
| US6118017A (en) * | 1998-04-14 | 2000-09-12 | Smithkline Beecham Corporation | Substituted-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylcyanocyclobutan-1-one |
| US6395273B1 (en) | 1998-06-10 | 2002-05-28 | Promega Corporation | Prevention and treatment of inflammatory bowel disease |
| US7115557B2 (en) * | 1998-09-25 | 2006-10-03 | Sciaticon Ab | Use of certain drugs for treating nerve root injury |
| US7811990B2 (en) * | 1998-09-25 | 2010-10-12 | Sciaticon Ab | Soluble cytokine receptors TNF-α blocking antibodies for treating spinal disorders mediated by nucleus pulposus |
| SE9803710L (en) * | 1998-09-25 | 2000-03-26 | A & Science Invest Ab | Use of certain substances for the treatment of nerve root damage |
| US7906481B2 (en) * | 1998-09-25 | 2011-03-15 | Sciaticon Ab | Specific TNF-A inhibitors for treating spinal disorders mediated by nucleous pulposus |
| KR20010085852A (en) | 1998-10-06 | 2001-09-07 | 도모따께 다께시 | 2,3-disubstituted pyridine derivatives, process for the preparation thereof, drug compositions containing the same and intermediates for the preparation |
| MY121142A (en) * | 1999-02-23 | 2005-12-30 | Smithkline Beecham Corp | Controlled release formulation for treating copd |
| US6419934B1 (en) * | 1999-02-24 | 2002-07-16 | Edward L. Tobinick | TNF modulators for treating neurological disorders associated with viral infection |
| DZ3019A1 (en) * | 1999-03-01 | 2005-05-20 | Smithkline Beecham Corp | Use of a pde4 inhibitor in the preparation of a drug against copd. |
| AR035987A1 (en) | 1999-03-01 | 2004-08-04 | Smithkline Beecham Corp | USE OF A PDE 4 INHIBITING COMPOUND FOR THE MANUFACTURE OF A MEDICINAL PRODUCT AND THE MEDICINAL PRODUCT TO TREAT ASTHMA INDUCED BY EXERCISE |
| US7125895B1 (en) * | 1999-05-14 | 2006-10-24 | Bristol-Myers Squibb Pharma Research Labs, Inc. | Cyclic amine derivatives and their uses |
| AR024076A1 (en) * | 1999-05-25 | 2002-09-04 | Smithkline Beecham Corp | CIS- [4-CIANO-4- (3-CICLOPENTILOXI-4-METOXIFENIL) CICLOHEXAN-1-CARBOXYLATE SALTS] |
| US20040220424A1 (en) * | 1999-08-06 | 2004-11-04 | Smithkline Beecham Corporation | Process for preparing acids via alpha-chloroepoxy esters |
| ECSP003600A (en) * | 1999-08-06 | 2002-03-25 | Smithkline Beecham Corp | METHOD FOR PREPARING CYCLHEXAN-CARBOXYL ACIDS |
| ECSP003599A (en) * | 1999-08-06 | 2002-03-25 | Smithkline Beecham Corp | PROCEDURE TO PREPARE ACIDS THROUGH ALFA-COROEPOXI-ESTERES |
| US6740765B1 (en) * | 1999-08-06 | 2004-05-25 | Smithkline Beecham Corporation | Method for preparing cyclohexane carboxylic acids |
| MXPA02001830A (en) * | 1999-08-21 | 2002-08-12 | Byk Gulden Lomberg Chem Fab | Synergistic combination of pde inhibitors and beta 2 adrenoceptor agonist. |
| UY26333A1 (en) * | 1999-09-15 | 2001-07-31 | Smithkline Beecham Corp | PROCEDURE AND INTERMEDIATES TO PREPARE ACIDS (4-SUBSTITUTED CYAN) - CYCLOHEXANOICS |
| US20030050497A1 (en) * | 2002-07-11 | 2003-03-13 | Webb Kevin Scott | Process and intermediates for preparing a cyclohexylnitrile |
| AR029788A1 (en) * | 2000-01-12 | 2003-07-16 | Smithkline Beecham Corp | PROCEDURE TO REDUCE CARBOXYLIC CARBOXYLIC ACIDS ALPHA, BETA-INSATURATED, PROCEDURE TO PREPARE 4-NITRILE-4-ARYL-CYCLHEXANOIC ACIDS, PROCEDURE TO PREPARE CARBOXYLEDI-BIOPARIETHYLED INSTRUMENTED PROCEDURES |
| IL150400A0 (en) * | 2000-01-26 | 2002-12-01 | Smithkline Beecham Corp | Monohydrate of cis-lithium-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl] cyclohexanecarboxylate |
| JP2003522142A (en) * | 2000-02-08 | 2003-07-22 | スミスクライン・ビーチャム・コーポレイション | Methods and compositions for treating inflammatory diseases |
| AU2001238288A1 (en) * | 2000-02-16 | 2001-08-27 | University Of Nebraska Medical Center | Method and compositions for treating fibrotic diseases |
| EP2258689A1 (en) * | 2000-03-16 | 2010-12-08 | Biolipox AB | Benzylated PDE4 inhibitors |
| GB0011802D0 (en) * | 2000-05-16 | 2000-07-05 | Smithkline Beecham | Method for enhancing cognitive function |
| US20040005995A1 (en) * | 2001-07-26 | 2004-01-08 | Edelson Jeffrey D | Method for reducing exacerbations associated with copd |
| NZ523958A (en) | 2000-08-05 | 2004-11-26 | Glaxo Group Ltd | 17.beta.-carbothioate 17.alpha.-arylcarbonyloxyloxy androstane derviative as anti-inflammatory agents |
| US20040224316A1 (en) | 2000-08-10 | 2004-11-11 | Tully Timothy P. | Augmented cognitive training |
| PL365443A1 (en) | 2001-01-31 | 2005-01-10 | Pfizer Products Inc. | Thiazolyl-, oxazolyl-, pyrrolyl-, and imidazolyl-acid amide derivatives useful as inhibitors of pde4 isozymes |
| US7250518B2 (en) * | 2001-01-31 | 2007-07-31 | Pfizer Inc. | Nicotinamide acids, amides, and their mimetics active as inhibitors of PDE4 isozymes |
| SK8792003A3 (en) * | 2001-01-31 | 2004-09-08 | Pfizer Prod Inc | Nicotinamide biaryl derivatives useful as inhibitors of PDE4 isozymes and pharmaceutical composition containing them |
| CN1527830A (en) * | 2001-01-31 | 2004-09-08 | �Ʒ� | Ether derivatives useful as inhibitors of PDE4 isozymes |
| GB0103630D0 (en) * | 2001-02-14 | 2001-03-28 | Glaxo Group Ltd | Chemical compounds |
| ES2296923T3 (en) * | 2001-03-22 | 2008-05-01 | Glaxo Group Limited | FORMANILID DERIVATIVES AS AGONISTS OF THE BETA2 ADRENORRECEPTOR. |
| WO2002088167A1 (en) | 2001-04-30 | 2002-11-07 | Glaxo Group Limited | Anti-inflammatory 17.beta.-carbothioate ester derivatives of androstane with a cyclic ester group in position 17.alpha |
| JP4510383B2 (en) * | 2001-05-23 | 2010-07-21 | 田辺三菱製薬株式会社 | Composition for repairing cartilage disease |
| MXPA03010679A (en) * | 2001-05-23 | 2004-03-02 | Tanabe Seiyaku Co | Compositions for promoting healing of bone fracture. |
| CN101701006B (en) * | 2001-09-14 | 2014-03-05 | 葛兰素集团有限公司 | Phenethanolamine derivatives for treatment of respiratory diseases |
| GB0217199D0 (en) * | 2002-07-25 | 2002-09-04 | Glaxo Group Ltd | Medicament dispenser |
| GB0201677D0 (en) * | 2002-01-25 | 2002-03-13 | Glaxo Group Ltd | Medicament dispenser |
| EP1490090A4 (en) | 2002-02-22 | 2006-09-20 | New River Pharmaceuticals Inc | Active agent delivery systems and methods for protecting and administering active agents |
| GB0204719D0 (en) * | 2002-02-28 | 2002-04-17 | Glaxo Group Ltd | Medicinal compounds |
| ATE381535T1 (en) * | 2002-04-25 | 2008-01-15 | Glaxo Group Ltd | PHENETHANOLAMINE DERIVATIVES |
| US20030013905A1 (en) * | 2002-06-10 | 2003-01-16 | Huang Guishu Kris | Salts of cis-4-cyano-4[3(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid |
| GB0217225D0 (en) | 2002-07-25 | 2002-09-04 | Glaxo Group Ltd | Medicinal compounds |
| GB0217196D0 (en) * | 2002-07-25 | 2002-09-04 | Glaxo Group Ltd | Medicament dispenser |
| GB0217198D0 (en) * | 2002-07-25 | 2002-09-04 | Glaxo Group Ltd | Medicament dispenser |
| US20060205790A1 (en) * | 2002-10-22 | 2006-09-14 | Coe Diane M | Medicinal arylethanolamine compounds |
| AR041724A1 (en) | 2002-10-28 | 2005-05-26 | Glaxo Group Ltd | COMPOUNDS DERIVED FROM PHENETANOLAMINE AND ITS USE IN PHARMACEUTICAL COMPOSITIONS |
| WO2004047836A1 (en) * | 2002-11-22 | 2004-06-10 | Merck Frosst Canada & Co. | Use of phosphodiesterase-4 inhibitors as enhancers of cognition |
| US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
| GB0303396D0 (en) * | 2003-02-14 | 2003-03-19 | Glaxo Group Ltd | Medicinal compounds |
| MXPA05010373A (en) | 2003-04-01 | 2005-12-05 | Applied Research Systems | Inhibitors of phosphodiesterases in infertility. |
| WO2005002626A2 (en) * | 2003-04-25 | 2005-01-13 | Gilead Sciences, Inc. | Therapeutic phosphonate compounds |
| WO2004098606A1 (en) * | 2003-05-12 | 2004-11-18 | Altana Pharma Ag | Composition comprising a pde4 inhibitor and shuil-1r ii |
| WO2004098578A2 (en) * | 2003-05-12 | 2004-11-18 | Altana Pharma Ag | Composition comprising a pde4 inhibitor and a tnf-alfa antagonist selected from infliximab, adalimumab, cdp870 and cdp517 |
| US7923467B2 (en) | 2003-05-30 | 2011-04-12 | Ranbaxy Laboratories, Inc. | Substituted pyrrole derivatives and their use as HMG-CO inhibitors |
| GB0316290D0 (en) | 2003-07-11 | 2003-08-13 | Glaxo Group Ltd | Novel compounds |
| DE10331798B4 (en) * | 2003-07-14 | 2012-06-21 | Giesecke & Devrient Gmbh | Security element, valuable item, transfer material and manufacturing process |
| GB0317374D0 (en) | 2003-07-24 | 2003-08-27 | Glaxo Group Ltd | Medicament dispenser |
| US20090274676A1 (en) * | 2003-07-31 | 2009-11-05 | Robinson Cynthia B | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a pde-4 inhibitor for treatment of asthma or chronic obstructive pulmonary disease |
| US20050085430A1 (en) * | 2003-07-31 | 2005-04-21 | Robinson Cynthia B. | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a PDE-4 inhibitor for treatment of asthma or chronic obstructive pulmonary disease |
| US20050026883A1 (en) * | 2003-07-31 | 2005-02-03 | Robinson Cynthia B. | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a PDE-4 inhibitor for treatment of asthma or chronic obstructive pulmonary disease |
| GB0324654D0 (en) * | 2003-10-22 | 2003-11-26 | Glaxo Group Ltd | Medicinal compounds |
| GB0324886D0 (en) * | 2003-10-24 | 2003-11-26 | Glaxo Group Ltd | Medicinal compounds |
| GB0401334D0 (en) | 2004-01-21 | 2004-02-25 | Novartis Ag | Organic compounds |
| JP2007530652A (en) * | 2004-04-02 | 2007-11-01 | グラクソ グループ リミテッド | Chemical substances, preparation methods and new crystalline forms |
| GB0411056D0 (en) | 2004-05-18 | 2004-06-23 | Novartis Ag | Organic compounds |
| AR049384A1 (en) | 2004-05-24 | 2006-07-26 | Glaxo Group Ltd | PURINA DERIVATIVES |
| TWI307630B (en) | 2004-07-01 | 2009-03-21 | Glaxo Group Ltd | Immunoglobulins |
| GB0418045D0 (en) | 2004-08-12 | 2004-09-15 | Glaxo Group Ltd | Compounds |
| KR101061850B1 (en) | 2004-09-08 | 2011-09-02 | 삼성전자주식회사 | Thin film transistor array panel and manufacturing method thereof |
| GT200500281A (en) | 2004-10-22 | 2006-04-24 | Novartis Ag | ORGANIC COMPOUNDS. |
| GB0424284D0 (en) | 2004-11-02 | 2004-12-01 | Novartis Ag | Organic compounds |
| GB0426164D0 (en) | 2004-11-29 | 2004-12-29 | Novartis Ag | Organic compounds |
| US7579335B2 (en) * | 2005-01-10 | 2009-08-25 | Glaxo Group Limited | Androstane 17α-carbonate derivatives for use in the treatment of allergic and inflammatory conditions |
| US20090124588A1 (en) * | 2005-01-10 | 2009-05-14 | Glaxo Group Limited | Androstane 17-Alpha-Carbonate for Use in the Treatment of Inflammatory and Allergic Conditions |
| CA2594484A1 (en) * | 2005-01-11 | 2006-07-20 | Glaxo Group Limited | Cinnamate salts of a beta-2 adrenergic agonist |
| TWI389690B (en) | 2005-03-25 | 2013-03-21 | Glaxo Group Ltd | Novel compounds |
| GB0507577D0 (en) | 2005-04-14 | 2005-05-18 | Novartis Ag | Organic compounds |
| GB0510390D0 (en) | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
| GB0514809D0 (en) | 2005-07-19 | 2005-08-24 | Glaxo Group Ltd | Compounds |
| RU2421464C2 (en) | 2005-10-21 | 2011-06-20 | Новартис Аг | Human il-13 antibodies and their therapeutic application |
| KR101329112B1 (en) | 2005-11-08 | 2013-11-14 | 랜박시 래보러터리스 리미티드 | Process for (3r,5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt |
| PE20071068A1 (en) | 2005-12-20 | 2007-12-13 | Glaxo Group Ltd | 3- (4 - {[4- (4 - {[3- (3,3-DIMETHYL-1-PIPERIDINYL) PROPYL] OXY} PHENYL) -1-PIPERIDINYL] CARBONYL} -1-NAPHTHALENYL) PROPANOIC OR PROPENOIC ACID, SALTS OF THE SAME, AS ANTAGONISTS OF THE H1 AND H3 RECEPTORS |
| GB0526244D0 (en) | 2005-12-22 | 2006-02-01 | Novartis Ag | Organic compounds |
| AU2007205114B2 (en) * | 2006-01-06 | 2012-11-08 | Sunovion Pharmaceuticals Inc. | Cycloalkylamines as monoamine reuptake inhibitors |
| GB0601951D0 (en) | 2006-01-31 | 2006-03-15 | Novartis Ag | Organic compounds |
| CA2649509A1 (en) | 2006-04-20 | 2007-11-01 | Glaxo Group Limited | Novel compounds |
| PL2013211T3 (en) | 2006-04-21 | 2012-08-31 | Novartis Ag | Purine derivatives for use as adenosin a2a receptor agonists |
| CN101500559B (en) | 2006-05-19 | 2014-01-08 | 海利空医疗公司 | Phosphodiesterase 4 inhibitors for cognitive and motor rehabilitation |
| GB0611587D0 (en) | 2006-06-12 | 2006-07-19 | Glaxo Group Ltd | Novel compounds |
| PE20080943A1 (en) | 2006-06-23 | 2008-09-27 | Smithkline Beecham Corp | SALT TOLUENOSULPHONATE OF 4 - {[6-CHLORO-3 - ({[(2-CHLORO-3-FLUOROPHENYL) AMINO] CARBONYL} AMINO) -2-HYDROXYPHENYL] SULFONYL} -1-PIPERAZINACARBOXYLATE 1,1-DIMETHYLETHYL ANTAGON IL-8 RECEIVER |
| DK2359826T3 (en) | 2006-07-05 | 2014-01-20 | Takeda Gmbh | Combination of HMG reductase inhibitor rosuvastatin with a phosphodiesterase-4 inhibitor such as roflumilast, roflumilast N-oxide for the treatment of inflammatory pulmonary diseases |
| CA2692430A1 (en) * | 2006-07-07 | 2008-01-10 | Bioassets Development Corporation | Methods for preventing, postponing or improving the outcome of spinal device and fusion procedures |
| EP2081933B1 (en) | 2006-09-29 | 2011-03-23 | Novartis AG | Pyrazolopyrimidines as pi3k lipid kinase inhibitors |
| JP2010508315A (en) | 2006-10-30 | 2010-03-18 | ノバルティス アーゲー | Heterocyclic compounds as anti-inflammatory agents |
| CA2670730A1 (en) * | 2006-12-13 | 2008-06-26 | Gilead Sciences, Inc. | Monophosphates as mutual prodrugs of anti-inflammatory signal transduction modulators (aistm's) and beta-agonists for the treatment of pulmonary inflammation and bronchoconstriction |
| US20080176901A1 (en) | 2007-01-10 | 2008-07-24 | Irm Llc | Compounds and compositions as channel activating protease inhibitors |
| PE20081889A1 (en) | 2007-03-23 | 2009-03-05 | Smithkline Beecham Corp | INDOL CARBOXAMIDES AS INHIBITORS OF IKK2 |
| TW200902025A (en) * | 2007-04-11 | 2009-01-16 | Alcon Res Ltd | Use of an inhibitor of TNF α plus an antihistamine to treat allergic rhinitis and allergic conjunctivitis |
| US20090182035A1 (en) * | 2007-04-11 | 2009-07-16 | Alcon Research, Ltd. | Use of a combination of olopatadine and cilomilast to treat non-infectious rhinitis and allergic conjunctivitis |
| AU2008248598B2 (en) | 2007-05-07 | 2011-11-17 | Novartis Ag | Organic compounds |
| CN103601792B (en) | 2007-06-04 | 2016-06-29 | 协同医药品公司 | It is effective to the guanylate cyclase agonist of gastrointestinal dysfunction, inflammation, cancer and other diseases treatment |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| KR101608702B1 (en) * | 2007-06-05 | 2016-04-04 | 사노피 | Di(hetero)arylcyclohexane derivatives, their preparation, their use and pharmaceutical compositions comprising them |
| US7943658B2 (en) * | 2007-07-23 | 2011-05-17 | Bristol-Myers Squibb Company | Indole indane amide compounds useful as CB2 agonists and method |
| TW200920369A (en) * | 2007-10-26 | 2009-05-16 | Amira Pharmaceuticals Inc | 5-lipoxygenase activating protein (flap) inhibitor |
| CN101939054B (en) | 2007-12-10 | 2014-10-29 | 诺华股份有限公司 | organic compounds |
| BRPI0906838A2 (en) | 2008-01-11 | 2015-07-14 | Novartis Ag | Pyrimidines as kinase inhibitors |
| EA019819B1 (en) | 2008-05-23 | 2014-06-30 | ПАНМИРА ФАРМАСЬЮТИКАЛЗ, ЭлЭлСи | C crystalline polymorphic form of protein inhibitor activating 5-lipoxygenase, pharmaceutical composition based thereon and use in treatment |
| CA2726917C (en) | 2008-06-04 | 2018-06-26 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| JP5502858B2 (en) | 2008-06-05 | 2014-05-28 | グラクソ グループ リミテッド | 4-Carboxamide indazole derivatives useful as inhibitors of PI3 kinase |
| WO2009147190A1 (en) | 2008-06-05 | 2009-12-10 | Glaxo Group Limited | Novel compounds |
| EA201001848A1 (en) | 2008-06-10 | 2011-08-30 | Новартис Аг | DERIVATIVES OF PIRAZINE AS EPITELIAL SODIUM CHANNEL BLOCKS |
| EP3241839B1 (en) | 2008-07-16 | 2019-09-04 | Bausch Health Ireland Limited | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
| EP2391366B1 (en) | 2009-01-29 | 2012-11-28 | Novartis AG | Substituted benzimidazoles for the treatment of astrocytomas |
| WO2010094643A1 (en) | 2009-02-17 | 2010-08-26 | Glaxo Group Limited | Quinoline derivatives and their uses for rhinitis and urticaria |
| JP5656880B2 (en) | 2009-03-09 | 2015-01-21 | グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ | 4-oxadiazol-2-yl-indazole as an inhibitor of PI3 kinase |
| EP2406249A1 (en) | 2009-03-10 | 2012-01-18 | Glaxo Group Limited | Indole derivatives as ikk2 inhibitors |
| JP2012520845A (en) | 2009-03-17 | 2012-09-10 | グラクソ グループ リミテッド | Pyrimidine derivatives used as Itk inhibitors |
| WO2010107952A2 (en) | 2009-03-19 | 2010-09-23 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF CONNECTIVE TISSUE GROWTH FACTOR (CTGF) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
| CA2755773A1 (en) | 2009-03-19 | 2010-09-23 | Merck Sharp & Dohme Corp. | Rna interference mediated inhibition of btb and cnc homology 1, basic leucine zipper transcription factor 1 (bach 1) gene expression using short interfering nucleic acid (sina) |
| US20120035247A1 (en) | 2009-03-19 | 2012-02-09 | Merck Sharp & Dohme Corp. | RNA Interference Mediated Inhibition of Signal Transducer and Activator of Transcription 6 (STAT6) Gene Expression Using Short Interfering Nucleic Acid (siNA) |
| JP2012520685A (en) | 2009-03-19 | 2012-09-10 | メルク・シャープ・エンド・ドーム・コーポレイション | RNA interference-mediated inhibition of GATA binding protein 3 (GATA3) gene expression using small interfering nucleic acids (siNA) |
| US20120022142A1 (en) | 2009-03-27 | 2012-01-26 | Merck Sharp & Dohme Corp. | RNA Interference Mediated Inhibition of Signal Transducer and Activator of Transcription 1 (STAT1) Gene Expression Using Short Interfering Nucleic Acid (siNA) |
| JP2012521760A (en) | 2009-03-27 | 2012-09-20 | メルク・シャープ・エンド・ドーム・コーポレイション | RNA interference-mediated inhibition of apoptosis signal-regulated kinase 1 (ASK1) gene expression using small interfering nucleic acids (siNA) |
| EA201171175A1 (en) | 2009-03-27 | 2012-05-30 | Мерк Шарп Энд Домэ Корп. | PHK-MEDIATED INTERFERENCE INHIBITING EXPRESSION OF A CELL INTERCEPTIVE ADHESION MOLECULE 1 (ICAM-1) WITH USING A SHORT INTERFERATING NUCLEINIC ACID (IC) -1 |
| WO2010111468A2 (en) | 2009-03-27 | 2010-09-30 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF THE NERVE GROWTH FACTOR BETA CHAIN (NGFß) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (SINA) |
| EP2411520A2 (en) | 2009-03-27 | 2012-02-01 | Merck Sharp&Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF THE THYMIC STROMAL LYMPHOPOIETIN (TSLP) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
| EP2421834A1 (en) | 2009-04-24 | 2012-02-29 | Glaxo Group Limited | Pyrazole and triazole carboxamides as crac channel inhibitors |
| US8399436B2 (en) | 2009-04-24 | 2013-03-19 | Glaxo Group Limited | N-pyrazolyl carboxamides as CRAC channel inhibitors |
| AU2010243613B2 (en) | 2009-04-30 | 2015-05-07 | Glaxo Group Limited | Oxazole substituted indazoles as PI3-kinase inhibitors |
| US8389526B2 (en) | 2009-08-07 | 2013-03-05 | Novartis Ag | 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives |
| WO2011018454A1 (en) | 2009-08-12 | 2011-02-17 | Novartis Ag | Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation |
| MX2012002066A (en) | 2009-08-17 | 2012-03-29 | Intellikine Inc | Heterocyclic compounds and uses thereof. |
| AU2010284972A1 (en) | 2009-08-20 | 2012-03-08 | Novartis Ag | Heterocyclic oxime compounds |
| JP5721722B2 (en) * | 2009-10-01 | 2015-05-20 | アルコン リサーチ， リミテッド | Olopatadine composition and use thereof |
| JP2013508414A (en) | 2009-10-22 | 2013-03-07 | バーテックス ファーマシューティカルズ インコーポレイテッド | Compositions for the treatment of cystic fibrosis and other chronic diseases |
| US20120238559A1 (en) | 2009-12-03 | 2012-09-20 | Glaxo Group Limited | Novel compounds |
| JP2013512880A (en) | 2009-12-03 | 2013-04-18 | グラクソ グループ リミテッド | Indazole derivatives as PI3-kinase inhibitors |
| EP2507223A1 (en) | 2009-12-03 | 2012-10-10 | Glaxo Group Limited | Benzpyrazole derivatives as inhibitors of p13 kinases |
| EP2512438B1 (en) | 2009-12-16 | 2017-01-25 | 3M Innovative Properties Company | Formulations and methods for controlling mdi particle size delivery |
| WO2011110575A1 (en) | 2010-03-11 | 2011-09-15 | Glaxo Group Limited | Derivatives of 2-[2-(benzo- or pyrido-) thiazolylamino]-6-aminopyridine, useful in the treatment of respiratoric, allergic or inflammatory diseases |
| US8247436B2 (en) | 2010-03-19 | 2012-08-21 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF |
| GB201007203D0 (en) | 2010-04-29 | 2010-06-16 | Glaxo Group Ltd | Novel compounds |
| US9326987B2 (en) | 2010-09-08 | 2016-05-03 | Glaxo Group Limited | Indazole derivatives for use in the treatment of influenza virus infection |
| JP5965402B2 (en) | 2010-09-08 | 2016-08-03 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ | N- [5- [4- (5-{[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl ] -2- (Methyloxy) -3-pyridinyl] methanesulfonamide polymorphs and salts |
| WO2012034095A1 (en) | 2010-09-09 | 2012-03-15 | Irm Llc | Compounds and compositions as trk inhibitors |
| UY33597A (en) | 2010-09-09 | 2012-04-30 | Irm Llc | COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF THE TRK |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| WO2012035055A1 (en) | 2010-09-17 | 2012-03-22 | Glaxo Group Limited | Novel compounds |
| US8372845B2 (en) | 2010-09-17 | 2013-02-12 | Novartis Ag | Pyrazine derivatives as enac blockers |
| JP5795643B2 (en) | 2010-10-21 | 2015-10-14 | グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ | Pyrazole compounds acting on allergic, immune and inflammatory conditions |
| WO2012052459A1 (en) | 2010-10-21 | 2012-04-26 | Glaxo Group Limited | Pyrazole compounds acting against allergic, inflammatory and immune disorders |
| GB201018124D0 (en) | 2010-10-27 | 2010-12-08 | Glaxo Group Ltd | Polymorphs and salts |
| JP2014505088A (en) | 2011-02-10 | 2014-02-27 | ノバルティス アーゲー | [1,2,4] Triazolo [4,3-b] pyridazine compounds as C-MET tyrosine kinase inhibitors |
| WO2012116237A2 (en) | 2011-02-23 | 2012-08-30 | Intellikine, Llc | Heterocyclic compounds and uses thereof |
| ES2551592T3 (en) | 2011-02-25 | 2015-11-20 | Novartis Ag | Pyrazolo [1,5-a] pyridines as TRK inhibitors |
| CN107090016A (en) | 2011-03-01 | 2017-08-25 | 辛纳吉制药公司 | The method for preparing guanosine cyclic mono-phosphate activator |
| JP2014507458A (en) | 2011-03-11 | 2014-03-27 | グラクソ グループ リミテッド | Pyrido [3,4-B] pyrazine derivatives as Syk inhibitors |
| GB201104153D0 (en) | 2011-03-11 | 2011-04-27 | Glaxo Group Ltd | Novel compounds |
| US8883819B2 (en) | 2011-09-01 | 2014-11-11 | Irm Llc | Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension |
| ES2691650T3 (en) | 2011-09-15 | 2018-11-28 | Novartis Ag | 3- (quinolin-6-yl-thio) - [1,2,4] -triazolo- [4,3-a] -pyridines 6-substituted as inhibitors of tyrosine kinase c-Met |
| WO2013038381A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine/pyrazine amide derivatives |
| WO2013038373A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
| JP5886433B2 (en) | 2011-09-16 | 2016-03-16 | ノバルティス アーゲー | Heterocyclic compounds for the treatment of cystic fibrosis |
| JP6165733B2 (en) | 2011-09-16 | 2017-07-19 | ノバルティス アーゲー | N-substituted heterocyclylcarboxamides |
| WO2013038378A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
| WO2013078440A2 (en) | 2011-11-23 | 2013-05-30 | Intellikine, Llc | Enhanced treatment regimens using mtor inhibitors |
| WO2013084182A1 (en) | 2011-12-08 | 2013-06-13 | Glenmark Pharmaceuticals S.A. | Pharmaceutical composition that includes a pde4 enzyme inhibitor and an analgesic agent |
| US8809340B2 (en) | 2012-03-19 | 2014-08-19 | Novartis Ag | Crystalline form |
| EP3964513A1 (en) | 2012-04-03 | 2022-03-09 | Novartis AG | Combination products with tyrosine kinase inhibitors and their use |
| JP6499591B2 (en) | 2013-02-25 | 2019-04-10 | シナジー ファーマシューティカルズ インコーポレイテッド | Guanylate cyclase receptor agonists for use in colon lavage |
| US9073921B2 (en) | 2013-03-01 | 2015-07-07 | Novartis Ag | Salt forms of bicyclic heterocyclic derivatives |
| AU2014235215A1 (en) | 2013-03-15 | 2015-10-01 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| EP2968340A4 (en) | 2013-03-15 | 2016-08-10 | Intellikine Llc | Combination of kinase inhibitors and uses thereof |
| WO2014151200A2 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
| CN105764916B (en) | 2013-06-05 | 2021-05-18 | 博士医疗爱尔兰有限公司 | Ultra-pure agonists of guanylate cyclase C, methods of making and using the same |
| EP3030252B1 (en) | 2013-08-09 | 2018-11-07 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
| EP3046921A4 (en) | 2013-09-22 | 2017-02-22 | Calitor Sciences, LLC | Substituted aminopyrimidine compounds and methods of use |
| EP3057587A1 (en) | 2013-10-17 | 2016-08-24 | GlaxoSmithKline Intellectual Property Development Limited | Pi3k inhibitor for treatment of respiratory disease |
| WO2015055691A1 (en) | 2013-10-17 | 2015-04-23 | Glaxosmithkline Intellectual Property Development Limited | Pi3k inhibitor for treatment of respiratory disease |
| TW201605450A (en) | 2013-12-03 | 2016-02-16 | 諾華公司 | Combination of Mdm2 inhibitor and BRAF inhibitor and their use |
| WO2015148869A1 (en) | 2014-03-28 | 2015-10-01 | Calitor Sciences, Llc | Substituted heteroaryl compounds and methods of use |
| US10112926B2 (en) | 2014-04-24 | 2018-10-30 | Novartis Ag | Amino pyridine derivatives as phosphatidylinositol 3-kinase inhibitors |
| CN106458979B (en) | 2014-04-24 | 2020-03-27 | 诺华股份有限公司 | Aminopyrazine derivatives as phosphatidylinositol 3-kinase inhibitors |
| BR112016023967A2 (en) | 2014-04-24 | 2017-08-15 | Novartis Ag | pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors |
| CN107072976A (en) | 2014-05-12 | 2017-08-18 | 葛兰素史克知识产权第二有限公司 | The pharmaceutical composition for including Danirixin for treating communicable disease |
| WO2016011658A1 (en) | 2014-07-25 | 2016-01-28 | Novartis Ag | Combination therapy |
| EP3174869B1 (en) | 2014-07-31 | 2020-08-19 | Novartis AG | Combination therapy of a met inhibitor and an egfr inhibitor |
| JP2018527362A (en) | 2015-09-11 | 2018-09-20 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． | Substituted heteroaryl compounds and methods of use |
| EP3165224A1 (en) | 2015-11-09 | 2017-05-10 | Albert-Ludwigs-Universität Freiburg | Use of pde4 inhibitors for the prophylaxis and/or therapy of dyslipoproteinaemia and related disorders |
| WO2017089347A1 (en) | 2015-11-25 | 2017-06-01 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and pharmaceutical compositions for the treatment of braf inhibitor resistant melanomas |
| GB201602527D0 (en) | 2016-02-12 | 2016-03-30 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
| WO2018029126A1 (en) | 2016-08-08 | 2018-02-15 | Glaxosmithkline Intellectual Property Development Limited | Chemical compounds |
| WO2018094392A1 (en) | 2016-11-21 | 2018-05-24 | Lupin Inc. | Medicament dispenser |
| GB201706102D0 (en) | 2017-04-18 | 2017-05-31 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
| GB201712081D0 (en) | 2017-07-27 | 2017-09-13 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
| US10683297B2 (en) | 2017-11-19 | 2020-06-16 | Calitor Sciences, Llc | Substituted heteroaryl compounds and methods of use |
| WO2019143874A1 (en) | 2018-01-20 | 2019-07-25 | Sunshine Lake Pharma Co., Ltd. | Substituted aminopyrimidine compounds and methods of use |
| WO2019195711A1 (en) | 2018-04-06 | 2019-10-10 | Lupin Inc. | Medicament dispenser |
| TW201943686A (en) * | 2018-04-11 | 2019-11-16 | 日商三菱瓦斯化學股份有限公司 | Method for producing 1,4-cyclohexanedicarboxylic acid derivative, 1,4-dicyanocyclohexane, and1,4-bis(aminomethyl)cyclohexane |
| WO2020058823A1 (en) | 2018-09-17 | 2020-03-26 | Lupin, Inc. | Dose indicator assembly for a medicament dispenser |
| EP3972599A1 (en) | 2019-05-21 | 2022-03-30 | Ardelyx, Inc. | Combination for lowering serum phosphate in a patient |
| CA3139634A1 (en) | 2019-06-10 | 2020-12-17 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of cf, copd, and bronchiectasis |
| CA3146109A1 (en) | 2019-08-28 | 2021-03-04 | Novartis Ag | Substituted 1,3-phenyl heteroaryl derivatives and their use in the treatment of disease |
| BR112022019277A2 (en) | 2020-03-25 | 2022-12-06 | Lupin Inc | DISTRIBUTORS OF MULTI-CARRIER MEDICINES |
| EP4125919A1 (en) | 2020-03-26 | 2023-02-08 | GlaxoSmithKline Intellectual Property Development Limited | Cathepsin inhibitors for preventing or treating viral infections |
| WO2022020506A1 (en) | 2020-07-23 | 2022-01-27 | Lupin Inc. | Dose counter assemblies for medicament dispensers |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3862239A (en) * | 1967-08-22 | 1975-01-21 | Ortho Pharma Corp | Aryl substituted cyclohexenecarbinols |
| US3979444A (en) * | 1974-05-28 | 1976-09-07 | The Upjohn Company | 4-Arylcyclohexylamines |
| US4795757A (en) * | 1984-09-04 | 1989-01-03 | Rorer Pharmaceutical Corporation | Bisarylamines |
| CA2120351A1 (en) * | 1991-10-02 | 1993-04-15 | Siegfried B. Christensen, Iv | Cyclopentane and cyclopentene derivatives with antiallergic antiinflammatory and tumor necrosis factor inhibiting activity |
| JP3199380B2 (en) * | 1992-04-02 | 2001-08-20 | スミスクライン・ビーチャム・コーポレイション | Compound |
| JP3192424B2 (en) * | 1992-04-02 | 2001-07-30 | スミスクライン・ビーチャム・コーポレイション | Compounds for the treatment of allergic or inflammatory diseases |
| WO1993019748A1 (en) * | 1992-04-02 | 1993-10-14 | Smithkline Beecham Corporation | Compounds useful for treating inflammatory diseases and for inhibiting production of tumor necrosis factor |
-
1993
- 1993-03-05 MX MX9301943A patent/MX9301943A/en unknown
- 1993-03-05 US US08/313,094 patent/US5552438A/en not_active Expired - Lifetime
- 1993-03-05 HU HU9402817A patent/HU225869B1/en unknown
- 1993-03-05 WO PCT/US1993/001991 patent/WO1993019749A1/en active IP Right Grant
- 1993-03-05 SK SK1171-94A patent/SK279958B6/en not_active IP Right Cessation
- 1993-03-05 AU AU37910/93A patent/AU677776B2/en not_active Expired
- 1993-03-05 NZ NZ251092A patent/NZ251092A/en not_active IP Right Cessation
- 1993-03-05 EP EP93907233A patent/EP0633776B1/en not_active Expired - Lifetime
- 1993-03-05 CZ CZ942397A patent/CZ283425B6/en not_active IP Right Cessation
- 1993-03-05 CA CA002133439A patent/CA2133439C/en not_active Expired - Lifetime
- 1993-03-30 AP APAP/P/1996/000794A patent/AP519A/en active
- 1993-03-30 AP APAP/P/1993/000508A patent/AP516A/en active
- 1993-03-30 IL IL10522193A patent/IL105221A/en not_active IP Right Cessation
- 1993-04-02 CN CN93105725A patent/CN1066436C/en not_active Expired - Lifetime
- 1993-04-02 SI SI9300169A patent/SI9300169B/en active Search and Examination
-
1994
- 1994-09-29 BG BG99080A patent/BG62235B1/en unknown
- 1994-09-30 FI FI944549A patent/FI944549A/en unknown
- 1994-09-30 NO NO943663A patent/NO303116B1/en not_active IP Right Cessation
-
1995
- 1995-05-18 US US08/443,636 patent/US5643946A/en not_active Expired - Lifetime
- 1995-05-18 US US08/443,641 patent/US5602157A/en not_active Expired - Lifetime
- 1995-05-18 US US08/457,942 patent/US5614540A/en not_active Expired - Lifetime
-
2001
- 2001-08-08 GR GR20010401199T patent/GR3036347T3/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2133439C (en) | Compounds useful for treating allergic and inflammatory diseases | |
| AU708544B2 (en) | Compounds useful for treating allergic or inflammatory diseases | |
| JP3192424B2 (en) | Compounds for the treatment of allergic or inflammatory diseases | |
| US6300372B1 (en) | 3-Cyano-3-(3,4-disubstituted) phenylcyclohexyl-1-carboxylates | |
| WO1993019751A1 (en) | Compounds useful for treating inflammatory diseases and inhibiting production of tumor necrosis factor | |
| EP0633771A1 (en) | Compounds | |
| WO1995009623A1 (en) | Anti-allergic, anti-inflammatory compounds, compositions and uses | |
| EP0919544B1 (en) | Compounds useful for treating allergic and inflammatory diseases | |
| WO1995009837A1 (en) | Cyano compounds | |
| AU675640C (en) | Compounds useful for treating allergic or inflammatory diseases | |
| JPH10511390A (en) | 1,4,4- (Trisubstituted) cyclohex-1-endimer and related compounds | |
| SI9300166A (en) | New compounds useful for treating or inhibiting phosphodiesterase iv (pde iv) enzyme activity | |
| NZ299781A (en) | 4-(substituted phenyl)-cyclohexanone derivatives and pharmaceutical compositions thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |