WO1996019988A1 - 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds - Google Patents

4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds Download PDF

Info

Publication number
WO1996019988A1
WO1996019988A1 PCT/US1995/016711 US9516711W WO9619988A1 WO 1996019988 A1 WO1996019988 A1 WO 1996019988A1 US 9516711 W US9516711 W US 9516711W WO 9619988 A1 WO9619988 A1 WO 9619988A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyclopentyloxy
methoxyphenyl
cis
cyclohexan
ylethynyl
Prior art date
Application number
PCT/US1995/016711
Other languages
French (fr)
Inventor
Siegfried B. Christensen, Iv
Joseph M. Karpinski
M. Dominic Ryan
Paul E. Bender
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to US08/860,287 priority Critical patent/US5891883A/en
Priority to AT95944363T priority patent/ATE306260T1/en
Priority to JP8520529A priority patent/JPH10511658A/en
Priority to MX9704729A priority patent/MX9704729A/en
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to EP95944363A priority patent/EP0794774B1/en
Priority to SK795-97A priority patent/SK79597A3/en
Priority to NZ301096A priority patent/NZ301096A/en
Priority to DE69534518T priority patent/DE69534518D1/en
Priority to AU46433/96A priority patent/AU703246C/en
Priority to BR9510257A priority patent/BR9510257A/en
Priority to UA97066495A priority patent/UA48157C2/en
Publication of WO1996019988A1 publication Critical patent/WO1996019988A1/en
Priority to FI972676A priority patent/FI972676A/en
Priority to NO972906A priority patent/NO972906L/en
Priority to BG101716A priority patent/BG62034B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/56—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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

Definitions

  • the present invention relates to novel 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds, pharmaceutical compositions containing these compounds, and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).
  • TNF Tumor Necrosis Factor
  • Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli.
  • Cyclic AMP adenosine cyclic 3',5'-monophosphate
  • Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973].
  • adenylate cyclase is activated, which converts Mg+2-A TP to cAMP at an accelerated rate.
  • Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of c AMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation.
  • beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation.
  • phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammarory cells.
  • the principal cellular mechanism for the inactivation of c AMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
  • PDE IV cyclic nucleotide phosphodiesterase
  • PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo.
  • PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated.
  • Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market
  • the compounds of this invention also inhibit the production of Tumor Necrosis
  • TNF Tumor Factor
  • 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 saicoidosis
  • bone resorption diseases reperfusion injury
  • graft vs a serum glycoprotein.
  • 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 acquired immune deficiency syndrome
  • AIDS AIDS
  • ARC AIDS related complex
  • keloid formation scar tissue formation
  • Crohn's disease Crohn's disease
  • ulcerative colitis ulcerative colitis
  • pyresis in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
  • HIV Immunodeficiency Virus
  • HIV-1 HIV-1
  • HIV-2 HIV-2
  • HIV-3 HIV-3
  • HIV-1 HIV-1
  • HIV-2 HIV-2
  • HIV-3 HIV-3
  • HIV entry into the T lymphocyte requires T lymphocyte activation.
  • Viruses such asHIV-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.
  • the T lymphocyte Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/orHIV replication.
  • Cytokines are implicated in activated T-cell-mediated HIV protein expression and/or virus replication by playing a role in maintaining T
  • lymphocyte activation Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV-infected individual aids in 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.
  • Monocytes, macrophages, and related cells, such as kupffer and glial cells have also been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, VoL 57, 1989].
  • Monokines such as TNF have been shown to activate HIV replication in monocytes and/or macrophages [See Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990], therefore, inhibition of monolrine 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 (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
  • CMV cytomegalovirus
  • influenza virus influenza virus
  • adenovirus adenovirus
  • herpes virus herpes virus
  • TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al.. Infection and Immunity, 58(9):2750-54, 1990; and Jafari et al.. Journal of Infectious Diseases, 164:389-95, 1991. See also Wasan et al., Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Luke et al.. Journal of Infectious Diseases, 162:211-214,1990].
  • R 1 is -(CR 4 R 5 ) n C(O)O(CR 4 R 5 ) m R 6 , -(CR 4 R 5 ) n C(O)NR 4 (CR 4 R 5 ) m R 6 , -(CR 4 R 5 ) n O(CR 4 R 5 ) m R 6 , or -(CR 4 R 5 ) r R 6 wherein the alkyl moieties unsubstituted or substituted with one or more halogens;
  • n 0 to 2;
  • n 0 to 4.
  • r is 0 to 6;
  • R 4 and R 5 are independently selected hydrogen or C 1-2 alkyl;
  • R 6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC 1-3 alkyl, halo substituted aryloxyC 1-3 alkyl, indanyl, indenyl, C 7-11 polycycloalkyl,
  • X is YR 2 , fluorine, NR 4 R 5 , or formyl amine
  • Y is O or S(O) m' ;
  • n' 0, 1, or 2;
  • X 2 is O or NR 8 ;
  • X 3 is hydrogen or X
  • X4 is H, R 9 , OR 8 , CN, C(O)R 8 , C(O)OR 8 , C(O)NR 8 R 8 , or NR 8 R 8 ;
  • R 2 is independently selected from -CH 3 or -CH 2 CH 3 optionally substituted by 1 or more halogens;
  • s is 0 to 4.
  • W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;
  • R 3 is COOR 14 , C(O)NR 4 R 14 or R 7 ;
  • Z is OR 14 , OR 15 , SR 14 , S(O) m' R 7 , S(O) 2 NR 10 R 14 , NR 10 R 14 ,
  • Y is O or S
  • R 7 is -(CR 4 R 5 ) q R 12 or C 1-6 alkyl wherein the R 12 or C 1-6 alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, -F, -Br, -Cl, -NO 2 , -NR 10 R 11 , -C(O)R 8 , -CO 2 R 8 , -O(CH 2 ) 2-4 OR 8 , -O(CH 2 )qR 8 , -CN, -C(O)NR 10 R 11 , -O(CH 2 ) q C(O)NR 10 R 11 , - O(CH 2 ) q C(O)R 9 , -NR 10 C(O)NR 10 R 11 , -NR 10 C(O)R 11 , -NR 10 C(O)OR 9 , -NR 10 C(O)R 13 , -
  • q 0, 1, or 2;
  • R 12 is R 13 , C 3 -C 7 cycloalkyl, or an unsubstituted or substituted aryl or heteroaryl group selected from the group consisting of (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, and phenyl;
  • R 8 is independently selected from hydrogen or R 9 ;
  • R 9 is C 1-4 alkyl optionally substituted by one to three fluorines
  • R 10 is OR 8 or R 11 ;
  • R 1 1 is hydrogen, or C 1-4 alkyl unsubstituted or substituted by one to three fluorines; or when R 10 and R 1 1 are as NR 10 R 1 1 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S;
  • R 13 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and where R 13 is substituted on R 12 or R 13 the rings are connected through a carbon atom and each second R 13 ring may be unsubstituted or substituted by one or two C 1-2 alkyl groups unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms;
  • R 14 is hydrogen or R 7 ; or when R 8 and R 14 are as NR 8 R 14 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S;
  • R 15 is C(O)R 14 , C(O)NR s R 14 , S(O) q NR s R 14 or S(O) q R 7 where q is 0, 1 or 2; provided that:
  • R 7 is not C 1-4 alkyl unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof.
  • This invention also relates to the pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent
  • the invention also relates to a method of mediation or inhibition of the enzymatic activity (or catalytic activity) of PDE IV in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I) as shown below.
  • the invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I).
  • the invention also provides a method for the treatment of asthma which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I).
  • This invention also relates to a method of inhibiting TNF production in a mammal, including humans, which method comprises administering to a mammal in need of such treatment, an effective TNF inhibiting amount of a compound of Formula (I).
  • This method may be used for the prophylactic treatment or prevention of certain TNF mediated disease states amenable thereto.
  • This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HIV), which comprises administering to such human an effective TNF inhibiting amount of a compound of Formula (I).
  • HAV human immunodeficiency virus
  • Compounds of Formula (I) are also useful in the treatment of additional viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • compounds of Formula (I) are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • This invention also relates to a method of mediating or inhibiting the enzymatic activity (or catalytic activity) of PDE IV in a mammal in need thereof and to inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
  • Phosphodiesterase IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic
  • PDE TV inhibitors are useful in the treatment of diabetes insipidus and central nervous system disorders such as depression and multi-infarct dementia.
  • viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (I).
  • viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV). influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.
  • CMV cytomegalovirus
  • influenza adenovirus
  • Herpes group of viruses such as, but not limited to, Herpes zoster and Herpes simplex.
  • This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I).
  • HAV human immunodeficiency virus
  • TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
  • viruses include, but are not limited to feline
  • FMV immunodeficiency virus
  • retro viral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
  • the compounds of this invention are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • a preferred disease state for treatment is fungal meningitis.
  • the compounds of Formula (I) may be administered in conjunction with other drugs of choice for systemic yeast and fungal infections.
  • Drugs of choice for fungal infections include but are not limited to the class of compounds called the polymixins, such as Polymycin B, the class of compounds called the imidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; 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 liposomal Amphotericin B.
  • polymixins such as Polymycin B
  • imidazoles such as clotrimazole, econazole, miconazole, and ketoconazole
  • triazoles such as fluconazole, and itranazole
  • Amphotericins in particular Amphotericin B and liposomal Amphotericin B.
  • the compounds of Formula (I) may also be used for inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti-viral agent by administering an effective amount of a compound of Formula (I) to a mammal in need of such treatment
  • a compound of Formula (I) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.
  • C 1-3 alkyl C 1-4 alkyl
  • C 1-6 alkyl or “alkyl” groups as used herein is meant to 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 means both straight or branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl, 1-propenyl, 2-propenyl, or 3-methyl-2-propenyl.
  • cycloalkyl or "cycloalkyl alkyl” means groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl.
  • the alkyl chain is meant to include both straight or branched chain radicals of 1 to 4 carbon atoms.
  • Heteroaryl means an aromatic ring system containing one or more
  • Halo means all halogens, i.e., chloro, fluoro, bromo, or iodo.
  • TNF mediated disease or disease states means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytoldne to be released, such as but not limited to IL-1 or IL-6.
  • TNF-ß also known as lymphotoxin
  • TNF- ⁇ also known as cachectin
  • both TNF- ⁇ and TNF-ß are inhibited by the compounds of the present invention and thus are herein referred to collectively as 'TNF" unless specifically delineated otherwise.
  • TNF- ⁇ is inhibited.
  • Cytoldne 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 cytoldne includes, but is not limited to, monokines and lympho-rines regardless of which cells produce them.
  • the cytokine inhibited by the present invention for use in the treatment of a HIV-infected human must be a cytoldne which is implicated in (a) the initiation and/or maintenance of T 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.
  • his cytokine is TNF- ⁇ .
  • All of the compounds of Formula (I) are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal, including humans, in need thereof. All of the con-pounds of Formula (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.
  • salts of the instant compounds where they can be prepared, are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its
  • Preferred compounds are as follows:
  • R 1 is an alkyl substituted by 1 or more halogens
  • the halogens are preferably fluorine and chlorine, more preferably a C 1-4 alkyl substituted by 1 or more fluorines.
  • the preferred halo-substituted alkyl chain length is one or two carbons, and most preferred are the moieties -CF 3 , -CH 2 F, -CHF 2 , -CF 2 CHF 2 , -CH 2 CF 3 , and - CH 2 CHF 2 .
  • R 1 substitutents for the compounds of Formula (I) are CH 2 - cyclopropyl, CH 2 -C 5-6 cycloalkyl, C 4-6 cycloalkyl unsubstituted or substituted with OHC 7-11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-2 alkyl unsubstituted or substituted by 1 or more fluorines,
  • R 1 term contains the moiety (CR 4 R 5 )
  • the R 4 and R 5 terms are independendy hydrogen or alkyl. This allows for branching of the individual methylene units as (CR 4 R 5 ) n or (CR 4 R 5 ) m ; each repeating methylene unit is independent of the other, e.g., (CR 4 R 5 ) n wherein n is 2 can be -CH 2 CH(-CH 3 )-, for instance.
  • hydrocarbon can unsubstituted or be substituted by fluorine independent of each other to yield, for instance, the preferred R 1 substitutions, as noted above.
  • R 1 is a C 7- 11 polycycloalkyl
  • examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0 2, 6 ]decyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987.
  • W is preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, and where it is alkenyl or alkynyl, that one or two double or triple bonds be present It is most preferred that W is ethynyl or 1,3-butadiynyl.
  • Z is preferably OR 14 , OR 15 , SR 14 , S(O) m 'R 7 , S(O) 2 NR 10 R 14 , NR 10 R 14 , NR 14 C(O)R 9 , NR 10 C(O)R 14 , NR 10 C(O)OR 7 , NR 10 C(O)NR 10 R 14 ,
  • NR 10 C(NR 10 )NR 10 R 14 NR 10 C(O)C(O)NR 10 R 14 , or NR 10 C(O)C(O)OR 14 .
  • Preferred X groups for Formula (I) are those wherein X is YR 2 and Y is oxygen.
  • the preferred X 2 group for Formula (I) is that wherein X 2 is oxygen.
  • the preferred X 3 group for Formula (I) is that wherein X3 is hydrogen.
  • Preferred R 2 groups, where applicable, is a C 1-2 alkyl unsubstituted or substituted by 1 or more halogens.
  • the halogen atoms are preferably fluorine and chlorine, more preferably fluorine.
  • R 2 groups are those wherein R 2 is mediyl, or the fluoro substituted alkyls, specifically a C 1-2 alkyl, such as a -CF 3 , -CHF 2 , or -CH 2 CHF 2 moiety. Most preferred are the -CHF 2 and -CH 3 moieties.
  • R 7 moieties include unsubstituted or substituted -(CH 2 ) 0-2 (2-, 3- or 4-pyridyl), (CH 2 ) 1-2 (2-imidazolyl), (CH 2 ) 2 (4-moapholinyl), (CH 2 ) 2 (4-piperazinyl), (CH 2 ) 1-2 (2-thienyl), (CH 2 ) 1-2 (4-thiazolyl), unsubstituted or substituted pyrimidinyl, and substituted or unsubstituted (CH 2 ) 0-2 phenyl.
  • Preferred rings when R 10 and R 11 in the moiety -NR 10 R 11 together with the nitrogen to which they are attached form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 2-(R 8 )-1-imidazolyl, 1-pyrazolyl, 3-(R 8 )-1-pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R 8 )-1-triazolyl, 5-(R 8 )-2-triazolyl, 5-(R 8 )-1-tetrazolyl, 5-(R 8 )-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(R 8 )-1-piperazinyl, or pyrrolyl ring.
  • R 10 and R 14 in the moiety -NR 10 R 14 together with the nitrogen to which they are attached may form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl,
  • substitutions includes, but is not limited to, 2-(R 7 )-1-imidazolyl, 4-(R 7 )-1-imidazolyl, 5-(R 7 )-1-imidazolyl, 3-(R 7 )-1-pyrazolyl, 4-(R 7 )-1-pyrazolyl, 5-(R 7 )-1-pyrazolyl, 4-(R 7 )-2-triazolyl, 5-(R 7 )-2-triazolyl, 4-(R 7 )-1-triazolyl, 5-(R 7 )-1-triazolyl,
  • R 7 5-(R 7 )-1-tetrazolyl, and 5-(R 7 )-2-tetrazolyl.
  • Applicable nitrogen substitution by R 7 includes, but is not limited to, 1-(R 7 )-2-tetrazolyl, 2-(R 7 )-1-tetrazolyl, 4-(R 7 )-1-piperazinyl, Where applicable, the ring may be substituted one or more times by R 7 .
  • Preferred groups for NR 10 R 14 which contain a heterocyclic ring are 5-(R 14 )-1-tetrazolyl, 2-(R 14 )-1-imidazolyl, 5-(R 14 )-2-tetrazolyl, 4-(R 14 )-1-piperazinyl, or 4-(R 15 )-1-piperazinyl.
  • Preferred rings for R 13 include (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl),
  • the heterocyclic ring itself may be unsubstituted or substituted by R 8 on an available nitrogen or carbon atom, such as 1-(R 8 )-2-imidazolyl, 1-(R 8 )-4-imidazolyl, 1-(R 8 )-5-imidazolyl,
  • R 1 is -CH 2 - cyclopropyl, -CH 2 -C 5-6 cycloalkyl, -C 4-6 cycloalkyl unsubstituted or substituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -C 1-2 alkyl unsubstituted or substituted by 1 or more fluorines, and -(CH 2 ) 2-4 OH;
  • R 2 is methyl or fluorosubstituted alkyl, W is ethynyl or 1,3-butadiynyl;
  • R 3 is R 7 where R 7 is an unsubstituted or substituted aryl or heteroaryl ring,
  • X is YR 2
  • Z is OR 14 , OR 15 , NR 10 R 14 , or NR 14 C(O)R 9 .
  • R 1 is -CH 2 -cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF 2 H
  • X is YR 2
  • Y is oxygen
  • X 2 is oxygen
  • X 3 is hydrogen
  • R 2 is CF 2 H or methyl
  • W is ethynyl or 1,3-butadiynyl
  • R 3 is a substituted or unsubstituted pyrimidinyl ring.
  • the parent compound dissolved in a suitable solvent, is treated with an excess of an organic or inorganic acid, in the case of acid addition salts of a base, or an excess of organic or inorganic base where the molecule contains a COOH for example.
  • compositions of the present invention comprise a
  • compositions may be made up as a solid, liquid or in a gaseous form. Or one of these three forms may be transformed to another at the time of being administered such as when a solid is delivered by aerosol means, or when a liquid is delivered as a spray or aerosol.
  • compositions and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.
  • the pharmaceutical composition will be in the form of a cream, ointment liniment, lotion, pastes, aerosols, and drops suitable for topical administration.
  • the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or non-aqueous liquid suspension.
  • a sterile injectable liquid such as an ampule or an aqueous or non-aqueous liquid suspension.
  • the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
  • examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water, for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof wit water; for solid systems, lactose, kaolin and mannitoL and for aerosol systems, dkhlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide.
  • the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.
  • the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient
  • the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient
  • a compound of formula I is administered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor.
  • Topical formulations will contain between about 0.01 to 5.0% by weight of the active ingredient and will be applied as required as a preventative or curative agent to the affected area.
  • me dosage of the composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration. For convenience, equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 50 mg to about 5000 mg.
  • Compounds of Formula (I) may be prepared by the processes disclosed herein which comprise reacting a terminal acetylene, wherein Z represents Z as defined in relation to Formula (I) or a group convertible to Z, as, e.g., compound 1-Scheme 1. with an appropriate halide, R 3 X, wherein R 3 represents R 3 as defined in relation to Formula (I) or a group convertible to R 3 , in the presence of a suitable catalyst, such as a copper (I) halide and a bivalent or zerovalent palladium compound in the presence of, e.g., triphenylphosphine, in a suitable solvent, such as an amine, as in the pr° Cedure of Brandsma et al. (Syn.
  • a suitable catalyst such as a copper (I) halide and a bivalent or zerovalent palladium compound in the presence of, e.g., triphenylphosphine, in a suitable solvent, such as an amine, as in
  • compounds of the Formula (I), wherein Z and R 3 represent Z and R 3 as defined in relation to Formula (I) or a group convertible to Z or R 3 may be prepared from the corresponding ketones as, e.g., compound 1 -Scheme 2. by the synthetic pr° Cedures described in PCT application number PCT/US93/01990 and PCT/US93/02325 published as WIPO publication number WO93/19750 .
  • oxidative carbonylation of a terminal acetylene as, e.g., compound 1-Scheme 3. using an appropriate metal salt such as a copper salt with a catalytic amount of a palladium salt, in the presence of a suitable base as an acid trap, such as sodium acetate, in a suitable alcohol, such as methanol, then provides the compound of the Formula 2-Scheme 3: such compounds may men be converted to other compounds of the Formula (I) by manipulation of the ketone as described above and by independent manipulation of the carboxylic ester moiety using standard txansesterification or amidation conditions. Syntheses of such ketone starting materials are described in published PCT application PCT/US93/02O45 (WIPO publication number WO
  • PCT/US93/001990 (WIPO publication number WO 93/19748) or PCT/US93/02325 (WIPO publication number WO/93/19750) in 1,2-dimethoxyethane (5 mL) under an argon atmosphere was added sodium borohydride (0.08 g, 2.2 mmol) and the mixture was stirred at room temperature for 0.5 h. Water was added, the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated.
  • triphenylphosphine The mixture was refluxed for 5 h, then concentrated in vacua. The residue was diluted with ethyl acetate (100 mL), was washed with brine, was dried (MgSO 4 ) and was evaporated. Purification by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, foliowed by trituration from ether/hexanes, provided the tide compound as white solid (0.09 g, 58%), m.p. 90-91° C.
  • Methyl 3-iodobenzoate was prepared by standard chemistry well known to those versed in the an and is a white solid, cap.40-41° C
  • the enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a white solid, m.p. 97-99° C.
  • the enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a white solid, m.p. 117-119° C.
  • the enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a white solid, mp. 122-123° C.
  • the enantiomer was prepared in similar manner, starting with the compound from Example 3 (E2), as a clear yellow glass.
  • the enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a yellow solid, mp. 46-48° C.
  • 3-acetamido-1-iodobenzene was prepared by standard chemistry well known to those versed in the an and is a white solid, mp. 117-118° C.
  • 1-iodo-3-methanesulfonamidobenzene was prepared by standard chemistry well known to those versed in the an and is light-pink solid, mp. 102-103° C.
  • 1-iodo-3-trifluoroacetamidobenzene was prepared by standard chemistry well known to those versed in the art and is a white solid, m.p. 120-121° C
  • triphenylphosphine (1.25 g, 4.77 mmol) in tetrahydrofuran (32 mL) was dropwise added diethyl azodicarboxylate (0.75 mL, 4.77 mmol), and the solution was stirred under an argon atmosphere at room temperature for 2 h. Evaporation and purification by flash chromatography, eluting with 2:8 ethyl acetate hexanes, provided the intermediate phthalimide (1.43 g) as a waxy white solid, mp 45-52° C.
  • hydroxide:methanol:dichloromethane provided cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexyl-1-amine] as a colorless oil (0.71 g, 72%).
  • dichloromethane (5 mL) at 0° C under an argon atmosphere was added trifluoroacetic acid (0.60 mL, 7.89 mmol). The reaction was stirred at room temperature for 6 h, was cooled to 0° C, quenched with sodium bicarbonate, was diluted with water, was extracted with three times dichloromethane, was dried (magnesium sulfate) and was evaporated.
  • cyanoborohydride (0.17 g, 2.63 mmol) and several 4 ⁇ molecular sieves in methanol (10 mL) was stirred under an argon atmosphere at room temperature for 3 days.
  • hydroxide:methanol:dichloromethane provided cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine] as a colorless glass (0.11 g, 0.24 mmol, 69%).
  • This intermediate was dissolved in acetone (0.5 mL) and was added to a solution of cyclohexylsulfamic acid (0.045 g, 0.24 mmol) in acetone (1 mL).
  • 5-Bromo-2-propionamidopyrimidine was prepared by standard chemistry weli known to those versed in the an and was a white solid, mp 161-164° C.
  • hydroxide:methanol:dichloromethane provided trans-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl-1-amine] as a very viscous, colorless oil (0.13 g, 0.33 mmoL 95%).
  • This intermediate was dissolved in acetone (0.5 mL) and treated with a solution of cyclohexylsulfamic acid (0.059 g, 0.33 mmol) in acetone (1.0 mL). Dilution with ether and filtration, followed by trituration from dichloromethane/hexanes provided the tide compound as a white solid mp >230° C (dec.).
  • cyclohexylsulfamate salt cis-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexyl-1-amine], cyclohexylsulfamate salt cis-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl-1-amine], cyclohexylsulfamate salt is prepared in the same manner as trans-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl-1- amine], except starting from cis -[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-e
  • inhibitory effect of compounds of Formula (I) on in vitro TNF production by human monocytes may be determined by the protocol as described in Badger et al.,
  • Example 1 demonstrated a positive in vivo response in reducing serum levels of TNF induced by the injection of endotoxin.
  • the phosphodiesterase inhibitory activity and selectivity of the compounds of Formula (I) can be determined using a battery of five distinct PDE isozymes.
  • the tissues used as sources of the different isozymes are as follows: 1) PDE lb, porcine aorta; 2) PDE Ic, guinea-pig heart; 3) PDE III, guinea-pig heart; 4) PDE IV, human monocyte; and 5) PDE V (also called "la”), canine trachealis.
  • PDEs la, lb, Ic and m are partially purified using standard chromatographic techniques [Torphy and
  • PDE IV is purified to kinetic homogeneity by the sequential use of anion-exchange foliowed by heparin-Sepharose chromatography [Torphy et al., J. Biol. Chem., 267:1798-1804, 1992].
  • Phosphodiesterase activity is assayed as described in the protocol of Torphy and

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)

Abstract

The present invention relates to novel 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds, pharmaceutical compositions containing these compounds, and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).

Description

4,4-(disubstituted)cyclohexan-1-oIs monomers and related compounds Field of Invention
The present invention relates to novel 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds, pharmaceutical compositions containing these compounds, and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).
Background of the Invention
Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli.
Identification of novel therapeutic agents for asthma is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all three components of chronic asthma. An alternative to the "mediator approach" is to regulate the activity of the cells responsible for the pathophysiology of the disease.
One such way is by elevating levels of c AMP (adenosine cyclic 3',5'-monophosphate). Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg+2-A TP to cAMP at an accelerated rate.
Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of c AMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit
phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammarory cells. The principal cellular mechanism for the inactivation of c AMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
It has now been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Thus PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market
The compounds of this invention also inhibit the production of Tumor Necrosis
Factor (TNF), a serum glycoprotein. Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary saicoidosis, 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-1, HIV-2 and HIV-3. As a consequence of HIV infection, T-cell-mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T lymphocyte requires T lymphocyte activation. Viruses such asHIV-1 or HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/orHIV replication.
Cytokines, specifically TNF, are implicated in activated T-cell-mediated HIV protein expression and/or virus replication by playing a role in maintaining T
lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV-infected individual aids in 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. Monocytes, macrophages, and related cells, such as kupffer and glial cells, have also been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, VoL 57, 1989]. Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages [See Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990], therefore, inhibition of monolrine 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 (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al.. Infection and Immunity, 58(9):2750-54, 1990; and Jafari et al.. Journal of Infectious Diseases, 164:389-95, 1991. See also Wasan et al., Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Luke et al.. Journal of Infectious Diseases, 162:211-214,1990].
The ability to control the adverse effects of TNF is furthered by the use of the compounds which inhibit TNF in mammals who are in need of such use. There remains a need for compounds which are useful in treating TNF-mediated disease states which are exacerbated or caused by the excessive and/or unregulated production of TNF. Summary of the Invention
Compounds of the Formula (I):
Figure imgf000005_0001
wherein:
R1 is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)mR6, or -(CR4R5)rR6 wherein the alkyl moieties unsubstituted or substituted with one or more halogens;
m is 0 to 2;
n is 0 to 4;
r is 0 to 6;
R4 and R5 are independently selected hydrogen or 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 or heterocyclic moiety is unsubstituted or substituted by 1 to 3 methyl groups, one ethyl group, or an hydroxyl group;
provided that:
a) when R6 is hydroxyl, then m is 2; or
b) when R6 is hydroxyl, then r is 2 to 6; or
c) when R6 is 2-tetrahydropyranyl, 2-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)nO(CR4R5)mR6;
X is YR2, fluorine, 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 H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NR8R8, or NR8R8;
R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens;
s is 0 to 4;
W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;
R3 is COOR14, C(O)NR4R14 or R7;
Z is OR14, OR15, SR14, S(O)m'R7, S(O)2NR10R14, NR10R14,
NR14C(O)R9, NR10COOR14, NR10C(O)OR7, NR10COONR10R14,
NR10S(O)2NR10R14, NR10C(NCN)NR10R14, NR10S(O)2R7,
NR10C(CR4NO2)NR10R14, NR10C(NCN)SR9, NR10C(CR4NO2)SR9,
NR10C(NR10)NR10R14, NR10C(O)C(O)NR10R14,or NR10C(O)C(O)OR14;
Y is O or S;
R7 is -(CR4R5)qR12 or C1-6 alkyl wherein the R12 or C1-6 alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, -F, -Br, -Cl, -NO2, -NR10R11, -C(O)R8, -CO2R8, -O(CH2)2-4OR8, -O(CH2)qR8, -CN, -C(O)NR10R11, -O(CH2)qC(O)NR10R11, - O(CH2)qC(O)R9, -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, or R13;
q is 0, 1, or 2;
R12 is R13, C3-C7 cycloalkyl, or an unsubstituted or substituted aryl or heteroaryl group selected from the group consisting of (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, and phenyl;
R8 is independently selected from hydrogen or R9;
R9 is C1-4 alkyl optionally substituted by one to three fluorines;
R10 is OR8 or R11;
R1 1 is hydrogen, or C1-4 alkyl unsubstituted or substituted by one to three fluorines; or when R10 and R1 1 are as NR10R1 1 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S;
R13 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and where R13 is substituted on R12 or R13 the rings are connected through a carbon atom and each second R13 ring may be unsubstituted or substituted by one or two C1-2 alkyl groups unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms;
R14 is hydrogen or R7; or when R8 and R14 are as NR8R14 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S;
R15 is C(O)R14, C(O)NRsR14, S(O)qNRsR14 or S(O)qR7 where q is 0, 1 or 2; provided that:
(f) R7 is not C1-4 alkyl unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof.
This invention also relates to the pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent
The invention also relates to a method of mediation or inhibition of the enzymatic activity (or catalytic activity) of PDE IV in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I) as shown below.
The invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I). The invention also provides a method for the treatment of asthma which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I).
This invention also relates to a method of inhibiting TNF production in a mammal, including humans, which method comprises administering to a mammal in need of such treatment, an effective TNF inhibiting amount of a compound of Formula (I). This method may be used for the prophylactic treatment or prevention of certain TNF mediated disease states amenable thereto.
This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HIV), which comprises administering to such human an effective TNF inhibiting amount of a compound of Formula (I).
Compounds of Formula (I) are also useful in the treatment of additional viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo.
In addition, compounds of Formula (I) are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
Detailed Description of the Invention
This invention also relates to a method of mediating or inhibiting the enzymatic activity (or catalytic activity) of PDE IV in a mammal in need thereof and to inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
Phosphodiesterase IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic
glomerulonephritis, endotoxic shock and adult respiratory distress syndrome. In addition, PDE TV inhibitors are useful in the treatment of diabetes insipidus and central nervous system disorders such as depression and multi-infarct dementia.
The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (I). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV). influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex. This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I).
The compounds of this invention may also be used in association with the veterinary treatment of animals, other than in humans, in need of inhibition of TNF production. TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections. Examples of such viruses include, but are not limited to feline
immunodeficiency virus (FIV) or other retro viral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
The compounds of this invention are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo. A preferred disease state for treatment is fungal meningitis. Additionally, the compounds of Formula (I) may be administered in conjunction with other drugs of choice for systemic yeast and fungal infections. Drugs of choice for fungal infections, include but are not limited to the class of compounds called the polymixins, such as Polymycin B, the class of compounds called the imidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; 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 liposomal Amphotericin B.
The compounds of Formula (I) may also be used for inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti-viral agent by administering an effective amount of a compound of Formula (I) to a mammal in need of such treatment Preferably, a compound of Formula (I) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.
The term "C1-3 alkyl", " C1-4 alkyl", "C1-6 alkyl" or "alkyl" groups as used herein is meant to 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" means both straight or branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl, 1-propenyl, 2-propenyl, or 3-methyl-2-propenyl.
The term "cycloalkyl" or "cycloalkyl alkyl" means groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl.
"Aryl" or "aralkyl", unless specified otherwise, means an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl, or naphthyl. The alkyl chain is meant to include both straight or branched chain radicals of 1 to 4 carbon atoms. "Heteroaryl" means an aromatic ring system containing one or more
heteroatoms. "Halo" means all halogens, i.e., chloro, fluoro, bromo, or iodo.
"Inhibiting the production of IL-1" or "inhibiting the production of TNF' means:
a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels by inhibition of the in vivo release of IL-1 by all cells, including but not limited to monocytes or macrophages;
b) a down regulation, at the translational or transcriptional level, of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels; or
c) a down regulation, by inhibition of the direct synthesis of IL-1 or TNF levels as a postranslational event
The phrase "TNF mediated disease or disease states" means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytoldne to be released, such as but not limited to IL-1 or IL-6. A disease state in which IL-1, for instance is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF. As TNF-ß (also known as lymphotoxin) has close structural homology with TNF-α (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-α and TNF-ß are inhibited by the compounds of the present invention and thus are herein referred to collectively as 'TNF" unless specifically delineated otherwise. Preferably TNF-α is inhibited.
"Cytoldne" 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 cytoldne includes, but is not limited to, monokines and lympho-rines regardless of which cells produce them.
The cytokine inhibited by the present invention for use in the treatment of a HIV-infected human must be a cytoldne which is implicated in (a) the initiation and/or maintenance of T 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, his cytokine is TNF-α.
All of the compounds of Formula (I) are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal, including humans, in need thereof. All of the con-pounds of Formula (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.
Pharmaceutically acceptable salts of the instant compounds, where they can be prepared, are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its
application and use in treating diseases.
Preferred compounds are as follows:
When R1 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 halo-substituted alkyl chain length is one or two carbons, and most preferred are the moieties -CF3, -CH2F, -CHF2, -CF2CHF2, -CH2CF3, and - CH2CHF2. Preferred R1 substitutents for the compounds of Formula (I) are CH2- cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl unsubstituted or substituted with OHC7-11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C1-2 alkyl unsubstituted or substituted by 1 or more fluorines,
-(CH2)1-3C(O)O(CH2)0-2CH3, -(CH2)1-3O(CH2)0-2CH3, and -(CH2)2-4OH.
When R1 term contains the moiety (CR4R5), the R4 and R5 terms are independendy hydrogen or alkyl. This allows for branching of the individual methylene units as (CR4R5)n or (CR4R5)m; each repeating methylene unit is independent of the other, e.g., (CR4R5)n wherein n is 2 can be -CH2CH(-CH3)-, for instance. The individual hydrogen atoms of the repeating methylene unit or the branching
hydrocarbon can unsubstituted or be substituted by fluorine independent of each other to yield, for instance, the preferred R1 substitutions, as noted above.
When R1 is a C7- 11 polycycloalkyl, examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.02, 6]decyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987.
W is preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, and where it is alkenyl or alkynyl, that one or two double or triple bonds be present It is most preferred that W is ethynyl or 1,3-butadiynyl.
Z is preferably OR14, OR15, SR14, S(O)m'R7, S(O)2NR10R14, NR10R14, NR14C(O)R9, NR10C(O)R14, NR10C(O)OR7, NR10C(O)NR10R14,
NR10S(O)2NR10R14, NR10C(NCN)NR10R14, NR10S(O)2R7,
NR10C(CR4NO2)NR10R14, NR10C(NCN)SR9, NR10C(CR4NO2)SR9,
NR10C(NR10)NR10R14, NR10C(O)C(O)NR10R14, or NR10C(O)C(O)OR14.
Preferred X groups for 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 R2 groups, where applicable, is a C1-2 alkyl unsubstituted or substituted by 1 or more halogens. The halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R2 groups are those wherein R2 is mediyl, or the fluoro substituted alkyls, specifically a C1-2 alkyl, such as a -CF3, -CHF2, or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.
Preferred R7 moieties include unsubstituted or substituted -(CH2)0-2 (2-, 3- or 4-pyridyl), (CH2)1-2(2-imidazolyl), (CH2)2(4-moapholinyl), (CH2)2(4-piperazinyl), (CH2)1-2(2-thienyl), (CH2)1-2(4-thiazolyl), unsubstituted or substituted pyrimidinyl, and substituted or unsubstituted (CH2)0-2phenyl.
Preferred rings when R10 and R11 in the moiety -NR10R11 together with the nitrogen to which they are attached form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 2-(R8)-1-imidazolyl, 1-pyrazolyl, 3-(R8)-1-pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R8)-1-triazolyl, 5-(R8)-2-triazolyl, 5-(R8)-1-tetrazolyl, 5-(R8)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(R8)-1-piperazinyl, or pyrrolyl ring.
Preferred rings when R10 and R14 in the moiety -NR10R14 together with the nitrogen to which they are attached may form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl,
2-tetrazolyl, morpholinyl, piperazinyl, and pyrrolyl. The respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I). Illustrations of such carbon
substitutions includes, but is not limited to, 2-(R7)-1-imidazolyl, 4-(R7)-1-imidazolyl, 5-(R7)-1-imidazolyl, 3-(R7)-1-pyrazolyl, 4-(R7)-1-pyrazolyl, 5-(R7)-1-pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-1-triazolyl, 5-(R7)-1-triazolyl,
5-(R7)-1-tetrazolyl, and 5-(R7)-2-tetrazolyl. Applicable nitrogen substitution by R7 includes, but is not limited to, 1-(R7)-2-tetrazolyl, 2-(R7)-1-tetrazolyl, 4-(R7)-1-piperazinyl, Where applicable, the ring may be substituted one or more times by R7.
Preferred groups for NR10R14 which contain a heterocyclic ring are 5-(R14)-1-tetrazolyl, 2-(R14)-1-imidazolyl, 5-(R14)-2-tetrazolyl, 4-(R14)-1-piperazinyl, or 4-(R15)-1-piperazinyl.
Preferred rings for R13 include (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl),
(4- or 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]), (5-tetrazolyl), (2-, 4- or
5-oxazolyl), (3-, 4- or 5 -isoxazolyl), (3- or 5-oxadiazolyl[1,2,4]),
(2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).
When the R7 group is unsubstituted or substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, the heterocyclic ring itself may be unsubstituted or substituted by R8 on an available nitrogen or carbon atom, such as 1-(R8)-2-imidazolyl, 1-(R8)-4-imidazolyl, 1-(R8)-5-imidazolyl,
1-(R8)-3-pyrazolyl, 1-(R8)-4-pyrazolyl, 1-(R8)-5-pyrazolyl, 1-(R8)-4-triazolyl, or 1-(R8)-5-triazolyl. Where applicable, the ring may be substituted one or more times by R8.
Preferred are those compounds of Formula (I) wherein R1 is -CH2- cyclopropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl unsubstituted or substituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -C1-2 alkyl unsubstituted or substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluorosubstituted alkyl, W is ethynyl or 1,3-butadiynyl; R3 is R7 where R7 is an unsubstituted or substituted aryl or heteroaryl ring, X is YR2, and Z is OR14, OR15, NR10R14, or NR14C(O)R9.
Most preferred are those compounds wherein R1 is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl, W is ethynyl or 1,3-butadiynyl, and R3 is a substituted or unsubstituted pyrimidinyl ring.
It will be recognized that some of the compounds of Formula (I) may exist in both racemic and optically active forms; some may also exist in distinct diastereomeric forms possessing distinct physical and biological properties. All of these compounds are considered to be within the scope of the present invention.
Pharmaceutically acceptable salts are prepared in a standard manner.
The parent compound, dissolved in a suitable solvent, is treated with an excess of an organic or inorganic acid, in the case of acid addition salts of a base, or an excess of organic or inorganic base where the molecule contains a COOH for example.
Pharmaceutical compositions of the present invention comprise a
pharmaceutical carrier or diluent and some amount of a compound of the formula (I). The compound may be present in an amount to effect a physiological response, or it may be present in a lesser amount such that the user will need to take two or more units of the composition to effect the treatment intended. These compositions may be made up as a solid, liquid or in a gaseous form. Or one of these three forms may be transformed to another at the time of being administered such as when a solid is delivered by aerosol means, or when a liquid is delivered as a spray or aerosol.
The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.
For topical administration the pharmaceutical composition will be in the form of a cream, ointment liniment, lotion, pastes, aerosols, and drops suitable for
administration to the skin, eye, ear, or nose.
For pare nteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or non-aqueous liquid suspension. For oral administration the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water, for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof wit water; for solid systems, lactose, kaolin and mannitoL and for aerosol systems, dkhlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or diluent, the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.
The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired en product.
In these compositions, the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient When the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient
Usually a compound of formula I is administered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor. Topical formulations will contain between about 0.01 to 5.0% by weight of the active ingredient and will be applied as required as a preventative or curative agent to the affected area. When employed as an oral, or other ingested or injected regimen, me dosage of the composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration. For convenience, equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 50 mg to about 5000 mg.
No unacceptable toxicological effects are expected when these compounds are administered in accordance with the present invention.
Methods Of Preparation
Synthetic Scheme(s) With Textual Description
Compounds of Formula (I) may be prepared by the processes disclosed herein which comprise reacting a terminal acetylene, wherein Z represents Z as defined in relation to Formula (I) or a group convertible to Z, as, e.g., compound 1-Scheme 1. with an appropriate halide, R3X, wherein R3 represents R3 as defined in relation to Formula (I) or a group convertible to R3, in the presence of a suitable catalyst, such as a copper (I) halide and a bivalent or zerovalent palladium compound in the presence of, e.g., triphenylphosphine, in a suitable solvent, such as an amine, as in the pr° Cedure of Brandsma et al. (Syn. Comm., 1990, 20, 1889), provides a compound of the Formula 2-Scheme 1. Compounds of the Formula 1-Scheme 1 may be prepared by pr° Cedures analogous to those described in copending U.S. application 07/862111 , 07/968761 and PCT application number PCT/US93/02516 published under WIPO publication number WO93/19751.
Figure imgf000015_0001
a) Pd(PPh 3)4, PPh 3, Cul, R 3X, piperdine
Alternatively, compounds of the Formula (I), wherein Z and R3 represent Z and R3 as defined in relation to Formula (I) or a group convertible to Z or R3, may be prepared from the corresponding ketones as, e.g., compound 1 -Scheme 2. by the synthetic pr° Cedures described in PCT application number PCT/US93/01990 and PCT/US93/02325 published as WIPO publication number WO93/19750 .
Figure imgf000015_0002
Alternatively, oxidative carbonylation of a terminal acetylene as, e.g., compound 1-Scheme 3. using an appropriate metal salt such as a copper salt with a catalytic amount of a palladium salt, in the presence of a suitable base as an acid trap, such as sodium acetate, in a suitable alcohol, such as methanol, as in the method of Tsuji et al. (Tet Lett, 1980, 21, 849), then provides the compound of the Formula 2-Scheme 3: such compounds may men be converted to other compounds of the Formula (I) by manipulation of the ketone as described above and by independent manipulation of the carboxylic ester moiety using standard txansesterification or amidation conditions. Syntheses of such ketone starting materials are described in published PCT application PCT/US93/02O45 (WIPO publication number WO
93/19748) or published PCT application PCT/US93/02325 (WIPO publication numbe WO/93/19750).
Figure imgf000016_0001
a) PdCI 2 , CuCl 2, NaO 2CCH 3, CO, CH 3OH; as in Scheme 2 Likewise, oxidative carbonylation of a terminal acetylene as, e.g., compound 1-Scheme 4, wherein Z represents Z as defined in relation to Formula (I) or a group convertible to Z, using an appropriate metal salt, such as a copper salt with a catalytic amount of a palladium salt, in the presence of a suitable base as an acid trap, such as sodium acetate, in a suitable alcohol, such as methanol, as in the method of Tsuji et al. (Tet Lett., 1980, 21, 849), then provides the compound of the Formula 2-Scheme 4: such compounds may men be converted to other compounds of the Formula (I) by manipulation of the carboxylic ester moiety using standard txansesterification or amidation conditions.
Figure imgf000017_0001
a) PdCI 2, CuCI 2, NaO 2CCH 3 , CO, CH 3OH
Compounds where Z is a group other than -OH can be prepared by methods known in the art and in particular by manipulation of the -OH. Such methods are described in co-pending U.S. application 07/968753 and PCT application serial number PCT/US93/02325 (WIPO publication number WO/93/19750).
Preparation of the remaining compounds of the Formula (I) may be
accomplished by procedures analogous to those described above and in the Examples, infra.
It will be recognized that some compounds of the Formula (I) may exist in distinct diastereomeric forms possessing distinct physical and biological properties; such isomers may be separated by standard chromatographic methods.
The following examples are given to further illustrate the described invention. These examples are interned solely for illustrating the invention and should not be read to limit the invention in any manner. Reference is made to the claims for what is reserved to the inventors hereunder.
Experimentals
Example 1
Preparation of cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)- cyclohexan-1-ol]
1a) trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] and cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol]
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-edιynylcyclohexan-1-one (0.34 g, 1.1 mmol, prepared as described in published PCT application
PCT/US93/001990 (WIPO publication number WO 93/19748) or PCT/US93/02325 (WIPO publication number WO/93/19750) in 1,2-dimethoxyethane (5 mL) under an argon atmosphere was added sodium borohydride (0.08 g, 2.2 mmol) and the mixture was stirred at room temperature for 0.5 h. Water was added, the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:7 ethyl acetate:hexanes, provided trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] (described in U. S. Patent application in PCT application number PCT/US93/02516 published under WIPO publication number WO93/19751_as cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol]) as a wax. 1H-NMR (400 MHz, CDCI3) δ 7.14 (d, J=2.3 Hz, 1H), 7.04 (dd, J=8.5, 2.3 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 4.79 (m, 1H), 3.83 (s, 3H), 3.68 (m, 1H), 2.46 (s, 1H), 1.7 - 2.1 (m, 14H), 1.6 (m, 2H).
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] also was isolated from this pr° Cedure as a colorless oil. 1H-NMR (400 MHz, CDCI3) δ 7.17 (d, J=1.9 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.80 (m, 1H), 4.13 (br s, 1H), 3.84 (s, 3H), 2.38 (s, 1H), 2.15 (m, 4H), 1.7 - 2.0 (m, 10H), 1.75 (m, 2H).
1b) cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexan-1-ol] To a solution of trans[-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] (0.15 g, 0.48 mmol) and 4-bromopyridine (0.75g, 5 mmol) in piperidine (2 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)-paliadium(0) (0.022 g, 4%), copper (I) iodide (0.005 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 0.5 h. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:1 ethyl acetate/hexanes, provided cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)-cyclohexan-1-ol] as a pale yellow solid, which was triturated from ether-hexanes. mp 183 - 184° C. 1H-NMR (400 MHz, CDCI3) δ 8.6 (br, 2H), 7.35 (m, 2H), 7.14 (d, J=2 Hz, 1H), 7.06 (dd, J=8.5, 2Hz, 1H), 6.85 (d, J=8.5Hz, 1H), 4.79 (m, 1H), 3.85 (s, 3H), 3.7 (m, 1H), 1.8 -2.1 (m, 14H), 1.6 (m, 2H).
Example 2
cis-[4-(3-cyclopentyloxy-4-memoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexan-1-oil
To a solution of trans-[-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] (0.14 g, 0.43 mmol) and 2-bromopyridine (0.40 mL, 4.3 mmol) in piperidine (2 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.020 g, 4%), copper(I) iodide (0.005 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 0.5 h.
Ammonium chloride was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 75:25 ethyl acetate:hexanes, provided cis-[4-(3- cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexan-1-ol] as a white solid (0.14 g, 84%), mp 49-51° C. Anal. (C25H29NO3·0.5 H2O) calcd: C, 74.97; H, 7.55; N, 3.50; found: C, 74.90; H, 7.52; N, 3.33. Example 3
Resolution of (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethunylcyclohexan-1-one
The compound from Example 1b was resolved in the following manner to give enantiomeric oils: HFLC Rt = 15.5 min (enantiomer 1 = E1), 23.2 min (enantiomer 2 = E2) (Diacel Chiralpak AS®; 21.2 × 250 mm. hexaneasopropanol, 4:1; 10 mL/min; UV detection at 295 nm).
Example 4
Preparation of (+/-) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylcyclohexan-1-one
To a solution of the compound of Example 1b (0.125 g, 0.4 mmol) and iodobenzene (0.4 mL, 2.0 mmol) in piperidine (6 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and
triphenylphosphine. The mixture was refluxed for 5 h, then concentrated in vacua. The residue was diluted with ethyl acetate (100 mL), was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, foliowed by trituration from ether/hexanes, provided the tide compound as white solid (0.09 g, 58%), m.p. 90-91° C.
Example 5
Preparation of (+/-) 3-(3-cyclopcntyloxy-4-methoxyphenyl)-3-(3- carbomethoxyphenyl)ethynylcyclohexan-1-one
5a) methyl 3-iodobenzoate
Methyl 3-iodobenzoate was prepared by standard chemistry well known to those versed in the an and is a white solid, cap.40-41° C
5b) (+/-) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3-carbomethoxyphenyl)ethynylcyclohexan-1-one
To a solution of the compound from Example 1b (0.30 g, 0.96 mmol) and methyl 3-iodobenzoate (0.30 g, 1.15 mmol) in triethylamine (10 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was refluxed for 0.5 h and was then concentrated in vacua. The residue was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and was evaporated. Purification by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, provided the tide compound as a pale yellow oil (0.35 g, 80%). Anal (C28H30O5·1.0 H2O) calcd: C, 72.39; H, 6.94; found: C, 72.47; H, 6.80.
Example 6
Preparation of (+/-) 3-(3-carboxyphenylethynyl)-3-(3-cyclopentyloxy-4- methoxyphenyla)cyclohexan-1-one To a solution of the compound from Example 5(b) in 5:5:2
THF/methanol/water (10 mL) under an argon atmosphere was added sodium hydroxide (0.60 g, 1.5 mmol). The mixture was heated at 60° C for 2 h and was then concentrated in vacua. The residue was extracted from 3N HCl with ethyl acetate, was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting win.98:2:0.3 chloroform/methanol/acetic acid, provided a white solid, m.p. 71-73° C
Example 7
Preparation of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3[3-(5-methyl-[1,3,4]thiadiazol- 2-yl)phenylethynyl]cyclohexan-1-one
7a) 1-iodo-3-(5-methyl-[1,3,4]thiadiazooll-2-yl)benzene
1-Iodo-3-(5-methyl-[1,3,4]dιiadiazol-2-yl)benzene was prepared by standard chemistry well known to those versed in the art and is white solid, mp. 86-89° C. 7b) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(5-methyl-[1,3,4]thiadiazol-2-yl)phenylethynyl]cyclohexan-1-one
To a solution of the compound from Example 3 (E1) ( 0.10 g, 0.32 mmol) and 1-iodo-3-(5-methyl[1,3,4]thiadiazol-2-yl)benzene (0.10 g, 0.32 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace
tetrakis(triphenylphosphine)palldium(0), copper(I) iodide and triphenylphosphine. The mixture was refluxed for 0.20 h, was cooled to room temperature and was
concentrated in vacua. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 1:1 hexanes/ethyl acetate provided the tide compound as a white solid (0.135 g, 87%), m.p. 97-99° C.
The enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a white solid, m.p. 97-99° C.
Example 8
Preparation of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(5-methyl- [1,3,4]oxadiazol-2-yl)phenylethynyl]cyclohexan-1-one 8a) 1-Iodo-3-(5-methyl[1,3,4]oxadizol-2-yl)benzene
1-Iodo-3-(5-methyl[1,3,4]oxadiazol-2-yl)benzene was prepared by standard chemistry well known to those versed in the an and is a white solid, mp. 104-105° C. 8b) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(5-methyl[1,3,4]oxadiazol-2-yl)phenylethynyl]cyclohexan-1-one
To a solution of the compound from Example 3 (0.125 g, 0.4 mmol) and 1- iodo-3-(5-methyl-[1,3,4]oxadiazol-2-yl)benzene (0.09 g, 0.32 mmol) in triethylamine (3 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)-paliadium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80°C for 0.2 h , was cooled to room temperature and was concentrated in vacua. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 2:1 ethyl acetate/hexanes, followed by recrystallization from ethyl acetate/hexanes, provided the tide compound as a white solid (0.11 g, 61%), m.p. 117-119° C
The enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a white solid, m.p. 117-119° C.
Example 9
Preparation of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(3-methyl- [1,2,4]oxadiazol-5-yl)phenylethynyl]cyclohexan-1-one 9a) 1-iodo-3-(3-methyl-[1,2,4]oxadiazol-5-yl)benzene
1-Iodo-3-(3-methyl-[1,2,4]oxadiazol-5-yl)benzene was prepared by standard chemistry well known to those versed in the an and is a white solid, mp. 101.5-103° C.
9b) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenylethynyl]cyclohexan-1-one
To a solution of the compound from Example 3 (0.125 g, 0.4 mmol) and 1-iodo-3-(3-methyl-[1,2,4]oxadiazol-5-yl)benzene (0.09 g, 0.32 mmol) in triethylamine (3mL) under an argon atmosphere was added trace tetrakis(mphenylphosphine)-palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.2 h, was cooled to room temperature and was concentrated in vacua. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, followed by trituration from hexanes/ethyl acetate, to provide the tide compound as a white solid, m.p. 122 123° C.
The enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a white solid, mp. 122-123° C.
Example 10
Preparation of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-[3-(5-methyl- [1,2,4]oxadiazol-3-yl) phenylethynyl]cyclohexan-1-one 10a) 1-iodo-3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzene
1-iodo-3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzene was prepared by standard chemistry well known to those versed in the an and is a white solid, mp. 86-87° C. 10b) 3-(3-cyclopentyloxy-4-medιoxyphenyl)-3-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylethynyl]cyclohexan-1-one
To a solution of the compound from Example 3 (0.125 g, 0.4 mmol) and 1-iodo-3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzene (0.09 g, 0.32 mmol) in triethylamine (3 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)-palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.2 h, was cooled to room temperature and was concentrated in vacua. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, followed by trituration from hexanes/ethyl acetate, provided the tide compound as colorless crystals (0.12 g, 67%), m.p. 116-118° C. The enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as colorless crystals, m.p.116-118° C.
Example 11
Preparation of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3- cyanophenylethynyl)cyclohexan-1-one
To a solution of the compound from Example 3 (E1) (0.125 g, 0.4 mmol) and 3-iodobenzonitrile (Trans world, 0.09 g, 0.4 mmol) in triethylamine (3mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.2 h, was cooled to room temperature and was concentrated in vacua. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, to provide the tide compound as a clear yellow glass (0.12 g, 73%). MS(E1) m/e 414 [M+H]+.
The enantiomer was prepared in similar manner, starting with the compound from Example 3 (E2), as a clear yellow glass.
Example 12
Preparation of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3- nitrophenylethynyl)cyclohexan-1-one
To a solution of the compound from Example 3 (E1) (0.2 g, 0.64 mmol) and 3-iodonitrobenzene (Aldrich, 0.16 g, 0.64 mmol) in triethylamine (4 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)paliadium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.2 h, was cooled to room temperature and was concentrated in vacua. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, provided the tide compound as yellow solid (0.25 g, 90%), mp. 46-48° C
The enantiomer was prepared in a similar manner, starting with the compound from Example 3 (E2), as a yellow solid, mp. 46-48° C.
Example 13
Preparation of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(2- hydroxyethoxyphenylethynyl)cyclohexan-1-one
13a) 2-hydroxyedιoxy-1-iodobenzene
2-hydroxyedιoxy-1-iodobenzene was prepared by standard chemistry well known to those versed in the an and is a colorless oil. 1H NMR( 400 MHz, CDCI3) δ 7.77 (dd, J=7.9, 1.3 Hz, 1H), 7.3 (t, J=7H, 1H), 6.84 (d, J=7.9 Hz, 1H), 6.74 (t J=7.9 Hz, 1H), 4.13 (t, J=4.3 Hz, 2H), 3.99 (t, J=4.3 Hz, 2H), 2.2 (br s, 1H). 13b) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(2-hydroxyethoxyphenylethynyl)- cyclohexan-1-one
To a solution of the compound from Example 3 (E1) (0.25 g, 0.8 mmol) and 2- hydroxyethoxy-1-iodobenzene (0.21 g, 0.8 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 1 h, was cooled to room temperature and was concentrated in vacua. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, provided the tide compound as a white solid (0.05 g, 14%), m.p. 93-94° C.
Example 14
Preparation of 3-(3-acetamidophenylethynyl)-3-( 3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-1-one
14a) 3-acetamido-1-iodobenzene
3-acetamido-1-iodobenzene was prepared by standard chemistry well known to those versed in the an and is a white solid, mp. 117-118° C.
14b) 3-(3-acetamidcphenylethynyl)-3-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-1-one
To a solution of the compound from Example 3 (E1) (0.2 g, 0.64 mmol) and 3-acetamido-1-iodobenzene (0.17 g, 0.64 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.3 h, was cooled to room temperature and was concentrated in vacua. The residue was purified by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, to provide the tide compound as tan solid (0.17 g, 60%), m.p. 58-60° C
Example 15
Preparation of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-( 3- methanesulfonamidophenylethynyl)cyclohexan-1-one
15a) 1-iodo-3-methanesulfonamidobenzene
1-iodo-3-methanesulfonamidobenzene was prepared by standard chemistry well known to those versed in the an and is light-pink solid, mp. 102-103° C.
15b) 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3- methanesulfonamidophenylethynyl)cyclohexan-1-one
To a solution of the compound from Example 3 (E1) (0.2 g, 0.64 mmol) and 1-iodo-3-methanesulfonamidobenzene (0.19 g, 0.64 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.3 h, was cooled to room temperature and was concentrated in vacua. The residue was purified by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, to provide the title compound as a tan solid (0.18 g, 58%), m.p. 59-62° C.
Example 16
Preparation of 3-(3-aminophenylethynyl)-3-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-1-one
16a) 1-iodo-3-trifluoroacetamidobenzene
1-iodo-3-trifluoroacetamidobenzene was prepared by standard chemistry well known to those versed in the art and is a white solid, m.p. 120-121° C
16b) 3-(3-cyclopentyloxy-4-methoxyphenyl) 3-(3-trifluoroacetamidophenylethynyl)- - cyclohexan-1-one
To a solution of the compound from Example 3 (E1) (0.5 g. 1.6 mmol) and 1- iodo-3-trifluoroacetamidobenzene (0.5 g, 1.6 mmol) in triethylamine (10 mL) under an argon atmosphere was added a small amount of
tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C for 0.2 h, was cooled to room temperature and was concentrated in vacua. The residue was purified by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, to give the tide compound as a pale yellow solid (0.62 g, 78%), m.p. 63-65° C.
16c) 3-(3-aminophenylethynyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one
To a solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(3-trifluoroacetamidophenylethynyl)cyclohexan-1-one (0.62 g, 1.24 mmol) in 95:5 memanol/water (10 mL) under an argon atmosphere was added potassium carbonate (0.86 g, 6.2 mmol). The mixture was refluxed for 6 h and was stirred for 18 h at room temperature. The solid precipitate was collected and purified by trituration from ethyl acetate/hexanes to provide the tide compound as a white solid (0.39 g, 77%), m.p. 100-102° C.
Example 17
cis-[4-(4-cyanothien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)- cyclohexan-1-ol]
17a) 2-bromo-4-cyanothiophene
2-Bromo-5-cyanothiophene was prepared by standard chemistry well known to those versed in the an and is a colorless oil. 1H-NMR (400 MHz, CDCI3) δ 7.85 (d,
J=2.2Hz, 1 H), 7.25 (d, J=2.2 Hz, 1H) ppm.
17b) cis-[4-(4-cyanothien-2-ylethynyl)-4-(3-cyclopentyloxy-4-medιoxyphenyl)-cyclohexan-1-ol]
To a solution of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] (0.20 g, 0.64 mmol) and 2-bromo-4-cyanothiophene (0.12 g, 0.64 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenyl-phosphine)palladium(0) (0.030 g, 4%), copper(I) iodide (0.008 g, 6%), and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 0.5 h. Hydr° Chloric acid (5 %) was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 1:1 ethyl acetate:hexanes, followed by trituration from dichloromethane-hexanes, provided cis-[4-(4-cyanothien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol] as a pale yellow solid (0.12 g, 45%), mp 70-71° C. Anal. (C25H27NO3S) calcd: C, 71.23; H, 6.46; N, 3.30; found: C, 71.24; H, 6.72; N, 3.14.
Example 18
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[1,2,4]oxadiazol-2- yl)thien-2-ylethynyl] cyclohexan-1-ol]
18a) 2-bromo-4-{5-methyl-[1,2,4]oxadiazol-2-yl)thiophene
2-Bromo-4-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene was prepared by standard chemistry well known to those versed in the an and is a white solid, mp 72-73°C.
18b) cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl] cyclohexan-1-ol]
To a solution of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] (0.25 g, 0.8 mmol) and 2-bromo-4-{5-methyl-[1,2,4]oxadiazol-2-yl)thiophene (0.20 g, 0.8 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.038 g, 4%), copper(I) iodide (0.009 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 70-75° C for 0.5 h. Hydrchloric acid (5%) was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 1:1 ethyl acetate:hexanes, provided cis [4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexan-1-ol], which was further triturated from
dichloromethane-hexanes to give a white solid (0.20 g, 53%), mp 142-143° C. Anal. (C27H30N2O4S · 0.75 H2O) calcd: C, 65.90; H, 6.45; N, 5.69; found: C, 66.06; H, 6.42; N, 5.50
Example 19
cis-[4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)- cyclohexan-1-ol]
19a) 4-iodo-2-thiomethylpyrimidine
4-Iodo-2-thiomethylpyrimidine was prepared following a literature procedure (A.J. Majeed, Ø. Antonsen, T. Benneche, K. Undheim. Tetrahedron 1989, 45, 993-1006). 19b) cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylthiopyrimidin-4- ylethynyl) cyclohexan-1-ol]
To a solution of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] (0.30 g, 0.95 mmol) and and 4-iodo-2-thiomethylpyrimidine (0.50 g, 2.5 mmol, as a mixture of 4-iodo-2-dιiomethylpyrimidine and 4-chloro-2- thiomethylpyrimidine) in triethylamine (2 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.044 g, 4%) and copper(I) iodide (0.010 g, 6%), and the mixture was heated at 80-85° C for 0.5 h. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 1:1 ethyl acetate:hexanes, provided cis-[4-(3-cyclopentyloxy-4- methoxyphenyl)-4-(2-methylthiopyrimidin-4-ylethynyl)cyclohexan-1-ol] as a yellow oil (0.36 g, 87%). 1H-NMR (400 MHz, CDCl3) δ 8.45 (d, J=5.0 Hz, 1 H), 7.15 (d, J=2.3 Hz, 1 H), 7.03 (dd, J=8.5, 2.3 Hz, 1 H), 7.01 (d, J=5.0 Hz, 1 H), 6.84 (d, J=8.5 Hz, 1 H), 4.81 (m, 1 H), 3.84 (s, 3 H), 3.72 (m, 1 H), 2.57 (s, 3 H), 2.14 (br d, J=12 Hz, 2 H), 2.05 (m, 2 H), 1.8 - 2.0 (m, 10 H), 1.6 (m, 2 H) ppm.
19c) cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylsulfonylpyrimidin-4-ylethynyl)cyclohexan-1-ol]
To a solution of cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylthiopyrimidin-4-ylethynyl)cyclohexan-1-ol] (0.36 g, 0.82 mmol) in chloroform (5mL) at -10° C under an argon atmosphere was dropwise added over 20 min. a solution of 3-chloroperoxybenzoic acid (0.34 g, 1.97 mmol) in chloroform (3 mL). The reaction was stirred 3h at -10° C, then 3 h at room temperature. A second portion of 3-chloroperoxybenzoic acid (0.11 g, 0.62 mmol) in chloroform (1 mL) was added and stirring was continued for 1.5 h. The reaction was quenched with sodium carbonate (5%), was extracted three times with dichloromethane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 2.5:97.5 medianol:dichloromethane, provided cis-[4-(3-cyclopentyloxy-4- methoxyphenyl)-4-(2-methylsulfonylpyrimidin-4-ylethynyl)cyclohexan-1-ol] as a white foam (0.31 g, 81%), mp 75-77° C. 1H-NMR (400 MHz, CDCI3) δ 8.84 (d, J=5.3 Hz, 1 H), 7.54 (d, J=5.3 Hz, 1H), 7.10 (d, J=2.3 Hz, 1 H), 7.04 (dd, J=8.5, 2.3 Hz, 1 H), 6.85 (d, J=8.5 Hz, 1 H), 4.81 (m, 1 H), 3.85 (s, 3 H), 3.73 (m, 1 H), 3.38 (s, 3 H), 2.20 (br d, J=12 Hz, 2 H), 2.06 (m, 2 H), 1.8 - 2.0 (m, 10 H), 1.6 (m, 2 H) ppm.
19d) cis- [4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-ol]
Into a solution of cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylsulfonylpyrimidin-4-ylethynyl) cyclohexan-1-ol] (0.31 g, 0.66mmol) in methanol (5 mL) at -78° C was condensed liquid ammonia (5 mL). The pressure tube was sealed and the reaction was stirred at room temperature for 2 h. After cooling, the solvents were evaporated. Purification by flash chromatography, eluting with 4:% methanol:dichloromethane, followed by trituration from dichloromethane-ether-hexanes, provided cis-[4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol] as a white solid (0.19 g, 74%), mp 173-174° C. Anal. (C24H29N3O3 · 0.25 H2O) calcd: C, 69.96; H, 7.22; N, 10.20; found: C 69.66; H, 7.10; N, 10.11.
Example 20
cis-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)- cyclohexan-1-ol]
To a solution of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] (0.20 g, 0.64 mmol) and and 2-amino-5-bromopyrimidine (0.55 g, 3.2 mmol) in piperidine (2 mL) under an argon atmosphere were added
tetrakis(triphenyl-phosphine)palladium(0) (0.030 g, 4%), copper(I) iodide (0.006 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 0.5 h. Water was added and the mixture was extracted three times with
dichloromediane, was dried (potassium carbonate) and was evaporated. Purification by two successive flash chromatographies, eluting first with 5:95
medianohdichloromethane, then with 3:97 medianol:dichloromethane, provided cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-aminopyrimidin-5-ylethynyl) cyclohexan-1-ol] as a tan-brown solid (0.076 g, 29%), mp 136-137° C Anal. (C24H29N3O3 · 0.75 H2O) calcd: C, 68.47; H, 7.30; N, 9.98; found: C, 68.25; H, 7.09; N, 9.78.
Example 21
cis-[4-(thiazol-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol]
To a solution of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl- cyclohexan-1-ol] (0.15 g, 0.48 mmol) and and 2-bromothiazole (0.20 mL, 2.4 mmol) in triethylamine (1.5 mL) under an argon atmosphere were added tetrakis(triphenyl phosphine)palladium(0) (0.022 g, 4%), copper(I) iodide (0.006 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 1 h.
Ammonium chloride was added and the mixture was extracted three times with dichloromethane, dried (magnesium sulfate), and evaporated. Purification by two successive flash chromatographies, eluting first with 6:4 ethyl acetate:hexanes, then with 2:98 medianol:dichloromethane, provided cis-[4-(3-cyclopentyloxy-4- methoxyphenyl)-4-(2-aminopyrimidin-5-ylethynyl)cyclohexan-1-ol] as an off-white foam (0.13 g, 68%), mp 45-48° C. Anal. (C23H27NO3S · 0.5 H2O) calcd: C, 67.95; H, 6.94; N, 3.45; found: C, 67.91; H, 6.76; N, 3.39. Example 22
trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1- amine]
22a) cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexyl-1-amine]
To a solution of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] (1.0 g, 3.18 mmol), phthalimide (0.70 g, 4.77 mmol) and
triphenylphosphine (1.25 g, 4.77 mmol) in tetrahydrofuran (32 mL) was dropwise added diethyl azodicarboxylate (0.75 mL, 4.77 mmol), and the solution was stirred under an argon atmosphere at room temperature for 2 h. Evaporation and purification by flash chromatography, eluting with 2:8 ethyl acetate hexanes, provided the intermediate phthalimide (1.43 g) as a waxy white solid, mp 45-52° C. This was dissolved in 2:1 edianohtetrahydrofuran (30mL), was treated with hydrazine hydrate (1.55 mL, 32 mmol) and was stirred under an argon atmosphere at room temperature for 4 days. Water was added and the mixture was extracted three times with 10:90 methanol:dichloromethane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 0.5:5:95 ammonium
hydroxide:methanol:dichloromethane, provided cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexyl-1-amine] as a colorless oil (0.71 g, 72%). 1H-NMR (400 MHz, CDCI3) δ 7.17 (d, J=2.2 Hz, 1H), 7.09 (dd, J=8.5, 2.2 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 4.81 (m, 1H), 3.82 (s, 3 H), 3.26 (br s, 1H), 2.36 (s, 1H), 2.1-2.2 (m, 4 H), 1.8 - 2.0 (m, 10 H), 1.6, (m, 2H) ppm.
22b) cis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane]
A mixture of cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexyl-1-amine] (0.55 g, 1.75 mmol) and di-tert-butyldicarbonate (0.42 g, 1.93mmol) in dichloromethane (8mL) was stirred 20 h and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes provided, cis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane] as a colorless oil (0.70 g, 97%). 1H-NMR (400 MHz, CDCI3) δ 7.13 (d, J=2.2 Hz, 1H), 7.02(dd, J=8.5, 2.2 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.81 (m, 1H), 4.64 (m, 1 H),3.84 (s, 3 H), 2.36 (s, 1H), 2.05 (m, 2 H), 1.6 - 2.0 (m, 14 H), 1.45, (s, 9 H) ppm. 22c) trans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl-cyclohexane]
To a solution of cis -[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane] (0.35 g, 0.85 mmol) and 2-bromopyridine (0.80 mL, 8.5 mmol) in piperidine (2.5 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.039 g, 4%), copper(I) iodide (0.010 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 0.5 h in the dark. Water was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate:hexanes .provided trans-[1-tert- butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl-cyclohexane] as a light yellow solid (0.30 g, 72%), mp 69-70° C. 1H-NMR (400 MHz, CDCl3) δ 8.57 (d, J=4 Hz, 1 H), 7.66 (dt, J=8, 4 Hz, 1 H), 7.42 (d, J=8 Hz, 1 H), 7.26 (br, 1 H), 7.17 (d, J-2.2 Hz, 1H), 7.09 (dd, J-8.5, 2.2 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.82 (m, 1H), 4.64 (br s, 1 H), 3.85 (s, 3 H), 2.2 (m, 2H), 1.8 - 2.1 (m, 12 H), 1.6 (m, 2H),1.45, (s, 9 H) ppm.
22d) trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4- (pyrid-2-ylethynyl)cyclohexyl-1-amine]
To a solution of trans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynylcyclohexane] (0.30 g, 0.61mmol) in
dichloromethane (5 mL) at 0° C under an argon atmosphere was added trifluoroacetic acid (0.60 mL, 7.89 mmol). The reaction was stirred at room temperature for 6 h, was cooled to 0° C, quenched with sodium bicarbonate, was diluted with water, was extracted with three times dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 0.7:7:93 ammonium hydroxide:methanol:dichloromethane provided trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1-amine] as a very viscous oil (0.19 g, 82%). 1H-NMR (400 MHz, CDCI3) δ 8.59 (d, J=4 Hz, 1 H), 7.63 (dt, J=7.8, 4 Hz,
1 H), 7.41 (d, J=7.8 Hz, 1 H), 7.26 (m, 1 H), 7.22 (m, 2H), 6.81 (d, J=8.5 Hz, 1H), 4.84 (m, 1H), 3.81 (s, 3 H), 3.4 (br s, 1 H), 2.31 (m, 4H), 1.8 - 2.0 (m, 10 H), 1.6 (m,
2 H) ppm Anal. (C25H30N2O2 · 0.5 H2O) calcd: C, 75.16; H, 7.82; N, 7.01; found: C, 75.42; H, 7.77; N, 6.91.
Example 23
trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1- formamide],
To a preparation of acetic formic anhydride (0.035 mL, 0.38 mmol) at 0° C under an argon atmosphere was added a solution of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1-amine] (0.096 g, 0.24 mmol) in tetrahydrofuran (1.5 mL). The mixture was stirred for 3 h at room temperature, was diluted with dichloromethane, was washed with sodium bicarbonate and water, was dried (magnesium sulfate) and was evaporated Purification by flash chromatograhy, eluting with 5:95 methanol:dichloromethane, provided trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1-formamide] (which contains a trace of acetamide) as a white foam (0.08 g, 79%), mp 75-76° C Anal.
(C26H30N2O3·0.375 H2O) calcd: C, 73.43; H, 7.26; N, 6.59; found: C, 73.46; H, 7.29; N, 6.25. Example 24
trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2- yl)thien-2-ylethynyl]cyclohexyl-1-amine]. cyclohexylsulfamate salt
24a) 2-bromo-5-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene
2-Bromo-5-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene was prepared by standard chemistry well known to those versed in the an and was a white solid, mp 48* 49° C
24b) trans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5- (5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexane]
To a solution of cis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane] (0.30 g, 0.73 mmol) and 2-bromo-5-(5-methyl- [1,2,4]oxadiazol-2-yl)thiophene (0.18 g, 0.73 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.033 g, 4%) and copper(I) iodide (0.008 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 1 h. Water was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated Purification by flash chromatography, eluting with 2:8 ethyl
acetate:hexanes, followed by trituration from dichloromethane-hexanes, provided trans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexane] as a yellow foam (0.38 g), containing ~ 40 % of 1,4-bis-{[t-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cyclohexyl-1-amine]-4-yl}buta-1,3-diyne by 1H-NMR.
24c) trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine], cyclohexylsulfamate salt
A solution of trans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl] cyclohexane] (0.38 g, containing 40 % of the dimer) in dichloromethane (10 mL) at 0° C under an argon atmosphere was treated with trifluoroacetic acid (0.50 mL, 6.5 mmol) and the mixture was stirred far 24 h at room temperature. The solution was quenched with sodium bicarbonate at 0° C, was diluted with water, was extracted three times with 10:90 methanol:dichloromediane, was dried (potassium carbonate) and was
evaporated. Purification by flash chromatogaphy, eluting with 0.5:5:95 ammonium hydroxide:medianol:dichloromediane, provided trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine] as a glassy solid (0.18 g, 59 %). TMs was dissolved in acetone (0.5 mL) and added to a solution of cyclohexylsulfamic acid (0.066 g, 0.37 mmol) in acetone (0.5 mL). The salt was isolated and the free amine was recovered. A second
chromatography using the same solvent system provided free amine (0.048 g), which was treated with cyclohexylsulfamic acid (0.018 g, 0.10 mmol) in acetone (1 mL). After the addition of ether (20 mL), the precipitate was filtered off to provide trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine], cyclohexylsulfamate salt (0.043 g, 18%) as a white solid, mp 134-135° C Anal. (C33H44N4O6S2·0.5 H2O) calcd: C, 59.52; H, 6.81; N, 8.41 ; found. C, 59.37; H, 6.71; N, 8.46.
Example 25
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1-amine]
25a) cis-[ 1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexane]
A solution of 4-(3-cyclopentytoxy-4-methoxyphenyl)-4-ethynyl-cyclohexan-1-one (0.82g, 2.63 mmol), ammonium acetate (2.03 g, 26 mmol), sodium
cyanoborohydride (0.17 g, 2.63 mmol) and several 4Å molecular sieves in methanol (10 mL) was stirred under an argon atmosphere at room temperature for 3 days.
Several crystals of methyl orange were added, then hydrogen chloride-saturated methanol to ~ pH 3. The reaction was made basic with sodium hydroxide (10 %), was extracted with 10:90 methanol:dichloromethane, was dried (potassium carbonate) and was evaporated to provide crude trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexyl-1-amine] as a yellow oil (0.88 g, 100 %). A solution of the intermediate in dichloromethane (15 mL) was treated with di-terr.-butyldicarbonate (0.63g, 2.89 mmol), was stirred 5 h and was evaporated. Purification by flash chromatography, eluting with 15: 85 ethyl acetate:hexanes, provided trans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)- 4-ethynylcyclohexane] as a white foam (0.57 g, 53%, 1H-NMR shows ~ 20 % cis isomer), mp.39-43° C. 1H-NMR (400 MHz, CDCl3) δ 7.11 (d, J=2.2 Hz, 1H), 7.04 (dd, J=8.5, 2.2 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 4.80 (m, 1H), 4.6 (m, 0.2 H), 4.5 (m, 0.8 H), 4.0 (m, 0.2 H), 3.84 (s, 0.6 H), 3.83 (s, 2.4 H), 2.43 (s, 0.8 H), 2.36 (s, 0.2 H), 1.6 - 2.1 (m, 16 H), 1.46, (s, 9 H) ppm
25b) cis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynylcyclohexane
To a solution of trans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane] (0.45 g, 1.09 mmol) and 2-bromopyridine (1.0 mL, 11 mmol) in piperidine (3 mL) under an argon atmosphere were added
tetrakis(triphenylphosphine)paliadium(0) (0.050 g, 4%), copperl(I) iodide (0.012 g, 6%) and a smali crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 0.5 h in the dark. Water was added and the mixture was extracted tiiree times withdichloromediane, was dried (magnesium sulfate) and was evaporated Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided cis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2- ylethynylcyclohexane] as a yellow foam (0.41 g, 78%, contains ~ 35 % trans isomer by 1H-NMR), mp 40-43° C. 1H-NMR (400 MHz, CDCl3) δ 8.4 (m , 1 H), 7.65 (m, 1 H), 7.4 (d, 1 H), 7.1 (m, 3 H), 6.85 (m, 1 H), 4.8 (m, 1H), 4.6 (m, 0.65 H), 3.85 (s, 1 H), 3.84 (s, 2 H), 3.55 (m. 0.65 H), 1.5 - 2.2 (m, 16 H), 1.45, (s, 9 H) ppm
25c) cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2- ylethynyl)cyclohexyl-1-amine]
To a solution of cis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4- methoxyphenyl)-4-(pyrid-2-ylethynylcyclohexane] (0.41 g, 0.84 mmol) in
dichloromethane (5 mL) at 0° C under an argon atmosphere was added trifluoroacetic acid (0.65 mL, 8.4 mmol). The reaction was stirred at room temperature for 20 h, was cooled to 0° C, was quenched with sodium bicarbonate, was diluted with water, was extracted twice with 10:90 methanol:dichloromethane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 0.5:5:95 ammonium hydroxide:memanol:dichloromethane, followed by trituration from ether, provided cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2- ylethynyl)cyclohexyl-1-amine] as a white solid (0.23 g, 69%, containing ~ 20 % of the trans isomer), mp 78-80° C. Anal. (C25H30N2O2) calcd: C, 66.06; H, 6.65; N, 6.16; found: C, 65.73; H, 6.96; N, 5.98.
Example 26
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4- (pyrid-2-ylethynyl)cyclohexyl-1- formamide]
To a preparation of acetic formic anhydride (0.057 mL, 0.64 mmol) at 0° C under an argon atmosphere was added a solution of cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1-amine] (0.16 g, 0.40 mmol) in tetrahydrofuran (1.5 mL). The mixture was stirred for 3 h at room temperature, was diluted with dichloromethane, was washed with sodium bicarbonate and water, was dried (magnesium sulfate) and was evaporated Purification by flash chromatograhy, eluting with 5:95 methanol.dichloromethane, provided cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1-formamide] (which contains a trace of acetamide) as a white foam (0.08 g, 79%), mp 80-81° C. Anal.
(C26H30N2O3·0.375 H2O) calcd: C, 73.43; H, 7.26; N, 6.59; found: C, 73.46; H, 7.29; N, 6.25.
Example 27
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2- yl)thien-2-ylethynyl]cyclohexyl-1-amine]. cyclohexylsulfamate salt
27a) 2-bromo-5-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene
2-Bromo-5-{5-methyl-[1,2,4]oxadiazol-2-yl)thiophene was prepared by standard chemistry well known to those versed in the an and is a white solid, mp 48-49° C. 27b) cis-[ 1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5- (5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexane]
To a solution of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl- cyclohexyl-1-amine] (0.21 g, 0.52 mmol) and 2-bromo-5-{5-methyl-[1,2,4]oxadiazol- 2-yl)thiophene (0.13 g, 0.52 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.024 g, 4%), copper(I) iodide (0.006 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85° C for 1 h. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated Purification by two successive flash chromatographies, eluting first with 2:8 ethyl acetate:hexanes, then with 2:8 acetone:hexanes, provided cis-[1-tert- butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl- [1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexane] as a white foam (0.20 g, 69%, contains - 20 % dimer impurity by 1H-NMR), mp 60-68° C .
27c) cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2- yl)thien-2-ylethynyl]cyclohexyl-1-amine], cyclohexylsulfamate salt
A solution of cis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexane] (0.21 g, containing 20 % of the dimer) in dichloromethane (5 mL) at 0° C under an argon atmosphere was treated with trifluoroacetic acid (0.28 mL, 3.6 mmol) and was stirred 24 h at room temperature. The solution was quenched with sodium bicarbonate at 0° C, was diluted with water, was extracted three times with 10:90
methanol:dichloromethane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatogaphy, eluting with 0.3:3:97 ammonium
hydroxide:methanol:dichloromethane, provided cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine] as a colorless glass (0.11 g, 0.24 mmol, 69%). This intermediate was dissolved in acetone (0.5 mL) and was added to a solution of cyclohexylsulfamic acid (0.045 g, 0.24 mmol) in acetone (1 mL). After the addition of ether, the precipitate was filtered off to provide cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl- [1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine], cyclohexylsulfamate salt (0.14 g, 58%) as a white solid, mp 152-154° C. Anal. (C33H44N4O6S2) calcd: C, 60.34; H, 6.75; N, 8.53; found: C, 60.01; H, 6.63; N, 8.32.
Example 28
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-methyl[1,2,4]oxadiazol-5- yl)phenyl]ethynyl)cyclohexan-1-ol].
28a) 5-(3-iodophenyl)-3-methyl[1,2,4]oxadiazole
5-(3-Iodophenyl)-3-methyl[1,2,4]oxadiazole was prepared by standard chemistry weli known to tiiose versed in the an and was a white solid, mp 102-103° C. 28b) cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-methyl[1,2,4]oxadiazol-5- yl)phenyl]ethynyl)cyclohexan-1-ol]
To a solution of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] (0.11 g, 0.35 mmol) and 5-(3 -iodophenyl)-3-methyl[1,2,4]oxadiazole (0.15 g, 0.52 mmol) in triethylamine (4 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium (0.017 g, 0.015 mmol), copper(I) iodide (0.004 g, 0.021 mmol) and a small crystal of triphenylphosphine. After heating the mixture at
70° C for 1.5 h„ the reaction was quenched by addition of aqueous ammonium chloride solution, and the solvent was concentrated. The mixture was extracted three times with methylene chloride, and the organic phase was washed with water, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography, eluting with 45:55 ethyl acetate:hexanes and crystallizing from ethyl ether, provided cis-[4-(3-cyclopentyloxy-4-methoxyphenyI)-4-(2-[3-(3-methyl[1,2,4]oxadiazol-5- yl)phenyl]ethynyl)cyclohexan-1-ol] as a white solid (0.144 g, 87%), mp 71.5-73.5 ° C. Anal. (C29H32N2O4) calcd: C, 73.71; H, 6.83, N, 5.93 found: C, 73.60; H, 6.91, N, 5.76.
Example 29
cis-[4-( 3-cyclopentyloxy-4-methoxyphenyl)-4-( 2-[3-(5-methyl[ 1 ,3,4]oxadiazol-2- yl)phenyl]ethynyl)cyclohexan-1-ol].
29a) 2-(3-iodophenyl)-5-methyl[1,3,4]oxadiazole
2-(3-Iodophenyl)-5-methyl[1,3,4]oxadiazole was prepared by standard chemistry weli known to those versed in the an and is a white solid, mp 112- 113.5 ° C. 29b) cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-ol]
To a solution of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] (0.125 g, 0.40 mmol) and 2-(3-iodophenyl)-5-methyl[1,3,4]oxadiazole (0.171 g, 0.60 mmol) in triethylamine (7 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)paliadium (0.020 g, 0.017 mmol), copper(I) iodide (0.0042 g, 0.022 mmol) and a small crystal of triphenylphosphine. After heating the mixture at 75° C for 1.75 h, the reaction was quenched by addition of aqueous ammonium chloride solution, and the solvent was concentrated The mixture was extracted three times with methylene chloride, and the organic phase was washed with water, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography, eluting with 40 to 50% ethyl acetate in methylene chloride and crystallizing from ethyl ether, provided cis-[4-(3-cyclopentyloxy-4-medιoxyphenyl)-4-(2-[3-(5-methyl[1,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-ol] as a white solid (0.119 g, 63%), mp 117.5-119 ° C. Anal. (C29H32N2O4·1/8H2O) calcd: C, 73.36; H, 6.85, N, 5.90 found: C, 73.25; H, 6.94, N, 5.75. 1H-NMR (400 MHz, 3) δ 8.12 (s . 1H), 7.98 (d-d. J=1.4 Hz;J=7.9 Hz, 1H), 7.60 (d-d, J=1.3 Hz, J=7.8 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.19 (d, J=2.2, 1H), 7.10 (d-d, J=2.1 Hz, J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.81 (p, J=4.3 Hz, 1H), 3.85 (s, 3H), 3.73 (m, 1H), 2.63 (s, 3H), 2.2-1.8 (m, 14H), 1.7-1.5 (m, 7H with H2O).
Example 30
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,2,4]oxadiazol-3- yl)phenyl]ethynyl)cyclohexan-1-ol],
To a solution of 4-(3-cyclopentytoxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-1-one (0.084 g, 0.18 mmol, prepared as described in co-pending application P50283 filed on even date herewith) in 1 ,2-dimethoxyethane (3 mL) under an argon atmosphere was added dropwise a solution of sodium borohydride (0.015 g, 0.40 mmol) in 1,2-dimethoxy ethane (5 mL). After 2 h stirring at room temperature, the reaction was quenched by addition of aqueous ammonium chloride solution. The solvent was concentrated and the residue was extracted into methylene chloride, was washed with water, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35% ethyl acetate in hexanes and crystallizing from ethyl ether, provided cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-1-ol] as a white solid (0.050 g, 58%), mp 101-103 ° C. Anal. (C29H32N2O4·1/5H2O) calcd: C, 73.15; H, 6.86, N, 5.88 found: C, 73.11; H, 6.85, N, 5.85. 1H-NMR (400 MHz, CDCl3) δ 8.18 (s , 1H), 8.00 (d, J=7.9 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.19 (d, J=2.2, 1H), 7.10 (d-d, J=2.1 Hz, J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.82 (p, J=4.3 Hz, 1H), 3.85 (s, 3H), 3.72 (m, 1H), 2.67 (s, 3H), 2.2-1.8 (m, 13H), 1.7-1.5 (m, 6H with H2O).
The other compounds of this invention may be prepared by proceeding in a similar manner, but substituting the appropriate starting materials and intermediates for those recited in this Example. Examples are:
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-trifluoromethyl[1,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-1-ol],
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-trifluoromethyl[1,2,4]oxadiazol-5-yl)phenyl]ethynyl)cyclohexan-1-ol],
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5- trifluoromethyl[1,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-ol], and
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5- trifluoromethyl[1,3,4]thiadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-ol].
Example 31
Preparation of cis-4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-trifluoromethyl- [1,2,4]oxadiazol-3-yl)phenylethynyl)cyclohexan-1-ol
31a) 3-(3-iodophenyl)-5-trifluoromethyl-[1,2,4]oxadiazole 3-(3-Iodophenyl)-5-trifluoromethyl-[1,2,4]oxadiazole was prepared by standard chemistry well known to those versed in the an and was a white solid, mp 36- 37° C.
31b) cis-4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-trifluoromethyl- [1,2,4]oxadiazol-3-yl)phenylethynyl)cyclohexan-1-ol
A stirred mixture of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] (0.22 g, 0.7 mmol) and 3-(3-iodophenyl)-5-trifluoromethyl- [1,2,4]oxadiazole (0.24 g, 0.7 mmol) in dry triethylamine (5 mL) was treated under an argon atmosphere trace tetrakis(triphenylphosphine)palladium and copper(I) iodide. The mixture was refluxed for 0.2 h, was cookd to RT and was evaporated. The residue was adsorbed onto silica gel and was purified by flash chromatography eluting with 1 :1 hexanes/ethyl acetate and trituration from hexanes/ethyl acetate provided the tide compound as a white solid (0.26g, 71%), mp 85-86° C
Example 32
Preparation of cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-methyl- [1,3,4]thiadiazol-2-yl)phenylethynyl]cyclohexan-1-ol 32a) 1-iodo-3-(5-methyl-[1,3,4]thiadiazol-2-yl)benzene
1-lodo-3-(5-methyl-[1,3,4]thiadiazol-2-yl)benzene was prepared by standard chemistry weli known to those versed in the an and was white solid, mp. 86-89° C. 32b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-methyl-[1,3,4]thiadiazol-2-yl)phenylethynyl]cyclohexan-1-ol
To a solution of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol] (0.15 g, 0.48 mmol) and 1-iodo-3-(5-methyl-[1,3,4]thiadiazol-2-yl)benzene (0.15 g, 0.48 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palldium(0) and copper(I) iodide. The mixture was refluxed for 0.20 h, was cooled to room temperature and was
concentrated in vacua. Purification by flash chromatography, eluting with 1:1 hexanes/ethyl acetate and trituration from hexanes/ethyl acetate provided the tide compound as a white solid (0.17g, 74%), m.p. 129-130° C.
Example 33
Preparation of trans-[4-(2-acetamidopyrimidin-5-ylethynyl)-4-(3-cyclopentyloy-4- methoxyphenyl)cyclohexan-1-ol]
To a suspension of cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl¬cyclohexan-1-ol] (0.50 g, 1.59 mmol) and 2-acetamido-5-bromopyrimidine (0.35 g, 1.59 mmol) in triethylamine (7 mL) under an argon atmosphere was added
tetrakis(triphenylphosphine)palladium(0) (0.073 g, 4%) and copper(I) iodide (0.019 g, 6%) and the mixture was heated at 80-85° C for 0.75 h. Water was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. The residue was pre-adsorbed onto silica and purified by chromatoraphy on silica gel, eluting the nonpolar impurities with 30:70 to 50:50 ethyl acetrø:dichloromethane, and eluting the desired product in 60:40:1 ethyl
acetate:dichloromethane:methanol. This was crystallized from ethyl acetate:hexanes to provide trans-[40(2-acetamidopyrimidin-5-yl-ethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol] as a white solid (0.47g, 66%), mp 163-164° C. Anal. (C26H31N3040.25 H20) calcd: VC, 69.47; H, 6.95; n, 9.35; found: C, 69.27; H, 6.98; N, 8.97.
Example 34
Preparation of trans-[4-(2-aminopyrimidin-5-yl-ethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)-cyclohexan-1-ol
To a solution of sodium methoxide (0.137 g, 2.5 mmol) in dry methanol (3.8 mL) was added via cannula a solution of trans-[4-(2-acetamidopyrimidin-5-ylethynyl)-4-(3-cyclopentyIoxy-4-methoxyphenyl)cyclohexan-1-ol] (0.32 g, 0.71 mmol) in dry methanol (7.6 mL including rinses). After stirring for 3 h at 25°C, the reaction was quenched into cold water, extracted with methylene chloride, filtered, dried
(magnesium sulfate) and concentrated in vacua. The resulting sotid was recrystallized from ethyl acetate:hexandes and dried in vacua at 80° C to afford the desired product as a white solid (0.154 g, 53%), mp 170.5- 172.0°C. Anal. (C24H29N3030.1251120) calcd: C, 70.35; H, 7.20; N, 10.25; found: C, 70.34; H, 7.18; N, 10.14.
Example 35
Preparation of cis-[4-(2-methylaminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-1-ol]
35(a) 5-bromo-2-methylacetamidopyrimidine,
A mixture of 2-acetamido-5-bromopyrimidine (0.22g, 1 mmol,) potassium carbonate (0.21g, 1.5 mmol) and iodomediane (0.10mL, 1.6 mmol) in tetrahydrofuran was stirred at room temperature for three days. The mixture was filtered, was evaporated and was purified by flash chromatography, eluted with 2:8 ethyl
acetate:hexanes, to provide the desired product as a white solid (0.03g, 13%) 1H-NMR (CDCl3, 400 Mhz) δ 8.58 (s, 2H), 3.39 (s, 3H), 2.39 (s, 3H) ppm
37b) cis -[4-(2-methylacetamidopyrirmdin-5-yl-ethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-ol],
To a suspension of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-ol) (0.20 g, 0.64 mmol) and a mixture (~6:4) of 2-acetamido-5-bromopyrimidine and 5-bromo-2-methylacetamidopyrimidine (0.14 g, -0.32 mmol of each component) in triethylamine (5 mL) under an argon atmosphere was added tetrakis(triphenylphospMine)palladium(0) (0.03 g, 4%) and copper(I) iodide (0.008 g, 6%) and the mixture was heated at 80-85° C for 0.5 h. The reaction was cooled, water was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. The residue was purified by chromatography on silica gel with 1:1 and 1:3 ethyl acetate:hexanes, to provide the desired compound as a colorless oli (which contains a trace amount of 2-acetamido-5 bromopyrimidine). 1H- NMR (CDCl3, 400 Mhz) δ 8.65 (s, 2H), 7.12 (d, J=2.0 Hz, 1H), 7.07 (dd, J=8.3, 2.0 Hz, 1H), 6.85, d, J=8.3Hz, 1H), 4.80 (m, 1H), 3.85 (s, 3H), 3.83 (m, 1H), 3.49 (s, 3H), 2.48 (s, 3H), 1.8 - 2.2 (m, 14H, 1.65 (m, 2H) ppm
37c) cis-[4-(2-methylaminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)-cyclohexan-1-ol]
To a stirred mixture of sodium methoxide (0.025 g, 0.43 mmol) in dry methanol (2 mL) under an argon atmosphere was added a solution of cis-4-(2- methylacetamidopyrimidin-5-ylethynyl)-4-(3-cyclopentyyloxy-4- methoxyphenyl)cyclohexan-1-ol (0.07 g, 0.15 mmol). The mixture was refluxed for 0.5 h, was cooled to room temperature, wa diluted with water, was extracted three times with dichloromediane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:1 ethyl acetate:hexanes, foliowed by trituration from ethyl acetate/hexanes, provided the title compound as a white solid (0.032 g, 61%), m.p. 118-119°C. Anal. (C25H31N3O30.75 H2O) calcd:C, 69.02; H, 7.52; N, 9.66; found: C, 68.84; H, 7.11; N, 9.53.
Example 36
Preparation of trans-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexyI-1-amine], cyclohexylsulfamate salt
34a) 5-bromo-2-propionamidopyrimidine
5-Bromo-2-propionamidopyrimidine was prepared by standard chemistry weli known to those versed in the an and was a white solid, mp 161-164° C.
34b) trans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-propionamidopyrimidin-5-ylethynyl-cyclohexane]
To a solution of cis-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4- methoxyphenyl)-4-ethynylcyclohexane] (0.29 g, 0.69 mmol) and 5-bromo-2-propionamidopyrimidine (0.16 g, 0.69 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.032 g, 4%), and copper(I) iodide (0.008 g, 6%) and the mixture was heated at 80-85° C for 0.5 h.
Water was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided trans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-propionamidopyrimidin-5-ylethynyl)-cyclohexane] as a white solid (0.21 g, 54%), mp 87-89° C. 1H-NMR (400 MHz, CDCl3) δ 8.57 (s, 2H), 8.17 (m, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.03 (dd, J=8.5, 2.2 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 4.81 (m, 1H), 4.63 (m, 1H), 3.85 (s, 3H), 2.75 (q, J=7.4 Hz, 2H), 1.8 - 2.1 (m, 14H), 1.62 (m, 2H), 1.46, (s, 9H), 1.24 (t, J=7.4 Hz, 3H) ppm 34c) trans-[4-(2-aminopyrimidin-5-ylethynyl)-1-tert-butoxycarbonylamino-4-(3- cyclopentyloxy-4-methoxyphenyl) cyclohexane]
A mixture of trans-[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4- methoxyphenyl)-4-(2-propionamidopyrimidin-5-ylethynyl)cyclohexane] (0.21 g, 0.37 mmol) and sodium methoxide (0.07g, 1.29 mmol) in methanol (5 mL) was refluxed under an argon atmosphere for 0.5 h, then cooled Water was added and the reaction was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated to provide pure trans-[4-(2-aminopyrimidin-5-ylethynyl)-1-tert- butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane] (0.18 g, 97%) as a white solid mp 183-185° C 1H-NMR (400 MHz, CDCl3) δ 8.34 (s, 2H), 7.13 (d J=2.3 Hz, 1H), 7.03 (dd J-8.5, 2.3 Hz, 1H), 6.86 (d J=8-5 Hz, 1H), 5.27 (d J=2.2 Hz, 2H), 4.81 (m, 1H), 4.64 (m, 1H). 3.85 (s, 3H), 1.8 - 2.1 (m, 14H), 1.61 (m, 2H), 1.46 (s, 9H) ppm
34d) trans-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexyl-1-amine], cyclohexylsulfamate salt
To a solution of trans-[4-(2-aminopyrimidin-5- ylethynyl)-1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexane] (0.18 g, 0.35mmol) in dichloromethane (5 mL) at 0° C under an argon atmosphere was added trifluoroacetic acid (0.27 mL, 3.52 mmol). The reaction was stirred at room temperature for 24 h, was cooled to 0° C, was quenched with sodium bicarbonate, was diluted with water, was extracted with three times 10/90 methanol/dichloromethane, was dried (magnesium sulfate) and was evaporated Purification by flash
chromatography, eluting with 0.5:10:90 ammonium
hydroxide:methanol:dichloromethane provided trans-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl-1-amine] as a very viscous, colorless oil (0.13 g, 0.33 mmoL 95%). This intermediate was dissolved in acetone (0.5 mL) and treated with a solution of cyclohexylsulfamic acid (0.059 g, 0.33 mmol) in acetone (1.0 mL). Dilution with ether and filtration, followed by trituration from dichloromethane/hexanes provided the tide compound as a white solid mp >230° C (dec.).
Example 37
cis-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexyl-1-amine], cyclohexylsulfamate salt cis-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl-1-amine], cyclohexylsulfamate salt is prepared in the same manner as trans-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl-1- amine], except starting from cis -[1-tert-butoxycarbonylamino-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexane]. UTILITY EXAMPLES
EXAMPLE A
Inhibitory effect of compounds of Formula (I) on in vitro TNF production by human monocytes
The inhibitory effect of compounds of Formula (I) on in vitro TNF production by human monocytes may be determined by the protocol as described in Badger et al.,
EPO published Application 0411 754 A2, February 6, 1991, and in Hanna, WO
90/15534, December 27, 1990.
EXAMPLE B
Two models of endotoxic shock have been utilized to determine in vivo TNF activity for the compounds of Formula (I). The prototocol used in these models is described in Badger et al., EPO published Application 0411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990.
The compound of Example 1 herein demonstrated a positive in vivo response in reducing serum levels of TNF induced by the injection of endotoxin.
EXAMPLE C
Isolation of PDE Isozymes
The phosphodiesterase inhibitory activity and selectivity of the compounds of Formula (I) can be determined using a battery of five distinct PDE isozymes. The tissues used as sources of the different isozymes are as follows: 1) PDE lb, porcine aorta; 2) PDE Ic, guinea-pig heart; 3) PDE III, guinea-pig heart; 4) PDE IV, human monocyte; and 5) PDE V (also called "la"), canine trachealis. PDEs la, lb, Ic and m are partially purified using standard chromatographic techniques [Torphy and
Oeslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE IV is purified to kinetic homogeneity by the sequential use of anion-exchange foliowed by heparin-Sepharose chromatography [Torphy et al., J. Biol. Chem., 267:1798-1804, 1992].
Phosphodiesterase activity is assayed as described in the protocol of Torphy and
Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Positive IC50's in the nanomolar to μM range for compounds of the workings examples described herein for Formula (I) have been demonstrated.

Claims

What is claimed is:
1. A compound of Formula I
Figure imgf000042_0001
wherein:
R1 is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)mR6, or -(CR4R5)rR6 wherein the alkyl moieties unsubstituted or substituted with one or more halogens;
m is 0 to 2;
n is 0 to 4;
r is 0 to 6;
R4 and R5 are independendy selected hydrogen or C1-2 alkyl;
R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC1-3 alky halo substituted aryloxyC1-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrodiienyl, diienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted or substituted by 1 to 3 methyl groups, one ethyl group, or an hydroxyl group;
provided that:
a) when R6 is hydroxyl, then m is 2; or
b) when R6 is hydroxyl, then r is 2 to 6; or
c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrodιiopyranyl,
2-tetrahydrofuranyl, or 2-tetrahydrodιienyl, then m is 1 or 2; or
d) when R5 is 2-tetrahydropyranyl, 2-tetrahydrodιiσpyranyl,
2-tetrahydrofuranyl, or 2-tetrahydroduenyl, then r is 1 to 6;
e) when n is 1 and m is 0, men R6 is other than H in
-(CR4R5)nO(CR4R5)mR6;
X is YR2, fluorine, NR4R5, or formyl amine;
Y is O or S(O)m';
m' is 0, 1, or 2;
X2 is O or NR8;
X3 is hydrogen or X;
X4 is H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NR8R8, or NR8R8; R2 is independendy selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens;
s is 0 to 4;
W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;
R3 is COOR14, C(O)NR4R14 or R7;
Zis OR14, OR15, SR14, S(O)m'R7, S(O)2NR10R14, NR10R14,
NR14C(O)R9, NR10C(Y')R14, NR10C(O)OR7, NR10C(Y')NR10R14.
NR10S(O)2NR10R14, NR10C(NCN)NR10R14, NR10S(O)2R7,
NR10C(CR4NO2)NR10R14, NR10C(NCN)SR9, NR10C(CR4NO2)SR9,
NR10C(NR10)NR10R14, NR10C(O)C(O)NR10R14, or NR10C(O)C(O)OR14;
Y' is O or S;
R7 is -(CR4R5)qR12 or C1-6 alkyl wherein the R12 or C1-6 alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstimted or substituted by 1-3 fluorines, -F, -Br, -O, -NO2, -NR10R1 1, -C(O)R8, -CO2R8.
-O(CH2)2-4OR8, -O(CH2)qR8, -CN, -C(O)NR10R1 1, -O(CH2)qC(O)NR10R11, - O(CH2)qC(O)R9, -NR10C(O)NR10R11, -NR10C(O)R11, -NR10C(O)OR9,
-NR10C(O)R13, -C(NR10)NR10R11, -C(NCN)NR10R1 1, -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, or R13;
q is 0, 1, or 2;
R12 is R13, C3-C7 cycloalkyl, or an unsubstituted or substituted aryl or heteroaryl group selected from the group consisting of (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-dιienyl), quinolinyl, naphthyl, and phenyl;
R8 is independendy selected from hydrogen or R9;
R9 is C1-4 alkyl optionally substituted by one to three fluorines;
R10 is OR8 or R 11;
R11 is hydrogen, or C1-4 alkyl unsubstituted or substituted by one to three fluorines; or when R10 and R1 1 are as NR10R11 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S;
R13 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, diiazolidinyl, isoxazolyl, oxadiazolyl, and diiadiazolyl, and where R13 is substituted on R12 or R13 the rings are connected through a carbon atom and each second R13 ring may be unsubstituted or substituted by one or two C1-2 alkyl groups unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms; R14 is hydrogen or R7; or when R8 and R14 are as NR8R14 they may togeth with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and on or more additional heteroatoms selected from O, N, or S;
R15 is C(O)R14, C(O)NR8R14, S(O)qNR8R14 or S(O)qR7 where q is 0, 1 or 2; provided that:
(f) R7 is not C1-4 alkyl unsubstimted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof .
2. A compound according to claim 1 wherein R1 is -CH2-cyclopropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl unsubstituted or substituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -C1-2 alkyl unsubstituted cosubstituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluorosubstituted alkyl, W is ethynyl or 1,3-butadiynyl, R3 is R7 where R7 is an unsubstimted or substituted aryl or heteroaryl heteroaryl ring, X is YR2, and Z is OR14, OR15, NR10R14, or NR14C(O)R9.
3. A compound according to claim 2 wherein R7 is unsubstituted or substimted -(CH2)0-2 (2-, 3- or 4-pyridyl), (CH2)1-2(2-imidazolyl), (CH2)2(4-morpholinyl), (CH2)2(4-piperazinyl), (CH2)1-2(2-dιienyl), (CH2)1-2(4-thiazolyl), substituted or unsubstituted pyrimidinyl, or unsubstimted or substimted
(CH2)0-2phenyl.
4. A compound according to claim 3 wherein R7 is substimted or unsubstimted pyrimidin-5-yl.
5. A compound according to claim 4 wherein Z is OH and which is cis-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- medιoxyphenyl)cyclohexan-1-ol],
cis-[4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-ol],
trans-[4-(2-acetamidopyrimidin-5-ylethynyl)-4-(3-cyclopentyloy-4- methoxyphenyl)cyclohexan-1-ol],
trans-[4-(2-aminopyrimidin-5-yl-ethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)-cyclohexan-1-ol, or
cis-[4-(2-methylaminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol].
6. A compound according to claim 1, 2 or 3 wherein Z is OH and which is cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-4-ylethynyl)cyclohexan-1-ol],
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexan-1-ol],
cis-[4-(4-cyanothien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-ol], cis-[4-(thiazol-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1-ol],
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[1,2,4]oxadiazol-2- yl)thien-2-ylethynyl] cyclohexan-1-ol],
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-methyl[1,2,4]oxadiazol- 5-yl)phenyl]ethynyl)cyclohexan-1-ol],
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,3,4]oxadiazol- 2-yl)phenyl]ethynyl)cyclohexan-1-ol],
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,2,4]oxadiazol- 3-yl)phenyl]ethynyl)cyclohexan-1-ol],
cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-trifluoromethyl- [1,2,4]oxadiazol-3-yl)phenylethynyl)cyclohexan-1-ol, or
cis-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-methyl-[1,3,4]thiadiazol-2- yl)phenylethynyl]cyclohexan-1-ol.
7. A compound according to claim 1, 2 or 3 wherein Z is NR10R14, or
NR14C(O)R9 which is
trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl- 1-amine],
trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1-formamide],
trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine], cyclohexylsulfamate salt cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1-amine],
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2-ylethynyl)cyclohexyl-1-formamide],
cis-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-1-amine], cyclohexylsulfamate salt,
trans-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl-1-amine], cyclohexylsulfamate salt, or
cis-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl-1-amine], cyclohexylsulfamate salt
8. A pharmaceutical composition comprising a compound of Formula I according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient
9. A method for treating asthma wMch comprises administering to a mammal in need thereof a compound of formula (I) according to any one of claims 1 to 7 alone or admixed with a pharmaceutically acceptable excipient
PCT/US1995/016711 1994-12-23 1995-12-21 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds WO1996019988A1 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
SK795-97A SK79597A3 (en) 1994-12-23 1995-12-21 4,4-(disubstituted)cyclohexan-1-ols monomers and pharmaceutical compositions containing same
JP8520529A JPH10511658A (en) 1994-12-23 1995-12-21 4,4- (disubstituted) cyclohexane-1-ol monomer and related compounds
MX9704729A MX9704729A (en) 1994-12-23 1995-12-21 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds.
DE69534518T DE69534518D1 (en) 1994-12-23 1995-12-21 MONOMERS OF THE 4,4- (DISUBSTITUTED) CYCLOHEXAN-1-OLE AND RELATED COMPOUNDS
EP95944363A EP0794774B1 (en) 1994-12-23 1995-12-21 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds
AT95944363T ATE306260T1 (en) 1994-12-23 1995-12-21 MONOMERS OF 4,4-(DISUBSTITUTED)CYCLOHEXAN-1-OLS AND RELATED COMPOUNDS
NZ301096A NZ301096A (en) 1994-12-23 1995-12-21 4,4-(disubstituted)cyclohexan-1-ol monomer and related derivatives; medicaments containing them
US08/860,287 US5891883A (en) 1995-12-21 1995-12-21 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds
AU46433/96A AU703246C (en) 1994-12-23 1995-12-21 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds
BR9510257A BR9510257A (en) 1994-12-23 1995-12-21 Cyclohexan-1-ois 4,4- (di-substituted) monomers and related compounds
UA97066495A UA48157C2 (en) 1994-12-23 1995-12-21 4,4-(disubstituted)cyclohexan-1-ols monomers, pharmaceutical compositions and method for treating asthma
FI972676A FI972676A (en) 1994-12-23 1997-06-19 4,4- (disubstituted) cyclohexane olonomers and the like
NO972906A NO972906L (en) 1994-12-23 1997-06-20 4,4- (Disubstituted) Cyclohexan-1-ol Monomers and Related Compounds
BG101716A BG62034B1 (en) 1994-12-23 1997-07-01 4,4-(DISUBSTITUTED)CYCLOHEXAN-l-OLS MONOMERS AND RELATED COMPOUNDS

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US36350694A 1994-12-23 1994-12-23
US08/363,506 1994-12-23

Publications (1)

Publication Number Publication Date
WO1996019988A1 true WO1996019988A1 (en) 1996-07-04

Family

ID=23430511

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/016711 WO1996019988A1 (en) 1994-12-23 1995-12-21 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds

Country Status (21)

Country Link
EP (1) EP0794774B1 (en)
JP (1) JPH10511658A (en)
CN (1) CN1090020C (en)
AT (1) ATE306260T1 (en)
BG (1) BG62034B1 (en)
BR (1) BR9510257A (en)
CA (1) CA2208444A1 (en)
CZ (1) CZ196097A3 (en)
DE (1) DE69534518D1 (en)
DZ (1) DZ1959A1 (en)
FI (1) FI972676A (en)
HU (1) HUT77350A (en)
MA (1) MA23755A1 (en)
MX (1) MX9704729A (en)
NO (1) NO972906L (en)
NZ (1) NZ301096A (en)
PL (1) PL320996A1 (en)
SK (1) SK79597A3 (en)
UA (1) UA48157C2 (en)
WO (1) WO1996019988A1 (en)
ZA (1) ZA9510878B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0828493A1 (en) * 1995-05-31 1998-03-18 Smithkline Beecham Corporation 4.4-(disubstituted)cyclohexan-1-ols-monomers and related compounds
EP1202955A2 (en) * 1999-08-10 2002-05-08 SmithKline Beecham Corporation 1,4-substituted 4,4-diaryl cyclohexanes

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5449687A (en) * 1992-04-02 1995-09-12 Smithkline Beecham Corporation 4-phenyl-1,2-cyclohexyl derivatives and anti-inflammatory compositions and methods thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69331265T2 (en) * 1992-04-02 2002-08-08 Smithkline Beecham Corp., Philadelphia COMPOUNDS FOR TREATING INFLAMMABLE DISEASES AND INHIBITING THE PRODUCTION OF TUMORNESCROSE FACTOR
AR004471A1 (en) * 1995-05-31 1998-12-16 Smithkline Beecham Corp CYCLOHEXAN-1-OL-4,4-DISSTITUTED COMPOUNDS, USEFUL IN THE TREATMENT OF ALLERGIC AND INFLAMMATORY DISEASES AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5449687A (en) * 1992-04-02 1995-09-12 Smithkline Beecham Corporation 4-phenyl-1,2-cyclohexyl derivatives and anti-inflammatory compositions and methods thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0828493A1 (en) * 1995-05-31 1998-03-18 Smithkline Beecham Corporation 4.4-(disubstituted)cyclohexan-1-ols-monomers and related compounds
EP0828493A4 (en) * 1995-05-31 1998-09-02 Smithkline Beecham Corp 4.4-(disubstituted)cyclohexan-1-ols-monomers and related compounds
EP1202955A2 (en) * 1999-08-10 2002-05-08 SmithKline Beecham Corporation 1,4-substituted 4,4-diaryl cyclohexanes
EP1202955A4 (en) * 1999-08-10 2004-02-11 Smithkline Beecham Corp 1,4-substituted 4,4-diaryl cyclohexanes

Also Published As

Publication number Publication date
MA23755A1 (en) 1996-07-01
PL320996A1 (en) 1997-11-24
CN1090020C (en) 2002-09-04
UA48157C2 (en) 2002-08-15
BG101716A (en) 1998-03-31
BR9510257A (en) 1997-11-04
DE69534518D1 (en) 2006-02-23
EP0794774B1 (en) 2005-10-12
FI972676A0 (en) 1997-06-19
HUT77350A (en) 1998-03-30
ZA9510878B (en) 1997-06-17
ATE306260T1 (en) 2005-10-15
CN1175210A (en) 1998-03-04
NO972906D0 (en) 1997-06-20
MX9704729A (en) 1997-10-31
NZ301096A (en) 1999-01-28
SK79597A3 (en) 1998-01-14
NO972906L (en) 1997-08-15
DZ1959A1 (en) 2002-02-17
BG62034B1 (en) 1999-01-29
AU703246B2 (en) 1999-03-25
EP0794774A1 (en) 1997-09-17
FI972676A (en) 1997-08-19
AU4643396A (en) 1996-07-19
CA2208444A1 (en) 1996-07-04
CZ196097A3 (en) 1998-01-14
JPH10511658A (en) 1998-11-10
EP0794774A4 (en) 1998-04-29

Similar Documents

Publication Publication Date Title
US5863926A (en) 4,4-(disubstituted)cyclohexan-1-carboxylate monomers and related compounds
US5861421A (en) 4,4-(disubstituted) cyclohexan-1-one monomers and related compounds
US5977122A (en) 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds
US5891883A (en) 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds
US5869677A (en) 3,3-(disubstituted)cyclohexan-1-carboxylate monomers and related compounds
AU703246C (en) 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds
WO1996019988A1 (en) 4,4-(disubstituted)cyclohexan-1-ols monomers and related compounds
US5646158A (en) 1,3,3-(trisubstituted)cyclohex-1-ene monomers and related compounds
US5990119A (en) 1,4,4-(trisubstituted)cyclohexane monomers and related compounds
US5892098A (en) 3,3-(disubstituted)cyclohexan-1-one monomers and related compounds
AU693706C (en) 4.4-(disubstituted)cyclohexan-1-ols-monomers and related compounds
US5719184A (en) 3,3-(disubstituted)cyclohexan-1-carboxylate dimers and related compounds
AU4688396A (en) 4,4-(disubstituted)cyclohexan-1-one monomers and related compounds
EP0799205B1 (en) 1,4,4-(trisubstituted)cyclohex-1-ene derivatives as pde iv- and tnf-inhibitors
US5777176A (en) 4,4-(disubstituted)cyclohexan-1-ol dimers and related compounds
US5900417A (en) 1,3,3-(Trisubstituted)cyclohexanemonomers and related compounds
WO1996020159A1 (en) 3,3-(disubstituted)cyclohexan-1-ylidine acetate monomers and related compounds
IL116490A (en) Cyclohexanol derivatives and pharmaceutical compositions comprising them
WO1996019994A1 (en) 3,3-(disubstituted)cyclohexan-1-carboxylate monomers and related compounds

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 95197683.4

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AM AU BB BG BR BY CA CN CZ EE FI GE HU IS JP KE KG KP KR KZ LK LR LT LV MD MG MN MX NO NZ PL PT RO RU SD SG SI SK TJ TM TT UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 79597

Country of ref document: SK

Ref document number: 301096

Country of ref document: NZ

Ref document number: 972676

Country of ref document: FI

ENP Entry into the national phase

Ref document number: 2208444

Country of ref document: CA

Ref document number: 2208444

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PV1997-1960

Country of ref document: CZ

WWE Wipo information: entry into national phase

Ref document number: 1019970704318

Country of ref document: KR

Ref document number: 97-01170

Country of ref document: RO

WWE Wipo information: entry into national phase

Ref document number: 1995944363

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 08860287

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1995944363

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: PV1997-1960

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1019970704318

Country of ref document: KR

WWW Wipo information: withdrawn in national office

Ref document number: 1019970704318

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: PV1997-1960

Country of ref document: CZ

WWG Wipo information: grant in national office

Ref document number: 1995944363

Country of ref document: EP