EP0800393A1 - Monomeres de 4,4-(disubstitue)cyclohexan-1-one et composes correspondants - Google Patents

Monomeres de 4,4-(disubstitue)cyclohexan-1-one et composes correspondants

Info

Publication number
EP0800393A1
EP0800393A1 EP95944527A EP95944527A EP0800393A1 EP 0800393 A1 EP0800393 A1 EP 0800393A1 EP 95944527 A EP95944527 A EP 95944527A EP 95944527 A EP95944527 A EP 95944527A EP 0800393 A1 EP0800393 A1 EP 0800393A1
Authority
EP
European Patent Office
Prior art keywords
cyclohexan
cyclopentyloxy
methoxyphenyl
substimted
unsubstimted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95944527A
Other languages
German (de)
English (en)
Other versions
EP0800393A4 (fr
Inventor
Siegfried B. Christensen, Iv
Joseph M. Karpinski
M.Dominic Ryan
Paul E. Bender
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0800393A1 publication Critical patent/EP0800393A1/fr
Publication of EP0800393A4 publication Critical patent/EP0800393A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
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    • 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
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    • 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
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    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
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    • 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
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    • 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
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
    • C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
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    • 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
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    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/708—Ethers
    • C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
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    • 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
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
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    • 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
    • C07D239/26—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
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    • 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
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    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to novel 4,4-(disubstituted)cyclohexan-l-ones 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-ATP to cAMP at an accelerated rate.
  • Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma.
  • 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.
  • compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells.
  • the principal cellular mechanism for the inactivation of cAMP 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 die pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on die aiket
  • 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 sarcoidosis
  • bone res ⁇ rption diseases reperfusion injury, graft vs.
  • 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), ADDS, 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
  • ADDS human acquired immune deficiency syndrome
  • 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 Human Immunodeficiency Virus
  • HTV-2 Human Immunodeficiency Virus
  • HTV-3 Human Immunodeficiency Virus
  • HTV entry into the T lymphocyte requires T lymphocyte activation.
  • Viruses such as HTV-1 or HTV-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 HTV gene expression and/or HTV replication.
  • Cytokines are implicated in activated T-cell-mediated HTV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HTV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing die progression of HTV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HTV infection.
  • Monocytes, macrophages, and related cells such as kupffer and glial cells, have also been implicated in maintenance of the HTV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon die activation state of the cells. [See Rosenberg etal., The Immunopathogenesis of HTV Infection,
  • TNF cytomegal ⁇ virus
  • influenza virus influenza virus
  • adenovirus adenovirus
  • herpes virus a virus that has been implicated in various roles with other viral infections, such as the cytomegal ⁇ virus (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
  • CMV cytomegal ⁇ 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].
  • Rj is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, (CR4R5) n O(CR4R5)mR6, or -(CR4R5)r 6 wherein the alkyl moieties may be unsubstituted or substituted with one or more fluorines; m is 0 to 2; n is 0 to 4; r is 0 to 6; R4 and R5 are independently hydrogen or Ci-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, a ⁇ yloxyC ⁇ _3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7.11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrodiieny
  • X is YR2, fluorine, NR4R5, or formyl amine
  • X3 is hydrogen or X
  • R2 is -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more fluorines; s is 0 to 4;
  • R3 is COOR14, C(O)NR4Ri4 or R7;
  • W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;
  • R7 is -(CR4R5)qRl2 or C ⁇ _6 alkyl wherein the R12 or C ⁇ . 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, -NRIQRH, -C(O)R8, -CO2R -O(CH2)2-4 ⁇ R 8 , -O(CH 2 ) q R8, -CN, -C(O)NRl ⁇ Rll, -O(CH 2 )qC(O)NRi ⁇ Rn, - O(CH2) q C(O)R9, -NRl ⁇ C(O)NRi ⁇ Rl 1, -NR ⁇ oC(O)Rl l, -NRioC(O)OR9, -NRi ⁇ C(O)Ri3, -C(NRi ⁇ )NR ⁇ oRl l
  • Rg is hydrogen or R9;
  • R9 is C 1 -4 alkyl unsubstituted or substituted by one to three fluorines;
  • RlO is OR ⁇ or R ⁇
  • Rl 1 is hydrogen, or C ⁇ _4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Rl 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S;
  • Rl3 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, i idazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and where R13 is substituted on R ⁇ 2 or R ]3 die rings are connected through a carbon atom and each second R ⁇ _ ring may be unsubstituted or substituted by one or two C ⁇ _2 alkyl groups unsubstituted or substituted on die methyl with 1 to 3 fluoro atoms;
  • Rj4 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 only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S; provided that: (0 R7 is not C ⁇ _4 alkyl unsubstituted or substituted by one to tiiree fluorines; or or the pharmaceutically acceptable salts thereof.
  • R! is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4 5)nC(O)NR4(CR4 5)m 6, - (CR4R5) n O(CR4R5)_nR6, or -(CR4R5) ⁇ *R»5 wherein die alkyl moieties may be unsubstituted or substituted with one or more fluorines; m is 0 to 2; n is 0 to 4; r is 0 to 6;
  • R4 and R5 are independendy selected hydrogen or Ci-2 alkyl
  • R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, a ⁇ yloxyCi-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydr ⁇ pyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties is unsubstituted or substituted by 1 to 3 methyl groups, an 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
  • 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;
  • R2 is independendy selected from -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more fluorines; s is 0 to 4;
  • R3 is COOR14, C(O)NR4Ri4 or R7;
  • W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;
  • Z" is C(Y * )Rl4, C(O)ORi4, C(Y')NRl ⁇ Rl4, C(NR ⁇ o)NR ⁇ oRi4, CN, C(NOR8)Rl4, C(0)NR8NR8C(0)R8, C(O)NRgNRi ⁇ Rl4, C(NORl4)R8.
  • R7 is -(CR4R5) q Rl2 or C ⁇ _6 alkyl wherein the R12 or C ⁇ _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, -NRIQRI 1, -C(O)R8, -CO2R8, -O(CH2)2 ⁇ 0Rg, -O(CH 2 ) q R8, -CN, -C(O)NR ⁇ oRn, -O(CH 2 ) q C(O)NR ⁇ oRll, - 0(CH2) q C(O)R9, -NR ⁇ oC(O)NRi ⁇ R ⁇ , -NR ⁇ oC(O)Rn, -NR ⁇ oC(O)OR9, -NRioC(O)Ri3, -C(NR ⁇ o)NRi ⁇ Rn
  • Rl2 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; Rg is independendy selected from hydrogen or R9;
  • R9 is C]_4 alkyl unsubstituted or substituted by one to three fluorines
  • RlO is OR ⁇ or Rn
  • R is hydrogen, or Cj_4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Rl 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S;
  • Rl3 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 R- 2 or R-,3 the rings are connected through a carbon atom and each second R ⁇ 3 ring may be unsubstituted or substituted by one or two Cj_2 alkyl groups unsubstituted or substituted on d e methyl with 1 to 3 fluoro atoms;
  • R 4 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 only of carbon atoms or carbon atoms and at least one heteroatoms selected from O, N, or S; provided that:
  • R7 is not C .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 (II) and a pharmaceutically acceptable carrier or diluent
  • the invention also relates to a method of mediation or inhibition of d e 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) and (II) as shown below.
  • the invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I) and (II).
  • the invention also provides a metiiod 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) and CO).
  • 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) and (II).
  • This metiiod 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) and (II).
  • HAV human immunodeficiency virus
  • Compounds of Formula (I) and (II) are also useful in die 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) and (H) 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 die production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) and (II).
  • 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.
  • PDE IV 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, direcdy or indirecdy, by the TNF inhibitors of Formula (I) and (U).
  • viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and die 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 widi a human immunodeficiency vims (HTV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I) and ( ⁇ ).
  • HTV human immunodeficiency vims
  • 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 immunodeficiency virus (FTV) or other retroviral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
  • FTV feline immunodeficiency virus
  • retroviral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
  • the compounds of this invention are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • a preferred disease state for treatment is fungal meningitis.
  • the compounds of Formula (I) and (II) may be administered in conjunction with other drugs of choice for systemic yeast and fungal infections.
  • Drugs of choice for fungal infections include but are not limited to the class of compounds called the polymixins, such as Polymycin B, the class of compounds called the imidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; 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) and (II) may also be used for inhibiting and/or reducing d e toxicity of an anti-fungal, anti-bacterial or anti- viral agent by administering an effective amount of a compound of Formula (I) and (II) to a mammal in need of such treatment
  • a compound of Formula (I) and (II) is administered for inhibiting or reducing die toxicity of the Amphotericin class of compounds, in particular Amphotericin B.
  • C ⁇ _3 alkyl C ⁇ _4 alkyl
  • C ⁇ _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-pr ⁇ pyl, isopropyl, n-butyl, sec-butyl, isobutyl, rerr-butyl, and die like.
  • Alkenyl means both straight or branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl, 1- propenyl, 2-propenyl, or 3-methyl-2-propenyl.
  • cycloalkyl or "cycloalkyl alkyl” means groups of 3-7 carbon atoms, such as cyclopropyl, cycl ⁇ propylmethyl, cyclopentyl, or cyclohexyl.
  • Aryl or “aralkyl”, unless specified otherwise, means an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl, or naphthyl. Preferably the aryl is monocyclic, i.e, phenyl.
  • the alkyl chain is meant to include both straight or branched chain radicals of 1 to 4 carbon atoms.
  • Heteroaryl means an aromatic ring system containing one or more heteroatoms.
  • 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 die 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 E -l 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
  • TNF mediated disease or disease states means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6.
  • TNF- ⁇ also known as lymphotoxin
  • TNF- ⁇ also known as cachectin
  • both TNF- ⁇ and TNF- ⁇ are inhibited by die compounds of die present invention and thus are herein referred to collectively as "TNF' unless specifically delineated otherwise.
  • TNF- ⁇ is inhibited
  • Cytokine means any secreted polypeptide that affects the functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses.
  • a cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce diem.
  • the cytokine inhibited by die present invention for use in the treatment of a HTV-infected human must be a cytokine which is implicated in (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HTV gene expression and/or replication, and or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration.
  • his cytokine is TNF- ⁇ .
  • All of the compounds of Formula (I) and (II) are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal, including humans, in need thereof. All of the compounds of Formula (I) and (II) are useful in the method of inhibiting or mediating die enzymatic or catalytic activity of PDE IV and in treatment of disease states mediated thereby.
  • Preferred compounds are as follows:
  • Rl for the compounds of Formula (I) and (II) is an alkyl substituted by 1 or more halogens
  • the halogens are preferably fluorine and chlorine, more preferably a Ci-4 alkyl substituted by 1 or more fluorines.
  • the preferred halo-substituted alkyl chain length is one or two carbons, and most preferred are the moieties -CF3, -CH2F, - CHF2, -CF2CHF2, -CH2CF3, and -CH2CHF2.
  • Rl substitutents for the compounds of Formula (I) and (II) are CH2-cyclopr ⁇ pyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl unsubstituted or substituted with OH, C7-11 polycycloalkyl, (3- or 4- cycl ⁇ pentenyl), phenyl, tetrahydroruran-3-yl, benzyl or Ci-2 alkyl unsubstituted or substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2)0-2CH3, -(CH2)1-3O(CH2)0-2CH3, and -(CH2)2-4 ⁇ H.
  • Rl term is (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 die other, e.g., (CR4R5) n wherein n is 2 can be -CH2CH(-CH3)-, for instance.
  • the individual hydrogen atoms of die repeating methylene unit or the branching hydrocarbon can be unsubstituted or be substituted by fluorine independent of each other to yield, for instance, the preferred Rl substitutions, as noted above.
  • Rl is a C7-11 polycycloalkyl
  • examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2. l]octyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987, whose disclosure is incorporated herein by reference in its entirety.
  • Preferred Z terms are O, NCN, NR7, NOR14, NOR15, NNR4R14, NNR4R15, 2-(l,3-did ⁇ iane), dimethyldiio ketal, 2-(l,3-dioxolane), or dimediyl ketal. More preferred are O, NR7, NOR14, NOR15, and 2-(l,3-dioxolane).
  • Preferred X groups for Formula (I) and (II) are those wherein X is YR2 and Y is oxygen.
  • the preferred X2 group for Formula (I) and (II) is that wherein X2 is oxygen.
  • the preferred X3 group for Formula (I) and (II) is that wherein X3 is hydrogen.
  • Preferred R2 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.
  • R2 groups are those wherein R2 is methyl, or the fluoro-substituted alkyls, specifically a Ci-2 alkyl, such as a -CF3, - CHF2, or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.
  • R7 moieties include R13, unsubstituted or substituted -(CH2)0-2(2-, 3- or 4-pyridyl), (CH2)l-2(2-imidazolyl), (CH2)2(4-morpholinyl), (CH2)2(4- piperazinyl), (CH2)l-2(2-thienyl), (CH2)l-2(4-thiazolyl), unsubstituted or substituted pyrimidinyl, and substituted or unsubstituted (CH2)0-2phenyl.
  • Preferred rings when Rio and Rl 1 in the moiety -NRioRl 1 together with the nitrogen to which they are attached form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 2-(R8)-l-imidazolyl, 1-pyrazolyl, 3-(R8)-l-pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R8)-l-triazolyl, 5-(R8)-2-tria2 ⁇ lyl, 5-(R8)-l-tetrazolyl, 5-(R8)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(R8)- 1 -piperazinyl, or pyrrolyl ring.
  • Preferred rings when R8 and Rl4 in the moiety -NR8R14 together with the nitrogen to which they are attached may form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms 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) and (II).
  • Illustrations of such carbon substitutions includes, but is not limited to, 2-(R7)-l-irrridazolyl, 4-(R7)-l-imidazolyl, 5-(R7)-l-imidazolyl, 3-(R7)-l-pyrazolyl, 4-(Rrj)-l -pyrazolyl, 5-(R7)-l -pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-l-triazolyl,
  • R7 includes, but is not limited to, l-(R7)-2-tetrazolyl, 2-(R7)-l -tetrazolyl, -(Rrj)-l -piperazinyl. Where applicable, the ring may be substituted one or more times by R7.
  • Preferred groups for NR8R14 which contain a heterocyclic ring are 5-(Ri4)-l- tetrazolyl, 2-(Ri4)-l-imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(Ri4)-l-piperazinyl, or 4-(R 15)- 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]),
  • the heterocyclic ring itself may be unsubstituted or substituted by R8 either on an available nitrogen or carbon atom, such as l-(R8)-2-imidazolyl, l-(R8)*-4-imidazolyl, l-(R8)-5-imidazolyl, l-(R8)-3-pyrazolyl, l-(R8)-4-pyrazolyl, l-(R8)-5-pyrazolyl, l-(R8)-4-triazolyl, or l-(R8)-5-triazolyl.
  • the ring may be substituted one or more times by
  • R8- 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 tiiat W is ethynyl or 1,3-butadiynyL
  • tiiose compounds of Formula (I) and (II) wherein Ri is -CH2- cycl ⁇ propyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl unsubstituted or substituted with OH, tetrahydroruran-3-yl, (3- or 4-cyclopentenyl), benzyl or -Ci-2 alkyl unsubstimted or substimted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluoro- substituted alkyl, R 3 is R 7 where R 7 is an unsubstimted or substituted aryl or heteroaryl ring, X is YR2, and Z is O, NR7. Z' is preferably COOR14.
  • Ri 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 ediynyl or 1,3-butadiynyl, R3 is a substimted or unsubstimted pyrimidinyl ring, and Z is O, NR7.
  • Pharmaceutically acceptable salts of the instant compounds, where they can be prepared, are also intended to be covered by titis 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 die salt will not have untoward or deleterious effects in its application and use in treating diseases.
  • compositions 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.
  • compositions of die present invention comprise a pharmaceutical carrier or diluent and some amount of a compound of d e Formula (I) and (II).
  • 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 die 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 die pharmaceutical carrier or diluent will, of course, depend upon die 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 administration to the skin, eye, ear, or nose.
  • parenteral administration die 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.
  • oral administration die pharmaceutical composition will be in die 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 with water, for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chl ⁇ rotriflu ⁇ roethane and compressed carbon dioxide.
  • die 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 d e 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 When the diluent is a solid it may be present in lesser, equal or greater amounts than die 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.
  • die dosage of die 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.
  • tiiat d e 2-position of die ring in the exocyclic form can be substimted (R) such as in the compounds of Formula (I) or (II).
  • Compounds of Formula (I) may be prepared by die processes disclosed herein which comprise reacting a terminal acetylene as, e.g., compound 1 -Scheme 1. with an aryl halide, such as phenyl iodide, in the presence of a suitable catalyst, such as a copper D 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 procedure of Brandsma et al. (Syn. Comm., 1990, 20, 1889), followed by hydrolysis of the ketal protecting group under standard conditions, provides a compound of die Formula 2_ Scheme 1.
  • an aryl halide such as phenyl iodide
  • a suitable catalyst such as a copper D halide
  • a bivalent or zerovalent palladium compound in the presence of, e.g., triphenylphosphine
  • compounds of Formula (I) may be prepared by reacting a terminal acetylene as, e.g., compound 1 -Scheme 2. 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 procedure of Brandsma et al. (Syn. Comm., 1990, 20, 1889), to provide a compound of me Formula 2-Scheme 2: such compounds of d e Formula (I) may then be converted to other compounds of the Formula (I) by standard manipulation of the functional groups on the R3 moiety.
  • a suitable catalyst such as a copper (I) halide and a bivalent or zerovalent palladium compound in the presence of, e.g
  • Compounds of die Formula 1-Scheme 2 may be prepared by procedures analogous to diose described in prior filed co-pending U.S. applications 07/862,083, 07/968,753 and PCT/US93/01990 designating the United States and filed 05 March 1993 (WIPO publication No. WO 93/19748) or PCT application PCT/US93/02325 published as WO 93/19750..
  • an appropriate metal salt such as a copper salt with a catalytic amount of a palladium salt
  • a suitable base such as an acid trap, such as sodium acetate
  • a suitable alcohol such as methanol
  • D ⁇ sobutylaluminum hydride (1.0 M in toluene, 8.13 mL, 8.13 mmol) was added dropwise to a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l- (ethylenedioxy)cyclohexane (1.16 g, 3.19 mmol) dissolved in toluene (20 mL) under an argon atmosphere. After 18 h at room temperature, saturated aqueous sodium bisulfite (100 mL) was added and die mixture was extracted three times with dichloromethane. The combined organic extract was washed widi brine, was dried (potassium carbonate) and was evaporated.
  • the reaction mixture was chilled to 0°C was poured into ice- water, was acidified wid 3N hydrochloric acid and was extracted five times widi methylene chloride.
  • the organic phase was washed wid dilute hydrochloric acid, water, saturated brine, was dried over magnesium sulfate, was filtered and concentrated in vacua.
  • the residue was preadsorbed and chromatographed on silica gel, eluting the with 15 to 20% ethyl acetate in hexanes, to afford a Ught yeUow oil.
  • Example 12 Preparation of 4-f 3-cvclopentvloxv-4-methoxvphenvn-4-f3-carbomed ⁇ oxvphenvl- ethvnvltavclohexan- 1 -one
  • Example 13 Preparation of 4-(3-cvclopentyloxy-4-methoxvphenvlVl.l-(ethylenedioxy'>-4-G- carboxyphenylethynyDcyclohexane
  • a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-l,l-(ethylenedioxy)-4-(3- carbomethoxyphenylethynyl)cyclohexane (0.12 g, 0.245 mmol) in medianol (5 mL) was treated with 10% aqueous sodium hydroxide (0.3 mL, 0.734 mmol) under an argon atmosphere and was heated at 55-60 °C for 2.5 h.
  • the cooled reaction mixture was concentrated in an argon stream and d e residue was partitioned between cold water acidified widi dilute hydrochloric acid and methylene chloride.
  • the aqueous phase was extracted another two times with methylene chloride and die combined organic phase was dried over magnesium sulfate to afford die tided compound as an oil.
  • Example 15 4-f3-Cvclopentyloxy-4-methoxvphenvlV4-f4- ⁇ vridvlethvnvl)cvclohexan-l-one 15a) 4-(3-cyclopentyloxy-4-med ⁇ oxyphenyl)-4-(4-pyridylethynyl)-l,l- (ed ⁇ ylenedioxy)cyclohexane To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl- 1,1-
  • 2-Bromo-5-carboxymethylthiophene was prepared by standard chemistry weU known to those versed in the art and was a white solid, mp 59-60°C. 17b) 4-(2-ca ⁇ bomethoxyd ⁇ ien-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -one
  • Example 18 4-(2-Ca ⁇ boxvthien-5- vlethvnvtt- (3-cvclopen oxv-4-methox vphenvncvclohexan- 1 - one, sodium salt
  • Example 19 4-(2-Cyanod ⁇ ien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -one 19a) 2-bromo-5-cyanothiophene 2-Bromo-5-cyanod ⁇ iophene was prepared by standard chemistry weU known to those versed in the art and was a colorless oil, - ⁇ -NMR (400 MHz, CD ⁇ 3): ⁇ 7.40
  • Example 21 4-(2-C ⁇ tx>med ⁇ oxythien-4-yled ⁇ ynvn-4-G-cvclopentvloxv-4-me oxvphenvlV:vclo- hexan-1-one
  • 21a 4-bromo-2-carboxymethyld ⁇ iophene 4-Bromo-2-carboxymethyld ⁇ iophene was prepared by standard chemistry well known to tiiose versed in the an and was a brown oU.
  • 21b 4-(2- ⁇ * arbomemoxythien- -yled ⁇ ynyl)-4-(3- ⁇ l ⁇ entyloxy--4- methoxyphenyl)cyclo-hexan-l-one.
  • Example 24 4-(3-( clopen oxv-4-n ⁇ thoxvphenvlV4-r2-f5-methv1-ri .2.41oxar * 1ia7 ⁇ 1-2-v thien-4- vlethvnyll cyclohexan-1-one 24a) 4-bromo-2-f 5-methyl-[ 1 ,2,4]oxadiazol-2-yl)thi ⁇ phene
  • [l,2,4]oxadiazol-2-yl)ti ⁇ iophene (020 g, 0.8 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)paUadium(0) (0.038 g, 4%), copper(I) iodide (0.009 g, 6%), and a small crystal of triphenylphosphine, and die mixture was heated at 70-75°C for 0.5 h. Hydrochloric acid (5%) was added and die mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated.
  • Example 26 4-(4-Cartx)xytMen-2-ylethynyl -(3-cyclopentyloxy- -me oxypheny 1 - one
  • 4-(4-ca_boniethoxythien-2-ylediynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one (0.12 g, 0.427 mmol) and coarsely ground potassium hydroxide (0.045 g, 0.81 mmol) in tetrahydrofuran (2.5mL), methanol (2.5mL), and water (0.5mL) was stirred at room temperature under an argon atmosphere for three days.
  • Example 27 4>(3-cvclopentvloxv-4-med ⁇ oxvphenvn-4-r4-f5-me vl-ri .2.41oxadia7 ⁇ l-2-vnthien-2- yletf ⁇ y ⁇ yllcyclQhexa ⁇ -1-pne 27a) 2-bromo-4-£5-methyl-[12,4]oxadiazol-2-yl)d ⁇ iophene
  • Example 30 4-f 3-cvclopentyloxy- -methoxvphenvlV4-f 1 -methvlimidazol-2- vleth vnvDcvclohexan- 1 - one 30a) l-med ⁇ yl-2-iodoimidazole l-Methyl-2-iodoimidazole was prepared by standard chemistry weU known to those versed in the an and was a white soUd, mp 58-59°C.
  • Example 31 4- ( 3-cvclopentvloxv-4-med ⁇ oxyphenylV*4-rimiHa y n1-2-ylethvnyl ⁇ rw:lohexan- 1 -one.
  • hydrochloride salt 31a l-t -butylcarbonyl-2-iodoimidazole l-tert-Butylcarbonyl-2-iodoimidazole was prepared by standard chemistry weU known to those versed in the an and was a white solid, mp 77-78°C.
  • a melt of ethylene carbonate (6.5 g, 74 mmol) in a smaU flask under Argon was treated with 4-iodophenol (0.400 g, 1.82 mmol) and powdered potassium carbonate (1.26 g, 9.1mmol) and was stirred at 90°C for 3 hr.
  • the crude acid was purified by chromatography (silica, ethyl acetate/methylene chloride/formic acid; 10:90: 1), the product fractions washed widi water three times, was stripped in vacua , was crystaUzed with ether and was dried in vacua to afford the tided compound as a white soUd (0.077 g, 55%), mp 170-171 O C.
  • Anal. (C27H28O5) calcd: C 74.98, H 6.53 found: C 74.78, H 6.54.
  • the erode product was chromatographed (siUca 50 to 75% ethyl acetate in petroleum ether) and was stripped in vacua to afford die tided intermediate as a viscous yeUow oU (0232 g, 96%).
  • Example 37 Preparation of 4-f 2-r4-carbomethoxymemyloxyphenvnethvnvn-4-(3-cvclopentvloxv-4- methoxyphen ylteyclohexan- 1 -one
  • Example 39 Preparation of 4-f 3-cvclopentvloxv-4-methoxvphenvn-4-f2-r3 - dicaibomethoxvphenvnethvnvlkryclohexan- 1 -one
  • a mixture of 4-(4-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-l- one (0.075 g, 0.24 mmol) and dimethyl 5-iodoisophthalate (Trans World Chemicals, 0.107 g, 0.33 mmol) in triethylamine (1.9 mL, dry) was treated with a mixture of tetrakis(triphenylphosphine)palladium (0.012 g, 0.010 mmol), cuprous iodide (0.0025 g, 0.013 mmol), and triphenylphosphine ( a small crystal) under an argon atmosphere and was stirred at 80°C for 1 h.
  • Example 42 Preparation of 4-f 3-cvclopentvloxv-4-methoxvphenvlV4-f2-r3-f3-med ⁇ vl- ⁇ .Z. ⁇ l ⁇ a- ⁇ ole ⁇ - l ⁇ phenvllethvnvl ⁇ cvclohexan-l-one 42a) 5-(3-iodophenyl)-3-methyl-[ 1 ,2,4]oxadiazole 5-(3-Iodophenyl)-3-methyl-[12,4]oxadiazole was prepared by standard chemistry weU known to those versed in die an and was a white soUd, mp 102-103°C.
  • 3,5-Dicyanophenyl iodide was prepared by standard chemistry weU known to those versed in the an and was a white soUd, mp 145.5- 146.5°C. 44b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-5-dicyanphenyl]ethynyl cyclohexan- 1-one
  • die foUowing compounds may be prepared:
  • the inhibitory effect of compounds of Formula (I) and (II) on in vitro TNF production by human monocytes may be determined by die protocol as described in
  • Example 1 demonstrated a positive in vivo response in reducing serum levels of TNF induced by die injection of endotoxin.
  • Formula (I) and (II) 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 m, guinea-pig heart; 4) PDE IV, human monocyte; and 5) PDE V (also called "Ia"), canine tracheaUs.
  • PDEs la, lb, Ic and III are partially purified using standard chromatographic techniques [Torphy and OesUnski, MoL Pharmacol., 37:206-214, 1990].
  • PDE IV is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-Sepharose chromatography [Torphy et al., J.

Abstract

L'invention porte sur des dérivés de 4,4-(disubstitué)cyclohexan-1-one et les composés correspondants, utiles pour traiter des maladies allergiques et inflammatoires.
EP95944527A 1994-12-23 1995-12-21 Monomeres de 4,4-(disubstitue)cyclohexan-1-one et composes correspondants Withdrawn EP0800393A4 (fr)

Applications Claiming Priority (6)

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US36313094A 1994-12-23 1994-12-23
US45623494A 1994-12-23 1994-12-23
US45579695A 1995-05-31 1995-05-31
US455796 1995-05-31
PCT/US1995/016858 WO1996019995A1 (fr) 1994-12-23 1995-12-21 Monomeres de 4,4-(disubstitue)cyclohexan-1-one et composes correspondants
US456234 1999-12-07

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CZ2002460A3 (cs) * 1999-08-10 2002-06-12 Smithkline Beecham Corporation 1,4-Substituované 4,4-diarylcyklohexany
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WO1993019750A1 (fr) * 1992-04-02 1993-10-14 Smithkline Beecham Corporation Composes efficaces dans le traitement de maladies allergiques ou inflammatoires

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WO1993019750A1 (fr) * 1992-04-02 1993-10-14 Smithkline Beecham Corporation Composes efficaces dans le traitement de maladies allergiques ou inflammatoires

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Title
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FI972673A0 (fi) 1997-06-19
BR9510521A (pt) 1998-07-14
MX9704733A (es) 1997-10-31
HUT78042A (hu) 1999-06-28
FI972673A (fi) 1997-08-19
CZ196297A3 (cs) 1998-01-14
PL321001A1 (en) 1997-11-24
CN1175211A (zh) 1998-03-04
NZ301453A (en) 1999-02-25
AU708349B2 (en) 1999-08-05
CA2208456A1 (fr) 1996-07-04
NO972898L (no) 1997-08-20

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