WO1996020163A1 - Dimeres 4,4-(disubstitue)cyclohexane-1-carboxylate et composes apparentes - Google Patents

Dimeres 4,4-(disubstitue)cyclohexane-1-carboxylate et composes apparentes Download PDF

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Publication number
WO1996020163A1
WO1996020163A1 PCT/US1995/013384 US9513384W WO9620163A1 WO 1996020163 A1 WO1996020163 A1 WO 1996020163A1 US 9513384 W US9513384 W US 9513384W WO 9620163 A1 WO9620163 A1 WO 9620163A1
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cr4r5
alkyl
hydrogen
substituted
independendy selected
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PCT/US1995/013384
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English (en)
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Siegfried B. Christensen, Iv
Joseph M. Karpinski
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Smithkline Beecham Corporation
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Priority to JP8520436A priority Critical patent/JPH10511392A/ja
Priority to EP95938781A priority patent/EP0799187A4/fr
Publication of WO1996020163A1 publication Critical patent/WO1996020163A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/34—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/36—Unsaturated compounds containing —CHO groups

Definitions

  • the present invention relates to novel 4,4-(disubstituted)cyclohexan-l- carboxylate dimers 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.
  • cAMP cyclic nucleotide phosphodiesterases
  • PDE isozyme
  • PDE IV is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells.
  • Phosphodiesterase Isozymes Potential Targets for Novel Anti-asthmatic Agents” in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989.
  • 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 signi icant therapeutic advantages over agents currently on the market.
  • TNF Tumor Necrosis 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 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
  • AIDS AIDS
  • ARC AIDS related complex
  • keloid formation scar tissue formation
  • Crohn's disease Crohn's disease
  • ulcerative colitis or pyresis
  • AIDS results from the infection of T lymphocytes with Human
  • HTV Immunodeficiency Virus
  • HTV-1 a type or strain of HTV
  • HTV-2 a type or strain of HTV
  • HTV-3 a type or strain of HTV
  • T-cell- mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms.
  • HTV entry into the T lymphocyte requires T lymphocyte activation.
  • Viruses such as HTV- 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 HTV, 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 the 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.
  • T cells like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells.
  • Monokines such as TNF, have been shown to activate HTV replication in monocytes and or macrophages [See Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990], therefore, inhibition of monokine production or activity aids in limiting HTV progression as stated above for T cells.
  • TNF has also been implicated in various roles with other viral infections, such as the cvtomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
  • CMV cvtomegalovirus
  • 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]. 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
  • the compounds of this invention are represented by Formulas (la) and (lb):
  • Rj is independently selected from -(CR4R5)nC(O)O(CR4R5)mR6» -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)m 6, or -(CR4R5)r 6 wherein the alkyl moieties is unsubstituted or substituted with one or more fluorines; m is 0 to 2; n is 1 to 4; r is 0 to 6;
  • R4 and R5 are independently selected from hydrogen or C 1-2 alkyl
  • R6 is independently selected from hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCl-3 alkyl, halo substituted aryloxyCi-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
  • X is independently selected from YR2, fluorine, NR4R5, or formyl amine; Y is independently selected from O or S(O) ⁇ ; m' is 0, 1, or 2;
  • X2 is independently selected from O or NR8;
  • X3 is independently selected from hydrogen or X;
  • X4 is independently selected from H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NR8R8, or NR8R8;
  • R2 is independently selected from the group consisting of -CH3 and -CH2CH3 optionally substituted by 1 or more fluorines; 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;
  • Z is independently selected from C(Y')Rl4.
  • Y * is independently selected from O or S;
  • R7 is -(C 4R5)qRi2 or C ⁇ __ 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, -NRl0 R l 1.
  • Rl2 is independently selected from R13, C3-7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl;
  • R is independently selected from hydrogen or R9;
  • R9 is independently selected from Cj .4 alkyl optionally substituted by one to three fluorines;
  • RjO is independently selected from OR8 or Ri 1;
  • R] 1 is independently selected from hydrogen, or Cj_4 alkyl optionally substituted by one to three fluorines; or when Rio and Ri ] are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and at least one additional heteroatom selected from O, N, or S;
  • Rl3 is independently selected from oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and R14 is hydrogen or R7; or when Rs and R] 4 are as NRsRl4 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; or the pharmaceutically acceptable salts thereof.
  • This invention also relates to the pharmaceutical compositions comprising a compound of Formula (la) or (lb) 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 (la) or (lb) 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 (la) or (lb).
  • 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 (la) or (lb).
  • 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 (la) or (lb).
  • 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 (la) or (lb).
  • Compounds of Formulas (la) or (lb) 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 Formulas (la) or (lb) 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 TV in a mamma] 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 (la) or (lb).
  • 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, directly or indirectly, by the TNF inhibitors of Formula (I).
  • viruses include, but are not limited to HIV-1, HTV-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 (HTV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (la) or Ob).
  • HTV 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 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 Formulas (la) or (lb) 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 Formulas (la) or (lb) 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 (la) or (lb) to a mammal in need of such treatment.
  • a Compound of Formula (la) or (lb) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.
  • Cj-3 alkyl, C1.4 alkyl, “C ⁇ 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, wt-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, 2-propynyl, or 3-methyl-2-propenyl.
  • 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 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.
  • ⁇ eteroaryr means an aromatic ring system containing one or more heteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl.
  • ' ⁇ alo 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 D 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 the compounds of the present invention and thus are herein referred to collectively as 'TNF' unless specifically delineated otherwise.
  • TNF- ⁇ is inhibited.
  • Cytokine means any secreted polypeptide that afreets the functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses.
  • a cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce them.
  • the cytokine inhibited by the 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 HIV gene expression and/or replication, and/or (b) any cytolrine-mediated disease associated problem such as cachexia or muscle degeneration.
  • this cytokine is TNF- ⁇ .
  • All of the compounds of Formulas (la) or (lb) 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 Formulas (la) or (lb) 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.
  • Preferred compounds are as follows:
  • R ⁇ may be a cyclopentyl group and a CF3 group within the same molecule of a given embodiment of Formula (la), (lb) or (Ic).
  • each and every one of the other groups may be independently selected, or may be the same, in any given embodiment of this invention.
  • 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.
  • Preferred Ri substitutents are CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl with or without an OH group, C7.11 polycycloalkyl, (3- or 4- cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or Ci-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2)0-2CH3, -(CH2)1-3O(CH2)0-2CH3, and -(CH2)2-4OH.
  • 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 optionally be substituted by fluorine independent of each other to yield, for instance, the preferred R] substitutions, as noted above.
  • Ri is a C7-11 polycycloalkyl
  • examples are bicyclo[2.2J]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2J]octyl, 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.
  • Z is preferably C(O)Ri4, C(O)ORi4, C(O)NR ⁇ oRl4, C(NRi ⁇ )NRi()Rl4, CN, C(NOR8)R8. C(O)NR ⁇ NR8C(O)R8, C(NR8)NRi ⁇ Rl4.
  • R8 group of Z is R4.
  • Z is preferably C(O)Ri4, C(O)ORl4, or C(O)NR ⁇ oRl4*
  • Preferred X groups are those wherein X is YR2 and Y is oxygen.
  • the preferred X2 group is oxygen.
  • the preferred X3 is hydrogen.
  • Preferred R2 groups, where applicable, are Cl-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 methyl, or the fluoro-substituted alkyls, specifically a Cl-2 alkyl, such as a -CF3, -CHF2, or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.
  • 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.
  • R7 moieties include optionally substituted -(CH2)l-2(cyclopropyl), -(CH2)0-2(cyclobutyl), -(CH2)0-2(cyclopentyl) with or without an OH group, -(CH2)0-2(cyclohexyl), -(CH2)0-2(2-, 3- or 4-pyridyl), -(CH2)l-2(2-imidazolyl), -(CH2)2(4-morpholinyl), -(CH2)2(4-piperazinyl), -(CH2) 1 -2(2-thienyl), -(CH2) 1 -2(4- thiazolyl), and -(CH2)0-2phenyl;
  • Preferred rings when Rio and Rl l in the moiety -NRioRl 1 together with the nitrogen to which they are attached form a 5 to 7 membered ring containing at least one additional heteroatom selected from O, N or S include, but are not limited to 1- imidazolyl, 2-(Rs)- 1 -imidazolyl, 1-pyrazolyl, 3-(R8)- 1 -pyrazolyl, 1 -triazolyl, 2- triazolyl, 5-(R8)-l-triazolyl, 5-(R8)-2-triazolyl, 5-(R8)-l-tetrazolyl, 5-(R8)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(R ⁇ )-l- piperazinyl, or pyrrolyl ring.
  • Preferred rings when Rio and R14 in the moiety -NR10R14 together with the nitrogen to which they are attached form a 5 to 7 membered ring containing at least one additional 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 are not limited to, 2-(R7)-l-imidazolyl, 4-(R7)-l -imidazolyl, 5-(R7)-l -imidazolyl, 3-(R7)-l-pyrazolyl, 4-(R7)-l -pyrazolyl, 5-(R7)-l -pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-l -triazolyl, 5-(R7)-l -triazolyl, 5-(R7)-lJetrazolyl, and 5-(R7)-2-tetrazolyl.
  • Applicable nitrogen substitution by R7 includes, but is not limited to. l-(R7)-2-tetrazolyl, 2-(R7)-l-tetrazolyl, 4-(R7)-l -piperazinyl. Where applicable, tlie ring can be substituted one or more times by R7.
  • Preferred groups for NR10R1 which contain a heterocyclic ring are 5-(Rl4)- 1-tetrazolyl, 2-(R ⁇ 4)- 1 -imidazolyl, 5-(Ri4)-2-tetrazolyl, or 4-(R 14 )- 1 -piperazinyl.
  • Preferred rings for R13 include (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl),
  • the heterocyclic ring itself may be optionally 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 Rs*
  • R is -CH2- cyclopropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl unsubstituted or substituted with an hydroxyl group, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -Cl-2 alkyl optionally substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or flu ⁇ ro-substituted alkyl, and W is alkynyl of 2 to 4 carbon atoms.
  • Ri is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H
  • X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; X4 is hydrogen, R2 is CF2H or methyl and W is acetylene or 1,3-butadiy ⁇ yl, and Z is C(O)ORi4.
  • Exemplified compounds are:
  • Compounds of Formula (la), wherein W is a 1,3-butadiynyl and wherein A and B represent Z as defined above or a group convertible to Z, may be prepared by the processes disclosed herein which comprise, for example, coupling of a molecule of the Formula 1 -Scheme 1 with a molecule of the Formula 2-Scheme 1 using an appropriate metal salt, such as cupric acetate, in a suitable solvent, such as DMF or pyridine, or a combination, such as pyridine/methanol/water, as in the method of Eglington and Galbraith (J. Chem. Soc., 1959, 889), to provide a compound of the Formula 3_; Scheme 1-
  • compounds of Formula (lb), wherein W is a 1,3-butadiynyl and wherein A and B represent Z as defined above or a group convertible to Z and wherein X4 represents X4 as defined above or a group convertible to X4, may be prepared by the processes disclosed herein which comprise, for example, coupling of a molecule of the Formula 1 -Scheme 2 with a molecule of the Formula 2-Scheme 2 using an appropriate metal salt, such as cupric acetate, in a suitable solvent, such as DMF or pyridine, or a combination, such as pyridine/methanol/water, as in the method of Eglington and Galbraith (J. Chem. Soc., 1959, 889), to provide a compound of the Formula 3-Schcmc 2- Schema 2
  • Reduction of a compound of the Formula (lb), wherein W is a 1,3-butadiynyl and wherein Z represents Z as defined above or a group convertible to Z, to a compound of the Formula (I) wherein W is a fully saturated hydrocarbon chain (i.e., n- butyl) may be accomplished using, e.g., palladium metal according to the method of Tedeschi (J. Org. Chem., 1962, 27, 2398), or, e.g., platinum oxide according to the method of Jutz (Ber., 1958, 91, 1867) or that of Suzuki and Kurosawa (Chem. Lett., 1980, 1177).
  • Reduction of a compound of the Formula (lb), wherein W is a 1,3- butadiynyl and wherein Z represents Z as defined above or a group convertible to Z, to provide a compound of the Formula (lb) wherein W is a 1 ,3-butadiene may be accomplished using, e.g., the hydroboration-protonolysis procedure of Zweifel and Polston (J. Am. Chem. Soc., 1970, 92, 4068), or, e.g., the hydroalumination- protonolysis procedure of Zweifel et al. (Synthesis, 1977, 52).
  • compounds of the Formula (la), wherein W and Z represent W and Z as defined above or a group convertible to W or Z may be prepared from the corresponding ketones as, e.g., compound 1 -Scheme 3. by the synthetic procedures described in co-pending U.S patent application number 07/862,030 filed 2 April 1992 and its progeny USSN 07/968,762 filed 30 October 1992 and PCT appliation number PCT/US93/01991 designating the United States as a continuing application and filed 05 March 1993; syntheses of such ketone starting materials are described in co- pending U.S application serial number 07/862,083 and 07/968,753 and PCT application serial number PCT/US93/02045 filed 05 March 1993 (designating the U.S. as a continuation application) now published.
  • compounds of Formula (lb) wherein W, X4 and Z represent W, X4 and Z as defined in relation to Formula (lb) or a group convertible to W, X4 or Z may be prepared from the corresponding ketones as, e.g., compound 1- Scheme 4. by the synthetic procedures described in United States patent application cited above, i.e., 07/862,030 filed 2 April 1992 ; syntheses of such ketone starting materials are described in the aforementioned co-pending application (s) USSN 07/862,083 and its noted progeny.
  • the Z and X4 groups may require protection during the coupling and/or reductive steps described herein, followed by deprotection, to provide the Formula (la) and (lb) compounds, as in processes described in a co-pending application U.S. assigned to the same owner and filed on even date herewith; such protective groups are well known to those skilled in the art. (See: Greene, T. and Wuts, P.G.M., Protecting Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons, New York, 1991.)
  • diat compounds of die Formula (I) and (lb) 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 illustrate the invention and are not intended to limit it in any fashion. Reference is made to the claims for what is reserved to the inventor hereunder.
  • the inhibitory effect of compounds of Formulas (la) or (lb) on in vitro TNF production by human monocytes may be determined by the protocol as described in
  • Example 1 demonstrated a positive in vivo response in reducing serum levels of TNF induced by the injection of endotoxin.
  • Formulas (la) or (lb) 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 HI, 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 163 homogeneity by the sequential use of anion-exchange followed by heparin-Sepharose chromatography [Torphy etal, 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 ⁇ M range for compounds of the workings examples described herein for Formula (I) have been demonstrated.

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Abstract

La présente invention se rapporte à de nouveaux dimères 4,4-(disubstitué)cyclohexane-1-carboxylate et à leurs composés apparentés, aux compositions pharmaceutiques contenant ces composés, et à leur utilisation dans le traitement des allergies et des états inflammatoires ainsi que dans l'inhibition de la production du facteur de nécrose tumorale (TNF).
PCT/US1995/013384 1994-12-23 1995-10-10 Dimeres 4,4-(disubstitue)cyclohexane-1-carboxylate et composes apparentes WO1996020163A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP8520436A JPH10511392A (ja) 1994-12-23 1995-10-10 ４，４−（二置換）シクロヘキサン−１−カルボキシレートダイマーおよび関連化合物
EP95938781A EP0799187A4 (fr) 1994-12-23 1995-10-10 Dimeres 4,4-(disubstitue)cyclohexane-1-carboxylate et composes apparentes

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US36271294A 1994-12-23 1994-12-23
US08/362,712 1994-12-23

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WO1996020163A1 true WO1996020163A1 (fr) 1996-07-04

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Publication number Priority date Publication date Assignee Title
JP3333510B2 (ja) * 1991-10-02 2002-10-15 スミスクライン・ビーチャム・コーポレイション 抗アレルギー、抗炎症および腫瘍壊死因子抑制活性を有するシクロペンタンおよびシクロペンテン誘導体
US5552438A (en) * 1992-04-02 1996-09-03 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Abstract No. 143338, Volume 123, issued 13 April 1995, CHRISTENSEN S., "Preparation of Cyanocyclohexane Compounds as Tumor Necrosis Factor Inhibitors". *
See also references of EP0799187A4 *

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