EP0799031A1 - Dimeres de 1,4,4-(trisubstitue)cyclohexane et composes apparentes - Google Patents

Dimeres de 1,4,4-(trisubstitue)cyclohexane et composes apparentes

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Publication number
EP0799031A1
EP0799031A1 EP95943946A EP95943946A EP0799031A1 EP 0799031 A1 EP0799031 A1 EP 0799031A1 EP 95943946 A EP95943946 A EP 95943946A EP 95943946 A EP95943946 A EP 95943946A EP 0799031 A1 EP0799031 A1 EP 0799031A1
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EP
European Patent Office
Prior art keywords
independently selected
cr4r5
alkyl
crδrδ
hydrogen
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.)
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Application number
EP95943946A
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German (de)
English (en)
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EP0799031A4 (fr
Inventor
Siegfried B. Christensen, Iv
Joseph M. Karpinski
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of EP0799031A1 publication Critical patent/EP0799031A1/fr
Publication of EP0799031A4 publication Critical patent/EP0799031A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/52—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C43/253—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring containing hydroxy or O-metal groups
    • 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 1 ,4,4-(trisubstituted)cyclohexane 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.
  • an elevation of cAMP 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 the pharmacotherapy of bronchial asthma and possess significant 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
  • 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 as HIV-1 or HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation.
  • 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/or HIV 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.
  • 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, 162:21 1-214,1990]. 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
  • Rj is independently selected from -(CR4R5)nC(O)O(CR4R5) m R6,
  • 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, C7-1 1 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
  • X is independently selected from YR2. fluorine, NR4R5, or formyl amine; Y is independently selected from O or S(O)m'; m' is O, 1, or 2;
  • X2 is independently selected from O or NRs
  • X3 is independently selected from hydrogen or X;
  • 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 CR8R8OR14, CR8R8OR15, CR8R8SR14, CR8R8SR15, CR8R8S(O) m -R7, CRsR8NRi ⁇ Rl4, CR8R8NRl ⁇ S(O)2NR ⁇ oRl4,
  • CRsR8NRi ⁇ S(O)2R7 CR8R8NRl ⁇ C(Y')Rl4, CRgR8NR ⁇ oC(O)OR7, CRgR ⁇ NR 1 oC( Y')NR 1 oR 14, CRgR ⁇ NR l ⁇ C(NCN)NR 1 oR 14, CR8R8NR 10C(CR4NO2)NR 1 oR 14, CRsR ⁇ NR l oC(NCN)SR9, CR8R8NR ⁇ C(CR4N ⁇ 2)SR9, CRgR8C(O)ORi4, CR8R8C(Y )NR ⁇ oRl4, CR8R8C(NRio)NRioRl4.
  • CR8R8NR 1 oQNR i o)SR9 CR ⁇ R ⁇ NR 1 OQNR i o)NR i OR 14, CR8R8NRl ⁇ C(O)C(O)NRioRl4, or CRsR8NRl ⁇ C(O)C(O)ORi4;
  • X5 is H, R9, OR8, CN, C(O)R8, C(O)OR ⁇ , C(O)NRsR8, or NR8R8;
  • X is independently H, R9, OR8, CN, C(O)R ⁇ , C(O)OR8, C(O)NRsR8, or NR 8 R8;
  • Y' is independently selected from O or S;
  • R7 is -(CR4R5)qRi2 or Cj.g alkyl wherein the R12 or C ⁇ .g 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, -NRJQR I 1, -C(O)R8, -CO2R8. -O(CH 2 ) q R8.
  • 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;
  • Rg is independently selected from hydrogen or R9; R9 is independently selected from C ⁇ .4 alkyl optionally substituted by one to three fluorines;
  • RjO is independently selected from ORs or Ri 1 ;
  • Rj is independently selected from hydrogen, or C 1.4 alkyl optionally substituted by one to three fluorines; or when Rio and Ri 1 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
  • Rj4 is hydrogen or R7; or when R8 and R 14 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;
  • R 15 is C(O)Ri4, C(O)NR4Ri4, S(O)2R7, or S(O)2NR4Rl4; 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 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, 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).
  • 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 immunodeficiency virus (FIV) or other retroviral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
  • FMV 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) 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.
  • C1.3 alkyl C ⁇ . alkyl
  • C ⁇ g 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, 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. 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, such as imidazolyl, triazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl.
  • 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.
  • 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
  • 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 affects the functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses.
  • a cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce them.
  • the cytokine inhibited by the present invention for use in the treatment of a HIV-infected human must be a cytokine which is implicated in (a) the initiation and/or maintenance of 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.
  • this 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 compounds 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.
  • 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 (I).
  • 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 Cj-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, C7-1 1 polycycloalkyl, (3- or 4- cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2) ⁇ -2CH3, -(CH2)1-3O(CH )0-2CH , and -(CH 2 )2-4OH.
  • the R4 and R5 terms are independently hydrogen or alkyl.
  • 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 Ri substitutions, as noted above.
  • R ⁇ is a C7-1 1 polycycloalkyl
  • examples are bicyclo[2.2J]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2J]octyl, tricyclo[5.2J. ⁇ 2 ⁇ ]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.
  • Z is preferably CR8R8OR14, CR ⁇ R ⁇ ORlS, CR ⁇ R ⁇ SRl4, CR ⁇ R8SRl5, CR8R8S(O) m 'R7, CR R ⁇ NRl ⁇ Rl4, CR ⁇ R ⁇ NS(O)2NRl ⁇ Rl4, CRsR8NS(O)2R7.
  • X 4 is preferably H, OH, OCH3, CN, C(O)R8, C(O)OH, C(O)OCH3, C(O)NH2, CON(CH3)2, NH2, or N(CH3)2-
  • the most preferred X 4 groups are H, OH, CN, C(O)OH, C(O)NH2 or NH2.
  • 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 C 1-2 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 Cj-2 alkyl, such as a -CF3, -CHF2, or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.
  • R7 moieties include optionally substituted -(CH2)l-2( c ydopropyl), -(CH2)0-2( c yclobutyl), -(CH2)0-2(cyclopentyl) with or without an OH group, -(CH2)0-2(cyclohexyl), -(CH2)0-2(2-, 3- or 4-pyridyl), -(CH2) 1 -2(2-imidazolyl),
  • 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-(R ⁇ )-l-imidazolyl, 1 -pyrazolyl, 3-(R ⁇ )-l -pyrazolyl, 1-triazolyl, 2- triazolyl, 5-(R ⁇ )-l-triazolyl, 5-(R ⁇ )-2-triazolyl, 5-(R8)-l-tetrazolyl, 5-(R ⁇ )-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(Rs)-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, 2JR7)- 1 -imidazolyl, 4JR7)- 1 -imidazolyl, 5-(R7)- 1 -imidazolyl, 3-(R7)- 1 -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)-l-tetrazolyl, and 5-(R7)-2-tetrazolyl.
  • R7 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, the ring can be substituted one or more times by R7.
  • Preferred groups for NR10R14 which contain a heterocyclic ring are 5-(Ri4)- 1-tetrazolyl, 2-(R ⁇ 4)- 1 -imidazolyl, 5-(Ri4)-2-tetrazolyl, or 4-(Ri4)-l-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[l,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).
  • the heterocyclic ring itself may be optionally substituted by R ⁇ either on an available nitrogen or carbon atom, such as l-(R8)-2-imidazolyl, l-(R ⁇ )-4-imidazolyl, l-(R ⁇ )-5-imidazolyl, l-(R ⁇ )-3-pyrazolyl, l-(R ⁇ )-4-pyrazolyl, l-(R ⁇ )-5-pyrazolyl, l-(R ⁇ )-4-triazolyl, or l-(R ⁇ )-5-triazolyl.
  • the ring may be substituted one or more times by Rs-
  • Rj is -CH2- cyclopropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl unsubstituted or substituted with an hydroxyl group, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyI), benzyl or -Ci-2 alkyl optionally substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluoro-substituted alkyl, and W is alkynyl of 2 or 4 carbon atoms.
  • R ⁇ 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, W is 1,3-butadiynyl, and in Z the R ⁇ group is H and the R14 group of Z is R4.
  • 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.
  • 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 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.
  • 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 administration to the skin, eye, ear, or nose.
  • 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 with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, 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 pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.
  • 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.
  • the 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), wherein W is a 1,3-butadiyne and wherein A and B represent Z as defined in relation to Formula (I) or a group convertible to Z and wherein X4 represents X4 as defined in relation to Formula (I) 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 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.
  • Scheme 1
  • Reduction of a compound of the Formula (I), wherein W is a 1,3-butadiyne and wherein Z represents Z as defined in relation to Formula (I) or a group convertible to Z and wherein X4 represents X4 as defined in relation to Formula (I) or a group convertible to X4, 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.
  • Reduction of a compound of the Formula (I), wherein W is a 1,3-butadiyne and wherein Z represents Z as defined in relation to Formula (I) or a group convertible to Z and wherein X4 represents X4 as defined in relation to Formula (I) or a group convertible to X4, to provide a compound of the Formula (I) 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 ( 1 ), wherein W, X4 and Z represent W, X4 and Z as defined in relation to Formula (I) or a group convertible to W, X4 or Z may be prepared from the corresponding ketones as, e.g., compound 1 -Scheme 2. by the synthetic procedures described in copending United States patent applications 07/862112, 07/968760 and PCT application PCT US93/01988 ; syntheses of such ketone starting materials are described in co-pending U.S. applications 07/ ⁇ 620 ⁇ 3, 07/986753 and PCT application number PCT/US93/02325.
  • Scheme 2
  • the Zand X4 groups may require protection during the coupling and or reductive steps described herein, followed by deprotection, to provide the Formula (I) compound, as in processes described in co-pending application described in copending United States patent applications 07/ ⁇ 62112, 07/968760 and PCT application PCT/US93/01988 ; 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.)
  • Example 1 Preparation of 1 ⁇ -bis- ⁇ [c-4-(3-cyclopentyloxy-4-methoxyphenyl)-r- 1 - hydroxymethylcyclohexanl -4-yl ⁇ buta- 1.3-diyne
  • a suspension of 1 ,4-bis- ⁇ [methyl c-4-(3-cyclopentyloxy-4-methoxyphenyl)-r- 1 -cyclohexane ca ⁇ boxylate]-4-yl ⁇ buta-l,3-diyne (0.35 g, 0.52 mmol, prepared as described in a co-pending application filed on even date herewith and identified as P50297) in tetrahydrofuran (3.0 mL) with methanol (0.025 mL) and lithium borohydride (0.04 g, 1.56 mmol) is stirred overnight at room temperature under an argon atmosphere. The reaction mixture is partitioned between methylene chloride and acidic water
  • the reaction flask is covered with foil and the mixture is stirred at room temperature for 30 h.
  • the solvent is evaporated and the residue is purified by flash column chromatography, to provide the product phthalimide, which is dissolved in ethanol (0.5 mL) under an argon atmosphere and is stirred with hydrazine hydrate (0J6 mL, 0.3 mmol) for 3 days.
  • the precipitate is removed by filtration, the filtrate is applied to a silica column and the product is eluted.
  • 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 lc, 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, lc and III are partially purified using standard chromatographic techniques [Torphy and Cieslinski, 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. Biol. Chem., 267: 179 ⁇ -1804, 1992].
  • Phosphodiesterase activity is assayed as described in the protocol of Torphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Positive ICso'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 concerne certains dimères de 1,4,4-(trisubstitué)cyclohexane et leurs composés apparentés, lesquels sont utiles dans le traitement d'allergies et de maladies inflammatoires, ainsi que pour inhiber la production de facteur de nécrose tumorale (TNF).
EP95943946A 1994-12-23 1995-12-21 Dimeres de 1,4,4-(trisubstitue)cyclohexane et composes apparentes Withdrawn EP0799031A4 (fr)

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US36316794A 1994-12-23 1994-12-23
PCT/US1995/016715 WO1996019979A1 (fr) 1994-12-23 1995-12-21 Dimeres de 1,4,4-(trisubstitue)cyclohexane et composes apparentes

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993019747A1 (fr) * 1992-04-02 1993-10-14 Smithkline Beecham Corporation Composes destines a traiter les maladies allergiques et inflammatoires

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993019747A1 (fr) * 1992-04-02 1993-10-14 Smithkline Beecham Corporation Composes destines a traiter les maladies allergiques et inflammatoires

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Title
See also references of WO9619979A1 *

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