EP0796092A1 - Dimeres de 3,3-(disubstitue)cyclohexan-one et composes apparentes - Google Patents

Dimeres de 3,3-(disubstitue)cyclohexan-one et composes apparentes

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Publication number
EP0796092A1
EP0796092A1 EP95943940A EP95943940A EP0796092A1 EP 0796092 A1 EP0796092 A1 EP 0796092A1 EP 95943940 A EP95943940 A EP 95943940A EP 95943940 A EP95943940 A EP 95943940A EP 0796092 A1 EP0796092 A1 EP 0796092A1
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EP
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Prior art keywords
independendy
substituted
alkyl
unsubstituted
cr4r5
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EP95943940A
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German (de)
English (en)
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EP0796092A4 (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 EP0796092A1 publication Critical patent/EP0796092A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • 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
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—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 change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—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 by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups

Definitions

  • the present invention relates to novel dimers of certain 3,3- (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. Identification of novel therapeutic agents for asthma is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all three components of chronic asthma.
  • An alternative to the "mediator approach” is to regulate the activity of the cells responsible for the pathophysiology of the disease. One such way is by elevating levels of cAMP (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.
  • 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 resorption 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), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
  • AIDS acquired immune deficiency syndrome
  • AIDS AIDS
  • ARC AIDS related complex
  • keloid formation scar tissue formation
  • Crohn's disease Crohn's disease
  • ulcerative colitis ulcerative colitis
  • pyresis in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
  • HIV Human Immunodeficiency Virus
  • HTV Human Immunodeficiency Virus
  • 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 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 HTV 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, 162:211-214,1990]. 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 die excessive and/or unregulated production of TNF.
  • Rl is independendy -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4RR4R5)mR6, or -(CR4R5)rR6 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 selected hydrogen or C 1-2 alkyl;
  • R6 is independendy hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCl-3 alkyl, halo substituted aryloxyCl-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 may be unsubstituted or substituted by 1 to 3 methyl groups, an ethyl group, or an hydroxyl group; provided tiiat: a) when R6 is
  • X is independendy YR2, fluorine, NR4R5, or formyl amine
  • Y is independendy O or S(O)m'; m' is 0, 1, or 2;
  • X2 is independendy O or NR8;
  • X3 is independendy hydrogen or X
  • R2 is independendy selected from -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more fluorines; s is 0 to 4;
  • R7 is independendy -(CR4R5)qRl2 or C 1. alkyl wherein the R 12 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, -NRJQRI 1, -C(O)R8, -CO2R8, -O(CH 2 ) q R8, -CN, -C(O)NRi()Rl 1.
  • Rl2 is independendy R13, C3-C7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, mo holinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl;
  • R is independendy selected from hydrogen or R9;
  • R9 is independendy Cj_4 alkyl unsubstituted or substituted by one to tiiree fluorines;
  • RjO is independendy OR8 or Ri 1;
  • R ⁇ 1 is independently hydrogen, or C 1.4 alkyl unsubstituted or substituted by one to tiiree fluorines; or when Rio and Ri 1 are as NR10R11 they may together with the nitrogen form a 5 to 7 membered ring unsubstituted comprised of carbon or carbon and at least one heteroatom selected from O, N, or S;
  • Rl3 is independendy oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or diiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C ⁇ _2 alkyl groups;
  • Rj4 is independendy hydrogen or R7; or when Re 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 at least one heteroatoms selected from O, N, or S;
  • Rl5 is independendy C(O)Ri4, C(O)NR4Rl4, S(O)2R7, or S(O)2NR4Rl4; or the pharmaceutically acceptable salts thereof.
  • Rl is independendy -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(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 independendy selected hydrogen or C 1-2 alkyl;
  • R6 is independendy hydrogen, mediyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCl-3 alkyl, indanyl, indenyl, C7-H polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloallcyl containing one or two unsaturated bonds, wherein die cycloalkyl and heterocyclic moieties may be 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 hydroxy
  • X is independendy YR2, fluorine, NR4R5, or formyl amine; Y is independendy O or S(O)m'; m' is O, l, or 2;
  • X2 is independently O or NR8;
  • X3 is independendy hydrogen or X;
  • W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;
  • R2 is independendy selected from -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more fluorines; s is 0 to 4;
  • Z' is independendy COOR14, C(O)ORi4, C(Y * )NR ⁇ oRl4, C(NR ⁇ o)NRi()Rl4, CN, C(NOR8)Rl4, C(O)NRsNR8C(O)R8, C(O)NRsNR ⁇ oRl4, C(NORi4)R8, C(NR8)NRioRl4, C(NRi4)NR ⁇ R8 C(NCN)NR ⁇ oRl4, C(NCN)SR9, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[ 1,2,3]), (3- or 5-triazolyl[ 1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[ 1,2,4]), (2-oxadiazolyl[l,3,4]), (2-thiadiazolyl[ 1,3,4]), (2-
  • Rl2 is independendy C3-7 cycloall yl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, mo ⁇ holinyl, furanyl, (2- or 3-thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl;
  • Rg is independendy selected from hydrogen or R9;
  • R9 is independendy C .4 alkyl unsubstituted or substituted by one to three fluorines;
  • R o is independendy OR8 or Ri 1;
  • Rl 1 is independendy hydrogen, or C 1-4 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 of carbon or carbon and at least one heteroatom selected from O, N, or S;
  • R 13 is independendy oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C ⁇ _2 alkyl groups;
  • Rl4 is independendy hydrogen or R7; or when R8 and R14 are as NR8R14 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and at least one 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 (I) and a pharmaceutically acceptable carrier or diluent
  • the invention also relates to a method of mediation or inhibition of die enzymatic activity (or catalytic activity) of PDE TV 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 Q).
  • 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 (HTV), which comprises administering to such human an effective TNF inhibiting amount of a compound of Formula (I).
  • HTV 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 die 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).
  • 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 d e 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 indirecdy, by the TNF inhibitors of Formula (I).
  • viruses include, but are not limited to HTV-1, HTV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and die He ⁇ es 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 (I).
  • HTV human immunodeficiency virus
  • the compounds of this invention may also be used in association widi the veterinary treatment of animals, other than in humans, in need of inhibition of TNF production.
  • TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
  • 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.
  • d e 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 die 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.
  • Preferred compounds are as follows:
  • 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 for the compounds of Formula (I) are CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, C7-11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-2 alkyl unsubstituted or substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2)0-2CH3, -(CH2) l-3 ⁇ (CH2)0-2CH3, and -(CH2)2-4OH.
  • R4 and R5 terms are independendy hydrogen or alkyl.
  • the individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon can unsubstituted or be substituted by fluorine independent of each other to yield, for instance, the preferred Ri substitutions, as noted above.
  • Ri is a C7-11 polycycloalkyl
  • examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2. l]octyl, tricyclo[5.2.1. ⁇ 2.6] c ⁇ eC y t 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, NNR4Rl5,C(CN)2, C(-CN)OC(O)R9, C(-CN)OR9, CRi4C(O)OR8, CR9C(O)NRi3Ri4, 2-(l,3-dithiane), dimediylthio ketal, 2-(l,3-dioxolane), or dimethyl ketal. More preferred are O, NR7, NORi4, NORi5, and 2-(l,3-dioxolane).
  • Preferred X groups for Formula (I) are those wherein X is YR2 and Y is oxygen.
  • the preferred X2 group for Formula (I) is that wherein X2 is oxygen.
  • the preferred X3 group for Formula (I) is that wherein X3 is hydrogen.
  • Preferred R2 groups, where applicable, is a Ci-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 Ci-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 It is most preferred that W be 1,3-butadiynyl.
  • Z' is preferably O or NOR8-
  • R7 moieties include R13, unsubstituted or substituted -(CH2)l- 2(cycl ⁇ propyl), -(CH2)0-2(cyclobutyl), -(CH2)0-2(cyclopentyl), -(CH2)0-2(cyclohexyl), -(CH2)0-2(2-, 3- or 4-pyridyl), (CH2) l-2(2-imidazolyl), (CH2)2(4-m ⁇ holinyl),
  • aPreferred rings when Rio and Ri 1 in the moiety -NR10R11 together witii the nitrogen to which they are attached form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 2-(R8)-l-imidazolyl, 1-pyrazolyl, 3-(R8)-l -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, mo ⁇ holinyl, piperazinyl, 4-
  • the respective rings may be additionally substituted, where applicable, cm an available nitrogen or carbon by the moiety R7 as described herein for Formula (I).
  • R7 includes, but is not limited to, l-(R7)-2-tetrazolyl, 2-(R7)-l-tetrazolyl, 4-(R7)-l-piperazinyl. Where applicable, the ring may be substituted one or more times by R7.
  • Preferred groups for NR8R 14 which contain a heterocyclic ring are 5-(R 14)- 1 - tetrazolyl, 2-(Ri4)-l-imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(Ri4)-l-piperazinyl, or
  • Preferred rings for R 13 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]),
  • 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-
  • Ri is -CH2-cyclopropyl, -CH2-3- hydroxycyclopropyl, -CH2-3-hydroxycyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H;
  • X is YR2;
  • Y is oxygen;
  • X2 is oxygen;
  • X3 is hydrogen;
  • W is 1,3- butadiynyl, and R2 is CF2H or methyl, and R3 is COOR14 or R7.
  • the compound specifically illustrated herein is l,4-bis- ⁇ [3-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-one]-3-yl ⁇ buta-l,3-diyne.It will be recognized tiiat some of the compounds of Formula (I) or (II) may exist in both racemic and optically active forms; some may also exist in distinct diastereomeric forms possessing distinct physical and biological properties. All of these compounds are considered to be within the scope of the present invention.
  • C1.3 alkyl C1.4 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 die chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl, rerr-butyl, and the like.
  • Alkenyl means both straight or branched chain radicals of 1 to 6 carbon lengths, unless die 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.
  • Heteroaryl means an aromatic ring system containing one or more heteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or diienyl.
  • Halo means all halogens, i.e., chloro, fluoro, bromo, or iodo.
  • “Inhibiting die production of IL-1” or “inhibiting die 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, eidier 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
  • bodi 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 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) are useful in the method of inhibiting die 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 die enzymatic or catalytic activity of PDE IV and in treatment of disease states mediated thereby.
  • salts of the instant compounds where they can be prepared, are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt wdl retain the biological activity of d e parent compound and the 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 the present invention comprise a pharmaceutical carrier or diluent and some amount of a compound of the formula (I).
  • the compound may be present in an amount to effect a physiological response, or it may be present in a lesser amount such that the user will need to take two or more units of the composition to effect the treatment intended.
  • These compositions may be made up as a solid, liquid or in a gaseous form. Or one of these three forms may be transformed to another at the time of being administered such as when a solid is delivered by aerosol means, or when a liquid is delivered as a spray or aerosol.
  • the nature of d e composition and the pharmaceutical carrier or diluent will, of course, depend upon die intended route of administration, for example parenterally, topically, orally or by inhalation.
  • composition wdl 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.
  • 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 paraf ⁇ ns and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide.
  • die pharmaceutical carrier or diluent 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 die instant compositions.
  • additional ingredients do not have a detrimental effect on the therapeutic action of die instant compositions.
  • the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of die active ingredient.
  • the dduent 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 die symptoms of a disease in which leukotrienes are a factor.
  • Topical formulations will contain between about 0.01 to 5.0% by weight of die active ingredient and will be applied as required as a preventative or curative agent to die affected area.
  • the dosage of the composition is selected from die 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, may be prepared by the processes disclosed herein which comprise, for example, coupling of a molecule of die Formula 1- Scheme 1 with a molecule of die 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/metiianol/water, as in the method of Eglington and Galbraith (J. Chem. So ⁇ , 1959, 889), to provide a compound of die Formula __ Scheme 1.
  • an appropriate metal salt such as cupric acetate
  • a suitable solvent such as DMF or pyridine
  • a combination such as pyridine/metiianol/water
  • 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 to a compound of die 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 metiiod of Jutz (Bex., 1958, 91, 1867) or that of Suzuki and Kurosawa (Chem. Lett., 1980, 1177).
  • Reduction of a compound of die 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, to provide a compound of die 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 Formula (II), wherein W is a 1,3-butadiyne and wherein Z' represents Z' as defined in relation to Formula (IT) 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 2 with a molecule of d e 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 die Formula __ Scheme 2.
  • an appropriate metal salt such as cupric acetate
  • a suitable solvent such as DMF or pyridine
  • a combination such as pyridine/methanol/water
  • a) Cu(OAc )_*H 2 0, DMF or C 5 H 5 N Reduction of a compound of die Formula (II), wherein W is a 1,3-butadiyne to a compound of the Formula (II) 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 die method of Jutz (Ber., 1958, 91, 1867) or that of Suzuki and Kurosawa (Chem. Lett., 1980, 1177).
  • Reduction of a compound of die Formula (II), wherein W is a 1 ,3- butadiyne, to provide a compound of die Formula (II) 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 die Formula (II), wherein W and Z' represent W and Z' as defined in relation to Formula (II) or a group convertible to W or Z' may be prepared from the corresponding ketones of the Formula (I) as, e.g., compound 1-Scheme 2, by the synthetic procedures described in United States patent application 08/130213 filed 01 October 1993 and its progeny USSN 08209039 filed 09 March 1994.
  • this solution was cannulated into a solution of dimethylaluminum chloride (1.0 M in hexanes, 13.96 mL, 13.96 mmol). After 3.5 h at room temperature, the mixture was filtered through Celite® under an argon atmosphere. In a separate flask, diisobutylaluminum hydride (1.0 in toluene, 1.4 mL, 1.4 mmol) was added dropwise to a stirred mixture of nickel acetylacetonate (360 mg, 1.4 mmol) in dry edier (25 mL) at 0°C under an argon atmosphere.
  • diisobutylaluminum hydride 1.0 in toluene, 1.4 mL, 1.4 mmol
  • Formula (I) can be determined using a battery of five distinct PDE isozymes.
  • the tissues used as sources of die different isozymes are as follows: 1 ) PDE lb, porcine aorta; 2) PDE
  • Ic guinea-pig heart
  • PDE HI guinea-pig heart
  • PDE TV human monocyte
  • PDE V canine trachealis.
  • PDEs la, lb, Ic and m are partially purified using standard chromatographic techniques [To ⁇ hy and Cieslinski, Mol. Pharmacol.,
  • PDE IV is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-Sepharose chromatography [To ⁇ hy et al., J. Biol.
  • Phosphodiesterase activity is assayed as described in the protocol of To ⁇ hy and

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Abstract

Cette invention concerne certains dimères de phénylcyclohexan-3-ones, utiles dans le traitement d'allergies et de maladies inflammatoires, entre autres.
EP95943940A 1994-12-23 1995-12-21 Dimeres de 3,3-(disubstitue)cyclohexan-one et composes apparentes Withdrawn EP0796092A4 (fr)

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US363166 1982-03-29
US36316694A 1994-12-23 1994-12-23
PCT/US1995/016708 WO1996019980A1 (fr) 1994-12-23 1995-12-21 Dimeres de 3,3-(disubstitue)cyclohexan-one et composes apparentes

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993019750A1 (fr) * 1992-04-02 1993-10-14 Smithkline Beecham Corporation Composes efficaces dans le traitement de maladies allergiques ou inflammatoires
WO1996020159A1 (fr) * 1994-12-23 1996-07-04 Smithkline Beecham Corporation Monomeres d'acetate 3,3-hexamethylene (bisubstitue)-1-ylidine et composes connexes

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US4391827A (en) * 1980-09-08 1983-07-05 Pfizer Inc. 3-(2-Hydroxy-4-(substituted)phenyl)-cycloalkanone and cycloalkanol analgesic agents and intermediates therefor
GB9007762D0 (en) * 1990-04-05 1990-06-06 Beecham Group Plc Novel compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993019750A1 (fr) * 1992-04-02 1993-10-14 Smithkline Beecham Corporation Composes efficaces dans le traitement de maladies allergiques ou inflammatoires
WO1996020159A1 (fr) * 1994-12-23 1996-07-04 Smithkline Beecham Corporation Monomeres d'acetate 3,3-hexamethylene (bisubstitue)-1-ylidine et composes connexes
WO1996020690A2 (fr) * 1994-12-23 1996-07-11 Smithkline Beecham Corporation Monomeres de 3,3-(disubstitue)cyclohexan-1-ylidine acetate et composes apparentes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9619980A1 *

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