WO1995009837A1 - Composes cyano - Google Patents

Composes cyano Download PDF

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Publication number
WO1995009837A1
WO1995009837A1 PCT/US1994/010817 US9410817W WO9509837A1 WO 1995009837 A1 WO1995009837 A1 WO 1995009837A1 US 9410817 W US9410817 W US 9410817W WO 9509837 A1 WO9509837 A1 WO 9509837A1
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Prior art keywords
cr4r5
alkyl
optionally substituted
hydrogen
formula
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PCT/US1994/010817
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English (en)
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Siegfried Benjamin Christensen, Iv
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Smithkline Beecham Corporation
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Publication of WO1995009837A1 publication Critical patent/WO1995009837A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
    • 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
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to novel 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 modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of 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.
  • PDEs cyclic nucleotide phosphodiesterases
  • PDE -TV 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 resoiption 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.
  • HTV Human Immunodeficiency Virus
  • HIV-1 HIV-1
  • HIV-2 HIV-2
  • HTV-3 Human Immunodeficiency Virus
  • T- cell-mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms.
  • HIV entry into the T lymphocyte requires T lymphocyte activation.
  • Viruses such as HTV-1 or HTV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HTV 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 HTV 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 have also been implicated in maintenance of the HTV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al., The Immunopathogenesis of . HTV Infection, Advances in Immunology, Vol. 57, 1989]. Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages [See Poli et al., Proc. Na . 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 cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
  • CMV cytomegalovirus
  • influenza virus influenza virus
  • adenovirus adenovirus
  • 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,
  • This invention relates to the novel compounds of Formulas (I) and (II) as shown below, useful in the mediation or inhibition of the enzymatic activity (or catalytic activity) of phosphodiesterase IV (PDE IV). These compounds also have Tumor Necrosis Factor (TNF) inhibitory activity.
  • TNF Tumor Necrosis Factor
  • This invention also relates to the pharmaceutical compositions comprising a compound of Formulas (I) or (II) 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 TV in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I) or (II) as shown below.
  • the invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I) or (II).
  • 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) or (II).
  • 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) or (II).
  • 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) or (II).
  • HTV human immunodeficiency virus
  • Compounds of Formula (I) or ( ⁇ ) 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) or (II) 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.
  • R! is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5) n O(CR4R5) m R6, or -(CR4R5) r R6 wherein the alkyl moieties may be optionally substituted with one or more halogens; m is 0 to 2; n is 1 to 4; r is 0 to 6;
  • R4 and R5 are independently selected from hydrogen or a Cl-2 alkyl
  • R6 s hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-H 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 and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when R is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is
  • X is YR2, halogen, nitro, NR4R5, or formyl a ine; Y is O or 8(0) 1 x 1 '; m' is 0, 1, or 2;
  • X2 is O or NR8;
  • X3 is hydrogen or X;
  • R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4;
  • Z is S(O)m'R9, OS(O)2R9, OR9, OC(O)NR7R9, OC(O)(O) q R7, O(CR4R5)nOR9, or NR9R9;
  • Z' is O, NR8, NNR8R8, NOR8, NCN, C(-CN)2, CR ⁇ CN, CR8NO2, CR8C(O)OR8, CR8C(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NR8R8; q is 0 or 1;
  • R7 is independently hydrogen or R9;
  • R is independently selected from hydrogen or C 1.4 alkyl optionally substituted by one to three fluorines, or when R8 and Rio are as -NRsRlO they may together with the nitrogen form a a 5 to 7 membered ring optionally containing one or more additional heteroatom selected from O, N, or S; R 1 is R8 or fluorine;
  • R9 is independently Cl-10 alkyl, C2-10 alkenyl, C3-7cycloalkyl, C4-6 cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which may be optionally substituted by one or more fluorine atoms, or two R9 terms appearing as NR9R9 may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S;
  • R 10 is OR8 or R8; provided that: f) when q is 1 in OC(O)(O)qR7 , then R7 is not hydrogen; g) when Z' is NR ⁇ , then R8 is not hydrogen; or the pharmaceutically acceptable salts thereof.
  • the other set of compounds of this invention are represented by Formula (II):
  • Z" is C(Y')Rl4, C(O)ORi4, C(Y')NRioRl4, C(NRio)NR ⁇ oRl4, CN, C(NOR8)Rl4, C(NORi4)R8, C(NR8)NR ⁇ oRl4, C(NRi4)NRsR8 C(NCN)NRioRl4, C(NCN)SRn, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[l,2,3]), (3- or 5-triazolyl[l,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[ 1,2,4]),
  • Rll i s Cl-4 alkyl optionally substituted by one to three fluorines
  • Rl2 is C3-7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2- imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl;
  • R13 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon
  • R 4 is hydrogen or R15; or when Rio and R14 are as NR10R14 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O/N/or S;
  • Rl5 is -(CR4R5) t Rl2 or C ⁇ . alkyl wherein the R12 or C ⁇ _6 alkyl group is optionally substituted one or more times by C ⁇ _2 alkyl optionally substituted by one to three fluorines, -F, -Br, -Cl, -NO2, -Si(R4)2, -N sRio, -C(O)R8, -C(O)OR8, - OR8, -CN, -C(O)NR 8 Ri 0 , -OC(O)NR 8 R ⁇ 0 , -OC(O)Rg, -NRioC(O)NR 8 R 10 , -NRi ⁇ C(O)R8, -NRi ⁇ C(O)OR9, -NRioC(O)Ri3, -C(NR ⁇ o)NR 8 R ⁇ 0 , -C(NCN)NR 8 R ⁇ o, -C(NCN)SRn, -NRi
  • This invention also relates to a method of mediating or inhibiting the enzymatic activity (or catalytic activity) of PDE TV 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) or (II).
  • Phosphodiesterase TV 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) or (II).
  • viruses include, but are not limited to HTV-1, HTV-2 and HTV-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) or ( ⁇ ).
  • 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.
  • 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) or (II) may be administered in conjunction with other drugs of choice for systemic yeast and fungal infections.
  • Drugs of choice for fungal infections include but are not limited to the class of compounds called the polymixins, such as Polymycin B, the class of compounds called the imidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; the class of compounds called the triazoles, such as fluconazole, and itranazole, and the class of compound called the Amphotericins, in particular Amphotericin B and liposomal Amphotericin B.
  • 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) or (II) 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) or (II) to a mammal in need of such treatment.
  • a compound of Formula (I) or (II) 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.
  • Rl substitutents for the compounds of the Formula (I) are CH2-cyclopropyl, CH2- C5-6 cycloalkyl, C4-6 cycloalkyl, C7-H 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)l-3 ⁇ (CH2)0-2CH3, and -(CH 2 )2-4OH.
  • 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 Rl substitutions, as noted above.
  • Rl is a C7-H polycycloalkyl
  • examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0 2 » 6 ]decyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987, whose disclosure is incorporated herein by reference in its entirety.
  • Z is S(O)m'R9, OS(O)2R9, OR9, OC(O)NR7R9, OC(O)(O) q R7, O(CR4R5) n OR9, or NR9R9 in compounds of the Formula (I) and also NHR14 in compounds of the Formula (II).
  • q is 0.
  • Preferred Z terms are S(O) m 'R9, OS(O)2R9, OR9, OC(O)NR7R9, 0(CR4R5) n OR9, or NR9R9 in compounds of the Formula (I) and also NHR14 in compounds of the Formula (II).
  • Z" in Formula (II) is preferably C(O)Ri4, C(O)ORi4, C(O)NR ⁇ oRl4,
  • Preferred X groups for Formulas (I) and (II) are those wherein X is YR2 and Y is oxygen.
  • the preferred X2 group Formulas (I) and (II) is that wherein X2 is oxygen.
  • the preferred X3 group is hydrogen.
  • Preferred R2 groups, where applicable, are a C 1-2 alkyl optionally 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.
  • R3 moieties are C(O)NH2, C ⁇ CR ⁇ , CN, C(Z')H, CH2OH, CH2F, CF2H, and CF3.
  • Z' is preferably O or NOR8- More preferred are C ⁇ CH and CN.
  • R15 moieties include optionally substituted -(CH2)l- 2(cyclopropyl), -(CH2)0-2(cyclobutyl), -(CH2)0-2(cyclopentyl), -(CH2)0- 2(cyclohexyl), -(R4R5)0-2(2-, 3- or 4-pyridyl), (R4R5)i-2(2-imidazolyl), (R4R5)2(4-morpholinyl), (R4R5)2(4-piperazinyl), (R4R5)i-2(2-thienyl), (R4R5)i-2(4-thiazolyl), and (R4R5) ⁇ -2phenyl; Preferred rings when the two R9 terms in the moiety NR9R9 together with the nitrogen to which they are attached form a a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N or S include, but are not limited to, the morpholinyl, piperazinyl, or
  • Preferred rings when R8 and Rio in the moiety -NR8R10 together with the nitrogen to which they are attached form a a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 2-(R8)-l-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-(R8)-l -piperazinyl, or pyrrolyl ring.
  • the respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R15 as described herein for Formula (II).
  • Illustrations of such carbon substitutions includes, but is not limited to, 2-(Ri5)-l-imidazolyl, 4-(Rl5)-l-imidazolyl, 5-(Rl5)-l-imidazolyl, 3-(Rl5)-l-pyrazolyl, 4-(Rl5)- 1-pyrazolyl, 5-(R 15)- 1-pyrazolyl, 4-(Ri5)-2-triazolyl, 5-(Rl5)-2-triazolyl, 4-(R 15)- 1-triazolyl, 5-(Ri5)-l-triazolyl, 5-(Ri5)- 1-tetrazolyl, and 5-(Ri5)-2-tetrazolyl.
  • R15 includes, but is not limited to, l-(Ri5)-2-tetrazolyl, 2-(Ri5)-l-tetrazolyl, 4-(Ri5)-l-piperazinyl. Where applicable, the ring may be substituted one or more times by R15.
  • Preferred groups for -NR10R14 which contain a heterocyclic ring are 5- (Rl4)-l-tetrazolyl, 2-(R 14)- 1-imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(Ri4)-l- piperazinyl, or 4-(Ri5)-l-piperazinyl.
  • Preferred rings for R13 include (2-, 4- or 5-imidazolyl), (3-, 4- or
  • 5-pyrazolyl (4- or 5-triazolyl[l,2,3]), (3- or 5-triazolyl[l,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 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-C5-6 cycloalkyl, -C4-6 cycloalkyl, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -Ci-2 alkyl optionally substituted by 1 or more fluorines, and -(CH2)2-4 OH;
  • R2 is methyl or fluoro-substituted alkyl, R3 is CN or C ⁇ CR ⁇ ; and
  • X is YR2.
  • Rl is -CH2-cyclopropyl, cyclopentyl, methyl or CF2H
  • R3 is CN or C ⁇ CH
  • X is YR2
  • Y is oxygen
  • X2 is oxygen
  • X3 is hydrogen
  • R2 is CF2H or methyl.
  • a preferred subgenus of the compounds of the Formula (I) is the compounds of the Formula (la)
  • Rl is CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, C7-H polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or Ci- 2 alkyl optionally substituted by 1 or more fluorines, -(CH2)1-3C(O)O(CH2)0-2CH3, -(CH2)l-3 ⁇ (CH2)0-2CH3, and -(CH2)2-4OH;
  • X is YR2 » halogen, nitro, NR4R5, or formyl amine
  • R2 is -CH3 or -CH2CH3 optionally substituted by 1 or more halogens;
  • R3 is hydrogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, fluoro-substituted C1-4 alkyl, CN, CH2OR8, C(Z')H, C(O)ORs, C(O)NR8Rl0, or C ⁇ CR ⁇ ;
  • Z is S(O) m -R9, OS(O)2R9, OR9, OC(O)NR7R9, OC(O)(O) q R7, O(CR4R5)nOR9, or NR9R9; Z' is O or NOR8; q is O or 1;
  • R7 is independently hydrogen or R9;
  • Rg is independently selected from hydrogen or C .4 alkyl optionally substituted by one to three fluorines;
  • R8' is R8 or fluorine
  • R9 is independently Ci-io alkyl, C2-10 alkenyl, C3-7cycloalkyl, C4-6 cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which may be optionally substituted by one or more fluorine atoms, or two R9 terms appearing as NR9R9 may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O/N/or S;
  • Rl ⁇ is OR8 or R8; provided that: f) when q is 1 in OC(O)(O)qR7 , then R7 is not hydrogen; g) when Z' is NR8 then R8 is not hydrogen; or the pharmaceutically acceptable salts thereof.
  • Exemplified compounds of Formula (I) are:
  • C1.3 alkyl includes 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.
  • 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.
  • Hetero 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 EL-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 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 Formulas (I) and (II) are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal, including humans, in need thereof. All of the compounds of Formulas (I) and (II) are useful in the method of inhibiting or mediating the enzymatic or catalytic activity of PDE TV and in treatment of disease states mediated thereby.
  • Rl represents Rl as defined in relation to Formula (I) or a group convertable to Rl and X
  • X2 and X3 represent X, X2 and X3 as defined in relation to Formula (I) or a group convertable to X
  • X2 or X3 and R2 and R3 represent R2 and R3 as defined in relation to Formula (I) or a group convertable to R2 or R3 andwherein X or X3 is other than Br, I, NO2, amino, or S(O)m'R2 when m' is 0, 1 or 2, with a suitable base in a suitable non-reacting solvent followed by reaction with a suitable alkylating or acylating agent [LS(O)2R9, LR9, L(CR4R5)nOR9, LC(O)(O)qR7, or LC(O)NR7R9, wherein L is a leaving group] to provide compounds of the Formula (I) wherein Z is OS(O)2R9, OR9
  • Compounds of the Formula (2) may be prepared in turn by the processes described in the application filed on even date herewith and identified as P50109.
  • Some compounds of the Formula (II) may be prepared by processes analogous to those above by reacting the appropriate reagent with a compound of the Formula (3)
  • Rl represents Rl as defined in relation to Formula (I) or a group convertable to Rl and X
  • X2 and X3 represent X, X2 and X3 as defined in relation to Formula (I) or a group convertable to X
  • X2 or X3 and R3 represents R3 as defined in relation to Formula (I) or a group convertable to R3 and Z" represents Z" as defined in relation to Formula (I) or a group convertable to Z".
  • Compounds of the Formula (3) may be prepared in turn by the processes described in the application filed on even date herewith and identified as P50197.
  • Some compounds of Formula (II) may be prepared from other compounds of the Formula (II) by, e.g., functional group manipulation of the Z" group either preceeding functional group manipulation of the Z group or, in some cases, with appropriate protection and deprotection of chemically sensitive Z group functionality during functional group manipulation of the Z" group.
  • Some such manipulations of the Z" group may be accomplished by the processes described in U.S. application serial number 862,030 filed 2 April 1992 and its corresponding continuation-in-part application USSN 968,762 filed 30 October 1992.
  • the compounds of Formula (I) or (II), or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylatic or therapeutic treatment of any disease state in a human or other mammal which is mediated by inhibition of PDE TV, such as but not limited to asthma, allergic, or inflammatory diseases.
  • the compounds of Formula (I) or (II) are administered in an amount sufficient to treat such a disease in a human or other mammal.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the amount of a compound of Formula (I) or (II) required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the condition and the animal undergoing treatment, and is ultimately at the discretion of the physician.
  • the daily dosage regimen for oral administration is suitably about .001 mg kg to lOOmg kg, preferably 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof calculated as the free acid or base, which ever is appropriate.
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit activity.
  • inhibitory effect of compounds of Formula (I) or (II) on in vitro TNF production by human monocytes may be determined by the protocol as described in Badger et al., EPO published Application 0411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990.
  • EXAMPLE B Two models of endotoxic shock have been utilized to determine in vivo TNF activity for the compounds of this invention. The protocol used in these models is described in Badger et al., EPO published Application 0411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990.
  • Example 1 demonstrated a positive in vivo response in reducing serum levels of TNF induced by the injection of endotoxin.
  • the phosphodiesterase inhibitory activity and selectivity of the compounds of of this invention.s 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 HI 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., 267:1798- 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 compounds of this invention have been demonstrated.
  • EXAMPLE D The ability of selected PDE TV inhibitors to increase cAMP accumulation in intact tissues is assessed using U-937 cells, a human monocyte cell line that has been shown to contain a large amount of PDE IV.
  • U-937 cells a human monocyte cell line that has been shown to contain a large amount of PDE IV.
  • nondifferentiated U-937 cells approximately 10*5 cells/reaction tube
  • PDE inhibitors for one minute
  • l ⁇ M prostaglandin E2 for an additional four minutes.
  • Five minutes after initiating the reaction cells were lysed by the addition of 17.5% perchloric acid, the pH was neutralized by the addition of 1M potassium carbonate and cAMP content was assessed by RIA.

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Abstract

L'invention concerne des nouveaux composés inhibant la production du facteur de nécrose tumorale. Ces composés sont utiles dans le traitement de pathologies induites ou aggravées par la production dudit facteur ainsi que pour induire ou inhiber l'activité enzymatique et catalytique de la phosphodiestérase IV.
PCT/US1994/010817 1993-10-01 1994-09-23 Composes cyano WO1995009837A1 (fr)

Applications Claiming Priority (2)

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US13034693A 1993-10-01 1993-10-01
US08/130,346 1993-10-01

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WO2004016596A1 (fr) * 2002-08-19 2004-02-26 Glenmark Pharmaceuticals Limited Composes condenses heterocycliques utilises comme inhibiteurs de pde-iv dans le traitement de troubles inflammatoires et allergiques
US7223789B2 (en) 2003-04-11 2007-05-29 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
US7238725B2 (en) 2002-10-23 2007-07-03 Glenmark Pharmaceuticals Ltd. Tricyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
US7563900B2 (en) 2004-10-13 2009-07-21 Glenmark Pharmaceuticals S.A. Process for the preparation N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methane sulfonamido-dibenzo[b,d]furan-1-carboxamide
US7943634B2 (en) 2004-12-17 2011-05-17 Glenmark Pharmaceuticals S.A. Substituted benzo[4,5]furo[3,2-c]pyridine derivatives as PDE 4 inhibitors
US8129401B2 (en) 2004-12-17 2012-03-06 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them

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CHEMICAL ABSTRACTS, Vol, 115, issued 1991, SOLOMINA et al., "Synthesis of 6,7-Dimethoxy-2-Methyl-4,4'-Spiro-1'-(3-Amino-2- Hydroxypropoxy)Cyclohexane-1,2,3,4- Tetrahydroisoquinolines and Their Biological Activity", Abstract No. 8542s. *
CHEMICAL ABSTRACTS, Vol. 120, issued 1994, CHRISTENSEN et al., "Cyclohexylbenzones Useful for Treating Allergic or Inflammatory Diseases", Abstract No. 191326q. *
CHEMICAL ABSTRACTS, Vol. 120, issued 1994, CHRISTENSEN et al., "Preparation of Arylcyclohexanes Useful and for Inhibiting Production of Tumor Necrosis Factor", Abstract No. 163532k. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004016596A1 (fr) * 2002-08-19 2004-02-26 Glenmark Pharmaceuticals Limited Composes condenses heterocycliques utilises comme inhibiteurs de pde-iv dans le traitement de troubles inflammatoires et allergiques
US7238725B2 (en) 2002-10-23 2007-07-03 Glenmark Pharmaceuticals Ltd. Tricyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
US7223789B2 (en) 2003-04-11 2007-05-29 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
US7384962B2 (en) 2003-04-11 2008-06-10 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
US7393846B2 (en) 2003-04-11 2008-07-01 Glenmark Pharmaceuticals, S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders
US7563900B2 (en) 2004-10-13 2009-07-21 Glenmark Pharmaceuticals S.A. Process for the preparation N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methane sulfonamido-dibenzo[b,d]furan-1-carboxamide
US7943634B2 (en) 2004-12-17 2011-05-17 Glenmark Pharmaceuticals S.A. Substituted benzo[4,5]furo[3,2-c]pyridine derivatives as PDE 4 inhibitors
US8129401B2 (en) 2004-12-17 2012-03-06 Glenmark Pharmaceuticals S.A. Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them

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