WO2008134354A1 - TNF-α PRODUCTION INHIBITOR - Google Patents

TNF-α PRODUCTION INHIBITOR Download PDF

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Publication number
WO2008134354A1
WO2008134354A1 PCT/US2008/061257 US2008061257W WO2008134354A1 WO 2008134354 A1 WO2008134354 A1 WO 2008134354A1 US 2008061257 W US2008061257 W US 2008061257W WO 2008134354 A1 WO2008134354 A1 WO 2008134354A1
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Prior art keywords
optionally substituted
compound
group
inhibitor
groups
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PCT/US2008/061257
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French (fr)
Inventor
David A. Mareska
Robert D. Groneberg
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Array Biopharma, Inc.
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Publication of WO2008134354A1 publication Critical patent/WO2008134354A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a TNF- ⁇ production inhibitor.
  • the present invention relates to a novel compound of formula (I):
  • TNF- ⁇ Tumor necrosis factor alpha
  • MAP Mytogen-activated protein
  • TNF- ⁇ have also been implicated in many other disorders and disease conditions, including metabolic diseases (for example, diabetes mellitus such as insulin-resistant diabetes mellitus or non-insulin- resistant diabetes mellitus), hyperlipemia, other insulin-resistant diseases, inflammatory diseases [for example, inflammation, dermatitis, atopic dermatitis, hepatitis, nephritis, glomerulonephritis, pancreatitis, psoriasis, gout, Addison's disease, arthrititis (for example, rheumatoid arthritis, osteoarthritis, rhumatoid spondylitis, gouty arthritis, synovitis, etc.), inflammatory ocular diseases, inflammatory pulmonary diseases (for example, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), etc.), inflammatory bowel diseases
  • metabolic diseases
  • inhibitors of TNF- ⁇ are potentially useful in the treating of a wide variety of diseases such as metabolic diseases and inflammatory disease.
  • a protein kinase is an enzyme that catalyzes the reaction to transfer a phosphate group from adenosine triphosphate (ATP) to an amino acid residue, such as tyrosine, serine, threonine, and/or histidine in a protein. More than 500 protein kinases have been identified to date.
  • ATP adenosine triphosphate
  • protein kinases play essential and important roles in various and diverse cell functions, such as cell division, cell differentiation, cell death (apoptosis), the alteration of cell motility and cytoskeleton structure, the control of DNA replication, splicing and translation, protein transportation from endoplasmic reticulum or Golgi apparatus into the membrane or extracellular space migration of protein into the nucleus and exportation out of the nucleus, and metabolic reactions.
  • RTK Receptor tyrosine kinases
  • EGFR epidermal growth factor receptor
  • PDGF platelet-derived growth factor receptor
  • RTK Receptor tyrosine kinases
  • EGFR epidermal growth factor receptor
  • PDGF platelet-derived growth factor receptor
  • MAP kinases also play vital roles in the pathophysiology of many diseases by regulating cellular functions such as proliferation, apoptosis, and inflammatory cytokine production.
  • c-Jun which forms transcription factor AP-I complex by associating with c-Fos, is one of the main substrates of MAP kinases, phosphorylation and subsequent activation of c-Jun are suggested to be one of the most important steps of the signaling process of MAP kinases.
  • a compound which inhibits c-Jun phosphorylation is considered to be potentially useful for the therapy of diseases which are triggered by the protein phosphorylation.
  • a compound which inhibits c- Jun phosphorylation would be expected to be useful as a preventing and/or treating agent for metabolic diseases (for example, diabetes mellitus such as insulin-resistant diabetes mellitus or non-insulin-resistant diabetes mellitus), hyperlipemia, other insulin- resistant diseases, inflammatory diseases (for example, rhinitis, pharyngitis, bronchitis, pneumonia, pleuritis, bronchial asthma, chronic pulmonary emphysema, pulmonary fibrosis, inflammatory bowel disease, acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, chronic thyroiditis, autoimmune gastritis), scleroderma, deep lupus erythematosus, Graves' disease, autoimmune neutropenia, thrombocytopenia, myasthenia gravis, multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, chronic myeloc
  • metabolic diseases for example
  • MAP kinases Lipopolysaccharide (LPS)- induced TNF- ⁇ production by human monocytes involves activation of MAP kinases.
  • LPS Lipopolysaccharide
  • TNF- ⁇ is a key mediator of autoimmune disease
  • blocking the MAP kinases pathway has potential for the treating of inflammatory and immunological diseases such as lupus, rheumatoid arthritis, psoriasis and destruction of pancreatic islet beta cells in Type I diabetes.
  • inhibiting MAP kinases activity is expected to be useful in the treating of the diseases relating to TNF- ⁇ , because MAP kinases are considered to have a relationship with TNF- ⁇ production. Accordingly, a compound which inhibits c-Jun phosphorylation is considered to be potentially useful for the therapy of diseases which has a relationship with TNF- ⁇ production.
  • R 1A is phenyl optionally substituted with one or more halogen(s), (C)-C 6 )alkyl, (C r C 6 )alkoxy, (d-C ⁇ alkylthio, etc.
  • R 2A is a hydrogen, halogen, (d-C 9 )alkyl optionally substituted with trifluoromethyl, or with one or more fluorine(s), etc.
  • R 3A is a hydrogen, (Ci-C 6 )alkyl, or benzyl
  • R 4A is (C 2 -C 6 )alkyl(s) group, cyclic (C 3 -C 7 )alkyl group which is optionally substituted with one or more (C !
  • Ar B is an aryl or heteroaryl ring;
  • CYC B is a hydrogen or a carbocyclic, heterocyclic, aryl or heteroaryl ring;
  • R 1B is selected from the group consisting of a hydrogen, Ci -7 alkyl, C 2 - 7 alkenyl, C 2-7 alkynyl, C 3- 7 cycloalkyl, C 3-7 cycloalkylC 1-7 alkyl, C 3-7 cycloaklenyl, C 3-7 cycloalkenylC 1-7 alkyl and benzo-fusedC 4-7 cycloalkyl, each optionally mono-, di-, or tri-substituted with R pB ;
  • R 2B is selected from the group consisting of a hydrogen, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkyny
  • R is lower alkyl, aryl lower alkyl of from 7 to 12 carbon atoms, phenyl, lower alkylphenyl, halophenyl, lower alkoxyphenyl, naphthyl, halonaphthyl, lower alkoxynaphthyl, or lower alkylnaphthyl;
  • R is lower alkyl, phenyl, halophenyl, lower alkoxyphenyl, lower alkylphenyl, naphthyl, halonaphthyl, lower alkylnaphthyl, or lower alkoxynaphthyl;
  • R 2C is a hydrogen, lower alkyl, -CHO, -CH-NOH, or -CH 2 OR 5C wherein R 5C is a hydrogen or lower alkyl;
  • R 3C is a hydrogen, lower alkyl, benzoyl, aryl lower alkyl of from 7 to 12 carbon
  • TNF- ⁇ production inhibitor As an agent for the preventing and/or treating metabolic diseases, inflammatory diseases or the like.
  • the present inventors have made extensive studies to find a compound that can become a treating agent for various diseases by inhibiting the production of TNF- ⁇ , and as a result, have found that the object is achieved by the compounds of the present invention represented by the formula (I), and then have completed the present invention.
  • the present invention relates to the followings.
  • (I)
  • R 1 is a hydrogen atom or R 5 -X-;
  • R 5 is an optionally substituted alkyl group, an optionally substituted alkoxy carbonyl group, an optionally substituted acyl group or
  • X is bond or -NR 8 CO-
  • R is a hydrogen atom or an optionally substituted alkyl group; ring 1 is a cyclic group which may be optionally substituted;
  • R 6 is a hydrogen atom, an optionally substituted alkoxycarbonyl group, a carboxyl group, a nitrile group, an optionally substituted alkylsulfonyl group, an optionally substituted alkyl group, an optionally substituted acyl group, a halogen atom, an optionally substituted alkoxy group or
  • n is an integer of from 1 to 4, wherein when n is 2 or more, R 6 's are the same or different; ring 3 is a cyclic group which may be optionally substituted; R 7 is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted alkoxycarbonyl group; Z is -SO 2 -, -O-, -CH 2 -, -CO-, -CH 2 O- or -OCH 2 -;
  • R 2 is an optionally protected carbamoyl group, an optionally protected aminocarbonothioyl group or an optionally protected amino(imino)methyl group;
  • R 3 is an optionally substituted alkyl group, a halogen atom, a nitrile group or an optionally substituted alkoxy group
  • R 4 is a hydrogen atom, an optionally substituted alkyl group or
  • ring 2 is a cyclic group which may be optionally substituted
  • Y is bond or -CH 2 -, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.
  • ring 1 is cyclohexane, benzene, pyridine, indole, benzimidazole or piperidine; ring 2 is benzene; and ring 3 is benzene or piperazine.
  • a method for preventing and/or treating a TNF- ⁇ mediated disease which comprises administering to a mammal an effective amount of the compound of formula (I) according to (1) above, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.
  • diabetes mellitus is insulin- resistant diabetes mellitus.
  • a method for inhibiting TNF- ⁇ production which comprises administering to a mammal an effective amount of the compound of the formula (I) according to (1) above, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.
  • a pharmaceutical composition which comprises the compound of formula (I) according to (1) above, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.
  • R 1 is a hydrogen atom or R 5 -X-.
  • R 5 is an optionally substituted alkyl groups, an optionally substituted alkoxycarbonyl groups, an optionally substituted acyl groups or
  • alkyl groups in "the optionally substituted alkyl groups" as R 5 include, for example, straight-chain or branched C 1-20 alkyl groups, such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl, etc., where as substituents on the alkyl groups, there may be mentioned, for example, hydroxyl group, amino group, carboxyl group, nitro group, azido group, mono- or di-Cl-6 alkylamin
  • C3-15 monocyclic, bicyclic or tricyclic aromatic carbon rings which may be partially or fully saturated.
  • the partially or fully saturated C3-15 monocyclic, bicyclic or tricyclic aromatic carbon rings include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, inden
  • the C3-15 monocyclic, bicyclic or tricyclic aromatic carbon rings which may be partially or fully saturated embrace spiro-bonded bicyclic carbon rings and crosslinked bicyclic carbon rings, and include, for example, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane, bicyclo[2,2, 1 Jheptane, bicyclo[2,2, 1 ]hept-2-ene, bicyclo[3 ,1,1 Jheptane, bicyclo[3,3,l]heptane, bicyclo[3.1.1]hept-2-ene, bicyclo[2.2.2]octane, bicyclo- [2.2.2]oct-2-ene, adamantane or noradamantane ring, etc.
  • the substitutes on the carbon rings as a substituent on the alkyl groups include, for example, C 1-8 alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc.), hydroxyl group, amino group, carboxyl group, nitro group, mono- or di-Cl-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), C 1-6 alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, hexyloxy, etc.), C 1-6 alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbony
  • heterocyclic rings as a substituent on the alkyl groups include, for example, 3- to 15-membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be partially or fully saturated.
  • the 3- to 15-membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms include, for example, a pyrrole, imidazole, triazole, tetrazole, pyrazol, pyridine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxx
  • 3- to 15-membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms which may be partially or fully saturated
  • examples of the 3- to 15- membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which are partially or fully saturated include aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyrida
  • the substitutes on the heterocyclic ring as a substituent on the alkyl groups include, for example, C 1-8 alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc.), hydroxyl group, amino group, carboxyl group, nitro group, mono- or di-Cl-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), C 1-6 alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, hexyloxy, etc.), C 1-6 alkoxycarbonyl groups (e.g., methoxycarbonyl, eth
  • alkoxycarbonyl groups in "the optionally substituted alkoxycarbonyl groups" as R 5 include, for example, straight-chain or branched C 1-20 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, tert-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, tridecyloxycarbonyl, tetradecyloxycarbonyl, pentadecyloxycarbonyl, hexadecyloxycarbonyl, hept
  • the substituents on the alkoxycarbonyl groups are as defined above for the substituents in the "the optionally substituted alkyl groups" as R 5 , and these arbitrary substituents may be replaced at any substitutable positions.
  • acyl groups in "optionally substituted acyl groups" as R 5 include, for example, (1) optionally substituted alkylcarbonyl groups, (2) optionally substituted alkenylcarbonyl groups, (3) optionally substituted alkynylcarbonyl groups, (4) optionally substituted carbon ring carbonyl groups or (5) optionally substituted heterocyclic carbonyl groups.
  • alkyl groups in "optionally substituted alkylcarbonyl groups” are as defined for the alkyl groups in the “optionally substituted alkyl groups” as R 5 .
  • the substituents on the alkylcarbonyl groups are as defined above for the substituents in the "the optionally substituted alkyl groups” as R 5 , and these arbitrary substituents may be replaced at any substitutable positions.
  • alkenyl groups in the "optionally substituted alkenylcarbonyl groups” include, for example, straight-chain or branched C2-20 alkenyl groups such as ethenyl, propenyl, butenyl, pentenyl or hexenyl, etc.
  • the substituents on the alkenylcarbonyl groups are as defined above for the substituents in the "the optionally substituted alkyl groups” as R 5 , and these arbitrary substituents may be replaced at any substitutable positions.
  • alkynyl groups in the "optionally substituted alkynylcarbonyl groups” include, for example, straight-chain or branched C2-20 alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl or hexynyl, etc.
  • the substituents on the alkenylcarbonyl groups are as defined above for the substituents in the "the optionally substituted alkyl groups” as R 5 , and these arbitrary substituents may be replaced at any substitutable positions.
  • the carbon ring in the "optionally substituted carbon ring carbonyl groups” include, for example, C3-15 monocyclic, dicyclic or tricyclic aromatic carbon rings, which may be partially or fully saturated.
  • Examples of the C3-15 monocyclic, dicyclic or tricyclic aromatic carbon rings, which may be partially or fully saturated include cyclopropane, cuclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cycloodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene
  • the C3-15 monocyclic, bicyclic or tricyclic aromatic carbon rings which may be partially or fully saturated contain spiro-bonded bicyclic carbon rings and crosslinked bicyclic carbon rings, as well and include, for example, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane, bicycle[2.2.1]heptane, bicycle[2.2.1]- hept-2-ene, bicycle[3.1.1 ]heptane, bicycle[3.1.1 ]hept-2-ene, bicycle[2.2.2]octane, bicycle[2.2.2]oct-2-ene, adamantane or noradamantane ring, etc.
  • the substituents on the carbon rings include, for example, C 1-4 alkyl groups (e.g., methyl, ethyl, propyl, butyl, etc.), C2-4 alkenyl groups (e.g., ethenyl, propenyl, butenyl, etc.), C2-4 alkynyl groups (e.g., ethynyl, propynyl, butyunyl, etc.), hydroxyl group, C 1-4 alkoxy groups (e.g., methoxy, ethoxy, propxy, butoxy, etc.), Cl-6 alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), thiol group, C 1-4 alkylthio groups (e.g., methylthio, ethylthio, propylthio, butylthio, etc.), amino group, mono-
  • heterocyclic ring in the "optionally substituted heterocyclic carbonyl groups” include, for example, 3- to 15-membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be partially or fully saturated, and the like.
  • the 3- to 15-membered, monocyclic, bicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms include, for example, a pyrrole, imidazole, triazole, tetrazole, pyrazol, pyridine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazol, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiaze
  • 3- to 15-membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms which may be partially or fully saturated
  • examples of the 3- to 15- membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which are partially or fully saturated include aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, te
  • the substituents on the heterocyclic ring include, for example, C 1-4 alkyl groups (e.g., methyl, ethyl, propyl, butyl, etc.), C2-4 alkenyl groups (e.g., ethenyl, propenyl, butenyl, etc.), C2-4 alkynyl groups (e.g., ethynyl, propynyl, butyunyl, etc.), hydroxyl group, Cl-4 alkoxy groups (e.g., methoxy, ethoxy, propxy, butoxy, etc.), C 1-6 alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), thiol group, Cl-4 alkylthio groups (e.g., methylthio, ethylthio, propylthio, butylthio, etc.), amino group,
  • R 5 -ring 1 is cyclic group which may be further optionally substituted.
  • the cyclic group in "cyclic group which may be further optionally substituted” as ring 1 include, for example, optionally substituted carbon ring radicals and optionally substituted heterocyclic radicals, etc.
  • optionally substituted carbon ring radicals as ring 1 are as defined for “optionally substituted carbon ring radicals” as the substituents of the the optionally substituted alkyl groups as R 5 .
  • Optionally substituted heterocyclic radicals” as ring 1 are as defined for “optionally substituted heterocyclic radicals” as the substituents of the the optionally substituted alkyl groups as R 5 .
  • R 6 is a hydrogen atom, optionally substituted alkoxycarbonyl groups, carboxyl group, nitrile group, optionally substituted alkylsulfonyl groups, optionally substituted alkyl groups, optionally substituted acyl groups, halogen atoms, optionally substituted alkoxy groups or
  • alkylsulfonyl groups in "the optionally substituted alkylsulfonyl groups" as R 6 include, for example, straight-chain or branched C 1-20 alkylsulfonyl groups, such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl, nonylsulfonyl, decylsulfonyl, undecylsulfonyl, dodecylsulfonyl, tridecyls
  • the substituents on the alkylsulfonyl groups are as defined above for the substituents in the "the optionally substituted alkyl groups” as R 5 .
  • the “optionally substituted alkyl groups” as R 6 is as defined for the “optionally substituted alkyl groups” as R 5 .
  • the “optionally sub ssttiituted acyl groups” as R 6 is as defined for the “optionally substituted acyl groups” as R 5 .
  • the "halogen atoms" as R >6 is fluorine, chlorine, bromine or iodine.
  • the alkoxy groups in "the optionally substituted alkoxy groups” as R 6 include, for example, straight-chain or branched C 1-20 alkoxy groups, such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy or eicosyloxy, etc.
  • the substituents on the alkoxy groups is as defined above for the substituents in the "the optionally substituted alkyl groups" as R 5 , and these arbitrary substituents may be replaced at any substitutable positions.
  • ring 3 is cyclic group which may be further optionally substituted.
  • the "cyclic group which may be further optionally substituted" as ring 3 is as defined for "cyclic group which may be further optionally substituted” as ring 1.
  • Z is -SO 2 -, -O-, -CH 2 -, -CO-, -CH 2 O- or -OCH 2 -.
  • R 6 or R 7 is a hydrogen atom, optionally substituted alkyl groups or optionally substituted alkoxycarbonyl groups.
  • R 7 is as defined for the "optionally substituted alkyl groups" as R 5 .
  • n is an integer from 1 to 4. When n is 2 or more, R 6 's may be the same or different.
  • X is bond or -NR 8 CO-.
  • R is a hydrogen atom or optionally substituted alkyl groups.
  • R 2 is optionally protected carbamoyl group, optionally protected aminocarbonothioyl group or optionally protected amino(imino)methyl group.
  • protection groups in “optionally protected carbamoyl group”, “optionally protected aminocarbonothioyl group” or “optionally protected amino(imino)methyl group” as R include, for example, optionally substituted alkyl groups (it is as defined above for “the optionally substituted alkyl groups” as R 5 ), optionally substituted carbon ring radicals (it is as defined above for “optionally substituted carbon ring radicals” as the substituents of the optionally substituted alkyl groups as R 5 ), optionally substituted heterocyclic radicals (it is as defined above for "optionally substituted heterocyclic radicals” as the substituents of the the optionally substituted alkyl groups as R 5 ), alkylsulfonyl groups (e.g., C 1-4 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, etc., and the like), aromatic-ring sulfonyl groups (e.g., C6-10 aromatic
  • R 3 is optionally substituted alkyl groups, halogen atoms, nitrile group or optionally substituted alkoxy groups.
  • the "optionally substituted alkyl groups" as R 3 is as defined for the "optionally substituted alkyl groups" as R 5 .
  • halogen atoms as R 3 is as defined for the “halogen atoms” as R 6 .
  • the “optionally substituted alkoxy groups” as R 3 is as defined for the “optionally substituted alkoxy groups” as R 6 .
  • R 4 is a hydrogen atom, optionally substituted alkyl groups or
  • ring 2 is cyclic group which may be optionally substituted.
  • cyclic group which may be optionally substituted as ring 2 is as defined for "cyclic group which may be further optionally substituted” as ring 1.
  • R 4 Y is bond or -CH 2 -. is preferably R 5 -X-, more preferably
  • R 5 is preferably
  • ring 1 is preferably C3-15 monocyclic or bicyclic aromatic carbon rings which may be partially or fully saturated, or 3- to 15-membered monocyclic or bicyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be partially or fully saturated, more preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, benzene, indene, indane, naphthalene, pyrrole, imidazole, triazole, tetrazole, pyrazol, pyridine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane
  • R 6 is preferably optionally substituted alkoxycarbonyl groups, optionally substituted alkylsulfonyl groups, optionally substituted alkyl groups, optionally substituted acyl groups, optionally substituted alkoxy groups or
  • ring 3 is preferably C3-15 monocyclic aromatic carbon rings which may be partially or fully saturated, or 3- to 15-membered monocyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be partially or fully saturated, more preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, benzene, pyrrole, imidazole, triazole, tetrazole, pyrazol, pyridine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxadiazin
  • Z is preferably -SO 2 -, -CH 2 -, or -CO-.
  • R 7 is preferably a hydrogen atom or optionally substituted alkyl groups.
  • n is preferably an integer from 1 to 2.
  • X is preferably -NR CO-.
  • R 8 is preferably a hydrogen atom.
  • R 2 is preferably optionally protected carbamoyl group.
  • R 3 is preferably optionally substituted alkyl groups, or halogen atoms.
  • R 4 is preferably
  • ring 2 is preferably C3-15 monocyclic aromatic carbon rings which may be partially or fully saturated, or 3- to 15-membered monocyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be partially or fully saturated, more preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, benzene, pyrrole, imidazole, triazole, tetrazole, pyrazol, pyridine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxadiazin
  • Y is preferably bond or -CH 2 -.
  • the formula (I) is preferably the formula (1-1).
  • the prodrug for the compound of the formula (I) means a compound which is converted to the compound represented by the formula (I) by the reaction with an enzyme, a gastric acid, or the like, in the living body.
  • Examples of the prodrug for the compound represented by the formula (I) include a compound wherein the amino group of the compound represented by the formula (I) is acylated, alkylated, phosphorylated, or the like (e.g., a compound wherein the amino group of the compound represented by the formula (I) is substituted with eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo- 1 ,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, acetoxymethylation, tert-butylatiion, etc.); a compound wherein the hydroxy group of the compound represented
  • the prodrug for the compound represented by the formula (I) may take a hydrate form or a non-hydrate form.
  • the prodrug for the compound represented by the formula (I) may be a compound which is converted into the compound represented by the formula (I) under the physiological conditions as described in Pharmaceutical Research and Development, Vol.7 "Molecular Design", pages 163-198 published in 1990 by Hirokawa Publishing Co.
  • a compound (I) may be labeled with an isotope (e.g., 3 H, 14 C, 35 S, 125 I, etc) and the like.
  • alkyl, alkoxy and alkynylene includes straight or branched one.
  • isomers on double bond, ring, fused ring (E-, Z-, cis-, trans-isomers), isomers generated due to asymmetric carbon atom(s) (R-, S-, ⁇ -, ⁇ -isomers, enantiomer, diastereomer), optically active isomers with optical rotation (D-, L-, d-, 1-isomers), polar compounds generated by chromatographic separation (more polar compound, less polar compound), equilibrium compounds, mixtures thereof with arbitrary ratio and racemic mixtures are also included in the present invention. Further, isomers due to the tautomerism are all included in the present invention.
  • the compound represented by the formula (I) may form a salt thereof, and may be N-oxide form thereof or quaternary ammonium salt thereof. Furthermore, these compounds may be a solvate thereof.
  • the compounds of the present invention include all pharmacologically acceptable salts of the compound represented by the formula (I). As pharmacologically acceptable salts, water-soluble salts with little toxicity are preferred.
  • Suitable pharmacologically acceptable salts in the compound of the present invention include, for example, salts with alkali metals (such as potassium, sodium, lithium, and the like); salts with alkaline earth metals (such as calcium, magnesium, and the like); ammonium salts (such as tetramethylammonium salts, tetrabutylammonium salts, and the like); salts with organic amines (such as triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine, and the like); and acid addition salts such as salts with inorganic acid (such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, and the like), and salts with organic acid (such as a
  • the N-oxide form of the compound represented by the formula (I) means the compound wherein the nitrogen atom was oxidized.
  • the N-oxide form of the compound represented by the formula (I) may additionally form a salt described above.
  • the quaternary ammonium salt of the compound represented by the formula (I) means the compound wherein the nitrogen atom of the compound represented by the formula (I) is quaternized by R 0 (R 0 represents alkyl, alkenyl, alkynyl (which has the same meaning as described above) which each may have a substituent(s), and cyclic ring (which has the same meaning as described above) which may have a substituent(s).)
  • the quaternary ammonium salt of the compound represented by the formula (I) may additionally form the salt described above and the N-oxide form described above.
  • the appropriate solvate of the compound represented by the formula (I), a salt thereof, an N-oxide form thereof, and a quaternary ammonium salt thereof, include hydrate, alcoholate (such as ethanolate) and the like.
  • the solvates are preferably low toxic and water-soluble.
  • the compounds represented by the formula (I) can be converted into the salt described above, the N-oxide form described above thereof, the solvates described above by conventional means.
  • the compounds of the present invention as represented by the formula (I) can be produced, for example, in accordance with the below-described processes or processes similar thereto, or the processes to be described in examples.
  • the starting compounds may be used as a salt, wherein as such salts, there may be used the pharmaceutically allowable salts of the compounds represented by the formula (I) to be described below.
  • R 2 is a carbamoyl group and R 4 is ring 2, i.e., the compound represented by the formula
  • the compounds represented by the formula (1-1) can be produced by subjecting a compound represented by the formula (II):
  • ring 1 ! , ring 3 1 , Z 1 , R 7"1 and R 8'1 are as defined for ring 1, ring 3, Z, R 7 and R 8 , respectively, and the carboxy, hydroxy, amino or thiol groups to be comprised by ring I 1 , ring 3', Z 1 , R 7"1 and R 8"1 are understood to be protected, if required so, the compound represented by the formula (III):
  • R 10 and R 11 each independently, is 1-imidazolyl, a halogen atom or trihalomethoxy (such as trichloromethoxy and the like) to a reaction, followed by a deprotection reaction for the protecting group(s), as the case may be.
  • a reaction with a compound represented by formula (II), a compound represented by formula (III) and a compound represented by formula (IV) is carried out, for example, in an organic solvent (such as ethyl acetate, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, benzene, toluene and the like), or in the absence of a solvent and a base (such as pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, and the like) at the temperature of -78°C to reflux temperature.
  • an organic solvent such as ethyl acetate, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, benzene, toluene and the like
  • a base such as pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropyle
  • This reaction is preferred to be carried out under an inert gas (argon, nitrogen, etc.) atmosphere on anhydrous condition.
  • inert gas argon, nitrogen, etc.
  • the deprotection reaction through alkali hydrolysis is carried out, for example,in an organic solvent (e.g., methanol, tetrahydrofuran, dioxane, etc.) with use of a hydroxide of an alkali metal (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), a hydroxide of an alkaline earth metal (barium hydroxide, calcium hydroxide, etc.) or a carbonate (sodium carbonate, potassium carbonate, etc.), an aqueous solution thereof, or their mixtures at a temperature of about 0 to 40°C.
  • an organic solvent e.g., methanol, tetrahydrofuran, dioxane, etc.
  • the deprotection reaction under acidic conditions is conducted into practice, for example, in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, anisole, etc.) and in an organic acid (e.g., acetic acid, trifluroacetic acid, methanesulfonic acid, p-tosyl acid, etc.), inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.) or their mixtures (hydrobromic acid/acetic acid, etc.) at a temperature of about 0 to 100°C.
  • organic solvent e.g., dichloromethane, chloroform, dioxane, ethyl acetate, anisole, etc.
  • organic acid e.g., acetic acid, trifluroacetic acid, methanesulfonic acid, p-tosyl acid, etc.
  • inorganic acid e.g., hydro
  • the deprotection reaction through hydrogenolysis is carried out, for example, in a solvent (e.g., ethers (e.g., tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (e.g., methanol, ethanol, etc.), benzenes (e.g., benzene, toluene, etc.), ketones (acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), amides (e.g., dimethylformamide, etc.), water, ethyl acetate, acetic acid or solvent mixtures of not less than two thereof, etc.) in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium hydroxide- carbon, platinum oxide, Raney-nickel, etc.), under an atmosphere of hydrogen at atmospheric pressure or applied
  • the deprotection reaction for a silyl group is conducted into practice, for example, in a water-miscible organic solvent (e.g., tetrahydrofuran, acetonitrile, etc.) with use of tetrabutylammonium fluoride at a temperature of about 0 to 40°C.
  • a water-miscible organic solvent e.g., tetrahydrofuran, acetonitrile, etc.
  • tetrabutylammonium fluoride at a temperature of about 0 to 40°C.
  • the deprotection reaction with use of a metal is performed, for example, in an acidic solvent (e.g., acetic acid, a buffer of pH about 4.2 to 7.2 or mixed solutions thereof with organic solvents, such as tetrahydrofuran, etc.) in the presence of powdered zinc at a temperature of about 0 to 40°C, under application of ultrasonics, if necessary.
  • the deprotection reaction with use of a metal complex is carried out, for example, in an organic solvent (e.g., dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or solvent mixtures thereof in the presence of a trap reagent (tribuityltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), organic acid (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and/or organic acid salt (sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.), in the presence or absence of a phosphine-based reagent (e.g., triphenylphosphine, etc.), at a temperature of about 0 to 4O 0
  • the protective groups for carboxy group may be exemplified by methyl, ethyl, allyl, t-butyl, trichloroethyl, benzyl (Bn), phenacyl, methoxybenzyl, trityl or 2- chlorotrityl group, or solid-phase carriers having these chemical structures bonded thereto.
  • the protecting groups for hydroxy group include, for example, methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2- tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDPS), t-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), methoxybenzyl, allyloxy- carbonyl (Alloc) or 2,2,2-trichloroethoxycarbonyl (Troc) group, and the like.
  • MOM methoxymethyl
  • EE 1-ethoxyethyl
  • MEM methoxyethoxymethyl
  • TMS trimethylsilyl
  • TES triethylsily
  • protective groups for amino group there may be mentioned, for example, benzyloxycarbonyl, t-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 1- methyl- l-(4-biphenyl)-ethoxycarbonyl (Bpoc), trifluroacetyl, 9-fluorenylmethoxy- carbonyl, benzyl (Bn), methoxybenzyl, benzyloxymethyl (BOM) or 2- (trimethylsilyl)ethoxymethyl (SEM) group, etc.
  • the shareholders groups for thiol group may be exemplified by benzyl (Bn), methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyranyl (THP), diphenylmethyl or acetyl group, etc.
  • the protective groups for carboxy, hydroxy, amino or thiol group are not limited particularly to the above-mentioned ones, only if they are easily and selectively removabale. For example, use may be made of those described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.
  • a reaction with a compound represented by formula (III) and a compound represented by formula (V) can be carried out in an organic solvent (such as toluene, benzene, xylene, tetrahydrofuran, dichloromethane, chloroform, diethyl ether, 1,2- dichloroethane, and the like) and in the presence of a base (such as pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, and the like) at the temperature of 0°C to reflux temperature.
  • This reaction is preferred to be carried out under an inert gas (argon, nitrogen, etc.) atmosphere on anhydrous condition.
  • the deprotection reaction of a protective group can be carried out in the same manner as the above mentioned.
  • the compounds wherein R 3"1 is optionally substituted alkyl groups i.e., the compound represented by the formula (III- 1 ) can be produced by the method as illustrated in the Reaction Scheme 1.
  • P N is protective groups for amino group
  • R 3a is optionally substituted alkyl groups
  • R 9 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • halo is a halogen atom and the other symbols represent same meaning as the above-mentioned.
  • the compounds wherein R 3'1 is a halogen atom i.e., the compound represented by the formula (III-2) can be produced by the method as illustrated in the Reaction Scheme 2.
  • R >3b is a halogen atom and the other symbols represent same meaning as the above-mentioned.
  • any compounds other than the above-indicated compounds can be produced by utilizing in combination the procedures or methods as described in Examples to be given in the present specification or the conventionally known methods, such as those described in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2 nd Edition (Richard C. Larock, John Wiley & Sons inc., 1999).
  • any reactions being accompanied by heating can be carried out with use of a water bath, oil bath, sand bath or microwave, as is apparent to those skilled in the art.
  • reaction products can be purified by ordinarily employed purification means, such as distillation under atmospheric pressure or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, ion exchange resins, scavenger resins or column chromatography, or such techniques as washing, recrystallization, etc. Purification may be performed in the reaction-by- reaction manner or after completion of several reactions.
  • purification means such as distillation under atmospheric pressure or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, ion exchange resins, scavenger resins or column chromatography, or such techniques as washing, recrystallization, etc. Purification may be performed in the reaction-by- reaction manner or after completion of several reactions.
  • a pharmacological test except for the Biological Examples hereinafter described includes, for example, the following method. By the method shown below, the in vivo effect of the compound represented by the formula (I) can be proved.
  • a vehicle used for the administration of the compound represented by the formula (I) to an animal may be any material so long as it can suspend or dissolve the compound into safe and administrable state.
  • vehicles which those skilled in the art use for the administration to an animal, and examples of such vehicles are methylcellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, propylene glycol, polyethylene glycol, sugar, sugar alcohol, edible oil, distilled water, physiological saline solution, and a mixture thereof and the like.
  • mice Male, 8-weeks old KKAy/Ta JcI mice are pre-breaded individually in single cages for approximately one week. During pre-breaded and test term, mice are provided pellet diet and tap water from bottle of feed water ad libitum. On the first day of the experiment (Day 0), the body weight of mice are measured. Blood samples are collected from coccygeal vein using a microcapillary to measure plasma glucose concentration. Based on plasma glucose concentration, mice are divided into some groups (five mice per group) using a stratified randomization method and started dosing.
  • the dosing can be carried out by oral gavage administration compulsorily or parenteral administration by subcutaneous injection, after suspending or dissolving the test compound in the above described vehicle.
  • the control group receives preferably only the vehicle.
  • the doses and the administration frequency can be increased or decreased appropriately by the effect of the test compound, preferably, for example, about 0.1 mg/kg body weight to 100 mg/kg body weight, about 1 to 3 times par day, every day.
  • the endpoints of the efficacy on the present model include body weight, food intakes, blood glucose level, triglycereide of plasma, blood insulin level, and weight of liver. These endpoints can be measured after arbitrary days from starting the dosing.
  • pioglitazone can show the efficacy such as body weight gain, decline of blood glucose level and insulin level, and the like, by oral administration one time per day and from 50 mg/kg body weight.
  • mice Male balb/c mice are administrated (preferably orally administrated) the test compound suspended or dissolved in the above described vehicle, and after 30 minutes, LPS (055 :B5, Difco) is administrated intraperitoneally at the dose of 1 mg/kg body weight (five mice per group). The control group (five mice) receives only the vehicle. After 30 minutes from LPS treatment, under ether anesthesia, blood samples are collected from vein abdominalis with heparin and centrifuged (12000 r.p.m., 3 minutes, 4 0 C) to obtain plasma samples. Obtained samples are conserved at -80°C before use. The amount of TNF- ⁇ can be quantitatively analyzed by using a commercial ELISA kit (such as R&D: #MTA00) and the like. (3) Consideration of the inhibition of the TNF- ⁇ production on cytokine-producing rat model
  • mice Female Lew rats are administrated (preferably orally administrated) the test compound suspended or dissolved in the above described vehicle, and after 2 hours, LPS (055:B5, Difco) is administrated intravenously at the dose of 10 ⁇ g/kg body weight (five rats per group). The control group (five rats) receives only the vehicle. After 90 minutes from LPS treatment, under ether anesthesia, blood samples are collected from vein abdominalis with heparin and centrifuged (12000 r.p.m., 3 minutes, 4°C) to obtain plasma samples. Obtained samples are conserved at -80 0 C before use. The amount of TNF- ⁇ can be quantitatively analyzed by using a commercial ELISA kit (such as Genzyme/Techne: #10516) and the like.
  • a commercial ELISA kit such as Genzyme/Techne: #10516
  • the toxicity of the compound represented by the formula (I) of the present invention is very low, and thus it is considered that the compound is sufficiently safe to be used as a pharmaceutical.
  • the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof can be used as an agent for preventing and/or treating a TNF- ⁇ -mediated diseases, for example, inflammatory disease (for example, diabetic complication (e.g. retinopathy, nephropathy, nervous disorder, macrovascular disease, etc.), inflammation, dermatitis, atopic dermatitis, hepatic inflammation, inflammation of the kidneys, glomerulonephritis, pancreatitis, psoriasis, gout, Addison's disease, osteitis syndrome (e.g.
  • inflammatory disease for example, diabetic complication (e.g. retinopathy, nephropathy, nervous disorder, macrovascular disease, etc.), inflammation, dermatitis, atopic dermatitis, hepatic inflammation, inflammation of the kidneys, glomerulonephritis, pancreatitis, ps
  • osteitis such as osteomyelitis, osteomalacia, periostitis, etc.
  • arthritis e.g. rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, synovitis, etc.
  • inflammatory eye disease e.g. chronic pneumonia , pulmonary silicosis, pulmonary sarcoidosis, lung tuberculosis , adult respiratory distress syndrome(ARDS), severe acute respiratory syndrome (SARS), etc.
  • inflammatory enteropathy e.g. Crohn's disease, chronic ulcerative colitis, etc.
  • allergy disease e.g.
  • autoimmune diseases autoimmune hemolytic anemia, systemic erythematosus, rheumatism, Castleman's disease, immune rejection accompanied with implanting (e.g. graft-versus- host reaction, etc.) and the like); nervous disorder (e.g. central nervous system damage (e.g. cerebrovascular disorder such as cerebral hemorrhage and cerebral infarction, etc., head injury, spinal cord injury, brain edema, multiple sclerosis, etc.), neurodegenerative disease (e.g.
  • central nervous system damage e.g. cerebrovascular disorder such as cerebral hemorrhage and cerebral infarction, etc., head injury, spinal cord injury, brain edema, multiple sclerosis, etc.
  • neurodegenerative disease e.g.
  • Alzheimer disease Parkinson's disease, amyotrophic lateral sclerosis (ALS), AIDS encephalosis, etc.), cerebral meningitis, Creutzfeldt- Jakob disease etc.); pulmonary problems (e.g. asthma, chronic obstructive pulmonary disease (COPD), etc.); circulatory system disease (e.g.
  • angina pectoris cardiac failure, congestive cardiac failure, acute cardiac failure, chronic cardiac failure, cardiac infarction, acute cardiac infarction, cardiac infarction prognosis, intraatrial myxoma, arterial sclerosis, hypertension, dialysis hypotension, thrombosis, diffuse intravascular coagulation syndrome (DIC), reperfusion injury, post-PTCA restenosis, etc.); urinary system disease (e.g. renal failure, etc.); metabolic disorder and endocrine disease (e.g. diabetes, hyperlipemia, etc.); bone disease (e.g. osteoporosis, etc.); cancer disease (e.g.
  • malignancy such as growth and metastasis of malignant tumor, etc.), multiple myeloma, plasma cell leukemia, cancerous cachexia, etc.
  • infectious disease e.g. virus infection caused by cytomegalovirus, influenza virus, herpes virus, corona virus, etc., cachexia accompanied with infection, cachexia related to acquired immunodeficiency syndrome(AIDS), blood poisoning such as sepsis, septic shock, endotoxic shock, gram- negative sepsis, toxic shock syndrom, severe acute respiratory syndrome(SARS) accompanied with virus infection, etc.
  • infectious disease e.g. virus infection caused by cytomegalovirus, influenza virus, herpes virus, corona virus, etc., cachexia accompanied with infection, cachexia related to acquired immunodeficiency syndrome(AIDS), blood poisoning such as sepsis, septic shock, endotoxic shock, gram- negative sepsis, toxic shock syndrom, severe acute respiratory syndrome(SARS) accompanied with virus infection,
  • the compound of the present invention can be used as an agent for preventing and/or treating c-Jun related diseases, for example, metabolic disease (e.g. diabetes mellitus such as insulin-resistant diabetes mellitus or non-insulin-resistant diabetes mellitus, hyperlipemia, other insulin-resistant diseases, and the like), inflammatory diseases (e.g.
  • rhinitis pharyngitis, bronchitis, pneumonia, pleurisy, bronchial asthma, chronic pulmonary emphysema, pulmonary fibrosis, inflammatory bowel disease, acute pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, chronic thyroiditis, autoimmune gastritis, and the like), scleroderma, deep lupus erythematosus, Graves' disease, autoimmune neutropenia, thrombocytopenia, myasthenia gravis, multiple myeloma, acute myeloblasts leukemia, chrome sarcoma, chronic myelocytic leukemia, metastatic melanoma, Kaposi's sarcoma, debilitating disease, Huntington's disease, ischemic/reperfusion disorders of stroke, myocardial ischemic symptom, ischemic heart disease, renal ischemia, neovascular glaucoma, infantile hemangio
  • the compound of the present invention can have the inhibitory activity on eosinophil infiltration according to the TNF- ⁇ production-inhibitory activity. By this activity, the compound of the present invention can be used as a remedial agent for nasal obstruction. Therefore, the compound of the present invention can be used as an agent for preventing and/or treating an eosinophil infiltration-related diseases, for example, chronic urticaria, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, hypersensitivity pneumonitis, eczema, herpetic dermatitis, psoriasis, eosinophilic pneumonia (PIE syndrom), chronic obstructive pulmonary disease (COPD), asthma, contact dermatitis, pruritus, dry dermatitis, acute urticaria, prurigo, etc. and also can be used as a remedial agent for nasal obstruction.
  • an eosinophil infiltration-related diseases for example, chronic urticaria, atopic
  • the compound of the present invention When used for the aforementioned purposes, normally it is administered systemically or locally by oral route or parenteral route.
  • the compound of the present invention is safe and low in toxicity so that it may be administrated to a mammal including human or a non-human animal (e.g. simian, sheep, bos, horse, dog, cat, rabbit, rat, mouse, etc.).
  • a mammal including human or a non-human animal (e.g. simian, sheep, bos, horse, dog, cat, rabbit, rat, mouse, etc.).
  • the doses to be administered are determined depending upon, for example, age, body weight, symptom, the desired treating effect, the route of administration, the duration of the treating, and the like.
  • 1 mg to 1000 mg per dose is orally administered once to several times a day, or 1 mg to 100 mg per dose is parenterally (preferably intravenously) administered once to several times a day, or intravenously administered continuously for 1 to 24 hours a day.
  • the doses to be administered depend upon various conditions. Therefore, there may be cases where doses lower than or greater than the ranges specified above are applied.
  • the compound of the present invention may be safely administered orally or parenterally (e.g. local, rectal, intravenous administration) alone or by mixing with a pharmaceutically acceptable carrier to be made into a medicinal preparation, for example, solid agents for oral administration (for example, tablets including those coated with sugar or film, powder, pills, granules, capsules, etc.), liquid agents for oral administration, injections, suppositories, sustained release drug, etc., in accordance with a known method generally used as a manufacturing method of a medicinal preparation.
  • a pharmaceutically acceptable carrier for example, solid agents for oral administration (for example, tablets including those coated with sugar or film, powder, pills, granules, capsules, etc.), liquid agents for oral administration, injections, suppositories, sustained release drug, etc., in accordance with a known method generally used as a manufacturing method of a medicinal preparation.
  • the amount of the compound of the present invention in such preparations is about 0.01 % of part weight to about 100 % of part weight, preferablely about 0.1 % of part weight to about 50 % of part weight, and more preferably, about 0.5 % of part weight to about 20 % of part weight, relative to the whole of the preparation.
  • the compound of the present invention used in the production of those medicinal preparations is not limited to substantially pure and single substance, and may include impurities (e.g. by-product, solvent, raw material, etc. which is derived from the production steps) as far as they are pharmaceutically acceptable as pharmaceutical bulk.
  • impurities e.g. by-product, solvent, raw material, etc. which is derived from the production steps
  • the carrier which is used in the production of the medicinal preparation includes various conventional organic or inorganic carrier materials, such as vehicles, lubricants, binders and disintegrants of solid preparation, or solvents, solution adjuvants, suspending or emulsifying agents, tonicity agent, buffering agents and soothing agents, etc. of liquid preparation. If necessary, conventional preservatives, antioxidants, coloring agents, sweetening agents, absorbents, and humectants can be used appropriately on adequate dose.
  • Solid agents for oral administration include tablets, pills, capsules, dispersible powders and granules. Capsules include hard capsules and soft capsules.
  • one or more of the active compound(s) may be alone, or admixed with vehicles (such as lactose, mannitol, glucose, microcrystalline cellulose, starch, corn starch, light anhydrous silicic acid, etc.), binders (such as hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate, crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropylmethyl cellulose, starch, sucrose, gelatin, methylcellulose, sodium carboxymethyl cellulose, etc.), disintegrants (such as cellulose calcium glycolate, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, L-hydroxypropyl cellulose, etc.), lubricants (such as magnesium stearate, calcium
  • the solid agents may, if desired, be coated with coating agents (such as white sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
  • coating agents such as white sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate
  • Liquid agents for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs, etc.
  • one or more of the active compound(s) may be dissolved, suspended or emulsified into diluent(s) commonly used in the art (such as purified water, ethanol or a mixture thereof).
  • the liquid agents may further comprise some additives, such as wetting agents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, aroma, preservatives or buffering agents.
  • Injections for parenteral administration include any types of injections including drops. Examples of injections include intramuscular injections, subcutaneous injections, intradermal injections, intraarterial injections, intravenous injections, intraabdominal injections, intraspinal injections, intravenous drips, etc. Injections for parenteral administration also include sterile aqueous, suspensions, emulsions and solid forms which are dissolved or suspended into solvent(s) for injection immediately before use. In injections, one or more of the active compound(s) may be dissolved, suspended or emulsified into solvent(s). Examples of the solvents include distilled water for injection, physiological saline, macrogol, vegetable oil (e.g.
  • injections may comprise some additives, such as stabilizing agents (e.g. D- sorbitol, D-mannitol, L-alanine, ascorbic acid, albumin, inositol, sodium gluconic acid, sodium thioglycolate, polyoxyethylene hardened castor oil, etc.), solution adjuvants (e.g.
  • surface-active agents such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate, etc.; hydrophilic polymer such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.; and the like), soothing agents (e.g. benzyl alcohol, etc.), tonicity agents (e.g. glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.), buffering agents (e.g.
  • phosphate buffer acetate buffer, carbonate buffer, citrate buffer, etc.
  • preservatives e.g. parahydroxybenzoate esters, chlorobutanol, benzylalcohol, phenethyl alcohol, dehydroacetate, sorbic acid, etc.
  • antioxidants e.g. sulfite salt, ascorbic acid, ⁇ -tocopherol, etc.
  • They may be sterilized at a final step, or may be prepared and compensated according to aseptic manipulations. They may also be manufactured into sterile solid agents, for example, freeze-dried products, which may be dissolved in sterile water or some other sterile diluent(s) for injection immediately before use.
  • Freeze drying can be carried out by the known method. Generally, a preferable method is to dry by freezing at -25 °C or below, and then raising the temperature of a drying rack to 25°C to 40°C, while holding the vacuum pressure of a dry warehouse.
  • the other preparations for parenteral administration include liquids for external use, ointments, liniments, insufflations, spray preparations, suppositories and pessaries for vaginal administration which comprise one or more of the active substance(s) and may be prepared by methods known per se.
  • Spray preparations may comprise, in addition to a diluent used in general, a stabilizer such as sodium bisulfite and an isotonization buffer, for example, tonicity agents such as sodium chloride, sodium citrate or citric acid.
  • the compound of the present invention may be administered as a combination preparation by combining with other pharmaceuticals for the purpose of 1) supplementing and/or enhancing the preventing and/or treating effect of the compound,
  • the compound of the present invention may be combined and administered as a combination preparation for the purose of
  • the combination preparations of the compound of the present invention and a concomitant drug(s) may be administered as one combination preparation comprising these components, or may be administered separately. When they are administered separately as independent preparations, they may be administered simultaneously or with time lag. Administration with time lag includes the method of administering the compound of the present invention before other drugs and vice versa, and each administration route may be the same or different.
  • the concomitant drug(s) is not limited to a low molecular weight compound, and may be a macromolecule protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy, antibody, vaccine, and the like.
  • the dosage of the concomitant drug(s) can be properly selected according to the clinical dosage.
  • the compounding ratio of the compound of the present invention and the concomitant drug(s) can be properly selected by the age and body weight of the object, administration route, administration term, target disease, symptom, combination, and the like.
  • the amount of the concomitant drug(s) may be used 0.01 parts by weight to 100 parts by weight relative to 1 part by weight of the compound of the present invention.
  • the concomitant drug(s) may be administrated in the proper combination of arbitrary one or two or more member(s) selected from the same or different groups in arbitrary proportion.
  • the concomitant drug(s) for supplementing and/or enhancing of the preventing and/or treating effect of the compound of the present invention includes not only those which have so far been found but also those which will be found on the basis of the aforementioned mechanism.
  • the concomitant drug(s) which can be used in combination with the compounds of the present invention include, for example, those given below.
  • Examples of the concomitant drug(s) for supplementing and/or enhancing the preventing and/or treating effect of the compound of the present invention on rheumatoid arthritis, osteoarthritis, arthritis includes a steroid, an elastase inhibitor, a cannabinoid-2 receptor stimulator, a prostaglandin, a prostaglandin synthase inhibitor, a phosphodiesterase inhibitor, a metalloproteinase inhibitor, an adhesion molecule inhibitor, an anti-cytokine protein preparation such as an anti-TNF- ⁇ preparation, an anti-interleukin (IL)-I preparation, an anti-IL-6 preparation; an anti-cytokine agent, an immunomodulatory agent, a disease modifying anti-rheumatic drug, a non-steroidal antiinflammatory drug, a c-Jun N-terminal kinase inhibitor, and the like.
  • a steroid an elastase inhibitor, a cannabinoid-2 receptor stimulator,
  • Examples of the concomitant drug(s) for supplementing and/or enhancing the preventing and/or treating effect of the compound of the present invention on inflammatory bowel disorder, Crohn's disease, ulcerative colitis, etc. include a steroid, an elastase inhibitor, a cannabinoid-2 receptor stimulator, a prostaglandin, a prostaglandin synthase inhibitor, a phosphodiesterase inhibitor, a metalloproteinase inhibitor, an adhesion molecule inhibitor, an anti-cytokine protein preparation, an anti- cytokine agent, an immunomodulatory agent, a leukotriene receptor inhibitor, an anticholinergic agent, a 5 -lipoxygenase inhibitor, a nitric oxide synthase inhibitor, an IL-8 antagonist, a poly(ADP)-ribose polymerase inhibitor, a mitochondrial benzodiazepine receptor agonist, an antioxidant drug, a local anesthetic agent, a gastrointestinal ulcer agent, an
  • Examples of the concomitant drug(s) for supplementing and/or enhancing the preventing and/or treating effect of the compound of the present invention on asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome include a steroid, an elastase inhibitor, a cannabinoid-2 receptor stimulator, a prostaglandin, a prostaglandin synthase inhibitor, a phosphodiesterase inhibitor, a metalloproteinase inhibitor, an adhesion molecule inhibitor, a leukotriene receptor inhibitor, an anticholinergic agent, a thromboxane A2 receptor antagonist, a thromboxane synthetase inhibitor, a ⁇ 2-adrenaline receptor stimulator, a xanthine derivative, an expectorant, an antibacterial agent, an anti-histaminic agent, an anti-cytokine protein preparation, an anti-cytokine agent, a forskolin preparation, a mediator release inhibitor, and the like.
  • Examples of the concomitant drug(s) of the compound of the present invention as a preventing and/or treating agent for hyperlipemia includes, for example, a MTP (Microsomal Triglyceride Transfer Protein) inhibitor, an HMG-CoA reductase inhibitor, a squalene synthetase inhibitor, a fibrate preparation, an ACAT (Acyl-CoA: cholesterol 0-acyltransferase) inhibitor, a 5 -lipoxygenase inhibitor, a cholesterol absorption inhibitor, a bile acid absorption inhibitor, an ileum Na + /bile acid cotransporter (IBAT) inhibitor, an LDL receptor activator/enhanced expression, a lipase inhibitor, a probucol preparation, a niacin preparation.
  • MTP Mericrosomal Triglyceride Transfer Protein
  • HMG-CoA reductase inhibitor an HMG-CoA reductase inhibitor
  • Examples of the concomitant drug(s) of the compound of the present invention as a preventing and/or treating agent for diabetes mellitus (insulin-resistant diabetes mellitus or non-insulin-resistant diabetes mellitus), diabetes complication and the like include a sulfonylurea hypoglycemic drug, a biguanide preparation, an ⁇ -glucosidase inhibitor, a rapid-acting insulin secretagogue, an insulin preparation, a GPR 40 agonist(G protein coupled receptor 40 agonist), a SGLT(sodium-dependent glucose transporter, for example, SGLTl, SGLT2) inhibitor, a DPP4 (dipeptidyl peptidase) inhibitor, a PTPlB inhibitor, a ⁇ 3 adrenoceptor agonist, a PPAR (for example, PPAR ⁇ , PPAR ⁇ , PPAR ⁇ ) agonist, and diabetes complication therapeutic agent and the like.
  • Examples of the MTP inhibitor include B
  • HMG-CoA reductase inhibitor examples include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and the like.
  • Examples of the ACAT inhibitor include F-12511, F- 1394, CI-IOl 1, melinamide, FCE27677, RP73163, and the like.
  • Examples of the squalene synthetase inhibitor include TAK-475 and the like.
  • fibrate preparation examples include gemfibrozil, clofibrate, bezafibrate, fenofibrate, and the like.
  • Examples of the cholesterol absorption inhibitor include SCH48461 and the like.
  • Examples of the bile acid absorption inhibitor include cholestyramine, cholestagel, and the like.
  • LDL receptor activator/enhanced expression agent examples include MD-700, LY295427, and the like.
  • lipase inhibitor examples include orlistat and the like.
  • sulfonylurea hypoglycemic agent examples include acetohexamide, glibenclamide, gliclazide, glyclopyramide, chlorpropamide, tolazamide, tolbutamide, glimepiride, and the like.
  • Examples of the biguanide preparation include buformin hydrochloride, metformin hydrochloride, and the like.
  • Examples of the ⁇ -glucosidase inhibitor include acarbose, voglibose, and the like.
  • Examples of the rapid-acting insulin secretagogue include nateglinide, repaglinide, and the like.
  • GPR 40 agonist examples include the compounds described in WO04/41266, WO04/106276, WO05/51890, WO05/63725, WO06/83612, WO07/13689, and the like.
  • Examples of the SGLT inhibitor include T-1095, AVE-2268, KGT-1251/KGT- 1681, and the like.
  • DPP4 inhibitor examples include NVP-DPP728A, vildagliptin, and the like.
  • Examples of the ⁇ 3 adrenoceptor agonist include AJ9677, L750355, CP331648, and the like.
  • Examples of the PPAR agonist include pioglitazone, troglitazone, rosiglitazone, JTT-501, and the like.
  • diabetes complication therapeutic agent examples include epalrestat and the like.
  • steroid examples include clobetasol propionate, diflorasone diacetate, fluocinonide, mometasone furoate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednate, diflucortolone valerate, amcinonide, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, deprodone propionate, prednisolone valerate-acetate, fluocinolone acetonide, beclometasone dipropionate, triamcinolone acetonide, flumetasone pivalate, alclometasone
  • Examples of the elastase inhibitor include ONO-5046 (sivelestat sodium), ONO-6818, MR-889, PBI-1101, EPI-HNE-4, R-665, ZD-0892, ZD-8321, GW-311616, DMP-777, L-659286, L-658758, L-680833, L-683845, AE-3763, and the like.
  • Examples of the prostaglandins (hereinafter, abbreviated as PG) include PG receptor agonists, PG receptor antagonists, and the like.
  • Examples of the PG receptor include PGE receptors (EP 1 , EP 2 , EP 3 and EP 4 ), PGD receptors (DP, CRTH2), PGF receptors (FP), PGI receptors (IP), TX receptors (TP), and the like.
  • prostaglandin synthase inhibitor examples include, salazosulfapyridine, mesalazine, olsalazine, 4-aminosalicylic acid, JTE-522, auranofin, carprofen, diphenpyramide, flunoxaprofen, flurbiprofen, indometacin, ketoprofen, lornoxicam, loxoprofen, meloxicam, oxaprozin, parsalmide, piproxen, piroxicam, piroxicam betadex, piroxicam cinnamate, tropineindometacinate, zaltoprofen, pranoprofen, and the like.
  • Examples of the phosphodiesterase inhibitor include PDE4 inhibitors such as rolipram, cilomilast (trade name: Ariflo), Bayl9-8004, NIK-616, roflumilast (BY-217), cipamfylline (BRL-61063), atizoram (CP-80633), SCH-351591, YM-976, V-11294A, PD-168787, D-4396, IC-485, PDE5 inhibitors such as sildenafil, and the like.
  • PDE4 inhibitors such as rolipram, cilomilast (trade name: Ariflo), Bayl9-8004, NIK-616, roflumilast (BY-217), cipamfylline (BRL-61063), atizoram (CP-80633), SCH-351591, YM-976, V-11294A, PD-168787, D-4396, IC-485, PDE5 inhibitors such as
  • adhesion molecule inhibitor examples include an antagonist such as ⁇ 4 integrin, and the like.
  • anti-TNF- ⁇ preparation examples include antibody against TNF- ⁇ , soluble TNF- ⁇ receptor, antibody against TNF- ⁇ receptor, soluble TNF- ⁇ receptor binding protein, and specifically, infliximab, etanercept, and the like.
  • anti-IL-1 preparation examples include antibody against IL-I, soluble IL-I receptor, antibody against IL-IRa and/or IL-I receptors, and specifically, for example, anakinra and the like.
  • anti-IL-6 preparation examples include antibody against IL-6, soluble IL-6 receptor, antibody against IL-6 receptor, and for example, MRA and the like.
  • immunosuppressing agent examples include methotrexate, cyclosporin, ascomycin, leflunomide, bucillamine, salazosulfapyridine, azathioprine, tacrolimus, cyclophosphamide, and the like.
  • Examples of the disease modifying anti-rheumatic drug include gold thioglucose, sodium aurothiomalate, auranofin, chloroquine, actarit, D-penicillamine preparation, lobenzarit disodium, bucillamine, hydroxychloroquine, salazosulfapyridine, and the like.
  • non-steroidal antiinflammatory drug examples include sasapyrine, sodium salicylate, aspirin, aspirin-dialminate, diflunisal, indometacin, suprofen, ufenamate, dimethyl isopropylazulene, bufexamac, felbinac, diclofenac, tolmetin sodium, clinoril, fenbufen, napumetone, proglumetacin, indometacin farnesil, acemetacin, proglumetacin maleate, amfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol, naproxen, flurbiprofen, flurbiprofenaxetil, ketoprofen, fenoprofen calcium, tiaprofen, oxaprozin, pranoprofen, loxoprofen sodium, alminoprofen, zal
  • Examples of the leukotriene receptor antagonist include pranlukast hydrate, montelukast, zafirlukast, seratrodast, MCC-847, KCA-757, CS-615, YM-158, L- 740515, CP-195494, LM-1484, RS-635, A-93178, S-36496, BIIL-284, ONO-4057, and the like.
  • Examples of the anticholinergic agent include ipratropium bromide, oxitropium bromide, flutropium bromide, cimetropium bromide, temiverine, tiotropium bromide, revatropate (UK-112166), and the like.
  • Examples of the local anesthetics include cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, and the like.
  • Examples of the enhancing agent of defensive factor include sucralfate, aldioxa, teprenone, cetraxate hydrochloride, and the like.
  • thromboxane A2 receptor antagonist examples include seratrodast, ramatroban, domitroban calcium hydrate, KT-2-962, and the like.
  • examples of the thromboxane synthase inhibitor include ozagrel hydrochloride, ozagrel sodium, imitrodast sodium, and the like.
  • Examples of the ⁇ 2 adrenaline receptor stimulator include fenoterol hydrobromide, salbutamol sulfate, terbutaline sulfate, formoterol fumarate, salmeterol xinafoate, isoproterenol sulfate, orciprenaline sulfate, clorprenaline sulfate, epinephrine, trimetoquinol hydrochloride, hexoprenalinemesyl sulfate, procaterol hydrochloride, tulobuterol hydrochloride, tulobuterol, pirbuterol hydrochloride, clenbuterol hydrochloride, mabuterol hydrochloride, ritodrine hydrochloride, bambuterol, dopexamine hydrochloride, meluadrine tartrate, AR-C68397, levosalbutamol, formoterol, KUR-1246, KUL-7
  • Examples of the xanthine derivative include aminophylline, theophylline, doxofylline, sipamphylline, diprophylline, and the like.
  • Examples of the expectorant include foeniculated ammonia spirit, sodium hydrogen carbonate, bromhexine hydrochloride, carbocysteine, ambroxol hydrochloride, ambroxol hydrochloride sustained preparation, methylcysteine hydrochloride, acetylcysteine, ethyl L-cysteine hydrochloride, tyloxapol, and the like.
  • antibacterial agent examples include sodium cefuroxime, meropenem trihydrate, netilmicin sulfate, sisomicin sulfate, ceftibuten, PA-1806, IB-367, tobramycin, PA- 1420, doxorubicin, astromicin sulfate, cefetamet pivoxil hydrochloride, and the like.
  • anti-histaminic agent examples include ketotifen fumarate, mequitazine, azelastine hydrochloride, oxatomide, terfenadine, emedastine difumarate, epinastine hydrochloride, astemizole, ebastine, cetirizine hydrochloride, bepotastine, fexofenadine, loratadine, desloratadine, olopatadine hydrochloride, TAK-427, ZCR- 2060, NIP-530, mometasone furoate, mizolastine, BP-294, andolast, auranofin, acrivastine, and the like.
  • anti-cytokine agent examples include any non-protein preparation which inhibits the activity of cytokine, for example, MAP kinase inhibitor, gene modulator, cytokine production inhibitor, TNF- ⁇ conversion enzyme inhibitor, IL-I ⁇ conversion enzyme inhibitor, IL-6 antagonist, IL-8 antagonist, chemokine antagonist, gene therapy agents, antisense compound, and the like.
  • MAP kinase inhibitor examples include PD-98059 and the like.
  • Examples of the gene modulator include inhibitors of a molecule which relates to signal transduction, for example, NF- ⁇ B, IKK-I, IKK-2, AP-I, and the like.
  • cytokine production inhibitor examples include suplatast tosylate (trade name: IPD), T-614, SR-31747, sonatimod, and the like.
  • chemokine antagonist examples include ONO-4128 (aplaviroc),
  • Examples of the gene therapy agent include those which is aimed to increase the expression of gene having anti-inflammatory effect, such as IL-4, IL-10, soluble IL- 1 receptor, soluble TNF- ⁇ receptor, and the like.
  • Examples of the mediator release inhibitor include tranilast, sodium cromoglicate, amlexanox, repirinast, ibudilast, dazanolast, pemirolast potassium, and the like.
  • Examples of the c-Jun N-terminal kinase inhibitor include the compounds described in WOOO/35906, WO00/35909, WO00/35921, WO00/64872, WO00/75118, WO03/068750, WO06/47354, WO06/83673, and the like.
  • the concomitant use can decrease the dose compared to administration of the compound alone of the present invention or the concomitant drug(s) alone;
  • the compound of the present invention and the concomitant drug can be selected according to a patient's symptom (mild case, severe case etc.); (3) The selection of the concomitant drug(s) of which mechanism of the action is different from that of the compound of the present invention can decrease the dose in patients and extend the treating period;
  • the concomitant drug(s) is a steroid
  • CoA reductase inhibitor it is known that rhabdmyolysis may occur as a side effect. However, the incidence and the degree of rhabdmyolysis can be decreased by using the above described concomitant drugs.
  • the combination preparation of the present invention there is no particular limitation for administration time of the compound of the present invention or and a concomitant drug(s).
  • the administration of the compound of the present invention or pharmaceutical composition thereof and a concomitant drug(s) or pharmaceutical composition thereof to the administration object includes a simultaneous administration and administrations with time difference.
  • the dose of a concomitant drug can be properly selected according to object of the administration, route of the administration, disease, combination, etc., as far as it conforms to the clinical dose.
  • the way of administration as far as the compound of the present invention and a concomitant drug(s) are combined in vivo.
  • the concomitant drug(s) of the present invention and/or the concomitant drug(s) can be safely administered as they are or after being mixed with a pharmaceutically acceptable carrier according to a per se known method usually employed in the production of pharmaceutical preparations, orally or parenterally (for example, topical administration, rectal administration, intravenous administration, etc.) in the form of solid preparations for internal use (e.g. tablets including sugar coated tablets and film-coating tablets), powders, pills, granules, capsules, etc.), liquid preparations for internal use, liquid preparations for external use, injections, suppositories, delayed-release preparations or the like.
  • a pharmaceutically acceptable carrier e.g. tablets including sugar coated tablets and film-coating tablets
  • powders, pills, granules, capsules, etc. e.g. tablets including sugar coated tablets and film-coating tablets
  • liquid preparations for internal use e.g. tablets including sugar coated tablets and film-coating tablets
  • liquid preparations for internal use
  • the carrier which is used in the production of the pharmaceutical preparation includes various conventional organic or inorganic carrier materials, such as excipients, lubricants, binders and disintegrators for solid preparations, solvents, solubilizers, suspending or emulsifying agents, isotonic agents, buffers and soothing agents, etc. If necessary, conventional preservatives, antioxidants, coloring agents, sweetening agents, adsorbents, wetting agents, and the like can be used appropriately in a suitable amount.
  • the excipient includes, for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, corn starch, light anhydrous silicic acid, and the like.
  • the binder includes, for example, hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate, crystalline cellulose, white soft sugar, D-mannitol, dextrin, hydroxypropylmethyl cellulose starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like.
  • the disintegrator includes, for example, cellulose calcium glycolate, starch, carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethylstarch, L-hydroxypropyl cellulose, and the like.
  • the lubricant includes, for example, magnesium stearate, calcium stearate, talc, colloid silica, and the like.
  • the solvent medium includes, for example, distilled water for injection, physiological saline solution, macrogol, vegetable oil (e.g. sesame oil, corn oil, olive oil, etc.), alcohols (e.g. propylene glycol, polyethylene glycol, ethanol, etc.) or a mixture thereof.
  • the stabilizer includes, for example, D-sorbitol, D-mannitol, L-alanine, ascorbic acid, albumin, inositol, sodium gluconate, sodium thioglycolate, polyoxyethylene hardened caster oil, etc.
  • the solubilizer includes, for example, glutamic acid, aspartic acid, Polysolbate 80 (trade name), polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, citric sodium, etc.
  • the emulsifying or suspending agent includes, for example, surfactants (for example, stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc.), hydrophilic polymers (for example, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose etc.) and the like.
  • the soothing agents include, for example, benzyl alcohol, and the like.
  • the isotonic agents include, for example, glucose, D-sorbitol, sodium chloride, glycerin, D- mannitol, and the like.
  • the buffers include, for example, a buffer solution of phosphates, acetates, carbonates, citrates, or the like.
  • the preservative includes, for example, p-hydroxybenzoic acid ester, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.
  • the antioxidant includes, for example, sulfites, ascorbic acid, ⁇ -tocopherol, and the like.
  • the compounding ratio of the compound of the present invention in a combination preparation varies depending on the dosage form. It is usually about
  • 0.01% by weight to 100% by weight relative to the whole preparation preferably about 0.1% by weight to 50% by weight relative to the whole preparation, more preferably about 0.5% by weight to 20% by weight relative to the whole preparation.
  • the compounding ratio of the concomitant drug(s) in the combination preparation of the present invention varies depending on the dosage form. It is usually about 0.01% by weight to 100% by weight, preferably about 0.1% by weight to 50% by weight relative to the whole preparation, more preferably about 0.5% by weight to 20% by weight relative to the whole preparation.
  • the content of the additive such as carrier, etc. in the combination preparation of the present invention varies depending on the dosage form. It is usually about 1% by weight to 99.99% by weight, preferably about 10% by weight to 90% by weight relative to the whole preparation. In addition, it may be the same in the formulation of the compound of the present invention and the concomitant drug(s) independently.
  • the tablet can be prepared by mixing uniformly the compound of the present invention and/or the concomitant drug(s) in the presence or absence of excipients, disintegrators, or other appropriate additives to prepare granulated powder in an appropriate manner, and then compacting with a lubricant, etc.; by mixing uniformly the compound of the present invention and/or the concomitant drug(s), in the presence or absence of excipients, disintegrators, or other appropriate additives in an appropriate manner, and then compacting the mixture directly; or by optionally adding an appropriate additive to previously granulated powder, mixing the mixture uniformly and then compacting into tablets.
  • the tablet may be prepared with coloring agents, flavoring substance, etc. Furthermore, it can be coated by using appropriate coating agents.
  • the injection preparation can be prepared by the following method. A certain amount of the compounds of the present invention and/or a concomitant drug(s) is dissolved, suspended or emulsified usually in an aqueous medium such as distilled water for injection, physiological saline solution, and Ringer solution, or in a nonaqueous medium such as vegetable oil, etc.; or a certain amount of the compound of the present invention and/or a concomitant drug(s) is sealed in a container for injection.
  • an aqueous medium such as distilled water for injection, physiological saline solution, and Ringer solution
  • a nonaqueous medium such as vegetable oil, etc.
  • the carrier for the preparation for oral administration includes a conventional material used in the field of pharmaceutical formulation such as starch, mannitol, crystalline cellulose, sodium carboxymethylcellulose, etc.
  • the carrier for injections includes, for example, distilled water, physiological saline solution, glucose solution, infusion, and the like.
  • the dose of the combination preparation of the present invention depends on the age, weight, disease symptom, treating effect, administration route, therapy period, and the like
  • the compound of the present invention and the concomitant drug(s) are usually administered orally once or several times per day at a dose per administration of from 0.1 mg to 1000 mg per human adult, or parenterally (preferably intravenous administration) once or several times per day at a dose per administration of from 0.1 mg to 100 mg per human adult, or continuously administered intravenously for 1 hour to 24 hours per day.
  • the dose of these compounds may be less than the aforementioned value or may need to exceed the aforementioned range because the dose varies under various conditions as mentioned above.
  • the concomitant drug(s) can be administrated at arbitrary dose as far as the side effect is not a serious problem and the purpose of the present invention can be achieved.
  • the daily dose as a concomitant drug(s) differs depending on age, sex, body weight, different sensitivity, time and interval of administration object, characteristics of pharmaceutical preparation, dispensing, kind, and type of active ingredient of medicinal preparation; and the like, so that it is not particularly limited.
  • the concomitant drug(s) of the present invention can be administered within 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 hour after the administration of the compound of the present invention, and the like.
  • the TNF- ⁇ production inhibitor of the present invention comprising the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof can be very useful as a preventing and/or treating for various diseases including, for example, metabolic diseases such as diabetes, inflammatory diseases such as rheumatoid arthritis, and the like, because of inhibitory activity against TNF- ⁇ production, and low toxicity.
  • Solvents given in parentheses concerning chromatographic separation and TLC indicate each the elution solvent or the developing solvent employed is expressed in ratio by volume. Unless otherwise indicated, the NMR data are 1 H-NMR data. Solvents given in parentheses concerning NMR indicate each solvent employed in measurement.
  • Example 2 A mixture of the compound prepared in Example 2 (0.399 g) in ethanol (4 mL) and 2.5 M aqueous potassium hydroxide (4 mL) was refluxed for 20 hours. The reaction was cooled to 0 °C and brought to pH 1 via the addition of 1 M hydrochloric acid. The mixture was diluted with water and ethyl acetate and solid sodium chloride was added to salt out the organic phase. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (0.355 g) having the following physical data.
  • Trifluoroacetic acid (0.6 mL) was added to a solution of the compound prepared in Example 4 (0.051 g) in dichloromethane (1.5 mL). The reaction was stirred at room temperature for 45 minutes and then concentrated. The residue was concentrated to obtain the title compound (0.050 g) having the following physical data.
  • Example 18 methyl 6-(3 -carbamoyl-2-methyl- 1 -phenyl-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridin- 5(4H)-yl)nicotinate
  • a solution of the compound prepared in Example 5 (0.050 g), ethyl 6- chloronicotinate (0.023 g) and diisopropylethylamine (0.059 mL) in dimethylacetamide (0.7 mL) was heated to 140 °C for 3.5 hours. The reaction was cooled to room temperature, diluted with ethyl acetate and washed sequentially with a saturated aqueous sodium bicarbonate solution and water.
  • Example 6 using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained.
  • Example 6 According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin- 1 -yl)methanone, the title compound having the following physical data was obtained.
  • Example 6 According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained.
  • 1 H NMR (CDCl 3 ): ⁇ 7.57-7.46 (m, 3H), 7.33 (d, J 8.4 Hz, 2H), 7.29-7.21 (m, 4H),
  • Example 6 using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained.
  • Example 6 According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained.
  • 1H NMR (DMSO-d 6 ): ⁇ 8.59 (s, IH), 7.96 (d, J 1.7 Hz, IH), 7.83-7.78 (m, 2H), 7.63-
  • Example 33 tert-butyl 4-(4-(3 -carbamoyl-2-chloro- 1 -phenyl-4,5 ,6,7-tetrahydro- 1 H-pyrrolo [3 ,2- c]pyridine-5 -carboxamido)phenylsulfonyl)piperazine- 1 -carboxylate
  • the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline (prepared according to the reported preparation in Jones, T. R.; et al. J. Med. Chem.
  • Example 6 using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained.
  • Example 6 According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained.
  • Example 6 using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline (prepared according to the reported preparation in Ferlin, M. G.; et al. Bioorg. Med. Chem. 2005, 13, 3531) instead of (4-aminophenyl)(4- methylpi ⁇ erazin-l-yl)methanone, the title compound having the following physical data was obtained.
  • Example 37 tert-butyl 4-(3-carbamoyl-2-chloro-l-phenyl-4,5,6,7-tetrahydro-lH-pyrrolo[3,2- c]pyridine-5-carboxamido)piperidine- 1 -carboxylate
  • Example 6 using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding amine instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained.
  • Mass data (APCI, Pos.): m/z 445 (M + Na) + .
  • Example 49 2-chloro-N 5 -(4-phenoxyphenyl)-l-phenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine- 3,5(4H)-dicarboxamide According to the same procedure described in Example 39, using the corresponding isocyanate instead of l-Isocyanato-4-(trifluoromethyl)benzene, the title compound having the following physical data was obtained.
  • Benzyl bromide (0.44 mL) was added to a mixture of 5-nitro-lH- benzo[d] imidazole (0.60 g) and potassium carbonate (0.76 g) in dimethylformamide (10 mL). The mixture was stirred at room temperature for 88 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate.
  • Example 52 using the compound prepared in Example 57 instead of the compound prepared in Example 51, the title compound having the following physical data was obtained.
  • Example 6 According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the compound prepared in Example 52 instead of (4-aminophenyl)(4-methylpiperazin-l- yl)methanone, the title compound having the following physical data was obtained.
  • Example 65 2-chloro-N 5 -(3 -(2-(dimethylamino)ethyl)- 1 -(pyridin-2-ylmethyl)- 1 H-indol-5-yl)- 1 - phenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-3,5(4H)-dicarboxamide bis(2,2,2- trifluoroacetate)
  • Example 6 while using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the compound prepared in Example 54 instead of (4- aminophenyl)(4-methylpiperazin-l-yl)methanone.
  • Example 6 while using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the compound prepared in Example 61 instead of (4- aminophenyl)(4-methylpiperazin-l-yl)methanone.
  • the compound of the present invention of the formula (I) possesses TNF- ⁇ production-inhibitory activity.
  • the procedures were conducted by conventionally used method on the basis of basic biological methods. Furthermore, the measuring method of the present invention was modified to improve the accuracy and/or sensitivity of measurement for evaluating the compound of the present invention.
  • the detailed experimental method was as follows.
  • PBMC Human peripheral blood mononuclear cells
  • Isolated PBMCs were suspended in RPMI 1640 medium (Gibco Cat# 11875) with 1% fetal bovine serum (Hyclone Cat# SH30070.03) and plated at 1 million cells per well in 1 mL in 24-well plates. Compounds (dimethyl sulfoxide solution) were put on the cells (final dimethyl sulfoxide concentration was 0.1%) for 1 hour followed by stimulation by lipopolysaccharide (LPS, Sigma Cat# L2018) at a final concentration of 100 ng/mL. After 24-hour incubation, plates were spun and the supernatant was collected and frozen at -80 0 C. The amount of TNF- ⁇ in the supernatant was quantified by using an ELISA kit. Results were expressed as percent of control calculated using the following equation:
  • TNFcompound amount of TNF- ⁇ in the presence of test compounds
  • TNFcontrol amount of TNF- ⁇ in the absence of test compounds
  • TNFbackground amount of TNF- ⁇ without LPS stimulation
  • the following components were admixed in conventional method and punched out to obtain 10,000 tablets each containing 10 mg of an active ingredient.
  • the following components were admixed in conventional method.
  • the solution was sterilized in conventional manner, filtered through dust removal equipment, placed
  • the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof has a TNF- ⁇ production inhibitory activity, and are furthermore safe, it is useful as a preventing and/or treating agent for, for example, a metabolic disease such as diabetes, etc, an inflammatory disease such as rheumatoid arthritis, etc.

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Abstract

A novel compound of formula (I): wherein all symbols have the same meanings as defined in the specification; a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof has a TNF-α production inhibitory activity, it is useful as a method for preventing and/or treating for a diabetes of metabolic disease, etc.

Description

DESCRIPTION
TNF-α production inhibitor
TECHNICAL FIELD
The present invention relates to a TNF-α production inhibitor. For more detail, the present invention relates to a novel compound of formula (I):
Figure imgf000002_0001
wherein all symbols are as hereinafter defined; a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.
BACKGROUND ART
Tumor necrosis factor alpha (TNF-α) plays a central role in the inflammatory response and has been targeted as a point of intervention in inflammatory disease. TNF-α is a polypeptide hormone released from macrophages and other cells via activation of Mytogen-activated protein (MAP) kinases. TNF-α also stimulates the synthesis of acute-phase proteins. Elevated levels of TNF-α have also been implicated in many other disorders and disease conditions, including metabolic diseases (for example, diabetes mellitus such as insulin-resistant diabetes mellitus or non-insulin- resistant diabetes mellitus), hyperlipemia, other insulin-resistant diseases, inflammatory diseases [for example, inflammation, dermatitis, atopic dermatitis, hepatitis, nephritis, glomerulonephritis, pancreatitis, psoriasis, gout, Addison's disease, arthrititis (for example, rheumatoid arthritis, osteoarthritis, rhumatoid spondylitis, gouty arthritis, synovitis, etc.), inflammatory ocular diseases, inflammatory pulmonary diseases (for example, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), etc.), inflammatory bowel diseases (for example, Crohn's disease, ulcerative colitis, etc.), allergic diseases (for example, allergic dermatitis, allergic rhinitis, etc.), autoimmune disease, autoimmune hemolytic anemia, systemic lupus erythematosus, rheumatism, Castleman's disease, immune rejection accompanying transplantation (for example, graft versus host reaction, etc.), and so forth], central nervous system disorders [for example, central neuropathy (for example, cerebrovascular disease such as cerebral hemorrhage and cerebral infarction, head trauma, spinal cord injury, cerebral edema, multiple sclerosis, etc), neurodegenerative disease (for example, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), AIDS encephalopathy, etc.), meningitis, Creutzfeldt- Jakob syndrome, and so forth], respiratory diseases [for example, asthma, chronic obstructive pulmonary disease (COPD), and so forth], cardiovascular diseases [for example, angina, heart failure (for example, congestive heart failure, acute heart failure, chronic heart failure, etc.), myocardial infarction (for example, acute myocardial infarction, myocardial infarction prognosis, etc.), atrial myxoma, arteriosclerosis, hypertension, dialysis-induced hypotension, thrombosis, disseminated intravascular coagulation (DIC), reperfusion injury, restenosis after percutaneous transluminal coronary angioplasty (PTCA), and so forth], urinary diseases [for example, renal failure, and so forth], bone diseases [for example, osteoporosis, and so forth], cancerous diseases [for example, malignant tumor (for example, tumor growth and metastasis, etc.), multiple myeloma, plasma cell leukemia, carcinemia, and so forth], and infectious diseases [for example, viral infection (for example, cytomegalovirus infection, influenza virus infection, herpes virus infection, corona virus infection, etc.), cachexia associated with infections, cachexia caused by acquired immune deficiency syndrome (AIDS), toxemia (for example, sepsis, septic shock, endotoxin shock, gram negative bacterial sepsis, toxic shock syndrome, severe acute respiratory syndrome (SARS) accompanying virus infection, etc.), and so forth].
Therefore, it can be seen that inhibitors of TNF-α are potentially useful in the treating of a wide variety of diseases such as metabolic diseases and inflammatory disease.
In contrast, a protein kinase is an enzyme that catalyzes the reaction to transfer a phosphate group from adenosine triphosphate (ATP) to an amino acid residue, such as tyrosine, serine, threonine, and/or histidine in a protein. More than 500 protein kinases have been identified to date. These protein kinases play essential and important roles in various and diverse cell functions, such as cell division, cell differentiation, cell death (apoptosis), the alteration of cell motility and cytoskeleton structure, the control of DNA replication, splicing and translation, protein transportation from endoplasmic reticulum or Golgi apparatus into the membrane or extracellular space migration of protein into the nucleus and exportation out of the nucleus, and metabolic reactions.
It is well known that the dysfunction of protein phosphorylation has an essential role in the etiology of many diseases, such as tumors, immunological disorders, nervous affection, and metabolic disease. For example, Receptor tyrosine kinases (RTK), such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGF) over-express in various types of tumor cells, and gain- of-function mutations of tyrosine kinases are observed in tumor cells [Druker, Nat. Med., 2, 561 (1996)]. Furthermore, the deletion of protein serine/threonine kinase genes is reported to relate to several diseases such as myotonic dystrophy, cancer, and Alzheimer's disease [Sanpei, Biochem. Biophys. Res. Commun., 212, 341 (1995); Sperber, Neurosci. Lett., 197, 149 (1995); Grammas, Neurobiol. Aging, 16, 563 (1995); Govoni, Ann. N. Y. Acad. Sci., 777, 332 (1996)].
MAP kinases also play vital roles in the pathophysiology of many diseases by regulating cellular functions such as proliferation, apoptosis, and inflammatory cytokine production. c-Jun, which forms transcription factor AP-I complex by associating with c-Fos, is one of the main substrates of MAP kinases, phosphorylation and subsequent activation of c-Jun are suggested to be one of the most important steps of the signaling process of MAP kinases.
Therefore, a compound which inhibits c-Jun phosphorylation is considered to be potentially useful for the therapy of diseases which are triggered by the protein phosphorylation.
According to the information presented above, a compound which inhibits c- Jun phosphorylation would be expected to be useful as a preventing and/or treating agent for metabolic diseases (for example, diabetes mellitus such as insulin-resistant diabetes mellitus or non-insulin-resistant diabetes mellitus), hyperlipemia, other insulin- resistant diseases, inflammatory diseases (for example, rhinitis, pharyngitis, bronchitis, pneumonia, pleuritis, bronchial asthma, chronic pulmonary emphysema, pulmonary fibrosis, inflammatory bowel disease, acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, chronic thyroiditis, autoimmune gastritis), scleroderma, deep lupus erythematosus, Graves' disease, autoimmune neutropenia, thrombocytopenia, myasthenia gravis, multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, chronic myelocytic leukemia, metastatic melanoma, Kaposi's sarcoma, debilitating disease, Huntington's disease, ischemic/reperfusion disorders of stroke, myocardial ischemic symptom, ischemic heart disease, renal ischemia, neovascular glaucoma, infantile hemangioma, vascular proliferation, cardiac hypertrophy, abnormal immune response, pyrexia, cellular senescence, apoptosis- related diseases, and the like. In addition, activation of lymphocyte and macrophage immune response to pathogens involve complex intracellular signaling pathways involving a cascade of various phosphorylating enzymes, kinases that ultimately regulate cytokine production and cell apoptosis. Key kinases include MAP kinases. Lipopolysaccharide (LPS)- induced TNF-α production by human monocytes involves activation of MAP kinases. As TNF-α is a key mediator of autoimmune disease, blocking the MAP kinases pathway has potential for the treating of inflammatory and immunological diseases such as lupus, rheumatoid arthritis, psoriasis and destruction of pancreatic islet beta cells in Type I diabetes. That is to say, inhibiting MAP kinases activity is expected to be useful in the treating of the diseases relating to TNF-α, because MAP kinases are considered to have a relationship with TNF-α production. Accordingly, a compound which inhibits c-Jun phosphorylation is considered to be potentially useful for the therapy of diseases which has a relationship with TNF-α production.
It has been described that a compound represented by formula (A):
Figure imgf000005_0001
wherein, R1A is phenyl optionally substituted with one or more halogen(s), (C)-C6)alkyl, (CrC6)alkoxy, (d-C^alkylthio, etc.; R2A is a hydrogen, halogen, (d-C9)alkyl optionally substituted with
Figure imgf000005_0002
trifluoromethyl, or with one or more fluorine(s), etc.; R3A is a hydrogen, (Ci-C6)alkyl, or benzyl; XA is -C(=O)- or CH2; provided that when XA is CH2; R4A is (C2-C6)alkyl(s) group, cyclic (C3-C7)alkyl group which is optionally substituted with one or more (C!-C6)alkyl(s), hydroxy, (Ci- C6)alkoxy, trifluoromethyl, cyano, or fluorine, etc.; with the proviso that only required symbols in the group are extracted; is useful for suppressing appetite and inducing weight loss (see WO 03/027114). und represented by formula (B):
Figure imgf000006_0001
wherein, mB is 0, 1 or 2; nB is 1, 2 or 3; qB is 0 or 1 ; ArB is an aryl or heteroaryl ring; CYCB is a hydrogen or a carbocyclic, heterocyclic, aryl or heteroaryl ring; R1B is selected from the group consisting of a hydrogen, Ci-7alkyl, C2-7alkenyl, C2-7alkynyl, C3- 7cycloalkyl, C3-7cycloalkylC1-7alkyl, C3-7cycloaklenyl, C3-7cycloalkenylC1-7alkyl and benzo-fusedC4-7cycloalkyl, each optionally mono-, di-, or tri-substituted with RpB; R2B is selected from the group consisting of a hydrogen, C1-7alkyl, C2-7alkenyl, C2-7alkynyl and C3.7cycloalkyl; with the proviso that only required formulae and symbols in the group are extracted; is useful as a serotonin modulator (see WO 2005/040169).
Furthermore, it was described that a compound represented by formula (C):
(C)
Figure imgf000006_0002
wherein, R is lower alkyl, aryl lower alkyl of from 7 to 12 carbon atoms, phenyl, lower alkylphenyl, halophenyl, lower alkoxyphenyl, naphthyl, halonaphthyl, lower alkoxynaphthyl, or lower alkylnaphthyl; R is lower alkyl, phenyl, halophenyl, lower alkoxyphenyl, lower alkylphenyl, naphthyl, halonaphthyl, lower alkylnaphthyl, or lower alkoxynaphthyl; R2C is a hydrogen, lower alkyl, -CHO, -CH-NOH, or -CH2OR5C wherein R5C is a hydrogen or lower alkyl; R3C is a hydrogen, lower alkyl, benzoyl, aryl lower alkyl of from 7 to 12 carbon atoms or aryl lower alkyl of from 7 to 12 carbon atoms wherein the aryl portion is substituted by halogen, lower alkyl or lower alkoxy; R4C is a hydrogen or lower alkyl; with the proviso that only required symbols in the group are extracted; is useful for the treating of hypertension (see US 3992544).
DISCLOSURE OF THE INVENTION
It is desired to develop a TNF-α production inhibitor as an agent for the preventing and/or treating metabolic diseases, inflammatory diseases or the like.
The present inventors have made extensive studies to find a compound that can become a treating agent for various diseases by inhibiting the production of TNF-α, and as a result, have found that the object is achieved by the compounds of the present invention represented by the formula (I), and then have completed the present invention.
Namely, the present invention relates to the followings. (I) :
Figure imgf000007_0001
wherein R1 is a hydrogen atom or R5 -X-;
R5 is an optionally substituted alkyl group, an optionally substituted alkoxy carbonyl group, an optionally substituted acyl group or
Figure imgf000008_0001
X is bond or -NR8CO-;
R is a hydrogen atom or an optionally substituted alkyl group; ring 1 is a cyclic group which may be optionally substituted;
R6 is a hydrogen atom, an optionally substituted alkoxycarbonyl group, a carboxyl group, a nitrile group, an optionally substituted alkylsulfonyl group, an optionally substituted alkyl group, an optionally substituted acyl group, a halogen atom, an optionally substituted alkoxy group or
Figure imgf000008_0002
n is an integer of from 1 to 4, wherein when n is 2 or more, R6's are the same or different; ring 3 is a cyclic group which may be optionally substituted; R7 is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted alkoxycarbonyl group; Z is -SO2-, -O-, -CH2-, -CO-, -CH2O- or -OCH2-;
R2 is an optionally protected carbamoyl group, an optionally protected aminocarbonothioyl group or an optionally protected amino(imino)methyl group;
R3 is an optionally substituted alkyl group, a halogen atom, a nitrile group or an optionally substituted alkoxy group; R4 is a hydrogen atom, an optionally substituted alkyl group or
Figure imgf000008_0003
ring 2 is a cyclic group which may be optionally substituted; and
Y is bond or -CH2-, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof. (2) The compound according to (1) above, wherein R is an optionally protected carbamoyl group.
(3) The compound according to (1) above, wherein R1 is
above, wherein
Figure imgf000009_0001
(5) The compound according to (1) above, wherein R1 is
Figure imgf000009_0002
(6) The compound according to (1) above, wherein Y is bond.
(7) The compound according to (4) above, which is a compound represented by the following formula (1-1):
Figure imgf000010_0001
(8) The compound according to (7) above, wherein ring 1 is cyclohexane, benzene, pyridine, indole, benzimidazole or piperidine; ring 2 is benzene; and ring 3 is benzene or piperazine. (9) A method for preventing and/or treating a TNF-α mediated disease, which comprises administering to a mammal an effective amount of the compound of formula (I) according to (1) above, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.
(10) The method according to (9) above, wherein the TNF-α mediated disease is metabolic disease.
(11) The method according to (10), wherein the metabolic disease is diabetes mellitus.
(12) The method according to (11), wherein the diabetes mellitus is insulin- resistant diabetes mellitus. (13) A method for inhibiting TNF-α production, which comprises administering to a mammal an effective amount of the compound of the formula (I) according to (1) above, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.
(14) The method according to (9) above, wherein the compound of formula (I) according to (1) above, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof is administrated in combination with one or two or more medicaments selected from the group consisting of an MTP inhibitor, an HMG-CoA reductase inhibitor, a squalene synthetase inhibitor, a fibrate preparation, an ACAT inhibitor, a 5- lipoxygenase inhibitor, a cholesterol absorption inhibitor, a bile acid absorption inhibitor, an ileum NaVbile acid cotransporter inhibitor, an LDL receptor activator/expression enhancer, a lipase inhibitor, a probucol preparation, a nicotinic acid preparation, a hypoglycemic sulfonylurea agent, a biguanide preparation, an α- glucosidase inhibitor, a rapid-acting insulin secretagogue, a GPR 40 agonist, a SGLTl inhibitor, a SGLT2 inhibitor, an insulin preparation, a DPP4 inhibitor, a PTPlB inhibitor, a β3 adrenoceptor agonist, a PPAR agonist, and a therapeutic agent for diabetes complications.
(15) A pharmaceutical composition which comprises the compound of formula (I) according to (1) above, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.
(16) Use of the compound of formula (I) according to (1) above, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, for the manufacture of an agent for preventing and/or treating a TNF-α mediated disease.
Throughout the present specification, R1 is a hydrogen atom or R5-X-. Throughout the present specification, R5 is an optionally substituted alkyl groups, an optionally substituted alkoxycarbonyl groups, an optionally substituted acyl groups or
Figure imgf000011_0001
The alkyl groups in "the optionally substituted alkyl groups" as R5 include, for example, straight-chain or branched C 1-20 alkyl groups, such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl, etc., where as substituents on the alkyl groups, there may be mentioned, for example, hydroxyl group, amino group, carboxyl group, nitro group, azido group, mono- or di-Cl-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), N-aromatic-ring amino groups (e.g., N-phenylamino, etc.), N-aromatic-N-alkylamino groups (e.g., N-phenyl-N- methylamino, N-phenyl-N-ethylamino, N-phenyl-N-propylamino, N-phenyl-N - butylamino, N-phenyl-N-pentylamino, N-phenyl-N-hexylamino, etc.), acylamino groups (e.g., formylamino, acetylamino, propionylamino, benzoylamino, etc.), N-acyl- N-alkylamino groups (e.g., N-formyl-N-methylamino, N-acetyl-N-methylamino, N- propionyl-N-methylamino, N-benzoyl-N-methylamino, etc.), alkoxycarbonylamino groups (e.g., methoxycarbonylamino, benzyloxycarbonylamino, tert- butyloxycarbonylamino, etc.), C 1-6 alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, hexyloxy, etc.), C3-7 cycloalkyl-Cl-6 alkoxy groups (e.g., cyclohexylmethyloxy, cyclopentylethyloxy, etc.), C3-7 cycloalkyloxy groups (e.g., cyclohexyloxy, etc.), C7-15 aralkyloxy groups (e.g., benzyloxy, phenetyloxy, phenylpropyloxy, naphthylmethyloxy, naphthylethyloxy, etc.), phenoxy group, C 1-6 alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), Cl-6 alkoxylcarbonyloxy groups (e.g., acetoxy, ethyl- carbonyloxy, etc.), Cl-4 alkylthio groups (e.g., methylthio, ethylthio, propylthio, butylthio, etc.), halogen atoms ( fluorine, chlorine, bromine and iodine), alkylsulfonyl groups (e.g., Cl-4 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, etc., and the like), aromatic-ring sulfonyl groups (e.g., C6-10 aromatic-ring sulfonyl groups such as phenylsulfonyl, etc.), acyl groups (e.g., Cl-6 alkanoyl groups such as formyl, acetyl, propanoyl, pivaloyl, etc., C6- 10 aromatic-ring carbonyl groups such as benzoyl, etc., and the like), oxo group, imino group (HN=), optionally substituted carbon ring radicals, and optionally substituted heterocyclic radicals, and the like, and these arbitrary substituents in number of 1 to 4 may be replaced at any substitutable positions. The carbon rings as a substituent on the alkyl groups include, for example, C3-
15 monocyclic, bicyclic or tricyclic aromatic carbon rings which may be partially or fully saturated. The partially or fully saturated C3-15 monocyclic, bicyclic or tricyclic aromatic carbon rings include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphtahlene, perhydro- naphtahlene, heptalene, perhydroheptalene, biphenylene, as-indacene, s-indacene, acenaphthylene, acenaphthene, fluorene, phenalene, phenanthlene or anthracene ring, etc. Also, the C3-15 monocyclic, bicyclic or tricyclic aromatic carbon rings which may be partially or fully saturated embrace spiro-bonded bicyclic carbon rings and crosslinked bicyclic carbon rings, and include, for example, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane, bicyclo[2,2, 1 Jheptane, bicyclo[2,2, 1 ]hept-2-ene, bicyclo[3 ,1,1 Jheptane, bicyclo[3,3,l]heptane, bicyclo[3.1.1]hept-2-ene, bicyclo[2.2.2]octane, bicyclo- [2.2.2]oct-2-ene, adamantane or noradamantane ring, etc.
The substitutes on the carbon rings as a substituent on the alkyl groups include, for example, C 1-8 alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc.), hydroxyl group, amino group, carboxyl group, nitro group, mono- or di-Cl-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), C 1-6 alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, hexyloxy, etc.), C 1-6 alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), Cl-6 alkoxylcarbonyloxy groups (e.g., acetoxy, ethylcarbonyloxy, etc.), Cl-4 alkylthio groups (e.g., methylthio, ethylthio, propylthio, butylthio, etc.), halogen atoms (fluorine, chlorine, bromine, iodine) or trihalomethyl groups (e.g., trifluoromethyl, etc.), and the like, and these arbitrary substituents in number of 1 to 4 may be replaced at any substitutable positions.
The heterocyclic rings as a substituent on the alkyl groups include, for example, 3- to 15-membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be partially or fully saturated. Among the 3- to 15-membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be partially or fully saturated, the 3- to 15-membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms include, for example, a pyrrole, imidazole, triazole, tetrazole, pyrazol, pyridine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thaizine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolidine, purine, phthaladine, pteridine, naphthylidine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromen, benzoxepine, benzoxazepine, benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, benzofurazane, benzothiadiazole, benzotriazole, carbazole, β-carboline, acridine, phenazine, dibenzofuran, xanthene, dibenzothiophene, phenothiadine, phenoxazine, phenoxathyin, thiathrene, phenathoridine, phenanthroline or perimidine ring, etc.
Among 3- to 15-membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be partially or fully saturated, examples of the 3- to 15- membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which are partially or fully saturated, include aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydroxepine, tetrahydroxepine, perhydroxepine, thiirane, thiethane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazane, tetrahydrofurazane, dihydroxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine, tetrahydroxadiazine, dihydroxazepine, tetrahydroxazepine, perhydroxazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolizine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomoφholine, oxathian, indoline, isoindoline, dihydrobenzofuran, tetrahydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, tetrahydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroiosquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthylidine, tetrahydronaphthylidine, perhydronaphthylidine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomoφholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, dihydrobenzothiazepine, tetrahydrobenzothiazepine, dihydrobenzazepine, tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepan, dihydrobenzoxazepine, tetrahyrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhyddroacridine, dihydrobenzofuran, dihydrodibenzothiophene, tetrahydrobenzofuran, tetrahydrodibenzothiophene, perhydrodibenzofuran, perhydrodibenzothiophene, dioxorane, dioxane, dithiorane, dithiane, dioxaindane, benzoxane, chromane, benzothiorane or benzothiane ring, and the like.
The substitutes on the heterocyclic ring as a substituent on the alkyl groups include, for example, C 1-8 alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc.), hydroxyl group, amino group, carboxyl group, nitro group, mono- or di-Cl-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), C 1-6 alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, hexyloxy, etc.), C 1-6 alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), C 1-6 alkoxylcarbonyloxy groups (e.g., acetoxy, ethylcarbonyloxy, etc.), C 1-4 alkylthio groups (e.g., methylthio, ethylthio, propylthio, butylthio, etc.) or halogen atoms (fluorine, chlorine, bromine, iodine) and the like, and these arbitrary substituents in number of 1 to 4 may be replaced at any substitutable positions.
The alkoxycarbonyl groups in "the optionally substituted alkoxycarbonyl groups" as R5 include, for example, straight-chain or branched C 1-20 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, tert-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, tridecyloxycarbonyl, tetradecyloxycarbonyl, pentadecyloxycarbonyl, hexadecyloxycarbonyl, heptadecyloxycarbonyl, octadecyloxycarbonyl, nonadecyloxycarbonyl or eicosyloxycarbonyl, etc.
On the above occasion, the substituents on the alkoxycarbonyl groups are as defined above for the substituents in the "the optionally substituted alkyl groups" as R5, and these arbitrary substituents may be replaced at any substitutable positions.
The acyl groups in "optionally substituted acyl groups" as R5 include, for example, (1) optionally substituted alkylcarbonyl groups, (2) optionally substituted alkenylcarbonyl groups, (3) optionally substituted alkynylcarbonyl groups, (4) optionally substituted carbon ring carbonyl groups or (5) optionally substituted heterocyclic carbonyl groups.
(1) The alkyl groups in "optionally substituted alkylcarbonyl groups" are as defined for the alkyl groups in the "optionally substituted alkyl groups" as R5. On the above occasion, the substituents on the alkylcarbonyl groups are as defined above for the substituents in the "the optionally substituted alkyl groups" as R5, and these arbitrary substituents may be replaced at any substitutable positions.
(2) The alkenyl groups in the "optionally substituted alkenylcarbonyl groups" include, for example, straight-chain or branched C2-20 alkenyl groups such as ethenyl, propenyl, butenyl, pentenyl or hexenyl, etc. On the above occasion, the substituents on the alkenylcarbonyl groups are as defined above for the substituents in the "the optionally substituted alkyl groups" as R5, and these arbitrary substituents may be replaced at any substitutable positions. (3) The alkynyl groups in the "optionally substituted alkynylcarbonyl groups" include, for example, straight-chain or branched C2-20 alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl or hexynyl, etc. On the above occasion, the substituents on the alkenylcarbonyl groups are as defined above for the substituents in the "the optionally substituted alkyl groups" as R5, and these arbitrary substituents may be replaced at any substitutable positions.
(4) The carbon ring in the "optionally substituted carbon ring carbonyl groups" include, for example, C3-15 monocyclic, dicyclic or tricyclic aromatic carbon rings, which may be partially or fully saturated. Examples of the C3-15 monocyclic, dicyclic or tricyclic aromatic carbon rings, which may be partially or fully saturated, include cyclopropane, cuclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cycloodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, heptalene, perhydroheptalene, biphenylene, as-indasene, s- indasene, acenaphthylene, acenaphthene, fluorene, phenalene, phenathrene or anthracene ring, etc. Also, the C3-15 monocyclic, bicyclic or tricyclic aromatic carbon rings which may be partially or fully saturated contain spiro-bonded bicyclic carbon rings and crosslinked bicyclic carbon rings, as well and include, for example, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane, bicycle[2.2.1]heptane, bicycle[2.2.1]- hept-2-ene, bicycle[3.1.1 ]heptane, bicycle[3.1.1 ]hept-2-ene, bicycle[2.2.2]octane, bicycle[2.2.2]oct-2-ene, adamantane or noradamantane ring, etc.
On the above occasion, the substituents on the carbon rings include, for example, C 1-4 alkyl groups (e.g., methyl, ethyl, propyl, butyl, etc.), C2-4 alkenyl groups (e.g., ethenyl, propenyl, butenyl, etc.), C2-4 alkynyl groups (e.g., ethynyl, propynyl, butyunyl, etc.), hydroxyl group, C 1-4 alkoxy groups (e.g., methoxy, ethoxy, propxy, butoxy, etc.), Cl-6 alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), thiol group, C 1-4 alkylthio groups (e.g., methylthio, ethylthio, propylthio, butylthio, etc.), amino group, mono- or di-Cl-4 alkylamino groups (e.g., methylamino, ethylamino, propylamino, dimethylamino, etc.), amino-Cl-4 alkyl groups (e.g., aminomethyl, etc.), mono- or di-Cl-4 alkylamino-Cl-4 alkyl groups (e.g., dimethylaminomethyl, mehtylaminomethyl, etc.), imino group, alkyl groups substituted by imino group (e.g., ethaneimidoyl, etc.), oxo group, halogen atoms (fluorine, chlorine, bromine, iodine), trihalomethyl groups (e.g., trifluoromethyl, etc.), trihalomethoxy groups (e.g., trifluoromethoxy, etc.), trihalomethylthio groups (e.g., trifluoromethylthio, etc.), dihalomethylthio groups (e.g., difluoromethylthio, etc.), cyano group, Cl-4 alkylsulfonyl groups (e.g., methylsulfonyl, ethylsulfonyl, etc.) or nitro group, and the like, and these arbitrary substituents in number of 1 to 4 may be replaced at any substitutable positions.
(5) The heterocyclic ring in the "optionally substituted heterocyclic carbonyl groups" include, for example, 3- to 15-membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be partially or fully saturated, and the like. Among the optionally partially or fully saturated 3- to 15-membered, monocyclic, bicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, the 3- to 15-membered, monocyclic, bicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from an oxygen, nitrogen or sulfur atom include, for example, a pyrrole, imidazole, triazole, tetrazole, pyrazol, pyridine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazol, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thaizine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolidine, purine, phthaladine, pteridine, naphthylidine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromen, benzoxepine, benzoxazepine, benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, benzofurazane, benzothiadiazole, benzotriazole, carbazole, β-carboline, acridine, phenazine, dibenzofuran, xanthene, dibenzothiophene, phenothgiadine, phenoxazine, phenoxathyin, thiathrene, phenathoridine, phenanthroline, perimidine, oxazolopyridine, thiazolopyrimidine or imidazopyridine ring, etc. Among 3- to 15-membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be partially or fully saturated, examples of the 3- to 15- membered, monocyclic, dicyclic or tricyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which are partially or fully saturated, include aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran, tetrahydroforan, dihydropyran, tetrahydropyran, dihydroxepine, tetrahydroxepine, perhydroxepine, thiirane, thiethane, dihydrothiophene, tetrahydrothiophene, dihydroothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazane, tetrahydrofurazane, dihydroxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydroxazepine, perhydroxazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolizine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathian, indoline, isoindoline, dihydrobenzofuran, tetrahydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, tetrahydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroiosquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthylidine, tetrahydronaphthylidine, perhydronaphthylidine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane, dihydrobenzoxadine, dihydrobenzothiadine, pyrazinomoφholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, perhydrobenzimidazole, dihydrobenzazepine, tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepan, dihydrobenzoxazepine, tetrahyrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, dihydrobenzofuran, dihydrodibenzothiophene, tetrahydrobenzofuran, tetrahydrodibenzothiophene, perhydrodibenzofuran, perhydrodibenzothiophene, dioxorane, dioxane, dithiorane, dithiane, dioxaindane, benzoxane, chromane, benzothiorane, benzothiane, benzothiazine, tetrahydroxazolopyridine, tetrahydrothiazolopyrimidine, oxazinane or oxazepan ring, and the like.
On the above occasion, the substituents on the heterocyclic ring include, for example, C 1-4 alkyl groups (e.g., methyl, ethyl, propyl, butyl, etc.), C2-4 alkenyl groups (e.g., ethenyl, propenyl, butenyl, etc.), C2-4 alkynyl groups (e.g., ethynyl, propynyl, butyunyl, etc.), hydroxyl group, Cl-4 alkoxy groups (e.g., methoxy, ethoxy, propxy, butoxy, etc.), C 1-6 alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), thiol group, Cl-4 alkylthio groups (e.g., methylthio, ethylthio, propylthio, butylthio, etc.), amino group, mono- or di-Cl-4 alkylamino groups (e.g., methylamino, ethylamino, propylamine, dimethylamino, etc.), amino-Cl-4 alkyl groups (e.g., aminomethyl, etc.), mono- or di-Cl-4 alkylamino-Cl-4 alkyl groups (e.g., dimethylaminomethyl, mehtylaminomethyl, etc.), imino group, alkyl groups substituted by imino group (e.g., ethaneimidoyl, etc.), oxo group, halogen atoms (fluorine, chlorine, bromine, iodine), trihalomethyl groups (e.g., trifluoromethyl, etc.), trihalomethoxy groups (e.g., trifluoromethoxy, etc.), trihalomethylthio groups (e.g., trifluoromethylthio, etc.), dihalomethylthio groups (e.g., difluoromethylthio, etc.), cyano group, Cl-4 alkylsulfonyl groups (e.g., methylsulfonyl, ethylsulfonyl, etc.) or nitro group, and the like, and these arbitrary substituents in number of 1 to 4 may be replaced at any substitutable positions. Among
Figure imgf000020_0001
represented by R5, -ring 1 is cyclic group which may be further optionally substituted.
The cyclic group in "cyclic group which may be further optionally substituted" as ring 1 include, for example, optionally substituted carbon ring radicals and optionally substituted heterocyclic radicals, etc. On the above occasion, "optionally substituted carbon ring radicals" as ring 1 are as defined for "optionally substituted carbon ring radicals" as the substituents of the the optionally substituted alkyl groups as R5. "Optionally substituted heterocyclic radicals" as ring 1 are as defined for "optionally substituted heterocyclic radicals" as the substituents of the the optionally substituted alkyl groups as R5.
Among
Figure imgf000021_0001
represented by R5, R6 is a hydrogen atom, optionally substituted alkoxycarbonyl groups, carboxyl group, nitrile group, optionally substituted alkylsulfonyl groups, optionally substituted alkyl groups, optionally substituted acyl groups, halogen atoms, optionally substituted alkoxy groups or
Figure imgf000021_0002
The "optionally substituted alkoxycarbonyl groups" as R6 is as defined for the "optionally substituted alkoxycarbonyl groups" as R5.
The alkylsulfonyl groups in "the optionally substituted alkylsulfonyl groups" as R6 include, for example, straight-chain or branched C 1-20 alkylsulfonyl groups, such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl, nonylsulfonyl, decylsulfonyl, undecylsulfonyl, dodecylsulfonyl, tridecylsulfonyl, tetradecylsulfonyl, pentadecylsulfonyl, hexadecylsulfonyl, heptadecylsulfonyl, octadecylsulfonyl, nonadecylsulfonyl or eicosylsulfonyl, etc.
On the above occasion, the substituents on the alkylsulfonyl groups are as defined above for the substituents in the "the optionally substituted alkyl groups" as R5. The "optionally substituted alkyl groups" as R6 is as defined for the "optionally substituted alkyl groups" as R5. The "optionally sub ssttiituted acyl groups" as R6 is as defined for the "optionally substituted acyl groups" as R5.
The "halogen atoms" as R >6 is fluorine, chlorine, bromine or iodine. The alkoxy groups in "the optionally substituted alkoxy groups" as R6 include, for example, straight-chain or branched C 1-20 alkoxy groups, such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy or eicosyloxy, etc.
On the above occasion, the substituents on the alkoxy groups is as defined above for the substituents in the "the optionally substituted alkyl groups" as R5, and these arbitrary substituents may be replaced at any substitutable positions. Among
Figure imgf000022_0001
represented by R6, ring 3 is cyclic group which may be further optionally substituted. The "cyclic group which may be further optionally substituted" as ring 3 is as defined for "cyclic group which may be further optionally substituted" as ring 1. Among
Figure imgf000022_0002
represented by R6, Z is -SO2-, -O-, -CH2-, -CO-, -CH2O- or -OCH2-.
Figure imgf000022_0003
represented by R6, or R7 is a hydrogen atom, optionally substituted alkyl groups or optionally substituted alkoxycarbonyl groups.
The "optionally substituted alkyl groups" as R7 is as defined for the "optionally substituted alkyl groups" as R5.
The "optionally substituted alkoxycarbonyl groups" as R is as defined for the "optionally substituted alkoxycarbonyl groups" as R5. Throughout the present specification, n is an integer from 1 to 4. When n is 2 or more, R6's may be the same or different.
Throughout the present specification, X is bond or -NR8CO-.
Among -NR CO- as X, R is a hydrogen atom or optionally substituted alkyl groups.
The "optionally substituted alkyl groups" as R8 is as defined for the "optionally substituted alkyl groups" as R5.
Throughout the present specification, R2 is optionally protected carbamoyl group, optionally protected aminocarbonothioyl group or optionally protected amino(imino)methyl group.
The protection groups in "optionally protected carbamoyl group", "optionally protected aminocarbonothioyl group" or "optionally protected amino(imino)methyl group" as R include, for example, optionally substituted alkyl groups (it is as defined above for "the optionally substituted alkyl groups" as R5), optionally substituted carbon ring radicals (it is as defined above for "optionally substituted carbon ring radicals" as the substituents of the optionally substituted alkyl groups as R5), optionally substituted heterocyclic radicals (it is as defined above for "optionally substituted heterocyclic radicals" as the substituents of the the optionally substituted alkyl groups as R5), alkylsulfonyl groups (e.g., C 1-4 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, etc., and the like), aromatic-ring sulfonyl groups (e.g., C6-10 aromatic- ring sulfonyl groups such as phenylsulfonyl, etc.) or optionally substituted acyl groups (it is as defined above for "the optionally substituted acyl groups" as R5), etc.
Throughout the present specification, R3 is optionally substituted alkyl groups, halogen atoms, nitrile group or optionally substituted alkoxy groups. The "optionally substituted alkyl groups" as R3 is as defined for the "optionally substituted alkyl groups" as R5.
The "halogen atoms" as R3 is as defined for the "halogen atoms" as R6. The "optionally substituted alkoxy groups" as R3 is as defined for the "optionally substituted alkoxy groups" as R6. Throughout the present specification, R4 is a hydrogen atom, optionally substituted alkyl groups or
Figure imgf000024_0001
The "optionally substituted alkyl groups" as R4 is as defined for the "optionally substituted alkyl groups" as R5. Among
Figure imgf000024_0002
represented by R4, ring 2 is cyclic group which may be optionally substituted.
The "cyclic group which may be optionally substituted" as ring 2 is as defined for "cyclic group which may be further optionally substituted" as ring 1.
Among
Figure imgf000024_0003
represented by R4, Y is bond or -CH2-. is preferably R5 -X-, more preferably
Figure imgf000024_0004
Figure imgf000024_0005
and most preferably
Figure imgf000024_0006
In the present invention, R5 is preferably
Figure imgf000025_0001
In the present invention, ring 1 is preferably C3-15 monocyclic or bicyclic aromatic carbon rings which may be partially or fully saturated, or 3- to 15-membered monocyclic or bicyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be partially or fully saturated, more preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, benzene, indene, indane, naphthalene, pyrrole, imidazole, triazole, tetrazole, pyrazol, pyridine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thaizine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolidine, purine, phthaladine, pteridine, naphthylidine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromen, benzoxepine, benzoxazepine, benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, benzofurazane, benzothiadiazole, benzotriazole, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydroxepine, tetrahydroxepine, perhydroxepine, thiirane, thiethane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazane, tetrahydrofurazane, dihydroxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine, tetrahydroxadiazine, dihydroxazepine, tetrahydroxazepine, perhydroxazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolizine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathian, indoline, isoindoline, dihydrobenzofuran, tetrahydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, tetrahydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroiosquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthylidine, tetrahydronaphthylidine, perhydronaphthylidine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, dihydrobenzothiazepine, tetrahydrobenzothiazepine, dihydrobenzazepine, tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepan, dihydrobenzoxazepine or tetrahyrobenzoxazepine, and most preferably cyclohexane, benzene, pyridine, indole, benzimidazole or piperidine.
In the present invention, R6 is preferably optionally substituted alkoxycarbonyl groups, optionally substituted alkylsulfonyl groups, optionally substituted alkyl groups, optionally substituted acyl groups, optionally substituted alkoxy groups or
and more preferably optionally substituted alkoxycarbonyl
Figure imgf000026_0001
In the present invention, ring 3 is preferably C3-15 monocyclic aromatic carbon rings which may be partially or fully saturated, or 3- to 15-membered monocyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be partially or fully saturated, more preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, benzene, pyrrole, imidazole, triazole, tetrazole, pyrazol, pyridine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thaizine, thiadiazine, thiazepine, thiadiazepine, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydroxepine, tetrahydroxepine, perhydroxepine, thiirane, thiethane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazane, tetrahydrofurazane, dihydroxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine, tetrahydroxadiazine, dihydroxazepine, tetrahydroxazepine, perhydroxazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolizine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine or oxathian, and most preferably benzene or piperazine.
In the present invention, Z is preferably -SO2-, -CH2-, or -CO-.
In the present invention, R7 is preferably a hydrogen atom or optionally substituted alkyl groups.
In the present invention, n is preferably an integer from 1 to 2.
In the present invention, X is preferably -NR CO-. In the present invention, R8 is preferably a hydrogen atom. In the present invention, R2 is preferably optionally protected carbamoyl group. In the present invention, R3 is preferably optionally substituted alkyl groups, or halogen atoms. In the present invention, R4 is preferably
Figure imgf000028_0001
In the present invention, ring 2 is preferably C3-15 monocyclic aromatic carbon rings which may be partially or fully saturated, or 3- to 15-membered monocyclic aromatic heterocyclic rings containing 1 to 5 of hetero atoms selected from oxygen, nitrogen and sulfur atoms, which may be partially or fully saturated, more preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, benzene, pyrrole, imidazole, triazole, tetrazole, pyrazol, pyridine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thaizine, thiadiazine, thiazepine, thiadiazepine, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydroxepine, tetrahydroxepine, perhydroxepine, thiirane, thiethane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazane, tetrahydrofurazane, dihydroxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine, tetrahydroxadiazine, dihydroxazepine, tetrahydroxazepine, perhydroxazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolizine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine or oxathian, and most preferably benzene.
In the present invention, Y is preferably bond or -CH2-.
In the present invention, the formula (I) is preferably the formula (1-1).
In the present invention, the compounds described in Examples are preferred.
The prodrug for the compound of the formula (I) means a compound which is converted to the compound represented by the formula (I) by the reaction with an enzyme, a gastric acid, or the like, in the living body. Examples of the prodrug for the compound represented by the formula (I) include a compound wherein the amino group of the compound represented by the formula (I) is acylated, alkylated, phosphorylated, or the like (e.g., a compound wherein the amino group of the compound represented by the formula (I) is substituted with eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo- 1 ,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, acetoxymethylation, tert-butylatiion, etc.); a compound wherein the hydroxy group of the compound represented by the formula (I) is acylated, alkylated, phosphorylated, borated, or the like (e.g., a compound wherein the hydroxy group of the compound represented by the formula (I) is modified by acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumaration, alanylation, dimethylaminomethylcarbonylation, etc.); a compound wherein the carboxyl of the compound represented by the formula (I) is modified by esterification, amidation, or the like (e.g., a compound wherein the carboxyl of the compound represented by the formula (I) is esterified or amidated with ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl ester, cyclohexyloxycarbonylethyl ester, methyl amide, etc.), and the like. These compounds may be prepared by known method. In addition, the prodrug for the compound represented by the formula (I) may take a hydrate form or a non-hydrate form. In addition, the prodrug for the compound represented by the formula (I) may be a compound which is converted into the compound represented by the formula (I) under the physiological conditions as described in Pharmaceutical Research and Development, Vol.7 "Molecular Design", pages 163-198 published in 1990 by Hirokawa Publishing Co. In addition, a compound (I) may be labeled with an isotope (e.g., 3H, 14C, 35S, 125I, etc) and the like.
All isomers are included in the present invention, unless otherwise specified. For example, alkyl, alkoxy and alkynylene includes straight or branched one. In addition, isomers on double bond, ring, fused ring (E-, Z-, cis-, trans-isomers), isomers generated due to asymmetric carbon atom(s) (R-, S-, α-, β-isomers, enantiomer, diastereomer), optically active isomers with optical rotation (D-, L-, d-, 1-isomers), polar compounds generated by chromatographic separation (more polar compound, less polar compound), equilibrium compounds, mixtures thereof with arbitrary ratio and racemic mixtures are also included in the present invention. Further, isomers due to the tautomerism are all included in the present invention.
SALT
In the present invention, the compound represented by the formula (I) may form a salt thereof, and may be N-oxide form thereof or quaternary ammonium salt thereof. Furthermore, these compounds may be a solvate thereof. The compounds of the present invention include all pharmacologically acceptable salts of the compound represented by the formula (I). As pharmacologically acceptable salts, water-soluble salts with little toxicity are preferred. Suitable pharmacologically acceptable salts in the compound of the present invention include, for example, salts with alkali metals (such as potassium, sodium, lithium, and the like); salts with alkaline earth metals (such as calcium, magnesium, and the like); ammonium salts (such as tetramethylammonium salts, tetrabutylammonium salts, and the like); salts with organic amines (such as triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine, and the like); and acid addition salts such as salts with inorganic acid (such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, and the like), and salts with organic acid (such as acetate, trifuloroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methansulfonate, ethansulfonate, benzenesulfonate, toluenesulfonate, isethionate, gulcuronate, gluconate and the like), and the like. The N-oxide form of the compound represented by the formula (I) means the compound wherein the nitrogen atom was oxidized. The N-oxide form of the compound represented by the formula (I) may additionally form a salt described above. The quaternary ammonium salt of the compound represented by the formula (I) means the compound wherein the nitrogen atom of the compound represented by the formula (I) is quaternized by R0 (R0 represents alkyl, alkenyl, alkynyl (which has the same meaning as described above) which each may have a substituent(s), and cyclic ring (which has the same meaning as described above) which may have a substituent(s).) The quaternary ammonium salt of the compound represented by the formula (I) may additionally form the salt described above and the N-oxide form described above. The appropriate solvate of the compound represented by the formula (I), a salt thereof, an N-oxide form thereof, and a quaternary ammonium salt thereof, include hydrate, alcoholate (such as ethanolate) and the like. The solvates are preferably low toxic and water-soluble.
The compounds represented by the formula (I) can be converted into the salt described above, the N-oxide form described above thereof, the solvates described above by conventional means.
Process for Producing the Compounds of the Present Invention
The compounds of the present invention as represented by the formula (I) can be produced, for example, in accordance with the below-described processes or processes similar thereto, or the processes to be described in examples. In the below- described production processes, the starting compounds may be used as a salt, wherein as such salts, there may be used the pharmaceutically allowable salts of the compounds represented by the formula (I) to be described below.
Among the compounds represented by the formula (I), for example, the the formula:
Figure imgf000031_0001
R2 is a carbamoyl group and R4 is ring 2, i.e., the compound represented by the formula
Figure imgf000032_0001
wherein all the symbols have the same meanings as the above mentioned can be produced by the below-described process.
The compounds represented by the formula (1-1) can be produced by subjecting a compound represented by the formula (II):
Figure imgf000032_0002
wherein ring 1 !, ring 31, Z1, R7"1 and R8'1 are as defined for ring 1, ring 3, Z, R7 and R8, respectively, and the carboxy, hydroxy, amino or thiol groups to be comprised by ring I1, ring 3', Z1, R7"1 and R8"1 are understood to be protected, if required so, the compound represented by the formula (III):
Figure imgf000032_0003
wherein ring 2 and R "' are as defined for ring 2 and R , respectively, and the carboxy, hydroxy, amino or thiol groups to be comprised by ring 21 and R3"1 are understood to be protected, if required so and the compound represented by the formula (IV):
Figure imgf000033_0001
wherein R10 and R11, each independently, is 1-imidazolyl, a halogen atom or trihalomethoxy (such as trichloromethoxy and the like) to a reaction, followed by a deprotection reaction for the protecting group(s), as the case may be.
A reaction with a compound represented by formula (II), a compound represented by formula (III) and a compound represented by formula (IV) (such as a phosgene compound (such as phosgene, triphosgene (bis(trichloromethyl) carbonate), and the like) or an imidazole compound (such as CDI (carbonyldiimidazole), and the like) is carried out, for example, in an organic solvent (such as ethyl acetate, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, benzene, toluene and the like), or in the absence of a solvent and a base (such as pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, and the like) at the temperature of -78°C to reflux temperature.
This reaction is preferred to be carried out under an inert gas (argon, nitrogen, etc.) atmosphere on anhydrous condition.
The deprotection reactions for the protective groups for carboxy, hydroxy, amino or thiol group are well known, and are exemplified by:
(1) Deprotection reaction through alkali hydrolysis,
(2) Deprotection reaction under acidic conditions,
(3) Deprotection reaction through hydrogenolysis,
(4) Deprotection reaction for a silyl group, (5) Deprotection reaction with a metal, and
(6) Deprotection reaction with a metal complex.
Specific description of these reactions is to be made below.
(1) The deprotection reaction through alkali hydrolysis is carried out, for example,in an organic solvent (e.g., methanol, tetrahydrofuran, dioxane, etc.) with use of a hydroxide of an alkali metal (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), a hydroxide of an alkaline earth metal (barium hydroxide, calcium hydroxide, etc.) or a carbonate (sodium carbonate, potassium carbonate, etc.), an aqueous solution thereof, or their mixtures at a temperature of about 0 to 40°C. (2) The deprotection reaction under acidic conditions is conducted into practice, for example, in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, anisole, etc.) and in an organic acid (e.g., acetic acid, trifluroacetic acid, methanesulfonic acid, p-tosyl acid, etc.), inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.) or their mixtures (hydrobromic acid/acetic acid, etc.) at a temperature of about 0 to 100°C.
(3) The deprotection reaction through hydrogenolysis is carried out, for example, in a solvent (e.g., ethers (e.g., tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (e.g., methanol, ethanol, etc.), benzenes (e.g., benzene, toluene, etc.), ketones (acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), amides (e.g., dimethylformamide, etc.), water, ethyl acetate, acetic acid or solvent mixtures of not less than two thereof, etc.) in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium hydroxide- carbon, platinum oxide, Raney-nickel, etc.), under an atmosphere of hydrogen at atmospheric pressure or applied pressure, or in the presence of ammonium formate at a temperature of about 0 to 200°C.
(4) The deprotection reaction for a silyl group is conducted into practice, for example, in a water-miscible organic solvent (e.g., tetrahydrofuran, acetonitrile, etc.) with use of tetrabutylammonium fluoride at a temperature of about 0 to 40°C. (5) The deprotection reaction with use of a metal is performed, for example, in an acidic solvent (e.g., acetic acid, a buffer of pH about 4.2 to 7.2 or mixed solutions thereof with organic solvents, such as tetrahydrofuran, etc.) in the presence of powdered zinc at a temperature of about 0 to 40°C, under application of ultrasonics, if necessary. (6) The deprotection reaction with use of a metal complex is carried out, for example, in an organic solvent (e.g., dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or solvent mixtures thereof in the presence of a trap reagent (tribuityltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), organic acid (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and/or organic acid salt (sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.), in the presence or absence of a phosphine-based reagent (e.g., triphenylphosphine, etc.), at a temperature of about 0 to 4O0C , while using a metal complex (e.g., tetrakis-triphenylphosphine palladium (0), palladium (II) bis(triphenylphosphine) dichloride, palladium (II) acetate, rhodium (I) tris(triphenylphosphine) chloride, etc.). In addition to the above-described procedures, the deprotection reaction can be carried out, for example, by the methods described in T. W. Greene, Protective Groups in Organic synthesis, Wiley, New York, 1999.
The protective groups for carboxy group may be exemplified by methyl, ethyl, allyl, t-butyl, trichloroethyl, benzyl (Bn), phenacyl, methoxybenzyl, trityl or 2- chlorotrityl group, or solid-phase carriers having these chemical structures bonded thereto.
The protecting groups for hydroxy group include, for example, methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2- tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDPS), t-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), methoxybenzyl, allyloxy- carbonyl (Alloc) or 2,2,2-trichloroethoxycarbonyl (Troc) group, and the like.
As the protective groups for amino group, there may be mentioned, for example, benzyloxycarbonyl, t-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 1- methyl- l-(4-biphenyl)-ethoxycarbonyl (Bpoc), trifluroacetyl, 9-fluorenylmethoxy- carbonyl, benzyl (Bn), methoxybenzyl, benzyloxymethyl (BOM) or 2- (trimethylsilyl)ethoxymethyl (SEM) group, etc.
The protectie groups for thiol group may be exemplified by benzyl (Bn), methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyranyl (THP), diphenylmethyl or acetyl group, etc. The protective groups for carboxy, hydroxy, amino or thiol group are not limited particularly to the above-mentioned ones, only if they are easily and selectively removabale. For example, use may be made of those described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.
As may be easily understandable by an ordinarily skilled person, proper use of these deprotection reactions can facilitate the objective compounds of the present invention to be produced.
Among the compounds represented by the formula (1-1), the compounds
Figure imgf000036_0001
wherein all the symbols have the same meanings as the above mentioned can be produced by subjecting a compound represented by the formula (V):
Figure imgf000036_0002
wherein all the symbols have the same meanings as the above mentioned and the compound represented by the formula (III) to a reaction, followed by a deprotection reaction for the protecting group(s), as the case may be.
A reaction with a compound represented by formula (III) and a compound represented by formula (V) can be carried out in an organic solvent (such as toluene, benzene, xylene, tetrahydrofuran, dichloromethane, chloroform, diethyl ether, 1,2- dichloroethane, and the like) and in the presence of a base (such as pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, and the like) at the temperature of 0°C to reflux temperature. This reaction is preferred to be carried out under an inert gas (argon, nitrogen, etc.) atmosphere on anhydrous condition.
The deprotection reaction of a protective group can be carried out in the same manner as the above mentioned. Among the compounds represented by the formula (III), the compounds wherein R3"1 is optionally substituted alkyl groups, i.e., the compound represented by the formula (III- 1 ) can be produced by the method as illustrated in the Reaction Scheme 1. In the Reaction Scheme 1 , PN is protective groups for amino group, R3a is optionally substituted alkyl groups, R9 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, halo is a halogen atom and the other symbols represent same meaning as the above-mentioned.
Reaction Scheme 1
Figure imgf000037_0001
for
Figure imgf000037_0002
Figure imgf000037_0003
Among the compounds represented by the formula (III), the compounds wherein R3'1 is a halogen atom, i.e., the compound represented by the formula (III-2) can be produced by the method as illustrated in the Reaction Scheme 2. In the Reaction Scheme 2, R >3b is a halogen atom and the other symbols represent same meaning as the above-mentioned.
Reaction Scheme
1) Deprotection reaction for the carboxyl-protecting group
2) Carbamoylation reaction
Figure imgf000038_0001
Ml C
Figure imgf000038_0002
Figure imgf000038_0003
The above-mentioned compounds represented by the formulae (II), (IV), and
(V), as well as the compounds represented by the formulae (VI), (VII), (IX), (XII), (XIII) and (XIV) which are usable as a starting compound in the Reaction Schemes 1 to 2 are conventionally known or can be easily produced by utilizing the conventionally known methods, such as the procedures as described in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc., 1999)".
Among the compounds of the present invention represented by the formula (I), any compounds other than the above-indicated compounds can be produced by utilizing in combination the procedures or methods as described in Examples to be given in the present specification or the conventionally known methods, such as those described in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons inc., 1999).
In the respective reactions described in the present specification, any reactions being accompanied by heating can be carried out with use of a water bath, oil bath, sand bath or microwave, as is apparent to those skilled in the art.
In the respective reactions described in the present specification, appropriate use may be made of solid-phase supported reagents having chemicals supported on high molecular polymers (e.g., polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.). In the respective reations described in the present specification, the reaction products can be purified by ordinarily employed purification means, such as distillation under atmospheric pressure or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, ion exchange resins, scavenger resins or column chromatography, or such techniques as washing, recrystallization, etc. Purification may be performed in the reaction-by- reaction manner or after completion of several reactions.
PHARMACOLOGICAL ACTIVITY
A pharmacological test except for the Biological Examples hereinafter described includes, for example, the following method. By the method shown below, the in vivo effect of the compound represented by the formula (I) can be proved. A vehicle used for the administration of the compound represented by the formula (I) to an animal may be any material so long as it can suspend or dissolve the compound into safe and administrable state. For example, it is possible to appropriately select and use vehicles which those skilled in the art use for the administration to an animal, and examples of such vehicles are methylcellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, propylene glycol, polyethylene glycol, sugar, sugar alcohol, edible oil, distilled water, physiological saline solution, and a mixture thereof and the like. (1) Consideration of the improvement in insulin-resistance on diabetes model of KKAy mice Male, 8-weeks old KKAy/Ta JcI mice are pre-breaded individually in single cages for approximately one week. During pre-breaded and test term, mice are provided pellet diet and tap water from bottle of feed water ad libitum. On the first day of the experiment (Day 0), the body weight of mice are measured. Blood samples are collected from coccygeal vein using a microcapillary to measure plasma glucose concentration. Based on plasma glucose concentration, mice are divided into some groups (five mice per group) using a stratified randomization method and started dosing. The dosing can be carried out by oral gavage administration compulsorily or parenteral administration by subcutaneous injection, after suspending or dissolving the test compound in the above described vehicle. The control group receives preferably only the vehicle. The doses and the administration frequency can be increased or decreased appropriately by the effect of the test compound, preferably, for example, about 0.1 mg/kg body weight to 100 mg/kg body weight, about 1 to 3 times par day, every day. The endpoints of the efficacy on the present model include body weight, food intakes, blood glucose level, triglycereide of plasma, blood insulin level, and weight of liver. These endpoints can be measured after arbitrary days from starting the dosing. For example, on the second day (Day 2) to seventh day (Day 7) from starting dosing, the efficacy on the model can be confirmed by measuring these endpoints. On the model, pioglitazone can show the efficacy such as body weight gain, decline of blood glucose level and insulin level, and the like, by oral administration one time per day and from 50 mg/kg body weight.
(2) Consideration of the inhibition of the TNF-α production on cytokine-producing mouse model
Male balb/c mice are administrated (preferably orally administrated) the test compound suspended or dissolved in the above described vehicle, and after 30 minutes, LPS (055 :B5, Difco) is administrated intraperitoneally at the dose of 1 mg/kg body weight (five mice per group). The control group (five mice) receives only the vehicle. After 30 minutes from LPS treatment, under ether anesthesia, blood samples are collected from vein abdominalis with heparin and centrifuged (12000 r.p.m., 3 minutes, 40C) to obtain plasma samples. Obtained samples are conserved at -80°C before use. The amount of TNF-α can be quantitatively analyzed by using a commercial ELISA kit (such as R&D: #MTA00) and the like. (3) Consideration of the inhibition of the TNF-α production on cytokine-producing rat model
Female Lew rats are administrated (preferably orally administrated) the test compound suspended or dissolved in the above described vehicle, and after 2 hours, LPS (055:B5, Difco) is administrated intravenously at the dose of 10 μg/kg body weight (five rats per group). The control group (five rats) receives only the vehicle. After 90 minutes from LPS treatment, under ether anesthesia, blood samples are collected from vein abdominalis with heparin and centrifuged (12000 r.p.m., 3 minutes, 4°C) to obtain plasma samples. Obtained samples are conserved at -800C before use. The amount of TNF-α can be quantitatively analyzed by using a commercial ELISA kit (such as Genzyme/Techne: #10516) and the like.
TOXICITY
The toxicity of the compound represented by the formula (I) of the present invention is very low, and thus it is considered that the compound is sufficiently safe to be used as a pharmaceutical.
APPLICATION TO PHARMACEUTICALS
The compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof (hereinafter, which may be abbreviated to the compound of the present invention) can be used as an agent for preventing and/or treating a TNF-α-mediated diseases, for example, inflammatory disease (for example, diabetic complication (e.g. retinopathy, nephropathy, nervous disorder, macrovascular disease, etc.), inflammation, dermatitis, atopic dermatitis, hepatic inflammation, inflammation of the kidneys, glomerulonephritis, pancreatitis, psoriasis, gout, Addison's disease, osteitis syndrome (e.g. osteitis such as osteomyelitis, osteomalacia, periostitis, etc.), arthritis (e.g. rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, synovitis, etc.), inflammatory eye disease, inflammatory pulmonary disease (e.g. chronic pneumonia , pulmonary silicosis, pulmonary sarcoidosis, lung tuberculosis , adult respiratory distress syndrome(ARDS), severe acute respiratory syndrome (SARS), etc.), inflammatory enteropathy (e.g. Crohn's disease, chronic ulcerative colitis, etc.), allergy disease (e.g. allergic dermatitis, allergic rhinitis, etc.), autoimmune diseases, autoimmune hemolytic anemia, systemic erythematosus, rheumatism, Castleman's disease, immune rejection accompanied with implanting (e.g. graft-versus- host reaction, etc.) and the like); nervous disorder (e.g. central nervous system damage (e.g. cerebrovascular disorder such as cerebral hemorrhage and cerebral infarction, etc., head injury, spinal cord injury, brain edema, multiple sclerosis, etc.), neurodegenerative disease (e.g. Alzheimer disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), AIDS encephalosis, etc.), cerebral meningitis, Creutzfeldt- Jakob disease etc.); pulmonary problems (e.g. asthma, chronic obstructive pulmonary disease (COPD), etc.); circulatory system disease (e.g. angina pectoris, cardiac failure, congestive cardiac failure, acute cardiac failure, chronic cardiac failure, cardiac infarction, acute cardiac infarction, cardiac infarction prognosis, intraatrial myxoma, arterial sclerosis, hypertension, dialysis hypotension, thrombosis, diffuse intravascular coagulation syndrome (DIC), reperfusion injury, post-PTCA restenosis, etc.); urinary system disease (e.g. renal failure, etc.); metabolic disorder and endocrine disease (e.g. diabetes, hyperlipemia, etc.); bone disease (e.g. osteoporosis, etc.); cancer disease (e.g. malignancy such as growth and metastasis of malignant tumor, etc.), multiple myeloma, plasma cell leukemia, cancerous cachexia, etc.); infectious disease (e.g. virus infection caused by cytomegalovirus, influenza virus, herpes virus, corona virus, etc., cachexia accompanied with infection, cachexia related to acquired immunodeficiency syndrome(AIDS), blood poisoning such as sepsis, septic shock, endotoxic shock, gram- negative sepsis, toxic shock syndrom, severe acute respiratory syndrome(SARS) accompanied with virus infection, etc.); and the like, because the compound has TNF-α production-inhibitory activity in mammal (e.g. human, non-human animal such as simian, sheep, bos, horse, dog, cat, rabbit, rat, mouse, etc.). The compound of the present invention can be used as an agent for preventing and/or treating c-Jun related diseases, for example, metabolic disease (e.g. diabetes mellitus such as insulin-resistant diabetes mellitus or non-insulin-resistant diabetes mellitus, hyperlipemia, other insulin-resistant diseases, and the like), inflammatory diseases (e.g. rhinitis, pharyngitis, bronchitis, pneumonia, pleurisy, bronchial asthma, chronic pulmonary emphysema, pulmonary fibrosis, inflammatory bowel disease, acute pancreatitis, chronic pancreatitis, adult respiratory distress syndrome, chronic thyroiditis, autoimmune gastritis, and the like), scleroderma, deep lupus erythematosus, Graves' disease, autoimmune neutropenia, thrombocytopenia, myasthenia gravis, multiple myeloma, acute myeloblasts leukemia, chrome sarcoma, chronic myelocytic leukemia, metastatic melanoma, Kaposi's sarcoma, debilitating disease, Huntington's disease, ischemic/reperfusion disorders of stroke, myocardial ischemic symptom, ischemic heart disease, renal ischemia, neovascular glaucoma, infantile hemangioma, vascular proliferation, cardiac hypertrophy, abnormal immune response, pyrexia, cellular senescence, apoptosis-related diseases, and the like, because the compound has outstanding c-Jun phosphorylation inhibitory activity in mammal (for example, human, non-human animal such as simian, sheep, bos, horse, dog, cat, rabbit, rat, mouse, etc.). TNF-oc-mediated diseases and c-Jun related disease are not limited the above described diseases, and include all diseases in which the involvement of those diseases has so far been suggested or will be found afterward.
Furthermore, the compound of the present invention can have the inhibitory activity on eosinophil infiltration according to the TNF-α production-inhibitory activity. By this activity, the compound of the present invention can be used as a remedial agent for nasal obstruction. Therefore, the compound of the present invention can be used as an agent for preventing and/or treating an eosinophil infiltration-related diseases, for example, chronic urticaria, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, hypersensitivity pneumonitis, eczema, herpetic dermatitis, psoriasis, eosinophilic pneumonia (PIE syndrom), chronic obstructive pulmonary disease (COPD), asthma, contact dermatitis, pruritus, dry dermatitis, acute urticaria, prurigo, etc. and also can be used as a remedial agent for nasal obstruction.
When the compound of the present invention is used for the aforementioned purposes, normally it is administered systemically or locally by oral route or parenteral route.
The compound of the present invention is safe and low in toxicity so that it may be administrated to a mammal including human or a non-human animal (e.g. simian, sheep, bos, horse, dog, cat, rabbit, rat, mouse, etc.).
The doses to be administered are determined depending upon, for example, age, body weight, symptom, the desired treating effect, the route of administration, the duration of the treating, and the like. For a human adult, generally 1 mg to 1000 mg per dose is orally administered once to several times a day, or 1 mg to 100 mg per dose is parenterally (preferably intravenously) administered once to several times a day, or intravenously administered continuously for 1 to 24 hours a day.
As mentioned above, the doses to be administered depend upon various conditions. Therefore, there may be cases where doses lower than or greater than the ranges specified above are applied.
The compound of the present invention may be safely administered orally or parenterally (e.g. local, rectal, intravenous administration) alone or by mixing with a pharmaceutically acceptable carrier to be made into a medicinal preparation, for example, solid agents for oral administration (for example, tablets including those coated with sugar or film, powder, pills, granules, capsules, etc.), liquid agents for oral administration, injections, suppositories, sustained release drug, etc., in accordance with a known method generally used as a manufacturing method of a medicinal preparation. The amount of the compound of the present invention in such preparations is about 0.01 % of part weight to about 100 % of part weight, preferablely about 0.1 % of part weight to about 50 % of part weight, and more preferably, about 0.5 % of part weight to about 20 % of part weight, relative to the whole of the preparation.
The compound of the present invention used in the production of those medicinal preparations is not limited to substantially pure and single substance, and may include impurities (e.g. by-product, solvent, raw material, etc. which is derived from the production steps) as far as they are pharmaceutically acceptable as pharmaceutical bulk.
The carrier which is used in the production of the medicinal preparation includes various conventional organic or inorganic carrier materials, such as vehicles, lubricants, binders and disintegrants of solid preparation, or solvents, solution adjuvants, suspending or emulsifying agents, tonicity agent, buffering agents and soothing agents, etc. of liquid preparation. If necessary, conventional preservatives, antioxidants, coloring agents, sweetening agents, absorbents, and humectants can be used appropriately on adequate dose.
Solid agents for oral administration include tablets, pills, capsules, dispersible powders and granules. Capsules include hard capsules and soft capsules. In such solid agents, one or more of the active compound(s) may be alone, or admixed with vehicles (such as lactose, mannitol, glucose, microcrystalline cellulose, starch, corn starch, light anhydrous silicic acid, etc.), binders (such as hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate, crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropylmethyl cellulose, starch, sucrose, gelatin, methylcellulose, sodium carboxymethyl cellulose, etc.), disintegrants (such as cellulose calcium glycolate, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, L-hydroxypropyl cellulose, etc.), lubricants (such as magnesium stearate, calcium stearate, talc, colloidal silica, etc.), and formulated according to common methods. The solid agents may, if desired, be coated with coating agents (such as white sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
Liquid agents for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs, etc. In such liquid agents, one or more of the active compound(s) may be dissolved, suspended or emulsified into diluent(s) commonly used in the art (such as purified water, ethanol or a mixture thereof). The liquid agents may further comprise some additives, such as wetting agents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, aroma, preservatives or buffering agents.
Injections for parenteral administration include any types of injections including drops. Examples of injections include intramuscular injections, subcutaneous injections, intradermal injections, intraarterial injections, intravenous injections, intraabdominal injections, intraspinal injections, intravenous drips, etc. Injections for parenteral administration also include sterile aqueous, suspensions, emulsions and solid forms which are dissolved or suspended into solvent(s) for injection immediately before use. In injections, one or more of the active compound(s) may be dissolved, suspended or emulsified into solvent(s). Examples of the solvents include distilled water for injection, physiological saline, macrogol, vegetable oil (e.g. sesame- seed oil, corn oil, olive oil, etc.), propylene glycol, polyethylene glycol, alcohol such as ethanol, or a mixture thereof. Injections may comprise some additives, such as stabilizing agents (e.g. D- sorbitol, D-mannitol, L-alanine, ascorbic acid, albumin, inositol, sodium gluconic acid, sodium thioglycolate, polyoxyethylene hardened castor oil, etc.), solution adjuvants (e.g. glutamic acid, aspartic acid, POLYSORBATE 80 (registered trade mark), polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.), emulsifying agents or emulsifying agents (e.g. surface-active agents such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate, etc.; hydrophilic polymer such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.; and the like), soothing agents (e.g. benzyl alcohol, etc.), tonicity agents (e.g. glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.), buffering agents (e.g. phosphate buffer, acetate buffer, carbonate buffer, citrate buffer, etc.), preservatives (e.g. parahydroxybenzoate esters, chlorobutanol, benzylalcohol, phenethyl alcohol, dehydroacetate, sorbic acid, etc.), antioxidants (e.g. sulfite salt, ascorbic acid, α-tocopherol, etc.), and the like. They may be sterilized at a final step, or may be prepared and compensated according to aseptic manipulations. They may also be manufactured into sterile solid agents, for example, freeze-dried products, which may be dissolved in sterile water or some other sterile diluent(s) for injection immediately before use.
Freeze drying can be carried out by the known method. Generally, a preferable method is to dry by freezing at -25 °C or below, and then raising the temperature of a drying rack to 25°C to 40°C, while holding the vacuum pressure of a dry warehouse.
The other preparations for parenteral administration include liquids for external use, ointments, liniments, insufflations, spray preparations, suppositories and pessaries for vaginal administration which comprise one or more of the active substance(s) and may be prepared by methods known per se. Spray preparations may comprise, in addition to a diluent used in general, a stabilizer such as sodium bisulfite and an isotonization buffer, for example, tonicity agents such as sodium chloride, sodium citrate or citric acid. The compound of the present invention may be administered as a combination preparation by combining with other pharmaceuticals for the purpose of 1) supplementing and/or enhancing the preventing and/or treating effect of the compound,
2) improving pharmacokinetics and absorption of the compound and reducing the dose of the compound, and/or 3) reducing side effect of the compound.
In addition, the compound of the present invention may be combined and administered as a combination preparation for the purose of
1) supplementing and/or enhancing the preventing and/or treating effect of the other pharmaceuticals to be combined (hereinafter, which may be abbreviated to a concomintant drug(s)),
2) improving pharmacokinetics and absorption of the concomitant drug(s) and reducing the dose of the concomitant drug(s), and/or
3) reducing side effect of the concomitant drug(s).
The combination preparations of the compound of the present invention and a concomitant drug(s) may be administered as one combination preparation comprising these components, or may be administered separately. When they are administered separately as independent preparations, they may be administered simultaneously or with time lag. Administration with time lag includes the method of administering the compound of the present invention before other drugs and vice versa, and each administration route may be the same or different. There is no limitation on a disease on which the combination preparations of the compound of the present invention and a concomitant drug(s) have preventing and/or treating effects, so long as the preventing and/or treating effect of the combination preparation is supplemented and/or enhanced in the disease. There is no limitation on the weight ratio between the compound of the present invention and the concomitant drug(s) in a combined preparation by combining the compound of the present invention with the concomitant drug(s).
Furthermore, the concomitant drug(s) is not limited to a low molecular weight compound, and may be a macromolecule protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy, antibody, vaccine, and the like. The dosage of the concomitant drug(s) can be properly selected according to the clinical dosage. The compounding ratio of the compound of the present invention and the concomitant drug(s) can be properly selected by the age and body weight of the object, administration route, administration term, target disease, symptom, combination, and the like. For example, the amount of the concomitant drug(s) may be used 0.01 parts by weight to 100 parts by weight relative to 1 part by weight of the compound of the present invention. The concomitant drug(s) may be administrated in the proper combination of arbitrary one or two or more member(s) selected from the same or different groups in arbitrary proportion.
The concomitant drug(s) for supplementing and/or enhancing of the preventing and/or treating effect of the compound of the present invention includes not only those which have so far been found but also those which will be found on the basis of the aforementioned mechanism. The concomitant drug(s) which can be used in combination with the compounds of the present invention include, for example, those given below.
Examples of the concomitant drug(s) for supplementing and/or enhancing the preventing and/or treating effect of the compound of the present invention on rheumatoid arthritis, osteoarthritis, arthritis includes a steroid, an elastase inhibitor, a cannabinoid-2 receptor stimulator, a prostaglandin, a prostaglandin synthase inhibitor, a phosphodiesterase inhibitor, a metalloproteinase inhibitor, an adhesion molecule inhibitor, an anti-cytokine protein preparation such as an anti-TNF-α preparation, an anti-interleukin (IL)-I preparation, an anti-IL-6 preparation; an anti-cytokine agent, an immunomodulatory agent, a disease modifying anti-rheumatic drug, a non-steroidal antiinflammatory drug, a c-Jun N-terminal kinase inhibitor, and the like.
Examples of the concomitant drug(s) for supplementing and/or enhancing the preventing and/or treating effect of the compound of the present invention on inflammatory bowel disorder, Crohn's disease, ulcerative colitis, etc. include a steroid, an elastase inhibitor, a cannabinoid-2 receptor stimulator, a prostaglandin, a prostaglandin synthase inhibitor, a phosphodiesterase inhibitor, a metalloproteinase inhibitor, an adhesion molecule inhibitor, an anti-cytokine protein preparation, an anti- cytokine agent, an immunomodulatory agent, a leukotriene receptor inhibitor, an anticholinergic agent, a 5 -lipoxygenase inhibitor, a nitric oxide synthase inhibitor, an IL-8 antagonist, a poly(ADP)-ribose polymerase inhibitor, a mitochondrial benzodiazepine receptor agonist, an antioxidant drug, a local anesthetic agent, a gastrointestinal ulcer agent, an enhancing agent of defensive factor, mesalazine, salazosulfapyridine, and the like.
Examples of the concomitant drug(s) for supplementing and/or enhancing the preventing and/or treating effect of the compound of the present invention on asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome include a steroid, an elastase inhibitor, a cannabinoid-2 receptor stimulator, a prostaglandin, a prostaglandin synthase inhibitor, a phosphodiesterase inhibitor, a metalloproteinase inhibitor, an adhesion molecule inhibitor, a leukotriene receptor inhibitor, an anticholinergic agent, a thromboxane A2 receptor antagonist, a thromboxane synthetase inhibitor, a β2-adrenaline receptor stimulator, a xanthine derivative, an expectorant, an antibacterial agent, an anti-histaminic agent, an anti-cytokine protein preparation, an anti-cytokine agent, a forskolin preparation, a mediator release inhibitor, and the like.
Examples of the concomitant drug(s) of the compound of the present invention as a preventing and/or treating agent for hyperlipemia includes, for example, a MTP (Microsomal Triglyceride Transfer Protein) inhibitor, an HMG-CoA reductase inhibitor, a squalene synthetase inhibitor, a fibrate preparation, an ACAT (Acyl-CoA: cholesterol 0-acyltransferase) inhibitor, a 5 -lipoxygenase inhibitor, a cholesterol absorption inhibitor, a bile acid absorption inhibitor, an ileum Na+/bile acid cotransporter (IBAT) inhibitor, an LDL receptor activator/enhanced expression, a lipase inhibitor, a probucol preparation, a niacin preparation.
Examples of the concomitant drug(s) of the compound of the present invention as a preventing and/or treating agent for diabetes mellitus (insulin-resistant diabetes mellitus or non-insulin-resistant diabetes mellitus), diabetes complication and the like, include a sulfonylurea hypoglycemic drug, a biguanide preparation, an α-glucosidase inhibitor, a rapid-acting insulin secretagogue, an insulin preparation, a GPR 40 agonist(G protein coupled receptor 40 agonist), a SGLT(sodium-dependent glucose transporter, for example, SGLTl, SGLT2) inhibitor, a DPP4 (dipeptidyl peptidase) inhibitor, a PTPlB inhibitor, a β3 adrenoceptor agonist, a PPAR (for example, PPARα, PPARγ, PPARδ) agonist, and diabetes complication therapeutic agent and the like. Examples of the MTP inhibitor include BMS-201038, BMS-212122, BMS-
200150, GW-328713, R-103757, and the like. Examples of the HMG-CoA reductase inhibitor include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and the like.
Examples of the ACAT inhibitor include F-12511, F- 1394, CI-IOl 1, melinamide, FCE27677, RP73163, and the like. Examples of the squalene synthetase inhibitor include TAK-475 and the like.
Examples of the fibrate preparation include gemfibrozil, clofibrate, bezafibrate, fenofibrate, and the like.
Examples of the cholesterol absorption inhibitor include SCH48461 and the like. Examples of the bile acid absorption inhibitor include cholestyramine, cholestagel, and the like.
Examples of the LDL receptor activator/enhanced expression agent include MD-700, LY295427, and the like.
Examples of the lipase inhibitor include orlistat and the like. Examples of the sulfonylurea hypoglycemic agent include acetohexamide, glibenclamide, gliclazide, glyclopyramide, chlorpropamide, tolazamide, tolbutamide, glimepiride, and the like.
Examples of the biguanide preparation include buformin hydrochloride, metformin hydrochloride, and the like. Examples of the α-glucosidase inhibitor include acarbose, voglibose, and the like.
Examples of the rapid-acting insulin secretagogue include nateglinide, repaglinide, and the like.
Examples of the GPR 40 agonist include the compounds described in WO04/41266, WO04/106276, WO05/51890, WO05/63725, WO06/83612, WO07/13689, and the like.
Examples of the SGLT inhibitor include T-1095, AVE-2268, KGT-1251/KGT- 1681, and the like.
Examples of the DPP4 inhibitor include NVP-DPP728A, vildagliptin, and the like.
Examples of the β3 adrenoceptor agonist include AJ9677, L750355, CP331648, and the like. Examples of the PPAR agonist include pioglitazone, troglitazone, rosiglitazone, JTT-501, and the like.
Examples of the diabetes complication therapeutic agent include epalrestat and the like. Examples of the steroid include clobetasol propionate, diflorasone diacetate, fluocinonide, mometasone furoate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednate, diflucortolone valerate, amcinonide, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, deprodone propionate, prednisolone valerate-acetate, fluocinolone acetonide, beclometasone dipropionate, triamcinolone acetonide, flumetasone pivalate, alclometasone dipropionate, clobetasone butyrate, prednisolone, fludroxycortide, cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fludrocortisone acetate, prednisolone acetate, prednisolone sodium succinate, prednisolone butylacetate, prednisolone sodium phosphate, halopredone acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, paramethasone acetate, betamethasone, fluticasone propionate, budesonide, flunisolide, ST-126P, ciclesonide, dexamethasone palomithionate, mometasone furoate, prasterone sulfonate, deflazacort, methylprednisolone suleptanate, methylprednisolone sodium succinate, and the like.
Examples of the elastase inhibitor include ONO-5046 (sivelestat sodium), ONO-6818, MR-889, PBI-1101, EPI-HNE-4, R-665, ZD-0892, ZD-8321, GW-311616, DMP-777, L-659286, L-658758, L-680833, L-683845, AE-3763, and the like. Examples of the prostaglandins (hereinafter, abbreviated as PG) include PG receptor agonists, PG receptor antagonists, and the like.
Examples of the PG receptor include PGE receptors (EP1, EP2, EP3 and EP4), PGD receptors (DP, CRTH2), PGF receptors (FP), PGI receptors (IP), TX receptors (TP), and the like. Examples of the prostaglandin synthase inhibitor include, salazosulfapyridine, mesalazine, olsalazine, 4-aminosalicylic acid, JTE-522, auranofin, carprofen, diphenpyramide, flunoxaprofen, flurbiprofen, indometacin, ketoprofen, lornoxicam, loxoprofen, meloxicam, oxaprozin, parsalmide, piproxen, piroxicam, piroxicam betadex, piroxicam cinnamate, tropineindometacinate, zaltoprofen, pranoprofen, and the like.
Examples of the phosphodiesterase inhibitor include PDE4 inhibitors such as rolipram, cilomilast (trade name: Ariflo), Bayl9-8004, NIK-616, roflumilast (BY-217), cipamfylline (BRL-61063), atizoram (CP-80633), SCH-351591, YM-976, V-11294A, PD-168787, D-4396, IC-485, PDE5 inhibitors such as sildenafil, and the like.
Examples of the adhesion molecule inhibitor include an antagonist such as α4 integrin, and the like. Examples of the anti-TNF-α preparation include antibody against TNF-α, soluble TNF-α receptor, antibody against TNF-α receptor, soluble TNF-α receptor binding protein, and specifically, infliximab, etanercept, and the like.
Examples of the anti-IL-1 preparation include antibody against IL-I, soluble IL-I receptor, antibody against IL-IRa and/or IL-I receptors, and specifically, for example, anakinra and the like.
Examples of the anti-IL-6 preparation include antibody against IL-6, soluble IL-6 receptor, antibody against IL-6 receptor, and for example, MRA and the like.
Examples of the immunosuppressing agent include methotrexate, cyclosporin, ascomycin, leflunomide, bucillamine, salazosulfapyridine, azathioprine, tacrolimus, cyclophosphamide, and the like.
Examples of the disease modifying anti-rheumatic drug include gold thioglucose, sodium aurothiomalate, auranofin, chloroquine, actarit, D-penicillamine preparation, lobenzarit disodium, bucillamine, hydroxychloroquine, salazosulfapyridine, and the like. Examples of the non-steroidal antiinflammatory drug include sasapyrine, sodium salicylate, aspirin, aspirin-dialminate, diflunisal, indometacin, suprofen, ufenamate, dimethyl isopropylazulene, bufexamac, felbinac, diclofenac, tolmetin sodium, clinoril, fenbufen, napumetone, proglumetacin, indometacin farnesil, acemetacin, proglumetacin maleate, amfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol, naproxen, flurbiprofen, flurbiprofenaxetil, ketoprofen, fenoprofen calcium, tiaprofen, oxaprozin, pranoprofen, loxoprofen sodium, alminoprofen, zaltoprofen, mefenamic acid, mefenamic acid aluminium, tolfenamic acid, floctafenine, ketophenylbutazone, oxyphenbutasone, piroxicam, tenoxicam, ampiroxicam, napageln ointment, epirizole, tiaramide hydrochloride, tinoridine hydrochloride, emorfazone, sulpyrine, migrenin, Saridon, Sedes G, Amipylo N, sorbone, pyrin derivatives for cough and cold preparations, acetaminophen, phenacetin, dimetotiazine mesilate, simetride, non-pilin derivatives for cough and cold preparations, and the like.
Examples of the leukotriene receptor antagonist include pranlukast hydrate, montelukast, zafirlukast, seratrodast, MCC-847, KCA-757, CS-615, YM-158, L- 740515, CP-195494, LM-1484, RS-635, A-93178, S-36496, BIIL-284, ONO-4057, and the like. Examples of the anticholinergic agent include ipratropium bromide, oxitropium bromide, flutropium bromide, cimetropium bromide, temiverine, tiotropium bromide, revatropate (UK-112166), and the like.
Examples of the local anesthetics include cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, and the like.
Examples of the enhancing agent of defensive factor include sucralfate, aldioxa, teprenone, cetraxate hydrochloride, and the like.
Examples of the thromboxane A2 receptor antagonist include seratrodast, ramatroban, domitroban calcium hydrate, KT-2-962, and the like. Examples of the thromboxane synthase inhibitor include ozagrel hydrochloride, ozagrel sodium, imitrodast sodium, and the like.
Examples of the β2 adrenaline receptor stimulator include fenoterol hydrobromide, salbutamol sulfate, terbutaline sulfate, formoterol fumarate, salmeterol xinafoate, isoproterenol sulfate, orciprenaline sulfate, clorprenaline sulfate, epinephrine, trimetoquinol hydrochloride, hexoprenalinemesyl sulfate, procaterol hydrochloride, tulobuterol hydrochloride, tulobuterol, pirbuterol hydrochloride, clenbuterol hydrochloride, mabuterol hydrochloride, ritodrine hydrochloride, bambuterol, dopexamine hydrochloride, meluadrine tartrate, AR-C68397, levosalbutamol, formoterol, KUR-1246, KUL-7211, AR-C89855, S-1319, and the like. Examples of the xanthine derivative include aminophylline, theophylline, doxofylline, sipamphylline, diprophylline, and the like. Examples of the expectorant include foeniculated ammonia spirit, sodium hydrogen carbonate, bromhexine hydrochloride, carbocysteine, ambroxol hydrochloride, ambroxol hydrochloride sustained preparation, methylcysteine hydrochloride, acetylcysteine, ethyl L-cysteine hydrochloride, tyloxapol, and the like. Examples of the antibacterial agent include sodium cefuroxime, meropenem trihydrate, netilmicin sulfate, sisomicin sulfate, ceftibuten, PA-1806, IB-367, tobramycin, PA- 1420, doxorubicin, astromicin sulfate, cefetamet pivoxil hydrochloride, and the like.
Examples of the anti-histaminic agent includes ketotifen fumarate, mequitazine, azelastine hydrochloride, oxatomide, terfenadine, emedastine difumarate, epinastine hydrochloride, astemizole, ebastine, cetirizine hydrochloride, bepotastine, fexofenadine, loratadine, desloratadine, olopatadine hydrochloride, TAK-427, ZCR- 2060, NIP-530, mometasone furoate, mizolastine, BP-294, andolast, auranofin, acrivastine, and the like. Examples of the anti-cytokine agent include any non-protein preparation which inhibits the activity of cytokine, for example, MAP kinase inhibitor, gene modulator, cytokine production inhibitor, TNF-α conversion enzyme inhibitor, IL-I β conversion enzyme inhibitor, IL-6 antagonist, IL-8 antagonist, chemokine antagonist, gene therapy agents, antisense compound, and the like. Examples of the MAP kinase inhibitor include PD-98059 and the like.
Examples of the gene modulator include inhibitors of a molecule which relates to signal transduction, for example, NF-κB, IKK-I, IKK-2, AP-I, and the like.
Examples of the cytokine production inhibitor include suplatast tosylate (trade name: IPD), T-614, SR-31747, sonatimod, and the like. Examples of the chemokine antagonist include ONO-4128 (aplaviroc),
Maraviroc, and the like.
Examples of the gene therapy agent include those which is aimed to increase the expression of gene having anti-inflammatory effect, such as IL-4, IL-10, soluble IL- 1 receptor, soluble TNF-α receptor, and the like. Examples of the mediator release inhibitor include tranilast, sodium cromoglicate, amlexanox, repirinast, ibudilast, dazanolast, pemirolast potassium, and the like. Examples of the c-Jun N-terminal kinase inhibitor include the compounds described in WOOO/35906, WO00/35909, WO00/35921, WO00/64872, WO00/75118, WO03/068750, WO06/47354, WO06/83673, and the like.
The following excellent effects can be obtained by combining the compound of the present invention with the concomitant drug(s).
(1) The concomitant use can decrease the dose compared to administration of the compound alone of the present invention or the concomitant drug(s) alone;
(2) The compound of the present invention and the concomitant drug can be selected according to a patient's symptom (mild case, severe case etc.); (3) The selection of the concomitant drug(s) of which mechanism of the action is different from that of the compound of the present invention can decrease the dose in patients and extend the treating period;
(4) The selection of the concomitant drug(s) of which mechanism of the action is different from that of the compound of the present invention can maintain the treating effect;
(5) The combination of the compound of the present invention with the concomitant drug(s) can obtain the synergistic effect.
Especially, in the case that the concomitant drug(s) is a steroid, it is possible to take a steroid of weak action as compared with administration of the steroid alone. Generally, in the case of the combination of fibrate preparations with a HMG-
CoA reductase inhibitor, it is known that rhabdmyolysis may occur as a side effect. However, the incidence and the degree of rhabdmyolysis can be decreased by using the above described concomitant drugs.
Hereinafter, to use the compound of the present invention in conjunction with a concomitant drug(s) is termed "the combination preparation of the present invention". In the case of using the combination preparation of the present invention, there is no particular limitation for administration time of the compound of the present invention or and a concomitant drug(s). The administration of the compound of the present invention or pharmaceutical composition thereof and a concomitant drug(s) or pharmaceutical composition thereof to the administration object includes a simultaneous administration and administrations with time difference. The dose of a concomitant drug can be properly selected according to object of the administration, route of the administration, disease, combination, etc., as far as it conforms to the clinical dose. There is no particular limitation on the way of administration, as far as the compound of the present invention and a concomitant drug(s) are combined in vivo.
In the administration of the combination preparation of the present invention, the concomitant drug(s) of the present invention and/or the concomitant drug(s) can be safely administered as they are or after being mixed with a pharmaceutically acceptable carrier according to a per se known method usually employed in the production of pharmaceutical preparations, orally or parenterally (for example, topical administration, rectal administration, intravenous administration, etc.) in the form of solid preparations for internal use (e.g. tablets including sugar coated tablets and film-coating tablets), powders, pills, granules, capsules, etc.), liquid preparations for internal use, liquid preparations for external use, injections, suppositories, delayed-release preparations or the like.
The carrier which is used in the production of the pharmaceutical preparation includes various conventional organic or inorganic carrier materials, such as excipients, lubricants, binders and disintegrators for solid preparations, solvents, solubilizers, suspending or emulsifying agents, isotonic agents, buffers and soothing agents, etc. If necessary, conventional preservatives, antioxidants, coloring agents, sweetening agents, adsorbents, wetting agents, and the like can be used appropriately in a suitable amount. The excipient includes, for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, corn starch, light anhydrous silicic acid, and the like. The binder includes, for example, hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate, crystalline cellulose, white soft sugar, D-mannitol, dextrin, hydroxypropylmethyl cellulose starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like. The disintegrator includes, for example, cellulose calcium glycolate, starch, carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethylstarch, L-hydroxypropyl cellulose, and the like. The lubricant includes, for example, magnesium stearate, calcium stearate, talc, colloid silica, and the like. The solvent medium includes, for example, distilled water for injection, physiological saline solution, macrogol, vegetable oil (e.g. sesame oil, corn oil, olive oil, etc.), alcohols (e.g. propylene glycol, polyethylene glycol, ethanol, etc.) or a mixture thereof. The stabilizer includes, for example, D-sorbitol, D-mannitol, L-alanine, ascorbic acid, albumin, inositol, sodium gluconate, sodium thioglycolate, polyoxyethylene hardened caster oil, etc. The solubilizer includes, for example, glutamic acid, aspartic acid, Polysolbate 80 (trade name), polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, citric sodium, etc. The emulsifying or suspending agent includes, for example, surfactants (for example, stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc.), hydrophilic polymers (for example, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose etc.) and the like. The soothing agents include, for example, benzyl alcohol, and the like. The isotonic agents include, for example, glucose, D-sorbitol, sodium chloride, glycerin, D- mannitol, and the like. The buffers include, for example, a buffer solution of phosphates, acetates, carbonates, citrates, or the like. The preservative includes, for example, p-hydroxybenzoic acid ester, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. The antioxidant includes, for example, sulfites, ascorbic acid, α-tocopherol, and the like.
The compounding ratio of the compound of the present invention in a combination preparation varies depending on the dosage form. It is usually about
0.01% by weight to 100% by weight relative to the whole preparation, preferably about 0.1% by weight to 50% by weight relative to the whole preparation, more preferably about 0.5% by weight to 20% by weight relative to the whole preparation.
The compounding ratio of the concomitant drug(s) in the combination preparation of the present invention varies depending on the dosage form. It is usually about 0.01% by weight to 100% by weight, preferably about 0.1% by weight to 50% by weight relative to the whole preparation, more preferably about 0.5% by weight to 20% by weight relative to the whole preparation.
The content of the additive such as carrier, etc. in the combination preparation of the present invention varies depending on the dosage form. It is usually about 1% by weight to 99.99% by weight, preferably about 10% by weight to 90% by weight relative to the whole preparation. In addition, it may be the same in the formulation of the compound of the present invention and the concomitant drug(s) independently.
These drug preparations can be prepared by the usual method (e.g. the method described in Japanese Pharmacopoeia, etc.). The tablet can be prepared by mixing uniformly the compound of the present invention and/or the concomitant drug(s) in the presence or absence of excipients, disintegrators, or other appropriate additives to prepare granulated powder in an appropriate manner, and then compacting with a lubricant, etc.; by mixing uniformly the compound of the present invention and/or the concomitant drug(s), in the presence or absence of excipients, disintegrators, or other appropriate additives in an appropriate manner, and then compacting the mixture directly; or by optionally adding an appropriate additive to previously granulated powder, mixing the mixture uniformly and then compacting into tablets. If necessary, the tablet may be prepared with coloring agents, flavoring substance, etc. Furthermore, it can be coated by using appropriate coating agents. The injection preparation can be prepared by the following method. A certain amount of the compounds of the present invention and/or a concomitant drug(s) is dissolved, suspended or emulsified usually in an aqueous medium such as distilled water for injection, physiological saline solution, and Ringer solution, or in a nonaqueous medium such as vegetable oil, etc.; or a certain amount of the compound of the present invention and/or a concomitant drug(s) is sealed in a container for injection. The carrier for the preparation for oral administration includes a conventional material used in the field of pharmaceutical formulation such as starch, mannitol, crystalline cellulose, sodium carboxymethylcellulose, etc. The carrier for injections includes, for example, distilled water, physiological saline solution, glucose solution, infusion, and the like.
Although the dose of the combination preparation of the present invention depends on the age, weight, disease symptom, treating effect, administration route, therapy period, and the like, the compound of the present invention and the concomitant drug(s) are usually administered orally once or several times per day at a dose per administration of from 0.1 mg to 1000 mg per human adult, or parenterally (preferably intravenous administration) once or several times per day at a dose per administration of from 0.1 mg to 100 mg per human adult, or continuously administered intravenously for 1 hour to 24 hours per day.
It goes without saying that the dose of these compounds may be less than the aforementioned value or may need to exceed the aforementioned range because the dose varies under various conditions as mentioned above. The concomitant drug(s) can be administrated at arbitrary dose as far as the side effect is not a serious problem and the purpose of the present invention can be achieved. The daily dose as a concomitant drug(s) differs depending on age, sex, body weight, different sensitivity, time and interval of administration object, characteristics of pharmaceutical preparation, dispensing, kind, and type of active ingredient of medicinal preparation; and the like, so that it is not particularly limited.
In the case where the compound of the present invention is administered firstly, the concomitant drug(s) of the present invention can be administered within 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 hour after the administration of the compound of the present invention, and the like.
EFFECT OF THE INVENTION
The TNF-α production inhibitor of the present invention comprising the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof can be very useful as a preventing and/or treating for various diseases including, for example, metabolic diseases such as diabetes, inflammatory diseases such as rheumatoid arthritis, and the like, because of inhibitory activity against TNF-α production, and low toxicity.
BEST MODE FOR CARRYING OUT THE INVENTION
Now, the present invention is described in greater detail by reference to the following Examples, although the present invention is not construed as being restricted thereto.
Solvents given in parentheses concerning chromatographic separation and TLC indicate each the elution solvent or the developing solvent employed is expressed in ratio by volume. Unless otherwise indicated, the NMR data are 1H-NMR data. Solvents given in parentheses concerning NMR indicate each solvent employed in measurement.
Example 1 : 5-tert-butyl 3-ethyl 2-methyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-3,5(4H)- dicarboxylate
A mixture of tert-butyl 3-bromo-4-oxopiperidine-l-carboxylate (3.0 g), (Z)- ethyl 3-aminobut-2-enoate (6.8 mL), and sodium bicarbonate (1.1 g) was heated to 80
°C for 24 hours. The reaction was cooled to room temperature and diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate and concentrated.
Excess (Z)-ethyl 3-aminobut-2-enoate was removed via distillation and the resulting residue was purified by column chromatography on silica gel (1 : 2 = ethyl acetate: hexanes) to obtain the title compound (0.73 g) having the following physical data. 1H NMR (CDCl3): δ 7.87 (bs, IH), 4.55 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.76-3.60 (m,
2H), 2.66-2.54 (m, 2H), 2.51 (s, 3H), 1.47 (s, 9H), 1.34 (t, J = 7.2 Hz, 3H);
Mass data (ESI, Pos.): m/z 331 (M + Na)+.
Example 2: 5-tert-butyl 3-ethyl 2-methyl-l-phenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-3,5(4H)- dicarboxylate
A mixture of the compound prepared in Example 1 (0.30 g), copper (I) iodide (0.019 g), and powdered potassium phosphate (0.45 g) was placed in a sealable flask and purged with argon. A solution of ( 1 R,2R)-N ' ,N2-dimethylcy clohexane- 1,2- diamine (0.055 g) and iodobenzene (0.16 mL) in toluene (3.5 mL) was added and the system was purged with argon. The reaction was sealed and heated to 100 °C overnight. The reaction was cooled to room temperature, filtered through filter paper and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate: hexanes = 1 : 8) to obtain the title compound (0.12 g) having the following physical data.
1H NMR (CDCl3): δ 7.52-7.41 (m, 3H), 7.22-7.13 (m, 2H), 4.63 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.73-3.56 (m, 2H), 2.40-2.30 (m, 5H), 1.49 (s, 9H), 1.37 (t, J = 7.1 Hz, 3H); +
Mass data (ESI, Pos.): m/z 407 (M + Na)+.
Example 3:
5-(tert-butoxycarbonyl)-2-methyl-l-phenyl-4,5,6,7-tetrahydro-lH-pyrrolo[3,2- c]pyridine-3-carboxylic acid
A mixture of the compound prepared in Example 2 (0.399 g) in ethanol (4 mL) and 2.5 M aqueous potassium hydroxide (4 mL) was refluxed for 20 hours. The reaction was cooled to 0 °C and brought to pH 1 via the addition of 1 M hydrochloric acid. The mixture was diluted with water and ethyl acetate and solid sodium chloride was added to salt out the organic phase. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (0.355 g) having the following physical data.
1H NMR (CDCl3): δ 7.55-7.42 (m, 3H), 7.23-7.15 (m, 2H), 4.74-4.60 (m, 2H), 3.73- 3.56 (m, 2H), 2.42-2.28 (m, 5H), 1.50 (s, 9H);
Mass data (ESI, Pos.): m/z 379 (M + Na)+.
Example 4: tert-butyl 3-carbamoyl-2-methyl- 1 -phenyl-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridine- 5(4H)-carboxylate
1-Hydroxybenzotriazole hydrate (0.052 g), l-ethyl-3-(3'- dimethylaminopropyl)carbodiimide (0.065 g), and diisopropylethylamine (0.25 mL) were added to a 0 °C solution of the compound prepared in Example 3 (0.081 g) in dichloromethane (0.7 mL). The solution was stirred at room temperature overnight. Ammonia (7 M methanol, 1 mL) was added and the reaction was stirred for one hour. The solution was concentrated and the residue was partitioned between ethyl acetate and a saturated aqueous ammonium choride solution. The layers were separated and the organic phase was washed with a saturated sodium bicarbonate solution. The aqueous phases were extracted twice with ethyl acetate. The organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate: hexanes = 4: 1) to obtain the title compound (0.052 g) having the following physical data. 1H NMR (CDCl3): δ 7.70-7.38 (m, 3H), 7.21-7.13 (m, 2H), 5.71 (bs, 2H), 4.65 (s, 2H), 3.75-3.54 (m, 2H), 2.43-2.29 (m, 5H), 1.47 (s, 9H); Mass data (ESI, Pos.): m/z 378 (M + Na)+.
Example 5:
2-methyl-l-phenyl-4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridine-3-carboxamide trifluoroacetic acid salt
Trifluoroacetic acid (0.6 mL) was added to a solution of the compound prepared in Example 4 (0.051 g) in dichloromethane (1.5 mL). The reaction was stirred at room temperature for 45 minutes and then concentrated. The residue was concentrated to obtain the title compound (0.050 g) having the following physical data.
1U NMR (CD3OD): δ 7.64-7.49 (m, 3H), 7.34-7.23 (m, 2H), 4.38 (s, 2H), 3.49-3.39 (m,
2H), 2.72-2.56 (m, 2H), 2.25 (s, 3H);
Mass data (ESI, Pos.): m/z 256 (M + H)+.
Example 6:
2-methyl-N5-(4-(4-methylpiperazine- 1 -carbonyl)phenyl)- 1 -phenyl-6,7-dihydro- 1 H- pyrrolo [3 ,2-c]pyridine-3 , 5 (4H)-dicarboxamide
A solution of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone (0.037 g) and triethylamine (0.012 mL) in dichloromethane (1.5 mL) was added over 45 minutes to a -78 °C solution of triphosgene (0.017 g) in dichloromethane (1 mL). The reaction was stirred for 45 minutes more at -78 °C to obtain a carbamic chloride solution. The compound prepared in Example 5 (0.042 g) was suspended in dichloromethane (1 mL) and treated with triethylamine (0.050 mL). The mixture was vigorously stirred for five minutes and was then added dropwise to the carbamic chloride solution aforementioned at -78 °C. The reaction was warmed to room temperature, stirred for 1.5 hours and then diluted with ethyl acetate and water. The layers were separated and the aqueous phase was extracted with ethyl acetate three times. The combined organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (methanol: dichloromethane: triethylamine = 1 :
19: 0.04) to obtain the title compound (0.029 g) having the following physical data. 1H NMR (CDCl3): δ 7.56-7.40 (m, 5H), 7.33 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 6.9 Hz,
2H), 7.12 (s, IH), 5.62 (s, 2H), 4.78 (s, 2H), 3.88-3.37 (m, 6H), 2.73-2.56 (m, IH),
2.53-2.24 (m, 1 IH);
Mass data (ESI, Pos.): m/z 501 (M + H)+.
Example 7:
2-methyl-N5-(4-(methylsulfonyl)phenyl)- 1 -phenyl-6,7-dihydro- 1 H-pyrrolo [3 ,2- c]pyridine-3 ,5 (4H)-dicarboxamide
According to the same procedure described in Example 6, using the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin- 1 -yl)methanone, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 7.78 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.9 Hz, 2H), 7.56-7.44 (m,
4H), 7.21-7.15 (m, 2H), 5.71 (s, 2H), 4.81 (s, 2H), 3.84-3.75 (m, 2H), 3.01 (s, 3H),
2.49-2.41 (m, 2H), 2.31 (s, 3H); Mass data (APCI, Pos.): m/z 453 (M + H)+.
Example 8:
2-methyl- 1 -phenyl-N5-(4-(trifluoromethyl)phenyl)-6,7-dihydro- 1 H-pyrrolo [3 ,2- c]pyridine-3,5(4H)-dicarboxamide According to the same procedure described in Example 6, using the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained.
1H NMR (CD3OD): δ 7.63-7.45 (m, 7H), 7.27 (d, J - 7.3 Hz, 2H), 4.73 (s, 2H), 3.81-
3.72 (m, 2H), 2.49-2.41 (m, 2H), 2.25 (s, 3H); Mass data (ESI, Pos.): m/z 443 (M + H)+.
Example 9:
5-tert-butyl 3 -ethyl 1 -benzyl-2-methyl-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]ρyridine-3 ,5(4H)- dicarboxylate Sodium hydride (60% dispersion in oil, 0.037 g) was added to a room temperature solution of the compound prepared in Example 1 (0.24 g) in dimethylformamide (3 mL). The reaction was stirred for 45 minutes and then benzyl bromide (0.10 mL) was added all at once. The reaction was stirred overnight, quenched with a few drops of a saturated aqueous ammonium chloride solution and then partitioned between ethyl acetate and water. The organic phase was washed sequentially with water and brine and then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate: hexanes = 1 : 6) to obtain the title compound (0.16 g) having the following physical data.
1H NMR (CDCl3): δ 7.42-7.22 (m, 3H), 6.90 (d, J = 7.3 Hz, 2H), 5.00 (s, 2H), 4.59 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.77-3.58 (m, 2H), 2.55-2.40 (m, 5H), 1.46 (s, 9H), 1.36 (t, J = 7.1 Hz, 3H);
Mass data (ESI, Pos.): m/z 421 (M + Na)+.
Example 10: l-benzyl-5-(tert-butoxycarbonyl)-2-methyl-4,5,6,7-tetrahydro-lH-pyrrolo[3,2- c]pyridine-3-carboxylic acid
According to the same procedure described in Example 3, using the compound prepared in Example 9 instead of the compound prepared in Example 2, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 7.40-7.22 (m, 3H), 6.95-6.86 (m, 2H), 5.02 (s, 2H), 4.62 (s, 2H), 3.76-3.59 (m, 2H), 2.55-2.42 (m, 5H), 1.58-1.37 (m, 9H);
Mass data (ESI, Pos.): m/z 393 (M + Na)+.
Example 11 : tert-butyl 1 -benzyl-3 -carbamoyl-2-methyl-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridine- 5(4H)-carboxylate
According to the same procedure described in Example 4, using the compound prepared in Example 10 instead of the compound prepared in Example 3, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 7.38-7.22 (m, 3H), 6.90 (d, J = 7.2 Hz, 2H), 5.38 (s, 2H), 4.60 (s, 2H), 3.76-3.59 (m, 2H), 2.57-2.36 (m, 5H), 1.47 (s, 9H);
Mass data (ESI, Pos.): m/z 392 (M + Na)+. Example 12: l-benzyl-2-methyl-4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridine-3-carboxamide trifluoroacetic acid salt
According to the same procedure described in Example 5, using the compound prepared in Example 11 instead of the compound prepared in Example 4, the title compound having the following physical data was obtained.
1H NMR (CD3OD): δ 7.39-7.23 (m, 3H), 6.98 (d, J = 7.3 Hz, 2H), 5.16 (s, 2H), 4.33 (s,
2H), 3.54-3.39 (m, 2H), 2.91-2.74 (m, 2H), 2.39 (s, 3H);
Mass data (ESI, Pos.): m/z 270 (M + H)+.
Example 13:
1 -benzyl-2-methyl-N5-(4-(4-methylpiperazine- 1 -carbonyl)phenyl)-6,7-dihydro- 1 H- pyrrolo [3 ,2-c]pyridine-3 , 5 (4H)-dicarboxamide
According to the same procedure described in Example 6, using the compound prepared in Example 12 instead of the compound prepared in Example 5, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 7.43 (d, J = 8.6 Hz, 2H), 7.38-7.23 (m, 5H), 6.91 (d, J = 7.1 Hz,
2H), 6.81 (s, IH), 5.42 (s, 2H), 5.03 (s, 2H), 4.72 (s, 2H), 3.89-3.81 (m, 2H), 3.79-3.42
(m, 4H), 2.62-2.55 (m, 2H), 2.51-2.28 (m, 8H); Mass data (APCI, Pos.): m/z 515 (M + H)+.
Example 14:
5-(tert-butoxycarbonyl)-2-methyl-4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridine-3- carboxylic acid According to the same procedure described in Example 3, using the compound prepared in Example 1 instead of the compound prepared in Example 2, the title compound having the following physical data was obtained.
1H NMR (CD3OD): δ 4.50 (s, 2H), 3.74-3.57 (m, 2H), 2.61-2.49 (m, 2H), 2.42 (s, 3H),
1.47 (s, 9H); Mass data (APCI, Pos.): m/z 281 (M + H)+.
Example 15: tert-butyl 3 -carbamoyl-2-methyl-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridine-5 (4H)- carboxylate
According to the same procedure described in Example 4, using the compound prepared in Example 14 instead of the compound prepared in Example 3, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 8.17 (bs, IH), 5.36 (s, 2H), 4.57 (s, 2H), 3.79-3.59 (m, 2H), 2.69- 2.55 (m, 2H), 2.51 (s, 3H), 1.47 (s, 9H); Mass data (APCI, Pos.): m/z 280 (M + H)+.
Example 16:
2-methyl-4,5,6,7-tetrahydro- 1 H-pyrrolo [3 ,2-c]pyridine-3 -carboxamide trifluoroacetic acid salt
According to the same procedure described in Example 5, using the compound prepared in Example 15 instead of the compound prepared in Example 4, the title compound having the following physical data was obtained.
1H NMR (CD3OD): δ 4.31 (s, 2H), 3.52-3.37 (m, 2H), 2.95-2.79 (m, 2H), 2.43 (s, 3H);
Mass data (APCI, Pos.): m/z 180 (M + H)+.
Example 17: 2-methyl-N5-(4-(methylsulfonyl)phenyl)-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridine-
3,5(4H)-dicarboxamide
According to the same procedure described in Example 6, using the compound prepared in Example 16 instead of the compound prepared in Example 5 and 4-
(methylsulphonyl)aniline instead of (4-aminophenyl)(4-methylpiperazin- 1 - yl)methanone, the title compound having the following physical data was obtained.
1H NMR (CD3OD): δ 7.82 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H), 4.66 (s, 2H),
3.85-3.75 (m, 2H), 3.08 (s, 3H), 2.73-2.62 (m, 2H), 2.42 (s, 3H);
Mass data (ESI, Pos.): m/z 377 (M + H)+.
Example 18: methyl 6-(3 -carbamoyl-2-methyl- 1 -phenyl-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridin- 5(4H)-yl)nicotinate A solution of the compound prepared in Example 5 (0.050 g), ethyl 6- chloronicotinate (0.023 g) and diisopropylethylamine (0.059 mL) in dimethylacetamide (0.7 mL) was heated to 140 °C for 3.5 hours. The reaction was cooled to room temperature, diluted with ethyl acetate and washed sequentially with a saturated aqueous sodium bicarbonate solution and water. The organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate: hexanes = 2: 1, then 4: 1) to obtain the title compound (0.019 g) having the following physical data.
1H NMR (CD3OD): δ 8.79 (d, J = 2.0 Hz, IH), 8.02 (dd, J = 2.3, 9.0 Hz, IH), 7.55-7.41 (m, 3H), 7.22-7.14 (m, 2H), 6.73 (d, J = 9.1 Hz, IH), 5.58 (bs, 2H), 4.83 (s, 2H), 4.12- 4.02 (m, 2H), 3.87 (s, 3H), 2.52-2.44 (m, 2H), 2.33 (s, 3H); Mass data (APCI, Pos.): m/z 391 (M + H)+.
Example 19: 5-(lH-benzo[d]imidazol-2-yl)-2-methyl-l-ρhenyl-4,5,6,7-tetrahydro-lH-pyrrolo[3,2- c]pyridine-3 -carboxamide
According to the same procedure described in Example 18, using 2-chloro-lH- benzofd] imidazole instead of ethyl 6-chloronicotinate, the title compound having the following physical data was obtained. 1H NMR (CD3OD): δ 7.59-7.43 (m, 3H), 7.31-7.19 (m, 4H), 7.06-6.93 (m, 2H), 4.72 (s,
2H), 3.89-3.78 (m, 2H), 2.56-2.46 (m, 2H), 2.23 (s, 3H);
Mass data (APCI, Pos.): m/z 372 (M + H)+.
Example 20: methyl 6-(3-carbamoyl-2-methyl-l -phenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-
5(4H)-yl)-4-(trifluoromethyl)nicotinate
According to the same procedure described in Example 18, using the corresponding chloropyridine instead of ethyl 6-chloronicotinate, the title compound having the following physical data was obtained. 1H NMR (CDCl3): δ 8.79 (s, IH), 7.56-7.43 (m, 3H), 7.22-7.14 (m, 2H), 6.96 (s, IH),
5.55 (bs, 2H), 4.88 (s, 2H), 4.10-4.06 (m, 2H), 3.87 (s, 3H), 2.54-2.46 (m, 2H), 2.33 (s,
3H); Mass data (APCI, Pos.): m/z 459 (M + H)+.
Example 21:
5-(5-cyanopyridin-2-yl)-2-methyl-l-phenyl-4,5,6,7-tetrahydro-lH-pyrrolo[3,2- c]pyridine-3-carboxamide
According to the same procedure described in Example 18, using the corresponding chloropyridine instead of ethyl 6-chloronicotinate, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 8.40 (d, J = 2.2 Hz, IH), 7.62 (dd, J = 2.3, 9.0 Hz, IH), 7.55-7.43 (m, 3H), 7.18 (d, J = 7.0 Hz, 2H), 6.74 (d, J - 9.1 Hz, IH), 5.49 (bs, 2H), 4.81 (s, 2H), 4.10-4.02 (m, 2H), 2.53-2.42 (m, 2H), 2.32 (s, 3H); Mass data (APCI, Pos.): m/z 358 (M + H)+.
Example 22: 6-(3-carbamoyl-2-methyl-l-phenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-5(4H)- yl)nicotinic acid
A mixture of the compound prepared in Example 18 (0.015 g) and lithium hydroxide monohydrate (0.005 g) in tetrahydrofuran: methanol (1 : 1.5, 0.5 mL) was stirred at room temperature for five hours. The reaction was treated with aqueous 1 M sodium hydroxide (0.4 mL), stirred at room temperature for 88 hours and then concentrated. The residue was dissolved in water and adjusted to pH 2 via the addition of 1 M hydrochloric acid. Sodium chloride was added and the mixture was shaken with ethyl acetate. The mixture was filtered, the layers separated and the aqueous phase was extracted once more with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (0.005 g) having the following physical data.
1H NMR (CD3OD): δ 8.70 (d, J = 2.1 Hz, IH), 8.05 (dd, J = 2.3, 9.10 Hz, IH), 7.59- 7.45 (m, 3H), 7.31-7.22 (m, 2H), 6.89 (d, J = 9.12 Hz, IH), 4.80 (s, 2H), 4.06-3.97 (m, 2H), 2.52-2.42 (m, 2H) 2.25 (s, 3H); Mass data (APCI, Pos.): m/z 377 (M + H)+.
Example 23: 5-tert-butyl 3 -ethyl 1 -phenyl-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridine-3 ,5(4H)- dicarboxylate
Ethyl bromopyruvate (0.811 mL) was added dropwise to a 0 °C mixture of aniline (0.489 mL), tert-butyl 4-oxopiperidine-l-carboxylate (1.07 g) and sodium bicarbonate (0.451 g) in dimethylformamide (5 mL). The reaction was stirred at room temperature overnight and then diluted with water and diethyl ether. The layers were separated and the organic phase was washed sequentially with 5% aqueous sodium bisulfite and water. The organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane: hexanes = 3: 1) to obtain the title compound (0.476 g) having the following physical data.
1H NMR (CDCl3): δ 7.51-7.43 (m, 3H), 7.40-7.35 (m, IH), 7.32-7.25 (m, 2H), 4.68 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.74-3.60 (m, 2H), 2.67-2.55 (m, 2H), 1.51 (s, 9H), 1.36 (t, J = 7.1 Hz, 3H); Mass data (ESI, Pos.): m/z 393 (M + Na)+.
Example 24:
5-(tert-butoxycarbonyl)-l-phenyl-4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridine-3- carboxylic acid A mixture of the compound prepared in Example 23 (0.286 g) and lithium hydroxide monohydrate (0.292 g) in ethanol: water (1 : 1, 2 mL) was heated at 75 °C overnight. The reaction was cooled to room temperature and adjusted to pH 1 via the addition of concentrated hydrochloric acid. The mixture was then diluted with ethyl acetate and water. The layers were separated and the organic phase was washed once with brine. The organics were dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (0.265 g) having the following physical data.
1H NMR (CDCl3): δ 7.56-7.43 (m, 3H), 7.42-7.35 (m, IH), 7.30 (d, J = 7.7 Hz, 2H),
4.68 (s, 2H), 3.74-3.59 (m, 2H), 2.68-2.53 (m, 2H), 1.51 (m, 9H);
Mass data (APCI, Pos.): m/z 365 (M + Na)+.
Example 25: tert-butyl 3-carbamoyl-l-phenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-5(4H)- carboxylate
According to the same procedure described in Example 4, using the compound prepared in Example 24 instead of the compound prepared in Example 3, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 7.52-7.43 (m, 2H), 7.41-7.35 (m, IH), 7.30-7.21 (m, 3H), 5.50 (bs, 2H), 4.72 (s, 2H), 3.75-3.60 (m, 2H), 2.68-2.56 (m, 2H), 1.50 (s, 9H); Mass data (ESI, Pos.): m/z 364 (M + Na)+.
Example 26: tert-butyl 3-carbamoyl-2-chloro- 1 -phenyl-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridine-
5 (4H)-carboxylate
N-Chlorosuccinimide (0.047 g) was added to a mixture of the compound prepared in Example 25 (0.10 g) in dichloromethane (0.6 mL). The reaction was protected from light and stirred at room temperature for 64 hours. The mixture was diluted with ethyl acetate and washed sequentially with 5% aqueous sodium bisulfite and water. The organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate: hexanes = 2: 1) to obtain the title compound (0.052 g) having the following physical data.
1H NMR (CDCl3): δ 7.58-7.45 (m, 3H), 7.32-7.19 (m, 2H), 6.39 (bs, IH), 5.53 (bs, IH),
4.71 (s, 2H), 3.76-3.57 (m, 2H), 2.46-2.29 (m, 2H), 1.49 (s, 9H);
Mass data (ESI, Pos.): m/z 398 (M + Na)+.
Example 27:
2-chloro- 1 -phenyl-4,5 ,6,7-tetrahydro- 1 H-pyrrolo [3 ,2-c]pyridine-3-carboxamide trifluoroacetic acid salt
According to the same procedure described in Example 5, using the compound prepared in Example 26 instead of the compound prepared in Example 4, the title compound having the following physical data was obtained.
1H NMR (CD3OD): δ 7.64-7.53 (m, 3H), 7.40-7.30 (m, 2H), 4.43 (s, 2H), 3.51-3.43 (m,
2H), 2.71-2.62 (m, 2H); Mass data (ESI, Pos.): m/z 276 (M + H)+.
Example 28:
2-chloro-N5-(4-(methylsulfonyl)phenyl)- 1 -phenyl-6,7-dihydro- 1 H-pyrrolo[3 ,2- c]pyridine-3,5(4H)-dicarboxamide
According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained. 1H NMR (DMSOd6): δ 9.17 (s, IH), 7.77 (d, J = 8.9 Hz, 2H), 7.70 (d, J = 8.9 Hz, 2H), 7.62-7.50 (m, 3H), 7.43-7.38 (m, 2H), 7.34 (bs, IH), 6.92 (bs, IH), 4.67 (s, 2H), 3.75- 3.65 (m, 2H), 3.13 (s, 3H), 2.45-2.37 (m, 2H); Mass data (ESI, Pos.): m/z 473 (M + H)+.
Example 29:
N5-(4-(benzyloxy)phenyl)-2-chloro-l-phenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-
3,5(4H)-dicarboxamide
According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin- 1 -yl)methanone, the title compound having the following physical data was obtained.
1H NMR (DMSOd6): δ 8.49 (s, IH), 7.63-7.48 (m, 2H), 1 Al-I. Th (m, 9H), 7.01-6.77
(m, 3H), 5.04 (s, 2H), 4.60 (s, 2H), 3.71-3.56 (m, 2H), 2.41-2.26 (m, 2H);
Mass data (ESI, Pos.): m/z 523 (M + Na)+.
Example 30:
N5-(4-benzylphenyl)-2-chloro-l-phenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-
3,5(4H)-dicarboxamide
According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained. 1H NMR (CDCl3): δ 7.57-7.46 (m, 3H), 7.33 (d, J = 8.4 Hz, 2H), 7.29-7.21 (m, 4H),
7.20-7.13 (m, 3H), 7.11-7.05 (m, 2H), 6.84 (s, IH), 6.50 (bs, IH), 5.76 (bs, IH), 4.76 (s,
2H), 3.91 (s, 2H), 3.84-3.72 (m, 2H), 2.49-2.38 (m, 2H);
Mass data (ESI, Pos.): m/z 485 (M + H)+.
Example 31 :
2-chloro-l-phenyl-N5-(4-(phenylsulfonyl)phenyl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridine-3 ,5(4H)-dicarboxamide
According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 7.94-7.86 (m, 2H), 7.85-7.80 (m, 2H), 7.62-7.41 (m, 8H), 7.38-
7.18 (m, 3H), 6.52 (bs, IH), 5.64 (bs, IH), 4.80 (s, 2H), 3.84-3.72 (m, 2H), 2.51-2.38 (m, 2H);
Mass data (ESI, Pos.): m/z 535 (M + H)+.
Example 32:
2-chloro-N5-(2-chloro-4-(methylsulfonyl)phenyl)- 1 -phenyl-6,7-dihydro- 1 H- pyrrolo [3 ,2-c]pyridine-3 , 5 (4H)-dicarboxamide
According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained. 1H NMR (DMSO-d6): δ 8.59 (s, IH), 7.96 (d, J = 1.7 Hz, IH), 7.83-7.78 (m, 2H), 7.63-
7.50 (m, 3H), 7.44-7.37 (m, 2H), 7.33 (bs, IH), 6.91 (bs, IH), 4.68 (s, 2H), 3.78-3.66
(m, 2H), 3.25 (s, 3H), 2.46-2.38 (m, 2H);
Mass data (ESI, Pos.): m/z 507 (M + H)+.
Example 33: tert-butyl 4-(4-(3 -carbamoyl-2-chloro- 1 -phenyl-4,5 ,6,7-tetrahydro- 1 H-pyrrolo [3 ,2- c]pyridine-5 -carboxamido)phenylsulfonyl)piperazine- 1 -carboxylate According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline (prepared according to the reported preparation in Jones, T. R.; et al. J. Med. Chem. 1996, 39, 904) instead of (4-aminophenyl)(4-methylpiperazin-l- yl)methanone, the title compound having the following physical data was obtained. 1H NMR (CDCl3): δ 7.70-7.61 (m, 4H), 7.59-7.49 (m, 3H), 7.31 (s, IH), 7.29-7.23 (m, 2H), 6.64-6.43 (bs, IH), 5.63 (bs, IH), 4.82 (s, 2H), 3.88-3.77 (m, 2H), 3.56-3.45 (m, 4H), 3.03-2.86 (m, 4H), 2.53-2.42 (m, 2H), 1.41 (s, 9H); Mass data (ESI, Pos.): m/z 665 (M + Na)+.
Example 34:
2-chloro-N5-(lH-indol-5-yl)-l-phenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-3,5(4H)- dicarboxamide
According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained. 1H NMR (CD3OD): δ 7.61-7.51 (m, 3H), 7.49 (d, J = 2.0 Hz, IH), 7.35 (d, J = 7.0 Hz, 2H), 7.30 (d, J = 8.6 Hz, IH), 7.19 (d, J = 3.1 Hz, IH), 7.06 (dd, J = 1.9, 8.6 Hz, IH), 6.38 (d, J = 3.1 Hz, IH), 4.75 (s, 2H), 3.83-3.73 (m, 2H), 2.51-2.43 (m, 2H); Mass data (ESI, Pos.): m/z 434 (M + H)+.
Example 35:
N5-( 1 -benzyl- 1 H-indol-5-yl)-2-chloro- 1 -phenyl-6,7-dihydro- 1 H-pyrrolo[3 ,2-c]pyridine- 3,5(4H)-dicarboxamide
According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained. 1H NMR (CDCl3): δ 7.68 (d, J - 1.4 Hz, IH), 1.51-1 Al (m, 3H), 7.32-7.21 (m, 5H),
7.20-7.10 (m, 2H), 7.09-7.04 (m, 3H), 6.69 (s, IH), 6.56-6.38 (m, 2H), 5.59 (bs, IH),
5.28 (s, 2H), 4.79 (s, 2H), 3.87-3.76 (m, 2H), 2.50-2.41 (m, 2H); Mass data (ESI, Pos.): m/z 524 (M + H)+.
Example 36:
2-chloro-N5-( 1 -ethyl- 1 H-indol-5-yl)- 1 -phenyl-6,7-dihydro- 1 H-pyrrolo[3 ,2-c]pyridine- 3,5(4H)-dicarboxamide
According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding aniline (prepared according to the reported preparation in Ferlin, M. G.; et al. Bioorg. Med. Chem. 2005, 13, 3531) instead of (4-aminophenyl)(4- methylpiρerazin-l-yl)methanone, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 7.64 (s, IH), 7.57-7.46 (m, 3H), 7.32-7.22 (m, 3H), 7.19 (dd, J =
1.5, 8.7 Hz, IH), 7.07 (d, J = 3.0 Hz, IH), 6.72 (s, IH), 6.57-6.35 (m, 2H), 5.66 (bs,
IH), 4.79 (s, 2H), 4.12 (q, J = 7.3 Hz, 2H), 3.90-3.75 (m, 2H), 2.52-2.37 (m, 2H), 1.44 (t, J = 7.2 Hz, 3H);
Mass data (ESI, Pos.): m/z 484 (M + Na)+.
Example 37: tert-butyl 4-(3-carbamoyl-2-chloro-l-phenyl-4,5,6,7-tetrahydro-lH-pyrrolo[3,2- c]pyridine-5-carboxamido)piperidine- 1 -carboxylate
According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the corresponding amine instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained. 1H NMR (CDCl3): δ 7.58-7.46 (m, 3H), 7.30-7.19 (m, 2H), 6.49 (bs, IH), 5.49 (bs, IH), 4.63-4.49 (m, 3H), 4.21-3.96 (m, 2H), 3.92-3.79 (m, IH), 3.78-3.68 (m, 2H), 2.93-2.72 (m, 2H), 2.46-2.32 (m, 2H), 1.99-1.87 (m, 2H), 1.47 (s, 9H), 1.40-1.23 (m, 2H); Mass data (APCI, Pos.): m/z 524 (M + Na)+.
Example 38:
2-chloro- 1 -phenyl-N5-(4-(piperazin- 1 -ylsulfonyl)phenyl)-6,7-dihydro- 1 H-pyrrolo [3 ,2- c]pyridine-3,5(4H)-dicarboxamide trifluoroacetic acid salt According to the same procedure described in Example 5, using the compound prepared in Example 33 instead of the compound prepared in Example 4, the title compound having the following physical data was obtained.
1H NMR (DMSOd6): δ 9.25 (s, IH), 8.67-8.48 (m, 2H), 7.74 (d, J = 8.9 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 7.62-7.50 (m, 3H), 7.39 (d, J = 7.0 Hz, 2H), 7.34 (bs, IH), 6.93 (bs, IH), 4.67 (s, 2H), 3.76-3.63 (m, 2H), 3.27-3.13 (m, 4H), 3.13-2.98 (m, 4H), 2.45-2.36 (m, 2H); Mass data (ESI, Pos.): m/z 543 (M + H)+.
Example 39:
2-chloro- 1 -phenyl-N5-(4-(trifluoromethyl)phenyl)-6,7-dihydro- 1 H-pyrrolo [3 ,2- c]pyridine-3,5(4H)-dicarboxamide l-Isocyanato-4-(trifluoromethyl)benzene (0.021 mL) was added to a room temperature solution of the compound prepared in Example 27 (0.044 g) and diisopropylethylamine (0.039 mL) in chloroform (1 mL). The solution was stirred 30 minutes and then was treated with Tris(2-aminoethyl)amine resin (Argopore, SR- 1038;
0.225 g). The mixture was vigorously stirred for one hour, filtered, diluted with chloroform and washed with a saturated aqueous sodium bicarbonate solution. The organics were dried over anhydrous magnesium sulfate and concentrated. The residue was stirred in diethyl ether for one hour and the resulting white solid was collected via filtration to obtain the title compound (0.036 g) having the following physical data.
1H NMR (DMSO-d6): δ 9.05 (s, IH), 7.67 (d, J = 8.7 Hz, 2H), 7.62-7.49 (m, 5H), 7.44-
7.37 (m, 2H), 7.33 (bs, IH), 6.91 (bs, IH), 4.66 (s, 2H), 3.77-3.63 (m, 2H), 2.44-2.35
(m, 2H); Mass data (APCI, Pos.): m/z 485 (M + Na)+.
Example 40:
2-chloro-N5-methyl- 1 -phenyl-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridine-3 ,5(4H)- dicarboxamide According to the same procedure described in Example 39, using the corresponding isocyanate instead of l-Isocyanato-4-(trifluoromethyl)benzene, the title compound having the following physical data was obtained. 1H NMR (CDCl3): δ 7.61-7.43 (m, 3H), 7.36-7.15 (m, 2H), 6.47 (bs, IH), 5.50 (bs,
IH), 4.80-4.69 (m, IH), 4.56 (s, 2H), 3.81-3.69 (m, 2H), 2.90-2.79 (m, 3H), 2.44-2.35
(m, 2H);
Mass data (ESI, Pos.): m/z 355 (M + Na)+.
Example 41 :
N5-(3 -acetylphenyl)-2-chloro- 1 -phenyl-6,7-dihydro- 1 H-pyrrolo[3 ,2-c]pyridine-3 ,5 (4H)- dicarboxamide
According to the same procedure described in Example 39, using the corresponding isocyanate instead of l-Isocyanato-4-(trifluoromethyl)benzene, the title compound having the following physical data was obtained.
1H NMR (DMSO-d6): δ 8.88 (s, IH), 8.03 (s, IH), 7.80-7.74 (m, IH), 7.62-7.50 (m,
4H), 7.44-7.37 (m, 3H), 7.33 (bs, IH), 6.91 (bs, IH), 4.65 (s, 2H), 3.74-3.66 (m, 2H),
2.54 (s, 3H), 2.44-2.35 (m, 2H); Mass data (ESI, Pos.): m/z 459 (M + Na)+.
Example 42:
2-chloro-N5,l-diphenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-3,5(4H)-dicarboxamide
According to the same procedure described in Example 39, using the corresponding isocyanate instead of l-Isocyanato-4-(trifluoromethyl)benzene, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 7.57-7.49 (m, 3H), 7.45-7.38 (m, 2H), 7.36-7.23 (m, 4H), 7.08-
6.99 (m, IH), 6.65 (s, IH), 6.50 (bs, IH), 5.48 (bs, IH), 4.78 (s, 2H), 3.88-3.77 (m, 2H),
2.53-2.41 (m, 2H); Mass data (ESI, Pos.): m/z 395 (M + H)+.
Example 43:
2-chloro-N5-(4-cyanophenyl)- 1 -phenyl-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridine-3 , 5 (4H)- dicarboxamide According to the same procedure described in Example 39, using the corresponding isocyanate instead of l-Isocyanato-4-(trifluoromethyl)benzene, the title compound having the following physical data was obtained. 1H NMR (CDCl3): δ 7.66-7.48 (m, 7H), 7.34-7.18 (m, 2H), 6.98 (s, IH), 6.53 (bs, IH), 5.50 (bs, IH), 4.81 (s, 2H), 3.89-3.76 (m, 2H), 2.57-2.40 (m, 2H); Mass data (ESI, Pos.): m/z 420 (M + H)+.
Example 44:
2-chloro-N5-(4-fluorophenyl)-l-phenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-3,5(4H)- dicarboxamide
According to the same procedure described in Example 39, using the corresponding isocyanate instead of l-Isocyanato-4-(trifluoromethyl)benzene, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 7.59-7.47 (m, 3H), 7.41-7.32 (m, 2H), 7.27-7.23 (m, 2H), 7.03-
6.94 (m, 2H), 6.52 (bs, IH), 5.47 (bs, IH), 4.77 (s, 2H), 3.88-3.77 (m, 2H), 2.52-2.40
(m, IH);
Mass data (ESI, Pos.): m/z 413 (M + H)+.
Example 45:
2-chloro-N5-(4-methoxyphenyl)- 1 -phenyl-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridine-
3 ,5 (4H)-dicarboxamide
According to the same procedure described in Example 39, using the corresponding isocyanate instead of l-Isocyanato-4-(trifluoromethyl)benzene, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 7.57-7.47 (m, 3H), 7.30 (d, J = 8.9 Hz, 2H), 7.26-7.21 (m, 2H),
6.84 (d, J = 8.9 Hz, 2H), 6.61-6.41 (m, 2H), 5.50 (bs, IH), 4.76 (s, 2H), 3.86-3.74 (m,
5H), 2.50-2.40 (m, 2H); Mass data (ESI, Pos.): m/z 447 (M + Na)+.
Example 46:
2-chloro-N5-(4-ethylphenyl)- 1 -phenyl-6,7-dihydro- 1 H-pyrrolo[3 ,2-c]pyridine-3 ,5(4H)- dicarboxamide According to the same procedure described in Example 39, using the corresponding isocyanate instead of l-Isocyanato-4-(trifluoromethyl)benzene, the title compound having the following physical data was obtained. 1H NMR (CDCl3): δ 1.51-1 Al (m, 3H), 7.32 (d, J = 8.4 Hz, 2H), 7.28-7.22 (m, 2H),
7.10 (d, J = 8.4 Hz, 2H), 6.77 (s, IH), 6.50 (bs, IH), 5.70 (bs, IH), 4.77 (s, 2H), 3.87-
3.75 (m, 2H), 2.59 (q, J = 7.6 Hz, 2H), 2.49-2.40 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H);
Mass data (APCI, Pos.): m/z 445 (M + Na)+.
Example 47:
N5-(4-acetylphenyl)-2-chloro-l-phenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-3,5(4H)- dicarboxamide
According to the same procedure described in Example 39, using the corresponding isocyanate instead of l-Isocyanato-4-(trifluoromethyl)benzene, the title compound having the following physical data was obtained.
1K NMR (DMSOd6): δ 9.06 (s, IH), 7.86 (d, J = 8.7 Hz, 2H), 7.65-7.50 (m, 5H), 7.40
(d, J = 7.0 Hz, 2H), 7.36 (bs, IH), 6.92 (bs, IH), 4.66 (s, 2H), 3.76-3.63 (m, 2H), 2.51
(s, 3H), 2.44-2.35 (m, 2H); Mass data (ESI, Pos.): m/z 459 (M + Na)+.
Example 48:
2-chloro-N5-cyclohexyl- 1 -phenyl-6,7-dihydro- 1 H-pyrrolo[3 ,2-c]pyridine-3 ,5(4H)- dicarboxamide According to the same procedure described in Example 39, using the corresponding isocyanate instead of l-Isocyanato-4-(trifluoromethyl)benzene, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 7.57-7.45 (m, 3H), 7.30-7.20 (m, 2H), 6.49 (bs, IH), 5.57 (bs, IH),
4.59 (d, J = 7.7 Hz, IH), 4.54 (s, 2H), 3.79-3.71 (m, 2H), 3.71-3.62 (m, IH), 2.43-2.34 (m, 2H), 2.01-1.90 (m, 2H), 1.80-1.67 (m, 2H), 1.66-1.57 (m, IH), 1.44-1.28 (m, 2H),
1.25-1.06 (m, 3H);
Mass data (ESI, Pos.): m/z 423 (M + Na)+.
Example 49: 2-chloro-N5-(4-phenoxyphenyl)-l-phenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine- 3,5(4H)-dicarboxamide According to the same procedure described in Example 39, using the corresponding isocyanate instead of l-Isocyanato-4-(trifluoromethyl)benzene, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 7.59-7.47 (m, 3H), 7.42-7.35 (m, 2H), 7.34-7.23 (m, 4H), 7.06 (t, J = 7.4, 7.38 Hz, IH), 7.01-6.92 (m, 4H), 6.72 (s, IH), 6.52 (bs, IH), 5.52 (bs, IH), 4.78 (s, 2H), 3.88-3.77 (m, 2H), 2.52-2.39 (m, 2H); Mass data (ESI, Pos.): m/z 509 (M + Na)+.
Example 50: N5-(4-benzoylphenyl)-2-chloro-l-phenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-
3,5(4H)-dicarboxamide
According to the same procedure described in Example 39, using the corresponding isocyanate instead of l-Isocyanato-4-(trifiuoromethyl)benzene, the title compound having the following physical data was obtained. 1H NMR (CDCl3): δ 9.14 (s, IH), 7.77-7.62 (m, 7H), 7.61-7.50 (m, 5H), 7.40 (d, J = 7.1
Hz, 2H), 7.34 (bs, IH), 6.92 (bs, IH), 4.67 (bs, 2H), 3.78-3.65 (m, 2H), 2.46-2.37 (m,
2H);
Mass data (ESI, Pos.): m/z 521 (M + Na)+.
Example 51 :
1 -benzyl-5-nitro- 1 H-benzo[d] imidazole
Benzyl bromide (0.44 mL) was added to a mixture of 5-nitro-lH- benzo[d] imidazole (0.60 g) and potassium carbonate (0.76 g) in dimethylformamide (10 mL). The mixture was stirred at room temperature for 88 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate.
The combined organics were then washed twice with water, twice with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate: hexanes = 3: 1) to obtain the title compound (0.43 g) having the following physical data. 1H NMR (CDCl3): δ 8.74 (d, J = 1.6 Hz, IH), 8.19 (dd, J = 1.6, 8.6 Hz, IH), 8.12 (s, IH), 7.41-7.34 (m, 4H), 7.22-7.18 (m, 2H), 5.42 (s, 2H); Mass data (APCI, Pos.): m/z 254 (M + H)+
Example 52:
1 -benzyl-lH-benzo[d]imidazol-5-amine A mixture of the compound prepared in Example 51 (0.43 g) and tin (II) chloride dihydrate (1.9 g) in ethanol (20 mL) was refluxed overnight. The reaction was cooled to room temperature and concentrated. The residue was stirred with ethyl acetate and a saturated sodium bicarbonate solution. The resulting mixture was filtered and the layers were separated. The organics were washed with brine, dried over anhydrous magnesium sulfate, and concentrated to obtain the title compound (0.37 g) having the following physical data.
1H NMR (CDCl3): δ 7.82 (s, IH), 7.34-7.29 (m, 3H), 7.17-7.14 (m, 2H), 7.11-7.09 (m, IH), 7.03 (d, J = 8.6 Hz, IH), 6.66 (d, J = 8.6 Hz, IH), 5.27 (s, 2H), 3.48 (bs, 2H); Mass data (ESI, Pos.): m/z 224 (M + H)+.
Example 53: N,N-dimethyl-2-(5-nitro-l-(pyridin-2-ylmethyl)-lH-indol-3-yl)ethanamine
Sodium hydride (60% in oil, 0.058 g) was added to a 0 °C mixture of N,N- dimethyl-2-(5-nitro-lH-indol-3-yl)ethanamine (prepared according to the reported preparation in Holenz, J.; et al. J. Med. Chem. 2005, 48, 1781, 0.34 g) in dimethylformamide (5 mL). The reaction was stirred at room temperature for 30 minutes. A solution of 2-(bromomethyl)pyridine (0.29 g) in dimethylformamide (4 mL) was then added. The reaction was stirred at room temperature overnight, diluted with ethyl acetate, and washed with a saturated sodium bicarbonate solution. The organic phase was then washed sequentially with water and brine. The organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (triethylamine: methanol: dichloromethane = 1 : 10: 90) to obtain the title compound (0.16 g) having the following physical data. 1H NMR (CDCl3): δ 8.60 (d, J = 3.9 Hz, IH), 8.58 (d, J = 2.3 Hz, IH), 8.08 (dd, J = 2.3, 9.2 Hz, IH), 7.62-7.58 (m, IH), 7.30 (d, J = 8.8 Hz, IH), 7.26 (s, IH), 7.23-7.20 (m, IH), 6.83 (d, J = 7.8 Hz, IH), 5.43 (s, 2H), 3.10-3.05 (m, 2H), 2.84-2.79 (m, 2H), 2.47 (s, 6H); Mass data (ESI, Pos.): m/z 325 (M + H)+.
Example 54:
3-(2-(dimethylamino)ethyl)-l-(pyridin-2-ylmethyl)-lH-indol-5-amine
A mixture of platinum oxide (0.050 g) and the compound prepared in Example 53 (0.16 g) in 2: 1 tetrahydrofuran: methanol (4.5 mL) was purged with hydrogen. The mixture was stirred at room temperature for 4.5 hours, then filtered and concentrated to obtain the title compound (0.13 g) having the following physical data.
1U NMR (CDCl3): δ 8.57 (d, J = 4.7 Hz, IH), 7.55-7.49 (m, IH), 7.17- 7.12 (m, IH),
7.04-7.00 (m, IH), 6.98-6.95 (m, IH), 6.92 (d, J = 2.3 Hz, IH), 6.71- 6.66 (m, IH), 6.62 (dd, J= 2.2, 8.8 Hz, IH), 5.32 (s, 2H), 3.17-3.00 (m, 2H), 2.95-2.81 (m, 2H), 2.51 (s,
6H);
Mass data (APCI, Pos.): m/z 295 (M + H)+.
Example 55: 2,4-dinitro-N-(pyridin-2-ylmethyl)aniline
A mixture of pyridin-2-ylmethanamine (0.94 mL), l-chloro-2,4-dinitrobenzene (1.9 g), and diisopropylethylamine (1.6 mL) in ethanol (30 mL) was stirred at reflux overnight. The mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate and washed with water. The aqueous phase was extracted again with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (1.1 g) having the following physical data. 1H NMR (DMSO-d6): δ 9.70 (t, J = 5.5 Hz, IH), 8.90 (d, J = 2.3 Hz, IH), 8.60 (d, J -
4.7 Hz, IH), 8.29 (dd, J = 2.3, 9.4 Hz, IH), 7.85-7.80 (m, IH), 7.43 (d, J = 7.8 Hz, IH),
7.35 (dd, J = 4.7, 7.0 Hz, IH), 7.15 (d, J = 9.4 Hz, IH), 4.86 (d, J = 5.5 Hz, 2H);
Mass data (ESI, Pos.): m/z 275 (M + H)+.
Example 56:
4-nitro-N1-(pyridin-2-ylmethyl)benzene- 1 ,2-diamine
A 3.7 M aqueous sodium sulfide solution (8 mL) was added to an 80 °C mixture of the compound prepared in Example 55 (0.89 g), ammonium carbonate (0.46 g), and ammonium chloride (0.91 g) in a 10: 1 solution of water: concentrated ammonium hydroxide (4.4 mL). The reaction was stirred for one hour at 80 °C. Additional 3.7
M aqueous sodium sulfide (4 mL) and concentrated ammonium hydroxide solutions
(0.8 mL) were added and the reaction was heated for 30 minutes more at 80 °C. The reaction was cooled to 0 0C and filtered to obtain the title compound (0.52 g) having the following physical data.
1H NMR (DMSOd6): δ 8.55 (d, J = 3.9 Hz, IH), 7.79-7.74 (m, IH), 7.47-7.42 (m, 2H),
7.33 (d, J = 7.8 Hz, IH), 7.27 (dd, J = 5.5, 7.8 Hz, IH), 6.73 (t, J = 6.3 Hz, IH), 6.37 (d,
J = 7.8 Hz, IH), 5.25 (s, 2H), 4.56 (d, J = 6.3 Hz, 2H);
Mass data (ESI, Pos.): m/z 245 (M + H)+.
Example 57:
5-nitro- 1 -(pyridin-2-ylmethyl)- 1 H-benzo [djimidazole
A mixture of the compound prepared in Example 56 (0.50 g), K 10 montmorillonite clay (0.50 g), and triethyl orthoformate (2 mL) was subjected to microwave irradiation for 6 minutes at 90 °C. The reaction was cooled to room temperature, diluted with methanol, filtered, and concentrated to obtain the title compound (0.46 g) having the following physical data. 1H NMR (DMSOd6): δ 8.70 (s, IH), 8.57 (d, J = 2.3 Hz, IH), 8.49 (d, J = 4.7 Hz, IH),
8.16 (dd, J = 2.3, 9.4 Hz, IH), 7.84-7.79 (m, IH), 7.75 (d, J = 8.6 Hz, IH), 7.41 (d, J -
7.8 Hz, IH), 7.32 (dd, J = 6.3, 7.8 Hz, IH), 5.73 (s, 2H);
Mass data (ESI, Pos.): m/z 255 (M + H)+.
Example 58:
1 -(pyridin-2-ylmethyl)- 1 H-benzo [d] imidazol-5 -amine
According to the same procedure described in Example 52, using the compound prepared in Example 57 instead of the compound prepared in Example 51, the title compound having the following physical data was obtained.
1H NMR (DMSOd6): δ 8.53-8.51 (m, IH), 8.11 (s, IH), 7.78-7.73 (m, IH), 7.30 (dd, J
= 4.7, 6.3 Hz, IH), 7.18 (d, J = 7.8 Hz, IH), 7.10 (d, J = 7.8 Hz, IH), 6.78 (d, J - 1.6 Hz,
IH), 6.53 (dd, J = 1.6, 7.8 Hz, IH), 5.44 (s, 2H), 4.76 (bs, 2H);
Mass data (APCI, Pos.): m/z 225 (M + H)+.
Example 59:
5-nitro-2-(phenylsulfonyl)benzaldehyde
Concentrated sulfuric acid (40 μL) was added dropwise to a mixture of 5-nitro-
2-(phenylthio)benzaldehyde (0.51 g) in acetic anhydride (4 mL). The reaction was stirred for two hours at room temperature. Ice water (15 mL) was added and the mixture was adjusted to pH 6.5 via the addition of solid sodium carbonate. The aqueous mixture was then extracted twice with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate and concentrated (0.74 g). This material was used in the next step without characterization. A 36% hydrogen peroxide solution (4 mL) was added to a solution of the compound prepared in the above paragraph (0.71 g) in acetic acid (20 mL). The reaction was stirred at 90 0C overnight. The solution was cooled with an ice bath and water was added dropwise. The mixture was stirred at 0 °C for 30 minutes and then at room temperature for 30 minutes more. The mixture was filtered and the solids were air-dried for 1 hour (0.20 g). This material was used in the next step without characterization.
A mixture of the compound prepared in the above paragraph (0.20 g) in a solution 6 M sulfuric acid (8 mL) and acetic acid (8 mL) was refluxed for one hour. The reaction was cooled to 0 0C and diluted with ice water. The mixture was stirred for one hour and then filtered to obtain the title compound (0.14 g) having the following physical data.
1H NMR (CDCl3): δ 10.89 (s, IH), 8.80 (d, J = 2.3 Hz, IH), 8.54 (dd, J = 2.3, 8.6 Hz,
IH), 8.35 (d, J = 8.6 Hz, IH), 7.95-7.91 (m, 2H), 7.71-7.67 (m, IH), 7.63-7.58 (m, 2H);
Example 60:
1 -(5 -nitro-2-(phenylsulfonyl)benzyl)pyrrolidine
Sodium triacetoxyborohydride (0.15 g) was added to a solution of the compound prepared in Example 59 (0.14 g), pyrrolidine (43 μL), and acetic acid (40 μL) in dichloroethane (4 mL). The reaction was stirred at room temperature for 2.5 hours.
Saturated sodium bicarbonate was added the mixture was stirred for 30 minutes. The mixture was diluted with saturated sodium bicarbonate and dichloromethane. The aqueous phase was extracted once again with dichloromethane. The combined organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane: methanol = 66:
1) to obtain the title compound (0.098 g) having the following physical data.
1H NMR (CDCl3): δ 8.62 (d, J = 2.3 Hz, IH), 8.35 (d, J = 8.6 Hz, IH), 8.23 (dd, J = 2.3,
8.6 Hz, IH), 7.91-7.86 (m, 2H), 7.65-7.61 (m, IH), 7.55-7.51 (m, 2H), 3.95 (s, 2H),
2.40-2.36 (m, 4H), 1.71-1.66 (m, 4H); Mass data (ESI, Pos.): m/z 347 (M + H)+.
Example 61 :
4-(phenylsulfonyl)-3 -(pyrrolidin- 1 -ylmethyl)aniline A mixture of the compound prepared in Example 60 (0.098 g) and platinum oxide (0.032 g) in a 2:1 solution of tetrahydrofuran: methanol (2 mL) was purged with hydrogen. The mixture was stirred at room temperature for one hour, then filtered and concentrated to obtain the title compound (0.11 g) having the following physical data. 1H NMR (CDCl3): δ 7.99 (d, J = 8.6 Hz, IH), 7.82-7.77 (m, 2H), 7.53-7.47 (m, IH), 7.45-7.40 (m, 2H), 6.93 (d, H - 2.3 Hz, IH), 6.59 (dd, J = 3.1, 8.6 Hz, IH), 4.19 (s, 2H), 3.74 (s, 2H), 2.31-2.27 (m, 4H), 1.60-1.56 (m, 4H); Mass data (ESI, Pos.): m/z 317 (M + H)+.
Example 62:
2-chloro- 1 -phenyl-N5-( 1 -(pyridin-2-ylmethyl)- 1 H-indol-5-yl)-6,7-dihydro- 1 H- pyrrolo [3 ,2-c]pyridine-3 , 5 (4H)-dicarboxamide
According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and l-(pyridin- 2-ylmethyl)-lH-indol-5-amine (prepared as described in WO 2007064045) instead of
(4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 8.58 (d, J = 3.9 Hz, IH), 7.69 (s, IH), 7.55-7.48 (m, 4H), 7.28-7.23
(m, 2H), 7.17-7.11 (m, 4H), 6.73 (s, IH), 6.62 (d, J = 7.8 Hz, IH), 6.56-6.43 (bs, IH), 6.51 (d, J = 3.1 Hz, IH), 5.75-5.53 (bs, IH), 5.42 (s, 2H), 4.79 (s, 2H), 3.85-3.80 (m,
2H), 2.47-2.42 (m, 2H);
Mass data (ESI, Pos.): m/z 547 (M + Na)+.
Example 63: N5-(l -benzyl- 1 H-benzo[d]imidazol-5-yl)-2-chloro- 1 -phenyl-6,7-dihydro- IH- pyrrolo [3 ,2-c]pyridine-3 , 5 (4H)-dicarboxamide
According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the compound prepared in Example 52 instead of (4-aminophenyl)(4-methylpiperazin-l- yl)methanone, the title compound having the following physical data was obtained. 1H NMR (CD3OD): δ 8.21 (s, IH), 7.71 (s, IH), 7.60-7.48 (m, 3H), 7.35-7.23 (m, 9H), 5.45 (s, 2H), 4.75 (s, 2H), 3.78-3.74 (m, 2H), 2.47-2.43 (m, 2H); Mass data (ESI, Pos.): m/z 525 (M + H)+.
Example 64:
2-chloro-l-phenyl-N5-(l-(pyridin-2-ylmethyl)-lH-benzo[d]imidazol-5-yl)-6,7-dihydro-
1 H-pyrrolo [3 ,2-c]pyridine-3 , 5 (4H)-dicarboxamide According to the same procedure described in Example 6, using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the compound prepared in Example 58 instead of (4-aminophenyl)(4-methylpiperazin-l- yl)methanone, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 8.61 (d, J = 4.7 Hz, IH), 8.01 (s, IH), 7.80 (s, IH), 7.65-7.49 (m, 4H), 7.37- 7.33 (m, IH), 7.30-7.19 (m, 4H), 6.90-6.84 (m, 2H), 6.52 (bs, IH), 5.61 (bs,
IH), 5.46 (s, 2H), 4.81 (s, 2H), 3.86-3.80 (m, 2H), 2.51-2.43 (m, 2H);
Mass data (ESI, Pos.): m/z 526 (M + H)+.
Example 65: 2-chloro-N5-(3 -(2-(dimethylamino)ethyl)- 1 -(pyridin-2-ylmethyl)- 1 H-indol-5-yl)- 1 - phenyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-3,5(4H)-dicarboxamide bis(2,2,2- trifluoroacetate)
The title compound was prepared according to the same procedure described in
Example 6 while using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the compound prepared in Example 54 instead of (4- aminophenyl)(4-methylpiperazin-l-yl)methanone. The isolated material was purified further by column chromatography on Cl 8 silica gel (a gradient of 10000: 1 = water: trifluoroacetic acid, then 5000: 5000: 1 = acetonitrile: water: trifluoroacetic acid) to obtain the title compound having the following physical data. 1HNMR (CD3OD): δ 8.50 (d, J = 5.5 Hz, IH), 7.83-7.77 (m, IH), 7.69 (d, J = 1.6 Hz, IH), 7.61-7.52 (m, 3H), 7.39-7.31 (m, 4H), 7.23 (d, J - 8.6 Hz, IH), 7.12 (d, J = 8.6 Hz, IH), 7.06 (dd, J = 1.6, 8.6 Hz, IH), 5.49 (s, 2H), 4.77 (s, 2H), 3.82-3.77 (m, 2H), 3.51- 3.46 (m, 2H), 3.23-3.18 (m, 2H), 2.94 (s, 6H), 2.51-2.45 (m, 2H); Mass data (ESI, Pos.): m/z 618 (M + Na)+.
Example 66:
2-chloro- 1 -phenyl-N5-(4-(phenylsulfonyl)-3 -(pyrrolidin- 1 -ylmethyl)phenyl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridine-3,5(4H)-dicarboxamide 2,2,2-trifluoroacetate The title compound was prepared according to the same procedure described in
Example 6 while using the compound prepared in Example 27 instead of the compound prepared in Example 5 and the compound prepared in Example 61 instead of (4- aminophenyl)(4-methylpiperazin-l-yl)methanone. The isolated material was purified further by column chromatography on Cl 8 silica gel (a gradient of 10000: 1 = water: trifluoroacetic acid, then 7000: 3000: 1 = acetonitrile: water: trifluoroacetic acid) to obtain the title compound having the following physical data.
1H NMR (CD3OD): δ 8.14 (d, J = 9.4 Hz, IH), 7.99-7.93 (m, 2H), 7.88 (d, J = 2.3 Hz, IH), 7.71-7.52 (m, 7H), 7.34-7.31 (m, 2H), 4.78 (s, 2H), 4.56 (s, 2H), 3.82-3.77 (m, 2H), 3.72-3.63 (m, 2H), 3.37-3.28 (m, 2H), 2.50-2.45 (m, 2H), 2.27-2.17 (m, 2H), 2.12-2.02 (m, 2H);
Mass data (ESI, Pos.): m/z 618 (M + H)+.
Example 67:
2-chloro- 1 -(cyclopent-2-enyl)-N5-(4-(phenylsulfonyl)phenyl)-6,7-dihydro- 1 H- pyrrolo[3,2-c]pyridine-3,5(4H)-dicarboxamide
According to the same procedures described in Examples 23 — >■ 24 -» 25 — >• 26 -> 27 and Example 6, using cyclopent-2-enamine (prepared as described in Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089) instead of aniline and 4- (phenylsulfonyl)aniline instead of (4-aminophenyl)(4-methylpiperazin-l-yl)methanone, the title compound having the following physical data was obtained. 1H NMR (CDCl3): δ 7.90-7.86 (m, 2H), 7.79 (d, J = 9.4 Hz, 2H), 1.51-1 A3 (m, 5H), 7.38 (s, IH), 6.47 (bs, IH), 6.09-6.05 (m, IH), 5.74-5.70 (m, IH), 5.65 (bs, IH), 5.60- 5.33 (m, IH), 4.72 (s, 2H), 3.83-3.68 (m, 2H), 2.77-2.48 (m, 4H) 2.12-1.85 (m, 2H); Mass data (ESI, Pos.): m/z 547 (M + Na)+.
Example 68:
2-chloro- 1 -(cyclopent-2-enyl)-N5-(l -(pyridin-2-ylmethyl)- 1 H-benzo[d]imidazol-5-yl)- 6,7-dihydro- 1 H-pyrrolo[3,2-c]pyridine-3 ,5(4H)-dicarboxamide
According to the same procedures described in Examples 23 -» 24 -» 25 -» 26
-> 27 and Example 6, using cyclopent-2-enamine (prepared as described in Trost, B.
M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089) instead of aniline and and 1-
(pyridin-2-ylmethyl)-lH-indol-5-amine (prepared as described in WO 2007064045) instead of (4-aminophenyl)(4-methylpiperazin- 1 -yl)methanone, the title compound having the following physical data was obtained.
1H NMR (CDCl3): δ 8.57 (d, J = 3.9 Hz, IH), 7.67 (s, IH), 7.52-7.46 (m, IH), 7.17-7.11
(m, 4H), 6.78 (s, IH), 6.61 (d, J = 7.8 Hz, IH), 6.50 (d, J = 3.1 Hz, IH), 6.46 (bs, IH),
6.07-6.04 (m, IH), 5.74-5.71 (m, IH), 5.66 (bs, IH), 5.60-5.54 (m, IH), 5.40 (s, 2H), 4.71 (s, 2H), 3.88-3.74 (m, 2H), 2.77-2.46 (m, 4H), 2.09-1.86 (m, 2H);
Mass data (ESI, Pos.): m/z 537 (M + Na)+.
Example 69:
2-chloro-l-(3-fluorophenyl)-N5-(4-(phenylsulfonyl)phenyl)-6,7-dihydro-lH- pyrrolo [3 ,2-c]pyridine-3 , 5(4H)-dicarboxamide
According to the same procedures described in Examples 23 → 24 -» 25 -» 26 -» 27 and Example 6, using 3-fluoroaniline instead of aniline and 4- (phenylsulfonyl)aniline instead of (4-aminophenyl)(4-methylpiperazin-l -yl)methanone, the title compound having the following physical data was obtained. 1H NMR (CDCl3): δ 7.91-7.87 (m, 2H), 7.81 (d, J = 8.6 Hz, 2H), 7.58-7.43 (m, 6H), 7.26-7.21 (m, IH), 7.06 (d, J = 7.8 Hz, IH), 7.03-6.98 (m, IH), 6.50 (bs, IH), 5.76 (bs, IH), 5.67 (s, IH), 4.79 (s, 2H), 3.81-3.73 (m, 2H), 2.49-2.43 (s, 2H); Mass data (ESI, Pos.): m/z 553 (M + H)+.
Example 70:
2-chloro- 1 -(2-fluorophenyl)-N5-(4-(phenylsulfonyl)phenyl)-6,7-dihydro- 1 H- pyrrolo [3 ,2-c]pyridine-3 , 5(4H)-dicarboxamide
According to the same procedures described in Examples 23 -» 24 -» 25 -» 26 -» 27 and Example 6, using 2-fluoroaniline instead of aniline and 4-
(phenylsulfonyl)aniline instead of (4-aminophenyl)(4-methylpiperazin- 1 -yl)methanone, the title compound having the following physical data was obtained. 1H NMR (CDCl3): δ 7.91-7.87 (m, 2H), 7.81 (d, J = 9.4 Hz, 2H), 7.58-7.43 (m, 6H), 7.40 (s, IH), 7.34-7.28 (m, 3H), 6.49 (bs, IH), 5.73 (bs, IH), 4.83 (d, J = 15.7 Hz, IH), 4.76 (d, J = 15.7 Hz, IH), 3.89-3.82 (m, IH), 3.77-3.71 (m, IH), 2.50-2.34 (m, 2H); Mass data (APCI, Pos.): m/z 553 (M + H)+.
Example 71:
2-chloro-N5-(4-(phenylsulfonyl)phenyl)- 1 -(4-(trifluoromethyl)phenyl)-6,7-dihydro- 1 H- pyrrolo[3,2-c]pyridine-3,5(4H)-dicarboxamide
According to the same procedures described in Examples 23 — > 24 — » 25 — > 26
— > 27 and Example 6, using 4-trifiuoromethylaniline instead of aniline and 4-
(phenylsulfonyl)aniline instead of (4-aminophenyl)(4-methylpiperazin- 1 -yl)methanone, the title compound having the following physical data was obtained. 1H NMR (CDCl3): δ 9.19 (s, IH), 7.95 (d, J= 8.6 Hz, 2H), 7.92-7.88 (m, 2H), 7.84-7.80
(m, 2H), 7.70-7.58 (m, 7H), 7.38 (bs, IH), 6.97 (bs, IH), 4.64 (s, 2H), 3.72-3.65 (m,
2H), 2.47-2.41 (m, 2H);
Mass data (ESI, Pos.): m/z 603 (M + H)+.
PHARMACOLOGICAL ACTIVITIES The compound of the present invention of the formula (I) possesses TNF-α production-inhibitory activity. An effect of the compound of the present invention of the formula (I), for example, was confirmed by following tests.
AU the procedures were conducted by conventionally used method on the basis of basic biological methods. Furthermore, the measuring method of the present invention was modified to improve the accuracy and/or sensitivity of measurement for evaluating the compound of the present invention. The detailed experimental method was as follows.
EXPERIMENTAL METHOD
Human peripheral blood mononuclear cells (PBMC) were isolated as follows: Blood was collected in heparin tubes. The blood was diluted 1 :2 in phosphate buffered saline with Ca2+ and Mg2+ (PBS). Thirty mL of diluted blood was added to a 50 mL conical tube. The sample was underlayed with 14 mL of Histopaque (Sigma Cat# L10771). The tubes were spun at 30Og room temperature with the brake off. The buffy coat was removed and then spun for 10 min at 300g with the brake on. Cells were washed in 50 mL PBS and spun for 10 min at 150g twice with one final wash and spun at 300g.
Isolated PBMCs were suspended in RPMI 1640 medium (Gibco Cat# 11875) with 1% fetal bovine serum (Hyclone Cat# SH30070.03) and plated at 1 million cells per well in 1 mL in 24-well plates. Compounds (dimethyl sulfoxide solution) were put on the cells (final dimethyl sulfoxide concentration was 0.1%) for 1 hour followed by stimulation by lipopolysaccharide (LPS, Sigma Cat# L2018) at a final concentration of 100 ng/mL. After 24-hour incubation, plates were spun and the supernatant was collected and frozen at -800C. The amount of TNF-α in the supernatant was quantified by using an ELISA kit. Results were expressed as percent of control calculated using the following equation:
Percent of control = (TNFcompound-TNFbackgroud)/(TNFcontrol- TNFbackground)xl00 TNFcompound: amount of TNF-α in the presence of test compounds
TNFcontrol: amount of TNF-α in the absence of test compounds TNFbackground: amount of TNF-α without LPS stimulation The results indicate that these compounds of the present invention possess potent inhibitory activities on TNF-α production from human PBMC. For example, the percent of control values of a compound prepared in Example 31 at concentrations of 0.3 and 1.5 μmol/L were 8 and 39, respectively.
Formulation example 1
The following components were admixed in conventional method and punched out to obtain 10,000 tablets each containing 10 mg of an active ingredient.
■ 2-chloro- 1 -phenyl-N5-(4-(phenylsulfonyl)phenyl)-6,7-dihydro- 1 H- pyrrolo[3,2-c]pyridine-3,5(4H)-dicarboxamide 100 g
■ Carboxymethylcellulose calcium (disintegrating agent) 2O g
■ Magnesium stearate (lubricating agent) 1O g
■Microcrystalline cellulose 870 g
Formulation example 2
The following components were admixed in conventional method. The solution was sterilized in conventional manner, filtered through dust removal equipment, placed
5 ml portions into ampoules and sterilized by autoclave to obtain 10,000 ampoules each containing 20 mg of an active ingredient. ■ 2-chloro- 1 -phenyl-N5-(4-(phenylsulfonyl)phenyl)-6,7-dihydro- 1 H- pyrrolo[3,2-c]pyridine-3,5(4H)-dicarboxamide 200 g
•mannitol 20 g
■ distilled water 50 L
INDUSTRIALAPPLICABILITY
Since the compound represented by the formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, has a TNF-α production inhibitory activity, and are furthermore safe, it is useful as a preventing and/or treating agent for, for example, a metabolic disease such as diabetes, etc, an inflammatory disease such as rheumatoid arthritis, etc.

Claims

(I):
Figure imgf000092_0001
wherein R1 is a hydrogen atom or R5 -X-;
R5 is an optionally substituted alkyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted acyl group or
Figure imgf000092_0002
X is bond or -NR8CO-;
R8 is a hydrogen atom or an optionally substituted alkyl group; ring 1 is a cyclic group which may be optionally substituted;
R6 is a hydrogen atom, an optionally substituted alkoxycarbonyl group, a carboxyl group, a nitrile group, an optionally substituted alkylsulfonyl group, an optionally substituted alkyl group, an optionally substituted acyl group, a halogen atom, an optionally substituted alkoxy group or
Figure imgf000092_0003
n is an integer of from 1 to 4, wherein when n is 2 or more, R6's are the same or different; ring 3 is a cyclic group which may be optionally substituted;
R7 is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted alkoxycarbonyl group;
Z is -SO2-, -O-, -CH2-, -CO-, -CH2O- or -OCH2-; R2 is an optionally protected carbamoyl group, an optionally protected aminocarbonothioyl group or an optionally protected ammo(imino)methyl group;
R3 is an optionally substituted alkyl group, a halogen atom, a nitrile group or an optionally substituted alkoxy group;
R4 is a hydrogen atom, an optionally substituted alkyl group or
Figure imgf000093_0001
ring 2 is a cyclic group which may be optionally substituted; and
Y is bond or -CH2-, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.
2. The compound according to claim 1 , wherein R2 is an optionally protected carbamoyl group.
3. The compound according to claim 1, wherein R1 is
Figure imgf000093_0002
4. The compound according to claim 3, wherein
Figure imgf000093_0003
5. The compound according to claim 1, wherein R1 is
Figure imgf000094_0001
6. The compound according to claim 1 , wherein Y is bond.
7. The compound according to claim 4, which is a compound represented by the following formula (1-1):
Figure imgf000094_0002
8. The compound according to claim 7, wherein ring 1 is cyclohexane, benzene, pyridine, indole, benzimidazole or piperidine; ring 2 is benzene; and ring 3 is benzene or piperazine.
9. A method for preventing and/or treating a TNF-α mediated disease, which comprises administering to a mammal an effective amount of the compound of formula (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.
10. The method according to claim 9, wherein the TNF-α mediated disease is metabolic disease.
11. The method according to claim 10, wherein the metabolic disease is diabetes mellitus.
12. The method according to claim 11 , wherein the diabetes mellitus is insulin-resistant diabetes mellitus.
13. A method for inhibiting TNF-α production, which comprises administering to a mammal an effective amount of the compound of the formula (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.
14. The method according to claim 9, wherein the compound of formula (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof is administrated in combination with one or two or more medicaments selected from the group consisting of an MTP inhibitor, an HMG-CoA reductase inhibitor, a squalene synthetase inhibitor, a fibrate preparation, an ACAT inhibitor, a 5- lipoxygenase inhibitor, a cholesterol absorption inhibitor, a bile acid absorption inhibitor, an ileum NaVbile acid cotransporter inhibitor, an LDL receptor activator/expression enhancer, a lipase inhibitor, a probucol preparation, a nicotinic acid preparation, a hypoglycemic sulfonylurea agent, a biguanide preparation, an α- glucosidase inhibitor, a rapid-acting insulin secretagogue, a GPR 40 agonist, a SGLTl inhibitor, a SGLT2 inhibitor, an insulin preparation, a DPP4 inhibitor, a PTPlB inhibitor, a β3 adrenoceptor agonist, a PPAR agonist, and a therapeutic agent for diabetes complications.
15. A pharmaceutical composition which comprises the compound of formula (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.
16. Use of the compound of formula (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, for the manufacture of an agent for preventing and/or treating a TNF-α mediated disease.
PCT/US2008/061257 2007-04-27 2008-04-23 TNF-α PRODUCTION INHIBITOR WO2008134354A1 (en)

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US10092574B2 (en) 2012-09-26 2018-10-09 Valorisation-Recherche, Limited Partnership Inhibitors of polynucleotide repeat-associated RNA foci and uses thereof
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