WO2000069815A1 - Derives d'amines cycliques ureido-substituees et leur utilisation en tant que medicament - Google Patents

Derives d'amines cycliques ureido-substituees et leur utilisation en tant que medicament Download PDF

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WO2000069815A1
WO2000069815A1 PCT/US2000/006714 US0006714W WO0069815A1 WO 2000069815 A1 WO2000069815 A1 WO 2000069815A1 US 0006714 W US0006714 W US 0006714W WO 0069815 A1 WO0069815 A1 WO 0069815A1
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group
amino
glycyl
pyrrolidine
alkyl
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PCT/US2000/006714
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Tatsuki Shiota
Minoru Furuya
Minoru Imai
Mitsuru Sakai
Yumiko Muroga
Masaki Sudoh
Christine M. Tarby
Eddine Saiah
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Teijin Limited
Dupont Pharmaceuticals Research Laboratories
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Priority to AU47967/00A priority Critical patent/AU4796700A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms

Definitions

  • This invention relates to novel cyclic amine derivatives substituted with a ureido group.
  • This invention also relates to chemokine receptor antagonists that may be effective as a therapeutic agent and/or preventive agent for diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy) , multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, and sepsis in which tissue infiltration of blood leukocytes, such as monocytes and lymphocytes, play a major role in the initiation, progression or maintenance of the disease.
  • diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy) , multiple sclerosis, pulmonary
  • Chemokines are a group of inflammatory/immunomodulatory polypeptide factors which have a molecular weight of 6-15 kD and are produced by a variety of cell types, such as macrophages, monocytes, eosinophils, neutrophiles, fibroblasts, vascular endotherial cells, smooth muscle cells, and mast cells, at inflammatory sites.
  • the chemokines can be classified into two major subfamilies, the CXC chemokines (or ⁇ -chemokines) and CC chemokines (or ⁇ - chemokines) , by the common location of the four conserved cysteine residues and by the differences in the chromosomal locations of the genes encoding them.
  • the first two cysteines of CXC chemokines are separated by one amino acid and those of CC chemokines are adjacent.
  • IL-8 abbreviation for inter- leukin-8
  • CC chemokines include MlP-l ⁇ / ⁇ (abbreviation for macrophage inflammatory protein-l ⁇ / ⁇ ) , MCP-1 (abbreviation for monocyte chemoattractant protein-1) , and RANTES (abbreviation for regulated upon activation, normal T-cell expressed and secreted).
  • MlP-l ⁇ / ⁇ abbreviation for macrophage inflammatory protein-l ⁇ / ⁇
  • MCP-1 abbreviation for monocyte chemoattractant protein-1
  • RANTES abbreviation for regulated upon activation, normal T-cell expressed and secreted
  • lymphotactin which has only two cysteines and defines the C chemokine
  • fractalkine that has a chemokine-like domain in the mucin structure in which the first two cysteines are separated by three amino acids and hence defines CX 3 C chemokine.
  • These chemokines promote chemotaxis, cell migration, increase the expression of cellular adhesion molecules such as integrins, and cellular adhesion, and are thought to be the protein factors intimately involved in the adhesion and infiltration of leukocytes into the pathogenic sites in such as inflammatory tissues (for references, see for example, Vaddi, K. , et al.
  • Pathol. 1996, 148, 681; Taub, D.D., Cytokine & Growth Factor Rev., 1996, 7, 335; Strieter, R.M., et al. , J. Immunol. , 1996, 156, 3583; Furie, M.B. , et al . , Am. J. Pathol. , 1995, 146, 1287; Schall , T.J., et al.. Current Opinion in Immunology, 1994, 6, 865; Edginton, S.M., Biotechnology, 1993, 11, 676).
  • MlP-l ⁇ causes a transient increase in intracellular calcium ion concentration levels and induces migration of T lymphocytes, B lymphocytes (see for example, Taub, D.D. , et al.. Science, 1993, 260, 355; Schall, T.J., et al., J. Exp. Med., 1993, 177, 1821), and eosinophiles (see for example. Rot, A., et al., J. Exp. Med., 1992, 176, 1489), chemotaxis of natural killer cells (see for example, Maghazachi, A.A. , et al., J.
  • MlP-l ⁇ also enhances IgE and IgG4 production in B cells (see for example, Kimata, H. , et al., J. Exp. Med., 1996, 183, 2397) and inhibits hematopoietic stem cell proliferation (see for example, Mayani, H., et al., Exp.
  • MlP-l ⁇ With respect to the activity of MlP-l ⁇ in vivo and its role in the pathogenesis of disease, it has been reported that it is a pyrogen in rabbits (see for example Davatelis, G. , et al.. Science, 1989, 243, 1066); that MlP-l ⁇ injection into mouse foot pads results in an inflammatory reaction such as infiltration by neutrophils and mononuclear cells (see for example Alam, R. , et al., J. Immunol., 1994, 152, 1298); that MlP-l ⁇ neutralizing antibody has an inhibitory effect or a therapeutic effect in animal models of granuloma (see for example Lukacs, N.W. , et al., J. Exp.
  • idiopathic pulmonary fibrosis see for example Smith, R.E., et al., J. Immunol., 1994, 153, 4704; Smith, R.E., Biol. Signals, 1996, 5, 223), acute lung injury (see for example Shanley, T.P., et al., J. Immunol., 1995, 154, 4793; Standiford, T.J., et al . , J. Immunol., 1995, 155, 1515), and rheumatoid arthritis (see for example Kasama, T. , et al. , J. Clin. Invest.
  • MCP-1 also known as MCAF (abbreviation for macrophage chemotactic and activating factor) or JE
  • MCAF abbreviation for macrophage chemotactic and activating factor
  • JE vascular endothelial cells
  • T lymphocytes see for example Loetscher, P., et al. , FASEB J., 1994, 8, 1055
  • natural killer cells see for example Loetscher, P., et al., J. Immunol., 1996, 156, 322; Allavena, P., et al., Eur. J. Immunol., 1994, 24, 3233
  • mediating histamine release by basophils see for example Alam, R. , etal., J. Clin. Invest., 1992, 89, 723; Bischoff, S.C., et al., J. Exp. Med., 1992, 175, 1271; Kuna, P., et al., J. Exp. Med., 1992, 175, 489).
  • myocarditis see for example Seino, Y. , et al., Cytokine, 1995, 7, 301
  • endometriosis see for example Jolicoeur, C, et al.. Am. J. Pathol., 1998, 152, 125
  • intraperitoneal adhesion see for example Zeyneloglu, H.B. , et al.. Human Reproduction, 1998, 13, 1194
  • congestive heart failure see for example Aurust, P., et al.. Circulation, 1998, 97, 1136
  • chronic liver disease see for example Marra, F., et al. , Am. J. Pathol..
  • Asthma see for example Gonzalo, J.-A., et al., J. Exp. Med., 1998, 188, 157; Lukacs, N.W., J. Immunol., 1997, 158, 4398
  • atherosclerosis see for example Guzman, L.A. , et al . , Circulation, 1993, 88 (suppl.), 1-371
  • delayed type hypersensitivity see for example Rand, M.L., et al.. Am. J. Pathol., 1996, 148, 855
  • pulmonary hypertension see for example Kimura, H. , et al.. Lab.
  • chemokines such as MlP-l ⁇ and MCP-1 attract monocytes and lymphocytes to disease sites and mediate their activation and thus are thought to be intimately involved in the initiation, progression and maintenance of diseases deeply involving monocytes and lymphocytes , such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy) , multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, and sepsis (see for example Rovin, B.H.
  • drugs which inhibit the action of chemokines on target cells may be effective as a therapeutic and/or preventive drug in the diseases .
  • CXCR1-CXCR5 CXCR1-CXCR5
  • CCR1-CCR8 CC chemokine receptors
  • IL-8 is a ligand for CXCR1 and CXCR2
  • MlP-l ⁇ is that for CCR1 and CCR5
  • MCP-1 is that for CCR2A and CCR2B (for reference, see for example. Holmes, W.E. , et al.
  • compound which inhibit the binding of chemokines such as MlP-l ⁇ and/or MCP-1 to these receptors may be useful as drugs which inhibit the action of chemokines such as MlP-l ⁇ and/or MCP-1 on the target cells, but there are no drugs known to have such effects.
  • the cyclic amine derivatives provided by the present invention is quite novel. Recently, it has been reported that the diphenylmethane derivatives (W09724325; Hesselgesser, J., et al., J. Biol.
  • the present inventors discovered that a cyclic amine derivative having a ureido-aryl group, its pharmaceutically acceptable C ⁇ Ce alkyl addition salt or its pharmaceutically acceptable acid addition salt has an excellent activity to inhibit the binding of chemokines such as MlP-l ⁇ and/or MCP-1 and the like to the receptor of a target cell, which has led to the completion of this invention.
  • the present invention is a compound of the formula (I) below:
  • 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof in which the phenyl or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, aromatic heterocyclic group, or condensed ring may be substituted with one or more of a group represented by the formula: X R b —N-C-N R a R c , a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, a Ci-C ⁇ alkyl group, a Ci-C ⁇ alkyl group, a C 3 -C 8 cycloalkyl group, a C
  • R a , R b , and R c are the same or different from each other and are a hydrogen atom, a C- . -C 6 alkyl group, a carbamoyl group, or R b and R c taken together with the adjacent nitrogen atom form a pyrrolidine, a piperidine, a morpholine, a thiomoropholine, or a hexamethyleneimine;
  • X is a oxygen atom or a sulfur atom
  • R 2 is a hydrogen atom or a C-.-C 6 alkyl group; j represents an integer of 0-2; k represents an integer of 0-2; m represents an integer of 2-4; n represents 0 or 1;
  • R 3 is a hydrogen atom or a C ! -C 6 alkyl group
  • R 4 and R 5 are the same or different from each other and are a hydrogen atom, a phenyl group, or a C- . -C 6 alkyl group, in which the C ⁇ -C 6 alkyl group is optionally substituted with one or more of a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, a mercapto group, a guanidino group, a C 3 -C ⁇ cycloalkyl group, a C ! -C 6 alkoxy group, a C !
  • -C 6 alkylthio group a phenyl group optionally substituted with one or more of a halogen atom, a hydroxy group, a C ! -C 6 alkyl group, a C- . -C 6 alkoxy group, or a benzyloxy group, a phenoxy group, a benzyloxy group, a benzyloxycarbonyl group, a C 2 -C 7 alkanoyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 alkanoyloxy group, a C 2 -C 7 alkanoylamino group, a C ⁇ -C 6 alkylsulfonyl group, an amino group, a mono(C ⁇ - C 6 alkyl)amino group, a alkyl)amino group, or an aromatic heterocyclic group having 1-3 of heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom,
  • R 5 represents C 2 -C 5 alkylene group
  • R 6 is a phenyl group or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, aromatic heterocyclic group, or condensed ring may be substituted with one or more of a group represented by the formula:
  • halogen atom a hydroxy group, a mercapto group, a cyano group, a nitro group, a thiocyanato group, a carboxy group, a carbamoyl group, a trifluoromethyl group, a C- . -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a C 2 -C 6 alkenyl group, a C ! -C 6 alkoxy group, a C 3 -C 8 cycloalkyloxy group, a C ! -C 6 alkylthio group, a C !
  • -C 3 alkylenedioxy group a phenyl group, a phenoxy group, a benzyl group, a benzoyl group, a phenylsulfinyl group, a phenylsulfonyl group, a 3-phenylureido group, a 3- phenyl-thioureido group, a C 2 -C 7 alkanoyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 alkanoyloxy group, a C 2 -C 7 alkanoyla ino group, aCi-Cj alkylsulfonyl group, an amino group, a mono(C !
  • the present invention is a method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell using a pharmaceutical preparation containing a therapeutically effective amount of a compound represented by the above formula ( I ) , a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable C ! -C 6 alkyl addition salt thereof (Invention 2).
  • the present invention is a method of treating a disease, in which a chemokine plays a major role, which comprises administering a pharmaceutical preparation containing a therapeutically effective amount of a compound represented by the above formula ( I ) , a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable C ! -C 6 alkyl addition salt thereof (Invention 3).
  • the compound represented by the above formula (I) has activities to inhibit the binding of chemokines such as MlP-l ⁇ and/or MCP-1 and the like to the receptor of a target cell and activities to inhibit physiological activities of cells caused by chemokines such as MlP-l ⁇ and/or MCP-1 and the like.
  • the compound represented by the above formula (I) is also effective as a therapeutic agent and/or preventive agent for disease such as atherosclerosis, rheumatoid arthritis, -psoriasis, asthma, ulcerative colitis, nephritis (nephropathy) , multiple sclerosis, pulmonary fibrosis , myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, and sepsis in which tissue infiltration of blood leukocytes plays a major role in the initiation, progression or maintenance of the disease.
  • disease such as atherosclerosis, rheumatoid arthritis, -psoriasis, asthma, ulcerative colitis, nephritis (nephropathy) , multiple sclerosis, pulmonary fibrosis , myocarditis,
  • R 1 is a phenyl group or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, aromatic heterocyclic group , or condensed ring may be substituted with one or more of a group represented by the formula:
  • halogen atom a hydroxy group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, a C ⁇ -C 6 alkyl group, a C 3 -C 8 cycloalkyl group, a C 2 -C 6 alkenyl group, a C !
  • -C 6 alkylsulfonyl group a ⁇ " -phenylcarbamoyl group, an amino group, a monofCi-C e alkyl) amino group, or a di(C- . -C 6 alkyl) amino group.
  • the "aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof" for R 1 is specifically, for example, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazinyl, triazolyl, oxadiazolyl (furazanyl), thiadiazolyl group and the like , preferably including a thienyl , furyl , pyrrolyl , isoxazolyl, and pyridyl group.
  • the "condensed ring" for R 1 means a ring obtained by the condensation with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom of a phenyl group or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom and/or a nitrogen atom, at any possible sites, suitably and specifically for example, naphthyl, indolyl, benzofuranyl, benzothienyl, quinolyl, benzimidazolyl, benzoxazolyl, benzotriazolyl, benzoxadiazolyl (benzofurazanyl) , and ben- zothiadiazolyl group.
  • a phenyl group can be listed as a preferred specific example for R 1 .
  • halogen atom as a substituent for the phenyl group, aromatic heterocyclic group, or condensed ring in R 1 includes a fluorine atom, chlorine atom, bromine atom, and iodine atom, suitably including a fluorine atom, chlorine atom, and bromine atom.
  • C ⁇ -C 6 alkyl group as a substituent for R 1 means a C ⁇ -C 6 straight-chain or a branched alkyl group such as a methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, 2-methylpentyl, 1-ethylbutyl group, and the like, suitably specifically including a methyl, ethyl, propyl, and isopropyl group.
  • the "C 3 -C 8 cycloalkyl group” as a substituent for R 1 means a cyclic alkyl group such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl group, specifically including a cyclopropyl, cyclopentyl, and cyclohexyl group.
  • the "C 2 -C 6 alkenyl group” as a substituent for R 1 means a C 2 -C 6 straight-chain or a branched alkenyl group such as a vinyl, allyl , 1-propenyl,
  • 3-pentenyl group and the like, suitably specifically including a vinyl and 2-methyl-l-propenyl group.
  • C ! -C 6 alkoxy group as a substituent for R 1 means group consisting of the aforementioned C ! -C 6 alkyl group and oxy group, specifically, for example, a methoxy and ethoxy group.
  • C ! -C 6 alkylthio group as a substituent for R 1 means group consisting of the aforementioned C ! -C 6 alkyl group and thio group, specifically, for example, a methylthio and ethylthio group.
  • C 2 -C 4 alkylenoxy group as a substituent for R 1 means group consisting of a C 2 -C 4 divalent alkylene group and oxy group such as a ethylenoxy (-CH 2 CH 2 ⁇ -) , trimethylenoxy ( -CH 2 CH 2 CH 2 0- ) , tetramethylenoxy ( -CH 2 CH 2 CH 2 CH 2 ⁇ - ) , and 1,1- dimethylethylenoxy ( -CH 2 C(CH 3 ) 2 0- ) group, specifically, for example, a ethylenoxy and trimethylenoxy group.
  • the "C ! -C 3 alkylenedioxy group" as a substituent for R 1 means group consisting of a Ci-C divalent alkylene group and two oxy groups such as a methylenedioxy ( -OCH 2 0- ) , ethylenedioxy ( -OCH 2 CH 2 0- ) , trimethylenedioxy ( - OCH 2 CH 2 CH 2 0- , and propylenedioxy ( -OCH 2 CH(CH 3 )0- ) group, specifically, for example, a methylenedioxy and ethylenedioxy group.
  • C 2 -C 7 alkanoyl group as a substituent for R 1 means C 2 -C 7 straight-chain or branched alkanoyl group such as an acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, isobutyryl, 3-methylbutanoyl, 2-methylbutanoyl, pivaloyl, 4-methylpentanoyl, 3 , 3-dimethylbutanoyl, 5-methylhexanoyl group, and the like, where the preferred and specific example includes an acetyl group.
  • C 2 -C 7 alkoxycarbonyl group as a substituent for R 1 means group consisting of the aforementioned C ⁇ -C 6 alkoxy group and carbonyl group, preferably and specifically for example, a methoxycarbonyl and ethoxycarbonyl group .
  • C 2 -C 7 alkanoyloxy group as a substituent for R 1 means group consisting of the aforementioned C 2 -C 7 alkanoyl group and oxy group, specifically, for example, an acetyloxy group.
  • C 2 -C 7 alkanoylamino group as a substituent for R 1 means group consisting of the aforementioned C 2 -C 7 alkanoyl group and amino group, specifically, for example, an acetylamino group.
  • C- . -C 6 alkylsulfonyl group as a substituent for R 1 means group consisting of the aforementioned C ! -C 6 alkyl group and sulfonyl group, preferably and specifically, for example, a methylsulfonyl group.
  • the "mono(C- . -C 6 alkyl) amino group" as a substituent for R 1 means amino group substituted with one of the aforementioned C ! -C 6 alkyl group, preferably and specifically, for example, a methylamino and ethyl amino group.
  • KCj-Ce alkyl)amino group as a substituent for R 1 means amino group substituted with the same or different two C-.-C 6 alkyl group aforementioned, preferably and specifically, for example, a dimethylamino, diethylamino, and W-ethyl-W-methylamino group.
  • a halogen atom a hydroxy group, a C ! -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C ! -C 6 alkoxy group, a C- . -C 6 alkylthio group, a C 2 -C 4 alkylenoxy group, a methylenedioxy group, a ⁇ T-phenylcarbamoyl group, an amino group, a mono(C ! -C 6 alkyl)amino group, and a di(C ! -C 6 alkyl)amino group can be listed as a preferred specific example for substituent for the phenyl group, aromatic heterocyclic group, or condensed ring in R 1 .
  • substituent for the phenyl group, aromatic heterocyclic group, or condensed ring in R 1 are optionally substituted with one or more of a halogen atom, a hydroxy group, an amino group, a trifluoromethyl group, a Ci-C 6 alkyl group, or a C ! -C 6 alkoxy group.
  • the halogen atom, C ⁇ -C 6 alkyl group, and C ⁇ alkoxy group are the same as defined for the aforementioned substituents for the phenyl group, aromatic heterocyclic group, or condensed ring in R 1 , and the same examples can be listed as preferred specific examples.
  • R a , R b , and R c are the same or different from each other and are a hydrogen atom, a C ! -C 6 alkyl group, a carbamoyl group, or R b and R c taken together with the adjacent nitrogen atom form a pyrrolidine, a piperidine, a morpholine, a thiomoropholine, or a hexamethyleneimine .
  • the C ! -C 6 alkyl group for R a , R , and R c is the same as defined for the aforementioned substituent for the phenyl group, aromatic heterocyclic group, or condensed ring in R 1 .
  • a hydrogen atom can be listed as a preferred specific example for R a
  • a hydrogen atom, a methyl group, ethyl group, and isopropyl group can be listed as a preferred specific example for R a and R b .
  • X represents a oxygen atom or a sulfur atom.
  • R 2 represents a hydrogen atom or a C-.-C 6 alkyl group .
  • the Ci-C f * alkyl group for R 2 is the same as defined for the aforementioned substituent for the phenyl group, aromatic heterocyclic group, or condensed ring in R 1 , and the same examples can be listed as preferred specific examples. Among them, a hydrogen atom is a preferred specific example for R 2 .
  • j represents an integer of 0-2. It is particularly preferred for j to be 0.
  • k represents an integer of 0-2 and m represents an integer of 2-4. It is preferred to use a 2-substituted pyrrolidine in which k is 0 and m is 3 , a 3-substituted pyrrolidine in which k is 1 and m is 2, a 3-substituted piperidine in which k is 1 and m is 3, a 4-substituted piperidine in which k is 2 and m is 2, or 3-substituted hexahydroazepine in which k is 1 and m is 4.
  • n in the above formula (I) represents 0 or 1.
  • 3-amidopyrrolidines in which k is 1, m is 2, and n is 0 and 4-(amidomethyl)piperidines in which k is 2 , m is 2, and n is 1 can be listed as a particularly preferred example.
  • R 3 in the above formula (I) represents a hydrogen atom or a Ci-C f * alkyl group .
  • the Cj-C e alkyl group for R 3 is the same as defined for the aforementioned substituent for the phenyl group, aromatic heterocyclic group, or condensed ring in R 1 , and the same examples can be listed as preferred specific examples.
  • a hydrogen atom is a preferred specific example for R 3 .
  • R 4 and R 5 are the same or different from each other and are a hydrogen atom, a hydroxy group, a phenyl group, or a C ! -C 6 alkyl group, in which the C ! -C 6 alkyl group is optionally substituted with one or more of a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, a mercapto group, a guanidino group, a C 3 -C 8 cycloalkyl group, a Ci-C f - alkoxy group, a C !
  • -C 6 alkylthio group a phenyl group optionally substituted with one or more of a halogen atom, a hydroxy group, a C ! -C 6 alkyl group, a C ! -C 6 alkoxy group, or a benzyloxy group, a phenoxy group, a benzyloxy group, a benzyloxycarbonyl group, a C 2 -C 7 alkanoyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 alkanoyloxy group, a C 2 -C 7 alkanoylamino group, a C- .
  • -C 6 alkylsulfonyl group an amino group, a monofCj-C ⁇ alkyl) amino group, a di(C ! -C 6 alkyl) amino group, or an aromatic heterocyclic group having 1-3 of heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof and optionally condensed with benzene ring, or R 4 and R 5 taken together form a 3 to 6 membered cyclic hydrocarbon.
  • the C-.-C 6 alkyl group for R 4 and R 5 is the same as defined for the aforementioned substituent for the phenyl group, aromatic heterocyclic group, or condensed ring in R 1 , and the same examples can be listed as preferred specific examples .
  • the halogen atom, C 3 -C 8 cycloalkyl group, C ! -C 6 alkoxy group, C ! -C 6 alkylthio group, C 2 -C 7 alkanoyl group, C 2 -C 7 alkoxycarbonyl group, C 2 -C 7 alkanoyloxy group, C 2 -C 7 alkanoylamino group, C x -C 6 alkylsulfonyl group, mono(C ⁇ -C 6 alkyl) amino group, and di(C ! -C 6 alkyl) amino group as a substituent for the C ! -C 6 alkyl group in R 4 and R 5 are the same as defined for the aforementioned substituent for the phenyl group, aromatic heterocyclic group, or condensed ring in R 1 , and the same examples can be listed as preferred specific examples.
  • the aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof as substituent for the C ! -C 6 alkyl group in R 4 and R 5 is the same as defined for the aforementioned group for R 1 , and the same examples can be listed as preferred specific examples.
  • the halogen atom, C ! -C 6 alkyl group, and C-.-C 6 alkoxy group for the substituent for the phenyl group which is substituent for the C-.-C 6 alkyl group in R 4 and R 5 are the same as defined for the aforementioned substituent for the phenyl group, aromatic heterocyclic group, or condensed ring in R 1 , and the same examples can be listed as preferred specific examples .
  • the "3 to 6 membered cyclic hydrocarbon" consisting of R 4 , R 5 , and the adjacent carbon atom includes a cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
  • a hydrogen atom can be listed as a preferred specific example for R 4 and R 5 .
  • R 7 is a hydrogen atom or a Ci-C 6 alkyl group, or R 7 taken together with R 5 represents a C 2 -C 5 alkylene group.
  • the Cj-Ce alkyl group for R 7 are the same as defined for the aforementioned substituent for the phenyl group, aromatic heterocyclic group, or condensed ring in R 1 , and the same examples can be listed as preferred specific examples.
  • C 2 -C 5 alkylene group consisting of R 5 and R 7 means C 2 -C 5 straight-chain or branched alkylene group such as a methylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, pentamethylene group, and the like, suitably and specifically including a ethylene, trimethylene and tetramethylene group.
  • a hydrogen atom is a preferred specific example for R 7 .
  • R 6 is a phenyl group or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, aromatic heterocyclic group , or condensed ring may be substituted with one or more of a group represented by the formula:
  • a halogen atom a hydroxy group, a mercapto group, a cyano group, a nitro group, a thiocyanato group, a carboxy group, a carbamoyl group, a trifluoromethyl group, a C ! -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a C 2 -C 6 alkenyl group, a Ci-C,- alkoxy group, a C 3 -C 8 cycloalkyloxy group, a C- .
  • -C 6 alkylthio group a Ci-C 3 alkylenedioxy group, a phenyl group, a phenoxy group, a benzyl group, a benzoyl group, a phenylsulfinyl group, a phenylsulfonyl group, a 3-phenylureido group, a 3- phenyl-thioureido group, a C 2 -C 7 alkanoyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 alkanoyloxy group, a C 2 -C 7 alkanoylamino group, a C- .
  • -C 6 alkylsulfonyl group an amino group, a mono(C ! -C 6 alkyl)amino group, a di(C ⁇ C 6 alkyl) amino group, a C 2 -C 7 (alkoxycarbonyl)amino group, or a C ! -C 6 (alkylsulfonyl) amino group.
  • the aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, and the condensed ring for R ⁇ is the same as defined for the aforementioned R 1 , and the same examples can be listed as preferred specific examples . Among them, a phenyl group can be listed as a preferred specific example for R 6 .
  • C 3 -C 8 cycloalkyloxy group as a substituent for R 6 means group consisting of the aforementioned C 3 -C 8 cycloalkyl group and oxy group, specifically, for example, a cyclopropyloxy, cyclopentyloxy, and cyclohexyloxy group .
  • C 2 -C 7 ( alkoxycarbonyl )amino group as a substituent for R 6 means group consisting of the aforementioned C 2 -C 7 alkoxycarbonyl group and amino group, specifically, for example, a (methoxycarbonyl) amino and ( ethoxycarbonyl ) amino group .
  • C ! -C 6 (alkylsulfonyl) amino as a substituent for R 6 means group consisting of the aforementioned Cj.-C 6 alkylsulfonyl group and amino group, specifically, for example, a (methylsulfonyl) amino group.
  • a halogen atom, a mercapto group, a nitro group, a thiocyanato group, a trifluoromethyl group, a C ⁇ C,- alkyl group, a C ⁇ -C 6 alkoxy group, a phenyl group, a phenylsulfonyl group, a C 2 -C 7 alkanoylamino group, an amino group, or a trifluoromethoxy group can be listed as preferred specific example for substituent for the phenyl group, aromatic heterocyclic group, or condensed ring in R 6 .
  • substituents for the phenyl group, aromatic heterocyclic group, or condensed ring in R 6 are optionally substituted with one or more of a halogen atom, a cyano group, a hydroxy group, an amino group, trifluoromethyl group, a C- . -C 6 alkyl group, a Ci-C 6 alkoxy group, a Ci-Cg alkylthio group, a mono(C ⁇ -C 6 alkyl) amino group, or a di(C:*-C 6 alkyl) amino group.
  • the halogen atom, C ! -C 6 alkyl group, C ! -C 6 alkoxy group, a Ci-C 6 alkylthio group, mono(C ⁇ -C 6 alkyl)amino group, and di(C ⁇ -C 6 alkyl)amino group are the same as defined for the aforementioned substituents for the phenyl group, aromatic heterocyclic group, or condensed ring in R 1 , and the same examples can be listed as preferred specific examples.
  • the phenyl group, aromatic heterocyclic group, or condensed ring in at least one of R 1 and R 6 is substituted with a 3- phenyl-thioureido group or a group represented by the formula:
  • the compound represented by the formula (I) of the present invention always has one or more of a 3-phenyl-thioureido group or a group represented by the formula: 0 R b
  • a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ! -C 6 alkyl addition salt can be used to prepare a chemokine receptor antagonist preparation of the present invention by formulating the therapeutically effected amount and a carrier and/or diluent into a pharmaceutical composition.
  • the ureido-substituted cyclic amine derivatives shown by the above formula (I) , a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ⁇ -C 6 alkyl addition salt can be administered orally or by parenterally, for example, intravenously, subcutaneously, intramuscularly, percutaneously or intrarectally.
  • the oral administration can be accomplished in the form of tablets , pills , granules, powder, solution, suspension, capsules, etc.
  • the tablets for example can be prepared using a vehicle such as lactose, starch and crystallized cellulose; binder such as carboxymethylcellulose, methylcellulose, and polyvinylpyrrolidone; disintegrator such as sodium alginate, sodium bicarbonate and sodium lauryl sulfate, etc. Pills, powder and granule preparations can be prepared by a standard method using the vehicles mentioned above. Solution or suspension can be prepared by a standard method using glycerin ester such as tricaprylin and triacetin or alcohols such as ethanol . Capsules can be made by charging granules , powder or solution in gelatin, etc.
  • a vehicle such as lactose, starch and crystallized cellulose
  • binder such as carboxymethylcellulose, methylcellulose, and polyvinylpyrrolidone
  • disintegrator such as sodium alginate, sodium bicarbonate and sodium lauryl sulfate, etc.
  • Subcutaneous, intramuscular or intravenous preparations can be prepared as an injection using aqueous or nonaqueous solution.
  • Aqueous solution for example may include isotonic sodium chloride solution.
  • Nonaqueous solutions may include for example, propyleneglycol, polyethyleneglycol, olive oil, ethyl oleate, etc., and optionally, one can add antiseptics and stabilizers.
  • For injection one can be sterilized by filtration through a bacterial filter or combination of disinfectant.
  • Percutaneous administration may be in the form of an ointment or cream, and ointment can be prepared in the standard manner using fatty oils such as castor oil and olive oil, or Vaseline, while creams can be made using fatty oils or emulsifying agent such as diethyleneglycol and sorbitan esters of fatty acid.
  • fatty oils such as castor oil and olive oil, or Vaseline
  • creams can be made using fatty oils or emulsifying agent such as diethyleneglycol and sorbitan esters of fatty acid.
  • the ureido-substituted cyclic amine derivatives of the present invention, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C ! -C 6 alkyl addition salt is administered at a dose that varies depending on the type of disease, route of administration, age and sex of patient, and severity of disease, but is likely to be 1-500 mg/day in an average adult.
  • Preferred specific examples for the ureido-substituted cyclic amine compound in the above formula ( I ) includes :
  • the present invention can also use acid addition salt of the cyclic amine compound substituted with ureido group where such acids include, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, and the like, as well as organic acids such as maleic acid, citric acid, malic acid, tartaric acid, fumaric acid, methanesulfonic acid, trifluoroacetic acid, formic acid, and the like.
  • mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, and the like
  • organic acids such as maleic acid, citric acid, malic acid, tartaric acid, fumaric acid, methanesulfonic acid, trifluoroacetic acid, formic acid, and the like.
  • the present invention can also use a C ⁇ C e alkyl addition salt of the cyclic amine compound, such as 1- (4-chlorobenzyl)-l-methyl-4- [ ⁇ At- (5-trifluoromethyl-2-ureidobenzoyl) glycyl ⁇ aminomethyl]piperidinium iodide, where such alkyl include, for example, a methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert- butyl, isopentyl, neopentyl, tert-pentyl, 2-methylpentyl, 1-ethylbutyl, and the like, suitably specifically including, a methyl and ethyl group.
  • the present invention may use racemates and all possible optically active forms of the compound represented by the above formula (I).
  • Compound represented by the above general formula (I) can be synthesized by any of the general preparations given below.
  • the reactive derivative for the carboxylic acid in the above formula ( III ) include highly reactive carboxylic acid derivatives, which are usually used in synthetic organic chemistry, such as acid halides, acid anhydrides, mixed acid anhydrides .
  • Such reactions can be more smoothly run by using suitable amounts of a dehydrating agent such as molecular sieve, coupling reagent such as dicyclohexylcarbodiimide (DCC), At-ethyl- t' - (3- dimethylaminopropyl )carbodiimide (EDCI or WSC), carbonyldiimidazole (CDI), At-hydroxysuccinimide (HOSu), At-hydroxybenzotriazole (HOBt), benzotriazol-1- yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP * ) , 2- ( lH- benzotriazol-l-yl)-l, 1, 3 ,3-tetramethyluronium hexafluorophosphate (HBTU) , 2- ( ltf-benzotriazol-1-yl ) -1 , 1 , 3 , 3-tetramethyluronium tetra
  • R 1 , R 2 , and j are the same as defined respectively in the above formula (I) ⁇ ;
  • X represents a halogen atom, alkylsulfonyloxy group, or arylsulfonyloxy group ⁇ , with 0.1-10 equivalents of a compound represented by the formula (V) below:
  • Such reactions can be more smoothly run if a base similar to that used in the above preparation 1 is present.
  • the reactions in these preparations can also be promoted by iodide such as potassium iodide, sodium iodide, and the like.
  • X represents a halogen atom, alkylsulfonyloxy group, arylsulfonyloxy group.
  • halogen atoms include preferably chlorine, bromine, and iodine atoms.
  • alkylsulfonyloxy groups include methylsulfonyloxy, trifluoromethylsulfonyloxy group, and the like.
  • a preferred specific example for the arylsulfonyloxy group includes a tosyloxy group.
  • R 1 is the same as defined in the above formula (I); j represents 0 ⁇ , with 0.1-10 equivalents of a compound represented by the formula (V) either in the absence or presence of solvent under reductive conditions.
  • Such reactions are in general called reductive amination reactions and such reductive conditions may be generated by catalytic hydrogenation using a catalyst containing a metal such as palladium, platinum, nickel, rhodium, or the like, using complex hydrides, such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like, boranes, or electrolytic reduction, and the like.
  • complex hydrides such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like, boranes, or electrolytic reduction, and the like.
  • R 6 is the same as defined in the above formula (I) ⁇ , or its reactive derivative, either in the absence or presence of solvent.
  • the reactive derivative for the carboxylic acid in the above formula (IX) include highly reactive carboxylic acid derivative, which are usually used in synthetic organic chemistry, such as acid halides, acid anhydrides, mixed acid anhydrides . Such reactions can be more smoothly run by using suitable amounts of a dehydrating agent, coupling reagent, or base which are similar to those used in the above preparation 1.
  • the arylurea moiety of the ureido-substituted cyclic amine derivative of the present invention is generally derived from the corresponding arylamine with the known method using sodium cyanate, sodium thiocyanate, trimethylsilyl isocyanate, alkyl isocaynate, alkyl isothiocyanate, and the like or N.
  • N- dialkylcarbonyl halide such as N,N-dimethylcarbamoyl chloride, 1- pyrrolidinecarbonyl chloride, and the like.
  • the arylurea derivatives can be also synthesized by conversion of arylamine into aryl isocyanate or aryl isothiocyanate followed by reaction with the corresponding amine . These methods to synthesize urea derivatives are well known in synthetic organic chemistry.
  • a compound of the present invention can be prepared by the further conversion of the substituent(s) of the compound, prepared with the above preparations 1-4, using known reactions which are usually used in synthetic organic chemistry, such as alkylation, acylation, reduction, and so on.
  • Each of the above preparations may use solvents for the reaction such as halogenated hydrocarbons such as dichloromethane, chloroform, and the like, aromatic hydrocarbons such as benzene, toluene, and the like, ethers such as diethyl ether, tetrahydrofuran, and the like, esters such as ethyl acetate, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, and the like, alcohols such as methanol, ethanol, isopropyl alcohol , and the like.
  • solvents for the reaction such as halogenated hydrocarbons such as dichloromethane, chloroform, and the like, aromatic hydrocarbons such as benzene, toluene, and the like, ethers such as diethyl ether, tetrahydrofuran, and the like, esters such as ethyl acetate, aprotic polar solvents such
  • the reaction temperature in either of the preparations should be in the range of -78 ° C - +150 ° C, preferably 0 " C - 100 °C.
  • the usual isolation and purification operations such as concentration, filtration, extraction, solid-phase extraction, recrystallization, chromatography, and the like may be used, to isolate the desired compound represented by the above formula (I). These can be converted into pharmaceutically acceptable acid addition salt or C ! -C 6 alkyl addition salt by the usual method.
  • the chemokine receptor antagonist which contain the cyclic amine compound possessing ureido group, its pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable C ! -C 6 alkyl addition salt of this invention, which inhibits chemokines such as MlP-l ⁇ and/or MCP-1 and the like from action on target cells, are useful as therapeutic agents and/or preventive preparation for diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis , congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, sepsis, and the like, in which tissue infiltration of blood monocytes , lymphocytes , and the like plays a major role in the
  • Optically active ( R) -3-amino-l- ( -chlorobenzyl)pyrrolidine dihydrochloride and ( 5) -3-amino-l- ( 4 -chlorobenzyl) yrrolidine dihydrochloride were also prepared pursuant to the above method using the corresponding reactant respectively.
  • the products showed the same ⁇ H NMR with that of the racemate.
  • the aqueous layer was adjusted to pH 10 with a 5 N aqueous NaOH solution and the mixture was extractes with ethyl acetate ( 2 times ) .
  • the combined organic layers were washed with brine , dried over Na 2 S0 , filtered, and concentrated.
  • Example 1 Preparation of (J?) -3- [ ⁇ At- ( 2-Amino-5- trifluoromethylbenzoyl)glycyl ⁇ amino] -1- ( -methyl-3- ureidobenzyl)pyrrolidine.
  • Example 2 Preparation of ⁇ R) -3- [ ⁇ J-/-(2-Amino-5- trifluoromethylbenzoyl) glycyl ⁇ amino] - 1- ( 4-hydroxy-3- ureidobenzyl)pyrrolidine .
  • Example 3 Preparation of ( ⁇ ) -3- [ ⁇ At- ( 2-Amino-5 - trifluoromethylbenzoyl) glycyl ⁇ amino] - 1- ( -methoxy-3- ureidobenzyl)pyrrolidine .
  • Example 5 Preparation of (.R) -3-[ ⁇ #-( 2-Amino-5- trifluoromethylbenzoyl) glycyl ⁇ amino] - 1- ⁇ -methyl-3- ( 3- ethylureido)benzyl ⁇ pyrrolidine.
  • Example 6 Preparation of ⁇ ?)-3- [ ⁇ JV-(2-Amino-5- trifluoromethylbenzoyl) glycyl ⁇ amino] -l- ⁇ 4-methyl-3- (3- isopropylureido )benzyl ⁇ pyrrolidine.
  • Example 7 Preparation of (.R)-3-[ ⁇ tf-(2-Araino-5- trifluoromethylbenzoyl) glycyl ⁇ amino ] -1- ⁇ 4-hydroxy-3- ( 3- isopropylureido)benzylIpyrrolidine.
  • Example 8 Preparation of (J?) -3- [ ⁇ At- ( 2-Amino- 5- trifluoromethylbenzoyl)glycyl ⁇ amino]-l- ⁇ 3- ⁇ 3-ethylureido) -4- hydroxybenzyl ⁇ pyrrolidine .
  • Example 10 Preparation of (i?) -3 - [ ⁇ At- ( 2-Amino- 5 - trifluoromethylbenzoyl) glycyl ⁇ amino] -l- ⁇ 3- ( 3-ethyl-thioureido) -4- methylbenzyl ⁇ pyrrolidine .
  • Example 11 Preparation of ( R) -3 - [ ⁇ iV-(2-Amino-5- trifluoromethylbenzoyl) glycyl ⁇ amino ] -1- ⁇ 3- ⁇ 3-isopropyl-thioureido) -4- methylbenzyl ⁇ pyrrolidine .
  • Example 12 Preparation of (/?) -3- [ ⁇ N- (2-Amino-5- trifluoromethylbenzoyl) glycyl ⁇ amino] -l- ⁇ 4-chloro-3- (3-phenyl- thioureido)benzyl ⁇ pyrrolidine.
  • Example 13 Preparation of (J7)-3- [ ⁇ N- ⁇ 2-Amino-5- trifluoromethylbenzoyl) glycyl ⁇ amino] -1- ⁇ 4-methyl-3- ( 3-phenyl- thioureido)benzyl ⁇ pyrrolidine.
  • Example 14 Preparation of (.R)-3-[ ⁇ 2-Amino-5- trifluoromethylbenzoyl)glycyl ⁇ amino] -l- ⁇ 3- ( 1 , 1-dimethylureido) -4- hydroxylbenzyl ⁇ pyrrolidine .
  • Example 16 Preparation of ( R) -3- [ ⁇ At- (2-Aamino-5- trifluoromethylbenzoyl) glycyl ⁇ amino] -1- ⁇ 4-methyl-3- ( 1- pyrrolidinecarboxaraido)benzyl ⁇ pyrrolidine .
  • Example 17 Preparation of (J?)-3- [ ⁇ At- (2-Amino-5- trifluoromethylbenzoyl) glycyl ⁇ amino]-l- ⁇ 3-(l,l-diethylureido) -4- hydroxybenzyl ⁇ pyrrolidine .
  • Example 18 Preparation of ( R) -3- [ ⁇ At- (2-Amino-5- trifluoromethylbenzoyl) glycyl ⁇ amino] -l- ⁇ 4-hydroxy-3- ( 1- pyrrolidinecarboxamido)benzyl ⁇ pyrrolidine.
  • Example 19 Preparation of ( ⁇ ) -3-[ ⁇ w-(2-Amino-5- trifluoromethylbenzoyl)glycyl ⁇ amino] -1- ⁇ 4-methyl-3- ( 4- morpholinecarboxamido)benzyl ⁇ pyrrolidine .
  • Example 20 Preparation of (J?)-3- [ ⁇ w-(2-Amino-5- trifluoromethylbenzoyl) glycyl ⁇ amino ]-l- ⁇ 3-(l,l-dimethylureido ) -4- methylbenzyl ⁇ pyrrolidine.
  • Example 21 Preparation of ( R) -l-(4-Chlorobenzyl)-3-[ ⁇ JV-(5- trifluoromethyl-2-ureidobenzoyl) glycyl ⁇ amino]pyrrolidine.
  • Example 22 Preparation of (J?) -1- ( 4 -Chlorobenzyl) -3- [ ⁇ At- (2- (3- isopropylureido) -5-trifluoromethylbenzoyl ) glycyl ⁇ amino ]pyrrolidine .
  • Example 24 Preparation of (J?)-l-(4-Ethylbenzyl)-3-[ ⁇ At-(2-(3- isopropylureido) -5-trifluoromethylbenzoyl)glycyl ⁇ amino]pyrrolidine.
  • ⁇ R) -l- ( 4-Ethylbenzyl ) -3- [ ⁇ At- ( 2- ( 3-isopropylureido) - 5- trifluoromethylbenzoyl) glycyl ⁇ amino]pyrrolidine was synthesized pursuant to methods of Example 22 using the corresponding starting material: ESI/MS m/e 534.1 (M + +H, C 27 H 34 F 3 N 5 0 3 ) .
  • Example 25 Preparation of (J?)-l-(4-chlorobenzyl)-3-[ ⁇ At-(2-(3- ethylureido) -5-trifluoromethylbenzoyl) glycyl ⁇ amino]pyrrolidine .
  • Example 27 Preparation of (i?)-l-(4-Ethylbenzyl)-3- [ ⁇ At- ( 2 - ( 3- ethylureido) -5-trifluoromethylbenzoyl) glycyl ⁇ amino ]pyrrolidine .
  • Example 28 Measurement of Inhibition of MlP-l ⁇ Binding to THP-1 Cells by Test Compounds.
  • Human monocytic leukemia cell line THP-1 was suspended in assay buffer (RPMI-1640 (Gibco-BRL Co.) containing 0.1% BSA and 25 mM HEPES adjusted to pH 7.4) to give a cell suspension of a concentration of 1 x 10 7 cells/mL.
  • the test compound was diluted in the assay buffer and used as the test compound solution.
  • Iodinated human MlP-l ⁇ (DuPont NEN Co. ) was diluted in assay buffer to 250 nCi/mL and used as the labeled ligand solution. In a 96 well filter plate (Millipore Co.).
  • test compound solution 25 ⁇ L of test compound solution, 25 ⁇ L of labeled ligand solution and 50 ⁇ L of cell suspension were aliquoted into each well in this order, stirred (total reaction volume 100 ⁇ L), and incubated for one hour at 18 °C.
  • the reaction solution was filtered, and the filter was washed twice with 200 ⁇ L of cold PBS (200 ⁇ L of cold PBS was added and then filtered) .
  • the filter was air-dried and 25 ⁇ L of liquid scintillator was added into each well. The- radioactivity retained by the cells on the filter were measured using TopCount (Packard Instrument Co.).
  • test compounds to inhibit binding of human MlP-l ⁇ to THP-1 cells
  • non-specific binding determined by adding 100 ng of unlabeled human MlP-l ⁇ (Peprotech Co.) in place of the test compound was subtracted, while the counts with no test compound added was taken as 100%.
  • Inhibition (%) ⁇ 1 - (A - B)/(C - B) ⁇ x 100 (A, counts with test compound added; B, counts with 100 ng of unlabeled human MlP-l ⁇ added; C, counts with [ 125 I ] -labeled human MlP-l ⁇ added).
  • Example 29 Measurement of Inhibition of MCP-1 Binding to THP-1 Cells.
  • Human monocytic leukemia cell line THP-1 was suspended in assay buffer
  • test compound solution 25 ⁇ L of test compound solution, 25 ⁇ L of labeled ligand solution and 50 ⁇ L of cell suspension were aliquoted into each well in this order, stirred (total reaction volume 100 ⁇ L), and incubated for one hour at 18 °C.
  • the reaction solution was filtered, and the filter was washed twice with 150 ⁇ L of cold PBS (150 ⁇ L of cold PBS was added and then filtered) .
  • the filter was air-dried and 25 ⁇ L of liquid scintillator was added into each well. The radioactivity retained by the cells on the filter were measured using TopCount (Packard Instrument Co.).
  • test compound to inhibit binding of human MCP-1 to THP-1 cells.
  • non-specific binding determined by adding 100 ng of unlabeled human MCP-1 in place of the test compound was subtracted, while the counts with no test compound added was taken as 100%.
  • Inhibition (%) ⁇ 1 - (A - B)/(C - B) ⁇ x 100
  • Example 30 Measurement of Inhibition of Binding of [ 125 I] -Labeled Human MCP-1 to Cells Expressing the MCP-1 Receptor.
  • 1. Derivation of cells expressing the MCP-1 receptor cDNA fragment containing the MCP-1 receptor reported by S. Yamagami et al.. Biochemical Biophysical Research Communications 1994, 202, 1156-1162) was cloned into the expression plasmid pCEP4 (Invitrogen Co. ) at the Notl site, and the plasmid obtained was transfected into the human kidney epithelial cell line 293-EBNA using the Lipofectamine reagent (Gibco-BRL Co.). The cells were cultured in the presence of the selective agent (Hygromycin), and a stably expressing transfectant line was obtained. The expression of the receptor was confirmed by binding of [ 125 I] -labeled human MCP-1.
  • the MCP-1 receptor expressing cells on tissue culture dishes were scraped using a cell ⁇ craper and suspended in assay buffer (D-MEM(Gibco-BRL Co.) containing 0.1% BSA and 25 mM HEPES adjusted to pH 7.4 ) to give a cell suspension of a concentration of 6 x 10 6 cells/mL.
  • assay buffer D-MEM(Gibco-BRL Co.) containing 0.1% BSA and 25 mM HEPES adjusted to pH 7.4
  • the test compound was diluted in the assay buffer. The remainder of the procedure was as described in Example 29.
  • the filter was removed, and the cells which had migrated to the underside of the filter was fixed, stained using Diff Quick (Kokusai Shiyaku Co. ) and then quantitated using a plate reader (Molecular Device Co. ) at a wavelength of 550 nm to determine the index of cell migration as a mean of 3 wells.
  • test compounds were placed in the upper and lower chambers along with THP-1 and MCP-1, respectively, and the inhibition of cell migration (inhibition IC 50 ( ⁇ M) ) was determined.
  • the 50% inhibition concentration (IC 50 ) for the following compounds were IC 50 ⁇ 0.1 ⁇ M.

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Abstract

Cette invention concerne un composé représenté par la formule générale (I), un sel d'addition acide pharmaceutiquement acceptable de celui-ci, ou un sel d'addition C1-C6 alkyle de celui-ci, et ses applications médicales. Comme ces composés inhibent l'action des chimiokines telles que MIP-1α et/ou MCP-1 sur des cellules cibles, ils peuvent convenir comme médicament thérapeutique et/ou comme médicament prophylactique pour des maladies telles que l'artériosclérose, l'arthrite rhumatoïde ou des maladies de ce type dans lesquelles les monocytes et les lymphocytes s'infiltrent dans les tissus.
PCT/US2000/006714 1999-05-13 2000-05-12 Derives d'amines cycliques ureido-substituees et leur utilisation en tant que medicament WO2000069815A1 (fr)

Priority Applications (1)

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AU47967/00A AU4796700A (en) 1999-05-13 2000-05-12 Ureido-substituted cyclic amine derivatives and their use as drug

Applications Claiming Priority (2)

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US31097599A 1999-05-13 1999-05-13
US09/310,975 1999-05-13

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WO2000069815A1 true WO2000069815A1 (fr) 2000-11-23

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AU (1) AU4796700A (fr)
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EP1179341A1 (fr) * 1999-05-18 2002-02-13 Teijin Limited Moyens de traitement et de prevention contre les maladies associees a des chimiokines
WO2002050019A2 (fr) * 2000-12-20 2002-06-27 Bristol-Myers Squibb Pharma Co. Diamines servant de modulateurs de l'activité récepteur des chimiokines
WO2002060859A2 (fr) * 2000-12-20 2002-08-08 Bristol-Myers Squibb Company Derives cycliques utilises comme modulateurs de l'activite des recepteurs de chimiokines
EP1483241A2 (fr) * 2002-03-08 2004-12-08 Bristol-Myers Squibb Company Derives cycliques servant de modulateurs de l'activite du recepteur de la chimiokine
WO2005018642A1 (fr) * 2003-08-22 2005-03-03 Schering Aktiengesellschaft Derives de piperazine inhibant les chimiokines et leur utilisation en traitement de myocardites
EP1617803A2 (fr) * 2003-05-01 2006-01-25 Bristol-Myers Squibb Company Utilisation de malonamides et de leurs derives en tant que modulateurs de l'activite des recepteurs aux chimiokines
WO2006059164A2 (fr) 2004-12-02 2006-06-08 Prosidion Limited Amides d'acide pyrrolopyridine-2-carboxylique
WO2006129679A1 (fr) 2005-05-31 2006-12-07 Ono Pharmaceutical Co., Ltd. Compose de spiropiperidine et son utilisation medicinale
US7183270B2 (en) 2003-02-12 2007-02-27 Bristol-Myers Squibb Company Cyclic derivatives as modulators of chemokine receptor activity
WO2007049771A1 (fr) 2005-10-28 2007-05-03 Ono Pharmaceutical Co., Ltd. Compose contenant un groupe basique et son utilisation
WO2007058322A1 (fr) 2005-11-18 2007-05-24 Ono Pharmaceutical Co., Ltd. Composé contenant un groupe basique et son utilisation
US7230022B2 (en) 2004-02-19 2007-06-12 Bristol-Myers Squibb Company Substituted fused bicyclic amines as modulators of chemokine receptor activity
WO2007105637A1 (fr) 2006-03-10 2007-09-20 Ono Pharmaceutical Co., Ltd. Derive heterocyclique azote et agent pharmaceutique comprenant le derive en tant que principe actif
US7288563B2 (en) 2004-02-19 2007-10-30 Bristol-Myers Squibb Company Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity
US7291615B2 (en) 2003-05-01 2007-11-06 Bristol-Myers Squibb Company Cyclic derivatives as modulators of chemokine receptor activity
WO2007132846A1 (fr) 2006-05-16 2007-11-22 Ono Pharmaceutical Co., Ltd. Composé ayant un groupe acide qui peut être protégé et utilisation dudit composé
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WO2008016006A1 (fr) 2006-07-31 2008-02-07 Ono Pharmaceutical Co., Ltd. Composé auquel un groupe cyclique est lié par une liaison spiro et son utilisation
US7338975B2 (en) 2003-02-12 2008-03-04 Bristol-Myers Squibb Co. Lactams as modulators of chemokine receptor activity
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US7405210B2 (en) 2003-05-21 2008-07-29 Osi Pharmaceuticals, Inc. Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase
US7435831B2 (en) 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
US7435830B2 (en) 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
US7449576B1 (en) 2002-06-12 2008-11-11 Chemocentryx, Inc. Substituted piperazines
US7479496B2 (en) 2004-02-19 2009-01-20 Bristol-Myers Squibb Company Substituted spiro azabicyclics as modulators of chemokine receptor activity
AU2003293129B2 (en) * 2002-11-27 2009-03-12 Incyte Holdings Corporation 3-aminopyrrolidine derivatives as modulators of chemokine receptors
US7576117B1 (en) 1999-08-04 2009-08-18 Teijin Limited Cyclic amine CCR3 antagonist
US7576089B2 (en) 2003-12-18 2009-08-18 Incyte Corporation 3-cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors
US7589199B2 (en) 2002-06-12 2009-09-15 Chemocentryx, Inc. Substituted piperazines
US7842693B2 (en) 2002-06-12 2010-11-30 Chemocentryx, Inc. Substituted piperazines
US7884112B2 (en) 2004-03-08 2011-02-08 Stuart Edward Bradley Pyrrolopyridine-2-carboxylic acid hydrazides
EP2364982A1 (fr) 2003-04-18 2011-09-14 ONO Pharmaceutical Co., Ltd. Dérivés de spiropipéridine comme antgonistes du recepteur chémokine et leur usage médical
EP2385040A1 (fr) 2003-03-14 2011-11-09 ONO Pharmaceutical Co., Ltd. Dérivés hétérocycliques renfermant de l'azote et médicaments contenant ces dérivés comme principe actif
JP2012524111A (ja) * 2009-04-17 2012-10-11 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Ｃｃｒ２の４−アゼチジニル−１−フェニル−シクロヘキサンアンタゴニスト
EP2546234A1 (fr) 2004-09-13 2013-01-16 Ono Pharmaceutical Co., Ltd. Dérivés hétérocycliques azotés et médicament le contenant comme ingrédient actif
US8481035B2 (en) 2004-04-27 2013-07-09 Northwestern University Methods for treating chronic pelvic pain syndrome with antibodies that binds MCP-1 or MIP-1A
US10117931B2 (en) 2009-04-28 2018-11-06 Kameran Lashkari Methods for treatment of age-related macular degeneration

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US7390830B1 (en) 1999-05-18 2008-06-24 Teijin Limited Remedies or prophylactics for diseases in association with chemokines
US7576117B1 (en) 1999-08-04 2009-08-18 Teijin Limited Cyclic amine CCR3 antagonist
US6706712B2 (en) 2000-12-20 2004-03-16 Bristol-Myers Squibb Pharma Company Cyclic derivatives as modulators of chemokine receptor activity
WO2002060859A3 (fr) * 2000-12-20 2003-03-27 Bristol Myers Squibb Co Derives cycliques utilises comme modulateurs de l'activite des recepteurs de chimiokines
WO2002050019A3 (fr) * 2000-12-20 2003-03-13 Bristol Myers Squibb Pharma Co Diamines servant de modulateurs de l'activité récepteur des chimiokines
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US6974836B2 (en) 2000-12-20 2005-12-13 Bristol-Myers Squibb Pharma Company Diamines as modulators of chemokine receptor activity
WO2002060859A2 (fr) * 2000-12-20 2002-08-08 Bristol-Myers Squibb Company Derives cycliques utilises comme modulateurs de l'activite des recepteurs de chimiokines
US7045521B2 (en) 2000-12-20 2006-05-16 Bristol-Myers Squibb Pharma Company Cyclic derivatives as modulators of chemokine receptor activity
WO2002050019A2 (fr) * 2000-12-20 2002-06-27 Bristol-Myers Squibb Pharma Co. Diamines servant de modulateurs de l'activité récepteur des chimiokines
EP1483241A4 (fr) * 2002-03-08 2006-12-13 Bristol Myers Squibb Co Derives cycliques servant de modulateurs de l'activite du recepteur de la chimiokine
US7776884B2 (en) 2002-03-08 2010-08-17 Bristol-Myers Squibb Company Cyclic derivatives as modulators of chemokine receptors activity
EP1483241A2 (fr) * 2002-03-08 2004-12-08 Bristol-Myers Squibb Company Derives cycliques servant de modulateurs de l'activite du recepteur de la chimiokine
US8324216B2 (en) 2002-06-12 2012-12-04 Chemocentryx, Inc. Substituted piperazines
US7449576B1 (en) 2002-06-12 2008-11-11 Chemocentryx, Inc. Substituted piperazines
US7589199B2 (en) 2002-06-12 2009-09-15 Chemocentryx, Inc. Substituted piperazines
US7842693B2 (en) 2002-06-12 2010-11-30 Chemocentryx, Inc. Substituted piperazines
US7985730B2 (en) 2002-11-27 2011-07-26 Incyte Corporation 3-aminopyrrolidine derivatives as modulators of chemokine receptors
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US8362003B2 (en) 2002-11-27 2013-01-29 Incyte Corporation 3-aminopyrrolidine derivatives as modulators of chemokine receptors
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AU2003293129B2 (en) * 2002-11-27 2009-03-12 Incyte Holdings Corporation 3-aminopyrrolidine derivatives as modulators of chemokine receptors
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US7338975B2 (en) 2003-02-12 2008-03-04 Bristol-Myers Squibb Co. Lactams as modulators of chemokine receptor activity
US7338947B2 (en) 2003-02-12 2008-03-04 Bristol-Myers Squibb Co. Cyclic derivatives as modulators of chemokine receptor activity
EP2385040A1 (fr) 2003-03-14 2011-11-09 ONO Pharmaceutical Co., Ltd. Dérivés hétérocycliques renfermant de l'azote et médicaments contenant ces dérivés comme principe actif
EP2364982A1 (fr) 2003-04-18 2011-09-14 ONO Pharmaceutical Co., Ltd. Dérivés de spiropipéridine comme antgonistes du recepteur chémokine et leur usage médical
EP1617803A4 (fr) * 2003-05-01 2007-01-24 Bristol Myers Squibb Co Utilisation de malonamides et de leurs derives en tant que modulateurs de l'activite des recepteurs aux chimiokines
EP1617803A2 (fr) * 2003-05-01 2006-01-25 Bristol-Myers Squibb Company Utilisation de malonamides et de leurs derives en tant que modulateurs de l'activite des recepteurs aux chimiokines
US7468440B2 (en) 2003-05-01 2008-12-23 Bristol-Myers Squibb Company Malonamides and malonamide derivatives as modulators of chemokine receptor activity
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US7696205B2 (en) 2003-05-01 2010-04-13 Bristol-Myers Squibb Company Cyclic derivatives as modulators of chemokine receptor activity
US7291615B2 (en) 2003-05-01 2007-11-06 Bristol-Myers Squibb Company Cyclic derivatives as modulators of chemokine receptor activity
US7405210B2 (en) 2003-05-21 2008-07-29 Osi Pharmaceuticals, Inc. Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase
US8158622B2 (en) 2003-05-21 2012-04-17 Prosidion Limited Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase
US7378409B2 (en) 2003-08-21 2008-05-27 Bristol-Myers Squibb Company Substituted cycloalkylamine derivatives as modulators of chemokine receptor activity
WO2005018642A1 (fr) * 2003-08-22 2005-03-03 Schering Aktiengesellschaft Derives de piperazine inhibant les chimiokines et leur utilisation en traitement de myocardites
JP2007503397A (ja) * 2003-08-22 2007-02-22 シエーリング アクチエンゲゼルシャフト ケモカインを阻害するピペラジン誘導体、及び、この誘導体の心筋炎治療のための使用
US7576089B2 (en) 2003-12-18 2009-08-18 Incyte Corporation 3-cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors
US7479496B2 (en) 2004-02-19 2009-01-20 Bristol-Myers Squibb Company Substituted spiro azabicyclics as modulators of chemokine receptor activity
US7381738B2 (en) 2004-02-19 2008-06-03 Bristol-Myers Squibb Company Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity
US7230022B2 (en) 2004-02-19 2007-06-12 Bristol-Myers Squibb Company Substituted fused bicyclic amines as modulators of chemokine receptor activity
US7288563B2 (en) 2004-02-19 2007-10-30 Bristol-Myers Squibb Company Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity
US7435831B2 (en) 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
US7435830B2 (en) 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
US7884112B2 (en) 2004-03-08 2011-02-08 Stuart Edward Bradley Pyrrolopyridine-2-carboxylic acid hydrazides
US8969340B2 (en) 2004-04-27 2015-03-03 Northwestern University Methods for treating chronic pelvic pain syndrome
US8481035B2 (en) 2004-04-27 2013-07-09 Northwestern University Methods for treating chronic pelvic pain syndrome with antibodies that binds MCP-1 or MIP-1A
US7307086B2 (en) 2004-05-11 2007-12-11 Incyte Corporation 3-(4-heteroarylcyclohexylamino)cyclopentanecarboxamides as modulators of chemokine receptors
EP2546234A1 (fr) 2004-09-13 2013-01-16 Ono Pharmaceutical Co., Ltd. Dérivés hétérocycliques azotés et médicament le contenant comme ingrédient actif
WO2006059164A2 (fr) 2004-12-02 2006-06-08 Prosidion Limited Amides d'acide pyrrolopyridine-2-carboxylique
WO2006129679A1 (fr) 2005-05-31 2006-12-07 Ono Pharmaceutical Co., Ltd. Compose de spiropiperidine et son utilisation medicinale
WO2007049771A1 (fr) 2005-10-28 2007-05-03 Ono Pharmaceutical Co., Ltd. Compose contenant un groupe basique et son utilisation
WO2007058322A1 (fr) 2005-11-18 2007-05-24 Ono Pharmaceutical Co., Ltd. Composé contenant un groupe basique et son utilisation
WO2007105637A1 (fr) 2006-03-10 2007-09-20 Ono Pharmaceutical Co., Ltd. Derive heterocyclique azote et agent pharmaceutique comprenant le derive en tant que principe actif
WO2007132846A1 (fr) 2006-05-16 2007-11-22 Ono Pharmaceutical Co., Ltd. Composé ayant un groupe acide qui peut être protégé et utilisation dudit composé
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