EP1052992A1 - Amines cycliques utilisees en tant que modulateurs de l'activite du recepteur de chemokine - Google Patents

Amines cycliques utilisees en tant que modulateurs de l'activite du recepteur de chemokine

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Publication number
EP1052992A1
EP1052992A1 EP99906697A EP99906697A EP1052992A1 EP 1052992 A1 EP1052992 A1 EP 1052992A1 EP 99906697 A EP99906697 A EP 99906697A EP 99906697 A EP99906697 A EP 99906697A EP 1052992 A1 EP1052992 A1 EP 1052992A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
substituted
phenyl
hydroxy
substituents
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99906697A
Other languages
German (de)
English (en)
Inventor
Charles G. Caldwell
Paul E. Finke
Malcolm Maccoss
Sander G. Mills
Bryan Oates
Dooseop Kim
Shankaran Kothandaraman
Liping Wang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9810890.5A external-priority patent/GB9810890D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1052992A1 publication Critical patent/EP1052992A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D405/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cvtokine. 3, 165-183 (1991) and Murphy, Rev. Immun.. 12, 593-633 (1994)).
  • ⁇ -chemokines such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils, whereas ⁇ -chemokines, such as RANTES, MlP-l ⁇ , MIP- l ⁇ , monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al., Nature. 381. 661-666 (1996)).
  • IL-8 interleukin-8
  • NAP-2 neutrophil-activating protein-2
  • MGSA melanoma growth stimulatory activity protein
  • chemokines bind specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane- domain proteins (reviewed in Horuk, Trends Pharm. Sci.. 15. 159-165 (1994)) which are termed "chemokine receptors.” On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration.
  • CCR-1 or "CKR-1" or "CC-CKR-1”
  • MlP-l ⁇ , MlP-l ⁇ , MCP-3, RANTES a human chemokine receptor that bind or respond to ⁇ -chemokines with the following characteristic pattern: CCR-1 (or "CKR-1" or "CC-CKR-1") [MlP-l ⁇ , MlP-l ⁇ , MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem.. 270.
  • the ⁇ -chemokines include eotaxin, MIP ("macrophage inflammatory protein”), MCP ("monocyte chemoattractant protein”) and RANTES ("regulation-upon-activation, normal T expressed and secreted").
  • Chemokine receptors such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR-4, have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases.
  • HIV-1 human immunodeficiency virus
  • AIDS acute immune deficiency syndrome
  • Certain compounds have been demonstrated to inhibit the replication of HIV, including soluble CD4 protein and synthetic derivatives (Smith, et al., Science. 238. 1704-1707 (1987)), dextran sulfate, the dyes Direct Yellow 50, Evans Blue, and certain azo dyes (U.S. Patent No. 5,468,469). Some of these antiviral agents have been shown to act by blocking the binding of gpl20, the coat protein of HIV, to its target, the CD4 gyycoprotein of the cell.
  • the principal cofactor for entry mediated by the envelope glycoproteins of primary macrophage-trophic strains of HIV-1 is CCR5, a receptor for the ⁇ - chemokines RANTES, MlP-l ⁇ and MlP-l ⁇ (Deng, et al., Nature. 381. 661-666 (1996)). HIV attaches to the CD4 molecule on cells through a region of its envelope protein, gpl20. It is believed that the CD-4 binding site on the gpl20 of HIV interacts with the CD4 molecule on the cell surface, and undergoes conformational changes which allow it to bind to another cell-surface receptor, such as CCR5 and/or CXCR-4.
  • Macrophage-tropic H-TV and SIV envelope proteins have been shown to induce a signal through CCR-5 on CD4+ cells resulting in chemotaxis of T cells which may enhance the replication of the virus (Weissman, et al., Nature. 389. 981-985 (1997)). It has been shown that ⁇ - chemokine ligands prevent HIV-1 from fusing with the cell (Dragic, et al., Nature. 381. 667-673 (1996)).
  • chemokine receptors may be used by some strains of HIV-l or may be favored by non-sexual routes of transmission. Although most HIV-l isolates studied to date utilize CCR-5 or fusin, some can use both as well as the related CCR-2B and CCR-3 as co-receptors (Nature Medicine. 2(11), 1240-1243 (1996)). Nevertheless, drugs targeting chemokine receptors may not be unduly compromised by the genetic diversity of HIV-l (Zhang, et al., Nature. 383. 768 (1996)). The ⁇ -chemokine macrophage-derived chemokine (MDC) has been shown to inhibit HIV-l infection (Pal, et al., Science. 278 (5338), 695-698 (1997).
  • MDC ⁇ -chemokine macrophage-derived chemokine
  • chemokines RANTES, MlP-l ⁇ , MlP-l ⁇ , vMIP-I, vMIP-II, SDF-1 have also been shown to suppress HIV.
  • a derivative of RANTES, (AOP)-RANTES is a subnanomolar antagonist of CCR-5 function in monocytes (Simmons, et al., Science. 276. 276-279 (1997)).
  • Monoclonal antibodies to CCR-5 have been reported to block infection of cells by HIV in vitro. Accordingly, an agent which could block chemokine receptors in humans who possess normal chemokine receptors should prevent infection in healthy individuals and slow or halt viral progression in infected patients (see Science. 275. 1261-1264 (1997)).
  • peptides eotaxin, RANTES, MlP-l ⁇ , MlP-l ⁇ , MCP-1, and MCP-3 are known to bind to chemokine receptors.
  • the inhibitors of HIV-l replication present in supernatants of CD8+ T cells have been characterized as the ⁇ -chemokines RANTES, MlP-l ⁇ and MlP-l ⁇ .
  • PCT Patent Publication WO 97/10211 and EPO Patent Publication EP 0,673,928 disclose certain piperidines as tachykinin antagonists.
  • PCT Patent Publications WO 97/24325 and WO 97/44329, and Japan Patent Publication JP 09,249,566 disclose certain compounds as chemokine antagonists.
  • the present invention is directed to compounds which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory
  • the invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved.
  • the present invention is further concerned with compounds which inhibit the entry of human immunodeficiency virus (HIV) into target cells and are of value in the prevention of infection by HIV, the treatment of infection by HIV and the prevention and/or treatment of the resulting acquired immune deficiency syndrome (AIDS).
  • HIV human immunodeficiency virus
  • the present invention also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the prevention and treatment of AIDS and viral infection by HIV.
  • the present invention is directed to compounds of formula I:
  • Rl is selected from a group consisting of: linear or branched Ci_8 alkyl, linear or branched C2-8 alkenyl, wherein the Ci-8 alkyl or C2-8 alkenyl is optionally mono, di, tri or tetra substituted, where the substituents are independently selected from: (a) hydroxy, (b) oxo,
  • halogen which is selected from F, Cl, Br, and I,
  • heteroaryl wherein heteroaryl is selected from the group consisting of: (l 1 ) benzimidazolyl,
  • Ci-6 alkyl J (4) substituted Cl-6 alkyl, where the substituents are independently selected from:
  • R 4 and R 5 are independently selected from hydrogen, Cl-6 alkyl, and Cl-6 alkyl substituted with C5-8 cycloalkyl, (g) -N(R 4 )-CO-O-(R 5 ), and (h) -N(R 4 ')-CO-N(R )(R 5 ), wherein R 4 ' is selected from the definitions of R 4 ,
  • R3 is selected from the group consisting of:
  • Ar is selected from the group consisting of:
  • heteroaryl is selected from the group consisting of:
  • heteroaryl group of items (l 1 ) to (37') is unsubstituted, or mono, di or tri-substituted, where the substituents are selected from:
  • R7 is selected from the group consisting of:
  • R 6 and R7 may be joined together to form a 5-, 6-, or 7- membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono or di-substituted, the substituents independently selected from:
  • R8 is selected from the group consisting of:
  • n is an integer selected from 0, 1 and 2 and pharmaceutically acceptable salts thereof.
  • Preferred compounds of the present invention include those of formula la:
  • Rl is selected from a group consisting of: C3, C4, C5. C ⁇ , C7, or C8 linear or branched alkyl, which is unsubstituted or mono, di or tri-substituted, where the substituents are independently selected from:
  • R7 is Cl-6 alkyl, benzyl or phenyl which is unsubsituted or substituted with halo, CF3, Cl-6alkyl, or Ci_3alkoxy,
  • heteroaryl is selected from the group consisting of:
  • R3 is selected from the group consisting of:
  • Ar is selected from the group consisting of:
  • Ci-io alkyl C2-10 alkenyl or C2-10 alkynyl, where the substituents are independently selected from
  • n is an integer selected from 0, 1 and 2, with the proviso that the sum of m + n is 2; and pharmaceutically acceptable salts thereof.
  • More preferred compounds of the present invention include those of formula Ib:
  • Rl, R2 and R ⁇ are as defined herein; and pharmaceutically acceptable salts thereof.
  • Rl is selected from the group consisting of:
  • C3, C4, C5. C ⁇ , C7, or Cs linear or branched alkyl, which is unsubstituted or mono, di or tri-substituted, where the substituents are independently selected from: (a) hydroxy, (b) Cl or F,
  • heteroaryl is selected from the group consisting of:
  • Rl bears at least one substituent which is selected from:
  • Rl is selected from the group consisting of:
  • R 6 is Cl-3 alkyl, unsubstituted or substituted with cyclohexyl, and R is Cl-6 alkyl, benzyl or phenyl which is unsubsituted or substituted with halo, CF3, Ci-3alkyl, or Ci-3alkoxy,
  • Rl is selected from the group consisting of:
  • Rl is C4 linear alkyl, which is substituted, where the substituents are independently selected from: (a) phenyl,
  • Rl is:
  • B is selected from the group consisting of: (a) phenyl, and (b) di or tri-substituted phenyl, wherein the substituents on phenyl are independently selected from: chloro, methyl, phenyl, Ci-3alkoxy, and CF3;
  • R 6 is Ci-3 alkyl, unsubstituted or substituted with cyclohexyl
  • RlO is selected from the group consisting of:
  • RH and R ⁇ 2 are independently selected from the group consisting of:
  • Rl is selected from the group consisting of:
  • Rl is selected from the group consisting of:
  • R2 is selected from the group consisting of:
  • R2 is selected from the group consisting of:
  • R2 is hydrogen
  • (m) -CH2-heteroaryl, with the heteroaryl is selected from the group consisting of: (10 imidazolyl, (20 oxazolyl,
  • Ar is selected from: phenyl, mono substituted phenyl or di-substituted phenyl, wherein the substituents are selected from the group consisting of:
  • Ar is selected from: phenyl, or mono substituted phenyl wherein the substituent is selected from : -NO2. -CONH2, and -CO2H.
  • Ar is selected from: phenyl, or para-NO2 phenyl.
  • R 3 is:
  • R3 is:
  • R3 is selected from: (1) -N(R 8 )-CO-O-(CH2)-phenyl,
  • R 8 is selected from the group consisting of:
  • Ci-io alkyl C2-10 alkenyl or C2-10 alkynyl, where the substituents are independently selected from:
  • R 8 is selected from the group consisting of: (1) C2-10 alkenyl,
  • Ci-io alkyl C2-IO alkenyl or C2-10 alkynyl, where the substituents are independently selected from: (a) C3-4 cycloalkyl,
  • R 8 is selected from the group consisting of:
  • R 8 is selected from the group consisting of:
  • n is an integer selected from 0, 1 and 2 with the proviso that the sum of m + n is 2.
  • n is 1.
  • halo as used herein are intended to include chloro, fluoro, bromo and iodo.
  • Cl-6, as in Cl-6alkyl is defined to identify the group as having 1, 2, 3, 4, 5, or 6 carbons, such that Cl-6alkyl specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, and cyclohexyl.
  • Preferred compounds of the present invention include the compounds of the formula:
  • Specific compounds within the present invention include a compound which selected from the group consisting of:
  • N N o c A N

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Virology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Cette invention concerne des amines cycliques de formule (I). Dans la formule (I), R?1,R2, R3¿, m et n sont tels que dans le descriptif. Ces amines cycliques sont utiles en tant que modulateurs de l'activité du récepteur de chémokine, et de manière plus spécifique elles sont utiles en tant que modulateurs des récepteurs de chémokine CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3 et/ou CXCR-4.
EP99906697A 1998-02-02 1999-02-01 Amines cycliques utilisees en tant que modulateurs de l'activite du recepteur de chemokine Withdrawn EP1052992A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US7344698P 1998-02-02 1998-02-02
US73446P 1998-02-02
GB9810890 1998-05-20
GBGB9810890.5A GB9810890D0 (en) 1998-05-20 1998-05-20 Cyclic amine modulators of chemokine receptor activity
PCT/US1999/002165 WO1999038514A1 (fr) 1998-02-02 1999-02-01 Amines cycliques utilisees en tant que modulateurs de l'activite du recepteur de chemokine

Publications (1)

Publication Number Publication Date
EP1052992A1 true EP1052992A1 (fr) 2000-11-22

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EP99906697A Withdrawn EP1052992A1 (fr) 1998-02-02 1999-02-01 Amines cycliques utilisees en tant que modulateurs de l'activite du recepteur de chemokine

Country Status (5)

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EP (1) EP1052992A1 (fr)
JP (1) JP2002501898A (fr)
AU (1) AU2654399A (fr)
CA (1) CA2319781A1 (fr)
WO (1) WO1999038514A1 (fr)

Families Citing this family (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6025154A (en) 1995-06-06 2000-02-15 Human Genome Sciences, Inc. Polynucleotides encoding human G-protein chemokine receptor HDGNR10
US6743594B1 (en) 1995-06-06 2004-06-01 Human Genome Sciences, Inc. Methods of screening using human G-protein chemokine receptor HDGNR10 (CCR5)
CZ20012502A3 (cs) * 1999-01-13 2002-03-13 Millennium Pharmaceuticals, Inc. Funkcionalizované heterocykly jako modulátory chemokinových receptorů
SE9902987D0 (sv) 1999-08-24 1999-08-24 Astra Pharma Prod Novel compounds
AR025884A1 (es) 1999-10-01 2002-12-18 Takeda Pharmaceutical Compuestos de amina ciclica, su produccion y su uso
FR2802206B1 (fr) 1999-12-14 2005-04-22 Sod Conseils Rech Applic Derives de 4-aminopiperidine et leur utilisation en tant que medicament
GB0004152D0 (en) 2000-02-23 2000-04-12 Astrazeneca Uk Ltd Novel compounds
GB0004153D0 (en) 2000-02-23 2000-04-12 Astrazeneca Uk Ltd Novel use
GB0004151D0 (en) 2000-02-23 2000-04-12 Astrazeneca Uk Ltd Novel use
GB0013060D0 (en) 2000-05-31 2000-07-19 Astrazeneca Ab Chemical compounds
GB0021670D0 (en) 2000-09-04 2000-10-18 Astrazeneca Ab Chemical compounds
DE60137435D1 (de) 2000-09-15 2009-03-05 Anormed Inc Chemokin rezeptor bindenden heterozyklische verbindungen
US6734191B2 (en) * 2000-09-15 2004-05-11 Anormed, Inc. Chemokine receptor binding heterocyclic compounds
RU2297413C2 (ru) * 2000-09-15 2007-04-20 Анормед, Инк. Гетероциклические соединения, моделирующие активность хемокинового рецептора, их применение и содержащая их фармацевтическая композиция
HK1052011A1 (zh) * 2000-09-15 2003-08-29 Anormed Inc. 趋化因子受体结合杂环化合物
RU2277092C2 (ru) * 2000-09-15 2006-05-27 Анормед, Инк. Гетероциклические соединения, их применение и фармацевтическая композиция для лечения состояний, опосредованных схсr4 и ccr5
AU2002213467A8 (en) 2000-10-11 2009-07-30 Chemocentryx Inc Modulation of ccr4 function
US7175988B2 (en) 2001-02-09 2007-02-13 Human Genome Sciences, Inc. Human G-protein Chemokine Receptor (CCR5) HDGNR10
GB0104050D0 (en) 2001-02-19 2001-04-04 Astrazeneca Ab Chemical compounds
GB0107228D0 (en) 2001-03-22 2001-05-16 Astrazeneca Ab Chemical compounds
GB0108099D0 (en) * 2001-03-30 2001-05-23 Hoffmann La Roche Aminopiperidine derivatives
US7144903B2 (en) 2001-05-23 2006-12-05 Amgen Inc. CCR4 antagonists
ATE319703T1 (de) 2001-07-02 2006-03-15 Piperidinverbindungen, die sich als modulatoren der chemokinrezeptoraktivität eignen
GB0117899D0 (en) * 2001-07-23 2001-09-12 Astrazeneca Ab Chemical compounds
SE0102640D0 (sv) 2001-07-31 2001-07-31 Astrazeneca Ab Novel compounds
GB0120461D0 (en) 2001-08-22 2001-10-17 Astrazeneca Ab Novel compounds
GB0122503D0 (en) 2001-09-18 2001-11-07 Astrazeneca Ab Chemical compounds
SE0103818D0 (sv) 2001-11-15 2001-11-15 Astrazeneca Ab Chemical compounds
US7393934B2 (en) 2001-12-21 2008-07-01 Human Genome Sciences, Inc. Human G-protein chemokine receptor (CCR5) HDGNR10
SE0200843D0 (sv) 2002-03-19 2002-03-19 Astrazeneca Ab Chemical compounds
SE0200844D0 (sv) 2002-03-19 2002-03-19 Astrazeneca Ab Chemical compounds
RU2366655C2 (ru) 2003-03-14 2009-09-10 Оно Фармасьютикал Ко., Лтд. Азотсодержащие гетероциклические производные и лекарственные средства, содержащие их в качестве активного ингредиента
SE0300957D0 (sv) 2003-04-01 2003-04-01 Astrazeneca Ab Chemical compounds
WO2004092169A1 (fr) 2003-04-18 2004-10-28 Ono Pharmaceutical Co., Ltd. Compose de spiropiperidine et son utilisation medicinale
SE0301369D0 (sv) 2003-05-09 2003-05-09 Astrazeneca Ab Chemical compounds
EP1723178A4 (fr) 2004-03-12 2007-12-12 Human Genome Sciences Inc Recepteur humain (ccr5) hdgnr10 de chimiokine de la proteine g
TW200538098A (en) * 2004-03-22 2005-12-01 Astrazeneca Ab Therapeutic agents
SE0400925D0 (sv) * 2004-04-06 2004-04-06 Astrazeneca Ab Chemical compounds
TW200610761A (en) 2004-04-23 2006-04-01 Astrazeneca Ab Chemical compounds
US8143404B2 (en) 2004-09-13 2012-03-27 Ono Pharmaceutical Co., Ltd Nitrogenous heterocylic derivative and medicine containing the same as an active ingredient
EP1889622A4 (fr) 2005-05-31 2009-12-23 Ono Pharmaceutical Co Compose de spiropiperidine et son utilisation medicinale
WO2006138350A2 (fr) * 2005-06-15 2006-12-28 Anormed Inc. Composes de liaison au recepteur de la chimiokine
JP2009501793A (ja) 2005-07-21 2009-01-22 アストラゼネカ・アクチエボラーグ 新規ピペリジン誘導体
EP2657235A1 (fr) 2005-10-28 2013-10-30 Ono Pharmaceutical Co., Ltd. Composé 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
CA2644368A1 (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
JP5245827B2 (ja) 2006-07-31 2013-07-24 小野薬品工業株式会社 スピロ結合した環状基を含有する化合物およびその用途
US8278302B2 (en) 2009-04-08 2012-10-02 Boehringer Ingelheim International Gmbh Substituted piperidines as CCR3 antagonists
WO2010129351A1 (fr) 2009-04-28 2010-11-11 Schepens Eye Research Institute Procédé pour identifier et pour traiter une dégénérescence maculaire liée à l'âge
UA109290C2 (uk) 2010-10-07 2015-08-10 Спільні кристали і солі інгібіторів ccr3
WO2013024022A1 (fr) 2011-08-12 2013-02-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour traiter l'hypertension pulmonaire
US8680280B2 (en) 2012-04-02 2014-03-25 Boehringer Ingelheim International Gmbh Process for the manufacturing of CRR inhibitors
US10213421B2 (en) 2012-04-04 2019-02-26 Alkahest, Inc. Pharmaceutical formulations comprising CCR3 antagonists
DK3209655T3 (da) 2014-10-24 2020-09-28 Landos Biopharma Inc Lanthioninsyntease C-lignende 2-baserede Therapeutica
KR20230026522A (ko) 2019-12-20 2023-02-24 란도스 바이오파마, 인크. 란티오닌 c-유사 단백질 2 리간드, 이로 제조된 세포, 및 이를 사용하는 치료법
US11629196B2 (en) 2020-04-27 2023-04-18 Incelldx, Inc. Method of treating SARS-CoV-2-associated hypercytokinemia by administering a human monoclonal antibody (PRO-140) that inhibits CCR5/CCL5 binding interactions

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2719311B1 (fr) * 1994-03-18 1998-06-26 Sanofi Sa Composés antagonistes sélectifs du récepteur NK3 humain et leur utilisation comme médicaments et outils de diagnostic.
FR2738819B1 (fr) * 1995-09-14 1997-12-05 Sanofi Sa Nouveaux composes antagonistes selectifs du recepteur nk3 humain, procede pour leur obtention et compositions pharmaceutiques les contenant
JPH09249566A (ja) * 1996-03-19 1997-09-22 Takeda Chem Ind Ltd ピペリジン化合物含有ケモカイン受容体拮抗剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9938514A1 *

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CA2319781A1 (fr) 1999-08-05

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