WO2005058881A1 - Composes chimiques - Google Patents

Composes chimiques Download PDF

Info

Publication number
WO2005058881A1
WO2005058881A1 PCT/SE2004/001860 SE2004001860W WO2005058881A1 WO 2005058881 A1 WO2005058881 A1 WO 2005058881A1 SE 2004001860 W SE2004001860 W SE 2004001860W WO 2005058881 A1 WO2005058881 A1 WO 2005058881A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
optionally substituted
alkoxy
phenyl
halo
Prior art date
Application number
PCT/SE2004/001860
Other languages
English (en)
Inventor
Alan Faull
Original Assignee
Astrazeneca Ab
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
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of WO2005058881A1 publication Critical patent/WO2005058881A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • 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

  • the present invention relates to heterocyclic derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.
  • Pharmaceutically active piperidine derivatives are disclosed in PCT/SE01/01053, EP-A1-1013276, WO00/08013, WO99/38514 and WO99/04794.
  • 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 and also play a role in the maturation of cells of the immune system.
  • Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C, or ⁇ ) and Cys-Cys (C-C, or ⁇ ) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
  • the C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
  • the C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins l ⁇ and l ⁇ (MlP-l ⁇ and MlP-l ⁇ ).
  • chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4.
  • CCR5 receptor is expressed on T-lymphocytes, monocytes, macrophages, dendritic cells, microglia and other cell types.
  • chemokines principally "regulated on activation normal T-cell expressed and secreted” (RANTES), macrophage inflammatory proteins (MIP) MlP-l ⁇ and MlP-l ⁇ and monocyte chemoattractant protein-2 (MCP-2).
  • RANTES normal T-cell expressed and secreted
  • MIP macrophage inflammatory proteins
  • MCP-l ⁇ monocyte chemoattractant protein-2
  • CCR5 is also a co-receptor for HIV-1 and other viruses, allowing these viruses to enter cells. Blocking the receptor with a CCR5 antagonist or inducing receptor internalisation with a CCR5 agonist protects cells from viral infection.
  • the present invention provides a compound of formula (I):
  • A is CH 2 CH 2 or A is absent;
  • R 1 is C 3-7 cycloalkyl in which at least one ring carbon is replaced by the same or different O, S, S(O), S(O) 2 , CHF or CF 2 ; wherein R 1 is optionally substituted by halogen, cyano, Q- 6 alkyl [optionally substituted by phenyl ⁇ which itself optionally substituted by halo, C ⁇ -4 alkyl, C alkoxy, cyano, nitro, CF 3 , OCF 3 , (C alkyl)C(O)NH, S(O) 2 NH 2 , C M alkylthio, S(O)(C ⁇ .
  • R 3 is hydrogen or C ⁇ -4 alkyl
  • R 4 is hydrogen, methyl, ethyl, allyl or cyclopropyl
  • R 5 is aryl, aryl(C 1- )alkyl, heteroaryl or heteroaryl(C].
  • aryl and heteroaryl moieties are independently optionally substituted by one or more of halo, cyano, nitro, hydroxy, OC(O)NR ⁇ R 12 , NR 13 R 14 , NR 15 C(O)R 16 , NR 17 C(O)NR 18 R 19 , S(O) 2 NR 20 R 21 , NR 22 S(O) 2 R 23 , C(O)NR 24 R 25 , CO 2 R 26 , NR 27 CO 2 R 28 , S(O) q R 29 , OS(O) 2 R 30 , Cue alkyl (optionally mono-substituted by S(O) 2 R 31 or C(O)NR 32 R 33 ), C 2-6 alkenyl, C 2-6 alkynyl, C 3 .
  • R 7 and R 10 are, independently, hydrogen, Cue alkyl [optionally substituted by halo (such as fluoro), C alkoxy, phenyl ⁇ which itself optionally substituted by halo, CM alkyl, C 1-4 alkoxy, cyano, nitro, CF 3 , OCF 3 , (CM alkyl)C(O)NH, S(O) 2 NH 2 , CM alkylthio, S(O)(C M alkyl) or S(O) 2 (CM alkyl) ⁇ or heteroaryl ⁇ which itself optionally substituted by halo, CM alkyl, CM alkoxy, cyano, nitro, CF 3 , (CM alkyl)C(O)NH, S(O) 2 NH 2 ,
  • R 8 and R are, independently, hydrogen or CM alkyl; or R 8 and R 9 join to form a 5- or 6- membered ring which may additionally comprise an oxygen or sulphur atom (for example to form a morpholine, thiomorpholine ring) or NR 39 group (for example to form a piperazine ring), wherein the ring is optionally substituted with halogen, CM alkyl or
  • R n , R 13 , R 15 , R 17 , R 18 , R 20 , R 22 , R 24 , R 27 , R 32 and R 35 are, independently, hydrogen or d -6 alkyl;
  • R 12 , R 14 , R 16 , R 19 , R 21 , R 23 , R 25 , R 26 , R 28 , R 29 , R 30 , R 31 , R 33 , R 34 , R 36 , R 37 and R 38 are, independently, alkyl (optionally substituted by halo, hydroxy, Cue alkoxy, C ⁇ -6 haloalkoxy, C 3-6 cycloalkyl, C 5 .
  • R 12 , R 14 , R 16 , R 19 , R 21 , R 25 , R 26 , R 33 , R 34 , R 36 and R 38 may additionally be hydrogen; and, R 39 is hydrogen, C alkyl, C(O)(C ⁇ -4 alkyl) or S(O) 2 (C ⁇ -4 alkyl); or a pharmaceutically acceptable salt thereof.
  • Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions.
  • Suitable salts include acid addition salts such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate ovp- toluenesulphonate.
  • acid addition salts are succinate, glutarate or malonate.
  • the invention includes solvates (such as hydrates) of compounds of formula (I) and the present invention covers all such solvates.
  • Alkyl groups and moieties are straight or branched chain and are, for example, methyl (sometimes abbreviated to Me), ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl.
  • Cycloalkyl is for example, cyclopropyl, cyclopentyl or cyclohexyl.
  • Haloalkyl includes CF 3
  • haloalkoxy includes OCF 3 .
  • Fluoroalkyl includes, for example, one to six, such as one to three, fluorine atoms, and comprises, for example, a CF 3 group. Fluoroalkyl is, for example, CF 3 or CH 2 CF 3 .
  • Alkoxyalkyl groups include methoxymethyl and ethoxymethyl.
  • Heterocyclyl is, for example, piperidine, piperazine, pyrrolidine, azetidine, tetrahydrofuran, morpholine or thiomorpholine. Further examples of heterocyclyl are tetrahydropyran and tetrahydrothiopyran.
  • Aryl includes phenyl and naphthyl. In one aspect of the invention aryl is phenyl.
  • Heteroaryl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, [l,2,4]-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[l,2a]pyridinyl), thieno[3,2-b]pyridin-6
  • Aryl(Cu 4 alkyl), aryl(Cu4)alkyl, phenyl(Cu4)alkyl and phenyl(Cu 4 alkyl) are, independently, for example, benzyl, l-(phenyl)eth-l-yl or l-(phenyl)eth-2-yl.
  • Heteroaryl(Cj-4 alkyl)alkyl is, for example, pyridinylmethyl, pyrimidinylmethyl or 1- (pyridinyl)eth-2-yl. Phenyl(C].
  • the present invention provides a compound of formula (I) wherein A is absent.
  • the present invention provides a compound of formula (I) wherein, unless specified otherwise, aryl, phenyl and heteroaryl moieties are independently optionally substituted by one or more of halo, hydroxy, nitro, S(C 1-6 alkyl), S(O)(C 1-6 alkyl), S(O) 2 (C 6 alkyl), S(O) 2 NH 2 , S(O) 2 NH(Cue alkyl), S(O) 2 N(Cue alkyl) 2 , cyano, C 1-6 alkyl, C ]-6 alkoxy, CH 2 S(O) 2 (Cu6 alkyl), OS(O) 2 (Cue alkyl), OCH 2 heteroaryl (such as OCH 2 tetrazolyl), OCH 2 CO 2 H, OCH 2 CO 2 (Cu6 alkyl), OCH 2 C(O)NH 2 , OCH 2 C(O)NH 2
  • the present invention provides a compound of formula (I) wherein, unless specified otherwise, aryl, phenyl and heteroaryl moieties are independently optionally substituted by one or more of halo, hydroxy, nitro, S(Cu 4 alkyl), S(O)(C ⁇ -4 alkyl), S(O) 2 (C 1- alkyl), S(O) 2 NH 2 , S(O) 2 NH(C, -4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , cyano, C M alkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(Ci -4 alkyl), CO 2 H, CO 2 (Cu 4 alkyl), NHC(O)(C 1-4 alkyl), NHS(O) 2 (C ⁇ - alkyl), CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 or OCF 3 .
  • R 1 is tetrahydropyranyl, tetrahydrothiopyranyl or 1,1-dioxidotetrahydrothiopyranyl, each optionally substituted by halogen or CM alkyl (such as methyl).
  • R 2 is phenyl optionally substituted in the 2-, 3-, 2,5- or 3,5- position by the same or different: halo (such as fluoro or chloro), CM alkyl, CM alkoxy, S(O) n (C 1-4 alkyl), nitro, cyano or CF 3 ; where n is 0, 1 or 2.
  • R 2 is phenyl optionally substituted in the 3- or 3,5- position by the same or different: halo (such as fluoro or chloro), C M alkyl or CF3.
  • R 2 is phenyl, mono-fiuorophenyl (for example 3-fluorophenyl), difluorophenyl (for example 3,5-difluorophenyl), mono-chlorophenyl (for example 3- chlorophenyl) or di-halophenyl (such as 3-chloro-5-fluorophenyl).
  • R 3 is hydrogen or methyl.
  • R 3 is hydrogen.
  • R 3 is methyl.
  • R 4 is ethyl.
  • R 5 is phenyl or benzyl, either of which is optionally substituted by halogen (such as chloro or fluoro), cyano, C 1-4 alkyl (mono- substituted by S(O) 2 (C 1-4 alkyl) or C(O)NH(C 1-4 alkyl)), C 1-4 alkoxy, S(C alkyl), S(O) 2 (C ⁇ -4 alkyl), OS(O) 2 (C M alkyl), OCH 2 COOH, OCH 2 -tetrazolyl (itself optionally substituted by C M alkyl), carboxamide or tetrazolyl (itself optionally substituted by C alkyl).
  • halogen such as chloro or fluoro
  • R 5 is phenyl or benzyl, either of which is optionally substituted by halogen (such as chloro or fluoro), cyano, C 1-4 alkyl (mono-substituted by S(O) 2 (CM alkyl) or C(O)NH(CM alkyl)), C M alkoxy, S(C 1- alkyl), S(O) 2 (C M alkyl) or OS(O) 2 (C ⁇ -4 alkyl).
  • halogen such as chloro or fluoro
  • cyano C 1-4 alkyl (mono-substituted by S(O) 2 (CM alkyl) or C(O)NH(CM alkyl))
  • C M alkoxy S(C 1- alkyl)
  • the present invention provides a compound of the invention wherein R 5 is phenyl ⁇ optionally substituted by S(O) 2 (C 1-4 alkyl) (such as CH 3 S(O) 2 , for example in the 4-position), CM alkoxy (such as CH 3 O, for example in the 4-position), OS(O)2(C 1- alkyl) (such as OSO 2 CH 3 , for example in the 4-position), halogen (such as chloro or fluoro) or cyano ⁇ .
  • S(O) 2 (C 1-4 alkyl) such as CH 3 S(O) 2 , for example in the 4-position
  • CM alkoxy such as CH 3 O, for example in the 4-position
  • OS(O)2(C 1- alkyl) such as OSO 2 CH 3 , for example in the 4-position
  • halogen such as chloro or fluoro
  • the present invention provides a compound of the invention wherein R 5 is benzyl ⁇ optionally substituted by S(O) 2 (CM alkyl) (such as CH 3 S(O) 2 , for example in the 4-position), C alkoxy (such as CH 3 O, for example in the 4-position), OS(O) 2 (C ⁇ - alkyl) (such as OSO2CH 3 , for example in the 4-position), halogen (such as chloro or fluoro) or cyano ⁇ .
  • CM alkyl such as CH 3 S(O) 2 , for example in the 4-position
  • C alkoxy such as CH 3 O, for example in the 4-position
  • OS(O) 2 (C ⁇ - alkyl) such as OSO2CH 3 , for example in the 4-position
  • halogen such as chloro or fluoro
  • the present invention provides a compound of formula (I) wherein R 1 is tetrahydropyranyl, tetrahydrothiopyranyl or 1,1-dioxidotetrahydrothiopyranyl; R 2 is phenyl optionally substituted by halo (such as fluoro); R 3 is hydrogen; R 4 is ethyl; R 5 is benzyl optionally substuituted by S(O) 2 (C M alkyl) (such as S(O) 2 CH 3 ).
  • R 1 is tetrahydropyranyl, tetrahydrothiopyranyl or 1,1-dioxidotetrahydrothiopyranyl
  • R 2 is phenyl optionally substituted by halo (such as fluoro)
  • R 3 is hydrogen
  • R 4 is ethyl
  • R 5 is benzyl optionally substuituted by S(O) 2 (C M alkyl) (such as S(
  • R 1 is tetrahydropyranyl, tetrahydrothiopyranyl or 1,1-dioxidotetrahydrothiopyranyl; wherein R 1 is optionally substituted by C 1-6 alkyl (for example by 1 or 2 CH 3 groups); R 2 is phenyl optionally substituted by halo (for example by 2 chloro atoms or 2 fluoro atoms); R 3 is hydrogen; R 4 is C alkyl (for example ethyl); and R 5 is benzyl optionally substituted by S(O) 2 (CM alkyl) (for example S(O) 2 CH 3 ).
  • the compounds of formula (I) have a chiral centre at * (see below).
  • a compound of the invention can be prepared by coupling a compound of formula (IV):
  • the starting materials for the preparative methods are either commercially available or can be prepared by literature methods, adapting literature methods or by following or adapting the Method herein described.
  • the invention provides processes for preparing the compounds of the invention. Many of the intermediates in the processes are novel and these are provided as further features of the invention.
  • the compounds of the invention have activity as pharmaceuticals, in particular as modulators (such as agonists, partial agonists, inverse agonists or antagonists) of chemokine receptor (especially CCR5) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)).
  • modulators such as agonists, partial agonists, inverse agonists or antagonists
  • CCR5 chemokine receptor
  • a method for modulating chemokine receptor activity in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, as a medicament, especially a medicament for the treatment of transplant rejection, respiratory disease, psoriasis or rheumatoid arthritis (especially rheumatoid arthritis).
  • Respiratory disease is, for example, COPD, asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ or rhinitis ⁇ acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, f ⁇ brinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis ⁇ ; and is particularly asthma or rhinitis].
  • COPD chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇
  • the present invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man).
  • a compound of the invention, or a pharmaceutically acceptable salt thereof for use as a medicament, especially a medicament for the treatment of rheumatoid arthritis.
  • the present invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man).
  • therapy for example modulating chemokine receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man).
  • the invention further provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of:
  • obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ ; bronchitis ⁇ such as eosinophilic bronchitis ⁇ ; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer
  • COPD chronic
  • arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as anky losing spondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis;
  • Alzheimer's disease multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle; in a warm blooded animal, such as man.
  • AIDS Acquired Immunodeficiency Syndrome
  • Lupus disorders such as lupus erythematosus or systemic lupus
  • erythematosus Hashimoto's thyroiditis
  • myasthenia gravis myasthenia gravis
  • type I diabetes nephrotic syndrome
  • the present invention further provides a method of treating a chemokine mediated disease state (especially a CCR5 mediated disease state) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • a compound of the invention, or a pharmaceutically acceptable salt thereof for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR5 receptor) activity, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
  • topical such as to the lung and/or airways or to the skin
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and lg of active ingredient.
  • a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of O.Olmgkg "1 to lOOmgkg "1 of the compound, preferably in the range of O.lmgkg "1 to 20mgkg " ' of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • Buffers such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl ⁇ - cyclodextrin may be used to aid formulation.
  • the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
  • the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
  • the invention further relates to combination therapies or compositions wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered concurrently (possibly in the same composition) or sequentially with an agent for the treatment of any one of the above disease states.
  • a compound of the invention can be combined with a TNF- ⁇ inhibitor (such as an anti-TNF monoclonal antibody (such as Remicade, CDP-870 and D.sub2.E.sub7.), or a TNF receptor immunoglobulin molecule (such as Enbrel.reg.)), a non-selective COX-1 / COX-2 inhibitor (such as piroxicam or diclofenac; a propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprofen or ibuprofen; a fenamate such as mefenamic acid, indomethacin, sulindac or apazone; a pyrazolone such as phenylbutazone; or a salicylate such as aspirin), a COX-1 / COX-2 inhibitor
  • a non-selective COX-1 / COX-2 inhibitor such as piroxicam or diclofenac
  • the present invention still further relates to the combination of a compound of the invention together with: • a leukotriene biosynthesis inhibitor, a 5-lipoxygenase (5-LO) inhibitor or a 5- lipoxygenase activating protein (FLAP) antagonist, such as zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175, Abbott-85761, anN-(5-substituted)-thiophene-2- alkylsulfonamide, a 2,6-di-tert-butylphenol hydrazones, a methoxytetrahydropyran such as Zeneca ZD-2138, SB-210661, a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; an indole or quinoline compound such as MK-591, MK-886 or BAY x 100
  • LTE.sub4. selected from the group consisting of a phenothiazin-3-one such as L- 651,392; an amidino compound such as CGS-25019c; a benzoxalamine such as ontazolast; a benzenecarboximidamide such as BIIL 284/260; or a compound such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro- 245913, iralukast (CGP 45715A) or BAY x 7195; • a PDE4 inhibitor including an inhibitor of the isoform PDE4D; • an antihistaminic H.subl.
  • a phenothiazin-3-one such as L- 651,392
  • an amidino compound such as CGS-25019c
  • a benzoxalamine such as ontazolast
  • receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine or chlorpheniramine; • a gastroprotective H.sub2. receptor antagonist; • an ⁇ .subl.- and ⁇ .sub2.-adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride or ethylnorepinephrine hydrochloride; • an anticholinergic agent such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine; • a ⁇ .subl
  • MMP matrix metalloprotease
  • a matrix metalloprotease such as a stromelysin, a collagenase, or a gelatinase or aggrecanase
  • MMP-1 collagenase- 1
  • MMP- 8 collagenase-2
  • MMP-13 collagenase-3
  • MMP-3 stromelysin-1
  • MMP-10 stromelysin-2
  • MMP-11 stromelysin-3
  • a modulator of chemokine receptor function such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1 , CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CR1 for the C-X 3 -C family;
  • an osteoporosis agent such as roloxifene, droloxifene, lasofoxifene or fosomax;
  • an immunosuppressant agent such as FK-506, rapamycin, cyclosporine, azathioprine or methotrexate
  • a compound useful in the treatment of AIDS and/or HIN infection for example: an agent which prevents or inhibits the viral protein gpl20 from engaging host cell CD4 ⁇ such as soluble CD4 (recombinant); an anti-CD4 antibody (or modified / recombinant antibody) for example PRO542; an anti-groupl20 antibody (or modified / recombinant antibody); or another agent which interferes with the binding of groupl20 to CD4 for example BMS806 ⁇ ; an agent which prevents binding to a chemokine receptor, other than CCR5, used by the HIV virus ⁇ such as a CXCR4 agonist or antagonist or an anti-CXCR4 antibody ⁇ ; a compound which interferes in the fusion between the HIV viral envelope and a cell membrane ⁇ such as an anti- group 41 antibody; enfuvirtide (T-20) or T
  • the present invention still further relates to the combination of a compound of the invention together with: (i) a tryptase inhibitor; (ii) a platelet activating factor (PAF) antagonist; (iii) an interleukin converting enzyme (ICE) inhibitor; (iv) an IMPDH inhibitor; (v) an adhesion molecule inhibitor including a VLA-4 antagonist; (vi) a cathepsin; (vii) a MAP kinase inhibitor; (viii) a glucose-6 phosphate dehydrogenase inhibitor; (ix) a kinin- B.subl. - and B.sub2.
  • a -receptor antagonist comprising: (x) an anti-gout agent, e.g., colchicine; (xi) a xanthine oxidase inhibitor, e.g., allopurinol; (xii) an uricosuric agent, e.g., probenecid, sulfinpyrazone or benzbromarone; (xiii) a growth hormone secretagogue; (xiv) a transforming growth factor (TGF ⁇ ); (xv) a platelet-derived growth factor (PDGF); (xvi) a fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF); (xvii) a granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) a capsaicin cream; (xix) a Tachykinin NK.subl.
  • an anti-gout agent e.g., colchicine
  • NKP-608C selected from the group consisting of NKP-608C; SB-233412 (talnetant); and D-4418;
  • an elastase inhibitors selected from the group consisting of UT- 77 and ZD-0892;
  • TACE TNF ⁇ converting enzyme inhibitor
  • iNOS induced nitric oxide synthase inhibitor
  • a chemoattractant receptor-homologous molecule expressed on TH2 cells a CRTH2 antagonist.
  • temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C;
  • IsoluteTM SCX column a column containing benzenesulphonic acid (non-endcapped) obtained from International Sorbent Technology Ltd., 1st House, Duffryn Industial Estate, Ystrad Mynach, Hengoed, Mid Glamorgan, UK.
  • ArgonautTM PS-tr ⁇ -amine scavenger resin this means a trzs-(2-aminoethyl)amine polystyrene resin obtained from Argonaut Technologies Inc., 887 Industrial Road, Suite G, San Carlos, California, USA.
  • (2E)-3-(tetrahydro-2H-pyran-4-yl)acrylic acid (2.76g) in anhydrous tetrahydrofuran (25ml) was added l-chloro-NN-2-trimethyl-l-propenylamine (2.31ml) and the resulting mixture was stirred for 3 hours to give Solution A.
  • tetramethylethylenediamine 0.81ml
  • EXAMPLE 2 This Example illustrates the preparation ofN- ⁇ l-[(3R)-3-(3,5-difluorophenyl)-3- (tetrahydro-2H-thiopyran-4-yl)propyl]piperidin-4-yl ⁇ -N-ethyl-2-[4- (methylsulphonyl)phenyl]acetamide.
  • EXAMPLE 3 This Example illustrates the preparation of N- ⁇ l-[(3R)-3-(phenyl)-3-(tetrahydro-2H- pyran-4-yl)propyl]piperidin-4-yl ⁇ -N-ethyl-2-[4-(methylsulphonyl)phenyl]acetamide.
  • EXAMPLE 4 This Example illustrates the preparation of N- ⁇ l-[(3R)-3-(phenyl)-3-(l,l- dioxidotetrahydro-2H-thiopyran-4-yl)propyl]piperidin-4-yl ⁇ -N-ethyl-2-[4- (methylsulphonyl) ⁇ henyl]acetamide.
  • EXAMPLE 5 This Example illustrates the preparation ofN- ⁇ l-[(3i?)-3-(3,5-dichlorophenyl)-3- (tetrahydro-2H-pyran-4-yl)propyl]piperidin-4-yl ⁇ -N-ethyl-2-[4- (methylsulfonyl)phenyl]acetamide.
  • EXAMPLE 6 This Example illustrates the preparation of N-(l- ⁇ (3i?)-3-(3,5-difluorophenyl)-3- [(2S,4S)-2-methyltetrahydro-2H-pyran-4-yl]propyl ⁇ piperidin-4-yl)-N-ethyl-2-[4- (methylsulfonyl)phenyl]acetamide.
  • EXAMPLE 8 This Example illustrates the preparation of N- ⁇ l-[(3i?)-3-(3,5-difluorophenyl)-3-(4- methy ltetrahy dro-2H-pyran-4-yl)propy l]piperidin-4-yl ⁇ -N-ethyl-2- [4-
  • EXAMPLE 9 This Example illustrates the preparation of N- ⁇ (3-exo)-8-[3-(3,5-difluorophenyl)-3- (tetrahydro-2H-pyran-4-yl)propyl]-8-azabicyclo[3.2.1]oct-3-yl ⁇ -N-ethyl-2-[4- (methylsulfonyl)phenyl]acetamide.
  • Step 1 Preparation of l-phenylmethyl-4-ethylaminopiperidine dihydrochloride To a solution of l-phenylmethyl-4-piperidone (25.0g, 132mmol) in THF (250mL) was added ethylamine hydrochloride (12.0g, 147 mol) and methanol (50mL) and the resulting mixture stirred at room temperature for lOmin. Sodium triacetoxyborohydride (40g, 189mmol) was added portionwise and the resulting mixture stirred at room temperature for lh. 2M Sodium hydroxide solution (250mL) was added and the resulting mixture extracted with diethyl ether.
  • Step 2 Preparation of N-(l-Phenylmethyl-4-piperidinyl)-N-ethyl-4- methanesulfonylphenylacetamide
  • l-phenylmethyl-4-ethylaminopiperidine dihydrochloride 32.0g, 1 lOmmol
  • DCM 500mL
  • N.N-diisopropvlethylamine 60mL
  • 4-Methanesulfonylphenylacetic acid 25. Og, 117mmol
  • 4- Dimethylaminopyridine 2.0g
  • dicyclohexylcarbodiimide 25.
  • Step 3 Preparation of the title compound To a solution of N-(l-phenylmethyl-4-piperidinyl)-N-ethyl-4-methanesulfonylphenyl- acetamide (34g, 82mmol) in ethanol (600mL) was added ammonium formate (40g). The mixture was purged with argon and 30% Pd on carbon (4.2g) was added. The resulting mixture was stirred at reflux for 4h, then allowed to cool and filtered through diatomaceous earth.
  • Step 1 Preparation of 4-methyl-tetrahydropyran-4-carboxylic acid methyl ester.
  • Tetrahydropyran-4-carboxylic acid methyl ester (14.42g) was dissolved in anhydrous tetrahydrofuran (250ml) and cooled to -78°C under an atmosphere of argon. To this stirred solution was added, via syringe, lithium bis(trimethylsilyl)amide (IM solution in THF, 100ml). The solution was allowed to warm to 0°C, stirred for 15 minutes, then cooled to -78°C. To the cooled solution was added, dropwise via syringe, iodomethane (6.2ml). The solution was stirred for 30 minutes then allowed to warm slowly to room temperature and stirred for a further 3 hours.
  • IM solution in THF 100ml
  • iodomethane 6.2ml
  • Step 2 Preparation of (4-methyl-tetrahydropyran-4-yl)-methanol.
  • Step 4 Preparation of N-(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-N-ethyl-2-(4- methanesulfonyl-phenyl)-acetamide
  • Step 5 Preparation of title compound.
  • ethanol 20mL
  • 20% palladium hydroxide on carbon 0.04g
  • the catalyst was removed by filtration and the resulting solution was adsorbed onto silica. The residue was purified by silica gel chromatography
  • EXAMPLE 10 The ability of compounds to inhibit the binding of RANTES was assessed by an in vitro radioligand binding assay. Membranes were prepared from Chinese hamster ovary cells which expressed the recombinant human CCR5 receptor. These membranes were incubated with 0. InM iodinated RANTES, scintillation proximity beads and various concentrations of the compounds of the invention in 96-well plates. The amount of iodinated RANTES bound to the receptor was determined by scintillation counting. Competition curves were obtained for compounds and the concentration of compound which displaced 50% of bound iodinated RANTES was calculated (IC 50 ). Preferred compounds of formula (I) have an IC 50 of less than 50 ⁇ M.
  • EXAMPLE 11 The ability of compounds to inhibit the binding of MlP-l ⁇ was assessed by an in vitro radioligand binding assay. Membranes were prepared from Chinese hamster ovary cells which expressed the recombinant human CCR5 receptor. These membranes were incubated with O.lnM iodinated MlP-l ⁇ , scintillation proximity beads and various concentrations of the compounds of the invention in 96-well plates. The amount of iodinated MlP-l ⁇ bound to the receptor was determined by scintillation counting. Competition curves were obtained for compounds and the concentration of compound which displaced 50% of bound iodinated MlP-l ⁇ was calculated (IC 50 ).
  • Preferred compounds of formula (I) have an IC 50 of less than 50 ⁇ M. Results from this test for certain compounds of the invention are presented in Table I. In Table I the results are presented as Pic50 values. A Pic50 value is the negative log (to base 10) of the IC 50 result, so an IC50 of l ⁇ M (that is 1 x 10 "6 M) gives a Pic50 of 6. If a compound was tested more than once then the data below is an average of the probative tests results. Table I

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des composés représentés par la formule (I) suivante: [veuillez insérer la formule ici. Voir la copie papier s'il vous plaît]. Cette invention concerne aussi des compositions comprenant ces composés, un processus de préparation de ces compositions et l'utilisation de ces compositions dans une thérapie médicale (par exemple de modulation de l'activité du récepteur CCR5 chez un animal à sang chaud)..
PCT/SE2004/001860 2003-12-16 2004-12-14 Composes chimiques WO2005058881A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0303396-6 2003-12-16
SE0303396A SE0303396D0 (sv) 2003-12-16 2003-12-16 Chemical compounds

Publications (1)

Publication Number Publication Date
WO2005058881A1 true WO2005058881A1 (fr) 2005-06-30

Family

ID=30439713

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2004/001860 WO2005058881A1 (fr) 2003-12-16 2004-12-14 Composes chimiques

Country Status (2)

Country Link
SE (1) SE0303396D0 (fr)
WO (1) WO2005058881A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7385059B2 (en) 2003-07-22 2008-06-10 Astex Therapeutics Limited 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US8013163B2 (en) 2005-01-21 2011-09-06 Astex Therapeutics Limited 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors
US8367863B2 (en) 2007-12-20 2013-02-05 Envivo Pharmaceuticals, Inc. Tetrasubstituted benzenes
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001087839A1 (fr) * 2000-05-17 2001-11-22 Astrazeneca Ab Derives de piperidine pharmaceutiquement actifs, en particulier sous forme de modulateurs de l'activite des recepteurs de chimiokine
EP1238970A1 (fr) * 1999-12-08 2002-09-11 Teijin Limited Antagonistes du recepteur ccr5 de la cycloamine
WO2003042205A1 (fr) * 2001-11-15 2003-05-22 Astrazeneca Ab Derives de la piperidine et leur utilisation comme modulateurs de l'activite du recepteur de chimiokine (notamment de ccr5)
WO2003042177A1 (fr) * 2001-11-15 2003-05-22 Astrazeneca Ab Derives de la piperidine et leurs utilisations comme modulateurs de l'activite du recepteur de la chemokine (specialement du ccr5)
WO2003080574A1 (fr) * 2002-03-25 2003-10-02 Astrazeneca Ab Derives de piperidine ou 8-aza-bicyclo[3.2.1]oct-3-yle convenant comme modulateurs de l'activite des recepteurs de la chimiokine (plus paritculierement ccr5)

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1238970A1 (fr) * 1999-12-08 2002-09-11 Teijin Limited Antagonistes du recepteur ccr5 de la cycloamine
WO2001087839A1 (fr) * 2000-05-17 2001-11-22 Astrazeneca Ab Derives de piperidine pharmaceutiquement actifs, en particulier sous forme de modulateurs de l'activite des recepteurs de chimiokine
WO2003042205A1 (fr) * 2001-11-15 2003-05-22 Astrazeneca Ab Derives de la piperidine et leur utilisation comme modulateurs de l'activite du recepteur de chimiokine (notamment de ccr5)
WO2003042177A1 (fr) * 2001-11-15 2003-05-22 Astrazeneca Ab Derives de la piperidine et leurs utilisations comme modulateurs de l'activite du recepteur de la chemokine (specialement du ccr5)
WO2003080574A1 (fr) * 2002-03-25 2003-10-02 Astrazeneca Ab Derives de piperidine ou 8-aza-bicyclo[3.2.1]oct-3-yle convenant comme modulateurs de l'activite des recepteurs de la chimiokine (plus paritculierement ccr5)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7385059B2 (en) 2003-07-22 2008-06-10 Astex Therapeutics Limited 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US7745638B2 (en) 2003-07-22 2010-06-29 Astex Therapeutics Limited 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US7825140B2 (en) 2003-07-22 2010-11-02 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US8080666B2 (en) 2003-07-22 2011-12-20 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US8779147B2 (en) 2003-07-22 2014-07-15 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US9051278B2 (en) 2003-07-22 2015-06-09 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US8013163B2 (en) 2005-01-21 2011-09-06 Astex Therapeutics Limited 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors
US8293767B2 (en) 2005-01-21 2012-10-23 Astex Therapeutics Limited 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
US8367863B2 (en) 2007-12-20 2013-02-05 Envivo Pharmaceuticals, Inc. Tetrasubstituted benzenes
US8664249B2 (en) 2007-12-20 2014-03-04 Envivo Pharmaceuticals, Inc. Tetrasubstituted benzenes

Also Published As

Publication number Publication date
SE0303396D0 (sv) 2003-12-16

Similar Documents

Publication Publication Date Title
US7615555B2 (en) Piperidine derivatives as modulators of chemokine receptor CCR5
EP1539695A1 (fr) Composes de n-4-piperidinyle modulateurs du ccr5
JP2008503573A (ja) ケモカイン・レセプターｃｃｒ５のモジュレーターとしての新規ピペリジン／８−アザビシクロ［３．２．１］オクタン誘導体
US20060189650A1 (en) Novel piperidine derivatives as modulators of chemokine receptor ccr5
US7294636B2 (en) Chemical compounds
US20060052413A1 (en) Novel piperidine derivatives as modulators of chemokine receptor ccr5
US20060069120A1 (en) Novel piperidine derivaties as modulators of chemokine receptor ccr5
US20080200460A1 (en) Chemical Compounds
WO2005058881A1 (fr) Composes chimiques
ES2293301T3 (es) Derivados de piperidina o 8-aza-biciclo(3.2.1)oct-3-ilo utiles como moduladores de la actividad receptora de quimioquinas.
EP1654229B1 (fr) Derives de piperidine en tant que modulateurs du recepteur ccr5
US20100093795A1 (en) Piperidine Derivative Used for Treating Chemokine Receptor 5 Mediated Diseases
US20100099708A1 (en) Piperidine Derivative Used for Treating Chemokine Receptor 5 Mediated Diseases

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase