WO2004018425A1 - N-4-piperidinyl compounds as ccr5 modulators - Google Patents
N-4-piperidinyl compounds as ccr5 modulators Download PDFInfo
- Publication number
- WO2004018425A1 WO2004018425A1 PCT/SE2003/001287 SE0301287W WO2004018425A1 WO 2004018425 A1 WO2004018425 A1 WO 2004018425A1 SE 0301287 W SE0301287 W SE 0301287W WO 2004018425 A1 WO2004018425 A1 WO 2004018425A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- phenyl
- compound
- formula
- alkoxy
- Prior art date
Links
Classifications
-
- 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P31/04—Antibacterial agents
- A61P31/08—Antibacterial agents for leprosy
-
- 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
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- A61P37/08—Antiallergic agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07D211/58—Nitrogen atoms attached in position 4
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/SEO 1/01053, EP-A1-1013276, WO00/08013, WO99/38514 and O99/04794.
- 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 r ⁇ le 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).
- IL-8 interleukin-8
- NAP-2 neutrophil-activating peptide 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.
- 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.
- the CCR5 receptor is expressed on T-lymphocytes, monocytes, macrophages, dendritic cells, microglia and other cell types. These detect and respond to several chemokines, principally "regulated on activation normal T-cell expressed and secreted” (RANTES), macrophage inflammatory proteins (MIP) MDP-la and MLP-lb and monocyte chemoattractant protein-2 (MCP-2).
- RANTES normal T-cell expressed and secreted
- MIP macrophage inflammatory proteins
- MDP-la and MLP-lb monocyte chemoattractant protein-2
- CCR5 is also a co-receptor for HTV-l 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):
- R 1 is Cj . . 6 alkoxy (optionally substituted by C M alkoxy or phenyl), C 3 . 6 alkenyloxy, phenoxy or piperidin-4-yl ( 1 -substituted by C(O)R 7 or S(O) R 8 ) ;
- R 2 is optionally substituted phenyl, optionally substituted heteroaryl or cycloalkyl
- R 2a , R 4 and R 4a are, independently, hydrogen or C ⁇ - alkyl
- R 3 and R 3a are, independently, hydrogen or C alkyl or CM alkoxy
- R 5 is hydrogen, C alkyl (optionally substituted by halogen, hydroxy, C M alkoxy, C 3 . 7 cycloalkyl, SH, CM alkylthio, cyano or S(O) q (C ⁇ . alkyl)), C 3 . 4 alkenyl, C 3 _ 4 alkynyl or C 3 . 7 cycloalkyl;
- R 6 is phenyl, heteroaryl, phenylNH, heteroarylNH, phenyl(C ⁇ _ 2 )alkyl, heteroaryl(C ⁇ _ 2 )alkyl, phenyl(C ⁇ . 2 alkyl)NH or heteroaryl(C ⁇ . 2 alkyl)NH;
- R 7 is C ⁇ - 6 alkyl (optionally substituted by phenyl, heteroaryl, C alkoxy, or C alkoxy(C ⁇ profession 4 alkoxy)), Q- ⁇ alkoxy, phenyl, heteroaryl or C 3 . 6 cycloalkyl;
- R 8 is C ⁇ -6 alkyl (optionally substituted by phenyl) or phenyl; wherein the phenyl and heteroaryl rings of any of the foregoing are independently optionally substituted by halo, cyano, nitro, hydroxy, CM alkyl, CM alkoxy, S(O) m Ci_ alkyl,
- S(0) 2 NR 9 R 10 NHS(O) 2 (C ⁇ - 4 alkyl), NH 2 , NH(C M alkyl), N(C alkyl) 2 , NHC(0)NH 2 , C(O)NH 2 , C(O)NH(d. 4 alkyl), NHC(0)(CM alkyl), C0 2 H, CO 2 (C M alkyl), C(O)(C M alkyl), CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 or OCF 3 ;
- R and R 10 are, independently, hydrogen or C alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C M alkyl, C(O)H or C(0)(C w alkyl); m, p and q are, independently, 0, l or 2; or a pharmaceutically acceptable salt thereof or a solvate 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 o ⁇ p- toluenesulphonate.
- the compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.
- Alkyl groups and moieties preferably contain, unless otherwise specified, 1-6, especially 1-4, carbon atoms.
- Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl or tert-butyl.
- Alkenyl and alkynyl groups and moieties preferably contain, unless otherwise specified, 2-6, especially 2-4, carbon atoms.
- Alkenyl includes prop-2-en-l-yl, allyl, but-3-en- 1-yl, but-1-en-l-yl, 2-methylallyl, l-methyl-but-3-en-l-yl, 1-methyl-but-l-en-l-yl, pent-2-en- 1-yl and hex-1-en-l-yl.
- Alkynyl includes propargyl, but-3-yn-l-yl, pent-4-yn-l-yl and hex-5- yn-l-yl.
- Alkenyl and alkynyl groups and moieties are, for example, vinyl, allyl or propargyl.
- Cycloalkyl preferably contains, unless otherwise specified, 3-7, especially 3-6, carbon atoms. Cycloalkyl is, for example, cyclopropyl, cyclobutyl or cyclopentyl.
- Cycloalkyl fused to a phenyl ring is, for example, benzocyclobuten-1-yl, indan-1-yl or indan-2-yl.
- Heteroaryl is an aromatic 5 or 6 membered ring comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur.
- Heteroaryl is, for example, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, quinazolinyl, quinoxalinyl, indolyl, isoindolyl, benzimidazolyl, benzofbjfuryl, benzo[b]thienyl, phthalazinyl
- Phenylalkyl is, for example, benzyl, l-(phenyl)eth-l-yl or l-(phenyl)eth-2-yl.
- Heteroarylalkyl is, for example, pyridinylmethyl, pyrirnidinylmethyl or 1- (pyridinyl)eth-2-yl.
- the group S(O) 2 NR 9 R 10 is, for example, S(O) 2 NH 2 , S(O) 2 NH(C ! . 4 alkyl), S(O) 2 N(C ⁇ _ 4 alkyl) 2 , S(O) 2 (4-C(O)H-piperazin-l-yl) or S(O) 2 (4-C(O)CH 3 -piperazin-l-yl).
- Phenyl(Ci_ 2 alkyl)NH is, for example, ben ' zylamino.
- Heteroaryl(C ⁇ . 2 alkyl)NH is, for example, pyridinylCH 2 NH, pyrimidinylCH 2 NH or pyridinylCH(CH 3 )NH.
- the present invention provides a compound of formula (I), wherein R 1 is piperidin-4-yl (1 -substituted by C(O)R 7 or S(O) 2 R 8 ), wherein R 7 and R 8 are as defined above.
- R 1 is piperidin-4-yl 1 -substituted by C(O)R 7 , wherein R 7 is as defined above.
- R 7 is, for example, C ⁇ - 6 alkyl (optionally mono-substituted by phenyl), Cj-e alkoxy, phenyl or C 3 . 6 cycloalkyl, wherein the phenyl rings are optionally substituted by halogen.
- R is piperidin-4-yl 1 -substituted by S(O) 2 R , wherein R is as defined above.
- R is, for example, phenyl or C ⁇ .g alkyl (optionally mono-substituted by phenyl), wherein the phenyl rings are optionally substituted by halogen, S(O) 2 (C ⁇ 4 alkyl) or NHC(O)(C ⁇ . 4 alkyl).
- R 1 is C ⁇ . 6 alkoxy (optionally substituted by C alkoxy or phenyl),
- R 1 is piperidin-4-yl.1 -substituted by C(O)R 7 ⁇ wherein R 7 is . 6 alkyl (optionally mono-substituted by phenyl), C ⁇ - 6 alkoxy, phenyl or C 3 . 6 cycloalkyl, wherein the phenyl rings are optionally substituted by halogen ⁇ or S(0) 2 R 8 (wherein R 8 is phenyl or . 6 alkyl (optionally mono-substituted by phenyl), wherein the phenyl rings are optionally substituted by halogen, S(O) 2 (C ⁇ . alkyl). or NHC(O)(C ⁇ . 4 alkyl) ⁇ , or R 1 is C ⁇ _ 6 alkoxy (optionally substituted by C alkoxy or phenyl), C 3 . 6 alkenyloxy or phenoxy (optionally substituted by halogen).
- R 2 is phenyl optionally substituted (such as in the ortho or meta position) by halo, C alkyl, C M alkoxy, S(O) ⁇ (C ⁇ . alkyl) (wherein n is 0, 1 or 2), nitro, cyano or CF 3 .
- Halo is especially fluorine or chlorine.
- R 2 is unsubstituted phenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl or 4-CF 3 -phenyI.
- R 2 can additionally be 3,5- difluorophenyl.
- R 2 is phenyl optionally substituted (such as in one of both meta positions) by halo (for example fluorine), C alkyl, cyano or CF 3 .
- halo for example fluorine
- C alkyl for example C alkyl
- cyano for example C alkyl
- CF 3 CF 3
- R 2 is unsubstituted phenyl, 3-fluorophenyl or 3,5-difluorophenyl.
- R 2 is phenyl optionally substituted in the ortho or meta position by fluorine or chlorine.
- R 2 is unsubstituted phenyl, 3-fluorophenyl or 3- chlorophenyl.
- R 2 is phenyl optionally substituted (such as in one of both meta positions) by halo (for example, fluorine).
- R 2 is unsubstituted phenyl, 3- fluorophenyl or 3,5-difluorophenyl.
- R 2a is hydrogen.
- R 3 and R 3a are both hydrogen.
- R 4 and R 4a are, independently, hydrogen or methyl (for example R 4 is hydrogen and R 4a is methyl, or, R 4 and R 4a are both hydrogen).
- R 4 is hydrogen or methyl and R 4 is hydrogen.
- R 2a , R 3 , R 3a , R 4 and R 4a are all hydrogen.
- R 5 is hydrogen, CM alkyl (such as methyl, ethyl or iso-pr ⁇ pyl), C 3 . alkenyl, C 3 . alkynyl, C 3 . 7 cycloalkyl or C 3 . 7 cycloalky ⁇ C alkyl).
- R 5 is hydrogen, methyl, ethyl, allyl, propargyl, cyclopropyl or cyclopropylCH 2 .
- R 5 is hydrogen, methyl, ethyl, allyl or cyclopropyl. In still further aspects of the invention R 5 is ethyl.
- R 6 is phenyl or benzyl; the phenyl rings of these being optionally substituted by one or more of: halo, cyano, nitro, hydroxy, C M alkyl, CM alkoxy, S(0) m C ⁇ alkyl, S(O) 2 NR 9 R 10 , NHS(O) 2 (C M alkyl), NH 2 , NH(C ⁇ _ 4 alkyl), N(C W alkyl) 2 , NHC(O)NH 2 , C(O)NH 2 , C(O)NH(C ⁇ - 4 alkyl), NHC(O)(d.
- R 6 is benzyl the phenyl ring of which is optionally substituted by one or more of: halo, cyano, nitro, hydroxy, CM alkyl, C alkoxy, S(O) m C ⁇ . alkyl, S(O) 2 NR 9 R 10 , NHS(O) 2 (C alkyl), NH 2 , NH( . 4 alkyl), N(CM alkyl) 2 , NHC(O)NH 2 , C(O)NH 2 , C(O)NH(CM alkyl), HC(O)(CM alkyl), CO 2 H; CO 2 (d. 4 alkyl), C(O)(C M alkyl), CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 or OCF 3 ; wherein m, R 9 and R 10 are as defined above or below.
- R 9 and R 10 are, independently, hydrogen or C alkyl.
- R 6 is benzyl singly substituted (such as in the 4- position) by S(O) 2 (C ⁇ . 4 )alkyl (such as S(O) 2 CH 3 ) or S(O) 2 NR 9 R 10 ⁇ R 9 and R 10 are, independently, hydrogen or C alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C alkyl, C(O)H or C(0)(C ⁇ alkyl) ⁇ (such as S(O) 2 NH 2 , S(O) 2 NH(CH 3 ), S(O) 2 N(CH 3 ) 2 , S(O) 2 (4-C(0)H- piperazin-1-yl) or S(O) 2 (4-C(O)CH 3 -piperazin-l-yl).
- the 5- or 6-membered ring is, for example
- R 6 is benzyl singly substituted (such as in the 4- position) by S(O) 2 (C ⁇ . )alkyl (such as S(O) 2 CH 3 ).
- the present invention provides a compound of formula (I) wherein R 1 is pi ⁇ eridin-4-yl 1-substituted by C(O)R 7 ⁇ wherein R 7 is C ⁇ _ 6 alkyl (optionally mono- substituted by phenyl), . 6 alkoxy, phenyl or C 3 . 6 cycloalkyl, wherein the phenyl rings are optionally substituted by halogen ⁇ or S(O) 2 R ⁇ wherein R is phenyl or ⁇ alkyl (optionally mono-substituted by phenyl), wherein the phenyl rings are optionally substituted by halogen, S(O) 2 (Ci.
- R 1 is d- ⁇ alkoxy ⁇ optionally substituted by CM alkoxy or phenyl), C 3 . 6 alkenyloxy or phenoxy (optionally substituted by halogen ⁇ ;
- R is phenyl or phenyl substituted in one or both meta-positions by halogen (for example 3- fluorophenyl);
- R 2a , R 3 , R 3a , R 4 and R 4a are all hydrogen;
- R 5 is ethyl; and, R ⁇ benzyl wherein the phenyl ring is substituted by S(O) 2 (C 1 . alkyl) (for example S(O) 2 CH 3 ); or a pharmaceutically acceptable salt thereof (such as a salt of a hydro-halogen acid, for example a hydrochloride).
- the present invention provides a compound of formula (la):
- the invention provides a compound of formula (I) wherein R 1 , R 5 and R 6 are as defined above, and R 2 is unsubstituted phenyl, 3-fluorophenyl or 3,5-difluorophenyl.
- the compounds of formula (la) have S absolute configuration at the asterisked carbon (that is, the carbon labelled '*').
- R la is piperidin-4-yl 1-substimted by:C(O)R 7 or S(O) 2 R 8 , wherein R 7 is as defined above ⁇ for example R 7 is C ⁇ - 6 alkyl (optionally mono- substituted by phenyl), C ⁇ . 6 alkoxy, phenyl or C .
- R 1 is as defined above ⁇ for example R 1 is C ⁇ . 6 alkoxy (optionally substituted by CM alkoxy or phenyl), C 3 . 6 alkenyloxy or phenoxy (optionally substituted by halogen); and R 2b is hydrogen or halogen (for example fluoro).
- R 1 is as defined above ⁇ for example R 1 is C ⁇ . 6 alkoxy (optionally substituted by CM alkoxy or phenyl), C 3 . 6 alkenyloxy or phenoxy (optionally substituted by halogen); and R 2b is hydrogen or halogen (for example fluoro).
- Table I comprises compounds of formula (lb), all having S absolute configuration at *.
- a compound of formula (I), (la), (lb) or (Ic) can be prepared by treating a compound of formula (II):
- an acid chloride or chloroformate of formula R 1 C(0)C1 in the presence of a base (such as a tertiary amine, such as N(d_6 alkyl) 3 where the alkyl groups can be the same, two of the same or all different, for example triethylamine) and in a suitable solvent (such as a chlorinated hydrocarbon, for example dichloromethane); or when R 1 is a 1 -substituted piperidin-4-yl, an acid of formula R J CO 2 H in the presence of a suitable coupling agent (such as O-(7-azabenzotriazol-l-yl)-N,N,N',N-tetramethyluronium hexafluorophosphate [HATU] or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate [PyBrop]) in the presence of a suitable base (such as a tertiary amine, for example diiso
- a compound of formula (IT) can be prepared by treating a compound of formula (HI):
- a compound of formula (HI) can be prepared by reductively animating a compound of formula (IV):
- a compound of formula (H) wherein R a is hydrogen can be prepared by reductive amination of a compound of formula (NI): for example by reacting a compound of formula (VI) with hydroxylamine and hydrogenating the product so formed with hydrogen in the presence of a suitable metal catalyst (such as palladium or platinum catalyst, for example palladium on charcoal).
- a suitable solvent such as an aliphatic alcohol such as methanol
- a suitable organic acid such as an aliphatic acid, for example acetic acid
- a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride
- a compound of formula (VT), wherein R 4 is hydrogen can be prepared by reacting a compound of formula (N) with: an alkyl halide of formula R 2 C(O)CR 3 R 3a CHR 4 X (wherein X is halogen, such as chloro, bromo or iodo) in the presence of a suitable base (such as potassium carbonate) and a suitable solvent (such as acetone); or, compounds of formula R 2 C(O)CHR 3 R 3a and R CHO in the presence of a suitable acid (such as acetic acid.
- a suitable base such as potassium carbonate
- a suitable solvent such as acetone
- a suitable solvent such as an aliphatic alcohol, for example ethanol
- a compound of formula (I) can be prepared by reacting a compound of formula (V I):
- a compound of formula (VH) can be prepared by deprotecting a compound of formula (NTH):
- a suitable acid such as hydrochloric acid or trifluoracetic acid.
- a compound of formula (VHI) can be prepared by reacting a compound of formula (IX):
- l-Boc-piperidine-4-carboxylic acid and a suitable coupling reagent (such as O-(7- azabenzotriazoI-l-yl)-N,N,N',N-tetramethyluronium hexafluorophosphate [HATU] or bromo- tris-pyrrolidino-phosphonium hexafluorophosphate [PyBrop]).
- HATU O-(7- azabenzotriazoI-l-yl)-N,N,N',N-tetramethyluronium hexafluorophosphate
- PyBrop bromo- tris-pyrrolidino-phosphonium hexafluorophosphate
- the starting materials for these processes are commercially available, can be prepared by literature methods or can be prepared by adapting literature methods.
- the invention provides processes for preparing the compounds of formulae (I), (la), (lb) and
- 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
- the compounds of the present invention are also of value in inhibiting the entry of viruses (such as human immunodeficiency virus (HIV)) into target calls and, therefore, are of value in the prevention of infection by viruses (such as HIV), the treatment of infection by viruses (such as HIV) and the prevention and/or treatment of acquired immune deficiency syndrome (AIDS).
- viruses such as human immunodeficiency virus (HIV)
- HIV human immunodeficiency virus
- the present invention further provides a method of treating a chemokine mediated disease state (especially a CCR5 mediated disease state, such as rheumatoid arthritis) in a warm blooded animal (such as man) suffering from, or at risk of, said disease, which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of formula (I), (la), (lb) or (Ic) ⁇ for example (I), (la) or (lb) ⁇ , or a pharmaceutically acceptable salt thereof or solvate thereof.
- a chemokine mediated disease state especially a CCR5 mediated disease state, such as rheumatoid arthritis
- a warm blooded animal such as man suffering from, or at risk of, said disease
- the invention also provides a compound of the formula (I), (la), (lb) or (Ic) ⁇ for example (I), (la) or (lb) ⁇ , or a pharmaceutically acceptable salt thereof or a solvate thereof, for use in therapy (including prophylaxis); for example in the treatment of a chemokine mediated disease state (especially a CCR5 mediated disease state) in a warm blooded animal, such as man, such as in the treatment of rheumatoid arthritis.
- a chemokine mediated disease state especially a CCR5 mediated disease state
- the present invention provides the use of a compound of the formula (I), (la), (lb) or (Ic) ⁇ for example (I), (la) or (lb) ⁇ , or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example hi modulating chemokine receptor activity (especially CCR5 receptor activity (especially in the treatment of rheumatoid arthritis)) in a warm blooded animal, such as man).
- chemokine receptor activity especially CCR5 receptor activity (especially in the treatment of rheumatoid arthritis)
- the invention further provides the use of a compound of formula (I), (la), (lb) or (Ic) ⁇ for example (I), (la) or (lb) ⁇ , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of one or more of the following disease states: (1) (the respiratory tract) 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
- arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing 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 (ADDS), 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.
- ADDS 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
- a compound of the invention or a pharmaceutically acceptable salt thereof or solvate 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 formula (I), (la), (lb) or (Ic) ⁇ for example (1), (la) or (lb) ⁇ , or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.
- a pharmaceutical composition which comprises a compound of the formula (I), (la), (lb) or (Ic) ⁇ for example (1), (la) or (lb) ⁇ , or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.
- 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.
- 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 “1 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.
- 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, solvate or a solvate of a salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate or a solvate of a 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 antibodie (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 aspir
- a TNF- ⁇ inhibitor such as an anti-TNF monoclonal antibodie (such as Remicade, CDP-870 and D.sub2.E.sub7.
- the present invention still further relates to the combination of a compound of the invention together with:
- a leukotriene biosynthesis inhibitor such as zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175, Abbott-85761, an N-(5-substitated)-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 asX-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 1005;
- a receptor antagonist for a leukotriene LTB.sub4., LTC.sub4., LTD.sub4. or 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 BHL 284/260; or a compound such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715 A) or BAY x 7195;
- a phenothiazin-3-one such as L-651,392
- an amidino compound such as CGS-25019c
- a benzoxalamine such as ontazolast
- a PDE4 inhibitor including an inhibitor of the isoform PDE4D
- an antihistaminic H.subl. receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine or chlorpheniramine; • a gastroprotective H.sub2. receptor antagonist;
- 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.- to ⁇ .sub4.-adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate or pirbuterol, or a methylxanthanine including theophylline and aminophylline; sodium cromoglycate; or a muscarinic receptor (Ml, M2, and M3) antagonist;
- Ml, M2, and M3 muscarinic receptor
- IGF- 1 insulin-like growth factor type 1
- an inhaled glucocorticoid with reduced systemic side effects such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate or mometasone furoate;
- 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); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and
- an osteoporosis agent such as roloxifene, droloxifene, lasofoxifene or fosomax;
- NS ADD's non- steroidal anti-inflammatory agent
- 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, a salicylate such as aspirin, a COX-2 inhibitor such as celecoxib, valdecoxib, rofecoxib or etoricoxib, an analgesic or intra-articular therapy such as a corticosteroid or a hyaluronic acid such
- 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
- NK.sub3. receptor antagonist selected from the group consisting of NKP-608C; SB-233412 (talnetant); and D-4418; (xx) an elastase inhibitors selected from the group consisting of UT- . 77 and ZD-0892; (xxi) a TNF ⁇ converting enzyme inhibitor (TACE); (xxii) an induced nitric . oxide synthase inhibitor (iNOS); or (xxiii) a chemoattractant receptor-homologous molecule expressed on TH2 cells (a CRTH2 antagonist).
- TACE TNF ⁇ converting enzyme inhibitor
- iNOS induced nitric . oxide synthase inhibitor
- a chemoattractant receptor-homologous molecule expressed on TH2 cells a CRTH2 antagonist.
- (x) LCMS characterisation was performed using a pair of Gilson 306 pumps with Gilson 233 XL sampler and Waters ZMD4000 mass spectrometer.
- the LC comprised water symmetry 4.6x50 column C18 with 5 micron particle size.
- the eluents were: A, water with 0.05% formic acid and B, acetonitrile with 0.05% formic acid.
- the eluent gradient went from 95% A to 95% B in 6 minutes.
- EXAMPLE 3 This Example illustrates the preparation of (S)- 1 -benzenesulf onyl-piperidine-4- carboxylic acid [3-(4- ⁇ ethyl-[2-(4-methanesulf onyl-phenyl)-acetyl] -amino ⁇ -piperidin- 1 -yl)- 1 - phenyl-pro ⁇ yl]-amide (Compound No.3 of Table I).
- Example 3 The procedure described in Example 3 can be repeated using different sulfonyl chlorides (such as methanesulfonyl chloride, ethanesulfonyl chloride, 4- methanesulfonylbenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride etc.) in place of benzenesulfonyl chloride.
- sulfonyl chlorides such as methanesulfonyl chloride, ethanesulfonyl chloride, 4- methanesulfonylbenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride etc.
- Example 4 The procedure described in Example 4 can be repeated using different acid chlorides (such as phenylacetyl chloride, benzoyl choride, cyclopropanecarbonyl chloride, 4- chlorobenzoyl chloride etc.) in place of isobutyryl chloride.
- EXAMPLE 5 This Example illustrates the preparation of (S)-[3-(4- ⁇ ethyl-[2-(4-methanesulfonyl- ⁇ henyl)-acetyl]-amino ⁇ -piperidin-l-yl)-l-phenyl-propyl]-carbamic acid tert-butyl ester (Compound No.1 of Table H). To a stirred solution of (S)-(3-oxo-l-phenyl-propyl)-carbamic acid tert-butyl ester
- This Example illustrates the preparation of (S)-[3-(4- ⁇ ethyl-[2-(4-methanesulfonyl- phenyl)-acetyl] -amino ⁇ -piperidin- 1 -yl)- 1 -phenyl-propyl] -carbamic acid 1 ' , 1 ' , 1 ' - trichloroethoxy ester hydrochloride (Compound No.7 of Table II).
- the mixture was then filtered through a diatomaceous earth cartridge, which had been preloaded with saturated sodium bicarbonate solution, followed by a second cartridge loaded with IN HCl.
- the crude product was purified by Bond Elut (dichloromethane then 5% methanol in DCM) and the resulting product was isolated as an HCl salt by addition of IN HCl in diethyl ether followed by trituration to give the title compound as a white solid (130 mg, 65%).
- Example 6 The procedure described in Example 6 can be repeated using different chloroformates (such as phenyl chloroformate, benzyl chloroformate, methoxyethyl chloroformate, 4- fluorophenyl chloroformate etc.) in place of trichloroethyl chloroformate.
- chloroformates such as phenyl chloroformate, benzyl chloroformate, methoxyethyl chloroformate, 4- fluorophenyl chloroformate etc.
- This Example illustrates the preparation of (S -[3-(4- ⁇ ethyl-[2-(4-methanesulfonyl- phenyl)-acetyl]-amino ⁇ -piperidin-l-yl)-l-(3-fluoro-phenyl)-propyl]-carbamic acid tert-butyl ester (Compound No.11 of Table H).
- the reaction mixture was quenched with water and the organic phase was washed with sodium hydrogen carbonated solution (saturated aqueous) and water, dried (MgSO4) and concentrated.
- the crude product was purified by Bond Elut (ethyl acetate then 8% methanol in ethyl acetate) to give the title compound as a solid (l.OOg, 55%).
- Step 2 Preparation of N-(l-benzyl-piperidin-4-yl)-N-ethyl-2-(4-methanesulfonyl-phenyl)- acetamide
- Step 3 Preparation of 3-tert-butoxycarbonylamino-3-(3-fluoro-phenyl)-propionic acid tert- butyl ester
- Step 4 Preparation of (S)-[l-(3-fluoro-phenyl)-3-hydroxy-propyl]-carbamic acid tert-butyl ester
- EXAMPLE 8 The ability of compounds to inhibit the binding of RANTES or 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 RANTES or MlP-l ⁇ , scintillation. proximity beads and various concentrations of the compounds of the invention in 96-well plates. The amount of iodinated RANTES or 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 RANTES or MlP-l ⁇ was calculated (IC 50 ).
- the compounds of formula (I) had an IC 50 of less than 50 ⁇ M.
- Compound 1 of Table I has an IC 50 of 39nM (that is 39 nanoM);
- Compound 5 of Table I has an IC 50 of 28nM;
- Compound 3 of Table LI has an IC 50 of 1 lOnM.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/525,121 US20060167048A1 (en) | 2002-08-21 | 2003-08-19 | N-4-piperidinyl compounds as ccr5 modulators |
EP03792923A EP1539695A1 (en) | 2002-08-21 | 2003-08-19 | N-4-piperidinyl compounds as ccr5 modulators |
AU2003253535A AU2003253535A1 (en) | 2002-08-21 | 2003-08-19 | N-4-piperidinyl compounds as ccr5 modulators |
JP2004530710A JP2005539038A (en) | 2002-08-21 | 2003-08-19 | N-4-piperidinyl compounds as CCR5 modulators |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE0202483-4 | 2002-08-21 | ||
SE0202483A SE0202483D0 (en) | 2002-08-21 | 2002-08-21 | Chemical compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2004018425A1 true WO2004018425A1 (en) | 2004-03-04 |
Family
ID=20288766
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE2003/001287 WO2004018425A1 (en) | 2002-08-21 | 2003-08-19 | N-4-piperidinyl compounds as ccr5 modulators |
Country Status (6)
Country | Link |
---|---|
US (1) | US20060167048A1 (en) |
EP (1) | EP1539695A1 (en) |
JP (1) | JP2005539038A (en) |
AU (1) | AU2003253535A1 (en) |
SE (1) | SE0202483D0 (en) |
WO (1) | WO2004018425A1 (en) |
Cited By (64)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006056471A1 (en) | 2004-11-29 | 2006-06-01 | Novartis Ag | 5-hydroxy-benzothiazole derivatives having beta-2-adrenorecptor agonist activity |
WO2006066948A1 (en) * | 2004-12-20 | 2006-06-29 | Schering Aktiengesellschaft | Piperidine derivatives as antagonists of the cc chemokine receptor ccr1 and their use as anti-inflammatory agents |
WO2006122806A2 (en) | 2005-05-20 | 2006-11-23 | Novartis Ag | 1,3-dihydro-imidazo [4,5-c] quinolin-2-ones as lipid kinase inhibitors |
WO2007045573A1 (en) | 2005-10-19 | 2007-04-26 | F. Hoffmann-La Roche Ag | Phenyl-acetamide nnrt inhibitors |
WO2007049771A1 (en) * | 2005-10-28 | 2007-05-03 | Ono Pharmaceutical Co., Ltd. | Compound containing basic group and use thereof |
WO2007071400A1 (en) | 2005-12-22 | 2007-06-28 | Novartis Ag | Pyrazine derivatives as epithelial sodium channel blocker |
WO2007121920A2 (en) | 2006-04-21 | 2007-11-01 | Novartis Ag | Purine derivatives for use as adenosin a2a receptor agonists |
WO2008019968A1 (en) | 2006-08-16 | 2008-02-21 | F. Hoffmann-La Roche Ag | Non-nucleoside reverse transcriptase inhibitors |
WO2008037477A1 (en) | 2006-09-29 | 2008-04-03 | Novartis Ag | Pyrazolopyrimidines as p13k lipid kinase inhibitors |
WO2008071587A2 (en) | 2006-12-13 | 2008-06-19 | F. Hoffmann-La Roche Ag | 2-(piperidin-4-yl)-4-phenoxy- or phenylamino-pyrimidine derivatives as non-nucleoside reverse transcriptase inhibitors |
WO2009010478A2 (en) * | 2007-07-13 | 2009-01-22 | Euroscreen S.A. | Use of piperidine derivatives as agonists of chemokine receptor activity |
WO2009010480A1 (en) * | 2007-07-13 | 2009-01-22 | Euroscreen S.A. | 1-{2-[(diphenyl)amino]-ethyl}-piperidine-4-carboxylic acid benzylamide derivatives and related compounds as ccr5 agonists for the treatment of immune and inflammatory diseases |
WO2009052708A1 (en) * | 2007-10-18 | 2009-04-30 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | 1-(3-amino-propyl)-piperidin-4-yl-amides, pharmaceutical compositions, processes for their preparation and uses |
WO2009150137A2 (en) | 2008-06-10 | 2009-12-17 | Novartis Ag | Organic compounds |
WO2010088335A1 (en) | 2009-01-29 | 2010-08-05 | Novartis Ag | Substituted benzimidazoles for the treatment of astrocytomas |
CN101812054A (en) * | 2010-04-30 | 2010-08-25 | 北京工业大学 | 1-acetyl-N-phenyl-N-(3-(4-(3-phenyl-1-H-pyrazole-5-radial)piperidine-1-radical)propyl)-4-amide derivative and preparation method thereof |
US7790747B2 (en) * | 2005-06-15 | 2010-09-07 | Genzyme Corporation | Chemokine receptor binding compounds |
EP2253612A1 (en) | 2005-04-14 | 2010-11-24 | Novartis AG | Organic compounds |
EP2279777A2 (en) | 2007-01-10 | 2011-02-02 | Irm Llc | Compounds and compositions as channel activating protease inhibitors |
WO2011015652A1 (en) | 2009-08-07 | 2011-02-10 | Novartis Ag | 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives as c-met tyrosine kinase modulators |
WO2011018454A1 (en) | 2009-08-12 | 2011-02-17 | Novartis Ag | Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation |
WO2011022439A1 (en) | 2009-08-17 | 2011-02-24 | Intellikine, Inc. | Heterocyclic compounds and uses thereof |
WO2011020861A1 (en) | 2009-08-20 | 2011-02-24 | Novartis Ag | Heterocyclic oxime compounds |
EP2292619A1 (en) | 2004-10-22 | 2011-03-09 | Novartis AG | Purine derivatives for use as adenonsin A-2A receptor agonists |
WO2011050325A1 (en) | 2009-10-22 | 2011-04-28 | Vertex Pharmaceuticals Incorporated | Compositions for treatment of cystic fibrosis and other chronic diseases |
EP2332933A1 (en) | 2007-05-07 | 2011-06-15 | Novartis AG | Epithelial sodium channel (ENaC) inhibitors |
WO2011079007A1 (en) | 2009-12-23 | 2011-06-30 | Ironwood Pharmaceuticals, Inc. | Crth2 modulators |
WO2011113894A1 (en) | 2010-03-19 | 2011-09-22 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of cf |
WO2012009137A1 (en) | 2010-07-12 | 2012-01-19 | Ironwood Pharmaceuticals, Inc. | Crth2 modulators |
WO2012007539A1 (en) | 2010-07-14 | 2012-01-19 | Novartis Ag | Ip receptor agonist heterocyclic compounds |
WO2012009134A1 (en) | 2010-07-12 | 2012-01-19 | Ironwood Pharmaceuticals, Inc. | Crth2 modulators |
WO2012035158A1 (en) | 2010-09-17 | 2012-03-22 | Novartis Ag | Pyrazine derivatives as enac blockers |
EP2444120A1 (en) | 2007-12-10 | 2012-04-25 | Novartis AG | Spirocyclic amiloride analogues as ENac blockers |
WO2012107500A1 (en) | 2011-02-10 | 2012-08-16 | Novartis Ag | [1, 2, 4] triazolo [4, 3 -b] pyridazine compounds as inhibitors of the c-met tyrosine kinase |
WO2012116237A2 (en) | 2011-02-23 | 2012-08-30 | Intellikine, Llc | Heterocyclic compounds and uses thereof |
EP2532679A1 (en) | 2005-10-21 | 2012-12-12 | Novartis AG | Human antibodies against il13 and therapeutic uses |
WO2013030802A1 (en) | 2011-09-01 | 2013-03-07 | Novartis Ag | Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension |
WO2013038381A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine/pyrazine amide derivatives |
WO2013038362A1 (en) | 2011-09-15 | 2013-03-21 | Novartis Ag | 6 - substituted 3 - (quinolin- 6 - ylthio) - [1,2,4] triazolo [4, 3 -a] pyradines as tyrosine kinase |
WO2013038390A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | N-substituted heterocyclyl carboxamides |
WO2013038373A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
WO2013038378A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
WO2013038386A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Heterocyclic compounds for the treatment of cystic fibrosis |
WO2013105058A1 (en) | 2012-01-13 | 2013-07-18 | Novartis Ag | 7,8- dihydropyrido [3, 4 - b] pyrazines as ip receptor agonists for the treatment of pulmonary arterial hypertension (pah) and related disorders |
WO2013105057A1 (en) | 2012-01-13 | 2013-07-18 | Novartis Ag | Fused pyrroles as ip receptor agonists for the treatment of pulmonary arterial hypertension (pah) and related disorders |
WO2013105063A1 (en) | 2012-01-13 | 2013-07-18 | Novartis Ag | Fused piperidines as ip receptor agonists for the treatment of pulmonary arterial hypertension (pah) and related disorders |
WO2013105065A1 (en) | 2012-01-13 | 2013-07-18 | Novartis Ag | Fused piperidines as ip receptor agonists for the treatment of pah and related disorders |
WO2013105061A1 (en) | 2012-01-13 | 2013-07-18 | Novartis Ag | Fused dihydropyrido [2,3 -b] pyrazines as ip receptor agonists for the treatment of pulmonary arterial hypertension (pah) and related disorders |
WO2013105066A1 (en) | 2012-01-13 | 2013-07-18 | Novartis Ag | Salts of an ip receptor agonist |
WO2013140319A1 (en) | 2012-03-19 | 2013-09-26 | Novartis Ag | Crystalline form of a succinate salt |
WO2013149581A1 (en) | 2012-04-03 | 2013-10-10 | Novartis Ag | Combination products with tyrosine kinase inhibitors and their use |
WO2014125413A1 (en) | 2013-02-13 | 2014-08-21 | Novartis Ag | Ip receptor agonist heterocyclic compounds |
WO2014132220A1 (en) | 2013-03-01 | 2014-09-04 | Novartis Ag | Solid forms of bicyclic heterocyclic derivatives as pdgf receptor mediators |
WO2014151147A1 (en) | 2013-03-15 | 2014-09-25 | Intellikine, Llc | Combination of kinase inhibitors and uses thereof |
CN102140104B (en) * | 2010-02-03 | 2014-11-12 | 中国科学院上海药物研究所 | 1-(3-(S)-amino propyl)-piperidine-4-aminoacid amide compound and pharmaceutical composition thereof as well as preparation methods and applications of compound and pharmaceutical composition |
WO2015084804A1 (en) | 2013-12-03 | 2015-06-11 | Novartis Ag | Combination of mdm2 inhibitor and braf inhibitor and their use |
WO2015162456A1 (en) | 2014-04-24 | 2015-10-29 | Novartis Ag | Amino pyridine derivatives as phosphatidylinositol 3-kinase inhibitors |
WO2015162461A1 (en) | 2014-04-24 | 2015-10-29 | Novartis Ag | Pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors |
WO2015162459A1 (en) | 2014-04-24 | 2015-10-29 | Novartis Ag | Amino pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors |
US9174994B2 (en) | 2011-11-23 | 2015-11-03 | Intellikine, Llc | Enhanced treatment regimens using mTor inhibitors |
WO2016011956A1 (en) | 2014-07-25 | 2016-01-28 | Novartis Ag | Combination therapy |
WO2016016822A1 (en) | 2014-07-31 | 2016-02-04 | Novartis Ag | Combination therapy |
WO2020250116A1 (en) | 2019-06-10 | 2020-12-17 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of cf, copd, and bronchiectasis |
WO2021038426A1 (en) | 2019-08-28 | 2021-03-04 | Novartis Ag | Substituted 1,3-phenyl heteroaryl derivatives and their use in the treatment of disease |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040192738A1 (en) * | 2003-03-18 | 2004-09-30 | Aventis Pharma Deutschland Gmbh | 2-(Butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl] benzamide, its use as a medicament, and pharmaceutical preparations comprising it |
EP2124996A4 (en) | 2007-02-20 | 2010-03-24 | Merrimack Pharmaceuticals Inc | Methods of treating multiple sclerosis by administration of alpha-fetoprotein in combination with an integrin antagonist |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1013276A1 (en) * | 1998-12-23 | 2000-06-28 | Pfizer Inc. | Aminoazacycloalkanes as CCR5 modulators |
WO2000076513A1 (en) * | 1999-06-11 | 2000-12-21 | Merck & Co., Inc. | Cyclopentyl modulators of chemokine receptor activity |
WO2000076973A1 (en) * | 1999-06-11 | 2000-12-21 | Merck & Co., Inc. | N-cyclopentyl modulators of chemokine receptor activity |
WO2001087839A1 (en) * | 2000-05-17 | 2001-11-22 | Astrazeneca Ab | Pharmaceutically active piperidine derivatives, in particular as modulators of chemokine receptor activity |
WO2002070479A1 (en) * | 2001-03-01 | 2002-09-12 | Astrazeneca Ab | N-4-piperidinyl compounds as ccr5 modulators |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6288083B1 (en) * | 1998-09-04 | 2001-09-11 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
GB0107228D0 (en) * | 2001-03-22 | 2001-05-16 | Astrazeneca Ab | Chemical compounds |
SE0103819D0 (en) * | 2001-11-15 | 2001-11-15 | Astrazeneca Ab | Chemical compounds |
-
2002
- 2002-08-21 SE SE0202483A patent/SE0202483D0/en unknown
-
2003
- 2003-08-19 EP EP03792923A patent/EP1539695A1/en not_active Withdrawn
- 2003-08-19 JP JP2004530710A patent/JP2005539038A/en active Pending
- 2003-08-19 WO PCT/SE2003/001287 patent/WO2004018425A1/en not_active Application Discontinuation
- 2003-08-19 AU AU2003253535A patent/AU2003253535A1/en not_active Abandoned
- 2003-08-19 US US10/525,121 patent/US20060167048A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1013276A1 (en) * | 1998-12-23 | 2000-06-28 | Pfizer Inc. | Aminoazacycloalkanes as CCR5 modulators |
WO2000076513A1 (en) * | 1999-06-11 | 2000-12-21 | Merck & Co., Inc. | Cyclopentyl modulators of chemokine receptor activity |
WO2000076973A1 (en) * | 1999-06-11 | 2000-12-21 | Merck & Co., Inc. | N-cyclopentyl modulators of chemokine receptor activity |
WO2001087839A1 (en) * | 2000-05-17 | 2001-11-22 | Astrazeneca Ab | Pharmaceutically active piperidine derivatives, in particular as modulators of chemokine receptor activity |
WO2002070479A1 (en) * | 2001-03-01 | 2002-09-12 | Astrazeneca Ab | N-4-piperidinyl compounds as ccr5 modulators |
Non-Patent Citations (2)
Title |
---|
AKIRA NAYA ET AL.: "Design, Synthesis and Discovery of a Novel CCR1 Antagonist", J. MED. CHEM., vol. 44, 2001, pages 1429 - 1435, XP002946303 * |
JOHN T. LAI: "Totally hindered phenols. 2,6-Di-t-butyl-4-(1,1-dialkyl-1-acetamide)-phenols and their persistent phenoxy radicals", TETRAHEDRON LETTERS, vol. 42, 2001, pages 557 - 560, XP004314733 * |
Cited By (82)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2292619A1 (en) | 2004-10-22 | 2011-03-09 | Novartis AG | Purine derivatives for use as adenonsin A-2A receptor agonists |
EP2305659A1 (en) | 2004-11-29 | 2011-04-06 | Novartis AG | 5-hydroxy-benzothiazole derivatives having beta-2-adrenoreceptor agonist activity |
WO2006056471A1 (en) | 2004-11-29 | 2006-06-01 | Novartis Ag | 5-hydroxy-benzothiazole derivatives having beta-2-adrenorecptor agonist activity |
WO2006066948A1 (en) * | 2004-12-20 | 2006-06-29 | Schering Aktiengesellschaft | Piperidine derivatives as antagonists of the cc chemokine receptor ccr1 and their use as anti-inflammatory agents |
EP2253612A1 (en) | 2005-04-14 | 2010-11-24 | Novartis AG | Organic compounds |
WO2006122806A2 (en) | 2005-05-20 | 2006-11-23 | Novartis Ag | 1,3-dihydro-imidazo [4,5-c] quinolin-2-ones as lipid kinase inhibitors |
EP2292617A1 (en) | 2005-05-20 | 2011-03-09 | Novartis AG | 1,3-dihydro-imidazo[4,5-c]quinolin-2-ones as lipid kinase and/or pi3 kinase inhibitors |
EP2270008A1 (en) | 2005-05-20 | 2011-01-05 | Novartis AG | 1,3-dihydro-imidazo[4,5-c]quinolin-2-ones as lipid kinase and/or pi3 kinases inhibitors |
US7790747B2 (en) * | 2005-06-15 | 2010-09-07 | Genzyme Corporation | Chemokine receptor binding compounds |
WO2007045573A1 (en) | 2005-10-19 | 2007-04-26 | F. Hoffmann-La Roche Ag | Phenyl-acetamide nnrt inhibitors |
EP2532677A1 (en) | 2005-10-21 | 2012-12-12 | Novartis AG | Human antibodies against il13 and therapeutic uses |
EP2532679A1 (en) | 2005-10-21 | 2012-12-12 | Novartis AG | Human antibodies against il13 and therapeutic uses |
US8318931B2 (en) | 2005-10-28 | 2012-11-27 | Ono Pharmaceutical Co., Ltd. | Chemokine receptor antagonists and use thereof |
EP2657235A1 (en) * | 2005-10-28 | 2013-10-30 | Ono Pharmaceutical Co., Ltd. | Compound containing basic group and use thereof |
US8614323B2 (en) | 2005-10-28 | 2013-12-24 | Ono Pharmaceutical Co., Ltd. | Chemokine receptor antagonists and use thereof |
US8871210B2 (en) | 2005-10-28 | 2014-10-28 | Ono Pharmaceutical Co., Ltd. | Chemokine receptor antagonists and use thereof |
WO2007049771A1 (en) * | 2005-10-28 | 2007-05-03 | Ono Pharmaceutical Co., Ltd. | Compound containing basic group and use thereof |
WO2007071400A1 (en) | 2005-12-22 | 2007-06-28 | Novartis Ag | Pyrazine derivatives as epithelial sodium channel blocker |
EP2322525A1 (en) | 2006-04-21 | 2011-05-18 | Novartis AG | Purine derivatives for use as adenosin A2A receptor agonists |
WO2007121920A2 (en) | 2006-04-21 | 2007-11-01 | Novartis Ag | Purine derivatives for use as adenosin a2a receptor agonists |
WO2008019968A1 (en) | 2006-08-16 | 2008-02-21 | F. Hoffmann-La Roche Ag | Non-nucleoside reverse transcriptase inhibitors |
WO2008037477A1 (en) | 2006-09-29 | 2008-04-03 | Novartis Ag | Pyrazolopyrimidines as p13k lipid kinase inhibitors |
WO2008071587A2 (en) | 2006-12-13 | 2008-06-19 | F. Hoffmann-La Roche Ag | 2-(piperidin-4-yl)-4-phenoxy- or phenylamino-pyrimidine derivatives as non-nucleoside reverse transcriptase inhibitors |
EP2279777A2 (en) | 2007-01-10 | 2011-02-02 | Irm Llc | Compounds and compositions as channel activating protease inhibitors |
EP2332933A1 (en) | 2007-05-07 | 2011-06-15 | Novartis AG | Epithelial sodium channel (ENaC) inhibitors |
WO2009010480A1 (en) * | 2007-07-13 | 2009-01-22 | Euroscreen S.A. | 1-{2-[(diphenyl)amino]-ethyl}-piperidine-4-carboxylic acid benzylamide derivatives and related compounds as ccr5 agonists for the treatment of immune and inflammatory diseases |
WO2009010478A2 (en) * | 2007-07-13 | 2009-01-22 | Euroscreen S.A. | Use of piperidine derivatives as agonists of chemokine receptor activity |
WO2009010478A3 (en) * | 2007-07-13 | 2010-03-04 | Euroscreen S.A. | Use of piperidine derivatives as agonists of chemokine receptor activity |
WO2009052708A1 (en) * | 2007-10-18 | 2009-04-30 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | 1-(3-amino-propyl)-piperidin-4-yl-amides, pharmaceutical compositions, processes for their preparation and uses |
CN101412692B (en) * | 2007-10-18 | 2012-10-17 | 中国科学院上海药物研究所 | 1-(3-amino propyl) piperidine-4-aminoamide compounds, and pharmaceutical composition, preparation and use thereof |
EP2444120A1 (en) | 2007-12-10 | 2012-04-25 | Novartis AG | Spirocyclic amiloride analogues as ENac blockers |
EP2520574A1 (en) | 2007-12-10 | 2012-11-07 | Novartis AG | Amiloride analogues substituted on the cyclic guanidine moiety as ENaC blockers for treating respiratory diseases |
WO2009150137A2 (en) | 2008-06-10 | 2009-12-17 | Novartis Ag | Organic compounds |
WO2010088335A1 (en) | 2009-01-29 | 2010-08-05 | Novartis Ag | Substituted benzimidazoles for the treatment of astrocytomas |
WO2011015652A1 (en) | 2009-08-07 | 2011-02-10 | Novartis Ag | 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives as c-met tyrosine kinase modulators |
WO2011018454A1 (en) | 2009-08-12 | 2011-02-17 | Novartis Ag | Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation |
WO2011022439A1 (en) | 2009-08-17 | 2011-02-24 | Intellikine, Inc. | Heterocyclic compounds and uses thereof |
WO2011020861A1 (en) | 2009-08-20 | 2011-02-24 | Novartis Ag | Heterocyclic oxime compounds |
WO2011050325A1 (en) | 2009-10-22 | 2011-04-28 | Vertex Pharmaceuticals Incorporated | Compositions for treatment of cystic fibrosis and other chronic diseases |
EP2813227A1 (en) | 2009-10-22 | 2014-12-17 | Vertex Pharmaceuticals Incorporated | Compositions for treatment of cystic fibrosis and other chronic diseases |
US8674115B2 (en) | 2009-12-23 | 2014-03-18 | Ironwood Pharmaceuticals, Inc. | CRTH2 modulators |
WO2011079007A1 (en) | 2009-12-23 | 2011-06-30 | Ironwood Pharmaceuticals, Inc. | Crth2 modulators |
CN102140104B (en) * | 2010-02-03 | 2014-11-12 | 中国科学院上海药物研究所 | 1-(3-(S)-amino propyl)-piperidine-4-aminoacid amide compound and pharmaceutical composition thereof as well as preparation methods and applications of compound and pharmaceutical composition |
WO2011113894A1 (en) | 2010-03-19 | 2011-09-22 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of cf |
EP2845593A1 (en) | 2010-03-19 | 2015-03-11 | Novartis AG | Pyridine and pyrazine derivative for the treatment of chronic obstructive pulmonary disease |
CN101812054A (en) * | 2010-04-30 | 2010-08-25 | 北京工业大学 | 1-acetyl-N-phenyl-N-(3-(4-(3-phenyl-1-H-pyrazole-5-radial)piperidine-1-radical)propyl)-4-amide derivative and preparation method thereof |
WO2012009137A1 (en) | 2010-07-12 | 2012-01-19 | Ironwood Pharmaceuticals, Inc. | Crth2 modulators |
WO2012009134A1 (en) | 2010-07-12 | 2012-01-19 | Ironwood Pharmaceuticals, Inc. | Crth2 modulators |
WO2012007539A1 (en) | 2010-07-14 | 2012-01-19 | Novartis Ag | Ip receptor agonist heterocyclic compounds |
WO2012035158A1 (en) | 2010-09-17 | 2012-03-22 | Novartis Ag | Pyrazine derivatives as enac blockers |
WO2012107500A1 (en) | 2011-02-10 | 2012-08-16 | Novartis Ag | [1, 2, 4] triazolo [4, 3 -b] pyridazine compounds as inhibitors of the c-met tyrosine kinase |
US9127000B2 (en) | 2011-02-23 | 2015-09-08 | Intellikine, LLC. | Heterocyclic compounds and uses thereof |
WO2012116237A2 (en) | 2011-02-23 | 2012-08-30 | Intellikine, Llc | Heterocyclic compounds and uses thereof |
WO2013030802A1 (en) | 2011-09-01 | 2013-03-07 | Novartis Ag | Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension |
WO2013038362A1 (en) | 2011-09-15 | 2013-03-21 | Novartis Ag | 6 - substituted 3 - (quinolin- 6 - ylthio) - [1,2,4] triazolo [4, 3 -a] pyradines as tyrosine kinase |
WO2013038373A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
WO2013038390A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | N-substituted heterocyclyl carboxamides |
WO2013038381A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine/pyrazine amide derivatives |
WO2013038386A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Heterocyclic compounds for the treatment of cystic fibrosis |
WO2013038378A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
US9669032B2 (en) | 2011-11-23 | 2017-06-06 | Intellikine Llc | Enhanced treatment regimens using mTOR inhibitors |
US9174994B2 (en) | 2011-11-23 | 2015-11-03 | Intellikine, Llc | Enhanced treatment regimens using mTor inhibitors |
WO2013105063A1 (en) | 2012-01-13 | 2013-07-18 | Novartis Ag | Fused piperidines as ip receptor agonists for the treatment of pulmonary arterial hypertension (pah) and related disorders |
WO2013105065A1 (en) | 2012-01-13 | 2013-07-18 | Novartis Ag | Fused piperidines as ip receptor agonists for the treatment of pah and related disorders |
WO2013105061A1 (en) | 2012-01-13 | 2013-07-18 | Novartis Ag | Fused dihydropyrido [2,3 -b] pyrazines as ip receptor agonists for the treatment of pulmonary arterial hypertension (pah) and related disorders |
WO2013105057A1 (en) | 2012-01-13 | 2013-07-18 | Novartis Ag | Fused pyrroles as ip receptor agonists for the treatment of pulmonary arterial hypertension (pah) and related disorders |
WO2013105058A1 (en) | 2012-01-13 | 2013-07-18 | Novartis Ag | 7,8- dihydropyrido [3, 4 - b] pyrazines as ip receptor agonists for the treatment of pulmonary arterial hypertension (pah) and related disorders |
WO2013105066A1 (en) | 2012-01-13 | 2013-07-18 | Novartis Ag | Salts of an ip receptor agonist |
WO2013140319A1 (en) | 2012-03-19 | 2013-09-26 | Novartis Ag | Crystalline form of a succinate salt |
WO2013149581A1 (en) | 2012-04-03 | 2013-10-10 | Novartis Ag | Combination products with tyrosine kinase inhibitors and their use |
EP3964513A1 (en) | 2012-04-03 | 2022-03-09 | Novartis AG | Combination products with tyrosine kinase inhibitors and their use |
WO2014125413A1 (en) | 2013-02-13 | 2014-08-21 | Novartis Ag | Ip receptor agonist heterocyclic compounds |
WO2014132220A1 (en) | 2013-03-01 | 2014-09-04 | Novartis Ag | Solid forms of bicyclic heterocyclic derivatives as pdgf receptor mediators |
WO2014151147A1 (en) | 2013-03-15 | 2014-09-25 | Intellikine, Llc | Combination of kinase inhibitors and uses thereof |
WO2015084804A1 (en) | 2013-12-03 | 2015-06-11 | Novartis Ag | Combination of mdm2 inhibitor and braf inhibitor and their use |
WO2015162459A1 (en) | 2014-04-24 | 2015-10-29 | Novartis Ag | Amino pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors |
WO2015162461A1 (en) | 2014-04-24 | 2015-10-29 | Novartis Ag | Pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors |
WO2015162456A1 (en) | 2014-04-24 | 2015-10-29 | Novartis Ag | Amino pyridine derivatives as phosphatidylinositol 3-kinase inhibitors |
WO2016011956A1 (en) | 2014-07-25 | 2016-01-28 | Novartis Ag | Combination therapy |
WO2016016822A1 (en) | 2014-07-31 | 2016-02-04 | Novartis Ag | Combination therapy |
WO2020250116A1 (en) | 2019-06-10 | 2020-12-17 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of cf, copd, and bronchiectasis |
WO2021038426A1 (en) | 2019-08-28 | 2021-03-04 | Novartis Ag | Substituted 1,3-phenyl heteroaryl derivatives and their use in the treatment of disease |
Also Published As
Publication number | Publication date |
---|---|
EP1539695A1 (en) | 2005-06-15 |
JP2005539038A (en) | 2005-12-22 |
AU2003253535A1 (en) | 2004-03-11 |
US20060167048A1 (en) | 2006-07-27 |
SE0202483D0 (en) | 2002-08-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2004018425A1 (en) | N-4-piperidinyl compounds as ccr5 modulators | |
US6960602B2 (en) | Piperidine derivatives as modulators of chemokine receptors | |
KR20060128992A (en) | Novel piperidines as chemokine modulators (ccr) | |
AU2003288856B2 (en) | Novel piperidine derivatives as modulators of chemokine receptor CCR5 | |
EP1368314A1 (en) | N-4-piperidinyl compounds as ccr5 modulators | |
EP1572683B1 (en) | Novel piperidine derivatives as modulators of chemokine receptor ccr5 | |
EP1572684A1 (en) | Novel piperidine derivatives as modulators of chemokine receptor ccr5 | |
KR20060009318A (en) | Chemical compounds | |
US20080200460A1 (en) | Chemical Compounds | |
EP1648871B1 (en) | Piperidine or 8-aza-bicyclo 3.2.1 oct-3-yl derivatives useful as modulators of chemokine receptor activity | |
EP1654229B1 (en) | Piperidine derivatives as ccr5 receptor modulators | |
WO2005058881A1 (en) | Chemical compounds | |
ZA200504616B (en) | Novel piperidine derivatives as modulators of chemokine receptor CCR5 |
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 BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE 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 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): GH GM KE LS MW MZ 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 IT LU MC NL 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 | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2003792923 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2006167048 Country of ref document: US Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10525121 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004530710 Country of ref document: JP |
|
WWP | Wipo information: published in national office |
Ref document number: 2003792923 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2003792923 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 10525121 Country of ref document: US |