WO1996031469A1 - Nouveaux composes heterocycliques - Google Patents

Nouveaux composes heterocycliques Download PDF

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Publication number
WO1996031469A1
WO1996031469A1 PCT/DK1996/000142 DK9600142W WO9631469A1 WO 1996031469 A1 WO1996031469 A1 WO 1996031469A1 DK 9600142 W DK9600142 W DK 9600142W WO 9631469 A1 WO9631469 A1 WO 9631469A1
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WO
WIPO (PCT)
Prior art keywords
propyl
compound according
ylidene
piperidinecarboxylic acid
compound
Prior art date
Application number
PCT/DK1996/000142
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English (en)
Inventor
Henrik Sune Andersen
Knud Erik Andersen
Peter Madsen
Tine Krogh JØRGENSEN
Rolf Hohlweg
Hans Petersen
Uffe Bang Olsen
Original Assignee
Novo Nordisk A/S
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 Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU52707/96A priority Critical patent/AU5270796A/en
Publication of WO1996031469A1 publication Critical patent/WO1996031469A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel N-substituted azaheterocyclic carboxylic acids and esters thereof in which a substituted alkyl chain forms part of the N- substituent or salts thereof, to methods for their preparation, to comp ositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation.
  • the invention also relates to the use of the present compounds for the treatment of insulin resistance in non-insulin- dependent diabetes mellitus (NIDDM) or aging, the present compounds knowing to interfere with neuropeptide containing C-fibres and hence inhibit the secretion and circulation of insulin antagonizing peptides li e CGRP or amylin.
  • NIDDM non-insulin- dependent diabetes mellitus
  • the nervous system exerts a profound effect on the inflammatory response
  • Antidromic stimulation of sensory nerves results in localized vasodilation and increased vascular permeability (Janecso et al. Br. J Pharmacol 1967, 31 , 138- 151) and a similar response is observed following injection of peptides known to be present in sensory nerves
  • peptides released from sensory nerve endings mediate many inflammatory responses in tissues like skin, joint, urinary tract, eye, meninges, gastro-intestinal and respiratory tracts
  • inhibition of sensory nerve peptide release and/or activity may be useful in treatment of, for example arthritis, dermatitis, rhinitis asthma, cystitis, gingivitis, thrombo-phlelitis, glaucoma, gastro-intestinal diseases or migraine
  • the potent effects of CGRP on skeletal muscle glycogen sy ⁇ thase activity and muscle glucose metabolism together with the notion that this peptide is released from the
  • This peptide may represent an important physiological modulator of intracellular glucose trafficking in physiological conditions, such as exercise, and may also contribute to the decreased insulin action and skeletal muscle glycogen synthase in pathophysiological conditions like NIDDM or aging-associated obesity (Melnyk et al Obesity Res 3, 337-344 1995) where circulating plasma levels of CGRP are markedly increased. Hence inhibition of release and/or activity of the neuropeptide CGRP may be useful in the treatment of insulin resistance related to type 2 diabetes or aging.
  • N-substituted azaheterocyclic carboxylic acids in which an oxime ether group and vinyl ether group forms part of the N-substituent respectively are claimed as inhibitors of GABA uptake
  • N-substituted azacyciic carboxylic acids are claimed as GABA uptake inhibitors
  • Tne present invention relates to novel N-substituted azaheterocyclic carboxylic acids and esters thereof of formula I
  • R and R 2 independently are hydrogen, halogen, trifluoromethyl, hydroxy, Ca. 6 -alkyl or C ⁇ -alkoxy;
  • a together with the double bond represents a cyclic system selected from benzene, pyridine, pyrimidine, pyrazine, pyridazine, thiophene, pyrrole, furan, oxazole, isoxazole, imidazole, pyrazole or thiazole; and
  • B together with the double bond represents a cyclic system selected from pyridine, pyrimidine, pyrazine, pyridazine, thiophene, pyrrole, furan, oxazole, isoxazole, imidazole, pyrazole or thiazole; and C together with the double bond represents a bicyclic system selected from naphthalene, quinoline, isoquinoline, dihydrobenzofuran, indole, benzofuran or benzothiophene; and
  • R 9 independently are hydrogen or C, .6 -alkyl; and r is , 2 or 3; and m is 1 or 2; and n is 1 when m is 1 and n is 0 when m is 2; and
  • R 3 and R 4 each represents hydrogen or may - when m is 2 - together represent a bond
  • R 5 is -OH or Ca .6 -alkoxy; or a pharmaceutically acceptable salt thereof.
  • the compounds of formula I may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separated by means of standard methods such as chromatographic techniques or frac ⁇ tional crystallization of suitable salts.
  • the compounds of formula I exist as the individual geometric or optical isomers.
  • the compounds according to the invention may optionally exist as pharmaceuti ⁇ cally acceptable acid addition salts or - when the carboxylic acid group is not esterified - as pharmaceutically acceptable metal salts or - optionally alkylated - ammonium salts.
  • salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are hereby incorporated by reference.
  • .6 -alkyr refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms such as e g methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1 ,2-d ⁇ methylpropyl, 2,2-d ⁇ methylpropyl and 1 ,2,2-tr ⁇ methylpropyl
  • C.. 6 -alkoxy refers to a straight or branched monovalent substituent comprising a C, 6 -alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e g methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy
  • halogen means fluorine, chlorine, bromine or iodine
  • the term "patient” includes any mammal which could benefit from treatment of neurogenic pain or inflammation or insulin resistance in NIDDM.
  • the term particularly refers to a human patient, but is not intended to be so limited.
  • the novel compounds of formula I inhibit neurogenic inflammation which involves the release of neuropeptides from peripheral and central endings of sensory C-fibres. Experimentally this can be demonstrated in animal models of formalin induced pain or paw oedema (Wheeler and Cowan, Agents Actions 1991 , 34, 264-269) in which the novel compounds of formula I exhibit a potent inhibitory effect.
  • Compounds of formula I may be used to treat all painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation, i.e.: Acutely painful conditions exemplified by migraine, postoperative pain, burns, bruises, post-herpetic pain (Zoster) and pain as it is generally associated with acute inflammation; chronic, painful and/or inflammatory conditions exemplified by various types of neuropathy (diabetic, post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, coughing, asthma, chronic pancreatitis, inflam ⁇ matory skin disease including psoriasis and autoimmune dermatoses, osteoporotic pain
  • Acutely painful conditions exemplified by migraine, postoperative pain, burns, bruises, post-herpetic pain (Zoster) and pain
  • the compounds of general formula I im- proves the glucose tolerance in diabetic ob/ob mice and that this may result from the reduced release of CGRP from peripheral nervous endings Hence the compounds of general formula I may be used in the treatment of NIDDM as well as aging-associated obesity. Experimentally this has been demonstrated by the subcutaneous administration of glucose into ob/ob mice with or without previous oral treatment with a compound of general formula I
  • the compounds of formula I may be prepared by the following methods Method A:
  • a compound of formula II wherein R 1 , R 2 , X, Y, A, B and r are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate may be reacted with an azaheterocyclic compound of formula III wherein R 3 , R 4 , R 5 , m and n are as defined above.
  • This alkylation reaction may be carried out in a solvent such as acetone, dibutylether, 2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran (THF) or toluene in the presence of a base e.g.
  • esters have been prepared in which R 5 is alkoxy
  • compounds of formula I wherein R 5 is OH may be prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol, for example, for about 0.5 to 6 h.
  • a compound of formula II wherein R 1 , R 2 , X, Y, C and r are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate may be reacted with an azaheterocyclic compound of formula III wherein R 3 , R 4 , R 5 , m and n are as defined above.
  • This alkylation reaction may be carried out in a solvent such as acetone, dibutylether, 2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran (THF) or toluene in the presence of a base e.g.
  • esters have been prepared in which R 5 is alkoxy
  • compounds of formula I wherein R 5 is OH may be prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol, for example, for about 0.5 to 6 h
  • mice About 20 g NMRI female mice were injected 20 ⁇ l 1 % formalin into the left hind paw. The animals were then placed on a heated (31°C) table, and the pain response was scored. After 1 h they were killed and bled. Left and right hind paws were removed and the weight difference between the paws was used as indication of the oedema response of the formalin injected paw.
  • dosage forms suitable for oral administra ⁇ tion comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of formula I admixed with a pharmaceutical carrier or diluent.
  • the compounds of formula I may be administered in a pharmaceutically accept ⁇ able acid addition salt form or where possible as a metal or a lower alkylammo- nium salt. Such salt forms exhibit approximately the same order of activity as the free base forms.
  • This invention also relates to pharmaceutical compositions comprising a com ⁇ pound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent.
  • the compo ⁇ sitions containing the compounds of this invention may be prepared by conven- tional techniques and appear in conventional forms, for example capsules, tablets, solutions or suspensions.
  • the pharmaceutical carrier employed may be a conventional solid or liquid carrier.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.
  • liquid carriers are syrup, peanut oil, olive oil and water.
  • the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the compounds of this invention are dispensed in unit dosage form comprising 50-200 mg of active ingredient in or together with a pharmaceuti ⁇ cally acceptable carrier per unit dosage.
  • the dosage of the compounds according to this invention is 1-500 mg/day, e.g. about 100 mg per dose, when administered to patients, e.g. humans, as a drug.
  • a typical tablet which may be prepared by conventional tabletting techniques contains
  • Active compound (as free compound 100 mg or salt thereof)
  • the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • oral or parenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • Triethyl phosphite (154 ml) was added to the above crude bromomethyl- thiophene and the mixture was heated at reflux temperature for 4 h and then allowed to cool to ambient temperature. The mixture was distilled in vacuo to give 123.5 g diethyl 2-bromo-3-thiophenylmethylphosphonate as an oil.
  • Potassium iej_t-butoxide (56.1 g, 0.5 mol) was suspended in toluene (1 I) under an atmosphere of nitrogen and the mixture was cooled to 5 °C.
  • a solution of the above phosphonate (123 g, 0.39 mol) and thiophene-3-carboxaldehyde (43.8 g, 0.39 mol) in toluene (200 ml) was added dropwise over 1 h, keeping the temperature below 10 °C. Stirring was continued at 5 °C for 0.5 h and then at ambient temperature for 16 h.
  • the reaction mixture was poured into icewater (1.2 I), the phases were separated and the aqueous phase was extracted with toluene (0.5 I).
  • E-(R)-1-(3-(10,11-Dihydro-5H-benzo[4,5]cyclohepta[2, 1-c]pyridin-5-ylidene)-1 - propyl)-3-piperidinecarboxylic acid ethyl ester (0.15 g, 0.38 mmol, prepared as described in example 7) was dissolved in ethanol (25 ml) and a solution of sodium hydroxide (18 mg, 0.46 mmol) in water (10 ml) was added. The reac ⁇ tion mixture was stirred for 48 h at room temperature and the solvent was removed in vacuo. Water (70 ml) was added and the mixture was washed with diethyl ether (50 ml).
  • the aqueous phase was evaporated in vacuo.
  • the residue was dissolved in 2-propanol (20 ml), filtered, and the solvent was evaporated in vacuo.
  • the residue was suspended in acetone (10 ml) and stirred for 2 h at room temperature. The precipitate was filtered and dried in vacuo at 50°C for 24 h, to give 0.04 g (24%) of the title compound as a solid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé de formule (I) dans laquelle Z est sélectionné parmi les groupes de la formule (II). L'invention porte sur de nouveaux acides carboxyliques azahétérocycliques N-substitués et leurs esters, dans lesquels une chaîne alkyle substituée constitue une partie des N-substituants ou de leurs sels, sur leurs modes de préparation, sur des compositions les contenant, et sur leur emploi pour le traitement clinique d'états douloureux hyperalgésiques et/ou inflammatoires dans lesquels les fibres C jouent un rôle pathophysiologique dans l'apparition de douleurs ou d'inflammations neurogènes.
PCT/DK1996/000142 1995-04-07 1996-04-01 Nouveaux composes heterocycliques WO1996031469A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU52707/96A AU5270796A (en) 1995-04-07 1996-04-01 N-substituted azaheterocyclic carboxylic acids and esters th ereof

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
DK40295 1995-04-07
DK40895 1995-04-07
DK40495 1995-04-07
DK0404/95 1995-04-07
DK0402/95 1995-04-07
DK0408/95 1995-04-07
DK1004/95 1995-09-11
DK100795 1995-09-11
DK1007/95 1995-09-11
DK100495 1995-09-11

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6281212B1 (en) 1996-07-12 2001-08-28 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6288083B1 (en) 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6323206B1 (en) 1996-07-12 2001-11-27 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6329385B1 (en) 1998-01-21 2001-12-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6433165B1 (en) 1998-01-21 2002-08-13 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6503926B2 (en) 1998-09-04 2003-01-07 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6509346B2 (en) 1998-01-21 2003-01-21 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
WO2003045942A2 (fr) * 1998-09-04 2003-06-05 Millennium Pharmaceuticals, Inc. Antagonistes des recepteurs de la chimiokine et methodes d'utilisation de ces antagonistes
US6593337B1 (en) 1999-10-19 2003-07-15 Bristol-Myers Squibb Pharma Company Tricyclic compounds useful as HIV reverse transcriptase inhibitors
US6613905B1 (en) 1998-01-21 2003-09-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6825210B2 (en) 2001-04-19 2004-11-30 Bristol-Myers Squibb Pharma Company Tricyclic compounds useful as HIV reverse transcriptase inhibitors
EP1688418A2 (fr) * 2001-11-21 2006-08-09 Millennium Pharmaceuticals, Inc. Antagonistes de récepteur de chemokine et leurs procédés d'utilisation
US7355042B2 (en) 2001-10-16 2008-04-08 Hypnion, Inc. Treatment of CNS disorders using CNS target modulators
US7541365B2 (en) 2001-11-21 2009-06-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US7732459B2 (en) 2002-11-13 2010-06-08 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use therefor

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Cited By (32)

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US6281212B1 (en) 1996-07-12 2001-08-28 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6323206B1 (en) 1996-07-12 2001-11-27 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6509346B2 (en) 1998-01-21 2003-01-21 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6613905B1 (en) 1998-01-21 2003-09-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6329385B1 (en) 1998-01-21 2001-12-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6433165B1 (en) 1998-01-21 2002-08-13 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6503926B2 (en) 1998-09-04 2003-01-07 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
WO2003045942A2 (fr) * 1998-09-04 2003-06-05 Millennium Pharmaceuticals, Inc. Antagonistes des recepteurs de la chimiokine et methodes d'utilisation de ces antagonistes
US6288084B1 (en) 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
WO2003045942A3 (fr) * 1998-09-04 2003-09-12 Millennium Pharm Inc Antagonistes des recepteurs de la chimiokine et methodes d'utilisation de ces antagonistes
US6288083B1 (en) 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
EA008060B1 (ru) * 1998-09-04 2007-02-27 Милленниум Фармасьютикалз, Инк. Антагонисты хемокинного рецептора и способы их применения
US6593337B1 (en) 1999-10-19 2003-07-15 Bristol-Myers Squibb Pharma Company Tricyclic compounds useful as HIV reverse transcriptase inhibitors
US6825210B2 (en) 2001-04-19 2004-11-30 Bristol-Myers Squibb Pharma Company Tricyclic compounds useful as HIV reverse transcriptase inhibitors
US7355042B2 (en) 2001-10-16 2008-04-08 Hypnion, Inc. Treatment of CNS disorders using CNS target modulators
EP1688418A3 (fr) * 2001-11-21 2008-05-14 Millennium Pharmaceuticals, Inc. Antagonistes de récepteur de chemokine et leurs procédés d'utilisation
SG165152A1 (en) * 2001-11-21 2010-10-28 Millennium Pharm Inc Chemokine receptor antagonists and methods of use thereof
US7541365B2 (en) 2001-11-21 2009-06-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
KR100919346B1 (ko) * 2001-11-21 2009-09-25 밀레니엄 파머슈티컬스 인코퍼레이티드 케모카인 수용체 길항제 및 이의 사용 방법
KR100952767B1 (ko) * 2001-11-21 2010-04-14 밀레니엄 파머슈티컬스 인코퍼레이티드 케모카인 수용체 길항제 및 이의 사용 방법
EP1688418A2 (fr) * 2001-11-21 2006-08-09 Millennium Pharmaceuticals, Inc. Antagonistes de récepteur de chemokine et leurs procédés d'utilisation
JP2010229136A (ja) * 2001-11-21 2010-10-14 Millennium Pharmaceuticals Inc ケモカイン受容体アンタゴニストおよびその使用方法
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EP2286811A1 (fr) * 2001-11-21 2011-02-23 Millennium Pharmaceuticals, Inc. Antagonistes de récepteur de chemokine et leurs procédés d'utilisation
US9663537B2 (en) 2001-11-21 2017-05-30 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use
US8058287B2 (en) 2001-11-21 2011-11-15 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
JP4889920B2 (ja) * 2001-11-21 2012-03-07 ミレニアム ファーマシューティカルズ， インコーポレイテッド ケモカイン受容体アンタゴニストおよびその使用方法
JP2013209393A (ja) * 2001-11-21 2013-10-10 Millennium Pharmaceuticals Inc ケモカイン受容体アンタゴニストおよびその使用方法
JP2015083577A (ja) * 2001-11-21 2015-04-30 ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． ケモカイン受容体アンタゴニストおよびその使用方法
US7732459B2 (en) 2002-11-13 2010-06-08 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use therefor
US9334283B2 (en) 2002-11-13 2016-05-10 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use thereof
US7977350B2 (en) 2002-11-13 2011-07-12 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use therefor

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