WO2001034598A1 - Azetidines [(indol-3-yl)-cycloalkyl]-3-substituees pour le traitement de troubles du systeme nerveux central - Google Patents

Azetidines [(indol-3-yl)-cycloalkyl]-3-substituees pour le traitement de troubles du systeme nerveux central Download PDF

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Publication number
WO2001034598A1
WO2001034598A1 PCT/US2000/029954 US0029954W WO0134598A1 WO 2001034598 A1 WO2001034598 A1 WO 2001034598A1 US 0029954 W US0029954 W US 0029954W WO 0134598 A1 WO0134598 A1 WO 0134598A1
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Prior art keywords
carbon atoms
compound
pharmaceutically acceptable
acceptable salt
azetidin
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PCT/US2000/029954
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English (en)
Inventor
Magda Asselin
John Watson Ellingboe
Richard Eric Mewshaw
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Wyeth
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Priority to BR0015401-6A priority Critical patent/BR0015401A/pt
Priority to EP00976731A priority patent/EP1228065A1/fr
Priority to AU14466/01A priority patent/AU1446601A/en
Priority to MXPA02004555A priority patent/MXPA02004555A/es
Priority to CA002390531A priority patent/CA2390531A1/fr
Priority to JP2001536545A priority patent/JP2003513970A/ja
Publication of WO2001034598A1 publication Critical patent/WO2001034598A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants

Definitions

  • This invention relates to new N-(indolyl-cycloalkyl) azetidine derivatives which are useful as pharmaceuticals for the treatment of diseases caused by disorders of the serotonin-affected neurological systems, such as depression and anxiety.
  • compositions which enhance serotonergic neurotransmission are useful for the treatment of many psychiatric disorders, including depression and anxiety.
  • the first generation of non-selective serotonin-affecting drugs operated through a variety of physiological functions which endowed them with several side-effect liabilities.
  • the present invention relates to a new class of molecules which have the ability to act at the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
  • R and R are each independently hydrogen or C, 4 alkyl, or R and R, are linked to form an azetidine ring. These compounds are reported to have activity at the 5HT. receptor and be useful for the treatment of migraine, headache and headache associated with vascular disorder.
  • X is N-R, O, S(O) ra ; m is an integer of 0 to 2; n is an integer of 0 to 4;
  • Ar is an aryl group of 6 to 12 carbon atoms optionally substituted with 1 to 3 groups selected independently from R 3 , R 4 and R s , or a heteroaryl group of 4 to 10 carbon atoms optionally substituted with 1 to 3 selected independently from R 3 , R. and R 5 ;
  • R and R 2 are independently H, straight chain alkyl of 1 to 6 carbon atoms, branched alkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, aminocarbonyl, or alkylaminocarbonyl of 1 to 4 carbon atoms;
  • R R 3 , R 4 and R 5 are independently H, straight chain alkyl of 1 to 4 carbon atoms, branched alkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, halogen, alkoxy group of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, hydroxy, nitro, amino, sulfonyl, cyano, carboxy, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, aminocarbonyl, or alkylaminocarbonyl of 1 to 4 carbon atoms; and all crystalline forms or a pharmaceutically acceptable salt thereof.
  • X is O, or NR; n is an integer of 0 to 1 ; Ar is an aryl group of 6 to 10 carbon atoms optionally substituted with 1 to 3 groups selected independently from R 3 , R 4 and R 5 , or a heteroaryl group of 5 to 10 carbon atoms optionally substituted with 1 to 3 groups selected independently from R 3 , R, and R 5 ;
  • R and R. are independently H, straight chain alkyl of 1 to 6 carbon atoms, branched alkyl of 3 to 6 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms;
  • R,, R 3 , R 4 and R 5 are independently H, straight chain alkyl of 1 to 6 carbon atoms, branched alkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, hydroxy, nitro, nitrile, amino, sulfonyl, cyano, carboxy, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, aminocarbonyl, or alkylaminocarbonyl of 1 to 4 carbon atoms;
  • X is S(O) m ; m is an integer of 0 to 2; n is an integer of 0 or 1;
  • Ar is an aryl group of 6 to 10 carbon atoms optionally substituted with 1 to 3 groups selected independently from R 3 , R 4 and R 5 , or a heteroaryl group of 5 to 10 carbon atoms optionally substituted with 1 to 3 groups selected independently from R 3 , R 4 and R 5 ;
  • R and R 2 are independently H, straight chain alkyl of 1 to 6 carbon atoms, branched alkyl of 3 to 6 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms;
  • R 1? R 3 , R 4 and R 5 are independently selected from H, straight chain alkyl of 1 to 6 carbon atoms, branched alkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, hydroxy, nitro, nitrile, amino, sulfonyl, cyano, carboxy, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, aminocarbonyl, or alkylaminocarbonyl of 1 to 4 carbon atoms; and all crystalline forms or a pharmaceutically acceptable salt thereof.
  • a subset of these preferred compounds includes those in which X is S(O) m ; m is an integer from 0 to 2; and Ar is a phenyl ring optionally substituted by from 1 to 3 groups independently selected from R 3 , R 4 and R 5 , defined above.
  • Aryl refers to single or multiple 6 to 12 membered aromatic ring radicals including but not limited to phenyl, naphthalene, anthracene, phenanthrene, indene and indacene, in some embodiments of the present invention, the aryl group may be substituted with one to three groups selected from R 3 , R 4 and R,
  • Heteroaryl as used herein refers to single or multiple 5 to 10 membered aromatic ring radicals having from 1 to 3 hetero atoms independently selected from nitrogen, oxygen and sulfur, including, but not limited to, furan, thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole, pyrazole, isothiazole, oxadiazole, triazole, thiadiazole, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, napthyridine, pteridine, pyridine, pyrazine, pyrimidine, pyridazine, pyran, triazine, indole, isoindole, indazole, indolizine, and isobenzofuran.
  • the heteroaryl group is substituted with one to three groups selected from those of R 3
  • Alkyl whether used alone or as part of another group includes straight and branched chain alkyl groups containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, /-butyl and t-butyl are encompassed by the term alkyl.
  • alkyl-containing groups herein, such as alkylcarbonyl and alkylaminocarbonyl groups the number of carbon atoms listed refers to the alkyl group, itself, and not including the carbonyl carbon.
  • alkyl may refer to substituted or unsubstituted alkyl.
  • the substituted alkyl groups in these compounds may be fully substituted, such as with perhalogenated compounds.
  • Other alkyl groups in these definitions may be substituted by from 1 to 3 substituents selected from halogen, hydroxy, CN, NO 2 , or NH 3 .
  • the number of carbon number refers to carbon backbone and does not include carbon atoms of substituents such as alkoxy substitutions and the like.
  • Halogen is preferably fluoro, chloro, bromo or iodo.
  • salts are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, succinic, maleic, malonic, oxalic, fumaric, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
  • R, R., R 2 or R 3 contain a carboxyl group
  • salts of the compounds of this invention may be formed with bases such as alkali metals (Na, K, Li) or the alkaline earth metals (Ca or Mg).
  • the compounds of formula I have been found to have affinity for the 5-HT reuptake transporter. They are therefore useful in the treatment of diseases affected by disorders of the serotonin affected neurological systems, such as depression, anxiety, sleep disorders, sexual dysfunction, alcohol and cocaine addiction, cognition enhancement and related problems.
  • the present invention accordingly provides methods of treatment or prevention of these maladies, the methods comprising administering to a mammal, preferably a human, in need thereof pharmaceutically effective amount of a compound of this invention, or a pharmaceutically acceptable salt thereof.
  • compositions which comprise one or more compounds of this invention, or a pharmaceutically acceptable salt thereof, in combination or association with one or more pharmaceutically acceptable carriers or excipients.
  • the compositions are preferably adapted for oral or subcutaneous administration. However, they may be adapted for other modes of administration.
  • compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent , a binder, a lubricant, a flavoring agent and the like. They are formulated in conventional manner, for example, in a manner similar to that use for known antihypertensive agents, diuretics and ⁇ - blocking agents.
  • Applicable solid carriers or excipients can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols
  • oils e.g. fractionated coconut oil and arachis oil
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
  • the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • a composition of the invention is in the form of a pharmaceutically effective unit dose.
  • suitable unit dose forms include tablets, capsules and powders in sachets or vials.
  • Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg.
  • Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention.
  • the compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg.
  • Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
  • a compound of formula (2) is reacted with a compound of formula (3) in the presence of a reducing reagent such as sodium triacetoxyborohydride, and acetic acid in a solvent such as dichloroethane at 23 °C to give a compound of formula I in accordance with the procedure described by Abdel-Magid, Carson, Harris, Maryanoff and Shah in J. Org. Chem. 1996, 61, 3849.
  • a reducing reagent such as sodium triacetoxyborohydride
  • acetic acid in a solvent such as dichloroethane at 23 °C
  • a compound of formula (4) is reacted with 1,4-cyclohexanedione monoethylene ketal, potassium hydroxide in methanol at 65 °C to give compounds of formula (5) as described by Wustrow et al. in J. Med. Chem. 1997, 40, 250.
  • Hydrogenation to a compound of formula (6) can be realized by treatment in suitable solvents such as an alcohol, but not limited to ethanol with H, and 5% Pd/C.
  • Hydrolysis to a compound of formula (3) can be carried out using IN HCl in a 1: 1 mixture of THF and water.
  • compounds of formula (2) may be prepared by Scheme III.
  • a compound of formula (7) is prepared by reaction of N-benzhydryl-3- hydroxyazetidine with methanesulfonyl chloride and triethylamine in a solvent such as dichloromethane.
  • Compound (7) is reacted with a compound of formula (9) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile to yield a compound of formula (8).
  • a base such as potassium carbonate
  • a solvent such as acetonitrile
  • Standard N-alkylation methods may be used to convert a compound of formula (9) where R is hydrogen to a compound of formula (9) where R is alkyl.
  • the present invention further provides a compound of the invention for use as an active therapeutic substance.
  • Compounds of formula I are of particular use in the treatment of diseases affected by disorders of the serotonin.
  • the present invention further provides a method of treating depression and anxiety in mammals including man, which comprises administering to the afflicted mammal an effective amount of a compound or a pharmaceutical composition of the invention.
  • the 5-HT transporter affinity of the compounds of this invention was established in accordance with standard pharmaceutically accepted test procedures with representative compounds as follows:
  • the following assay was used to determine a compound's affinity for the 5- HT transporter.
  • a human carcinoma cell line (Jar cells) possessing low endogenous levels of the 5-HT-transporter are seeded into 96 well plates and treated with staurosporine at least 18 h prior to assay. [Staurosporine greatly increases the expression of the 5-HT- transporter.]
  • vehicle, excess of fluoxetine, or test compound is added to various wells on the plate. All wells then receive ⁇ -5-HT and are incubated at 37 °C for 5 min. The wells are then washed with ice cold 50 mM Tris HCl (pH 7.4) buffer and aspirated to remove free 3 H-5-HT.
  • Example 10b 73 4600
  • Example la ⁇ l-[cis-4-(5-Fluoro-lH-indol-3-yl)-cyclohexyl]-azetidin-3-yl)-2-methoxy-phenyl)- amine
  • Step 2 4-(5-Fluoro-lH-3-indoIyl)-cyclohexanone ethylene ketal
  • Step 7 ⁇ l-[cis-4-(5-Fluoro-lH-indol-3-yl)-cyclohexyl]-azetidin-3-yl)-2-methoxy- phenyl)-amine
  • the product was filtered through 150 mL of silica gel using 50% ethyl acetate/hexanes, 75% ethyl acetate/hexanes, and finally 100% ethyl acetate to give 0.150 g of the desired product: mp 158-160 °C.
  • Step 2 4-(5-Cyano-lH-3-indolyl)-cyclohexanone ethylene ketal
  • Example 8b 5-Fluoro-3- ⁇ trans-4-[3-(3-methoxy-phenoxy)-azetidin-l-yl]-cyclohexyl ⁇ -lH- indole

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
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  • Pain & Pain Management (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne des composés, des compositions pharmaceutiques ainsi que toutes leurs formes cristallines ou l'un de leurs sels pharmaceutiquement acceptables et des modalités d'utilisation de ces composés pour le traitement de troubles du système nerveux central tels que l'anxiété et la dépression. Ces composés sont représentés par la formule générale (I). Dans cette formule, X est N-R, O, S(O)m; m vaut 0 à 2; n vaut 0 à 4. Ar est un groupe aryle en C6-C12 éventuellement substitué par 1 à 3 groupes R3, ou un groupe hérétoaryle en C4-C10 éventuellement substitué par 1 à 3 groupes R3. R et R2 sont indépendamment H, chaîne alkyle droite en C1-C6, alkyle ramifié en C3-C6, cycloalkyle en C3-C6, alcoxycarbonyle en C1-C6, alkylcarbonyle en C1-C6, aminocarbonyle, ou alkylaminocarbonyle en C1-C4. R1 et R3 sont indépendamment H, chaîne alkyle droite en C1-C4, alkyle ramifié en C3-C6, cycloalkyle en C3-C8, halo, groupe alcoxy en C1-C4, haloalkyle en C1-C4, OH, nitro, amino, sulfonyle, CN, carboxy, alkoxycarbonyle en C1-C4, alkylcarbonyle en C1-C4, aminocarbonyle, ou alkylaminocarbonyle en C1-C4.
PCT/US2000/029954 1999-11-08 2000-10-31 Azetidines [(indol-3-yl)-cycloalkyl]-3-substituees pour le traitement de troubles du systeme nerveux central WO2001034598A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
BR0015401-6A BR0015401A (pt) 1999-11-08 2000-10-31 [(indol-3-il)-cicloalquil]-3-azetidinas substituìdas para o tratamento de distúrbios do sistema nervoso central
EP00976731A EP1228065A1 (fr) 1999-11-08 2000-10-31 Azetidines (indol-3-yl)-cycloalkyl]-3-substituees pour le traitement de troubles du systeme nerveux central
AU14466/01A AU1446601A (en) 1999-11-08 2000-10-31 ((indol-3-yl)-cycloalkyl)-3-substituted azetidines for the treatment of central nervous system disorders
MXPA02004555A MXPA02004555A (es) 1999-11-08 2000-10-31 Azetidinas de [(indol-??3-il)cicloalquil]-3-substituidas para el tratamiento de padecimientos del sistema nervioso central.
CA002390531A CA2390531A1 (fr) 1999-11-08 2000-10-31 Azetidines ¬(indol-3-yl)-cycloalkyl|-3-substituees pour le traitement de troubles du systeme nerveux central
JP2001536545A JP2003513970A (ja) 1999-11-08 2000-10-31 中枢神経系障害の治療のための［（インドール−３−イル）−シクロアルキル］−３−置換アゼチジン

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US43611999A 1999-11-08 1999-11-08
US09/436,119 1999-11-08

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CN (1) CN1414962A (fr)
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CA (1) CA2390531A1 (fr)
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Cited By (12)

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WO2004113297A2 (fr) * 2003-06-24 2004-12-29 Neurosearch A/S Derives de noyaux aza et utilisation de ceux-ci comme inhibiteurs de la recapture des neurotransmetteurs monoaminergiques
US7858796B2 (en) 2004-09-21 2010-12-28 Glaxo Group Limited Chemical compounds
US8063071B2 (en) 2007-10-31 2011-11-22 GlaxoSmithKline, LLC Chemical compounds
US8071584B2 (en) 2007-03-23 2011-12-06 Glaxosmithkline Llc Indole carboxamides as IKK2 inhibitors
US8324186B2 (en) 2009-04-17 2012-12-04 Janssen Pharmaceutica N.V. 4-azetidinyl-1-heteroatom linked-cyclohexane antagonists of CCR2
US8354539B2 (en) 2009-03-10 2013-01-15 Glaxo Group Limited Indole derivatives as IKK2 inhibitors
US8436023B2 (en) 2010-06-09 2013-05-07 Janssen Pharmaceutica N.V. Cyclohexyl-azetidinyl antagonists of CCR2
US8450304B2 (en) 2008-12-10 2013-05-28 Janssen Pharmaceutica N.V. 4-azetidinyl-1-heteroaryl-cyclohexanol antagonists of CCR2
US8501780B2 (en) 2004-06-24 2013-08-06 Glaxosmithkline Llc Indazole carboxamides and their use
US8513229B2 (en) 2009-04-17 2013-08-20 Janssen Pharmaceutica Nv 4-Azetidinyl-1-phenyl-cyclohexane antagonists of CCR2
US8518969B2 (en) 2010-06-17 2013-08-27 Janssen Pharmaceutica Nv Cyclohexyl-azetidinyl antagonists of CCR2
US11306088B2 (en) 2016-06-21 2022-04-19 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof

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US11332470B2 (en) * 2016-06-21 2022-05-17 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof

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WO1999051576A1 (fr) * 1998-04-08 1999-10-14 American Home Products Corporation N-aryloxyethylamines utilisees pour le traitement de la depression
WO2000040554A1 (fr) * 1999-01-07 2000-07-13 American Home Products Corporation Derives d'indole arylpiperazinyl-cyclohexyle pour le traitement des depressions

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004113297A3 (fr) * 2003-06-24 2006-01-19 Neurosearch As Derives de noyaux aza et utilisation de ceux-ci comme inhibiteurs de la recapture des neurotransmetteurs monoaminergiques
WO2004113297A2 (fr) * 2003-06-24 2004-12-29 Neurosearch A/S Derives de noyaux aza et utilisation de ceux-ci comme inhibiteurs de la recapture des neurotransmetteurs monoaminergiques
US8501780B2 (en) 2004-06-24 2013-08-06 Glaxosmithkline Llc Indazole carboxamides and their use
US7858796B2 (en) 2004-09-21 2010-12-28 Glaxo Group Limited Chemical compounds
US8354406B2 (en) 2005-06-30 2013-01-15 Glaxosmithkline Llc Chemical compounds
US8372875B2 (en) 2007-03-23 2013-02-12 GlaxoSmithKline, LLC Indole carboxamides as IKK2 inhibitors
US8071584B2 (en) 2007-03-23 2011-12-06 Glaxosmithkline Llc Indole carboxamides as IKK2 inhibitors
US8063071B2 (en) 2007-10-31 2011-11-22 GlaxoSmithKline, LLC Chemical compounds
US8450304B2 (en) 2008-12-10 2013-05-28 Janssen Pharmaceutica N.V. 4-azetidinyl-1-heteroaryl-cyclohexanol antagonists of CCR2
US8354539B2 (en) 2009-03-10 2013-01-15 Glaxo Group Limited Indole derivatives as IKK2 inhibitors
US8324186B2 (en) 2009-04-17 2012-12-04 Janssen Pharmaceutica N.V. 4-azetidinyl-1-heteroatom linked-cyclohexane antagonists of CCR2
US8513229B2 (en) 2009-04-17 2013-08-20 Janssen Pharmaceutica Nv 4-Azetidinyl-1-phenyl-cyclohexane antagonists of CCR2
US8436023B2 (en) 2010-06-09 2013-05-07 Janssen Pharmaceutica N.V. Cyclohexyl-azetidinyl antagonists of CCR2
US8518969B2 (en) 2010-06-17 2013-08-27 Janssen Pharmaceutica Nv Cyclohexyl-azetidinyl antagonists of CCR2
US9062048B2 (en) 2010-06-17 2015-06-23 Janssen Pharmaceutica Nv Cyclohexyl-azetidinyl antagonists of CCR2
US11306088B2 (en) 2016-06-21 2022-04-19 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
US11780837B2 (en) 2016-06-21 2023-10-10 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof

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EP1228065A1 (fr) 2002-08-07
BR0015401A (pt) 2002-07-02
CA2390531A1 (fr) 2001-05-17
JP2003513970A (ja) 2003-04-15
MXPA02004555A (es) 2004-09-10
CN1414962A (zh) 2003-04-30
AU1446601A (en) 2001-06-06

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