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WO2010040989A1 - Composés de quinolin-2-one - Google Patents

Composés de quinolin-2-one Download PDF

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Publication number
WO2010040989A1
WO2010040989A1 PCT/GB2009/002368 GB2009002368W WO2010040989A1 WO 2010040989 A1 WO2010040989 A1 WO 2010040989A1 GB 2009002368 W GB2009002368 W GB 2009002368W WO 2010040989 A1 WO2010040989 A1 WO 2010040989A1
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Prior art keywords
oxo
dihydroquinolin
acetic acid
yloxy
group
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Ceased
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PCT/GB2009/002368
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English (en)
Inventor
George Hynd
John Gary Montana
Harry Finch
Michael Colin Cramp
Stuart Ward
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Pulmagen Therapeutics Asthma Ltd
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Argenta Oral Therapeutics Ltd
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Publication of WO2010040989A1 publication Critical patent/WO2010040989A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to quinolin-2-one compounds and their use in therapy.
  • PGD 2 mediates it effects through two receptors, the PGD 2 (or DP) receptor (Boie et al; J. Biol. Chem., 1995, 270, 18910-18916) and the chemoattractant receptor-homologous molecule expressed on Th2 (or CRTH2) (Nagata et al; J. Immunol., 1999, 162, 1278-1289; Powell; Prostaglandins Luekot. Essent. Fatty Acids, 2003, 69, 179-185). Therefore, it has been postulated that agents that antagonise the effects of PGD 2 at its receptors may have beneficial effects in number of disease states.
  • the CRTH2 receptor has been shown to be expressed on cell types associated with allergic inflammation, such as basophils, eosinophils, and Th2- type immune helper cells (Hirai et al; J. Exp. Med., 2001, 193, 255-261).
  • the CRTH2 receptor has been shown to mediate PGD 2 -mediated cell migration in these cell types (Hirai et at, J. Exp. Med., 2001 , 193, 255-261 ), and also to play a major role in neutrophil and eosinophil cell recruitment in a model of contact dermatitis (Takeshita et at, Int. Immunol., 2004, 16, 947-959).
  • Transgenic mice over expressing PGD 2 synthase exhibit an enhanced pulmonary eosinophilia and increased levels of Th2 cytokines in response to allergen challenge (Fujitani et a/; J. Immunol., 2002, 168, 443-449).
  • exogenously administered CRTH2 agonists enhance the allergic response in sensitised mice (Spik et a/; J. Immunol., 2005, 174, 3703-3708).
  • CRTH2 antagonists may have valuable properties for the treatment of diseases mediated by PGD 2 .
  • CRTH2 antagonists include: benzimidazole-acetic acids (WO2006/021418; WO2006/034418), indole-acetic acids (WO2003/022813; WO2003/066046; WO2003/066047; WO2003/097042; WO2003/097598; WO2003/101961; WO2003/101981; WO2004/007451; WO2004/078719; WO2004/106302; WO2005/019171; GB2407318; WO2005/040112; WO2005/040114; WO2005/044260; WO2005/094816; WO2006/034419; WO2006/036994; WO2006/095183; WO2007/045867), indolizine-acetic acids (WO2006/136859; WO2007/031747), pyrrole-acetic acids (WO2006/063763); pyrrolo
  • A represents a direct bond, an optionally substituted alkylene or alkenylene group, or a group of formula Z-(optionally substituted)alkylene
  • B represents a direct bond, an optionally substituted alkylene or alkenylene group, or a group of formula Z-(optionally substituted)alkylene or
  • Z represents an oxygen atom, an NH or N-alkyl group, a group of formula
  • n 0 to 2 or a group of formula -0-SO 2 -;
  • W represents an optionally substituted aryl or heteroaryl group or an optionally substituted alkyl group
  • Y represents an optionally substituted aryl or heteroaryl group, or an optionally substituted aryl-fused-heterocycloalkyl, heteroaryl-fused-cycloalkyl, heteroaryl-fused-heterocycloalkyl, aryl-fused-cycloalkyl or cycloalkyl group;
  • R a , R b , and R c independently represent hydrogen, acyl, alkoxy, alkylsulphinyl, alkylsulphonyl, alkylthio, -NH 2 , aminoalkyl, hydroxyalkyl, arylalkyl cyano, dialkylamino, halo, haloalkoxy, haloalkyl, alkyl, alkenyl, -OH, -CHO, -NO 2 , aryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heterocycloalkyl, aminoacyl, aminosulphonyl, acylamino, sulphonylamino, heteroarylalkyl, cyclic amine, aryloxy, heteroaryloxy, arylal
  • the groups X-A- and Y-B- may be attached to the bicyclic ring core at any available position; and corresponding ⁇ /-oxides, pharmaceutically acceptable salts, solvates and prodrugs of such compounds.
  • a second aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula [1] or an ⁇ /-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof, in admixture with a pharmaceutically acceptable carrier or excipient.
  • a third aspect of the invention is a compound of formula [1] or an N-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof for use in therapy.
  • a fourth aspect of the invention is the use of a compound of formula [1], or an ⁇ /-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for the treatment of a disease in which a
  • CRTH2 antagonist can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease.
  • a fifth aspect of the invention is a method for treating a disease in a patient in which a CRTH2 antagonist can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the patient a therapeutically effective amount of compound of formula [1] or an ⁇ /-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof.
  • a sixth aspect of the invention is a method of preparing a compound of formula [1] or an ⁇ /-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof.
  • a seventh aspect of the invention is a method of making a pharmaceutical composition
  • a pharmaceutical composition comprising combining a compound of formula [1], or an ⁇ /-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof, with a pharmaceutically acceptable carrier or excipient.
  • acyl means a -CO-alkyl group in which the alkyl group is as described herein.
  • exemplary acyl groups include -COCH 3 and -COCH(CH 3 ) 2 .
  • acylamino means a -NR-acyl group in which R and acyl are as described herein.
  • exemplary acylamino groups include -NHCOCH 3 and N(CH 3 )COCH 3 .
  • Alkoxy and “alkyloxy” means an -O-alkyl group in which alkyl is as defined below.
  • exemplary alkoxy groups include methoxy (OCH 3 ) and ethoxy (OC 2 H 5 ).
  • Alkoxycarbonyl means a -COO-alkyl group in which alkyl is as defined below.
  • exemplary alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.
  • Alkyl as a group or part of a group refers to a straight or branched chain saturated hydrocarbon group having from 1 to 12, preferably 1 to 6, carbon atoms, in the chain.
  • exemplary alkyl groups include methyl, ethyl, 1 -propyl and 2-propyl.
  • alkenyl as a group or part of a group refers to a straight or branched chain hydrocarbon group having from 1 to 12, preferably 1 to 6, carbon atoms and one carbon-carbon double bond in the chain.
  • alkenyl groups include ethenyl, 1-propenyl, and 2-propenyl.
  • Alkylamino means a -NH-alkyl group in which alkyl is as defined above.
  • exemplary alkylamino groups include methylamino and ethylamino.
  • Alkylene means an -alkyl- group in which alkyl is as defined previously.
  • Exemplary alkylene groups include -CH 2 -, -(CH 2 J 2 - and -C(CH 3 )HCH 2 -.
  • Alkenylene means an -alkenyl- group in which alkenyl is as defined previously.
  • Alkylsufinyl means a -SO-alkyl group in which alkyl is as defined above.
  • Exemplary alkylsulfinyl groups include methylsulfinyl and ethylsulfinyl.
  • Alkylsufonyl means a -SO 2 -alkyl group in which alkyl is as defined above.
  • exemplary alkylsulfonyl groups include methylsulfonyl and ethylsulfonyl.
  • Alkylthio means a -S-alkyl group in which alkyl is as defined above.
  • alkylthio groups include methylthio and ethylthio.
  • aminoacyl means a -CO-NRR group in which R is as herein described.
  • exemplary aminoacyl groups include -CONH 2 and -CONHCH 3 .
  • Aminoalkyl means an alkyl-NH 2 group in which alkyl is as previously described.
  • exemplary aminoalkyl groups include -CH 2 NH 2 .
  • aminosulfonyl means a -SO 2 -NRR group in which R is as herein described.
  • exemplary aminosulfonyl groups include -SO 2 NH 2 and -SO 2 NHCH 3 .
  • Aryl as a group or part of a group denotes an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, such as phenyl or naphthyl, and in one embodiment preferably phenyl.
  • the aryl group may be substituted by one or more substituent groups.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C 1 ⁇ alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphthlenemethyl.
  • Arylalkyloxy means an aryl-alkyloxy- group in which the aryl and alkyloxy moieties are as previously described. Preferred arylalkyloxy groups contain a C 1 ⁇ alkyl moiety. Exemplary arylalkyl groups include benzyloxy.
  • Aryl-fused-cycloalkyl means a monocyclic aryl ring, such as phenyl, fused to a cycloalkyl group, in which the aryl and cycloalkyl are as described herein. Exemplary aryl-fused-cycloalkyl groups include tetrahydronaphthyl and indanyl. The aryl and cycloalkyl rings may each be substituted by one or more substituent groups. The aryl-fused-cycloalkyl group may be attached to the remainder of the compound of formula [1] by any available carbon atom.
  • Aryl-fused-heterocycloalkyl means a monocyclic aryl ring, such as phenyl, fused to a heterocycloalkyl group, in which the aryl and heterocycloalkyl are as described herein.
  • Exemplary aryl-fused-heterocycloalkyl groups include tetrahydroquinolinyl, indolinyl, benzodioxinyl, benxodioxolyl, dihydrobenzofuranyl and isoindolonyl.
  • the aryl and heterocycloalkyl rings may each be substituted by one or more substituent groups.
  • the aryl-fused-heterocycloalkyl group may be attached to the remainder of the compound of formula [1] by any available carbon or nitrogen atom.
  • Aryloxy means an -O-aryl group in which aryl is described above.
  • Exemplary aryloxy groups include phenoxy.
  • Cyclic amine means an optionally substituted 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen, and which may optionally contain an additional heteroatom selected from O, S or NR (where R is as described herein).
  • Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine and N- methylpiperazine.
  • the cyclic amine group may be substituted by one or more substituent groups.
  • Cycloalkyl means an optionally substituted saturated monocyclic or bicyclic ring system of from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms.
  • Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the cycloalkyl group may be substituted by one or more substituent groups.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described.
  • Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • Dialkylamino means a -N(alkyl) 2 group in which alkyl is as defined above.
  • exemplary dialkylamino groups include dimethylamino and diethylamino.
  • Halo or "halogen” means fluoro, chloro, bromo, or iodo.
  • Haloalkoxy means an -O-alkyl group in which the alkyl is substituted by one or more halogen atoms.
  • exemplary haloalkyl groups include trifluoromethoxy and difluoromethoxy.
  • Haloalkyl means an alkyl group which is substituted by one or more halo atoms.
  • Exemplary haloalkyl groups include trifluoromethyl.
  • Heteroaryl as a group or part of a group denotes an optionally substituted aromatic monocyclic or multicyclic organic moiety of from 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, in which one or more of the ring atoms is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups.
  • heteroaryl group may be substituted by one or more substituent groups.
  • the heteroaryl group may be attached to the remainder of the compound of formula [1] by any available carbon or nitrogen atom.
  • Heteroarylalkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described.
  • Preferred heteroarylalkyl groups contain a lower alkyl moiety.
  • Exemplary heteroarylalkyl groups include pyridylmethyl.
  • ⁇ eteroarylalkyloxy means a heteroaryl-alkyloxy- group in which the heteroaryl and alkyloxy moieties are as previously described.
  • Preferred heteroarylalkyloxy groups contain a lower alkyl moiety.
  • Exemplary heteroarylalkyloxy groups include pyridylmethyloxy.
  • Heteroaryloxy means a heteroaryloxy- group in which the heteroaryl is as previously described.
  • Exemplary heteroaryloxy groups include pyridyloxy.
  • ⁇ eteroaryl-fused-cycloalkyl means a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a cycloalkyl group, in which heteroaryl and cycloalkyl are as previously described.
  • Exemplary heteroaryl-fused-cycloalkyl groups include tetrahydroquinolinyl and tetrahydrobenzofuranyl.
  • the heteroaryl and cycloalkyl rings may each be substituted by one or more substituent groups.
  • the heteroaryl-fused-cycloaikyl group may be attached to the remainder of the compound of formula [1] by any available carbon or nitrogen atom.
  • Heteroaryl-fused-heterocycloalkyl means a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a heterocycloalkyl group, in which heteroaryl and heterocycloalkyl are as previously described.
  • Exemplary heteroaryl-fused-heterocycloalkyl groups include dihydrodioxinopyridinyl, dihydropyrrolopyridinyl, dihydrofuranopyridinyl and dioxolopyridinyl.
  • the heteroaryl and heterocycloalkyl rings may each be substituted by one or more substituent groups.
  • the heteroaryl-fused-heterocycloalkyl group may be attached to the remainder of the compound of formula [1] by any available carbon or nitrogen atom.
  • ⁇ eterocycloalkyl means: (i) an optionally substituted cycloalkyl group of from 4 to 8 ring members which contains one or more heteroatoms selected from O, S or NR; (ii) a cycloalkyl group of from 4 to 8 ring members which contains CONR and CONRCO (examples of such groups include succinimidyl and 2- oxopyrrolidinyl).
  • the heterocycloalkyl group may be substituted by one or more substituent groups.
  • the heterocycloalkyl group may be attached to the remainder of the compound of formula [1] by any available carbon or nitrogen atom.
  • ⁇ eterocycloalkylalkyl means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
  • “Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 4 carbon atoms in the chain, i.e. methyl, ethyl, propyl (n-propyl or /so-propyl) or butyl ( ⁇ - butyl, /so-butyl or fert-butyl).
  • “Sulfonylamino” means a -NR-sulfonyl group in which R and sulfonyl are as described herein.
  • Exemplary sulfonylamino groups include -NHSO 2 CH 3 .
  • salt includes base addition, acid addition and quaternary salts.
  • Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides, e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L- arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.
  • bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides, e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L- arginine, L-lysine, N-e
  • Specific salts with bases include the benzathine, calcium, diolamine, meglumine, olamine, potassium, procaine, sodium, tromethamine and zinc salts.
  • Those compounds of the invention which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g.
  • acceptable counter-ions may be, for example, chlorides, bromides, sulfates, methanesulfonates, benzenesulfonates, toluenesulfonates (tosylates), napadisylates (naphthalene- 1 ,5-disulfonates or naphthalene- 1 -(sulfonic acid)-5-sulfonates), edisylates (ethane-1 ,2-disulfonates or ethane-1 -(sulfonic acid)-2-sulfonates), isethionates (2-hydroxyethylsulfonates), phosphates, acetates, citrates, lactates, tartrates, mesylates, maleates, malates, fumarates, succinates, xinafoates, p- acetamidobenzoates and the like;
  • Salts are discussed in the "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", P. Heinrich Stahl & Camille G. Wermuth, Wiley- VCH, 2002.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water. It will be understood that, as used in herein, references to the compounds of formula [1] are meant to also include the hydrate and solvate forms.
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of formula [1].
  • metabolic means e.g. by hydrolysis, reduction or oxidation
  • an ester prodrug of a compound of formula [1] containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of formula [1] containing a hydroxy group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ - hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluene- sulphonates, cyclohexylsulphamates and quinates.
  • ester prodrug of a compound of formula [1] containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, 379.
  • “Saturated” pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds.
  • cyclic groups referred to above namely, aryl, heteroaryl, cycloalkyl, aryl-fused-cycloalkyl, heteroaryl-fused-cycloalkyl, heterocycloalkyl, aryl-fused- heterocycloalkyl, heteroaryl-fused-heterocycloalkyl and cyclic amine may be substituted by one or more substituent groups.
  • Suitable optional substituent groups include acyl (e.g. -COCH 3 ), alkoxy (e.g. -OCH 3 ), alkoxycarbonyl (e.g. -COOCH 3 ), alkylamino (e.g.
  • alkylsulfinyl e.g. -SOCH 3
  • alkylsulfonyl e.g. -SO 2 CH 3
  • alkylthio e.g. -SCH 3
  • -NH 2 aminoalkyl (e.g. -CH 2 NH 2 ), arylalkyl (e.g. -CH 2 Ph or -CH 2 -CH 2 -Ph), cyano, dialkylamino (e.g. -N(CH 3 ) 2 ), halo, haloalkoxy (e.g. -OCF 3 or -OCHF 2 ), haloalkyl (e.g.
  • alkyl e.g. -CH 3 or -CH 2 CH 3
  • -OH, -CHO, -NO 2 aryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heterocycloalkyl, aminoacyl (e.g. -CONH 2 , -CONHCH 3 ), aminosulfonyl (e.g. -SO 2 NH 2 , -SO 2 NHCH 3 ), acylamino (e.g.
  • -NHCOCH 3 sulfonylamino
  • sulfonylamino e.g. -NHSO 2 CH 3
  • heteroarylalkyl e.g. cyclic amine (e.g. mo ⁇ holine), aryloxy, heteroaryloxy, arylalkyloxy (e.g. benzyloxy) and heteroarylalkyloxy.
  • Alkylene or alkenylene groups may be optionally substituted.
  • Suitable optional substituent groups include alkoxy (e.g. -OCH 3 ), alkylamino (e.g. -NHCH 3 ), alkylsulfinyl (e.g. -SOCH 3 ), alkylsulfonyl (e.g. -SO 2 CH 3 ), alkylthio (e.g. -SCH 3 ), -NH 2 , aminoalkyl (e.g. -CH 2 NH 2 ), arylalkyl (e.g. -CH 2 Ph or -CH 2 -CH 2 - Ph), cyano, dialkylamino (e.g.
  • Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and frans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms.
  • a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof.
  • such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques).
  • such isomers may be prepared by the application of adaptation of known methods (e.g. asymmetric synthesis).
  • the group -B-Y is attached to the 3-position of the quinolin-2-one ring system.
  • the group -B-Y is attached to the 4-position of the quinolin-2-one ring system.
  • the group -A-X is attached to the 5-position of the quinolin-2-one ring system.
  • R c represents a lower alkyl group.
  • R d represents a hydrogen atom or a lower alkyl group.
  • R d represents an arylalkyl group.
  • A represents an alkylene group.
  • Y represents an aryl or heteroaryl group.
  • Y represents a cycloalkyl group.
  • X represents a carboxylic acid.
  • A represents the group -0-CH 2 -.
  • A represents the group -CH 2 -.
  • B represents the group -CH 2 -.
  • the group -B-Y is attached to the 3- position and the group -A-X is attached to the 5-position of the quinolin-2-one ring system
  • R d is selected from a hydrogen atom or a lower alkyl group.
  • Specific compounds of the invention include those of the Examples herein, and pharmaceutically acceptable salts thereof. Utilities of the Invention
  • the compounds of the present invention may be shown to antagonise the effects of the CRTH2 receptor according to the tests described in the Biological Methods section of this document, the mechanism of action by which the compounds act is not a limiting embodiment of the present invention.
  • compounds of the present invention may also have beneficial effects at other prostanoid receptors, such as the PGD 2 receptor or the thromboxane A 2 receptor.
  • the therapeutic application of these compounds is pertinent to any disease that is known to be at least partially mediated by the activation of the CRTH2 receptor.
  • diseases include, but are not limited to: asthma, chronic obstructive pulmonary disease, bronchitis, cystic fibrosis, emphysema, rhinitis, psoriasis, dermatitis (atopic and non-atopic), Crohn's disease, ulcerative colitis, and irritable bowel disease.
  • the present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions.
  • the present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions.
  • compositions for preventing and treating PGD 2 -mediated diseases comprising a therapeutically effective amount of a compound of the invention of formula [1] and one or more other therapeutic agents.
  • Suitable therapeutic agents for a combination therapy with compounds of formula [1] include, but are not limited to: (1) corticosteroids, such as fluticasone, ciclesonide or budesonide; (2) ⁇ 2- adrenoreceptor agonists, such as salmeterol, indacaterol or formoterol; (3) leukotriene modulators, for example leukotriene antagonists such as montelukast, zafirulast or pranlukast or leukotriene biosynthesis inhibitors such as Zileuton or BAY-1005; (4) anticholinergic agents, for example muscarinic-3 (M3) receptor antagonists such as tiotropium bromide; (5) phosphodiesterase-IV (PDE-IV) inhibitors, such as roflumilast or cilomilast; (6) antihistamines, for example selective histamine- 1 (H 1) receptor antagonists, such as fexofenadine, citirizine, lorat
  • the weight ratio of the compound of the invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the present invention is also concerned with pharmaceutical formulations comprising one of the compounds as an active ingredient.
  • the magnitude of prophylactic or therapeutic dose of a compound may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific amount for any particular patient will depend upon a variety of factors, including the activity of the specific compound that is used, the age, body weight, diet, general health and sex of the patient, time of administration, the route of administration, the rate of excretion, the use of any other drugs, and the severity of the disease undergoing treatment.
  • the daily dose range will lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • a suitable dosage range is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of formula [1] per kg of body weight per day.
  • a suitable dosage range is, for example, from about 0.01 mg to about 300 mg of a compound of formula [1] per day, preferably from about 0.1 mg to about 30 mg per day.
  • the compositions are preferably provided in the form of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0 or 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds of the invention may be administered by inhalation at a dose range from 0.0005 mg to 10 mg (preferably 0.005 mg to about 0.5 mg) per kg of body weight per day.
  • compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier.
  • composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the invention, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • compositions of the present invention comprise a compound of the invention as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable nontoxic bases or acids including inorganic bases or acids and organic bases or acids.
  • Compounds of the invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which present compounds are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the invention is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the invention.
  • any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention.
  • the active compound may be administered by any convenient, suitable or effective route.
  • the compositions include those compositions suitable for routes of administration known to those skilled in the art, and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non- aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet contains from about 1 mg to about 500 mg of the active ingredient and each cachet or capsule contains from about 1 to about 500 mg of the active ingredient.
  • the active compound is preferably in the form of microparticles. They may be prepared by a variety of techniques, including spray-drying, freeze-drying and micronisation. Aerosol generation can be carried out using, for example, pressure-driven jet atomizers or ultrasonic atomizers, preferably using propellant-driven metered aerosols or propellant-free administration of micronized active compounds from, for example, inhalation capsules or other "dry powder" delivery systems.
  • composition of the invention may be prepared as a suspension for delivery from a nebuliser or as an aerosol in a liquid propellant, for example for use in a pressurised metered dose inhaler (PMDI).
  • PMDI pressurised metered dose inhaler
  • Propellants suitable for use in a PMDI are known to the skilled person, and include CFC-12,
  • HFA-134a HFA-227, HCFC-22 (CCI 2 F 2 ) and HFA-152 (CH 2 F 2 and isobutane).
  • Microparticles for delivery by administration may be formulated with excipients that aid delivery and release, such as, for example, propellants (e.g.
  • Frigen in the case of metered aerosols surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.
  • microparticles may be formulated with large carrier particles that aid flow from the DPI into the lung.
  • Suitable carrier particles are known, and include lactose particles; they may have a mass median aerodynamic diameter of greater than 90 ⁇ m.
  • a preferred composition is: Compound of the invention 24 mg/canister
  • the compounds of formula [1] can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such, as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • the compounds of formula [1] may also be administered by controlled release means and/or delivery devices such as those described in US patents 3845770, 3916899, 3536809, 3598123, 3630200 and 4008719. Methods of Synthesis
  • the present invention is also concerned with processes for preparing the compounds of this invention.
  • the compounds of formula [1] of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The compounds of the invention of formula [1] may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above.
  • the free acid form corresponding to isolated salts can be generated by acidification with a suitable acid such as acetic acid and hydrochloric acid and extraction of the liberated free acid into an organic solvent followed by evaporation.
  • a suitable acid such as acetic acid and hydrochloric acid
  • the free acid form isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic or aqueous solvent followed by addition of the appropriate base and subsequent evaporation, precipitation, or crystallisation.
  • Compounds of the invention of general formula [1a], in which group A is represented by a group of formula O-(optionally substituted)alkylene, may conveniently be prepared by the reaction between a compound of formula [2] and a suitable alkylating agent of formula [3], where group LG represents a suitable leaving group (for example, chloro, bromo, or methanesulfonyloxy).
  • group LG represents a suitable leaving group (for example, chloro, bromo, or methanesulfonyloxy).
  • the alkylation reaction is carried out in the presence of a base (for example, potassium carbonate) in an inert solvent (for example, acetone or N 1 N- dimethylformamide).
  • Intermediate compounds of formula [2a] may conveniently be prepared by the reaction between an aminophenol of formula [4] and a ⁇ -ketoester of formula [5], in which PG represents an appropriate ester function (such as methyl and ethyl).
  • the reaction may be run neat or in the presence of a suitable dehydrating agent, such as polyphosphoric acid, aluminium chloride, trifluoroacetic acid, hydrochloric acid or sulphuric acid.
  • intermediate compounds of formula [2b] may conveniently be prepared by the reaction between an aminophenol of formula [4] and a ⁇ - ketoester of formula [6], in which PG represents an appropriate ester function (such as methyl and ethyl).
  • the reaction may be run neat or in the presence of a suitable dehydrating agent, such as polyphosphoric acid, aluminium chloride, trifluoroacetic acid, hydrochloric acid or sulphuric acid.
  • Compounds of the invention of general formula [1b] may be prepared by the reaction between an intermediate compound of formula [7], in which group T represents a chloro, bromo, or iodo atom, or a trifluoromethanesulfonyloxy group, and 1-(tert-butyldimethylsilyloxy)-1-methoxyethane.
  • the reaction may conveniently be carried out in the presence of a suitable catalyst (for example a palladium compound) and a base (such as sodium acetate).
  • Intermediates of formula [7], in which T is trifluoromethanesulfonyloxy may be prepared from the reaction of intermediates of formula [2] with N- phenyltrifluoromethanesulfonimide in the presence of a base, such as potassium carbonate.
  • compounds of the invention may be prepared by transformations of other compounds of the invention.
  • compounds of the invention of formula [1d], in which group A represents an optionally substituted alkylene group may conveniently be prepared by the reduction of compounds of the invention of formula [1c], in which group A represents an optionally substituted alkenylene group.
  • the transformation of compounds of formula [1c] to those of formula [1d] may conveniently be achieved by reduction with hydrogen in the presence of a suitable catalyst, such as palladium supported on carbon. ally )alkylene
  • compounds of formula [1f] may be conveniently prepared by, for example, the reaction between a compound of formula [1e] and an a Iky I halide in the presence of a suitable base such as potassium carbonate. It will be understood by those who are practiced in the art that it may be convenient to carry out the transformation of intermediate [1e] to final compound [1f] using a form of intermediate [1e] in which the X group is suitably protected (for example, an ethyl or tert-butyl ester). It is to be understood that if the reaction is carried out on a protected form of intermediate [1e] an appropriate deprotection step will be required to obtain the desired compound [1f] of the invention.
  • Method A experiments were performed on a Micromass Platform LCT spectrometer with positive ion electrospray and single wavelength UV 254 nm
  • Method B experiments were performed on a Micromass Platform LC spectrometer with positive and negative ion electrospray and ELS/Diode array detection using a Phenomenex Luna C18(2) 30 x 4.6 mm column and a 2 mL/minute flow rate.
  • the solvent system was 95% solvent A and 5% solvent B5 for the first 0.50 minutes followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 0.50 minutes
  • Preparation 2a [3-(4-chlorobenzyl)-1,4,7-trimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid tert-butyl ester
  • a mixture of [3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid tert-butyl ester (0.10 g), iodomethane (0.40 ml_), potassium carbonate (0.13 g) and acetone (4.0 ml_) was sealed in a tube and heated at 5O 0 C for 21 hours.
  • the title compound was prepared by the method of Preparation 3d using ⁇ -( ⁇ chlorobenzyO-i-ethyMJ-dimethyl- ⁇ -oxo-i ⁇ -dihydroquinolin-S-yllacetic acid methyl ester.
  • the title compound was prepared by the method of Preparation 3c using [3-(4-chlorobenzyl) ⁇ 7 ⁇ limethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy]acetic acid terf-butyl ester and bromoethane.
  • the title compound was prepared by the method of Preparation 3c using [S- ⁇ -chlorobenzyO ⁇ J-dimethyl ⁇ -oxo-i ⁇ -dihydroquinolin- ⁇ -yloxylacetic acid terf-butyl ester and bromomethylbenzene.
  • a suspension of potassium tert-butoxide (0.79 g) in anhydrous tetrahydrofuran (20 ml.) at O 0 C was treated with a mixture of fert-butanol (0.1 mL) and 3-oxo-butyric acid methyl ester (0.76 ml_). The mixture was stirred at O 0 C for 30 minutes, treated with 2-bromomethyl-5-fluorobenzothiazole (1.7 g) and then heated at 7O 0 C overnight. The mixture was cooled to room temperature, diluted with water and concentrated under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate.
  • the title compound was prepared by the method of Preparation 1b using 3-amino-5-methylphenol and 2-(5-fluorobenzothiazol-2-ylmethyl)-3-oxo-butyric acid methyl ester.
  • the title compound was prepared by the method of Preparation 1c using 3-(5-fluorobenzothiazol-2-ylmethyl)-5-hydroxy-4,7-dimethyl-1 H-quinolin-2-one and bromoacetic acid methyl ester.
  • the title compound was prepared by the method of Preparation 3d using [3-(5-fluorobenzothiazol-2-ylmethyl)-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid methyl ester.
  • the title compound was prepared by the method of Preparation 1 b using 3-amino-5-methylphenol and 2-(6-fluoroquinolin-2-ylmethyl)-3-oxo-butyric acid methyl ester.
  • the title compound was prepared by the method of Preparation 1c using 3-(6-fluoroquinolin-2-ylmethyl)-5-hydroxy-4,7-dirnethyl-1 H-quinolin-2-one and bromoacetic acid methyl ester.
  • the title compound was prepared by the method of Preparation 3d using [3-(6-fluoroquinolin-2-ylmethyl)-1,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid methyl ester.
  • the title compound was prepared by the method of Preparation 1b using 3-amino-5-methylphenol and 4-(4-chlorophenyl)-2-methyl-3-oxo-butyric acid ethyl ester.
  • the title compound was prepared by the method of Preparation 1b using 3-amino-5-methylphenol and 2-(2-chlorobenzyl)-3-oxo-butyric acid ethyl ester.
  • the title compound was prepared by the method of Preparation 1 c using 3-(2-chlorobenzyl)-5-hydroxy-4,7-dimethyl-1 H-quinolin-2-one and bromoacetic acid methyl ester.
  • the title compound was prepared by the method of Preparation 1 b using 3-amino-5-methylphenol and 2-(2,4-dichlorobenzyl)-3-oxo-butyric acid ethyl ester.
  • the title compound was prepared by the method of Preparation 3c using S- ⁇ -chlorobenzyO ⁇ J-dimethyl ⁇ -oxo-i ⁇ -dihydroquinolin- ⁇ -yloxyjacetic acid methyl ester and iodomethane.
  • the title compound was prepared by the method of Preparation 3d using [3-(3-chlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy]acetic acid methyl ester.
  • the title compound was prepared by the method of Preparation 3c using ⁇ (S ⁇ -dichlorobenzyO ⁇ J-dimethyl ⁇ -oxo-i ⁇ -dihydroquinolin- ⁇ -yloxylacetic acid methyl ester and iodomethane.
  • the title compound was prepared by the method of Preparation 1c using 5-hydroxy-4,7-dimethyl-3-naphthalen-1 -ylmethyl-1 H-quinolin-2-one and bromoacetic acid methyl ester.
  • the title compound was prepared by the method of Preparation 3c using (4,7-dimethyl-3-naphthalen-1-ylmethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy)acetic acid methyl ester and iodomethane.
  • the title compound was prepared by the method of Preparation 3d using (1 ,4,7-trimethyl-3-naphthalen-1-ylmethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy)acetic acid methyl ester.
  • Example 24 [[7-chloro-3-[(4-chlorophenyl)methyl]-1,2-dihydro-1,4- dimethyl-2-oxo-5-quinolinyl]oxy]acetic acid.
  • the title compound was prepared by the method of Preparation 25b using: 3-amino-4-fluorophenol and 3-oxo-2-(4-pyrazol-1-ylbenzyl)thiobutyric acid S-te/f-butyl ester.
  • the title compound was prepared by the method of Preparation 25b using: 3-amino-4-fluorophenol and 2-(4-methanesulfonylbenzyl)-3-oxo- thiobutyric acid S-te/f-butyl ester.
  • the title compound was prepared by the method of Preparation 3d using [[8-fluoro-3-(4-methanesulfonylbenzyl)-1 ,4-dimethyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid methyl ester.
  • the receptor binding assay is performed in a final volume of 200 ⁇ l_ binding buffer [10 mM BES (pH 7.4), 1 mM EDTA 1 10 mM manganese chloride, 0.01% BSA] and 1 nM [ 3 H]-PGD 2 (Amersham Biosciences UK Ltd). Ligands are added in assay buffer containing a constant amount of DMSO (1% by volume). Total binding is determined using 1% by volume of DMSO in assay buffer and non-specific binding is determined using 10 ⁇ M of unlabeled PGD 2 (Sigma).
  • HEK Human embryonic kidney
  • HEK cell membranes 3.5 ⁇ g expressing the CRTH2 receptor are incubated with 1.5 mg wheatgerm agglutinin SPA beads and 1 nM [ 3 H]-PGD 2 (Amersham Biosciences UK Ltd) and the mixture incubated for 3 hours at room temperature.
  • Bound [ 3 H]-PGD 2 is detected using a Microbeta TRILUX liquid scintillation counter (Perkin Elmer).
  • Compound IC 50 value is determined using a 6-point dose response curve in duplicate with a semi-log compound dilution series. IC 50 calculations are performed using Excel and XLfit (Microsoft), and this value is used to determine a Ki value for the test compound using the Cheng-Prusoff equation.
  • the GTP ⁇ S Assay is performed in a final volume of 200 mL assay buffer (20 mM HEPES pH 7.4, 10 mM MgCI 2 , 100 mM NaCI, 10 ⁇ g/mL saponin). DMSO concentrations are kept constant at 1% by volume.
  • Human embryonic kidney (HEK) cell membranes (3.5 ⁇ g) expressing the CRTH2 receptor are incubated with the compounds for 15 min at 3O 0 C prior to addition of PGD 2 (30 nM final concentration) and GTP (10 ⁇ M final concentration). The assay solutions are then incubated for 30 minutes at 30 0 C, followed by addition of [ 35 S]- GTP ⁇ S (0.1 nM final concentration).
  • the assay plate is than shaken and incubated for 5 minutes at 30 0 C. Finally, SPA beads (Amersham Biosciences, UK) are added to a final concentration of 1.5 mg/well and the plate shaken and incubated for 30 minute at 30 0 C. The sealed plate is centrifuged at 1000g for 10 minutes at 30°C and the bound [ 35 S]-GTPyS is detected on Microbeta scintillation counter (Perkin Elmer).
  • Compound IC 50 value is determined using a 6-point dose response curve in duplicate with a semi-log compound dilution series. IC 50 calculations are performed using Excel and XLfit (Microsoft), and this value is used to determine a Ki value for the test compound using the Cheng- Prusoff equation.
  • Biological Results The compounds of the Examples above were tested in the CRTH2 radioligand binding described above; the compounds all have Ki values of less than 10 ⁇ M in the binding assay. For example, compounds of Examples 5 and 16 have Ki values of 100 and 49 nM, respectively. The compounds also have Ki values of less than 10 ⁇ M in the GTP ⁇ S functional assay. For example, compounds of Examples 5 and 16 have Ki values of 52 and 140 nM, respectively.

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Abstract

L'invention porte sur un composé représenté par la formule de structure [1] : dans laquelle : A représente une liaison directe, un groupe alkylène ou alcénylène éventuellement substitué ou un groupe représenté par la formule Z-(alkylène éventuellement substitué); B représente une liaison directe, un groupe alkylène ou alcénylène éventuellement substitué ou un groupe représenté par la formule Z-(alkylène éventuellement substitué) ou (alkylène éventuellement substitué)–Z; Z représente un atome d'oxygène, un groupe NH ou N-alkyle, un groupe représenté par la formule S(O)n, dans laquelle n = 0 à 2, ou un groupe représenté par la formule -O-SO2-; X représente un groupe acide carboxylique, tétrazole, 3-hydroxyisoxazole, acide hydroxamique, phosphinate, phosphonate, phosphonamide, acide sulfonique ou un groupe représenté par la formule C(=O)NHSO2W ou SO2NHC(=O)W; W représente un groupe aryle ou hétéroaryle éventuellement substitué ou un groupe alkyle éventuellement substitué; Y représente un groupe aryle ou hétéroaryle éventuellement substitué ou un groupe aryle condensé avec hétérocycloalkyle, hétéroaryle condensé avec cycloalkyle, hétéroaryle condensé avec hétérocycloalkyle, aryle condensé avec cycloalkyle ou cycloalkyle éventuellement substitué; Ra, Rb et Rc représentent indépendamment hydrogène, acyle, alcoxy, alkylsulfinyle, alkylsulfonyle, alkylthio, -NH2, aminoalkyle, hydroxyalkyle, arylalkyle, cyano, dialkylamino, halo, haloalcoxy, haloalkyle, alkyle, alcényle, -OH, -CHO, -NO2, aryle (éventuellement substitué par alcoxy, haloalcoxy, halogène, alkyle ou haloalkyle), hétéroaryle (éventuellement substitué par alcoxy, haloalcoxy, halogène, alkyle ou haloalkyle), hétérocycloalkyle, aminoacyle, aminosulfonyle, acylamino, sulfonylamino, hétéroarylalkyle, amine cyclique, aryloxy, hétéroaryloxy, arylalkyloxy ou hétéroarylalkyloxy.
PCT/GB2009/002368 2008-10-07 2009-10-05 Composés de quinolin-2-one Ceased WO2010040989A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2457900A1 (fr) 2010-11-25 2012-05-30 Almirall, S.A. Nouveaux dérivés de pyrazole présentant un comportement antagoniste CRTH2
EP2526945A1 (fr) * 2011-05-25 2012-11-28 Almirall, S.A. Nouveaux antagonistes de CRTH2
EP2720695A4 (fr) * 2011-06-15 2014-11-12 Nono Inc Agents et méthodes de traitement de maladies ischémiques et d'autres maladies
US10029995B2 (en) 2015-09-03 2018-07-24 Forma Therapeutics, Inc. [6,6] fused bicyclic HDAC8 inhibitors

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Publication number Priority date Publication date Assignee Title
WO2007036743A2 (fr) * 2005-09-30 2007-04-05 Argenta Discovery Limited Quinoleines et leur utilisation therapeutique

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2007036743A2 (fr) * 2005-09-30 2007-04-05 Argenta Discovery Limited Quinoleines et leur utilisation therapeutique

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2457900A1 (fr) 2010-11-25 2012-05-30 Almirall, S.A. Nouveaux dérivés de pyrazole présentant un comportement antagoniste CRTH2
WO2012069175A1 (fr) 2010-11-25 2012-05-31 Almirall, S.A. Nouveaux dérivés de pyrazole possédant un comportement antagoniste de crth2
EP2526945A1 (fr) * 2011-05-25 2012-11-28 Almirall, S.A. Nouveaux antagonistes de CRTH2
EP2720695A4 (fr) * 2011-06-15 2014-11-12 Nono Inc Agents et méthodes de traitement de maladies ischémiques et d'autres maladies
US10029995B2 (en) 2015-09-03 2018-07-24 Forma Therapeutics, Inc. [6,6] fused bicyclic HDAC8 inhibitors
US10370343B2 (en) 2015-09-03 2019-08-06 Forma Therapeutics, Inc. [6,6] Fused bicyclic HDAC8 inhibitors
US10829460B2 (en) 2015-09-03 2020-11-10 Valo Early Discovery, Inc. [6,6] fused bicyclic HDAC8 inhibitors
US11414392B2 (en) 2015-09-03 2022-08-16 Valo Health, Inc. [6,6] fused bicyclic HDAC8 inhibitors

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