WO2007144625A1 - Composés de 2-oxo-2h-chromène - Google Patents

Composés de 2-oxo-2h-chromène Download PDF

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WO2007144625A1
WO2007144625A1 PCT/GB2007/002212 GB2007002212W WO2007144625A1 WO 2007144625 A1 WO2007144625 A1 WO 2007144625A1 GB 2007002212 W GB2007002212 W GB 2007002212W WO 2007144625 A1 WO2007144625 A1 WO 2007144625A1
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oxo
compound
chromen
group
optionally substituted
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PCT/GB2007/002212
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English (en)
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George Hynd
Neil Victor Harris
Richard James Bull
Sophie Gardan
Balraj Krishan Handa
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Argenta Discovery Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics

Definitions

  • This invention relates to 2-Oxo-2H-chromene 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 al; 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 al; 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 al; J. Immunol., 2002, 168, 443-449).
  • exogenously administered CRTH2 agonists enhance the allergic response in sensitised mice (Spik et al; J. Immunol., 2005, 174, 3703-3708).
  • rats exogenously applied CRTH2 agonists cause a pulmonary eosinophilia but a DP agonist (BW 245C) or a TP agonist (I-BOP) showed no effect (Shirashi et al; J. Pharmacol.
  • Examples include: 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); tetrahydroquinolines (EP1413306; EP1435356; WO2004/032848; WO2004/035543; WO2005/007094), and phenylacetic acids (WO2004/058164; WO2004/089884; WO2004/089885; WO2005/018529).
  • 2-oxo-2H- chromene compounds of general formula [1] represent a novel class of compounds active at the CRTH2 receptor. Summary of
  • One aspect of the invention provides the use of a compound of structural formula [1] or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of conditions responsive to modulation of CRTH2 activity:
  • 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 (optionally substituted)alkylene-Z;
  • W represents an optionally substituted aryl or heteroaryl group or an optionally substituted alkyl or cycloalkyl group
  • Y represents an optionally substituted phenyl or 5- or 6-membered heteroaryl group
  • R a , R b , and R° independently represent hydrogen, acyl (e.g. -COCH 3 ), alkoxy (e.g. -OCH 3 ), alkoxycarbonyl (e.g. -COOCH 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 ), hydroxyalkyl (e.g.
  • alkoxyalkyl e.g. -CH 2 OCH 3
  • arylalkyl e.g. -CH 2 Ph or -CH 2 -CH 2 -Ph
  • cyano dialkylamino (e.g. -N(CHg) 2 ), halo, haloalkoxy (e.g. -OCF 3 or -OCHF 2 ), haloalkyl (e.g. -CF 3 ), alkyl (e.g. -CH 3 or -CH 2 CH 3 ), alkenyl (e.g.
  • -CH CH 2 ), -OH, 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 (e.g.
  • heteroarylalkyl cyclic amine (e.g. morpholine), aryloxy, heteroaryloxy, arylalkyloxy (e.g. benzyloxy) and heteroarylalkyloxy;
  • substituted as applied to any moiety herein means substituted with up to four compatible substituents, each of which independently may be, for example, alkyl, cycloalkyl, (d-C 6 )alkoxy, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, alkylthio, phenyl, monocyclic heteroaryl having 5 or 6 ring atoms, halo (including fluoro, bromo and chloro), haloalkyl such as trifluoromethyl, haloalkoxy such as trifluoromethoxy, nitro, nitrile (-CN), oxo, -COOH, -COOR A , -COR A , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -CONHR A ,
  • Alkylene or alkenylene groups may be optionally substituted.
  • Suitable optional substituent groups include alkoxy, alkylamino, alkylsulfinyl, alkylsulfonyl, alkylthio, -NH 2 , aminoalkyl, arylalkyl, cyano, dialkylamino, halo, haloalkoxy, haloalkyl, alkyl, and -OH.
  • the invention includes compounds [1] as defined above, and pharmaceutically acceptable salts thereof, independent of use, excluding: 2-(7-methyl-2-oxo-4-phenyl-2H-chromen-5- yloxy)propionic acid; (7-methyl-2-oxo-4-phenyl-2H-chromen-5-yloxy)acetic acid; 2-(3-benzyl-4,7-dimethyl-2-oxo-2/-/-chromen-5-yloxy)propionic acid; 3-benzyl- 4,7-dimethyl-2-oxo-2H-chromen-5-yloxy)acetic acid; (4,7-dimethyl-2-oxo-3- phenyl-2H-chromen-5-yloxy) acetic acid.
  • Also part of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula [1] or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier or excipient.
  • a compound of formula [1] or a pharmaceutically acceptable salt thereof for use in therapy is also part of the invention.
  • Also part 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 a pharmaceutically acceptable salt thereof.
  • Conditions responsive to modulation of CRTH2 activity include asthma, chronic obstructive pulmonary disease, allergic airway syndrome, bronchitis, cystic fibrosis, emphysema and rhinitis, as well as psoriasis, atopic and non- atopic dermatitis Crohn's disease, ulcerative colitis, and irritable bowel disease.
  • 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 ) 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.
  • exemplary alkylthio groups include methylthio and ethylthio.
  • Aminoacyl means a -CO-NR 2 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 -NR 2 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 4 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 4 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 sustitued 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.
  • the 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.
  • Heteroarylalkyloxy means a heteroaryl-alkyloxy- group in which the heteroaryl and alkyloxy moieties are as previously described. Preferred heteroarylalkyloxy groups contain a lower alkyl moiety.
  • heteroarylalkyloxy groups include pyridylmethyloxy.
  • Heteroaryloxy means a heteroaryloxy- group in which the heteroaryl is as previously described.
  • exemplary heteroaryloxy groups include pyridyloxy.
  • Heteroaryl-fused-cycloalkyl means a monocyclic heteroaryi 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 sustitued by one or more substituent groups.
  • the heteroaryl-fused-cycloalkyl 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.
  • Heterocycloalkyl 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.
  • Heterocycloalkylalkyl means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
  • “Hydroxamate” means a group -C(O)NHOR where R is as described herein. Exemplary groups are -C(O)NHOH and -C(O)NHOCH 3 .
  • “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 (n- butyl, /so-butyl or te/f-butyl).
  • Phosphinate means a -P(O)R(OR) group in which R is as described herein.
  • exemplary groups are -P(O)(OH)CH 3 and -P(O)(OH)H.
  • Phosphonate means a -P(O)(OH)OR group in which R is as described herein.
  • exemplary groups are -P(O)(OH) 2 and -P(O)(OH)OC 2 H 5.
  • Phosphonamide means a -P(O)(OR)NR 2 group in which R is as described herein.
  • An exemplary group is -P(O)(OH)NH 2 .
  • “Sulfonate” means a -S(O) 2 OR group whre R is as described herein. Exemplary groups are -S(O) 2 OH (sulfonic acid) and -S(O) 2 OCH 3 .
  • “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-ethy
  • 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; where
  • 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-toluoyl- tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluene- sulfonates, cyclohexylsulfamates and quinates.
  • ester prodrug of a compound of formula [1] containing a carboxyalkyl 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.
  • 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. morpholine)
  • aryloxy, heteroaryloxy, arylalkyloxy e.g. benzyloxy
  • heteroarylalkyloxy e.g. benzyloxy
  • Alkylene or alkenylene groups may be optionally substituted.
  • Suitable optional substituent groups include alkoxy, alkylamino, alkylsulfinyl, alkylsulfonyl, alkylthio, -NH 2 , aminoalkyl, arylalkyl, cyano, dialkylamino, halo, haloalkoxy, haloalkyl, alkyl, and -OH.
  • Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and transforms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers may be prepared by the application or adaptation of known methods (e.g. asymmetric synthesis).
  • the radical -B-Y may be bonded, for example, to the carbon in the 3- position of the 2-oxo-2/-/-chromene ring system.
  • Y may be, for example, optionally substituted phenyl, pyridyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, or pyrrolyl. Presently preferred is the case where Y is optionally substituted phenyl.
  • Optional substituents in Y may be selected from, for example, fluoro, methylsulfonyl, ethylsulfonyl, carbamate, methylcarbamate, methylaminosulfonyl, ethylaminosulfonyl, methylsulfonylamino, ethylsulfonylamino, morpholin-1-ylsulfonyl, piperidin-1- ylsulfonyl, piperizin-1-ylsulfonyl, 4-methylpiperizin-1-ylsulfonyl ( and tetrahydropyrroMylsulfonyl.
  • Optional substituents in Y may also be selected from, for example, chloro, methyl, methoxy, fluoro, cyano, bromo, tert-butyl, and phenyl.
  • Y examples include 4-methylphenyl, 2-, 3- or 4- methoxyphenyl, 2-, 3-, or 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4- phenylphenyl, 4-cyanophenyl, or 4-tert-butylphenyl.
  • B may be, for example, a bond, -CH 2 -, or -CH 2 CH 2 -.
  • R c may be, for example, hydrogen, methyl or ethyl.
  • A may be, for example, -CH 2 -, -CH 2 CH 2 -, -OCH 2 -, -OCH 2 CH 2 CH 2 - wherein the oxygen is attached to the ring carrying R a and R b .
  • R a may be in the 8-position, for example, and R b may be in the 7-position, for example, of the 2-oxo-2H-chromene ring system.
  • R a may be selected from, for example, hydrogen, chloro and fluoro.
  • R b may be selected from, for example, hydrogen, methyl, trifluormethyl, chloro and fluoro.
  • the compounds of the present invention can 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 DP 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.
  • 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 B AY- 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 (H1) receptor antagonists, such as fexofenadine, citirizine, lor
  • 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.
  • 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
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • a 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.
  • propellants e.g. Frigen in the case of metered aerosols
  • surface-active substances e.g. 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.
  • composition In the case of an aerosol-based formulation, 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. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • 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 nonaqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion.
  • 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. Desirably, 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.
  • Benzalkonium chloride 1.0 mg / ml_ Plus water for injection to a total volume of 1 mL
  • 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.
  • the free acid form isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic 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 a benzene-1 ,3-diol of formula [4] and a ⁇ -ketoester of formula [5], in which PG represents an appropriate ester function (such as methyl and ethyl) in the presence of a suitable dehydrating agent, such as phosphorus oxychloride, phosphorus pentoxide, or sulfuric acid.
  • PG represents an appropriate ester function (such as methyl and ethyl) in the presence of a suitable dehydrating agent, such as phosphorus oxychloride, phosphorus pentoxide, or sulfuric acid.
  • intermediate compounds of formula [2b] may conveniently be prepared by the reaction between a benzene-1 ,3-diol of formula [4] and a ⁇ - ketoester of formula [6], in which PG represents an appropriate ester function (such as methyl and ethyl) in the presence of a suitable dehydrating agent, such as phosphorus oxychloride or phosphorus pentoxide.
  • PG represents an appropriate ester function (such as methyl and ethyl) in the presence of a suitable dehydrating agent, such as phosphorus oxychloride or phosphorus pentoxide.
  • the reaction may conveniently be carried out in the presence of a suitable catalyst (for example a palladium compound) in the presence of a base such as triethylamine.
  • compounds of the invention of general formula [1c] 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 trifluoromethane- sulfonyloxy group, and (i-tert-butoxyvinyloxy)-fert-butyldimethylsilane.
  • 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).
  • 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 [1b], in which group A represents an optionally substituted alkenylene group.
  • the transformation of compounds of formula [1b] 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.
  • Method A experiments were performed on a Micromass Platform LCT spectrometer with positive ion electrospray and single wavelength UV 254 nm detection using a Higgins Clipeus C18 5 ⁇ m 100 x 3.0 mm column and a 2 mL / minute flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 14 minutes.
  • the final solvent system was held constant for a further 2 minutes.
  • 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 B 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
  • Microwave experiments were carried out using a Personal Chemistry Smith SynthesizerTM, which uses a single-mode resonator and dynamic field tuning, both of which give reproducibility and control. Temperatures from 40-250 0 C can be achieved, and pressures of up to 20 bar can be reached. Two types of vial are available for this processor, 0.5-2.0 mL and 2.0-5.0 mL.
  • Reverse-phase preparative HPLC purifications were carried out using Genesis 7 micron C-18 bonded silica stationary phase in columns 10 cm in length and 2 cm internal diameter.
  • the mobile phase used was mixtures of acetonitrile and water
  • Lithium hydroxide monohydrate (0.010 g) was added to a stirred suspension of ethyl [3-(4-methoxybenzyl)-4,7-dimethyl-2-oxo-2H-chromen-5-yloxy)]acetate
  • reaction mixture was diluted with ethyl acetate, and this solution was washed with water, dried over magnesium sulfate, and evaporated to give a black semi-solid.
  • tert-Butyl-3-benzyl-4,7-dimethyl-2-oxo-2H-chromen-5-yl)acetate (0.13 g) was dissolved in a 4 M solution of hydrogen chloride in dioxane (1.5 mL) and the resulting solution was allowed to stand at room temperature overnight. The solution was evaporated to dryness and the residue triturated with ether. The resulting solid was collected by filtration, washed with pentane, and dried to give S-benzyMy-dimethyl ⁇ -oxo ⁇ H-chromen- ⁇ -yOacetic acid as a pale yellow solid, 0.085 g.
  • Ethyl 2-(2-methylbenzyl)acetoacetate was prepared by the reaction between ethyl acetoacetate (1.0 g) and 2-methylbenzyl bromide (1.0 ml_) using the method described in Preparation (5a) as a pale yellow oil, 1.4g.
  • Ethyl [4,7-dimethyl-3-(2-methylbenzyl)-2-oxo-2H-chromen-5-yloxy]acetate was prepared by the reaction of 5-hydroxy-3-(2-methylbenzyl)-4,7-dimethyl-2-oxo-2/-/- chromen-2-one (0.13 g) and ethyl bromoacetate following the method described in Preparation (5c) as a white solid, 0.14 g.
  • Ethyl 2-(4-methylbenzyl)acetoacetate was prepared from the reaction between ethyl acetoacetate (1.0 g) and 4-methylbenzyl chloride (1.0 mL) using the method described in Preparation (5a) as a colourless oil, 0.97 g.
  • 5-Hydroxy-3-(4-methylbenzyl)-4,7-dimethyl-2-oxo-2/-/-chromen-2-one was prepared from the reaction between ethyl 2-(4-methylbenzyl)acetoacetate (0.90 g) and 5-methylbenzene-1 ,3-diol (0.37 g) following the method described in Preparation (6b). Two crops of materiel were obtained as orange solids, 0.062 g and 0.037 g.
  • Ethyl [4,7-dimethyl-3-(4-methylbenzyl)-2-oxo-2H-chromen-5-yloxy]acetate was prepared from the reaction between 5-hydroxy-3-(4-methylbenzyl)-4,7-dimethyl- 2-oxo-2H-chromen-2-one (0.084 g) and ethyl bromoacetate (0.063 ml_) following the method described in Preparation (5c) as a white solid, 0.062 g.
  • fert-Butanol (0.10 mL) and ethyl acetoacetate (1.3 g) were added with stirring and ice-cooling under a nitrogen atmosphere to a suspension of potassium tert- butoxide (1.1 g) in anhydrous tetrahydrofuran (25 mL).
  • 4-chlorobenzyl chloride was added (1.6 g) and the mixture stirred at 7O 0 C overnight.
  • After cooling to room temperature the mixture was treated with water ( ⁇ 5 mL) and evaporated to low bulk. The residue was partitioned between ethyl acetate and water, the layers separated, and the organic layer dried over sodium sulfate and evaporated.
  • Ethyl 2-(3-methoxybenzyJ)acetoacetate was prepared from the reaction between ethyl acetoacetate (1.0 g) and 3-methoxybenzyl chloride (1.1 ml_) following the method described in Preparation (5a) as a colourless oil, 0.55 g.
  • Ethyl [3-(3-methoxybenzyl)-4,7-dimethyl-2-oxo-2H-chromen-5-yloxy]acetate was prepared by the reaction between 5-hydroxy-3-(3-methoxybenzyl)-4,7-dimethyl- chromen-2-one (0.16 g) and ethyl bromoacetate (0.14 ml_) following the method described in Preparation (5c).
  • Ethyl [3-(4-fluorobenzyl)-4,7-dimethyl-2-oxo-2H-chromen-5-yloxy]acetate was prepared by the reaction between 3-(4-fluorobenzyl)-5-hydroxy-4,7-dimethyl- chromen-2-one (0.98 g) and ethyl bromoacetate (0.73 ml_) following the method described in Preparation (5c) as a white solid, 1.1 g.
  • [3-(4-Fluorobenzyl)-4,7-dimethyl-2-oxo-2/-/-chromen-5-yloxy]acetic acid was prepared from the hydrolysis of ethyl [3-(4-fluorobenzyl)-4,7-dimethyl-2-oxo-2/-/- chromen-5-yloxy]acetate (1.1 g) following the method described in Preparation (5d) as a white solid, 0.76 g.
  • Ethyl (4,7-dimethyl-2-oxo-3-phenethyl-2/-/-chromen-5-yloxy)acetate was prepared from the reaction between 5-hydroxy-4,7-dimethyl-3- phenethylchromen-2-one (0.54 g) and ethyl bromoacetate (0.41 ml_) following the method described in Preparation (5c) as a white solid, 0.67 g.
  • Ethyl phenylacetate (2.0 g) was added dropwise under nitrogen at -78 0 C to a stirred solution of lithium bis(trimethylsilazide) in anhydrous tetrahydrofuran (30 ml_). This mixture was stirred at -78 0 C for one hour, and was then treated with acetyl chloride (1.0 ml_). The resulting mixture was stirred at -78 0 C for a further one and one-half hours, and was then poured onto a saturated aqueous ammonium chloride solution.
  • 5-Hydroxy-4,7-dimethyl-3-phenylchromen-2-one was prepared from the reaction between ethyl 2-phenylacetoacetate (0.03 g) and 5-methylbenzene-1 ,3-diol (0.14 g) following the method described in Preparation (5b).
  • the crude product was purified by flash chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1 :2 by volume), to give 5-hydroxy-4,7-dimethyl-3- phenylchromen-2-one as a pale brown semi-solid, 0.081 g.
  • Ethyl (4,7-dimethyl-2-oxo-3-phenyl-2H-chromen-5-yloxy)acetate was prepared from the reaction between 5-hydroxy-4,7-dimethyl-3-phenylchromen-2-one (0.075 g) and ethyl bromoacetate (0.063 ml_) following the method described in Preparation (5c).
  • the crude product was purified by flash chromatography on silica gel eluting with a mixture of ethyl acetate and cyclohexane (1 :3 by volume) to give ethyl (4,7-dimethyl-2-oxo-3-phenyl-2H-chromen-5-yloxy)acetate as a white solid, 0.019 g.
  • reaction mixture was taken to pH ⁇ 1 by the addition of dilute hydrochloric acid and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and evaporated.
  • Activated zinc powder (67 g) was suspended in anhydrous tetrahydrofuran (200 ml_) under an atmosphere of nitrogen. A few drops of benzyl cyanide and one crystal of iodine were added, and the mixture sonicated until the reaction was initiated. The mixture was then brought to reflux with stirring, and benzyl cyanide (2.0 ml_) was added in one portion, followed by the dropwise addition over one hour of ethyl 2-bromopropionate (4.9 ml_). The mixture was then stirred at reflux for a further two hours, allowed to cool to room temperature, and quenched by pouring onto saturated aqueous potassium carbonate solution (100 ml_).
  • Radioligand Binding Assay The receptor binding assay is performed in a final volume of 200 ⁇ l_ binding buffer [10 mM BES (pH 7.4), 1 mM EDTA, 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).
  • the GTP ⁇ S Assay is performed in a final volume of 200 mL assay buffer (2OmM HEPES pH 7.4, 1OmM MgCI 2 , 10OmM 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 30 0 C prior to addition of PGD 2 (3OnM 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]-GTPYS (0.1nM final concentration).
  • the assay plate is than shaken and incubated for 5 minutes at 30°C. Finally, SPA beads (Amersham Biosciences, UK) are added to a final concentration of 1.5mg/well and the plate shaken and incubated for 30 minute at 30 0 C. The sealed plate is centrifuged at 1000g for IOmins at 30 0 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 4 and 23 have Ki values of 32 and 53 nM, respectively. The compounds also have Ki values of less than 10 ⁇ M in the GTP ⁇ S functional assay. For example, compounds of Examples 4 and 23 have Ki values of 89 and 190 nM, respectively.

Abstract

Les composés représentés par la formule structurelle (1) modulent l'activité de CRTH2 et sont utiles, par exemple, dans les maladies respiratoires. Dans la formule (1), A représente une liaison directe, un groupe alkylène ou alcénylène éventuellement substitué, ou un groupe de formule Z-alkylène(éventuellement substitué); B représente une liaison directe, un groupe alkylène ou alcénylène éventuellement substitué, ou un groupe de formule Z-alkylène(éventuellement substitué) ou alkylène(éventuellement substitué)-Z; Z représente un atome d'oxygène, un groupe NH ou N-alkyle, ou un groupe de formule S(O)n, dans lequel n = 0 à 2; X représente un groupe acide carboxylique, tétrazole, 3-hydroxyisoxazole, acide hydroxamique, phosphinate, phosphonate, phosphonamide, acide sulfonique ou un groupe de formule C(=O)NHSO2W ou SO2NHC(=O)W; W représente un groupe aryle ou hétéroaryle éventuellement substitué ou un groupe alkyle ou cyclooalkyle éventuellement substitué; Y représente un groupe phényle ou hétéroaryle à 5 ou 6 chaînons éventuellement substitué, Ra, Rb, et Rc représentent indépendamment un atome d'hydrogène, un groupe acyle, alcoxy, alcoxycarbonyle, alkylamino, alkylsulfinyle, alkylsulfonyle, alkylthio, -NH2, aminoalkyle, hydroxyalkyle, alcoxyalkyle, arylalkyle, cyano, dialkylamino, halogéno, halogénoalcoxy, halogénoalkyle, alkyle, alcényle, -OH, aryle éventuellement substitué, hétéroaryle éventuellement substitué, hétérocycloalkyle, aminoacyle, aminosulfonyle, acylamino, sulfonylamino, hétéroarylalkyle, amino cyclique, aryloxy, hétéroaryloxy, arylalkyloxy ou hétéroarylalkyloxy.
PCT/GB2007/002212 2006-06-14 2007-06-13 Composés de 2-oxo-2h-chromène WO2007144625A1 (fr)

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