Back to results
US 2010/0305133 A1Published application
Prolyl Hydroxylase Inhibitors
AssigneeSmithKline Beecham Corporation
InventorsMariela Colón, Duke M. Fitch
Life of this patent
Estimating the term…
Abstract
The invention described herein relates to certain quinoxaline-5-carboxamide derivatives of formula (I) which are antagonists of HIF prolyl hydroxylases and are useful for treating diseases benefiting from the inhibition of this enzyme, anemia being one example.
Claims7
A compound of formula (I):
- wherein:
- R1 is —NR6R7 or —OR8;
- R2, R3, R4, and R5 are each independently selected from the group consisting of hydrogen, nitro, cyano, halogen, —C(O)R11, —C(O)OR11, —OR11, —SR11, —S(O)R11, —S(O)2R11, —NR9R10, —CONR9R10, —N(R9)C(O)R11, —N(R9)C(O)OR11, —OC(O)NR9R10, —N(R9)C(O)N9R10, —P(O)(OR11)2, —SO2NR9R10, —N(R9)SO2R11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C5-C8 cycloalkenyl, aryl, and heteroaryl;
- R6 and R7 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, and heteroaryl;
- R8 is hydrogen, or a cation, or C1-C4 alkyl;
- R9 and R10 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C8 cycloalkyl, C1-C10 alkyl-C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C1-C10 alkyl-C3-C8 heterocycloalkyl, aryl, C1-C10 alkyl-aryl, heteroaryl, C1-C10 alkyl-heteroaryl, —CO(C1-C4 alkyl), —CO(C3-C6 cycloalkyl), —CO(C3-C6 heterocycloalkyl), —CO(aryl), —CO(heteroaryl), and —SO2(C1-C4 alkyl);
- or R9 and R10 taken together with the nitrogen to which they are attached form a 5- or 6- or 7-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen or sulphur;
- each R11 is independently selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —CO(C1-C4 alkyl), —CO(aryl), —CO(heteroaryl), —CO(C3-C6 cycloalkyl), —CO(C3-C6 heterocycloalkyl), —SO2(C1-C4 alkyl), C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, aryl, C1-C10 alkyl-aryl, heteroaryl, and C1-C10 alkyl-heteroaryl;
- any carbon or heteroatom of R2, R3, R4, R5, R6, R7, R8, R9, R10, or R11 is unsubstituted or, where possible, is substituted with one or more substituents independently selected from C1-C6 alkyl, aryl, heteroaryl, halogen, —NR9R10, cyano, nitro, —C(O)R11, —C(O)OR11, —SR11, —S(O)R11, —S(O)2R11, —CONR9R10, —N(R9)C(O)R11, —N(R9)C(O)OR11, —OC(O)NR9R10, —N(R9)C(O)NR9R10, —SO2NR9R10, —N(R9)SO2R11, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C5-C8 cycloalkenyl, aryl or heteroaryl, wherein R9, R10, and R11 are the same as defined above;
- or a pharmaceutically acceptable salt or solvate thereof.
7 more elements
A process for preparing a compound of formula (I)
- wherein R1, R2, R3, R4, and R5 are the same as defined above for formula (I), the process comprising treating a compound of formula A:
- wherein R4 and R5 are the same as for those groups in formula (I), in a hydrogen atmosphere with an appropriate catalyst, such as palladium on charcoal, in an appropriate solvent, such as ethyl acetate or with an appropriate reducing agent, such as tin(II) chloride dihydrate, in an appropriate solvent, such as ethanol with or without acetonitrile, followed by addition of an appropriately substituted 1,2-dicarbonyl compound or a hydrate thereof, such as phenylglyoxal monohydrate, methyl glyoxal, glyoxal, glyoxylic acid ethyl ester, 2,3-butanedione, 3,4-difluorophenylglyoxal hydrate, 2,4-difluorophenylglyoxal hydrate, t-butylglyoxal, 4-cyclohexylphenylglyoxal hydrate, or 4-fluorophenylglyoxal hydrate, in an appropriate solvent, such as acetonitrile/water or methanol, with heating under either conventional thermal conditions or by microwave irradiation, to form a compound of formula B:
- wherein R2, R3, R4, and R5 are the same as for those groups in formula (I), which undergoes ether cleavage/ester hydrolysis with an appropriate reagent, such as boron tribromide, in an appropriate solvent, such as dichloromethane, and is then coupled with an appropriate glycine ester, such as glycine ethyl ester hydrochloride, and an appropriate base, such as triethylamine or diisopropylethylamine, and an appropriate coupling reagent, such as HATU or PyBOP, in an appropriate solvent, such as N,N-dimethylformamide or dichloromethane, followed by ester hydrolysis with an appropriate base, such as sodium hydroxide, in an appropriate solvent, such as ethanol or tetrahydrofuran/methanol, to form a compound of formula (I) where R1 is —OH.
Dependencies are inferred from the claim text.