US 2014/0228303 A1 · NOVEL SGLT INHIBITORS

Abstract

The present invention relates to novel compounds of Formula I, their pharmaceutically acceptable derivatives, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof. The invention also relates to the processes for the synthesis of novel compounds of Formula I, their pharmaceutically acceptable derivatives, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof. The present invention also provides pharmaceutical compositions comprising novel compounds of Formula I and methods of treating or preventing one or more conditions or diseases that may be regulated or normalized via inhibition of Sodium Glucose Cotransporter-2 (SGLT-2).

A compound of Formula I,

wherein:
‘---’ is either a single bond or absent;
ring A represents monocyclic or polycyclic C3-20 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl or 3-14 membered heterocyclyl ring;
ring B represents monocyclic or polycyclic C3-20 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl or 3-14 membered heterocyclyl ring;
U, V and W are independently selected from —H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, —OH, —CN, —N3, —NO2, —OCONH2, —F, —Cl, —Br, —I, —COOH, —CONH2, —CONHNH2, —NH2, —NHCONH2, —NHCSNH2, —NH(C═NH)NH2, —NHNH2, —NHCHO, —NHCOOH, —SH, —SO3H, —CH(═NOH), —CORa, —OR9, —COORa, —CONRaRb, —NRaRb, —NRaSO2Rb, —NRaCONRbRc, —NRaCORb, —NRaCOORb, —OCORa, —OCOORa, —OCONRaRb, —SRa, —S(O)Ra, —S(O)2Ra, —SO2NRaRb, —CRa(═NORb), —NHP(O)RaRb;
wherein the said C1-12 alkyl, C2-12 alkenyl and C2-12 alkynyl, may optionally be substituted at any available position by one or more suitable substituents selected from R10;
provided that at least two out of U, V and W represent —OR9;
Z represents —(CH2)nORa, —ORa, —OCORa, —OCOORa, —OCONRaRb, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, —CN, —OCONH2, —CHO, —COOH, —CONH2, —CONHNH2, —NH2, —NHCOOH, —CH2OH, —OH, —SH, —SO3H, —CH(═NOH), —CH(═NCN), —CORa, —COORa, —CONRaRb, —NRaRb, —NRaSO2Rb, —NRaCONRbRc, —NRaNRbRc, —NRaCORb, —NRaCOORb, —SRa, —S(O)Ra, —S(O)2Ra, —SO2NRaRb or —CRa(═NORb);
wherein the said C1-12 alkyl, C2-12 alkenyl and C2-12 alkynyl, may optionally be substituted at any available position by one or more suitable substituents selected from R10;
R1, R2, R3 and R4 are independently selected from —H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl, —CN, —COCN, —N3, —NO2, —OCONH2, —F, —Cl, —Br, —I, —CHO, —COOH, —CONH2, —NH2, —NHCONH2, —NHCHO, —NHCOOH, —OH, —ORa, —SH, —SO3H;
wherein the said C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl and 5-10 membered heteroaryl, may optionally be substituted at any available position by one or more suitable substituents selected from R10;
R5 represents —H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl, or 5-10 membered heteroaryl;
wherein the said C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl and 5-10 membered heteroaryl, may optionally be substituted at any available position by one or more suitable substituents selected from R10;
R6 represents —H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl, —CN, —NH2, —NHCONH2, —NHCHO, —OH, —SH, —NRaRb, —NRaCONRbRc, —NRaCORb, —ORa or —SRa;
wherein the said C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl and 5-10 membered heteroaryl, may optionally be substituted at any available position by one or more suitable substituents selected from R10;
R7 represents —H, —OH or —OR9;
R8 represents —H, —CHO, —COOH, —CONH2, —OH, —CH(═NOH), —CORa, —COORa, —CONRaRb, —CRa(═NORb), —ORa, or —(CH2)nORa;
or
R7 and R8 can be joined together to form a saturated or unsaturated ring, in which one or more methylene groups or methyne groups can be replaced with O, S, NRa or oxo;
the ring thus formed may optionally be substituted at any available position by one or more suitable substituents selected from R11;
or
R8 and Z can be joined together to form a saturated or unsaturated ring, in which one or more methylene groups or methyne groups can be replaced with O, S, NRa or oxo;
the ring thus formed may optionally be substituted at any available position by one or more suitable substituents selected from R11;
R9 represents —H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl, —CHO, —CONH2, —CORa, —CONRaRb, —S(O)2Ra, SO2NRaRb, —P(O)RaRb, —P(O)ORaORb, —P(O)RaORb, —P(O)NRaORb or —P(O)NRaRb;
wherein the said C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl and 5-10 membered heteroaryl, may optionally be substituted at any available position by one or more suitable substituents selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl, —CHO, —CONH2, —CORa, —CONRaRb, —S(O)2Ra, —SO2NRaRb, —P(O)RaRb, —P(O)ORaORb, —P(O)RaORb, —P(O)NRaORb, —P(O)NRaRb;
further wherein the said C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl and 5-10 membered heteroaryl, may optionally be substituted at any available position by one or more suitable substituents selected from R12;
R10 represents C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl, —CN, —COCN, —N3, —NO2, —OCN, —NCO, —SCN, —NCS, —OCONH2, —ONO2, —F, —Cl, —Br, —I, —CO—, —CS—, —CHO, —CHS, —COOH, —COSH, —CONH2, —CONHNH2, —CSNHNH2, —CSNH2, —NH2, —NHCONH2, —NHCSNH2, —NH(C═NH)NH2, —NHNH2, —NHCHO, —NHCHS, —NHCOOH, —NHCSOH, —OH, —SH, —SO3H, —CH(═NOH), —CH(═NCN), —CORa, —CSRa, —COORa, —CSORa, —COSRa, —CONRaRb, —CSNRaRb, —COCORa, —CONRaNRbRc, —CSNRaNRbRc, —CSNRaRb, —NRaRb, —NRaSO2Rb, —NRaCONRbRc, —NRaCSNRbRc, —NRa(C═NRb)NRcRd, —NRaNRbRc, —NRaCORb, —NRaCSRb, —NRaCOORb, —NRaCSORb, —ORa, —OCORa, —OCOORa, —OCONRaRb, —OCSRa, —OCSORa, —ONO2, —OCSNRaRb, —SRa, —S(O)Ra, —S(O)2Ra, —SO2NRaRb, —CRa(═NORb), —CRa(═NCOORb), —CRa(═NSORb), —CRa(═NSO2Rb), —C(═NRa)—NRbRc, —C(═NORa)—NRbRc, —CRa(═NCN), —NCRa, —P(O)RaRb, —P(O)ORaORb, —P(O)RaORb, —P(O)NRaORb, —P(O)NRaRb, —OP(O)RaRb or —NHP(O)RaRb;
wherein the said C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl and 5-10 membered heteroaryl, may optionally be substituted at any available position by one or more suitable substituents selected from R12;
R11 represents C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl, —CN, —COCN, —N3, —NO2, —OCN, —NCO, —SCN, —NCS, —OCONH2, —ONO2, —F, —Cl, —Br, —I, —CO—, —CS—, —CHO, —CHS, —COOH, —COSH, —CONH2, —CONHNH2, —CSNHNH2, —CSNH2, —NH2, —NHCONH2, —NHCSNH2, —NH(C═NH)NH2, —NHNH2, —NHCHO, —NHCHS, —NHCOOH, —NHCSOH, —OH, —SH, —SO3H, —CH(═NOH) or —CH(═NCN);
wherein the C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl and 5-10 membered heteroaryl, may optionally be substituted at any available position by one or more suitable substituents selected from R12;
R12 represents C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl, —CN, —COCN, —N3, —NO2, —OCN, —NCO, —SCN, —NCS, —OCONH2, —ONO2, —F, —Cl, —Br, —I, —CO—, —CS—, —CHO, —CHS, —COOH, —COSH, —CONH2, —CONHNH2, —CSNHNH2, —CSNH2, —NH2, —NHCONH2, —NHCSNH2, —NH(C═NH)NH2, —NHNH2, —NHCHO, —NHCHS, —NHCOOH, —NHCSOH, —OH, —SH, —SO3H, —CH(═NOH) or —CH(═NCN);
Ra, Rb, Rc and Rd are independently selected from —H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-10 aryl, C3-20 cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl, —CN, —COCN, —N3, —NO2, —OCN, —NCO, —SCN, —NCS, —OCONH2, —ONO2, —F, —Cl, —Br, —I, —CO—, —CS—, —CHO, —CHS, —COOH, —COSH, —CONH2, —CONHNH2, —CSNHNH2, —CSNH2, —NH2, —NHCONH2, —NHCSNH2, —NH(C═NH)NH2, —NHNH2, —NHCHO, —NHCHS, —NHCOOH, —NHCSOH, —OH, —SH, —SO3H, —CH(═NOH), —CH(═NCN);
each of which may optionally be substituted at any available position by one or more suitable substituents selected from R12;
or
Ra and Rb when attached to the same atom, can be joined together to form a monocyclic or polycyclic ring, in which one or more methylene groups or methyne groups can be replaced with O, S, SO, SO2, NRa, PRa, P(═O)Ra or oxo;
the ring thus formed may optionally be substituted at any available position by one or more suitable substituents selected from R11;
or
Rb and Rc when attached to the same atom, can be joined together to form a monocyclic or polycyclic ring, in which one or more methylene groups or methyne groups can be replaced with O, S, SO, SO2, NRa, PRa, P(═O)Ra or oxo;
the ring thus formed may optionally be substituted at any available position by one or more suitable substituents selected from R11;
or
Rc and Rd when attached to the same atom, can be joined together to form a monocyclic or polycyclic ring, in which one or more methylene groups or methyne groups can be replaced with O, S, SO, SO2, NRa, PRa, P(═O)Ra or oxo;
the ring thus formed may optionally be substituted at any available position by one or more suitable substituents selected from R11;
n represents 1, 2, 3, 4 or 5;
its pharmaceutically acceptable derivatives, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof.

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Novel sglt inhibitors

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Novel sglt inhibitors

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Abstract

Claims19