Method for treating post-prandial hypoglycemia

A method of treating a subject with post-prandial hypoglycemia associated with a gastric surgery, comprising the step of orally administering a sodium-dependent glucose transporter (SGLT)1 inhibitor compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, to said subject,

• wherein the compound of Formula I is:
• wherein
• R1 represents H, or an optionally substituted C1-6 alkyl group;
• one of Q and T represents a group:
• while the other represents a C1-6 alkyl group, a halo(C1-6 alkyl) group, a C1-6 alkoxy-substituted (C1-6 alkyl) group or a C3-7 cycloalkyl group;
• R2 represents a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a halo(C1-6 alkyl) group, a halo(C1-6 alkoxy) group, a C1-6 alkoxy-substituted (C1-6 alkoxy) group, a C3-7 cycloalkyl-substituted (C2-6 alkoxy) group or -A-RA in which A represents a single bond, an oxygen atom, a methylene group, an ethylene group, —OCH2— or —CH2O—;
• and RA represents a C3-7 cycloalkyl group, a C2-6 heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a halo(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group, a carboxy group, a C2-7 alkoxycarbonyl group, a cyano group and a nitro group, or a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom and a C1-6 alkyl group;
• X represents a single bond, an oxygen atom or a sulfur atom;
• Y represents a C1-6 alkylene group which may be substituted by a hydroxy group or a C2-6 alkenylene group;
• Z represents —RB, —CORC, —SO2RC, —CON(RD)RE, —SO2NHRF or —C(═NRG)N(RH)RI;
• RC represents an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6 alkylsulfonylamino group, a C1-6 alkyl group and a C1-6 alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6 alkyl group, or a C1-6 alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i), wherein substituent group (i) consists of:
• a hydroxy group, a C1-6 alkoxy group, a C1-6 alkylthio group, an amino group, a mono or di(C1-6 alkyl)amino group, a mono or di[hydroxy(C1-6 alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(C1-6 alkyl)ureido group, a mono or di(C1-6 alkyl)sulfamide group, a C2-7 acylamino group, a C1-6 alkylsulfonylamino group, a C1-6 alkylsulfonyl group, a carboxy group, a C2-7 alkoxycarbonyl group, —CON(RJ)RK in which RJ and RK are the same or different, and each represents a hydrogen atom or a C1-6 alkyl group which may have the same or different 1 to 3 substituents selected from the group consisting of a hydroxy group, an amino group, a mono or di(C1-6 alkyl)amino group, a mono or di[hydroxy(C1-6 alkyl)]amino group, an ureido group, a mono or di(C1-6 alkyl)ureido group, a C2-7 acylamino group, a C1-6 alkylsulfonylamino group and a carbamoyl group, or both of RJ and RK bind together with the neighboring nitrogen atom to form a C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group, an aryl(C1-6 alkoxy) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6 alkyl group and a C1-6 alkoxy group on the ring, an aryl(C1-6 alkylthio) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6 alkyl group and a C1-6 alkoxy group on the ring, a C3-7 cycloalkyl group, a C2-6 heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6 alkylsulfonylamino group, a C1-6 alkyl group and a C1-6 alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6 alkyl group, a C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group, and a C1-4 aromatic cyclic amino group which may have a C1-6 alkyl group as a substituent;
• R4, RB, RD, RE and RF are the same or different, and each represents a hydrogen atom, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6 alkylsulfonylamino group, a C1-6 alkyl group and a C1-6 alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6 alkyl group, or a C1-6 alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i), wherein substituent group (i) consists of:
• a hydroxy group, a C1-6 alkoxy group, a C1-6 alkylthio group, an amino group, a mono or di(C1-6 alkyl)amino group, a mono or di[hydroxy(C1-6 alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(C1-6 alkyl)ureido group, a mono or di(C1-6 alkyl)sulfamide group, a C2-7 acylamino group, a C1-6 alkylsulfonylamino group, a C1-6 alkylsulfonyl group, a carboxy group, a C2-7 alkoxycarbonyl group, —CON(RJ)RK in which RJ and RK are the same or different, and each represents a hydrogen atom or a C1-6 alkyl group which may have the same or different 1 to 3 substituents selected from the group consisting of a hydroxy group, an amino group, a mono or di(C1-6 alkyl)amino group, a mono or di[hydroxy(C1-6 alkyl)]amino group, an ureido group, a mono or di(C1-6 alkyl)ureido group, a C2-7 acylamino group, a C1-6 alkylsulfonylamino group and a carbamoyl group, or both of RJ and RK bind together with the neighboring nitrogen atom to form a C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group, an aryl(C1-6 alkoxy) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6 alkyl group and a C1-6 alkoxy group on the ring, an aryl(C1-6 alkylthio) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6 alkyl group and a C1-6 alkoxy group on the ring, a C3-7 cycloalkyl group, a C2-6 heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6 alkylsulfonylamino group, a C1-6 alkyl group and a C1-6 alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6 alkyl group, a C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group, and a C1-4 aromatic cyclic amino group which may have a C1-6 alkyl group as a substituent,
• or both of R4 and RB bind together with the neighboring nitrogen atom to form a C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group, or both of RD and RE bind together with the neighboring nitrogen atom to form a C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group;
• RG, RH and RI are the same or different, and each represents a hydrogen atom, a cyano group, a carbamoyl group, a C2-7 acyl group, a C2-7 alkoxycarbonyl group, an aryl(C2-7 alkoxycarbonyl) group, a nitro group, a C1-6 alkylsulfonyl group, a sulfamide group, a carbamimidoyl group, or a C1-6 alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i) wherein substituent group (i) consists of:
• a hydroxy group, a C1-6 alkoxy group, a C1-6 alkylthio group, an amino group, a mono or di(C1-6 alkyl)amino group, a mono or di[hydroxy(C1-6 alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(C1-6 alkyl)ureido group, a mono or di(C1-6 alkyl)sulfamide group, a C2-7 acylamino group, a C1-6 alkylsulfonylamino group, a C1-6 alkylsulfonyl group, a carboxy group, a C2-7 alkoxycarbonyl group, —CON(RJ)RK in which RJ and RK (are the same or different, and each represents a hydrogen atom or a C1-6 alkyl group which may have the same or different 1 to 3 substituents selected from the group consisting of a hydroxy group, an amino group, a mono or di(C1-6 alkyl)amino group, a mono or di[hydroxy(C1-6 alkyl)]amino group, an ureido group, a mono or di(C1-6 alkyl)ureido group, a C2-7 acylamino group, a C1-6 alkylsulfonylamino group and a carbamoyl group, or both of RJ and RK bind together with the neighboring nitrogen atom to form a C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group, an aryl(C1-6 alkoxy) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6 alkyl group and a C1-6 alkoxy group on the ring, an aryl(C1-6 alkylthio) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6 alkyl group and a C1-6 alkoxy group on the ring, a C3-7 cycloalkyl group, a C2-6 heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6 alkylsulfonylamino group, a C1-6 alkyl group and a C1-6 alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6 alkyl group, a C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group, and a C1-4 aromatic cyclic amino group which may have a C1-6 alkyl group as a substituent,
• or both of RG and RH bind to form an ethylene group, or both of RH and RI bind together with the neighboring nitrogen atom to form a C2-6 cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6 alkyl group, an oxo group, a carbamoyl(C1-6 alkyl) group, a hydroxy(C1-6 alkyl) group and a C1-6 alkylsulfonylamino-substituted (C1-6 alkyl) group;
• R3, R5 and R6 are the same or different, and each represents a hydrogen atom, a halogen atom, a C1-6 alkyl group or a C1-6 alkoxy group;
• and wherein the compound of Formula II is:
• wherein
• R7 is hydrogen or optionally substituted C1-10-alkyl, C1-5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R7A;
• each R7A is independently amino, ester, amide, thiol, carboxylic acid, cyano, halo, hydroxyl, or optionally substituted C1-4-alkoxy, C1-5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R7B;
• each R7B is independently C1-4-alkyl, halo, or hydroxyl;
• n is 0, 1, or 2;
• each R8 is independently F or OR8A, wherein each R8A is independently hydrogen, C1-4-alkyl, or acyl;
• each R9 is independently halo, hydroxyl, or optionally substituted C1-10-alkyl or C1-10-alkoxy, which optional substitution is with one or more R9A;
• each R9A is independently amino, ester, amide, thiol, carboxylic acid, cyano, halo, hydroxyl, or optionally substituted C1-4-alkoxy, C1-5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R9B;
• each R9B is independently C1-4-alkyl, amino, cyano, halo, or hydroxyl;
• p is 0, 1, or 2;
• each R10 is independently R10A, —N(R10A)(R10B), —OR10A, —SR10A, —S(O)R10A, or —S(O)2R10A;
• R10A is optionally substituted C4-20-alkyl or 4-20-membered heteroalkyl, which optional substitution is with one or more R10C, and which is optionally attached to another R10A moiety to provide a dimer or trimer;
• R10B is hydrogen or R10A;
• each R10C is independently amino, amido, azo, carbonyl, carboxyl, cyano, formyl, guanidino, halo, hydroxyl, imido, imino, isothiocyanate, nitrile, nitro, nitroso, nitroxy, oxo, sulfanyl, sulfinyl, sulfonyl, thial, thiocyanate, thione, thiourea, urea, or X1, X1-L1-X2, or X1-L1-X2-L2-X3, wherein each of X1, X2 and X3 is independently optionally substituted C1-4-alkyl, C1-6-cycloalkyl, 5- or 6-membered heterocycle, or aryl, which optional substitution is with one or more Rim, and each of L1 and L2 is independently optionally substituted C1-6-alkyl or 1-10-membered heteroalkyl, which optional substitution is with one or more of R10E;
• each R10D is independently R10E or C1-6-alkyl optionally substituted with one or more of R10E;
• each R10E is independently amino, amido, azo, carbonyl, carboxyl, cyano, formyl, guanidino, halo, hydroxyl, imido, imino, isothiocyanate, nitrile, nitro, nitroso, nitroxy, oxo, sulfanyl, sulfinyl, sulfonyl, thial, thiocyanate, thione, or urea;
• and m is 1, 2 or 3;
• wherein the SGLT1 inhibitor compound inhibits SGLT1 in the intestinal lumen of the subject.