Compounds and methods of treating diabetes

摘要

Hydrogenated pyrido[4,3-b]indoles, pyrido[3,4-b]indoles and azepino[4,5-b]indoles are described. The compounds may bind to and are antagonists of the adrenergic receptor α2A. The compounds may also bind to and are an antagonist of the adrenergic receptor α2B; or the compounds are not antagonists of the adrenergic receptor α2B and the compounds are administered in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual. The compounds may find use in therapy, e.g., to regulate blood glucose level, increase insulin secretion and treat diseases or conditions that are, or are expected to be, responsive to an increase in insulin production. Use of the compounds to treat type 2 diabetes is particularly described.

主权项

1. A method of regulating blood glucose levels in an individual in need thereof comprising administering to the individual an effective amount of a compound of the formula (A-III):or a salt, solvate or N-oxide thereof, wherein:
R1 is H; C1-C5 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl; C3-C8 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl; C2-C5 alkenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl; or —C(O)O—C1-C5 alkyl; or is taken together with R2a or R3a to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; or is taken together with R4a or R5a, where present, to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; each n and m is 1, or n is 0 and m is 1, or n is 1 and m is 0; R2a is H; optionally substituted C1-C5 alkyl; optionally substituted C2-C5 alkenyl; or optionally substituted aryl; or is taken together with R1 or R5a, where present, to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; or is taken together with R3a to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; or is taken together with R4a, where present, to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; R3a is H; optionally substituted C1-C5 alkyl; optionally substituted C2-C5 alkenyl; or optionally substituted aryl; or is taken together with R1 or R4a, where present, to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; or is taken together with Rea to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; or is taken together with R5a, where present, to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; R4a is H; optionally substituted C1-C5 alkyl; optionally substituted C2-C5 alkenyl; or optionally substituted aryl; or is taken together with R3a to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; or is taken together with R1 to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; or is taken together with R2a to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; or is taken together with R3a, where present, to form a methylene (—CH2—) moiety; R5a is H; optionally substituted C1-C5 alkyl; optionally substituted C2-C5 alkenyl; or optionally substituted aryl; or is taken together with R2a to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety; or is taken together with R1 to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety; or is taken together with R3a to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety; or is taken together with R4a, where present, to form a methylene (—CH2—) moiety; each R2b, R3b, R4b, and R5b, is independently H, optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted aryl; X is N or CR6a; t is 1, 2 or 3; each R6 and R6a is independently H; hydroxyl; halo; C1-C5 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl; C2-C5 alkenyl; optionally substituted C1-C5 alkoxy; or optionally substituted —C(O)C1-C5 alkyl; R7 is H; halo; optionally substituted C1-C5 alkyl; or optionally substituted aryl; or is taken together with R8 and the carbon atom to which they are attached to form a dioxolane ring or a carbonyl moiety; or is taken together with R9 to form a C3-C5 alkylene when R8 and R10 are taken together to form a bond; R8 is H; halo; hydroxyl; N(R11)R12; SR13, S(O)R13; SO2R13; —OC(O)N(R14)R15; —OC(O)-aryl; —OC(O)-heteroaryl; or —OC(O)C1-C5 alkyl optionally substituted with amino; or is taken together with R7 and the carbon atom to which they are attached to form a dioxolane ring or a carbonyl moiety; or is taken together with R10 to form a bond; R9 is H or optionally substituted C1-C5 alkyl; or is taken together with R7 to form a C3-C5 alkylene when R8 and R10 are taken together to form a bond; R10 is H or optionally substituted C1-C5 alkyl; or is taken together with R8 to form a bond; each R11 and R12 is independently H or optionally substituted C1-C5 alkyl; or R11 and R12 are taken together to form C3-C5 alkylene; R13 is H or optionally substituted C1-C5 alkyl; each R14 and R15 is independently H or optionally substituted C1-C5 alkyl; or R14 and R15 are taken together to form a C3-C5 alkylene; and Q is unsubstituted aryl; unsubstituted heteroaryl; aryl substituted with 1 to 3 substituents independently selected from the group consisting of halo, C1-C5 alkyl, C3-C8 cycloalkyl, halo-substituted C1-C5 alkyl, halo-substituted C3-C8 cycloalkyl, C1-C5 alkoxy, C3-C8 cycloalkoxy, cyano, carboxyl, aminoacyl and acylamino; or heteroaryl substituted with 1 to 3 substituents independently selected from the group consisting of halo, C1-C5 alkyl, C3-C8 cycloalkyl, halo-substituted C1-C5 alkyl, halo-substituted C3-C8 cycloalkyl, C1-C5 alkoxy, C3-C8 cycloalkoxy, cyano, carboxyl, aminoacyl and acylamino.