Fused tetracyclic pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
AssigneeMedivation Technologies, Inc.
InventorsSarvajit Chakravarty, Barry Patrick Hart, Rajendra Parasmal Jain
Life of this patent
Estimating the term…
Abstract
This disclosure is directed to fused tetracyclic pyrido[4,3-b>]indole and pyrido[3,4-b]indole derivatives. Pharmaceutical compositions comprising the compounds are also provided, as are methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.
Claims16
A compound of the formula (VA):
- or a salt thereof;
- wherein:
- R1 is H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;
- each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2—CH2—) moiety or a propylene (—CH2CH2—CH2—) moiety, or R2a and R4 are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety;
- each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
- R4 is H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R4 and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4 and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R4 and R7a are taken together to form a bond;
- each R5a and R5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl, or sulfonylamino, or R5a and a vicinal R7(a-h), where applicable, are taken together to form a bond;
- each X1, X2, X3 and X4 is independently N, CH or CR6;
- Y1 is CR7aR7b, NR8, O, S, S(O) or SO2, provided that when Y1 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d or is taken together with Y3 and Y4 to form a bond,
- Y2 is CR7cR7d, NR8, O, S, S(O) or SO2, or Y2 is taken together with Y3 and Y4 to form a bond, provided that when Y2 is NR8, O, S, S(O) or SO2, then Y1 is CR7aR7b and Y3 is CR7eR7f or is taken together with Y4 to form a bond;
- Y3 is CR7eR7f, NR8, O, S, S(O) or SO2, or Y3 is taken together with Y4 to form a bond, provided that when Y3 is NR8, O, S, S(O) or SO2, then Y2 is CR7cR7d and Y4 is CR7gR7h or a bond;
- Y4 is CR7gR7h, NR8, O, S, S(O) or SO2, or Y4 is a bond, provided that when Y4 is NR8, O, S, S(O) or SO2, then Y3 is CR7eR7f;
- each R6 is independently hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
- each R7a and R7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl, or sulfonylamino, or R7a and R7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7a and R4 are taken together to form a bond, or R7a and R7c, where applicable, are taken together to form a bond, or R7a and a vicinal R5a, where applicable, are taken together to form a bond;
- each R7c and R7d, where applicable, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl, or sulfonylamino, or R7c and R7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7c and R7a are taken together to form a bond, or R7c and R7e, where applicable, are taken together to form a bond, or R7c and a vicinal R5a, where applicable, are taken together to form a bond;
- each R7e and R7f, where applicable, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl, or sulfonylamino, or R7e and R7f are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7e and R7c are taken together to form a bond, or R7e and R7g, where applicable, are taken together to form a bond, or R7e and a vicinal R5a, where applicable, are taken together to form a bond;
- each R7g and R7h, where applicable, is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, C1-C8 perhaloalkyl, C1-C8 perhaloalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl, or sulfonylamino, or R7g and R7h are taken together with the carbon to which they are attached to form a carbonyl moiety, or R7g and R7e are taken together to form a bond, or R7g and R5a are taken together to form a bond;
- and
- each R8 is independently H, hydroxyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
- provided that (1) at least one of X1, X2, X3 and X4 is CH or CR6;
- and (2) at least one of R5a, R5b, R7a, R7b, R7c, R7d, R7e, R7f, R7g and R7h is a group containing a cyclic moiety.
A compound selected from the group consisting of compounds 1-12, 15-16, 18-21, 23-26, 28-62, 64-67, 69-72, 74-85, 87-90, 92-107, 109-112, 114-117, 119-122, 124-127, 129-132, 134-137, 139-142, 144-153, 155-166, 169-170, 173, 175, 177-178, 180, and 187-236, or a pharmaceutically acceptable salt thereof.
A method of treating a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder in an individual comprising administering to an individual in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds 15-16, 18-21, 23-26, 28-62, 64-67, 69-72, 74-85, 1-12, 87-90, 92-107, 109-112, 114-117, 119-122, 124-127, 129-132, 134-137, 139-142, 144-153, 155-166, 169-170, 173, 175, 177-178, 180, and 187-236.
Dependencies are inferred from the claim text.