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US 8,557,842 B2Granted
Cocaine analogs and methods of preparation and uses thereof
AssigneeTemple University of the Commonwealth System of Higher Education
InventorsFranklin A. Davis, Naresh Theddu, Maarten E. A. Reith
Life of this patent
Estimating the term…
Abstract
The invention provides novel cocaine analogs. The invention also provides a method of preparing cocaine analogs with control over the substituents installed at the C-1, C-2, C-3, C-4 and N-8 positions of the tropane bicyclic scaffold. The invention further provides methods of providing anesthesia, blocking reuptake of a monoamine neurotransmitter, and treating depression, by administering to a subject in need of such treatment a pharmaceutical composition comprising a compound of the invention.
Claims48
A compound of Formula (I):
- wherein:
- R1a is (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, (C2-6) alkenyl, substituted (C2-6) alkenyl, (C2-6) alkynyl, substituted (C2-6) alkynyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl;
- R2 is cyano, —C(═O)H, alkoxycarbonyl, aroxycarbonyl, heterocycloxycarbonyl, acyl, aroyl, heterocycloyl, —C(═NR9)R7, —C(═O)NR7R8, —C(═S)NR7R8, —C(═O)N(OMe)Me, —C(═S)N(OMe)Me, —SO2R9, —SO2NR7R8, or —P(═O)(OR9)2;
- R3 is acyloxy, substituted acyloxy, aroyloxy, substituted aroyloxy, heteroaroyloxy, substituted heteroaroyloxy, —OC(═O)—NR7R8, (C1-6) alkoxy, substituted (C1-6) alkoxy, (C3-6) cycloalkoxy, substituted (C3-6) cycloalkoxy, aroxy, substituted aroxy, heterocycloxy, substituted heterocycloxy, (alkoxycarbonyl)oxy, (aroxycarbonyl)oxy, or (heterocycloxycarbonyl)oxy;
- R3′ is H;
- R4 is H, (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, (C2-6) alkenyl, substituted (C2-6) alkenyl, (C2-6) alkynyl, substituted (C2-6) alkynyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, (C1-6) alkoxy, aroxy, or heteroaroxy;
- R6 is H, (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, (C2-6) alkenyl, substituted (C2-6) alkenyl, (C2-6) alkynyl, substituted (C2-6) alkynyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, —C(═O)NR7R8, —SO2R9, —SO2NR7R8, —P(═O)(OR9)2, alkoxycarbonyl, aroxycarbonyl, heterocycloxycarbonyl, acyl, aroyl, or heterocycloyl;
- R7 and R8 are independently H, (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl;
- and
- each occurrence of R9 is independently (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl;
- or a salt thereof.
8 more elements
A method of providing anesthesia to a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising a compound of Formula (I):
- wherein:
- R1a is (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, (C2-6) alkenyl, substituted (C2-6) alkenyl, (C2-6) alkynyl, substituted (C2-6) alkynyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl;
- R2 is cyano, —C(═O)H, alkoxycarbonyl, aroxycarbonyl, heterocycloxycarbonyl, acyl, aroyl, heterocycloyl, —C(═NR9)R7, —C(═O)NR7R8, —C(═S)NR7R8, —C(═O)N(OMe)Me, —C(═S)N(OMe)Me, —SO2R9, —SO2NR7R8, or —P(═O)(OR9)2;
- R3 is acyloxy, substituted acyloxy, aroyloxy, substituted aroyloxy, heteroaroyloxy, substituted heteroaroyloxy, —OC(═O)—NR7R8, (C1-6) alkoxy, substituted (C1-6) alkoxy, (C3-6) cycloalkoxy, substituted (C3-6) cycloalkoxy, aroxy, substituted aroxy, heterocycloxy, substituted heterocycloxy, (alkoxycarbonyl)oxy, (aroxycarbonyl)oxy, or (heterocycloxycarbonyl)oxy;
- R3′ is H;
- R4 is H, (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, (C2-6) alkenyl, substituted (C2-6) alkenyl, (C2-6) alkynyl, substituted (C2-6) alkynyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, (C1-6) alkoxy, aroxy, or heteroaroxy;
- R6 is H, (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, (C2-6) alkenyl, substituted (C2-6) alkenyl, (C2-6) alkynyl, substituted (C2-6) alkynyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, —C(═O)NR7R8, —SO2R9, —SO2NR7R8, —P(═O)(OR9)2, alkoxycarbonyl, aroxycarbonyl, heterocycloxycarbonyl, acyl, aroyl, or heterocycloyl;
- R7 and R8 are independently H, (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl;
- and
- each occurrence of R9 is independently (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl;
- or a salt thereof.
8 more elements
A method of blocking uptake of a monoamine neurotransmitter in a subject in need thereof, wherein the neurotransmitter is selected from the group consisting of serotonin, norepinephrine and dopamine, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising a compound of Formula (I):
- wherein:
- R1a is (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, (C2-6) alkenyl, substituted (C2-6) alkenyl, (C2-6) alkynyl, substituted (C2-6) alkynyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl;
- R2 is cyano, —C(═O)H, alkoxycarbonyl, aroxycarbonyl, heterocycloxycarbonyl, acyl, aroyl, heterocycloyl, —C(═NR9)R7, —C(═O)NR7R8, —C(═S)NR7R8, —C(═O)N(OMe)Me, —C(═S)N(OMe)Me, —SO2R9, —SO2NR7R8, or —P(═O)(OR9)2;
- R3 is acyloxy, substituted acyloxy, aroyloxy, substituted aroyloxy, heteroaroyloxy, substituted heteroaroyloxy, —OC(═O)—NR7R8, (C1-6) alkoxy, substituted (C1-6) alkoxy, (C3-6) cycloalkoxy, substituted (C3-6) cycloalkoxy, aroxy, substituted aroxy, heterocycloxy, substituted heterocycloxy, (alkoxycarbonyl)oxy, (aroxycarbonyl)oxy, or (heterocycloxycarbonyl)oxy;
- R3′ is H;
- R4 is H, (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, (C2-6) alkenyl, substituted (C2-6) alkenyl, (C2-6) alkynyl, substituted (C2-6) alkynyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, (C1-6) alkoxy, aroxy, or heteroaroxy;
- R6 is H, (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, (C2-6) alkenyl, substituted (C2-6) alkenyl, (C2-6) alkynyl, substituted (C2-6) alkynyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, —C(═O)NR7R8, —SO2R9, —SO2NR7R8, —P(═O)(OR9)2, alkoxycarbonyl, aroxycarbonyl, heterocycloxycarbonyl, acyl, aroyl, or heterocycloyl;
- R7 and R8 are independently H, (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl;
- and
- each occurrence of R9 is independently (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl;
- or a salt thereof.
8 more elements
A method of treating depression in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising a compound of Formula (I):
- wherein:
- R1a is (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, (C2-6) alkenyl, substituted (C2-6) alkenyl, (C2-6) alkynyl, substituted (C2-6) alkynyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl;
- R2 is cyano, —C(═O)H, alkoxycarbonyl, aroxycarbonyl, heterocycloxycarbonyl, acyl, aroyl, heterocycloyl, —C(═NR9)R7, —C(═O)NR7R8, —C(═S)NR7R8, —C(═O)N(OMe)Me, —C(═S)N(OMe)Me, —SO2R9, —SO2NR7R8, or —P(═O)(OR9)2;
- R3 is acyloxy, substituted acyloxy, aroyloxy, substituted aroyloxy, heteroaroyloxy, substituted heteroaroyloxy, —OC(═O)—NR7R8, (C1-6) alkoxy, substituted (C1-6) alkoxy, (C3-6) cycloalkoxy, substituted (C3-6) cycloalkoxy, aroxy, substituted aroxy, heterocycloxy, substituted heterocycloxy, (alkoxycarbonyl)oxy, (aroxycarbonyl)oxy, or (heterocycloxycarbonyl)oxy;
- R3′ is H;
- R4 is H, (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, (C2-6) alkenyl, substituted (C2-6) alkenyl, (C2-6) alkynyl, substituted (C2-6) alkynyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, (C1-6) alkoxy, aroxy, or heteroaroxy;
- R6 is H, (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, (C2-6) alkenyl, substituted (C2-6) alkenyl, (C2-6) alkynyl, substituted (C2-6) alkynyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, —C(═O)NR7R8, —SO2R9, —SO2NR7R8, —P(═O)(OR9)2, alkoxycarbonyl, aroxycarbonyl, heterocycloxycarbonyl, acyl, aroyl, or heterocycloyl;
- R7 and R8 are independently H, (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl;
- and
- each occurrence of R9 is independently (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, substituted (C3-6) cycloalkyl, aryl, substituted aryl, heterocyclyl, or substituted heterocyclyl;
- or a salt thereof.
8 more elements
Dependencies are inferred from the claim text.