Microtubule polymerization inhibitor prodrugs and methods of using the same
AssigneeUniversity of Maryland, Baltimore
InventorsJoseph Pao Yung KAO, Christopher William WARD, Ramzi KHAIRALLAH
Life of this patent
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Abstract
Prodrugs of colchicine, de-acetyl colchicine, colcemid, and nocodazole are provided as therapies for the treatment of diseases ameliorated by the inhibition of microtubule polymerization.
Claims43
A prodrug of formula:
- wherein R1 is a substituent selected from the group consisting of carboxyl, ester, and —C(═O)O-alkyl-OC(═O)-alkyl;
- R2 is a substituent selected from the group consisting of H, and optionally substituted alkyl, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkenyl-cycloalkyl, alkynyl, alkynyl-cycloalkyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, aryl, heteroaryl, acyloxy, acyl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylheterocycloalkyl, heteroalkylcycloalkyl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkyl;
- R3a and R3b are substituents independently selected from the group consisting of H, and optionally substituted alkyl, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkenyl-cycloalkyl, alkynyl, alkynyl-cycloalkyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, aryl, heteroaryl, acyloxy, acyl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylheterocycloalkyl, heteroalkylcycloalkyl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkyl;
- R4 is a substituent selected from the group consisting of H, and optionally substituted alkyl, alkoxy, -(alkoxy)n-alkyl, heteroalkyl, and -(alkyl)n-alkyl;
- n is an integer of 1-250;
- and the pharmaceutically acceptable salts thereof.
The prodrug of any one of the preceding claims, wherein n is an integer of 1 to 10, or 10 to 20, or 20 to 30, or 30 to 40, or 40 to 50, or 50 to 60, or 60 to 70, or 70 to 80, or 80 to 90, or 90 to 100, or 100 to 110, or 110 to 120, or 120 to 130, or 130 to 140, or 140 to 150, or 150 to 160, or 160 to 170, or 170 to 180, or 180 to 190, or 190 to 200, or 200 to 210, or 210 to 220, or 220 to 230, or 230 to 240, or 240 to 250.
The prodrug of any one of the preceding claims, wherein the active-metabolite of the prodrug is colchicine, de-acetyl colchicine, or colcemid.
A prodrug of formula:
- wherein R1 is a substituent selected from the group consisting of H, and optionally substituted alkyl, -alkyl-CN, alkyl-ester, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkenyl-cycloalkyl, alkynyl, alkynyl-cycloalkyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, aryl, heteroaryl, acyloxy, acyl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylheterocycloalkyl, heteroalkylcycloalkyl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkyl;
- R2 is a substituent selected from the group consisting of H, and optionally substituted alkyl, carboxyl, ester, and —C(═O)O-alkyl-OC(═O)-alkyl;
- R3 is a substituent selected from the group consisting of H, and optionally substituted alkyl, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkenyl-cycloalkyl, alkynyl, alkynyl-cycloalkyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, aryl, heteroaryl, acyloxy, acyl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylheterocycloalkyl, heteroalkylcycloalkyl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkyl;
- R4 is a substituent selected from the group consisting of H, and optionally substituted alkyl, carboxyl, ester, and —C(═O)O-alkyl-OC(═O)-alkyl;
- R5a and R5b are substituents independently selected from the group consisting of H, and optionally substituted alkyl, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkenyl-cycloalkyl, alkynyl, alkynyl-cycloalkyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, aryl, heteroaryl, acyloxy, acyl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylheterocycloalkyl, heteroalkylcycloalkyl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkyl;
- R6 is a substituent selected from the group consisting of H, and optionally substituted alkyl, alkoxy, -(alkoxy)n-alkyl, heteroalkyl, and -(alkyl)n-alkyl;
- n is an integer of 1-250;
- and the pharmaceutically acceptable salts thereof.
A pharmaceutical composition for treating a disease selected from the group consisting of Duchenne's Muscular Dystrophy (DMD), Becker's Muscular Dystrophy, Congenital Muscular Dystrophy, heart failure, desminopathy, cardiomyopathy, inclusion body myositis, autoimmune myositis, tau related myopathies, Limb Girdle Muscular Dystrophy, Sarcopenia, Osteoporosis, Atrial Fibrillation, pericarditis, Behcet's disease, inflammatory gout, and Familial Mediterranean Fever (FMF), in a patient in need of such treatment, comprising a therapeutically effective amount of a prodrug of formula:
- wherein R1 is a substituent selected from the group consisting of carboxyl, ester, and —C(═O)O-alkyl-OC(═O)-alkyl;
- R2 is a substituent selected from the group consisting of H, and optionally substituted alkyl, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkenyl-cycloalkyl, alkynyl, alkynyl-cycloalkyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, aryl, heteroaryl, acyloxy, acyl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylheterocycloalkyl, heteroalkylcycloalkyl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkyl;
- R3a and R3b are substituents independently selected from the group consisting of H, and optionally substituted alkyl, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkenyl-cycloalkyl, alkynyl, alkynyl-cycloalkyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, aryl, heteroaryl, acyloxy, acyl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylheterocycloalkyl, heteroalkylcycloalkyl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkyl;
- R4 is a substituent selected from the group consisting of H, and optionally substituted alkyl, alkoxy, -(alkoxy)n-alkyl, heteroalkyl, and -(alkyl)n-alkyl;
- n is an integer of 1-250;
- or the pharmaceutically acceptable salts thereof;
- and a pharmaceutically acceptable carrier.
A pharmaceutical composition for treating a disease selected from the group consisting of Duchenne's Muscular Dystrophy (DMD), Becker's Muscular Dystrophy, Congenital Muscular Dystrophy, heart failure, desminopathy, cardiomyopathy, inclusion body myositis, autoimmune myositis, tau related myopathies, Limb Girdle Muscular Dystrophy, Sarcopenia, Osteoporosis, Atrial Fibrillation, pericarditis, Behcet's disease, inflammatory gout, and Familial Mediterranean Fever (FMF), in a patient in need of such treatment, comprising a therapeutically effective amount of a prodrug of formula:
- wherein R1 is a substituent selected from the group consisting of H, and optionally substituted alkyl, -alkyl-CN, alkyl-ester, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkenyl-cycloalkyl, alkynyl, alkynyl-cycloalkyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, aryl, heteroaryl, acyloxy, acyl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylheterocycloalkyl, heteroalkylcycloalkyl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkyl;
- R2 is a substituent selected from the group consisting of H, and optionally substituted alkyl, carboxyl, ester, and —C(═O)O-alkyl-OC(═O)-alkyl;
- R3 is a substituent selected from the group consisting of H, and optionally substituted alkyl, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkenyl-cycloalkyl, alkynyl, alkynyl-cycloalkyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, aryl, heteroaryl, acyloxy, acyl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylheterocycloalkyl, heteroalkylcycloalkyl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkyl;
- R4 is a substituent selected from the group consisting of H, and optionally substituted alkyl, carboxyl, ester, and —C(═O)O-alkyl-OC(═O)-alkyl;
- R5a and R5b are substituents independently selected from the group consisting of H, and optionally substituted alkyl, alkylaryl, alkylhetaryl, alkylheterocycloalkyl, alkenyl, alkenyl-cycloalkyl, alkynyl, alkynyl-cycloalkyl, cycloalkyl, cycloalkyl-alkenyl, cycloalkyl-heterocycloalkyl, cycloalkyl-heteroaryl, aryl, heteroaryl, acyloxy, acyl, aralkyl, ester, fluoroalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, heteroalkylheteroaryl, heteroalkylheterocycloalkyl, heteroalkylcycloalkyl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkyl;
- R6 is a substituent selected from the group consisting of H, and optionally substituted alkyl, alkoxy, -(alkoxy)n-alkyl, heteroalkyl, and -(alkyl)n-alkyl;
- n is an integer of 1-250;
- or the pharmaceutically acceptable salts thereof;
- and a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.