US 12,433,873 B2
Microtubule polymerization inhibitor prodrugs and methods of using the same
Joseph Kao, Silver Spring, MD (US); Christopher William Ward, Baltimore, MD (US); and Ramzi Khairallah, New Market, MD (US)
Assigned to University of Maryland, Baltimore, Baltimore, MD (US)
Filed by University of Maryland, Baltimore, Baltimore, MD (US)
Filed on Apr. 10, 2023, as Appl. No. 18/298,157.
Application 18/298,157 is a continuation of application No. 16/624,787, granted, now 11,622,960, previously published as PCT/US2018/038300, filed on Jun. 19, 2018.
Claims priority of provisional application 62/521,749, filed on Jun. 19, 2017.
Claims priority of provisional application 62/521,731, filed on Jun. 19, 2017.
Prior Publication US 2023/0241034 A1, Aug. 3, 2023
Int. Cl. A61K 31/4184 (2006.01); A61K 31/135 (2006.01); A61K 31/165 (2006.01); A61K 45/06 (2006.01); A61P 21/00 (2006.01); C07D 235/04 (2006.01)
CPC A61K 31/4184 (2013.01) [A61K 31/135 (2013.01); A61K 31/165 (2013.01); A61K 45/06 (2013.01); A61P 21/00 (2018.01); C07D 235/04 (2013.01)] 9 Claims
 
1. A prodrug of formula:

OG Complex Work Unit Chemistry
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.