US Patent No. 10,363,318

ENHANCED ACTIVE AGENTS


Patent No. 10,363,318
Issue Date July 30, 2019
Title Enhanced Active Agents
Inventorship Mamoun M. Alhamadsheh, Stockton, CA (US)
Miki S. Park, Stockton, CA (US)
William K. Chan, Elk Grove, CA (US)
Xiaoling Li, Dublin, CA (US)
Sravan C. Penchala, Stockton, CA (US)
Mark R. Miller, Stockton, CA (US)
Assignee Mamoun M. Alhamadsheh, Stockton, CA (US)

Claim of US Patent No. 10,363,318

1. An enhanced active agent, comprising:a drug conjugated to a delivery system to form a conjugated drug, the delivery system including
a ligand that is selective for transthyretin in the serum of a subject; and,
a linker configured for operatively attaching the ligand covalently to the drug, the linker selected to cause release of the drug from the transthyretin in the subject as the conjugated drug, wherein the linker ranges from 14-20 angstroms in length;
wherein, the delivery system has a structure comprising:

where,
n is 1 to 8;
R1 and R3 are independently selected from a short chain alkyl having 1 to 4 carbon atoms;
R2 is selected from the group consisting of a hydrogen, a short chain alkyl having 1 to 4 carbon atoms, and an aryl;
Xa is C(R4)(R5), O, N—R5, or S; where R4 and R5 are independently selected from hydrogen, an alkyl having 1 to 4 carbon atoms, a substituted alkyl, an alkoxy, hydroxyl, an alkoxycarbonyl, an amino;
Ra is CHO, COOH, COOCH3, COOR6, CONR7R8, tetrazolyl, CONHOH, B(OH)2, CONHSO2Ar, CONHCH(R9)COOH, halogen, acyl, substituted acyl, carboxyl, heterocyclic group, sulfonamide, sulfonyl fluoride, thioester, alkoxycarbonyl or substituted alkoxycarbonyl;
Rb is the linker and is positioned ortho or meta to Ra, the linker including a CHO, COOH, COOCH3, COOR6, CONR7R8, tetrazolyl, CONHOH, B(OH)2, CONHSO2Ar, CONHCH(R9)COOH, CF3, hydrogen, halogen, alkyl, substituted alkyl, acyl, substituted acyl, carboxyl, heterocyclic group, sulfonamide, sulfonyl fluoride, ester, thioester, ether, thioether, triazolyl, alkoxycarbonyl or substituted alkoxycarbonyl;
R6 is alkyl, haloalkyl, cycloalkyl, or heterocyclyl;
R7 and R8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl; and,
R9 is the side chain of a naturally occurring ?-amino carboxylic acid;
or, a pharmaceutically acceptable salt, ester, enol ether, enol ester, amide, acetal, ketal, orthoester, hemiacetal, hemiketal, hydrate, solvate or prodrug thereof.