US Pat. No. 10,172,959

SYSTEMS FOR STABILIZING AND DELIVERING ACTIVE AGENTS

Mamoun M. Alhamadsheh, S...

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

US Pat. No. 10,363,318

ENHANCED ACTIVE AGENTS

Mamoun M. Alhamadsheh, S...

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.