Targeted delivery of tertiary amine-containing drug substances

A Ligand Drug Conjugate (LDC) composition, wherein the LDC composition is represented by the structure of Formula 1:

• wherein
• LU is a Linker Unit;
• “Ligand” is a Ligand Unit (L) from a targeting moiety, wherein L selectively binds to a target moiety;
• Lb is a ligand covalent binding moiety;
• Q1 is Aa-Ww, wherein A is an optional Stretcher unit so that subscript a is 0 when A is absent or 1 when A is present and is optionally comprised of two, three or four subunits;
• Q2 is W′w′-E-, wherein Q2, when present, is bonded to V, Z1, Z2 or Z3;
• Ww and W′w′ are Cleavable units, wherein
• Ww of Q1 is capable of selective cleavage by an intracellular or regulatory protease in comparison to serum proteases, or by glutathione through disulfide exchange, or is more reactive to hydrolysis under lower pH (i.e., under more acidic) conditions present in lysosomes in comparison to physiological pH of serum,
• W′-E of Q2 provides a glycosidic bond cleavable by a glycosidase located intracellularly, and
• subscript w is 0 or 1 so that W is absent when w is 0 or W is present when w is 1, and subscript w′ is 0 or 1, wherein W′-E is absent when w′ is 0 or W′-E is present when w′ is 1, and wherein w+w′ is 1 (i.e., one and only one of W, W′ is present);
• V, Z1, Z2 and Z3 are ═N— or ═C(R24)—, wherein R24 is hydrogen or alkyl, alkenyl or alkynyl, optionally substituted, or halogen, —NO2, —CN or other electron withdrawing group, an electron donating group, -Q2, or —C(R8)(R9)-D+, wherein at least one of V, Z1, Z2 and Z3 is ═C(R24)— when w is 1, and at least two of V, Z1, Z2 and Z3 are ═C(R24)— when w′ is 1,
• provided that when w is 1, Q2 is absent and one and only one R24 is —C(R8)(R9)-D+ so that —C(R8)(R9)-D+ is bonded to one of V, Z1, Z2, Z3 when that variable group is ═C(R24)— and the Q1-J- and —C(R8)(R9)-D+ substituents are ortho or para to each other,
• provided that when w′ is 1, one any only one R24 is —C(R8)(R9)-D+ so that —C(R8)(R9)-D+ is bonded to one of V, Z1, Z2, Z3 when that variable group is ═C(R24)— and one and only one other R24 is Q2 so that Q2 is bonded to another one of V, Z1, Z2, Z3 when that variable group is ═C(R24)—, and the Q2 and —C(R8)(R9)-D+ substituents are ortho or para to each other;
• R8 and R9 independently are hydrogen, alkyl, alkenyl or alkynyl, optionally substituted, or aryl or heteroaryl, optionally substituted;
• R′ is hydrogen or is halogen, —NO2, —CN or other electron withdrawing group, or is an electron donating group;
• E and J independently are —O—, —S— or —N(R33)—, wherein R33 is hydrogen or optionally substituted alkyl;
• D+ represents a structure of a quaternized tertiary amine-containing drug;
• and
• subscript p is an average drug loading having a number ranging from 1 to 24;
• and
• wherein said protease cleavage, disulfide exchange, acid hydrolysis or glycosidase cleavage results in release of tertiary amine-containing drug (D) from a Ligand Drug Conjugate compound of the composition.