Novel co-drug, co-administration, and sequential administration of bispecific rbp4/ttr ligand and c20-d3-retinol for elimination of mechanism-based ocular adverse effects in treating macular degeneration and ttr amyloidosis

A method for producing a compound having the structure (P-)2M-Q wherein:

• P represents a single-valence group formed by eliminating a hydroxyl group from a bispecific RBP4/TTR ligand;
• Q represents a single-valence group formed by eliminating a hydrogen atom bonded to a heteroatom from a C20-D3-visual-chromophore-producing compound;
• M represents a triple-valence group that is
• wherein x is 1 and y is 1;
• each P is bonded to M via an ester linkage that is cleavable at an acidic pH or is enzymatically cleavable;
• Q is bonded to M via a silyl ether linkage that is cleavable at an acidic pH or is enzymatically cleavable;
• the bispecific RBP4/TTR ligand is a compound having the structure:
• wherein
• X is CR6 or N;
• R1, R2, R3, R4, and R6 are each independently —H, —F, —Cl, —Br, —I, —NO2, —CN, —CF3, —CF2H, —OCF3, -(alkyl), -(haloalkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(cycloalkyl), -(cycloalkylalkyl), -(heteroalkyl), heterocycle, heterocycloalkyl, -(alkylheteroalkyl), -(alkylaryl), —OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —SH, —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —NH2, —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(aryl), —NH-(heteroaryl), —C(O)R7, —S(O)R7, —SO2R7, —NHSO2R7, —OC(O)R7, —SC(O)R7, —NHC(O)R8, or —NHC(S)R8,
• wherein R7 is H, -(alkyl), —OH, —O(alkyl), —NH2, —NH(alkyl), or —N(alkyl)2, and
• wherein R8 is -(alkyl), —O-(alkyl), —NH2, —NH(alkyl), or —N(alkyl)2;
• Y is O, S, N, NH, or a bond;
• Z is O, S, N, NH, (CH2)o, or a bond;
• R5 is H, OH, halogen, or alkyl, or R5 is (CH2)p and is bound to Y when Y is N to form a ring together with Z;
• o and p are independently 0, 1, 2, or 3;
• m and n are independently 0, 1, 2, 3, or 4;
• A, C, and D are each independently N or CR9;
• R9 is H, halogen, —OH, alkyl, cycloalkyl, cycloalkylalkyl, —O-(alkyl), —S-(alkyl), —NH2, —NH(alkyl), —NH(alkyl)2, —CO2H, or —CO(O-alkyl);
• B is N, CR9, or C—F-G;
• F is absent or present, and when present, is
• G is H, substituted or unsubstituted monocycle, bicycle, heteromonocycle, heterobicycle, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, CO2H, COOR10, OH, OR10, NH2, NHR10, NR10R11, SO2 (alkyl), SO2 (cycloalkyl), SO2 (cycloalkylalkyl), CH2NHR10, CH2NR10R11, or CH2COOR10,
• wherein R10 and R11 are each independently H, alkyl, cycloalkyl, —C(O)-alkyl, —C(O) -cycloalkyl, —C(O)OH, —C(O)—O-alkyl, —C(O)—O-cycloalkyl, —C(O)NH2, —C(O)NH(alkyl), —C(O)NH(cycloalkyl), —C(O)N(alkyl)2, —CH2NH(alkyl), —CH2COOH, —SO2CH3, —OH, —O(alkyl), —NH2, —NH(alkyl), or —N(alkyl)2;
• and
• E is C—F—CO2H;
• or a pharmaceutically acceptable salt thereof;
• and
• the C20-D3-visual-chromophore-producing compound is selected from the group consisting of C20-D3-retinol, C20-D3-9-cis-retinol, and C20-D3-11-cis-retinol;
• the method comprising the steps of:
• modifying one of three hydroxyl groups of 2-(hydroxymethyl)-1,3-propanediol by a protecting group;
• performing a dehydration reaction between the protecting-group-modified 2-(hydroxymethyl)-1,3-propanediol and the bispecific RBP4/TTR ligand to form a diester product;
• removing the protecting group from the diester product;
• and
• reacting the deprotected diester product with dichlorodimethylsilane and the C20-D3-visual-chromophore-producing compound to form the compound (P-)2M-Q, and/or
• wherein:
• P represents a single-valence group formed by eliminating a hydroxyl group from a bispecific RBP4/TTR ligand;
• Q represents a single-valence group formed by eliminating a hydrogen atom bonded to a heteroatom from a C20-D3-visual-chromophore-producing compound;
• M represents a triple-valence group that is
• wherein x is 1 and y is 1;
• each P is bonded to M via an ester linkage that is cleavable at an acidic pH or is enzymatically cleavable;
• Q is bonded to M via a carbonate linkage that is cleavable at an acidic pH or is enzymatically cleavable;
• the bispecific RBP4/TTR ligand is a compound having the structure:
• wherein
• X is CR6 or N;
• R1, R2, R3, R4, and R6 are each independently —H, —F, —Cl, —Br, —I, —NO2, —CN, —CF3, —CF2H, —OCF3, -(alkyl), -(haloalkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(cycloalkyl), -(cycloalkylalkyl), -(heteroalkyl), heterocycle, heterocycloalkyl, -(alkylheteroalkyl), -(alkylaryl), —OH, —OAc, —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —SH, —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), —S-(heteroaryl), —NH2, —NH-(alkyl), —NH-(alkenyl), —NH-(alkynyl), —NH-(aryl), —NH-(heteroaryl), —C(O)R7, —S(O)R7, —SO2R7, —NHSO2R7, —OC(O)R7, —SC(O)R7, —NHC(O)R8, or —NHC(S)R8, wherein R7 is H, -(alkyl), —OH, —O(alkyl), —NH2, —NH(alkyl), or —N(alkyl)2, and
• wherein R8 is -(alkyl), —O-(alkyl), —NH2, —NH(alkyl), or —N(alkyl)2;
• Y is O, S, N, NH, or a bond;
• Z is O, S, N, NH, (CH2)o, or a bond;
• R5 is H, OH, halogen, or alkyl, or R5 is (CH2)p and is bound to Y when Y is N to form a ring together with Z;
• o and p are independently 0, 1, 2, or 3;
• m and n are independently 0, 1, 2, 3, or 4;
• A, C, and D are each independently N or CR9;
• R9 is H, halogen, —OH, alkyl, cycloalkyl, cycloalkylalkyl, —O-(alkyl), —S-(alkyl), —NH2, —NH(alkyl), —NH(alkyl)2, —CO2H, or —CO(O-alkyl);
• B is N, CR9, or C—F-G;
• F is absent or present, and when present, is
• G is H, substituted or unsubstituted monocycle, bicycle, heteromonocycle, heterobicycle, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, CO2H, COOR10, OH, OR10, NH2, NHR10, NR10R11, SO2 (alkyl), SO2 (cycloalkyl), SO2 (cycloalkylalkyl), CH2NHR10, CH2NR10R11, or CH2COOR10,
• wherein R10 and R11 are each independently H, alkyl, cycloalkyl, —C(O)-alkyl, —C(O) -cycloalkyl, —C(O)OH, —C(O)—O-alkyl, —C(O)—O-cycloalkyl, —C(O)NH2, —C(O)NH(alkyl), —C(O)NH(cycloalkyl), —C(O)N(alkyl)2, —CH2NH (alkyl), —CH2COOH, —SO2CH3, —OH, —O(alkyl), —NH2, —NH(alkyl), or —N(alkyl)2;
• and
• E is C—F—CO2H;
• or a pharmaceutically acceptable salt thereof;
• and
• the C20-D3-visual-chromophore-producing compound is selected from the group consisting of C20-D3-retinol, C20-D3-9-cis-retinol, and C20-D3-11-cis-retinol;
• the method comprising the steps of:
• performing a dehydration reaction between 2-(benzyloxymethyl)-1,3-propanediol and the bispecific RBP4/TTR ligand or a derivative thereof modified by protecting groups, to form a diester product;
• reacting the diester product with the C20-D3-visual-chromophore-producing compound to form a mono-carbonate-linked diester product;
• and
• removing the protecting groups, if present, from the mono-carbonate-linked diester product;
• to form the compound (P-)2M-Q.