Conjugates containing hydrophilic spacer linkers
Described herein are compositions and methods for use in targeted drug delivery using cell-surface receptor binding drug delivery conjugates containing hydrophilic spacer linkers for use in treating disease states caused by pathogenic cell populations.
1. A compound of the formula
wherein X and Y are each-independently selected from the group consisting of halo, R 2 , OR 2 , SR 3 , and NR 4 R 5 ;
U, V, and W represent divalent moieties each independently selected from the group consisting of —(R 6a )C═, —N═, —(R 6a )C(R 7a )—, and —N(R 4a )—; Q is selected from the group consisting of C and CH; T is selected from the group consisting of S, O, N, and —C═C—;
A 1 and A 2 are each independently selected from the group consisting of oxygen, sulfur, —C(Z)—, —C(Z)O—, —OC(Z)—, —N(R 4b )—, —C(Z)N(R 4b )—, —N(R 4b )C(Z)—, —OC(Z)N(R 4b )—, —N(R 4b )C(Z)O—, —N(R 4b )C(Z)N(R 5b )—, —S(O)—, —S(O) 2 —, —N(R 4a )S(O) 2 —, —C(R 6b )(R 7b )—, —N(C≡CH)—, —N(CH 2 C≡CH)—, C 1 -C 12 alkylene, and C 1 -C 12 alkyeneoxy, where Z is oxygen or sulfur;
R 1 is selected-from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy;
R 2 , R 3 , R 4 , R 4a , R 4b , R 5 , R 5b , R 6b , and R 7b are each independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 12 alkanoyl, C 1 -C 12 alkenyl, C 1 -C 12 alkynyl, (C 1 -C 12 alkoxy)carbonyl, and (C 1 -C 12 alkylamino)carbonyl;
R 6 and R 7 are each independently selected from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy; or, R 6 and R 7 are taken together to form a carbonyl group; R 6a and R 7a are each independently selected from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy; or R 6a and R 7a are taken together to form a carbonyl group;
L is a divalent linker comprising at least three hydrophilic spacer linkers that are polyhydroxyl groups;
n is 1;
p is 1;
r is 1;
s is 1;
t is 0;
* indicates a point of attachment to an additional spacer linker selected from the group consisting of aspartic acid, glutamic acid, lysine, cysteine, norleucine, isovaline, β-methyl threonine, β-methyl cystein, and β, β-dimethyl cystein, or a stereoisomer thereof,
wherein at least one polyhydroxyl group is selected from the group consisting of
and
wherein each ** represents a point of attachment to an additional spacer linker.
2. The compound of claim 1 , wherein at least one polyhydroxyl group is of the formula
wherein each ** represents a point of attachment to an additional spacer linker.
3. The compound of claim 2 , wherein L further comprises a L a , wherein L a is a naturally occurring amino acid, or a stereoisomer thereof, covalently linked to A 2 through the alpha-amino group of the naturally occurring amino acid by an amide bond.
4. The compound of claim 3 , wherein the naturally occurring amino acid is aspartic acid, glutamic acid, lysine or cysteine.
5. The compound of claim 3 , wherein the naturally occurring amino acid is glutamic acid.
6. The compound of claim 1 , wherein L further comprises at least one L s selected from the group consisting of aspartic acid, glutamic acid, lysine and cysteine, or a stereoisomer thereof.
7. The compound of claim 6 , wherein the at least one L s is glutamic acid.
8. The compound of claim 5 , wherein L further comprises at least one L s selected from the group consisting of aspartic acid, glutamic acid, lysine and cysteine, or a stereoisomer thereof.
9. The compound of claim 8 , wherein the at least one L s is glutamic acid.
10. A compound of the formula
wherein X and Y are each-independently selected from the group consisting of halo, R 2 , OR 2 , SR 3 , and NR 4 R 5 ;
U, V, and W represent divalent moieties each independently selected from the group consisting of —(R 6a )C═, —N═, —(R 6a )C(R 7a )—, and —N(R 4a )—; Q is selected from the group consisting of C and CH; T is selected from the group consisting of S, O, N, and —C═C—;
A 1 is independently selected from the group consisting of oxygen, sulfur, —C(Z)—, —C(Z)O—, —OC(Z)—, —N(R 4b )—, —C(Z)N(R 4b )—, —N(R 4b )C(Z)—, —OC(Z)N(R 4b )—, —N(R 4b )C(Z)O—, —N(R 4b )C(Z)N(R 5b )—, —S(O)—, —S(O) 2 —, —N(R 4a )S(O) 2 —, —C(R 6b )(R 7b )—, —N(C≡CH)—, —N(CH 2 C≡CH)—, C 1 -C 12 alkylene, and C 1 -C 12 alkyeneoxy;
A 2 is —C(Z)— and Z is oxygen;
R 1 is selected-from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy;
R 2 , R 3 , R 4 , R 4a , R 4b , R 5 , R 5b , R 6b , and R 7b are each independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 12 alkanoyl, C 1 -C 12 alkenyl, C 1 -C 12 alkynyl, (C 1 -C 12 alkoxy)carbonyl, and (C 1 -C 12 alkylamino)carbonyl;
R 6 and R 7 are each independently selected from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy; or, R 6 and R 7 are taken together to form a carbonyl group; R 6a and R 7a are each independently selected from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy; or R 6a and R 7a are taken together to form a carbonyl group;
L is a divalent linker comprising at least three hydrophilic spacer linkers that are polyhydroxyl groups;
n is 1;
p is 1;
r is 1;
s is 1;
t is 0; and
* indicates a point of attachment to an additional spacer linker selected from the group consisting of aspartic acid, glutamic acid, lysine and cysteine, norleucine, isovaline, β-methyl threonine, β-methyl cystein, β, β-dimethyl cystein, or a stereoisomer thereof.
11. The compound of claim 9 , wherein A 2 is —C(Z)—, wherein Z is oxygen.
12. The compound of claim 1 , wherein A 1 is —N(R 4b )—, and R 4b is H.
13. The compound of claim 11 , wherein A 1 is —N(R 4b )—, and R 4b is H.
14. The compound of claim 1 , wherein each R 6 and R 7 is H.
15. The compound of claim 1 , wherein U and W are —N═.
16. The compound of claim 11 , wherein V is —(R 6a )C═, wherein R 6a is H.
17. The compound of claim 13 , wherein U and W are —N═, and V is —(R 6a )C═, wherein R 6a is H.
18. A compound of the formula
wherein A 2 is selected from the group consisting of oxygen, sulfur, —C(Z)—, —C(Z)O—, —OC(Z)—, —N(R 4b )—, —C(Z)N(R 4b )—, —N(R 4b )C(Z)—, —OC(Z)N(R 4b )—, —N(R 4b )C(Z)O—, —N(R 4b )C(Z)N(R 5b )—, —S(O)—, —S(O) 2 —, —N(R 4a )S(O) 2 —, —C(R 6b )(R 7b )—, —N(C≡CH)—, —N(CH 2 C≡CH)—, C 1 -C 12 alkylene, and C 1 -C 12 alkyeneoxy, where Z is oxygen or sulfur;
R 4a , R 4b , R 5b , R 6b , and R 7b are each independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 12 alkanoyl, C 1 -C 12 alkenyl, C 1 -C 12 alkynyl, (C 1 -C 12 alkoxy)carbonyl, and (C 1 -C 12 alkylamino)carbonyl;
L is a divalent linker comprising at least three hydrophilic spacer linkers that are polyhydroxyl groups; and
* indicates a point of attachment to an additional spacer linker selected from the group consisting of aspartic acid, glutamic acid, lysine, cysteine, norleucine, isovaline, β-methyl threonine, and β-methyl cystein, β, β-dimethyl cystein, or a stereoisomer thereof.
19. The compound of claim 17 , of the formula
20. A compound of the formula
21. A compound of the formula