Conjugates Containing Hydrophilic Spacer Linkers
Described herein are compositions and methods for use in targeted drug delivery using cell receptor binding drug delivery conjugates containing hydrophilic spacer linkers for use in imaging, diagnosing, and/or treating diseases and disease states caused by pathogenic cell populations.
1 .- 39 . (canceled)
40 . A compound of the formula
B-L-A
wherein
B is a vitamin receptor binding ligand;
L is a linker comprising a disulfide and at least one fragment of a formula selected from the group consisting of
wherein
each d, e, and f is independently an integer from 1 to 5;
* is the point of attachment to the rest of the compound; and
** is the disulfide bond;
wherein
each d′, e′, and f′ is independently an integer from 1 to 5;
* is the point of attachment to the rest of the compound; and
** is the disulfide bond;
wherein
each g and h is independently an integer from 1 to 5;
i is an integer from 1 to 4;
* is the point of attachment to the rest of the compound; and
** is the disulfide bond;
wherein
each g′ and h′ is independently an integer from 1 to 5;
i′ is an integer from 1 to 4;
* is the point of attachment to the rest of the compound; and
** is the disulfide bond;
wherein
each v, w, x, and y is independently an integer from 1 to 3;
each * is the point of attachment to the rest of the compound; and
** is the disulfide bond;
wherein
each v′, x′, and y′ is independently an integer from 1 to 3;
* is the point of attachment to the rest of the compound; and
** is the disulfide bond; and
A is an agent selected from the group consisting of a diagnostic, a therapeutic, and an imaging agent;
wherein L is covalently bonded to A by a bond selected from the group consisting of amide, ester, disulfide, and imino bonds, and L is covalently bonded to B by an amide or ester bond.
41 . The compound of claim 40 , wherein the disulfide bond comprises 3-dithioalkyloxycarbonylhydrazide.
42 . The compound of claim 40 , wherein the linker and the agent are attached to each other through nitrogen heteroatoms forming a radical of the formula —(NH 2 NH 2 )—.
43 . The compound of claim 40 , wherein the linker comprises one or more independently selected naturally occurring amino acids.
44 . The compound of claim 43 , wherein each of the naturally occurring amino acids is aspartic acid or arginine.
45 . The compound of claim 40 , wherein the linker comprises one or more divalent 1,4-piperazines.
46 . The compound of claim 40 , wherein the ligand is a folate.
47 . The compound of claim 46 , wherein the folate is of the formula
wherein
each X and Y is independently selected from the group consisting of halo, R 2 , OR 2 , SR 3 , and NR 4 R 5 ;
each U, V, and W is independently selected from the group consisting of —(R 6a )C═, —N═, —(R 6a )C(R 7a )—, and —N(R 4a )—;
Q is C or CH;
T is selected from the group consisting of S, O, N, and —C═C—;
each A 1 and A 2 is independently selected from the group consisting of O, S, —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 alkyleneoxy;
Z is O or S;
R 1 is selected from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy;
each R 2 , R 3 , R 4 , R 4a , R 4b , R 5 , R 5b , R 6b , and R 7b is independently selected from the group consisting of hydrogen, halo, 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;
each R 6 , R 7 , R 6a , and R 7a is 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; or R 6a and R 7a are taken together to form a carbonyl group;
each p, r, s, and t is independently 0 or 1; and
* is the point of attachment to the rest of the compound.
48 . The compound of claim 47 , wherein the folate is of the formula
wherein * is the point of attachment to the rest of the compound.
49 . The compound of claim 40 , wherein the agent is a drug.
50 . The compound of claim 40 , wherein the agent is a vinca alkaloid.
51 . The compound of claim 40 , wherein the linker comprises a fragment of the formula
each d′, e′, and f′ is independently an integer from 1 to 5;
* is the point of attachment to the rest of the compound; and
** is the disulfide bond.
52 . The compound of claim 51 , wherein the compound comprises a fragment of the formula
wherein
each X and Y is independently selected from the group consisting of halo, R 2 , OR 2 , SR 3 , and NR 4 R 5 ;
each U, V, and W is independently selected from the group consisting of —(R 6a )C═, —N═, —(R 6a )C(R 7a )—, and —N(R 4a )—;
Q is C or CH;
T is selected from the group consisting of S, O, N, and —C═C—;
each A 1 and A 2 is independently selected from the group consisting of O, S, —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 alkyleneoxy;
Z is O or S;
R 1 is selected from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy;
each R 2 , R 3 , R 4 , R 4a , R 4b , R 5 , R 5b , R 6b , and R 7b is independently selected from the group consisting of hydrogen, halo, 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 2 alkoxy)carbonyl, and (C 1 -C 12 alkylamino)carbonyl;
each R 6 , R 7 , R 6a , and R 7a is 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; or R 6a and R 7a are taken together to form a carbonyl group;
each d′, e′, and f′ is independently an integer from 1 to 5;
each p, r, s, and t is independently 0 or 1; and
** is the disulfide bond.
53 . The compound of claim 40 , wherein the linker comprises a fragment of the formula
wherein
each d, e, and f is independently an integer from 1 to 5;
* is the point of attachment to the rest of the compound; and
** is the disulfide bond.
54 . The compound of claim 53 , wherein the compound comprises a fragment of the formula
wherein
each X and Y is independently selected from the group consisting of halo, R 2 , OR 2 , SR 3 , and NR 4 R 5 ;
each U, V, and W is independently selected from the group consisting of —(R 6a )C═, —N═, —(R 6a )C(R 7a )—, and —N(R 4a )—;
Q is C or CH;
T is selected from the group consisting of S, O, N, and —C═C—;
each A and A 2 is independently selected from the group consisting of O, S, —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 alkyleneoxy;
Z is O or S;
R 1 is selected from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy;
each R 2 , R 3 , R 4 , R 4a , R 4b , R 5 , R 5b , R 6b , and R 7b is independently selected from the group consisting of hydrogen, halo, 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;
each R 6 , R 7 , R 6a , and R 7a is 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; or R 6a and R 7a are taken together to form a carbonyl group;
each d, e, and f is independently an integer from 1 to 5;
each p, r, s, and t is independently 0 or 1; and
** is the disulfide bond.
55 . The compound of claim 40 , wherein the linker comprises at least one fragment of a formula selected from the group consisting of
wherein
each R a and R b is independently hydrogen or C1-C 4 alkyl;
each z and z′ is independently an integer from 1 to 4;
* is the point of attachment to the rest of the compound; and
** is the disulfide bond.
56 . The compound of claim 55 , wherein the compound comprises a fragment of the formula
wherein
each R a and R b is independently hydrogen or C 1 -C 4 alkyl;
z is an integer from 1 to 4;
** is the disulfide bond; and
A is an agent selected from the group consisting of a diagnostic, a therapeutic, and an imaging agent.
57 . The compound of claim 56 , wherein the compound comprises a fragment of the formula
wherein
each R a and R b is independently hydrogen or C 1 -C 4 alkyl;
each d′, e′, and f′ is independently an integer from 1 to 5;
z is an integer from 1 to 4;
* is the point of attachment to the rest of the compound; and
A is an agent selected from the group consisting of a diagnostic, a therapeutic, and an imaging agent.
58 . The compound of claim 56 , wherein the compound comprises a fragment of the formula
wherein
each R a and R b is independently hydrogen or C 1 -C 4 alkyl;
each d, e, and f is independently an integer from 1 to 5;
z is an integer from 1 to 4;
* is the point of attachment to the rest of the compound; and
A is an agent selected from the group consisting of a diagnostic, a therapeutic, and an imaging agent.
59 . The compound of claim 40 , wherein the compound is of the formula
wherein
each X and Y is independently selected from the group consisting of halo, R 2 , OR 2 , SR 3 , and NR 4 R 5 ;
each U, V, and W is independently selected from the group consisting of —(R 6a )C═, —N═, —(R 6a )C(R 7a )—, and —N(R 4a )—;
Q is C or CH;
T is selected from the group consisting of S, O, N, and —C═C—;
each A 1 and A 2 is independently selected from the group consisting of O, S, —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 alkyleneoxy;
Z is O or S;
R 1 is selected from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy;
each R 2 , R 3 , R 4 , R 4a , R 4b , R 5 , R 5b , R 6b , and R 7b is independently selected from the group consisting of hydrogen, halo, 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;
each R 6 , R 7 , R 6a , and R 7a is 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; or R 6a and R 7a are taken together to form a carbonyl group;
each R a and R b is independently hydrogen or C 1 -C 4 alkyl;
each d′, e′, and f′ is independently an integer from 1 to 5;
each p, r, s, and t is independently 0 or 1;
z is an integer from 1 to 4; and
A is an agent selected from the group consisting of diagnostic, therapeutic, and imaging agents.
60 . The compound of claim 59 , wherein the compound is of the formula
61 . A compound of the formula
B-L-X
wherein
B is a vitamin receptor binding ligand;
L is a linker comprising a disulfide and at least one fragment of a formula selected from the group consisting of
wherein
each d, e, and f is independently an integer from 1 to 5; and
* is the point of attachment to the rest of the compound;
wherein
each d′, e′, and f′ is independently an integer from 1 to 5; and
* is the point of attachment to the rest of the compound;
wherein
each g and h is independently an integer from 1 to 5;
i is an integer from 1 to 4; and
* is the point of attachment to the rest of the compound;
wherein
each g′ and h′ is independently an integer from 1 to 5;
i′ is an integer from 1 to 4; and
* is the point of attachment to the rest of the compound;
wherein
each v, w, x, and y is independently an integer from 1 to 3; and
each * is the point of attachment to the rest of the compound;
wherein
each v′, x′, and y′ is independently an integer from 1 to 3; and
* is the point of attachment to the rest of the compound; and
X is selected from the group consisting of an exogenous nucleophile, an endogenous nucleophile, glutathione, and a bioreducing agent;
wherein L is covalently bonded to B by an amide or ester bond.