VITAMIN RECEPTOR DRUG DELIVERY CONJUGATES FOR TREATING INFLAMMATION
Described herein are compositions, methods, compounds, conjugates, and kits for use in targeted drug delivery using drug delivery conjugates containing hydrophilic spacer linkers for use in treating disease states caused by pathogenic cell populations, such as inflammatory cells.
1 .- 43 . (canceled)
44 . A method for treating a patient with an inflammatory disease, the method comprising the step of administering to the patient a composition comprising a drug delivery conjugate of the formula
B-L-A 3
or a pharmaceutically acceptable salt, isomer, mixture of isomers, crystalline form, non crystalline form, hydrate, or solvate thereof; wherein
B is a folate;
L is a linker that comprises one or more hydrophilic spacer linkers; and
A 3 has the formula
wherein
Y A is OR C or OCH 2 CH 2 OR C ;
one of R A , R B , or R C is a bond connected to L; and
the other two of R A , R B , and R C are independently selected in each case from the group consisting of hydrogen, optionally substituted heteroalkyl, prodrug forming group, and C(O)R D , where R D is in each instance independently selected from the group consisting of hydrogen, and alkyl, alkenyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted.
45 . The method of claim 44 wherein L is a bivalent linker of the formula
wherein * indicates the point of attachment to the folate and ** indicates the point of attachment to A; and F and G are each independently 1, 2, 3 or 4;
46 . (canceled)
47 . The method of claim 45 wherein the folate is of the formula
wherein * indicates the point of attachment to the linker.
48 . The method of claim 45 wherein R A and R B are hydrogen; Y A is OCH 2 CH 2 OR C ; and R C is a bond connected to L.
49 . The method of claim 45 wherein F is 2 and G is 1.
50 . The method of claim 45 wherein the drug delivery conjugate is of the formula
51 . The method of claim 50 wherein the composition further comprises one or more carriers, diluents, or excipients, or a combination thereof.
52 . The method of claim 50 wherein the purity of the drug delivery conjugate is at least 98%.
53 . The method of claim 50 wherein the composition is in a dosage form adapted for parenteral administration.
54 . The method of claim 50 wherein the dose of the drug delivery conjugate is in the range of 1 to 5 μg/kg.
55 . The method of claim 50 wherein the dose of the drug delivery conjugate is in the range of 1 to 3 μg/kg.
56 . The method of claim 50 wherein the disease is selected from the group consisting of arthritis, including rheumatoid arthritis and osteoarthritis, glomerulonephritis, proliferative retinopathy, restenosis, ulcerative colitis, Crohn's disease, fibromyalgia, psoriasis and other inflammations of the skin, osteomyelitis, Sjögren's syndrome, multiple sclerosis, diabetes, atherosclerosis, pulmonary fibrosis, lupus erythematosus, sarcoidosis, systemic sclerosis, organ transplant rejection (GVHD), and chronic inflammations.
57 . A pharmaceutical composition comprising a drug delivery conjugate of the formula
B-L-A
or a pharmaceutically acceptable salt, isomer, mixture of isomers, crystalline form, non crystalline form, hydrate, or solvate thereof; wherein
B is a folate;
L is a linker that comprises one or more hydrophilic spacer linkers; and
A has the formula
wherein
Y A is OR C or OCH 2 CH 2 OR C ;
one of R A , R B , or R C is a bond connected to L; and
the other two of R A , R B , and R C are independently selected in each case from the group consisting of hydrogen, optionally substituted heteroalkyl, prodrug forming group, and C(O)R D , where R D is in each instance independently selected from the group consisting of hydrogen, and alkyl, alkenyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted.
58 . The composition of claim 57 wherein L is a bivalent linker of the formula
wherein * indicates the point of attachment to the folate and ** indicates the point of attachment to A; and F and G are each independently 1, 2, 3 or 4;
59 . (canceled)
60 . The composition of claim 58 wherein the folate is of the formula
wherein * indicates the point of attachment to the linker.
61 . The composition of claim 58 wherein R A and R B are hydrogen; Y A is OCH 2 CH 2 OR C ; and R C is a bond connected to L.
62 . The composition of claim 58 wherein F is 2 and G is 1.
63 . The composition of claim 58 wherein the drug delivery conjugate is of the formula
64 . The composition of claim 63 wherein the composition further comprises one or more carriers, diluents, or excipients, or a combination thereof.
65 . The composition of claim 63 wherein the purity of the drug delivery conjugate is at least 98%.
66 .- 81 . (canceled)