Bifunctional resorcinol, thioresorcinol, and dithioresorcinol derivative metal chelating conjugates
View Patent ↗The present invention is directed to metal chelating conjugates for use as metallopharmaceutical diagnostic or therapeutic agents. Specifically, conjugates of the present invention include one or more carriers, a linker, and metal coordinating moiety comprising a resorcinol, thioresorcinol, or dithioresorcinol derivative through which the metal coordinating moiety is bonded to the linker.
1. A conjugate comprising a bio-directing carrier, a metal coordinating moiety, and a linker chemically linking the metal coordinating moiety to the carrier, the metal coordinating moiety comprising a resorcinol, thioresorcinol, or dithioresorcinol derivative, wherein:
(i) the metal coordinating moiety comprises a substituted heterocyclic ring having the following structure:
wherein
each Z is independently oxygen or sulfur;
n is 0, 1 or 2;
m is 0-20 wherein when m is greater than 0, each A is C 1-20 alkyl or aryl optionally substituted by one or more aryl, C 1-20 alkyl, carbaldehyde keto, carboxyl, cyano, halo, nitro, amido, sulfato, sulfito, phosphato, phosphito, hydroxyl, oxy, ether, C 4-20 carbohydrate, mercapto or thiol;
q is 0-3 wherein when q is greater than 0, each D is independently selected from the group consisting of fluoro, chloro, bromo, iodo, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfato, sulfito, phosphato, phosphito, ether C 4-20 carbohydrate, aryl, and C 1-20 alkyl optionally substituted with one or more of C 1-20 alkyl, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfato, sulfito, phosphato, and phosphito;
X 1 , X 2 , X 3 and X 4 are independently optionally substituted methylene where the substituents are selected from the group consisting of aryl, C 1-20 alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, sulfato, sulfito, phosphato, phosphito, hydroxyl, oxy, ether, C 4-20 carbohydrate, mercapto and thio;
Q 2 -Q 4 are independently selected from the group consisting of:
q 2 is 0-4 wherein when q 2 is greater than 0, each E is independently selected from the group consisting of fluoro, chloro, bromo, iodo, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfito, phosphito, phosphato, ether, C 4-20 carbohydrate, and C 1-20 alkyl optionally substituted with one or more of C 1-20 alkyl, carboxy, cyano, nitro, amido, hydroxyl, sulfito, phospito, sulfato, and phosphate; or
(ii) the metal coordinating moiety comprises a substituted chain of carbon and nitrogen atoms having the following structure:
wherein
each Z is independently oxygen or sulfur;
n is 0, 1 or 2;
m is 0-12 wherein when m is greater than 0, each A is C 1-20 alkyl or aryl optionally substituted by one or more aryl, C 1-20 alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, sulfato, sulfito, phosphato, phosphito, hydroxyl, oxo, ether, C 4-20 carbohydrate, mercapto or thio;
q is 0-3 wherein when q is greater than 0, each D is independently selected from the group consisting of fluoro, chloro, bromo, iodo, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfato, sulfito, phosphato, phosphito, ether, C 4-20 carbohydrate, aryl, and C 1-20 alkyl optionally substituted with one or more of C 1-20 alkyl, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfato, sulfito, phosphato, and phosphito;
X 1 , X 2 , X 3 , X 4 , and X 5 are independently optionally substituted methylene where the substituents are selected from the group consisting of aryl, C 1-20 alkyl, carbaldehyde keto, carboxyl, cyano, halo, nitro, amido, sulfato, sulfito, phosphato, phosphito, hydroxyl, oxo, ether, C 4-20 carbohydrate, mercapto and thio;
Q 2 -Q 5 are independently from the group consisting of:
q 2 is 0-4 wherein when q 2 is greater than 0, each E is independently selected from the group consisting of fluoro, chloro, bromo, iodo, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfito, phosphito, phosphato, ether, C 4-20 carbohydrate, and C 1-20 alkyl optionally substituted with one or more of C 1-20 alkyl, carboxy cyano, nitro, amido, hydroxyl, sulfito, phospito, sulfato, and phosphate.
2. The conjugate of claim 1 wherein the bio-directing carrier is selected from the group consisting of imidazole, triazole, antibodies, proteins, peptides, carbohydrates, vitamins, hormones, drugs, and small organic molecules.
3. The conjugate of claim 1 wherein the conjugate comprises more than one bio-directing carrier.
4. The conjugate of claim 1 wherein the metal coordinating moiety is complexed with a metal, the metal consisting of a radioisotope or a paramagnetic metal.
5. The conjugate of claim 4 wherein the metal is selected from the group consisting of Lu, Lu-177, Y, Y-90, In, In-111, Tc, Tc=O, Tc-99m, Tc-99m=O, Re, Re-186, Re-188, Re═O, Re-186=O, Re-188=0, Ga, Ga-67, Ga-68, Cu, Cu-62, Cu-64, Cu-67, Gd, Gd-153, Dy, Dy-165, Dy-166, Ho, Ho-166, Eu, Eu-169, Sm, Sm-153, Pd, Pd-103, Pm, Pm-149, Tm, Tm-170, Bi, Bi-212, As and As-211.
6. The conjugate of claim 1 wherein the linker is selected from the group consisting of C 1-10 alkylene, oxygen, sulfur, keto, amino, amido, urea, thiourea, and ester, the alkylene, amino, amido, urea, and thiourea groups being optionally substituted with aryl, C 1-7 alkyl, C 1-7 hydroxyalkyl or C 1-7 alkoxyalkyl.
7. The conjugate of claim 6 wherein the linker is selected from the group consisting of C1-10 alkylene, oxygen, sulfur, keto, amino, amido, thiourea, and ester.
8. The conjugate of claim 1 wherein the metal coordinating moiety is complexed with a metal, M, forming a metal complex having the formula
wherein
each Z is independently oxygen or sulfur;
n is 0, 1 or 2;
m is 0-20 wherein when m is greater than 0, each A is C 1-20 alkyl or aryl optionally substituted by one or more aryl, C 1-20 alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, sulfato, sulfito, phosphato, phosphito, hydroxyl, oxy, ether, C 4-20 carbohydrate, mercapto or thio;
q is 0-3 wherein when q is greater than 0, each D is independently selected from the group consisting of fluoro, chloro, bromo, lode, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfato, sulfito, phosphato, phosphito, ether, C 4-20 carbohydrate, aryl, and C 1-20 alkyl optionally substituted with one or more of C 1-20 alkyl, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfato, sulfito, phosphato, and phosphito;
X 1 , X 2 , X 3 and X 4 are independently optionally substituted methylene where the substituents are selected from the group consisting of aryl, C 1-20 alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, sulfato, sulfito, phosphato, phosphito, hydroxyl, oxy, ether, C 4-20 carbohydrate, mercapto and thio;
Q 2 -Q 4 are independently selected from the group consisting of:
q 2 is 0-4 wherein when q 2 is greater than 0, each E is independently selected from the group consisting of fluoro, chloro, bromo, iodo, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfito, phosphito, phosphato, ether, C 4-20 carbohydrate, and C 1-20 alkyl optionally substituted with one or more of C 1-20 alkyl, carboxy, cyano, nitro, amido, hydroxyl, sulfito, phospito, sulfato, and phosphate; and
M is selected from the group consisting of Lu, Lu-177, Y, Y-90, In, In-111, Tc, Tc=O, Tc-99m, Tc-99m=O, Re, Re-186, Re-188, Re═O, Re-186=O, Re-188=O, Ga, Ga-67, Ga-68, Cu, Cu-62, Cu-64, Cu-67, Gd, Gd-153, Oy, Dy-165, Dy-166, Ho, Ho-166, Eu, Eu-169, Sm, Sm-153, Pd, Pd-103, Pm, Pm-149, Tm, Tm-170, Bi, Bi-212, As and As-211.
9. The conjugate of claim 1 wherein the metal coordinating moiety is complexed with a metal, M, forming a metal complex having the formula
wherein
each Z is independently oxygen or sulfur;
n is 0, 1 or 2;
m is 0-12 wherein when m is greater than 0, each A is C 1-20 alkyl or aryl optionally substituted by one or more aryl, C 1-20 alkyl, carbaldehyde, keto, carboxyl, cyano, halo; nitro, amido, sulfato, sulfito, phosphato, phosphito, hydroxyl, oxy, ether, C 4-20 carbohydrate, mercapto or thio;
q is 0-3 wherein when q is greater than 0, each D is independently selected from the group consisting of fluoro, chloro, bromo, lode, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfato, sulfito, phosphato, phosphito, ether, C 4-20 carbohydrate, aryl, and C 1-20 alkyl optionally substituted with one or more of C 1-20 alkyl, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfato, sulfito, phosphato, and phosphito;
X 1 , X 2 , X 3 , X 4 and X 5 are independently optionally substituted methylene where the substituents are selected from the group consisting of aryl, C 1-20 alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, sulfato, sulfito, phosphato, phosphito, hydroxyl, oxy, ether, C 4-20 carbohydrate, mercapto and thio;
Q 2 -Q 5 are independently selected from the group consisting of:
q 2 is 0-4 wherein when q 2 is greater than 0, each E is independently selected from the group consisting of fluoro, chloro, bromo, iodo, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfito, phosphito, phosphato, ether, C 4-20 carbohydrate, and C 1-20 alkyl optionally substituted with one or more of C 1-20 alkyl, carboxy, cyano, nitro, amido, hydroxyl, sulfito, phospito, sulfato, and phosphato; and
M is selected from the group consisting of Lu, Lu-177, Y, Y-90, In, In-111, Tc, Tc=O, Tc-99m, Tc-99m=O, Re, Re-186, Re-188, Re═O, Re-186=O, Re-188=O, Ga, Ga-67, Ga-68, Cu, Cu-62, Cu-64, Cu-67, Gd, Gd-153, Oy, Oy-165, Oy-166, Ho, Ho-166, Eu, Eu-169, Sm, Sm-153, Pd, Pd-103, Pm, Pm-149, Tm, Tm-170, Bi, Bi-212, As and As-211.
10. The conjugate of claim 1 wherein the metal coordinating complex comprises a resorcinol derivative.
11. A pharmaceutical composition comprising the conjugate of claim 1 and a pharmaceutically acceptable carrier.
12. A method for diagnosing cancer, the method comprising administering the pharmaceutical composition of claim 11 to a subject.
13. A method for treating of cancer, the method comprising administering the pharmaceutical composition of claim 11 to a subject afflicted with cancer.
14. A kit comprising a metal coordinating moiety having a resorcinol, thioresorcinol, or dithioresorcinol derivative, a reactive electrophile, a deprotecting acid, and a buffer wherein the metal coordinating moiety comprises one of the following structures:
wherein
each Z is independently oxygen or sulfur;
n is 0, 1 or 2;
m is 0-20 wherein when m is greater than 0, each A is C 1-20 alkyl or aryl optionally substituted by one or more aryl, C 1-20 alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, sulfato, sulfito, phosphato, phosphito, hydroxyl, oxy, mercapto or thio;
q is 0-3 wherein when q is greater than 0, each D is independently selected from the group consisting of fluoro, chloro, bromo, iodo, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfato, sulfito, phosphato, phosphito, aryl, and C 1-20 alkyl optionally substituted with one or more of C 1-20 alkyl, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfato, sulfito, phosphato, and phosphito;
X 1 , X 2 , X 3 and X 4 are independently optionally substituted methylene where the substituents are selected from the group consisting of aryl, C 1-20 alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, sulfato, sulfito, phosphato, phosphito, hydroxyl, oxy, mercapto and thio;
Q 2 -Q 4 are independently selected from the group consisting of:
q 2 is 0-4 wherein when q 2 is greater than 0, each E is independently selected from the group consisting of fluoro, chloro, bromo, iodo, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfito, phosphito, phosphato, and C 1-20 alkyl optionally substituted with one or more of C 1-20 alkyl, carboxy, cyano, nitro, amido, hydroxyl, sulfito, phospito, sulfato, and phosphato; or
wherein
each Z is independently oxygen or sulfur;
n is 0, 1 or 2;
m is 0-12 wherein when m is greater than 0, each A is C 1-20 alkyl or aryl optionally substituted by one or more aryl, C 1-20 alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, sulfato, sulfito, phosphato, phosphito, hydroxyl, oxy, mercapto or thio;
q is 0-3 wherein when q is greater than 0, each D is independently selected from the group consisting of fluoro, chloro, bromo, iodo, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfato, sulfito phosphato, phosphito, aryl, and C 1-20 alkyl optionally substituted with one or more of C 1-20 alkyl, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfato, sulfito, phosphato, and phosphito;
X 1 , X 2 , X 3 , X 4 , and X 5 are independently optionally substituted methylene where the substituents are selected from the group consisting of aryl, C 1-20 alkyl, carbaldehyde, keto, carboxyl, cyano, halo, nitro, amido, sulfato, sulfito, phosphato, phosphito, hydroxyl, oxy, mercapto and thio;
Q 2 -Q 5 are independently selected from the group consisting of:
q 2 is 0-4 wherein when q 2 is greater than 0, each E is independently selected from the group consisting of fluoro, chloro, bromo, iodo, carboxyl, cyano, nitro, amido, hydroxyl, amino, sulfito, phosphito, phosphato, and C 1-20 alkyl optionally substituted with one or more of C 1-20 alkyl, carboxy, cyano, nitro, amido, hydroxyl, sulfito, phospito, sulfato, and phosphato.
15. The kit of claim 14 wherein the buffer is selected from the group consisting of citrate, phosphate and borate.
16. The kit of claim 14 wherein the reactive electrophile is selected from the group consisting of active urea, active ester, and active alkylhalide.
17. The kit of claim 14 wherein the metal coordinating moiety, the reactive electrophile, the deprotecting acid, and the buffer are in unit dosage form.
18. The kit of claim 14 wherein the kit additionally comprises a solution of a radioactive metal.
19. The kit of claim 18 wherein the radioactive metal is selected from the group consisting of Lu, Lu-177, Y, Y-90, In, In-111, Tc, Tc=O, Tc-99m, Tc-99m=O, Re, Re-186, Re-188, Re═O, Re-186=O, Re-188=O, Ga, Ga-67, Ga-68, Cu, Cu-62, Cu-64, Cu-67, Gd, Gd-153, Dy, Dy-165, Dy-166, Ho, Ho-166, Eu, Eu-169, Sm, Sm-153, Pd, Pd-103, Pm, Pm-149, Tm, Tm-170, Bi, Bi-212, As and As-211.
20. The kit of claim 19 wherein the metal coordinating moiety comprises a resorcinol derivative.