Bifunctional chelating compounds containing hydroxamic acid residues
New types of hydroxamic acid-based bifunctional chelators are provided. These chelators are designed to chelate metal ions that can be detected either by their paramagnetic or radioactive properties. Conjugation with peptides or protein can be achieved by the presence of a linker moiety in the molecular structure of these chelators.
1. A compound having the formula:
where:
n, m and o are, independently, an integer from 1 to about 4;
X is CH 2 , N(R 4 ), oxygen or sulfur;
Y is hydrogen, hydroxyl, ═O N(R 4 )(R 5 ), or ═S;
R 1 is hydrogen, alkyl having 1 to 5 carbon atoms, or a protective group;
R 2 is an activated ester, a carboxylic acid, an alkyl isothiocyanate, an aromatic isothiocyanate or a leaving group;
R 3 is hydrogen or a protective group;
R 4 is hydrogen, alkyl having 1 to 5 carbon atoms, or a protective group; and
R 5 is hydrogen, alkyl having 1 to 5 carbon atoms, or a protective group,
wherein:
said protective group is benzyloxycarbonyl or
said activated ester is
and
said leaving group is halo, mesylate, tosylate, or trifluorosulfonate.
2. The compound of claim 1 wherein the carboxylic acid group is:
3. The compound of claim 1 wherein the isothiocyanato group is:
4. The compound of claim 1 wherein the protective group is tert-butoxycarbonyl or benzyloxycarbonyl.
5. The compound of claim 1 wherein n is equal to 1 or 2 and m is equal to 1 or 2.
6. The compound of claim 1 wherein:
n or m or o is 1 or 2;
X is N(R 4 ) or oxygen;
Y is hydrogen or ═O;
R 1 is hydrogen or methyl;
R 2 is p-nitrophenyl ester;
R 3 is hydrogen or tert-butyldiphenylsilyl; and
R 4 is methyl, ethyl, propyl or butyl.
7. A compound having the formula:
where:
n, m and o are, independently, an integer from 1 to about 4;
X is CH 2 , N(R 4 ), oxygen or sulfur;
Y is hydrogen, —OH, ═O, N(R 4 )(R 5 ), or ═S;
R 1 is hydrogen, alkyl having 1 to 5 carbon atoms, or a protective group;
R 2 is an activated ester, a carboxylic acid, an alkyl isothiocyanate, an aromatic isothiocyanate or a leaving group;
R 3 is hydrogen or a protective group;
R 4 is hydrogen, alkyl having 1 to 5 carbon atoms, or a protective group; and
R 5 is hydrogen, alkyl having 1 to 5 carbon atoms, or a protective group;
wherein
said protective group is benzyloxycarbonyl or
said activated ester is
and
said leaving group is halo, mesylate, tosylate, or trifluorosulfonate.
8. The compound of claim 7 wherein the carboxylic acid group is:
9. The compound of claim 7 wherein the isothiocyanato group is:
10. The compound of claim 7 , wherein the protecting group is tert-butoxycarbonyl or benzyloxycarbonyl.
11. The compound of claim 7 wherein:
n or m or o is 1 or 2;
X is N(R 4 ) or oxygen;
Y is hydrogen or carbonyl;
R 1 is hydrogen or methyl;
R 2 is p-nitrophenyl ester;
R 3 is hydrogen or tert-butyldiphenylsilyl; and
R 4 is methyl, ethyl, propyl or butyl.
12. A compound having the formula:
where n, m and o are, independently, an integer from 1 to about 4;
X is CH 2 , N(R 4 ), oxygen or sulfur;
Y is hydrogen, —OH, ═O, N(R 4 )(R 5 ), or ═S;
R 1 is hydrogen, alkyl having 1 to 4 carbon atoms, or a protective group;
R 2 is an activated ester, a carboxylic acid, or a leaving group;
R 3 is hydrogen or a protective group;
R 4 is hydrogen, alkyl having 1 to 5 carbon atoms, or a protective group;
R 5 is hydrogen, alkyl having 1 to 5 carbon atoms, or a protective group;
Z 1 is hydrogen, N(R 4 )(R 5 ), —OH, ═O, or ═S; and
Z 2 is hydrogen, N(R 4 )(R 5 ), —OH, ═O, or ═S;
wherein
said protective group is benzyloxycarbonyl or
said activated ester is
and
said leaving group is halo, mesylate, tosylate, or trifluorosulfonate.
13. The compound of claim 12 wherein the carboxylic acid group is:
14. The compound of claim 12 wherein:
n or m or o is 1 or 2;
X is N(R 4 ) or oxygen;
Y is hydrogen or ═O;
R 1 is hydrogen or methyl;
R 2 is p-nitrophenyl ester;
R 3 is hydrogen or tert-butyldiphenylsilyl;
R 4 is methyl, ethyl, propyl or butyl;
Z 1 is —OH; and
Z 2 is hydrogen or —OH.
15. A pharmaceutical composition comprising a compound according to claim 1 in free or in pharmaceutically acceptable salt form and one or more pharmaceutically acceptable carriers or diluents.
16. A pharmaceutical composition comprising a compound according to claim 7 in free or in pharmaceutically acceptable salt form and one or more pharmaceutically acceptable carriers or diluents.
17. A pharmaceutical composition comprising a compound according to claim 12 in free or in pharmaceutically acceptable salt form and one or more pharmaceutically acceptable carriers or diluents.
18. The compound of claim 1 wherein:
said carboxylic acid is selected from the group consisting of
and
said isothiocyanate is selected from the group consisting of
19. The compound of claim 7 wherein
said carboxylic acid is selected from the group consisting of
and
said isothiocyanate is selected from the group consisting of
20. The compound of claim 12 wherein
said carboxylic acid is selected from the group consisting of
21. A method of treating a disease comprising administering to an animal in need thereof an amount of a compound according to claim 1 complexed with a radionuclide, wherein said amount is effective to treat the disease and the disease is selected from the group consisting of pituitary tumors, gastroenteropancreatic tumors, central nervous system tumors, breast tumors, prostatic tumors, ovarian tumors, colonic tumors, small cell lung cancer, paragangliomas, neuroblastomas, pheochromocytomas, medullary thyroid carcinomas, myelomas, metastases, or lymphomas.
22. A method of treating a disease comprising administering to an animal in need thereof an amount of a compound according to claim 7 complexed with a radionuclide, wherein said amount is effective to treat the disease and the disease is selected from the group consisting of pituitary tumors, gastroenteropancreatic tumors, central nervous system tumors, breast tumors, prostatic tumors, ovarian tumors, colonic tumors, small cell lung cancer, paragangliomas, neuroblastomas, pheochromocytomas, medullary thyroid carcinomas, myelomas, metastases, or lymphomas.
23. A method of treating a disease comprising administering to an animal in need thereof an amount of a compound according to claim 12 complexed with a radionuclide, wherein said amount is effective to treat the disease and the disease is selected from the group consisting of pituitary tumors, gastroenteropancreatic tumors, central nervous system tumors, breast tumors, prostatic tumors, ovarian tumors, colonic tumors, small cell lung cancer, paragangliomas, neuroblastomas, pheochromocytomas, medullary thyroid carcinomas, myelomas, metastases, or lymphomas.