Patent EA-004589-B1 (EA)
Title: Water soluble transplatinum complexes with anti-cancer activity and use thereof
Inventor: FARRELL NICHOLAS P
IPC: C07F15/00
Filed: 2000-03-02
Abstract: 1. A platinum coordination compound having the general formula: [PtBXm (NR*3)], wherein X is an anionic ligand, m is 1 or 2, R* is selected from the group consisting of hydrogen and C1-12 alkyls and R* can be the same or different, B is a planar, heterocyclic ring moiety selected from the group consisting of pyridines, thiazoles, benzothiazoles, quinolines, isoquinolines, acridines, imidazoles, oxazoles and pyrazines and containing at least one nitrogen atom as a ring member, and a pendant chelating group, and a nitrogen atom of B is covalently bonded to Pt and is trans-to NR*3. 2. The compound of Claim 1 wherein said planar, heterocyclic ring moiety is a pyridine. 3. The compound of claim 1 wherein said pendant chelating group is selected from the group consisting of: carboxylates (CH2)nCOO-, wheren=1-3; phosphonates (CH2)nP (OR)O2-, where n=1-3 and R is a C1-12 alkyl; and sulfonates (CH2)nSO3-, where n=1-3. 4. The compound of Claim 4 wherein said pendant chelating group is CH2COO-. 5. The compound of claim 1 wherein X is selected from the group consisting of halogens, NO3, C1O4, alkoxides (OR), sulfhydryls (SR) and carboxylates (RCOO-), where R is (C1-12) alkyl. 6. The compound of claim 4 wherein X is chloride. 7. The compound of claim 1 wherein said Pt coordination compound is trans- [Pt (PyAc-N,O) Cl (NH3)], having the formula: 8. The compound of claim 1 wherein said Pt coordination compound is trans-[PtCl2(NH3)(PyAcH)] H2O. 9. A pharmaceutical composition for the treatment of tumors in patients, comprising a platinum coordination compound having the general formula: [PtBXm(NR*3)] wherein, X is an anionic ligand, M is 1 or 2, R* is selected from the group consisting of hydrogen and C1-12 alkyls and R* can be the same or different, B is a planar, heterocyclic ring moiety selected from the group consisting of pyridines, thiazoles, benzothiazoles, quinolines, isoquinolines, acridines, imidazoles, oxazoles and pyrazines and containing at least one nitrogen atom as a ring member, and a pendant chelating group, and a nitrogen atom of B is covalently bonded to Pt and is trans-to NR*3. and a suitable pharmaceutical carrier. 10. The pharmaceutical composition of claim 8 wherein said Pt coordination compound is trans- [Pt (PyAc-N,O) Cl(NH3). 11. The pharmaceutical composition of claim 9 wherein said Pt coordination compound is trans-[PtCl2(NH3)(PyAcH)] H2O. 12. A method of preparing a trans-platinum compound having the general formula: [PtBX (NR*3)] wherein, X is an anionic ligand, m is 1or 2, R* is selected from the group consisting of hydrogen and C1-12 alkyls and R* can be the same or different, B is a planar, heterocyclic ring moiety selected from the group consisting of pyridines, thiazoles, benzothiazoles, quinolines, isoquinolines, acridines, imidazoles, oxazoles and pyrazines and containing at least one nitrogen atom as a ring member, and a pendant chelating group, and a nitrogen atom of B is covalently bonded to Pt and is trans-to NR*3, comprising the steps of: forming a mixture of cisplatin and a heterocyclic chelating ligand; reacting said mixture at high temperature; and precipitating said trans-platinum compound by adjusting the pH of said mixture. 13. A method of preparing a trans-platinum compound having the formula: comprising the steps of: heating a mixture having 40% by weight cisplatin and 60% by weight pyridine-2-yl-acetic acid methyl ester in water at 90-100 degree C; adding concentrated HCl to said mixture and continuing heating; reducing by evaporation the volume of this mixture by 80%; filtering and washing in ethanol/diethyl ketone a yellow crystalline solid; and dissolving said yellow crystalline solid in a solution of Na2HPO4 and water with heating. 14. A method for treating tumors in patients, comprising the step of administering to a patient in need thereof an effective amount of a platinum coordination compound of the general formula: [PtBXm(NR*3)] wherein, X is an anionic ligand, m is 1 or 2, R* is selected from the group consisting of hydrogen and C1-12 alkyls and R* can be the same or different, B is a planar, heterocyclic ring moiety selected from the group consisting of pyridines, thiazoles, benzothiazoles, quinolines, isoquinolines, acridines, imidazoles, oxazoles and pyrazines and containing at least one nitrogen atom as a ring member, and a pendant chelating group, and a nitrogen atom of B is covalently bonded to Pt and is trans-to NR*3. 15. The method of claim 14 wherein said Pt coordination compound is trans- [Pt(PyAc-N,O)Cl(NH3)]. 16. The method of claim 14 wherein said Pt coordination compound is trans-[PtCl2(NH3)(PyAcH)]H2O. 17. The method of claim 14 wherein said step of administration is oral or parenteral.