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(12) United States Patent (10) Patent No.: US 7.651,979 B2 Lippard Et Al

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(12) United States Patent (10) Patent No.: US 7.651,979 B2 Lippard Et Al USOO7651979B2 (12) United States Patent (10) Patent No.: US 7.651,979 B2 Lippard et al. (45) Date of Patent: *Jan. 26, 2010 (54) COORDINATION COMPLEXES, AND Friedhelm Balkenhohl et al., "Combinatorial Synthesis of Small METHODS FOR PREPARING BY Organic Molecules'. Angew. Chem. Int. Ed, Engl., 35, pp. 2289-2337 COMBINATORIAL METHODS,ASSAYING (1996). AND USING THE SAME Steven F. Bellon et al., “Bending studies of DNA site-specifically modified by cisplatin, trans-diamminedichloroplatinum(II) and cis (75) Inventors: Stephen J. Lippard, Cambridge, MA Pt(NH)(N3-cytosine) C1)” Biophysical Chemistry, vol. 35, pp. (US); Christopher J. Ziegler, Waltham, 179-188 (1990). MA (US) (Continued) (73) Assignee: Massachusetts Institute of Technology, Primary Examiner Jeffrey S. Lundgren Cambridge, MA (US) (74) Attorney, Agent, or Firm—Dana M. Gordon; Foley Hoag LLP (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 (57) ABSTRACT U.S.C. 154(b) by 447 days. This patent is Subject to a terminal dis The present invention relates to novel coordination com claimer. plexes, methods for synthesizing and identifying coordina tion complexes, using combinatorial techniques, and assay (21) Appl. No.: 10/928,929 ing their activity. In certain embodiments, the invention relates to a library comprising a plurality of platinum-con (22) Filed: Aug. 27, 2004 taining coordination complexes represented by the general formula {PtLA}, wherein, independently for each (65) Prior Publication Data occurrence, each L is a non-labile ligand understandard con US 2005/0227290 A1 Oct. 13, 2005 ditions, each n is equal to 1, 2 or 3; each A is a labile ligand under standard conditions; and each Pt is Pt(II) or Pt(IV); Related U.S. Application Data provided that when Pt is Pt(IV), two additional ligands in the trans axial positions of the general formula depicted are (63) Continuation of application No. 09/907,515, filed on present; and at least one of the plurality of platinum-contain Jul. 16, 2001, now Pat. No. 6,806,289. ing coordination complexes is represented by the formula (60) Provisional application No. 60/218,335, filed on Jul. 14, 2000. (51) Int. Cl. C40B 40/8 (2006.01) Y (52) U.S. Cl. ............................. 506/22:506/13:506/21; 514/492; 424/649; 423/22 (58) Field of Classification Search ....................... None See application file for complete search history. (56) References Cited wherein, independently for each occurrence: X represents U.S. PATENT DOCUMENTS halogen or other labile ligand under standard conditions; W 5,359,047 A 10, 1994 Donahue et al. ........... 536,235 represents S, N, or P;Y represents —OR7. —SR7, a halogen 5,625,048 A 4, 1997 Tsien et al. ................ 536,234 or —N(R9)R10; R9 and R10, each independently, represent 5,955,604 A 9, 1999 Tsien et al. ................. 540,222 —H, alkyl, alkenyl, —(CH), R7, or R9 and R10, taken 6,806,289 B1* 10/2004 Lippard et al. .............. 514,492 together with the Natom to which they are attached complete a heterocycle having from 4 to about 8 atoms in the ring structure, all optionally substituted; L represents a non-labile FOREIGN PATENT DOCUMENTS ligand under standard conditions; R7 represents —H, alkyl, WO WO96,30540 10, 1996 aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; the ligand V comprises W.Y. and a heterocycle having from 4 to OTHER PUBLICATIONS about 8 atoms in the ring structure, optionally aromatic and optionally substituted; and the symbol Raynaud et al., Clinical Cancer Research 3:2063-2074 (1997).* Trevor G. Appleton et al., “Reactions of Platinum (II) Aqua Com plexes. 2. ' Pt NMR Study of Reactions between the Tetraaquaplatinum (II) Cation and Chloride, Hydrozide, Percholarate, Nitrate, Sulfate, Phosphate, and Acetate'. Inorganic Chemistry, vol. 2, No. 22, pp. 3521-3525 (1984). x Robert W. Armstrong et al., “Multiple-Component Condensation Strategies for Combinatorial Library Synthesis'. Acc., Chem. Res. American Chemical Society, vol. 29, No. 3, pp. 123-131 (1996). represents a single or a double bond. R. Bakhtiar et al., “Pharmacological applications of inorganic com plexes”. General Pharmacology, vol. 32, pp. 525-540 (1999). 2 Claims, 13 Drawing Sheets US 7.651,979 B2 Page 2 OTHER PUBLICATIONS Harold C. Harder et al., “Inhibitory Effects of Anti-Tumor Platinum Compounds on DNA, RNA and Protein Syntheses in Mammalian Erich E. Blatter et al., “Interaction of the Antitumor Agents cis, cis, Cells In Vitro”, Int. J. 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