USOO94995.74B2 (12) United States Patent (10) Patent No.: US 9,499,574 B2 Miodragovic et al. (45) Date of Patent: Nov. 22, 2016 (54) ARSENOPLATIN ANTI-CANCERAGENTS OTHER PUBLICATIONS (71) Applicant: Northwestern University, Evanston, IL Miodragovic et al. Angewandte Chemie, International Edition (US) (2013), 52(41), 10749-10752.* International Search Report dated Nov. 13, 2013. (72) Inventors: Denana U. Miodragovic, Chicago, IL Anderson et al., “An expanded genetic code with a functional (S. home V. O'Halloran,9 Chicago, 7571quadruplet (2004). codon.” Proc. Natl. Acad. Sci. U.S.A. 101 (20):7566 Bacher et al., “Selection and Characterization of Escherichia coli Variants Capable of Growth on an Otherwise Toxic Trvptophan (73) Assignee: Northwestern University, Evanston, IL Analogue.” Bacteriol. 183(18):5414-5425 (2001). ryptop (US) Budisa et al., “Proteins with (beta)-(thienopyrrolyl)alanines as alter native chromophores and pharmaceutically active amino acids.” (*) Notice: Subject to any disclaimer, the term of this Protein Sci. 10(7): 1281-1292 (2001). patent is extended or adjusted under 35 Chin et al., “An Expanded Eukaryotic Genetic Code.” Science U.S.C. 154(b) by 0 days. 301(5635):964-967 (2003). Hamano-Takaku et al., “A Mutant Escherichia coli Tyrosyl-tRNA (21) Appl. No.: 14/421,982 Synthetase Utilizes the Unnatural Amino Acid AZatyrosine More Efficiently than Tyrosine,” J. Biol. Chem. 275(51):40324-40328 (22) PCT Filed: Aug. 14, 2013 (2000). Ibba et al., “Genetic code: introducing pyrrolysine.” Curr Biol. 12(13):R464-R466 (2002). (86). PCT No.: PCT/US2013/0549.99 Ikeda et al., “Synthesis of a novel histidine analogue and its efficient S 371 (c)(1), incorporation into a protein in vivo..” Protein Eng. Des. Sel. (2) Date: Feb. 16, 2015 16(9):699-706 (2003). James et al., “Kinetic characterization of ribonuclease S mutants (87) PCT Pub. No.: WO2014/028653 containing photoisomerizable phenylaZophenylalanine residues.” Protein Eng. Des. Sel. 14(12):983-991 (2001). PCT Pub. Date: Feb. 20, 2014 Stadtman, “Selenocysteine.” Annu Rev Biochem. 65:83-100 (1996). (65) Prior Publication Data Stryer et al., Biochemistry, 5. Sup,th ed., Freeman and Company (2002). US 2015/0218195 A1 Aug. 6, 2015 Zhang et al., “Selective incorporation of 5-hydroxytryptophan into O O proteins in mammalian cells.” Proc. Natl. Acad. Sci. U.S.A. Related U.S. Application Data 101(24):8882-8887 (2004). (60) Provisional application No. 61/683,031, filed on Aug. * cited by examiner 14, 2012. (51) Soon (2006.01) Primary Examiner — Sudhakar Katakam C07F 15/00 (2006.01) F.74). 2. Att Orney, Agent,Agent or Firm - Klintworth1WO & ROZa blat C07F 15/04 (2006.01) C07F 9/90 (2006.01) C07F 9/94 (2006.01) (57) ABSTRACT C07F 9/70 (2006.01) (52) U.S. Cl. Disclosed are compound having the structure of formula (I): CPC ............... C07F 19/005 (2013.01); C07F 9/70 (2013.01); C07F 9/902 (2013.01); C07F 9/94 (2013.01); C07F 15/0013 (2013.01); C07F X (I) 15/0066 (2013.01); C07F 15/045 (2013.01) (58) Field of Classification Search Al-y- & CPC ........ C07F 19/005; CO7F 9/70; C07F 9/902; L w L2 C07F 9/94; C07F 15/045; CO7F 15/0013; \,, g s CO7F 15/0066 Z -j-Z See application file for complete search history. Yi Y2 (56) References Cited wherein M is Pt, Pd or Ni; Q is As, Sb or Bi; Z' is N: Z is U.S. PATENT DOCUMENTS O or S; L and L are independently C(O), C R' or C R: X is a Lewis base and Y and Y are independently oxygen 2004/0258759 A1 12, 2004 SuSlick et al. or Sulfur-containing Substituents, conjugates containing FOREIGN PATENT DOCUMENTS compounds of formula (I) and their use as chemotherapy agents. CA 1196004 10, 1985 CN 1.01434622 5, 2009 EP O306605 3, 1989 12 Claims, 8 Drawing Sheets U.S. Patent Nov. 22, 2016 Sheet 1 of 8 US 9,499,574 B2 C1 FIG. 1A U.S. Patent Nov. 22, 2016 Sheet 2 of 8 US 9,499,574 B2 FIG. B U.S. Patent Nov. 22, 2016 Sheet 3 of 8 US 9,499,574 B2 O O-2cs Y5 -& C FIG. 1C U.S. Patent Nov. 22, 2016 Sheet 4 of 8 US 9,499,574 B2 FIG. 1D U.S. Patent Nov. 22, 2016 Sheet S of 8 US 9,499,574 B2 H 2.18(ppm) 2.14 2.10 Nois & Sois & -3724 ppm -386 ppm Jaspesin a 456 Hz -3710 -3750 -3790 -3830 -38to FIG 2 U.S. Patent Nov. 22, 2016 Sheet 6 of 8 US 9,499,574 B2 A2780CP K Complex 1 00 e Cisplatin & Arsenic trioxide 50 haarara Control.0 5 2.0 2.5 3.0 LogM/u M HTC 116 K Complex 1 e Cisplatin & Arsenic trioxide LogM/LM FG. 3 U.S. Patent Nov. 22, 2016 Sheet 7 of 8 US 9,499,574 B2 U87 a Complex 1 9 Cisplatin 00- s : x & Arsenic trioxide 50 O NS i. orrooroo LogM/u M D A2780 50 Complex 1 0 Cisplatin C & Arsenic trioxide ass 00 -k-k s XX 98. xA as a O) as N. N. St 50 O 8 On . aga i. hoovoo Control O 2 3 LogM/u M FIG. 3 (Cont.) U.S. Patent Nov. 22, 2016 Sheet 8 of 8 US 9,499,574 B2 E MDA-MB-231-mCherry 150 Complex 1 e Cisplatin 100 is is S- a Arsenic trioxide SS58 l r re. Control - O 2 3 LogM/M F RPM 8226 150 Complex 1 C e Cisplatin is 100 = -s & Arsenic trioxide 9 & X O) as a teen O Control -1 O 2 3 LogM/u M FIG. 3 (Cont.) US 9,499,574 B2 1. 2 ARSENOPLATIN ANT-CANCERAGENTS X (I) CROSS-REFERENCE TO RELATED APPLICATIONS A.z-- y The present application is the National Stage of Interna Z2-Q-Z2 tional Application No. PCT/US2013/054999, filed Aug. 14, M. v. 2013, and entitled “ARSENOPLATIN ANTI-CANCER Yi Y2 AGENTS, which claims the benefit of U.S. Provisional 10 Application No. 61/683,031 filed Aug. 14, 2012, and entitled wherein M is Pt, Pd or Ni; Q is As, Sb or Bi; Z' is N: Z is ARSENOPLATINS-A NEW CLASS OF ANTI-CANCER O or S; L and L are independently C(O), C R' or C R: AGENTS. The content of the U.S. Provisional Patent X is a Lewis base; Y' and Y are independently selected Application is hereby incorporated by reference in its from —OR. -OR', SR and SR, wherein R' and Rare entirety. 15 independently selected from hydrogen, halogen, cyano, keto, ester, ether, thiol, thioether, thioester, imino, C-Co STATEMENT REGARDING FEDERALLY alkyl, C-Co alkenyl, alkynyl, alkoxyl, amino, amidyl, SPONSORED RESEARCH OR DEVELOPMENT immino, Sulfonyl, Sulfoxyl, phosphoryl, phosphoryl ester, glycosyl, aryl, C-C cycloalkyl, heteroaryl, and C-Cls This invention was made with government Support under heterocycloalkyl: grant numbers U01 CA151461, U54 CA119341, U54 wherein R and Rare independently selected from hydro CA143869, P50 CA090386 awarded by the National Insti gen, C-C alkyl, C-Coalkenyl, alkynyl, alkoxyl, amino, tutes of Health and grant number W81XWH-08-1-0672 amidyl, immino, Sulfonyl, Sulfoxyl, phosphoryl, phosphoryl awarded by the US Army Medical Research and Materiel ester, glycosyl, aryl, C-C cycloalkyl, heteroaryl, and Command. The government has certain rights in the inven 25 C-Cls heterocycloalkyl; tion. wherein the Lewis base can be halogen, N-bonded cyano, nitroso, nitroxyl, N-bonded C-C alkyl, C-C alkenyl, BACKGROUND N-bonded C-C cycloalkyl, N-bonded C-Coheteroalkyl, N-bonded C-Co heteroalkenyl, N-bonded aryl, N-bonded 1. Technical Field 30 heteroaryl, N-bonded C-Cls heterocycloalkyl, NR'R''. The disclosure relates to arsenoplatin and related com N-bonded ligand, S-bonded cyano, sulfonyl, sulfoxyl, thiol, pounds and methods for their use as chemotherapy agents. S-bonded thioether, S-bonded thioester, S-bonded C-Co 2. Description of Relevant Prior Art alkyl, C-Co alkenyl, S-bonded C-Co cycloalkyl, Cis-diamminedichloroplatinum(II) ("Cisplatin') and S-bonded C-Coheteroalkyl, S-bonded C-C heteroalk 35 enyl, S-bonded aryl, S-bonded heteroaryl, S-bonded C-Cls arsenic trioxide (ASOs) are highly successful agents for heterocycloalkyl, - SR, S-bonded ligand, O-bonded treatment of cancer. Cisplatin is used in combination che C-C cycloalkyl, O-bonded C-C heteroalkyl, O-bonded motherapy to treat ovarian, testicular, head, neck, and blad C-Co heteroalkenyl, O-bonded aryl, O-bonded heteroaryl, der cancers. Unfortunately, these and other cancers fre O-bonded C-Cls heterocycloalkyl, —OR, O-bonded car quently develop resistance to this widely used agent and 40 boxylato, O-bonded polycarboxylato, O-bonded carboxy there are intensive efforts to develop new agents that over lato, O-bonded polycarboxylato, O-bonded carboxylato, come this resistance. Arsenic trioxide, which was discovered O-bonded polycarboxylato, O-bonded ligand, or P-bonded as a traditional Chinese medicine, is a front line treatment phosphine having formula P(R)-(R), where x is 0, 1, 2 for acute promyelocytic leukemia and has also shown pre or 3: liminary efficacy in the treatment of blood cancers such as 45 wherein R and Rare independently selected from hydro multiple myeloma and myelodysplastic syndromes. gen, O. —CO.R. —COR, C-Clo alkyl, C-Coalkenyl, Both compounds induce apoptotic cell death, but through aryl, heteroaryl, C-C cycloalkyl and C-Cls heterocy different pathways. Cisplatin reacts with DNA and causes cloalkyl; intra- and inter-strand DNA cross-links. The principal com wherein R and Rare independently selected from C-Co ponent of aqueous Solutions of ASO at pH 7.