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(12) Patent Application Publication (10) Pub. No.: US 2013/0196938 A1 GREEN Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2013/0196938 A1 GREEN Et Al US 2013 0196938A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0196938 A1 GREEN et al. (43) Pub. Date: Aug. 1, 2013 (54) COMBINATION COMPRISING CNDAC (52) U.S. Cl. (2-CYANO-2-DEOXY-N4-PALMITOYL-1- CPC ......... A61 K3I/7068 (2013.01); A61 K3I/7048 BETA-D-ARABINOFURANOSYL-CYTOSINE) (2013.01); A61K 45/06 (2013.01); A61 K AND A CYTOTOXCAGENT 31/4375 (2013.01) USPC ............................................... 514/27: 514/49 (71) Applicant: Cyclacel Limited, London (GB) (57) ABSTRACT (72) Inventors: Simon Richard GREEN, Dundee (GB); prisingA first aspect 2-cyano-2'-deoxy-N-palmitoyl-1-B-D-arabinofura of the invention relates to a combination com Ian Neil FLEMING, Angus (GB) nosyl-cytosine, or a metabolite thereof, or a pharmaceutically acceptable salt thereof, and a cytotoxic agent selected from: (73) Assignee: CYCLACEL LIMITED, London (GB) (a) a HDAC inhibitor; and (b) a topoisomerase inhibitor selected from etoposide, topotecan and SN-38, or a prodrug (21) Appl. No.: 13/709,883 thereof. A second aspect relates to a pharmaceutical product comprising (i) 2'-cyano-2'-deoxy-N-palmitoyl-1-(B-D-ara (22) Filed: Dec. 10, 2012 binofuranosyl-cytosine, or a metabolite thereof, or a pharma ceutically acceptable salt thereof, and (ii) a cytotoxic agent selected from: (a) a HDAC inhibitor; and (b) a topoisomerase Related U.S. Application Data inhibitor selected from etoposide, topotecan and SN-38, or a (63) Continuation of application No. 12/517,196, filed on prodrug thereof, as a combined preparation for simultaneous, Nov. 19, 2009, now Pat. No. 8,349,792, filed as appli sequential or separate use in therapy. A third aspect relates to cation No. PCT/GB07/04883 on Dec. 19, 2007. a method of treating a proliferative disorder, said method comprising simultaneously, separately or sequentially (30) Foreign Application Priority Data administering to a subject 2'-cyano-2'-deoxy-N-palmitoyl 1-B-D-arabinofuranosyl-cytosine, or a metabolite thereof, or Dec. 19, 2006 (GB) ................................... O625283.7 a pharmaceutically acceptable salt thereof, and a cytotoxic agent selected from: (a) a HDAC inhibitor; and (b) a topoi Publication Classification Somerase inhibitor selected from etoposide, topotecan and SN-38, or a prodrug thereof. A fourth aspect of the invention (51) Int. Cl. relates to the use of a subject 2'-cyano-2'-deoxy-N-palmi A6 IK3I/7068 (2006.01) toyl-1-B-D-arabinofuranosyl-cytosine, or a metabolite A6 IK 45/06 (2006.01) thereof, or a pharmaceutically acceptable salt thereof, in the A6 IK3I/4375 (2006.01) preparation of a medicament for treating cutaneous T-cell A6 IK3I/7048 (2006.01) lymphoma (CTCL). Patent Application Publication Aug. 1, 2013 Sheet 1 of 5 US 2013/0196938A1 figure i xiii Sii com bination in Hutts ceis (72hr) *.*.*------------...-a-a-M'-''''''''' Patent Application Publication Aug. 1, 2013 Sheet 2 of 5 US 2013/0196938A1 Figure 2 28:8: po 1000 --- - * 8 l : is --os-Mo.............................--Sapacitabre cycé82 is rig: €83.3 sergkg cert------------------ & CY882 888A sigkg 8 skiia & CY882 - 8:3& $3 8x8 x3 8 s3 gx2 sa--a ------aa----------------------------a-va-vaaaaaaaa---------------------------- Patent Application Publication Aug. 1, 2013 Sheet 4 of 5 US 2013/0196938A1 - - - - - - - - - - - - Exxix. Sixx: s: 888 six &xixg: Xix: p-2AX :X g(x-K- acety; -istex88 -i-. Patent Application Publication Aug. 1, 2013 Sheet 5 of 5 US 2013/0196938A1 figures x-axis& -8:888& sergks 8-38x32 US 2013/0196938 A1 Aug. 1, 2013 COMBINATION COMPRISING CNDAC 0006 EP 536936 (Sankyo Company Limited) discloses (2-CYANO-2'-DEOXY-N4-PALMITOYL-1-BETA various 2'-cyano-2'-deoxy-derivatives of 1-?3-D-arabinofura D-ARABINOFURANOSYL-CYTOSINE) AND A nosylcytosine which have been shown to exhibit valuable CYTOTOXCAGENT anti-tumour activity. One particular compound disclosed in EP 536936 is 2'-cyano-2'-deoxy-N-palmitoyl-1-(B-D-ara 0001. The present invention relates to a combination suit binofuranosylcytosine (referred to hereinafter as "sapacitab able for the treatment of proliferative disorders. ine'), this compound is currently under further investigation. 0007 Sapacitabine, also known as CYC682 and 1-(2-C- BACKGROUND TO THE INVENTION cyano-2-dioxy-3-D-arabino-pentofuranosyl)-N'-palmitoyl 0002 The therapeutic use of pyrimidine nucleosides in the cytosine (Hanaoka, K., et al. Int. J. Cancer, 1999:82:226-236; treatment of proliferative disorders has been well docu Donehower R, et al., Proc Am Soc Clin Oncol, 2000: abstract mented in the art. By way of example, commercially available 764; Burch, PA, etal, Proc AmSoc. Clin Oncol, 2001: abstract antitumor agents of the pyrimidine series include 5-fluorou 364), is an orally administered novel 2’-deoxycytidine anti racil (Duschinsky, R., et al., J. Am. Chem. Soc., 79, 4559 metabolite prodrug of the nucleoside CNDAC, 1-(2-C-cyano (1957)), Tegafur (Hiller, S.A., et al., Dokl. Akad. Nauk USSR, 2-deoxy-3-D-arabino-pentafuranosyl)-cytosine. 176,332 (1967)), UFT (Fujii, S., et al., Gann, 69,763 (1978)), Carmofur (Hoshi, A., et al., Gann, 67, 725 (1976)), Doxyflu ridine (Cook, A. F., et al., J. Med. Chem., 22, 1330 (1979)), Cytarabine (Evance, J. S., et al., Proc. Soc. Exp. Bio. Med., 106. 350 (1961)), Ancytabine (Hoshi, A., et al., Gann, 63, 353, (1972)) and Enocytabine (Aoshima, M., et al., Cancer Res., 36,2726 (1976)). 0003 Nucleoside analogues that show antimetabolic activity in cancer cells have been Successfully used in the treatment of various human malignancies. Nucleosides Such as 1-beta-D-arabinofuranosylcytosine (Ara-C), fludarabine and cladribine play an important role in the treatment of leukemias, while gemcitabine is extensively used in the treat ment of many types of solid tumors. These compounds are metabolized in a similar manner to endogenous nucleosides Sapacitabine and nucleotides. Active metabolites interfere with the denovo synthesis of nucleosides and nucleotides and/or inhibit DNA chain elongation after being incorporated into DNA strands, acting as chain terminators. Furthermore, nucleoside antime tabolites incorporated into DNA strands induce strand-breaks that may eventually result in induction of apoptosis. 0004 Nucleoside antimetabolites target one or more spe cific enzyme(s) (Galmarini et al. Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol. 2002 July; 3(7):415-24: Review). The mode of inhibitory action on tar get enzymes may differ between nucleoside antimetabolites, which have the same nucleoside base, such as Ara-C and gemcitabine. Although both nucleosides are phosphorylated by deoxycytidine kinase and are also good Substrates of cyti dine deaminase, only gemcitabine shows antitumor activity 0008 Sapacitabine has a unique mode of action over other against Solid tumors. This Suggests that there are differences nucleoside metabolites such as gemcitabine in that it has a in the pharmacological activity of these nucleoside antime spontaneous DNA strand breaking action, resulting in potent tabolites, which may reflect different modes of action on anti-tumour activity in a variety of cell lines, Xenograft and target molecules. metastatic cancer model (Hanaoka et al., 1999: Kaneko et al. 0005. It has been shown that dCK deficiency is associated 1997; Wu et al., 2003). Because of its unique mode of action, with resistance to Ara-C in various cell and animal models sapacitabine causes a block at the G2/M phase of the cell (Galmarini et al. In vivo mechanisms of resistance to cytara cycle rather than in S phase of the cell cycle, which is seen for bine in acute myeloid leukaemia, Br J Haematol. 2002 June; gemcitabine and ara-C (AZuma et al 2001). 117(4):860-8). Alterations in expression of the dCK gene or 0009 Sapacitabine has been the focus of a number of significant decrease in the activity of this enzyme in Ara-C- studies in view of its oral bioavailability and its improved treated AML patients have also been correlated with clinical activity over gemcitabine (the leading marketed nucleoside outcome. These data are consistent with the concept that analogue) and 5-FU (a widely-used antimetabolite drug) intracellular phosphorylation of Ara-C by dCK is essential for based on preclinical data in Solid tumours. Recently, investi cytotoxicity in cellular models and in patients. Deficiency of gators reported that Sapacitabine exhibited Strong anticancer hENT1 in blast cell plasma membranes has also been sug activity in a model of colon cancer. In the same model, Sapa gested as a mechanism of cellular resistance to Ara-C. Other citabine was found to be superior to either gemcitabine or authors have suggested that mechanisms of drug resistance to 5-FU in terms of increasing Survival and also preventing the Ara-C are associated with increased levels of Ara-C catabolic spread of colon cancer metastases to the liver (Wu M. et al. enzymes such as CDA. Cancer Research, 2003:63:2477-2482). To date, phase I data US 2013/0196938 A1 Aug. 1, 2013 from patients with a variety of cancers suggest that sapacit and (b) a topoisomerase inhibitor selected from etoposide, abine is well tolerated in humans, with myelosuppression as topotecan and SN-38, or a prodrug thereof. the dose limiting toxicity. 0019. A seventh aspect relates to the use of a cytotoxic 0010. It well established in the art that active pharmaceu agent selected from: (a) a HDAC inhibitor; and (b) a topoi tical agents can often be administered in combination in order Somerase inhibitor selected from etoposide, topotecan and to optimise the treatment regime. For example, combinations SN-38, or a prodrug thereof, in the preparation of a medica comprising a CDK inhibitor and 1-(2-C-cyano-2-dioxy-f-D- ment for the treatment of a proliferative disorder, wherein arabino-pentofuranosyl)-N4-palmitoyl cytosine, or a said treatment comprises simultaneously, separately or metabolite thereof, and their use in the treatment of prolifera sequentially administering to a subject 2'-cyano-2'-deoxy tive disorders are disclosed in WO 2005/053699 (Cyclacel N-palmitoyl-1-?3-D-arabinofuranosyl-cytosine, O a Limited).
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