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Use of Chk2 Kinase Inhibitors for Cancer Treatment

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Use of Chk2 Kinase Inhibitors for Cancer Treatment (19) TZZ__ ¥_T (11) EP 1 912 635 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/17 (2006.01) A61K 31/175 (2006.01) 05.03.2014 Bulletin 2014/10 A61K 31/4184 (2006.01) A61P 9/10 (2006.01) A61P 3/10 (2006.01) A61P 35/00 (2006.01) (2006.01) (21) Application number: 06800452.2 A61P 29/00 (22) Date of filing: 27.07.2006 (86) International application number: PCT/US2006/029401 (87) International publication number: WO 2007/016338 (08.02.2007 Gazette 2007/06) (54) USE OF CHK2 KINASE INHIBITORS FOR CANCER TREATMENT VERWENDUNG VON CHK2-KINASEHEMMERN ZUR KREBSBEHANDLUNG UTILISATION D INHIBITEURS DE LA CHK2 KINASE POUR LE TRAITEMENT DU CANCER (84) Designated Contracting States: • CARDELINA, John AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Walkersville, MD 21793 (US) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • JOBSON, Andrew SK TR Walkersville, MD 21793 (US) (30) Priority: 29.07.2005 US 703556 P (74) Representative: Zacco Denmark A/S Hans Bekkevolds Allé 7 (43) Date of publication of application: 2900 Hellerup (DK) 23.04.2008 Bulletin 2008/17 (56) References cited: (73) Proprietor: The Government of the United States WO-A-03/006426 US-A- 3 560 566 of America as US-A1- 2004 214 857 representedby the Secretary of the Department of Health and Human Services • KORYTNYK W ET AL: "Guanylhydrazones with Rockville, MD 20852 (US) potential antileukemic activity. 2. Synthesis and structure-activity relationships of analogs of 4,4’- (72) Inventors: diacetyl-N,N’-diphenylurea bis • POMMIER, Yves (guanylhydrazone)" JOURNAL OF MEDICINAL Bethesda, MD 20814 (US) CHEMISTRY, AMERICAN CHEMICAL SOCIETY. • SHOEMAKER, Robert, H. WASHINGTON, US, vol. 21, no. 6, 1978, pages Boyds, MD 02841 (US) 507-513, XP002206328 ISSN: 0022-2623 • SCUDIERO, Dominic • MIHICH E: "Combined effects of chemotherapy Frederick, MD 21703 (US) and immunity against leukemia L1210 in DBA-2 • CURRENS, Michael mice." CANCER RESEARCH APR 1969, vol. 29, Frederick, MD 21702 (US) no. 4, April 1969 (1969-04), pages 848-854, XP009080242 ISSN: 0008-5472 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 912 635 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 912 635 B1 Description [0001] The present application claims priority of U.S. provisional application number 60/703,556 filed July 29, 2006. 5 Statement Regarding Federally Sponsored Research or Development [0002] Research supporting this application was carried out by the United States of America as represented by the Secretary, Department of Health and Human Services. 10 Background of the Invention [0003] Tumorigenesis is an evolutionary process that selects for genetic and epigenetic changes, allowing evasion of anti-proliferative and cell death inducing mechanisms that normally limit clonal expansion of somatic cells. Lowe et al., Nature, 432, 307-315 (2004). 15 [0004] It has been hypothesized that DNA damage checkpoints might become activated in the early stages of tumor- igenesis, leading to cell- cycle blockade or apoptosis, either of which might constrain tumor progression. The ATM- Chk2 kinase pathway has been implicated in this process. As such, members of that pathway, including Chk2, are thought to play a role in tumorigenesis. Thus, modulators of members of the ATM- Chk2 pathway may be implicated as anticancer agents, and their use, either alone or in combination with other anticancer agents, may provide new strategies for 20 treatment or prevention of cancer, and other diseases, disorders, and symptoms thereof where apoptotic cell death is associated. [0005] Korytnyk, W. et al. (J. Med. Chem. (1978) 21 (6) 507-512) discloses compound DDUG having the formula: 25 30 [0006] DDUG has known antileukemic activity which correlates with its ability to inhibit DNA biosynthesis catalyzed by DNA polymerase. Korytnyk does not discuss or suggest DDUG’s inhibition of Chk2 kinase. [0007] Mihich, E. et al. (Cancer Research (1969) 29(4): 848-854) discloses DDUG in combination with cytarabine for 35 use in treating leukemia. D2 does not disclose or suggest the use of DDUG in combination with any other active agent and not discuss or suggest the use of DDUG for treatment of lung cancer, breast cancer, bladder cancer or melanoma. [0008] US patent no. 3,560,566 discusses the use of DDUG for treating tumors, but does not point out any specific type of tumors that may be treated with this compound. [0009] WO 03/006426 to Axxima Pharmaceuticals, AG discusses the use of DDUG for treating cancer generally but 40 does not discuss or suggest the use of DDUG for treating lung cancer, breast cancer, bladder cancer or melanoma. Summary of the Invention [0010] Described herein are compounds, and compositions and methods of generating the compounds thereof, meth- 45 ods of treating disease and disease symptoms, and compounds useful for modulating biological processes for treating disease and disease symptoms. [0011] The present invention is reflected in appending claims 1 to 12. [0012] One embodiment is a compound of formula (I), or (II), or pharmaceutically acceptable salt, solvate or hydrate thereof: 50 55 2 EP 1 912 635 B1 5 10 or 15 20 25 wherein, each R1 and R2 is independently is 30 35 40 each R3 is independently alkyl; and each R is independently H or alkyl; for use as recited in the appending claims 1 to 11. [0013] In other embodiments, the compounds are those of Formula (I) or (II): 45 wherein each R is independently H; wherein each R is independently alkyl; wherein each R3 is independently C 1-C6alkyl; wherein each R is independently alkyl and each R 3 is methyl; 50 wherein each R is independently alkyl and each R 3 is ethyl; wherein each R is independently alkyl and each R 3 is propyl; wherein each R is independently alkyl and each R 3 is butyl; wherein each R is independently H and each R 3 is methyl; wherein each R is independently H and each R 3 is ethyl; 55 wherein each R is independently H and each R 3 is propyl; wherein each R is independently H and each R 3 is butyl; wherein each R is independently H and one R 3 is ethyl and the other R 3 is methyl; wherein each R is independently H and one R 3 is propyl and the other R 3 is methyl; 3 EP 1 912 635 B1 wherein each R is independently H and one R 3 is propyl and the other R 3 is ethyl; wherein one R is independently alkyl and the other R is independently H; wherein each R is independently alkyl. 5 [0014] Another aspect is a composition including a compound of Formula (II) as defined in claim 9 and a pharmaceu- tically acceptable carrier. The composition can also include an additional therapeutic agent (e.g., anticancer agents). Additional anticancer agents include, for example, an antiangiogenesis agent, selective estrogen-receptor modulator (SERM), breast cancer therapeutic agent, aromatase inhibitor, biologic response modifiers, hormonal therapies agent, anthracycline, taxane, alkylating agent, taxol, cis-platin, arabinofuranosyl cytosine (ara-C), 5-fluorouracil (5-FU), altret- 10 amine, busulfan, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, thiotepa, cladribine, fluor- ouracil, floxuridine, gemcitabine, thioguanine, pentostatin, methotrexate, 6-mercaptopurine, cytarabine, carmustine, lomustine, streptozotocin, carboplatin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, JM216, JM335, fludarabine, ami- nooglutethimide, flutamide, goserelin, leuprolide, megestrol acetate, cyproterone acetate, tamoxifen, anastrozole, bical- utamide, dexamethasone, diethylstilbestrol, prednisone, bleomycin, dactinomycin, daunorubicin, doxirubicin, idarubicin, 15 mitoxantrone, losoxantrone, mitomycin-c, plicamycin, paclitaxel, docetaxel, CPI-11, epothilones, topotecan, irinotecan, 9-amino camptothecan, 9-nitro camptothecan, GS-211, etoposide, teniposide, vinblastine, vincristine, vinorelbine, pro- carbazine, asparaginase, pegaspargase, methoxtrexate, octreotide, estramustine, hydroxyurea, tamoxifen, raloxifene, toremifene, exemestane, letrozole, anastrozole, megestrol, trastuzumab, goserelin acetate, fulvestrant, doxorubicin, epirubicin, or cyclophosphonamide and the like. 20 [0015] Disclosed is a method of treating a subject suffering from or susceptible to a disease or disorder, or symptom thereof, or preventing a disease or disorder, or symptom thereof, in a subject susceptible to a disease or disorder, or symptom thereof, or reducing the risk of development in a subject of a disease or disorder, or symptom thereof. The method includes the step of administering to the subj ect a therapeutic amount of a compound herein sufficient to treat the disease or disorder or symptom thereof under conditions such that the disease or disorder or symptom thereof is 25 treated. In certain embodiments, the disease or disorder is a cancer or proliferative disease or disorder. In certain embodiments, the subject is a human. In certain embodiments, the subject is identified as being in need of such treatment. In certain embodiments, the subject is not suffering from a cancer. In certain embodiments, the subj ect is "at risk" of developing cancer. In certain embodiments, the method includes administration of an additional therapeutic agent. In certain embodiments, the step of administering comprises administering the compound orally, intravenously or intra- 30 muscularly. [0016] The methods as disclosed herein also may include the step of identifying that the subject is in need of treatment of diseases or disorders described herein, e.g., identifying that the subject is in need of Chk2 inhibitor administration; or in need of treatment of cancer including (e.g. cancer of colon, lung, breast, bladder, melanoma, prostate or other solid malignancies); or in need of modulated Chk2 phosphorylation; or in need of protecting non-cancerous tissue e.g.
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