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W O 2 11/ 28571Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date / 10 March 2011 (10.03.2011) W O 2 1 1/ 28 57 1 A l (51) International Patent Classification: (74) Agents: UDAL, Robert, P., Ph. D. et al; Morgan, Lewis A 43/02 (2006.01) & Bockius LLP, 1701 Market Street, Philadelphia, PA 19103 (US). (21) International Application Number: PCT/US20 10/046627 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, 25 August 2010 (25.08.2010) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (25) Filing Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (26) Publication Language: English KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (30) Priority Data: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 61/238,787 1 September 2009 (01 .09.2009) US NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (71) Applicant (for all designated States except US): TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. TAPESTRY PHARMACEUTICALS, INC. [US/US]; 6304 Spine Road, Unit A, Boulder, CO 80301 (US). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors; and GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, (75) Inventors/ Applicants (for US only): MCCHESNEY, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, James, D. [US/US]; 147 Country Road 245, Etta, MS TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 38627 (US). VENKATARAMAN, Sylesh [US/US]; EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, , LT, LU, 13853 Dogleg Ln, Broomfield, CO 80023 (US). HENRI, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, John, T. [US/US]; 3549 Larkspur Drive, Longmont, CO SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, 80503 (US). GW, ML, MR, NE, SN, TD, TG). [Continued on next page] (54) Title: TAXANE ANALOGUES, THEIR USE, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND PROCESSES FOR THEIR PREPARATION (57) Abstract: The present invention relates to novel taxane analogues, processes of making the novel taxane analogues, compo sitions containing the novel taxane an a logues, and their use in treating cancer and neurodegenerative disorders. In some em bodiments, the taxane analogues are repre sented by the generic structure of formula (I) : wherein R 1, R ,R3 and A are defined here in; and esters especially pro -drugs thereof wherein one or more of the hydroxy! groups is esterified to form an in-vivo hydrolysable ester group; or pharmaceutically acceptable salts thereof. Fig - 1 0 < A R2 00 © PhOCO o TAXANE ANALOGUES, THEIR USE, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND PROCESSES FOR THEIR PREPARATION Field of the Invention The present invention is directed, in part, to novel taxane analogues useful in treatment of cancer and/or neurodegenerative disorders. The present invention is also directed, in part, to compositions containing the taxane analogues and processes of making the taxane analogues. BACKGROUND OF THE INVENTION US Patent No 5,352,806 discloses 10β- substituted taxanes which may have bridges between the 7- and 9- hydroxyl groups of the formula: wherein R and R 2 are independently hydrogen, alkyl, phenyl or substituted phenyl; or, taken together, R 1 and R 2 or a single atom selected from the group consisting of oxygen or sulphur; or one of R1 and R 2 is hydrogen, alkyl, phenyl or substituted phenyl, and the other is -OR 13 or -NR R14 where R 3 and R 4 are independently alkyl, alkanoyi, substituted alkanoyi, phenyl or substituted phenyl. It was expected that these compounds would be useful in connection with the treatment, or in the preparation of taxol derivatives for use in the treatment of cancer. Although the above formula does not extend t o compounds in which R or R12 is a hydroxyalkyi group, a compound was drawn in reaction Schemes 3 of US Patent No 5,352,806 which had one of the R and R 2 groups as hydrogen and the other as CH2CHOHCH 2OH. This was also prepared in Example 13 and tested in-vitro where Table 3 showed it was not amongst the most active compounds prepared. This is seen by the following extract relating to bridged compounds and their parent dihydrotaxol : 9-Dihydrotaxol with I n vitro tumor cell cytotoxicity 7,9-bridge (IC50 g/ m ) A549 P-388 3,4-Dihydroxy butylidene 0.3 0.18 acetal Propylidene acetal 0.023 0.022 Isopropylidene ketal 0.025 0.042 7,9-Benzylidene 1.0 1.0 None (i.e dihydrotaxol) 0.016 0.049 Other taxanes are described in EP 1 228 759; EP 1 285 920; EP 1 148 055; WO 01/56564; WO 01/57027; WO 94/10996; FR 2 715 846; US 5,352,806; FR 2 707 293; WO 94/08984; WO 92/09589; WO 94/20485; WO 93/21 173; Klein LL, "Synthesis of 9- Dihydrotaxol: a novel bioactive taxane", Tetrahedron letters, vol. 34, no. 13, 1993, pages 2047-2050; Datta A et al, "Synthesis of novel C-9 and C-10 modified bioactive taxanes", Tetrahedron letters, vol. 36, no. 12, 1995, pages 1985-1988; Klein LL et al, Journal of Medicinal Chemistry, no. 38, 1995, pages 1482-1492; J Demattei et al, An efficient synthesis of the taxane-derived anticancer agent Abt-271", Journal of Organic Chemistry, vol. 66, no. 10, 2001, pages 3330-3337; Gunda I Georg et al, "The chemistry of the taxane diterpene: stereoselective reductions of taxanes", Journal of Organic Chemsitry, vol. 63, no. 24, 1998, pages 8926-8934. However, apart from paclitaxel and docetaxel, no taxane has received regulatory approval to be marketed for use as an anticancer agent and no taxane has received regulatory approval to be marketed for use by oral administration. WO 2005/03150 and US Application No 2005/0148657 Al disclose taxane analogues and derivatives possessing a 9a, 10a configuration and an acetal or ketal bridge between the hydroxyl groups at the 7- and 9- positions. Synthesis of taxane analogues is also disclosed in WO 2007/073383, WO 2007/126893 and WO 2007/075870. Zamir et al, Tetrahedron Letters, 37, 6435-6438 (1996) discloses taxane analogues containing a five membered A-ring and a position 1 C(CH3)2OH group. These analogues were abeo-taxanes lacking the four membered oxatane ring. The compounds possessed a 10β- , stereochemistry. No anti-cancer activity was ascribed to the compounds. Zamir er al, Tetrahedron Letters, 53. 15991-16008 (1997) discloses abeo-taxane analogues and also trapped intermediates containing a 5 membered A-ring and a position 1 C(CH 3)20H group. The compounds possessed a 10β- stereochemistry and an acetoxy group at position 13. Numerous structural analogues were disclosed but no biological data was provided on any compound. Wahl et al, Tetrahedron, 48, 6965-6974 ( 1992) discloses a wide range of modified taxane analogues including one which had a 5 membered A-ring and a 1 position C(CH 3)2OH group. The compound had a 10β- hydroxyl group and a 9-keto group and was said to be active in the tubulin disassembly assay although no data was provided. The compounds were said to being studied in order to obtain new analogues of taxol and taxotere. The new compounds were thought to provide information regarding structure-activity relationships from structural modifications of the ester groups at C-2 and C-4. Other publications relating to taxane analogues include Hue et al, Magne Reson Chemis, 45, 527-530 (2007); Nicolaou et al, Ang. Chem. Int. Ed. 44, 1012-1044 (2005) ; Zamir et al, Tetrahedron Letters, 40, 7917-9920 (1999) ; Torregiani e al, Gaz. Chim. Italiana, 126, 809-814 (1996) ; Appendino et al, 3, Chem. Soc. Comman., 1587-1589 (1993) ; Samaranayake et al, J. Org. Chem., 56, 5 114-5119 (1991) ; Georg et al, Bioorg. Med. Chem. Lett. 3, 1345-1349 (1993); and Georg et al, Bioorg. Med. Chem. Lett. 3, 1349-1350 (1993); None of these publications on taxane analogues relate to compounds having a lOa-configuration, none relate to compounds having an acetal bridge between 7- and 9- hydroxy groups, none provide data showing the compounds are active in-vivo, none suggest the compounds can be employed orally and none relate to the treatment of brain or pancreatic cancers. None of the five drugs approved by the U.S. Food and Drug Administration (FDA) for treating the cognitive symptoms of Alzheimer's disease (Namenda®, Reminyl®, Exelon®, Aricept® and Cognex®) is a taxane analogue. All are cholinesterase inhibitors except Namenda®, which acts by a different mechanism. Each of the cholinesterase inhibitors acts in a different way to delay the breakdown of acetylcholine, a neurotransmitter important for memory. Namenda® protects neurons from overexposure to another neurotransmitter, called glutamate, excess levels of which reportedly contribute to the death of brain cells in people with Alzheimer's. However, Reminyl®, Exelon® and Aricept ® are most effective when treatment is begun in the early stages. Additionally, at least half of the people who take these drugs do not respond to them. Therefore, there is an urgent need for pharmaceutical agents for treating Alzheimer's disease and other neurodegenerative disorders.
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