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Ep 2921486 B1 (19) TZZ __T (11) EP 2 921 486 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 303/18 (2006.01) A61K 31/336 (2006.01) 27.09.2017 Bulletin 2017/39 A61P 25/28 (2006.01) C07D 303/48 (2006.01) (21) Application number: 14188202.7 (22) Date of filing: 06.08.2010 (54) Compositions and methods for treating beta-amyloid related diseases Zusammensetzungen und Verfahren zur Behandlung von durch beta-Amyloid vermittelter Erkrankungen Compositions et procédés pour le traitement de maladies liées au bêta-amyloïde (84) Designated Contracting States: (56) References cited: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB WO-A2-2004/084830 GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR • YAMAMOTO D ET AL: "Crystal Structure and Molecular Conformation of E-64,a Cysteine (30) Priority: 07.08.2009 US 232388 P Protease Inhibitor", CHEMICAL & 07.08.2009 US 232383 P PHARMACEUTICAL BULLETIN, vol. 37, no. 10, 25 11.01.2010 US 293783 P October 1989 (1989-10-25), pages 2577-2581, XP008152644, PHARMACEUTICAL SOCIETY OF (43) Date of publication of application: JAPAN, JP ISSN: 0009-2363 23.09.2015 Bulletin 2015/39 • Anonymous: "Precision Deuterium Chemistry Backgrounder", CoNCERT Pharmaceuticals, Ic. , (60) Divisional application: 2007, pages 1-6, XP002687117, lexington, MA 17182879.1 02421, USA Retrieved from the Internet: URL:http://www.concertpharma.com/about/doc (62) Document number(s) of the earlier application(s) in uments/ConcertProductPlatformBackgrounder. accordance with Art. 76 EPC: pdf [retrieved on 2012-11-14] 10807219.0 / 2 462 131 • G. R. HOOK ET AL: "the cysteine protease cathepsin B is a key drug target and cystein (73) Proprietor: American Life Science protease inhibitors are potential therapeutics for Pharmaceuticals, Inc. traumatic brain injury", JOURNAL OF San Diego, CA 92122-4614 (US) NEUROTRAUMA, vol. 31, 1 March 2014 (2014-03-01), pages 515-529, (72) Inventors: • S. L. Harbeson R. D. Tung: "Deuterium in Drug • Ternansky, Robert J Discovery and Development", 2011, Concert San Diego, CA California 92122-4614 (US) Pharmaceuticals, Lexington vol. 24 • Allan, Amy San Diego, CA California 92122-4614 (US) Remarks: •Hook,Greg Thefile contains technical information submitted after San Diego, CA California 92122-4614 (US) the application was filed and not included in this specification (74) Representative: Atkinson, Jennifer Barker Brettell LLP 100 Hagley Road Edgbaston Birmingham B16 8QQ (GB) 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 2 921 486 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 921 486 B1 Description GOVERNMENT RIGHTS 5 [0001] This invention was made with government support under grant number 4R44AG032784 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention. FIELD OF THE TECHNOLOGY 10 [0002] The invention generally relates to medicinal chemistry, veterinary medicine and cell biology. In alternative embodiments the description provides compositions and methods for ameliorating diseases and conditions having a beta-amyloid component, including Alzheimer’s disease (AD), Vascular Dementia (VD), dementia, pre-dementia, Cog- nitive Dysfunction Syndrome (CDS) and loss of cognition, in humans and in non-human animals. In alternative embod- iments the description provides analogs of AB-007 (E64d, or loxistatin) and its acid form E64c (loxistatin acid), their 15 preparation, and pharmaceutical compositions thereof and methods of making and using same. In alternative embodi- ments compositions of the description are deuterated analogs of AB-007 (or E64d or loxistatin) and E64c (or loxistatin acid). In alternative embodiments compositions of the description are metabolically blocked forms as compared to AB- 007 and loxistatin. In alternative embodiments compositions of the description are used to ameliorate (including treat, slow, reverse or prevent) a disease or condition which can be ameliorated by partial or complete inhibition of a cysteine 20 protease, e.g., Alzheimer’s disease (AD), Vascular Dementia (VD), dementia, pre-dementia, Cognitive Dysfunction Syndrome (CDS) and loss of cognition in humans and in non-human animal. The description also provides alternative dosage forms and formulations for AB-007 (E64d, loxistatin) and loxistatin acid (E64c), and for compounds of the description. 25 BACKGROUND [0003] AB-007 (also called loxistatin, E64d, EST or ((2S,3S)-trans-epoxysuccinyl-L-leucyl-amido-3-methylbutane ethyl ester) is an ethyl ester prodrug, 342.4 mol wt (MW), which is completely convertedin vivo to its acid form E64c (also called loxistatin acid or Ep 475, 314.4 mol wt, which irreversibly inhibits proteases belonging to the cysteine protease 30 class by covalently binding to sulfhydryl groups in the proteases’ active sites. 35 40 45 [0004] Two hydroxylated metabolites of loxistatin (or E64d) have been observed: 50 55 2 EP 2 921 486 B1 5 10 15 20 Reference: Fukushima, K. et al. "Metabolic fate of loxistatin in rat", Xenobiotica, 1990, 20, 1043-1051 [0005] This metabolism, or in vivo hydroxylation, can result in lowering the effective concentration of the drug and 25 shortens its half life in vivo. [0006] Cathepsin B is co-localized with beta amyloid (A) in plaques of AD brains and is elevated in cerebrospinal fluid (CSF) of Alzheimer Disease (AD) patients. Also, age-related changes in cathepsin B expression are consistent with the late age of onset of Alzheimer’s. These findings, among others, indicate a role for cathepsin B in AD. [0007] Yamamoto et al., 1989 Chemical and Pharmaceutical Bulletin, Vol. 37, no. 10 pages 2577-2581 discloses the 30 crystal structure and molecular conformation of E-64, a cysteine protease inhibitor. [0008] WO2004/084830 discloses methods for treatment and prevention of dementia and, more specifically, to novel strategies for treatment and prevention of Alzheimer’s disease. [0009] Hook et al., 2014 Journal of Neurotrauma, vol 31, Issue 5, pages 515-529 discloses the cysteine protease cathepsin B is a key drug target and cysteine protease inhibitors are potential therapeutics for traumatic brain injury. 35 SUMMARY [0010] In alternative embodiments the description provides compositions and methods for treating, preventing, revers- ing, slowing the progression of and/or ameliorating diseases and conditions having a beta-amyloid (β-amyloid, or Aβ) 40 component, including Alzheimer’s disease (AD), Vascular Dementia (VD), dementia, pre-dementia, Cognitive Dysfunc- tion Syndrome (CDS) and loss of cognition. [0011] In alternative embodiments, the invention provides a therapeutic formulation or combination for use in prevent- ing, slowing the progression of, treating or ameliorating a traumatic brain injury, a posttraumatic stress disorder, a traumatic war neurosis, or a post-traumatic stress syndrome (PTSS), wherein the therapeutic formulation or combination 45 comprises: (a) a compound of Formula I: 50 55 3 EP 2 921 486 B1 5 10 15 wherein R is -H or alkyl, and R 1, R2, R3 is D; each of R4, R5, R6, R7, R8, R9, and R10 is independently selected from the group consisting of -H,and -D; 20 (b) a carboxylic acid hydrolysis product of (a); or (c) a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate of (a) or (b). [0012] In alternative embodiments, the compounds have the stereochemistry of Formula I’: 25 30 35 40 [0013] In alternative embodiments, each of R4, R5, R6, R7, R8, R9, and R10 is independently selected from the group 45 consisting of -H and -D. In alternative embodiments, each of R4, and R5, is -H and each of R6, R7, R8, R9, and R10 is independently selected from the group consisting of -H and -D. In alternative embodiments, each of R 4, R5, and R10 is -H and each of R6, R7, R8, and R9 is independently selected from the group consisting of -H and -D. In alternative embodiments, the invention provides a compound selected from the group consisting of: 50 55 4 EP 2 921 486 B1 5 10 15 20 25 30 35 40 45 50 55 5 EP 2 921 486 B1 5 10 and or a pharmaceutically acceptable salts, hydrates, stereoisomers or solvates thereof. [0014] In alternative embodiments, the description provides pharmaceutical compositions, dosage form or formulation 15 comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, stereoisomer or solvate thereof, with a pharmaceutically acceptable carrier or excipient, and optionally the pharmaceutical composition, dosage form or formulation further comprises at least one other phar- maceutical composition, dosage form or formulation used to treat or ameliorate, or treat the symptoms of, or be palliative for, a cognitive dysfunction or a loss of cognition, a dementia or a pre-dementia, Alzheimer’s disease (AD), Vascular 20 Dementia (VD), and/or a Cognitive Dysfunction Syndrome (CDS) in humans or in a non-human animal, wherein optionally the at least one other pharmaceutical composition, dosage form or formulation comprises a selegiline (e.g., selegiline hydrochloride) or deprenyl, or ANIPRYL™; a donepezil (ARICEPT™); a carbamate; edrophonium or comparable re- versible acetylcholinesterase inhibitor (e.g., TENSILON™,
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