Methods and Compositions for Treating Nephrogenic

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Methods and Compositions for Treating Nephrogenic (19) TZZ Z_T (11) EP 2 750 676 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/7076 (2006.01) A61K 31/64 (2006.01) 10.01.2018 Bulletin 2018/02 A61K 31/519 (2006.01) A61K 31/517 (2006.01) A61K 31/4365 (2006.01) A61K 33/00 (2006.01) (2006.01) (2006.01) (21) Application number: 12828322.3 A61P 13/12 A61K 45/06 (22) Date of filing: 29.08.2012 (86) International application number: PCT/US2012/052819 (87) International publication number: WO 2013/033178 (07.03.2013 Gazette 2013/10) (54) METHODS AND COMPOSITIONS FOR TREATING NEPHROGENIC DIABETES INSIPIDUS VERFAHREN UND ZUSAMMENSETZUNGEN ZUR BEHANDLUNG VON NEPHROGENEM DIABETES INSIPIDUS PROCÉDÉS ET COMPOSITIONS POUR TRAITER LE DIABÈTE INSIPIDE NÉPHROGÉNIQUE (84) Designated Contracting States: (56) References cited: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB WO-A2-2005/076007 WO-A2-2010/075861 GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO US-A1- 2009 297 497 PL PT RO RS SE SI SK SM TR • ALAN D MICHELSON: "New P2Y12 antagonists", (30) Priority: 30.08.2011 US 201161529227 P CURRENT OPINION IN HEMATOLOGY, vol. 16, no. 5, 1 September 2009 (2009-09-01), pages (43) Date of publication of application: 371-377, XP055165128, ISSN: 1065-6251, DOI: 09.07.2014 Bulletin 2014/28 10.1097/MOH.0b013e32832ea2f2 • CHOUDHURY DEVASMITA ET AL: (73) Proprietor: University of Utah Research "Drug-associated renal dysfunction and injury", Foundation NATURE CLINICAL PRACTICE NEPHROLOGY, Salt Lake City, UT 84108 (US) NATURE PUBLISHING GROUP, LONDON, GB, vol. 2, no. 2, 1 February 2006 (2006-02-01), pages (72) Inventors: 80-91, XP007907333, ISSN: 1745-8323, DOI: • KISHORE, Bellamkonda, K. 10.1038/NCPNEPH0076 Sandy, UT 84094 (US) • TIAN ET AL.: ’Downregulation of renal • CARLSON, Noel, G. vasopressin V2 receptor and aquaporin-2 Salt Lake City, UT 84124 (US) expression parallels age-associated defects in • ZHANG, Yue urine concentration.’ AM J PHYSIOL RENAL Salt Lake City, UT 84115 (US) PHYSIOL. vol. 287, 2004, pages F797 - F805, XP055144677 (74) Representative: Michalski Hüttermann & Partner Patentanwälte mbB Speditionstraße 21 40221 Düsseldorf (DE) 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 2 750 676 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 750 676 B1 Description BACKGROUND 5 [0001] Acquired nephrogenic diabetes insipidus (acquired NDI) is a common debilitating and morbid condition in the clinic due to a variety of causes. The salient feature of all forms of acquired NDI is resistance of the kidney to the action of the anti-diuretic hormone (ADH or arginine vasopressin, AVP), and so it is often associated with increased blood ADH levels. Acquired NDI is characterized by polydipsia (increased water intake), polyuria (increased urine output) and impaired concentrating ability of the kidney (decreased urine osmolality), associated with marked decrease in ADH- 10 regulated AQP2 water channel in the kidney medulla. This is due to the resistance of the kidney to the action of the anti- diuretic hormone (ADH or AVP). Vasopressin (AVP or ADH), acting through its V2 receptor in the collecting duct principal cells of the kidney, and the associated cAMP signaling pathway and aquaporin (AQP) water channels, plays a central role in water homeostasis (for reviews see Schrier, R.W. (2007) Curr Opin Investig Drugs. 8:304-11; Boone M. and Deen, P.M. (2008) Pflugers Arch. 456:1005-24). However, a variety of autocrine and paracrine agents, acting through 15 their respective membrane receptors in the collecting duct have been shown to modulate the action of AVP. [0002] Acquired NDI is a common condition in the clinic with significant degree of morbidity, or even mortality if not treated properly. Apart from social inconvenience, NDI is a debilitating condition, with an elevated risk of dehydration, hypernatremia, altered consciousness, and hemodynamic instability from hypovolemia, especially in elderly patients. The most common causes of acquired NDI are lithium-induced or hypokalemic or hypercalcemic nephropathy or post- 20 obstructive uropathy. [0003] International patent application WO 2010/075861 relates to compounds for treatment that protects the endothe- lium, prevent pathologic thrombus formation in the microcirculation and preserve platelet number and function. It discloses compounds for the treatment of or prophylaxis of organ failure due to renal diseases such as inter alia acute/chronic kidney failure or nephrogenic diabetes insipidus. Michelson, AD, Current Opinion in Hematology (2009) 16, 5, 371-377, 25 reviews the status in 2009 of clopidogrel and new P2Y12 antagonists. Choudhury, D, and Ahmed, Z, Nature Clinical Practice Nephrology, (2006) 2, 2, 80-91, review the clinical features and basic processes underlying renal injury related to the use of common drugs. [0004] Currently used therapies for acquired NDI, such as administration of cyclooxygenase (COX) inhibitors or thi- azides or amiloride, are associated with varying degrees of success as well as adverse effects, especially in critically ill 30 and elderly patients. Hence, there is a need to introduce newer therapies with fewer side effects and better tolerability in all patients. [0005] Despite advances in the treatment of renal disease and disorders, there is still a scarcity of compounds that are effective in the treatment of acquired NDI. These needs and other needs are satisfied by the present invention. 35 SUMMARY [0006] In accordance with the purpose(s) of the invention the invention, in one aspect, relates to an ADP-(P2Y 12)-like receptor modulator for use in the treatment of lithium-induced nephrogenic diabetes insipidus in a subject having a neurological disorder, comprising the step of administering to a mammal a ADP-(P2Y 12)-like receptor modulator, thereby 40 treating nephrogenic diabetes insipidus. The exogenously administered ADP-(P2Y 12)-like receptor modulator for use is a compound or agent that decreases the activity of an ADP-(P2Y12)-like receptor compared to the activity of an ADP-(P2Y12)-like receptor in the absence of the exogenously administered modulator of the ADP-(P2Y 12)-like receptor. Disclosed is also the treatment of nephrogenic diabetes insipidus (NDI).Also disclosed are methods of co-treatment of nephrogenic diabetes insipidus and a neurological or psychiatric disorder comprising the step of co-administering to the 45 mammal an effective amount of a ADP-(P2Y12)-like receptor modulator and an effective amount of a lithium salt, thereby treating, respectively, the nephrogenic diabetes insipidus and the neurological or psychiatric disorder. [0007] Also disclosed are methods of treating nephrogenic diabetes insipidus comprising the step of administering an effective amount of a ADP-(P2Y12)-like receptor modulator to a mammal that is administered a lithium salt, thereby treating the nephrogenic diabetes insipidus. 50 [0008] Also disclosed are methods for the treatment of nephrogenic diabetes insipidus in a mammal comprising the step of administering to the mammal an effective amount of a compound selected from clopidogrel, ticlopidine, prasugrel, ticagrelor, cangrelor, and elinogrel. [0009] Also disclosed are methods for co-treatment of nephrogenic diabetes insipidus and a neurological or psychiatric disorder comprising the step of co-administering to the mammal an effective amount of a lithium salt and an effective 55 amount of a compound selected from clopidogrel, ticlopidine, prasugrel, ticagrelor, cangrelor, and elinogrel, thereby treating, respectively, the neurological or psychiatric disorder and the nephrogenic diabetes insipidus. [0010] Also disclosed are methods for treating nephrogenic diabetes insipidus comprising the step of administering an effective amount of a compound selected from clopidogrel, ticlopidine, prasugrel, ticagrelor, cangrelor, and elinogrel 2 EP 2 750 676 B1 to a mammal that is administered a lithium salt, thereby treating the nephrogenic diabetes insipidus. [0011] Also disclosed are pharmaceutical compositions comprising an effective amount of a lithium salt in combination with an effective amount of a second agent that is a ADP-(P2Y12)-like receptor modulator. [0012] In a further aspect, the invention relates to a pharmaceutical composition comprising an effective amount of a 5 lithium salt in combination with an effective amount of a second agent comprising the ADP-(P2Y 12)-likereceptor modulator according to the above aspect, and a pharmaceutically acceptable carrier. [0013] Disclosed are also pharmaceutical compositions comprising an effective amount of a lithium salt in combination with an effective amount of a second agent selected from clopidogrel, ticlopidine, prasugrel, ticagrelor, cangrelor, and elinogrel. In a still further aspect, disclosed are pharmaceutical compositions comprising a therapeutically effective 10 amount of a disclosed compound and a pharmaceutically acceptable carrier, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. [0014] Also disclosed are uses of a disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. Disclosed is also a pharmaceutical compositions comprising
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