(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 WO 2012/069150 A2 31 May 20 12 (31.05.2012) W P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/575 (2006.01) A61P 19/08 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/663 (2006.01) A61P 19/10 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 45/06 (2006.01) A61K 31/495 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (21) International Application Number: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, PCT/EP20 11/005721 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 14 November 201 1 (14.1 1.201 1) OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (25) Filing Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 10014829.5 22 November 2010 (22. 11.2010) EP GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 11004058. 1 17 May 201 1 (17.05.201 1) EP UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant (for all designated States except US): POWER- DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, PORE GMBH; Nordliche Munchner Strasse 33, 8203 1 LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Griinwald (DE). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventor; and (75) Inventor/Applicant (for US only): HUTZEN, Dominic Declarations under Rule 4.17 : [DE/DE]; Delle 25-27, 45468 Muhlheim an der Ruhr (DE). — as to the identity of the inventor (Rule 4.1 7(Ϊ)) (74) Agent: KOMPTER, Michael; Law Offices Heumann, — as to applicant's entitlement to applyfor and be granted a Benz, Spessartring 63, 64287 Darmstadt (DE). patent (Rule 4.1 7(H)) [Continued on nextpage] (54) Title: CYTOPROTECTANT AGENTS FOR THE PREVENTION OF DRUG-ASSOCIATED SIDE-EFFECTS (57) Abstract: The invention relates to cytopro- Scratch assay in hOB tectant agents as medicaments for the prevention of drug-associated osteonecrosis of the jaw and/or 10 the femur, to pharmaceutical compositions com T J prising a cytoprotectant agent and a bisphosphon- ate or denosumab, and to a method for the treat 80 ment or prevention of osteoporosis by the concur rent or subsequent adminstration of a cytoprotect o to ant agent and a bisphosphonate or denosumab. 0 CD c 4( c Φ Q_ 0 time course (days) w o 2012/069150 A2 1inn iiiiiii 1mil i mil il i 1 ill i i mil il i imill mi i i as to the applicant's entitlement to claim the priority of Published. the earlier application (Rule 4.1 7(Hi)) — without international search report and to be republished of inventorship (Rule 4.1 7(iv)) uPo n °f that r ePort (Rule 4 8 CYTOPROTECTANT AGENTS FOR THE PREVENTION OF DRUG-ASSOCIATED SIDE-EFFECTS BACKGROUND OF THE INVENTION 1. TECHNICAL FIELD The invention relates to cytoprotectant agents as medicaments for the prevention or reduction of drug-associated side effects, in particular bisphosphonate-associated side effects such as osteonecrosis of the jaw and/or thefemur, to pharmaceutical compositions comprising a cytoprotectant agent and a bisphosphonate and to a method for the treatment or prevention of cancer or osteoporosis, or osteodystrophia deformans (Morbus Paget) or of tumor-associated hypercalcemia by the concurrent or subsequent adminstration of a cytoprotectant agent and a bisphosphonate. 2. PRIOR ART Over 190 million oral bisphosphonate prescriptions have been dispensed worldwide and intravenous application is also significant in numbers [1-3]. Bisphosphonates are synthetic analogs of pyrophosphonate that bind to the hydoxyapathite in bone. They act as specific inhibitors of osteoclast-mediated bone resorption and are an important class of drugs in oncology and osteoporosis. They inhibit the growth of bone tumors and bone loss by limiting bone remodelling and degradation [1, 3]. Approximately 70% of lung, breast and prostate cancer patients develop bone metastases during the course of the disease [1, 4]. 350.000 patients die from bone metastases annually in the USA alone. Multiple myeloma is a hematological indication for bisphosphonate therapy with an incidence rate around 4/100.000 [4-6]. Osteoporosis is the bisphosphonate indication with the highest incidences around 700/100.000 [7-1 1]. The bisphosphonate drugs are accumulated in the bone matrix [2, 3]. While this is the basis of the effective working mechanism, it also resulted in the main side effect of the therapy known as bisphosphonate-related osteonecrosis of the jaw (BRONJ, also called BONJ) [12, 13]. The problem is described for all indication fields. BRONJ results in significant clinical problems and sickness of the patient. This condition mostly occurs after teeth extraction in bisphosphonate-treated patients, mostly with nitrogene-containing bisphosphonates (nBPs) CONFIRMATION COPY and is associated with exposed jaw bone, limited healing of the mucosa, and osteomyelitis. A drug holiday with stop of bisphonate application can be beneficial for the prevention of BRONJ [14, 15]. There is no specific therapy for the prevention of the problem yet this issue is a field of ongoing research [16]. Furthermore, a similar incidence of osteonectrosis of the jaw has been observed upon subcutaneous administration of denosumab [27]. Certain cholesterol eco-norcholstan derivatives are known as cytoprotectant agents for example from the US patent applications US 2006/0217358 Al, US 2008/0275130 Al, US 2009/0186863 Al, US 2009/0203662 A1,US 2009/0203747 Al, US 2009/0312434 Al and US 2010/0099652 Al. Olesoxime (TRO 19622) is a mitochondrial pore modulator in development phase III for the indicationsamyotrophic lateral sclerosis, multiple sclerosis and spinal muscular atrophy. Another group of cytoprotectant agents are selected from the group consisting of bisdioxopiperazines, quinolines, aclarubicin and acridines. SHORT SUMMARY OF THE INVENTION The problem underlying the present invention was to provide a medicament which alleviates or prevents drug-associated osteonecrosis of the jaws and / or thefemur, in particular the severe side-effects associated with the administration of bisphosphonates in the treatment or prevention of cancer or osteoporosis, in particular BONJ. Surprisingly, it has been shown in in-vitro assays that a concurrent or subsequent administration of cytoprotectant agent with bisphosphonates or denosumab will prevent or at least drastically reduce the severe side-effects associated with the bisphosphonates without influencing its beneficial efficacy against cancer or osteoporosis. Accordingly the invention relates to a cytoprotectant agent as medicament for the prevention or reduction of drug-associated osteonecrosis of the jaws and / or thefemur, preferably the bisphosphonate -associated side-effects, in particular osteonecrosis of the jaw (BONJ) and / orfemur. Furthermore, the invention relates to a pharmaceutical composition or a kits of parts comprising (a) one or more cytoprotectant agent or a pharmaceutically acceptable salt thereof; (b) one or more bisphosphonate or a pharmaceutically acceptable salt thereof. In addition, the invention relates to a pharmaceutical composition or a kits of parts comprising (a) one or more cytoprotectant agent or a pharmaceutically acceptable salt thereof; (b) denosumab. Moreover, the invention relates to a method for the treatment or prevention of cancer, osteoporosis, osteodystrophia deformans or of tumor-associated hypercalcemia in a patient and to a method of inhibiting post-menopausal bone loss in a post-menopausal woman in the treatment or prevention of post-menopausal osteoporosis, which methods comprise concurrently or subsequently administering an effective amount of at least one cytoprotectant agent and an effective amount of (i) at least one one bisphosphonate or a pharmaceutically acceptable salt thereof or (ii) denosumab to said patient or post-menopausal woman suffering from osteoporosis, osteodystrophia deformans or of tumor-associated hypercalcemia. Furthermore, the invention relates to a method SHORT DESCRIPTION OF THE DRAWINGS Fig. 1 shows the results of a scratch assay in human osteoblasts (example 1). Fig. 2 shows the results of an MTT assay in human osteoblasts (example 2). DETAILED DESCRIPTION OF THE INVENTION Preferred embodiments of the invention are: (A) A cytoprotectant agent, which is capable of reducing anthracycline-induced cardiotoxicity. (B) A cytoprotectant agent, which is bisdioxopiperazine, preferably a bis(3,5- dioxopiperazine-l-yl)alkane of formula 2 1 wherein R and R are each independently hydrogen or C \ alkyl, preferably R being methyl and R2 being hydrogen, most preferably selected from the group consisting of dexrazoxane, razoxane and probimane or a pharmaceutically acceptable salt thereof. (C) A cytoprotectant agent, which is a cholesterol or seco-norcholestan derivative or a pharmaceutically acceptable salt thereof, in particular cholesterol or olesoxime (TRO 19622) of formula or a pharmaceutically acceptable salt thereof. (D) A pharmaceutical composition, wherein the bisphosphonate is a compound of formula 2 1 2 R R C(P0 3H2)2 2 wherein R1 represent hydrogen, chloro or hydroxy, R2 represents chloro, a Ci - C alkyl group, which is optionally substituted by one or more substituents selected from the group consisting of amino, C - C alkylamino, di-(C! - C6 alkyl)-amino, carboxyl, pyridinyl, imidazolyl and imidazopyridinyl, a thiophenyl group, which is optionally substituted by one or more halogen atoms, or a C3 - C cycloalkylamino group, or a pharmceutically acceptable salt thereof.