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Wo 2015/068142 A2 (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 W O 2015/068142 A2 14 May 2015 (14.05.2015) P O P C T (51) International Patent Classification: (74) Agents: THACKER, Ankita et al; K&S Partners | Intel A61K 31/00 (2006.01) lectual Property Attorneys, 4121/B, 6th Cross, 19A Main, HAL II Stage (Extension), Bangalore 560038 (IN). (21) International Application Number: PCT/IB2014/065924 (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, BN, BR, BW, BY, 10 November 2014 (10.1 1.2014) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (25) Filing Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, EST, IR, IS, JP, KE, KG, KN, KP, KR, (26) Publication Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (30) Priority Data: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 5103/CHE/2013 11 November 2013 ( 11. 1 1.2013) IN PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 4949/CHE/2014 1 October 2014 (01. 10.2014) IN SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: CELLWORKS GROUP, INC. [US/US]; 2025 Gateway Place Suite 265, San Jose, CA 95 110 (US). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors: KUMAR, Ansu; C/o Cellworks Research India GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Private Limited, 3rd floor, West Wing, Neil - Rao Tower, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 118, Road # 3, EPIP, Whitefield, Karnataka, Bangalore TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 560066 (IN). SINGH, Neeraj Kumar; C/o Cellworks Re DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, search India Private Limited, 3rd floor, West Wing, Neil - LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Rao Tower, 118, Road # 3, EPIP, Whitefield, Karnataka, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Bangalore 560066 (IN). TYAGI, Anuj; C/o Cellworks Re GW, KM, ML, MR, NE, SN, TD, TG). search India Private Limited, 3rd floor, West Wing, Neil - Rao Tower, 118, Road # 3, EPIP, Whitefield, Karnataka, Declarations under Rule 4.17 : Bangalore 560066 (IN). VALI, Shireen; C/o Cellworks — of inventorship (Rule 4.17(iv)) Research India Private Limited, 3rd floor, West Wing, Neil - Rao Tower, 118, Road # 3, EPIP, Whitefield, Karnataka, Published: Bangalore 560066 (IN). ABBASI, Taher; C/o Cellworks — without international search report and to be republished Research India Private Limited, 3rd floor, West Wing, Neil upon receipt of that report (Rule 48.2(g)) - Rao Tower, 118, Road # 3, EPIP, Whitefield, Karnataka, Bangalore 560066 (IN). < 00 (54) Title: COMPOSITIONS, PROCESS OF PREPARATION OF SAID COMPOSITIONS, USES AND METHOD OF MAN © AGEMENT OF MYELOPROLIFERATIVE DISORDER (57) Abstract: The present disclosure relates to a pharmaceutical composition and a method to manage Myeloproliferative disorder o or any associated condition, particularly, JAK2 (Janus Kinase 2) dominant (including JAK2V61 7F mutant) Myeloproliferative Dis order (MPD) and associated conditions. The disclosure provides composition comprising at least two components selected from a group comprising Phosphodiesterase Type 4 (PDE4) inhibitor, Autophagy inhibitor and AMPK agonist. The disclosure further relates to a process of preparing the said composition and a method of managing JAK2 dominant (including JAK2 V617F mutant) Myeloproliferative Disorder; existing alone or along with any other mutation. "COMPOSITIONS, PROCESS OF PREPARATION OF SAID COMPOSITIONS, USES AND METHOD OF MANAGEMENT OF MYELOPROLIFERATIVE DISORDER" TECHNICAL FIELD The present disclosure relates to composition and method for management of Myeloproliferative disorders (MPD) or any associated condition. Specifically, it relates to management of JAK2 (Janus Kinase 2) dominant (including JAK2V617F mutant) Myeloproliferative Disorders (MPD) The disclosure provides individual compounds and combination of compounds for use in preparation of medicament for management of MPD or any associated condition. More particularly, the present disclosure employs Phosphodiesterase Type 4 inhibitor, Autophagy inhibitor and AMPK Agonist, individually and in combinations for managing said MPD or any associated condition. BACKGROUND OF THE DISCLOSURE Myeloproliferative disorders (MPDs) are clonal hematopoietic diseases characterized by the excess production of 1 or more lineages of mature blood cells. The human myeloproliferative disorders consist of three main classes of disorders, which are Essential Thrombocythemia (ET), PolycythemiaVera (PV), and Myelofibrosis (MF). A valine to phenylalanine substitution at position 6 7 (V617F) of JAK2 in the pseudokinase domain is the most common mutation across all three classes of this disorder. JAK2V617F mutation is a subset of JA K2 dominance. Occurrence of JAK2V617F mutation isobserved in more than 95% of Polycythemia Vera cases and in approximately 50% of patients with Thrombocythemia and Myelofibrosis. Other mutations, such as K539L and T875N of JAK2 have also been identified, but in a very small subset of PolycythemiaVera patients. Polycythemia Vera is the most common of the chronic myeloproliferative disorders. JAK2 Mutation- positive patients have multiple features resembling Polycythemia Vera, with significantly increased haemoglobin, increased neutrophil counts, increased bone marrow erythropoiesis and increased granulopoiesis. Also, more venous thrombosis, and higher rate of polycythemic transfonnation than in those without the mutation has been detected. Mutation-positive patients have lower serum erythropoietin and comparatively lower ferritin than those of mutation-negative patients. This disorder predisposes patients to vascular diseases such as thrombosis, atherosclerosis, coronary heart disease, and cerebral ischemia. In addition, patients with MPD often have high levels of i circulating inflammatory cytokines in their microenvironment, such as interleukin 6 (IL-6), which has been associated with symptoms such as cachexia and listlessness. MPD can also progress into Acute Myeloid Leukemia. MPD is associated with a chronic inflammatory state due to the continuous release of inflammatory mediators in the microenvironment by other stromal cells. Chronic inflammation is characterized by persistently activated immune and stromal cells in the bone marrow microenvironment called 'inflamed bone marrow'. Chronic inflammation in the bone marrow is likely associated with increased N -kappa- beta (NF B) activity in hematopoietic and stromal cells. Furthermore, increased NFKB activity causes increased production of TNF-alpha, IL-6, IFNG and other cytokines, which in turn further increase NFKB and STAT3 and this positive feedback further worsens the myeloproliferation. Existing standard of care for Essential Thrombocvthemia, PolycvthemiaVera. and Myelofibrosis (MPD) Conventionally, treatment of MPD disorder involves reducing the thickness of the blood and preventing bleeding and clotting. Phlebotomy is used to decrease blood thickness, wherein, one unit of blood (about 1 pint) is removed weekly until the hematocrit level is less than 45 (for males) or 42 (for females). Then therapy is continued as needed. Chemotherapy (specifically Hydroxyurea) is also given to reduce the number of red blood cells made by the bone marrow. However, chemotherapy or phlebotomy is not curative in MPD and does not reduce the risk of clonal evolution into Myelodysplastic syndrome and Acute Leukemia. Besides the conventional approach, targeted approach for treatment of MPD is being developed. Inhibition of mutant JAK2 is considered as one of the approaches in the treatment of MPDs harboring JAK2 mutations. Various JAK2 inhibitors are currently under development and/or investigation in phase i and 2 clinical trials. Although preliminary results show measurable clinical benefits of the targeted approach, but over time these agents become resistant. Protective microenvironment of the stromal bone marrow niche against JAK2 inhibitor therapy via stromal cell secreted humoral factors is considered to be the major cause of resistance mechanism for JAK2 inhibitors over the MPD conditions. In summary, the existing conventional treatment of phlebotomy and chemotherapy or targeted treatment with JAK2 inhibitors, although provides measurable symptomatic relief for a subject with MPD or associated condition, but it is not able to stop disease progression. Further, the success achieved with attempted doses of single agents in the targeted approach is limited, and the obstacles to increasing the doses of the single agents include legitimate concerns about exceeding the therapeutic windows and/or concerns about the manifestation of undesirable side effects at higher doses like fluid retention, heart and blood pressure problem.In some cases, instance of drug overdose is associated with increased risk of developing Acute Leukemia. In vie of the above mentioned limitations observed towards the treatment of MPD or its associated condition, improved or technically advanced treatment protocols for this complex disorder is needed. A safe and effective treatment and protocol that could alleviate suffering and improve outcomes
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