Pacritinib

Pacritinib

A Jak2 inhibitor potentially for the treatment of acute myeloid Leukemia and myelofibrosis.

ONX-0803; SB-1518
CAS No. 937272-79-2

472.57868 g/mol, C28H32N4O3

S*Bio Pte Ltd. and concert innovator

11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene

(16E)-11-[2-(1-Pyrrolidinyl)ethoxy]-14,19-Dioxa-5,7,27-triazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6(27),8,10,12(26),16,21,23-decaene

11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene

SB-1518|||(16E)-11-[2-(1-Pyrrolidinyl)ethoxy]-14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6(27),8,10,12(26),16,21,23-decaene

Pacritinib (SB1518) is a potent and selective inhibitor of Janus Kinase 2 (JAK2) and Fms-Like Tyrosine Kinase-3 (FLT3) with IC50s of 23 and 22 nM, respectively.

Pacritinib (INN[1]) is a macrocyclic Janus kinase inhibitor that is being developed for the treatment of myelofibrosis. It mainly inhibits Janus kinase 2(JAK2). The drug is in Phase III clinical trials as of 2013.[2] The drug was discovered in Singapore at the labs of S*BIO Pte Ltd. It is a potent JAK2 inhibitor with activity of IC50 = 23 nM for the JAK2WT variant and 19 nM for JAK2V617F with very good selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively).[3][4] The drug is acquired by Cell Therapeutics, Inc. (CTI) and Baxter international and could effectively address an unmet medical need for patients living with myelofibrosis who face treatment-emergent thrombocytopenia on marketed JAK inhibitors.[5]

Pacritinib is an orally bioavailable inhibitor of Janus kinase 2 (JAK2) and the JAK2 mutant JAK2V617F with potential antineoplastic activity. Oral JAK2 inhibitor SB1518 competes with JAK2 for ATP binding, which may result in inhibition of JAK2 activation, inhibition of the JAK-STAT signaling pathway, and so caspase-dependent apoptosis. JAK2 is the most common mutated gene in bcr-abl-negative myeloproliferative disorders; the JAK2V617F gain-of-function mutation involves a valine-to-phenylalanine modification at position 617. The JAK-STAT signaling pathway is a major mediator of cytokine activity.

Pacritinib is an orally bioavailable inhibitor of Janus kinase 2 (JAK2) and the JAK2 mutant JAK2V617F with potential antineoplastic activity. Oral JAK2 inhibitor SB1518 competes with JAK2 for ATP binding, which may result in inhibition of JAK2 activation, inhibition of the JAK-STAT signaling pathway, and so caspase-dependent apoptosis. JAK2 is the most common mutated gene in bcr-abl-negative myeloproliferative disorders; the JAK2V617F gain-of-function mutation involves a valine-to-phenylalanine modification at position 617. The JAK-STAT signaling pathway is a major mediator of cytokine activity.

The compound 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (Compound I) was first described in PCT/SG2006/000352 and shows significant promise as a pharmaceutically active agent for the treatment of a number of medical conditions and clinical development of this compound is underway based on the activity profiles demonstrated by the compound.

• In the development of a drug suitable for mass production and ultimately commercial use acceptable levels of drug activity against the target of interest is only one of the important variables that must be considered. For example, in the formulation of pharmaceutical compositions it is imperative that the pharmaceutically active substance be in a form that can be reliably reproduced in a commercial manufacturing process and which is robust enough to withstand the conditions to which the pharmaceutically active substance is exposed.
• In a manufacturing sense it is important that during commercial manufacture the manufacturing process of the pharmaceutically active substance be such that the same material is reproduced when the same manufacturing conditions are used. In addition it is desirable that the pharmaceutically active substance exists in a solid form where minor changes to the manufacturing conditions do not lead to major changes in the solid form of the pharmaceutically active substance produced. For example it is important that the manufacturing process produce material having the same crystalline properties on a reliable basis and also produce material having the same level of hydration.
• In addition it is important that the pharmaceutically active substance be stable both to degradation, hygroscopicity and subsequent changes to its solid form. This is important to facilitate the incorporation of the pharmaceutically active substance into pharmaceutical formulations. If the pharmaceutically active substance is hygroscopic (“sticky”) in the sense that it absorbs water (either slowly or over time) it is almost impossible to reliably formulate the pharmaceutically active substance into a drug as the amount of substance to be added to provide the same dosage will vary greatly depending upon the degree of hydration. Furthermore variations in hydration or solid form (“polymorphism”) can lead to changes in physico-chemical properties, such as solubility or dissolution rate, which can in turn lead to inconsistent oral absorption in a patient.
• Accordingly, chemical stability, solid state stability, and “shelf life” of the pharmaceutically active substance are very important factors. In an ideal situation the pharmaceutically active substance and any compositions containing it, should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the physico-chemical characteristics of the active substance such as its activity, moisture content, solubility characteristics, solid form and the like.
• In relation to 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene initial studies were carried out on the hydrochloride salt and indicated that polymorphism was prevalent with the compound being found to adopt more than one crystalline form depending upon the manufacturing conditions. In addition it was observed that the moisture content and ratio of the polymorphs varied from batch to batch even when the manufacturing conditions remained constant. These batch-to-batch inconsistencies and the exhibited hygroscopicity made the hydrochloride salt less desirable from a commercial viewpoint.
• Accordingly it would be desirable to develop one or more salts of 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene which overcome or ameliorate one or more of the above identified problems.

PATENT

US 2011263616

http://www.google.com/patents/US20110263616

11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26triaza-tetra-cyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (Compound I) which have been found to have improved properties. In particular the present invention relates to the maleate salt of this compound. The invention also relates to pharmaceutical compositions containing this salt and methods of use of the salt in the treatment of certain medical conditions.

PATENT

http://www.google.com/patents/US8415338

Representative Procedure for the Synthesis of Compounds Type (XVIIId) [3-(2-Chloro-pyrimidin-4-yl)-phenyl]-methanol (XIIIa2)

Compound (XIIIa2) was obtained using the same procedure described for compound (XIIIa1); LC-MS (ESI positive mode) m/z 221 ([M+H]+).

4-(3-Allyloxymethyl-phenyl)-2-chloro-pyrimidine (XVa2)

Compound (XVa2) was obtained using the same procedure described for compound (XVa1); LC-MS (ESI positive mode) m/z 271 ([M+H]+).

[4-(3-Allyloxymethyl-phenyl)-pyrimidin-2-yl]-[3-allyloxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (XVIId1)

Compound (XVIId1) was obtained using the same procedure described for compound (XVIIb1); LC-MS (ESI positive mode) m/z 501.

Macrocycle Example 3 Compound 13

Compound (13) was obtained using the same procedure described for compound (1) HPLC purity at 254 nm: 99%; LC-MS (ESI positive mode) m/z 473 ([M+H]+); 1H NMR (MeOD-d4) δ 8.79 (d, 1H), 8.46 (d, 1H), 8.34-8.31 (m, 1H), 7.98-7.96 (m, 1H), 7.62-7.49 (m, 2H), 7.35 (d, 1H), 7.15-7.10 (m, 1H), 7.07-7.02 (m, 1H), 5.98-5.75 (m, 2H, 2×=CH), 4.67 (s, 2H), 4.67 (s, 2H), 4.39-4.36 (m, 2H), 4.17 (d, 2H), 4.08 (d, 2H), 3.88-3.82 (m, 2H), 3.70 (t, 2H), 2.23-2.21 (m, 2H), 2.10-2.07 (m, 2H).

PAPER

J MC 2011, 54 4638

http://pubs.acs.org/doi/abs/10.1021/jm200326p

Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2V617F), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC50 = 23 and 19 nM for JAK2WT and JAK2V617F, respectively) and FLT3 (IC50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c(SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.

Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma

Anthony D. William*, Angeline C.-H. Lee, Stéphanie Blanchard, Anders Poulsen,Ee Ling Teo, Harish Nagaraj,Evelyn Tan, Dizhong Chen, Meredith Williams, Eric T. Sun, Kee Chuan Goh, Wai Chung Ong, Siok Kun Goh,Stefan Hart, Ramesh Jayaraman, Mohammed Khalid Pasha, Kantharaj Ethirajulu, Jeanette M. Wood, and Brian W. Dymock

S*BIO Pte. Ltd., 1 Science Park Road, #05-09, The Capricorn, Singapore Science Park II, Singapore 117528

J. Med. Chem., 2011, 54 (13), pp 4638–4658

DOI: 10.1021/jm200326p

Publication Date (Web): May 23, 2011

Copyright © 2011 American Chemical Society

Tel: (0065) 6827-5021. Fax: (0065) 6827-5005. E-mail:anthony_william@sbio.com.

(21c)

The title compound was synthesized from 21a and pyrrolidine (yield, 83%; mixture of trans/cis85:15 by NMR). LC-MS (ESI positive mode) m/z 473 ([M + H]+). HRMS: theoretical C28H32N4O3MW, 472.2474; found, 473.2547. 1H NMR (MeOD-d4): δ 8.79 (d, 1H), 8.46 (d, 1H), 8.34–8.31 (m, 1H, CH), 7.98–7.96 (m, 1H), 7.62–7.49 (m, 2H), 7.35 (d, 1H), 7.15–7.10 (m, 1H), 7.07–7.02 (m, 1H), 5.98–5.75 (m, 2H), 4.67 (s, 2H), 4.67 (s, 2H), 4.39–4.36 (m, 2H), 4.17 (d, 2H), 4.08 (d, 2H), 3.88–3.82 (m, 2H), 3.70 (t, 2H), 2.23–2.21 (m, 2H), 2.10–2.07 (m, 2H); chloride content (titration) 7.7% (1.18 equivs); water content (Karl Fischer) 6.1% (1.85 equivs); Anal. Calcd. for C28H32N4O3·1.18HCl·1.85H2O: C, 61.46; H, 6.46; N, 10.24; Cl, 7.65. Found: C, 61.99; H, 6.91; N, 10.25; Cl, 7.45.

References

 1 “International Nonproprietary Names for Pharmaceutical Substances (INN) List 104” (PDF). WHO Drug Information 24 (4): 386. 2010.

2“JAK-Inhibitoren: Neue Wirkstoffe für viele Indikationen”. Pharmazeutische Zeitung (in German) (21). 2013.

3William, A. D.; Lee, A. C. -H.; Blanchard, S. P.; Poulsen, A.; Teo, E. L.; Nagaraj, H.; Tan, E.; Chen, D.; Williams, M.; Sun, E. T.; Goh, K. C.; Ong, W. C.; Goh, S. K.; Hart, S.; Jayaraman, R.; Pasha, M. K.; Ethirajulu, K.; Wood, J. M.; Dymock, B. W. (2011). “Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma”. Journal of Medicinal Chemistry 54 (13): 4638–58. doi:10.1021/jm200326p. PMID 21604762.

4Poulsen, A.; William, A.; Blanchard, S. P.; Lee, A.; Nagaraj, H.; Wang, H.; Teo, E.; Tan, E.; Goh, K. C.; Dymock, B. (2012). “Structure-based design of oxygen-linked macrocyclic kinase inhibitors: Discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3)”.Journal of Computer-Aided Molecular Design 26 (4): 437–50.doi:10.1007/s10822-012-9572-z. PMID 22527961.

5http://www.pmlive.com/pharma_news/baxter_licenses_cancer_drug_from_cti_in_$172m_deal_519143

US8153632 *	Nov 15, 2006	Apr 10, 2012	S*Bio Pte Ltd.	Oxygen linked pyrimidine derivatives
US8415338 *	Apr 4, 2012	Apr 9, 2013	Cell Therapeutics, Inc.	Oxygen linked pyrimidine derivatives
US20110294831*	Dec 9, 2009	Dec 1, 2011	S*Bio Pte Ltd.	11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene citrate salt

PATENT	SUBMITTED	GRANTED
OXYGEN LINKED PYRIMIDINE DERIVATIVES [US8153632]	2009-03-19	2012-04-10
ANTIVIRAL JAK INHIBITORS USEFUL IN TREATING OR PREVENTING RETROVIRAL AND OTHER VIRAL INFECTIONS [US2014328793]	2012-11-30	2014-11-06
OXYGEN LINKED PYRIMIDINE DERIVATIVES [US2013172338]	2013-02-20	2013-07-04
METHOD OF SELECTING THERAPEUTIC INDICATIONS [US2014170157]	2012-06-15	2014-06-19
CYCLODEXTRIN-BASED POLYMERS FOR THERAPEUTIC DELIVERY [US2014357557]	2014-05-30	2014-12-04
11-(2-PYRROLIDIN-1-YL-ETHOXY)-14,19-DIOXA-5,7,26-TRIAZA-TETRACYCLO[19.3.1.1(2,6).1(8,12)]HEPTACOSA-1(25),2(26),3,5,8,10,12(27),16,21,23-DECAENE MALEATE SALT [US2011263616]	2011-10-27
11-(2-PYRROLIDIN-1-YL-ETHOXY)-14,19-DIOXA-5,7,26-TRIAZA-TETRACYCLO[19.3.1.1(2,6).1(8,12)]HEPTACOSA-1(25),2(26),3,5,8,10,12(27),16,21,23-DECAENE CITRATE SALT [US2011294831]	2011-12-01
BIOMARKERS AND COMBINATION THERAPIES USING ONCOLYTIC VIRUS AND IMMUNOMODULATION [US2014377221]	2013-01-25	2014-12-25
Oxygen linked pyrimidine derivatives [US8415338]	2012-04-04	2013-04-09

PACRITINIB

SYSTEMATIC (IUPAC) NAME
(16E)-11-[2-(1-Pyrrolidinyl)ethoxy]-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
CLINICAL DATA
LEGAL STATUS	Investigational
ROUTES OF ADMINISTRATION	Oral
IDENTIFIERS
ATC CODE	None
PUBCHEM	CID: 46216796
CHEMSPIDER	28518965
CHEMBL	CHEMBL2035187
SYNONYMS	SB1518
CHEMICAL DATA
FORMULA	C28H32N4O3
MOLECULAR MASS	472.58 g/mol

S*Bio Pte Ltd  

Address: 1 Science Park Rd, Singapore 117528

Phone:+65 6827 5000

S*BIO Pte Ltd. provides research and clinical development services for small molecule drugs for the treatment of cancer in Singapore. The company’s products include JAK2 inhibitors, such as SB1518 for leukemia/myelofibrosis, lymphoma, and polycythemia; and SB1578 for RA/psoriasis. The company also offers SB939, a histone deacetylases for MDS/AML+combo, prostate cancer, sarcoma, pediatric tumor, and myelofibrosis; SB2602, a mTOR inhibitor; SB2343, a mTOR/PI3K inhibitor; and SB1317, a CDK/Flt3 inhibitor. The company was founded in 2000 and is based in Singapore. S*BIO Pte Ltd. operates as a subsidiary of Chiron Corporation Limited.

SEE..........http://newdrugapprovals.org/2016/01/17/pacritinib/
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c1cc2cc(c1)-c3ccnc(n3)Nc4ccc(c(c4)COC/C=C/COC2)OCCN5CCCC5

C1CCN(C1)CCOC2=C3COCC=CCOCC4=CC=CC(=C4)C5=NC(=NC=C5)NC(=C3)C=C2