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摘要： 2012年12月14日,FDA批准ponatinib hydrochloride（商品名为Iclusig）在美国上市,该药由Ariad制药公司开发,该药为片剂,用于慢性髓细胞白血病（CML）和费城染色体阳性急性淋巴细胞白血病（Ph＋ALL）的治疗。Ponatinib hydrochloride的中文名称：3-（咪唑并[1,2-b]哒嗪-3-基乙炔基）-4-甲基-N-{4-[（4-甲基哌嗪-1-基）甲基]-
关键词: 药品 ；白血病 ；商品名 ；Iclusig
【期刊论文】 • Stirk, Alexander J. 1Holmes, Sean T. 2,3Souza, Fabio E. S. 1Hung, Ivan 3
+4位作者
• CRYSTENGCOMM 中科院3区
JCR:Q2
• Volume 26
(9)，
2024 ，pp. 1219
- 1233
摘要： This study describes the discovery of a unique ionic cocrystal of the active pharmaceutical ingredient (API) ponatinib hydrochloride (pon center dot HCl), and characterization using single-crystal X-ray diffraction (SCXRD) and solid-state NMR (SSNMR) spectroscopy. Pon center dot HCl is a multicomponent crystal that features an unusual stoichiometry, with an asymmetric unit containing both monocations and dications of the ponatinib molecule, three water molecules, and three chloride ions. Structural features include (i) a charged imidazopyridazine moiety that forms a hydrogen bond between the ponatinib monocations and dications and (ii) a chloride ion that does not feature hydrogen bonds involving any organic moiety, instead being situated in a "square" arrangement with three water molecules. Multinuclear SSNMR, featuring high and ultra-high fields up to 35.2 T, provides the groundwork for structural interpretation of complex multicomponent crystals in the absence of diffraction data. A 13C CP/MAS spectrum confirms the presence of two crystallographically distinct ponatinib molecules, whereas 1D 1H and 2D 1H-1H DQ-SQ spectra identify and assign the unusually deshielded imidazopyridazine proton. 1D 35Cl spectra obtained at multiple fields confirm the presence of three distinct chloride ions, with density functional theory calculations providing key relationships between the SSNMR spectra and HMIDLINE HORIZONTAL ELLIPSISCl- hydrogen bonding arrangements. A 2D 35Cl -> 1H D-RINEPT spectrum confirms the spatial proximities between the chloride ions, water molecules, and amine moieties. This all suggests future application of multinuclear SSNMR at high and ultra-high fields to the study of complex API solid forms for which SCXRD data are unavailable, with potential application to heterogeneous mixtures or amorphous solid dispersions. We characterize an ionic cocrystal of ponatinib HCl using X-ray diffraction and solid-state NMR. Multinuclear NMR, with ultra-high fields up to 35.2 T, lays the groundwork for characterization of complex crystals in the absence of diffraction data.
关键词: Hydrogen bonds
被引量
14
关键词: MARKETING ；PROTEIN-tyrosine kinase inhibitors ；DRUG counterfeiting
【专利/发明】 • US17835480 • •
申请日：2022-06-08,
公开日：2022-12-08
申请人： DR. REDDY'S LABORATORIES LIMITED
公开（公告）号： US20220389022A1
摘要： The present application relates to crystalline Form P1 and Form P3 of Ponatinib hydrochloride and process for its preparation. The said forms are also used for making pharmaceutical composition of Ponatinib hydrochloride.
【专利/发明】 • PCT/IB2021/059921 •
+5位作者
•
申请日：2021-10-27,
公开日：2022-05-05
申请人： ALEMBIC PHARMACEUTICALS LTD
公开（公告）号： WO2022090953A1
摘要： The present subject matter relates to a solid oral pharmaceutical composition comprising ponatinib or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient. The present subject matter also relates to pharmaceutical compositions comprising a solid dispersion of ponatinib or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient. Furthermore, it also relates to process of preparation of such compositions, and uses thereof.
【专利/发明】 • US16621183 •
+3位作者
•
申请日：2018-06-15,
公开日：2021-07-27
申请人： Apotex Inc.
公开（公告）号： US11072620B2
摘要： The present invention provides novel crystalline forms of Ponatinib hydrochloride. Specific crystalline forms provided by the present invention include Ponatinib hydrochloride Form APO-I, APO-III and APO-IV, each of which is obtained from acetonitrile/formic acid solutions. Additionally, Form APO-V is provided, which is obtained from concentrated hydrochloric acid.
【专利/发明】 • US16621183 •
+3位作者
•
申请日：2018-06-15,
公开日：2020-03-26
申请人： Apotex Inc.
公开（公告）号： US20200095255A1
摘要： The present invention provides novel crystalline forms of Ponatinib hydrochloride. Specific crystalline forms provided by the present invention include Ponatinib hydrochloride Form APO-I, APO-III and APO-IV, each of which is obtained from acetonitrile/formic acid solutions. Additionally, Form APO-V is provided, which is obtained from concentrated hydrochloric acid.
【专利/发明】 • US15862355 •
+3位作者
•
申请日：2018-01-04,
公开日：2019-03-05
申请人： Apicore US LLC
公开（公告）号： US10221184B2
摘要： Novel crystalline ponatinib hydrochloride forms designated Form alpha and Form beta are disclosed. Form alpha is characterized by data selected from an XRPD pattern with peaks at about 6.5, 9.0, 12.25, 14.4, 16.70, 19.6, 22.2, 24.5, 28.2±0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 1; and/or a combination thereof. Form beta is characterized by data selected from an XRPD pattern with peaks at about 10.7, 15.2, 15.8, 16.4 23.1, 25.0, 27.8±0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 3; and/or combinations thereof. Processes for making Form alpha and Form beta are disclosed.
【专利/发明】 • CA3067271 •
+3位作者
•
申请日：2018-06-15,
公开日：2018-12-27
申请人： APOTEX INC.
公开（公告）号： CA3067271A1
摘要： The present invention provides novel crystalline forms of Ponatinib hydrochloride. Specific crystalline forms provided by the present invention include Ponatinib hydrochloride Form APO-I, APO-III and APO-IV, each of which is obtained from acetonitrile/formic acid solutions. Additionally, Form APO-V is provided, which is obtained from concentrated hydrochloric acid.
【专利/发明】 • PCT/CA2018/050728 •
+3位作者
•
申请日：2018-06-15,
公开日：2018-12-27
申请人： APOTEX INC
公开（公告）号： WO2018232501A1
摘要： The present invention provides novel crystalline forms of Ponatinib hydrochloride. Specific crystalline forms provided by the present invention include Ponatinib hydrochloride Form APO-I, APO-III and APO-IV, each of which is obtained from acetonitrile/formic acid solutions. Additionally, Form APO-V is provided, which is obtained from concentrated hydrochloric acid.
【专利/发明】 • US15862355 •
+3位作者
•
申请日：2018-01-04,
公开日：2018-07-26
申请人： Apicore US LLC
公开（公告）号： US20180208599A1
摘要： Novel crystalline ponatinib hydrochloride forms designated Form alpha and Form beta are disclosed. Form alpha is characterized by data selected from an XRPD pattern with peaks at about 6.5, 9.0, 12.25, 14.4, 16.70, 19.6, 22.2, 24.5, 28.2±0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 1; and/or a combination thereof. Form beta is characterized by data selected from an XRPD pattern with peaks at about 10.7,15.2, 15.8, 16.4 23.1, 25.0, 27.8±0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 3; and/or combinations thereof. Processes for making Form alpha and Form beta are disclosed.
【专利/标准专利】 • AU2014286047 • •
申请日：2014-07-04,
公开日：2018-02-08
申请人： Sandoz AG
公开（公告）号： AU2014286047B2
摘要： The present disclosure relates to polymorphic forms of the hydrochloride salt of ponatinib ("compound 1") and to processes for the preparation of these polymorphic forms. The present disclosure also generally relates to a pharmaceutical composition comprising the forms, as well of methods of using the form(s) in the treatment of disorders associated with pathological cellular proliferation, such as neoplasms, and cancer.
【专利/发明】 • US14902790 • •
申请日：2014-07-04,
公开日：2017-08-08
申请人： SANDOZ AG
公开（公告）号： US9725454B2
摘要： The present disclosure relates to polymorphic forms of the hydrochloride salt of ponatinib (“compound 1”) and to processes for the preparation of these polymorphic forms. The present disclosure also generally relates to a pharmaceutical composition comprising the forms, as well of methods of using the form(s) in the treatment of disorders associated with pathological cellular proliferation, such as neoplasms, and cancer.
【专利/发明】 • US14902790 • •
申请日：2014-07-04,
公开日：2016-10-13
申请人： SANDOZ AG
公开（公告）号： US20160297821A1
摘要： The present disclosure relates to polymorphic forms of the hydrochloride salt of ponatinib (“compound 1”) and to processes for the preparation of these polymorphic forms. The present disclosure also generally relates to a pharmaceutical composition comprising the forms, as well of methods of using the form(s) in the treatment of disorders associated with pathological cellular proliferation, such as neoplasms, and cancer.
【专利/标准专利】 • AU2014286047 • •
申请日：2014-07-04,
公开日：2016-01-21
申请人： Sandoz AG
公开（公告）号： AU2014286047A1
摘要： The present disclosure relates to polymorphic forms of the hydrochloride salt of ponatinib ("compound 1") and to processes for the preparation of these polymorphic forms. The present disclosure also generally relates to a pharmaceutical composition comprising the forms, as well of methods of using the form(s) in the treatment of disorders associated with pathological cellular proliferation, such as neoplasms, and cancer.
【专利/发明】 • CA2916329 • •
申请日：2014-07-04,
公开日：2015-01-08
申请人： SANDOZ AG
公开（公告）号： CA2916329A1
摘要： The present disclosure relates to polymorphic forms of the hydrochloride salt of ponatinib ("compound 1") and to processes for the preparation of these polymorphic forms. The present disclosure also generally relates to a pharmaceutical composition comprising the forms, as well of methods of using the form(s) in the treatment of disorders associated with pathological cellular proliferation, such as neoplasms, and cancer.
【专利/发明】 • PCT/EP2014/064358 • •
申请日：2014-07-04,
公开日：2015-01-08
申请人： SANDOZ AG
公开（公告）号： WO2015001098A1
摘要： The present disclosure relates to polymorphic forms of the hydrochloride salt of ponatinib ("compound 1") and to processes for the preparation of these polymorphic forms. The present disclosure also generally relates to a pharmaceutical composition comprising the forms, as well of methods of using the form(s) in the treatment of disorders associated with pathological cellular proliferation, such as neoplasms, and cancer.
【期刊论文】 • Stepanian, Alec 1,3Travers, Richard J. 1,2Tesfu, Angelina 1Wolter, Nicole L. 1,3
+7位作者
• Circulation SCIE
中科院1区
JCR:Q1
PubMed
• Volume 152
(11)，
2025 ，pp. 765
- 783
摘要： BACKGROUND:Imatinib, the first Abl-tyrosine kinase inhibitor (TKI), improved leukemia outcomes without cardiovascular side effects. Newer agents, including ponatinib, addressed imatinib resistance, improving cancer remission, but substantially increased arterial thrombotic events, including myocardial infarction (MI) and stroke. The mechanism behind ponatinib-induced thrombosis and the cardiovascular effect of asciminib, a newly approved Abl-TKI, remain unknown.METHODS:The effect of clinically relevant plasma concentrations of imatinib, ponatinib, and asciminib were compared with vehicle in vivo using SR-BI-mut/LDLR-knockout (KO) mice to assess spontaneous MI and stroke risk. The mechanism was interrogated in C57BL/6J mice, assessing leukocyte trafficking and thromboinflammation by intravital microscopy and flow cytometry, respectively, and in ApoE-KO mice, assessing plaque phenotype by flow cytometry and histology. In vitro effects on human umbilical vein endothelial cells (ECs) and human coronary artery ECs were determined by flow cytometry, PCR, and immunoblotting. The role of TNF (tumor necrosis factor) signaling was evaluated by pharmacological inhibition and small interfering RNA knockdown.RESULTS:In SR-BI-mut/LDLR-KO mice, ponatinib significantly accelerated death from MI and stroke compared with vehicle, imatinib, and asciminib. In human ECs, only ponatinib increased expression of TNF receptors (TNFRs) and adhesion molecules (P-selectin, ICAM1 [intercellular adhesion molecule 1], and VCAM1 [vascular cell adhesion molecule 1]). Ponatinib rapidly induced TNFR2 membrane trafficking and TNF signaling in human umbilical vein ECs. TNFR inhibition or TNFR2 knockdown prevented ponatinib induction of EC adhesion molecules. In vivo, ponatinib increased mesenteric vessel adhesion molecules, leukocyte rolling and adhesion to vessels, leukocyte and platelet activation, and platelet-leukocyte aggregates. In ApoE-KO mice, ponatinib increased plaque necrotic core and inflammation, consistent with a rupture-prone phenotype. Asciminib-treated mice developed none of these in vitro or in vivo toxicities. In C57BL/6J mice, TNFR inhibition blocked ponatinib-induced mesenteric adhesion molecule expression and leukocyte trafficking, but not platelet-leukocyte aggregation. TNFR blockade prevented ponatinib-induced plaque inflammation in ApoE-KO mice and MI and stroke in SR-BI-mut/LDLR-KO mice.CONCLUSIONS:Ponatinib, a potent anticancer therapy, activates ECs, platelets, and leukocytes, driving plaque inflammation and death from MI and stroke in mice, mirroring clinical cardiotoxicities in patients with cancer. Asciminib did not induce these effects, suggesting it might be a safer option for imatinib-resistant patients with cancer. Inhibition of TNFR-mediated endothelial activation is sufficient to prevent ponatinib-induced major adverse cardiovascular events.
关键词: asciminib hydrochloride ；atherosclerosis ；cardio-oncology ；endothelial cells ；imatinib mesylate ；inflammation ；ponatinib hydrochloride
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2
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