1228779-96-1Relevant articles and documents
Development of a Convergent Large-Scale Synthesis for Venetoclax, a First-in-Class BCL-2 Selective Inhibitor
Ku, Yi-Yin,Chan, Vincent S.,Christesen, Alan,Grieme, Timothy,Mulhern, Mathew,Pu, Yu-Ming,Wendt, Michael D.
, p. 4814 - 4829 (2019)
The process development of a new synthetic route leading to an efficient and robust synthetic process for venetoclax (1: the active pharmaceutical ingredient (API) in Venclexta) is described. The redesigned synthesis features a Buchwald-Hartwig amination to construct the core ester 23c in a convergent fashion by connecting two key building blocks (4c and 26), which is then followed by a uniquely effective saponification reaction of 23c using anhydrous hydroxide generated in situ to obtain 2. Finally, the coupling of the penultimate core acid 2 with sulfonamide 3 furnishes drug substance 1 with consistently high quality. The challenges and solutions for the key Pd-catalyzed C-N cross-coupling will also be discussed in detail. The improved synthesis overcomes many of the initial scale-up challenges and was accomplished in 46% overall yield from 3,3-dimethyldicyclohexanone (6), more than doubling the overall yield of the first generation route. The new process was successfully implemented for producing large quantities of 1 with >99% area purity.
CONDENSED HETEROCYCLES AS BCL-2 INHIBITORS
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Page/Page column 225, (2021/04/10)
The disclosure includes compounds of Formula (A) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11, h, j, m, n, k, v, s, g, V, W, L, Z1 Q1, Q2, Q3, Q4, Q5, Q6, and Q7, are defined herein. Also disclosed is a method for treating a neoplastic disease, an autoimmune disease, or a neorodegenerative disease with these compounds.
1H-PYRROLO[2,3-B]PYRIDINE DERIVATIVES AS BCL-2 INHIBITORS FOR THE TREATMENT OF NEOPLASTIC AND AUTOIMMUNE DISEASES
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Page/Page column 152-153, (2021/07/02)
The present invention relates to lH-pyrrolo[2,3-b]pyridine derivatives and related compounds as BCL-2 inhibitors for treating neoplastic, autoimmune or neurodegenerative diseases. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. pages 162 to 233; examples 1 to 8; table; compound examples cpd-1 to cpd-135; biological examples 1 to 4).
HOT MELT EXTRUDED SOLID DISPERSIONS CONTAINING A BCL2 INHIBITOR
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Page/Page column 38-39, (2021/09/04)
A pro-apoptotic solid dispersion comprises, a Bcl -2 family protein inhibitory compound of Formula A as defined herein, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier, and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises subjecting to elevated temperature the compound of Formula A, the water-soluble polymeric carrier, and the surfactant to provide an extrudable semi-solid mixture; extruding the semi-solid mixture; and cooling the resulting extrudate to provide a solid matrix comprising the polymeric carrier, and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl -2 family proteins, for example cancer or an immune or autoimmune disease.
Discovery of potent and selective Bcl-2 inhibitors with acyl sulfonamide skeleton
Wang, Bin,Feng, Weiwei,Wang, Jinan,Dong, Yuanzhen,Liu, Yanlong,Yao, Yiyan,Zhang, Jianqing,Shi, Wei,Liu, Limin,Zhang, Hongying,He, Xiangyi,Chang, Xiayun,Wang, Xiaojin,Xu, Hongjiang,Liu, Fei,Feng, Jun
, (2021/09/20)
The antiapoptotic protein B-cell lymphoma 2 (Bcl-2), overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, a series of novel derivatives with acyl sulfonamide skeleton was designed, synthesized, and evaluated as Bcl-2 inhibitors by means of bioisosteric replacement. Among them, compound 24g demonstrated equal efficient inhibition activity against RS4;11 cell line compared to positive control ABT-199. Moreover, it showed improved selectivity for Bcl-2/Bcl-xL inhibitory effects, the result of which was consistent with platelet toxicity studies. In vitro and in vivo pharmacokinetic properties of compound 24g had a significantly improved profiles. Taken together, those results suggested it as a promising candidate for development of novel therapeutics targeting Bcl-2 in cancer.
BCL-2 INHIBITORS
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Page/Page column 190, (2020/03/15)
The disclosure includes compounds of Formula (A), (A) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11, h, j, m, n, k, v, s, g, V, W, L, Z1, Q1, Q2, Q3, Q4, Q5, Q6, and Q7, are defined herein. Also disclosed is a method for treating a neoplastic disease, an autoimmune disease, or a neorodegenerative disease with these compounds.
BCL-2 INHIBITORS
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Page/Page column 52, (2020/07/15)
The disclosure includes compounds of Formula (I), (I) wherein Z, Q1, Q3, Q4, Q5, Q6, Q7, R0, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, g, k, m, n, s, v, j, L, Z1, and, W are defined herein. Also disclosed is a method for treating a neoplastic disease and autoimmune disease with these compounds.
CONDENSED HETEROCYCLIC DERIVATIVES AS BCL-2 INHIBITORS FOR THE TREATMENT OF NEOPLASTIC DISEASES
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Page/Page column 61; 62, (2019/03/12)
The disclosure includes compounds of Formula (A) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12, j, k, m, n, Y, W, W1, W2, W3, V, L, Z1, Q1, Q2, Q3, and Q4, are defined herein. Also disclosed is a method for treatinga neoplastic disease, an autoimmune disease, or a neorodegenerative disease with these compounds.
Bcl-2 INHIBITORS
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Paragraph 0550; 0551, (2019/11/19)
Disclosed herein is a compound of Formula (I) for inhibiting Bcl-2 and treating disease associated with undesirable bcl-2 activity (Bcl-2 related diseases), a method of using the compounds disclosed herein for treating dysregulated apoptotic diseases including cancers and treating autoimmune disease, and a pharmaceutical composition comprising the same.
Efficient synthesis of carbon-11 labelled acylsulfonamides using [11C]CO carbonylation chemistry
Van Der Wildt, Berend,Shen, Bin,Chin, Frederick T.
supporting information, p. 3124 - 3127 (2019/03/28)
Herein, a novel method for carbon-11 labeling of acyl sulfonamides by a one-step insertive [11C]CO carbonylative cross-coupling reaction between aryl halides and sulfonamides is presented. Various model compounds as well as drug molecules LY573636 (tasisulam) and ABT-199 were obtained in excellent yields. This method provides a valuable and widely applicable contribution to the continuously expanding radiochemical toolbox for PET research.