- Anti-apoptosis protein Bcl - 2 inhibitor as well as preparation method and application thereof
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The invention provides an anti-apoptotic protein Bcl - 2 inhibitor and a preparation method and application thereof, and particularly provides a compound shown by the following formula (I) or an optical isomer thereof. A tautomer, or a pharmaceutically acceptable salt thereof. The compounds have excellent Bcl - 2 inhibitory activity and are therefore useful in the treatment or prevention of related mammalian diseases or disorders due to abnormal expression of anti-apoptotic protein Bcl - 2.
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Paragraph 0101-0102; 0106; 0110
(2021/09/29)
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- A PROCESS FOR THE PREPARATION OF VENETOCLAX AND ITS POLYMORPHS THEREOF
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The present invention relates to a process for the preparation of 4-(4-{[2-(4-chlorophenyl)-4,4dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b] pyridin-5-yloxy)benzamide) compound of formula-1 which is represented by the following structural formula: Formula-1.
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- VENETOCLAX BASIC SALTS AND PROCESSES FOR THE PURIFICATION OF VENETOCLAX
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The invention relates to basic salts of Venetoclax and processes for the purification of Venetoclax through said salts.
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Page/Page column 20-22
(2020/02/16)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF VENETOCLAX
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An improved process for the preparation of Venetoclax. The present invention also relates to an improved process for the preparation of a compound of formula I or its salts, (I) wherein R is C1-4 alkyl; and its use for the preparation of the compound of formula V. (v)
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- SUBSTANTIALLY PURE VENETOCLAX AND AMORPHOUS VENETOCLAX IN A FREE DRUG PARTICULATE FORM
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The present invention provides substantially pure venetoclax, process for the preparation of substantially pure venetoclax and pharmaceutical formulation of substantially pure venetoclax. In another aspect present invention provides amorphous venetoclax in a free drug particulate form, process for the preparation of amorphous venetoclax in a free drug particulate form and pharmaceutical formulation of amorphous venetoclax in a free drug particulate form.
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- PHARMACEUTICAL COMPOSITION COMPRISING VENETOCLAX
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The present subject matter provides amorphous solid dispersions of venetoclax or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising said amorphous solid dispersions. The present subject matter also provides methods for the preparation of said solid dispersions and compositions. The present subject matter further provides pharmaceutical compositions comprising mixture of solid dispersions.
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Page/Page column 37-38
(2020/11/23)
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- Preparation method of BCL-2 inhibitor venetoclax
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The invention discloses a preparation method of a BCL-2 inhibitor venetoclax. The method mainly comprises the following six steps: 1) VM1 and VM2 used as reaction starting materials undergo a dockingreaction under the catalytic action of an alkali to prepare an intermediate V1; 2) the intermediate V1 reacts with Boc piperazine under the catalytic action of the alkali to prepare an intermediate V2; 3) Boc protection is removed from the intermediate V2 under the action of an acid reagent to prepare an intermediate V3; 4) the intermediates V3 and VM3 are heated to react to form a Schiff base, and the Schiff base is converted into secondary amine under the action of a reducing agent to prepare an intermediate V4; 5) the intermediate V4 reacts with the intermediate VM4 under the action of a condensing agent to prepare an amide compound intermediate V5; and 6) a phenylsulfonyl protecting group is removed from the intermediate V5 under the catalysis of a catalyst to obtain the final productvenetoclax. Compared with the prior art, the preparation method has the advantages of short steps, simple and feasible reaction, and suitableness for large-scale industrial production.
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Paragraph 0055; 0066-0067
(2020/03/23)
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- PROCESS FOR THE PREPARATION OF 4-(4-{[2-(4-CHLOROPHENYL)-4,4-DIMETHYLCYCLOHEX-1-EN-1- YL]METHYL}PIPERAZIN-1-YL)-N-({3-NITRO-4-[(TETRAHYDRO-2H-PYRAN-4-YLMETHYL)AMINO] PHENYL}SULFONYL)-2-(1H-PYRROLO[2,3-B]PYRIDIN-5-YLOXY)BENZAMIDE)
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The present invention relates to novel crystalline forms of 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran -4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide compound of formula-1 represented by the following structural formula-1, which is referred to as Venetoclax Formula-1 The present invention also relates to an improved process for the preparation of Venetoclax compound of formula-1 which is free of Impurity-I, Impurity-II, Impurity-III and Impurity-IV.
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Page/Page column 32; 38
(2020/03/29)
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- Development of a Convergent Large-Scale Synthesis for Venetoclax, a First-in-Class BCL-2 Selective Inhibitor
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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.
- Ku, Yi-Yin,Chan, Vincent S.,Christesen, Alan,Grieme, Timothy,Mulhern, Mathew,Pu, Yu-Ming,Wendt, Michael D.
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p. 4814 - 4829
(2019/02/05)
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- Solid dispersions containing an apoptosis-inducing agent
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A pro-apoptotic solid dispersion comprises, in essentially non-crystalline form, a Bcl-2 family protein inhibitory compound of Formula I 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 dissolving the compound, the polymeric carrier and the surfactant in a suitable solvent, and removing the solvent 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.
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- Preparation method and product of venetoclax
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A preparation method of venetoclax comprises the following steps: dissolving 2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl]methyl]piperazin-1-yl]benzoicacid and 4-fluoro-3-nitrobenzenesulfonamide/4-chloro-3-nitrobenzenesulfonamide in a solvent, and performing a condensation reaction and separation to obtain 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-1-yl]methyl]piperazin-1-yl])-N-[(3-nitro-4-fluoro(or chloro)phenyl) sulfonyl)]-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy) benzamide; performing a substitution reaction on 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-1-yl]methyl]piperazin-1-yl])-N-[(3-nitro-4-fluoro(or chloro)phenyl) sulfonyl)]-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy) benzamide and 4-(aminomethyl)tetrahydro-2H-pyran, and performing separation and refining to obtain venetoclax.
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- SOLID STATE FORMS OF AN APOPTOSIS-INDUCING AGENT AND PROCESSES THEREOF
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Various crystalline and amorphous solid state forms of an apoptosis-inducing agent and preparations thereof are disclosed. Also discloses the use of crystalline forms for the preparation of amorphous form of apoptosis-inducing agent. Further discloses a process for preparation of the apoptosis-inducing agent. (Formula I)
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- PROCESS FOR THE PREPARATION OF VENETOCLAX
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The present disclosure provides novel synthetic process for the preparation of venetoclax. The disclosed processes involve the use of novel intermediates. Processes for the preparation of these intermediates are also disclosed as well as methods for the preparation of particularly useful salts thereof.
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- Preparation method of B cell lymphoma factor-2 inhibitor ABT-199
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The invention discloses a preparation method of a B cell lymphoma factor-2 inhibitor ABT-199, and belongs to the field of pharmaceutical synthesis. The method comprises the following steps: substituting a starting material methyl 4-fluorosalicylate that is compound II with tert-butyl-1-piperazinecarboxylate that is compound III in the presence of a phase transfer catalyst, then de-protecting underthe acidic condition to obtain a compound IV, performing reductive amination on the compound IV and a synthesized key intermediate compound V in the presence of a catalyst (sodium triacetoxyborohydride) to obtain an intermediate VI, substituting the intermediate VI with a raw material VII that is 5-bromo-azaindole, then directly hydrolyzing and acidifying the obtained esterified product to obtainan intermediate VIII, and finally amidating the intermediate VIII and a raw material compound IX to obtain a target product compound I. The raw materials are easy to purchase or synthesize, the synthesis steps are short, the total yield is more than or equal to 40%, the use of expensive or difficult-to-purchase raw materials is avoided, and the method is suitable for industrial production.
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Paragraph 0065; 0067; 0075; 0084; 0094; 0103; 0113
(2019/01/08)
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- SOLID FORMS OF VENETOCLAX AND PROCESSES FOR THE PREPARATION OF VENETOCLAX
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Aspects of the present application relate to solid forms of Venetoclax and preparative processes thereof. Specific aspects relate to an amorphous form of Venetoclax, its solid dispersion and crystalline forms of Venetoclax or salts thereof. Further aspects of the present application relate to processes for the preparation of Venetoclax.
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- Synthesis method for BCL-2 inhibitor Venetoclax
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The invention discloses a new synthesis method for a BCL-2 inhibitor Venetoclax. The synthesis method includes the steps that 2,4-difluoro methyl benzoate serves as a raw material, the 2,4-difluoro methyl benzoate and 5-hydroxy-7-azaindole are subjected to a condensation reaction, Ven-16 is obtained, and 4-substituted isomer and other impurities are removed through recrystallization; the product and N-Boc-piperazine are reacted and hydrolyzed, and Ven-18 is obtained; Ven-18 and Ven-21 are condensed, Boc of trifluoroacetic acid is removed, and Ven-20 is obtained; the product and Ven-7 are reacted, reaction intermediates in all the steps have the good crystal forms, purification can be carried out through crystal to achieve the center control requirements of the technology, and a final product Venetoclax can also be subjected to recrystallization to obtain the product Venetoclax, wherein the HPLC purity of the Venetoclax is larger than 99.5%, and the individual impurity of the Venetoclax is smaller than 0.1%; the Venetoclax has the industrialized application value.
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- SOLID STATE FORMS OF VENETOCLAX AND PROCESSES FOR PREPARATION OF VENETOCLAX
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Solid state forms of Venetoclax, pharmaceutical compositions thereof, and uses thereof are disclosed. Also disclosed are processes for the preparation of Venetoclax.
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- THERAPEUTIC COMBINATIONS OF A BTK INHIBITOR, A PI3K INHIBITOR, A JAK-2 INHIBITOR, AND/OR A BCL-2 INHIBITOR
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Therapeutic combinations of a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms (PI3K-γ,δ, PI3K-γ, and PI3K-δ), a Janus kinase-2 (JAK-2) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, and/or a B-cell lymphoma-2 (BCL-2) inhibitor are described. In some embodiments, the invention provides therapeutic combinations of a PI3K-δ inhibitor and a BTK inhibitor, a JAK-2 and a BTK inhibitor, and a BCL-2 and BTK inhibitor.
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- Bcl-2 inhibitor ABT-199 synthesis of
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The invention discloses a synthesis method of a Bcl-2 inhibitor ABT-199. The method comprises the following steps: by using methyl 2-fluoro-4-nitrobenzoate and 5-hydroxy-7-azaindole as raw materials, carrying out substitution, reduction, cyclization, substitution, hydrolysis, condensation and the like to synthesize the ABT-199. The method has the characteristics of mild reaction conditions, simple operating technique, low cost and high yield.
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Paragraph 0030; 0031; 0036; 0037
(2017/02/24)
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- Processes For The Preparation Of An Apoptosis-Inducing Agent
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Provided herein is a process for the preparation of an apoptosis-inducing agent, and chemical intermediates thereof. Also provided herein are novel chemical intermediates related to the process provided herein.
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- MELT-EXTRUDED SOLID DISPERSIONS CONTAINING AN APOPTOSIS-INDUCING AGENT
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A pro-apoptotic solid dispersion comprises, in essentially non-crystalline form, a Bcl-2 family protein inhibitory compound of Formula I 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 I, 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.
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- METHODS OF TREATMENT USING SELECTIVE BCL-2 INHIBITORS
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This invention pertains to methods of treating systemic lupus erythematosus, lupus nephritis or Sjogren's Syndrome with compounds that selectively inhibit the activity of Bcl-2 anti-apoptotic proteins. Specifically, the current invention is directed to treatment with compounds that selectively inhibit the activity of Bcl-2 proteins, with a lesser affinity for inhibiting the activity of other BCL-2 family proteins, including Bcl-xL.
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- SALTS AND CRYSTALLINE FORMS OF AN APOPTOSIS-INDUCING AGENT
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Salts and crystalline forms of 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}- sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide are suitable active pharmaceutical ingredients for pharmaceutical compositions useful in treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, for example cancer.
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- APOPTOSIS-INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE AND AUTOIMMUNE DISEASES
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Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-2 protein.
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- APOPTOSIS INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE AND AUTOIMMUNE DISEASES
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Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-2 protein.
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Page/Page column 122
(2010/12/29)
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