1257044-40-8

Basic information

• Product Name: ABT-199
• Synonyms: ABT-199;ABT199,GDC0199;GDC 0199;GDC0199;GDC-0199;4-[4-[[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-benzamide;Benzamide, 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-;4-[4-[[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-benzamide ABT-199 (GDC-0199)
• CAS NO: 1257044-40-8
• Molecular Formula: C₄₅H₅₀ClN₇O₇S
• Molecular Weight: 868.4392
• EINECS: 1592732-453-0
• Product Categories: Apis;Inhibitor;Inhibitors;API
• Mol File: 1257044-40-8.mol

Chemical Properties

• Appearance: /
• Density: 1.340±0.06 g/cm3(Predicted)
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly)
• PKA: 4.09±0.10(Predicted)
• CAS DataBase Reference: ABT-199(CAS DataBase Reference)
• NIST Chemistry Reference: ABT-199(1257044-40-8)
• EPA Substance Registry System: ABT-199(1257044-40-8)

Safety Data

• Hazardous Substances Data: 1257044-40-8(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
ABT-199 is used as an anti-cancer agent for the treatment of chronic lymphocytic leukemia (CLL) cells and estrogen receptor-positive breast cancer. It is particularly effective in patients with the 17p deletion genetic mutation, as it restores the ability of malignant cells to undergo apoptosis by selectively inhibiting the overexpressed B cell lymphoma subtype 2 (BCL-2) protein.
Used in Clinical Trials:
ABT-199 is also being considered for approval in Europe and Canada for similar indications and is in various stages of development for the treatment of non-Hodgkin lymphomas (NHL), acute myeloid leukemia (AML), multiple myeloma (MM), and several other disorders, either as a combination therapy or a stand-alone treatment.

BCL-2 inhibitor

Venetoclax is a first-in-class, oral, selective BCL-2 inhibitor (BH3-only mimetic). The drug is approved in numerous countries, including those of the EU and in the USA, for the treatment of adults with relapsed or refractory (RR) CLL. The drug arose from research by Abbott Laboratories (now AbbVie) during a collaboration with Genentech and is being codeveloped by AbbVie and Genentech/Roche primarily.

Mechanism of action

Venetoclax has high affinity for BCL-2, binding to the protein with an affinity more than three orders of magnitude greater than to BCL-XL or BCL-W in vitro. By binding to BCL-2, the drug displaces BCL-2-bound proapoptotic proteins (such as BIM), resulting in the permeabilization of mitochondrial outer membranes, activation of caspases, and restoration of cancer cell apoptosis, with this process requiring the apoptosis regulators BAX or BAK.

Clinical evaluation

As a specific Bcl-2 inhibitor of Bcl-2, ABT-199 was approved by FDA to treat CLL in 2015. ABT-199 was designed to avoid the nonselective binding of ABT-263 with Bcl-XL, which could induce the adverse effect of thrombocytopenia. The X-ray crystal structure of a Bcl-2 dimer in complex with ABT-263 and that with a modified ABT-263 lacking the thiophenyl moiety elucidated an alternative bind site in the hotspot p4-binding pocket that could be utilized for selective binding of Bcl-2. This led to the development of ABT-199 that tightly binds to Bcl-2 but not Bcl-XL. Consistent with its lower affinity to Bcl-XL, ABT-199 spared human platelets both in vivo and in vitro. In clinical trials, ABT-199 exhibited immediate antileukemic activity after a single dose in three refractory CLL patients with only minor changes in platelet counts. ABT-199 as a single agent showed promising clinical response in many malignancies, such as diffused large B-cell lymphoma, follicular lymphoma, CLL, acute myeloblastic leukemia (AML), and multiple myeloma. Studies also showed that ABT-199 had a significant sensitizing effect in combination with other antitumor drugs, such as rituximab, obinutuzumab, in CLL and AML patients. However, ABT-199 did show adverse effects, especially tumor lysis syndrome (TLS). Furthermore, neutropenia or infections have also been observed in patients using ABT-199.Chapter 10?-?Bcl-2 Inhibitors as Sensitizing Agents for Cancer Chemotherapy

Cytotoxic Activity

Venetoclax displayed cytotoxic activity in various tumour samples/cell lines, including some derived from CLLs, various other NHL subtypes, acute lymphoblastic leukaemias (ALLs), AMLs, chronic myeloid leukaemias (CMLs) and MMs. Notably, the sensitivity of venetoclax correlated with higher BCL-2 expression, with a BCL-2 high status [i.e. BCL-2 gains, BCL-2 amplifications, or the t translocation, which is a notable cause of deregulated BCL-2 expression] and higher BCL-2/MCL-1 ratios being potentially predictive of sensitivity to the drug.

References

https://en.wikipedia.org/wiki/VenetoclaxVogler, M, et al. "ABT-199 selectively inhibits BCL2 but not BCL2L1 and efficiently induces apoptosis of chronic lymphocytic leukaemic cells but not platelets." British Journal of Haematology 163.1(2013):139-42.Vaillant, François, et al. "Targeting BCL-2 with the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer." Cancer Cell 24.1(2013):120-9.Lindeman, G. J., et al. "Abstract P2-09-01: Targeting BCL-2 with the BH3 mimetic ABT-199 in ER-positive breast cancer." Cancer Research 73.24 Supplement (2013):P2-09-01-P2-09-01.

Clinical Use

Selective inhibitor of B-cell lymphoma protein: Treatment of chronic lymphocytic leukaemia

Synthesis

The manufacturing route to venetoclax takes place by coupling of three key structural subunits: azaindole 162, sulfonamide 165, and piperazine 172. The first of these subunits was generated in two steps from commercially available 4-bromo-2-fluoro-1-iodo-benzene (159). Grignard formation of iodide 159 (i-PrMgCl) followed by quenching with Boc2O provided the desired tert-butyl ester 160 without the need for chromatographic purification. Aromatic substitution of crude 160 with azaindole 161 provided access to 162 in 86% yield after recrystallization from EtOAc/heptane. Sulfonamide 165 was formed in 91% yield and 99.9% purity via aromatic substitution of commercially available 163 with amine 164 at 80 °C (DIPEA, MeCN). Synthesis of the third venetoclax subunit, piperazine amine hydrochloride salt 172, began with commercial cyclohexanone 166. Vilsmeier-Haack formylation of the sterically more accessible enol tautomer of 166 delivered vinyl chloride 167 in quantitative yield. Coupling of this chloride with commercial aryl boronate 168 gave rise to transient enal 169 in 87% assay yield, which was not isolated. Crude 169 was then carried into a reductive amination reaction with commercial N-Boc piperazine (170). Precipitation and recrystallization from acetonitrile ultimately furnished piperazinyl alkene 171 in 74% yield from 167. Finally, subunit 172 was obtained via Boc removal with concentrated HCl in IPA at 65 °C and subsequent filtration, conditions that provided a 95% yield of high purity intermediate 172 (>99.5%).The final approach to venetoclax involved a palladiumcatalyzed coupling of amine 172 with aryl bromide 162, ester hydrolysis, and coupling of the resulting carboxylic acid with sulfonamide 165. In practice, Buchwald-Hartwig amination of 162 with 172 proceeded smoothly and relied upon workup with cysteine to enable cleansing of residual palladium from the reaction mixture. This reaction gave rise to advanced intermediate 173 in 89% yield after crystallization from cyclohexane. Treatment of 173 with t- BuOK/H2O/2-MeTHF at 55 °C provided the corresponding free acid, which was immediately activated with EDC/DMAP/ Et3N to promote coupling with sulfonamide 165 at room temperature. The final drug target could be accessed by crystallization from EtOAc and washing with 1:1 DCM/EtOAc, yielding venetoclax (XVIII) in free base form in 71% over the two final steps. This synthetic route was capable of fashioning the drug target in 52% overall yield based on the longest linear sequence (7 steps).

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration possibly increased by ciprofloxacin, clarithromycin and erythromycin - reduce venetoclax dose; avoid with rifampicin. Anticoagulants: avoid with dabigatran; concentration of warfarin increased. Antidepressants: avoid with St John’s wort. Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin and phenytoin - avoid. Antifungals: concentration possibly increased by fluconazole, itraconazole, ketoconazole, posaconazole and voriconazole - reduce venetoclax dose. Antipsychotics: increased risk of agranulocytosis with clozapine - avoid. Antivirals: concentration possibly reduced by efavirenz and etravirine - avoid; concentration possibly increased by ritonavir - reduce venetoclax dose. Bosentan: concentration of venetoclax possibly reduced by bosentan - avoid. Calcium channel blockers: concentration possibly increased by diltiazem and verapamil - reduce venetoclax dose. Cardiac glycosides: avoid with digoxin. Cytotoxics: avoid with everolimus. Grapefruit juice: avoid concomitant use. Modafinil: concentration of venetoclax possibly reduced - avoid. Sirolimus: avoid concomitant use. Vaccines: avoid with live vaccines.

Metabolism

In vitro studies show that venetoclax is mainly metabolised by cytochrome P450 CYP3A4. M27 was identified as a major metabolite in plasma with an inhibitory activity against BCL-2 that is at least 58-fold lower than venetoclax in vitro. Excretion is mainly by the faecal route (>99.9%; 20.8% unchanged).

Upstream product

• 1228779-96-1 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide 
• 1235865-77-6 [2-((1H-pyrrolo [2,3-b]pyridin-5-yl)oxy)-4-(4-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid] 
• 130290-79-8 4-tetrahydropyranmethylamine 
• 406233-31-6 4-fluoro-3-nitrobenzenesulfonamide 
• 183208-35-7 5-bromo-1H-pyrrolo[2,3-b]pyridine 
• 858116-66-2 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine 
• 32767-46-7 methyl 4,4-dimethyl-2-oxocyclohexancarboxylate 
• 1228780-46-8 methyl 4,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1-ene-1-carboxylate 
• 1228780-49-1 4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylic acid methyl ester 
• 1228780-51-5 (4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methanol 
• 1228780-71-9 tert-butyl 4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazine-1-carboxylate 
• 1228780-72-0 1-((4’-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1‘-biphenyl]-2-yl)methyl)piperazine 
• 685514-01-6 1-[tris(propan-2-yl)silyl]-1H-pyrrolo[2,3-b]pyridin-5-ol 
• 1235865-75-4 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid methyl ester 

Downstream Products

• 1379647-80-9 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 sulfate 

Relevant articles and documents

Anti-apoptosis protein Bcl - 2 inhibitor as well as preparation method and application thereof

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.

A PROCESS FOR THE PREPARATION OF VENETOCLAX AND ITS POLYMORPHS THEREOF

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.

SUBSTANTIALLY PURE VENETOCLAX AND AMORPHOUS VENETOCLAX IN A FREE DRUG PARTICULATE FORM

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.

AN IMPROVED PROCESS FOR THE PREPARATION OF VENETOCLAX

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)

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)

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.

PHARMACEUTICAL COMPOSITION COMPRISING VENETOCLAX

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.

Preparation method of BCL-2 inhibitor venetoclax

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.

VENETOCLAX BASIC SALTS AND PROCESSES FOR THE PURIFICATION OF VENETOCLAX

The invention relates to basic salts of Venetoclax and processes for the purification of Venetoclax through said salts.

Development of a Convergent Large-Scale Synthesis for Venetoclax, a First-in-Class BCL-2 Selective Inhibitor

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.

Solid dispersions containing an apoptosis-inducing agent

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.