1256580-46-7

Usage

Uses

Used in Oncology:
9-Ethyl-6,11-dihydro-6,6-dimethyl-8-[4-(4-morpholinyl)-1-piperidinyl]-11-oxo-5H-benzo[b]carbazole-3-carbonitrile is used as a potent ALK inhibitor for the treatment of patients with anaplastic lymphoma kinase-positive, metastatic non-small cell lung cancer. It is particularly effective in overcoming resistance mutations from prior crizotinib exposure, making it a valuable option for patients who have developed resistance to other ALK inhibitors.
Used in Drug Development:
As a highly selective and potent ALK inhibitor, 9-Ethyl-6,11-dihydro-6,6-dimethyl-8-[4-(4-morpholinyl)-1-piperidinyl]-11-oxo-5H-benzo[b]carbazole-3-carbonitrile plays a significant role in drug development for targeted cancer therapies. Its ability to block resistant gatekeeper mutants and reduce cell growth makes it a promising candidate for further research and development in the field of oncology.

Bioactivity

Alectinib (CH5424802) is an efficient ALK inhibitor. Its IC50 is 1.9nM and it is sensitive to the L1196M mutant, which is highly selective for ALK than PF-02341066, NVP-TAE684 and PHA-E429.

Solubility

In vitro (25 ° C): DMSO-2 mg/mL heating (4.14 mM); Water-<1 mg/mL (<1 mM); Ethanol-<1 mg/mL (<1 mM) In vivo (25 ° C): 30% PEG 400/0.5% Tween 80/5% propylene glycol-30 mg/mL.

In vitro

Alteinib (CH5424802) can act on ALK and it is ATP-competitive, with a dissociation constant (KD) of 2.4 nM. CH5424802 has a strong inhibitory effect on ALK and L1196M. The Ki is 0.83 and 1.56 nM, respectively. CH5424802 acts on NCI-H2228 NSCLC cells expressing EML4-ALK, inhibiting ALK autophosphorylation. CH5424802 can also inhibit STAT3 and AKT, rather than ERK1/2 phosphorylation. CH5424802 completely inhibited Tyr705, a phosphorylation site of STAT3. CH5424802 preferentially acted on NCI-H2228 cells expressing EML4-ALK without acting on negative NSCLC cell lines that contains ALK, including monolayer cultured HCC827 cells (deletion of EGFR exon19), A549 cells (KRAS mutations) or NCI-H522 cells (EGFR wild type, KRAS wild type, and ALK wild type). CH5424802 acted on NCI-H2228 spherocytes, causing apoptosis-caspase-3/7-like activation. CH5424802 cam inhibit the growth of two lymphoma cells, KARPAS-299 and SR, containing NPM-ALK fusion protein and does not affect the growth of HDLM-2 lymphoma cells without ALK fusion. CH5424802 acted on KARPAS-299 with highly targeted selectivity and stronger antiproliferative activity. When CH5424802 inhibits KAPRAS-299, the IC50 is 3 nM. When inhibit KDR, IC50 was 1.4 μM. The metabolic stability of CH5424802 was high.

In vivo

The oral treatment of CH5424802 can inhibit tumor growth. This role is dose-dependent, and the ED50 is 0.46 mg/kg. CH5424802 was treated at a dose of 20 mg/kg, causing a rapid regression of the tumor, with a recurrent rate of 168%. After 11 days of treatment (at day 28), the tumor volume in each mouse was less than 30 mm3, maintaining an effective anti-tumor effect; no tumor regurgitation occurs in no drug treatment period whitin 4 weeks.The half-life and oral bioavailability for CH5424802 treated mice were 8.6 hours and 70.8%, respectively. The mean plasma levels were 1.7, 1.5, and 0.3 nM after the treatment of 6 mg/kg repeated doses for 2, 7, and 24 hours.CH5424802 treatment inhibited tumor growth.Use CH5424802 to treat KARPAS-299 and NB-1 at a dose of 20 mg/kg, and on day 20, tumor growth was inhibited by 119% and 104%.CH5424802 inhibited STAT3 phosphorylation, which is dose-dependent (2-20 mg/kg), a decrease in phosphorylation of AKT was observed in the xenografts treated with CH5424802.

ALK Inhibitor

Rizotinib is a first-generation anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) and plays an important role inthe treatment of ALK-positive advanced non-small cell lung cancer (NSCLC). However, as with other TKIs, resistance development can-not be avoided with crizotinib. Alectinib is a second-generation ALK-TKI developed by Roche, which can effectively solve the problem of crizotinib resistance.

Indications

Alectinib (Alecensa(R), Roche) was approved first in Japan in 2014 and then by US FDA in 2015 as a second-generation ALK inhibitor for NSCLC treatment on patients who have progressed or do not tolerate crizotinib. Developed through a structure-based drug design approach, alectinib is a benzocarbazolone derivative that has shown potent inhibitory activity against ALK (IC50 value of 1.9 nM) and gatekeeper mutant L1196M ALK (IC50 value of 1.6 nM). Alectinib is effective with crizotinib-resistant ALK mutations on L1196M, F1174L, R1275Q, and C1156Y. In addition, an array of small-molecule inhibitors are currently being evaluated by several clinical trials for ALK-driven tumors.

in vitro

in cell free assays the ic50 of ch5424802 for enzyme activity of alk was 1.9 nm; the dissociation constant (kd) value for alk in an atp-competitive manner was 2.4 nm. the inhibitory activity for two hot spot-activating mutations (f1174l and r1275q) in neuroblastoma was comparable to that for wildtype alk [1].

in vivo

in the nci-h2228 model, oral administration of ch5424802 resulted in dose-dependent tumor growth inhibition (ed50 = 0.46 mg/kg) and tumor regression. moreover, treatment of 20 mg/kg ch5424802 showed rapid tumor regression and tumor regrowth did not occur throughout the 4-week drug-free period [2].

References

1) Sakamoto?et al.?(2011),?CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant; Cancer Cell,?19?679 2) Kodama?et al.?(2014),?Alectinib Shows Potent Antitumor Activity against RET-Rearranged Non-Small Cell Lung Cancer., Mol. Cancer Ther.?13?2910 3) Lu?et al.?(2017),?The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model; Cancer Lett,?400?61

Upstream product

• 1256580-24-1 9-ethynyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile 
• 67-64-1 acetone 
• 619-42-1 4-methoxycarbonylphenyl bromide 
• 1256579-62-0 9-bromo-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile 
• 1066-54-2 trimethylsilylacetylene 

Downstream Products

• 1256589-74-8 alectinib hydrochloride 

Relevant academic research and scientific papers

Synthesis method of Alectinib

The invention relates to a method for preparing Alectinib or pharmaceutically acceptable salt thereof. The invention also relates to intermediate compounds useful in this process and to the preparation of such intermediate compounds.

PROCESS FOR THE PREPARATION OF ALECTINIB

The present invention relates to a process for preparing alectinib, or a pharmaceutically acceptable salt thereof, and to related intermediates.

A NOVEL PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF ALECTINIB

The present invention provides a novel process for the preparation of 2-(4-Ethyl-3-iodophenyl)-2-methylpropanoic acid of Formula (I), (I) which is a key intermediate in the synthesis of Alectinib or its salt of Formula (II).

Preparation method of alectinib

The invention provides a preparation method of alectinib. The method comprises the following steps: taking 3-(4-ethylphenyl)-3-methylbutane-2-one as an initial raw material, carrying out an iodinationreaction on the initial raw material and an iodination reagent, and reacting obtained 3-(3-iodo-4-ethylphenyl)-2-methylbutane-2-one with a carbonylation reagent; carrying out a substitution reactionon obtained 4-(3-iodo-4-ethylphenyl)-4-methyl-3-oxovalerate and 4-chloro-3-nitro-benzonitrile in an alkaline environment, carrying out a reduction condensation reaction on obtained 4-(3-iodo-4-ethylphenyl)-2-(2-nitro-4-cyanophenyl)-4-methyl-3-oxovalerate, carrying out a cyclization reaction on obtained 6-cyano-2-(2-(4-ethyl-3-iodophenyl)prop-2-yl)-1H-methyl indole-3-carboxylate, and carrying out asubstitution reaction on obtained 9-ethyl-8-iodo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile and 4-(4-piperidyl)morpholine to obtain a finished product, namely the alectinib.The preparation method of alectinib has the main beneficial effects that the raw materials are cheap and are easy to obtain, the synthetic route is simple, the synthetic process is green and environmentally friendly, and industrial production is facilitated.

Preparation method of imatinib intermediate and imatinib (by machine translation)

The invention relates to an imatinib intermediate and a preparation method thereof. The method comprises 2 - the 2 - following steps: carrying out condensation, hydrolysis of ester groups) and dimethylamine hydrochloride/through the condensation, hydrolys

A PROCESS FOR PREPARING ALECTINIB OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

The present invention relates to a process for preparing the Alectinib or a pharmaceutically acceptable salt thereof using lesser reaction steps and also eliminating expensive and time- consuming column chromatography. The invention also relates to novel polymorphic forms of Alectinib and Alectinib hydrochloride.

Method for preparing key alectinib intermediate

The invention discloses a method for preparing a key alectinib intermediate. The method comprises the following steps: (1) enabling a compound c to react with hydrazine hydrate so as to obtain a compound d; (2) performing a cyclization reaction on the compound d with 3-bromobenzylcyanide so as to generate a compound e; (3) performing an acidification reaction and a F-C acylation cyclization reaction on the compound e in sequence so as to obtain a compound f, namely the key alectinib intermediate. The method disclosed by the invention is cheap and easy in initial raw material obtaining, relatively short in synthesis route, simple and convenient to operate, relatively low in cost, capable of meeting the idea of green chemicals and applicable to industrial production.

Preparation method of novel anaplastic lymphoma kinase (ALK) inhibitor alectinib

The invention provides a preparation method of a novel anaplastic lymphoma kinase (ALK) inhibitor alectinib. The chemical name of the novel anaplastic lymphoma kinase (ALK) inhibitor alectinib is 9-ethyl-6,6-dimethyl-8-(4-morpholine-4-yl-piperidine-1-yl)-11-oxa-6,11-dihydro-5H-benzo[b]carbazole-3-formonitrile. The preparation method comprises the following steps: taking 2-methoxy-5-hydroxy-8-dimethyl-7,8dihydronaphthalene-7-one as a starting raw material and carrying out chlorination reaction, oxidization reaction, substitution reaction, alkylation reaction, cyclization reaction, substitutionreaction, reduction reaction and cyanation reaction to obtain 9-ethyl-6,6-dimethyl-8-hydroxy-11-oxa-6,11-dihydro-5H-benzo[b]carbazole-3-formonitrile; then carrying out condensation on the 9-ethyl-6,6-dimethyl-8-hydroxy-11-oxa-6,11-dihydro-5H-benzo[b]carbazole-3-formonitrile and 4-morpholine-4-yl-piperidine to obtain a product. According to the preparation method provided by the invention, a reaction process is simplified and reaction conditions are moderate; meanwhile, the product is convenient to treat after reaction is finished and is easier to purify; the yield is high so that the preparation method is suitable for industrial production; the preparation method has important practical significance on improvement of economic and social benefits of the alectinib.

The treatment of non-small cell lung cancer drug [...] preparation method (by machine translation)

The treatment of non-small cell lung cancer drug [...] preparation method, the treatment of non-small cell lung cancer drug [...] the chemical name is 9 - ethyl - 6, 6 - dimethyl - 8 - (4 - morpholine - 4 - yl - piperidine - 1 - yl) - 11 - oxa - 6, 11 - dihydro - 5 H - benzo [b] carbazole - 3 - carbonitrile, its structural formula is: ; The invention adopts the raw materials are easy, economic and environmental-friendly and of high quality preparation technology, sought can be applicable to the industrial production process method, its preparation process is novel, simplified reaction process, thus improving the reaction yield, to [...] economic and social benefits the improvement of the important practical significance. (by machine translation)

Medicine for treating lung cancers

The invention provides a medicine for treating lung cancers. The medicine is characterized in that a chemical structural formula of the medicine for treating the lung cancers is shown in (A) in the attached figuredescription. The medicine has the advantag