Binimetinib

Array BioPharma Inc;PHASE 3 Cancer, ovary (serous)

Novartis PHASE 3 Melanoma

MEK-1 protein kinase inhibitor; MEK-2 protein kinase inhibitor

Liver injury; Melanoma; Noonan syndrome; Ovary tumor; Solid tumor

On June 27, 2018, the Food and Drug Administration approved encorafenib and binimetinib in combination patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test

Binimetinib, also known as Mektovi and ARRY-162, is an anti-cancer small molecule that was developed by Array Biopharma to treat various cancers.^[1] Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway.^[2] Inappropriate activation of the pathway has been shown to occur in many cancers.^[2] In June 2018 it was approved by the FDA in combination with encorafenib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.^[3]

Binimetinib, also known as Mektovi, is a potent is a potent and selective oral mitogen-activated protein kinase 1/2 (MEK 1/2) inhibitor which is combined with Encorafenib ^[4],^[8].

On June 27, 2018, the Food and Drug Administration approved the combination of Encorafeniband binimetinib (BRAFTOVI and MEKTOVI, from Array BioPharma Inc.) in combination for patients with unresectable or metastatic melanoma with the BRAF V600E or V600K mutations, as detected by an FDA-approved test ^[8].

Binimetinib was originally developed by Array BioPharma, then licensed to Novartis for worldwide development in 2010. But Array Biopharma regained full worldwide rights of the product in 2015. And in 2015, Pierre Fabre acquired exclusive rights to commercialize the product.

Mechanism of action

Binimetinib is an orally available inhibitor of mitogen-activated protein kinase kinase (MEK), or more specifically, a MAP2K inhibitor.^[4]MEK is part of the RAS pathway, which is involved in cell proliferation and survival. MEK is upregulated in many forms of cancer.^[5]Binimetinib, uncompetitive with ATP, binds to and inhibits the activity of MEK1/2 kinase, which has been shown to regulate several key cellular activities including proliferation, survival, and angiogenesis.^[6] MEK1/2 are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types.^[7] Inhibition of MEK1/2 prevents the activation of MEK1/2 dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling.^[8] As demonstrated in preclinical studies, this may eventually lead to an inhibition of tumor cell proliferation and an inhibition in production of various inflammatory cytokines including interleukin-1, -6 and tumor necrosis factor.^[8]

Development

In 2015, it was in phase III clinical trials for ovarian cancer,^[9] BRAF mutant melanoma,^[10] and NRAS Q61 mutant melanoma.^[11]

In December 2015, the company announced that the mutant-NRAS melanoma trial was successful.^[12] In the trial, those receiving binimetinib had a median progression-free survival of 2.8 months versus 1.5 months for those on the standard dacarbazinetreatment.^[13] NDA submitted Jun 2016,^[14] and the FDA should decide by 30 June 2017.^[15]

In April 2016, it was reported that the phase III trial for low-grade ovarian cancer was terminated due to lack of efficacy.^[16]

Binimetinib was studied for treatment of rheumatoid arthritis, but a phase II trial did not show benefit.

In 2017, the FDA informed Array Biopharma that the phase III trial data was not sufficient and the New Drug Application was withdrawn.^[17]

In June 2018 it was approved for the treatment of certain melanomas by the FDA in combination with encorafenib.^[3]

Growth factor-mediated proliferative signals are transmitted from the extracellular environment to the nucleus through several pathways, including the RAS/RAF/ MEK pathway. The RAS/RAF/MEK kinase signal transduction pathway is activated through initial extracellular binding and stimulation of tyrosine receptor kinases (RTKs) by their respective cognate ligands. Upon autophosphorylation of specific tyrosine residues in the cytosolic domain of RTKs, the Grb2-Sos complex translocates to the plasma membrane, and converts the inactive RAS’GDP to active RAS’GTP. The interaction between the Grb2 docking protein and the activated kinases or the phosphorylated receptor associated proteins is mediated by the Src Homology (SH2) domain of the signaling protein that recognizes specific phosphotyrosine sequences. RAS undergoes a conformational change upon guanosine 5 ‘-triphosphate (GTP) binding and causes the recruitment of RAF- 1 to the cytoplasmic membrane where it is phosphorylated by several kinases and simultaneous disphosphorylated at key residues by protein phosphatase-2B. Activated RAF phosphorylates the mitogen- activated protein kinase kinase (MEK) on two serine residues in the activation loop, which results in the activation of this protein kinase. MEK then phosphorylates and activates extracellular signal-regulated kinase (ERK), allowing its translocation to the nucleus where it phosphorylates transcriptional factors permitting the expression of a variety of genes.

The RAS/RAF/MEK signal transduction pathway is deregulated, often through mutations that result in ectopic protein activation, in roughly 1/3 of human cancers. This deregulation in turn results in a wide array of cellular changes that are integral to the etiology and maintenance of a cancerous phenotype including, but not limited to, the promotion of proliferation and evasion of apoptosis (Dhillon et al., Oncogene, 2007, 26: 3279-3290).

Accordingly, the development of small molecule inhibitors of key members of the RAS/ RAF/ MEK signal transduction pathway has been the subject of intense effort within the pharmaceutical industry and oncology community.

MEK is a major protein in the RAS/ RAF/ MEK pathway, which signals toward cell proliferation and survival, and frequently activated in tumors that have mutations in the RAS or RAF oncogenes or in growth receptor tyrosine kinases. MEK is a key player in the RAS/RAF/MEK pathway as it is downstream of RAS and RAF. Despite being only rarely mutated in cancer (Murugan et al., Cell Cycle, 2009, 8: 2122-2124; Sasaki et al., J. Thorac. Oncol., 2010, 5: 597-600), inhibitors of the MEK1 and MEK2 proteins have also been targeted for small molecule inhibition owing to their central position within the RAS/ RAF/ MEK signal transduction pathway signaling cascade (Fremin and Meloche, J. Hematol.

Oncol., 2010, 3:8). Recently a potent MEK inhibitor failed to demonstrate efficacy in clinical trials in patients with advanced non-small cell lung cancer (Haura et al., Clin. Cancer Res., 2010, 16: 2450-2457). The reason for failure in this trial is not clear.

6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (hereinafter, “Compound A”) is a benzimidazole compound that is a known potent and selective inhibitor of the MEK1 and MEK2 proteins, and useful in the treatment of hyperproliferative diseases, particularly cancer, in mammals. For example, in a recently published Phase I study of 28 patients suffering from unresectable, locally advanced or metastatic biliary cancer and who had received < 1 prior systemic therapy, oral Compound A treatment (60 mg twice daily) resulted in 1 complete regression, 1 partial regression and 11 stable disease diagnoses after at least 6 weeks of treatment (Finn et al., J. Clin. Oncol. 30, 2012 (Supplement 4, 2012 Gastrointestinal Cancers Symposium, Abstract No. 220). Compound A has also been demonstrated to be effective in the treatment of patients with either BRAFV600 or NRAS-mutant melanoma (Ascierto et al., J. Clin. Oncol. 30, 2012 (Supplement, 2012 ASCO Annual Meeting, Abstract No. 8511).

The compound, as well as a process for its preparation, is disclosed in PCT Pub. No. WO 03/077914

MEK-162, a potent, orally active MEK1/2 inhibitor, is in phase III clinical trials at Array BioPharma and licensee Novartis for the treatment of metastatic or unresectable cutaneous melanoma with NRAS mutations and in combination with LGX-818 in adult patients with BRAF V600. Phase III studies are also under way at Array BioPharma for the treatment of low grade serous carcinomas of the ovary, fallopian tube or primary peritoneum following at least one prior platinum-based chemotherapy regimen and no more than three lines of prior chemotherapy regimens. Novartis and Array BioPharma are also conducting phase II clinical studies for the treatment of locally advanced and unresectable or metastatic malignant cutaneous melanoma, harboring BRAFV600E mutations; in BRAF mutated melanoma in combination with AMG-479 and for the treatment of Noonan’s syndrome, and in non-small cell lung cancer harboring KRAS or EGFR mutation and in combination with erlotinib. MEK-162 is being evaluated in phase I/II as first line treatment of advanced biliary tract carcinoma and for the treatment of adult patients with mutant or wild-type RAS metastatic colorectal cancer. The product is in early clinical trials at Array Biopharma for the treatment of biliary cancer.

According to Array, MEK-162 may also provide broad therapeutic benefits in the treatment of chronic degenerative diseases. However, a phase II trial for the treatment of stable rheumatoid arthritis (RA) did not meet its primary endpoint. Based on these data, the company focused development of MEK-162 solely in oncology.

In 2010, MEK-162 was licensed to Novartis by Array BioPharma for worldwide development. In 2013, orphan drug designation was assigned in Japan for the treatment of malignant melanoma with NRAS or BRAF V600 mutation.

WO-2014063024 DEALS WITH Preparation, crystalline forms, and formulations comprising binimetinib. Binimetinib is a MEK-1/2 inhibitor originally claimed in WO03077914, which Array and Novartis are developing for the treatment of cancer, including melanoma, low-grade serous ovarian cancer, and other solid tumors, as well as Noonan syndrome hypertrophic cardiomyopathy and hepatic impairment. See also WO2014018725 for the most recent filing on the agent

SYNTHESIS

PATENT

WO 03/077914

http://www.google.com/patents/WO2003077914A1?cl=en

Schemes 1-4.

Scheme 1

Scheme la

Scheme 2

Scheme 3

17 18

Scheme 4

25

Scheme 5

General synthetic methods which may be referred to for preparing some of the compounds of the present invention are provided in PCT published application number WO 00/42022 (published July 20, 2000). The foregoing patent application is incorporated herein by reference in its entirety.

 similar ie chloro instead of fluoro

Example 52

6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid (2-hydroxy-ethoxy)-amide (lOcc) Step A: 3-Chloro-2,4-difluoro-5-nitro-benzoic acid 2a

3-Chloro-2,4-difluoro-benzoic acid la (3.00 g, 15.6 mmol) is added to a stirred solution of concentrated H₂SO₄ (16 mL) and fuming nitric acid (0.85 mL, 20.3 mmol). After 3 hours a precipitate forms. The yellow slurry is poured onto ice water (100 mL). The aqueous mixture is extracted with diethyl ether (3x). The organic extracts are dried (Na₂SO₄) and concentrated under reduced pressure to give 3.50 g (95%) of clean desired product as a pale yellow solid.

Step B: 4-Amino-3-chloro-2-fluoro-5-nitro-benzoic acid 3a

Ammonium hydroxide solution (6.88 g, -30% in water, 58.9 mmol) is added to a solution of 3-chloro-2,4-difluoro-5-nitro-benzoic acid 2a (3.5 g, 14.7 mmol) in water (16 mL) at 0 °C with stirring. Upon completion of the ammonium hydroxide addition the reaction mixture is warmed to room temperature. After 5 hours the reaction mixture is cooled to 0 °C and concentrated HCl is carefully added until the pH of the reaction mixture is near zero. The solid is collected by filtration and washed with water and diethyl ether. The solids are transferred to a round bottom flask as a solution in MeOH and EtOAc and concentrated under reduced pressure to give 2.96 g of a yellow solid. The filtrate is partitioned between diethyl ether and water and the organic layer is washed with brine. The combined organic extracts are dried (Na₂SO ) and concentrated under reduced pressure to give 0.65 g of product. Recovered a total of 3.61 g (104%) of pure desired product, that is carried forward without further purification.

Step C: 4~Amino-3-chloro-2-fluoro-5-nitro-benzoic acid methyl ester 4a

To a stirred solution of 4-amino-3-chloro-2-fluoro-5-nitro-benzoic acid 3a (3.61 g, 15.4 mmol) in THF (30 mL) and MeOH (10 mL), TMS diazomethane (9.23 mL, 2.0 M solution in hexanes, 18.5 mmol) is added. After completion of reaction, the reaction mixture is concentrated via rotary evaporation with acetic acid in the trap. The recovered oily solid is triturated with diethyl ether to provide 1.51 g of a yellow solid. The filtrate is concentrated and triturated with diethyl ether to give an additional 0.69 g of yellow solid. A total of 2.20 g (57%) of pure desired product is recovered.

Step D: 4-Amino-3-chloro-5-nitro-2-phenylamino-benzoic acid methyl ester 5c

4-Amino-3-chloro-2-fluoro-5-nitro-benzoic acid methyl ester 4a (2.20 g, 8.84 mmol) is suspended in MeOH (9.4 mL) and aniline (3.22 mL, 35.4 mmol) is added. The reaction mixture is heated to reflux with stirring under a nitrogen atmosphere. After 19 hours, the reaction is complete. Distilled water (3.22 mL) is added to the reaction mixture and refluxing is continued for one hour. The reaction mixture is cooled to 0 °C in an ice bath for 20 minutes. The reaction mixture is filtered and washed with 3:10 distilled water/MeOH (65 mL total) and then with MeOH. The solid is dissolved with CH₂C1₂ and concentrated under reduced pressure to give 2.40 g (84%) of pure desired product. MS APCI (-) m/z 320.3 (M-l) detected.

Step E: 4, 5-Diamino-3-chloro-2-phenylamino-benzoic acid methyl ester 6b

4-Amino-3-chloro-5-nitro-2-phenylamino-benzoic acid methyl ester 5c (0.50 g, 1.55 mmol) is dissolved into 2:1 EtOH/MeOH (15.5 mL). Saturated aqueous NH₄C1 (15 mL), Zn powder (1.02 g, 15.6 mmol), and THF (10 mL) are added. After stirring for 20 hours, the reaction mixture is diluted with CH C1₂/THF and water. The organic layer is washed with water (3x). The combined organic extracts are dried (Na₂SO₄) and concentrated under reduced pressure. The solids are triturated with ether to give 0.32 g (70%) clean desired product. Step F: 7-Chloro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester 7c

4,5-Diamino-3-chloro-2-phenylamino-benzoic acid methyl ester 6b (0.32 g, 1.09 mmol) and formamidine acetate (72 mg, 1.64 mmol) in EtOH (36 mL) are heated, with stirring, to 80 °C. After 44 hours, the reaction mixture is cooled to room temperature and diluted with EtOAc and washed with water (3x), saturated NaHCO₃, and brine. The combined organic extracts are dried (Na₂SO₄) and concentrated under reduced pressure to give 0.33 g (99%) clean desired product as a solid. MS APCI (+) m/z 302.3 (M+l) detected.

Step G: 6-(4-Bromo-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylic acid methyl ester 8g

7-Chloro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester 7c (0.327 g, 1.08 mmol) is dissolved into DMF (16 mL) and NBS (0.193 g, 1.08 mmol) is added. After one hour, the reaction mixture is quenched by the addition of saturated aqueous NaHSO₃. The reaction mixture is then partitioned between EtOAc/THF and water. The organic layer is washed with water and brine. The combined organic extracts are dried (Na₂SO ) and concentrated under reduced pressure. The recovered solid is triturated with ether to give 0.225 g (54%) pure desired product. MS ESI (+) m/z 382, 384 (M+, Br pattern) detected.

Step H: 6-(4-Bromo-2-chloro-phenylamino)- 7 -chloro-3H-benzoimidazole-5 -carboxylic acid methyl ester lOdd 6-(4-Bromo-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylic acid methyl ester 8g (0.225 g, 0.591 mmol) is dissolved in DMF (2 mL) and NCS (79 mg, 0.591 mmol) is added. After the NCS is in solution concentrated HCl (0.005 mL, 0.059 mmol) is added. After 2 hours, sodium bicarbonate, water and NaHSO₃ are added to the reaction mixture. Solids are filtered and washed with water and ether to give 0.141 g (57%) of clean desired product as a tan solid. MS APCI (-) m/z 414, 416 (M-, Br pattern) detected.

Step I: 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid methyl ester lOee

6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylic acid methyl ester lOdd (0.141 g, 0.34 mmol), potassium carbonate (0.141 g, 1.02 mmol), and iodomethane (0.063 mL, 1.02 mmol) are dissolved in dimethylformamide (3 mL). After 20 hours, the reaction mixture is diluted with EtOAc and washed with water (3x), potassium carbonate, and brine. The organic layer is dried (Na₂SO₄) and concentrated to a brown oil. The N3 and Nl alkylated regioisomers are separated by flash chromatography (EtOAc). The recovery of the N3 alkylated regioisomer is 20.4 mg (28%). MS ESI (+) m/z 428, 430 (M+, Br pattern) detected.

Step J: 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid 10 ff

6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid methyl ester lOee (21 mg, 0.048 mmol) is dissolved into 2:1 THF/water (1.2 mL) and NaOH (0.190 mL, 1.0 M aqueous solution, 0.190 mmol) is added. After stirring for 4 hours the reaction is diluted with water and acidified to pH 2 by addition of 1.0 M HCl. The mixture is then extracted with 3:1 EtOAc/THF (3x), dried (Na₂SO ) and concentrated to give quantitative yield of desired prodcut as a white solid. MS APCI (+) m/z 414, 416 (M+, Br pattern) detected.

Step K: 6-(4-Bromo-2’chloro-phenylamino)- 7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid (2-vinyloxy-ethoxy) -amide lOgg

6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid lOff (32 mg, 0.077 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (0.010 mL, 0.092 mmol), HOBt (13 mg, 0.093 mmol), triethylamine (0.011 mL, 0.077 mmol), and EDCI (19 mg, 0.10 mmol) are dissolved into dimethylformamide (1.0 mL) and allowed to stir under a nitrogen atmosphere at room temperature for 24 hours. The reaction mixture is diluted with EtOAc, washed with water (3x), 10% potassium carbonate (2x), saturated ammonium chloride, brine, dried (Na₂SO₄), and concentrated under reduced pressure to give 39 mg of 85% pure material. MS APCI (-) m/z 497, 501 (M-, Br pattern) detected.

Step L: 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid (2-hydroxy-ethoxy)-amide lOcc

Hydrochloric acid (0.78 mL, 1.0 M aqueous solution, 0.78 mmol) is added to a suspension of 6-(4-bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H- benzoimidazole-5-carboxylic acid lOgg (2-vinyloxy-ethoxy)-amide (39 mg, 0.078 mmol) in MeOH (1 mL). After one hour, the reaction mixture is neutralized to pH 7 and concentrated under reduced pressure. The solids are dissolved in EtOAc, washed with brine, dried (Na SO₄), and concentrated under reduced pressure. Flash chromatography (20:1 CH₂Cl₂/MeOH) provides 9 mg (23%) of pure product: MS APCI (+) m/z 473, 475 (M+, Br pattern) detected; 1H NMR (400 MHz, CDC1₃) δ 8.30 (s, IH), 8.08 (s, IH), 7.57

(d, IH), 7.15 (dd, IH), 6.21 (d, IH), 3.97 (s, 3H) 3.86 (m, 2H), 3.57 (m, 2H).

actual is below

Example 18

The following compounds are prepared by methods similar to those described in

Example 10 by using methyl ester 8d and the appropriate alkylating agent (Step A) and

the appropriate hydroxylamine (Step C):

PATENT

WO2014063024

http://patentscope.wipo.int/search/en/detail.jsf;jsessionid=E10680BCA177F821C7FEFA1AFC44A438.wapp2nA?docId=WO2014063024&recNum=6&maxRec=53841&office=&prevFilter=%26fq%3DICF_M%3A%22C07D%22&sortOption=Pub+Date+Desc&queryString=&tab=PCTDescription

COMPD A

Example 1. Preparation of 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-

In an inertized (N₂) reaction vessel at internal temperature 20°C and under exclusion of humidity and air, Compound 1 (1.0 eq.) and Compound 2 (1.2 eq.) are reacted in the presence of cesium carbonate (2.4 eq.), tris(dibenzylidenaceton) dipalladium(O) (0.035 eq.) and Xantphos (0.07 eq.) in a mixture of toluene and 1 ,4-dioxane at internal temperature of 99°C. After 8 hours, the mixture is cooled to internal temperature of 60°C.

Subsequently, dimethylformamide (DMF), filter aid (CEFOK) and activated charcoal (EKNS) are added, and the mixture is stirred and cooled to internal temperature of 35 °C. The solids are filtered off and washed with a mixture of dimethylformamide and toluene. To the filtrate, which contains the product Compound 3, is introduced at internal temperature of

25 °C hydrogen chloride gas (CLC) whereupon the HQ salt of Compound 3 crystallizes. The palladium residue mainly remains in solution. After warming to 60 °C and cooling to 0°C, the solids are filtered using a centrifuge and are washed with a mixture of toluene and dimethylformamide.

The damp Compound 3 HC1 salt is charged to a reactor (equipped with pH probe) together with dimethylformamide and is heated to 60°C. By adding a 4 wt% of aqueous tripotassium phosphate solution, the pH is adjusted to a pH range of 6.8-7.6 (with a target of pH 7.2) while Compound 3 crystallizes as free base. After cooling to 22°C and stirring, the solids are filtered using a centrifuge and are washed with drinking water. The moist solids are dried at 50 °C under vacuum to give dry, crude Compound 3.

In order to remove residual palladium, dry, crude Compound 3 is dissolved in dimethylformamide at internal temperature of 60°C and stirred together with Smopex-234 (commercially available from Johnson Matthey) and activated charcoal for 90 minutes. The solids are filtered off at internal temperature of 60°C and are washed with

dimethylformamide. To the filtrate are added drinking water and Compound 3 seed crystals. More drinking water is added while Compound 3 crystallizes. After cooling to internal temperature of 20 °C, the solids are filtered using a centrifuge and are washed with a mixture of deionized water and dimethylformamide and with deionized water. The moist solids are dried at 50°C under vacuum, providing 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (Compound 3).

Example 2. Preparation of 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide

A. “One-pot” Synthesis

In an inertized reaction vessel at internal temperature 20-25 °C under nitrogen, 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (Compound 3, 1.0 eq.) is added to a mixture of DMF and THF. To this slurry, a solution of potassium trimethylsilanolate (1.05 eq.) in THF is added to the mixture at internal temperature of 25 °C over a period of about 40 minutes, and the resulting mixture is stirred for about 1 hour, providing a potassium salt solution of Intermediate 1. A THF/methanol mixture is then sequentially distilled off from the mixture at 85-120°C during about 2 hours.

The potassium salt solution is then added to a suspension of CDI (1.25 eq.) and imidazole hydrochloride (1.40 eq.) in THF at internal temperature of 25 °C over a period of about 1 hour. The resulting mixture is then stirred for approximately 1 hour at 50°C, and the following imidazolide intermediate

The imidazolide intermediate is not further isolated.

Subsequently, 1.2 eq. of 0-(2-tert-butoxyethyl)hydroxylamine (Compound 4, CAS No. 1023742-13-3, available from suppliers such as Huhu Technology, Inc.®) is added over a period of about 30 minutes at 50°C and stirred for 1.5 hours. Demineralized water is then added at 50°C, producing a precipitate. After cooling to 20°C and stirring for about 3-16 hours, the slurry is filtered off, washed with THF/ demineralized water (1 :2) in 2 portions and with demineralized water in three portions, and dried at 50°C / <70 mbar for about 17 hours, providing 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) as monohydrate.

B. A synthesis method with isolation of the intermediate of step a) from the reaction mixture of step a) prior to the reaction of step b)

Alternatively, 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5 -carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) can be made by the synthesis method as shown below. Compound 3, which is a methyl ester, is first converted to a carboxylic acid, which is then isolated by a crystallization to form Compound

6. Compound 6 is then coupled with Compound 4 to form Compound 5 as monohydrate.

The crystallization step in this method removes starting materials such as Compound 1, process impurities, and the dba ligand from the prior catalyst before the coupling reaction with Compound 4, and at the same time maintains the overall yield of the synthesis.

6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-memy acid In an inertized (N₂) reaction vessel at internal temperature of 60°C, Compound 3 (1.0 eq.) is dissolved in DMF and stirred with a fiber, which is sold under the trademark

SMOPEX 234, and activated charcoal for the removal of palladium to not more than 100 ppm. The fiber and activated charcoal are removed by filtration at 60°C and washed with DMF.

The filtrate (containing Compound 3) is transferred to a second inertized (N₂) reaction vessel and cooled to an internal temperature of 30°C. A thin suspension can form at this point of time. 30% sodium hydroxide (1.1 eq.) and water (for rinsing) are added, and the resulting reaction mixture is vigorously stirred for 3 hours at an internal temperature of 30 °C. The methyl ester is saponified. Conversion is checked by an IPC (HPLC). As soon as the IPC criterion is met, a filter aid, which is sold under the trademark HYFLO, is added. The mixture is stirred for 15 minutes and then filtered at 30°C via a plate filter and polish filter to a third reaction inertized (N₂) vessel.

An aqueous HC1 solution 7.5 % is added to the clear filtrate in the third vessel at an internal temperature of 30 °C until a pH value of 8 is reached. Then the solution is seeded at an internal temperature of 30°C with Compound 6, and an aqueous HC1 solution 7.5 % is added under vigorous stirring until a pH value of pH 2.8 is reached. The product gradually crystalizes. The suspension is cooled over 60 min to an internal temperature of 25 °C and

water is added. The suspension is stirred for at least 4 hours at an internal temperature of 25°C.

The resulting solid is collected by centrifugation or filtration. The filter cake is first washed with DMF/water 1 :1 (w/w) and then with water, discharged and dried in a vacuum at 50°C. The water content is controlled by IPC. The crystalline product Compound 6 is discharged as soon as the IPC criterion is met.

6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid- (2-tert-butoxyethoxy) – amide

An inertized (N₂) reaction vessel is charged with Compound 6 (1.0 eq.), DMF, and

THF at room temperature. The suspension is heated to 25 °C under stirring with flow of nitrogen. After CDI (1.13 eq.) is added, the suspension can get thinner and slight evolution of gases can be observed. After the suspension finally becomes a solution, it is then monitored by IPC (HPLC).

As soon as the IPC (HPLC) criterion is met, the reaction mixture is heated to 50°C over 20 minutes and imidazole hydrochloride (0.3 eq.) is added, forming a solution of

Intermediate 2.

To the solution of Intermediate 2, Compound 4 (1.3 eq.) is added over 60 minutes at internal temperature of 50°C under stirring at a speed of 300 rpm with flow of nitrogen. As soon as the IPC (HPLC) criterion is met, the mixture is cooled to 20-25 °C over 30 minutes. The mixture is then stored at ambient temperature overnight under nitrogen without stirring. DMF is added to the mixture followed by heating it to 50 °C over 30 minutes. Complete conversion of Intermediate 2 to Compound 5 is confirmed by IPC (HPLC).

Water is added to the mixture at internal temperature of 50 °C over 20 minutes. Then the solution is seeded with Compound 5. After stirring at 50 °C for 60 minutes, more water is added to the suspension at 50 °C over 90 minutes. After vigorous stirring, the suspension is cooled to 20 °C over 2 hours and filtered. The filter cake is washed twice with THF/water (v/v: 1 :2) at 20 °C, and twice with water at 20 °C. Finally, the filter cake is dried at 50 °C under vacuum to provide 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) as monohydrate.

Example 3. Preparation of 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (Compound A)

Compound 5 Compound A

6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) monohydrate is added in 3 portions to a premixed solution of Acetonitrile and excess Phosphoric acid (85 % aqueous solution) at internal temperature 20-25 °C. After stirring for about 15 minutes, the suspension is heated to internal temperature 50-53 °C. The suspension is maintained at this temperature for 6 hours, cooled to internal temperature 20-25 °C. The mixture is then heated to internal temperature 35-37°C and diluted with Ethanol- Water (3 :1 v/v). EKNS and CEFOK are added, the reaction mixture is stirred approximately 15 minutes and filtered over a funnel coated with CEFOK. The filtrate is cooled to approximately 30°C. 3 N aqueous potassium hydroxide (ΚΟΗ) is added to the cooled filtrate over a period of 90 minutes until a pH- value of about 8.1 is reached. The suspension is heated to internal temperature 60-63 °C, stirred at this temperature for a period of about 2 hours, cooled to 20-23 °C over a period of about 45 minutes, filtered over a funnel, and dried at 50°C pressure <100 mbar over a period of about 17 hours, providing 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (Compound A) as a white powder.

Example 4. Preparation of Crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (Compound A) In a dry vessel at room temperature, Compound A is added to a premixed solvent solution of methanol/THF/water (35/35/30 w/w). The suspension is heated to internal temperature 53-55°C, and the resulting solution is hot filtered by deep and membrane filtration (via a paper filter and PTFE membrane) at internal temperature 53-56°C. The clear solution is stirred and cooled to 47-48°C, and the seed crystals suspension (i.e., seed crystals of crystallized Compound A in water, 10% m/m) is added (0.2 to 0.5% of crystallized Compound A expected yield mass). After about 20 minutes, water is slowly added within 25 hours (33.3% within 15 hours and 66.6% within 10 hours with at least 10 minute stirring after addition of water) to obtain a final ratio of methanol THF/water (20/20/60 w/w). After the water is added, the suspension is cooled down to internal temperature 3-5 °C within 10 hours and stirred for 0.5 hours. The white suspension is filtered over a sinter glass nutsche (75 ml, diameter = 6 cm, pore 3) suction filter and washed once with ice cold methanol/THF/water (15/15/70 w/w at 2-4 °C), and two times with ice cold water (2-4 °C). Drying takes place in a vacuum oven dryer at 20°C for 10 hours, and then at 40°C for 10 hours, and then at 60°C for at least 12 hours with pressure < lOmbar, providing crystallized Compound A.

CLIP

http://blog.sina.com.cn/s/blog_de171b9b0101dvov.html

CLIP

https://www.pharmacodia.com/yaodu/html/v1/chemicals/675f9820626f5bc0afb47b57890b466e.html

References

Binimetinib

Clinical data
ATC code	L01XE41 (WHO)
Legal status
Legal status	Investigational
Identifiers
IUPAC name[show]
CAS Number	606143-89-9
PubChem CID	10288191
DrugBank	DB11967
ChemSpider	8463660
KEGG	D10604
ChEMBL	CHEMBL3187723
Chemical and physical data
Formula	C17H15BrF2N4O3
Molar mass	441.23 g/mol
3D model (JSmol)	Interactive image

1. Koelblinger P, Dornbierer J, Dummer R: A review of binimetinib for the treatment of mutant cutaneous melanoma. Future Oncol. 2017 Aug;13(20):1755-1766. doi: 10.2217/fon-2017-0170. Epub 2017 Jun 7. [PubMed:28587477]
2. Queirolo P, Spagnolo F: Binimetinib for the treatment of NRAS-mutant melanoma. Expert Rev Anticancer Ther. 2017 Nov;17(11):985-990. doi: 10.1080/14737140.2017.1374177. Epub 2017 Sep 8. [PubMed:28851243]
3. Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, Rutkowski P, Del Vecchio M, Gutzmer R, Mandala M, Thomas L, Demidov L, Garbe C, Hogg D, Liszkay G, Queirolo P, Wasserman E, Ford J, Weill M, Sirulnik LA, Jehl V, Bozon V, Long GV, Flaherty K: Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):435-445. doi: 10.1016/S1470-2045(17)30180-8. Epub 2017 Mar 9. [PubMed:28284557]
4. Bendell JC, Javle M, Bekaii-Saab TS, Finn RS, Wainberg ZA, Laheru DA, Weekes CD, Tan BR, Khan GN, Zalupski MM, Infante JR, Jones S, Papadopoulos KP, Tolcher AW, Chavira RE, Christy-Bittel JL, Barrett E, Patnaik A: A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. Br J Cancer. 2017 Feb 28;116(5):575-583. doi: 10.1038/bjc.2017.10. Epub 2017 Feb 2. [PubMed:28152546]
5. Gardner AM, Vaillancourt RR, Lange-Carter CA, Johnson GL: MEK-1 phosphorylation by MEK kinase, Raf, and mitogen-activated protein kinase: analysis of phosphopeptides and regulation of activity. Mol Biol Cell. 1994 Feb;5(2):193-201. [PubMed:8019005]
6. Wang ZQ, Wu DC, Huang FP, Yang GY: Inhibition of MEK/ERK 1/2 pathway reduces pro-inflammatory cytokine interleukin-1 expression in focal cerebral ischemia. Brain Res. 2004 Jan 16;996(1):55-66. [PubMed:14670631]
7. Cancer.gov link [Link]
8. FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations [Link]
9. A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor [Link]
10. Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression [Link]
11. Binimetinib [File]
12. EMA assessment [File]

/////////////BINIMETINIB, FDA 2018, MEK-162, биниметиниб , بينيميتينيب , 美替尼 , ビニメチニブ , 606143-89-9 , 9764, ARRY-162, ARRY-438162, NVP-MEK162

CN1C=NC2=C(F)C(NC3=CC=C(Br)C=C3F)=C(C=C12)C(=O)NOCCO

https://cen.acs.org/articles/95/i23/Array-licenses-cancer-compounds-Ono.html

Array BioPharma has licensed Japan’s Ono Pharmaceutical the right to develop two late-stage oncology compounds, binimetinib and encorafenib, in Japan and South Korea. Array will get $32 million up front and up to $156 million in milestone payments. The compounds are in Phase III studies of patients with BRAF-mutant cancers. Array recently struck a deal to assess binimetinib with two Bristol-Myers Squibb immuno-oncology agents.