Canlitinib

Cas 2222730-78-9

• Kanitinib
• PFR26A3AWM
• GTPL12865
• CX1003
• CX-1003

6-[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxyquinolin-7-yl]oxyhexanoic acid

CANLITINIB is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.

Canlitinib is a tyrosine kinase inhibitor, extracted from patent WO2018072614 (IV-2). Canlitinib has the potential for cancer study.

Kanitinib is a tyrosine kinase inhibitor targeting the oncoprotein c-Met (hepatocyte growth factor receptor; HGFR; MET) and vascular endothelial growth factor receptor 2 (VEGFR2), with potential anti-angiogenic and antineoplastic activities. Upon oral administration, kanitinib targets and binds to c-Met and VEGFR2, thereby disrupting c-Met- and VEGFR2-dependent signal transduction pathways. This may induce cell death in tumor cells overexpressing c-Met and/or VEGFR2 protein. c-Met and VEGFR2 are both overexpressed in many tumor cell types and play key roles in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis

SCHEME

INT

PATENT

WO2020216188

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020216188&_cid=P20-MA3XXD-35471-1

Example 1 

[0064]The preparation method of compound 1 is shown in Example 9 of compound patent WO 2018/072614 A1. Specifically, the preparation method of compound 1 is as follows. 

[0065]

[0066]Under stirring, NaOH (4.4 g, 110 mmol) was added dropwise to a solution of methyl 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoate (IV-1, 35.0 g, 55.2 mmol, prepared according to the method described in WO2013/040801A1) in ethanol (350 mL). After the addition was complete, water (50 mL) was added. The resulting mixture was stirred at 20-25°C for 18 h, the reaction solution was diluted with water (100 mL), stirred for 20 min, and the pH was adjusted to 3-4 with 1N HCl. The reaction mixture was concentrated under reduced pressure to distill off about 300 mL of ethanol. The solid product was collected by filtration to give 28.4 g of crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate:methanol = 1:1, v/v) to give 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoic acid (Compound 1), 9.6 g (yield: 28.1%). 

[0067]Analytical data of compound 1: molecular weight 619.61; NMR hydrogen spectrum is shown in Figure 1, and NMR hydrogen spectrum data are as follows: 

[0068]

¹H-NMR(δ,DMSO-d6,400MHz):12.03(s,1H,OH),10.40(s,1H,NH),10.02(s,1H,NH),8.47～8.46(d,J＝4,1H,CH),7.89-7.92(d,J＝12,1H,CH),7.63-7.67(d,J＝16,2H,2CH),7.51-7.52(d,J＝4,2H2CH),7.39-7.43(t,2H,2CH),7.13-7.17(t,2H,2CH),6.41-6.42(d,J＝4,1H,CH),4.12-4.15(t,2H,CH ₂),3.95(s,3H,CH ₃),2.24-2.28(t,2H,CH ₂),1.78-1.85(m,2H,CH ₂),1.57-1.64(m,2H,CH ₂),1.43-1.51(m,6H,3CH ₂)。

PATENT

CN111825609 

PATENT

WO2018072614

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018072614&_cid=P20-MA3XZQ-37082-1

Example 9 

[0438]Preparation of 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoic acid (IV-2), the reaction formula is as follows: 

[0439]

[0440]Under stirring, NaOH (4.4 g, 110 mmol) was added dropwise to a solution of methyl 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoate (IV-1, 35.0 g, 55.2 mmol, prepared according to the method described in WO2013/040801A1) in ethanol (350 mL). After the addition was complete, water (50 mL) was added. The resulting mixture was stirred at 20-25°C for 18 h, the reaction solution was diluted with water (100 mL), stirred for 20 min, and the pH was adjusted to 3-4 with 1N HCl. The reaction mixture was concentrated under reduced pressure to distill off about 300 mL of ethanol. The solid product was collected by filtration to give 28.4 g of crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate:methanol = 1:1, v/v) to give 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoic acid (IV-2), 9.6 g (yield: 28.1%). Analytical data: 

¹ H-NMR (400 MHz, DMSO-d 

₆ ): δ=8.17 (d, J=8.0 Hz, 1H), 7.81 (dd, J=2.8, 13.4 Hz, 1H) 7.62 (m, 2H), 7.51 (m, 4H), 7.39 (t, J=2.4 Hz, 2H), 6.44 (d, J=20.0 Hz, 1H), 4.13 (t, J=8.5 Hz, 2H), 3.85 (s, 3H), 2.27 (t, J=4.0 Hz, 2H), 1.83 (m, 2H), 1.68-1.46 (m, 8H). Mass spectrum (ESI) m/z: 620.2 [M+H] 

⁺ .

PATENT

WO2013/040801

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013040801&_cid=P20-MA3Y3E-39505-1

[1]. Zhang, Zhiqiang, et al. Quinolinyl-substituted carboxylic acid compound or pharmaceutically acceptable salt thereof, pharmaceutical composition thereof, and use thereof. WO2017-CN104518

////////Canlitinib, GTPL12865, CX1003, CX-1003