尼达尼布 ニンテダニブ NINTEDANIB

NINTEDANIB, BBIF 1120, Intedanib
Boehringer Ingelheim Corp

As a potential treatment for a range of different solid tumour types

CAS 656247-17-5

1377321-64-6 (nintedanib bisethanesulfonate)

3(Z)-[1-[4-[N-Methyl-N-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenylamino]-1-phenylmethylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester

launched 2014….Idiopathic pulmonary fibrosis
尼达尼布    ニンテダニブ

NMR, HPLC, MS http://www.medkoo.com/uploads/product/Nintedanib/qc/QC-Nintedanib-TZC50128Web.pdf
http://file.selleckchem.com/downloads/nmr/S101002-BIBF1120-NMR-Selleck.pdf
http://jocpr.com/vol7-iss8-2015/JCPR-2015-7-8-774-782.pdf

Synthesis
http://newdrugapprovals.org/2014/12/10/%E5%B0%BC%E8%BE%BE%E5%B0%BC%E5%B8%83-%E3%83%8B%E3%83%B3%E3%83%86%E3%83%80%E3%83%8B%E3%83%96-nintedanib-for-idiopathic-pulmonary-fibrosis/

http://newdrugapprovals.org/

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO

COSY PREDICT

 1H NMR PREDICT

 13C NMR PREDICT

Nintedanib (formerly BIBF 1120) is a small molecule tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR) being developed by Boehringer Ingelheim as an anti-angiogenesis anti-cancer agent under the trade name Vargatef, and recently approved for treatment of idiopathic pulmonary fibrosis as Ofev

see

http://www.google.com/patents/US20110201812


EXAMPLE 7Synthesis of the “anilino” (3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone)

Method 1
A suspension of methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (10.0 g; 0.032 mol) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (8.6 g; 0.032 mol) in a mixture of methanol (72 ml) and N,N-dimethylformamide (18 ml) is heated to reflux. After 7 h of refluxing the suspension is cooled down to 0° C. and stirring is maintained for additional 2 h. The solid is filtered, washed with methanol (40 ml) and dried to afford 15.4 g (88.1%) of the “anilino” compound as yellow crystals.

¹H-NMR (500 MHz, DMSO-d₆) δ: 11.00 (s, 1H, 23-H); 12.23 (s, 19-H); 7.61 (t; J=7.1 Hz, 1H, 33-H); 7.57 (t, J=7.5 Hz, 2H, 32-H+34-H); 7.50 (d, J=7.7 Hz, 2H, 31-H+35-H); 7.43 (d, J=1.6 Hz, 1H, 29-H); 7.20 (dd, J=8.3; 1.6 Hz, 1H, 27-H); 7.13 (d, J=8.3 Hz, 2H, 14-H+18-H); 6.89 (d, 8.3 Hz, 2H, 15-H+17-H); 5.84 (d, J=8.3 Hz, 1H, 26-H); 3.77 (s, 3H, 40-H₃); 3.06 (m, 3H, 12-H₃); 2.70 (m, 2 H, 8-H₂); 2.19 (m, 8H, 2-H₂, 3-H₂, 5-H₂, 6-H₂); 2.11 (s, 3H, 7-H₃).


¹³C-NMR (126 MHz, DMSO-d₆) δ: 54.5 (C-2+C-6); 52.2 (C-3+C-5); 45.6 (C-7); 59.1 (C-8); 168.5 (C-9); 36.6 (C-12); 140.1 (C-13); 127.6 (C-14+C-18); 123.8 (C-17+C-15); 137.0 (C-16); 158.3 (C-20); 97.5 (C-21); 170.1 (C-22); 136.2 (C-24); 128.9 (C-25); 117.2 (C-26); 121.4 (C-27); 124.0 (C-28); 109.4 (C-29); 131.9 (C-30); 128.4 (C-31+C-35); 129.4 (C-32+C-34); 130.4 (C-33); 166.3 (C-37); 51.7 (C-40).

MS (m/z): 540 (M+H)⁺.

Anal. calcd. for C₃₁H₃₃N₅O₄: C, 69.00; H, 6.16; N, 12.98. Found: C, 68.05; H, 6.21; N, 12.81.
Method 2
A suspension of methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (20.0 g; 0.064 mol) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (17.1 g; 0.065 mol) in methanol (180 ml) is heated to reflux for 7.5 h. The resulting suspension is cooled down to 10° C. within 1 h and stirring is maintained for 1 h. After filtration, the solid is washed with ice cold methanol (80 ml) and dried to afford 31.0 g (89.0%) of the “anilino” compound as yellow crystals.


EXAMPLE 8
Synthesis of the 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, monoethanesulfonate

A suspension of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone (30.0 g; 0.055 mol) in methanol (200 ml) and water (2.4 ml) is heated to 60° C. Aqueous ethanesulfonic acid (70% (w/w); 8.75 g; 0.056 mol) is added to the reaction mixture. The resulting solution is cooled to 50° C., seeded and then diluted with isopropanol (200 ml). The mixture is further cooled to 0° C. and stirred for 2 h at this temperature. The precipitate is isolated, washed with isopropanol (120 ml) and dried to furnish 35.1 g (97.3%) of the monoethanesulfonate salt of the compound as yellow crystals.


 ¹H-NMR (400 MHz, DMSO-d₆) δ: 12.26 (s, 11-H); 10.79 (s, 1H, 1-H); 9.44 (s, 1H, 24-H); 7.64 (m, 1H, 32-H); 7.59 (m, 2H, 31-H+33-H); 7.52 (m, 2H, 30-H+34-H); 7.45 (d, J=1.6 Hz, 1H, 7-H); 7.20 (dd, J=8.2; 1.6 Hz, 1H, 5-H); 7.16 (m, 2H, 14-H+16-H); 6.90 (m, 2H, 13-H+17-H); 5.85 (d, J=8.2 Hz, 1H, 4-H); 3.78 (s, 3H, 37-H₃); 3.45-2.80 (broad m, 4H, 23-H₂+25-H₂); 3.08 (s, 3H, 28-H₃); 2.88 (s, 2H, 20-H₂); 2.85-2.30 (broad m, 4H, 22-H₂+26-H₂); 2.75 (s, 3H, 27-H₃); 2.44 (q, J=7.4 Hz, 2H, 39-H₂); 1.09 (t, J=7.4 Hz, 3H, 38-H₃).


¹³C-NMR (126 MHz, DMSO-d₆) δ: 9.8 (C-38); 36.6 (C-28); 42.3 (C-27); 45.1 (C-39); 51.7 (C-37); 48.9 (C-22+C-26); 52.6 (C-23+C-25); 57.5 (C-20); 97.7 (C-3); 109.5 (C-7); 117.3 (C-4); 121.4 (C-5); 123.8 (C-13+C-17); 124.1 (C-6); 127.7 (C-14+C-16); 128.4 (C-30+C-34); 128.8 (C-9); 129.5 (C-31+C-33); 130.5 (C-32); 132.0 (C-29); 168.5 (C-9); 136.3 (C-8); 137.3 (C-12); 139.5 (C-15); 158.1 (C-10); 166.3 (C-35); 168.0 (C-19); 170.1 (C-2).


MS (m/z): 540 (M_(base)+H)⁺.


Anal. calcd. for C₃₃H₃₉N₅O₇S: C, 60.17; H, 6.12; N, 10.63; S, 4.87. Found: C, 60.40; H, 6.15; N, 10.70; S, 4.84.

http://newdrugapprovals.org/

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO

see

http://newdrugapprovals.org/2014/12/10/%E5%B0%BC%E8%BE%BE%E5%B0%BC%E5%B8%83-%E3%83%8B%E3%83%B3%E3%83%86%E3%83%80%E3%83%8B%E3%83%96-nintedanib-for-idiopathic-pulmonary-fibrosis/




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 CN1CCN(CC1)CC(=O)N(C)C2=CC=C(C=C2)N/C(=C\3/C4=C(C=C(C=C4)C(=O)OC)NC3=O)/C5=CC=CC=C5