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Indolone compounds or derivatives thereof and applications thereof

A technology of indolinone and compounds, applied in organic chemistry, drug combinations, medical preparations containing active ingredients, etc., can solve the problem of half-life of drugs that affect the efficacy of drugs, no indolinone compounds, reduction of single administration dose, etc. Problems, to achieve the effect of prolonging the half-life of anti-cancer, prolonging the efficacy and long action time

Active Publication Date: 2014-08-27
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] 4) The deuterium-enriched drug may reduce the single administration dose compared with the parent;
[0014] Although deuterated compounds have the above advantages, not all deuterated compounds have better effects than the original compounds, and the difference in deuterated position directly affects the efficacy of the drug and the half-life of the drug
So far, there is no report on the deuteration of the indolinone compound Nintedanib

Method used

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  • Indolone compounds or derivatives thereof and applications thereof
  • Indolone compounds or derivatives thereof and applications thereof
  • Indolone compounds or derivatives thereof and applications thereof

Examples

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preparation example Construction

[0084] The preparation method of indolinone compound of the present invention, comprises the steps:

[0085] The synthetic route of compound shown in general formula (a) is as follows:

[0086]

[0087] The deuterated methanol suspensions of compound 9 and compound 15 were heated to reflux for 6-10 h, cooled, continuously stirred, suction filtered, washed with methanol, and dried to obtain the product, namely the compound with the structure shown in general formula (a).

[0088] Further, the preferred synthetic route of compound 9 is as follows:

[0089]

[0090] Dissolve CH in KOH 3 The OH solution was added to the deuterated methanol suspension of compound 8, and the reaction system was continuously stirred for 15-45 min, cooled, continued to stir for 1-3 h, filtered with suction, washed with methanol, and dried to obtain compound 9.

[0091] Further, it is preferred that the synthesis of compound 8 comprises the following steps:

[0092] The synthetic route of the ...

Embodiment 1

[0125] Example 1 Compound A: (Z)-3-((4-(N-methyl-2-(4-methylpiperazine-1-substituted)acetamido)anilino)(phenyl)methylene)-2- Preparation of Trideuteromethyl Indolinone-6-carboxylate

[0126] The synthetic route of compound 9-1 is as follows:

[0127]

[0128] Compound 2-1: Preparation of trideuteromethyl m-nitrobenzoate

[0129] 2.0g m-nitrobenzoic acid (1-1) was added to 10mLCD 3 OD, where, CD 3 OD commercially available, add 80mg of 98wt% concentrated sulfuric acid, microwave reaction at 100°C for 10 minutes, add 100mL CH 2 Cl 2 Extraction, successively with saturated NaHCO 3 Washed with saturated brine, anhydrous Na 2 SO 4 Drying, suction filtration, and spin-drying gave 1.95 g of the product compound trideuteriomethyl m-nitrobenzoate (2-1) with a yield of 88.5%.

[0130] 1 HNMR (CDCl 3 ,400MHz); 8.86(s,1H); 8.40(m,2H); 7.68(t,1H); HRMS: 184.0560.

[0131] Compound 4-1: Preparation of 4-(2-trideuteromethoxy-2-acetyl)-3-benzoic acid trideuteromethyl ester

...

Embodiment 2

[0161] Example 2 Compound B: (Z)-3-((4-(N-methyl-2-(4-trideuteromethylpiperazine-1-substituted)acetamido)anilino)(phenyl)methylene)- Preparation of 2-indolinone-6-carboxylic acid methyl ester

[0162] The synthetic route of compound 9-2 is as follows:

[0163]

[0164] Compound 2-2: Preparation of m-nitrobenzoic acid methyl ester

[0165] Add 2.0g of m-nitrobenzoic acid (1-1) to 10mL of methanol, add 80mg of 98wt% concentrated sulfuric acid, react with microwave at 100°C for 10 minutes, add 100mL of CH 2 Cl 2 Extraction, sequentially with saturated NaHCO 3 Washed with saturated brine, anhydrous Na 2 SO 4 Dry, filter with suction, and spin dry to obtain 1.95 g of the product compound methyl m-nitrobenzoate (2-2), with a yield of 88.5%.

[0166] 1H NMR (CDCl3, 400 MHz); 4.00 (s, 3H); 8.86 (s, 1H); 8.40 (m, 2H); 7.68 (t, 1H); HRMS: 181.0360.

[0167] Compound 4-2: Preparation of 4-(2-methoxy-2-acetyl)-3-benzoic acid methyl ester

[0168] 3.93g of potassium tert-butox...

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Abstract

The invention relates to indolone compounds shown as a general formula (a) or derivatives thereof and applications thereof. According to the invention, indolone compounds are substituted with deuterium to obtain deuterium-enriched indolone compounds; the indolone compounds can simultaneously act on the following three key receptor families involved in angiogenesis process: vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR), so as to inhibit angiogenesis and achieve the effect of treating cancers. The deuterated indolone compounds or the derivatives thereof have the advantage of high efficiency when used asdrugs. The general formula (a) is as shown in the specification.

Description

technical field [0001] The invention relates to indolinone compounds or derivatives thereof and uses thereof, belonging to the technical field of chemistry and medicine. Background technique [0002] Nintedanib (BIBF1120), its structural formula is as follows: [0003] [0004] It is a new type of oral and effective blood vessel inhibitor, which can simultaneously act on three key receptor families involved in angiogenesis - vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet Derived Growth Factor Receptor (PDGFR). Angiogenesis inhibitors inhibit the formation of blood vessels around and inside the tumor, thereby reducing the supply of oxygen and nutrients to the tumor, resulting in the shrinkage and death of tumor cells. This anti-tumor treatment has fewer side effects than conventional chemotherapy. [0005] Nintedanib (BIBF1120) has a good effect on a variety of tumors such as liver cancer, lung cancer, rectal c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/34A61K31/496A61P35/00
CPCA61K31/496C07D403/12C07D209/34A61P35/00
Inventor 陈元伟谢永美魏于全
Owner SICHUAN UNIV
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