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Tumor-treating compound and application thereof

A technology of compounds and uses, applied in antitumor drugs, medical preparations containing active ingredients, organic chemistry, etc., can solve the problems of lack of exploration in the research of Veliparib analogs, and achieve excellent pharmacokinetic properties, good therapeutic activity, The effect of reducing the frequency of dosing

Active Publication Date: 2015-09-23
HINOVA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, research on Veliparib analogues is still lacking

Method used

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  • Tumor-treating compound and application thereof
  • Tumor-treating compound and application thereof
  • Tumor-treating compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Embodiment 1 Preparation method one of the compound of the present invention

[0065]

[0066] Deuterated or substituted 2,3-diaminobenzamide or (10mmol) and deuterated or substituted R-1-tert-butoxycarbonyl-2-methylproline.(10mmol) were dissolved in 50mL of dichloro Methane, dicyclohexylcarbodiimide (12mmol), hydroxybenzotriazole (12mmol), triethylamine (13mmol) were added. After stirring at room temperature for 12 hours, the precipitate produced by the reaction was filtered off. The mother liquor was washed with 5% dilute hydrochloric acid, the organic phase was separated and concentrated under reduced pressure. The crude product was dissolved in 10 mL of acetic acid, heated to 70°C, and the reaction was monitored by TLC, then concentrated under reduced pressure. Dissolve the crude product in 10 mL of tetrahydrofuran, add 6M hydrochloric acid, and stir at room temperature until the reaction is complete. Add ethyl acetate with 10% Na 2 CO 3 Neutralized, the org...

Embodiment 2

[0072] Embodiment 2 is used for the preparation of the intermediate of compound of the present invention

[0073] 1. Synthesis of (R)-1-(benzyloxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (compound 2)

[0074]

[0075] Add (R)-2-methyl-2-pyrrolidine carboxylic acid hydrochloride (compound 1) (4g, 24mmol), sodium carbonate (10.2g, 96mmol), tetrahydrofuran (40mL) and water ( 40mL), benzyl chloroformate (CbzCl) (6.2g, 36mmol) was added under stirring, the mixture was separated at room temperature overnight, separated, extracted with ethyl acetate (3×30mL), the organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated , after purification with a silica gel column, white solid compound 2 (3.5 g, yield 56%) was obtained, mass spectrum: 264.1 (M+H + ).

[0076] 2, Synthesis of 2-amino-3-nitrobenzamide (compound 4)

[0077]

[0078] Add 2-amino-3-nitrobenzoic acid (compound 3) (9g, 50mmol) and tetrahydrofuran (70mL) into a 500mL single-neck...

Embodiment 3

[0085] Example 3 Synthesis of 2-[(2R)-2-methyl-5,5-dideutero-2-pyrrolidinyl]-1H-benzimidazole-4-carboxamide (compound D0002)

[0086]

[0087] 1. Synthesis of (2R)-2-methyl-2-pyrrolidine-methyl formate (compound 11)

[0088]

[0089] Add (2R)-2-methyl-2-tetrahydropyrrole carboxylate hydrochloride (compound 1) (5g, 30mmol) and methanol (50mL) to a 100mL single-necked bottle, and add dichlorohydrin dropwise under an ice bath. Sulfone (5.4g, 45mmol), return to room temperature overnight after the dropwise addition, spin out the solvent, dissolve the residue in dichloromethane (50mL), wash with a small amount of aqueous sodium bicarbonate until neutral, separate liquid, organic The layer was dried over anhydrous sodium sulfate, and the solvent was concentrated to obtain compound 11 (4.1 g, yield 95%). Mass spectrum: 144.2 (M+H + ).

[0090] 2. Synthesis of (2R)-1-tert-butoxycarbonyl-2-methylpyrrolidine-2-carboxylic acid methyl ester (compound 12)

[0091]

[0092] Add...

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PUM

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Abstract

Provided in the present invention are a compound for treating tumours and a use thereof, and also provided are a compound as shown in formula I or a pharmaceutically acceptable salt thereof. The compound provided in the present invention has a high medicine peak concentration, a high medicine absorption and a long elimination half life, and can improve the efficacy of the medicine in clinical use and reduce the frequency of the dosages. The compound or the pharmaceutically acceptable salt thereof prepared by the present invention can act as a PARP inhibitor medicine, have a certain anti-tumour activity, and especially have a good therapeutic activity on triple negative, primary or metastatic breast cancer, colon cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, leukemia, melanoma, solid tumors or intracranial tumors, and provide a new choice for clinical medication.

Description

technical field [0001] The present invention relates to a compound for treating tumor and its use. Background technique [0002] Poly ADP-ribose polymerase (PARP, poly ADP-ribose polymerase) is a new target for the treatment of cancer today. The function of this enzyme is to catalyze the transfer of ADP-ribose from nicotinamide adenine dinucleotide Body protein, and can repair single-stranded DNA by base excision repair. In tumor cells, when PARP activity is inhibited, DNA damage repair is prone to errors, and as DNA damage increases, tumor cells will die, thereby achieving the purpose of treating tumors. Current research shows (Han Wei etc., PARP inhibitor is used in the research progress of tumor treatment, Chinese Journal of New Drugs, 2011, 20 (12), 1086-1091), PARP inhibitor is not only the sensitizer of radiochemotherapy, but also in It can be used alone in breast cancers with BRCA1 and BRCA2 gene mutations to selectively kill cancer cells that are deficient in DNA r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/4184A61P35/00A61P35/02A61P35/04
CPCC07B2200/05C07D403/04A61P35/00A61P35/02A61P35/04C07D235/06
Inventor 樊磊胥珂馨龚瑜陈元伟
Owner HINOVA PHARM INC
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