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Benzimidazole-2-piperazine compound, pharmaceutical composition of compound and preparing method and application of pharmaceutical composition

A technology of benzimidazoles and compounds, applied in the field of poly(ADP-ribose) polymerase (PARP) inhibitors, can solve problems such as inability to perform repair process

Active Publication Date: 2014-08-27
SHANGHAI HUILUN BIOLOGICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

PARP without poly(ADP-ribosylation) modification cannot dissociate from the DNA damage site, which will cause other proteins involved in the repair to be unable to enter the damage site, and thus cannot perform the repair process

Method used

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  • Benzimidazole-2-piperazine compound, pharmaceutical composition of compound and preparing method and application of pharmaceutical composition
  • Benzimidazole-2-piperazine compound, pharmaceutical composition of compound and preparing method and application of pharmaceutical composition
  • Benzimidazole-2-piperazine compound, pharmaceutical composition of compound and preparing method and application of pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Compound (1): 3-(4-(4-carbamoyl-1hydro-benzimidazol-2-yl)piperazine-1-carbonyl)pyrrolidine-1-tert-butyl carbonate, the reaction formula is as follows:

[0105]

[0106] Step 1: Compound a: 2-oxo-2,3-dihydro-1hydro-benzimidazole-4-carboxylic acid methyl ester

[0107] Add carbonyl diimidazole (1.56g, 9.6mmol) to an anhydrous tetrahydrofuran solution (20mL) with methyl 2,3-diaminobenzoate (0.8g, 4.8mmol) dissolved, heat to reflux, and react for 8 hours After cooling, the solvent was removed under reduced pressure, and the residue was separated by flash column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a pale yellow solid compound a (0.3 g, yield 33%). MS(ESI)m / z:[M+H] + =193.

[0108] Step 2: Compound b: 2-chloro-1hydro-benzimidazole-4-carboxylic acid methyl ester

[0109] Compound a (1.1g, 5.7mmol) was added to phosphorus oxychloride (8mL), heated to reflux, reacted for 8 hours and then cooled, the solvent was removed under reduced pressure, and the residue...

Embodiment 2

[0117] Compound (2): (S)-2-(4-(4-carbamoyl-1hydro-benzimidazol-2-yl)piperazine-1-carbonyl)pyrrolidine-1-tert-butyl carbonate

[0118]

[0119] A method similar to the preparation of compound (1) in Example 1 was adopted, that is, compound (2) (21 mg, yield 11%) was obtained by condensation of compound d with (S)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid. MS(ESI)m / z:[M+H] + =443. 1 H NMR (300MHz, DMSO-d6): δ11.99(br,1H), 9.10(br,1H), 7.61(d,1H,J=7.5Hz), 7.51(br,1H), 7.33(d,1H) ,J=7.5Hz),6.98(t,1H,J=7.5Hz),4.70-4.63(m,1H),3.70-3.56(m,10H),2.19-2.11(m,2H),1.79-1.73( m, 2H), 1.36 (s, 9H).

Embodiment 3

[0121] Compound (3): (R)-2-(4-(4-carbamoyl-1hydro-benzimidazol-2-yl)piperazine-1-carbonyl)pyrrolidine-1-tert-butyl carbonate

[0122]

[0123] Using a method similar to the preparation of compound (1) in Example 1, compound (3) (18 mg, yield 10%) was obtained by condensation of compound d and (R)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid. MS(ESI)m / z:[M+H] + =443. 1 H NMR (300MHz, DMSO-d6): δ11.84(br,1H), 9.10(br,1H), 7.61(d,1H,J=7.5Hz), 7.51(br,1H), 7.32(d,1H) ,J=7.5Hz),6.99(t,1H,J=7.5Hz),4.69-4.65(m,1H),3.70-3.55(m,10H),2.21-2.09(m,2H),1.79-1.74( m, 2H), 1.29 (s, 9H).

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PUM

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Abstract

The invention relates to a benzimidazole-2-piperazine derivative and a preparing method and application of the benzimidazole-2-piperazine derivative in medicine, in particular to a novel benzimidazole-2-piperazine derivative shown in the general formula (I), a preparing method of the derivative, a pharmaceutical composition containing the derivative and application of the derivative serving as a therapeutic agent, especially serving as a poly (ADP-ribose) polymerase (PARP) inhibitor. In the general formula (I), R refers to hydrogen or halogen, G refers to carbonyl or methylene, m is 1-2, n is 1-3, and Q refers to hydrogen or C1-C4 alkyl. When X is methylene and Y is NR1 or methylene, X is NR1; R1 refers to hydrogen, C1-C6 alkyl, benzyl, COR2 or SO2R2; R2 refers to the following groups which are not substituted or groups substituted by 1-3 substituent groups, including C1-C6 alkyl, C3-C8 naphthenic base, phenyl, benzyl, naphthyl and C5-C10 aromatic heterocycle base, heterocycle in the C5-C10 aromatic heterocycle base comprises 1-3 heteroatoms selected from N, O and S, and the substituent groups are selected from the following atoms or groups of C1-C6 alkyl, C1-C6 alkoxy, halogen, amidogen, nitryl, sulfydryl, hydroxyl, cyanogroup and trifluoromethyl. The general formula (I) is shown in the specification.

Description

Technical field [0001] The invention relates to a benzimidazole-2-piperazine derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent and as a poly(ADP-ribose) polymerase (PARP) inhibitor . Background technique [0002] Chemotherapy drugs and ionizing radiation therapy are two common methods of treating cancer. Both of these treatment methods can induce DNA single-strand and / or double-strand breaks and thus produce cytotoxic effects. Target tumor cells die due to chromosomal damage. As an important result of responding to DNA damage signals, the cell cycle control site signals are activated, which aims to protect cells from mitosis in the case of DNA damage to avoid cell damage. In most cases, tumor cells have a high rate of proliferation while showing signal defects at cell cycle control sites. Therefore, it can be inferred that there is a specific DNA repair mechanism in tumor cells that can quickly ...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D403/14C07D401/14C07D401/12A61K31/496A61K31/551A61P9/00A61P31/00A61P29/00A61P9/10A61P25/00A61P7/00A61P35/00
CPCC07D401/12C07D401/14C07D403/12C07D403/14
Inventor 樊兴秦继红
Owner SHANGHAI HUILUN BIOLOGICAL TECH CO LTD
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