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Benzimidazole-2-piperazine compound, pharmaceutical composition of compound and preparing method and application of pharmaceutical composition
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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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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
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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:
[0107] Add carbonyl diimidazole (1.56g, 9.6mmol) to an anhydroustetrahydrofuran 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 (petroleumether: ethyl acetate = 5:1) to obtain a pale yellow solidcompound a (0.3 g, yield 33%). MS(ESI)m / z:[M+H] + =193.
[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...
[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).
[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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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 cellcycle 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 cellcycle control sites. Therefore, it can be inferred that there is a specific DNA repair mechanism in tumor cells that can quickly ...
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