CN103169703B

CN103169703B - New application of sertindole drug

Info

Publication number: CN103169703B
Application number: CN201110435411.XA
Authority: CN
Inventors: 蒋宇扬; 张存龙; 陈宇综; 谭春燕; 马晓华; 辛甜
Original assignee: Shenzhen Graduate School Tsinghua University
Current assignee: Shenzhen Graduate School Tsinghua University
Priority date: 2011-12-22
Filing date: 2011-12-22
Publication date: 2014-10-08
Anticipated expiration: 2031-12-22
Also published as: CN103169703A

Abstract

The invention discloses a new application of a sertindole drug. The new application is an application of sertindole or pharmaceutically acceptable salt, ester and solvate thereof in preparation of a eucaryon tumour cell proliferation inhibitor and preparation of a drug used for preventing and/or treating tumour. Tumour cell proliferation inhibition test results show that sertindole has a good inhibitory effect on multiple tumour cells, is a potential antitumour drug and has a potential clinical application prospect.

Description

The purposes of medicine Sertindole

Technical field

The present invention relates to a kind of purposes of medicine Sertindole.

Background technology

Sertindole (Serdolect/Sertindole) is atypical antipsychotic of new generation, molecular formula: C ₂₄h ₂₆clFN ₄o; Chemical name is: the chloro-1-of 1-[2-[4-[5-(4-fluorophenyl)-1H-indol-3-yl]-piperidino] ethyl]-2-imidazolone; English name is: 1-[2-[4-[5-Chloro-1-(4-fluorophenyl)-1h-indol-3-yl]-1-piperidinyl] ethyl]-2-imidazolidinone; Chemical structural formula is as shown in formula I:

Sertindole is by the research and development of Denmark Ling Bei (Lundbeck) pharmaceuticals, and 1996 Nian European Union member countries go on the market.But owing to may causing patient's Q-T interval prolongation, Abbott laboratory in 1998 has initiatively stopped it at the new drug application of U.S. FDA, and manufacturer also suspends supply Sertindole.But through further systematic study and evaluation, EU Committee in June, 2002 solution except Sertindole being suspended to the restriction of producing, Sertindole is common medicine just in Europe.2009 Nian Lingbei pharmaceuticals have resubmited new drug application to U.S. FDA, are nowadays in the III phase clinical research stage.

Sertindole is typical many target drugs, is potent central dopamine D ₂and 5-hydroxy tryptamine (5-HT ₂) receptor antagonist, to 5-HT ₂a and 5-HT ₂c receptor and dopamine-D ₂receptor and α ₁-adrenoreceptor has strong affinity, and it optionally suppresses dopaminergic nerve, acts on specifically the dopamine neuron of middle cortex.Sertindole can not cause A ₉dopamine neuron nigrostriatum approach depolarization inactivation, anti-neuron untoward reaction is low, and therefore,, there is not tardive dyskinesia (TD) in less generation EPS (EPS) substantially; But to A ₁₀neuron (path of middle edge system and intermediate skins) has activity, has strong local antipsycholic action.Experiment showed, that it has the effect of the strong psychosis positive symptom, its importance is similar to haloperidol, and it is greater than traditional psychosis haloperidol to the therapeutical effect of negative symptoms.From clinical observation, Sertindole is obviously better than traditional psychosis in safety and problem of resistance, all effective in cure to symptoms such as negative symptoms and anxiety, depression, Cognitive function damagies.At present, in more than 20 countries and regions, the whole world, having ratified Sertindole is antischizophrenic medicine.

High along with the increasing of new drug development difficulty, development cost, transfers to the emphasis of drug development the secondary development of product all over the world, as expands the new indication, exploitation novel form etc. of old medicine, to obtaining new effective medicine.The clinical observation of old medicine for a long time a large amount of cases after listing, its safety is guaranteed, and untoward reaction understanding is comprehensive, and low price.Old medicine is developed new purposes, and its clinical cost front and that front clinical trial phase expends also can be saved relatively.Therefore, study old medicine, expand its new indication, not only greatly promote the development of clinical therapeutics, also for saving the cycle of health resources and the old medicine life of prolongation, in market, produce important value.

Summary of the invention

The purposes that the object of this invention is to provide medicine Sertindole.

A purposes of Sertindole provided by the present invention is: Sertindole or its pharmaceutically acceptable salt, ester, the application of solvate in preparing eukaryote tumor cell proliferation inhibitor.

Described eukaryote is mammal.

Described tumor cell is cancerous cell; Described cancerous cell includes, but are not limited to: glioma cell, blood cell, breast cancer cell, lung carcinoma cell, hepatoma carcinoma cell, ovarian cancer cell, stomach cancer cell, esophageal cancer cell, colon-cancer cell, cervical cancer cell, malignant lymphatic oncocyte, nasopharyngeal carcinoma cell etc.

Wherein, described glioma specifically can be human glioma cells U251; Described blood cell specifically can be human chronic myelogenous leukemia's (CML) cell line k562 or people's acute lymphoblastic leukemia (ALL) cell line CCRF-CEM; Described breast cancer cell specifically can be human breast cancer cell MCF-7 and human breast cancer cell MDA-MB-231.

Another purposes of Sertindole provided by the present invention is: Sertindole or its pharmaceutically acceptable salt, ester, solvate prevent and/or treat the application in tumour medicine in preparation.

Described tumor is cancer; Described cancer includes, but are not limited to: cerebroma, leukemia, breast carcinoma, pulmonary carcinoma, hepatocarcinoma, ovarian cancer, gastric cancer, the esophageal carcinoma, intestinal cancer, cervical cancer, malignant lymphoma, nasopharyngeal carcinoma etc.

Take the medicine that prevents and/or treats tumor that Sertindole or its pharmaceutically acceptable salt, ester, solvate prepared as effective ingredient, also belong to protection scope of the present invention.

The described tumour medicine that prevents and/or treats can import by the method for injection, injection, collunarium, eye drip, infiltration, absorption, physics or chemistry mediation body as muscle, Intradermal, subcutaneous, vein, mucosal tissue; Or by other materials, mixed or wrap up after import body.

When needing, in said medicine, can also add one or more pharmaceutically acceptable carriers.Described carrier comprises diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant of pharmaceutical field routine etc.

With Sertindole or its pharmaceutically acceptable salt, ester, solvate, to be active fraction preparation prevent and/or treat tumour medicine can make the various ways such as injection, tablet, powder, granule, capsule, oral liquid, unguentum, cream.The medicine of above-mentioned various dosage forms all can be according to the conventional method preparation of pharmaceutical field.

The present invention is a kind of potential antitumor drug through kinds of tumor cells system test proof Sertindole.The Sertindole of usining especially has following two advantages for cerebroma as antitumor drug: (1) tumour medicine all there will be drug resistance phenomenon in clinical life-time service, one of the main reasons is exactly the effect of pumping of medicine, and thereby the effect substrate that Sertindole is not glycoprotein can be avoided pumping of medicine, increase curative effect; (2) the most of inhibitors of kinases using is clinically difficult to break through blood brain barrier, thereby cerebroma is difficult to play a role, and Sertindole is easy to break through blood brain barrier as antipsychotic drug, therefore to cerebroma, more may have potential anti-tumor activity.Because Sertindole is becoming marketed drug aspect treatment atypical antipsychotic, therefore, as in antitumor drug research, can greatly reduce the research cost in preclinical study, economize on resources, shorten the R&D cycle.All experimental data proof Sertindoles have good antitumous effect, have potential potential applicability in clinical practice.

The specific embodiment

Below by specific embodiment, the present invention will be described, but the present invention is not limited thereto.

Experimental technique described in following embodiment, if no special instructions, is conventional method; Described reagent and biomaterial, if no special instructions, all can obtain from commercial channels.

Embodiment 1, mtt assay detect Sertindole to tumor cell proliferation inhibition activity

Body outer cell proliferation suppresses experiment and adopts mtt assay, with below five kinds represent cell be example: human glioma cells U251, human chronic myelogenous leukemia (CML) cell line k562, people's acute lymphoblastic leukemia (ALL) cell line CCRF-CEM, breast cancer cell MCF-7 and MDA-MB-231.

Above cell Zhu Juncong Chinese Academy of Sciences cell bank is bought and is obtained.

1.K562 cell and CCRF-CEM cell are suspension cell, with being the RPIM-1640 culture fluid of 10% hyclone containing volume fraction, and the CO that is 5% at 37 ℃, volume fraction ₂cellar culture under condition.

2.MCF-7 cell and U251 cell are adherent growth cell, with the DMEM culture fluid of the hyclone that is 10% containing volume fraction, and the CO that is 5% at 37 ℃, volume fraction ₂cellar culture under condition.

3.MDA-MB-231 cell is adherent growth cell, with Leibovitz ' the s L15 culture fluid of the hyclone that is 10% containing volume fraction, and the CO that is 5% at 37 ℃, volume fraction ₂cellar culture under condition.

The take the logarithm U251 cell of trophophase, MDA-MB-231 cell, MCF-7 cell, CCRF-CEM cell or K562 cell, be inoculated in 96 orifice plates, and density is 1.5 * 10 ⁵individual/mL, 99 μ L/well, every hole adds Sertindole solution 1 μ L, and making drug effect final concentration is 0.5,1,5,10,25,50 μ M.Every kind of sample is established five multiple holes, and positive control and blank are set.After effect 48h, add MTT solution, 10 μ L/well, continue to cultivate after 4 hours, 2000rpm, 4 ℃, centrifugal 5 minutes, add DMSO after sucking supernatant, 100 μ L/well, 37 ℃ are incubated approximately 10 minutes, and vibrate and make dissolving crystallized complete in approximately 5 minutes with micro oscillator, measure OD value by microplate reader in 490nm place, be calculated as follows cell proliferation inhibition rate (Inhibition Rate, IR%):

The blank OD of IR%=[(contrast OD-)-(the blank OD of sample OD-)]/(the blank OD of contrast OD-) * 100%

As calculated, the suppression ratio result of Sertindole tumor cell and 50 3nhibitory dose IC ₅₀in Table 1.

Table 1

Claims

1. Sertindole or its pharmaceutically acceptable salt are the application of unique active component in preparing eukaryote tumor cell proliferation inhibitor;

Described eukaryote is mammal;

Described tumor cell is cancerous cell; Described cancerous cell be selected from following any one: glioma cell and breast cancer cell.

2. Sertindole or its pharmaceutically acceptable salt are that unique active component prevents and/or treats the application in tumour medicine in preparation;

Described tumor is cancer; Described cancer is cerebroma or breast carcinoma.