CN101951991A - 用于治疗缺血性心脏病的3-(2，2，2-三甲基肼)丙酸盐的盐 - Google Patents
用于治疗缺血性心脏病的3-(2，2，2-三甲基肼)丙酸盐的盐 Download PDFInfo
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Abstract
本发明涉及通过3-(2，2，2-三甲基肼)丙酸盐氢富马酸盐和3-(2，2，2-三甲基肼)丙酸盐二氢磷酸盐来高效治疗缺血性心脏病。
Description
技术领域
本发明涉及3-(2，2，2-三甲基肼)丙酸盐氢富马酸盐和3-(2，2，2-三甲基肼)丙酸盐二氢磷酸盐在治疗缺血性心脏病中的应用。
背景技术
心肌梗死是由长时间缺血引起心肌不可逆坏死的一种病症。
心肌梗死(心脏病发作)是冠心病的严重结果。心肌梗死(MI)是由长时间缺血所继发的心肌不可逆坏死。心脏病发作或心肌梗死是医学突发事件，其中供给心脏的血液突然且急剧地减少或阻断，导致心肌因缺氧而死亡。每年有超过110万人经历心脏病发作(心肌梗死)，其中有许多人，其心脏病发作是冠心病的最初症状。心脏病发作可严重到足以引起死亡，或者根本不发作。每五个人中仅一人有轻微症状，或完全没有症状，且只有在一段时间后通过常规心电图才能发现心脏病发作。
心脏病发作(心肌梗死)通常由阻塞心脏动脉的血块引起。动脉壁上的脂肪沉积物通常已使动脉变狭窄。这些沉积物可破裂或破开，降低血流，并释放使血小板粘稠且更易形成凝块的物质。有时，凝块形成在心脏内部，随后脱离并粘在通向心脏的动脉中。这些动脉中某个发生痉挛会引起血流停止。
已知3-(2，2，2-三甲基肼)丙酸盐二水合物是具有心脏保护性质的化合物(此物质的国际非专属名称是米曲肼二水合物)。3-(2，2，2-三甲基肼)丙酸盐公开在US 4481218(INST ORGANICHESKOGO SINTEZA)06.11.1984中。
已知3-(2，2，2-三甲基肼)丙酸盐作为二水合物被广泛用于控制体内肉毒碱和γ-丁基甜菜碱浓度比和随后脂肪酸β-氧化的速度。DAMBROVA M.，LIEPINSH E.，KALVINSH I.I.Mildronate：cardioprotective action throughcarnitine-lowering effect.Trends in Cardiovascular Medicine，.2002，vol.12，no.6，p.275-279。
由于这些性质，米曲肼二水合物被广泛用在医学中以作为抗缺血、应力保护和心脏保护药物来治疗各种心血管疾病和包括组织缺血的其它病状。KARPOV R.S.，KOSHELSKAYA O.A.，VRUBLEVSKY A.V.，SOKOLOV A.A.，TEPLYAKOV AT.，SKARDA I.，DZERVE V.，KLINTSARE D.，VITOLS A.，KALNINS U.，KALVINSH I.，MATVEYA L.，URBANE D..Clinical Efficacyand Safety of Mildronate in Patients With Ischemic Heart Disease and ChronicHeart Failure.Kardiologiya.2000，no.6，p.69-74。在心血管疾病的治疗中，3-(2，2，2-三甲基肼)丙酸盐的作用机制基于对肉毒碱生物合成速率的限制并涉及通过线粒体膜的长链脂肪酸转运的限制。SIMKHOVICH B.Z.，SHUTENKOZ.V.，MEIRENA D.V.，KHAGI K.B.，MEZHAPUKE R.J.，MOLODCHINA T.N.，KALVINS I.J.，LUKEVICS E.3-(2，2，2，-Trimethylhydrazinium)propionate(THP)-a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotectiveproperties.Biochemical Pharmacology.1988，vol.37，p.195-202.，KIRIMOTOT.，ASAKA N.，NAKANO M.，TAJIMA K.，MIYAKE H.，MATSUURA N.Beneficial effects of MET-88，a γ-butyrobetaine hydroxylase inhibitor in rats withheart failure following myocardial infarction.European Journal ofPharmacology.2000，vol.395，no.3，p.217-224。
WO 00/003063A(SIGMA TAU IND FARMACEUTI)02.06.2000专利公开了L-肉毒碱酸富马酸盐(L-carnitine acid fumarate)和其烷酰基衍生物在制备组合物中的应用，所述组合物适用于在大范围使用者和/或患者中降低器官缺血发生的风险以及预防和/或治疗器官缺血，特别是影响心脏循环的器官。L-肉毒碱和米曲肼二水合物在结构上非常类似。然而，米曲肼二水合物的药理作用却对抗L-肉毒碱的作用。因此，将逆转录酶抑制剂与米曲肼二水合物结合对本领域技术人员并非显而易见的。
作为比米曲肼二水合物更稳定的物质，米曲肼的氢富马酸盐和二氢磷酸盐公开于EP 1667960A(JOINT STOCK COMPANY GRINDEKS)14.06.2006。
发明内容
已知米曲肼二水合物用于治疗缺血性心脏病；然而没有资料显示米曲肼的盐用于治疗缺血性心脏病。
出乎我们意料，通过在心肌梗死和/或缺血治疗中使用米曲肼氢富马酸盐，其显示出意想不到的效果，且在体内心肌缺血模型中比米曲肼二水合物更有效。米曲肼的氢富马酸盐和二氢磷酸盐是药学上可接受的盐，与米曲肼二水合物是生物等效的，应显示出与米曲肼二水合物相同的医学作用，但却意想不到地显示出比米曲肼二水合物在统计学上更好的疗效。
本发明的最佳实施方式
以下实施例进一步举例说明本发明。
抗缺血活性
实验在初始体重为300-350g的成年雄性Wistar大鼠上进行。在实验期间，将动物以每组8只置于标准条板箱中。饲料是标准的膳食R70(LABFOR，Lactamin AB，Sweden)。保持室温在21-23℃，相对湿度在65±10％，12小时光/暗循环。
实验步骤根据欧洲共同体准则和地方法律和规则进行，并得到拉脱维亚动物保护伦理委员会，食物和兽医服务机构(Latvian Animal Protection EthicalCommittee，the Food and Veterinary Service)的许可。
实验1
体内心肌梗死
将约300g重的大鼠随机分为4组，每组8只。第一组口服盐水(对照组)，第二组口服100mg/kg米曲肼二水合物，第三组口服100mg/kg米曲肼氢富马酸盐，第四组口服100mg/kg米曲肼二氢磷酸盐，持续14天。
将大鼠用戊巴比妥钠麻醉(60mg/kg，腹腔注射)。对它们插管，并以55次呼吸/分钟的呼吸速率用15ml/kg室内空气通过啮齿类呼吸器(RodentVentilator 7025，Ugo Basile，Itally)人工呼吸。
需要时，通过切断第四和第五根肋骨在胸骨的左侧开胸。打开心包，将5/0聚丙烯缝合线(Surgipro II，Syneture)从左前降冠状动脉下通过，并穿过小塑料管以允许冠状动脉的可逆闭合。冠状流量使用来自ADInstruments的超声流量检测器(HSE)和PowerLab 8/30系统测量。
通过收缩穿过塑料管的线来进行闭合。
在120分钟再灌注结束时，再灌注后，将心脏切下并在50mm Hg的恒定压力下经由大动脉逆向灌注37℃、pH 7.3-7.5、充氧的Krebs-Henseleit缓冲液(含量以mmol/L计：NaCl 118、CaCl22.52、MgCl21.64、NaHCO324.88、KH2PO41.18、葡萄糖10.0、EDTA 0.05)。在10分钟后，将左前降冠状动脉松开，并将风险区用经由大动脉根灌输的4ml 0.1％亚甲蓝溶液的Krebs-Henseleit缓冲液标出。将心脏从顶端到底部以2mm厚度横切，并在1％氯化三苯基四氮唑的磷酸盐缓冲溶液(pH 7.4，37℃)中孵育10分钟，以将活组织染红和将坏死组织染白。随后，将右心室切下，并用Minolta 7D相机对左心室切片拍照。使用Image-Pro Plus 4.5.1软件对照片进行计算机化平面计量分析，以确定风险面积(AR)和坏死面积(AN)，将其表示为左心室(LV)的百分数。随后，根据以下公式，使用所得数值计算梗塞大小(IS)，将其表示为风险面积的百分数。
通过持续14天施用米曲肼二水合物、米曲肼氢富马酸盐和米曲肼二氢磷酸盐的体内心肌梗死的结果总结在表1中。
表1
体内心肌梗死的结果
| 风险面积/左心室面积 | 基于风险面积的坏死面积％ | 基于对照的梗塞大小％ | |
| 对照 | 52.0±2.5 | 64.3±2.7 | 100.0±4.1 |
| 米曲肼二水合物 | 58.0±2.2 | 64.0±2.7 | 99.0±4.2 |
| 米曲肼氢富马酸盐 | 62.0±3.5 | 52.2±4.3*# | 81.0±6.6*# |
| 米曲肼二氢磷酸盐 | 57.0±3.0 | 50.9±2.6*# | 79.0±4.1*# |
与对照组相比*p＜0.01；与米曲肼二水合物组相比#p＜0.01。
Claims (5)
1.3-(2，2，2-三甲基肼)丙酸盐的盐在制备治疗缺血性心脏病的药物中的应用，所述3-(2，2，2-三甲基肼)丙酸盐的盐选自由二氢磷酸盐和氢富马酸盐组成的组。
2.一种3-(2，2，2-三甲基肼)丙酸盐的盐，其用于治疗缺血性心脏病。
3.如权利要求1或2所述的应用，其中所述缺血性心脏病是心肌梗死。
4.如权利要求1至3中任一项所述的3-(2，2，2-三甲基肼)丙酸盐的盐，其中所述3-(2，2，2-三甲基肼)丙酸盐的盐是3-(2，2，2-三甲基肼)丙酸盐氢富马酸盐。
5.如权利要求1至3中任一项所述的3-(2，2，2-三甲基肼)丙酸盐的盐，其中所述3-(2，2，2-三甲基肼)丙酸盐的盐是3-(2，2，2-三甲基肼)丙酸盐二氢磷酸盐。
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP07122359 | 2007-12-05 | ||
| EP07122359.8 | 2007-12-05 | ||
| EP07122360 | 2007-12-05 | ||
| EP07122360.6 | 2007-12-05 | ||
| PCT/EP2008/066712 WO2009071586A2 (en) | 2007-12-05 | 2008-12-03 | 3-(2,2,2-trimethylhydrazinium) propionate salts for treating ischemic heart disease |
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| Publication Number | Publication Date |
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| CN101951991A true CN101951991A (zh) | 2011-01-19 |
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| CN200880119405XA Pending CN101951991A (zh) | 2007-12-05 | 2008-12-03 | 用于治疗缺血性心脏病的3-(2，2，2-三甲基肼)丙酸盐的盐 |
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| Country | Link |
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| US (1) | US20110028438A1 (zh) |
| EP (1) | EP2222376B1 (zh) |
| JP (1) | JP2011506285A (zh) |
| KR (1) | KR20100084687A (zh) |
| CN (1) | CN101951991A (zh) |
| AR (1) | AR069548A1 (zh) |
| AT (1) | ATE503473T1 (zh) |
| AU (1) | AU2008333263A1 (zh) |
| BR (1) | BRPI0819055A2 (zh) |
| CA (1) | CA2706357C (zh) |
| CL (1) | CL2008003552A1 (zh) |
| CO (1) | CO6280507A2 (zh) |
| DE (1) | DE602008005930D1 (zh) |
| DK (1) | DK2222376T3 (zh) |
| DO (1) | DOP2010000162A (zh) |
| EA (1) | EA016971B1 (zh) |
| GE (1) | GEP20125646B (zh) |
| HR (1) | HRP20110468T1 (zh) |
| IL (1) | IL205962A0 (zh) |
| MA (1) | MA31992B1 (zh) |
| MX (1) | MX2010006257A (zh) |
| MY (1) | MY158799A (zh) |
| NZ (1) | NZ586518A (zh) |
| PA (1) | PA8806001A1 (zh) |
| PE (1) | PE20091209A1 (zh) |
| PL (1) | PL2222376T3 (zh) |
| PT (1) | PT2222376E (zh) |
| RS (1) | RS51785B (zh) |
| SI (1) | SI2222376T1 (zh) |
| SV (1) | SV2010003585A (zh) |
| TN (1) | TN2010000249A1 (zh) |
| TW (1) | TWI391131B (zh) |
| UA (1) | UA100249C2 (zh) |
| UY (1) | UY31499A1 (zh) |
| WO (1) | WO2009071586A2 (zh) |
| ZA (1) | ZA201003640B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140088125A1 (en) * | 2011-04-27 | 2014-03-27 | Jsc Grindeks | Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease |
| RU2457198C1 (ru) * | 2011-05-31 | 2012-07-27 | Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Белгородский государственный национальный исследовательский университет" | Производное 3-(2,2,2-триметилгидразиний)пропионата - глицинат 3-(2,2,2-триметилгидразиний)пропионат калия, обладающее противоишемической активностью |
| RU2467748C1 (ru) * | 2011-08-08 | 2012-11-27 | Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Белгородский государственный национальный исследовательский университет" | Производное 3-(2,2,2-триметилгидразиний)пропионата - глицинат 3-(2,2,2-триметилгидразиний)пропионат калия, обладающее эндотелиопротекторной активностью |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829683A (zh) * | 2003-08-04 | 2006-09-06 | 联合股份公司格林代克斯 | 米屈肼盐及其制备方法以及基于米屈肼盐的药物组合物 |
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| PT1667960E (pt) * | 2003-08-04 | 2008-05-02 | Grindeks Jsc | Métodos para a preparação de sais de meldonium e composições farmacêuticas com base nos mesmos |
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- 2008-12-03 CA CA2706357A patent/CA2706357C/en not_active Expired - Fee Related
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829683A (zh) * | 2003-08-04 | 2006-09-06 | 联合股份公司格林代克斯 | 米屈肼盐及其制备方法以及基于米屈肼盐的药物组合物 |
Non-Patent Citations (1)
| Title |
|---|
| MAIJA DAMBROVA等: ""Mildronate: Cardioprotective Action through Carnitine -Lowering Effect"", 《TCM》 * |
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