WO2016062281A1 - 心血管疾病用药物在制备抑制癌症的医药组合物中的应用 - Google Patents

心血管疾病用药物在制备抑制癌症的医药组合物中的应用 Download PDF

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WO2016062281A1
WO2016062281A1 PCT/CN2015/092768 CN2015092768W WO2016062281A1 WO 2016062281 A1 WO2016062281 A1 WO 2016062281A1 CN 2015092768 W CN2015092768 W CN 2015092768W WO 2016062281 A1 WO2016062281 A1 WO 2016062281A1
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hcl
cancer
use according
drug
hydrochloride
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French (fr)
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陈丘泓
庄秀美
萧乃文
梁瑞岳
陈筱彤
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朗齐生物医学股份有限公司
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Priority to US15/521,536 priority Critical patent/US20170304388A1/en
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Definitions

  • the present invention relates to novel indications for a variety of cardiovascular disease drugs, particularly the use of the plurality of drugs for clinical trials and for inhibiting a variety of cancers.
  • Cancer has long been the leading cause of death worldwide, and the number of cancer patients has increased year by year. Therefore, treating cancer has become an important issue.
  • the treatment of cancer can be divided into surgical treatment, radiation therapy, chemotherapy and target treatment.
  • cancer drug treatment is intended to prevent cancer cells from replicating and dividing to block the spread and spread of tumors.
  • chemotherapy chemotherapy or target treatment
  • cancer drug treatment is intended to prevent cancer cells from replicating and dividing to block the spread and spread of tumors.
  • chemotherapeutic drugs and target treatment hoping to kill cancer cells by different mechanisms to improve the therapeutic effect, but in fact, patients often react to the treatment of drugs Not good.
  • many cancer cells successively develop drug resistance, which greatly reduces the effectiveness of drug use, and ultimately leads to failure of cancer treatment.
  • cardiovascular disease The purpose of cardiovascular disease is to control symptoms and prevent or delay the progression of the disease. Drugs can play an important role in the treatment of complications of coronary heart disease. For example, cardiovascular disease drugs can prevent high blood pressure and promote heart failure in patients with blood flow.
  • the present invention aims at the development of new indications for various drugs through clinical trials, and achieves the goal of new use of old drugs.
  • cardiovascular disease drugs have no or only minimal toxicity to normal cells, but whether the cardiovascular disease drugs have selective effects between normal cells and tumor cells remains to be further studied. Not all cardiovascular disease drugs can effectively inhibit tumor cells under the same conditions, and many problems need to be overcome.
  • Cardiovascular disease drugs can be divided into 10 categories according to their characteristics: free peripheral vasodilator circulatory enhancer, angiotensin converting sputum inhibitor, hypotension and shock therapeutics, diuretics, antiarrhythmia, anti-strain Medicine, antihypertensive agent, anticoagulant thrombolytic agent, cardiotonic and venous disease (acne) therapeutic agent.
  • a peripheral vasodilator circulating enhancer that acts directly or indirectly on peripheral blood vessels to increase blood flow.
  • the cardiovascular disease drugs of the present invention include Cilnidipine, Minoxidil, Prazosin HCl, Sildenafil citrate, Tadalafil (Cialis), Nicorandil (Ikorel), and Lacifiline (Lacipil, Motens), Benidipine hydrochloride, Cilazapril monohydrate (Inhibace), Fosinopril sodium (Monopril), Almotriptan malate (Axert), Milrinone (Primacor), Avanafil, Lomerizine HCl, Histamine Phosphate, Chromocarb and Pinacidil.
  • Angiotensin-converting sputum inhibitors angiotensin-converting sputum inhibitors, the main pharmacological action is to inhibit ACE activity, reduce the production of angiotensin II, reduce the hydrolysis of bradykinin, lead to vasodilation, blood volume reduction, blood pressure drop .
  • the cardiovascular disease drugs of the present invention include Benazepril hydrochloride, Losartan potassium, Perindopril Erbumine (Aceon), Irbesartan (Avapro), Candesartan (Atacand), Olmesartan medoxomil (Benicar), Enalaprilat dihydrate, Telmisartan (Micardis), and the like.
  • the cardiovascular disease drugs of the present invention are included in this category of L-Adrenaline (Epinephrine), DL-Adrenaline and Methoxamine HCl.
  • the cardiovascular disease drugs of the present invention include Bumetanide, Furosemide (Lasix), Metolazone (Zaroxolyn), Silodosin (Rapaflo), Chlorothiazide, Trichlormethiazide (Achletin), Torsemide (Demadex), Hydrochlorothiazide, Indapamide (Lozol), and the like.
  • Dichlorphenamide Diclofenamide
  • Amiloride hydrochloride dihydrate Solifenacin succinate, Methyclothiazide, Benzthiazide, Meticrane, Bendroflumethiazide and Potassium Canrenoate.
  • An antiarrhythmic agent that inhibits abnormal heartbeat rhythm (arrhythmia) of the heart, such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation.
  • Heart in the invention Vascular disease drugs included in this category are Adenosine (Adenocard), Dofetilide (Tikosyn), Amiodarone HCl, Ibutilide fumarate, Propafenone (Rytmonorm) and Disopyramide Phosphate.
  • the cardiovascular disease drugs of the present invention include Dexrazoxane Hydrochloride, Ranolazine dihydrochloride, Nisoldipine (Sular), Ranolazine (Ranexa), Acadesine, Nifedipine (Adalat), Amlodipine besylate (Norvasc), Diltiazem HCl (Tiazac), Ticagrelor. And Oxprenolol HCl.
  • An antihypertensive agent is a drug used to treat hypertension. Antihypertensive therapy is to prevent complications of hypertension such as stroke and myocardial infarction.
  • the cardiovascular disease drugs of the present invention include Bisoprolol, Doxazosin mesylate, Alfuzosin hydrochloride (Uroxatral), Nebivolol (Bystolic), Reserpine, Methyldopa (Aldomet), Eplerenone, Nimodipine (Nimotop), Betaxolol hydrochloride (Betoptic), Carvedilol, Metoprolol tartrate, Felodipine (Plendil), Amlodipine (Norvasc), Phentolamine mesilate, Imidapril (Tanatril) HCl, Aliskiren hemifumarate, Sodium Nitroprusside, Propranolol HCl, Levobetaxolol HCl, Es
  • Anticoagulant thrombolytic agent A drug used to prevent blood clotting (coagulation), which is present in leeches and blood-sucking insects. Anticoagulants can treat thrombotic diseases.
  • the cardiovascular disease drugs of the present invention include Prasugrel (Effient), Cilostazol, Nafamostat mesylate, Clopidogrel (Plavix), Apixaban, Aminocaproic acid (Amicar), Dipyridamole (Persantine), Phenindione (Rectadione), Ticlopidine HCl, and the like.
  • Cardiotonic agent the cardiovascular disease drug of the present invention is included in this category with Pimobendan (Vetmedin), pilocycline, Ampiroxicam, Digoxigenin, and Pindolol.
  • a venous disease (acne) therapeutic agent the cardiovascular disease drug of the present invention is included in this category: Edaravone (MCI-186) (Edaravone (MCI-186)), Daidzein (Kudzu Soybean Meal, Soybean ⁇ ), Ginkgolide A (ginkgolide A) and Bisacodyl (pyridine methylene bisphenolate; bisacitol).
  • the cancer is one or more of lung cancer, intestinal cancer, colorectal cancer, prostate cancer, liver cancer, bladder cancer, cervical cancer, breast cancer, and blood cancer.
  • Figure 1 shows that various cardiovascular disease drugs have different inhibitory effects on various cancer cells.
  • the present invention provides a use of a medicament for cardiovascular diseases for the preparation of a pharmaceutical composition for inhibiting cancer, wherein the medicament is a cardiovascular disease drug.
  • the cardiovascular disease drugs of the present invention include Lenalidomide (lenalidomide), Valproic acid sodium salt (Sodium valproate) (sodium valproate), Decitabine (decitabine), Bisoprolol, Dexrazoxane Hydrochloride, Prasugrel (Effient) , Benazepril hydrochloride, Bumetanide, Cilnidipine, Cilostazol, Doxazosin mesylate, Edaravone (MCI-186), Losartan potassium, Minoxidil, Nafamostat mesylate, Bimatoprost, Alfuzosin hydrochloride (Uroxatral), Clopidogrel (Plavix), Prazosin HCl, Ranolazine dihydrochloride, Sildenafil citrate, Perindopril Erbu
  • the original culture solution in the 96-well plate was aspirated, and a commercially available drug having a concentration of 10 uM and a volume of 100 ul was added to each well. After 72 hours, 100 ul of diluted WST-1 reagent was added to each well, and the dilution ratio was the culture solution and The volume ratio of the WST-1 stock solution was 9:1, and finally the total volume of each well plate was 200 ⁇ l. Then, the 96-well plate was placed at 37 ° C for 30-90 minutes, and the absorbance was detected by OD450 using an ELISA analyzer. The survival rate of each cancer cell line was calculated.
  • Cardiovascular disease drugs are used to inhibit cancer cell analysis results
  • the ten major cardiovascular diseases obtained include free radical vasodilator circulatory enhancer, angiotensin converting sputum inhibitor, hypotension and shock therapeutic agent, diuretic, antiarrhythmia, anti-drug
  • the drug for narrow-heart disease, antihypertensive agent, anticoagulant thrombolytic agent, cardiotonic agent, and venous disease (acne) is tested to inhibit the growth of cancer cells.
  • the relative cardiovascular disease drugs have different inhibitory effects on various cancer cells (Fig. 1).
  • the cardiovascular disease drugs Lenalidomide, Valproic acid sodium salt (Sodium valproate), Decitabine, Bisoprolol, Dexrazoxane Hydrochloride, Prasugrel (Effient), Benazepril hydrochloride, Bumetanide, Cilnidipine, Cilostazol, Doxazosin mesylate, Edaravone (MCI-186), Losartan potassium, Minoxidil, Nafamostat mesylate, Bimatoprost, Alfuzosin hydrochloride (Uroxatral), Clopidogrel (Plavix ), Prazosin HCl, Ranolazine dihydrochloride, Sildenafil citrate, Perindopril Erbumine (Aceon), Irbesartan (Avapro), Tadalafil (Cialis), Nebivolol (Bystolic

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Abstract

提供多种心血管疾病药物的临床应用。该多种心血管疾病药物均是经过卫生署通过核准上市的心血管疾病药物。提供多种心血管疾病药物有效的抑制不同类型的癌细胞。

Description

心血管疾病用药物在制备抑制癌症的医药组合物中的应用 技术领域
本发明涉及多种心血管疾病药物的新适应症应用，尤其该多种药物为通过临床实验且具有抑制多种癌症的用途。
背景技术
癌症长期高居全球死因之首，且罹患癌症人数更是逐年攀升，因此治疗癌症俨然成为重要的课题。癌症的治疗可区分为手术治疗、放射线治疗、化学治疗及标靶治疗。
一般来说，癌症药物治疗无论是化学治疗或标靶治疗，目的多是让癌细胞无法复制、分裂，来阻断肿瘤的蔓延扩张。在临床治疗选择上，通常会结合一到数种化疗药物以及标靶治疗，希望能藉由不同机制来杀死癌细胞以提高治疗效果，但事实上，还是常遇到患者对于治疗药物的反应不佳。进一步，许多癌细胞相继产生抗药性，使药物的使用成效大幅降低，最终导致癌症治疗失败。
心血管疾病的目的是控制症状，阻止或延缓疾病的进展。药物可用于治疗冠心病的并发症中起重要作用。例如，心血管疾病药物可防治高血压，促进血液流动的患者心脏衰竭。
发明人依据长年的研究经验，人类的癌症细胞常常有与正常细胞具有不同的表现性状，型态上的差异或是作用机转的变化或许也有可能被视为一种外来的侵入者，而每一种癌症细胞所在的位置不同，变异的状态又与所处的环境有关，因此，第一个提出使用心血管疾病药物抑制癌症细胞的发明概念并且进行实验。
相对的，在这些已经使用数十年心血管疾病药物，是早已被FDA所认可的用药，具有大量药物机转及人体研究成果数据，因此，若应用在癌症方面，这 项新发展会更省时、减少成本，也能和其他治疗方式结合来提高效果。
尽管如此，药物开发依然是重要的医学议题，必须经过繁复的临床前试验才能进入临床试验，根据统计，平均每一万个新药约只有五个能够进入第一期临床试验。此外，除了药物本身是否能大量制造的难题外，还需克服药物安全性、病人筛选、试用剂量等问题，即便药物已经通过FDA的核准并上市，亦有可能因上市后于人体发现不良反应而强制下架回收，由此可见药物开发具有一定的困难程度。
发明内容
为解决上述的问题，本发明针对通过临床实验的多种药物进行新适应症的研发，而达到老药新用的目标。
经过实验设计结果显示心血管疾病药物对正常细胞没有或仅有微小的毒性，但至于心血管疾病药物在正常细胞与肿瘤细胞之间是否具有选择性的影响，还待更多的研究厘清，而且并非所有的心血管疾病药物在相同的条件下均能有效的抑制肿瘤细胞，需要有许多的问题进行克服。
名词定义
心血管疾病药物可依照特性分为10大类，分别为自由末梢血管扩张剂循环增强剂、血管张力素转换脢抑制剂、低血压及休克治疗剂、利尿剂、抗心律不整剂、抗狭心症药物、抗高血压剂、抗凝血剂血栓溶解剂、强心剂及静脉疾患(痔疮)治疗剂。
1.末梢血管扩张剂循环增强剂，其可直接或间接作用于周边血管以增加血流。本发明中的心血管疾病药物包含在本类别的有Cilnidipine、Minoxidil、Prazosin HCl、Sildenafil citrate、Tadalafil(Cialis)、Nicorandil(Ikorel)、Lacidipine(Lacipil, Motens)、Benidipine hydrochloride、Cilazapril monohydrate(Inhibace)、Fosinopril sodium(Monopril)、Almotriptan malate(Axert)、Milrinone(Primacor)、Avanafil、Lomerizine HCl、Histamine Phosphate、Chromocarb及Pinacidil。
2.血管张力素转换脢抑制剂，血管张力素转换脢抑制剂主要的药理作用是抑制ACE活性，减少血管张力素II的生成，减少缓激肽的水解，导致血管舒张，血容量减少血压下降。本发明中的心血管疾病药物包含在本类别的有Benazepril hydrochloride、Losartan potassium、Perindopril Erbumine(Aceon)、Irbesartan(Avapro)、Candesartan(Atacand)、Olmesartan medoxomil(Benicar)、Enalaprilat dihydrate、Telmisartan(Micardis)、Ramipril(Altace)、Valsartan(Diovan)、Enalapril maleate(Vasotec)、Candesartan cilexetil(Atacand)、Conivaptan HCl(Vaprisol)、Azilsartan Medoxomil(TAK-491)及Eprosartan Mesylate。
3.低血压及休克治疗剂，本发明中的心血管疾病药物包含在本类别的有L-Adrenaline(Epinephrine)、DL-Adrenaline及Methoxamine HCl。
4.利尿剂，其促进尿液的生成，增加人体水分的排出。本发明中的心血管疾病药物包含在本类别的有Bumetanide、Furosemide(Lasix)、Metolazone(Zaroxolyn)、Silodosin(Rapaflo)、Chlorothiazide、Trichlormethiazide(Achletin)、Torsemide(Demadex)、Hydrochlorothiazide、Indapamide(Lozol)、Dichlorphenamide(Diclofenamide)、Amiloride hydrochloride dihydrate、Solifenacin succinate、Methyclothiazide、Benzthiazide、Meticrane、Bendroflumethiazide及Potassium Canrenoate。
5.抗心律不整剂，其可抑制心脏的不正常心跳节律(心律不整)，例如心房颤动、心房扑动、室性心动过速(ventricular tachycardia)和心室颤动。本发明中的心 血管疾病药物包含在本类别的有Adenosine(Adenocard)、Dofetilide(Tikosyn)、Amiodarone HCl、Ibutilide fumarate、Propafenone(Rytmonorm)及Disopyramide Phosphate。
6.抗狭心症药物，其用于治疗缺血性心脏疾病的症状。本发明中的心血管疾病药物包含在本类别的有Dexrazoxane Hydrochloride、Ranolazine dihydrochloride、Nisoldipine(Sular)、Ranolazine(Ranexa)、Acadesine、Nifedipine(Adalat)、Amlodipine besylate(Norvasc)、Diltiazem HCl(Tiazac)、Ticagrelor及Oxprenolol HCl。
7.抗高血压剂是一种用于治疗高血压的药物。降压治疗在于防止高血压并发症，如中风和心肌梗塞。本发明中的心血管疾病药物包含在本类别的有Bisoprolol、Doxazosin mesylate、Alfuzosin hydrochloride(Uroxatral)、Nebivolol(Bystolic)、Reserpine、Methyldopa(Aldomet)、Eplerenone、Nimodipine(Nimotop)、Betaxolol hydrochloride(Betoptic)、Carvedilol、Metoprolol tartrate、Felodipine(Plendil)、Amlodipine(Norvasc)、Phentolamine mesilate、Imidapril(Tanatril)HCl、Aliskiren hemifumarate、Sodium Nitroprusside、Propranolol HCl、Levobetaxolol HCl、Esmolol HCl、(R)-(+)-Atenolol、Guanethidine Sulfate及Lofexidine HCl。
8.抗凝血剂、血栓溶解剂用于防止血液凝固(凝血)的药物，此类物质存在于水蛭与吸血昆虫。抗凝血剂可治疗血栓性疾病。本发明中的心血管疾病药物包含在本类别的有Prasugrel(Effient)、Cilostazol、Nafamostat mesylate、Clopidogrel(Plavix)、Apixaban、Aminocaproic acid(Amicar)、Dipyridamole(Persantine)、Phenindione(Rectadione)、Ticlopidine HCl、Ozagrel HCl、Argatroban、Bexarotene、Gabexate mesylate及Ozagrel及Anisindione。
9.强心剂，本发明中的心血管疾病药物包含在本类别的有Pimobendan (Vetmedin)(匹莫苯)、Ampiroxicam(安吡昔康)、Digoxigenin(异羟基洋地黄毒甙元)及Pindolol(品多洛尔)。
10.静脉疾患(痔疮)治疗剂，本发明中的心血管疾病药物包含在本类别的有Edaravone(MCI-186)(依达拉奉(MCI-186))、Daidzein(葛根黄豆甙元、黄豆甙元)、Ginkgolide A(银杏苦内酯A)及Bisacodyl(吡啶亚甲双酚酯；比沙可定)。
癌症为肺癌、肠道癌、大肠直肠癌、前列腺癌、肝癌、膀胱癌、子宫颈癌、乳癌及血癌中的一种或多种。
附图说明
图1为各种心血管疾病药物对于各种癌症细胞的抑制效果不尽相同。
具体实施方式
本发明提供一种心血管疾病用药物在制备抑制癌症的医药组合物中的应用，其中所述药物为心血管疾病药物。本发明所述的心血管疾病药物包括Lenalidomide(来那度胺)、Valproic acid sodium salt(Sodium valproate)(丙戊酸钠)、Decitabine(地西他滨)、Bisoprolol、Dexrazoxane Hydrochloride、Prasugrel(Effient)、Benazepril hydrochloride、Bumetanide、Cilnidipine、Cilostazol、Doxazosin mesylate、Edaravone(MCI-186)、Losartan potassium、Minoxidil、Nafamostat mesylate、Bimatoprost、Alfuzosin hydrochloride(Uroxatral)、Clopidogrel(Plavix)、Prazosin HCl、Ranolazine dihydrochloride、Sildenafil citrate、Perindopril Erbumine(Aceon)、Irbesartan(Avapro)、Tadalafil(Cialis)、Nebivolol(Bystolic)、Pimobendan(Vetmedin)、Candesartan(Atacand)、Apixaban、Reserpine、Furosemide(Lasix)、Olmesartan medoxomil(Benicar)、Pyridostigmine Bromide(Mestinon)、Metolazone(Zaroxolyn)、Silodosin(Rapaflo)、Chlorothiazide、Methyldopa(Aldomet)、Adenosine(Adenocard)、Ezetimibe(Zetia)、 Enalaprilat dihydrate、Dofetilide (Tikosyn)、Trichlormethiazide (Achletin)、Aminocaproic acid (Amicar)、Busulfan (Myleran, Busulfex)、Torsemide (Demadex)、Eplerenone、Hydrochlorothiazide、Gemfibrozil (Lopid)、Indapamide (Lozol)、Telmisartan (Micardis)、Nimodipine (Nimotop)、Nisoldipine (Sular)、Pitavastatin calcium (Livalo)、Simvastatin(Zocor)、 Ramipril (Altace)、 Fenofibrate (Tricor, Trilipix)、 Ranolazine (Ranexa)、Acadesine、Acipimox、Nifedipine (Adalat)、Amlodipine besylate (Norvasc)、Clofibrate(Atromid-S)、Betaxolol hydrochloride (Betoptic)、Carvedilol、Daidzein、toprolol tartrate、Diltiazem HCl (Tiazac)、Tranexamic acid (Transamin)、Felodipine (Plendil)、Valsartan(Diovan)、 Dipyridamole (Persantine)、 Amlodipine (Norvasc)、 Fluvastatin sodium(Lescol)、Phenindione (Rectadione)、Enalapril maleate (Vasotec)、Nicorandil (Ikorel)、Amiodarone HCl、Ticlopidine HCl、Lacidipine (Lacipil， Motens)、Suplatast tosylate、Benidipine hydrochloride、Ginkgolide A、Candesartan cilexetil (Atacand)、Phentolamine mesilate、Nimesulide、Cytidine、Bromhexine HCl、Tiopronin (Thiola)、Ozagrel HCl、Argatroban、Mitiglinide calcium、Rosiglitazone HCl、Atorvastatin calcium (Lipitor)、Famotidine (Pepcid)、 Cleviprex (Clevidipine)、 Cilazapril monohydrate (Inhibace)、Adiphenine HCl、Rivastigmine tartrate (Exelon)、Detomidine HCl、Fosinopril sodium(Monopril)、Almotriptan malate (Axert)、Bexarotene、Gabexate mesylate、Rasagiline mesylate、Imidapril (Tanatril) HCl、Conivaptan HCl (Vaprisol)、Ibutilide fumarate、Probucol、Arbidol HCl、S-(+)-Rolipram、Tebipenem pivoxil (L-084)、Dichlorphenamide(Diclofenamide)、 Aliskiren hemifumarate、 DL-Carnitine hydrochloride、 D-Mannitol(Osmitrol)、 L-carnitine (Levocarnitine)、 Amantadine hydrochloride (Symmetrel)、Clozapine (Clozaril)、Milrinone (Primacor)、Mitoxantrone Hydrochloride、Novobiocin  sodium(Albamycin)、Ozagrel、Pancuronium(Pavulon)、Propafenone(Rytmonorm)、Quinine hydrochloride dihydrate、Spectinomycin hydrochloride、Xylazine HCl、L-Adrenaline(Epinephrine)、DL-Adrenaline、Trospium chloride(Sanctura)、Amiloride hydrochloride dihydrate、Cloxacillin sodium(Cloxacap)、Zidovudine(Retrovir)、Thiamphenicol(Thiophenicol)、Oseltamivir phosphate(Tamiflu)、Lonidamine、Peramivir Trihydrate、Carfilzomib(PR-171)、Pazopanib、Fosaprepitant dimeglumine、Otilonium Bromide、Solifenacin succinate、Besifloxacin HCl(Besivance)、Azilsartan Medoxomil(TAK-491)、Creatinine、Adrenalone HCl、Ampiroxicam、Desloratadine、Avanafil、Bisacodyl、Methyclothiazide、Sodium Nitroprusside、Vitamin D3(Cholecalciferol)、Deferiprone、Propranolol HCl、Mefenamic acid、Ticagrelor、sulfacetamide sodium、Lomerizine HCl、Levobetaxolol HCl、Dexlansoprazole、Esmolol HCl、Eprosartan Mesylate、Histamine Phosphate、Sevelamer HCl、Deoxyarbutin、Clorprenaline HCL、Ethamsylate、Chromocarb、Mevastatin、Mexiletine HCl、Phenazopyridine HCl、(R)-(+)-Atenolol、Anisindione、Benzthiazide、Disopyramide Phosphate、Guanethidine Sulfate、Isoetharine Mesylate、Methoxamine HCl、Meticrane、Oxprenolol HCl、Pinacidil、Bendroflumethiazide、Potassium Canrenoate、Digoxigenin、Lofexidine HCl及Pindolol。
1.建立细胞株
请参考表一，将不同癌症类型的细胞株进行继代培养，计算细胞数目后，回种2×106个细胞数，然后加入培养该细胞株的培养液补至体积为10ml，继续培养2-3天。之后将细胞计数，并分装至96孔盘，其中每孔的细胞数目固定为3000颗，且体积为100ul，发明人仍在建立其他细胞株以进行后续试验。
表一、细胞株及其培养所用的培养液
Figure PCTCN2015092768-appb-000001
2.细胞存活分析
将96孔盘中原有的培养液吸掉，每孔加入浓度10uM、体积100ul的市售药物，放置72小时后，每孔再加入100ul已稀释的WST-1试剂，该稀释比例为培养液与WST-1原液的体积比为9：1，最后每个孔盘的总体积为200μl，然后将96孔盘放置于37℃，30～90分钟，利用ELISA分析仪于OD450侦测吸光值，并计算各癌症细胞株的存活率。
3.心血管疾病药物应用于抑制癌细胞分析结果
依据细胞存活分析方法针对取得的十大类心血管疾病药物，包含自由末梢血管扩张剂循环增强剂、血管张力素转换脢抑制剂、低血压及休克治疗剂、利尿剂、抗心律不整剂、抗狭心症药物、抗高血压剂、抗凝血剂血栓溶解剂、强心剂、静脉疾患(痔疮)治疗剂进行测试抑制癌细胞生长的效果。
实验结果明显的显示有许多的心血管疾病药物无法有效的抑制癌症的细胞的生长，如表二。
表二、对癌症细胞株无抑制效果的心血管疾病药物
心血管疾病药物 抑制癌症细胞株的数量
Bisoprolol 0
Benazepril hydrochloride 0
Bumetanide 0
Furosemide(Lasix) 0
Trichlormethiazide(Achletin) 0
Aminocaproic acid(Amicar) 0
Indapamide(Lozol) 0
Simvastatin(Zocor) 0
Ramipril(Altace) 0
Fenofibrate(Tricor,Trilipix) 0
Acadesine 0
Acipimox 0
Ticlopidine HCl 0
Adiphenine HCl 0
Rivastigmine tartrate(Exelon) 0
Detomidine HCl 0
Gabexate mesylate 0
Rasagiline mesylate 0
S-(+)-Rolipram 0
Tebipenem pivoxil(L-084) 0
Aliskiren hemifumarate 0
Milrinone(Primacor) 0
Novobiocin sodium(Albamycin) 0
Ozagrel 0
Pancuronium(Pavulon) 0
Propafenone(Rytmonorm) 0
Xylazine HCl 0
L-Adrenaline(Epinephrine) 0
Lonidamine 0
Bisacodyl 0
Sodium Nitroprusside 0
Mefenamic acid 0
Ticagrelor 0
sulfacetamide sodium 0
Levobetaxolol HCl 0
Dexlansoprazole 0
Chromocarb 0
Guanethidine Sulfate 0
Isoetharine Mesylate 0
而相对的各种的心血管疾病药物对于各种癌症细胞的抑制效果也不尽相同(如图1)，经过发明人实验结果，证实心血管疾病药物Lenalidomide、Valproic acid sodium salt(Sodium valproate)、Decitabine、Bisoprolol、Dexrazoxane Hydrochloride、Prasugrel(Effient)、Benazepril hydrochloride、Bumetanide、Cilnidipine、Cilostazol、Doxazosin mesylate、Edaravone(MCI-186)、Losartan potassium、Minoxidil、Nafamostat mesylate、Bimatoprost、Alfuzosin hydrochloride(Uroxatral)、Clopidogrel(Plavix)、Prazosin HCl、Ranolazine dihydrochloride、Sildenafil citrate、Perindopril Erbumine(Aceon)、Irbesartan(Avapro)、Tadalafil(Cialis)、Nebivolol(Bystolic)、Pimobendan(Vetmedin)、Candesartan(Atacand)、Apixaban、Reserpine、Furosemide(Lasix)、Olmesartan medoxomil(Benicar)、Pyridostigmine Bromide(Mestinon)、Metolazone(Zaroxolyn)、Silodosin(Rapaflo)、Chlorothiazide、Methyldopa(Aldomet)、Adenosine(Adenocard)、Ezetimibe(Zetia)、Enalaprilat dihydrate、Dofetilide(Tikosyn)、Trichlormethiazide(Achletin)、Aminocaproic acid(Amicar)、Busulfan(Myleran, Busulfex)、 Torsemide (Demadex)、 Eplerenone、 Hydrochlorothiazide、 Gemfibrozil(Lopid)、Indapamide (Lozol)、Telmisartan (Micardis)、Nimodipine (Nimotop)、Nisoldipine(Sular)、Pitavastatin calcium (Livalo)、Simvastatin (Zocor)、Ramipril (Altace)、Fenofibrate(Tricor, Trilipix)、Ranolazine (Ranexa)、Acadesine、Acipimox、Nifedipine (Adalat)、Amlodipine besylate (Norvasc)、 Clofibrate (Atromid-S)、 Betaxolol hydrochloride(Betoptic)、Carvedilol、Daidzein、toprolol tartrate、Diltiazem HCl (Tiazac)、Tranexamic acid (Transamin)、Felodipine (Plendil)、Valsartan (Diovan)、Dipyridamole (Persantine)、Amlodipine (Norvasc)、Fluvastatin sodium (Lescol)、Phenindione (Rectadione)、Enalapril maleate (Vasotec)、Nicorandil (Ikorel)、Amiodarone HCl、Ticlopidine HCl、Lacidipine(Lacipil， Motens)、 Suplatast tosylate、 Benidipine hydrochloride、 Ginkgolide A、Candesartan cilexetil (Atacand)、 Phentolamine mesilate、 Nimesulide、 Cytidine、Bromhexine HCl、Tiopronin (Thiola)、Ozagrel HCl、Argatroban、Mitiglinide calcium、Rosiglitazone HCl、 Atorvastatin calcium (Lipitor)、Famotidine (Pepcid)、 Cleviprex(Clevidipine)、Cilazapril monohydrate (Inhibace)、Adiphenine HCl、Rivastigmine tartrate(Exelon)、Detomidine HCl、Fosinopril sodium (Monopril)、Almotriptan malate (Axert)、Bexarotene、 Gabexate mesylate、 Rasagiline mesylate、 Imidapril (Tanatril) HCl、Conivaptan HCl (Vaprisol)、Ibutilide fumarate、Probucol、Arbidol HCl、S-(+)-Rolipram、Tebipenem pivoxil (L-084)、Dichlorphenamide (Diclofenamide)、Aliskiren hemifumarate、DL-Carnitine hydrochloride、 D-Mannitol (Osmitrol)、 L-carnitine (Levocarnitine)、Amantadine hydrochloride (Symmetrel)、Clozapine (Clozaril)、Milrinone (Primacor)、Mitoxantrone Hydrochloride、Novobiocin sodium (Albamycin)、Ozagrel、Pancuronium(Pavulon)、Propafenone (Rytmonorm)、Quinine hydrochloride dihydrate、Spectinomycin  hydrochloride、Xylazine HCl、L-Adrenaline(Epinephrine)、DL-Adrenaline、Trospium chloride(Sanctura)、Amiloride hydrochloride dihydrate、Cloxacillin sodium(Cloxacap)、Zidovudine(Retrovir)、Thiamphenicol(Thiophenicol)、Oseltamivir phosphate(Tamiflu)、Lonidamine、Peramivir Trihydrate、Carfilzomib(PR-171)、Pazopanib、Fosaprepitant dimeglumine、Otilonium Bromide、Solifenacin succinate、Besifloxacin HCl(Besivance)、Azilsartan Medoxomil(TAK-491)、Creatinine、Adrenalone HCl、Ampiroxicam、Desloratadine、Avanafil、Bisacodyl、Methyclothiazide、Sodium Nitroprusside、Vitamin D3(Cholecalciferol)、Deferiprone、Propranolol HCl、Mefenamic acid、Ticagrelor、sulfacetamide sodium、Lomerizine HCl、Levobetaxolol HCl、Dexlansoprazole、Esmolol HCl、Eprosartan Mesylate、Histamine Phosphate、Sevelamer HCl、Deoxyarbutin、Clorprenaline HCL、Ethamsylate、Chromocarb、Mevastatin、Mexiletine HCl、Phenazopyridine HCl、(R)-(+)-Atenolol、Anisindione、Benzthiazide、Disopyramide Phosphate、Guanethidine Sulfate、Isoetharine Mesylate、Methoxamine HCl、Meticrane、Oxprenolol HCl、Pinacidil、Bendroflumethiazide、Potassium Canrenoate、Digoxigenin、Lofexidine HCl及Pindolol能有效的抑制癌症的细胞的生长，具有抑制癌症的效果，试验结果如表三。
发明所揭露的所有特征应可以任何结合方式实现。本发明所揭露的每一特征应可以相同、均等或相似目的的取代物所取代。因此，除非有明确的指定，否则所揭露的每一个特征仅仅只是均等物或相似特征的一个种类的一实施例。
由上述内容可知，任何所属本领域技术人员，将可轻易从本发明所揭露的内容中了解到本发明的特征，在不偏离随附权利要求书所界定的本发明的精神与范围下，当可在此进行各种改变、取代以及修正。因此，其他实施例亦落于本 发明权利要求书所要求保护的范围之内。
Figure PCTCN2015092768-appb-000002
Figure PCTCN2015092768-appb-000003
Figure PCTCN2015092768-appb-000004
Figure PCTCN2015092768-appb-000005
Figure PCTCN2015092768-appb-000006

Claims (13)

  1. 一种心血管疾病用药物在制备抑制癌症的医药组合物中的应用，其特征是，所述药物为心血管疾病药物。
  2. 如权利要求1所述的应用，其特征是，所述心血管疾病药物为末梢血管扩张剂循环增强剂、血管张力素转换脢抑制剂、低血压及休克治疗剂、利尿剂、抗心律不整剂、抗狭心症药物、抗高血压剂、抗凝血剂血栓溶解剂、强心剂、静脉疾患(痔疮)治疗剂中的一种或多种。
  3. 如权利要求2所述的应用，其特征是，所述末梢血管扩张剂循环增强剂为Cilnidipine、Minoxidil、Prazosin HCl、Sildenafil citrate、Tadalafil(Cialis)、Nicorandil(Ikorel)、Lacidipine(Lacipil,Motens)、Benidipine hydrochloride、Cilazapril monohydrate(Inhibace)、Fosinopril sodium(Monopril)、Almotriptan malate(Axert)、Milrinone(Primacor)、Avanafil、Lomerizine HCl、Histamine Phosphate、Chromocarb及Pinacidil中的一种或多种所组成的药物。
  4. 如权利要求2所述的应用，其特征是，所述血管张力素转换脢抑制剂为Benazepril hydrochloride、Losartan potassium、Perindopril Erbumine(Aceon)、Irbesartan(Avapro)、Candesartan(Atacand)、Olmesartan medoxomil(Benicar)、Enalaprilat dihydrate、Telmisartan(Micardis)、Ramipril(Altace)、Valsartan(Diovan)、Enalapril maleate(Vasotec)、Candesartan cilexetil(Atacand)、Conivaptan HCl(Vaprisol)、Azilsartan Medoxomil(TAK-491)及Eprosartan Mesylate中的一种或多种所组成的药物。
  5. 如权利要求2所述的应用，其特征是，所述低血压及休克治疗剂系选自由 L-Adrenaline(Epinephrine)(L-肾上腺素)、DL-Adrenaline(DL-肾上腺激素)及Methoxamine HCl(甲氧胺盐酸盐)所组成之药物。
  6. 如权利要求2所述的应用，其特征是，所述利尿剂为Bumetanide、Furosemide(Lasix)、Metolazone(Zaroxolyn)、Silodosin(Rapaflo)、Chlorothiazide、Trichlormethiazide(Achletin)、Torsemide(Demadex)、Hydrochlorothiazide、Indapamide(Lozol)、Dichlorphenamide(Diclofenamide)、Amiloride hydrochloride dihydrate、Solifenacin succinate、Methyclothiazide、Benzthiazide、Meticrane、Bendroflumethiazide及Potassium Canrenoate中的一种或多种所组成的药物。
  7. 如权利要求2所述的应用，其特征是，所述抗心律不整剂是选自由Adenosine(Adenocard)、Dofetilide(Tikosyn)、Amiodarone HCl、Ibutilide fumarate、Propafenone(Rytmonorm)及Disopyramide Phosphate中的一种或多种所组成的药物。
  8. 如权利要求2所述的应用，其特征是，所述抗狭心症药物为Dexrazoxane Hydrochloride、Ranolazine dihydrochloride、Nisoldipine(Sular)、Ranolazine(Ranexa)、Acadesine、Nifedipine(Adalat)、Amlodipine besylate(Norvasc)、Diltiazem HCl(Tiazac)、Ticagrelor及Oxprenolol HCl中的一种或多种所组成的药物。
  9. 如权利要求2所述的应用，其特征是，所述抗高血压剂为Bisoprolol、Doxazosin mesylate、Alfuzosin hydrochloride(Uroxatral)、Nebivolol(Bystolic)、Reserpine、Methyldopa(Aldomet)、Eplerenone、Nimodipine(Nimotop)、Betaxolol hydrochloride(Betoptic)、Carvedilol、Metoprolol tartrate、Felodipine(Plendil)、Amlodipine(Norvasc)、Phentolamine mesilate、Imidapril(Tanatril)HCl、Aliskiren hemifumarate、Sodium  Nitroprusside、Propranolol HCl、Levobetaxolol HCl、Esmolol HCl、(R)-(+)-Atenolol、Guanethidine Sulfate及Lofexidine HCl中的一种或多种所组成的药物。
  10. 如权利要求2所述的应用，其特征是，所述抗凝血剂血栓溶解剂为Prasugrel(Effient)、Cilostazol、Nafamostat mesylate、Clopidogrel(Plavix)、Apixaban、Aminocaproic acid(Amicar)、Dipyridamole(Persantine)、Phenindione(Rectadione)、Ticlopidine HCl、Ozagrel HCl、Argatroban、Bexarotene、Gabexate mesylate及Ozagrel及Anisindione中的一种或多种所组成的药物。
  11. 如权利要求2所述的应用，其特征是，所述强心剂为Pimobendan(Vetmedin)(匹莫苯)、Ampiroxicam(安吡昔康)、Digoxigenin(异羟基洋地黄毒甙元)及Pindolol(品多洛尔、心得静)中的一种或多种所组成的药物。
  12. 如权利要求2所述的应用，其特征是，所述静脉疾患(痔疮)治疗剂为Edaravone(MCI-186)(依达拉奉(MCI-186))、Daidzein(葛根黄豆甙元、黄豆甙元)、Ginkgolide A(银杏苦内酯A)及Bisacodyl(吡啶亚甲双酚酯；比沙可定)中的一种或多种所组成的药物。
  13. 如权利要求1所述的应用，其特征是，所述癌症为肺癌、肠道癌、大肠直肠癌、前列腺癌、肝癌、膀胱癌、子宫颈癌、乳癌及血癌中的一种或多种。
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WO2016062277A1 (zh) 2016-04-28
WO2016062285A1 (zh) 2016-04-28
TW201615191A (zh) 2016-05-01
TW201615225A (zh) 2016-05-01
TW201615218A (zh) 2016-05-01
US10105357B2 (en) 2018-10-23
US20170304228A1 (en) 2017-10-26
WO2016062275A1 (zh) 2016-04-28
WO2016062271A1 (zh) 2016-04-28
WO2016062283A1 (zh) 2016-04-28
TW201615196A (zh) 2016-05-01
TWI621434B (zh) 2018-04-21
TW201615223A (zh) 2016-05-01
EP3222278A1 (en) 2017-09-27
TW201615221A (zh) 2016-05-01
TW201615188A (zh) 2016-05-01
KR20170084034A (ko) 2017-07-19
TWI663984B (zh) 2019-07-01
WO2016062274A1 (zh) 2016-04-28
TW201615192A (zh) 2016-05-01

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