CN102036993B - 纳美芬二酯前药 - Google Patents
纳美芬二酯前药 Download PDFInfo
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- CN102036993B CN102036993B CN200980114294.8A CN200980114294A CN102036993B CN 102036993 B CN102036993 B CN 102036993B CN 200980114294 A CN200980114294 A CN 200980114294A CN 102036993 B CN102036993 B CN 102036993B
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Abstract
本发明涉及式(I)的纳美芬的前药,包括这些化合物的药物组合物,制备这些化合物的化学方法和它们在治疗物质滥用障碍如酒精滥用和酒精依赖和脉冲控制障碍如病理性投机和购物上瘾中的用途。
Description
本发明涉及式(I)的纳美芬的前药,包括这些化合物的药物组合物,制备这些化合物的化学方法和它们在治疗物质滥用障碍如酒精滥用和酒精依赖和脉冲控制障碍如病理性投机和购物上瘾中的用途。
纳美芬是鸦片样物质受体拮抗体,其已经可利用数年,作为注射用于逆转鸦片样物质作用和用于鸦片样物质过度使用。纳美芬还描述于文献中用于治疗物质滥用障碍如酒精依赖和滥用,和脉冲控制障碍如病理性投机和购物上瘾。它具有IUPAC名称17-环丙基甲基-4,5α-环氧-6-亚甲基吗啡喃(morphinan)-3,14-二醇并且具有以下结构:
Arch.Gen.Psychiatry,56,719-724(1999)公开了对于酒精依赖的双盲的、安慰剂-对照的研究,其中志愿者口服给予20或80mg每日剂量的纳美芬达12周来评估安全和效力。
Alcoholism:Clinical and Experimental Research,31,1179-1187(2007)描述了酗酒者的多位置、随机化双盲研究,所述酗酒者被教导当它们认为喝酒迫在眉睫时口服10至40mg的纳美芬。该研究的结论是纳美芬似乎在降低酗酒方面是有效且安全的。
EP-0,250,796公开了许多3-羟基吗啡喃的脂族、芳族、碳酸酯、氨基甲酸酯和磺酸酯前药,其缺乏苦味并且因此适用于口服如口腔(buccal)、鼻用或舌下给药。
WO-03/070191公开了包括鸦片样物质的用于治疗或预防疼痛的抗干扰经皮输送装置。所公开的输送装置还包括当滥用者干扰该设备以便企图从输送装置中提取鸦片样物质时释放的酰基鸦片样物质拮抗剂。鸦片样物质拮抗剂由此削弱或抑制鸦片样物质的精神愉快的作用。
不幸地,纳美芬的商品化使用的制剂仅仅在有限的时间间隔期间获得治疗有效的血浆水平。长效的纳美芬剂型在治疗中将是有用的并且将提高患者的配合性,这在治疗物质滥用障碍和脉冲控制障碍中是非常重要的。
现在已经发现式(I)的纳美芬前药化合物在长时间期间内提供了纳美芬的治疗相关的血浆水平。当式(I)的化合物肌内给予时,它们可以在数周直至数月的期间内提供纳美芬的治疗相关的血浆水平。同样,当式(I)的化合物口服给予时,它们可以在数天的期间内提供纳美芬的治疗相关的血浆水平。
本发明涉及式(I)的化合物
包括其任何立体化学异构形式,其中
R1是C16-20烷氧基羰基C2-4烷基;
或其药用可接受的酸加成盐,或其溶剂化物。
如用于上述定义中的:
C2-4烷基定义了具有2至4个碳原子的直和支链饱和烃基团,例如乙基、丙基、丁基、1-甲基乙基、2-甲基丙基等;
C3烷基定义了具有3个碳原子的直和支链饱和烃基团,例如丙基、或甲基乙基;
C16-20烷基定义了具有16至20个碳原子的直和支链饱和烃基团,例如十六烷基、十七烷基、十八烷基、十九烷基、二十烷基等。
如以上使用的术语“立体化学异构形式”定义了式(I)的化合物可以具有的全部可能的异构形式。除非另作说明或标明,化合物的化学命名表示全部可能的立体化学异构形式的混合物,所述混合物包含了基本分子结构的全部非对映体和对映体。更特别地,立体异构(stereogenic)中心可以具有R-或S-构型。立体化学异构形式的式(I)的化合物明显地意图包含在本发明范围内。
式(I)的化合物和用于其制备的中间体的绝对立体化学构型可以由本领域技术人员使用众所周知的方法如X射线衍射容易地测定。
如在上文提及的药用可接受的酸加成盐意图包括式(I)的化合物能够形成的治疗活性无毒性的酸加成盐形式。这些药用可接受的酸加成盐能够便利地通过用这样的合适的酸处理碱形式来获得。适当的酸包括,例如,无机酸如氢卤酸,例如氢氯酸或氢溴酸、硫酸、硝酸、磷酸和类似的酸;或有机酸,例如乙酸、丙酸、羟基乙酸、乳酸、丙酮酸、草酸(即乙二酸)、丙二酸、琥珀酸(即丁二酸)、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环拉酸、水杨酸、对氨基水杨酸、扑酸和类似的酸。
相反地,通过用合适的碱处理,所述盐形式可以被转化为游离碱形式。
式(I)的化合物可以以未溶剂化和溶剂化的形式存在。本文中使用术语“溶剂化物”来描述分子缔合,其包括本发明的化合物和一种或多种药用可接受的溶剂分子,例如水或乙醇。当所述溶剂是水时,使用术语“水合物”。
前药是药理学物质(药物),其以非活性(或显著较小活性)的形式给予。一旦给予,前药体内代谢为其活性母体药物。前药常常是有用的,因为,在一些情况中,它们比母体药物可以更容易地给予。它们可以,例如,是通过口服生物可利用的,然而母体不是。前药也可具有在药物组合物中改进的溶解性,相比于母体药物来说,或者可能显示出提高的适口性或者更容易地配制。
在一种实施方案中,本发明涉及式(I)的那些化合物,其中一种或多种以下限制适用:
a)R1是C18烷氧基羰基C3烷基;或
b)R1是正十八烷氧基羰基丙基。
式(I)的化合物可以通过技术上已知的酯化方法制备,包括使纳美芬(II)与式(III)的酰基卤在碱存在下反应而采集在反应期间释放的酸。式(III)的酰基卤中的R1取代基被定义为C16-20烷氧基羰基C2-4烷基。
本发明的化合物显示出是长效鸦片样物质受体拮抗体的优点,其用于治疗物质滥用障碍如酒精滥用和酒精依赖,和脉冲控制障碍如病理性投机和购物上瘾。这可以例如通过在肌内给药给狗后测量血浆水平来证明,如实施例C.1中所显示的。
同样,式(I)的前药化合物的口服已经显示出当纳美芬(nalfmene)本身口服给药时,如实施例C.2中显示的,在式(I)的前药化合物的给药后,相比于数小时来说,可以测量纳美芬的血浆水平达多于8天。
因此,本发明的化合物使得能够在较大时间间隔,例如在数天、数周直至数月给药,给药的实际时间取决于所用的化合物的物理性质,给药途径,药用剂型的组成和待治疗的受试者的状况。因此,本发明的化合物允许更有效的治疗:纳美芬的持续释放促进了将稳定的血浆浓度保持在无毒性、治疗有效的水平并且给药途径提高了待用处方药物疗法治疗的受试者的配合性。因此本发明的化合物可被用作具有持续释放能力的药物,或者作为持续释放药物。
术语纳美芬的“治疗相关的”或“治疗有效的”血浆水平,是指纳美芬(从本发明的式(I)的前药释放的游离的纳美芬)的血浆水平应当高于大约0.1ng/mL。
因此式(I)的本发明的化合物,或其药用可接受的酸加成盐或其溶剂化物,可以用作药物,特别地可以用作药物来治疗物质滥用障碍如酒精依赖和酒精滥用,和脉冲控制障碍如病理性投机和购物上瘾。同样,式(I)的化合物可以用作药物来在酒精-依赖患者中降低酒精渴望和消费,和在酒精-依赖患者中减少酒精消费。
本发明还提供式(I)的化合物或其药用可接受的盐用于制造用于治疗物质滥用障碍如酒精依赖和酒精滥用,和脉冲控制障碍如病理性投机和购物上瘾的药物的用途。
进一步地,本发明提供了在哺乳动物受体中治疗物质滥用障碍或脉冲控制障碍的方法,其包括向需要这样的治疗的哺乳动物给予治疗有效量的式(I)的化合物或其药用可接受的盐。物质滥用障碍包括酒精依赖和酒精滥用。脉冲控制障碍包括病理性投机和购物上瘾(addition)。
如本文中使用的术语“治疗”是指治疗性、缓和性和预防性治疗,包括逆转、减轻、抑制这样的术语适用于的疾病、障碍或状况,或者这样的疾病、障碍或状况的一种或多种症状的进程,或者预防这样的术语适用于的疾病、障碍或状况,或者这样的疾病、障碍或状况的一种或多种症状。
另外,本发明提供了药物组合物,其包括至少一种药用可接受的载体和治疗有效量的式(I)的化合物。
为制备本发明的药物组合物,有效量的特定的化合物,以游离碱或酸加成盐形式的,作为活性成分,与至少一种药用可接受的载体以紧密混合的方式合并,所述载体可以采取各种形式,这取决于给药所期望的制剂的形式。这些药物组合物令人想望地是单一剂型的,其适合于,优选地,口服给药,直肠给药,经皮给药或肠胃外注射。
例如,在制备口服剂型中的组合物中,可以使用任何通常的液体药物载体,例如水,二醇,油,醇等,在口服液体制剂的情况下如悬浮液,糖浆,酏剂和溶液;或在粉末,丸剂,胶囊和片剂的情况下,固体药物载体如淀粉,糖,高岭土,润滑剂,粘结剂,崩解剂等。因为其容易给药,片剂和胶囊代表了最有利的口服剂量单位形式,在该情况下显然使用固体药物载体。对于肠胃外注射组合物来说,药物载体将主要地包括无菌水,尽管其它成分可以包括在内以便改进活性成分的溶解性。可以制备可注射的溶液,例如,通过使用含盐水溶液、葡萄糖溶液或两者的混合物的药物载体。通过使用适当的液体载体、悬浮剂等,还可制备可注射的悬浮液。在适用于经皮给药的组合物中,药物载体可任选地包括穿透提高剂和/或合适的润湿剂,任选地结合以较小比例的合适的添加剂,所述添加剂没有引入对皮肤的显著的有害作用。可以选择所述添加剂以便促进活性成分给药于皮肤和/或有益于制备期望的组合物。这些局部组合物可以以多种方式给药,例如以经皮贴片、滴剂(spot-on)或软膏的形式。式(I)的化合物的加成盐,由于其相比于相应的碱形式具有提高的水溶性,在制备水性组合物中是明显更合适的。
特别有益的是以剂量单位形式配制本发明的药物组合物以便容易给药和剂量一致性。如本文中使用的“剂量单位形式”是指适合作为单一剂量的物理上离散的单位,每一个单位包含预定数量的活性成分,其适于与所需要的药物载体一起产生期望的治疗效果。这样的剂量单位形式的实例是片剂(包括刻痕或糖衣片剂),胶囊,丸剂,粉末袋,干胶片(wafer),可注射的溶液或悬浮液等,茶匙,汤匙和其分离的多重体(segregated multiples)。
对于口服给药来说,本发明的药物组合物可以采取固体剂型的形式,例如,片剂(可吞咽和可咀嚼形式),胶囊或囊形片(gelcaps),其是通过常规方法用药用可接受的赋形剂和载体如粘合剂(例如预胶凝玉米淀粉,聚乙烯吡咯烷酮,羟基丙基甲基纤维素等等),填料(例如乳糖,微晶纤维素,磷酸钙等等),润滑剂(例如硬脂酸镁,滑石,二氧化硅等等),崩解剂(例如马铃薯淀粉,淀粉乙醇酸钠等等),润湿剂(例如十二烷硫酸钠)等等制备的。这样的片剂也可通过本领域众所周知的方法包衣。
用于口服给药的液体制剂可以采取例如溶液,糖浆或悬浮液的形式,或者它们可以被配制为无水产品以便在使用前与水和/或另一个合适的液体载体混合。这样的液体制剂可以通过传统方法,任选地与其它药用可接受的添加剂如悬浮剂(例如山梨糖醇糖浆,甲基纤维素,羟基丙基甲基纤维素或氢化食用脂肪),乳化剂(例如卵磷脂或阿拉伯胶),无水载体(例如杏仁油,油酯或乙醇),甜味剂,香料,掩蔽剂和防腐剂(例如对-羟基苯甲酸甲或丙酯或山梨酸)一起,来制备。
可用于本发明的药物组合物的药用可接受的甜味剂包括优选地至少一种强力甜味剂如阿斯巴甜、乙酰磺胺酸钾、环拉酸钠、阿力甜、二氢查耳酮甜味剂、甜蛋白、甜菊糖三氯蔗糖(4,1′,6′-三氯-4,1′,6′-三脱氧半乳蔗糖)或,优选地,糖精、糖精钠或钙,和任选地至少一种填充型甜味剂如山梨糖醇,甘露糖醇,果糖,蔗糖,麦芽糖,异麦芽糖醇(isomalt),葡萄糖,氢化葡萄糖浆,木糖醇,焦糖或蜂蜜。强力甜味剂便利地以低浓度使用。例如,在糖精钠的情况下,所述浓度可以为约0.04%至0.1%(重量/体积)的最终制剂。填充型甜味剂可以有效地用于较大的浓度中,约10%-约35%,优选地约10%至15%(重量/体积)。
在低剂量制剂中可以掩蔽苦味成分的药用可接受的香料优选地是水果香料如樱桃,覆盆子,红醋栗或草莓香料。两种香料的组合可以获得非常好的结果。在高剂量制剂中,可能要求更强烈的药用可接受的香料如Caramel(焦糖),Chocolate(巧克力),Mint Cool(薄荷酷),Fantasy等。每种香料可以存在于最终组合物中,浓度为约0.05%至1%(重量/体积)。有利地使用所述强烈香料的组合。优选地,使用这样的香料,其在制剂的情况中没有经历任何味道和/或颜色的变化或损失。
式(I)的化合物可以配制用于通过注射来肠胃外给药,便利地静脉内,肌内或皮下注射,例如通过弹丸注射或持续静脉内输注。注射用制剂可以以单位剂型呈现,例如在安瓿或多剂量容器中,包括所添加的防腐剂。它们可以采取如在油或水性赋形剂中的悬浮液、溶液或乳液的形式,并且可以包含配制剂如等渗压(isotonizing)、悬浮、稳定和/或分散剂。备选地,活性成分可以以粉末形式存在以便在使用前与合适的赋形剂混合,例如无菌的无热原的水。肌内或皮下给药用的制剂是特别令人感兴趣的。这样的药物组合物应当在注射位置处引起很小或没有引起组织刺激或炎症。合适的溶剂例如是芝麻油或米格列醇(migliol)。
式(I)的化合物也可在直肠组合物中配制,如栓剂或保留灌肠,例如包含常规的栓剂底物(bases)如可可脂和/或其它甘油酯。
实验部分
A.合成中间体
实施例A.1
加热1-十八醇(16.4g,60.6mmol)、甲苯(800ml,49ml/g)、戊二酸(80.1g,10当量)和对甲苯磺酸(1.0g,0.1当量)溶液至100℃达16小时。将反应混合物冷却至环境温度并且用水洗涤。用硫酸镁干燥有机层,过滤并且浓缩至干燥,得到21.5g(92%)的中间体(1)。
NMR:
1H NMR(400MHz,氯仿-d)δppm 0.90(t,J=6.55Hz,3H)1.19-1.41(m,30H)1.59-1.68(m,J=7.05,7.05,7.05,7.05Hz,2H)1.93-2.03(m,J=7.05,7.05,7.05,7.05Hz,2H)2.41(t,J=7.30Hz,2H)2.45(t,J=7.30Hz,2H)4.09(t,J=6.67Hz,2H)9.57(br.s.,1H)
在环境温度在惰性气氛下向中间体(1)(23.3g,60.6mmol)、甲苯(233ml,10mL/g)和三乙胺(8.5ml,1.0当量)溶液中滴加亚硫酰氯(8.8ml,2.0当量)。在80℃加热混合物2小时。在冷却至环境温度后,过滤盐并且用甲苯洗涤。通过蒸发浓缩滤液,得到24.4g(100%)的中间体(2),其直接用于下一步中。
B.合成最终的化合物
实施例B.1
在1.5小时内向纳美芬盐酸盐(20g,53.2mmol)、甲苯(200ml,10mL/g)和三乙胺(16.3ml,2.2当量)的悬浮液滴加中间体(2)(21.4g,1当量)/甲苯(200ml,10mL/g)溶液。在环境温度搅拌反应混合物16小时。然后,将其用水(400ml,20ml/g)洗涤。用甲苯萃取水层两次,然后丢弃。蒸发合并的有机层,之前用硫酸镁干燥,和过滤。用甲醇(100ml,5ml/g)研磨残余物。沉淀物被过滤,用甲醇(100ml,5ml/g)洗涤和在50℃在减压下干燥16小时,得到30.5g(81%)的化合物(1)。
NMR:
1H NMR(400MHz,DMSO-d6)δppm 0.06-0.17(m,2H)0.42-0.54(m,2H)0.80-0.89(m,4H)1.14-1.34(m,32H)1.49-1.60(m,3H)1.83-1.92(m,J=7.30,7.30,7.30,7.30Hz,2H)1.97(td,J=11.90,3.90Hz,1H),2.07(dt,J=13.53,3.34,3.02Hz,1H)2.24(td,J=12.59,5.04Hz,1H)2.35(t,J=6.04Hz,2H)2.44(t,J=7.30Hz,2H)2.47-2.53(m,1H)2.54-2.60(m,1H)2.60(t,J=7.18Hz,2H)2.63-2.68(m,1H)3.03(dd,J=11.96,6.67Hz,2H)4.02(t,J=6.55Hz,2H)4.80(d,J=1.26Hz,1H)4.90(s,1H)4.97(s,1H)5.05(d,J=1.01Hz,1H)6.67(d,J=8.31Hz,1H)6.78(d,J=8.31Hz,1H)
LC-MS:
HR-MS(ES+):C44H68NO6 +的计算值:706.5047,实测值:706.5034.
元素分析:
C44H67NO6的分析计算值:C,74.85;H,9.57;N,1.98.实测值:C,75.88;H,10.13;N,1.50.
表F-1:最终的化合物
C.1.在狗中的体内PK研究(IM注射):纳美芬的血浆水平
浓度为在芝麻油(sesam oil)或米格列醇(migliol)中的20mg纳美芬eq./ml的单肌内剂量的式化合物即化合物(1)每一制剂以1mg当量纳美芬/kg体重的剂量给到3只狗。
参照物是浓度为在盐水中的0.40mg/ml的纳美芬的立即释放制剂(IR),以0.02mg当量纳美芬/kg体重通过肌内给药(IM)服用单剂量。
在服用前药制剂后的27天的期间内和在服用纳美芬的立即释放制剂后48小时内取血样。处理血样而获得血浆。通过合格的(qualified)LC-MS/MS-方法,对纳美芬分别分析血浆样品。
使用合法的WinNonlin软件(V.4.0.1a)通过非房室药动分析在个体血浆浓度分布图上进行药动数据分析。
结果:
在肌内(IM)服用本发明的前药化合物之一或纳美芬的IR制剂后纳美芬的血浆分布图(ng/mL)示于图1中。
纳美芬的血浆浓度可以量化直至在服用化合物(1)后的27天。
C.2.在狗中的体内PK研究(口服):纳美芬的血浆水平
使用在20%HP-β-CD(羟丙基-β-环糊精)溶液中的式(I)的化合物或纳美芬本身的10mg/kg或20mg/kg体重的剂量并且口服给药于狗。
在口服给药后的192小时的期间内取血样。处理血样而获得血浆。通过合格的(qualified)LC-MS/MS-方法,对纳美芬分别分析血浆样品。
纳美芬的血浆浓度可以量化直至在服用化合物(1)后的72小时。
附图说明
图1显示在IM给药含纳美芬(nalfmene)或化合物(1)的制剂后的28天期间内测量的纳美芬的血浆浓度(ng/mL)。
Claims (13)
2.权利要求1的化合物,其中R1是C18烷氧基羰基C3烷基。
4.一种药物组合物,其包括药用可接受的载体和治疗活性量的权利要求1至3中任一项的化合物。
5.一种制备权利要求4的药物组合物的方法,其中治疗活性量的权利要求1至3中任一项的化合物与药用可接受的载体紧密混合。
6.权利要求1至3中任一项的化合物在制备药物中的用途。
7.权利要求1至3中任一项的化合物在制备药物中的用途,所述药物用于治疗物质滥用障碍。
8.权利要求7的用途,其中所述障碍是酒精滥用或酒精依赖。
9.权利要求1至3中任一项的化合物在制备药物中的用途,所述药物用于在酒精-依赖患者中降低酒精渴望和酒精消费。
10.权利要求1至3中任一项的化合物在制备药物中的用途,所述药物用于治疗脉冲控制障碍。
11.权利要求10的用途,其中所述障碍是病理性投机或购物上瘾。
12.权利要求1至3中任一项的化合物在制备药物中的用途,所述药物用于治疗物质滥用障碍和脉冲控制障碍。
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RS (1) | RS52171B (zh) |
RU (1) | RU2495041C2 (zh) |
SI (1) | SI2307420T1 (zh) |
WO (1) | WO2009130270A1 (zh) |
Families Citing this family (11)
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JP6009764B2 (ja) * | 2008-04-24 | 2016-10-19 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプJanssen Pharmaceutica Naamloze Vennootschap | ナルメフェンプロドラッグ |
AR096851A1 (es) * | 2013-07-11 | 2016-02-03 | H Lundbeck As | Sales que no forman hidratos ni solvatos de nalmefeno |
US10226456B2 (en) | 2015-04-27 | 2019-03-12 | 3St Research Llc | Methods and compositions for preventing opioid abuse |
US10017519B2 (en) | 2015-04-27 | 2018-07-10 | 3St Research Llc | Alpha-hydroxy carboxylic acid and derivatives and other GRAS based prodrugs of oxycodone and uses thereof |
US10449190B2 (en) | 2015-04-27 | 2019-10-22 | John K. Thottathil | Alpha-hydroxy carboxylic acid and derivatives and other GRAS-based prodrugs of opioids and uses thereof |
WO2018183264A1 (en) * | 2017-03-29 | 2018-10-04 | Thottathil John K | Novel alpha-hydroxy carboxylic acid and derivatives and other gras- based prodrugs of opioids and uses thereof |
AU2018359336B2 (en) | 2017-11-03 | 2024-06-20 | Nirsum Laboratories, Inc. | Opioid receptor antagonist prodrugs |
TW202015684A (zh) * | 2018-06-21 | 2020-05-01 | 景凱生物科技股份有限公司 | 那曲酮、納美芬及其衍生物之前藥 |
WO2020226628A1 (en) * | 2019-05-07 | 2020-11-12 | Nirsum Laboratories, Inc. | Opioid receptor antagonist prodrugs for treating opioid dependence |
WO2020223894A1 (en) | 2019-05-07 | 2020-11-12 | Nirsum Laboratories, Inc. | Opioid receptor antagonist prodrugs |
WO2023183795A1 (en) * | 2022-03-22 | 2023-09-28 | Elysium Therapeutics, Inc. | Opioid antagonist prodrugs and formulations for the reversal of opioid overdoses |
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EP0615756A1 (en) * | 1993-03-15 | 1994-09-21 | National Science Council | Nalbuphine esters and long-acting pharmaceutical compositions containing them |
WO2007110636A1 (en) * | 2006-03-28 | 2007-10-04 | Reckitt Benckiser Healthcare (Uk) Limited | Buprenorphine derivatives and uses thereof |
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US5086058A (en) * | 1990-06-04 | 1992-02-04 | Alko Ltd. | Method for treating alcoholism with nalmefene |
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HUP0401022A3 (en) * | 2001-08-14 | 2006-11-28 | Biotie Therapies Corp | Method for the preparation of pharmaceutical compositions containing opioid antagonist for treating alcoholism or alcohol abuse |
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- 2009-04-23 WO PCT/EP2009/054875 patent/WO2009130270A1/en active Application Filing
- 2009-04-23 JP JP2011505508A patent/JP5426660B2/ja active Active
- 2009-04-23 AT AT09734161T patent/ATE535528T1/de active
- 2009-04-23 EP EP09734161A patent/EP2307420B1/en active Active
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EP0615756A1 (en) * | 1993-03-15 | 1994-09-21 | National Science Council | Nalbuphine esters and long-acting pharmaceutical compositions containing them |
WO2007110636A1 (en) * | 2006-03-28 | 2007-10-04 | Reckitt Benckiser Healthcare (Uk) Limited | Buprenorphine derivatives and uses thereof |
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Also Published As
Publication number | Publication date |
---|---|
EP2307420A1 (en) | 2011-04-13 |
HRP20120126T1 (hr) | 2012-02-29 |
RU2495041C2 (ru) | 2013-10-10 |
KR20100134769A (ko) | 2010-12-23 |
WO2009130270A1 (en) | 2009-10-29 |
DK2307420T3 (da) | 2012-02-27 |
PT2307420E (pt) | 2012-02-14 |
CY1113040T1 (el) | 2016-04-13 |
CN102036993A (zh) | 2011-04-27 |
KR101598138B1 (ko) | 2016-02-29 |
US20110053971A1 (en) | 2011-03-03 |
CA2722243C (en) | 2016-05-31 |
PL2307420T3 (pl) | 2012-04-30 |
EP2307420B1 (en) | 2011-11-30 |
ATE535528T1 (de) | 2011-12-15 |
CA2722243A1 (en) | 2009-10-29 |
ES2377599T3 (es) | 2012-03-29 |
RS52171B (en) | 2012-08-31 |
AU2009239927B2 (en) | 2014-03-13 |
SI2307420T1 (sl) | 2012-05-31 |
AU2009239927A1 (en) | 2009-10-29 |
ME01295B (me) | 2012-08-31 |
RU2010147832A (ru) | 2012-05-27 |
JP2011518804A (ja) | 2011-06-30 |
JP5426660B2 (ja) | 2014-02-26 |
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