CN103249697B - 适用作多巴胺能稳定剂的普利多匹定(pridopidine)氘化类似物 - Google Patents

适用作多巴胺能稳定剂的普利多匹定(pridopidine)氘化类似物 Download PDF

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CN103249697B
CN103249697B CN201180042460.5A CN201180042460A CN103249697B CN 103249697 B CN103249697 B CN 103249697B CN 201180042460 A CN201180042460 A CN 201180042460A CN 103249697 B CN103249697 B CN 103249697B
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克拉斯·索内松
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Prilenia Neurotherapeutics Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms

Abstract

本发明提供普利多匹定(Pridopidine)，即4-(3-甲烷磺酰基-苯基)-l-丙基-哌啶的新颖氘化类似物。普利多匹定是当前处于临床开发中的用于治疗亨廷顿氏病(Huntingtonˊs？disease)的原料药。在其它方面，本发明涉及包含本发明的普利多匹定氘化类似物的医药组合物10，和这些类似物的治疗应用。

Description

适用作多巴胺能稳定剂的普利多匹定(pridopidine)氘化类似物
技术领域
本发明提供普利多匹定，即4-(3-甲烷磺酰基-苯基)-1-丙基-哌啶(4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine)的新颖氘化类似物。普利多匹定是当前处于临床开发中的用于治疗亨廷顿氏病(Huntington'sdisease)的原料药。
在其它方面，本发明涉及包含本发明的普利多匹定氘化类似物的医药组合物，和这些类似物的治疗应用。
背景技术
氘，也称为“重氢”，是氢的一种稳定同位素，它在地球海洋中的天然丰度是6,500个氢中有约1个原子(约154ppm)。氘因此在地球海洋中天然存在的所有氢中占到约0.0154%(或者，按质量计：0.0308%)。氘的核(称为氘核)含有一个质子和一个中子，而氢核不含中子。
氘与碳形成键，这些键与C-H键相比以较低频率振动，因而较强。因此，药物的“重氢”型式可能对降解更稳定且在生物体内维持更长时间。并入氘来代替氢因此可改善药物的药效学和药代动力学概况，因此改变代谢归宿，同时保持生理学活性化合物的药理活性和选择性。氘化药物因此可对安全性、功效和/或耐受性有正面影响。
普利多匹定，即4-(3-甲烷磺酰基-苯基)-1-丙基-哌啶，是当前处于临床开发中的用于治疗亨廷顿氏病的一种多巴胺能稳定剂。所述化合物描述于例如WO01/46145中，且在例如WO2006/040155中描述一种用于其合成的替代方法。
发明内容
本发明的目标是提供药效学和药代动力学概况有所改善的普利多匹定类似物。
因此，第一方面，本发明提供如由下式1表示的4-(3-甲烷磺酰基-苯基)-1-丙基-哌啶的部分或完全氘化类似物。
另一方面，本发明提供一种医药组合物，其包含治疗有效量的本发明的4-(3-甲烷磺酰基-苯基)-1-丙基-哌啶的氘化类似物，或其医药学上可接受的盐，以及至少一种医药学上可接受的载剂、赋形剂或稀释剂。
从另一方面来看，本发明涉及本发明的4-(3-甲烷磺酰基-苯基)-1-丙基-哌啶的氘化类似物作为药剂或用于制造药剂的用途。
另一方面，本发明提供一种治疗、预防或缓解活动物体的由多巴胺介导的病症的方法，所述活动物体包括人类，所述方法包括向有需要的这种活动物体投予治疗有效量的根据本发明的4-(3-甲烷磺酰基-苯基)-1-丙基-哌啶的氘化类似物或其医药学上可接受的盐的步骤。
所属领域的技术人员通过以下详细描述和实例将显而易知本发明的其它方面。
具体实施方式
普利多匹定的氘化类似物
第一方面，本发明提供普利多匹定的氘化类似物。本发明的氘化类似物可为完全或部分氘取代的衍生物。本发明的氘化类似物尤其可以由式I表征
或其医药学上可接受的盐，其中
R1-R23中的至少一者表示氘(D)；且
R1-R23中的其余各者表示氢(H)。
在本发明的上下文中，当一特定位置表示为持有氘时，可理解为在这一位置上氘的丰度实质上大于氘的天然丰度，氘的天然丰度为约0.015%。
在一个优选实施例中，在这一位置上氘的丰度为氘的天然丰度的至少3340倍(即，至少50.1%氘并入量)。在本发明的其它优选实施例中，在这一位置上氘的丰度为至少3500倍(52.5%氘并入量)、至少4000倍(60%氘并入量)、至少4500倍(67.5%氘并入量)、至少5000倍(75%氘)、至少5500倍(82.5%氘并入量)、至少6000倍(90%氘并入量)、至少6333.3倍(95%氘并入量)、至少6466.7倍(97%氘并入量)、至少6600倍(99%氘并入量)，或至少6633.3倍(99.5%氘并入量)。
在一个优选实施例中，本发明的氘化类似物为式I化合物，或其医药学上可接受的盐，其中
R1-R2表示氘(D)；且
R3-R23都表示氢(H)。
在另一个优选实施例中，本发明的氘化类似物为式I化合物，或其医药学上可接受的盐，其中
R1-R7中的至少一者表示氘(D)；且
R1-R23中的其余各者表示氢(H)。
在第三优选实施例中，本发明的氘化类似物为式I化合物，或其医药学上可接受的盐，其中
R1-R7都表示氘(D)；且
R8-R23都表示氢(H)。
在第四优选实施例中，本发明的氘化类似物为式I化合物，或其医药学上可接受的盐，其中
R8、R9、R10和R11表示氘(D)；且
R1-R7和R12-R23都表示氢(H)。
在第五优选实施例中，本发明的氘化类似物为式I化合物，或其医药学上可接受的盐，其中
R12表示氘(D)；且
R1-R11和R13-R23都表示氢(H)。
在第六优选实施例中，本发明的氘化类似物为式I化合物，或其医药学上可接受的盐，其中
R17-R20表示氘(D)；且
R1-R16和R21-R23都表示氢(H)。
本文中所述的两个或更多个实施例的任意组合都被视为处于本发明的范围内。
医药学上可接受的盐
本发明的氘化类似物可以适于预期投药的任何形式提供。适合形式包括医药学上(即生理学上)可接受的盐，和本发明的氘化类似物的前药(pre/prodrug)形式。
医药学上可接受的盐的实例包括(但不限于)无毒的无机和有机酸加成盐，如盐酸盐、氢溴酸盐、硝酸盐、高氯酸盐、磷酸盐、硫酸盐、甲酸盐、乙酸盐、阿康酸盐(aconate)、抗坏血酸盐、苯磺酸盐、苯甲酸盐、肉桂酸盐、柠檬酸盐、双羟萘酸盐、庚酸盐、反丁烯二酸盐、谷氨酸盐、乙醇酸盐、乳酸盐、顺丁烯二酸盐、丙二酸盐、扁桃酸盐、甲烷磺酸盐、萘-2-磺酸盐、邻苯二甲酸盐、水杨酸盐、山梨酸盐、硬脂酸盐、丁二酸盐、酒石酸盐、对甲苯磺酸盐等。这些盐可以通过所属领域中熟知并描述的程序形成。
可能不被视为医药学上可接受的其它酸(如乙二酸)可能适用于制备在获得本发明的氘化类似物和其医药学上可接受的酸加成盐的过程中适用作中间物的盐。
本发明的氘化类似物的医药学上可接受的阳离子盐的实例包括(但不限于)含有阴离子基团的本发明的氘化类似物的钠盐、钾盐、钙盐、镁盐、锌盐、铝盐、锂盐、胆碱盐、赖氨酸鎓盐(lysinium)和铵盐等。这些阳离子盐可以通过所属领域中熟知并描述的程序形成。
本发明的氘化类似物可以可溶或不可溶形式连同医药学上可接受的溶剂(如水、乙醇等)一起提供。可溶形式还可以包括水合形式，如一水合物、二水合物、半水合物、三水合物、四水合物等。总体而言，出于本发明的目的，可溶形式被视为与不可溶形式等效。
制备方法
本发明的氘化类似物可以通过用于化学合成的常规方法，例如工作实例中所述的那些方法来制备。本申请案中所述的方法的起始物质是已知的或可以容易地通过常规方法从市售化学物质制备。
另外，本发明的一种化合物可以使用常规方法转化成本发明的另一种化合物。
本文中所述的反应的最终产物可以通过常规技术，例如通过萃取、结晶、蒸馏、色谱法等来分离。
生物活性
WO01/46145、WO01/46146、WO2005/121087、WO2007/042295、WO2008/127188和WO2008/155357都描述了经取代的4-苯基-N-烷基-哌嗪和4-苯基-N-烷基-哌啶，据报道所述化合物为多巴胺神经传递的调节剂且适用于治疗中枢神经系统的多种病症的症状。本发明的氘化类似物被视为适用于与这些公开案中所述相同的医学适应症，且这些公开案因此通过引用的方式并入。
根据这些公开案涵盖的神经学适应症包括治疗亨廷顿氏病和其它运动障碍，以及由药物诱发的运动障碍。
因此，在一个优选实施例中，本发明涉及本发明的氘化类似物用作治疗亨廷顿氏病的药剂的用途。
医药组合物
从另一方面来看，本发明提供用作药剂的氘化类似物。因此，另一方面，本发明提供包含治疗有效量的本发明化合物的新颖的医药组合物。
虽然在治疗中使用的本发明的氘化类似物可以原始化合物的形式投予，但优选的是在医药组合物中，连同一种或多种佐剂、赋形剂、载剂、缓冲剂、稀释剂和/或其它惯用的医药助剂一起引入活性成分，所述成分视情况呈生理学上可接受的盐形式。
本发明的医药组合物尤其可以如WO01/46145中所述加以调配。
关于调配和投药技术的更多细节可以在最新版的雷明顿氏药学科学(Remington's PharmaceuticalSciences)(麦克出版公司(MaackPublishingCo.),伊斯顿(Easton),宾夕法尼亚州(PA))中找到。
当然必须谨慎地根据所治疗个体的年龄、体重和状况以及投药途径、剂型和给药方案，和所要的结果来调整投予剂量，且确切剂量当然应该由专业人员确定。
实际剂量取决于所治疗疾病的性质和严重性，且在医师的判断范围内，并且可以通过根据本发明的特定情况调定剂量来改变，从而产生所要的治疗效果。然而，当前预期每一个别剂量含有约1到约500mg活性成分，优选地约10到约100mg，最优选地约25到约50mg活性成分的医药组合物适合于治疗性处理。每日剂量将优选地以个别剂量每天投予1到4次。
治疗方法
另一方面，本发明提供一种治疗、预防或缓解活动物体的由多巴胺介导的病症的方法，所述活动物体包括人类，所述方法包括向有需要的这种活动物体投予治疗有效量的本发明的氘化类似物的步骤。
在一个优选实施例中，所述由多巴胺介导的病症是亨廷顿氏病。
实例
本发明在以下实例中进一步说明，这些实例决不欲限制本发明的范围。
实例1
制备实例
4-(3-甲烷磺酰基-苯基)-1-丙基-d7-哌啶×HCl(4-(3-Methanesulfonyl-phenyl)-1 -propyl-d7-piperidinexHCI)
将4-(3-甲烷磺酰基-苯基)-哌啶(0.43g)、CH3CN(4ml)、K2CO3(0.49g)和1-碘丙烷-d7(0.19g)混合且在微波炉中在120℃下加热30分钟。将混合物过滤且蒸发到干燥，并在硅胶柱上使用含有5%NEt3的异辛烷:EtOAc(1:1)作为洗脱剂进行纯化。在蒸发含有纯产物的洗脱份后，将残余物再溶解于EtOAc中并用10%Na2CO3溶液洗涤。分离有机相并用Na2SO4干燥，过滤并蒸发以得到纯产物(0.33g)。接着将所述胺转化成盐酸盐，且在EtOH:Et2O中再结晶。熔点为198-199℃。

Claims (20)

1.一种药物组合物，所述药物组合物包括由式1表示的化合物
或其医药学上可接受的盐，其中
R1-R23中的至少一者表示氘(D)；且
R1-R23中的其余各者表示氢(H)；
其中具有R1-R23中的至少一者表示的位置上的氘的所述化合物分子的丰度实质上大于氘在这一位置上的天然丰度。
2.根据权利要求1所述的药物组合物，其中
R1-R2表示氘(D)；且
R3-R23都表示氢(H)。
3.根据权利要求1所述的药物组合物，其中
R1-R7中的至少一者表示氘(D)；且
R1-R23中的其余各者表示氢(H)。
4.根据权利要求1所述的药物组合物，其中
R1-R7都表示氘(D)；且
R8-R23都表示氢(H)。
5.根据权利要求1所述的药物组合物，其中
R8、R9、R10和R11表示氘(D)；且
R1-R7和R12-R23都表示氢(H)。
6.根据权利要求1所述的药物组合物，其中
R12表示氘(D)；且
R1-R11和R13-R23都表示氢(H)。
7.根据权利要求1所述的药物组合物，其中
R17-R20表示氘(D)；且
R1-R16和R21-R23都表示氢(H)。
8.根据权利要求1所述的药物组合物，其中所述化合物或其医药学上可接受的盐是4-(3-甲烷磺酰基-苯基)-1-丙基-d7-哌啶盐酸盐。
9.根据权利要求1-8任一所述的药物组合物，其中所述具有R1-R23中的至少一者表示的位置上的氘的化合物分子的丰度为氘的天然丰度这一位置上的至少3,340倍。
10.根据权利要求9所述的药物组合物，其中所述具有R1-R23中的至少一者表示的位置上的氘的化合物分子的丰度为氘的天然丰度这一位置上的至少3,500倍。
11.根据权利要求10所述的药物组合物，其中所述具有R1-R23中的至少一者表示的位置上的氘的化合物分子的丰度为氘的天然丰度这一位置上的至少4,000倍。
12.根据权利要求11所述的药物组合物，其中所述具有R1-R23中的至少一者表示的位置上的氘的化合物分子的丰度为氘的天然丰度这一位置上的至少5,000倍。
13.根据权利要求12所述的药物组合物，其中所述具有R1-R23中的至少一者表示的位置上的氘的化合物分子的丰度为氘的天然丰度这一位置上的至少6,000倍。
14.根据权利要求13所述的药物组合物，其中所述具有R1-R23中的至少一者表示的位置上的氘的化合物分子的丰度为氘的天然丰度这一位置上的至少6,466.7倍。
15.根据权利要求14所述的药物组合物，其中所述具有R1-R23中的至少一者表示的位置上的氘的化合物分子的丰度为氘的天然丰度这一位置上的至少6,633.3倍。
16.根据权利要求1-8任一所述的药物组合物，所述药物组合物包括所述化合物的医药学上可接受的盐。
17.根据权利要求1-8任一所述的药物组合物，所述药物组合物包括所述化合物。
18.根据权利要求1到8中任一权利要求所述的药物组合物，所述药物组合物包括至少一种医药学上可接受的载剂、赋形剂或稀释剂。
19.根据权利要求9所述的药物组合物，所述药物组合物包括所述化合物的医药学上可接受的盐。
20.根据权利要求9所述的药物组合物，所述药物组合物进一步包括至少一种医药学上可接受的载剂、赋形剂或稀释剂。
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