CN1231604A - 医药治疗 - Google Patents
医药治疗 Download PDFInfo
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- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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Abstract
通式(Ⅰ)化合物或其药物上可接受的盐,式中R1和R2独立地是H或甲基(例如N,N-二甲基-1-[1-(4-氯苯基)环丁基]-3-甲基丁胺盐酸盐,也可以呈其一水合物形式),用于降低人体中,例如患有痛风、高尿酸血或冠状心脏病或有发展这些病症的风险的人体中的尿酸水平。
Description
本发明涉及一种降低人体中尿酸水平的方法。
按照本发明,提供的是一种降低人体中尿酸水平的方法,其中包括向有这种需要的人给药治疗有效量的通式Ⅰ化合物,包括其对映体及其药物上可接受的盐,式中R1和R2独立地是H或甲基,并配合药物上可接受的稀释剂或载体。
抑郁症治疗中通式Ⅰ化合物例如〔N,N-二甲基-1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺〕(或者N-{1-〔1-(4-氯苯基)环丁基〕-3-甲基丁基}-N,N-二甲基胺)及其盐的制备与使用详见英国专利说明书2098602。通式Ⅰ化合物例如〔N,N-二甲基-1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺〕及其盐在帕金森病治疗中的用途详见欧洲专利No.282206。N,N-二甲基-1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺及其盐在大脑功能失调治疗中的用途详见美国专利No.4939175。N,N-二甲基-1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺盐酸盐在肥胖治疗中的用途详见欧洲专利No.397831。这种化合物的一种特别好的形式是N,N-二甲基-1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺盐酸盐一水合物(西布曲明(sibutramine)盐酸盐一水合物),详见欧洲专利No.230742。N,N-二甲基-1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺及其盐用于改善有受损葡萄糖耐量或非胰岛素依赖型糖尿病的人的葡萄糖耐量的用途,详见PCT申请公报WO95/20949。
熟悉本门技术的人员也许知道,通式Ⅰ化合物可以作为与药物上可接受的酸的盐存在。此类盐的实例包括盐酸盐、氢溴酸盐、硫酸盐、甲磺酸盐、硝酸盐、马来酸盐、乙酸盐、柠檬酸盐、富马酸盐、酒石酸盐〔例如(+)-酒石酸盐、(-)-酒石酸盐或其混合物,包括外消旋混合物〕、琥珀酸盐、苯甲酸盐及其与谷氨酸等氨基酸的盐。通式Ⅰ化合物及其盐可以呈溶剂合物(例如水合物)形式存在。
熟悉本门技术的人员将会知道,通式Ⅰ化合物包含一个手性中心。当一种通式Ⅰ化合物包含一个单一手性中心时,它可能以两种对映体形式存在。本发明包括个体对映体和对映体混合物的用途。这些对映体可以用熟悉本门技术的有人员已知的方法解析,例如,通过生成可以诸如用结晶法分离的非对映体盐或配合物;通过生成可以诸如用结晶法、气-液或液相色谱法分离的非对映体衍生物;一种对映体与一种对映体专性试剂的选择性反应,例如酶促氧化或还原,随后分离改性和未改性的对映体;或者手性环境中的气-液或液相色谱法,例如,在一种手性支撑体例如有结合手性配体的二氧化硅上或在一种手性溶剂的存在下。要知道的是,在所希望的对映体用以上所述分离程序之一转化成另一种化学实体的情况下,需要一个进一步的步骤来释放出所希望的对映体形式。替而代之的是,可以通过用旋光性试验、基质、催化剂或溶剂进行的不对称合成,或通过利用不对称转化而使一种对映体转化成另一种对映体,来合成特定的对映体。
令人惊讶的是,现在已经发现,通式Ⅰ化合物有使人体中尿酸水平降低的能力,因而有作为尿酸降低剂的效用。这种活性的存在表明,通式Ⅰ化合物可用于治疗和预防尿酸水平偏高的症状,例如高尿酸血和痛风。这些化合物也可能可用于降低有冠状心脏病或有发展冠状心脏病危险的人体内的尿酸水平。
较好的是,本发明提供一种治疗和/或预防痛风或高尿酸血的方法,包括向有此需要的人给药一种与药物上可接受的稀释剂或载体配合的、治疗有效量的通式Ⅰ化合物。
本发明进一步包括通式Ⅰ化合物包括其对映体及其药物上可接受的盐,式中R1和R2独立地是H或甲基,用于制造一种能使人体中例如患有痛风、高尿酸血或冠状心脏病或有发展这些疾病的较大风险的人体内的尿酸水平的药物的用途。较好的是,这种药物用于治疗和/或预防尿酸水平偏高的病症,例如高尿酸血或痛风。这些化合物也可以用于降低患有冠状心脏病或有发展冠状心脏病风险的人体内的尿酸水平。
通式Ⅰ的特定化合物是N,N-二甲基-1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺、N-{1-〔1-(4-氯苯基)环丁基〕-3-甲基丁基}-N-甲基胺、和1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺,包括外消旋体、各种对映体及其混合物,及其药物上可接受的盐。较好的通式Ⅰ化合物是N,N-二甲基-1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺或其盐,例如盐酸盐。这种盐酸盐的一种较好形式是其一水合物。
通式Ⅰ化合物可以用已知的任何一种药物剂型给药。该化合物的给药量取决于许多因素,包括患者的年龄、病症的严重性和患者的既往病史,而且总是要在给药医师的医嘱范围内,但一般的设想是,该化合物的给药剂量范围为0.1~50mg、较好为1~30mg/日,以一个或多个剂量给药。
经口剂型是本发明中使用的较好组合物,而且这些是这样的给药的已知药物形式,例如片剂、胶囊剂、颗粒剂、糖浆剂和水悬浮液剂或油悬浮液剂。这些组合物制备中使用的赋形剂是药剂师技术上已知的赋形剂。片剂可以从活性化合物与填料例如磷酸钙、崩解剂例如玉米淀粉料、润滑剂例如硬脂酸镁、粘结剂例如微晶纤维素或聚乙烯基吡咯烷酮和技术上已知的其它任选成分的混合物,用已知方法对该混合物压片来制备。这些片剂,如果希望,还可以用已知方法和赋形剂包衣,该赋形剂可以包括使用了诸如羟丙基甲基纤维素邻苯二甲酸酯的肠溶性包衣剂。这些片剂可以熟悉本门技术的人员已知的方式配制,从而给出本发明化合物的缓释剂型。这样的片剂,如果希望,可以用已知方法,例如使用乙酸·邻苯二甲酸纤维素酯,来提供肠溶性包衣。类似地,含有活性化合物而有或无添加赋形剂的胶囊剂,例如硬的和软的明胶胶囊剂,可以用已知方法制备,且如果希望,还可以用已知方式提供肠溶性包衣。胶囊剂的内容物可以用已知方法配制,从而给出活性化合物的缓释剂型。这些片剂和胶囊剂可以方便地每个含有1~50mg活性化合物。
其它经口给药剂型包括诸如在一种无毒悬浮剂例如羧甲基纤维素钠的存在下在一种水介质中含有活性化合物的水悬浮液,和在一种适用植物油例如花生油中含有本发明化合物的油悬浮液。这种活性化合物可以配制成有或无附加赋形剂的颗粒剂。这些颗粒剂可以由患者直接摄入,也可以先将它们添加到适用液体载体(例如水)中然后再摄入。这些颗粒剂可以含有崩解剂,例如由一种酸和一种碳酸盐或碳酸氢盐形成的一种泡腾偶合,以利于在液体介质中分散。
有治疗活性的通式Ⅰ化合物可以配制成一种可以让患者含在嘴里的组合物,从而使该活性化合物能通过嘴粘膜给药。
适用于经直肠给药的剂型是此类给药用的已知药物形式,例如,有可可脂或聚乙二醇基剂的栓剂。
适用于非经肠给药的剂型是此类给药用的已知药物形式,例如无菌悬浮液剂或适用溶剂中的无菌溶液剂。
局部给药用的剂型可以包含一种用来分散本发明的药理学活性化合物的基体,使得这些化合物能保持与皮肤的接触,以期经皮给药这些化合物。适用的经皮组合物可以这样制备:使该药物活性化合物混合一种局部载体,例如矿物油、黄凡士林和/或一种蜡如石蜡或蜂蜡,以及一种潜在经皮促进剂,例如二甲基亚砜或丙二醇。替而代之的是,可以将活性化合物分散在一种药物上可接受的霜剂、凝胶或软膏基剂中。局部配方中活性化合物的含量应当是使得在该局部配方预期要在皮肤上滞留的期间内能输送治疗有效量的该化合物。
有治疗活性的通式Ⅰ化合物可以配制成一种能以气雾剂形式分散到患者口腔或鼻腔中的组合物。这样的气雾剂可以从一种泵包或一种含有挥发性推进剂的加压包给药。
本发明方法中使用的有治疗活性的通式Ⅰ化合物也可以通过或者来自一个外源的连续输注例如经静脉内输注或者来自一个置于体内的该化合物来源的连续输注给药。内源包括植入式贮药器,其中含有可诸如通过渗透连续释放的待输注化合物,和如下植入物:这可以是(a)液体,例如呈水溶性非常小的衍生物如十二烷酸盐或亲油酯等形式的待输注化合物的油悬浮液,或者(b)固体,呈待输注化合物的植入式支撑体例如合成树脂或蜡状材料等形式。该支撑体可以是一个含有该化合物全部的单一体,也可以是各含有待输送化合物一部分的一系列若干个体。一个内源中存在的活性化合物的数量应当是使得在一段长时期内能输送治疗有效量的该化合物。
在一些配方中,可能有益的是使用呈粒径非常小的微粒形式的本发明化合物,例如用流体能量研磨法得到的那种。
在本发明的组合物中,活性化合物,如果希望,也可以与其它可兼容的药理学活性成分并用。
另一方面,本发明提供一种用于降低人体中,例如患有痛风或高尿酸血或者有发展痛风或高尿酸血的较大风险的人体内尿酸水平的药物组合物,其中包含与药物上可接受的稀释剂或载体配合的通式Ⅰ化合物包括其对映体及其药物上可接受的盐,式中R1和R2独立地是H或甲基。
通式Ⅰ化合物在降低血浆尿酸水平方面的药效已经在如下临床试验中得到证实。要知道的是,10mg剂量或15mg剂量呈盐酸盐一水合物形式的西布曲明分别等效于8.37mg或12.55mg游离碱形式的西布曲明。
试验1
在有临床监督的试验中,485名轻度到中度肥胖患者随机抽样在12个月内每天一次经口接受安慰剂、西布曲明盐酸盐一水合物(10mg)或西布曲明盐酸盐一水合物(15mg)。尿酸水平的降低是在第6个月观察的,并在第12个月被保持;西布曲明组的降低量大于安慰剂组。对于第6个月西布曲明盐酸盐一水合物10mg与安慰剂之间的差异以及第6个月、终点和最终评价的西布曲明盐酸盐一水合物15mg与安慰剂之间的差异来说,差异是统计上显著的。最终评价时,西布曲明盐酸盐一水合物15mg与10mg之间的差异也是统计上显著的(p<0.05)。按照体重降低,对数据进行了回顾分析。
血浆尿酸-长期研究(LOCF)中从基线到终点的平均百分率变化总结
小组 | 安慰剂 | 西布曲明(10mg) | 西布曲明(15mg) |
全体患者 | -1.7 | -5.6* | -7.8** |
≥5%体重降低 | -3.9 | -9.5*** | -10.0*** |
≥10%体重降低 | -4.7 | -14.1*** | -11.1*** |
‘西布曲明’和‘西布’系指西布曲明盐酸盐一水合物。基线值(μmol/l):
安慰剂312.8;西布10mg 310.7;西布15mg 307.4
*p≤0.05相对于全体安慰剂而言
**p≤0.01相对于全体安慰剂而言
***p≤0.001相对于全体安慰剂而言
试验2
在进一步临床监督试验中,160名进食非常低热值食谱的肥胖患者随机抽样,在12个月内每天一次经口接受安慰剂或西布曲明盐酸盐一水合物(10mg)。在第6个月和终点,与安慰剂比较而言,在西布由明组中观察到统计上有意义的尿酸水平降低。按照体重降低,对数据进行了回顾分析。
血浆尿酸-长期研究(LOCF)中从基线到终点的平均百分率变化总结
小组 | 安慰剂 | 西布曲明(10mg) |
全体患者 | -11.1 | -19.0** |
≥5%体重降低 | -22.5 | -21.7* |
≥10%体重降低 | -28.2 | -27.1*** |
‘西布曲明’系指西布曲明盐酸盐一水合物。基线值(μmol/l):安慰剂328.5;西布曲明10mg 335.4*p≤0.05相对于全体安慰剂而言**p≤0.01相对于全体安慰剂而言***p ≤ 0.001相对于全体安慰剂而言以上结果支持通式Ⅰ化合物有降低尿酸水平的效用。
Claims (15)
2.按照权利要求1的方法,其中,所述的人患有痛风或高尿酸血症。
3.按照权利要求1或2的方法,其中,通式Ⅰ化合物是N,N-二甲基-1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺盐酸盐。
4.按照权利要求1或2的方法,其中,通式Ⅰ化合物是呈其一水合物形式的N,N-二甲基-1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺盐酸盐。
6.按照权利要求5的用途,其中,该药物是用于治疗痛风或高尿酸血的药物。
7.按照权利要求5或6的用途,其中,通式Ⅰ化合物是N,N-二甲基-1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺盐酸盐。
8.按照权利要求5或6的用途,其中,通式Ⅰ化合物是N,N-二甲基-1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺盐酸盐一水合物。
10.按照权利要求9的药物组合物,用于降低患有痛风或高尿酸血的人体中的尿酸水平。
11.按照权利要求9或10的药物组合物,其中,通式Ⅰ化合物是N,N-二甲基-1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺盐酸盐。
12.按照权利要求9或10的药物组合物,其中,通式Ⅰ化合物是N,N-二甲基-1-〔1-(4-氯苯基)环丁基〕-3-甲基丁胺盐酸盐一水合物。
13.在发展痛风、高尿酸血或冠状心脏病的风险增大的人体中预防这些病症的方法,包括对有此需要的人给药治疗有效量的、权利要求1中定义的通式Ⅰ化合物,和与其配合的药物上可接受的稀释剂或载体。
14.权利要求5中定义的通式Ⅰ化合物的用途,用于制造在发展痛风、高尿酸血或冠状心脏病的风险增大的人体中预防这些病症的药物。
15.用于在发展痛风、高尿酸血或冠状心脏病的风险增大的人体中预防这些病症的药物组合物,包含权利要求9中定义的、治疗有效量的通式Ⅰ化合物,和与其配合的药物上可接受的稀释剂或载体。
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US11103542B2 (en) | 2002-03-13 | 2021-08-31 | Kibow Biotech, Inc. | Composition and method for maintaining healthy kidney function |
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1996
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1997
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- 1997-09-15 CA CA002266438A patent/CA2266438A1/en not_active Abandoned
- 1997-09-15 JP JP10515217A patent/JP2001501608A/ja active Pending
- 1997-09-15 KR KR1019990702491A patent/KR20000048568A/ko not_active Application Discontinuation
- 1997-09-15 DE DE69721838T patent/DE69721838T2/de not_active Expired - Fee Related
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- 1997-09-15 WO PCT/EP1997/005034 patent/WO1998013033A1/en not_active Application Discontinuation
- 1997-09-15 US US09/269,339 patent/US6162831A/en not_active Expired - Fee Related
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- 1997-09-15 AU AU43851/97A patent/AU722129B2/en not_active Ceased
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-
1999
- 1999-03-24 NO NO991425A patent/NO991425L/no unknown
- 1999-03-24 BG BG103278A patent/BG103278A/xx unknown
Also Published As
Publication number | Publication date |
---|---|
EP1007023B1 (en) | 2003-05-07 |
ES2199374T3 (es) | 2004-02-16 |
IL128851A0 (en) | 2000-01-31 |
BG103278A (en) | 2000-01-31 |
TR199900649T2 (xx) | 1999-07-21 |
CA2266438A1 (en) | 1998-04-02 |
AU722129B2 (en) | 2000-07-20 |
NO991425D0 (no) | 1999-03-24 |
SK32199A3 (en) | 1999-12-10 |
PT1007023E (pt) | 2003-08-29 |
WO1998013033A1 (en) | 1998-04-02 |
DE69721838D1 (de) | 2003-06-12 |
ATE239460T1 (de) | 2003-05-15 |
US6162831A (en) | 2000-12-19 |
HRP970519A2 (en) | 1998-08-31 |
TW415842B (en) | 2000-12-21 |
NZ334668A (en) | 2000-07-28 |
GB9619962D0 (en) | 1996-11-13 |
PL332423A1 (en) | 1999-09-13 |
KR20000048568A (ko) | 2000-07-25 |
HUP9904545A3 (en) | 2000-12-28 |
DK1007023T3 (da) | 2003-08-25 |
BR9711414A (pt) | 2000-04-25 |
ZA978573B (en) | 1999-03-25 |
EP1007023A1 (en) | 2000-06-14 |
IL128851A (en) | 2001-08-26 |
DE69721838T2 (de) | 2004-01-22 |
NO991425L (no) | 1999-03-24 |
JP2001501608A (ja) | 2001-02-06 |
AU4385197A (en) | 1998-04-17 |
HUP9904545A2 (hu) | 2000-11-28 |
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