CN101980704A - 选择性s1p1受体激动剂的给药方案 - Google Patents
选择性s1p1受体激动剂的给药方案 Download PDFInfo
- Publication number
- CN101980704A CN101980704A CN2009801101149A CN200980110114A CN101980704A CN 101980704 A CN101980704 A CN 101980704A CN 2009801101149 A CN2009801101149 A CN 2009801101149A CN 200980110114 A CN200980110114 A CN 200980110114A CN 101980704 A CN101980704 A CN 101980704A
- Authority
- CN
- China
- Prior art keywords
- selectivity
- stimulating agent
- receptor stimulating
- dose
- target dose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- 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
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- 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
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Abstract
本发明涉及一种选择性S1P1受体激动剂的给药方案,其以下述方式将选择性S1P1受体激动剂施用至个体:在初始治疗期期间,以诱导心脏脱敏的剂量(该剂量低于目标剂量)及维持心脏脱敏的给药频率施用该选择性S1P1受体激动剂,直至不再发生急性心率降低,随后上调滴定剂量,至该选择性S1P1受体激动剂的目标剂量。
Description
技术领域
本发明涉及一种选择性S1P1受体激动剂的给药方案,其以下述方式将选择性S1P1受体激动剂施用至个体:在初始治疗期期间,以诱导心脏脱敏的剂量(该剂量低于目标剂量)及维持心脏脱敏的给药频率施用该选择性S1P1受体激动剂,直至不再发生急性心率降低,随后上调滴定剂量,至该选择性S1P1受体激动剂的目标剂量。本发明亦提供一种含有选择性S1P1受体激动剂的不同给药单位以供根据本发明施用的试剂盒,其含有供初始治疗期使用的一或多个低于该选择性S1P1受体激动剂目标剂量的剂量强度的单位,及随后使用的给药单位,其含有高达该选择性S1P1受体激动剂目标剂量的较高剂量强度。
背景技术
本发明提供一种选择性S1P1受体激动剂的给药方案,该给药方案使得个体在初始治疗期期间或停药后重新起始投药时,不良反应最小化。
选择性S1P1受体激动剂在1-磷酸-神经鞘胺醇敏感性人类G蛋白偶联受体的S1P1、S1P2、S1P3、S1P4及S1P5家族成员中优先活化人类S1P1受体亚型的化合物。S1P受体激动剂(例如)在口服施用后减少人类或动物周边血液中的循环淋巴细胞数目,因此其具有多种与错调免疫系统相关的疾病的治疗潜力。举例而言,已发现非选择性S1P受体激动剂FTY720降低多发性硬化症患者的临床复发率(Kappos L等人,N Engl J Med.2006年9月14日,355(11):1124-40)。
然而,已描述S1P受体激动剂在啮齿动物模型中降低心率,这是一种由于S1P3受体在心脏的窦房结组织中活化所引起的效应,其增加IK,ACh内向整流电流且减缓窦房节律点(Hale JJ等人,Bioorg Med Chem Lett.2004,14(13):3501-5;Bünem ann M等人,J Physiol 1995,489:701-707;Guo J等人,Pflugers Arch 1999,438:642-648;Ochi R等人,Cardiovasc Res 2006,70:88-96)。此外,非选择性S 1P受体激动剂FTY720降低人类心率(Koyrakh L等人,Am J Transplant 2005,5:529-536),且有文献提出与非选择性S 1P受体激动剂相比,S1P1选择性化合物对人类心率具有减弱的效应(Himmel HM等人,Mol Pharmacol 2000,58:449-454;Peters SL,Alewijnse AE,Curr Opin Pharmacol.2007,7(2):186-92;Fujishiro J等人,Transplantation 2006,82(6):804-12;S anna MG等人,J Biol Chem.2004,279(14):13839-48)。
发明内容
化合物(R)-5-[3-氯-4-(2,3-二羟基-丙氧基)-苯[Z]亚甲基]-2-([Z]-丙基亚胺基)-3-邻-甲苯基-噻唑烷-4-酮(下文亦称为“化合物1”;化合物1的制备及其医药用途描述于已公开的PCT申请WO 2005/054215中)为一种选择性S1P1受体激动剂,且重复每日向人类口服给药5mg或5mg以上可导致周边血液淋巴细胞数目一致的、持续的及剂量依赖性的降低。然而,已惊奇地发现选择性S1P1受体激动剂化合物1短暂地降低人类心率,最大效应在施用后1-3小时。在一些个体中,此效应伴有心电图(ECG)中PR间隔的类似短暂增加,及相关不规则心律(所谓文氏节律(Wenckebach rhythm))。在给药后时期内亦出现偶发性疲劳或头昏。10mg化合物1对心率及心律及疲劳/头昏的这些急性效应比20mg轻。所有这些效应均随着重复给药而减弱。因此,每日口服给药5mg至20mg2至4天后,与给药前值相比,施用化合物1后不再观察到急性心率降低。类似地,重复每日口服给药5mg至20mg化合物1,相对于给药前值,未观察到ECG的PR间隔的短暂增加,亦未报导疲劳或头昏。尽管对心率、房室传导或疲劳及头昏的急性效应并非严重不良,但却并非所需要的,且最小化这些效应的方法将有利于最大化化合物1及其它选择性S1P1受体激动剂的耐受性及安全性,及最小化给药起始早期或药物中断后重新起始药物治疗时相关的监控需要。
因此,本发明的主题提供一种选择性S1P1受体激动剂(诸如且尤其为化合物1)的给药方案,其最小化所述不良反应的发生率或严重性。本发明的给药方案提供将选择性S1P1受体激动剂以一定方式施用个体,使得在初始治疗期期间以诱导心脏脱敏的剂量(其中该剂量低于目标剂量)且以维持心脏脱敏的给药频率来施用选择性S1P1受体激动剂,直至不再发生急性心率降低,随后剂量上调滴定至选择性S1P1受体激动剂的目标剂量。本发明的给药方案具有以下优点:在低于目标剂量的剂量下可诱导及维持心脏脱敏,当与不使用该给药方案而给与目标剂量相比时出现较少的明显急性心率降低。因此,本发明的给药方案通过最小化给药选择性S1P1受体激动剂最初数日期间或停药后重新起始给药时个体/患者的不良反应而产生经改良的耐受性。
初始治疗期期间给药方案(亦即,剂量量值及给药频率)的选择可根据经验通过比较所给初始剂量间急性心率降低的量值来达成。给药频率应适宜于患者,其应长于急性心率降低的持续时间,且其应短于心脏自脱敏恢复所需的时间。因此,根据经验选择的给药频率将反映数个独立过程的相对速率常数:体内S1P1受体激动剂浓度超过与脱敏相关的浓度临限值的速率常数;心脏脱敏的速率常数;及自心脏脱敏恢复的速率常数。后两种速率常数(对于心脏脱敏及自脱敏恢复)为产生这些现象的基本生物过程的内在特性。第一种速率常数(对于超过浓度临限值)可由S1P1受体激动剂的药物动力学,亦即由药物吸收、分布、代谢及排泄的速率来决定。鉴于上述三种速率常数,合适给药间隔的持续时间将具有剂量依赖性。
举例而言,化合物1在通过口服途径以20-mg每日一次的剂量给与时,在第1天导致急性心率降低,且在24小时后施用第二次20-mg剂量时,未观察到急性心率降低。在此24小时给药间隔内已维持脱敏。然而,当第一次给药后7天施用第二次20-mg剂量时,其导致具有与第1天类似的量值的急性心率降低。在20-mg剂量的此7天给药间隔内未维持脱敏。此实例说明合适的给药间隔是维持心脏脱敏所必需的。
i)具体而言,本发明涉及一种用作药物的选择性S1P1受体激动剂,由此将该选择性S1P1受体激动剂以一定方式施用至个体(尤其人类个体)使得在初始治疗期期间以诱导心脏脱敏的剂量(其中该剂量低于目标剂量)且以维持心脏脱敏的给药频率来施用选择性S1P1受体激动剂,直至不再发生急性心率降低,随后剂量上调滴定至选择性S1P1受体激动剂的目标剂量。
i i)在另一实施方式中,本发明涉及根据实施方式i)的用作药物的选择性S1P1受体激动剂,由此低于目标剂量的初始剂量在比目标剂量低2至5倍的间。
iii)在另一实施方式中,本发明涉及根据实施方式i)的用作药物的选择性S1P1受体激动剂,由此低于目标剂量的初始剂量在比目标剂量低5至16倍的问。
iv)在另一实施方式中,本发明涉及根据实施方式i)至iii)中任一项的用作药物的选择性S1P1受体激动剂,由此在治疗的最初2至4天期间向个体施用低于目标剂量的剂量。
v)在另一实施方式中,本发明涉及根据实施方式i)至iv)中任一项的用作药物的选择性S1P1受体激动剂,由此以每日一次或两次的给药频率施用低于目标剂量的剂量。
vi)在另一实施方式中,本发明涉及根据实施方式i)至v)中任一项的用作药物的选择性S1P1受体激动剂,其中该选择性S1P1受体激动剂为(R)-5-[3-氯-4-(2,3-二羟基-丙氧基)-苯[Z]亚甲基]-2-([Z]-丙基亚胺基)-3-邻-甲苯基-噻唑烷-4-酮或其医药学上可接受的盐。
vii)在另一实施方式中,本发明涉及选择性S1P1受体激动剂于制造药物的用途,由此将该药物如实施方式i)至v)中任一项中所规定施用个体。
viii)在另一实施方式中,本发明涉及根据实施方式vii)的用途,其中选择性S1P1受体激动剂为(R)-5-[3-氯-4-(2,3-二羟基-丙氧基)-苯[Z]亚甲基]-2-([Z]-丙基亚胺基)-3-邻-甲苯基-噻唑烷-4-酮或其医药学上可接受的盐。
ix)本发明亦涉及一种含有选择性S1P1受体激动剂的不同药物单位以供根据实施方式i)施用的试剂盒,由此在初始治疗期提供一或多个低于该选择性S1P1受体激动剂的目标剂量的剂量强度的单位,且随后提供至多该选择性S1P1受体激动剂的目标剂量的较高剂量强度的药物单位。
x)在另一实施方式中,本发明涉及根据实施方式ix)的试剂盒,其中选择性S1P1受体激动剂为(R)-5-[3-氯-4-(2,3-二羟基-丙氧基)-苯[Z]亚甲基]-2-([Z]-丙基亚胺基)-3-邻-甲苯基-噻唑烷-4-酮或其医药学上可接受的盐。
xi)在另一实施方式中,本发明涉及根据实施方式ix)或x)的试剂盒,由此随后提供比初始剂量强度高2至5倍的剂量强度的药物单位。
xii)在另一实施方式中,本发明涉及根据实施方式ix)或x)的试剂盒,由此随后提供比初始剂量强度高5至16倍的剂量强度的药物单位。
xiii)在另一实施方式中,本发明涉及根据实施方式ix)至xii)中任一项的试剂盒,由此在治疗的最初2至4天提供低于目标剂量的剂量强度单位。
xiv)在另一实施方式中,本发明涉及根据实施方式ix)至xiii)中任一项的试剂盒,由此以每日一次或两次的给药频率施用低于目标剂量的剂量强度单位。
xv)本发明另外亦涉及一种施用选择性S1P1受体激动剂的方法,由此将选择性S1P1受体激动剂如实施方式i)至v)中任一项中所规定施用个体。
xvi)在另一实施方式中,本发明涉及根据实施方式xv)的方法,其中选择性S1P1受体激动剂为(R)-5-[3-氯-4-(2,3-二羟基-丙氧基)-苯[Z]亚甲基]-2-([Z]-丙基亚胺基)-3-邻-甲苯基-噻唑烷-4-酮或其医药学上可接受的盐。
具体实施方式
在本发明中,上文及下文中所用的一般术语优选具有以下含义:
如本文中所用的术语“心脏脱敏”指在施用药物后不出现急性心率降低。
如本文中所用的术语“急性心率降低”指心率自(例如)10次/分(bp m)或10次/分以上的给药前值降低,其在施用药物后数小时(例如,1-3小时)内最大,且随后心率返回给药前值。
如本文中所用的术语“目标剂量”指达成目标周边血液淋巴细胞计数(例如,每微升400-800个淋巴细胞)的选择性S1P1受体激动剂的剂量。给定S1P1受体激动剂的目标剂量可视所治疗疾病的性质及严重性而变化。
剂量上调滴定至目标剂量可以一或数个剂量增量来达成。举例而言,化合物1的合适给药方案可为口服5mg(每日一次历时3天,初始治疗期),随后上调滴定至口服10mg(每日一次历时3天),随后上调滴定至口服20mg(目标剂量),每日一次不限期地给与。化合物1的合适给药方案的另一实例可为口服5mg(每日一次历时3天,初始治疗期),随后上调滴定至口服20mg(目标剂量),每日一次不限期地给与。
本发明的选择性S1P1受体激动剂为在S1P1、S1P2、S1P3、S1P4及S1P5家族成员中优先活化人类S1P1受体亚型的化合物,尤其为在合适测定中具有超过其它家族成员至少5倍的S1P1受体活化功效的化合物。用于测定S1P受体激动剂活性的该种合适测定是本领域所已知的。具体而言,化合物的S1P1受体激动剂活性可使用如(例如)WO 2007/080542中针对人类S1P1受体所述的GTPγS测定来测试。可使用相同测定通过分别使用表现重组人类S1P2、S1P3、S1P4及S1P5受体的CHO细胞来测定化合物关于其它S1P家族成员的激动剂活性。
本发明的优选选择性S1P1受体激动剂,其制备及医学用途披露于已公开的PCT申请WO 2005/054215、WO2005/123677、WO 2006/010544、WO 2006/100635、WO2006/100633、WO 2006/100631、WO 2006/137019、WO2007/060626、WO 2007/086001、WO 2007/080542、WO2008/029371、WO 2008/029370、WO 2008/029306、WO2008/035239、WO 2008/114157及WO 2009/024905中。
选择性S1P1受体激动剂及其医药学上可接受的盐可用作(例如)用于经肠或肠胃外施用的医药组合物形式的药物,且适用于预防及/或治疗与活化免疫系统相关的疾病或病症。
术语“医药学上可接受的盐”指无毒、无机或有机酸及/或碱加成盐。可参考“Salt selection for basic drugs”,Int.J.Pharm.(1986),33,201-217。
医药组合物的制造可以任何本领域技术人员所熟知的方式(例如参见Remington,The Science and Practiceof Pharmacy,第21版(2005),第5部分,“PharmaceuticalManufacturing”[Lippincott Williams&Wilkins出版])通过将选择性S1P1受体激动剂或其医药学上可接受的盐可选地组合其它治疗上有价值的物质与合适的无毒惰性医药学上可接受的固体或液体载剂材料及(若需要)常用医药佐剂一起制成盖伦(galenical)给药形式来实现。
可使用选择性S1P1受体激动剂治疗及/或预防的该种与活化免疫系统相关的疾病或病症描述于(例如)WO2005/054215中。
可使用选择性S1P1受体激动剂治疗及/或预防的优选疾病或病症选自由下列各疾病或病症组成的群:移植器官(诸如肾、肝、心脏、肺、胰脏、角膜及皮肤)的排斥反应;干细胞移植所引起的移植物抗宿主疾病;自体免疫综合症,包括类风湿性关节炎、多发性硬化症、炎症性肠病(诸如克罗恩氏病(Crohn′s disease)及溃疡性结肠炎)、牛皮癣、牛皮癣性关节炎、甲状腺炎(诸如乔本氏甲状腺炎(Hashimoto′s thyroiditis))、葡萄膜视网膜炎;异位性疾病,诸如鼻炎、结膜炎及皮炎;哮喘;I型糖尿病;感染后自体免疫疾病,包括风湿热及感染后丝球体肾炎;实体癌症及肿瘤转移。
可使用选择性S1P1受体激动剂治疗及/或预防的尤其优选的疾病或病症选自由下列各疾病或病症组成的群:选自肾、肝、心脏及肺的移植器官的排斥反应;干细胞移植所引起的移植物抗宿主疾病;选自类风湿性关节炎、多发性硬化症、牛皮癣、牛皮癣性关节炎、克罗恩氏病及乔本氏甲状腺炎的自体免疫综合症;及异位性皮炎。可使用选择性S1P1受体激动剂治疗及/或预防的非常优选的疾病或病症选自多发性硬化症及牛皮癣。
此外,选择性S1P1受体激动剂亦适用于与一或数种免疫调节剂组合来预防及/或治疗本文中所述的疾病及病症。根据本发明的一优选实施方式,该种药剂选自由下列各药剂组成的群:免疫抑制剂、皮质类固醇、非类固醇消炎药、细胞毒性药物、黏附分子抑制剂、细胞激素、细胞激素抑制剂、细胞激素受体拮抗剂及重组细胞激素受体。
至今为止,化合物1已在3项一期研究中施用至人类。总计已有85名个体接受至多75mg单剂量及至多40mg多剂量历时至多15天的化合物1治疗。
在单一递增剂量(SAD)研究(AC-058-101)中,将化合物1口服施用6个组中的6名健康男性个体(年龄21-47岁)。以随机、双盲、安慰剂对照设计将1mg、3mg、8mg、20mg、50mg及75mg的剂量给与循序组中的8名个体(6名接受活性药物且2名接受安慰剂)。20mg剂量在空腹及饱食状态下各给与一次,以评定对化合物1的药物动力学的任何食物效应。记录ECG,测定临床实验参数、生命体征、肺功能、神经学评分(在75-mg剂量组中)、化合物1的血浆含量及周边淋巴细胞计数(总数及子集)。所有48名随机个体均可评估且无个体退出或停止研究。药物动力学(PK)及药效学(PD)分析中包括所有经化合物1治疗的个体(n=36)。
在多个递增剂量(MAD)研究(AC-058-102)的A部分中,以随机、双盲、安慰剂对照设计将化合物1以5mg、10mg及20mg的剂量每日一次口服施用健康男性及女性个体(年龄22-58岁,性别比率1∶1)历时7天。在各剂量水平上,每组10名个体随机接受化合物1(8)或安慰剂(2)。在A部分中,所有30名随机个体均完成研究且在PK分析中包括24名经化合物1治疗的个体。
在MAD研究的B部分中,执行上调滴定方案以降低化合物1对窦房结自律性及房室(AV)传导的首剂效应。化合物1的治疗以每日一次10mg开始历时4天,随后每日一次20mg历时4天,及每日一次40mg历时7天。将17名个体(9名女性及8名男性,年龄18-43岁)随机化。13名个体接受活性治疗且4名个体接受匹配安慰剂。17名个体中总计15名按预定完成研究。活性治疗中的两名个体因不良事件停止给药,一例为中度牙齿感染及口腔水肿,且另一例为周边血涂片中的中度粒细胞左移(其已处于基线处)。在化合物1的P K分析中包括11名完成研究的经40-mg化合物1治疗的个体。
表1展示40-mg剂量组(AC-058-102,B部分)中各滴定步骤后(10mg为第1天,20mg为第5天及40mg为第9天)给药后2.5小时相对于给药前的平均心率(HR)降低与不使用上调滴定时第1天(AC-058-102的A部分10mg及20mg及AC-058-101的50mg)的HR降低的比较。
表1使用与不使用上调滴定时给药后2.5小时平均HR降低的比较
40-mg剂量组(AC-058-102,B部分)在第2天、第3天及第4天(10mg)的给药后2.5小时相对于给药前的平均HR降低分别为2bpm、1bpm及1bpm,且在第6天、第7天及第8天(20mg)的平均HR降低分别为4bpm、3bpm及3bpm。
在研究的B部分期间,仅一名个体在第1天施用第一剂10mg化合物1后报导第一度短暂AV-阻断,从而表明上调滴定降低化合物1对窦房结自律性与AV传导的效应。在研究的B部分期间未观察到第二度或第三度AV阻断。对于B部分中的多次给药未记录到对其他ECG变量的相关效应。
Claims (14)
1.一种作为药物的选择性S1P1受体激动剂,该选择性S1P1受体激动剂以下述方式施用至个体:在初始治疗期期间,以诱导心脏脱敏的剂量(该剂量低于目标剂量)及维持心脏脱敏的给药频率施用该选择性S1P1受体激动剂,直至不再发生急性心率降低,随后上调滴定剂量,至该选择性S1P1受体激动剂的目标剂量。
2.如权利要求1的作为药物的选择性S1P1受体激动剂,其中该低于目标剂量的初始剂量比目标剂量低2至5倍。
3.如权利要求1的作为药物的选择性S1P1受体激动剂,其中该低于目标剂量的初始剂量比目标剂量低5至16倍。
4.如权利要求1至3中任一项的作为药物的选择性S1P1受体激动剂,其中在治疗的最初2至4天期间,向该个体施用低于目标剂量的剂量。
5.如权利要求1至4中任一项的作为药物的选择性S1P1受体激动剂,其中以每日一次或两次的给药频率施用低于目标剂量的剂量。
6.如权利要求1至5中任一项的作为药物的选择性S1P1受体激动剂,其中该选择性S1P1受体激动剂为(R)-5-[3-氯-4-(2,3-二羟基-丙氧基)-苯[Z]亚甲基]-2-([Z]-丙基亚胺基)-3-邻-甲苯基-噻唑烷-4-酮或其医药学上可接受的盐。
7.一种选择性S1P1受体激动剂在制造药物中的用途,其中该药物用于依如权利要求1至5中任一项中所界定的方式施用个体。
8.如权利要求7的用途,其中该选择性S1P1受体激动剂为(R)-5-[3-氯-4-(2,3-二羟基-丙氧基)-苯[Z]亚甲基]-2-([Z]-丙基亚胺基)-3-邻-甲苯基-噻唑烷-4-酮或其医药学上可接受的盐。
9.一种含有选择性S1P1受体激动剂的不同给药单位以供依如权利要求1所界定的方式施用的试剂盒,其含有供初始治疗期使用的一或多个低于该选择性S1P1受体激动剂目标剂量的剂量强度的单位,及后续使用的给药单位,其含高达该选择性S1P1受体激动剂目标剂量的较高剂量强度。
10.如权利要求9的试剂盒,其中该选择性S1P1受体激动剂为(R)-5-[3-氯-4-(2,3-二羟基-丙氧基)-苯[Z]亚甲基]-2-([Z]-丙基亚胺基)-3-邻-甲苯基-噻唑烷-4-酮或其医药学上可接受的盐。
11.如权利要求9或10的试剂盒,其含有较初始剂量强度高2至5倍的剂量强度的后续给药单位。
12.如权利要求9或10的试剂盒,其含有较初始剂量强度高5至16倍的剂量强度的后续给药单位。
13.如权利要求9至12中任一项的试剂盒,其含有供治疗的最初2至4天使用的低于目标剂量的剂量强度单位。
14.如权利要求9至13中任一项的试剂盒,其中低于目标剂量的剂量强度单位的给药频率为每日一次或两次。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510090161.9A CN104800208A (zh) | 2008-03-17 | 2009-03-12 | 选择性s1p1受体激动剂的给药方案 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IBPCT/IB2008/050995 | 2008-03-17 | ||
IB2008050995 | 2008-03-17 | ||
PCT/IB2009/051030 WO2009115954A1 (en) | 2008-03-17 | 2009-03-12 | Dosing regimen for a selective s1p1 receptor agonist |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510090161.9A Division CN104800208A (zh) | 2008-03-17 | 2009-03-12 | 选择性s1p1受体激动剂的给药方案 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101980704A true CN101980704A (zh) | 2011-02-23 |
Family
ID=40786618
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2009801101149A Pending CN101980704A (zh) | 2008-03-17 | 2009-03-12 | 选择性s1p1受体激动剂的给药方案 |
CN201510090161.9A Pending CN104800208A (zh) | 2008-03-17 | 2009-03-12 | 选择性s1p1受体激动剂的给药方案 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510090161.9A Pending CN104800208A (zh) | 2008-03-17 | 2009-03-12 | 选择性s1p1受体激动剂的给药方案 |
Country Status (27)
Country | Link |
---|---|
US (6) | US8785484B2 (zh) |
EP (1) | EP2278960B2 (zh) |
JP (2) | JP4846063B2 (zh) |
KR (3) | KR101718639B1 (zh) |
CN (2) | CN101980704A (zh) |
AR (1) | AR070842A1 (zh) |
AU (1) | AU2009227629B2 (zh) |
BR (1) | BRPI0909625B1 (zh) |
CA (1) | CA2716448A1 (zh) |
CY (1) | CY1118648T1 (zh) |
DK (1) | DK2278960T4 (zh) |
ES (1) | ES2617628T5 (zh) |
HR (1) | HRP20170246T4 (zh) |
HU (1) | HUE033168T2 (zh) |
IL (1) | IL208154A (zh) |
LT (1) | LT2278960T (zh) |
MA (1) | MA32233B1 (zh) |
MX (1) | MX2010009853A (zh) |
MY (1) | MY177360A (zh) |
NZ (1) | NZ588505A (zh) |
PL (1) | PL2278960T5 (zh) |
PT (1) | PT2278960T (zh) |
RU (1) | RU2519660C2 (zh) |
SI (1) | SI2278960T2 (zh) |
TW (1) | TWI434688B (zh) |
WO (1) | WO2009115954A1 (zh) |
ZA (1) | ZA201007367B (zh) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106999461A (zh) * | 2014-12-11 | 2017-08-01 | 埃科特莱茵药品有限公司 | 选择性s1p1受体激动剂的给药方案 |
CN110545848A (zh) * | 2017-02-16 | 2019-12-06 | 艾尼纳制药公司 | 用于治疗具有肠外表现的炎症性肠病的化合物和方法 |
US11534424B2 (en) | 2017-02-16 | 2022-12-27 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of primary biliary cholangitis |
US11674163B2 (en) | 2010-01-27 | 2023-06-13 | Arena Pharmaceuticals, Inc. | Processes for the preparation of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and salts thereof |
US11884626B2 (en) | 2015-06-22 | 2024-01-30 | Arena Pharmaceuticals, Inc. | Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE43833E1 (en) | 2003-11-21 | 2012-11-27 | Actelion Pharmaceuticals Ltd. | Thiazolidin-4-one derivatives |
DE602004029493D1 (de) | 2003-11-21 | 2010-11-18 | Actelion Pharmaceuticals Ltd | 5-(benz- (z) -yliden) -thiazolidin-4-onderivate als das immunsystem unterdrückende mittel |
DK2094676T3 (da) * | 2006-11-23 | 2013-06-10 | Actelion Pharmaceuticals Ltd | Ny fremgangsmåde til fremstillingen af 2-iminothiazolidin-4-on-derivater |
US8912340B2 (en) | 2006-11-23 | 2014-12-16 | Actelion Pharmaceuticals Ltd. | Process for the preparation of 2-imino-thiazolidin-4-one derivatives |
WO2009115954A1 (en) | 2008-03-17 | 2009-09-24 | Actelion Pharmaceuticals Ltd | Dosing regimen for a selective s1p1 receptor agonist |
GB0819182D0 (en) | 2008-10-20 | 2008-11-26 | Actelion Pharmaceuticals Ltd | Crystalline forms |
SI3409274T1 (sl) * | 2008-12-22 | 2020-03-31 | Novartis Ag | Režim odmerjanja za S1P receptor agonist |
CN102917698A (zh) * | 2010-05-06 | 2013-02-06 | 诺瓦提斯公司 | 二芳基硫醚衍生物的给药方案 |
PT2885266T (pt) | 2012-08-17 | 2020-05-29 | Actelion Pharmaceuticals Ltd | Processo para a preparação de (2z,5z)-5-(3-cloro-4-((r)-2,3-di-hidropropoxi)benzilideno)-2-(propilimino)-3-(o-tolil)tiazolidin-4-ona e intermediário utilizado no referido processo |
US20170165236A1 (en) | 2013-11-01 | 2017-06-15 | Celgene International Ii Sàrl | Selective sphingosine 1 phosphate receptor modulators and combination therapy therewith |
MA41139A (fr) | 2014-12-11 | 2017-10-17 | Actelion Pharmaceuticals Ltd | Combinaison pharmaceutique comportant un agoniste sélectif du récepteur sip1 |
EP3242666A1 (en) * | 2015-01-06 | 2017-11-15 | Arena Pharmaceuticals, Inc. | Methods of treating conditions related to the s1p1 receptor |
US20180042895A1 (en) | 2015-02-26 | 2018-02-15 | Novartis Ag | Treatment of autoimmune disease in a patient receiving additionally a beta-blocker |
JOP20190207A1 (ar) | 2017-03-14 | 2019-09-10 | Actelion Pharmaceuticals Ltd | تركيبة صيدلانية تشتمل على بونيسيمود |
US11014897B1 (en) | 2018-10-16 | 2021-05-25 | Celgene Corporation | Solid forms comprising a thiazolidinone compound, compositions and methods of use thereof |
US11013723B1 (en) | 2018-10-16 | 2021-05-25 | Celgene Corporation | Solid forms of a thiazolidinone compound, compositions and methods of use thereof |
US11014940B1 (en) | 2018-10-16 | 2021-05-25 | Celgene Corporation | Thiazolidinone and oxazolidinone compounds and formulations |
US11186556B1 (en) | 2018-10-16 | 2021-11-30 | Celgene Corporation | Salts of a thiazolidinone compound, solid forms, compositions and methods of use thereof |
CA3156298A1 (en) | 2019-10-31 | 2021-05-06 | Laetitia POUZOL | Combination of a cxcr7 antagonist with an s1p1 receptor modulator |
US11951097B2 (en) | 2021-10-11 | 2024-04-09 | Vanda Pharmaceuticals Inc. | Methods of treating multiple sclerosis |
EP4212156A1 (en) | 2022-01-13 | 2023-07-19 | Abivax | Combination of 8-chloro-n-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and its derivatives with a s1p receptor modulator |
Family Cites Families (54)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR0155015B1 (ko) | 1992-10-21 | 1998-12-01 | 고우야 마사시 | 2-아미노-1,3-프로판디올 화합물 및 면역 억제제 |
ATE279185T1 (de) | 1995-12-28 | 2004-10-15 | Mitsubishi Pharma Corp | 2-amino-2-(2-(4-octylphenyl)ethyl)propan-1,3-di l enthaltendes arzneimittel zur topischen anwendung zur behandlung von erkrankungen die durch eine störung des immunsystems hervorgerufen werden |
US6476004B1 (en) | 1996-07-18 | 2002-11-05 | Mitsubishi Pharma Corporation | Pharmaceutical composition |
JPH11209277A (ja) * | 1998-01-19 | 1999-08-03 | Yoshitomi Pharmaceut Ind Ltd | 医薬組成物 |
EP0990440B1 (en) | 1997-02-27 | 2008-10-29 | Novartis AG | Pharmaceutical composition comprising 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, a lecithin and a saccharide |
EP1012150A4 (en) | 1997-05-19 | 2002-05-29 | Sugen Inc | HETEROARYLCARBOXAMIDE COMPOUNDS THAT ARE EFFECTIVE OF DISEASES CAUSED BY PROTEIN-TYROSIN-KINASE |
JPH1180026A (ja) | 1997-09-02 | 1999-03-23 | Yoshitomi Pharmaceut Ind Ltd | 新規免疫抑制剤、その使用方法およびその同定方法 |
WO2002012545A2 (en) * | 2000-08-03 | 2002-02-14 | Cytovia, Inc. | Method of identifying immunosuppressive agents |
ATE507839T1 (de) | 2001-04-02 | 2011-05-15 | Genentech Inc | Kombinationstherapie |
PL365330A1 (en) | 2001-04-02 | 2004-12-27 | Astrazeneca Ab | Solid pharmaceutical composition comprising 4 -cyano-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropiono- m toluidide and pvp |
US6495025B2 (en) | 2001-04-20 | 2002-12-17 | Aerovironment, Inc. | Electrochemical oxygen generator and process |
WO2002092018A2 (en) * | 2001-05-16 | 2002-11-21 | Plotnikoff Nicholas P | Methods for inducing sustained immune response |
CN1524002A (zh) | 2001-06-08 | 2004-08-25 | ��˹��ŵ�� | 治疗或预防产胰岛素细胞的移植排斥反应 |
MXPA04002679A (es) | 2001-09-27 | 2004-07-30 | Kyorin Seiyaku Kk | Derivados de sulfuro de diarilo, sales de los mismos y agentes inmunosupresores que utilizan los mismos. |
JP4152884B2 (ja) | 2001-09-27 | 2008-09-17 | 杏林製薬株式会社 | ジアリールエーテル誘導体とその付加塩及び免疫抑制剤 |
US7479504B2 (en) | 2002-01-18 | 2009-01-20 | Merck & Co., Inc. | Edg receptor agonists |
EP1469863A2 (en) | 2002-01-18 | 2004-10-27 | Merck & Co., Inc. | Selective s1p1/edg1 receptor agonists |
GB0217152D0 (en) * | 2002-07-24 | 2002-09-04 | Novartis Ag | Organic compounds |
KR20080103117A (ko) | 2002-09-24 | 2008-11-26 | 노파르티스 아게 | 탈수초성 장애의 치료에 있어서의 스핑고신-1-포스페이트 수용체 아고니스트 |
HUE028247T2 (en) | 2003-04-08 | 2016-12-28 | Novartis Ag | A solid oral composition comprising S1P receptor agonist and sugar alcohol |
MY150088A (en) | 2003-05-19 | 2013-11-29 | Irm Llc | Immunosuppressant compounds and compositions |
DE602004029493D1 (de) | 2003-11-21 | 2010-11-18 | Actelion Pharmaceuticals Ltd | 5-(benz- (z) -yliden) -thiazolidin-4-onderivate als das immunsystem unterdrückende mittel |
USRE43833E1 (en) | 2003-11-21 | 2012-11-27 | Actelion Pharmaceuticals Ltd. | Thiazolidin-4-one derivatives |
WO2005123677A1 (en) | 2004-06-16 | 2005-12-29 | Actelion Pharmaceuticals Ltd | 4-carbonyl substituted 1,1,2-trimethyl-1a,4,5,5a-tetrahydro-1h-4-aza-cyclopropa'a!pentalene derivatives as agonists for the g-protein-coupled receptor s1p1/edg1 and immunosuppressive agents |
WO2006010379A1 (en) | 2004-07-29 | 2006-02-02 | Actelion Pharmaceuticals Ltd. | Novel thiophene derivatives as immunosuppressive agents |
WO2006041015A1 (ja) | 2004-10-12 | 2006-04-20 | Kyorin Pharmaceutical Co., Ltd. | アミノアルコール誘導体とその付加塩及び免疫抑制剤 |
US20060090658A1 (en) * | 2004-11-01 | 2006-05-04 | Michael Phillips | Tissue marking system |
JP2008521827A (ja) * | 2004-11-29 | 2008-06-26 | ノバルティス アクチエンゲゼルシャフト | S1p受容体アゴニストの投与レジメン |
JP5047941B2 (ja) | 2005-03-23 | 2012-10-10 | アクテリオン ファーマシューティカルズ リミテッド | 免疫調節物質としての水素付加されたベンゾ(c)チオフェン誘導体 |
RU2404178C2 (ru) | 2005-03-23 | 2010-11-20 | Актелион Фармасьютиклз Лтд | Новые производные тиофена в качестве агонистов рецептора сфингозин-1-фосфата-1 |
CN101180050B (zh) | 2005-03-23 | 2011-07-27 | 埃科特莱茵药品有限公司 | 作为鞘氨醇-1-磷酸盐-1受体激动剂的新颖噻吩衍生物 |
AU2006260573A1 (en) | 2005-06-24 | 2006-12-28 | Actelion Pharmaceuticals Ltd. | Novel thiophene derivatives |
AR057894A1 (es) | 2005-11-23 | 2007-12-26 | Actelion Pharmaceuticals Ltd | Derivados de tiofeno |
TWI404706B (zh) | 2006-01-11 | 2013-08-11 | Actelion Pharmaceuticals Ltd | 新穎噻吩衍生物 |
EP1979345B1 (en) | 2006-01-24 | 2009-11-04 | Actelion Pharmaceuticals Ltd. | Novel pyridine derivatives |
US7879821B2 (en) * | 2006-01-26 | 2011-02-01 | University Of Medicine And Dentistry Of New Jersey | Method for modulating inflammatory responses by altering plasma lipid levels |
AR061841A1 (es) | 2006-09-07 | 2008-09-24 | Actelion Pharmaceuticals Ltd | Derivados de tiofen-oxadiazoles, agonistas del receptor s1p1/edg1, composiciones farmaceuticas que los contienen y usos como agentes inmunomoduladores. |
AU2007292993B2 (en) | 2006-09-07 | 2013-01-24 | Idorsia Pharmaceuticals Ltd | Pyridin-4-yl derivatives as immunomodulating agents |
CA2661315C (en) | 2006-09-08 | 2015-11-24 | Actelion Pharmaceuticals Ltd | Pyridin-3-yl derivatives as immunomodulating agents |
RU2442780C2 (ru) | 2006-09-21 | 2012-02-20 | Актелион Фармасьютиклз Лтд | Фенильные производные и их применение в качестве иммуномодуляторов |
DK2094676T3 (da) | 2006-11-23 | 2013-06-10 | Actelion Pharmaceuticals Ltd | Ny fremgangsmåde til fremstillingen af 2-iminothiazolidin-4-on-derivater |
US8912340B2 (en) | 2006-11-23 | 2014-12-16 | Actelion Pharmaceuticals Ltd. | Process for the preparation of 2-imino-thiazolidin-4-one derivatives |
DK2125797T3 (da) | 2007-03-16 | 2014-02-10 | Actelion Pharmaceuticals Ltd | Aminopyridinderivater som s1p1/edg1-receptoragonister |
SI2195311T1 (sl) | 2007-08-17 | 2011-07-29 | Actelion Pharmaceuticals Ltd | Derivati piridina kot modulatorji receptorja s1p1/edg1 |
WO2009048993A2 (en) | 2007-10-12 | 2009-04-16 | Novartis Ag | Compositions comprising sphingosine 1 phosphate (s1p) receptor modulators |
WO2009115954A1 (en) | 2008-03-17 | 2009-09-24 | Actelion Pharmaceuticals Ltd | Dosing regimen for a selective s1p1 receptor agonist |
SI2342205T1 (sl) * | 2008-08-27 | 2016-09-30 | Arena Pharmaceuticals, Inc. | Substituirani triciklični kislinski derivati kot agonisti S1P1 receptorja, uporabni v zdravljenju avtoimunskih in vnetnih obolenj |
GB0819182D0 (en) | 2008-10-20 | 2008-11-26 | Actelion Pharmaceuticals Ltd | Crystalline forms |
PL2379069T3 (pl) | 2008-12-22 | 2015-08-31 | Novartis Ag | Schemat dawkowania agonisty receptora S1P |
SI3409274T1 (sl) | 2008-12-22 | 2020-03-31 | Novartis Ag | Režim odmerjanja za S1P receptor agonist |
JP5416600B2 (ja) | 2010-01-22 | 2014-02-12 | 株式会社日立ハイテクノロジーズ | 欠陥検査装置およびその方法 |
PT2885266T (pt) | 2012-08-17 | 2020-05-29 | Actelion Pharmaceuticals Ltd | Processo para a preparação de (2z,5z)-5-(3-cloro-4-((r)-2,3-di-hidropropoxi)benzilideno)-2-(propilimino)-3-(o-tolil)tiazolidin-4-ona e intermediário utilizado no referido processo |
MA41139A (fr) | 2014-12-11 | 2017-10-17 | Actelion Pharmaceuticals Ltd | Combinaison pharmaceutique comportant un agoniste sélectif du récepteur sip1 |
AU2015359346B2 (en) | 2014-12-11 | 2020-05-07 | Actelion Pharmaceuticals Ltd | Dosing regimen for a selective S1P1 receptor agonist |
-
2009
- 2009-03-12 WO PCT/IB2009/051030 patent/WO2009115954A1/en active Application Filing
- 2009-03-12 PL PL09721703T patent/PL2278960T5/pl unknown
- 2009-03-12 JP JP2011500324A patent/JP4846063B2/ja active Active
- 2009-03-12 KR KR1020157002281A patent/KR101718639B1/ko active IP Right Grant
- 2009-03-12 SI SI200931616T patent/SI2278960T2/sl unknown
- 2009-03-12 NZ NZ588505A patent/NZ588505A/xx unknown
- 2009-03-12 RU RU2010141579/15A patent/RU2519660C2/ru active
- 2009-03-12 EP EP09721703.8A patent/EP2278960B2/en active Active
- 2009-03-12 CA CA2716448A patent/CA2716448A1/en not_active Abandoned
- 2009-03-12 CN CN2009801101149A patent/CN101980704A/zh active Pending
- 2009-03-12 CN CN201510090161.9A patent/CN104800208A/zh active Pending
- 2009-03-12 US US12/922,777 patent/US8785484B2/en active Active
- 2009-03-12 HU HUE09721703A patent/HUE033168T2/en unknown
- 2009-03-12 LT LTEP09721703.8T patent/LT2278960T/lt unknown
- 2009-03-12 KR KR1020107022801A patent/KR20100134032A/ko active IP Right Grant
- 2009-03-12 MY MYPI2010004328A patent/MY177360A/en unknown
- 2009-03-12 AU AU2009227629A patent/AU2009227629B2/en active Active
- 2009-03-12 ES ES09721703T patent/ES2617628T5/es active Active
- 2009-03-12 MX MX2010009853A patent/MX2010009853A/es active IP Right Grant
- 2009-03-12 DK DK09721703.8T patent/DK2278960T4/da active
- 2009-03-12 AR ARP090100886A patent/AR070842A1/es unknown
- 2009-03-12 KR KR1020147005406A patent/KR101653071B1/ko active IP Right Grant
- 2009-03-12 PT PT97217038T patent/PT2278960T/pt unknown
- 2009-03-12 BR BRPI0909625-6A patent/BRPI0909625B1/pt active IP Right Grant
- 2009-03-16 TW TW098108497A patent/TWI434688B/zh active
-
2010
- 2010-09-15 IL IL208154A patent/IL208154A/en active IP Right Grant
- 2010-10-14 ZA ZA2010/07367A patent/ZA201007367B/en unknown
- 2010-10-15 MA MA33253A patent/MA32233B1/fr unknown
-
2011
- 2011-08-30 JP JP2011186874A patent/JP4938905B2/ja active Active
-
2014
- 2014-06-18 US US14/308,598 patent/US20140303217A1/en not_active Abandoned
- 2014-07-02 US US14/322,801 patent/US20140315964A1/en not_active Abandoned
- 2014-07-02 US US14/322,722 patent/US10660880B2/en active Active
-
2015
- 2015-06-05 US US14/732,013 patent/US10251867B2/en active Active
-
2017
- 2017-02-02 CY CY20171100154T patent/CY1118648T1/el unknown
- 2017-02-15 HR HRP20170246TT patent/HRP20170246T4/hr unknown
-
2021
- 2021-09-09 US US17/470,905 patent/US20210401811A1/en not_active Abandoned
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11674163B2 (en) | 2010-01-27 | 2023-06-13 | Arena Pharmaceuticals, Inc. | Processes for the preparation of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and salts thereof |
CN106999461A (zh) * | 2014-12-11 | 2017-08-01 | 埃科特莱茵药品有限公司 | 选择性s1p1受体激动剂的给药方案 |
US11771683B2 (en) | 2014-12-11 | 2023-10-03 | Actelion Pharmaceuticals Ltd | Dosing regimen for a selective S1P1 receptor agonist |
US11884626B2 (en) | 2015-06-22 | 2024-01-30 | Arena Pharmaceuticals, Inc. | Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders |
CN110545848A (zh) * | 2017-02-16 | 2019-12-06 | 艾尼纳制药公司 | 用于治疗具有肠外表现的炎症性肠病的化合物和方法 |
US11478448B2 (en) | 2017-02-16 | 2022-10-25 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of inflammatory bowel disease with extra-intestinal manifestations |
US11534424B2 (en) | 2017-02-16 | 2022-12-27 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of primary biliary cholangitis |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101980704A (zh) | 选择性s1p1受体激动剂的给药方案 | |
TWI314054B (en) | Novel methods and compositions for alleviating pain | |
CA2724133C (en) | Medicine consisting of concomitant use or combination of dpp-iv inhibitor and other diabetic medicine | |
CN109316480A (zh) | 组合als疗法 | |
KR20050106038A (ko) | 심장질환 및 신장질환의 치료를 위한 아데노신 a1 수용체길항제 | |
WO2007056454A2 (en) | Use of cicletanine and other furopyridines for treatment of hypertension | |
US7998973B2 (en) | Tivozanib and temsirolimus in combination | |
JP6420923B1 (ja) | 医薬 | |
KR20220128984A (ko) | sGC 자극제를 사용한 당뇨병성 신장병증의 치료 | |
WO2000028984A1 (fr) | Remedes agissant contre un trouble fonctionnel du tractus digestif |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20110223 |