CN1225010A - 治疗环加氧酶-2介导的疾病的每天一次的组合物 - Google Patents
治疗环加氧酶-2介导的疾病的每天一次的组合物 Download PDFInfo
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- CN1225010A CN1225010A CN97196315A CN97196315A CN1225010A CN 1225010 A CN1225010 A CN 1225010A CN 97196315 A CN97196315 A CN 97196315A CN 97196315 A CN97196315 A CN 97196315A CN 1225010 A CN1225010 A CN 1225010A
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Abstract
本发明涉及治疗环加氧酶-2介导的疾病的药用组合物,所述组合物适于每天给药一次,所述组合物包含环加氧酶-2抑制化合物,其特征在于高效性、长的半衰期和优先于环加氧酶-1而抑制环加氧酶-2的高度特异性。此类化合物的示例为3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮。一方面,本发明涉及治疗环加氧酶-2介导的疾病的药用组合物,所述组合物适于每天口服给药一次,所述组合物含有5—125mg上述的化合物。本发明也涉及治疗环加氧酶-2介导的疾病的方法,该方法包括每天给予5—125mg的上述化合物一次。本发明还涉及上述化合物在生产用于治疗环加氧酶-2介导的疾病的药物中的用途,所述药物含有5—125mg上述化合物,所述药物每天口服给药一次。
Description
本发明的背景
本发明涉及用于治疗环加氧酶-2介导疾病的药用组合物及化合物在药物生产中的用途。
具体的讲,本发明涉及用于治疗环加氧酶-2介导疾病的药用组合物,所述组合物适于每天给药一次,所述组合物包含环加氧酶-2抑制剂,其特征在于高效抑制环加氧酶-2、长的半衰期和优先于环加氧酶-1而抑制环加氧酶-2的高度特异性。此类化合物的示例为3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮。
非甾体抗炎药通常每天给药2-4次。大多数非甾体抗炎药的相对较短的半衰期意味着每天给药一次是不实际的,甚至每天给药两次也是不寻常的。每天一次的常规的非甾体抗炎药物的治疗需要相当大的剂量也将导致副作用,因此普遍认为每天给药因此是不可能实现的。
令人吃惊地是已经鉴定了可以每天使用一次,并且在此给药方案时不会产生不能接受的副作用,且特别是不会引起不能接受的胃肠副作用的化合物。
US5474995(1995年12月12日授权)、WO95/00501(1995年1月5日公开)和WO95/18799(1995年7月13日公开)公开了3,4-二取代的呋喃酮及其衍生物,为环加氧酶-2的有效的和选择性的抑制剂。我们发现3-苯基4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮具有惊人的特性的组合,使得能将其制成制剂并以令人吃惊的方式使用该组合物。该化合物不仅在每天5-125mg的合适口服剂量时具有高效、安全和有效性,而且此活性药物在人体中的半衰期足够长,使其在每天口服5-125mg的单一剂量时在24小时内可以提供有效安全的抗炎治疗。此类活性药物特别用于治疗慢性适应症,包括关节炎、疼痛、Alzheimer氏病等。
本发明的概述
本发明涉及用于治疗环加氧酶-2介导的疾病的药用组合物,所述组合物适于每天口服给药一次,所述组合物含有环加氧酶抑制化合物,其特征在于对环加氧酶-2抑制的高效性、长的半衰期和优先于环加氧酶-1,而抑制环加氧酶-2的高度特异性。此类化合物的示例为3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮。
一方面,本发明涉及治疗环加氧酶-2介导的疾病的药用组合物,所述组合物适于每天口服给药一次,所述组合物含有5-125mg的上述化合物。
本发明也涉及治疗环加氧酶-2介导的疾病的方法,该方法包括每天口服给予5-125mg的上述化合物一次。
本发明还涉及上述化合物在生产用于治疗环加氧酶-2介导的疾病的药物中的用途,所述药物含有5-125mg上述化合物,每天给药一次。
本发明的详述
在一个实施方案中,本发明涉及用于治疗环加氧酶-2介导的疾病的药用组合物,所述组合物适于每天给药一次,所述组合物含有环加氧酶-2抑制剂,其特征在于对环加氧酶-2抑制的高效性、长的半衰期和优先于环加氧酶-1,而抑制环加氧酶-2的高度特异性。
在该实施方案一种情况下,本发明涉及用于治疗环加氧酶-2介导的疾病的药用组合物,所述组合物适于每天口服给药一次,所述组合物含有环加氧酶-2抑制化合物,其特征在于:
(a)根据所述化合物的单一治疗剂量提供的缓解伴随去除两个或三个磨牙的手术后疼痛的能力,测定对环加氧酶-2的抑制的高效力,所述缓解效果在统计学上等于或大于用单一剂量的400mg布洛芬获得的缓解效果;
(b)半衰期为9或更多个小时,优选15小时或更长时间,更优选18小时或更长时间;和
(c)根据治疗剂量的所述化合物抑制血清血栓烷B2的产生不具有统计学意义,测定优先于环加氧酶-1而抑制环加氧酶-2的高度特异性。
一个此类化合物为3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮
如本领域技术人员可以理解的,本发明仅仅涉及通过抑制环加氧酶-2起作用的化合物。因此,除非所述化合物的作用模式为环加氧酶-2的抑制剂,否则不能说满足上述的特征要求。例如,中枢神经系统药物可以以等于或大于布洛芬的效力缓解疼痛,然而不能满足上述要求,因为它不作用于环加氧酶-2见Inflamm.Res.45:68-74(1996),结合在此作参考,它公开了(LPS)-激发实验用于环加氧酶-2抑制和血液中血栓烷B2的水平的临床鉴定和评价。也可以使用等效实验。本发明的化合物在治疗剂量时无肝毒性。而且,当根据WO95/00501公开的方法测定时,本发明的化合物在大鼠爪水肿测定中的ED30为0.4mg/kg或更小,根据WO95/00501公开的方法测定时,对COX-2抑制的选择性超过对COX-1的抑制50∶1或更大。
在一个实施方案中,本发明涉及用于治疗环加氧酶-2介导的疾病的药用组合物,所述组合物适合每天口服给药一次,所述组合物含有5-125mg的3-苯基-4-(4-甲磺酰基)苯基2-(5H)-呋喃酮和药用载体。
3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮、其实用性以及其制备方法公开于US5474995(1995年12月12日授权)、WO95/00501(1995年1月5日公开)和WO95/18799(1995年7月13日公开),在此引入作参考。
公开于US5474995中的化合物,包括3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮可以用于缓解疼痛、发烧和各种炎症性疾病,包括类风湿性发烧、与流感或其它病毒感染有关的症状、感冒、下背部和颈部疼痛、痛经、头痛、牙痛、扭伤和劳损、肌炎、神经痛、滑膜炎、关节炎包括类风湿性关节炎、变性性关节疾病(骨关节炎)、痛风和关节强硬性脊椎炎、滑囊炎、烧伤、外科和牙科手术后损伤。此外,此类化合物可以抑制细胞瘤转移和转移性瘤生长,因此可以用于治疗癌症。它也可以用于治疗痴呆,包括早老性痴呆和老年性痴呆,特别是用于与Alzheimer病有关的痴呆(即Alzheimer氏痴呆)。
该化合物也可以通过阻止收缩性的前列腺素类的合成而抑制前列腺素类诱导的平滑肌的收缩,因此可以用于治疗痛经、早产和哮喘。
由于其对环加氧酶-2(COX-2)的高抑制活性和/或对COX-2的抑制超过对环加氧酶-1(COX-1)抑制的选择性,该特定的化合物也可以用作传统的非甾体抗炎药物(NSAID’S)的替代药物,特别是对该NSAIDS为禁忌的病人,例如具有消化道溃疡、胃炎、局限性肠炎、溃疡性结肠炎、憩室炎或有胃肠损害复发史;GI出血、凝血疾病包括贫血,例如血凝血酶原过少、血友病或其它出血问题(包括那些与血小板功能降低或损伤有关的问题);肾脏疾病(例如肾功能受损);那些手术前或服用抗凝药物以及那些对NSAID诱导哮喘敏感的病人。
对治疗这些环加氧酶介导的任何疾病而言,该化合物可以口服给药或静脉输注给药。
如上所述,用于治疗上述定义的COX-2介导的疾病的药用组合物可任选包含上述成分中的一种或多种。
含有上述活性成分的药用组合物可以为适于口服的形式,例如为片剂、锭剂、糖锭、水溶液或油悬浮液、可分散的粉剂或颗粒剂、乳剂、硬或软胶囊剂或糖浆剂或酏剂。该组合物可以用于口服,可以根据本领域已知的任何生产药用组合物的方法制备,此类组合物可以含有一种或多种选自下列的成分:甜味剂、矫味剂、着色剂和防腐剂以提供药用的精致和可口的的制剂。片剂含有与非毒性的适合片剂生产的药学上可接受的赋形剂混合的活性成分。这些赋形剂可以为例如惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;粒化剂和崩解剂,例如玉米淀粉或藻酸;粘合剂例如淀粉、明胶或阿拉伯胶或润滑剂例如硬脂酸镁、硬脂酸或滑石粉。
其它的适合的制剂在美国专利5474995号中提出。然而,从3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮所具有的独特的一系列性质,包括半衰期、低溶解性、高效性、低的胃肠道(GI)副作用来看,我们发现下列口服制剂特别有用:
Rapidisc-从上述特性来看,3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮特别适合快速溶解的舌下制剂。例如,由于无GI副作用,该药物不需要同时饮用大量的水。适当的Rapidisc制剂和其制备方法公开于US4305502、US4371516、US4470202、US4758598、US4754597、US5046618和US5188882,所有这些在此引入作参考。
如在背景部分所介绍的,我们发现3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮具有这些惊人的特性的组合。这些活性药物不仅以每天5-125mg的合适口服剂量下安全有效,而且这些活性药物在人体中具有足够长的半衰期,使其每天口服5-125mg单一剂量的活性药物可以在24小时内提供有效安全的抗炎治疗。此类药物特别用于治疗慢性适应症,例如风湿性关节炎和骨关节炎以及Alzheimer氏病。
需要口服和静脉给予3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮的水平为每天每个病人约5-125量。
可以与载体物质混合以产生单一剂型的活性成分的量随所治疗的宿主和特定的给药方式而变化。例如,用于人口服给药的制剂可以含有5-125mg与适当和方便量的载体物质混合的药物,所述载体物质可以以总组合物的约5-约95%之间变化。单位剂型一般含有5、10、12.5、20、25、50、75、100或125mg活性成分。
然而,可以理解对于任何特定病人的特定的剂量水平随各种因素变化,包括年龄、体重、一般身体状况、性别、饮食、给药时间、排泄率、联合用药、所治疗的特定疾病的类型和严重程度。对多数病人而言,优选每天剂量范围为5-50或12.5-25或25-75mg。
对于长期治疗,如在治疗慢性疾病包括类风湿性关节炎、骨关节炎或Alzheimer病而言,优选每天剂量为5-50或12.5-25mg。更具体地说,对于治疗骨关节炎而言,优选每天剂量为5、10、12.5、25或50mg,而对于治疗类风湿性关节炎而言,优选每天剂量为10、12.5、25或50mg。对于治疗非慢性(non-chronic)适应症例如头痛或手术后肿胀和疼痛时,优选每天10、12.5、25或50mg。
因此,本发明的一个方面涉及单位口服剂型,它包含5-50或5-22.5mg环加氧酶抑制剂,例如12.5或20mg或12.5-25。
本发明的另一方面涉及治疗环加氧酶-2介导的疾病的药用组合物,所述组合物适于每天口服给药一次,所述组合物含有5-50或25-75mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮以及药用载体。
在该方面,第一类包括含有5-50mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮的组合物。
在该方面,第二类包括含有10-50mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮的组合物。
在该类中,还包括含有5-22.5mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮的组合物。
在该类中,也包括含有12.5-25mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮的组合物。
在该类中,也还包括含有5、10、12.5、25或50mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮的组合物。
实施例1
湿法制粒的片剂组合物每片的含量 组分25mg COX-2抑制剂79.7mg 微晶纤维素79.7mg 乳糖一水合物6mg 羟丙基纤维素8mg 交联羧甲基纤维素钠0.6mg 氧化铁1mg 硬脂酸镁
根据总片重和前三个组分的比例可以调节片剂的剂量强度在5-125mg之间。一般而言,优选维持微晶纤维素:乳糖一水合物的比例为1∶1。
实施例1a
湿法制粒的片剂组合物每片的含量 组分12.5mg COX-2抑制剂86mg 微晶纤维素86mg 乳糖一水合物6mg 羟丙基纤维素8mg 交联羧甲基纤维素钠0.6mg 氧化铁1mg 硬脂酸镁
实施例1b
湿法制粒的片剂组合物每片的含量 组分10mg COX-2抑制剂87.2mg 微晶纤维素87.2mg 乳糖一水合物6mg 羟丙基纤维素8mg 交联羧甲基纤维素钠0.6mg 氧化铁1mg 硬脂酸镁
实施例1c
湿法制粒的片剂组合物每片的含量 组分5mg COX-2抑制剂89.7mg 微晶纤维素89.7mg 乳糖一水合物6mg 羟丙基纤维素8mg 交联羧甲基纤维素钠0.6mg 氧化铁1mg 硬脂酸镁
实施例2
直接压制的片剂组合物每片的含量 组分25mg COX-2抑制剂106.9mg 微晶纤维素106.9mg 无水乳糖7.5mg 交联羧甲基纤维素钠3.7mg 硬脂酸镁
根据总片重和前三个组分的比例可以调节片剂的剂量强度在5-125mg之间。一般而言,优选维持微晶纤维素:乳糖一水合物的比例为1∶1。
实施例2a
直接压制的片剂组合物每片的含量 组分12.5mg COX-2抑制剂113.2mg 微晶纤维素113.2mg 无水乳糖7.5mg 交联羧甲基纤维素钠3.7mg 硬脂酸镁
实施例2b
直接压制的片剂组合物每片的含量 组分10mg COX-2抑制剂42.5mg 微晶纤维素42.5mg 无水乳糖4mg 交联羧甲基纤维素钠1mg 硬脂酸镁
实施例2c
直接压制的片剂组合物每片的含量 组分5mg COX-2抑制剂45mg 微晶纤维素45mg 无水乳糖4mg 交联羧甲基纤维素钠1mg 硬脂酸镁
实施例3
硬明胶胶囊组合物每片的含量 组分25mg COX-2抑制剂37mg 微晶纤维素37mg 无水乳糖1mg 硬脂酸镁1个胶囊 硬明胶胶囊
根据总填充物重和前三个组分的比例可以调节胶囊的剂量强度在1-50mg之间。一般而言,优选维持微晶纤维素:乳糖一水合物的比例为1∶1。
实施例4
口服溶液每5m1剂量的用量 组分50mg COX-2抑制剂加至5ml 用聚环氧乙烷400
通过改变两个组分的比例可以调节溶液的剂量强度在1-50mg/5ml之间。
实施例5
口服悬浮液每5ml剂量的用量 组分101mg COX-2抑制剂150mg 聚乙烯吡咯烷酮2.5mg 聚氧乙烯山梨糖醇酐一月桂酸酯10mg 苯甲酸用山梨醇溶液(70%)加至5ml
通过改变前两个组分的比例可以调节悬浮液的剂量强度在1-50mg/5ml之间。
实施例6
静脉输注液每200ml剂量的用量 组分1mg COX-2抑制剂0.2mg 聚环氧乙烷4001.8mg 氯化钠至200ml 纯净水
原料
制备1
3-(苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮
步骤1:2-溴代-1-(4-(甲磺酰基)苯基)乙酮
用30分钟,在197g的4-(甲硫基)苯乙酮(参考:J.Am.Chem.Soc.,1952,74,p.5475)的700ml甲醇和3500ml二氯甲烷的溶液中加入881g的MMPP。于室温下3小时后,过滤该反应混合物,用2L饱和的碳酸氢钠水溶液和1L盐水洗涤滤液。用2L二氯甲烷进一步萃取水相。经硫酸钠干燥合并的萃取物,浓缩得到240g为白色固体的4-(甲磺酰基)苯乙酮。
向174g的4-(甲磺酰基)苯乙酮的2.5L氯仿的冷却(-5℃)溶液中加入20mg三氯化铝,接着加入40ml溴的300ml氯仿溶液。然后用1.5L水处理该反应混合物,分离氯仿层。用1L乙酸乙酯萃取水层。用硫酸钠干燥合并的有机萃取物并浓缩。使粗品产物从50/50乙酸乙酯/己烷中重结晶,得到为白色固体的目标化合物210g。
步骤2:3-(苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮
于25℃,缓慢向苯乙酸(27.4g,201mmol)和2-溴代-1-(4-(甲磺酰基)苯基)乙酮(步骤1)(60g,216mmol,1.075eq)的乙腈(630ml)溶液中加入Et3N(30.8ml,1.1eq)。于室温下将该混合物搅拌20分钟,然后于冰浴上冷却。缓慢加入DBU(60.1ml,3eq)。于冰浴中搅拌20分钟后,该反应完成,用1NHCl酸化该混合物(颜色由深棕变为黄色)。然后加入2.4L冰和水,将该混合物搅拌数分钟,过滤沉淀,用水洗涤,得到64g粗品湿产物。将该固体溶于750ml二氯甲烷中,经硫酸镁干燥,过滤,向滤液中加入300g硅胶。蒸发溶剂至近干(硅胶有点粘),将残留物上于烧结玻璃漏斗中的硅胶上,用10%乙酸乙酯/二氯甲烷洗脱,蒸发溶剂并用乙酸乙酯漂洗后得到36.6g(58%)目标化合物。
分析:C17H14O4S计算值:C,64.95;H,4.49;S,10.20
实测值:C,64.63;H,4.65;S,10.44
制备2
3-(苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮
于氮气环境下,向20ml的玻璃安瓿中加入1g的2-(4-(甲磺酰基)苯基)-苯乙炔(J.Am.Chem.Soc.,1971,93,p.2979)、20mg的Rh4(CO)12、1.5gEt3N、10mlTHF和1mlH2O,将安瓿置于100ml不锈钢高压釜中。用CO吹洗该反应体系三次,然后于室温充满至初始CO压力为100atm。反应于100℃进行5小时。然后用50ml的苯稀释该溶液,并用盐水和1N HCl洗涤。将该苯溶液用硫酸钠干燥并浓缩。用硅胶柱层析分离该粗品产物,用2∶1乙酸乙酯/己烷洗脱得到目标化合物及其区域异构体(rigioisomer)。
制备3
3-(苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮
步骤1:2-三甲基硅烷基氧基-4-(4-(甲硫基)苯基)-3,4-二氢呋喃
向3.86g(19mmol)的4-溴代苯硫基甲烷的90ml乙醚的于-78℃冷却的溶液中滴加22ml的1.7M叔丁基锂的戊烷(38mmol)溶液。于-78℃将该反应混合物搅拌15分钟,加入3.8g的CuI,然后用30分钟将该反应混合物加热至-40℃。力入1.7g2(5H)-呋喃酮的10mlTHF溶液。搅拌1小时后,滴加2ml新蒸馏的TMSCl。然后用2mlEt3N和50ml饱和的碳酸氢钠处理该反应混合物,用100ml乙醚萃取。用硫酸钠干燥乙醚层,浓缩得到粗品目标化合物,将其不经进一步纯化而用于下一步。
步骤2:4-(4-(甲硫基)苯基)-2-(5H)-呋喃酮
于室温、氮气环境下,向4gPd(OAc)2的100ml乙腈溶液中滴加来自步骤1的粗品产物(5g)。于室温下10小时后,减压浓缩该混合物,残留物经硅胶快速层析纯化,用2∶1己烷/乙酸乙酯洗脱得到目标化合物。
步骤3:3-碘代-4-(4-(甲硫基)苯基)-2-(5H)-呋喃酮
向3g步骤2的产物的30ml吡啶溶液中加入8.7g的I2。将该混合物搅拌24小时,然后用200ml乙醚稀释,用100ml 5N HCl和50ml 5N硫代硫酸钠洗涤。用硫酸钠干燥乙醚层,浓缩得到目标化合物。
步骤4:3-(苯基)-4-(4-(甲硫基)苯基)-2-(5H)-呋喃酮
将4g步骤3的产物、3.7g的PhB(OH)2、0.4g的Ph3As、0.4g的PdCl2(PhCN)2的100ml苯和15ml的2N NaOH的混合液回流6小时。冷却至室温后,向该反应混合物中加入乙醚(200ml),用100ml饱和的碳酸氢钠洗涤该混合物。经硫酸镁干燥有机层,浓缩。残留物经硅胶快速层析纯化,用4∶1己烷/乙酸乙酯洗脱得到目标化合物。
步骤5:3-(苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮
向3g步骤4产物的80ml 10∶1二氯甲烷/甲醇溶液中加入5.5gMMPP。于室温下,将该反应混合物搅拌2小时,然后用100ml 1∶1己烷/乙酸乙酯洗释。过滤并浓缩后,残留物经快速层析纯化,用2∶1乙酸乙酯/己烷洗脱得到目标产物。
缩写
DBU=1,8-二氮杂双环[5.4.0]十一碳-7-烯
Et3N=三乙胺
MMPP=一过邻苯二甲酸镁(magnesium monoperoxyphthalate)
THF=四氢呋喃
TMSCl=三甲基硅烷基氯
Claims (36)
1.用于治疗环加氧酶-2介导的疾病的药用组合物,所述组合物适合每天口服给药一次,所述组合物含有5-125mg的化合物3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮。
2.权利要求1的组合物含有5、10、12.5或25mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮。
3.权利要求1的组合物含有10-125mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮。
4.权利要求1的组合物含有10-75mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮。
5.权利要求1的组合物含有10、25或50mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮。
6.权利要求1的组合物含有25、50或75mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮。
7.权利要求1、2、3、4、5或6的药用组合物还包含:
(a)微晶纤维素,
(b)乳糖一水合物,
(c)羟丙基纤维素,
(d)交联羧甲基纤维素钠,
(e)氧化铁,和
(f)硬脂酸镁;或另外包含:
(a)微晶纤维素,
(b)无水乳糖,
(c)交联纤维素钠,和
(d)硬脂酸镁;或另外包含:
聚环氧乙烷400;或另外包含:
(a)山梨醇溶液,
(b)聚乙烯吡咯烷酮,
(c)聚氧乙烯山梨糖醇酐一月桂酸酯,和
(d)苯甲酸。
8.治疗对用非甾体抗炎药物治疗敏感的炎症性疾病的方法,该方法包括每天经口给予需要此治疗的病人5-125mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮一次。
9.权利要求8的方法包括每天经口给予需要此治疗的病人5、10、12.5或25mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮一次。
10.权利要求8的方法包括每天经口给予需要此治疗的病人10-125mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮一次。
11.权利要求8的方法包括每天经口给予需要此治疗的病人10-75mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮一次。
12.权利要求8的方法包括每天经口给予需要此治疗的病人10、25或50mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮一次。
13.权利要求8的方法包括每天经口给予需要此治疗的病人25、50或75mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮一次。
14.治疗对用非甾体抗炎药物治疗敏感的炎症性疾病的方法,该方法包括每天经口给予需要此治疗的病人权利要求7的组合物一次。
15.权利要求9的方法用于治疗非慢性头痛、疼痛或肿胀。
16.权利要求12的方法用于治疗骨关节炎。
17.权利要求13的方法用于治疗类风湿性关节炎。
18.使用5-125mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮生产用于治疗对用非甾体抗炎药物治疗敏感的炎症性疾病的每天给药一次的口服剂型药物。
19.权利要求18的5、10、12.5或25mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮生产用于治疗对用非甾体抗炎药物治疗敏感的炎症性疾病的每天给药一次的口服剂型药物。
20.使用权利要求18的10-125mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮生产用于治疗对用非甾体抗炎药物治疗敏感的炎症性疾病的每天给药一次的口服剂型药物。
21.使用权利要求18的10-75mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮生产用于治疗对用非甾体抗炎药物治疗敏感的炎症性疾病的每天给药一次的口服剂型药物。
22.使用权利要求18的10、12.5、25或50mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮生产用于治疗对用非甾体抗炎药物治疗敏感的炎症性疾病的每天给药一次的口服剂型药物。
23.使用权利要求18的10、12.5、25或50mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮生产用于治疗骨关节炎的每天给药一次的口服剂型药物。
24.使用权利要求18的25、50或75mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮生产用于治疗对用非甾体抗炎药物治疗敏感的炎症性疾病的每天给药一次的口服剂型药物。
25.使用权利要求18的25、50或75mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮生产用于治疗类风湿性关节炎的每天给药一次的口服剂型药物。
26.使用权利要求18的5、10、12.5或25mg的3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮生产用于治疗非慢性头痛、疼痛或肿胀的每天给药一次的口服剂型药物。
27.用于治疗环加氧酶-2介导的疾病的药用组合物,所述组合物适于每天给药一次,所述组合物包含环加氧酶-2抑制化合物,其特征在于:
(a)根据所述化合物的单一治疗剂量提供的缓解伴随去除两个或三个磨牙的手术后疼痛的能力测定对环加氧酶-2的抑制的高效力,所述缓解效果在统计学上等于或大于用单一剂量的400mg布洛芬获得的缓解效果;
(b)半衰期为15小时或更长时间;和
(c)根据治疗剂量的所述化合物抑制血清血栓烷B2的产生不具有统计学意义,测定优先于环加氧酶-1而抑制环加氧酶-2的高度特异性。
28.权利要求27的组合物包含5、10、12.5或25mg的所述环加氧酶-2抑制剂。
29.权利要求27的组合物包含10-125mg的所述环加氧酶-2抑制剂。
30.权利要求27的组合物包含10-75mg的所述环加氧酶-2抑制剂。
31.权利要求27的组合物包含10、25或50mg的所述环加氧酶-2抑制剂。
32.权利要求27的组合物包含25、50或75mg的所述环加氧酶-2抑制剂。
33.权利要求27、28、29、30、31或32的药用组合物还包含:
(a)微晶纤维素,
(b)乳糖一水合物,
(c)羟丙基纤维素,
(d)交联纤维素钠,
(e)氧化铁,和
(f)硬脂酸镁;或另外包含:
(a)微晶纤维素,
(b)无水乳糖,
(c)交联纤维素钠,和
(d)硬脂酸镁;或另外包含:
聚环氧乙烷400;或另外包含:
(a)山梨醇溶液,
(b)聚乙烯吡咯烷酮,
(c)聚氧乙烯山梨糖醇酐一月桂酸酯,和
(d)苯甲酸。
34.单位剂量口服形式包含5-22.5mg所述环加氧酶抑制剂,其特征在于:
(a)根据所述化合物的单一治疗剂量提供的缓解伴随去除两个或三个磨牙的手术后疼痛的能力测定对环加氧酶-2的高效力,所述缓解效果在统计学上等于或大于用单一剂量的400mg布洛芬获得的缓解效果;
(b)半衰期为15小时或更长时间;和
(c)根据治疗剂量的所述化合物抑制血清血栓烷B2的产生不具有统计学意义,测定优先于环加氧酶-1而抑制环加氧酶-2抑制的高度特异性。
35.权利要求34的单位剂型包含12.5或20mg的环加氧酶-2抑制剂。
36.权利要求35的单位剂型包含3-苯基-4-(4-甲磺酰基)苯基-2-(5H)-呋喃酮。
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US1787896P | 1996-05-17 | 1996-05-17 | |
US60/017,878 | 1996-05-17 | ||
GB9612063.9 | 1996-06-10 | ||
GBGB9612063.9A GB9612063D0 (en) | 1996-06-10 | 1996-06-10 | Compositions for a once a day treatment of cyclooxygenase-2 mediated diseases |
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US (1) | US6063811A (zh) |
EP (1) | EP0910368A1 (zh) |
JP (1) | JPH11512754A (zh) |
KR (1) | KR100373622B1 (zh) |
CN (1) | CN1140267C (zh) |
AR (1) | AR012014A1 (zh) |
AU (1) | AU3004997A (zh) |
BG (1) | BG103000A (zh) |
BR (1) | BR9709097A (zh) |
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CO (1) | CO5050370A1 (zh) |
CZ (1) | CZ291463B6 (zh) |
DZ (1) | DZ2200A1 (zh) |
EA (1) | EA001596B1 (zh) |
EE (1) | EE03746B1 (zh) |
HK (1) | HK1021623A1 (zh) |
HR (1) | HRP970262A2 (zh) |
HU (1) | HUP9902889A3 (zh) |
ID (1) | ID16921A (zh) |
IL (1) | IL126899A (zh) |
IS (1) | IS4891A (zh) |
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NZ (1) | NZ332670A (zh) |
PE (1) | PE66998A1 (zh) |
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CN100335136C (zh) * | 2001-01-18 | 2007-09-05 | 法马西亚公司 | 具有降低的药物结晶趋势的药物组合物 |
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EP1061908A4 (en) * | 1998-03-13 | 2007-01-24 | Merck & Co Inc | COMBINATION THERAPY AND COMPOSITION FOR ACUTE CORONARY MIXING SYNDROME AND ASSOCIATED CONDITIONS |
SA99191255B1 (ar) * | 1998-11-30 | 2006-11-25 | جي دي سيرل اند كو | مركبات سيليكوكسيب celecoxib |
CO5190664A1 (es) | 1999-06-30 | 2002-08-29 | Pfizer Prod Inc | Terapia de combinacion para el tratamiento de migrana administracion de un receptor 5ht, cafeina y un inhibidor de ciclooxigenasa-2 |
GB9920558D0 (en) * | 1999-08-31 | 1999-11-03 | Bradford Particle Design Ltd | Methods for particle formation and their products |
MXPA02006150A (es) * | 1999-12-22 | 2004-09-06 | Pharmacia Corp | Formulaciones de liberacion sostenida de un inhibidor de ciclooxigenasa-2. |
US6924303B2 (en) | 2000-06-13 | 2005-08-02 | Wyeth | Analgesic and anti-inflammatory compositions containing COX-2 inhibitors |
CN1638739A (zh) * | 2000-08-18 | 2005-07-13 | 法玛西雅厄普约翰美国公司 | 治疗成瘾性障碍的化合物 |
DK1309315T3 (da) * | 2000-08-18 | 2006-10-09 | Pharmacia Corp | Hurtigt disintegrerende oral valdecoxib-formulering |
US8680081B2 (en) * | 2000-08-29 | 2014-03-25 | Peter Van Patten | Prophylactic treatment of migraine |
AR030630A1 (es) * | 2000-09-11 | 2003-08-27 | Novartis Ag | Composiciones farmaceuticas |
US20040132780A1 (en) * | 2001-05-04 | 2004-07-08 | Allen Christopher P. | Method and compositions for treating migraines |
AR036312A1 (es) * | 2001-08-31 | 2004-08-25 | Novartis Ag | Composicion farmaceutica |
KR20040044990A (ko) * | 2001-09-26 | 2004-05-31 | 파마시아 코포레이션 | 구강내 붕해성 발데콕시브 조성물 |
CN1602187A (zh) * | 2001-10-10 | 2005-03-30 | 法马西亚公司 | 通过喷雾干燥法制备的口内崩解的伐地考昔组合物 |
EP1492520A1 (en) * | 2002-03-07 | 2005-01-05 | Novartis AG | Pharmaceutical compositions |
ES2213485B1 (es) | 2003-02-13 | 2005-12-16 | Almirall Prodesfarma, S.A. | Derivados de la 2-fenilpiran-4-ona. |
ES2214129B1 (es) * | 2003-02-13 | 2005-12-01 | Almirall Prodesfarma, S.A. | 3-fenilfuran-2-onas. |
PL1534305T3 (pl) | 2003-05-07 | 2007-03-30 | Osteologix As | Leczenie zaburzeń chrząstek i kości solami strontu rozpuszczalnymi w wodzie |
TR200301552A1 (tr) * | 2003-09-18 | 2005-10-21 | Nobel İlaç Sanayi̇ Ve Ti̇caret A. Ş. | Rofekoksib' in yeni oral farmakolojik formülasyonları. |
CA2676413A1 (en) * | 2007-01-19 | 2008-07-31 | Mallinckrodt Inc. | Diagnostic and therapeutic cyclooxygenase-2 binding ligands |
WO2020106522A1 (en) | 2018-11-21 | 2020-05-28 | Tremeau Pharmaceuticals, Inc. | Purified forms of rofecoxib, methods of manufacture and use |
WO2020210373A1 (en) * | 2019-04-09 | 2020-10-15 | Tremeau Pharmaceuticals, Inc. | Treatment of viral hemorrhagic fevers with etoricoxib |
US10945992B1 (en) | 2019-11-13 | 2021-03-16 | Tremeau Pharmaceuticals, Inc. | Dosage forms of rofecoxib and related methods |
US11161833B1 (en) | 2021-04-09 | 2021-11-02 | Tremeau Pharmaceuticals, Inc. | Deuterated etoricoxib, methods of manufacture, and use thereof |
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US5474995A (en) * | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
WO1995018799A1 (en) * | 1994-01-10 | 1995-07-13 | Merck Frosst Canada Inc. | Phenyl heterocycles as cox-2 inhibitors |
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CN100335136C (zh) * | 2001-01-18 | 2007-09-05 | 法马西亚公司 | 具有降低的药物结晶趋势的药物组合物 |
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