CN1546030A - 噁唑烷酮衍生物在治疗关节炎和减少癌症化学疗法毒性中的应用 - Google Patents
噁唑烷酮衍生物在治疗关节炎和减少癌症化学疗法毒性中的应用 Download PDFInfo
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- CN1546030A CN1546030A CNA2004100027903A CN200410002790A CN1546030A CN 1546030 A CN1546030 A CN 1546030A CN A2004100027903 A CNA2004100027903 A CN A2004100027903A CN 200410002790 A CN200410002790 A CN 200410002790A CN 1546030 A CN1546030 A CN 1546030A
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- Prior art keywords
- oxazolidone
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- acetamide
- oxo
- fluoro
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Abstract
本发明涉及噁唑烷酮,特别是(S)-N-[[3-[3-氟-4-(4-吗啉基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺在制备治疗关节炎或减少癌症化学疗法毒性的药物中的用途。
Description
本申请是申请日为1998年11月10日、申请号为98810013.4、发明创造名称为“噁唑烷酮衍生物在治疗牛皮癣、关节炎和减少癌症化学疗法毒性中的应用”的申请的分案申请。
技术领域
本发明是已知的噁唑烷酮的用途,用于治疗牛皮癣、关节炎和减少癌症化学疗法的毒性。
背景技术
美国专利5,164,510、5,231,188、5,565,571、5,652,238和5,688,792都公开了本领域技术人员所熟知的各种噁唑烷酮抗生素。
牛皮癣是一种熟知的疾病,它是一种病因未知的皮肤增生性疾病。人们不知道或不认为它是由微生物引起的。
患有牛皮癣的患者所体验到的问题是强烈的瘙痒和不适、不雅观的皮肤斑点和习惯性的搔抓,导致皮肤感染。
目前,对于患者所表现出来的临床症状,只有治疗方法,还没有治愈。这些治疗方法包括避免皮肤干燥和皮肤刺激、局部施用甾族化合物乳剂和软膏的使用、局部施用粗煤焦油(占软膏基质的1-5%)的使用、紫外线疗法、局部施用维生素D(卡泊三醇)、严重时口服甲氨蝶呤(这种疗法的一个缺点是如果不小心的话,甲氨蝶呤会导致严重的肝损伤)、严重时使用阿维A酯(一种合成的树脂样物)(不过,这种疗法的一个缺点是如果女性患者怀孕了的话,它与严重的胎儿畸形有关)。
虽然没有治愈牛皮癣,但是治疗可以缓解一些时间。由于牛皮癣的病理学是未知的,因此各种疗法没有取得完全成功的原因也是未知的,但是目前的疗法可能不是针对牛皮癣的根本病因来治疗的。
尽管可以得到大量用于治疗牛皮癣的药剂,然而没有一个能治疗该疾病并且使牛皮癣患者或医师愿意使用的。
关节炎是关节组织的炎症,其病因有多种,包括细菌感染(脓毒性关节炎)、关节表面变性(骨关节炎)、对抗关节组织的免疫反应(类风湿性关节炎)、结晶诱发的关节炎(痛风性关节炎、假痛风)和其他各种病因(莱特尔氏综合征等)。所有这些的一个共性是关节内部和周围的炎症。现今对关节炎的治疗不是治愈性的,除非关节炎是感染性的,而且用一种抗生素杀死该病原体。对其他类型的关节炎来说,药物疗法能够减轻疼痛或炎症,但是不能治愈该疾病。噁唑烷酮能够用于治疗由关节炎引起的炎症和疼痛,包括那些不是由感染引起的关节炎类型。这一点很重要,因为目前可得到的用于治疗关节炎的所有药物疗法都具有严重的副作用。甾族药物(糖皮质激素,如泼尼松和皮质醇)引起胃溃疡、白内障、抗感染能力降低、体重增加和皮肤变薄。非甾族抗炎药物(NSAIDS,其中例如消炎痛或布洛芬)可导致胃溃疡、肾功能降低和对骨髓的影响。化疗剂(如甲氨蝶呤)可对骨髓和肝功能产生严重的不利影响。噁唑烷酮提供了缓解对其他类型的关节炎药物疗法不耐受的患者炎症症状的机会。
患有癌症和需要接受抗癌化学疗法的患者所面临的问题是,治疗中的剂量限制因素是对骨髓的抑制作用。本发明预防和减少了对骨髓的抑制作用和对肠腺细胞(产生新的肠细胞的细胞)的损伤。通过预防对一般造血细胞的损害,特别是骨髓细胞,医师能够预防或减少化疗剂的毒性,因此在治疗癌症患者时,能够更长时间和/或用更大剂量和减少并发症危险性。所有这些意味着对患者而言更为成功的结果。
目前,市场上没有产品能够预防抗癌化疗剂对造血细胞和/或肠细胞所造成的损害。已有这样的产品,在抗癌化学疗法后给药,以尝试和帮助患者恢复,不过这与本发明的预防性方法是不一样的。这些药剂包括骨髓集落刺激因子,例如GM-CSF。已知有保护性药剂,但是不用于临床,用于对放射疗法进行处理,例如谷胱甘肽衍生物,但是它们不能预防有关抗癌化学疗法的问题。
发明内容
本发明公开了治疗牛皮癣患者的方法,该方法包括将抗牛皮癣有效量的噁唑烷酮对该患者给药,该噁唑烷酮选自下组:
(S)-N-[[3-[3-氟-4-[4-(羟乙酰基)-1-哌嗪基]-苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,
(S)-N-[[3-[3-氟-4-(4-吗啉基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,
[4(S)-顺式]-(-)-N-[[3-[3-氟-4-(四氢-1-氧桥-2H-噻喃-4-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,
N-((5S)-3-(3-氟-4-(4-(2-氟乙基)-3-氧哌嗪-1-基)苯基)-2-氧噁唑烷-5-基甲基)乙酰胺,
(S)-N-[[3-[5-(3-吡啶基)噻吩-2-基]-2-氧代-5-噁唑烷基]甲基]乙酰胺和
(S)-N-[[3-[5-(4-吡啶基)吡啶-2-基]-2-氧代-5-噁唑烷基]甲基]乙酰胺及其药学上可接受的盐。
本发明也公开了治疗关节炎患者的方法,该方法包括将抗关节炎有效量的噁唑烷酮对该患者给药,该噁唑烷酮选自由上述六种噁唑烷酮组成的组。
本发明进一步公开了减少对接受一种或多种抗癌化疗剂治疗的患者造血细胞和肠细胞的损害的方法,该方法包括将抗细胞毒有效量的噁唑烷酮对该患者给药,该噁唑烷酮选自由上述六种噁唑烷酮组成的组。
本发明的噁唑烷酮是已知的,见实施例1至6(噁唑烷酮)及其药学上可接受的盐。
适当的药学上可接受的盐包括来自无机酸和有机酸的酸加成盐,酸包括盐酸、氢溴酸、硫酸、磷酸、磺酸、甲磺酸、葡糖酸、半乳糖醛酸、柠檬酸、草酸和乙酸。
优选地,用噁唑烷酮治疗的牛皮癣或关节炎或接受抗癌化疗剂治疗的患者在接受治疗时没有革兰氏阳性菌感染。
在治疗牛皮癣时,噁唑烷酮既可以单独使用,也可以彼此或与非噁唑烷酮类结合使用。
在治疗牛皮癣时,噁唑烷酮的给药方式是口服、胃肠外(IV)、局部施用或直肠方式。
当口服给药时,噁唑烷酮可以以片剂、胶囊或液体(混悬液、糖浆或溶液)剂型给药。不管剂型如何,噁唑烷酮的抗牛皮癣有效量为约50mg至约1,200mg/天。优选地,噁唑烷酮分两个或更多个均分剂量给药,更优选地分两个均分剂量给药。
当胃肠外给药时,噁唑烷酮应当是IV给药的。应当将IV输注调节至使流速所释放的抗牛皮癣有效量为约50mg至约1200mg/天。事实上,(S)-N-[[3-[3-氟-4-(4-吗啉基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺的生物利用度为100%。因此,无论口服还是胃肠外给药,都能实现患者的血液水平与剂量大致相等。
当局部施用时,噁唑烷酮可以以多种不同的药物剂型使用,这些剂型都是本领域技术人员所熟知的。包括溶液、霜剂、软膏、凝胶、洗液、混悬液或乳液等。不管所选择的局部施用药物剂型如何,噁唑烷酮的浓度应当为约0.01%至约10%(wt/wt)。不管药物剂型如何,局部施用制剂应当每天施用一至四次。
当直肠给药时,噁唑烷酮应当以栓剂方式给药,所释放的抗牛皮癣有效量为约50mg至约1,200mg/天。
当全身给药时,无论口服、胃肠外还是直肠方式,噁唑烷酮都应当连续给药或者以每1至12个月7-28天的周期给药。当局部施用时,噁唑烷酮应当每天施用或每1-12个月施用7至28天。
在治疗关节炎时,噁唑烷酮既可以单独使用,也可以彼此或与非噁唑烷酮类结合使用。
在治疗关节炎时,噁唑烷酮的给药方式是口服、胃肠外(IV)、局部施用或直肠方式。
当口服给药时,噁唑烷酮可以以片剂、胶囊或液体(混悬液、糖浆或溶液)剂型给药。不管剂型如何,噁唑烷酮的抗关节炎有效量为约50mg至约1,200mg/天。优选地,噁唑烷酮分两个或更多个均分剂量给药,更优选地分两个均分剂量给药。
当胃肠外给药时,噁唑烷酮应当是IV给药的。应当将IV输注调节至使流速所释放的抗关节炎有效量为约50mg至约1,200mg/天。做到这一点的方法可以是连续输注,或者按均分剂量给药,每次短期输注30-90分钟,优选为一天两次。
当局部施用时,噁唑烷酮可以以多种不同的药物剂型使用,这些剂型都是本领域技术人员所熟知的。包括溶液、霜剂、软膏、凝胶、洗液、混悬液或乳液。不管所选择的药物剂型如何,噁唑烷酮的浓度应当为约0.01%至约10%(wt/wt)。不管药物剂型如何,局部施用制剂应当每天施用一至四次。
当直肠给药时,噁唑烷酮应当以栓剂方式给药,所释放的抗关节炎有效量为约50mg至约1,200mg/天。
当全身给药时,无论口服、胃肠外还是直肠方式,噁唑烷酮都应当连续给药或者以每1至12个月7-28天的周期给药。当局部施用时,噁唑烷酮应当每天施用或每1-12个月施用7至28天。
确切的给药剂量和频率取决于所用的具体噁唑烷酮、所治疗疾病的严重性、具体患者的年龄、体重、一般身体状况、个体可能采用的其他药物疗法,这对本领域的技术人员来说是熟知的,而且通过测量患者血液中噁唑烷酮的血液水平或浓度和/或患者对所治疗具体疾病的反应,可以更加准确地确定给药剂量和频率。
患有癌症并接受抗癌化疗剂治疗的个体经历了对他们的造血细胞和肠细胞的损害。造血细胞有三种类型。它们是骨髓细胞、脾细胞和肝细胞。优选地,造血细胞是骨髓细胞。本方法也预防/减少了对肠腺细胞的损害。它们是位于肠部的细胞,能够产生新的肠细胞。
通过预防对一般造血细胞的损害,特别是骨髓细胞,医师能够预防或减少化疗剂的毒性,因此在治疗癌症患者时,能够更长时间和/或用更大剂量和减少并发症的危险性。所有这些意味着给患者带来更为成功的疗效。
在预防/减少抗癌化疗剂对造血细胞和肠细胞的损害时,噁唑烷酮既可以单独使用,也可以彼此或与非噁唑烷酮类结合使用。
在某些情况下,本方法将预防损害的发生;在其他情况下,本方法将减少如果患者没有用噁唑烷酮治疗过就可能已经发生的损害。这里所用的“减少”是“预防”的一种方式;预防是最终的减少。
本方法优选是在用抗癌化疗剂治疗患者之前预先治疗患者约2至约20天。更优选的是在用抗癌化疗剂治疗患者之前预先治疗约5至约7天。另一种选择是,噁唑烷酮可以与抗癌化疗剂同时给药。
包括在按照本发明的减少损害的方法中的抗癌化疗剂选自四种不同类型的化疗剂。它们是:
(1)DNA-相互作用剂(包括烷基化剂、DNA链断裂剂、DNA拓扑异构酶I和II抑制剂、DNA小沟结合剂),例如苯丁酸氮芥、环磷酰胺、噻替派、白消安、卡莫司汀、顺铂、卡铂、丝裂霉素、丙卡巴肼、博来霉素、安吖啶、柔红霉素、阿霉素、依托泊苷、普卡霉素、喜树碱和伊立替康;
(2)抗代谢物(包括叶酸盐拮抗剂、嘌呤拮抗剂、嘧啶拮抗剂),例如甲氨蝶呤、巯嘌呤、eloxuridine和氟尿嘧啶;
(3)微管蛋白-相互作用剂,例如长春碱、长春新碱和紫杉醇;
(4)激素类剂,例如己二烯雌酚、己烯雌酚、雌二醇、他莫昔芬和氟甲睾酮。
优选地,抗癌化疗剂选自下组:苯丁酸氮芥、环磷酰胺、噻替派、白消安、卡莫司汀、顺铂、卡铂、丝裂霉素、丙卡巴肼、博来霉素、安吖啶、柔红霉素、阿霉素、依托泊苷、普卡霉素、喜树碱、伊立替康、甲氨蝶呤、巯嘌呤、eloxuridine、氟尿嘧啶、长春碱、长春新碱、紫杉醇、己二烯雌酚、己烯雌酚、雌二醇、他莫昔芬和氟甲睾酮。更优选地,抗癌化疗剂选自由依托泊苷、伊立替康、氟尿嘧啶和紫杉醇组成的组。
在预防/减少抗癌化疗剂对造血细胞和肠细胞的损害时,噁唑烷酮是口服、胃肠外(IV)或直肠给药的。优选地,噁唑烷酮是口服或IV给药的,更优选为口服。
当口服给药时,噁唑烷酮可以以固体(片剂或胶囊)或液体(混悬液、糖浆或溶液)剂型给药。不管剂型如何,噁唑烷酮的抑制细胞或抗细胞毒有效量为约50mg至约1,200mg/天。优选地,噁唑烷酮分两个或更多个均分剂量给药,更优选地分两个均分剂量给药。
当胃肠外给药时,噁唑烷酮应当是IV给药的。应当将IV输注调节至使流速所释放的抗细胞毒有效量为约50mg至约1,200mg/天。做到这一点的方法可以是连续输注,或者按均分剂量给药,每次短期输注30-90分钟,优选为一天两次。
当直肠给药时,噁唑烷酮应当以栓剂方式给药,所释放的抗细胞毒有效量为约50mg至约1,200mg/天。
当全身给药时,无论口服、胃肠外还是直肠方式,噁唑烷酮都应当连续给药或者以每1至12个月7-28天的周期给药。
确切的给药剂量和频率取决于所用的具体噁唑烷酮、所用的具体抗癌化疗剂、抗癌化疗剂的剂量、所治疗疾病的严重性、具体患者的年龄、体重、一般身体状况、个体可能采用的其他药物疗法,这对本领域的技术人员来说是熟知的,而且通过测量患者血液中噁唑烷酮的血液水平或浓度和/或患者对所治疗具体疾病的反应,可以更加准确地确定给药剂量和频率。
定义和约定
下列定义和解释是针对整篇文件中所用的术语而言的,包括说明书和权利要求书。
定义
“药学上可接受的”指关于组成、制剂、稳定性、患者接受性和生物利用度的性质和/或物质,该性质和/或物质从药理学/毒理学观点上看,对患者来说是可接受的,从物理学/化学观点上看,对生产药物化学家来说也是可接受的。
当用到固体在溶剂中的溶解度时,固体与溶剂的比例是重量/体积(wt/v)。
当提到药物制剂的%活性成分时,它是全部药物制剂的活性成分的比例,以重量/重量(wt/wt)表示。
醇指乙醇。
IV指通过静脉内途径的胃肠外给药。
噁唑烷酮指实施例1至6的化合物。
抗细胞毒指减少和/或预防正常细胞死亡。
具体实施方式
实施例
无需赘述,本领域技术人员利用前文的说明能够充分实施本发明。下列详细的实施例描述了怎样制备各种化合物和/或实现不同的本发明方法,被理解为仅供举例说明之用,无论如何都不是对前文公开的限制。关于反应物和反应条件及工艺,本领域技术人员将迅速地由这些操作举一反三。
实施例1:(S)-N-[[3-[3-氟-4-[4-(羟乙酰基)-1-哌嗪基]-苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺
(S)-N-[[3-[3-氟-4-[4-(羟乙酰基)-1-哌嗪基]-苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺是已知的,见美国专利5,652,238实施例1。
实施例2:(S)-N-[[3-[3-氟-4-(4-吗啉基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺
(S)-N-[[3-[3-氟-4-(4-吗啉基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺是已知的,见美国专利5,688,792实施例5。
实施例3:[4(S)-顺式]-(-)-N-[[3-[3-氟-4-(四氢-1-氧桥-2H-噻喃-4-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺
将(S)-(-)-N-[[3-[3-氟-4-(3,6-二氢-2H-噻喃-4-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺S-氧化物(国际专利公报WO97/09328,4.50g)和氧化铂(697mg)在甲醇(164ml)中的混合物在Parr仪器上、在氢气、40psi下震动18小时。然后通过硅藻土过滤除去催化剂,滤液在减压下浓缩,残余物在硅胶(230-400目,350g)上用色谱法纯化,用甲醇/二氯甲烷梯度(3/97-7/93)洗脱。收集适当的级分(TLC测得那些级分的Rf=0.44;甲醇/氯仿10/90),浓缩,得到标题化合物,熔点203-204°。
实施例4:N-((5S)-3-(3-氟-4-(4-(2-氟乙基)-3-氧哌嗪-1-基)苯基)-2-氧噁唑烷-5-基甲基)乙酰胺
N-((5S)-3-(3-氟-4-(4-(2-氟乙基)-3-氧哌嗪-1-基)苯基)-2-氧噁唑烷-5-基甲基)乙酰胺是已知的,见国际专利公报WO97/27188(实施例4)。
将1-叔丁氧羰基-3-氧哌嗪(21.6g)溶于无水DMF(500ml),加入叔丁醇钾(24.2g)。混合物在20-25°下搅拌30分钟,然后加入1-(4-甲基苯磺酰氧基)-2-氟乙烷(《医药化学杂志》23(9),985-90(1980),25.9g),继续在同一温度下搅拌24小时。除去溶剂,使残余物在乙酸乙酯与水之间分配。有机相用水洗涤,浓缩。将残余物溶于异丙醇,用异己烷稀释,过滤除去所生成的沉淀。混合物用色谱法纯化(二氧化硅;用极性增加的梯度0至50%异丙醇的异己烷溶液洗脱),得到1-叔丁氧羰基-4-(2-氟乙基)-3-氧哌嗪。
将1-叔丁氧羰基-4-(2-氟乙基)-3-氧哌嗪(6.65g)溶于二氯甲烷(500ml),在冰浴中冷却,加入三氟乙酸(150ml)。混合物在同一温度下搅拌2小时。除去溶剂,得到粗产物,将其溶于少量乙酸乙酯。缓慢加入乙醚,生成1-(2-氟乙基)-2-氧哌嗪沉淀,为单三氟乙酸盐。
将1-(2-氟乙基)-2-氧哌嗪三氟乙酸盐(6.1g)溶于乙腈(100ml)。向混合物中加入N,N-二异丙基乙胺(13ml),然后加入3,4-二氟硝基苯(3.39g),混合物加热回流18小时。除去溶剂,残余物用色谱法纯化(二氧化硅;用极性增加的梯度0至4%甲醇的二氯甲烷溶液洗脱),得到3-氟-4-(4-{2-氟乙基}-3-氧哌嗪-1-基)硝基苯。
将3-氟-4-(4-{2-氟乙基}-3-氧哌嗪-1-基)硝基苯(4.35g)溶于乙酸乙酯(250ml)与DMF(5ml)的混合物,溶液用氩冲洗。加入钯(碳上10%,200mg),混合物在环境压力下进行氢化。气体摄入停止后,混合物通过硅藻土过滤,除去溶剂。将残余物溶于乙酸乙酯,用水洗涤两次,经硫酸镁干燥,除去溶剂,得到5-氨基-2-[4-(2-氟乙基)-3-氧哌嗪-1-基]氟苯,使用时无需进一步纯化。
在氩条件下,将5-氨基-2-(4-[2-氟乙基]-3-氧哌嗪-1-基]氟苯(2.6g)溶于无水二氯甲烷(50ml)。加入吡啶(1.03ml),将混合物冷却至-20°。加入氯甲酸苄基酯(1.6ml),混合物在-20°下搅拌10分钟,然后经过1.5小时使温度升至20-25°。除去溶剂,将残余物溶于二氯甲烷,用碳酸氢钠溶液洗涤。经硫酸镁干燥和除去溶剂后,残余物用色谱法纯化(二氧化硅;用极性增加的梯度0至5%甲醇的二氯甲烷溶液洗脱),得到5-苄氧羰基氨基-2-(4-[2-氟乙基]-3-氧哌嗪-1-基)氟苯。
在-10°、氩条件下,向搅拌着的叔丁醇(0.43g)的无水THF(10ml)溶液中加入正丁基锂(1.6M己烷溶液,2.9ml),制得叔丁醇锂溶液。冷却至-70°后,加入5-苄氧羰基氨基-2-(4-[2-氟乙基]-3-氧哌嗪-1-基)氟苯(1.5g)的无水THF(15ml)溶液。10分钟后,向所得混合物中加入(R)-缩水甘油丁酸酯(0.67g)的无水THF(15ml)溶液,继续在-70°下搅拌15分钟,然后经过16小时使温度升至20-25°。加入甲醇(10ml),然后加入饱和碳酸氢钠溶液(20ml)和水(10ml)。分离有机相,用乙酸乙酯萃取(3×25ml),用盐水洗涤,经硫酸镁干燥。除去溶剂,残余物用色谱法纯化(二氧化硅;用极性增加的梯度0至3%甲醇的二氯甲烷溶液洗脱),得到(5R)-3-(3-氟-4-[4-(2-氟乙基)-3-氧哌嗪-1-基]苯基)-5-羟甲基噁唑烷-2-酮。
将(5R)-3-(3-氟-4-[4-(2-氟乙基)-3-氧哌嗪-1-基]苯基)-5-羟甲基噁唑烷-2-酮(0.8g)溶于吡啶(15ml),将混合物冷却至0°。向混合物中加入三乙胺(0.38ml)和甲磺酰氯(0.19ml),继续在20-25°下搅拌2小时。除去溶剂,将残余物溶于二氯甲烷,用水、盐水洗涤,经硫酸镁干燥,浓缩。所得残余物用乙醚研制,得到(5R)-3-(3-氟-4-[4-(2-氟乙基)-3-氧哌嗪-1-基]苯基)-5-(甲磺酰氧基甲基)噁唑烷-2-酮(0.76g),使用时无需进一步纯化。
将(5R)-3-(3-氟-4-[4-(2-氟乙基)-3-氧哌嗪-1-基]-5-(甲磺酰氧基甲基)噁唑烷-2-酮(719mg)溶于无水DMF(15ml),向混合物中加入叠氮化钠(647mg)。混合物在80°下加热6小时,然后浓缩至干。将所得残余物溶于乙酸乙酯,用水洗涤两次,经硫酸镁干燥。除去溶剂,得到(5R)-5-叠氮甲基-3-(3-氟-4-(4-(2-氟乙基)-3-氧哌嗪-1-基)苯基)噁唑烷-2-酮(413mg),使用时无需进一步纯化。
将(5R)-5-叠氮甲基-3-(3-氟-4-[4-(2-氟乙基)-3-氧哌嗪-1-基]苯基)噁唑烷-2-酮(360mg)溶于无水DMF(20ml),混合物用氩净化。加入钯(碳上10%,72mg),然后加入乙酸酐(0.17ml),混合物在20-25°、限于气球内的氢条件下搅拌3小时。混合物通过硅藻土过滤,浓缩至干,使其在乙酸乙酯与水之间分配。有机萃取液用盐水洗涤,经硫酸镁干燥,浓缩。残余物用色谱法纯化(硅胶;用极性增加的梯度0至2.5%甲醇/二氯甲烷洗脱)。收集适当的级分浓缩,得到标题化合物。
实施例5:(S)-N-[[3-[5-(3-吡啶基)噻吩-2-基]-2-氧代-5-噁唑烷基]甲基]乙酰胺
(S)-N-[[3-[5-(3-吡啶基)噻吩-2-基]-2-氧代-5-噁唑烷基]甲基]乙酰胺是已知的,见美国专利5,698,574(实施例124)。
实施例6:盐酸(S)-N-[[3-[5-(4-吡啶基)吡啶-2-基]-2-氧代-5-噁唑烷基]甲基]乙酰胺
按照美国专利5,627,181实施例36和52的一般操作,并作非关键性的改变,但是使用4-吡啶基加合物,制备盐酸(S)-N-[[3-[5-(4-吡啶基)吡啶-2-基]-2-氧代-5-噁唑烷基]甲基]乙酰胺。
实施例A:47岁白人男性-牛皮癣
某47岁白人男性的牛皮癣病史始于32岁。他的双肘、腹股沟、左腿、右腿和背部下方都有慢性牛皮癣损害。损害部位过去曾用煤焦油和局部施用甾类治疗过,但是没有用紫外线治疗过。他对甾族局部施用制剂的赋形剂过敏。
每天IV两次625mg(S)-N-[[3-[3-氟-4-(4-吗啉基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,共五天,然后每天口服两次625mg该药物,共九天。因此,患者每天两次接受625mg(S)-N-[[3-[3-氟-4-(4-吗啉基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺共十四天,注意到他一开始服药,牛皮癣就立即有改善。从服药到此后三个月,牛皮癣完全清除,这时逐渐开始复发。六个月后已恢复为预治疗状态。在他服用噁唑烷酮期间,未采用其他任何牛皮癣治疗。
实施例B:50岁白人男性-关节炎
某50岁白人男性(1912号患者)具有慢性阻塞性肺病(即他是一名吸烟者)、高血压、冠状动脉疾病和“腿、臂与肩”关节炎的病史,为此服用过非甾族抗炎剂,包括阿司匹林,发展为肺炎链球菌感染的普遍性获得性肺炎,这由异常的胸X射线得以证实。每天静脉内两次625mg(S)-N-[[3-[3-氟-4-(4-吗啉基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺治疗,共3天,然后口服8天相同剂量的(S)-N-[[3-[3-氟-4-(4-吗啉基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺。
长期随访患者,自述关节炎已痊愈,不再服药。
图表A
实施例1
实施例2
图表A(续)
实施例6
Claims (18)
1.噁唑烷酮在制备治疗关节炎的药物中的用途,该噁唑烷酮选自:
(S)-N-[[3-[3-氟-4-[4-(羟乙酰基)-1-哌嗪基]-苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,
(S)-N-[[3-[3-氟-4-(4-吗啉基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,
[4(S)-顺式]-(-)-N-[[3-[3-氟-4-(四氢-1-氧桥-2H-噻喃-4-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,
N-((5S)-3-(3-氟-4-(4-(2-氟乙基)-3-氧哌嗪-1-基)苯基)-2-氧噁唑烷-5-基甲基)乙酰胺,
(S)-N-[[3-[5-(3-吡啶基)噻吩-2-基]-2-氧代-5-噁唑烷基]甲基]乙酰胺和
(S)-N-[[3-[5-(4-吡啶基)吡啶-2-基]-2-氧代-5-噁唑烷基]甲基]乙酰胺及
其药学上可接受的盐,其中被治疗的人没有革兰氏阳性菌感染。
2.根据权利要求1的噁唑烷酮的用途,其中该药物是口服给药的。
3.根据权利要求2的噁唑烷酮的用途,其中噁唑烷酮的每日剂量为约50至约1,200mg/天。
4.根据权利要求1的噁唑烷酮的用途,其中该药物是局部施用的溶液、霜剂、软膏、凝胶、洗液、混悬液或乳液。
5.根据权利要求4的噁唑烷酮的用途,其中局部施用量为约0.01%至约10%。
6.根据权利要求1的噁唑烷酮的用途,其中该药物是IV给药的。
7.根据权利要求6的噁唑烷酮的用途,其中IV给药量为约50至约1,200mg/天。
8.根据权利要求1的噁唑烷酮的用途,其中该噁唑烷酮是(S)-N-[[3-[3-氟-4-(4-吗啉基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺。
9.噁唑烷酮在制备药物中的用途,该噁唑烷酮选自:
(S)-N-[[3-[3-氟-4-[4-(羟乙酰基)-1-哌嗪基]-苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,
(S)-N-[[3-[3-氟-4-(4-吗啉基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,
[4(S)-顺式]-(-)-N-[[3-[3-氟-4-(四氢-1-氧桥-2H-噻喃-4-基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺,
N-((5S)-3-(3-氟-4-(4-(2-氟乙基)-3-氧哌嗪-1-基)苯基)-2-氧噁唑烷-5-基甲基)乙酰胺,
(S)-N-[[3-[5-(3-吡啶基)噻吩-2-基]-2-氧代-5-噁唑烷基]甲基]乙酰胺和
(S)-N-[[3-[5-(4-吡啶基)吡啶-2-基]-2-氧代-5-噁唑烷基]甲基]乙酰胺及
其药学上可接受的盐,该药物用于减少对接受一种或多种抗癌化疗剂治疗的人造血细胞和肠细胞的损害,其中被治疗的人没有革兰氏阳性菌感染。
10.根据权利要求9的噁唑烷酮的用途,其中造血细胞是骨髓细胞。
11.根据权利要求9的噁唑烷酮的用途,其中造血细胞是脾细胞。
12.根据权利要求9的噁唑烷酮的用途,其中该药物是在用抗癌化疗剂治疗之前给药约2至约20天。
13.根据权利要求12的噁唑烷酮的用途,其中该药物是在用抗癌化疗剂治疗之前给药约5至约7天。
14.根据权利要求9的噁唑烷酮的用途,其中该药物是与抗癌化疗剂同时给药的。
15.根据权利要求9的噁唑烷酮的用途,其中该抗癌化疗剂选自下组:
苯丁酸氮芥、环磷酰胺、噻替派、白消安、卡莫司汀、顺铂、卡铂、丝裂霉素、丙卡巴肼、博来霉素、安吖啶、柔红霉素、阿霉素、依托泊苷、普卡霉素、喜树碱、伊立替康、甲氨蝶呤、巯嘌呤、eloxuridine、氟尿嘧啶、长春碱、长春新碱、紫杉醇、己二烯雌酚、己烯雌酚、雌二醇、他莫昔芬和氟甲睾酮。
16.根据权利要求15的噁唑烷酮的用途,其中该抗癌化疗剂选自由依托泊苷、伊立替康、氟尿嘧啶和紫杉醇组成的组。
17.根据权利要求9的噁唑烷酮的用途,其中该药物是以约50mg至约1,200mg/天给药的。
18.根据权利要求9的噁唑烷酮的用途,其中该噁唑烷酮是
(S)-N-[[3-[3-氟-4-(4-吗啉基)苯基]-2-氧代-5-噁唑烷基]甲基]乙酰胺。
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- 1998-11-10 CN CNB988100134A patent/CN1142777C/zh not_active Expired - Fee Related
- 1998-11-10 CN CNA2004100027903A patent/CN1546030A/zh active Pending
- 1998-11-10 DE DE69811717T patent/DE69811717T2/de not_active Expired - Fee Related
- 1998-11-10 KR KR1020007005366A patent/KR100574307B1/ko not_active IP Right Cessation
- 1998-11-10 AT AT98960157T patent/ATE233092T1/de not_active IP Right Cessation
- 1998-11-10 AU AU15823/99A patent/AU743941B2/en not_active Ceased
- 1998-11-10 CA CA002303961A patent/CA2303961A1/en not_active Abandoned
- 1998-11-10 ES ES98960157T patent/ES2193592T3/es not_active Expired - Lifetime
- 1998-11-10 EP EP98960157A patent/EP1032386B1/en not_active Expired - Lifetime
- 1998-11-10 SI SI9830387T patent/SI1032386T1/xx unknown
- 1998-11-10 KR KR1020057017426A patent/KR100589545B1/ko not_active IP Right Cessation
- 1998-11-10 DK DK98960157T patent/DK1032386T3/da active
- 1998-11-10 WO PCT/US1998/023233 patent/WO1999025344A1/en active IP Right Grant
-
2001
- 2001-10-26 HK HK01107458A patent/HK1036591A1/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
AU1582399A (en) | 1999-06-07 |
JP2001522886A (ja) | 2001-11-20 |
ATE233092T1 (de) | 2003-03-15 |
HK1036591A1 (en) | 2002-01-11 |
BR9815615A (pt) | 2000-10-24 |
EP1032386B1 (en) | 2003-02-26 |
NZ504612A (en) | 2002-08-28 |
DK1032386T3 (da) | 2003-05-26 |
CN1142777C (zh) | 2004-03-24 |
CA2303961A1 (en) | 1999-05-27 |
KR20050100009A (ko) | 2005-10-17 |
PT1032386E (pt) | 2003-07-31 |
KR20010032178A (ko) | 2001-04-16 |
KR100574307B1 (ko) | 2006-04-27 |
AU743941B2 (en) | 2002-02-07 |
ES2193592T3 (es) | 2003-11-01 |
CN1299281A (zh) | 2001-06-13 |
DE69811717T2 (de) | 2003-10-16 |
DE69811717D1 (de) | 2003-04-03 |
EP1032386A1 (en) | 2000-09-06 |
SI1032386T1 (en) | 2003-06-30 |
KR100589545B1 (ko) | 2006-06-19 |
WO1999025344A1 (en) | 1999-05-27 |
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