CN1217922C - 2-氨基-2-烷基-4-己烯酸和己炔酸衍生物用作氧化氮合酶抑制剂 - Google Patents
2-氨基-2-烷基-4-己烯酸和己炔酸衍生物用作氧化氮合酶抑制剂 Download PDFInfo
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- CN1217922C CN1217922C CN018187587A CN01818758A CN1217922C CN 1217922 C CN1217922 C CN 1217922C CN 018187587 A CN018187587 A CN 018187587A CN 01818758 A CN01818758 A CN 01818758A CN 1217922 C CN1217922 C CN 1217922C
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Abstract
本发明涉及2-氨基-2-烷基-4-己烯酸和己炔酸衍生物及其在治疗中的用途,特别是其作为氧化氮合酶抑制剂的用途。
Description
与相关申请的交叉参考
本申请要求2000年9月15日申请的美国临时申请No.60/232,680的利益。
发明领域
本发明涉及2-氨基-2-烷基-4-己烯酸和己炔酸衍生物及其在治疗中的用途,特别是其作为氧化氮合酶抑制剂的用途。
背景技术
早在20世纪80年代,人们就已知道乙酰胆碱引起的血管舒张依赖于血管内皮。内皮细胞舒血管因子(EDRF),现称为氧化氮(NO),通过氧化氮合酶(NOS)的作用产生于血管内皮中。一百多年来,NO作为血管舒张剂的活性是熟知的。此外,NO是得自亚硝酸戊酯、三硝酸甘油酯及其它硝基血管舒张剂的活性物质。将EDRF定义为NO,这与NO由氨基酸L-精氨酸经NO合酶合成的生化路径的发现相符。
氧化氮是可溶性鸟苷酸环化酶的内源性刺激剂。除内皮依赖性舒张外,NO参与一系列生物作用,包括吞噬细胞的细胞毒性以及中枢神经系统中的细胞与细胞之间的信息传递。
至少有如下三类NO合酶:
(i)组成性、Ca++/钙调蛋白依赖性酶,位于内皮中,其对受体或物理刺激产生应答,释放NO。
(ii)组成性、Ca++/钙调蛋白依赖性酶,位于大脑,其对受体或物理刺激产生应答,释放NO。
(iii)Ca++非依赖性酶,它在内毒素和细胞因子激活血管平滑肌、巨噬细胞、内皮细胞和一些其它细胞后诱导。一旦表达,此诱导性氧化氮合酶(下文中称为“iNOS”)长期连续产生NO。
基于若干生理反应,两种组成性酶各释放的NO以传导机制起作用。诱导性酶产生的NO对于肿瘤细胞和侵入微生物来说是细胞毒分子。很大程度上讲,iNOS合成的NO似乎也会导致管理NO产生的副作用,特别是病理性舒张和组织损伤。
越来越多的证据表明NO可能参与软骨的退化,该现象是某些病症如关节炎造成的后果,还已知在类风湿性关节炎和骨关节炎中NO的合成增加。
已建议治疗用的一些NO合酶抑制剂是非选择性的;它们同时抑制组成性和诱导性NO合酶。使用此类非选择性NO合酶抑制剂需非常小心,以避免组成性NO合酶的过度抑制的潜在严重后果,这些后果包括高血压和可能发生的血栓形成及组织损伤。具体地讲,在用L-NMMA(抑制非选择性NO合酶抑制剂)治疗脓毒性休克时,要建议患者在整个治疗过程中必须进行连续的血压监控。因此,虽然如果预防得当则非选择性NO合酶抑制剂可以用于治疗,但是选择性NO合酶抑制剂,即对诱导性NO合酶比NO合酶的组成性异构形式抑制性更强的抑制剂,会具有更大的治疗利益且易于应用(S.Moncada and E.Higgs,FASEB J.,9,1319-1330,1995)。
PCT国际申请WO 93/13055和美国专利5132453(将其公开内容以其整体引入作为参考,就如同记载在本文中),公开了抑制氧化氮合成并优先抑制氧化氮合酶的诱导形式的化合物。
PCT国际申请WO 95/25717公开了用于抑制诱导氧化氮合酶的脒基衍生物。
通过向抑制剂的结构中加入一种或多种稳定性元素,人们进行了多种尝试来改善NOS抑制剂的效力和选择性。Y.Lee等的文章(Bioorg.Med.Chem.7,1097(1999))和R.J.Young等的文章(Bioorg.Med.Chem.Lett.10,597(2000))教导通过一个或多个碳碳双键来影响构象稳定性对赋予NOS抑制剂选择性来说是不利的。
发明概述
现在我们发现在人软骨移植试验(一种骨关节炎模型)中非常有效的化合物。
本发明表明碳-碳双键可以用作稳定性元素,而所得化合物对抑制诱导性NOS具有意外的效力和选择性。
本发明表明碳-碳双键更有利于与诱导性NOS的作用,从而使所得化合物对诱导性NO较对组成性异构形式的抑制具有意外的效力和选择性。
此外,本发明化合物的优点是在人软骨移植试验(一种骨关节炎模型)中其是非常有效的iNOS抑制剂。同时,令人惊奇的是,本发明化合物透过试验系统中某些非靶向器官的能力很差,特别是与WO 93/13055的化合物相比。在靶向器官(软骨)与其它器官之间预期接近性方面的惊人差异是本发明化合物的意外优点。
总的来说,本发明化合物表示如下:
或其药用盐,其中:
R1选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;
R2选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;
R3是C1-C5烷基或被烷氧基或者一个或多个卤原子取代的C1-C5烷基。
在式I表示的一个实施方案中,本发明涉及:
或其药用盐,其中:
R1选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;
R2选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;
R3是C1-C5烷基或被烷氧基或者一个或多个卤原子取代的C1-C5烷基。
在式II表示的一个实施方案中,本发明涉及:
或其药用盐,其中:R3是C1-C5烷基,所述C1-C5烷基任选地被卤原子或烷氧基取代,所述烷氧基任选地被一个或多个卤原子取代。
在式III表示的一个实施方案中,本发明涉及:
或其药用盐,其中:
R1选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;
R2选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;
R3是C1-C5烷基或被烷氧基或者一个或多个卤原子取代的C1-C5烷基。
在式IV表示的一个实施方案中,本发明涉及:
或其药用盐,其中:
R3是C1-C5烷基或被烷氧基或者一个或多个卤原子取代的C1-C5烷基。
在式V表示的一个实施方案中,本发明涉及:
或其药用盐,其中:
R1选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;
R2选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;
R3是C1-C5烷基或被烷氧基或者一个或多个卤原子取代的C1-C5烷基。
在式VI表示的一个实施方案中,本发明涉及:
或其药用盐,其中:
R3是C1-C5烷基或被烷氧基或者一个或多个卤原子取代的C1-C5烷基。
总的来说,本发明涉及新的化合物、药物组合物、制备新化合物的方法、制备药物组合物的方法,以及用所述化合物和组合物抑制或调节需要此抑制或调节的对象的氧化氮合成的方法,该方法使用较氧化氮合酶的组成性异构形式而言优先抑制或调节氧化氮合酶的诱导性异构形式的化合物。本发明的另一个目的也在于降低需要此降低的对象的氧化氮水平。本发明化合物具有可利用的氧化氮合酶抑制活性,并预计可用于治疗或预防氧化氮的合成或过度合成是部分病因的疾病或病症。
一般来说,本发明化合物会用于治疗患者的炎症,或者用于治疗氧化氮合成介导的疾病,如作为疼痛和头痛治疗中的止痛剂。本发明化合物可用于治疗疼痛,包括躯体原性的(感受伤害的或神经病的),急性的和慢性的,并可以用于包括通常用普通NSAID、阿片类止痛剂或某些抗惊厥剂治疗的神经病性疼痛的情况。
本发明的范围中包括用于合成本发明化合物的新中间体。
本发明化合物会在抑制由L-精氨酸产生NO方面为其提供益处的病症,包括关节病。例如,本发明化合物会用于治疗关节炎,包括但不限于类风湿性关节炎、脊椎关节病、痛风性关节炎、骨关节炎、系统性红斑狼疮、少年关节炎、急性风湿性关节炎、肠病性关节炎、神经病关节炎、牛皮癣性关节炎和生脓性关节炎。
本发明化合物还可用于治疗哮喘,支气管炎,月经痛性痉挛(例如,痛经),早产,腱炎,滑囊炎,皮肤病如牛皮癣、湿疹、烧伤、晒伤、皮炎,胰腺炎,肝炎及术后炎症包括眼科手术如白内障手术和屈光手术后的炎症。本发明化合物还可用于治疗胃肠病症如炎性肠疾病、节段性回肠炎、胃炎、应激性肠综合征和溃疡性结肠炎。
本发明化合物可在如下疾病中用于治疗炎症和组织损伤:血管性疾病、偏头痛、结节性动脉外膜炎、甲状腺炎、成形性贫血、何杰金氏病、硬化病、风湿热、I型糖尿病、神经肌肉结合病包括重症肌无力、白化病包括多发性硬化、肉样瘤病、肾病综合征、贝切特氏病、多肌炎、齿龈炎、肾炎、过敏症、外伤后发生的红肿、心肌局部缺血等。这些化合物还可用于治疗眼科疾病,如青光眼、视网膜炎、视网膜病、眼色素层炎、眼恐光症,以及与对眼组织的急性损伤有关的炎症和疼痛。本发明化合物的这些用途中,特别有利的是治疗青光眼,特别是青光眼症状是由氧化氮的产生引起的,如氧化氮介导的神经损伤。这些化合物还可用于治疗肺部炎症,如与病毒感染和囊性纤维变性有关的炎症。这些化合物还可用于治疗某些中枢神经系统紊乱,如皮层痴呆包括包括早老性痴呆,及中风、局部缺血和外伤导致的中枢神经系统损伤。这些化合物还可用于治疗过敏性鼻炎、呼吸窘迫综合症、内毒素休克综合征和动脉粥样硬化。这些化合物也可用于治疗疼痛,包括但不限于术后疼痛、牙痛、肌肉痛、颞下颌关节综合征引起的疼痛、以及癌症引起的疼痛。这些化合物可用于预防痴呆,如早老性痴呆。
除了用于人的治疗,这些化合物还可用于包括哺乳动物及其它脊椎动物的宠物、野生动物和驯养动物的兽医治疗。更优选的动物包括马、狗和猫。
本发明化合物还可以用药联合治疗中,部分或者完全代替其它常规抗炎疗法,例如,与甾族化合物、NSAID、COX-2选择性抑制剂、基质金属蛋白酶抑制剂、5-脂氧合酶抑制剂、LTB4拮抗剂和LTA4水解酶抑制剂一起使用。
本发明化合物能够在抑制NO方面提供益处的其它病症,包括心血管局部缺血、糖尿病(I型或II型)、充血性心力衰竭、心肌炎、动脉粥样硬化、偏头痛、青光眼、主动脉动脉瘤、反流性食管炎、腹泻、应激性肠综合征、胰囊性纤维变性、肺气肿、哮喘、支气管扩张、痛觉过敏(异常性疼痛)、脑局部缺血(病灶性局部缺血、血栓形成性中风和脑球局部缺血(例如,继发的心搏停止))、多发性硬化及NO介导的其它中枢神经系统疾病,如帕金森氏病。可能得益于NO抑制的其它神经变性疾病包括神经退化和神经坏死,例如,发生于如下疾病中:低氧症、低血糖症、癫痫,及枢神经系统(CNS)外伤(如脊柱和头部损伤)、高压纯氧性惊厥和中毒、痴呆如早老性痴呆及与AIDS相关的痴呆、恶病质、西登哈姆氏舞蹈病、杭廷顿氏舞蹈病、肌萎缩性侧索硬化、科尔萨科夫氏精神病、与脑血管病有关的痴愚、睡眠紊乱、精神分裂症、抑郁或与月经前综合征(PMS)有关的其它症状、焦虑和脓毒性休克。
可由本发明化合物有利治疗的其它疾病或病症,包括治疗或预防需要长期阿片类止痛药的患者的阿片耐受性,以及服用苯并二氮杂环庚三烯类患者中的苯并二氮杂环庚三烯耐受性,以及其它上瘾行为,例如,尼古丁成瘾、酗酒及进食紊乱。本发明的化合物和方法还可用于治疗或预防阿片类、酒精或烟草上瘾的戒断症状。当与抗菌或抗病毒剂联合治疗时,本发明化合物还可用于预防组织损伤。
本发明化合物也可用于抑制由L-精氨酸产生NO,包括多种制剂引起的、与脓毒性和/或中毒性出血性休克有关的系统性低血压;与细胞因子如TNF、IL-1和IL-2一起治疗;并作为移植疗法中短期免疫抑制的辅药。
本发明化合物用于预防或治疗癌症,如结肠直肠癌、乳腺癌、肺癌、前列腺癌、膀胱癌、宫颈癌和皮肤癌。本发明还涉及本发明化合物治疗和预防瘤形成的用途。本发明化合物和方法能够治疗或预防的瘤形成包括脑癌,骨癌,白血病如慢性淋巴细胞白血病,淋巴瘤,源自上皮细胞的瘤形成(上皮细胞癌)如基底细胞癌,腺癌,胃肠癌如唇癌、口腔癌、食道癌、小肠癌和胃癌,结肠癌,肝癌,膀胱癌,胰腺癌,泌尿生殖器癌如卵巢癌、宫颈癌、阴道癌,及肺癌,乳腺癌和皮肤癌如鳞状细胞、黑素瘤和基底细胞癌,前列腺癌,肾细胞癌,及其它已知的通过身体作用于上皮细胞的癌症。本发明化合物还能有效治疗源自间质的瘤形成。优选,所治疗的肿瘤选自胃肠癌,肝癌,膀胱癌,胰腺癌,卵巢癌,前列腺癌,宫颈癌,阴道癌,肺癌,乳腺癌和皮肤癌,如鳞状细胞和基底细胞癌。本发明的化合物和方法还可用于治疗放疗时发生的纤维化。本发明化合物和方法可用于治疗患有腺瘤性息肉的患者,包括遗传性腺瘤息肉病(FAP)的患者。此外,本发明化合物和方法可用于预防存在FAP发病危险性的患者中息肉的形成。
本发明化合物与其它抗肿瘤剂的联合治疗会产生协同作用,或降低会引起副作用的制剂达到有效治疗所需要的治疗剂量,或者直接降低会引起副作用的制剂引起的毒副作用。本发明的化合物还可用作放疗的辅药以降低副作用或提高疗效。在本发明中,可以与本发明化合物联合治疗的其它制剂,包括能够抑制环加氧酶-2(“COX-2”)的任何治疗剂。优选此类COX-2抑制剂相对于环加氧酶-1(“COX-1”)选择性抑制COX-2。此类COX-2抑制剂称为“COX-2选择性抑制剂”。更优选,本发明的化合物可以与COX-2选择性抑制剂联合治疗,相对于抑制COX-1来说,其中所述COX-2选择性抑制剂在体外试验中以至少10∶1的比例选择性抑制COX-2,更优选至少30∶1,并更优选至少50∶1。在与本发明化合物联合治疗中使用的COX-2选择性抑制剂包括celecoxib,valdecoxib,deracoxib,etoricoxib,rofecoxib,ABT-963(2-(3,4-二氟苯基)-4-(3-羟基-3-甲基-1-丁氧基)-5-[4-(甲基磺酰基)苯基-3(2H)-哒嗪酮;描述于PCT专利申请WO 00/24719),或meloxicam。本发明的化合物还可以有利地用于与COX-2选择性抑制剂的前药如parecoxib的联合治疗中。
用于与本发明化合物联合治疗中的其它化疗剂,例如,选自下列非穷举和非限制性目录中:α-二氟甲基鸟氨酸(DFMO),5-FU-纤维蛋白原,acanthifolicacid,氨基噻二唑,布喹那(brequinar sodium),卡莫氟,Ciba-Geigy CGP-30694,环戊基胞嘧啶,硬脂酸磷酸阿糖胞苷,阿糖胞苷轭合物,Lilly DATHF,Merrel Dow DDFC,地扎呱宁,二脱氧胞苷,二脱氧鸟苷,didox,Yoshitomi DMDC,去氧氟尿苷,Wellcome EHNA,Merck & Co.EX-015,法扎拉滨,氟尿苷,磷酸氟达拉滨,5-氟尿嘧啶,N-(2’-四氢呋喃基)-5-氟尿嘧啶,DaiichiSeiyaku FO-152,异丙基pyrrolizine,Lilly LY-188011,LillyLY-264618,methobenzaprim,甲氨蝶呤,Wellcome MZPES,norspermidine,NCI NSC-127716,NCI NSC-264880,NCI NSC-39661,NCI NSC-612567,Warner-Lambert PALA,喷司他丁,吡曲克辛,扑卡霉素,Asahi Chemical PL AC,Takeda TAC-788,硫鸟嘌呤,噻唑呋林,Erbamont TIF,三甲昔林,酪氨酸激酶抑制剂,酪氨酸蛋白激酶抑制剂,Taiho UFT,uricytin,Shionogi 254-S,氧代-磷酰胺类似物,六甲蜜胺,阿那昔酮,Boehringer Mannheim BBR-2207,bestrabucil,布度钛,Wakunaga CA-102,卡铂,卡莫司汀,Chinoin-139,Chinoin-153,苯丁酸氮芥,顺铂,环磷酰胺,American Cyanamid CL-286558,Sanofi CY-233,cyplatate,Degussa D-19-384,Sumimoto DACHP(Myr)2,二苯基螺莫司汀,二铂细胞抑制剂,Erba司他霉素衍生物,Chugai DWA-2114R,ITI E09,依莫司汀,Erbamont FCE-24517,雌莫司汀磷酸钠,福莫司汀,UnimedG-6-M,Chinoin GYKI17230,hepsul-fam,异环磷酰胺,异丙铂,罗氮芥,马磷酰胺,二溴卫矛醇,Nippon Kayaku NK-121,NCI NSC-264395,NCI NSC-342215,奥沙利铂,Upjohn PCNU,泼尼莫司汀,Proter PTT-119,雷莫司汀,司莫司汀,SmithKline SK & F101772,Yakult Honsha SN-22,螺莫司汀,Tanabe Seiyaku TA-077,牛磺莫司汀,替莫唑胺,替罗昔隆,tetraplatin,trimelamol,Taiho4181-A,阿柔比星,放线菌素D,actinoplanone,Erbamont ADR-456,aeroplysinin衍生物,Ajinomoto AN-201-II,Ajinomoto AN-3,Nippon Soda茴香霉素,蒽环类(anthracycline),azino-mycin-A,bisucaberin,Bristol-Myers BL-6859,Bristol-Myers BMY-25067,Bristol-Myers BMY-25551,Bristol-Myers BMY-26605,BristolMyers BMY-27557,Bristol-Myers BMY-28438,硫酸博来霉素,薯司他丁-1,Taiho C-1027,calichemycin,chromoximycin,更生霉素,柔红霉素,Kyowa Hakko DC-102,Kyowa Hakko DC-79,KyowaHakko DC-88A,Kyowa Hakko DC89-A1,Kyowa Hakko DC92-B,ditrisarubicin B,Shionogi DOB-41,阿霉素,阿霉素-纤维蛋白原,elsamicin-A,表柔比星,erbstatin,依索比星,esperamicin-A1,esperamicin-Alb,Erbamont FCE-21954,Fujisawa FK-973,福司曲星,Fujisawa FR-900482,滑行菌素,gregatin-A,grincamycin,herbimycin,伊达比星,隐徒头菌素,kazusamycin,kesarirhodins,Kyowa Hakko KM-5539,Kirin Brewery KRN-8602,Kyowa HakkoKT-5432,Kyowa Hakko KT-5594,Kyowa Hakko KT-6149,AmericanCyanamid LL-D49194,Meiji Seika ME 2303,美诺立尔,丝裂霉素,米托蒽醌,SmithKline M-TAG,neoenactin,Nippon Kayaku NK-313,Nippon Kayaku NKT-01,SRI International NSC-357704,氧代赖氨酸,oxaunomycin,培洛霉素,pilatin,吡柔比星,porothramycin,pyrindamycin A,Tobishi RA-I,雷怕霉素,rhizoxin,罗多比星,sibanomicin,siwenmycin,Sumitomo SM-5887,Snow Brand SN-706,Snow Brand SN-07,sorangicin-A,稀疏霉素,SS PharmaceuticalSS-21020,SS Pharmaceutical SS7313B,SS Pharmaceutical SS-9816B,司替霉素B,Taiho 4181-2,他利霉素,Takeda TAN-868A,terpentecin,thrazine,tricrozarin A,Upjohn U-73975,KyowaHakko UCN-10028A,Fujisawa WF-3405,Yoshitomi Y-25024佐柔比星,α胡萝卜素,α-二氟甲基-精氨酸,阿维A,Biotec AD-5,KyorinAHC-52,鸡骨常山硷,氨萘非特,amphethinile,安吖啶,Angiostat,ankinomycin,antineoplaston A10,antineoplaston A2,antineoplaston A3,antineoplaston A5,antineoplaston AS2-1,Henkel APD,甘氨酸阿非迪霉素,天冬酰胺酶,Avarol,baccharin,batracylin,benfluron,benzotript,Ipsen-Beaufour BIM-23015,比生群,Bristo-Myers BMY-40481,Vestar boron-10,bromofosfamide,Wellcome BW-502,Wellcome BW-773,卡醋胺,carmethizole盐酸盐,Ajinomoto CDAF,chlorsulfaquinoxalone,Chemex CHX-2053,Chemex CHX-100,Warner-Lambert C1-921,Warner-Lambert CI-937,Warner-Lambert CI-941,Warner-LambertCI-958,clanfenur,claviridenone,ICN化合物1259,ICN化合物4711,Contracan,Yakult Honsha CPT-11,crisnatol,curaderm,细胞松弛素B,阿糖胞苷,环胞菌素(cytocytin),Merz D-609,DABIS马来酸盐,达卡巴嗪,达替铵(datelliptinium),didemnin-B,dihaematoporphyrin ether,二氢氟苯哌丁酮,地那林,司他霉素,Toyo Pharmar DM-341,Toyo Pharmar DM-75,Daiichi SeiyakuDN9693,elliprabin,依利醋铵,Tsumura EPMTC,麦角胺,依托泊苷,阿维A酯,芬维A胺,Fujisawa FR-57704,硝酸镓,genkwadaphnin,Chugai GLA-43,Glaxo GR-63178,grifolan NMF-5N,十六烷基磷酸胆碱,Green Cross HO-221,高三尖杉酯碱,羟基脲,BTG ICRF-187,伊莫福新,异谷氨酰胺,异维甲酸,Otsuka JI-36,Ramot K-477,Otsuak K-76COONa,Kureha Chemical K-AM,MECT CorpKI-8110,American Cyanamid L-623,leukoregulin,氯尼达明,Lundbeck LU-23-112,Lilly LY-186641,NCI(US)MAP,marycin,Merrel Dow MDL-27048,Medco MEDR-340,merbarone,份菁衍生物,甲基苯氨基吖啶,Molecular Genetics MG1-136,minactivin,米托萘胺,米托喹酮,莫哌达醇,莫维A胺,Zenyaku Kogyo MST-16,N-(视黄酰基)氨基酸,Nisshin Flour Milling N-021,N-酰基化脱氢丙氨酸,那法扎琼,Taisho NCU-190,诺考达唑衍生物,Normosang,NCI NSC-145813,NCI NSC-361456,NCI NSC-604782,NCI NSC95580,奥曲肽,Ono ONO-112,oquizanocine,Akzo Org-10172,pancratistatin,帕折普汀,Warner-Lambert PD-111707,Warner-Lambert PD-115934,Warner-Lambert PD-131141,PierreFabre PE-1001,ICRT肽D,吡罗蒽醌,polyhaematoporphyrin,polypreic acid,Efamol卟啉,probimane,丙卡巴肼,丙谷酰胺,Invitron蛋白酶连接蛋白I,Tobishi RA-700,雷佐生,SapporoBreweries RBS,restrictin-P,retelliptine,视黄酸,Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976,SmithKline SK &F-104864,Sumitomo SM-108,Kuraray SMANCS,SeaPharm SP-10094,spatol,螺环丙烷衍生物,螺旋锗,Unimed,SS PharmaceuticalSS-554,strypoldinone,Stypoldione,Suntory SUN 0237,SuntorySUN 2071,过氧化物歧化酶,Toyama T-506,Toyama T-680,紫杉醇,Teijin TE1-0303,替尼泊苷,thaliblastine,Eastman KodakTJB-29,生育三烯酚类,Topostin,Teijin TT-82,Kyowa HakkoUCN-01,Kyowa Hakko UCN-1028,ukrain,Eastman Kodak USB-006,硫酸长春碱,长春新碱,长春地辛,vinestramide,长春瑞滨,长春曲醇,长春利定,withanolides,Yamanouchi YM-534,uroguanylin,combretastatin,dolastatin,伊达比星,表柔比星,雌莫司汀,环磷酰胺,9-氨基-2-(S)-喜树碱,托泊替堪,伊立替康(Camptosar),伊西美坦,6-D-色氨酸高那瑞林(tryptorelin)或ω-3-脂肪酸。
可用于与本发明化合物联合治疗中的放射性保护剂的实例,包括AD-5,adchnon,氨磷汀类似物,detox,地美司钠,1-102,MM-159,N-酰化-脱氢丙氨酸,TGF Genentech,噻丙莫德,氨磷汀,WR-151327,FUT-187,透皮酮洛芬,萘丁美酮,过氧化物歧化酶(Chiron)和过氧化物歧化酶Enzon。
本发明化合物也可用于治疗或预防血管生成相关疾病或病症,例如,肿瘤生长、转移,黄斑变性和动脉粥样硬化。
在另一个实施方案中,本发明还提供了治疗眼科疾病或病症如青光眼的联合治疗。例如,本发明化合物可以与降低青光眼患者眼内压的药物一起有利地用于联合治疗中。此类眼内压降低药非限制性地包括:拉坦前列素,travoprost,bimatoprost或unoprostol。本发明的化合物加眼内压降低药的联合治疗是可利用的,因为其中每种药物通过不同的机制起作用。
在本发明的另一种联合治疗中,本发明化合物可以用于与抗高血脂药或降胆固醇药如苯并硫杂环庚三烯类抗高血脂药物的联合治疗中。用于本发明联合治疗中的苯并硫杂环庚三烯的抗高血脂药的实例,见美国专利No.5,994,391,引入本文作为参考。一些苯并硫杂环庚三烯类抗高血脂药描述于WO 93/16055。或者,用于与本发明化合物联合治疗中的抗高血脂或降胆固醇药可以是HMG Co-A还原酶抑制剂。用于本发明联合治疗中的HMG Co-A还原酶抑制剂分别包括苯氟雷司,氟伐他汀,洛伐他汀,普法他汀(provastatin),辛伐他汀,阿托伐他汀(atorvastatin),cerivastatin,bervastatin,ZD-9720(见PCT专利申请WO 97/06802),ZD-4522(钙盐的CAS No.为147098-20-2;钠盐的CAS No.为147098-18-8;见欧洲专利EP 521471),BMS180431(CAS No.129829-03-4),或NK-104(CAS No.141750-63-2)。本发明的化合物加抗高血脂或降胆固醇药的联合治疗,例如,可用于降低血管中动脉粥样硬化损伤的形成危险。例如,在血管的炎性部位常常引起动脉粥样硬化损伤。人们认为抗高血脂或降胆固醇药通过降低血脂水平来降低动脉粥样硬化损伤的形成危险。
在不降本发明限制为某种单一的作用机理的前提下,我们相信本发明联合治疗的化合物协同作用从而改善动脉粥样硬化损伤的控制的一个作用途径,例如,是通过在降低血脂水平的同时降低了血管炎症。
在本发明的另一个实施方案中,本发明化合物可以与治疗中枢神经病症或疾病如偏头痛的其它化合物或治疗方法联合使用。例如,本发明化合物可以与下列药物一起用于联合治疗中:咖啡因,5-HT-1B/1D激动剂(例如,曲坦类(triptan)如舒马普坦,那拉曲坦,zolmitriptan,rizatriptan,almotriptan或frovatriptan),多巴胺D4拮抗剂(例如,sonepiprazole),阿司匹林,对乙酰氨基酚,布洛芬,消炎痛,萘普生钠,异美汀,氯醛比林,布他比妥,麦角生物碱(例如,麦角胺,二氢麦角胺,溴隐亭,麦角新碱或甲基麦角新碱),三环抗抑郁药(例如,阿米替林或去甲替林),5-羟色胺能拮抗剂(例如,美西麦角或赛庚啶),β-肾上腺素能拮抗剂(例如,普萘洛尔,噻吗洛尔,阿替洛尔,纳多洛尔或metprolol),或一元胺氧化酶抑制剂(例如,苯乙肼或异卡波肼)。
另一个实施方案提供了本发明化合物与阿片类化合物的联合治疗。用于此联合的阿片类化合物非限制性地包括吗啡,美沙酮,氢吗啡酮,羟吗啡酮,左吗啡,左洛啡烷,可待因,二氢可待因,二氢羟基可待因酮,喷他佐辛,氢可酮,羟可酮,纳美芬,唉托啡,左吗啡,芬太尼,舒芬太尼,DAMGO,布托啡诺,丁丙诺啡,纳洛酮,纳曲酮,CTOP,二丙诺啡,β-funaltrexamine,naloxonazine,纳洛芬,镇痛新,纳布啡,纳洛酮苯甲酰腙,布马佐辛,乙基ketocyclazocine,U50,488,U69,593,spiradoline,nor-binaltorphimine,naltrindole,DPDPE,[D-1a2,glu4]deltorphin,DSLET,met-脑啡肽,leuenkaphalin,β-内啡肽,强啡肽A,强啡肽B,及α-新内啡肽。本发明与阿片类化合物联合的一个优点是,本发明化合物将降低阿片类化合物的剂量,从而降低阿片副作用如阿片成瘾性的危险或严重性。
发明详述
一般来说,本发明化合物表示如下:
或其药用盐,其中:
R1选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;R2选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;R3是C1-C5烷基或被烷氧基或者一个或多个卤原子取代的C1-C5烷基。
在式I表示的一个实施方案中,本发明涉及:
或其药用盐,其中:
R1选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;R2选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;
R3是C1-C5烷基或被烷氧基或者一个或多个卤原子取代的C1-C5烷基。
在由式I表示的本发明的一个实施方案中,所述化合物是Z异构体。
在由式I表示的本发明的另一个实施方案中,所述化合物是E异构体。
在由式I表示的本发明的另一个实施方案中,R1是氢原子、卤原子或C1-C5烷基,所述C1-C5烷基任选地被卤原子或烷氧基取代,所述烷氧基任选地被一个或多个卤原子取代;R2是氢、卤原子或C1-C5烷基,所述C1-C5烷基任选地被卤原子或烷氧基取代,所述烷氧基任选地被一个或多个卤原子取代;且R3是C1-C5烷基,所述C1-C5烷基任选地被卤原子或烷氧基取代。
在由式I表示的本发明的另一个实施方案中,R1是氢、卤原子或C1-C3烷基;R2是氢、卤原子或C1-C3烷基;且R3是C1-C5烷基,所述C1-C5烷基任选地被氟或烷氧基取代。
在由式I表示的本发明的另一个实施方案中,R1是氢、卤原子或C1-C3烷基;R2是氢、卤原子或C1-C3烷基;且R3是C1-C3烷基。
在由式I表示的本发明的另一个实施方案中,R1是氢;R2是氢、卤原子或C1-C3烷基;且R3是C1-C3烷基。
在由式I表示的本发明的另一个实施方案中,R1是氢;R2是氢或卤原子;且R3是C1-C3烷基。
在由式I表示的本发明的另一个实施方案中,R1是氢;R2是氢或氟原子;且R3是C1-C3烷基。
在由式I表示的本发明的另一个实施方案中,R1是氢原子;R2是氢或氟原子;且R3是甲基。
在由式I表示的本发明的另一个实施方案中,R1是氢;R2是氢;且R3是甲基。
在由式I表示的本发明的另一个实施方案中,R1是氢原子;R2是氟原子;且R3是甲基。
在由式I表示的本发明的另一个实施方案中,R1是卤原子;R2是氢、卤原子或C1-C3烷基;且R3是C1-C3烷基。
在由式I表示的本发明的另一个实施方案中,R1是卤原子;R2是卤原子;且R3是C1-C3烷基。
在由式I表示的本发明的另一个实施方案中,R1是氟原子;R2是氟原子;且R3是甲基。
在由式I表示的本发明的另一个实施方案中,R1是氟原子;R2是氢或C1-C3烷基;且R3是甲基。
在由式I表示的本发明的另一个实施方案中,R1是氟原子;R2是氢;且R3是甲基。
在由式I表示的本发明的另一个实施方案中,R1是甲基;R2是氢;且R3是甲基。
在由式I表示的本发明的另一个实施方案中,R1是氢;R2是甲基;且R3是甲基。
在由式I表示的本发明的另一个实施方案中,R1是甲基;R2是甲基;且R3是甲基。
在由式I表示的本发明的另一个实施方案中:R1是氢原子、卤原子或C1-C5烷基,所述C1-C5烷基任选地被烷氧基或者一个或多个氟原子取代;R2是氢、卤原子或C1-C5烷基,所述C1-C5烷基任选地被烷氧基或者一个或多个氟原子取代;且R3是甲基,其任选地被一个或多个烷氧基或者卤原子取代。
在由式I表示的本发明的另一个实施方案中,R1是氢或氟原子;R2是C1-C3烷基,其被一个或多个卤原子取代;且R3是甲基。
在由式I表示的本发明的另一个实施方案中,R1是氢;R2是CH2F;且R3是甲基。
在由式I表示的本发明的另一个实施方案中,R1是CH2F;R2是氢;且R3是甲基。
在由式I表示的本发明的另一个实施方案中,R1是氢;R是氢;且R3是CH2F。
在由式I表示的本发明的另一个实施方案中,R1是氢;R2是甲氧基甲基;且R3是甲基。
在由式I表示的本发明的另一个实施方案中,R1是甲氧基甲基;R2是氢;且R3是甲基。
在由式I表示的本发明的另一个实施方案中,R1是氢;R2是氢;且R3是甲氧基甲基。
在式II表示的一个实施方案中,本发明涉及:
或其药用盐,其中:R3是C1-C5烷基,所述C1-C5烷基任选地被卤原子或烷氧基取代,所述烷氧基任选地被一个或多个卤原子取代。
在由式II表示的本发明的另一个实施方案中,R3是C1-C5烷基,其被一个或多个卤原子取代。
在由式II表示的本发明的另一个实施方案中,R3是C1-C5烷基,其被一个或多个氟原子取代。
在由式II表示的本发明的另一个实施方案中,R3是甲基,其被一个或多个卤原子取代。
在由式II表示的本发明的另一个实施方案中,R3是甲基,其被一个或多个氟原子取代。在由式II表示的本发明的另一个实施方案中,R3是CH2F。
在由式II表示的本发明的另一个实施方案中,R3是C1-C5烷基,其被烷氧基取代。
在由式II表示的本发明的另一个实施方案中,R3是甲氧基甲基。
在由式II表示的本发明的另一个实施方案中,R3是C1-C5烷基。
在由式II表示的本发明的另一个实施方案中,R3是甲基。
在式III表示的一个实施方案中,本发明涉及:
或其药用盐,其中:
R1选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;
R2选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;
R3是C1-C5烷基或被烷氧基或者一个或多个卤原子取代的C1-C5烷基。
在由式III表示的本发明的一个实施方案中,所述化合物是Z异构体。
在由式III表示的本发明的另一个实施方案中,所述化合物是E异构体。
在由式III表示的本发明的另一个实施方案中,R1是氢原子、卤原子或C1-C5烷基,所述C1-C5烷基任选地被卤原子或烷氧基取代,所述烷氧基任选地被一个或多个卤原子取代;R2是氢、卤原子或C1-C5烷基,所述C1-C5烷基任选地被卤原子或烷氧基取代,所述烷氧基任选地被一个或多个卤原子取代;且R3是C1-C5烷基,所述C1-C5烷基任选地被卤原子或烷氧基取代。
在由式III表示的本发明的另一个实施方案中,R1是氢、卤原子或C1-C3烷基;R2是氢、卤原子或C1-C3烷基;且R3是C1-C5烷基,所述C1-C5烷基任选地被氟或烷氧基取代。
在由式III表示的本发明的另一个实施方案中,R1是氢、卤原子或C1-C3烷基;R2是氢、卤原子或C1-C3烷基;且R3是C1-C3烷基。
在由式III表示的本发明的另一个实施方案中,R1是氢;R2是氢、卤原子或C1-C3烷基;且R3是C1-C3烷基。
在由式III表示的本发明的另一个实施方案中,R1是氢;R2是氢或卤原子;且R3是C1-C3烷基。
在由式III表示的本发明的另一个实施方案中,R1是氢;R2是氢或氟原子;且R3是C1-C3烷基。
在由式III表示的本发明的另一个实施方案中,R1是氢;R2是氢或氟原子;且R3是甲基。
在由式III表示的本发明的另一个实施方案中,R1是氢;R2是氢;且R3是甲基。
在由式III表示的本发明的另一个实施方案中,R1是氢;R2是氟原子;且R3是甲基。
在由式III表示的本发明的另一个实施方案中,R1是卤原子;R2是氢、卤原子或C1-C3烷基;且R3是C1-C3烷基。
在由式III表示的本发明的另一个实施方案中,R1是卤原子;R2是卤原子;且R3是C1-C3烷基。
在由式III表示的本发明的另一个实施方案中,R1是氟原子;R2是氟原子;且R3是甲基。
在由式III表示的本发明的另一个实施方案中,R1是氟原子;R2是氢或C1-C3烷基;且R3是甲基。
在由式III表示的本发明的另一个实施方案中,R1是氟原子;R2是氢;且R3是甲基。
在由式III表示的本发明的另一个实施方案中,R1是甲基;R2是氢;且R3是甲基。
在由式III表示的本发明的另一个实施方案中,R1是氢;R2是甲基;且R3是甲基。
在由式III表示的本发明的另一个实施方案中,R1是甲基;R2是甲基;且R3是甲基。
在由式III表示的本发明的另一个实施方案中,R1是氢、卤原子或C1-C5烷基,所述C1-C5烷基任选地被烷氧基或者一个或多个氟原子取代;R2是氢、卤原子或C1-C5烷基,所述C1-C5烷基任选地被烷氧基或者一个或多个氟原子取代;且R3是甲基,其任选地被一个或多个烷氧基或者卤原子取代。
在由式III表示的本发明的另一个实施方案中,R1是氢或氟原子;R1是C1-C3烷基,其被一个或多个卤原子取代;且R3是甲基。
在由式III表示的本发明的另一个实施方案中,R1是氢;R2是CH2F;且R3是甲基。
在由式III表示的本发明的另一个实施方案中,R1是CH2F;R2是氢;且R3是甲基。
在由式III表示的本发明的另一个实施方案中,R1是氢;R2是氢;且R3是CH2F。
在由式III表示的本发明的另一个实施方案中,R1是氢;R2是甲氧基甲基;且R3是甲基。
在由式III表示的本发明的另一个实施方案中,R1是甲氧基甲基;R2是氢;且R3是甲基。
在由式III表示的本发明的另一个实施方案中,R1是氢;R2是氢;且R3是甲氧基甲基。
在式IV表示的一个实施方案中,本发明涉及:
或其药用盐,其中:
R3是C1-C5烷基或C1-C5烷基,其被烷氧基或一个或多个卤原子取代。
在由式II表示的本发明的另一个实施方案中,R3是C1-C5烷基,其被一个或多个卤原子取代。
在由式II表示的本发明的另一个实施方案中,R3是C1-C5烷基,其被一个或多个氟原子取代。
在由式II表示的本发明的另一个实施方案中,R3是甲基,其被一个或多个卤原子取代。
在由式II表示的本发明的另一个实施方案中,R3是甲基,其被一个或多个氟原子取代。在由式II表示的本发明的另一个实施方案中,R3是CH2F。
在由式II表示的本发明的另一个实施方案中,R3是C1-C5烷基,其被烷氧基取代。
在由式II表示的本发明的另一个实施方案中,R3是甲氧基甲基。
在由式II表示的本发明的另一个实施方案中,R3是C1-C5烷基。
在由式II表示的本发明的另一个实施方案中,R3是甲基。
在式V表示的一个实施方案中,本发明涉及:
或其药用盐,其中:
R1选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;
R2选自氢、卤原子、C1-C5烷基和被烷氧基或者一个或多个卤原子取代的C1-C5烷基;
R3是C1-C5烷基或被烷氧基或者一个或多个卤原子取代的C1-C5烷基。
在由式V表示的本发明的一个实施方案中,所述化合物是Z异构体。
在由式V表示的本发明的另一个实施方案中,所述化合物是E异构体。
在由式V表示的本发明的另一个实施方案中,R1是氢原子、卤原子或C1-C5烷基,所述C1-C5烷基任选地被卤原子或烷氧基取代,所述烷氧基任选地被一个或多个卤原子取代;R2是氢、卤原子或C1-C5烷基,所述C1-C5烷基任选地被卤原子或烷氧基取代,所述烷氧基任选地被一个或多个卤原子取代;且R3是C1-C5烷基,所述C1-C5烷基任选地被卤原子或烷氧基取代。
在由式V表示的本发明的另一个实施方案中,R1是氢、卤原子或C1-C3烷基;R2是氢、卤原子或C1-C3烷基;且R3是C1-C5烷基,所述C1-C5烷基任选地被氟或烷氧基取代。
在由式V表示的本发明的另一个实施方案中,R1是氢、卤原子或C1-C3烷基;R2是氢、卤原子或C1-C3烷基;且R3是C1-C3烷基。
在由式V表示的本发明的另一个实施方案中,R1是氢;R2是氢、卤原子或C1-C3烷基;且R3是C1-C3烷基。
在由式V表示的本发明的另一个实施方案中,R1是氢;R2是氢或卤原子;且R3是C1-C3烷基。
在由式V表示的本发明的另一个实施方案中,R1是氢;R2是氢或氟原子;且R3是C1-C3烷基。
在由式V表示的本发明的另一个实施方案中,R1是氢;R2是氢或氟原子;且R3是甲基。
在由式V表示的本发明的另一个实施方案中,R1是氢;R2是氢;且R3是甲基。
在由式V表示的本发明的另一个实施方案中,R1是氢;R2是氟原子;且R3是甲基。
在由式V表示的本发明的另一个实施方案中,R1是卤原子;R2是氢、卤原子或C1-C3烷基;且R3是C1-C3烷基。
在由式V表示的本发明的另一个实施方案中,R1是卤原子;R2是卤原子;且R3是C1-C3烷基。
在由式V表示的本发明的另一个实施方案中,R1是氟原子;R2是氟原子;且R3是甲基。
在由式V表示的本发明的另一个实施方案中,R1是氟原子;R是氢或C1-C3烷基;且R3是甲基。
在由式V表示的本发明的另一个实施方案中,R1是氟原子;R2是氢;且R3是甲基。
在由式V表示的本发明的另一个实施方案中,R1是甲基;R2是氢;且R3是甲基。
在由式V表示的本发明的另一个实施方案中,R1是氢;R2是甲基;且R3是甲基。
在由式V表示的本发明的另一个实施方案中,R1是甲基;W是甲基;且R3是甲基。
在由式V表示的本发明的一个实施方案中:R1是氢、卤原子或C1-C5烷基,所述C1-C5烷基任选地被烷氧基或者一个或多个氟原子取代;R2是氢、卤原子或C1-C5烷基,所述C1-C5烷基任选地被烷氧基或者一个或多个氟原子取代;且R3是甲基,其任选地被一个或多个烷氧基或者卤原子取代。
在由式V表示的本发明的另一个实施方案中,R1是氢或氟原子;R2是C1-C3烷基,其被一个或多个卤原子取代;且R3是甲基。
在由式V表示的本发明的另一个实施方案中,R1是氢;R2是CH2F;且R3是甲基。
在由式V表示的本发明的另一个实施方案中,R1是CH2F;R是氢;且R3是甲基。
在由式V表示的本发明的另一个实施方案中,R1是氢;R2是氢;且R3是CH2F。
在由式V表示的本发明的另一个实施方案中,R1是氢;R2是甲氧基甲基;且R3是甲基。
在由式V表示的本发明的另一个实施方案中,R1是甲氧基甲基;R2是氢;且R3是甲基。
在由式V表示的本发明的另一个实施方案中,R1是氢;R2是氢;且R3是甲氧基甲基。
在式VI表示的一个实施方案中,本发明涉及:
或其药用盐,其中:R3是C1-C5烷基或C1-C5烷基,其被烷氧基或一个或多个卤原子取代。
在由式VI表示的本发明的另一个实施方案中,R3是C1-C5烷基,其被一个或多个卤原子取代。
在由式VI表示的本发明的另一个实施方案中,R3是C1-C5烷基,其被一个或多个氟原子取代。
在由式VI表示的本发明的另一个实施方案中,R3是甲基,其被一个或多个卤原子取代。
在由式VI表示的本发明的另一个实施方案中,R3是甲基,其被一个或多个氟原子取代。在由式VI表示的本发明的另一个实施方案中,R3是CH2F。
在由式VI表示的本发明的另一个实施方案中,R3是C1-C5烷基,其被烷氧基取代。
在由式VI表示的本发明的另一个实施方案中,R3是甲氧基甲基。
在由式VI表示的本发明的另一个实施方案中,R3是C1-C5烷基。
在由式VI表示的本发明的另一个实施方案中,R3是甲基。
本发明还包括含有式I、II、III、IV、V或VI的化合物的药物组合物。
使用式I、II、III、IV、V或VI化合物的方法,包括通过使用治疗有效量的本发明化合物的抑制需要此抑制的患者中氧化氮合成的用途;在需要此抑制的患者中通过使用治疗有效量的式I、II、III、IV、V或VI的化合物,较氧化氮合酶的组成性形式产生氧化氮而言,选择性抑制诱导性氧化氮合酶产生的氧化氮合成的用途;在需要的患者中通过使用治疗有效量的,含有式I、II、III、IV、V或VI化合物的药物组合物,降低有此需要的患者中氧化氮水平的用途;在需要的患者中通过使用治疗有效量的式I、II、III、IV、V或VI的化合物,降低有此需要的患者中氧化氮水平的用途。
本发明化合物也可以有利地与第二种药物活性物质联合使用,特别是与环加氧酶(COX-2)的诱导性异构形式选择性抑制剂联合。因此,在本发明的另一个方面中,本发明提供了本发明的化合物或其药用盐与COX-2抑制剂联合治疗炎症、炎性疾病和与炎症相关疾病的用途。并还为所述疾病或病症的患者或有此危险的对象,提供了治疗和降低炎症、炎性疾病及炎性相关疾病的方法,其中该方法包括给此人使用与COX-2抑制剂联合的治疗有效量的本发明化合物或其药用盐。COX-2抑制剂非限制性地例如Celecoxib Vioxx。NOS抑制剂和COX-2抑制剂也可以一起配制在同一药物组合物中,以独立的单位剂量进行给药;或者各组分可以单独配制为独立药物,可以同时或依次给药。
术语“烷基”,单独或与其它术语联合使用时,指无环烷基,其为直链或支链,含有1至5个或者1至3个碳原子。所述烷基可以任选地被一个或多个卤原子取代。
术语“烷氧基”包括直链或支链的含有氧原子的基团,其具有含1至5碳原子的烷基部分,如甲氧基。此类基团的实例包括甲氧基,乙氧基,丙氧基,丁氧基和叔丁氧基烷基。
术语“卤原子”指卤素如氟原子、氯原子、溴原子或碘原子。
在式I、II、III、IV、V或VI化合物中,还包括其药用盐。术语“药用盐”包括常用来形成碱金属盐和形成游离酸或游离碱的加成盐的盐。盐的性质并不是决定性的,只要可药用即可。式I、II、III、IV、V或VI化合物的适宜的药用酸加成盐,可以由无机酸或有机酸来制备。此类无机酸的实例为氢氯酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸和磷酸。适当的有机酸可以选自脂肪族、环脂肪族、芳香族、芳脂族、杂环、羧酸和磺酸类的有机酸,其实例为甲酸、乙酸、丙酸、琥珀酸、乙醇酸、葡糖酸、乳酸、苹果酸、酒石酸、枸椽酸、抗坏血酸、葡糖醛酸(glucoronic)、马来酸、富马酸、丙酮酸、天门冬氨酸、谷氨酸、苯甲酸、邻氨基苯甲酸、甲磺酸、水杨酸、对羟基苯甲酸、苯乙酸、杏仁酸、扑酸(双羟耐酸)、甲磺酸、乙磺酸、苯磺酸、对氨基苯磺酸、硬脂酸、环己基氨基磺酸、藻酸(algenic)、半乳糖醛酸。式I、II、III、IV、V或VI化合物的适宜的药用碱加成盐,包括由铝、钙、锂、镁、钾、钠和锌制备的金属盐,或者由N,N′-二苄基亚乙基二胺、胆碱、氯普鲁卡因、二乙醇胺、亚乙基二胺、葡甲胺(N-甲基葡糖胺)和普鲁卡因制备的有机盐。所有这些盐可以由相应的式I、II、III、IV、V或VI化合物按照常规方法制备,例如,适当的酸或碱与式I、II、III、IV、V或VI化合物反应。
虽然氮原子保护基示例为叔丁氧羰基或t-BOC,但是可以在本发明化合物合成中可使用任何适宜的氮原子保护基。用于本发明的一些被保护的氨基由Theodora W.Greene和Peter G.M.Wuts进行了描述(有机合成中的保护基,第3版,John Wiley & Sons,New York,1999,pp.494-653)。例如,NZ可以是4-氯苄基亚氨基基团。在本发明的一个实施方案中,被保护的氨基是得自醛与相应的氨基反应形成Schiff碱的任何基团。大量的脱保护试剂可以有利地用于本发明,将中间体转变为所需的化合物。很多此类脱保护试剂由Greene和Wuts作了描述(出处同上)。例如,当被保护的氨基是4-氯苄基亚氨基基团或叔丁氧羰基氨基基团时,优选该脱保护试剂是酸。优选可以利用的酸脱保护试剂非限制性地包括氢氯酸、氢溴酸、硫酸、三氟乙酸、磷酸和乙酸。
当化合物用结构和命名进行描述时,名称要适应所指示的结构,同样该结构要适应给出的名称。
虽然式I、II、III、IV、V或VI的化合物可以以化学原料使用,但是优选以药物组合物的形式。按照另一个方面,本发明提供了含式I、II、III、IV、V或VI的化合物或其药用盐或溶剂化物,及一种或多种药用载体以及任选地存在的一种或多种其它治疗成分的药物组合物。载体(一种或多种)必须与该制剂的其它组分相容且对接受者无毒害。
制剂包括适于口服、非胃肠(包括皮下、真皮内、肌肉内、静脉内和关节内)、直肠和局部(包括皮肤、颊部、舌下和眼内)给药的形式,但最适宜的途经可根据,例如,接受者的病症和疾病而定。这些制剂可以便利地以单位剂型的形式存在,并可以通过制药领域中熟知的任何方法来制备。所有的方法包括将式I、II、III、IV、V或VI的化合物或其药用盐或溶剂化物与载体组配到一起的步骤,载体构成了一种或多种辅助性组分。一般来说,按照如下步骤制备制剂:通过均匀并紧密地将活性组分与液体载体或细分的固体载体(或者需要时二者兼而有之)组配到一起,产品成形为所需的制剂。
适于口服的本发明制剂可以以离散单元的形式存在,如胶囊、小药囊或片剂,其中各含有预定量的活性组分;如散剂或颗粒剂;如存在于水性液体或非水性液体中的溶液剂或混悬剂;或者如水包油乳液或油包水乳液。活性组分也可以以大丸剂、干药糖剂或糊剂的形式存在。
任选地与一种或多种辅助组分一起压制或模铸,可以制备片剂。在适宜的机器中压制自由流动形式如粉末或颗粒状活性组分可以制备压缩片,其中该活性组分任选地与粘合剂、润滑剂、惰性稀释剂、助流剂、表面活性剂或分散剂混合。在适宜的机器中将用惰性液体稀释剂湿润的粉末状化合物进行模铸可以制备模铸片。片剂可以任选地进行包衣或刻痕,并可以进行配制以提供活性组分缓释或控释特性。
非胃肠给药的制剂包括水性和非水性灭菌注射液,其中可以含有抗氧剂、缓冲剂、制菌剂和溶质,该溶质使该制剂与接受者的血液等渗;以及水性和非水性灭菌混悬剂,其中可以含有助悬剂和增稠剂。这些制剂可以存在于单位剂量和多剂量容器中,例如,密封的安瓿和小瓶,并可以在冷冻干燥(冻干)条件下保存,在使用前只需要加入灭菌液体载体,如盐水、注射用水。即配的注射用溶液剂和混悬剂可以由上述类型的灭菌粉末、颗粒剂和片剂制备。
直肠给药的制剂可以是含有常规载体如可可脂或聚乙二醇的栓剂形式。
在口腔中(如颊部或舌下)局部给药的制剂,包括在矫味基质如蔗糖和阿拉伯胶或黄蓍胶中含有活性组分的锭剂,以及在基质如明胶和甘油或者蔗糖和阿拉伯胶中含有活性组分的软锭剂。
优选的单位剂型是含有活性组分的如下文中所述有效量或者其适当部分的。
应理解除了上述具体提及的组分外,根据所述制剂的类型,本发明的制剂可以含有本领域常规的其它制剂,例如,适于口服的制剂可以含有矫味剂。
本发明化合物可以以0.001至2500mg/kg每天的剂量口服或通过注射给药。成人用剂量范围一般味0.005mg至10g/天。以离散单元提供的片剂或其它形式可以便利地含有在该剂量或多个该剂量下有效的本发明化合物的量,例如,含有0.5mg至200mg,通常含有约0.5mg至100mg的单元。
式I、II、III、IV、V或VI的化合物优选口服或通过注射(静脉内或皮下)给药。给患者使用的化合物的实际药量将由主治医师确定。但是,所用剂量应根据一些因素变化,包括患者的年龄和性别、所治疗的疾病及其严重性。另外,给药途径可以根据病症及其严重性而变化。
本发明化合物可以存在互变异构、几何异构或立体异构形式。本发明包括所有此类化合物,包括顺式和反式几何异构体及其混合物、E-和Z-几何异构体及其混合物、R-和S-对映异构体、非对映异构体、d-异构体、1-异构体、其外消旋混合物及其混合物,它们都包括在本发明的范围内。此类互变异构、几何异构或立体异构形式的药用盐也包括在本发明的范围内。
术语“顺式”和“反式”指几何异构的一种形式,其中两个碳原子通过双键连接,其中各具有两个最高等级基团在该双键的同侧(“顺式”或“Z”)或在该双键的相反两侧(“反式”或“E”)。所述的一些化合物含有链烯基,并包括顺式和反式或者“E”和“Z”几何异构体。其它本发明化合物包括顺式/Z和反式/E异构体的混合物。
所述化合物含有立体中心并包括R、S异构体即R和S异构体的混合物。一些所述化合物含有几何异构体并对于所存在的每个立体中心包括E、Z异构体及E和Z异构体的混合物。
下列方案用于实施本发明。其中没有明确异构体时,用适当的色谱方法将得到单一的异构体。
方案1
方案2
方案3
方案4
方案5
方案6
(a)硝基甲烷/碱;b)Zn/乙酸;c)Boc2O,碱;d)DIBAL,低温;e)MsCl,碱;f)碱;g)酸;h)亚氨基乙酸乙酯,碱;i)酸水解。)
方案7
方案8
下列实施例是举例说明,并不是要限定本发明的范围。
实施例1
(E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐
实施例1a)
将DL-丙氨酸乙酯盐酸盐(5g,32.5mmol)悬浮于甲苯(50mL)中。加入三乙胺(4.5mL,32.5mmol),接着加入邻苯二甲酸酐(4.8g,32.5mL)。反应烧瓶装备Dean-Stark收集器和回流冷凝器并将反应混合物加热回流过夜。收集约10mL的甲苯/水。将此反应混合物冷却至室温并用氯化铵水溶液和乙酸乙酯稀释。分层并用乙酸乙酯(3X)萃取水层。乙酸乙酯萃取物用盐水洗涤,用硫酸镁干燥,过滤并真空浓缩得到标题邻苯二甲酰基-保护的氨基酯,为白色结晶固体,接近定量收率。
1H NMR(400MHz,CDCl3,δppm):1.2(t,3H),1.6(d,3H),4.2(m,2H),4.9(q,1H),7.7(m,2H),7.9(m,2H)
实施例1b)
向装有1,4-丁烯二氯(25g,0.2mol)的250mL圆底烧瓶中,加入邻苯二甲酰亚胺钾(18.5g,0.1mol)。将此反应混合物加热至150℃,保持1.5小时。将此混合物冷却至室温并在盐水和乙醚之间分配。有机层用硫酸镁干燥,过滤并真空浓缩。残余物用热乙醇重结晶得到标题1-氯-4-邻苯二甲酰亚胺基丁烯(8.9g,39%),为桔黄色结晶。
HRMS理论值C12H10ClNO2:m/z=236.0478[M+H]。实测值:236.0449
1H NMR(300MHz,CDCl3,δppm):4.1(d,2H),4.3(d,2H),5.9(m,2H),7.7(m,2H),7.9(m,2H)
实施例1c)
将实施例1b产品的样品(2.3g,9.8mmol)溶解于丙酮(50mL)。加入NaI(3.2g,21mmol)并将此混合物回流过夜。冷却至室温后,加入乙醚并将此混合物依次用硫代硫酸钠和盐水洗涤。有机层用硫酸镁干燥,过滤并真空浓缩得到标题碘化物(2.8g,87.5%),为淡黄色固体,其不经进一步纯化而直接使用。
1H NMR(400MHz,CDCl3,δppm):3.8(d,2H),4.2(d,2H),5.7(m,1H),6.0(m,1H),7.7(m,2H),7.9(m,2H)
MS(M+1)=328
实施例1d)
将存在于THF(50mL)中的KHMDS(2.6g,13.3mmol)溶液冷却至-78℃。加入实施例1a产品(2.2g,8.87mmol)的THF(15mL)溶液,此后立即加入1,3-二甲基-3,4,5,6-四氢-2(1H)-嘧啶酮(DMPU,1.0mL,8.87mL)。将此溶液在-78℃下搅拌40分钟后,加入实施例1c(2.9g,8.87mmol)的THF(15mL)溶液。将烧瓶从该冷浴中移出并在室温下搅拌3小时。将此反应混合物在饱和碳酸氢钠水溶液和乙酸乙酯之间分配。有机萃取物用盐水洗涤,用硫酸镁干燥,过滤并真空浓缩得到所需的双-邻苯二甲酰基保护的氨基酯,为黄色固体。将此残余物在硅胶上进行色谱(1∶1己烷∶EtOAc)并得到1.4g(35%)的标题物质,为白色固体。
1H NMR(300MHz,CDCl3,δppm):1.2(t,3H),1.6(d,3H),2.8(dd,1H),3.1(dd,1H),4.2(m,4H),5.6(m,1H),5.8(m,1H),7.6(m,4H),7.7(m,2H),7.9(m,2H)
MS(M+H)=447
实施例1e)
将实施例1d的产物(0.78g,1.76mmol)溶解于甲酸(10mL,95%)和HCl(20mL,浓HCl)的混合物中并回流3天。将此反应混合物冷却至0℃并过滤除去邻苯二甲酸酐。真空浓缩(T<40℃)后,得到标题不饱和的α甲基赖氨酸,为白色固体(0.38g,95%),其不经进一步纯化直接使用。
1H NMR(300MHz,D2O,δppm):1.4(s,3H),2.4(dd,1H),2.6(dd,1H),3.5(d,2H),5.7(m,2H)
MS(M+H)=317
实施例1)
将实施例1e的产物(0.2g,0.86mmol)溶解于H2O(8mL)并用2.5N氢氧化钠调节pH至9。在1小时内,分4批加入亚氨基乙酸乙酯-HCl(0.42g,3.4mmol)。1小时后,将此混合物用10%HCl酸化至pH4并真空浓缩。然后将此残余物通过水洗后的DOWEX 50WX4-200柱(H型,0.5N氢氧化铵洗脱液)。将此残余物真空浓缩,用10%HCl酸化至pH4,并浓缩得到标题产物(17mg,6%),为油状物。
HRMS理论值C9H17N3O2:m/z=200.1399[M+H]。实测值:200.1417
1H NMR(400MHz,D2O,δppm):1.4(s,3H),2.1(s,3H),2.5(dd,1H),2.6(dd,1H),3.8(d,2H),5.6(m,2H)
实施例2
(S,E)-2-氨基-2-甲基-5-氟-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐
实施例3
(S,E)-2-氨基-2-甲基-4-氟-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐
实施例4
(S,E)-2-氨基-2-甲基-4,5-二氟-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐
实施例5
(R,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐
实施例5a)
(2S,4S)-3-苯甲酰基-2-(叔丁基)-4-甲基-1,3-噁唑烷-5-酮按照Seebach的方法制备。见Seebach,D.;Fadel,A.HelveticaChimica Acta 1985,68,1243。
实施例5b)
将KHMDS(0.65g,3.24mmol)、DMPU(0.33mL,2.7mmol)和THF(40mL)的溶液冷却至-78℃。滴加(2S,4S)-3-苯甲酰基-2-(叔丁基)-4-甲基-1,3-噁唑烷-5-酮5a(0.70g,2.7mmol)的THF(10mL)溶液。45分钟后,加入实施例1c产物(0.88g,2.7mmol)的THF(10mL)溶液。将此反应混合物室温下搅拌2小时并用饱和碳酸氢钠水溶液停止反应。分层并用乙酸乙酯萃取水层。合并有机层并用盐水洗涤,用硫酸镁干燥,过滤并真空浓缩。将所得黄色油状物在硅胶上进行色谱(9∶1,然后4∶1己烷/乙酸乙酯)得到标题保护的不饱和α甲基D-赖氨酸(0.26g,20%),为无色油状物。
HRMS理论值C27H28N2O5:m/z=461.2076[M+H]。实测值:461.2033
1H NMR(400MHz,CDCl3,δppm):0.9(s,9H),1.5(s,3H),4.3(m,2H),5.5(m,2H),5.6(m,2H),6.1(m,1H),7.5(m,5H),7.7(m,2H),7.9(m,2H)
实施例5c)
将实施例5b的产物(0.255mg,0.55mmol)溶解于6N HCl(6mL)和甲酸(6mL)并加热回流24小时。将此反应混合物冷却至室温并真空浓缩。将此残余物悬浮于水并用二氯甲烷洗涤。浓缩水层并通过经水洗涤的DOWEX 50WX4-200柱(H型,0.5N氢氧化铵洗脱液)。将此残余物真空浓缩,用10%HCl酸化至pH4,并浓缩得到标题不饱和D-赖氨酸(71mg,55%),为油状物,其不经进一步纯化直接使用。
1H NMR(400MHz,D2O,δppm):1.4(s,3H),2.5(dd,1H),2.6(dd,1H),3.4(d,2H),5.6(m,2H),5.7(m,2H)
实施例5)
将实施例5c的产物(13mg,0.056mmol)溶解于水(5mL)并用2.5N氢氧化钠调节pH至9。在2小时内分4批加入亚氨基乙酸乙酯-HCl(27mg,0.2mmol)。2小时后,用10%盐酸将此混合物酸化至pH4并真空浓缩。将此残余物通过经水洗的DOWEX 50WX4-200柱(H型,0.5N氢氧化铵洗脱液)。将此残余物真空浓缩,用10%HCl酸化至pH4,并浓缩得到标题产物(45mg),为油状物。
HRMS理论值C9H17N3O2:m/z=200.1399[M+H]。实测值:200.1386
1H NMR(400MHz,D2O,δppm):1.4(s,3H),2.1(s,3H),2.5(dd,1H),2.6(dd,1H),3.8(d,2H),5.6(m,2H)
实施例6
(S,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐
实施例6a)
(2R,4R)-3-苯甲酰基-2-(叔丁基)-4-甲基-1,3-噁唑烷-5-酮按照Seebach的方法制备。Seebach,D.;Fadel,A.Helvetica ChimicaActa 1985,68,1243。
实施例6b)
将实施例6a的(2R,4R)-3-苯甲酰基-2-(叔丁基)-4-甲基-1,3-噁唑烷-5-酮产物(2.0g,7.6mmol)的THF(50mL)溶液冷却至-78℃。滴加KHMDS(0.65g,3.24mmol)的THF(25mL)的-78℃溶液。30分钟后,加入实施例1c产物(2.8g,8.6mmol)的THF(25mL)溶液。将此反应混合物室温下搅拌1小时并用饱和碳酸氢钠水溶液停止反应。分层并用乙酸乙酯萃取水层。合并有机层并用盐水洗涤,用硫酸镁干燥,过滤并真空浓缩。将所得桔黄色油状物在硅胶上进行色谱(9∶1,然后4∶1己烷/乙酸乙酯)得到保护的标题不饱和α甲基L-赖氨酸(0.5g,15%),为白色固体。
HRMS理论值C27H28N2O5:m/z=461.2076[M+H]。实测值:461.2043
1H NMR(400MHz,CDCl3,δppm):0.9(s,9H),1.5(s,3H),4.3(m,2H),5.5(m,2H),5.6(m,2H),6.1(m,1H),7.5(m,5H),7.7(m,2H),7.9(m,2H)
实施例6c)
将实施例6b的产物(0.5g,1mmol)溶解于12N HCl(10mL)和甲酸(5mL)中并将此混合物加热回流12小时。将此反应混合物在冰箱中冷却3小时,并过滤移出固体。将此残余物用二氯甲烷和乙酸乙酯洗涤。将此水层真空浓缩并得到标题不饱和α甲基L-赖氨酸(0.26g,99%),为油状物,其不经进一步纯化直接使用。
1H NMR(300MHz,D2O,δppm):1.4(s,3H),2.5(dd,1H),2.6(dd,1H),3.4(d,2H),5.7(m,2H)
实施例6)
将实施例6c的产物(0.13g,0.56mmol)溶解于H2O(1mL)并用2.5N氢氧化钠将pH调节至9。在1小时内分4批加入亚氨基乙酸乙酯-HCl(0.28g,2.2mmol)。1小时后,将此混合物用10%HCl酸化至pH4并真空浓缩。将此残余物通过经水洗涤的DOWEX 50WX4-200柱(0.5N氢氧化铵洗脱液)。将此残余物真空浓缩,用10%HCl酸化至pH4,并浓缩得到标题产物,为油状物(40mg)。
HRMS理论值C9H17N3O2:m/z=222.1218[M+Na]。实测值:222.1213
1H NMR(300MHz,D2O,δppm):1.4(s,3H),2.1(s,3H),2.4(dd,1H),2.6(dd,1H),3.8(d,2H),5.6(m,2H)
实施例7
2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己炔酸,二盐酸盐
实施例7a)
N-boc-1-氨基-4-氯丁-2-炔按照Tetrahedron Lett.21,4263(1980)描述的方法制备。
实施例7b)
N-(二苯基亚甲基)-L-丙氨酸甲酯按照J.Org.Chem.,47,2663(1982)描述的方法制备。
实施例7c)
将干燥的THF(1000mL)置于充满氩气的烧瓶中,并加入分散于矿物油中的60%NaH(9.04g,0.227mol)。向此混合物中加入实施例7b的产物(30.7g,0.114mol)。再将此反应混合物在10℃-15℃搅拌30分钟。加入碘化钾(4g)和碘(2g)并立即加入实施例7a的产物(23g,0.113mol,在200mL THF中),加入时间为30分钟。然后将此反应混合物在55℃下搅拌至起始物消失(约2小时)。再将此反应混合物冷却至室温并蒸发溶剂。加入乙酸乙酯(500mL)并将此混合物小心地用2×200mL去离子水洗涤。有机层用无水硫酸镁干燥,过滤并蒸发得到44g的粗品。用存在于己烷中的20%乙酸乙酯通过色谱进行纯化得到标题保护的不饱和α-甲基赖氨酸(28g,57%)。
元素分析理论值C26H30N2O4和0.5乙酸乙酯:C,70.42;H,7.14;N,5.91。实测值:C,70.95;H,7.73;N,6.09
IR(纯,λmax,cm-1):2981,1714,1631
1H NMR(CDCl3,δppm):1.28(s,9H),1.4(s,3H),2.65-2.76(m,2H),3.15(s,3H),3.7(bs,2H),4.6(bs,1H),6.95-7.4(m,10H)
13C NMR(CDCl3,δppm):24.29,28.33,28.39,33.24,51.60,53.55,127.79,127.97,128.26,128.36,128.43,128.54,128.66,130.05,130.22,132.39
MS(M+1)=435
DSC纯度:261.95℃
实施例7d)
将实施例7c的产物(16g,0.0368mol)溶解于1N HCl(300mL)并在25℃下搅拌保持2小时。将此反应混合物用乙醚(2×150mL)洗涤并分离水层,并用活性炭脱色。浓缩后得到约9g(100%收率)的脱保护的不饱和α赖氨酸甲基酯7d,为白色泡沫状固体。
元素分析理论值C8H14N2O2,含2.26HCl和1.19H2O:C,35.06;H,6.86;N,10.22;Cl,29.24。实测值:C,35.31;H,7.38;N,10.70;Cl,29.77
1H NMR(D2O,δppm):1.56(s,3H),2.8-3.0(2 dt,2H),3.75(s,2H),3.79(s,3H)
13C NMR(D2O,δppm):23.89,29.81,32.05,57.08,61.90,79.57,82.43,173.92
MS(M+1)=171
DSC纯度:114.22℃
UV=206nm,abs 0.013
[α]25在甲醇中=0,在365nm下
实施例7e)
将实施例7d的产物(2.43g,0.01mol)溶解于去离子水(25mL)。在25℃下加入NaOH(400mg,0.01mol)的去离子水(25mL)溶液,将pH调节至约7.95,并再继续搅拌10分钟。将亚氨基乙酸乙酯盐酸盐(988mg,0.008mol)加入到此反应混合物,同时加入1N氢氧化钠调节pH至约8.5。在亚氨基乙酸酯加入后,将此反应混合物在pH8至8.5之间搅拌3小时。将1N HCl加入到此反应混合物(4.1pH)中。在50℃下蒸发溶剂得到黄色粗品易吸潮的残余物(4g,收率>100%)。在Gilson色谱系统上用0.1%AcOH/CH3CN/H2O进行纯化。
元素分析理论值C10H17N3O2含2.25HCl和1.7H2O:C,37.08;H,7.05;N,12.97;Cl,24.63。实测值:C,37.01;H,6.79;N,12.76;Cl,24.87
IR(纯,λmax,cm-1):2953,2569,1747,1681,1631
1H NMR(D2O,δppm):1.52(s,3H),2.12(s,3H),2.74-2.96(2dt,2H),3.75(s,3H),3.95(t,2H)
13C NMR(D2O,δppm):23.89,29.81,32.05,57.08,61.90,79.57,82.43,173.92
MS(M+1)=212
实施例7)
将实施例7e的产物(100mg,0.0005mol)溶解于8N HCl(20mL)并在回流下搅拌10小时。将此反应混合物冷却至室温并用旋转蒸发器蒸发盐酸。将此残余物溶解于去离子水(10mL)和水中,并真空浓缩得到标题产物,为黄色玻璃状固体,几乎是定量收率(88mg)。
元素分析理论值C9H15N3O2含2.4HCl和1.8H2O:C,34.08;H,6.67;N,13.25;Cl,26.83。实测值:C,34.32;H,6.75;N,13.63;Cl,26.47
IR(纯,λmax,cm-1):1738,1677,1628,1587
1H NMR(D2O,δppm):1.6(s,3H),2.24(s,3H),2.8-3.0(2 dt,2H),4.1(s,2H)
13C NMR(D2O,δppm):21.22,24.10,29.88,34.58,80.04,80.99,128.39,168.07,176.13
MS(M+1)=198
实施例8(Z)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐
实施例9(S,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐
实施例9a)
3-甲基-1,2,4-噁二唑-5(4H)-酮的钾盐按照Moussebois,C.,Eloy,F.Helv.Chim.Acta,47(3),838-48,(1964)的描述制备。
实施例9b)
向1L烧瓶中加入反式-1,4-二溴-2-丁烯(50g,0.23mol)和丙酮(500mL)。加入实施例9a的杂环产物(16g,0.12mol),接着加入四正丁基溴化铵(3.9g,0.012mol,0.1当量)。将此反应混合物室温下搅拌18小时,用盐水稀释并用乙酸乙酯萃取。有机萃取物用盐水洗涤,用硫酸镁干燥,过滤并真空浓缩得到黄色半固体残余物。加入二氯甲烷并滤出固体产物。浓缩滤液并将此残余物用热己烷处理以溶解未反应的二溴丁烯。倾析己烷层,并将所得油状物在硅胶上进行色谱,用7∶3己烷/EtOAc洗脱。分离标题产物(14.2g,50%),为黄色油状物。
1H NMR(300MHz,CDCl3,δppm)2.2(s,3H),3.9(d,2H),4.2(d,2H),5.7(dt,1H),5.9(dt,1H)
实施例9c)
向D,L-丙氨酸甲基酯盐酸盐(16.83g,120.5mmol)的二氯甲烷(400mL)浆液中加入三乙胺(16.2mL,116.4mmol),接着加入3,4-二氯苯甲醛(19.07g,109mmol)和MgSO4(20g)。将此浆液室温下搅拌18小时并过滤。滤液用水(250mL)和盐水(250mL)洗涤,干燥(MgSO4)并蒸发,得到27.65g(97%)的所需的亚胺,为油状物。
1H NMR(300MHz,C6D6,δppm):1.40(d,3H),3.32(s,3H),3.81(q,1H),6.82(d,1H),7.18(dd,1H),7.53(d,1H),7.58(s,1H)
实施例9d)
(1S,2S)-(+)Cu(II)C6Salen手性相转移催化剂按照无机化学1996,35,387描述的方法制备。
实施例9e)
在充入N2的烘箱干燥的玻璃器皿中,将甲醇钠(7.3g,134mmol)悬浮于干燥的甲苯(300mL)中。加入实施例9d的手性相转移催化剂产物(800mg,1.9mmol,5%基于亚胺),接着加入实施例9c产物(10g,38.5mmol)在干燥甲苯(50mL)中的溶液。加入实施例9b的产物(10g,42.9mmol)的50mL的甲苯溶液,并将该反应室温下搅拌18小时。再将此反应混合物通过硅藻土垫过滤,除去NaBr和催化剂。将甲苯层用200mL的6N HCl处理40分钟。分层,将甲苯层用200mL的6N HCl的洗涤,并将合并的水层真空干燥。将此残余物用100mL的水稀释并用饱和碳酸钾水溶液调节pH为7。用硅藻土垫滤出固体并将滤液调节为pH9。将此用EtOAc(6X)萃取,用硫酸钠干燥,过滤并真空浓缩得到标题游离碱,为淡绿色油状物(5.77g,59%)。在手性柱(ChiralPak AD,70∶30己烷∶iPrOH,30min)进行色谱纯化,得到产物,比例47∶1(S∶R)。(S tr=12.2min,R tr=16.5min)。
1H NMR(300MHz,CDCl3,δppm):1.4(s,3H),2.2(s,3H),3.7(s,3H),4.2(d,2H),5.6(m,2H)
实施例9f)
(2S,4E)-2-氨基-2-甲基-6(3-甲基-5-氧代-1,2,4-噁二唑-4(5H)-基)己-4-烯酸甲酯的(2S)-羟基(苯基)乙酸盐
向实施例9e产物(2.51g,9.84mmol)的MeOH(40mL)溶液中,加入(S)-(+)-杏仁酸(1.5g,9.84mmol)。将此样品真空浓缩,再用MTBE-MeOH(4∶1)重结晶,得到标题产物,为白色粉末(2.65g,66%)。在手性柱(ChiralPak AD,70∶30己烷∶iPrOH,30min)上进行色谱纯化,显示了99∶1(S∶R)的标题产物。(S tr=12.2min,R tr=16.5min)。
1H NMR(300MHz,CD3OD,δppm):1.5(s,3H),2.2(s,3H),2.6(m,2H),3.8(s,3H),4.2(d,2H),5.6(m,2H),7.2(m,3H),7.6(d,2H)
HRMS理论值C10H19N3O2:m/z=214.1550[M+H]。实测值:214.1525
实施例9g)
(S,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸甲酯的(2S)-羟基(苯基)乙酸,甲酸盐
向500mL烧瓶中,加入Lindlar催化剂(217mg,5wt%,5%Pd在碳酸钙上,用Pb中毒)、MeOH(80mL)和甲酸(2mL,5当量)。加入实施例9f产物(4.34g,10.7mmol)的MeOH(20mL)浆液并将此反应混合物在60℃下加热。4小时后,再加入30mg的Lindlar催化剂和甲酸(200μL)。将此反应混合物与硅藻土成浆,过滤并真空浓缩得到标题物质,为黄色油状物,其不经进一步纯化直接使用(97%)。
元素分析理论值C19H29N3O7含1.3H2O:C,52.48;H,7.32;N,9.66。
实测值:C,52.71;H,7.01;N,9.29
1H NMR(300MHz,D2O,δppm):1.4(s,3H),2.1(s,3H),2.5(m,2H),3.7(s,3H),3.8(d,2H),4.9(s,1H),5.6(m,2H),7.3(m,5H),8.2(s,2H)
HRMS理论值C10H19N3O2:m/z=214.1550[M+H]。实测值:214.1544
实施例9h)
干燥的充入氮气的烧瓶中,加入NaOMe(71.7g,mmol,1.3mol)和干燥的甲苯(2L)。加入实施例9d的催化剂产物(5.88g,15mmol),接着加入实施例9c产物(100g,0.38mol)的200mL甲苯溶液。滴加实施例9b溴化物(100g,0.43mol)的200mL甲苯溶液。在温度维持在25℃的同时,用甲苯和冰醋酸稀释停止反应。室温下搅拌15分钟后,将此反应混合物过滤并将此滤饼用甲苯洗涤。用水稀释此滤液并搅拌1小时。分层并用水洗涤甲苯层。合并水层并真空浓缩。将此残余物溶解于120mL的MeOH中并加入(S)-(+)-杏仁酸。加入热甲基叔丁基醚(450mL),将此溶液冷却至室温并在冰箱中过夜保存。收集标题产物沉淀并用冷甲基叔丁基醚洗涤(43.94g,28%)。在手性柱(ChiralPakAD,70∶30己烷∶iPrOH,30min)上进行色谱纯化,显示标题产物,99∶1(S∶R)。(S tr=12.2min,R tr=16.5min)。
1H NMR(300MHz,CD3OD,δppm):1.5(s,3H),2.2(s,3H),2.6(m,2H),3.8(s,3H),4.2(d,2H),5.6(m,2H),7.2(m,3H),7.6(d,2H)
HRMS理论值C10H19N3O2:m/z=214.1550[M+H]。实测值:214.1525
实施例9i)
将实施例9h产品的样品(36.8g,90mmol)溶解于水(370mL),用饱和碳酸钾水溶液调节pH为9并用二氯甲烷萃取。将有机萃取物真空浓缩得到游离碱。将此残余物溶解于1-丁醇(184mL)、冰醋酸(148mL)和水(184mL)的混合物中。剧烈搅拌反应混合物的条件下加入锌粉(37g,0.57mol),并加热至50℃过夜。用硅藻土过滤此溶液并用甲醇洗涤滤饼。浓缩滤液,溶解于水(250mL)和MeOH(55mL),并用饱和碳酸氢钠水溶液调节pH为8。将此溶液过滤并用6N HCl将滤液pH调节为2,之后将其真空浓缩得到标题物质。
1H NMR(300MHz,D2O,δppm):1.4(s,3H),2.1(s,3H),2.5(m,2H),3.7(s,3H),3.8(d,2H),4.9(s,1H),5.6(m,2H),7.3(m,5H),8.2(s,2H)
HRMS理论值C10H19N3O2:m/z=214.1550[M+H]。实测值:214.1544
实施例9)
将实施例9g产物的样品(8g,20.4mmol)溶解于6N HCl(100mL)并回流3小时。将此溶液真空浓缩得到该氨基酸,将其在Dowex50WX4-200H型离子交换树脂上纯化。用25%HCl洗涤该树脂(120g),接着加入水并调节pH为6。将此化合物在水中上样。该树脂依次用0、1.7、3.3、5、6.6和8.3%HCl洗涤。在5%HCl时开始洗脱出产物。收集馏分,并真空浓缩得到标题产物,为二盐酸盐(4.3g,84%)。
元素分析理论值C9H17N3O2带有2.1HCl和0.1H2O:C,38.94;H,7.01;N,15.14,Cl,26.82。实测值:C,38.68;H,7.17;N,14.74,Cl,27.28
1H NMR(300MHz,D2O,δppm):1.5(s,3H),2.1(s,3H),2.5(dd,1H),2.6(dd,1H),5.6(m,2H)
HRMS理论值C9H17N3O2:m/z=200.1394[M+H]。实测值:200.1371[α]25在H2O中:+17.3,在365nm
实施例10
(2S,4E)-2-氨基-2-甲基-6-(3-甲基-5-氧代-1,2,4-噁二唑-4(5H)-基)己-4-烯酸盐酸盐
将实施例9e产物的样品(0.5g,1.23mmol)溶解于3N HCl(50mL)并回流4小时。将此溶液真空浓缩得到氨基酸,将其在Dowex50WX4-200H型离子交换树脂上纯化。用100mL的25%HCl洗涤该树脂(10g),接着加入300mL的H2O调节至pH6。将此化合物在水中上样,接着加入50mL水。该树脂依次用1.7、3.3、5、6.6和8.3%HCl洗涤。在5%HCl时开始洗脱出产物。收集馏分,并真空浓缩得到标题产物,为二盐酸盐(264mg,88%)。
元素分析理论值C10H15N3O4带有1.1HCl和0.5H2O:C,41.37;H,5.94;N,14.47,Cl,13.43。实测值:C,41.41;H,6.14;N,14.88,Cl,13.14
1H NMR(300MHz,D2O,δppm):1.4(s,3H),2.1(s,3H),2.5(ddd,2H),4.1(d,2H),5.5-5.6(m,2H)
HRMS理论值C10H19N3O2:m/z=214.1550[M+H]。实测值:214.1544
实施例11
(2S,4E)-2-氨基-6-{[(1Z-N-羟基)乙亚胺酰基]氨基}-2-甲基己-4-烯酸
通过加样到Dowex 50WX4-200H型并5%HCl洗涤,将实施例9e产物的样品(1.0g,2.46mmol)转变为游离碱。将洗脱液真空浓缩得到残余物,将其溶解于2.5N NaOH(4mL,9.84mmol,4当量)和4mL的H2O中。4小时后,浓缩该溶液,并用冷水沉淀标题产物(0.215g)。
元素分析理论值C9H17N3O3带有5NaCl:C,21.30;H,3.38;N,8.28,Cl,33.93。实测值:C,20.30;H,3.26;N,7.70,Cl,33.46
1H NMR(400MHz,D2O,δppm):1.3(s,3H),1.8(s,3H),2.4(m,2H),3.7(d,2H),5.4(m,1H),5.6(m,1H)
HRMS理论值C9H17N3O3:m/z=216.1343[M+H]。实测值:216.1354
新的中间体
用于制备本发明化合物的新的中间体包括:
2-(1,3-二氧代-1,3-二氢-2H-异吲哚-2-基)丙酸甲酯
2-[(2E)-4-氯丁-2-烯基]-1H-异吲哚-1,3(2H)-二酮
2-[(2E)-4-碘丁-2-烯基]-1H-异吲哚-1,3(2H)-二酮
(4E)-2,6-双(1,3-二氧代-1,3-二氢-2H-异吲哚-2-基)-2-甲基己-4-烯酸乙酯
(4E)-2,6-二氨基-2-甲基己-4-烯酸,二盐酸盐
2-{(3E)-5-[(2S,4R)-3-苯甲酰基-2-叔丁基-4-甲基-5-氧代-1,3-噁唑烷-4-基]戊-3-烯基}-1H-异吲哚-1,3(2H)-二酮
(2R,4E)-2,7-二氨基-2-甲基庚-4-烯酸,二盐酸盐
2-{(3E)-5-[(2R,4S)-3-苯甲酰基-2-叔丁基-4-甲基-5-氧代-1,3-噁唑烷-4-基]戊-3-烯基}-1H-异吲哚-1,3(2H)-二酮
(2S,4E)-2,7-二氨基-2-甲基庚-4-烯酸,二盐酸盐
2-氨基-6-[(叔丁氧羰基)氨基]-2-甲基己-4-炔酸甲酯与(1-苯基乙烯基)苯(1∶1)的化合物
2,6-二氨基-2-甲基己-4-炔酸甲酯,二盐酸盐
2-氨基-6-(乙亚胺酰基氨基)-2-甲基己-4-炔酸甲酯
3-甲基-1,2,4-噁二唑-5(4H)-酮的钾盐
4-[(2E)-4-溴丁-2-烯基]-3-甲基-1,2,4-噁二唑-5(4H)-酮
N-(2,6-二氯亚苄基)丙氨酸甲酯
(4E)-2-氨基-2-甲基-6-(3-甲基-5-氧代-1,2,4-噁二唑-4(5H)-基)己-4-烯酸甲酯
(2S,4E)-2-氨基-2-甲基-6-(3-甲基-5-氧代-1,2,4-噁二唑-4(5H)-基)己-4-烯酸甲酯(2S)-羟基(苯基)乙酸盐
(S,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸甲酯,二盐酸盐
生物数据
下列试验中的一些或全部用来显示本发明化合物的氧化氮合酶的抑制活性,并显示有利的药学性质。
针对氧化氮合酶的瓜氨酸试验
可以通过监控L-[2,3-3H]-精氨酸向L-[2,3-3H]-瓜氨酸的转化检测氧化氮合酶(NOS)活性(Bredt和Snyder,Proc.Natl.Acad.Sci.U.S.A.,87,682-685,1990及Moore等,J.Med.Chem.,39,669-672,1996)。人诱导性NOS(hiNOS),人内皮组成性NOS(hecNOS)和人神经元组成性NOS(hncNOS)各由人组织提取的RNA克隆。人诱导性NOS(hiNOS)的cDNA分离自λcDNA库,其由提取自溃疡性结肠炎患者结肠样品的RNA制备。人内皮组织性NOS(hecNOS)的cDNA分离自λcDNA库,其由人脐静脉内皮细胞(HUVEC)提取RNA制备,而人神经元组织性NOS(hncNOS)的cDNA分离自λcDNA库,其由得自人尸体的小脑提取的RNA制备。用杆状病毒载体在Sf9昆虫细胞中表达重组酶(Rodi等,氧化氮生物学,Pt.4:Enzymology,Biochemistry andImmunology:Moncada,S.,Feelisch,M.,Busse,R.,HiggS,E.,Eds.;Portland Press Ltd.:London,1995;pp 447-450)。酶活性分离自可溶性细胞提取物并通过DEAE-琼脂糖色谱进行部分纯化。为了检测NOS活性,将10μL酶加入到40μL的50mM Tris(pH7.6)中,其中存在或不存在被测化合物,并通过加入50μL的反应混合物开始反应,反应混合物包括50mM Tris(pH7.6)、2.0mg/mL牛血清白蛋白、2.0mM DTT、4.0mM CaCl2、20μM FAD、100μM四氢生喋呤、0.4mMNADPH和60μM L-精氨酸(其中含0.9μCi的L-[2,3-3H]-精氨酸)。该试验中L-精氨酸的最终浓度是30μM。对于hecNOS或hncNOS,包括钙调蛋白,其最终浓度为40-100nM。在37℃下孵育15分钟后,加入400μL的Dowex 50W X-8阳离子交换树脂(钠型)在停止反应缓冲液(含10mM EGTA、100mM HEPES,pH5.5和1mM L-瓜氨酸)的悬浮液(1份树脂,3份缓冲液)终止反应。混合后,让树脂沉淀并通过液体闪烁计数器计数上清夜的等分部分来测定L-[2,3-3H]-瓜氨酸形成。以若干浓度,可以测定各被测化合物的IC50值。结果见表I,其中为化合物对hiNOS、hecNOS和hncNOS的IC50值。
表I
实施例 | IC50[μM] | ||
hiNOS | hecNOS | hncNOS | |
实施例1 | 2.9 | 29 | 9.9 |
实施例6 | 1.4 | 18 | 5.8 |
实施例5 | 10 | 74 | 31 |
实施例7 | 16 | 86 | 45 |
体内试验
给大鼠腹膜内注射1-12.5mg/kg的内毒素(LPS)诱发诱导性氧化氮合酶的系统表达,结果血浆亚硝酸盐/硝酸盐水平显著升高。使用LPS0.5至1小时前口服化合物,并在使用LPS5小时后测定血浆亚硝酸盐/硝酸盐水平。其结果可以用来表明使用氧化氮合酶抑制剂降低了血浆亚硝酸盐/硝酸盐水平的升高,该水平是内毒素诱导的氧化氮产生的可靠指标。抑制LPS-诱导的血浆亚硝酸盐/硝酸盐水平升高的ED50值(mg/kg)见表II。
表II
在内毒素处理大鼠中测定的实施例的ED50
除非另行说明所有化合物口服给药
实施例 | ED50(mg/kg) |
实施例1 | <3 |
实施例6 | 0.2 |
RAW细胞亚硝酸盐试验
在LPS存在下,在96孔组织培养板上生长过夜(17小时),RAW264.7细胞融合,诱导NOS。3-6孔的一排可以保持不处理并作为对照以从中减掉非特异性背景。从每个孔中可以除去培养基并用含2mg/ml葡萄糖的Kreb-Ringers-Hepes(25mM,pH7.4)洗涤两次。然后,将细胞置于冰上并用含L-精氨酸(30μM)+/-抑制剂的50μL缓冲剂培养1小时。在水浴中将培养板加温至37℃并保持1小时,开始该试验。细胞内iNOS产生的亚硝酸盐与时间成线性关系。为了终止该试验,将细胞的培养板置于冰上,并移出含亚硝酸盐的缓冲液,用公知的检测亚硝酸盐的荧光检测法分析亚硝酸盐(T.P.Misko等,AnalyticalBiochemistry,214,11-16,1993)。
人软骨移植物试验
将骨片用Dulbecco′s磷酸缓冲盐水(GibcoBRL)洗涤两次,并用Dulbecco′s改良Eagles培养基(GibcoBRL)洗涤一次,并置于陪替氏培养皿中,其中加有不含酚红的极限必需培养基(MEM)(GibcoBRL)。将软骨切成约15-45mg重的小移植物,并置于96或48孔培养板中,每孔1或2个移植物,每孔中加有200-500μL培养基。培养基是用Earle′s盐(GibcoBRL)常规改良的极限必需培养基(Eagle),其中不含L-精氨酸、不含L-谷酰胺并不含酚红,或者是血清含量很低Neuman andTytell(GibcoBRL)培养基的常规改良形式,其中不含有L-精氨酸、不含胰岛素、不含抗坏血酸、不含L-谷酰胺并不含酚红。在使用前,都补充100μM L-精氨酸(Sigma)、2mM 1-谷酰胺、1X HL-1添加物(BioWhittaker)、50mg/ml抗坏血酸(Sigma)和150pg/ml重组人IL-1β(RD Systems)以诱发氧化氮合酶。然后,以10μL等分加入化合物,并将移植物在37℃下用5%二氧化碳培养18-24小时。
倾析培养1天的上清液,并换之以含人重组IL-1β和化合物的新鲜培养基,并再培养20-24小时。用荧光分析试验(Misko等,Anal.Biochem.,214,11-16,1993)分析上清液的亚硝酸盐。所有的样本进行一式四份。在不存在重组人IL-1β的培养基中培养作为无刺激的对照组。根据抑制剂的6个不同浓度绘制亚硝酸盐产生的百分抑制曲线来测定IC50(表III)。
表III
实施例号 | IC50[μM] |
实施例1 | 0.5 |
实施例6 | 0.5 |
实施例5 | 1.8 |
时间依赖性抑制试验
评价化合物对人NOS异构形式的时间依赖性抑制:在瓜氨酸酶试验组分(去掉L-精氨酸)存在下,将化合物和该酶在37℃下预孵育0-60分钟。在第0、10、21和60分钟移出样品等分(10μL),并立即加入到含L-[2,3-3H]-精氨酸的瓜氨酸试验酶反应混合物中,且在最终体积100μL中最终L-精氨酸浓度为30μM。让该反应在37℃下进行15分钟,并通过加入上述瓜氨酸NOS试验所述的Dowex 50W X-8阳离子交换树脂停止反应。抑制剂的NOS活性的抑制百分率为,与不存在抑制剂的情况下预孵育相同时间的对照组酶相比,活性方面的抑制百分率。时间依赖性抑制可以显示为随着预孵育时间的增加带来抑制的增加。
Claims (5)
1.式I的化合物或其药用盐:
其中:
R1选自氢或氟;
R2选自氢或氟;而
R3是C1烷基。
2.式III的化合物或其药用盐,
其中:
R1选自氢和氟;
R2选自氢和氟;且
R3是C1烷基。
3.式V的化合物或其药用盐,
其中:
R1选自氢和氟;
R2选自氢和氟;且
R3是C1烷基。
4.选自如下的化合物:
(E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸;
(R,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸;
(S,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸;
2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己炔酸;
(S,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸;
(2S,4E)-2-氨基-6{[(1Z-N-羟基)乙亚胺酰基]氨基}-2-甲基己-4-烯酸;
(E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐;
(R,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐;
(S,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐;
2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己炔酸,二盐酸盐;和
(S,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐。
5.药物组合物,其中含有至少一种选自如下的化合物:
(E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸;
(R,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸;
(S,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸;
2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己炔酸;
(S,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸;
(2S,4E)-2-氨基-6{[(1Z-N-羟基)乙亚胺酰基]氨基}-2-甲基己-4-烯酸;
(E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐;
(R,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐;
(S,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐;
2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己炔酸,二盐酸盐;和
(S,E)-2-氨基-2-甲基-6-[(1-亚氨基乙基)氨基]-4-己烯酸,二盐酸盐。
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US (3) | US6756406B2 (zh) |
EP (1) | EP1317416A2 (zh) |
JP (1) | JP2004509097A (zh) |
KR (1) | KR20030059141A (zh) |
CN (1) | CN1217922C (zh) |
AR (1) | AR031129A1 (zh) |
AU (1) | AU2001289086A1 (zh) |
BR (1) | BR0113890A (zh) |
CA (1) | CA2420007A1 (zh) |
CZ (1) | CZ2003647A3 (zh) |
EA (1) | EA006548B1 (zh) |
IL (1) | IL154842A0 (zh) |
MX (1) | MXPA03002210A (zh) |
NO (1) | NO20031139L (zh) |
NZ (1) | NZ524559A (zh) |
PL (1) | PL366028A1 (zh) |
WO (1) | WO2002022559A2 (zh) |
ZA (1) | ZA200301576B (zh) |
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US8022058B2 (en) | 2000-05-10 | 2011-09-20 | The Trustees Of Columbia University In The City Of New York | Agents for preventing and treating disorders involving modulation of the RyR receptors |
US20040048780A1 (en) * | 2000-05-10 | 2004-03-11 | The Trustees Of Columbia University In The City Of New York | Method for treating and preventing cardiac arrhythmia |
US7393652B2 (en) | 2000-05-10 | 2008-07-01 | The Trustees Of Columbia University In The City Of New York | Methods for identifying a chemical compound that directly enhances binding of FKBP12.6 to PKA-phosphorylated type 2 ryanodine receptor (RyR2) |
US7718644B2 (en) | 2004-01-22 | 2010-05-18 | The Trustees Of Columbia University In The City Of New York | Anti-arrhythmic and heart failure drugs that target the leak in the ryanodine receptor (RyR2) and uses thereof |
US20040229781A1 (en) * | 2000-05-10 | 2004-11-18 | Marks Andrew Robert | Compounds and methods for treating and preventing exercise-induced cardiac arrhythmias |
US20060293266A1 (en) * | 2000-05-10 | 2006-12-28 | The Trustees Of Columbia | Phosphodiesterase 4D in the ryanodine receptor complex protects against heart failure |
US6489125B1 (en) * | 2000-05-10 | 2002-12-03 | The Trustees Of Columbia University In The City Of New York | Methods for identifying chemical compounds that inhibit dissociation of FKBP12.6 binding protein from type 2 ryanodine receptor |
US7879840B2 (en) | 2005-08-25 | 2011-02-01 | The Trustees Of Columbia University In The City Of New York | Agents for preventing and treating disorders involving modulation of the RyR receptors |
AR031129A1 (es) * | 2000-09-15 | 2003-09-10 | Pharmacia Corp | Derivados de los acidos 2-amino-2-alquil-4-hexenoico y -hexinoico utiles como inhibidores de oxido nitrico sintetasa |
BR0310061A (pt) * | 2002-05-16 | 2005-03-01 | Pharmacia Corp | Métodos para o tratamento de doenças e condições respiratórias com um inibidor seletivo da inos e um inibidor da pde e suas composições |
MXPA05001255A (es) * | 2002-08-02 | 2005-06-08 | Pharmacia Corp | Metodos para el tratamiento y prevencion de condiciones gastrointestinales. |
US7544678B2 (en) | 2002-11-05 | 2009-06-09 | The Trustees Of Columbia University In The City Of New York | Anti-arrythmic and heart failure drugs that target the leak in the ryanodine receptor (RyR2) |
JP2007525165A (ja) | 2003-03-07 | 2007-09-06 | トラスティーズ・オブ・コロンビア・ユニバーシティ・イン・ザ・シティ・オブ・ニューヨーク | タイプ1ライアノジン受容体に基づく方法 |
US8710045B2 (en) | 2004-01-22 | 2014-04-29 | The Trustees Of Columbia University In The City Of New York | Agents for preventing and treating disorders involving modulation of the ryanodine receptors |
WO2005110396A2 (en) | 2004-04-28 | 2005-11-24 | Uab Research Foundation | Nitrated lipids and methods of making and using thereof |
US7740849B2 (en) * | 2004-09-24 | 2010-06-22 | Beth Israel Deaconess Medical Center | Use of compounds that bind soluble endoglin and SFLT-1 for the treatment of pregnancy related hypertensive disorders |
DE602005024850D1 (de) * | 2004-09-24 | 2010-12-30 | Beth Israel Hospital | Verfahren zur diagnose und behandlung von schwangerschaftsskomplikationen |
US7704990B2 (en) | 2005-08-25 | 2010-04-27 | The Trustees Of Columbia University In The City Of New York | Agents for preventing and treating disorders involving modulation of the RyR receptors |
US20090286271A1 (en) * | 2006-05-31 | 2009-11-19 | Karumanchi Ananth S | Methods of Diagnosing and Treating Complications of Pregnancy |
EP2679224A1 (en) | 2007-08-01 | 2014-01-01 | University of Pittsburgh of the Commonwealth System of Higher Education | Nitro oleic acid modulation of type II diabetes |
EP2280928B1 (en) | 2008-05-01 | 2018-07-25 | Complexa Inc. | Vinyl substituted fatty acids |
CN102099024B (zh) | 2008-06-19 | 2015-11-25 | 犹他大学研究基金会 | 硝化脂质在毒性医疗疗法的副作用的治疗上的用途 |
US20140024713A1 (en) | 2008-06-19 | 2014-01-23 | University Of Utah Research Foundation | Use of nitrated lipids for treatment of side effects of toxic medical therapies |
KR20120016053A (ko) * | 2009-05-14 | 2012-02-22 | 코오롱생명과학 주식회사 | 알킬아민 유도체의 제조방법 |
EP2459189A4 (en) | 2009-07-31 | 2013-01-16 | Univ Pittsburgh | FATTY ACIDS AS ANTI-INFLAMMATORY ACTIVE SUBSTANCES |
CA2781276A1 (en) | 2009-10-02 | 2011-04-07 | Complexa, Inc. | Heteroatom containing substituted fatty acids |
WO2013028501A1 (en) | 2011-08-19 | 2013-02-28 | The University Of Utah Research Foundation | Combination therapy with nitrated lipids and inhibitors of the renin-angiotensin-aldosterone system |
EP4335497A3 (en) | 2015-07-07 | 2024-05-01 | H. Lundbeck A/S | Pde9 inhibitor with imidazo pyrazinone backbone for treatment of peripheral diseases |
GB201512635D0 (en) | 2015-07-17 | 2015-08-26 | Ucl Business Plc | Uses of therapeutic compounds |
MX2018004043A (es) | 2015-10-02 | 2018-11-09 | Complexa Inc | Prevencion, tratamiento y reversion de enfermedad usando cantidades terapeuticamente efectivas de acidos grasos activados. |
EP3398941A1 (en) * | 2017-05-03 | 2018-11-07 | AXXAM S.p.A. | Heterocyclic p2x7 antagonists |
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US5132453A (en) | 1991-03-22 | 1992-07-21 | Cornell Research Foundation, Inc. | N6 -(hydrazinoiminomethyl)lysine and method of inhibiting nitric oxide formation in body |
JP2648897B2 (ja) | 1991-07-01 | 1997-09-03 | 塩野義製薬株式会社 | ピリミジン誘導体 |
GB9127376D0 (en) * | 1991-12-24 | 1992-02-19 | Wellcome Found | Amidino derivatives |
GB9203347D0 (en) | 1992-02-17 | 1992-04-01 | Wellcome Found | Hypolipidaemic compounds |
ATE188467T1 (de) * | 1994-03-24 | 2000-01-15 | Searle & Co | Amidino-derivative als no-synthese-inhibitoren |
US5994391A (en) | 1994-09-13 | 1999-11-30 | G.D. Searle And Company | Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
GB9516709D0 (en) | 1995-08-15 | 1995-10-18 | Zeneca Ltd | Medicament |
HUP0101467A3 (en) * | 1998-03-11 | 2003-03-28 | G D Searle & Co Skokie | Halogenated amidino amino acid derivatives useful as nitric monoxide synthase inhibitors |
DE69926903T2 (de) | 1998-10-27 | 2006-07-13 | Abbott Laboratories, Abbott Park | Prostaglandin endoperoxyde h synthase biosynthese inhibitoren |
AR031129A1 (es) * | 2000-09-15 | 2003-09-10 | Pharmacia Corp | Derivados de los acidos 2-amino-2-alquil-4-hexenoico y -hexinoico utiles como inhibidores de oxido nitrico sintetasa |
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- 2001-09-14 AR ARP010104367A patent/AR031129A1/es unknown
- 2001-09-15 WO PCT/US2001/028733 patent/WO2002022559A2/en not_active Application Discontinuation
- 2001-09-15 AU AU2001289086A patent/AU2001289086A1/en not_active Abandoned
- 2001-09-15 NZ NZ524559A patent/NZ524559A/xx unknown
- 2001-09-15 BR BR0113890-1A patent/BR0113890A/pt not_active IP Right Cessation
- 2001-09-15 CA CA002420007A patent/CA2420007A1/en not_active Abandoned
- 2001-09-15 KR KR10-2003-7003788A patent/KR20030059141A/ko not_active Application Discontinuation
- 2001-09-15 PL PL01366028A patent/PL366028A1/xx not_active Application Discontinuation
- 2001-09-15 US US09/952,906 patent/US6756406B2/en not_active Expired - Fee Related
- 2001-09-15 IL IL15484201A patent/IL154842A0/xx unknown
- 2001-09-15 EP EP01968875A patent/EP1317416A2/en not_active Withdrawn
- 2001-09-15 CZ CZ2003647A patent/CZ2003647A3/cs unknown
- 2001-09-15 EA EA200300375A patent/EA006548B1/ru not_active IP Right Cessation
- 2001-09-15 CN CN018187587A patent/CN1217922C/zh not_active Expired - Fee Related
- 2001-09-15 JP JP2002526760A patent/JP2004509097A/ja not_active Withdrawn
- 2001-09-15 MX MXPA03002210A patent/MXPA03002210A/es active IP Right Grant
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2003
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2005
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Also Published As
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AR031129A1 (es) | 2003-09-10 |
WO2002022559A2 (en) | 2002-03-21 |
MXPA03002210A (es) | 2003-06-24 |
US20050256199A1 (en) | 2005-11-17 |
KR20030059141A (ko) | 2003-07-07 |
NO20031139D0 (no) | 2003-03-12 |
US7005450B2 (en) | 2006-02-28 |
EA200300375A1 (ru) | 2003-10-30 |
ZA200301576B (en) | 2004-03-08 |
US6756406B2 (en) | 2004-06-29 |
PL366028A1 (en) | 2005-01-24 |
WO2002022559A3 (en) | 2003-01-23 |
AU2001289086A1 (en) | 2002-03-26 |
CZ2003647A3 (cs) | 2003-10-15 |
EA006548B1 (ru) | 2006-02-24 |
EP1317416A2 (en) | 2003-06-11 |
NO20031139L (no) | 2003-05-09 |
US20040192779A1 (en) | 2004-09-30 |
NZ524559A (en) | 2004-12-24 |
BR0113890A (pt) | 2003-07-22 |
CA2420007A1 (en) | 2002-03-21 |
JP2004509097A (ja) | 2004-03-25 |
IL154842A0 (en) | 2003-10-31 |
CN1474804A (zh) | 2004-02-11 |
US20020128510A1 (en) | 2002-09-12 |
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