CN1301966C - 用作氧化氮合酶抑制剂的2-氨基-2-烷基-5-庚烯酸和庚炔酸衍生物 - Google Patents
用作氧化氮合酶抑制剂的2-氨基-2-烷基-5-庚烯酸和庚炔酸衍生物 Download PDFInfo
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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Classifications
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Abstract
本发明涉及2-氨基-2-烷基-5-庚烯酸和庚炔酸衍生物和它们在治疗中的用途,尤其是它们作为氧化氮合酶抑制剂的用途。
Description
相关申请的交叉参考
本申请要求2000年9月15日提交的美国临时申请系列号60/232,683的权益。
技术领域
本发明涉及2-氨基-2-烷基-5-庚烯酸和庚炔酸衍生物和它们在治疗中的用途,尤其是它们作为氧化氮合酶抑制剂的用途。
相关技术
自20世纪80年代初期以来,人们就已知乙酰胆碱引起的血管舒张与血管内皮有关。现已知为氧化氮(NO)的内皮衍生的舒张因子(EDRF)在血管内皮中通过氧化氮合酶(NOS)产生。对作为血管舒张剂的NO活性的深入了解已有100多年。此外,NO是衍生自亚硝酸异戊酯、甘油三硝酸酯和其它硝基血管舒张剂的活性物质。将EDRF鉴定为NO这一结果与合成NO的生物化学途径的发现一致,通过该途径,经NO合酶,由氨基酸L-精氨酸合成NO。
一氧化氮是可溶性鸟苷酸环化酶的内生刺激物。除内皮依赖性舒张外,NO还与多种生物作用有关,包括吞噬细胞的细胞毒性和中枢神经系统内细胞与细胞间的通讯。
至少有如下三种类型的NO合酶:
(i)位于内皮的、组成性Ca++/钙调蛋白依赖酶,它对受体或物理刺激作出反应而释放NO。
(ii)位于大脑的、组成性Ca++/钙调蛋白依赖酶,它对受体或物理刺激作出反应而释放NO。
(iii)在血管平滑肌、巨噬细胞、内皮细胞及大量的其它细胞被内毒素和细胞因子激活后诱导的不依赖于Ca++的酶,一旦被表达,这种诱导型氧化氮合酶(此后称为“iNOS”)可在长时期内连续地产生NO。
由两种组成酶各自释放的NO作为几种生理学响应基础的转导机制。由诱导酶产生的NO为肿瘤细胞和侵入微生物的细胞毒性分子。过量NO产生的副作用,尤其是病理血管舒张和组织损伤,似乎大部分由iNOS合成的NO所引起。
越来越多的证据表明,NO可能涉及到因某种疾病如关节炎引起的软骨变性,并且还知道在类风湿性关节炎和骨关节炎中,NO合成增多。
所提出的用于治疗的部分NO合酶抑制剂是非选择性的;它们抑制组成性和诱导型NO合酶。这类非选择性NO合酶抑制剂的使用需极为小心,以避免过分抑制组成性NO合酶的潜在严重后果,这样的后果包括高血压和可能的血栓形成和组织损伤。特别是在用L-NMMA(非选择性NO合酶抑制剂)治疗中毒性休克时,建议在整个疗程中必须对患者连续地进行血压监测。因此,虽然非选择性NO合酶抑制剂具有治疗功用的前提是要采取适当的预防措施,但NO合酶抑制剂在如下意义上说是有选择性的,它们对诱导型NO合酶的抑制远大于对NO合酶的组成同工型的抑制,因而它们甚至具有更大的治疗益处且更易于使用(S.Moncada和E.Higgs,FASEB J.,9,1319-1330,1995)。
PCT国际公布号WO 93/13055和美国专利号5,132,453(其公开通过引用全文结合到本文中,如同写入本文中一样)公开了抑制一氧化氮合成并优先抑制氧化氮合酶的诱导同工型的化合物。
PCT国际公布号WO 95/25717公开了某些用于抑制诱导型氧化氮合酶的脒基衍生物。
已进行多种尝试,试图通过将一个或者多个刚性元素引入抑制剂的结构来改善NOS抑制剂的效力和选择性。由Y.Lee等(Bioorg.Med.Chem.7,1097(1999))和R.J.Young等(Bioorg.Med.Chem.Lett.10,597(2000))的出版物教导采用具有一个或者更多个碳-碳双键的构象刚性并非是产生对NOS抑制剂的选择性的良好办法。
发明概述
目前已发现了在人体软骨外植体试验(一种用于骨关节炎的模型)中具有非常有效的优点的化合物。
本发明证实碳-碳双键可以用作刚性元素,而得到的化合物对抑制诱导型NOS具有意想不到的效力和选择性。
此外,Y.Lee等(Bioorg.Med.Chem.7,1097(1999))的出版物叙述了当碳-碳双键用于限制精氨酸骨架时,以顺式或Z取向定位碳骨架的几何异构体与NOS产生较小的有利的相互作用。作为对照,以反式或E构型定位碳骨架的精氨酸的烯烃衍生物是更好的底物。本发明证实,碳-碳双键产生与诱导型NOS的有利的相互作用,这使得生成的化合物对于抑制诱导型NOS具有超过组成性同工型的意想不到的效力和选择性。
而且,本发明的化合物作为iNOS抑制剂,在用于骨关节炎的模型的人体软骨外植体试验中具有非常有效的优点。同时,本发明的化合物在试验系统中令人意外地很少能够渗透到某些非-靶器官内,特别是在与WO 93/13055的化合物比较时。这个在预期进入靶器官(软骨)和其他器官之间的令人惊讶的区别是本发明化合物的意想不到的优点。
在一个广义的方面,本发明的化合物由下式或其药学上可接受的盐表示:
其中:
R1为卤代基、C1-C5烷基或被烷氧基或一个或多个卤代基取代的C1-C5烷基;
R2为氢、卤代基、C1-C5烷基或被烷氧基或一个或多个卤代基取代的C1-C5烷基;和
R3为C1-C5烷基或被烷氧基或一个或多个卤代基取代的C1-C5烷基。
在一个由式I代表的实施方案中,本发明涉及式I化合物或其药学上可接受的盐:
其中:
R1为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;和
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在一个由式II代表的实施方案中,本发明涉及式II化合物或其药学上可接受的盐:
其中:
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在一个由式III代表的实施方案中,本发明涉及下式的化合物或其药学上可接受的盐:
其中:
R1为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;和
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在一个由式IV代表的实施方案中,本发明涉及下式的化合物或其药学上可接受的盐:
其中:
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在一个由式V代表的实施方案中,本发明涉及下式的化合物或其药学上可接受的盐:
其中:
R1为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;和
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在一个由式VI代表的实施方案中,本发明涉及式VI化合物或其药学上可接受的盐:
其中:
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在一个广义的方面,本发明涉及新的化合物、药用组合物、制备新化合物的方法、制备药用组合物的方法以及用所述化合物和组合物抑制或者调节需要此种抑制或调节的患者的一氧化氮合成的方法,该方法包括给予相对于氧化氮合酶的组成同工型可优先抑制或调节氧化氮合酶的诱导同工型的化合物。本发明的另一个目的是降低需要此种降低的患者的一氧化氮的水平。本发明化合物具有有用的氧化氮合酶抑制活性,并预期可用于其中一氧化氮的合成或过分合成为部分病因的疾病或病症的治疗或预防。
除此之外,本发明的化合物将用于治疗患者的炎症,或治疗其它氧化氮合酶介导的疾病,例如作为治疗疼痛和头痛的镇痛药。本发明的化合物将用于治疗包括急性和慢性躯体原(感受伤害的或神经病的)疼痛在内的疼痛,并且能够用于包括传统给予普通NSAID、类阿片镇痛药或某些抗惊厥剂的神经病疼痛在内的病症。
其中本发明的化合物将提供在抑制从L-精氨酸产生NO方面的优点的病症包括关节炎病症。例如,本发明的化合物将用来治疗关节炎,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、神经病性关节炎、牛皮癣性关节炎和化脓性关节炎。
本发明的化合物将进一步用于治疗哮喘、支气管炎、月经痉挛(例如,痛经)、早产、腱炎、粘液囊炎、与皮肤有关的病症如银屑病、湿疹、灼伤、晒斑、皮炎、胰腺炎、肝炎和术后炎症包括眼外科手术如白内障手术和屈光手术后的炎症。本发明的化合物也可用于治疗胃肠疾病如炎症性肠病、Crohn病、胃炎、过敏性大肠综合征和溃疡性结肠炎。
本发明的化合物将用于治疗如下疾病中的炎症和组织损伤,这类疾病有血管病、偏头痛、结节性动脉外膜炎、甲状腺炎、再生障碍性贫血、Hodgkin病、硬皮病(sclerodoma)、风湿热、I型糖尿病、神经肌接点病包括重症肌无力、白质病包括多发性硬化、肉样瘤病、肾病综合征、Behcet综合征、多肌炎、龈炎、肾炎、过敏性、损伤后肿胀、心肌缺血等。这些化合物也可用于治疗眼病,如青光眼、视网膜炎、视网膜病、眼色素层炎、眼畏光症及与眼组织急性损伤相关的炎症和疼痛。本发明化合物的用途中特别重要的是治疗青光眼,尤其是由一氧化氮的产生引起的青光眼的症状,如一氧化氮介导的神经损伤。这些化合物也可用于治疗肺炎,如与病毒感染和囊性纤维化有关的肺炎。这些化合物还可用于治疗某些中枢神经系统疾病,如包括Alzheimer病在内的皮质性痴呆(cortical dementias)及由中风、局部缺血和创伤引起的中枢神经系统损伤。这些化合物也可用于治疗变应性鼻炎、呼吸窘迫综合征、内毒素性休克综合征和动脉粥样硬化。所述化合物还可用于治疗疼痛,包括但不限于术后疼痛、牙痛、肌肉痛、temperoramandibular关节综合征引起的疼痛及癌症引起的疼痛。所述化合物将用于预防痴呆如Alzheimer病。
除用于人类治疗外,这些化合物也可用于陪伴动物、外来动物和农畜,包括哺乳动物和其它脊椎动物的兽医治疗。更优选的动物包括马、狗和猫。
本发明化合物也可,例如与类固醇、NSAIDs、COX-2选择性抑制剂、基质金属蛋白酶抑制剂、5-脂氧化酶抑制剂、LTB4拮抗剂和LTA4水解酶抑制剂一起用于联合治疗,部分或完全地代替其它常规抗炎治疗。
其中本发明化合物将提供抑制NO抑制作用的优点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、主动脉瘤、回流性食管炎、腹泻、过敏性大肠综合征、囊性纤维化、肺气肿、哮喘、支气管扩张、痛觉过敏(异常性疼痛)、脑局部缺血(双病灶缺血、血栓性中风和全身性缺血(例如,继发性心搏停止))、多发性硬化和由NO介导的其它中枢神经系统疾病,如Parkinson病。其中NO抑制可能有用的其它神经变性疾病包括在如下疾病中的神经变性或神经坏死,这些疾病有缺氧、低血糖、癫痫及在中枢神经系统(CNS)创伤的情况(如脊髓和头部创伤)、高压氧惊厥和中毒、痴呆如早老性痴呆和与AIDS相关的痴呆、恶病质、Sydenham舞蹈病、Huntington舞蹈病、肌萎缩侧索硬化、Korsakoff病、与大脑血管疾病有关的痴愚、睡眠障碍、精神分裂症、抑郁症、与经前期综合征(PMS)有关的抑郁症或其它症状、焦虑症和败血症性休克。
可用本发明化合物有利地治疗的其它疾病或病症还包括对长期需要阿片镇痛药的患者的鸦片剂耐受性及用苯并二氮杂_类的患者的苯并二氮杂_类耐受性,和其它成瘾行为,如尼古丁瘾、酒精中毒和进食障碍的治疗或预防。本发明的化合物和方法也可用于药物戒断综合症状的治疗或预防,如鸦片瘾、酒瘾或烟瘾的戒断症状的治疗或预防。当与抗菌药或抗病毒药联合治疗时,本发明的化合物还可用于预防组织损伤。
本发明的化合物还可用于抑制由L-精氨酸产生NO,包括与由许多种药物诱发的脓毒性和/或毒性出血性休克有关的系统性低血压;用细胞因子如TNF、IL-1和IL-2的治疗;和移植治疗中,作为短期免疫抑制的辅药。
本发明的化合物用于预防或治疗癌症,如结肠直肠癌、乳癌、肺癌、前列腺癌、膀胱癌、宫颈癌和皮肤癌。本发明进一步涉及本发明化合物治疗和预防瘤形成的用途。可用本发明的化合物和方法治疗或预防的瘤形成包括脑癌、骨癌、白血病如慢性淋巴白血病、淋巴瘤、上皮细胞衍生的瘤形成(上皮癌)如基底细胞癌、腺癌、胃肠癌如唇癌、口腔癌、食管癌、小肠癌和胃癌、结肠癌、肝癌、膀胱癌、胰腺癌、尿生殖癌如卵巢癌、宫颈癌、外阴癌和肺癌、乳癌和皮肤癌,如扁平细胞癌、黑素瘤和基底细胞癌、前列腺癌、肾细胞癌及其它影响全身上皮细胞的已知癌症。本发明化合物也有效用于治疗间质衍生的瘤形成。优选所治疗的瘤形成选自胃肠癌、肝癌、膀胱癌、胰腺癌、卵巢癌、前列腺癌、宫颈癌、外阴癌、肺癌、乳癌和皮肤癌,如扁平细胞癌和基底细胞癌。本发明的化合物和方法也可用于治疗放射疗法引起的纤维化。本发明的化合物和方法可用来治疗患有腺瘤性息肉的患者,包括患家族腺瘤性息肉病(FAP)的患者。另外,本发明化合物和方法可用于预防有FAP风险的患者形成息肉。
本发明化合物与另一种抗肿瘤药的联合治疗,将通过减少疗效所需但引起副作用的药物的治疗剂量,或者通过直接减轻引起副作用的药物产生的毒副作用的症状,产生协同作用或者降低与化疗有关的毒副作用。本发明的化合物还可用作放射治疗的辅助剂,以减少副作用或增加效果。在本发明中,可与本发明的化合物联合治疗的另一种药物包括能抑制环氧合酶-2(“COX-2”)的任何治疗药物。优选此种COX-2抑制剂相对环氧合酶-1(“COX-1”)而言可选择性地抑制COX-2。这种COX-2抑制剂称作“COX-2选择性抑制剂”。更优选,在体外试验中,本发明的化合物可与COX-2选择性抑制剂联合治疗,其中的COX-2选择性抑制剂以相对于对COX-1的抑制至少10∶1,更优选至少30∶1,甚至更优选至少50∶1的比例选择性地抑制COX-2。用于与本发明的化合物联合治疗的COX-2选择性抑制剂包括塞来考昔、伐地考昔、deracoxib,艾托考昔、罗非考昔,ABT-963(2-(3,4-二氟苯基)-4-(3-羟基-3-甲基-1-丁氧基)-5-[4-(甲磺酰基)苯基-3(2H)-哒嗪酮;描述于PCT专利申请号WO 00/24719),或美洛昔康。本发明的化合物也可有利地用于与COX-2选择性抑制剂的前药如帕瑞考昔的联合治疗。
例如,可从下面选择能用于与本发明的化合物联用的另一化疗药,所列药物并非包罗一切,并且是非限定性的:
α-二氟甲基鸟氨酸(DFMO)、5-FU-血纤维蛋白原、acanthifolicacid、氨基噻二唑、布喹那钠、卡莫氟、Ciba-Geigy CGP-30694、环戊基胞嘧啶、磷酸硬脂酸阿糖胞苷、阿糖胞苷轭合物、Lilly DATHF、Merrel Dow DDFC、地扎呱宁、双脱氧胞苷、双脱氧鸟苷、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’-呋喃烷基(furanidyl))-5-氟尿嘧啶、Daiichi Seiyaku FO-152、isopropylpyrrolizine、Lilly LY-188011、Lilly LY-264618、methobenzaprim、甲氨蝶呤、Wellcome MZPES、norspermidine、NCI NSC-127716、NCINSC-264880、NCI NSC-39661、NCI NSC-612567、Warner-LambertPALA、喷司他丁、吡曲克辛、普卡霉素、Asahi Chemical PL-AC、TakedaTAC-788、硫鸟嘌呤、噻唑呋林、Erbamont TIF、三甲曲沙、酪氨酸激酶抑制剂、酪氨酸蛋白激酶抑制剂、Taiho UFT、uricvtin、Shionogi254-S、氧代-磷酰胺类似物、六甲蜜胺、阿那昔酮、Boehringer MannheimBBR-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、AmericanCyanamid CL-286558、Sanofi CY-233、cyplatate、Degussa D-19-384、Sumimoto DACHP(Myr)2、二苯螺莫司汀(diphenylspiromustine)、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 GYKI-17230、hepsul-fam、异环磷酰胺、异丙铂、洛莫司汀、马磷酰胺、二溴卫矛醇、Nippon Kayaku NK-121、NCINSC-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&F-101772、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、四铂、trimelamol、Taiho 4181-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、NipponSoda茴香霉素、蒽环霉素、阿嗪霉素-A、bisucaberin、Bristol-MyersBL-6859、Bristol-Myers BMY-25067、Bristol-Myers BMY-25551、Bristol-Myers BMY-26605、Bristol-Myers BMY-27557、Bristol-MyersBMY-28438、硫酸博来霉素、苔藓抑素1、Taiho C-1027、calichemycin、chromoximycin、放线菌素D、柔红霉素、Kyowa Hakko DC-102、KyowaHakko DC-79、Kyowa Hakko DC-88A、Kyowa Hakko DC89-A1、KyowaHakko DC92-B、蒽环霉素B、Shionogi DOB-41、多柔比星、多柔比星-纤维蛋白原、elsamicin-A、表柔比星、erbstatin、依索比星、esperamicin-A1、esperamicin-A1b、Erbamont FCE-21954、FujisawaFK-973、福司曲星、Fujisawa FR-900482、滑行菌素、gregatin-A、grincamycin、除莠霉素、伊达比星、隐杯伞素、kazusamycin、kesarirhodins、Kyowa Hakko KM-5539、Kirin Brewery KRN-8602、Kyowa Hakko KT-5432、Kyowa Hakko KT-5594、Kyowa Hakko KT-6149、American Cyanamid LL-D49194、Meiji Seika ME2303、美诺立尔、丝裂霉素、米托蒽醌、SmithKline M-TAG、neoenactin、NipponKayaku NK-313、Nippon Kayaku NKT-01、SRI International NSC-357704、_溶菌素、oxaunomycin、培洛霉素、pilatin、吡柔比星、porothramycin、pyrindamycin A、Tobishi RA-I、雷帕霉素、根霉素、罗多比星、西班米星、siwenmycin、Sumitomo SM-5887、Snow BrandSN-706、Snow Brand SN-07、sorangicin-A、司帕霉素、SS PharmaceuticalSS-21020、SS Pharmaceutical SS-7313B、SS Pharmaceutical SS-9816B、司替霉素B、Taiho 4181-2、他利霉素、Takeda TAN-868A、terpentecin、thrazine、tricrozarin A、Upiohn U-73975、Kyowa Hakko 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、Kyorin AHC-52、鸡骨常山碱、氨萘非特、amphethinile、安吖啶、Angiostat、ankinomycin、抗瘤酮A10、抗瘤酮A2、抗瘤酮A3、抗瘤酮A5、抗瘤酮AS2-1、Henkel APD、阿非迪霉素甘氨酸盐、天冬酰胺酶、Avarol、baccharin、batracylin、苯氟伦、苯佐色氨酸、Ipsen-Beaufour BIM-23015、比生群,Bristo-Myers BMY-40481、Vestar boron-10、bromofosfamide、Wellcome BW-502、Wellcome BW-773、卡醋胺、盐酸carmethizole、Ajinomoto CDAF、chlorsulfaquinoxalone、Chemex CHX-2053、ChemexCHX-100、Warner-Lambert CI-921、Warner-Lambert CI-937、Warner-Lambert CI-941、Warner-Lambert CI-958、克兰氟脲、claviridenone、ICN化合物1259、ICN化合物4711、Contracan、Yakult Honsha
CPT-11、克立那托、curaderm、松胞素B、阿糖胞苷、cytocytin、MerzD-609、马来酸DABIS、达卡巴嗪、达替氯铵、didemnin-B、双血卟啉醚(dihaematoporphyrin ether)、二氢仑派隆、地那林、偏端霉素、ToyoPharmar DM-341、Toyo Pharmar DM-75、Daiichi Seiyaku DN-9693、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、ChugaiGLA-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A酸、Otsuka JI-36、Ramot K-477、OtsuakK-76COONa、Kureha Chemical K-AM、MECT Corp KI-8110、AmericanCyanamid L-623、白细胞调节素、氯尼达明、Lundbeck LU-23-112、Lilly LY-186641、NCI(US)MAP、marycin、Merrel Dow MDL-27048、Medco MEDR-340、麦尔巴隆、部花青衍生物、甲基苯胺基吖啶、Molecular Genetics MGI-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、TaishoNCU-190、诺考达唑衍生物、精氨酸血红素、NCI NSC-145813、NCINSC-361456、NCI NSC-604782、NCI NSC-95580、奥曲肽、OnoONO-112、oquizanocine、Akzo Org-10172、pancratistatin、帕折普汀、Warner-Lambert PD-111707、Warner-Lambert PD-115934、Warner-Lambert PD-131141、Pierre Fabre PE-1001、ICRT肽D、吡罗蒽醌、多血卟啉、polypreic acid、Efamol卟啉、probimane、丙卡巴肼、丙谷胺、Invitron蛋白酶连接蛋白I,Tobishi RA-700、雷佐生、SapporoBreweries RBS、restrictin-P、瑞替普汀、视黄酸、Rhone-Poulenc RP-49532、Rhone-Poulenc RP-56976、SmithKline SK&F-104864、SumitomoSM-108、Kuraray SMANCS、SeaPharm SP-10094、spatol、螺环丙烷衍生物、锗螺胺、Unimed、SS Pharmaceutical SS-554、strypoldinone、Stypoldione、Suntory SUN 0237、Suntory SUN 2071、超氧化物歧化酶、Toyama T-506、Toyama T-680、泰素、Teijin TEI-0303、替尼泊苷、thaliblastine、Eastman Kodak TJB-29、生育三烯酚、Topostin、TeijinTT-82、Kyowa Hakko UCN-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、YamanouchiYM-534、uroguanylin、考布他汀、多拉司他汀、伊达比星、表柔比星、雌莫司汀、环磷酰胺、9-氨基-2-(S)-喜树碱、托泊替康、伊立替康(Camptosar)、依西美坦、达必佳(曲普瑞林)、或一种ω-3脂肪酸。
可用于与本发明的化合物联合治疗的放射保护剂的实例包括AD-5、adchnon、氨磷汀类似物、detox、地美司钠、1-102、MM-159、N-酰化-去氢丙氨酸、TGF-Genentech、噻丙莫德、氨磷汀、WR-151327、FUT-187、经皮酮洛芬、萘丁美酮、超氧化物歧化酶(Chiron)及超氧化物歧化酶Enzon。
本发明的化合物也可用于治疗或预防与血管生成相关的疾病或病症,例如,瘤的生长、转移、黄斑变性和动脉粥样硬化。
在另一实施方案中,本发明也提供治疗或预防眼病或眼疾如青光眼的联合治疗方法。例如,本发明的化合物将有利地用于与降低患青光眼的患者的眼内压的药物一起联合治疗。这类降低眼内压的药物包括(但不限于)拉坦前列素、曲伏前列素、比马前列素或乌诺前列醇(unoprostol)。本发明的化合物加上一种降低眼内压药物的联合治疗将是有用的,因为认为它们各自通过不同的机理发挥其作用。
在本发明的另一联合治疗方案中,本发明的化合物可用于与降高血脂药物或降胆固醇药物如benzothiepine或苯并噻氮_苯并噻氮_降高血脂药一起的联合治疗。用于本发明的联合治疗的benzothiepine降高血脂药的实例可在美国专利第5,994,391号中找到,该文献通过引用结合到本文中。某些苯并噻氮_降高血脂药描述于WO 93/16055。或者,用于与本发明化合物联合的降高血脂药物或降胆固醇药物可为HMG Co-A还原酶抑制剂。用于本发明的联合治疗的HMG Co-A还原酶抑制剂的实例分别包括苯氟雷司、氟伐他汀、洛伐他汀、普伐他汀、辛伐他汀、阿托伐他汀、西立伐他汀、贝伐他汀、ZD-9720(描述于PCT专利申请号WO 97/06802)、ZD-4522(对于钙盐为CAS第147098-20-2号;对钠盐为CAS第147098-18-8号;描述于欧洲专利第EP 521471号)、BMS 180431(CAS第129829-03-4号)或NK-104(CAS第141750-63-2号)。本发明化合物加上降高血脂药物或降胆固醇药物的联合治疗可用于,例如,降低在血管中形成动脉粥样硬化损害的危险。例如,动脉粥样硬化损害往往最初发生于血管中的发炎部位。已确认降高血脂药物或降胆固醇药物通过降低血液中的脂质水平来减少形成动脉粥样硬化损害的危险。本发明并不限于单一作用机理,但是相信本发明化合物作用的一种方式是通过例如同时降低血脂水平和减少血管中的炎症,提供了对动脉粥样硬化损害的更有效的控制。
在本发明的另一实施方案中,本发明化合物可用于与其它化合物或治疗方法联合治疗中枢神经病症或疾病如偏头痛。例如,本发明化合物可用于与咖啡因、5-HT-1B/1D激动剂(例如,曲普坦如舒马普坦、那拉曲坦、佐米曲普坦、利扎曲普坦、阿莫曲普坦或夫罗曲普坦)、多巴胺D4拮抗剂(例如,索奈哌唑)、阿司匹林、对乙酰氨基酚、布洛芬、吲哚美辛、萘普生钠、异美汀、氯醛比林、布他比妥、麦角生物碱(如麦角胺、二氢麦角胺、溴隐亭、麦角新碱或甲麦角新碱)、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、纳多洛尔或美托洛尔)或单胺氧化酶抑制剂(例如,苯乙肼或异卡波肼)一起联合治疗。
另一实施方案提供本发明的化合物与类阿片化合物一起的联合治疗。可用于该联合治疗的类阿片化合物包括(但不限于)吗啡、美沙酮、氢吗啡酮、羟吗啡酮、左啡诺、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、羟考酮、纳美芬、埃托啡、左啡诺、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、烯丙吗啡、喷他佐辛、纳布啡、纳洛酮苯甲酰腙、布马佐辛、乙基酮基环佐辛、U50,488、U69,593、螺朵林、nor-binaltorphimine、纳屈吲哚、DPDPE、[D-la2,glu4]deltorphin、DSLET、甲硫脑啡呔、亮脑啡肽(leu-enkaphalin)、β-内啡肽、强啡肽A、强啡肽B及α-新内啡肽。本发明与一种类阿片化合物的联合的一个优点是本发明的化合物可减少类阿片化合物的剂量,因而降低类阿片副作用如类阿片成瘾的风险或者严重性。
发明详述
在一个广义的方面,本发明的化合物由下式或其药学上可接受的盐表示:
其中:
R1为氢、卤代基、C1-C5烷基或被烷氧基或一个或多个卤代基取代的C1-C5烷基;
R2为氢、卤代基、C1-C5烷基或被烷氧基或一个或多个卤代基取代的C1-C5烷基;和
R3为C1-C5烷基或被烷氧基或一个或多个卤代基取代的C1-C5烷基。
在一个由式I代表的实施方案中,本发明涉及式I化合物或其药学上可接受的盐:
其中:
R1为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;和
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在由式I代表的本发明的一个实施方案中,所述化合物为Z异构体。
在由式I代表的本发明的另一个实施方案中,所述化合物为E异构体。
在由式I代表的本发明的另一个实施方案中,R1为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;R2为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;而R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代。
在由式I代表的本发明的另一个实施方案中,R1为氢、卤代基或C1-C3烷基;R2为氢、卤代基或C1-C3烷基;及R3为C1-C5烷基,所述C1-C5烷基任选由氟或烷氧基取代。
在由式I代表的本发明的另一个实施方案中,R1为氢、卤代基或C1-C3烷基;R2为氢、卤代基或C1-C3烷基;及R3为C1-C3烷基。
在由式I代表的本发明的另一个实施方案中,R1为氢;R2为氢、卤代基或C1-C3烷基;及R3为C1-C3烷基。
在由式I代表的本发明的另一个实施方案中,R1为氢;R2为氢或卤代基;及R3为C1-C3烷基。
在由式I代表的本发明的另一个实施方案中,R1为氢;R2为氢或氟;及R3为C1-C3烷基。
在由式I代表的本发明的另一个实施方案中,R1为氢;R2为氢或氟;及R3为甲基。
在由式I代表的本发明的另一个实施方案中,R1为氢;R2为氢;及R3为甲基。
在由式I代表的本发明的另一个实施方案中,R1为氢;R2为氟;及R3为甲基。
在由式I代表的本发明的另一个实施方案中,R1为卤代基;R2为氢、卤代基或C1-C3烷基;及R3为C1-C3烷基。
在由式I代表的本发明的另一个实施方案中,R1为卤代基;R2为卤代基;及R3为C1-C3烷基。
在由式I代表的本发明的另一个实施方案中,R1为氟;R2为氟;及R3为甲基。
在由式I代表的本发明的另一个实施方案中,R1为氟;R2为氢或C1-C3烷基;及R3为甲基。
在由式I代表的本发明的另一个实施方案中,R1为氟;R2为氢;及R3为甲基。
在由式I代表的本发明的另一个实施方案中,R1为甲基;R2为氢;及R3为甲基。
在由式I代表的本发明的另一个实施方案中,R1为氢;R2为甲基;及R3为甲基。
在由式I代表的本发明的另一个实施方案中,R1为甲基;R2为甲基;及R3为甲基。
在由式I代表的本发明的另一个实施方案中,R1为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由烷氧基或一个或多个氟取代;R2为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由烷氧基或一个或多个氟取代;及R3为任选由一个或多个烷氧基或卤代基取代的甲基。
在由式I代表的本发明的另一个实施方案中,R1为氢或氟;R2为由一个或多个卤代基取代的C1-C3烷基;及R3为甲基。
在由式I代表的本发明的另一个实施方案中,R1为氢;R2为CH2F;及R3为甲基。
在由式I代表的本发明的另一个实施方案中,R1为CH2F;R2为氢;及R3为甲基。
在由式I代表的本发明的另一个实施方案中,R1为氢;R2为氢;及R3为CH2F。
在由式I代表的本发明的另一个实施方案中,R1为氢;R2为甲氧基甲基;及R3为甲基。
在由式I代表的本发明的另一个实施方案中,R1为甲氧基甲基;R2为氢;及R3为甲基。
在由式I代表的本发明的另一个实施方案中,R1为氢;R2为氢;及R3为甲氧基甲基。
在由式II代表的一个实施方案中,本发明涉及
或其药学上可接受的盐,其中:
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在由式II代表的本发明的另一个实施方案中,R3为由一个或多个卤代基取代的C1-C5烷基。
在由式II代表的本发明的另一个实施方案中,R3为由一个或多个氟取代的C1-C5烷基。
在由式II代表的本发明的另一个实施方案中,R3为由一个或多个卤代基取代的甲基。
在由式II代表的本发明的另一个实施方案中,R3为由一个或多个氟取代的甲基。
在由式II代表的本发明的另一个实施方案中,R3为CH2F。
在由式II代表的本发明的另一个实施方案中,R3为由烷氧基取代的C1-C5烷基。
在由式II代表的本发明的另一个实施方案中,R3为甲氧基甲基。
在由式II代表的本发明的另一个实施方案中,R3为C1-C5烷基。
在由式II代表的本发明的另一个实施方案中,R3为甲基。
在由式III代表的一个实施方案中,本发明涉及
或其药学上可接受的盐,其中:
R1为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;和
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在由式III代表的本发明的一个实施方案中,所述化合物为Z异构体。
在由式III代表的本发明的另一个实施方案中,所述化合物为E异构体。
在由式III代表的本发明的另一个实施方案中,R1为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;R2为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;及R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代。
在由式III代表的本发明的另一个实施方案中,R1为氢、卤代基或C1-C3烷基;R2为氢、卤代基或C1-C3烷基;及R3为C1-C5烷基,所述C1-C5烷基任选由氟或烷氧基取代。
在由式III代表的本发明的另一个实施方案中,R1为氢、卤代基或C1-C3烷基;R2为氢、卤代基或C1-C3烷基;及R3为C1-C3烷基。
在由式III代表的本发明的另一个实施方案中,R1为氢;R2为氢、卤代基或C1-C3烷基;及R3为C1-C3烷基。
在由式III代表的本发明的另一个实施方案中,R1为氢;R2为氢或卤代基;及R3为C1-C3烷基。
在由式III代表的本发明的另一个实施方案中,R1为氢;R2为氢或氟;及R3为C1-C3烷基。
在由式III代表的本发明的另一个实施方案中,R1为氢;R2为氢或氟;及R3为甲基。
在由式III代表的本发明的另一个实施方案中,R1为氢;R2为氢;及R3为甲基。
在由式III代表的本发明的另一个实施方案中,R1为氢;R2为氟;及R3为甲基。
在由式III代表的本发明的另一个实施方案中,R1为卤代基;R2为氢、卤代基或C1-C3烷基;及R3为C1-C3烷基。
在由式III代表的本发明的另一个实施方案中,R1为卤代基;R2为卤代基;及R3为C1-C3烷基。
在由式III代表的本发明的另一个实施方案中,R1为氟;R2为氟;及R3为甲基。
在由式III代表的本发明的另一个实施方案中,R1为氟;R2为氢或C1-C3烷基;及R3为甲基。
在由式III代表的本发明的另一个实施方案中,R1为氟;R2为氢;及R3为甲基。
在由式III代表的本发明的另一个实施方案中,R1为甲基;R2为氢;及R3为甲基。
在由式III代表的本发明的另一个实施方案中,R1为氢;R2为甲基;及R3为甲基。
在由式III代表的本发明的另一个实施方案中,R1为甲基;R2为甲基;及R3为甲基。
在由式III代表的本发明的另一个实施方案中,R1为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由烷氧基或一个或多个氟取代;R2为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由烷氧基或一个或多个氟取代;及R3为任选由一个或多个烷氧基或卤代基取代的甲基。
在由式III代表的本发明的另一个实施方案中,R1为氢或氟;R2为由一个或多个卤代基取代的C1-C3烷基;及R3为甲基。
在由式III代表的本发明的另一个实施方案中,R1为氢;R2为CH2F;及R3为甲基。
在由式III代表的本发明的另一个实施方案中,R1为CH2F;R2为氢;及R3为甲基。
在由式III代表的本发明的另一个实施方案中,R1为氢;R2为氢;及R3为CH2F。
在由式III代表的本发明的另一个实施方案中,R1为氢;R2为甲氧基甲基;及R3为甲基。
在由式III代表的本发明的另一个实施方案中,R1为甲氧基甲基;R2为氢;及R3为甲基。
在由式III代表的本发明的另一个实施方案中,R1为氢;R2为氢;及R3为甲氧基甲基。
在由式IV代表的一个实施方案中,本发明涉及:
或其药学上可接受的盐,其中:
R3为C1-C5烷基或由烷氧基或一个或多个卤代基取代的C1-C5烷基。
在由式IV代表的本发明的另一个实施方案中,R3为由一个或多个卤代基取代的C1-C5烷基。
在由式IV代表的本发明的另一个实施方案中,R3为由一个或多个氟取代的C1-C5烷基。
在由式IV代表的本发明的另一个实施方案中,R3为由一个或多个卤代基取代的甲基。
在由式IV代表的本发明的另一个实施方案中,R3为由一个或多个氟取代的甲基。
在由式IV代表的本发明的另一个实施方案中,R3为CH2F。
在由式IV代表的本发明的另一个实施方案中,R3为由烷氧基取代的C1-C5烷基。
在由式IV代表的本发明的另一个实施方案中,R3为甲氧基甲基。
在由式IV代表的本发明的另一个实施方案中,R3为C1-C5烷基。
在由式IV代表的本发明的另一个实施方案中,R3为甲基。
在由式V代表的一个实施方案中,本发明涉及:
或其药学上可接受的盐,其中:
R1为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;及
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在由式V代表的本发明的一个实施方案中,所述化合物为Z异构体。
在由式V代表的本发明的另一个实施方案中,所述化合物为E异构体。
在由式V代表的本发明的另一个实施方案中,R1为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;R2为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;及R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代。
在由式V代表的本发明的另一个实施方案中,R1为氢、卤代基或C1-C3烷基;R2为氢、卤代基或C1-C3烷基;及R3为C1-C5烷基,所述C1-C5烷基任选由氟或烷氧基取代。
在由式V代表的本发明的另一个实施方案中,R1为氢、卤代基或C1-C3烷基;R2为氢、卤代基或C1-C3烷基;及R3为C1-C3烷基。
在由式V代表的本发明的另一个实施方案中,R1为氢;R2为氢、卤代基或C1-C3烷基;及R3为C1-C3烷基。
在由式V代表的本发明的另一个实施方案中,R1为氢;R2为氢或卤代基;及R3为C1-C3烷基。
在由式V代表的本发明的另一个实施方案中,R1为氢;R2为氢或氟;及R3为C1-C3烷基。
在由式V代表的本发明的另一个实施方案中,R1为氢;R2为氢或氟;及R3为甲基。
在由式V代表的本发明的另一个实施方案中,R1为氢;R2为氢;及R3为甲基。
在由式V代表的本发明的另一个实施方案中,R1为氢;R2为氟;及R3为甲基。
在由式V代表的本发明的另一个实施方案中,R1为卤代基;R2为氢、卤代基或C1-C3烷基;及R3为C1-C3烷基。
在由式V代表的本发明的另一个实施方案中,R1为卤代基;R2为卤代基;及R3为C1-C3烷基。
在由式V代表的本发明的另一个实施方案中,R1为氟;R2为氟;及R3为甲基。
在由式V代表的本发明的另一个实施方案中,R1为氟;R2为氢或C1-C3烷基;及R3为甲基。
在由式V代表的本发明的另一个实施方案中,R1为氟;R2为氢;及R3为甲基。
在由式V代表的本发明的另一个实施方案中,R1为甲基;R2为氢;及R3为甲基。
在由式V代表的本发明的另一个实施方案中,R1为氢;R2为甲基;及R3为甲基。
在由式V代表的本发明的另一个实施方案中,R1为甲基;R2为甲基;及R3为甲基。
在由式V代表的本发明的另一个实施方案中,R1为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由烷氧基或一个或多个氟取代;R2为氢、卤代基或C1-C5烷基,所述C1-C5烷基任选由烷氧基或一个或多个氟取代;及R3为任选由一个或多个烷氧基或卤代基取代的甲基。
在由式V代表的本发明的另一个实施方案中,R1为氢或氟;R2为由一个或多个卤代基取代的C1-C3烷基;及R3为甲基。
在由式V代表的本发明的另一个实施方案中,R1为氢;R2为CH2F;及R3为甲基。
在由式V代表的本发明的另一个实施方案中,R1为CH2F;R2为氢;及R3为甲基。
在由式V代表的本发明的另一个实施方案中,R1为氢;R2为氢;及R3为CH2F。
在由式V代表的本发明的另一个实施方案中,R1为氢;R2为甲氧基甲基;及R3为甲基。
在由式V代表的本发明的另一个实施方案中,R1为甲氧基甲基;R2为氢;及R3为甲基。
在由式V代表的本发明的另一个实施方案中,R1为氢;R2为氢;及R3为甲氧基甲基。
在由式VI代表的一个实施方案中,本发明涉及:
或其药学上可接受的盐,其中:
R3为C1-C5烷基或由烷氧基或一个或多个卤代基取代的C1-C5烷基。
在由式VI代表的本发明的另一个实施方案中,R3为由一个或多个卤代基取代的C1-C5烷基。
在由式VI代表的本发明的另一个实施方案中,R3为由一个或多个氟取代的C1-C5烷基。
在由式VI代表的本发明的另一个实施方案中,R3为由一个或多个卤代基取代的甲基。
在由式VI代表的本发明的另一个实施方案中,R3为由一个或多个氟取代的甲基。
在由式VI代表的本发明的另一个实施方案中,R3为CH2F。
在由式VI代表的本发明的另一个实施方案中,R3为由烷氧基取代的C1-C5烷基。
在由式VI代表的本发明的另一个实施方案中,R3为甲氧基甲基。
在由式VI代表的本发明的另一个实施方案中,R3为C1-C5烷基。
在由式VI代表的本发明的另一个实施方案中,R3为甲基。
本发明的另一个实施方案在于式VII化合物:
或其药学上可接受的盐,其中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;及
R5选自卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在由式VII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5选自卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代。
在由式VII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢和卤代基;及
R5选自卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代。
在由式VII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在由式VII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5为C1-C5烷基,所述C1-C5烷基任选由一个或多个取代基取代。
在由式VII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;及
R5为卤代基。
在由式VII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;及
R5为氟。
在由式VII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5为由卤代基取代的C1-C5烷基。
在由式VII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5为CH2F。
在由式VII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为氢;及
R5为CH2F。
在由式VII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为卤代基;及
R5为卤代基。
在由式VII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为氟;及
R5为卤代基。
在由式VII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为氟;及
R5为氟。
在由式VII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为氢;及
R5为甲基。
本发明的另一个实施方案在于式VIII化合物:
或其药学上可接受的盐,其中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;及
R5选自卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在由式VIII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5选自卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代。
在由式VIII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢和卤代基;及
R5选自卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代。
在由式VIII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在由式VIII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5为C1-C5烷基,所述C1-C5烷基任选由一个或多个卤代基取代。
在由式VIII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;及
R5为卤代基。
在由式VIII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;及
R5为氟。
在由式VIII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5为由卤代基取代的C1-C5烷基。
在由式VIII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5为CH2F。
在由式VIII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为氢;及
R5为CH2F。
在由式VIII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为卤代基;及
R5为卤代基。
在由式VIII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为氟;及
R5为卤代基。
在由式VIII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为氟;及
R5为氟。
在由式VIII代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为氢;及
R5为甲基。
本发明的另一个实施方案在于式IX化合物:
或其药学上可接受的盐,其中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;及
R5选自卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在由式IX代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5选自卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代。
在由式IX代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢和卤代基;及
R5选自卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代。
在由式IX代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代。
在由式IX代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5为C1-C5烷基,所述C1-C5烷基任选由一个或多个取代基取代。
在由式IX代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;及
R5为卤代基。
在由式IX代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;及
R5为氟。
在由式IX代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5为由卤代基取代的C1-C5烷基。
在由式IX代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代;及
R5为CH2F。
在由式IX代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为氢;及
R5为CH2F。
在由式IX代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为卤代基;及
R5为卤代基。
在由式IX代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为氟;及
R5为卤代基。
在由式IX代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为氟;及
R5为氟。
在由式IX代表的本发明的另一个实施方案中:
R1选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R2选自氢、卤代基和C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R3为C1-C5烷基,所述C1-C5烷基任选由卤代基或烷氧基取代,所述烷氧基任选由一个或多个卤代基取代;
R4为氢;及
R5为甲基。
本发明也包括药用组合物,它包括式I、II、III、IV、V、VI、VII、VIII或IX的化合物。
使用式I、II、III、IV、V、VI、VII、VIII或IX的化合物的方法包括在需要此种抑制的患者中,通过给予治疗有效量的本发明化合物来抑制一氧化氮合成的应用;在需要此种抑制的患者中,通过给予治疗有效量的式I、II、III、IV、V或VI的化合物,选择性地抑制由诱导型氧化氮合酶产生的一氧化氮合成,而超过对由组成型氧化氮合酶产生的一氧化氮合成的抑制;通过给予治疗有效量的式I、II、III、IV、V、VI、VII、VIII或IX的化合物,在有此需要的患者中降低一氧化氮水平;通过给予治疗有效量的包含式I、II、III、IV、V、VI、VII、VIII或IX化合物的药用组合物,在有此需要的患者中降低一氧化氮水平。
除此之外,本发明的化合物将用于治疗患者的炎症,或治疗其它氧化氮合酶介导的疾病,例如作为治疗疼痛和头痛的镇痛药,或者作为治疗发热的解热剂。例如,本发明的化合物将用来治疗关节炎,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、神经病性关节炎、牛皮癣性关节炎和化脓性关节炎。其中本发明的化合物将提供在抑制由L-精氨酸产生NO方面的优点的病症包括关节炎病症。
本发明的化合物将进一步用于治疗哮喘、支气管炎、月经痉挛(例如,痛经)、早产、腱炎、粘液囊炎、与皮肤有关的病症如银屑病、湿疹、灼伤、晒斑、皮炎、胰腺炎、肝炎和术后炎症包括眼外科手术如白内障手术和屈光手术后的炎症。本发明的化合物也可用于治疗胃肠疾病如炎症性肠病、Crohn病、胃炎、过敏性大肠综合征和溃疡性结肠炎。本发明的化合物将用于预防或治疗癌症,如结肠直肠癌、乳癌、肺癌、前列腺癌、膀胱癌、宫颈癌和皮肤癌。本发明的化合物将用于治疗如下疾病中的炎症和组织损伤,这类疾病有血管病、偏头痛、结节性动脉外膜炎、甲状腺炎、再生障碍性贫血、Hodgkin病、硬皮病、风湿热、I型糖尿病、神经肌接点病包括重症肌无力、白质病包括多发性硬化、肉样瘤病、肾病综合征、Behcet综合征、多肌炎、龈炎、肾炎、过敏性、损伤后肿胀、心肌缺血等。这些化合物也可用于治疗眼病,如青光眼、视网膜炎、视网膜病、眼色素层炎、眼畏光症及与眼组织急性损伤相关的炎症和疼痛。本发明化合物的用途中特别重要的是治疗青光眼,尤其是由一氧化氮的产生引起的青光眼的症状,如一氧化氮介导的神经损伤。这些化合物也可用于治疗肺炎,如与病毒感染和囊性纤维化有关的肺炎。这些化合物还可用于治疗某些中枢神经系统疾病,如包括Alzheimer病在内的皮质性痴呆及由中风、局部缺血和创伤引起的中枢神经系统损伤。本发明的化合物可用作具有显著降低的有害副作用的附加优点的抗炎药,例如用于治疗关节炎。这些化合物也可用于治疗变应性鼻炎、呼吸窘迫综合征、内毒素性休克综合征和动脉粥样硬化。所述化合物还可用于治疗疼痛,但不限于术后疼痛、牙痛、肌肉痛及癌症引起的疼痛。所述化合物将用于预防痴呆如Alzheimer病。
除用于人类治疗外,这些化合物也可用于陪伴动物、外来动物和农畜,包括哺乳动物、啮齿动物等的兽医治疗。更优选的动物包括马、狗和猫。
本发明化合物也可以与例如类固醇、NSAIDs、COX-2选择性抑制剂、5-脂氧化酶抑制剂、LTB4拮抗剂和LTA4水解酶抑制剂一起用于联合治疗,部分或完全地代替其它常规抗炎治疗。
其中本发明化合物将提供抑制NO抑制作用的优点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、主动脉瘤、回流性食管炎、腹泻、过敏性大肠综合征、囊性纤维化、肺气肿、哮喘、支气管扩张、痛觉过敏(异常性疼痛)、脑局部缺血(双病灶缺血、血栓性中风和全身性缺血(例如,继发性心搏停止))、多发性硬化和由NO介导的其他中枢神经系统疾病,如Parkinson病。其中NO抑制可能有用的其它神经变性疾病包括在如下疾病中的神经变性或神经坏死,这些疾病有缺氧、低血糖、癫痫及在中枢神经系统(CNS)创伤的情况(如脊髓和头部创伤)、高压氧惊厥和中毒、痴呆如早老性痴呆和与AIDS相关的痴呆、恶病质、Sydenham舞蹈病、Huntington舞蹈病、肌萎缩侧索硬化、Korsakoff病、与大脑血管疾病有关的痴愚、睡眠障碍、精神分裂症、抑郁症、与经前期综合征(PMS)有关的抑郁症或其它症状、焦虑症和败血症性休克。
本发明的化合物将用于治疗包括急性和慢性躯体原(感受伤害的或神经病的)疼痛在内的疼痛。一氧化氮抑制剂可用于包括传统给予普通NSAID或类阿片镇痛药的神经病疼痛在内的病症。
可用本发明化合物有利地治疗的其它疾病或病症还包括对长期需要阿片镇痛药的患者的鸦片剂耐受性及用苯并二氮杂_类的患者的苯并二氮杂_类耐受性,和其它成瘾行为,如尼古丁瘾、酒精中毒和进食障碍的治疗或预防。本发明的化合物和方法也可用于药物戒断综合症状的治疗或预防,如鸦片瘾、酒瘾或烟瘾的戒断症状的治疗或预防。当与抗菌药或抗病毒药联合治疗时,本发明的化合物还可用于预防组织损伤。
本发明的化合物还可用于抑制由L-精氨酸产生NO,包括与由许多种药物诱发的脓毒性和/或毒性出血性休克有关的系统性低血压;用细胞因子如TNF、IL-1和IL-2的治疗;和移植治疗中,作为短期免疫抑制的辅药。
本发明进一步涉及本发明化合物治疗和预防瘤形成的用途。可用本发明的化合物和方法治疗或预防的瘤形成包括脑癌、骨癌、白血病、淋巴瘤、上皮细胞衍生的瘤形成(上皮癌)如基底细胞癌、腺癌、胃肠癌如唇癌、口腔癌、食管癌、小肠癌和胃癌、结肠癌、肝癌、膀胱癌、胰腺癌、卵巢癌、宫颈癌、肺癌、乳癌和皮肤癌,如扁平细胞癌和基底细胞癌、前列腺癌、肾细胞癌及其它影响全身上皮细胞的已知癌症。优选所述瘤形成选自胃肠癌、肝癌、膀胱癌、胰腺癌、卵巢癌、前列腺癌、宫颈癌、肺癌、乳癌和皮肤癌,如扁平细胞癌和基底细胞癌。本发明的化合物和方法也可用于治疗放射疗法引起的纤维化。本发明的化合物和方法可用来治疗患有腺瘤性息肉的患者,包括患家族腺瘤性息肉病(FAP)的患者。另外,本发明化合物和方法可用于预防有FAP风险的患者形成息肉。
本发明化合物与另一种抗肿瘤药的联合治疗,将通过减少疗效所需但引起副作用的药物的治疗剂量,或者通过直接减轻引起副作用的药物产生的毒副作用的症状,产生协同作用或者降低与化疗有关的毒副作用。本发明的化合物还可用作放射治疗的辅助剂,以减少副作用或增加效果。在本发明中,可与本发明的化合物联合治疗的另一种药物包括能抑制环氧合酶-2(“COX-2”)的任何治疗药物。优选此种COX-2抑制剂相对环氧合酶-1(“COX-1”)而言可选择性地抑制COX-2。这种COX-2抑制剂称作“COX-2选择性抑制剂”。更优选,在体外试验中,本发明的化合物可与COX-2选择性抑制剂联合治疗,其中的COX-2选择性抑制剂以相对于对COX-1的抑制至少10∶1,更优选至少30∶1,甚至更优选至少50∶1的比例选择性地抑制COX-2。用于与本发明的化合物联合治疗的COX-2选择性抑制剂包括塞来考昔、伐地考昔、deracoxib,艾托考昔、罗非考昔,ABT-963(2-(3,4-二氟苯基)-4-(3-羟基-3-甲基-1-丁氧基)-5-[4-(甲磺酰基)苯基-3(2H)-哒嗪酮;描述于PCT专利申请号WO 00/24719),或美洛昔康。本发明的化合物也可有利地用于与COX-2选择性抑制剂的前药如帕瑞考昔的联合治疗。
例如,可从下面选择能用于与本发明的化合物联用的另一化疗药,所列药物并非包罗一切,并且是非限定性的:
α-二氟甲基鸟氨酸(DFMO)、5-FU-血纤维蛋白原、acanthifolicacid、氨基噻二唑、布喹那钠、卡莫氟、Ciba-Geigy CGP-30694、环戊基胞嘧啶、磷酸硬脂酸阿糖胞苷、阿糖胞苷轭合物、Lilly DATHF、Merrel Dow DDFC、地扎呱宁、双脱氧胞苷、双脱氧鸟苷、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’-呋喃烷基)-5-氟尿嘧啶、Daiichi Seiyaku FO-152、isopropyl pyrrolizine、LillyLY-188011、Lilly LY-264618、methobenzaprim、甲氨蝶呤、WellcomeMZPES、norspermidine、NCI NSC-127716、NCI NSC-264880、NCINSC-39661、NCI NSC-612567、Warner-Lambert PALA、喷司他丁、吡曲克辛、普卡霉素、Asahi Chemical PL-AC、Takeda TAC-788、硫鸟嘌呤、噻唑呋林、Erbamont TIF、三甲曲沙、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、AmericanCyanamid CL-286558、Sanofi CY-233、cyplatate、Degussa D-19-384、Sumimoto DACHP(Myr)2、二苯螺莫司汀、二铂细胞抑制剂、Erba司他霉素衍生物、Chugai DWA-2114R、ITI E09、依莫司汀、ErbamontFCE-24517、雌莫司汀磷酸钠、福莫司汀、Unimed G-6-M、ChinoinGYKI-17230、hepsul-fam、异环磷酰胺、异丙铂、洛莫司汀、马磷酰胺、二溴卫矛醇、Nippon Kayaku NK-121、NCI NSC-264395、NCINSC-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&F-101772、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、四铂、trimelamol、Taiho 4181-A、阿柔比星、放线菌素D、actinoplanone、Erbamont ADR-456、aeroplysinin衍生物、AjinomotoAN-201-II、Ajinomoto AN-3、Nippon Soda茴香霉素、蒽环霉素、阿嗪霉素-A、bisucaberin、Bristol-Myers BL-6859、Bristol-Myers BMY-25067、Bristol-Myers BMY-25551、Bristol-Myers BMY-26605、Bristol-Myers BMY-27557、Bristol-Myers BMY-28438、硫酸博来霉素、苔藓抑素1、Taiho C-1027、calichemycin、chromoximycin、放线菌素D、柔红霉素、Kyowa Hakko DC-102、Kyowa Hakko DC-79、KyowaHakko DC-88A、Kyowa Hakko DC89-A1、Kyowa Hakko DC92-B、蒽环霉素B、Shionogi DOB-41、多柔比星、多柔比星-纤维蛋白原、elsamicin-A、表柔比星、erbstatin、依索比星、esperamicin-A1、esperamicin-A1b、Erbamont FCE-21954、Fujisawa FK-973、福司曲星、Fujisawa FR-900482、滑行菌素、gregatin-A、grincamycin、除莠霉素、伊达比星、隐杯伞素、kazusamycin、kesarirhodins、Kyowa HakkoKM-5539、Kirin Brewery KRN-8602、Kyowa Hakko KT-5432、KyowaHakko KT-5594、Kyowa Hakko KT-6149、American Cyanamid LL-D49194、Meiji Seika ME2303、美诺立尔、丝裂霉素、米托蒽醌、SmithKline M-TAG、neoenactin、Nippon Kayaku NK-313、NipponKayaku NKT-01、SRI International NSC-357704、_溶菌素、oxaunomycin、培洛霉素、pilatin、吡柔比星、porothramycin、pyrindamycinA、Tobishi RA-I、雷帕霉素、根霉素、罗多比星、西班米星、siwenmycin、Sumitomo SM-5887、Snow Brand SN-706、Snow Brand SN-07、sorangicin-A、司帕霉素、SS Pharmaceutical SS-21020、SSPharmaceutical SS-7313B、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、Kyowa Hakko UCN-10028A、FujisawaWF-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、Kyorin AHC-52、鸡骨常山碱、氨萘非特、amphethinile、安吖啶、Angiostat、ankinomycin、抗瘤酮A10、抗瘤酮A2、抗瘤酮A3、抗瘤酮A5、抗瘤酮AS2-1、Henkel APD、阿非迪霉素甘氨酸盐、天冬酰胺酶、Avarol、baccharin、batracylin、苯氟伦、苯佐色氨酸、Ipsen-Beaufour BIM-23015、比生群,Bristo-MyersBMY-40481、Vestar boron-10、bromofosfamide、Wellcome BW-502、Wellcome BW-773、卡醋胺、盐酸carmethizole、Ajinomoto CDAF、chlorsulfaquinoxalone、Chemex CHX-2053、Chemex CHX-100、Warner-Lambert CI-921、Warner-Lambert CI-937、Warner-Lambert CI-941、Warner-Lambert CI-958、克兰氟脲、claviridenone、ICN化合物1259、ICN化合物4711、Contracan、Yakult Honsha CPT-11、克立那托、curaderm、松胞素B、阿糖胞苷、cytocytin、Merz D-609、马来酸DABIS、达卡巴嗪、达替氯铵、didemnin-B、双血卟啉醚、二氢仑派隆、地那林、偏端霉素、Toyo Pharmar DM-341、Toyo PharmarDM-75、Daiichi Seiyaku DN-9693、elliprabin、依利醋铵、TsumuraEPMTC、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、grifolanNMF-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A酸、OtsukaJI-36、Ramot K-477、Otsuak K-76COONa、Kureha Chemical K-AM、MECT Corp KI-8110、American Cyanamid L-623、白细胞调节素、氯尼达明、Lundbeck LU-23-112、Lilly LY-186641、NCI(US)MAP、marycin、Merrel Dow MDL-27048、Medco MEDR-340、麦尔巴隆、部花青衍生物、甲基苯胺基吖啶、Molecular Genetics MGI-136、minactivin、米托萘胺、米托喹酮、莫哌达醇、莫维A胺、Zenyaku KogyoMST-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、精氨酸血红素、NCI NSC-145813、NCI NSC-361456、NCI NSC-604782、NCI NSC-95580、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、Pierre FabrePE-1001、ICRT肽D、吡罗蒽醌、多血卟啉、polypreic acid、Efamol卟啉、probimane、丙卡巴肼、丙谷胺、Invitron蛋白酶连接蛋白I,TobishiRA-700、雷佐生、Sapporo Breweries RBS、restrictin-P、瑞替普汀、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、锗螺胺、Unimed、SSPharmaceutical SS-554、strypoldinone、Stypoldione、Suntory SUN 0237、Suntory SUN 2071、超氧化物歧化酶、Toyama T-506、Toyama T-680、泰素、Teijin TEI-0303、替尼泊苷、thaliblastine、Eastman KodakTJB-29、生育三烯酚、Topostin、Teijin TT-82、Kyowa Hakko UCN-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、witanolides、Yamanouchi YM-534、uroguanylin、考布他汀、多拉司他汀、伊达比星、表柔比星、雌莫司汀、环磷酰胺、9-氨基-2-(S)-喜树碱、托泊替康、伊立替康(Camptosar)、依西美坦、达必佳(曲普瑞林)、或一种ω-3脂肪酸。
可用于与本发明的化合物联合治疗的放射保护剂的实例包括AD-5、adchnon、氨磷汀类似物、detox、地美司钠、1-102、MM-159、N-酰化-去氢丙氨酸、TGF-Genentech、噻丙莫德、氨磷汀、WR-151327、FUT-187、经皮酮洛芬、萘丁美酮、超氧化物歧化酶(Chiron)及超氧化物歧化酶Enzon。
本发明的化合物也可用于治疗或预防与血管生成相关的疾病或病症,例如,瘤的生长、转移、黄斑变性和动脉粥样硬化。
在另一实施方案中,本发明也提供治疗或预防眼病或眼疾如青光眼的联合治疗方法。例如,本发明的化合物将有利地用于与降低患青光眼的患者的眼内压的药物一起联合治疗。这类降低眼内压的药物包括(但不限于)拉坦前列素、曲伏前列素、比马前列素或乌诺前列醇。本发明的化合物加上一种降低眼内压药物的联合治疗将是有用的,因为认为它们各自通过不同的机理发挥其作用。
在本发明的另一联合治疗方案中,本发明的化合物可用于与降高血脂药物或降胆固醇药物如benzothiepine或苯并噻氮_苯并噻氮_降高血脂药一起的联合治疗。用于本发明的联合治疗的benzothiepine降高血脂药的实例可在美国专利第5,994,391号中找到,该文献通过引用结合到本文中。某些苯并噻氮_降高血脂药描述于WO 93/16055。或者,用于与本发明化合物联合的降高血脂药物或降胆固醇药物可为HMG Co-A还原酶抑制剂。用于本发明的联合治疗的HMG Co-A还原酶抑制剂的实例分别包括苯氟雷司、氟伐他汀、洛伐他汀、普伐他汀、辛伐他汀、阿托伐他汀、西立伐他汀、贝伐他汀、ZD-9720(描述于PCT专利申请号WO 97/06802)、ZD-4522(对于钙盐为CAS第147098-20-2号;对钠盐为CAS第147098-18-8号;描述于欧洲专利第EP 521471号)、BMS 180431(CAS第129829-03-4号)或NK-104(CAS第141750-63-2号)。本发明化合物加上降高血脂药物或降胆固醇药物的联合治疗可用于,例如,降低在血管中形成动脉粥样硬化损害的危险。例如,动脉粥样硬化损害往往最初发生于血管中的发炎部位。已确认降高血脂药物或降胆固醇药物通过降低血液中的脂质水平来减少形成动脉粥样硬化损害的危险。本发明并不限于单一作用机理,但是相信本发明化合物作用的一种方式是通过例如同时降低血脂水平和减少血管中的炎症,提供了对动脉粥样硬化损害的更有效的控制。
在本发明的另一实施方案中,本发明化合物可用于与其它化合物或治疗方法联合治疗中枢神经病症或疾病如偏头痛。例如,本发明化合物可用于与咖啡因、5-HT-1B/1D激动剂(例如,曲普坦如舒马普坦、那拉曲坦、佐米曲普坦、利扎曲普坦、阿莫曲普坦或夫罗曲普坦)、多巴胺D4拮抗剂(例如,索奈哌唑)、阿司匹林、对乙酰氨基酚、布洛芬、吲哚美辛、萘普生钠、异美汀、氯醛比林、布他比妥、麦角生物碱(如麦角胺、二氢麦角胺、溴隐亭、麦角新碱或甲麦角新碱)、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、纳多洛尔或美托洛尔)或单胺氧化酶抑制剂(例如,苯乙肼或异卡波肼)一起联合治疗。
另一实施方案提供本发明的化合物与类阿片化合物一起的联合治疗。可用于该联合治疗的类阿片化合物包括(但不限于)吗啡、美沙酮、氢吗啡酮、羟吗啡酮、左啡诺、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、羟考酮、纳美芬、埃托啡、左啡诺、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、烯丙吗啡、喷他佐辛、纳布啡、纳洛酮苯甲酰腙、布马佐辛、乙基酮基环佐辛、U50,488、U69,593、螺朵林、nor-binaltorphimine、纳屈吲哚、DPDPE、[D-la2,glu4]deltorphin、DSLET、甲硫脑啡呔、亮脑啡肽、β-内啡肽、强啡肽A、强啡肽B及α-新内啡肽。本发明与一种类阿片化合物的联合的一个优点是本发明的化合物可减少类阿片化合物的剂量,因而降低类阿片副作用如类阿片成瘾的风险或者严重性。
定义
单独或结合使用的术语“烷基”指线性或分支的无环脂族基团,优选含1-约10个碳原子,更优选含1-约6个碳原子。烷基可任选由如下定义的基团所取代。这类基团的实例包括甲基、乙基、氯代乙基、羟基乙基、正丙基、异丙基、正丁基、氰基丁基、异丁基、仲丁基、叔丁基、戊基、氨基戊基、异戊基、己基、辛基等。
术语“链烯基”指线性或分支的不饱和无环烃基,它含有至少一个双键。这类基团含2-约6个碳原子,优选2-约4个碳原子,更优选2-约3个碳原子。链烯基可任选由如下定义的基团所取代。适当的链烯基实例包括丙烯基、2-氯代丙烯基、丁烯-1-基、异丁烯基、戊烯-1-基、2-甲基丁烯-1-基、3-甲基丁烯-1-基、己烯-1-基、3-羟基己烯-1-基、庚烯-1-基和辛烯-1-基等。
术语“炔基”指线性或分支的不饱和无环烃基,它含一个或多个叁键,这类基团含2-约6个碳原子,优选2-约4个碳原子,更优选2-约3个碳原子。炔基可任选由如下定义的基团所取代。适当的炔基的实例包括乙炔基、丙炔基、羟基丙炔基、丁炔-1-基、丁炔-2-基、戊炔-1-基、戊炔-2-基、4-甲氧基戊炔-2-基、3-甲基丁炔-1-基、己炔-1-基、己炔-2-基、己炔-3-基、3,3-二甲基丁炔-1-基等。
术语“氧代”指双键结合的氧。
术语“烷氧基”指包括连接于氧原子的烷基的基团,如甲氧基。更优选的烷氧基是有1-约10个碳原子的“低级烷氧基”。更优选的烷氧基具有1-约6个碳原子。这类基团的非限制性实例包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基和叔丁氧基。
短语“任选取代的”意为指定的基团可以,但并非必需取代氢。因此,短语“由一个或多个任选取代”意为,如果在指定的部分进行取代,也包括一次以上的取代。在这点上,如果存在一个以上的任选取代基,则可以选择取代基,或可以选择多个取代基的组合,或者可以选择一个以上的相同取代基。举例来说,但并非限制,短语“由一个或多个卤代基或烷氧基任选取代的C1-C5烷基”应当用来表示,例如甲基、乙基、丙基、丁基或戊基可以在所有可取代的位置具有:氢、氟、氯或其它卤代基、甲氧基、乙氧基、丙氧基、异丁氧基、叔丁氧基、戊氧基或其它烷氧基,以及其组合。非限制性的实例包括:丙基、异丙基、甲氧基丙基、氟代甲基、氟代丙基、1-氟代-甲氧基甲基等。
虽然已举例说明氮保护基团为叔丁氧羰基或t-BOC,但任何合适的氮保护基团都可以在本发明化合物的合成中被取代。Theodora W.Greene和Peter G.M.Wuts(
Protective Groups in Organic Synthesis(有 机合成的保护基团),第3版.,John Wiley & Sons,New York,1999,第494-653页)描述了本发明使用的大量的被护氨基。例如,NZ可以为4-氯代苄基亚氨基。在本发明的一个实施方案中,被护氨基为醛与相关的氨基作用形成席夫碱的反应所产生的任何这样的基团。大量的去保护剂可有利地用于本发明以促进中间体转变为要求的化合物。Greene和Wuts描述了许多这类去保护剂(见上文)。例如,当被护氨基为4-氯代苄基亚氨基或叔丁氧羰基氨基时,所述的去保护剂优选为酸。一些有用的酸去保护剂包括(但不限于)盐酸、氢溴酸、硫酸、三氟乙酸、磷酸、亚磷酸(phosphorus acid)和乙酸。
当用结构和名称来描述一个化合物时,打算使名称与指定的结构相对应,并且类似地,打算使结构与指定的名称一致。
术语“联合治疗”指给予两种或更多种治疗药物以治疗本公开所述的病症或疾病,例如动脉粥样硬化、疼痛、炎症、偏头痛、瘤形成、与血管生成相关的病症或疾病,或者其他指定的病症。这类给药包括以基本同时的方式联合给予两种或更多种治疗药物,例如以具有固定比例的活性成分的单个胶囊(或其它传递方式)或以多个各自含活性成分的独立胶囊(或其它传递方式)联合给药。此外,这类给药也包括各种类型的治疗药物的顺序使用。不论哪种情况,所述治疗方案都会为治疗本文所述的病症或疾病提供有益的药物联合使用的效果。
在联合治疗中的短语“治疗有效的”用来限定联合治疗中的各活性成分的联合用量。所述联合用量将达到减轻或消除所述疾病,或缓解所述疾病症状的目的。
示例性实施例
下面的合成流程和实施例是用于说明的目的,而决不是打算限制本发明的范围。其中异构体并未限定,采用合适的层析法将提供单一的异构体。
通用流程1
a)二氯甲烷,三苯膦,咪唑,I2
b)1.NMP,BTPP,合适的N-[(3,4-二氯苯基)亚甲基]丙氨酸甲酯
2.HCl水溶液
c)手性层析
d)锌粉,乙酸,水,加热
e)HCl水溶液,加热
f)NaOH水溶液
g)Lindlar催化剂与H2或Lindlar催化剂,MeOH或钯黑,MeOH或Zn,HOAc。
流程2
a)2-氟代膦酰基乙酸三乙酯,叔丁基锂,THF和己烷
b)硼氢化钠,甲醇,水
c)聚合物-附载的三苯膦,3-甲基-1,2,4-_二唑啉-5-酮,偶氮二甲酸二乙酯,THF
d)乙酸∶THF∶水(3∶1∶1)
e)二氯甲烷,三苯膦,咪唑,I2
f)(3S,6R)-6-异丙基-3-甲基-5-苯基-3,6-二氢-2H-1,4-_嗪-2-酮,
BEMP,1-甲基-2-吡咯烷酮
g)Lindlar催化剂,甲醇,加热
h)HCl水溶液,加热
实施例1
(2S,5E)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例-1A)向冷却(-78℃)的2-氟代膦酰基乙酸三乙酯(25.4g,105mmol)的THF(100mL)溶液中加入正丁基锂(63mL的1.6M己烷溶液,101mmol)。将该混合物于-78℃搅拌20分钟,得到嫩黄色溶液。然后用10分钟滴加入粗制3-[(叔丁基二甲基甲硅烷基)氧基]丙醛(J.Org.Chem.,1994,59,1139-1148)(20.0g,105mmol)的THF(120mL)溶液,于-78℃将得到的混合物搅拌1.5小时,此时经薄层层析(5%乙酸乙酯的己烷溶液)分析显示,没有起始原料剩余。于-78℃用饱和氯化铵水溶液(150mL)猝灭反应物。收集有机层,用乙醚(300mL)提取水层。合并的有机物用盐水(200mL)洗涤,经硫酸镁干燥,过滤并浓缩。粗品物质通过硅胶柱(150g)过滤,用己烷(2L)洗脱,得到14.38g(52%)所需的(2E)-5-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]-2-氟代-2-戊烯酸乙酯产物,为澄清油状物。1H NMR和19F NMR显示分离的产物具有约95∶5的E∶Z比例。
对于C13H26FO3Si的HRMS计算值:m/z=277.1635[M+H]+,实测值:277.1645。
1H NMR(CDCl3)δ0.06(s,6H),0.94(s,9H),1.38(t,3H),2.74(m,2H),3.70(m,2H),4.31(q,2H),6.0(dt,乙烯基,1H)。
19F NMR(CDCl3)δ-129.78(d,0.05F,J=35Hz,5%Z-异构体),-121.65(d,0.95F,J=23Hz,95%E-异构体)。
实施例-1B)于室温下,用3小时向实施例-1A(6.76g,24.5mmol)的甲醇(100mL)溶液中加入固体硼氢化钠(4.2g,220mmol),每次加入1.4g。3.5小时后,加入水(10mL)。用3小时加入额外的固体硼氢化钠(4.2g,220mmol),每次加入1.4g。反应物用150mL饱和氯化铵水溶液猝灭,用乙醚(2×250mL)提取。合并有机层,经硫酸镁干燥,过滤并浓缩。粗品物质,4.81g的澄清油,经硅胶快速柱层析纯化,用10%乙酸乙酯的己烷溶液洗脱,得到2.39g(42%)所需的(2E)-5-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]-2-氟代-2-戊烯-1-醇产物,为澄清油状物,19F NMR显示该油状物含有约93∶7的E∶Z比例。
对于C11H24FO2Si的HRMS计算值:m/z=235.1530[M+H]+,实测值:235.1536。
1H NMR(CDCl3)δ0.06(s,6H),0.88(s,9H),2.35(m,2H),3.62(t,2H),4.19(dd,2H),5.2(dt,乙烯基,1H)。
19F NMR(CDCl3)δ-120.0(dt,0.07F,7%Z-异构体),-109.82(q,0.93F,J=21Hz,93%E-异构体)。
实施例-1C)向实施例-1B(2.25g,9.58mmol)、聚合物附载的三苯膦(3mmol/g,1.86g,15mmol)和3-甲基-1,2,4-_二唑啉-5-酮(1.25g,12.5mmol)在60mL THF中的混合物中滴加入偶氮二甲酸二乙酯(2.35mL,14.7mmol)。于室温下,将该反应化合物搅拌1小时,加入额外的3-甲基-1,2,4-_二唑啉-5-酮(0.30g,3.0mmol)。30分钟后,通过硅藻土过滤该混合物,浓缩滤液。用乙醚(30mL)研磨得到的黄色油状物,过滤除去固体。浓缩滤液,用己烷(30mL)研磨并过滤。将滤液浓缩成油状物,将其经硅胶快速柱层析纯化,用15%乙酸乙酯的己烷溶液洗脱,得到1.83g(60%)所需的4-[(2E)-5-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]-2-氟代-2-戊烯基]-3-甲基-1,2,4-_二唑-5-(4H)-酮产物,为澄清油状物,经19F NMR分析,该油状物只含有所需的E异构体。
对于C14H26FN2O3Si的HRMS计算值:m/z=317.1697[M+H]+,实测值:317.1699。
1H NMR(CDCl3)δ0.04(s,6H),0.85(s,9H),2.28(s,3H),2.37(m,2H),3.64(t,2H),4.32(d,2H),5.4(dt,乙烯基,1H)。
19F NMR(CDCl3)δ-110.20(q,1F,J=21Hz)。
实施例-1D)将实施例-1C(1.83g,5.78mmol)在乙酸(6mL)、THF(2mL)和水(2mL)的混合物中的溶液在室温下搅拌2.5小时。真空浓缩生成的溶液成油状物,使其溶于乙醚(50mL)中。用饱和碳酸氢钠水溶液洗涤有机层,水层用乙醚(2×50mL)和乙酸乙酯(2×50mL)提取。干燥(硫酸镁)合并的有机层,过滤并蒸发,得到1.15g(98%)所需的4-[(2E)-2-氟代-5-羟基-2-戊烯基]-3-甲基-1,2,4-_二唑-5(4H)-酮产物,为澄清的无色油状物。
对于C8H12FN2O3的HRMS计算值:m/z=203.0832[M+H]+,实测值:203.0822。
1H NMR(CDCl3)δ2.31(3H),2.4(m,2H),3.66(t,2H),4.37(d,2H),5.42(dt,乙烯基,1H).19F NMR(CDCl3)δ-110.20(q,1F,J=21Hz)。
实施例-1E)于0℃,向三苯膦(238mg,0.91mmol)和咪唑(92mg)的二氯甲烷(2mL)溶液中加入固体碘(230mg,0.91mmol),搅拌该混合物5分钟。向生成的黄色浆状物中加入实施例-1D(0.15g,0.74mmol)的二氯甲烷(1.5mL)溶液。使该浆状物温热至室温并搅拌30分钟。反应混合物用二氯甲烷(10mL)稀释,用饱和硫代硫酸钠(5mL)和盐水(5mL)洗涤,干燥(硫酸镁),过滤并蒸发成油状物。将乙醚(10mL)加入到该油状物中,得到白色沉淀,将其过滤除去,浓缩滤液成油状物。粗品物质经硅胶快速柱层析纯化,用30%乙酸乙酯的己烷溶液洗脱,得到0.18g(78%)所需的4-[(2E)-2-氟代-5-碘代-2-戊烯基]-3-甲基-1,2,4-_二唑-5(4H)-酮产物,为澄清油状物,它在静置下固化,mp=58.1-58.6℃。
对于C8H10FIN2O2的分析计算值:C,30.79;H,3.23;N,8.98.实测值:C,30.83;H,3.11;N,8.85。对于C8H11FIN2O2的HRMS计算值:m/z=330.0115[M+H]+,实测值:330.0104。
1H NMR(CDCl3)δ2.31(s,3H),2.75(q,2H),3.21(t,2H),4.31(d,2H),5.39(dt,乙烯基,1H).19F NMR(CDCl3)δ-108.21(q,1F,J=21Hz)。
实施例-1F)向在冰浴中的(3S,6R)-6-异丙基-3-甲基-5-苯基-3,6-二氢-2H-1,4-_嗪-2-酮(Synthesis,1999,4,704-717)(1.10g,4.76mmol)、LiI(0.63g,4.76mmol)和实施例-1E(0.85g,2.72mmol)的1-甲基-2-吡咯烷酮(12mL)溶液中加入2-叔丁基亚氨基-2-二乙基氨基-1,3-二甲基全氢-1,3,2-二氮杂膦杂苯(diazaphosphorine)(1.38mL,4.76mmol)。加入碱后,黄色溶液变为橙色,于室温下搅拌生成的溶液1小时。反应混合物用乙酸乙酯(100mL)稀释,用水(2×30mL)洗涤,干燥(硫酸镁),过滤并蒸发成黄色油状物。粗品物质经硅胶快速柱层析纯化,用30%乙酸乙酯的己烷溶液洗脱,得到0.64g(57%)所需的烷基化产物,为澄清油状物。
1H NMR(C6D6)δ0.57(d,3H),0.89(d,3H),1.30(s,3H),1.65(s,3H),1.8(m,2H),2.0(m,2H),2.1(m,1H),3.22(m,2H),4.88(dt,乙烯基,1H),5.49(d,1H),7.1(m,3H),7.6(m,2H).19F NMR(CDCl3)δ-110.37(q,1F,J=21Hz)。
实施例-1G)向实施例-1F(0.13g,0.31mmol)的甲醇(20mL)溶液中加入Lindlar催化剂(1.0g)。将搅拌的浆状物加热至60℃1小时,加入额外的Lindlar催化剂(0.30g)。于60℃再搅拌该浆状物1小时,然后冷却至室温。通过硅藻土过滤除去催化剂,汽提滤液,得到0.58g(100%)所需的去保护的脒产物,为淡黄色油状物。
MS:m/z=374.2[M+H]+
1H NMR(CD3OD)δ0.77(d,3H),1.07(d,3H),1.58(s,3H),2.02(s,3H),1.8-2.2(m,5H),3.83(d,2H),5.20(dt,乙烯基,1H),5.69(d,1H),7.4(m,3H),7.7(m,2H)
19F NMR(CDCl3)δ-109.4(m,1F,J=21Hz)
实施例-1)将得自实施例-1G(0.58g,1.54mmol)的1.5N HCl(25mL)溶液用乙醚(2×20mL)洗涤,回流1小时。汽提溶剂,使粗制氨基酸酯溶于6N HCl(15mL)中,加热至回流。6小时后,真空除去溶剂,经反相HPLC纯化得到的泡沫物,用30分钟的0-40%CH2CN/水(0.25%乙酸)梯度液洗脱。收集含有产物的流分,浓缩成泡沫物。使产物溶于1N HCl中,真空(2x)除去溶剂,得到0.15g(29%)所需的(2S,5E)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐产物。
对于C10H19FN3O2的HRMS计算值:m/z=232.1461[M+H]+,实测值:232.1485。
1H NMR(D2O)δ1.43(s,3H),2.10(s,3H),1.8-2.1(m,4H),3.98(d,2H),5.29(dt,乙烯基,1H).19F NMR(CDCl3)δ-109.97(q,1F,J=21Hz)。
流程3
a)2-氟代膦酰基乙酸三乙酯,DBU,LiCl,THF,-78℃
b)RED-AL,THF,-5℃
c)1.MsCl,三乙胺,5-10℃
2.3-甲基-1,2,4-_二唑啉-5-酮的钾盐,DMSO,50℃
d)乙酸∶THF∶水(3∶1∶1)
e)二氯甲烷,三苯膦,咪唑,I2或1.MsCl,三乙胺2.NaI
f)1.NMP,BTPP,N-[(3,4-二氯苯基)亚甲基]丙氨酸甲酯
2.HCl水溶液
g)手性层析(如ChiralPak-AD,100%乙腈)
h)锌粉,乙酸,水,加热或者另一种选择,Lindlar催化剂,甲酸,甲醇
i)HCl水溶液,加热
实施例2
(2S,5E)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例-2A)在氮气下,向N-[(3,4-二氯苯基)-亚甲基]-丙氨酸甲酯(748.5g,2.88mol)的1-甲基-2-吡咯烷酮(7500mL)溶液中加入LiI(385.5g,2.88mol),搅拌得到的浆状物约20分钟,得到澄清溶液。然后加入得自实施例-1E(750g,2.40mol)的固体,在冰浴中将生成的溶液冷却至约0℃。用25分钟滴加入纯BTPP(900g,2.88mol),以维持内温低于5℃。于5℃再搅拌1.5小时后,通过HPLC测定反应的完成。此后,加入7500mL甲基叔丁基醚(MTBE),接着加入9750mL水/碎冰混合物。在操作期间,温度上升至20℃。剧烈搅拌5-10分钟后,分离各层,用6000mL的MTBE洗涤水层两次。合并MTBE层,用7500mL水洗涤两次。然后将产生的MTBE溶液浓缩至约5000mL,用11625mL的1.0N HCl处理,于室温下剧烈搅拌1小时。分离各层,用7500ml的MTBE洗涤含水层,将约1kg氯化钠加入水层中,搅拌得到的混合物,直至所有的盐溶解。此时,加入7500mL的乙酸乙酯,使得到的混合物冷却至10℃,在充分搅拌下加入2025mL的6.0N氢氧化钠。产生的pH应该为大约9。分离各层,将水层用氯化钠饱和,再用7500mL乙酸乙酯提取。将合并的乙酸乙酯提取物干燥(硫酸镁),浓缩至浅色油状物。应该注意到乙酸乙酯并未完全除去。然后在搅拌下加入3000ml的己烷,以生成浆状物,将其冷却至10℃。过滤收集颗粒状固体,用1500mL己烷洗涤。得到约564g(82%收率)所需的纯氨基酯(HPLC分析纯度>95%),为白色固体,m.p.82.9-83.0℃。
LCMS:m/z=288.2[M+H]+。手性HPLC(Chiralpak-AD正相柱,100%乙腈,210nm,1mL/分钟):两个主要峰在4.71和5.36分钟(1∶1)。
1H NMR(CDCl3):δ1.40(s,3H),1.7-1.8(m,2H),2.0(br s,2H),2.2(m,2H),2.29(s,3H),3.73(s,3H),4.34(dd,2H),5.33(dt,1H)。
实施例-2B)采用手性HPLC层析(ChiralPak-AD,正相柱,100%乙腈),在制备级上实现来自实施例-2A的产物的单一对映体的分离,得到所需的纯(2S)-2-甲基氨基酯产物标题产物。ChiralPak-AD,正相柱,100%乙腈,210nm,1mL/分钟):5.14分钟(99%)。
实施例-2C)于室温下,将实施例-2B的产物(2.30g,8.01mmol)在0.993M NaOH(30.0ml,29.79mmol)中的悬浮液搅拌2小时。向生成的澄清无色溶液中加入1.023M HCl(29.10mL,29.76mmol)。浓缩生成的澄清溶液,直至开始形成沉淀(约30mL)。温热浆状物,得到澄清溶液,使其在室温下静置过夜。过滤分离沉淀。用冷水(2×10mL)、冷甲醇(2×10mL)和乙醚(2×20mL)洗涤该固体。于40℃真空干燥白色固体4小时,得到1.04g(53%)所需的N-羟基示例产物。mp=247.2℃。
对于C10H18FN3O3的分析计算值:C,48.57;H,7.34;N,16.99;Cl,0.0.实测值:C,48.49;H,7.37;N,16.91;Cl,0.0。
对于C10H19FN3O3的HRMS计算值:m/z=248.1410[M+H]+,实测值:248.1390。
1H NMR(D2O)δ1.35(s,3H),1.81(s,3H),1.7-2.0(m,4H),3.87(d,2H),5.29(dt,乙烯基,1H).19F NMR(CDCl3)δ-112.51(q,1F,J=21Hz)。
实施例-2)向实施例-2C的甲醇溶液中加入Lindlar催化剂。使搅拌的浆状物回流2小时,然后冷却至室温。通过硅藻土过滤除去催化剂,汽提滤液。使生成的固体溶于水中,从1.0N HCl中反复浓缩,得到所需的(2R,5E)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐产物。
实施例-2D)将73.5g(0.3mol)得自实施例-2B的产物溶于300mL甲醇中,并滴加到预先形成的13.7g的Lindlar催化剂和73.5g甲酸(1.53mol)在312mL甲醇中的混合物中,同时维持反应温度在22℃至26℃之间。于室温下再搅拌约15小时后,经F19 NMR测定该反应完成。通过硅藻土过滤得到的反应混合物,用125mL甲醇洗涤硅藻土3次。合并甲醇滤液,浓缩得到115g所需的脒标题产物,为粘稠油状物。MS:m/z=246(M+H)+。
1H NMR(CD3OD)δ1.6(s,3H),2.0-2.2(m,4H),2.3(s,3H),3.9(s,3H),4.2(d,2H),5.4(dt,乙烯基),8.4(s,3H)。
F19 NMR(CD3OD)δ-110.4(q,J=21Hz),-111.7(q,J=21Hz)。
为除去痕量水平的铅,使粗产物溶于750mL甲醇中,加入150g基于硫醇的树脂(Deloxan THP 11)。于室温下搅拌3小时后,滤去树脂。用500mL甲醇洗涤两次。收集滤液,浓缩至99g所需的脒标题产物,为粘稠油状物。
替代方法:
将总共5.0g得自实施例-2B的产物(0.0174摩尔,1.0当量)与5.0g锌粉(0.0765摩尔,4.39当量)在40mL 1-丁醇和10mL乙酸中混合。于50℃搅拌5小时后,LC分析指示该反应完成。迅速过滤除去固体。在冰水中冷却至7℃后,在剧烈搅拌下,用一份30mL的6N NaOH(0.180摩尔)处理滤液。在将反应混合物从33℃冷却至20℃后,分离除去澄清的丁醇层,再用40mL的1-丁醇提取水层。合并丁醇提取物,用30mL盐水和大约10mL的6N HCl先后洗涤。于70℃浓缩后,得到澄清的玻璃状物,经鉴定其为所需的脒标题产物。实施例-2)将99g得自实施例-2D的产物的6N HCl溶液回流1小时,此时LC分析指示该反应完成。真空除去溶剂,得到89.2g玻璃状油,将其溶于1466mL乙醇和7.5ml去离子水的混合物中。于室温下将THF加入到该搅拌的溶液中,直至达到浊点(5.5升)。加入额外的30ml去离子水,于室温下搅拌溶液过夜。过滤生成的浆状物,用200mL THF洗涤,得到65g鉴定为所需的标题产物的白色固体。
[α]D 25=+7.2(c=0.9,H2O)
mp=126-130℃。
MS:m/z=232(M+H)+。
对C10H22N3F1O3Cl2的分析计算值:C,37.28;H,6.88;N,13.04;Cl,22.01.实测值:C,37.52,H,6.84,N,13.21,Cl,21.81。
1H NMR(D2O)δ1.4(s,3H),1.8-2.1(m,4H),1.9(s,3H),4.0(d,2H),5.3(dt,乙烯基,1H)。
F19 NMR(D2O)δ-109.6(q,J=21Hz),-112.1(q,J=21Hz)。
流程4
a)2-氟代膦酰基乙酸三乙酯,DBU,LiCl,THF,-78℃
b)RED-AL,THF,-5℃
c)1.MsCl,三乙胺,5-10℃。
2.3-甲基-1,2,4-_二唑啉-5-酮的钾盐,DMSO,50℃
d)乙酸∶THF∶水(3∶1∶1)
e)二氯甲烷,三苯膦,咪唑,I2或1.MsCl,三乙胺2.NaI
f)1.NMP,BTPP,N-[(3,4-二氯苯基)亚甲基]丙氨酸甲酯
2.HCl水溶液
g)手性层析(如ChiralPak-AD,100%乙腈)
h)锌粉,乙酸,水,加热或者另一种选择,Lindlar催化剂,甲酸,甲醇
i)HCl水溶液,加热
实施例3
(2R,5E)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例-3A)采用手性HPLC层析,在制备级上实现来自实施例-2A的产物的单一对映体的分离,得到所需的纯(2R)-2-甲基氨基酯产物。
实施例-3B)使得自实施例-3A的产物溶于水和乙酸中。加入锌粉,于60℃加热该混合物,直至HPLC分析显示几乎没有起始原料剩余。通过硅藻土从反应混合物中过滤锌,浓缩滤液。粗品物质经反相HPLC柱层析纯化。合并含有产物的部分,浓缩得到所需的(2R)-2-甲基乙脒产物。
实施例-3)将实施例-3B在2.0N HCl中的溶液回流2小时。真空除去溶剂。使得到的固体溶于水中,反复由1.0N HCl浓缩,得到所需的(2R,5E)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐产物。
流程5
a)1.NMP,BEMP,N-[(4-氯苯基)亚甲基]甘氨酸甲酯
2.HCl水溶液
b)4-氯代苯甲醛,CH2Cl2,硫酸镁
c)1.NMP,BTPP,甲基碘,O(9)-烯丙基-N-(9-蒽基甲基)-辛可尼定_溴化物
2.HCl水溶液
d)锌粉,乙酸,水,加热
e)HCl水溶液,加热
实施例4
(2R/S,5E)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例-4A)在冰浴中,向N-[(4-氯代苯基)亚甲基]-甘氨酸甲酯(0.33g,1.6mmol)、LiI(0.20g,1.0mmol)和实施例-1E产物的样品(0.30g,0.96mmol)的1-甲基-2-吡咯烷酮(5mL)溶液中加入2-叔丁基亚氨基-2-二乙基氨基-1,3-二甲基全氢-1,3,2-二氮杂膦杂苯(0.433mL,1.5mmol)。于室温下搅拌该溶液1.5小时。反应混合物用乙酸乙酯(30mL)稀释,用水(2×20mL)洗涤,干燥(硫酸镁),过滤并蒸发,得到所需的粗制外消旋烷基化亚胺,为黄色油状物。
使粗品物质溶于乙酸乙酯(10mL)中,加入1N HCl(10mL)。将该混合物于室温下搅拌2小时,分离有机层。用固体碳酸氢钠中和水层,用乙酸乙酯(2×30mL)提取。干燥(硫酸镁)有机层,过滤并蒸发,得到0.13g所需的标题外消旋氨基酯产物,为黄色油状物。该产物无须进一步纯化而用于下一步骤。LCMS:m/z=288.2[M+H]+。
实施例-4B)向实施例-4A(1.36g,4.98mmol)的二氯甲烷(15mL)溶液中加入4-氯代苯甲醛(0.70g,5.0mmol)和硫酸镁(约5g)。在室温下搅拌该淤浆18小时。过滤该淤浆,汽提滤液,得到1.98g(100%)所需的标题亚胺产物,为淡黄色油状物。该产物无须进一步纯化而用于下一步骤。
1H NMR(C6D6)δ1.34(s,3H),2.0(br m,4H),3.32(s,3H),3.42(m,2H),3.83(t,1H),4.98(dt,乙烯基,1H)。
实施例-4C)向实施例-4B产物(0.25g,0.63mmol)的二氯甲烷(2mL)溶液中加入甲基碘(0.200mL,3.23mmol)和O(9)-烯丙基-N-(9-蒽基甲基)-辛可尼定_溴化物(40mg,0.066mmol)。将该溶液冷却至-78℃,加入纯BTPP(0.289mL,0.95mmol)。将生成的橙色溶液于-78℃搅拌2小时,然后温热至-50℃。于-50℃经2小时后,用二氯甲烷(10mL)稀释该溶液,用水(10mL)洗涤,干燥(硫酸镁),过滤并蒸发,得到所需的粗制外消旋烷基化亚胺,为黄色油状物。
使粗品物质溶于乙酸乙酯(10mL)中,加入1N HCl(10mL)。将该混合物于室温下搅拌1小时,分离有机层。用固体碳酸氢钠中和水层,用乙酸乙酯(2×30mL)提取。干燥(硫酸镁)有机层,过滤并蒸发,得到0.16g所需的外消旋2-甲基氨基酯产物,为黄色油状物。该产物无须进一步纯化而用于下一步骤。LCMS:m/z=288.2[M+H]+。
实施例-4D)将得自实施例-4C的外消旋产物溶于水和乙酸中。加入锌粉,于60℃加热该混合物直至HPLC分析显示几乎无起始原料剩余。通过硅藻土从反应混合物中过滤锌,浓缩滤液。粗品物质经反相HPLC柱层析纯化。合并含有产物的部分,浓缩得到所需的乙脒产物。
实施例-4)将实施例-4D的外消旋物在2.0N HCl中的溶液回流1小时。真空除去溶剂。使得到的固体溶于水中,反复由1.0N HCl浓缩,得到所需的标题(2R/S,5E)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐产物。
流程6
a)2-氟代膦酰基乙酸三乙酯,正丁基锂,THF和己烷
b)DIBAL-H,THF
c)二氯甲烷,三苯膦,咪唑,I2
d)Zn/CuI/CuCN,THF;(S)-2-碘代甲基-N-Boc-丙氨酸甲酯
e)乙酸∶THF∶水(3∶1∶1)
f)聚合物附载的三苯膦,3-甲基-1,2,4-_二唑啉-5-酮,偶氮二甲酸二乙酯,THF
g)手性层析
h)锌粉,乙酸,甲醇,水,加热
i)HCl水溶液,加热
流程7
a)DBU,二氯甲烷
b)硼氢化锂(2M,在THF中)
c)PPh3Br2,吡啶
d)Mg,DMF
e)硼氢化锂(2M,在THF中)
f)PPh3Br2,吡啶
g)NaH,THF
h)1N HCI
i)乙酰胺酸乙酯,碳酸铜
j)1N HCl,回流
实施例5
(2R/S,5E)-2-氨基-2-甲基-5-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例-5A)使膦酰基氟代乙酸酯(10.75mL,53mmol)溶于90mL二氯甲烷中并在氩气下冷却至0℃。加入DBU(8mL,53mmol)。观察到放热,温度升至5℃。于5-10℃搅拌该反应物10分钟。然后将其再次冷却至-5℃。将溶于90mL二氯甲烷中的N-叔丁氧羰基甘氨醛(glycinal)(7g,44mmol)滴加到上述阴离子溶液中。加入期间维持温度在0-5℃之间。将该反应化合物缓慢升至室温并搅拌12小时。得到的混合物用175mL 0.5N硫酸氢钾水溶液提取。用50%氯化钠溶液洗涤有机层,干燥(硫酸钠),过滤并真空汽提,得到深色油状物,为标题物质(10g,92%粗制收率)。
1H NMR(CDCl3)δ:1.3-1.4(m,3H),1.45(s,9H),3.95-4.0(m,2H),4.2-4.4(m,2H),6.0-6.2(m,1H)
实施例-5B)在氩气下,将溶于四氢呋喃中的得自实施例5A的标题物质(8.1g,33mmol)冷却至0℃。然后将在四氢呋喃(20mL,39.6mmol)中的硼氢化锂滴加到该溶液中,同时维持温度在0-5℃之间。使该反应混合物缓慢温热至室温并搅拌12小时。真空除去溶剂。然后使残留物溶于150mL二氯甲烷中,用100mL的0.5N硫酸氢钾水溶液提取该溶液。干燥(硫酸钠)有机层,过滤并真空汽提,得到13g深色油状物,将其经硅胶纯化,以60/40的比例得到Z和E两种异构体的标题物质,总收率(包括重复部分)97%。
Z-异构体:
1H NMR(CDCl3)δ:1.4-1.5(s,9H),3.75-3.85(m,2H),4.24-4.32(m,2H),5.15-5.25(m,1H)
E-异构体:
1H NMR(CDCl3)δ:1.4-1.5(s,9H),3.75-3.78(m,2H),4.1-4.15(m,2H),4.95-5.1(m,1H)
实施例-5C)将得自实施例-5B的E-异构体溶于乙腈中并冷却至0℃。然后加入吡啶(1.5当量),接着用10分钟分批加入固体二溴代三苯基正膦(1.3当量)。于室温、氩气下,将反应混合物搅拌24小时。过滤除去形成的沉淀。真空浓缩滤液,得到一种油状物,将其经硅胶纯化,得到标题物质。
实施例-5D)使得自实施例-5B的化合物溶于无水四氢呋喃中。然后将镁屑(2当量)加入反应容器中。然后将反应混合物加热至回流并维持1小时。加入N,N-二甲基甲酰胺(2当量)。将反应混合物再回流2小时,然后使其冷却至室温。过滤该混合物,真空汽提滤液,得到标题物质。
实施例-5E)在氩气下,将得自实施例-5D的产物溶于四氢呋喃中并冷却至0℃。然后缓慢加入在THF中的硼氢化锂(1.05当量),同时维持温度在0-5℃之间。然后使该反应混合物温热至室温并搅拌该混合物过夜。真空除去溶剂。使残留物溶于二氯甲烷中,用0.5N硫酸氢钾水溶液提取。有机层用50%氯化钠溶液洗涤,干燥(硫酸钠)并汽提,得到标题物质。
实施例-5F)将得自实施例-5E的产物溶于乙腈中。将该溶液冷却至0℃,然后加入吡啶(1.5当量),接着用10分钟分批加入固体二溴代三苯基正膦(1.3当量)。于室温、氩气下,将反应混合物搅拌24小时。过滤除去形成的沉淀。真空浓缩滤液,得到一种油状物,将其经硅胶纯化,得到所需的溴代衍生物。
实施例-5G)将N-对-氯代苯基亚胺丙氨酸甲酯溶于四氢呋喃中,用氩气清洗该溶液。然后加入NaH(1.2当量),由此该溶液变为亮橙色,接着变为深红色。将得自实施例-5F的标题物质的四氢呋喃溶液加入到上面的阴离子溶液中。预计放热会使温度上升至接近40℃。将反应混合物维持在48-52℃之间2小时,然后使其冷却至室温并过滤。真空汽提滤液,得到标题物质。
实施例-5H)用1N盐酸处理实施例-5G的产物,于室温下搅拌该溶液1小时。用乙酸乙酯提取该溶液,于56℃真空汽提水层,得到标题物质。
实施例-5I)使实施例-5H的产物溶于蒸馏水中,然后用1N NaOH将pH调节为7,之后加入碳酸铜(0.5当量)。将反应混合物回流2小时,然后冷却至室温并过滤。搅拌下,将乙酰胺酸乙酯盐酸盐(1.1当量)分批加入到该滤液中,在每批加入后将pH调节至8.5。搅拌反应混合物1小时,然后将其上样于阳离子交换树脂柱,用0.8N氨水溶液洗脱。从洗脱液中真空除去氨。随后将洗脱液用2N盐酸酸化至pH 2,浓缩至干。然后使残留物经反相HPLC纯化,得到标题物质。
实施例-5)将实施例-5I的产物溶于2N盐酸中。将该反应化合物加热至回流并搅拌6小时,然后使其冷却至室温。接着真空除去溶剂。使残留物溶于水中,接着在旋转蒸发器上汽提,除去过量的盐酸。使残留物再次溶于水中并冻干,得到标题E-异构体产物。
实施例6
(2R/S,5Z)-2-氨基-2-甲基-5-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例6A)使得自实施例5B的Z-异构体溶于乙腈中,将该溶液冷却至0℃。然后加入吡啶(1.5当量),接着用10分钟分批加入固体二溴代三苯基正膦(1.3当量)。于室温、氩气下,将反应混合物搅拌24小时。过滤除去形成的沉淀。真空浓缩滤液,得到一种油状物,将其经硅胶纯化,得到标题物质。
实施例6B)使得自实施例6A的产物溶于无水四氢呋喃中。然后将镁屑(2当量)加入该溶液中。将反应混合物加热至回流并维持1小时。然后加入N,N-二甲基甲酰胺(2当量)。将反应混合物再回流2小时,冷却至室温并过滤该混合物,真空汽提滤液,得到标题物质。
实施例6C)在氩气下,将实施例6B的产物溶于四氢呋喃中并将该溶液冷却至0℃。缓慢加入在THF中的硼氢化锂(1.05当量),同时维持温度在0-5℃之间。使该反应混合物升至室温,搅拌该混合物过夜。真空除去溶剂。使残留物溶于二氯甲烷中,用0.5N硫酸氢钾水溶液提取。有机层用50%氯化钠溶液洗涤,干燥(硫酸钠)并汽提,得到标题物质。
实施例6D)将实施例6C的产物溶于乙腈中。将该溶液冷却至0℃,然后加入吡啶(1.5当量),接着分批加入固体二溴代三苯基正膦(1.3当量)。于室温、氩气下,将反应混合物搅拌24小时。过滤除去形成的沉淀。真空浓缩滤液,得到一种油状物,将其经硅胶纯化,得到所需的标题溴代衍生物。
实施例-6E)将N-对-氯代苯基亚胺丙氨酸甲酯溶于四氢呋喃中,用氩气清洗该溶液。然后加入NaH(1.2当量),由此该溶液变为亮橙色,接着变为深红色。将实施例6D的产物的四氢呋喃溶液加入到上面的阴离子溶液中。观察到放热,将反应化合物维持在48-52℃之间2小时。将反应物冷却至室温并过滤。真空汽提滤液,得到标题物质。
实施例6F)用1N盐酸处理实施例6E的产物,于室温下搅拌该溶液1小时,然后用乙酸乙酯提取该溶液。于56℃真空汽提水层,得到标题物质。
实施例6G)使实施例6F的产物溶于蒸馏水中。用1N NaOH将pH调节为7,然后加入碳酸铜(0.5当量)。将反应混合物回流2小时,然后冷却至室温并过滤。搅拌下,将乙酰胺酸乙酯盐酸盐(1.1当量)分批加入到该滤液中,在每批加入后将pH调节至8.5。搅拌反应混合物1小时,然后将其上样于阳离子交换树脂柱,用0.8N氨水溶液洗脱。从洗脱液中真空除去氨。随后将洗脱液用2N盐酸酸化至pH 2,浓缩至干。然后使残留物经反相HPLC纯化,得到标题物质。
实施例6)将实施例6G的产物溶于15mL 2N盐酸中。将该溶液加热至回流并搅拌6小时,然后使其冷却至室温。接着真空除去溶剂。使残留物溶于25mL水中,接着在旋转蒸发器上汽提,以除去过量的盐酸。使残留物溶于水中并冻干,得到标题Z-异构体。
实施例7
(2R,5E)-2-氨基-2-甲基-5-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例8
(2S,5E)-2-氨基-2-甲基-5-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
流程8
a)1.DAST
2.NBS,过氧化苯甲酰
b)3-甲基-1,2,4-_二唑啉-5-酮的钾盐,DMSO,加热
c)DIBAL-H,THF
d)二氯甲烷,三苯膦,咪唑,I2
e)Zn/CuI/CuCN,THF;(S)-2-碘代甲基-N-Boc-丙氨酸甲酯
f)锌粉,乙酸,水,加热
g)HCl水溶液,加热
实施例9
(2S,5Z)-2-氨基-2-甲基-5,6-二氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例10
(2R,5Z)-2-氨基-2-甲基-5,6-二氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例11
(2R/S,5Z)-2-氨基-2-甲基-5,6-二氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
流程9
a)2-氟代膦酰基乙酸三乙酯,DBU,THF和己烷
b)硼氢化钠,甲醇,水
c)聚合物附载的三苯膦,3-甲基-1,2,4-_二唑啉-5-酮,偶氮二甲酸二乙酯,THF
d)乙酸∶THF∶水(3∶1∶1)
e)二氯甲烷,三苯膦,咪唑,I2
f)1.NMP,BEMP,N-[(4-氯代苯基)亚甲基]丙氨酸甲酯
2.HCl水溶液
g)1.二氯甲烷,碳酸二叔丁酯,三乙胺
2.手性层析
h)锌粉,乙酸,甲醇,加热
i)HCl水溶液,加热
实施例12
(2S,5Z)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
流程10
a)KOH
b)MeI
c)TBSCl
d)DIBAL
e)MsCl
f)3-甲基-1,2,4-_二唑啉-5-酮钾盐
g)AcOH
h)Tf2O
i)KHMDS/(2S,4S)-3-苯甲酰基-2-叔丁基-4-甲基-1,3-_唑烷-5-酮
j)Lindlar催化剂
k)6N HCl
实施例13
(2S,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例-13A)通过Harold,Mohr和Tamm Helvetica Chimica Acta 66,2,1983 744-754的方法,由5,5-二氢-2-吡喃酮(Aldrich)制备标题化合物,(Z)-5-叔丁基二甲基甲硅烷基氧基-2-戊烯-1-醇。
实施例-13B)向实施例-13A(720mg,3.3mmol)的二氯甲烷(25mL)溶液中加入三乙胺(525mg,5.3mmol)和甲磺酰氯(561mg,4.90mmol)。将反应混合物于0℃搅拌15分钟,然后于室温下搅拌16小时。加入额外的二氯甲烷。用碳酸氢钠和盐水提取该溶液,然后干燥,得到790mg黄色油状物。使该油状物溶于DMF(20mL)中,将3-甲基-1,2,4-_二唑啉-5-酮的钠盐(513mg,3.7mmol)加入该反应混合物中。于50℃搅拌所得溶液16小时。真空除去溶剂,使残留物分配于乙酸乙酯和盐水之间。干燥(硫酸钠)有机层,浓缩得到一种油状物,将其经硅胶快速柱层析纯化,用乙醚∶己烷(1∶1)洗脱,得到780mg(79%)所需的被护Z-烯丙型的环脒产物,为澄清油状物,经1H NMR分析该油仅含有所需的Z-异构体。
实施例-13C)将实施例-13B(100mg,0.34mmol)在乙酸(1mL),THF(3mL)和水(1mL)的混合液中的溶液在室温下搅拌16小时。将生成的溶液真空浓缩至油状物,使其溶于EtOAc中。用饱和碳酸氢钠水溶液洗涤有机层,干燥(硫酸钠),过滤并蒸发,得到80mg(定量)所需的醇标题产物,为澄清无色油状物。
实施例-13D)于0℃,向实施例-13C(80mg,0.43mmol)的二氯甲烷(3mL)溶液中加入三乙胺(44mg)和三氟甲磺酸酐(triflic anhydride)(146mg,0.52mmol),将该混合物搅拌1.5小时。真空浓缩该溶液。粗品物质经硅胶快速柱层析纯化,用EtOAc∶己烷(1∶1)洗脱,得到62mg(44%)所需的三氟甲磺酸酯产物,为澄清油状物。
实施例-13E)于-78℃,向(2S,4S)-3-苯甲酰基-2-叔丁基-4-甲基-1,3-_唑烷-5-酮(Ref.)(532mg,2.04mmol)的THF(10mL)溶液中加入KHMDS(4.48mL,2.2mmol,0.5M,在THF中)。将生成的橙色溶液搅拌15分钟,接着加入实施例13D的产物(580mg,1.8mmol)。使生成的溶液温热至室温,接着加入硫酸氢钾(10%,1.5mL)、盐水和分离有机层,干燥,真空浓缩,得到960mg的黄色油状物。粗品物质经硅胶快速柱层析纯化,用EtOAc。
EtOAc∶己烷(1∶1)洗脱,得到138mg(18%)所需的烷基化标题产物,为澄清油状物。
实施例-13)向实施例-13E的产物(138mg,0.32mmol)的甲醇(10mL)溶液中加入Lindlar催化剂(260mg)。将搅拌的浆状物回流2小时,然后冷却至室温。通过硅藻土过滤除去催化剂,汽提滤液,得到所需的去保护的脒产物,为淡黄色油状物。将黄色油状物的HCl(6N,10mL)溶液回流1.75小时。真空除去溶剂,生成的泡沫物经反相HPLC纯化,用30分钟的0-40%乙腈/水(0.25%乙酸)梯度液洗脱,合并含有产物的流分,浓缩至泡沫物,得到34mg(20%)标题产物。对于C10H19N3O2的MS计算值:m/z=214[M+H]+,实测值:214.(100%)
使一盐酸盐产物溶于1N HCl中,真空(2x)除去溶剂,得到所需的(2S,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐产物。
对于C10H19N3O2
的MS计算值:m/z=214[M+H]+,实测值:214(100%)
1H NMR(D2O)δ1.40(s,3H),1.5-2.0(m,4H),1.90(s,3H),3.55(m,2H),5.15-5.25(m,乙烯基,1H),5.30-5.45(m,乙烯基,1H)。
流程11
(a)3,4-二氢-2-H-吡喃,浓HCl
(b)EtMgCl,(CH2O)n,THF
(c)Lindlar/H2
(d)MsCl,三乙胺,THF
(e)3-甲基-1,2,4-_二唑啉-5-酮的钠盐,DMF
(f)PTSA,MeOH
(g)MsCl,三乙胺,THF
(h)NaI,丙酮
(i)2-[(3,4-二氯-亚苄基)-氨基]-丙酸甲酯,碳酸铯,DMF,2-PTSA
(j)手性分离
(k)Lindlar催化剂,甲酸
(l)HCl
实施例14
(2S,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
4-[(四氢吡喃基)氧基]丁炔
实施例14A)将4-二氢-2H-吡啶(293.2g,3.5mol)和浓HCl(1.1mL)的混合物冷却至5℃。在继续外部冷却的同时,用30分钟加入3-丁炔-1-醇(231.5g,3.3mol),使温度达到50℃。于室温下维持反应物混合2.5小时,然后用MTBE(1.0L)稀释。使得到的混合物用饱和碳酸氢钠(2×150rnL)洗涤。经硫酸钠干燥有机相,减压浓缩,得到500g(98%粗品收率)产物;GC面积%为96%。
5-(四氢-吡喃-2-基氧基)-戊-2-炔-1-醇
实施例14B)在氮气氛下,用30分钟向实施例14A的4-[(四氢吡喃基)氧基]丁炔产物(50.0g,0.33mol)的THF(125mL)溶液中加入2NEtMgCl的THF(242mL,0.48mol)溶液,使温度升至48℃。将该混合物进一步加热至66℃,于该温度下维持2小时,然后冷却至室温。加入低聚甲醛(14.5g,0.48mol)(观察到稍稍放热),将得到的混合物加热至45℃。将温度控制在45-55℃之间1小时后,该混合物变得澄清。此时,将该混合物加热至66℃,并搅拌2.5小时。将该混合物冷却至室温,用30分钟缓慢加入饱和氯化铵(125mL)(观察到强放热),保持温度低于40℃。通过倾析分离液相;加入乙酸乙酯(250mL)和盐水(50mL)。分离有机相,用盐水(2×50mL)和水(1×50mL)洗涤,经硫酸钠干燥有机层,减压浓缩,得到51g淡黄色油状物(85%粗品收率);GC面积%=88%标题产物,6%起始原料。
5-(四氢-吡喃-2-基氧基)-戊-2-烯-1-醇
实施例14C)在氮气氛下,向一个500mL Parr瓶中加入实施例14B的5-(四氢-吡喃-2-基氧基)-戊-2-炔-1-醇产物(40.2g,0.22mol)、Lindlar催化剂(2.0g)、乙醇(120mL)、己烷(120mL)和2,6-二甲基吡啶(457mg)。用氮气和氢气分别清洗该反应混合物5次。用氢气使Parr瓶加压至5psi并振摇直至98%的理论氢被消耗。从该瓶中释放氢,用氮气清洗该反应物5次。通过Solka Floc垫过滤该混合物,用乙醇(2×50mL)淋洗催化剂。合并滤液和洗液,减压浓缩,得到40.3g(99%收率)标题物质,为黄色油状物(GC面积%=96%)。
3-甲基-4-[5-(四氢-吡喃-2-基氧基)-戊-2-烯基]-4H-[1,2,4]_二唑-5-酮
实施例14D)向实施例14C的5-(四氢-吡喃-2-基氧基)-戊-2-烯-1-醇产物(11.8g,0.063mol)的甲苯(42mL)溶液中加入三乙胺(6.4g,0.063mol)。将该混合物冷却至-5℃,以保持温度低于10℃的速率,通过注射器加入甲磺酰氯(7.3g,0.63mol)。将该混合物温热至室温并搅拌2小时。通过抽吸过滤该混合物,并用甲苯(2×20mL)在过滤器上淋洗。将滤液和洗液加入到3-甲基-1,2,4-_二唑啉-5-酮的钠盐(8.6g,0.063mol)在DMF(10mL)中的混合物中。用机械搅拌器搅拌该混合物,于45℃加热5小时。加入水(40mL),搅拌该混合物5分钟,然后分离各层。甲苯层用水(3×20mL)洗涤,经硫酸镁干燥,浓缩,得到16.5g(97.3%)橙色粗产物(面积%GC由71%标题产物,18%甲苯和4%杂质组成)。
4-(5-羟基-戊-2-烯基)-3-甲基-4H-[1,2,4]_二唑-5-酮
实施例14E)向实施例14D的3-甲基-4-[5-(四氢-吡喃-2-基氧基)-戊-2-烯基]-4H-[1,2,4]_二唑-5-酮产物(16g,0.06mol)的甲醇(48mL)溶液中加入对甲苯磺酸(0.34g,2.0mmol)。在室温下搅拌该混合物4小时。加入碳酸氢钠(0.27g,3.0mmol),在旋转蒸发器上浓缩该混合物。用饱和碳酸氢钠(20mL)稀释残留物,将得到的混合物用乙酸乙酯(2×60mL)提取。合并提取物,用水(2×25mL)洗涤,经硫酸镁干燥,浓缩得到8.4g粗橙色油产物(面积%GC=80%)。
甲磺酸5-(3-甲基-5-氧代-[1,2,4]_二唑-4-基)-戊-3-烯基酯
实施例14F)向实施例14E的4-(5-羟基-戊-2-烯基)-3-甲基-4H-[1,2,4]_二唑-5-酮产物(8.27g,0.045mol)的二氯甲烷(33mL)溶液中加入三乙胺(5.0g,0.49mol)。将该混合物冷却至-5℃,以保持温度低于8℃的速率加入甲磺酰氯(5.5g,0.048mol)。移去冷却浴,当混合物温热至室温时将其搅拌3小时。加入水(15mL),将该混合物搅拌5分钟,然后分离各层。用水(10mL)洗涤有机相,经硫酸镁干燥,浓缩,得到浅琥珀色残留物。使残留物溶于乙酸乙酯(8mL)中,维持于5℃过夜。通过抽吸滤出沉淀的固体,用最少体积的乙酸乙酯在过滤器上淋洗,然后在过滤器上风干,得到6.8g(58%收率)标题产物。
1H NMR(CDCl3)δ5.76(dtt,J=10.9,7.5,1.5Hz,1H),δ5.59(dtt,J=10.9,7.0,1.5Hz,1H),δ4.31(t,J=6.3Hz,2H),δ4.27(dd,J=7.0,1.5Hz,2H),δ3.04(s,3H),δ2.67(q,J=6.7Hz,2H),δ2.28(s,3H)
13C(CDCl3)δ159.0,156.3,129.9,125.1,68.4,38.9,37.2,27.5,10.2。IR(cm-1)1758,1605,1342,1320,1170。
对于C9H14N2O5S的分析计算值:C,41.21;H,5.38;N,10.68.实测值:C,41.15;H,5.41;N,10.51。
4-(5-碘代-戊-2-烯基)-3-甲基-4H-[1,2,4]_二唑-5-酮
实施例14G)向实施例14F的甲磺酸5-(3-甲基-5-氧代-[1,2,4]_二唑-4-基)-戊-3-烯基酯产物(20.0g,0.076mol)的丙酮(160ml)溶液中加入碘化钠(17.15g,0.114mol)。将该混合物加热至回流并搅拌3小时。停止外部加热,将混合物维持在室温下过夜。过滤除去固体,并在过滤器上淋洗。合并滤液和洗液,浓缩,用乙酸乙酯(120mL)提取多相残留物,用水(60mL),15%硫代硫酸钠水溶液(60mL)和水(60mL)洗涤有机层;经硫酸镁干燥,减压浓缩,得到22.1g(98%收率)标题油状产物。
2-[(3,4-二氯-亚苄基)-氨基]-丙酸甲酯
实施例14H)在氮气氛下,用12分钟向机械搅拌的L-丙氨酸甲酯盐酸盐(200.0g,1.43mol)的二氯甲烷(2.1L)浆液中加入三乙胺(199.7mL,1.43mol)(加入期间,固体部分溶解,然后再沉淀)。10分钟后,加入3,4-二氯代苯甲醛(227.5g,1.30mol)和硫酸镁(173.0g,1.43mol)(在30分钟内温度升高6℃)。2.5小时后,过滤该混合物。用水(1×1L)和盐水(1×500mL)洗涤滤液,经硫酸钠干燥,过滤、浓缩,得到313.3g(92.4%收率)的油状产物。
1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.91(d,1H),7.58(dd,1H),7.49(d,1H),4.17(t,1H),3.76(s,3H),1.53(d,3H)。对C11H11Cl2NO2的分析计算值:C,50.79;H,4.26;Cl,27.26;N,5.38.实测值:C,50.37;H,4.10;Cl,26.87;N,5.38。
外消旋-2-氨基-2-甲基-7-(3-甲基-5-氧代-[1,2,4]_二唑-4-基)-庚-5-烯酸甲酯
实施例14I)方法A.在氮气氛下,将实施例14G的产物(114.2g,0.39mol)和实施例14H的产物(151.5g,0.58mol)的二甲基甲酰胺(1.4L)溶液冷却至-8℃。然后用19分钟,分3等份加入碘化锂(78.1g,0.58mol)。
于-7℃搅拌该混合物20分钟,然后用36分钟加入(叔丁基亚氨基)-三(吡咯烷基)正膦(194.0mL,0.62)(最高温度=-2.6℃)。10分钟后,移去冷却浴,于室温下将该溶液搅拌1小时。然后将该混合物倾入冷水(1.4L)中,用乙酸乙酯(2×1.0L)提取。合并的有机层用水(2×400mL)和盐水洗涤。用1N HCl(780mL)处理乙酸乙酯层并搅拌1小时。分离水层,用乙酸乙酯(2×400mL)提取,然后用碳酸氢钠(110g)中和。用乙酸乙酯(1×500mL)提取该混合物。有机层经硫酸钠干燥,过滤、浓缩,然后用甲基叔丁基醚处理,得到结晶产物:第一次收获14.4g;第二次收获6.6g(GC纯度分别=96.2和91.9%)。用氯化钠饱和水相,用乙酸乙酯(4×500mL)提取。合并的有机层经硫酸钠干燥,过滤、浓缩,接着用甲基叔丁基醚处理,得到结晶产物:第一次收获33.4g;第二次收获10.8g(GC纯度分别=89.6和88.8%)。总粗品产量65.2g,62.4%。
方法B.在氮气氛下,向实施例14G的产物(20.7g,0.070mol)和实施例14H的产物(22.9g,0.088mol)的二甲基甲酰胺(207mL)溶液中加入碳酸铯(29.8g,0.092)。于室温下搅拌该混合物16小时,然后用水(300mL)稀释,用乙酸乙酯(2×200mL)提取。合并的乙酸乙酯层用水(3×100mL)和盐水洗涤,然后用1N HCl(184mL)处理。1小时后,分离各层,用乙酸乙酯(3×100mL)提取水层,然后用碳酸氢钠(15.5g)中和。用乙酸乙酯(1×150mL)提取该混合物。水层用氯化钠饱和,用乙酸乙酯(3×100mL)提取。合并的有机层经硫酸钠干燥,过滤并浓缩,得到黄色固体,11.9g,62.9%;GC纯度=96.6%.粗产物从温热的甲基叔丁基醚或乙酸乙酯中重结晶。
1H NMR(400MHz,CDCl3)δ5.68(m,1H),5.36(m,1H),4.23(d,2H),3.73(s,3H),2.43(s,3H),2.18(m,2H),1.81(m,1H),1.69(s,br,2H),1.66(m,1H),(1.36,3H)
13C NMR(400MHz,CDCl3)δ177.60,159.01,156.10,135.12,121.82,57.48,52.29,40.12,39.00,26.62,22.56,10.41
外消旋-2-氨基-2-甲基-7-(3-甲基-5-氧代-[1,2,4]_二唑-4-基)-庚-5-烯酸
实施例14J)在氩气下,使实施例14J的产物(0.269g,1mmol)溶于5mL2N HCl中并加热至回流。回流6小时后,于室温下搅拌72小时,取一等分试样,经1H NMR检查。剩余约6%未反应的原料酯以及所需的产物(经LC-MS证实)。真空除去含水部分,得到0.38g稠的琥珀色油状物。经反相层析纯化,之后冻干,得到0.23g,90.2%的标题化合物,为白色不易潮解的固体。
对于C11H17N3O4.0.77H2O的分析计算值:C,49.09;H,6.94;N,15.61.实测值:C,48.71;H,6.94;N,15.98
质谱:M+1=256。
(2S,5Z)-2-氨基-2-甲基-7-(3-甲基-5-氧代-[1,2,4]_二唑-4-基)-庚-5-烯酸甲酯
实施例14K)使用Novaprep 200设备在稳态再循环选项下经制备手性层析,从标题化合物的R对映体分离标题化合物(827.3g)。使该物质以40mg/ml的浓度溶于无水乙醇中并上样到50×500mm预填充的Chiral Technologies不锈钢柱上。吸附剂为20μChiralPak AD。流动相为乙醇/三乙胺100/0.1;流速为125ml/分钟。每12分钟将粗制溶液(25mL)上样到该柱上一次。采用稳态再循环技术。用rotovap除去溶剂。分离出为金色油状物的最终产物,它在静置下固化;399.0g(96.4%回收率)。
1H(400MHz,CD3OD)δ5.68(dtt,1H,J烯属的=10.7Hz),5.43(dtt,1H,J烯 属的=10.7Hz),4.82(s,br,2H),4.28(d,2H,J=5.5Hz),3.73(s,3H),2.27(s,3H),2.26(m,1H),2.14(m,1H),1.82(ddd,1H,J=13.6,11.3,5.4Hz),1.67(ddd,1H,J=13.6,11.2,5.5Hz),1.34(s,3H)
13C NMR(400MHz,CD3OD)δ178.49,161.13,158.70,135.92,123.47,58.55,52.77,41.38,39.96,26.23,23.47,10.23
对C12H19N3O4的分析计算值:C,53.52;H,7.11;N,15.60。实测值:C52.35;H,7.20;N,15.60。
(2S,5Z)-7-亚氨代乙酰基氨基-2-氨基-2-甲基-庚-5-烯酸甲酯,二盐酸盐水合物
实施例14L)于室温下,向实施例14K的产物(114.5g,0.425mol)的甲醇(2.4L)溶液中加入固体二苯甲酰基-L-酒石酸(152.5g,0.425mol)和88%甲酸(147mL,3.428mol)。在氩气下制备Lindlar催化剂(被乙酸铅毒害的载于碳酸钙上的5%重量钯,37.9g)在甲醇(200mL)中的淤浆。然后于室温下将起始原料的溶液加入到浅灰色的催化剂淤浆中,接着经甲醇清洗(200mL)。于45℃加热多相反应混合物1.5小时。在约40℃时开始观察到稳定的气体放出,这表明反应正在进行。将该混合物在冰/水浴中冷却,然后通过Supercell HyFlo柱过滤。真空浓缩黄色的溶液,得到粘性油状物,使其溶解并分配于2N HCl水溶液(2L)和乙酸乙酯(0.8L)之间。分离各层,水层用乙酸乙酯(0.8L)洗涤1次。于升高的温度(=70℃)下真空除去溶剂和挥发物。中间体产物无须进一步纯化或鉴定而用于下一步骤。LC-MS[M+H]+=228。实施例14)使实施例14L的粗产物(170g)溶于2N HCl水溶液(1L)中。将生成的橙色溶液回流过夜,然后使其再冷却至室温。将反应混合物浓缩至其体积的约1/3,使该酸性溶液通过固相提取柱(25g的C18硅胶),以除去颜色和其它杂质。真空除去溶剂(=70℃),得到208g为黄色胶状物的粗产物。
使粗制胶状物(31.3g)溶于水(250mL)中,将该物质上样到填充有酸性树脂Dowex 50WX4-400(约600g)的预处理离子交换柱上。该树脂先用水(1L)洗涤,然后用稀HCl水溶液(1L的10/90v/v浓HCl/水)洗涤。用较高离子浓度的HCl水溶液(1.5L的20/90v/v至25/75v/v浓HCl/水)洗脱产物。真空除去含水溶剂(=70℃),使胶状残留物溶于4%体积三氟乙酸水溶液(100mL)中。真空(=70℃)除去含水溶剂,重复该步骤1次,然后在高真空下干燥残留物,得到32.2g胶状物,为三氟乙酸盐。
粗制(2S,5Z)-7-亚氨代乙酰基氨基-2-氨基-2-甲基-庚-5-烯酸,双三氟乙酸盐水合物(32.2g)经反相制备层析纯化。使粗品溶于0.1%TFA水溶液(50ml)中,并上样到填充有吸收剂(BHK极性W/S,50μ,1.16kg)的2英寸IDx1米不锈钢柱上。用0.1%TFA水溶液-25/75/0.1乙腈/水/TFA的分级梯度液,以120mL/分钟的流速洗脱产物。上样比例为36∶1w/w硅胶/样品。真空除去溶剂,通过反复用稀HCl水溶液淋洗,将所述物质转化为HCl盐,真空除去溶剂。在高真空下干燥得到27.4g标题二盐酸盐水合物,为黄色胶状物。
LC-MS[M+H]+=214.16Da
1H NMR(D2O,δ):1.48(s,3H),1.8-1.9(AB,2H),2.10(s,3H),2.01/2.12(AB,2H),3.78(d,2H),旋转异构体3.87(d,2H),5.6/5.5(dt,2H,11Hz)
13C NMR(D2O)δ:18.7,21.5,21.6,36.4,39.1,59.8,122.6,134.3,164.5,173.7
对于C10H19N3O2·2.2HCl·2H2O的元素分析计算值:C,36.21;H,8.33;N,12.67;Cl,23.51.实测值:C,36.03;H,7.72;N,12.67;Cl, 23.60。
实施例15
(2R,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
将在实施例14K中所述分离期间分离的R-对映体(1.13g,4.2mmol)溶于11mL 25%乙酸水溶液中,加热至60℃。然后以30分钟的间隔分4等份加入锌粉(1.10g)。总共加热3小时后,取出1等分试样,经LC-MS检查,表明仅有剩余的痕量未反应起始原料和所需的产物。将该混合物冷却至室温,过滤并真空汽提,得到2.31g浆状白色固体。用稀的热HCl将甲酯水解为标题化合物。经反相层析纯化后,接着冷冻干燥,得到0.31g标题化合物,为玻璃状固体。
对于C10H19N3O2·1.22HCl·1.15H2O的分析计算值:C,46.13;H,8.15;N,15.09;Cl,15.53。
实测值:C,46.38;H,8.51;N,15.13;Cl,15.80
质谱:M+1=214
实施例16
(2R/S,5E)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例16A)通过Harold,Mohr和Tamm Helvetica Chimica Acta 66,2,1983 744-754的方法,从5,5-二氢-2-吡喃酮(Aldrich)制备(E/Z)-5-叔丁基二甲基甲硅烷基氧基-2-戊烯-1-醇样品。
实施例16B)于0℃,向实施例16A的产物(17.7gm,81.8mmol)的THF(230mL)溶液中加入三乙胺(12.4gm,122.7mmol),接着加入甲磺酰氯(11.25gm,98.2mmol),以使ΔT<+10℃(约30分钟)。于0℃将反应混合物再搅拌1小时。然后加入饱和碳酸氢钾的25mL等分试样,接着加入25mL去离子水。分离各层,用25mL 5%柠檬酸溶液洗涤有机物,接着用25mL盐水洗涤。然后经硫酸镁干燥有机层,过滤、接着真空浓缩,得到23.3gm(79.1mmol)黄色油状物。1H NMR指示甲磺酰化的醇以2∶1比例(E∶Z)存在。使该油状物溶于DMF(225mL)中,向该溶液中加入3-甲基-1,2,4-_二唑啉-5-酮的钠盐(17.7gm,118.6mmol),搅拌该混合物48小时。然后浓缩该混合物,使其分配于EA和水之间。分离有机层,然后用盐水洗涤,经硫酸镁干燥。过滤悬浮液,真空浓缩,得到23gm所需的烷基化产物(2∶1,E∶Z,经1HNMR分析)。该物质经柱层析(5%IPA:庚烷)纯化,得到3g纯的所需标题E异构体(经1H NMR分析)。
实施例16C)向实施例16B的产物(3gm)的THF(6mL)溶液中加入冰乙酸(6mL)和5mL水。在室温下搅拌该反应物5小时,然后真空浓缩,得到2.25g所需物质(经1H NMR分析)。然后该粗制混合物无须纯化而使用。
实施例16D)向-10℃的咪唑(1.49gm,21.96mmol)和三苯膦(3.84g,14.65mmol)的二氯甲烷(25mL)溶液中加入碘(3.71g,14.65mmol)。向该混合物中滴加入实施例16C(2.25g,12.2mmol)的二氯甲烷溶液。然后于室温下搅拌混合物5小时。将粗制混合物倾入到5X10cm的硅胶垫上,用20%EA:己烷洗脱产物。然后浓缩有机物,得到3.6gm油性碘代衍生物。然后使碘化锂(2.46gm,18.36mmol)溶于DMF(30mL)中并冷却至-10℃。向该溶液中加入实施例14H的产物(4.8g,18.36mmol),接着加入碘代化合物(3.6gm,12.2mmol)。然后滴加入BTTP(6.1gm,19.5mmol)。从-10℃至室温搅拌18小时后,将反应混合物转移至分液漏斗中,用120mL EA稀释。有机层用80ml水洗涤,经硫酸镁干燥,过滤并CIV得到4.1g产物。1H NMR显示该产物为所需的化合物,它可用于随后的反应。
实施例16E)使实施例16D的产物(4.1g)溶于15mL EA中。向其中加入50mL的1N HCl,在室温下搅拌该混合物4.5小时。将反应物转移至分液漏斗中,分离酸性层,用15mL 1N HCl洗涤有机层,用碳酸氢钾将合并的水层调节至pH为约7.5。通过用50mL二氯甲烷洗涤水层3次来分离游离的碱。将其经硫酸镁干燥,过滤并经CIV得到3.2g。残留物经反相HPLC纯化,得到1g纯的所需E标题化合物。
1H NMR(CDCl3)δ1.33(s,3H),1.6-1.7(m,1H),1.75-1.85(m,1H),1.95-2.2(m,2H),2.25(s,3H),3.7(s,3H),4.12(d,2H,J=6Hz),5.45-5.55(m,1H),5.65-5.75(m,1H)
实施例16F)向反应管中加入在10mL甲醇中的180mg实施例16E的产物。向该溶液中加入360mg Lindlar催化剂(200mol%)和300μL甲酸。密封该试管并加热至60℃18小时。使该反应物冷却并通过硅藻土过滤。向滤液中加入2mL的1N HCl,经CIV得到150mg标题产物。1H NMR指示了所需的向脒的转化。该物质无须纯化用于下一步反应。
1H NMR(D2O)δ1.5(s,3H),1.85-2.05(m,3H),2.1-2.2(m,1H),2.15(s,3H),3.7(s,3H),3.9(d,2H,J=6Hz),5.55-5.65(m,1H),5.70-5.80(m,1H)。
实施例16)使实施例16F的产物(100mg)溶于10mL 2N HCl中并回流24小时。对等分试样的1H NMR表明水解完全。因此,CIV得到90mg粗制氨基酸。该物质经反相HPLC纯化,得到78mg纯的所需标题E异构体。
1H NMR(D2O)δ1.5(s,3H),1.90-2.15(m,3H),2.18-2.29(m,1H),2.22(s,3H),3.95(d,2H,J=6Hz),5.55-5.65(m,1H),5.70-5.80(m,1H)元素分析(对于所需的含有2.3mol HCl和0.5mol水的标题产物);C%(计算值)39.23,(实测值)39.21,H%(计算值)7.34(实测值)7.51,N%(计算值)13.73(实测值)13.48。
流程13
(a)Li/NH3
(b)BrCH2CH2Cl
(c)Boc2O
(d)N-(二苯基亚甲基)-L-丙氨酸甲酯
(e)HCl
(f)乙酰亚胺酸乙酯盐酸盐
(g)HCl
实施例17
(2R/S)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚炔酸,二盐酸盐
实施例18
(2S,5E)-2-氨基-2-乙基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例19
(2S,5E)-2-氨基-2-甲氧基甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例20
(2S,5E)-2-氨基-2-氟代甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例21
(2S,5E)-2-氨基-2,5-二甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例22
(2S,5Z)-2-氨基-5-氟代甲基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例23
(2S,5E)-2-氨基-2,6-二甲基-5-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例24
(2S,5Z)-2-氨基-6-氟代甲基-2-甲基-5-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例25
(2S,5Z)-2-氨基-2-乙基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例26
(2S,5Z)-2-氨基-2-甲氧基甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例27
(2S,5Z)-2-氨基-2-氟代甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例28
(2S,5Z)-2-氨基-2,5-二甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例29
(2S,5E)-2-氨基-5-氟代甲基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例30
(2S,5Z)-2-氨基-2,6-二甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例31
(2S,5E)-2-氨基-6-氟代甲基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸,二盐酸盐
实施例32
(2S)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚炔酸,二盐酸盐新的中间体
用于合成本发明化合物的新中间体包括:
4-[(2E)-5-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]-2-氟代-2-戊烯基]-3-甲基-1,2,4-_二唑-5(4H)-酮;
4-[(2E)-2-氟代-5-羟基-2-戊烯基]-3-甲基-1,2,4-_二唑-5(4H)-酮;
4-[(2E)-2-氟代-5-碘代-2-戊烯基]-3-甲基-1,2,4-_二唑-5(4H)-酮;
(3S,6R)-3-[(3E)-4-氟代-5-(3-甲基-5-氧代-1,2,4-_二唑-4(5H)-基)-3-戊烯基]-3,6-二氢-3-甲基-6-(1-甲基乙基)-5-苯基-2H-1,4-_嗪-2-酮;
N-[(2E)-5-[(3S,6R)-3,6-二氢-3-甲基-6-(1-甲基乙基)-2-氧代-5-苯基-2H-1,4-_嗪-3-基]-2-氟代-2-戊烯基]乙脒;
(5E)-2-氨基-6-氟代-2-甲基-7-(3-甲基-5-氧代-1,2,4-_二唑-4(5H)-基)-5-庚烯酸甲酯;
(2S,5E)-2-氨基-6-氟代-2-甲基-7-(3-甲基-5-氧代-1,2,4-_二唑-4(5H)-基)-5-庚烯酸甲酯;
(2S,5E)-2-氨基-6-氟代-7-[[(1E)-1-(羟基亚氨基)乙基]氨基]-2-甲基-5-庚烯酸;
(2S,5E)-2-氨基-6-氟代-7-[(1-亚氨基乙基)氨基]-2-甲基-5-庚烯酸甲酯;
(2R,5E)-2-氨基-6-氟代-2-甲基-7-(3-甲基-5-氧代-1,2,4-_二唑-4(5H)-基)-5-庚烯酸甲酯;
(2R,5E)-2-氨基-6-氟代-7-[(1-亚氨基乙基)氨基]-2-甲基-5-庚烯酸乙酯;
(5E)-2-氨基-6-氟代-7-(3-甲基-5-氧代-1,2,4-_二唑-4(5H)-基)-5-庚烯酸甲酯;
(5E)-2-[[(1Z)-(4-氯代苯基)亚甲基]氨基]-6-氟代-7-(3-甲基-5-氧代-1,2,4-_二唑-4(5H)-基)-5-庚烯酸甲酯;
(5E)-2-氨基-6-氟代-2-甲基-7-(3-甲基-5-氧代-1,2,4-_二唑-4(5H)-基)-5-庚烯酸甲酯;
(5E)-2-氨基-6-氟代-7-[(1-亚氨基乙基)氨基]-2-甲基-5-庚烯酸甲酯;
(5E)-7-[(叔丁氧羰基)氨基]-2-{[(1Z)-(2,4-二氯苯基)亚甲基]氨基}-5-氟代-2-甲基庚-5-烯酸甲酯;
(5E)-2,7-二氨基-5-氟代-2-甲基-5-庚烯酸甲酯二盐酸盐;
(5E)-2-氨基-5-氟代-7-[(1-亚氨基乙基)氨基]-2-甲基-5-庚烯酸甲酯一盐酸盐;
(5Z)-2-[[(1E)-(2,4-二氯苯基)亚甲基]氨基]-7-[[(1,1-二甲基乙氧基)羰基]氨基]-5-氟代-2-甲基-5-庚烯酸甲酯;
(5Z)-2,7-二氨基-5-氟代-2-甲基-5-庚烯酸甲酯二盐酸盐;
(5Z)-2-氨基-5-氟代-7-[(1-亚氨基乙基)氨基]-2-甲基-5-庚烯酸甲酯二盐酸盐;
4-[(2Z)-5-羟基-2-戊烯基]-3-甲基-1,2,4-_二唑-5(4H)-酮;
三氟乙酸(3Z)-5-(3-甲基-5-氧代-1,2,4-_二唑-4(5H)-基)-3-戊烯基酯;
4-[(2Z)-5-[(2R,4S)-3-苯甲酰基-2-(1,1-二甲基乙基)-4-甲基-5-氧代-4-_唑烷基]-2-戊烯基]-3-甲基-1,2,4-_二唑-5(4H)-酮;
3-甲基-4-[5-(四氢-吡喃-2-基氧基)-戊-2-烯基]-4H-[1,2,4]_二唑-5-酮;
4-(5-羟基-戊-2-烯基)-3-甲基-4H-[1,2,4]_二唑-5-酮;
甲磺酸5-(3-甲基-5-氧代-[1,2,4]_二唑-4-基)-戊-3-烯基酯;
4-(5-碘代-戊-2-烯基)-3-甲基-4H-[1,2,4]_二唑-5-酮;
外消旋-2-氨基-2-甲基-7-(3-甲基-5-氧代-[1,2,4]_二唑-4-基)-庚-5-烯酸甲酯;
外消旋-2-氨基-2-甲基-7-(3-甲基-5-氧代-[1,2,4]_二唑-4-基)-庚-5-烯酸;
(2S,5Z)-2-氨基-2-甲基-7-(3-甲基-5-氧代-[1,2,4]_二唑-4-基)-庚-5-烯酸甲酯;
(2S,5Z)-7-亚氨代乙酰基氨基-2-氨基-2-甲基-庚-5-烯酸甲酯二盐酸盐水合物;
(2S,5Z)-2-氨基-7-[[(1E)-1-(羟基亚氨基)乙基]氨基]-2-甲基-5-庚烯酸;
4-[(2E)-5-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]-2-戊烯基]-3-甲基-1,2,4-_二唑-5(4H)-酮;
4-[(2E)-5-羟基-2-戊烯基]-3-甲基-2,4-_二唑-5(4H)-酮;
(5E)-2-[[(1E)-(3,4-二氯苯基)亚甲基]氨基]-2-甲基-7-(3-甲基-5-氧代-1,2,4-_二唑-4(5H)-基)-5-庚烯酸甲酯;
(5E)-2-氨基-2-甲基-7-(3-甲基-5-氧代-1,2,4-_二唑-4(5H)-基)-5-庚烯酸甲酯;
及(5E)-2-氨基-7-(亚氨基乙氨基)-2-甲基庚-5-烯酸甲酯。
生物学数据
下列试验的部分或全部用来证明本发明化合物的氧化氮合酶抑制活性,并证实有用的药理学性质。
氧化氮合酶的瓜氨酸试验
可通过监测L-[2,3-3H]-精氨酸向L-[2,3-3H]-瓜氨酸的转化测定氧化氮合酶(NOS)的活性(Bredt和Snyder,Proc.Natl.Acad.Sci.U.S.A,87,682-685,1990和Moore等,J.Med.Chem.,39,669-672,1996)。从人体组织提取的RNA中分别克隆出人诱导型NOS(hiNOS)、人内皮组成型NOS(hecNOS)和人神经元组成型NOS(hncNOS)。人诱导型NOS(hiNOS)的cDNA分离自λcDNA库,该λcDNA库由患溃疡性结肠炎患者的结肠样品提取的RNA制得。人内皮组成型NOS(hecNOS)的cDNA分离自λcDNA库,该λcDNA库由人脐静脉内皮细胞(HUVEC)提取的RNA制得。人神经元组成型NOS(hncNOS)的cDNA分离自λcDNA库,该λcDNA库由尸体获得的人小脑提取的RNA制得。用杆状病毒载体将重组酶表达在Sf9昆虫细胞中(Rodi等,TheBiology of Nitric Oxide,Pt.4:Enzymology,Biochemistry andImmunology(一氧化氮的生物学,Pt4:酶学、生物化学和免疫学);Moncada,S.,Feelisch,M.,Busse,R.,Higgs,E.,Eds.;Portland PressLtd.:London,1995;第447-450页)。从可溶解细胞提取物中分离出酶的活性,并用DEAE-Sepharose层析法部分纯化。为测量NOS活性,存在或不存在受试化合物时,将10μL的酶加入到40μL的50mMTris(pH 7.6)中,通过加入50μL含50mM Tris(pH 7.6)、2.0mg/mL牛血清白蛋白、2.0mM DTT、4.0mM CaCl2、20μM FAD、100μM四氢生物蝶呤、0.4mM NADPH和含0.9μCi的L-[2,3-3H]-精氨酸的60μM L-精氨酸的反应混合物开始反应。本试验中L-精氨酸的最终浓度为30μM。对于hecNOS或hncNOS,包含最终浓度40-100nM的钙调蛋白。于37℃孵育15分钟后,通过加入400μL在含10mMEGTA、100mM HEPES、pH 5.5和1mM L-瓜氨酸的终止缓冲液中的Dowex 50W X-8阳离子交换树脂的悬浮液(1份树脂,3份缓冲液)终止该反应。混合后沉淀该树脂,并用液体闪烁计数器计算出上清液的等分部分来确定L-[2,3-3H]-瓜氨酸的形成。可以通过在不同浓度测试各化合物来确定IC50值。结果以化合物对hiNOS、hecNOS和hncNOS的IC50值报道在表I中。
表I
实施例 | IC50[μM] | ||||
编号 | hiNOS | hecNOS | hncNOS | ||
1 | 0.4 | 37 | 7.6 | ||
3 | 56 | 352 | 584 | ||
4 | 0.57 | 52 | 13 | ||
14 | 0.7 | 31 | 12 | ||
15 | 121 | 1930 | 1480 |
体内试验
可对大鼠腹膜内注射1-12.5mg/kg内毒素(LPS)进行处理,以诱导诱导型氧化氮合酶的系统表达,引起血浆亚硝酸盐/硝酸盐水平的显著升高。在给予LPS前0.5-1小时经中给予化合物,并在LPS给予后5小时时测定血浆亚硝酸盐/硝酸盐水平。该结果可用于证明氧化氮合酶抑制剂的给药使血浆中亚硝酸盐/硝酸盐水平(内毒素诱导的一氧化氮的产生的一种可靠指标)的上升有所降低。抑制LPS诱导的血浆亚硝酸盐/硝酸盐水平增加的ED50值(mg/kg)示于表II中。
表II
在内毒素处理的大鼠中测定的实施例化合物的ED50值除非另外指明所有化合物均口服给药
1 | 0.4 |
4 | 0.3 |
14 | 0.3 |
Raw细胞的亚硝酸盐试验
在LPS存在下,将RAW 264.7细胞接种于96-孔组织培养板上,使之生长过夜(17小时)至汇合,以诱导NOS。留下一排3-6孔不作处理并用作扣除非特异性本底的对照。从各孔中移去培养基,并用含2mg/ml葡萄糖的Kreb-Ringers-Hepes(25mM,pH 7.4)洗细胞两次。再将细胞放在冰上,用50μL含L-精氨酸(30μM)+/-抑制剂的缓冲液孵育1小时。通过在水浴中加热该板至37℃1小时可开始该试验。因细胞内iNOS产生的亚硝酸盐的量将与时间呈线性关系。可将该细胞板放在冰上终止该细胞试验,取出含亚硝酸盐的缓冲液,用以前公开的荧光定量法对亚硝酸盐进行分析(T.P.Misko等,Analytical Biochemistry,214,11-16(1993))。
人体软骨外植体试验
用Dulbecco’s磷酸盐缓冲盐水(GibcoBRL)漂洗骨片两次再用Dulbecco’s Modified Eagles Medium(GibcoBRL)漂洗一次,再与无酚红的极限必需培养基(MEM)(GibcoBRL)一起置于陪替氏培养皿中。将软骨切成重量约15-45mg的小外植体,按每孔1-2片外植体放入每孔有200-500μL培养基的96或48孔培养板中。培养基是一种常规制备的不具有L-精氨酸、L-谷氨酰胺和酚红的Earle’s盐的极限必需培养基(Eagle)的改良培养基,或制备的一种不具有L-精氨酸、胰岛素、抗坏血酸、L-谷氨酰胺及酚红的无血清的Neuman和Tytell(GibcoBRL)常规改良培养基。在使用前用100μM L-精氨酸(Sigma)、2mM L-谷氨酰胺、1X HL-1补充液(Bio Whittaker)、50mg/ml抗坏血酸(Sigma)和150pg/ml重组人IL-1β(RD系统)对二者进行补充,以诱导氧化氮合酶。再以10μL等分液加入化合物,在5%CO2环境于37℃孵育外植体18-24小时。
然后弃去经过一天的上清液,用含重组人IL-1β和化合物的新鲜培养基替换,再培养20-24小时。对上清液的亚硝酸盐进行荧光分析(Misko等,Anal.Biochem.,214,11-16,1993)。所有样品均按一式四份进行。未刺激的对照物在无重组人IL-1β的培养基中培养。通过绘制六个不同浓度的抑制剂对亚硝酸盐产生的百分抑制率的图来确定IC50值(表III)。
表III
实施例编号 | IC50[μM] |
1 | 0.4 |
14 | 0.8 |
对依赖于时间的抑制的分析
在瓜氨酸酶分析成分(无L-精氨酸)的存在下,通过将所述化合物与酶在37℃预孵育0-60分钟,评价化合物对人NOS同工型的时间依赖性抑制。于0、10、21和60分钟时取出等分试样(10μl)并立即加入到含有L-[2,3-3H]-精氨酸的瓜氨酸分析酶反应混合物中,L-精氨酸的最终浓度为30μM/100μl最终体积。使该反应于37℃进行15分钟,通过加入如上所述的用于瓜氨酸NOS分析的Dowex 50W X-8阳离子交换树脂的悬浮液终止反应。抑制剂的NOS活性的%抑制应认为是与对照酶在无抑制剂时预孵育相同的时间比较的活性百分抑制率。由于抑制作用随预孵育时间的增加而增加,可证明为时间-依赖性抑制。
Claims (22)
2.权利要求1的化合物,其中所述化合物为Z异构体。
3.权利要求2的化合物,其中:
R1为氢;
R2选自氢和氟;及
R3为甲基。
4.权利要求3的化合物,其中:
R1为氢;
R2为氢;及
R3为甲基。
5.权利要求3的化合物,其中:
R1为氢;
R2为氟;及
R3为甲基。
6.权利要求1的化合物,其中所述化合物为E异构体。
7.权利要求6的化合物,其中:
R1为氢;
R2选自氢和氟;及
R3为甲基。
8.权利要求7的化合物,其中:
R1为氢;
R2为氢;及
R3为甲基。
9.权利要求7的化合物,其中:
R1为氢;
R2为氟;及
R3为甲基。
10.权利要求6的化合物,其中:
R1为氟;
R2为氢;及
R3为甲基。
11.一种式III的化合物
或其药学上可接受的盐,其中:
R1选自氢和氟;
R2选自氢和氟;及
R3为甲基。
12.权利要求11的化合物,其中所述化合物为Z异构体。
13.权利要求12的化合物,其中:
R1为氢;
R2为氢;及
R3为甲基。
14.权利要求11的化合物,其中所述化合物为E异构体。
15.权利要求14的化合物,其中:
R1为氟;
R2为氢;及
R3为甲基。
17.权利要求16的化合物,其中所述化合物为Z异构体。
18.权利要求17的化合物,其中:
R1为氢;
R2为氢;及
R3为甲基。
19.权利要求16的化合物,其中所述化合物为E异构体。
20.权利要求19的化合物,其中:
R1为氟;
R2为氢;及
R3为甲基。
21.一种化合物,它选自:
(2S,5E)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;
(2R,5E)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;
(2R/S,5E)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;
(2R/S,5E)-2-氨基-2-甲基-5-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;
(2R/S,5Z)-2-氨基-2-甲基-5-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;
(2S,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;
(2R,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;及
(2R/S,5E)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸。
22.一种药用组合物,它含有至少一种选自以下的化合物:
(2S,5E)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;
(2R,5E)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;
(2R/S,5E)-2-氨基-2-甲基-6-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;
(2R/S,5E)-2-氨基-2-甲基-5-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;
(2R/S,5Z)-2-氨基-2-甲基-5-氟代-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;
(2S,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;
(2R,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;及
(2R/S,5E)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸。
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AT (1) | ATE289587T1 (zh) |
AU (2) | AU2001290883A1 (zh) |
BR (1) | BR0113925A (zh) |
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CY (1) | CY1106056T1 (zh) |
CZ (1) | CZ2003646A3 (zh) |
DE (1) | DE60109046T2 (zh) |
DK (1) | DK1317421T3 (zh) |
EA (1) | EA006244B1 (zh) |
ES (1) | ES2238477T3 (zh) |
HK (1) | HK1062910A1 (zh) |
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MY (1) | MY131964A (zh) |
NO (1) | NO20031140L (zh) |
NZ (1) | NZ524562A (zh) |
PL (1) | PL207391B1 (zh) |
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SI (1) | SI1317421T1 (zh) |
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AR032318A1 (es) * | 2000-04-13 | 2003-11-05 | Pharmacia Corp | Compuesto derivado halogenado del acido 2-amino-5,6 heptenoico; composicion farmaceutica que lo comprende y su uso en la fabricacion de un medicamento util como inhibidor de la oxido nitrico sintetasa |
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 |
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 |
US20060293266A1 (en) * | 2000-05-10 | 2006-12-28 | The Trustees Of Columbia | Phosphodiesterase 4D in the ryanodine receptor complex protects against heart failure |
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 |
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 |
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 |
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) |
US20040229781A1 (en) * | 2000-05-10 | 2004-11-18 | Marks Andrew Robert | Compounds and methods for treating and preventing exercise-induced cardiac arrhythmias |
WO2003097163A2 (en) * | 2002-05-16 | 2003-11-27 | Pharmacia Corporation | Using a selective inos inhibitor for the treatment of respiratory diseases and conditions |
WO2003097050A2 (en) * | 2002-05-16 | 2003-11-27 | Pharmacia Corporation | A selective inos inhibitor and a pde inhibitor in combination for the treatment of respiratory diseases |
US20040127569A1 (en) * | 2002-08-02 | 2004-07-01 | Manning Pamela T. | Methods for treatment and prevention of gastrointestinal conditions |
TWI340133B (en) | 2002-08-23 | 2011-04-11 | Pharmacia Corp | Crystalline solid form of (2s,5z)-2-amino-7-(ethanimidoylamino)-2-methylhept-5-enoic acid. |
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) |
US20040235139A1 (en) * | 2002-12-23 | 2004-11-25 | Demain Arnold L. | Clostridium difficile culture and toxin production methods |
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 |
US7935821B2 (en) * | 2005-06-09 | 2011-05-03 | Mallinckrodt Inc. | Method for separation and purification of naltrexone by preparative chromatography |
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 |
AR059224A1 (es) * | 2006-01-31 | 2008-03-19 | Jerini Ag | Compuestos para la inhibicion de integrinas y uso de estas |
US9895324B2 (en) * | 2014-03-26 | 2018-02-20 | University Of Kentucky Research Foundation | Halogenated diarylacetylenes and methods of treating cancer |
GB201512635D0 (en) | 2015-07-17 | 2015-08-26 | Ucl Business Plc | Uses of therapeutic compounds |
EP3398941A1 (en) * | 2017-05-03 | 2018-11-07 | AXXAM S.p.A. | Heterocyclic p2x7 antagonists |
CN113861064B (zh) * | 2021-10-14 | 2024-05-10 | 南京医科大学 | 一类神经保护剂及其药物用途 |
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WO1993013055A1 (en) * | 1991-12-24 | 1993-07-08 | The Wellcome Foundation Limited | Amidino derivatives and their use as nitric oxide synthase inhibitors |
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