CN1802353A - 氟烷氧基取代的1,3-二氢-异吲哚化合物及其药物用途 - Google Patents
氟烷氧基取代的1,3-二氢-异吲哚化合物及其药物用途 Download PDFInfo
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- CN1802353A CN1802353A CNA2003801099071A CN200380109907A CN1802353A CN 1802353 A CN1802353 A CN 1802353A CN A2003801099071 A CNA2003801099071 A CN A2003801099071A CN 200380109907 A CN200380109907 A CN 200380109907A CN 1802353 A CN1802353 A CN 1802353A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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Abstract
本发明包括新化合物、可药用盐、水合物、溶剂化物、笼形包合物、对映异构体、非对映体、外消旋体或其立体异构体的混合物,上述化合物的药物组合物,以及在哺乳动物中使用上述化合物治疗或预防与PDE4有关的疾病的方法。
Description
1.发明领域
本发明包括新的氟烷氧基取代的1,3-二氢-异吲哚化合物、上述化合物的药物组合物,以及在哺乳动物中使用上述化合物和组合物治疗或预防与PDE4抑制、异常的TNF-α水平和/或MMP抑制有关的疾病的方法。
2.发明背景
2.1TNF-α
肿瘤坏死因子α(TNF-α)是主要由炎症和单核吞噬细胞应答免疫刺激剂而释放的细胞因子。TNF-α能增强大多数细胞的进程,例如分化、募集、增殖、和蛋白水解。在低水平下,TNF-α提供针对感染源、肿瘤和组织损伤的保护作用。但是,TNF-α还在许多疾病中起着作用。当将其对哺乳动物如人给药时,TNF-α会引起或恶化炎症、发热、心血管效应、出血、血凝固以及类似于急性感染和休克期间所见到的急性应答。因此,过多的或非调节的TNF-α生成,牵连到诸多疾病和医学病症,例如癌症如实体瘤和来自血液的(blood born)瘤;心脏病如充血性心力衰竭;以及病毒性、遗传性、炎性、过敏性和自身免疫疾病。
癌症是一种极具破坏性的疾病,并且增加血液中TNF-α的水平,而这与癌症的发病和扩散有关。在健康受试者中,癌细胞在循环系统中不能存活,原因之一是血管内皮作为肿瘤细胞外渗的屏障。但是,体外已经证实,升高的细胞因子水平实质上增加了癌细胞对内皮的粘附。一种解释是细胞因子例如TNF-α刺激被称作ELAM-1(内皮白细胞粘着分子)的细胞表面受体的生物合成和表达。ELAM-1是钙依赖性细胞粘着受体(称之为LEC-CAMs,包括LECCAM-1和GMP-140)中的一员。在炎症反应期间,内皮细胞上的ELAM-1作为白细胞的“归巢受体”。已证实,内皮细胞上的ELAM-1介导增加结肠癌细胞对经细胞因子处理的内皮的粘着力(Rice等,1989,Science 246:1303-1306)。
炎性疾病例如关节炎、相关的关节炎症(例如骨关节炎和类风湿性关节炎)、炎性肠病、败血病、牛皮癣、慢性阻塞性肺疾病、慢性炎性肺疾病也是流行的疑难疾病。TNF-α在炎性应答和给药其拮抗剂阻断炎性疾病的动物模型中的慢性和急性应答中起着重要的作用。
增多的或非调节的TNF-α生成,牵连到病毒性、遗传性、炎性、过敏性和自身免疫疾病。上述疾病的例子包括,但不限于:HIV;肝炎;成人呼吸窘迫综合征;骨吸收疾病;慢性阻塞性肺疾病;慢性炎性肺疾病;皮炎;囊性纤维病;败血症性休克;败血病;内毒素性休克;血流动力性休克;败血病综合征;缺血后再灌注损伤;脑膜炎;牛皮癣;纤维化疾病;恶病质;移植物抗宿主病(GVHD);移植排斥;自身免疫疾病;类风湿性脊椎炎;关节炎症,如类风湿性关节炎、类风湿性脊椎炎和骨关节炎;骨质疏松症;炎性肠病;克罗恩病;溃疡性结肠炎;多发性硬化症;全身性红斑狼疮;麻风结节性红斑;辐射损伤;哮喘;高氧肺泡损伤。Tracey等,1987,Nature 330:662-664和Hinshaw等,1990,Circ.Shock 30:279-292(内毒素性休克);Dezube等,1990,Lancet,335:662(恶病质);Millar等,1989,Lancet 2:712-714和Ferrai-Baliviera等,1989,Arch.Surg.124:1400-1405(成人呼吸窘迫综合征);Bertolini等,1986,Nature 319:516-518,Johnson等,1989,Endocrinology 124:1424-1427,Holler等,1990,Blood 75:1011-1016,和Grau等,1989,N.Engi.J.Med.320:1586-1591(骨吸收疾病);Pignet等,1990,Nature,344:245-247,Bissonnette等,1989,Inflammation13:329-339和Baughman等,1990,J.Lab.Clin.Med.115:36-42(慢性肺炎性疾病);Elliot等,1995,Int.J.Pharmac.17:141-145(类风湿性关节炎);Dullemen等,1995,Gastroenterology,109:129-135(克罗恩病);Duh等,1989,Proc.Nat.Acad.Sci.86:5974-5978,Poll等,1990,Proc.Nat.Acad.Sci.87:782-785,Monto等,1990,Blood 79:2670,Clouse等,1989,J.Immunol.142,431-438,Poll等,1992,AIDS Res.Hum.Retrovirus,191-197,Poli等,1990,Proc.Natl.Acad.Sci.87:782-784,Folks等,1989,PNAS 86:2365-2368(HIV和由HIV导致的机会性感染)。
2.3PDE4
腺苷3′,5′-环一磷酸(cAMP)也在许多疾病和病症中起着作用,例如,但不限于哮喘和炎症(Lowe和Cheng,Drugs ofihe Future,17(9),799-807,1992)。已经证实,对于炎性白细胞,cAMP的升高能够抑制其活化和随后释放炎性介质,包括TNF-α和核因子κB(NF-κB)的释放。CAMP浓度升高还引起气管平滑肌的松弛。
cAMP失活的主要细胞机理是,被称为环状核苷磷酸二酯(PDE)的一族同工酶引起的cAMP裂解(Beavo和Reitsnyder,Trends in Pharm.,11,150-155,1990)。PDE族有12种已知成员,经证实,抑制PDE IV型对于抑制炎症介导的释放和松弛气管平滑肌两者均有显著效果(Verghese等,Journal of Pharmacology and ExperimentalTherapeutics,272(3),1313-1320,1995)。因此,对PDE4有特异抑制作用的化合物可抑制炎症作用和松弛气管平滑肌,而带来最小的不良副作用,如对心血管的作用和抗血小板的作用。
对cAMP特异的PDE4族是目前最大的一族并具有至少4种同工酶(a-d)和多种剪接变体(Houslay,M.D.等,Advances in Pharmacology44,eds.J.August等,225页,1998)。总共可能存在20个以上PDE4同工酶,它们由许多不同的启动子调控以细胞特异性模式表达。已经发现选择性的PDE4抑制剂适用的疾病包括:哮喘、特应性皮炎、忧郁症、再灌注损伤、败血症性休克、中毒性休克、内毒素性休克、成人呼吸窘迫综合征、自身免疫糖尿病、尿崩症、多发性脑梗塞性痴呆、AIDS、癌症、克罗恩病、多发性硬化症、脑缺血、牛皮癣、同种异体移植排斥、再狭窄、溃疡性结肠炎(ulceratiave colitis)、恶病质、脑疟疾、变应性鼻结膜炎、骨关节炎、类风湿性关节炎、慢性阻塞性肺疾病(COPD)、慢性支气管炎、嗜酸性肉芽肿(cosinophilic granuloma)和自身免疫脑脊髓炎(Houslay等,1998)。PDE4存在于脑和多数炎性细胞中,并且已经发现在许多疾病包括特应性皮炎或湿疹、哮喘、尤其是枯草热中其水平异常升高(参见OHSU flyer和Grewe等,J ofAllergy and Clinical Immunology,70:452-457,1982)。在患有特应性疾病的个体中,发现在他们的周围血液单核白细胞、T细胞、肥大细胞、嗜中性细胞和嗜碱细胞中PDE-4活性增高。升高的PDE活性降低了cAMP浓度并导致这些细胞中控制的cAMP裂解。这导致了血液和那些受感染组织中的免疫应答增加。
PDE4抑制剂的临床应用已经证实了其对于哮喘、慢性阻塞性肺疾病(COPD)和其它变应性紊乱例如特异性皮炎和枯草热的模型是具有强烈活性的广谱抗炎药。已经使用的PDE4抑制剂包括茶碱,咯利普兰,登布茶碱,ARIFLO,罗氟司特,CDP 840(一种三芳基乙烷)和CP80633(一种嘧啶酮)。已经证实,PDE4抑制剂能影响嗜酸性细胞应答,减少嗜碱细胞组胺释放,减少IgE、PGE2、ILlO合成,和减少抗-CD3刺激的Il-4产生。类似地,已经证实,PDE4抑制剂阻断中性白细胞功能。中性白细胞在哮喘、慢性阻塞性肺疾病(COPD)和其它变应性紊乱中起着主要的作用。已证实,PDE4抑制剂抑制粘着分子、活性氧簇、白细胞介素(IL)-8和中性白细胞弹性酶的释放,伴随着中性白细胞破坏肺以及气管功能的结构。PDE抑制剂影响多种功能途径,作用于多重免疫和炎症途径,并且影响许多免疫介质的合成或释放。J.M.Hanifin和S.C.Chan,Atopic Dermatitis-TherapeuticImplication for New Phosphodiesterase Inhibitors,MonocyteDysregulation of T Cells in AACI News,7/2,1995;J.M.Hanifin等,Type 4Phosphodiesterase Inhibitors Have clinical and In Vitro Anti-inflammatory Effects in Atopic Dermatitis,Journal of InvestigativeDermatology,1996,107,51-56页)。
第一代PDE-4抑制剂已显示出有效的抑制PDE4活性和减缓由该种酶过度表达导致的许多炎性问题。但是,其有效性受到副作用恶心和呕吐的限制,特别是当用于全身时(Huang等,Curr.Opin.In Chem.Biol.2001,5:432-438)。实际上,至今所有的PDE-4抑制剂均是小分子化合物,具有中枢神经系统和胃肠道副作用,即头痛、恶心/呕吐、和胃液分泌。
2.3MMP
基质金属蛋白酶(MMPs)是一族涉及结缔组织降解和重塑的蛋白酶(酶)。由MMPs导致的细胞外基质过度降解牵涉到许多疾病的发病机理,这些疾病包括类风湿性关节炎、骨关节炎、癌症、多发性硬化、骨吸收疾病(例如骨质疏松)、慢性阻塞性肺疾病、再狭窄、伴随中风的脑出血、牙周病、畸形血管发生、肿瘤侵入和转移、角膜和胃溃疡、皮肤溃疡、动脉瘤病、和糖尿病并发症。因此,MMP抑制剂被认为是这类疾病的治疗介入的良好靶子。已经报道了许多具有MMP抑制活性的化合物(R.A.Nigel等,Current Opinion on Therapeutic Patents,第4卷,7-16,(1994),R.P.Beckett等,Drug Discovery Today,第1卷,16-26,(1996))。但是,它们中大多数为根据构建MMP底物的胶原分子中的酶切位点的氨基酸序列而设计的肽衍生物,因此需要MMP的小分子抑制剂。
因此,在PDE4抑制剂领域,仍需要调控TNF-α的产生和抑制MMP的产生的化合物。特别是,仍需要不具有副作用或具有减少的副作用的体内有活性的抑制剂。
3.发明概述
本发明提供了可用于治疗由PDE4抑制介导的疾病和由TNF-α和MMP介导的疾病的化合物。本发明还提供了包含上述化合物的药物组合物和使用上述化合物和组合物治疗多种疾病的方法。
本文所提供的化合物具有式(I):
其中:
Y是-C(O)-,-CH2,-CH2C(O)-,-C(O)CH2-,或SO2;
Z是-H,-C(O)R3,-(C0-1-烷基)-SO2-(C1-4-烷基),-C1-8-烷基,-CH2OH,CH2(O)(C1-8-烷基)或-CN;
R1和R2各自独立地是-CHF2,-C1-8-烷基,-C3-18-环烷基,或-(C1-10-烷基)(C3-18-环烷基),且R1和R2中的至少一个是CHF2;
R3是-NR4R5,-烷基,-OH,-O-烷基,苯基,苄基,取代的苯基,或取代的苄基;
R4和R5各自独立地是H,-C1-8-烷基,-OH,-OC(O)R6;
R6是-C1-8-烷基,-氨基(C1-8-烷基),-苯基,-苄基,或-芳基;
X1、X2、X3和X4各自独立地是-H,-卤素,-硝基,-NH2,-CF3,-C1-6-烷基,-(C0-4-烷基)-(C3-6-环烷基),(C0-4-烷基)-NR7R8,(C0-4-烷基)-N(H)C(O)-(R8),(C0-4-烷基)-N(H)C(O)N(R7R8),(C0-4-烷基)-N(H)C(O)O(R7R8),(C0-4-烷基)-OR8,(C0-4-烷基)-咪唑基,(C0-4-烷基)-吡咯基,(C0-4-烷基)-噁二唑基,或(C0-4-烷基)-三唑基,或者X1、X2、X3和X4中的两个可以连接在一起形成环烷基或杂环烷基环(例如,X1和X2、X2和X3、X3和X4、X1和X3、X2和X4、或X1和X4可形成3、4、5、6或7元环,该环可以是芳香性的,由此形成具有异吲哚环的双环体系);以及R7和R8各自独立地是H,C1-9-烷基,C3-6-环烷基,(C1-6-烷基)-(C3-6-环烷基),(C1-6-烷基)-N(R7R8),(C1-6-烷基)-OR8,苯基,苄基或芳基;或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
在另一个实施方案中,本发明涉及调节、尤其是抑制哺乳动物细胞中PDE4产生或降低其水平的方法,其包括向所述哺乳动物给药有效量的本发明化合物。
在另一个实施方案中,本发明涉及调节哺乳动物细胞中TNF-α产生或降低其水平的方法,其包括向所述哺乳动物给药有效量的本发明化合物。
在再一个实施方案中,本发明涉及调节哺乳动物细胞中MMP产生、尤其是抑制或降低其水平的方法,其包括向所述哺乳动物给药有效量的本发明化合物。
药物组合物、给药方式、制剂、和单独或联合使用上述化合物的方法在下面进行了更详细的描述。
3.1缩写和定义
除非另有定义,本文中所用的缩写是常规使用的。
本文所用的术语“治疗”的含义包括:
(1)减缓或消除疾病和/或其伴随的症状;
(2)阻止受试者患病;
(3)减少受试者患病危险;
(4)减少将感染疾病的可能性或消除该可能性;
(5)预防疾病,即使暴露于或易感染疾病但还没有经历或显示出该疾病症状的哺乳动物没有发展为该疾病的临床症状。
(6)抑制疾病,即阻止或减少疾病或其临床症状的发展;或
(7)减轻疾病,即使疾病或其临床症状消退。
术语“治疗有效量”是指给药化合物的量足以在某种程度上预防治疗病症或失调的一种或多种症状的发展或减缓治疗病症或紊乱的一种或多种症状,以及减缓或消除该疾病的病因。
本文所用的术语“PDE4-应答性病症或紊乱”或“由PDE4抑制介导的”或“由抑制PDE4介导的”是指对PDE4活性的调节给予应答的病症或紊乱。对PDE4调节给予的应答包括减缓或消除疾病或其伴随的症状,抑制疾病,即阻止或减少疾病或其临床症状的发展,和消退疾病或其临床症状。PDE4-应答的病症或疾病可对PDE4调节完全或部分应答。PDE4-应答的病症或紊乱可能与PDE4-活性的不适当,例如比正常PDE4-活性低或高有关。不适当的PDE4功能活性可引起通常不表达PDE4的细胞表达PDE4、PDE4表达减少(例如导致脂质和代谢紊乱和疾病)或PDE4表达增加。PDE4-应答的病症或疾病包括PDE4-介导的病症或疾病。
除非另有指示,单独或作为其它取代基部分的术语“烷基”是指直链或支链的、非环状或环状烃基,或其组合,其可以是完全饱和的、单或多不饱和的并且可包括二价或多价基团,并具有指定的碳原子数(即C0-10是指1-10个碳,或不存在,即当C等于0时,存在直接键)。饱和烃基的例子包括例如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、环己基、(环己基)甲基、环丙基甲基、例如正戊基、正己基、正庚基、正辛基等的同系物和异构体。不饱和烷基是具有一个或多个不饱和双键或三键的烷基。不饱和烷基的例子包括乙烯基、2-丙烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-丙炔基和3-丙炔基、3-丁炔基、以及高级同系物和异构体。除非另有指示,术语“烷基”还包括下面更详细定义为“杂烷基”、“环烷基”和“亚烷基”的烷基衍生物。单独或作为其它取代基部分的术语“亚烷基”是指来自烷烃的二价基团,例如-CH2CH2CH2CH2-。通常,烷基具有1-24个碳原子,在本发明中优选具有10个或更少碳原子的烷基。“低级烷基”或“低级亚烷基”是较短链的烷基或亚烷基,一般具有8个或更少的碳原子。
除非另有指示,单独或与其它术语组合的术语“杂烷基”是指稳定的直链或支链的、非环状或环状烃基,或其组合,其具有指定的碳原子数和1-3个选自O、N、Si和S的杂原子,并且其中氮原子和硫原子可任选被氧化,以及氮杂原子可任选地被季铵化。杂原子O、N和S可位于杂烷基的任何内部位置。杂原子Si可位于杂烷基的任何位置,包括烷基与该分子的残余部分连接的位置。例子包括-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH=CH-O-CH3、-Si(CH3)3、-CH2-CH=N-OCH3和-CH=CH-N(CH3)-CH3。可以至多有两个杂原子相邻,例如-CH2-NH-OCH3和-CH2-O-Si(CH3)3。术语“杂烷基”中还包括下面更详细定义为“杂亚烷基”和“杂环烷基”的那些基团。单独或作为其它取代基部分的术语“杂亚烷基”是指来自杂烷基的二价基团,例如-CH2-CH2-S-CH2CH2-和-CH2-S-CH2-CH2-NH-CH2-。对于杂亚烷基,杂原子还可以占据链的任一末端或两个末端。更进一步,对于亚烷基和杂亚烷基连接基团,没有暗示连接基的方向。
除非另有指示,单独或与其它术语组合的术语“环烷基”和“杂环烷基”分别代表环状的“烷基”和“杂烷基”。因此,术语“环烷基”和“杂环烷基”分别包含于术语“烷基”和“杂烷基”中。此外,术语“C3-18环烷基”是指具有3-18个碳原子的环烷基。另外,对于杂环烷基,杂原子可以杂环与该分子的残余部分连接的位置。环烷基的例子包括环丙基、环丁基、环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环烷基的例子包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基、3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃-3-基、四氢噻吩-2-基、四氢噻吩-3-基、1-哌嗪基、2-哌嗪基等。
除非另有指示,单独或作为其它取代基部分的术语“卤代”或“卤素”是指氟、氯、溴、或碘原子。另外,术语“卤代烷基”包括被1至(2m′+1)个卤素原子取代的烷基,其中卤素原子可以相同或不同,m′是该烷基的碳原子总数。例如,术语“卤代(C1-C4)烷基”包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。因此,术语“”卤代烷基包括一卤代烷基(被1个卤素原子取代的烷基)和多卤代烷基(被2至(2m′+1)个卤素原子取代的烷基,其中m′是该烷基的碳原子总数)。除非另有指示,术语“全卤代烷基”是指被(2m′+1)个卤素原子取代的烷基,其中m′是该烷基的碳原子总数。例如,术语“全卤代(C1-C4)烷基”包括三氟甲基、五氯乙基、1,1,1-三氟-2-溴-2-氯乙基等。
除非另有指示,单独使用或与其它术语(例如芳氧基、芳硫基、芳烷基)组合的术语“芳基”是指可以是单环或相互稠合或共价连接的多环(至多达3个环)的芳香取代基。所述环可以各自含有0至4个选自N、O和S的杂原子,其中氮原子和硫原子任选被氧化,以及氮杂原子任选被季铵化。含有杂原子的芳基可被称为“杂芳基”且可以通过杂原子与分子的残余部分连接。芳基的非限制性例子包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-噁唑基、4-噁唑基、2-苯基-4-噁唑基、5-噁唑基、噁二唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、三唑基、1-异喹啉基、5-异喹啉基、2-喹噁啉基、5-喹噁啉基、3-喹啉基和6-喹啉基。上述提及的芳环体系各自的取代基选自下述合适的取代基。
术语“芳烷基”包括其中芳基与烷基相连的那些基团(例如苄基、苯乙基、吡啶甲基等)或与杂烷基相连的那些基团(例如苯氧基甲基、2-吡啶氧基甲基、3-(1-萘氧基)丙基等)。
上述每种术语(例如,“烷基”、“杂烷基”和“芳基”)包括上述基团的取代和未取代的形式。各种类型基团的优选取代基如下。
烷基和杂烷基(包括那些常称为亚烷基、烯基、杂亚烷基、杂烯基、炔基、环烷基、杂环烷基、环烯基、和杂环烯基的基团)的取代基可以是0至(2N+1)个选自下述的基团:-OR′、=O、=NR′、=N-OR′、-NR′R″、-SR′、-卤素、-SiR′R″R、-OC(O)R′、-C(O)R′、-CO2R′、-CONR′R″、-OC(O)NR′R″、-NR″C(O)R′,-NR′-C(O)NR″R、-NR″C(O)2R′、-NH-C(NH2)=NH、-NR′C(NH2)=NH、-NHC(NH2)=NR′、-S(O)R′、-S(O)2R′、-S(O)2NR′R″、-CN和-NO2,其中N是上述基团的碳原子总数。R′、R″和R各自独立地是氢、未取代的(C1-C8)烷基和杂烷基、未取代的芳基、被1-3个卤素取代的芳基、未取代的烷基、烷氧基或硫代烷氧基、或芳基-(C1-C4)烷基。当R′和R″与同一个氮原子相连时,它们可与相连的碳原子以及氮原子组合形成5-、6-或7-元环,该环含有1-3个选自N、O和S的的杂原子。例如,-NR′R″包括1-吡咯烷基和4-吗啉基。通过上述取代基的讨论,本领域熟练技术人员将理解,术语“烷基”涵盖包括氯代烷基(例如,-CF3和-CH2CF3)和酰基(例如,-C(O)CH3、-C(O)CF3、-C(O)CH2OCH3等)的取代的烷基。
类似地,芳基的取代基是变化的,且选自:-卤素、-OR′、-OC(O)R′、-NR′R″、-SR′、-R′、-CN、-NO2、-CO2R′、CONR′R″、-C(O)R′、-OC(O)NR′R″、-NR″C(O)R′、-NR″C(O)2R′、-NR′C(O)NR″R、-NH-C(NH2)=NH、-NR′C(NH2)=NH、-NH-C(NH2)=NR′、-S(O)R′、-S(O)2R′、-S(O)2NR′R″、-N3、-CH(Ph)2、氟代(C1-C4)烷氧基、和氟代(C1-C4)烷基,所述取代基的数量为0至该芳环体系中打开价的总数;并且其中各个R′、R″和R独立地选自氢、(C1-C8)烷基和杂烷基、未取代的芳基、(未取代的芳基)-(C1-C4)烷基和(未取代的芳基)氧-(C1-C4)烷基。
本文所用术语“杂原子”包括氧(O)、氮(N)、硫(S)和硅(Si)。
术语“可药用盐”包涵活性化合物的盐,其是根据本文所述化合物中的特定取代基由相对无毒性的酸或碱制备而得的。当本发明化合物含有相对酸性的官能团时,在适合的惰性溶剂中或不加其它物质的情况下,通过将上述中性形式的化合物与足量的所需碱接触而获得碱加成盐。可药用碱加成盐的例子包括钠盐、钾盐、钙盐、铵盐、有机胺盐或镁盐、或类似的盐。当本发明化合物含有相对碱性的官能团时,在适合的惰性溶剂中或不加其它物质的情况下,通过将上述中性形式的化合物与足量的所需酸接触而获得酸加成盐。可药用酸由加成盐的例子包括那些衍生于无机酸例如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢碘酸、或亚磷酸等的盐,以及衍生于相对无毒性有机酸例如乙酸、丙酸、异丁酸、草酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等的盐。还包括氨基酸盐例如精氨酸盐等,和有机酸例如葡萄糖醛酸和半乳糖醛酸等的盐(例如参见Berge等,(1977)J Pharm.Sci.66:1-19)。本发明的某些具体化合物既含有碱性官能团又含有酸性官能团,这使得上述化合物可转变为碱性或酸性加成盐。
中性形式的化合物可通过将盐与碱或酸接触而再生,并按照常规方式分离母体化合物。在某些物理性质,例如在极性溶剂中的溶解性方面,化合物的母体形式不同于各种盐形式,然而在其它方面,出于本发明目的,所述盐等价于化合物的母体形式。
除了盐形式之外,本发明还提供了呈前药形式的化合物。除非另有指示,本文中所用术语“前药”是指化合物的衍生物,该衍生物可水解、氧化、或在生理条件(体外或体内)下反应而得到该化合物。前药的例子包括,但不限于本发明化合物的衍生物,该衍生物包含可生物水解的基团,例如可生物水解的酰胺、可生物水解的酯、可生物水解的氨基甲酸酯、可生物水解的碳酸酯、可生物水解的酰脲、和可生物水解的磷酸酯类似物。前药的其它例子包括含有-NO、-NO2、-ONO、或-ONO2基团的本发明化合物的衍生物。前药通常可使用已知的方法制备,例如描述于I Burger′s Medicinal Chemistry and DrugDiscovery,172-178,949-982(Manfred E.Wolff编辑,第5版.1995),和Design of Prodrugs(H.Bundgaard 编辑,Elselvier,New York1985)的方法。
除非另有指示,本文所用的术语“可生物水解的酰胺”、“可生物水解的酯”、“可生物水解的氨基甲酸酯”、“可生物水解的碳酸酯”、“可生物水解的酰脲”、“可生物水解的磷酸酯”分别是指化合物的酰胺、酯、氨基甲酸酯、碳酸酯、酰脲、或磷酸酯,其要么:1)不干扰化合物的生物活性,但可赋予化合物具有有利的体内性质,例如作用上升、持续、或作用发作;要么2)无生物活性,但在体内转化为生物活性化合物。可生物水解的酯的例子包括,但不限于,低级烷基酯、低级酰氧烷基酯(例如乙酰氧甲酯、乙酰氧乙酯、氨基甲酰氧甲酯、新戊酰氧甲酯、和新戊酰氧乙酯)、内酯(例如苯酞酸酯和硫代苯酞酸酯)、低级烷氧酰氧烷基酯(例如甲氧甲酰氧甲酯、乙氧甲酰氧乙酯和异丙氧甲酰氧乙酯)、烷氧烷基酯、胆碱酯、和酰氨基烷基酯(例如乙酰氨基甲酯)。可生物水解的酰胺的例子包括,但不限于,低级烷基酰胺、-氨基酸酰胺、烷氧基酰胺、和烷基氨基烷基甲酰胺。可生物水解的氨基甲酸酯的例子包括,但不限于,低级烷基胺、取代的乙二胺、氨基酸、羟基烷基胺、杂环和杂芳族胺、和聚醚胺。
本发明的某些化合物可以以非溶剂化形式和溶剂化形式,包括水合物形式存在。总之,溶剂化形式等价于非溶剂化形式,并包含在本发明范围中。本发明的某些化合物可以以多晶形或无定形形式存在。总之,所有的物理形态对于本发明所预期的用途均是等价的,并包含在本发明的范围中。
本发明的某些化合物具有不对称碳原子(光学中心)或双键;外消旋体、对映异构体、非对映异构体、几何异构体和各个异构体均包括在本发明范围中。这些异构体可使用常规方法拆分或不对称合成,从而得到“光学纯”的异构体,即基本上不含其它异构体;优选85%、90%、95%或97%ee。优选地,本发明化合物以基本是纯(R)或(S)对映异构体、基本上不含其反向对映异构体的形式给药。
本发明化合物还可含有一个或多个非自然比例的同位素原子来构成上述化合物。例如,所述化合物用放射性同位素例如氚(3H)、碘-125(125I)或碳-14(14C)放射标记。放射标记的化合物用作治疗剂,例如癌症治疗剂、研究试剂例如检验试剂和诊断试剂,例如体内成像试剂。本发明化合物的所有同位素物,不管是否具有放射性,均包括在本发明范围中。
4.发明详述
本发明包括用于治疗或预防哺乳动物包括人类的疾病的新化合物及其组合物。本发明还包括上述化合物用于治疗或预防疾病或紊乱的用途,所述疾病或紊乱包括但不限于癌症;病毒性、遗传性、炎性、过敏性和自身免疫疾病;和细菌感染。本发明化合物特别有用于治疗或预防由过多、不足或非调节的PDE4、TNF-α或MMP水平导致或恶化的疾病。
本文所提供的化合物具有式(I):
其中:
Y是-C(O)-,-CH2,-CH2C(O)-,-C(O)CH2-,或SO2;
Z是-H,-C(O)R3,-(C0-1-烷基)-SO2-(C1-4-烷基),-C1-8-烷基,-CH2OH,CH2(O)(C1-8-烷基)或-CN;
R1和R2各自独立地是-CHF2,-C1-8-烷基,-C3-18-环烷基,或-(C1-10-烷基)(C3-18-环烷基),且至少一个R1和R2是CHF2;
R3是-NR4R5,-烷基,-OH,-O-烷基,苯基,苄基,取代的苯基,或取代的苄基;
R4和R5各自独立地是H,-C1-8-烷基,-OH,-OC(O)R6;
R6是-C1-8-烷基,-氨基(C1-8-烷基),-苯基,-苄基,或-芳基;
X1、X2、X3和X4各自独立地是-H,-卤素,-硝基,-NH2,-CF3,-C1-6-烷基,-(C0-4-烷基)-(C3-6-环烷基),(C0-4-烷基)-NR7R8,(C0-4-烷基)-N(H)C(O)-(R8),(C0-4-烷基)-N(H)C(O)N(R7R8),(C0-4-烷基)-N(H)C(O)O(R7R8),(C0-4-烷基)-OR8,(C0-4-烷基)-咪唑基,(C0-4-烷基)-吡咯基,(C0-4-烷基)-噁二唑基,或(C0-4-烷基)-三唑基,或者X1、X2、X3和X4中的两个可以连接在一起形成环烷基或杂环烷基环(例如,X1和X2、X2和X3、X3和X4、X1和X3、X2和X4、或X1和X4可形成3、4、5、6或7元环,该环可以是芳香性的,由此形成具有异吲哚环的双环体系);以及
R7和R8各自独立地是H,C1-9-烷基,C3-6-环烷基,(C1-6-烷基)-(C3-6-环烷基),(C1-6-烷基)-N(R7R8),(C1-6-烷基)-OR8,苯基,苄基或芳基;或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
在优选的实施方案中,X1、X2、X3和X4中的至少一个是(C0-4-烷基)-N(R7R8)2。
在另一优选的实施方案中,X1、X2、X3和X4中的至少一个是(C0-4-烷基)-NHC=O-(R8)。
在另一优选的实施方案中,X1、X2、X3和X4中的至少一个是(C0-4-烷基)-NHC=ON(R7R8)。
在另一优选的实施方案中,X1、X2、X3和X4中的至少一个是(C0-4-烷基)-NHC=OO(R7R8)。
在另一优选的实施方案中,X1、X2、X3和X4中的至少一个是(C0-4-烷基)-O-R8。
在另一优选的实施方案中,X1、X2、X3和X4中的至少一个是NH2。
在另一优选的实施方案中,X1、X2、X3和X4中的至少一个是(C0-4-烷基)-NHC(O)(R8)。
在另一优选的实施方案中,X1、X2、X3和X4中的至少一个是-卤素。
在另一优选的实施方案中,X1、X2、X3和X4中的至少一个是(C0-4-烷基)-咪唑基,(C0-4-烷基)-吡咯基,(C0-4-烷基)-噁二唑基,或(C0-4-烷基)-三唑基。
在另一优选的实施方案中,X1、X2、X3和X4中的至少一个是(C0-4-烷基)-环丙基。
在另一优选的实施方案中,X1、X2、X3和X4中的至少一个是(C0-4-烷基)-NHC(O)(R8)且X1、X2、X3和X4中的之一是卤素。
在再一优选的实施方案中,X1、X2、X3和X4中的三个是H。
在另选实施方案中,X1或X2是被取代的。
在优选的实施方案中,R1或R2是-CHF2且另一个是C1-4烷基或C3-6环烷基。更优选,R1或R2独立地是甲基、乙基、环戊基或-CHF2。最优选,R1或R2中的一个必须是-CHF2。
在另一优选的实施方案中,Y是-C(O)-或CH2。
在另一优选的实施方案中,Z是-C(O)R3、-(C0-1-烷基)-SO2-烷基、-CH2OH、-CHNH2、-S02CH3、-C(O)CH3、-C(O)NHOH或-CH2N(CH3)2。
在另选实施方案中,Z是具有1-6个碳原子的羟烷基。
本发明化合物通常以固体形式存在,并可根据已知的方法重结晶得到高纯度,优选大于95%纯、更优选大于98%纯的晶体。窄的熔点范围是纯度的指示,因此本发明化合物通常具有3℃-4℃的熔点范围,更优选2℃内的熔点范围。
本发明的多种化合物含有一个或多个手性中心,并可以以对映异构体的外消旋混合物或非对映异构体的混合物的形式存在。本发明包括上述化合物的立体纯形式的用途,以及这些形式的混合物的用途。例如,包含等量或不等量的特定化合物的对映异构体的混合物可用于本发明方法和组合物。这些异构体可以以不对称合成或使用标准技术例如手性柱或手性拆分试剂拆分。例如参见Jacques,J.等,Enantiomers,Racemates and Resohitions(Wiley-Interscience,NewYork,1981);Wilen,S.H.等,Tetrahedron 33:2725(1977);Eliel,E.L.,Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);和Wilen,S.H.,Tables of Resolving Agents and OpticalResoluitions 268页(E.L.Eliel,Ed.,Univ.of Notre Dame Press,NotreDame,IN,1972)。
本发明的化合物可以含有一个或多个手性中心和/或双键,因此以立体异构体如双键异构体(即几何异构体)、对映异构体或非对映异构体形式存在。根据本发明,本文所示的化学结构以及本发明化合物包括所有对应的对映异构体和立体异构体,也即是立体纯形式(例如,几何纯体、对映体纯体、或非对映体纯体)以及对映异构和立体异构的混合物,例如外消旋体。
当本发明化合物相对于特定手性中心是80%ee(对映体过量)或更多,优选等于或大于90%ee,更优选相对于特定手性中心是95%ee时,该化合物被认为是光学活性或对映体纯的(例如,基本是R-型或基本是S-型)。因此,本发明包括式I化合物的所有对映体纯体、对映体富集的、和外消旋的混合物。
本发明化合物的对映异构体和立体异构体混合物可通过已知的方法,例如手性相气相色谱、手性相高效液相色谱、以手性盐复合物结晶化合物、或在手性溶剂中结晶化合物被拆分为其组分对映异构体或立体异构体。对映异构体和立体异构体还可以通过已知的不对称合成方法,由立体或对映体纯的中间体、试剂和催化剂制得。
本发明还包括落入式I的化合物的前药。术语“前药”是指给药于哺乳动物通过体内生物转换转变为落入式I的化合物的化合物。落入式I的化合物的前药可使用已知的方法合成,例如所述方法记载于Burger′sMedicinal Chemistry and Drug Chemistry,第5版,第1卷,172-178页,949-982(1995)。
在本文中,本发明化合物由其化学结构和/或化学名称定义。当化合物既有化学结构又有化学名称,且化学结构和化学名称矛盾时,化学结构确定该化合物的身份。
在另一实施方案中,本发明还提供了含有治疗有效量或预防有效量的一种或多种本发明化合物和可药用赋形剂或载体的药物组合物。可药用赋形剂或载体可包括赋形剂、稀释剂、或其混合物。术语“治疗有效量”是指将引起兽医或临床医师治疗的哺乳动物出现生物或医学应答的本发明化合物的量。术语“预防有效量”是指将预防、或抑制或减轻患有兽医或临床医师试图预防、抑制、或减轻的医学病症的哺乳动物痛苦的本发明化合物的量。
在另一实施方案中,本发明涉及抑制哺乳动物PDE4的方法,其包括向所述哺乳动物给药有效量的本发明化合物。
在另一实施方案中,本发明涉及调节哺乳动物TNF-α产生或降低其水平的方法,其包括向所述哺乳动物给药有效量的本发明化合物。
在再一个实施方案中,本发明涉及抑制哺乳动物MMP的方法,其包括向所述哺乳动物给药有效量的本发明化合物。
在再一个实施方案中,本发明涉及治疗哺乳动物不希望的血管生成的方法,其包括向所述哺乳动物给药有效量的本发明化合物。与血管生成相关的疾病是本领域已知的。
本发明的单独实施方案包括治疗或预防骨髓发育异常综合征(MDS)的方法,其包括向需要上述治疗或预防的病人给药治疗或预防有效量的本发明化合物,或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。MDS是指多种造血干细胞紊乱。MDS的特征是形态受损且成熟的骨髓(骨髓细胞生成障碍症)、外周血球减少、和发展为急性白血病可变危险性,这是由无效的血细胞生成导致的。The Merck Manual 953(第17版,1999)和List等,1990,J.Clin.Oncol.8:1424。
本发明的单独实施方案包括治疗或预防骨髓增生性疾病(MPD)的方法,其包括向需要上述治疗或预防的病人给药治疗或预防有效量的本发明化合物,或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。骨髓增生性疾病(MPD)是指一类以造血干细胞克隆异常为特征的紊乱。例如,参见Current Medical Diagnosis &Treatment,499页(第37版,Tierney等编辑,Appleton&Lange,1998)。
本发明还包括治疗、预防或管理复杂区域疼痛综合征的方法,其包括在旨在减少或避免病人的复杂区域疼痛综合征的症状的外科手术或物理治疗之前、期间或之后,向需要上述治疗、预防或管理的病人给药治疗或预防有效量的本发明化合物,或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
在另一个实施方案中,本发明涉及治疗或预防哺乳动物癌症的方法,其包括向所述哺乳动物给药治疗有效量的本发明化合物。本发明化合物可用于治疗任何癌症,例如实体瘤和来自血液的瘤。可由本发明化合物治疗或预防的癌症的具体例子包括,但不限于皮肤癌,例如黑素瘤;淋巴结癌;乳腺癌;宫颈癌;子宫癌;胃肠道癌;肺癌;卵巢癌;前列腺癌;结肠癌;直肠癌;口腔癌;脑癌;头颈癌;咽喉癌;睾丸癌;肾癌;胰腺癌;骨癌;脾癌;肝癌;膀胱癌;喉癌;鼻道癌;和与AIDS有关的癌症。化合物特别有用于治疗血液和骨髓的癌症,例如多发性骨髓瘤和急慢性白血病,例如成淋巴细胞性白血病、骨髓性白血病、淋巴细胞性白血病和髓细胞性白血病。本发明化合物可用于治疗或预防原发性肿瘤和转移性肿瘤。
在再一个实施方案中,本发明提供了治疗或预防哺乳动物癌症的方法,其包括向有上述需求的哺乳动物给药治疗有效量的本发明化合物和其它的治疗剂。
在再一个实施方案中,本发明涉及治疗或预防哺乳动物炎性紊乱的方法,其包括向所述哺乳动物给药治疗有效量的本发明化合物。本发明化合物特别有效于治疗或预防与TNF-α上调有关的炎性疾病,包括但不限于,关节炎症,例如类风湿性关节炎和骨关节炎;类风湿性脊椎炎;牛皮癣;缺血后再灌注损伤;炎性肠病;和慢性炎性肺疾病。
在再一个实施方案中,本发明提供了治疗或预防哺乳动物炎性紊乱的方法,其包括向有上述需求的哺乳动物给药治疗有效量的本发明化合物和其它的抗炎剂。
在另一个实施方案中,本发明涉及治疗或预防哺乳动物心脏病的方法,其包括向所述哺乳动物给药治疗有效量的本发明化合物。例如,本发明化合物可用于治疗或预防充血性心力衰竭、心肌病、肺水肿、内毒素介导的败血症性休克、急性病毒性心肌炎、心脏同种异体移植物排斥、和心肌梗塞。
在另一个实施方案中,本发明涉及治疗或预防哺乳动物骨质疏松的方法,其包括向所述哺乳动物给药治疗有效量的本发明化合物。
在另一个实施方案中,本发明涉及治疗或预防病毒性、遗传性、过敏性和自身免疫疾病的方法。例如,包括向所述哺乳动物给药治疗有效量的本发明化合物,该化合物有用于治疗或预防下述疾病:哺乳动物中的HIV;肝炎;成人呼吸窘迫综合征;骨吸收疾病;慢性阻塞性肺疾病;皮炎;囊性纤维病;败血症性休克;败血病;内毒素性休克;血流动力性休克;败血病综合征;缺血后再灌注损伤;脑膜炎;牛皮癣;纤维化疾病;恶病质;移植物抗宿主病;移植排斥;自身免疫疾病;类风湿性脊椎炎;克罗恩病;溃疡性结肠炎;炎性肠病;多发性硬化;全身性红斑狼疮;麻风结节性红斑;辐射损伤;癌症;哮喘;高氧肺泡损伤,但不局限于此。
在再一个实施方案中,本发明涉及治疗或预防哺乳动物疟疾、分枝杆菌感染、或由HIV导致的机会性感染,其包括向所述哺乳动物给药治疗有效量的本发明化合物。
在再一个实施方案中,本发明涉及治疗或预防患有本发明可治疗的一种以上病症的哺乳动物。
在上述实施方案中,优选所述哺乳动物需要所述治疗或预防,即所述哺乳动物实际上患有或易患本发明化合物可提供治疗或预防的医学病症。但是,本发明化合物还可以给药于不必需上述治疗或预防的测试动物。
在再一个实施方案中,本发明包括调节哺乳动物细胞或组织中PDE4产生、优选抑制或降低PDE4水平的方法,其包括将所述哺乳动物细胞或组织与有效量的本发明化合物接触。
在再一个实施方案中,本发明包括调节哺乳动物细胞或组织中TNF-α产生或降低TNF-α水平的方法,其包括将所述哺乳动物细胞或组织与有效量的本发明化合物接触。
在再一个实施方案中,本发明包括调节哺乳动物细胞或组织中MMP产生或降低MMP水平的方法,其包括将所述哺乳动物细胞或组织与有效量的本发明化合物接触。
在这些实施方案中,术语“有效量”是指将减少研究者、兽医、内科医生、或临床医师所寻找的生物应答的化合物的量。应理解的是,所述细胞可处于细胞培养物或组织培养物(体外)或有机体(体内)包括人体中。
参考详细描述和实施例理解本发明,所述详细描述和实施例旨在示例说明非限制性的本发明实施方案。
4.1化合物的制备
可以使用通常已知的制备酰亚胺和2,3-二氢-1H-异吲哚满酮的方法来制备本发明化合物。但是,本发明还涉及最终化合物制备的改进,这在下面有更详细的讨论。
因此,基本上按照Shealy等,Chem. & Ind.,(1965)1030-1031和Shealy等,J.Pharm.Sci.57,757-764(1968)所述,在碱例如碳酸钠或碳酸氢钠存在下,将N-烷氧羰基酰亚胺和胺反应得到N-取代的酰亚胺。另外,环状酸酐可与适合的胺反应,形成酰亚胺。环状酰亚胺的生成还可以通过在含有N,N’-羰基二咪唑的无水四氢呋喃中,回流合适取代的二羧酸一酰胺的溶液而实现。并且,2-溴甲基-苯甲酸酯可与合适的胺反应,形成如下所示的2,3-二氢-1H-异吲哚满酮。
其它制备方法描述于美国专利第5,605,914号和国际公开WO01/34606Al中,上述文献整体引入本文作为参考。
4.2药物组合物
另一方面,本发明提供了含有可药用载体、赋形剂或稀释剂以及本发明的一种或多种化合物的药物组合物。
在一个实施方案中,主题化合物与可药用赋形剂组合,所述可药用赋形剂例如为无菌盐水、甲基纤维素溶液、清洁溶液或其它介质、水、明胶、油脂等。该化合物或组合物可以单独给药或与任何适宜的载体、稀释剂等联合给药,并且上述给药可采用单一或多剂量。所述组合物是无菌的,特别是当用于肠胃外给药时。然而,口服的单位剂型不必要无菌的。有用的载体包括水溶性和水不溶性固体、脂肪酸、胶束、反相胶束、脂质体和半固体或液体介质包括含水溶液和非毒性有机溶剂。所有的上述制剂可经超声、搅拌、混合、高切力混合、加热、研磨、粉碎、雾化、粉化、冻干等处理,形成可药用组合物。
用于由本发明化合物制备药物组合物时,可药用载体可以是固体或液体。固态制剂包括粉剂、片剂、丸剂、胶囊、扁囊剂、栓剂、和分散颗粒。固体载体可以是一种或多种物质,其还可作为稀释剂、调味剂、粘合剂、防腐剂、片剂崩解剂、或密封材料。
对于粉剂,载体是粉碎很细的固体,其与粉碎很细的活性成分混合。对于片剂,以合适的比例将活性成分和具有必需粘合性能的载体混合,并将其压制成所需的形状和大小。
粉剂和片剂优选含有5%或10%至70%的活性成分。合适的载体是碳酸镁、硬脂酸镁、滑石粉、糖、乳糖、粘胶质、糊精、淀粉、明胶、西黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。术语“制剂”包括具有活性化合物和作为胶囊载体的密封材料的剂型,所述胶囊中活性成分伴随或不伴随其它载体被载体包裹,由此与载体组合。类似地,包括扁囊剂和锭剂。片剂、粉剂、胶囊、丸剂、扁囊剂和锭剂可用作适合口服给药的固体剂型。
关于栓剂制备,首先将低熔点蜡,例如脂肪酸甘油酯或可可脂的混合物熔融,然后例如通过搅拌,将活性成分均匀地分散其中。然后将熔融的均匀混合物倒入适宜大小的模型中,冷却从而固化。
液态制剂包括溶液、悬浮液、和乳液,例如水或水/丙二醇溶液。对于肠道外注射,液体制剂可在含水聚乙二醇溶液中配制。
适合口服应用的含水溶液的制备方法可以是将活性成分溶于水中并加入预期合适的着色剂、调味剂、稳定剂、和增稠剂。适合口服应用的含水悬浮液的制备方法可以是将粉碎很细的活性成分分散于含有粘性材料的水中,例如天然或合成树胶、树脂、甲基纤维素、羧甲基纤维素钠、和其它已知的悬浮剂。
另外还包括在使用之前被转换为口服给药的液态制剂的固态制剂。所述液体制剂包括溶液、悬浮液、和乳液。除了活性成分之外,这些制剂还包含着色剂、调味剂、稳定剂、缓冲剂、人造或天然甜味剂、分散剂、增稠剂、促溶剂等。
优选药物制剂呈单位剂量型。呈上述剂型的制剂被细分成含有合适量活性成分的单位剂量。单位剂量型可以是包装的制剂,所述包装含有分离量的制剂,例如成包装的剂、胶囊和置于小瓶或安瓿中的粉剂。并且,单位剂量型可以是单独的胶囊、片剂、扁囊剂或锭剂,或者可以是封装形式的合适数量的任何上述剂型。
单位剂量制剂中活性成分的数量可以在0.1mg-1000mg,优选在1.0mg-100mg变化或调节,这取决于具体的应用和活性成分的效力。如果需要,该组合物还可以含有可配伍的治疗剂。
本发明的药物组合物和方法还包括如本文中提及的用于治疗代谢紊乱、心血管疾病、炎症或肿瘤性疾病和与其相关的病状(例如糖尿病性神经病)的其它治疗活性化合物或其它佐剂。在许多情况下,包含本发明化合物和替代剂的组合物在给药时具有附加或协同效应。
4.3应用方法
根据本发明,本发明的化合物或组合物给药于患有或易患疾病或医学病症的哺乳动物,优选人类,所述疾病或医学病症例如为癌症如实体瘤和来自血液的瘤。通过给药本发明化合物可治疗或可预防的癌症的具体例子包括,但不限于皮肤癌,例如黑素瘤;淋巴结癌;乳腺癌;宫颈癌;子宫癌;胃肠道癌;肺癌;卵巢癌;前列腺癌;结肠癌;直肠癌;口腔癌;脑癌;头颈癌;咽喉癌;睾丸癌;肾癌;胰腺癌;骨癌;脾癌;肝癌;膀胱癌;喉癌;鼻道癌;和与AIDS有关的癌症。化合物特别有用于治疗血液和骨髓的癌症,例如多发性骨髓瘤和急慢性白血病,例如成淋巴细胞性白血病、骨髓性白血病、淋巴细胞性白血病和髓细胞性白血病。
通过本发明方法可治疗、预防或管理的具体癌症的其它例子包括,但不限于高级恶性肿瘤、淀粉样变性病、成神经细胞瘤、脑膜瘤、血管外皮细胞瘤、多发性脑转移、多形性成胶质细胞瘤、成胶质细胞瘤、脑干胶质瘤、恶性脑肿瘤预后不良、恶性胶质瘤、多形性成胶质细胞瘤、间变性少突神经胶质瘤、神经内分泌肿瘤、直肠腺癌、杜克斯C & D结肠直肠癌、不能切除的结肠直肠癌、转移性肝细胞癌、卡波济氏肉瘤、核型急性成髓细胞白血病、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、皮肤T淋巴细胞瘤、非皮肤T淋巴细胞瘤、皮肤B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、低度滤泡性淋巴瘤、恶性黑色素瘤、恶性间皮瘤、恶性肿瘤性胸腔积液间皮瘤综合征、多发性骨髓瘤、腹膜癌、乳头状浆液性癌、妇科肉瘤、软组织肉瘤、scelroderma、和皮肤脉管炎。
本发明化合物还有用于治疗或预防心脏病,例如充血性心力衰竭、心肌病、肺水肿、内毒素介导的败血症性休克、急性病毒性心肌炎、心脏同种异体移植物排斥、和心肌梗塞。
本发明化合物还可用于治疗或预防病毒性、遗传性、炎性、过敏性和自身免疫疾病。例如,所述化合物有用于治疗或预防包括下述的疾病:HIV;肝炎;成人呼吸窘迫综合征;骨吸收疾病;慢性阻塞性肺疾病;慢性炎性肺疾病;皮炎;囊性纤维病;败血症性休克;败血病;内毒素性休克;血流动力性休克;败血病综合征;缺血后再灌注损伤;脑膜炎;牛皮癣;纤维化疾病;恶病质;移植排斥;自身免疫疾病;类风湿性脊椎炎;关节炎症,如类风湿性关节炎和骨关节炎;骨质疏松症;炎性肠病;克罗恩病;溃疡性结肠炎;炎性肠病;多发性硬化症;全身性红斑狼疮;麻风结节性红斑;辐射损伤;哮喘;高氧肺泡损伤,但不局限于此。
本发明化合物还有用于治疗或预防细菌感染,包括但不限于疟疾、分枝杆菌感染、或由HIV导致的机会性感染。
本发明的另一个实施方案包括治疗、管理或预防与不希望的血管生成有关的或以不希望的血管生成为特征的疾病和紊乱,该方法包括向需要上述治疗、管理或预防的病人给药治疗或预防有效量的本发明免疫调节化合物,或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
与不希望的血管生成有关的或以不希望的血管生成为特征的疾病和紊乱的例子包括,但不限于炎性疾病、自身免疫疾病、病毒性疾病、遗传性疾病、过敏性疾病、细菌性疾病、眼睛新生血管疾病、脉络膜新生血管疾病、视网膜新生血管疾病、和潮红(角新血管形成),它们是由不希望的和不受控制的血管生成介导的。在本发明的某些实施方案中,具体的疾病不包括充血性心力衰竭、心肌病、肺水肿、内毒素介导的败血症性休克、急性病毒性心肌炎、心脏同种异体移植物排斥和心肌梗塞、HIV;肝炎;成人呼吸窘迫综合征;骨吸收疾病;慢性阻塞性肺疾病;慢性炎性肺疾病;皮炎;囊性纤维病;败血症性休克;败血病;内毒素性休克;血流动力性休克;败血病综合征;缺血后再灌注损伤;脑膜炎;牛皮癣;纤维化疾病;恶病质;移植排斥;类风湿性脊椎炎;骨质疏松症;克罗恩病;溃疡性结肠炎;炎性肠病;多发性硬化症;全身性红斑狼疮;麻风结节性红斑;辐射损伤;哮喘;高氧肺泡损伤、疟疾和分支杆菌感染。
本发明化合物还有用于预防心脏病,例如充血性心力衰竭、心肌病、肺水肿、内毒素介导的败血症性休克、急性病毒性心肌炎、心脏同种异体移植物排斥、和心肌梗塞。
4.4本发明化合物和组合物的治疗性/预防性给药
本发明化合物的给药方式可以是全身性的和局部的。在大多数情况下,向哺乳动物给药将导致本发明化合物的全身性释放(即进入血流)。给药方法包括肠道途径,例如口、面颊、舌下和直肠;局部给药,例如透皮和真皮内;和肠道外给药。适合的肠道外途径包括通过皮下针头和导管注射,例如静脉注射、肌肉注射、皮下注射、真皮内注射、腹腔注射、动脉注射、心室内注射、鞘内注射和前眼房注射以及非注射途径,例如阴道内直肠或鼻给药。优选,本发明化合物和组合物口服给药。在特定的实施方案中,可能会希望向需要治疗的区域局部给药一种或多种本发明化合物。上述给药方式的实现例如可通过外科手术期间局部灌注,在外科手术之后例如随同创伤敷料一起局部敷用,通过注射,利用导管、栓剂或植入物,所述植入物是多孔、无孔或胶状材料,包括膜,例如sialastic膜、或纤维。
本发明化合物可通过标准及非标准输送体系给药,例如脂质体内的包囊、微粒、微胶囊、胶囊等。例如,本发明化合物和组合物可在囊中输送,尤其是脂质体(参见Langer,1990,Science
249:1527-1533;Treat等,in Liposomes in Therapy of Infectious Disease and Cancer,Lopez-Berestein and Fidler(eds.),Liss,New York,353-365页(1989);Lopez-Berestein,同上,317-327页;一般参见同上)。在其它实施例中,本发明化合物和组合物可在控释体系中输送。在一个实施方案中,可使用泵(参见Langer,supra;Sefton,1987,CRC Crit.Ref.Biomed.Eng.14:201;Buchwald等,1980,Surgery
88:507;Saudek等,1989,N.Engl.J.Med.
321:574)。在另一实施例中,可使用聚合材料(参见MedicalApplications of Controlled Release,Langer and Wise(eds.),CRCPress.,Boca Raton,Florida(1974);Controlled Drug Bioavailability,Drug Product Design and Performance,Smolen and Ball(eds.),Wiley,New York(1984);Ranger and Peppas,1983,J.Macromol.Sci.Rev.Macromol.Chem.
23:61;还参见Levy等,1985,Science
228:190;During等,1989,Ann.Neurol.25:351Howard等,1989,J Neurosurg.
71:105)。在另一实施例中,控释体系可位于邻近待治疗靶点例如肝脏的区域,由此仅需要全身剂量的一部分(例如参见Goodson,MedicalApplications of Controlled Release,supra,第2卷,115-138页(1984))。在综述(Langer,1990,Science
249;1527-1533)中讨论的其它控释体系也可以使用。
当作为组合物给药时,本发明化合物与合适量的可药用赋形剂或载体一起配制,从而得到适合给药于哺乳动物的剂型。术语“可药用”是指由联邦政府或州立政府的管理机构批准或列于美国药典或其它公认药典中可用于哺乳动物、且尤其是人类。术语“赋形剂”是指稀释剂、佐剂、赋形剂、或载体,本发明化合物可随同上述物质配制成给药哺乳动物的制剂。上述药用赋形剂可以是液体,例如水和油,包括石油、动物、植物或合成来源的油,如花生油、豆油、矿物油、芝麻油等。上述载体可以是盐水、阿拉伯胶、明胶、淀粉糊、滑石粉、角质素、胶体硅、尿素等。此外,可使用辅助剂、稳定剂、增稠剂、润滑剂和着色剂。优选地,当向哺乳动物给药时,本发明化合物和组合物以及可药用赋形剂、辅料或稀释剂是无菌的。当本发明化合物静脉给药时,优选的载体是含水介质,例如水、盐水溶液和含水葡萄糖和甘油溶液。
本发明化合物和组合物可呈胶囊、片剂、丸剂、弹丸剂、锭剂、粉剂、颗粒、糖浆、酏剂、溶液、悬浮液、乳液、栓剂、或其缓释剂型、或任何其它适于向哺乳动物给药的形式。在优选的实施方案中,按照适合向人类口服或静脉给药的药物组合物的常规方法配制本发明化合物和组合物用于给药。在一个实施方案中,可药用赋形剂是硬明胶胶囊。合适的药用赋形剂及其生产方法的例子记载于Remington:The Science and Practice of Pharmacy,Alfonso R.Gennaro编辑,MackPublishing Co.Easton,PA,第19版,1995,第86、87、88、91和92章,该文献引入本文作为参考。
配制成用于口服输送的本发明化合物和组合物优选呈胶囊、片剂、丸剂、或任何压制的药用形式。此外,呈片剂或丸剂形式时,可以将所述化合物和组合物包衣以延迟在胃肠道中的崩解和吸收,从而在延长的期间获得持续的作用。包裹于渗透压活性驱动的化合物周围的选择性渗透膜还适用于口服给药的本发明化合物和组合物。在这些后述的平台中,通过驱动化合物膨胀穿过小孔替换所述试剂或试剂组合物,将流体从包裹胶囊的环境中吸入。相对于立即释放剂型的尖峰图形,这些输送平台可获得基本上零级输送图形。还可以使用延时材料,例如单硬脂酸甘油酯或硬脂酸甘油酯。口服组合物可包括标准赋形剂、辅料、和稀释剂,例如硬脂酸镁、糖精钠、纤维素、碳酸镁、乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯树胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、水、糖浆和甲基纤维素,另外,所述制剂还可以包含润滑剂、例如滑石粉、硬脂酸镁、矿物油、湿润剂、乳化剂和悬浮剂、防腐剂例如对羟基苯甲酸甲酯和对羟基苯甲酸丙酯。优选上述赋形剂是药用级。本发明的口服化合物和组合物可任选包含一种或多种甜味剂,例如果糖、天冬甜二肽或糖精;一种或多种调味剂例如薄荷、冬青油、或樱桃;或一种或多种着色剂,从而获得药用可口的制剂。
治疗特定紊乱或病症的治疗有效剂量方案取决于疾病的性质和严重度,并且该方案可根据医师的判断由标准临床技术来确定。此外,体外或体内测试可有助于鉴别最佳剂量。当然,构成有效剂量的本发明化合物的量还取决于给药途径。一般,合适的口服剂量范围为约0.001微克至约20微克本发明化合物/公斤体重·天,优选约0.7微克至约6微克,更优选约1.5微克至4.5微克。在优选实施方案中,哺乳动物、优选人类口服约0.01mg至约1000mg本发明化合物/天,更优选约0.1mg至约300mg/天,或约1mg至约100mg按一剂或多个分剂量服用。这里所述的剂量是指给药总剂量;即如果给药一种以上本发明化合物,优选剂量对应于给药本发明化合物的总量。口服组合物优选含有10%重量至95%重量的本发明化合物。优选单位口服剂量型包括丸剂、片剂和胶囊,更优选胶囊。通常,上述单位剂型含有约0.01mg、0.1mg、1mg、5mg、10mg、15mg、20mg、50mg、100mg、250mg或500mg的本发明化合物,优选约5mg至约200mg化合物/单位剂量。
在另一实施方案中,本发明化合物和组合物可肠道外给药(例如通过肌肉、鞘内、静脉和动脉途径),优选静脉给药。通常,静脉给药的本发明化合物和组合物是处于无菌等渗含水赋形剂如水、盐水、林格氏溶液、或葡萄糖溶液中的溶液。需要时,所述组合物还可包含促溶剂。静脉给药的组合物可任选地包含局部麻醉剂例如利多卡因以减轻注射处的疼痛。对于静脉给药,本发明化合物和组合物可以制成密封容器中的无菌冻干粉末或无水浓缩物,所述容器例如为安瓿或小囊,并且容器指示活性剂的量。然后在静脉给药之前,用合适的含水介质稀释上述粉末或浓缩物。在给药之前,无菌水、盐水溶液、或其它合适含水介质的安瓿可随同粉末或浓缩物一起提供用于稀释。或者可将组合物制成预混形式,准备给药。本发明化合物或组合物将通过静脉灌注给药时,例如其可用含有无菌药用级水、盐水或其它合适介质的输液瓶进行分散。
通过使用栓剂实现直肠给药,所述栓剂由常规载体例如可可脂、改性的植物油、和其它脂肪基质配制而成。栓剂可通过已知的方法使用已知的配比配制而成,例如参见Remington:The Science and Practiceof Pharmacy,Alfonso R.Gennaro ed.,Mack Publishing Co.Easton,PA,第19版,1995,1591-1597页,其引入本文作为参考。
为了配制和给药局部剂型,可使用已知的透皮或真皮内输送介质例如洗剂、乳膏和软膏以及透皮输送装置例如贴片(Gbosh,T.K.;Pfister,W.R.;Yum,S.I.Transdermal and Topical Drug DeliverySystems,Interpharm Press,Inc.249-297页,其引入本文作为参考)。例如,储存型贴片可被设计成包括涂覆了粘合剂的底膜和包含本发明化合物或组合物的储存室,其利用半透膜与皮肤分隔(例如美国专利第4,615,699号,其引入本文作为参考)。涂覆底层的粘合剂延伸至储存室边界周围,从而为皮肤提供同心密封并将储存室保持在皮肤附近。
本发明的粘膜剂型包括,但不限于眼用溶液、喷雾剂和气雾剂、或本领域技术人员已知的其它剂型。例如参见Remington′sPharmaceutical Sciences,第18版,Mack Publishing,Easton PA(1990);和Introduction to Pharmaceutical Dosage Forms,第4版,Lea & Febiger,Philadelphia(1985)。适合治疗口腔内粘膜组织的剂型可制成口腔清洗剂和口腔凝胶。在一个实施方案中,气雾剂包括载体。在另一个实施方案中,气雾剂没有载体。
本发明化合物还可以通过吸入直接给药于肺部。对于吸入给药,本发明化合物可通过许多不同的装置便利地输送到肺部。例如,可使用压力定量吸入器(“MDI”)将式I化合物直接输入肺部,所述压力定量吸入器利用金属罐,罐内含有合适的低沸点推进剂,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体。MDI装置可从许多供应商购得,例如3M公司、Aventis、BoehringerIngleheim、Forest Laboratories、Glaxo-Welleome、Schering Plough和Vectura。
另外,干粉吸入器(DPI)可用于将本发明化合物给药到肺部(例如参见Raleigh等,Proc.Amer. Assoc.Cancer Research AnnualMeeting,1999,40,397,其引入本文作为参考)。DPI装置通常利用诸如下述的机制:气体爆炸从而在容器内产生干粉云团,随后其被病人吸入。DPI装置也是本领域公知的,可以从许多厂家购买,例如包括Fisons、Glaxo-Wellcome、Inhale Therapeutic Systems、MLLaboratories、Qdose和Vectura。普及的改进装置是多剂量DPI(“MDDPI”)体系,其可以输送一种以上治疗剂量。MDDPI可以从诸如下述公司购得:AstraZeneca、Glaxo Wellcome、IVAX、ScheringPlough、Skyepharma和Vectura。例如,用于吸入器和吹入器的明胶胶囊和药筒可含有化合物和合适的粉末基质,如用于上述体系的乳糖或淀粉的粉末混合物。
可用于将本发明化合物输送到肺部的其它类型装置是液体喷雾装置,例如由Aradigm公司提供。液体喷雾系统使用极小的喷嘴孔以雾化液体药物制剂,然后其可被直接吸入肺部。
在优选的实施方案中,雾化器用于输送本发明化合物到肺部。雾化器例如通过使用超声能量形成易被吸入的细微颗粒,从液体药物制剂产生气溶胶(例如参见,Verschoyle等,British J Cancer,1999,80,Suppl 2,96,其引入本文作为参考)。喷雾器的例子包括由Sheffield/Systemic Pulmonary Delivery Ltd.(参见,Armer等,美国专利5,954,047号;van der Linden等,美国专利5,950,619号;van derLinden等,美国专利5,970,974号,上述文献均被引入本文作为参考)、Aventis和Batelle Pulmonary Therapeutics提供的装置。
在特别优选的实施方案中,电流体动力学(“EHD”)气溶胶装置被用于输送本发明化合物到肺部。EHD气溶胶装置使用电能来雾化液体药物溶液或悬浮液(例如参见,Noakes等,美国专利4,765,539号;Coffee,美国专利4,962,885号;Coffee,PCT申请WO 94/12285;Coffee,PCT申请WO94/14543;Coffee,PCT申请WO 95/26234,Coffee,PCT申请WO95/26235,Coffee,PCT申请WO 95/32807,上述文献均被引入本文作为参考)。当用EHD气溶胶装置输送药物到肺部时,式I化合物制剂的电化学性质是最优化的重要参数,并且最优化通常由本领域技术人员实施。EHD气溶胶装置可比目前的肺输送技术更有效地将药物输送到肺部。
适合用于喷雾器和液体喷雾装置以及EHD气溶胶装置的液体药物制剂通常包括氟烷氧基取代的1,3-二氢-异吲哚化合物以及可药用载体。优选,可药用载体是液体例如乙醇、水、聚乙二醇或全氟化碳。任选地,可加入其它材料以改变本发明化合物的溶液或悬浮液的气雾剂性质。优选,所述材料是液体,例如乙醇、乙二醇、聚乙二醇或脂肪酸。适合用于气溶胶装置的液体药物溶液或悬浮液的其它配制方法是本领域技术人员已知的(例如参见Biesalski,美国专利5,112,598号;Biesalski,美国专利5,556,611号,上述文献引入本文作为参考)。式I化合物可制成直肠或阴道组合物例如栓剂或保留灌肠剂,上述制剂例如含有常规栓剂基质如可可脂或其它甘油酯。
除了上述制剂之外,本发明化合物还可被制成长效制剂。上述长效制剂可通过植入(例如皮下或肌内)或肌肉注射给药。因此,化合物例如可与合适的聚合或疏水材料(例如成为合适油中的乳剂)或离子交换树脂一起配制,或者制成微溶的衍生物例如微溶盐。
另外,可采用其它药物输送体系。脂质体和乳剂是可用于输送本发明化合物的输送载体的已知实例。还可以采用某些有机溶剂,例如二甲亚砜,虽然代价是较大的毒性。本发明化合物还可以在控释体系中输送。在一个实施方案中,可使用泵(Sefton,CRC Crit.Ref.Biomed.Eng.1987,14,201;Buchwald等,Surgery,1980,88,507;Saudek等,N.Engl.J.Med.,1989,321,574)。在另一实施例中,可使用聚合材料(参见Medicai Applications of Controlled Release,Langer andWise(eds.),CRC Press.,Boca Raton,Fla.(1974);Controlled DrugBioavailability,Drug Product Design and Performance,Smolen and Ball(eds.),Wiley,New York(1984);Ranger and Peppas,J.Macromol.Sci.Rev.Macromol.Chem.,1983,23,61;还参见Levy等,Science,1985,228,190;During等,Ann.Neurol.,1989,25,351;Howard等,1989,J Neurosurg.71,105)。在另一实施例中,控释体系可位于邻近本发明化合物靶点例如肝脏的区域,由此仅需要全身剂量的一部分(例如参见Goodson,Medical Applications of Controlled Release,supra,第2卷,115页(1984))。也可以使用其它控释体系(例如参见,Langer,Science,1990,249,1527)。
对于制药领域技术人员来说,用于提供包括在本发明内的粘膜剂型的合适辅料(例如载体和稀释剂)及其它材料是已知的,并且取决于将给药的特定药物组合物或剂型的特定位置或方法。考虑到上述情况,常用的辅料包括,但不限于水、乙醇、乙二醇、丙二醇、丁烷-1,3-二醇、豆蔻酸异丙酯、棕榈酸异丙酯、矿物油、及其混合物,它们是无毒性且可药用的。上述附加成分的例子在本领域是已知的,例如参见Remington′s Pharmaceutical Sciences,第18版,Mack Publishing,Easton PA(1990)。
还可以调节药物组合物或剂型的pH或者该药物组合物或剂型施用组织的pH以改进一种或多种活性成分的输送。类似地,可以调节溶剂载体的极性、离子强度、或毒性以改进输送。还可以将诸如硬脂酸酯的化合物加入药物组合物或剂型以有利地改变一种或多种活性成分的亲水性或亲油性,从而改进输送。在这方面,硬脂酸酯可用作制剂的脂质载体、乳化剂或表面活性剂、以及促进输送剂或促进渗透剂。活性成分的不同盐、水合物或溶剂化物可用于进一步调节所得组合物的性质。
本发明还提供了包含装有一种或多种本发明化合物的一种或多种容器的药包或药盒。任选地,上述容器中可以有管理药品或生物制品的生产、使用或销售的政府机关规定形式的通告,该通告反映了人类用药的生产、使用或销售机构的核准。在一个实施方案中,药盒含有一种以上本发明化合物。在另一个实施方案中,药盒包含本发明化合物和其它的生物活性药剂。
优选地,在用于人类之前,在体外和体内对本发明化合物进行所需治疗或预防活性的测试。例如,体外测试可用于确定给药本发明的特定化合物还是给药本发明化合物的组合物是否是优选的。还可以使用动物模型系统来证实本发明化合物和组合物是有效并安全的。其它方法是本领域熟练技术人员已知的并包括在本发明的范围中。
4.5联合治疗
在某些实施方案中,本发明化合物联同一种或多种其它治疗剂、或联同一种或多种其它本发明化合物、或者联同上述两种物质一起给药于哺乳动物,优选人类。“联同”是指本发明化合物和其它试剂依次且在一时间间隔内给药于哺乳动物,以致本发明化合物可与其它试剂一起作用,从而提供比其它给药情况增强或协同的益处。例如,每种组分可以同时或在不同时间点以任何次序相继给药;但是,如果不是同时给药,它们应在时间上足够紧凑以提供所需的治疗效果。优选地,所有的组分同时给药;如果不是同时给药,优选它们相互间隔约6小时至约12小时给药。
当用于联合其它治疗剂时,本发明化合物和其它治疗剂可以以加和方式作用或更优选以协同方式作用。在一个实施方案中,本发明的化合物或组合物联同其它治疗剂在同一药物组合物中给药。在另一个实施方案中,本发明化合物或组合物联同其它治疗剂以分开的药物组合物形式给药。在再一个实施方案中,本发明的化合物或组合物在其它治疗剂给药之前或之后给药。由于本发明的化合物和组合物用于治疗的许多紊乱是慢性紊乱,在一个实施方案中,联合治疗涉及本发明化合物或组合物与包含其它治疗剂的药物组合物交替给药,从而例如最小化与特定药物相关的毒性。在某些实施方案中,当本发明组合物联同有可能产生副作用(包括,但不限于毒性)的其它治疗剂一起给药时,有利地,该其它治疗剂以低于引发副作用的阈值的剂量给药。附加治疗剂包括,但不限于造血生长因子、细胞因子、抗癌剂、抗生素、免疫抑制剂、甾类、抗组胺剂、lukatriene抑制剂和其它本文中所讨论的治疗剂。
优选的附加治疗剂包括,但不限于Remicade TM、多西紫杉醇、塞来考昔TM、美法仑、地塞米松、甾类、吉西他滨、顺铂、替莫唑胺、依托泊苷、环磷酰胺、替莫唑胺、碳铂、甲基苄肼、卡氮芥糯米纸胶囊剂、它莫西芬、托泊替康、甲氨喋呤、Arisa,紫杉酚TM,泰索帝、氟尿嘧啶、亚叶酸、依立替康、希罗达、CPT-l 1,干扰素α、聚乙二醇化的干扰素α、卡培他滨、顺铂、塞替派、氟达拉滨、碳铂、柔红霉素脂质体、阿糖胞苷、doxetaxol、紫杉醇、长春碱、IL-2、GM-CSF、达卡巴嗪、长春瑞滨、唑来膦酸、palmitronate、克拉霉素制剂、白消安、泼尼松、二膦酸盐、三氧化二砷、PEG INTRON-A、盐酸多柔比星脂质体、长春新碱、地卡特隆、多柔比星、紫杉醇、更昔洛韦、阿霉素、磷雌氮芥、Emcyt,舒林酸、和依托泊苷。
本发明还包括天然存在的蛋白质的突变体和衍生物(例如,修饰的形式),上述突变体和衍生物在体内表现出至少一些基于所述蛋白质的药理活性。突变体的例子包括,但不限于具有一个或多个不同于天然存在的蛋白质形式中对应残基的氨基酸残基的蛋白质。术语“突变体”还包括缺乏通常存在于天然存在形式中的糖基团(例如非糖基化形式)。衍生物的例子包括,但不限于聚乙二醇化衍生物和融合蛋白,例如通过IGl或IG3融合于蛋白质或所需蛋白质的活性部位而形成的蛋白质。例如,参见Penichet,M.L.和Morrison,S.L.,J.Immunol.Methods248:91-101(2001)。
G-CSF的重组体和突变体可如美国专利4,810,643、4,999,291、5,528,823、和5,580,755中所述制备;上述所有文献均引入本文作为参考。GM-CSF的重组体和突变体可如美国专利5,391,485、5,393,870、和5,229,496中所述制备;上述所有文献均引入本文作为参考。事实上,G-CSF和GM-CSF的重组体目前在美国出售,用于治疗与特异性化学药物治疗有关的症状。被称为非格司亭的G-CSF重组体在美国以商品名NEUPOGEN出售,并显示出了降低患有非骨髓恶性肿瘤的病人由于发热性嗜中性白血球减少症导致的感染发病率,所述病人接受了与伴有发热的严重嗜中性白血球减少症的显著发病率有关的骨髓抑制抗癌药物。Physicians′Desk Reference,587-592(第56版,2002)。被称为沙格司亭的GM-CSF重组体也在美国以商品名LEUKINE出售。LEUKINE用于患有急性骨髓性白血病的老年病人的诱导化学药物治疗以缩短中性白细胞恢复时间。Physicians′Desk Reference,1755-1760(第56版,2002)。被称为阿尔法依伯汀的EPO重组体在美国以商品名EPOGEN出售。EPOGEN通过刺激定向红细胞前体细胞的分裂和成熟来刺激红细胞生成。Physicians′Desk Reference,582-587(第56版,2002)。
诸如G-CSF、GM-CSF和EPO的生长因子或细胞因子还可以呈疫苗的形式给药。例如,分泌细胞因子(例如G-CSF和GM-CSF)或导致细胞因子分泌的疫苗可用于本发明方法、药物组合物和药盒中。例如参见Emens,L.A.等,Curr.Opinion Mol.Ther.3(1):77-84(2001)。
可用于本发明各种实施方案(包括本发明方法、剂量方案、鸡尾酒疗法、药物组合物和剂型以及药盒)中的抗癌药物的例子包括,但不限于阿西维辛、阿柔比星、盐酸阿考达唑、阿克罗宁、阿多来新、阿地白介素、六甲密胺、安波霉素、乙酸阿美蒽醌、安吖啶、阿那曲唑、安曲霉素、门冬酰胺酶、曲林菌素、阿扎胞苷、阿替派、阿佐霉素、巴马司他、苄替派、比卡鲁胺、比卡鲁胺、二甲磺酸双奈法德、比折来新、硫酸博来霉素、布喹那钠、溴匹立明、白消安、放线菌素C、卡普睾酮、卡醋胺、卡贝替姆、碳铂、卡氮芥、盐酸卡柔比星、卡折来新、西地芬戈、塞来考昔、苯丁酸氮芥、西罗里霉素、顺铂、克拉屈滨、甲磺酸克立那托、甲磺酸、阿糖胞苷、达卡巴嗪、更生霉素、盐酸柔红霉素、地西他滨、右奥马铂、地扎呱宁、甲磺酸地扎呱宁、地吖醌、达卡巴嗪、多西他奇、多柔比星、盐酸多柔比星、屈洛昔芬、柠檬酸屈洛昔芬、丙酸甲雄烷酮、偶氮霉素、依达曲沙、盐酸依洛尼塞、依沙芦星、恩洛铂、苯环丙炔酯、双环氧哌啶、盐酸表柔比星、厄布洛唑、盐酸依索比星、磷雌氮芥、雌氮芥磷酸钠、依他硝唑、依托泊苷、磷酸依托泊苷、氯苯乙嘧胺、盐酸法倔唑、法扎拉滨、芬维A胺、氟脲嘧啶脱氧核苷、磷酸氟达拉滨、氟尿嘧啶、氟西他滨、磷喹酮、福司曲星钠、吉西他滨、吉西他滨、羟基脲、盐酸伊达比星、异磷酰胺、依莫佛新、白细胞介素II(包括重组白细胞介素I或rIL2))、白细胞介素α-2a、白细胞介素α-2b、白细胞介素α-n1、白细胞介素α-n3、白细胞介素β-Ia、白细胞介素γ-Ib、异丙铂、依立替康、盐酸依立替康、醋酸兰瑞肽、来曲唑、醋酸亮丙瑞林、盐酸利阿唑、盐酸利阿唑、罗莫司丁、盐酸洛索蒽醌、马丙考、美登素、盐酸氮芥、醋酸甲地孕酮、醋酸美仑孕酮、美法仓、美诺立尔、巯嘌呤、甲氨喋呤、甲氨蝶呤钠、氯苯氨啶、美妥替哌、米丁度胺、mitocarcin、丝裂红素、丝裂吉菌素、丝裂马菌素、丝裂霉素C、丝裂帕菌素、米托坦、盐酸米托蒽醌、霉酚酸、噻氨酯哒唑、诺加霉素、奥马铂、奥昔舒仑、紫杉醇、天门冬酰胺酶、佩利霉素、溴新斯的明、硫酸培来霉素、培磷酰胺、溴丙哌嗪、嗪消安、盐酸吡罗蒽醌、光辉霉素、普洛美坦、卟吩姆钠、泊非霉素、泼尼莫司汀、盐酸甲基苄肼、嘌呤霉素、盐酸嘌呤霉素、吡唑呋喃菌素、异戊烯腺苷、沙芬戈、盐酸沙芬戈、司莫司汀、辛曲秦、磷乙酰天冬氨酸钠、稀疏霉素、盐酸螺旋锗、螺莫司汀、顺螺铂、链黑菌素、链唑霉素、磺氯苯脲、他利霉索、替可加兰钠、泰索帝、喃氟啶、盐酸替洛蒽醌、替莫泊芬、鬼臼噻吩甙、替罗昔隆、睾内酯、硫咪嘌呤、硫鸟嘌呤、塞替派、噻唑呋林、替拉扎明、柠檬酸托瑞米芬、醋酸曲托龙、磷酸曲西立滨、曲美沙特、葡萄糖醛酸曲美沙特、曲普瑞林、盐酸妥布氯唑、尿嘧啶氮芥、尿烷亚胺、伐普肽、维替泊芬、硫酸长春碱、硫酸长春新碱、长春地辛、硫酸长春地辛、硫酸长春匹定、硫酸长春甘酯、硫酸环氧长春碱、酒石酸长春瑞滨、硫酸异长春碱、硫酸长春利定、伏氯唑、折尼拉汀、新制癌菌素、和盐酸柔红霉素苯腙。其它的抗癌药物包括,但不限于:20-表-1,25二羟维生素D3、5-乙炔尿嘧啶、阿比特龙、阿柔比星、acylfulvene、adecypenol、阿多来新、阿地白介素、ALL-TK拮抗剂、六甲密胺、氨莫司汀、amidox、阿米斯丁、氨基乙酰丙酸、氨柔比星、安吖啶、阿那格雷、阿那曲唑、a穿心莲内酯、血管生产抑制剂、拮抗剂D、拮抗剂G、安雷利克斯、抗背侧化形成蛋白-1、前列腺癌抗雄激素物质、抗雌激素物质、抗瘤酮、反义寡核苷、甘氨酸阿非迪霉素、调亡基因调节剂、调亡基因调节剂、脱嘌呤核酸、ara-CDP-DL-PTBA、精氨酸脱氨基酶、asulacrine、阿他美坦、阿曲氮芥、axinastatin 1、axinastatin2、axinastatin 3、阿扎司琼、阿扎毒素、重氮酪氨酸、浆果赤霉素III衍生物、balanol、巴马司他、BCR/ABL拮抗剂、苯并二氢卟酚、苯甲酰十字孢碱、β-内酰胺衍生物、β-alethine、betaclamycin B、白桦脂酸、bFGF抑制剂、比卡鲁胺、比山群、双氮丙啶基精胺、双奈法德、bistrateneA、比折来新、breflate、溴匹立明、布多替钛、丁硫氨酸亚矾胺、卡泊三醇、calphostin C、喜树碱衍生物、金丝雀痘IL-2、卡培他滨、氨甲酰-氨基-三唑、羰基氨基三唑、来自软骨的抑制剂、卡折来新、酪蛋白激酶抑制剂(ICOS)、澳粟精胺、澳粟精胺B、澳粟精胺、chlorlns、氯喹噁啉氨苯磺胺、西卡前列素、顺-卟啉、克拉屈滨、氯米芬类似物、克霉唑、collismycin A、collismycin B、考布他汀A4、考布他汀类似物、conagenin、crambescidin 816、立那托、隐藻素8(cryptophycin 8)、隐藻素A衍生物、curacin A、环戊基蒽醌、cycloplatam、cypemycin、cytarabine ocfosfate、溶细胞因子、磷酸己烷雌酚、达昔单抗、地西他滨、去氢代代宁B、地洛瑞林、地塞米松、右异环磷酰胺、右丙亚胺、右维拉帕米、地吖醌、代代宁B、二乙基去甲精胺(diethylnorspermine)、二氢-5-5-氮杂胞苷、二氢紫杉酚、dioxamycin、联苯基螺莫司汀、多西他奇、二十二烷醇、多拉司琼、多拉司琼、阿霉素、屈洛昔芬、屈大麻酚、duocarmycin SA、依布硒啉、依考莫司汀、依地福新、依决可单抗、依洛尼塞、榄烯、乙嘧替氟、表柔比星、依立雄胺、磷雌氮芥类似物、雌激素激动剂、雌激素拮抗剂、依他硝唑、磷酸依托泊苷、依西美坦、法倔唑、法扎拉滨、芬维A胺、非格司亭、非那司提、flavopiridol、氟卓斯汀、fluasterone、氟达拉滨、盐酸fluorodaunorunicin、福酚美克、福美坦、福司曲星、福替目丁、钆替沙林、硝酸镓、加洛他滨、加尼瑞克、明胶酶抑制剂、吉西他滨、谷光苷肽抑制剂、hepsulfam、heregulin、六甲撑二乙酰胺、金丝桃素、伊班膦酸、去甲氧正定霉素、碘昔芬、伊决孟酮、依莫佛新、伊洛马司他、咪喹莫特、免疫促进肽、胰岛素样生长因子-1受体抑制剂、干扰素激动剂、干扰素、白细胞介素、碘苄胍、碘阿霉素、4-甘薯苦醇、伊罗普拉、伊索格拉定、isobengazole、isohomohalicondrin B、伊他司琼、jasplakinolide、kahalalide F、片螺素-N三乙酸盐、laureotide、leinamycin、来诺拉提、硫酸香菇多糖、leptolstatin、来曲唑、白血病抑制因子、白血病α干扰素、亮丙瑞林+雌激素+黄体酮、亮丙瑞林、左旋咪唑、利阿唑、线性多胺类似物、亲脂双糖肽、亲脂铂化合物、lissoclinamide 7、洛铂、蚯蚓磷脂、洛美曲索、氯尼达明、洛索蒽醌、罗唑利宾、勒托替康、texaphyrin镥、lysofylline、溶解肽、美坦新、mannostatin A、马马司他、马丙考、maspin、基质溶解因子抑制剂、基质金属蛋白酶抑制剂、美诺立尔、麦尔巴隆(merbarone)、美替瑞林、蛋氨酸酶、甲氧氯普胺、MIF抑制剂、米非司酮、米替福新、米立司亭、丙米腙、二溴卫矛醇、丝裂霉素C类似物、胺硝萘酞胺、mitotoxin成纤维细胞生长因子-皂草素、米托蒽醌、莫法罗汀、莫拉司亭、艾比特思,人绒毛膜促性腺激素、单哌潘生丁、芥类抗癌剂、mycaperoxide B、分枝杆菌细胞壁提取物、myriaporone、N-乙酰地那林、N-取代的苯酰胺类、纳发阮林、nagrestip、纳洛酮+喷他佐辛、napavin、naphterpin、那托司亭、奈达铂、奈莫柔比星、奈立膦酸、尼鲁米特、nisamycin、一氧化氮调节剂、一氧化二氮抗氧化剂、nitrullyn、O6-苄基鸟嘌呤、善得定、okicenone、寡核苷酸、奥那司酮、奥坦西隆、奥坦西隆、oracin、口服细胞因子诱导剂、奥马铂、奥沙特隆、奥沙利铂、oxaunomycin、紫杉醇、紫杉醇类似物、紫杉醇衍生物、palauamine、棕榈酰根霉素、帕米膦酸、人参炔三醇、帕诺米芬、副菌铁素(parabactin)、帕折普汀、天门冬酰胺酶、培得星、戊聚硫钠、喷司他丁、pentrozole、潘氟隆、过磷酰胺、紫苏乙醇、phenazinomycin、乙酸苯酯、磷酸酶抑制剂、溶链菌、盐酸匹罗卡品、吡喃阿霉素、吡曲克辛、placetin A、placetin B、纤溶酶原活化因子抑制剂、铂笼形包合物、铂化合物、铂-三胺笼形包合物、卟吩姆钠、泊非霉素、泼尼松、丙基双吖啶酮、前列腺素J2、蛋白酶体抑制剂、基于蛋白质A的免疫调节剂、蛋白激酶C抑制剂、蛋白激酶C抑制剂-microalgal、蛋白酪氨酸磷酸酶抑制剂、嘌呤核苷磷酸化酶抑制剂、红紫素、吡唑啉吖啶、吡醇羟乙酯化血红素聚氧乙烯结合物、raf拮抗剂、雷替曲塞、雷莫司琼、ras法呢基蛋白质转化酶抑制剂、ras抑制剂、ras-GAP抑制剂、去甲基化瑞替普汀、铼Re 186依替膦酸、根霉、核酶、RII维胺脂、rohitukine、胞壁酰基二肽、罗喹美克、rubiginone B 1、ruboxyl、沙芬戈、saintopin、SarCNU、sarcophytol A、沙莫司亭、Sdi1模仿物、司莫司汀、老年化来源的抑制剂1、有义寡核苷酸、信号转导抑制剂、西佐喃、索布佐生、硼卡钠、苯乙酸钠、solverol、生长调节素结合蛋白、索纳明、膦门冬酸、spicamycin D、螺莫司汀、splenopentin、spongistatin 1、角鲨胺、stipiamide、基质分解素抑制剂、sulfinosine、强效血管活性肠肽拮抗剂、suradista、苏拉灭、苦马豆碱、他莫司汀、它莫西芬碘甲烷盐、牛碘莫司汀、他佐罗汀、替可加兰钠、喃氟啶、tellurapyrylium、端粒酶抑制剂、替莫泊芬、鬼臼噻吩甙、tetrachlorodecaoxide、tetrazomine、thaliblastine、噻可拉林、血小板生成素血小板生成素模仿物、胸腺法新、胸腺生成素受体激动剂、胸腺曲南、促甲状腺激素、本紫红素乙酯锡、替拉扎明、二氯环戊二烯钛、topsentin、托瑞米芬、翻译抑制剂、维甲酸、三乙酰胆碱、曲西立滨、曲美沙特、曲普瑞林、托吡西隆、妥罗雄脲、酪氨酸激酶抑制剂、酪氨酸磷酸化抑制剂、UBC抑制剂、乌苯美司、泌尿生殖窦来源的生长抑制因子、尿激酶受体拮抗剂、伐普肽、variolin B、维拉雷琐、藜芦明、verdins、维替泊芬、长春瑞滨、vinxaltine、vitaxin、伏氯唑、扎诺特隆、折尼拉汀、亚苄维C、和净司他丁斯酯。
在本发明的一个实施方案中,本发明化合物不仅可直接用于治疗上述紊乱,而且可以减少其它化学治疗剂的剂量或毒性。例如,可给药本发明化合物以减少与拓扑异构酶抑制剂如依立替康有关的胃肠道毒性。
4.6生物学试验
化合物对PDE4、TNF-α和MMP的抑制活性可使用本领域通常已知的方法进行测定,包括但不限于:酶免疫测定法、放射免疫测定法、放射免疫测定法、和亲和标记法。可利用的其它检验方法包括LPS-诱导的PDE4和TNF-α酶检测法,该方法在国际专利公开WO01/90076Al、WO 01/34606A1中给出,上述专利均整体引入本文作为参考。
通过Ficoll-Hypaque高强度离心分离获得正常供体的PBMC。在补充有10%AB+血清、2mM L-谷氨酰胺、100U/mL青霉素和100mg/mL链霉素的RPMI中进行细胞培养。
将测试化合物溶解于二甲亚砜(Sigma Chemical),再用补充的RPMI作进一步稀释。在含有或不含有药物的PBMC的悬浮液中,二甲亚砜的最终浓度为0.25wt%。从50mg/mL开始,对测试化合物进行半对数稀释测定。在加入LPS前一小时,将测试化合物加入至96孔板中的PBMC(106细胞/mL)。
通过使用1mg/mL的明尼苏打R595沙门氏菌[Salmonellaminnesota R595(List Biological Labs,Campbell,CA)]的LPS处理,对含有或不含有测试化合物的PBMC(106细胞/mL)进行刺激。然后将细胞在37℃孵育18-20小时,收取上层清液,并马上测定TNFα水平或在测定前将其冷冻在-70℃保存(不超过4天)。
按照制造商的指示方法,用人TNFαELISA试剂盒(ENDOGEN,Boston,MA)测定上层清液的TNFα浓度。
可以按照常规模型对磷酸二酯酶进行测定,例如,采用Hill和MitChell方法,将人的前单核细胞系的U937细胞培养至1×106细胞/mL,并通过离心分离收集。将1×109的细胞团在磷酸盐缓冲生理盐水中漂洗,然后在-70℃冷冻以进行后续净化,立即将或者溶解于冷的匀化缓冲液中(20mM Tris-HCI、pH 7.1、3mM 2-巯基乙醇、1mM氯化镁、0.1mM乙二醇-二(β-氨基乙基醚)-N,N,N=,N=-四乙酸(EGTA)、1μM苯甲磺酰氟(PMSF)和1μg/mL亮抑酶肽)。在Dounce匀化器中,将细胞打浆20次,进行匀化,离心分离获得含有细胞质成分的上层清液。然后将上层清液装入用匀化缓冲液平衡过的Sephacryl S-200柱,用匀化缓冲液以大约0.5mL/min的速度,将磷酸二酯酶洗脱,并测定洗脱馏分的磷酸二酯酶活性-/+咯利普兰。将具有磷酸二酯酶活性的馏分(咯利普兰敏感)合并、等分备用。
磷酸二酯酶的测定在总体积为100μl的溶液中进行,其中含有不同浓度的测试化合物、50mM Tris-HCI,pH 7.5、5mM氯化镁和1μMcAMP,其中的1%是3H cAMP。反应在30℃孵育30分钟,煮沸2分钟终止反应。用于这些试验的含有提取物的磷酸二酯酶IV的用量是预定的,以使反应在线性范围内进行,并且消耗的底物小于总量的15%。反应终止后,将样品冷却至4℃,然后在30℃用10μl 10mg/mL蛇毒处理15分钟。加入200μl季铵离子交换树脂(AGI-X8,BioRad)15分钟,除去未用的底物。然后将样品在3000rpm转速下旋转5分钟,取出50μl水相进行计数。每个数据点均进行重复测定,将活性表示为对照样的百分比。然后,从三次独立试验的最小值所给出的剂量应答曲线,来确定化合物的IC50。
以下实施例是用来举例说明,而不能理解为对本发明范围的限定。
5.实施例
下面所用试剂和溶剂可由商业供应商获得,例如Aldrich ChemicalCo.(Milwaukee,Wisconsin,USA)。1H-NMR和13C-NMR谱由BrukerAC 250MHz NMR光谱仪记录。明显的峰以下述顺序列出:化学位移、多重性(s,单峰;d,双重峰;t,三重峰;q,四重峰;m,多重峰;br s,宽单峰)、偶合常数(Hz)和质子数。
5.1实施例1:4-二氟甲氧基-3-羟基-苯甲醛
将3,4-二羟基苯甲醛(25g,0.18mol)和碳酸钾(25g,0.18mol)在二甲基甲酰胺(125ml)中的混合物剧烈搅拌,在氯二氟甲烷气氛下使用-78℃冷凝器在100℃下加热5.5小时。冷却混合物,用浓盐酸酸化至pH5-6,并减压浓缩。残留物在乙醚和3N盐酸溶液之间分配,并用乙醚萃取5次。有机萃取物经硫酸镁干燥,真空除去溶剂。残留物经快速色谱纯化,2∶1己烷/乙酸乙酯洗脱,得到白色固体的4-二氟甲氧基-3-羟基-苯甲醛(5g,15%)。1HNMR(DMSO-d6):δ7.22(t,JH-F=75Hz,1H),7.31(d,J=10Hz,1H),7.41-7.43(m,2H),9.87(s,1H),10.50(s,IH)。
5.2实施例2:3-环丙基甲氧基-4-二氟甲氧基-苯甲醛
在惰性气氛和60℃下,向4-二氟甲氧基-3-羟基-苯甲醛(5.0g,27rnmol)和碳酸钾(5.5g,40mmol)在二甲基甲酰胺(30ml)的混合物中加入溴乙基环丙烷(5g,37mmol)。在65℃下,加热搅拌该混合物。1.5小时之后,冷却混合物并过滤。减压浓缩滤液。用乙酸乙酯(2×25ml)和水(25ml)萃取该混合物。用水(25ml)、盐水(25ml)洗涤有机层,并经硫酸镁干燥。真空除去溶剂,得到油状的3-环丙基甲氧基-4-二氟甲氧基-苯甲醛(6.4g,100%)。1HNMR(CDCI3):δ0.38-0.44(rn,2H),0.62-0.75(m,2H),1.15-1.36(m,1H),3.98(d,J=4.5Hz,2H),6.78(t,JH-F=75Hz,1H),7.30-7.50(m,3H),9.96(s,1H)。
5.3实施例3:3-氨基-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸
在惰性气氛,40℃下,向3-环丙基甲氧基-4-二氟甲氧基-苯甲醛(6.4g,27mmol)和乙酸铵(4.3g,55mmol)在95%乙醇(30ml)中的混合物中加入丙二酸(2.9g,28mmol)。搅拌该混合物并在回流温度下加热20小时。冷却混合物并过滤,得到白色固体的3-氨基-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸(4.3g,52%)。1HNMR(DMSO-d6):δ0.31-0.35(m,2H),0.52-0.58(m,2H),1.15-1.36(m,1H),2.33-2.37(m,2H),3.87(d,J=7.5Hz,2H),4.20-4.26(rn,1H),6.94-6.98(m,1H),7.03(t,JH-F=75Hz,1H),7.13(d,J=10Hz,1H),7.23(d,J=2.5Hz,1H)。
5.4实施例4:3-(4-乙酰氨基-1,3-二氧代-l,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸
向3-氨基-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸(500mg1.0mmol)的乙酸(10ml)溶液中加入3-乙酰氨基-邻苯二甲酸酐(390mg,1.9mmol)和乙酸钠(160mg,1.9mmol)。在回流温度下加热混合物过夜。真空除去溶剂。将所得油状物用乙酸乙酯(50ml)和水(30ml)萃取。有机层用水(30ml×4)、盐水(30ml)洗涤,并经硫酸镁干燥。真空除去溶剂,用乙醚浆化所得油状物2小时。过滤悬浮液得到白色固体的3-(4-乙酰氨基-1,3-二氧代-l,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸(720mg,85%)。1HNMR(CDCl3):δ0.35-0.39(m,2H),0.64-0.68(m,2H),1.15-1.36(m,1H),2.27(s,3H),3.24(dd,J=5.8,17Hz,1H),3.82(dd,J=10,17Hz,IH),3.88(d,J=8.3Hz,2H),5.70(dd,J=5.8,10Hz,1H),6.59(t,JH-F=75Hz,1H),7.06-7.14(m,3H),7.48(d,J=7.3Hz,1H),7.65(t,J=7.5Hz,1H),8.76(d,J=8.3Hz,lH),9.47(s,1H)。
5.5实施例5:3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-N,N-二甲基-丙酰胺
在室温下,向3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸(470mg,1.04mmol)的四氢呋喃(10ml)溶液中加入羰基二咪唑(250mg,1.56mmol)。在室温下搅拌该溶液2小时。向混合物中加入二甲胺(2.0N的THF溶液,1.0ml,2.0mmol)。所得混合物在室温下搅拌3小时。向反应混合物中加入水(20ml)。真空除去溶剂。将所得混合物溶于乙酸乙酯(30ml)并有水(20ml)萃取。有机层用饱和碳酸氢钠溶液(3×20ml)、水(20ml)、盐水(20ml)洗涤,并经硫酸镁干燥。真空除去溶剂。将所得油状物在乙醚中搅拌过夜。过滤悬浮液,得到浅黄色固体。该固体经HPLC纯化(CH3CN∶水=45∶55),得到白色固体的3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-N,N-二甲基-丙酰胺(160mg,30%):熔点:80-82℃;
1H NMR:δ(CDCl3):δ0.33-0.39(m,2H),0.60-0.68(m,2H),1.21-1.30(m,1H),2.25(s,3H),2.90(s,3H),2.97(dd,J=5Hz,另一个双峰被掩盖了,1H),3.05(s,3H),3.87(d,J=7.5Hz,2H),3.94(dd,J=10Hz,另一个双峰被掩盖了,1H),5.83(dd,J=5,10Hz,1H),6.69(t,JH-F=75Hz,1H),7.12-7.15(m,3H),7.45(d,J=7.5Hz,1H),7.62(t,J=7.5Hz,1H),8.73(d,J=8.5Hz,1H),9.53(s,1H).13C NMR(CDCl3):δ3.8,3.9,10.8,25.6,35.4,36.1,37.7,51.9,74.5,112.6,116.7,120.8,114.9,116.0,118.5,120.9,123.4,125.3,131.9,136.4,138.0,138.6,140.7,151.2,168.7,169.8,169.9,170.6;
C26H27F2N3O6的分析计算值:C,60.58;H,5.28;N,8.15;测定值:C,60.23;H,5.26;N,8.02。
5.6实施例6:3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酰胺
在室温下,向3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸(100mg,0.22mmol)的四氢呋喃溶液中加入羰基二咪唑(53mg,0.33mmol)。在室温下搅拌该溶液2小时。向混合物中加入氢氧化铵(0.05ml,0.66mmol)。所得混合物在室温下搅拌2小时。向反应混合物中加入水(5ml)。真空除去THF。将所得混合物用乙酸乙酯(20ml)萃取。有机层用饱和碳酸氢钠溶液(3×10ml)、水(10ml)、盐水(10ml)洗涤,并经硫酸镁干燥。真空除去溶剂。将所得油状物经HPLC纯化(乙腈∶水=45∶55),得到白色固体的3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酰胺(80mg,81%):熔点:77-79℃;
1HNMR(CDCl3):δ0.32-0.38(m,2H),0.60-0.67(m,2H),1.20-1.31(m,1H),2.27(s,3H),3.03(dd,J=5.5,15.5Hz,1H),3.70(dd,J=8.4,15.5Hz,1H),5.28-5.40(m,1H),5.74-5.80(m,1H),5.79(dd,J=5.8,10.5Hz,1H),6.60(t,JH-F=75Hz,1H),7.09-7.13(m,3H),7.47(d,J=7.3Hz,1H),7.63(t,J=7.5Hz,1H),8.75(d,J=8.5Hz,1H),9.49(s,1H).13C NMR(CDCl3):δ3.8,3.9,10.74,25.6,38.1,51.9,474.5,112.5,114.8,115.8,116.7,118.7,120.8,123.5,125.6,131.8,136.7,137.8,138.1,140.8,151.2,168.6,169.9,170.5,172.1;
C24H23F2N3O6+0.5H2O的分析计算值:C,58.06%;H,4.87;N,8.46;测定值:C,57.77;H,4.60;N,8.33;1%H2O。
5.7实施例7:3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-丙酸
向3-氨基-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸(0.78g,2.9mmol)和N-乙氧基-羰基-苯邻二甲酰亚胺(0.64g,2.9mmol)的30ml水和乙腈(1∶1)溶液中加入碳酸钠(0.33g,31mmol)。在室温下搅拌该混合物5小时。滴加1N HCl直到pH=2。用乙醚(2×25ml)萃取混合物。有机层用水(2×20ml)、盐水(20ml)洗涤,并经硫酸镁干燥。真空除去溶剂,得到无色油状的3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-丙酸(1.1g,91%)。
1HNMR(CDCl3):δ0.32-0.38(m,2H),0.60-0.67(m,2H),1.17-1.28(m,1H),3.33(dd,J=6,17Hz,1H),3.79(dd,J=10,17Hz,1H),3.86(d,J=8Hz,2H),4.92(宽峰,1H),5.74(dd,J=6,10Hz,1H),6.58(t,JH-F=75Hz,1H),7.10(s,2H),7.16(s,1H),7.69-7.74(m,2H),7.78-7.83(m,2H).
5.8实施例8:3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-N-羟基-丙酰胺
在室温下,向3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-丙酸(1.1g,2.6mmol)的四氢呋喃溶液中加入羰基二咪唑(0.73g,4.5rnmol)。在室温下搅拌该溶液2小时。向混合物中加入氢氧化铵盐酸盐(0.4g,2.3rnmol)。所得混合物在室温下搅拌4小时。向反应混合物中加入水(20ml)。真空除去THF。将所得混合物用乙酸乙酯(30ml)萃取。用饱和碳酸氢钠溶液(3×20ml)、水(20ml)、盐水(20ml)洗涤该混合物。有机层经硫酸镁干燥,过滤、和真空浓缩。所得油状物经硅胶色谱纯化(乙酸乙酯∶己烷=2∶1),得到白色固体的3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-N-羟基-丙酰胺(700mg,61%):熔点:129-131℃;
1HNMR(DMSO-d6):δ0.33-0.35(m,2H),0.54-0.57(m,2H),1.15-1.30(m,1H),3.11(d,J=5Hz,2H),3.87(d,J=7.5Hz,2H),5.71(t,J=7.5Hz,1H),6.95-6.98(m,1H),7.03(t,JH-F=75Hz,1H),7.11-7.17(m,2H),7.85(s,4H),8.80(s,1H),10.60(s,1H).13C NMR(CDCl3):δ0.7,3.9,3.9,10.8,35.7,52.0,74.6,112.6,114.9,116.7,120.8,120.9,123.6,124.2,132.3,135.00,137.7,140.9,151.3,169.0;
C22H20F2N2O6的分析计算值:C,59.19;H,4.52;N,6.28;测定值:C,58.98;H,4.41;N,6.16。
5.9实施例9:3-氨基-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸甲酯盐酸盐
在氮气氛,0℃下,向搅拌的3-氨基-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸(500mg,1.7mmol)的甲醇(10ml)悬浮液中滴加乙酰氯。加完后,在0℃搅拌该混合物15分钟并除去冰浴。在室温下搅拌混合物过夜。真空除去溶剂。所得固体在乙醚(30ml)中搅拌2小时。过滤悬浮液,得到白色固体的3-氨基-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸甲酯盐酸盐(540mg,90%)。
1HNMR(DMSO-d6):δ0.30-0.36(m,2H),0.54-0.61(m,2H),1.22-1.32(m,1H),3.01-3.10(m,1H),3.56(s,3H),3.89(d,J=7.5Hz,2H),4.53-4.63(m,1H),7.04(d,J=7.5Hz,1H),7.09(t,JH-F=75Hz,1H),7.19(d,J=7.5Hz,1H),7.39(s,1H),8.55(宽峰,3H).
5.10实施例10:3-氨基-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸甲酯
向3-氨基-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸甲酯盐酸盐(540mg1.5mmol)的二氯甲烷(20ml)溶液中加入水(20ml)和碳酸钠(160mg,1.5mmol)。在室温下搅拌混合物30分钟,然后分液漏斗分离。有机层用水(20ml)、盐水(20ml)洗涤,并经硫酸镁干燥。真空除去溶剂。所得油状物不用进一步纯化用于下一步中。
5.11实施例11:3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸甲酯
向3-氨基-3-(3-环丙基甲氧基-4-氟甲氧基-苯基)-丙酸甲酯(490mg,1.5mmol)和三乙胺(0.43ml,3.1minol)的DMF(10ml)溶液中加入2-溴甲基-6-硝基苯甲酸乙酯(460mg,1.6mmol)。在氮气氛下,于90℃加热该混合物过夜。真空除去溶剂。所得油状物用乙酸乙酯(50ml)和1N HCl(50ml)萃取。有机层用水(30ml)、盐水(30ml)洗涤,并经硫酸镁干燥。真空除去溶剂。所得油状物经硅胶色谱纯化(己烷∶乙酸乙酯=2∶1),得到浅黄色的3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸甲酯。
1HNMR(CDCl3):δ0.31-0.37(m,2H),0.59-0.67(m,2H),1.22-1.28(m,1H),3.09(dd,J=7,15Hz,1H),3.28(dd,J=9,15Hz,1H),3.65(s,3H),3.79-3.91(m,2H),4.18(d,J=17Hz,1H),4.46(d,J=17Hz,1H),5.83(dd,J=7,9Hz,1H),6.61(t,JH-F=75Hz,1H),7.04-7.05(m,3H),7.58-7.76(m,3H).
5.12实施例12:3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸
在0℃下,向3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸甲酯(550mg,1.2mmol)的甲醇(5ml)悬浮液中滴加1N NaOH(0.23ml,2.3mmol)。在0℃下,搅拌该混合物1小时。然后让其升温至室温并搅拌2小时。加入4N HCl直至pH=5。用二氯甲烷(30ml)和1N HCl(30ml)萃取混合物。有机层用水(2×30ml)、盐水(30ml)洗涤,并经硫酸镁干燥。真空除去溶剂,得到黄色固体的3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸(480mg,90%)。
1HNMR(CDCl3):δ0.31-0.37(m,2H),0.59-0.67(m,2H),1.22-1.28(m,1H),3.11(dd,J=6.5,15Hz,1H),3.33(dd,J=9,15Hz,1H),3.78-3.87(m,2H),4.18(d,J=17.5Hz,1H),4.46(d,J=17.5Hz,1H),5.83(dd,J=6.5,9Hz,1H),6.61(t,JH-F=75Hz,1H),6.91-7.17(m,3H),7.59-7.76(m,3H).
5.13实施例13:3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-N,N-二甲基-丙酰胺
在室温下,向3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸(480mg,1.0mmol)的四氢呋喃(5ml)溶液中加入羰基二咪唑(250mg,1.6mmol)。在室温下搅拌溶液2小时。向混合物中加入二甲胺(2.0M的THF溶液,1.0ml,2.0mmol)。在室温下搅拌所得混合物3小时。向反应混合物中加入水(20ml)。真空除去THF,将所得混合物用乙酸乙酯(30ml)萃取。混合物用饱和碳酸氢钠溶液(3×20ml)、水(20ml)、盐水(20ml)洗涤。有机层经硫酸镁干燥,过滤和真空浓缩。所得油状物在乙醚中搅拌过夜。过滤悬浮液,得到黄色固体的3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-N,N-二甲基-丙酰胺(330mg,65%)。
1HNMR(CDCl3):δ0.32-0.38(m,2H),0.60-0.67(m,2H),1.15-1.35(m,1H),2.89(s,3H),3.00(dd,J=5,15Hz,1H),3.10(s,3H),3.79(dd,J=10,15Hz,1H),3.85-3.89(m,2H),4.44(d,J=17.5Hz,1H),4.57(d,J=17.5Hz,1H),5.47(dd,J=5,10Hz,1H),6.61(t,JH-F=75Hz,1H),6.98-7.02(m,1H),7.12-7.20(m,2H),7.56-7.72(m,3H).
5.14实施例14:3-(7-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-N,N-二甲基-丙酰胺
向3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-N,N-二甲基-丙酰胺(330mg,0.67rnmol)的乙酸乙酯(100ml)溶液中加入10%钯碳(100mg)。在室温下,于约50psi氢气氛下,将该悬浮液振荡过夜。将悬浮液滤过硅藻土垫。除去溶剂,所得油状物经HPLC纯化(CH3CN∶水=40∶60),得到白色固体的3-(7-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-N,N-二甲基-丙酰胺(300mg,65%):熔点:70-72℃;
1HNMR(CDCl3):δ0.31-0.37(m,2H),0.58-0.65(m,2H),1.21-1.28(m,1H),2.90(s,3H),3.05(dd,J=6.3,15.8Hz,1H),3.09(s,3H),3.52(dd,J=8.5,15.3Hz,1H),3.85(d,J=7Hz,2H),4.20(d,J=16.8Hz,1H),4.35(d,J=16.8Hz,1H),5.20(宽峰,2H),5.56(dd,J=6.3,8.5Hz,1H),6.52-6.63(m,2H),6.59(t,JH-F=75Hz,1H),6.90-6.98(m,1H),7.09-7.26(m,3H);13C NMR(CDCl3):δ10.8,36.2,37.0,38.1,49.8,54.3,114.0,114.9,116.3,116.9,120.1,121.0,123.3,133.4,139.4,140.5,143.4,146.6,151.3,170.4,170.9;
C24H27F2N304+0.18H2O的分析计算值:C,62.30;H,5.96;N,9.08;H2O 0.7;测定值:C,62.30;H,5.89;N,9.02;H2O,0.7。
5.15实施例15:4-二氟甲氧基-3-乙氧基-苯甲醛
向3-乙氧基-4-羟基苯甲醛(100g,0.61mol)的二氧杂环己烷(1000ml)溶液中加入相转移催化剂苄基三甲基氯化铵(3.4g,0.018mol),然后加入NaOH水溶液(72g,溶于72ml水中,1.8mol)。加入NaOH之后溶液变浑。在剧烈搅拌下,向该悬浮液中通入气体二氟氯甲烷(100g,钢筒中)。在通入气体期间密封该体系,小心控制气体的放出。所得悬浮液在室温下搅拌过夜。将该悬浮液倒入1000ml碎冰中并用EtOAc(300ml×4)萃取。合并有机层,MgSO4干燥,过滤并浓缩。所得棕色油状物经硅胶色谱纯化(100%甲苯洗脱),得到40g无色油状产物(31%)。
5.16实施例16:3-氨基-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸
将4-二氟甲氧基-3-乙氧基-苯甲醛(10g,0.046mol)加入95%乙醇(100ml)中,然后加入NH4OAc(7.1g,0.092mol)。将混合物加热到40℃1小时,然后加入丙二酸(4.8g,0.046mol)。在76℃下搅拌混合物过夜。得到黄色悬浮液。过滤并用乙醇(10ml)漂洗固体,得到白色固体的3-氨基-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(9.7g,77%)。
1HNMR(DMSO-d6):δ1.41(t,J=7.5Hz,3H),3.32(d,J=7Hz,1H),2.67(s,1H),4.09(q,J=7.5Hz,2H),4.20-4.24(m,1H),6.97(d,J=8.0Hz,1H),7.03(t,JH-F=75Hz,1H),7.13(d,J=8.0Hz,1H),7.23(s,1H).
5.17实施例17:3-氨基-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯
将3-氨基3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(7.6g,28mmol)悬浮于甲醇(50ml)中。在室温下,向混合物中滴加乙酰氯(4.9ml,69mmol)。加完后,混合物变成澄清的溶液并在室温下搅拌5小时。HPLC显示所有的起始物质均消失。真空除去溶剂,所得固体在乙醚(10ml)中搅拌1小时。过滤悬浮液,得到9g固体。然后将固体悬浮于二氯甲烷(100ml)中。向其中加入Na2CO3水溶液(3.3g溶于50ml水中)。搅拌该混合物30分钟并分离。有机层用水(50ml×2),盐水(50ml)洗涤,Na2SO4干燥并浓缩得到3-氨基-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯(7.3g,92%)。
1HNMR(CDCl3):δ1.41(t,J=7.5Hz,3H),2.62-2.64(m,1H),3.69(s,3H),4.10(q,J=7.5Hz,2H),4.37-4.32(m,1H),6.55(t,JH-F=75Hz,1H),6.89(dd,J=1.8,8Hz,1H),7.01(d,J=1.8Hz,1H),7.11(d,J=8Hz,1H).
5.18实施例18:3-(4-二氟甲氧基-3-乙氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸甲酯
按照实施例11的方法,由3-氨基-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯(7.3g,0.025mol)、2-溴甲基-6-硝基-苯甲酸乙酯(7.6g,0.028mol)和三乙胺(7ml,0.05mol)在DMF(50ml)中制备3-(4-二氟甲氧基-3-乙氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸甲酯,得到黄色油状的3-(4-二氟甲氧基-3-乙氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸甲酯。
1HNMR(CDCl3):δ1.42(t,J=7.5Hz,3H,OCH2CH3),3.09(dd,J=6.8,15Hz,2H,CH2CO),3.29(dd,J=6.8,15Hz,1H,CH2CO),3.65(s,3H,OCH3),4.10(q,J=7.5Hz,2H,OCH2CH3),4.26(d,J=17Hz,2H,CH2N),4.46(d,J=17Hz,2H,CH2N),5.80-5.86(m,1H,CHN),6.55(t,JH-F=75Hz,1H,OCF2H),6.92(dd,J=1.8,8.2Hz,1H,Ar),7.06(d,J=1.8Hz,1H,Ar),7.14(d,J=8.25,1H,Ar),7.58-7.76(m,3H,Ar).
5.19实施例19:3-(7-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯
按照实施例14的方法,在氢气压(50psi)下,由3-(4-二氟甲氧基-3-乙氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸甲酯(9.1g,0.02mol)和钯碳制备3-(7-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯。该产物不用进一步纯化就用于下一步中。
5.20实施例20:3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯
向3-(7-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4--氟甲氧基-3-乙氧基-苯基)-丙酸甲酯(2.8g,7mmol)的THF溶液中滴加环丙烷基羰基氯(0.72ml,8mmol)。然后将反应混合物加热回流1小时。真空除去溶剂。将混合物溶于EtOAc(50ml)并用水(50ml×2)洗涤。有机层经Na2SO4干燥并真空浓缩。所得固体在乙醚(20ml)中搅拌1小时并过滤得到总共2.5g(77%产率)的白色固体,不用进一步纯化用于下一步中。
5.21实施例21:3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯
按照实施例20的方法,由3-(7-氨基-1-氧代-1,3--二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯(2.8g,7mmol)和乙酰氯(0.57ml,8mmol)在THF(20ml)中制备3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯,得到白色固体的上述标题化合物(2.5g,81%)。该产物不用进一步纯化用于下一步中。
5.22实施例22:3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸
向3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯(2.5g,5.4mmol)的THF溶液中滴加10N NaOH(1ml,10mmol)并在室温下搅拌过夜。过滤所得悬浮液,将固体溶于水(20ml)中。将水溶液酸化至pH=4,得到乳状悬浮液。用EtOAc(50ml×3)萃取悬浮液。有机层用水(50ml×2)、盐水(30ml)洗涤,Na2SO4干燥并浓缩得到白色固体(2.3g,96%产率):熔点:105-107℃;
1HNMR(CDCl3):δ1.42(J=7.5Hz,3H,OCH2CH3),2.22(s,3H),3.11(dd,J=5,12Hz,1H,CH2),3.25(dd,J=10,15Hz,1H,CH2),4.08(q,J=7.5Hz,2H,OCH2CH3),4.12(d,J=17.5Hz,1H,CH2N),4.38(d,J=17.5Hz,1H,CH2N),5.81(m,1H,CHN),6.55(t,JH-F=75Hz,1H,CF2H),6.96(m,3H,Ar),7.13(d,J=7.5Hz,1H,Ar),7.45(m,1H,Ar),8.43(d,J=7.5Hz,1H,Ar),10.25(s,1H,NHCO)13CNMR(CDCl3):δ14.6,24.8,36.7,46.8,51.7,64.9,111.8,111.3,115.9,117.1,117.3,118.0,118.9,120.1,122.8,133.5,136.7,137.8,140.1,141.2,150.9,169.47,169.49,173.5;
C22H22F2N2O6+0.22H2O的分析计算值:C 58.41,H 5.00,N 6.19;测定值:C 58.06,H 4.92,N 5.90。
5.23实施例23:3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸
3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸的制法如下:按照实施例22的方法,由3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯(2.47g,5mmol)和NaOH(10N,1ml,10mmol)在THF(50ml)中制备,得到白色固体的3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(2.5g),不用进一步纯化用于下一步中。
5.24实施例24:环丙烷羧酸{2-[2-氨基甲酰基-1-(4-二氟甲氧基-3-乙氧基-苯基)-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺
环丙烷羧酸{2-[2-氨基甲酰基-1-(4-二氟甲氧基-3-乙氧基-苯基)-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺的制法如下:按照实施例6的方法,由3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(0.8g,1.7mmol)、CDI(0.41g,2.5mmol)和NH4OH(0.25ml,3.4mmol)在THF(30ml)中制备,得到白色固体的环丙烷羧酸{2-[2-氨基甲酰基-1-(4-二氟甲氧基-3-乙氧基-苯基)-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺(0.56g,70%):熔点:179-181℃;
1MR(CDCl3):δ0.92(m,2H,c-CH2),1.44(t,J=6.8Hz,3H,OCH2CH3),1.68(m,1H,c-CH),2.99(dd,J=5,15Hz,1H,CH2),3.44(dd,J=10,15Hz,1H,CH2),4.08(q,J=7.0Hz,2H,OCH2CH3),4.20(d,J=17.5Hz,1H,CH2N),4.40(d,J=17.5Hz,1H,CH2N),5.42(宽峰,1H,NH2),5.58(m,1H,CHN),6.07(宽峰,1H),6.56(t,JH-F=75Hz,1H,CF2H),6.98(m,3H,Ar),7.15(d,J=7.5Hz,1H,Ar),7.46(t,J=7.5Hz,1H,Ar),8.45(d,J=8Hz,1H,Ar),10.49(s,1H,NHCO).13CNMR(CDCl3):δ8.31,.14.6,16.2,38.9,48.6,53.9,64.8,101.57,102.3,113.2,116.7,117.3,117.8,119.2,122.9,113.5,137.3,138.1,141.4,141.2,150.9,170.9,171.4,172.7;
C24H25F2N3O5的分析计算值:C 60.88,H 5.32,N 8.87;测定值:C 60.82,H 5.11,N 8.80。
5.25实施例25:环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-二甲基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基]-酰胺
环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-二甲基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺的制法如下:按照实施例13的方法,由3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(0.8g,1.7mmol)、CDI(0.41g,2.5mmol)和二甲胺(1.7ml,3.4mmol)在THF(30ml)中制备,得到白色固体的环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-二甲基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺(0.4g,50%产率);熔点:135-137℃;
1HNMR(CDCl3):δ0.89(m,2H,c-CH2),1.43(t,J=7.0Hz,3H,OCH2CH3),1.66(m,1H,c-CH),2.93(s,3H,CH3CO),3.04(dd,J=5,15Hz,1H,CH2),3.10(s,3H,NCH3),3.60(dd,J=10,15Hz,1H,CH2),4.09(q,J=7.0Hz,2H,OCH2CH3),4.33(d,J=17.5Hz,1H,CH2N),4.44(d,J=17.5Hz,1H,CH2N),5.60(m,1H,CHN),6.55(t,JH-F=75Hz,1H,CF2H),7.07(m,4H,Ar),7.43(t,J=7.5Hz,1H,Ar),8.42(d,J=7.5Hz,1H,Ar),10.57(s,1H,NHCO).13CNMR(CDCl3):δ8.2,14.6,16.1,35.6,36.1,37.3,49.2,54.0,58.6,64.7,111.9,113.5,116.1,116.7,117.5,117.6,117.8,119.2,120.2,122.7,133.1,138.0,138.2,139.7,141.5,159.7,169.4,169.7,172.6;
C26H29F2N3O5的分析计算值:C 62.27,H 5.83,N 8.38;测定值:C 62.07,H 5.65,N 8.28.
5.26实施例26:环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-羟氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺
环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-羟氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺的制法如下:按照实施例8的方法,由3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(0.8g,1.7mmol)、CDI(0.41g,2.5mmol)和盐酸羟胺(0.23g,3.6mmol)在THF(30ml)中制备,得到白色固体的环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-羟氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺(0.60g,80%产率):熔点:116-118℃;
1HNMR(CDCl3):δ0.82(m,2H,c-CH2),1.02(m,2H,c-CH2),1.36(t,J=6.8Hz,3H,OCH2CH3),1.58(m,1H,c-CH),2.86(dd,J=5,15Hz,1H,CH2),3.15(dd,J=10,15Hz,1H,CH2),3.30(宽峰,1H,NHOH),4.01(q,J=7.0Hz,2H,OCH2CH3),4.02(d,J=17.5Hz,1H,CH2N),4.34(d,J=17.5Hz,1H,CH2N),5.42(宽峰,1H,NH2),5.71(m,1H,CHN),6.07(宽峰,1H,NHOH),6.53(t,JH-F=75Hz,1H,CF2H),6.88(m,3H,Ar),7.07(d,J=7.5Hz,1H,Ar),7.30(t,J=7.5Hz,1H,Ar),8.28(d,J=8Hz,1H,Ar),10.35(s,1H,NHCO).13CNMR(CDCl3):δ8.27,8.39,14.5,16.0,35.4,47.3,52.4,64.8,111.8,113.3,115.9,116.9,117.0,118.9,120.0,122.6,133.3,136.6,137.6,140.0,141.5,150.8,167.5,169.7,172.8;
C24H25F2N3O6+0.34H2O的分析计算值:C 58.16,H 5.22,N 8.48;测定值:C 58.25,H 5.37,N 8.58,1.25H2O
5.27实施例27:3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酰胺
3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酰胺的制法如下:按照实施例6的方法,由3-[7-(乙酰氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(0.6g,1.3mmol)、CDI(0.3g,2mmol)和NH4OH(0.20ml,2.6mmol)在THF(30ml)中制备,得到白色固体的3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酰胺(0.43g,72%):熔点:129-131℃;
1HNMR(CDCl3):δ1.44(t,J=7.0Hz,3H,OCH2CH3),2.25(s,3H,CH3CO),2.97(dd,J=5,15Hz,1H,CH2),3.42(dd,J=10,15Hz,1H,CH2),4.08(q,J=7.0Hz,2H,OCH2CH3),4.20(d,J=17.5Hz,1H,CH2N),4.40(d,J=17.5Hz,1H,CH2N),5.40(宽峰,1H,NH2),5.56(m,1H,CHN),6.01(宽峰,1H),6.56(t,JH-F=75Hz,1H,CF2H),6.95(m,3H,Ar),7.15(d,J=7.5Hz,1H,Ar),7.47(t,J=7.5Hz,1H,Ar),8.47(d,J=7.5Hz,1H,Ar),10.25(s,1H,NHCO).13CNMR(DMSO-d6):δ3.2,14.4,16.2,24.4,37.7,46.7,51.7,64.2,93.9,113.0,116.6,117.2,117.5,119.2,121.3,132.8,137.0,138.2,139.0,142.2,149.8,168.0,168.5,171.0;
C22H23F2N3O5的分析计算值:C 59.06,H 5.18,N 9.39;测定值:C 58.48,H 5.12,N 9.65。
5.28实施例28:3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N,N-二甲基-丙酰胺
3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N,N-二甲基-丙酰胺的制法如下:按照实施例13的方法,由3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(0.1g,0.22mmol)、CDI(0.05g,0.33mmol)和二甲胺(0.33ml,0.66mmol)在THF(10ml)中制备,得到白色固体的3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N,N-二甲基-丙酰胺(0.05g,50%产率):熔点:141-143℃;
1HNMR(CDCl3):δ1.44(t,J=7.0Hz,3H,OCH2CH3),2.25(s,3H,CH3CO),2.93(s,3H,NCH3),3.04(dd,J=5,15Hz,1H,CH2),3.10(s,3H,NCH3),3.60(dd,J=10,15Hz,1H,CH2),4.09(q,J=7.0Hz,2H,OCH2CH3),4.33(d,J=18Hz,1H,CH2N),4.44(d,J=18Hz,1H,CH2N),5.59(m,1H,CHN),6.55(t,JH-F=75Hz,1H,CF2H),7.04(m,4H,Ar),7.45(t,J=7.5Hz,1H,Ar),8.45(d,J=7.5Hz,1H,Ar),10.35(s,1H,NHCO).13CNMR(DMSO-d6):δ14.5,24.8,35.5,35.9,37.2,49.0,53.8,64.7,111.9,113.4,113.5,116.0,116.8,117.5,117.8,119.1,119.1,120.1,122.6,133.0,137.7,138.2,139.7,138.2,139.6,139.7,141.5,150.6,168.9,169.2,169.5;
C24H27F2N3O5的分析计算值:C 60.62,H 5.72,N 8.84;测定值:C 59.90,H 5.46,N 8.66。
5.29实施例29:3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N-羟基-丙酰胺
3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N-羟基-丙酰胺的制法如下:按照实施例8的方法,由3-[7-(乙酰氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(0.6g,1.3mmol)、CDI(0.32g,2.0mmol)和盐酸羟胺(0.19g,2.6mmol)在THF(30ml)中制备,得到白色固体的3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N-羟基-丙酰胺(0.22g,40%产率):熔点:121-123℃;
1HNMR(DMSO-d6):δ1.34(t,J=7.5Hz,3H,OCH2CH3),2.16(s,3H,CH3),2.89(d,J=7.5Hz,2H,CH2),4.10(q,J=7.0Hz,2H,OCH2CH3),4.24(d,J=17.5Hz,1H,CH2N),4.59(d,J=17.5Hz,1H,CH2N),5.69(m,1H,CHN),6.93(m,1H,Ar),7.03(t,JH-F=75Hz,1H,CF2H),7.15(m,3H,Ar),7.52(t,J=7.5Hz,1H,Ar),8.26(d,J=8Hz,1H,Ar),8.85(s,1H,NHOH),10.26(s,1H,NHOH),10.35(s,1H,NHCO).13CNMR(DMSO-d6):δ14.4,24.4,34.5,51.5,64.2,93.9,113.0,116.6,117.3,117.5,120.7,121.3,122.5,132.8,134.0,137.0,137.8,142.2,149.8,165.7,168.0,168.5;
C22H23F2N3O6+0.13H2O的分析计算值:C 56.73,H 5.03,N 9.02;测定值:C 56.35,H 4.89,N 8.75,H2O 0.34。
5.30实施例30:3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸的制法如下:按照实施例4的方法,由3-氨基-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(2.7g,13mmol)、3-乙酰氨基-邻苯二甲酸酐(4.0g,14.5mmol)和乙酸钠(1.2g,14.5mmol)在乙酸(50ml)中制备,得到浅黄色固体的3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸。熔点:89-91℃;
1HNMR(CDCl3):δ1.42(t,J=7.5Hz,3H,OCH2CH3),2.51(s,3H,CH3CO),3.19(dd,J=5.8,15.5Hz,1H,CH2),3.79(dd,J=8.4,15.5Hz,1H,CH2),4.08(q,J=7.5Hz,2H,OCH2CH3),5.65-5.71(m,1H,CHN),6.52(t,JH-F=75Hz,1H,CF2H),7.03-7.11(m,3H,Ar),7.45(d,J=7.5Hz,1H,Ar),7.63(t,J=7.5Hz,1H,Ar),8.72(d,J=8.3Hz,1H,Ar),9.46(s,1H,NHCO),13C NMR(CDCl3):δ14.6,24.8,35.6,50.3,64.7,98.4,99.1,111.8,113.5,115.2,115.9,118.2,120.1,120.2,122.7,125.0,131.0,136.0,136.5,137.4,138.1,140.0,140.1,140.2,150.6,167.4,169.5,169.7,175.1;
C22H20F2N2O7+0.17H2O的分析计算值:C 56.77,H 4.40,N 6.06,H2O0.66;测定值:C 56.60,H 4.43,N 6.02,H2O 0.66。
5.31实施例31:3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酰胺
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酰胺的制法如下:按照实施例6的方法,由3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(0.5g,1.1mmol)、CDI(0.19g,1.2mmol和NH4OH(0.1ml,1.2mmol)在THF(30ml)中制备,得到白色固体的3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酰胺(0.40g,80%):熔点:178-180℃;
1HNMR(CDCl3):δ1.44(t,J=7.0Hz,3H,OCH2CH3),2.26(s,3H,CH3CO),3.03(dd,J=5,15Hz,1H,CH2),3.70(dd,J=10,15Hz,1H,CH2),4.09(q,J=7.0Hz,2H,OCH2CH3),5.38(宽峰,1H,NH2),5.61(宽峰,1H,NH2),5.76-5.83(m,1H,CHN),6.83(t,JH-F=75Hz,1H,CF2H),7.06-7.14(m,3H,Ar),7.46(d,J=7.5Hz,1H,Ar),7.65(t,J=7.5Hz,1H,Ar),7.74(d,J=7.5Hz,1H,Ar),9.45(s,1H,NHCO)13CNMR(DMSO-d6):δ14.4,24.2,36.7,50.0,64.2,93.9,112.5,113.2,116.7,116.7,118.0,119.4,121.2,125.9,131.4,135.8,136.4,137.6,139.0,149.7,167.2,168.2,169.2,171.0;
C22H21F2N3O6的分析计算值:C,57.27;H,4.59;N,9.11。测定值:C,57.04;H,4.41;N,8.93。
5.32实施例32:3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N,N-二甲基-丙酰胺
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N,N-二甲基-丙酰胺的制法如下:按照实施例13的方法,由3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(0.5g,1.1mmol)、CDI(0.2g,0.1.3mmol)和二甲胺(2N的THF溶液,0.7ml,1.4mmol)在THF(10ml)中制备,得到3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N,N-二甲基-丙酰胺(0.35g,67%产率):熔点:163-165℃;
1HNMR(CDCl3):δ1.44(t,J=7.0Hz,3H,OCH2CH3),2.25(s,3H,CH3CO),2.90(s,3H,NCH3),2.98(dd,J=5,15Hz,1H,CH2),3.05(s,4H,NCH3+CH2),3.91(dd,J=10,15Hz,1H,CH2),4.09(q,J=7.0Hz,2H,OCH2CH3),5.81-5.87(m,1H,CHN),6.53(t,JH-F=75Hz,1H,CF2H),7.11-7.17(m,3H,Ar),7.45(d,J=7.0Hz,1H,Ar),7.62(t,J=8.0Hz,1H,Ar),8.73(d,J=8.8Hz,1H,Ar),9.53(s,1H,NHCO).13CNMR(DMSO-d6):δ14.5,24.8,34.8,35.5,37.1,51.3,64.7,111.9,113.8,115.4,116.1,117.9,120.1,120.2,122.7,124.7,131.3,135.8,137.5,138.1,150.6,168.1,169.2,169.3,170.0;
C24H25F2N3O6的分析计算值:C,58.89;H,5.15;N,8.58。测定值:C,58.53;H,4.78;N,8.51。
5.33实施例33:3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N-羟基-丙酰胺
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N-羟基-丙酰胺的制法如下:按照实施例8的方法,由3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(0.5g,1.1mmol)、CDI(0.2g,1.3mmol)和盐酸羟胺(0.1g,1.4mmol)在THF(30ml)中制备,得到白色固体的3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N-羟基-丙酰胺(0.25g,50%产率):熔点:148-150℃;
1HNMR(CDCl3):δ1.44(t,J=7.0Hz,3H,OCH2CH3),2.19(s,3H,CH3CO),3.19(dd,J=5,15Hz,1H,CH2),3.47(dd,J=10,15Hz,1H,CH2),4.02(q,J=7.0Hz,2H,OCH2CH3),5.75-5.82(m,1H,CHN),6.52(t,JH-F=75Hz,1H,CF2H),7.02-7.07(m,3H,Ar),7.36(d,J=7.5Hz,1H,Ar),7.54(t,J=7.5Hz,1H,Ar),8.64(d,J=8.8Hz,1H,Ar),9.40(s,1H,NHCO).13CNMR(CDCl3):δ14.5,24.8,34.6,51.1,64.7,111.8,113.5,115.1,115.9,120.1,122.6,124.9,131.0,136.0,136.7,137.4,140.0,150.5,167.1,167.7,169.3,169.6
C22H21F2N3O7+0.3H2O的分析计算值:C,54.73;H,4.51;N,8.70。测定值:C,54.36;H,4.25;N,8.54,0.1%H2O。
5.34实施例34:1-(4-二氟甲氧基-3-乙氧基-苯基)-2-甲烷磺酰基-乙胺
在0℃,向4-二氟甲氧基-3-乙氧基-苯甲醛(21.0g,0.1mol)的THF溶液(100ml)中滴加LiN(TMS)2(1M的THF溶液,100ml,0.1mol)。搅拌15分钟后,将BF3·THF复合物(22ml,0.2mol)加入反应混合物(1)中。在-78℃,向甲基砜(9.4g,0.lmol)的THF溶液(100ml)中加入LiN(TMS)2(1M的THF溶液,100ml,0.1mol)。在-78℃,搅拌该混合物(2)1小时。通过2-通针将混合物(1)加入混合物(2)中。所得混合物升至室温,并在室温下搅拌18小时。加入MeOH(20ml)使反应淬火。真空浓缩混合物直至余下1/4。向所得混合物中加入HCl溶液(20%,150ml),然后加入浓盐酸直至pH=3。用乙醚萃取混合物(100ml×3)。水层用NaOH(15M)中和直到pH=8。混合物用二氯甲烷(100ml×3)萃取。合并有机层,用水(100ml×2)、盐水(100ml)洗涤,Na2SO4干燥并真空浓缩。所得油状物经硅胶柱纯化,得到黄色油状的1-(4-二氟甲氧基-3-乙氧基-苯基)-2-甲烷磺酰基-乙胺(2.8g,10%)。
1HNMR(CDCl3)δ1.41(t,J=6.8Hz,3H,OCH2CH3),3.30-3.40(m,2H,CH2SO2),3.45(s,3H,CH3),4.58-4.64(m,1H,CHN),6.53(t,J=75Hz,1H,CF2H),6.84-7.12(m,3H,Ar).
5.35实施例35:环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-甲烷磺酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺
向1-(4-二氟甲氧基-3-乙氧基-苯基)-2-甲烷磺酰基-乙胺(0.80g,2.7mmol)的DMF溶液(20ml)中加入Et3N(1.6ml,12mmol),然后加入2-溴甲基-6-(环丙烷羰基-氨基)-苯甲酸甲酯(1.0g,3.2mmol)。在90℃加热混合物12小时,然后冷却到室温。混合物用EtOAc(50ml)和水(50ml)萃取。有机层用水(50ml)和盐水(50ml)洗涤,Na2SO4干燥并真空浓缩。所得油状物经硅胶色谱纯化,得到白色固体的环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-甲烷磺酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺(0.35g,30%):熔点:115-117℃;
1HNMR(CDCl3)δ0.83-0.92(m,2H,c-CH2),1.09-1.13(m,2H,c-CH2),1.45(t,J=7.0Hz,3H,CH3),1.66-1.70(m,1H,c-CH),2.98(s,3H,SO2CH3),3.64(dd,J=3.8,14Hz,1H,CH2),4.10(q,J=6.8Hz,2H,OCH2),4.33(dd,J=10,14Hz,1H,CH2),4.37(dd,J=5,50Hz,2H,CH2N),5.69-5.74(m,1H,NCH),6.57(t,JH-F=75Hz,1H,CF2H),6.94-7.04(m,3H,Ar),7.18(d,J=7.5Hz,1H,Ar),7.47(t,J=7.5Hz,1H,Ar),8.45(d,J=8.5Hz,1H,Ar),10.42(s,1H,NH);13C NMR(CDCl3)δ9.06,15.3,16.9,42.4,49.0,52.5,56.3,65.6,112.4,113.9,116.6,117.5,117.6,118.7,119.9,120.7,123.8,134.5,136.5,138.9,141.1,141.9,151,9,170.9,173.4;
C24H26F2N2O6S的分析计算值:C,56.68;H,5.15;N,5.51。测定值:C,56.72;H,5.15;N,5.38。
5.36实施例36:N-{2-[1-(4-二氟甲氧基-3-乙氧基-苯基-2-甲烷磺酰基-乙基]-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基}-乙酰胺
N-{2-[1-(4-二氟甲氧基-3-乙氧基-苯基-2-甲烷磺酰基-乙基]-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基}-乙酰胺的制法如下:按照实施例4的方法,由1-(4-二氟甲氧基-3-乙氧基-苯基)-2-甲烷磺酰基-乙胺(0.6g,0.2mmol)、3-乙酰氨基-邻苯二甲酸酐(0.4g,0.2mmol)和乙酸钠(0.16g,0.2mmol)在乙酸(15ml)中制备,得到白色固体的N-{2-[1-(4-二氟甲氧基-3-乙氧基-苯基-2-甲烷磺酰基-乙基]-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基}-乙酰胺(0.4g,40%):熔点:118-120℃;
1HNMR(CDCl3)δ1.45(t,J=7.0Hz,3H,CH3),2.27(s,3H,CH3CO),2.92(s,3H,SO2CH3),3.66(dd,J=3.8,14Hz,1H,CH2),4.11(q,J=6.8Hz,2H,OCH2),5.88-5.94(m,1H,NCH),6.55(t,JH-F=75Hz,1H,CF2H),7.12-7.16(m,3H,Ar),7.49(d,J=7.5Hz,1H,Ar),7.66(t,J=7.5Hz,1H,Ar),8.77(d,J=8.5Hz,1H,Ar),9.44(s,1H,NH);13CNMR(CDCl3)δ14.5,24.9,41.7,48.3,54.1,64.9,11.5,113.6,115.0,115.8,118.3,120.0,120.2,123.1,125.1,130.9,135.4,136.2,137.7,140.4,150.9,167.4,169.1,169.4;
C22H22F2N2O7S的分析计算值:C,53.22;H,4.47;N,5.64。测定值:C,53.18;H,4.20;N,5.64。
5.37实施例37环丙烷羧酸{2-[2-氨基甲酰基-1-(4-二氟甲氧基-3-乙氧基-苯基)-2-甲烷磺酰基-乙基]-7-氯-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺
环丙烷羧酸{2-[2-氨基甲酰基-1-(4-二氟甲氧基-3-乙氧基-苯基)-2-甲烷磺酰基-乙基]-7-氯-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺的制法如下:按照实施例6的方法,由3-[4-氯-7-(环丙烷羰基-氨基)-1-氧代-l,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(0.55g,1.1mmol)、CDI(0.26g,1.6mmol)和NH4OH(0.35ml,3.3mmol)在THF中制备,得到白色固体的环丙烷羧酸{2-[2-氨基甲酰基-1-(4-二氟甲氧基-3-乙氧基-苯基)-2-甲烷磺酰基-乙基]-7-氯-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺(0.10g,20%):熔点:198-200℃;
1HNMR(CDCl3):δ0.89-0.93(m,2H,c-CH2),1.10-1.20(m,2H,c-CH2),1.44(t,J=7.5Hz,3H,OCH2CH3),1.66-1.68(m,1H,c-CH),2.98(dd,J=5,15Hz,1H,CH2),3.43(dd,J=10,15Hz,1H,CH2),4.09(q,J=7.5Hz,2H,OCH2CH3),4.18(d,J=17.5Hz,1H,CHHN),4.37(d,J=17.5Hz,1H,CHHN),5.48(br,1H,NHH),5.57-5.53(m,1H,CHN),5.92(br,1H,NHH),6.86(t,JH-F=75Hz,1H,CF2H),6.94-7.02(m,3H,Ar),7.16(d,J=10Hz,1H,Ar),7.38(t,J=8Hz,1H,Ar),8.45(d,J=8Hz,1H,Ar),10.40(s,1H,NHCO).13CNMR(CDCl3):δ8.5,14.6,16.2,38.6,47.9,54.1,64.9,101.57,102.3,113.2,116.0,119.2,119.8,121.8,123.0,133.2,136.8,137.1,139.1,150.9,169.4,171.1,172.6;
C24H26ClF2N3O5的分析计算值:C,56.75;H,4.76;N,8.27。测定值:C,56.68;H,4.63;N,8.04。
5.38实施例38:N-{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-3-吗啉-4-基-3-氧代-丙基]-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基}-乙酰胺
在室温下,向3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(400mg,0.86mmol)的四氢呋喃溶液中加入羰基二咪唑(160mg,1mmol)。在室温下搅拌该溶液2小时。向混合物中加入吗啉(0.12ml,1.3mmol)。在室温下搅拌所得混合物2小时。将水(5ml)加入反应混合物中。真空除去THF,并用乙酸乙酯(20ml)萃取所得混合物。有机层用饱和碳酸氢钠溶液(3×10ml)、水(10ml)、盐水(10ml)洗涤,并经硫酸镁干燥。真空除去溶剂。所得油状物经HPLC纯化(乙腈∶水=45∶55),得到白色固体的N-{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-3-吗啉-4-基-3-氧代-丙基]-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基}-乙酰胺(200mg,44%):熔点:109-111℃;
1HNMR(CDCl3):1.44(t,J=7.5Hz,3H,OCH2CH3),2.26(s,3H,CH3CO),3.02(dd,J=5,17.5Hz,1H,CHHCO),3.49-3.68(m,8H,吗啉环),3.9(dd,J=7.5,17.5Hz,1H,CHHCO),4.09(q,J=7.5Hz,2H,OCH2CH3),5.84(dd,J=5,10Hz,1H,CHN),6.54(t,JH-F=75Hz,1H,OCF2H),7.11-7.16(m,3H,Ar),7.45(d,J=7.5Hz,1H,Ar),7.63(t,J=7.5Hz,1H,Ar),8.75(d,J=7.5Hz,1H,Ar),9.50(s,1H,NHCO).13C NMR(CDCl3):15.3,25.6,35.1,42.7,46.6,51.9,65.5,67.2,67.5,112.6,114.4,115.9,116.7,118.6,120.8,120.9,123.5,125.5,131.9,136.6,138.2,138.5,140.6,151.3,168.6,168.7,169.9,170.6;
C26H27F2N3O7的分析计算值:C,58.75;H,5.12;N,7.91;测定值:C,58.48;H,5.09;N,7.79。
5.39实施例39:N-{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-3-吗啉-4-基-3-氧代-丙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-乙酰胺
在室温下,向3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸(300mg,0.67mmol)的四氢呋喃溶液中加入羰基二咪唑(130mg,0.80mmol)。在室温下搅拌该溶液2小时。向混合物中加入吗啉(0.1ml,1.0mmol)。在室温下搅拌所得混合物2小时。将水(5ml)加入反应混合物中。真空除去THF,并用乙酸乙酯(20ml)萃取所得混合物。有机层用饱和碳酸氢钠溶液(3×10ml)、水(10ml)、盐水(10ml)洗涤,并经硫酸镁干燥。真空除去溶剂。所得油状物经HPLC纯化(乙腈∶水=45∶55),得到白色固体的N-{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-3-吗啉-4-基-3-氧代-丙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-乙酰胺(250mg,72%):熔点:164-166℃;
1HNMR(CDCl3):1.43(t,J=7.5Hz,3H,OCH2CH3),2.25(s,3H,CH3CO),3.04(dd,J=6,10Hz,1H,CHHCO),3.54-3.72(m,9H,吗啉环+CHHCO),4.08(q,J=7.5Hz,2H,OCH2CH3),4.27(d,J=17Hz,1H,CHHN),4.44(d,J=17Hz,1H,CHHN),5.54-5.59(m,1H,CHN),6.85(t,JH-F=75Hz,1H,OCF2H),6.94-7.16(m,3H,Ar),7.14(d,J=8Hz,1H,Ar),7.46(t,J=7.5Hz,1H,Ar),8.45(d,J=7.5Hz,1H,Ar),10.60(s,1H,NHCO)13CNMR(CDCl3):15.3,25.6,36.5,42.8,46.9,49.8,54.7,65.5,67.2,67.4,112.6,114.1,116.7,117.6,118.3,118.4,119.9,120.8,123.5,133.9,138.5,140.5,142.2,151.5,166.7,169.7,170.4;
C26H29F2N3O6的分析计算值:C,60.34;H,5.65;N,8.12;测定值:C,60.04;H,5.71;N,8.19。
5.40实施例40:3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3,4-二-(二氟甲氧基)-苯基)-N,N-二甲基-丙酰胺
在室温下,向3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3,4-二-(二氟甲氧基)-苯基)-丙酸(350mg,0.72mmol)的四氢呋喃溶液中加入羰基二咪唑(175mg,1.08mmol)。在室温下搅拌该溶液2小时。向混合物中加入二甲胺的THF溶液(0.73ml,1.45mmol)。在室温下搅拌所得混合物2小时。将水(5ml)加入反应混合物中。真空除去THF,并用乙酸乙酯(20ml)萃取所得混合物。有机层用饱和碳酸氢钠溶液(3×10ml)、水(10ml)、盐水(10ml)洗涤,并经硫酸镁干燥。真空除去溶剂。所得油状物经HPLC纯化(乙腈∶水=45∶55),得到白色固体的3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3,4-二-(二氟甲氧基)-苯基)-N,N-二甲基-丙酰胺(200mg,55%):熔点:83-85℃;
1HNMR(CDCl3):2.25(s,3H,CH3CO),2.91(s,3H,NCH3),3.06-3.13(m,4H,CHHCO+NCH3),3.85(dd,J=10,15Hz,1H,CH-HCO),5.85-5.91(m,1H,CHN),6.80(t,JH-F=75Hz,1H,OCF2H),6.84(t,JH-F=75Hz,1H,OCF2H),7.23(d,J=7.5Hz,1H,Ar),7.41-7.47(m,3H,Ar),7.63(t,J=7.5Hz,1H,Ar),8.72(d,J=7.5Hz,1H,Ar),9.51(s,1H,NHCO).13CNMR(CDCl3):24.8,34.5,35.4,36.9,50.5,111.4,111.5,115.2,115.6,115.7,117.9,119.8,119.9,122.0,122.4,124.7,126.1,131.1,135.8,137.4,138.2,141.9,142.2,167.7,168.8,169.1,169.7;
C23H21F4N3O6的分析计算值:C,54.02;H,4.14;N,8.22;测定值:C,53.89;H,3.88;N,8.13。
5.41实施例41:3-(3,4-二-(二氟甲氧基)-苯基)-3-[4-氯-7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-丙酸甲酯
向3-氨基-3-(3,4-二-(二氟甲氧基)-苯基)-丙酸甲酯(50mg,0.16mmol)和三乙胺(0.09ml,3.1mmol)的DMF(2ml)溶液中加入2-溴甲基-3-氯-6-(环丙烷羰基-氨基)-苯甲酸甲酯(67mg,0.19mmol)。在氮气氛下于90℃加热混合物过夜。真空除去溶剂。所得油状物用乙酸乙酯(50ml)和1N HCl(50ml)萃取。有机层用水(30ml)、盐水(30ml)洗涤,并经硫酸镁干燥。真空除去溶剂,所得油状物经硅胶色谱纯化(己烷∶乙酸乙酯=2∶1),得到灰白色固体的3-(3,4-二-(二氟甲氧基)-苯基)-3-[4-氯-7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-丙酸甲酯(15mg,17%)。熔点:175-177℃;
1HNMR(CDCl3):δ0.88-0.94(m,2H,环丙基环CH2),1.07-1.13(m,2H,环丙基环CH2),1.65-1.68(m,1H,环丙基环CH),3.14(dd,J=6,15Hz,1H,CHHCO),3.28(dd,J=10,15Hz,1H,CHHCO),3.70(s,3H,OCH3),4.13(d,J=17Hz,1H,CHHN),4.36(d,J=17Hz,1H,CHHN),5.79-5.85(m,1H,CHN),6.23(t,JH-F=75Hz,1H,OCF2H),6.26(t,JH-F=75Hz,1H,OCF2H),7.28-7.41(m,4H,Ar),8.45(d,J=9Hz,1H,Ar),10.38(s,1H,NHCO);13CNMR(CDCl3):8.45,15.25,16.16,36.46,46.34,51.62,52.31,65.38,111.38,111.42,115.57,115.61,118.64,119.76,119.80,121.76,121.81,122.77,125.45,133.14,136.89,137.03,138.86,142.29,142.21,168.79,170.20,172.73;
C24H21ClF4N2O6的分析计算值:C,52.90;H,3.88;N,5.14;测定值:C,52.78;H,3.80;N,5.01。
5.42实施例42:环丙烷羧酸{2-[1-(3,4-二-(二氟甲氧基)-苯基)-2-二甲基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺
在室温下,向3-(3,4-二-(二氟甲氧基)-苯基)-3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-丙酸(400mg,0.81mmol)的四氢呋喃(10ml)溶液中加入羰基二咪唑(200mg,1.21mmol)。在室温下搅拌该溶液2小时。向混合物中加入二甲胺的THF溶液(0.8ml,1.6mmol)。在室温下搅拌所得混合物3小时。将水(20ml)加入反应混合物中。真空除去THF,并用乙酸乙酯(30ml)萃取并用水(20ml)洗涤所得混合物。有机层用饱和碳酸氢钠溶液(3×20ml)、水(20ml)、盐水(20ml)洗涤,并经硫酸镁干燥。真空除去溶剂。所得油状物在乙醚中搅拌过夜。过滤悬浮液得到浅黄色固体。该固体经HPLC纯化(CH3CN∶水=45∶55),得到白色固体的环丙烷羧酸{2-[1-(3,4-二-(二氟甲氧基)-苯基)-2-二甲基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺(200mg,50%):熔点:158-160℃;
1HNMR(CDCl3):δ0.86-0.92(m,2H,环丙基环CH2),1.08-1.12(m,2H,环丙基环CH2),1.66-1.70(m,1H,环丙基环CH),2.93(s,3H,NCH3),3.04(dd,J=5,15Hz,1H,CHHCO),3.10(s,3H,NCH3),3.64(dd,J=8,15Hz,1H,CHHCO),4.13(t,J=15Hz,2H,CHHN),5.56-5.62(m,1H,CHN),6.51(t,JH-F=75Hz,1H,OCF2H),6.54(t,JH-F=75Hz,1H,OCF2H),7.01(d,J=8Hz,1H,Ar),7.23-7.36(m,3H,Ar),7.44(t,J=8Hz,1H,Ar),8.43(d,J=8Hz,1H,Ar),10.52(s,1H,NHCO);13CNMR(CDCl3):8.22,16.16,35.58,35.92,37.27,49.59,53.83,58.94,111.0,115.65,117.64,117.67,119.90,119.80,121.66,122.58,125.64,133.27,138.05,138.69,141.49,169.11,169.81,172.65;
C25H25F4N3O5的分析计算值:C,57.36;H,4.81;N,8.03;测定值:C,57.22;H,4.76;N,8.11。
5.43实施例43:环丙烷羧酸{2-[1-(3,4-二-(二氟甲氧基)-苯基)-2-氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺
在室温下,向3-(3,4-二-(二氟甲氧基)-苯基)-3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-丙酸(400mg,0.81mmol)的四氢呋喃(10ml)溶液中加入羰基二咪唑(200mg,1.21mmol)。在室温下搅拌该溶液2小时。向混合物中加入氢氧化铵(0.12ml,1.6mmol)。在室温下搅拌所得混合物2小时。将水(5ml)加入反应混合物中。真空除去THF,并用乙酸乙酯(20ml)。有机层用饱和碳酸氢钠溶液(3×10ml)、水(10ml)、盐水(10ml)洗涤,并经硫酸镁干燥。真空除去溶剂。所得油状物经HPLC纯化(乙腈∶水=45∶55),得到白色固体的环丙烷羧酸{2-[1-(3,4-二-(二氟甲氧基)-苯基)-2-氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺(230mg,46%):熔点:198-200℃;
1HNMR(DMSO-d6):δ0.87(d,J=5Hz,4H,环丙基环CH2CH2),1.74-1.79(m,1H,环丙基环CH),2.99(d,J=7.5Hz,2H,CH2CONH2),4.29(d,J=18Hz,1H,CHHN),4.61(d,J=18Hz,1H,CHHN),5.69-5.75(m,1H,CHN),6.97(宽峰,1H,NHH),7.19(t,JH-F=75Hz,1H,OCF2H),7.22(t,JH-F=75Hz,1H,OCF2H),7.34-7.37(m,3H,Ar),7.47-7.58(m,2H,NHH+1Ar),8.23(d,J=8Hz,1H,Ar),10.51(s,1H,NHCO);13CNMR(CDCl3):8.26,15.95,38.10,47.37,51.89,112.77,112.90,116.90,117.03,117.40,117.70,117.99,120.57,121.03,121.16,121.74,125.72,133.38,137.51,138.81,141.60,141.65,141.70,142.15,142.20,142.25,142.79,168.74,171.37,172.24;
C23H21F4N3O5的分析计算值:C,55.76;H,4.27;N,8.48;测定值:C,55.98;H,4.00;N,8.46。
5.44实施例44:环丙烷羧酸{2-[1-(3,4-二-(二氟甲氧基)-苯基)-2-羟基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺
在室温下,向3-(3,4-二-(二氟甲氧基)-苯基)-3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-丙酸(400mg,0.81mmol)的四氢呋喃(10ml)溶液中加入羰基二咪唑(200mg,1.21mmol)。在室温下搅拌该溶液2小时。向混合物中加入羟胺(120mg,1.6mmol)。在室温下搅拌所得混合物2小时。将水(5ml)加入反应混合物中。真空除去THF,并用乙酸乙酯(20ml)。有机层用饱和碳酸氢钠溶液(3×10ml)、水(10ml)、盐水(10ml)洗涤,并经硫酸镁干燥。真空除去溶剂。所得油状物经HPLC纯化(乙腈∶水=45∶55),得到白色固体的环丙烷羧酸{2-[1-(3,4-二-(二氟甲氧基)-苯基)-2-羟基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺(230mg,46%):熔点:191-193℃;
1HNMR(CDCl3):δ0.88-0.93(m,2H,环丙基环CH2),1.09-1.12(m,2H,环丙基环CH2),1.64-1.67(m,1H,环丙基环CH),2.84-2.92(m,1H,CHHCO),3.38-3.48(m,1H,CHHCO),4.18(d,J=18Hz,1H,CHHN),4.36(d,J=18Hz,1H,CHHN),5.47-5.49(m,1H,CHN),6.52(t,JH-F=75Hz,1H,OCF2H),6.54(t,JH-F=75Hz,1H,OCF2H),6.99(d,J=8Hz,1H,Ar),7.25-7.31(m,3H,Ar),7.45(t,J=8Hz,1H,Ar),8.43(d,J=8Hz,1H,Ar),9.20(宽峰,1H,NHOH),10.35(s,1H,NHCO);13CNMR(DMSO):30.82,35.26,38.47,46.17,47.50,51.68,112.50,116.83,117.01,117.39,117.66,117.99,120.56,120.97,121.73,125.73,133.41,137.47,138.38,142.76,146.83,166.12,168.68,172.21,179.98.
C23H21F4N3O6的分析计算值:C,54.02;H,4.14;N,8.22;测定值:C,53.89;H,3.96;N,8.22。
5.45实施例45:3-(3,4-二-(二氟甲氧基)-苯基)-3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-丙酸
在室温下,向3-(3,4-二-(二氟甲氧基)-苯基)-3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-丙酸甲酯(2.0g,4mmol)的四氢呋喃(20ml)溶液中加入NaOH(10N,0.8ml)。在室温下搅拌溶液过夜。过滤所得悬浮液,得到白色固体。将该固体溶解于水(30ml)中,并滴加浓HCl直到pH大约4。用CH2C12(3×40ml)萃取所得混合物。有机层用Na2SO4干燥,过滤并浓缩得到白色固体的3-(3,4-二-(二氟甲氧基)-苯基)-3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-丙酸(1.4g,70%):熔点:94-96℃;
1HNMR(CDCl3)δ0.86-0.93(m,2H,环丙基环CH2),1.06-1.12(m,2H,环丙基环CH2),1.65-1.71(m,1H,环丙基环CH),3.13(dd,J=6,16Hz,1H,CHHCO),3.32(dd,J=9,16Hz,1H,CHHCO),4.15(d,J=15Hz,1H,CHHN),4.36(d,J=15Hz,1H,CHHN),5.78-5.84(m,1H,CHN),6.21(t,JH-F=75Hz,1H,OCF2H),6.24(t,JH-F=75Hz,1H,OCF2H),7.01(d,J=7.5Hz,1H,Ar),7.26-7.28(m,3H,Ar),7.44(t,J=7.5Hz,1H,Ar),8.43(d,J=7.5Hz,1H,Ar),10.42(s,1H,NHCO);13CNMR(CDCl3):8.35,8.38,16.14,36.55,47.00,51.29,99.24,111.36,111.42,115.60,116.84,117.02,118.03,119.74,119.79,121.59,122.76,125.46,133.61,137.09,138.03,141.12,142.21,142.38,142.43,169.63,173.03,173.82.
C23H20F4N2O6的分析计算值:C,55.65;H,4.06;N,5.64;测定值:C,55.33;11,3.96;N,5.38。
5.46实施例4650mg固体片剂
每片含有50mg环丙烷羧酸{2-[2-氨基甲酰基-1-(4-二氟甲氧基-3-乙氧基-苯基)-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺的片剂可以按照下述方式制备:
组分(1000片)
环丙烷羧酸{2-[2-氨基甲酰基-1-(4-二氟甲氧基-3-乙氧基-苯基)-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺
.............................................50.0g
乳糖.........................................50.7g
小麦淀粉.....................................7.5g
聚乙二醇6000.................................5.0g
滑石粉.......................................5.0g
硬脂酸镁.....................................1.8g
软化水.......................................q.s.
首先,将固体成分加压通过0.6mm目宽的筛网。然后将活性成分、乳糖、滑石粉、硬脂酸镁和一半淀粉混合。将另一半淀粉悬浮于40mL水中并将该悬浮液加入聚乙二醇在100mL水中的沸腾溶液中。将所得糊剂加入上述粉状物质中并将混合物造粒,如果需要添加水的话。在35EC下将颗粒干燥过夜,加压通过1.2mm目宽的筛网,并压成大约6mm直径、两侧均凹入的片剂。
5.47实施例47:100mg固体片剂
每片含有100mg环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-二甲基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺的片剂可以按照下述方式制备:
组分(1000片)
环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-二甲基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺
..........................................50.0g
乳糖......................................100.7g
小麦淀粉..................................47.0g
硬脂酸镁..................................3.0g
首先,将所有固体成分加压通过0.6mm目宽的筛网。然后将活性成分、乳糖、硬脂酸镁和一半淀粉混合。另一半淀粉悬浮于40mL水中并将该悬浮液加入100mL沸水中。将所得糊剂加入上述粉状物质中并将混合物造粒,如果需要添加水的话。在35EC下将颗粒干燥过夜,加压通过1.2mm目宽的筛网,并压成大约6mm直径、两侧均凹入的片剂。
5.48实施例4875mg固体片剂
每片含有75mg环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-羟氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺的咀嚼片剂可以按照下述方式制备:
组成(1000片)
环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-羟氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺
.........................................75.0g
甘露醇...................................230.0g
乳糖.....................................150.5g
滑石粉...................................21.0g
甘氨酸...................................12.5g
硬脂酸...................................10.0g
糖精.....................................1.5.
5%明胶溶液..............................q.s.
首先,将所有固体成分加压通过0.25mm目宽的筛网。然后将甘露醇和乳糖混合,加入明胶溶液造粒,加压通过2mm目宽的筛网,于50EC下干燥,再次加压通过1.7mm目宽的筛网。将环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-羟氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺、甘氨酸和糖精小心地混合,加入甘露醇、乳糖颗粒、硬脂酸和滑石粉,将其充分混合并压成大约10mm直径的片剂,其两侧均凹入并在上侧具有断裂槽。
5.49实施例4910mg固体片剂
每片含有10mg 3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酰胺的片剂可以按照下述方式制备:
组成(1000片)
3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酰胺
.............................................10.0g
乳糖.........................................328.5g
玉米淀粉.....................................17.5g
聚乙二醇6000.................................5.0g
滑石粉.......................................25.0g
硬脂酸镁.....................................4.0g
软化水.......................................q.s.
首先,将固体成分加压通过0.6mm目宽的筛网。然后将活性酰胺成分、乳糖、滑石粉、硬脂酸镁和一半淀粉立即混合。另一半淀粉悬浮于65mL水中并将该悬浮液加入聚乙二醇在260mL水中的沸腾溶液中。将所得糊剂加入上述粉状物质中并混合、造粒,如果需要添加水的话。在35EC下将颗粒干燥过夜,加压通过1.2mm目宽的筛网,并压成大约10mm直径的片剂,其两侧均凹入并且上侧具有断裂槽。
5.50实施例50100mg明胶胶囊
每个含有100mg环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-二甲基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺的明胶干填胶囊可以按照下述方式制备:
组成(1000片)
环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-二甲基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺
.........................................100.0g
微晶纤维素.................................30.0g
硫酸月桂酯钠...............................2.5g
硬脂酸镁...................................8.0g
将硫酸月桂酯钠筛过0.2mm目宽的筛网加入环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-二甲基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺中,并立即将这两种组分混合10分钟。然后通过0.9mm目宽的筛网加入微晶纤维素,并立即在将它们混合10分钟。最后,通过0.8mm目宽的筛网加入硬脂酸镁,再混合3分钟后,将混合物按照每份140mg加入0号(细长的)明胶干填胶囊中。
5.51实施例51注射溶液
0.2%注射液或灌输液例如按照下述方式制备:
环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-二甲基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺
...........................................5.0g
氯化钠.....................................22.5g
磷酸盐缓冲液pH7.4..........................300.0g
软化水.....................................至2500.0mL
将环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-二甲基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺溶于1000mL水中并经微滤器过滤。加入缓冲液并加入水使其达到2500mL。以每份1.0或2.5mL加入玻璃安瓿(每份分别含有2.0或5.0mg酰胺)以制备剂量单位剂型。
本说明书中引用的所有出版物和专利申请均引入本文作为参考,相当于各个出版物或专利申请被特别地和单独地结合参考。为了清楚理解,虽然上述发明已经通过说明和实施例进行了详细地描述,但根据本发明的教导,在不脱离本发明精神或范围的前提下,本领域普通技术人员很容易作出某些改变和改进。
Claims (47)
1.具有式(I)的化合物:
其中:
Y是-C(O)-,-CH2,-CH2C(O)-,-C(O)CH2-,或SO2;
Z是-H,-C(O)R3,-(C0-1-烷基)-SO2-(C1-4-烷基),-C1-8-烷基,-CH2OH,CH2(O)(C1-8-烷基)或-CN;
R1和R2各自独立地是-CHF2,-C1-8-烷基,-C3-18-环烷基,或-(C1-10-烷基)(C3-18-环烷基),且R1和R2中的至少一个是CHF2;
R3是-NR4R5,-烷基,-OH,-O-烷基,苯基,苄基,取代的苯基,或取代的苄基;
R4和R5各自独立地是H,-C1-8-烷基,-OH,-OC(O)R6;
R6是-C1-8-烷基,-氨基(C1-8-烷基),-苯基,-苄基,或-芳基;
X1、X2、X3和X4各自独立地是-H,-卤素,-硝基,-NH2,-CF3,-C1-6-烷基,-(C0-4-烷基)-(C3-6-环烷基),(C0-4-烷基)-NR7R8,(C0-4-烷基)-N(H)C(O)-(R8),(C0-4-烷基)-N(H)C(O)N(R7R8),(C0-4-烷基)-N(H)C(O)O(R7R8),(C0-4-烷基)-OR8,(C0- 4-烷基)-咪唑基,(C0-4-烷基)-吡咯基,(C0-4-烷基)-噁二唑基,或(C0-4-烷基)-三唑基,或者X1和X2或X2和X3或X3和X4可与连接它们的原子在一起形成3、4、5、6或7个原子的环烷基或杂环烷基;和
R7和R8各自独立地是H,C1-9-烷基,C3-6-环烷基,(C1-6-烷基)-(C3-6-环烷基),(C1-6-烷基)-N(R7R8),(C1-6-烷基)-OR8,苯基,苄基或芳基;或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
2.权利要求1的化合物,其中X1、X2、X3和X4中的一个是(C0-4-烷基)-NR7R8。
3.权利要求1的化合物,其中X1、X2、X3和X4中的一个是(C0-4-烷基)-NHC(O)-(R8)。
4.权利要求1的化合物,其中X1、X2、X3和X4中的一个是(C0-4-烷基)-NHC(O)-(R8)且X1、X2、X3和X4中的一个是卤素。
5.权利要求1的化合物,其中X1、X2、X3和X4中的一个是(C0-4-烷基)-NHC(O)NR7R8。
6.权利要求1的化合物,其中X1、X2、X3和X4中的一个是(C0-4-烷基)-NHC(O)O(R7R8)。
7.权利要求1的化合物,其中X1、X2、X3和X4中的一个是(C0-4-烷基)-OR8。
8.权利要求1的化合物,其中X1、X2、X3和X4中的一个是(C0-4-烷基)-咪唑基、(C0-4-烷基)-吡咯基、(C0-4-烷基)-噁二唑基或(C0- 4-烷基)-三唑基。
9.权利要求1的化合物,其中X1、X2、X3和X4中的一个是(C0-4-烷基)-环丙基。
10.权利要求1的化合物,其中X1、X2、X3和X4中的一个是NH2。
11.权利要求1的化合物,其中X1、X2、X3和X4中的三个是H。
12.权利要求1的化合物,其中X1和X2是H或者X3和X4是氢。
13.基本上不含R异构体的式I化合物的对映体纯S异构体,或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
14.基本上不含S异构体的式I化合物的对映体纯R异构体,或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
15.选自下述的化合物:
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸;
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-N,N-二甲基-丙酰胺;
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酰胺;
3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-丙酸;
3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-N-羟基-丙酰胺;
3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸甲酯;
3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸;
3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-N,N-二甲基-丙酰胺;
3-(7-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-N,N-二甲基-丙酰胺;
3-(4-二氟甲氧基-3-乙氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸甲酯;
3-(7-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯;
3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯;
3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯;
3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸;
3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸;
环丙烷羧酸{2-[2-氨基甲酰基-1-(4-二氟甲氧基-3-乙氧基-苯基)-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺;
环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-二甲基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺;
环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-羟基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺;
3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酰胺;
3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N,N-二甲基-丙酰胺;
3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N-羟基-丙酰胺;
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸;
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酰胺;
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N,N-二甲基-丙酰胺;
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N-羟基-丙酰胺;
环丙烷羧酸{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-甲烷磺酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺;
N-{2-[1-(4-二氟甲氧基-3-乙氧基-苯基-2-甲烷磺酰基-乙基]-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基}-乙酰胺;
环丙烷羧酸{2-[2-氨基甲酰基-1-(4-二氟甲氧基-3-乙氧基-苯基)-2-甲烷磺酰基-乙基]-7-氯-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺;
N-{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-3-吗啉-4-基-3-氧代-丙基]-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基}-乙酰胺;
N-{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-3-吗啉-4-基-3-氧代-丙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-乙酰胺;
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3,4-二-(二氟甲氧基)-苯基)-N,N-二甲基-丙酰胺;
3-(3,4-二-(二氟甲氧基)-苯基)-3-[4-氯-7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-丙酸甲酯;
环丙烷羧酸{2-[1-(3,4-二-(二氟甲氧基)-苯基)-2-二甲基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺;
环丙烷羧酸{2-[1-(3,4-二-(二氟甲氧基)-苯基)-2-氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺;
环丙烷羧酸{2-[1-(3,4-二-(二氟甲氧基)-苯基)-2-羟基氨基甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-酰胺;
3-(3,4-二-(二氟甲氧基)-苯基)-3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-丙酸。
16.一种药物组合物,其包含可药用载体、赋形剂、或稀释剂以及具有式(I)的化合物:
其中:
Y是-C(O)-,-CH2,-CH2C(O)-,-C(O)CH2-,或SO2;
Z是-H,-C(O)R3,-(C0-1-烷基)-SO2-(C1-4-烷基),-C1-8-烷基,-CH2OH,CH2(O)(C1-8-烷基)或-CN;
R1和R2各自独立地是-CHF2,-C1-8-烷基,-C3-18-环烷基,或-(C1-10-烷基)(C3-18-环烷基),且R1和R2中的至少一个是CHF2;
R3是-NR4R5,-烷基,-OH,-O-烷基,苯基,苄基,取代的苯基,或取代的苄基;
R4和R5各自独立地是H,-C1-8-烷基,-OH,-OC(O)R6;
R6是-C1-8-烷基,-氨基(C1-8-烷基),-苯基,-苄基,或-芳基;
X1、X2、X3和X4各自独立地是-H,-卤素,-硝基,-NH2,-CF3,-C1-6-烷基,-(C0-4-烷基)-(C3-6-环烷基),(C0-4-烷基)-NR7R8,(C0-4-烷基)-N(H)C(O)-(R8),(C0-4-烷基)-N(H)C(O)N(R7R8),(C0-4-烷基)-N(H)C(O)O(R7R8),(C0-4-烷基)-OR8,(C0- 4-烷基)-咪唑基,(C0-4-烷基)-吡咯基,(C0-4-烷基)-噁二唑基,或(C0-4-烷基)-三唑基,或者X1和X2或X2和X3或X3和X4可与连接它们的原子在一起形成3、4、5、6或7个原子的环烷基或杂环烷基;和
R7和R8各自独立地是H,C1-9-烷基,C3-6-环烷基,(C1-6-烷基)-(C3-6-环烷基),(C1-6-烷基)-N(R7R8),(C1-6-烷基)-OR8,苯基,苄基或芳基;或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
17.权利要求16的药物组合物,还包含附加的治疗剂。
18.权利要求17的药物组合物,其中附加的治疗剂是抗癌剂、消炎剂。
19.权利要求18的药物组合物,其中抗癌剂是紫杉醇、顺铂、它莫西芬、多西紫杉醇、pirubicin、阿霉素、依立替康、亮丙瑞林、比卡鲁胺、goserlin植入物、吉西他滨、沙莫司亭或甾类。
20.一种抑制哺乳动物中PDE4的方法,其包括向所述哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
21.一种调节哺乳动物中TNF-α生成的方法,其包括向所述哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
22.一种抑制哺乳动物中MMP的方法,其包括向所述哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
23.一种治疗或预防MDS的方法,其包括向需要上述治疗或预防的病人给药治疗或预防有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
24.一种治疗或骨髓增生性疾病(MPD)的方法,其包括向需要上述治疗或预防的病人给药治疗或预防有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
25.一种治疗、预防或管理复杂区域疼痛综合征的方法,其包括向需要上述治疗、预防或管理的病人给药治疗或预防有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
26.权利要求25的方法,其中在旨在减少或避免病人的复杂区域疼痛综合征的症状的外科手术或物理治疗之前、期间或之后,向上述病人给药治疗或预防有效量的权利要求1的化合物。
27.一种治疗不希望的哺乳动物中血管生成的方法,其包括向需要上述治疗的病人给药治疗有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
28.一种治疗哺乳动物癌症的方法,其包括向需要上述治疗的病人给药治疗有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
29.权利要求28的方法,其中癌症是实体瘤或来自血液的瘤。
30.权利要求29的方法,其中癌症是皮肤癌;淋巴结癌;乳腺癌;宫颈癌;子宫癌;胃肠道癌;肺癌;卵巢癌;前列腺癌;结肠癌;直肠癌;口腔癌;脑癌;头颈癌;咽喉癌;睾丸癌;肾癌;胰腺癌;骨癌;脾癌;肝癌;膀胱癌;喉癌;或鼻道癌。
31.一种治疗哺乳动物疾病的方法,所述疾病选自炎性疾病、自身免疫疾病、关节炎、类风湿性关节炎、炎性肠病、克罗恩病、口疮性溃疡、恶病质、移植物抗宿主病、哮喘、成人呼吸窘迫综合征和获得性免疫缺陷综合征,该方法包括向哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
32.一种治疗哺乳动物肺炎的方法,其包括向哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
33.一种治疗哺乳动物忧郁症的方法,其包括向哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
34.一种治疗哺乳动物慢性阻塞性肺疾病的方法,其包括向哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
35.一种治疗哺乳动物的炎性肠病的方法,其包括向哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
36.一种治疗哺乳动物的特应性皮炎的方法,其包括向哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
37.一种治疗哺乳动物的牛皮癣的方法,其包括向哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
38.一种治疗哺乳动物的克罗恩病的方法,其包括向哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
39.一种治疗哺乳动物的类风湿性关节炎的方法,其包括向哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
40.一种治疗哺乳动物的哮喘的方法,其包括向哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
41.一种治疗哺乳动物的多发性硬化症的方法,其包括向哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
42.一种治疗哺乳动物的心脏病的方法,其包括向哺乳动物给药有效量的权利要求1的化合物或其可药用盐、溶剂化物、水合物、立体异构体、笼形包合物或前药。
43.权利要求20-42中任一项的方法,其中权利要求1的化合物的有效量是约0.1mg至约300mg/天。
44.权利要求43的方法,其中有效量是约1mg至约250mg/天。
45.权利要求20-42任一项的方法,其中权利要求1的化合物是口服给药的。
46.权利要求20-42任一项的方法,其中权利要求1的化合物是粘膜给药的。
47.权利要求20-42任一项的方法,其中所述的哺乳动物或哺乳动物细胞是人类。
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KR (1) | KR20050090435A (zh) |
CN (1) | CN1802353A (zh) |
AT (1) | ATE449081T1 (zh) |
AU (1) | AU2003303511B2 (zh) |
BR (1) | BR0317885A (zh) |
CA (1) | CA2511843C (zh) |
DE (1) | DE60330187D1 (zh) |
ES (1) | ES2333220T3 (zh) |
IL (1) | IL169439A0 (zh) |
MX (1) | MXPA05006998A (zh) |
NZ (1) | NZ541487A (zh) |
TW (1) | TW200418779A (zh) |
WO (1) | WO2004060313A2 (zh) |
ZA (1) | ZA200505308B (zh) |
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- 2003-12-29 EP EP03808605A patent/EP1587474B1/en not_active Expired - Lifetime
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CN110423213B (zh) * | 2019-08-22 | 2021-06-04 | 上海英诺富成生物科技有限公司 | 一种阿普斯特衍生物及其制备方法与应用 |
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JP5269281B2 (ja) | 2013-08-21 |
JP2006515310A (ja) | 2006-05-25 |
US7173058B2 (en) | 2007-02-06 |
JP2013151497A (ja) | 2013-08-08 |
US20040204448A1 (en) | 2004-10-14 |
ATE449081T1 (de) | 2009-12-15 |
US7893102B2 (en) | 2011-02-22 |
IL169439A0 (en) | 2007-07-04 |
CA2511843C (en) | 2012-04-24 |
DE60330187D1 (de) | 2009-12-31 |
US7504427B2 (en) | 2009-03-17 |
AU2003303511B2 (en) | 2009-06-04 |
US20070072902A1 (en) | 2007-03-29 |
US20110124645A1 (en) | 2011-05-26 |
AU2003303511A1 (en) | 2004-07-29 |
WO2004060313A2 (en) | 2004-07-22 |
TW200418779A (en) | 2004-10-01 |
CA2511843A1 (en) | 2004-07-22 |
NZ541487A (en) | 2008-11-28 |
EP1587474A2 (en) | 2005-10-26 |
EP1587474A4 (en) | 2006-11-22 |
KR20050090435A (ko) | 2005-09-13 |
US20090143382A1 (en) | 2009-06-04 |
BR0317885A (pt) | 2005-12-06 |
EP1587474B1 (en) | 2009-11-18 |
ZA200505308B (en) | 2006-10-25 |
MXPA05006998A (es) | 2005-08-18 |
ES2333220T3 (es) | 2010-02-18 |
WO2004060313A3 (en) | 2005-09-15 |
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