CN100372836C - 新的免疫治疗剂亚酰胺/酰胺类 - Google Patents
新的免疫治疗剂亚酰胺/酰胺类 Download PDFInfo
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- CN100372836C CN100372836C CNB971803234A CN97180323A CN100372836C CN 100372836 C CN100372836 C CN 100372836C CN B971803234 A CNB971803234 A CN B971803234A CN 97180323 A CN97180323 A CN 97180323A CN 100372836 C CN100372836 C CN 100372836C
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- 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
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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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
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
Abstract
新颖的式(I)亚酰胺/酰胺醚和醇类,其中R2是-H、1-8个碳原子的烷基、苄基、吡啶基甲基或烷氧基甲基;R4是-CX-、-CH2-或-CH2CX-;X是O或S;n是0、1或2,它是包括肿瘤坏死因子α的细胞因子的抑制剂,可用来抗恶病质、内毒素性休克、关节炎、哮喘和逆转录病毒复制。典型的具体方案是3-苯二甲酰亚氨基-2-(3′,4′-二甲氧基苯基)丙-1-醇。
Description
本申请是待批美国专利申请08/366,667(1994,12,30)提交的部分续展申请
发明背景
本发明涉及一种减少哺乳动物中TNFα水平并抑制磷酸二酯酶的方法,以及用于该方法的化合物和组合物。
TNFα,肿瘤坏死因子α,是主要由单核吞噬细胞应答免疫刺激剂而释放的细胞因子。当将其施加于动物或人时,TNFα会引起炎症、发热、心血管影响、出血、凝血以及类似于急性感染和休克时所见的急性反应。
很多疾病状态均伴有TNFα产生过量或失控。这些疾病包括内毒素血症和/或中毒性休克综合征{Tracey等,Nature330,662-664(1987)和Hinshaw等,Ci rc.Shock30,279-292(1990)};恶病质{Dezube等,Lancet,335(8690),662(1990)}和成人呼吸窘迫综合征(ARDS)(其中从ARDS患者肺呼出气中检出TNFα的浓度超出12,000pg/mL){Millar等,Lancet2(8665),712-714(1989)}.重组TNFα全身输注也会导致ARDS中所见的变化{Ferrai-Baliviera等,Arch.Surg.124(12),1400-1405(1989)}。
TNFα似乎还涉及骨吸收疾病,包括关节炎,已经测得,当发作时,白细胞会产生骨再吸收活性,资料表明TNFα与该发作有关{Bertolini等,Nature319,516-518(1986)和Johnson等,Endocrinology124(3),1424-1427(1989)}。在体内、外试验中已经测得,TNFα通过刺激成骨细胞的形成和激活,并同时抑制成骨细胞功能,从而刺激骨吸收,抑制骨生成。尽管TNFα可能涉及很多骨吸收疾病(包括关节炎),但最令人非信不可的与疾病的联系是肿瘤或宿主组织产生TNFα与伴有高钙血症的恶性肿瘤之间的联系{Calci.Tissue Int.(US)46(Suppl.),S3-10(1990)}。在移植物对宿主反应中,血清TNFα水平的提高与急性同种异型骨髓移植后的主要并发症有关{Holler等,Blood,75(4),1011-1016(1990)}。
脑疟疾是伴有TNFα高血浓度的致死性超急性神经综合征,是疟疾患者中出现的最严重的并发症。血清TNFα水平与患急性疟疾患者疾病的严重程度和预后直接相关{Grau等N.Engl.J.Med.320(24),1586-1591(1989)}。
TNFα还在慢性肺部炎症性疾病方面起作用。硅石颗粒的沉积导致硅肺,一种纤维变性反应引起的进行性呼吸衰竭疾病。抗TNFα抗体完全阻断小鼠体内硅石诱导的肺纤维变性{Pignet等,Nature,344:245-247(1990)}。在硅石和石棉引起的纤维变性的动物模型中已经得到证明,血清和分离出的巨噬细胞中有高水平TNFα的产生{Bissonnette等,Inflammation13(3),329-339(1989)}。还有人发现,从肺部肉瘤病患者获得的肺泡巨噬细胞与来自正常供体的巨噬细胞相比,会自发性地释放大量TNFα{Baughman等,J.Lab.Clin.Med.115(1),36-42(1990)}。
TNFα还与再灌注后的炎症反应(称作再灌注损伤)有关,是缺血流后组织损伤的主要原因{Vedder等,PNAS87,2643-2646(1990)}。TNFα还能改变内皮细胞的性质,具有各种促凝血活性,如提高组织因子促凝血活性和抑制抗凝血蛋白C途径,以及下调血栓调节蛋白(thrombomodulin)的表达{Sherry等,J.Cell Biol.107,1269-1277(1988)}。TNFα具有促炎症活性,该活性与TNFα的早期产生(在炎症初期)使其更象是几种重要疾病(包括但不限于心肌梗塞、中风和循环休克)中组织损伤的介质。特别重要的是TNFα诱导的粘合分子(如细胞间粘合分子(ICAM)或内皮白细胞粘合分子(ELAM))在内皮细胞上的表达{Munro等,Am.J.Path.135(1),121-132(1989)}。
此外,现已知道,TNFα是逆转录病毒复制(包括HIV-1激活)的潜在激活剂{Duh等,Proc.Nat.Acad.Sci.86,5974-5978(1989);Poll等,Proc.Nat.Acad.Sci.87,782-785(1990);Monto等,Blood79,2670(1990);Clouse等,J.Immunol.142,431-438(1989);Poll等,AIDS Res.Hum.Retrovirus,191-197(1992)}。AIDS由人免疫缺陷病毒(HIV)感染T淋巴细胞而引起。至少有三种类型或三株HIV已被鉴定出来,即HIV-1,HIV-2和HIV-3。作为HIV感染的结果,T细胞介导的免疫受损,受感染的个体出现严重的机会性感染和/或异常新生物。HIV进入T淋巴细胞需要T淋巴细胞激活。其他病毒(如HIV-1和HIV-2)在T细胞激活后感染T淋巴细胞,这些病毒蛋白的表达和/或复制由这种T细胞激活所介导或维持。一旦被激活的T淋巴细胞被HIV感染,该T淋巴细胞必须继续维持激活状态,以使HIV基因表达和/或HIV复制。细胞因子,特别是TNFα,通过在维持T淋巴细胞活化上起作用而参与活化T细胞介导的HIV蛋白表达和/或病毒复制。因此,在HIV感染的个体上,诸如通过阻止或抑制细胞因子(值得注意的是TNFα)的产生来干扰细胞因子的活性,有助于限制HIV感染引起的T淋巴细胞激活的维持。
单核细胞、巨噬细胞和相关的细胞(如枯否氏细胞和胶质细胞)也参与HIV感染的维持。这些细胞象T细胞一样,是病毒复制的靶细胞,病毒复制的水平依赖于细胞的激活状态{Rosenberg等,The Immunopathogenesis of HIV Infection,Advances in Immunology,57(1989)}。细胞因子(如TNFα)已被证明在单核细胞和/或巨噬细胞上激活HIV复制{Poli等,Proc.Natl.Acad.Sci.,87,782-784(1990)},因此,阻止或抑制细胞因子的产生或其活性有助于限制上述的HIV侵入T细胞。另外的研究将TNFα鉴定为体外HIV激活的共同因子,并提供了细胞的胞质中已发现的核调节蛋白起作用的明确的作用机制(Osborn等,PNAS862336-2340)。该证据揭示,TNFα合成的减少通过减少转录从而减少病毒产生,可在HIV感染中具有抗病毒效应。
在T细胞和巨噬细胞株内潜伏的HIV病毒复制可被TNFα诱导{Folks等,PNAS86,2365-2368(1989)}。有人提出,该病毒诱导活性的分子机理是通过TNFα激活细胞胞质中所见基因调节蛋白(NFκB)的能力,其能通过结合于病毒调节基因序列(LTR)而促进HIV复制{Osborn等,PNAS86:2336-2340(1989)}。有人提出,伴有恶病质的AIDS和癌症中TNFα系患者血清TNFα的提高及外周血液单核细胞中高水平自发性TNFα产生所致{Wright等,J.Immunol.141(1).99-104(1988)}。{Eur J.Gastroen Hepat,6(9),821-829(1994)},{J.Exp.Med.,1121-1227(1988)}。
出于上述提到的类似的理由,TNFα在其他病毒,如细胞肥大包涵体病毒(CMV)、流感病毒、腺病毒和疱疹病毒族感染里起了各种作用。
预防或抑制TNFα的产生或作用,因此预示着对于许多炎症、感染、免疫病或恶性肿瘤病是有效的治疗策略。这些包括,但不限于,脓毒性休克、脓毒症、内毒素性休克、血液动力学休克和脓毒综合征、缺血后再灌注损伤、疟疾、分支杆菌感染、脑脊膜炎、牛皮癣、充血性心力衰竭、纤维化疾病、恶病质、移植物排斥、癌症、自身免疫性疾病、AIDS中的机会性感染、类风湿性关节炎、类风湿性脊椎炎、骨关节炎、其他关节炎病症、炎性肠疾患克罗恩氏病、溃疡性结肠炎、多发性硬化、全身红斑狼疮、麻风中的ENL、放射损伤、哮喘和高氧性肺泡损伤。针对抑制TNFα的努力从采用类固醇(如地塞米松和脱氢可的松)到使用多克隆和单克隆抗体已经用于该目的,{Beutler等,Science234,470-474(1985);WO92/11383},(临床和实验类风湿学(Clinical and ExperimentalRheumatology)1993,11(增补8),5173-5175),(PNAS1992,89,9784-88),(Annals ofthe Rheumatic Diseases1990,49,480-486)。
核因子κB(NFκB)是多效转录激活剂(Lenardo等,Cell1989,58,227-29),已经证实它会参与各种疾病和炎症作为转录激活剂。NFκB被认为能调节细胞因子(包括但不限于TNFα)的水平,并且也是HIV转录的激活剂(Dbaibo等,J.Biol.Chem.1993,17762-66;Duh等,Proc,.Natl.Acad.Sci.1989,86,5974-78;Bachelerie等,Nature1991,350,709-12;Boswas等,J.Acquired Immune Deficiency Syndrome1993,6,778-786;Suzuki等,Biochem.And Biophys.Res.Comm.1993.193.277-83;SuZuki等,Biochem.And Biophys.Res Comm.1992.189,1709-15;Suzuki等,Biochem.Mol.Bio.Int.1993;31(4),693-700;Shakhov等,Proc.Natl.Acad.Sci.USA1990,171,35-47;和Staal等,Proc.Natl.Acad.Sci.USA1990,87,9943-47)。因此,NFκB结合的抑制可调节细胞因子基因的转录,通过这一调节和其他机制,它能用于抑制众多疾病。本发明的化合物可抑制NFκB在核里的作用,因此可用于治疗各种疾病,包括但不局限于类风湿性关节炎、类风湿性脊椎炎、骨关节炎、其它关节炎病症、脓毒性休克、脓毒症、内毒素性休克、移植物抗宿主疾病、消耗性疾病、克罗恩氏病、溃疡性结肠炎、多发性硬化、全身性红斑狼疮、麻风病中的ENL、HIV、AIDS及AIDS中的机会感染。
TNFα和NFκB的水平受相互反馈环的影响。如上所述,本发明的化合物对TNFα和NFκB都起作用,但本发明的化合物如何调节TNFα、NFκB的水平则迄今而未知。
很多细胞功能由3′,5′-环磷酸腺苷(cAMP)水平介导。这些细胞功能可造成炎性状态和包括哮喘、炎症和其他病状在内的疾病(Lowe和Cheng,Drugs of theFuture,17(9),799-807,1992)。现已证明,炎性白细胞中cAMP水平的升高抑制了这些细胞的激活以及炎性介体的随后释放。cAMP水平的升高还导致呼吸道平滑肌的松驰。
cAMP灭活的主要细胞机制是cAMP被称为环核苷酸磷酸二酯酶(PDE)的同工酶家族破坏(Beavo和Reitsnyder,Trends in Pharm.,11,150-155,1990)。PDE家族中有7种酶是已知的。例如,认为IV型PDE的抑制在炎性介体释放抑制和呼吸道平滑肌松弛中是特别有效的(Verghese等,药学和实验治疗学杂志,272(3),1313-1320,1995)。因此,抑制PDE IV的化合物能表现出所需的炎症抑制和呼吸道平滑肌松弛,而只有最少程度的不希望产生的副作用,如心血管或抗血小板效应。目前使用的PDE IV抑制剂在可接受的治疗剂量下缺乏选择作用。
本发明的化合物可用来抑制磷酸二酯酶,特别是PDE III和PDE IV,并用于治疗其介导的疾病状态。
详述
本发明基于这样的发现,本文详述的一类非-多肽亚酰胺/酰胺能抑制TNFα的作用。
本发明涉及下式化合物:
其中R1是(i)直链、支链或环化、取代或非取代的有1-12个碳原子的烷基,(ii)苯基或被一个或多个取代基取代的苯基,其中每个取代基各自独立地选自硝基、氰基、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨甲酰基、乙酰氧基、羧基、羟基、氨基、取代氨基、酰氨基、烷基(二烷基)氨基、1-10个碳原子的烷基、3-10个碳原子的环烷基、5-12个碳原子的双环烷基、1-10个碳原子的烷氧基、3-10个碳原子的环烷氧基、5-12个碳原子的双环烷氧基或卤素;
-R2是-H、1-8个碳原子的烷基、苄基、吡啶基甲基或烷氧基甲基;
-R3是i)亚乙基,ii)亚乙烯基,iii)3-10个碳原子的支链亚烷基,iv)3-10个碳原子的支链亚链烯基(alkenylene),v)4-9个碳原子非取代或被一个或多个取代基取代的环亚烷基,所述的取代基各自独立地选自硝基、氰基、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨甲酰基、乙酰氧基、羧基、羟基、氨基、1-6个碳原子的取代氨烷基、1-6个碳原子的取代氨基酰基、1-10个碳原子的烷基、1-12个碳原子的烷氧基或卤素,vi)非取代或被一个或多个取代基取代的4-9个碳原子的环亚链烯基(cycloalkenylene),所述的取代基选自硝基、氰基、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨甲酰基、乙酰氧基、羧基、羟基、氨基、有1-6个碳原子的取代氨烷基、有1-6个碳原子的取代氨基酰基,1-10个碳原子的烷基、1-12个碳原子的烷氧基或卤素,vii)非取代或被一个或多个取代基取代的邻-亚苯基,所述的取代基选自硝基、氰基、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨甲酰基、乙酰氧基、羧基、羟基、氨基、有1-6个碳原子的取代氨烷基、有1-6个碳原子的取代氨基酰基,1-10个碳原子的烷基、1-12个碳原子的烷氧基或卤素,viii)萘基,或ix)吡啶基;
R4是-CX-,-CH2-或-CH2CX-;
X是O或S;
n是0,1,2或3。
式II第一优选的亚类涉及式中R3是邻-亚苯基的化合物,其中:
R1是3,4-二乙氧基苯基或3-乙氧基-4-甲氧基苯基和
R4是-CO-、-CH2-或-CH2CO-。
本发明典型的化合物包括:
3-苯二甲酰亚氨基-3-(3’,4’-二甲氧基苯基)丙-1-醇;
2-苯二甲酰亚氨基-2-(3’,4’-二甲氧基苯基)乙醇;
3-苯二甲酰亚氨基-3-(3’,4’-二乙氧基苯基)丙-1-醇;
3-苯二甲酰亚氨基-3-(3’,4’-二甲氧基苯基)-1-甲氧基丙烷;
2-苯二甲酰亚氨基-2-(3’,4’-二甲氧基苯基)-1-甲氧基乙烷;
3-苯二甲酰亚氨基-3-(3’,4’-二乙氧基苯基)-1-甲氧基丙烷;
3-苯二甲酰亚氨基-3-(3’,4’-二甲氧基苯基)-1-乙氧基丙烷;
3-苯二甲酰亚氨基-3-(3’,4’-二甲氧基苯基)-1-(3-毗啶基甲氧基)丙烷;
3-苯二甲酰亚氨基-3-(3’,4’-二乙氧基苯基)-1-(3-吡啶基甲氧基)丙烷;
3-苯二甲酰亚氨基-3-萘基丙-1-醇;
3-苯二甲酰亚氨基-3-(3’,4’-二乙基苯基)丙-1-醇;
3-苯二甲酰亚氨基-3-(3’,4’-二丙基苯基)丙-1-醇;
3-苯二甲酰亚氨基-3-(3’,4’-二乙基苯基)-1-甲氧基丙烷;
3-苯二甲酰亚氨基-3-(3’,4’-二乙氧基苯基)-1-乙氧基丙烷;
3-苯二甲酰亚氨基-3-环己基-1-甲氧基丙烷;
3-苯二甲酰亚氨基-3-(3’,4’-二乙基环己基)-1-甲氧基丙烷;
3-(1’-氧基异二氢氮杂茚基)-3-(3’,4’-二甲氧基苯基)丙-1-醇;
2-(1’-氧基异二氢氮杂茚基)-2-(3’,4’-二甲氧基苯基)乙醇;
3-(1’-氧基异二氢氮杂茚基)-3-(3’,4’-二乙氧基苯基)丙-1-醇;
3-(1’-氧基异二氢氮杂茚基)-3-(3’,4’-二甲氧基苯基)-1-甲氧基丙烷;
2-(1’-氧基异二氢氮杂茚基)-2-(3’,4’-二甲氧基苯基)-1-甲氧基乙烷;
3-(1’-氧基异二氢氮杂茚基)-3-(3’,4’-二乙氧基苯基)-1-甲氧基丙烷;
3-(1’-氧基异二氢氮杂茚基)-3-(3’,4’-二甲氧基苯基)-1-乙氧基丙烷;
3-(1’-氧基异二氢氮杂茚基)-3-(3’,4’-二甲氧基苯基)-1-(3-吡啶基甲氧基)丙烷;
3-(1’-氧基异二氢氮杂茚基)-3-(3’,4’-二乙氧基苯基)-1-(3-吡啶基甲氧基)丙烷;
3-(1’-氧基异二氢氮杂茚基)-萘基丙-1-醇;
3-(1’-氧基异二氢氮杂茚基)-3-(3’,4’-二乙基苯基)丙-1-醇;
3-(1’-氧基异二氢氮杂茚基)-3-(3’,4’-二丙基苯基)丙-1-醇;
3-(1’-氧基异二氢氮杂茚基)-3-(3’,4’-二乙基苯基)-1-甲氧基丙烷;
3-(1’-氧基异二氢氮杂茚基)-3-(3’,4’-二乙氧基苯基)-1-乙氧基丙烷;
3-苯二甲酰亚氨基-3-(3’-乙氧基-4’-甲氧基苯基)丙-1-醇;
3-苯二甲酰亚氨基-3-(3’-乙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-苯二甲酰亚氨基-3-(3’-丙氧基-4’-甲氧基苯基)丙-1-醇;
3-苯二甲酰亚氨基-3-(3’-丙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-苯二甲酰亚氨基-3-(3’-环戊氧基-4’-甲氧基苯基)丙-1-醇;
3-苯二甲酰亚氨基-3-(3’-环戊氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-苯二甲酰亚氨基-3-(3’-异丙氧基-4’-甲氧基苯基)丙-1-醇;
3-苯二甲酰亚氨基-3-(3’-异丙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-苯二甲酰亚氨基-3-(3’-乙氧基-4’-乙苯基)丙-1-醇;
3-苯二甲酰亚氨基-3-(3’-乙氧基-4’-乙苯基)-1-甲氧基丙烷;
3-(1’-氧基异二氢氮杂茚基)-3-(3’-乙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(1’-氧基异二氢氮杂茚基)-3-(3’-丙氧基-4’-甲氧基苯基)丙-1-醇;
3-(1’-氧基异二氢氮杂茚基)-3-(3’-丙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(1’-氧基异二氢氮杂茚基)-3-(3’-环戊氧基-4’-甲氧基苯基)丙-1-醇;
3-(1’-氧基异二氢氮杂茚基)-3-(3’-环戊氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(1’-氧基异二氢氮杂茚基)-3-(3’-异丙氧基-4’-甲氧基苯基)丙-1-醇;
3-(1’-氧基异二氢氮杂茚基)-3-(3’-异丙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(1’-氧基异二氢氮杂茚基)-3-(3’-乙氧基-4’-乙苯基)丙-1-醇;
3-(1’-氧基异二氢氮杂茚基)-3-(3’-乙氧基-4’-乙苯基)-1-甲氧基丙烷;
3-(3-氨基苯二甲酰亚氨基)-3-(3’-乙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(3-氨基苯二甲酰亚氨基)-3-(3’-丙氧基-4’-甲氧基苯基)丙-1-醇;
3-(3-氨基苯二甲酰亚氨基)-3-(3’-丙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(3-氨基苯二甲酰亚氨基)-3-(3’-环戊氧基-4’-甲氧基苯基)丙-1-醇;
3-(3-氨基苯二甲酰亚氨基)-3-(3’-环戊氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(3-氨基苯二甲酰亚氨基)-3-(3’-异丙氧基-4’-甲氧基苯基)丙-1-醇;
3-(3-氨基苯二甲酰亚氨基)-3-(3’-异丙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(3-氨基苯二甲酰亚氨基)-3-(3’-乙氧基-4’-乙苯基)丙-1-醇;
3-(3-氨基苯二甲酰亚氨基)-3-(3’-乙氧基-4’-乙苯基)-1-甲氧基丙烷;
3-(3-羟基苯二甲酰亚氨基)-3-(3’-乙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(3-羟基苯二甲酰亚氨基)-3-(3’-丙氧基-4’-甲氧基苯基)丙-1-醇;
3-(3-羟基苯二甲酰亚氨基)-3-(3’-丙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(3-羟基苯二甲酰亚氨基)-3-(3’-环戊氧基-4’-甲氧基苯基)丙-1-醇;
3-(3-羟基苯二甲酰亚氨基)-3-(3’-环戊氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(3-羟基苯二甲酰亚氨基)-3-(3’-异丙氧基-4’-甲氧基苯基)丙-1-醇;
3-(3-羟基苯二甲酰亚氨基)-3-(3’-异丙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(3-羟基苯二甲酰亚氨基)-3-(3’-乙氧基-4’-乙苯基)丙-1-醇;
3-(3-羟基苯二甲酰亚氨基)-3-(3’-乙氧基-4’-乙苯基)-1-甲氧基丙烷;
3-高苯二甲酰亚氨基-3-(3’-乙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-高苯二甲酰亚氨基-3-(3’-丙氧基-4’-甲氧基苯基)丙-1-醇;
3-高苯二甲酰亚氨基-3-(3’-丙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-高苯二甲酰亚氨基-3-(3’-环戊氧基-4’-甲氧基苯基)丙-1-醇;
3-高苯二甲酰亚氨基-3-(3’-环戊氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-高苯二甲酰亚氨基-3-(3’-异丙氧基-4’-甲氧基苯基)丙-1-醇;
3-高苯二甲酰亚氨基-3-(3’-异丙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-高苯二甲酰亚氨基-3-(3’-乙氧基-4’-乙苯基)丙-1-醇;
3-高苯二甲酰亚氨基-3-(3’-乙氧基-4’-乙苯基)-1-甲氧基丙烷;
3-(4-氨基苯二甲酰亚氨基)-3-(3’-乙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(4-氨基苯二甲酰亚氨基)-3-(3’-丙氧基-4’-甲氧基苯基)丙-1-醇;
3-(4-氨基苯二甲酰亚氨基)-3-(3’-丙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(4-氨基苯二甲酰亚氨基)-3-(3’-环戊氧基-4’-甲氧基苯基)丙-1-醇;
3-(4-氨基苯二甲酰亚氨基)-3-(3’-环戊氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(4-氨基苯二甲酰亚氨基)-3-(3’-异丙氧基-4’-甲氧基苯基)丙-1-醇;
3-(4-氨基苯二甲酰亚氨基)-3-(3’-异丙氧基-4’-甲氧基苯基)-1-甲氧基丙烷;
3-(4-氨基苯二甲酰亚氨基)-3-(3’-乙氧基-4’-乙苯基)丙-1-醇;
3-(4-氨基苯二甲酰亚氨基)-3-(3’-乙氧基-4’-乙苯基)-1-甲氧基丙烷;
这里所用的术语烷基指单价饱和的直链或支链烃。除非另有所述,这些链可以含有1-18碳原子。这些烷基的典型例子是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、叔戊基、己基、异己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基等。当定为“低级”时,烷基则含有1-6个碳原子。相同的碳含量适用于母代术语“链烷”和衍生物术语如“烷氧基”。
在专业技术人员的管理下,该化合物可用来抑制TNFα的不良效应。化合物可以单独地或与其它包括抗生素、类固醇等在内的治疗剂组合对需要治疗的哺乳动物进行口服给药、直肠给药或肠胃外给药。口服剂型包括片剂、胶囊剂、糖衣剂,及类似形状的压制的药物剂型。可用含20-100mg/ml的等渗盐水溶液作为非胃肠道给药,包括肌肉、鞘内、静脉和动脉途径给药。使用从常规载体如可可脂制成的栓剂可进行直肠给药。
剂量方案必须根据患者特定的适应征、年龄、体重和总的生理状况和需要的应答来定,但是剂量通常在约1-500毫克/天内,一天可按需给药一次或几次。通常,最初的治疗方案可以来自用本发明化合物治疗其它TNFα介导的病征使有效干扰TNFα活性的已知量。定期检查受治疗者的T细胞数目和T4/T8比,和/或测定病毒血症如逆转录酶或病毒蛋白的水平,和/或细胞因子介导的疾病伴随的问题(如恶病质或肌肉退化)的进展。如果在正常治疗方案后没有观察到有任何效果,则增加细胞因子活性干扰剂的给药量,例如1星期增加50%。
本发明的化合物还可局部用于由过量TNFα的产生分别介导或加剧的局部病症的治疗或预防,例如病毒感染(如由疱疹病毒引起的感染)或病毒性结膜炎等。
这些化合物还可用于需要阻止或抑制TNFα产生的人以外的哺乳动物的兽医治疗。处理(治疗或预防)TNFα介导的动物体内的疾病包括上面所述的那些病症,但特别是病毒感染。例子包括猫免疫缺陷病毒、马感染性贫血病毒、羊关节炎病毒、绵羊脱髓鞘性脑白质炎病毒和羊进行性间质肺炎病毒,以及其它慢病毒(lentiviruse)。
这些化合物中的特定化合物具有一个或多个手性中心,因此可以存在旋光异构体。这些异构体的外消旋体和各异构体本身以及非对映异构体(当有两个或多个手性中心时)包括在本发明范围内。外消旋体可直接使用,或可用物理方法,如通过使用手性吸附剂的色谱法将其分离成各个异构体。或者,可以将各个异构体制成手性形式,或用化学方法,通过与手性酸成盐从混合物中分离各个异构体,例如,10-樟脑磺酸、樟脑酸、α-溴代樟脑酸、甲氧基乙酸、酒石酸、二乙酰基酒石酸、苹果酸、吡啶烷酮-5-羧酸等的各个对映体,然后使解析的一种或两种碱游离出来,任意地重复此过程,以获得基本不含另一种的任何一种或两种异构体,即光学纯度>95%的形式。
可用抗TNFα抗体来容易地分析这些化合物对TNFα产生的预防或抑制。例如,用5微克/毫升纯化的兔抗-TNFα抗体在4℃下对板(Nunc免疫板,Roskilde,DK)处理12-14小时。然后用含5毫克/毫升BSA的PBS/0.05%Tween在25℃下使板抑制2小时。洗涤后,100微升未知物和对照物施加到板上在4℃培养12-14小时。对板洗涤,用(马的)过氧化酶和小鼠的抗-TNFα单克隆抗体进行配对分析,用在含0.012%过氧化氢的磷酸盐-柠檬酸盐缓冲液里的邻-苯二胺进行显色,在492nm下读数。
可用制备亚胺的公知方法来制备化合物。优选的一般反应流程包括:使取代胺与合适的酸酐反应。也可使用其它本技术领域公知的合成方法,如通过使取代胺与邻苯二甲酸酐、N-乙酯基邻苯二甲酰亚胺或邻苯二甲酸二羧醛反应,如下所示:
下列实施例进一步阐述了本发明的性质,但它们不用于限定本发明的范围,所述的范围由所附的权利要求书限定。
实施例1
3-氨基-3-(3’,4’-二甲氧基苯基)丙酸
使搅拌的3’,4’-二甲氧基苯甲醛(131克,788毫摩尔)和乙酸铵(121.5克,1576毫摩尔)在乙醇(95%,400毫升)里的搅拌的悬浮液在45-50℃下加热得到橙色溶液。向该溶液里加入丙二酸(82.0克,788毫摩尔),使溶液回流过夜。在加热下析出白色固体沉淀,让浆状物冷却到室温并过滤。固体用乙醇洗涤,空气干燥,真空干燥(60℃,<1mm)得到3-氨基-3-(3’,4’-二甲氧基苯基)丙酸的白色固体(100.14克,得率56%),不需要进一步的纯化:熔点:208.0-210.0℃;
1HNMR(D2O/NaOD/TSP)δ7.08-6.91(m,3H),4.22(t,J=7Hz,1H),3.87(s,3H),3.83(s,3H),2.55(dd,J=2,7Hz,2H);13C NMR(D2O/NaOD/TSP)δ182.9,150.8,149.8,140.7,121.6,114.6,112.8,58.6,55.4,49.8。
实施例2
3-氨基-3-(3’,4’-二甲氧基苯基)丙酸甲酯
在0℃下,向搅拌着的3-氨基-3-(3’,4’-二甲氧基苯基)丙酸(70.1克,312毫摩尔)在甲醇(400毫升)里的悬浮液滴加入乙酰氯(47.6毫升,667毫摩尔)。过了15分钟后,除去冰浴。使所得的澄清溶液在室温下搅拌2小时。打开系统,用氮气整夜吹去溶剂。向固体中加入甲醇(50毫升)和醚(300毫升)。所得的悬浮液在室温下搅拌1小时。过滤悬浮液,用醚(100毫升)洗涤固体。使固体溶于碳酸钠(200毫升,饱和)、水(200毫升)和二氯甲烷(250毫升)的混合物里。分离有机层。水相用二氯甲烷(3×250毫升)萃取。合并的有机层在硫酸镁上干燥。除去溶剂得到油状3-氨基-3(3’,4’-二甲氧基苯基)丙酸甲酯(60.2克,得率81%):1HNMR(CDCl3)δ1.77(s,2H,NH2),2.65(d,J=7Hz,2H,CH2),3.68(s,3H,CH3),3.87(s,3H,CH3),3.89(s,3H,CH3),4.39(t,J=Hz,1H,CH),6.81-6.93(m3H,Ar);13CNMR(CDCl3)δ44.00,51.48,52.18,55.72,55.76,109.20,111.02,118.02,137.21,148.11,148.93,172.34。C11H17NO4·0.1H2O的计算值:C59.19;H,7.19;N,5.81。测定值:C,59.38;H,7.09;N5.97。
实施例3
3-氨基-3-(3’,4’-二甲氧基苯基)丙-1-醇
将3-氨基-3-(3’,4’-二甲氧基苯基)丙酸酯(4.12克,17.2毫摩尔)在甲醇(50毫升)里的溶液慢慢加到搅拌着的氢硼化钠(6.51克,17.2毫摩尔)里。在最初的沸腾停止后,使混合物回流1小时。通过TLC(20%乙酸乙酯/己烷,紫外)监测反应进程,1小时后完成。冷却反应混合物,然后加入20毫升水。真空除去甲醇,得到胶体,用二氯甲烷(3×20毫升)萃取。合并的萃取物经硫酸镁干燥,浓缩得到油状物,经冰冻形成蜡状固体,经真空干燥(60℃,<1mm)得到3.30克(86%)白色固体产物。
1H NMR(CDCl3)δ6.91-6.78(m,3H),4.15-4.04(m,1H),3.89(s,3H),3.88(s,3H),3.84-3.71(s,2H),3.91-2.45(宽m,1H),1.95-1.78(m,2H)。
实施例4
3-氨基-3-(3’,4’-二甲氧基苯基)-1-丙醇
在0℃和搅拌下向氢硼化钠(94.18克,2.49毫摩尔)固体里加入甲醇(50毫升)。在0℃下,1小时里向该混合物加入3-氨基-3(3’,4’-二甲氧基苯基)丙酸甲酯(59.5克,249毫摩尔)在甲醇(950毫升)里的溶液。使混合物在冰水浴里搅拌,直至反应混合物的温度保持在35℃或更低达30分钟。(小心:若冰水浴除去得太早,会发生极厉害的放热反应)。然后除去水浴,使溶液回流16小时。让溶液冷却到室温。在0℃下向该溶液里加入水(300毫升),然后加入二氯甲烷(250毫升)。过滤所得的悬浮液。真空除去一半滤液。所得的溶液溶于二氯甲烷(500毫升)和水(300毫升)。分离有机层。水相用二氯甲烷(3×500毫升)萃取。合并的有机层用盐水(100毫升)洗涤,用硫酸镁干燥。除去溶剂得到油状物。所得的油状物真空干燥得到3-氨基-3(3’,4’-二甲氧基苯基)-1-丙醇的白色固体(42.15克;80%得率);熔点63.5-65.5℃;
1HNMR(CDCl3)δ6.91-6.78(m,3H),4.15-4.04(m,1H),3.89(s,3H),3.88(s,3H),3.84-3.71(s,2H),2.91-2.45(m,1H),1.95-1.78(m,2H);C11H17NO3的计算值:C,62.54;H,8.11;N,6.63。测定值:C,62.01;H,7.80;N,6.49。
实施例5
3-苯二甲酰亚氨基-3-(3’,4’-二甲氧基苯基)-丙-1-醇
使3-氨基-3(3’,4’-二甲氧基苯基)-丙-1-醇(1.11克,5毫摩尔)和邻苯二甲酸酐(0.74克,5毫摩尔)混合物一起熔融,搅拌5分钟。冷却后,形成绿色/黄草色半固体,在醚里搅拌得到1.62克(95%)白色固体粗制品。使粗制品经快速色谱层析纯化(硅胶,40%乙酸乙酯/二氯甲烷)得到1.25克(73%)白色固体产品。
1H NMR(CDCl3)δ7.85-7.63(m,4H),7.18-7.07(m,2H),6.86-6.76(m,1H),5.62-5.49(m,1H),3.88(s,3H),3.85(s,3H),3.79-3.63(m,2H),2.89-2.71(m,1H),2.64-2.47(m,′H),1.87-1.73(brm,1H)。13C NMR(CDCl3)δ168.5,148.8,148.6,133.9,131.8,131.7,123.2,120.7,111.6,110.8,59.8,55.0,55.8,51.4,33.9。C19H19NO5的计算值,理论上为:C,66.85;H,5.61;N,4.10.测定值:C,66.70;H,5.60;N,4.60。HPLC100%。
实施例6
3-氨基-3-(3’-乙氧基-4’-甲氧基苯基)丙酸
在45℃下加热3-乙氧基-4-甲氧基苯甲醛(119.5克,664毫摩尔)和乙酸铵(148.3克,1.92毫摩尔)在乙醇(300毫升,95%)里的搅拌着的混合物。向混合物里加入丙二酸(69克,664毫摩尔),然后加入乙醇(100毫升,95%)。使混合物回流18小时。让混合物冷却到室温,并搅拌2小时。过滤悬浮液,用冷乙醇(5×50毫升)洗涤固体,得到3-氨基-3-(3’-乙氧基-4’-甲氧基苯基)丙酸的白色固体在真空烘箱里干燥过夜:(94.75克,60%得率),熔点,224.0-225.5℃;1HNMR(D2O/NaOD)δ1.41(t,J=7Hz,3H,CH3),2.52-2.56(m,2H,CH2),3.83(s,3H,CH3),4.14(q,J=7Hz,2H,CH2),4.19(t,J=7Hz,1H,NCH),6.98-7.04(m,3H,Ar);13C NMR(D2O/NaOD)δ16.75,49.81,55.45,58.46,67.63,114.17,114.71,121.76,140.69,149.91,150.09,182.97;分析:C12H17NO4的计算值:C,60.24;H,7.16;N,5.85。测定值:C,60.21;H,7.12;N,5.88。
实施例7
3-氨基-3-(3’-乙氧基-4’-甲氧基苯基)丙酸甲酯
在0℃下,向搅拌着的3-氨基-3-(3’-乙氧基-4’-甲氧基苯基)丙酸(89.47克,374.4毫摩尔)在甲醇(500毫升)里的悬浮液滴加入乙酰氯(54毫升,757毫摩尔)。过了15分钟后,除去冰浴。使所得的澄清溶液在室温下搅拌2小时。打开系统,用氮气整夜吹去溶剂。向固体中加入甲醇(50毫升)和醚(300毫升)。所得的悬浮液在室温下搅拌1小时。过滤悬浮液,用醚(100毫升)洗涤固体。使固体溶于饱和碳酸钠水溶液(200毫升)、水(200毫升)和二氯甲烷(250毫升)的混合物里。分离有机层。水相用二氯甲烷(3×250毫升)萃取。合并的有机层在硫酸镁上干燥。除去溶剂得到3-氨基-3(3’-乙氧基-4’-甲氧基苯基)丙酸甲酯的油状物(80.84克,得率85%):1H NMR(CDCl3)δ1.46(t,J=7Hz,3H,Ch3),1.75(s,2H,NH2),2.64(d,J=7Hz,2H,CH2),3.68(s,3H,CH3),3.86(s,3H,CH3),4.10(q,J=7Hz,2H,NH2),5.36(t,J=7Hz,1H,NCH),6.80-6.91(m,3H,Ar);13C NMR(CDCl3)δ14.74,44.09,51.55,52.23,55.91,64.23,110.77,111.39,118.07,137.21,148.31,148.49,172.44.
实施例8
3-氨基-3-(3’-乙氧基-4’-甲氧基苯基)-1-丙醇
在0℃和搅拌下向氢硼化钠(121克,3.19毫摩尔)固体里加入甲醇(50毫升)。在0℃下,1小时里向该混合物加入3-氨基-3(3’-乙氧基-,4’-甲氧基苯基)丙酸甲酯(80.84克,319.5毫摩尔)在甲醇(1500ml)里的溶液。使混合物在冰水浴里搅拌,直至反应混合物的温度保持在35℃或更低达30分钟。(过早除去冰浴会发生极厉害的放热反应)。然后除去水浴,使溶液回流16小时。让溶液冷却到室温。在0℃下向该溶液里加入水(300毫升),然后加入二氯甲烷(250毫升)。过滤所得的悬浮液。真空除去一半滤液。所得的溶液溶于二氯甲烷(500毫升)和水(300毫升)。分离有机层。水相用二氯甲烷(3×500毫升)萃取。合并的有机层用盐水(100毫升)洗涤,用硫酸镁干燥。除去溶剂得到油状物。所得的油状物真空干燥得到3-氨基-3(3’-乙氧基-4’-甲氧基苯基)-1-丙醇的白色固体(53克;74%得率);
1H NMR(CDCl3)δ1.47(t,J=6.8Hz,3H,CH3),1.84-1.90(m,2H,CH2),2.58(br s,3H,NH2,OH),3.78(t,J=5.5Hz,2H,OCH2),3.86(s,3H,CH3),4.04-4.15(m,3H,CH2,NCH),6.84(s,3H,Ar);13C NMR(CDCl3)δ14.74,39.78,55.84,55.84,55.91,61.86,64.28,110.55,111.47,117.58,138.82,148.27,148.32;分析:C12H19NO3的计算值:C,63.98;H,8.50;N,6.22。测定值:C,63.73;H,8.44;N,6.14。
实施例9
3-(3’-乙氧基-4’-甲氧基苯基)-3-苯二甲酰亚氨基-1-丙醇
在室温下使3-氨基-3-(3’-乙氧基-4’-甲氧基苯基)-1-丙醇(8.4克,37.3毫摩尔)和碳酸钠(3.95克,37.3毫摩尔)在乙腈和水(各个为40毫升)里的混合物搅拌15分钟。向该溶液里加入N-乙酯基苯二甲酰亚氨基的固体(8.18克,37.3毫摩尔)。20分钟后,真空除去乙腈。用二氯甲烷(3×50毫升)萃取水溶液。合并的有机层用盐酸(40毫升,1N)洗涤,用硫酸镁干燥。除去溶剂得到绿色油。向油中加入醚(25毫升),然后加入己烷(2毫升)。形成了悬浮液,过滤固体得到3-(3’-乙氧基-4’-甲氧基苯基)-3-苯二甲酰亚氨基-1-丙醇的白色固体,1克。母液经色谱层析纯化(硅胶500克,10,15,20%EtOAc/CH2Cl2),得到3-(3’-乙氧基-4’-甲氧基苯基)-3-苯二甲酰亚氨基-1-丙醇的固体,2.54克,总得率为3.54克(27%得率);熔点112.0-114.0℃;1H NMR(CDCl3)δ1.45(t,J=7Hz,3H,CH3),1.59-1.65(br s,1H,OH),2.49-2.59(m,1H,CHH),2.71-2.83(m,1H,CHH),3.66-3.69(m,2H,OCH2),3.84(s,3H,CH3),4.10(q,J=7Hz,2H,MeCH2),5.53(dd,J=6.5,9.5Hz,1H,NCH),6.81(d,J=8.2Hz,1H,Ar),7.09-7.27(m,2H,Ar),7.66-7.72(m,2H,Ar),7.76-7.82(m,2H,Ar);13CNMR(CDCl3)δ14.72,33.86,51.88,59.84,64.34,111.16,113.05,120.68,123.20,131.64,131.86,133.94,148.17,148.97,168.49;分析:C20H21NO5:C,67.59;H,5.96;N,3.94.测定值:C,65.40;H,5.81;N,3.84。
实施例10
3-氨基-3-(3-环戊基氧基-4-甲氧基苯基)丙酸
在45℃下加热搅拌着的3-环戊氧基-4-甲氧基苯甲醛(54.9克,249毫摩尔)和乙酸铵(58.2克,784毫摩尔)在乙醇(200毫升,95%)里的混合物。向该黄色悬浮液加入丙二酸(25.9克,249毫摩尔)的固体。使混合物回流16小时。使混合物冷却到室温。过滤悬浮液,固体用冷乙醇(200毫升)洗涤,直至脱去颜色。在真空烘箱里干燥白色固体(45℃,ltorr)以得到3-氨基-3-(3-环戊基氧基-4-甲氧基苯基)丙酸的白色固体(41.97克,得率61%);熔点,234.0-235.0℃;1HNMR(CDCl3)δ1.62-1.98(m,8H,C5H8),2.53(d,J=7Hz,2H,CH2),3.80(s,3H,CH3),4.21(t,J=7Hz,1H,OCH),4.84-4.86(m,1H,NCH),6.96-7.03(m,3H,Ar);13C NMR(CDCl3)δ26.33,34.97,49.78,55.32,58.48,83.99,114.99,116.04,121.63,140.63,149.12,150.75,182.87;分析:C15H21NO4的计算值:C,64.50;H,7.58;N,5.01。测定值:C,64.54;H,7.68;N,4.93。
实施例11
3-氨基-3-(3’-环戊氧基-4’-甲氧基苯基)丙酸甲酯
在0℃下,向搅拌着的3-氨基-3-(3’-环戊氧基-4’-甲氧基苯基)丙酸(30克,279毫摩尔)在甲醇(150毫升)里的悬浮液滴加入乙酰氯(15.2毫升,212毫摩尔)。过了15分钟后,除去冰浴。使所得的澄清溶液在室温下搅拌2小时。打开系统,用氮气整夜吹去溶剂。向固体中加入甲醇(50毫升)和醚(300毫升)。所得的悬浮液在室温下搅拌1小时。过滤悬浮液,用醚(100毫升)洗涤固体。使固体溶于碳酸钠水溶液(200毫升,饱和)、水(200毫升)和二氯甲烷(250毫升)的混合物里。分离有机层。水相用二氯甲烷(3×250毫升)萃取。合并的有机层在硫酸镁上干燥。除去溶剂得到3-氨基-3(3’-环戊氧基-4’-甲氧基苯基)丙酸甲酯的油状物(28.41克,得率90%):1H NMR(CDCl3)δ156-1.97(m,10H,NH2,C5H8),2.62(d,J=7Hz,2H,CH2),3.67(s,3H,CH3),3.81(s,3H,CH3),4.34(t,J=6.8Hz,1H,CH),4.74-4.79(dd,J=5,8.5Hz,1H,NCH),6.78-6.90(m,3H,Ar);13C NMR(CDCl3)δ23.97,32.76,44.17,51.58,52.25,56.07,80.37,111.96,113.08,119.08,137.25,147.72,149.27,172.49。
实施例12
3-氨基-3-(3’-环戊氧基-4’-甲氧基苯基)-1-丙醇
在0℃和搅拌下向氢硼化钠(37克,978毫摩尔)固体里加入甲醇(50毫升)。在0℃下,1小时里向该混合物加入3-氨基-3(3’-环戊氧基-4’-甲氧基苯基)丙酸甲酯(27克,92.2毫摩尔)在甲醇(500ml)里的溶液。使混合物在冰水浴里搅拌,直至反应混合物的温度保持在35℃或更低达30分钟。(注意:若过早除去冰浴会发生极厉害的放热反应)。然后除去水浴,使溶液回流16小时。让溶液冷却到室温。在0℃下向该溶液里加入水(125毫升),然后加入二氯甲烷(250毫升)。过滤所得的悬浮液。真空除去一半滤液。所得的溶液溶于二氯甲烷(250毫升)和水(200毫升)。分离有机层。水相用二氯甲烷(3×250毫升)萃取。合并的有机层用盐水(100毫升)洗涤,用硫酸镁干燥。除去溶剂得到油状物。所得的油状物真空干燥得到3-氨基-3(3’-环戊氧基-4’-甲氧基苯基)-1-丙醇的白色固体(22.3克;91%得率);熔点,216.0-217.5℃;1HNMR(CDCl3)δ1.52-1.68(m,2H,CH2),1.76-1.91(m,8H,C5H8),2.92(brs,3H,NH2,OH),3.76(t,J=5.5Hz,2H,CH2),3.82(s,3H,CH3),4.06(t,J=Hz,1H,OCH),4.76-4.79(m,1H,NCH),6.82-6.84(m,3H,Ar);13CNMR(CDCl3)δ23.96,32.75,39.91,5.59,56.10,61.62,80.46,112.11,112.99,117.75,138.65,147.74,149.12;分析:C15H23NO3·0.05CH2Cl2的计算值:C,67.05;H,8.64;N,5.20。测定值:C,67.02;H,8.41;N,5.08。
实施例13
3-(3’-环戊氧基-4’-甲氧基苯基)-3-苯二甲酰基亚氨基-1-丙醇
用加热枪使3-氨基-3-(3’-环戊氧基-4’-甲氧基苯基)-1-丙醇(4.31克,16.24毫摩尔)和邻苯二甲酸酐(2.41克,16.27毫摩尔)混合物熔融6分钟。让该混合物冷却到室温。色谱层析(硅胶100克,1:5EtOAc:CH2Cl2)得到3-(3’-环戊氧基-4’-甲氧基苯基)-3-苯二甲酰基亚氨基-1-丙醇的固体(4.97克,得率77%);熔点,59.0-61.0℃;1H NMR(CDCl3)δ1.56-1.98(m,9H,OH,C5H8),2.48-2.59(m,1H,CHH),2.71-2.83(m,1H,CHH),3.66-3.74(m,2H,OCH2),3.80(s,3H,CH3),4.74-4.80(m,1H,CHH),3.66-3.74(m,2H,OCH2),3.80(s,3H,CH3),4.74-4.80(m,1H,CH),5.51(dd,J=6.5,9.4Hz,1H,NCH),6.78(d,J=8.3Hz,1H,Ar),7.05-7.09(m,1H,Ar),7.16-7.17(m,1H,Ar),7.64-7.70(m,2H,Ar),7.75-7.81(m,2H,Ar);13C NMR(CDCl3)δ24.02,32.71,38.84,51.44,55.94,59.75,80.35,111.58,115.06,120.54,123.12,131.60,131.80,133.86,147.48,149.55,168.43;分析,C23H25NO5的计算值:C,69.86;H,6.37;N,3.54。测定值:C,69.51;H,6.41;N,3.54。
实施例14
3-(3’-乙氧基-4’-甲氧基苯基)-3-(3”-硝基-苯二甲酰基亚氨基)-1-丙醇
用加热枪使3-氨基-3-(3’-乙氧基-4’-甲氧基苯基)-1-丙醇(4.0克,17.8毫摩尔)和3-硝基邻苯二甲酸酐(3.44克,19.8毫摩尔)混合物熔融6分钟。让该混合物冷却到室温。色谱层析(硅胶80克,1∶5EtOAc:CH2Cl2)得到3-(3’-乙氧基-4’-甲氧基苯基)-3-(3”-硝基-苯二甲酰基亚氨基)-1-丙醇的黄色固体(3.67克,得率52%);熔点,143.0-145.0℃;1H NMR(CDCl3)δ1.47(t,J=7Hz,3H,CH3),1.48-1.52(brs,1H,OH),2.51-2.62(m,1H,CHH),2.72-2.84(m,1H,CHH),3.69-3.73(m,2H,CH2),3.85(s,3H,CH3),4.12(q,J=7Hz,2H,CH2),5.56(dd,J=6.5,9Hz,1H,NCH),6.82(d,J=8Hz,1H,Ar),7.11-7.15(m,2H,Ar),7.85-7.91(m,1H,Ar),8.06-8.09(m,2H,Ar);;13CNMR(CDCl3)δ14.71,33.51,52.61,55.91,59.87,64.43,111.26,113.08,120.91,123.52,126.91,128.45,130.82,133.97,135.21,145.13,148.27,149.25,163.02,165.97;分析,C20H20N2O7的计算值:C,60.00;H,5.03;N,7.00。测定值:C,59.83;H,4.97;N,6.86。
实施例15
3-(3”-氨基-苯二甲酰基亚氨基)-3-(3’-乙氧基-4’-甲氧基苯基)-1-丙醇
在氢气下(50psi)振摇3-(3’-乙氧基-4’-甲氧基苯基)-3-(3”-硝基苯基二甲酰基亚氨基)-1-丙醇(600毫克,1.5毫摩尔)和Pd/C(100毫克,10%)在乙酸乙酯(40毫升)里的混合物达16小时。使混合物经硅藻土垫过滤。除去溶剂,经色谱层析(硅胶80克,1∶3EtOAc:CH2Cl2)得到3-(3”-氨基-苯二甲酰基亚氨基)-3-(3’-乙氧基-4’-甲氧基苯基)-1-丙醇的黄色固体,(495毫克,得率89%);熔点:81.0-83.0℃;
1H NMR(CDCl3)δ1.45(t,J=6.8Hz,3H,CH3),1.80(brs,1H,OH),2.45-2.52(m,1H,CHH),2.71-2.80(m,1H,CHH),3.66-3.75(m,2H,OCH2),3.84(s,3H,CH3),4.09(q,J=6.8Hz,2H,CH2),5.23(brs,2H,NH2),5.47(dd,J=6.4,9.8Hz,1H,CH),6.78-6.83(m,2H,Ar),7.07-7,13(m,3H,Ar),7.33-7.39(m,1H,Ar);13C NMR(CDCl3)δ14.72,33.92,50.79,55.87,59.76,64.34,111.03,111.14,112.01,113.07,120.52,121.60,131.94,132.49,135.09,145.24,148.11,148.84,168.76,170.31;分析,C20H20N2O5的计算值:C,64.85,H,5.99;N,7.56。测定值:C,64.44,;H,6.14;N,6.88.
实施例16
3-(3’-乙氧基-4’-甲氧基苯基)-3-(3’,4’,5’,6’-四氢苯二甲酰基亚氨基)-1-丙醇
用加热枪使3-氨基-3-(3’-乙氧基-4’-甲氧基苯基)-1-丙醇(4.0克,17.76毫摩尔)和3,4,5,6-四氢邻苯二甲酸酐(2.80克,18.4毫摩尔)混合物熔融6分钟。让该混合物冷却到室温。色谱层析(硅胶150克,1∶3EtOAc:CH2Cl2)得到3-(3’-乙氧基-4’-甲氧基苯基)-3-(3’,4’,5’,6’-四氢苯二甲酰基亚氨酰基)-1-丙醇的油(4.96克,得率75%);
1H NMR(CDCl3)δ1.45(t,J=6.8Hz,3H,CH3),1.70-1.80(m,4H,CH2CH2),1.91(brs,1H,OH),2.27-2.32(m,4H,CH2CH2),2.41-2.58(m,1H,CHH),2.61-2.68(m,1H,CHH),3.59-3.65(m,2H,CH2),3.84(s,3H,CH3),4.09(q,J=6.9Hz,2H,CH2),5.26(dd,J=6.6,9.5Hz,1H,NCH),6.79(d,J=8Hz,1H,Ar),7.00-7.09(m,2H,Ar);13CNMR(CDCl3)δ14.64,19.83,21.19,34.10,50.90,55.79,59.69,64.24,111.04,112.86,120.41,132.11,141.28,148.01,148.73,171.19;分析,C20H25NO5的计算值:C,66.84;H,7.01;N,3.90。测定值:C,66.89;H,6.84;N,3.77。
实施例17
3-(3’,4’-二甲氧基苯基)-3-(1’-氧基异二氢氮杂茚基)-1-丙醇
在-10℃到15℃(冰-盐浴)下向3-(3’,4’-二甲氧基苯基)-3-(1’-氧基异二氢氮杂茚基)丙酸(3.74g,10.96毫摩尔)在THF(60毫升)里的搅拌的悬浮液中加入在THF中的硼烷(11毫升,1M,11毫摩尔)。让悬浮液慢慢温热到室温,过夜。向所得的澄清溶液里加入水(20毫升),然后加入碳酸钾(6克)。分离有机层。水相用二氯甲烷(2×50毫升)萃取。合并的有机层用碳酸钠(20毫升,饱和)、盐水(20毫升)洗涤,用硫酸镁干燥。除去溶剂,经色谱层析(硅胶,100克,1∶2,1∶1EtOAc/CH2Cl2)得到3-(3’,4’-二甲氧基苯基)-3-(1’-氧基异二氢氮杂茚基)-1-丙醇的油(2.52克,70%)。向油里加入乙醚(6ml)和2滴甲醇。加入己烷直至溶液变浑浊。让混合物搅拌30分钟得到白色固体,过滤固体;熔点,101.5-103.0℃;
1H NMR(CDCl3)δ1.99-2.36(m,3H,CH2,OH),3.49-3.80(m,2H,OCH2),3.85(s,3H,CH3),3.89(s,3H,CH3),3.91(d,J=17.2Hz,1H,CHH),4.19(d,J=17.2Hz,1H,CHH),5.75(dd,J=4,11.5Hz,1H,NCH),6.86-7.00(m,3H,Ar),7.27-7.56(m,3H,Ar),7.86-7.89(m,1H,Ar);13C NMR(CDCl3)δ33.87,46.22,50.61,55.91,56.01,58.55,111.04,111.73,119.66,122.81,123.89,128.64,131.33,131.56,132.09,141.35,148.81,148.24,169.45;分析,C19H21NO4的计算值:C,69.71;H,6.47;N,4.28。测定值:C,69.51;H,6.27;N,4.12。
实施例18
3-(3’,4’-二甲氧基苯基)-1-甲氧基-3-苯二甲酰亚氨基丙烷
在室温下,向3-(3’,4’-二甲氧基苯基)-3-苯二甲酰基亚氨基-1-丙醇(1.02克,2.99毫摩尔)和碘甲烷(0.37ml,5.94毫摩尔)在THF(10毫升)里的溶液里加入NaH(358毫克,60%8.95毫摩尔)。在室温下使混合物搅拌45分钟,然后回流2小时。向冷却的混合物里加入数滴NH4Cl,然后加入HCl(1N,25毫升)。分离有机层。用乙酸乙酯(3×25毫升)萃取水相。合并的有机层用盐水(25毫升)洗涤,用硫酸镁干燥。除去溶剂,经色谱层析(硅胶100克,1∶5EtOAc:己烷)得到3-(3’,4’-二甲氧基苯基)-1-甲氧基-3-苯二甲酰亚氨基丙烷的白色固体(750毫克,得率71%):熔点,91.5-92.5℃;
1H NMR(CDCl3)δ2.50-2.59(m,1H,CHH),2.70-2.86(m,1H,CHH),3.27(s,3H,CH3),3.39(t,J=6Hz,2H,CH2),3.85(s,3H,CH3),3.88(s,3H,CH3),5.49(dd,J=6.8,9.2Hz,1H,NCH),6.81(d,J=8Hz,1H,Ar2),7.11-7.15(m,2H,Ar),7.67-7.72(m,2H,Ar);13C NMR(CDCl3)δ31.29,51.93,55.80,58.69,69.64,110.84,115.56,120.62,123.12,131.90,132.03,133.84,148.58,148.81,168.38;分析,C20H21NO5的计算值:C,67.59;H,5.96;N,3.94。测定值:C,67.54;H,5.97;N,3.84。
实施例19
3-(3’-乙氧基-4’-甲氧基苯基)-1-甲氧基-3-苯二甲酰亚氨基丙烷
在室温下,向搅拌着的氢化钠(110mg,60%,2.75毫摩尔)在THF(8ml)中的混合物里加入碘甲烷(0.54克,3.78毫摩尔),然后加入3-(3’-乙氧基-4’-甲氧基苯基)-3-苯二甲酰基亚氨基-1-丙醇(850毫克,2.39毫摩尔)。在室温下使混合物搅拌15小时。向混合物里加入NH4Cl(20毫升,饱和)。分离有机层。用二氯甲烷(2×50毫升)萃取水相。合并的有机层用盐水(50毫升)洗涤,用硫酸镁干燥。除去溶剂,经色谱层析(硅胶200克,1∶12EtOAc:CH2Cl2)得到3-(3’-乙氧基-4’-甲氧基苯基)-1-甲氧基-3-苯二甲酰亚氨基丙烷的油(360毫克,得率41%)。在室温下放置过周末,所得的油固化:熔点,67.5-70.0℃;
1H NMR(CDCl3)δ1.45(t,J=7Hz,3H,CH3),2.50-2.60(m,1H,CHH),2.71-2.85(m,1H,CHH),3.26(s,3H,CH3),3.39(t,J=6Hz,2H,CH2),3.84(s,3H,CH3),4.10(q,J=7Hz,2H,CH2),5.47(dd,J=7,9.3Hz,1H,NCH),6.81(d,J=Hz,1H,Ar),7.09-7.16(m,2H,Ar),7.66-7.69(m,2H,Ar),7.76-7.82(m,2H,Ar);13C NMR(CDCl3)δ(APT)14.67(CH3),31.23(CH2),51.89(CH),58.63(CH),64.25(CH2),69.62(CH2),111.13(CH),112.98(CH),120.58(CH),123.06(CH),131.87(C),131.92(C),133.78(CH),148.09(C),148.84(C),168.33(C);分析,C21H23NO50.05H2O的计算值:C,67.66;H,6.23;N,3.75。测定值:C,67.91;H,6.00;N,3.71。
实施例20
3-(3’-环戊氧基-4’-甲氧基苯基)-1-甲氧基-3-苯二甲酰亚氨基丙烷
在室温下,向3-(3’-环戊氧基-4’-甲氧基苯基)-3-苯二甲酰基亚氨基-1-丙醇(786毫克,1.99毫摩尔)和碘甲烷(0.25ml,4.0毫摩尔)在THF(10毫升)里的溶液里加入NaH(160毫克,60%4.0毫摩尔)。在室温下使该混合物搅拌1小时,然后回流35分钟。让混合物冷却到室温。向所得的混合物里加入数滴NH4Cl,然后加入HCl(1N,25毫升)。分离有机层。用乙酸乙酯(3×30毫升)萃取水相。合并的有机层用盐水(25毫升)洗涤,用硫酸钠干燥。除去溶剂,经色谱层析(硅胶100克,1∶5EtOAc:己烷)得到3-(3’-环戊氧基-4’-甲氧基苯基)-1-甲氧基-3-苯二甲酰亚氨基丙烷的油(510毫克,得率63%)。在室温下油固化得到白色固体:熔点,77.5-80.0℃;
1H NMR(CDCl3)δ1.58-1.96(m,8H,C5H8),2.45-2.55(m,1H,CHH),2.70-2.85(m,1H,CHH),3.26(s,3H,CH3),3.39(t,J=6Hz,2H,CH2),3.81(s,3H,CH3),4.78-4.80(m,1H,OCH),5.46(dd,J=7,9.3Hz,1H,NCH),6.79(d,J=8.3Hz,1H,Ar),7.06-7.10(m,1H,Ar),7.17-7.26(m,1H,Ar),7.67-7.69(m,2H,Ar),7.78-7.82(m,2H,Ar);13C NMR(CDCl3)δ24.08,31.30,32.76,51.94,56.00,58.71,69.71,80.37,111.63,115.09,120.53,123.12,131.92,131.96,133.81,147.53,149.55,169.37;分析,C24H27NO5的计算值:C,70.40;H,6.65;N,3.42。测定值:C,70.32;H,6.61;N,3.31。
实施例21
1-乙氧基-3-(3’-乙氧基-4’-甲氧基苯基)-3-苯二甲酰基亚氨基丙烷在室温下,向3-(3’-乙氧基-4’-甲氧基苯基)-3-苯二甲酰基亚氨基-1-丙醇(1克,2.82毫摩尔)、溴乙烷(0.42毫升,5.63毫摩尔)和叔丁基碘化铵(200mg,0.54毫摩尔)在THF(10毫升)里的搅拌着的溶液里加入NaH(270毫克,60%6.75毫摩尔)。在室温下使混合物搅拌45分钟,然后加热至回流4小时。向所得的混合物里加入数滴NH4Cl,然后加入HCl(1N,25毫升)。分离有机层。用乙酸乙酯(3×25毫升)萃取水相。合并的有机层用盐水(25毫升)洗涤,用硫酸镁干燥。除去溶剂,经色谱层析(硅胶100克,1∶5EtOAc:己烷)得到1-乙氧基-3-(3’-乙氧基-4’-甲氧基苯基)-3-苯二甲酰亚氨基丙烷的油(800毫克,得率74%)。
1H NMR(CDCl3)δ1.06(t,J=7Hz,3H,CH3),1.46(t,J=7Hz,3H,CH3),2.46-2.58(m,1H,CHH),2.75-2.95(m,1H,CHH),3.37(1,J=7Hz,2H,CH2),3.44(q,J=7Hz,2H,CH2),3.85(s,3H,CH3),4.12(q,J=7Hz,2H,CH2),5.49(dd,J=6.4,9.5Hz,1H,NCH),6.81(d,J=8.2Hz,1H,Ar),7.10-7.48(m,2H,Ar),7.68-7.72(m,2H,Ar),7.77-7.83(m,2H,Ar);13C NMR(CDCl3)δ14.73,14.98,31.31,52.24,55.89,64.30,66.33,67.73,111.1,112.99,120.61,123.11,132.00,132.09,133.80,148.11,148.84,168.44;分析,C22H25NO5的计算值:C,68.91;H,6.57;N,3.65。测定值:C,68.77;H,6.47;N,3.57。
实施例22
1-苄基氧基-3-(3’-乙氧基-4’-甲氧基苯基)-3-苯二甲酰基亚氨基丙烷
在室温下,向3-(3’-乙氧基-4’-甲氧基苯基)-3-苯二甲酰基亚氨基-1-丙醇(680毫克,1.92毫摩尔)、苄基溴(0.46毫升,3.86毫摩尔)和叔丁基碘化铵(80mg,0.21毫摩尔)在THF(20毫升)里的搅拌着的溶液里加入NaH(240毫克,60%6.0毫摩尔)。在室温下使混合物搅拌15小时。向该混合物里加入数滴NH4Cl,然后加入HCl(1N,25毫升)。分离有机层。用乙酸乙酯(3×25毫升)萃取水相。合并的有机层用盐水(25毫升)洗涤,用硫酸镁干燥。除去溶剂,经色谱层析(硅胶100克,1∶5EtOAc:己烷)得到1-苄基氧基-3-(3’-乙氧基-4’-甲氧基苯基)-3-苯二甲酰基亚氨基丙烷的油(510毫克,得率60%)。
1H NMR(CDCl3)δ1.46(t,J=6.9Hz,3H,CH3),2.51-2.59(m,1H,CHH),2.86-2.96(m,1H,CHH),3.51(t,J=5.5Hz,CH2),3.85(s,3H,CH3),4.10(q,J=7Hz,CH2),4.43(s,2H,PhCH2),5.54(dd,J=6.5,9.5Hz,1H,NCH),6.80(d,J=8Hz,1H,Ar),7.09-7.27(m,7H,Ar),7.65-7.79(m,4H,Ar);13C NMR(CDCl3)δ14.73,31.37,52.12,55.88,64.29,67.31,73.10,111.11,112.95,120.59,123.09,127.42,127.62,128.22,131.92,132.09,133.77,138.09,148.12,148.84,168.42;分析,C27H27NO5的计算值:C,72.79;H,6.11;N,3.14。测定值:C,72.66;H,6.32;N,3.16。
实施例23
3-(3’,4’-二甲氧基苯基)-1-乙氧基-3-(1’-氧基异二氢氮杂茚基)丙烷
在室温下,向搅拌着的3-(3’,4’-二甲氧基苯基)-3-(1’-氧基异二氢氮杂茚基)-1-丙醇(500毫克,1.53毫摩尔)、溴乙烷(0.27毫升,3.62毫摩尔)和叔丁基碘化铵(60mg,0.16毫摩尔)在THF(10毫升)里的溶液里加入NaH(160毫克,60%4.0毫摩尔)。在室温下使混合物搅拌4小时。向该混合物里加入数滴NH4Cl(20毫升,饱和)。分离有机层。用二氯乙烷(2×25毫升)萃取水相。合并的有机层用硫酸镁干燥。除去溶剂,经色谱层析(硅胶120克,1∶6EtOAc:己烷)得到3-(3’,4’-二甲氧基苯基)-1-乙氧基-3-(1’-氧基异二氢氮杂茚基)丙烷的油(420毫克,得率77%)。
1H NMR(CDCl3)δ1.09(t,J=7Hz,3H,CH3),22.35(m,2H,CH2),3.35-3.58(m,4H,Ch2OCH2),3.84(s,3H,Ch3),3.86(s,3H,Ch3),4.00(d,J=16.8Hz,1H,NCHH),4.35(d,J=16.8Hz,1H,NCHH),5.66(dd,J=6,9.3Hz,1H,NCH),6.82-6.98(m,3H,Ar),7.35-7.53(m,3H,Ar),7.84-7.88(m,1H,Ar);13C NMR(CDCl3)δ15.02,31.62,45.82,51.51,55.82,55.90,66.39,67.86,110.90,111.27,119.15,122.68,123.71,127.86,131.16,132.28,132.73,141.28,148.49,149.08,168.38;分析,C27H27NO5的计算值:C,69.90;H,7.15;N,3.88。测定值:C,69.69;H,6.80;N,3.73。
实施例24
用下列方式可制备每片含50毫克活性组分的片剂:
构成(1000片)
活性组分 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 适量
首先使固体组分经0.6mm筛网宽度的筛子。然后混合活性组分、乳糖、滑石粉、硬脂酸镁和一半的淀粉。另一半淀粉悬浮在40毫升水中,将该悬浮液加到聚乙二醇在100毫升水里的沸腾溶液里。所得的糊状物被加到粉状的物质里,使混合物制粒,需要时加入水。使颗粒在35℃下干燥过夜,过1.2mm筛孔的筛子,将它们压制成约6毫米直径、双面都凹的片剂。
实施例25
用下列方式可制备每片含100毫克活性组分的片剂:
构成(1000片)
活性组分 100.0g
乳糖 100.0g
小麦淀粉 47.0g
硬脂酸镁 3.0g
首先使固体组分经0.6mm筛网宽度的筛子。然后混合活性组分、乳糖、滑石粉、硬脂酸镁和一半的淀粉。另一半淀粉悬浮在40毫升水中,将该悬浮液加到100毫升沸水里。所得的糊状物被加到粉状的物质里,使混合物制粒,需要时加入水。使颗粒在35℃下干燥过夜,过1.2mm筛孔的筛子,将它们压制成约6毫米直径、双面都凹的片剂。
实施例26
用下列方式可制备每片含75毫克活性组分的片剂:
构成(1000片)
活性组分 75.0g
甘露醇 230.0g
乳糖 150.0g
滑石粉 21.0g
甘氨酸 12.5g
硬脂酸 10.0g
糖精 1.5g
5%明胶溶液 适量
所有的固体组分经0.25mm筛孔宽度的筛子。使甘露醇和乳糖混合,加入明胶溶液下制粒,过2mm筛孔的筛子,在50℃下干燥,再过1.7mm筛孔宽度的筛子。仔细地混合活性组分、甘氨酸和糖精,加入甘露醇、乳糖的颗粒化物、硬脂酸和滑石粉,将整个组成压制成约10毫米直径、双面都凹的、在上表面上有断裂凹槽的片剂。
实施例27
用下列方法制备每片含10毫克活性组分的片剂:
组成(1000片)
活性组分 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 适量
使固体组分首先经0.6mm筛孔宽度的筛子。然后使活性组分、乳糖、滑石粉、硬脂酸镁和一半淀粉紧密地混合。另一半淀粉悬浮在65毫升水里,将该悬浮液加到聚乙二醇在260毫升水里的沸腾溶液里,所得的糊状物被加到粉状的物质里,使整个组成混合并制粒,需要时加入水。使颗粒在35℃下干燥过夜,经1.2mm筛孔宽度过筛,并压制成约10毫米直径、双面都凹的、上表面有凹痕的片剂。
实施例28
用下列方法可制备明胶干燥填充胶囊,每粒含100毫克活性组分:
组成(1000个胶囊)
活性组分 100.0g
微晶纤维素 30.0g
月桂酸硫酸钠 2.0g
硬脂酸镁 8.0g
使月桂酸硫酸钠过0.2mm筛孔的筛,筛入活性组分中,使两种组分密切混合10分钟。然后通过0.9mm筛孔的筛子加入微晶纤维素,使整个组分密切混合10分钟。最后,通过0.8mm筛孔的筛加入硬脂酸镁,再混合3分钟后,将混合物以每份140毫克填入0号(伸长型)明胶干燥填充胶囊里。
实施例29
用下列方法可制备0.2%注射液或灌注液:
活性组分 5.0g
氯化钠 22.5g
磷酸盐缓冲液pH7.4 300.0g
软化水 加到2500.0毫升
使活性组分溶于1000毫升水,经微滤器过滤。加入缓冲液,用水使体积达到2500毫升。为了制备单剂,在每个玻璃安瓿里加入1.0或2.5毫升的液体(每个分别含2.0或5.0毫升活性组分)。
Claims (15)
2.根据权利要求1所述的化合物,其中所述化合物为外消旋体或光学活性异构体。
3.根据权利要求1所述的化合物,其中R4是-CO-,R1是3,4-二乙氧基苯基。
4.根据权利要求1所述的化合物,其中R4是-CO-,R1是3-乙氧基-4-甲氧基苯基。
5.根据权利要求1所述的化合物,其中R4是-CO-,R1是3-环戊氧基-4-甲氧基苯基。
6.根据权利要求1所述的化合物,其中R1是3,4-二甲氧基苯基。
7.根据权利要求1所述的化合物,其中R1是3-乙氧基-4-甲氧基苯基
8.根据权利要求1所述的化合物,其中R1是3-异丙氧基-4-甲氧基苯基。
9.根据权利要求1所述的化合物,其中R1是3-环戊氧基-4-甲氧基苯基。
10.根据权利要求1所述的化合物,其中R1是3-乙氧基-4-乙苯基。
11.根据权利要求1所述的化合物,其中所述的化合物是选自下列化合物中的一种:
3-(3’-乙氧基-4’-甲氧基苯基)-3-苯二甲酰亚氨基-1-丙醇;
3-(3’-环戊氧基-4’-甲氧基苯基)-3-苯二甲酰基亚氨基-1-丙醇;
3-(3’-乙氧基-4’-甲氧基苯基)-3-(3”-硝基-苯二甲酰基亚氨基)-1-丙醇;
3-(3”-氨基-苯二甲酰基亚氨基)-3-(3’-乙氧基-4’-甲氧基苯基)-1-丙醇;
3-(3’-乙氧基-4’-甲氧基苯基)-3-(3’,4’,5’,6’-四氢苯二甲酰基亚氨基)-1-丙醇;
3-(3’,4’-二甲氧基苯基)-3-(1’-氧基异二氢氮杂茚基)-1-丙醇;
3-(3’,4’-二甲氧基苯基)-1-甲氧基-3-苯二甲酰亚氨基丙烷;
3-(3’-乙氧基-4’-甲氧基苯基)-1-甲氧基-3-苯二甲酰亚氨基丙炕;
3-(3’-环戊氧基-4’-甲氧基苯基)-1-甲氧基-3-苯二甲酰亚氨基丙烷;
1-乙氧基-3-(3’-乙氧基-4’-甲氧基苯基)-3-苯二甲酰基亚氨基丙烷;
1-苄基氧基-3-(3’-乙氧基-4’-甲氧基苯基)-3-苯二甲酰基亚氨基丙烷;或
3-(3’,4’-二甲氧基苯基)-1-乙氧基-3-(1’-氧基异二氢氮杂茚基)丙烷。
12.如权利要求1-10任一所述的化合物在制备降低哺乳动物TNFα水平的药物中的应用。
13.如权利要求1-10任一所述的化合物在制备抑制哺乳动物中TNFα-活化的逆转录病毒的药物中的应用。
14.如权利要求1-10任一所述的化合物在制备抑制哺乳动物磷酸二酯酶的药物中的应用。
15.一种药物组合物,它包含单剂或多剂有效地抑制TNFα量的如权利要求1-10任一所述的化合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/759,788 US5703098A (en) | 1994-12-30 | 1996-12-03 | Immunotherapeutic imides/amides |
US08/759,788 | 1996-12-03 |
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CN1254333A CN1254333A (zh) | 2000-05-24 |
CN100372836C true CN100372836C (zh) | 2008-03-05 |
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CNB971803234A Expired - Fee Related CN100372836C (zh) | 1996-12-03 | 1997-12-03 | 新的免疫治疗剂亚酰胺/酰胺类 |
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US (1) | US5703098A (zh) |
EP (1) | EP0942902A2 (zh) |
JP (1) | JP2001506611A (zh) |
KR (1) | KR20000069374A (zh) |
CN (1) | CN100372836C (zh) |
AU (1) | AU735540B2 (zh) |
CA (1) | CA2273002A1 (zh) |
FI (1) | FI991187A (zh) |
HU (1) | HUP0000232A3 (zh) |
NZ (1) | NZ336713A (zh) |
RU (1) | RU2177471C2 (zh) |
SK (1) | SK73299A3 (zh) |
WO (1) | WO1998024763A2 (zh) |
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- 1997-12-03 JP JP52584498A patent/JP2001506611A/ja not_active Ceased
- 1997-12-03 AU AU55945/98A patent/AU735540B2/en not_active Ceased
- 1997-12-03 RU RU99113849/04A patent/RU2177471C2/ru not_active IP Right Cessation
- 1997-12-03 EP EP97952302A patent/EP0942902A2/en not_active Ceased
- 1997-12-03 CN CNB971803234A patent/CN100372836C/zh not_active Expired - Fee Related
- 1997-12-03 WO PCT/US1997/022369 patent/WO1998024763A2/en not_active Application Discontinuation
- 1997-12-03 NZ NZ336713A patent/NZ336713A/en unknown
- 1997-12-03 HU HU0000232A patent/HUP0000232A3/hu unknown
- 1997-12-03 SK SK732-99A patent/SK73299A3/sk unknown
- 1997-12-03 CA CA002273002A patent/CA2273002A1/en not_active Abandoned
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Also Published As
Publication number | Publication date |
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CN1254333A (zh) | 2000-05-24 |
RU2177471C2 (ru) | 2001-12-27 |
FI991187A0 (fi) | 1999-05-25 |
HUP0000232A2 (hu) | 2000-09-28 |
AU735540B2 (en) | 2001-07-12 |
WO1998024763A2 (en) | 1998-06-11 |
NZ336713A (en) | 2001-02-23 |
HUP0000232A3 (en) | 2000-10-30 |
JP2001506611A (ja) | 2001-05-22 |
FI991187A (fi) | 1999-07-16 |
CA2273002A1 (en) | 1998-06-11 |
SK73299A3 (en) | 1999-12-10 |
EP0942902A2 (en) | 1999-09-22 |
AU5594598A (en) | 1998-06-29 |
WO1998024763A3 (en) | 1998-08-06 |
KR20000069374A (ko) | 2000-11-25 |
US5703098A (en) | 1997-12-30 |
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