CN106061962B - 戊二酰亚胺衍生物、其用途、基于所述衍生物的药物组合物及戊二酰亚胺衍生物的制备方法 - Google Patents
戊二酰亚胺衍生物、其用途、基于所述衍生物的药物组合物及戊二酰亚胺衍生物的制备方法 Download PDFInfo
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- A61P31/12—Antivirals
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- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
本发明涉及通式(I)的新的生物活性戊二酰亚胺衍生物或其可药用盐,其作为用于治疗上呼吸道疾病的药剂的用途,包含通式(I)的戊二酰亚胺衍生物的药物组合物,通过加热通式(II)的二羧酸单酰胺与脱水剂来制备通式(I)的戊二酰亚胺衍生物的方法。
Description
本发明涉及新的生物活性化合物,特别涉及戊二酰亚胺衍生物或其可药用盐,其作为预防和治疗上呼吸道疾病的药剂的用途以及制备所述化合物的方法。
技术背景
上呼吸道慢性疾病是全世界的儿童和成人中最常见的疾病。上呼吸道慢性疾病特别地包括鼻窦炎。
鼻窦炎是鼻和鼻旁窦(paranasal sinuses,PNS)的粘膜层炎症,并且是耳鼻喉科最实际的问题(Fokkens W.J.,Lund V.J.,Mullol J.等,European Position Paper onRhinosinusitis and Nasal Polyps.Rhinology 2007;45;20:1-139)。鼻窦炎的起因通常是当粘液纤毛清除机制受损害时的粘膜充血、PNS的天然窦口堵塞及其通气障碍,原因是所述机制是保护呼吸道免受吸入的污染物、变应原和病原生物损害作用的重要的原发性先天机制。
急性鼻窦炎是急性呼吸道病毒感染(ARVI)的常见并发症。
如今,鼻窦炎治疗由施用皮质激素开始,因为皮质激素具有显著的抗炎效果。皮质激素作为单一治疗使用或与抗生素组合使用。更严重形式的鼻窦炎需要使用抗生素。主要的皮质激素为氟替卡松、布地奈德和莫米松。在鼻窦炎的治疗中,规定要长期使用皮质激素,这可能引起副作用和耐受性。通常,副作用是这些药物表现出固有的糖皮质激素作用,但程度超出生理常态。
一般来说,规定的抗生素为青霉素类抗生素(阿莫西林、青霉素V)或非青霉素类抗生素(大环内酯类、四环素类)(Fokkens W.J.,Lund V.J.,Mullol J.等,EuropeanPosition Paper on Rhinosinusitis and Nasal Polyps.Rhinology 2007;45;20:1-139)。
因此,需要这样的新制剂,其将强化鼻窦炎的治疗并削弱炎性反应,同时降低化脓性炎症和坏死缺陷形式的内层损伤,并且将防止该疾病变为慢性。因此,本发明的目的是开发用于治疗鼻窦炎的新药物并将其引入实践中。
病毒感染是严重的健康问题。还没有开发出对抗大多数有害且危险的病毒感染的抗病毒药物,并且现有药物往往对人类有毒或不够有效。大部分现有的或正在开发的药物通过与特定病毒蛋白的特异性相互作用而起作用。这样的药物具有有限的作用谱,并且加快了抗性病毒变体的迅速出现。巴尔的摩病毒分类系统(cиcтeмe клaccификaции виpycoв по )的第IV类和第V类包括含有单链(+)RNA或单链(-)RNA的病毒。第IV类包括冠状病毒科(Coronaviridae family)和小核糖核酸病毒科(Picornaviridaefamily)的肠道病毒属(Enterovirus genus)的代表,第V类包括副粘病毒科(Paramyxoviridae family)的呼吸道合胞病毒(RSV)和正粘病毒科(Orthomyxoviridaefamily)的流感病毒。
所述的病毒组形成了抑制细胞抗病毒程序的有效策略。这种抑制细胞抗病毒保护之系统的侵略性策略导致了这些病毒组的高接触传染性和高致病性,该事实通过由属于肠道病毒属的病毒引起的疾病列表(脊髓灰质炎、病毒性鼻炎(鼻病毒感冒))得到确定。现今,在肠道病毒属的病毒中,人鼻病毒引起了最大的问题。在鼻咽粘膜细胞中复制的鼻病毒是人上呼吸道疾病的致病物。鼻病毒是至少80%的寒冷相关疾病的致病物。除了巨大的经济损失(在美国每年每小时2000万人)之外,鼻病毒感染引起多种并发症如鼻窦炎和中耳炎,而且鼻病毒感染在患有肺炎的儿童的病毒学检查中经常检测到。在哮喘儿童中,鼻病毒感染也是80%病例恶化的原因。在成人中,鼻病毒可能引起哮喘和慢性阻塞性肺病二者的恶化、慢性支气管炎和粘液粘稠病。从具有免疫缺陷病症的肺炎患者中分离出了鼻病毒。
由于存在超过100种抗原型的鼻病毒,这使得不可能开发出有效的疫苗(Palmenberg,A.C;Spiro,D;Kuzmickas,R;Wang,S;Djikeng,A;Rathe,JA;Fraser-Liggett,CM;Liggett,SB(2009).“Sequencing and Analyses of All Known Human rhinovirusGenomes Reveals Structure and Evolution”,Science 324(5923):55-9.doi:10.1126/science.1165557.PM1D 19213880)。此外,没有有效治疗鼻病毒感染的化学治疗剂。
柯萨奇病毒感染(HCXV)是一大类以显著的临床多态性为特征的疾病。柯萨奇病毒感染自身可表现为脑膜炎、麻痹、急性呼吸系统疾病、肺炎、出血性结膜炎、心肌炎、肝炎、糖尿病和其它综合征。根据病毒的现代分类,属于肠道病毒属的人肠道病毒分为5种:1)脊髓灰质炎病毒;2)人肠道病毒A;3)人肠道病毒B;4)人肠道病毒C;和5)人肠道病毒D。柯萨奇病毒的多种血清型属于以下肠道病毒种:人肠道病毒A(柯萨奇病毒A2-8、10、12、14和16);人肠道病毒B(柯萨奇病毒A9、B1-6);人肠道病毒C(柯萨奇病毒A1、11、13、15、17-22和24)。
像其它人肠道病毒一样,柯萨奇病毒在全世界普遍存在。在温带国家,在夏季-秋季观察到其最大传播。该病毒的特征在于高侵袭性,从而促进其在人群中迅速传播。柯萨奇病毒往往是在有组织的儿童群体和医院中“突然”爆发的原因;还发生感染的科间传播。病毒基因组的高变异性在柯萨奇病毒和其它肠道病毒感染的流行病学中起重要作用。因此,各种血清型在某些情况下能够引起不同的病理学。另一方面,相同的临床症状可能是由不同的血清型和不同种的肠道病毒引起的。经修饰病毒的遗传变异性、选择性和快速传播导致疾病的大规模爆发,其病原学与这些病毒无关,或者长久以来没有记录到它们的传播。
柯萨奇病毒的原代复制发生在与鼻咽和肠相关的淋巴组织中。它引起表现为ARD、疱疹性咽峡炎、咽炎等症状的局部病变。在喉咙中,该病毒直至第七天才被检测出来,并且在3至4周中随着粪便排泄出来(在免疫缺陷的情况下,在数年中排泄出来)。病毒血症的结果是病毒侵入靶器官中,然后进行该病毒的原代复制。对于柯萨奇病毒,这样的靶器官可以是脑和脊髓、脑膜、上呼吸道、肺、心脏、肝脏、皮肤等。柯萨奇病毒B可以引起新生儿严重的全身病理过程,导致心脏、脑和脊髓、肝和肾的坏死。该病毒引起以下临床综合征:无菌性脑膜炎(柯萨奇病毒A2、3、4、6、7、9、10和B1-6);患有心肌炎和脑膜脑炎的儿童的急性全身性疾病(柯萨奇病毒D1-5);麻痹(柯萨奇病毒A1、2、5、7、8、9、21和B2-5);疱疹性咽峡炎(柯萨奇病毒A2、3、4、5、6、8和10);急性咽炎(柯萨奇病毒A10、21);传染性鼻炎(柯萨奇病毒A21、24);上呼吸道损伤(柯萨奇病毒A9、16和B2-5)(16);心包炎、心肌炎(柯萨奇病毒B1-5);肝炎(柯萨奇病毒A4、9、20和B5);新生儿和婴儿的腹泻(柯萨奇病毒A18、20、21、24);急性出血性结膜炎(柯萨奇病毒A24);手足口病(柯萨奇病毒A5、10、16);发疹(柯萨奇病毒A4、5、6、9、16);胸膜痛(柯萨奇病毒B3、5);皮疹(柯萨奇病毒B5);发烧(柯萨奇病毒B1-6)。还不存在用于治疗柯萨奇病毒感染的特定化学治疗剂。根据疾病的临床形式,应用病原性疗法和对症疗法。
副粘病毒科包括呼吸道病毒属(人类副流感病毒类型1、2、3、4和5)和肺炎病毒属(呼吸道合胞病毒)的代表。
副粘病毒是与呼吸系统疾病有关的一类重要的病毒。呼吸道合胞病毒(RSV)是全世界已知的下呼吸道的优势病原体。
RSV是新生儿和婴儿的病原体,并且是至少70%的严重病毒性支气管炎和/或肺炎的致病物,其大部分的特征在于喘鸣和呼吸困难。这些支气管炎是儿童一岁期间在冬季住院治疗的最常见原因。RSV还在所有年龄的人中引起细支气管炎、肺炎和慢性阻塞性呼吸系统疾病,并且是造成冬季超额死亡率的重要原因。
在婴幼儿中,RSV是罗音和哮喘恶化的主要诱导物。据报道,相对于健康患者,感染RSV的成人哮喘恶化而导致住院的风险提高(Falsey AR,Hennessey PA,Formica MA,CoxC,Walsh EE.Respiratory syncytial virus infection in elderly and high-riskadults.N Engl J Med.2005;352(17):1749-1759)。
RSV在病毒感染的死亡病例数量中占首要地位。仅在美国就花费24亿美元用于治疗儿童的病毒性下呼吸道疾病。到一岁时,50%至65%的儿童感染此病毒,并且到两岁时,几乎100%的儿童感染此病毒。除了早产儿和老年人之外,高危群体还包括患有心血管、呼吸和免疫系统疾病的人。根据公开的和未公开的数据,已计算出RSV在世界上引起了3380万偶发性急性下呼吸道感染(LRTI)病例,340万需要住院治疗的严重LRTI病例,以及5岁以下儿童中66,000至99,000例致死病例(Nair H,Nokes DJ,Gessner BD,Dherani M,Madhi SA,Singleton RJ,O′Brien KL,Roca A,Wright PF,Bruce N,Chandran A,Theodoratou E,Sutanto A,Sedyaningsih ER,Ngama M,Munywoki PK,Kartasasmita C,Simoes EA,RudanI,Weber MW,Campbell H.Global burden of acute lower respiratory infections dueto respiratory syncytial virus in young children:a systematic review andmeta-analysis.Lancet;375:1545-55)。仅在美国,每年就有90,000名早产儿、125,000名住院新生儿、超过350万名2岁以下的儿童和175,000名住院就医的成人需要治疗(StoreyS.Respiratory syncytial virus market.Nat Rev Drug Discov 2010;9:15-6.)。在1岁时,约三分之一因急性细支气管炎而住院治疗的儿童出现偶发性呼吸困难并且对常见变应原的敏感性增加(Schauer U,Hoffjan S,Bittscheidt J,Kochling A,Hemmis S,BongartzS,Stephan V.RSV bronchiolitis and risk of wheeze and allergic sensitisationin the first year of life.Eur Respir J 2002;20:1277-83)。这些症状在接下来几年中可能会重新出现(Sigurs N,Gustafsson PM,Bjarnason R,Lundberg F,Schmidt S,Sigurbergsson F,Kjellman B.Severe respiratory syncytial virus bronchiolitisin infancy and asthma and allergy at age 13.Am J Respir Crit Care Med 2005;171:137-41)。细支气管炎还可以由鼻病毒、冠状病毒、流感和副流感病毒和腺病毒引起。然而,在所有的所述病毒中,RSV是由于细支气管炎而住院治疗的最常见原因。儿童(免疫系统不成熟)和成人中由于过去的RSV感染而形成的适应性免疫都是短期的,并且不提供完整的抗病毒保护。这一事实导致在整个生命中会发生再感染。在生命的最初几个月,新生儿的血液包含母体的抗RSV抗体;然而,其并不保护儿童。
应注意到,在由(+)RNA病毒和(-)RNA病毒引起的感染中发挥一些有益效果的唯一化学治疗剂是利巴韦林。然而,利巴韦林是相对有毒的药物,经常引起贫血。其主要特征是在红血细胞中的长期存储。结果,甚至在治疗结束后6个月还检测到痕量的利巴韦林。另外,还有一些关于利巴韦林致畸性的报道。
属于正粘病毒科的流感病毒包括四个属:流感病毒A、B和C以及托高土病毒(有时称为流感D病毒)。人类可以感染流感病毒A、B和C,但只有A型引起对人类构成严重威胁的流行病。根据WHO的数据,流感每年在全世界造成3至5百万例严重疾病和250,000至500,000例致死病例。
流感病毒还由哮喘恶化患者呼出,然而,病例数目是其它病毒的1%至9%。
流感病毒的两种主要表面糖蛋白(血凝素和神经氨酸酶)负责病毒附着及其从宿主细胞释放,并且同时是抗体的主要靶标。基于16种血凝素变体和9种神经氨酸酶变体的不同组合,将A型病毒再分为亚型。所有已知的亚型对于野生鸟类(其被视为流感A型病毒的天然宿主)已得到了确定。只有三种亚型,特别是A(H1N1)、A(H2N2)和A(H3N2)在人类群体中是已知的。这些病毒与流感B型病毒一起造成每年不同严重程度的疾病流行。流感病毒的多样性是遗传决定的特征。流感病毒的片段化负链RNA基因组结构有助于混合感染期间不同菌株之间基因组区段的交换(所谓的重组)。此外,在流感病毒的聚合酶中缺乏校正活性导致了病毒基因的高突变率,从而导致定期出现具有“新”抗原性质的流感菌株。如果该变化足以战胜人类群体中预先存在的免疫力,病毒就能够引起流行病。当人类群体对于新出现的变异体完全缺乏免疫时,该病毒可以容易地引起感染并且可以由感染人员传染给未感染人员,并引起流行病。以上指出的独特性决定了难以制造抗流感疫苗。已知存在两类抑制流感病毒的M2蛋白或神经氨酸酶的药物。金刚烷衍生物(金刚烷胺和金刚乙胺)可有效对抗流感A型病毒(但不对抗B型流感病毒)。神经氨酸酶抑制药物为扎那米韦和奥司他韦。两种药物在早期阶段都是比较有效的。
用于合成二羧酸酰亚胺的最常见方法是热环化方法,其包括加热二羧酸或其衍生物(例如酸酐、二酯等)与伯胺或其酰胺。环状酰亚胺的产率通常为80%;然而,由于该方法在高温下进行,其仅可以用于合成热稳定的酰亚胺[Weigand-Hilgetag,ExperimentalMethods in Organic Chemistry[Russian translation],(N.N.Suvorov,编辑),Moscow,Khimiya,1968;446页]。
Yong Sup Lee等的文献,Studies on the site-selective N-acyliminium ioncyclazation:synthesis of(±)-glochidine and(±)-glochidicine.Heterocycles.第37卷.第1期.1994,公开了通过将初始反应物加热至200℃至230℃保持40分钟使组胺二盐酸盐和琥珀酸酐融合来制备琥珀酰亚胺组胺。
专利申请WO2007/000246的国际公开公开了用于合成戊二酰亚胺的方法,其通过用含相应卤代衍生物的DMF使哌啶-2,6-二酮和吡咯烷-2,5-二酮烷基化,随后通过制备型色谱分离目标取代酰亚胺来完成,这种方法不适用于大量戊二酰亚胺的合成。
Shimotori等的文献,Asymmetric synthesis of 5-lactones with lipasecatalyst,Flavour and Fragrance Journal.2007.第22卷.第6期.531-539页,描述了使用脱水剂作为羧基活化反应物(例如乙酸酐)通过相应二羧酸的单酰胺环化来制备环状酰亚胺的方法。
Ito等,Chemoselective Hydrogenation of Imides Catalyzed by CpRu(PN)Complexes and Its Application to the Asymmetric Synthesis of Paroxetine..//Journal of the American Chemical Society.2007.第129卷.第2期.290-291页的文章描述了使用脱水剂作为羧基活化反应物(例如乙酰氯)通过相应二羧酸的单酰胺环化来制备环状酰亚胺的方法。
Polniaszek等的文献,Stereoselective nucleophilic additions to thecarbon-nitrogen double bond.3.Chiral acyliminium ions.//Journal of OrganicChemistry.1990.第55卷.第1期.215-223页,教导了使用脱水剂作为羧基活化反应物(例如羰基二咪唑)通过相应二羧酸的单酰胺环化来制备环状酰亚胺的方法。
Ainhoa Ardeo等的文献,A practical approach to the fused P-carbolinesystem.Asymmetric synthesis of indolo[2,3-α]indolizidinones via adiastereoselective intramolecular α-amidoalkylation reaction./TetrahedronLetters.2003.44.8445-8448,公开了由伯胺和相应的酸酐制备环状酰亚胺的方法,其中脱水剂是过量的戊二酸酐或琥珀酸酐。特别地,该文献提供了在乙酸中在沸腾下由色胺和相应酸的酸酐合成戊二酰亚胺色胺和琥珀酰亚胺色胺的方案。通过所述方法制备的戊二酰亚胺色胺和琥珀酰亚胺色胺的产率分别为67%和81%。
国际申请WO 2007/007054公开文本公开了对细胞(特别是肿瘤细胞)中DNA甲基化具有抑制作用的通式(I)的琥珀酰亚胺和戊二酰亚胺衍生物。所述文献中公开的化合物通过以下过程制备:使包含烃链的氨基衍生物与相应的酸酐或酸或醚发生加成反应,随后任选地在碱的存在下任选地进行环化。
因此,本发明的目的是提供有效地治疗上呼吸道疾病的新的无毒的戊二酰亚胺衍生物。
发明内容
本发明涉及通式I的戊二酰亚胺衍生物或其可药用盐:
其中m是0至2的整数;
Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1各自独立地代表氢、C1-C6烷基、-NH2、-NHC1-C6烷基、羟基或C1-C6烷氧基;
R2是氢、C1-C6烷基、-C(O)OH、-C(O)OC1-C6烷基;
R3是:
1)包含1至4个选自N、O和S的杂原子的五元饱和或不饱和杂环基,其任选地被1至3个选自卤素、C1-C6烷基、C1-C6烷氧基、-C(O)OH、-C(O)OC1-C6烷基、NHC(O)C1-C6烷基、苯基或吡啶基的取代基取代;
2)包含1至2个选自N和O的杂原子的六元饱和或不饱和杂环基,其任选地被选自卤素和C1-C6烷基的基团取代;
3)与六元不饱和含氮环基或杂环基缩合的包含1至3个选自N和S的杂原子的五元不饱和杂环基,其任选地被1或2个选自C1-C6烷基的取代基取代,所述六元不饱和含氮环基或杂环基任选地被1或2个选自羟基、卤素或C1-C6烷基的取代基取代;
4)与包含1至3个选自N和S的杂原子的五元或六元不饱和杂环基缩合的包含1至2个氮原子的六元不饱和环基或杂环基;或者
5)下式的基团:
前提是所述化合物不是这样的化合物,其中:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为-C(O)OCH3时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1为氨基且Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢,或者Re 1为氨基且Ra 1、Rb 1、Rc 1、Rd 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为-C(O)OH时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为-C(O)OH时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为2,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为2,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
本发明还涉及用于治疗上呼吸道疾病的药物,其中所述药物是通式(I)的戊二酰亚胺衍生物或其可药用盐。
本发明的另一个目的是用于治疗上呼吸道疾病的药物组合物,其包含有效量的通式(I)的戊二酰亚胺衍生物或其可药用盐和可药用载体。
本发明还涉及用于治疗上呼吸道疾病的方法,其包括向患者施用有效量的通式(I)的戊二酰亚胺衍生物或其可药用盐。
本发明还涉及通过加热有机溶剂中的通式(II)的二羧酸单酰胺与脱水剂来制备通式(I)的戊二酰亚胺衍生物或其可药用盐的方法:
其中m是0至2的整数;
Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1各自独立地代表氢、C1-C6烷基、-NH2、-NHC1-C6烷基、羟基或C1-C6烷氧基;
R2是氢、C1-C6烷基、-C(O)OH、-C(O)C1-C6烷基;
R3是:
1)包含1至4个选自N、O和S的杂原子的五元饱和或不饱和杂环基,其任选地被1至3个选自卤素、C1-C6烷基、C1-C6烷氧基、-C(O)OH、-C(O)OC1-C6烷基、NHC(O)C1-C6烷基、苯基或吡啶基的取代基取代;
2)包含1至2个选自N和O的杂原子的六元饱和或不饱和杂环基,其任选地被选自卤素和C1-C6烷基的基团取代;
3)与六元不饱和含氮环基或杂环基缩合的包含1至3个选自N和S的杂原子的五元不饱和杂环基,其任选地被1或2个选自C1-C6烷基的取代基取代,所述六元不饱和含氮环基或杂环基任选地被1或2个选自羟基、卤素或C1-C6烷基的取代基取代;
4)与包含1至3个选自N和S的杂原子的五元或六元不饱和杂环基缩合的包含1至2个氮原子的六元不饱和环基或杂环基;或者
5)下式的基团:
发明详述
根据本发明的优选化合物为通式I化合物,其中
m是0至2的整数;
Ra 1和Rb 1是氢、甲基、氨基或羟基;
Rc 1和Rd 1是氢、甲基、氨基或羟基;
Re 1和Rf 1是氢或甲基;
R2是氢、甲基、羧基、甲氧羰基或乙氧羰基;
R3是选自以下的基团:
根据本发明的最优选化合物为表1中所示的化合物。
表1
根据本发明的化合物的可药用盐可以选自:有机酸的加成盐(例如,甲酸盐、乙酸盐、马来酸盐、酒石酸盐、甲磺酸盐、苯磺酸盐、甲苯磺酸盐等),无机酸的加成盐(例如,盐酸盐、氢溴酸盐、硫酸盐、磷酸盐等),以及与氨基酸形成的盐(例如天冬氨酸盐、谷氨酸盐等),优选水合氯化物(chlorohydrates)和乙酸盐。
可以用于根据本发明的药物组合物和治疗方法的最优选的已知化合物为表2中所示的戊二酰亚胺衍生物。
表2
根据本发明的化合物可以通过包括以下的方法来制备:加热有机溶剂中或脱水剂中的通式II的初始二羧酸单酰胺与脱水剂和任选的乙酸钠。
国际申请WO 1999/001103的公开文本中公开了通式II的化合物及其制备方法。
加热步骤优选在90℃至120℃的温度下,更优选地在100℃的温度下,并且更优选地在沸腾下进行。
在该方法中使用的脱水剂可以选自二羧酸酐、有机酸氯代酸酐和羰基二咪唑。
在该方法中使用的优选脱水剂为戊二酸酐、丙酸酐、乙酸酐、氯代乙酸酐或羰基二咪唑。最优选的变体是的含丙酸酐的甲苯,含戊二酸酐的优选二甲基甲酰胺、含乙酸酐的二氧六烷或含氯代乙酸酐的乙酸。
该方法最优选的变体是这样的方法,其中脱水剂和溶剂为乙酸且加热在90℃至100℃下进行。
如果化合物包含另外的官能团(例如OH、NH2、COOH),则其必须预先用有机合成中常用的常规保护基(如苄氧羰基、苄基和乙酰基)进行保护。合成完成后,任选地将这些基团除去,例如,通过氢化。
所要求保护的用于制备在氮原子上取代的通式I的N-取代戊二酰亚胺的方法容易实施,在相当温和的条件下进行,无副产物,容易重现,并且提供高产率(高达82%)和高纯度的目标产物。
通式I的戊二酰亚胺衍生物对上呼吸道疾病有治疗活性。
特别地,根据本发明的化合物可用于治疗细菌、病毒或病毒和细菌病因或由其他因素引起的上呼吸道疾病。特别地,这样的疾病为鼻窦炎、由含RNA的病毒(例如鼻病毒、柯萨奇病毒、呼吸道合胞病毒和流感病毒)引起的疾病,例如由鼻病毒、流感病毒和/或呼吸道合胞病毒引起的哮喘恶化、慢性阻塞性肺病、支气管炎和粘液粘稠病。
以提供期望治疗效果的有效量施用根据本发明的化合物。
通式(I)的化合物可以以包含无毒可药用载体的单位剂型口服、外用、肠胃外、鼻内、吸入和直肠施用。本发明中使用的术语“口服施用”是指皮下、静脉内、肌内或胸腔注射或输注。
根据本发明的化合物可以按0.1mg/kg体重至100mg/kg体重的剂量向患者施用,每日一次;优选以0.25mg/kg至25mg/kg的剂量施用,每日一次或更多次。
此外,应注意,特定患者的特定剂量取决于多种因素,包括某种化合物的活性,患者的年龄、体重、性别、总体健康状况和饮食,药剂的施用时间和途径及其从体内排泄的速率、药物的特定组合及待治疗个体的疾病严重程度。
根据本发明的药物组合物包含有效实现期望技术结果的量的通式(I)的化合物,并且可以以单位剂型(例如,以固体、半固体或液体形式)施用,所述单位剂型包含作为活性剂的根据本发明的化合物,所述化合物与适合于肌内、静脉内、口服和舌下施用,通过吸入施用,鼻内和直肠内施用的载体或赋形剂混合。活性成分可以与常规无毒的可药用载体一起存在于组合物中,所述载体适合于制备溶液剂、片剂、丸剂、胶囊剂、包衣丸、乳剂、混悬剂、软膏剂、凝胶剂及任何其他剂型。
作为赋形剂,可以使用各种化合物,例如糖类,如葡萄糖、乳糖、蔗糖;甘露醇或山梨醇;纤维素衍生物;和/或磷酸钙,如磷酸三钙或磷酸氢钙。作为粘合剂,可以使用以下化合物,例如淀粉糊(例如,玉米、小麦、大米或马铃薯淀粉)、明胶、西黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮。任选使用的崩解剂为上述的淀粉和羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂、或者藻酸或其盐(例如藻酸钠)。
可任选使用的添加剂为流动性控制剂和润滑剂,例如二氧化硅、滑石、硬脂酸及其盐(如硬脂酸镁或硬脂酸钙)和/或丙二醇。
包衣丸的核通常涂覆有抵抗胃酸作用的层。为此目的,可以使用糖类的浓溶液,其中所述溶液可以任选地包含阿拉伯胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、及合适的有机溶剂或其混合物。
稳定剂、增稠剂、着色剂和香料也可用作添加剂。
作为软膏基质,可使用烃软膏基质,例如白凡士林和黄凡士林(分别为Vaselinumalbum和Vaselinum flavum)、凡士林油(Oleum Vaselini)以及白软膏剂和液体软膏剂(分别为Unguentum album和Unguentum flavum),其中固体石蜡或蜡可以用作提供更坚硬质感的添加剂;吸收性软膏基质,例如亲水性凡士林(Vaselinum hydrophylicum)、羊毛脂(Lanolinum)和冷霜(Unguentum leniens);可去除水的软膏基质,例如亲水性软膏(Unguentum hydrophylum);水溶性软膏基质,例如聚乙二醇软膏(Unguentum GlycolisPolyaethyleni);膨润土基质等。
凝胶基质可以选自甲基纤维素、羧甲基纤维素钠、丙氧基纤维素、聚乙二醇或聚环氧乙烷和卡波普。
在制备单位剂型时,与载体组合使用的活性剂的量可根据待治疗受体和治疗剂的特定施用途径而变化。
例如,当根据本发明的化合物以注射用溶液的形式使用时,该溶液中活性剂的量为至多5重量%。稀释剂可以选自0.9%的氯化钠溶液、蒸馏水、注射用奴佛卡因溶液、林格液、葡萄糖溶液和特定的增溶助剂。当根据本发明的化合物以片剂或栓剂形式施用时,其量为每单位剂型至多200mg。
根据本发明的剂型通过常规方法来制备,例如混合、制粒、形成包衣丸、溶解和冷冻干燥。
应注意,根据本发明的化合物的生物活性剂量比比较的已知药物的剂量低两到三个数量级,但具有几乎相同的功效。此外,没有登记过由这些化合物引起的副作用,并且其也没有施用禁忌。此外,根据本发明的化合物的毒性测试表明在口服剂量为3000mg/kg时,实验动物中没有显示出出登记的致死病例。
以下实施例中公开了根据本发明的化合物,其制备方法及其活性研究的详细描述,这些实施例仅用于举例说明的目的,而并非旨在限制本发明的范围。
通式I的戊二酰亚胺衍生物的合成实施例
材料和方法
在溶剂系统:氯仿-甲醇(8∶2)(1)和氯仿-甲醇(9∶1)(2)中,在平板“硅胶60F 254”(“Merck”,德国)上通过薄层色谱(TLC)法对所得化合物的种类进行了评估。
色谱和电泳图谱用氯四甲苯试剂和Pauly试剂进行了染色。
用KBr片(“Nicolet”(美国))在“Magna 750”光谱仪上记录了傅立叶红外光谱。
使用Shimadzu分析型HPLC SCL10Avp LC/MS系统在质谱仪PE SCIEX API 165(150)(加拿大)上分析了多组分混合物。
在下列条件下在Shimadzu HPLC色谱仪上进行了分析级反相HPLC:柱:对称C18,250×4.6mm;梯度洗脱系统:含0.1%HCOOH的水:含0.1%HCOOH的乙腈(条件A);柱:Merk.LiChroCART 250×4mm 5μm。LiChrospher 100RP-8E 5μm.C8,序列号1.50837.0001;梯度洗脱系统:乙酸铵缓冲液(pH 7.5):乙腈(条件B);含0.0025M 1-己基磺酸钠的缓冲液(pH为3):乙腈(条件C);以及柱:Luna C18(2)100A,250×4.6mm(序列号599779-23),梯度洗脱体系:磷酸盐缓冲溶液(pH 3.0):甲醇(条件D)。
在Bruker AMX-400(德国)光谱仪上记录了1H NMR谱。
在Ultraflex质谱仪(“Bruker”,德国)上,用2,5-二羟基苯甲酸作为基质通过基质激光解吸电离方法,在飞行时间辅助质谱仪上获得了高分辨率质谱。
实施例1
1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮(化合物1)的制备
向平底烧瓶中加入溶解于5ml乙酸中的1,5-戊二酸的2-(咪唑-4-基)乙酰胺(1g;4.4mmol)。滴加一个半当量的乙酰氯。使反应物料在90℃于搅拌下放置12小时。通过1H-NMR光谱法来控制该反应。使反应混合物冷却并在真空下除去溶剂。将形成的残余物溶解于最少量的水中,在搅拌下分批加入碳酸钠以使pH值达到8至9。过滤沉淀物,用少量的水洗涤并干燥。过滤后,用二氯甲烷将原液萃取3次。合并的原液经硫酸钠干燥并在真空下除去溶剂。干燥形成的残余物,与第一部分(过滤后)合并,得到的淡色粉末形式的1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮的量为0.52g(产率为56%)。LC/MS,保留时间为1.57分钟处的单个峰,[M+H]+=208,1H-NMR(CD3OD),δ,m.d.:1.87-1.93(m,2H,4’-CH2),2.61-2.65(t,4H,3’,5’-CH2),2.76-2.80(t,2H,1-CH2),3.96-4.00(t,2H,2-CH2),6.8(s,1H,5”-CH-Im),7.55(s,1H,2”-CH-Im)。
实施例2
1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮(化合物1)的制备
向平底烧瓶中加入1,5-戊二酸的2-(咪唑-4-基)乙酰胺(1g;4.4mmol)和10ml丙酸酐。加入三当量的乙酸钠,并使混合物在120℃于搅拌下放置12小时。通过1H-NMR光谱法来控制该反应。在冷却和搅拌下,用3倍过量的水稀释反应混合物,并且分批加入碳酸钠以使pH值达到8至9。将反应混合物用乙酸乙酯萃取三次。合并的有机原液经硫酸钠干燥并除去溶剂。得到的淡黄色晶体形式的1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮的量为0.37g(产率为40%)。[M]+207.9。1H-NMR(CD3OD),δ,m.d.:1.85-1.91(m,2H,4’-CH2),2.60-2.63(t,4H,3’,5’-CH2),2.73-2.77(t,2H,1-CH2),3.95-4.00(t,2H,2-CH2),6.8(s,1H,5”-CH-Im),7.52(s,1H,2”-CH-Im)。
实施例3
1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮(化合物1)的制备
将1,5-戊二酸的2-(咪唑-4-基)乙酰胺(100g,0.44mol)、80ml(0.85mol)乙酸酐(80ml,0.85mol)和甲苯(200ml)加入到配备有回流冷凝器的1L锥形瓶中。加热所得悬液直至固体溶解,并使该溶液回流6至8小时。在真空下除去溶剂,向所得油状物中加入300ml甲醇,并在真空下反复除去溶剂。将残余物溶解在300ml二氯甲烷中,并向其中加入65ml三乙胺。在真空下浓缩所得溶液并在+4℃下静置18小时。将残余物滤过布氏漏斗(d=10cm),用异丙醇洗涤三次并在+70℃下干燥。通过TLC法来控制纯度(Rf产物,0.54;(1))。在需要额外的纯化和净化的情况下,将产物重结晶,并同时用碳黑/碳处理了产物的热溶液。得到的1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮的量为73.6g(产率为80%)。[M+H]+=208,1H-NMR(CD3OD),δ,m.d.:1.87-1.93(m,2H,4’-CH2),2.61-2.65(t,4H,3’,5’-CH2),2.76-2.80(t,2H,1-CH2),3.96-4.00(t,2H,2-CH2),6.8(s,1H,5”-CH-Im),7.55(s,1H,2”-CH-Im)。
通过以上公开的方法制备了下列化合物:
实施例4
1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮(化合物1)的制备
将戊二酸酐(3.5g,0.031mol)加入到在加热下溶解在25ml N,N′-甲酰胺中的1,5-戊二酸的2-(咪唑-4-基)乙酰胺(4.5g;0.020mol)中,并将反应混合物加热至100℃保持4至6小时。通过TLC或电泳法检查了反应的完成。在真空下除去溶剂,将油状残余物溶解于50ml水中,并使溶液通过填充有70ml Amberlite IRA-96的柱。收集包含目标化合物的洗脱液,并在真空下除去溶剂。将所得固体残余物在氯仿中重结晶。得到的1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮的量为3.1g(75.6%)。
Rf 0.43(2).[M]+207.9。
1H-NMR(CD3OD),δ,m.d.:1.87-1.93(m,2H,4’-CH2),2.61-2.65(t,4H,3’,5’-CH2),2.76-2.80(t,2H,1-CH2),3.96-4.00(t,2H,2-CH2),6.8(s,1H,5”-CH-Im),7.55(s,1H,2”-CH-Im)。
条件A下的HPLC:保留时间为15.5分钟的单个峰。
傅立叶红外光谱(在KBr片中,v,cm-1):3136,3070,2833(-NH-val.),1720,1670(CO,环状酰亚胺),1339,1257(-CH2-)。测定值,%:S,57.60;H,6.12;N,21.17。C10H13N3O2。计算值%:S,57.96;H,6.32;N,20.28。
实施例5
1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮(化合物1)的制备
将1,5-戊二酸的2-(咪唑-4-基)乙酰胺(100g,0.44mol)、丙酸酐(102ml,0.80mol)和甲苯(200ml)加入到配备有回流冷凝器的1L锥形瓶中。加热所得悬液直到固体溶解,并使该溶液回流8至9小时。在真空下除去溶剂,并向所得油状物中加入300ml甲醇,并在真空下反复除去溶剂。将残余物溶解在300ml二氯甲烷中,并向其中加入65ml三乙胺。将所得溶液在真空下浓缩以蒸发掉约70%的二氯甲烷,然后将其在0℃至+4℃下静置18小时。过滤残余物,用异丙醇洗涤三次,冷却到0至-5℃。将粗产物重结晶,同时用碳黑/碳处理该产物的热溶液。通过TLC法来控制纯度(Rf产物,0.54;(1))。使该产物的溶液在“MILLIPORE”过滤系统(0.45μm)上进行热过滤,并在+70℃的干燥箱中进行真空干燥。得到的1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮的量为60.0g,产率65%。1H-NMR(400.13MHz,DMSO-d6,δ,m.d.,J/Hz):1.81(m,2H,CH2CH2CH2);2.58(m,6H,CH2C,CH2CH2CH2);3.83(t,2H,CH2N,J=7.8Hz);6.77(bs,1H,CCH)7.48(bs,1H,NCHN);11.8(bs,1H,NH)。
实施例6
1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮(化合物1)的制备
将12ml乙酸酐中的Nβ-戊二酰组胺(5.0g;0.022mol)加热至100℃保持4至6小时。通过TLC或电泳法检查反应的完成。在真空下将溶剂从反应混合物中除去,并将所得固体残余物在异丙醇中重结晶。所得到的1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮的量为3.7g(80%)。Rf 0.43(2).测定值%:C 57.73;H 6.15;N 20.17.C10H13N3O2。计算值%:S,57.96;H,6.32;N,20.28。
实施例7
1-[2-(1H-苯并噻唑-2-基)乙基]哌啶-2-二酮(化合物7)
将5-{[2-(1,3-苯并噻唑-2-基)乙基]氨基}-5-氧代戊酸(22g;0.075mol)和乙酸酐(23g;0.225mol)的混合物在150ml二氧六环中煮沸3小时。在真空下除去二氧六环,加入200ml水,并用30%氢氧化钠将混合物中和至中性pH。将沉淀的油状物研磨成晶体。通过色谱(SiCO2 60-100μm,洗脱剂:乙酸乙酯-己烷(1∶1))纯化残余物。得到的1-[2-(1H-噻唑-2-基)乙基]哌啶-2,6-二酮的量为16.5g(79.9%)。LC/MS:保留时间为2.26分钟的单个峰,[M+H]+=275。条件A下的HPLC:保留时间为9.34分钟的单个峰。1H-NMR(400.13MHz,DMSO-d6,δ,m.d.,J/Hz):1.85(五重峰,2H,CH2CH2CH2,J=6.8Hz);2.59(t,4H,CH2CH2CH2,J=6.8Hz);3.24(t,2H,CH2S,J=7.3Hz);4.08(t,2H,CH2N,J=7.3Hz);7.43,7.49(t,1H,Ar,J=7.6Hz);7.96,8.04(d,1H,Ar,J=7.6Hz)。
通过以上公开的方法制备了下列化合物:
实施例8
1-[2-(1H-吡啶基-3-基)乙基]哌啶-2,6-二酮(化合物10)
将1,5-戊二酸的2-(吡啶基-3-基)乙酰胺(29.00g,0.12mol)和无水乙酸钠(5.9g;0.07mol)溶解在200ml乙酸酐中。将反应混合物加热至徐沸,并进一步回流18小时。反应完成后,在真空下除去溶剂,将残余物溶于500ml二氯甲烷中,用100ml份的3%苏打溶液洗涤2次并经硫酸钠干燥。在真空下除去溶剂,将所得油状物溶解在二氧六环中。添加含3M HCl的二氧六环溶液,过滤沉淀物并自125g异丙醇中重结晶。得到了量为25g(产率为80%)的盐酸盐形式的产物。LC/MS:保留时间为0.5分钟的单个峰,[M+H]+=218。在条件D下的HPLC:保留时间为16.72分钟的单个峰。1H-NMR(400.13MHz,DMSO-d6,δ,m.d.,J/Hz):1.78(五重峰,2H,CH2CH2CH2,J=6.4Hz);2.56(t,4H,CH2CH2CH2,J=6.4Hz);2.73(t,2H,CH2C,J=7.3Hz);3.86(t,2H,CH2N,J=7.3Hz);7.30(dd,1H,5-Pyr,J=7.8,4.5Hz);7.60(d,1H,4-Pyr,J=7.8Hz);8.37(d,1H,2-Pyr,J=1.5Hz);8.41(dd,1H,6-Pyr,J=4.5,1.5Hz)。
通过以上公开的方法制备了下列化合物:
实施例9
1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮(化合物1)
将1,5-戊二酸的2-(咪唑-4-基)-乙酰胺(20g)和N,N’-二甲基甲酰胺(60ml)加入到平底烧瓶(250ml)中。在剧烈搅拌下加入羰基二咪唑(17.3g;1.2当量)。将反应混合物加热至90℃保持2小时。通过1H-NMR光谱法控制该反应(用硫醚稀释样品(0.5ml),并将沉淀物溶解在DMSO-d6中)。当反应物料中不存在初始的1,5-戊二酸的2-(咪唑-4-基)-乙酰胺时,将物料冷却并倒入3倍体积的甲基叔丁基醚(180ml)中。将反应混合物静置1小时,并过滤沉淀物,用60ml甲基叔丁基醚洗涤并干燥。粗品1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮的产率为12.4g(67%)。
将该粗品1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮(12g)和异丙醇(36mg)加入100ml的平底烧瓶中。加热混合物以使残余物完全溶解,然后加入1.2g活性炭,并将混合物静置一小时。将热溶液滤过预热的陶瓷过滤器。过滤器上的残余物用6ml热异丙醇洗涤。使热原液冷却至室温,并使其在搅拌下静置一晚以结晶。过滤析出的晶体,用6ml的冷异丙醇洗涤并干燥。重结晶后,得到的1-(2-(1H-咪唑-4-基)乙基)哌啶-2,6-二酮的量为10.1g(84%)。产物用LC/MS方法进行分析:保留时间为1.57分钟的单个峰,[M+H]+=208。1H-NMR(CD3OD),δ,m.d.:1.87-1.93(m,2H,4’-CH2);2.61-2.65(t,4H,3’,5’-CH2);2.76-2.80(t,2H,1-CH2);3.96-4.00(t,2H,2-CH2);6.8(c,1H,5”-CH-Im);7.55(c,1H,2”-CH-Im)。
通过类似方法合成了表3中示出的化合物9、12至115。
表3
实施例10
化合物在急性鼻窦炎大鼠模型中的效力评估
采用Leica DMLS光学显微镜(Leica Microsystems,德国)对组织学制备物的形态进行了研究。微形态学评估通过在Leica DMLB显微镜上使用目镜测微尺进行。
通过向大鼠各鼻通道鼻内施用20μl 7.5%福尔马林溶液(包含40%甲醛、8%甲醇和52%水的水溶液)诱导了急性鼻窦炎。
向大鼠鼻通道施用福尔马林导致炎症向邻近组织散播,产生类似于人类鼻窦炎症状的临床模式。
在环境适应期之后,形成了下列组:
-胃内施用量为0.2ml的盐水的完整动物,不进行急性鼻窦炎诱导;
-对照组,由在诱导急性鼻窦炎之后胃内施用量为0.2ml的盐水7天的动物组成;
-在诱导急性鼻窦炎之后以0.33mg/kg的剂量肌内施用地塞米松7天的动物;以及
-在诱导急性鼻窦炎之后以27mg/kg的剂量施用测试化合物7天的动物。
每天对每只动物进行临床观察,每天至少两次。
在Wistar大鼠实验中,通过向鼻通道施用7.5%福尔马林溶液来诱导急性鼻窦炎在对照组动物中引起了明显的病理变化,特征在于在鼻粘膜上产生了急性炎症过程。所引起的病理学的特征在于鼻道粘膜的堵塞、增生、局部坏死,杯状细胞的数量增多,单核细胞和白细胞的明显浸润以及粘膜下腺体的粘液增生。
对实验动物的两个鼻通道(呼吸区和嗅觉区)的粘膜和粘膜下膜进行了形态学分析以评价化合物的比活性。
实验的临床阶段完成后,将来源于动物的材料(鼻、鼻唇三角)切片并在10%福尔马林溶液中固定24小时,然后在12%“De Castro”溶液中进行脱钙,此后使材料在浓度逐渐提高(70%至95%)的醇、二甲苯和石蜡中经过标准处理以制备厚度为3μm至5μm的连续石蜡切片的组织学制备物。为了进行显微镜检查,将切片用苏木精和伊红染色。通过用阿尔新蓝(pH值2.5)对制备物进行组织化学染色来进行酸性粘多糖(其产生在炎症中增多)的检测。进行了相对于完整大鼠组之变化的比较和组织学评估。
处死后,研究了每只动物的鼻通道内炎症的大体外观。大鼠的组织学、组织化学和形态学研究旨在评估鼻通道的以下特征:粘膜充血、鼻上皮的增生和坏死、鼻中隔的1mm粘膜内的杯状细胞数目及炎症的特征。
在该研究中,通过杯状细胞的数目和作为结果的鼻通道粘膜的微观变化评价了粘液纤毛系统的效率。
表4
鼻中隔的1mm粘膜内的杯状细胞的数目
表4大鼠鼻中隔的1mm粘膜内的杯状细胞的数目,M±m
(多次实验的数据)
组 | N | 杯状细胞的数目 |
完整 | 58 | 24.4±0.7 |
对照 | 58 | 43.3±0.6 |
地塞米松 | 6 | 34.8±2.1* |
化合物1 | 18 | 31.2±1.2* |
化合物3 | 12 | 35.8±0.9* |
化合物6 | 6 | 36.5±0.8* |
化合物8 | 6 | 34.5±0.8* |
化合物124 | 12 | 37.6±1.4* |
n是动物数,*-相对于对照,p<0.05
n是动物数
表5
不同组大鼠中鼻通道粘膜变化的宏观特征
(多次测试的数据)
n是动物数
从表4和表5中可以看出,通式I的化合物(不限于所研究的化合物)有效地保持粘液纤毛系统的效率并在鼻窦炎模型中显示出治疗功效。所研究化合物的药理作用表现为更加明显的上皮再生、杯状细胞数目的减少和粘液分泌过多。
实施例11
式(I)化合物在体内对抗柯萨奇病毒的抗病毒活性
本研究使用了预先调整并由柯萨奇病毒感染造成小鼠死亡的胰蛋白酶依赖性毒株HCXV A2。
使用重6g至7g的小白鼠进行实验。以0.1ml/小鼠的剂量肌内感染动物。实验中使用的感染剂量为引起小鼠致死的10LD50。
化合物提供治疗效果的能力通过对照组中感染HCXV A2病毒的小鼠相对于未处理组小鼠的死亡率来评估。
根据治疗方案,通过口服施用所研究的化合物和安慰剂。向小鼠施用的安慰剂由盐水组成。作为阴性对照的完整动物在单独的房间中保持在与实验动物相同的条件下。
将实验中所用的动物按每组14至15只动物进行分组。以30mg/kg体重的剂量施用化合物。所研究的化合物每日一次口服施用,持续7天(第一次施用是在感染后24小时进行)。监测动物15天,在此期间每天对动物进行称重并记录死亡率。
在研究所测试化合物在HCXV A2病毒感染中的有效性期间,在完整动物的对照组中不记录非特异性致死病例。
通式(I)化合物通过降低动物的死亡率和提高其平均预期寿命而对实验的柯萨奇病毒感染具有保护作用。表(表6)中示出了一些具体的式(I)化合物(不限于所述化合物)的数据。
所描述的测试化合物的抗病毒活性表明,这些化合物可用作HCXV肠道病毒感染的有效药物。
表6.
在小鼠模型中通式(I)化合物对抗柯萨奇A2-病毒感染的效力
实施例12
通式(I)化合物对小鼠适应性RS病毒的抗病毒作用
在体内在实验性小鼠模型中测定了抗RSV的化合物对人类病毒hRSV的抗病毒效率,人类病毒hRSV预先经过调整以适应于在小鼠肺中生长。在短暂乙醚麻醉下,以0.05ml/小鼠的体积使动物经鼻内以5.0logTCID50的剂量感染病毒。根据治疗方案,测试化合物以30mg/kg的剂量每日一次口服施用,持续5天。第一次施用在感染后24小时进行。向小鼠施用的安慰剂由盐水组成。作为阴性对照的完整动物在单独的房间中保持在与实验动物相同的条件下。实验组包含12只动物。使用剂量为40mg/kg的利巴韦林作为参照制剂。
通过在感染后第5天和第7天测量实验组相对于对照组的病毒滴度,通过防止体重减轻的效率以及通过对hRSV在小鼠肺中繁殖的抑制确定了测试化合物的抗病毒活性。
表7示出了对于一些具体的式(I)化合物(不限于所述化合物),测量动物体重的结果。与完整动物相比,病毒对照组的小鼠有统计学显著的体重减轻。与对照动物相比,通式(I)化合物的抗病毒活性在小鼠体重提高方面是显而易见的。
表7
小鼠在感染后第5天和第7天的平均体重
#-对比对照动物统计学上的显著差异(t-标准,p<0.05)
此外,通式(I)化合物的治疗作用通过其在感染后第5天和第7天抑制hRSV病毒在小鼠肺中的繁殖的能力来评价。病毒滴度通过滴定Hep-2细胞培养物中肺的10%悬液来确定。记录了在37℃下用TCID孵育2天后的结果。表8中列出了施用测试化合物和参照制剂后,在Hep-2细胞培养物中的小鼠肺悬液中的hRSV感染活性的测定结果。向动物施用通式I化合物导致hRSV感染活性降低。
通式(I)化合物在小鼠hRSV的感染模型中的抗病毒活性研究表明,所要求保护的化合物防止体量减轻并减少病毒在动物肺中的繁殖。
表8
hRSV病毒在小鼠肺中繁殖的抑制
*-相对于对照动物具有统计学显著差异(t-标准,p<0.05)
实施例13
在具有受抑制免疫系统的小鼠模型中通式(I)化合物对抗RS病毒的抗病毒作用
在Balb/c小鼠的病毒性肺炎模型中评估了化合物对抗人类呼吸道合胞病毒(毒株A2,感染滴度为5×106TCID50/ml的ATCC VR-1540)的抗病毒活性。在短暂乙醚麻醉下将体积为50μl的病毒经鼻内接种给动物。为了抑制对RS病毒的免疫应答,在感染前以100mg/kg的剂量向动物经腹腔施用环磷酰胺5天。按照治疗方案在感染后24小时开始将测试化合物以30mg/kg的剂量一日一次施用5天。通过在感染后第5天与对照相比感染呼吸道合胞病毒的肺部水肿的减少评估了化合物的活性。
表9示出的一些具体的通式(I)化合物(不限于所述化合物)的结果表明,动物的病毒感染导致了严重肺水肿(以可能的4计,3.15至2.05分)的形成。所使用的通式(I)化合物对肺组织的结构具有标准化作用。
表9
在施用测试化合物和参照制剂的情况下Balb/c小鼠在感染后第5天的RS-病毒性肺炎的水肿程度(M±SD,n=5)
*根据t标准(p<0.05),标记值不同于对照值。
实施例14
式(I)化合物对抗鼻病毒的抗病毒活性
本研究通过使用作者保藏于国家病毒保藏中心(GKV)(登记号2730)的hRV毒株进行。在短暂乙醚麻醉下以0.05ml/小鼠的体积使动物经鼻内感染病毒。
将该病毒在小鼠体内预先滴定以确定化合物在体内实验模型中对抗hRV的效力,然后感染小鼠并口服施用制剂。在感染后第2,3,4天,通过在Hela细胞培养物中滴定肺悬液来评估感染滴度。
在诱导后12小时开始将所研究的化合物和安慰剂(盐水)向小鼠口服施用,一日一次,保持5天。所述化合物以30mg/kg体重的剂量施用。将在单独的房间中保持在与实验动物相同的条件下的十只完整动物作为阴性对照。
在感染后第2、3和4天,通过小鼠身体和肺的重量变化的动态以及通过在Hela细胞培养物中测定的病毒感染活性降低评价了测试化合物的抗病毒活性。通过TCID测定与对照组的滴度相比,RV病毒在实验组肺中的感染滴度。制剂的抗病毒效率的标准是以对数单位-Δlg TCID50表示的对照组(不含制剂)与实验组的滴度之差。所述差是根据式(log A)-(logB)来计算的。
表10示出了对于一些特定的式(I)化合物(不限于所述化合物)的动物体重测量结果。
表10
感染hRV后小鼠的体重
#-相对于完整动物具有统计学显著差异(t-标准,p<0.05)
*-相对于对照动物具有统计学显著差异(t-标准,p<0.05)
在病毒对照组中,感染过程的发展与动物的体重降低有关,其中在第3天和第4天,用通式(I)的测试化合物处理的小鼠的体重与对照动物的体重有统计学显著差异。
鼻病毒感染的小鼠肺重量的研究和施用制剂的治疗方案表明,在实验过程中被感染的小鼠的肺重量超过了完整小鼠的肺重量,表明是活性感染过程。在第4天,在所研究制剂作用下的小鼠的肺重量与病毒对照组的肺重量显著不同,但与完整动物的肺重量几乎相同。表11中示出了一些特定化合物(不限于所述化合物)的数据。
表11
感染hRV后小鼠的肺重量
#-相对于完整动物具有统计学显著差异(t-标准,p<0.05)
*-相对于对照动物具有统计学显著差异(t-标准,p<0.05)
表12中示出了在施用一些特定的通式(I)化合物(不限于所述化合物)之后,在Hela细胞培养物中在小鼠肺悬液中hRV感染活性的测定结果。
表12
小鼠肺中hRV病毒繁殖的抑制
用通式(I)化合物处理导致在感染后第3天和第4天hRV感染活性降低。
在小鼠hRV感染模型中通式(I)化合物的抗病毒活性研究表明,所要求保护的化合物防止体重减轻并防止肺重量增加到在完整动物组中观察到的值,并降低病毒在动物肺中的繁殖。
实施例15
式(I)化合物对抗流感病毒的抗病毒活性
本研究通过使用流感病毒毒株A/加利福尼亚/07/09(H1N1)pdm09来进行。将实验中使用的重14g至16g的白色远交雌性小鼠按每组20只动物进行分组。
在实验过程中,每天对每只动物进行观察。观察包括评估动物的一般行为和身体状况。在施用制剂的几天内,在施用制剂前的一定时间内和在施用后约2小时进行观察。动物按照国际标准进行处理。
以包含5LD50的0.05ml体积使小鼠经鼻内感染流感病毒A/加利福尼亚/07/09(H1N1)pdm09。
通过在感染病毒后24、48、72、96和120小时以30mg/kg/小鼠的剂量向感染小鼠每日一次口服施用通式(I)化合物研究了其治疗效果。对照组的小鼠在相同条件下施用安慰剂(0.2ml盐水)。在感染后对动物进行14天的监测,并记录了处理组和对照组中由流感肺炎引起的致死病例。死亡动物肺的解剖病理变化的登记支持了流感肺炎造成的动物死亡特异性。
通过比较施用制剂和安慰剂的动物组之间的死亡率评价了化合物的活性。
施用安慰剂的受感染动物的预期寿命为7.2±2.2天,死亡率为95%。
施用通式(I)化合物的动物组的死亡率降低了30%至60%,并且预期寿命高于对照小鼠的预期寿命。表13示出了一些特定的通式(I)化合物(不限于所述化合物)的数据。
表13
实验组动物的死亡率
编号 | 制剂 | 剂量(mg/ml) | 死亡率,% |
1 | 化合物1(KhS-8) | 30 | 35.0 |
2 | 化合物5(KhS-221-GI) | 30 | 45.0 |
3 | 化合物4(KhS-217) | 30 | 65.0 |
4 | 化合物12 | 30 | 60.0 |
5 | 化合物20 | 30 | 50.0 |
6 | 化合物23 | 30 | 40.0 |
7 | 化合物24 | 30 | 55.0 |
8 | 化合物30 | 30 | 50.0 |
9 | 化合物35 | 30 | 55.0 |
10 | 化合物36 | 30 | 60.0 |
11 | 化合物83 | 30 | 45.0 |
12 | 病毒对照 | 95.0 | |
13 | 完整 | 0.0 |
实施例16
根据本发明的化合物的剂型
根据本发明的化合物可以经口服、肌内或静脉内以包含无毒的可药用载体的单位剂型施用。
所述化合物可以以0.1mg/kg至10mg/kg体重的日剂量施用于患者,每日一次或更多次,优选的剂量为0.5mg/kg至5mg/kg。
此外,应注意,特定患者的特定剂量取决于多种因素,包括特定化合物的活性,患者的年龄、体重、性别、总体健康状况和饮食,药剂的施用时间和途径及其从身体排泄的速率、药物的特定组合以及待治疗个体的疾病严重程度。
根据本发明的药物组合物包含有效实现期望技术结果的量的通式(I)化合物,并且可以以单位剂型(例如,以固体、半固体或液体形式)施用,所述单位剂型包含作为活性剂的根据本发明的化合物,所述化合物与适合于肌内、静脉内、口服和舌下施用,通过吸入施用,鼻内和直肠内施用的载体或赋形剂混合。活性成分可以与常规无毒的可药用载体一起存在于组合物中,所述载体适合于制备溶液剂、片剂、丸剂、胶囊剂、包衣丸剂、乳剂、混悬剂、软膏剂、凝胶剂和任何其他剂型。
作为赋形剂,可以使用多种化合物,例如糖类,如葡萄糖、乳糖或蔗糖;甘露醇或山梨醇;纤维素衍生物;和/或磷酸钙,如磷酸三钙或磷酸氢钙。作为粘合剂,可以使用以下的化合物:例如淀粉糊(例如,玉米、小麦、大米或马铃薯淀粉)、明胶、西黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮。任选使用的崩解剂为上述的淀粉和羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂、或者藻酸或其盐(如藻酸钠)。
可任选使用的添加剂为流动性控制剂和润滑剂,例如二氧化硅、滑石、硬脂酸及其盐(如硬脂酸镁或硬脂酸钙)和/或丙二醇。
在制备单位剂型时,与载体组合使用的活性剂的量可以根据待治疗受体和施用治疗剂的特定途径而变化。
例如,当根据本发明的化合物以注射用溶液的形式使用时,该溶液中活性剂的量为0.01重量%至5重量%。稀释剂可以选自0.9%的氯化钠溶液、蒸馏水、注射用奴佛卡因溶液、林格氏液、葡萄糖溶液和特定的增溶助剂。当根据本发明的化合物以片剂形式施用时,其量为每单位剂型5.0mg至500mg。
根据本发明的剂型通过常规方法来制备,例如混合、制粒、形成包衣丸、溶解和冷冻干燥。
片剂形式
通过使用以下成分来制备片剂形式:
将组分混合并压缩以形成片剂。
栓剂
栓剂组合物的实例
根据本发明的化合物或其可药用盐 | 1-100mg |
可可油 | 制备栓剂所需的量 |
必要时,使用相应赋形剂来制备经直肠、经阴道和经尿道栓剂。
注射用溶液
注射用溶液组合物的实例:
根据本发明的化合物或其可药用盐 | 1-50mg |
注射用水 | 2ml |
Claims (28)
1.通式I的化合物或其可药用盐:
I
其中m是1至2的整数;
Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1各自独立地代表氢、C1-C6烷基、-NH2、-NHC1-C6烷基、羟基或C1-C6烷氧基;
R2是氢、C1-C6烷基、-C(O)OH、-C(O)OC1-C6烷基;
R3是:
1)包含1至4个选自N、O和S的杂原子的五元饱和或不饱和杂环基,其任选地被1至3个选自卤素、C1-C6烷基、C1-C6烷氧基、-C(O)OH、-C(O)OC1-C6烷基、-NHC(O)C1-C6烷基、苯基或吡啶基的取代基取代;
2)包含1至2个选自N和O的杂原子的六元饱和或不饱和杂环基,其任选地被选自卤素和C1-C6烷基的基团取代;
3)与六元不饱和含氮环基或杂环基缩合的包含1至3个选自N和S的杂原子的五元不饱和杂环基,其任选地被1或2个选自C1-C6烷基的取代基取代,所述六元不饱和含氮环基或杂环基任选地被1或2个选自羟基、卤素或C1-C6烷基的取代基取代;
4)与包含1至3个选自N和S的杂原子的五元或六元不饱和杂环基缩合的包含1至2个氮原子的六元不饱和环基或杂环基;或者
5)下式的基团:
,
前提是所述化合物不是这样的化合物,其中:
当m为 1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为-C(O)OCH3时,R3不为:
当m为 1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1为氨基且Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢,或者Re 1为氨基且Ra 1、Rb 1、Rc 1、Rd 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为-C(O)OH时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为-C(O)OH时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为2,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为2,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
当m为1,Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1为氢且R2为氢时,R3不为:
;
并且前提是所述化合物不是以下化合物:
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、和
。
2.根据权利要求1所述的化合物或其可药用盐,其中m是1至2的整数;
Ra 1和Rb 1是氢、甲基、氨基或羟基;
Rc 1和Rd 1是氢、甲基、氨基或羟基;
Re 1和Rf 1是氢或甲基;
R2是氢、甲基、羧基、甲氧羰基或乙氧羰基;
R3是选自以下的基团:
3.根据权利要求1所述的化合物,其为:
4.用于治疗呼吸道疾病的药物组合物,其包含可药用载体和有效量的通式I的化合物或其可药用盐:
,
I
其中m是1至2的整数;
Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1各自独立地代表氢、C1-C6烷基、-NH2、-NHC1-C6烷基、羟基或C1-C6烷氧基;
R2是氢、C1-C6烷基、-C(O)OH、-C(O)OC1-C6烷基;
R3是:
1)包含1至4个选自N、O和S的杂原子的五元饱和或不饱和杂环基,其任选地被1至3个选自卤素、C1-C6烷基、C1-C6烷氧基、-C(O)OH、-C(O)OC1-C6烷基、-NHC(O)C1-C6烷基、苯基或吡啶基的取代基取代;
2)包含1至2个选自N和O的杂原子的六元饱和或不饱和杂环基,其任选地被选自卤素和C1-C6烷基的基团取代;
3)与六元不饱和含氮环基或杂环基缩合的包含1至3个选自N和S的杂原子的五元不饱和杂环基,其任选地被1或2个选自C1-C6烷基的取代基取代,所述六元不饱和含氮环基或杂环基任选地被1或2个选自羟基、卤素或C1-C6烷基的取代基取代;
4)与包含1至3个选自N和S的杂原子的五元或六元不饱和杂环基缩合的包含1至2个氮原子的六元不饱和环基或杂环基;或者
5)下式的基团:
。
5.根据权利要求4所述的药物组合物,其中所述式(I)的化合物是根据权利要求1至3中任一项所限定的化合物。
6.根据权利要求5所述的药物组合物,其中所述呼吸道疾病是鼻窦炎。
7.根据权利要求5或6所述的药物组合物,其中所述呼吸道疾病是由含RNA的病毒引起的。
8.根据权利要求7所述的药物组合物,其中所述病毒选自鼻病毒、柯萨奇病毒、呼吸道合胞病毒和流感病毒。
9.根据权利要求5或6所述的药物组合物,其中所述疾病是由鼻病毒、流感病毒和/或呼吸道合胞病毒引起的哮喘恶化、慢性阻塞性肺病、支气管炎和粘液粘稠病。
10.通式I的化合物或其可药用盐在制备用于治疗呼吸道疾病的药物中的用途:
,
I
其中m是1至2的整数;
Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1各自独立地代表氢、C1-C6烷基、-NH2、-NHC1-C6烷基、羟基或C1-C6烷氧基;
R2是氢、C1-C6烷基、-C(O)OH、-C(O)OC1-C6烷基;
R3是:
1)包含1至4个选自N、O和S的杂原子的五元饱和或不饱和杂环基,其任选地被1至3个选自卤素、C1-C6烷基、C1-C6烷氧基、-C(O)OH、-C(O)OC1-C6烷基、-NHC(O)C1-C6烷基、苯基或吡啶基的取代基取代;
2)包含1至2个选自N和O的杂原子的六元饱和或不饱和杂环基,其任选地被选自卤素和C1-C6烷基的基团取代;
3)与六元不饱和含氮环基或杂环基缩合的包含1至3个选自N和S的杂原子的五元不饱和杂环基,其任选地被1或2个选自C1-C6烷基的取代基取代,所述六元不饱和含氮环基或杂环基任选地被1或2个选自羟基、卤素或C1-C6烷基的取代基取代;
4)与包含1至3个选自N和S的杂原子的五元或六元不饱和杂环基缩合的包含1至2个氮原子的六元不饱和环基或杂环基;或者
5)下式的基团:
。
11.根据权利要求10所述的用途,其中所述式I的化合物是根据权利要求1至3中任一项所限定的化合物。
12.根据权利要求10或11所述的用途,其中所述呼吸道疾病是鼻窦炎。
13.根据权利要求10或11所述的用途,其中所述呼吸道疾病是由含RNA的病毒引起的。
14.根据权利要求13所述的用途,其中所述病毒选自鼻病毒、柯萨奇病毒、呼吸道合胞病毒和流感病毒。
15.根据权利要求10或11所述的用途,其中所述疾病是由鼻病毒、流感病毒和/或呼吸道合胞病毒引起的哮喘恶化、慢性阻塞性肺病、支气管炎和粘液粘稠病。
16.用于制备根据权利要求1所述的通式I的化合物或其可药用盐的方法,其包括加热有机溶剂中的通式II的二羧酸单酰胺与脱水剂:
,
II
其中
m是1至2的整数;
Ra 1、Rb 1、Rc 1、Rd 1、Re 1和Rf 1各自独立地代表氢、C1-C6烷基、-NH2、-NHC1-C6烷基、羟基或C1-C6烷氧基;
R2是氢、C1-C6烷基、-C(O)OH、-C(O)OC1-C6烷基;
R3是:
1)包含1至4个选自N、O和S的杂原子的五元饱和或不饱和杂环基,其任选地被1至3个选自卤素、C1-C6烷基、C1-C6烷氧基、-C(O)OH、-C(O)OC1-C6烷基、-NHC(O)C1-C6烷基、苯基或吡啶基的取代基取代;
2)包含1至2个选自N和O的杂原子的六元饱和或不饱和杂环基,其任选地被选自卤素和C1-C6烷基的基团取代;
3)与六元不饱和含氮环基或杂环基缩合的包含1至3个选自N和S的杂原子的五元不饱和杂环基,其任选地被1或2个选自C1-C6烷基的取代基取代,所述六元不饱和含氮环基或杂环基任选地被1或2个选自羟基、卤素或C1-C6烷基的取代基取代;
4)与包含1至3个选自N和S的杂原子的五元或六元不饱和杂环基缩合的包含1至2个氮原子的六元不饱和环基或杂环基;或者
5)下式的基团:
。
17.根据权利要求16所述的方法,其中所述脱水剂是戊二酸酐,并且所述方法在有机溶剂中加热进行。
18.根据权利要求17所述的方法,其中所述有机溶剂是二甲基甲酰胺。
19.根据权利要求16所述的方法,其中所述脱水剂是丙酸酐,并且所述方法在有机溶剂中加热进行。
20.根据权利要求19所述的方法,其中所述有机溶剂是甲苯。
21.根据权利要求19所述的方法,其中所述方法在添加乙酸钠的情况下进行。
22.根据权利要求16所述的方法,其中所述脱水剂是乙酸酐,并且所述方法在有机溶剂中加热进行。
23.根据权利要求22所述的方法,其中所述有机溶剂是二氧六环。
24.根据权利要求22所述的方法,其中所述方法在添加乙酸钠的情况下进行。
25.根据权利要求16所述的方法,其中所述脱水剂是氯代乙酸酐,并且所述方法在有机溶剂中加热进行。
26.根据权利要求25所述的方法,其中所述有机溶剂是乙酸。
27.根据权利要求16所述的方法,其中所述脱水剂和所述溶剂为乙酸酐,并且所述方法在90°C至100°C下进行。
28.根据权利要求16所述的方法,其中所述脱水剂为羰基二咪唑。
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CN110229140B (zh) * | 2013-04-12 | 2022-06-10 | 制药有限责任公司 | 戊二酰亚胺衍生物、其用途、基于所述衍生物的药物组合物及戊二酰亚胺衍生物的制备方法 |
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Granted publication date: 20190906 |