CN1665829A - 非甾类抗炎物质、组合物及其使用方法 - Google Patents
非甾类抗炎物质、组合物及其使用方法 Download PDFInfo
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- CN1665829A CN1665829A CN038160927A CN03816092A CN1665829A CN 1665829 A CN1665829 A CN 1665829A CN 038160927 A CN038160927 A CN 038160927A CN 03816092 A CN03816092 A CN 03816092A CN 1665829 A CN1665829 A CN 1665829A
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- 239000002260 anti-inflammatory agent Substances 0.000 title description 4
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Abstract
本发明涉及(a)通式I表示的新化合物、(b)其药学上可接受的盐、前体药物和溶剂化物、(c)其制备方法和中间体和(d)它们在治疗人和动物的炎性疾病和失调中的应用:其中M表示来源于具有在炎性细胞内累积特性的大环内酯的大环内酯亚单位(大环内酯部分),D表示来源于具有抗炎、止痛和/或解热活性的非甾类药物(NSAID)的非甾类亚单位(非甾类部分),且L表示共价连接M和D的连接基。
Description
本申请要求2002年7月8日提交的美国临时申请的60/394,671的优先权。
技术问题
本发明涉及一般通式I表示的抗炎化合物、其药学上可接受的盐和溶剂化物、其制备方法和中间体以及这些化合物在治疗人和动物炎性疾病和病症中的应用。
现有技术
具有不同作用机制的非甾类抗炎药物对特定的炎症介体起作用,由此提供治疗作用。由于不仅在作用机制、而且在所抑制的特定炎症介体方面存在差异,所以甾类和非甾类药物具有不同的抗炎作用特性,由此对特定的病症而言,某些药物可能比其它药物更为合适。此外,大部分非甾类抗炎药物并非绝对具有特异性,并且在以较大剂量或长期使用时其应用伴随有不利的副作用。已知许多非甾类抗炎药物起内源性COX-1酶抑制剂的作用,而内源性COX-1酶在维持胃粘膜完整性方面极为重要。因此,这些药物的应用通常导致胃粘膜受损乃至出血。(Warner T.D.《美国国家科学院学报》(Proc.Natl.Acad.Sci.U.S.A.)1999,96,7563-7568)。因此,选择性抑制COX-2、而不抑制COX-1的活性剂对治疗炎性疾病是优选的。另外,已知某些抗炎化合物(诸如茶碱)具有极窄的治疗指数,其应用受限。
近来,FDA批准特异性阻断COX-2的非甾类抗炎药塞来考昔(celecoxib)用于治疗类风湿性关节炎(Luong等《药物治疗学年鉴》(Ann.Pharmacother.)2000,34,743-760)。COX-2还在许多癌症和癌前期损害中得到表达,并且存在选择性COX-2抑制剂可以用于治疗和预防结肠直肠癌和其它癌症的确定证据(Taketo,M.M.,《国家癌症研究院杂志》(J.Natl.Cancer Inst.)1998,90,1609-1620,Fournier等《细胞生物化学杂志》(J.Cell Biochem.)增刊2000,34,97-102)。
大环内酯类、诸如大环内酯类抗生素优选累积在给予这类分子的受试者的不同细胞中,尤其是在吞噬细胞中,诸如单核外周血细胞、腹膜和肺泡巨噬细胞;以及支气管肺泡上皮周围的液体中(Glaude R.P.等《抗菌剂与化疗》(Antimicrob.Agents Chemother.),1989,33,277-282;Olsen K.M.等《抗菌剂与化疗》(Antimicrob.AgentsChemother.)1996,40,2582-2585)。此外,描述了某些大环内酯类相对弱的炎性作用。例如,近来描述了红霉素衍生物(Labro M.T.《抗菌药与化疗杂志》(J.Antimicrob.Chemother.),1998,41,37-46;WO00/42055)和阿奇霉素衍生物(EP 0283055)的抗炎作用。还从实验性动物模型的体外和体内研究中得知了某些大环内酯类的抗炎作用,诸如zimosane-诱导的小鼠腹膜炎(Mikasa等《抗菌药与化疗杂志》(J.Antimicrob.Chemother.)1992,30,339-348)和内毒素-诱导的大鼠气管中性白细胞累积(《免疫学杂志》(J.Immunol.)1997,159,3395-4005)。大环内酯类对细胞因子、诸如白细胞介素8(IL-8)(《美国呼吸疾病保健药物标准杂志》(Am.J.Respir.Crit.Care Med.)1997,156,266-271)或白细胞介素5(IL-5)(EP 0775489和EP 0771564)的调节作用也是已知的。
在1975年,将TNF-α定义为内毒素诱导并在体外和体内导致肿瘤坏死的血清因子(Carswell EA等,《美国国家科学院学报》(Proc.Natl.Acad.Sci.U.S.A.),1975,72:3666-3670)。除抗肿瘤作用外,TNF-α还具有许多其它在生物体内稳态和病理生理状况方面重要的生物作用。TNF-α的主要来源为单核细胞-巨噬细胞、T-淋巴细胞和肥大细胞。
抗-TNF-α抗体(cA2)对患有类风湿性关节炎(RA)的患者具有治疗作用这一发现(Elliott M等,《柳叶刀》(Lancet),1994,344:1105-1110)导致对寻找能够作为RA的有效药物的新TNF-α抑制剂的兴趣增加。类风湿性关节炎是一种自身免疫性慢性炎症疾病,其特征在于关节发生不可逆的病理改变。除RA疗法外,TNF-α拮抗剂还可以用于许多病理状况和疾病,诸如脊椎炎、骨关节炎、痛风和其它关节炎性疾病、脓毒症、脓毒性休克、毒性休克综合征、特应性皮炎、接触性皮炎、牛皮癣、肾小球肾炎、红斑狼疮、硬皮病、哮喘、恶病质、慢性阻塞性非失调、充血性心力衰竭、胰岛素抵抗、肺纤维化、多发性硬化、克罗恩病、溃疡性结肠炎、病毒感染和AIDS。
通过对小鼠进行的体内实验获得了表示TNF-α的生物重要性的证据,其中用于TNF-α或其受体的小鼠基因失活。这类动物耐受胶原蛋白诱发的关节炎(Mori L等,《免疫学杂志》(J.Immunol.),1996,157:3178-3182)并耐受内毒素导致的休克(Pfeffer K等,《细胞》(Cell),1993,73:457-467)。在TNF-α水平增加的动物试验中,发生慢性炎性多关节炎,其通过抑制TNF-α产生得到减轻(Georgopoulos S等,《炎症杂志》(J.Inflamm.),1996,46:86-97;Keffer J等,《欧洲分子生物学协会杂志》(EMBO J.),1991,10:4025-4031)。对这类炎症和病理状况的治疗通常包括施用非类固醇抗炎药且在更严重的情况中给予金盐、D-青霉胺或甲氨蝶呤。所述的药物根据症状起作用,但它们不会使病理状况停止。类风湿性关节炎疗法中的新手段基于药物,诸如替尼达普、来氟米特、环孢素、FK-506并基于抵消TNF-α作用的生物分子。目前存在商购的依那西普(etanercept)(Enbrel,Immunex/Wyeth)、即可溶性TNF-α受体的融合蛋白和英夫利昔单抗(infliximab)(Remicade,Centocor)、即小鼠和人嵌合单克隆抗体。除用于RA疗法外,依那西普和英夫利昔单抗已被批准用于克罗恩病疗法(Exp.Opin.Invest.Drugs,2000,9:103)。
迄今为止尚未描述代表本发明主题的通式I表示的新化合物、其药学上可接受的盐、水合物、前体药物和包括它们的药物组合物。
此外,尚未将代表本发明主题的化合物描述为抗炎物质或TNF-α抑制剂或COX-1/COX-2抑制剂或IL-1β抑制剂。因此,尚未描述或提示这类“杂化”(hybrid)大环内酯/NSAID化合物在抗炎中的应用,也没有描述或提示含有有效量的杂化大环内酯/NSAID化合物的用于治疗哺乳动物对象、包括人的炎症状态的药物剂型。
技术方案
通式I的化合物不同于迄今为止已知化合物的方面在于它们在对患有炎症状态的器官或组织联用时结合了NSAID部分的抗炎特性和大环内酯部分提供的补充的(与大环内酯类优先累积的免疫系统细胞一起)累积特性,并且导致基本上更多地局限于炎症部分和/或强化对炎症的缓解作用。由结构I表示的新化合物的这类作用来源于大环内酯部分M,这是由于大环内酯类累积在炎症分布的免疫细胞内的特定药动学特性所致,所述的免疫细胞诸如吞噬细胞,包括多形核细胞、嗜酸性细胞、肺泡吞噬细胞等。通式I的化合物具有改善的药动学和/或安全性分布(甚至对那些作为更具选择性的COX-2抑制剂的NSAID而言),并且存在较少和/或更为良性的副作用。
传统的非甾类抗炎药(NSAID)将COX-1和COX-2抑制至改变的程度。吲哚美辛也是非选择性COX抑制剂,但当与大环内酯部分连接时,它成为应显著减少乃至消除母体化合物胃肠副作用的更具选择性的COX-2抑制剂。然而,甚至更具选择性的COX-2抑制剂的NSAID也得益于按照本发明与大环内酯轭合(conjugation),至少因为它们″靶向″至炎症部位,在那里它们可以发挥抗炎作用,而同时它们与其它组织或生理过程的相互作用可以产生副作用。认为尚未描述属于本发明主题的通式I表示的化合物、这类化合物的异构体形式、其药学上可接受的盐、溶剂化物和包括它们的药物组合物。此外,尚未将本发明的化合物描述为抗炎物质或嗜酸性细胞在器官或组织中累积的抑制剂。
本发明涉及:
(a)通式I表示的新″杂化″化合物:
其中M表示具有在炎性细胞中累积特性的大环内酯亚单位,D表示具有抗炎、止痛和/或解热活性的非甾类抗炎亚单位(NSAID),且L表示共价连接M和D的连接基;
(b)含有上述化合物中的一种或多种的组合物,所述化合物的用量可有效抗炎并由此治疗涉及哺乳动物、包括人的炎症的失调和病症;和
(c)使用这些化合物治疗这类失调和病症的方法。
本发明的化合物可有利地提供改善的治疗作用和/或改善的副作用分布。
可以并不限于从多元内酯环分子中选择用于本发明杂化化合物的合适的大环内酯亚单位,其中″元″指的是环上的碳原子或杂原子,且″多″是原子数超过约10个,优选10-约50个,更优选12-、14-、15-、16-、17-和18-元内酯环的大环内酯类。特别优选14-和15-元环的大环内酯亚单位,最优选阿奇霉素及其衍生物和红霉素及其衍生物。
可以从中选择的大环内酯亚单位的更具体的非限制性实例如下:
(i)大环内酯抗菌素,包括:氮杂内酯类(azalides),例如红霉素、地红霉素、阿奇霉素、9-二氢-9-脱氧-9a-氮杂-9a-高红霉素、HMR 3004、HMR 3647、HMR 3787、交沙霉素、红霉胺(erythromycylamine)、ABT 773、氟红霉素、克拉霉素、泰洛星、替米考星、竹桃霉素、脱碳霉糖泰乐菌素(desmycosin)、CP-163505、罗红霉素、美奥卡霉素和洛他霉素及其衍生物,诸如酮内酯类(例如3-酮);内酰胺类(例如8a-或9a-内酰胺类)和缺乏一个或多个糖部分的衍生物。
(ii)大环内酯免疫抑制剂,诸如FK 506、环孢菌素、两性霉素和雷帕霉素;
(iii)具有宿主细胞抑制特性的大环内酯抗真菌药,诸如巴弗洛霉素、刀球肮霉素、制霉菌素、那他霉素、克念菌素、非律平(filipin)、鲁斯霉素(etruscomycin)、曲古霉素(trichomycin)。
用于合成上述并非商购的大环内酯类的方法和大环内酯的合成操作一般是本领域技术人员所公知的或可以在下列文献中找到:Denis A等《生物有机和药物化学通讯》(Bioorg.& Med.Chem.Lett)1999,9,3075-3080;Agouridas C.等《药物化学杂志》(J.Med.Chem.)1998,41,4080-4100;和EP-00680967(1998);Sun Or Y.等《药物化学杂志》(J.Med.Chem.)2000,43,1045-1049;US-05747467(1998);McFarland J.W.等《药物化学杂志》(J.Med.Chem.)1997,40,1041-1045;Denis A.等《生物有机和药物化学通讯》(Bioorg.& Med.Chem.Lett)1998,8,2427-2432;WO-09951616(1999);Lartey等《药物化学杂志》(J.Med.Chem.)1995,38,1793-1798;EP 0984019;WO 98/56801,将这些文献的全部内容引入本文作为参考。
其它合适的大环内酯类是已知的,某些公开在下列文献中:Bryskier,A.J.等的《大环内酯类、化学、药理学和临床应用》(Macrolides,Chemistry,Pharmacology and Clinical Use);Arnette Blackwell:Paris,1993,pp 485-491,14(R)-羟基克拉霉素、红霉素-11,12-碳酸酯、三-O-乙酰基竹桃霉素、螺旋霉素、白霉素、麦迪霉素、rasaramycin,将该文献的全部内容引入作为参考;Ma,Z.等《最新药物化学-抗感染药》(Current Medicinal Chemisty-Anti-Infective Agents),2002,1,15-34,也将该文献的全部内容引入作为参考;苦霉素、那波霉素、HMR-3562、CP-654743、CP-605006、TE-802、TE-935、TE-943、TE-806、6,11-桥连的酮内酯类、CP-544372、FMA-199、A-179461;和Romo,D.等《美国化学协会杂志》(J.Am.Chem.Soc.)1998,120;12237-12254,也将该文献的全部内容引入作为参考。特别参见:Brys kier等在487-491页上描述的14-和16-元环的大环内酯类的结构和衍生物;和Ma等描述的各种酮内酯衍生物和合成,注意所有的结构表和所有的反应方案。与NSAIDs轭合后的所有这些大环内酯类属于本发明的范围。上述特别具体命名或参照的大环内酯化合物是商购的或其合成方法是已知的。
重要的是大环内酯亚单位来源于具有累积在补充至炎症部位的免疫系统细胞、尤其是吞噬细胞内特性的大环内酯。已知上述定义的大部分内酯类化合物具有这种特性。例如:14-元大环内酯类,诸如红霉素及其衍生物;15-元大环内酯类,诸如阿奇霉素及其衍生物以及8a-和9a-内酰胺类及其衍生物;16-元大环内酯类,诸如替米考星、脱碳霉糖泰乐菌素;和螺旋霉素。
累积在特定类细胞中的大环内酯类的其它实例可以在下列文献中找到:Pascual A.等《临床微生物感染》(Clin.Microbiol.Infect.)2001,7,65-69.(“酮内酯HMR 3647在人吞噬和非吞噬细胞中的吸收和胞内活性”(Uptake and intracellular activity of ketolide HMR 3647in human phagocytic and non-phagocytic cells));Hand W.L.等《国际抗菌药杂志》(Int.J.Antimicrob.Agents),2001,18,419-425.(“阿奇霉素在人多形核白细胞中累积和流出的特性和机制”(Characteristics and mechanisms of azithromycin accumulation andefflux in human polymorphonuclear leukocytes));Amsden G.W.《国际抗菌药杂志》(Int.J.Antimicrob.Agents),2001,18,11-15.(“新一代大环内酯类:定向于组织的抗菌素”(Advanced-generationmacrolides:tissue-directed antibiotics));Johnson J.D.等《实验室临床药物杂志》(J.Lab.Clin.Med.)1980,95,429-439.(“肺泡巨噬细胞的抗生素吸收”(Antibiotic uptake by alveolarmacrophages));Wildfeuer A.等《抗菌药与化疗》(Antimicrob.AgentsChemother.)1996,40,75-79.(“体内条件下各种细胞对阿奇霉素的吸收及其胞内活性”(Uptake of azithromycin by various cells和itsintracellular activity under in vivo conditions));Scorneaux B.等《家禽科学》(Poult.Sci.)1998,77,1510-1521.(“替米考星在鸡吞噬细胞中的胞内累积、亚细胞分布和流出”(Intracellularaccumulation,subcellular distribution,and efflux of in chickenphagocytes));Mtairag E.M.等《抗菌剂与化疗杂志》(J.Antimicrob.Chemother.)1994,33,523-536。(“人中性白细胞体外地红霉素和红霉胺吸收的研究”(Investigation of dirithromycin and红霉胺uptake by human neutrophils in vitro));Anderson R.等《抗菌剂与化疗杂志》(J.Antimicrob.Chemother.)1988,22,923-933.(“新大环内酯抗菌药克拉霉素(A-56268,TE-031)的细胞吸收和吞噬细胞内生物活性的体外评价”(An in-vitro evaluation of the cellularuptake and intraphagocytic bioactivity of clarithromycin(A-56268,TE-031),a new macrolide antimicrobial agent));TasakaY.等《日本抗生素杂志》(Jpn.J.Antibiot.)1988,41,836-840.(“肺泡巨噬细胞的洛他霉素吸收”(Rokitamycin uptake by alveolarmacrophages));Harf R.等《抗菌剂与化疗杂志》(J.Antimicrob.Chemother.)1988,22,135-140.(“肺泡巨噬细胞的螺旋霉素吸收”(Spiramycin uptake by alveolar macrophages)),将这些文献的全部内容引入本文作为参考。
此外,补充至炎症部位的免疫系统细胞、尤其是吞噬细胞内累积活性的存在易于由本发明领域的普通技术人员使用用于该目的的众所周知的试验之一测定。例如,可以使用Olsen,K.M.等在《抗菌剂与化疗》(Anitmicrob.Agents & Chemother.)1996,40,2582-2585中所述的具体步骤。简单的说,可以通过Ficoll-Hypaque离心从健康志愿者的静脉血中获得受测试的细胞、例如多形核白细胞,随后进行2%葡聚糖沉降。通过渗透裂解除去红细胞并通过锥虫蓝排除法评价PMN。另一方面,可以分离其它细胞级分并按照类似方式测试。将氚代的大环内酯化合物(例如10μM)与2.5×106个细胞一起保温120分钟(37℃,5%CO2,90%相对湿度)且随后通过离心、例如通过硅油-石蜡层(86vol%∶14vol%)从含有化合物的上清液中除去细胞。例如,通过闪烁计数测定化合物的量,并且显著高于背景的得分表明大环内酯累积在测试细胞中。参见Bryskier等《大环内酯、化学、药理学和临床应用》(Mcrolides,Chemistry,Pharmacology and Clinical Use);Arnette Blackwell:Paris,1993pp 375-386,381页,第2栏,第3行。另一方面,不对该化合物进行放射性标记,而可以通过HPLC测定化合物的量。
可以使用的其它试验方法公开在Bryskier,A.J.等的《大环内酯、化学、药理学和临床应用》(Mcrolides,Chemistry,Pharmacology andClinical Use);Arnette Blackwell:Paris,1993 pp 375-386中,将该文献引入作为参考。特别参见380-381页上的吞噬细胞吸收测定和381、383和385页以及382和383页上的表对大环内酯类吸收和定位的具体描述。
本发明在某些优选的实施方案中涉及通式I表示的化合物、其盐和溶剂化物,其中M特别表示14-或15-元内酯环的大环内酯亚单位,最优选通式II表示的化合物:
其中:
Rt和Rs独立为H或烷基(优选甲基或H);
RM为OH、ORP、烷氧基或取代的烷氧基(Syn或Anti构型或其混合物);
RN为H、RP、烷基、链烯基、炔基、烷氧基、烷氧基烷基或-C(=X)-NRtRs;
X为O或S;
(ii)U和Y独立为H、卤素、烷基或羟基烷基(优选H、甲基或羟基甲基);
(iii)R1为羟基ORP、-O-S2或=O;
(iv)S1为如下通式的糖苷配基(例如去氧糖胺基团)环C/5位上的糖部分:
其中:
R8和R9均为氢或一起形成键或R9为氢且R8为-N(CH3)Ry,其中:
Ry为RP、RZ或-C(O)RZ,其中RZ为氢或环烷基(优选环己基)或烷基(优选C1-C7烷基)或链烯基(优选C2-C7链烯基)或炔基(优选C2-C7炔基)芳基或杂芳基或可以为被C1-C7烷基或C2-C7链烯基或C2-C7炔基或芳基或杂芳基取代的烷基。(Ry优选氢、甲基或乙基);
R10为氢或RP;
(v)S2为如下通式的糖苷配基(例如克拉定糖基)环C/3位上的糖部分:
其中R3’可以为氢或甲基;且R11和R12独立为氢,R11可以为RP或R11和R12共同形成键;
(vi)R2为氢、羟基、ORP或烷氧基(优选C1-C4烷氧基,最优选甲氧基)、取代的烷氧基;
(vii)A为H或甲基;
(viii)B为甲基或环氧基;
(ix)E为氢或卤素(优选氟);
(x)R3为羟基、ORP或烷氧基(优选C1-C4烷氧基,最优选甲氧基),取代的烷氧基或R3为可以与R5一起形成″桥″(例如环碳酸酯或环氨基甲酸酯)的基团或如果W或Z为
那么R3为与W或Z一起形成″桥″(例如环氨基甲酸酯)的基团;
(xi)R4为C1-C4烷基(优选甲基);
(xii)R5为氢、羟基、ORP、C1-C4烷氧基、取代的烷氧基或可以与R3一起形成″桥″(例如环碳酸酯或环氨基甲酸酯)的基团;
(xiii)R6为H或C1-C4烷基(优选甲基或乙基);
其中亚单位M含有连接位置,它通过该位置经连接基L与亚单位D连接;所述的连接位置位于下列基团中的一个或多个上:
a.位于S1、S2或糖苷配基氧上的任意活性羟基、N或环氧基团,条件是S2(或条件是S2和S1均)被裂解;
b.位于Z或W上的活性>N-RN、-NRtRs或=O;
c.位于R1、R2、R3和R5中任意一个上的活性羟基;
一个或多个RP基团可以独立地存在于通式II的大环内酯亚单位上,其中RP表示保护基,其可以选自烷基(优选甲基)、烷酰基(优选乙酰基)、烷氧羰基(优选甲氧羰基或叔丁氧羰基)、芳基甲氧羰基(优选苄氧羰基)、芳酰基(优选苯甲酰基)、芳烷基(优选苄基)、烷基甲硅烷基(优选三甲基甲硅烷基)或烷基甲硅烷基烷氧基烷基(优选三甲基甲硅烷基乙氧基甲基)。可以通过常规技术除去氨基保护基。因此,可以通过溶剂解、例如通过在酸性或碱性条件下水解除去例如酰基,如烷酰基、烷氧羰基或芳酰基。可以在有催化剂、诸如钯/活性炭存在的情况下通过氢解裂解芳基甲氧羰基(苄氧羰基)。
可以将L选为通式IV表示的连接基:
X1-(CH2)m-Q- (CH2)n-X2 IV
其中:
X1选自-CH2-、-OC(=O)-、-C(=O)-、NO-、-OC(=O)NH-或-C(=O)NH-;
X2选自-NH-、-CH2-、-NHC(=O)-、-OC(=O)-、-C(=O)-或-O;
Q为-NH-或-CH2-或不存在;
其中-CH2-或-NH-基团各自可以任选被C1-C7-烷基、C2-C7-链烯基、C2-C7-炔基、C(O)RX、C(O)ORX、C(O)NHRX取代,其中RX可以为C1-C7-烷基、芳基或杂芳基;
符号m和n独立为0-4的整数,
条件是如果Q=NH,那么n不能为0。
不仅对通式II的NSAIDs和大环内酯类的杂化物、而且对通式I中的任意轭合物优选该连接基的定义。正如本领域中众所周知的,可以使用其它连接基,条件是它们提供必要的间隔基且可以用于连接通式I的一个亚单位与另一个亚单位。例如,参见美国专利US 6,297,260,将该文献的全部内容引入本文作为参考,尤其是其权利要求1和NSAID的具体目录。
在通式I中,D表示非甾类抗炎亚单位,即非甾类抗炎药(NSAID)的部分。合适的NSAID包括但不限于抑制环加氧酶的那些药物,所述的酶可以导致前列腺素和某些自体激素抑制剂的生物合成,包括各种环加氧酶的各种同工酶(包括但不限于环加氧酶-1和-2)抑制剂;且作为环加氧酶和脂氧化酶抑制剂涉及非甾类抗炎药(NSAID),诸如商购的NSAID醋氯芬酸、阿西美辛、对乙酰氨基酚、醋氨沙洛、乙酰水杨酸、乙酰基-水杨-2-氨基-4-甲基吡啶-酸、5-氨基乙酰水杨酸、阿氯芬酸、氨洛芬、氨芬酸、氨基安替比林、安吡昔康、阿尼利定、苄达酸、苯噁洛芬、柏莫洛芬、α-没药醇(α-bisabolol)、溴芬酸、5-溴水杨酸乙酸酯、溴水杨苷、布氯酸、丁布芬、卡洛芬、塞来考昔、chromoglycate、桂美辛、clindanac、氯吡酸、双氯芬酸钠、二氟尼柳、地他唑、屈噁昔康、恩芬那酸、依托度酸、依托芬那酯、联苯乙酸、芬布芬、芬克洛酸、芬度柳、非诺洛芬、芬替酸、非普地醇、flufenac、氟芬那酸、氟尼辛、氟诺洛芬、氟比洛芬、glutametacin、水杨酸乙二醇酯、异丁芬酸、布洛芬、异丁普生、吲哚美辛、吲哚洛芬、三苯唑酸、伊索克酸、伊索昔康、酮洛芬、酮咯酸、氯诺昔康、洛索洛芬、甲氧芬那酸、甲芬那酸、美洛昔康、5-氨基水杨酸、甲嗪酸、莫苯唑酸、孟鲁司特、萘丁美酮、萘普生、尼氟酸、尼美舒利、奥沙拉秦、奥沙西罗、噁丙嗪、羟布宗、对乙酰氨基酚、帕沙米特、哌立索唑、苯乙酰水杨酸酯(phenyl-acethyl-salicylate)、保泰松、水杨酸苯酯、吡拉唑酸、吡罗西康、吡洛芬、普拉洛芬、丙替嗪酸、reserveratol、醋水杨胺、水杨酰胺、水杨酰胺-O-乙酸(salicylamide-O-acetyl acid)、水杨酰硫酸酯(salicysulphuric acid)、水杨苷、水杨酰胺、双水杨酯、舒林酸、舒洛芬、suxibutazone、他莫昔芬、替诺昔康、噻洛芬酸、噻拉米特、ticlopridine、替诺立定、托芬那酸、托美丁、tropesin、联苯丁酸、希莫洛芬、扎托洛芬、佐美酸、托莫普罗、扎鲁司特和环孢菌素。其它NSAID类和特定的NSAID化合物公开在美国专利US 6,297,260中,将该文献全部引入作为参考(尤其是在其权利要求1的一般通式和其中包含的对NSAID的具体目录的详述中);且thiazulidene NSAIDs公开在国际专利申请WO 01/87890中,将该文献的全部内容引入本文作为参考。
优选的NSAID为乙酰水杨酸、吲哚美辛、萘普生、布洛芬、氟比洛芬、酮洛芬、舒林酸、依托度酸、酮咯酸、舒洛芬、氟尼辛、双氯芬酸钠和托美丁。
本文中包含的通式中的黑体键表示位于纸面水平上;绘制的虚线键(dash-drawn bond)表示位于纸面水平下,而虚线(broken line)表示可以位于纸面水平下或其上的键。平行实线和虚线表示单键或双键。除非本文另有说明,下列术语具有下文对其所解释的含义:
″烷基″指的是1-10个碳原子、更优选1-6个碳原子的直链或支链饱和一价烃基。优选的直链或支链烷基包括甲基、乙基、丙基、异丙基、丁基、仲丁基和叔丁基。最优选甲基。烷基可以被至多5个取代基取代,包括卤素(优选氟或氯)、羟基、烷氧基(优选甲氧基或乙氧基)、酰基、酰氨基、氰基、氨基、N-(C1-C4)烷氨基(优选N-甲氨基或N-乙氨基)、N,N-二(C1-C4-烷基)氨基(优选二甲氨基或二乙氨基)、芳基(优选苯基)或杂芳基、硫代羰基氨基、酰氧基、氨基、脒基、烷基脒基、硫代脒基、氨基酰基、氨基羰基氨基、氨基硫代羰基氨基、氨基羰基氧基、芳基、杂芳基、芳氧基、芳氧基芳基、硝基、羧基、羧基烷基、羧基取代的烷基、羧基-环烷基、羧基取代的环烷基、羧基芳基、羧基取代的芳基、羧基杂芳基、羧基取代的杂芳基、羧基杂环基、羧基取代的杂环基、环烷基、环烷氧基、杂芳氧基、杂环基氧基和氧基羰基氨基。这类取代的烷基属于本发明″烷基″的定义范围。本发明烷基的定义可以扩展至其它带有烷基部分的基团,诸如烷氧基。
″链烯基″指的是2-10且优选2-6个碳原子的含有至少一个碳-碳双键的直链或支链一价烃基。链烯基可以被与烷基相同的基团取代且这类任选取代的链烯基包括在术语″链烯基″中。优选乙烯基、丙烯基、丁烯基和环己烯基。
″炔基″指的是带有2-10且优选2-6个碳原子的直链或支链且含有至少一个且优选不超过三个碳-碳三键的直链或支链一价烃基。炔基可以被与烷基相同的基团取代且这些取代的基团属于该炔基的定义中。优选乙炔基、丙炔基和丁炔基。
″环烷基″指的是带有3-8个碳原子的含有任选与芳基或杂芳基稠合的单环的环状基团。环烷基可以被如下对″芳基″所述的取代基取代,并且取代的环烷基属于该″环烷基″的定义范围。优选的环烷基为环戊基和环己基。
″芳基″指的是带有6-14个碳原子的含有单环、诸如苯基或多稠合环、诸如萘基的不饱和芳族碳环基。芳基可以任选进一步与脂族基团或芳基稠合或可以被一个或多个取代基取代,诸如卤素(氟、氯和/或溴)、羟基、C1-C7烷基、C1-C7烷氧基或芳氧基、C1-C7烷硫基或芳硫基、烷基磺酰基、氰基或伯氨基或非伯氨基。
″杂芳基″指的是含有2-10个碳原子和1-4个杂原子、诸如O、S或N的单环或二环芳烃环。杂芳环可以任选与另一个杂芳基、芳基或脂族环状基团稠合。该类的实例为呋喃、噻吩、吡咯、咪唑、吲哚、吡啶、噁唑、噻唑、吡咯、吡唑、四唑、嘧啶、吡嗪和三嗪,优选呋喃、吡咯、吡啶和吲哚。该术语包括被如对上述芳基所述相同的取代基取代的基团。
″杂环基″指的是含有单环或多环以及1-10个碳原子和1-4个选自氮、硫或氧的杂原子的饱和或不饱和基团,其中在稠合环系中,另一个环或其它环可以为芳基或杂芳基。杂环基可以被如对烷基所述的取代基取代且由此取代的杂环基属于本定义的范围。
本发明还包括本发明化合物的药学上可接受的盐。本发明化合物的药学上合适的盐包括与无机酸(例如盐酸、氢溴酸、磷酸、偏磷酸、硝酸或硫酸)或有机酸(例如酒石酸、乙酸、甲磺酸、三氟乙酸、柠檬酸、马来酸、乳酸、富马酸、苯甲酸、琥珀酸、甲磺酸、草酸和对甲苯磺酸)形成的盐。
本发明还包括通式I化合物的前体药物,即在对哺乳动物受试者给药时在体内释放通式(I)的活性母体药物的化合物。通过修饰存在于通式I化合物上的官能基制备通式I化合物的前体药物,按照这类方式使所述的修饰物可以在体内被裂解以释放母体化合物。前体药物包括通式I的化合物,其中通式I化合物的羟基、氨基或羧基与任意可以在体内被裂解而分别重新生成羟基、氨基或羧基的基团结合。前体药物的实例包括但不限于通式I化合物的酯类(例如乙酸酯、甲酸酯和苯甲酸酯衍生物)或在接触生理pH时或通过酶作用被转化成活性母体药物的任意其它衍生物。
本发明还包括通式I化合物或其盐的溶剂化物(优选水合物)。
通式I的化合物带有一个或多个手性中心且随各取代基性质的不同,它们还可以具有几何异构体。在原子空间排列上不同的异构体称作″立体异构体″。彼此不为镜像的立体异构体称作″非对映体″且那些彼此为不能重叠的镜像的称作″对映体″。当化合物带有一个手性中心时,出现一对对映体是可能的。对映体的特征可以在于其不对称中心的绝对构型且由Cahn和Prelog的R-和S-顺序法则描述或通过分子绕偏振光面旋转的方式描述并命名为右旋或左旋(即分别称作(+)或(-)-异构体)。手性化合物可以作为单个对映体或作为对映体混合物存在。含有等比例的对映体的混合物称作″外消旋混合物″。本发明包括通式I化合物的所有各异构体。在本说明书和权利要求中对特定化合物的描述或命名用以包括各对映体及其混合物,否则就是其外消旋物。用于测定立体异构体的立体化学及其拆分的方法是本领域众所周知的。
本发明还包括遇到的syn-anti型立体异构体及其混合物,此时存在肟或类似基团。将与肟的末端双键原子连接的最高Cahn Ingold Prelog优先顺序法则的基团与肟的羟基比较。将该立体异构体命名为Z(zusammen=共同)或Syn,条件是肟羟基位于通过C=N双键的参考面的同侧上作为最优先基团;将另一种立体异构体命名为E(entgegen=相反)或Anti。
″药学上可接受的赋形剂″指的是用于制备一般安全、无毒性且既无生物上又无其它不需要的作用的药物组合物的赋形剂且包括对兽药应用和人药应用而言可接受的赋形剂。本申请中所用的″药学上可接受的赋形剂″包括一种和一种以上这类赋形剂。
″治疗(Treating)″或″治疗(treatment)″状态、失调或病症包括:
(1)预防或延缓在哺乳动物中发生的状态、失调或病症的临床症状的表现,所述的哺乳动物可以患有或倾向于所述的状态、失调或病症,但尚未发生或出现所述状态、失调或病症的临床或亚临床症状;
(2)抑制状态、失调或病症,即阻止或减缓疾病或其至少一种临床或亚临床症状的发生;或
(3)减轻疾病,即使状态、失调或病症或其至少一种临床或亚临床症状退化。
对治疗的受试者的有益性或具有统计学意义或至少对患者或临床医师而言是可感受到的。
″治疗有效量″指的是当对哺乳动物给药治疗状态、失调或病症时足以进行这类治疗的用量。″治疗有效量″随化合物、疾病及其严重程度和所治疗哺乳动物的身体情况和反应性的不同而改变。
急性炎症的四种传统症状为患病区域发红、升温、肿胀和疼痛且患病器官功能丧失。
与具体病症相关的炎症症状和征候包括:
·类风湿性关节炎-涉及的关节疼痛、肿胀、温热和触痛;全身性强直和晨僵;
·胰岛素依赖性糖尿病-胰岛炎;该病可以导致各种与炎性成分相关的并发症,包括视网膜病、神经病、肾病;冠状动脉疾病、外围血管疾病和脑血管疾病;
·自身免疫性甲状腺炎-虚弱、便秘、气短、面部、手和足浮肿(puffiness)、外周性水肿、心律过缓;
·多发性硬化-痉挛状态、视力模糊、眩晕、肢体虚弱、感觉异常;
·眼色素层视网膜炎-夜视力下降、周边视力降低;
·红斑狼疮-关节痛、疹、光敏感性、发热、肌痛、手和足浮肿、尿液分析异常(血尿、管型尿(cylinduria)、蛋白尿)、肾小球肾炎、认知功能障碍、血管血栓形成、心包炎;
·硬皮病-雷诺氏病;手、臂、腿和面部肿胀;皮肤增厚;手指和膝疼痛、肿胀强直、胃肠功能障碍、限制性肺病;心包炎;肾衰竭;
·具有炎性成分的其它关节炎性疾病,诸如类风湿性脊椎炎、骨关节炎、脓毒性关节炎和多关节炎-发热、疼痛、肿胀、触痛;
·其它炎性脑病,诸如脑膜炎、阿尔茨海默病、AIDS痴呆性脑炎-畏光、认知功能障碍、记忆损失;
·其它炎性的眼部炎症,诸如视网膜炎-视力下降;
·炎性皮肤病,诸如湿疹、其它皮炎(例如特应性皮炎、接触性皮炎)、牛皮癣、UV照射诱发的灼伤(日光射线和类似的UV源)-红斑、疼痛、脱屑、肿胀、触痛;
·炎症性肠病,诸如克罗恩病、溃疡性结肠炎-疼痛、腹泻、便秘、直肠出血、发热、关节炎;
·哮喘-气短、喘鸣;
·其它过敏性疾病,诸如过敏性鼻炎-喷嚏、痒、鼻漏;
·与急性哮喘相关的疾病,诸如中风后的损伤-感觉缺失、运动丧失、认知丧失;
·因心肌缺血导致的心脏组织损伤-疼痛、气短;
·肺损伤,诸如发生成人呼吸窘迫综合征的肺损伤-气短、换气过度、氧合作用下降、肺浸润;
·伴有感染的炎症,诸如脓毒症、脓毒性休克、中毒性休克综合征-发热、呼吸衰竭、心动过速、低血压、白细胞增多;
·其它与特定器官或组织相关的炎性疾病,诸如肾炎(例如肾小球肾炎)-少尿、尿液分析异常;
附件炎-发热、疼痛、触痛、白细胞增多;
痛风-涉及的关节疼痛、触痛、肿胀和红斑、血清和/或尿的尿酸升高;
胆囊炎-腹痛和触痛、发热、恶心、白细胞增多;
慢性阻塞性肺病-气短、喘鸣;
充血性心力衰竭-气短、啰音、外周性水肿;
II型糖尿病-晚期器官并发症,包括心血管、眼、肾和周围血管疾病;
肺纤维化-换气过度、气短、氧合作用下降;
血管疾病,诸如动脉粥样硬化和再狭窄-疼痛、感觉丧失、脉搏下降、功能丧失;
和导致移植物排斥的同种异体免疫-疼痛、触痛、发热。
亚临床症状包括、但不限于用于炎症的诊断标记,其表现可以先于临床表现。一类亚临床症状为免疫学症状,诸如促炎淋巴样细胞在器官或组织中的侵入或累积或识别对器官或组织特异性的病原体或抗原的活化促炎淋巴样细胞局部或周围的存在。可以通过本领域中公知的技术测定淋巴样细胞的活化。
″转运″至宿主内特定部位的活性组分的治疗有效量指的是在特定部位产生治疗上有效的活性组分的血药浓度。例如,可以通过对宿主局部或全身给予活性组分达到上述目的。
在通式II表示的化合物中,优选Z和W共同为-N(RN)C(O)-、-C(O)N(RN)-、>C-NRsRt、-C(O)-、>C=N-RM、-CH2NRN-或-NRNCH2-,最优选-NCH3CH2-、-NHCH2-、-CH2NH-、-C(O)NH、-NHCO-;
Rs、Rt为甲基或H;
RM为OH或甲氧基;
X为O;
RN为H、甲基或-C(=X)-NRtRs;
A为H或甲基;
U、Y为H、F、甲基或羟甲基;
R1为羟基、-O-S2或=O;
R2为H、羟基或甲氧基;
R3为OH、甲氧基或与W或Z形成环氨基甲酸酯桥的基团;
R4为甲基;
R5为H、OH、甲氧基或与R3形成环碳酸酯或环氨基甲酸酯桥的基团;
连接键通过N/9a或N/8a位上Z的氮或通过均位于S2糖C/4″位上R12的碳或R11的氧;
R6为H、甲基或乙基;
R8为H、N(CH3)2、NH(CH3)或N(CH3)CH2CH3;
R9为H;
连接位置优选位于C/3位上,或通过S1糖C/3′位上或C/11位或W或Z上的氨基或通过S2糖C/4″位。
还优选通式I中的化合物,其中M具有通式II且:(i)Z为NCH3,W为CH2,R2为羟基;或(ii)Z为NH,W为=CO且R2为甲氧基。(该段中所述的化合物可以满足或可以不满足前一部分中剩余的上述优选条件,但优选它们满足这些条件。)
本发明的另一个方面涉及通式I表示的化合物的制备方法。一般来说,可以通过下列方式获得通式I的化合物:首先使链L的一端与大环内酯亚单位M连接,然后使该链的另一端与非甾类亚单位D连接;或首先使链L的一端与非甾类抗炎亚单位D连接,然后使该链的另一端与大环内酯亚单位M连接;或最后,使该链的一个部分与大环内酯亚单位M连接,而使该链的另一个部分与非甾类亚单位D连接,然后使链部分的末端以化学方式连接形成链L。
本领域技术人员可以理解需要使用用于制备通式I化合物的中间体的被保护的衍生物。可以通过本领域中公知的方法对官能基进行保护和脱保护。羟基或氨基可以被任意羟基或氨基保护基保护,例如,如GreenT.W.;Wuts P.G.M.在《有机合成中的保护基》(Protective Groups inOrganic Synthesis):John Wiley和Sons,New York,1999中所述。可以通过常规技术除去氨基保护基。例如,可以通过溶剂解、例如通过在酸性或碱性条件下水解除去酰基、诸如烷酰基、烷氧羰基和芳酰基。可以在有催化剂、诸如钯/活性炭存在的情况下通过氢解裂解芳基甲氧羰基(例如苄氧羰基)。
更具体地说,可以通过下列方法制备通式I中的化合物。
a)可以通过使通式V表示的非甾类抗炎亚单位与通式VIa表示的大环内酯的游离氨基反应生成其中X2为-NH-的通式I化合物,
其中通式V的结构式如下:
其中L1表示离去基团(诸如羟基),
且通式VIa的结构式如下:
该反应一般与具有活化非甾类抗炎亚单位的羧酸基能力的酸性衍生物进行,诸如卤化物、混合的酸酐类且尤其是碳化二亚胺类(诸如-(3-二甲氨基丙基)-3-乙基-碳环二亚胺(EDC)和苯并三唑类)。该反应在室温和惰性气体、诸如氮或氩气环境中并有碱、诸如有机碱(例如三乙胺)存在的情况下进行。该反应可能需要几小时至几天才能完成。
通式V表示的非甾类抗炎亚单位是商购的。非甾类抗炎亚单位D可以含有-C(O)L1基团(诸如游离羧酸基团)或通过本领域中公知的方法衍生。
方案I
按照方案I,可选择地通过下列步骤衍生含有羟基的NSAID化合物:在有吡啶存在情况下的琥珀酸酐的作用,随后使由此产生的中间体与三乙胺、4-吡咯并吡啶在二氯甲烷中反应而生成含有游离羧酸基团的NSAID(Huang C.M.等《化学与生物学》(Chem.& Biol.)2000,7,453-461,Hess S.等《生物有机和药物化学》(Bioorg.& Med.Chem.)2001,9,1279-1291)。可以使由此产生的NSAID衍生物与连接基大环内酯化合物、诸如通式VIa偶联或直接与大环内酯偶联。
方案II
按照方案II,可选择地通过下列步骤衍生含有氨基的NSAID化合物:氢化钠和叔丁基碘乙酸酯在N,N-二甲基甲酰胺中的作用而产生NSAID的丁氧羰基衍生物,然后使其与三氟乙酸在二氯甲烷中反应生成含有游离羧酸基团的NSAID(Hess S.等《生物有机和药物化学》(Bioorg.& Med.Chem.)2001,9,1279-1291)。可以使由此产生的NSAID衍生物与连接基大环内酯化合物、诸如通式VIa偶联或直接与大环内酯偶联。
方案III
可选择地,可以按照方案III衍生含有氨基的NSAID化合物,通过琥珀酸酐在有二甲氨基吡啶、N,N′-二异丙基乙胺存在下的二甲基甲酰胺中的作用产生含有游离羧酸基团的NSAID来进行(Pandori M.W.等《化学与生物学》(Chem.& Biol.)2002,9,567-573)。可以使由此产生的NSAID衍生物与连接基大环内酯化合物、诸如通式VIa偶联或直接与大环内酯偶联。
VIa结构的原料大环内酯亚单位的制备已经描述在PCT/HR02/00001中,将该文献的全部内容引入作为参考,将其复制件作为附录1。另外参见Bright的美国专利US4,474,768和Bright,G.M.等《抗生素杂志》(J.Antibiot.)1988,41,1029-1047,将每篇文献的全部内容引入作为参考。
例如,当L为-K-NH-(其中K为与大环内酯结合的连接分子L的部分)时,可以通过将大环内酯环上的>NH基团衍生成N-K-NH2基团、并使衍生的大环内酯与通式V表示的非甾类抗炎亚单位反应而生成通式I的化合物,其中L1为方案IV的离去基团。
方案IV
当大环内酯上的NH基团连接在大环内酯糖环S1(即去氧糖胺糖)的3′位上时,也可以按照方案IV进行该反应:
方案V
或当大环内酯上的NH基团连接在糖环S2的4′位上时,可以按照方案VI进行该反应:
方案VI
可以通过下列步骤生成反应物大环内酯亚单位:将含有克拉定糖上4″位上的羟基取代基的相应大环内酯氧化得到4″位上的=O取代基,将4″位上的
转化成环氧基
并用合适的反应物裂解环氧基而得到反应物大环内酯亚单位(M-CH2-NH-K-NH2)。
b)可以通过使通式V表示的非甾类抗炎亚单位与通式VIb表示的大环内酯亚单位的游离羟基反应生成其中X2为-OC(O)-的通式I表示的化合物:
该反应一般与具有活化非甾类抗炎亚单位的羧酸基能力的酸性衍生物进行,诸如卤化物(诸如二氯化乙烯EDC))、混合的酸酐类且尤其是碳化二亚胺类。该反应一般在室温和惰性气体、诸如氮或氩气环境中进行。该反应可能需要几小时至几天才能完成。
通式VIb结构表示的原料大环内酯亚单位是已知的或可以按照对类似化合物所述的步骤获得,诸如Costa A.M.等在《四面体通讯》(Tetrahedron Letters)2000,41,3371-3375中所述,将该文献引入本文作为参考。
例如,当连接部分L为-K-O-时,可以通过(1)将大环内酯环上的>NH基团衍生成N-K-OH基团和(2)使衍生的大环内酯与非甾类抗炎亚单位D上的游离羧酸基团按照方案VII反应而生成通式I的化合物:
方案VII
连接基-K-OH可以如下所述与大环内酯亚单位的伯或仲氮原子连接。使大环内酯亚单位与链烯酰基衍生物反应,诸如CH2=CH(CH2)mC(O)O-烷基(例如,甲基丙烯酸酯)。然后诸如使用金属氢化物(例如LiAlH4)在无水有机溶剂中还原酯基(即-C(O)O-烷基)而得到含有连接基-K-OH的大环内酯亚单位(即M-K-OH)。该还原反应一般在低温且优选在0℃或0℃以下进行。
当NH连接在大环内酯糖环(诸如大环内酯5位上的糖)的3′位上时,也可以进行该反应。
c)可以通过使如下通式表示的大环内酯亚单位与如下通式表示的含有游离氨基的衍生的非甾类抗炎亚单位在诸如乙腈这类溶剂中反应制备其中X1为-OC(O)-,Q为-CH2-或NH,且X2为-NH-的通式I表示的化合物;
其中表示大环内酯亚单位的通式如下:
其中4″为糖S2、诸如克拉定糖上的4位;
其中含有游离氨基的衍生的非甾类抗炎亚单位的通式如下:
从而得到:
可以通过使合适的胺(含有连接基-K-NH2)与非甾类抗炎药的羧酸基团反应生成衍生的非甾类抗炎亚单位(即D-C(O)-NH-K-NH2)。
d)可以通过使大环内酯亚单位和衍生的含有氨基的非甾类抗炎亚单位如下所示反应制备其中X1为-OC(O)NH-且X2为-NH-的通式I表示的化合物。
e)还可以通过使大环内酯亚单位和含有游离羧酸基团的非甾类抗炎亚单位如下所示反应制备其中X1为-OC(O)NH-且X2为-NH-的通式I表示的化合物。
f)可以通过使含有离去基团L2(诸如Br)的大环内酯亚单位和非甾类抗炎药如下所示反应制备通式I表示的化合物。
可以通过裂解连接在大环内酯环3-位上的糖基且然后使所述的大环内酯与L2-L-L1的试剂反应制备原料大环内酯亚单位,其中L2为离去基团。
g)可以通过使含有离去基团L2(诸如Br)的大环内酯亚单位和非甾类抗炎药如下所示反应制备通式I表示的化合物。
h)可以通过使含有离去基团L2(诸如Br)的大环内酯亚单位和非甾类抗炎药如下所示反应制备通式I表示的化合物。
传统上基于糖苷配基的取代模式将16-元环大环内酯类分成亚家族。该家族的主要原型以白霉素、螺旋霉素和泰洛星为代表。
泰洛星是有代表性的16-元大环内酯类,其含有带有两个双键(tylonolide)和第三个糖取代基(β-D-mycinose)β-D-mycinose以及与5-羟基连接的二糖的高度取代的糖苷配基。从二糖中水解mycarose得到desmycarosyl-泰洛星(脱碳霉糖泰乐菌素)。
脱碳霉糖泰乐菌素上可能的修饰位置:
例如,可以通过对C-20位醛基进行还原氨基化制备16-元环的大环内酯杂化物。
该反应还可以用于17-元氮杂内酯类,如8a-氮杂-高脱碳霉糖泰乐菌素及其衍生物(诸如二-和四氢衍生物)。
R14为氢或羟基
16-元环大环内酯衍生的其它可能性为通过环氧化转化双键和使用合适的反应物(诸如二胺类)裂解环氧基而得到反应剂大环内酯亚单位(M-CH2-NH-K-NH2)。
还可以用羟基胺盐酸盐修饰9位上的酮而得到肟且然后还原成胺。
本发明的另一个方面涉及通式I的化合物在治疗炎性疾病、失调和病症中的应用,所述的性疾病、失调和病症的特征在于不需要的炎症免疫反应或与之相关,尤其是TNF-α和IL-1过度分泌诱导或与之相关的所有疾病和病症。
可以通过本领域中公知的方法测定本发明化合物的治疗有效量。由于可以将本发明的化合物比相应单独的非甾类抗炎药更有效地转运至所需部位,所以可以给予比非甾类抗炎药摩尔量更少的化合物而仍然可以获得相同的治疗作用。此外,由于给予该化合物可以产生比使用相应非甾类抗炎药更少的副作用,所以可以增加NSAID的量。因此,下表仅用作指导。以摩尔为基准,化合物、其药学上可接受的盐、其溶剂化物或其前体药物的治疗有效量阈值一般等于或小于非甾类抗炎药的治疗有效量。化合物、其药学上可接受的盐、其溶剂化物或其前体药物的宽和优选有效量如下表中所示。
化合物、其药学上可接受的盐、其溶剂化物或其前体药物的用量 | ||
mg/kg体重/天的NSAID(单独给药) | μmol/kg体重/天的杂化物或(NSAID) | |
宽 | 约0.001-约1000 | 约0.004-约4000 |
优选 | 约0.01-约100 | 约0.04-约400 |
更优选 | 约1-约100 | 约4-约400 |
最优选 | 约3-约30 | 约12-约120 |
因此,例如,吲哚美辛的优选剂量范围为50-200mg/天,相当于140-560μmol/天的范围。相同的基于摩尔的范围140-560mol的本发明杂化化合物为测定优选剂量范围的起点。对该手段的精化也属于本领域技术人员的范围。
此外,本发明涉及药物组合物,它含有有效量的本发明化合物和药学上可接受的赋形剂、诸如载体或稀释剂。
本发明药物组合物的制备包括混合、成粒、压片和溶解组分的步骤。化学载体可以是固体或液体形式。固体载体可以为乳糖、蔗糖、滑石、明胶、琼脂、果胶、硬脂酸镁、脂肪酸,并不限于此。液体载体可以为:糖浆;油,诸如橄榄油、向日葵籽油或大豆油;水;或生理盐水,并不限于此。类似地,载体还可以含有使活性成分缓释的成分,诸如硬脂酸甘油酯或甘油二硬脂酸酯。可以制备几种剂型的药物组合物。如果使用固体载体,那么这些剂型可以包括可以口服给药的片剂、胶囊形片剂、硬胶囊、粉剂或颗粒,并不限于此。固体载体的量可以改变,但主要在25mg-1g的范围。如果使用液体载体,那么制剂可以为糖浆剂、乳剂、软胶囊或无菌可注射液体或非水液体混悬剂形式。
可以通过局部或全身给予本发明的化合物,例如口服、非肠道、皮下粘膜,例如口含、鼻内、直肠内和阴道内。″非肠道″指的是通过静脉内、肌内或皮下途经。本发明化合物的相应制剂可以用于预防和治疗(预防、延缓、抑制或减轻)因异常或不需要(过度、未调节或调节不良)的炎性免疫反应导致或与之相关的几种失调(疾病和其它病理性炎症情况),所述的异常或不需要炎性免疫反应包括炎症细胞因子或其它炎症介体产生,包括但不限于TNF-α和IL-1β。这些疾病包括:自身免疫疾病,诸如类风湿性关节炎、胰岛素依赖性糖尿病、自身免疫性甲状腺炎、多发性硬化、眼色素层视网膜炎、红斑狼疮、硬皮病;其它具有炎性成分的关节炎病,诸如类风湿性脊椎炎、骨关节炎、脓毒性关节炎和多关节炎;其它炎性脑病,诸如脑膜炎、阿尔茨海默病、AIDS痴呆性脑炎;其它炎性眼部炎症,诸如视网膜炎;炎性皮肤病,诸如湿疹、其它皮炎(例如特异性皮炎、接触性皮炎)、牛皮癣、UV照射诱发的灼伤(日光射线和类似的UV源);炎症性肠病,诸如克罗恩病、溃疡性结肠炎;哮喘;其它过敏性疾病,诸如过敏性鼻炎;与急性哮喘相关的疾病,诸如中风后的大脑损伤;因心肌缺血导致的心脏组织损伤;肺损伤,诸如发生成人呼吸窘迫综合征的肺损伤;伴有感染的炎症,诸如脓毒症、脓毒性休克、中毒性休克综合征;其它与特定器官或组织相关的炎性疾病,诸如肾炎(例如肾小球肾炎);附件炎;痛风;胆囊炎;慢性阻塞性肺病;充血性心力衰竭;II型糖尿病;肺纤维化;血管疾病,诸如动脉粥样硬化和再狭窄;和导致移植物排斥的同种异体免疫。
可以通过用于评价炎症或抗炎作用的任意方法评价本发明化合物的功效。存在许多用于该目的的已知方法,包括但不限于使用超声造影并结合注射微气泡、测定炎症细胞因子(诸如TNF-α、IL-1、IFN-γ)、测定活化的免疫系统细胞并观察(水肿减少、红斑减少、痒或烧灼感减轻、体温下降、患病器官功能改善)以及下面提供的任意方法。
在体外和体内实验、诸如下列实验中测定本发明化合物的治疗作用。TNF-α和IL-1β在体外人外周血单核细胞中分泌的测定
由用Ficoll-PaqueTMPlus(Amersham-Pharmacia)分离PBMC后的肝素化全血制备外周血单核细胞(PBMC)。为了测定TNF-α水平,在具有平底的微量滴定板(96孔,Falcon)中的RPMI 1640培养基内将总体积为200μl的3.5-5×104个细胞培养18-24小时,所述的培养基中补充了10%加热失活的人AB血清(Croatian Centre For Transfusion Medicine,Zagreb)、100个单位/ml的青霉素、100mg/ml链霉素和20mMHEPES(Invitrogen Life Technologies)。在37℃和含有5%CO2的气体环境以及90%湿度下保温细胞。在阴性对照中,仅在培养基(NC)中培养细胞,而在阳性对照中,通过添加1μg/ml脂多糖(LPS,大肠杆菌血清型0111:B4,SIGMA)(PC)刺激TNF-α分泌并在将它们加入到用LPS(TS)刺激的细胞培养物后测定测试物质对TNF-α分泌的作用。通过ELISA步骤、按照制造商(R & D Systems)的建议测定细胞上清液中TNF-α的水平。测试灵敏度<3pg/ml TNF-α。如对TNF-α测定所述进行IL-1β水平的测定,仅使用1×105个细胞/孔和0.1ng/ml的LPS。通过ELISA(R & D Systems)测定IL-1β水平。通过下列等式计算TNF-α或IL-1β产生的抑制百分比:
抑制%=[1-(TS-NC)/(PC-NC)]*100。
将IC50值定义为抑制50%TNF-α产生的物质浓度。将表现出20μM或20dμM以下浓度的IC50的化合物视为具有活性。使用Graph Pad Prism软件计算IC50。
RAW 264.7细胞TNF-α分泌的测定
使细胞生长在37℃下含有5%CO2的气体环境以及90%湿度下在DMEM培养基中的(Invitrogen Life Technologies)10%胎牛血清(FBS)中。将20000个细胞/孔平板固定在96孔平板(Falcon)中。在阴性对照中,仅在培养基(NC)中培养细胞,而在阳性对照中,通过添加500pg/ml脂多糖(LPS,大肠杆菌血清型0111:B4,SIGMA)(PC)刺激TNF-α分泌,并在将它们加入到用LPS(TS)刺激的细胞培养物后测定测试物质对TNF-α分泌的作用。通过ELISA、按照制造商(R & D Systems)的建议测定细胞上清液中TNF-α的水平。通过下列等式计算TNF-α产生的抑制百分比:
抑制%=[1-(TS-NC)/(PC-NC)]×100。
将IC50值定义为抑制50%TNF-α产生的物质浓度。将表现出10μM或10μM以下浓度的IC50的化合物视为具有活性。
人前列腺素-H合酶-1(hPGH-1)和人前列腺素-H合酶-2(hPGH-2)抑制试验
使用PCR、应用来自人胎盘cDNA文库(Stratagene)的Platinum pfxDNA聚合酶(Invitrogen Life Technologies)扩增编码hPGH-1和hPGH-2的基因。用于PGH-1的引物序列为:5′ATATAAGCTTGCGCCATGAGCCGGAGTCTTC3′和5′ATATGGATCCTCAGAGCTCTGTGGATGGTCGC3′;用于hPGH-2的引物序列为:5′ATATAAGCTTGCTGCGATGCTCGCCCGC3′和5′ATATGGATCCCTACAGTTCAGTTCAGTCGAACGTTC 3′。将PCR产物克隆入pcDNA3.1 Hygro(+)质粒(Invitrogen Life Technologies)的HindIII和BamHI限制位点,通过测序证实序列。
对COS-7细胞(ATCC)进行转染,在37℃下含有5%CO2的气体环境以及90%湿度下,使细胞在24孔平板(Falcon)内的DMEM培养基中的(Invitrogen Life Technologies)中的10%胎牛血清(FBS)中生长至中完全融合。按照制造商的建议将1μg质粒DNA(含有PGH-1或PGH-2基因或pcDNA Hygro 3.1(+)的pcDNA Hygro 3.1(+)作为阴性对照样品)与1,5μl Lipofectamine 2000(Invitrogen Life Technologies)合并。转染后24-48小时,将在DMEM中的测试化合物加入到细胞中,但不除去培养基并在40分钟后,加入花生四烯酸(Sigma)至终浓度为20μM。30分钟后,取出上清液并用PGE-2试验试剂盒(Cayman)。按照制造商的说明测定PGE-2。在阴性对照中没有检测到PGE-2。
通过下列等式计算抑制%:
抑制%=(1-样品PGE-2浓度/阳性对照PGE-2浓度)*100
小鼠体内LPS-诱导的TNF-α过度分泌的体内模型
按照已经上述方法诱导小鼠体内TNF-α分泌(Badger AM等,J.Pharmac.And Env.Therap.,1996,279:1453-1461)。在本试验中,使用8-12周龄的分成6-10只动物一组的雄性Balb/C小鼠。仅用溶剂口服给药治疗动物(阴性对照和阳性对照中)或在用LPS(大肠杆菌血清型0111:B4,Sigma)处理前30分钟给予物质溶液,剂量为1-25μg/动物。2小时后通过腹膜内注射Roumpun(Bayer)和盐酸氯胺酮(ketanest)(Parke-Davis)对动物实施安乐死。将每只动物的血样取入“vacutainer”管(BectonDickinson)并按照制造商的建议分离血浆。通过ELISA(Biosource,R & D Systems)、按照制造商所述的方法测定血浆中的TNF-α水平。测试灵敏度<3pg/ml TNF-α。通过下列等式计算TNF-α产生的抑制百分比:
抑制%=[1-(TS-NC)/(PC-NC)]*100。
将在10mg/kg剂量下表现出30%或30%以上TNF-α产生抑制的化合物视为具有活性。
将对上述试验中的四个和下面的举例化合物中的三种定量表示的有代表性的结果列在下面:
化合物 | TNF-αPBMCIC50 | hPGH-1 IC50 | hPGH-2 IC50 | LPS-诱导的TNF-α过度分泌抑制% |
S-(+)-布洛芬 | >30μM | 0.5μM | 0.8μM | ND |
实施例4 | 1μM | >30μM | 1μM | 70 |
实施例5 | 1μM | 10μM | 10μM | 66 |
实施例10 | 10μM | >30μM | >30μM | 47 |
ND-未测定
用于止痛活性的扭体试验
在本试验中,通过将刺激剂、最常见的是乙酸注入小鼠腹腔诱发疼痛。动物具有指定试验名称的特征扭体反应(Collier HOJ等,《药物与化疗》(Pharmac.Chemother.),1968,32:295-310;Fukawa K等,《药理学方法杂志》(J.Pharmacol.Meth.),1980,4:251-259;SchweizerA等,《活性剂的作用》(Agents Actions),1988,23:29-31)。本试验适合于测定化合物的止痛活性。方法:使用8-12周龄的雄性Balb/C小鼠(Charles River,Italy)。对对照组在腹膜内给予0.6%浓度的乙酸前30分钟口服给予甲基纤维素,而对验组在腹膜内给予0.6%乙酸(体积0.1ml/10g)前30分钟口服给予标准品(乙酰水杨酸)或在甲基纤维素中的测试物质。将小鼠各自置于玻璃漏斗中并在20分钟期限中记录每只动物扭体的次数。按照下列等式计算扭体抑制的百分比:
抑制%=(对照组中扭体次数-试验组中扭体次数的平均值)/对照组中扭体的次数×100。
将表现出与乙酰水杨酸相同活性或优于其活性的化合物视为具有活性。
LPS-诱发的小鼠休克的体内模型
使用8-12周龄的雄性Balb/C小鼠(Charles River,Italy)。用无菌盐水稀释分离自粘质沙雷氏菌(Serratie marcessans)(Sigma,1-6136)的LPS。首先真皮内给予剂量为4μg/小鼠的LPS注射。18-24小时后,通过静脉内给予200μg/小鼠剂量的LPS。按照上述方式对对照组给予两次LPS注射。对试验组在各自给予LPS前半小时口服所述物质。24小时后观察存活率。
将在30mg/kg剂量下产生存活率为40%或更好存活率的物质视为具有活性。
实施例1-12的化合物至少在两次研究试验中表现出活性。不过,这些结果仅是对化合物生物活性的解释,而不应以任何方式来限定本发明。
制备方法与实施例
前体
非甾类抗炎亚单位
化合物D2为S-(+)-布洛芬;带有手性中心的其余化合物为外消旋混合物。化合物D1为吲哚美辛;D3为氟比洛芬;D4为萘普生;D5为酮洛芬;D6为乙酰水杨酸;D7为舒林酸;D8为依托度酸;D9为酮咯酸;D10为舒洛芬;D11为氟尼辛;D12为双氯芬酸钠;且D13为托美丁钠。
大环内酯亚单位
表1,通式IIA
Com. | M | R1 | R2 | R3 | R4 | R6 | R13 | R11 | R12 |
ML1 | M1 | L1 | H | H | H | CH3 | S2 | H | H |
ML2 | M1 | L2 | H | H | H | CH3 | S2 | H | H |
ML3 | M2 | L2 | H | H | H | CH3 | OH | / | / |
ML4 | M3 | L2 | H | H | H | H | S2 | H | H |
ML5 | M4 | L2 | H | H | H | C2H5 | S2 | H | H |
ML6 | M5 | H | C=O | CH3 | C2H5 | S2 | H | L3 | |
ML7 | M6 | CH3 | H | H | H | CH3 | S2 | L4 | H |
L1=-(CH2)3-OH
L2=-(CH2)3-NH2
L3=-CH2-NH-(CH2)2-NH2
L4=-C(O)-(CH2)2-NH-(CH2)2-NH2
名称M1-M6相应于通式IIA的大环内酯亚单位,其中变量R1-R13如表中指定。
实施例1
化合物1:(通式1:M=M1,L=L1,D=D1)
在氩气环境中向吲哚美辛(D1)(200mg;0.56mmole)在干燥DMF(3ml)中的溶液中加入1,1-羰基二咪唑(187mg;在5ml DMF中1.15mmol)。将该反应混合物在-5℃下搅拌24小时,然后将其加入到化合物ML1(443mg;在3ml DMF中0.56mmole)中。将该反应混合物在100℃下加热48小时、蒸发并用硅胶柱纯化(洗脱剂:CHCl3∶MeOH∶NH4OH=6∶1∶0.1)。得到56mg化合物1; MS(m/z):1133[MH]+.IR(KBr)cm-1:3449,2972,2936,1731,1686,1622,1564,1546,1512,1478,1460,1374,1323,1263,1225,1168,1089,1057,1013,958,925,834,804,756,732。
实施例2
化合物2:(通式I;M=MI,L=L1,D=D2)
在氩气环境中向S-(+)-布洛芬(D2)(115mg;0.56mmole)在干燥DMF(3ml)中的溶液中加入1,1-羰基二咪唑(187mg;在5ml DMF中1.15mmol)。将该反应混合物在-5℃下搅拌24小时,然后将其加入到化合物ML1(443mg;在3ml DMF中0.56mmole)中。将该反应混合物在100℃下加热48小时、蒸发并用硅胶柱纯化(洗脱剂:CHCl3∶MeOH∶NH4OH=6∶1∶0.1)。得到43mg化合物2; MS(m/z):981.7[MH]+.IR(KBr)cm-1:3483,2971,2937,2873,2787,1733,1655,1638,1561,1511,1459,1421,1379,1332,1248,1167,1109,1055,1013,1000,958,900,836,803,756,728,640。
实施例3
化合物3:(通式I;M=M1,L=L1,D=D3)
在氩气环境中向氟比洛芬(D3)(137mg;0.56mmole)在干燥DMF(3ml)中的溶液中加入1,1-羰基二咪唑(187mg;在5ml DMF中1.15mmol)。将该反应混合物在-5℃下搅拌24小时,然后将其加入到化合物ML1(443mg;在3ml DMF中0.56mmole)中。将该反应混合物在100℃下加热48小时、蒸发并用硅胶柱纯化(洗脱剂:CHCl3∶MeOH∶NH4OH=6∶1∶0.1)。得到46mg化合物3; MS(m/z):1119.5[MH]+.IR(KBr)cm-1:3452,2973,2937,2879,2829,2777,1734,1688,1659,1625,1582,1565,1546,1512,1461,1420,1379,1329,1267,1171,1109,1054,1013,999,959,899,834,801,767,726,699,640。
实施例4
化合物4:(通式I;M=M1,L=L2.D=D1)
在氩气环境中向吲哚美辛(D1)(104mg;0.29mmole)在干燥CH2Cl2(5ml)中的溶液中加入0.380mL(2.73mmole)三乙胺、80mg(0.59mmole)1-羟基苯并三唑、230mg(0.29mmole)ML2和235mg(1.23mmole)1-(3-二甲氨基丙基)-3-乙基-碳化二亚胺盐酸盐。将该反应混合物在室温下和氩气流中搅拌24小时,然后在减压条件下蒸发至小体积并用硅胶柱纯化(洗脱剂:CHCl3∶MeOH∶NH4OH=6∶1∶0.1)。得到127mg化合物4;MS(m/z):1131.8[MH]+.IR(KBr)cm-1:3451,2971,2936,2829,1722,1675,1659,1542,1595,1563,1546,1529,1478,1461,1374,1323,1260,1227,1168,1110,1089,1054,1013,957,927,899,834,806,755。
实施例5
化合物5:(通式1;M=M1,L=L2.D=D2)
在氩气环境中向(S)-(+)-布洛芬(D2)(60mg;0.29mmole)在干燥CH2Cl2(5ml)中的溶液中加入0.380mL(2.73mmole)三乙胺、80mg(0.59mmole)1-羟基苯并三唑、230mg(0.29mmole)ML2和235mg(1.23mmole)1-(3-二甲氨基丙基)-3-乙基-碳化二亚胺盐酸盐。将该反应混合物在室温下和氩气流中搅拌24小时且然后蒸发。用硅胶柱纯化(洗脱剂:CHCl3∶MeOH∶NH4OH=6∶1∶0.1)而得到239mg化合物5;
MS(m/z):981.0[MH]+.IR(KBr)cm-1:3433,2971,2936,2872,1720,1686,1655,1561,1545,1511,1460,1378,1264,1167,1109,1054,1013,1000,958,902,835,642。
实施例6
化合物6:(通式I;M=M1,L=L2,D=D3)
在氩气环境中向氟比洛芬(D3)(70mg;0.29mmole)在干燥CH2Cl2(5ml)中的溶液中加入0.380mL(2.73mmole)三乙胺、80mg(0.59mmole)1-羟基苯并三唑、230mg(0.29mmole)ML2和235mg(1.23mmole)1-(3-二甲氨基丙基)-3-乙基-碳化二亚胺盐酸盐。将该反应混合物在室温下和氩气流中搅拌24小时且然后蒸发。用硅胶柱纯化,使用CHCl3∶MeOH∶NH4OH=6∶1∶0.1洗脱而得到160mg化合物6;
MS(m/z):1018.9[MH]+.IR(KBr)cm-1:3448,2973,2937,2881,2834,2782,1720,1655,1625,1581,1560,1544,1484,1458,1419,1378,1267,1167,1109,1053,1012,958,900,835,767,726,699,641。
实施例7
化合物7:(通式1;M=M1,L=L2,D=D4)
在氩气环境中向萘普生(D4)(67mg;0.29mmole)在干燥CH2Cl2(5ml)中的溶液中加入0.380mL(2.73mmole)三乙胺、80mg(0.59mmole)1-羟基苯并三唑、230mg(0.29mmole)ML2和235mg(1.23mmole)1-(3-二甲氨基丙基)-3-乙基-碳化二亚胺盐酸盐。将该反应混合物在室温下和氩气流中搅拌24小时且然后在减压条件下浓缩。用硅胶柱纯化,使用CHCl3∶MeOH∶NH4OH=6∶1∶0.1洗脱而得到162mg化合物7;
MS(m/z):1004.9[MH]+.IR(KBr)cm-1:3433,2972,2937,2876,2829,2788,1719,1655,1607,1560,1542,1508,1459,1377,1265,1230,1167,1109,1053,1013,1000,958,928,895,853,809,755,640。
实施例8
化合物8:(通式I;M=M1 L=L2,D=D5)
在氩气环境中向酮洛芬(D5)(74mg;0.29mmole)在干燥CH2Cl2(5ml)中的溶液中加入0.380mL(2.73mmole)三乙胺、80mg(0.59mmole)1-羟基苯并三唑、230mg(0.29mmole)ML2和235mg(1.23mmole)1-(3-二甲氨基丙基)-3-乙基-碳化二亚胺盐酸盐。将该反应混合物在室温下和氩气流中搅拌24小时且然后在减压条件下浓缩。用硅胶柱纯化,使用CHCl3∶MeOH∶NH4OH=6∶1∶0.1洗脱而得到114mg化合物8;
MS(m/z):1028.9[MH]+.IR(KBr)cm-1:3450,3062,2972,2937,2876,2834,2788,1722,1658,1598,1580,1544,1458,1378,1319,1284,1168,1109,1081,1053,1013,1000,957,902,834,755,723,705,643。
实施例9
化合物9:(通式I;M=M1,L=L2,D=D6)
在氩气环境中向乙酰水杨酸(D6)(52mg;0.29mmole)在干燥CH2Cl2(5ml)中的溶液中加入0.380mL(2.73mmole)三乙胺、80mg(0.59mmole)1-羟基苯并三唑、230mg(0.29mmole)ML2和235mg(1.23mmole)1-(3-二甲氨基丙基)-3-乙基-碳化二亚胺盐酸盐。将该反应混合物在室温下和氩气流中搅拌24小时且然后在减压条件下浓缩。用硅胶柱纯化,使用CHCl3∶MeOH∶NH4OH=6∶1∶0.1洗脱而得到127mg化合物9;MS(m/z):955[MH]+.
实施例10
化合物10:(通式I;M=M2,L=L2,D=D1)
将化合物4(120mg;0.1mmole)溶于3mL 0.5 M HCl。将该反应混合物在室温下搅拌24小时。然后向该反应混合物中加入二氯甲烷并分离各层。将水层调节至pH 10并用CH2Cl2提取。用饱和NaHCO3洗涤合并的有机提取物、用MgSO4干燥并在减压条件下蒸发。用硅胶柱纯化(洗脱剂:EtOAc∶TEA=96∶4)而得到32mg化合物10。MS(m/z):973.8[MH]+.
实施例11
化合物11:(通式I;M=M2,L=L2,D=D2)
将化合物5(120mg;0.1mmole)溶于3mL 0.5 M HCl。将该反应混合物在室温下搅拌24小时。然后向该反应混合物中加入二氯甲烷并分离各层。将水层调节至pH 10并用CH2Cl2提取。用饱和NaHCO3洗涤合并的有机提取物、用MgSO4干燥并在减压条件下蒸发。用硅胶柱纯化(洗脱剂:EtOAc∶TEA=96∶4)而得到28mg化合物11。
MS(m/z):822.1[MH]+.IR(KBr)cm-1:3450,2971,2873,1710,1656,1544,1511,1459,1380,1350,1262,1173,1111,1073,1050,978,957,934,898,803,755,634。
实施例12
化合物12:(通式I;M=M2,L=L2,D=D5)
将化合物8(150mg;0.15mmole)溶于5mL 0.5 M HCl。将该反应混合物在室温下搅拌24小时。然后向该反应混合物中加入二氯甲烷并分离各层。将水层调节至pH 10并用CH2Cl2提取。用饱和NaHCO3洗涤合并的有机提取物、用MgSO4干燥并在减压条件下蒸发。用硅胶柱纯化(洗脱剂:EtOAc∶TEA=96∶4)而得到42mg化合物12。
MS(m/z):870.1[MH]+.IR(KBr)cm-1:3439,3067,2972,2936,2876,1721,1657,1598,1580,1544,1458,1378,1349,1319,1283,1173,1136,1111,1074,1050,1000,956,904, 863,723,705,643。
实施例13
化合物13:(通式I;M=M3,L=L2,D=D1)
将化合物4(68mg;0.06mmole)溶于10mL甲醇。加入38mg(0.28mmole)的NaOACx3H2O和15mg(0.06mmole)的I2。用500W的卤素灯将该反应混合物照射2小时。然后加入2-3滴0.1 M Na2S2O3。随后在减压条件下蒸发溶剂并将残余物溶于乙酸乙酯,用水和饱和NaHCO3溶液洗涤。用无水Na2SO4干燥有机层并蒸发。用硅胶柱纯化产物,溶剂系统为CHCl3∶MeOH∶NH4OH=6∶1∶0.1。分离到32mg量的化合物13;
MS(m/z):1117.9[MH]+。
实施例14
化合物14:(通式1;M=M4,L=L2,D=D1)
将化合物13(100mg;0.09mmole)溶于3mL甲醇。向该溶液中加入127μl N,N-二异丙基乙胺和45μl乙基碘。将该反应混合物在50℃的温度下搅拌20小时。随后用30mL乙酸乙酯稀释该体系并用30mL饱和碳酸氢钠水溶液和30mL水洗涤。用无水硫酸钠干燥有机层。通过减压蒸发溶剂。用硅胶柱纯化得到的混合物,洗脱剂为CHCl3∶MeOH∶NH4OH=6∶1∶0.1。分离到48mg的化合物14;MS(m/z):1145.7[MH]+。
实施例15
化合物15:(通式I;M=M5,L=L3,D=D1)
在惰性气体环境中的10mL干燥二氯甲烷中溶解84mg吲哚美辛D1(0.2mmole)。随后向该溶液中加入0.25mL三乙胺、53mg羟基苯并三唑、200mg大环内酯ML6(0.2mmole)和157mg 1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐。将该反应混合物在室温下搅拌过夜。在减压条件下蒸发溶剂,并用硅胶柱纯化得到的混合物,洗脱剂为CHCl3∶MeOH∶NH4OH=6∶1∶0.1。分离到130mg的化合物15;MS(m/z):1188.6[MH]+。
实施例16
化合物16:(通式1;M=M6,L=L4.D=D1)
在惰性气体环境中的10mL干燥二氯甲烷中溶解43mg吲哚美辛D1(0.1mmole)。随后向该溶液中加入0.12mL三乙胺、32mg羟基苯并三唑、103mg大环内酯ML7(0.1mmole)和82mg1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐。将该反应混合物在室温下搅拌过夜。在减压条件下蒸发溶剂并用硅胶柱纯化得到的混合物,洗脱剂为CHCl3∶MeOH∶NH4OH=6∶1∶0.1。分离到80mg的化合物16;
MS(m/z):1203.1[MH]+;MS(m/z):981.0[MH]+.IR(KBr)cm-1:3424,2972,2936,2833,1734,1678,1595,1562,1544,1526,1477,1459,1374,1324,1258,1225,1179,1108,1090,1073,1039,1015,959,926,902,836,798,755,693,666,642。
实施例17
化合物17:(通式I;M=M1,L=L2,D=D7)
在氩气环境中向舒林酸(D7)(103mg;0.29mmole)在干燥CH2Cl2(5ml)中的溶液中加入0.380mL(2.73mmole)三乙胺、80mg(0.59mmole)1-羟基苯并三唑、230mg(0.29mmole)ML2和235mg(1.23mmole)1-(3-二甲氨基丙基)-3-乙基-碳化二亚胺盐酸盐。将该反应混合物在室温下和氩气流中搅拌24小时,然后在减压条件下蒸发至小体积并用硅胶柱纯化(洗脱剂:CHCl3∶MeOH∶NH4OH=6∶1∶0.1)。得到262mg化合物17;MS(m/z):1130.3[MH]+。
实施例18
化合物18:(通式I;M=M1,L=L2,D=D8)
在氩气环境中向依托度酸(D8)(83mg;0.29mmole)在干燥CH2Cl2(5ml)中的溶液中加入0.380mL(2.73mmole)三乙胺、80mg(0.59mmole)1-羟基苯并三唑、230mg(0.29mmole)ML2和235mg(1.23mmole)1-(3-二甲氨基丙基)-3-乙基-碳化二亚胺盐酸盐。将该反应混合物在室温下和氩气流中搅拌24小时,然后在减压条件下蒸发至小体积并用硅胶柱纯化(洗脱剂:CHCl3∶MeOH∶NH4OH=6∶1∶0.1)。得到78mg化合物18;MS(m/z):1061.4[MH]+。
实施例19
化合物19:(通式I;M=M1,L=L2,D=D9)
在氩气环境中向酮咯酸(D9)(74mg;0.29mmole)在干燥CH2Cl2(5ml)中的溶液中加入0.380mL(2.73mmole)三乙胺、80mg(0.59mmole)1-羟基苯并三唑、230mg(0.29mmole)ML2和235mg(1.23mmole)1-(3-二甲氨基丙基)-3-乙基-碳化二亚胺盐酸盐。将该反应混合物在室温下和氩气流中搅拌24小时,然后在减压条件下蒸发至小体积并用硅胶柱纯化(洗脱剂:CHCl3∶MeOH∶NH4OH=6∶1∶0.1)。得到110mg化合物19;
MS(m/z):1029.5[MH]+.IR(KBr)cm-1:3448,2972,2936,2876,1719,1655,1624,1572,1561,1544,1492,1465,1430,1400,1379,1342,1272,1167,1109,1052,1013,1000,958,894,835,797,758,724,699,670。
实施例20
化合物20:(通式1;M=M1,L=L2,D=D10)
在氩气环境中向舒洛芬(D10)(75mg;0.29mmole)在干燥CH2Cl2(5ml)中的溶液中加入0.380mL(2.73mmole)三乙胺、80mg(0.59mmole)1-羟基苯并三唑、230mg(0.29mmole)ML2和235mg(1.23mmole)1-(3-二甲氨基丙基)-3-乙基-碳化二亚胺盐酸盐。将该反应混合物在室温下和氩气流中搅拌24小时,然后在减压条件下蒸发至小体积并用硅胶柱纯化(洗脱剂:CHCl3∶MeOH∶NH4OH=6∶1∶0.1)。得到128mg化合物20;
MS(m/z):1034.4[MH]+.IR(KBr)cm-1:3448,3082,2972,2937,2877,2833,2789,1719,1655,1638,1606,1560,1542,1517,1458,1415,1378,1355,1289,1167,1109,1053,1013,1000,958,901,886,860,845,806,753,724,665,640。
实施例21
化合物21:(通式I;M=M1,L=L2,D=D11)
在氩气环境中向氟尼辛(D11)(86mg;0.29mmole)在干燥CH2Cl2(5ml)中的溶液中加入0.380mL(2.73mmole)三乙胺、80mg(0.59mmole)1-羟基苯并三唑、230mg(0.29mmole)ML2和235mg(1.23mmole)1-(3-二甲氨基丙基)-3-乙基-碳化二亚胺盐酸盐。将该反应混合物在室温下和氩气流中搅拌24小时,然后在减压条件下蒸发至小体积并用硅胶柱纯化(洗脱剂:CHCl3∶MeOH∶NH4OH=6∶1∶0.1)。得到76mg化合物21;MS(m/z):1070,4[MH]+.IR(KBr)cm-1:3451,2973,2938,2881,1722,1642,1593,1524,1462,1379,1321,1321,1278,1259,1168,1121,1081,1053,1020,958,899,835,795,772,721,666,640。
实施例22
化合物22:(通式1:M=M1,L=L2,D=D12)
在氩气环境中向双氯芬酸钠(D12)(92mg;0.29mmole)在干燥CH2Cl2(5ml)中的溶液中加入0.380mL(2.73mmole)三乙胺、80mg(0.59mmole)1-羟基苯并三唑、230mg(0.29mmole)ML2和235mg(1.23mmole)1-(3-二甲氨基丙基)-3-乙基-碳化二亚胺盐酸盐。将该反应混合物在室温下和氩气流中搅拌24小时,然后在减压条件下蒸发至小体积并用硅胶柱纯化(洗脱剂:CHCl3∶MeOH∶NH4OH=6∶1∶0.1)。得到140mg化合物22;MS(m/z):1069.1[MH]+.IR(KBr)cm-1:3426,3073,2972,2937,2876,2829,2788,1722,1658,1578,1562,1546,1511,1454,1378,1301,1281,1167,1110,1053,1013,999,958,898,836,750,668。
实施例23
化合物23:(通式I:M=M1,L=L2,D=D13)
在氩气环境中向托美丁钠(D13)(80mg;0.29mmole)在干燥CH2Cl2(5ml)中的溶液中加入0.380mL(2.73mmole)三乙胺、80mg(0.59mmole)1-羟基苯并三唑、230mg(0.29mmole)ML2和235mg(1.23mmole)1-(3-二甲氨基丙基)-3-乙基-碳化二亚胺盐酸盐。将该反应混合物在室温下和氩气流中搅拌24小时,然后在减压条件下蒸发至小体积并用硅胶柱纯化(洗脱剂:CHCl3∶MeOH∶NH4OH=6∶1∶0.1)。得到183mg化合物23;
MS(m/z):1031.3[MH]+.IR(KBr)cm-1:3448,2972,2937,2876,1774,1719,1655,1624,1601,1561,1545,1509,1477,1458,1376,1265,1180,1167,1110,1076,1053,1012,1000,957,883,834,794,751,669,639,620。
Claims (38)
1.通式I的化合物及其药学上可接受的盐和溶剂化物及其各非对映异构体:
其中:
M表示大环内酯亚单位;
D表示非甾类亚单位;
L为与M和D中的每一个共价连接的连接分子。
2.如权利要求1中所述的化合物,其中M表示通式II的基团:
其中:
(i)Z和W独立为:>C=O、>CH2、>CH-NRtRs、>N-RN或>C=N-RM或键,其中:
Rt和Rs独立为氢或烷基;
RM为羟基、烷氧基、取代的烷氧基或ORP;
RN为氢、RP、烷基、链烯基、炔基、烷氧基、烷氧基烷基或-C(X)-NRtRs;其中X为=O或=S;
条件是Z和W不能同时为>C=O、>CH2、>CH-NRtRs、>N-RN或>C=N-RM或键;
(ii)U和Y独立为氢、卤素、烷基或羟基烷基;
(iii)R1为羟基、ORP、-O-S2基团或=O;
(iv)S1为下列通式的糖部分:
其中:
R8和R9均为氢或彼此形成键,或R9为氢且R8为-N(CH3)Ry,其中:
Ry为RP、RZ或-C(O)RZ,其中RZ为氢或烷基或链烯基或炔基或环烷基或芳基或杂芳基或被C2-C7-烷基、C2-C7-链烯基、C2-C7-炔基、芳基或杂芳基取代的烷基;
R10为氢或RP;
(v)S2为下列通式的糖部分:
其中:
R3’为氢或甲基;
R11为氢、RP或O-R11为与R12和与C/4″碳原子形成>C=O或环氧基的基团;
R12为氢或与O-R11和与C/4″碳原子形成>C=O或环氧基的基团;
(vi)R2为氢、羟基、ORP或烷氧基;
(vii)A为氢或甲基;
(viii)B为甲基或环氧基;
(ix)E为氢或卤素;
(x)R3为羟基、ORP、烷氧基或R3为与R5和与C/11和C/12碳原子形成环碳酸酯或环氨基甲酸酯的基团;或如果W或Z为>N-RN,则R3为与W或Z形成环氨基甲酸酯的基团;
(xi)R4为C1-C4烷基;
(xii)R5为氢、羟基、ORP、C1-C4-烷氧基或与R3和与C/11和C/12碳原子形成环碳酸酯或环氨基甲酸酯的基团;
(xiii)R6为氢或C1-C4-烷基;
其中M含有连接位置,它通过该位置经连接基L与D连接;条件是连接位置位于下列基团中的一个或多个上:
a)位于S1、S2或糖苷配基氧上的任意活性羟基、氮或环氧基,条件是S1或/和S2被裂解;
b)位于Z或W上的活性>N-RN或-NRtRs或=O;
c)位于R1、R2、R3和R5中任意一个上的活性羟基;
d)可以首先被衍生成羟基或-NRtRs基团的任意其它基团;且
RP为羟基或氨基保护基。
3.如权利要求1中所述的化合物,其中L表示通式IV的基团:
X1-(CH2)m-Q-(CH2)n-X2
IV
其中:
X1选自-CH2-、-C(O)-、OC(O)-、N-O-、-OC(O)NH-或-C(O)NH-;
X2为-NH-或-NHC(O)-、-OC(O)-、-C(O)-、-O或-CH2-;
Q为-NH-或-CH2-或不存在;
其中-CH2-或-NH-基团各自可以任选被C1-C7-烷基、C2-C7-链烯基、C2-C7-炔基、C(O)RX、C(O)ORX、C(O)NHRX取代,其中RX可以为C1-C7-烷基、芳基或杂芳基;
符号m和n独立为0-4的整数,条件是如果Q为NH,那么n不能为0。
4.如权利要求1中所述的化合物,其中D来源于NSAID,所述的NSAID选自醋氯芬酸、阿西美辛、对乙酰氨基酚、醋氨沙洛、乙酰水杨酸、乙酰基-水杨-2-氨基-4-甲基吡啶-酸、5-氨基乙酰水杨酸、阿氯芬酸、氨洛芬、氨芬酸、氨基安替比林、安吡昔康、阿尼利定、苄达酸、苯噁洛芬、柏莫洛芬、α-没药醇、溴芬酸、5-溴水杨酸乙酸酯、溴水杨苷、布氯酸、丁布芬、卡洛芬、塞来考昔、chromoglycate、桂美辛、clindanac、氯吡酸、双氯芬酸钠、二氟尼柳、地他唑、屈噁昔康、恩芬那酸、依托度酸、依托芬那酯、联苯乙酸、芬布芬、芬克洛酸、芬度柳、非诺洛芬、芬替酸、非普地醇、flufenac、氟芬那酸、氟尼辛、氟诺洛芬、氟比洛芬、glutametacin、水杨酸乙二醇酯、异丁芬酸、布洛芬、异丁普生、吲哚美辛、吲哚洛芬、三苯唑酸、伊索克酸、伊索昔康、酮洛芬、酮咯酸、氯诺昔康、洛索洛芬、甲氧芬那酸、甲芬那酸、美洛昔康、5-氨基水杨酸、甲嗪酸、莫苯唑酸、孟鲁司特、萘丁美酮、萘普生、尼氟酸、尼美舒利、奥沙拉秦、奥沙西罗、噁丙嗪、羟布宗、对乙酰氨基酚、帕沙米特、哌立索唑、苯乙酰水杨酸酯、保泰松、水杨酸苯酯、吡拉唑酸、吡罗西康、吡洛芬、普拉洛芬、丙替嗪酸、reserveratol、醋水杨胺、水杨酰胺、水杨酰胺-O-乙酸、水杨酰硫酸酯、水杨苷、水杨酰胺、双水杨酯、舒林酸、舒洛芬、suxibutazone、他莫昔芬、替诺昔康、噻洛芬酸、噻拉米特、ticlopridine、替诺立定、托芬那酸、托美丁、tropesin、联苯丁酸、希莫洛芬、扎托洛芬、佐美酸、托莫普罗、扎鲁司特和环孢菌素。
5.如权利要求2中所述的化合物,其中Z和W共同为:-N(CH3)-CH2-、-NH-CH2-、-CH2-NH-、-C(O)-NH-或-NH-C(O)-;
A和B为甲基;
E为氢;
R为羟基或甲氧基;
S1表示去氧糖胺糖,其中R8选自氢、甲基、氨基、C1-C6烷氨基或C1-C6二烷氨基;
R9和R10为氢;
R1为羟基或O-S2基团,其中S2表示克拉定糖,其中:
R11为氢或O-R11为与R12和与C/4″碳原子形成>C=或环氧基的基团;R12为氢或与O-R11和与C/4″碳原子形成>C=O或环氧基的基团;
R13为甲基;
U为氢;
Y为甲基;
R6为羟基、甲基或乙基;
R5为氢、羟基、甲氧基或与R3和与C/11和C/12碳原子形成环碳酸酯或环氨基甲酸酯桥的基团;
R3为羟基或与W或Z形成环氨基甲酸酯桥的基团,或R3为与R5和与C/11和C/12碳原子形成环碳酸酯或环氨基甲酸酯桥的基团;
R4为甲基;
条件是连接键通过N/9a位上Z的氮或通过均在S2糖C/4″位上的R12的碳或R11的氧。
6.如权利要求3中所述的化合物,其中:
X1为-CH2-或-OC(O)-;
X2为-NHC(O)-;
Q为-NH-或不存在。
7.如权利要求4所述的化合物,其中D来源于NSAID,所述的NSAID选自S-(+)-布洛芬、吲哚美辛、氟比洛芬、萘普生、酮洛芬、乙酰水杨酸、舒林酸、依托度酸、酮咯酸、舒洛芬、氟尼辛、双氯芬酸钠和托美丁钠。
8.特征在于如下式的化合物1:
9.特征在于如下式的化合物2:
11.特征在于如下式的化合物4:
18.特征在于如下式的化合物11:
19.特征在于如下式的化合物12:
20.特征在于如下式的化合物13:
24.特征在于如下式的化合物17:
25.特征在于如下式的化合物18:
26.特征在于如下式的化合物19:
27.特征在于如下式的化合物20:
29.特征在于如下通式的化合物22:
30.特征在于如下式的化合物23:
31.通式I化合物的制备方法:
该方法包括:
a)为了得到其中X2为-NHC(O)-的通式I化合物,使通式V的化合物与通式VIa表示的大环内酯的游离氨基反应,
其中通式V如下:
其中L1表示离去基团,
且通式VIa如下:
b)为了得到其中X2为-OC(O)-的通式I化合物,使通式V的化合物与通式VIb表示的大环内酯的游离羟基反应,
c)为了得到其中X1为-OC(O)-,Q为-NH-且X2为-NHC(O)-的通式I化合物,使如下通式表示的大环内酯:
与如下通式表示的化合物的游离氨基反应,
d)为了得到其中X1为-OC(O)NH-且X2为-NHC(O)-的通式I化合物,使如下通式表示的大环内酯:
与如下通式表示的化合物的游离氨基反应,
e)为了得到其中X1为-CH2-,Q为-NH-且X2为-NHC(O)-的通式I化合物,使如下通式表示的大环内酯:
与通式V的化合物反应;
f)为了得到通式I的化合物,使具有离去基团L2的通式VIIf或通式VIIg或通式VIIh表示的大环内酯与非甾类抗炎亚单位的游离羧酸反应,其中通式VIIf、通式VIIg、通式VIIh如下:
32.药物组合物,包含如权利要求1-30中所述的化合物及其药学上可接受的盐或溶剂化物以及药学上可接受的稀释剂或载体。
33.如权利要求1-30中所述的化合物用于制备治疗炎性疾病、失调和病症的药物的用途,所述的炎性疾病、失调和病症的特征在于不需要的炎性免疫反应或与之相关,尤其是TNF-α和IL-1过度分泌诱导或与之相关的所有疾病和病症。
34.通式I表示的化合物或其药学上可接受的盐或溶剂化物用于制备治疗有此需要的对象中与白细胞浸润入发炎组织相关的炎性病症和免疫或过敏性失调的药物的用途,包括给予所述的对象治疗有效量的通式I表示的化合物或其药学上可接受的盐或溶剂化物。
35.权利要求34所述的用途,其中炎性病症和免疫失调选自哮喘、成人呼吸窘迫综合征、支气管炎和囊性纤维化。
36.权利要求34所述的用途,其中所述的炎性病症和免疫失调选自肺、关节、眼、肠、皮肤和心脏的炎性病症或免疫失调。
37.权利要求34所述的用途,其中所述的炎性病症和免疫失调选自哮喘、成人呼吸窘迫综合征、支气管炎、囊性纤维化、类风湿性关节炎、类风湿性脊椎炎、骨关节炎、痛风性关节炎、眼色素层炎、结膜炎、炎性肠病、克罗恩病、溃疡性结肠炎、远端直肠炎、牛皮癣、湿疹、皮炎、冠状动脉梗死性损害、慢性炎症、内毒素休克和平滑肌增生性失调。
38.通式I表示的化合物或其药学上可接受的盐或溶剂化物用于制备减轻患病器官或组织炎症的药物的用途,包括将治疗有效量的通式I表示的化合物或其药学上可接受的盐或溶剂化物递送至所述的器官或组织。
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CN1780846A (zh) * | 2003-03-05 | 2006-05-31 | Rib-X医药品有限公司 | 双官能杂环化合物及其制备和使用方法 |
HRP20030324A2 (en) | 2003-04-24 | 2005-02-28 | Pliva-Istra�iva�ki institut d.o.o. | Compounds of antiinflammatory effect |
WO2005042554A1 (en) * | 2003-10-30 | 2005-05-12 | Rib-X Pharmaceuticals, Inc. | Bifunctional macrolide heterocyclic compounds and methods of making and using the same |
JP2007512256A (ja) * | 2003-11-18 | 2007-05-17 | リブ−エックス ファーマシューティカルズ,インコーポレイテッド | 二官能性マクロライド複素環化合物ならびにこれらを製造する方法およびこれらを使用する方法 |
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AU2005273592A1 (en) * | 2004-08-12 | 2006-02-23 | Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. | Use of cell-specific conjugates for treatment of inflammatory diseases of the gastrointestinal tract |
US20060183696A1 (en) * | 2004-08-12 | 2006-08-17 | Pliva-Istrazivacki Institut D.O.O. | Use of immune cell specific conjugates for treatment of inflammatory diseases of gastrointestinal tract |
CA2585711A1 (en) | 2004-10-27 | 2006-05-04 | Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. | Conjugates with anti-inflammatory activity |
JP2008532927A (ja) * | 2005-01-13 | 2008-08-21 | グラクソスミスクライン・イストラジヴァッキ・センタル・ザグレブ・ドルズバ・ゼー・オメイェノ・オドゴヴォルノスティオ | 抗炎症マクロライド接合体 |
CN101228171A (zh) * | 2005-07-26 | 2008-07-23 | 默克勒有限公司 | 作为5-脂氧化酶和环加氧酶抑制剂的吡咯里嗪和中氮茚化合物的大环内酯偶联物 |
WO2009006403A2 (en) * | 2007-06-29 | 2009-01-08 | Georgia Tech Research Corporation | Non-peptide macrocyclic histone deacetylase (hdac) inhibitors and methods of making and using thereof |
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CA2489398A1 (en) | 2004-01-15 |
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