CN103479654B - 作为抗炎药的含硼的小分子 - Google Patents
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- CN103479654B CN103479654B CN201310283871.4A CN201310283871A CN103479654B CN 103479654 B CN103479654 B CN 103479654B CN 201310283871 A CN201310283871 A CN 201310283871A CN 103479654 B CN103479654 B CN 103479654B
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Abstract
披露了通过使用含硼的小分子处理抗炎疾患的方法。
Description
本申请是申请号为200780013339.3、申请日为2007年02月16日、发明名称为“作为抗炎药的含硼的小分子”的中国专利申请的分案申请。
相关申请的交叉参考
本申请请求2006年8月29日提交的美国临时专利申请顺序号US60/823,888和2006年2月16日提交的美国临时专利申请顺序号US60/774,532的优先权,为所有目的而将这些文献完整地引入本文作为参考。
发明背景
不规则的炎症为广泛的人体疾病的主要因素。患有变性病症的人通常在其血液中展示出过量水平的促炎调节剂。一类这样的促炎调节剂为细胞因子,包括IL-1α,β,IL-2,IL-3,IL-6,IL-7,IL-9,IL-12,IL-17,IL-18,IL-23,TNF-α,LT,LIF,制癌蛋白和IFNc1α,β,γ。
直接因炎性细胞因子导致的常见医学问题的非限制性实例包括:关节炎,其中炎性细胞因子可以导致滑膜中的损害并且破坏关节软骨和骨;肾衰竭,其中炎性细胞因子限制循环和损害肾单位;狼疮,其中炎性细胞因子加剧免疫复合物沉积和损害;哮喘,其中炎性细胞因子阻塞气道;银屑病,其中炎性细胞因子诱导皮炎;胰腺炎,其中炎性细胞因子诱导胰腺细胞损伤;过敏症,其中炎性细胞因子诱导血管通透性和充血;纤维化,其中炎性细胞因子攻击受创伤的组织;手术并发症,其中炎性细胞因子阻止愈合;贫血,其中炎性细胞因子攻击红细胞生成素产生;和纤维肌痛,其中炎性细胞因子在纤维肌痛患者中升高。
与慢性炎症相关的其他疾病包括:癌症;心脏病发作,其中慢性炎症促成冠状动脉粥样硬化;阿尔茨海默病,其中慢性炎症破坏脑细胞;充血性心力衰竭,其中慢性炎症导致心肌萎缩;中风,其中慢性炎症促进血栓-栓塞情况;和主动脉瓣狭窄,其中慢性炎症损害血栓。动脉硬化,骨质疏松症,帕金森病,感染,炎症性肠病,包括克罗恩病和溃疡性结肠炎以及多发性硬化(典型自身免疫炎症-相关疾病)也涉及炎症(Bebo,B.F.,Jr.,J NeurosciRes,45:340-348,(1996);Mennicken,F.,Trends Pharmacol Sci,20:73-78,(1999);Watanabe,T,Int J Cardiol,66Suppl1:S45-53;discussion S55,(1998);Sullivan,G.W.,J Leukoc Biol,67:591-602,(2000);Franceschi,C.,Ann N Y Acad Sci,908:244-254,(2000);Rogers,J,Ann N Y Acad Sci,924:132-135,(2000);Li,Y.J.,Hum Mol Genet,12:3259-3267,(2003);Maccarrone,M.,Curr Drug Targets Inflamm Allergy,1:53-63,(2002);Lindsberg,P.J.,Stroke,34:2518-2532,(2003);DeGraba,T.J.,Adv Neurol,92:29-42,(2003);Ito,H.,Curr Drug Targets Inflamm Allergy,2:125-130,(2003);vonder Thusen,J.H.,Pharmacol Rev,55:133-166,(2003);Schmidt,M.I.,Clin Chem LabMed,41:1120-1130,(2003);Virdis,A.,Curr Opin Nephrol Hypertens,12:181-187,(2003);Tracy,R.P.,Int J Clin Pract,Suppl10-17,(2003);Haugeberg,G.,Curr OpinRheumatol,15:469-475,(2003);Tanaka,Y.,J Bone Miner Metab,21:61-66,(2003);Williams,J.D.,Clin Exp Dermatol,27:585-590,(2002))。在晚期阶段中的某些疾病可以威胁生命。可利用几种方法治疗这类炎性疾病;然而,正如缺乏功效和与之相关的药物相关副作用所证实的,结果一般不令人满意。
炎症性肠病
炎性肠病(IBD)包括克罗恩病(CD)和溃疡性结肠炎(UC),它们两者均为在世界上许多地区发生频率增加的特发性慢性疾病。在美国,每年有超过600,000人受到侵害。IBD可以涉及小肠,大肠或它们两者。CD可以涉及胃肠道的任何部分,但最频繁地涉及小肠和结肠。它忽略了直肠或导致直肠周围引流的炎症或感染。UC通常导致通常在直肠开始的大肠下部中的溃疡。症状可变,但可以包括腹泻,发热和疼痛。具有延长的UC的患者发生结肠癌的风险增加。目前没有令人满意的治疗,因为IBD的远因仍然不清楚,不过,已经提出了感染和免疫学机制。IBD治疗的目的在于通常使用皮质类固醇,氨基水杨酸盐和标准免疫抑制剂,诸如硫唑嘌呤(6-巯嘌呤),甲氨蝶呤和环孢素控制炎性症状。在它们中,唯一改变疾病的疗法为免疫抑制剂,硫唑嘌呤和甲氨蝶呤,它们均具有短效作用和仅适度的功效。长效疗法可以导致肝损害(纤维化或肝硬化)和骨髓抑制。患者海通常拒绝这类治疗。其他治疗方案仅为解决症状(Rutgeerts,P.A,J Gastroenterol Hepatol,17Suppl:S176-185(2002);Rutgeerts,P.,Aliment Pharmacol Ther,17:185-192(2003))。
银屑病
银屑病是最常见的免疫-介导的慢性皮肤病,它以不同形式出现并且严重性水平可变,在美国侵害约2%的人群或超过450万人,其中的150万人被视为具有中度到重度形式的该病。具有银屑病的患者的10-30%还出现关节炎形式-牛皮癣性关节炎,它损害关节周围的骨和结缔组织。银屑病作为覆盖有白色鳞片状累积物的隆起的红色皮肤斑出现。它还可以具有小脓疱(脓疱性银屑病)或烧灼(红皮病型)表现。银屑病还可以导致强烈瘙痒和烧灼。患者在心理上和生理上均患病。目前可利用几种形式治疗银屑病,包括局部治疗,光疗法和全身施用。然而,它们一般被视为仅抑制疾病和改变疾病;其中无一可治愈疾病。此外,许多治疗从美容角度来不理想,不便于长期应用或育明显的毒性相关。
在过去的二十年内随着对银屑病生物学特性的理解不断增加,已经可以利用靶向导致该病的炎症特性的T淋巴细胞和细胞因子活性的生物学疗法。目前,为银屑病开据的处方药包括最初用于风湿性关节炎(RA)治疗的TNF-α抑制剂,(依那西普),(英夫利昔单抗)和(阿达木单抗)和Biogen在2002年批准的T-细胞抑制剂(阿来法塞)和Genentech/Xoma在2003年批准的(依法珠单抗)(Weinberg,J.M.,J Drugs Dermatol,1:303-310,(2002))。AMEVIVE为由与人IgG(1)铰链区,C(H)2和C(H)3结构域融合的人LFA-3的第一胞外域组成的免疫球蛋白融合蛋白。它通过NK细胞抑制T细胞增殖(Cooper,J.C.,Eur J Immunol,33:666-675,(2003))。也称作抗-CD11a,即靶向T细胞黏着分子,即白细胞功能-相关抗原-1(LFA-1)的人源化单克隆抗体。防止LFA-1与其配体(ICAM-1,胞间黏着分子-1)结合抑制了白细胞活化和迁移,导致淋巴细胞浸润减少,由此限制了最终产生银屑病征兆和症状的后果串连(Cather,J.C.,Expert Opin Biol Ther,3:361-370,(2003))。然而,目前现有技术的TNF-α抑制剂的可能副作用严重,包括发生淋巴瘤(Brown,S.L.,Arthritis Rheum,46:3151-3158,(2002)),加剧的充血性心力衰竭,导致严重感染和脓毒病和多发性硬化加剧和中枢神经系统问题(Weisman,M.H.,J Rheumatol Suppl,65:33-38,(2002);Antoni,C.,Clin Exp Rheumatol,20:S152-157,(2002))。尽管的T-细胞抑制剂的副作用在银屑病治疗中更可耐受,但是为免疫抑制剂。免疫抑制剂具有感染风险增加,潜在复发性,慢性感染或发生癌症的风险增加的可能性。
尽管在过去二十年内对银屑病的生物学特性的理解有了许多进展并且如上所述的可利用银屑病的非常规治疗,但是它所产生的大量病害仍然不足以得到解决。1998年在National Psoriasis Foundation进行的对具有银屑病的40,000美国人的观察表明79%的较为年轻的患者因其治疗无效感觉失败。其中具有严重性疾病的32%感觉其治疗攻击性不足(Mendonca,C.O.,Pharmacol Ther,99:133-147,(2003);Schon,M.P.,J InvestDermatol,112:405-410,(1999))。
风湿性关节炎
风湿性关节炎(RA)代表了另一个麻烦的炎性病症的实例。它通常为慢性炎症相关疾病,其特征在于关节和/或其他内脏器官的膜内层(滑膜)中的慢性炎症。炎性细胞害可以侵入和损害骨和软骨。涉及的关节可能失去其形状和排列,导致丧失运动能力。具有RA的患者在关节中存在疼痛,僵硬,温热,发红和肿胀以及其他全身症状,如发热,疲劳和贫血。在美国约1%的人群或210万人目前受到侵害,其中女性(15万)多于男性(60万)。RA的病理学尚未得到完全理解,不过,已经将不适当的免疫反应串连推定为机制。常规的治疗在RA中令人遗憾地无效(Bessis,N.,J Gene Med,4:581-591,(2002))(29)。该病对针对症状的因为无法完全起反应,包括自上世纪50年代以来使用的皮质类固醇和非类固醇抗炎药(NSAIDs)。此外,这些药物携带严重性副作用的风险。改变疾病的抗风湿药(DMARDs),诸如甲氨蝶呤(MTX)的治疗作用通常不一致和短效。
近期已经基于对炎症过程中的细胞因子TNF-α和IL-1作用的理解研发了一类新的用于治疗RA的生物学DMARDs(改变疾病的抗风湿药)。FDA已经批准了几种这类DMARDs,包括来自Immunex/Amgen Inc.的1998年的(依那西普),来自Centocor/Johnson&Johnson的英夫利昔单抗),来自Abbott Laboratories Inc.的2002年的(阿达木单抗)和来自Amgen的2001年的(阿那白滞素)。为可溶性TNF受体(TNFR)重组蛋白。为人源化小鼠(嵌合)抗-TNF-α单克隆抗体。为使用噬菌体展示技术生成的完整人抗-TNF单克隆抗体,使得抗体可以人衍生的重链和轻链可变区和人IgG1:k恒定区。所有这3种基于蛋白质的药物靶向并且结合TNF-α以便阻断TNF-α的作用。为重组IL-1受体拮抗剂,其与天然人IL-1Ra类似,但不包括在其氨基末端上添加单一甲硫氨酸残基。通过竞争性抑制IL-1结合IL-1 I型受体(IL-1RI)和由此减少IL-1的促炎作用而阻断IL-1的生物学活性。
使用这些生物学DMARDs治疗缓解了症状,抑制了结构损害发展并且改善了具有中度到重度活动性RA的患者的躯体功能。3种商购的TNF-α阻滞剂在与MTX,即广泛应用的DMARD联用时在治疗具有RA的患者中具有类似的功效(Hochberg,M.C.,Ann Rheum Dis,62Suppl2:ii13-16,(2003))。尽管在许多具有RA的患者中提供了显著的功效和短期和中期上提供了良好的总体安全特性,但是这些生物学治疗可能产生严重问题和长期的副作用,诸如在肝脏中,所以仍然需要评估。在使用或与发生淋巴瘤之间存在令人不安的相关性(S.L.,Arthritis Rheum,46:3151-3158,(2002))。如上所述的,几个报导已经证实使用或治疗的患者恶化了其充血性心力衰竭并且发生严重感染和脓毒病且增加了多发性硬化恶化和其他中枢神经系统问题(Antoni,C.,Clin Exp Rheumatol,20:S152-157,(2002);Mendonca,C.O.,PharmacolTher,99:133-147,(2003))。
多发性硬化
多发性硬化(MS)为在美国350,000-500,000人中诊断的自身免疫疾病。炎症的多发区域和在脑和脊髓中的髓磷脂缺失表明了该病。具有MS的患者根据髓磷脂缺失位置和程度的不同而表现出可变的神经损伤程度。MS的常见症状包括疲劳,虚弱,痉挛状态,平衡问题,膀胱和肠问题,麻木,视力丧失,颤动和抑郁症。MS的目前治疗仅为缓解症状或延迟残疾发生,而几种新的MS疗法,包括干细胞移植和基因疗法为保守性的(Fassas,A.,Blood Rev,17:233-240,(2003);Furlan,R.,Curr Pharm Des,9:2002-2008,(2003))。尽管已经证实抗-TNF抗体在实验性自身免疫性脑炎(EAE)中的预防作用,但是它们加剧MS患者中的该病,从而提示仅抑制TNF-α是不够的(Ghezzi,P.,Neuroimmunomodulation,9:178-182,(2001))。
神经变性病症
阿尔茨海默病(AD)和帕金森病(PK)为两种最常见的神经变性病症。AD严重侵害人进行每日活动的能力。它涉及控制思维,记忆和语言的脑的部分。据估计通常年龄常规60岁的约4百万美国人患有AD。
PK为在美国影响超过150万以人的中枢神经系统病症。在临床上,该病的特征在于自发活动减少,步态困难,姿势的不稳定性,强直和颤动。PK因脑黑质中色素沉着神经元变性而导致多巴胺利用度减少所致。这些神经变性病症的原因尚不了解且目前对该病无法治愈。
因此,需要治疗上述和其他炎症相关疾病的新手段。尽管炎症相关疾病机制仍然不清楚并且通常彼此改变,但是已经证实因细胞因子失调导致的免疫系统功能障碍在炎症开始和进展中起重要作用(Schon,M.P.,J Invest Dermatol,112:405-410,(1999);Andreakos,E.T.,Cytokine Growth Factor Rev,13:299-313,(2002);Najarian,D.J.,JAm Acad Dermatol,48:805-821,(2003))。
一般将细胞因子分成3类:促炎(IL-1α,β,IL-2,IL-3,IL-6,IL-7,IL-9,IL-12,IL-17,IL-18,IL-23,TNF-α,LT,LIF,制癌蛋白和IFNc1α,β,γ);抗炎(IL-4,IL-10,IL-11,W-13和TGF-β);和趋化因子(IL-8,Gro-α,MIP-1,MCP-1,ENA-78和RANTES)。
在许多炎症情况中,促炎细胞因子,尤其是TNF-α,IL-1β和IL-6以及抗炎细胞因子IL-10表现出在各种炎症相关疾病发病机制中起重要作用且由此可以用作潜在的治疗剂。例如,已经在几种炎症相关疾病中观察到了某些促炎细胞因子(TNF-α,IFNγ,IL-1,IL-2,IL-6和IL-12)和趋化因子(IL-8,MCP-1和RANTES)水平升高,诸如CD,银屑病,RA,格雷夫斯病和桥本甲状腺炎(Andreakos,E.T.,Cytokine Growth Factor Rev,13:299-313,(2002)),它们的可溶性TNF受体,IL-1受体拮抗剂和抗炎细胞因子IL-10平行增加(Noguchi,M.,Gut,43:203-209,(1998);Autschbach,F.,Am J Pathol,153:121-130,(1998))。已经证实IL-10在体外LPMC培养物和患者体内抑制促炎细胞因子产生增加(Schreiber,S.,Gastroenterology,108:1434-1444,(1995))。使用IL-10治疗的CD患者的阳性反应证实在CD中的促炎与抗炎细胞因子产生之间还存在不平衡。
总之,治疗炎症相关疾病的手段在近年来已经部分发生了进展性的改变,结果是对这些疾病严重性的关注增加并且部分是因为在理解细胞因子在其免疫发病机制中的重要作用有了理解。大部分努力集中于靶向TNF-α和IL-1(Baugh,J.A.,Curr Opin DrugDiscov Devel,4:635-650,(2001))且目前销售了几种产物(TNF-α抑制剂:英夫利昔单抗,即单克隆抗-TNF-α抗体;和依那西普,即p75TNF-α受体)或如上所述的在临床试验中用于治疗RA,银屑病和IBD。靶向IL-1(Gabay,C.,Curr Opin Investig Drugs,4:593-597,(2003)),IL-6或IL-10的几种其他药物候选物或策略处于研发中(Gabay,C.,Curr OpinInvestig Drugs,4:593-597,(2003);Palladino,M.A.,Nat Rev Drug Discov,2:736-746,(2003);Girolomoni,G.,Curr Opin Investig Drugs,3:1590-1595,(2002))。这些生物学治疗在许多具有RA的患者中提供了显著的短期和中期功效(Elliott,M.J.,Lancet,344:1125-1127,(1994);Moreland,L.W.,N Engl J Med,3377:141-147,(1997);Campion,G.V.,Arthritis Rheum,39:1092-1101,(1996);Feldmann,M.,Nat Immunol,2:771-773,(2001))。尽管这些因为得到充分接受并且具有氯化的总体安全特性,但是本领域中仍然存在对可以抑制促炎细胞因子或刺激抗炎细胞因子的其他因为的需求。
基于这一观念我们检验了几种类型的小分子以便测试其在调节多个细胞因子中的能力并且研究了它们在治疗各种炎症相关疾病中的潜在临床应用。
发明概述
本发明在第一个方面中提供了治疗或预防人或动物与炎症相关的疾病的方法,该方法包括对所述的人或动物给予治疗有效量的本文所述的化合物。在一个典型的实施方案中,所述的化合物为选自C1-C100中的成员。在一个典型的实施方案中,所述的化合物具有式I的结构:
其中B为硼。R1a为选自负电荷,盐抗衡离子,H,氰基,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。M为选自氧,硫和NR2a中的成员。R2a为选自H,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。J为选自(CR3aR4a)n1和CR5a中的成员。R3a,R4a和R5a为独立地选自H,氰基,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。指数n1为选自0-2的整数。W为选自C=O(羰基),(CR6aR7a)m1和CR8a中的成员。R6a,R7a和R8a为独立地选自H,氰基,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。指数m1为选自0和1的整数。A为选自CR9a和N中的成员。D为选自CR10a和N中的成员。E为选自CR11a和N中的成员。G为选自CR12a和N中的成员。R9a,R10a,R11a和R12a为独立地选自H,OR*,NR*R**,SR*,-S(O)R*,-S(O)2R*,-S(O)2NR*R**,-C(O)R*,-C(O)OR*,-C(O)NR*R**,硝基,卤素,氰基,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。R*和R**各自为独立地选自H,硝基,卤素,氰基,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。氮(A+D+E+G)之和为选自0-3的整数。选自R3a,R4a和R5a中的成员和选自R6a,R7a和R8a中的成员与连接它们的原子一起任选地连接成4-7元环。R3a和R4a与连接它们的原子一起任选地连接成4-7元环。R6a和R7a与连接它们的原子一起任选地连接成4-7元环。R9a和R10a与连接它们的原子一起任选地连接成4-7元环。R10a和R11a与连接它们的原子一起任选地连接成4-7元环。R11a和R12a与连接它们的原子一起任选地连接成4-7元环。
本发明在第二个方面中提供了治疗或预防人或动物与炎症相关的疾病的方法,该方法包括对所述的人或动物给予治疗有效量的具有式II的结构的化合物:
其中B为硼。R20,R21和R22为独立地选自负电荷,盐抗衡离子,H,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。A为选自CR9a和N中的成员。D为选自CR10a和N中的成员。E为选自CR11a和N中的成员。G为选自CR12a和N中的成员。R9a,R10a,R11a和R12a为独立地选自H,OR*,NR*R**,SR*,-S(O)R*,-S(O)2R*,-S(O)2NR*R**,-C(O)R*,-C(O)OR*,-C(O)NR*R**,硝基,卤素,氰基,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。R*和R**各自为独立地选自H,硝基,卤素,氰基,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。氮(A+D+E+G)之和为选自0-3的整数。选自R3a,R4a和R5a中的成员和选自R6a,R7a和R8a中的成员与连接它们的原子一起任选地连接成4-7元环。R3a和R4a与连接它们的原子一起任选地连接成4-7元环。R6a和R7a与连接它们的原子一起任选地连接成4-7元环。R9a和R10a与连接它们的原子一起任选地连接成4-7元环。R10a和R11a与连接它们的原子一起任选地连接成4-7元环。R11a和R12a与连接它们的原子一起任选地连接成4-7元环。
本发明还提供了使用本文所述的化合物和这些化合物的药物制剂的额外方法。
附图简述
图1描述了本发明化合物抑制4种细胞因子每一种的程度:TNF-α,IL-1β,IFN-γ和IL-4。
图2展示了本发明的典型化合物。
图3展示了本发明的典型化合物。
发明详述
I.定义和缩写
本文所用的缩写一般具有其在化学和生物学领域中常用的含义。
本文所用的“本发明化合物”意旨本文讨论的化合物,这些化合物的药学上可接受的盐和前体药物。
“抑制”和“阻断”在本文中可以互换使用,其指的是用本发明的方法部分或完全阻断促炎细胞因子表达,它导致受试者或患者细胞因子的量减少。
如果取代基由其常规的从左到右书写的化学式指定,那么它们等同地包括化学上相同的取代基,它们可以从右到左书写结构产生,例如-CH2O-指定还描述为-OCH2-。
本文所用的术语“多”意旨至少2个。例如,多价金属离子为具有至少为2的化合价的金属离子。
“结构部分”意旨与另一结构部分连接的分子基团。
符号,无论是作为键还是展示出与键垂直均表示展示的结构部分与分子的剩余部分连接的点。
除非另作陈述,否则术语“烷基”作为其自身或作为另一取代基的组成部分意旨直链或支链或环状烃基或其组合,它可以为完全饱和的,单-或多不饱和的并且可以包括具有指定碳原子数的二-和多价基团(即C1-C10意旨1-10个碳)。饱和烃基的实例包括,但不限于诸如如下这类基团:甲基,乙基,正-丙基,异丙基,正-丁基,叔-丁基,异丁基,仲-丁基,环己基,(环己基)甲基,环丙基甲基,例如正-戊基,正-己基,正-庚基,正-辛基的同系物和异构体等。不饱和烷基为具有一个或多个双键或三键的基团。不饱和烷基的实例包括,但不限于乙烯基,2-丙烯基,巴豆基,2-异戊烯基,2-(丁二烯基),2,4-戊二烯基,3-(1,4-戊二烯基),乙炔基,1-丙炔基和3-丙炔基,3-丁炔基和高级同系物和异构体。除非另作陈述,否则术语“烷基”的含义还包括那些在下文中更详细定义的烷基的衍生物,诸如“杂烷基”。限于烃基的烷基称作“高烷基(homoalkyl)”。
术语“亚烷基”作为其自身或作为另一取代基的组成部分意旨衍生自烷的二价基团,作为典型,但不限于-CH2CH2CH2CH2-并且进一步包括那些在下文中描述为“杂亚烷基”的基团。一般而言,烷基(或亚烷基)具有1-24个碳原子,其中本发明优选那些具有10个或10个以下碳原子的基团。“低级烷基”或“低级亚烷基”为一般性具有8个或8个以下碳原子的较短链烷基或亚烷基。
术语“烷氧基”,“烷氨基”和“烷硫基”(或硫代烷氧基)以其常用含义使用并且意旨那些分别通过氧原子,氨基或硫原子与分子剩余部分连接的烷基。
除非另作陈述,否则术语“杂烷基”作为其自身或与另一术语的组合意旨稳定的直链或支链或环状烃基或其组合,它们由所述的量的碳原子和至少一个杂原子组成。在一个典型的实施方案中,杂原子可以选自B,O,N和S并且其中氮和硫原子可以任选被氧化且氮原子可以任选被季铵化。杂原子B,O,N和S可以在杂烷基的任意内部位置上被取代,在该位置上烷基与分子的剩余部分连接。实例包括,但不限于-CH2-CH2-O-CH3,-CH2-CH2-NH-CH3,-CH2-CH2-N(CH3)-CH3,-CH2-S-CH2-CH3,-CH2-CH2,-S(O)-CH3,-CH2-CH2-S(O)2-CH3,-CH=CH-O-CH3,-CH2-CH=N-OCH3和-CH=CH-N(CH3)-CH3。至多2个杂原子可以为连接的,诸如,例如为-CH2-NH-OCH3。类似地,术语“杂亚烷基”作为其自身或作为另一取代基的组成部分意旨衍生自杂烷基的二价基团,作为典型,但不限于-CH2-CH2-S-CH2-CH2-和-CH2-S-CH2-CH2-NH-CH2-。就杂亚烷基而言,杂原子还可以占据链末端的任一或两个位置(例如亚烷基氧基,亚烷二等)。此外,就亚烷基和杂亚烷基连接基而言,连接基的方向并不意味着由书写连接基式的方向。例如,式-C(O)2R’-表示-C(O)2R’-和-R’C(O)2-。
除非另作陈述,否则术语“环烷基”和“杂环烷基”作为其自身或与其他术语组合分别表示“烷基”和“杂烷基”的环状形式。另外,就杂环烷基而言,杂原子可以占据杂环与分子剩余部分连接的位置。环烷基的实例包括,但不限于环戊基,环己基,1-环己烯基,3-环己烯基,环庚基等。杂环烷基的实例包括,但不限于1-(1,2,5,6-四氢吡啶基),1-哌啶基,2-哌啶基,3-哌啶基,4-吗啉基,3-吗啉基,四氢呋喃-2-基,四氢呋喃-3-基,四氢噻吩-2-基,四氢噻吩-3-基,1-哌嗪基,2-哌嗪基等。
除非另作陈述,否则术语“卤素(halo)”或“卤素(halogen)”作为其自身或作为另一取代基的组成部分意旨氟,氯,溴或碘原子。另外,术语,诸如“卤代烷基”的含义包括一卤代和多卤代烷基。例如,术语“卤代(C1-C4)烷基”的含义包括,但不限于三氟甲基,2,2,2-三氟乙基,4-氯丁基,3-溴丙基等。
除非另作陈述,否则术语“芳基”意旨多不饱和芳族取代基,它可以为单环或多环(优选1-3个环),它们彼此稠合或共价连接。术语“杂芳基”意旨包含1-4个杂原子的芳基(或环)。在一个典型的实施方案中,杂原子选自B,N,O和S,其中氮和硫原子任选被氧化并且氮原子任选被季铵化。杂芳基可以通过杂原子与分子的剩余部分连接。芳基和杂芳基的非限制性实例包括苯基,1-萘基,2-萘基,4-苯硫基,1-吡咯基,2-吡咯基,3-吡咯基,3-吡唑基,2-咪唑基,4-咪唑基,吡嗪基,2-噁唑基,4-噁唑基,2-苯基-4-噁唑基,5-噁唑基,3-异噁唑基,4-异噁唑基,5-异噁唑基,2-噻唑基,4-噻唑基,5-噻唑基,2-呋喃基,3-呋喃基,2-噻吩基,3-噻吩基,2-吡啶基,3-吡啶基,4-吡啶基,2-嘧啶基,4-嘧啶基,5-苯并噻唑基,嘌呤基,2-苯并咪唑基,5-吲哚基,1-异喹啉基,5-异喹啉基,2-喹喔啉基,5-喹喔啉基,3-喹啉基和6-喹啉基。上述芳基和杂芳基环系各自的取代基选自下述可接受的取代基。
为简便起见,术语“芳基”在与其他术语联用时(例如芳氧基,芳硫氧基,芳基烷基)包括如上述定义的芳基和杂芳基。因此,术语“芳基烷基”的含义包括芳基与烷基连接的那些基团(例如苄基,苯乙基,吡啶基甲基等),包括那些碳原子(例如亚甲基)被例如氧原子取代的烷基(例如苯氧基甲基,2-吡啶基氧基甲基,3-(1-萘氧基)丙基等)。
上述术语(例如“烷基”,“杂烷基”,“芳基”和“杂芳基”)的含义各自包括所示基团的取代和未被取代形式。在下文中提供了各类基团的优选取代基。
烷基和杂烷基的取代基(包括通常称作亚烷基,烯基,杂亚烷基,杂烯基,炔基,环烷基,杂环烷基,环烯基和杂环烯基的那些基团)一般称作“烷基取代基”,并且它们可以为各种基团中的一个或多个,它们选自,但不限于:-OR’,=O,=NR’,=N-OR’,-NR’R”,-SR’,-卤素,-OC(O)R’,-C(O)R’,-CO2R’,-CONR’R”,-OC(O)NR’R”,-NR”C(O)R’,-NR’-C(O)NR”R”’,-NR”C(O)2R’,-NR-C(NR’R”R’”)=NR””,-NR-C(NR’R”)=NR’”,-S(O)R’,-S(O)2R’,-S(O)2NR’R”,-NRSO2R’,-CN和-NO2,其中数值范围从0到(2m’+1),其中m’为这类基团中的碳原子总数。R’,R”,R”’和R””各自优选独立地指氢,取代或未取代的杂烷基,取代或未取代的芳基,例如被1-3个卤素取代的芳基,取代或未取代的烷基,烷氧基或硫代烷氧基或芳基烷基。例如,当本发明化合物包括一个以上R基团时,R基团作为R’,R”,R’”和R””各自独立地选择,此时这些基团中的一个以上存在。当R’和R”与相同的氮原子连接时,它们可以与氮原子合并成5-,6-或7-元环。例如,-NR’R”的含义包括,但不限于1-吡咯烷基和4-吗啉基。从上述取代基讨论中可以看出,本领域技术人员理解术语“烷基”的含义包括基团,这些基团包括与非氢基结合的碳原子,诸如卤代烷基(例如-CF3和-CH2CF3)和酰基(例如-C(O)CH3,-C(O)CF3,-C(O)CH2OCH3等)。
与对烷基所述的取代基类似,芳基和杂芳基的取代基一般称作“芳基取代基”。取代基选自,例如:卤素,-OR’,=O,=NR’,=N-OR’,-NR’R”,-SR’,-卤素,-OC(O)R’,-C(O)R’,-CO2R’,-CONR’R”,-OC(O)NR’R”,-NR”C(O)R’,-NR’-C(O)NR”R”’,-NR”C(O)2R’,-NR-C(NR’R”R’”)=NR””,-NR-C(NR’R”)=NR’”,-S(O)R’,-S(O)2R’,-S(O)2NR’R”,-NRSO2R’,-CN和-NO2,-R’,-N3,-CH(Ph)2,氟(C1-C4)烷氧基和氟(C1-C4)烷基,其数值范围从0到芳族环系上的开放化合价总数;并且其中R’,R”,R”’和R””优选独立地选自氢,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的芳基和取代或未取代的杂芳基。例如,当本发明化合物包括一个以上R基团时,R基团作为R’,R”,R’”和R””各自独立地选择,此时这些基团中的一个以上存在。
芳基或杂芳基环的相邻原子上的取代基中的两个可以任选被式-T-C(O)-(CRR’)q-U-的取代基取代,其中T和U独立为-NR-,-O-,-CRR’-或单键且q为0-3的整数。可选择地,芳基或杂芳基环的相邻原子上的取代基中的两个可以任选被式-A-(CH2)r-B-的取代基取代,其中A和B独立为-CRR’-,-O-,-NR-,-S-,-S(O)-,-S(O)2-,-S(O)2NR’-或单键且r为1-4的整数。由此形成的新环的单键可以任选被双键取代。可选择地,芳基或杂芳基环的相邻原子上的取代基中的两个可以任选被式-(CRR’)s-X-(CR”R’”)d-的取代基取代,其中s和d独立为0-3的整数且X为-O-,-NR’-,-S-,-S(O)-,-S(O)2-或-S(O)2NR’-。取代基R,R’,R”和R’”优选独立地选自氢或取代或未取代的(C1-C6)烷基。
本文所用的“环”意旨取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基或取代或未取代的杂芳基。环包括稠合环部分。环上的原子数一般由环成员数确定。例如,“5-至7-元环”意旨在环内排列上存在5-7个原子。该环任选包括杂原子。因此,术语“5-至7-元环”包括,例如吡啶基和哌啶基。术语“环”进一步包括含一个以上“环”的环系,其中“环”各自独立地如上述定义。
本文所用的术语“杂原子”包括非碳(C)和氢(H)的原子。实例包括氧(O),氮(N),硫(S),硅(Si),锗(Ge),铝(Al)和硼(B)。
符号“R”为表示取代基的一般缩写,所述的取代基选自取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的芳基,取代或未取代的杂芳基,取代或未取代的环烷基和取代或未取代的杂环烷基。
所谓药物,制剂或持久的“有效”量指的是活性剂提供所需局部或全身作用的足量。“局部有效”,“美容有效”,“药物有效”或“治疗有效”量意旨影响所需治疗效果所需的药物用量。
“局部有效”意旨在施用于皮肤,指甲,毛发,爪或蹄时在施用部位上产生局部所需药理学效果或作为物质中的活性组分经皮通道的全身效果的物质。
“美容有效”意旨在施用于皮肤,指甲,毛发,爪或蹄时在作为物质中的活性组分施用部位上产生局部所需美容效果的物质。
术语“药学上可接受的盐”的含义包括由相对无毒性酸或碱制备的本发明化合物的盐,这取决于本文所述的化合物上发现的特定取代基。当本发明化合物包含相对酸性功能性时,可以通过使这类化合物的中性形式接触足量的净的所需碱或在合适的惰性溶剂中接触足量的碱获得碱加成的盐。药学上可接受的碱加成的盐的实例包括钠,钾,钙,铵,有机氨基或镁盐或类似盐。当本发明化合物包含相对碱性的功能性时,可以通过使这类化合物的中性形式接触足量的净的所需酸或在合适的惰性溶剂中接触足量的酸获得酸加成的盐。药学上可接受的酸加成的盐的实例包括衍生自无机酸的那些和衍生自相对无毒性的有机酸的盐,所述的无机酸如盐酸,氢溴酸,硝酸,碳酸,一氢碳酸,磷酸,一氢磷酸,二氢磷酸,硫酸,一氢硫酸,氢碘酸或亚磷酸,所述的有机酸如乙酸,丙酸,异丁酸,马来酸,丙二酸,苯甲酸,琥珀酸,辛二酸,富马酸,乳酸,扁桃酸,苯二甲酸,苯磺酸,对-甲苯磺酸,柠檬酸,酒石酸,甲磺酸等。还包括氨基酸的盐,诸如精氨酸盐和有机酸,如葡糖醛酸或半乳糖醛酸的盐等(例如,参见Berge等,“Pharmaceutical Salts”,Journal of PharmaceuticalScience66:1-19(1977))。本发明的某些具体化合物包含将这些化合物转化成碱或酸加成的盐的碱性和酸性官能基。
优选通过使盐接触碱或酸并且按照常规方式分类母体化合物使所述的化合物的中性形式再生。化合物的母体形式与各种盐形式不同的方面在于某些物理特性,诸如在极性溶剂中的溶解度。
除盐形式外,本发明提供了前体药物形式的化合物。本文所述的化合物或的前体药物或复合物用于在生理条件下进行化学改变成本发明化合物。另外,可以通过在离体环境中的化学或生化方法将前体药物转化成本发明化合物。
本发明的某些化合物可以以未溶剂化形式和溶剂化形式存在,包括水化形式。一般而言,溶剂化形式与非溶剂化形式等效并且包括在本发明范围内。本发明的某些化合物可以以多晶形或非晶形形式存在。一般而言,所有物理形式就本发明关注的应用而言均等效,并且指定它们包括在本发明范围内。
本发明的某些化合物具有不对称碳原子(光学中心)或双键;外消旋物,非对映体,几何异构体和各异构体包括在本发明范围内。
本发明化合物还可以包含非天然比例的构成这类化合物的原子中的一个或多个的原子同位素。例如,可以使用放射性同位素放射性标记所述的化合物,诸如,例如氚(3H),碘-125(125I)或碳-14(14C)。本发明化合物的所有同位素变化形式,无论是否为放射性的均被指定包括在本发明范围内。
术语“药学上可接受的载体”或“药学上可接受的媒介物”意旨任意的制剂或载体介质,它提供本文定义的活性剂有效量的适当递送,不干扰活性剂生物活性的有效性并且对宿主或患者而言充分无毒性。有代表性的载体包括水,植物和矿物油,霜剂基质,洗剂基质,软膏剂基质等。这些基质包括悬浮剂,增稠剂,渗透促进剂等。其制剂为化妆品和局部用药物领域众所周知的。有关载体的额外信息可以在Remington:The Science and Practiceof Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)中找到,将该文献引入本文作为参考。
“药学上可接受的局部用载体”和等效术语意旨如上文所述的适合于局部施用的药学上可接受的载体。能够悬浮或溶解活性剂并且在施用于皮肤,指甲,毛发,爪或蹄时不具有毒性和炎性特性的无活性液体或霜剂媒介物为药学上可接受的局部用载体的实例。特别将该术语指定为包括批准也用于局部用化妆品的载体物质。
术语“药学上可接受的添加剂”意旨防腐剂,抗氧化剂,香料,乳化剂,染料和赋形剂,它们是药物制剂领域中已知或使用的并且不会不适当地干扰活性剂的生物活性有效性并且对宿主或患者而言充分无毒性。局部制剂用添加剂为本领域众所周知的并且可以加入到局部用组合物中,只要它们为药学上可接受的并且对上皮细胞或其功能而言无害。此外,它们不应在组合物稳定性方面产生降低。例如,惰性填充剂,抗刺激剂,增粘剂,赋形剂,香料,遮光剂,抗氧化剂,胶凝剂,稳定剂,表面活性剂,软化剂,着色剂,防腐剂,缓冲剂,其他渗透促进剂和其他局部或透皮用递送制剂的常用成分为本领域公知的。
术语“促进”,“穿透促进”或“渗透促进”涉及皮肤,指甲,毛发,爪或蹄对药物的渗透性增加,以便增加药物透过皮肤,指甲,毛发,爪或蹄的速率。例如,可以通过使用扩散池仪器测定药物通过动物或人皮肤,指甲,毛发,爪或蹄的扩散速率观察到通过使用这类促进剂实现的渗透促进。扩散池由Merritt等描述在Diffusion Apparatus for SkinPenetration,J of Controlled Release,1(1984)pp.161-162中。术语“渗透促进剂”或“穿透促进剂”意旨单独或以组合形式起增加皮肤,只见爱,毛发或蹄对药物的渗透性的活性剂或活性剂混合物。
术语“赋形剂”通常已知意旨用于配制有效用于所需应用而配制药物组合物的载体,稀释剂和/或媒介物。
术语“局部给药”意旨将药物活性剂施用于皮肤,指甲,毛发,爪或蹄表面,使得该活性剂通过皮肤,指甲,毛发,爪或蹄外表面并且进入下面的组织。局部给药包括将组合物施用完整皮肤,指甲,毛发,爪或蹄表面或皮肤,指甲,毛发,爪或蹄破裂,粗糙或开放伤口。药物活性剂的局部给药导致活性剂的分布限于皮肤和周围组织,或在从治疗区域除去活性剂时可以导致活性剂通过血流在全身分布。
术语“透皮递送”意旨活性剂因局部给药或其他组合物施用通过皮肤,指甲,毛发,爪或蹄的屏障扩散。角质层作为屏障起作用并且几乎没有药物活性剂能够穿透完整皮肤。相反,表皮和真皮可透过许多溶质并且吸收药物,由此更易于通过擦伤,否则就是剥离角质层以暴露真皮的皮肤,指甲,毛发,爪或蹄。透皮递送包括通过皮肤,指甲,毛发,爪或蹄或粘膜的任何部分注射或其他递送和通过剩余部分吸收或渗透。通过完整皮肤,指甲,毛发,爪或蹄吸收可以通过将活性剂放入适当的药学上可接受的媒介物得到促进,此后施用于皮肤,指甲,毛发,爪或蹄。被动局部给药可以由将活性剂与软化剂或渗透促进剂一起直接施用于治疗部位组成。本文所用的透皮递送指定包括通过经外皮渗透或通过皮肤,指甲,毛发,爪或蹄。
II.引言
本发明涉及治疗与促炎细胞因子表达和/或减少的抗炎表达相关的炎症相关疾病的方法。本发明的方法包括对有这类治疗需要的人或动物给予单独或作为药物制剂组成部分的一种或多种本发明化合物。在一个优选的实施方案中,给予的化合物的用量足以通过抑制促炎细胞因子表达和/或通过刺激抗炎细胞因子治疗炎症相关疾病,但低于足以基本上抑制细胞周期蛋白依赖性激酶(CDKs)的量。
III.本发明应用的化合物
本发明在第一个方面中提供了本文所述的化合物。在一个典型的实施方案中,该化合物具有式I的结构:
其中B为硼。R1a为选自负电荷,盐抗衡离子,H,氰基,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。M为选自氧,硫和NR2a中的成员。R2a为选自H,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。J为选自(CR3aR4a)n1和CR5a中的成员。R3a,R4a和R5a为独立地选自H,氰基,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。指数n1为选自0-2的整数。W为选自C=O(羰基),(CR6aR7a)m1和CR8a中的成员。R6a,R7a和R8a为独立地选自H,氰基,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。指数m1为选自0和1的整数。A为选自CR9a和N中的成员。D为选自CR10a和N中的成员。E为选自CR11a和N中的成员。G为选自CR12a和N中的成员。R9a,R10a,R11a和R12a为独立地选自H,OR*,NR*R**,SR*,-S(O)R*,-S(O)2R*,-S(O)2NR*R**,-C(O)R*,-C(O)OR*,-C(O)NR*R**,硝基,卤素,氰基,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。R*和R**各自为独立地选自H,硝基,卤素,氰基,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。氮(A+D+E+G)之和为选自0-3的整数。选自R3a,R4a和R5a中的成员和选自R6a,R7a和R8a中的成员与连接它们的原子一起任选地连接成4-7元环。R3a和R4a与连接它们的原子一起任选地连接成4-7元环。R6a和R7a与连接它们的原子一起任选地连接成4-7元环。R9a和R10a与连接它们的原子一起任选地连接成4-7元环。R10a和R11a与连接它们的原子一起任选地连接成4-7元环。R11a和R12a与连接它们的原子一起任选地连接成4-7元环。
在一个典型的实施方案中,该化合物具有式(Ia)的结构:
在另一个典型的实施方案中,R3a和R4a各自为独立地选自H,氰基,取代或未取代的甲基,取代或未取代的乙基,三氟甲基,取代或未取代的羟甲基,取代或未取代的羟基烷基,取代或未取代的苄基,取代或未取代的苯基,取代或未取代的巯基甲基,取代或未取代的巯基烷基,取代或未取代的氨基甲基,取代或未取代的烷基氨基甲基,取代或未取代的二烷基氨基甲基,取代或未取代的芳基氨基甲基,取代或未取代的吲哚基和取代或未取代的酰氨基中的成员。在另一个典型的实施方案中,R3a和R4a各自为独立地选自氰基,取代或未取代的甲基,取代或未取代的乙基,三氟甲基,取代或未取代的羟甲基,取代或未取代的羟基烷基,取代或未取代的苄基,取代或未取代的苯基,取代或未取代的巯基甲基,取代或未取代的巯基烷基,取代或未取代的氨基甲基,取代或未取代的烷基氨基甲基,取代或未取代的二烷基氨基甲基,取代或未取代的芳基氨基甲基,取代或未取代的吲哚基,取代或未取代的酰氨基中的成员。
在另一个典型的实施方案中,R3a和R4a各自为选自H,取代或未取代的甲基,取代或未取代的乙基,取代或未取代的丙基,取代或未取代的异丙基,取代或未取代的丁基,取代或未取代的叔丁基,取代或未取代的苯基和取代或未取代的苄基中的成员。在另一个典型的实施方案中,R3a和R4a为选自甲基,乙基,丙基,异丙基,丁基,叔丁基,苯基和苄基中的成员。在另一个典型的实施方案中,R3a为H和R4a为选自甲基,乙基,丙基,异丙基,丁基,叔丁基,苯基和苄基中的成员。在另一个典型的实施方案中,R3a为H且R4a H。
在另一个典型的实施方案中,R9a,R10a,R11a和R12a各自为独立地选自如下的成员:H,OR*,NR*R**,SR*,-S(O)R*,-S(O)2R*,-S(O)2NR*R**,-C(O)R*,-C(O)OR*,-C(O)NR*R**,卤素,氰基,硝基,取代或未取代的甲氧基,取代或未取代的甲基,取代或未取代的乙氧基,取代或未取代的乙基,三氟甲基,取代或未取代的羟甲基,取代或未取代的羟基烷基,取代或未取代的苄基,取代或未取代的苯基,取代或未取代的苯氧基,取代或未取代的苯基甲氧基,取代或未取代的硫代苯氧基,取代或未取代的吡啶氧基,取代或未取代的嘧啶氧基,取代或未取代的苄基呋喃,取代或未取代的甲硫基,取代或未取代的巯基甲基,取代或未取代的巯基烷基,取代或未取代的苯硫基,取代或未取代的硫代苯硫基,取代或未取代的苯基甲硫基,取代或未取代的吡啶硫基,取代或未取代的嘧啶硫基,取代或未取代的苄硫基呋喃基,取代或未取代的苯基磺酰基,取代或未取代的苄基磺酰基,取代或未取代的苯基甲基磺酰基,取代或未取代的苯硫基磺酰基,取代或未取代的吡啶基磺酰基,取代或未取代的嘧啶基磺酰基,取代或未取代的磺酰氨基,取代或未取代的苯基亚磺酰基,取代或未取代的苄基亚磺酰基,取代或未取代的苯基甲基亚磺酰基,取代或未取代的苯硫基亚磺酰基,取代或未取代的吡啶基亚磺酰基,取代或未取代的嘧啶基亚磺酰基,取代或未取代的氨基,取代或未取代的烷基氨基,取代或未取代的二烷基氨基,取代或未取代的三氟甲基氨基,取代或未取代的氨基甲基,取代或未取代的烷基氨基甲基,取代或未取代的二烷基氨基甲基,取代或未取代的芳基氨基甲基,取代或未取代的苄氨基,取代或未取代的苯基氨基,取代或未取代的苯硫基氨基,取代或未取代的吡啶基氨基,取代或未取代的嘧啶基氨基,取代或未取代的吲哚基,取代或未取代的吗啉代,取代或未取代的烷基酰氨基,取代或未取代的芳基酰氨基,取代或未取代的脲基,取代或未取代的氨基甲酰基和取代或未取代的哌嗪基。在一个典型的实施方案中,R9a,R10a,R11a和R12a选自上述取代基,但不包括-C(O)R*,-C(O)OR*,-C(O)NR*R**。
在另一个典型的实施方案中,R9a,R10a,R11a和R12a为独立地选自如下基团中的成员:氟,氯,溴,硝基,氰基,氨基,甲基,羟基甲基,三氟甲基,甲氧基,三氟甲氧基,乙基,二乙氨基甲酰基,吡啶-2-基,吡啶-3-基,吡啶-4-基,嘧啶基,哌嗪并,哌嗪基,哌嗪基羰基,哌嗪基羰基,羧基,1-四唑基,1-乙氧羰基甲氧基,羧基甲氧基,苯硫基,3-(丁基羰基)苯基甲氧基,1H-四唑-5-基,1-乙氧羰基甲氧基-,1-乙氧羰基甲基-,1-乙氧羰基-,羧基甲氧基-,噻吩-2-基,噻吩-2-基硫代-,噻吩-3-基,噻吩-3-基硫代,4-氟苯硫基,丁基羰基苯基甲氧基,丁基羰基苯基甲基,丁基羰基甲基,1-(哌啶-1-基)羰基)甲基,1-(哌啶-1-基)羰基)甲氧基,1-(哌啶-2-基)羰基)甲氧基,1-(哌啶-3-基)羰基)甲氧基,1-(4-(嘧啶-2-基)哌嗪-1-基)羰基)甲氧基,1-(4-(嘧啶-2-基)哌嗪-1-基)羰基)甲基,1-(4-(嘧啶-2-基)哌嗪-1-基)羰基,1-4-(嘧啶-2-基)哌嗪-1-基,1-(4-(吡啶-2-基)哌嗪-1-基)羰基),1-(4-(吡啶-2-基)哌嗪-1-基)羰基甲基,(1-(4-(吡啶-2-基)哌嗪-1-基)羰基)-甲氧基),1-(4-(吡啶-2-基)哌嗪-1-基,1H-吲哚-1-基,吗啉代-,吗啉基,吗啉代羰基,吗啉基羰基,苯基脲基,苯基氨基甲酰基,乙酰氨基,3-(苯硫基)-1H-吲哚-1-基,3-(2-氰基乙硫基)-1H-吲哚-1-基,苄氨基,5-甲氧基-3-(苯硫基)-1H-吲哚-1-基,5-甲氧基-3-(2-氰基乙硫基)-1H-吲哚-1-基)),5-氯-1H-吲哚-1-基,5-氯-3-(2-氰基乙硫基)-1H-吲哚-1-基)),二苄氨基,苄氨基,5-氯-3-(苯硫基)-1H-吲哚-1-基)),4-(1H-四唑-5-基)苯氧基,4-(1H-四唑-5-基)苯基,4-(1H-四唑-5-基)苯硫基,2-氰基苯氧基,3-氰基苯氧基,4-氰基苯氧基,2-氰基苯硫基,3-氰基苯硫基,4-氰基苯硫基,2-氯苯氧基,3-氯苯氧基,4-氯苯氧基,2-氟苯氧基,3-氟苯氧基,4-氟苯氧基,2-氰基苄氧基,3-氰基苄氧基,4-氰基苄氧基,2-氯苄氧基,3-氯苄氧基,4-氯苄氧基,2-氟苄氧基,3-氟苄氧基,4-氟苄氧基,未被取代的苯基,未被取代的苄基。在一个典型的实施方案中,R9a为H且R12a为H。
在一个典型的实施方案中,式(I)或式(Ia)的化合物为选自如下的成员:
在一个典型的实施方案中,所述的化合物具有式I-Io之一的结构,其中R9a,R10a,R11a和R12a的取代基选择包括除H外的段落69中包含的所有可能性。在一个典型的实施方案中,所述的化合物具有式Ib-Io之一的结构,其中R9a,R10a,R11a和R12a的取代基选择包括除H外的段落70中包含的所有可能性。
在一个典型的实施方案中,所述的化合物具有式(Ib)-(Ie)的结构式,其中R1a为选自H,负电荷和盐抗衡离子中的成员且剩余的R基团(Ib中的R9a,Ic中的R10a,Id中的R11a和Ie中的R12a)为选自如下基团中的成员:氟,氯,溴,硝基,氰基,氨基,甲基,羟甲基,三氟甲基,甲氧基,三氟甲氧基,乙基,二乙氨基甲酰基,吡啶-2-基,吡啶-3-基,吡啶-4-基,嘧啶基,哌嗪并,哌嗪基,哌嗪基羰基,哌嗪基羰基,羧基,1-四唑基,1-乙氧羰基甲氧基,羧基甲氧基,苯硫基,3-(丁基羰基)苯基甲氧基,1H-四唑-5-基,1-乙氧羰基甲氧基-,1-乙氧羰基甲基-,1-乙氧羰基-,羧基甲氧基-,噻吩-2-基,噻吩-2-基硫代-,噻吩-3-基,噻吩-3-基硫代,4-氟苯硫基,丁基羰基苯基甲氧基,丁基羰基苯基甲基,丁基羰基甲基,1-(哌啶-1-基)羰基)甲基,1-(哌啶-1-基)羰基)甲氧基,1-(哌啶-2-基)羰基)甲氧基,1-(哌啶-3-基)羰基)甲氧基,1-(4-(嘧啶-2-基)哌嗪-1-基)羰基)甲氧基,1-(4-(嘧啶-2-基)哌嗪-1-基)羰基)甲基,1-(4-(嘧啶-2-基)哌嗪-1-基)羰基,1-4-(嘧啶-2-基)哌嗪-1-基,1-(4-(吡啶-2-基)哌嗪-1-基)羰基),1-(4-(吡啶-2-基)哌嗪-1-基)羰基甲基,(1-(4-(吡啶-2-基)哌嗪-1-基)羰基)-甲氧基),1-(4-(吡啶-2-基)哌嗪-1-基,1H-吲哚-1-基,吗啉代-,吗啉基,吗啉代羰基,吗啉基羰基,苯基脲基,苯基氨基甲酰基,乙酰氨基,3-(苯硫基)-1H-吲哚-1-基,3-(2-氰基乙硫基)-1H-吲哚-1-基,苄氨基,5-甲氧基-3-(苯硫基)-1H-吲哚-1-基,5-甲氧基-3-(2-氰基乙硫基)-1H-吲哚-1-基)),5-氯-1H-吲哚-1-基,5-氯-3-(2-氰基乙硫基)-1H-吲哚-1-基)),二苄氨基,苄氨基,5-氯-3-(苯硫基)-1H-吲哚-1-基)),4-(1H-四唑-5-基)苯氧基,4-(1H-四唑-5-基)苯基,4-(1H-四唑-5-基)苯硫基,2-氰基苯氧基,3-氰基苯氧基,4-氰基苯氧基,2-氰基苯硫基,3-氰基苯硫基,4-氰基苯硫基,2-氯苯氧基,3-氯苯氧基,4-氯苯氧基,2-氟苯氧基,3-氟苯氧基,4-氟苯氧基,2-氰基苄氧基,3-氰基苄氧基,4-氰基苄氧基,2-氯苄氧基,3-氯苄氧基,4-氯苄氧基,2-氟苄氧基,3-氟苄氧基和4-氟苄氧基。
在一个典型的实施方案中,所述的化合物具有式(If)-(Ik)的式,其中R1a为选自H,负电荷和盐抗衡离子中的成员且剩余两个R基团各自(If中的R9a和R10a,Ig中的R9a和R11a,Ih中的R9a和R12a,Ii中的R10a和R11a,Ij中的R10a和R12a,Ik中的R11a和R12a)为独立地选自如下的成员:氟,氯,溴,硝基,氰基,氨基,甲基,羟基甲基,三氟甲基,甲氧基,三氟甲氧基,乙基,二乙氨基甲酰基,吡啶-2-基,吡啶-3-基,吡啶-4-基,嘧啶基,哌嗪并,哌嗪基,哌嗪基羰基,哌嗪基羰基,羧基,1-四唑基,1-乙氧羰基甲氧基,羧基甲氧基,苯硫基,3-(丁基羰基)苯基甲氧基,1H-四唑-5-基,1-乙氧羰基甲氧基-,1-乙氧羰基甲基-,1-乙氧羰基-,羧基甲氧基-,噻吩-2-基,噻吩-2-基硫代-,噻吩-3-基,噻吩-3-基硫代,4-氟苯硫基,丁基羰基苯基甲氧基,丁基羰基苯基甲基,丁基羰基甲基,1-(哌啶-1-基)羰基)甲基,1-(哌啶-1-基)羰基)甲氧基,1-(哌啶-2-基)羰基)甲氧基,1-(哌啶-3-基)羰基)甲氧基,1-(4-(嘧啶-2-基)哌嗪-1-基)羰基)甲氧基,1-(4-(嘧啶-2-基)哌嗪-1-基)羰基)甲基,1-(4-(嘧啶-2-基)哌嗪-1-基)羰基,1-4-(嘧啶-2-基)哌嗪-1-基,1-(4-(吡啶-2-基)哌嗪-1-基)羰基),1-(4-(吡啶-2-基)哌嗪-1-基)羰基甲基,(1-(4-(吡啶-2-基)哌嗪-1-基)羰基)-甲氧基),1-(4-(吡啶-2-基)哌嗪-1-基,1H-吲哚-1-基,吗啉代-,吗啉基,吗啉代羰基,吗啉基羰基,苯基脲基,苯基氨基甲酰基,乙酰氨基,3-(苯硫基)-1H-吲哚-1-基,3-(2-氰基乙硫基)-1H-吲哚-1-基,苄氨基,5-甲氧基-3-(苯硫基)-1H-吲哚-1-基,5-甲氧基-3-(2-氰基乙硫基)-1H-吲哚-1-基)),5-氯-1H-吲哚-1-基,5-氯-3-(2-氰基乙硫基)-1H-吲哚-1-基)),二苄氨基,苄氨基,5-氯-3-(苯硫基)-1H-吲哚-1-基)),4-(1H-四唑-5-基)苯氧基,4-(1H-四唑-5-基)苯基,4-(1H-四唑-5-基)苯硫基,2-氰基苯氧基,3-氰基苯氧基,4-氰基苯氧基,2-氰基苯硫基,3-氰基苯硫基,4-氰基苯硫基,2-氯苯氧基,3-氯苯氧基,4-氯苯氧基,2-氟苯氧基,3-氟苯氧基,4-氟苯氧基,2-氰基苄氧基,3-氰基苄氧基,4-氰基苄氧基,2-氯苄氧基,3-氯苄氧基,4-氯苄氧基,2-氟苄氧基,3-氟苄氧基和4-氟苄氧基。
在一个典型的实施方案中,所述的化合物具有式(Il)-(Io)的式,其中R1a为选自H,负电荷和盐抗衡离子中的成员且剩余的三个R基团各自((Il)中的R9a,R10a,R11a,(Im)中的R9a,R10a,R12a,(In)中的R9a,R11a,R12a,(Io)中的R10a,R11a,R12a)为独立地选自如下的成员:氟,氯,溴,硝基,氰基,氨基,甲基,羟甲基,三氟甲基,甲氧基,三氟甲氧基,乙基,二乙氨基甲酰基,吡啶-2-基,吡啶-3-基,吡啶-4-基,嘧啶基,哌嗪并,哌嗪基,哌嗪基羰基,哌嗪基羰基,羧基,1-四唑基,1-乙氧羰基甲氧基,羧基甲氧基,苯硫基,3-(丁基羰基)苯基甲氧基,1H-四唑-5-基,1-乙氧羰基甲氧基-,1-乙氧羰基甲基-,1-乙氧羰基-,羧基甲氧基-,噻吩-2-基,噻吩-2-基硫代-,噻吩-3-基,噻吩-3-基硫代,4-氟苯硫基,丁基羰基苯基甲氧基,丁基羰基苯基甲基,丁基羰基甲基,1-(哌啶-1-基)羰基)甲基,1-(哌啶-1-基)羰基)甲氧基,1-(哌啶-2-基)羰基)甲氧基,1-(哌啶-3-基)羰基)甲氧基,1-(4-(嘧啶-2-基)哌嗪-1-基)羰基)甲氧基,1-(4-(嘧啶-2-基)哌嗪-1-基)羰基)甲基,1-(4-(嘧啶-2-基)哌嗪-1-基)羰基,1-4-(嘧啶-2-基)哌嗪-1-基,1-(4-(吡啶-2-基)哌嗪-1-基)羰基),1-(4-(吡啶-2-基)哌嗪-1-基)羰基甲基,(1-(4-(吡啶-2-基)哌嗪-1-基)羰基)-甲氧基),1-(4-(吡啶-2-基)哌嗪-1-基,1H-吲哚-1-基,吗啉代-,吗啉基,吗啉代羰基,吗啉基羰基,苯基脲基,苯基氨基甲酰基,乙酰氨基,3-(苯硫基)-1H-吲哚-1-基,3-(2-氰基乙硫基)-1H-吲哚-1-基,苄氨基,5-甲氧基-3-(苯硫基)-1H-吲哚-1-基,5-甲氧基-3-(2-氰基乙硫基)-1H-吲哚-1-基)),5-氯-1H-吲哚-1-基,5-氯-3-(2-氰基乙硫基)-1H-吲哚-1-基)),二苄氨基,苄氨基,5-氯-3-(苯硫基)-1H-吲哚-1-基)),4-(1H-四唑-5-基)苯氧基,4-(1H-四唑-5-基)苯基,4-(1H-四唑-5-基)苯硫基,2-氰基苯氧基,3-氰基苯氧基,4-氰基苯氧基,2-氰基苯硫基,3-氰基苯硫基,4-氰基苯硫基,2-氯苯氧基,3-氯苯氧基,4-氯苯氧基,2-氟苯氧基,3-氟苯氧基,4-氟苯氧基,2-氰基苄氧基,3-氰基苄氧基,4-氰基苄氧基,2-氯苄氧基,3-氯苄氧基,4-氯苄氧基,2-氟苄氧基,3-氟苄氧基和4-氟苄氧基。
在一个典型的实施方案中,本发明化合物具有为选自如下成员的结构:
其中q为0-1的数值。Rg为卤素。Ra,Rb,Rc,Rd和Re为独立地选自H,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。在一个典型的实施方案中,条件是所述的化合物不为选自和中的成员。
在一个典型的实施方案中,所述的化合物具有为选自如下成员的结构:
在一个典型的实施方案中,Ra,Rd和Re各自为独立地选自如下的成员:
在一个典型的实施方案中,Rb和Rc为独立地选自H,甲基, 和中的成员。
在另一个典型的实施方案中,Rb为H和Rc为选自H,甲基, 和中的成员。在另一个典型的实施方案中,Rb和Rc与连接它们的氮原子一起任选地连接成选自如下基团中的成员
在一个典型的实施方案中,Ra为选自 中的成员。
在一个典型的实施方案中,Rd为选自 中的成员。
在一个典型的实施方案中,Re为选自如下基团中的成员
在一个典型的实施方案中,所述的化合物为选自如下化合物中的成员:
在一个典型的实施方案中,所述的化合物具有图2中所述的结构。在一个典型的实施方案中,所述的化合物具有图3中所述的结构。
在一个典型的实施方案中,所述的化合物具有选自式I(b),I(c),I(d)和I(e)中的成员的结构,其中所述的剩余的R基团(I(b)的R9a,I(c)的R10a,I(d)的R11a和I(e)的R12a)为羧基甲氧基。
在一个典型的实施方案中,所述的化合物具有为选自式(If)-(Ik)中的成员的结构,其中式(If)的R9a或R10a,式(Ig)的R9a或R11a,式(Ih)的R9a或R12a,式(Ii)的R10a或R11a,式(Ij)的R10a或R12a,式(Ik)的R11a或R12a为卤素且配对的另一个取代基(不包括:如果R9a为式(If)中的F,那么R10a选自如下所列的取代基)为选自NH2,N(CH3)H和N(CH3)2中的成员。
在另一个典型的实施方案中,所述的化合物具有为选自如下的成员的结构:
其中R*和R**为选自如下的成员:H,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基。在一个典型的实施方案中,所述的化合物为选自如下中的成员:
其中R1a为选自负电荷,H和盐抗衡离子中的成员。
在另一个典型的实施方案中,所述的化合物具有为选自如下的成员的结构:
(Iak),
其中q为1且Rg为选自氟,氯和溴中的成员。
在另一个典型的实施方案中,式(I)-(Io)中的上述化合物和实施方案可以与水形成水合物,与醇形成溶剂合物(例如甲醇,乙醇,丙醇);与氨基化合物形成加合物(例如氨,甲胺,乙胺);与酸形成加合物(例如甲酸,乙酸);与乙醇胺,喹啉,氨基酸等形成复合物。
在另一个典型的实施方案中,所述的化合物具有式(Ip)的结构:
其中Rx2为选自取代或未取代的C1-C5烷基和取代或未取代的C1-C5杂烷基;Ry2和Rz2为独立地选自中的成员H,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。
在另一个典型的实施方案中,所述的化合物具有式(Iq)的结构:
其中B为硼。Rx2为选自取代或未取代的C1-C5烷基和取代或未取代的C1-C5杂烷基中的成员。Ry2和Wz2为独立地选自H,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。在另一个典型的实施方案中,选自R3a,R4a,R5a,R6a,R7a,R8a,R9a,R10a,R11a和R12a中的至少一个成员为选自硝基,氰基和卤素中的成员。
在另一个典型的实施方案中,所述的化合物具有为选自下式中的成员的结构:
在另一个典型的实施方案中,所述的化合物具有式(Ib)-(Ie)的式,其中至少一个选自R3a,R4a,R5a,R6a,R7a,R8a,R9a,R10a,R11a和R12a中的成员为选自硝基,氰基,氟,氯,溴和氰基苯氧基中的成员。在另一个典型的实施方案中,所述的化合物为选自如下中的成员:
在另一个典型的实施方案中,所述的化合物为选自 中的成员。
在另一个典型的实施方案中,本发明提供了本发明化合物的聚-或多-价种类。在一个典型的实施方案中,本发明提供了本文所述的化合物的二聚体。在一个典型的实施方案中,本发明提供了本文所述的化合物的二聚体。在一个典型的实施方案中,本发明提供了为选自C1-C100中的成员的化合物的二聚体。在一个典型的实施方案中,所述的二聚体为选自如下的成员:
和
在一个典型的实施方案中,本发明提供了本文所述的化合物的酸酐。在一个典型的实施方案中,本发明提供了本文所述的化合物的酸酐。在一个典型的实施方案中,本发明提供了为选自C1-C100中的成员的化合物的酸酐。在一个典型的实施方案中,所述的酸酐为选自如下的成员:
和
在一个典型的实施方案中,在一个典型的实施方案中,本发明提供了本文所述的化合物的三聚体。在一个典型的实施方案中,本发明提供了本文所述的化合物的三聚体。在一个典型的实施方案中,本发明提供了为选自C1-C100中的成员的化合物的三聚体。在一个典型的实施方案中,所述的三聚体为选自如下的成员:
在另一个典型的实施方案中,所述的化合物具有为选自如下的成员的结构:
在另一个典型的实施方案中,所述的化合物为
在另一个典型的实施方案中,所述的化合物为选自如下的成员:
在另一个典型的实施方案中,所述的化合物为选自如下的成员:
在另一个典型的实施方案中,R1a为H。在另一个典型的实施方案中,R10a和R11a为H。在另一个典型的实施方案中,选自R10a和R11a的一个成员为H且选自R10a和R11a的另一个成员为选自卤素,甲基,氰基,甲氧基,羟甲基和对-氰基苯氧基中的成员。在另一个典型的实施方案中,R10a和R11a为独立地选自氟,氯,甲基,氰基,甲氧基,羟甲基和对-氰基苯基中的成员。
用于本发明方法的额外化合物披露在2005年2月16日提交的美国临时专利申请US60/654,060(Attorney Docket No.064507-5014PR);2006年2月16日提交的美国临时专利申请US11/357,687(Attorney Docket No.064507-5014US);2006年8月16日提交的美国专利申请US11/505,591(Attorney Docket No.064507-5014US01)中,为所有目的而将这些文献完整地引入本文作为参考。在这些专利申请中还描述了生产本发明化合物的方法。
IIIa.物质组合物
本发明还提供了新颖的物质组合物。在一个典型的实施方案中,该物质组合物如本文所述的。在另一个典型的实施方案中,该物质组合物具有式II的结构:
其中B为硼。R20,R21和R22为独立地选自负电荷,盐抗衡离子,H,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。A为选自CR9a和N中的成员。D为选自CR10a和N中的成员。E为选自CR11a和N中的成员。G为选自CR12a和N中的成员。R9a,R10a,R11a和R12a为独立地选自H,OR*,NR*R**,SR*,-S(O)R*,-S(O)2R*,-S(O)2NR*R**,-C(O)R*,-C(O)OR*,-C(O)NR*R**,硝基,卤素,氰基,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。R*和R**各自为独立地选自H,硝基,卤素,氰基,取代或未取代的烷基,取代或未取代的杂烷基,取代或未取代的环烷基,取代或未取代的杂环烷基,取代或未取代的芳基和取代或未取代的杂芳基中的成员。氮(A+D+E+G)之和为选自0-3的整数。R9a和R10a与连接它们的原子一起任选地连接成4-7元环。R10a和R11a与连接它们的原子一起任选地连接成4-7元环。R11a和R12a与连接它们的原子一起任选地连接成4-7元环。
在另一个典型的实施方案中,所述的化合物具有式(IIa)的结构:
在另一个典型的实施方案中,所述的化合物具有下式的结构:
其中R10z为选自取代或未取代的氰基苯氧基和取代或未取代的氰基苯硫基中的成员且R22为选自H,取代或未取代的甲基,取代或未取代的乙基和取代或未取代的丙基中的成员。在一个典型的实施方案中,R10z为选自对-氰基苯氧基和对氰基苯硫基中的成员。在一个典型的实施方案中,R20和R21为独立地选自负电荷,盐抗衡离子和H中的成员。
在另一个典型的实施方案中,所述的化合物具有为选自如下的成员的结构:
其中R22为选自H,取代或未取代的甲基,取代或未取代的乙基和取代或未取代的丙基中的成员。在一个典型的实施方案中,R20和R21为独立地选自负电荷,盐抗衡离子和H中的成员。
在另一个典型的实施方案中,所述的化合物具有为选自如下的成员的结构:
在一个典型的实施方案中,R22为H。在一个典型的实施方案中,R22为取代或未取代的甲基。在一个典型的实施方案中,R22为甲基。在一个典型的实施方案中,R20和R21为独立地选自中负电荷,盐抗衡离子和H的成员。
在另一个典型的实施方案中,所述的化合物具有为选自如下的成员的结构:
在一个典型的实施方案中,R22为H。在一个典型的实施方案中,R22为取代或未取代的甲基。在一个典型的实施方案中,R22为甲基。
在另一个典型的实施方案中,所述的化合物为选自如下的成员:
可以通过与用于合成本文所述的氧杂硼杂环戊二烯类(oxaboroles)(2)类似的途径合成本文所述的化合物。然而,在没有被(1)上存在的保护邻-羟甲基存在下碱化苯基硼酸和苯基溴前体的合成。因此,在许多情况中,可以合成类似范围的邻位-,间位-和对位-取代的硼酸(4)。
PG=保护基
在实施例部分中提供了这些硼酸的生产实施例。另外,可以通过使用苯氧基衍生物方案并且用其噻吩(thienolic)类似物取代酚类反应剂合成苯硫基衍生物。例如,可以使用本文所述的4-(4-氰基苯氧基)苯基硼酸的方案并且用4-溴噻吩取代4-溴苯酚合成4-(4-氰基苯硫基)苯基硼酸。
在另一个典型的实施方案中,本文所述的物质组合物可以用于本文所述的本发明方法。在另一个典型的实施方案中,本发明提供了治疗或预防人或动物与炎症相关的疾病的方法,该方法包括对所述的人或动物给予治疗有效量的在本文IIIa部分所述的化合物。在另一个典型的实施方案中,所述的化合物具有式II或式IIa的结构。在另一个典型的实施方案中,所述的化合物具有为选自如下成员的结构:
和
在另一个典型的实施方案中,该方法进一步包括给予作为药物制剂的一部分的所述的化合物,所述的制剂进一步包含药学上可接受的赋形剂。在另一个典型的实施方案中,IIIa部分中所述的化合物的用量足以通过抑制促炎细胞因子表达或通过刺激抗炎细胞因子表达治疗炎症相关疾病,但该用量低于足以基本上抑制细胞周期蛋白依赖性激酶的用量。在另一个典型的实施方案中,所述的疾病为选自关节炎,风湿性关节炎,炎症性肠病,银屑病,多发性硬化,神经变性病症,充血性心力衰竭,中风,主动脉瓣狭窄,肾衰竭,狼疮,胰腺炎,过敏症,纤维化,贫血,动脉粥样硬化,代谢病,骨病,心血管病,化疗/放疗相关并发症,I型糖尿病,II型糖尿病,肝病,胃肠道病症,眼科疾病,过敏性结膜炎,糖尿病性视网膜病,肖格伦(Sjogren)综合征,葡萄膜炎(uvetitis),肺病,肾脏疾病,皮炎,HIV-相关恶病质,脑型疟疾,强直性脊柱炎,麻风病,贫血和纤维肌痛中的成员。在另一个典型的实施方案中,所述的疾病为光化性角化病。另一个典型的实施方案中,所述的疾病为特应性皮炎。在另一个典型的实施方案中,所述的化合物具有为选自如下成员的结构:
和
在另一个典型的实施方案中,所述的神经变性病症为选自阿尔茨海默病和帕金森病中的成员,所述的炎性肠病为选自克罗恩病或溃疡性结肠炎中的成员;所述的胃肠并发症为腹泻;所述的肝病为选自自身免疫性肝炎,丙型肝炎,原发性胆汁性肝硬变,原发性硬化性胆管炎和暴发性肝衰竭中的成员;所述的胃肠病症为选自乳糜泻和非特异性结肠炎中的成员;所述的肺病为选自过敏性鼻炎,哮喘,慢性阻塞性肺疾病,慢性肉芽肿性炎症,囊性纤维化和结节病中的成员;所述的心血管疾病为选自动脉硬化性心脏病,充血性心力衰竭和再狭窄中的成员;且所述的肾脏疾病为选自肾小球肾炎和脉管炎中的成员。在另一个典型的实施方案中,给予所述的化合物,其浓度足以抑制为选自IL-1α,β,IL-2,IL-3,IL-6,IL-7,IL-9,IL-12,IL-17,IL-18,IL-23,TNF-α,LT,LIF,制癌蛋白和IFNc1α,β,γ中的成员的细胞因子。在另一个典型的实施方案中,给药所述的化合物,其浓度足以刺激为选自IL-4,IL-10,IL-11,W-13和TGF-β中的成员的细胞因子表达。在另一个典型的实施方案中,本发明提供了治疗与细胞因子表达水平相关的炎症相关疾病的方法,该方法包括对有这类治疗需要的人或动物给予IIIa部分中所述的化合物。在一个典型的实施方案中,所述的化合物的用量足以通过抑制促炎细胞因子表达或通过刺激抗炎细胞因子表达治疗炎症相关疾病,但该用量低于足以基本上抑制细胞周期蛋白依赖性激酶的用量。在一个典型的实施方案中,所述的动物为人。在另一个典型的实施方案中,所述的化合物具有选自如下成员的结构:
和
在另一个典型的实施方案中,本发明提供了抑制能够产生炎性细胞因子蛋白的细胞产生所述的炎性细胞因子蛋白的方法,该方法包括:将所述的细胞与治疗有效量的部分IIIa中的化合物合并,其中所述的细胞产生所述的炎性细胞因子得到抑制。在另一个典型的实施方案中,所述的治疗有效量足以抑制约50%-约99%的所述的炎性细胞因子蛋白产生。在另一个典型的实施方案中,本发明提供了抑制人或动物炎症反应的方法,该方法包括:将所述的细胞与治疗有效量的部分IIIa中的化合物合并,其中所述的炎症反应得到抑制。在另一个典型的实施方案中,所述的化合物具有为选自如下成员的结构:
和
IV.本发明化合物的治疗适应征
应理解本发明的方法包括,但不限于使用本发明化合物治疗炎症相关疾病。
本发明在另一个方面中提供了预防或治疗细胞因子介导的疾病的方法,该方法包括对有这类治疗需要的受试者给予治疗有效量的本发明化合物。在一个典型的实施方案中,所述的化合物为选自C1-C100中的成员。在一个典型的实施方案中,所述的化合物为5-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(benzoxaborole)。这类细胞因子-阶段的疾病包括牙周炎,干眼病,风湿性关节炎,骨关节炎,克罗恩病,溃疡性结肠炎,牛皮癣性关节炎,创伤性关节炎,风疹性关节炎,炎性肠病,多发性硬化,银屑病,移植物抗宿主病,系统性红斑狼疮,中毒性休克,肠易激综合征,肌肉变性,同种异体移植物排斥,胰腺炎,胰岛炎(insulinitis),肾小球肾炎,糖尿病性肾病,肾纤维化,慢性肾脏功能衰竭,痛风,麻风病,急性滑膜炎,赖特综合征,痛风性关节炎,贝切特病,脊柱炎,子宫内膜异位症,非关节炎症疾病,诸如椎间盘综合征疾患,滑囊炎,肌腱炎,腱鞘炎或纤维肌痛综合征;和急性或慢性痛,包括,但不限于神经性疼痛,神经病,多发性神经病,糖尿病相关多发性神经病,创伤,偏头痛,紧张性和丛集性头痛,霍顿病,静脉曲张性溃疡,神经痛,肌骨骼疼痛,骨-创伤性疼痛,骨折,痛性营养障碍,脊柱关节炎,纤维肌痛,幻肢痛,背痛,脊椎痛,术后痛,脱垂性椎间盘-诱导的坐骨神经痛,癌症-相关疼痛,血管痛,内脏痛,分娩或HIV-相关疼痛。其他细胞因子介导的疾病为过敏症,代谢病,化疗/放疗相关并发症;I型糖尿病;II型糖尿病;肝病;胃肠道病症;眼科疾病;过敏性结膜炎;糖尿病性视网膜病;肖格伦综合征;葡萄膜炎;肺病,肾脏疾病;皮炎;HIV-相关恶病质;脑型疟疾;强直性脊柱炎;麻风病;贫血;纤维肌痛,肾衰竭,中风,慢性心脏衰弱,内毒素血症,再灌注损伤,缺血性再灌注,心肌缺血,再狭窄,血栓形成,血管发生,冠心病,冠状动脉疾病,急性冠脉综合征,高安动脉炎,心力衰竭,诸如心脏衰弱,主动脉瓣狭窄,心肌病,心肌炎,脉管炎,血管再狭窄,心瓣膜病或冠状动脉旁路;高胆甾醇血症,与血液凝固或纤维蛋白溶解相关的疾病或疾患,诸如,例如,急性静脉血栓形成,肺栓塞,妊娠过程中的血栓形成,出血性皮肤坏死,急性或慢性弥散性血管内凝血(DIC),因手术导致的血块形成,长期卧床休息或长期固定,静脉血栓形成,暴发性脑膜炎球菌血症,急性血栓性中风,急性冠脉闭塞,急性外周动脉闭塞,块状肺栓塞,腋静脉血栓形成,块状髂股静脉血栓形成,闭塞动脉或静脉套管,心肌病,肝静脉闭塞疾病,低血压,心输出量减少,血管抵抗力减少,肺动脉高压,肺血管顺度下降,白细胞减少或血小板减少;或动脉粥样硬化。其他疾病为过敏性结膜炎,葡萄膜炎,青光眼,视神经炎,视网膜缺血,糖尿病性视网膜病,激光诱导的视力损害或手术或创伤-诱导的增生性玻璃体视网膜病变。细胞因子介导的疾病进一步包括过敏性鼻炎,哮喘,成人呼吸窘迫综合征,慢性肺炎,慢性阻塞性肺疾病,肺气肿,支气管炎,粘液分泌过多,硅肺病,SARS感染和呼吸道炎症。还包括银屑病,湿疹,特应性皮炎,接触性皮炎或痤疮。其他细胞因子介导的疾病为格-巴综合征,帕金森病,阿尔茨海默病,肌萎性缩侧索硬化,多发性硬化和其他脱髓鞘疾病,病毒和细菌性脑膜炎,CNS创伤,脊髓损伤,癫痫,惊厥,橄榄体脑桥小脑萎缩,艾滋病痴呆综合征,MERRF和MELAS综合征,莱贝尔病,韦尼克脑病,雷特综合征,高半胱氨酸尿,高脯氨酸血症,高同种半胱氨酸血症,非酮性高甘氨酸血症,羟基丁酸氨基酸尿症,亚硫酸盐氧化酶缺乏,合并的系统性疾病,铅脑病,图雷特综合征,肝性脑病,药物成瘾,药物耐受,药物依赖,抑郁症,焦虑和神经分裂症,动脉瘤或癫痫症。在本发明的另一个方面中,细胞因子介导的疾病包括骨质吸收病,骨硬化症,骨质疏松症或骨关节炎。还包括糖尿病,全身性恶病质,感染或恶性肿瘤继发性恶病质,获得性免疫缺陷综合征(AIDS)继发性恶病质,肥胖,厌食症或贪食症。另外,细胞因子介导的疾病可以为脓毒病,HIV,HCV,疟疾,感染性关节炎,利什曼病,莱姆病,癌症,包括,但不限于乳腺癌,结肠癌,肺癌,前列腺癌,多发性骨髓瘤,急性髓性白血病,脊髓发育不良综合征,非何杰金淋巴瘤或滤泡淋巴瘤,卡斯尔曼病或抗药性。
本发明在另一个方面中提供了治疗嗜中性粒细胞-介导的疾病的方法,该方法包括对有这类治疗需要的受试者给予治疗有效量的本发明化合物,其中嗜中性粒细胞-介导的疾病为支气管哮喘,鼻炎,流感,中风,心肌梗死,热损伤,成人呼吸窘迫综合征(ARDS),创伤继发性多器官损伤,急性肾小球肾炎,具有急性炎性成分的皮肤病,急性化脓性脑膜炎,血液透析,白细胞单采术,粒细胞输注相关综合征或坏死性小肠结肠炎。
优选神经变性疾病选自:阿尔茨海默病和帕金森病;炎性肠病选自:克罗恩病或溃疡性结肠炎;胃肠并发症为腹泻;肝病选自:自身免疫性肝炎,丙型肝炎,原发性胆汁性肝硬变,原发性硬化性胆管炎和暴发性肝衰竭中的成员;胃肠病症选自乳糜泻和非特异性结肠炎;骨病为骨质疏松症;肺病选自过敏性鼻炎,哮喘,慢性阻塞性肺疾病,慢性肉芽肿性炎症,囊性纤维化和结节病;心血管疾病选自动脉硬化性心脏病,充血性心力衰竭和再狭窄;且肾脏疾病选自肾小球肾炎和脉管炎。
在一个优选的实施方案中,所述的疾病为炎性肠病(IBD),特别是包括克罗恩病和溃疡性结肠炎。在另一个优选的实施方案中,所治疗的疾病为关节炎,风湿性关节炎,银屑病,阿尔茨海默病或帕金森病。在另一个优选的实施方案中,所述的疾病为放疗后相关疾病或动脉粥样硬化。在另一个优选的实施方案中,所述的疾病为特应性皮炎。在另一个优选的实施方案中,所述的疾病为光化性角化病。
优选所述的化合物的用量可抑制促炎细胞因子表达和/或刺激抗炎细胞因子表达。在一个典型的实施方案中,所述的化合物为选自C1-C100中的成员。在一个典型的实施方案中,所述的化合物为5-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯。在一个实施方案中,所述的化合物的优选用量可抑制至少30-100%的促炎细胞因子中的一种或多种的表达,所述的促炎细胞因子选自:IL-1α,β,IL-2,IL-3,IL-6,IL-7,IL-9,IL-12,IL-17,IL-18,IL-23,TNF-α,LT,LIF,制癌蛋白和IFNc1α,β,γ。在一个典型的实施方案中,所述的化合物的用量可抑制至少40-100%促炎细胞因子中的一种或多种的表达。在一个典型的实施方案中,所述的化合物用量可抑制至少50-100%的促炎细胞因子中的一种或多种的表达。在一个典型的实施方案中,所述的化合物的用量可抑制至少60-100%。在一个典型的实施方案中,所述的化合物用量可抑制至少70-100%。在一个典型的实施方案中,所述的化合物的用量可抑制至少30-70%促炎细胞因子中的一种或多种的表达。在一个典型的实施方案中,所述的化合物的用量可抑制至少40-90%的促炎细胞因子中的一种或多种的表达。在一个典型的实施方案中,所述的化合物的用量可抑制至少45-80%的促炎细胞因子中的一种或多种的表达。在一个典型的实施方案中,所述的化合物的用量可抑制至少55-75%的促炎细胞因子中的一种或多种的表达。在一个典型的实施方案中,所述的化合物的用量可抑制至少75-98%的促炎细胞因子中的一种或多种的表达。在一个典型的实施方案中,所述的化合物的用量可抑制约50%-约99%的促炎细胞因子中的一种或多种的表达。在另一个实施方案中,所述的化合物的优选用量可刺激抗炎细胞因子表达。在该实施方案中,所述的化合物的优选用量可增加选自细胞因子IL-4,IL-10,IL-11,W-13或TGF-β的抗炎细胞因子至少25%,更优选至少50%且最优选至少75%。
本发明提供了使用一类含硼的小分子治疗人或动物各种炎症-相关疾病的方法。在一个典型的实施方案中,所述的小分子为本文所述的化合物。在一个典型的实施方案中,所述的化合物为选自C1-C100中的成员。在一个典型的实施方案中,所述的化合物为5-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯。这些炎症-相关疾病包括,但不限于炎性肠病(IBD),银屑病,风湿性关节炎(RA),多发性硬化(MS),神经变性病症,心血管疾病(CVD)和动脉粥样硬化和代谢病(代谢综合征和糖尿病)以及感染-相关炎症。
本发明还提供了治疗与细胞因子表达水平相关的炎症的方法,该方法包括对有这类治疗需要的人或动物给予本发明化合物。
本发明还提供了一种方法,其中所治疗的动物选自人,马,牛和猪中的成员。在一个典型的实施方案中,所述的动物为人。
在一个典型的实施方案中,本发明提供了抑制为选自IL-1β,IL-4,TNF-α和IFNγ中的成员的细胞因子的方法。在该方法中,使所述的细胞因子接触本发明化合物。在一个典型的实施方案中,所述的化合物为选自C1-C100中的成员。在一个典型的实施方案中,所述的化合物为5-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯。肿瘤坏死因子-α(TNF-α)和白细胞介素-1(IL-1)为介导与病原体和其他细胞应激相关的炎症反应的促炎细胞因子。认为诸如IL-1和TNF-α这类细胞因子的超表达基于许多炎性疾病的进展,包括风湿性关节炎(RA),克罗恩病,炎性肠病,多发性硬化,内毒素性休克,骨质疏松症,阿尔茨海默病,充血性心力衰竭和银屑病等(Dinarello,C.A.等,Rev.Infect.Diseases1984,6:51;Salituro等,Curr.Med.Chem.1999,6:807-823;Henry等,Drugs Fut.1999,24:1345-1354)。在这些情况中可接受的可能药物干预治疗手段在于减少促炎细胞因子,诸如TNF-α(也称作TNFa)和白细胞介素-1β(IL-1b)。
炎性肠病(IBD):IBD包括克罗恩病(CD)和溃疡性结肠炎(UC),它们是因免疫系统失调导致的两种重叠的胃肠道慢性炎症相关疾病(Rutgeerts,P.,Aliment PharmacolTher,17:185-192(2003))。具有IBD的患者具有缺陷性肠上皮屏障功能,这使得上皮细菌定居。作为结果,细菌产物和促炎细胞因子(TNF-α,IL-1和IL-6)导致持续性炎症刺激。细菌抗原被粘膜树突细胞和巨噬细胞导入免疫系统。在反应中,肠吞噬细胞(主要是单核细胞和中性白细胞)增殖并且增加促炎细胞因子表达和分泌。
银屑病:细胞因子为在皮肤炎症发生和维持中具有重要作用的胞间信使。已经报导了大量细胞因子在炎症皮肤病发病机制中起关键作用。IL-1,TNF-α和IFN-γ诱导ICAM-1和主要组织相容性复合物(MHC)II类表达(Dustin,M.L.,J Immunol,137:245-254,(1986);Strange,P.,J Invest Dermatol,102:150-154,(1994))。IL-1,TNF-α和粒细胞-巨噬细胞集落刺激因子能够诱导树突细胞活化,成熟和迁移,并且IL-1活化肥大细胞(50)。IL-6和TGF-α增强角化细胞增殖。IL-1,TNF-α,TGF-α和VEGF诱导血管发生和吸引炎性细胞(Grossman,R.M.,Proc Natl Acad Sci USA,86:6367-6371,(1989);Schreiber,A.B.,Science,232:1250-1253,(1986);Detmar,M.,J Exp Med,180:1141-1146,(1994))。在引起皮肤免疫应答中细胞因子的首要性使得它们成为新生物应答调节剂的高度有吸引力的靶标(Williams,J.D.,Clin Exp Dermatol,27:585-590,(2002))。
风湿性关节炎(RA):细胞因子网状结构在介导RA中的炎症和关节破坏中的作用在近年来得到广泛研究。除TNF-α外,IL-1在RA的发病机制和临床表现中起中枢作用(54)。IL-1促成炎症和关节腐蚀和抑制组织修复过程的能力在体外系统和动物模型中得到显著确立,并且通过阻断IL-1实现了RA患者中炎症症状的缓解(Bresnihan,B.,Arthritis Rheum,41:2196-2204,(1998))。IL-6为调节免疫应答,造血,急性期反应和炎症的多功能细胞因子。IL-6产生的失调涉及几种疾病,包括RA的病理学。通过使用RA等疾病的人源化抗-IL-6R抗体实施阻断IL-6信号的治疗手段(Ito,H.,Curr Drug Targets Inflamm Allergy,2:125-130,(2003);Ishihara,K Cytokine Growth Factor Rev,13:357-368,(2002))。IL-10为抗炎细胞因子。已经证实表达IL-10可预防关节炎或改善动物模型中的该病(57,58)。尽管显然诸如TNF-α,IL-1,IL-6和IL-10这类细胞因子具有独立的作用,但是在介导RA中的某些病理生理学过程中起一致性的作用。本发明中所述的能够调节这些不同细胞因子的类型分子的发现导致在治疗RA的过程中的显著治疗进展。
多发性硬化(MS):MS为自身免疫性炎性病症。尽管MS患者中身体攻击其自身髓磷脂的原因不清楚,但是失调的细胞因子显然涉及疾病过程。使用实验性自身免疫性脑炎(EAE),即基于自身免疫,组织病理学,遗传和临床相似性广泛用于研究MS的模型,EAE和MS的特征在于存在CNS中弥散性的血管周炎性套,即化学引诱物细胞因子(趋化因子)起重要作用的过程。存在CNS自身免疫性炎症过程中趋化因子(IL-8家族成员)表达受到某些炎性细胞因子,诸如TNF调节的证据(Glabinski,A.R.,Scand J Immunol,58:81-88,(2003))。其他促-/抗-炎细胞因子,诸如IL-1.β.,IL-6和IL-10的作用也在EAE动物模型(Diab,A.,JNeuropathol Exp Neurol,56:641-650,(1997);Samoilova,E.B.,J Immunol,161:6480-6486,(1998);Robertson,J.,J Cell Biol,155:217-226,(2001))以及人(de Jong,B.A.,JNeuroimmunol,126:172-179,(2002))中得到证实。IL-1β存在于MS损害中。IL-1受体拮抗剂(IL-1Ra)适度节制诱导实验性自身免疫性脑炎(EAE)。在具有高IL-1的个体中观察到MS风险增加(超过IL-1Ra产生比的3和超过IL-10产生比的高TNF(de Jong,B.A.,JNeuroimmunol,126:172-179,(2002))。
神经变性病症:阿尔茨海默病(AD)和帕金森病(PK)为2种最常见的与神经炎症相关的神经变性病症。神经炎症是几种神经变性病症种受到病理性侵害的组织的特征。这些改变特别在AD病例中受侵害的脑区域中观察到(McGeer,E.G.,Prog Neuropsycho-pharmacol Biol Psychiatry,27:741-749,(2003))。细胞因子的作用涉及AD发病机制,不过,细胞因子促成该发病机制的机理尚未得到完全理解。在AD中,小胶质,尤其是与淀粉样蛋白沉积物相关的那些具有与活化状态,包括与II类主要组织相容性抗原的抗体和炎性细胞因子IL-1β和TNF-α的免疫反应性一致的表型(Dickson,D.W.,Glia,7:75-83,(1993))。AD的主要神经病理学特征之一为主要由毒性淀粉样蛋白β-肽(Aβ)组成的衰老斑脑沉积,所述的毒性淀粉样蛋白β-肽(Aβ)由含前体蛋白的Aβ家族(AβPP)产生。已经证实细胞因子刺激AβPP转录的基因表达。对控制AD和PK中随年龄发作的基因座的遗传连锁的分析揭示出AD与谷胱甘肽S-转移酶,ω-1和2(GSTO1,GSTO2)基因显著相关。GSTO1的功能显示出与促炎细胞因子IL-1β的翻译后加工相关(Laliberte,R.E.,J Biol Chem,278:16567-16578,(2003))。
放疗后相关炎症:与放射损伤相关的直肠和乙状结肠炎性疾病为使用盆腔区域中的癌症的放疗最常见的并发症,包括宫颈癌,子宫癌,前列腺癌,膀胱癌和睾丸癌。放射性直肠乙状结肠炎为盆腔放射后结肠损害的最常见临床表现形式,发病率为5%-20%。患者一般表现出里急后重,出血,低容量腹泻和直肠痛的症状。罕见发生进入相邻器官的低度阻塞或瘘道。
放疗机制通过其对主动增殖细胞中的DNA损害进行。可以将局部放疗对肠/结肠的病理性损害分成急性和慢性期。最初的病理性改变包括粘膜固有层中的淋巴细胞缺失和对内膜上皮细胞和血管内皮细胞的微观损伤。这些改变表现为绒毛钝化和隐窝再生细胞减少,且随后是和具有血管通透性增加的显著粘膜下层水肿。
进行性动脉内膜炎表现为长期作用发生的主要机制,随后表现为进行性纤维化,从而导致粘膜萎缩,狭窄形成和血栓形成,导致继发性缺血性损害。在慢性期中的放射性结肠炎表现出极为显著的隐窝变形,毛细管扩张和粘膜固有层纤维化。有意义的是,这些病理性改变中的某些也存在于长期IBD中(Haboubi,N.Y.,J Clin Pathol,45:272,(1992)。
因此,细胞因子在各种炎症表现为明显的部分的胃肠道疾病中起关键作用。近期研究集中于细胞因子在慢性IBD中的关键作用(Brynskov,J.,Gut,33:55-58,(1992);Matsuura,T.,Gastroenterology,104:448-458,(1993);Beagley,K.W.,GastroenterolClin North Am,21:347-366,(1992);MacDermott,R.P.,Med Clin North Am,78:1207-1231,(1994);Isaacs,K.L.,Gastroenterology,103:1587-1595,(1992);Indaram,A.V.,World J Gastroenterol,6:49-52,(2000))。为了阐明细胞因子在放射性直肠炎中的作用,Indaram等(Indaram,A.V.,Am J Gastroenterol,95:1221-1225,(2000))检验了具有放射性直肠炎的患者中的结肠粘膜细胞因子水平并且将这些值与获自正常对照组和具有IBD的患者的那些值进行比较。他们发现IL-2,IL-6和IL-8的粘膜水平在放射性直肠炎组中的患病(5.62.+-.0.13,1.60.+-.0.31,21.45.+-.4.03pg/mg)和表现为正常的粘膜(3.83.+-.0.78,1.36.+-.0.34,13.45.+-.3.18pg/mg)明显高于正常对照组(1.74.+-.0.23,0.67.+-.0.05,4.99.+-.1.39pg/mg)并且具有统计学显著性(p<0.05)。
因此,这些发现证实具有放射性直肠炎和IBD的患者中细胞因子的活化类似。在放射性直肠炎患者中,证实粘膜中的IL-2,IL-6和IL-8水平明显高于正常对照组。比较而言,IBD(UC和CD)患者表现出明显高于正常对照组的细胞因子水平,包括IL-1,IL-2,IL-6和IL-8。
在这两种疾病中粘膜细胞因子表达中的相似性可能直接与疾病的强烈炎症性质相关。推断在这两种疾病中这种细胞因子活化的相似性可能转化成在慢性IBD和放射性直肠炎中观察到的类似病理性改变。这一推断得到了如下事实的支持:尽管相当不令人满意,但是放射性直肠炎的医疗控制包括使用各种氨基水杨酸衍生物和口服或局部给予的皮质类固醇治疗。这些治疗选择与IBD的控制相同。
其他细胞因子失调相关疾病:心血管疾病(CVD),动脉粥样硬化和代谢病(代谢综合征)也与不适当的促/抗炎细胞因子/表达相关(DeGraba,T.J.,Adv Neurol,92:29-42,(2003);von der Thusen,J.H.,Pharmacol Rev,55:133-166,(2003);Schmidt,M.I.,ClinChem Lab Med,41:1120-1130,(2003);Virdis,A.,Curr Opin Nephrol Hypertens,12:181-187,(2003);Ito,T.,Curr Drug Targets Inflamm Allergy,2:257-265,(2003))。
糖尿病:II型糖尿病中的基本缺陷在于胰岛素抵抗,通过这一机制胰岛素难以抑制从肝中的葡萄糖产生和促进外周组织的消耗,从而导致高血糖症。胰腺β细胞通过分泌更多的胰岛素来克服胰岛素抵抗的作用对过量血糖做出反应。当胰岛素抵抗发展并且P细胞不再能够满足增加量的胰岛素分泌要求时,血糖水平增加并且发生II型糖尿病。
许多因素可以促成II型糖尿病发作。由于80%具有II型糖尿病的患者为肥胖并且肥胖始终与胰岛素抵抗相关,所以肥胖与胰岛素抵抗关连的分子介体已经处于广泛研究中。已经将各种因素鉴定为肥胖和与肥胖相关的II型糖尿病中的胰岛素抵抗的原因,特别是那些由脂肪组织产生的那些,FFAs(游离脂肪酸),TNF-α,IL-6,瘦蛋白,脂连素和抵抗素。TNF-α的mRNA和蛋白质水平在肥胖动物(Hotamisligil,G.S.,Science,259:87-91,(1993))和人体受试者(Hotamisligil,G.S.,J Clin Invest,95:2409-2415,(1995))的脂肪组织中显著增加。脂肪组织中所有不同类型的细胞能够产生细胞因子。脂肪细胞表达TNF-α受体并且还为TNF-α的主要来源,认为它主要在脂肪组织中以自分泌/旁分泌方式起作用。
培养的细胞(Hotamisligil,G.S.,Proc Natl Acad Sci USA,91.4854-4858,(1994))或动物(Lang,C.H.,Endocrinology,130:43-52,(1992))长期接触TNF-α诱导胰岛素抵抗,而TNF-α的中和增加了胰岛素敏感性并且减轻了II型糖尿病动物模型中的高血糖症(Hotamisligil,G.S.,Diabetes,43:1271-1278,(1994))。通过基因敲除使TNF-α或TNF-α受体不存在显著改善了肥胖动物模型中的胰岛素敏感性(Uysal,K.T.,Nature,389:610-614,(1997))。
已经提出了在脂肪细胞和全身TNF-α诱导的胰岛素抵抗的机制(Ruan,H.,Cytokine Growth Factor Rev,14:447-455,(2003))。TNF-α通过抑制剂kB激酶-β(IKK-β)抑制胰岛素受体和胰岛素受体底物-1(IRS-1)磷酸化。TNF-α活化NF-kB是抑制脂肪细胞功能必不可少的大量脂肪细胞基因所必需的并且也足以抑制PPAR-γ-介导的基因转录。TNF-α还刺激脂解和其他脂肪组织中的细胞因子表达并且引起FFA释放。实际上,血浆FFVs水平在某些胰岛素抵抗动物模型中的明显高血糖症前就增加(Ruan,H.,Cytokine GrowthFactor Rev,14:447-455,(2003))。存在涉及全身胰岛素抵抗诱导和进行中过量血浆FFA的广泛证据。在肝细胞中,FFAs促成过量葡萄糖和VLDL产生。在肌细胞中,高水平的FFA损害了胰岛素信号传导并且促进了FFA氧化,从而导致明显的葡萄糖氧化(glucose ox)减少。
目前属于PPAR-γ激动剂的商购胰岛素致敏药物通过NF-kB途径抑制TNF-α-诱导的脂肪细胞基因表达概况(Ruan,H.,J Biol Chem,278:28181-28192,(2003)。当脂肪细胞-衍生的TNF-α作为自分泌或旁分泌因子起作用时,TNF-α的全身递送无法有效阻断脂肪组织中局部表达的TNF-α的生物活性(Ofei,F.,Diabetes,45:881-885,(1996))。代表一类通过简单扩散发布的新的小分子TNF-α抑制剂的NATURA由此可以为阻断局部表达的TNF-α的功能和能够用于治疗2型糖尿病的有效活性剂。
I型糖尿病为自身免疫疾病,其特征在于胰岛中的单核细胞浸润和产生胰岛素的β细胞选择性破坏。尽管CD8+T细胞可以为重要的引发剂,但是CD4+T细胞(Suri,A.,ImmunolRev,169:55-65,(1999))和巨噬细胞(Jun,H.S.,Diabetes,48:34-42,(1999);Yoon,J.W.,Autoimmunity,27:109-122,(1998))为导致β细胞死亡的免疫过程的主要细胞效应物。活化的巨噬细胞直接分泌IL-1β,IL-6,IL-12,TNF-α,间接引起INF-γ从活化的T细胞中产生。细胞因子,如TNF-α,INF-γ,IL-β,IL-6和IL-10涉及1型糖尿病发病机制通过细胞因子表达和I型糖尿病发展研究,细胞因子增加研究和细胞因子缺乏研究的相关性研究得以充分阐明(Rabinovitch,A.,Rev Endocr Metab Disord,4:291-299,(2003))。除细胞因子中和抗体和可溶性细胞因子受体外,抗炎化合物还表现出延缓或防止动物模型中的1型糖尿病发作的作。
概括地说,细胞因子失调涉及各种疾病,包括炎症相关疾病和那些通常并不视为与炎症相关的疾病。能够调节促炎和抗炎细胞因子的分子应对所有与这些炎性成分失调相关类型的疾病提供具有最低副作用的治疗有益性。
V.药物制剂
本发明的药物制剂可以采用适合于选择的给药途径的各种形式。本领域技术人员认识到了可以用于制备掺入本文所述的化合物的无毒性药物制剂的各种合成方法。本领域技术人员会认识到可以引诱制备本发明化合物溶剂合物的各种无毒性药学上可接受的溶剂,诸如水,乙醇,丙二醇,矿物油,植物油和二甲亚砜(DMSO)。
本发明的组合物可以通过口服,局部,非肠道,通过吸入或喷雾剂或通过直肠以单位剂型给药,所述的单位剂型包含常规的无毒性药学上可接受的载体,佐剂和媒介物。进一步理解最佳给药方法可以为方法的组合。特别优选以丸剂,胶囊,酏剂,糖浆剂,锭剂,药片等的形式进行口服给药。本文所用的术语非肠道包括皮下注射,真皮内,血管内(例如静脉内),肌内,脊柱,鞘内注射等或输注技术。
包含本发明化合物的药物制剂优选为适合于口服应用的形式,例如为片剂,药片,锭剂,水或油混悬液,可分散粉末或颗粒,硬或软胶囊或糖浆剂或酏剂。
可以按照本领域公知制备药物制剂的任意方法制备指定口服应用的组合物,并且这类组合物可以包含一种或多种选自甜味剂,矫味剂,着色剂和防腐剂的试剂,以便提供美观和适口的药物制剂。片剂可以包含活性组分与适合于制备片剂的无毒性药学上可接受的赋形剂的混合物。这些赋形剂可以为:例如惰性稀释剂,诸如碳酸钙,碳酸钠,乳糖,磷酸钙或磷酸钠;成粒和崩解剂,例如玉米淀粉或藻酸;粘合剂,例如淀粉,明胶或阿拉伯胶;和润滑剂,例如硬脂酸镁,硬脂酸或滑石粉。可以不对片剂包衣或可以通过公知技术给它们包衣,以便延缓在胃肠道中崩解和吸收且由此提供较长期限内的持续作用。例如,可以使用延时材料,诸如单硬脂酸甘油酯或二硬脂酸甘油酯。
还可以将口服应用的制剂制成硬胶囊,其中将活性组分与惰性固体稀释剂混合,例如碳酸钙,磷酸钙或高岭土;或制成软胶囊,其中将活性组分与水或油介质混合,例如花生油,液体石蜡或橄榄油。
含水混悬液包含活性物质与适合于制备含水混悬液的赋形剂的混合物。这类赋形剂为悬浮剂,例如羧甲基纤维素钠,甲基纤维素,羟丙基甲基纤维素,藻酸钠,聚乙烯吡咯烷酮,黄蓍树胶和阿拉伯树胶;和分散或湿润剂,它们可以为天然存在的磷脂,例如,卵磷脂或环氧烷烃与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯或环氧乙烷与长链脂族醇类,例如十七乙烯氧基鲸蜡醇的缩合产物或环氧乙烷与来源于脂肪酸和己糖醇的偏酯类,诸如聚氧乙烯山梨醇单油酸酯的缩合产物或环氧乙烷与来源于脂肪酸和己糖酐类的偏酯类,例如聚氧乙烯失水山梨糖醇单油酸酯的缩合产物。含水混悬液还可以包含一种或多种防腐剂,例如苯甲酸乙酯或对-羟基苯甲酸正-丙酯,一种或多种着色剂,一种或多种矫味剂和一种或多种甜味剂,诸如蔗糖或糖精。
可以通过将活性组分悬浮于植物油,例如花生油,橄榄油,芝麻油或椰子油或矿物油,诸如液体石蜡中配制油混悬液。油混悬液可以包含增稠剂,例如蜂蜡,硬石蜡或鲸蜡醇。可以加入将甜味剂,诸如上述那些和矫味剂以便提供适口的口服制剂。可以通过添加诸如抗坏血酸这类抗氧化剂对这些组合物防腐。
适合于通过添加水制备含水混悬液的可分散粉末和颗粒提供了活性组分与分散或湿润剂,悬浮剂和一种或多种防腐剂的混合物。合适的分散或湿润剂和悬浮剂以上述那些为典型。还可以存在额外的赋形剂,例如甜味剂,矫味剂和着色剂。
本发明的药物制剂还可以为水包油型乳剂和油包水型乳剂的形式。油相可以为植物油,例如橄榄油或花生油或矿物油,例如液体石蜡或其混合物。合适的软化剂可以为天然存在的树胶,例如阿拉伯树胶或黄蓍树胶;天然存在的磷脂类,例如大豆,卵磷脂和来源于脂肪酸和己糖醇的酯类或偏酯类;酸酐类,例如失水山梨糖醇单油酸酯;和所述的偏酯类与环氧乙烷的缩合产物,例如聚氧乙烯失水山梨糖醇单油酸酯。所述的乳剂还可以包含甜味剂和矫味剂。
可以使用甜味剂,例如甘油,丙二醇,山梨醇或蔗糖配制添加剂和酏剂。这类制剂还可以包含缓和剂,防腐剂和矫味剂和着色剂。药物制剂可以为无菌可注射水或油混悬液形式。可以按照本领域公知的方式,使用上述那些合适的分散或湿润剂和悬浮剂配制该混悬液。无菌可注射制剂还可以为在无毒性非肠道可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液,例如为在1,3-丁二醇中的溶液。在可接受的可以使用的媒介物和溶剂中有水,林格液和等渗氯化钠溶液。此外,无菌固定油常用作溶剂或悬浮介质。就该目的而言,可以使用任意的缓和的固定油,包括合成的单酸甘油酯或二脂酰甘油酯。此外,诸如油酸这类脂肪酸应用于制备注射剂。
还可以以栓剂的形式给予本发明的组合物,例如用于直肠给药。可以通过将药物与合适的无刺激性赋形剂混合制备这些组合物,所述的赋形剂在常温下为固体,而在直肠温度下为液体且由此在直肠中熔化而释放药物。这类物质为可可脂和聚乙二醇类。
可选择地,可以通过非肠道给予在无菌介质中的组合物。根据媒介物和所用浓度的不同,可以将药物悬浮于或溶于该媒介物。有利的是,可以将诸如局部麻醉剂,防腐剂和缓冲剂这类佐剂溶于媒介物。
为了对非人的动物给药,可以将包含治疗化合物的组合物添加到动物饲料或饮用水中。此外,便利的是配制动物塑料和饮用水产品,使得动物在其膳食中服用适量的所述的化合物。进一步便利的是将在组合物中的化合物作为预混合物提供给速率或饮用水。还可以将该组合物作为人用的食品或饮料补充剂添加。
约5mg-约250mg/千克体重/天且更优选约25mg-约150mg/千克体重/天等级的剂量水平用于治疗上述疾患。可以与载体物质合并产生单一剂型的活性组分用量根据所治疗疾患和特定给药方式的不同而改变。单位剂型一般包含约1mg-约500mg的活性组分。
剂量频率也可以根据所用化合物和所治疗特定疾病的不同而改变。然而,为了治疗大部分病症,优选每天4次或4次以下的剂量方案。然而,可以理解针对任何特定患者的具体剂量水平取决于各种因素,包括所用的具体化合物的活性,年龄,体重,一般健康状况,性别,膳食,给药时间,给药途径和排泄速率,药物组合和进行疗法的特定疾病的严重性。
本发明优选的化合物具有所需的药理学特性,包括,但必需要口服生物利用度,低毒性,低血清蛋白结合率和所需的体外和体内半衰期。用于治疗CNS病症的化合物透过血脑屏障是必不可少的,而通常优选用于治疗外周病症的化合物的低脑水平。
测定法可以用于预测这些所需药理学特性。用于预测生物利用度的测定法包括通过人肠细胞单层,包括Caco-2细胞单层的转运。对培养的肝细胞的毒性可以用于预测化合物的毒性。可以根据经静脉内接受化合物的实验室动物的脑水平预测化合物在人体中的血脑屏障的透过。
可以根据球蛋白结合测定法预测血清蛋白结合率。这类测定法综合描述在Oravcova等(Journal of Chromatography B(1996),677卷,1-27页)中。
化合物半衰期与化合物的剂量频率成正比。可以根据如Kuhnz和Gieschen(DrugMetabolism and Disposition,(1998),26卷,1120-1127页)所述的微粒体半衰期测定法预测化合物的体外半衰期。
用于治疗所需的组合物的量不仅随选择的特定化合物,而且随给药途径,治疗疾患的性质以及患者年龄和情况的不同而改变,并且最终由巡诊医生或临床医师决定。
V.a)局部用制剂
在一个优选的实施方案中,可以通过局部施用本文所述的化合物应用本发明的方法。
本发明的组合物包含流体或半固体媒介物,它们可以包括,但不限于聚合物,增稠剂,缓冲剂,中和剂,螯合剂,防腐剂,表面活性剂或乳化剂,抗氧化剂,蜡或油,软化剂,防晒剂和溶剂或混合溶剂系统。溶剂或混合溶剂系统对成形而言是重要的,因为它主要使药物溶解。尽管难以将溶剂添加到制剂中,但是最佳溶剂或溶剂系统还是能够维持药物在溶液中的临床相关水平。可以将用于本发明主题的局部用组合物制成各种产品类型。它们包括,但不限于洗剂,霜剂,凝胶,棒,喷雾剂,软膏剂,糊剂,泡沫,摩丝和清洁剂。这些产品类型可以包括几种类型的载体系统,包括,但不限于颗粒,纳米粒和脂质体。如果需要,可以加入崩解剂,诸如交联聚乙烯吡咯烷酮,琼脂或藻酸或其盐,诸如藻酸钠。用于配制和给药的技术可以在上文的Remington:The Science and Practice of Pharmacy中找到。可以选择制剂以便最大限度地递送至体内的所需靶部位。
在无摩擦下施用于皮肤,指甲,毛发,爪或蹄表面的制剂洗剂一般为液体或半-液体制剂,其中分散了固体细粉,蜡或液体。洗剂一般包含产生更好分散体的悬浮剂和用于局限于和保持活性剂接触皮肤,指甲,毛发,爪或蹄的化合物,例如甲基纤维素,羧甲基-纤维素钠等。
包含按照本发明递送的活性剂的霜剂为粘性液体或半固体,为水包油型或油包水型。霜剂基质为可用水洗的并且包含油相,乳化剂和水相。油相一般由凡士林油或脂肪醇,诸如鲸蜡醇或十八烷醇组成;尽管不一定,但水相通常在在体积上超过油相并且一般包含保湿剂。如上文的Remington:The Science and Practice of Pharmacy中解释的,霜剂中的乳化剂一般为非离子型,阴离子型,阳离子型或两性表面活性剂。
凝胶剂也可以与本发明结合使用。正如局部用药物制剂领域技术人员可以理解的,凝胶为半固体。单一-固相包含基本上均匀分布在载体液体中的有机大分子,所述的载体液体一般为水,而且可以为溶剂或溶剂混合物。
为半固体制剂的软膏剂一般基于凡士林油或其他凡士林油衍生物。正如本领域技术人员可以理解的,所用具体软膏剂基质为指定制剂选择的活性剂提供最佳递送并且优选也提供其他所需特性,例如软化性(emolliency)等的软膏剂基质。就载体或媒介物而言,软膏剂基质应为惰性的,稳定的无刺激性和非敏感性的。正如在Remington:The Science andPractice of Pharmacy,19th Ed.(Easton,Pa.:Mack Publishing Co.,1995),1399-1404页中解释的,可以将软膏剂基质分成4类:油基质;可乳化的基质;乳剂基质;和水溶性基质。油基质包括,例如植物油,获自动物的脂肪和获自石油的半固体烃类。可乳化的基质,也称作吸收剂软膏剂基质几乎不含或不含水并且包括,例如,羟基硬脂精硫酸酯,无水羊毛脂和亲水性软石蜡。乳剂软膏剂基质为油包水型(W/O)乳剂或水包油型(O/W)乳剂并且包括,例如鲸蜡醇,单硬脂酸甘油酯,羊毛脂和硬脂酸。由不同分子量的聚丙二醇类制备优选的水溶性软膏剂基质;此外,可以参照上文的The Science and Practice of Pharmacy额外信息。
本发明有用的制剂还包括喷雾剂。喷雾剂一般提供在水和/或醇溶液中的活性剂,可以使该制剂在皮肤,指甲,毛发,爪或蹄雾化以便递送。这类喷雾剂包括为在递送后的给药部位上提供活性剂溶液浓度配制的那些,例如喷雾剂溶液可以主要由醇或其他类挥发性液体组成,其中可以溶解有药物或活性剂。在递送至皮肤,指甲,毛发,爪或蹄时,载体蒸发,从而在给药部位上遗留浓缩的活性剂。
局部用药物组合物还可以包含合适的固体或凝胶相载体。这类载体的实例包括,但不限于碳酸钙,磷酸钙,各种糖类,淀粉,纤维素衍生物,明胶和聚合物,诸如聚乙二醇类。
局部用药物组合物还可以包含合适的乳化剂,即强化或有利于混合和悬浮水包油或油包水的试剂。本文所用的乳化剂可以由单一乳化剂组成或可以为非离子型,阴离子型,阳离子型或两性表面活性剂或两种或多种这类表面活性剂混合物;本文优选使用非离子型或阴离子型乳化剂。这类表面活性剂描述在“McCutcheon’s Detergent andEmulsifiers”,North American Edition,1980Annual中,由McCutcheon Division,MCPublishing Company,175Rock Road,Glen Rock,N.J.07452,USA出版。
本文优选使用高分子量醇类,诸如十六醇十八醇混合物(cetearyl alcohol),鲸蜡醇,十八烷醇,乳化蜡,单硬脂酸甘油酯。其他实例为乙二醇二硬脂酸酯,三硬脂山梨坦,丙二醇单硬脂酸酯,油酸山梨坦,硬脂山梨坦(SPAN60),单月桂酸二甘醇酯,山梨糖醇酐单棕榈酸酯,二油酸蔗糖酯,蔗糖硬脂酸酯(CRODESTA F-160),聚氧乙烯月桂基醚(BRIJ30),聚氧乙烯(2)十八烷基醚(BRIJ72),聚氧乙烯(21)十八烷基醚(BRIJ721),聚氧乙烯单硬脂酸酯(Myrj45),聚氧乙烯硬脂山梨坦TWEEN60),聚氧乙烯油酸山梨坦(TWEEN80),聚氧乙烯月桂山梨坦(TWEEN20)和油酸钠。胆固醇和胆固醇衍生物也可以用于外用乳剂并且促进促成w/o乳化。
尤其合适的非离子型乳化剂为对w/o系统如而言具有约3-6的亲水亲油平衡值(HLB)和对o/w系统系统而言具有8-18的亲水亲油平衡值(HLB)的那些,正如通过PaulL.Lindner在“Emulsions and Emulsion”,Kenneth Lissant编辑,Dekker,New York,N.Y.,1974出版,188-190页中所述的方法测定的。本文庚优选使用产生具有约8至约18的HLB的系统的一种或多种非离子型表面活性剂。
这类非离子型乳化剂的实例包括,但不限于:BRIJ72”,具有4.9的HLB的聚氧乙烯(2)十八烷烷基醚的商品名;“BRIJ721”,具有15.5的HLB的聚氧乙烯(21)十八烷烷基醚的商品名,“Brij30”,具有9.7的HLB的聚氧乙烯月桂基醚的商品名;“Polawax”,具有8.0的HLB的乳化蜡的商品名;“Span60”,具有4.7的HLB的硬脂山梨坦的商品名;“Crodesta F-160”,具有14.5的HLB的蔗糖硬脂酸酯的商品名。所有这些材料均购自Ruger Chemicals Inc.;Croda;ICI Americas,Inc.;Spectrum Chemicals;和BASF。当本发明的局部用制剂包含至少一种乳化剂时,各乳化剂的存在量约为0.5-约2.5wt%,优选0.5-2.0%,更优选1.0%或1.8%。优选乳化剂包括steareth21(约1.8%)和steareth2(约1.0%)的混合物
局部用药物组合物还可以包含合适的软化剂。软化剂为用于防止或减缓干燥以及用于保护皮肤,指甲,毛发,爪或蹄的物质。有用的软化剂包括,但不限于鲸蜡醇,肉豆蔻酸异丙酯,十八烷醇等。各种合适的软化剂为已知的并且可以在本文中使用。例如,参见Sagarin,Cosmetics,Science and Technology,2nd Edition,Vol.1,pp.32-43(1972)和Deckner等的1990年4月24日授权的美国专利US4,919,934,将这两篇文献完整地引入本文作为参考。这些物质购自Ruger Chemical Co,(Irvington,NJ)。
当本发明的局部用制剂包含至少一种软化剂时,每种软化的存在量约为0.1-15%,优选0.1-约3.0,更优选0.5,1.0或2.5wt%。优选软化剂为鲸蜡醇,肉豆蔻酸异丙酯和十八烷醇按照1/5/2之比的混合物。软化剂还可以为鲸蜡醇和十八烷醇按照1/2之比的混合物。
局部用药物组合物还可以包含合适的抗氧化剂,即已知抑制氧化的物质。适用于本发明的抗氧化剂包括,但不限于丁羟甲苯,抗坏血酸,抗坏血酸钠,抗坏血酸钙,棕榈酸抗坏血酸酯,丁基羟基茴香醚,2,4,5-三羟基丙基苯基酮,4-羟甲基-2,6-二-叔丁基苯酚,异抗坏血酸,愈创木脂,棓酸丙酯,硫代二丙酸,硫代二丙酸二月桂酯,叔丁基氢醌和生育酚类,诸如维生素E等,包括这些化合物的药学上可接受的盐和酯类。优选抗氧化剂为丁羟甲苯,丁基羟基茴香醚,棓酸丙酯,抗坏血酸,其药学上可接受的盐或其混合物。更优选抗氧化剂为丁羟甲苯。这些物质购自Ruger Chemical Co,(Irvington,NJ)。
当本发明的局部用制剂包含至少一种抗氧化剂时,抗氧化剂的存在总量约为0.001-0.5wt%,优选0.05-约0.5wt%,更优选0.1%。
局部用药物组合物还可以包含合适的防腐剂。防腐剂为添加到药物制剂中起抗微生物剂作用的化合物。在本领域已知为非肠道制剂中有效和可接受的防腐剂中有苯扎氯铵,苄索氯铵,氯己定,苯酚,间-甲酚,苄醇,对羟基苯甲酸甲酯,对羟基苯甲酸丙酯,氯丁醇,邻-甲酚,对-甲酚,氯甲酚,硝酸苯汞,硫柳汞,苯甲酸及其各种混合物。例如,参见Wallhausser,K.-H.,Develop.Biol.Standard,24:9-28(1974)(S.Krager,Basel)。优选所述的防腐剂选自对羟基苯甲酸甲酯,对羟基苯甲酸丙酯及其混合物。这些物质购自InolexChemical Co(Philadelphia,PA)或Spectrum Chemicals。
当本发明的局部用制剂包含至少一种防腐剂时,防腐剂的存在总量约为0.01-约0.5wt%,优选约0.1-0.5%,更优选约0.03-约0.15。优选防腐剂为对羟基苯甲酸甲酯和对羟基苯甲酸丙酯之按照5/1之比的混合物。然后将醇用作防腐剂,其用量通常为15-20%。
局部用药物组合物还可以包含合适的螯合剂以便与不通过脂双层的金属阳离子复合。合适的螯合剂的实例包括乙二胺四乙酸(EDTA),乙二醇-双(β-氨乙基醚)-N,N,N’,N’-四乙酸(EGTA)和8-氨基-2-[(2-氨基-5-甲基苯氧基)甲基]-6-甲氧基喹啉-N,N,N’,N’-四乙酸四钾盐(QUIN-2)。优选螯合剂为EDTA和柠檬酸。这些物质购自Spectrum Chemicals。
当本发明的局部用制剂包含至少一种螯合剂时,螯合剂的存在总量约为0.005%-2.0wt%,优选约0.05%-约0.5wt%,更优选约0.1wt%。
局部用药物组合物还可以包含合适的用于将制剂pH调整至药学上可接受的范围内的中和剂。中和剂的实例包括,但不限于三乙醇胺,氨丁三醇,氢氧化钠,盐酸,柠檬酸和乙酸。这类物质购自Spectrum Chemicals(Gardena,CA)。
当本发明的局部用制剂包含至少一种中和剂时,中和剂的存在总量约为0.1wt-10wt%,优选0.1wt%-约5.0wt%且更优选约1.0wt%。一般加入中和剂,无论其用量是否为使制剂达到所需pH所需的。
局部用药物组合物还可以包含合适的增粘剂。这些成分为能够通过活性剂与聚合物的相互作用增加含聚合物的溶液的粘度的可扩散化合物。CARBOPOL ULTREZ10可以用作增粘剂。这些物质购自Noveon Chemicals,Cleveland,OH。
当本发明的局部用制剂包含至少一种增粘剂时,增粘剂的存在总量约为0.25%-约5.0wt%,优选约0.25%-约1.0wt%且更优选约0.4%-约0.6wt%。
局部用药物组合物还可以包含合适的指甲穿透促进剂。指甲穿透促进剂的实例包括硫醇化合物,亚硫酸盐和亚硫酸氢盐,角质溶解药和表面活性剂。适用于本发明的指甲穿透促进剂更具体地描述在Malhotra等,J.Pharm.Sci.,91:2,312-323(2002)中,将该文献完整地引入本文作为参考。
局部用药物组合物还可以包含一种或多种合适的溶剂。固体物质(溶质)溶于任何液体物质(溶剂)的能力取决于该溶质和溶剂的物理特性。当溶质和溶剂具有类似的物理特性时,溶质在溶剂中的溶解度最大。这就产生了传统的“相似相溶”的理解。溶剂的特征在于作为非极性的脂溶性油的一种极端,而作为极性的亲水性溶剂的另一种极端。油溶剂溶解通过范德华相互作用其他非极性物质,而水和其他亲水性溶剂通过离子,偶极子或氢键相互作用溶解极性物质。可以将所有溶剂沿从最低极性,即烃类,诸如癸烷到为水的最具极性溶剂列出。溶质在具有相当极性的溶剂中具有其最大溶解度。因此,就在水中具有最低溶解度的药物而言,较低极性的溶剂提供了具有近似与提供最大溶解度等同的极性的溶剂的改善的溶解度。大部分药物在溶剂中具有中间极性且由此在诸如丙二醇或乙醇这类极性明显低于水的溶剂中具有最大溶解度。如果药物在丙二醇中(例如8%(w/w))具有大于水(例如0.1%(w/w))的溶解度,那么将水添加到丙二醇中与丙二醇相比应降低药物在溶剂混合物中的溶解度的最大量。将差溶剂添加到极佳溶剂中与在极佳溶剂中的最大溶解度相比会降低该混合物的最大溶解度。
当将化合物掺入局部用制剂中时,活性组分在制剂中的浓度可能受到活性组分在选择的溶剂和/或载体中的溶解度的限制。非亲脂性药物一般在药学上可接受的溶剂和/或载体中展示出极低的溶解度。例如,本发明的某些化合物在水中的溶解度低于0.00025%wt/wt。本发明中的相同化合物的在丙二醇或肉豆蔻酸异丙酯中的溶解度低于约2%wt/wt。在本发明的一个实施方案中,二甘醇一乙醚(DGME)为用于溶解本文所述的化合物的溶剂。在本发明的一个实施方案中,二甘醇一乙醚(DGME)为用于溶解本文所述的化合物,诸如,例如式(I)或式(II)的化合物的溶剂。认为用于本发明制剂的化合物在DGME中具有约10%wt/wt-约25%wt/wt的溶解度。在另一个实施方案中,DGME水共溶剂系统用于溶解本文所述的化合物。在另一个实施方案中,DGME水共溶剂系统用于溶解本文所述的化合物,诸如,例如式(I)或式(II)的化合物。在加入水时DGME的溶剂容量下降;然而,可以设计DGME/水共溶剂系统以维持约0.1%-约5%wt/wt活性组分的所需浓度。优选活性组分以约0.5%-约3%wt/wt且更优选约1%wt/wt存在于作为施用的局部制剂中。因为DGME的挥发性低于水,所以如果在施用时局部用制剂蒸发,那么活性剂变得更溶于霜剂。这种增加的溶解度降低了因药物沉淀在皮肤,指甲,毛发,爪或蹄上导致的生物利用度下降的可能性。
液体剂型,诸如适合于局部给药或适合于化妆品施用的洗剂可以包括具有缓冲剂,悬浮剂和分散剂,增稠剂,渗透促进剂等的合适的水或非水媒介物。固体剂型,诸如霜剂或糊剂等可以包括,例如任意下列组分:水,油,醇或脂膏作为具有表面活性剂的基质;聚合物,诸如聚乙二醇;增稠剂;固体等。液体或固体制剂可以包括增强的递送技术,诸如脂质体,微粒体,微小海绵等。
另外,可以使用缓释系统递送化合物,诸如包含治疗剂的固体疏水性聚合物的半透性基质。已经确立了各种缓释材料并且为本领域技术人员众所周知。
按照本发明实施的局部治疗方案包括将所述的组合物直接施用于皮肤,指甲,毛发,爪或蹄的施用部位,每日一次到几次。
本发明的制剂可以用于治疗,改善或预防与细菌感染,痤疮,炎症等相关的情况或症状。
在一个典型的实施方案中,所述的药物制剂为单纯溶液。在一个典型的实施方案中,该单纯溶液包括聚醚。在一个典型的实施方案中,所述的聚醚为聚乙二醇或聚丙二醇。在一个典型的实施方案中,所述的单纯溶液包括醇。在一个典型的实施方案中,所述的醇为甲醇,乙醇,丙醇,异丙醇或丁醇。在一个典型的实施方案中,所述的单纯溶液包括聚醚和醇。在另一个典型的实施方案中,所述的单纯溶液包括聚丙二醇和乙醇。在另一个典型的实施方案中,所述的单纯溶液为选自约10%聚丙二醇和约90%乙醇;约20%聚丙二醇和约80%乙醇;约30%聚丙二醇和约70%乙醇;约40%聚丙二醇和约60%乙醇;约50%聚丙二醇和约50%乙醇;约60%聚丙二醇和约40%乙醇;约70%聚丙二醇和约30%乙醇;约80%聚丙二醇和约20%乙醇;约90%聚丙二醇和约10%乙醇中的成员。
在一个典型的实施方案中,所述的药物制剂为漆(lacquer)。
V.b)额外的活性剂
下面是可以加入到本发明的化妆品和局部用药物制剂中的实例。下列活性剂为公知的化合物并且易于商购。
抗炎药包括,但不限于没药醇,薄荷脑,氨苯砜,芦荟,氢化可的松等。
维生素包括,但不限于维生素B,维生素E,维生素A,维生素D等和维生素衍生物,诸如他扎罗汀,卡泊三烯,维甲酸,阿达帕林等。
防老剂包括,但不限于烟酰胺,视黄醇和类视色素衍生物,AHA,抗坏血酸,硫辛酸,辅酶Q10,β羟基酸,水杨酸,铜结合肽类,二甲氨基乙基(DAEA)等。
防晒剂和或晒伤缓解剂包括,但不限于PABA,加州希蒙得木,芦荟,二甲氨苯酸辛酯,甲氧基肉桂酸酯,proxamine HCl,利多卡因等。防晒鞣剂包括,但不限于二羟丙酮(DHA)。
银屑病治疗剂和/或痤疮治疗剂包括,但不限于水杨酸,苄基过氧化物,煤焦油,硫化硒,氧化锌,巯氧吡啶(锌和/或钠),他扎罗汀,卡泊三烯,维甲酸,阿达帕林等。
有效控制或改变角化的活性剂包括,但不限于:维甲酸,他扎罗汀和阿达帕林。
通过局部给予包含本文所述的化合物/活性剂,诸如,例如式(I)或式(II)中的化合物和任选至少一种这些额外活性剂中的至少一种的组合物。在最初的施用中,这使得本发明化合物和任意其他活性剂对皮肤,指甲,毛发,爪或蹄起作用并且治疗它们。可选择地,还可以通过透皮途径经全身递送局部施用的活性剂中的任意一种。
在这类组合物中,额外的化妆品或药物有效活性剂,诸如,例如抗炎药,维生素,防老剂,防晒剂和/或痤疮治疗剂通常为最少的成分(约0.001%-约20wt%或优选约0.01%-约10wt%),剩余部分为各种媒介物或载体和有助于形成所需给药剂型的加工助剂。
V.c)测试
用于本发明局部用制剂的优选化合物具有某些药理学特性。这类特性包括,但不限于低毒性,低血清蛋白结合率和所需的体外和体内半衰期。测定法可以用于预测这些所需的药理学特性。用于预测生物利用度的测定法包括通过人肠细胞单层,包括Caco-2细胞单层转运。可以根据清蛋白结合测定法预测血清蛋白结合率。这类测定法综合描述在Oravcova等(1996,J.Chromat.B677:1-27)中。化合物半衰期与化合物的剂量频率成反比。可以根据如Kuhnz和Gleschen(Drug Metabolism and Disposition,(1998),26卷,1120-1127页)所述的微粒体半衰期测定法预测化合物的体外半衰期。
可以通过在细胞培养物或实验动物中的标准药物操作测定这类化合物的毒性和治疗功效,例如测定LD50(50%群体致死的剂量)和ED50(在50%群体中治疗有效的剂量)。毒性与治疗作用之间的剂量比为治疗指数并且可以将其表示为LD50与ED50之比。优选表现出高治疗指数的化合物。获自这些细胞培养试验和动物研究的数据可以用于配制应用于人体的剂量范围。这类化合物的剂量优选属于包括几乎没有或无毒性的ED50的循环浓度范围。剂量可以在该范围内改变,这取决于所用的剂型和所用的给药途径。可以由各临床医师根据患者的情况选择给药途径和剂量(例如,参见Fingl等,1975,“The Pharmacological Basisof Therapeutics”,Ch.1,p.1)。
V.d)给药
就用于本发明的任意化合物而言,最初可以根据如本文披露的细胞培养测定法估计治疗有效剂量。例如,可以在动物模型中配制剂量以便获得包括如在细胞培养物中测定的EC50(50%增加的有效剂量)的循环浓度范围,即,对细菌细胞生长实现半数最大抑制的测试化合物浓度。这类信息可以用于更精确地测定在人体中的有用剂量。
一般而言,通过任何可接受的用于类似应用的活性剂给药方式,以治疗或化妆品有效量给予通过本文所述的方法和中间体制备的化合物。然而,可以理解用于任何特定患者的具体剂量水平取决于各种因素,包括所用具体化合物的活性,年龄,体重,一般健康状况,性别,膳食,给药时间,给药途径和排泄速率,进行疗法的特定疾病的严重性和开据处方的临床医师的判断。可以每天一次或每天两次或每天达3或4次给药。
可以分别调整剂量和间隔以便提供足以维持细菌细胞生长抑制作用的活性结构部分的血浆水平。常用的患者全身给药剂量范围在0.1-1000mg/天,优选1-500mg/天,更优选10-200mg/天,甚至更优选100-200mg/天。就患者身体表面积而言所述的常用剂量范围在50-91mg/m2/天。
制剂中化合物的量可以在本领域技术人员所用的全范围内改变。一般而言,以重量百分比(wt%)计,制剂包约占总制剂0.01-10wt%的药物,其中平衡物为一种或多种合适的药物赋形剂。优选所述的化合物的存在水平约为0.1-3.0wt%,更优选约为1.0wt%。
通过下面的实施例进一步例证本发明。并不指定这些实施例定义或限制本发明的范围。
实施例
用Varian AS300光谱仪记录质子NMR并且将化学位移报导为来自四甲基硅烷的δ(ppm)低场。用Micromass Quattro II测定质谱。
实施例1
由1制备3
1.1羧酸的还原
在0℃下向在氮气环境中的1(23.3mmol)在无水THF(70mL)中的溶液中滴加BH3THF溶液(1.0M,55mL,55mmol)并且将该反应混合物在室温下搅拌过夜。然后再用冰浴冷却该混合物并且滴加MeOH(20mL)以便分解过量的BH3。搅拌所得混合物,直到不再释放出气泡且然后加入10%NaOH(10mL)。浓缩该混合物并且将残余物与水(200mL)混合且用EtOAc萃取。通过硅胶快速色谱法纯化来自旋转蒸发的残余物而得到20.7mmol的3。
1.2结果
下文提供了通过上述方法制备的结构3的典型化合物。
1.2.a 2-溴-5-氯苄醇
1H NMR(300MHz,DMSO-d6):δ7.57(d,J=8.7Hz,1H),7.50-7.49(m,1H),7.28-7.24(m,1H),5.59(t,J=6.0Hz,1H)和4.46(d,J=6.0Hz,2H)ppm。
1.2.b 2-溴-5-甲氧基苄醇
1H NMR(300MHz,DMSO-d6):δ7.42(d,J=8.7Hz,1H),7.09(d,J=2.4Hz,1H),6.77(dd,J1=3Hz,J2=3Hz,1H),5.43(t,J=5.7Hz,1H),4.44(d,J=5.1Hz,2H),3.76(s,3H)。
实施例2
由2制备3
2.1.醛的还原
向2(Z=H,10.7mmol)在甲醇(30mL)中的溶液中加入硼氢化钠(5.40mol)并且将该混合物在室温下搅拌1小时。加入水并且用乙酸乙酯萃取该混合物。用盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂而得到9.9mmol的3。
2.2结果
下文提供了通过上述方法制备的结构3的典型化合物。
2.2.a 2-溴-5-(4-氰基苯氧基)苄醇
1H-NMR(300MHz,CDCl3):δ(ppm)2.00(br s,1H),4.75(s,2H),6.88(dd,J=8.5,2.9Hz,1H),7.02(d,J=8.8Hz,1H),7.26(d,J=2.6Hz,1H),7.56(d,J=8.5Hz,1H),7.62(d,J=8.8Hz,2H)。
2.2.b 2-溴-4-(4-氰基苯氧基)苄醇
1H NMR(300MHz,DMSO-d6):δ7.83(d,2H),7.58(d,1H),7.39(d,1H),7.18(dd,1H),7.11(d,2H),5.48(t,1H)和4.50(d,2H)ppm。
2.2.c 5-(4-氰基苯氧基)-1-茚满醇
M.p.50-53℃。MS(ESI+):m/z=252(M+1)。HPLC:在254nm下99.7%纯度和在220nm下99.0%纯度。1H NMR(300MHz,DMSO-d6):δ7.80(d,2H),7.37(d,1H),7.04(d,2H),6.98-6.93(m,2H),5.27(d,1H),5.03(q,1H),2.95-2.85(m,1H),2.75-2.64(m,1H),2.39-2.29(m,1H)和1.85-1.74(m,1H)ppm。
2.2.d 2-溴-5-(叔丁基二甲基甲硅烷氧基)苄醇
1H-NMR(300MHz,CDCl3):δ(ppm)0.20(s,6H),0.98(s,9H),4.67(br s,1H),6.65(dd,J=8.2,2.6Hz,1H),6.98(d,J=2.9Hz,1H),7.36(d,J=8.8Hz,1H)。
可以通过该方法生产的化合物的额外实例包括2-溴-4-(3-氰基苯氧基)苄醇;2-溴-4-(4-氯苯氧基)苄醇;2-溴-4-苯氧基苄醇;2-溴-5-(3,4-二氰基苯氧基)苄醇;2-(2-溴-5-氟苯基)乙醇;2-溴-5-氟苄醇;和1-溴-2-萘甲醇。
实施例3
由3制备4
3.1保护性烷基化
将化合物3(20.7mmol)溶于CH2Cl2(150mL)并且用冰浴冷却至0℃。向在氮气环境中的该溶液中依次加入N,N-二-异丙基乙胺(5.4mL,31.02mmol,1.5eq)和氯甲基甲基醚(2mL,25.85mmol,1.25eq)。将该反应混合物在室温下搅拌过夜并且用NaHCO3-饱和水溶液洗涤然后用NaCl-饱和水溶液洗涤。通过硅胶快速色谱法纯化旋转蒸发后的残余物而得到17.6mmol的4。
3.2结果
下文提供了通过上述方法制备的结构4的典型化合物。
3.2.a 2-溴-5-氯-1-(甲氧基甲氧基甲基)苯
1H NMR(300MHz,DMSO-d6):δ7.63(d,J=8.7Hz,1H),7.50(dd,J=2.4&0.6Hz,1H),7.32(dd,J=8.4&2.4Hz,1H),4.71(s,2H),4.53(s,2H)和3.30(s,3H)ppm。
3.2.b 2-溴-5-氟-1-[1-(甲氧基甲氧基)乙基]苯
1H-NMR(300.058MHz,CDCl3):δppm1.43(d,J=6.5Hz,3H),3.38(s,3H),4.55(d,J=6.5Hz,1H),4.63(d,J=6.5Hz,1H),5.07(q,J=6.5Hz,1H),6.85(m,1H),7.25(dd,J=9.7,2.6Hz,1H),7.46(dd,J=8.8,5.3Hz,1H)。
3.2.c 2-溴-5-氟-1-[2-(甲氧基甲氧基)乙基]苯
1H-NMR(300.058MHz,CDCl3):δppm3.04(t,J=6.7Hz,2H),3.31(s,3H),3.77(t,J=6.7Hz,2H),4.62(s,2H),6.82(td,J=8.2,3.2Hz,1H),7.04(dd,J=9.4,2.9Hz,1H),7.48(dd,J=8.8,5.3Hz,1H)。
3.2.d 2-溴-4,5-二氟-1-(甲氧基甲氧基甲基)苯
1H-NMR(300.058MHz,CDCl3):δppm3.42(s,3H),4.57(d,J=1.2Hz,2H),4.76(s,2H),7.3-7.5(m,2H)。
3.2.e 2-溴-5-氰基-1-(甲氧基甲氧基甲基)苯
1H-NMR(300.058MHz,CDCl3):δppm3.43(s,3H),4.65(s,2H),4.80(s,2H),7.43(dd,J=8.2,4.1Hz,1H),7.66(d,J=8.2Hz,1H),7.82(d,J=4.1Hz,1H)。
3.2.f 2-溴-5-甲氧基-1-(甲氧基甲氧基甲基)苯
1H NMR(300MHz,DMSO-d6):δ7.48(dd,J1=1.2Hz,J2=1.2Hz,1H),7.05(d,J=2.7Hz,1H),6.83(dd,J1=3Hz,J2=3Hz,1H),4.69(d,J=1.2Hz,2H),4.5(s,2H),3.74(d,J=1.5Hz,3H),3.32(d,J=2.1Hz,3H)ppm。
3.2.g 1-苄基-1-(2-溴苯基)-1-(甲氧基甲氧基)乙烷
1H NMR(300MHz,DMSO-d6):δ7.70-7.67(m,1H),7.25-7.09(m,6H),6.96-6.93(m,2H),4.61(d,1H),4.48(d,1H),3.36-3.26(m,2H),3.22(s,3H)和1.63(s,3H)ppm。
3.2.h 2-溴-6-氟-1-(甲氧基甲氧基甲基)苯
1H-NMR(300MHz,CDCl3):δ(ppm)3.43(s,3H),4.74(s,2H),4.76(d,J=2.1Hz,2H),7.05(t,J=9.1Hz,1H),7.18(td,J=8.2,5.9Hz,1H),7.40(d,J=8.2Hz,1H)。
3.2.i 2-溴-4-(4-氰基苯氧基)-1-(甲氧基甲氧基甲基)苯
1H NMR(300MHz,DMSO-d6):δ7.84(d,2H),7.56(d,1H),7.44(d,1H),7.19-7.12(m,3H),4.69(s,2H),4.56(s,2H)和3.31(s,3H)ppm。
3.2.j 2-溴-5-(叔丁基二甲基甲硅烷氧基)-1-(甲氧基甲氧基甲基)苯
1H-NMR(300MHz,CDCl3):δ(ppm)0.19(s,6H),0.98(s,9H),3.43(s,3H),4.59(s,2H),4.75(s,2H),6.64(dd,J=8.5,2.9Hz,1H),6.98(d,J=2.9Hz,1H),7.36(d,J=8.5Hz,1H)。
3.2.k 2-溴-5-(2-氰基苯氧基)-1-(甲氧基甲氧基甲基)苯
1H-NMR(300MHz,CDCl3):δ(ppm)3.41(s,3H),4.64(s,2H),4.76(s,2H),6.8-6.9(m,2H),7.16(td,J=7.6,0.9Hz,1H),7.28(d,J=2.9Hz,1H),7.49(ddd,J=8.8,7.6,1.8Hz,1H),7.56(d,J=8.5Hz,1H),7.67(dd,J=7.9,1.8Hz,1H)。
3.2.l 2-溴-5-苯氧基-1-(甲氧基甲氧基甲基)苯
1H-NMR(300MHz,CDCl3):δ(ppm)3.40(s,3H),4.62(s,2H),4.74(s,2H),6.80(dd,J=8.8,2.9hz,1H),7.01(d,J=8.5Hz,2H),7.12(t,J=7.9Hz,1H),7.19(d,J=2.9hz,1H),7.35(t,J=7.6Hz,2H),7.48(d,J=8.5Hz,1H)。
可以通过该方法生产的化合物的额外实例包括2-溴-1-(甲氧基甲氧基甲基)苯;2-溴-5-甲基-1-(甲氧基甲氧基甲基)苯;2-溴-5-(甲氧基甲氧基甲基)-1-(甲氧基甲氧基甲基)苯;2-溴-5-氟-1-(甲氧基甲氧基甲基)苯;1-溴-2-(甲氧基甲氧基甲基)萘;2-溴-4-氟-1-(甲氧基甲氧基甲基)苯;2-苯基-1-(2-溴苯基)-1-(甲氧基甲氧基)乙烷;2-溴-5-(4-氰基苯氧基)-1-(甲氧基甲氧基甲基)苯;2-溴-4-(3-氰基苯氧基)-1-(甲氧基甲氧基甲基)苯;2-溴-4-(4-氯苯氧基)-1-(甲氧基甲氧基甲基)苯;2-溴-4-苯氧基-1-(甲氧基甲氧基甲基)苯;2-溴-5-(3,4-二氰基苯氧基)-1-(甲氧基甲氧基甲基)苯。
实施例4
由4通过5制备I
4.1金属化和硼基化
向在-78℃下和氮气环境中的4(17.3mmol)在无水THF(80mL)中的溶液中滴加叔-BuLi或n-BuLi(11.7mL)并且该溶液变棕色。然后一次性注射B(OMe)3(1.93mL,17.3mmol)并且除去冷却浴。将该混合物在搅拌下逐步温热30分钟且然后用水浴搅拌2小时。在添加6NHCl(6mL)后,将该混合物在室温下搅拌过夜并且通过TLC分析证实约50%发生水解。旋转蒸发该溶液并且将残余物溶于MeOH(50mL)和6N HCl(4mL)。将该溶液回流1小时并且如通过TLC分析所证实的水解完全。旋转蒸发得到残余物,将其溶于EtOAc,用水洗涤,干燥且然后蒸发。通过硅胶快速色谱法纯化粗产物而得到具有80%纯度的固体。通过用己烷洗涤进一步纯化该固体而得到7.2mmol的I。
4.2结果
下文提供了结构I的典型化合物的分析数据。
4.2.a 5-氯-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C1)
M.p.142-150℃。MS(ESI):m/z=169(M+1,正)和167(M-1,负)。HPLC(220nm):99%纯度。1H NMR(300MHz,DMSO-d6):δ9.30(s,1H),7.71(d,J=7.8Hz,1H),7.49(s,1H),7.38(d,J=7.8Hz,1H)和4.96(s,2H)ppm。
4.2.b 1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C2)
M.p.83-86℃。MS(ESI):m/z=135(M+1,正)和133(M-1,负)。HPLC(220nm):95.4%纯度。1H NMR(300MHz,DMSO-d6):δ9.14(s,1H),7.71(d,J=7.2Hz,1H),7.45(t,J=7.5Hz,1H),7.38(d,J=7.5Hz,1H),7.32(t,J=7.1Hz,1H)和4.97(s,2H)ppm。
4.2.c 5-氟-1,3-二氢-1-羟基-3-甲基-2,1-苯并氧杂硼杂环戊二烯(C3)
1H-NMR(300MHz,DMSO-d6):δppm1.37(d,J=6.4Hz,3H),5.17(q,J=6.4Hz,1H),7.14(m,1H),7.25(dd,J=9.7,2.3Hz,1H),7.70(dd,J=8.2,5.9Hz,1H),9.14(s,1H)。
4.2.d 6-氟-1-羟基-1,2,3,4-四氢-2,1-苯并氧杂硼因(C4)
1H-NMR(300MHz,DMSO-d6):δppm2.86(t,J=5.9Hz,2H),4.04(t,J=5.9Hz,2H),7.0-7.1(m,2H),7.69(dd,J=8.2,7.2Hz,1H),8.47(s,1H)。
4.2.e 5,6-二氟-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C5)
1H-NMR(300MHz,DMSO-d6):δppm4.94(s,2H),7.50(dd,J=10.7,6.8Hz,1H),7.62(dd,J=9.7,8.2Hz,1H),9.34(s,1H)。
4.2.f 5-氰基-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C6)
1H-NMR(300MHz,DMSO-d6):δppm5.03(s,2H),7.76(d,J=8.2Hz,1H),7.89(d,J=8.2Hz,1H),7.90(s,1H),9.53(s,1H)。
4.2.g 1,3-二氢-1-羟基-5-甲氧基-2,1-苯并氧杂硼杂环戊二烯(C7)
M.p.102-104℃。MS ESI:m/z=165.3(M+1)和162.9(M-1)。1H NMR(300MHz,DMSO-d6):δ8.95(s,1H),7.60(d,J=8.1Hz,1H),6.94(s,1H),6.88(d,J=8.1Hz,1H),4.91(s,2H),3.77(s,3H)ppm。
4.2.h 1,3-二氢-1-羟基-5-甲基-2,1-苯并氧杂硼杂环戊二烯(C8)
M.p.124-128℃。MS ESI:m/z=148.9(M+1)和146.9(M-1)。1H NMR(300MHz,DMSO-d6):δ9.05(s,1H),7.58(d,J=7.2Hz,1H),7.18(s,1H),7.13(d,J=7.2Hz,2H),4.91(s,2H),2.33(s,3H)ppm。
4.2.i 1,3-二氢-1-羟基-5-羟甲基-2,1-苯并氧杂硼杂环戊二烯(C9)
MS:m/z=163(M-1,ESI-)。1H NMR(300MHz,DMSO-d6):δ9.08(s,1H),7.64(d,1H),7.33(s,1H),7.27(d,1H),5.23(t,1H),4.96(s,2H),4.53(d,2H)ppm。
4.2.j 1,3-二氢-5-氟-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C10)
M.p.110-114℃。MS ESI:m/z=150.9(M-1)。1H NMR(300MHz,DMSO-d6):δ9.20(s,1H),7.73(dd,J1=6Hz,J2=6Hz,1H),7.21(m,1H),7.14(m,1H),4.95(s,2H)ppm。
4.2.k 1,3-二氢-2-氧杂-1-环戊萘(C11)
M.P.139-143℃。MS ESI:m/z=184.9(M+1)。1H NMR(300MHz,DMSO-d6):δ9.21(s,1H),8.28(dd,J1=6.9Hz,J2=0.6Hz,1H),7.99(d,J=8.1Hz,1H),7.95(d,J=7.5Hz,1H),7.59-7.47(m,3H),5.09(s,2H)ppm。
4.2.l 7-羟基-2,1-氧杂环戊硼烷并[5,4-c]吡啶(C12)
1H-NMR(300MHz,DMSO-d6):δppm5.00(s,2H),7.45(d,J=5.0Hz,1H),8.57(d,J=5.3Hz,1H),8.91(s,1H),9.57(s,1H)。ESI-MS m/z134(M-H)-,C6H6BNO2=135。
4.2.m 1,3-二氢-6-氟-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C13)
M.p.110-117.5℃。MS(ESI):m/z=151(M-1,负)。HPLC(220nm):100%纯度。1H NMR(300MHz,DMSO-d6):δ9.29(s,1H),7.46-7.41(m,2H),7.29(td,1H)和4.95(s,2H)ppm。
4.2.n 3-苄基-1,3-二氢-1-羟基-3-甲基-2,1-苯并氧杂硼杂环戊二烯(C14)
MS(ESI):m/z=239(M+1,正)。HPLC:在220nm下99.5%纯度和在254nm下95.9%纯度。1H NMR(300MHz,DMSO-d6):δ8.89(s,1H),7.49-7.40(m,3H),7.25-7.19(m,1H),7.09-7.05(m,3H),6.96-6.94(m,2H),3.10(d,1H),3.00(d,1H)和1.44(s,3H)ppm。
4.2.o 3-苄基-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C15)
MS(ESI+):m/z=225(M+1)。HPLC:在220nm下93.4%纯度。1H NMR(300MHz,DMSO-d6):δ9.08(s,1H),7.63(dd,1H),7.43(t,1H),7.35-7.14(m,7H),5.38(dd,1H),3.21(dd,1H)和2.77(dd,1H)ppm。
4.2.p 1,3-二氢-4-氟-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C16)
1H-NMR(300MHz,DMSO-d6):δ(ppm)5.06(s,2H),7.26(ddd,J=9.7,7.9,0.6Hz,1H),7.40(td,J=8.2,4.7Hz,1H),7.55(d,J=7.0Hz,1H),9.41(s,1H)。
4.2.q 5-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C17)
1H-NMR(300MHz,DMSO-d6):δppm4.95(s,2H),7.08(dd,J=7.9,2.1Hz,1H),7.14(d,J=8.8Hz,1H),7.15(d,J=2.1Hz,1H),7.78(d,J=7.9Hz,1H),7.85(d,J=9.1Hz,2H),9.22(s,1H)。
4.2.r 6-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C18)
M.p.148-151℃。MS:m/z=252(M+1)(ESI+)和m/z=250(M-1)(ESI-)。HPLC:在254nm下100%纯度和在220nm下98.7%纯度。1H NMR(300MHz,DMSO-d6):δ9.26(s,1H),7.82(d,2H),7.50(d,1H),7.39(d,1H),7.26(dd,1H),7.08(d,2H)和4.99(s,2H)ppm
4.2.s 6-(3-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C19)
M.P.146-149℃。MS:m/z=252(M+1)(ESI+)和m/z=250(M-1)(ESI-)。HPLC:在254nm下100%纯度和在220nm下97.9%纯度。1H NMR(300MHz,DMSO-d6):δ9.21(s,1H),7.60-7.54(m,2H),7.50-7.45(m,2H),7.34-7.30(m,2H),7.23(dd,1H)和4.98(s,2H)ppm。
4.2.t 6-(4-氯苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C20)
M.P.119-130℃。MS:m/z=261(M+1)(ESI+)和m/z=259(M-1)(ESI-)。HPLC:在254nm下100%纯度和在220nm下98.9%纯度。1H NMR(300MHz,DMSO-d6):δ9.18(s,1H),7.45-7.41(m,3H),7.29(d,1H),7.19(dd,1H),7.01(d,2H)和4.96(s,2H)ppm。
4.2.u 6-苯氧基-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C21)
M.P.95-99℃。MS:m/z=227(M+1)(ESI+)和m/z=225(M-1)(ESI-)。HPLC:在254nm下100%纯度和在220nm下98.4%纯度。1H NMR(300MHz,DMSO-d6):δ9.17(s,1H),7.43-7.35(m,3H),7.28(s,1H),7.19-7.09(m,2H),6.99(d,2H)和4.96(s,2H)ppm。
4.2.v 5-(4-氰基苄氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C22)
1H-NMR(300MHz,DMSO-d6):δ(ppm)4.90(s,2H),5.25(s,2H),6.98(dd,J=7.9,2.1Hz,1H),7.03(d,J=1.8Hz,1H),7.62(d,J=7.9Hz,1H),7.64(d,J=8.5Hz,2H),7.86(d,J=8.5Hz,1H),9.01(s,1H)。
4.2.w 5-(2-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C23)
1H-NMR(300MHz,DMSO-d6):δ(ppm)4.95(s,2H),7.0-7.2(m,3H),7.32(td,J=7.6,1.2Hz,1H),7.68(ddd,J=9.1,7.6,1.8Hz,1H),7.77(d,J=7.9Hz,1H),7.91(dd,J=7.9,1.8Hz,1H)。
4.2.x 5-苯氧基-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C24)
1H-NMR(300MHz,DMSO-d6):δ(ppm)4.91(s,2H),6.94(s,1H),6.96(d,J=8.8Hz,1H),7.05(d,J=7.6Hz,2H),7.17(t,J=7.3Hz,1H),7.41(t,J=7.3Hz,2H),7.70(d,J=8.5Hz,1H),9.11(s,1H)。
4.2.y 5-[4-(N,N-二乙基氨基甲酰基)苯氧基]-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C25)
1H-NMR(300MHz,DMSO-d6):δ(ppm)1.08(br s,6H),3.1-3.5(m,4H),4.93(s,2H),7.0-7.1(m,4H),7.37(d,J=8.5Hz,2H),7.73(d,J=7.9Hz,1H),9.15(s,1H)。
4.2.z 1,3-二氢-1-羟基-5-[4-(吗啉代羰基)苯氧基]-2,1-苯并氧杂硼杂环戊二烯(C26)
1H-NMR(300MHz,DMSO-d6):δ(ppm)3.3-3.7(m,8H),4.93(s,2H),7.0-7.1(m,4H),7.44(d,J=8.8Hz,2H),7.73(d,J=7.9Hz,1H),9.16(s,1H)。
4.2.aa 5-(3,4-二氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C27)
1H-NMR(300MHz,DMSO-d6):δ(ppm)4.97(s,2H),7.13(dd,J=7.9,2.1Hz,1H),7.21(d,J=1.5Hz,1H),7.43(dd,J=8.8,2.6Hz,1H),7.81(d,J=7.9Hz,1H),7.82(d,J=2.6Hz,1H),8.11(d,J=8.5Hz,1H),9.26(s,1H)。
4.2.ab 6-苯硫基-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C28)
M.p.121-124℃。MS:m/z=243(M+1)(ESI+)和m/z=241(M-1)(ESI-)。HPLC:在254nm下99.6%纯度和在220nm下99.6%纯度。1H NMR(300MHz,DMSO-d6):δ9.25(s,1H),7.72(dd,1H),7.48(dd,1H),7.43(dd,1H),7.37-7.31(m,2H),7.29-7.23(m,3H)和4.98(s,2H)ppm。
4.2.ac 6-(4-三氟甲氧基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C29)
M.P.97-101℃。MS:m/z=311(M+1)(ESI+)和m/z=309(M-1)(ESI-)。HPLC:在254nm下100%纯度和在220nm下100%纯度。1H NMR(300MHz,DMSO-d6):δ9.20(s,1H),7.45(d,1H),7.37(d,2H),7.33(d,1H),7.21(dd,1H),7.08(d,2H)和4.97(s,2H)ppm。
4.2.ad 5-(N-甲基-N-苯基磺酰基氨基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C30)
M.P.85-95℃。MS:m/z=304(M+1)(ESI+)和m/z=302(M-1)(ESI-)。HPLC:在254nm下96.6%纯度和在220nm下89.8%纯度。1H NMR(300MHz,DMSO-d6):δ9.23(s,1H),7.72-7.63(m,2H),7.56(t,2H),7.50(d,2H),7.16(s,1H),7.03(d,1H),4.91(s,2H)和3.14(s,3H)ppm。
4.2.ae 6-(4-甲氧基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C31)
M.P.126-129℃。MS:m/z=257(M+1)(ESI+)和m/z=255(M-1)(ESI-)。HPLC:在254nm下98.4%纯度和在220nm下98.4%纯度。1H NMR(300MHz,DMSO-d6):δ9.14(s,1H),7.36(d,1H),7.19(s,1H),7.12(d,1H),6.98(d,2H),6.95(d,2H),4.93(s,2H)和3.73(s,3H)ppm。
4.2.af 6-(4-甲氧基苯硫基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C32)
M.P.95-100℃。MS:m/z=272(M+),273(M+1)(ESI+)和m/z=271(M-1)(ESI-)。HPLC:在254nm下100%纯度和在220nm下99.2%纯度。1H NMR(300MHz,DMSO-d6):δ9.20(s,1H),7.51(d,1H),7.39-7.28(m,4H),6.98(d,2H),4.93(s,2H)和3.76(s,3H)ppm。
4.2.ag 6-(4-甲氧基苯基磺酰基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C33)
M.P.180-192℃。MS:m/z=305(M+1)(ESI+)和m/z=303(M-1)(ESI-)。HPLC:在254nm下96.8%纯度和在220nm下95.5%纯度。1H NMR(300MHz,DMSO-d6):δ9.46(s,1H),8.28(s,1H),7.99(d,1H),7.85(d,2H),7.61(d,1H),7.11(d,2H),5.02(s,2H)和3.80(s,3H)ppm。
4.2.ah 6-(4-甲氧基苯基亚磺酰基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C34)
1H NMR(300MHz,DMSO-d6):δ9.37(s,1H),8.02(d,1H),7.71(dd,1H),7.59(d,2H),7.53(d,1H),7.07(d,2H),5.00(s,2H)和3.76(s,3H)ppm。
4.2.ai 5-三氟甲基-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C35)
M.P.113-118℃。MS:m/z=203(M+1)(ESI+)和m/z=201(M-1)(ESI-)。HPLC:在254nm下100%纯度和在220nm下100%纯度。1H NMR(300MHz,DMSO-d6):δ9.48(s,1H),7.92(d,1H),7.78(s,1H),7.67(d,1H)和5.06(s,2H)ppm。
4.2.aj 4-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C36)
就4-氟苄腈与取代的苯酚之间的偶联反应得到原料2而言,参见Igarashi,S.等Chemical&Pharmaceutical Bulletin(2000),48(11),1689-1697。
1H-NMR(300MHz,DMSO-d6)(ppm)4.84(s,2H),7.08(d,J=8.2Hz,2H),7.18(d,J=7.9Hz,1H),7.45(t,J=7.3Hz,1H),7.63(d,J=7.3Hz,1H),7.82(d,J=8.5Hz,2H)。
7-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C100)
就4-氟苄腈与取代的苯酚之间的偶联反应得到原料2而言,参见Igarashi,S.等Chemical&Pharmaceutical Bulletin(2000),48(11),1689-1697。
1H NMR(300MHz,DMSO-d6):δ(ppm)5.02(s,2H),6.97(d,J=7.9Hz,1H),7.01(d,J=8.5Hz,2H),7.30(d,J=7.3Hz,1H),7.56(t,J=7.6Hz,1H),7.77(d,J=8.5Hz,2H)。
4.2.ak 5-(3-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C37)
就3-氟苄腈与取代的苯酚之间的偶联反应得到原料2而言,:Li,F.等,OrganicLetters(2003),5(12),2169-2171。
1H-NMR(300MHz,DMSO-d6):δ(ppm)4.93(s,2H),7.0-7.1(m,2H),7.3-7.4(m,1H),7.5-7.7(m,3H),7.75(d,J=8.2Hz,1H)。
4.2.al 5-(4-羧基苯氧基)-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C38)
向C17中获得的5-(4-氰基苯氧基)-1-羟基-2,1-苯并氧杂硼杂环戊二烯(430mg,1.71mmol)在乙醇(10mL)中的溶液中加入6mol/L氢氧化钠(2mL)并且将该混合物回流3小时。加入盐酸(6mol/L,3mL)并且用乙酸乙酯萃取该混合物。用盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂并且通过硅胶柱色谱法纯化残余物(乙酸乙酯),随后与二异丙醚一起研磨而得到目标化合物(37mg,8%)。
1H-NMR(300MHz,DMSO-d6):δ(ppm)4.94(s,2H),7.0-7.1(m,4H),7.76(d,J=7.9Hz,1H),7.94(d,J=8.8Hz,2H),9.19(s,1H),12.8(br s,1H)。
4.2.am 1-羟基-5-[4-(四唑-1-基)苯氧基]-2,1-苯并氧杂硼杂环戊二烯(C39)
将5-(4-氰基苯氧基)-1-羟基-2,1-苯并氧杂硼杂环戊二烯(200mg,0.797mmol),叠氮化钠(103mg,1.59mmol)和氯化铵(85mg,1.6mmol)在N,N-二甲基甲酰胺(5mL)中的混合物在80℃下搅拌2天。加入水并且用乙酸乙酯萃取该混合物。用水和盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂并且通过硅胶柱色谱法(乙酸乙酯)纯化残余物,随后与乙酸乙酯一起研磨而得到目标化合物(55mg,23%)。
1H-NMR(300MHz,DMSO-d6):δ(ppm)4.95(s,2H),7.0-7.1(m,2H),7.23(d,J=8.8Hz,2H),7.76(d,J=7.9Hz,1H),8.05(d,J=8.5Hz,2H),9.18(br s,1H)。
实施例5
由2通过6制备I
5.1催化硼基化,还原和环化
将2(10.0mmol),双(频哪酸)二硼(2.79g,11.0mmol),PdCl2(dppf)(250mg,3mol%)和乙酸钾(2.94g,30.0mmol)在1,4-二噁烷(40mL)中的混合物在80℃下搅拌过夜。加入水并且用乙酸乙酯萃取该混合物。用盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂。将粗产物溶于四氢呋喃(80mL),然后加入高碘酸钠(5.56g,26.0mmol)。在室温下搅拌30分钟后,加入2N HCl(10mL)并且将该混合物在室温下搅拌过夜。加入水并且用乙酸乙酯萃取该混合物。用盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂并且用乙醚处理残余物而得到6.3mmol相应的硼酸。向获得的硼酸(0.595mmol)在甲醇(5mL)中的溶液中加入硼氢化钠(11mg,0.30mmol)并且将该混合物在室温下搅拌1小时。加入水并且用乙酸乙酯萃取该混合物。用盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂并且通过硅胶柱色谱法纯化残余物而得到0.217mmol的I。
5.2结果
下文提供了结构I的典型化合物的分析数据。
5.2.a1,3-二氢-5-氟-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C10)
将该化合物的分析数据列在4.2.j中。
实施例6
由3制备I
6.1一锅法硼基化和环化
在-78℃下和氮气环境中在15分钟内向3(4.88mmol)和硼酸三异丙酯(1.35mL,5.86mmol)在四氢呋喃(10mL)中的溶液中滴加正-丁基锂(在己烷中1.6mol/L;6.7mL,10.7mmol)并且将该混合物搅拌2小时,同时温至室温。用2N HCl使反应猝灭并且用乙酸乙酯萃取。用盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂并且通过硅胶柱色谱法纯化且用戊烷处理而得到0.41mmol的I。
6.2结果
下文提供了结构I的典型化合物的分析数据。
6.2.a 1,3-二氢-5-氟-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C10)
将该化合物的分析数据列在4.2.j中。
实施例7
由3制备I
7.1一锅法硼基化和使用蒸馏的环化
在-78℃下和氮气环境中在15分钟内向3(4.88mmol)在甲苯(20mL)中的溶液中加入硼酸三异丙酯(2.2mL,9.8mmol)并且将该混合物回流1小时。在减压下除去溶剂,生成的异丙醇和过量的硼酸三异丙酯。将残余物溶于四氢呋喃(10mL)并且冷却至-78℃。在10分钟内滴加正-丁基锂(3.2mL,5.1mmol),并且将该混合物搅拌1小时,同时温至室温。用2N HCl使反应猝灭并且用乙酸乙酯萃取。用盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂并且通过硅胶柱色谱法纯化且用戊烷处理而得到1.54mmol的I。
7.2结果
下文提供了结构I的典型化合物的分析数据。
7.2.a 1,3-二氢-5-氟-1-羟基-2,1-苯并氧杂硼杂环戊二烯(C10)
将该化合物的分析数据列在4.2.j中。
实施例8
由7制备8
8.1溴化
向7(49.5mmol)在四氯化碳(200mL)中的溶液中加入N-溴琥珀酰亚胺(8.81g,49.5mmol)和N,N-偶氮异丁腈(414mg,5mol%)并且将该化合物回流下加热3小时。加入水并且用氯仿萃取该混合物。用盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂而得到粗的甲基-溴化中间体8。
实施例9
由8制备3
9.1羟基化
向粗的8(49.5mmol)中加入二甲基甲酰胺(150mL)和乙酸钠(20.5g,250mmol)并且将该混合物在80℃下搅拌过夜。加入水并且用乙醚萃取该混合物。用水和盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂。向残余物中加入甲醇(150mL)和1N氢氧化钠(50mL)并且将该混合物在室温下搅拌1小时。在减压下浓缩该反应混合物至约体积的三分之一。加入水和盐酸并且用乙酸乙酯萃取该混合物。用水和盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂并且通过硅胶柱色谱法纯化残余物,随后与二氯甲烷一起研磨而得到21.8mmol的3。
9.2结果
下文提供了通过上述方法制备的结构3的典型化合物。
9.2.a 2-溴-5-氰基苄醇
1H-NMR(300MHz,DMSO-d6):δppm4.51(d,J=5.9Hz,2H),5.67(t,J=5.6Hz,1H),7.67(dd,J=8.2,2.0Hz,1H),7.80(s,J=8.2Hz,1H),7.83(d,J=2.0Hz,1H)。
通过该方法生产的化合物的额外实例包括2-溴-5-(4-氰基苯氧基)苄醇。
实施例10
由2制备9
10.1反应
2(20.0mmol),(甲氧基甲基)三苯基磷鎓氯化物(8.49g,24.0mmol)和叔丁醇钾(2.83g,24.0mol)在N,N-二甲基甲酰胺(50mL)中的混合物在室温下搅拌过夜。用6N HCl使反应猝灭并且用乙酸乙酯萃取该混合物。用水(x2)和盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂。向残余物中加入四氢呋喃(60mL)和6N HCl并且将该混合物回流8小时。加入水并且用乙醚萃取该混合物。用盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂而得到16.6mmol的9。
实施例11
制备方法的步骤13
11.1反应
在氮气环境中回流I在适当的醇溶剂(R1-OH)中的溶液且然后蒸馏以便除去醇而得到相应的酯。
实施例12
由Ia制备Ib
12.1反应
向Ia在甲苯中的溶液中加入氨基醇并且收集沉淀的固体而得到Ib。
12.2结果
在80℃下将(500mg,3.3mmol)溶于甲苯(37mL)并且加入乙醇胺(0.20mL,3.3mmol)。将该混合物冷却至室温,然后用冰浴冷却并且过滤而得到C38,为白色粉末(600.5mg,94%)。
12.2a (C38)
1H-NMR(300MHz,DMSO-d6):δ(ppm)2.88(t,J=6.2Hz,2H),3.75(t,J=6.3Hz,2H),4.66(s,2H),5.77(br,2H),6.85-6.91(m,2H),7.31(td,J=7.2,1.2Hz,1H)。
实施例13
5-(4-羧基苯氧基)-1-羟基-2,1-苯并氧杂硼杂环戊二烯
向C17中获得的5-(4-氰基苯氧基)-1-羟基-2,1-苯并氧杂硼杂环戊二烯(430mg,1.71mmol)在乙醇(10mL)中的溶液中加入6mol/L氢氧化钠(2mL)并且将该混合物回流3小时。加入盐酸(6mol/L,3mL)并且用乙酸乙酯萃取该混合物。用盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂并且通过硅胶柱色谱法纯化残余物(乙酸乙酯),随后与二异丙醚一起研磨而得到目标化合物(37mg,8%)。
1H-NMR(300MHz,DMSO-d6):δ(ppm)4.94(s,2H),7.0-7.1(m,4H),7.76(d,J=7.9Hz,1H),7.94(d,J=8.8Hz,2H),9.19(s,1H),12.8(br s,1H)。
实施例14
1-羟基-5-[4-(四唑-1-基)苯氧基]-2,1-苯并氧杂硼杂环戊二烯
将5-(4-氰基苯氧基)-1-羟基-2,1-苯并氧杂硼杂环戊二烯(200mg,0.797mmol),叠氮化钠(103mg,1.59mmol)和氯化铵(85mg,1.6mmol)在N,N-二甲基甲酰胺(5mL)中的混合物在80℃下搅拌2天。加入水并且用乙酸乙酯萃取该混合物。用水和盐水洗涤有机层并且用无水硫酸钠干燥。在减压下除去溶剂并且通过硅胶柱色谱法(乙酸乙酯)纯化残余物,随后与乙酸乙酯一起研磨而得到目标化合物(55mg,23%)。
1H-NMR(300MHz,DMSO-d6):δ(ppm)4.95(s,2H),7.0-7.1(m,2H),7.23(d,J=8.8Hz,2H),7.76(d,J=7.9Hz,1H),8.05(d,J=8.5Hz,2H),9.18(br s,1H)。
实施例15
4-(4-氰基苯氧基)苯基硼酸(C97)
(a)(4-氰基苯基)(4-溴苯基)醚。在氮气环境中将4-氟苄腈(7.35g,60.68mmol),4-溴苯酚(10g,57.8mmol)和碳酸钾(12g,1.5eq)在DMF(100mL)中的混合物在100℃下搅拌16小时且然后过滤。在旋转蒸发后,将残余物溶于乙酸乙酯并且用1N NaOH溶液洗涤以便除去未反应的苯酚。干燥该有机溶液并且使其通过短硅胶柱以便除去颜色和少量苯酚杂质。蒸发该溶液得到(4-氰基苯基)(4-溴苯基)醚(13.82g,产率87.2%),为白色固体。1H NMR(300MHz,DMSO-d6):δ7.83(d,2H),7.63(d,2H),7.13(d,2H)和7.10(d,2H)ppm。
(b)4-(4-氰基苯氧基)苯基硼酸。将实施例2d中所述的操作步骤用于使用(4-氰基苯基)(4-溴苯基)醚作为原料合成4-(4-氰基苯氧基)苯基硼酸。获得标题化合物,为白色固体。M.p.194-198℃。MS:m/z=239(M+),240(M+1)(ESI+)和m/z=238(M-1)(ESI-)。HPLC:在254nm下95.3%纯度和在220nm下92.1%纯度。1H NMR(300MHz,DMSO-d6+D2O):δ7.83-7.76(m,4H),7.07(d,2H)和7.04(d,2H)ppm。
实施例16
3-(4-氰基苯氧基)苯基硼酸(C98)
通过对合成C21所述的操作步骤由使用3-溴苯酚和4-氟苄腈作为原料制备的(4-氰基苯基)(3-溴苯基)醚制备标题化合物。获得产物,为白色固体。M.P.153-162℃。MS:m/z=239(M+),240(M+1)(ESI+)和m/z=238(M-1)(ESI-)。HPLC:在254nm下98.5%纯度和在220nm下97.5%纯度。1H NMR(300MHz,DMSO-d6+D2O):δ7.78(d,2H),7.64(d,1H),7.45-7.40(m,2H),7.18-7.14(dd,1H)和7.03(d,2H)ppm。
实施例17
4-(4-氰基苯氧基)-2-甲基苯基硼酸(C99)
通过对合成C21所述的操作步骤由使用4-溴-3-甲基苯酚和4-氟苄腈作为原料制备的(4-氰基苯基)(4-溴-3-甲基苯基)醚制备标题化合物。获得产物,为白色固体。M.P.161-165℃。MS:m/z=253(M+),254(M+1)(ESI+)和m/z=252(M-1)(ESI-)。HPLC:在254nm下97.1%纯度和在220nm下95.1%纯度。1H NMR(300MHz,DMSO-d6+D2O):δ7.95(d,2H),7.81(d,1H),7.09(d,2H),6.92-6.88(m,2H)和2.65(s,3H)ppm。
实施例18
抗炎测试
测试本发明化合物抑制促炎细胞因子的能力。检验化合物对在冷冻人外周血单核细胞(PBMC)中IL-1β,IL-4,TNFα和IFNγ细胞因子释放特性的作用。使PBMC细胞接触10μM浓度的各样品,此后用20μg/mL植物凝集素(PHA)刺激。使用Luminex4-plex测定法测定细胞因子释放特性(IL-1β,IFNγ,IL-4,TNF-α)。将测试结果提供在图1中。
方法:
测试物质和给药模式
冷冻的人PBMC将融化并离心。从低温保存的培养基中抽出细胞沉淀并且重新悬浮于新鲜的培养基中。PBMC培养基(CM)为RPMI1640,10%FBS,1%P/S,2mM L-谷氨酰胺。将细胞在37℃,5%CO2下孵育。将本文所述的干固体化合物,诸如式(I)或式(II)溶于DMSO而形成20mM样品(DMSO,100%)。将20mM样品在CM(DMSO,1%)中稀释至200μM(10X)。将10μL稀释的样品加入到190μL CM+细胞(n=3)中至最终样品浓度为10μM(最终DMSO0.05%)。将样品与细胞一起在37℃下孵育15-30分钟,此后添加诱导物(PHA,20ug/mL)。将诱导物+媒介物(PHA+0.05%DMSO)用作本实验的对照品。将不含诱导物的媒介物用作阴性对照。将地塞米松(50nM,n=3)用作阳性对照。在24小时和48小时时提取上清液并且储存在-80℃下。融化上清液并且使用Alamar Blue测定样品的细胞毒性。然后使用Luminex4-plex测定法测定上清液的IL-1β,IL-4,TNF-α和IFNγ。
结果:
地塞米松对细胞因子分泌的抑制在预计范围内,证实本测定法确切。将本发明各化合物对IL-1β,IL-4,TNF-α和IFNγ的抑制%提供在图1中。
实施例19
局部佛波酯小鼠耳试验
方法:
测试物质和给药模式
Anacor Pharmaceuticals,Inc.提供了5-(4-氰基苯氧基)-1-羟基-2,1-二氢苯并氧杂硼杂环戊二烯和倍他米松。倍他米松用于治疗各种皮肤病的瘙痒,发红,干燥,结痂,脱屑,炎症和不适。
在施用(12-)十四酸佛波酯(-13-)乙酸盐(PMA)前30分钟和之后15分钟将测试物质局部施用于测试动物的右耳。给药体积就溶剂媒介物而言为20μl/耳或就霜剂而言为20mg/耳。
动物
体重为24±2g的雄性CD-1(Crl.)来源小鼠由BioLasco Taiwan提供(在CharlesRiver Laboratories Technology Licensee中)。10只动物的空间分配为29x18x13cm。使小鼠寄居在APECR笼中。将所有动物维持在受控温度(22℃-23℃)和湿度(70%-80%)环境中,具有12小时光照黑暗循环,在MDS Pharma Services-Taiwan Laboratory中持续至少1周,此后使用。允许小鼠自由取实验室食物(Lab Diet,Rodent Diet,PMI NutritionInternational,USA)和自来水。一般按照Care and Use of Laboratory Animals(National Academy Press,Washington,D.C.,1996)指导原则实施该项工作的所有方面,包括动物的寄居,实验和处理。
化学物质
丙酮(Wako,Japan),无水乙醇(Merck,Germany),地塞米松(Sigma,USA)和(12-)十四酸佛波酯(-13-)乙酸盐(Sigma,USA)。
仪器
动物笼(Allentown,USA),染色型微米测量仪(Peacock,Japan)和自动移液器(Gilson,France)。
炎症试验:局部,佛波酯
使用体重为24±2g的5只CD-1(Crl.)来源的雄性小鼠的组。将PMA(在20μl丙酮中4pg)局部施用于每只动物右耳的前表面和后表面。在PMA施用前30分钟和之后15分钟各自施用媒介物(乙醇:丙酮/1:1,20μL/耳或霜剂,20mg/耳)和测试物质,包括5-(4-氰基苯氧基)-1-羟基-2,1-二氢苯并氧杂硼杂环戊二烯和地塞米松。类似地将地塞米松(3mg在20μL/耳丙酮:乙醇/1:1中3mg/耳)作为阳性对照同时施用。然后在PMA施用后6小时时用染色型微米测量仪测定耳肿胀作为炎症指标。按照下式计算抑制百分比:([Ic-It]/Ic)x100%,其中Ic和It分别意旨对照组和治疗组小鼠中的耳厚度增加(mm)。将30%或30%以上(≥30%)抑制视为具有显著抗炎活性。
结论
与相应媒介物(乙醇:丙酮/1:1)或霜剂安慰剂对照组相比,5-(4-氰基苯氧基)-1-羟基-2,1-苯并氧杂硼杂环戊二烯,(1mg/耳x2),地塞米松(0.2mg/耳x2)导致PMA-诱导的耳肿胀显著抑制。
同时,地塞米松(3mg/耳)还导致耳肿胀比媒介物-治疗组(乙醇:丙酮/1:1)显著下降(72%)。
总之,5-(4-氰基苯氧基)-1-羟基-2,1-二氢苯并氧杂硼杂环戊二烯在1mg/耳x2和地塞米松在0.2mg/耳x2下展示出显著的(≥30%抑制)抗炎活性,而5-(4-氰基苯氧基)-1-羟基-2,1-二氢苯并氧杂硼杂环戊二烯在0.2mg/耳x2下产生中度(22%),但非显著性的由在小鼠中局部使用佛波酯诱导的耳肿胀抑制。
实施例20
环硼酸酯类
可以通过本文所述的方法生产额外的化合物。通过选择合适的原料,诸如1或3,本文所述的方法可以用于配制下列化合物。在可得到的情况下,对这些化合物提供熔点特征。
20.结果
下文提供了结构I的典型和化合物的分析数据。
20a 2-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-5-基氧基)乙酸乙酯(C41)
M.P.134-137℃。典型原料:2-(4-溴-3-(羟甲基)苯氧基)乙酸乙酯。
20b 2-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-5-基氧基)乙酸(C42)
M.P.163-166℃。典型原料:2-(4-溴-3-(羟甲基)苯氧基)乙酸乙酯。在皂化相应酯后获得标题化合物。
20c 6-(噻吩-2-基硫)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C43)
M.P.99-104℃。典型原料:(2-溴-4-(噻吩-2-基硫)苯基)甲醇。
20d 6-(4-氟苯硫基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C44)
M.P.135-138℃。典型原料:(2-溴-4-(4-氟苯硫基)苯基)甲醇。
20e 1-(3-((1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-5-基氧基)甲基)苯基)戊-1-酮(C45)
M.P.96-98℃。典型原料:1-(3-((4-溴-3-(羟甲基)苯氧基)甲基)苯基)戊-1-酮。
20f 2-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-5-基氧基)-1-(哌啶-1-基)乙酮(C46)
M.P.158-163℃。典型原料:2-(4-溴-3-(羟甲基)苯氧基)-1-(哌啶-1-基)乙酮。
20g 2-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-5-基氧基)-1-(4-(嘧啶-2-基)哌嗪-1-基)乙酮(C47)
M.P.190-195℃。典型原料:2-(4-溴-3-(羟甲基)苯氧基)-1-(4-(嘧啶-2-基)哌嗪-1-基)乙酮。
20h 6-(4-(吡啶-2-基)哌嗪-1-基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C48)
M.P.135-138℃。典型原料:(2-溴-4-(4-(吡啶-2-基)哌嗪-1-基)苯基)甲醇。
20i 6-硝基苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C49)
M.P.163-171℃。典型原料:苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。参见JACS82,2172,1960中的制备。
20j 6-氨基苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C50)
M.P.145-148℃。典型原料:6-硝基苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。
20k 6-(二甲氨基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C51)
M.P.120-123℃。典型原料:6-氨基苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。
20l N-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-6-基)苯甲酰胺(C52)
M.P.186-193℃。典型原料:6-氨基苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。
20m 6-(4-苯基哌嗪-1-基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C53)
M.P.159-161℃。典型原料:(2-溴-4-(4-苯基哌嗪-1-基)苯基)甲醇。
20n 6-(1H-吲哚-1-基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C55)
M.P.135-140℃。典型原料:(2-溴-4-(1H-吲哚-1-基)苯基)甲醇。
20o 6-吗啉代苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C56)
M.P.128-132℃。典型原料:(2-溴-4-吗啉代苯基)甲醇。
20p 6-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-5-基氧基)烟腈(C57)
M.P.193-198℃。典型原料:6-(4-溴-3-(羟甲基)苯氧基)烟腈。
20q 5-氟-6-硝基苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C58)
M.P.162-167℃。典型原料:5-氟苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。
20r 5-溴-6-(羟甲基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C59)
M.P.>257℃。典型原料:(2,5-二溴-4-(甲氧基甲基)苯基)甲醇。
20s 3,7-二氢-1,5-二羟基-1H,3H-苯并[1,2-c:4,5-c']双[1,2]氧杂硼杂环戊二烯(C60)
M.P.>250℃。典型原料:(2,5-二溴-1,4-亚苯基)二甲醇。
20t 1-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-6-基)-3-苯基脲(C61)
M.P.213-215℃。典型原料:6-氨基苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。
20u N-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-6-基)苯磺酰胺(C62)
M.P.175-184℃。典型原料:6-氨基苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。
20v N-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-6-基)乙酰胺(C63)
M.P.176-185℃。典型原料:6-氨基苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。
20w 7-(羟甲基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C64)
M.P.241-250℃。典型原料:(2-溴-1,3-亚苯基)二甲醇。
20x 7-甲基苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C65)
M.P.107-111℃。典型原料:(2-溴-3-甲基苯基)甲醇。
20y 6-(3-(苯硫基)-1H-吲哚-1-基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C66)
M.P.159-163℃。典型原料:(2-溴-4-(3-(苯硫基)-1H-吲哚-1-基)苯基)甲醇。
20z 3-(1-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-6-基)-1H-吲哚-3-基硫)丙腈(C67)
M.P.135-141℃。典型原料:3-(1-(3-溴-4-(羟甲基)苯基)-1H-吲哚-3-基硫)丙腈
20aa 6-(5-甲氧基-1H-吲哚-1-基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C68)
M.P.120-124℃。典型原料:(2-溴-4-(5-甲氧基-1H-吲哚-1-基)苯基)甲醇。
20bb 5,6-亚甲二氧基苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C69)
M.P.185-189℃。典型原料:(6-溴苯并[d][1,3]间二氧杂环戊烯-5-基)甲醇。
20cc 6-氨基-5-氟苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C70)
M.P.142-145℃。典型原料:6-硝基-5-氟苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。
20dd 6-(苄氨基)-5-氟苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C71)
M.P.159-164℃。典型原料:6-氨基-5-氟苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。
20ee 6-(5-甲氧基-3-(苯硫基)-1H-吲哚-1-基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C72)
M.P.135-141℃。典型原料:(2-溴-4-(5-甲氧基-3-(苯硫基)-1H-吲哚-1-基)苯基)甲醇。
20ff 3-(1-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-6-基)-5-甲氧基-1H-吲哚-3-基硫)丙腈(C73)
M.P.149-154℃。典型原料:3-(1-(3-溴-4-(羟甲基)苯基)-5-甲氧基-1H-吲哚-3-基硫)丙腈。
20gg 4-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-7-基氧基)苄腈(C74)
M.P.148-153℃。典型原料:4-(2-溴-3-(羟甲基)苯氧基)苄腈。
20hh 6-(5-氯-1H-吲哚-1-基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C75)
M.P.149-154℃。典型原料:(2-溴-4-(5-氯-1H-吲哚-1-基)苯基)甲醇。
20ii 3-(5-氯-1-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-6-基)-1H-吲哚-3-基硫)丙腈(C76)
M.P.>225℃。典型原料:3-(1-(3-溴-4-(羟甲基)苯基)-5-氯-1H-吲哚-3-基硫)丙腈。
20jj 6-(苄氨基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C77)
M.P.126-133℃。典型原料:6-氨基苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。
20kk 6-(二苄氨基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C78)
M.P.115-123℃。典型原料:6-氨基苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。
20ll 7-(4-(1H-四唑-5-基)苯氧基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C79)
M.P.在215℃下分解。典型原料:4-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-7-基氧基)苄腈。
20mm 6-(5-氯-3-(苯硫基)-1H-吲哚-1-基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C80)
M.P.145-151℃。典型原料:(2-溴-4-(5-氯-3-(苯硫基)-1H-吲哚-1-基)苯基)甲醇。
20nn 6-(4-(嘧啶-2-基)哌嗪-1-基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C82)
M.P.NA℃。典型原料:(2-溴-4-(4-(嘧啶-2-基)哌嗪-1-基)苯基)甲醇。
20oo 7-(苄氧基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C83)
M.P.NA℃。典型原料:(3-(苄氧基)-2-溴苯基)甲醇。
20pp 4-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-6-基硫)吡啶鎓氯化物(C84)
M.P.NA℃。典型原料:(2-溴-4-(吡啶-4-基硫)苯基)甲醇。
20qq 6-(吡啶-2-基硫)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C85)
M.P.NA℃。典型原料:(2-溴-4-(吡啶-2-基硫)苯基)甲醇。
20rr 7-氟苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C86)
M.P.120-124℃。典型原料:(2-溴-3-氟苯基)甲醇。
20ss 6-(4-(三氟甲基)苯氧基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C87)
M.P.98-105℃。典型原料:(2-溴-4-(4-(三氟甲基)苯氧基)苯基)甲醇。
20tt 6-(4-氯苯硫基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C88)
M.P.157-161℃。典型原料:(2-溴-4-(4-氯苯硫基)苯基)甲醇。
20uu 6-(4-氯苯基亚磺酰基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C89)
M.P.154-161℃。典型原料:6-(4-氯苯硫基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。
20vv 6-(4-氯苯基磺酰基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C90)
M.P.157-163℃。典型原料:6-(4-氯苯硫基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。
20ww N-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-5-基)-N-(苯基磺酰基)苯磺酰胺(C91)
M.P.142-152℃。典型原料:N-(4-溴-3-(羟甲基)苯基)-N-(苯基磺酰基)苯磺酰胺。
20xx 6-(4-(三氟甲基)苯硫基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C92)
M.P.111-113℃。典型原料:(2-溴-4-(4-(三氟甲基)苯硫基)苯基)甲醇。
20yy 6-(4-(三氟甲基)苯基亚磺酰基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C93)
M.P.79-88℃。典型原料:6-(4-(三氟甲基)苯硫基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇。
20zz 6-(4-(甲硫基)苯硫基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C94)
M.P.117-120℃。典型原料:(2-溴-4-(4-(甲硫基)苯硫基)苯基)甲醇。
20aaa 6-(对-甲苯硫基)苯并[c][1,2]氧杂硼杂环戊二烯-1(3H)-醇(C95)
M.P.139-144℃。典型原料:(2-溴-4-(对-甲苯硫基)苯基)甲醇。
20bbb 3-((1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-5-基氧基)甲基)苄腈(C96)
M.P.147-150℃。典型原料:3-((4-溴-3-(羟甲基)苯氧基)甲基)苄腈。
应理解本文所述的实施例和实施方案仅用于例证目的并且提示本领域技术人员可以以此为依据进行各种变型或改变,且它们包括在本申请的精神和范围和待批权利要求范围内。为所有目的而将本文引述的所有公开文献,专利和专利申请完整地引入本文作为参考。
Claims (54)
1.6-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-5-基氧基)烟腈或其药学上可接受的盐在制备用于治疗人与炎症相关的疾病的药物中的用途,其中所述的与炎症相关的疾病为选自如下的成员:银屑病,关节炎,皮炎,过敏性鼻炎,强直性脊柱炎,克罗恩病,溃疡性结肠炎,慢性阻塞性肺疾病,葡萄膜炎,结节病,贝切特病,过敏性结膜炎,干眼病和哮喘。
2.权利要求1所述的用途,其中所述的疾病为银屑病。
3.权利要求1所述的用途,其中所述的疾病为关节炎,所述关节炎为风湿性关节炎。
4.权利要求1所述的用途,其中所述的疾病为关节炎,所述关节炎为牛皮癣性关节炎。
5.权利要求1所述的用途,其中所述的疾病为皮炎,所述皮炎为接触性皮炎。
6.权利要求1所述的用途,其中所述的疾病为皮炎,所述皮炎为湿疹。
7.权利要求1所述的用途,其中所述的疾病为皮炎,所述皮炎为特应性皮炎。
8.权利要求1所述的用途,其中所述的疾病为哮喘,所述哮喘为支气管哮喘。
9.6-(1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊二烯-5-基氧基)烟腈或其药学上可接受的盐在制备用于治疗动物与炎症相关的疾病的药物中的用途,其中所述的与炎症相关的疾病为选自如下的成员:银屑病,关节炎,皮炎,过敏性鼻炎,强直性脊柱炎,克罗恩病,溃疡性结肠炎,慢性阻塞性肺疾病,葡萄膜炎,结节病,贝切特病,过敏性结膜炎,干眼病和哮喘。
10.权利要求9所述的用途,其中所述的疾病为银屑病。
11.权利要求9所述的用途,其中所述的疾病为关节炎,所述关节炎为风湿性关节炎。
12.权利要求9所述的用途,其中所述的疾病为关节炎,所述关节炎为牛皮癣性关节炎。
13.权利要求9所述的用途,其中所述的疾病为皮炎,所述皮炎为接触性皮炎。
14.权利要求9所述的用途,其中所述的疾病为皮炎,所述皮炎为湿疹。
15.权利要求9所述的用途,其中所述的疾病为皮炎,所述皮炎为特应性皮炎。
16.权利要求9所述的用途,其中所述的疾病为哮喘,所述哮喘为支气管哮喘。
17.5-(4-氰基苯硫基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯或5-(3-氰基苯硫基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯或5-(2-氰基苯硫基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯或其药学上可接受的盐在制备用于治疗人与炎症相关的疾病的药物中的用途,其中所述的与炎症相关的疾病为选自如下的成员:银屑病,关节炎,皮炎,过敏性鼻炎,强直性脊柱炎,克罗恩病,溃疡性结肠炎,慢性阻塞性肺疾病,葡萄膜炎,结节病,贝切特病,过敏性结膜炎,干眼病和哮喘。
18.权利要求17所述的用途,其中所述的疾病为银屑病。
19.权利要求17所述的用途,其中所述的疾病为关节炎,所述关节炎为风湿性关节炎。
20.权利要求17所述的用途,其中所述的疾病为关节炎,所述关节炎为牛皮癣性关节炎。
21.权利要求17所述的用途,其中所述的疾病为皮炎,所述皮炎为接触性皮炎。
22.权利要求17所述的用途,其中所述的疾病为皮炎,所述皮炎为湿疹。
23.权利要求17所述的用途,其中所述的疾病为皮炎,所述皮炎为特应性皮炎。
24.权利要求17所述的用途,其中所述的疾病为哮喘,所述哮喘为支气管哮喘。
25.5-(4-氰基苯硫基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯或5-(3-氰基苯硫基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯或5-(2-氰基苯硫基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯或其药学上可接受的盐在制备用于治疗动物与炎症相关的疾病的药物中的用途,其中所述的与炎症相关的疾病为选自如下的成员:银屑病,关节炎,皮炎,过敏性鼻炎,强直性脊柱炎,克罗恩病,溃疡性结肠炎,慢性阻塞性肺疾病,葡萄膜炎,结节病,贝切特病,过敏性结膜炎,干眼病和哮喘。
26.权利要求25所述的用途,其中所述的疾病为银屑病。
27.权利要求25所述的用途,其中所述的疾病为关节炎,所述关节炎为风湿性关节炎。
28.权利要求25所述的用途,其中所述的疾病为关节炎,所述关节炎为牛皮癣性关节炎。
29.权利要求25所述的用途,其中所述的疾病为皮炎,所述皮炎为接触性皮炎。
30.权利要求25所述的用途,其中所述的疾病为皮炎,所述皮炎为湿疹。
31.权利要求25所述的用途,其中所述的疾病为皮炎,所述皮炎为特应性皮炎。
32.权利要求25所述的用途,其中所述的疾病为哮喘,所述哮喘为支气管哮喘。
33.6-(2-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯或其药学上可接受的盐在制备用于治疗人与炎症相关的疾病的药物中的用途,其中所述的与炎症相关的疾病为选自如下的成员:银屑病,关节炎,皮炎,过敏性鼻炎,强直性脊柱炎,克罗恩病,溃疡性结肠炎,慢性阻塞性肺疾病,葡萄膜炎,结节病,贝切特病,过敏性结膜炎,干眼病和哮喘。
34.权利要求33所述的用途,其中所述的疾病为银屑病。
35.权利要求33所述的用途,其中所述的疾病为关节炎,所述关节炎为风湿性关节炎。
36.权利要求33所述的用途,其中所述的疾病为关节炎,所述关节炎为牛皮癣性关节炎。
37.权利要求33所述的用途,其中所述的疾病为皮炎,所述皮炎为接触性皮炎。
38.权利要求33所述的用途,其中所述的疾病为皮炎,所述皮炎为湿疹。
39.权利要求33所述的用途,其中所述的疾病为皮炎,所述皮炎为特应性皮炎。
40.权利要求33所述的用途,其中所述的疾病为哮喘,所述哮喘为支气管哮喘。
41.6-(2-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯或其药学上可接受的盐在制备用于治疗动物与炎症相关的疾病的药物中的用途,其中所述的与炎症相关的疾病为选自如下的成员:银屑病,关节炎,皮炎,过敏性鼻炎,强直性脊柱炎,克罗恩病,溃疡性结肠炎,慢性阻塞性肺疾病,葡萄膜炎,结节病,贝切特病,过敏性结膜炎,干眼病和哮喘。
42.权利要求41所述的用途,其中所述的疾病为银屑病。
43.权利要求41所述的用途,其中所述的疾病为关节炎,所述关节炎为风湿性关节炎。
44.权利要求41所述的用途,其中所述的疾病为关节炎,所述关节炎为牛皮癣性关节炎。
45.权利要求41所述的用途,其中所述的疾病为皮炎,所述皮炎为接触性皮炎。
46.权利要求41所述的用途,其中所述的疾病为皮炎,所述皮炎为湿疹。
47.权利要求41所述的用途,其中所述的疾病为皮炎,所述皮炎为特应性皮炎。
48.权利要求41所述的用途,其中所述的疾病为哮喘,所述哮喘为支气管哮喘。
49.化合物或其药学上可接受的盐在制备用于治疗人与炎症相关的疾病的药物中的用途,其中所述的与炎症相关的疾病为选自如下的成员:痤疮和狼疮,其中所述的化合物为选自如下的成员:
50.权利要求49所述的用途,其中所述化合物为5-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯。
51.权利要求49所述的用途,其中所述化合物为5-(3,4-二氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯。
52.化合物或其药学上可接受的盐在制备用于治疗动物与炎症相关的疾病的药物中的用途,其中所述的与炎症相关的疾病为选自如下的成员:痤疮和狼疮,其中所述的化合物为选自如下的成员:
53.权利要求52所述的用途,其中所述化合物为5-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯。
54.权利要求52所述的用途,其中所述化合物为5-(3,4-二氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯。
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