CN1434797A - 用作amp特异性磷酸二酯酶抑制剂的吡咯烷的腙衍生物和肟衍生物 - Google Patents
用作amp特异性磷酸二酯酶抑制剂的吡咯烷的腙衍生物和肟衍生物 Download PDFInfo
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Abstract
本发明公开了为有效选择性PDE4抑制剂的式(I)化合物,以及制备所述化合物的方法。还公开了应用所述化合物治疗炎性疾病和其它涉及细胞因子水平升高的疾病以及中枢神经系统(CNS)疾病。
Description
相关申请的交叉引用
本申请要求1999年12月23日递交的美国临时申请顺序号60/171,955的权益。
发明领域
本发明涉及一系列为有效的选择性环腺苷3’,5’-一磷酸特异性磷酸二酯酶(cAMP特异性PDE)抑制剂的化合物。本发明尤其涉及一系列可用于抑制cAMP特异性PDE功能、尤其是PDE4功能的新型肟化合物和腙化合物以及制备它们的方法、含有它们的药用组合物和它们用作例如治疗炎性疾病和其它涉及细胞因子和促炎介质水平升高的疾病的治疗药物的用途。
发明背景
慢性炎症为一种多因素病症,其特征为激活多种类型的炎性细胞,尤其是淋巴系细胞(包括T淋巴细胞)和骨髓系细胞(包括粒性白细胞、巨噬细胞和单核细胞)。包括细胞因子例如肿瘤坏死因子(TNF)和白介素-1(IL-1)在内的促炎介质由这些活化细胞产生。因此,抑制这些细胞的激活或抑制它们产生促炎细胞因子的药物可用于治疗性治疗炎性疾病和其它涉及细胞因子水平升高的疾病。
环腺苷酸(cAMP)为一种介导细胞对于广泛的胞外刺激的生物反应的第二信使。当合适的激动剂与特异性细胞表面受体结合时,激活腺苷酸环化酶,使腺苷三磷酸(ATP)转化为cAMP。理论上在细胞内诱导cAMP作用的激动剂主要由cAMP-依赖性蛋白激酶作用介导。cAMP的细胞内作用因为cAMP转运到细胞外或环核苷酸磷酸二酯酶(PDE)酶促裂解作用而中止,PDE水解3’-磷酸二酯键以形成5’-腺苷酸(5’-AMP)。5’-AMP为一种无活性代谢物。以下图示说明cAMP和5’-AMP的结构。
在人骨髓系细胞和淋巴系细胞中cAMP水平升高与抑制细胞激活有关。因此,细胞内PDE酶家族调节细胞内cAMP的水平。PDE4为这些细胞中的主要PDE同种型并且主要影响cAMP降解。因此,抑制PDE功能可防止cAMP转化为无活性代谢物5’-AMP,从而维持较高的cAMP水平,因而抑制细胞激活(参见Beavo等,“CyclicNucleotide Phosphodiesterases:Structure,Regulation and Drug Action,”Wiley and Sons,Chichester,第3-14页(1990));Torphy等,Drug Newsand Perspectives,6,第203-214页(1993);Giembycz等,Clin.Exp.Allergy,22,第337-344页(1992))。
具体来说,已证明PDE4抑制剂例如咯利普兰抑制TNFα的产生并且部分抑制单核细胞释放IL-1β(参见Semmler等,Int.J.Immuopharmacol.,15,第409-413页,(1993);Molnar-Kimber等,Mediators of Inflammation,1,第411-417页,(1992))。还证明了PDE4抑制剂抑制人多形核白细胞产生超氧化物自由基(参见Verghese等,J.Mol.Cell.Cardiol.,21(增刊2),S61(1989);Nielson等,J.AllergyImmunol.,86,第801-808页(1990));抑制人嗜碱性粒细胞释放血管活性胺和前列腺素类(参见Peachell等,J.Immunol.,148,第2503-2510页(1992));抑制嗜酸性粒细胞的呼吸爆发(参见Dent等,J.Pharmacol.,103,第1339-1346页(1991));以及抑制人T-淋巴细胞的激活(参见Robicsek等,Biochem.Pharmacol.,42,第869-877页(1991))。
炎性细胞的激活和过量或非调节性细胞因子(例如TNFα和IL-1β)产生参与变应性疾病、自身免疫病和炎性疾病,例如类风湿性关节炎、骨关节炎、痛风性关节炎、脊椎炎、甲状腺相关性眼病、贝切特氏病、脓毒病、败血症性休克、内毒素性休克、革兰氏阴性脓毒病、革兰氏阳性脓毒病、中毒性休克综合征、哮喘、慢性支气管炎、成人呼吸窘迫综合征、慢性肺部炎性疾病例如慢性阻塞性肺炎、硅肺、肺结节病、心肌、脑和肢端再灌注损伤、纤维变性、囊性纤维变性、瘢痕疙瘩形成、疤痕形成、动脉粥样硬化、移植排斥病例如移植物抗宿主反应和同种异体移植排斥、慢性肾小球肾炎、狼疮、炎性肠病例如节段性回肠炎和溃疡性结肠炎、增生性淋巴细胞疾病例如白血病以及炎性皮肤病例如特应性皮炎、牛皮癣和荨麻疹。
特征在于细胞因子水平升高的其它疾病包括由于中度外伤引起的脑损伤(参见Dhillon等,J Neurotrauma,12,第1035-1043页(1995);Suttorp等,J.Clin.Invest.,91,第1421-1428页(1993))、心肌病例如充血性心力衰竭(参见Bristow等,Circulation,97,第1340-1341页(1998))、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、ARC(AIDS相关综合征)继发性恶病质、由于感染引起的发烧和肌痛、脑型疟、骨质疏松和骨吸收疾病、瘢痕疙瘩形成、疤痕组织形成和发热。
具体来说,已经证实TNFα对于人获得性免疫缺陷综合征(AIDS)具有作用。AIDS是由于人免疫缺陷病毒(HIV)感染T-淋巴细胞引起的。尽管HIV也感染并存在于骨髓系细胞中,已经证实TNF上调T-淋巴细胞和单核细胞中的HIV感染(参见Poli等,Proc.Natl.Acad.Sci.USA,87,第782-785页(1990))。
TNFα的几种性质例如刺激胶原酶、刺激体内血管生成、刺激骨吸收和能够增强肿瘤细胞与内皮细胞的附着,与TNF对肿瘤在宿主体内形成和转移扩散的作用是一致的。最近报道,TNFα直接参与促进肿瘤细胞生长和转移(参见Orosz等,J Exp.Med.,177,第1391-1398(1993))。
PDE4具有广泛的组织分布。对于PDE4具有至少4种基因,任一给定基因的PDE4多种转录物能够产生共有相同催化部位的几种不同的蛋白。4种可能催化部位之间的氨基酸同一性大于85%。它们对抑制剂的同样敏感性及其动力学相似性反映了这个水平氨基酸同一性的功能方面作用。推测这些可变表达的PDE4蛋白的作用在于细胞通过这种作用可以区别性细胞内定位这些酶和/或通过翻译后修饰调节催化效率。表达PDE4酶的任一给定细胞类型通常表达编码这些蛋白的4种可能基因中的一种以上基因。
研究者已经表现出对使用PDE4抑制剂作为消炎药的极大兴趣。早期的证据显示,抑制PDE4对于各种炎性细胞例如单核细胞、巨噬细胞、Th-1系T-细胞和粒性白细胞具有有益的作用。许多促炎介质例如细胞因子、脂质介质、超氧化物和生物胺例如组胺的合成和/或释放通过PDE4抑制剂的作用在这些细胞中减少。PDE4抑制剂也影响其它细胞功能包括T-细胞增殖、粒性白细胞在化学毒性物质作用下的移行和脉管系统内内皮细胞连接的完整性。
已经报告了各种PDE4抑制剂的设计、合成和筛选。甲基黄嘌呤例如咖啡因和茶碱是最早被发现的PDE抑制剂,但是,这些化合物对于抑制PDE是非选择性。药物咯利普兰(抗抑郁药)是最早报道的特异性PDE4抑制剂之一。已经报道,具有以下结构式的咯利普兰抑制重组人PDE4的50%抑制浓度(IC50)为约200nM(纳摩尔)。咯利普兰
研究者一直在寻找这样的PDE4抑制剂:抑制PDE4的选择性更高,IC50比咯利普兰更低,没有使用咯利普兰有关的不需要的中枢神经系统(CNS)副作用,例如干呕、呕吐和镇静作用。在Feldman等的美国专利号5,665,754中公开了一类化合物。其中所公开的化合物为具有与咯利普兰结构类似的取代吡咯烷。一种具有结构式(I)的具体化合物对人重组PDE4的IC50为约2nM。由于观察到催吐副作用与效果明显分离,所以这些化合物没有降低不需要的中枢神经系统作用。
此外,有几家公司正在对其它PDE4抑制剂进行临床试验。然而,效果和毒副作用方面的问题例如呕吐和中枢神经系统紊乱仍未解决。
因此,选择性抑制PDE4并降低或消除与在先的PDE4抑制剂有关的不利的中枢神经系统副作用的化合物可用于治疗变应性疾病和炎性疾病以及其它与细胞因子例如TNF过度或非调节性产生有关的疾病。此外,选择性PDE4抑制剂可用于治疗与在具体靶组织中cAMP水平增高或PDE4功能增强有关的疾病。
发明概述
本发明涉及可用于治疗其中抑制PDE4活性是非常有益的疾病和病症的有效的选择性PDE4抑制剂。本发明的PDE4抑制剂出人意料地降低或消除与在先的PDE4抑制剂有关的不利的中枢神经系统副作用。
本发明尤其涉及具有结构式(II)化合物:
其中Y为OR5或NR5R6;
R1为低级烷基、桥连烷基(例如降冰片基)、芳烷基(例如茚满基)、环烷基、5-或6-元饱和杂环基(例如3-四氢呋喃基)、C1-3亚烷基环烷基(例如环戊基甲基)、芳基-或杂芳基-取代的炔丙基(例如-CH2C≡C-C6H5)、芳基-或杂芳基-取代的烯丙基(例如-CH2CH=CH-C6H5)或卤代环烷基(例如氟代环戊基);
R2为氢、甲基或卤基取代的甲基,例如CHF2;
R3为C(=O)OR7、C(=O)R7、C(=NH)NR8R9、C(=O)NR8R9、芳基或杂芳基;
R4为氢、低级烷基、卤代烷基、环烷基或芳基;
R5和R6独立地为氢、低级烷基、卤代烷基、环烷基、芳基、杂芳基或烷芳基,或者R5和R6一起形成5-元环或6-元环;
R7为支链或直链低级烷基或芳基,或者R7可以任选用一个或多个OR8、NR8R9或SR8取代;
R8和R9相同或不同,它们选自氢、低级烷基、环烷基、芳基、杂芳基和芳烷基,或者R8和R9一起形成4-元环至7-元环;
R10为氢、烷基、卤代烷基、环烷基、芳基、C(=O)烷基、C(=O)环烷基、C(=O)芳基、C(=O)O烷基、C(=O)O环烷基、C(=O)芳基、CH2OH、CH2O烷基、CHO、CN、NO2或SO2R11;和
R11为烷基、环烷基、三氟甲基、芳基、芳烷基或NR8R9。
本发明也涉及含有一种或多种结构式(II)化合物的药用组合物、所述化合物和含所述化合物的组合物在治疗疾病中的用途以及化合物和参与合成结构式(II)化合物的中间体的制备方法。
本发明也涉及通过给予哺乳动物治疗有效量的结构式(II)化合物或含有结构式(II)化合物的组合物,从而治疗所述哺乳动物病症的方法,其中所述哺乳动物患有的病症如果抑制PDE4,可有益地调节哺乳动物体内的cAMP水平、降低哺乳动物体内的TNFα水平、抑制哺乳动物体内的炎性细胞激活和抑制哺乳动物体内的PDE4功能。
优选实施方案的详述
本发明涉及具有结构式(II)化合物:
其中,Y为OR5或NR5R6;
R1为低级烷基、桥连烷基(例如降冰片基)、芳烷基(例如茚满基)、环烷基、5-或6-元饱和杂环基(例如3-四氢呋喃基)、C1-3亚烷基环烷基(例如环戊基甲基)、芳基-或杂芳基-取代的炔丙基(例如-CH2C≡C-C6H5)、芳基-或杂芳基-取代的烯丙基(例如-CH2CH=CH-C6H5)或卤代环烷基(例如氟代环戊基);
R2为氢、甲基或卤基取代的甲基,例如CHF2;
R3为C(=O)OR7、C(=O)R7、C(=NH)NR8R9、C(=O)NR8R9、芳基或杂芳基;
R4为氢、低级烷基、卤代烷基、环烷基或芳基;
R5和R6独立地为氢、低级烷基、卤代烷基、环烷基、芳基、杂芳基或烷芳基,或者R5和R6一起形成5-元环或6-元环;
R7为支链或直链低级烷基或芳基,或者R7可以任选用一个或多个OR8、NR8R9或SR8取代;和
R8和R9相同或不同,它们选自氢、低级烷基、环烷基、芳基、杂芳基和芳烷基,或者R8和R9一起形成4-元环至7-元环;
R10为氢、烷基、卤代烷基、环烷基、芳基、C(=O)烷基、C(=O)环烷基、C(=O)芳基、C(=O)O烷基、C(=O)O环烷基、C(=O)芳基、CH2OH、CH2O烷基、CHO、CN、NO2或SO2R11;和
R11为烷基、环烷基、三氟甲基、芳基、芳烷基或NR8R9。
本文单独或者结合使用的术语“烷基”,定义为包括含1-16个碳原子的直链和支链饱和烃基。术语“低级烷基”本文定义为具有1-6个碳原子(C1-C6)的烷基。低级烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、异丁基、正丁基、新戊基、正己基等。术语“炔基”是指含有碳-碳三键的不饱和烷基。
术语“桥连烷基”本文定义为C6-C16的双环或多环烃基,例如降冰片基、金刚烷基、双环[2.2.2]辛基、双环[2.2.1]庚基、双环[3.2.1]辛基或十氢萘基。
术语“环烷基”本文定义为包括C3-C7环烃基。环烷基的实例包括但不限于环丙基、环丁基、环己基和环戊基。
术语“亚烷基”是指具有一个取代基的烷基。例如术语“C1-3亚烷基环烷基”是指含有1-3个碳原子并用一个环烷基取代的烷基。
术语“卤代烷基”本文定义为用一个或多个卤代取代基例如氟代基、氯代基、溴代基、碘代基或者其组合取代的烷基。同样,“卤代环烷基”定义为具有一个或多个卤代取代基的环烷基。
单独或结合使用的术语“芳基”,本文定义为单环或多环的芳族基团,优选单环或双环的芳族基团,例如苯基或萘基,它们可以为未取代或者取代芳族基团,例如被一个或多个、尤其是一个至三个选自以下的取代基取代:卤代基、烷基、羟基、羟基烷基、烷氧基、烷氧基烷基、卤代烷基、硝基、氨基、烷基氨基、酰基氨基、烷硫基、烷基亚磺酰基和烷基磺酰基。示例性的芳基包括苯基、萘基、四氢萘基、2-氯代苯基、3-氯代苯基、4-氯代苯基、2-甲基苯基、4-甲氧基苯基、3-三氟甲基苯基、4-硝基苯基等。
术语“杂芳基”本文定义为含有一个或两个芳族环并且在芳环上含有至少一个氮原子、氧原子或硫原子的单环或双环系,所述环系可以为未取代或者取代环系,例如被一个或多个、尤其是1-3个如下的取代基取代:卤代基、烷基、羟基、羟基烷基、烷氧基、烷氧基烷基、卤代烷基、硝基、氨基、烷基氨基、酰基氨基、烷硫基、烷基亚磺酰基和烷基磺酰基。杂芳基的实例包括噻吩基、呋喃基、吡啶基、噁唑基、喹啉基、异喹啉基、吲哚基、三唑基、异噻唑基、异噁唑基、咪唑基、苯并噻唑基、吡嗪基、嘧啶基、噻唑基和噻二唑基。
术语“芳烷基”本文定义为这样的在先定义的烷基:其中所述烷基的一个氢原子被本文定义的芳基取代,例如任选具有一个或多个取代基(例如卤代基、烷基、烷氧基等)的苯基。芳烷基的实例是苄基。
术语“烷芳基”本文定义为这样的在先定义的芳基:其中所述芳基的一个氢原子被烷基、环烷基、卤代烷基或卤代环烷基取代。
术语“杂芳烷基”和“杂烷芳基”的定义类似术语“芳烷基”和“烷芳基”,然而,所述芳基被在先定义的杂芳基取代。
术语“杂环基”定义为环中含有一个或多个杂原子的5-或6-元非芳族环,所述杂原子选自氧原子、氮原子和硫原子。非限制性实例包括四氢呋喃、哌啶、哌嗪、环丁砜、吗啉、四氢吡喃、二氧六环等。
术语“卤素”或“卤代基”本文定义为包括氟、氯、溴和碘。
术语“烷氧基”定义为-OR,其中R为烷基。
术语“烷氧基烷基”定义为连接烷基的烷氧基。术语“芳氧基烷基”和“芳烷氧基烷基”类似地定义为连接烷基的芳氧基或芳烷氧基。
术语“羟基”定义为-OH。
术语“羟基烷基”定义为连接烷基的羟基。
术语“氨基”定义为-NH2。
术语“烷基氨基”定义为-NR2,其中至少一个R为烷基,第二个R为烷基或氢。
术语“酰基氨基”定义为RC(=O)N,其中R为烷基或芳基。
术语“硝基”定义为-NO2。
术语“烷硫基”定义为-SR,其中R为烷基。
术语“烷基亚磺酰基”定义为R-SO2,其中R为烷基。
术语“烷基磺酰基”定义为R-SO3,其中R为烷基。
在最优选的实施方案中,R1选自环戊基、四氢呋喃基、茚满基、降冰片基、苯乙基和苯基丁基;R2选自甲基和二氟甲基;R3选自CO2CH3、C(=O)CH2OH、C(=O)CH(CH3)OH、C(=O)C(CH3)2OH和R4为氢或甲基;R5和R6独立地为氢或甲基,或者R5和R6一起形成5-元环或6-元环;R10为氢。
本发明包括结构式(II)化合物的所有可能的立体异构体和几何异构体,并且不仅包括外消旋化合物而且也包括旋光异构体。当需要结构式(II)化合物的单一对映体时,通过拆分终产物或者通过由异构体纯的原料或者使用手性辅助剂立体有择合成可以得到单一对映体(例如参见Z.Ma等,Tetrahedron:Asymmetry,8(6),第883-888页(1997))。终产物、中间体或者原料的拆分可以通过本领域已知的任何合适的方法完成。此外,在其中结构式(II)化合物的互变异构体可能存在的情况下,本发明包括所述化合物的所有互变异构形式。如此后所证明的,特定的立体异构体显示抑制PDE4的优越能力,而没有通常与PDE4抑制剂有关的不利中枢神经系统副作用。
具体来说,普遍认为生物系统对于绝对立体化学性化合物具有非常敏感的活性。(参见E.J.Ariens,Medicinal Research Reviews,6:451-466(1986);E.J.Ariens,Medicinal Research Reviews,7:367-387(1987);K.M.Fowler,Handbook of Stereoisomers:Therapeutic Drugs,CRC Press,Donald P.Smith主编,第35-63页(1989);S.C.Stinson,Chemical and Engineering News,75:38-70(1997))。
例如,咯利普兰为含有一个手性中心的立体有择PDE4抑制剂。咯利普兰的(-)-对映体比其(+)-对映体在涉及其潜在的抗抑郁作用方面具有更强的药理学作用。Schultz等,Naunyn-Schmiedeberg’s ArchPharmacol,333:23-30(1986)。此外,咯利普兰的代谢作用似乎是立体特异性的,(+)-对映体显示比(-)-对映体更快的清除率。Krause等,Xenobiotica,18:561-571(1988)。最后,最新的观察显示,咯利普兰的(-)-对映体(R-咯利普兰)比其(+)-对映体(S-咯利普兰)的催吐作用强大约十倍。A.Robichaud等,Neuropharmacology,38:289-297(1999)。这个观察结果与试验动物对咯利普兰异构体的处理和咯利普兰抑制PDE4酶的能力方面的差异非常不一致。本发明化合物可以具有三个手性中心。如下所示,特定立体化学取向的化合物能够显示类似的PDE4抑制活性和药理学活性,但是改变了中枢神经系统毒性和催吐潜能。
结构式(III)化合物为有效的选择性PDE4抑制剂并且没有结构式(III)化合物的立体异构体所显示的不利的中枢神经系统作用和催吐潜能。
含有酸性部分的结构式(II)化合物可以与合适的阳离子形成药学上可接受的盐。合适的药学上可接受的阳离子包括碱金属(例如钠或钾)和碱土金属(例如钙或镁)阳离子。含有碱性中心的结构式(II)化合物的药学上可接受的盐为与药学上可接受的酸形成的酸加成盐。实例包括盐酸盐、氢溴酸盐、硫酸盐或硫酸氢盐、磷酸盐或磷酸氢盐、乙酸盐、苯甲酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、柠檬酸盐、酒石酸盐、葡糖酸盐、甲磺酸盐、苯磺酸盐和对甲苯磺酸盐。根据前文所述,任何本文中提到的本发明化合物包括结构式(II)化合物以及其药学上可接受的盐和溶剂合物。
本发明的化合物可以以纯化学品治疗性给药,但是优选以药用组合物或制剂给予结构式(II)化合物。因此,本发明还提供含有结构式(II)化合物以及一种或多种药学上可接受的载体并任选其它治疗和/或预防成分的药用制剂。所述载体在与所述制剂中的其它成分相容并且对其接受者无害的意义上为“可接受的”。
具体来说,本发明的选择性PDE4抑制剂可以单独使用或与第二种抗炎治疗药物组合使用,例如所述第二种抗炎药物为靶向TNFα的治疗药物,如用于治疗类风湿性关节炎的ENBREL或REMICADE。同样,IL-1拮抗作用的治疗用途在类风湿性关节炎的动物模型中也已经得到证明。因此,设想IL-1的拮抗作用与减弱TNFα的PDE4抑制作用结合将是有效的。
本发明的PDE4抑制剂可用于治疗各种变应性疾病、自身免疫病和炎性疾病。
术语“治疗”包括预防、缓解、阻止或逆转所治疗疾病或症状发展进程。因此术语“治疗”包括适当的医学治疗和/或预防给药。
具体来说,炎症是一种局限化保护性反应,它是由组织损伤或破坏引起的,它可以破坏、稀释或隔绝(即隔离)损伤因子和受损的组织。本文所用的术语“炎性疾病”,是指任何其中过量或非调节性炎症反应导致过度炎性症状、宿主组织损伤或组织功能丧失的疾病。此外,本文所用的术语“自身免疫病”是指任何种类的其中组织损伤与对于身体自身成分的体液或细胞介导应答有关的疾病。本文所用的术语“变应性疾病”是指由变态反应引起的任何症状、组织损伤或组织功能丧失。本文所用的术语“关节疾病”是指特征在于各种病因引起的关节炎性损伤的一大类任何疾病。本文所用的术语“皮炎”是指特征在于各种病因引起的皮肤炎症的一大类任何皮肤疾病。本文所用的术语“移植排斥”是指特征在于移植组织和周围组织功能丧失、疼痛、肿胀、白细胞增多和血小板减少的直接针对移植组织(包括器官和细胞(例如骨髓))的任何免疫反应。
本发明也提供调节哺乳动物体内cAMP水平的方法以及治疗特征为细胞因子水平升高的疾病的方法。
本文所用的术语“细胞因子”是指任何分泌型多肽,该多肽影响其它细胞的功能并调节所述免疫或炎症反应中细胞之间的相互作用。细胞因子包括但不限于单核因子、淋巴因子和趋化因子,而不管是哪些细胞产生的。例如,单核因子通常指由单核细胞产生并分泌的因子,然而,许多其它细胞也产生单核因子,例如天然杀伤细胞、成纤维细胞、嗜碱性粒细胞、嗜中性粒细胞、内皮细胞、脑星形胶质细胞、骨髓基质细胞、表皮角质细胞和B-淋巴细胞。淋巴因子通常指由淋巴细胞产生的因子。细胞因子的实例包括但不限于白介素-1(IL-1)、白介素-6(IL-6)、肿瘤坏死因子α(TNFα)和肿瘤坏死因子β(TNFβ)。
本发明还提供降低哺乳动物体内TNF水平的方法,该方法包括给予所述哺乳动物有效量的结构式(II)化合物。本文所用的术语“降低TNF水平”是指以下情况之一:
a)通过抑制所有细胞(包括但不限于单核细胞或巨噬细胞)体内释放TNF,使哺乳动物体内过量的TNF水平降低至正常水平或者正常水平以下;或
b)在翻译或转录水平上诱导哺乳动物体内过量的TNF水平下调至正常水平或者正常水平以下;或
c)通过抑制作为翻译后事件的直接合成TNF诱导负调节。
此外,本发明化合物可用于抑制炎性细胞激活。本文所用的术语“炎性细胞激活”是指刺激(包括但不限于细胞因子、抗原或自身抗体)诱导的增殖性细胞反应,产生可溶性介质(包括但不限于细胞因子、氧自由基、酶、前列腺素类或血管活性胺)或者炎性细胞(包括但不限于单核细胞、巨噬细胞、T淋巴细胞、B淋巴细胞、粒性白细胞、多形核白细胞、肥大细胞、嗜碱性粒细胞、嗜酸性粒细胞、树突细胞和内皮细胞)细胞表面表达新的或数量增加的介质(包括但不限于主要组织相容性抗原或细胞粘着分子)。本领域技术人员知道,这些细胞表型中的一种或其组合的激活可引起炎症的发生、持续或恶化。
本发明化合物也可用于引起气道平滑肌松弛、支气管扩张和防止支气管收缩。
因此,本发明化合物可用于治疗以下疾病:例如关节疾病(如类风湿性关节炎)、骨关节炎、痛风性关节炎、脊椎炎、甲状腺相关性眼病、贝切特氏病、脓毒病、败血症性休克、内毒素性休克、革兰氏阴性脓毒病、革兰氏阳性脓毒病、中毒性休克综合征、哮喘、慢性支气管炎、过敏性鼻炎、过敏性结膜炎、春季结膜炎、嗜曙红细胞肉芽肿、成人(急性)呼吸窘迫综合征(ARDS)、慢性肺部炎性疾病(例如慢性阻塞性肺炎)、硅肺、肺结节病、心肌、脑或肢端再灌注损伤、由于轻度外伤引起的脑或脊髓损伤、包括囊性纤维变性的纤维变性、瘢痕疙瘩形成、疤痕组织形成、动脉粥样硬化、自身免疫病例如系统性红斑狼疮(SLE)和移植排斥病(例如移植物抗宿主(GvH)反应和同种异体移植排斥)、慢性肾小球肾炎、炎性肠病例如节段性回肠炎和溃疡性结肠炎、增生性淋巴细胞疾病如白血病(例如慢性淋巴细胞白血病;CLL)(参见Mentz等,Blood 88,第2172-2182(1996))以及炎性皮肤病例如特应性皮炎、牛皮癣或荨麻疹。
这类疾病或有关病症的其它实例包括心肌病例如充血性心力衰竭、发热、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、ARC(AIDS相关综合征)、脑型疟、骨质疏松和骨吸收疾病以及由于感染引起的发烧和肌痛。此外本发明化合物可用于治疗尿崩症和中枢神经系统疾病例如抑郁症和多发梗塞性痴呆。
本发明化合物也具有通常称作治疗药物以外的用途。例如,本发明化合物也可以用作器官移植的保存剂(参见Pinsky等,J.Clin.Invest.,92,第2994-3002页(1993))。
选择性PDE4抑制剂也可以用于治疗勃起机能障碍、尤其是血管原性阳萎(Doherty,Jr.等,美国专利第6,127,363号)、尿崩症(KidneyInt.,37,第362页,(1990);Kidney Int.,35,第494页,(1989))和中枢神经系统疾病例如多发梗塞性痴呆(Nicholson,Psychopharmacology,101,第147页(1990))、抑郁症(Eckman等,Curr.Ther.Res.,43,第291页(1988))、焦虑症和应激反应(Neuropharmacology,38,第1831页(1991))、脑缺血(Eur.J.Pharmacol.,272,第107页(1995))、迟发性运动障碍(J.Clin.Pharmacol.,16,第304页(1976))、帕金森氏病(参见Neurology,25,第722页(1975);Clin.Exp.Pharmacol.Physiol.,26,第421页(1999))和经前综合征。对于抑郁症而言,PDE4选择性抑制剂在各种抑郁症的动物模型例如“行为绝望”或Porsolt试验(Eur.J.Pharmacol.,47,第379页(1978);Eur.J.Pharmacol.,57,第431页(1979);Antidepressants:neurochemical,behavioral and clinicalprospectives,Enna,Malick,and Richelson,eds.,Raven Press,第121页(1981))和“尾悬浮试验”(Psychopharmacology,85,第367页(1985))中显示有效。最新的研究成果显示,各种抗抑郁药长期体内治疗增加PDE4的脑性表达(J.Neuroscience,19,第610页(1999))。因此,治疗中选择性PDE4抑制剂可以单独使用或者与第二种治疗方法联合使用,四种主要抗抑郁治疗为电惊厥方法、单胺氧化酶抑制剂和5-羟色胺或去甲肾上腺素的选择性重摄取抑制剂。选择性PDE4抑制剂也可以用于借助直接作用于支气管平滑肌细胞来调节支气管扩张活动,从而用于治疗哮喘。
适用于本发明中的化合物和药用组合物包括其中以有效量给予哺乳动物所述有效成分以便达到其预定治疗目的的化合物和药用组合物。更准确地说,“治疗有效量”是指有效防止所治疗患者已有症状发展或者缓解该症状的剂量。特别是参照本发明所公开的细节,有效剂量的确定完全在本领域技术人员的知识范围内。
本文所用的术语“哺乳动物”包括雄性和雌性,并且包括人、家养动物(例如猫、狗)、家畜(例如牛、马、猪)和野生生物(例如灵长类、大型猫科动物、动物园动物)。
“治疗有效剂量”是指达到所需作用的所述化合物量。这类化合物的毒性和治疗效果可以通过细胞培养或者实验动物标准药学方法测定,例如测定LD50(50%群体致死的剂量)和ED50(50%群体有效治疗的剂量)。毒性和治疗效果之间的剂量比率为治疗指数,它表示为LD50和ED50的比值。优选高治疗指数的化合物。由这类数据得出的资料可以用于计算用于人的剂量范围。这类化合物的剂量优选在包括几乎没有或者没有毒性的ED50的循环浓度范围内。根据所使用的剂型和所用的给药途径,所述剂量可以在该范围内变化。
每个医生可以根据患者的病情选择准确的制剂、给药途径和剂量。可以个别调整剂量和间隔时间以便提供足以维持治疗效果的活性部分的血浆浓度。
本领域技术人员知道,本文所述的治疗可以延伸为预防以及治疗确诊的疾病或者症状。进而还知道,所需用于治疗的本发明化合物剂量根据所治疗病症的性质、患者的年龄和状况而变化,并且最终由主治医生或兽医决定。然而,一般来说用于成人治疗的常用剂量在每日0.001mg/kg至约100mg/kg的范围内。所需剂量可以方便地以单一剂量给予或以合适的间隔时间,以多剂量给予,例如每日两个、三个、四个或更多个亚剂量给予。在实践中,医生决定最适合于每个患者的实际给药方案,所述剂量根据具体患者的年龄、体重和反应而改变。以上剂量为一般情况下的典型实例,个别情况可能需要较高或较低的剂量,这也在本发明的范围内。
本发明的制剂可以以标准方式给药,以用于治疗所指定疾病,例如口服、胃肠外、粘膜(例如舌下或者口腔含化给药)、局部、经皮、直肠、通过吸入(例如鼻或者肺深部吸入)。胃肠外给药包括但不限于静脉内、动脉内、腹膜内、皮下、肌内、鞘内和关节内。胃肠外给药也可以使用高压技术象POWDERJECTTM完成。
对于口腔含化给药而言,所述组合物可以是以常规方式配制的片剂或者锭剂形式。例如,用于口服的片剂和胶囊剂可以含有常规的赋形剂例如粘合剂(例如糖浆、阿拉伯胶、明胶、山梨糖醇、西黄蓍胶、淀粉浆或者聚乙烯吡咯烷酮)、填充剂(例如乳糖、蔗糖、微晶纤维素、纤维素、玉米淀粉、磷酸钙或者山梨糖醇)、润滑剂(例如硬脂酸镁、硬脂酸、滑石粉、聚乙二醇或者二氧化硅)、崩解剂(例如马铃薯淀粉或者羟基乙酸淀粉钠)或者润湿剂(例如月桂基硫酸钠)。可以根据本领域熟知的方法将所述片剂包衣。
或者,本发明的化合物可以掺入口服液体制剂例如水性或者油性悬浮液、溶液、乳剂、糖浆或者酏剂中。而且,含有这些化合物的制剂可以以干燥产品提供,使用前用水或者其它合适的溶媒配制。这类液体制剂可以含有常规的添加剂,例如悬浮剂,如山梨糖醇糖浆、甲基纤维素、葡萄糖/糖浆、明胶、羟乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、硬脂酸铝凝胶和氢化食用脂肪;乳化剂,例如卵磷脂、脱水山梨糖醇单油酸酯或者阿拉伯胶;非水性溶媒(可以包括食用油),例如杏仁油、分级分离的椰子油、油性酯、丙二醇和乙醇;和防腐剂,例如对羟基苯甲酸甲酯或者丙酯和山梨酸。
这类制剂也可以配制为栓剂,例如含有常规的栓剂基质如可可脂或者其它甘油酯。用于吸入的组合物一般可以以溶液、悬浮液或者乳液的形式提供,它们可以以干粉或者以使用常规抛射剂(例如二氯二氟甲烷或者三氯氟甲烷)的气雾剂形式给予。典型的局部和经皮制剂含有常规水性或者非水性介质,例如滴眼剂、乳油、软膏、洗剂和糊剂或者为加药的膏药、贴剂或者膜剂形式。
此外,本发明的组合物可以配制用于经注射或者连续输注胃肠外给药。注射剂可以是在油性或者水性溶媒中的悬浮剂、溶液剂或者乳剂形式并且可以含有组方剂,例如悬浮剂、稳定剂和/或分散剂。或者,所述有效成分可以是粉末形式,使用前用合适的溶媒(例如无菌、无热原水)配制。
本发明的组合物也可以配制为储库型制剂。这类长效制剂可以植入给予(例如皮下或肌内)或者通过肌内注射给予。因此,本发明的化合物可以用合适的聚合物或者疏水物质(例如在可接受的油中的乳剂)、离子交换树脂或者微溶衍生物(例如微溶性盐)配制。
对于兽用而言,式(II)化合物或其无毒性盐根据常规兽医实践以合适的可接受制剂给予。兽医可以容易地确定最适合具体动物的给药方案和给药途径。
因此,另一方面,本发明提供含有式(II)化合物及其药学上可接受的稀释剂或载体的药用组合物。本发明进一步提供制备含有式(II)化合物的药用组合物的方法,该方法包括将式(II)化合物与其药学上可接受的稀释剂或载体混合。
以下提供结构式(II)化合物的具体非限制性实施例,其合成根据以下给出的方法进行。
一般而言,结构式(II)化合物可以根据以下合成方案制备。在下述方案中,本领域内知道,当需要时根据合成化学的一般原理可以使用保护基。这些保护基在合成的最终步骤中可以在本领域技术人员显而易见的碱性、酸性或者氢解条件下去除。通过对任何化学官能团使用合适的处理和保护,未在本文中专门提到的结构式(II)化合物的合成可以通过与以下给出的方案的类似方法完成。
除非另有说明,所有的原料均得自商业供应商,并且无需进一步纯化就可使用。所有反应物和层析流分通过在250mm硅胶板上的薄层层析分析,用UV(紫外)光或者I2(碘)染色显现。产物和中间体经快速层析或者反相HPLC纯化。
如以下所提出的合成方案可以制备通用结构式(II)化合物。其它的合成途径对于本领域技术人员也是已知的。以下反应方案提供结构式(II)化合物,其中R1和R2即C2H5和环戊基由原料所决定。适当选择其它原料或者对中间体和实例进行转化反应可提供具有其它所述R1-R11取代基的通用结构式(II)的化合物。
以下说明结构式(II)的不同中间体和化合物的合成方法。提供下列说明性的实施例,不应该解释为对本发明的限制。实施例1 (S)-4-(3-环氧基-4-甲氧基苯基)-3-甲基-3-[1-(甲基亚肼基)乙基]-吡咯 烷-1-羧酸甲酯(1a)和(R)-4-(3-环戊氧基-4-甲氧基苯基)-3-甲基-3-[1-(甲 基亚肼基)乙基]-吡咯烷-1-羧酸甲酯(1b)的制备
向(R)-3-乙酰基-4-(3-环戊氧基-4-甲氧基苯基)-3-甲基-吡咯烷-1-羧酸甲酯(参见Feldman等的美国专利第5,665,654号的实施例12(该专利通过引用结合到本文中))(或(R)-3-乙酰基-4-(3-环戊氧基-4-甲氧基苯基)-3-甲基-吡咯烷-1-羧酸甲酯)(0.133mmol,50mg)的含有催化量的乙酸(20μl)的甲醇(2ml)搅拌溶液中加入甲肼(0.147mmol,7.8μl)。将反应物温和加热36小时,然后再加入三份甲肼。所形成的腙经HPLC纯化。题述产物通过HNMR加以证实。1H MR(300MHz,CDCl3)δ(ppm):6.8(d,1H);6.68(m,2H);4.73(bm,1H);3.91-4.03(m,2H);3.83(s,3H);3.75(s,3H);3.47-3.69(m,2H);2.98(s,3H);1.83-1.92(bm,8H);1.6(bm,2H);1.0(s,3H)。
实施例2
向(3S,4R)-3-乙酰基-4-(3-环戊氧基-4-甲氧基苯基)-3-甲基-吡咯烷-1-羧酸甲酯(50mg,0.133mmol)的0.5ml乙醇溶液中加入羟胺盐酸盐(103mg,1.5mmol)和0.1ml水。将悬浮液加热至50℃并搅拌过夜。然后让该溶液冷却至室温并减压浓缩。使用50-100%乙腈-水(0.05%TFA)的梯度洗脱液,在C18柱(Luna10μ,C128,250×10mm)上经HPLC纯化,得到冻干后为白色粉末的产物2(a)(24.4mg,得率47%)。用相同的方法制备实例2(b)。1H NMR(300MHz,CDCl3)δ(ppm):6.84-6.76(m,1H,芳族);6.70-6.59(m,2H,芳族);4.87-4.57(m,1H);3.96-3.60(m,3H);3.83(s,3H,OCH3);3.75(s,3H,OCH3);3.59-3.45(m,1H);340-3.21(m,1H);1.92(s,3H,CH3);1.90-1.48(m,8H,环戊基);0.96(s,3H,CH3)。中间体1 3-(茚满-2-基氧基)-4-甲氧基-苯甲醛的制备
3-羟基-4-甲氧基-苯甲醛(15.2g,100mmol,1当量)、2-茚满醇(12.1g,90mmol,0.9当量)和三苯膦(26.2g,100mmol,1当量)的无水THF(300ml)溶液用滴加的偶氮二羧酸二异丙酯(19.6ml,100mmol,1当量)处理。将反应混合物在回流下搅拌16小时,然后冷却,用乙醚(500ml)稀释。该溶液用水(2×150ml)、1M NaOH(24×125ml)和饱和NaCl(氯化钠)(2×100ml)洗涤,用CH2Cl2干燥,然后浓缩,得到存放时会固化的浆状物。将该固体悬浮于乙醚(350ml)中并搅拌过夜,以使所有的厚块状物全部崩裂。通过真空过滤收集固体,将其用乙醇/水重结晶(21.4g)。浓缩乙醚滤液,经快速层析纯化(硅胶,7.5×36cmBiotage KP-Sil柱,用25%乙酸乙酯的庚烷溶液洗脱),又得到5g产物。1H NMR(300MHz,CDCl3)δ9.86(s,1H),7.49-7.44(m,2H),7.25-7.16(m,4H),6.97(d,J=8.7Hz,1H),5.29-5.22(m,1H),3.89(s,1H),3.45(dd,J=16.7,6.6Hz,2H),3.24(dd,J=16.7,3.6 Hz,2H)。13C NMR(75MHz,CDCl3)δ190.9,155.5,147.9,140.4,130.0,126.9,126.8,124.7,112.1,111.0,78.9,56.1,39.7。中间体2 (E)-4-[3-(茚满-2-基氧基)-4-甲氧基苯基]-3-甲基丁-3-烯-2-酮
将中间体1(0.14mol,1当量)和2-丁酮(50ml,0.56mol,4当量)的无水THF(50ml)溶液冷却至-4℃。将氯化氢气体通入充分搅拌的溶液几分钟,然后给反应混合物加盖,于-4℃贮存16小时。将混合物倾至充分搅拌的冰冷饱和NaHCO3(约2L)溶液中。如有必要,用饱和NaHCO3将pH调至>7,然后用乙酸乙酯(3×300ml)萃取该混合物。乙酸乙酯层用NaHCO3(2×200ml)、水(2×200ml)和饱和NaCl(2×200ml)洗涤,用CH2Cl2干燥,然后浓缩,得到浆状物。将该粗品混合物经快速层析纯化(硅胶,7.5×36cm Biotage KP-Sil柱,用25%乙酸乙酯的庚烷溶液洗脱),得到一种固体产物。1H NMR(300MHz,CDCl3)δ7.49-7.43(m,2H),7.26-7.15(m,5H),6.90(d,J=8.2Hz,1H),5.25-5.16(M,1H),3.85(s,3H),3.38(dd,J=16.7,6.5Hz,2H),3.25(dd,J=16.7,3.8Hz,2H),2.45(S,3H),2.10(d,J=1.1Hz)。中间体3 1-{(3SR,4RS)-1-苄基-4-[3-(茚满-2-基氧基)-4-甲氧基苯基]-3-甲基-吡 咯烷-3-基}-乙酮
(外消旋体)
将中间体2(50.6mmol,1当量)和N-甲氧基甲基-N-苄基-三甲基甲硅烷基甲胺(50.6mmol,1当量)的二氯甲烷(85ml)溶液在0℃下用滴加的三氟乙酸(在二氯甲烷中1M,5ml,5.1mmol,0.1当量)溶液处理。在相同温度下搅拌30分钟后,反应混合物在室温下搅拌16小时。将该溶液再用N-甲氧基甲基-N-苄基三甲基甲硅烷基甲胺(25.3mmol,0.5当量)处理,在室温下搅拌1小时,第三次用N-甲氧基甲基-N-苄基-三甲基甲硅烷基甲胺(25.3mmol,0.5当量)处理。浓缩反应混合物,将残余物溶于乙酸乙酯(500ml)中。该溶液用1N HCl(2×60ml,含有加入的10ml饱和NaCl)、水(250ml)、1M NaOH(250ml)、水(250ml)、饱和NaCl(2×100ml)洗涤,用CH2Cl2干燥,然后真空浓缩。将该残余物经快速层析纯化(硅胶,7.5×36cm Biotage KP-Sil柱,用5-10%乙醚的二氯甲烷溶液洗脱),得到所述产物。1H NMR(300MHz,CDCl3)δ7.38-7.16(m,9H),6.88(br s,1H),6.78(brs,2H),5.18-5.13(m,1H),3.82-3.73(m,2H),3.79(s,3H),3.60(d,J=13.0Hz,1H),3.41-3.17(m,4H),3.14(d,J=9.7Hz,1H),3.05(t,J=8.3Hz,1H),2.84(t,J=8.3Hz,1H),2.44(d,J=9.7Hz,1H),2.24(s,3H),0.86(s,3H)。中间体4 反式-(±)-3-乙酰基-4-[3-(茚满-2-基氧基)-4-甲氧基苯基]-3-甲基-吡咯 烷-1-羧酸甲酯
外消旋体
将中间体3(40.5mmol,1当量)的乙腈(150ml)溶液用氯甲酸甲酯(15.6ml,202.5mmol,5当量)处理,然后将混合物在回流下搅拌1小时。浓缩反应混合物,将该残余物经快速层析纯化(硅胶,7.5×36cmBiotage KP-Sil柱,用50-60%乙酸乙酯的庚烷溶液洗脱),得到所述产物。1H NMR(300MHz,CDCl3)δ7.24-7.16(m,4H),6.82(d,J=8.8 Hz,1H),6.75-6.72(m,2H),5.18-5.10(m,1H),3.91(t,J=11.2Hz,1H),3.80(s,3H),3.77-3.65(m,3H),3.74(s,3H),3.42-3.16(m,5H),2.17(d,J=6.8Hz,3H),1.04(s,3H)。13C NMR(75 MHz,CDCl3)δ210.1/209.9,155.3,149.4,146.9/146.8,140.5/140.4,130.5/130.0,126.7,124.7,121.3/121.1,116.1/115.8,111.9,79.2,58.2/57.4,55.9,54.7/54.2,52.6,50.2/50.0,48.5/48.1,39.7,26.6/26.5,17.8。实施例3
向中间体4(102.4mg,0.24mmol)的0.5ml乙醇溶液中加入羟胺盐酸盐(83.8mg,1.2mmol)和0.1ml水。将悬浮液加热至50℃并搅拌过夜。然后让该溶液冷却至室温并减压浓缩。使用50-100%乙腈-水(0.05%TFA)的梯度洗脱液,在C18柱(Luna 10μ,C18,250×10mm)上经HPLC纯化,得到固体产物(60mg,得率57%)。1H NMR(300MHz,CDCl3)δ(ppm):7.26-7.16(m,4H,芳族),6.83-6.77(m,1H,芳族),6.74-6.71(m,2H),5.14-5.11(m,1H),3.92-3.64(m,3H),3.80(s,3H,OCH3),3.74(s,3H,OCH3),3.58-3.48(m,1H),3.38-3.16(m,5H),1.92(s,3H,CH3),0.96(s,3H,CH3)。
测试了结构式(II)化合物抑制PDE4的能力。一种化合物抑制PDE4活性的能力与该化合物的IC50值即抑制50%酶活性所需的抑制剂浓度有关。使用重组人PDE4测定结构式(II)化合物的IC50值。
本发明化合物一般抑制重组人PDE4的IC50值为低于约50μM,优选低于约25μM,更优选低于约15μM。本发明化合物一般抑制重组人PDE4的IC50值为低于约1μM,通常低于约0.05μM。为充分体现本发明的优点,本发明的PDF4抑制剂的IC50为约1nM至约15μM。
由一般使用在浓度范围0.1pM-500μM的浓度-反应曲线,确定所述化合物的IC50值。使用如Loughney等,J. Biol.Chem.,271,第796-806页(1996)中所述的标准方法,针对其它PDE酶的试验也表明本发明的化合物对于cAMP特异性PDE4酶具有高度选择性。
也测试了结构式(II)化合物降低人外周血淋巴细胞分泌TNFα的能力。降低分泌TNFα的能力与EC50值(即能够抑制50%总TNFα的化合物有效浓度)有关
本发明化合物一般EC50值为低于约50μM,优选低于约25μM,更优选低于约15μM。本发明化合物的PBL/TNFαEC50值优选为低于约1μM,通常低于约0.05μM。为充分体现本发明的优点,本发明的PDE4抑制剂的EC50为约1nM至约500nM。
通过本领域众所周知的方法可以完成重组人PDE的制备以及IC50和EC50的测定。典型方法介绍如下:人PDE的表达在杆状病毒感染的草地贪夜蛾(Spodoptera fugiperda)(Sf9)细胞中的表 达
使用pBlueBacIII(Invitrogen)或者pFastBac(BRL-Gibco)构建杆状病毒转移质粒。通过跨越所述载体接点进行测序并且通过对经PCR产生的所有区进行完全测序,证实所有质粒的结构。质粒pBB-PDE1A3/6在pBlueBacIII中含有PDE1A3的完整可读框(Loughney等,J.Biol.Chem.,27l,第796-806页(1996))。质粒Hcam3aBB在pBlueBacIII中含有PDE1C3的完整可读框(Loughney等(1996))。质粒pBB-PDE3A在pBlueBacIII中含有PDE3A的完整可读框(Meacci等,Proc.Natl.Acad. Sci.,USA,89,第3721-3725页(1992))。
按照生产商的方案,使用MaxBac系统(Invitrogen)或者FastBac系统(Gibco-BRL)生产重组病毒原液。在这两种情况下,重组人PDE在所得病毒中的表达由病毒多角体启动子驱动。当使用MaxBac系统时,为了确保野生型(occ+)病毒不污染制剂,将病毒噬斑纯化两次。如下进行蛋白表达。让Sf9细胞在补充如下成分的Grace’s昆虫培养基(Gibco-BRL)中于27℃生长:10%胎牛血清、0.33% TCyeastolate、0.33%水解乳白蛋白、4.2mM碳酸氢钠、10μg/ml庆大霉素、100单位/ml青霉素和100μg/ml链霉素。以每个细胞大约2-3个病毒颗粒的感染复数感染指数生长细胞,然后孵育48小时。通过离心收集细胞,用无补充组分的Grace’s培养基洗涤并且快速冷冻保存。在酿酒酵母(Saccharomyces cerevisiae)(酵母)中的表达
人PDE1B、PDE2、PDE4A、PDE4B、PDE4C、PDE4D、PDE5和PDE7的重组产生类似于美国专利第5,702,936号的实施例7中所述进行(该专利通过引用结合到本文中),只是使用酵母转化载体,该酵母转化载体衍生自Price等,Methods in Enzymology,185,第308-318页(1990)介绍的基础ADH2质粒,该质粒中加入酵母ADH2启动子和终止子序列,所述酿酒酵母宿主为蛋白酶缺陷型菌株BJ2-54,BJ2-54于1998年8月31日保藏在美国典型培养物保藏中心(Manassas,Virginia),保藏号为ATCC 74465。使转化宿主细胞在2x SC-leu培养基(pH6.2,含有微量金属和维生素)中生长。24小时后,加入含有甘油的YEP培养基至终浓度为2x YET/3%甘油。约24小时后,收获细胞,洗涤并且于-70℃保存。人磷酸二酯酶制剂 磷酸二酯酶活性的测定
如下测定所述制剂的磷酸二酯酶活性。利用活性炭分离技术的PDE测定基本如Loughney等(1996)所述进行。在该测定中,PDE活性将[32P]cAMP或者[32P]cGMP转化为相应的[32P]5’-AMP或者[32P]5’-GMP与存在的PDE活性量成正比。然后,在蛇毒5’-核苷酸酶的作用下,[32P]5’-AMP或者[32P]5’-GMP被定量转化为游离的[32P]磷酸和未标记的腺苷或鸟苷。因此,释放的[32P]磷酸的量与酶活性成正比。该测定在100μl含有(终浓度)以下组分的反应混合物中于30℃下进行:40mM Tris HCl(pH8.0)、1μM硫酸锌、5mM氯化镁和0.1mg/ml牛血清白蛋白(BSA)。或者,在评估PDE1比活的测定中,孵育混合物还包括使用0.1mM氯化钙和10μg/ml钙调蛋白。PDE酶以产率<30%总底物水解的量存在(线性测试条件)。通过加入底物(1mM[32P]cAMP或cGMP),并将该混合物孵育12分钟,开始所述测试。然后加入75μg大响尾蛇(Crotalus atrox)毒液,继续孵育3分钟(总共15分钟)。通过加入200μl活性炭(在0.1 M磷酸二氢钠pH4中的25mg/ml悬浮液)终止反应。离心(750Xg,3分钟)沉淀所述活性炭后,取出上清液样品,在闪烁计数器中测定放射性,然后计算PDE活性。
类似于Loughney等,J. Biol.Chem.,271,第796-806页(1996)所述的方法进行抑制剂的分析,只是同时使用cGMP和cAMP,底物浓度保持在低于32nM,该值远低于被测PDE的Km。人PDE4A、4B、4C、4D制剂 用酿酒酵母制备PDE4A
通过与50ml裂解缓冲液(50mM MOPS pH7.5,10μM硫酸锌,2mM氯化镁,14.2mM2-巯基乙醇,各5μg/ml的抑胃酶肽、亮抑蛋白酶肽、抑蛋白酶肽,各20μg/ml的钙蛋白酶抑制剂I和II和2mM苯甲脒盐酸盐)混合,在室温下,解冻酵母细胞(50g带有HDUN1.46的酵母菌株YI26)。将细胞在弗氏(French)压碎器(SLM-Aminco,Spectronic Instruments)中于10℃裂解。用Beckman JA-10转子,将所述提取物于4℃以9,000rpm离心22分钟。取出上清液,用BeckmanTI45转子,于4℃以36,000rpm离心45分钟。
通过加入固体硫酸铵(0.26g/ml上清液),同时在冰浴中搅拌并且维持pH在7.0-7.5之间,从高速上清液沉淀PDE4A。通过用BeckmanJA-10转子以9,000rpm离心22分钟,收集含有PDE4A的沉淀蛋白。将所述沉淀物重悬于50ml缓冲液G(50mM MOPS pH7.5,10μM硫酸锌,5mM氯化镁,100mM氯化钠,14.2mM 2-巯基乙醇,2mM苯甲脒盐酸盐,各5μg/ml的亮抑蛋白酶肽、抑胃酶肽和抑蛋白酶肽,以及各20μg/ml的钙蛋白酶抑制剂I和II)中,然后通过0.45μm滤膜。
将所述重悬浮样品(50-100ml)上样到在缓冲液G中平衡的5×100cm Pharmacia SEPHACRYLS-300柱中。以流速2ml/min洗脱酶活性并将其合并,以供稍后的分级分离用。
将经凝胶过滤层析分离的PDE4A上样到在缓冲液A(50mMMOPS pH7.5,10μM硫酸锌,5mM氯化镁,14.2mM2-巯基乙醇和100mM苯甲脒盐酸盐)中平衡的1.6×20cm Sigma Cibacron BlueAgarose-300型柱(10ml)中。依次用50-100ml缓冲液A、20-30ml含有20mM 5’-AMP的缓冲液A、50-100ml含有1.5M氯化钠的缓冲液A和10-20ml缓冲液C(50mM Tris HCl pH8,10μM硫酸锌、14.2mM2-巯基乙醇和2mM苯甲脒盐酸盐)洗涤所述柱子。用20-30ml含有20mM cAMP的缓冲液C洗脱所述酶。
合并PDE活性峰,用硫酸铵(0.33g/ml酶合并液)沉淀,以便去除过量的环核苷酸。将沉淀蛋白重悬于缓冲液X(25mM MOPS pH7.5,5μM硫酸锌,50mM氯化钠,1mM DTT和1mM苯甲脒盐酸盐)中,按照生产商的说明,通过在Pharmacia PD-10柱上凝胶过滤将其脱盐。将所述酶在干冰/乙醇浴中快速冷冻,然后于-70℃保存。
通过SDS-PAGE,所得制剂的纯度约>80%。这些制剂水解cAMP的比活约10-40μmol cAMP/每分钟/毫克蛋白。用酿酒酵母制备PDE4B
在室温下,通过与100ml玻璃珠(0.5mM,酸洗)和150ml裂解缓冲液(50mM MOPS pH7.2,2mM EDTA,2mM EGTA,1mMDTT,2mM苯甲脒盐酸盐、各5μg/ml的抑胃酶肽、亮抑蛋白酶肽、抑蛋白酶肽、钙蛋白酶抑制剂I和II)混合,解冻酵母细胞(150g带有HDUN2.32的酵母菌株YI23)。将所述混合物冷却至4℃,转移到Bead-Beater中,快速混合6个循环(每个循环30秒)使所述细胞裂解。在Beckman J2-21M离心机中,使用JA-10转子,将所述匀浆于4℃以9,000rpm离心22分钟。回收上清液,并且在Beckman XL-80超速离心机中,使用TI45转子,将其于4℃以36,000rpm离心45分钟。回收上清液并且通过加入固体硫酸铵(0.26g/ml上清液),同时在冰浴中搅拌并且维持pH在7.0-7.5的范围内,沉淀PDE4B。然后,在Beckman J2离心机中,使用JA-10转子,将该混合物以9,000rpm(12,000Xg)离心22分钟。弃去上清液,将沉淀溶于200ml缓冲液A(50mM MOPS pH7.5,5mM氯化镁,1mM DTT,1mM苯甲脒盐酸盐,以及各5μg/ml的亮抑蛋白酶肽、抑胃酶肽和抑蛋白酶肽)中。将pH和电导率分别校正为7.5和15-20mS。
将所述重悬浮样品上样到在缓冲液A中平衡的1.6×200cmSigma Cibacron Blue Agarose-300型柱(25ml)中。将所述样品在12个小时内循环通过所述柱4-6次。依次用125-250ml缓冲液A、125-250ml含有1.5M氯化钠的缓冲液A和25-50ml缓冲液A洗涤所述柱子。用50-75ml缓冲液E(50mM Tris HCl pH8,2mM EDTA,2mMEGTA,1mM DTT,2mM苯甲脒盐酸盐和20mM cAMP)和50-75ml含有1M氯化钠的缓冲液E洗脱所述酶。合并PDE活性峰,用硫酸铵(0.4g/ml酶合并液)沉淀,以便去除过量的环核苷酸。将沉淀蛋白重悬于缓冲液X(25mM MOPS pH7.5,5μM硫酸锌,50mM氯化钠,1mM DTT和1mM苯甲脒盐酸盐)中,并且按照生产商的说明,通过在Pharmacia PD-10柱上凝胶过滤将其脱盐。将该酶合并液对含有50%甘油的缓冲液X透析过夜。将所述酶在干冰/乙醇浴中快速冷冻,然后于-70℃保存。
通过SDS-PAGE,所得制剂的纯度约>90%。这些制剂水解cAMP的比活约10-50μmol cAMP/每分钟/毫克蛋白。用酿酒酵母制备PDE4C
在室温下,通过与100ml玻璃珠(0.5mM,酸洗)和150ml裂解缓冲液(50mM MOPS pH7.2,2mM EDTA,2mM EGTA,1mMDTT,2mM苯甲脒盐酸盐,各5μg/ml的抑胃酶肽、亮抑蛋白酶肽、抑蛋白酶肽、钙蛋白酶抑制剂I和II)混合,解冻酵母细胞(150g带有HDUN3.48的酵母菌株YI30)。将所述混合物冷却至4℃,转移到BEAD-BEATER中并且快速混合6个循环(每个循环30秒)使所述细胞裂解。在Beckman J2-21M离心机中,使用JA-10转子,将所述匀浆于4℃以9,000rpm离心22分钟。回收上清液,并且在BeckmanXL-80超速离心机中,使用TI45转子,将其于4℃以36,000rpm离心45分钟。
回收上清液,通过加入固体硫酸铵(0.26g/ml上清液),同时在冰浴中搅拌并且维持pH在7.0-7.5的范围内,沉淀PDE4C。30分钟后,在Beckman J2离心机中,使用JA-10转子,将该混合物以9,000rpm(12,000Xg)离心22分钟。弃去上清液,将沉淀溶于200ml缓冲液A(50mM MOPS pH7.5,5mM氯化镁,1mM DTT,2mM苯甲脒盐酸盐,以及各5μg/ml的亮抑蛋白酶肽、抑胃酶肽和抑蛋白酶肽)中。将pH和电导率分别校正为7.5和15-20mS。
将所述重悬浮样品上样到在缓冲液A中平衡的1.6×20cm SigmaCibacron Blue Agarose-300型柱(25ml)中。将所述样品在12个小时内循环通过所述柱4-6次。依次用125-250ml缓冲液A、125-250ml含有1.5M氯化钠的缓冲液A和25-50ml缓冲液A洗涤所述柱子。用50-75ml缓冲液E(50mM Tris HCl pH8,2mM EDTA,2mM EGTA,1mM DTT,2mM苯甲脒盐酸盐和20mM cAMP)和50-75ml含有1M氯化钠的缓冲液E洗脱所述酶。合并PDE4C活性峰,用硫酸铵(0.4g/ml酶合并液)沉淀,以便去除过量的环核苷酸。将沉淀蛋白重悬于缓冲液X(25mM MOPS pH7.2,5μM硫酸锌,50mM氯化钠,1mM DTT和1mM苯甲脒盐酸盐)中,并且按照生产商的说明,经在PharmaciaPD-10柱上凝胶过滤将其脱盐。将该酶合并液对含有50%甘油的缓冲液X透析过夜。将所述酶在干冰/乙醇浴中快速冷冻,然后于-70℃保存。
通过SDS-PAGE,所得制剂的纯度约>80%。这些制剂水解cAMP的比活约10-20μmol cAMP/每分钟/毫克蛋白。用酿酒酵母制备PDE4D
在室温下,通过与150ml玻璃珠(0.5mM,酸洗)和150ml裂解缓冲液(50mM MOPS pH7.2,10μM硫酸锌,2mM氯化镁,14.2mM2-巯基乙醇,2mM苯甲脒盐酸盐,各5μg/ml的抑胃酶肽、亮抑蛋白酶肽、抑蛋白酶肽、钙蛋白酶抑制剂I和II)混合,解冻酵母细胞(100g带有HDUN4.11的酵母菌株YI29)。将所述混合物冷却至4℃,转移到Bead-Beater中并且快速混合6个循环(每个循环30秒)使所述细胞裂解。在Beckman J2-21M离心机中,使用JA-10转子,将所述匀浆于4℃以9,000rpm离心22分钟。回收上清液,在Beckman XL-80超速离心机中,使用TI45转子,将其于4℃以36,000rpm离心45分钟。回收上清液,通过加入固体硫酸铵(0.33g/ml上清液),同时在冰浴中搅拌并且维持pH在7.0-7.5的范围内,沉淀PDE4D。30分钟后,在Beckman J2离心机中,使用JA-10转子,将该混合物以9,000rpm(12,000Xg)离心22分钟。弃去上清液,将沉淀溶于100ml缓冲液A(50mM MOPS pH7.5,10μM硫酸锌,5mM氯化镁,14.2mM 2-巯基乙醇,100mM苯甲脒盐酸盐,以及各5μg/ml的亮抑蛋白酶肽、抑胃酶肽、抑蛋白酶肽、钙蛋白酶抑制剂I和II)中。将pH和电导率分别校正为7.5和15-20mS。
以流速0.67ml/min,将所述重悬浮样品上样到在缓冲液A中平衡的1.6×20cm Sigma Cibacron Blue Agarose-300型柱(10ml)中。依次用50-100ml缓冲液A、20-30ml含有20mM 5’-AMP的缓冲液A、50-100ml含有1.5M氯化钠的缓冲液A和10-20ml缓冲液C(50mMTris HCl pH8,10μM硫酸锌,14.2mM2-巯基乙醇,2mM苯甲脒盐酸盐)洗涤所述柱子。用20-30ml含有20mM cAMP的缓冲液C洗脱所述酶。
合并PDE4D活性峰,用硫酸铵(0.4g/ml酶合并液)沉淀,以便去除过量的环核苷酸。将沉淀蛋白重悬于缓冲液X(25mM MOPS pH7.2,5μM硫酸锌,50mM氯化钠,1mM DTT和1mM苯甲脒盐酸盐)中,并且按照生产商的说明,通过在Pharmacia PD-10柱上凝胶过滤将其脱盐。将该酶合并液对含有50%甘油的缓冲液X透析过夜。将所述酶的制剂在干冰/乙醇浴中快速冷冻,然后于-70℃保存。
通过SDS-PAGE,所得制剂的纯度约>80%。该制剂水解cAMP的比活约20-50μmol cAMP/每分钟/毫克蛋白。脂多糖刺激人外周血淋巴细胞释放TNFα
为了评价化合物降低人外周血淋巴细胞(PBL)分泌TNFα的能力,进行以下试验。先前的研究已经证明,人PBL与cAMP升高的因子(例如前列腺素E21、毛喉素、8-溴-cAMP或二丁基-cAMP)一起孵育,当用脂多糖(LPS,内毒素)时抑制所述细胞分泌TNFα。因此,已进行的初步实验已证明,选择性PDE4抑制剂(例如咯利普兰)以依赖于剂量的方式抑制LPS诱导的人淋巴细胞分泌TNFα。因此,应用人PBL TNFα分泌量作为化合物升高细胞内cAMP浓度和/或抑制细胞内PDE4活性的能力的标准。
将取自人自愿者的肝素化血液(约30ml)以1∶1与Dulbecco氏改进磷酸缓冲盐水混合。将该混合物以1∶1与HISTOPAQUE混合,然后在Beckman TJ6型离心机的吊桶中,在室温下无需制动以1,500rpm离心。红细胞离心后位于试管底部,血清保留在试管的表面。含有淋巴细胞的一层沉降在血清层和HISTOPAQUE层之间,通过抽吸将其取出,置于一支新试管中。将该细胞定量并调至3×106细胞/ml,然后将100μl等份样品加到96孔板的各孔中。在加入细菌LPS(25mg/ml)前15分钟,将试验化合物和RPMI培养基(Gibco/BRL LifeSciences)加到各种孔中。让混合物在湿润室中于37℃孵育20小时。然后在室温下通过以800rpm离心5分钟分离细胞。将180μl等份上清液转移到一个新的板上,用于测定TNFα的浓度。采用市售的酶联免疫测定(ELISA)(CYTOSCREEN免疫测定试剂盒,BiosourceInternational),测定细胞上清液中的TNFα蛋白。
基于细胞的测定提供了以下本发明的各种吡咯烷化合物的结果。EC50值(即能够抑制50%总TNFα的化合物有效浓度)说明本发明化合物抑制人PBL释放LPS刺激性TNFα的能力。
下表说明了式(II)化合物抑制体外PDE4活性和释放TNFα的能力。在下表中,确定抑制人重组PDE4的IC50值。
实例编号 | PDE4IC50(M×10-9) | PBL/TNFαEC50(M×10-9) |
1a | 115.9 | 76.0 |
1b | 2.2 | 2.2 |
2a | 49.0 | 281.0 |
2b | 2.2 | 23.0 |
3 | 189.3 | 551.0 |
上述数据说明,本发明化合物为有效的PDE4抑制剂,例如所述化合物对人重组PDE4的IC50为约1nM至约15μM。优选化合物的IC50为约50nM或以下,特别优选化合物的IC50为约25nM或以下。
同样,优选的化合物的PBL/TNFαEC50为约1000nM或以下,最好是500nM或以下。更优选的化合物的PBL/TNFαEC50为约100nM或以下。
为充分体现本发明的优点,所述化合物对人重组PDE4的IC50为约50nM或以下,PBL/TNFαEC50为约1000nM或以下。更优选的是,所述化合物的IC50为约25nM或以下,PBL/TNFαEC50为约500nM或以下。动物模型 内毒素刺激性小鼠释放TNFα和运动能力联合测定
该项研究的目的是为了测定PDE4抑制剂在LPS小鼠模型中的体内作用,以及测定表现为固有运动能力减少的中枢神经系统(CNS)副作用。
试验动物为雌性Balb/c小鼠,平均体重约20g。以剂量为0.1mg/kg、1.0mg/kg、10.0mg/kg和100mg/kg,通过腹膜内(i.p.)注射给予配制在30% CremophorEL中的PDE4抑制剂。根据所测量的体重,调整各种剂量体积(约150μl)。1小时后,将5mg/kgLPS(终体积200μl)通过尾静脉注射到每只动物体内。LPS处理后90分钟,将动物放血,收集血清样品,然后于-70℃贮存待用于测定。
对于效果测定,将该血清样品稀释2倍,采用CYTOSCREEN免疫测定试剂盒(Biosource International),测定TNFα水平。每种试验化合物有三个复份,数据为三个复份样品的平均值。
X-Y平面的运动或后腿直立(rearing up on the hind legs)次数通过对每单位时间内“光束”交叉次数进行计数来对其定量。活动事件次数的减少与该动物的运动能力或不活动成正比。定量计分与上述客观测量有很好的相关性。
下表概述了通过上述方法获得的运动能力测定(运动性,%活动)结果:
1)比对照固有运动能力减少50%的有效剂量(mg/kg)。
实例编号 | 运动能力(50mg/kg剂量时的%活动)或ED50(50mg/kg) |
1a | 64%活动 |
1b | 6%活动 |
2a | ED50 1)(mg/kg)>50mg/kg |
2b | ED50(mg/kg)=7mg/kg |
还与咯利普兰和Feldman等的美国专利号5,665,754中公开的化合物相比,确定式(II)化合物具有较少的中枢神经系统副作用。还发现中枢神经系统副作用活性与本发明化合物的绝对立体化学有关。
以上总结的结果表明,本发明的化合物可用于选择性地抑制哺乳动物体内的PDE4活性,而没有与在先PDE4抑制剂有关的不利的中枢神经系统作用和催吐作用。
显然,在不偏离本发明的精神和范围的情况下,可以对本文以上提出的本发明内容作各种修改和变化,因此,本发明只受所附权利要求书的限制。
Claims (38)
1.一种具有以下结构式的化合物,
其中Y为OR5或NR5R6;
R1为低级烷基、桥连烷基、芳烷基、环烷基、5-或6-元饱和杂环基、C1-3亚烷基环烷基、芳基-或杂芳基-取代的炔丙基、芳基-或杂芳基-取代的烯丙基或卤代环烷基;
R2为氢、甲基或卤基取代的甲基;
R3选自C(=O)OR7、C(=O)R7、C(=NH)NR8R9、C(=O)NR8R9、芳基或杂芳基;
R4为氢、低级烷基、卤代烷基、环烷基或芳基;
R5和R6独立为氢、低级烷基、卤代烷基、环烷基、芳基、杂芳基或烷芳基,或者R5和R6一起形成5-元环或6-元环;
R7为支链或直链低级烷基或芳基,并且R7可以任选用一个或多个RO8、NR8R9或SR8取代;
R8和R9相同或不同,它们选自氢、低级烷基、环烷基、芳基、杂芳基和芳烷基,或者R8和R9一起形成4-元至7-元环;
R10为氢、烷基、卤代烷基、环烷基、芳基、C(=O)烷基、C(=O)环烷基、C(=O)芳基、C(=O)O烷基、C(=O)O环烷基、C(=O)芳基、CH2OH、CH2O烷基、CHO、CN、NO2或SO2R11;
R11为烷基、环烷基、三氟甲基、芳基、芳烷基或NR8R9。
5.权利要求1的化合物,其中R4选自氢、甲基、三氟甲基、环丙基、苄基和苯基。
6.权利要求1的化合物,其中R5和R6独立为氢或低级烷基。
7.权利要求1的化合物,其中R7为低级烷基。
8.权利要求1的化合物,其中R8和R9独立为氢或低级烷基,或者R8和R9一起形成5-元环或6-元环。
11.权利要求1的化合物,所述化合物对人重组PDE4的IC50为约1nM至约15μM。
12.权利要求1的化合物,所述化合物的PBL/TNFαEC50为约1nM至约20μM。
13.权利要求1的化合物,所述化合物对人重组PDE4的IC50为约1nM至约15μM,PBL/TNFαEC50为约1nM至约25μM。
14.权利要求1的化合物,所述化合物对人重组PDE4的IC50为100×10-6M或100×10-6M以下。
15.权利要求1的化合物,所述化合物对人重组PDE4的IC50为50×10-6M或50×10-6M以下。
16.一种药用组合物,它包含权利要求1的化合物、药学上可接受的载体和任选的第二种抗炎治疗药物。
17.权利要求16的组合物,其中所述第二种抗炎治疗药物能够靶向TNFα。
18.一种治疗患有抑制cAMP特异性PDE具有治疗益处的病症的哺乳动物的方法,所述方法包括给予所述哺乳动物治疗有效量的权利要求1化合物。
19.一种调节哺乳动物体内cAMP水平的方法,所述方法包括给予所述哺乳动物有效量的权利要求1化合物。
20.一种治疗患有抑制cAMP特异性PDE具有治疗益处的病症的哺乳动物的方法,所述方法包括给予所述哺乳动物有效量的包含权利要求1化合物和药学上可接受的载体的药用组合物。
21.权利要求20的方法,其中所述病症是变应性疾病、自身免疫病、炎性疾病、关节疾病或皮炎。
22.权利要求20的方法,其中所述病症是类风湿性关节炎、骨关节炎、痛风性关节炎或脊椎炎。
23.权利要求20的方法,其中所述病症是甲状腺相关性眼病、贝切特氏病、脓毒病、败血症性休克、内毒素性休克、革兰氏阴性脓毒病、革兰氏阳性脓毒病、中毒性休克综合征、过敏性结膜炎、春季结膜炎或嗜曙红细胞肉芽肿。
24.权利要求20的方法,其中所述病症是哮喘、慢性支气管炎、过敏性鼻炎、成人呼吸窘迫综合征、慢性肺部炎性疾病、慢性阻塞性肺部疾病、硅肺和肺结节病。
25.权利要求20的方法,其中所述病症是心肌、脑或肢端的再灌注损伤、由于外伤引起的脑或脊髓损伤。
26.权利要求20的方法,其中所述病症是纤维变性、瘢痕疙瘩形成或疤痕组织形成。
27.权利要求20的方法,其中所述病症是系统性红斑狼疮、移植排斥性病症、移植物抗宿主反应或同种异体移植排斥。
28.权利要求20的方法,其中所述病症是慢性肾小球肾炎、炎性肠病、节段性回肠炎或溃疡性结肠炎。
29.权利要求20的方法,其中所述病症是增生性淋巴细胞疾病或白血病。
30.权利要求20的方法,其中所述病症是炎性皮肤病、特应性皮炎、牛皮癣或荨麻疹。
31.权利要求20的方法,其中所述病症是心肌病、充血性心力衰竭、动脉粥样硬化、发热、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继发性恶病质、ARC、脑型疟、骨质疏松、骨吸收疾病、由于感染引起的发烧和肌痛、勃起机能障碍、尿崩症、中枢神经系统疾病、抑郁症、多发梗塞性痴呆、焦虑症或应激反应、脑缺血、迟发性运动障碍、帕金森氏病或经前综合征。
33.权利要求20的方法,其中所述哺乳动物表现出最小催吐反应。
34.权利要求20的方法,其中所述哺乳动物没有催吐反应。
35.权利要求20的方法,其中所述哺乳动物表现出最小的不利中枢神经系统副作用。
36.权利要求20的方法,其中所述哺乳动物没有不利的中枢神经系统副作用。
37.一种降低哺乳动物体内TNF水平的方法,所述方法包括给予所述哺乳动物治疗有效量的权利要求1化合物。
38.一种抑制哺乳动物体内炎性细胞激活的方法,所述方法包括给予所述哺乳动物治疗有效量的权利要求1化合物。
37.一种抑制哺乳动物体内PDE4功能的方法,所述方法包括给予所述哺乳动物治疗有效量的权利要求1化合物。
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US17195599P | 1999-12-23 | 1999-12-23 | |
US60/171,955 | 1999-12-23 |
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EP (1) | EP1242371A1 (zh) |
JP (1) | JP2003518090A (zh) |
CN (1) | CN1434797A (zh) |
AU (1) | AU778717B2 (zh) |
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WO (1) | WO2001046136A1 (zh) |
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WO2021218992A1 (zh) * | 2020-04-29 | 2021-11-04 | 东莞市东阳光新药研发有限公司 | 取代的吡咯烷类化合物及其在药物中的应用 |
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US6348602B1 (en) * | 1999-12-23 | 2002-02-19 | Icos Corporation | Cyclic AMP-specific phosphodiesterase inhibitors |
US20040014099A1 (en) * | 2001-03-19 | 2004-01-22 | Decode Genetics Ehf. | Susceptibility gene for human stroke; methods of treatment |
KR20040007583A (ko) * | 2001-05-23 | 2004-01-24 | 다나베 세이야꾸 가부시키가이샤 | 연골 질환의 재생치료용 조성물 |
MXPA03010679A (es) * | 2001-05-23 | 2004-03-02 | Tanabe Seiyaku Co | Una composicion para acelerar la cicatrizacion de fractura osea. |
MY140561A (en) * | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
SE0200667D0 (sv) * | 2002-03-05 | 2002-03-05 | A & Science Invest Ab | Novel use of cytokine inhibitors |
EA009985B1 (ru) | 2003-03-10 | 2008-04-28 | Никомед Гмбх | Новый способ получения рофлумиласта |
JP2006522594A (ja) * | 2003-04-10 | 2006-10-05 | デコデ ジェネティックス イーエイチエフ. | アテローム性動脈硬化症に対する薬剤のスクリーニングにおけるpde4dの使用方法 |
WO2005026132A1 (ja) * | 2003-09-17 | 2005-03-24 | Nippon Shinyaku Co., Ltd. | ホスホジエステラーゼのcAMP基質特異的阻害剤 |
CA2601250C (en) * | 2005-03-16 | 2014-10-28 | Nycomed Gmbh | Taste masked dosage form containing roflumilast |
JP2009506069A (ja) | 2005-08-26 | 2009-02-12 | ブレインセルス,インコーポレイティド | ムスカリン性受容体調節による神経発生 |
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EP1940810A2 (en) * | 2005-10-19 | 2008-07-09 | Ranbaxy Laboratories Limited | Inhibitors of phosphodiesterase type-iv |
AU2006304787A1 (en) | 2005-10-21 | 2007-04-26 | Braincells, Inc. | Modulation of neurogenesis by PDE inhibition |
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AU2007223036A1 (en) * | 2006-03-08 | 2007-09-13 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
US20100009983A1 (en) * | 2006-05-09 | 2010-01-14 | Braincells, Inc. | 5 ht receptor mediated neurogenesis |
EP2377531A2 (en) | 2006-05-09 | 2011-10-19 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
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US7998971B2 (en) * | 2006-09-08 | 2011-08-16 | Braincells Inc. | Combinations containing a 4-acylaminopyridine derivative |
US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
EP2066355A2 (en) * | 2006-09-19 | 2009-06-10 | Braincells, Inc. | Combination comprising a peroxisome proliferator activated receptor agent and a second neurogenic agent for treating a nervous system disorder, increasing neurodifferentiation and increasing neurogenesis |
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WO2009105647A1 (en) * | 2008-02-21 | 2009-08-27 | Janssen Pharmaceutica N.V. | Methods for the treatment of dermatological disorders |
US20100216805A1 (en) | 2009-02-25 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
EP2804603A1 (en) | 2012-01-10 | 2014-11-26 | President and Fellows of Harvard College | Beta-cell replication promoting compounds and methods of their use |
CN112220785B (zh) * | 2020-09-22 | 2021-12-31 | 北京鑫开元医药科技有限公司 | 一种pde4抑制剂药物组合物及其制备方法与用途 |
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PT100441A (pt) | 1991-05-02 | 1993-09-30 | Smithkline Beecham Corp | Pirrolidinonas, seu processo de preparacao, composicoes farmaceuticas que as contem e uso |
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US6348602B1 (en) * | 1999-12-23 | 2002-02-19 | Icos Corporation | Cyclic AMP-specific phosphodiesterase inhibitors |
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WO2021218992A1 (zh) * | 2020-04-29 | 2021-11-04 | 东莞市东阳光新药研发有限公司 | 取代的吡咯烷类化合物及其在药物中的应用 |
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WO2001046136A1 (en) | 2001-06-28 |
US20020065302A1 (en) | 2002-05-30 |
EP1242371A1 (en) | 2002-09-25 |
AU778717B2 (en) | 2004-12-16 |
CA2395202A1 (en) | 2001-06-28 |
AU4137001A (en) | 2001-07-03 |
US6500856B2 (en) | 2002-12-31 |
JP2003518090A (ja) | 2003-06-03 |
US6348602B1 (en) | 2002-02-19 |
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