CN1484644A - 新的7-氮杂吲哚、其作为磷酸二酯酶4的抑制剂的应用和其制备方法 - Google Patents
新的7-氮杂吲哚、其作为磷酸二酯酶4的抑制剂的应用和其制备方法 Download PDFInfo
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- CN1484644A CN1484644A CNA018215351A CN01821535A CN1484644A CN 1484644 A CN1484644 A CN 1484644A CN A018215351 A CNA018215351 A CN A018215351A CN 01821535 A CN01821535 A CN 01821535A CN 1484644 A CN1484644 A CN 1484644A
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- azaindole
- alkyl
- compound
- aryl
- dichloropyridine
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Abstract
本发明涉及新的7-氮杂吲哚化合物,其作为磷酸二酯酶4抑制剂的应用,及其制备方法。
Description
技术领域
本发明涉及通式1取代的7-氮杂吲哚化合物,
其合成方法,含有这些化合物的药物制剂,以及这些化合物的药物应用,所述化合物是磷酸二酯酶4的抑制剂,可作为活性组分用于治疗可通过用本发明化合物抑制免疫活性细胞(例如巨噬细胞和淋巴细胞)中的磷酸二酯酶4的活性来影响的疾病。
现有技术
递质激活细胞膜的受体会导致“第二信使”系统的激活。腺苷酸环化酶由AMP和GMP合成活性环AMP(cAMP)或环GMP(cGMP)。这导致例如平滑肌细胞松弛或炎性细胞中的介质的释放或合成受到抑制。磷酸二酯酶(PDE)打破“第二信使”cAMP和cGMP。迄今为止已知有11个PDE酶家族(PDE1-PDE11),它们的不同在于其底物特异性(cAMP、cGMP或二者)及其对其它底物的依赖性(例如钙调蛋白)。这些同工酶在体内具有不同功能,并且在个体类型细胞中有不同表现(Beavo J.A.,M.Conti和R.J.Heaslip,多样的环核苷酸磷酸二酯酶.Mol.Pharmacol.1994,46:399-405;Hall I.P.,同工酶选择性磷酸二酯酶抑制剂:可能的临床应用,Br.J.clin.Pharmacol.1993,35:1-7)。抑制不同类型的PDE同工酶导致cAMP和/或cGMP在细胞中聚集,这可用于治疗(Torphy TJ.,G.P.Livi,Christensen,用于治疗哮喘的新的磷酸二酯酶抑制剂,Drug News and Perspectives 1993,6:203-214)。
在对于过敏炎症很重要的细胞中(淋巴细胞、肥大细胞、嗜酸性粒细胞、巨噬细胞),主要的PDE同工酶是4型(Torphy,J.T.和Undem B.J.,磷酸二酯酶抑制剂:治疗哮喘的新选择.Thorax 1991,46:512-523)。因此,用合适的抑制剂抑制PDE4视为治疗多种变态反应引起的疾病的重要开始(Schudt Ch.,Dent G.和Rabe K.,磷酸二酯酶抑制剂,Academic Press London 1996)。
磷酸二酯酶4抑制剂的一个重要特征是抑制肿瘤坏死因子α(TNFα)从炎性细胞中释放。TNFα是影响多种生物过程的重要的促炎性细胞因子。TNFα从例如激活的巨噬细胞、激活的T淋巴细胞、肥大细胞、嗜碱粒细胞、成纤维细胞、内皮细胞和脑中的星形细胞释放。其自身对于中性白细胞、嗜酸性细胞、成纤维细胞和内皮细胞有激活作用,结果释放出不同的组织破坏性介质。在单核细胞、巨噬细胞和T淋巴细胞中,TNFα导致另外的促炎性细胞因子例如GM-CSF(粒细胞-巨噬细胞集落刺激因子)或白介素-8的生成增加。由于其促进炎症和分解代谢作用,TNFα在多种疾病中起着关键作用,这些疾病有例如呼吸道炎症、关节炎症、内毒素性休克、组织排斥、AIDS和多种其它免疫疾病。因此,磷酸二酯酶4抑制剂也适于治疗与TNFα有关的这样的疾病。
慢性堵塞性肺病(COPD)广布于人群中。例如,在发达国家中,COPD疾病占所有疾病花费的大约10-15%,在美国,有约25%的死亡是由该疾病引起的(Norman P.:COPD:新的发展和治疗机会,DrugNews Perspect.11(7),431-437,1998);然而,在死亡时,大多数患者的年龄大于55岁(Nolte,D.:慢性支气管炎-一种多因素起源全民性疾病.Atemw.-Lungenkrkh.20(5),260-267,1994)。据WHP估计,在未来20年中,COPD将成为第三大死因。
慢性堵塞性肺病(COPD)的合并了慢性支气管炎的不同综合征与排痰性咳嗽以及进行性和不可逆肺功能退化(特别是呼气受影响)的症状。该疾病的病程是发作性的,并且通常并发有细菌感染(Rennard S.I.:COPD:定义的概述,流行病学,以及影响其发展的因素.Chest,113(4)Suppl.,235S-241 S,1998)。在该疾病的病程中,肺功能稳定地降低,肺逐渐变得气肿,并且患者的呼吸窘迫很明显。该疾病明显损害患者的生命质量(呼吸浅促、锻炼耐力低),并显著缩短其估计寿命。除了环境因素以外,主要的危险因素是吸烟(Kummer F.:哮喘和COPD.Atemw.-Lungenkrkh.20(5),299-302,1994;Rennard S.I.:COPD:定义的概述,流行病学,以及影响其发展的因素.Chest,113(4)Suppl.,235S-241S,1998),并且男性患病的比例比女性高。在将来,由于习惯的改变以及女性吸烟者的不断增多,这种现象将会改变。
目前治疗的目标仅是减轻症状,而不是介入该疾病进行的原因。使用可与毒蕈碱拮抗剂(例如异丙阿托品)联合使用的长效β2激动剂(例如沙美特罗)能通过扩张支气管来改善肺功能,并且可日常使用(NormanP.:COPD:新的发展和治疗机会,Drug News Perspect.11(7),431-437,1998)。必须用抗生素治疗的细菌感染在COPD发作中起关键作用(Wilson R.:感染在COPD中的作用,Chest,113(4)Suppl.,242S-248S,1998;Grossman R.F.:抗生素的价值以及抗生素治疗加重COPD的结果.Chest,113(4)Suppl.,249S-255S,1998)。该疾病的治疗仍然不能令人满意,特别是在肺功能连续降低方面更是如此。攻击炎性介质、蛋白酶或粘着分子的新的治疗方法可能非常有前途(Barnes P.J.:慢性堵塞性疾病:药物开发的新机会,TiPS 10(19),415-423,1998),
在支气管中发现了通过嗜中性粒细胞支配的慢性炎症,其独立于与该疾病并发的细菌感染。除了别的之外,由嗜中性粒细胞释放的介质和酶是在呼吸道中观察到的结构性变化(肺气肿)的原因。因此,抑制嗜中性粒细胞的活动是预防或延迟COPD进行(肺功能参数退化)的合理起点。激活粒细胞的一个重要刺激是促炎性细胞因子THFα(肿瘤坏死因子)。例如,已知THFα刺激嗜中性粒细胞形成氧自由基(Jersmann,H.P.A.,D.A.Rathjen和FerranteA.:通过TNFα提高LPS-引起的中性白细胞氧自由基生成,Infection and Immunity,4,1744-1747,1998)。PDE4抑制剂可非常有效地抑制多种细胞释放TNAα,并因此抑制嗜中性粒细胞的活动。非特异性PDE抑制剂己酮可可碱能够抑制氧自由基生成以及嗜中性粒细胞噬吞细胞的能力(Wenisch,C.;K.Zedtwitz-Liebenstein,B.Parschalk和Graninger W.:通过流式细胞术评价的己酮可可碱在体外对中性白细胞反应性氧生成和噬吞细胞的能力的影响,Clin.Drug Invest.,13(2):99-104,1997)。
不同的PDE4抑制剂是已知的。主要有黄嘌呤衍生物、环戊苯吡酮类似物或Nitraquazone衍生物(Karlsson J-A,和Aldos D.,用于治疗哮喘的磷酸二酯酶4抑制剂,Exp.Opin.Ther.Patents 1997,7:989-1003中对其作了概述)。直到现在,还不能将任何这些化合物带到临床应用阶段。必须注意,已知的PDE4抑制剂还具有不同的副作用例如恶心和呕吐;到目前为止,不能充分地抑制这些副作用。处于该原因,需要发现具有更好的治疗范围的新的PDE4抑制剂。
迄今为止,仅有相当少的文件描述了使用7-氮杂吲哚化合物来开发用于不同适应症的新活性组分。
在日本专利JP 10120681(Fujisawa Pharmaceutical Co.,Ltd.)中,要求保护下述通式所示的5-和7-氮杂吲哚化合物
其中R1可代表氢或短的烷基,R2可代表氢、卤素、短的烷基、环烷基、烷基羰基或链烷酰基,R3代表链烷酰基、保护的羧基、氰基或取代的氨基甲酰基。L代表短的亚烷基。Q代表取代的芳基和杂环基。A1和A2当中,一个代表氮,另一个代表CH。这些化合物不同于本发明化合物,特别是取代基R2和R3不同,R1和A2部分不同。在该专利中,所述化合物是作为特定的cGMP磷酸二酯酶(PDE5)抑制剂要求保护。其中提出了不同的心脏循环疾病、支气管炎、哮喘、鼻炎、阳痿、糖尿病并发症和青光眼作为应用领域。
L.N.Yakhontov,S.S.Liberman,D.M.Krasnokutskaya等人在Khim.-Farm.Zh.8(11),1974,5-9描述了不同的3-氨基烷基-4-氮杂吲哚和3-氨基烷基-7-氮杂吲哚的合成。对于3-(2-氨基乙基)-7-氮杂吲哚,描述了抑郁或抗抑郁作用。其中提出了3-氨基甲基-7-氮杂吲哚的降血压作用。
A.J.Verbiscar在J.Med.Chem.15(2),1972,149-52中描述了下式所示化合物,
并确定了该化合物的抗疟疾作用。
在专利US 650223(Sterling Drug Inc.)中,描述了由相应的2-或3-氰基烷基-7-氮杂吲哚合成不同的2-(咪唑啉-2-基)-烷基-7-氮杂吲哚和3-(咪唑啉-2-基)-烷基-7-氮杂吲哚,并要求保护这些化合物作为血管收缩剂的应用。
至今7-氮杂吲哚化合物没有用作PDE4抑制剂。
本发明描述
本发明涉及通式1的取代的7-氮杂吲哚化合物,
其中n可以是1或2,且R1代表-C1-10直链或支链烷基,所述烷基可任选被下列基团取代一次或多次:-OH、-SH、-NH2、-NHC1-6烷基、-N(C1-6-烷基)2、-NHC6-14芳基、-N(C6-14芳基)2、-N(C1-6烷基)(C6-14芳基)、-NO2、-CN、-F、-Cl、-Br、-I、-O-C1-6-烷基、-O-C6-14-芳基、-S-C1-6-烷基、-S-C6-14芳基、-SO3H、-SO2C1-6烷基、-SO2C6-14芳基、-OSO2C1-6烷基、-OSO2C6-14芳基、-COOH、-(CO)C1-5烷基,具有有3-14个环单元的单环、二环或三环饱和或单不饱和或多不饱和的碳环,具有有5-15个环单元和1-6个优选为N、O和S的杂原子的单环、二环或三环饱和或单不饱和或多不饱和的杂环,其中,C6-14芳基和碳环取代基和杂环取代基本身可以任选地被R4单取代或多取代,-C2-10单不饱和或多不饱和直链或支链链烯基,所述链烯基可任选被下列基团取代一次或多次:-OH、-SH、-NH2、-NHC1-6烷基、-N(C1-6-烷基)2、-NHC6-14芳基、-N(C6-14芳基)2、-N(C1-6烷基)(C6-14芳基)、-NO2、-CN、-F、-Cl、-Br、-I、-O-C1-6-烷基、-O-C6-14-芳基、-S-C1-6-烷基、-S-C6-14芳基、-SO3H、-SO2C1-6烷基、-SO2C6-14芳基、-OSO2C1-6烷基、-OSO2C6-14芳基、-COOH、-(CO)C1-5烷基,具有有3-14个环单元的单环、二环或三环饱和或单不饱和或多不饱和的碳环,具有有5-15个环单元和1-6个优选为N、O和S的杂原子的单环、二环或三环饱和或单不饱和或多不饱和的杂环,其中,C6-14芳基和碳环取代基和杂环取代基本身可以任选被R4单取代或多取代,R2和R3可相同或不同,二者当中只有一个可代表氢,此外,R2和R3可代表-C1-5-烷基,所述烷基任选被下列基团单取代或多取代:-OH、-SH、-NH2、-NHC1-6-烷基、-N(C1-6-烷基)2、-NO2、-CN、-F、-Cl、-Br、-I、-O-C1-6-烷基、-S-C1-6-烷基、-苯基、-吡啶基,-苯基,所述苯基可任选被下列基团单取代或多取代:-OH、-SH、-NH2、-NHC1-3-烷基、-N(C1-3-烷基)2、-NO2、-CN、-COOH、-COOC1-3烷基、-F、-Cl、-Br、-O-C1-3-烷基、-S-C1-3-烷基,-吡啶基,所述吡啶基可任选被下列基团单取代或多取代:-NO2、-CN、-COOH、-COOC1-3烷基、-Cl、-Br、-O-C1-3-烷基、-S-C1-3-烷基,和
-NR2R3基可一起代表
其中R4代表-H、-OH、-SH、-NH2、-NHC1-6-烷基、-N(C1-6-烷基)2、-NHC6-14芳基、-N(C6-14芳基)2、-N(C1-6烷基)(C6-14芳基)、-NHCOC1-6烷基、-NO2、-CN、-COOH、-COOC1-6烷基、-(CO)C1-6烷基、-(CS)C1-6烷基、-F、-Cl、-Br、-I、-O-C1-6-烷基、-O-C6-14-芳基、-S-C1-6-烷基、-S-C6-14芳基、-SOC1-6烷基、-SO2C1-6烷基。
在本发明式17-氮杂吲哚中,R1优选为C1-C10-烷基。这样的烷基可以是直链、支链或环状,并且优选为直链的。尤其优选的是具有1-6个、甚至更优选1-4个碳原子的烷基。在另一优选的实施方案中,R1代表C2-C10链烯基、优选C2-C6链烯基、最优选C2-C4-链烯基。该链烯基可以是单不饱和或多不饱和的,例如二不饱和或三不饱和的。链烯基中,可以涉及直链、支链或环状烃基。尤其优选的是R1,其中烷基或链烯基是单取代或多取代的,例如二取代的、三取代的、四取代的或五取代的。在尤其优选的实施方案中,R1是取代的C1烷基-(即甲基)。在上文给出的R1烷基或链烯基的取代基当中,取代基-OH、-F、-Cl、-Br、-I、-C1-C4-烷氧基是特别优选的。此外,这样的取代基是优选的,其中任选存在的烷基具有1-4个碳原子,任选存在的芳基具有6-10个碳原子。在碳环当中,苯基是优选的,尤其是取代的苯基,其优选被下列基团取代:-F、-Cl、-Br、-I、C1-C6-烷氧基或羟基。在杂环基当中,具有至少一个选自N、O或S的杂原子的杂环基是优选的。在杂环基当中,特别优选的是吡啶基和异噁唑基,尤其是3,5-二甲基异噁唑基。稠合碳环取代基的一个实例是萘基。
特别优选地,R1代表包含环状烃基的基团,例如代表环丙基甲基,代表直链烃基,例如正己基,代表被烷氧基取代的直链烃基,例如2-甲氧基乙基,代表支链烃基,例如异丁基,代表不饱和烃基,例如代表2-甲基丙烯-3-基,或代表含有芳基的可任选被取代的烃基,例如代表4-氟苄基、3-甲氧基苄基、4-甲氧基苄基、4-氯苄基、4-甲基苄基、3-羟基苄基或4-羟基苄基,代表含有杂芳烃的基团,例如代表4-吡啶基甲基或3,5-二甲基异噁唑-4-甲基,或代表含有稠合芳烃的基团,例如1-萘基甲基。
在优选的实施方案中,氮原子上的取代基R2和R3可表示任选取代的C1-C5烷基、优选C1-C3烷基、特别优选C1烷基(即甲基)。
一个R2或/和R3优选代表包含杂芳烃的基团,例如4-吡啶基甲基,其中所述杂芳烃可进一步被取代,优选被卤素取代,例如3,5-二氯-4-吡啶基。在另一个优选的实施方案中,R2或/和R3是吗啉代基团。另外优选的是包含芳烃的R2和R3,其中所述芳烃优选被取代,特别是被卤素或羧基取代,例如2,6-二氯苯基、4-羧基苯基、4-乙氧基羰基苯基、3,4-二甲氧基苯基。另外优选地R2和R3都是甲氧基乙基。在另一优选的实施方案中,R2或R3代表下列基团:
或者基团-NR2R3一起代表
此外,本发明涉及式1化合物的生理可耐受盐。
生理可耐受盐可通过用无机酸或有机酸中和碱或者用无机碱或有机碱中和酸来以常规方法获得。可提及的无机酸有例如盐酸、硫酸、磷酸或氢溴酸,可提及的有机酸有例如羧酸、硫代酸或磺酸,例如乙酸、酒石酸、乳酸、丙酸、乙醇酸、丙二酸、马来酸、富马酸、鞣酸、琥珀酸、藻酸、苯甲酸、2-苯氧基苯甲酸、2-乙酰氧基苯甲酸、肉桂酸、扁桃酸、柠檬酸、苹果酸、水杨酸、3-氨基水杨酸、抗坏血酸、扑酸、烟酸、异烟酸、草酸、氨基酸、甲磺酸、乙磺酸、2-羟基乙磺酸、乙-1,2-二磺酸、苯磺酸、4-甲基苯磺酸或萘-2-磺酸。可提及的无机碱有例如氢氧化钠、氢氧化钾、氨,可提及的有机碱有例如胺,但优选叔胺,例如三甲胺、三乙胺、吡啶、N,N-二甲基苯胺、喹啉、异喹啉、α-甲基吡啶、β-甲基吡啶、γ-甲基吡啶、喹哪啶或嘧啶。
此外,式1化合物的生理可耐受盐可通过按照本身已知方法用季铵化剂将含有叔氨基的衍生物转化成相应的季铵盐来获得。可提及的季铵化剂有例如烷基卤,例如甲基碘、乙基溴和正丙基氯,以及芳基烷基卤,例如苄基氯或2-苯基乙基溴。
此外,对于具有不对称碳原子的式1化合物,本发明涉及D型、L型和D,L-混合物,当式1化合物具有几个不对称碳原子时,还涉及非对映异构体形式。可通过本身已知方法,例如用旋光性酸将含有不对称碳原子并且通常以外消旋体形式获得的式1化合物分离成旋光异构体。然而,也可以在开始时使用旋光性原料,之后获得相应的旋光性或非对映异构化合物作为终产物。
已经发现本发明化合物具有重要的药理性质,可用于治疗。
本发明化合物是TNFα释放抑制剂。
因此,本发明化合物可用于抑制TNFα释放。
因此,本发明的目的是,式1化合物及其盐,和含有这些化合物或其盐的药物制剂可用于治疗抑制TNFα对于其治疗有用的疾病。
这些疾病包括例如关节炎症,包括关节炎和类风湿性关节炎,以及其它关节炎性疾病,例如类风湿性脊椎炎和骨关节炎。其它可能的应用是治疗患有下列疾病的患者:骨质疏松、脓毒症、脓毒性休克、格兰氏阴性脓毒症、中毒性休克综合征、呼吸窘迫综合征、哮喘和其它慢性肺病、骨吸收疾病或移植排斥反应或其它自身免疫性疾病,例如红斑狼疮、多发性硬化、肾小球性肾炎和眼色素层炎、胰岛素依赖性糖尿病和慢性脱髓鞘。
此外,本发明化合物还可用于治疗感染,例如病毒感染和寄生虫感染,例如治疗疟疾、利什曼病、感染引起的发烧、感染引起的肌肉疼痛、AIDS和恶病质。
本发明化合物是磷酸二酯酶4抑制剂。
因此,本发明化合物可用于抑制磷酸二酯酶4。
因此,本发明的目的是,式1化合物和其盐,和含有这些化合物或其盐的药物制剂可用于治疗抑制磷酸二酯酶4对于其治疗有用的疾病。
因此,本发明化合物可用作支气管扩张剂和哮喘预防剂。式1化合物还是嗜酸性细胞聚集及其活性的抑制剂。所以本发明化合物还可用于治疗其中嗜酸性细胞起作用的疾病。这些疾病包括例如呼吸道炎性疾病例如支气管哮喘、过敏性鼻炎、过敏性结膜炎、特应性皮炎、湿疹、过敏性脉管炎、嗜酸性细胞引起的炎症,例如嗜酸细胞性筋膜炎、嗜酸细胞性肺炎和PIE综合征(嗜酸性细胞增多的肺浸润)、荨麻疹、溃疡性结膜炎、局限性回肠炎和增殖性皮肤病,例如牛皮癣和角化病。
本发明的目的是,式1化合物和其盐可在体外抑制TNFα释放和在大鼠体内抑制LPS引起的肺中性白细胞浸润。所发现的所有这些重要的药理性质证实了式1化合物和其盐,和含有这些化合物和其盐的药物制剂可用于治疗慢性堵塞性肺病。
此外,本发明化合物具有神经保护性质,并且可用于治疗保护神经对其治疗有用的疾病。这样的疾病是例如老年痴呆(阿尔茨海默氏病)、记忆遗失、帕金森氏病、抑郁症、中风和间歇性跛行。
本发明化合物的其它可能应用是预防和治疗前列腺疾病,例如良性前列腺增生、频尿、夜尿症,以及治疗失禁、尿石引起的绞痛和男性与女性性功能障碍。
本发明化合物还可用于抑制由于反复使用镇痛剂,例如吗啡而发展成药物依赖性,以及用于降低当反复使用这些镇痛剂时发展成耐药性。
为了制备药物,除了常规辅助剂、载体和添加剂外还使用有效剂量的本发明化合物或其盐。
活性组分的剂量可根据其给药途径、患者的年龄、体重、欲治疗的疾病的性质和严重程度以及类似因素而改变。
日剂量可作为每天施用一次的单一剂量给药,或者每天分成两次或更多次剂量给药,并且通常为0.001-100mg。
口服、非胃肠道、静脉内、透皮、局部、吸入和鼻内给药制剂是优选的施用形式。
可使用制剂的常用药物剂型,例如片剂、包衣片剂、胶囊、可分散粉剂、粒剂、水溶液、水或油悬浮液、糖浆、液剂或滴剂。
固体形式的药物可含有惰性组分和载体,例如碳酸钙、磷酸钙、磷酸钠、乳糖、淀粉、甘露醇、藻酸盐、明胶、瓜尔胶、硬脂酸镁、硬脂酸铝、甲基纤维素、滑石粉、高度分散的二氧化硅、硅油、较高分子量脂肪酸(例如硬脂酸)、明胶、琼脂、植物或动物脂肪和油、固体高分子量聚合物(例如聚乙二醇);适于口服给药的制剂如合适可含有另外的调味剂和/或甜料。
液体形式的药物可灭菌和/或可任选含有辅助剂,例如防腐剂、稳定剂、润湿剂、渗透剂、乳化剂、涂布剂、助溶剂,用于控制渗透压或用于起缓冲作用的盐、糖或糖醇和/或粘度调节剂。
这样的添加剂是例如酒石酸盐和柠檬酸盐缓冲剂、乙醇、络合剂(例如乙二胺四乙酸及其无毒的盐)。为了控制粘度,可使用高分子量聚合物,例如液体聚氧化乙烯、微晶纤维素例如羧甲基纤维素、聚乙烯吡咯烷酮、葡聚糖或明胶。固体载体物质是例如淀粉、乳糖、甘露醇、甲基纤维素、滑石粉、高度分散的二氧化硅、较高分子量脂肪酸(例如硬脂酸)、明胶、琼脂、磷酸钙、硬脂酸镁、动物和植物脂肪、固体高分子量聚合物例如聚乙二醇。
用于非胃肠道或局部施用的油悬浮液可含有植物的合成或半合成油,例如其在脂肪酸链中具有8-22个碳原子的液体脂肪酸酯,所述脂肪酸是例如棕榈酸、月桂酸、十三烷酸、十七烷酸、硬脂酸、二十烷酸、肉豆蔻酸、二十二烷酸、十五烷酸、亚油酸、反油酸、巴西勒酸、芥酸或油酸,这些脂肪酸被具有1-6个碳原子的一元-三元醇酯化,所述醇是例如甲醇、乙醇、丙醇、丁醇、戊醇或其异构体,乙二醇或甘油。这样的脂肪酸酯是例如常规市售Miglyole、肉豆蔻酸异丙酯、棕榈酸异丙酯、硬脂酸异丙酯、PEG-6癸酸、饱和脂肪醇的辛酸/癸酸酯、聚氧化乙烯甘油三油酸酯、油酸乙酯、蜡状脂肪酸酯例如合成的鸭尾腺脂肪、椰油脂肪酸的异丙酯、油酸油酯、油酸癸酯、乳酸乙酯、邻苯二甲酸二丁酯、己二酸二异丙酯、多元醇的脂肪酸酯等。同样合适的有不同粘度的硅油或脂肪醇,例如异十三烷醇、2-辛基十二烷醇、鲸蜡基硬脂醇或油醇、脂肪酸,例如油酸。此外,可使用植物油例如蓖麻油、杏仁油、橄榄油、芝麻油、棉子油、花生油或豆油。
作为溶剂、凝胶形成剂和助溶剂,可使用水或可与水混溶的溶剂。例如,可使用醇,例如乙醇或异丙醇、苯甲醇、2-辛基十二烷醇、聚乙二醇、邻苯二甲酸酯、己二酸酯、丙二醇、甘油、一缩二丙二醇、三丙二醇、蜡、甲基溶纤剂、溶纤剂、酯、吗啉、二氧杂环己烷、二甲亚砜、二甲基甲酰胺、四氢呋喃、环己酮等。
作为成膜剂,可以使用可溶解在或膨胀在水和有机溶剂中的纤维素醚,例如羟丙基甲基纤维素、甲基纤维素、乙基纤维素或可溶性淀粉。
介于凝胶形成剂和成膜剂之间的混合形式也完全是可能的。在本发明中可尤其使用离子大分子例如羧甲基纤维素钠、聚丙烯酸、聚异丁烯酸和其盐、支链淀粉半羟乙酸钠、藻酸或作为钠盐的丙二醇藻酸酯、阿拉伯胶、黄原胶、瓜尔胶或角叉菜胶。
作为其它制剂辅料,可使用下列物质:甘油、不同粘度的石蜡、三乙醇胺、胶原、尿囊素、Novantisolsure。为了制备所需制剂,可能还需要使用表面活性剂、乳化剂或润湿剂,例如月桂基硫酸钠、脂肪醇醚硫酸盐、N-月桂基-β-亚氨基二丙酸二钠、聚乙氧基化蓖麻油或脱水山梨醇一油酸酯、脱水山梨醇一硬脂酸酯、聚山梨醇酯(例如吐温)、鲸蜡醇、卵磷脂、甘油一硬脂酸酯、聚氧乙烯硬脂酸酯、烷基苯酚聚乙二醇醚、氯化鲸蜡基三甲基铵或一烷基或二烷基聚乙二醇醚正磷酸一乙醇胺盐,稳定剂例如蒙脱石或胶态二氧化硅来稳定乳液,或为防止活性物质分解,例如抗氧化剂,如生育酚或丁基羟基茴香醚,或防腐剂,例如对羟基苯甲酸酯同样也是任选地需要的,以便制备所需的制剂。
非胃肠道给药制剂还可以存在于分隔的剂量单位形式,例如安瓿或小瓶中。优选使用活性组分的溶液,尤其是水溶液,和特别是等渗溶液;然而,还可以使用悬浮液。这些注射剂型可作为最终的制剂获得,或者在使用前首先直接通过将任选与其它固体载体物质在一起的活性化合物例如冷冻干燥物与所需溶剂或悬浮剂混合来直接制得。
鼻内给药制剂可作为作为水或油溶液或者水或油悬浮液存在。其还可以作为在使用前用合适的溶剂或悬浮剂配制的冷冻干燥物存在。
制剂的制备、向容器内的填充和密封是在常规抗微生物和无菌条件下进行的。
本发明还涉及制备本发明化合物的方法。
依据本发明,其中R1、R2、R3具有上述含义,且n=1的通式1化合物是这样合成的:
首先通过本身已知方法,用酰氯,优选用亚硫酰氯或草酰氯将其中R1具有相同含义的式2所示7-氮杂吲哚-3-甲酸
转化成类似的式3所示7-氮杂吲哚-3-甲酰氯
然后通过与伯胺或仲胺反应将分离出的式3所示7-氮杂吲哚-3-甲酰氯转化成其中R1、R2、R3具有上述含义,且n=1的通式1的本发明化合物。该反应在辅助性碱存在下有利地进行。作为辅助性碱,可使用用作反应物的过量胺,叔胺,优选吡啶或三乙胺,和无机碱,优选碱金属氢氧化物或碱金属氢化物。
依据本发明,其中R1、R2、R3具有上述含义,且n=2的通式1化合物是这样合成的:
首先按照已知方法,通过用草酰氯酰化将其中R1具有相同含义的式4所示7-氮杂吲哚
转化成类似的式5所示7-氮杂吲哚-3-基乙醛酰氯
然后通过与伯胺或仲胺反应由式5所示7-氮杂吲哚-3-基乙醛酰氯形成其中R1、R2、R3具有上述含义,且n=2的通式1本发明化合物。该反应在辅助性碱存在下有利地进行。作为辅助性碱,可使用用作反应物的过量胺,叔胺,优选吡啶或三乙胺,和无机碱,优选碱金属氢氧化物或碱金属氢化物。
实施例
合成其中n=1的式1本发明化合物的方法的实施例
实施例1:N-(4-吡啶基甲基)-1-环丙基甲基-7-氮杂吲哚-3-甲酰胺
将1-环丙基甲基-7-氮杂吲哚-3-甲酸(1.87g,8.6mmol)悬浮在15ml二氯甲烷中。在用水冷却下加入1.8mL草酰氯(17.4mmol)。将该反应混合物搅拌8小时,期间结晶出1-环丙基甲基-7-氮杂吲哚-3-甲酰氯。分离出该结晶,并溶解在18ml四氢呋喃(THF)中。
将氢化钠(60%,1.14g)悬浮在21ml THF中。在约10℃搅拌下,滴加0.93g 4-氨基甲基吡啶(8.6mmol)在21ml THF中的溶液。约15分钟后,将先前制备的1-环丙基甲基-7-氮杂吲哚-3-甲酰氯溶液滴加到该反应混合物中。然后将整个混合物回流3小时。冷却后,将该反应混合物与36mL乙酸乙酯和36mL水混合。分离各相,用水洗涤有机相。蒸馏出溶剂,将残余物从乙醇中重结晶。
产量:1.3g(理论值的50%)
熔点:187-189℃
使用上述合成方法,可合成多种其它的其中n=1的式1化合物,例如下面列出的化合物:
实施例 | R1 | -NR2R3 | n | 熔点[℃] |
1 | 环丙基甲基- | 4-吡啶基甲基氨基- | 1 | 187-189乙醇 |
2 | 异丁基- | 3,5-二氯-4-吡啶基氨基- | 1 | 168-170乙醇 |
3 | 正己基- | 3,5-二氯-4-吡啶基氨基- | 1 | 136-137甲醇 |
4 | 环丙基甲基- | 3,5-二氯-4-吡啶基氨基- | 1 | 186-187乙醇 |
5 | 4-氟苄基- | 4-吡啶基甲基氨基- | 1 | 189-191乙醇 |
6 | 4-氟苄基- | 3,5-二氯-4-吡啶基氨基- | 1 | 232--233乙醇 |
7 | 4-甲氧基苄基- | 3,5-二氯-4-吡啶基氨基- | 1 | 193-195乙醇 |
8 | 4-氯苄基- | 4-吡啶基氨基- | 1 | 192-194甲醇 |
9 | 4-氟苄基- | 吗啉代- | 1 | 182-184乙醇 |
10 | 2-甲基丙烯-3-基- | 2,6-二氯苯基氨基- | 1 | 171-174乙醇 |
11 | 4-吡啶基甲基- | 3,5-二氯-4-吡啶基氨基- | 1 | 190-192甲醇 |
合成其中n=2的式1本发明化合物的方法的实施例
实施例12:N-(3,5-二氯吡啶-4-基)-[1-(3-甲氧基苄基)-7-氮杂吲哚-3-基]-
乙醛酰胺
将1-(3-甲氧基苄基)-7-氮杂吲哚(3.57g,15mmol)溶解在50mL叔丁基甲基醚中。在搅拌下于0℃滴加1.54mL草酰氯(18mmol)在10mL叔丁基甲基醚中的溶液。然后将该混合物回流2小时,之后将溶剂真空蒸馏。获得了1-(3-甲氧基苄基)-7-氮杂吲哚-3-基-乙醛酰氯,为固体残余物,将其悬浮在50mL四氢呋喃(THF)中。
在-5℃向2g氢化钠在20ml THF内的悬浮液中滴加2.4g 4-氨基-3,5-二氯吡啶(15mmol)在30mL THF中的溶液。然后在搅拌下将该混合物于20℃保持1小时。然后在约0℃滴加先前制备的1-(3-甲氧基苄基)-7-氮杂吲哚-3-基-乙醛酰氯的悬浮液。最后将该反应混合物回流4小时,然后真空除去溶剂。将残余物与50mL乙酸乙酯和50mL水搅拌。分离各相,用水洗涤有机相。将溶剂真空蒸馏掉,将残余物从异丙醇中重结晶。
产量:3.5g(理论值的51.5%)
熔点:165-167℃
使用上述合成方法,可合成多种其它的其中n=2的式1化合物,例如下面列出的化合物:
实施例 | R1 | -NR2R3 | n | 熔点[℃] |
12 | 3-甲氧基苄基- | 3,5-二氯-4-吡啶基氨基- | 2 | 165-167异丙醇 |
13 | 4-氟苄基- | 4-吡啶基氨基-×HCl | 2 | 275-278分解DMF |
14 | 4-氟苄基- | 3,5-二氯-4-吡啶基氨基- | 2 | 201-202乙醇 |
15 | 4-氯苄基- | 4-吡啶基氨基-×HCl | 2 | 280-283分解DMF |
16 | 4-氯苄基- | 3,5-二氯-4-吡啶基氨基- | 2 | 205-207乙醇 |
17 | 4-甲氧基苄基- | 3,5-二氯-4-吡啶基氨基- | 2 | 165-167乙醇 |
18 | 4-氯苄基- | 2,6-二氯苯基氨基- | 2 | 166-68乙醇 |
19 | 4-氟苄基- | 4-羧基苯基氨基- | 2 | 279-282异丙醇 |
20 | 4-氟苄基- | 4-乙氧基羰基苯基氨基- | 2 | 209-211乙醇 |
21 | 4-氟苄基- | 3,4-二甲氧基苯基氨基- | 2 | 173-176乙醇 |
本发明化合物是磷酸二酯酶4以及TNFα释放的强抑制剂。例如通过抑制哮喘晚期反应(嗜酸性细胞增多)以及通过作用于变应原引起的主动致敏的Brown Norway大鼠的血管渗透性来在体内证实治疗可能性。
抑制磷酸二酯酶
在得自人多形核淋巴细胞(PMNL)的酶制备物中测定PDE 4活性,用得自人血小板的PDE测定PDE2、3和5活性。用柠檬酸盐防止人血液凝结。通过在室温以700×g离心20分钟将上清液中的富含血小板的血浆与红细胞和白细胞分离开。通过超声将血小板裂解,并且在PDE3和PDE5测定中使用。为了测定PDE2活性,在阴离子交换柱上通过NaCl梯度纯化胞质血小板级分,获得了用于测定的PED2峰。之后通过葡聚糖沉降,然后用Ficoll-Paque梯度离心来分离出用于PDE4测定的PMNL。将细胞洗涤2次后,通过加入10mL低渗缓冲液(155mMNH4Cl,10mM NaHCO3,0.1mM EDTA,pH=7.4)将仍然含有的红细胞在4℃裂解6分钟。将仍然完整的PMNL用PBS洗涤两次,并通过超声裂解。通过在4℃以48000×g离心1小时所获得的上清液含有PDE4的胞质级分,并用于PDE 4测定。
使用作了某些改动的Thompson等人描述的方法来测定磷酸二酯酶活性(Thompson,W.J.和Appleman M.M.,环核苷酸磷酸二酯酶的测定和多种分子形式的酶的分离,Adv.Cycl.Nucl.Res.1979,10,69-92)。
反应混合物含有50 mM Tris-HCl(pH 7.4)、5mM MgCl2、不同浓度的抑制剂、相应的酶制备物以及测定各种同工酶所需的其它组分(见下文)。通过加入底物0.5μM[3H]-cAMP或[3H]-cGMP(每个测试约6000 CPM)来开始反应。终体积为100ml。将测试底物作为在DMSO中的贮备液混合。该反应混合物中的DMSO浓度为1%v/v。该浓度的DMSO不影响PDE活性。通过加入底物开始反应后,将样本在37℃培养30分钟。通过将测试管在110℃加热2分钟来停止反应。将样本在冰上再保持10分钟。加入30μL 5′-核苷酸酶(1mg/mL,从衲脊响尾蛇的蛇毒悬浮液制备的),然后在37℃培养10分钟。将样本在冰上停止反应,加入400μL Dowex-水-乙醇(1+1+1)的混合物,充分混合,在冰上再培养15分钟。将反应容器以3000×g离心20分钟。将等分试样的上清液(200μL)直接转移到闪烁容器中。加入3mL闪烁体后,在β计数器中测定样本。
使用[3H]-cAMP作为测定PDE4、3和2活性的底物,使用[3H]-cGMP作为测定PDE5活性的底物。对于PDE4的测定,在100μM环戊苯吡酮存在下测定非特异性酶活性,对于对于PDE3和5的测定,在100μM IBMX存在下测定非特异性酶活性,并从测试值中减去非特异性酶活性值。PDE3测定的培养混合物含有10μM环戊苯吡酮以抑制可能的PDE4沾污。用Amersham Company的SPA测定测试PDE2。该测定是在PDE2激活物(5μM cGMP)存在下进行的。
对于本发明化合物,测定的抑制磷酸二酯酶4的IC50值为10-9-10-5M。对2、3和5型PDE的选择性为100-10000的因数。
例如,下表中总结了所选实施例化合物的抑制PDE4的结果:
实施例 | 抑制PDE4IC50[μmol/L] |
1 | 0.710 |
2 | 1.400 |
12 | 0.005 |
13 | 0.058 |
14 | 0.004 |
15 | 0.031 |
16 | 0.002 |
17 | 0.008 |
18 | 0.031 |
22 | 0.002 |
23 | 0.001 |
24 | 0.003 |
25 | 0.004 |
26 | 0.021 |
27 | 0.002 |
28 | 0.003 |
32 | 0.113 |
37 | 0.987 |
抑制从鼻息肉细胞释放TNFα
该实验布置与Campbell,A.M.和Bousquet J.描述的方法基本上相同(H1-阻断剂的抗过敏活性,Int.Arch.Allergy Immunol.,1993,101,308-310)。鼻息肉形成原料(得自已经进行过手术治疗的患者的材料)。
将组织用RPMI 1640洗涤,然后用蛋白酶(2.0mg/ml)、胶原酶(1.5mg/ml)、透明质酸酶(0.75mg/ml)和DNA酶(0.05mg/ml)于37℃溶解(aufgeschlossen)2小时(1g组织和4mL含有酶的RPMI 1640)。将所得细胞—上皮细胞、单核细胞、巨噬细胞、淋巴细胞、成纤维细胞和粒细胞的混合物过滤,通过在培养溶液中反复离心来洗涤,加入人IgE来被动致敏,将细胞悬浮液在RPMI 1640(补充抗生素、10%胎牛血清、2mM谷氨酰胺和25mM Hepes)中稀释至2百万个细胞/mL的浓度。将悬浮液分配在6孔细胞培养平板上(1ml/孔)。将细胞与不同浓度的测试物预培养30分钟,然后通过加入抗-IgE(7.2μg/mL)进行刺激以释放TNFα。约18小时后发生了向培养基内的最大释放。在该期间,将细胞在37℃和5%二氧化碳下培养。通过离心(以4000rpm离心5分钟)来收集培养基(上清液),并在-70℃保持直至测定细胞因子。用所谓的三明治ELISA(基础材料Pharmingen)测定上清液中的TNFα,使用该方法可测定浓度为30-1000pg/mL的细胞因子。
未用抗IgE刺激的细胞几乎不产生任何THFα;另一方面,刺激的细胞分泌大量TNFα,可通过PDE4抑制剂减少TNFα的量,减少程度与剂量有关。由不同浓度测试物的抑制百分比(用抗IgE刺激的细胞的TNFα释放=100%)计算IC50(达到50%抑制的浓度)。
测定的本发明化合物的IC50值为10-7-10-5M。
例如,下表中总结了所选实施例化合物的抑制TNFα释放的结果:
实施例 | 抑制TNFα释放浓度 抑制[%] | |
14 | 0.3μmol/L | 92 |
16 | 1.0μmol/L | 90 |
17 | 1.0μmol/L | 91 |
27 | 1.0μmol/L | 91 |
抑制使用主动致敏的Brown Norway大鼠的吸入卵白蛋白攻击48小时
后的晚期嗜酸性细胞增多
在已经进行过抗卵白蛋白(OVA)的主动致敏的雄性Brown Norway大鼠(200-250g)中,测试本发明化合物对肺嗜酸性细胞增多浸润的抑制作用。通过在第1、14和21天给每只大鼠皮下注射10μg OVA和20mg氢氧化铝助剂在0.5mL生理盐水溶液中的悬浮液来给大鼠致敏。此外,每只动物同时接受0.25mL腹膜内注射的百日咳杆菌(Bordetellapertussis)疫苗稀释物。在实验的第28天,将动物单独置于开口的1L有机玻璃盒子中,该盒子与头鼻暴露装置连接。将动物暴露于1.0%卵白蛋白悬浮液的气雾剂中(变应原攻击)。卵白蛋白气雾剂是用通过压缩空气(0.2MPa)驱动的喷雾器(Bird Micronebulizer,Palm Springs CA,USA)产生的。暴露时间是1小时,标准对照是用0.9%盐溶液的气雾剂喷雾1小时。
变应原攻击48小时后,有大量嗜酸性粒细胞迁移到动物的肺内。同时,用过量乌拉坦(1.5g/kg体重,i.p.)将动物麻醉,用3×4mL Hank’s平衡溶液进行支气管肺泡灌洗。然后用自动细胞鉴别装置(BayerDiaghostics Technicon H1E)测定汇集的BAL液体的总细胞数目和嗜酸性粒细胞数目。对于每只动物,如下所示计算以百万/动物表示的BAL中的嗜酸性细胞(EOS):EOS/μl×收集的BAL(mL)=EOS/动物。
每次测试运行2个对照组(用生理盐水溶液喷雾和用OVA溶液喷雾)。
依据下述公式计算用测试物治疗的实验组的嗜酸性细胞增多的抑制百分比:
{((OVAC-SC)-(OVAD-SC))/(OVAC-SC)}×100%=%抑制(SC=用0.9%盐溶液攻击的载体治疗对照组;OVAC=用1%卵白蛋白悬浮液攻击的载体治疗对照组;OVAD=用1%卵白蛋白悬浮液攻击的测试物治疗的实验组)
测试物是在变应原攻击前2小时,作为在10%聚乙二醇300和0.5%5-羟基乙基纤维素中的悬浮液腹膜内或口服施用的。对照组是依据测试物的施用形式用载体治疗。
以10mg/kg的剂量腹膜内施用后,本发明化合物将晚期嗜酸性细胞增多抑制剂了30%-100%,以30mg/kg的剂量口服施用后,本发明化合物将晚期嗜酸性细胞增多抑制剂了30%-75%。
因此,本发明化合物特别适于制备用于治疗与嗜酸性细胞活动有关的疾病的药物。
例如,下表中总结了所选实施例化合物的抑制嗜酸性细胞增多的结果:
实施例 | 抑制嗜酸性细胞增多剂量/施用 抑制[%] | |
14 | 10mg/kg i.p.10mg/kg p.o. | 6259 |
16 | 10mg/kg i.p.10mg/kg p.o. | 10070 |
17 | 10mg/kg i.p.10mg/kg p.o. | 7532 |
27 | 10mg/kg i.p.10mg/kg p.o. | 5070 |
抑制Lewis大鼠中脂多糖(LPS)引起的中性白细胞增多
在雄性Lewis大鼠(250-350g)中测试本发明化合物对肺中性白细胞浸润的抑制作用。在实验的当天,将动物单独置于开口的1L有机玻璃盒子中,该盒子与头鼻暴露装置连接。将动物暴露于脂多糖悬浮液(100μg LPS/mL 0.1%羟基胺在PBS中的溶液)的气雾剂中(LPS攻击)中。LPS/羟基胺气雾剂是用通过压缩空气(0.2MPa)驱动的喷雾器(BirdMicronebulizer,Palm Springs CA,USA)产生的。暴露时间是40分钟,标准对照是用0.1%羟基胺在PBS中的溶液的气雾剂喷雾40分钟。
LPS攻击6小时后,有大量中性粒细胞迁移到动物的肺内。同时,用过量乌拉坦(1.5g/kg体重,i.p.)将动物麻醉,用3×4mL Hank’s平衡溶液进行支气管肺泡灌洗。然后用自动细胞鉴别装置(BayerDiagnostics Technicon H1E)测定汇集的BAL液体的总细胞数目和中性粒细胞数目。对于每只动物,如下所示计算以百万/动物表示的BAL中的中性白细胞(NEUTRO):NEUTRO/μl×收集的BAL(mL)=NEUTRO/动物。
每次测试运行2个对照组(用0.1%羟基胺在PBS中的溶液喷雾和用100μgLPS/mL 0.1%羟基胺在PBS中的溶液)。
依据下述公式计算用测试物治疗的实验组的中性白细胞增多的抑制百分比:
{((LPSC-SC)-(LPSD-SC))/(LPSC-SC)}×100%=%抑制(SC=用0.1%羟基胺溶液攻击的载体治疗对照组;LPSC=用LPS(100μg/mL 0.1%羟基胺溶液)攻击的载体治疗对照组;LPSD=用LPS(100μg/mL 0.1%羟基胺溶液)攻击的测试物治疗的实验组)
测试物是在LPS攻击前2小时,作为在10%聚乙二醇300和0.5%5-羟基乙基纤维素中的悬浮液口服施用的。对照组是依据测试物的施用形式用载体治疗。
以1mg/kg的剂量口服施用后,本发明化合物将中性白细胞增多抑制剂了40%-90%。因此,本发明化合物特别适于制备用于治疗与中性白细胞活动有关的疾病的药物。
例如,下表中总结了所选实施例化合物的抑制中性白细胞增多的结果:
实施例 | 抑制中性白细胞增多剂量/施用 抑制[%] | |
14 | 1mg/kg p.o. | 80 |
22 | 1mg/kg p.o. | 64 |
27 | 1mg/kg p.o. | 52 |
权利要求书
(按照条约第19条的修改)
17.制备权利要求16的药物的方法,其特征在于将一种或多种权利要求1-5任一项的化合物和常规生理可耐受载体和/或稀释剂或其它辅助剂一起加工成药物制剂或/和制成可治疗使用的形式。
18.单独或彼此组合或与载体和/或稀释剂或其它辅助剂组合的权利要求1-5任一项的化合物和/或权利要求16或17的药物制剂的应用。
19.权利要求1-3任一项的通式1化合物,其中所述化合物是N-(3,5-二氯吡啶-4-基)-[(1-(4-氟苄基)-7-氮杂吲哚-3-基)]乙醛酰胺。
Claims (18)
1.通式1的7-氮杂吲哚,
其中
n可以是1或2,且
R1代表
-C1-10直链或支链烷基,所述烷基未取代或被下列基团取代一次或多次:-OH、-SH、-NH2、-NHC1-6烷基、-N(C1-6-烷基)2、-NHC6-14芳基、-N(C6-14芳基)2、-N(C1-6烷基)(C6-14芳基)、-NO2、-CN、-F、-Cl、-Br、-I、-O-C1-6-烷基、-O-C6-14-芳基、-S-C1-6-烷基、-S-C6-14芳基、-SO3H、-SO2C1-6烷基、-SO2C6-14芳基、-OSO2C1-6烷基、-OSO2C6- 14芳基、-COOH、-(CO)C1-5烷基,具有有3-14个环单元的单环、二环或三环饱和或单不饱和或多不饱和的碳环,具有有5-15个环单元和1-6个优选为N、O和S的杂原子的单环、二环或三环饱和或单不饱和或多不饱和的杂环,其中,C6-14芳基和碳环取代基和杂环取代基本身可未取代或被R4单取代或多取代,
-C2-10单不饱和或多不饱和直链或支链链烯基,所述链烯基未取代或被下列基团取代一次或多次:-OH、-SH、-NH2、-NHC1-6烷基、-N(C1-6-烷基)2、-NHC6-14芳基、-N(C6-14芳基)2、-N(C1-6烷基)(C6-14芳基)、-NO2、-CN、-F、-Cl、-Br、-I、-O-C1-6-烷基、-O-C6-14-芳基、-S-C1-6-烷基、-S-C6-14芳基、-SO3H、-SO2C1-6烷基、-SO2C6-14芳基、-OSO2C1-6烷基、-OSO2C6-14芳基、-COOH、-(CO)C1-5烷基,具有有3-14个环单元的单环、二环或三环饱和或单不饱和或多不饱和的碳环,具有有5-15个环单元和1-6个优选为N、O和S的杂原子的单环、二环或三环饱和或单不饱和或多不饱和的杂环,其中,C6-14芳基和碳环取代基和杂环取代基本身可以是未取代的或被R4单取代或多取代,R2和R3可相同或不同,二者当中只有一个可代表氢,此外,R2和R3可代表-C1-5-烷基,所述烷基未取代或被下列基团单取代或多取代:-OH、-SH、-NH2、-NHC1-6-烷基、-N(C1-6-烷基)2、-NO2、-CN、-F、-Cl、-Br、-I、-O-C1-6-烷基、-S-C1-6-烷基、苯基、吡啶基,-苯基,所述苯基未取代或被下列基团单取代或多取代:-OH、-SH、-NH2、-NHC1-3-烷基、-N(C1-3-烷基)2、-NO2、-CN、-COOH、-COOC1-3烷基、-F、-Cl、-Br、-O-C1-3-烷基、-S-C1-3-烷基,-吡啶基,所述吡啶基未取代或被下列基团单取代或多取代:-NO2、-CN、-COOH、-COOC1-3烷基、-Cl、-Br、-O-C1-3-烷基、-S-C1-3-烷基,和
此外,-NR2R3基可一起代表
和R4代表-H、-OH、-SH、-NH2、-NHC1-6-烷基、-N(C1-6-烷基)2、-NHC6-14芳基、-N(C6-14芳基)2、-N(C1-6烷基)(C6-14芳基)、-NHCOC1-6烷基、-NO2、-CN、-COOH、-COOC1-6烷基、-(CO)C1-6烷基、-(CS)C1-6烷基、-F、-Cl、-Br、-I、-O-C1-6-烷基、-O-C6-14-芳基、-S-C1-6-烷基、-S-C6-14芳基、-SOC1-6烷基、-SO2C1-6烷基。
2.权利要求1的式1化合物的生理可耐受盐,其特征在于所述盐是通过用无机酸或有机酸中和碱或者通过用无机碱或有机碱中和酸或者通过将叔胺季铵化以生成季铵盐而获得的。
3.权利要求1或2的式1化合物,其中所述化合物具有不对称碳原子,并且呈D-形式、L-形式或D,L-混合物的形式,或者当具有几个不对称碳原子时,呈非对映异构体形式。
4.权利要求1-3任一项的式1化合物,其中n=1,并且所述化合物选自:
N-(4-吡啶基甲基)-1-环丙基甲基-7-氮杂吲哚-3-甲酰胺
N-(3,5-二氯吡啶-4-基)-1-异丁基-7-氮杂吲哚-3-甲酰胺
N-(3,5-二氯吡啶-4-基)-1-己基-7-氮杂吲哚-3-甲酰胺
N-(3,5-二氯吡啶-4-基)-1-环丙基甲基-7-氮杂吲哚-3-甲酰胺
N-(4-吡啶基甲基)-1-(4-氟苄基)-7-氮杂吲哚-3-甲酰胺
N-(3,5-二氯吡啶-4-基)-1-(4-氟苄基)-7-氮杂吲哚-3-甲酰胺
N-(3,5-二氯吡啶-4-基)-1-(4-甲氧基苄基)-7-氮杂吲哚-3-甲酰胺
N-(4-吡啶基甲基)-1-(4-氯苄基)-7-氮杂吲哚-3-甲酰胺
1-(4-氟苄基)-7-氮杂吲哚-3-甲酰吗啉
N-(2,6-二氯苯基)-1-(2-甲基丙烯-3-基)-7-氮杂吲哚-3-甲酰胺和
N-(3,5-二氯吡啶-4-基)-1-(4-吡啶基甲基)-7-氮杂吲哚-3-甲酰胺。
5.权利要求1-3任一项的式1化合物,其中n=2,并且所述化合物选自:
N-(3,5-二氯吡啶-4-基)-[1-(3-甲氧基苄基)-7-氮杂吲哚-3-基]-乙醛酰胺
N-(4-吡啶基)-[1-(4-氟苄基)-7-氮杂吲哚-3-基]-乙醛酰胺盐酸盐
N-(3,5-二氯吡啶-4-基)-[1-(4-氟苄基)-7-氮杂吲哚-3-基]-乙醛酰胺
N-(4-吡啶基)-[1-(4-氯苄基)-7-氮杂吲哚-3-基]-乙醛酰胺盐酸盐
N-(3,5-二氯吡啶-4-基)-[1-4-氯苄基)-7-氮杂吲哚-3-基]-乙醛酰胺
N-(3,5-二氯吡啶-4-基)-[1-(4-甲氧基苄基)-7-氮杂吲哚-3-基]-乙醛酰胺
N-(2,6-二氯苯基)-[l-(4-氯苄基)-7-氮杂吲哚-3-基]-乙醛酰胺
N-(4-羧基苯基)-[1-(4-氟苄基)-7-氮杂吲哚-3-基]-乙醛酰胺
N-(4-乙氧基羰基苯基)-[1-(4-氟苄基)-7-氮杂吲哚-3-基]-乙醛酰胺
N-(3,4-二甲氧基苯基)-[1-(4-氟苄基)-7-氮杂吲哚-3-基]-乙醛酰胺
N-(3,5-二氯吡啶-4-基)-[1-(4-甲基苄基)-7-氮杂吲哚-3-基]-乙醛酰胺
N-(3,5-二氯吡啶-4-基)-[1-(4-羟基苄基)-7-氮杂吲哚-3-基]-乙醛酰胺
N-(3,5-二氯吡啶-4-基)-[1-(3-羟基苄基)-7-氮杂吲哚-3-基)-乙醛酰胺
N-(3,5-二氯吡啶-4-基)-(1-环丙基甲基-7-氮杂吲哚-3-基)-乙醛酰胺
N-(3,5-二氯吡啶-4-基)-(1-己基-7-氮杂吲哚-3-基)-乙醛酰胺
N-(3,5-二氯吡啶-4-基)-(1-异丁基-7-氮杂吲哚-3-基)-乙醛酰胺
N-(3,5-二氯吡啶-4-基)-[1-(2-甲基丙烯-3-基)-7-氮杂吲哚-3-基]-乙醛酰胺
N-(3,5-二氯吡啶-4-基)-[1-(2-甲氧基乙基)-7-氮杂吲哚-3-基]乙醛酰胺
N-(3,5-二氯吡啶-4-基)-[1-(1-萘基甲基)-7-氮杂吲哚-3-基]乙醛酰胺
N-(3,5-二氯吡啶-4-基)-[1-(4-吡啶基甲基)-7-氮杂吲哚-3-基]-乙醛酰胺
N-(3,5-二氯吡啶-4-基)-[1-(3,5-二甲基异噁唑-4-基甲基)-7-氮杂吲哚-3-基]-乙醛酰胺
N,N-二(2-甲氧基乙基)-[1-(4-氟苄基)-7-氮杂吲哚-3-基]乙醛酰胺
[1-(4-氟苄基)-7-氮杂吲哚-3-基]-乙醛酰基吗啉
[1-(4-氟苄基)-7-氮杂吲哚-3-基]-乙醛酰基(S,S-二氧代吗啉)
[1-(4-氟苄基)-7-氮杂吲哚-3-基]-乙醛酰基(4-甲基哌嗪),
N-(6-甲基尿嘧啶-5-基)-[1-(4-氟苄基)-7-氮杂吲哚-3-基]-乙醛酰胺
N-(3,6-二甲基尿嘧啶-5-基)-[1-(4-氟苄基)-7-氮杂吲哚-3-基]-乙醛酰胺
N-(1,3,6-三甲基尿嘧啶-5-基)-[1-(4-氟苄基)-7-氮杂吲哚-3-基]-乙醛酰胺和
N-(1,2,4-4H-三唑-3-基)-[1-(4-氟苄基)-7-氮杂吲哚-3-基]-乙醛酰胺。
6.合成其中n=1的权利要求1-4任一项的式1化合物的方法,其特征在于用酰氯将7-氮杂吲哚-3-甲酸转化成类似的7-氮杂吲哚-3-甲酰氯,然后通过与伯胺或仲胺反应将其转化成其中n=1的式1本发明化合物。
7.根据权利要求6的方法合成式1化合物,其特征在于使用亚硫酰氯或草酰氯作为酰氯来合成7-氮杂吲哚-3-甲酰氯。
8.根据权利要求6或7的方法合成式1化合物,其特征在于在辅助性碱存在下,优选在用作反应物的过量胺,叔胺,例如吡啶或三乙胺,和无机碱,优选碱金属氢氧化物或碱金属氢化物存在下将7-氮杂吲哚-3-甲酰氯与伯胺或仲胺反应。
9.合成其中n=2的权利要求1-3和5任一项的式1化合物的方法,其特征在于用草酰氯将7-氮杂吲哚转化成类似的7-氮杂吲哚-3-基乙醛酰氯,然后通过与伯胺或仲胺反应将其转化成其中n=2的式1化合物。
10.根据权利要求9的方法合成式1化合物,其特征在于在辅助性碱存在下,优选在用作反应物的过量胺,叔胺,例如吡啶或三乙胺,和无机碱,优选碱金属氢氧化物或碱金属氢化物存在下将7-氮杂吲哚-3-基乙醛酰氯与伯胺或仲胺反应。
11.权利要求1-5任一项的式1化合物作为治疗活性组分在制备用于治疗其中抑制TNFα对其治疗有用的疾病的药物中的应用。
12.权利要求1-5任一项的式1化合物作为治疗活性组分在制备用于治疗其中抑制磷酸二酯酶4对其治疗有用的疾病的药物中的应用。
13.权利要求1-5任一项的式1化合物作为治疗活性组分在制备用于治疗与嗜酸性细胞的作用有关的疾病的药物中的应用。
14.权利要求1-5任一项的式1化合物作为治疗活性组分在制备用于治疗与中性白细胞的作用有关的疾病的药物中的应用。
15.权利要求1-5任一项的化合物作为活性组分在制备下述用于治疗和/或预防下列抑制TNFα对其治疗有用的疾病的药物和用作支气管扩张药的药物,用于抑制发展成药物依赖性和用于降低发展成耐药性的药物中的应用:尤其是关节炎症、关节炎、类风湿性关节炎、关节炎性疾病、类风湿性脊椎炎、骨关节炎、骨质疏松、脓毒症、脓毒性休克、格兰氏阴性脓毒症、中毒性休克综合征、呼吸窘迫综合征、哮喘、慢性肺病、骨吸收疾病、移植排斥反应、自身免疫性疾病、红斑狼疮、多发性硬化、肾小球性肾炎、眼色素层炎、胰岛素依赖性糖尿病、慢性脱髓鞘、病毒性疾病、病毒感染、寄生虫感染、疟疾、利什曼病、感染引起的发烧、感染引起的肌肉疼痛、AIDS、恶病质,可通过抑制磷酸二酯酶4来治疗的疾病、哮喘、其中嗜酸性细胞起作用的疾病、支气管哮喘、过敏性鼻炎、过敏性结膜炎、特应性皮炎、湿疹、过敏性脉管炎、嗜酸性细胞引起的炎症、嗜酸细胞性筋膜炎、嗜酸细胞性肺炎、PIE综合征、荨麻疹、溃疡性结膜炎、局限性回肠炎、增殖性皮肤病、牛皮癣、角化病、慢性堵塞性肺病、可通过神经保护治疗的疾病、老年痴呆、阿尔茨海默氏病、记忆遗失、帕金森氏病、抑郁症、中风、间歇性跛行、前列腺疾病、良性前列腺增生、频尿、夜尿症、失禁、绞痛、尿石性绞痛和男性或女性性功能障碍。
16.药物,其中除了常规生理可耐受载体和/或稀释剂或辅助剂外还含有一种或多种权利要求1-5的化合物。
17.制备权利要求16的药物的方法,其特征在于将一种或多种权利要求1-5任一项的化合物和常规生理可耐受载体和/或稀释剂或其它辅助剂一起加工成药物制剂或/和制成可治疗使用的形式。
18.单独或彼此组合或与载体和/或稀释剂或其它辅助剂组合的权利要求1-5任一项的化合物和/或权利要求16或17的药物制剂的应用。
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