CN1304311A - 桥连的茚并吡咯并咔唑 - Google Patents
桥连的茚并吡咯并咔唑 Download PDFInfo
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- CN1304311A CN1304311A CN99807036A CN99807036A CN1304311A CN 1304311 A CN1304311 A CN 1304311A CN 99807036 A CN99807036 A CN 99807036A CN 99807036 A CN99807036 A CN 99807036A CN 1304311 A CN1304311 A CN 1304311A
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- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 230000001361 thrombopoietic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 102000047459 trkC Receptor Human genes 0.000 description 1
- 108010064892 trkC Receptor Proteins 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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Abstract
本发明涉及新型稠合芳基和杂芳基桥连的茚并吡咯并咔唑,它尤其可以用作治疗剂,本发明还涉及制备和应用这种桥连的茚并吡咯并咔唑的方法。
Description
发明领域
本发明涉及新型稠合芳基和杂芳基桥连的茚并吡咯并咔唑,在本文中称作“桥连的茚并吡咯并咔唑”,本发明还涉及这种桥连的茚并吡咯并咔唑的制备和应用方法。
发明背景
在过去的几年里,称为“L-252a”的微生物产生的物质由于其具有多种功能活性而成为引起广泛关注的独一无二的化合物。K-252a是一种最初从Nocordiosis sp.培养物分离出来的吲哚并咔唑生物碱(Kase,H等,39,抗生素杂志(J.Antibiotics)1059,1986)。K-252a是几种酶的抑制剂,包括蛋白激酶C(PKC)和trk酪氨酸激酶,蛋白激酶C在调节细胞功能方面起重要作用。报道的K-252a及其衍生物的功能活性是多种多样的:抑制肿瘤(参见美国专利号4877776、4923986和5063330;欧洲公开专利238011,申请人是Nomato);抗-杀虫剂活性(参见美国专利4735939);抑制炎症(美国专利4816450);治疗与神经元细胞相关的疾病(参见美国专利5,461,146、5,621,100、5,621,101和WIPO公开专利WO94/02488,1994年2月3日,申请人为Cephalon,Inc.和Kyowa Hakko Kogyo Co.,Ltd.);以及治疗前列腺疾病(参见美国专5,516,771和5,654,427)。据报道K-252a还能够抑制t IL-2的生成(参见Grove,D.S.等,Experimental Cell Research 193:175-182,1991)。
已报道的吲哚并咔唑化合物具有几个共同的特性,特别是每个吲哚并咔唑均包含三个五元环,它们都包括氮原子部分;星形孢菌素(staurosporine)(链霉菌属Streptorrayces sp.产生)和K-252a各自进一步包括由两个N-糖苷键连接的糖基团。K-252a和星形孢菌素两者作为治疗剂的应用已进行了广泛的研究。吲哚并咔唑类一般是亲脂性的,这使得它们比较容易穿过生物膜,而不象蛋白物质。它们在体内表现为更长的半衰期。
尽管K-252a通常是经过发酵方法从培养媒介物中生成,但已经实现了天然异构体(+)和非天然异构体(-)(其中糖的三个手性碳原子具有相反的构型)的全合成(参见Wood等人,J.Am.Chem.Soc.117:10413,1995,和WIPO公开专利WO97/07081)。然而这种合成对商业用途并不实用。
除了K-252a和星形孢菌素代表的吲哚并咔唑生物碱之外,已经制备了一些具有生物活性并称为稠吡咯并咔唑的合成有机小分子(参见美国专利号5,475,110、5,591,855、5,594,009、5,705,511和5,616,724).
已知的还有稠合的异吲哚酮,它们是可以进行化学重复合成的不含吲哚结构的分子(参见WIPO公开专利WO97/21677)。
一些双吲哚基马来酰亚胺大环衍生物业已报道(例如,参见美国专利5,710,145、5,672,618、5,552,396;和5,545,636)。
已经报道的还有吲哚并吡咯并咔唑的糖衍生物(参见WIPO公开专利WO98/07433)。
仍需要新的具有有益性能的吡咯并咔唑衍生物,本发明正是针对这一需要以及其它重要的目的。
发明概要
构成部件和优选的实施方案在以下部分详细公开。该化合物可用于,尤其是,提高营养因子应答细胞的营养因子诱导活性,如胆碱能神经元;还可以作为其它类型神经元细胞,如多巴胺能和谷氨酰能神经元的促活剂,因而成为有益的药物和治疗剂。该化合物还适用于治疗与ChAT活性降低,或脊索运动神经元死亡或损伤相关的疾病。还用于治疗与中枢和末梢神经系统、免疫系统细胞的下垂蛋白(apoptotic)死亡相关的疾病,以及治疗炎症疾病。
本文所述的一些桥连的茚并吡咯并咔唑化合物还可用于治疗涉及恶性细胞增殖的病状,如癌症。
公开了含有主题化合物的组合物、和主题化合物的使用方法,还公开了该桥连的茚并吡咯并咔唑化合物的制备方法,对本领域技术人员而言,一旦获得本公开内容,其它有用的制备方法是显而易见的。本发明化合物的这些特征和其它特征在下面给予更为详细的阐明。
附图的简要说明
附图1所示是制备桥连的茚并吡咯并咔唑的一般线路图。
附图2所示是制备桥连的茚并吡咯并咔唑的一般线路图。
附图3所示是制备与树脂键合的茚并吡咯并咔唑的线路图。
附图4所示是制备被保护的、可溶的茚并吡咯并咔唑的线路图。
附图5所示是制备中间体V的线路图。
附图6所示是用方法A制备桥连的茚并吡咯并咔唑的线路图。
附图7所示是用方法B制备桥连的茚并吡咯并咔唑的线路图。
附图8所示是制备B环取代的桥连茚并吡咯并咔唑的线路图。
附图9所示是制备桥连茚并吡咯并咔唑的E环衍生的线路图。
发明详述
本文公开的是以下式Ⅰ表示的桥连茚并吡咯并咔唑:其中:
B环和F环,各自独立地与它们所连接的碳原子一起,为选自下面的基团:
(a)其中1-3个碳原子可以被氮原子置换的不饱和6-员芳香
碳环;
(b)不饱和5-员芳香碳环;和
(c)不饱和5-员芳香碳环,其中:
(1)一个碳原子被氧原子、氮原子、或硫原子置换;
(2)两个碳原子被一个氮原子和一个硫原子、一个氮原
子和一个氧原子、或两个氮原子置换;或
(3)三个碳原子被三个氮原子置换;
R1选自:
(a)H、取代或未取代的1-4个碳原子烷基、取代或未取代的
芳基、取代或未取代的芳基烷基、取代或未取代的杂芳
基、或取代或未取代的杂芳基烷基;
(b)-C(=O)R9,其中R9选自烷基、芳基和杂芳基;
(c)-OR10,其中R10选自H和1-4个碳原子烷基;
(d)-C(=O)NH2、-NR11R12、-(CH2)pN11R12、-(CH2)pOR10、
-O(CH2)pOR10和-O(CH2)pNR11R12,其中p是1-4;而且其
中:要么
1)R11和R12各自独立地选自H和1-4个碳原子烷基,要
么
2)R11和R12一起形成式-(CH2)2-X1-(CH2)2-的连接基,其
中X1选自-O-、-S-和-CH2-;
R2选自:H、1-4个碳原子烷基、羟基、具有1-4个碳原子烷氧基、-OC(=O)R9、-OC(=O)NR11R12、-O(CH2)pNR11R12、-O(CH2)pOR10、具有6-10个碳原子取代或未取代的芳基烷基,和取代或未取代的杂芳基烷基;
R3、R4、R5和R6各自独立地选自:
a)H、芳基、杂芳基、F、Cl、Br、I、-CN、CF3、-NO2、-OH、
-OR9、-O(CH2)pNR11R12、-OC(=O)R9、-OC(=O)NR2R7、
-OC(=O)NR11R12、-O(CH2)pOR10、-CH2OR10、-NR11R12、
-NR10S(=O)2R9、-NR10C(=O)R9
b)-CH2OR14,其中R14为移去羧基中的羟基后的氨基酸的残
基;
c)-NR10C(=O)NR11R12、-CO2R2、-C(=O)R2、-C(=O)NR11R12、
-CH=NOR2、-CH=NR9、-(CH2)pNR11R12、-(CH2)pNHR14、
或-CH=NNR2R2A,其中R2A同R2;
d)-S(O)yR2、-(CH2)pS(O)yR9、-CH2S(O)yR14,其中y是0、1或
2;
e)具有1-8个碳原子的烷基、具有2-8个碳原子的链烯基、
具有2-8个碳原子的炔基,其中:
1)各个烷基、链烯基或炔基是未取代的;或者
2)各个烷基、链烯基或炔基被1-3个选自以下的基团所
取代:
具有6-10个碳原子的芳基、杂芳基、芳基烷氧基、杂
环基烷氧基、羟基烷氧基、烷氧基-烷氧基、羟基烷硫
基、烷氧基-烷硫基、F、Cl、Br、I、-CN、-NO2、-OH、
-OR9、-X2(CH2)pNR11R12、-X2(CH2)pC(=O)NR11R12、
-X2(CH2)pOC(=O)NR11R12、-X2(CH2)pCO2R9、
-X2(CH2)pS(O)yR9、-X2(CH2)pNR10C(=O)NR11R12、
-OC(-O)R9、-OCONHR2,-O-四氢吡喃基、-NR11R12、
-NR10C(=O)R9、-NRCO2R9、-NR10C(=O)NR11R12、
-NHC(=NH)NH2、NR10S(O)2R9、-S(O)yR9、-CO2R2、
-C(=O)NR11R12、-C(=O)R2、-CH2OR10、-CH=NNR2R2A、
-CH=NOR2、-CH=NR9、-CH=NNHCH(N=NH)NH2、
-S(=O)2NR2R2A、-P(=O)(OR10)2、-OR14、和具有5-7个
碳原子的单糖,其中单糖的每个羟基各自独立地是未
取代的,或者被H、1-4个碳原子的烷基、2-5个碳原
子的烷羰氧基或具有1-4个碳原子的烷氧基所取代;
X2是O、S、或NR10;
R7和R8各自独立地选自:
H、具有1-4个碳原子的烷基、具有1-4个碳原子的烷氧基、具有6-10个碳原子的取代或未取代的芳烷基、取代或未取代的杂芳基烷基、-(CH2)pOR10、(CH2)pOC(=O)NR11R12和-(CH2)pNR11R12;或者R7和R8一起形成式-CH2-X3-CH2-的连接基,其中X3是X2或一个键。
m和n各自独立地是0、1或2。
Y选自:-O-、-S-、-N(R10)-、-N+(O-)(R10)-、-N(OR10)-和-CH2-;
Z选自:单键、-O-、-CH=CH-、-S-、-C(=O)-、-CH(OR10)-、-N(R10)-、-N(OR10)-、-CH(NR11R12)-、-C(=O)N(R17)-、-N(R17)C(=O)-、-N(S(O)yR9)-、-N(S(O)yNR11R12)-、-N(C(=O)R17)-、-C(R15R16)-、-N+(O-)(R10)-、-CH(OH)-CH(OH)-和-CH(O(C=O)R9)CH(OC(=O)R9A)-,其中R9A同R9;
R15和R16各自独立地选自H、-OH、-C(=O)R10、-O(C=O)R9、羟基烷基和-CO2R10;
R17选自H、烷基、芳基和杂芳基;
A1和A2选自H,H;H,-OR2;H,-SR2;H,-N(R2)2;和一个基团,其中A1和A2一起形成选自=O、=S和=NR2的部分;
B1和B2选自H,H;H,-OR2;H,-SR2;H,-N(R2)2;和一个基团,其中B1和B2一起形成选自=O、=S和=NR2的部分;
其前提条件是A1和A2,或B1和B2的至少一对形成=O。本发明化合物还包括位于取代基R2、R7和R8所连接的碳原子的所有非对映异构体和对映异构体。
在式Ⅱ化合物的其它优选的实施方案中,化合物具有下式的对映异构体:
在式Ⅰ和式Ⅱ化合物的一些优选实施方案中,R1为H。在更优选的实施方案中,R2为H、羟基、或者取代或未取代的烷基。
在其它优选的实施方案中,R3、R4、R5和R6各自独立地为H、取代或未取代的烷基、卤素、取代或未取代的烷氧基、取代或未取代的氨基、或者取代或未取代的芳基。在更优选的实施方案中,R7和R8各自独立地为H、或者取代或未取代的烷基。
在一些优选的实施方案中,Y为O。在更优选的实施方案中,Z为单键、O、S、或者取代或未取代的N。在进一步优选的实施方案中,m和n各自独立地是1或2。在一些特别优选的实施方案中,Y为O,Z为单键或O,且m和n各自独立地是1或2。在更优选的实施方案中,A1A2和B1B2各自独立地是=O或H,H。
在一些特别优选的实施方案中,R1、R4、R6和R7各自为H,Y是=O,n是1,A1A2和B1B2是=O或H,H,R2是H、OH、或低碳烷基,R3是H或取代烷基,R5和R8各自为H或烷氧基,并优选甲氧基,Z为单键或O,以及m是1或2。
a)H、杂芳基、F、Br、-CN、CF3、-NO2、-OH、-OR9、
-O(CH2)pNR11R12、-OC(=O)R9、-OC(=O)NR2R7、
-OC(=O)NR11R12、-O(CH2)pOR10、-CH2OR10、-NR11R12、
-NR10S(=O)2R9、-NR10C(=O)R9;
c)-NR10C(=O)NR11R12、-CO2R2、-C(=O)R2、-C(=O)NR11R12、
-CH=NOR2、-CH=NR9、-(CH2)pNR11R12、-(CH2)pNHR14、
或-CH=NNR R2A,其中R2A同R2;
d)-S(O)yR2-(CH2)pS(O)yR9、-CH2S(O)yR14,其中y是0,1或2;
e)具有1-8个碳原子的烷基、具有2-8个碳原子的链烯基、
具有2-8个碳原子的炔基,其中:
1)各个烷基、链烯基或炔基是未取代的;或者
2)各个烷基、链烯基或炔基被1-3个选自以下的基团所
取代:具有6-10个碳原子的芳基、杂芳基、芳基烷氧基、杂环基烷氧基、羟基烷氧基、烷氧基-烷氧基、羟基烷硫基、烷氧基-烷硫基、F、Cl、Br、I、-CN、-NO2、-OH、-OR9、-X2(CH2)pNR11R12、-X2(CH2)pC(=O)NR11R12、-X2(CH2)pOC(=O)NR11R12、-X2(CH2)pCO2R9、-X2(CH2)pS(O)yR9、-X2(CH2)pNR10C(=O)NR11R12、-OC(=O)R9、-OCONHR2,-O-四氢吡喃基、-NR11R12、-NR10C(=O)R9、-NR10CO2R9、-NR10C(=O)NR11R12、-NHC(=NH)NH2、NR10S(O)2R9、-S(O)yR9、-CO2R2、-C(=O)NR11R12、-C(=O)R2、-CH2OR10、-CH=NR9、-S(=O)2NR2R2A、-OR14、和具有5-7个碳原子的单糖,其中单糖的每个羟基各自独立地是未取代的,或者被H、1-4个碳原子的烷基、2-5个碳原子的烷羰氧基或具有1-4个碳原子的烷氧基所取代;
在更为优选的实施方案中,R5独立地选自基团:H、-OR9、-O(CH2)pNR11R12、-OC(=O)R9、-OC(=O)NR2R7、-OC(=O)NR11R12、-O(CH2)pOR10、-CH2OR10、-NR11R12、-NR10S(=O)2R9、-NR10C(=O)R9、-C(=O)NR11R12、-(CH2)pNR11R12、-S(O)yR2、-(CH2)pS(O)yR9和-CH2S(O)yR14,其中y是0、1或2。
式Ⅱ化合物的一些特别优选的实施方案为化合物Ⅱ-1、Ⅱ-1b、Ⅱ-2、Ⅱ-3、Ⅱ-4a、Ⅱ-4b、Ⅱ-5、Ⅱ-6、Ⅱ-7a、Ⅱ-7b、Ⅱ-8、Ⅱ-9、Ⅱ-10、Ⅱ-11、Ⅱ-12、Ⅱ-13、Ⅱ-14a、Ⅱ-14b、Ⅱ-15、Ⅱ-16a和Ⅱ-16b,它们的结构表述在下面的表8中。式Ⅱ化合物的一些具有手性特征的实施方案表述在下面的表9中。
在其它实施方案中,本发明提供了含有式Ⅰ或式Ⅱ化合物和可药用载体的药物组合物。
在一些优选的药物组合物中,组合物用来抑制trk激酶活性、VEGFR激酶活性或PDGFR活性中的一种或多种,在该组合物中含有式Ⅰ化合物和可药用载体。在其它优选的药物组合物中,组合物用来提高营养因子或脊索ChAT的活性,在该组合物中含有式Ⅰ化合物和可药用载体。
在其它优选的药物组合物中,组合物用来治疗或预防前列腺疾病,如前列腺癌或良性的前列腺增生。在其它优选的药物组合物中,组合物用来治疗或预防血管生成性疾病(angiogenic disorders),如固体肿瘤、子宫内膜异位、糖尿病视网膜病、牛皮癣、成血管细胞瘤、眼科疾病或斑状变性(macular degeneration)。在其它优选的药物组合物中,组合物用来治疗或预防瘤形成(neoplasia)、类风湿关节炎、肺纤维变性、脊髓纤维变性、意外创伤的愈合、动脉粥样硬化或再狭窄(restenosis)。在其它优选的药物组合物中,组合物用来治疗或预防阿尔茨海默氏病、肌萎缩性侧索硬化、帕金森病、中风、局部缺血、亨廷顿舞蹈病、爱滋病痴呆、癫痫、多发性硬化、末稍神经病、脑损伤或脊索损伤。
在其它实施方案中,本发明提供了抑制trk激酶活性的方法,包括:给予足够量的式Ⅰ化合物,以获得有效的抑制。在一个优选的实施方案中,用式Ⅰ化合物治疗炎症。在另一个优选的实施方案中,trk激酶的受体是trkA。
在其它实施方案中,本发明提供了治疗或预防前列腺疾病的方法,包括:对需要治疗或预防的宿主给予治疗有效量的式Ⅰ化合物。在优选的实施方案中,前列腺疾病是前列腺癌或良性前列腺增生。
在其它实施方案中,本发明提供了那些病理状态缘于VEGFR激酶活性的血管原生成性疾病的治疗或预防方法,包括:给予足够量的式Ⅰ化合物,使得血管内皮的生长因子受体与有效抑制量的化合物接触。在另一个实施方案中,本发明提供了治疗或预防血管生成性疾病的方法,包括:对需要治疗或预防的宿主给予治疗有效量的式Ⅰ化合物。在优选的实施方案中,所述血管生成性疾病是固体肿瘤、眼科疾病、斑状变性、子宫内膜异位、糖尿病视网膜病、牛皮癣或成血管细胞瘤。
在其它实施方案中,本发明提供了那些病理状态缘于PDGFR激酶活性的疾病的治疗或预防方法,包括:给予足够量的式Ⅰ化合物,使得血小板产生的生长因子受体与有效抑制量的化合物接触。在另一个实施方案中,本发明提供了治疗或预防疾病的方法,包括:对需要治疗或预防的宿主给予治疗有效量的式Ⅰ化合物。在优选的实施方案中,所述疾病是瘤形成、类风湿关节炎、肺纤维变性、脊髓纤维变性、意外创伤的愈合、动脉粥样硬化或再狭窄。
在其它实施方案中,本发明提供了那些特征为营养因子应答细胞活性异常的疾病的治疗或预防方法,包括:给予足够量的式Ⅰ化合物,使得营养因子细胞受体与有效活性-诱导量的化合物接触。在优选的实施方案中,所述营养因子应答细胞的活性为ChAT活性。在另一个实施方案中,本发明提供了治疗或预防阿尔茨海默氏病、肌萎缩性侧索硬化、帕金森病、中风、局部缺血、亨廷顿舞蹈病、爱滋病痴呆、癫痫、多发性硬化、末稍神经病、脑损伤或脊索损伤的方法,该方法包括:对需要治疗或预防的宿主给予治疗有效量的式Ⅰ化合物。
本发明的化合物包括所有的非对映异构体和对映异构体。本文中,式(Ⅰ)化合物也称为化合物(Ⅰ),这同样适用于其它式码的化合物。
本文所采用的术语“碳环”是指环部分仅仅由碳原子组成的环基团。术语“杂环”是指环部分至少包括一个杂原子(如O、N或S)的环基团。
本文所采用的术语“烷基”是指具有1-8个碳原子的直链、环状或支链化的烷基,如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、辛基、环丙基和环戊基。含烷基基团(如烷氧基、烷氧羰基和烷基氨基羰基)的烷基部分,其含义与上述定义的烷基相同。优选的低碳烷基是指上述定义的具有1-4个碳原子的烷基。术语“链烯基”是指至少具有一个C-C双键的直链或支链的烃链,链烯基的例子包括乙烯基和丙烯基。本文所用的术语“炔基”是指至少含有一个C-C叁键的直链或支链的烃链,炔基的例子包括乙炔基和丙炔基。
含酰基基团(如酰氧基)的酰基部分,是指具有1-6个碳原子的直链或支链的烷羰基,如甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、新戊酰基或己酰基。
本文所用的术语“芳基”是指具有6-12个碳原子的基团,如苯基、联苯基和萘基,优选的芳基包括取代或未取代的苯基和萘基。本文所用的术语“杂芳基”表示一个或多个环碳原子被杂原子(即非碳原子,如O、N或S)置换的芳基,优选的杂芳基包括吡啶基、嘧啶基、吡咯基、呋喃基、噻吩基、咪唑基、三唑基、四唑基、喹啉基、异喹啉基、苯并咪唑基、噻唑基、吡唑基和苯并噻唑基。
术语“芳烷基”表示具有7-15个碳原子的基团,由带有一个芳基的烷基所组成。芳烷基的例子包括苄基、苯乙基、二苯基甲基和萘甲基。含有取代基在内的烷基和烷基部分(如芳烷基、烷氧基、芳基烷氧基、羟基烷氧基、烷氧基-烷氧基、羟基-烷硫基、烷氧基-烷硫基、烷羰氧基、羟基烷基和酰氧基)可以是取代或未取代的。取代烷基具有1-3个独立选择的取代基,优选羟基、低碳烷氧基、低碳烷氧基-烷氧基、取代或未取代的芳基烷氧基-低碳烷氧基、取代或未取代的杂芳基烷氧基-低碳烷氧基、取代或未取代的芳基烷氧基、取代或未取代的杂芳基烷氧基、卤素、羧基、低碳烷氧羰基、硝基、氨基、一或二低碳烷基氨基、二氧戊环、二氧六环、二硫戊环、二硫六环、呋喃、内酯或内酰胺。
取代的芳基、取代的杂芳基、取代的芳烷基各自具有1-3个独立选择的取代基,它们优选低碳烷基、羟基、低碳烷氧基、羧基、低碳烷氧羰基、硝基、氨基、一或二低碳烷基氨基和卤素。
由氮原子形成的杂环基包括吡咯烷基、哌啶基、哌啶子基、吗啉基、吗啉代基、硫吗啉代基、N-甲基哌嗪基、吲哚基、异吲哚基、咪唑、咪唑啉、恶唑啉、恶唑、三唑、噻唑啉、噻唑、吡唑、吡唑酮和三唑基团。由氧原子形成的杂环基包括呋喃、四氢呋喃、吡喃和四氢吡喃。
“羟基烷基”是指含有羟基连接其上的烷基。“卤素”是指氟、氯、溴和碘。
本文所用的术语“杂芳基烷基”是指含有杂原子的芳烷基,术语“氧基oxy”表示存在的氧原子。因而“烷氧基”是通过氧原子连接的烷基,“羰氧基”是通过氧原子连接的羰基。
术语“杂环基烷氧基”是指杂环基连接到其烷基部分的烷氧基,而“芳基烷氧基”是指芳基连接到其烷基部分的烷氧基,术语“烷羰氧基”是指式“-O-C(=O)-烷基”的基团。
本文所用的术语“烷氧基-烷氧基”表示含有一个烷氧基取代基连接在其烷基部分的烷氧基。术语“烷氧基-烷硫基”是指含有一个烷氧基取代基连接在其烷基部分的烷硫基(即式“-S-烷基”基团)。术语“羟基-烷硫基”是指含有一个羟基取代基连接在其烷基部分的烷硫基(即式“-S-烷基”基团)。
本文所用的术语“单糖”是指具有习惯意义上的单糖。
本文所用的术语“氨基酸”表示同时含有氨基和羧基的分子,氨基酸的具体例子包括α-氨基酸,即,通式HOOC-CH(NH2)-(侧链)的羧酸。
氨基酸侧链包括天然的和非天然的侧链,非天然的氨基酸侧链是用来取代氨基酸同系物中的天然氨基酸侧链的基团。例如,参见Lehninger,Biochemistry,第二版,Worth Publishers,Inc,1975,pp73-75,在此引作参考。
优选的α-氨基酸包括甘氨酸、丙氨酸、脯氨酸、谷氨酸和赖氨酸,它们具有D构型、L构型,或者是外消旋体。
其它有代表性的α-氨基酸的侧链见表1所示。
在一些优选的实施方案中,式Ⅰ和式Ⅱ化合物的取代基包括脱除羧基中的羟基部分后形成的氨基酸残基,即,式-C(=O)C-CH(NH2)-(侧链)基团。
存在于式Ⅰ化合物上的功能基可以包含保护基,例如式Ⅰ化合物的氨基酸侧链取代基可以被保护基所代替,如苄氧羰基或叔丁氧羰基。保护基是一种公知的化学功能基,它可以选择性地附加到官能度(如羟基和羧基)或从官能度上离去,这些基团存在于化合物这种使得该官能度在化合物暴露的化学反应条件下保持惰性。本发明可以使用各种不同的保护基。这类保护基之一是苄氧羰基(Cbz;Z)。本发明其它优选的保护基可参见Greene,T.W.和Wuts,P.G.M.,“有机合成中的保护基(Protective Groups in organic Synthesis)”第二版,Wiley & Sons,1991。
桥连茚并吡咯并咔唑化合物已显示出重要功能的药理学活性,可用于不同的背景,包括研究和治疗领域。这些衍生物是有用的治疗剂,化合物的活性对营养因子应答细胞的功能和/或存活表现为正作用。对于营养因子应答细胞(如神经元直系细胞,)的功能和/或存活的作用,已采用以下试验予以揭示:(1)培养脊索胆碱乙酰转移酶(“ChAT”)试验;或者(2)培养基础前脑神经元ChAT活性试验。
本文所用的术语“作用(effect)”,当用于修饰术语“功能”和“存活”时,是指正的或负的改变或变化,正作用在这里可称为“增强作用”或“增强”;负作用在这里可称为“抑制作用”或“抑制”。
本文所用的术语“增强”,当用来修饰术语“功能”和“存活”时,是指桥连茚并吡咯并咔唑化合物存在对营养因子应答细胞的功能和/或存活,相比于没有该化合物存在下的细胞,具有正作用。例如(不作为限制)对于胆碱能神经元的存活,如果治疗群落比未治疗群落有相对更长的功能期,则表明该化合物对濒于死亡(例如由于损伤、疾病、退化或自然进行性死亡)的胆碱能神经元群,相比于没有该化合物存在下的胆碱能神经元群,具有增强存活作用。
本文所用的“抑制”和“抑制作用”是指在桥连茚并吡咯并咔唑化合物存在下,指定物质的特异反应(例如酶的活性)相对降低。
本文所用的术语“trk”指一族高亲和性的神经营养蛋白的受体,目前包括trkA、trkB和trkC,及其它可以被神经营养蛋白结合的膜结合蛋白。
在本文中,VEGFR抑制作用意味着疾病用途,例如,相关生成均匀重要作用的疾病,如固体肿瘤、子宫内膜异位、糖尿病视网膜病、牛皮癣、成血管细胞瘤,以及其它眼病和癌症。
对trk的抑制作用意味着疾病用途:前列腺疾病如前列腺癌和良性前列腺增生,以及治疗炎症疼痛。
对血小板生成的生长因子受体(PDGFR)的抑制作用意味着疾病用途,例如,瘤形成、类风湿关节炎、肺纤维变性、脊髓纤维变性、意外创伤愈合,与心血管端岔相关的疾病,如粥样动脉硬化、再狭窄、血管成形术后再狭窄等。
本文所用的术语“癌”或“癌性的”是指哺乳动物细胞的恶性增生,例子包括前列腺癌、良性前列腺增生、卵巢癌、乳腺癌、脑瘤、肺癌、胰腺癌、结肠直肠(colorectal)癌、胃癌、腹部肿瘤、固体肿瘤、头和颈部肿瘤、成神经细胞瘤、肾细胞癌、淋巴瘤、白血病,其它已确认的造血系统的恶性肿瘤。
本文所用的术语“神经元”,“神经元直系细胞”和“神经元细胞”包括(但不限于)具有单一传递质或多种传递质和/或单一或多种功能的神经元类型的不均匀群落,优选它们是胆碱能神经元和感觉神经元。这里所用的术语“胆碱能神经元”指神经介质是乙酰胆碱的中枢神经系统(CNS)和未梢神经系统(PNS)神经元;例如基础前脑神经元、纹状体神经元和脊髓神经元。这里所用的术语“感觉神经元”包括,例如对环境提示(例如温度,运动)产生应答的神经元,如来自皮肤、肌肉和关节的神经元;例如,来自脊神经节的神经元。
本文定义的“营养因子应答细胞”是含有能够被营养因子特异性结合的受体的细胞;例子包括神经元(例如,胆碱能神经元和感觉神经元)和非神经元细胞(例如单核细胞和致瘤性细胞)。
本发明所述的桥连茚并吡咯并咔唑化合物应用于研究和治疗领域,如在抑制酶活性方面。在研究领域,例如,化合物可用于开发测试方法和模型,以进一步弄清,在相关功能障碍和疾病机制中,抑制丝氨酸/苏氨酸或酪氨酸蛋白激酶(如PKC,trk酪氨酸激酶)所起到的作用。在治疗领域,抑制这些酶活性的化合物可用来抑制这些酶对疾病(如癌症)的有害后果。
如以下实施例所示,使用桥连茚并吡咯并咔唑化合物,对酶活性的抑制作用可以通过如下的试验方法测定:
1、trkA酪氨酸激酶活性抑制试验;
2、在全细胞制备过程中,NGF-激励的trk磷酸化作用的抑制;
3、血管内皮生长因子受体(VEGFR)激酶的抑制试验;
4、PKC活性抑制试验;和
5、PDGFR抑制试验。
所公开的桥连茚并吡咯并咔唑化合物可用来增强哺乳动物(如,人)的神经元细胞的功能和/或存活。在本文中,该化合物可以独立使用或与其它稠合的吡咯并咔唑和/或吲哚并咔唑一起使用,或者和其它能够对指定细胞的功能和/或存活显有作用的有益分子联合使用。
各种神经疾病的特征表现为神经元细胞的:趋于死亡、损伤、功能受害、轴索退化、濒于死亡等等。这些疾病包括(但不限于)阿尔茨海默氏病、运动神经元疾病(例如肌萎缩性侧索硬化)、帕金森病、脑血管疾病(例如中风,局部缺血)、亨廷顿舞蹈病、爱滋病痴呆、癫痫、多发性硬化;末稍神经疾病(例如,那些在化学治疗有关的未梢神经病中影响到DRG神经元的疾病)包括糖尿病神经病、兴奋性氨基酸诱导的疾病、与脑或脊索的震荡或穿透性损伤有关的疾病。
ChAT对神经介质乙先胆碱的合成起催化作用,并被认为是功能性胆碱能神经元的酶标物。功能神经元也能存活。神经元的存活是将活神经元对一种染料(例如,钙黄绿素AM)的特异性摄入和酶转化进行定量来分析的。
由于它们的不同用途,本发明的桥连茚并吡咯并咔唑化合物可用于不同的情况下。这些化合物可用于神经元细胞存活、功用、鉴定的体外模型的开发,或者用于筛选其它和茚并吡咯并咔唑化合物具有相似活性的合成化合物。这些化合物可用于研究领域,以研究、定义和测定与功能应答相关的分子靶。例如,通过放射标记一种与特定的细胞功能(例如,促有丝分裂作用)相关的桥连茚并吡咯并咔唑化合物,该衍生物所结合的靶物实体可以被鉴定、分离、和纯化而用于表征。
所述化合物不仅用于增强营养因子细胞(如胆碱能神经元)的营养因子诱导活性,而且可以作为其它神经元细胞类型(如多巴胺能和谷氨酰能神经元)的存活促进剂。生长因子以信号通知小GTP结合蛋白ras、rac和cdc42的级联下游,来调整神经元的存活(Denhardt,D.T.,Biochem.J.,1996,318,729)。具体讲,ras的激活导致磷酸化作用和细胞外受体活化激酶(ERK)的活化,而这些已经和生物的生长和分化过程相连接。rac/cdc42的兴奋使得JNK和p38的活化加强,产生和紧张、下垂蛋白(apoptosis)和炎症相关的应答。尽管生长因子主要是通过ERK途径,但是,对这些后面的过程的影响可以导致神经元存活的另一机制,这可以模拟生长因子增强存活的性能(Xia等人.,Science,1995,270,1326)。化合物还可以通过一种和生长因子介导存活相关的,但又不同于它的机制,作为神经元细胞和非神经元细胞的存活促进剂,例如,抑制JNK和p38途径,这可以通过抑制下垂蛋白(apoptotic)细胞死亡过程而导致存活。
本发明化合物用于治疗和ChAT活性降低或脊索运动神经元死亡、损伤相关的疾病,还用于,例如中枢和末梢神经系统、免疫系统的下垂蛋白(apoptotic)细胞死亡相关的疾病,以及炎症疾病。
本文所述的桥连茚并吡咯并咔唑化合物还可以用于治疗涉及恶性细胞增生的疾病,如许多癌症。
化合物(Ⅰ)的可药用盐包括可药用的酸加成盐、金属盐、铵盐、有机胺加成盐、和氨基酸加成盐。酸加成盐的例子为无机酸加成盐如盐酸盐、硫酸盐和磷酸盐,以及有机酸加成盐如乙酸盐、马来酸盐、富马酸盐、洒石酸盐,柠檬酸盐和乳酸盐;金属盐的例子是碱金属盐如锂盐、钠盐和钾盐,碱土金属盐如镁盐和钙盐,铝盐和锌盐;铵盐的例子是铵盐和四甲基铵盐;有机胺加成盐的例子是与吗啉和哌啶形成的盐;氨基酸加成盐的例子是与甘氨酸、苯丙氨酸、谷氨酸和赖氨酸形成的盐,
本文提供的化合物可与可药用的无毒赋形剂和载体混合,配制成药物组合物。该组合物可被制备成非肠道用药,特别是液状溶液或悬浮液的形式;或口服给药,尤其是片剂或胶囊的形式;或鼻内给药,尤其是粉剂、滴鼻剂或气雾剂的形式;或皮肤给药,如,通过透皮膏药。
该组合物可以方便地以单位剂量形式给药,也可通过任一种在药物领域中熟知的方法进行制剂,例如,在Remington’s PharmaceuticalSciences(Mack Pub.Co.,Easton,PA,1980)中所描述的方法。用于非肠道给药的制剂可以含有无菌水或盐水、聚亚烷基二醇(如聚乙二醇)、油和植物原料、氢化萘等作为一般的赋形剂。特别是具有生物相容性的、可生物降解的丙交酯聚合物、丙交酯/乙交酯共聚物或聚氧化乙烯-聚氧化丙烯共聚物,也可以用作赋型剂以控制活性化合物的释放。对于这些活性化合物,其它可采用的非肠道释药体系包括乙烯-乙酸乙烯酯共聚物颗粒、渗透泵、可植入输注体系和微脂粒。吸入给药制剂含有例如乳糖作为赋型剂,或者是含有包含如聚氧乙烯-9-月桂基醚、甘氨胆酸盐和脱氧胆酸盐的水溶液,或者是鼻滴剂形式给药的油性溶液,或者是用于鼻内的凝胶。用于非肠道给药的制剂还可以包括:用于口腔给药的甘氨胆酸盐、用于直肠给药的水杨酸盐、或用于阴道给药的柠檬酸。用于透皮给药的制剂优选是亲油性乳剂。
本发明的化合物可在药物组合物中作为唯一的活性剂。另外,它们也可以和其它的活性成份联合使用,例如,有利于疾病中的神经元存活或轴索再生的其它生长因子。
式Ⅰ化合物及其可药用盐可以用口服给药或非口服给药,例如油膏或注射。本发明的化合物的浓度在治疗组合物中可以变化,该浓度取决于,例如,用于给药的总剂量、所用化合物的化学性质(例如疏水性)、给药途径、病人的年龄、体重和症状等因素。对于非肠道给药,本发明的化合物一般提供以含约0.1-10%w/v化合物的水性生理缓冲溶液。一般剂量范围是每天每kg体重约1μg-1g,优选剂量是每天每kg体重0.01mg-100mg,优选约0.1-20mg每kg体重,每天一到四次给药。药物的优选剂量可能取决于变化因素,如疾病或病症的种类和发展程度、具体病人的整体健康状况、所选化合物的相对生物效能、化合物赋形剂的制剂及其给药途径等。
式Ⅰ化合物及其可药用盐可以其自身给药,或根据药物活性和给药目的,以不同的药物组合物形式给药。本发明的药物组合物可以将有效量的式Ⅰ化合物或其可药用盐,作为活性成分与可药用载体均匀混合来制备。根据适于给药的组合物形式,载体的形式可以是宽范围的形式。希望这样的药物组合物制成适于口服或非口服给药的单位剂量形式。用于非口服给药的形式包括油膏和注射剂。
片剂的制备可以按照常规方式,使用诸如乳糖、葡萄糖、蔗糖、甘露糖醇和甲基纤维素的赋形剂,诸如如淀粉,藻酸钠、羧甲基纤维素钙和结晶纤维素的崩解剂,诸如硬脂酸镁和滑石的润滑剂,诸如明胶、聚乙烯醇、聚乙烯吡咯烷酮、羟丙基纤维素和甲基纤维素的粘合剂,诸如蔗糖脂肪酸酯和山梨糖醇脂肪酸酯表面活性剂等等。最好是每片含有15-300mg活性成份。
颗拉的制备可以按照常规方式,使用诸如乳糖和蔗糖的赋形剂,诸如淀粉的崩解剂,诸如明胶等的粘结剂等等。粉末的制备可以按照常规方式,使用诸如乳糖和甘露糖醇的赋形剂。胶囊的制备可以按照常规方式,使用诸如明胶、水、蔗糖、阿拉伯树胶、山梨糖醇、甘油、结晶纤维素、硬脂酸镁、滑石等。最好是每个胶囊含有15-300mg的活性成份。
糖浆的制备可以按照常规方式,使用糖(如蔗糖)、水、乙醇等。
油膏的制备可以按照常规方式,使用诸如凡士林、液体石蜡、羊毛脂和大粒凝胶(原文macrogol有误,应当是macrogel)的油膏基质,诸如乳酸月桂酯钠盐、氯化苯甲烃铵、脱水山梨糖醇单脂肪酸酯、羧甲基纤维素钠盐和阿拉伯树胶的乳化剂。
注射制剂的制备可以按照常规方式,使用诸如水、生理盐水、植物油(例如橄榄油和花生油)、油酸乙酯和丙二醇的溶剂,诸如如苯甲酸钠、水杨酸钠和尿烷的加溶剂,使用诸如NaCl和葡萄糖的等渗试剂,使用诸如苯酚、甲苯酚、对羟基苯甲酸酯和三氯叔丁醇的防腐剂,使用诸如抗坏血酸和焦亚硫酸纳的抗氧化剂。
通过以下用来阐明本发明的实施例,对其予以进一步说明。这些实施例既不是用来限定,也不是用来解释所公开的范围。
实施例
实施例1
trkA酪氨酸激酶活性抑制
用以前描述的(Angeles等,Anal.Biochem.236:49-55,1996)ELISA基的分析方法,检测选择的桥接的茚并吡咯并咔唑化合物抑制杆状病毒表达的人trkA胞质区域激酶活性的能力。96-孔微量滴定板包被有底物溶液(混和的人的磷脂酶C-γ1/谷光甘肽S-转移酶融合蛋白(Rotin等,EMBO J.,11:559-567,1992)),在100μl含有50mM Hepes,pH7.440μm ATP,10mM MnCl2,0.1%BSA,2%DMSO和各种浓度抑制剂的分析混合物中进行抑制研究,通过加入trkA激酶激活反应并在37℃下进行15分钟,然后加入磷酸酪氨酸抗体(UBI),接着加入二级酶结合抗体和碱性磷酸酶标记的山羊抗大鼠IgG(Bio-Rad)。通过放大的检测系统(Gibco-BRL)来测量键合酶的活性,在Graphpad Prism用S形剂量-响应(可变的坡度)方程来分析抑制数据,将导致激酶活性50%抑制的浓度称为IC50,结果记录于表2。
表2
桥接的茚并吡咯并咔唑化合物对trkA激酶活性抑制效果
化合物号 | trkA(%Inh.@300nM)IC50,nM |
Ⅱ-1 | 13 |
Ⅱ-2 | (20) |
Ⅱ-3 | 9 |
Ⅱ-4a | 76 |
Ⅱ-4b | 16 |
Ⅱ-5 | 72 |
Ⅱ-6 | 6 |
Ⅱ-7a | 11 |
Ⅱ-7b | 5 |
Ⅱ-8 | 254 |
Ⅱ-9 | (34) |
Ⅱ-10 | (17) |
Ⅱ-11 | 121 |
Ⅱ-12 | 17 |
Ⅱ-14a | 14 |
Ⅱ-14b | 242 |
实施例2
在整个细胞制剂中NGF-刺激的trk磷酸化的抑制
用以前描述的(见US专利5516771)如下的修正方法,进行桥接的茚并吡咯并咔唑化合物对NGF-刺激的磷酸化抑制,在100mm培养皿培养trkA转染的NIH3T3细胞,在37℃下,用含有化合物(100nM和1μM)或DMSO(加入作为对照)的没有血清的0.05%BSA-DMEM作为介质,缺血清培养次融合细胞(Subconfluent cells)1小时,然后花5分钟以10ng/ml的浓度加入NGF(Harlan/Bioproducts for Science),在含有清洁剂和蛋白酶抑制的缓冲液中对细胞溶解,用BCA方法对澄清的细胞溶解物规范为蛋白并用抗trk抗体进行免疫沉淀。多克隆抗-trk抗体抵抗相应于trk羧基端的14氨基酸的缩氨酸(Martin Zanca等,Mol.Cell.Biol.9:24-33,1989),在蛋白A的琼脂糖珠上可收集到免疫配合物(Sigma Chem.Co.,St.Lois,MO),用SDS聚丙烯酰胺凝胶电泳(SDS-PAGE)分离,并转移到聚偏二氟乙烯(PVDF)膜上,用抗磷酸酪氨酸抗体(UBI)进行膜的免疫印染,接着通过加入辣根过氧化酶偶联的山羊抗大鼠IgG(Bio-Rad Laboratories,Hercules,CA)培养,用ECL(AmershamLite Science,Inc.,Arlington Heights,IL)来观察磷酸化蛋白,测量trk蛋白带区域并和NGF-刺激对照进行对比,基于trk蛋白带的降低百分率,记录抑制结果,如下:0=没有降低;1=1-25%;2=26-49%;3=50-75%;4=76-100%;结果列于表3。
表3在NIH3T3细胞中,桥接的茚并吡咯并咔唑化合物对NGF-刺激的trkA
磷酸化的作用
抑制记录 | ||
化合物号 | 在100nM | 在1000nM |
Ⅱ-1 | 3 | 4 |
Ⅱ-3 | 1 | 4 |
Ⅱ-4b | 0 | 2 |
Ⅱ-6 | 4 | 4 |
Ⅱ-7a | 3 | 4 |
Ⅱ-7b | 3 | 4 |
实施例3
血管内皮生长因子受体的激酶活性抑制
用上述描述的trkA激酶ELISA分析方法检测桥接的茚并吡咯并咔唑化合物对杆状病毒表达的VEGF受体(人flk-1,KDR,VEGFR2)激酶区域激酶活性的抑制效果。将包括50mM Hepes,pH7.4,40μmATP,10mM MnCl2,0.1%BSA,2%DMSO,和不同浓度抑制剂的激酶反应混合物转移到包被有PCL-γ/GST的板上,加入VEGFR激酶,在37℃下,反应进行15分钟,通过加入抗磷酸酪氨酸抗体(UBI)来检测形成的磷酸化产品。传递二级酶结合的抗体来捕获抗体-磷酸化PCL-γ/GST配合物。通过放大的检测系统(Gibco-BRL)来测量键合酶的活性,在Graphpad Prism用S形剂量-响应(可变的坡度)方程来分析抑制数据,结果记录于表4。
表4桥接的茚并吡咯并咔唑化合物对VEGF受体激酶活性抑制作用
化合物号 | VEGFR激酶(%Inh.@300nM)IC50,nM |
Ⅱ-1 | 30 |
Ⅱ-1b | 67 |
Ⅱ-2 | >10,000 |
Ⅱ-3 | 71 |
Ⅱ-4a | 17 |
Ⅱ-4b | 184 |
Ⅱ-5 | 398 |
Ⅱ-6 | 9 |
Ⅱ-7a | 87 |
Ⅱ-7b | 260 |
Ⅱ-8 | 26 |
Ⅱ-9 | 318 |
Ⅱ-10 | 601 |
Ⅱ-11 | 205 |
Ⅱ-12 | 20 |
Ⅱ-13 | 8 |
Ⅱ-14a | 32 |
Ⅱ-14b | 538 |
Ⅱ-15 | 25 |
Ⅱ-16a | 43 |
Ⅱ-16b | 57 |
实施例4
蛋白激酶C活性抑制
用如Pitt,A.M.和Lee,C.(J.Biomol.Screening,1:47-51,1996)描述的Millipore Multiscreen TCA“in-plate”方法检测蛋白激酶C活性。在96-孔Multiscreen-DP板(Millipore)来进行分析,每份40ml的分析混和物含有20mM Hepes,pH为7.4,10mM MgCl2,2.5mM EGTA,2.5mM CaCl2,80mg/ml磷脂酰基丝氨酸,3.2mg/ml甘油二油酸酯,200mg/ml组蛋白H-1(Fluka),5mM[γ-32P]ATP,1.5ng蛋白激酶C(UBI;混合a,b,g同功酶),0.1%BSA,2%DMSO,和要测试的桥式稠和吡咯咔唑化合物,在37℃下反应进行10分钟,再加入冰冷的50%三氯乙酸停止反应,在4℃下,将板均化30分钟,再用冰25%TCA洗涤,加入混和剂,用Wallac MicroBeta 1450 PLUS闪烁计数器测量放射性,在Graphpad Prism上用S形剂量-响应(可变的坡度)方程来分析数据计算IC50值,结果记录于表5。
表5桥接的茚并吡咯并咔唑化合物对蛋白激酶C活性抑制作用
化合物号 | PKC(%Inh.@1uM)IC50,nM |
Ⅱ-1 | 1300 |
Ⅱ-2 | (-9) |
Ⅱ-3 | (23) |
Ⅱ-4a | (18) |
Ⅱ-4b | (28) |
Ⅱ-5 | (37) |
Ⅱ-6 | 221 |
Ⅱ-7a | 696 |
Ⅱ-7b | 568 |
Ⅱ-8 | 1078 |
Ⅱ-9 | (5) |
Ⅱ-10 | (5) |
Ⅱ-11 | (19) |
Ⅱ-12 | 518 |
Ⅱ-13 | 576 |
Ⅱ-14a | 126 |
Ⅱ-14b | 1239 |
Ⅱ-15 | (02) |
Ⅱ-16a | 46 |
实施例5
血小板衍生的生长因子受体激酶活性抑制
用上述描述的trkA激酶ELISA分析方法检测桥接的茚并吡咯并咔唑化合物对杆状病毒表达的PDGFβ受体激酶区域激酶活性的抑制效果。分析在96孔的包被有PCL-γ/GST的微量滴定板上进行,每100μl的反应混合物包括50mM Hepes,pH为7.4,20μm ATP,10mMMnCl2,0.1%BSA,2%DMSO,和不同浓度的抑制剂。通过加入预磷酸化的人的酶的重组体(10ng/ml PDGFRβ)来引发反应,在37℃下,反应进行15分钟,在使用前先在4℃下,在含有20μM ATP和10mMMnCl2的缓冲溶液中孵化来制备磷酸化的酶,通过加入辣根过氧化酶(HRP)-结合抗磷酸酪氨酸抗体(UBI)来检测磷酸化产品的形成,后来加入含有3,3’-5,5’-四甲基对二氨基联苯和过氧化氢的HPR溶液,在室温下,将板孵化10分钟,用酸停止反应,用Microplate Bio-kineticsReader(Bio-Tek Instrument EL 312e)在450nm记录吸收值,在GraphpadPrism上用S形剂量-响应(可变的坡度)方程来分析抑制数据,结果记录于表6。
表6桥接的茚并吡咯并咔唑化合物的PDGFR抑制作用
化合物号 | PDGFR(%Inh.@luM)IC50,nM |
Ⅱ-1 | 1383 |
Ⅱ-2 | (7) |
Ⅱ-3 | (28) |
Ⅱ-4a | (0) |
Ⅱ-4b | (17) |
Ⅱ-5 | 1076 |
Ⅱ-6 | 96 |
Ⅱ-7a | (36) |
Ⅱ-7b | (34) |
Ⅱ-8 | (15) |
Ⅱ-9 | (24) |
Ⅱ-10 | (23) |
Ⅱ-11 | (15) |
Ⅱ-12 | 125 |
Ⅱ-13 | 1229 |
Ⅱ-14a | 81 |
Ⅱ-14b | 1406 |
实施例6
脊髓胆碱乙酰转移酶活性的提高
如上讨论,胆碱乙酰转移酶是功能性胆碱能神经元的特定生化指示剂。胆碱能神经元代表了进入海马形成、嗅觉细胞核、脑间细胞核、皮层、扁桃体和丘脑的各部位主要的胆碱能。在脊髓中,运动原神经元为含有胆碱乙酰转移酶(Phelps等,J.Comp.Neurol.273:459-472,1988)的胆碱能神经元,胆碱乙酰转移酶的活性用于研究神经营养蛋白(例如NGF和NT-3)对胆碱能神经元的存活和/或功能的影响,胆碱乙酰转移酶测试也作为胆碱能神经元内胆碱乙酰转移酶水平调节作用的一种指示。
在分离的大鼠胚胎脊髓培养实验中桥接的茚并吡咯并咔唑化合物提高了胆碱乙酰转移酶活性(表7),例如在这些实验中,将化合物直接加入到分离的脊髓培养物中,相对于对照,增加了胆碱乙酰转移酶活性至少120%的化合物被认为是有活性的,结果列于表7。
表7
桥接的茚并吡咯并咔唑化合物对的活性的提高
脊髓胆碱乙酰转移酶%对照
化合物号 在30nM的活性 最大活性
Ⅱ-1 114 139@300nM
方法:分离大鼠胎儿脊髓细胞,用(Smith等,J.Cell Biology 101:1608-1621(1985);Glicksman等,J.Neurochem.61:210-221(1993))描述的方法进行实验,用标准的胰蛋白酶分离技术(Smith等,supra.)从大鼠(14-15天的胚胎)切下来的脊髓上得到分离细胞,以6×105细胞/cm2的密度将细胞铺在已被涂有鸟氨酸的塑料组织培养孔中,其中没有血清的N2培养基用0.05%牛血清白蛋白(BSA)补充(Bottenstein等,PNASUSA 76:514-517(1979))。在37℃下,在5%CO2/95%空气的潮湿气氛中孵化培养物48小时,2天后,在体外用修正的根据McManaman等和Glicksman等(McManaman et al.,Developmental Biology 125:311-320(1988);Glicksman et al.,J.Neurochem.,supra.)的Fonnum方法(Fonnum,J.Neurochem.24:407-409(1975))检测胆碱乙酰转移酶的活性。
表8
化合物号 | A1A2 | B1B2 | R2 | R3 | R5 | R8 | Z | m |
Ⅱ-1 | H,H | O | H | H | H | H | 单键 | 1 |
Ⅱ-1b | H,H | O | H | H | H | H | 单键 | 1 |
Ⅱ-2 | H,H | O | Et | H | H | H | 单键 | 1 |
Ⅱ-3 | H,H | O | H | H | H | Me | 单键 | 1 |
Ⅱ-4a | H,H | O | H | H | H | Me | 单键 | 2 |
Ⅱ-4b | H,H | O | H | H | H | Me | 单键 | 2 |
Ⅱ-5 | H,H | O | H | 3-Br | H | Me | 单键 | 1 |
Ⅱ-6 | H,H | O | H | H | 10-OMe | H | 单键 | 1 |
Ⅱ-7a | H,H | O | H | H | H | Me | O | |
Ⅱ-7b | H,H | O | H | H | H | Me | O | 1 |
Ⅱ-8 | O | H,H | H | H | H | H | 单键 | 1 |
Ⅱ-9 | H,H | O | H | 3-(3′-NH2-Ph) | H | H | 单键 | 1 |
Ⅱ-10 | O | O | OH | H | H | H | 单键 | 1 |
Ⅱ-11 | H,H | O | H | H | H | CO2-Et | 单键 | 1 |
Ⅱ-12 | H,H | O | H | H | H | CH2-OH | 单键 | 1 |
Ⅱ-13 | H,H | O | H | H | 9-OMe | H | 单键 | 1 |
Ⅱ-14a | H,H | O | H | H | H | H | 单键 | 1 |
Ⅱ-14b | H,H | O | H | H | H | H | 单键 | 1 |
Ⅱ-15 | H,H | O | H | 3-CH2O-CH2OEt | H | H | 单键 | 1 |
Ⅱ-16a | H,H | O | H | H | H | H | O | 1 |
Ⅱ-16b | H,H | O | H | H | H | H | O | 1 |
合成方法和实施例的综合说明
制备本发明的桥接的茚并吡咯并咔唑的一般合成路线见图1和2,合成桥接的茚并吡咯并咔唑(Ⅲ)/(Ⅷ)的一般步骤如美国专利5,705,511所述,它公开的内容在这里作为参考,当R1为H时,茚并吡咯并咔唑(Ⅲ)/(Ⅷ)的内酰胺氮用合适的基团保护得到式(Ⅳ)/(Ⅸ),在无水有机溶剂中,用合适的碱处理保护的化合物,得到深红色溶液,肯定为碳负离子,碳负离子和双功能团的试剂(Ⅴ)反应,对(Ⅴ)的C=Y键亲电加成得到最初的中间体(Ⅵ)/(Ⅹ),用硫酸或例如三氟化硼乙醚络合物的路易斯酸处理中间体(Ⅵ)(Ⅹ)和/或(Ⅶ)/(Ⅺ)得到桥接的茚并吡咯并咔唑(Ⅰ)/(Ⅱ)。
可以用酸或碱催化的方法来保护内酰胺氮(见图3或4),用树脂键合的试剂进行酸催化反应,让茚并吡咯并咔唑(Ⅲ)/(Ⅷ)固定到聚合物载体上,例如聚苯乙烯基底、Rink酸性树脂(Ⅻ)(图3),得到(ⅩⅢ),另外用可溶试剂进行酸催化反应,得到化合物(ⅩⅣ)(图4),在碱催化下得到甲硅烷基保护的化合物(ⅩⅤ)(图4)。
图5描述了一些制备中间体(Ⅴ)的方法,步骤(a)描述了各种缩醛(ⅩⅥ)转变为(ⅩⅦ,Z=键)的步骤。例如酯-缩醛/缩酮(ⅩⅥ,D=COOR)被完全还原为相应的醇或接着被氧化(例如Swem或Dess-Martin氧化)为醛-缩醛/缩酮(ⅩⅦ,R8=H),另外用DIBAL部分还原酯-缩醛/缩酮(ⅩⅥ,D=COOR)直接得到醛(ⅩⅦ,R8=H),同样用DIBAL还原腈-缩醛(ⅩⅥ,D=CN)得到醛(ⅩⅦ,R8=H),将格氏试剂加入到Weinreb酰胺-缩醛/缩酮(ⅩⅥ,D=CON(OMe)Me)得酮-缩醛/缩酮。
通过步骤(b)的两步法也可以制备中间体(ⅩⅦ,Z=键),将有机金属试剂(ⅪⅩ)加入到缩醛/缩酮(ⅩⅧ)得到烯烃(ⅩⅩ),接着臭氧分解,还原分离纯化得到酮-缩醛/缩酮(ⅩⅦ)。用步骤(c)描述的两步法制备中间体(ⅩⅦ,Z=杂原子),用烯烃(ⅩⅪ)和缩醛(ⅩⅫ)偶合,接着所得烯烃进行臭氧分解(用还原分离纯化),得到酮-缩醛/缩酮(ⅩⅦ)。另外通过步骤(d)的两步法也可以制备中间体(ⅩⅦ,Z=杂原予),化合物(ⅩⅩⅣ)和缩醛/缩酮(ⅩⅧ)反应得到(ⅩⅩⅤ),它用步骤(a)的方法转变为酮-缩醛/缩酮(ⅩⅦ),用羟胺、肼、N-烷基-N-烷氧基胺和胺与酮-缩醛/缩酮(ⅩⅦ)缩合得到带有亲电C=N官能团的中间体(ⅩⅩⅥ)。
用过量的格氏试剂作为碱处理树脂键合的茚并吡咯并咔唑(ⅩⅢ)[图6,方法A],得到深红色碳负离子溶液,接着与(Ⅴ)反应,对C=Y基团进行亲电加成得到产品。经过水分离纯化和用稀释酸(在二氯甲烷中的1%TFA)从树脂上水解分离产品,分离得到化合物(ⅩⅩⅦ)和/或(ⅩⅩⅧ)。用硫酸或例如三氟化硼乙醚络合物的路易斯酸处理中间体(ⅩⅩⅦ)和/或(ⅩⅩⅧ)得到桥接的茚并吡咯并咔唑(Ⅱ)。
将相同的方法应用于可溶内酰胺保护的中间体例如(ⅩⅤ)(图7,方法B)的制备,然而在这种情况下,用在吡啶中的三通B作为碱来代替格氏试剂来处理中间体(ⅩⅤ),中间体(ⅩⅪⅩ)和/或(ⅩⅩⅩ)可以同内酰胺保护基分开,再经色谱纯化,如方法A(图6)一样,用路易斯酸(例如三氟化硼乙醚络合物)处理,得到桥接的茚并吡咯并咔唑(Ⅱ),其中R1=H。
可以用在这里作为参考的美国专利5,705,511和4,923,986描述的方法将R3,R4,R5和R6基团引入。也可以如图8所示,在形成桥接的茚并吡咯并咔唑后引入R3取代基,用NBS溴化B环的3位得到化合物(ⅩⅩⅪ)。通过运用钯-催化的Stille,Suzuki,Heck,Kumada或Castro-Stephens反应,先后引入含碳基团,可以得到化合物(ⅩⅩⅫ)、(ⅩⅩⅢ)等,另外,利用Buchwald的钯催化胺化反应,用化合物(ⅩⅩⅪ)可以得到以例如氨基碱为杂原子代替溴的化合物。
通过氧化方法,可以将含氧基团引入E环的茚碳,如图9化合物(ⅩⅩⅩⅣ)所示。这种化学反应也导致了内酰胺(A环)亚甲基的氧化,从而得到所示的亚酰胺衍生物。
实施例7
Rink树脂键合中间体的制备:(ⅩⅢ-A),(ⅩⅢ-B)和(ⅩⅢ-C),(图3)
实施例7-A
将Rink酸性树脂Ⅻ(10.00g,0.64mmol/g)、1-甲基-2-吡咯烷酮,苯(350mL),Ⅷ-A[A1,A2=H2,B1,B2=O,R3=R4=R5=R6=H](3.00g)和对甲苯磺酸(1.00g)逐个加入装有机械搅拌器和Dean-Stark阱的三口园底烧瓶,将反应混合物加热并回流20小时,然后过滤,用THF(5×175mL)洗涤树脂并放置洗涤液,顺序用DMSO(4×100mL)、2%碳酸氢钠水溶液(4×100mL)、水(4×100mL)、DMSO(2×200mL)、THF(4×100mL)和乙酸乙酯(4×100mL)洗涤,在真空下(24小时)干燥树脂得到11.70(0.47mmol/g)树脂键合Ⅷ-A的化合物(ⅩⅢ-A)。
蒸馏最初的THF洗涤液,用水(750mL)稀释残留物,并将得到的沉淀物过滤并顺序用水、2%碳酸氢钠水溶液(4×100mL)和水(4×100mL)洗涤,在真空下干燥后,回收到Ⅷ-A(1.28g)。
实施例7-B
以同样的方法,将Ⅷ-B[A1,A2=O,B1,B2=H2,R3=R4=R5=R6=H](0.5g)偶合到Rink酸性树脂Ⅻ(1.52g)上,得到1.58g树脂键合Ⅷ-B的化合物(ⅩⅢ-B)。
实施例7-C
以同样的方法,将Ⅷ-C[A1,A2=H2,B1,B2=O,R3=R4=R5=H,R6=10-OMe](1.02g)偶合到Rink酸性树脂Ⅻ(3.12g)上,得到3.70(0.46mmol/g)树脂键合Ⅷ-C的化合物(ⅩⅢ-C)(0.44g)。
实施例8
化合物(Ⅱ-1)、化合物(Ⅱ-2)、化合物(Ⅱ-3)、化合物(Ⅱ-4a)、化合物(Ⅱ-4b)、化合物(Ⅱ-6)和化合物(Ⅱ-8)的制备[方法A,图6]
实施例8-A
向含有(ⅩⅢ-A)(1.25g)的THF(24mL)悬浊液中加入1.0M EtMgBr(THF中6.25mL)溶液,在加入HMPA(5.0mL)前搅拌1小时,在搅拌10分钟后,加入二乙氧基丁醛(3.0g)[它通过文献Paquette,L.A.,Backhaus,D.,Braum,R.,Underliner,T.L.,和Fuchs,K.J.Am.Chem.Soc.1997,119,9662-71来制备],并搅拌20小时。用10%氯化铵水溶液(5mL)停止反应并过滤。树脂顺序用10%氯化铵水溶液(3×10mL)、水(3×10mL)、THF(3×10mL)、DMF(3×10mL)、水(3×10mL)、THF(3×10mL)和乙醚(3×10mL)洗涤,真空干燥树脂,用二氯甲烷(15mL)吸收,并用三氟乙酸(0.15mL)处理,搅拌1小时后,过滤反应物,蒸发滤液,得到的残留物用二氯甲烷(20mL)吸收,并用甲苯磺酸吡啶盐(50mL)处理,将得到的溶液搅拌4小时。同时用饱和碳酸氢钠水溶液和盐水洗涤,用硫酸镁干燥,过滤和蒸馏走溶剂后,用制备HPLC(Zorbax RX-8,4×25cm,用60%乙腈/水w/0.1%三氟乙酸洗脱)纯化。用碳酸氢钠中和,并用二氯甲烷(3×50mL)提取,用硫酸镁干燥,过滤并蒸发溶剂后,得到70.2mg化合物Ⅱ-1白色粉末,它具有下列特征:13C NMR(DMSO-d6)δ171.8,143.3,142.4,141.4,140.1,140.0,136.6,129.2,127.9,127.4,127.1,126.8,124.1(2C),122.7,121.6,121.5,118.3,112.1,88.1,79.2,56.6,45.6,33.4,24.8;1H NMR(DMSO-d6)δ9.21(d,J=7.5,1H),8.62(s,1H),7.98(d,J=7.7,1H),7.86(d,J=8.3,1H),7.71(d,J=7.3,1H),7.49(dd,J=7.9,7.4,1H),7.41(dd,J=7.5,7.4,1H),7.36-7.27(m,2H),6.86(d,J=6.0,1H),5.63-5.58(m,1H),4.91(s,2H),4.53(d,J=3.3,1H),2.23-2.14(m,1H),1.96-1.92(m,1H),0.96-0.88(m,1H),0.60-0.57(m,1H);MS m/z(M+H)calcd379, obsd379.
也是用制备HPLC分离产品混合物得到化合物Ⅱ-2(0.5mg)它具有下列特征:1H NMR(DMSO-d6)δ9.17(d,J=8.1,1H),8.62(s,1H),7.98(d,J=7.0,1H),7.85(d,J=6.8,1H),7.57(d,J=6.8,1H),7.49(dd,J=7.9,7.4,1H),7.44-7.26(m,3H),6.81(d,J=6.0,1H),5.43-5.33(m,1H),4.43(s,2H),2.23-2.14(m,1H),1.96-1.92(m,1H),1.45-1.55(m,2H),0.96-0.88(m,1H),0.60-0.57(m,1H),0.29(t,J=7.0,3H);MS m/z(M+H)calcd407,obsd407.
实施例8-B
用类似上述化合物Ⅱ-1方法,用1,1-二乙氧基-2-戊酮(0.75mL)[根据已知的Sworin,M.and Neuman,W.L.J.Org.Chem.1988,53,4894-6的方法制备]处理树脂(ⅩⅢ-A)得到化合物Ⅱ-3(3.5mg),通过制备TLC(硅胶,用50%乙酸乙酯/甲苯洗脱)分离,它具有以下性质:1HNMR(DMSO-d6)δ9.42(d,J=8.2,1H),8.58(s,1H),7.95(d,J=7.4,1H),7.79(d,J=8.3,1H),7.71(d,J=7.1),7.50-7.20(m,4H),6.81(d,J=5.9,1H),4.90(s,2H),4.46(s,1H),2.35-2.20(m,1H),1.98(s,3H),1.75-1.60(m,1H),1.25-1.00(m,1H),0.35-0.15(m,1H);MS m/z(M+H)计算值393,测量值393。
实施例8-C
用类似方法,将(ⅩⅢ-A)(74.3mg)用1,1-二乙氧基-2-己酮(0.75mL)[根据已知Brenner,J.E.,J.Org.Chem.1961,26,22-7的方法制备]处理得到化合物Ⅱ-4a(2.10mg)和化合物Ⅱ-4b(1.06mg),分别通过制备HPLC(Zorbax RX-8,4×25cm,用65%乙腈/水w/0.1%三氟乙酸洗脱)分离,化合物Ⅱ-4a具有以下性质:1H NMR(DMSO-d6)δ9.30(d,J=8.3,1H),8.55(s,1H),7.97(d,J=7.2,1H),7.65(d,J=8.5,1H),7.59(d,J=7.5),7.48(dd,J=7.8,7.2,1H)7.39-7.15(m,3H),6.31(dd,J=5.9,5.5,1H),5.02(s,1H),4.88(s,2H),0.88(s,3H)其它脂族信号消失在溶剂峰中:MS m/z(M+H)计算值407,测量值407。化合物Ⅱ-4b具有以下性质:1H NMR(DMSO-d6)δ9.43(d,J=8.1,1H),8.59(s,1H),7.99(d,J=7.3,1H),7.75-7.65(m,2H),7.49(dd,J=7.0,6.4,1H),7.43(dd,J=8.2,8.1,1H),7.36-7.25(m,2H),6.75(s,1H),4.91(s,2H),4.50(s,1H),1.95(s,3H)其它脂族信号消失在溶剂峰中:MS m/z(M+H)计算值407,测量值407。
实施例8-D
用类似的方法,用二乙氧基丁醛(3.65g)处理(ⅩⅢ-C)(1.00g)得到化合物Ⅱ-6(87.8mg),通过制备HPLC(Zorbax RX-8,2.5×25cm,用65%乙腈/水w/0.1%三氟乙酸洗脱)分离,它具有以下性质:1H NMR(DMSO-d6)δ9.09(d,J=8.6,1H),8.60(s,1H),7.95(d,J=7.4,1H),7.84(d,J=8.3,1H),7.47(dd,J=7.2,7.0,1H),7.35(s,1H),7.29(dd,J=7.0,7.0,1H),6.98(dd,J=8.6,1.9,1H),6.83(d,J=6.0,1H),5.65-5.55(m,1H),4.88(s,2H),4.48(d,J=3.9,1H),3.82(s,3H),2.25-2.10(m,1H),2.08-1.85(m,1H),0.96-0.75(m,1H),0.65-0.50(m,1H);MS m/z(M+Na)计算值431,测量值431。
实施例8-E
用类似的方法,用二乙氧基丁醛(1.5mL)处理树脂(ⅩⅢ-B)(153.2mg)得到化合物Ⅱ-8(3.6mg),通过制备HPLC(Zorbax RX-8,2.5×25cm,用65%乙腈/水w/0.1%三氟乙酸洗脱)分离,它具有以下性质:1HNMR (DMSO-d6)δ9.09(d,J=7.9,1H),8.81(s,1H),7.817.73(m,3H),7.48-7.35(m, 3H),7.24(dd,J=7.6,7.5,1H),6.85(d,J=6.2,1H),5.63-5.59(m,1H),4.86(s,2H),4.61(d,J=3.6,1H),3.82(s,3H),2.21-2.13(m,1H),1.96-1.90(m,1H),0.87-0.79(m,1H),0.61-0.56(m,1H);MS m/z(M+H)计算值379,测量值379。
实施例9
化合物Ⅱ-7a和化合物Ⅱ-7b的制备(方法A,图6)
实施例9-A
(1,1-二乙氧基乙氧基)丙酮的制备
向冷的(0℃)NaH(2.68g,60%)的THF(150mL)悬浊液中加入1,1-二乙氧基乙醇(根据已知的文献Zirkle,C.L.等J.Org.Chem.1961,26,395-407制备)(9.00g)的THF溶液(20mL),在室温下搅拌混合物1小时,然后加入甲代烯丙基氯(8.0mL),将反应混合物加热回流过夜,冷却并通过硅藻土填料过滤,通过旋转蒸馏去除溶剂,并用柱色谱(二氧化硅,20%乙醚/己烷)纯化,得到1,1-二乙氧基乙基甲代烯丙基醚(11.5,90%)。将冷却的(-30℃)醚(6.00g)的乙酸乙酯溶液(80mL)进行臭氧分解,直到用TCL检测(1小时)没有起始物为止,同时,用氧气净化反应,用pd(OH)2(150mg)处理,并在氢气气氛中搅拌过夜,过滤掉催化剂,旋转蒸馏浓缩滤液,用柱色谱(二氧化硅,20%乙酸乙酯/己烷)纯化得到的残留物,得到目标化合物(4.53g,82%)。
实施例9-B
根据方法A(图6),用EtMgBr(1.25mL)和(1,1-二乙氧基乙氧基)丙酮(实施例8-A)(1.2mL)处理树脂(ⅩⅢ-A)(230.2mg),纯化分离和树脂分离后,用二氯甲烷(20mL)提取出部分粗产品混合物(10.5mg),并用三氟化硼的醚络合物(20uL)处理,搅拌2.5小时后,用碳酸氢钠饱和水溶液和盐水洗涤,用硫酸镁干燥。经过滤并去除溶剂,用制备HPLC(Zorbax RX-8,4×25cm,用65%乙腈/水w/0.1%三氟乙酸洗脱)纯化得到的残留物得到化合物Ⅱ-7a(2.34mg)和化合物Ⅱ-7b(1.34mg),化合物(Ⅱ-7a)具有下列性质:1H NMR(CDCl3)δ9.35-9.20(m,1H),7.87(d,J=7.6,1H),7.62(d,J=7.0,1H),7.60-7.45(m,1H),7.49(dd,J=7.7,7.5,1H),7.40(d,J=8.1,1H),7.37-7.26(m,3H),6.22(s,1H),5.20-4.85(m,1H),4.47(s,1H),3.67(d,J=12.7,1H)3.52(d,J=11.8,1H),3.40(d,J=12.7,1H),3.38(d,J=11.8,1H),1.91(s,3H);MS m/z(M+H)计算值409,测量值409。化合物(Ⅱ-7b)具有下列性质:1H NMR (CDCl3)δ9.58-9.22(m,1H),7.82(d,J=7.4,1H),7.60-7.40(m,3H),7.37-7.27(m,3H),7.21(d,J=8.1,1H),5.81(s,1H),5.21(s,1H),5.10-4.80(m,1H),4.59(d,J=13.5,1H),4.38(dd,J=13.5,5.3,1H),4.21(d,J=13.1,1H),3.82(d,J=13.2,1H),1.13(s,3H);MS m/z(M+H)计算值409,测量值409。
实施例10
化合物Ⅱ-5的制备(图8)
向化合物Ⅱ-1(8.1mg)的THF(2mL)溶液中加入NBS(4.6mg),并搅拌过夜,再加入NBS(4.5mg)并搅拌2.5小时,过滤掉不溶解的物质,并旋转浓缩滤液,用柱色谱(C-18,用65%乙腈/水w/0.1%三氟乙酸洗脱)纯化得到的残留物,用碳酸氢钠中和合适的部分,用二氯甲烷(3×20mL)提取,并用硫酸镁干燥,经过滤和蒸发溶剂后,得到化合物Ⅱ-5(5.1mg)白色粉末,它具有下列性质:1H NMR(DMSO-d6)δ9.22(d,J=7.4,1H),8.67(s,1H),8.14(s,1H), 7.86(d,J=8.7,1H),7.72(d,J=7.0,1H),7.63(d,J=7.8,1H),7.42(dd,J=7.5,7.3,1H),7.35(dd,J=7.3,7.2,1H),6.86(d,J=6.0,1H),5.63-5.58(m,1H),4.94(s,2H),4.54(d,J=3.1,1H),2.30-2.14(m,1H),2.00-1.82(m,1H),0.96-0.88(m,1H),0.62-0.50(m,1H);MS m/z(M+H)计算值475/9(1∶1),测量值457/9(1∶1)。
实施例11
中间体ⅩⅤ的制备(图4)
向Ⅷ-A[A1,A2=H2,B1,B2=O,R3=R4=R5=R6=H](1.05g)的DMF(25mL)溶液中加入三乙基胺(0.75mL)和叔丁基二甲基甲硅烷氯化物(TMS-Cl)(0.65g),搅拌3小时后,用饱和碳酸氢钠水溶液停止反应,并用乙酸乙酯提取,用水和盐水洗涤有机层,并用硫酸镁干燥,经过滤和蒸发溶剂后,将残留物用乙醚破碎得到化合物ⅩⅤ(848mg),蒸发洗涤液,得到的残留物用柱色谱(二氧化硅,1%乙酸乙酯/二氯甲烷)纯化,得到产品(502mg,结和产率94%)具有下列性质:1H NMR(DMSO-d6)δ11.94(s,1H),9.32(d,J=7.6,1H),8.03(d,J=7.7,1H),7.64(d,J=7.2,1H),7.58(d,J=8.1,1H),7.44(dd,J=7.7,7.6,1H),7.39(dd,J=7.7,7.6,1H),7.32(d,J=7.3,1H),7.25(dd,J=7.6,7.3,1H),5.00(s,2H),4.14(s,2H),0.99(s,9H),0.46(s,6H);MS m/z(M+H)计算值425,测量值425。
实施例12
通过方法B(图7)制备化合物Ⅱ-1
将40%的三通B的甲醇(10mL)溶液溶解于吡啶(10mL)中,制备三通B的吡啶溶液(0.45M),在减压(20mmHg)下去除溶剂得到8mL溶液,然后用吡啶稀释到50mL,过滤并保存在氮气中。用氩气冲洗ⅩⅤ(20.3mg)的吡啶溶液(2.0mL)后,用300μL的三通B(吡啶中0.45M)和二乙氧基丁醛(50μL)处理,然后搅拌2小时,将反应物转移到乙酸乙酯中,并用1N盐酸水溶液、盐水洗涤,用硫酸镁干燥,经过滤和蒸发溶剂后,在二氯甲烷(10mL)中用三氟化硼的乙醚络合物(10μL)处理加和物,搅拌2小时后,用碳酸氢钠饱和水溶液和盐水洗涤,用硫酸镁干燥。经旋转蒸发去除溶剂,用制备HPLC(Zorbax RX-8,2.5×25cm,用65%乙腈/水w/0.1%三氟乙酸洗脱)纯化得到的残留物,用碳酸氢钠中和合适的部分,用二氯甲烷(3×20mL)提取,并用硫酸镁干燥,经过滤和蒸发溶剂后,得到化合物Ⅱ-1(11.8mg,65%产率),它的1HNMR和MS光谱和HPLC保留值和实施例8-A中用方法A制备的物质相同。
实施例13
化合物Ⅱ-9的制备(图8)
向溴代化合物Ⅱ-5(6.2mg)的1-丙醇(4.0mL)悬浊液中加入3-氨基苯基硼酸(3.8mg),搅拌0.25小时后,顺序加入乙酸钯(2.0mg)、三苯基磷(4.8mg)、碳酸钠(2.8mg)和水(2.0mL),将反应化合物加热回流0.75小时,冷却,用二氯甲烷提取,用水和盐水洗涤,用硫酸镁干燥有机层,通过旋转蒸馏去除溶剂,得到的残留物用制备HPLC(Zorbax RX-8,2.5×25cm,用50%乙腈/水w/0.1%三氟乙酸洗脱)纯化,用碳酸氢钠中和合适的部分,用二氯甲烷(3×20mL)提取,并用硫酸镁干燥,经过滤和蒸发溶剂后,得到化合物Ⅱ-9(3.1mg,49%产率),具有下述光谱性质:1H NMR(DMSO-d6)δ9.22(d,J=7.5,1H),8.66(s,1H),8.00-7.25(m,8H),7.12(dd,J=7.1,7.0,1H),6.95-6.80(m,3H),6.53(d,J=6.0,1H),5.63-5.58(m,1H),4.99(s,2H),4.55(s,1H),2.25-2.10(m,1H),1.95-1.90(m,1H),0..98-0.88(m,1H),0.65-0.57(m,1H);MS m/z(M+H)计算值470,测量值470。
实施例14
化合物Ⅱ-10的制备(图9)
向化合物Ⅱ-1(5.0mg)的DMSO(1mL)溶液中加入氰化钠(4.3mg),将混合物加热到145℃1小时,冷却混合物,并用乙酸乙酯提取,用水(3×20mL)和盐水洗涤,用硫酸镁干燥有机层,过滤并蒸发,得到的残留物用制备HPLC(Zorbax RX-8,2.5×25cm,用55%乙腈/水w/0.1%三氟乙酸洗脱)纯化,用碳酸氢钠中和合适的部分,用二氯甲烷(3×20mL)提取,并用硫酸镁干燥,经过滤和蒸发溶剂后,得到化合物Ⅱ-10(2.7mg,50%产率),具有下述光谱性质:1H NMR(DMSO-d6)δ11.4(s,1H),8.86(d,J=7.9,1H),8.79(d,J=7.6,1H),7.90(d,J=8.3,1H),7.62-7.55(m,2H),7.49(dd,J=7.6,7.4,3H),7.40(dd,J=7.4,7.3 1H),7.35(dd,J=7.5,7.4,1H),6.86(d,J=6.0,1H),6.03(s,1H),5.40-5.30(m,1H),2.25-2.14(m,1H),2.03-1.90(m,1H),1.10-0.98(m,1H),0.82-0.77(m,1H).
实施例15
化合物(Ⅱ-11)的制备(方法A,图6)
根据方法A(图6),用EtMgBr(1.0mL)和2,5-二氧杂戊酸己酯(1.5mL)和树脂(ⅩⅢa)(150.2mg)[Schmidt,U.,Reidl,B.Synthesis1993,809],纯化分离和树脂分离后,用二氯甲烷(20mL)提取出粗产品混合物,并用三氟化硼的醚络合物(20uL)处理,搅拌2.5小时后,用碳酸氢钠饱和水溶液和盐水洗涤,用硫酸镁干燥。经过滤并去除溶剂后,用制备HPLC(Zorbax RX-8,4×25cm,用55-75%乙腈/水w/0.1%三氟乙酸梯度洗脱)纯化得到的残留物,得到化合物Ⅱ-11(6.4mg),它具有下列性质:1H NMR(DMSO-d6)δ9.36(d,J=7.7,1H),8.68(s,1H),8.00(d,J=7.7,1H),7.83(d,J=8.3,1H),7.58-7.15(m,5H),6.97(d,J=5.9,1H),4.93(s,2H),4.82(s,1H),4.48(q,J=7.1,2H),2.42-1.91(m,2H),1.37(t,3H,J=7.1),1.25-0.63(m,2H).
实施例16
化合物Ⅱ-12的制备
用2M LiBH4(1.0mL的THF溶液)溶液处理化合物Ⅱ-11(3.4mg)的THF(2mL)溶液,并搅拌1.5小时。加入1N盐酸水溶液(4mL)冷却,搅拌20分钟后,加入10%的氢氧化钠(15mL),并用二氯甲烷(3×10mL)提取。用硫酸镁干燥后,经过滤并蒸馏溶剂后,得到化合物Ⅱ-12(0.32mg),它具有下列性质:1H NMR(DMSO-d6)δ9.35(d,J=7.7,1H),8.62(s,1H),7.98(d,J=7.7,1H),7.83(d,J=8.2,1H),7.75(d,J=8.2,1H),7.50-7.25(m,4H),6.84(d,J=7.7,1H),6.11(s,1H),4.91(s,2H),4.71(s,1H),4.50-4.40(m,1H),4.30-4.20(m,1H)2.42-1.91(m,2H),1.25-0.63(m,2H);MS m/z(M+H)计算值409,测量值409。
实施例17
化合物Ⅱ-13的制备
根据实施例11的方法,在DMF(45mL)中,用三乙基胺(0.85mL)和叔丁基二甲基甲硅烷氯化物(0.65g)将Ⅷ-C[A1,A2=H2,B1,B2=O,R3=R4=R5=H,R6=OMe]和Ⅷ-D[A1,A2=H2,B1,B2=O,R3=R4=R6=H,R5=OMe](1.25g)的约为95-5的混合物甲硅烷基化,得到ⅧB-TDBMS(1.41g),它具有下列光谱性质:1H NMR(DMSO-d6)δ11.91(s,1H),9.18(d,J=8.6,1H),7.99(d,J=7.8,1H),7.56(d,J=8.0,1H),7.42(dd,J=7.7,7.6,1H),7.30-7.20(m,2H),6.95(dd,J=7.6,2.5,1H),4.97(s,2H),4.09(s,2H),3.81(s,3H),0.99(s,9H),0.45(s,6H).也可以用柱色谱得
到ⅧD-TBDMS(65mg),它具有下列光谱性质:1H NMR(DMSO-d6)δ11.92(s,1H),9.01(d,J=1.8,1H),8.02(d,J=7.9,1H),7.58(d,J=8.1,1H),7.53(d,J=8.3,1H),7.44(dd,J=7.2,7.1,1H),7.25(dd,J=7.2,7.1,1H),6.91(dd,J=8.1,2.7,1H),4.99(s,2H),4.06(s,2H),3.78(s,3H),0.99(s,9H),0.46(s,6H).化合物Ⅱ-13的液相合成
根据实施例12的方法,用氩气冲洗ⅧD-TBDMS(10.3mg)的吡啶(2.0mL)溶液,并用350μL三通B(0.45M的吡啶溶液)和二乙氧基丁醛(50μL)(根据已知的方法制备,Paquette,L.A.,Backhaus,D.,Braum,R.,Underiner,T.L.,Fuchs,K.J.Am.Chem.Soc.1997,119,9662-71,它在这里作为参考)处理。搅拌2小时后,提取到乙酸乙酯中,用10%的硫酸酮水溶液(3×50mL)和盐水洗涤,并用硫酸镁干燥。过滤和蒸发溶剂后,通过硅胶(30%乙酸乙酯/己烷)洗提,浓缩UV活性部分,提取到二氯甲烷中(4mL),并用三氟化硼乙醚络合物(10μL)处理。搅拌2小时后,用饱和碳酸氢钠水溶液和盐水洗涤,用硫酸镁干燥,通过旋转蒸馏去除溶剂,得到的残留物用乙醚研磨,得到纯的化合物Ⅱ-13(4.6mg),它具有以下光谱性质:1H NMR(DMSO-d6)δ8.92(d,J=2.3,1H),8.59(s,1H),7.97(d,J=7.7,1H),7.86(d,J=8.3,1H),7.59(d,J=8.2,1H),7.47(dd,J=7.7,7.6,1H),7.28(dd,J=7.5,7.4,1H),6.89(dd,J=8.3,2.4,1H),6.82(d,J=6.0),5.55-5.50(m,1H),4.99(s,2H),4.53(d,J=3.5,1H),3.85(s,3H),2.30-2.20(m,1H),2.10-1.90(m,1H),1.10-0.90(m,1H),0.73-0.66(m,1H);MS m/z(M+H)计算值409,测量值409。
实施例18
化合物Ⅱ-14a和化合物Ⅱ-14b的合成
ⅧA-TBDPS的合成。向Ⅷ-A(6.2g)的DMF(150ml)溶液中加入TEA(9.7mL)、叔丁基氯代二苯基硅烷(tBDPS-Cl,10.5ml)和催化剂量的二甲基氨基吡啶。将化合物在50℃加热15小时。另外加入三乙基胺(5.0mL)和tBDPS-Cl(5.0mL),并在50℃下保持20小时,用碳酸氢钠冷却和用乙酸乙酯提取,用水(2×100mL)和盐水洗涤,用硫酸镁干燥。过滤和蒸发溶剂后,用1∶1的乙醚:己烷研磨残留物,得到ⅧA-TBDPS(9.1g,83%),它具有以下的光谱性质:1H NMR(DMSO-d6)δ11.95(s,1H),9.21(d,J=1.8,1H),7.80-7.20(m,16H),7.13(dd,J=8.1,2.7,1H),4.83(s,2H),4.13(s,2H),1.25(s,9H);MS m/z(M+H)计算值549,测量值549。Ⅱ-17的液相合成
用氩气冲洗ⅧA-TBDPS(102.5mg)的吡啶(4.0mL)溶液,并用1.0mL三通B(0.45M的吡啶溶液)和二乙氧基丁醛(140μL)(根据已知的方法制备,Paquette,L.A.,Backhaus,D.,Braum,R.,Underiner,T.L.,Fuchs,K.J.Am.Chem.Soc.1997,119,9662-71)处理,搅拌2小时后,提取到乙酸乙酯中,用10%的硫酸酮水溶液(3×50mL)和盐水洗涤,并用硫酸镁干燥,过滤和蒸发溶剂后,通过硅胶(30%乙酸乙酯/己烷)洗提,浓缩UV活性部分,提取到二氯甲烷中(10mL),并用三氟化硼乙醚络合物(10μL)处理,搅拌0.5小时后,用饱和碳酸氢钠水溶液和盐水洗涤,用硫酸镁干燥,通过旋转蒸馏去除溶剂,得到的残留物用柱色谱(硅胶,25%乙酸乙酯/己烷)纯化产品(75.5mg),它具有以下光谱性质:1H NMR(DMSO-d6)δ9.08(d,J=7.2,1H),7.86(d,J=8.2,1H),7.73(d,J=6.9,1H),7.70-7.24(m,15H),6.88(d,J=5.9,1H),5.72(m,1H),4.86(s,2H),4.55(d,J=3.3,1H),2.30-2.20(m,1H),2.10-1.90(m,1H),1.10-0.90(m,1H),0.73-0.66(m,1H);MS m/z(M+Na)计算值639,测量值639。
通过手性HPLC分离TBDPS保护的Ⅱ-1a对映异构体,并制备化合物Ⅱ-14a和Ⅱ-14b。
将TBDPS-保护的Ⅱ-1a溶于少量的(1∶4,v/v)三氯甲烷∶乙醇溶液中,并将500μL注射到CHIRACEL OD柱(1cm ID×25cm)中,用100%的乙醇(1.5mL/min)洗提,收集相应于对映体A(24.0-27.0分钟)和对映体B(36.0-39.0分钟)的馏份,并分别浓缩,将每一种TBDPS保护的Ⅱ-1a异构体提取到THF(12mL)中,并加入用HF(0.125mL的0.1M水溶液)缓冲的0.1M KF水溶液(4.6mL),将每份溶液搅拌40小时,提取到DCM中,并用碳酸氢钠水溶液洗涤,水层用DCM(3×100mL)提取,将混和的有机层溶液立刻过硫酸镁填料,蒸发后剩下残留物用1∶1的乙醚∶己烷研磨,并用如实施例8A所述的制备HPLC纯化,每种异构体的HPLC保留时间和MS光谱数据相应于真正的Ⅱ-1a。通过手性HPLC检测,得到的化合物Ⅱ-14a(2.84mg)为97%ee和化合物Ⅱ-14b(3.52mg)为90%ee,用CHIRACEL OD柱(0.46cm ID×5cm)检测每种异构体的手性纯度,用1∶1的甲醇/乙醇作为洗脱液(0.25mL/min),Ⅱ-14a的Rt为14.0分钟,Ⅱ-14b的Rt为20.5分钟。
实施例19
化合物Ⅱ-15的合成
向Ⅷ-A(1g,3.2mmol)的THF(40mL)悬浊液加入NBS(632mg,3.5mmol),在室温下搅拌反应混合物18小时,真空去除溶剂,并将桔黄色固体产品悬浮于甲醇(50mL)中。将浆状物过滤,并用更多的甲醇洗涤固体。干燥后,回收到浅黄色溴化物(R3=Br)(1.09g,2.8mmol,88%产率):(MS:m/z(M+H)389,391)。
向上述溴化物(1.09g,2.8mmol)的苯(60mL)和N-甲基吡咯烷酮(6mL)溶液中加入4,4’-二甲氧基二苯基甲醇(818mg,3.4mmol)和对甲苯磺酸(532mg,2.8mmol),将混合物加热回流。24小时后,冷却到室温,并用乙酸乙酯(200mL)稀释。用碳酸氢钠洗涤有机层2次,水洗2次,盐水洗2次。用无水硫酸镁干燥有机层,过滤并真空去除溶剂。通过柱色谱(10%乙酸乙酯-己烷)纯化粗产品,得到期望的DMB保护的3-溴吲哚衍生物(1.5g,2.4mmol,87%产率)它为桔色固体(MS m/z(M+H)615,617)。
将DMB保护的3-溴化合物(1.5g,2.4mmol)、二(三苯基磷酰基)钯二氯化物(100mg,0.14mmol)、无水乙酸钠(3.9g 4.8mmol和甲氧基乙醇(50mL)注入250mL可密封的试管。将试管抽真空并充满一氧化碳,并将其放置在一氧化碳气氛中。将其放置在150℃的油浴中。4小时后,将试管冷却到室温,继续充入一氧化碳,再重复反应共10小时。然后用乙酸乙酯(250mL)稀释,用水洗涤,无水硫酸镁干燥,过滤并真空干燥。用甲醇研磨得到3-羧基化合物(1.29g,2.02mmol,84%产率),它为黄色固体:MS m/z(M+H)639。
向上述酯(1.2g,1.9mmol)的二氯甲烷(20mL)溶液中加入苯硫基甲烷(1mL)和TFA(4mL)。在室温下搅拌1小时后,将反应混合物蒸发到干燥,并将残留物悬浮于乙醚中。过滤悬浊液,用乙醚洗涤固体直到滤液为无色。在真空下干燥固体得到白色固体的酯(636mg,1.54mmol):MS m/z(M+H)413。
将上述的酯(500mg,1.2mmol)悬浮于二氯甲烷(15mL)中,并加入二异丁基铝氢化物的二氯甲烷溶液(5.5mL,5.5mmol,1.0M)。在室温下2小时后,用甲醇冷却反应物,通过旋转蒸馏去除溶剂,并加入水到残留物中。将浆状物过滤,真空干燥固体,得到期望的产品(A1,A2=O,B1,B2=H2,R3=3-CH2OH,R4=R5=R6=H,Q=NH)(367mg,1.08mmol),为浅黄色固体:MS m/z(M+H)341m/e。
将上述醇(360mg,0.9mmol)[A1,A2=O,B1,B2=H2,R3=3-CH2OH,R4=R5=R6=H,Q=NH]与乙醇(15mL)一起放置在可密封的试管中。向这个悬浮液中加入三氟乙酸酐(254mL,1.8mmol)。在70℃下将反应混合物加热15小时。冷却试管,真空下去除溶剂,得到的固体与甲醇研磨,过滤和干燥得到期望的醚(239mg,0.65mmol,72%产率),桔黄色固体:MS m/z(M+H)369
根据实施例11的方法,在DMF(5mL)中,用三乙基胺(0.75mL,0.54mmol)和叔丁基二甲基甲硅烷基氯化物(81.0mg,0.54mmol)甲硅烷化上述的醚(100mg,0.27mmol),分离净化水之后,蒸发溶剂,用乙醚∶己烷(1∶1)研磨固体,得到桔黄色固体产品(114.6mg,0.24mmol,88%):MS m/z(M+H)483。
根据实施例12的方法,用氩气冲洗上述醚(23.0mg,0.048mmol)的吡啶(4.0mL)溶液,然后用200μL的三通B(在吡啶中0.45M)和5,5-二甲基-1,3-二氧六环-2-丙醛(50μL)处理。Khanna,I.K.;Weier,R.M.;Yu.Y.;Collins,P.W.;Miyashiro,J.M.;等,J.Med.Chem.1997,40,1619-33在这里作为参考。0.5小时后,另外加入三通B(200μL,在吡啶中0.45M),重复此操作2次,最后提取到乙酸乙酯中,用10%的硫酸酮水溶液(3×50mL)、盐水洗涤,用硫酸镁干燥。过滤和蒸发溶剂后,通过硅胶(30%乙酸乙酯/己烷)洗提残留物,浓缩UV活性部分,提取到二氯甲烷中(4mL),并用催化剂量的甲苯磺酸吡啶盐(1mg)处理。将混合物加热回流48小时,然后真空去除溶剂,将得到的残留物转移到THF(8.0mL)中,并加入用HF(0.09mL的0.1M水溶液)缓冲的0.1MKF水溶液(2.9mL)。将溶液搅拌20小时,提取到DCM中,并用碳酸氢钠水溶液洗涤,水层用DCM(3×100mL)提取,将混和的有机层溶液立刻过硫酸镁填料,蒸发后剩下残留物用1∶1的乙醚∶己烷研磨,并用如实施例8A所述的制备HPLC纯化,得到期望的产品Ⅱ-15(1.26mg,6.0%),它具有下列的光谱性质∶1H NMR(DMSO-d6)δ9.41(d,J=2.3,1H),8.53(s,1H),7.90(s,1H),7.80-7.25(m,5H),6.33(d,J=6.0,1H),5.31(m,1H),4.95(s,2H),4.66(s,2H),4.48(m,1H),3.50(q,J=6.8,2H),2.30-2.20(m,1H),2.10-1.90(m,1H),1.25(t,J=6.8,3H,1.10-0.90(m,1H),0.73-0.66(m,1H);MS m/z(M+H)计算值437,测量值437。
实施例20化合物Ⅱ-1b的合成
ⅩⅣ(DMB-ⅧA)的制备向装有机械搅拌器和Dean-Stark阱的三颈园底烧瓶中顺序加入DMB-OH(2.44g,10mmol),1-甲基-2-吡咯烷酮(30mL),苯(270mL),Ⅷ-A(3.10g,10mmol)和对甲苯磺酸(1.90g,10mmol)。将反应混合物加热回流。2小时后,反应混合物变为均质,继续加热2小时,将反应混合物冷却到室温,用乙酸乙酯(200mL)稀释,用饱和碳酸氢钠水溶液(4×100mL)、水(4×100mL)洗涤,有机层通过无水硫酸镁干燥,过滤并在真空浓缩,用乙酸乙酯/己烷将残留物研磨,过滤得到的固体并在高真空条件下干燥,得到ⅩⅣ(图4)[A1,A2=H2,B1,B2=O,R3=R4=R5=R6=H,Q=NH,R’=R”=H](5.2g,98%),它具有以下的光谱性质:1H NMR(CDCl3-d6)δ9.54(d,J=7.82,1H),8.55(s,1H),7.68(d,J=7.8 1H),7.60-6.70(m,15H),4.71(s,2H),4.03(s,2H),3.78(s,6H);MS m/z(M+H)计算值537,测量值537。
向ⅩⅣ(图4)(102.5mg)的THF(6.0mL)溶液中加入EtMgBr的THF(0.8mL的1.0M)溶液,并搅拌1小时,加入5,5-二甲基-1,3-二氧六环-2-丙醛(300μL)(它根据已知文献制备,I.K.;Weier,R.M.;Yu.y.;Collins,P.W.;Miyashiro,J.M.;等,J.Med.Chem.1997,40 1619-33),并将混合物搅拌3小时,用氯化铵水溶液冷却混合物,用乙酸乙酯提取,用饱和碳酸氢钠水溶液和盐水洗涤,再用硫酸镁干燥,通过旋转蒸馏蒸发溶剂,得到的残留物用柱色谱(硅胶,40%乙酸乙酯/己烷)纯化,得到两部分不同异构体的物质:MS m/z(M+H)709。更极性的部分(25mg)用二氯甲烷(10mL)提取,并用三氟化硼乙醚络合物(10μL)处理。
搅拌1.5小时后,用饱和碳酸氢钠水溶液和盐水洗涤,再用无水硫酸镁干燥有机层,过滤和在真空下浓缩,得到的残留物用实施例8-A描述的制备HPLC纯化,得到产品(1.75mg),它具有以下光谱性质:1H NMR(DMSO-d6)δ9.20(d,J=7.46,1H),8.56(s,1H),7.97(d,J=7.7,1H),7.69(d,J=8.2,1H),7.57(d,J=7.3,1H),7.52-7.20(m,4H),6.57(m,1H),5.1(m,1H),4.88(s,2H),4.67(s,1H),2.30-2.20(m,1H),2.10-1.90(m,1H),1.10-0.90(m,1H),0.73-0.66(m,1H);MSm/z(M+H)计算值379,测量值379。
实施例21
化合物Ⅱ-16a和Ⅱ-16b的合成
用氩气冲洗ⅧA-TBDPS(见实施例18)(214mg)的吡啶(4.0mL)溶液,在吡啶中(2mL),用750μL的三通B(在吡啶中0.45M)和2,2-二乙氧基-乙氧基-乙醛(200mg)[根据已知的文献方法制备:Aparico,F.J.L.;Benitez,F.Z.;Gonzalez,F.S.;Carbohydr.Res.1983,297-302,其公开的内容在这里作为参考]处理。2小时后,另外加入三通B(250μL)。另外搅拌0.5小时后,用乙酸乙酯提取反应混合物,用10%的硫酸铜水溶液(3×50mL)、盐水洗涤,用硫酸镁干燥,过滤和蒸发溶剂后,通过硅胶(35%乙酸乙酯/己烷)洗提,浓缩UV活性部分,提取到二氯甲烷中(10mL),并用三氟化硼乙醚络合物(10μL)处理。搅拌0.5小时后,用饱和碳酸氢钠水溶液和盐水洗涤,用硫酸镁干燥,通过旋转蒸馏去除溶剂,得到的残留物用柱色谱(硅胶,35%乙酸乙酯/己烷)纯化,得到两部分非对应异构体加合物,MS m/z(M+H)725。将每一种加合物提取到二氯甲烷中(10mL),并用三氟化硼乙醚络合物(10μL)处理。搅拌0.5小时后,通过旋转蒸馏去除溶剂,将得到的残留物转移到THF(15mL)中,并加入用HF(0.20mL的0.1M水溶液)缓冲的0.1M KF水溶液(5.8mL),将每种溶液搅拌20小时,提取到DCM中,并用碳酸氢钠水溶液洗涤,水层用DCM(3×100mL)提取,将混和的有机层溶液立刻过硫酸镁填料,蒸发后剩下残留物用二氯甲烷(10mL)提取,并用三氟化硼乙醚络合物(10μL)处理并搅拌48小时。
将每种反应混合物提取到二氯甲烷中,用饱和碳酸氢钠水溶液和盐水洗涤,然后用硫酸镁干燥,通过旋转蒸馏去除溶剂,得到的残留物用实施例8-A描述的制备HPLC纯化,一种非对映异构体化合物Ⅱ-16a(分离2.38mg)具有下述的光谱性质:13CNMR(DMSO-d6)δ172.0,142.6,142.5,142.1,141.0,139.8,134.8,130.6,128.0,127.2,127.0,126.6,124.4,124.2,122.7,121.7,121.0,116.8,112.1,80.0,70.0,69.1,65.6,54.1,45.7;1H NMR(DMSO-d6)δ9.23(d,J=7.7,1H),8.58(s,1H),7.99(d,J=7.7,1H),7.77(d,J=8.3,1H),7.63(d,J=7.22,1H),7.48-7.30(m,4H),6.56(s,1H),5.10(m,1H),4.90(s,2H),4.70(m,1H),3.80-3.60(m,2H),3.30-3.00(m,2H)MS m/z(M+Na)计算值395,测量值395。
另一种非对映异构体化合物Ⅱ-16b(分离1.00mg)具有下述的光谱性质:1H NMR(DMSO-d6)δ9.21(d,J=7.7,1H),8.59(s,1H),7.99(d,J=7.7,1H),7.77-7.30(m,6H),5.95(s,1H),5.05(m,1H),4.91(s,2H),4.63(m,1H),4.55-4.30(m,2H),另外的信号掩埋在溶剂峰中;MS m/z(M+Na)计算值395,测量值395。
参考表9可以进一步了解式Ⅱ化合物,它列出了式Ⅲ的一些优选实施方式,其中指出了手性中心(*)。R1,R4,R6和R7为H,Y为
表9
化合物号 | A1A2 | B1B2 | R2 | R3 | R5 | R8 | Z | m | R2R7R8 |
Ⅲ-A1 | H,H | O | H | H | H | H | 单键 | 1 | RSR |
Ⅲ-A2 | H,H | O | H | H | H | H | 单键 | 1 | SSR |
Ⅲ-A3 | H,H | O | H | H | H | H | 单键 | 1 | RRS |
Ⅲ-A4 | H,H | O | H | H | H | H | 单键 | 1 | SRS |
Ⅲ-B1 | H,H | O | Et | H | H | H | 单键 | 1 | RSR |
Ⅲ-B2 | H,H | O | Et | H | H | H | 单键 | 1 | SSR |
Ⅲ-B3 | H,H | O | Et | H | H | H | 单键 | 1 | RRS |
Ⅲ-B4 | H,H | O | Et | H | H | H | 单键 | 1 | SRS |
Ⅲ-C1 | H,H | O | H | H | H | Me | 单键 | 1 | RSR |
Ⅲ-C2 | H,H | O | H | H | H | Me | 单键 | 1 | SSR |
Ⅲ-C3 | H,H | O | H | H | H | Me | 单键 | 1 | RRS |
Ⅲ-C4 | H,H | O | H | H | H | Me | 单键 | 1 | SRS |
Ⅲ-D1 | H,H | O | H | H | H | Me | 单键 | 2 | RRS |
Ⅲ-D2 | H,H | O | H | H | H | Me | 单键 | 2 | SRS |
Ⅲ-D3 | H,H | O | H | H | H | Me | 单键 | 2 | RSR |
Ⅲ-D4 | H,H | O | H | H | H | Me | 单键 | 2 | SSR |
Ⅲ-E1 | H,H | O | H | 3-Br | H | Me | 单键 | 1 | RSR |
Ⅲ-E2 | H,H | O | H | 3-Br | H | Me | 单键 | 1 | SSR |
Ⅲ-E3 | H,H | O | H | 3-Br | H | Me | 单键 | 1 | RRS |
Ⅲ-E4 | H,H | O | H | 3-Br | H | Me | 单键 | 1 | SRS |
Ⅲ-F1 | H,H | O | H | H | 10-OMe | H | 单键 | 1 | RSR |
Ⅲ-F2 | H,H | O | H | H | 10-OMe | H | 单键 | 1 | SSR |
Ⅲ-F3 | H,H | O | H | H | 10-OMe | H | 单键 | 1 | RRS |
Ⅲ-F4 | H,H | O | H | H | 10-OMe | H | 单键 | 1 | SRS |
Ⅲ-G1 | H,H | O | H | H | H | Me | O | 1 | SSS |
Ⅲ-G2 | H,H | O | H | H | H | Me | O | 1 | RSS |
Ⅲ-G3 | H,H | O | H | H | H | Me | O | 1 | RRR |
Ⅲ-G4 | H-H | O | H | H | H | Me | O | 1 | SRR |
Ⅲ-H1 | O | H,H | H | H | H | H | 单键 | 1 | RSR |
Ⅲ-H2 | O | H,H | H | H | H | H | 单键 | 1 | SSR |
Ⅲ-H3 | O | H,H | H | H | H | H | 单键 | 1 | RRS |
Ⅲ-H4 | O | H,H | H | H | H | H | 单键 | 1 | SRS |
Ⅲ-I1 | H,H | O | H | 3-(3’NH2-Ph) | H | H | 单键 | 1 | RSR |
Ⅲ-I2 | H,H | O | H | 3-(3’NH2-Ph) | H | H | 单键 | 1 | SSR |
Ⅲ-I3 | H,H | O | H | 3-(3’NH2-Ph | H | H | 单键 | 1 | RRS |
Ⅲ-I4 | H,H | O | H | 3-(3’NH2-Ph | H | H | 单键 | 1 | SRS |
Ⅲ-J1 | O | O | OH | H | H | H | 单键 | 1 | SSR |
Ⅲ-J2 | O | O | OH | H | H | H | 单键 | 1 | RSR |
Ⅲ-J3 | O | O | OH | H | H | H | 单键 | 1 | RRS |
Ⅲ-J4 | O | O | OH | H | H | H | 单键 | 1 | SRS |
Ⅲ-K1 | H,H | O | H | H | H | CO2-Et | 单键 | 1 | RSR |
Ⅲ-K2 | H,H | O | H | H | H | CO2-Et | 单键 | 1 | SSR |
Ⅲ-K3 | H,H | O | H | H | H | CO2-Et | 单键 | 1 | RRS |
Ⅲ-K4 | H,H | O | H | H | H | CO2-Et | 单键 | 1 | SRS |
Ⅲ-L1 | H,H | O | H | H | H | CH2OH | 单键 | 1 | RSR |
Ⅲ-L2 | H,H | O | H | H | H | CH2OH | 单键 | 1 | SSR |
Ⅲ-L3 | H,H | O | H | H | H | CH2OH | 单键 | 1 | RRS |
Ⅲ-L4 | H,H | O | H | H | H | CH2OH | 单键 | 1 | SRS |
Ⅲ-M1 | H,H | O | H | H | 9-OMe | H | 单键 | 1 | RSR |
Ⅲ-M2 | H,H | O | H | H | 9-OMe | H | 单键 | 1 | SSR |
Ⅲ-M3 | H,H | O | H | H | 9-OMe | H | 单键 | 1 | RRS |
Ⅲ-M4 | H,H | O | H | H | 9-OMe | H | 单键 | 1 | SRS |
Ⅲ-N1 | H,H | O | H | H | H | H | 单键 | 1 | RSR |
Ⅲ-N2 | H,H | O | H | H | H | H | 单键 | 1 | SSR |
Ⅲ-N3 | H,H | O | H | H | H | H | 单键 | 1 | RRS |
Ⅲ-N4 | H,H | O | H | H | H | H | 单键 | 1 | SRS |
Ⅲ-P1 | H,H | O | H | 3-CH2O-CH2OEt | H | H | 单键 | 1 | RSR |
Ⅲ-P2 | H,H | O | H | 3-CH2O-CH2OEt | H | H | 单键 | 1 | SSR |
Ⅲ-P3 | H,H | O | H | 3-CH2O-CH2OEt | H | H | 单键 | 1 | RRS |
Ⅲ-P4 | H,H | O | H | 3-CH2O-CH2OEt | H | H | 单键 | 1 | SRS |
Ⅲ-Q1 | H,H | O | H | H | H | H | O | 1 | RSS |
Ⅲ-Q2 | H,H | O | H | H | H | H | O | 1 | SSS |
Ⅲ-Q3 | H,H | O | H | H | H | H | O | 1 | RRR |
Ⅲ-Q4 | H,H | O | H | H | H | H | O | 1 | SRR |
需要申明,在本专利文本中提到的专利、申请和公开文献都整个作为本发明的参考。本领域普通技术人员可以在不脱离本发明的宗旨的情况下,对优选的实施方式进行预见、改变或修改。需要申明,这些变化都在本发明的范围之内。
Claims (39)
其中:
B环和F环,各自独立地与它们所连接的碳原子一起,为选自下面的基团:
(a)其中1-3个碳原子可以被氮原子置换的不饱和6-员芳香
碳环;
(b)不饱和5-员芳香碳环;和
(c)不饱和5-员芳香碳环,其中:
(1)一个碳原子被氧原子、氮原子、或硫原子置换;
(2)两个碳原子被一个氮原子和一个硫原子、一个氮原
子和一个氧原子、或两个氮原子置换;或
(3)三个碳原子被三个氮原子置换;
R1选自:
(a)H、取代或未取代的1-4个碳原子烷基、取代或未取代的
芳基、取代或未取代的芳基烷基、取代或未取代的杂芳基、
或取代或未取代的杂芳基烷基;
(b)-C(=O)R9,其中R9选自烷基、芳基和杂芳基;
(c)-OR10,其中R10选自H和1-4个碳原子烷基;
(d)-C(=O)NH2、-NR11R12、-(CH2)pN11R12、-(CH2)pOR10、
-O(CH2)pOR10和-O(CH2)pNR11R12,其中p是1-4;而且其
中:要么
1)R11和R12各自独立地选自H和1-4个碳原子烷基,要么
2)R11和R12一起形成式-(CH2)2-X1-(CH2)2-的连接基,其中
X1选自-O-、-S-和-CH2-;
R2选自:H、1-4个碳原子烷基、羟基、具有1-4个碳原子烷氧基、-OC(=O)R9、-OC(=O)NR11R12、-O(CH2)pNR11R12、-O(CH2)pOR10、具有6-10个碳原子取代或未取代的芳基烷基,和取代或未取代的杂芳基烷基;
R3、R4、R5和R6各自独立地选自:
a)H、芳基、杂芳基、F、Cl、Br、I、-CN、CF3、-NO2、-OH、
-OR9、-O(CH2)pNR11R12、-OC(=O)R9、-OC(=O)NR2R7、-
OC(=O)NR11R12、-O(CH2)pOR10、-CH2OR10、-NR11R12、
-NR10S(=O)2R9、-NR10C(=O)R9;
b)-CH2OR14,其中R14为移去羧基中的羟基后的氨基酸的残基;
c)-NR10C(=O)NR11R12、-CO2R2、-C(=O)R2、-C(=O)NR11R12、
-CH=NOR2、-CH=NR9、-(CH2)pNR11R12、-(CH2)pNHR14、或
-CH=NNR2R2A,其中R2A同R2;
d)-S(O)yR2、-(CH2)pS(O)yR9、-CH2S(O)yR14,其中y是0、1或2;
e)具有1-8个碳原子的烷基、具有2-8个碳原子的链烯基、具
有2-8个碳原子的炔基,其中:
1)各个烷基、链烯基或炔基是未取代的;或者
2)各个烷基、链烯基或炔基被1-3个选自以下的基团所取代:
具有6-10个碳原子的芳基、杂芳基、芳基烷氧基、杂环基
烷氧基、羟基烷氧基、烷氧基-烷氧基、羟基烷硫基、烷氧
基-烷硫基、F、Cl、Br、I、-CN、-NO2、-OH、-OR9、
-X2(CH2)pNR11R12、-X2(CH2)pC(=O)NR11R12、-X2(CH2)pOC(=O)
NR11R12、-X2(CH2)pCO2R9、-X2(CH2)pS(O)yR9、
-X2(CH2)pNR10C(=O)NR11R12、-OC(=O)R9、-OCONHR2,-O-四氢吡喃基、
-NR11R12、-NR10C(=O)R9、-NR10CO2R9、-NR10C(=O)NR11R12、
-NHC(=NH)NH2、NR10S(O)2R9、-S(O)yR9、-CO2R2、
-C(=O)NR11R12、-C(=O)R2、-CH2OR10、-CH=NNR2R2A、-CH=NOR2、
-CH=NR9、-CH=NNHCH(N=NH)NH2、-S(=O)2NR2R2A、
-P(=O)(OR10)2、-OR14、和具有5-7个碳原子的单糖,其中单糖的
每个羟基各自独立地是未取代的,或者被H、1-4个碳原子
的烷基、2-5个碳原子的烷羰氧基或具有1-4个碳原子的烷
氧基所取代;
X2是O、S、或NR10;
R7和R8各自独立地选自:
H、具有1-4个碳原子的烷基、具有1-4个碳原子的烷氧基、具有6-10个碳原子的取代或未取代的芳烷基、取代或未取代的杂芳基烷基、-(CH2)pOR10、-(CH2)pOC(=O)NR11R12和-(CH2)pNR11R12;或者R7和R8一起形成式-CH2-X3-CH2-的连接基,其中X3是X2或一个键。
m和n各自独立地是0、1或2。
Y选自:-O-、-S-、-N(R10)-、-N+(O-)(R10)-、-N(OR10)-和-CH2-;
Z选自:单键、-O-、-CH=CH-、-S-、-C(=O)-、-CH(OR10)-、-N(R10)-、-N(OR10)-、-CH(NR11R12)-、-C(=O)N(R17)-、-N(R17)C(=O)-、-N(S(O)yR9)-、-N(S(O)yNR11R12)-、-N(C(=O)R17)-、-C(R15R16)-、-N+(O-)(R10)-、-CH(OH)-CH(OH)-和-CH(O(C=O)R9)CH(OC(=O)R9A)-,其中R9A同R9
R15和R16各自独立地选自H、-OH、-C(=O)R10、-O(C=O)R9、羟基烷基和-CO2R10;
R17选自H、烷基、芳基和杂芳基;
A1和A2选自H,H;H,OR2;H,-SR2;H,-N(R2)2;和一个基团,其中A1和A2一起形成选自=O、=S和=NR2的部分;
B1和B2选自H,H;H,-OR2;H,-SR2;H,-N(R2)2;和一个基团,其中B1和B2一起形成选自=O、=S和=NR2的部分;
其前提条件是A1和A2,或B1和B2的至少一对形成=O。
5.权利要求1的化合物,其中R1为H。
6.权利要求1的化合物,其中R2为H、羟基、或者取代或未取代的烷基。
7.权利要求1的化合物,其中R3、R4、R5和R6各自独立地选自H、取代或未取代的烷基、卤素、取代或未取代的烷氧基、取代或未取代的氨基、或者取代或未取代的芳基。
8.权利要求1的化合物,其中R7和R8各自独立地选自H、或者取代或未取代的烷基。
9.权利要求1的化合物,其中Y为O。
10.权利要求1的化合物,其中Z为单键、O、S、或者取代或未取代的N。
11.权利要求1的化合物,其中m和n各自独立地是1或2。
12.权利要求1的化合物,其中Y为O,Z为单键或O,且m和n各自独立地是1或2。
13.权利要求1的化合物,其中A1A2和B1B2各自独立地是=O或H,H。
14.权利要求1的化合物,其中R1、R4、R6和R7各自为H,Y是O,n是1,A1A2和B1B2各自独立地是=O或H,H,R2是H、OH、或低碳烷基,R3是H或取代烷基,R5和R8各自为H或烷氧基,Z为单键或O,以及m是1或2。
15.权利要求1的化合物,具有下式:
16.权利要求15的化合物,其中R3和R5各自独立地选自以下基团:
a)H、杂芳基、F、Br、-CN、CF3、
-NO2、-OH、-OR9、-O(CH2)pNR11R12、-OC(=O)R9、-OC(=O)NR2R7、-OC(=O)NR11R12、-O(CH2)pOR10、-CH2OR10、-NR11R12、-NR10S(=O)2R9、-NR10C(=O)R9;
c)-NR10C(=O)NR11R12、-CO2R2、-C(=O)R2、-C(=O)NR11R12、-CH=NOR2、-CH=NR9、-(CH2)pNR11R12、-(CH2)pNHR14;
d)-S(O)yR2、-(CH2)pS(O)yR9、-CH2S(O)yR14,其中y是0,1或2;
e)具有1-8个碳原子的烷基、具有2-8个碳原子的链烯基、具有2-8个碳原子的炔基,其中:
1)各个烷基、链烯基或炔基是未取代的;或者
2)各个烷基、链烯基或炔基被1-3个选自以下的基团所取代:
具有6-10个碳原子的芳基、杂芳基、芳基烷氧基、杂环基烷氧基、羟基烷氧基、烷氧基-烷氧基、羟基烷硫基、烷氧基-烷硫基、F、Cl、Br、I、-CN、-NO2、-OH、-OR9、-X2(CH2)pNR11R12、-X2(CH2)pC(=O)NR11R12、-X2(CH2)pOC(=O)NR11R12、-X2(CH2)pCO2R9、-X2(CH2)pS(O)yR9、-X2(CH2)pNR10C(=O)NR11R12、-OC(=O)R9、-OCONHR2,-O-四氢吡喃基、-NR11R12、-NR10C(=O)R9、-NR10CO2R9、-NR10C(=O)NR11R12、-NHC(=NH)NH2、NR10S(O)2R9、-S(O)yR9、-CO2R2、-C(=O)NR11R12、-C(=O)R2、-CH2OR10、-CH=NR9、-S(=O)2NR2R2A、-OR14、和具有5-7个碳原子的单糖,其中单糖的每个羟基各自独立地是未取代的,或者被H、1-4个碳原子的烷基、2-5个碳原子的烷羰氧基或具有1-4个碳原子的烷氧基所取代。
17.权利要求16的化合物,其中R5独立地选自下列基团:H、-OR9、-O(CH2)pNR11R12、-OC(=O)R9、-OC(=O)NR2R7、-OC(=O)NR11R12、-O(CH2)pOR10、-CH2OR10、-NR11R12、-NR10S(=O)2R9、-NR10C(=O)R9、-C(=O)NR11R12、-(CH2)pNR11R12、-S(O)yR2-(CH2)pS(O)yR9和-CH2S(O)yR14,其中y是0、1或2。
20.权利要求18的化合物,具有下式的非对映异构体:
21.药物组合物,含有权利要求1的化合物和可药用载体。
22.药物组合物,含有权利要求18的化合物和可药用载体。
23.用于治疗或预防前列腺疾病的药物组合物,含有权利要求1的化合物和可药用载体。
24.权利要求23的药物组合物,其中的前列腺疾病为前列腺癌或良性的前列腺增生。
25.用于治疗或预防血管生成性疾病的药物组合物,含有权利要求1的化合物和可药用载体。
26.权利要求25的药物组合物,其中的血管生成性疾病为固体肿瘤、子宫内膜异位、糖尿病视网膜病、牛皮癣、成血管细胞瘤、眼科疾病或斑状变性。
27.用于治疗或预防瘤形成、类风湿关节炎、肺纤维变性、脊髓纤维变性、意外创伤的愈合、动脉粥样硬化或再狭窄的药物组合物,含有权利要求1的化合物和可药用载体。
28.用于治疗或预防阿尔茨海默氏病、肌萎缩性侧索硬化、帕金森病、中风、局部缺血、亨廷顿舞蹈病、爱滋病痴呆、癫痫、多发性硬化、末稍神经病、脑损伤或脊索损伤的药物组合物,含有权利要求1的化合物和可药用载体。
29.抑制trk激酶活性的方法,包括提供足够量的权利要求1的化合物,以获得有效的抑制。
30.权利要求29的方法,其中trk激酶是trkA。
31.权利要求29的方法,其中提供权利要求1的化合物用来治疗炎症。
32.治疗或预防前列腺疾病的方法,包括对需要治疗或预防的宿主给予治疗有效量的权利要求1的化合物。
33.权利要求32的方法,其中的前列腺疾病是前列腺癌或良性前列腺增生。
34.治疗或预防血管生成性疾病的方法,包括对需要治疗或预防的宿主给予治疗有效量的权利要求1的化合物。
35.权利要求34的方法,其中的血管生成性疾病为固体肿瘤、子宫内膜异位、糖尿病视网膜病、牛皮癣、成血管细胞瘤、眼科疾病或斑状变性。
36.治疗或预防缘于PDGFR活性的疾病的方法,包括提供足够量的权利要求1的化合物,使得血小板产生的生长因子受体与有效抑制量的该化合物接触。
37.治疗或预防瘤形成、类风湿关节炎、肺纤维变性、脊髓纤维变性、意外创伤的愈合、动脉粥样硬化或再狭窄的方法,包括对需要治疗或预防的宿主给予治疗有效量的权利要求1的化合物。
38.治疗或预防具有营养因子应答细胞异常活性特征的疾病的方法,包括提供足够量的权利要求1的化合物,使得营养因子细胞受体与有效诱导活性量的该化合物接触。
39.治疗或预防阿尔茨海默氏病、肌萎缩性侧索硬化、帕金森病、中风、局部缺血、亨廷顿舞蹈病、爱滋病痴呆、癫痫、多发性硬化、末稍神经病、脑损伤或脊索损伤的方法,包括对需要治疗或预防的宿主给予治疗有效量的权利要求1的化合物。
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CN101641098B (zh) * | 2007-02-01 | 2012-02-15 | 辉凌国际制药(瑞士)有限公司 | 用于治疗子宫内膜异位的药物 |
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