CN1152042C - 部分或完全a1激动剂-n6杂环5’硫代腺苷衍生物 - Google Patents
部分或完全a1激动剂-n6杂环5’硫代腺苷衍生物 Download PDFInfo
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- CN1152042C CN1152042C CNB008139334A CN00813933A CN1152042C CN 1152042 C CN1152042 C CN 1152042C CN B008139334 A CNB008139334 A CN B008139334A CN 00813933 A CN00813933 A CN 00813933A CN 1152042 C CN1152042 C CN 1152042C
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- Prior art keywords
- tetrahydrofuran
- compound
- amino
- methyl
- purine
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- 125000000623 heterocyclic group Chemical group 0.000 title abstract description 31
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Abstract
N6杂环5′改性腺苷衍生物,是腺苷A1受体部分或完全激动剂,并且本身可用于改善哺乳动物尤其是人类的心脏活动,改善脂肪细胞功能,治疗中枢神经系统疾病,以及治疗糖尿病和肥胖症。
Description
技术领域
本发明包括是N6杂环5’硫代改性腺苷衍生物的稳定和有效的药物和前体药物。本发明的组合物是选择性的A1腺苷受体部分或完全激动剂,因而,可用于改善哺乳动物尤其是人类的心脏活动,改善脂肪细胞功能,治疗中枢神经系统疾病,以及治疗糖尿病和肥胖症。
背景技术
在心脏中至少有两种亚型的腺苷受体:A1和A2A。每个亚型影响不同的生理功能。A1腺苷受体介导两种不同的生理反应。儿茶酚胺心脏刺激作用的抑制通过抑制腺苷酸环化酶介导,而降低心率(HR)和延长AV节脉冲传播的直接作用很大程度归因于IKAdo。的活化。(B.Lerman和L.Belardinelli Circulation,Vol.83(1991),P 1499-1509和J.C.Shryock和L.Belardinelli,The Am.J.Cardiology,Vol.79(1997)p2-10)。抗-β-肾上腺素能作用和对SA和AV结功能的直接抑制作用两者都由A1受体介导;A2A受体在这种对腺苷的反应中不起作用。
A2A受体介导腺苷引起的冠状血管舒张。从而刺激A1腺苷受体缩短了持续时间,降低了AV结细胞的动作电位的振幅,并因此而延长了AV结细胞的不应期。这些效应所带来的结果是限制了心房传导到心室的脉冲数。这就形成了临床采用A1受体激动剂治疗室上性心动过速(包括折返性结性心动过速的末期)和在心房纤维性颤动和扑动期间控制心室速率的基础。
因此,A1激动剂的临床应用是治疗急慢性心脏节律疾病,特别是以心率加快为特征、且该心率加快由窦房结、心房和AV结组织异常引起的疾病。这些疾病包括(但并不限于)心房纤维性颤动、室上性心动过速和心房扑动。使用A1激动剂可降低心率,调整异常节律,从而改善心血管功能。
A1激动剂,通过其抑制儿茶酚胺效应的能力降低细胞cAMP,从而对交感神经张力增高引起细胞cAMP升高的衰竭心脏应具有有益的作用。后者已经被显示与室性心律失常和突然死亡的可能性增加有关。在关于腺苷对心脏电生理学的作用的综述中讨论了以上各方面(参见B.Lerman和L.Belardinelli Circulation,Vol.83(1991),P 1499-1509和J.C.Shryock和L.Belardinelli,Am.J.Cardiology,Vol.79(1997)p2-10)。
A1腺苷激动作用领域争论之处是在局部缺血之前对心脏预先调节的益处可能归因于腺苷与A1受体的结合。这种假设的证据来自家兔局部缺血模型,其中考虑到梗塞大小在局部缺血之前给予2-氯-N6-环戊基腺苷(CCPA)和R-PIA提供保护(J.D.Thomton等人.Circulation Vol.85(1992)659-665)。
A1激动剂,由于它们对环AMP产生的抑制作用而对脂肪细胞具有抗分解脂肪作用,这导致非酯化脂肪酸(NEFA)释放减少(E.A.van Schaick等人,J.Pharmacokinetics和Biopharmaceutics,Vol.25(1997)p673-694和P.Strong Clinical Science Vol.84(1993)p.663-669)。非胰岛素依赖性糖尿病(NIDDM)特征在于导致高血糖的胰岛素耐受性。引起观测到的高血糖的因素是正常葡萄糖摄取的缺乏和骨骼肌糖原合成酶(GS)的激活。已经证明NEFA水平的升高抑制胰岛素-刺激的葡萄糖摄取和糖原合成(D.Thiebaud等人Metab.Clin.Exp.Vol.31(1982)p1128-1136和G.Boden等人J.Clin.Invest.Vol.93(1994)p2438-2446)。P.J.Randle早在1963年就提出了葡萄糖脂肪酸循环的假说(P.J.Randle等人Lancet(1963)p.785-789)。该假说的原则是限制脂肪酸向外周组织的供应会促进碳水化合物的利用(P.Strong等人Clinical Science Vol.84(1993)p.663-669)。
A1激动剂在中枢神经疾病中的益处已有综述,其内容一并纳入本文作为参考(L.J.S.Knutsen和T.F.Murray,Purinergic Approaches inExperimental Therapeutics,K.A.Jacobson和M.F.Jarvis编著(1997)Wiley-Liss,N.Y.,p-423-470)。简言之,基于癫痫实验模型,混合的A2A∶A1激动剂腺苷地尔(metrifudil)已经显示是抗苯并二氮反向激动剂6,7-二甲氧基-4-乙基-β-咔啉-3-羧酸甲酯诱导的癫痫发作的一种有效的抗惊厥剂(DMCM,H.Klitgaard Eur.J.Pharmacol.(1993)Vol.224p.221-228)。在其它的采用CGS 21680(一种A2A激动剂)的研究中,可以推断抗惊厥剂的活性归于A1受体的激活(G.Zhang等人Eur.J.Pharmacol.Vol.255(1994)p.239-243)。此外,在DMCM模型中显示A1腺苷选择性激动剂具有抗惊厥活性(L.J.S.Knutsen,Adenosine andAdenne Nucleotides:From Molecular Biology to IntegrativePhysiology;L.Belardinelli和A.Pelleg,Kluwer编:Boston,1995,pp 479-487)。A1腺苷激动剂具有益处的第二方面是在前脑局部缺血动物模型中,如Knutsen等人介绍(J.Med.Chem.Vol.42(1999)p.3463-3477)。据信神经保护的益处部分由于抑制兴奋性氨基酸的释放(同上)。
现有技术公开了存在大量的A1完全激动剂。然而,所公开的激动剂通常在哺乳动物体是无效的形式。由于有A1激动剂的有效形式并不总是稳定、可溶的,或者它们具有其它的使其难以加入到治疗剂型中的性能,识别更容易加入到治疗剂型的化合物以便提供所需的治疗作用通常是必需的。同样,由于这些激动剂对一切生物学上可得到的组织中的A1腺苷受体的非选择性刺激所引起的副作用以及妨碍其作为慢性剂用途的所需反应的脱敏作用,因此不能用作有用的治疗剂。因此,对特异的和选择性的A1激动剂、在体内转化成有效治疗组合物的前体和/或前体药物仍有需求。
发明内容
发明概述
一方面,本发明包括有用的腺苷A1受体部分或完全激动剂杂环5’-硫代改性腺苷衍生物。
另一方面,本发明包括含一种或多种耐受性好、副作用少的杂环5’-硫代改性腺苷衍生物组分的药物组合物。
在另一个实施方案中,本发明包括杂环5’-硫代改性腺苷衍生物,它具有以下结构式:
在又一个实施方法中,本发明包括对哺乳动物尤其是人给予本发明的组合物以激发冠状活性、改善脂肪细胞功能、治疗中枢神经系统疾病及治疗糖尿病的方法。
在进一步的实施方案中,本发明是含有至少一种本发明的组分和一种或多种药用赋形剂的药物组合物。
当前实施方案的描述
本发明包括一类杂环5’-硫代改性腺苷衍生物,其具有如下结构式:
其中X1=S、S(O)、S(O2);
其中R1是含有3至15个碳原子的单环或多环杂环基,其中至少一个碳原子被选自N、O、P和S-(O)0-2的原子或分子取代,且R1不含有环氧基,R2选自氢、卤素、CF3和氰基;其中R3和R4独立地选自氢、-(CO)-R’和-(CO)-R”,其中R’和R”独立地选自C1-15烷基、C2-15烯基、C2-15炔基、杂环基、芳基和杂芳基,这类烷基、烯基、炔基、芳基、杂环基和杂芳基可任选地被1至3个独立地选自卤素、NO2、杂环基、芳基、杂芳基、CF3、CN、OR20、SR20、S(O)R22、SO2R22、SO2N(R20)2、SO2NR20COR22、SO2NR20CO2R22、SO2NR20CON(R20)2、N(R20)2、NR20COR22、NR20CO2R22、NR20CON(R20)2、NR20C(NR20)NHR23、COR20、CO2R20、CON(R20)2、CONR20SO2R22、NR20SO2R22、SO2NR20CO2R22、OCONR20SO2R22、OC(O)R20、C(O)OCH2OC(O)R20和OCON(R20)2的取代基取代,并且每个任选的杂芳基、芳基和杂环基取代基可任选地被卤素、NO2、烷基、CF3、氨基、单-或二-烷基氨基、烷基或芳基或杂芳基酰胺、NR20COR22、NR20SO2R22、COR20、CO2R20、CON(R20)2、NR20CON(R20)2、OC(O)R20、OC(O)N(R20)2、SR20、S(O)R22、SO2R22、SO2N(R20)2、CN或OR20取代;
其中R5选自C1-15烷基、C2-15烯基、C2-15炔基、杂环基、芳基和杂芳基,这类烷基、烯基、炔基、芳基、杂环基和杂芳基可任选地被1至3个分别选自卤素、烷基、NO2、杂环基、芳基、杂芳基、CF3、CN、OR20、SR20、S(O)3R20、S(O)R22、SO2R22、SO2N(R20)2、SO2NR20COR22、SO2NR20CO2R22、SO2NR20CON(R20)2、P(O)(OR20)2、N(R20)2、NR20COR22、NR20CO2R22、NR20CON(R20)2、NR20C(NR20)NHR23、COR20、CO2R20、CON(R20)2、CONR20SO2R22、NR20SO2R22、SO2NR20CO2R22、OCONR20SO2R22、OC(O)R20、C(O)OCH2OC(O)R20和OCON(R20)2的取代基取代,并且每个任选的杂芳基、芳基和杂环基取代基可任选地被卤素、NO2、烷基、CF3、氨基、单-或二-烷基氨基、烷基或芳基或杂芳基酰胺、NR20COR22、NR20SO2R22、COR20、CO2R20、CON(R20)2、NR20CON(R20)2、OC(O)R20、OC(O)N(R20)2、SR20、S(O)R22、SO2R22、SO2N(R20)2、CN或OR20取代;
其中R20选自H、C1-15烷基、C2-15烯基、C2-15炔基、杂环基、芳基和杂芳基,这类烷基、烯基、炔基、杂环基、芳基和杂芳基可任选地由1至3个分别选自卤素、烷基、单-或二烷基氨基、烷基或芳基或杂芳基酰胺、CN、O-C1-6烷基、CF3、芳基和杂芳基的取代基取代;和
R22选自C1-15烷基、C2-15烯基、C2-15炔基、杂环基、芳基和杂芳基,这类烷基、烯基、炔基、杂环基、芳基和杂芳基可任选地被1至3个分别选自卤素、烷基、单-或二烷基氨基、烷基或芳基或杂芳基酰胺、CN、O-C1-6烷基、CF3和杂芳基的取代基取代。
在优选的成分中,X1=S或SO2;R2是氢;R3和R1各自独立地选自氢、-(CO)-R’和-(CO)-R”,其中R’和R”各自独立地选自C1-6烷基,并且更优选地,R3和R4各为氢;R5选自C1-8烷基和芳基,其中烷基和芳基可任选地被1至2个分别选自以下基团的取代基取代:卤素、烷基、芳基、杂芳基、CF3、CN、OR20、S(O)R22、SO2R22、SO2N(R20)2、NR20CON(R20)2、CO2R20、CON(R20)2,并且其中每个任选的杂芳基和芳基取代基可任选地被卤素、烷基、CF3、CO2R20、CN和OR20进一步取代;R20选自H、C1-6烷基;R22选自C1-6基团。在上述成分中,R5更优选地选自C1-8烷基和芳基,其中烷基和芳基可任选地被1至2个分别选自卤素、烷基、CF3和OR20的取代基取代。
在更优选的成分中,X1=S或SO2;R2是氢;R3和R4独立地选自氢、-(CO)-R’和-(CO)-R”,其中R’和R”各自独立地选自可被1个选自芳基、CF3、CN、OR20、N(R20)2的取代基任选地取代的C1-6烷基,并且其中每个任选的芳基取代基可任选地进一步被卤素、NO2、烷基、CF3取代;R5是C1-8烷基,其中烷基由可任选地被1至2个分别选自卤素、烷基、芳基、杂芳基、CF3、CN、OR20、S(O)R22、SO2R22、SO2N(R20)2、NR20CON(R20)2、CO2R20、CON(R20)2的取代基取代,其中每个任选的杂芳基和芳基取代基可进一步任选地被卤素、烷基、CF3、CO2R20、CN和OR20取代;R20选自H、C1-6烷基;和R22选自C1-6基团。在上述成分中,R5更优选为被1至2个分别选自芳基、杂芳基、OR20、S(O)R22、CO2R20、CON(R20)2的取代基任选地取代的C1-8烷基,并且其中每个任选的杂芳基和芳基取代基可进一步任选地被卤素、烷基、CF3、CO2R20、CN和OR20取代,并且R5甚至更优选地为可被选自CO2R20和CON(R20)2的一个取代基任选地取代的C1-8烷基,R5还更优选地为C1-6烷基,最优选地为甲基或乙基或异丙基。同样在以上的成分中,R3和R1每个更优选地为氢,并且R20更优选地选自H和甲基。
在另一类优选成分中,R2是氢;R3和R1各自独立地选自氢、-(CO)-R’和-(CO)-R”,其中R’和R”分别选自C1-6烷基和芳基,这类烷基和芳基可任选地被1至2个分别选自以下基团的取代基取代:卤素、NO2、芳基、CF3、CN、OR20、N(R20)2、S(O)R22、SO2R22,并且其中每个任选的芳基取代基可进一步任选地被卤素、NO2、烷基、CF3取代;R5选自芳基和杂芳基,其中芳基和杂芳基可任选地被1至3个分别选自以下基团的取代基取代:卤素、烷基、芳基、杂芳基、CF3、CN、OR20、SR20、N(R20)2、S(O)R22、SO2R22、SO2N(R20)2、NR20CO2R22、NR20CON(R20)2、CO2R20、CON(R20)2,并且其中每个任选的杂芳基和芳基取代基可进一步任选地被卤素、烷基、CF3、CO2R20、CON(R20)2、S(O)R22、SO2R22、SO2N(R20)2、CN或OR20取代;R20选自H、C1-6烷基和芳基,这类烷基和芳基可任选地被一个选自卤素、烷基、单-或二-烷基氨基、CN、O-C1-6烷基、CF3的取代基取代;R22选自C1-6烷基和芳基,这类烷基和芳基可任选地被一个选自卤素、烷基或CN、O-C1-6烷基和CF3的取代基取代。在以上成分中,X1优选S;R3和R1更优选氢;R5更优选地选自芳基和杂芳基,其中芳基和杂芳基可任选地被1至3个分别选自以下基团的取代基取代:卤素、烷基、CF3、CN、OR20、SR20、CO2R20、CON(R20)2。甚至更优选R5是可任选地被1至2个分别选自卤素、烷基、CF3、OR20、CO2R20、CON(R20)2的取代基取代的芳基。最优选地,R5是可任选地被选自甲氧基、氯、氟、甲基和三氟甲基的取代基取代的苯基。在上述化合物中,R20优选选自H、C1-3烷基,最优选为H或甲基,同时R22优选C1-6烷基。
在本发明的成分中,R1较佳为被选自以下组的一种或多种化合物单取代或多取代:卤素、氧代、羟基、低级烷基、取代的低级烷基、烷氧基、芳基、酰基、芳氧基、羧基、取代的芳基、杂环、杂芳基、取代的杂芳基、环烷基、取代的环烷基、硝基、氰基和它们的混合物。更优选地,R1是含有3至15个碳原子的单环、双环或三环环烷基,其中至少一个碳原子被选自O和S-(O)0-2的原子或分子取代。优选的R1基团的一些例子包括:
或 或
其中R1’、R1″、R1和R1″″可各自独立地选自卤素、羟基、低级烷基、取代的低级烷基、烷氧基、芳基、酰基、芳氧基、羧基、取代的芳基、杂环、杂芳基、取代的杂芳基、环烷基、取代的环烷基、硝基和氰基,且X是O或S(-O)0-2,或者,R1和R1″″可以是单个氧原子。更优选地,R1’、R1″、R1和R1″″各自独立地选自氢、低级烷基和取代的低级烷基。在以上成分中,每个R独立地选自H、低级烷基和取代的低级烷基,并且其中X是O或S(-O)0-2。
本发明最优选的化合物包括下述化合物:
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(甲硫基甲基)氧杂环戊烷(oxolane)-3,4-二醇;
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(乙硫基)甲基]氧杂环戊烷-3,4-二醇;
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(甲基乙硫基)甲基]氧杂环戊烷-3,4-二醇;
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(苯硫基甲基)氧杂环戊烷-3,4-二醇;
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4-甲氧基苯硫基)甲基]氧杂环戊烷-3,4-二醇;
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4-氯苯硫基)甲基]氧杂环戊烷-3,4-二醇;
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4-氟苯硫基)甲基]氧杂环戊烷-3,4-二醇;
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4-甲基苯硫基)甲基]-氧杂环戊烷-3,4-二醇;
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4-(三氟甲基)苯硫基)甲基]氧杂环戊烷-3,4-二醇;
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(2-甲氧基苯硫基)甲基]氧杂环戊烷-3,4-二醇;
(5-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(2S,3S,4R,5R)-3,4-二羟基氧杂环戊烷-2-基)(乙磺酰基)甲烷;
2-{6-[((3R)-氧杂环戊烷-3-基)氨基嘌呤-9-基](4S,5S,2R,3R)-5-[(2,4-二氟苯硫基)甲基]氧杂环戊烷-3,4-二醇;
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(2,6-二氯苯硫基)甲基]氧杂环戊烷-3,4-二醇;
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基)(4S,5S,2R,3R)-5-[(3-氟苯硫基)甲基]氧杂环戊烷-3,4-二醇;
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(2-氟苯硫基)甲基]氧杂环戊烷-3,4-二醇;
5-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9基}(2S,3R,4R,5R)-4-乙酰氧基-2-[(氟苯硫基)甲基]氧杂环戊烷-3-基乙酸酯;
2[(5-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(2S,3S,4R,5R)-3,4-二羟基氧杂环戊烷-2-基)甲硫基]苯甲酸甲酯;
{2[(5-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9基}(2S,3S,4R,5R)-3,4-二羟基氧杂环戊烷-2-基)甲硫基]苯基}-N-甲基甲酰胺苯甲酸酯;
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(苯并噁唑-2-基硫甲基)氧杂环戊烷-3,4-二醇;
2-{6-[((3S)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(1-甲基咪唑-2-基-硫基)甲基]氧杂环戊烷-3,4-二醇;
2-{6-[((3S)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(嘧啶-2-基硫甲基)氧杂环戊烷-3,4-二醇;
2-{6-[((3S)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(2-吡啶基硫甲基)氧杂环戊烷-3,4-二醇;
2-{6-[((3S)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(4-吡啶基硫甲基)氧杂环戊烷-3,4-二醇;和
(5-{6-[((3R)氧杂环戊烷-3-基)氨基]嘌呤-9-基}(2S,3R,4R,5R)-4-乙酰氧基-2-[(4-氟苯硫基)甲基]氧杂环戊烷-3-基]乙酸酯。
下列定义适用于本文采用的术语。
″卤″或″卤素″-单独或组合地意指所有卤素,即,氯(Cl)、氟(F)、溴(Br)、碘(I)。
″羟基″指基团-OH。
″硫醇″或″巯基″指基团-SH。
″烷基″-单独或组合地意指含有1至20、优选1至15个碳原子的烷烃衍生的基团(除非具体限定)。它是直链烷基、支链烷基或环烷基。直链或支链烷基含有1-15个碳原子为宜,较佳为1至8、更佳为1-6、还要更佳为1-4、最佳为1-2个碳原子,例如甲基、乙基、丙基、异丙基、丁基、叔丁基等等。本文使用的术语″低级烷基″是以上刚描述的直链烷基。优选地,环烷基是单环、双环或三环体系,每个环优选3-8元,更优选3-6元环,例如环丙基、环戊基、环己基、金刚烷基(adamantyl)等等。烷基也包括含有或由环烷基部分中断的直链或支链烷基。这种直链或支链烷基连接在任何可利用的位置以产生稳定的化合物。其例子包括(但不限于)4-(异丙基)-环己基乙基或2-甲基环丙基戊基。取代的烷基是前述定义的直链烷基、支链烷基或环烷基,其独立地以1至3个基团或取代基取代,所述基团或取代基选自卤素,羟基,烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基,酰氧基,芳氧基,杂芳氧基,以烷基、芳基或杂芳基任选地单-或二取代的氨基,脒基,以烷基、芳基、杂芳基或杂环基任选取代的脲,以烷基、芳基或杂芳基任选地N-单-或N,N-二取代的氨基磺酰基,烷基磺酰氨基,芳基磺酰氨基,杂芳基磺酰氨基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基,等等。
″烯基″-单独或组合地意指直链、支链或环烃,其含有2-20、优选2-17、更优选2-10、还要优选2-8、最优选2-4个碳原子,并且至少一个、优选1-3、更优选1-2、最优选一个碳碳双键。在环烷基的情形下,多于一个碳碳双键的共轭未达到给予环芳香性的程度。碳碳双键可以是或者被包含在除了环丙基之外的环烷基部分之内,或者在直链或支链部分之内。烯基的例子包括乙烯基、丙烯基、异丙烯基、丁烯基、环己烯基、环己烯基烷基等等。取代的烯基是前述定义的直链烯基、支链烯基或环烯基,其独立地被1至3个连接在任何可利用位置以产生稳定化合物的基团或取代基取代,所述基团或取代基为卤素,羟基,烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基,酰氧基,芳氧基,杂芳氧基,以烷基、芳基或杂芳基任选地单-或二取代的氨基,脒基,以烷基、芳基、杂芳基或杂环基任选地取代的脲,以烷基、芳基或杂芳基任选地N-单-或N,N-二取代的氨基磺酰基,烷基磺酰氨基,芳基磺酰氨基,杂芳基磺酰氨基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基,羧基,烷氧基羰基,芳氧基羰基,杂芳氧基羰基等等。
″炔基″-单独或组合地意指直链或支链烃,其含有2-20、优选2-17、更优选2-10、还要优选2-8、最优选2-4个碳原子,含有至少一个、优选一个碳碳三键。炔基的例子包括乙炔基、丙炔基、丁炔基等等。取代的炔基指前述定义的直链或支链炔基,其独立地以1至3个连接在任何可利用位置以产生稳定化合物的基团或取代基取代,所述基团或取代基为卤素,羟基,烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基,酰氧基,芳氧基,杂芳氧基,以烷基、芳基或杂芳基任选地单-或二-取代的氨基,脒基,以烷基、芳基、杂芳基或杂环基任选地取代的脲,以烷基、芳基或杂芳基任选地N-单-或N,N-二取代的氨基磺酰基,烷基磺酰氨基,芳基磺酰氨基,杂芳基磺酰氨基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基等等。
″烷基烯基″指基团-R-CR’=CRR″″,这里R是低级烷基或取代的低级烷基,R’,R,R″″可分别是氢、卤素、低级烷基、取代的低级烷基、酰基、芳基、取代的芳基、杂芳基或如下定义的取代的杂芳基。
″烷基炔基″指基团-RC≡CR’,这里R是低级烷基或取代的低级烷基,R’是氢、低级烷基、取代的低级烷基、酰基、芳基、取代的芳基、杂芳基或如下定义的取代的杂芳基。
″烷氧基″表示基团-OR,这里R是如定义的低级烷基、取代的低级烷基、酰基、芳基、取代的芳基、芳烷基、取代的芳烷基、杂烷基、杂芳基烷基、环烷基、取代的环烷基、环杂烷基或取代的环杂烷基。
″烷硫基″表示基团-SR、-S(O)n=1-2-R,这里R是如本文定义的低级烷基、取代的低级烷基、芳基、取代的芳基、芳烷基或取代的芳烷基。
″酰基″表示基团-C(O)R,这里R是氢、如本文定义的低级烷基、取代的低级烷基、芳基、取代的芳基等等。
″芳氧基″表示基团-OAr,这里Ar是如本文定义的芳基、取代的芳基、杂芳基或取代的杂芳基。
″氨基″表示基团NRR’,这里R和R’可分别为氢、如本文定义的低级烷基、取代的低级烷基、芳基、取代的芳基、杂芳基或取代的杂芳基或酰基。
″酰氨基″表示基团-C(O)NRR’,这里R和R’可分别为氢、如本文定义的低级烷基、取代的低级烷基、芳基、取代的芳基、杂芳基、取代的杂芳基。
″羧基″表示基团-C(O)OR,这里R是氢、如本文定义的低级烷基、取代的低级烷基、芳基、取代的芳基、杂芳基和取代的杂芳基。
″芳基″-单独或组合地意指苯基或萘基,它们任选地与优选5-7、更优选5-6元环烷基的碳环稠合,和/或任选地被1至3个基团或取代基取代,所述基团或取代基为卤素,羟基,烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基,酰氧基,芳氧基,杂芳氧基,以烷基、芳基或杂芳基任选地单-或二-取代的氨基,脒基,以烷基、芳基、杂芳基或杂环基任选地取代的脲,以烷基、芳基或杂芳基任选地N-单-或N,N-二-取代的氨基磺酰基,烷基磺酰氨基,芳基磺酰氨基,杂芳基磺酰氨基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基,等等。
″取代的芳基″指以一个或多个官能基团任选地取代的芳基,所述官能基团为例如卤原子、低级烷基、低级烷氧基、烷硫基、乙炔、氨基、酰氨基、羧基、羟基、芳基、芳氧基、杂环、杂芳基、取代的杂芳基、硝基、氰基、硫醇、磺酰胺基等等。
″杂环″指饱和、不饱和或芳香碳环基团,其具有单环(例如吗啉代、吡啶基或呋喃基)或多稠合环(例如,萘吡啶基、喹喔啉基、喹啉基、吲嗪基或苯并[b]噻吩基),环内具有至少一个杂原子,例如N、O或S,它可任选地未取代或取代,例如以卤素、低级烷基、低级烷氧基、烷硫基、乙炔、氨基、酰氨基、羧基、羟基、芳基、芳氧基、杂环、杂芳基、取代的杂芳基、硝基、氰基、硫醇、磺酰胺基等等取代。
″杂芳基″-单独或组合地意指含有5至6个环原子的单环芳环结构,或者含有8至10个原子的双环芳香基团,其含有一个或多个,优选1-4、更优选1-3、还优选1-2个分别选自O、S和N的杂原子,并且可任选地以1至3个基团或取代基取代,所述基团或取代基为卤素,羟基,烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基,酰氧基,芳氧基,杂芳氧基,以烷基、芳基或杂芳基任选地单-或二-取代的氨基,脒基,以烷基、芳基、杂芳基或杂环基任选地取代的脲,以烷基、芳基或杂芳基任选地N-单-或N,N-二取代的氨基磺酰基,烷基磺酰氨基,芳基磺酰氨基,杂芳基磺酰氨基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基,等等。杂芳基也包括氧化的S或N,例如亚磺酰基、磺酰基和叔环氮的N-氧化物。碳或氮原子位于杂芳环结构的连接点,这样保持稳定的芳环。杂芳基基团的例子是吡啶基、哒嗪基、吡嗪基、喹唑啉基、嘌呤基、吲哚基、喹啉基、嘧啶基、吡咯基、噁唑基、噻唑基、噻吩基、异噁唑基、噁噻二唑基、异噻唑基、四唑基、咪唑基、三嗪基、呋喃基、苯并呋喃基、吲哚基等等。取代的杂芳环含有连接在可利用的碳原子或硝基上的取代基,以产生稳定的化合物。
″杂环基″-单独或组合地意指具有5至10个原子的非芳香环烷基基团,其中环上1至3个碳原子由杂原子O、S或N取代,并且被任选地苯并稠合或5-6元环杂芳基稠合和/或在环烷基情形下被任选地取代。杂环基也包括氧化的S或N,例如亚磺酰基、磺酰基和叔环氮的N-氧化物。连接点在碳或氮原子上。杂环基的例子是四氢呋喃基、二氢吡啶基、哌啶基、吡咯烷基、哌嗪基、二氢苯并呋喃基、二氢吲哚基等等。取代的杂环含有连接在可利用的碳或氮上的取代基氮以产生稳定的化合物。
″取代的杂芳基″指以一种或多种官能基团任选地单或多取代的杂环,这些官能基团为例如卤素、低级烷基、低级烷氧基、烷硫基、乙炔、氨基、酰氨基、羧基、羟基、芳基、芳氧基、杂环、取代的杂环、杂芳基、取代的杂芳基、硝基、氰基、硫醇、磺酰胺基等等。
″芳烷基″指基团-R-Ar,这里Ar是芳基基团,R是低级烷基或取代的低级烷基基团。芳基基团可任选地为未取代或以如卤素、低级烷基、烷氧基、烷硫基、乙炔、氨基、酰氨基、羧基、羟基、芳基、芳氧基、杂环、取代的杂环、杂芳基、取代的杂芳基、硝基、氰基、硫醇、磺酰氨基等等取代。
″杂烷基″指基团-R-Het,这里Het是杂环基团,R是低级烷基基团。杂烷基基团可任选地是未取代或以如卤素、低级烷基、低级烷氧基、烷硫基、乙炔、氨基、酰氨基、羧基、芳基、芳氧基、杂环、取代的杂环、杂芳基、取代的杂芳基、硝基、氰基、硫醇、磺酰氨基等等取代。
″杂芳基烷基″指基团-R-HetAr,这里HetAr是杂芳基,R是低级烷基或取代的低级烷基。杂芳基烷基基团可任选地是未取代或以例如卤素、低级烷基、取代的低级烷基、烷氧基、烷硫基、乙炔、芳基、芳氧基、杂环、取代的杂环、杂芳基、取代的杂芳基、硝基、氰基、硫醇、磺酰氨基等等取代。
″环烷基″指含有3至15个碳原子的二价环或多环烷基基团。
″取代的环烷基″指包括一个或多个取代基的环烷基,所述取代基是例如卤素、低级烷基、取代的低级烷基、烷氧基、烷硫基、乙炔、芳基、芳氧基、杂环、取代的杂环、杂芳基、取代的杂芳基、硝基、氰基、硫醇、磺酰氨基等等。
″环杂烷基″指环烷基基团,其中一个或多个环碳原子以杂原子(例如,N、O、S或P)取代。
″取代的环杂烷基″指如本文定义的环杂烷基基团,它含有一个或多个的取代基,例如卤素、低级烷基、低级烷氧基、烷硫基、乙炔、氨基、酰氨基、羧基、羟基、芳基、芳氧基、杂环、取代的杂环、杂芳基、取代的杂芳基、硝基、氰基、硫醇、磺酰氨基等等。
″烷基环烷基″表示基团-R-环烷基,这里环烷基是环烷基基团,且R是低级烷基或取代的低级烷基。环烷基基团可任意地是未取代的或以例如卤素、低级烷基、低级烷氧基、烷硫基、乙炔、氨基、酰氨基、羧基、羟基、芳基、芳氧基、杂环、取代的杂环、杂芳基、取代的杂芳基、硝基、氰基、硫醇、磺酰氨基等等取代。
″烷基环杂烷基″表示基团-R-环杂烷基,这里R是低级烷基或取代的低级烷基。环杂烷基基团可任选地是未取代或以例如卤素、低级烷基、低级烷氧基、烷硫基、氨基、酰氨基、羧基、乙炔、羟基、芳基、芳氧基、杂环、取代的杂环、杂芳基、取代的杂芳基、硝基、氰基、硫醇、磺酰氨基等等取代。
本发明的化合物可以如以下流程1-5所略述的制备。制备V和VI的一般概要如流程1所示。按照早期报道的方法,通过6-氯嘌呤核苷1与伯胺R1NH2反应,可制备化合物I(美国专利No.5,789,416,其说明书引入本文作为参考)。通过I与2,2’-二甲氧基丙烷在催化量的TsOH[Evans,Parrish和Long Carbobydrat.Res.,3,453(1967)]存在下反应来保护2’,3’羟基为丙酮化合物,以产生II。在吡啶中II的5’-羟基以MsCl活化,可以产生5’-甲磺酸酯III。以R5SNa置换5’-甲磺酸酯可以产生具有通式IV结构的硫化物。以酸处理IV可释放出2’,3’羟基以产生具有通式V的硫化物衍生物。V的酯化可产生具有通式VI的2’,3’二酯。
流程1
具有通式XV的2-取代的衍生物可以如流程2所示制备。1,2,3,5-四乙酰呋喃核苷(ribofuranaside)2与2-取代-6氯嘌呤VII的缩合可以产生2-取代-6-氯嘌呤核苷三乙酸酯VIII,它与伯胺R’NH反应,可产生2-取代-6-烷基氨基衍生物IX。接着2’,3’羟基保护为丙酮化合物的乙酸酯水解可产生XI。在吡啶中XI的5’-羟基以MsCl激活可以产生5’-甲磺酸酯XII。以R5SNa置换5’-甲磺酸酯可以产生具有通式XIII结构的硫化物,它可脱去保护产生具有通式XIV的硫化物。2’,3’位置的酯化可产生具有通式XV结构的2’,3’二酯。
流程2
以氧化剂氧化通式V,VI,XIV,XV的硫化物(流程3)(Drabowicz,等人,The chemistry of sulfones and sulfoxides,Wiley,New York,1988,233-378)可产生相应的具有通式XVI、XVII、XVIII、XIX的亚砜。这些亚砜进一步氧化后可产生具有通式XX、XXI、XMI、XXIII的砜。
流程3
本发明的一种化合物的具体合成例如流程4所示。始于化合物3的化合物7的制备如流程3所示。化合物3可以由6-氯嘌呤核苷1和3-(R)-氨基四氢呋喃,按照前述报道的方法制备(参见美国专利No.5,789,164)。在TsOH(cat.)存在下2’和3’羟基以二甲氧基丙烷来保护产生丙酮化合物4。在吡啶中4与MsCl于0℃反应产生甲磺酸酯5,它用甲硫醇钠(sodiummethanethiolate)在乙腈/水混合物中置换产生硫化物6。以80%乙酸/水使6脱保护产生目的化合物7。
流程4
乙硫醚8以过硫酸氢钾制剂(oxone)在MeOH中进行氧化(Trost,B.M.;Curran,D.P.Tetrahedron Letters 1981,22,1287)产生砜9(流程5)。
流程5
本发明也包括本发明的A1激动剂成分的前体药物。前体药物是一种经化学修饰并且在其作用部位无生物活性的药物,但是通过一种或多种酶促或体内过程,它会降解或修饰或生物活性形式。本发明的前体药物应该具有不同于母体的药动学特征,能够改善经粘膜上皮吸收,有较好的盐制剂和/或溶解度以及系统稳定性改善。本发明的化合物优选在一个或多个羟基基团上被修饰,以形成前体药物。这种修饰可以是(1)例如,可通过酯酶或脂肪酶裂解的酯或氨基甲酸酯衍生物;(2)可被特异性或非特异性蛋白酶识别的肽;或者(3)经过膜选择可蓄积在作用部位的衍生物或者前体药物形式或者经修饰的前体药物形式,或者以上(1)至(3)的任何组合。
如果本发明的化合物含有碱基,可以制成相应的酸加成盐。用标准方法,在适当的溶剂中,从母体化合物和过量的酸,例如盐酸、氢溴酸、硫酸、磷酸、乙酸、马来酸、琥珀酸或甲磺酸,制备该化合物的酸加成盐。盐酸盐形式是尤其有用的。如果本发明的化合物含有酸性基团,则可以制备相应的阳离子盐。一般地,将母体化合物以过量的含有适当阳离子的碱性试剂,例如氢氧化物、碳酸盐或醇盐处理。阳离子,例如Na+,K+,Ca+2和NH4 +,是药学上可接受的盐中存在的阳离子的例子。某些化合物形成惰性盐或两性离子,它们亦是可接受的。
本发明的成分可用于治疗A1腺苷受体介导的哺乳动物尤其是人的各种疾病。例如,本发明的成分可在患有可通过刺激A1腺苷受体治疗的冠脉电紊乱(coronary electrical disorder)的哺乳动物中用于改善心脏活性。通过本发明的成分治疗的冠脉电紊乱的例子包括室上心动过速,包括心房纤维性颤动、心房扑动和AV结折返性心动过速。此外,在治疗室上心律失常中显示良好的安全性的本发明的口服活性A1激动剂也可用作心肌缺血高危人群的预防剂。
本发明的成分也适用于通过刺激引起NEFA释放减少和瘦素释放增加的A1腺苷受体来改善脂肪细胞功能。与可用本发明的成分改善的脂肪细胞功能有关的疾病包括糖尿病和肥胖症。
在骨骼肌细胞,A1AdoR激动剂介导胰岛素的葡萄糖摄取和转移的协同刺激(Vergauwen,L.等人,J.Clin.Invest.1994,93,974-81;Challiss,R.A.等人,Eur.J.Pharacol.,1992,226,121-8)。本发明成分的另一治疗应用是在受糖尿病折磨的患者中更有效地调节葡萄糖和减少循环的胰岛素。
A1受体激动剂R-PIA1已经显示增加瘦素从白色脂肪细胞的释放和增加胰岛素-刺激的瘦素的产生(M.Ozeck Master’s Thesis Univ.ofFlorida 1999 with L.Belardinelli)。证据表明,儿茶酚胺类通过激活β-肾上腺素能受体抑制脂肪细胞产生瘦素。脂肪细胞上A1激动剂的抗肾上腺素能作用确信在增加瘦素的释放中起作用。瘦素的功能作用是多方面的,包括降低食欲、刺激能量利用和增加生育力。
本发明的成分通过刺激A1腺苷受体,亦可用于提供中枢神经系统神经保护。可以采用本发明的成分治疗的中枢神经系统疾病包括癫痫和发作。
在肾脏,有证据表明,刺激A1AdoR促进钠潴留,促进尿中的钠钾交换,及因排钠增加而减少肾小球滤过率(Gellai,M.等人,JPET,1998,286,1191-6;Wilcox,C.S.等人,J.Am.Soc.Nephrol.,1999,10,714-720)。据信,通过腺苷的慢性局部产生可以引发这些反应。换言之,在肾脏存在腺苷刺激A1AdoR的激励效应。因此,本发明成分的另一临床应用,是肾脏A1AdoR的选择性拮抗作用以抑制钠潴留,抑制钠钾交换,并且当排钠增加时保持肾小球滤过率,以产生保护肾功能的保钾利尿作用(potassium sparring diuretic)。
本发明的成分进一步适用于通过刺激A1腺苷受体对心肌细胞提供免受缺血影响的保护。用本发明的成分能治疗的局部缺血包括稳定性心绞痛、不稳定性心绞痛、心脏移植和心肌梗塞。
本发明化合物的一个重要方面是每个化合物具有与其相关的内在活性(参见T.P.Kenakin:刺激反应机制,Pharmacological Analysis ofDrug-Receptor Interaction,Kenakin,T.P.编著New York:RavenPress,p 39-68)。这种内在活性并非由其对受体的亲和性限定,而是限定为该化合物在一定的细胞类型中激活一定的效应器系统(例如cAMP产生)的定量效应。细胞类型与细胞类型之间和/或效应器系统与效应器系统之间给定化合物的内在活性可以不同。当化合物具有低于完全激动剂的内在活性(即次最大)时,这种激动剂称为部分激动剂。从而,部分激动剂是与受体结合引起小于完全激动剂的反应(次最大)、并且竞争性地拮抗完全激动剂引起的反应的分子。腺苷对于肾功能的激励作用是部分A1激动剂可望充当拮抗剂的最好例证。据信,本发明的化合物具有治疗学上有用的对腺苷A1受体的亲和性,并且它们具有从完全激动剂至部分激动剂的内在活性。换言之,一些化合物在某些细胞类型中可能不具有对特定效应器系统的作用,但是在另一种细胞类型和/或效应器系统中却是完全激动剂。这种可变性药理学性质的原因涉及在任何给定细胞类型(例如AV结细胞对脂肪细胞)中对于A1腺苷受体和给定反应的受体储备量。受体储备(空闲受体容量)是受体总数减去用完全激动剂引起最大反应所需的受体部分(L.E.Limbird,Cell Surface Receptors:A Short Course onTheory and Methods,Kluwer Acad.Pub.1996,Boston,Mass.)。因此,激动剂可以是引起反应的完全激动剂,和在其它组织或细胞引起另一反应的部分激动剂,以及还是对另一组织或细胞中的第三种反应的拮抗剂或对其无活性。因此,针对选定目标的部分激动剂与完全激动剂相比可能引起较少的副作用。作为必然的结果,完全激动剂引起由各自受体介导的所有反应,而部分激动剂则未必如此。本发明化合物基于其对A1受体的亲和性及其引起A1受体介导的反应的强度和选择性,在多种以上介绍的疾病中具有治疗干预潜力。
部分A1激动剂还有益于长期治疗,由于它们很少诱发A1受体脱敏(R.B.Clark,B.J.Knoll,R.Barber TiPS,Vol.20(1999)p.279-286)和产生副作用。完全激动剂R-N6-苯基异丙基腺苷(R-PIA)的7天慢性给药,通过豚鼠的变导性反应导致A1受体脱敏(注意:观察到受体数量的减少-D.M.Dennis,J.C.Shryock,L.Belardinelli JPET,Vol.272(1995)p.1024-1035)。A1激动剂引起脂肪细胞腺苷酸环化酶生成cAMP作用的抑制,已被证明在以A1激动剂长期治疗时产生脱敏(W.J.Parsons和G.L.Stiles J.Biol.Chem.Vol.262(1987)p.841-847)。
本发明的成分可以口服、静脉内、经皮、经鼻、吸入或者通过本领域已知的给予治疗剂的任何其它方式给药。这种治疗方法包括有效量的选定化合物的给药,优选分散在药用载体中。活性成分的剂量单位通常选自0.01至100mg/kg的范围,但是本领域熟练技术人员根据给药途径、患者年龄和病情可以容易地确定。
包括本发明化合物的药物组合物,和/或其衍生物,可配制成溶液或冻干粉用于非胃肠道给药。粉末可在使用之前加入适当的稀释剂或其它药学上可接受的载体重建。如果以液体形式使用,本发明的组合物优选掺入缓冲过的、等渗的水溶液。适当的稀释剂的例子是等渗生理盐水,5%标准葡萄糖水溶液和乙酸钠或乙酸铵缓冲溶液。这类液体制剂适于非胃肠道给药,但也可用于口服给药。较理想的是,向包括本发明化合物的药物组合物中加入赋形剂,例如聚乙烯吡咯烷酮、明胶、羟基纤维素、阿拉伯胶、聚乙二醇、甘露醇、氯化钠、枸椽酸钠或任何其它本领域熟练人员已知的赋形剂。或者,该药物化合物可以装胶囊、压片或制成乳剂或糖浆剂用于口服。可以加入药学上可接受的固体或液体载体以增强或稳定组合物,或者促进组合物的制备。液体载体包括糖浆、花生油、橄榄油、甘油、盐水、醇类和水。固体载体包括淀粉、乳糖、硫酸钙、二水合物、teffa alba、硬脂酸镁或硬脂酸、滑石粉、果胶、阿拉伯胶、琼脂或明胶。载体亦可包括持续释放的材料,例如甘油一硬脂酸酯或甘油二硬脂酸酯,单独或与蜡合用。固体载体的用量可变化,但优选每剂量单位约20mg至约1克之间。需要时,采用常规的技术,例如研磨、混合、制粒、压片制备片剂;或者研磨、混合和充填制备硬明胶胶囊。当使用液体载体时,制剂为糠浆剂、酏剂、乳剂或者水性或非水悬浮液。这样的液体制剂可以直接给药,或者填充入软明胶胶囊。
具体实施方式
以下的实施例有助于说明本发明。这些实施例决不意味对本发明范围的限制,而仅用来显示如何制备和使用本发明的化合物。
实施例1
中间体(4-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(1R,2R,5R)-7,7-二甲基-3,6,8-三噁二环[3.3.0]辛-2-基)甲-1-醇(4)
向化合物3(2.0g,6.0mmol)和2,2-二甲氧基丙烷(1.2g,11.8mmol)的二甲基甲酰胺(20mL)溶液中于70℃加入p-甲苯磺酸(50mg,0.26mmol)。70℃48小时之后,将反应物真空浓缩,产生一固体。将该固体溶解于甲醇(3mL),接着以乙醚(50mL)研碎。通过真空过滤收集产物晶体,得到中间体4。
向4(190mg,0.5mmol)的无水吡啶(5mL)溶液中于0℃加入MsCl(80mL,1mmol)。反应混合物在同样温度下搅拌2小时。减压除去吡啶,残余物溶于二氯甲烷(50mL),以水洗涤(3×20mL)并干燥(Na2SO4)。溶剂蒸发,得到白色泡沫状产品5:1H NMR(CDCl3)61.4(s,3H),1.6(s,3H),2.0-2.2(m,IH),2.3-2.5(m,1H),2.9(s,3H),3.7-4.2(m,4H),4.4-4.6(m,3H),4.8-5.0(bs,1H),5.1-5.2(bs,1H),5.4-5.5(bs,1H),6.1(s,1H),6.4-6.6(bs,1H),8.1(s,1H),8.4(s,1H)
将甲磺酸酯5(150mg)和甲硫醇盐(methanethiolate)(150mg)在乙腈(2mL)和水(1mL)中的混合物于70℃加热24小时。减压蒸发溶剂,通过制备性TLC纯化残余物[甲醇-二氯甲烷(1∶19)]以产生产物6:1H NMR(CDCl3)δ1.35(s,3H),1.60(s,3H),1.90-2.05(m,1H),2.05(s,3H),2.30-2.40(m,1H),2.70(AB四重峰的双峰,2H),3.75-3.90(m,2H),3.95-4.00(m,2H),4.3-4.4(m,1H),4.8-4.95(m,1H),5.00-5.05(m,IH),5.45-5.50(d,1H),6.00-6.10(m,2H),7.85(s,1H),8.3(s,1H)。
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(甲硫基甲基)氧杂环戊烷-3,4-二醇(7)
将化合物6(50mg)溶于乙酸(8mL)和水(2mL)的混合物中,并在90℃加热16小时。减压除去溶剂,通过制备性TLC纯化残余物[甲醇-二氯甲烷(1∶19)]以产生化合物7:1H NMR(CDCl3)δ1.90-2.05(m,1H),2.15(s,3H),2.30-2.40(m,1H),2.75-2.85(m,2H),3.80-3.90(m,2H),3.90-4.00(m,2H),4.30-4.45(m,2H),4.50-4.55(m,1H),4.75-4.95(m,1H),5.90-5.95(m,1H),6.30-6.60(m,1H),7.95(s,1H),8.25(s,1H)。
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(乙硫基)甲基]氧杂环戊烷-3,4-二醇(8)
用与7相同的方法,以乙硫醇盐代替甲硫醇盐制备化合物8。(M+1)=382.30
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5[(甲基乙硫基)甲基]氧杂环戊烷-3,4-二醇(10)
用与7相同的方法,以异丙硫醇盐代替甲硫醇盐制备化合物10。1HNMR(CDCl3)δ1.25(d,6H),1.90-2.05(m,1H),2.15(s,3H),2.30-2.40(m,1H),2.85-2.87(d,2H),2.95(七重峰,1H),3.80-3.90(m,2H),3.95-4.05(m,2H),4.35-4.40(m,2H),4.50-4.55(m,1H),4.75-4.85(m,1H),5.90-5.95(d,1H),6.85-6.95(m,1H),7.95(s,1H),8.25(s,1H)。
2-{6-[((3R)-氧杂环戊烷-3-yl)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(苯硫基甲基)氧杂环戊烷-3,4-二醇(11)
用与7相同的方法,以苯硫醇盐代替甲硫醇盐,制备化合物11。1HNMR(CDCl3)1.95-2.05(m,1H),2.30-2.40(m,1H),3.2(d,2H),3.80-3.90(m,2H),3.95-4.10(m,2H),4.35-4.40(d,1H),4.45(t,1H),4.50-4.55(m,1H),4.80-4.90(m,1H),5.85(d,1H),6.70-6.80(m,1H),7.15-7.30(m,3H),7.35(d,2H),7.75(s,1H),8.25(s,1H)。
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4-甲氧基苯硫基)甲基]氧杂环戊烷-3,4-二醇(12)
用与7相同的方法,以4-甲氧基苯硫醇盐代替甲硫醇盐制备此化合物。(M+1)=460.4
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4-氯苯硫基)甲基]氧杂环戊烷-3,4-二醇(13)
用与7相同的方法,以4-氯苯硫醇盐代替甲硫醇盐制备该化合物。(M+1)=464.3
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4-氟苯硫基)甲基]氧杂环戊烷-3,4-二醇(14)
用与7相同的方法,以4-氟苯硫醇盐代替甲硫醇盐制备这种化合物。(M+1)=448.3
2-{6[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4-甲基苯硫基)甲基]氧杂环戊烷-3,4-二醇(15)
用与7相同的方法,以4-甲基苯硫醇盐代替甲硫醇盐制备这种化合物。(M+1)=444.38
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4(三氟甲基)苯硫基)甲基]氧杂环戊烷-3,4-二醇(16)
用与7相同的方法,以4-三氟甲基苯硫醇盐代替甲硫醇盐制备这种化合物。(M+1)=488.36
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(2-甲氧基苯硫基)甲基]氧杂环戊烷-3,4-二醇(17)
用与7相同的方法,以2-甲氧基苯硫醇盐代替甲硫醇盐制备这种化合物。(M+1)=460.4
(5-{6-[((3R)氧杂环戊烷-3-基)氨基]嘌呤-9-基}(2S,3S,4R,5R)-3,4-二羟基氧杂环戊烷-2-基)(乙磺酰基)甲烷(9)
在0℃氮气下向冷却的硫化物8甲醇溶液中加入3当量的过硫酸氢钾制剂(Potassium peroxy monosulfate),反应混合物在同样温度下搅拌1小时。在原料消耗(用TLC检测)之后,浓缩反应混合物并经硅胶小塞过滤。通过制备性TLC[甲醇-二氯甲烷(1∶19)]产生黄白色吸湿性固体9。
(M+1)=414.28
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(2,4-二氟苯硫基)甲基]氧杂环戊烷-3,4-二醇(18)
用与7相同的方法,以2,4-二氟苯硫醇盐代替甲硫醇盐制备这种化合物。(M+1)=466.23
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(2,6-二氟苯硫基)甲基]氧杂环戊烷-3,4-二醇(19)
以与7相同的方法,以2,6-二氯苯硫醇盐代替甲硫醇盐,制备这种化合物。(M+1)=498.18。
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(3-二氟苯硫基)甲基]氧杂环戊烷-3,4-二醇(20)
用与7相同的方法,以3-氟苯硫醇盐代替甲硫醇盐,制备这种化合物。(M+1)=448.26。
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(2-氟苯硫基)甲基]氧杂环戊烷-3,4-二醇(21)
用与7相同的方法,以2-氟苯硫醇盐代替甲硫醇盐,制备这种化合物。(M+1)=448.24。
(5-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(2S,3S,4R,5R)-4-乙酰氧基-2-[(氟代苯硫基)甲基]氧杂环戊烷-3-基乙酸酯(22)
在23℃,向化合物21(139mg)的吡啶(2mL)溶液中加入醋酸酐(0.1mL)。23℃3小时之后,将反应物真空浓缩。残余物溶于二氯甲烷(50mL),以水洗涤(3×10mL),并干燥(Na2SO4)。真空浓缩之后,残余物经快速色谱法(二氯甲烷∶甲醇20∶1,之后9∶1)纯化产生化合物22(170mg):
2[(5-{6-[((3R)氧杂环戊烷-3-基)氨基]嘌呤-9-基}(2S,3S,4R,5R)-3,4-二羟基氧杂环戊烷-2-基)甲硫基]苯甲酸甲酯(23)
向化合物4(0.377g,1mmol)的5mL THF溶液中,加入三苯基膦(0.524g,2mmol)、DEAD(0.40mL,2mmoles),在加入2-甲酯基苯硫酚(0.5mL)之前搅拌5分钟。使反应液回流搅拌。回流72小时之后,将反应液真空浓缩,残余物通过快速柱色谱法(20%EtOAc/己烷)纯化产生澄明的粘油。它被置入乙酸(8mL)和水(2mL)的混合物中并在80℃加热16小时。真空除去溶剂,残余物通过制备性TLC[甲醇-二氯甲烷(1∶9)]纯化,得到化合物23。(M+1)=488.5。
{2[(5-{6-[((3R)[氧杂环戊烷-3-基)氨基]嘌呤-9-基}(2S,3S,4R,5R)-3,4-二羟基氧杂环戊烷-2-基)甲硫基]苯基}-N-甲基酰胺苯甲酸酯(24)
将化合物23置于甲胺(2mL)和1-丙醇(2mL)的40%水溶液中,70℃加热16小时。真空除去溶剂,残余物通过制备性TLC[甲醇-二氯甲烷(1∶9)]纯化以得到化合物24。(M+1)=487.5
2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(苯并噁唑-2-基硫代甲基)氧杂环戊烷-3,4-二醇(25)
用与23相同的方法,以2-巯基苯并噁唑代替2-甲酯基(carbmethoxy)苯硫酚制备这种化合物。(M+1)=471.4。
2-{6-[((3S)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(1-甲基咪唑-2-基-硫代)甲基]氧杂环戊烷-3,4-二醇(26)
用制备化合物23的方法,以2-巯基-1-甲基-咪唑代替2-甲酯基苯硫酚制备化合物26[MS 434.4(M+1)]。
2-{6-[((3S)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(嘧啶-2-基硫代甲基)氧杂环戊烷-3,4-二醇(27)
用制备化合物23的方法,以2-巯基嘧啶代替2-甲酯基苯硫酚制备化合物27[MS432.4(M+1)]。
2-{6-[((3S)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(2-吡啶基硫代甲基)氧杂环戊烷-3,4-二醇(28)
用制备化合物23的方法,以2-巯基吡啶代替2-甲酯基苯硫酚制备化合物28[MS431.4(M+1)]。
2-{6-[((3S)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(4-吡啶基硫代甲基)氧杂环戊烷-3,4-二醇(29)
用制备化合物23的方法,以4-巯基吡啶代替2-甲酯基苯硫酚制备化合物29[MS431.4(M+1)]。
5-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(2S,3R,4R,5R)-4-乙酰氧基-2-[(4-氟苯硫基)甲基]氧杂环戊烷-3-基]乙酸酯(30)(M+1)=532.17。
实施例2
结合试验-DDT1细胞
细胞培养
DDT细胞(仓鼠输精管平滑肌细胞系)在北特利平皿中采用含有2.5gml-1两性霉素B、100Uml-1青霉素G、0.1mg ml-1硫酸链霉素和5%牛胎血清的Dulbecco改进的Eagle培养基(DMEM),在95%空气和5%CO2的潮湿空气中以单分子层生长。每周两次将细胞分散到不含二价阳离子和含有1mMEDTA的Hank’s平衡盐溶液(HBSS)中进行次代培养。然后将这些细胞以每板1.2×105个细胞的密度种入生长培养基,在约一天的预汇合后4天进行实验。
膜制备
贴壁细胞以HBSS洗涤两次(2×10ml),在4℃借助于橡胶淀帚从板上刮离到50mM Tris-HCl缓冲液(pH 7.4,4℃)5ml中,将悬浮液匀化10秒。然后将悬浮液于27,000×g离心10分钟。通过涡旋将沉淀再悬浮于匀浆化缓冲液中,再如上所述进行离心。最后的沉淀再悬浮于1体积含5mM MgCl2的50mM Tris-HCl缓冲液(pH7.4),用于A1Ado R试验。对于[35S]GTPγS结合试验,最终沉淀在含有5mM MgCl2、100mM NaCl和1mM二硫苏糖醇的50mM Tris-HCl(pH7.4)中再悬浮。这种膜悬浮液置于液氮内10分钟,融化,用于试验。采用BradfordTM试验试剂盒以牛血清白蛋白作标准,测定蛋白含量。
竞争性结合试验
在50mM Tris缓冲液中匀浆化制备猪纹状体(5x体积的组织物质,pH=7.4)。于4℃、19,000rpm离心25分钟之后,弃去上清液,该步骤重复两次。试验本发明的成分以测定它们对猪纹状体膜制备或DDT1膜制备A1受体的亲和力。简言之,以腺苷脱氨基酶和50mM Tris缓冲液处理0.2mg猪纹状体膜或DDT1细胞膜,然后混合。向这种猪膜加入浓度为100μM至10nM的本发明化合物的连续稀释DMSO储液2μl。对照组仅接受2微升DMSO,然后加入拮抗剂[3H]8-环戊基黄嘌呤(CPX)(猪纹状体)或者激动剂[3H]2-氯-6-环戊基腺苷(CCPA)(DDT1膜)的Tris缓冲溶液(50mM,pH 7.4),以获得终浓度2nM。23℃培养2小时之后,将该溶液用膜收集器过滤,多次洗涤膜(3x)。滤板在闪烁混合物中计数,给出氚标记CPX的置换量,或者通过竞争性结合本发明成分的置换量。采用多于5点的曲线以产生Ki值,如下表1的标记的栏内表明实验编号:
表1
化合物# | Ki-DDT1细胞膜 | Ki-猪纹状体 |
7 | -- | 222nM |
10 | -- | 188nM |
11 | -- | 44nM |
12 | 820nM | -- |
14 | 363nM | -- |
15 | 922nM | -- |
16 | 7701nM | -- |
17 | 947nM | -- |
实施例3
[35S]GTPγS结合试验
A1-激动剂刺激[35S]GTPγS结合可用Giersckik等人(1991)和Lorenzen等人(1993)所述方法的改进法进行测量。在含有50mM Tris-HCl缓冲液(pH7.4)、5mM MgCl2、100mM NaCl、1mM二硫苏糖醇、0.2单位ml-1腺苷脱氨基酶、0.5%BSA、1mM EDTA、10mM GDP、0.3nM[35S]GTPγS以及含或不含各种浓度CPA的0.1ml体积溶液中,将膜蛋白(30-50μg)于30℃培养90分钟。加入10μM GTPγS,测量非特异性结合。测定激动剂刺激的结合,为CPA存在下的总结合和无CPA时测得的本底结合之间的差。早先的报道已经显示激动剂刺激的[35S]GTPγS结合取决于GDP的存在(Gierschik等人,1991;Lorenzen等人,1993;Traynor &Nahorski,1995)。在初步的实验中,发现10μM GDP产生CPA依赖性[35S]GTPγS结合的最佳刺激,这种浓度因此用于所有研究中。在饱和实验中,以0.5-1000nM GTPγS温孵0.5nM [35S]GTPγS。温孵结束时,过滤各悬浮液并且如上介绍测量保留的放射性。结果以完全激动剂N-6-环戊基腺苷(CPA)为标准表示。
表2
化合物# | GTPγS |
CPA | 100% |
8 | 104% |
12 | 52% |
13 | 69% |
14 | 61% |
15 | 48% |
16 | 31% |
17 | 52% |
实施例4
cAMP试验
采用家兔抗cAMP抗体,添加示踪剂腺苷3’,5’-环磷酸2’-O-琥珀酰-3-[125I]碘酪氨酸甲酯和含抗家兔特异性抗体的荧光微球体,如Amersham Pharmacia Biotech(Biotrak cellular assays)所描述的进行闪烁亲近测定(SPA)。简言之,在具有不透明孔、底部清晰的96孔微量滴定板中,以每孔104~106个细胞的浓度(在40μl HBSS中)于37℃(5%CO2和95%湿度)培养DDT1细胞。将本发明的部分或完全A1激动剂(5μl)以各种浓度与DDT1细胞在咯利普兰(rolipram)(50μM)和5μM弗司扣林(forskolin)存在下于37℃培养10分钟。用5μl 10%十二烷基三甲基铵溴化物处理后采用微板震荡器震荡微量板,使这些细胞立即溶解。培养5分钟之后,将免疫试剂溶液(150μl,含有等体积示踪剂、抗血清和SPA荧光球)加入每个孔,然后密封板。23℃下培养15-20小时之后,在微滴定板闪烁计数器中计数2分钟,测量与荧光微球结合的[125I]cAMP量。计数与采用同样方案产生的cAMP标准曲线比较,得出细胞溶解后的cAMP含量。显示的结果以完全激动剂N-6-环戊基腺苷(CPA)为标准表示。因此,完全激动剂CPA将弗司扣林诱导的cAMP生成减少至基础水平。
表3
化合物# | Camp |
CPA | 107% |
8 | 37% |
12 | -9% |
13 | 30% |
14 | 47% |
15 | 22% |
16 | 22% |
17 | 18% |
Claims (21)
1.一种具有如下结构式的化合物:
其中
R1是以碳原子连接的氧杂环戊烷基;
R2,R3和R4都为氢;
R5选自C1-6烷基、任选取代的苯基、吡啶基、嘧啶基、甲基咪唑基以及苯并噁唑基,其中苯基被选自卤素、甲基、甲氧基、CF3、CO2CH3以及CONHCH3的取代基任选取代;且
X1为S或S(O)2;
或其药用有效的盐。
2.如权利要求1所述的化合物,其中X1为S。
3.如权利要求1所述的化合物,其中X1为S(O)2。
4.如权利要求1至3中任意一项所述的化合物,其中R5为C1-6烷基。
5.如权利要求4所述的化合物,其中R5选自甲基、乙基或异丙基。
6.如权利要求1至3中任意一项所述的化合物,其中R5为任选取代的苯基。
7.如权利要求1所述的化合物,其中R1为氧杂环戊烷-3-基,R5为甲基,X1为S,命名为:2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(甲硫基甲基)氧杂环戊烷-3,4-二醇。
8.如权利要求1所述的化合物,其中R1为氧杂环戊烷-3-基,R5为乙基,X1为S,命名为2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(乙硫基)甲基]氧杂环戊烷-3,4-二醇。
9.如权利要求1所述的化合物,其中R1为氧杂环戊烷-3-基,R5为异丙基,X1为S,命名为2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(异丙基硫基)甲基]氧杂环戊烷-3,4-二醇。
10.如权利要求1所述的化合物,其中R1为氧杂环戊烷-3-基,R5为苯基,X1为S,命名为2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-(苯硫基甲基)氧杂环戊烷-3,4-二醇。
11.如权利要求1所述的化合物,其中R1为氧杂环戊烷-3-基,R5为甲氧基苯基,X1为S,命名为2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4-甲氧基苯硫基)甲基]氧杂环戊烷-3,4-二醇。
12.如权利要求1所述的化合物,其中R1为氧杂环戊烷-3-基,R5为4-氯苯基,X1为S,命名为2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4-氯苯硫基)甲基]氧杂环戊烷-3,4-二醇。
13.如权利要求1所述的化合物,其中R1为氧杂环戊烷-3-基,R5为4-氟苯基,X1为S,命名为2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4-氟苯硫基)甲基]氧杂环戊烷-3,4-二醇。
14.如权利要求1所述的化合物,其中R1为氧杂环戊烷-3-基,R5为4-甲基苯基,X1为S,命名为2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4-甲基苯硫基)甲基]-氧杂环戊烷-3,4-二醇。
15.如权利要求1所述的化合物,其中R1为氧杂环戊烷-3-基,R5为4-三氟甲基苯基,X1为S,命名为2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(4-(三氟甲基)苯硫基)甲基]氧杂环戊烷-3,4-二醇。
16.如权利要求1所述的化合物,其中R1为氧杂环戊烷-3-基,R5为2-甲氧基苯基,X1为S,命名为2-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(4S,5S,2R,3R)-5-[(2-甲氧基苯硫基)甲基]氧杂环戊烷-3,4-二醇。
17.如权利要求1所述的化合物,其中R1为氧杂环戊烷-3-基,R5为乙基,X1为S(O)2,命名为(5-{6-[((3R)-氧杂环戊烷-3-基)氨基]嘌呤-9-基}(2S,3S,4R,5R)-3,4-二羟基氧杂环戊烷-2-基)(乙磺酰基)甲烷。
18.如权利要求1所述的化合物在制备治疗下列A1腺苷受体介导的疾病的药物中的应用,所述的疾病选自:室上性心动过速、心房纤维性颤动、心房扑动、AV结折返性心动过速、糖尿病、前脑局部缺血、发作、稳定的心绞痛、不稳定心绞痛,以及心肌梗塞。
19.一种药物组合物,包括权利要求1所述的化合物以及一种或多种药用赋形剂。
20.如权利要求19所述的药物组合物,其中药物组合物为溶液形式。
21.如权利要求19所述的药物组合物,其中药物组合物为片剂形式。
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