CN1161962A - 磺酰氨衍生物 - Google Patents

磺酰氨衍生物 Download PDF

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CN1161962A
CN1161962A CN 96121984 CN96121984A CN1161962A CN 1161962 A CN1161962 A CN 1161962A CN 96121984 CN96121984 CN 96121984 CN 96121984 A CN96121984 A CN 96121984A CN 1161962 A CN1161962 A CN 1161962A
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phenyl
butyric acid
tetramethyleneimine
phenylester
carboxyl
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T·中江
M·加藤
T·藤田
K·川端
H·大野
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Ono Pharmaceutical Co Ltd
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Abstract

本申请公开了式(I)的磺酰胺衍生物,其中R1,n,,R2,R3,R4,m和
Figure 96121984.X_AB_0
的定义如说明书中所述。这些化合物是具有抑制弹性蛋白酶活性的新的药物化合物。

Description

磺酰氨衍生物
本发明涉及用作药的磺酰氨衍生物,更特别地,本发明涉及:
(1)下文所定义的式(I)磺酰氨衍生物,其无毒性盐,酸加成盐和其溶剂化物,
(2)它们的制备方法,以及
(3)含这些化合物作为活性成分的药物组合物
中性白细胞的溶酶体水解酶在机体抵抗由微生物或炎症引起的组织损伤的防御反应中具有重要作用。
局部存在于嗜苯胺蓝粒体中的中性丝氨酸蛋白酶即弹性蛋白酶和组织蛋白酶G,在结缔组织的分解中起作用。
具体而言,弹性蛋白酶通过裂解直接保持组织弹性例如肺组织弹性的弹性蛋白的交联,通过裂解蛋白质的疏水部分[J.Cell.Biol.,40,366(1969)]和选择性降解胶原蛋白以及弹性蛋白的交联[J.Biochem.,84.559(1978)]来降解弹性结缔组织。它也对蛋白多糖这样的组织蛋白质起作用[J.Clin.Invest.,57,615(1976)]。因此可以看出弹性蛋白酶在结缔组织代谢中起重要作用。
弹性蛋白酶被体内丝氨酸蛋白酶的普通抑制剂α1-蛋白酶抑制剂(α1-PI)灭活,且酶和抑制剂的失调引起组织损伤[Schweiz.Me d.Wshr.,114,895(1984)]。
正常组织弹性蛋白的更新非常慢[Endocrinology,120,92(1978)],但是
已发现在多种疾病情况中有弹性蛋白降解的病理学加速作用,例如肺气肿[Am.Rev.Respir.Dis.,110,254(1974)],动脉粥样硬化[Lab.Invest.22,228(1970)]和类风湿性关节炎[in Neutral Proteases of HumanPolymorphonuclear leukocytes,Urbanand Schwarzenberg,Baltimore-Munich(1978),page 390],这说明了弹性蛋白酶和疾病间的关系[Infection Inflammation Immunity,13-,13(1983)]。
根据这一背景,近来已进行了许多弹性蛋白酶抑制剂的开发研究,已提出了多种抑制弹性蛋白酶的物质,并已申请了很多专利。
例如,
(1)在EP-A-0347168中公开了式(A)化合物
Figure A9612198400471
(其中YA是磺酰基或羰基;(i)R1A和R2A,可以相同或不同,各自独立地特别为氢原子,C1-16烷基或下式基团(其中XA是一个键,磺酰基,C1-4亚烷基,被-COOH或苄氧羰基取代的C1-4烷基;
Figure A9612198400481
是碳环或杂环;nA是1-5;且R4A可以相同或不同,尤其分别是氢原子,C1-8烷基,C1-14烷氧基,C1-6烷硫基,羟基,卤原子,硝基,三卤甲基,-Z41A-COOR43A,-CONR41AR42A,下式基团
Figure A9612198400482
在该式基团中,
Figure A9612198400483
是-氨基酸残基;R49A是羟基,C1-4烷氧基,氨基,被一个或两个C1-4烷基取代的氨基或氨基甲酰基,等)或者(ii)R1A和R2A和与R1A和R2A键接的氮原子一起代表含至少一个氮原子并被-COOH取代的杂环或含至少一个氮原子的未被取代的杂环;R3A是氢原子,羟基,C1-6烷基,等;且mA是1-4)和其非毒性盐和酸加成盐,具有对弹性蛋白酶的抑制活性。(2)在EP-A-0465802中公开了式(B)化合物
Figure A9612198400491
其中R1B和R2B可以相同或不同,各自独立地为氢原子,C1-6烷基或C3-6环烷基,或R1B和R2B一起代表-(CH2)nB-(其中nB是1-6);R3B是1个至5个氢原子,卤原子,C1-12卤代烷基,C1-12烷基,C1-12烷氧基,C2-12链烯基,C3-12环烷基,单环或双环芳基,-ZBR5B(其中ZB是O,S,S(O)或SO2;R5B是氢原子,C1-18烷基,C3-12环烷基,或苯基),-NR6 BR 7B(其中R6B和R7B可以相同或不同,每个代表氢原子,C1-12烷基,C3-6环烷基,苯基,C1-12烷氧基或-C(O)-R3B,或R6B和R7B一起代表-C(O)CH2CH2-C(O)-,-C(O)-,C6H4-C(O)-或-(CH2)XB-(XB是2,3,4,5或6)),或在氮原子上与苯环键连的吗啉代,咪唑基或哌嗪基等;且R4B是一个至5个氢原子,卤原子,硝基,-C(O)CH3,S(O)pBR9B(pB是0,1或2;R9B是羟基,-ONa,C1-12任意被取代的烷基,任意被取代的环烷基))
和它们的非毒性药学上可接受的盐,具有对弹性蛋白酶的抑制活性;(3)EP-A-0484949中公开了式(C)化合物(其中R1C和R2C可以相同或不同,各自代表氢原子,C1-6烷基或C3-6环烷基,或R1C和R2C一起代表-(CH2)nc-(其中nC是1-6);ArC是任意取代的苯基;且HetC是含有至少一个氮原子,硫原子或氧原子的杂环)具有对弹性蛋白酶的抑制活性。
所知的对弹性蛋白酶具有抑制活性的化合物中没有几个显示出口服能对弹性蛋白酶具有抑制活性。大多数化合物口服不会显示出有效果。为了显示口服活性,药物试剂必须易于被消化器官吸收,且必须保持它们的活性,直到它们被输送到一个活性位点。因此,只有那些在消化器官中具有良好稳定性,吸收性和/或溶解性的化合物被期望显示足够的口服活性。
已进行了有力的试验去寻找对弹性蛋白酶具有良好抑制活性且也具有高安全性的新化合物。作为结果,本发明人发现可以通过式(I)磺酰氨衍生物实现这些目的。进一步地,我们发现这些新化合物具有良好的稳定性,可吸收性和溶解性,并且口服作为弹性蛋白酶抑制剂具有活性。
本发明提供了式(I)磺酰氨衍生物
Figure A9612198400502
其中R1是C1-8烷基,C1-8烷氧基,羟基,酮基,硝基,卤原子,三卤代甲基,氰基,脒基,-COOR7(其中R7是氢原子或C1-8烷基),或
Figure A9612198400511
(其中p是0至4的整数,且R8和R9各自独立地为氢原子,C1-4烷基,C2-5酰基,-COOR10(其中R10是氢原子或C1-8烷基),-CONR11R12(其中R11和R12各自独立地为氢原子或C1-4烷基),(其中是-α-氨基酸残基)或 R8和R9和它们所连接的氮原子一起代表禾取代的或被C1-4烷基或苯基C1-4烷基取代的脂族杂环);n是0至5的整数;
Figure A9612198400521
是-碳环或杂环;
Figure A9612198400522
其中R2和R3各自独立地为氢原子,C1-4烷基,C1-4烷氧基,卤原子,三卤代甲基或苯基,或R2和R3一起代表C1-4亚烷基,或其中R2和R3与和它们相连的碳原子一起代表C3-7环烷基;R4是C1-4烷基或C1-4烷氧基或两个R4彼此以邻位与苯核相连,一起代表C3-5亚烷基;m是0至4的整数;且
Figure A9612198400531
其中R5和R6各自独立地为1)氢原子,2)羟基,3)C1-8烷基,4)C1-8烷氧基,5)苯基C1-4烷氧基,6)脒基,7)-M-R16(其中M是一单键或C1-8亚烷基),且R16是i)-NR17R18(其中R17和R18各自独立地是氢原子或C1-4烷基),ii)-CONR19R20(其中R19和R20各自独立地为氢原子或C1-4烷基),iii)(其中
Figure A9612198400533
是一碳环,r是0至5的整数,且R21是C1-4烷基,C1-4烷氧基,硝基,脒基,-COOR22(其中R22是氢原子,C1-8烷基,苯基或苯基C1-4烷基),-SO3H,-CONR23-E-R24(其中R23是氢原子或C1-4烷基,E是1-4亚烷基且R24是-COOR25(其中R25是氢原子,C1-8烷基,苯基或苯基C1-4烷基)或四唑环),四唑环或吗啉代环),iv)未取代的或被一个至四个取代基取代的杂环,取代基选自C1-4烷基,C1-4烷氧基,羟基,苯基C1-4烷基,-COOR26(其中R26是氢原子,C1-8烷基,苯基或苯基C1-4烷基),羟基C1-4烷基或C2-4烷氧基烷基),8)被一个或两个-OR27取代的C1-8烷基(其中R27是氢原子,C1-4烷基,C2-4烷氧烷基或被-OR28取代的C2-4烷基(其中R28是氢原子或C2-4烷氧烷基)),9)-J-COOR29(其中R29是氢原子,C1-8烷基,苯基或苯基C1-4烷基,且J是一单键,-(CH2)s-或
Figure A9612198400541
(其中S是2至6的整数,且R30和R31各自独立地为i)氢原子,ii)C1-8烷基,iii)-COOR32(其中R32是氢原子,C1-8烷基,苯基或苯基C1-4烷基),iv)碳环或杂环,其未被取代或被一个或多个选自C1-4烷基,C1-4烷氧烷基,氨基,硝基,羟基,卤原子,腈,胍基和脒基的基团取代,或v)被一个或多个取代基取代的C1-8烷基,取代基选自羟基,-COOR33(其中R33是氢原子,C1-8烷基,苯基或苯基C1-4烷基),-NR34R35(其中R34和R35各自独立地为氢原子或C1-4烷基),碳环或杂环,未取代的或被选自C1-4烷基,C1-4烷氧烷基,氨基,硝基,羟基,卤原子,腈,胍基和脒基的一个或几个取代基取代的C1-8烷基,前提是C1-8烷基的碳原子可被硫原子取代),或
Figure A9612198400551
其中R5和R6与它们连接的氮原子一起代表一个杂环,q是0至4的整数,且R15是1)羟基2)酮基3)被保护酮基,4)C1-4烷基,5)C1-4烷氧基,6)苯基,7)苯氧基,8)苯基C1-4烷基,9)苯基C1-4烷氧基,10)硝基,11)-COOR36(其中R36是氢原子,C1-8烷基,被-CONR37R38取代的C1-4烷基(其中R37和R38各自独立地为氢原子或C1-4烷基),被-NR39R40取代的C1-4烷基(其中R39和R40各自独立地为氢原子或C1-4烷基),被-OR41取代的C1-4烷基(其中R41是被-OR42取代的C2-4烷基(其中R42是氢原子或C2-4烷氧烷基))或被哌嗪基环取代的C1-4烷基),12)-NR43R44(其中R43和R44各自独立地为氢原子,C1-4烷基或C2-5酰基),13)-CONR45R46(其中R45,R46各自独立地为氢原子,羟基,C1-4烷基,苯基C1-4烷氧基或被羟基或-COOR47(其中R47是氢原子或C1-8烷基)取代的C1-4烷基),14)C1-4烷基,其被一个或几个选自羟基,-COOR48(其中R48是氢原子或C1-8烷基),-NR49R50(其中R49和R50各自独立地为氢原子或C1-4烷基),-OSO3H或含一个或两个氮原子的5元或6元杂环取代基取代,15)含一个或两个氮原子的5元或6元杂环,16)卤原子,17-CHO,或18)-NR51-COOR52(其中R51和R52各自独立地为氢原子或C1-8烷基);或其非毒性盐,酸加成盐或溶剂化物。
与现有技术公开的化合物相比,本发明磺酰氨衍生物是新的。
总之,在EP-A-0347168中公开的式(A)化合物一定含有一个三甲基乙酰氧基。相反,本发明化合物具有一个可被各种取代基R1取代的D环。
因此本发明化合物具有与式(A)化合物完全不同的化学结构。
EP-A-0465802中公开的式(B)化合物包括R4B代表S(O)pBR9B的化合物。R9B代表羟基,-ONa,任意取代的C1-12烷基或任意取代的环烷基,但不代表氨基。而且EP-A-0484949中公开的化合物式(C)包括ArC取代基为S(O)pCR9C的那些化合物。R9C可代表羟基,-ONa,任意取代的C1-12烷基或任意取代的环烷基,但不代表氨基。
相反,本发明化合物具有可以被多种取代基取代的磺酰氨基团。因此本发明化合物具有与式(B)和(C)化合物完全不同的化学结构。
并且进一步地,有关化合物口服没有显出活性,但本发明的一些化合物具有良好的稳定性,吸收性和溶解性,因此口服作为弹性蛋白酶抑制剂具有活性。
在式(I)中,由R2,R3,R4,R8,R9,R11,R12,R15,R17,R18,R19,R20,R21,R23,R27,R34,R35,R36,R37,R38,R39,R40,R43,R44,R45,R46,R49,R50和脂族杂环,碳环或杂环的取代基代表的C1-4烷基是甲基,乙基,丙基,丁基和其异构体。
在式(I)中,由R1,R5,R6,R7,R10,R22,R25,R26,R29,R30,R31,R32,R33,R36,R47,R48,R51和R52代表的C1-8烷基是甲基,乙基,丙基,丁基,戊基,己基,庚基,辛基和其异构体。
在式(I)中,R27和R41代表的C2-4烷基指乙基,丙基,丁基和其异构体。
在式(I)中由彼此邻位连接的两个R4代表的C3-5亚烷基指1,3-亚丙基1,4-亚丁基,1,5-亚戊基,和其异构体。
在式(I)中M代表的C1-8亚烷基指亚甲基,亚乙基,1,3-亚丙基,1,4-亚丁基,1,5-亚戊基,1,6-亚己基,1,7-亚庚基,1,8-亚辛基和其异构体。
式(I)中E代表的C1-4亚烷基指亚甲基,亚乙基,1,3-亚丙基,1,4-亚丁基和其异构体。
在式(I)中,苯基C1-4烷基或苯基C1-4烷氧基指C1-4烷基或被苯基取代的C1-4烷氧基。
在式(I)中,由R29,R32,R33,R15和脂肪杂环或杂环的取代基代表的苯基C1-4烷基指甲基,乙基,丙基,丁基和其异构体,它们均被苯基取代。
在式(I)中,由R5,R6,R15,R45和R46代表的苯基C1-4烷氧基指甲氧基,乙氧基,丙氧基,丁氧基和其异构体,它们均是被苯基取代的。
在式(I)中,由R8,R9,R43和R44代表的C2-5酰基指乙酰基,丙酰基,丁酰基,戊酰基和其异构体。
在式(I)中,由R27,R28,R42和杂环取代基代表的C2-4烷氧烷基指甲氧甲基,乙氧甲基,丙氧甲基,甲氧乙基,乙氧乙基,甲氧丙基和其异构体。
在式(I)中,由R1,R5和R6代表的C1-8烷氧基指甲氧基,乙氧基,丙氧基,丁氧基,戊氧基,己氧基,庚氧基,辛氧基和其异构体。
在式(I)中,由R2,R3,R4,R15,R21和碳环或杂环取代基代表的C1-4烷氧基指甲氧基,乙氧基,丙氧基,丁氧基和其异构体。
在式(I)中,由R1,R2,R3和R15代表的卤原子指氟,氯,溴,和碘。在式(I)中,由代表的α-氨基酸残基可以是任何α-氨基酸残基。例如,它可以是甘氨酸,丙氨酸,丝氨酸,苏氨酸,胱氨酸,缬氨酸,蛋氨酸,亮氨酸,异亮氨酸,苯丙氨酸,酪氨酸,色氨酸,天冬氨酸,谷氨酸,精氨酸,谷氨酰胺,赖氨酸,组氨酸或脯氨酸。
在式(I)中,由R2和R3与它们连接的碳原子一起代表的C3-7环烷基指环丙基,环丁基,环戊基,环己基和环庚基。
在式(I)中,由R2和R3一起代表的C1-4亚烷基指亚甲基,亚乙基,亚丙基,亚丁基和其异构体。
在式(I)中,由R8和R9与它们连接的氮原子一起代表的脂肪族杂环优选为5至15元的单环或双环,该环为含一个或两个氮原子或一个氮原子和一个硫原子或氧原子的饱和的杂环或部分饱和的杂环。例子包括吡咯啉,吡咯烷,咪唑啉,咪唑烷,吡唑啉,吡唑烷,哌啶,哌嗪,四氢嘧啶,六氢嘧啶,四氢哒嗪,六氢哒嗪,六氢氢杂_,二氢噁唑,四氢噁唑,二氢异噁唑,四氢异噁唑,二氢噻唑,四氢噻唑,二氢异噻唑,四氢异噻唑,吗啉,硫代吗啉,二氢吲哚,异二氢吲哚,二氢吲唑,全氢吲唑,二氢喹啉,四氢喹啉,全氢喹啉,二氢异喹啉,四氢异喹啉,全氢异喹啉,二氢2,3-二氮杂萘,四氢2,3-二氮杂萘,全氢2,3-二氮杂萘,二氢1,5-二氮杂萘,四氢1,5-二氮杂萘,全氢1,5-二氮杂萘,二氢喹喔啉,四氢喹喔啉,全氢喹喔啉,二氢喹唑啉,四氢喹唑啉,全氢喹唑啉,二氢1,2-二氮杂萘,四氢1,2-二氮杂萘,全氢1,2-二氮杂萘,二氢苯并噁唑,全氢苯并噁脞,二氢苯并噻唑,全氢苯并噻唑,二氢苯并咪唑和全氢苯并咪唑环。
在式(I)中,由 ,R30,R31代表的碳环优选指3-l5元单环或多环芳烃环或脂肪烃环。例子包括1,3-环戊二烯,苯,环戊烯,茚,萘,
Figure A9612198400593
,环丙烷,环丁烷,环戊烷,环戊烯,环己烷,环己烯,环己二烯,环庚烷,二氢化
Figure A9612198400594
,全氢化茚,二氢化萘,四氢化萘,全氢化萘,双环[2.2.1]己烷,双环[3.2.2]壬烷和金刚烷环。
当上述碳环有两个当量时,键位点存在于相同碳原子或不同碳原子上,即当环含有两个自由价时,两个取代基可连接在相同碳原子上或不同碳原子上。在式(I)中,由
Figure A9612198400595
R16,R30和R31代表的杂环优选指5-15元单环或双环芳香杂环,饱和杂环或部分饱和杂环,环中含有一至四个氮原子,一或两个硫原子,一或两个氧原子或一个氮原子和一个硫原子或氧原子,例子包括吡咯,咪唑,吡唑,吡啶,哌嗪,嘧啶,哒嗪,氮杂_,二氮杂_,呋喃,吡喃,氮杂革,噻吩,噻喃(硫杂吡喃),噻品(thiepine),噁唑,异噁唑,噻唑,异噻唑,噁嗪,氧代氮杂_,噻嗪,噻氮杂_,吲哚,异吲哚,苯并呋喃,异苯并呋喃,苯并噻吩,异苯并噻吩,吲唑,喹啉,异喹啉,2,3-二氮杂革,1,5-二氮杂萘,喹噁啉,喹唑啉,1,2-二氮杂萘,苯并噁唑,苯并噻唑,苯并咪唑,吡咯啉,吡咯烷,咪唑啉,咪唑烷,吡唑啉,吡唑烷,哌啶,哌嗪,四氢嘧啶,六氢嘧啶,四氢哒嗪,六氢哒嗪,六氢氮杂_,六氢二氮杂_,二氢呋喃,四氢呋喃,二氢吡喃,四氢吡喃,二氢噻吩,四氢噻吩,二氢噻喃(二氢硫杂吡喃),四氢噻喃(四氢硫杂吡喃),二氢噁唑,四氢噁唑,二氢异噁唑,四氢异噁唑,二氢噻唑,四氢噻唑,二氢异噻唑,四氢异噻唑,吗啉,硫代吗啉,二氢吲哚,异二氢吲哚,二氢苯并呋喃,全氢苯并呋喃,二氢异苯并呋喃,全氢异苯并呋喃,二氢苯并噻吩,全氢苯并噻吩,二氢异苯并噻吩,全氢异苯并噻吩,二氢吲唑,全氢吲唑,二氢喹啉,四氢喹啉,全氢喹啉,二氢异喹啉,四氢异喹啉,全氢异喹啉,二氢2,3-二氮杂_,四氢2,3-二氮杂萘,全氢2,3-二氮杂萘,二氢1,5一二氮杂萘,四氢1,5-二氮杂萘,全氢l,5-二氮杂萘,二氢喹噁啉,四氢喹嚼啉,全氢喹噁啉,二氢喹唑啉,四氢喹唑啉,全氢喹唑啉,二氢1,2-二氮杂萘,四氢1,2-二氮杂萘全氢l,2-二氮杂萘,二氢苯并噁唑,全氢苯并噁唑,二氢苯并噻唑,全氢苯并噻唑,二氢苯并咪唑,全氢苯并咪唑,二氢苯并噁嗪,1,3-dioxaindan,1,4-苯并二噁烷,奎宁环,三唑和四唑环。
在式(I)中,由 代表的杂环,即R5和R6与它们连接的氮原子一起优选为3-15元单环或双环芳香杂环,饱和杂环或部分饱和的杂环,环中含有一个或两个氮原子或一个氮原子和一个硫原子或氧原子。实例包括吡咯,咪唑,吡唑,吡啶,哌嗪,嘧啶,哒嗪,氮杂_,二氮杂_,氮丙啶,氮杂环丁烷,吡咯啉,吡咯烷,咪唑啉,咪唑烷,吡唑啉,吡唑烷,哌啶,哌嗪,四氢嘧啶,六氢嘧啶,四氢哒嗪,六氢哒嗪,六氢氮杂_,六氢二氮杂_,噁唑,异噻唑,噻唑,异噻唑,噁嗪,噁氮杂_,噻嗪,噻氮杂_,吲哚,异吲哚,吲唑,喹啉,异喹啉,2,3-二氮杂萘,1,5-二氮杂萘,喹噁啉,喹唑啉,1,2-二氮杂萘,苯并噁唑,苯并噻唑,苯并咪唑,二氢噁唑,四氢噁唑,二氢异噁唑,四氢异噁唑,二氢噻唑,四氢噻唑,二氢异噻唑,四氢异噻唑,吗啉,硫代码啉,吲哚啉,异吲哚啉,全氢吲哚,二氢吲唑,全氢吲唑,二氢喹啉,四氢喹啉,全氢喹啉,二氢异喹啉,四氢异喹啉,全氢异喹啉,二氢2,3-二氮杂萘,四氢2,3-二氮杂萘,全氢2,3-二氮杂萘,氢1,5-二氮杂萘,四氢1,5-二氮杂萘,全氢1,5-二氮杂萘,二氢喹噁啉,四氢喹噁啉,全氢喹噁啉,二氢喹唑啉,四氢喹唑啉,全氢喹唑啉,二氢1,2-二氮杂萘,四氢1,2-二氮杂萘,全氢1,2-二氮杂萘,二氢苯并噁唑,全氢苯并噁唑,二氢苯并噻唑,全氢苯并噻唑,二氢苯并咪唑,全氢苯并咪唑,7-氮杂双环[3.2.1]辛烷,和3-氮杂双环[3.2.2]壬烷环。
在式(I)中,由R15代表的含一个或两个氮原子的5元或6元杂环指,例如,吡咯,咪唑,吡唑,吡啶,哌嗪,嘧啶,哒嗪,吡咯啉,吡咯烷,咪唑啉,咪唑烷,吡唑啉,吡唑烷,哌啶,哌嗪,四氢嘧啶或四氢哒嗪。
在式(I)中,被保护酮基键接的 代表的环例子包括1,3-二氧戊环和
Figure A9612198400611
螺环衍生物。一个或两个酮基(=0)可以与相同或不同的硫原子连接作为取代基R15。一个基团按照一个R15处理。
在式(I)中:m优选代表0,1或2,更优选0或1。R4优选代表1-4碳原子的烷基或烷氧基,例如甲基,乙基,异丙基,甲氧基,乙氧基,或异丙氧基。甲基是特别优选的。当存在一个或两个取代基R4时,它们优选占有与苯环连接的氧原子邻位的一个或两个位置;在与苯环相连的氧原子邻位和间位有两个取代基的化合物也构成了本发明的一个特征;两个这样的取代基可以一同构成与苯环稠合的五元环。
特别优选的化合物中m是1,R4代表甲基,处于和苯环连接的氧原子邻位上。
R2和R3中的一个优选代表氢原子,甲基,乙基,或甲氧基,另一个代表甲基、乙基,异丙基,苯基或三氟甲基或者R2和R3与它们连接的碳原子一起代表亚乙基或3-6碳原子环烷基。R2和R3中的一个代表的乙基优选β构型。
D优选代表苯基,萘基(优选1-或2-萘基),噻吩基(优选噻吩-2基),环己烷,吡啶基,(优选吡啶-3-基),噻唑基(优选噻唑-4-基),咪唑啉基(优选咪唑啉-2-基),苯并咪唑基(优选苯并咪唑-5-基),2H-1,4-苯并噁嗪-3-酮-6-基,或1,3-苯并二氧戊环-5-基,或1H-1-甲基-2-吡啶酮-3-基。苯基是特别优选的。
n优选代表0,1,2或3,优选0或1。R1优选代表1-4碳原子烷基,例如甲基;1-4碳原子烷氧基,例如甲氧基;氨基;两个1-4碳原子烷基取代的氨基,例如二甲氨基,氨基甲酰基取代的甲基;2-5碳原子烷酰基取代的甲基,例如乙酰基;硝基;羟基;氰基;羧基,三卤代甲基,例如三氟甲基;脒基;烷氧羰基取代的氨基;卤原子,例如氯;吡咯烷基,哌啶基;全氢氮杂_基;或吗啉基或在4位上被苄基任意取代的哌嗪基。
其中D代表一取代苯基的化合物也是本发明一个特征:当D是被取代的苯基时,至少一个取代基优选在4-位上。优选的4-取代苯基是那些其中取代基为5-,6-或7-元含氮环,含氮环与苯基通过氮原子连接:优选吡咯烷-1-基。
在基团NR5R6中,当R5和R6与它们相连的氮原子一起不代表一个杂环时,基团R5R6优选代表氢原子;甲基;乙基;丙基;甲氧基;苄基;甲氧甲氧乙基;1-羟乙基;氢原子是特别优选的,另一个代表苯基;被取代的苯基取代基,例如2-((1-羧甲基)氨基羰基)苯基,4-硝基苯基;杂环,例如奎宁环,哌啶,吡啶,咪唑,吗啉,四唑;被杂环取代的C1-8烷基,例如哌嗪-1-基乙基、哌啶-1-基乙基、吗啉-1-基乙基、吡啶-2-基乙基、吡咯-2-基乙基;吗啉-1-基乙基是特别优选的。
在基团NR5R6中,当R5和R6与和它们连接的氮原子一起代表杂环时,该环优选代表吡咯烷;吲哚;吲哚啉;全氢吲哚;苯并咪唑;吗啉;哌啶;哌嗪;7-氮杂双环[3.2.1]辛烷;3-氮杂双环[3.2.2]壬烷;四氢噁唑;四氢噻唑;咪唑;六氢二氮杂_;氮丙啶;氮杂环丁烷;哌嗪是特别优选的。
在基团NR5R6中,当R5和R6与它们相连的氮原子一起代表杂环时,R15优选代表羟基;羟基取代的C1-4烷基,例如羟甲基;杂环取代的C1-4烷基,例如吡咯烷-1-基甲基;苄氧基;氨基;甲氧基;二甲基氨基;乙酰氨基;甲基,硝基;卤原子,如氟;酮;羧基;酯,例如乙氧羰基、叔丁氧羰基、2-氨基乙氧羰基、2-(2-羟基乙氧基)乙氧羰基、2-(哌嗪-1-基)乙氧羰基;酰胺,例如羧甲基氨基羰基;羧基是特别优选的。
在基团NR5R6中,当R5和R6与它们连接的氮原子一起代表杂环时,q优选代表0,1或2,更优选0或1。
根据包括权利要求在内的整个说明书,本领域熟练技术人员容易理解:所有的异构体均包括在本发明中。例如,烷基,亚烷基和亚烯基包括直链也包括支链基团。亚烯基中的双键包括E,Z和E Z混合物。因此,当存在象支链烷基这样的基团时,由于不对称碳原子的存在而产生的所有异构体均包括在本发明中。
本发明式(I)化合物可以通过实质上已知的方法转化成相应的无毒盐或酸加成盐。
水溶性盐是优选的。合适的盐,例如,包括碱金属盐(例如钾或钠盐),碱土金属(如钙或镁)盐,铵盐,药学上可接受的有机胺(如四甲铵,三乙胺,甲胺,二甲胺,环戊胺,苄胺,苯乙胺,哌啶,一乙醇胺,二乙醇胺,三(羟甲基)胺,赖氨酸,精氨酸或N-甲基-D-葡糖胺)的盐。
水溶性酸加成盐也是优选的。合适的酸加成盐例如包括和无机酸形成的盐,无机酸如盐酸,氢溴酸,硫酸,磷酸和硝酸,以及和有机酸形成的盐,有机酸例如乙酸,三氟乙酸,乳酸,酒石酸,乙二酸,富马酸,马来酸,苯磺酸,甲苯磺酸,羟乙磺酸,葡糖醛酸和葡糖酸。
本发明式(I)化合物可以通过本质上已知的方法转化为相应的溶剂化物。
水溶性溶剂化物是优选的。合适的溶剂化物例如包括和水或和醇溶剂如乙醇形成的盐。
优选的本发明化合物是下面式(I-A1),(I-A2),(I-B1)和(I-B2)。
Figure A9612198400641
(其中所有符号如先前所定义)
本发明有代表性的化合物用下面表1-46中的化合物和其非毒盐及酸加成盐来说明。
在这些表中,Me是甲基,Et是乙基,Pr是丙基,iPr是异丙基和tBu是叔丁基。
                                  表1
Figure A9612198400652
                           表1(续)
Figure A9612198400661
Figure A9612198400662
                              表2
                          表2(续)
Figure A9612198400681
Figure A9612198400682
                                表3
Figure A9612198400692
                            表4
Figure A9612198400701
Figure A9612198400702
                              表5
Figure A9612198400711
                            表6
Figure A9612198400722
                            表7
Figure A9612198400731
                              表8
Figure A9612198400742
                               表9
Figure A9612198400751
Figure A9612198400752
                            表10
Figure A9612198400761
                           表11
Figure A9612198400771
                            表12
Figure A9612198400781
                            表13
Figure A9612198400791
                              表14
Figure A9612198400801
                            表15
Figure A9612198400812
                              表16
Figure A9612198400821
                          表17
Figure A9612198400831
                           表18
Figure A9612198400841
Figure A9612198400842
                              表19
Figure A9612198400852
                               表20
Figure A9612198400861
                            表21
Figure A9612198400871
Figure A9612198400872
                          表21(续)
Figure A9612198400881
                            表22
Figure A9612198400891
Figure A9612198400892
                              表23
Figure A9612198400901
                           表23(续)
Figure A9612198400911
Figure A9612198400912
                           表24
Figure A9612198400921
Figure A9612198400922
                              表25
                          表25(续)
Figure A9612198400942
                            表26
Figure A9612198400952
                            表27
                          表27(续)
Figure A9612198400972
                              表28
Figure A9612198400982
                           表28(续)
Figure A9612198400992
                           表29
Figure A9612198401001
                              表30
Figure A9612198401011
                              表31
                           表32
Figure A9612198401031
Figure A9612198401032
                            表33
Figure A9612198401041
Figure A9612198401042
                           表34
                           表35
Figure A9612198401061
                           表36
Figure A9612198401071
                               表37
                            表38
Figure A9612198401092
                              表39
Figure A9612198401101
Figure A9612198401102
                            表40
Figure A9612198401112
                            表41
Figure A9612198401121
Figure A9612198401122
                           表42
                            表43
Figure A9612198401142
                            表44
                            表45
Figure A9612198401162
                              表46
Figure A9612198401172
本发明式(I)化合物可以通过式(II)化合物的酯化而制备。
其中R1a是C1-8烷基,C1-8烷氧基,羟基,被保护羟基,酮,硝基,卤原子,三卤代甲基,氰基,脒基,-COOR7a(其中R7a是C1-8烷基或苄基),或
Figure A9612198401182
(其中p如上文所定义,R8a和R9a各自独立地为氢原子(前提是,R8a和R9a不同时代表氢原子),叔丁氧羰基,苄氧羰基,C1-4烷基,C2-5酰基,-COOR10a(其中R10a是C1-8烷基或苄基),-CONR11R12(其中R11和RU如上文所定义),或者
Figure A9612198401183
(其中
Figure A9612198401184
是被保护α-氨基酸残基),或者R8a和R9a和它们相连的氮原子一起代表未取代的或被C1-4烷基或苯基C1-4烷基取代的脂族杂环,其它符号如上文所定义。酯化作用是式(II)化合物与式(III)化合物反应其中
Figure A9612198401192
(其中R5a和R6a各自独立地是1)氢原子(前提是R5a和R6a不同时代表氢原子)。2)羟基,3)被保护的羟基,保护基团在酸条件下可去除,4)叔丁氧羰基,5)苄氧羰基,6)C1-8烷基,7)C1-8烷氧基,8)苯基C1-4烷氧基,9)脒基,10)-M-R16a(其中M如上文定义,且R16a是i)-NR17aR18a(其中R17a和R18a各自独立地为氢原子(前提是R17a和R18a不同时代表氢原子),叔丁氧羰基,苄氧羰基或C1-4烷基),ii)-CONR19R20(其中R19和R20如上文所定义),
Figure A9612198401201
(其中所有符号如上文所定义),iv)杂环,未取代的或被1至4个选自C1-4烷基,C1-4烷氧基,羟基,苯基C1-4烷氢-COOR26(其中R26如上文所定义),羟基C1-4烷基或C2-4烷氧烷基的取代基取代,其中羟基C1-4烷基中的羟基被在酸性条件下可去除的保护基团保护,11)C1-8烷基,被1个或两个-OR27a取代(其中R27a是氢原子,C1-4烷基,C2-4烷氧烷基,叔丁基二甲基甲硅烷基,THP,苄基,或被-OR28a取代的C2-4烷基(其中R28a是氢原子,C2-4烷氧烷基,叔丁基二甲基甲硅烷基,THP或苄基)),12)-Ja-COOR29(其中R29如上文定义,Ja是一单键,-(CH2)s-或
Figure A9612198401202
(其中S如上文定义,R30a和R31a各自独立地是i)氢原子,ii)C1-8烷基,iii)-COOR32(其中R32如上文所定义),iv)碳环或杂环,未取代的或被一个或几个选自C1-4烷基,C1-4烷氧烷基,氨基,硝基、羟基,被保护羟基,卤原子,腈、胍基和脒基的取代基取代,或者v)C1-8烷基,被一个或多个取代基取代,取代基选自羟基,被保护羟基,-COOR33(其中R33如上文所定义),-NR34aR35a(其中R34a和R35a各自独立地为氢原子(前提是R34a和R35a不同时为氢原子),叔丁氧羰基,苄氧羰基或C1-4烷基),碳环或杂环,该环为未取代的或被一个或几个选自C1-4烷基,C1-4烷氧烷基,被保护氨基,硝基,羟基,被保护羟基,卤原子,腈,胍基和脒基的基团取代,前提是C1-8烷基的碳原子可以被硫原子取代,或者其中R5a和R6a与它们相连的氮原子一起代表杂环,q如上文定义,R15a是1)羟基,2)被保护的羟基,保护基团在酸性条件下可去除3)酮,4)被保护酮,5)C1-4烷基,6)C1-4烷氧基,7)苯基,8)苯氧基,9)苯基C1-4烷基,10)苯基C1-4烷氧基,11)硝基,12)-COOR36a(其中R36a是氢原子,C1-8烷基,被-CONR37R38取代的C1-4烷基(其中R37和R38如上文所定义),被-NR39aR40a取代的C1-4烷基(其中R39a和R40a各自独立地是氢原子(前提是R39a和R40a不同时为氢原子),叔丁氧羰基,苄氧羰基或C1-4烷基),被-OR41a取代的C1-4烷基(其中R41a是-OR42a取代的C2-4烷基(其中R42a是氢原子,C2-4烷氧烷基或苄基))或被保护哌嗪环取代的C1-4烷基),13)-NR43aR44a(其中R43a,R44a各自独立地为氢原子(前提是,R43a和R44a不同时为氢原子),叔丁氧羰基,苄氧羰基,C1-4烷基或C2-5酰基),14)-CONR45aR46a(其中R45a和R46a各自独立地为氢原子,C1-4烷基,羟基,保护基在酸性条件下可去除的被保护的羟基,苯基C1-4烷氧基或被取代的C1-4烷基,取代基为羟基,被保护羟基或-COOR47a(其中R47a是氢原子,C1-8烷基或苄基)15)C1-4烷基,被一个或几个选自羟基,被保护羟基,-COOR48a(其中R48a是氢原子,C1-8烷基或苄基),-NR49aR50a(其中R49a和R50a各自独立地为氢原子(前提是R49a和R50a不同时代表氢原子),叔丁氧羰基,苄氧羰基或C1-4烷基),或含一个或两个氮原子的五元或六元杂环取代基取代,16)含一个或两个氮原子的五元或六元杂环,17)卤原子,18)-CHO,被酸性条件下可去除的保护基团保护,或者19)-NR51a-COOR52a(其中R51a和R52a各自独立地为氢原子或C1-8烷基),其它符号如上文所定义,或者
可通过式(II)化合物和式(III)化合物的酯化来获得具有保护基(S)的化合物,然后去除保护基(S)(例如通过叔丁酯的水解,用酸和/或氢解处理),或者可以通过式(II)化合物与式(III)化合物酯化,如果需要,消除保护基得含R15的化合物,R15代表被羟基取代的C1-4烷基,然后用硫酸进行酯化作用;可任意地将如此得到的式(I)化合物转化为它的非毒盐,酸加成盐或溶剂化物。
被保护羟基指,例如酸性条件下可去除的保护基保护的羟基(例如,C2-4烷氧烷基,叔丁基二甲基甲硅烷基,四氢吡喃(THP),三苯甲基)或者被可氢化去除的保护基保护的羟基(例如苄基)。
被酸性条件下可去除的保护基保护的羟基指,例如,被C2-4烷氧烷基,叔丁基二甲基甲硅烷基,四氢吡喃(THP)或三苯基甲基保护的羟基。
被保护氨基酸,α-氨基酸或哌嗪环指,例如,被叔丁氧羰基(Boc)或苄氧羰基(Cbz)保护的氨基酸,α-氨基酸或哌嗪环。
被酸性条件下可去除的保护基团保护的-CHO指,例如被缩醛(例如二甲醇缩醛或二乙醇缩醛)或缩酮(例如亚乙基二氧缩酮或三亚甲基二氧缩酮)保护的-CHO。
上述酯化作用实质上是已知的,可用例如下面的方法进行:(1)使用酰基卤,(2)使用混合酸酐,(3)使用缩合剂,
这些方法的每一种方法可以如下进行:
(1)可以使用酰基卤的方法,例如,使羧酸与酰卤(例如草酰氯或亚硫酰氯)在惰性有机溶剂(例如,氯仿,二氯甲烷,二乙醚或四氢呋喃)中或在无溶剂条件下,在-20℃至所用溶剂的回流温度下反应,然后将得到的酰基卤与相应的醇在叔胺(例如吡啶,三乙胺,二甲基苯胺或二甲基氨基吡啶)存在下,在惰性有机溶剂中(例如,氯仿,二氯甲烷,二乙醚或四氢呋喃),在0℃至40℃的温度下反应。(2)可以使用混合酸酐的方法,例如使羧酸和酰基卤(例如,三甲基乙酰氯,甲苯磺酰氯或甲磺酰氯)或酸衍生物(例如氯代甲酸乙酯或氯代甲酸异丁酯)在叔胺(例如吡啶,三乙胺,二甲基苯胺或二甲基氨基吡啶)存在下,在惰性有机溶剂(例如氯仿,二氯甲烷,二乙醚或四氢呋喃)中,或在无溶剂条件下,在0℃至40℃温度下反应,然后将得到的酸酐混合物与相应的醇在惰性有机溶剂中(例如氯仿,二氯甲烷,二乙醚或四氢呋喃),在0℃至40℃温度下反应,(3)可以使用缩合剂(例如,1,3-二环己基碳二亚胺(DCC),1-乙基-3-[3-(二甲氨基)丙基]碳二亚胺(EDC)或碘化2-氯-1-甲基吡啶)的方法,例如,使用缩合剂使羧酸和相应的醇反应,在叔胺(例如吡啶,三乙胺,二甲基苯胺或二甲基氨基吡啶)存在或不存在时,在惰性有机溶剂(例如氯仿,二氯甲烷,二甲基甲酰胺或二乙醚)中或无溶剂时,在0℃至40℃温度下进行反应。
上述反应(1),(2)和(3)可以优选在惰性气体(例如氩气或氮气)中在无水条件下进行。
叔丁酯基团的水解或用酸处理反应产物本质上是已知的(例如C2-4烷氧烷基,叔丁氧羰基或二甲缩醛的脱除)并可以实施,例如,用有机酸(例如三氟乙酸)或无机酸(例如盐酸),或其混合物,在惰性有机溶剂中(例如二氯甲烷,氯仿,甲醇,二噁烷,乙酸乙酯或苯甲醚)在0℃至90℃的温度下进行反应。
氢解实质上是已知的,并可以实施,例如在惰性溶剂[如醚(例如四氢呋喃,二噁烷,二乙氧乙烷或二乙醚),醇(例如甲醇或乙醇),苯类似物(例如苯或甲苯),酮(例如丙酮或甲乙酮),腈(例如乙腈),胺(例如二甲基甲酰胺),水,乙酸乙酯,乙酸或它们的两种或多种混合物]中,在氢化催化剂(例如活性炭上的钯,钯黑,钯,碳上的氢氧化钯,氧化铂,镍或阮内镍(注册商标))存在下,存在或不存在无机酸(例如盐酸,硫酸,高氯酸,硼酸或四氟硼酸)或有机酸(例如乙酸,对甲苯磺酸,草酸,三氟乙酸或甲酸),常压或加压氢气氛围下,在0℃至200℃温度下进行。当使用一种酸时,同时也可以使用其盐。
硫酸的酯化作用实质上是已知的,且可以例如通过三氧化硫吡啶配合物在叔胺(例如吡啶)存在下在0℃至40℃的温度下反应进行。
用作起始原料的式(II)和(III)化合物可以通过下面反应式1的方法或本质上已知的方法制备,或者它们是商业上可购得的。例如2-苯基丁酸可购得。这些化合物也可以通过本说明书实施例中说明的方法来制备。
                           反应式1
上述反应式1中W是碱金属,Y是苄基,苄氧羰基,或酸性条件下可去除的保护基(例如C2-4烷氧烷基,叔丁基二甲基甲硅烷基,四氢呋喃(THP)或三苯基甲基),其它符号如上文所定义。
已经证明本发明式(I)化合物对弹性蛋白酶有抑制活性。例如在实验室试验中获得了下列结果。(1)对人多形核弹性蛋白酶的抑制作用
在37℃将混合物0.5ml 0.2mM HEPES缓冲液(pH8.0),0.2ml 2.5M NaCl,0.1ml 1%聚乙二醇6000,0.13ml蒸馏水,溶于0.01ml二甲亚砜(DMSO)中的试验化合物和0.05ml 0.8单位/ml人多形核弹性蛋白酶(HSE)一起预温育20分钟。然后向上述混合物中加入5mM Meo-Suc-Ala-Ala-Pro-Val-pNA(DMSO溶液,0.01ml)并在37℃保温5分钟。用0.1ml 50%乙酸终止反应并在405nM处用分光光度法测定释放出的对-硝基酰苯胺(pNA)。用下面等式计算化合物抑制百分比。
抑制(%)=1-{ΔOD(试验化合物-空白)/
          ΔOD(对比化合物-空白)}×100
结果示于表47中[表47]
    实施例号     1C50(μM)
    1    (16)1    (40)1    (56)1    (78)1   (130)1   (139)22     (1)2    (42)2    (62)2    (69)2    (77)2   (111)2   (120)2   (157)2   (173)2   (179)2   (197)2   (274)2   (276)       0.0170.0190.0140.00800.0220.0240.0550.0120.0130.00680.0110.0180.00970.0230.0080.0140.0490.0100.0120.0093
(2)在仓鼠体内进行的对人多形核弹性蛋白酶诱导的肺出血的抑制作用。
给一组五只Syrian仓鼠口服试验化合物,化合物悬浮于0.5%羧甲基纤维素或80%聚乙二醇400或2%T Ween80中。服后60分钟时,在戊巴比妥麻醉条件下通过外科手术暴露气管,气管内注射10U/0.1ml HSE(巴比妥用量60mg/kg,i.p)以引起肺损伤。注射60分时后,仓鼠被放血杀死,并用2.5ml盐水进行支气管肺泡灌洗,并回收灌洗溶液(BALF)。回收的BALF(0.5ml)用2%碳酸钠水溶液稀释4倍并超声处理10秒钟。回收液再用2%碳酸钠水溶液稀释2.5倍,根据在414nM处的吸收值用标准曲线计算BALF中血的量
结果见表48和49。
【表48】
实施例序号 500mg/kg时的抑制作用(%)
   1    (68)     51
   1    (90)     65
   2     81
   2    (42)     67
   2    (69)     83
【表49】
  实施例序号        ED50
  1    (139)     192mg/kg
  2    (274)     132mg/kg
  2    (276)     73mg/kg
上述实验表明,即使口服时,本发明化合物对弹性蛋白酶也有抑制活性。
本发明化合物毒性非常低,因此,本发明化合物可以被认为足够安全且适于药用。
本发明式(I)化合物,其无毒盐和酸加成盐具有对弹性蛋白酶的抑制活性。因此它们可用来治疗和/或预防由弹性蛋白,胶原纤维和/或蛋白多糖异常增强的降解作用而产生的疾病,病因源于弹性蛋白酶对哺乳动物特别是人的作用,(例如慢性引起阻塞的肺部疾病,象肺象肿,类风湿性关节炎,动脉粥样硬化,成人呼吸窘迫综合症(ARDS),肾小球性肾炎,必肌梗塞形成,自发性溃疡性结肠炎或龈炎)。
根据上述目的,本发明式(I)化合物,或无毒盐,其酸加成盐或溶剂化物一般可以系统给药,或者通常局部口服或肠胃外给药。
给药剂量根据例如年龄,体重,症状,所期望的治疗效果,给药途径,治疗持续时间而决定。对于成年人,每天至多几次口服给药,每人剂量一般由1mg至1000mg,或每天至多几次非肠道给药或每天静脉内连续给药1至24小时,给药量为0.1mg至100mg。
如上所述,所用剂最取决于多种条件。因此有时剂量也可低于或高于上面使用的特殊范围。
本发明化合物可以以例如固体组合物,液体组合物或其它组合物的形式给药,用于口服,注射,搽剂或用于非肠道给药的栓剂。
口服固体组合物包括压片,丸,胶囊,可分散粉末和颗粒剂。胶囊包括硬胶囊和软胶囊。在这样的组合物中,一种或几种活性化合物可以与至少一种惰性溶剂混合(溶剂例如乳糖,甘露糖醇,葡萄糖,羟丙基纤维素,微晶纤维素,淀粉,聚乙烯吡咯烷酮或硅酸镁铝盐)。根据通常实践,该组合物也可以含有除惰性稀释剂以外的添加物质:例如润滑剂(如硬脂酸镁),崩解剂(象甘醇酸纤维素钙),稳定剂(象乳糖),和助溶剂(象谷氨酸或天冬氨酸)。
如果需要片剂或丸剂,可以用胃膜或肠膜材料包衣(象糖,明胶,羟丙基纤维素,羟丙基甲基纤维素邻苯二甲酸酯),或用两种或多种膜包衣。而且肠溶衣可以包括可吸收材料象明胶胶囊中的内含物。
口服液体组合物包括药学上可接受的溶液,乳液,悬浮液,糖浆和酏剂。在这种组合物中,一种或几种活性化合物含在本领域常用的惰性稀释剂中(例如纯化的乙醇或水)。除惰性稀释剂外,这种组合物也可以含有助剂(象湿润剂或悬浮剂,甜味剂,调味剂,香味剂和防腐剂)。
其它口服组合物包括喷雾剂组合物,其可通过已知方法制备且含有一种或多种活性化合物。喷雾组合物可以含有除惰性稀释剂外的添加物质:例如稳定剂(象硫酸钠),等渗缓冲液(象氯化钠,柠檬酸钠或柠檬酸),为制备这种喷雾组合物,例如可以使用美国专利No.2868691或3095355中说明的方法。
非肠道给药注射剂包括无菌水溶液和非水溶液,悬浮液和乳液。在这种组合物中,一种或几种活性化合物可以与至少一种惰性水溶液稀释剂(例如注射用蒸馏水或生理盐溶液)或惰性非水稀释剂(例如丙二醇,聚乙二醇,橄榄油,乙醇或POLYSORBATE80(注册商标)混合。
注射液可以含有惰性稀释剂以外的其它成分:例如防腐剂,湿润剂,乳化剂,分散剂,稳定剂(例如乳糖),助剂象助溶剂(例如谷氨酸或天冬氨酸)。
可以通过细菌截留过滤器过滤,与组合物中的消毒剂结合,或通过X光照射进行消毒。也可以制成无菌固体组合物的形式,例如通过冻干,其可以在使用前即刻溶解在注射用无菌水或一些其它无菌稀释剂中。
其它肠胃外给药组合物包括外用液体,和皮肤擦剂,软膏,栓剂和阴道栓剂,它们可以含有一种或几种活性化合物,且可以用本质上已知的方法制备。参考实施例和实施例
下面参考实施例和实施例说明但不限制本发明。
括号中的溶剂是展开剂或洗脱剂,所用溶剂比例以色谱分离和TLC中的体积表示。
NMR数据给出了在测定中用的溶剂,示于括号中。参考实施例13-甲基-4-羟基苯磺酸·钾盐
Figure A9612198401321
100℃时向搅拌着的浓硫酸中(26ml)缓慢加入邻甲酚(50ml),混合物在100℃搅拌5小时。反应后,混合物冷却至室温,缓慢加入氢氧化钾(27.5g)水(35ml)溶液中和混合物。向混合物中加入甲醇(100ml)后,滤出沉淀得到有下面物理数据的标题化合物(56.5g)。
TLC:Rf0.18(氯仿∶甲醇∶水=6∶4∶1)参考实施例2
3-甲基-4-(苄氧羰氧基)苯磺酸·钾盐
Figure A9612198401331
在室温下向参考实施例1中制备的化合物(12.2g)的四氢呋喃(THF)(100ml)悬浮液中加入2N氢氧化钠水溶液(28ml)后,在冰冷却下加入苄氧羰基氯化物(8ml)。将反应混合物搅拌30分钟。减压下浓缩反应混合物,用冰冷却,过滤出沉淀物得到具有下面物理数据的标题化合物(7.3g)。
TLC:Rf 0.51(氯仿∶甲醇∶水=6∶4∶1)。参考实施例3
3-甲基-4-(苄氧羰氧基)苯磺酰氯
Figure A9612198401332
在冰冷却下向参考实施例2中制备的化合物(46.1g)的二甲基甲酰胺(DMF)(100ml)的悬浮液中缓慢加入亚硫酰氯(15ml)。反应混合物在5℃搅拌30分钟。向反应混合物中加入冰水,滤出沉淀物得到具有下面物理数据的标题化合物(39.4g)。
TLC:Rf 0.56(氯仿∶甲醇∶水=6∶4∶1)。参考实施例44-(2S-叔丁氧羰基吡咯烷-1-基磺酰基)-2-甲基苯酚
Figure A9612198401341
在冰冷却下向L-脯氨酸叔丁酯(1.9g)的吡啶(10ml)溶液中加入参考实施例3中制备的化合物(3.7g)。将反应混合物搅拌30分钟。加入2N盐酸水溶液使混合物骤冷,并用乙酸乙酯(200ml)萃取混合物。有机层用饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤,用无水硫酸镁干燥并浓缩。向残余物(4.9g)的甲醇(200ml)溶液中加入10%活性炭
(500mg)上的钯,反应混合物在室温下氢气中搅拌2小时。混合物通过硅藻土(市售)过滤。浓缩滤液得有下面物理数据的标题化合物(3.4g)。TLC:Rf 0.35(己烷∶乙酸乙酯=1∶1)。参考实施例52RS-(4-硝基苯基)丁酸
Figure A9612198401342
在15℃,向2-苯基丁酸(200g)的乙酸溶液(200ml)和浓硫酸(150ml)的混合物溶液中缓慢加入浓硝酸(150ml)。在相同温度下将反应混合物搅拌10分钟。将反应混合物倾入到冰水中,过滤沉淀物。残余物从己烷/乙酸乙酯混合溶液中重结晶得具有下面物理数据的标题化合物(103g)。TLC:Rf 0.50(乙酸乙酯)。参考实施例62RS-(4-氨基苯基)丁酸甲酯
Figure A9612198401351
用冰冷却下,向在参考实施例5制备的化合物(15.7g)的DMF(60ml)溶液中加入碳酸钾(12g)。在相同温度下向混合物中加入碘代甲烷(5ml)。反应混合物在室温下搅拌2小时。混合物用1N盐酸水溶液(200ml)骤冷,并用己烷/乙酸乙酯(1∶1,200ml)混合物萃取。有机层用水和饱和氯化钠水溶液洗涤,用无水硫酸镁干燥并浓缩。向残余物的甲醇(300ml)溶液中加入活性炭(1.3g)上的5%钯,混合物在室温下在氢气中搅拌2小时。混合物经硅藻土(市售)过滤。浓缩滤液得有下面物理数据的标题化合物(14.2g)。TLC:Rf 0.47(己烷∶乙酸乙酯=1∶1)。参考实施例72RS-(4-(吡咯烷-1-基)苯基)丁酸
向参考实施例6中制备的化合物(14.2g)的DMSO(75ml)溶液中加入碳酸钾(11g)和1,4-二溴丁烷(9ml)。反应混合物在40℃搅拌1小时。向混合物中加入碘化钠(11.2g)。反应混合物在40℃搅拌3小时,并在60℃搅拌2小时。通过加水使反应混合物骤冷,并用己烷/乙酸乙酯(1∶1,1000ml)混合物萃取反应混合物。有机层用水和饱和氯化钠水溶液洗涤,用无水硫酸镁干燥并浓缩。向残余物的甲醇(80ml)溶液中加入5N氢氧化钠水溶液(20ml),混合物在室温下搅拌5小时。向混合物中加入盐酸水溶液至pH8,并用乙酸乙酯洗涤。加盐酸水溶液中和水层,并用乙酸乙酯萃取。用饱和氯化钠水溶液洗涤萃取液,用无水硫酸镁干燥并浓缩。残余物从己烷/乙酸乙酯(3∶1)混合溶液中重结晶,得具有下面物理数据的标题化合物(9.83g)。TLC:Rf 0.30(己烷∶乙酸乙酯=1∶1)。实施例12RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-叔丁氧羰基吡咯烷-1-基磺酰基)-2-甲基苯酯
Figure A9612198401361
室温下向参考实施例4中制备的化合物(748mg),参考实施例7中制备的化合物(537mg)和二甲基氨基吡啶(64mg)的二氯甲烷(20ml)溶液中加入1-乙基-3-(3-二甲基氨基丙基)-碳化二亚胺(482mg)。反应混合物在室温下搅拌2小时。向反应混合物中加入乙酸乙酯,并用1N盐酸水溶液洗涤(X2)。有机层用无水硫酸镁干燥并浓缩。残余物用硅胶柱层析纯化(己烷∶乙酸乙酯=5∶1)得有下面物理数据的标题化合物(1.04g)。TLC:Rf 0.23(己烷∶乙酸乙酯=5∶1)。实施例1  (1)~1  (147)
根据实施例1相同的方法及转化成相应盐或酸加成盐的已知方法,用相应的苯酚衍生物代替参考实施例4中制备的化合物,和使用相应的羧酸衍生物代替参考实施例7中制备的化合物,得到具有下面物理数据的化合物。实施例1  (1)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羟基甲基吡咯烷-1-基磺酰基)苯酯·盐酸盐
Figure A9612198401371
NMR(DMSO-d6):δ7.85(2H,d,J=9Hz),7.28(2H,d,J=9Hz),7.28(2H,d,J=9Hz),6.83(2H,d,J=9Hz),3.75(1H,t,J=7Hz),3.60-3.44(2H,m),3.40-3.20(6H,m),3.11-2.95(1H,m),2.21-1.90(5H,m),1.90-1.65(3H,m),1.55-1.30(2H,m),0.90(3H,t,J=7Hz);TLC:Rf 0.48(乙酸乙酯∶己烷=1∶1)。实施例1  (2)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代吡咯烷-1-基磺酰基)苯酯·盐酸盐
Figure A9612198401381
NMR(CDCl3):δ8.05(2H,d,J=8.8Hz),7.61(2H,d,J=8.6Hz),7.47(2H,d,J=8.6Hz),7.19(2H,d,J=8.8Hz),3.89(2H,t,J=7.2Hz),3.74(1H,t,J=7.8Hz),3.85-3.45(4H,brS),2.44(2H,t,J=7.8Hz),2.40-2.25(4H,m),2.35-1.75(2H,m),2.20-2.00.(2H,m),0.99(3H,t,J=7.4Hz);TLC:Rf 0.39(乙酸乙酯∶己烷=1∶1).实施例1  (3)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(吡咯烷-1-基磺酰基)-2-甲基苯酯
Figure A9612198401382
NMR(CDCl3):δ7.68-7.57(2H,m),7.23(2H,d,J=8Hz),7.06(1H,d,J=8Hz),6.55(2H,d,J=8Hz),3.61(1H,t,J=7Hz),3.35-3.13(8H,m),2.30-1.65(13H,m),0.98(3H,t,J=7Hz);TLC:Rf 0.49(乙酸乙酯∶己烷=3∶7)。实施例1  (4)2RS-(4-(吡咯烷-1-基)苯基丁酸4-(2S-(吡咯烷-1-基甲基)吡咯烷-1-基磺酰基)-2-甲基苯酯·二盐酸盐
Figure A9612198401391
NMR(CD3OD):δ7.95-7.75(2H,m),7.65(4H,s),7.22(1H,d,J=8.5Hz),4.26-3.90(2H,m),3.99(1H,t,J=7.5Hz),3.90-3.70(5H,m),3.50-3.10(6H,m),2.40-2.25(4H,m),2.40-1.35(10H,m),2.07(3H,s),1.00(3H,t,J=7.5Hz);TLC:Rf 0.43(水∶甲醇∶氯仿=1∶10∶90)。实施例1  (5)2RS-苯基丁酸4-(吡咯烷-1-基磺酰基)苯酯
Figure A9612198401401
NMR(CDCl3):δ7.85-7.74(2H,m),7.41-7.24(5H,m),7.23-7.10(2H,m),3.71(1H,t,J=7Hz),3.30-3.15(4H,m),2.39-2.10(1H,m),2.03-1.80(1H,m),1.80-1.68(4H,m),0.99(3H,t,J=7Hz);TLC:Rf  0.43(己烷∶乙酸乙酯=2∶1)。实施例1  (6)2RS-(4-(吡咯烷-1-基)苯基丁酸4-(二氢吲哚-1-基磺酰基)苯酯·盐酸盐
Figure A9612198401402
NMR(CDCl3):δ7.78(2H,d,J=8.8Hz),7.62(1H,d,J=8.0Hz),7.50-7.34(4H,m),7.24-7.12(1H,m),7.08(3H,d,J=8.8Hz),6.97(1H,dt,J=1.0 and7.2Hz),3.90(2H,d,J=8.4Hz),3.68(1H,t,J=7.6Hz),3.70-3.45(4H,m),2.89(2H,t,J=8.4Hz),2.40-2.20(4H,m),2.30-2.05 and 2.00-1.75(each 1H,m),0.96(3H,t,J=7.2Hz);TLC:Rf 0.47(乙酸乙酯∶己烷=1∶2)。实施例1  (7)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(乙氧羰基)二氢吲哚-1-基磺酰基)2-甲基苯酯
Figure A9612198401411
NMR(CDCl3):δ7.7-7.5(m,3H),7.2-6.9(m,6H),6.8-6.4(m,2H),4.71(q,J=5.2Hz,1H),4.23(q,J=7.2Hz,2H),3.57(t,J=7.6Hz,1H),3.4-3.0(m,6H),2 4-1.8(m,9H),1.29(t,J=7.2Hz,3H),1.0-0.9(m,3H);TLC:Rf 0.63(己烷∶乙酸乙酯=2∶1)。实施例1  (8)2RS-(4-(吡咯烷-1-基)苯基丁酸4-(2-(乙氧羰基)二氢吲哚-1-基磺酰基)苯酯
NMR(CDCl3):δ7.77(2H, d,J=8.5Hz),7.53(1 H,d,J=8.0Hz),7.24-6.93(7H,m),6,52(2H,d,J=8.5Hz),4.71(1H,dd,J=10.0,5.5Hz),4.24(2H,q,J=7.0Hz),3.54(1H,t,J=8.0Hz),3.32-3.22(4H,m),3.22(1H,dd,J=10.0,16.0Hz),3.06(1H,dd,J=16.0,5.5Hz),2.05-1.90(4H,m),2.25-1.70(2H,m),1.29(3H,t,J=7.0Hz),0.95(3H,t,J=7.5Hz);TLC:Rf 0.57(己烷∶乙酸乙酯=1∶1)。实施例1  (9)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N,N-二甲基氨基羰基甲氧羰基)二氢吲哚-1-基磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.7-7.5(m,3H),7.2-6.9(m,6H),6.54(d,J=8.6Hz,2H),4.85(d,J=14.5Hz,1H),4.82(dd,J=1.0,10.8Hz,1H),4.70(d,J=14.5Hz,1 H),3.58(t,J=7,7Hz,1H),3.65-3.50(m,1H),3.45(dd,J=10.8,16.1Hz,1H),3.4-3.2(m,4H),2.96(s,3H),2.94(s,3H),2.3-1.8(m,6H),1.97(s,3H),0.96(t,J=7.4Hz,3H);TLC:Rf 0.52(氯仿∶乙酸乙酯=1∶1)。实施例1  (10)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-苄氧氨甲酰基)二氢吲哚-1-基磺酰基)苯酯
NMR(CDCl3):δ9.22(1H,s),7.60(1H,d,J=8.0Hz),7.51(2H,d,J=9.0Hz),7.29(5H,s),7.17-7.00(8H,m),6.52(2H,d,J=9.0Hz),4.88(2H,s),4.60(1H,dd,J=10.0Hz,1.5Hz),3.53(1H,t,J=7.0Hz),3.26(5H,t-like,J=6.0Hz),2.74(1H,dd,J=16.0Hz,10.0Hz),2.20-1.77(2H,m),2.03-1.98(4H,m),0.92(3H,t,J=7.0Hz);TLC:Rf 0.44(己烷∶乙酸乙酯=1∶1)。实施例1  (11)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-硝基二氢吲哚-1-基磺酰基)-2-甲基苯酯
NMR(CDCl3):δ8.10(dd,J=2.4,8.8Hz,1H),7.96(s,1H),7.7-7.6(m,3H),7.1 8(d,J=8.4Hz,2H),7.05(d,J=8.0Hz,1H),6.52(d,J=8.4Hz,2H),4.01(t,J=8.6Hz,2H),3.58(t,J=7.8Hz,1H),3.3-3.2(m,4H),3.08(t,J=8.6Hz,2H),2.3-1.8(m,2H),2.00(S,3H),2.1-1.9(m,4H),0.96(t,J=7.4Hz,3H);TLC:Rf 0.33(己烷∶乙酸乙酯=3∶1)。实施例1  (12)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-氨基二氢吲哚-1-基磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.6-7.4(m,3H),7.20(d,J=8.7Hz,2H),6.94(d,J=8.4Hz,1H),6.53(d,J=8.7Hz,2H),6.6-6.4(m,2H),3.83(t,J=8.2Hz,2H),3.58(t,J=7.7Hz,1H),3.4-3.2(m,4H),2.64(t,J=8.2Hz,2H),2.3-1.8(m,6H),1.95(s,3H),0.97(t,J=7.4Hz,3H);TLC:Rf 0.59(己烷∶乙酸乙酯=1∶1)。实施例1  (13)2RS- (吡咯烷-1-基)苯基)丁酸4-(7-硝基二氢吲哚-1-基磺酰基)-2-甲基苯酯
Figure A9612198401451
NMR(CDCl3):δ 8.38(d,J=2.2Hz,1H),7.85(dd,J=2.0,8.4Hz,1H),7.8-7.6(m,2H),7.2-7.1(m,1H),7.18(d,J=8.6Hz,2H),7.03(d,J=8.2Hz,1H),6.52(d,J=8.6Hz,2H),3.99(t,J=8.6Hz,2H),3.58(t,J=7.6Hz,1H),3.3-3.2(m,4H),3.05(t,J=8.6Hz,2H),2.3-1.7(m,9H),0.96(t,J=7.4Hz,3H);TLC:Rf 0.49(己烷∶乙酸乙酯=1∶1)。实施例1  (14)2RS-(4-吡咯烷-1-基)苯基)丁酸4-(7-氨基二氢吲哚-1-基磺酰基)-2-甲基苯酯
NMR(CDCl3)δ7.6-7.5(m,2H),7.15(d,J=8.6Hz,2H),7.0-6.9(m,2H),6 82(d,J=8.0Hz,1H),6.52(d,J=8.6Hz,2H),6.29(dd,J=2.0,8.0Hz,1H),3.84(t,J=8.0Hz,2H),3.58(t,J=7.6Hz,1H),3.4-3.2(m,4H),2.76(t,J=7.6Hz,2H),2.3-1.8(m,9H),0.97(t,J=7.4Hz,3H);TLC:Rf 0.40(己烷∶乙酸乙酯=2∶1)。实施例1  (15)2RS-(4-吡咯烷-1-基)苯基)丁酸4-(苯并咪唑-1-基磺酰基)-2-甲基苯酯
Figure A9612198401471
NMR(CDCl3):δ8.35(1H,s),7.79(4H,m),7.35(2H,m),7.17(2H,d,J=8.8Hz),7.08(1H,d,J=9.4Hz),6.52(2H,d,J=8.8Hz),3.57(1H,t,J=7.8Hz),3.26(4H,m),2.10(1H,m),2.00(3H,s),1.97(4H,m),1.88(1 H,m),0.95(3H,t,J=7.4Hz);TLC:Rf 0.49(己烷∶乙酸乙酯=2∶1)。实施例1  (16)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(吗啉-4-基磺酰基)苯酯
Figure A9612198401472
NMR(DMSO-d6):δ7.75(2H,d,J=7Hz),7.27(2H,d,J=7Hz),7.16(2H,d,J=7Hz),6.52(2H,d,J=7Hz),3.67(1H,t,J=7Hz),3.61(4H,t-like),3.20(4H,t-like),2.83(4H,t-like),2.04(1H,m),1.94(4H,t-like),1.79(1H,m),0.88(3H,t,J=7Hz);TLC:Rf 0.54(己烷∶乙酸乙酯=1∶1)。实施例1  (17)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-氮杂-7-氧代-双环[3.2.1]辛烷-6-基磺酰基)苯酯·盐酸盐
Figure A9612198401481
NMR(CDCl3):δ8.19(2H,d,J=9Hz),7.38(2H,d,J=9Hz),7.19(4H,d,J=9Hz),4.65-4.55(1H,m),3.68(1H,t,J=7Hz),3.61-3.37(4H,m),2.59-2.49(1H,m),2.35-1.46(12H,m),1.35-1.10(2H,m),0.99(3H,t,J=7Hz);TLC:Rf 0.17(乙酸乙酯∶己烷=1∶3)。实施例1   (18)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-苄基哌嗪-1-基磺酰基)苯酯·二盐酸盐
Figure A9612198401482
NMR(CD3OD):δ7.83(2H,d,J=8.6Hz),7.75-7.40(9H,m),7.29(2H,d,J=8.6Hz),4.35(2H,s),4.00-3.62(7H,m),3.60-3.40(2H,m),3.30-3.10(2H,m),2.98-2.72(2H,m),2.38-2.10(5H,m),2.04-1.80(1H,m),0.99(3H,t,J=7.4Hz);TLC:Rf 0.40(乙酸乙酯∶己烷=3∶7)。实施例1  (19)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-(2-羟乙基)哌啶-1-基磺酰基)苯酯
Figure A9612198401491
NMR(CDCl3):δ7.71(2H,d,J=9.0Hz),7.72(2H,d,J=8.7Hz),7.15(2H,d,J=9.0Hz),6.55(2H,d,J=8.7Hz),3.74(2H,d,J=10.2Hz),3.63(2H,t,J=6.0Hz),3.58(1H,t,J=8.0Hz),3.36-3.22(4H,m),2.35-1.78(8H,m),1.72(2H,d,J=10.0Hz),1.54-1.20(5H,m),0.98(3H,t,J=7.4Hz);TLC:Rf 0.52(氯仿∶甲醇=19∶1)。实施例1  (20)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羟甲基哌啶-1-基磺酰基)苯酯·盐酸盐
Figure A9612198401501
NMR(DMSO-d6):δ7.85(2H,d,J=9Hz),7.27(2H,d,J=9Hz),7.22(2H,d,J=9Hz),6.83(2H,d,J=9Hz),3.93-3.80(1H,m),3.75(1H,t,J=7Hz),3.69-3.45(2H,m),3.45-3.20(5H,m),3.06-2.88(1H,m),2.21-1.80(5H,m),1.80-1.64(2H,m),1.55-1.30(3H,m),1.30-0.99(2H,m),0.90(3H,t,J=7Hz);TLC:Rf 0.46(乙酸乙酯∶己烷=1∶1)。实施例1  (21)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-(N,N-二甲基氨基)哌啶-1-基磺酰基)苯酯
NMR(CDCl3):δ7.71(2H,d,J=8.7Hz),7.20(2H,d,J=8.8Hz),7.16(2H,d,J=8.7Hz),6.54(2H,d,J=8.8Hz),3.75(2H,d,J=13.7Hz),3.58(1H,t,J=7.7Hz),3.29(4H,t,J=6.6Hz),2.36-1.53(19H,m),0.98(3H,t,J=7.4Hz);TLC:Rf 0.25(己烷∶乙酸乙酯=2∶1)。实施例1  (22)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-4-(嘧啶-2-基)哌嗪-1-基磺酰基)苯酯
Figure A9612198401512
NMR(CDCl3):δ8.26(2H,d,J=8.8Hz),7.72(2H,d,J=8.7Hz),7.22-7.12(4H,m),6.56-6.47(3H,m),3.93(4H,t,J=5.2Hz),3.57(1H,t,J=7.7Hz),3.31-3.25(4H,m),3.04(4H,t,J=5.1Hz),2.25-1.65(6H,m),0.97(3H,t,J=7.3Hz);TLC:Rf 0.43(己烷∶乙酸乙酯=1∶1)。实施例1  (23)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基磺酰基)苯酯
Figure A9612198401521
NMR(CDCl3):δ7.72(2H,d,J=8.7Hz),7.24-7.15(4H,m),6.56(2H,d,J=8.7Hz),3.89(4H,s),3.59(1H,t,J=7.7Hz),3.29(4H,t,J=6.6Hz),3.14(4H,t,J=5.7Hz),2.30-1.61(10H,m),0.98(3H,t,J=7.4Hz);TLC:Rf 0.48(己烷∶乙酸乙酯=1∶1)。实施例1  (24)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(3-氮杂双环[3.2.2]壬烷-3-基磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ7.73(2H,d,J=8.6Hz),7.53(2H,d,J=8.6Hz),7.45(2H,d,J=8.6Hz),7.15(2H,d,J=8.8Hz),3.72(1H,t,J=7.6Hz),3.75-3.50(4H,m),3.22(4H,d,J=4.2Hz),2.40-2.20(4H,m),2.40-1.75(2H,m),2.10-2.00(2H,m),1.80-1.50(8H,m),0.99(3H,t,J=7.4Hz);TLC:Rf 0.57(乙酸乙酯∶己烷=1∶3)。实施例1  (25)2RS(4-(吡咯烷-1-基)苯基)丁酸4-(1,3,3-三甲基-6-氮杂双环[3.2.1]辛烷-6-基磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ7.81(2H,d,J=8.8Hz),7.40(2H,d,J=8.4Hz),7.36-7.18(2H,brs),7.15(2H,d,J=8.8Hz),4.08(1H,t-like),3.69(1H,t,J=7.8Hz),3.64-3.38(4H,m),3.32(1H,d,J=9.6Hz),2.76(1H,dd,J=9.6 and 1.4Hz),2.36-2.08(5H,m),2.02-1.76(2H,m),1.52(2H,d,J=1 4.4Hz),1.34(2H,d,J=12.4Hz),1.22(3H,s),1.16-1.02(1H,m),0.99(3H,t,J=7.4Hz),0.94(3H,s),0.92(3H,s);TLC:Rf 0.54(乙酸乙酯∶己烷=1∶3)实施例1  (26)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代哌啶-1-基磺酰基)苯酯·盐酸盐
Figure A9612198401541
NMR(CDCl3):δ8.03(2H,d,J=9.0Hz),7.65(2H,d,J=8.6Hz),7.48(2H,d,J=8.6Hz),7.17(2H,d,J=9.0Hz),3.89(2H,t,J=5.8Hz),3.74(1H,t,J=7.8Hz),3.80-3.50(4H,m),2.42(2H,t,J=6.6Hz),2.50-2.25(4H,m),2.40-1.70(2H,m),2.00-1.70(4H,m),0.99(3H,t,J=7.4Hz);TLC:Rf 0.83(乙酸∶甲醇∶氯仿=1∶2∶40)实施例1  (27)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代-4S-苄基四氢噁唑-3-基磺酰基)苯酯·盐酸盐
Figure A9612198401551
NMR(CDCl3):δ8.13(2H,d,J=8.8Hz),7.64(2H,d,J=8.8Hz),7.48(2H,d,J=8.8Hz),7.23(2H,d,J=8.8Hz),7.40-7.16(5H,m),4.75-4.58(1H,m),4.24-4.05(2H,m),3.76(1H,t,J=7.6Hz),3.85-3.50(4H,brs),3.50(1H,dd,J=13.2,38Hz),2.83(1H,dd,J=13.2,10.2Hz),2.44-2.26(4H,m).2.34-2.10 and 2.10-1.76(each 1H,m),0.99(3H,t,J=7.4Hz);TLC:Rf 0.51(乙酸乙酯∶己烷=1∶2 )实施例1  (28)2RS-(4-吡咯烷-1-基)苯基)丁酸4-(2-氧代-4S-异丙基全氢噁唑-3-基磺酰基)苯酯·盐酸盐
Figure A9612198401552
NMR(CDCl3):δ8.10(2H,d,J=9.0Hz),7.63(2H,d,J=8.6Hz),7.48(2H,d,J=8.6Hz),7.22(2H,d,J=9.0Hz),4.43(1H.dt,J=8.2,3.0Hz),4.29(1H,t,J=8.8Hz),4.16(1H,dd,J=8.8,3.0Hz),3.75(1H,t,J=7.6Hz),3.90-3.45(4H,brs),2.56-1.76(7H,m),0.99(3H,t,J=7.2Hz),0.93(3H,d,J=6.8Hz),0.75(3H,d,J=6.8Hz);TLC:Rf 0.62(乙酸乙酯∶己烷=1∶1)实施例1  (29)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代-4S-甲基-5S-苯基全氢噁唑-3-基磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ8.13(2H,d,J=8.8Hz),7.72(2H,d,J=8.8Hz),7.51(2H,d,J=8.8Hz),7.46-7.34(3H,m),7.23(2H,d,J=8.8Hz),7.30-7.20(2H,m),5.71(1H,d,J=7.2Hz),4.78(1H,dq,J=7.2Hz),3.77(1H,t,J=7.2Hz),3.90-3.50(4H,brs),2.50-2.25(4H,brs),2.40-1.80(2H,m),1.00(3H,t,J=7.2Hz),0.97(3H,d,J=7.2Hz);TLC:Rf 0.66(乙酸乙酯∶己烷=1∶2)实施例1  (30)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(1RS-氧代-4S-甲氧羰基全氢噻唑-3-基磺酰基)苯酯
NMR(CDCl3):δ7.87(2H,d,J=9.0Hz),7.21(2H,d,J=9.0Hz),7.19(2H,d,J=9.0Hz),6.55(2H,d,J=9.0Hz),5.28-5.16(2H,m),4.09-4.01(1H,m),3.69-3.44(5H,m),3.33-3.26(4H,m),3.08-2.97(1H,m),2.24-1.80(6H,m),0.98(3H,t,J=7.4Hz);TLC:Rf 0.50(氯仿∶甲醇∶乙酸=40∶2∶1)实施例1  (31)2RS-(4-(吡咯烷-1-基)苯基)丁酸-4(吗啉-4-基磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.56-7.51(2H,m),7.26-7.21(2H,m),7.10(1H,d,J=8Hz),6.55(2H,d,J=8Hz),3.75-3.71(4H,m),3.62(1H,t,J=8Hz),3.32-3.26(4H,m),3.01-2.96(4H,m),2.37-1.73(2H,m),2.06(3H,s),2.04-1.96(4H,m),1.00(3H,t,J=8Hz);TLC:Rf 0.27(己烷∶乙酸乙酯=3∶1)实施例1  (32)2RS-(4-(吡啶烷-1-基)苯基)丁酸4-(咪唑-1-基磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.99(1H,m),7.75(1H,s),7.72(1H,m),7.27-7.08(5H,m),6.54(2H,d,J=8.8Hz),3.60(1H,t,J=7.6Hz),3.28(4H,m),2.14(1H,m),2.04(3H,s),2.01(4H,m),1.91(1H,m),0.97(3H,t,J=7.4Hz);TLC:Rf 0.36(己烷∶乙酸乙酯=2∶1)。实施例1  (33)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯酯·二盐酸盐
Figure A9612198401591
NMR(CD3OD):δ7.80-7.56(6H,m),7.18(1H,d,J=8.2Hz),4.00(1H,t,J=7.6Hz),3.90-3.72(4H,m),3.30(8H,s-like),2.43-2.15(5H,m),2.06(3H,s),2.15-1.84(1H,m),1.00(3H,t,J=7.2Hz);TLC:Rf 0.53(氯仿∶甲醇∶乙酸=15∶2∶1)实施例1  (34)2RS-(4-硝基苯基)丁酸4-(吗啉-4-基磺酰基)苯酯
Figure A9612198401592
NMR(CDCl3):δ8.26(2H,d,J=8Hz),7.77(2H,d,J=8Hz),7.59(2H,d,J=8Hz),7,20(2H,d,J=8Hz),3.86(1H,t,J=7Hz),3.80-3.68(4H,m),3.06-2.94(4H,m),2.30(1H,ddq,J=14Hz,7Hz,7Hz),1.97(1H,ddq,J=14Hz,7Hz,7Hz),1.03(3H,t,J=7Hz)TLC:Rf 0.16(己烷∶乙酸乙酯=7∶3)。实施例1  (35)1-(4-硝基苯基)环丁烷羧酸4-(吗啉-4-基磺酰基)苯酯
NMR(CDCl3):δ8.26(2H,d,J=8Hz),7.77(2H,d,J=8Hz),7.56(2H,d,J=8Hz),7.16(2H,d,J=8Hz),3.79-3.66(4H,m),3.15-2.91(6H,m),2.80-2.60(2H,m),2.39-1.91(2H,m);TLC:Rf 0.16(己烷∶乙酸乙酯=7∶3)实施例1  (36)2-(4-甲氧基苯基)-2-乙基丁酸4-(6-氮杂-7-氧代双环[3.2.1]辛烷-6-基磺酰基)苯酯
Figure A9612198401611
NMR(CDCl3):δ8.08(2H,d,J=8.8Hz),7.27(2H,d,J=8.8Hz),7.11(2H,d,J=8.8Hz),6.91(2H,d,J=8.8Hz),4.59(1H,brt,J=4.8Hz),3.82(3H,s),2.53(1H,brs),2.32-1.15(12H,m),0.84(6H,t.J=7.4Hz);TLC:Rf 0.85(乙酸∶甲醇∶氯仿=1∶2∶40)实施例1  (37)2RS-(4-甲基苯基)丁酸4-(吗啉-4-基磺酰基)-2-甲基苯酯
Figure A9612198401612
NMR(CDCl3):δ7.57-7.52(2H,m),7.30-7.08(5H,m),3.75-3.67(5H,m),3.01-2.96(4H,m),2.36(3H,s),2.32-2.13 and 2.03-1.82(each 1H,m),2.02(3H,s),1.00(3H,t,J=7Hz);TLC:Rf 0.30(己烷∶乙酸乙酯=3∶1)实施例(38)2RS-苯基丁酸4-(咪唑-1-基磺酰基)苯酯
Figure A9612198401621
NMR(CDCl3):δ7.99(1H,s),7.97-7.86(2H,m),7.40-7.28(5H,m),7.28-7.25(1H,m),7.25-7.15(2H,m),7.13-7.05(1H,m),3.68(1H,t,J=7Hz),2.34-2.05(1H,m),2.05-1.98(1H,m),0.96(3H,t,J=7Hz);TLC:Rf 0.29(己烷∶乙酸乙酯=6∶4)实施例1  (39)2RS-苯基丁酸4-(吗啉-4-基磺酰基)苯酯
Figure A9612198401631
NMR(CDCl3):δ7.78-7.67(2H,m),7.43-7.24(5H,m),7.24-7.15(2H,m),3.78-3.65(5H,m),3.03-2.93(4H,m),2.36-2.11(1H,m),2.05-1.80(1H,m),0.99(3H,t,J=7Hz);TLC:Rf 0.26(己烷∶乙酸乙酯=2∶1)实施例1  (40)2RS-(4-(吡咯烷-1-基)苯基)丁酸-4(N-1RS-(乙氧羰基)-2-(吗啉-4-基)乙基氨磺酰基)苯酯
NMR(CDCl3):δ7.84(2H,d,J=8.6Hz),7.20(2H,d,J=8.6Hz),7.12(2H,d,J=8.6Hz),6.55(2H,d,J=8.6Hz),4.01(3H,m),3.57(5H,m),3.29(4H,t,J=6.4Hz),2.63(2H,m),2.36(4H,m),2.14(1H,m),2.01(4H,m),1.89(1H,m),1.17(3H,t,J=7.0Hz),0.97(3H,t,J=7.4Hz);TLC:Rf 0.34(己烷∶乙酸乙酯=1∶1)实施例1  (41)2RS-(4-硝基苯基)丁酸4-(N-(RS-(乙氧羰基)-2-(吗啉-4-基)乙基氨磺酰基)苯酯
Figure A9612198401641
NMR(CDCl3):δ8.26(2H,d,J=8.8Hz),7.89(2H,d,J=8.6Hz),7.57(2H,d,J=8.8Hz),7.13(2H,d,J=8.6Hz),4.03(2H,q,J=7.2Hz),3.96(1H,t,J=7.0Hz),3.84(1H,t,J=7.0Hz),3.58(4H,m),2.68(1H,dd,J=13.1,7.0Hz),2.61(1H,dd,J=13.1,7.0Hz),2.36(4H,m),2.82(1H,m),1.95(1H,dq,J=13.6,7.2Hz),1.17(3H,t,J=7.2Hz),1.02(3H,t,J=7.2Hz);TLC:Rf 0.45(乙酸乙酯)实施例1  (42)1-(4-硝基苯基)环丁烷羧酸4-(N-1RS-(乙氧羰基)-2-(吗啉-4-基)乙基氨磺酰)苯酯
NMR(CDCl3):δ8.26(2H,d,J=8.8Hz),7.86(2H,d,J=8.8Hz),7.55(2H,d,J=8.8Hz),7.09(2H,d,J=8.8Hz),4.03(2H,q,J=7.2Hz),3.95(1H,t,J=6.2Hz),3.57(4H,t,J=5.2Hz),3.05(2H,m),2.67(2H,m),2.66(1H,dd,J=12.6,6.2Hz),2.60(1H,dd,J=12.6,6.2Hz),2.35(4H,t,J=5.2Hz),2.23(1H,m),2.04(1H,m),1.17(3H,t,J=7.2Hz);TLC:Rf 0.40(氯仿∶甲醇∶水=9∶1∶0.1)实施例1  (43)2RS-苯基-2-甲氧乙酸4-(N-1RS-(乙氧羰基)-2-(吗啉-4-基)乙基氨磺酰基)苯酯
Figure A9612198401652
NMR(CDCl3):δ7.86(2H,d,J=8.8Hz),7.52(2H,m),7.42(3H,m),7.12(2H,d,J=8.8Hz),5.00(1H,s),4.01(2H,q,J=7.0Hz),3.94(1H,t,J=6.6Hz),3.57(4H,t,J=5.2Hz),3.49(3H,s),2.66(1H,dd,J=12.8,6.6Hz),2.60(1H,dd,J=12.8,6.6Hz),2.34(4H,t,J=5.2Hz),1.16(3H,t,J=7.0Hz);TLC:Rf 0.26(己烷∶乙酸乙酯=1∶1)实施例1  (44)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄氧羰基氨磺酰基)苯酯·盐酸盐
Figure A9612198401661
NMR(CDCl3):δ8.3-8.0(1H,brs),8.00(2H,d,J=8.8Hz),7.56(2H,d-like),7.46(2H,d-like),7.38-7.22(5H,m),7.15(2H,d,J=8.8Hz),5.07(2H,s),3.74(1H,t,J=7.8Hz),3.8-3.5(4H,m),2.4-2.2(4H,m),2.40-2.10 and 2.10-1.80(each 1H,m),1.00(3H,t,J=7.2Hz);TLC:Rf 0.50(乙酸∶乙酸乙酯∶己烷=1∶8∶16)实施例1  (45)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-苯基-2RS-甲基丁基氨磺酰)苯酯·盐酸盐
NMR(CDCl3):δ7.80-7.57(2H,m),7.57-7.32(4H,m),7.12-6.93(3H,m),6.93-6.70(4H,m),5.38(1H,m),4.19-3.99(1H,m),3.90-3.30(5H,m),2.50-2.04(5H,m),1.96-1.40(3H,m),1.28-0.57(10H,m);TLC:Rf 0.24(乙酸乙酯∶己烷=1∶4)实施例1  (46)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-氨磺酰苯酯·盐酸盐
Figure A9612198401672
NMR(CD3OD):δ7.88(2H,d,J=8.6Hz),7.18(2H,d,J=8.8Hz),7.11(2H,d,J=8.8Hz),6.57(2H,d,J=8.6Hz),3.6 1(1H,t,J=7.6Hz),3.34-3.19(4H,m),2 26-2.00 and 2.00-1.70(each 1H,m),2.07-1.96(4H,m),0.96(3H,t,J=7.4Hz);TLC:Rf 0.22(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例1  (47)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-甲氧乙基氨磺酰基)苯酯
Figure A9612198401681
NMR(CDCl3):δ7.83(2H,d,J=9.0Hz),7.22(2H,d,J=8.6Hz),7.14(2H,d,J=9.0Hz),6.56(2h,d,J=8.6Hz),4.85(1H,b r),3.59(1H,t,J=7.7Hz),3.42-3 20(9H,m),3.11(21,m),2.28-1.70(6H,m),0.98(3H,t,J=7.6Hz);TLC:Rf 0.55(己烷∶乙酸乙酯=2∶3)。实施例1  (48)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-甲氧乙基-N-苄基氨磺酰基)苯酯
Figure A9612198401691
NMR(CDCl3):δ7.82(2H,d,J=6.8Hz),7.29(5H,s),7.19(2H,d,J=8.6Hz),7.13(2H,d,J=6.8Hz),6.56(2H,d,J=8.6Hz),4.40(2H,s),3.60(1H,t,/J=7.4Hz),3.2-3.4(8H,m),3.10(3H,s),1.8-2.3(6H,m),0.99(3H,t,J=7.3Hz);TLC:Rf 0.40(己烷∶乙酸乙酯=3∶1)。实施例1  (49)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-叔丁氧基氨磺酰基)苯酯·盐酸盐
Figure A9612198401701
NMR(CDCl3):δ7.88(2H,d,J=8.8Hz),7.24-7.15(4H,m),6.56(2H,d,J=8.2Hz),6.44(1H,s),3.59(1H,t,J=7.2Hz),3.33-3.26(4H,m),2.45-1.80(6H,m),1.21(9H.s),0.98(3H,t,J=7.2Hz);TLC:Rf 0.40(己烷∶乙酸乙酯∶乙酸=5∶2∶0.1)。实施例1  (50)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-4-羟基丁基氨磺酰基)苯酯
Figure A9612198401702
NMR(CDCl3):δ7.82(2H,d,J=8.7Hz).7.22(2H,d,J=8.6Hz),7.13(2H,d,J=8.7Hz),6.56(2H,d,J=8.6Hz),5.00(1H,t,J=5.2Hz),3.70-3.48(3H,m),3.40-3.12(4H,m),3.06-2.86(2H,m),2.30-1.76(6H,m),1.78-1.62(1H,brs),1.60-1.40(4H,m),0.97(3H,t,J=7.4Hz);TLC:Rf 0.48(乙酸乙酯)。实施例1  (51)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-羟甲基-2-甲基丙基氨磺酰基)苯酯
NMR(CDCl3):δ7.85(2H,d,J=8.4Hz),7.21(2H,d,J=8.6Hz),7.12(2H,d,J=8.4Hz),6.55(2H,d,J=8.6Hz),5 06(1H,d,J=8.4Hz),3.58(1H,t,J=5.8Hz),3.56-3.48(2H,m),3.36-3.22(4H,m),3.10-2.90(1H,m),2.23-1.65(8H,m),0.97(3H,t,J=7.2Hz),0.78(6H,d,J=6.8Hz);TLC:Rf 0.25(乙酸乙酯∶己烷=2∶3)。实施例1  (52)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2RS,3-二羟基丙基氨磺酰基)苯酯
Figure A9612198401721
NMR(CDCl3):δ7.80(2H,d,J=8.6Hz),7.20(2H,d,J=8.8Hz),7.11(2H,d,J=8.6Hz),6.54(2H,d,J=8.8Hz),5.63(1H,t,J=6.3Hz),3.80-3.64(1H,m),3.62-3.41(3H,m),3.35-3.20(4H,m),3.10-2.80(3H,m),2.30-1.70(7H,m),0.96(3H,t,J=7.4Hz);TLC:Rf 0.28(乙酸乙酯∶己烷=4∶1)。实施例1  (53)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄氧氨磺酰基)苯酯·盐酸盐
Figure A9612198401731
NMR(CDCl3):δ7.87(2H,d,J=8.8Hz),7.32-7.12(9H,m),6.93(1H,s),6.54(2H,d,J=8.8Hz),4.94(2H,s),3.57(1H,t,J=7.8Hz),3.31-3.25(4H,m),2.25-1.80(6H,m),0.968(3H,t,J=7.4Hz);TLC:Rf 0.55(己烷∶乙酸乙酯∶乙酸=5∶2∶0.2)。实施例1  (54)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(N’,N’ -二甲氨基)氨磺酰基)苯酯
Figure A9612198401732
NMR(CDCl3):δ7.92(2H,d,J=8.7Hz),7.23(2H,d,J=8.7Hz),7.15(2H,d,J=8.7Hz),6.55(2H,d,J=8.7Hz),3.58(1H,d,J=7.7Hz),3.29(4H,t,J=6.6Hz),2.37(6H,s),2.25-1.75(6H,m),0.98(3H,t,J=7.4Hz);TLC:Rf 0.45(己烷∶乙酸乙酯=1∶1)。实施例1  (55)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(N’-甲基氨基)氨磺酰基)苯酯
NMR(CDCl3):δ7.82(2H,d,J=8.7Hz),7.23(4H,m),6.56(2H,d,J=8.6Hz),3.60(1H,m),3.29(4H,t,J=6.6Hz),2.85(3H,s),2.25-1.80(6H,m),0.99(3H,t,J=7.4Hz);TLC:Rf 0.35(己烷∶乙酸乙酯=1∶1)。实施例1  (56)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(氨基甲酰甲基)氨磺酰基)苯酯
Figure A9612198401751
NMR(CDCl3):δ7.78(2H,d,J=8.7Hz),7.20(2H,d,J=8.6Hz),7.11(2H,d,J=8.7Hz),6.54(2H,d,J=8.6Hz),6.42-6.30(1H,brs),6.20-5.96(2H,m),3.58(1H,t,J=7.8Hz),3.50(2H,s),3.38-3.18(4H,m),2.26-1.74(6H,m),0.96(3H,t,J=7.3Hz);TLC:Rf 0.41(氯仿∶甲醇=9∶1)。实施例1  (57)2RS-(4-(吡咯烷-1-基)丁酸4-(N-叔丁基氨磺酰基)苯酯·盐酸盐
Figure A9612198401761
NMR(CDCl3):δ7.89(2H,d,J=8.8Hz),7.63(2H,d,J=8.6Hz),7.48(2H,d,J=8.6Hz),7.12(2H,d,J=8.8Hz),4.83(1H,s),3.74(1H,t,J=7.6Hz),3.80-3.50(4H,m),2.40-2.25(4H,m),2.40-2.10 and 2.05-1.75(each 1H,m),1.22(9H,s),1.00(3H,t,J=7.4Hz);TLC:Rf 0.55(乙酸乙酯∶己烷=1∶2)。实施例1  (58)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-金刚烷-1-基氨磺酰基)苯酯·盐酸盐
Figure A9612198401762
NMR(CDCl3)δ7.89(2H,d,J=8.6Hz),7.60-7.45(4H,m),7.12(2H,d,J=8.6Hz),4.64(1H,brs,NH),3.80-3.55(5H,m),2.40-1.48(21H,m),0.999(3H,t,J=7.2Hz);TLC:Rf 0.44(己烷∶乙酸乙酯∶乙酸=5∶2∶0.2)。实施例1  (59)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-胍基磺酰基-2-甲基苯酯·二盐酸盐
Figure A9612198401771
NMR(DMSO-d6):δ7.66-7.53(2H,m),7.28(2H,d,J=8.0Hz),7.04(1H,d,J=8.0Hz),7.10-6.50(6H,m),3.76(1H,t,J=7.5Hz),3.50-3.20(4H,m),2.20-1.70(2H,m),2.10-1.90(4H,m),1.93(3H,s),0.91(3H,t,J=7.5Hz);TLC:Rf 0.36(水∶甲醇∶氯仿=1∶10∶90)。实施例1  (60)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2RS,3-二羟基丙基氨磺酰基)-2-甲基苯酯
NMR(DMSO-d6):δ7.70-7.60(2H,m),7.47(1H,t,J=6.0Hz),7.18(2H,d,J=8.5Hz),7.13(1H,d,J=8.5Hz),6.55(2H,d,J=8.5Hz),3.70(1H,t,J=7.5Hz),3.55-3.35(6H,m),2.94-2.78(1 H,m),2.66-2.54(1H,m),2.25-1.60(2H,m),2.05-1.90(4H,m),1.96(3H,s),0.91(3H,t,J=7.5Hz);TLC:Rf 0.29(水∶甲醇∶氯仿=1∶10∶90)。实施例1  (61)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-双(2-(甲氧甲氧基)乙基)氨磺酰基)-2-甲基苯酯
Figure A9612198401791
NMR(CDCl3):δ7.70-7.58(2H,m),7.22(2H,d,J=9Hz),7.03(1H,d,J=8Hz),6 55(2H,d,J=9Hz),4.54(4H,s),3.67(4H,t,J=6Hz),3.60(1H,t,J=7Hz),3.43(4H,t,J=6Hz),3.35-3.20(10H,m),2.30-1.75(9H,m),0.99(3H,t,J=7Hz);TLC:Rf 0.27(己烷∶乙酸乙酯=2∶1)。实施例1  (62)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-双(2-(2-(甲氧甲氧基)乙氧基)乙基)氨磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.68-7.58(2H,m),7.22(2H,d,J=9Hz),7.03(1H,d,J=8Hz),6.55(2H,d,J=9Hz),4.63(4H,s),3.70-3.50(1 3H,m),3.45-3.20(8H,m),3.35(6H,s),2.30-1.75(9H,m),0.99(3H,t,J=7Hz);TLC:Rf 0.20(己烷∶乙酸乙酯=1∶1)。实施例1  (63)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-甲基-N-甲氧基氨磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.68(1H,s),7.66(1H,d,J=8.4Hz),7.22(2H,d,J=8.6Hz),7.11(1H,d,J=8.4Hz),6.55(2H,d,J=8.6Hz),3.78(3H,s),3.62(1H,tJ=7.7Hz),3.28(4H,t,J=6.6Hz),2.76(3H,s),2.3-2.1(1H,m),2.06(3H,s),2.1-1.9(4H,m),2.1-1.8(1H,m),0.99(3H,t,J=7.3Hz):TLC:Rf 0.36(己烷∶乙酸乙酯=4∶1)。实施例1  (64)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄基氨磺酰基)-2-甲基苯酯
Figure A9612198401811
NMR(CDCl3):δ7.66-7.62(2H,m),7.29-7.15(7H,m),7.05(1H,d,J=9.0Hz),6.55(2H,d,J=8.6Hz),4.65(1H,t,J=5.6Hz),4.11(2H,d,J=5.6Hz),3.62(1H,t,J=7.8Hz),3.33-3.26(4H,m),2.27-1.82(6H,m),2.00(3H,s),1.00(3H,t,J=7.4Hz);TLC:Rf 0.86(己烷∶乙酸乙酯=1∶1)。实施例1  (65)2RS-(4-硝基苯基)丁酸4-(N-2-(N’,N’-二甲基氨基)乙基氨磺酰基)苯酯·盐酸盐
NMR(CD3OD):δ8.27(2H,d,J=8.5Hz),7.93(2H,d,J=8.5Hz),7.68(2H,d,J=8.5Hz),7.28(2H,d,J=8.5Hz),4.04(1H,t,J=7.6Hz),3.22(4H,m),2.93(6H,s),2.28(1H,m),1.97(1H,m),1.00(3H,t,J=7.4Hz);TLC:Rf 0.39(氯仿∶甲醇∶水9∶1∶0.1)。实施例1  (66)1-(4-硝基苯基)环丁烷羧酸4-胍基磺酰基苯酯
Figure A9612198401822
NMR(CDCl3):δ8.26(2H,d,J=8.8Hz),7.85(2H,d,J=8.8Hz),7.57(2H,d,J=8.8Hz),7.04(2H.d,J=8.8Hz),6.34(1H,brs),3.14-2.96(2H,m),2.77-2.59(2H,m),2.38-1.90(2H,m);TLC:Rf 0.56(乙酸∶甲醇∶氯仿=1∶5∶25)。实施例1  (67)2RS-(4-硝基苯基)丁酸4-胍基磺酰基苯酯
NMR(DMSO-d6):δ8.27(2H,d,J=8.8Hz),7.78(2H,d,J=8.8Hz),7.71(2H,d,J=8.8Hz),7.19(2H,d,J=8.8Hz).7.0-6.4(4H,brs),4.15(1H,t,J=7.6Hz),2.30-2.05 and 2.05-1.75(each 1H,m),0.92(3H,t,J=7.6Hz);TLC:Rf 0.09(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例1  (68)2RS-(4-甲基苯基)丁酸4-(N-2RS,3-二羟基丙基氨磺酰基)-2-甲基苯酯
Figure A9612198401841
NMR(CDCl3):δ7.67-7.61(2H,m),7.27(2H,d,J=8Hz),7.17(2H,d,J=8Hz),7.04(1H,d,J=8Hz),5.54(1H,br),380-3.46(3H,m),3.42(1H,br),3.70(1H,t,J=8Hz),3.11-2.87(2H,m),2.83(1H,br),2.35(3H,s),2.32-2.11and 2.03-1.79(each 1H,m),1.98(3H,s),0.99(3H,t,J=8Hz);TLC:Rf 0.40(氯仿∶甲醇∶水=9∶1∶0.1)。实施例1  (69)2-(4-甲氧苯基)-2-乙基丁酸4-(N-2-甲氧乙基氨磺酰基)苯酯
Figure A9612198401842
NMR(CDCl3):δ7.83(2H,d,J=8.8Hz),7.27(2H,d,J=8.8Hz),7.08(2H,d,J=9.2Hz),6.90(2H,d,J=8.8Hz),4.92(1H,t,J=6.5Hz),3.82(3H,s),3.38(2H,t,J=5.4Hz),3.25(3H,s),3.11(2H,t,J=6.0Hz),2.28-2.04(4H,m),0.846(6H,t,J=7.4Hz);TLC:Rf 0.16(己烷∶乙酸乙酯=2∶1)。实施例1  (70)2-(4-甲氧苯基)-2-乙基丁酸4-(N-2-(N’,N’-二甲基氨基)乙基氨磺酰基)苯酯·乙酸盐
Figure A9612198401851
NMR(CDCl3):δ7.85(2H,d,J=8.6Hz),7.28(2H,d,J=8.8Hz,),7.09(2H,d,J=8.6Hz),6.92(2H,d,J=8.8Hz),3.83(3H,s),2.53-2.47(4H,m),2.24(6H,s),2.24-2.11(4H,m),0.847(6H,t,J=7.4Hz);TLC:Rf 0.26(氯仿∶甲醇∶水=25∶5∶1)。实施例1  (71)2RS-(4-甲氧苯基)丁酸4-(胍基磺酰基)-2-甲基苯酯·盐酸盐
Figure A9612198401861
NMR(DMSO-d6):δ7.62(1H,s),7.60(1H,d,J=8.0Hz),7.30(2H,d,J=8.5Hz),6.96(1H,d,J=8.0Hz),6.90(2H,d,J=8.5Hz),6.6-6.1(4H,brs),3.80(1H,t,J=7.5Hz),2.3-2.0 and 2.0-1.7(each 1H,m),1.65(3H,s),0.98(3H,t,J=7.5Hz);TLC:Rf 0.60(水∶甲醇∶氯仿=1∶10∶40)。实施例1  (72)2RS-苯基丁酸4-(N,N-二乙基氨磺基)苯酯
NMR(CDCl3):δ7.83-7.73(2H,m),7.40-7.23(5H,m),7.16-7.07(2H,m),3.69(1H,t,J=7Hz),3.20(4H,q,J=7Hz),2.35-1.75(2H,m),1.11(6H,t,J=7Hz),0.98(3H,t,J=7Hz);
TLC:Rf 0.39(己烷∶乙酸乙酯=7∶3)。实施例1  (73)2RS-苯基丁酸4-(N-苄基氨磺酰基)苯酯
Figure A9612198401871
NMR(CDCl3):δ7.89-7.79(2H,m),7.42-7.08(12H,m),4.61(1H,t,J=7Hz),4.13(2H,d,J=7Hz),370(1H,t,J=7Hz),2.36-2.11(1H,m),2.05-1.80(1H,m),0.99(3H,t,J=7Hz);
TLC:Rf 0.41(己烷∶乙酸乙酯=2∶1)。实施例1  (74)2RS-苯基丁酸4-(N-甲基-N-苄基氨磺酰基)苯酯
Figure A9612198401881
NMR(CDCl3):δ7.86-7.76(2H,m),7.43-7.14(12H,m),4.11(2H,s),3.73(1H,t,J=7Hz),2.59(3H,s),2.38-2.13(1H,m),2.06-1.81(1H,m),1.01(3H,t,J=7Hz);
TLC:Rf 0.57(己烷∶乙酸乙酯=2∶1)。实施例1  (75)2RS-苯基丁酸4-(N-2-苯乙基氨磺酰基)苯酯
Figure A9612198401882
NMR(CDCl3):δ7.81-7.71(2H,m),7.43-7.03(12H,m),4.40(1H,t,J=7Hz),3.71(1H,t,J=7Hz),3.21(2H,q,J=7Hz),2.76(2H,t,J=7Hz),2.24(1H,ddq,J=14Hz,7Hz,7Hz),1.93(1H,ddq,J=14Hz,7Hz,7Hz),1.00(3H,t,J=7Hz);
TLC:Rf 0.46(己烷∶乙酸乙酯=3∶2)。实施例1  (76)2RS-苯基丁酸4-(N-甲基-N-2-苯乙基氨磺酰基)苯酯
Figure A9612198401891
NMR(CDCl3):δ7.77-7.68(2H,m),7.41-7.08(12H,m),3.71(1H,t,J=7Hz),3.33-3.18(2H,m),2.92-279(2H,m),2.73(3H,s),2.24(1H,ddq,J=14Hz,7Hz,7Hz),1.92(1H,ddq,J=14Hz,7Hz,7Hz),0.99(3H,t,J=7Hz);
TLC:Rf 0.32(己烷∶乙酸乙酯=3∶2)。实施例1  (77)2RS-苯基丁酸4-(N-1RS-(4-甲基苯基)丁基氨磺酰基)苯酯
Figure A9612198401901
NMR(CDCl3):δ7.55(2H,d,J=8Hz),7.41-7.23(5H,m),6.98-6.78(6H,m),4.81(1H,d,J=7Hz),4.23(1H,q,J=7Hz),3.68(1H,t,J=7Hz),2.35-2.08(1H,m),2.20(3H,s),1.91(1H,ddq,J=14Hz,7Hz,7Hz),1.79-1.52(2H,m),1.38-1.06(2H,m),0.99(3H,t,J=7Hz),0.83(3H,t,J=7Hz);TLC:Rf 0.15(己烷∶乙酸乙酯=4∶1)。实施例1  (78)2RS-(4-(吡咯烷-1-基)苯基丁酸4-(N-2-(吡啶-2-基)乙基氨磺酰基)苯酯·二盐酸盐
Figure A9612198401902
NMR(DMSO-d6):δ8.79(1H,d,J=5.0Hz),8.50(1H,t,J=7.4Hz),8.04(1H,m),7.90(2H,m),7.79(2H,d,J=8.6Hz),7.28(2H,m),7.21(2H,d,J=8.4Hz),6.90(2H,m),3.76(1H,t,J=7.0Hz),3.34(4H,brs),3.23(4H,brs),2.01(5H,m),1.80(1H,m),0.91(3H,t,J=7.0Hz);T L C:R f 0.4 8  (氯仿∶甲醇∶水=9∶1∶0.1)。实施例1  (79)2RS-(4-(吡咯烷-1-基)苯基丁酸4-(N-2-(哌啶-1-基)乙基氨磺酰基)苯酯·二盐酸盐
Figure A9612198401911
NMR(CD3OD):δ7.92(2H,d,J=8.8Hz),7.71(2H,d,J=8.8Hz),7.63(2H,d,J=8.8Hz),7.26(2H,d,J=8.8Hz),3.95(1H,t,J=7.2Hz),3.81(4H,m),3.55(2H,brd,J=12.0Hz),3.24(4H,brs),2.98(2H,brt,J=12.0Hz),2.32(4H,m),1.89(7H,m),1.55(1H,m),0.99(3H,t,J=7.2Hz);/TLC:Rf 0.39(氯仿∶甲醇∶水=9∶1∶0.1)。实施例1  (80)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(四唑-5-基)氨磺酰基)苯酯
NMR(CD3OD):δ7.89(2H,d,J=8.6Hz),7.15(2H,d,J=8.6Hz),7.02(2H,d,J=8.6Hz),6.55(2H,d,J=8.6Hz),3.58(1H,t,J=7.8Hz),3.35-3.15(4H,m),2.20-1.95 and 1.95-1.70(each 1H,m),2.05-1.95(4H,m),0.93(3H,t,J=7.2Hz);
TLC:Rf 0.46(乙酸∶甲醇∶氯仿=1∶5∶25)。实施例1  (81)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(吗啉-4-基)氨磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ7.97(2H,d,J=8.6Hz),7.61(2H,d-like),7.48(2H,d-like),7.16(2H,d,J=8.6Hz),5.99(1H,s),3.74(1H,t,J=7.8Hz),3.76-3.63(4H,m),3.65-3.54(4H,m),2.70-2.58(4H,m),2.42-229(4H,m),2.37-2.10 and2.04-1.77(each 1H,m),1.00(3H,t,J=7.2Hz);TLC:Rf 0.45(甲醇∶氯仿=1∶20)。实施例1  (82)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(吡咯烷-3-基)氨磺酰基)苯酯·二盐酸盐
Figure A9612198401931
NMR(CDCl3)δ7.7-7.5(4H,m),7.42(2H,d,J=8 6Hz),6.96 and 6.92(2H,d,J=8.6Hz),4.35-4.13(1H,m),3.5-2.9(10H,m),2.40-2.25(4H,m),2.20-1.55(4H,m),0.94(3H,t,J=7.2Hz);TLC:Rf 0.35(甲醇∶氯仿=1∶10)。实施例1  (83)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1-苄基哌啶-4-基)氨磺酰基)苯酯
NMR(CDCl3):δ7.82(2H,d,J=9.0Hz),7.36-7.08(5H,m),7.21(2H,d,J=9.0Hz),7.13(2H,d,J=8.8Hz),6.55(2H,d,J=8.8Hz),4.50(1H,d,J=5.7Hz),3.58(1H,t,J=5.0Hz),3.43(2H,s),3.36-3.21(4H,m),3.21-3.02(1H,m),2.78-2.61(2H,m),2.28-1.65(10H,m),1.56-1.34(1H,m),0.97(3H,t,J=7.2Hz);TLC:Rf 0.60(乙酸乙酯∶己烷=9∶1)。实施例1  (84)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(吡啶-2-基)氨磺酰基)苯酯·二盐酸盐
NMR(CDCl3):δ8.26(1H,d,J=6.0Hz),7.96(2H,d,J=8.6Hz),7.83(1H,t,J=8.6Hz),7.72(2H,d,J=8.6Hz),7.55(1H,d,J=8.6Hz),7.48(2H,d,J=8.6Hz),7.12(2H,d,J=8.6Hz),6.95(1H,t,J=6.0Hz),3.74(1H,t,J=7.6Hz),3.80-3.60(4H,m),2.44-2.24(4H,m),2.32-2.02 and 2.02-1.72(each 1H,m),0.97(3H,t,J=7.2Hz);TLC:Rf 0.51(乙酸乙酯∶己烷=2∶1)。实施例1  (85)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(吗啉-4-基)乙基氨磺酰基)苯酯
Figure A9612198401952
NMR(CDCl3):δ7.83(2H,d,J=8.9Hz),7.21(2H,d,J=8.7Hz),7.13(2H,d,J=8.9Hz),6.55(2H,d,J=8.7Hz),6.23-5.06(1H,b rs),3.64-3.52(5H,m),3.36-3.20(4H,m),2.98(2H,t,J=6.0Hz),2.38(2H,t,J=6.0Hz),2.30-2.20(4H,m),2.20-1.70(6H,m),0.97(3H,t,J=7.2Hz);TLC:Rf 0.24(乙酸乙酯∶己烷=7∶3)。实施例1  (86)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(哌嗪-2-基)氨磺酰基)苯酯·三盐酸盐
Figure A9612198401961
NMR(CDCl3):δ8.46(1H,s),8.17(2H,s),8.01(2H,d,J=8.2Hz),7.7-7.4(4H,m),7.14(2H,d,J=8.2Hz),3.9-3.5(5H,m),2.5-2.2(4H,m),2.4-2.1 and2.1-1.8(each 1H,m),0.98(3H,t,J=7.2Hz);TLC:Rf 0.18(己烷∶乙酸乙酯=1∶1)。实施例1  (87)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(咪唑-2-基)氨磺酰基)苯酯
Figure A9612198401971
NMR(CDCl3):δ7.90(2H,d,J=8.8Hz),7.19(4H,d,J=8.8Hz),5.81(1H,d,J=2.0Hz),6.54(1H,d,J=2.0Hz),6.54(2H,d,J=8.8Hz),3.57(1H,t,J=7.8Hz),3.28(4H,t-like),2.30-2.00 and 2.00-1.70(each 1H,m),2.00(4H,t-like),0.96(3H,t,J=7.4Hz);TLC:Rf 0.67(甲醇∶氯仿=1∶10)。实施例1  (88)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(奎宁环3RS-基)氨磺酰基)苯酯
Figure A9612198401981
NMR(CDCl3):δ7.88(2H,d,J=8.8Hz),7.21(2H,d,J=8.8Hz),7.11(2H,d,J=8.8Hz),6,55(2H,d,J=8.8Hz),3.58(1H,t,J=7.6Hz),3.60-3.47(1H,m),3.35-3.20(4H,m),3.30-2.80(6H,m),2.10-1.95(4H,m),2.30-1.40(7H,m),0.98(3H,t,J=7.2Hz);TLC:Rf 0.43(乙酸∶甲醇∶氯仿=1∶5∶25)。实施例1  (89)2RS-(4-吡咯烷-1-基)苯基)丁酸4-(N-(2,2,6,6-四甲基哌啶-4-基)氨磺酰基)苯酯
Figure A9612198401982
NMR(CDCl3+CD3OD):δ7.85(2H,d,J=8.8Hz),7.22(2H,d,J=8.6Hz),7.14(2H,d,J=8.8Hz),6.57(2H,d,J=8.6Hz),3.59(1H,t,J=7.8Hz),3.60-3.42(1H,m),3.35-3.20(4H,m),2.30-1.75(2H,m),2.06-1.96(4H,m),1.63(2H,dd,J=13.2 and 3.8Hz),1.33-1.08(2H,m),1.19(12H,s),0.98(3H,t,J=7.3Hz);TLC:Rf 0.55(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例1  (90)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(奎宁环-3RS-基)氨磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.69(1H,d,J=2Hz),7.66(1H,dd,J=8 and 2Hz),7.30-7.13(2H,m),7.06(1H,d,J=8Hz),6.55(2H,d,J=9Hz),3.62(1H,t,J=8Hz),3.38-3.23(5H,m),3.23-3.05(1H,m),2.90-2.48(5H,m),2.32-2.08(1H,m),2.04(3H,s),2.08-1.03(10H,m),0.99(3H,t,J=7Hz);TLC:Rf 0.43(氯仿∶甲醇∶水=8∶2∶0.2)。实施例1  (91)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(吗啉-4-基)乙基氨磺酰基)-2-甲基苯酯·二盐酸盐
NMR(DMSO-d6):δ11.3-11.1(1H,brs),8.18(1H,brs),7.75(1H,s),7.70(1H,d,J=8.0Hz),7.27(2H,d,J=8.6Hz),7.18(2H,d,J=9.2Hz),4.0-3.7(5H,m),3.4-3.0(12H,m),2.2-2.0(1H,m),2.1-1.9(4H,brs),2.0-1.7(1H,m),1.98(3H,s),0.91(3H,t,J=7.3Hz);TLC:Rf 0.50(氯仿∶甲醇=9∶1)。实施例1  (92)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(哌嗪-4-基)乙基氨磺酰基)-2-甲基苯酯·三盐酸盐
Figure A9612198402011
NMR(DMSO-d6):δ9.6-9.2(2H,br),7.71(1H,s),7.67(1H,d,J=8.0Hz),7.18(2H,d,J=8.4Hz),7.14(1H,d,J=8.0Hz),6.53(2H,d,J=8.4Hz),3.69(1H,t,J=7.3Hz),3.7-2.6(16H,br),2.2-2.0(1H,m),2.0-1.9(4H,brs),1.96(3H,s),1.9-1.7(1H,m),0.90(3H,t,J=7.1Hz);TLC:Rf 0.46(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例1  (93)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(哌啶-4-基)氨磺酰基)-2-甲基苯酯·二盐酸盐
NMR(DMSO-d6):δ9.1-8.7(1H,br),8.00(1H,d,J=7.2Hz),7.71(1H,s),7.68(1H,d,J=8.4Hz),7.26(2H,d,J=8.4Hz),7.15(1H,d,J=8.4Hz),6.79(2H,d,J=8.4Hz),3.76(1H,t,J=7.8Hz),3.4-3.2(4H,brs),3.2-3.0(3H,br),3.0-2.7(2H,br),2.2-1.9(1H,m),1.99(4H,brs),1.97(3H,s),1.9-1.5(5H,m),0.91(3H,t,J=7.3Hz);
TLC:Rf0.46(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例1(94)2RS-(4-硝基苯基)丁酸4-(N-2-(吗啉-4-基)乙基氨磺酰基)苯酯·盐酸盐
Figure A9612198402021
NMR(CD3OD):δ8.27(2H,d,J=8.6Hz),7.92(2H,d,J=9.0Hz),7.67(2H,d,J=8.6Hz),7.27(2H,d,J=9.0Hz),4.03(1H,t,J=7.6Hz),3.90(2H,m),3.50(2H,m),3.28(8H,m),2.28(1H,m),1.99(1H,m),1.00(3H,t,J=7.4Hz);TLC:Rf0.61(氯仿∶甲醇∶水=9∶1∶0.1)。实施例1(95)1-(4-硝基苯基)环丁烷羧酸4-(N-2-(吡啶-2-基)乙基氨磺酰基)苯酯·盐酸盐
NMR(CD3OD):δ8.72(1H,d,J=8.0Hz),8.53(1H,t,J=8.0Hz),8.28(2H,d,J=8.6Hz),7.96(1H,d,J=8.0Hz),7.93(1H,d,J=8.0Hz),7.79(2H,d,J=8.6Hz),7.66(2H,d,J=8.6Hz),7.17(2H,d,J=8.6Hz),3.30(4H,m),3.06(2H,m),2.72(2H,m),2.23(1H,m),2.04(1H,m);
TLC:Rf0.54(氯仿∶甲醇∶水=9∶1∶0.1)。实施例1(96)1-(4-硝基苯基)环丁烷羧酸4-(N-2-(哌啶-1-基)乙基氨磺酰基)苯酯·盐酸盐
Figure A9612198402041
NMR(CD3OD):δ8.28(2H,d,J=8.4Hz),7.90(2H,d,J=8.4Hz),7.66(2H,d,J=8.4Hz),7.23(2H,d,J=8.4Hz),3.50(2H,m),3.30(4H,m),3.06(4H,m),2.73(2H,m),2.22(1H,m),1.99(1H,m),1.87(6H,m);
TLC:Rf0.45(氯仿∶甲醇∶水=9∶1∶0.1)。实施例1(97)1-(4-硝基苯基)环丁烷羧酸4-(N-2-(1-甲基吡咯-2-基)乙基氨磺酰基)苯酯
Figure A9612198402042
NMR(CDCl3):δ8.26(2H,d,J=9.0Hz),7.78(2H,d,J=9.0Hz),7.56(2H,d,J=9.0Hz),7.09(2H,d,J=9.0Hz),6.52(1H,dd,J=2.0,2.4Hz),6.01(1H,dd,J=2.4,2.6Hz),5.80(1H,m),4.64(1H,t,J=6.6Hz),3.42(3H,s),3.16(2H,q,J=6.6Hz),3.05(2H,m),2.74(2H,t,J=6.6Hz),2.66(2H,m),2.25(1H,m),2.03(1H,m);
TLC:Rf0.26(己烷∶乙酸乙酯=2∶1)。实施例1(98)2RS-(4-硝基苯基)丁酸4-(N(四唑-5-基甲基)氨磺酰基)苯酯
NMR(DMSO-d6):δ8.54(1H,t,J=5.8Hz),8.28(2H,d,J=8.8Hz),7.85(2H,d,J=8.8Hz),7.73(2H,d,J=8.8Hz),7.32(2H,d,J=8.8Hz),4.30(2H,d,J=5.8Hz),4.17(1H,t,J=7.6Hz),2.35-2.05 and 2.03-1.75(each 1H,m),0.92(3H,t,J=7.2Hz);TLC:Rf0.45(乙酸∶甲醇∶氯仿=1∶5∶25)。实施例1(99)1-(4-硝基苯基)环丁烷羧酸4-N-(四唑-5-基甲基)氨磺酰基)苯酯
NMR(CD3OD):δ8.28(2H,d,J=8.8Hz),7.85(2H,d,J=8.8Hz),7.67(2H,d,J=8.8Hz),7.19(2H,d,J=8.8Hz),4.37(2H,s),3.16-2.96(2H,m),2.82-2.62(2H,q-like),2.37-2.12 and 2.12-1.90(each 1H,m);
TLC:Rf0.11(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例1(100)1-(4-硝基苯基)环丁烷羧酸4-(N-(四唑-5-基)氨磺酰基)苯酯
NMR(DMSO-d6):δ8.26(2H,d,J=8.8Hz),7.84(2H,d,J=8.8Hz),7.69(2H,d,J=8.8Hz),7.12(2H,d,J=8.8Hz),3.08-2.88(2H,m),2.74-2.54(2H,q-like).2.24-2.04 and 2.04-1.84(each 1H,m);
TLC:Rf0.29(乙酸∶甲醇∶氯仿=1∶5∶25)。实施例1(101)2RS-(4-硝基苯基)丁酸4-(N-(四唑-5-基)氨磺酰基)苯酯
Figure A9612198402071
NMR(DMSO-d6):δ13.88(1H,brs),8.26(2H,d,J=8.8Hz),7.82(2H,d,J=8.8Hz),7.70(2H,d,J=8.8Hz),7.06(2H,d,J=8.8Hz),4.12(1H,t,J=7.4Hz),2.30-2.00 and 2.00-1.70(each 1H,m),0.91(3H,t,J=7.2Hz);TLC:Rf0.26(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例1(102)2RS-(4-甲基苯基)丁酸4-(N-奎宁环-3RS-基)氨磺酰基)-2-甲基苯酯
Figure A9612198402081
NMR(CDCl3):δ7.70(1H,d,J=2Hz),7.67(1H,dd,J=8 and 2Hz),7.27(2H,d,J=8Hz),7.18(2H,d,J=8Hz),7.06(1H,d,J=8Hz),3.70(1H,t,J=8Hz),3.38-3.23(1H,m),3.23-3.05(1H,m),2.90-2.49(5H,m),2.36(3H,s),2.35-2.11(1H,m),2.00(3H,s),2.05-1.22(6H,m),1.00(3H,t,J=7Hz);
TLC:Rf0.40(氯仿∶甲醇∶水=8∶2∶0.2)。实施例1(103)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2R-甲氧-3R-羟基-4S-羟基-5R-羟基全氢吡喃-6R-基甲基氨磺酰基)-2-甲基苯酯
Figure A9612198402082
NMR(CDCl3+6 drops of CD3OD):δ7.68-7.63(m,2H),7.22(d,J=8.8Hz,2H),7.05(d,J=8.1Hz,1H),6.55(d,J=8.8Hz,2H),4.63(d,J=3.7Hz,1H),3.70-3.50(m,3H),3.50-3.10(m,11H),2.30-1.80(m,9H),0.99(t,J=7.4Hz,3H);
TLC:Rf0.41(氯仿∶甲醇=8∶1)。实施例1(104)2RS-苯基丁酸4-(N-苯基氨磺酰基)苯酯
NMR(CDCl3):δ7.73(2H,dd,J=2Hz,8Hz),7.40-7.16(7H,m),7.16-7.00(5H,m),6.76(1H,s),3.67(1H,t,J=7Hz),2.20(1H,m),1.89(1H,m),0.96(3H,t,J=7Hz);
TLC:Rf0.57(己烷∶乙酸乙酯=1∶1)。实施例1(105)2RS-苯基丁酸4-(N-4-硝基苯基氨磺酰基)苯酯
NMR(CDCl3):δ8.10 and 7.85(each 2H,dd,J=2Hz,8Hz),7.75(1H,brs),7.35(5H,m),7.20 and 7.14(each 2H,dd,J=2Hz,J=8Hz),3.69(1H,t,J=7Hz),2.20 and 1.90(each 1H,m),0.96(3H,t,J=7Hz);
TLC:Rf0.59(己烷∶乙酸乙酯=1∶1)。实施例1(106)2RS-(4-氨基苯基)丁酸4-(N-苯基氨磺酰基)苯酯
NMR(DMSO-d6):δ7.72(2H,d,J=8Hz),7.42-6.91(9H,m),6.80-6.54(3H,m),3.56(1H,1,J=7Hz),2.23-1.64(2H,m),0.92(3H,t,J=7Hz);
TLC∶Rf0.39(己烷∶乙酸乙酯=1∶1)。实施例1(107)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(2-(四唑-5-基)苯基)氨磺酰基)苯酯
Figure A9612198402111
NMR(CDCl3):δ7.76(1H,d,J=7.8Hz),7.59(1H,d,J=7.8Hz),7.48(1H,t-like),7.35(2H,d,J=8.8Hz),7.26(1H,t-like),7.17(2H,d,J=8.4Hz),6.77(2H,d,J=8.6Hz),6.55(2H,d,J=8.4Hz),3.57(1H,t,J=7.2Hz),3.31-3.24(4H,t-like),2.25-1.75(2H,m),2.05-1.95(4H,m),0.97(3H,t,J=7.2Hz);
TLC:Rf0.33(乙酸∶甲醇∶氯仿=1∶20∶200)。实施例1(108)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-4-(吗啉-4-基)苯基氨磺酰基)苯酯·二盐酸盐
NMR(CD3OD):δ7.83(2H,d,J=8.8Hz),7.60(4H,s),7.55(2H,d,J=9.0Hz),7.29(2H,d,J=9.0Hz),7.16(2H,d,J=8.8Hz),4.05(4H,t-like),3.89(1H,t,J=7.4Hz),3.84-3.68(4H,m),3.58(4H,t-like),2.35-2.23(4H,m),2.30-2.09 and 2.04-1.78(each 1H,m),0.96(3H,t,J=7.2Hz);
TLC:Rf0.52(甲醇∶氯仿=1∶20)。实施例1(109)
2-(N-4-(2RS-(4-(吡咯烷-1-基)苯基)丁酰氧基)-3-甲基苯基磺酰基)氨基)苯磺酸钠盐
NMR(DMSO-d6):δ10.6(1H,s),7.81(1H,d,J=2Hz),7.71(1H,dd,J=9,2Hz),7.57(1H,dd,J=8,2Hz),7.37(1H,dd,J=8,1Hz),7.22(1H,td,J=8.1Hz),7.16(2H,d,J=9Hz),7.06(1H,d,J=9Hz),6.97(1H,td,J=8,1Hz),6.57(2H,d,J=9Hz),3.67(1H,t,J=7Hz),3.30-3.15(4H,m),2.18-1.90(5H,m),1.88(3H,s),1.87-1.65(1H,m),0.86(3H,t,J=7Hz);
TLC:Rf0.19(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例1(110)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-3,5-二甲氧苯基氨磺酰)-2-甲基苯基酯
NMR(CDCl3):δ7.62-7.55(2H,m),7.18(2H,d,J=8.4Hz),6.98(1H,d,J=8.2Hz),6.69(1H,s),6.52(2H,d,J=8.4Hz),6.21-6.16(3H,m),3.69(6H,s),3.57(1H,t,J=7.6Hz),3.31-3.24(4H,m),2.25-1.80(9H,m),0.97(3H,t,J=7.4Hz);TLC:Rf0.83(己烷∶乙酸乙酯=1∶1)。实施例1(111)
2RS-(4-吡咯烷-1-基)苯基)丁酸4-(N-苯基氨磺酰)-2-甲基苯基酯
Figure A9612198402141
NMR(CDCl3):δ7.56-7.49(2H,m),7.26-6.94(8H,m),6.68(1H,brs),6.52(2H,d,J=8.4Hz),3.57(1H,t,J=7.8Hz),3.31-3.24(4H,m),2.27-1.75(6H,m),1.95(3H,s),0.97(3H,t,J=7.4Hz);
TLC:Rf0.83(己烷∶乙酸乙酯=3∶1)。实施例1(112)
2RS-(4-硝基苯)丁酸4-(N-2-(N’-(四唑-5-基甲基)氨基甲酰基)苯-1-基-氨磺酰)苯基酯
NMR(DMSO-d6):δ9.60-9.48(1H,m),8.25(2H,d,J=8Hz),7.88-7.63(5H,m),7.55-7.45(2H,m),7.30-7.09(3H,m),4.79-4.65(2H,m),4.13(1H,t,J=7Hz),2.31-2.04(1H,m),2.04-1.78(1H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.28(乙酸∶甲醇∶氯仿=1∶2∶30)。实施例1(113)
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N’-(四唑-5-基甲基)氨基甲酰基)苯-1-基氨磺酰)苯基酯
Figure A9612198402151
NMR(DMSO-d6):δ9.60-9.48(1H,m),8.33-8.20(2H,m),7.85-7.62(5H,m),7.55-7.40(2H,m),7.30-7.10(3H,m),4.78-4.65(2H,m),3.06-2.85(2H,m),2.75-2.55(2H,m),2.26-2.03(1H,m),2.03-1.80(1H,m);
TLC:Rf0.39(乙酸∶甲醇;氯仿=1∶2∶20)。实施例1(114)
2RS-(4-硝基苯基)丁酸4-(N-(4-脒基苯基)氨磺酰)苯基酯·乙酸盐
NMR(DMSO-d6):δ9.40-9.10(2H,m),8.75-8.55(2H,m),8.24(2H,d,J=8Hz),7.78-7.61(4H,m),7.44(2H,d,J=8Hz),7.05(2H,d,J=8Hz),6.83(2H,d,J=8Hz),4.09(1H,t,J=7Hz),2.23-2.00(1H,m),1.95-1.65(4H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.52(乙酸∶甲醇∶氯仿=1∶2∶10)。实施例1(115)
1-(4-硝基苯基)环丁烷羧酸4-(N-(4-脒基苯基)氨磺酰)苯基酯·乙酸盐
Figure A9612198402162
NMR(CD3OD):δ8.26(2H,d,J=8Hz),7.87(2H,d,J=8Hz),7.63(4H,d,J=8Hz),7.23(2H,d,J=8Hz),7.12(2H,d,J=8Hz),3.10-2.94(2H,m),2.78-2.60(2H,m),2.35-1.95(5H,m);
TLC:Rf0.40(乙酸∶甲醇∶氯仿=1∶2∶15)。实施例1(116)
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(四唑-5-基)苯基氨磺酰)苯基酯
Figure A9612198402171
NMR(CD3OD):δ8.22(2H,d,J=8.8Hz),7.86-7.18(8H,m),6.96(2H,d,J=8.8Hz),3.08-2.88(2H,m),2.65(2H,q-like),2.28-2.08(2H,m),2.08-1.88(2H,m);
TLC:Rf0.43(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例1(117)
1-(4-硝基苯基)环丁烷羧酸4-(N-4-(吗啉-4-基)苯基氨磺酰)苯基酯·盐酸盐
NMR(CD3OD):δ8.25(2H,d,J=8.8Hz),7.82(2H,d,J=8.8Hz).7.61(2H,d,J=8.8Hz),7.54(2H,d,J=8.8Hz),7.28(2H,d,J=8.8Hz),7.12(2H,d,J=8.8Hz),4.08(4H,t,J=4.8Hz),3.57(4H,t,J=4.8Hz),3.02(2H,m),2.70(2H,m),2.21(1H,m),2.03(1H,m);
TLC:Rf0.35(己烷∶乙酸乙酯=1∶1)。实施例1(118)
2RS-(4-硝基苯基)丁酸4-(N-2-(四唑-5-基)苯基氨磺酰)苯基酯
Figure A9612198402182
NMR(CD3OD):δ8.22(2H,m),7.93(1H,d,J=7.8Hz),7.68(1H,d,J=7.8Hz),7.64-7.60(2H,t-like),7.60-7.56(2H,m),7.33(1H,t,J=7.8Hz),7.16(1H,t,J=7.8Hz),7.00-6.92(2H,m),3.92(1H,t,J=8.0Hz),2.30-2.05 and 2.05-1.75(each 1H,m),0.93(3H,t,J=7.2Hz);
TLC:Rf0.27(乙酸∶甲醇∶氯仿=1∶20∶200)。实施例1(119)2RS-(4-(N-叔丁基氧羰基氨基)苯基)丁酸4-(N-2-(N’-羧甲基氨基甲酰基(苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ10.77(1H,brs),9.34(1H,t-like),7.82(1H,d,J=7Hz),7.79(2H,d,J=8Hz),7.44(2H,d,J=8Hz),7.28-7.04(7H,m),6.78-6.70(1H,m),3.86(2H,d-like),3.72(1H,t,J=7Hz),2.11-1.90 and 1.81-1.67(each1H,m),1.47(9H,s),0.87(3H,t,j=7Hz);TLC:Rf0.21(氯仿∶甲醇∶水=8∶2∶0.2)。实施例1(120)
2RS-(4-吡咯烷-1-基)辛基)丁酸4-(3,5-二甲氧基苄基氨基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.67-7.62(2H,m),7.22(2H,d,J=8.6Hz),7.05(1H,d,J=9.4Hz),6.54(2H,d,J=8.6Hz),6.32(3H,s),4.64(1H,t,J=6.0Hz),4.05(2H,d,J=6.0Hz),3.72(6H,s),3.61(1H,t,J=7.6Hz),3.33-3.26(4H,m),2.27-1.81(6H,m),2.02(3H,s),0.99(3H,t,J=7.2Hz);
TLC:Rf0.86(己烷∶乙酸乙酯=1∶1)。实施例1(121)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((4-叔丁氧基羰基氨基哌啶-1-基)磺酰基)-2-甲基苯基酯
Figure A9612198402202
NMR(CDCl3):δ7.55(1H,s),7.53(1H,d,J=8.4Hz),7.23(2H,d,J=8.6Hz),7.08(1H,d,J=8.4Hz),6.55(2H,d,J=8.6Hz),4.40(1H,brs),3.7-3.6(2H,br),3.62(1H,t,J=7.7Hz),3.5-3.2(1H,br),3.28(4H,br),2.6-2.4(2H,m),2.3-2.1(1H,m),2.04(3H,s),2.00(4H,brs),2.1-1.8(1H,m),1.6-1.4(4H,m),1.41(9H,s),0.99(3H,t,J=7.3Hz);
TLC:Rf0.81(己烷∶乙酸乙酯=1∶1)。实施例1(122)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-甲氧基-N-苄基氨基磺酰基)-2-甲基苯基酯
Figure A9612198402211
NMR(CDCl3):δ7.74(1H,s),7.72(1H,d,J=9.0Hz),7.32(5H,s),7.24(2H,d,J=8.8Hz),7.14(1H,d,J=9.0Hz),6.56(2H,d,J=8.8Hz),3.98(2H,s),3.64(1H,t,J=7.7Hz),3.43(3H,s),3.29(4H,brs),2.3-2.1(1H,m),2.08(3H,s),2.00(4H,brs),2.1-1.8(1H,m),1.00(3H,t,J=7.4Hz);TLC:Rf0.79(己烷∶乙酸乙酯=2∶1)。实施例1(123)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄氧基-N-甲基氨基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3):δ7.71(1H,s),7.68(1H,d,J=8.2Hz),7.5-7.2(9H,brs),7.09(1H,d,J=8.2Hz),5.00(2H,s),3.73(1H,t,J=7.5Hz),3.7-3.4(4H,m),2.65(3H,s),2.4-2.1(5H,m),2.03(3H,s),2.1-1.8(1H,m),0.99(3H,t,J=7.2Hz);
TLC:Rf0.66(己烷∶乙酸乙酯=2∶1)。实施例1(124)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(N,N-二甲基氨基)乙基氨基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.69-7.63(2H,m),7.22(2H,d,J=8.6Hz),7.05(1H,d,J=8.4Hz),6.55(2H,d,J=8.6Hz),3.61(1H,t,J=8.2Hz),3.32-3.25(4H,m),2.95(2H,t,J=5.8Hz),2.30(2H,t,J=5.8Hz),2.27-1.65(15H,m),0.99(3H,t,J=7.2Hz);
TLC:Rf0.72(氯仿∶甲醇∶水=8∶2∶0.2)。实施例1(125)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(哌啶-1-基)乙基氨基磺酰基)-2-甲基苯基酯
Figure A9612198402231
NMR(CDCl3):δ7.7-7.4(m,2H),7.23(d,J=8.7Hz,2H),7.05(d,J=8.4Hz,1H),6.56(d,J=8.7Hz,2H),3.61(t,J=7.4Hz,1H),3.4-3.2(m,4H),3.1-2.9(m,2H),2.5-2.4(m,2H),2.4-2.3(m,4H),2.3-1.8(m,2H),2.1-1.9(m,4H),2.03(s,3H),1.6-1.3(m,6H),0.99(t,J=7.4Hz,3H);
TLC:Rf0.55(氯仿∶甲醇=7∶1)。实施例1(126)
2RS-(4-吡咯烷-1-基)苯基)丁酸4-(3-(吗啉-4-基)丙基氨基磺酰基)-2-甲基苯基酯·二盐酸盐
Figure A9612198402241
NMR(CDCl3):δ7.8-7.4(m,5H),7.3-7.0(m,3H),4.3-3.4(m,11H),3.2-2.8(m,6H),2.4-1.8(m,11H),0.99(t,J=7.2Hz,3H);
TLC:Rf0.56(氯仿∶甲醇=9∶1)。实施例1(127)
2RS-(4-(吡咯烷-1-基)苯基丁酸4-(二氢吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.66-7.51(3H,m),7.24-6.88(6H,m),6.53(2H,d,J=8.8Hz),3.88 (2H,t,J=8.4Hz),3.58(1H,t,J=7.8Hz),3.27(4H,m),2.89(2H,t,J=8.4Hz),2.29-1.72(9H,m),0.96(3H,t,J=7.2Hz);
TLC:Rf0.8(己烷∶乙酸乙酯=1∶1)。实施例1(128)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2-氧代-4R-异丙基全氢化恶唑-3-基)磺酰基)-2-甲基苯基酯
Figure A9612198402251
NMR(CDCl3):δ7.93(1H,s),7.86(1H,d,J=8.6Hz),7.22(2H,d,J=8.4Hz),7.11(1H,d,J=8.6Hz),6.55(2H,d,J=8.4Hz),4.43-4.33(1H,m),4.26(1H,t,J=8.6Hz),4.15(1H,dd,J=8.6,3.2Hz),3.61(1H,t,J=7.7Hz),3.40-3.20(4H,m),2.55-2.33(1H,m),2.33-1.70(9H,m),0.99(3H,t,J=7.4Hz),0.91(3H,d,J=6.9Hz),0.76(3H,d,J=6.9Hz);
TLC:Rf0.43(己烷∶乙酸乙酯=7∶3)。实施例1(129)
2RS-(4-(吡咯烷-1-基)苯基丁酸4-(N-2-(吗啉-4-基)乙基-N-甲氧基氨基磺酰基)-2-甲基苯基酯·2盐酸盐
Figure A9612198402261
NMR(DMSO-d6):δ7.85-7.65(2H,m),7.27(3H,d,J=8.0Hz),6.95-6.70(2H,brd),4.05-3.70(5H,m),3.85(3H,s),3.50-2.95(12H,m),2.30-1.65(6H,m),2.02(3H,s),0.92(3H,t,J=7.5Hz);
TLC:Rf0.52(己烷∶乙酸乙酯=2∶1)。实施例1(130)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(5-硝基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402262
NMR(CDCl3):δ8.10(1H,d,J=9.0Hz),7.95(1H,s),7.72-7.56(3H,m),7.18(2H,d,J=8.0Hz),7.05(1H,d,J=8.0Hz),6.52(2H,d,J=8.0Hz),4.01(2H,t,J=8.5Hz),3.58(1H,t,J=7.5Hz),3.35-3.18(4H,m),3.08(2H,t,J=8.5Hz),2.30-1.70(6H,m),2.00(3H,s),0.96(3H,t,J=7.5Hz);
TLC:Rf0.60(己烷∶乙酸乙酯=2∶1)。实施例1(131)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(吗啉-4-基氨基磺酰基)-2-甲基苯基酯·2盐酸盐
Figure A9612198402271
NMR(CD3OD):δ7.84-7.70(2H,m),7.64(4H,s-like),7.13(1H,d,J=8.2Hz),3.97(1H,t,J=7.4Hz),3.87-3.66(4H,m),3.54(4H,t,J=4.4Hz),2.55(4H,t,J=4.4Hz),2.43-2.14(5H,m),2.14-1.80(4H,m),1.00(3H,t,J=7.4Hz);
TLC:Rf0.51(己烷∶乙酸乙酯=1∶1)。实施例1(132)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-氟二氢吲哚-1-基-磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CD3OD∶CDCl3=1∶1):δ7.75-7.40(6H,m),7.29(1H,dd,J=10.0and 2.0Hz),7.15-7.01(2H,m),6.69(1H,td,J=8.6 and 2.0Hz),3.94(2H,t,J=8.4Hz),3.87(1H,t,J=7.6Hz),3.79-3.63(4H,m),2.89(2H,t,J=8.4Hz),2.40-2.12(5H,m),2.08-1.79(4H,m),0.99(3H,t,J=7.4Hz);
TLC:Rf0.29(己烷∶乙酸乙酯=3∶1)。实施例1(133)
2RS-(4-(吡咯烷-1-基)苯基)丁酸(4-(5-(N,N-二甲基氨基)二氢吲哚-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
Figure A9612198402282
NMR(CD3OD):δ7.78-7.64(3H,m),7.60(4H,s-like),7.52-7.42(2H,m),7.11(1H,d,J=8.4Hz),4.01(2H,t,J=8.5Hz),3.93(1H,t,J=8.4Hz),3.87-3.70(4H,m),3.23(6H,s),3.06(2H,t,J=8.5Hz),2.40-2.10(5H,m),2.10-1.80(4H,m),0.97(3H,t,J=7.2Hz);
TLC:Rf0.24(己烷∶乙酸乙酯=3∶1)。实施例1(134)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-甲基哌嗪-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
Figure A9612198402291
NMR(CD3OD):δ7.75-7.59(6H,m),7.23(1H,d,J=8.2Hz),4.06-3.84(3H,m),3.84-3.68(4H,m),3.64-3.49(2H,m),3.32-3.11(2H,m),2.89(3H,s),2.84-2.64(2H,m),2.44-2.14(5H,m),2.13-1.82(4H,m),1.00(3H,t,J=7.2Hz);
TLC:Rf0.36(乙酸乙酯)。实施例1(135)
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(5-硝基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402301
NMR(CDCl3):δ8.10(1H,dd,J=9.0,2.2Hz),7.95(1H,d,J=2.2Hz),7.66(1H,d,J=9.0HZ),7.66(1H,s),7.63(1H,d,J=8.2Hz),7.18(2H,d,J=8.8Hz),7.05(1H,d,J=8.2Hz),6.53(2H,d,J=8.8Hz),4.01(2H,t,J=8.5Hz),3.58(1H,t,J=7.7Hz),3.3-3.2(4H,brs),3.08(2H,t,J=8.5Hz),2.3-2.0(1H,m),2.1-1.9(4H,brs),2.00(3H,s),2.0-1.8(1H,m),0.96(3H,t,J=7.3Hz);TLC:Rf0.60(己烷∶乙酸乙酯=2∶1)。实施例1(136)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-乙基苯基酯·2盐酸盐
Figure A9612198402302
NMR(CD3OD):δ7.83-7.58(6H,m),7.18(1H,d,J=8.0Hz),4.12-3.70(9H,m),3.53(2H,d,J=12.0Hz),3.38-3.08(6H,m),2.45-1.80(8H,m),1.00(6H,t,J=7.5Hz);
TLC:Rf0.41(己烷∶乙酸乙酯=1∶4)。实施例1(137)
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-乙基苯基酯·2盐酸盐
Figure A9612198402311
NMR(CD3OD):δ7.83-7.58(6H,m),7.19(1H,d,J=8.0Hz),4.12-3.70(9H,m),3.53(2H,d,J=12.0Hz),3.40-3.08(6H,m),2.50-1.80(8H,m),0.99(6H,t,J=7.5Hz);
TLC:Rf0.41(己烷∶乙酸乙酯=1∶4)。实施例1(138)
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(DMSO-d6):δ11.0-10.8(1H,brs),7.75(1H,s),7.70(1H,d,J=8.6Hz),7.22(2H,d,J=8.4Hz),7.18(1H,d,J=8.6Hz),6.64(2H,d,J=8.4Hz),4.0-3.7(5H,m),3.4-3.0(12H,m),2.2-2.0(1H,m),2.1-1.9(4H,brs),2.0-1.7(1H,m),1.97(3H,s),0.91(3H,t,J=7.3Hz);
TLC:Rf0.50(氯仿∶甲醇=9∶1)。实施例1(139)2S-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-甲基苯基酯·2盐酸盐
Figure A9612198402322
NMR(DMSO-d6):δ11.4-11.2(1H,brs),7.76(1H,s),7.70(1H,d,J=8.6Hz),7.30(2H,d,J=8.4Hz),7.18(1H,d,J=8.6Hz),6.87(2H,d,J=8.4Hz),4.0-3.7(5H,m),3.5-3.3(6H,m),3.3-3.0(6H,m),2.2-2.0(1H,m),2.1-1.9(4H,brs),2.0-1.7(1H,m),1.98(3H,s),0.91(3H,t,J=7.2Hz);TLC:Rf0.50(氯仿∶甲醇=9∶1)。实施例1(140)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-甲基-1,4-全氢化二氮杂_-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(DMSO-d6):δ7.72(1H,d,J=2Hz),7.66(1H,dd,J=2 and 8Hz),7.25(2H,d,J=8Hz),7.19(1H,d,J=8Hz),6.76(2H,d-like),3.76(1H,t,J=7Hz),3.75-3.01(12H,m),2.76 and 2.74(total 3H,each s),2.21-1.66(8H,m),1.99(3H,s),0.91(3H,t,J=7Hz);
TLC:Rf0.52(氯仿∶甲醇∶水=9∶1∶0.1)。实施例1(141)2S-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-乙氧基羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402341
NMR(CDCl3):δ7.62-7.51(3H,m),7.23-7.15(3H,m),7.07-6.95(3H,m),6.52(2H,d,J=9Hz),4.75-4.67(1H,m),4.24(2H,q,J=7Hz),3.57(1H,t,J=7Hz),3.31-3.24(4H,m),3.21-3.00(2H,m),2.23-1.75(2H,m),2.04-1.99(4H,m),1.96(3H,s),1.29(3H,t,J=7Hz),0.96(3H,t,J=7Hz);
TLC:Rf0.29(己烷∶乙酸乙酯=3∶1)。实施例1(142)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(奎宁环-3RS-基氨基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(DMSO-d6):δ8.35(1H,d,J=7Hz),7.74-7.64(2H,m),7.26(2H,d,J=8Hz),7.17(1H,d,J=8Hz),6.82-6.70(2H,br),3.75(1H,t,J=7Hz),3.61-3.43(1H,br),3.40-3.22(5H,m),3.18-2.94(5H,m),2.90-2.79(1H,m),2.17-1.60(13H,m),0.91(3H,t,J=7Hz);
TLC:Rf0.35(氯仿∶甲醇∶水=8∶2∶0.2)。实施例1(143)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-甲基苯基酯·2甲磺酸盐
Figure A9612198402351
NMR(CD3OD):δ7.80-7.70(2H,m),7.67(4H,s),7.17(1H,d,J=8.0Hz),4.10-3.70(9H,m),3.54(2H,d,J=12.0Hz),3 40-3.10(6H,m),2.70(6H,s),2.40-1.80(6H,m),2.05(3H,s),1.00(3H,t,J=7.5Hz);
TLC:Rf0.31(氯仿∶甲醇∶乙酸乙酯=40∶2∶1)。实施例1(144)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(3,5-二甲氧基苯基氨基磺酰基)-2-甲基苯基酯·甲磺酸盐
NMR(CD3OD):δ7.70-7.50(6H,m),7.05(1H,d,J=8.5Hz),6.24(2H,d,J=2.0Hz),6.16(1H,t,J=2.0Hz),3.94(1H,t,J=7.5Hz),3.77(4H,t-like),3.67(6H,s),2.70(3H,s),2.40-1.80(6H,m),1.96(3H,s),0.98(3H,t,J=7.5Hz);
TLC:Rf0.73(己烷∶乙酸乙酯=1∶1)。实施例1(145)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(5-硝基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3):δ8.11(1H,dd,J=2.0,9.0Hz),7.96(1H,d,J=2.0Hz),7.72-7.60(3H,m),7.55(2H,d,J=8.0Hz),7.44(2H,d,J=8.0Hz),7.06(1H,d,J=8.0Hz),4.03(2H,t,J=8.5Hz),3.75(1H,t,J=7.5Hz),3.85-3.40(4H,m),3.10(2H,t,J=8.5Hz),2.45-2.20(4H,m),2.40-1.75(2H,m),2.02(3H,s),0.98(3H,t,J=7.5Hz);
TLC:Rf0.60(己烷∶乙酸乙酯=2∶1)。实施例1(146)
2RS-(4-(吡咯烷-1-基)苯基丁酸4-(5-硝基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·甲磺酸盐
Figure A9612198402371
NMR(CDCl3):δ8.11(1H,dd,J=2.5,9.0Hz),7.97(1H,d,J=2.5Hz),7.74-7.62(3H,m),7.57(2H,d,J=8.5Hz),7.49(2H,d,J=8.5Hz),7.07(1H,d,)J=8.0Hz),4.03(2H,t,J=8.5Hz),3.77(1H,t,J=7.5Hz),4.10-3.30(4H,m),3.11(2H,t,J=8.5Hz),2.85(3H,s),2.50-2.20(4H,m),2.40-2.10 and 2.10-1.80(each1H,m),2.04(3H,s),0.99(3H,t,J=7.5Hz);TLC:Rf0.60(己烷∶乙酸乙酯=2∶1)。实施例1(147)2RS-(4-(吡咯烷-1-基)苯基丁酸4-(二氢吲哚-1-基磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198402381
NMR(CDCl3):δ7.65-7.53(3H,m),7.32(2H,d,J=8.4Hz),7.24-6.90(6H,m),3.89(2H,t,J=8.5Hz),3.66(1H,t,J=8.2Hz),3.45(4H,brs),2.89(2H,t,J=8.5Hz),2.34-2.04(5H,m),1.97(3H,s),2.04-1.73(1H,m),0.97(3H,t,J=7.2Hz);
TLC:Rf0.42(己烷∶乙酸乙酯=3∶1)。实施例2
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198402382
在0℃下将三氟乙酸(5ml)缓慢地加到实施1中制备的化合物(1.04g)在二氯甲烷(5ml)和苯甲醚(5ml)中的混合物溶液中。在室温下,将反应混合物搅拌6小时,浓缩反应混合物,通过硅胶柱色谱(氯仿∶甲醇=20∶1)纯化残余物,得到N-{4-[2RS-(4-(1-吡咯烷基)苯基)丁酰氧基]-3-甲基苯基磺酰基}-L-脯氨酸。通过下面方法将得到的上述化合物转化成盐酸盐。在0℃下将4N盐酸的二恶烷溶液(1ml)加入到N-{4-[2RS-(4-(1-吡咯烷基)苯基)丁酰氧基]-3-甲基苯基磺酰基}-L-脯氨酸的二恶烷(5ml)的溶液中。将反应混合物搅拌5分钟,浓缩反应混合物,得到具有下面物理数据的标题化合物(1g)。
NMR(CDCl3):δ7.70(1H,s),7.67(1H,d,J=8.0Hz),7.59(2H,d,J=8.5Hz),7.49(2H,d,J=8.5Hz),7.07(1H,d,J=8.0Hz),4.26(1H,dd,J=3.5,7.0Hz),3.78(1H,t,J=7.5Hz),3.75-3.60(4H,m),3.52-3.40(1H,m),3.33-3.14(1H,m),2.40-2.25(4H,m),2.40-1.65(6H,m),2.04(3H,s),1.00(3H,t,J=7.5Hz);
TLC:Rf0.39(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(1)~2(296)
通过与实施例1和2相同的方法并通已知的方法转化成相应的盐、酸加成盐或溶剂化物,通过使用相应的酚衍生物代替参考例4制备的化合物及通过使用相应的羧酸衍生物代替参考例7制备的化合物,得到具有下列物理数据的化合物。实施例2(1)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯·盐酸盐
Figure A9612198402401
NMR(DMSO-d6):δ7.86(2H,d,J=8Hz),7.24(4H,d,J=8Hz),6.78(2H,d.J=8Hz),4.15-4.05(1H,m),3.73(1H,t,J=7Hz),3.40-3.05(6H,m),2.20-1.45(10H,m),0.89(3H,t,J=7Hz);
TLC:Rf0.26(乙酸∶甲醇∶氯仿=1∶2∶60)。实施例2(2)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2R-羧基吡咯烷-1-基磺酰基)苯基酯·盐酸盐
NMR(DMSO-d6):δ7.86(2H,d,J=8.8Hz),7.25(4H,d,J=8.8Hz),6.78(2H,d,J=8.8Hz),4.16-4.05(1H,m),3.74(1H,t,J=7.2Hz),3.44-3.06(2H,m),3.36-3.24(4H,m),2.22-1.46(10H,m),0.90(3H,t,J=7.2Hz);
TLC:Rf0.39(乙酸∶甲醇:氯仿=1∶2∶40)。实施例2(3)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基-4R-羟基吡咯烷-1-基磺酰基)苯基酯·盐酸盐
Figure A9612198402411
NMR(DMSO-d6):δ7.83(2H,d,J=9Hz),7.31-7.18(4H,m),6.85-6.68(2H,m),4.25-4.14(1H,m),4.04(1H,t,J=7Hz),3.73(1H,t,J=7Hz),3.50-3.38(5H,m),3.18-3.05(1H,m),2.20-1.65(8H,m),0.90(3H,t,J=7Hz);
TLC:Rf0.27(氯仿∶甲醇∶乙酸=20∶2∶1)。实施例2(4)
2RS-(4-吡咯烷-1-基)苯基)丁酸4-(2S-羧基-4R-苄氧基吡咯烷-1-基磺酰基)苯基酯·盐酸盐
Figure A9612198402421
NMR(CDCl3):δ7.84(2H,d,J=9Hz),7.62(2H,d,J=9Hz),7.47(2H,d,J=9Hz),7.34-7.19(3H,m),7.17-7.00(4H,m),4.30(1H,t,J=8Hz),4.23(2H,s),4.15-4.03(1H,m),3.86-3.42(7H,m),2.47-2.05(7H,m),2.05-1.74(1H,m),0.97(3H,t,J=7Hz);
TLC:Rf0.35(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(5)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基-4S-氨基吡咯烷-1-基磺酰基)苯基酯·2盐酸盐
Figure A9612198402422
NMR(DMSO-d6):δ8.55-8.20(2H,brs),7.89(2H,d,J=9Hz),7.29(2H,d,J=9Hz),7.25(2H,d,J=9Hz),6.73(2H,d,J=9Hz),5.80-4.40(1H,m),4.18(1H,t,J=7Hz),3.74(1H,t,J=7Hz),3.64-3.10(7H,m),2.67-2.40(1H,m),2.20-1.65(7H,m),0.90(3H,t,J=7Hz);TLC:Rf0.49(乙酸乙酯∶乙酸∶水=6∶2∶1)。实施例2(6)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基-4R-氨基吡咯烷-1-基磺酰基)苯基酯·2盐酸盐
Figure A9612198402431
NMR(DMSO-d6):δ8.60-8.30(2H,brs),7.88(2H,d,J=9Hz),7.28(2H,d,J=9Hz),7.23(2H,d,J=9Hz),6.72(2H,d,J=9Hz),5.40-4.20(1H,m),4.40(1H,dd,J=9Hz,4Hz),3.90-3.50(2H,m),3.50-3.10(6H,m),2.33-1.60(8H,m),0.90(3H,t,J=7Hz);
TLC:Rf0.42(乙酸乙酯∶乙酸∶水=6∶2∶1)。实施例2(7)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(N-羧基甲基氨基甲酰基)吡咯烷-1-基磺酰基)苯基酯
Figure A9612198402441
NMR(CDCl3+CD3OD):δ7.84(2H,d,J=8.8Hz),7.28-7.18(4H,m),6.72(2H,d,J=8.8Hz),4.09-3.85(3H,m),3.71-3.53(2H,m),3.41-3.31(4H,m),3.20-3.08(1H,m),2.26-1.59(10H,m),0.99(3H,t,J=7.4Hz);
TLC:Rf0.24(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(8)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(2-氨基乙氧基羰基)吡咯烷-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(DMSO-d6):δ8.21(2H,brs),7.75(1H,s),7.69(1H,d,J=8.2Hz),7.22(3H,m),6.70(2H,d,J=8.8Hz),4.26(3H,m),3.50-3.36(2H,m),3.31(4H,m),3.20(1H,m),3.08(2H,m),2.12(1H,m),2.00(3H,s),1.96(4H,m),1.87(4H,m),1.66(1H,m),0.92(3H,t,J=7.2Hz);
TLC:Rf0.31(氯仿∶甲醇∶乙酸=12∶1∶1)。实施例2(9)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(2-(2-羟基乙氧基)乙氧基羰基)吡咯烷-1-基磺酰基)-2-甲基苯基酯·盐酸盐
  NMR(CDCl3):δ7.69(1H,s),7.67(2H,d,J=8.4Hz),7.23(2H,d,J=8.4Hz),7.07(1H,d,J=8.2Hz),6.56(2H,d,J=8.4Hz),4.29(3H,m),3.75-3.58(7H,m),3.50(1H,m),3.29(4H,m),3.22(1H,m),2.16(1H,m),2.04(3H,s),2.01(4H,m),1.98-1.64(5H,m),0.99(3H,t,J=7.2Hz);TLC:Rf0.62(氯仿∶甲醇=9∶1)。实施例2(10)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羟基甲基吡咯烷-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402461
NMR(CDCl3):δ7.70-7.58(2H,m),7.22(2H,d,J=8.5Hz),7.09(1H,d,J=8.0Hz),6.55(2H,d,J=8.5Hz),3.80-3.52(3H,m),3.62(1H,t,J=7.5Hz),3.52-3.35(1H,m),3.35-3.12(5H,m),2.90-2.55(1H,brs),2.35-1.70(2H,m),2.05(3H,s),2.05-1.95(4H,m),1.80-1.30(4H,m),0.99(3H,t,J=7.5Hz);
TLC:Rf0.36(己烷∶乙酸乙酯=1∶1)。实施例2(11)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(2-(哌嗪-4-基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(CD3OD):δ7.82-7.63(6H,m),7.00(1H,d,J=8.2Hz),4.62(2H,m),4.41(1H,m),4.00(1H,t,J=7.6Hz),3.81-3.66(8H,m),3.57(1H,m),3.21(1H,m),2.33(7H,m),2.07(3H,s),2.03-1.89(5H,m),1.69(1H,m),1.00(3H,t,J=7.4Hz);
TLC:Rf0.48(氯仿∶甲醇∶水=40∶10∶1)。实施例2(12)
2-(2-甲氧基苯基)-2-乙基丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯
NMR(DMSO-d6):δ7.89(2H,d,J=9Hz),7.34-7.16(4H,m),7.06-6.95(2H,m),4.03(1H,dd,J=2 and 8Hz),3.82(3H,s),3.36-3.23 and 3.20-3.09(each 1H,m),2.23-1.91(4H,m),1.87-1.47(4H,m),0.72(6H,t,J=7Hz);TLC:Rf0.19(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(13)
2RS-(2-甲氧基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402481
NMR(CDCl3):δ7.69(1H,s),7.68(1H,d,J=9.0Hz),7.35-7.22(2H,m),7.10(1H,d,J=9.0Hz),6.98(1H,d,J=7.6Hz),6.92(1H,d,J=7.8Hz),4.28-4.16(1H,m),4.15(1H,t,J=7.6Hz),3.85(3H,s),3.60-3.43(1H,m),3.26-3.07(1H,m),2,35-1.56(4H,m).2.04(3H,s),0.98(3H,t,J=7.6Hz);TLC:Rf0.54(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(14)2RS-(4-甲氧基苯基)丁酸-4-(2S-羧基吡咯烷-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402482
NMR(DMSO-d6):δ7.74(1H,s),7.69(1H,d,J=8.2Hz),7.33(2H,d,J=8.8Hz),7.17(1H,d,J=8.2Hz),6.95(2H,d,J=8.8Hz),4.11(1H,m),4.14(1H,m),3.76(3H,s),3.30(1H,m),3.17(1H,m),2.10(1H,m),1.96(3H,s),1.82(4H,m),1.56(1H,m),0.91(3H,t,J=7.2Hz);
TLC:Rf0.58(氯仿∶甲醇∶乙酸=12∶1∶1)。实施例2(15)
2RS-(4-甲氧基苯基)丁酸4-(2S-(2-(哌嗪-1-基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
Figure A9612198402491
NMR(CD3OD):δ7.77(1H,s),7.75(1H,d,J=7.4Hz),7.32(2H,d,J=8.6Hz),7.16(1H,d,J=7.4Hz),6.93(2H,d,J=8.6Hz),4.62(2H,brs),4.5-4.3(1H,br),3.8-3.4(12H,br),3.79(3H,s),3.3-3.1(1H,br),2.3-1.8(6H,br),2.00(3H,s),0.98(3H,t,J=7.3Hz);
TLC:Rf0.16(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(16)
2RS-(4-甲氧基苯基)丁酸4-(2S-(2-(2-羟基乙氧基)乙氧基羰基)吡咯烷-1-基-磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.70(1H,s),7.68(1H,d,J=8.8Hz),7.31(2H,d,J=8.4Hz),7.01(1H,d,J=8.8Hz),6.90(2H,d,J=8.4Hz),4.3-4.2(3H,m),3.82(3H,s),3.8-3.7(6H,m),3.7-3.5(2H,m),3.3-3.2(1H,m),2.4-2.1(2H,m),2.00(3H,s),2.1-1.7(4H,m),0.99(3H,t,J=7.3Hz);
TLC:Rf0.24(己烷∶乙酸乙酯=1∶2)。实施例2(17)
2RS-(4-甲氧基苯基)丁酸4-(2S-(2-氨基乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3):δ8.40(2H,brs),7.73(1H,s),7.70(1H,d,J=9.2Hz),7.30(2H,d,J=8.6Hz),7.08(1H,d,J=9.2Hz),6.89(2H,d,J=8.6Hz),4.6-4.3(3H,br),3.80(3H,s),3.67(1H,t,J=7.6Hz),3.6-3.3(3H,br),3.2-3.1(1H,br),2.4-1.8(6H,br),2.00(3H,s),0.98(3H,t,J=7.3Hz);
TLC:Rf0.23(氯仿∶甲醇=9∶1)。实施例2(18)
2RS-(4-甲基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402511
NMR(CDCl3):δ7.69(1H,s),7.66(1H,d,J=9.0Hz),7.25(2H,d,J=8.0Hz),7.15(2H,d,J=8.0Hz),7.05(1H,d,J=9.0Hz),4.20(1H,m),3.67(1H,)t,J=8.0Hz),3.60-3.40(1H,m),3.20-3.00(1H,m),2.34(3H,s),2.30-1.50(6H,m),1.96(3H,s),0.97(3H,t,J=7.5Hz);
TLC:Rf0.39(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(19)
2RS-(4-甲基苯基)丁酸4-(2S-羟基甲基吡咯烷-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402521
NMR(CDCl3):δ7.67(1H,s),7.65(1H,d,J=8.0Hz),7.28(2H,d,J=8.0Hz),7.18(2H,d,J=8.0Hz),7.09(1H,d,J=8.0Hz),3.70(1H,t,J=7.5Hz),3.74-3.54(3H,m),3.54-3.38(1H,m),3.30-3.14(1H,m),2.71(1H,t-like),2.36(3H,s),2.40-1.80(2H,m),2.02(3H,s),1.90-1.60(3H,m),1.60-1.40(1H,m),1.00(3H,t,J=7.5Hz);
TLC:Rf0.23(乙酸乙酯∶己烷=1∶2)。实施例2(20)
2RS-(4-甲基苯基)丁酸4-(2S-(2-氨基乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(DMSO-d6):δ8.22(3H,brs),7.75(1H,d,J=1.8Hz),7.70(1H,dd,J=8.4 and 1.8Hz),7.30(2H,d,J=8.0Hz),7.20(3H,d,J=8.0Hz),4.33-4.15(1H,m),4.26(2H,t,J=5.0Hz),3.85(1H,t,J=7.6Hz),3.49-3.01(2H,m),3.09(2H,t,J=5.6Hz),2.32(3H,s),2.25-1.50(6H,m),1.98(3H,s),0.92(3H,t,J=7.2Hz);
TLC:Rf0.56(氯仿∶甲醇∶乙酸=15∶2∶1)。实施例2(21)
2RS-(4-甲基苯基)丁酸4-(2S-(2-(哌嗪-4-基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(CD3OD):δ7.78(1H,s),7.75(1H,dd,J=8.6 and 1.2Hz),7.29(2H,d,J=8.0Hz),7.24-7.12(3H,m),4.66-4.54(2H,m),4.45-4.32(1H,m),3.85-3.60(11H,m),3.60-3.38(1H,m),3.26 -3.15(1H,m),2.34(3H,s),2.30-1.55(6H,m),1.99(3H,s),0.98(3H,t,J=7.2Hz);
TLC:Rf0.45(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(22)
2RS-(4-甲基苯基)丁酸4-(2S-(2-(2-羟基乙氧基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.70(1H,s),7.68(1H,dd,J=7.4 and 2.4Hz),7.28(2H,d,J=8.2Hz),7.18(2H,d,J=8.2Hz),7.07(1H,d,J=8.8Hz),4.40-4.20(3H,m),3.73-3.37(8H,m),3.37-3.16(1H,m).2.24-1.63(6H,m),2.36(3H,s),2.02(3H,s),1.70(1H,s),1.00(3H,t,J=7.2Hz);
TLC:Rf0.28(乙酸乙酯∶己烷=2∶1)。实施例2(23)
2RS-(4-硝基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯
NMR(DMSO-d6):δ8.25(2H,d,J=8Hz),7.90(2H,d,J=8Hz),7.58(2Hd,J=8Hz),7.19(2H,d,J=8Hz),5.70-4.80(1H,brs),4.30(1H,dd,J=7Hz,4Hz),3.85(1H,t,J=7Hz),3.60-3.39(1H,m),3.39-3.15(1H,m),2.45-1.65(6H,m),1.01(3H,t,J=7Hz);
TLC:Rf0.34(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(24)
2R-(4-硝基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯
NMR(CDCl3):δ8.26(d,J=8.8Hz,2H),7.90(d,J=8.8Hz,2H),7.58(d,J=8.8Hz,2H),7.20(d,J=8.8Hz,2H),4.30(dd,J=4.0,7.8Hz,1H),3.86(t,J=7.6Hz,1H),3.5-3.4(m,1H),3.4-3.2(m,1H),2.4-1.7(m,6H)1.02(t,J=7.3Hz,3H);
TLC:Rf0.63(氯仿∶甲醇=6∶1)。实施例2(25)
2S-(4-硝基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯
Figure A9612198402561
NMR(CDCl3)δ8.26(d,J=8.8Hz,2H),7.90(d,J=8.8Hz,2H),7.58(d,J=8.8Hz,2H),7.19(d,J=8.8Hz,2H),4.31(dd,J=4.0,7.2Hz,1H),3.86(t,J=7.7Hz,1H),3.6-3.4(m,1H),3.4-3.2(m,1H),2.4-1.7(m,6H),1.03(t,J=7.6Hz,
TLC:Rf0.63(氯仿∶甲醇=6∶1)。实施例2(26)
1-(4-硝基苯基)环丁烷羧酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯
Figure A9612198402562
NMR(DMSO-d6):δ8.27(2H,d,J=8Hz),7.88(2H,d,J=8Hz),7.56(2H,d.J=8Hz),7.16(2H,d,J=8Hz),6.00-5.10(1H,brs),4.29(1H,dd,J=7Hz,4Hz),3.55-3.40(1H,m),3.34-3.19(1H,m),3.15-2.98(2H,m),2.80-2.60(2H,m),2.38-1.66(6H,m);
TLC:Rf0.40(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(27)
2RS-(4-硝基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯
Figure A9612198402571
NMR(DMSO-d6):δ8.27(2H,d,J=8.8Hz),7.74(2H,d,J=8.8Hz),7.79-7.66(2H,m),7.23(1H,d,J=8.4Hz),4.20(1H,t,J=7.6Hz),4.12-4.06(1H,m),3.40-3.07(2H,m),2.35-1.40(6H,m),2.00(3H,s),0.92(3H,t,J=7.2Hz);TLC:Rf0.19(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(28)
2RS-(4-硝基苯基)丁酸4-(2R-羧基吡咯烷-1-基磺酰基)苯基酯
Figure A9612198402581
NMR(DMSO-d6):δ13.5-11.6(1H,brs),8.27(2H,d,J=8.8Hz),7.88(2H,d,J=8.8Hz),7.73(2H,d,J=8.8Hz),7.32(2H,d,J=8.8Hz),4.16(1H,t,J=7.2Hz),4.16-4.06(1H,m),3.5-3.0(2H,m),2.35-1.45(6H,m),0.92(3H,t,J=7.2Hz);
TLC:Rf0.43(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(29)
1-(4-硝基苯基)环丁烷羧酸4-(2R-羧基吡咯烷-1-基磺酰基)苯基酯
NMR(DMSO-d6):δ12.9-12.6(1H,brs),8.28(2H,d,J=8.8Hz),7.87(2H,d,J=8.8Hz),7.71(2H,d,J=8.8Hz),7.31(2H,d,J=8.8Hz),4.16-4.04(1H,m),3.43-3.10(2H,m),3.10-2.90(2H,m),2.75-2.55(2H,q-like),2.28-1.46(6H,m);
TLC:Rf0.46(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(30)
2RS-苯基丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯
Figure A9612198402592
NMR(CDCl3):δ7.93-7.83(2H,m),7.50-7.14(5H,m),7.23-7.14(2H,m),7.14-6.70(1H,brs),4.26(1H,dd,J=10Hz,5Hz),3.71(1H,t,J=7Hz),3.56-3.43(1H,m),3.33-3.17(1H,m),2.35-1.65(6H,m),0.98(3H,t,J=7Hz);TLC:Rf0.67(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(31)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯·盐酸盐
Figure A9612198402601
  NMR(CDCl3):δ7.73(2H,d,J=8.6Hz),7.58(1H,d,J=8.2Hz),7.17(2H,d,J=8.6Hz),7.12-6.94(5H,m),6.53(2H,d,J=8.8Hz),4.73(1H,dd,J=8.9Hzand 6.8Hz),3.54(1H,t,J=7.8Hz),3.35-3.21(4H,m),3.17(2H,d,J=6.8Hz),2.25-1.70(2H,m),2.05-1.94(4H,m),0.95(3H,t,J=7.2Hz);TLC:Rf0.46(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(32)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-羧基吲哚-1-基磺酰基)苯基酯
NMR(DMSO-d6):δ8.08(2H,d,J=8.8Hz),8.01(1H,d,J=8.4Hz),7.68(1H,d,J=8.0Hz),7.46(1H,m),7.40-7.16(2H,m),7.24(2H,d,J=8.8Hz),7.20(2H,d,J=8.6Hz),6.85-6.60(2H,m),3.69(1H,t,J=7.4Hz),3.40-3.15(4H,m),2.20-1.84(5H,m),1.84-1.60(1H,m),0.86(3H,t,J=7.4Hz);
TLC:Rf0.20(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(33)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基二氢吲哚-1-基磺酰基)苯基酯
Figure A9612198402621
NMR(CDCl3):δ7.72(2H,d,J=8.6Hz),7.57(1H,d,J=7.8Hz),7.17(2H,d,J=8.6Hz),7.28-6.88(5H,m),6.53(2H,d,J=8.6Hz),4.72(1H,dd,J=5.8Hzand 9.1Hz),3.54(1H,t,J=7.8Hz),3.35-3.22(4H,m),3.22-3.08(2H,m),2.25-1.70(2H,m),2.05-1.95(4H,m),0.95(3H,t,J=7.2Hz);
TLC:Rf0.46(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(34)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基全氢化吲哚-1-基磺酰基)苯基酯·盐酸盐
NMR(CDCl3):δ7.89(2H,d,J=8.8Hz),7.71(2H,d,J=8.6Hz),7.51(2H,d,J=8.6Hz),7.17(2H,d,J=8.8Hz),4.20(1H,t,J=8.6Hz),4.0-3.5(6H,m),2.5-2.2(4H,m),2.4-1.0(13H,m),0.99(3H,t,J=7.4Hz);
TLC:Rf0.60(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(35)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198402631
NMR(DMSO-d6):δ7.79(1H,d-like),7.67(1H,dd,J=2.2 and 8.4Hz),7.35-6.95(7H,m),6.71-6.67(2H,m),4.97(1H,dd,J=4.4 and 10.7Hz),3.71(1H,t,J=7.6Hz),3.35-2.96(6H,m),2.14-1.68(2H,m),2.00-1.94(4H,m),1.91(3H,s),0.87(3H,t,J=7.2Hz);TLC:Rf0.45(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(36)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-羧基甲基氨基甲酰基)二氢吲哚-1-基磺酰基)苯基酯
NMR(CDCl3):δ7.70(1H,d,J=7.8Hz),7.58(2H,d,J=8.8Hz),7.28-7.02(8H,m),6.66(2H,d,J=8.8Hz),4.64(1H,dd,J=10.4,2.8Hz),4.02(2H,d,J=3.0Hz),3.56(1H,t,J=7.6Hz),3.37-3.05(5H,m),2.81(1H,dd,J=16.0,10.4Hz),2.35-1.74(6H,m),0.95(3H,t,J=7.6Hz);
TLC:Rf0.33(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(37)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯
Figure A9612198402651
NMR(CDCl3):δ7.72(2H,d,J=8Hz),7.59(1H,d,J=8Hz),7.27-7.03(7H,m),6.54(2H,d,J=8Hz),6.08(1H,br),4.77-4.69(1H,m),3.55(1H,t,J=8Hz),3.31-3.24(4H,m),3.19-3.15(2H,m),2.20-1.76(2H,m),2.03-1.96(4H,m),0.95(3H,t,J=8Hz);TLC:Rf0.45(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(38)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基-3,3-二甲基二氢吲哚-1-基磺酰基)苯基酯
NMR(CDCl3):δ7.83(2H,d,J=8.5Hz),7.55(1H,d,J=8.0Hz),7.25-6.93(3H,m),7.17(2H,d,J=8.5Hz),7.09(2H,d,J=8.5Hz),6.53(2H,d,J=8.5Hz),4.36(1H,s),3.54(1H,t,J=8.0Hz),3.35-3.10(4H,m),2.05-1.90(4H,m),2.25-1.70(2H,m),1.31(3H,s),1.04(3H,s),0.94(3H,t,J=7.5Hz);
TLC:Rf0.48(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(39)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲氧基苯基酯
Figure A9612198402661
NMR(CDCl3):δ7.7-7.6(m,1H),7.5-6.9(m,8H),6.5-6.4(m,2H),4.8-4.6(m,1H),3.8-3.5(m,4H),3.4-3.0(m,6H).2.2-1.7(m,6H),1.1-0.9(m,3H);TLC:Rf0.65(氯仿∶甲醇:=3∶1)。实施例2(40)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-2-羧基乙基氨基甲酰基)二氢吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402671
NMR(CDCl3):δ7.8-6.8(m,11H),4.7-4.5(m,1H),3.8-3.5(m,7H),3.3-3.1(m,1H),3.0-2.8(m,1H),2.7-2.5(m,2H),2.3-2.1(m,4H),2.1-1.8(m,5H),0.97(t,J=7.2Hz,3H);
TLC:Rf0.76(甲醇∶氯仿=1∶3)。实施例2(41)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-2-羟基乙基氨基甲酰基)二氢吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402672
NMR(CDCl3):δ7.72(1H,d,J=8.0Hz),7.45-6.92(9H,m),6.51(2H,d,J=8.6Hz),4.57(1H,dd,J=2.8,10.6Hz),3.77-3.52(5H,m),3.39-3.17(5H,m),2.88(1H,dd,J=10.6,16.8Hz),2.23-1.78(6H,m),1.92(3H,s),0.96(3H,t,J=7.4Hz);
TLC:Rf0.43(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例2(42)
2RS-(4-吡咯烷-1-基)苯基)丁酸4-(2-羧基-5,6-二甲氧基吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402681
NMR(CDCl3):δ7.78-7.62(3H,m),7.35(1H,s),7.18(2H,d,J=9Hz),7.00(1H,d,J=8Hz),6.95(1H,s),6.52(2H,d,J=9Hz),4.00(3H,s),3.91(3H,s),3.70-3.10(1H,brs),3.57(1H,t,J=7Hz),3.35-3.18(4H,m),2.25-1.75(9H,m),0.96(3H,t,J=7Hz).TLC:Rf0.19(乙酸乙酯∶己烷∶乙酸=5∶10∶0.5)。实施例2(43)
2RS-(4-吡咯烷-1-基)苯基)丁酸4-(2RS-(2-氨基乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(DMSO-d6):δ8.30(2H,brs),7.76(1H,s),7.66(1H,d,J=8.0Hz),7.37(1H,d,J=8.0Hz),7.23-7.00(6H,m),6.70(2H,d,J=8.0Hz),5.08(1H,dd,J=6.2,9.4Hz),4.37-4.32(2H,m),3.69(1H,t,J=7.2Hz),3.35-3.07(8H,m),2.14-1.69(9H,m),0.89(3H,t,J=7.2Hz);
TLC:Rf0.46(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例2(44)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-羧基吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402692
NMR(CDCl3):δ8.13(1H,d,J=9Hz),7.90-7.78(2H,m),7.60(1H,d,J=9Hz),7.46(1H,td,J=8.1Hz),7.39(1H,s),7.35-7.25(1H,m),7.21(2H,d,J=9Hz),6.75-6.50(2H,m),3.59(1H,t,J=7Hz),3.38-3.23(4H,m),3.23-2.90(1H,brs),2.25-1.75(6H,m),0.96(3H,t,J=7Hz);TLC:Rf0.20(乙酸乙酯∶己烷∶乙酸=5∶10∶0.5)。实施例2(45)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基-5,6-二甲氧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402701
NMR(CDCl3+CD3OD):δ7.6-7.4(m,2H),7.26(s,1H),7.19(d,J=8.7Hz,2H),6.96(dd,J=1.2,8.4Hz,1H),6.58(s,1H),6.54(d,J=8.7Hz,2H),4.7-4.6(m,1H),3.91(s,3H),3.79(s,3H),3.58(t,J=7.7Hz,1H),3.4-3.2(m,4H),3.1-2.9(m,2H),2.3-1.8(m,6H),1.94(s,3H),0.96(t,J=7.4Hz,3H);TLC:Rf0.45(氯仿∶甲醇=4∶1)。实施例2(46)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-羧基-5-羟基吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402711
NMR(CD3OD):δ7.85-7.63(3H,m),7.03(2H,d,J=8Hz),6.93(1H,d,J=8Hz),6.87-6.70(3H,m),6.53(2H,d,J=8Hz),3.56(1H,1,J=7Hz),3.30-3.10(4H,m),2.20-1.90(5H,m),1.90-1.65(1H,m),1.84(3H,s),0.91(3H,t,J=7Hz);
TLC:Rf0.23(乙酸乙酯∶己烷∶乙酸=10∶10∶0.5)。实施例2(47)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(2-(2-羟基乙氧基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198402712
NMR(CDCl3):δ7.61-7.51(3H,m),7.23-7.10(3H,m),7.10-6.95(3H,m),6.51(2H,d,J=8.0Hz),4.75(1H,dd,J=5.6,10.2Hz),4.38-4.33(2H,m),3.75-3.51(7H,m),3.30-3.22(5H,m),3.09(1H,dd,J=5.6,16.6Hz),2.23-1.78(6H,m),1.96(3H,s),0.96(3H,t,J=7.4Hz);
TLC:Rf0.65(氯仿∶甲醇=15∶1)。实施例2(48)
2RS-(4-吡咯烷-1-基)苯基)丁酸4-(2RS-羟基甲基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(DMSO-d6):δ7.60(1H,s-like),7.51-7.40(2H,m),7.22-6.97(6H,m), 6.51(2H,d,J=8Hz),4.40-4.24(1H,m),3.68-3.37(3H,m),3.65(1H,t,J=7Hz),3.23-3.17(4H,m),2.87-2.69(2H,m),2.19-1.62(each 1H,m),1.99-1.93(4H,m),1.86(3H,s),0.87(3H,t,J=7Hz);
TLC:Rf0.29(己烷∶乙酸乙酯=2∶1)。实施例2(49)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基-5-羟基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3+3 drops of CD3OD):δ7.5-7.4(m,3H),7.2-7.1(m,3H),7.0-6.9(m,1H),6.5-6.4(m,3H),4.7-4.6(m,1H),3.58(t,J=7.8Hz,1H),3.4-3.2(m,4H),3.1-2.9(m,2H),2.2-1.8(m,6H),1.94(s,3H),0.97(t,J=7.2Hz,3H);
TLC:Rf0.2(氯仿∶甲醇=6∶1)。实施例2(50)
2RS-(4-吡咯烷-1-基)苯基)丁酸4-(2RS-(2-(哌嗪-1-基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·3盐酸盐
NMR(CD3OD):δ7.72-7.64(3H,m),7.57-7.49(4H,m),7.26-7.00(4H,m),5.12(1H,dd,J=6.0,8.8Hz),4.63-4.59(2H,m),3.90(1H,t,J=8.0Hz),3.77-3.59(14H,m),3.23-3.20(2H,m),2.32-1.83(6H,m),1.96(3H,s),0.97(3H,t,J=7.4Hz);
TLC:Rf0.41(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例2(51)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-羟基氨基甲酰基)二氢吲哚-1-基磺酰基)苯基酯·盐酸盐
Figure A9612198402741
NMR(CD3OD):δ7.75(2H,d,J=8.6Hz),7.60(1H,d,J=8.0Hz),7.58-7.48(4H,m),7.21(1H,dd,J=6.5Hz,1.5Hz),7.12(2H,d,J=8.6Hz),7.09-7.01(2H,m),4.68(1H,dd,J=9.0Hz,5.0Hz),3.87(1H,t,J=7.0Hz),3.77-3.70(4H,m),3.03-2.98(2H,m),2.28-2.23(4H,m),2.20-2.13(0.5H,m),1.97-1.81(1.5H,m),0.90(3H,t,J=7.0Hz);TLC:Rf0.49(己烷∶乙酸乙酯∶乙酸=8∶8∶1)。实施例2(52)
2RS-(4-甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯
Figure A9612198402751
NMR(CDCl3):δ7.74(2H,d,J=8.8Hz),7.58(1H,d,J=8.0Hz),7.29-7.02(7H,m),6.87(2H,d,J=8.8Hz),4.90(1H,brs),4.73(1H,dd,J=9.2,5.8Hz),3.80(3H,s),3.60(1H,t,J=7.8Hz),3.20-3.15(2H,m),2.23-2.05(1H,m),1.94-1.76(1H,m).0.951(3H,t,J=7.6Hz);
TLC:Rf0.36(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(53)
2RS-(4-甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402752
NMR(DMSO-d6):δ7.82(1H,d-like),7.72(1H,d-like),7.38(2H,d,J=8.6Hz),7.32(1H,d,J=7.8Hz),7.23-7.10(3H,m),7.03-6.96(3H,m),4.73(1H,dd,J=5.2 and 9.3Hz),3.88(1H,t,J=7.6Hz),3.82(3H,s),3.14-3.05(2H,m),2.25-2.10 and 1.96-1.79(each 1H,m),0.96(3H,t,J=7.2Hz);
TLC:Rf0.41(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(54)
2RS-(4-甲氧基苯基)丁酸4-(2-羧基-5,6-二甲氧基吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402761
NMR(CDCl3):δ7.79-7.64(3H,m),7.36(1H,s),7.23(2H,d,J=9Hz),7.01(1H,d,J=9Hz),6.96(1H,s),6.88(2H,d,J=9Hz),4.00(3H,s),3.91(3H,s),3.80(3H,s),3.64(1H,t,J=7Hz),2.27-2.03(1H,m),2.00-1.80(1H,m),1.96(3H,s),0.96(3H,t,J=7Hz);
TLC:Rf0.10(乙酸乙酯∶己烷∶乙酸=5∶10∶0.5)。实施例2(55)
2RS-(4-甲氧基苯基)丁酸4-(2-羧基吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ8.14(1H,d,J=9Hz),7.90-7.78(2H,m),7.60(1H,d,J=9Hz),7.52-7.40(1H,m),7.38(1H,s),7.35-7.20(3H,m),7.03(1H,d,J=9Hz),6.87(2H,d,J=9Hz),3.79(3H,s),3.64(1H,t,J=7Hz),2.28-2.05(1H,m),2.00-1.79(1H,m),1.96(3H,s),0.96(3H,t,J=7Hz);
TLC:Rf0.26(乙酸乙酯∶己烷∶乙酸=5∶10∶0.5)。实施例2(56)
2RS-(4-甲氧基苯基)丁酸4-(2-羧基-5-羟基吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.94(1H,d,J=9Hz),7.80-7.69(2H,m),7.26(2H,d,J=9Hz),7.17(1H,s),6.99(1H,d,J=9Hz),6.96(1H,dd,J=9,2Hz),6.87(2H,d,J=9Hz),6.87(1H,d,J=2Hz),3.80-3.40(1H,brs),3.79(3H,s),3.64(1H,t,J=7Hz),2.26-2.05(1H,m),2.00-1.75(1H,m),1.93(3H,s),0.95(3H,t,J=7Hz);
TLC:Rf0.16(乙酸乙酯∶己烷∶乙酸=10∶10∶0.5)。实施例2(57)
2RS-(4-甲氧基苯基)丁酸4-(2RS-羟基甲基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402781
NMR(DMSO-d6):δ7.61(1H,s-like),7.50-7.40(2H,m),7.28(2H,d,J=8Hz),7.21-6.96(4H,m),6.92(2H,d,J=8Hz),5.02(1H,t-like),4.32(1H,m)3.78(1H,t,J=7Hz),3.74(3H,s),3.67-3.57 and 3.47-3.37(each 1H,m),2.83-2.70(2H,m),2.10-1.95 and 1.86-1.65(each 1H,m),1.85(3H,s),0.88(3H,tJ=7Hz);TLC:Rf0.21(己烷∶乙酸乙酯=2∶1)。实施例2(58)
2RS-(4-甲氧基苯基)丁酸4-(2RS-(2-氨基乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198402791
NMR(DMSO-d6):δ8.25(3H,brs),7.78-7.65(2H,m),7.39-7.00(5H,m),7.28(2H,d,J=8.8Hz),6.91(2H,d,J=8.8Hz),5.08(1H,dd,J=5.8,10.0Hz),4.34(2H,t,J=5.2Hz),3.83-3.74(1H,m),3.74(3H,s),3.30-3.09(4H,m),2.17-1.75(2H,m),1.90(3H,s),0.89(3H,t,J=7.2Hz);
TLC:Rf0.53(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例2(59)
2RS-(4-甲氧基苯基)丁酸4-(2RS-(2-(哌嗪-4-基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
Figure A9612198402792
NMR(CD3OD)∶δ7.68-7.63(2H,m),7.51(1H,d,J=7.8Hz),7.27(2H,d,J=8.4Hz),7.22-7.02(4H,m),6.90(2H,d,J=8.4Hz),5.10(1H,t,J=7.2Hz),4.60(2H,brs),3.78(3H,s),3.75-3.19(13H,m),2.23-1.78(2H,m),1.89(3H,s),0.95(3H,t,J=7.4Hz):
TLC:Rf0.16(氯仿∶甲醇=10∶1)。实施例2(60)
2RS-(4-甲氧基苯基)丁酸4-(2RS-(2-(2-羟基乙氧基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.62-7.51(3H,m),7.26(2H,d,J=8.4Hz),7.28-6.96(4H,m),6.87(2H,d,J=8.4Hz),4.76(1H,dd,J=5.4,10.6Hz),4.38-4.34(2H,m),3.80(3H,s),3.75-3.55(7H,m),3.31-3.04(2H,m),2.26-1.80(2H,m),1.93(3H,s),0.97(3H,t,J=7.4Hz);
TLC:Rf0.11(己烷∶乙酸乙酯=1∶1)。实施例2(61)
2RS-(3-甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯
Figure A9612198402811
NMR(CDCl3):δ7.75(2H,d,J=8.8Hz),7.57(1H,d,J=7.8Hz),7.30-6.79(9H,m),4.73(1H,t,J=8.0Hz),3.80(3H,s),3.62(1H,t,J=7.8Hz),3.20-3.17(2H,m),2.28-2.05(1H,m),1.99-1.77(1H,m),0.96(3H,t,J=7.4Hz);
TLC:Rf0.66(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(62)
2RS-(2-甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯
NMR(CDCl3):δ7.75(2H,d,J=8.8Hz),7.58(1H,d,J=8.0Hz),7.25(2H,d,J=8.8Hz),7.31-6.87(7H,m),4.74(1H,t,J=8.0Hz),4.04(1H,t,J=7.2Hz),3.84(3H,s),3.18(2H,brd,J=7.2Hz),2.22-2.05(1H,m),1.96-1.74(1H,m),0.95(3H,t,J=7.6Hz);
TLC:Rf0.48(氯仿∶甲醇∶乙酸=40∶2∶1)。
实施例2(63)
2RS-(2-甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402821
NMR(DMSO-d6):δ13.19(1H,br),7.79(1H,d,J=2.0Hz),7.68(1H,dd,J=2.0 and 8.5Hz),7.36-6.92(9H,m),4.96(1H,dd,J=4.2 and 10.9Hz).4.08(1H,t,J=7.6Hz),3.80(3H,s),3.39-2.96(2H,m),2.19-1.69(2H,m),1.95(3H,s),0.87(3H,t,J=7.2Hz);
TLC:Rf0.39(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(64)
 2RS-(3,4-二甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯
NMR(CDCl3):δ7.76(2H,d,J=8.8Hz),7.57(1H,d,J=8.0Hz),7.25-7.02(5H,m),6.86-6.85(3H,m),4.73(1H,t,J=8.0Hz),3.87(6H,s),3.59(1H,t,J=7.8Hz),3.21-3.17(2H,brd),2.24-2.05(1H,m),1.97-1.76(1H,m),0.97(3H,t,J=7.6Hz);
TLC:Rf0.50(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(65)
2RS-(3,4-二甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402831
NMR(DMSO-d6):δ13.14(1H,br),7.80(1H,s),7.68(1H,d-like),7.35-7.11(4H,m),7.02-6.86(4H,m),4.97(1H,dd,J=4.2 and 10.5Hz),3.79(1H,t,J=7.4Hz),3.74(6H,s),3.39-2.97(2H,m),2.16-1.98 and 1.95-1.72(each 1H,m),1.91(3H,s),0.89(3H,t,J=7.2Hz);TLC:Rf0.39(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(66)
2RS-(4-甲基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯
Figure A9612198402841
NMR(CDCl3):δ7.74(2H,d.J=8.8Hz),7.58(1H,d,J=8.0Hz),7.24-7.02(9H,m),4.74(1H,t,J=8.6Hz),3.62(1H,t,J=7.8Hz),3.18(2H,brd),2.34(3H,s),2.27-2.05(1H,m),1.97-1.75(1H,m),0.96(3H,t,J=7.4Hz);
TLC:Rf0.43(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例(67)
2RS-(4-甲基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(DMSO-d6):δ13.08(1H,br),7.73(1H,d,J=2.0Hz),7.61(1H,dd,J=2.0 and 8.6Hz),7.28-6.87(9H,m),4.90(1H,dd,J=4.0 and 10.8Hz),3.75(1H,t,J=7.6Hz),3.32-2.90(2H,m),2.22(3H,s),2.13-1.91 and 1.86-1.64(each1H,m),1.82(3H,s),0.80(3H,t,J=7.2Hz);
TLC:Rf0.43(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(68)
2RS-(4-甲基苯基)丁酸4-(2-羧基-5,6-二甲氧基吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402851
NMR(CDCl3):δ7.78-7.64(3H,m),7.35(1H,s),7.23(2H,d,J=9Hz),7.15(2H,d,J=9Hz),7.00(1H,d,J=9Hz),6.95(1H,s),4.00(3H,s),3.91(3H,s),3.85-3.30(1H,br),3.65(1H,t,J=7Hz),2.33(3H,s),2.30-2.10(1H,m),2.00-1.80(1H,m),1.96(3H,s),0.96(3H,t,J=7Hz),TLC:Rf0.23(乙酸乙酯∶己烷∶乙酸=5∶10∶0.5)。实施例2(69)
2RS-(4-甲基苯基)丁酸4-(2-羧基吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402861
NMR(CDCl3):δ8.14(1H,d,J=9Hz),7.90-7.78(2H,m),7.60(1H,d,J=9Hz),7.52-7.41(1H,m),7.39(1H,s),7.35-7.10(5H,m),7.03(1H,d,J=9Hz),4.00-3.60(1H,br),3.66(1H,t,J=7Hz),2.33(3H,s),2.30-2.07(1H,m),2.00-1.75(1H,m),1.97(3H,s),0.96(3H,t,J=7Hz);
TLC:Rf0.28(乙酸乙酯∶己烷∶乙酸=5∶10∶0.5)。实施例2(70)
2RS-(4-甲基苯基)丁酸4-(2-羧基-5-羟基吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402862
NMR(CDCl3)∶δ7.95(1H,d,J=9Hz),7.81-7.69(2H,m),7.22(2H,d,J=8Hz),7.20(1H,s),7.15(2H,d,J=8Hz),7.00(1H,d,J=8Hz),6.97(1H,dd,J=9,2Hz),6.89(1H,d,J=2Hz),3.80-3.30(1H,br),3.66(1H,t,J=7Hz),2.33(3H,s),2.28-2.10(1H,m),2.00-1.80(1H,m),1.94(3H,s),0.96(3H,t,J=7Hz);
TLC:Rf0.24(乙酸乙酯∶己烷∶乙酸=10∶10∶0.5)。实施例2(71)
2RS-(4-甲基苯基)丁酸4-(2RS-(2-氨基乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198402871
NMR(CDCl3+CD3OD):δ7.8-7.5(m,4H),7.3-7.0(m,7H),5.0-4.8(m,1H),4.6-4.4(m,2H),3.67(t,J=9.2Hz,1H),3.4-3.3(m,2H),3.3-3.2(m,2H),2.34(S,3H),2.3-1.8(m,2H),1.95(s,3H),0.97(1,J=7.0Hz,3H);
TLC:Rf0.5(氯仿∶甲醇=4∶1)。实施例2(72)
2RS-(4-甲基苯基)丁酸4-(2RS-羟基甲基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402881
NMR(DMSO-d6):δ7.61(1H,s-like),7.51-7.40(2H,m),7.27-6.96(8H,m),5.04(1H,t-like),4.34(1H,m),3.81(1H,t,J=7Hz),3.67-3.57 and 3.48-3.39(each 1H,m),2.83-2.68(2H,m),2.29(3H,s),2.20-1.97 and 1.88-1.67(each1H,m),1.86(3H,s),0.87(3H,t,J=7Hz);
TLC:Rf0.30(己烷∶乙酸乙酯=2∶1)。实施例2(73)
2RS-(4-甲基苯基)丁酸4-(2RS-(2-(2-羟基乙氧基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3)δ7.7-7.5(m,3H),7.3-6.9(m,8H),4.9-4.7(m,1H),4.4-4.3(m,2H),3.8-3 5(m,7H),3.4-3.0(m,2H),2.34(s,3H),2.4-1.8(m,2H),1.93(s,3H),0.97(t,J=7.2Hz,3H);
TLC:Rf0.25(己烷∶乙酸乙酯=1∶1)。实施例2(74)
2RS-(4-甲基苯基)丁酸4-(2RS-(2-(哌嗪-4-基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3)δ7.7-7.5(m,3H),7.5-7.4(m,1H),7.3-6.9(m,7H),5.2-5.0(m,1H),4.7-4.5(m,2H),4.0-3.5(m,11H),3.4-3.0(m,2H),2.30(s,3H),2.4-2.0(m,1H),1.88(s,3H),2.0-1.8(m,1H),0.93(t,J=7.2Hz,3H);
TLC:Rf0.3(氯仿∶甲醇=2∶1)。实施例2(75)
2RS-(4-羟基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402901
NMR(CDCl3):δ7.7-7.5(3H,m),7.3-7.1(3H,m),7.1-6.9(3H,m),6.80(2H,d,J=8.4Hz),4.8-4.7(1H,m),3.7-3.3(1H,m),3.3-3.1(2H,m),2.3-2.0(1H,m),2.0-1.8(1H,m),1.91(3H,s),0.96(3H,t,J=7.4Hz);
TLC:Rf0.42(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(76)
2RS-(4-氨基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯NMR(DMSO-d6):δ7.83(2H,d,J=8.4Hz),7.30(1H,d,J=8.2Hz),7.12(2H,d,J=8.4Hz),6.97(2H,d,J=8.4Hz),7.17-6.90(3H,m),6.53(2H,d,J=8.4Hz),4.80-4.73(1H,m),3.54(1H,t,J=7.6Hz),3.25-2.93(2H,m),2.09-1.90(1H,m),1.78-1.60(1H,m),0.86(3H,t,J=7.2Hz);
TLC:Rf0.20(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(77)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4S-羧基全氢化噻唑-3-基磺酰基)苯基酯·盐酸盐
Figure A9612198402911
NMR(CDCl3):δ7.85(2H,d,J=8.8Hz),7.21(2H,d,J=8.8Hz),7.17(2H,d.J=8.8Hz),6.57(2H,d,J=8.8Hz),4.83(1H,dd,J=7.0 and 3.4Hz),4.67(1H,d,J=9.0Hz),4.40(1H,d,J=9.0Hz),3.59(1H,t,J=7.6Hz),3.40-3.18(5H,m),3.01(1H,dd,J=11.4 and 7.0Hz),2.30-2.05 and 2.05-1.75(each 1H,m),2.10-1.95(4H,m),0.98(3H,t,J=7.6Hz);
TLC:Rf0.36(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(78)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-羧基哌啶-1-基磺酰基)苯基酯·盐酸盐
NMR(CDCl3):δ7.71(2H,d,J=8.8Hz),7.21(2H,d,J=8.8Hz),7.17(2H,d,J=8.8Hz),6.55(2H,d,J=8.8Hz),3.72-3.54(2H,m),3.59(1H,t,J=7.6Hz),3.36-3.20(4H,m),2.45(2H,t-like)2.38-1.70(7H,m),2.08-1.94(4H,m),0.98(3H,t,J=7.4Hz);
TLC:Rf0.34(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(79)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基哌啶-1-基磺酰基)苯基酯·盐酸盐
Figure A9612198402922
NMR(CDCl3):δ7.75(2H,d,J=8.8Hz),7.21(2H,d,J=8.8Hz),7.08(2H,d,J=8.8Hz),6.55(2H,d,J=8.8Hz),4.8-4.7(1H,m),3.8-3.7(1H,m),3.58(1H,t,J=7.5Hz),3.4-3.1(5H,m),2.3-1.2(12H,m),0.97(3H,t,J=7.4Hz);
TLC:Rf0.48(乙酸∶甲醇∶氯仿∶1∶2∶50)。实施例2(80)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(3RS-羧基哌啶-1-基磺酰基)苯基酯·盐酸盐
Figure A9612198402931
NMR(CDCl3):δ7.75(2H,d,J=8.4Hz),7.7-7.3(4H,m),7.19(2H,d,J=8.4Hz),4.0-3.4(8H,m),2.7-2.5(2H,m),2.5-2.1(5H,m),2.1-1.3(5H,m),1.00(3H,t,J=7.4Hz);
TLC:Rf0.32(乙酸∶甲醇∶氯仿=1∶2∶100)。实施例2(81)
2RS-(4-(吡咯烷-1-基)苯基丁酸4-(4S-羧基全氢化噻唑-3-基磺酰基)-2-甲基苯基酯
NMR(CDCl3+CD3OD):δ7.69(1H,s),7.66(1H,d,J=8.0Hz),7.21(2H,d,J=8.6Hz),7.07(1H,d,J=8.0Hz),6.55(2H,d,J=8.6Hz),4.71(1H,dd,J=7.2,3.2Hz),4.63(1H,d,J=9.8Hz),4.45(1H,d,J=9.8Hz),3.61(1H,t,J=7.7Hz),3.4-3.2(5H,m),2.84(1H,dd,J=11.2,7.2Hz),2.3-2.1(1H,m),2.1-1.8(4H,br),2.02(3H,s),0.98(3H,d,J=7.3Hz);
TLC:Rf0.55(氯仿∶甲醇∶乙酸=25∶5:1)。实施例2(82)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基吗啉-1-基磺酰基)-2-甲基苯基酯
Figure A9612198402942
NMR(CD3OD):δ7.65-7.54(2H,m),7.20(2H,d,J=8Hz),7.15(1H,d,J=8Hz),6.58(2H,d,J=8Hz),4.03-3.80(3H,m),3.71-3.38(3H,m),3.37-3.15(4H.m),2.50-1.78(11H,m),0.97(3H,t,J=7Hz);
TLC∶Rf0.25(甲醇∶氯仿=3∶17)。实施例2(83)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(1S-氧代-4S-羧基全氢化噻唑-3-基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CD3OD):δ7.90-7.75(2H,m),7.61(4H,s),7.18(1H,d,J=8.5Hz),5.25(1H,dd,J=8.5,2.0Hz),5.19(1H,d,J=12.0Hz),4.13(1H,d,J=12.0Hz),3.98(1H,t,J=7.5Hz),3.85-3.70(4H,m),3.41(1H,dd,J=14.5,2.0Hz),3.03(1H,dd,J=14.5,8.5Hz),2.35-2.20(4H,m),2.40-1.80(2H,m),2.04(3H,s),1.00(3H,t,J=7.5Hz);
TLC:Rf0.18(氯仿∶甲醇∶乙酸=40∶10∶1)。实施例2(84)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4S-羧基-1,1-二氧代全氢化噻唑-3-基磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198402961
NMR(CDCl3):δ7.75-7.65(2H,m),7.48(4H,s),7.10(1H,d,J=8.5Hz),5.06(1H,dd,J=8.5,4.0Hz),4.68(1H,d,J=11.0Hz),4.26(1H,d,J=11.0Hz),3.78(1H,t,J=7.5Hz),3.70-3.55(4H,m),3.55-3.35(2H,m),2.40-2.25(4H,m),2.40-1.80(2H,m),2.07(3H,s),1.01(3H,t,J=7.5Hz);
TLC:Rf0.14(氯仿∶甲醇∶乙酸=40∶10∶1)。实施例2(85)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-(2-羟基乙基)哌嗪-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
Figure A9612198402962
NMR(CD3OD):δ7.75-7.47(6H,m),7.23(1H,d,J=8.8Hz),4.03-3.79(5H,m),3.79-3.57(6H,m),3.40-3.14(4H,m),2.77(2H,t-like,J=13.8Hz),2.38-2.15(5H,m),2.06(3H,s),2.15-1.84(1H,m),1.00(3H,t,J=7.4Hz);
TLC:Rf0.21(己烷∶乙酸乙酯=1∶1)。实施例2(86)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-羧基甲基哌嗪-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(CD3OD):δ7.79-7.53(6H,m),7.24(1H,d,J=8.0Hz),4.14(2H,s),4.00(1H,t,J=7.8Hz),3.87-3.70(4H,m),3.52(8H,brs),2.44-2.15(5H,m),2.07(3H,s),2.15-1.82(1H,m),1.00(3H,t,J=7.2Hz);
TLC:Rf0.63(氯仿∶甲醇∶乙酸=15∶2∶1)。实施例2(87)
2RS-(4-硝基苯基)丁酸4-(4S-羧基全氢化噻唑-3-基磺酰基)苯基酯
NMR(CDCl3):δ8.27(2H,d,J=8.8Hz),7.94(2H,d,J=8.8Hz),7.68(2H,d,J=8.8Hz),7.26(2H,d,J=8.8Hz),4.86(1H,dd,J=3.6 and 7.4Hz),4.73(1H,d,J=8.0Hz),4.41(1H,d,J=8.0Hz),4.03(1H,t,J=7.6Hz),3.17(1H,dd,J=11.5and 3.6Hz),2.93(1H,dd,J=11.5 and 7.4Hz),2.40-2.15 and 2.10-1.85(each1H,m),1.00(3H,t,J=7.2Hz);
TLC:Rf0.38(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(88)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-2-甲氧基乙基氨磺酰)苯基酯·三氟乙酸盐
NMR(CD3OD):δ7.85(2H,d,J=8.6Hz),7.41(2H,d,J=8.6Hz),7.17(2H,d,J=8.6Hz),7.11(2H,d,J=8.6Hz),4.10(2H,s),3.77(1H,t,J=6.0Hz),3.46(8H,m),3.20(3H,s),2.20(1H,m),2.15(4H,m),1.90(1H,m),0.97(3H,t,J=7.0Hz);
TLC:Rf0.32(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(89)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS,2-二羧基乙基氨磺酰)苯基酯·三氟乙酸盐
Figure A9612198402991
NMR(CD3OD):δ7.87(2H,d,J=8.6Hz),7.36(2H,brd,J=8.6Hz),7.14(2H,d,J=8.6Hz),7.00(2H,brd,J=8.6Hz),4.21(1H,t,J=6.0Hz),3.74(1H,m),3.48(4H,m),2.72(2H,d,J=6.2Hz),2.18(1H,m),2.13(4H,m),1.87(1H,m),0.97(3H,t,J=7.4Hz);TLC:Rf0.26(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(90)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1-羧基环丁烷)氨磺酰)苯基酯·盐酸盐
NMR(CDCl3):δ7.81(2H,d,J=8.8Hz),7.15(2H,d,J=8.8Hz),7.05(2H,d,J=8.8Hz),6.55(2H,d,J=8.8Hz),5.66(1H,s),3.58(1H,t,J=7.6Hz),3.36-3.18(4H,t-like),2.30-2.00 and 2.00-1.75(each 1H,m),2.06-1.96(4H,m),1.56-1.35(4H,m),0.97(3H,t,J=7.4Hz);
TLC:Rf0.38(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(91)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-羧基-2-苯基乙基氨磺酰)苯基酯·盐酸盐
NMR(DMSO-d6):δ8.38(1H,d,J=10Hz),7.55(2H,d,J=9Hz),7.30-7.00(9H,m),6.76(2H,d,J=9Hz),3.95-3.79(1H,m),3.71(1H,t,J=7Hz),3.40-3.20(4H,m),2.94(1H,dd,J=15Hz,5Hz),2.70(1H,dd,J=15Hz,8Hz),2.20-1.90(5H,m),1.90-1.65(1H,m),0.90(3H,t,J=7Hz);
TLC:Rf0.19(乙酸乙酯∶己烷∶乙酸=5∶5∶0.1)。实施例2(92)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1S-羧基-2-甲基丙基氨磺酰)苯基酯·盐酸盐
Figure A9612198403012
NMR(DMSO-d6):δ8.05(1H,d,J=9Hz),7.78(2H,d,J=8Hz),7.25(2H,d,J=8Hz),7.17(2H,d,J=8Hz),6.86-6.70(2H,m),3.73(1H,t,J=7Hz),3.50(1Hdd,J=9Hz,6Hz),3.38-3.20(4H,m),2.20-1.68(7H,m),0.88(3H,t,J=7Hz),0.80(3H,d,J=7Hz),0.76(3H,d,J=7Hz);
TLC:Rf0.34(乙酸乙酯)实施例2(93)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1S-羧基-2-羧基甲硫基乙基)氨磺酰)苯基酯·盐酸盐
NMR(CD3OD):δ7.89(2H,d,J=8.8Hz),7.63(2H,d,J=15.0Hz),7.62(2H,d,J=15.0Hz),7.18(2H,d,J=8.8Hz),4.08(1H,dd,J=5.9,7.5Hz),3.91(1H,t,J=7.5Hz),3.82-3.70(4H,m),3.19(2H,s),3.00(1H,dd,J=5.9,14.0Hz),2.84(1H,dd,J=7.5,14.0Hz),2.40-2.12(5H,m),2.02-1.80(1H,m),0.98(3H,t,J=7.0Hz);TLC:Rf0.20(氯仿∶甲醇∶水=7∶3∶0.3)。实施例2(94)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-羧基-1-(噻吩-2-基)甲基氨磺酰)苯基酯·盐酸盐
Figure A9612198403031
NMR(DMSO-d6):δ8.88(1H,d,J=9.0Hz),7.77(2H,d,J=8.8Hz),7.40(1H,dd,J=1.2,5.0Hz),7.24(2H,d,J=8.4Hz),7.14(2H,d,J=8.8Hz),7.00-6.91(1H,m),6.88(1H,dd,J=3.7,5.0Hz),6.85-6.72(2H,m),5.16(1H,d,J=9.0Hz),3.71(1H,t,J=7.2Hz),3.40-3.20(4H,m),2.20-1.90(5H,m),1.88-1.70(1H,m),0.89(3H,t,J=7.2Hz);
TLC:Rf0.27(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2(95)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-羧基-1-(呋喃-2-基)甲基氨磺酰)苯基酯·盐酸盐
Figure A9612198403032
NMR(DMSO-d6):δ8.78(1H,d,J=9.0Hz),7.75(2H,d,J=8.6Hz),7.46(1H,m),7.24(2H,d,J=8.2Hz),7.12(2H,d,J=8.6Hz),6.90-6.70(2H,m),6.31-6.24(1H,m),6.19(1H,d,J=2.8Hz),5.02(1H,d,J=9.0Hz),3.71(1H,t,J=7.6Hz),3.40-3.20(4H,m),2.20-1.86(5H,m),1.86-1.68(1H,m),0.89(3H,t,J=7.4Hz);
TLC:Rf0.27(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2(96)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(羧基甲基-N-2-甲氧基乙基氨磺酰)-2-甲基苯基酯
NMR(CDCl3):δ7.64(1H,d,J=2.0Hz),7.61(1H,dd,J=8.0,2.0Hz),7.21(2H,d,J=8.5Hz),7.04(1H,d,J=8.0Hz),6.55(2H,d,J=8.5Hz),4.08(2H,s),3.61(1H,t,J=7.5Hz),3.55(2H,t,J=4.5Hz),3.40(2H,t,J=4.5Hz),3.35-3.20(4H,m),3.29(3H,s),2.30-1.70(2H,m),2.05-1.95(4H,m),2.01(3H,s),0.99(3H,t,J=7.5Hz);TLC∶Rf0.47(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(97)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-丙基-N-羧基甲基氨磺酰)-2-甲基苯基酯
Figure A9612198403051
NMR(CDCl3):δ7.70-7.55(2H,m),7.23(2H,d,J=8Hz),7.01(1H,d,J=8Hz),6.55(2H,d,J=8Hz),4.20-3.80(1H,br),3.98(2H,s),3.60(1H,t,J=7Hz),3.35-3.07(6H,m),2.28-1.75(9H,m),1.60-1.38(2H,m),0.98(3H,t,J=7Hz),0.90(3H,t,J=7Hz);
TLC:Rf0.23(氯仿∶甲醇=19∶1)。实施例2(98)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1S-羧基-5-氨基戊基氨磺酰)-2-甲基苯基酯·2盐酸盐
Figure A9612198403052
NMR(CD3OD):δ7.80-7.47(6H,m),7.10(1H,d,J=8Hz),3.95(1H,t,J=7Hz),3.90-3.68(5H,m),2.95-2.80(2H,m),2.35-2.20(5H,m),2.10-1.85(1H,m),1.99(3H,s),1.85-1.30(6H,m),0.98(3H,t,J=7Hz);
TLC:Rf0.22(氯仿∶甲醇∶水=8∶2∶0.1)。实施例2(99)
2-(4-甲氧基苯基)-2-乙基丁酸4-(N-羧基甲基氨磺酰)苯基酯
Figure A9612198403061
NMR(CDCl3):δ7.80(2H,d,J=8.8Hz),7.25(2H,d,J=8.8Hz),7.04(2H,d,J=8.6Hz),6.90(2H,d,J=8.8Hz),3.80(3H,s),3.73(2H,brs),2.25-2.00(4H,m),0.82(6H,t,J=7.4Hz);
TLC:Rf0.10(己烷∶乙酸乙酯=2∶1)。实施例2(100)
1-(4-硝基苯基)环丁烷羧酸4-(N-2-甲氧基乙基-N-羧基甲基氨磺酰)苯基酯
Figure A9612198403071
NMR(CDCl3)δ8.25(2H,d,J=9.0Hz),7.82(2H,d,J=9.0Hz),7.55(2H,d,J=9.0Hz),7.11(2H,d,J=9.0Hz),4.13(2H,s),3.53(2H,t,J=5.0Hz),3.41(2H,t,J=5.0Hz),3.27(3H,s),3.06(2H,m),2.67(2H,m),2.26(1H,m),2.04(1H,m);
TLC:Rf0.29(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(101)
1-(4-硝基苯基)环丁烷羧酸4-(N-1RS,2-二羧基乙基氨磺酰)苯基酯
Figure A9612198403072
NMR(CD3OD)):δ8.27(2H,d,J=8.8Hz),7.87(2H,d,J=8.8Hz),7.65(2H,d,J=8.8Hz),7.15(2H,d,J=8.8Hz),4.21(1H,t,J=5.8Hz),3.05(2H,m),2.71(4H,m),2.25(1H,m),2.04(1H,m);
TLC:Rf0.17(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(102)
2RS-苯基丁酸4-(N-羧基甲基氨磺酰)苯基酯
NMR(DMSO-d6):δ8.04(1H,brs),7.82(2H,d,J=8Hz),7.45-7.25(5H,m),7.21(2H,d,J=8Hz),3.86(1H,t,J=7Hz),3.56(2H,s),2.10 and 1.85(each1H,m),0.91(3H,t,J=7Hz);
TLC:Rf0.32(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(103)
2RS-苯基丁酸4-(N-丙基-N-羧基甲基氨磺酰)苯基酯
NMR(DMSO-d6):δ12.65(1H,brs),8.04(1H,brs),7.84(2H,d,J=8Hz),7.45-7.25(5H,m),7.21(2H,d,J=8Hz),3.92(2H,s),3.85(1H,t,J=7Hz),3.10(2H,t),2.10 and 1.86(each 1H,m),1.44(2H,m),0.92(3H,t,J=7Hz),0.77(3H,t,J=7Hz);
TLC:Rf0.54(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(104)
2RS-苯基丁酸4-(N-苄基-N-羧基甲基氨磺酰)苯基酯
NMR(CDCl3):δ7.90-7.79(2H,m),7.43-7.08(12H,m),6.34(1H,br),4.46(2H,s),3.90(2H,s),3.70(1H,t,J=7Hz),2.22(1H,ddq,J=14Hz,7Hz,7Hz),1.92(1H,ddq,J=14Hz,7Hz,7Hz),0.98(3H,t,J=7Hz);
TLC:Rf0.42(二氯甲烷∶甲醇=9∶1)。实施例2(105)
2RS-苯基丁酸4-(N-2-苯基乙基-N-羧基甲基氨磺酰)苯基
Figure A9612198403101
NMR(CDCl3):δ7.77(2H,d,J=8Hz),7.40-7.04(12H,m),5.89(1H,br),3.95(2H,s),3.69(1H,t,J=7Hz),3.53-3.40(2H,m),2.91-2.80(2H,m),2.21(1H,ddq,J=14Hz,7Hz,7Hz),1.90(1H,ddq,J=14Hz,7Hz,7hz),0.97(3H,t,J=7Hz);
TLC:Rf0.41(二氯甲烷∶甲醇=9∶1)。实施例2(106)
2RS-苯基丁酸4-(N-苯基-N-羧基甲基氨磺酰)苯基酯
NMR(CDCl3):δ7.63(2H,d,J=8Hz),7.45-7.04(12H,m),6.20(1H,br),4.40(2H,s),3.70(1H,t,J=7Hz),2.23(1H,ddq,J=14Hz,7Hz,7hz),1.91(1H,ddq,J=14Hz,7Hz,7Hz),0.99(3H,t,J=7Hz);
TLC:Rf0.41(二氯甲烷∶甲醇=9∶1)。实施例2(107)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-二(2-羟基乙基)氨磺酰)-2-甲基苯基酯·盐酸盐
NMR(CD3OD):δ7.78-7.50(6H,m),7.15(1H,d,J=8Hz),3.96(1H,tJ=7Hz),3.95-3.80(8H,m),3.35-3.18(4H,m),2.40-2.15(5H,m),2.10-1.80(1H,m),2.02(3H,s),0.99(3H,t,J=7Hz);
TLC:Rf0.23(己烷∶乙酸乙酯=1∶1)。实施例2(108)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-二(2-(2-羟基乙氧基)乙基)氨磺酰)-2-甲基苯基酯
Figure A9612198403112
NMR(CDCl3):δ7.70-7.55(2H,m),7.23(2H,d,J=9Hz),7.06(1H,d,J=8Hz),6.55(2H,d,J=9Hz),3.75-3.45(13H,m),3.43-3.23(8H,m),3.05(2H,brs),2.30-1.73(9H,m),0.98(3H,t,J=7Hz);
TLC:Rf0.33(乙酸乙酯)。实施例2(109)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(3RS-羧基-1,4-苯并二噁烷-5-基)氨磺酰)苯基酯·盐酸盐
Figure A9612198403121
NMR(DMSO-d6):δ9.67(1H,s),7.80(2H,d,J=9Hz),7.20(2H,d,J=9Hz),7.13(2H,d,J=9Hz),6.84-6.57(5H,m),4.78(1H,1,J=3Hz),4.28(1H,dd,J=11Hz,3Hz),4.13-4.00(1H,m),3.68(1H,t,J=7Hz),3.35-3.18(4H,m),2.15-1.88(5H,m),1.88-1.60(1H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.18(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(110)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2RS-羟基-4R-羟基-5R-羟基-6R-羟基甲基全氢化吡喃-3R-基氨磺酰)-2-甲基苯基酯
Figure A9612198403131
NMR(DMSO-d6+3 drop of CD3OD):δ7.80-7.60(2H,m),7.20(2H,d,J=8.5Hz),7.05(1H,d,J=8.5Hz),6.60(2H,d,J=8.5Hz),4.78(1H,d,J=3.5Hz),3.70(1H,t,J=7.5Hz),3.65-3.35(4H,m),3.30-3.15(4H,m),3.03(1H,t,J=9.0Hz),2.90(1H,dd,J=10.5,3.5Hz),2.20-1.60(2H,m),2.00-1.90(4H,m),1.94(3H,s),0.91(3H,t,J=7.5Hz);
TLC:Rf0.55(氯仿∶甲醇∶水=40∶10∶1)。实施例2(111)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-3-羧基金刚烷-1-基氨磺酰)苯基酯
NMR(CDCl3):δ7.85(2H,d,J=8.8Hz),7.22(2H,d,J=8.8Hz),7.12(2H,d,J=8.8Hz),6.54(2H,d,J=8.8Hz),4.60(1H,s),3.59(1H,t,J=7.4Hz),3.40-3.15(4H,m),2.30-1.40(20H,m),0.98(3H,t,J=7.6Hz);
TLC:Rf0.60(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(112)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1S,4R,3R-羧基二环[2.2.1]庚烷-2S-基)氨磺酰)苯基酯
NMR(CDCl3):δ7.83(2H,d,J=8.6Hz),7.21(2H,d,J=8.6Hz),7.11(2H,d,J=8.6Hz),6.55(2H,d,J=8.6Hz),7.6-7.4(1H,br),3.58(1H,t,J=7.6Hz),3.58(1H,t,J=8.0Hz),3.40-3.20(4H,m),2.64(1H,d,J=8.0Hz),2.42(1H,s),2.30-1.70(4H,m),2.10-1.90(4H,m),1.50-1.30(2H,m),1.30-0.90(3H,m),0.97(3H,t,J=7.3Hz);
TLC:Rf0.33(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(113)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-3S-羧基环己烷-1R-基氨磺酰)苯基酯·盐酸盐
NMR(DMSO-d6):δ7.90-7.70(3H,m),7.30-7.10(4H,m),6.70(2H,d,J=9Hz),3.71(1H,t,J=7Hz),3.35-3.15(4H,m),3.09-2.86(1H,m),2.27-1.45(11H,m),1.33-0.95(4H,m),0.89(3H,t,J=7Hz);
TLC:Rf0.36(乙酸乙酯∶己烷∶乙酸=5∶5∶0.1)。实施例2(114)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2RS-羧基环己烷-1RS-基氨磺酰)苯基酯
NMR(CDCl3):δ7.84(2H,d,J=8.8Hz),7.23-7.08(4H,m),6.55(2H,d,J=8.6Hz),5.70(1H,brs),3.59(1H,t,J=8.0Hz),3.45(1H,brs),3.32-3.26(4H,m),2.65(1H,brs),2.25-1.20(14H,m),0.98(3H,t,J=7.0Hz);
TLC:Rf0.22(己烷∶乙酸乙酯=1∶1)。实施例2(115)
2RS-(2H-1,4-苯并噁嗪-3-酮-6-基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯
Figure A9612198403161
NMR(DMSO-d6):δ10.73(1H,s),7.88(2H,d,J=8.6Hz),7.26(2H,d,J=8.6Hz),6.95(3H,s),4.57(2H,s),4.13-4.00(1H,m),3.79(1H,t,J=7.6Hz),3.40-3.08(2H,m),2.20-1.40(6H,m),0.91(3H,t,J=7.2Hz);
TLC:Rf0.35(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(116)
2RS-(2H-1,4-苯并噁嗪-3-酮-6-基)丁酸4-(2R-羧基吡咯烷-1-基磺酰基)苯基酯
Figure A9612198403162
NMR(DMSO-d6):δ13.4-12.2(1H,br),10.72(1H,s),7.88(2H,d,J=8.6Hz),7.29(2H,d,J=8.6Hz),6.95(3H,s),4.57(2H,s),4.16-4.08(1H,m),3.80(1H,t,J=7.6Hz),3.50-3.05(2H,m),2.05-1.45(6H,m),0.91(3H,t,J=7.2Hz);
TLC:Rf0.36(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(117)
2RS-(2-甲基苯并咪唑-5-基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯·盐酸盐
Figure A9612198403171
NMR(CD3OD):δ7.90-7.61(5H,m),7.23(2H,d,J=9Hz),4.23-4.17(1H,m),4.06(1H,t,J=8Hz),3.51-3.40(1H,m),3.31-3.20(2H,m),2.87(3H,s),2.38-2.24(1H,m),2.06-1.86(3H,m),1.76-1.64(1H,m),1.01(3H,t,J=7Hz);
TLC:Rf0.21(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(118)
2-(萘-1-基)乙酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403181
NMR(DMSO-d6):δ12.74(1H,br),11.58(1H,br),9.20(1H,t,J=5Hz),8.08-7.70(6H,m),7.63-7.42(6H,m),7.29(2H,d,J=9Hz),7.17-7.10(1H,m),4.46(2H,s),3.89(2H,d,J=6Hz);
TLC:Rf0.28(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(119)
2-(萘-2-基)乙酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403182
NMR(DMSO-d6):δ12.67(1H,b r),11.63(1H,br),9.24(1H,t-like),7.93-7.71(7H,m),7.54-7.43(5H,m),7.36-7.29(2H,m),7.18-7.10(1H,m),4.15(2H,s),3.90(2H,d,J=6Hz);
TLC:Rf0.31(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(120)
2RS-(1,3-苯并二氧戊环-5-基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ12.73(1H,br),11.62(1H,br),9.22(1H,t,J=6Hz),7.82-7.71(3H,m),7.53-7.42(2H,m),7.26-7.10(3H,m),6.94-6.79(3H,m),6.01(2H,s),3.89(2H,d,J=5Hz),3.75(1H,t,J=8Hz),2.16-1.95 and 1.86-1.64(each 1H,m),0.86(3H,t,J=7Hz);
TLC:Rf0.68(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(121)
2RS-(噻吩-2-基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403201
NMR(DMSO-d6):δ9.4-9.2(1H,br),7.9-7.7(3H,m),7.6-7.4(3H,m),7.3-7.0(5H,m),4.19(1H,t,J=7Hz),3.90(2H,d,J=5Hz),2.2-2.0(1H,m),2.0-1.8(1H,m),0.92(3H,t,J=7Hz);
TLC:Rf0.18(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(122)
2-(1,3-苯并二氧戊环-5-基)-2-乙基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403202
NMR(DMSO-d6):δ12.62(1H,br),11.66(1H,br),9.24(1H,t-like),7.82-7.71(3H,m),7.52-7.42(2H,m),7.31-7.10(3H,m),6.91-6.76(3H,m),6.01(2H,s),3.89(2H,d,J=5Hz),2.09-1.96(4H,m),0.75(6H,t,J=8Hz);
TLC:Rf0.39(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(123)
2RS-(噻吩-2-基)-3-甲基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ12.64(1H,br),11.70(1H,br),9.24(1H,t-like),7.82(2H,d,J=8Hz),7.74(1H,d,J=8Hz),7.54-7.43(3H,m),7.26-7.00(5H,m),3.95(1H,d,J=7Hz),3.90(2H,d,J=6Hz),2.36-2.18(1H,m),1.07 and 0.83(each 3H,each d,J=7Hz);
TLC:Rf0.24(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(124)
2RS-(环己烷-1-基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6)∶δ12.72(1H,br),11.64(1H,br),9.27(1H,br),7.83(2H,d,J=10Hz),7.75(1H,d,J=10Hz),7.51(1H,t,J=10Hz),7.48(1H,t,J=8Hz)7.27(2H,d,J=12Hz),7.15(1H,t,J=10Hz),3.90(2H,d,J=3Hz),2.35-2.30(1Hm),1.78(1H,d-like),1.71-1.55(7H,m),1.25-0.98(5H,m),0.92(3H,t,J=7Hz);
TLC:Rf0.30(乙酸∶甲醇∶氯仿=1∶2∶20)。实施例2(125)
2RS-(吡啶-3-基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403221
NMR(DMSO-d6):δ12.00(2H,br),9.36(1H,br),8.68-8.46(2H,br),7.85-7.78(4H,m),7.50-7.10(6H,m),4.04-3.75(3H,br),2.27-2.02 and 1.96-1.74(each 1H,m),0.90(3H,br);
TLC:Rf0.37(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(126)
2RS-(2H-1,4-苯并噁嗪-3-酮-6-基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ10.69(1H,s),9.53(1H,t-like),8.29(1H,s),7.83-7.73(3H,m),7.49-7.39(2H,m),7.20-6.91(6H,m),4.55(2H,s),3.90-3.86(2H,d-like),3.73(1H,t,J=7Hz),2.14-1.98 and 1.80-1.66(each 1H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.38(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(127)
2RS-(2-(N-甲氧基羰基氨基)噻唑-4-基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403232
NMR(DMSO-d6):δ12.30(1H,br),11.81(2H,br),9.24(1H,t-like),7.81(2H,d,J=7Hz),7.74(1H,d,J=8Hz),7.51-7.45(2H,m),7.25-7.10(3H,m),7.07(1H,s),3.90(1H,t,J=7Hz),3.89(2H,d,J=4Hz),3.73(3H,s),2.12-1.81(2H,m),0.90(3H,t,J=7Hz);
TLC:Rf0.28(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(128)
2RS-(2-甲基苯并咪唑-5-基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·盐酸盐
Figure A9612198403241
NMR(CD3OD):δ7.75-7.68(4H,m),7.63-7.57(3H,m),7.46-7.37(1H,m),7.16-7.07(3H,m),4.00(1H,t,J=8Hz),3.94(2H,s),2.85(3H,s),2.34-2.15and 2.06-1.88(each 1H,m),0.97(3H,t,J=7Hz);TLC:Rf0.26(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(129)
2RS-(1H-1-甲基-2-吡啶酮-3-基)丁酸4-(N-2-N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403251
NMR(DMSO-d6):δ12.59(1H,br),11.65(1H,br),9.23(1H,t-like),7.82-7.63(4H,m),7.49-7.40(3H,m),7.25-7.09(3H,m),6.23(1H,t,J=7Hz),3.90(2H,d,J=6Hz),3.72(1H,t,J=7Hz),3.45(3H,s),2.04-1.70(2H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.27(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(130)
2RS-苯基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CDCl3)δ7.67(3H,m),7.50-7.20(7H,m),7.08(1H,t,J=8Hz),6.97(2H,d,J=8Hz),6.60(1H,s),5.69(2H,brs),4.00(2H,m),3.66(1H,t,J=7Hz),2.16(1H,m),1.86(1H,m),0.94(3H,t,J=7Hz);
TLC:Rf0.23(氯仿∶甲醇=5∶1)。实施例2(131)
2-苯基-2-乙基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ12.63(1H,br),11.67(1H,br),9.22(1H,t-like),7.82-7.70(3H,m),7.51-7.07(10H,m),3.89(2H,d,J=6Hz),2.09(4H,m),0.76(6H,m);
TLC:Rf0.58(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(132)
2RS-苯基丙酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403271
NMR(d6-DMSO):δ12.73(1H,br),11.59(1H,br),9.25-9.19(1H,t-like),7.82-7.70(3H,m),7.50-7.10(10H,m),4.10(1H,q,J=7Hz),3.89(2H,d,J=5Hz),1.49(3H,d,J=7Hz);
TLC:Rf0.32(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(133)
2R-苯基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CDCl3):δ10.22(1H,s),7.71-7.65(3H,m),7.49-7.26(6H,m),7.15-7.10(2H,m),6.99-6.95(2H,m),6.49(1H,br),6.36(1H,br),4.01(2H,d,J=5Hz),3.65(1H,t,J=7Hz),2.24-2.11 and 1.95-1.81(each 1H,m),0.95(3H,t,J=7Hz);
TLC:Rf0.36(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(134)
2S-苯基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403281
NMR(CDCl3):δ10.29(1H,s),7.70-7.65(3H,m),7.45-7.26(6H,m),7.13-7.05(2H,m),7.00-6.96(2H,m),6.60(1H,br),4.01(2H,d,J=5Hz),3.66(1H,t,J=8Hz),2.24-2.10 and 1.95-1.81(each 1H,m),0.95(3H,t,J=7Hz);
TLC:Rf0.36(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(135)
2-苯基-2-甲基丙酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403282
NMR(DMSO-d6):δ12.67(1H,br),11.65(1H,br),9.22(1H,t-like)7.82-7.71(3H,m),7.52-7.09(10H,m),3.89(2H,d,J=6Hz),1.63(6H,s);
TLC:Rf0.34(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(136)
1-苯基环己烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403291
NMR(DMSO-d6):δ12.72(1H,br),11.61(1H,br),9.24(1H,t-like),7.81-7.70(3H,m),7.48-7.25(7H,m),7.14-7.10(3H,m),3.88(2H,d,J=6Hz),2.56-2.41(2H,m),1.85-1.23(8H,m);
TLC:Rf0.48(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(137)
1-苯基环丙烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403301
NMR(DMSO-d6):δ9.3-9.1(1H,brt),7.8-7.6(3H,m),7.5-7.0(10H,m),3.88(2H,d,J=5Hz),1.68(2H,dd,J=6,4Hz),1.39(2H,dd,J=6,4Hz);
TLC:Rf0.20(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(138)
1-苯基环戊烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403302
NMR(DMSO-d6):δ9.3-9.1(1H,bH),7.8-7.7(3H,m),7.5-7.2(7H,m),7.2-7.0(3H,m),3.87(2H,d,J=5Hz),2.7-2.5(2H,m),2.1-1.9(2H,m),1.9-1.6(4H,m);
TLC∶Rf0.21(乙酸∶甲醇∶氯仿=1∶2∶40)实施例2(139)
1-苯基环丁烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):9.3-9.1(1H,brt),7.8-7.6(3H,m),7.5-7.2(7H,m),7.2-7.1(3H,m),3.88(2H,d,J=5Hz),3.0-2.8(2H,m),2.6-2.4(2H,m),2.1-1.8(2H,m);
TLC:Rf0.19(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(140)
2-苯基乙酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ10.01-9.76(1H,br),7.82-7.76(4H,m),7.41-7.22(9H,m),7.03-6.90(1H,m),3.96(2H,s),3.86(2H,m);
TLC:Rf0.66(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(141)
2RS-氯-2-苯基乙酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403321
NMR(DMSO-d6):δ9.2-9.1(1H,brt),7.82(2H,d,J=8Hz),7.71(1H,d,J=8Hz),7.6-7.4(7H,m),7.29(2H,d,J=8Hz),7.2-7.1(1H,m),6.26(1H,s),3.88(2H,d,J=5Hz);
TLC:Rf0.18(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(142)
2RS-氯-2-苯基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403331
NMR(DMSO-d6):δ9.3-9.2(1H,br),7.93(2H,d,J=8Hz),7.72(1H,d,J=8Hz),7.65-7.55(2H,m),7.6-7.4(5H,m),7.37(2H,d,J=8Hz),7.2-7.1(1H,m),3.88(2H,d,J=5Hz),2.6-2.4(2H,m),0.97(3H,t,J=7Hz);
TLC:Rf0.20(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(143)
2,2-二苯基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403332
NMR(DMSO-d6):δ9.51-9.38(1H,m),7.86-7.68(4H,m),7.51-7.20(11H,m),7.19-7.01(4H,m),3.84(2H,d,J=6Hz),2.53-2.41(2H,m),0.79(3H,tJ=7Hz);
TLC:Rf0.44(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(144)
2RS-甲基-2-苯基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.3-9.2(1H,br),7.88(2H,d,J=8Hz),7.70(1H,d,J=8Hz),7.5-7.1(10H,m),3.88(2H,d,J=5Hz),2.2-1.9(2H,m),1.57(3H,s),0.85(3H,t,J=7Hz);
TLC:Rf0.15(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(145)
2R-三氟甲基-2-苯基-2-甲氧基乙酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CD3OD):δ7.81(2H,d,J=8.8Hz),7.62(4H,m),7.48(4H,m),7.27(2H,d,J=8.8Hz),7.15(1H,t,J=7.6Hz),3.97(2H,s),3.65(3H,s);
TLC:Rf0.28(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(146)
2S-三氟甲基-2-苯基-2-甲氧基乙酸4-(N-2-(N′-羧基甲基氨甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403351
NMR(CD3OD):δ7.81(2H,d,J=8.6Hz),7.62(4H,m),7.47(4H,m)7.27(2H,d,J=8.6Hz),7.15(1H,t,J=7.6Hz),3.97(2H,s),3.65(3H,s);
TLC:Rf0.27(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(147)
2RS-(4-甲氧基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403361
NMR(CDCl3):δ7.70-7.64(2H,m),7.42(2H,t,J=8Hz),7.27-7.06(4H,m),6.97(2H,d,J=9Hz),6.88(2H,d,J=9Hz),6.55(1H,t-like),4.82(2H,brs),3.99(2H,d,J=5Hz),3.79(3H,s),3.61(1H,t,J=8Hz),2.12 and 1.85(each 1H,m),0.94(3H,t,J=7Hz);TLC:Rf0.50(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(148)2RS-(4-甲氧基苯基)-3-甲基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403362
NMR(CDCl3):δ10.20(1H,s),7.73-7.64(3H,m),7.48-7.39(2H,m),7.33-7.22(2H,m),7.12(1H,t,J=8Hz),6.98-6.85(4H,m),6.46(1H,t-like),5.08(1H,br),4.00(2H,d,J=4Hz),3.80(3H,s),3.31(1H,d,J=10Hz),2.46-2.27(1H,m),1.12 and 0.76(each 3H,each d,J=7Hz);
TLC:Rf0.58(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(149)
2-(4-甲氧基苯基)-2-甲基丙酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403371
NMR(DMSO-d6):δ12.66(1H,br),11.64(1H,br),9.23(1H,t-like),7.81-7.70(3H,m),7.52-7.10(7H,m),6.92(2H,d,J=9Hz),3.89(2H,d,J=6Hz),3.74(3H,s),1.60(6H,s);
TLC:Rf0.35(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(150)
2RS-(4-甲氧基苯基)丙酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403372
NMR(DMSO-d6):δ12.67(1H,br),11.64(1H,br),9.21(1H,t-like),7.81-7.70(3H,m),7.52-7.41(2H,m),7.30-7.09(5H,m),6.91(2H,d,J=8Hz),4.00(1H,q,J=7Hz),3.88(2H,d,J=5Hz),3.73(3H,s),1.46(3H,d,J=7Hz);
TLC:Rf0.30(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(151)
2-(4-(甲氧基苯基)-2-乙基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403381
NMR(DMSO-d6):δ12.68(1H,br),11.62(1H,br),9.24(1H,t-like),7.82-7.71(3H,m),7.52-7.46(2H,m),7.30-7.09(5H,m),6.93(2H,d,J=9Hz),3.89(2H,d,J=6Hz),3.75(3H,s),2.10-1.98(4H,m),0.75(6H,t,J=7Hz);
TLC:Rf0.34(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(152)
1-(4-甲氧基苯基)环己烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403391
NMR(DMSO-d6):δ12.71(1H,br),11.57(1H,br),9.19(1H,t-like),7.77-7.66(3H,m),7.44-7.30(4H,m),7.13-7.04(3H,m),6.89(2H,d,J=8Hz),3.85(2H,d,J=6Hz),3.69(3H,s),2.47-2.36(2H,m),1.77-1.20(8H,m);
TLC:Rf0.51(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(153)
1-(4-(甲氧基苯基)环戊烷羧酸4-(N-2-(N’-羧甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403392
NMR(DMSO-d6):δ12.69(1H,br),11.66(1H,br),9.23(1H,t-like),7.80-7.71(3H,m),7.51-7.29(4H,m),7.18-7.07(3H,m),6.92(2H,dd,J=1 and8Hz),3.89(2H,d,J=5Hz),3.74(3H,s),2.66-2.53(2H,m),2.01-1.87(2H,m),1.79-1.67(4H,m);
TLC:Rf0.68(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(154)
1-(4-甲氧基苯基)环丁烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.2-9.1(1H,brt),7.8-7.7(3H,m),7.5-7.4(2H,m),7.30(2H,d,J=8Hz),7.2-7.0(3H,m),6.92(2H,d,J=8Hz),3.87(2H,d,J=5Hz),3.74(3H,s),2.9-2.7(2H,m),2.6-2.4(2H,br),2.1-1.7(2H,br);
TLC:Rf0.21(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(155)
1-(4-甲氧基苯基)环丙烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.53-9.38(1H,m),7.79-7.72(3H,m),7.51-7.28(4H,m),7.26-7.19(2H,m),7.16-7.00(1H,m),6.89-6.84(2H,m),3.88(2H,d,J=6Hz),3.73(3H,s),1.70-1.61(2H,m),1.38-1.29(2H,m);
TLC:Rf0.49(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(156)
2-(3,4-二甲氧基苯基)-2-乙基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403412
NMR(DMSO-d6):δ9.52-9.38(1H,br),7.83-7.71(3H,m),7.53-7.39(2H, m),7.19-7.02(3H,m),7.00-6.78(3H,m),3.89(2H,d,J=6Hz),3.76(6H,s),2.06(4H,q,J=7Hz),0.78(6H,t,J=7Hz);
TLC:Rf0.39(乙酸∶甲醇∶氯仿=1∶3∶30)。实施2(157)
2RS-(3,4-二甲氧基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CDCl3+CD3OD):δ7.45-7.41(2H,m),7.30-7.19(2H,m),7.18-7.01(1H,m),6.82-6.69(3H,m),6.56-6.52(3H,m),3.63(2H,s),3.53(6H,s),3.28(1H,t,J=7Hz),1.98-1.42(2H,m),0.63(3H,t,J=7Hz):
TLC:Rf0.64(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(158)
2-(3-甲氧基苯基)-2-乙基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403422
NMR(DMSO-d6):δ12.71(1H,br),11.65(1H,br),9.23(1H,t-like),7.83-7.71(3H,m),7.53-7.42(2H,m),7.35-7.10(4H,m),6,92-6,84(3H,m),3.89(2H,d,J=6Hz),3.75(3H,s),2.12-2.01(4H,m),0.76(6H,t,J=7Hz);
TLC:Rf0.39(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(159)
2RS-(2-甲氧基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403431
NMR(DMSO-d6):δ11.58(1H,s),9.24-9.18(1H,m),7.86-7.64(3H,m),7.57-7.44(2H,m),7.38-7.09(5H,m),7.08-6.91(3H,m),4.02-3.98(1H,m),3.88(2H,d,J=6Hz),3.77(3H,s),2.18-1.84(2H,m),0.87(3H,t,J=7Hz);
TLC:Rf0.41(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(160)
2-(2-甲氧基苯基)-2-乙基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403441
NMR(DMSO-d6):δ9.28-9.19(1H,m),7.82-7.69(3H,m),7.48-7.41(2H,m),7.28-7.08(4H,m),7.00-6.75(4H,m),3.89(2H,d,J=6Hz),3.77(3H,s),2.18-1.82(4H,m),0.86(6H,t,J=7Hz);
TLC:Rf0.39(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(161)
2RS-(3-甲氧基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403442
NMR(DMSO-d6):δ10.79(1H,b r),7.85-7.79(3H,m),7.33-7.25(2H,m),7.17-7.06(3H,m),6.95-6.85(3H,m),6.74(1H,t,J=7Hz),3.85(2H,d-like),3.80-3.69(1H,m),3.75(3H,s),2.15-2.01 and 1.91-1.71(each 1H,m),0.89(3H,t,J=7Hz);
TLC:Rf0.47(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(162)
1-(2-甲氧基苯基)环丁烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403451
NMR(DMSO-d6):δ12.9-12.5(1H,br),11.7-11.4(1H,br),9.20(1H,t-like),7.78(2H,d,J=8.6Hz),7.72(1H,d,J=7.4Hz),7.52-7.38(3H,m),7.28(1H,t-like),7.20-7.08(3H,m),7.00(2H,d,J=7.8Hz),3.89(2H,d,J=5.6Hz),3.77(3H,s),2.85-2.65(2H,m),2.55-2.35(2H,m)2.20-2.00 and 2.00-1.80(each 1H,m);
TLC:Rf0.30(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(163)
2RS-(4-甲氧基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-2,6-二甲基苯基酯
NMR(DMSO-d6):δ9.8-9.5(brs,1H),7.8-7.7(m,1H),7.5-7.2(m,6H),7.1-6.8(m,4H),4.0-3.7(m,3H),3.74(s,3H),2.2-1.7(m,8H),0.90(t,J=7.0Hz,3H);
TLC:Rf0.30(己烷∶乙酸乙酯=1∶1)。实施例2(164)
2RS-(4-甲氧基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-2-异丙基苯基酯
NMR(CDCl3):δ10.0-9.9(m,1H),7.8-7.7(m,1H),7.6-7.2(m,6H),7.2-7.0(m,1H),7.0-6.8(m,3H),6.5-6.3(m,1H),4.0-3.4(m,2H),3.80(s,3H),3.64(t,J=7.8Hz,1H),2.7-2.5(m,1H),2.3-2.1(m,1H),2.0-1.8(m,1H),0.95(t,J=7.6Hz,3H),0.83(dd,J=2.0,6.9Hz,6H);TLC:Rf0.49(氯仿∶甲醇=3∶1)实施例2(165)
2RS-(4-(2-甲基丙氧基)苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.25-9.07(1H,br),8.02-7.98(1H,d-like),7.89-7.80(2H,d-like),7.79-7.65(2H,m),7.59-7.38(3H,m),7.18-7.09(1H,m),7.01-6.77(2H,m), 3.97-3.65(3H,m),3.80(3H,s),3.97-3.65(3H,s),1.19(6H,d,J=7Hz):
TLC:Rf0.37(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(166)
2RS-(4-异丙氧基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403472
NMR(DMSO-d6):δ11.58(1H,s),9.22-9.13(1H,m),7.80-7.63(4H,m),7.49-7.40(2H,m),7.25-7.06(5H,m),6.88-6.84(2H,m),4.63-4.48(1H,m),3.88(2H,d,J=6Hz),3.72(1H,t,J=7Hz),2.18-1.63(2H,m),1.26(6H,d,J=6Hz),0.88(3H,t,J=7Hz);
TLC:Rf0.34(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(167)
2RS-(4-丙氧基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403481
NMR(DMSO-d6):δ9.38-9.20(1H,m),7.81-7.77(2H,d-like),7.77-7.70(2H,m),7.49-7.31(2H,m),7.28-7.03(5H,m),6.93-6.89(2H,d-like),3.94-3.87(4H,m),3.72(1H,t,J=6Hz),2.20-1.98(1H,m),1.83-1.62(3H,m),0.98(3H,t,J=7Hz),0.88(3H,t,J=7Hz);
TLC:Rf0.35(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(168)
2RS-(4-甲基苯基)戊酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CDCl3)δ10.20(1H,s),7.68(1H,d,J=8Hz),7.65(2H,d,J=8Hz),7.50-7.35(2H,m),7.25-7.05(5H,m),6.95(2H,d,J=8Hz),6.6-6.5(1H,br),4.00(2H,d,J=5Hz),3.72(1H,t,J=7Hz),2.35(3H,s),2.2-2.0(1H,m),1.9-1.7(1H,m),1.4-1.2(2H,m),0.92(3H,t,J=7Hz);
TLC:Rf0.25(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(169)
1-(4-甲基苯基)环戊烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403492
NMR(DMSO-d6):δ12.70(1H,br),11.66(1H,br),9.23(1H,t-like),7.80-7.70(3H,m),7.51-7.41(2H,m),7.33-7.29(2H,m),7.19-7.09(5H,m),3.89(2H,d,J=6Hz),2.65-2.55(2H,m),2.29(3H,s),2.04-1.90(2H,m),1.79-1.65(4H,m);
TLC:Rf0.69(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(170)1-(3-甲基苯基)环戊烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.22-9.18(1H,m),7.80-7.68(3H,m),7.49-7.41(2H,m),7.29-7.10(7H,m),3.89(2H,d,J=6Hz),2.70-2.51(2H,m),2.32(3H,s),2.04-1.83(2H,m),1.74-1.60(4H,m);
TLC:Rf0.40(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(171)
2RS-(2-甲基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403511
NMR(DMSO-d6):δ9.4-9.2(1H,br),7.8-7.7(3H,m),7.5-7.4(2H,m),7.3-7.0(7H,m),4.06(1H,t,J=7Hz),3.88(2H,d,J=5Hz),2.37(3H,s),2.2-2.0(1H,m),1.9-1.7(1H,m),0.87(3H,t,J=7Hz);
TLC:Rf0.16(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(172)
2-(2-甲基苯基)-2-乙基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403512
NMR(DMSO-d6):δ9.5-9.3(1H,br),7.9-7.6(3H,m),7.6-7.0(9H,br),4.0-3.8(2H,br),2.27(3H,s),2.3-1.9(4H,br),0.8-0.6(6H,br);
TLC:Rf0.15(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(173)
2RS-(4-甲基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ10.61-10.32(1H,m),7.85-7.74(3H,m),7.36-7.04(8H, m),6.90-6.75(1H,m),3.92-3.83(2H,m),3.77(1H,t,J=7.6Hz),2.29(3H,s),2.21-1.96 and 1.89-1.63(each 1H,m),0.87(3H,t,J=7.4Hz);
TLC:Rf0.23(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(174)
2RS-(4-硝基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403522
NMR(CDCl3+CD3OD):δ8.24(2H,d,J=8Hz),7.85-7.55(6H,m),7.10(4H,m),3.95(2H,s),3.87(1H,t,J=7Hz),2.25 and 1.98(each 1H,m),0.99(3H,t,J=7Hz);
TLC:Rf0.33(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(175)
2-(4-硝基苯基)-2-甲基丙酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403531
NMR(DMSO-d6):δ13.50-11.00(2H,br),9.30-9.16(1H,m),8.23(2H,d,J=8Hz),7.88-7.68(5H,m),7.55-7.40(2H,m),7.25(2H,d,J=8Hz),7.20-7.09(1H,m),3.89(2H,d,J=6Hz),1.68(6H,s),
TLC:Rf0.41(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(176)
1-(4-硝基苯基)环丙烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.2-9.1(1H,brt),8.18(2H,d,J=8Hz),7.8-7.6(5H,m),7.5-7.4(2H,m),7.29(2H,d,J=8Hz),7.2-7.0(1H,m),3.90(2H,d,J=5Hz),1.77(2H,dd,J=6,4Hz),1,48(2H,dd,J=6,4Hz);
TLC:Rf0.17(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(177)
1-(4-硝基苯基)环戊烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403541
NMR(DMSO-d6):δ9.2-9.1(1H,brt),8.22(2H,d,J=8Hz),7.8-7.6(5H,m),7.5-7.4(2H,m),7.2-7.1(3H,m),3.88(2H,d,J=5Hz),2.8-2.6(2H,m),2.2-1.9(2H,m),1.9-1.6(4H,m);
TLC:Rf0.20(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(178)
2-(4-硝基苯基)-2-乙基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403551
NMR(DMSO-d6):δ13.40-11.20(2H,br),9.35-9.15(1H,m),8.24(2H,d,J=8Hz),7.82(2H,d,J=8Hz),7.74(1H,t,J=8Hz),7.67(2H,d,J=8Hz),7.55-7.40(2H,m),7.23(2H,d,J=8Hz),7.19-7.08(1H,m),3.89(2H,d,J=6Hz),2.25-1.98(4H,m),0.76(6H,t,J=7Hz);
TLC:Rf0.28(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(179)
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.2-9.1(1H,brt),8.24(2H,d,J=8Hz),7.8-7.6(5H,m),7.5-7.4(2H,m),7.3-7.1(3H,m),3.88(2H,d,J=5Hz),3.0-2.8(2H,br),2.7-2.5(2H,m),2.2-1.8(2H,m);
TLC:Rf0.22(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(180)
2RS-(4-硝基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-2-甲基苯基酯
NMR(DMSO-d6):δ13.00-12.40(1H,br),11.80-11.40(1H,br),9.19(1H,t,J=5Hz),8.24(2H,d,J=8Hz),7.80-7.55(5H,m),7.55-7.40(2H,m),7.23-7.06(2H,m),4.15(1H,t,J=7Hz),3.88(2H,d,J=5Hz),2.19(1H,ddq,J=14Hz,7Hz,7Hz),2.05-1.75(4H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.20(乙酸∶甲醇∶氯仿=1∶2∶20)。实施例2(181)
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-2-甲基苯基酯
Figure A9612198403562
NMR(DMSO-d6):δ12.80-11.00(2H,br),9.20(1H,t,J=5Hz),8.24(2H,d,J=8Hz),7.80-7.55(5H,m),7.55-7.37(2H,m),7.25-7.05(2H,m),3.86(2H,d,J=5Hz),3.04-2.85(2H,m),2.74-2.54(2H,m),2.23-1.78(5H,m);
TLC:Rf0.20(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(182)
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-3-甲基苯基酯
NMR(DMSO-d6):δ13.30-12.30(1H,br),12.00-11.56(1H,br),9.34-9.16(1H,m),8.26(2H,d,J=8Hz),7.85-7.65(4H,m),7.50-7.35(2H,m),7.22(1H,d,J=8Hz),7.18-7.05(1H,m),6.85(1H,s),3.97(2H,d,J=5Hz),3.22-3.03(2H,m),2.78-2.58(2H,m),2.28(3H,s),2.28-2.08(1H,m),2.05-1.80(1H,m);
TLC:Rf0.43(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(183)
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-2,3-二甲基苯基酯
NMR(DMSO-d6):δ13.10-12.40(1H,br),12.00-11.70(1H,br),9.35-9.22(1H,m),8.27(2H,d,J=8Hz),7.88-7.73(3H,m),7.65(1H,d,J=8Hz),7.51-7.39(2H,m),7.20(1H,d,J=8Hz),7.15-7.06(1H,m),4.08-3.95(2H,m),3.18-2.99(1H,m),2.99-2.78(1H,m),2.66-2.47(1H,m),2.33-2.05(1H,m),2.18(3H,s),2.05-1.82(1H,m),1.35(3H,s);
TLC:Rf0.43(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(184)
1-(4-硝基苯基)环丁烷羧酸7-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2,3-二氢茚-4-基酯
Figure A9612198403582
NMR(DMSO-d6):δ13.10-12.30(1H,br),12.00-11.46(1H,br),9.22(1H,t,J=5Hz),8.25(2H,d,J=8Hz),7.80-7.60(4H,m),7.50-7.34(2H,m),7.18-7.02(2H,m),3.90(2H,d,J=5Hz),3.14-2.78(4H,m),2.74-2.33(4H,m),2.20-1.78(4H,m);
TLC:Rf0.20(乙酸∶甲醇∶氯仿=1∶2∶60)。实施例2(185)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·盐酸盐
NMR(d6-DMSO):δ11.60(1H,s),9.23(1H,t,J=6Hz),7.85-7.70(3H,m),7.55-7.40(2H,m),7.27-7.08(5H,m),6.80-6.55(2H,m),3.88(2H,d,J=6Hz),3.68(1H,t,J=7Hz),3.38-3.19(4H,m),2.20-1.86(5H,m),1.86-1.62(1H,m),0.86(3H,t,J=7Hz);
TLC:Rf0.44(氯仿∶甲醇∶乙酸=30∶2∶1)。实施例2(186)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N′羧基甲基氨基甲酰基)苯基氨磺酰)-2-甲基苯基酯·盐酸盐
Figure A9612198403601
NMR(DMSO-d6):δ11.56(1H,s),9.23(1H,t,J=5Hz),7.83-7.55(3H,m),7.55-7.40(2H,m),7.30-7.05(4H,m),6.84-6.60(2H,m),3.88(2H,d,J=5Hz),3.70(1H,t,J=7Hz),3.40-3.13(4H,m),2.20-1.65(9H,m),0.86(3H,t,J=7Hz);
TLC:Rf0.45(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(187)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-3-甲基苯基酯·盐酸盐
NMR(DMSO-d6):δ12.20(1H,s),9.28(1H,t,J=5Hz),7.85(2H,d,J=8Hz),7.50-7.35(2H,m),7.30-7.18(3H,m),7.18-7.03(1H,m),6.80(1H,s),6.73(2H,d,J=8Hz),4.00(2H,d,J=5Hz),3.93-3.75(1H,m),3.38-3.20(4H,m),2.28(3H,s),2.20-2.00(1H,m),2.03-1.92(4H,m),1.92-1.65(1H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.41(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(188)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-2,3-二甲基苯基酯·盐酸盐
Figure A9612198403611
NMR(DMSO-d6):δ12.09(1H,s).9.35-9.18(1H,m),7.92-7.77(1H,m),7.77-7.63(1H,m),7.46-7.38(2H,m),7.30-7.17(3H,m),7.17-7.03(1H,m),6.86-6.60(2H,m),4.02(2H,d,J=5Hz),3.93-3.80(1H,m),3.40-3.15(4H,m),2.19(3H,s),2.05-1.90(4H,m),1.90-1.50(1H,m),1.45(3H,s),1.30-0.98(1H,m),0.88(3H,t,J=7Hz);TLC:Rf0.40(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(189)
1-(4-(吡咯烷-1-基)苯基)环丁烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CD3OD):δ7.75-7.50(4H,m),7.50-7.25(3H,m),7.20-6.90(5H,m),3.92(2H,s),3.46(4H,brs),2.90(2H,m),2.56(2H,m),2.25-1.85(6H,m);TLC:Rf0.36(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(190)
2RS-4-(吡咯烷-1-基)苯基)丁酸7-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-2,3-二氢茚-4-基酯·盐酸盐
Figure A9612198403622
NMR(DMSO-d6):δ11.69(1H,s),9.24(1H,t,J=5Hz),7.75(1H,d,J=8Hz),7.69(1H,d,J=8Hz),7.50-7.38(2H,m),7.19(2H,d,J=8Hz),7.15-7.04(1H,m),6.98(1H,d,J=8Hz),6.68(2H,d,J=8Hz),3.89(2H,d,J=5Hz),3.66(1H,t,J=5Hz),3.35-3.15(4H,m),3.15-3.00(2H,m),2.55-2.40(2H,m),2.18-1.85(7H,m),1.85-1.60(1H,m),0.86(3H,t,J=7Hz);
TLC:Rf0.34(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(191)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-2,6-二甲基苯基酯·盐酸盐
Figure A9612198403631
NMR(DMSO-d6):δ11.49(s,1H),9.3-9.2(m,1H),7.8-7.1(m,10H),6.8-6.6(m,1H),4.0-3.7(m,3H),3.4-3.1(m,4H)2.2-1.7(m,12H),0.89(t,J=7.0Hz,3H);
TLC:Rf0.60(氯仿∶甲醇=2∶1)。实施例2(192)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2-异丙基苯基酯·盐酸盐
Figure A9612198403632
NMR(CDCl3):δ10.04(s,1H),7.8-7.7(m,3H),7.6-7.5(m,7H),7.2-7.1(m,1H),6.9-6.8(m,1H),6.4-6.3(m,1H),4.0-3.6(m,7H),2.8-2.7(m,1H),2.4-2.2(m,5H),2.0-1.8(m,1H),0.98(t,J=7.0Hz,3H),0.91(d,J=7.0Hz,6H);
TLC:Rf0.61(氯仿∶甲醇=2∶1)。实施例2(193)
2RS-(4-(哌啶-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·三氟乙酸盐
NMR(d6-DMSO):δ12.60-11.50(1H1,br),9.43-9.23(1H,br),7.83-7.68(3H,m),7.52-7.35(2H,m),7.30-7.02(5H,m),6.88(2H,d,J=8Hz),3.88(2H,d,J=7Hz),3.66(1H,t,J=8Hz),3.20-3.05(4H,m),2.15-1.91(1H,m),1.85-1.43(7H,m),0.93(3H,t,J=7Hz);
TLC:Rf0.28(氯仿∶甲醇∶乙酸=30∶3∶1)。实施例2(194)
2RS-(4-(全氢化吖庚因-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·三氟乙酸盐
Figure A9612198403651
NMR(DMSO-d6):δ11.57(1H,s),9.19(1H,t,J=7Hz),7.85-7.65(3H,m),7.55-7.40(2H,m),7.30-7.05(5H,m),6.64(2H,d,J=8Hz),3.88(2H,d,J=7Hz),3.60(1H,t,J=8Hz),3.48-3.28(4H,m),2.10-1.93(1H,m),1.88-1.55(5H,m),1.55-1.30(4H,m),0.86(3H,t,J=7Hz);
TLC:Rf0.35(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(195)
2-(4-氨基苯基)-2-丁基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403652
NMR(DMSO-d6):δ11.58(1H,br),9.22(1H,t,J=5Hz),7.80-7.70(3H,m),7.53-7.42(2H,m),7.18-7.14(3H,m),6.98(2H,d,J=8Hz),6.56(2H,d,J=8Hz),3.89(2H,d,J=6Hz),2.09-1.88(4H,m),0.74(6H,t,J=7Hz);
TLC:Rf0.40(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(196)
2RS-(4-氨基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·盐酸盐
Figure A9612198403661
NMR(DMSO-d6):δ10.65(1H,br),7.83-7.76(3H,m),7.31-6.96(6H,m),6.80-6.73(1H,m),6.53(2H,d,J=8.6Hz),3.86(2H,d-like),3.55(1H,t,J=7.4Hz),2.12-1.90 and 1.83-1.62(each 1H,m),0.87(3H,t,J=7.0Hz);
TLC:Rf0.16(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(197)
2RS-(4-(N,N-二甲基氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·盐酸盐
Figure A9612198403671
NMR(DMSO-d6):δ11.62(1H,s),9.25(1H,t,J=6Hz),7.80(2H,d,J=9Hz),7.76(1H,d,J=8Hz),7.50-7.44(5H,m),7.27-7.14(4H,m),3.89(2H,d,J=6Hz),3.86(1H,t,J=8Hz),3.04(6H,s),2.17-2.03 and 1.91-1.71(each 1H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.48(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(198)
1-(4-(N,N-二甲基氨基)苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·盐酸盐
Figure A9612198403681
NMR(DMSO-d6):δ11.62(1H,s),9.24(1H,t-like),7.79(2H,d,J=8.8Hz), 7.74(1H,d,J=8.0Hz),7.81-7.70(9H,m),3.89(2H,d,J=5.0Hz),3.02(6H,s), 2.93-2.80(2H,m),2.59-2.39(2H,m),2.09-1.81(2H,m);
TLC:Rf0.26(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(199)
2RS-4-(N,N-二乙基氨基甲基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·盐酸盐
NMR(DMSO-d6):δ13.00-11.00(2H,br),9.35-9.18(1H,m),7.90-7.71(3H,m),7.68-7.56(2H,m),7.56-7.38(4H,m),7.30-7.08(3H,m),4.24(2H,s),3.99-3.79(2H,m),3.71-3.65(1H,m),3.10-2.90(4H,m),2.11(1H,ddq,J=14Hz,7Hz,7Hz),1.82(1H,ddq,J=14Hz,7Hz,7Hz),1.23(6H,t,J=7Hz),0.88(3H,t,J=7Hz);
TLC:Rf0.18(乙酸∶甲醇∶氯仿=1∶2∶20)。实施例2(200)
2RS-(4-羟基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403691
NMR(DMSO-d6):δ12.90-11.20(2H,br),9.39(1H,br),9.22(1H,t-like),7.79(2H,d,J=8.8Hz),7.73(1H,d,J=7.8Hz),7.53-7.42(2H,m),7.19-7.12(5H,m),6.74(2H,d,J=8.6Hz),3.89(2H,d,J=5.6Hz),3.68(1H,t,J=7.6Hz),2.11-1.93 and 1.84-1.62(each 1H,m),0.86(3H,t,J=7.2Hz);
TLC:Rf0.12(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(201)
2RS-(4-氰基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403701
NMR(DMSO-d6):δ10.72-10.41(1H,m),7.88-7.69(5H,m),7.59(2H,d,J=8.2Hz),7.29(2H,d,J=8.2Hz),7.22-7.06(3H,m),6.78(1H,t,J=8.2Hz),4.01(1H,t,J=7.4Hz),3.91-3.77(2H,m),2.24-2.01 and 1.95-1.70(each 1H,m),0.88(3H,t,J=7.4Hz);
TLC:Rf0.24(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(202)
2RS-(4-羧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403711
NMR(DMSO-d6):δ11.36(1H,s),10.45(1H,s),9.16(1H,t-like),7.90(2H,d,J=8Hz),7.71(1H,d,J=8Hz),7.60-7.38(7H,m),7.18-7.03(1H,m),6.81(2H,d,J=8Hz),3.89(2H,d,J=6Hz),3.40(1H,t,J=7Hz),2.04-1.58(2H,m),0.83(3H,t,J=7Hz);TLC:Rf0.53(乙酸∶甲醇∶氯仿=1∶5∶15)。实施例2(203)
2RS-(4-三氟甲基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403712
NMR(DMSO-d6):δ10.75-10.45(1H,m),7.87-7.56(7H,m),7.35-7.07(4H,m),6.87-6.72(1H,m),4.02(1H,t,J=7.7Hz),3.93-3.82(2H,m),2.25-2.02and 1.95-1.71(each 1H,m),0.89(3H,t,J=7.0Hz),
TLC:Rf0.23 (氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(204)
2RS-(4-脒基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·三氟乙酸盐
NMR(DMSO-d6):δ10.42-10.20(1H,m),9.95-9.44(2H,m),9.44-8.90(2H,m),7.86-7.66(4H,m),7.66-7.30(4H,m),7.30-7.04(3H,m),6.88-6.75(1H,m),4.01(1H,t,J=7Hz),3.90-3.79(2H,m),2.26-2.03(1H,m),1.95-1.74(1H,m),0.96-0.76(3H,m);
TLC:0.40(乙酸∶甲醇∶氯仿=1∶2∶10)。实施例2(205)
2RS-(4-咪唑啉-2-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·三氟乙酸盐
NMR(DMSO-d6):δ10.60-10.34(1H,m),7.95(2H,d,J=8Hz),7.82-7.71(3H,m),7.64(2H,d,J=8Hz),7.34(1H,d,J=8Hz),7.26-7.00(4H,m),6.80(1H,t,J=8Hz),4.60-3.93(7H,m),2.15(1H,ddq,J=14Hz,7Hz,7Hz),1.94-1.71(1H,m),0.87(3H,t,J=7Hz);
TLC:Rf0.2(乙酸∶甲醇∶氯仿=1∶2∶10)。实施例2(206)
1-(4-氯苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.3-9.1(1H,bH),7.8-7.6(3H,m),7.5-7.3(6H,m),7.2-7.0(3H,m),3.88(2H,d,J=5Hz),3.0-2.8(2H,m),2.6-2.4(2H,m),2.2-1.8(2H,m):
TLC:Rf0.22(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(207)
2RS-(2-氯苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.4-9.2(1H,br),7.8-7.7(3H,m),7.5-7.3(6H,m),7.3-7.0(3H,m),4.24(1H,t,J=7Hz),3.88(2H,d,J=5Hz),2.2-2.0(1H,m),2.0-1.8(1H,m),0.87(3H,t,J=7Hz);
TLC:0.16(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(208)
2-(2-氯苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403751
NMR(DMSO-d6):δ9.5-9.3(1H,br),7.82(2H,d,J=8Hz),7.72(1H,d,J=8Hz),7.6-7.3(6H,m),7.23(2H,d,J=8Hz),7.09(1H,t,J=8Hz),3.90(2H,d,J=5Hz),2.4-2.1(2H,m),2.2-1.9(2H,m),0.70(6H,t,J=7Hz);
TLC:Rf0.12(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(209)
1-(2-氯苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CDCl3+CD3OD).δ7.72(2H,d,J=8.5Hz)7.68-7.05(8H,m),7.02(2H,d,J=8.5Hz),3.99(2H,s),3.01-2.82(2H,m),2.75-2.50(2H,m),2.41-2.15(1H,m),2.10-1.80(1H,m);
RLC:Rf0.30(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(210)
2RS-(4-氯苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ10.47-10.18(1H,m),7.86-7.74(3H,m),7.51-7.08(8H,m),6.93-6.81(1H,m),3.95-3.82(3H,m),2.20-1.96 and 1.90-1.66(each1H,m),0.87(3H,t,J=7.4Hz);TLC:Rf0.26(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(211)
2RS-(3-硝基-4-羟基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403771
NMR(DMSO-d6):δ9.36(1H,t-like),7.90-7.72(4H,m),7.58-7.40(3H,m),7.24-7.07(4H,m),3.90(2H,d,J=6Hz),2.20-1.97 and 1.89-1.69(each 1Hm),0.88(3H,t,J=7Hz);
TLC:Rf0.21(乙酸:甲醇∶氯仿=1∶2∶40)。实施例2(212)
2RS-(2-氯-5-硝基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ12.10(2H,br),9.26(1H,t-like),8.32(1H,t,J=3Hz),8.20(1H,dd,J=3 and 9Hz),7.85-7.79(3H,m),7.73(1H,d,J=8Hz),7.52-7.41(2H,m),7.27(2H,d,J=9Hz),7.15-7.08(1H,m),4.43(1H,t,J=6Hz),3.89(2H,d,J=6Hz),2.32-2.18 and 2.09-1.91(each 1H,m),0.90(3H,t,J=7Hz);
TLC:Rf0.51(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(213)
1-(2-氯-5-硝基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403781
NMR(CDCl3+CD3OD):δ8.32(1H,d,J=2.5Hz),8.14(1H,dd,J=2.5,8.5Hz),7.76(2H,d,J=8.5Hz),7.62(2H,t,J=8.5Hz),7.53(1H,d,J=8.5Hz),7.43(1H,d,J=8.5Hz),7.12(1H,d,J=8.5Hz),7.06(2H,d,J=8.5Hz),3.99(2H,brs),3.10-2.90(2H,m),2.80-2.59(2H,m),2.52-2.20(1H,m),2.15-1.90(1H,m);TLC:Rf0.23(乙酸∶甲醇;氯仿=1∶2∶40)。实施例2(214)
1-(3-硝基-4-氯苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403791
NMR(DMSO-d6):δ12.73(1H,brs),11.60(1H,brs),9.17(1H,t,J=7Hz),8.04(1H,s),7.90-7.65(4H,m),7.55-7.40(2H,m),7.35-7.05(4H,m),3.90(2H,d,J=7Hz),2.90(2H,m),2.60(2H,m),2.25-1.80(2H,m);TLC:Rf0.34(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(215)
2RS-(3-硝基-4-氯苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ10.79(1H,br),8.12(1H,s),7.85-7.75(5H,m),7.28-7.08(4H,m),6.74(1H,t-like),4.08(1H,t,J=7.4Hz),3.84(2H,d-like),2.22-2.04 and 1.98-1.76(each 1H,m),0.89(3H,t,J=7.2Hz);
TLC:Rf0.30(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(216)
2RS-(4-脲基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403801
NMR(DMSO-d6):δ10.5(1H,br),8.61(1H,s),7.81-7.70(3H,m),7.41-7.05(10H,m),6.80(1H,t,J=7.6Hz),5.85(2H,s),3.84(2H,s),3.70(1H,t,J=7.2Hz),2.30(2H,s),2.60-1.95 and 1.90-1.65(each 1H,m),0.88(3H,t,J=7.0Hz);RLC:Rf0.22(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(217)
1-(4-脲基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403811
NMR(DMSO-d6):δ10.0(1H,brs),8.50(1H,s),7.67(4H,d,J=8.8Hz),7.32-7.09(2H,m),7.30(2H,d,J=8.6Hz),7.11(2H,d,J=8.8Hz),6.96(2H,d,J=8.6Hz),6.76(1H,t,J=6.8Hz),5.74(2H,s),3.75-3.73(2H,m),2.80-2.63(2H,m),2.53-2.26(2H,m),2.23-2.00(2H,m);
TLC:Rf0.10(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(218)
2RS-(4-(N-(2S-氨基丙酰)氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·盐酸盐
Figure A9612198403812
NMR(DMSO-d6):δ10.92(1H,s),9.47-9.32(1H,m),7.85-7.73(3H,m),7.66(2H,d,J=9Hz),7.54-7.42(2H,m),7.34(2H,d,J=9Hz),7.27-7.04(4H,m),4.16-3.99(1H,m),3.89(2H,d,J=5Hz),3.81(1H,t,J=6Hz),2.19-1.98 and1.88-1.67(each 1H,m),1.47(3H,d,J=8Hz),0.97(3H,t,J=8Hz);
TLC:Rf0.11(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(219)
2RS-(4-(N-(2S-氨基-3-甲基丁酰基)氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·盐酸盐
NMR(DMSO-d6):δ10.96-10.85(1H,m),9.45-9.30(1H,m),7.85-7.72(2H,m),7.66(2H,d,J=8.4Hz),7.54-7.42(2H,m),7.34(2H,d,J=8.4Hz),7.27-7.06(4H,m),3.90(2H,d,J=6.0Hz),3.81(1H,t,J=7.8Hz),2.33-1.98 and 1.92-1.66(each 1H,m),1.01(6H,d,J=7.2Hz),0.87(3H,t,J=7.4Hz);
TLC:Rf0.19(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(220)
2RS-(4-(N-(吡咯烷-2S-基羰基)氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·盐酸盐
NMR(DMSO-d6):δ10.62-10.52(1H.m),9.95-9.70(1H,m),7.86-7.70(3H,m),7.62(2H,d,J=8.8Hz),7.48-7.27(4H,m),7.13(2H,d,J=8.8Hz),7.04-6.93(1H,m),4.34-4.20(1H,m),3.95-3.85(2H,m),3.81(1H,t,J=7.1Hz),3.33-3.16(2H,m),2.45-2.21(1H,m),2.21-1.68(5H,m),0.77(3H,t,J=7.1Hz);
TLC:Rf0.09(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(221)
2RS-(3,4,5-三甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403841
NMR(DMSO-d6):δ12.71(1H,br),11.69(1H,br),9.22(1H,t-like),7.80(2H,d,J=8Hz),7.73(1H,d,J=8Hz),7.53-7.41(2H,m),7.25-7.09(3H,m),6.63(2H,s),3.89(2H,d,J=5Hz),3.77(6H,s),3.65(3H,s),3.63(1H,t,J=7Hz),2.19-1.97 and 1.88-1.67(each 1H,m),0.90(3H,t,J=7Hz);TLC:Rf0.57(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(222)
2RS-(2,4,6-三甲基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403842
NMR(CD3OD):δ7.80-6.80(12H,m),4.21(1H,dd,J=8.0 and 6.0Hz),3.93(2H,s),2. 30-2.20(each 3H,s),1.90-1.60(2H,m),0.90(3H,t,J=7.2Hz);
TLC:Rf0.46(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(223)
2RS-(3-硝基-4-甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ12.72(1H,br),11.60(1H,br),9.18(1H,t-like),7.89-7.59(5H,m),7.53-7.46(2H,m),7.36(1H,d,J=9Hz),7.24(2H,d,J=9Hz),7.13(1H,t,J=8Hz),3.95(1H,t,J=8Hz),3.92(3H,s),3.89(2H,d,J=6Hz),2.23-2.02 and 1.94-1.72(each 1H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.51(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(224)
2RS-(3-硝基-4-氨基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·盐酸盐
Figure A9612198403861
NMR(DMSO-d6):δ12.14(2H,br),9.36(1H,t-like),7.95(1H ,d,J=2.0Hz),7.79(2H,d,J=8.8Hz),7.76(1H,d,J=6.6Hz),7.51-7.38(5H,m),7.21(2H,m),7.15-7.02(2H,m),3.89(2H,d,J=5.6Hz),3.80(1H,t,J=7.6Hz),2.13-1.99 and 1.84-1.69(each 1H,m),0.88(3H,t,J=7.6Hz);
TLC:Rf0.18(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(225)
2RS-(4-(N-乙酰基氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403862
NMR(DMSO-d6):δ12.76(1H,br),11.58(1H,s),9.94(1H,s),9.20(1H,t,J=6Hz),7.81-7.70(3H,m),7.58-7.46(4H,m),7.29-7.10(5H,m),3.89(2H,d,J=6Hz),3.76(1H,t,J=7Hz),2.14-1.99 and 1.83-1.69(each 1H,m),2.03(3H,s),0.87(3H,t,J=7Hz);
TLC:Rf0.20(氯仿∶甲醇∶水= 8∶2∶0.2)。实施例2(226)
2RS-(4-(N-甲基-N-乙酰基氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403871
NMR(DMSO-d6):δ11.59(1H,s),9.19(1H,t,J=5Hz),7.80(2H,d,J=9Hz),7.73(1H,d,J=8Hz),7.53-7.41(4H,m),7.34-7.10(5H,m),3.89(2H,d,J=6Hz),3.69(1H,t,J=7Hz),3.16(3H,s),2.18-2.01 and 1.92-1.71(each 1H,m),1.78(3H,s),0.90(3H,t,J=7Hz);
TLC:Rf0.27(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(227)
2RS-(4-(吗啉-4-基甲基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·三氟乙酸盐
Figure A9612198403881
NMR(DMSO-d6):δ12.00-11.20(2H,br),9.28-9.15(1H,m),7.88-7.68(3H,m),7.56-7.27(6H,m),7.27-7.08(3H,m),3.95-3.79(4H,m),3.68-3.59(5H,m),2.90-2.60(4H,m),2.20-1.95(1H,m),1.95-1.65(1H,m),0.95-0.80(3H,m);
TLC:Rf0.47(乙酸∶甲醇∶氯仿=1∶2∶20)。实施例2(228)
2RS-(4-(4-苄基哌嗪-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403891
NMR(CDCl3+CD3OD):δ9.21(1H,d-like),7.95-7.86(4H,m),7.78-7.71(1H,m),7.65-7.58(2H,n),7.54-7.46(6H,m),7.40-7.32(2H,m),7.21-7.10(2H,m),3.91(2H,d,J=7Hz),3.50-3.06(11H,m),1.68-1.45(2H,m),0.78(3H,t,J=7Hz);
TLC:Rf0.65(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(229)
2RS-(4-(吡咯烷-1-基甲基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403892
NMR(DMSO-d6):δ9.65(1H,brs),7.77(2H,d,J=8Hz),7.73(1H,d,J=8Hz),7.45-7.30(6H,m),7.14(2H,d,J=8Hz),6.99(1H,d,J=8Hz),4.03-3.93(2H,m),3,93-3.80(3H,m),2.88(4H,brs),2.09(1H,ddq,J=14Hz,7Hz,7Hz),1.88-1.73(5H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.10(乙酸∶甲醇∶氯仿=1∶2∶20)。实施例2(230)
2-(噻吩-2-基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
Figure A9612198403901
NMR(DMSO-d6):δ9.5-9.3(1H,brs),7.9-7.7(3H,m),7.5-7.4(3H,m),7.3-7.0(5H,m),3.87(2H,d,J=5Hz),2.3-1.9(4H,m),0.82(6H,t,J=7Hz);
TLC:Rf0.19(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(231)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((1R-氧代-4S-羧基全氢化噻唑-3-基)磺酰基)-2-甲基苯基酯
NMR(DMSO-d6):δ7.85-7.70(2H,m),7.18(2H,d,J=8.5Hz),7.09(1H,d,J=8.5Hz),6.53(2H,d,J=8.5Hz),4.85-4.65(2H,m),4.30(1H,d,J=12.5Hz),3.69(1H,t,J=7.5Hz),3.35-3.05(6H,m),2.20-1.60(2H,m),1.99(3H,s),2.00-1.85(4H,m),0.90(3H,t,J=7.5Hz);
TLC:Rf0.36(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例2(232)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198403912
NMR(CD3OD):δ7.89-7.69(2H,m),7.54 and 7.41(each 2H,d,J=8Hz),7.15(1H,d,J=8Hz),4.28-4.16(1H,m),3.90(1H,t,J=7Hz),3.69-3.64(4H,m),3.51-3.40 and 3.31-3.21(each 1H,m),2.28-2.21(5H,m),2.02(3H,s),2.01-1.89(4H,m),1.80-1.65(1H,m),0.99(3H,t,J=7Hz);
TLC:Rf0.17(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(233)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2R-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198403921
NMR(CD3OD):δ7.81-7.68(2H,m),7.56 and 7.45(each 2H,d,J=8Hz),7.15(1H,d,J=8Hz),4.28-4.16(1H,m),3.91(1H,t,J=7Hz),3.71-3.64(4H,m),3.50-3.40 and 3.33-3.22(each 1H,m),2.31-2.22(5H,m),2.03(3H,s),2.02-1.84(4H,m),1.80-1.64(1H,m),1.00(3H,t,J=7Hz);
TLC:Rf0.18(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(234)
2R-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198403931
NMR(CD3OD):δ7.80-7.68(2H,m),7.50 and 7.31(each 2H,d,J=8Hz),7.14(1H,d,J=8Hz),4.22-4.16(1H,m),3.87(1H,t,J=7Hz),3.68-3.56(4H,m),3.50-3.42 and 3.35-3.20(each 1H,n),2.32-2.18(5H,m),2.02(3H,s),2.01-1.83(4H,m),1.79-1.65(1H,m),0.99(3H,t,J=7Hz);
TLC:Rf0.17(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(235)
2R-(4-(吡咯烷-1-基)苯基)丁酸4-((2R-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯
NMR(CD3OD):δ7.77-7.68(2H,m),7.57 and 7.48(each 2H,d,J=8Hz),7.15(1H,d,J=8Hz),4.22-4.17(1H,m),3.93(1H,t,J=7Hz),3.74-3.66(4H,m),3.52-3.42 and 3.35-3.21(each 1H,m),2.28-2.22(5H,m),2.02(3H,s),2.01-1.87(4H,m),1.80-1.64(1H,m),0.99(3H,t,J=7Hz);
TLC:Rf0.18(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(236)
2RS-(4-吡咯烷-1-基)苯基)丁酸4-((2S-氨基甲基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·二盐酸盐
Figure A9612198403942
NMR(CD3OD):δ7.85-7.70(2H,m),7.64(4H,s),7.22(1H,d,J=8.0Hz),3.98(1H,t,J=8.0Hz),4.00-3.80(1H,m),3.85-3.70(4H,m),3.55-3.20(2H,m),3.15-2.95(2H,m),2.40-1.80(2H,m),2.35-2.25(4H,m),2.06(3H,s),2.00-1.40(4H,m),1.00(3H,t,J=7.5Hz);
TLC:Rf0.29(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2(237)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((4-氨基哌啶-1-基)磺酰基)-2-甲基苯基酯·二盐酸盐
NMR(DMSO-d6):δ8.14(2H,brs),7.63(1H,s),7.60(1H,d,J=8.4Hz),7.21(2H,d,J=8.4Hz),7.20(1H,d,J=8.4Hz),6.64(2H,d,J=8.4Hz),3.8-3.5(4H,br),3.3-3.2(5H,br),3.2-3.0(1H,br),2.5-2.3(2H,m),2.2-2.0(1H,m),2.0-1.9(4H,br),1.98(3H,s),1.9-1.7(1H,m),1.7-1.5(2H,m),0.90(3H,t,J=7.2Hz);
TLC:Rf0.20(氯仿∶甲醇=9∶1)。实施例2(238)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基氮杂环丁烷-1-基)磺酰基)-2-甲基苯基酯
NMR(CD3OD):δ7.72(1H,s),7.71(1H,d,J=8.0Hz),7.22(2H,d,J=8.8Hz),7.17(1H,d,J=8.0Hz),6.58(2H,d,J=8.8Hz),4.30(1H,t,J=8.5Hz),3.8-3.6(3H,m),3.4-3.2(4H,m),2.4-2.1(3H,m),2.1-2.0(4H,brs),2.0-1.8(1H,m),2.04(3H,s),1.00(3H,t,J=7.4Hz);
TLC:Rf0.59(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例2(239)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-羧基哌
Figure A9612198403962
NMR(CDCl3):δ7.65(1H,s),7.63(1H,d,J=8.2Hz),7.21(2H,d,J=8.6Hz),6.99(1H,d,J=8.2Hz),6.53(2H,d,J=8.6Hz),4.7-4.6(1H,brs),4.7-4.1(1H,br),3.59(1H,t,J=7.7Hz),3.5-3.2(6H,brs),2.3-2.1(1H,m),2.1-1.9(4H,brs),2.0-1.8(1H,m),1.98(3H,s),1.6-1.2(6H,br),0.96(3H,t,J=7.4Hz)
TLC:Rf0.12(氯仿∶甲醇=9∶1)。实施例2(240)
2R-(4-(吡咯烷-1-基)苯基)丁酸4-((2-氧代-5S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CD3OD):δ7.96-7.82(2H,m),7.57(2H,d,J=8.5Hz),7.42(2H,d,J=8.5Hz),7.13(1H,d,J=8.0Hz),4.90-4.80(1H,m),3.92(1H,t,J=7.5Hz),3.74-3.60(4H,m),2.65-1.80(10H,m),2.02(3H,s),0.99(3H,t,J=7.5Hz);
TLC:Rf0.35(氯仿∶甲醇∶乙酸=4∶1∶0.1)实施例2(241)
2RS-(3-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷1-基)磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.70-7.64(2H,m),7.20(1H,t,J=7.8Hz),7.09(1H,d,J=7.8Hz),6.66(1H,d,J=7.8Hz),6.53-6.47(2H,m),4.3-4.2(1H,m),3.8-3.4(2H,m),3.4-3.2(5H,m),2.3-1.7(13H,m),1.01(3H,t,J=7.4Hz);
TLC:Rf0.58(氯仿∶甲醇∶乙酸=9∶1∶0.2)。实施例2(242)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-甲氧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198403982
NMR(DMSO-d6):δ7.73(1H,s),7.66(1H,d,J=8.6Hz),7.26(2H,d,J=8.8Hz),7.15(1H,d,J=8.6Hz),6.78(2H,d,J=8.8Hz),5.00(1H,brs),4.02(1H,t,J=7Hz),3.82(1H,m),3.76(1H,t,J=7Hz),3.41(2H,m),3.31(4H,m),2.83(3H,s),2.15(2H,m),2.00(4H,m),1.98(3H,s),1.95(2H,m),0.92(3H,t,J=7.4Hz);
TLC:Rf0.34(氯仿∶甲醇∶水-4∶1∶0.1)。实施例2(243)
2RS-(4-(吡啶烷-1-基)苯基)丁酸4-((2R-羧基-4R-甲氧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198403991
NMR(DMSO-d6):δ7.77(1H,d,J=2.4Hz),7.70(1H,dd,J=8.4Hz,2.4Hz),7.26(2H,d,J=8.2Hz),7.16(1H,d,J=8.4Hz),6.75(2H,d,J=8.2Hz),4.80(1H,brs),4.31(1H,dd,J=9.2Hz,3.2Hz),3.76(2H,m),3.33(6H,m),3.12(3H,s),2.12(2H,m),2.02(4H,m),1.98(3H,s),1.80(2H,m),0.91(3H,t,J=7.2Hz);
TLC:Rf0.47(氯仿:甲醇∶水=4∶1∶0.1)。实施例2(244)
2RS-(2-甲基-4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198404001
NMR(CD3OD):δ7.76-7.66(2H,m),7.60-7.40(3H,m),7.15(1H,d,J=8.0Hz),4.30-4.10(2H,m),3.85-3.70(4H,m),3.55-3.15(2H,m),2.57(3H,s),2.40-2.15(5H,m),2.00(3H,s),2.10-1.60(5H,m),1.01(3H,t,J=7.5Hz);
TLC:Rf0.33(氯仿∶甲醇∶乙酸=4∶1∶0.1)。实施例2(245)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-羟基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198404011
NMR(CD3OD):δ7.72(1H,s),7.70(1H,m),7.20(2H,d,J=8.6Hz),7.09(1H,d,J=8.0Hz),6.58(2H,d,J=8.6Hz),4.32(1H,m),4.21(1H,m),3.73-3.42(2H,m),3.38-3.16(5H,m),2.35-1.68(11H,m),0.98(3H,t,J=7.0Hz);
TLC:Rf0.55(氯仿∶甲醇∶乙酸=15∶2∶1)。实施例2(246)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-甲氧基-N-羧基甲基氨基磺酰基)-2-甲基苯基酯·盐酸盐
      NMR(CDCl3):δ7.66(1H,s),7.63(1H,d,J=8.0Hz),7.22(2H,d,J=8.8Hz),7.08(1H,d,J=8.0Hz),6.54(2H,d,J=8.8Hz),5.3-4.6(1H,br),3.81(3H,s),3.70(2H,s),3.69(1H,t,J=7.8Hz),3.3-3.2(4H,brs), 2.2-2.0(1H,m),2.1-1.9(4H,brs),2.01(3H,s),2.0-1.8(1H,m),0.97(3H,t,J=7.4Hz);
     TLC:Rf0.44(hexane∶ethyl acetate=2∶1).
TLC:Rf0.44(己烷∶乙酸乙酯=2∶1)。实施例2  (247)
2RS-(2-甲氧基-4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
      NMR(DMSO-d6):δ7.74(1H,s),7.68(1H,d,J=8.5Hz),7.24-7.06(2Hm),6.50-6.30(2H,m),4.18-4.06(1H,m),4.00(1H,t,J=7.0Hz), 3.83(3H,s),3.40-3.05(6H,m),2.20-1.45(10H,m),2.05(3H,s),0.89(3H,t,J=7.5Hz);
TLC:Rf0.40(氯仿∶甲醇∶乙酸=4∶1∶0.1)。实施例2  (248)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基氮丙啶-1-基)磺酰基)-2-甲基苯基酯
      NMR(CDCl3+CD3OD):δ7.74(1H,s),7.70(1H,d,J=8.4Hz),7.20(2H,d,J=8.4Hz),7.08(1H,d,J=8.4Hz),6.54(2H,d,J=8.4Hz), 3.61(1H,t,J=7.5Hz),3.3-3.2(4H,brs),2.6-2.3(3H,brs),2.3-2.1(1H,m),2.1-1.9(4H,brs),2.0-1.8(1H,m), 1.99(3H,s),0.97(3H,t,J=7.4Hz);
TLC:Rf0.28(氯仿∶甲醇=4∶1)。实施例2  (249)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-二(2-氨基乙基)氨基磺酰基)-2-甲基苯基酯·三盐酸盐
Figure A9612198404041
      NMR(DMSO-d6):δ8.25(4H,m),7.80(1H,d,J=1.0Hz),7.71(1H,dd,J=8.6Hz,1.0Hz),7.26(3H,m),6.82(2H,m),3.78(1H,t,J=7.8Hz),3.35(8H,m),3.04(4H,m),2.13(1H,m),2.02(3H,s),1.98(4H,m),1.85(1H,m),0.92(3H,t,J=7.2Hz);
TLC:Rf0.31(氯仿∶甲醇∶水=6∶4∶1)。实施例2  (250)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-(2-(N’,N’-二甲基氨基)乙基)氨基磺酰基)-2-甲基苯基酯·三氟乙酸盐
     NMR(CDCl3):δ7.61-7.55(2H,m),7.21(2H,d,J=8.7Hz),7.07(1H,d,J=8.2Hz),6.54(2H,d,J=8.7Hz),3.80(2H,s),3.60(1H,t,J=7.8Hz),3.55-3.10(8H,m),2.83(6H,s),2.30-1.70(9H,m),0.98(3H,t,J=7.4Hz);
TLC:Rf0.43(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2  (251)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-乙基苯基酯
      NMR(CDCl3):δ7.8-7.6(m,2H),7.36(d,J=8.4Hz,2H),7.07(d,J=8.4Hz,1H),7.02(d,J=8.4Hz,2H),4.3-4.2(m,1H),3.70(t,J=7.2Hz,1H),3.6-3.4(m,5H),3.3-3.1(m,1H),2.37(q,J=7.6Hz,2H),2.3-1.6(m,10H),1.03(t,J=7.6Hz,3H),0.99(t,J=7.6Hz,3H);
TLC:Rf0.33(氯仿∶甲醇∶乙酸=50∶2∶1)。实施例2  (252)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-苄氧基氨基磺酰基)-2-甲基苯基酯·盐酸盐
      NMR(DMSO-d6):δ7.70(1H,s),7.68(1H,d,J=8.6Hz),7.32(5H,s),7.20(2H,d,J=8.2Hz),7.16(1H,d,J=8.6Hz),6.52(2H,d,J=8.2Hz),5.25(2H,s),3.8-3.4(2H,m),3.5-3.4(2H,brs),3.3-3.1(4H,brs),2.2-2.0(1H,m),2.0-1.8(4H,brs),1.9-1.7(1H,m),1.93(3H,s),0.89(3H,t,J=7.2Hz);
TLC:Rf0.29(氯仿∶甲醇=9∶1)。实施例2  (253)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(4-羧基丁基)氨基磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198404071
      NMR(DMSO-d6+2 drops of D2O):δ7.66(1H,s-like),7.63(1H,dd,J=2and8Hz),7.24(2H,d,J=8Hz),7.14(2H,d,J=8Hz),6.69(2H,d,J=8Hz),3.74(1H,t,J=7Hz),3.31-3.25(4H,m),2.71(2H,t,J=7Hz),2.18-1.72(2H,m),2.15(2H,t,J=7Hz),2.01-1.94(4H,m),1.96(3H,s),1.53-1.34(4H,m),0.91(3Ht,J=7Hz);
TLC:Rf0.38(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2  (254)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1,1-二甲基-1-羧基甲基)氨基磺酰基)-2-甲基苯基酯
  NMR(DMSO-d6):δ7.68(1H,s-like),7.64(1H,dd,J=2 and 8Hz),7.39(1H,br),7.18(2H,d,J=8Hz),7.07(1H,d,J=8Hz),6.53(2H,d,J=8Hz),3.69(1H,t,J=7Hz),3.24-3.18(4H,m),2.20-1.65(2H,m),1.98-1.91(4H,m),1.93(3H,s),1.18(6H,s),0.90(3H,t,J=7Hz);
TLC:Rf0.19(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2  (255)
2RS-(4-吡咯烷-1-基)苯基)丁酸4-(N-甲基-N-羟基氨基磺酰基)-2-甲基苯基酯
Figure A9612198404081
  NMR(CDCl3):δ7.71(1H,s),7.69(1H,d,J=8.6Hz),7.23(2H,d,J=8.8Hz),7.13(1H,d,J=8.6Hz),6.55(2H,d,J=8.8Hz),6.54(1H,s),3.63(1H,t,J=7.7Hz),3.3-3.2(4H,brs),2.81(3H,s),2.3-2.1(1H,m),2.1-1.9(4H,brs),2.06(3H,s),2.0-1.8(1H,m),0.99(3H,t,J=7.3Hz);
TLC:Rf0.43(己烷∶乙酸乙酯=2∶1)。实施例2  (256)
2RS-(2-甲基-4-硝基苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯
Figure A9612198404091
NMR(CDCl3):δ8.15-8.05(2H,m),7.75-7.65(2H,m),7.56(1H,d,J=8.0Hz),7.09(1H,d,J=9.0Hz),4.25(1H,dd,J=3.5,7.0Hz),4.13(1H,t,J=7.5Hz),3.60-3.40(1H,m),3.30-3.10(1H,m),2.59(3H,s),2.45-1.60(6H,m),1.99(3H,s),1.02(3H,t,J=7.5Hz);
TLC:Rf0.24(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2  (257)
2RS-(4-(吡啶烷-1-基)苯基)丁酸4-(N-羧基甲基氨基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.70-7.58(2H,m),7.25(2H,d,J=8Hz),7.01(1H,d,J=8Hz),6.65(2H,d,J=8Hz),5.43-5.23(1H,br),5.18-4.80(1H,br),3.75(2H,brs),3.63(1H,t,J=7Hz),3.40-3.20(4H,m),2.28-1.80(9H,m),0.98(3H,t,J=7Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2  (258)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1,1-二甲基-1-羧基甲基)-N-丙基氨基磺酰基)-2-甲基苯基酯
NMR(DMSO-d6+2 drops of D2O):δ7.80(1H,s-like),7.78(1H,dd,J=2 and 8Hz),7.18(2H,d,J=8Hz),7.11(1H,d,J=8Hz),6.54(2H,d,J=8Hz),3.70(1H,t,J=7Hz),3.25-3.17(4H,m),3.12-3.04(2H,m),2.20-1.70(2H,m),1.99-1.92(4H,m),1.95(3H,s),1.57-1.42(2H,m),1.45(6H,s),0.91(3H,t,J=7Hz),0.71(3H,t,J=7Hz);
TLC:Rf0.57(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2  (259)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4S-氨基吡啶烷-1-基)磺酰基)-2-甲基苯基酯·二盐酸盐
Figure A9612198404111
NMR(CD3OD):δ7.83-7.68(2H,m),7.63(4H,s-like),7.22(1H,d,J=8.2Hz),4.21(1H,dd,J=9.2 and 3.4Hz),3.98(1H,t,J=7.8Hz),3.90-3.43(7H,m),2.70-1.84(8H,m),2.06(3H,s),1.00(3H,t,J=7.4Hz);
TLC:Rf0.46(乙酸乙酯∶乙酸∶水=6∶2∶1)。实施例2  (260)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·二盐酸盐
NMR(CD3OD):δ7.84-7.68(2H,m),7.63(4H,s-like),7.18(1H,d,J=8.0Hz),4.55(1H,dd,J=8.4 and 4.2Hz),4.07-3.90(2H,m),3.90-3.63(5H,m),3.47-3.26(1H,m),2.53-1.82(8H,m),2.05(3H,s),1.00(3H,t,J=7.4Hz);
TLC:Rf0.42(乙酸乙酯∶乙酸∶水=6∶2∶1)。实施例2  (261)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-(2-(吗啉-4-基)乙基)氨基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3):δ7.66-7.52(2H,m),7.21(2H,d,J=8.5Hz),7.09(1H,d,J=8.5Hz),6.55(2H,d,J=8.5Hz),3.95-3.80(4H,m),3.75(2H,s),3.61(1H,t,J=7.5Hz),3.45-3.20(6H,m),3.10-2.70(6H,m),2.30-1.75(6H,m),2.04(3H,s),0.99(3H,t,J=7.5Hz);
TLC:Rf0.24(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2  (262)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4S-乙酰基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
NMR(DMSO-d6):δ8.02(1H,d,J=7.8Hz),7.74(1H,d,J=2.2Hz),6.69(1H,dd,J=8.4Hz,2.2Hz),7.17(2H,d,J=8.6Hz),7.17(1H,d,J=8.4Hz),6.54(2H,d,J=8.6Hz),4.13(1H,t,J=7.8Hz),3.82(1H,m),3.70(1H,t,J=7.6Hz),3.50(1H,m),3.22(4H,m),3.06(1H,m),2.31(1H,m),2.07(1H,m),1.99(3H,s),1.96(4H,m),1.82(2H,m),1.75(3H,s),0.91(3H,t,J=7.4Hz);
TLC:Rf0.18(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2  (263)
2RS-(4-(吡咯烷-1-基)苯基)-2-丁烯酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.80-7.65(2H,m),7.32(1H,q,J=7Hz),7.23(1H,d,J=8Hz),7.13(2H,d,J=8Hz),6.59(2H,d,J=8Hz),4.30-4.20(1H,m),4.10-3.60(1H,b),3.60-3.45(1H,m),3.40-3.20(5H,m),2.30-1.65(8H,m),2.25(3H,s),1.88(3H,d,J=7Hz);
TLC:Rf0.28(氯仿∶甲醇∶乙酸=4∶2∶0.1)。实施例2  (264)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-乙酰基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198404151
NMR(DMSO-d6):δ7.78(1H,d,J=5Hz),7.68(1H,s),7.64(1H,d,J=8.0Hz),7.19(2H,d,J=8.6Hz),7.16(1H,d,J=8.0Hz), 6.56(2H,d,J=8.6Hz),4.28(1H,t,J=7.8Hz),4.12(1H,m),3.75(1H,m),3.48(1H,m),3.23(4H,m),3.06(1H,m),2.12(1H,m),2.03(2H,m),1.99(3H,s),1.96(4H,m),1.80(1H,m),1.54(3H,s),0.91(3H,t,J=7.2Hz);
TLC:Rf0.19(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2  (265)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-羧基-5-硝基二氢吲哚-1-基)磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ8.33(1H,d,J=2Hz),7.89(1H,dd,J=8.2Hz),7.67(1H,s),7.62(1H,d,J=8Hz),7.20(1H,d,J=8Hz),7.18(2H,d,J=8Hz),7.02(1H,d,J=8Hz),6.55(2H,d,J=8Hz),4.85(1H,dd,J=10,5Hz),4.60-4.25(1H,br),3.59(1H,t,J=7Hz),3.40-3.15(6H,m),2.25-1.75(9H,m),0.95(3H,t,J=7Hz);
TLC:Rf0.30(氯仿∶甲醇∶乙酸=4∶2∶0.1)。实施例2  (266)
2RS-(2-甲氧基-4-硝基苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯
Figure A9612198404162
NMR(CDCl3):δ7.88(1H,dd,J=2.0,8.5Hz), 7.78(1H,d,J=2.0Hz),7.75-7.65(2H,m),7.49(1H,d,J=8.5Hz),7.12(1H,d,J=9.0Hz),4.30-4.15(2H,m),3.98(3H,s),3.60-3.40(1H,m),3.30-3.10(1H,m),2.40-1.60(6H,m),2.08(3H,s),1.00(3H,t,J=7.5Hz);
TLC:Rf0.38(氯仿∶甲醇∶乙酸=4∶2∶0.1)。实施例2  (267)
2RS-(4-(吡啶烷-1-基)苯基)丁酸4-((2S-羧基-4S-甲基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·二盐酸盐
Figure A9612198404171
NMR(CD3OD):δ7.77(1H,s),7.75(1H,d,J=8.0Hz),7.37(2H,d,J=8.6Hz),7.19(1H,d,J=8.0Hz),6.98(2H,d,J=8.6Hz),4.18(1H,m),3.69(3H,m),3.59(1H,m),3.46(4H,m),2.72(3H,s),2.57(1H,m),2.21(2H,m),2.13(4H,m),2.02(3H,s),1.93(1H,m),0.98(3H,t,J=7.4Hz);
TLC:Rf0.28(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2  (268)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4S-(N,N-二甲基氨基)吡咯烷-1-基)磺酰基)-2-甲基苯基酯·二盐酸盐
Figure A9612198404181
NMR(CD3OD):δ7.81(1H,s),7.78(1H,d,J=8.2Hz),7.62(4H,s),7.21(1H,d,J=8.2Hz), 4.25(1H,t,J=7Hz),3.98 (1H,t,J=7Hz),3.77(4H,m),3.65(3H,m),2.90(6H,s),2.80(1H,m),2.29(4H,m),2.24(2H,m),2.06(3H,s),1.99(1H,m),1.00(3H,t,J=7.4Hz);
TLC:Rf0.42(氯仿∶甲醇∶水=6∶4∶1)。实施例2  (269)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羟基氨基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3):δ7.73(1H,s),7.68(1H,d,J=8.6Hz),7.23(2H,d,J=8.0Hz),7.2-7.0(2H,br),7.04(1H,d,J=8.6Hz),6.63(2H,d,J=8.0Hz),3.63(1H,t,J=7.7Hz),3.4-3.2(4H,brs),2.3-2.1(1H,m),2.1-1.9(4H,brs),2.00(3H,s),2.0-1.8(1H,m),0.97(3H,t,J=7.3Hz);
TLC:Rf0.25(己烷∶乙酸乙酯=2∶1)。实施例2  (270)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S,6S-二甲基哌嗪-4-基)磺酰基)-2-甲基苯基酯·二甲磺酸盐
Figure A9612198404192
NMR(CDCl3):δ7.76-7.62(6H,m),7.23(1H,d,J=8.5Hz),4.01(1H,t,J=7.5Hz),4.00-3.75(6H,m),3.55-3.30(2H,m),2.68(6H,s),2.45-1.80(8H,m),2.07(3H,s),1.31(6H,d,J=6.5Hz),1.00(3H,t,J=7.5Hz);
TLC:Rf0.66(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2  (271)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-甲基哌嗪-4-基)磺酰基)-2-甲基苯基酯·二甲磺酸盐
NMR(CDCl3):δ7.76-7.60(6H,m),7.23(1H,d,J=8.0Hz),4.01(1H,t,J=7.5Hz),3.90-3.72(6H,m),3.55-3.35(2H,m),3.32-3.13(1H,m),2.82-2.62(1H,m),2.67(6H,s),2.49(1H,dd,J=13.0,10.0Hz),2.40-1.80(6H,m),2.07(3H,s),1.32(3H,d,J=6.5Hz),1.00(3H,t,J=7.5Hz);
TLC:Rf0.45(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2  (272)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-(N,N-二甲基氨基)吡咯烷-1-基)磺酰基)-2-甲基苯基酯·二盐酸盐
Figure A9612198404211
NMR(DMSO-d6):δ11.38(1H,m),7.77(1H,s),7.72(1H,d,J=8.2Hz),7.19(3H,m),6.63(2H,d,J=8.6Hz),4.38(1H,m),4.01(1H,m),3.82(1H,m),3.73(1H,t,J=7.4Hz),3.49(1H,t,J=8.6Hz),3.24(4H,m),2.70(6H,s),2.36(2H,m),2.11(1H,m),1.99(3H,s),1.97(4H,m),1.83(1H,m),0.91(3H,t,J=7.2Hz);
TLC:Rf0.44(氯仿∶甲醇∶水=6∶4∶1)。实施例2  (273)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-甲基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·二盐酸盐
NMR(CD3OD):δ7.76(1H,s),7.73(1H,d,J=8.0Hz),7.25(2H,d,J=8.4Hz),7.13(1H,d,J=8.0Hz),6.71(2H,d,J=8.4Hz),4.53(1H,m),3.97(1H,m),3.86(1H,m),3.70(1H,t,J=8Hz),3.41(1H,m),3.35(4H,m),2.70(3H,s),2.49(1H,m),2.31(1H,m),2.17(1H,m),2.06(4H,m),2.00(3H,s),1.92(1H,m),0.98(3H,t,J=7.2Hz);
TLC:Rf0.46(氯仿∶甲醇∶水=6∶4∶1)。实施例2  (274)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-乙基苯基酯·二盐酸盐
Figure A9612198404222
NMR(CD3OD):δ7.75-7.50(6H,m),7.25(1H,d,J=9.0Hz), 3.97(1H,t,J=7.5Hz),3.85-3.70(4H,m),3.35-3.15(8H,m),2.50-1.80(8H,m),1.00(6H,t,J=7.5Hz);
TLC:Rf0.46(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2  (275)
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-乙基苯基酯·二盐酸盐
Figure A9612198404231
NMR(CD3OD):δ7.75-7.58(6H,m),7.25(1H,d,J=9.0Hz),3.98(1H,t,J=7.5Hz),3.90-3.70(4H,m),3.40-3.20(8H,m),2.50-1.80(8H,m),1.00(6H,t,J=7.5Hz);
TLC:Rf0.46(氯仿∶甲醇∶水= 9∶1∶0.1)。实施例2  (276)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基·二盐酸盐
NMR(CD3OD):δ7.71(6H,m),7.22(1H,d,J=8.0Hz),4.00(1H,t,J=8Hz),3.81(4H,m),3.31(8H,s),2.33(4H,m),2.24(1H,m),2.07(3H,s),1.98(1H,m),1.01(3H,t,J=7.4Hz);
TLC:Rf0.66(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2  (277)
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·二盐酸盐
NMR(CD3OD):δ7.70(6H,m),7.22(1H,d,J=8.0Hz),4.00(1H,t,J=8Hz),3.81(4H,m),3.30(8H,s),2.32(4H,m),2.24(1H,m),2.06(3H,s),1.99(1H,m),1.00(3H,t,J=7.4Hz);
TLC:Rf0.66(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2  (278)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基甲基吡咯烷-1-基)磺酰基)-2-甲基苯基酯
Figure A9612198404252
NMR(CDCl3):δ7.70-7.58(2H,m),7.23(2H,d,J=8Hz),7.09(1H,d,J=8Hz),6.55(2H,d,J=8Hz),4.00-3.84(1H,m),3.62(1H,t,J=7Hz),3.50-3.35(1H,m),3.35-3.20(4H,m),3.18-3.03(2H,m),2.54(1H,dd,J=15,10Hz),2.30-1.40(13H,m),0.98(3H,t,J=7Hz);
TLC:Rf0.39(己烷∶乙酸乙酯∶乙酸=50∶50∶1)。实施例2  (279)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4-乙酰基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198404261
NMR(DMSO-d6):δ8.02(1H,d,J=6Hz),7.74(1H,s),7.69(1H,dJ=8.8Hz),7.24(2H,d,J=8.6Hz),7.18(1H,d,J=8.6Hz),6.69(1H,d,J=8.8Hz),4.15(1H,t,J=7Hz),3.75(2H,m),3.51(1H,m),3.28(4H,m),3.05(1H,m),2.33(1H,m),2.12(1H,m),1.99(7H,s-like),1.83(2H,m),1.75(3H,s),0.91(3H,t,J=7.4Hz);
TLC:Rf0.67(氯仿∶甲醇∶水=6∶4∶1)。实施例2  (280)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2-羧基-5,6-二甲氧基吲哚-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
Figure A9612198404271
NMR(DMSO-d6):δ7.87(1H,d,J=2.2Hz),7.79(1H,dd,J=8.6Hz,2.2Hz),7.50(1H,s),7.25-7.13(5H,m),6.66(2H,d,J=8.0Hz),3.88(3H,s),3.78(3H,s),3.71(1H,t,J=7.2Hz),3.26(4H,m),2.08(1H,m),1.97(4H,m),1.93(3H,s),1.78(1H,m),0.88(3H,t,J=7.6Hz),
TLC:Rf0.45(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2  (281)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-羧基二氢吲哚-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
NMR(DMSO-d6):δ7.78(1H,s),7.67(1H,dd,J=2 and 8Hz),7.35-6.94(7H,m),6.80-6.64(2H,br),5.00-4.93(1H,m),3.70(1H,t,J=7Hz),3.39-2.96(6H,m),2.17-1.64(2H,m),2.04-1.94(4H,m),1.91(3H,s),0.87(3H,t,J=7Hz);
TLC:Rf0.30(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2  (282)
2S-(4-(吡啶烷-1-基)苯基)丁酸4-((2RS-甲基哌嗪-4-基)磺酰基)-2-甲基苯基酯·二甲磺酸盐
Figure A9612198404282
NMR(CD3OD):δ7.75-7.60(6H,m),7.23(1H,d,J=8.5Hz),4.00(1H,t,J=7.5Hz),3.90-3.70(6H,m),3.55-3.35(2H,m),3.35-3.10(1H,m),2.80-2.65(1H,m),2.66(6H,s),2.47(1H,t,J=10.0Hz),2.06(3H,s),1.31(3H,d,J=6.5Hz)1.00(3H,t,J=7.5Hz);
TLC∶Rf0.45(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2  (283)
2RS-(4-(吡咯烷-1-基)苯基丁酸4-((4-甲酰基哌嗪-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CD3OD):δ7.96(1H,s),7.73-7.52(6H,m),7.19(1H,d,J=8.4Hz),3.97(1H,t,J=7.6Hz),3.88-3.67(4H,m),3.67-3.44(4H,m),3.12-2.93(4H,m),2.43-2.14(5H,m),2.12-1.81(4H,m),1.00(3H,t,J=7.2Hz);
TLC:Rf0.38(己烷∶乙酸乙酯=1∶2)。实施例2  (284)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·钠盐
NMR(d6-DMSO):δ7.78-7.64(2H,m),7.18(2H,d,J=8.0Hz),7.08(1H,d,J=8.0Hz),6.53(2H,d,J=8.0Hz),3.95-3.80(1H,m),3.69(1H,t,J=7.5Hz),3.50-3.00(6H,m),2.20-1.30(10H,m),1.96(3H,s),0.91(3H,t,J=7.5Hz);
TLC∶Rf0.32(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2  (285)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·甲磺酸盐
Figure A9612198404302
NMR(CDCl3):δ7.65(4H,d,J=8.5Hz),7.54(2H,d,J=8.5Hz),7.05(1H,d,J=8.5Hz),4.30-4.15(1H,m),4.10-3.50(4H,m),3.80(1H,t,J=7.5Hz),3.55-3.35(1H,m),3.30-3.10(1H,m),2.87(3H,s),2.50-1.60(10H,m),2.03(3H,s),0.99(3H,t,J=7.5Hz);
TLC:Rf0.32(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2  (286)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((哌嗪-4-基)磺酰基)-2-甲基苯基酯·二甲磺酸盐
NMR(CD3OD):δ7.75-7.60(6H,m),7.23(1H,d,J=8.0Hz),4.01(1H,tJ=7.5Hz),3.90-3.70(4H,m),3.35-3.20(8H,m),2.68(6H,s),2.40-1.80(6H,m),2.06(3H,s),1.00(3H,t,J=7.5Hz);
TLC∶Rf0.14(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2  (287)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·柠檬酸盐·乙醇盐
Figure A9612198404321
NMR(CD3OD):δ7.66(1H,brs),7.62(1H,brd,J=8.0Hz),7.20(2H,d,J=8.5Hz),7.18(1H,d,J=8.0Hz),6.58(2H,d,J=8.5Hz),3.67(1H,t,J=7.5Hz),3.60(2H,q,J=7.0Hz),3.40-3.15(12H,m),2.76(4H,dd,J=8.0,14.0Hz),2.30-1.70(9H,m),1.17(3H,t,J=7.0Hz),0.97(3H,t,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2  (288)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·琥珀酸盐
NMR(CD3OD):δ7.64(1H,brs),7.61(1H,brd,J=8.0Hz),7.19(2H,d,J=8.5Hz),7.17(1H,d,J=8.0Hz),6.57(2H,d,J=8.5Hz),3.64(1H,t,J=7.5Hz),3.40-3.20(4H,m),3.12(8H,s),2.51(4H,s),2.30-1.76(9H,m),0.97(3H,t,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2  (289)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·L-苹果酸盐
Figure A9612198404332
NMR(CD3OD):δ7.67(1H,brs),7.62(1H,brd,J=8.0Hz),7.22(2H,d,J=8.5Hz),7.19(1H,d,J=8.0Hz),6.58(2H,d,J=8.5Hz),4.28(1H,dd,J=5.0,7.5Hz),3.68(1H,t,J=7.5Hz),3.40-3.05(12H,m),2.78(1H,dd,J=5.0,15.0Hz),2.52(1H,dd,J=7.5,15.0Hz),2.40-1.72(9H,m),0.98(3H,t,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2  (290)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·富马酸盐
Figure A9612198404341
NMR(CD3OD):δ7.68(1H,brs),7.63(1H,brd,J=8.0Hz),7.21(2H,d,J=8.5Hz),7.19(1H,d,J=8.0Hz),6.82(2H,s),6.59(2H,d,J=8.5Hz),3.65(1H,t,J=7.5Hz),3.40-3.10(12H,m),2.30-1.70(9H,m),0.98(3H,t,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2  (291)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·草酸盐
NMR(CD3OD):δ7.68(1H,s),7.63(1H,brd,J=8.0Hz),7.20(2H,d,J=8.5Hz),7.19(1H,d,J=8.0Hz),6.60(2H,d,J=8.5Hz),3.66(1H,t,J=7.5Hz),3.45-3.10(12H,m),2.30-1.75(9H,m),0.98(3H,1,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2  (292)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·L-乳酸盐
Figure A9612198404352
 NMR(CD3OD):δ7.65(1H,s),7.61(1H,brd,J=8.0Hz),7.20(2H,d,J=8.5Hz),7.17(1H,d,J=8.0Hz),6.57(2H,d,J=8.5Hz),4.04(1H,q,J=7.0Hz),3.65(1H,t,J=7.5Hz),3.40-3.20(4H,m),3.14(8H,s),2.15(3H,s),2.20-1.75(6H,m),1.31(3H,d,J=7.0Hz),0.97(3H,t,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2  (293)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·L-酒石酸盐
Figure A9612198404361
NMR(CD3OD):δ7.68(1H,s),7.64(1H,brd,J=8.0Hz),7.21(2H,d,J=8.5Hz),7.18(1H,d,J=8.0Hz),6.59(2H,d,J=8.5Hz),4.43(2H,s),3.68(1H,t,J=7.5Hz),3.45-3.10(12H,m),2.40-1.78(9H,m),0.98(3H,t,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2  (294)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·二对甲苯磺酸盐
NMR(CD3OD):δ7.68(6H,d,J=8.0Hz),7.63(4H,d,J=9.0Hz),7.22(5H,d,J=8.0Hz),3.99(1H,t,J=7.4Hz),3.83-3.65(4H,m),3.30(8H,m),2.36(6H,s),2.36-2.20(5H,m),2.04(3H,s),1.95(1H,m),0.99(3H,t,J=7.4Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2  (295)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·磷酸盐
NMR(DMSO-d6):δ8.00-7.40(3H,m),7.67(1H,brs),7.62(1H,brd,J=8.8Hz),7.25(1H,d,J=8.8Hz),7.21(2H,d,J=8.8Hz),6.56(2H,d,J=8.8Hz),3.75(1H,t,J=7.4Hz),3.23(4H,brs),2.94(8H,brs),2.01(3H,s),2.20-1.80(6H,m),0.93(3H,t,J=7.4Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2  (296)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·马来酸盐
Figure A9612198404381
NMR(CD3OD):δ7.67(1H,s),7.62(1H,brd,J=8.0Hz),7.20(2H,d,J=8.5Hz),7.19(1H,d,J=8.0Hz),6.58(2H,d,J=8.5Hz),6.23(2H,s),3.65(1H,t,J=7.5Hz),3.40-3.05(12H,m),2.30-1.78(6H, m),1.98(3H,s),0.97(3H,t,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例3
2RS-(4-甲基苯基)丁酸4-(2S-羟基磺酰基氧甲基吡咯烷-1-基磺酰基)-2-甲基苯基酯
将三氧化硫吡啶配合物(766mg)加入到实施例2(19)制备的化合物(690mg)的吡啶(10ml)溶液中,在室温下搅拌反应混合物30分钟。浓缩反应混合物,通过硅胶柱色谱(氯仿∶甲醇=10∶1)纯化残余物,得到具有下面物理数据的标题化合物(700mg)。
NMR(DMSO-d6):δ7.74(1H,d,J=2.0Hz),7.67(1H,dd,J=8.5,2.0Hz),7.30(2H,d,J=8.5Hz),7.20(2H,d,J=8.5Hz),7.18(1H,d,J=8.5Hz),3.94-3.78(2H,m),3.76-3.60(1H,m),3.58(1H,t,J=7.0Hz),3.3-3.2(1H,m),3.12-2.94(1H,m),2.31(3H s),2.25-2.00 and 1.95-1.70(each 1H,m),1.97(3H,s),1.90-1.60(2H,m),1.60-1.30(2H,m),0.91(3H,t,J=7.5Hz);
TLC:Rf0.39(水∶甲醇∶氯仿=1∶10∶40)。实施例3  (1)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羟基磺酰基氧甲基吡咯烷-1-基磺酰基)-2-甲基苯基酯
Figure A9612198404401
通过与实施例3相同的方法,使用实施例2(10)制备的化合物,得到具有下面物理数据的标题化合物。
NMR(DMSO-d6):δ7.74(1H,s),7.67(1H,d,J=8.5Hz),7.25-7.10(3H,m),6.55(2H,d,J=8.0Hz),3.91(1H,d,J=8.5Hz),3.80-3.50(3H,m),3.40-3.20(1H,m),3.35-3.20(4H,m),3.15-2.90(1H,m),2.20-1.60(2H,m),1.98(3H,s),
2.05-1.90(4H,m),1.90-1.60(2H,m),1.60-1.30(2H,m),0.91
(3H,t,J=7.5Hz);
TLC:Rf0.38(水∶甲醇∶氯仿=1∶10∶40)。剂型实施例剂型实施例1
用常规方法混合下面组分,冲压得到每片含有50mg活性组分的100片片剂。
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·二盐酸盐    5.0g羧甲基纤维素钙(崩解剂)                   0.2g硬脂酸镁(润滑剂)                         0.1g微晶纤维素                               4.7g剂型实施例2
用常规方法混合下面组分。用常规方法将该溶液消毒,将5ml部分放入安瓿中,冻干得到每安瓿含有20mg活性组分的100安瓿。
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·2盐酸盐      2.0g甘露糖醇                                  20g蒸馏水                                    1000ml

Claims (13)

1.下列式(I)的磺酰胺衍生物,或其无毒盐、酸加成盐或溶剂化物式中R1为C1-8烷基、C1-8烷氧基、羟基、酮基、硝基、卤原子、三卤甲基、氰基、脒基、-COOR7(其中R7为氢原子或C1-8烷基),或(其中p为0至4的整数,且R8和R9各自独立地为氢原子、C1-4烷基、C2-5酰基、-COOR10(其中R10为氢原子或C1-8烷基)、-CONR11R12(其中R11和R12各自独立地为氢原子或C1-4烷基),
Figure A9612198400031
(其中为α-氨基酸残基),或R8和R9与它们相连的氮原子一起代表未取代或被C1-4烷基或苯基C1-4烷基取代的脂族杂环);n为0至5的整数;为碳环或杂环;
Figure A9612198400041
其中R2和R3各自独立地为氢原子、C1-4烷基、C1-4烷氧基、卤原子、三卤甲基或苯基,或R2和R3一起代表C1-4亚烷基,或
Figure A9612198400042
其中R2和R3与它们相连的碳原子一起代表C3-7环烷基;R4为C1-4烷基或C1-4烷氧基,或相互在邻位与苯核相连的2个R4一起代表C3-5亚烷基;m为0至4的整数;且
Figure A9612198400043
其中R5和R6各自独立地为1)氢原子,2)羟基,3)C1-8烷基,4)C1-8烷氧基,5)苯基C1-4烷氧基,6)脒基,7)-M-R16(其中M为单键或C1-8亚烷基),且R16为i)-NR17R18(其中R17和R18各自独立地为氢原子或C1-4烷基),ii)-CONR19R20(其中R19和R20各自独立地为氢原子或C1-4烷基),iii)(其中
Figure A9612198400052
为碳环,r为0至5的整数,且R21为C1-4烷基、C1-4烷氧基、硝基、脒基、-COOR22(其中R22为氢原子、C1-8烷基、苯基或苯基C1-4烷基)、-SO3H、-CONR23-E-R24(其中R23为氢原子或C1-4烷基,E为1-4个亚烷基,且R24为-COOR25(其中R25为氢原子、C1-8烷基、苯基或苯基C1-4烷基)或四唑环)、四唑环或吗啉代环),iv)杂环,该杂环为未取代的或被1-4个选自C1-4烷基、C1-4烷氧基、羟基、苯基C1-4烷基、-COOR26(其中R26为氢原子、C1-8烷基、苯基或苯基C1-4烷基)、羟基C1-4烷基或C2-4烷氧基烷基的取代基所取代),8)C1-8烷基,其被1个或2个-OR27(其中R27为氢原子、C1-4烷基、C2-4烷氧基烷基或被-OR28(其中R28为氢原子或C2-4烷氧基烷基)取代的C2-4烷基)所取代,9)-J-COOR29(其中R29为氢原子、C1-8烷基、苯基或苯基C1-4烷基,且J为单键、-(CH2)3-或(其中s为2至6的整数,且R30和R31各自独立地为i)氢原子,ii)C1-8烷基,iii)-COOR32(其中R32为氢原子、C1-8烷基、苯基或苯基C1-4烷基),iv)碳环或杂环,其为未取代或被1个或多个选自C1-4烷基、C1-4烷氧基烷基、氨基、硝基、羟基、卤原子、腈、胍基和脒基的取代基所取代,或v)C1-8烷基,其被1个或多个选自羟基、COOR33(其中R33为氢原子、C1-8烷基、苯基或苯基C1-4烷基)、NR34R35(其中R34和R35各自独立地为氢原子或C1-4烷基)、未取代或被1个或多个选自C1-4烷基、C1-4烷氧基烷基、氨基、硝基、羟基、卤原子、腈、胍基和脒基的取代基取代的碳环或杂环的取代基所取代,条件是C1-8烷基的碳原子可被硫原子替换,或
Figure A9612198400071
其中R5和R6与它们相连的氮原子一起代表杂环,q为0至4的整数,且R15为1)羟基,2)酮基,3)被护酮基,4)C1-4烷基,5)C1-4烷氧基,6)苯基,7)苯氧基,8)苯基C1-4烷基,9)苯基C1-4烷氧基,10)硝基,11)-COOR36(其中R36为氢原子,C1-8烷基,被-CONR37R38(其中R37和R38各自独立地为氢原子或C1-4烷基)取代的C1-4烷基,被-NR39R40(其中R39和R40各自独立地为氢原子或C1-4烷基)取代的C1-4烷基,被OR41(其中R41为被OR42(其中R42为氢原子或C2-4烷氧基烷基)取代的C1-4烷基),或被哌嗪环取代的C1-4烷基),12)-NR43R44(其中R43和R44各自独立地为氢原子、C1-4烷基或C2-5酰基),13)-CONR45R46(其中R45和R46各自独立地为氢原子、羟基、C1-4烷基、苯基C1-4烷氧基或被羟基或-COOR47(其中R47为氢原子或C1-8烷基)取代的C1-4烷基),14)C1-4烷基,其被1个或多个选自羟基、-COOR48(其中R48为氢原子或C1-8烷基)、-NR49R50(其中R49和R50各自独立地为氢原子或C1-4烷基)、OSO3H或含有1或2个氮原子的5或6元杂环的取代基所取代,15)含有1或2个氮原子的5或6元杂环,16)卤原子,17)-CHO,或18)-NR51-COOR52(其中R51和R52各自独立地为氢原子或C1-8烷基)。
2.根据权利要求1的化合物,其中为3-15元单或多环芳烃环或脂族烃环。
3.根据权利要求1的化合物,其中
Figure A9612198400091
为含有1至4个氮原子、1或2个硫原子、1个或2个氧原子或1个氮原子和1个硫原子或氧原子的5-15元单环或双环芳香杂环、饱和杂环或部分饱和杂环。
4.根据权利要求1-3任一项的化合物,其中
Figure A9612198400092
其中所有符号如权利要求1所定义。
5.根据权利要求1-3任一项的化合物,其中
Figure A9612198400093
其中所有符号如权利要求1所定义。
6.根据权利要求1-5任一项的化合物,其中R1为C1-8烷基、C1-8烷氧基、羟基、酮基、硝基、卤原子、三卤甲基、氰基、脒基、-COOR7(其中R7如权利要求1所定义),或
Figure A9612198400101
(其中p如权利要求1所定义,且R8和R9各自独立地为氢原子、C1-4烷基、C2-5酰基、-COOR10(其中R10如权利要求1所定义)、-CONR11R12(其中R11和R12如权利要求1所定义),(其中
Figure A9612198400103
如权利要求1所定义)。
7.根据权利要求1-5任一项的化合物,其中R1为
Figure A9612198400111
其中R8和R9与它们相连的氮原子一起代表未取代或被C1-4烷基或苯基C1-4烷基取代的脂族杂环。
8.根据权利要求1的化合物,其为下列化合物,或其无毒盐、酸加成盐或溶剂化物,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-叔丁氧基羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羟基甲基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(吡咯烷-1-基甲基)吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-苯基丁酸4-(吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基丁酸4-(2-(乙氧基羰基)二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(乙氧基羰基)二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N,N-二甲基氨基羰基甲氧基羰基)二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-苄氧基氨基甲酰基)二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-硝基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-氨基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(7-硝基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(7-氨基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(苯并咪唑-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(吗啉-4-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-氮杂-7-氧代-二环[3.2.1]辛烷-6-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-苄基哌嗪-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-(2-羟基乙基)哌啶-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羟基甲基哌啶-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-N,N-二甲基氨基)哌啶-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-(嘧啶-2-基)哌嗪-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(1,4-二噁-8-氮杂螺[4.5]癸烷-8-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(3-氮杂二环[3.2.2]壬烷-3-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(1,3,3-三甲基-6-氮杂二环[3.2.1]辛烷-6-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代哌啶-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代-4S-苄基四氢化唑-3-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代-4S-异丙基全氢化噁唑-3-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代-4S-甲基-5S-苯基全氢化唑-3-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(1RS-氧代-4S-甲氧基羰基全氢化噻唑-3-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(吗啉-4-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(咪唑-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯,
2RS-(4-硝基苯基)丁酸4-(吗啉-4-基磺酰基)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(吗啉-4-基磺酰基)苯基酯,
2-(4-甲氧基苯基)-2-乙基丁酸4-(6-氮杂-7-氧代二环[3.2.1]辛烷-6-基磺酰基)苯基酯,
2RS-(4-甲基苯基)丁酸4-(吗啉-4-基磺酰基)-2-甲基苯基酯,
2RS-苯基丁酸4-(咪唑-1-基磺酰基)苯基酯,
2RS-苯基丁酸4-(吗啉-4-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-(乙氧基羰基)-2-(吗啉-4-基)乙基氨磺酰)苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-1RS-(乙氧基羰基)-2-(吗啉-4-基)乙基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-1RS-(乙氧基羰基)-2-(吗啉-4-基)乙基氨磺酰)苯基酯,
2RS-苯基-2-甲氧基乙酸4-(N-1RS-(乙氧基羰基)-2-(吗啉-4-基)乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄氧羰基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-苯基-2RS-甲基丁基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-氨磺酰苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-甲氧基乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基丁酸4-(N-2-甲氧基乙基-N-苄基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-叔丁氧基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-4-羟基丁基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-羟基甲基-2-甲基丙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2RS,3-二羟基丙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄氧基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(N’,N’-二甲基氨基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(N’-甲基氨基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(氨基甲酰基甲基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-叔丁基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-金刚烷-1-基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-胍基磺酰基-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2RS,3-二羟基丙基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-二(2-(甲氧基甲氧基)乙基)氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-二(2-(2-(甲氧基甲氧基)乙氧基)乙基)氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-甲基-N-甲氧基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄基氨磺酰)-2-甲基苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-2-(N’,N’-二甲基氨基)乙基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-胍基磺酰基苯基酯,
2RS-(4-硝基苯基)丁酸4-胍基磺酰基苯基酯,
2RS-(4-甲基苯基)丁酸4-(N-2RS,3-二羟基丙基氨磺酰)-2-甲基苯基酯,
2-(4-甲氧基苯基)-2-乙基丁酸4-(N-2-甲氧基乙基氨磺酰)苯基酯,
2-(4-甲氧基苯基)-2-乙基丁酸4-(N-2-(N’,N’-二甲基氨基)乙基氨磺酰)苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(胍基磺酰基)-2-甲基苯基酯,
2RS-苯基丁酸4-(N,N  二乙基氨磺酰)苯基醌,
2RS-苯基丁酸4-(N-苄基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-甲基-N-苄基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-2-苯基乙基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-甲基-N-2-苯基乙基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-1RS-(4-甲基苯基)丁基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(吡啶-2-基)乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-哌啶-1-基)乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(四唑-5-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-吗啉-4-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-吡咯烷-3-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1-苄基哌啶-4-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-吡啶-2-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(吗啉-4-基)乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(吡嗪-2-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(咪唑-2-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(奎宁环-3RS-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(2,2,6,6-四甲基哌啶-4-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(奎宁环-3RS-基)氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(吗啉-4-基)乙基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(哌嗪-4-基)乙基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(哌啶-4-基)氨磺酰)-2-甲基苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-2-(吗啉-4-基)乙基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(吡啶-2-基)乙基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(哌啶-1-基)乙基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(1-甲基吡咯-2-基)乙基氨磺酰)苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-(四唑-5-基甲基)氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-(四唑-5-基甲基)氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-(四唑-5-基)氨磺酰)苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-(四唑-5-基)氨磺酰)苯基酯,
2RS-(4-甲基苯基)丁酸4-(N-(奎宁环-3RS-基)氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2R-甲氧基-3R-羟基-4S-羟基-5R-羟基全氢化吡喃-6R-基甲基氨磺酰)-2-甲基苯基酯,
2RS-苯基丁酸4-(N-苯基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-4-硝基苯基氨磺酰)苯基酯,
2RS-(4-氨基苯基)丁酸4-(N-苯基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(2-(四唑-5-基)苯基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-4-(吗啉-4-基)苯基氨磺酰)苯基酯,
2-(N-(4-(2RS-(4-(吡咯烷-1-基)苯基)丁酰氧基)-3-甲基苯基磺酰基)氨基)苯磺酸,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-3,5-二甲氧基苯基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苯基氨磺酰)-2-甲基苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-2-(N’-四唑-5-基甲基)氨基甲酰基)苯-1-基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2(N’-(四唑-5-基甲基)氨基甲酰基)苯-1-基氨磺酰)苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-(4-脒基苯基)氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-(4-脒基苯基)氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(四唑-5-基)苯基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-4(吗啉-4-基)苯基氨磺酰)苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-2-(四唑-5-基)苯基氨磺酰)苯基酯,
2RS-(4-(N-叔丁氧基羰基氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(3,5-二甲氧基苄基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((4-叔丁氧基羰基氨基哌啶-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-甲氧基-N-苄基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄氧基-N-甲基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(N,N-二甲基氨基)乙基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(哌啶-1-基)乙基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(3-(吗啉-4-基)丙基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2-氧代-4R-异丙基全氢化噁唑-3-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(吗啉-4-基)乙基-N-甲氧基氨基磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(5-硝基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(吗啉-4-基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-氟二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(5-(N,N-二甲基氨基)二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-甲基哌嗪-1-基磺酰基)-2-甲基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(5-硝基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-乙基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-乙基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-甲基-1,4-全氢化二氮杂草-1-基磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-乙氧基羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(奎宁环-3RS-基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-吡咯烷-1-基)苯基)丁酸4-(3,5-二甲氧基苯基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2R-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基-4R-羟基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基-4R-苄氧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基-4S氨基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基-4R-氨基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(N-羧基甲基氨基甲酰基)吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(2-氨基乙氧基羰基)吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(2-(2-羟基乙氧基)乙氧基羰基)吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羟基甲基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(2-(哌嗪-4-基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2-(2-甲氧基苯基)-2-乙基丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(2-甲氧基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2S-羧基吡咯-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2S-(2-(哌嗪-1-基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2S-(2-(2-羟基乙氧基)乙氧基羰基)吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2S-(2-氨基乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2S-羧基甲基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2S-(2-氨基乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2S-(2-(哌嗪-4-基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2S-(2-(2-羟基乙氧基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-硝基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2R-(4-硝基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2S-(4-硝基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-硝基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-硝基苯基)丁酸4-(2R-羧基吡咯烷-1-基磺酰基)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(2R-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-苯基丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-羧基吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基全氢化吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-羧基甲基氨基甲酰基)二氢吲哚-1-基磺酰基)苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基-3,3-二甲基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲氧基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-2-羧基乙基氨基甲酰基)二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-2-羟基乙基氨基甲酰基)二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-羧基-5,6-二甲氧基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(2-氨基乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-羧基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基-5,6-二甲氧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-羧基-5-羟基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(2-2-羟基乙氧基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羟基甲基二氢吲哚-1-基磺酰基)-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基-5-羟基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(2-哌嗪-1-基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-羟基氨基甲酰基)二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2-羧基-5,6-二甲氧基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2-羧基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2-羧基-5-羟基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2RS-羟基甲基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2RS-(2-氨基乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2RS-(2-(哌嗪-4-基)乙基)氧羰基二氧吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2RS-(2-(2-羟基乙氧基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(3-甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(2-甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(2-甲氧基苯基)丁酸4-(2RS-羧基-二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(3,4-二甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(3,4-二甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-甲基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2-羧基-5,6-二甲氧基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2-羧基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2-羧基-5-羟基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2RS-(2-氨基乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2RS-羟基甲基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2RS-(2-(2-羟基乙氧基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2RS-(2-哌嗪-4-基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-羟基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-氨基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4S-羧基全氢化噻唑-3-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-羧基哌啶-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基哌啶-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(3RS-羧基哌啶-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4S-羧基全氢化噻唑-3-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基吗啉-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(1S-氧代-4S-羧基全氢化噻唑-3-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4 S-羧基-1,1-二氧代全氢化噻唑-3-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-(2-羟基乙基)哌嗪-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-羧基甲基哌嗪-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-硝基苯基)丁酸4-(4S-羧基全氢化噻唑-3-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-2-甲氧基乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS,2-二羧基乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1-羧基环丁烷)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-羧基-2-苯基乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1S-羧基-2-甲基丙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1S-羧基-2-羧基甲硫基乙基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-羧基-1-(噻吩-2-基)甲基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-羧基-1-(呋喃-2-基)甲基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-2-甲氧基乙基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-丙基-N-羧基甲基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1S-羧基-5-氨基戊基氨磺酰)-2-甲基苯基酯,
2-(4-甲氧基苯基)-2-乙基丁酸4-(N-羧基甲基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-甲氧基乙基-N-羧基甲基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-1RS,2-二羧基乙基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-羧基甲基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-丙基-N-羧基甲基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-苄基-N-羧基甲基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-2-苯基乙基-N-羧基甲基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-苯基-N-羧基甲基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-二(2-羟基乙基)氨磺酰)-2-甲基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-二(2-(2-羟基乙氧基)乙基)氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(3RS-羧基-1,4-苯并二噁烷-5-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(2RS-羟基-4R-羟基-5R-羟基-6R-羟基甲基全氢化吡喃-3R-基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-3-羧基金刚烷-1-基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1S,4R,3R-羧基二环[2.2.1]庚烷-2S-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-3S-羧基环己烷-1R-基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2RS-羧基环己烷-1RS-基氨磺酰)苯基酯,
2-(萘-1-基)乙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(萘-2-基)乙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(环己烷-1-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-苯基-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-苯基丙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2R-苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2S-苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-苯基-2-甲基丙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-苯基环己烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-苯基环丙烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-苯基环戊烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-苯基环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-苯基乙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-氯-2-苯基乙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-氯-2-苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2,2-二苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-甲基-2-苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2R-三氟甲基-2-苯基-2-甲氧基乙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2S-三氟甲基-2-苯基-2-甲氧基乙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-甲氧基苯基)-3-甲基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(4-甲氧基苯基)-2-甲基丙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-甲氧基苯基)丙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(4-甲氧基苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-甲氧基苯基)环己烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-甲氧基苯基)环戊烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-甲氧基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-甲氧基苯基)环丙烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(3,4-二甲氧基苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(3,4-二甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(3-甲氧基苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2-甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(2-甲氧基苯基)-2-乙基丁酸4-(N-2-(N’ -羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(3-甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(2-甲氧基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2,6-二甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2-异丙基苯基酯,
2RS-(4-(2-甲基丙氧基)苯基)丁酸4-(N-2-(N’ -羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-异丙氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(丙氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-甲基苯基)戊酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-甲基苯基)环戊烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(3-甲基苯基)环戊烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2-甲基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(2-甲基苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-甲基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(4-硝基苯基)-2-甲基丙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-硝基苯基)环丙烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-硝基苯基)环戊烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(4-硝基苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2-甲基苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2-甲基苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-3-甲基苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2,3-二甲基苯基酯,
1-(4-硝基苯基)环丁烷羧酸7-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2,3-二氢茚-4-基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-3-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2,3-二甲基苯基酯,
1-(4-(吡咯烷-1-基)苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸7-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2,3-二氢茚-4-基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2,6-二甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2-异丙基苯基酯,
2RS-(4-(哌啶-1-基)苯基丁酸4-(N-2-(N’-羧基
甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(全氢化吖庚因-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(4-(氨基苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-氨基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(N,N-二甲基氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-(N,N-二甲基氨基)苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(N,N-二乙基氨基甲基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-羟基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-氰基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-羧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-三氟甲基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(脒基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-咪唑啉-2-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-氯苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2-氯苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(2-氯苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(2-氯苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-氯苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(3-硝基-4-羟基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2-氯-5-硝基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(2-氯-5-硝基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(3-硝基-4-氯苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(3-硝基-4-氯苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-脲基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-脲基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(N-(2S-氨基丙酰基)氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(N-(2S-氨基-3-甲基丁酰基)氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(N-(吡咯烷-2S-基羰基)氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(3,4,5-三甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2,4,6-三甲基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(3-硝基-4-甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(3-硝基-4-氨基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(N-乙酰基氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(N-甲基-N-乙酰基氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(吗啉-4-基甲基)苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(4-苄基哌嗪-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基甲基)苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((1R-氧代-4S-羧基全氢化噻唑-3-基)磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2R-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-((2R-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-氨基甲基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((4-氨基哌啶-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基氮杂环丁烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-羧基哌啶-1-基)磺酰基)-2-甲基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-((2-氧代-5S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(3-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-甲氧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基丁酸4-((2R-羧基-4R-甲氧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(2-甲基-4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-羟基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-甲氧基-N-羧基甲基氨基磺酰基)-2-甲基苯基酯,
2RS-(2-甲氧基-4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基氮丙啶-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-二(2-氨基乙基)氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-(2-(N’,N’-二甲基氨基)乙基)氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-乙基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-苄氧基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(4-羧基丁基)氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1,1-二甲基-1-羧基甲基)氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-甲基-N-羟基氨基磺酰基)-2-甲基苯基酯,
2RS-(2-甲基-4-硝基苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1,1-二甲基-1-羧基甲基)-N-丙基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4S-氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基)-N-(2-(吗啉-4-基)乙基)氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4S-乙酰基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)-2-丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-乙酰基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-羧基-5-硝基二氢吲哚-1-基)磺酰基)-2-甲基苯基酯,
2RS-(2-甲氧基-4-硝基苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4S-甲基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4S-(N,N-二甲基氨基)吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羟基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S,6S-二甲基哌嗪-4-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-甲基哌嗪-4-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-(N,N-二甲基氨基)吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-甲基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-乙基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-乙基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基甲基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4-乙酰基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2-羧基-5,6-二甲氧基吲哚-1-基)磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-羧基二氢吲哚-1-基)磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-甲基哌嗪-4-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((4-甲酰基哌嗪-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2S-羧基磺酰氧基甲基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基丁酸4-(2S-羟基磺酰氧基甲基吡咯烷-1-基磺酰基)-2-甲基苯基酯。
9.根据权利要求1的化合物,其为下列化合物,或其无毒盐、酸加成盐或溶剂化物,
2RS-(2H-1,4-苯并噁嗪-3-酮-6-基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(2 H-1,4-苯并噁嗪-3-酮-6-基)丁酸4-(2 R-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(2-甲基苯并咪唑-5-基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(1,3-苯并二氧环戊-5-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(噻吩-2-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(1,3-苯并间二氧杂环戊-5-基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(噻吩-2-基)-3-甲基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(吡啶-3-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2H-1,4-苯并噁嗪-3-酮-6-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2-(N-甲氧基羰基氨基)噻唑-4-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2-甲基苯并咪唑-5-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(1H-1-甲基-2-吡啶酮-3-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(噻吩-2-基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯。
10.一种药物组合物,其包括作为活性成分的有效量的权利要求1所定义的式(I)化合物,其无毒盐、酸加成盐或溶剂化物,以及载体或包衣。
11.式(I)化合物或其无毒盐或无毒酸加成盐或溶剂化物用于生产作为弹性蛋白酶抑制剂的药物组合物。
12.式(I)化合物或其无毒盐或无毒酸加成盐或溶剂化物用于生产预防和/或治疗由于哺乳动物,尤其是人类的弹性蛋白酶的作用导致的弹性蛋白、胶原纤维和/或蛋白多糖的降解的异常增加引起的疾病例如慢性阻塞肺病如肺气肿、风湿病样关节炎、动脉粥样硬化、成人呼吸不适综合症(ARDS)、血管小球肾炎、心肌梗塞、自发性溃疡性结肠炎或龈炎的药物组合物。
13.权利要求1所定义的式(I)的磺酰胺衍生物的制备方法,该方法包括酯化下式化合物
Figure A9612198400401
其中R1a为C1-8烷基、C1-8烷氧基、羟基、被护羟基、酮基、硝基、卤原子、三卤甲基、氰基、脒基、-COOR7a(其中R7a为C1-8烷基或苄基),或(其中p如权利要求1所定义,R8a和R9a各自独立地为氢原子(条件是R8a和R9a不同时代表氢原子)、叔丁氧基羰基、苄氧基羰基、C1-4烷基、C2-5酰基、-COOR10a(其中R10a为C1-8烷基或苄基)、-CONR11R12(其中R11和R12如权利要求1所定义),或
Figure A9612198400411
(其中为被护的α-氨基酸残基),或R8a和R9a与它们相连的氮原子一起代表未取代或被C1-4烷基或苯基C1-4烷基取代的脂族杂环,其它符号如权利要求1所定义,酯化所用的化合物为式(III)化合物
Figure A9612198400413
其中(其中R5a和R6a各自独立地为1)氢原子(条件是R5a,R6a不同时代表氢原子),2)羟基,3)被在酸性条件下可除去的保护基团保护的羟基,4)叔丁氧基羰基,5)苄氧基羰基,6)C1-8烷基,7)C1-8烷氧基,8)苯基C1-4烷氧基,9)胍基,10)-M-R16a(其中M如权利要求1所定义,R16a为i)-NR17aR18a(其中R17a和R18a各自独立地为氢原子(条件是R17a和R18a不同时代表氢原子)、叔丁氧基羰基、苄氧基羰基或C1-4烷基),ii)-CONR19R20(其中R19和R20如权利要求1所定义),(其中所有符号如前文所定义),iv)杂环,该杂环为未取代的或被1至4个选自C1-4烷基、C1-4烷氧基、羟基、苯基C1-4烷基、-COOR26(其中R26如权利要求1所定义)、其中羟基被在酸性条件下可除去的保护基团保护的羟基C1-4烷基或C2-4烷氧基烷基的取代基所取代),11)C1-8烷基,其被1个或2个-OR27a所取代,其中R27a为氢原子、C1-4烷基、C2-4烷氧基烷基、叔丁基二甲基甲硅烷基、THP、苄基或被-OR28(其中R28a为氢原子、C2-4烷氧基烷基、叔丁基二甲基甲硅烷基、THP或苄基)取代的C2-4烷基,12)-Ja-COOR29(其中R29如权利要求1所定义,Ja为单键、-(CH2)s-或
Figure A9612198400431
(其中s如权利要求1所定义,R30a和R31a各自独立地为i)氢原子,ii)C1-8烷基,iii)-COOR32(其中R32如权利要求1所定义),iv)碳环或杂环,其为未取代或被1个或多个选自C1-4烷基、C1-4烷氧基烷基、氨基、硝基、羟基、被护羟基、卤原子、腈、胍基和脒基的取代基所取代,或v)C1-8烷基,其被1个或多个选自羟基、被护羟基、-COOR33(其中R33如权利要求1所定义)、-NR34aR35a(其中R34a和R35a各自独立地为氢原子(条件是R34a和R35a不同时代表氢原子)、叔丁氧基羰基、苄氧基羰基或C1-4烷基)、未取代或被1个或多个选自C1-4烷基、C1-4烷氧基烷基、被护氨基、硝基、羟基、被护羟基、卤原子、腈、胍基和脒基的取代基取代的碳环或杂环的取代基所取代,条件是C1-8烷基的碳原子可被硫原子替换,或其中R5a和R6a与它们相连的氮原子一起代表杂环,q如权利要求1所定义,R15a为1)羟基,2)被在酸性条件下可被除去的保护基团保护的羟基,3)酮基,4)被护酮基,5)C1-4烷基,6)C1-4烷氧基,7)苯基,8)苯氧基,9)苯基C1-4烷基,10)苯基C1-4烷氧基,11)硝基,12)-COOR36a(其中R36a为氢原子、C1-8烷基、被-CONR37R38(其中R37和R38如权利要求1所定义)取代的C1-4烷基、被-NR39aR40a(其中R39a和R40a各自独立地为氢原子(条件是R39a和R40a不同时代表氢原子)、叔丁氧基羰基、苄氧基羰基或C1-4烷基)取代的C1-4烷基、被-OR41a(其中R41a为被-OR42a(其中R42a为氢原子、C2-4烷氧基烷基、苄基)取代的C2-4烷基)取代的C1-4烷基或被护哌嗪环取代的C1-4烷基),13)-NR43aR44a(其中R43a和R44a各自独立地为氢原子(条件是R43a和R44a不同时代表氢原子)、叔丁氧基羰基、苄氧基羰基、C1-4烷基或C2-5酰基),14)-CONR45aR46a(其中R45a和R46a各自独立地为氢原子、C1-4烷基、羟基、被在酸性条件可被除去的保护基团保护的羟基、苯基C1-4烷氧基或被羟基、被护羟基或-COOR47a(其中R47a为氢原子、C1-8烷基或苄基)取代的C1-4烷基),15)C1-4烷基,其被1个或多个选自羟基、被护羟基、-COOR48a(其中R48a为氢原子、C1-8烷基或苄基)、-NR49aR50a(其中R49a和R50a各自独立地为氢原子(条件是R49a和R50a不同时代表氢原子)、叔丁氧基羰基、苄氧基羰基或C1-4烷基),或含有1个或2个氮原子的5或6元杂环的取代基所取代,16)含有1个或2个氮原子的5或6元杂环,17)卤原子,18)被在酸性条件下可除去的保护基团保护的-CHO,19)-NR51a-COOR52a(其中R51a和R52a各自独立地为氢原子或C1-8烷基),并且其它符号如权利要求1所定义,
或者其制备通过用式(III)化合物酯化式(II)化合物,得到具有被保护基团的化合物,然后消去保护基团,
或者其制备通过用式(III)化合物酯化式(II)化合物,如果需要,消去保护基团,得到具有R15代表被羟基取代的C1-4烷基的化合物,然后进行硫酸酯化,并且任意将如此获得的式(I)化合物转化为其无毒盐、酸加成盐或溶剂化物。
CN 96121984 1995-09-27 1996-09-27 磺酰氨衍生物 Pending CN1161962A (zh)

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Cited By (2)

* Cited by examiner, † Cited by third party
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CN106631974A (zh) * 2017-02-17 2017-05-10 杭州中美华东制药有限公司 制备吲哚布芬的方法
CN115894607A (zh) * 2022-11-02 2023-04-04 四川大学 一种抗肿瘤的苯丙氨酸缬氨酰衍生物及其制备方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106631974A (zh) * 2017-02-17 2017-05-10 杭州中美华东制药有限公司 制备吲哚布芬的方法
CN106631974B (zh) * 2017-02-17 2019-03-19 杭州中美华东制药有限公司 制备吲哚布芬的方法
CN115894607A (zh) * 2022-11-02 2023-04-04 四川大学 一种抗肿瘤的苯丙氨酸缬氨酰衍生物及其制备方法
CN115894607B (zh) * 2022-11-02 2024-01-30 四川大学 一种抗肿瘤的苯丙氨酸缬氨酰衍生物及其制备方法

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