CN101659639A - 具有cb1-拮抗活性的新的4,5-二氢-1h-吡唑衍生物 - Google Patents

具有cb1-拮抗活性的新的4,5-二氢-1h-吡唑衍生物 Download PDF

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CN101659639A
CN101659639A CN200910141766A CN200910141766A CN101659639A CN 101659639 A CN101659639 A CN 101659639A CN 200910141766 A CN200910141766 A CN 200910141766A CN 200910141766 A CN200910141766 A CN 200910141766A CN 101659639 A CN101659639 A CN 101659639A
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C·G·克鲁斯
J·H·M·兰格
J·缇浦克
A·H·J·赫曼斯
H·H·范司徒温比尔格
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Abstract

本发明涉及具有CB1－拮抗活性的新的4，5－二氢－1H－吡唑衍生物。上述物质可用于治疗与大麻素系统的障碍有关的疾病。所述化合物具有通式(I)，其中的符号具有的含义在说明书中给出。本发明还涉及这些化合物的制备方法，以及含有一种或多种这些化合物作为活性成分的药物组合物。

Description

具有CB1-拮抗活性的新的4，5-二氢-1H-吡唑衍生物
本申请是申请号为02818189.1、申请日为2002年9月17日、发明名称为“具有CB1-拮抗活性的新的4，5-二氢-1H-吡唑衍生物”的中国专利申请的分案申请。
技术领域
本发明涉及一组新的4，5-二氢-1H-吡唑衍生物、其制备方法和含有一种或多种这些化合物作为活性成分的药物组合物。
上述4，5-二氢-1H-吡唑是有效的大麻素(CB1)受体拮抗剂，可用于治疗与大麻素系统的障碍有关的疾病。
背景技术
大麻素存在于印度大麻Cannabis sativa中并且被用作药剂已有数百年历史(Mechoulam，R.和Feigenbaum，J.J.Prog.Med.Chem.1987，24，159)。但是，仅仅在过去的十年中，大麻素领域的研究才揭示了大麻素受体及其(内源性)激动剂和拮抗剂的关键性信息。此发现和随后两种不同亚型大麻素受体(CB1和CB2)的克隆促进了对新大麻素受体拮抗剂的探求(Munro，S.等，Nature 1993，365，61.Matsuda，L.A.和Bonner，T.I.Cannabinoid Receptors，Pertwee，R.G.Ed.1995，117，Academic Press，伦敦)。此外，制药公司对开发用于治疗与大麻素系统障碍有关疾病的大麻素药物产生兴趣(Consroe，P.Neurobiology ofDisease 1998，5，534.Pop，E.Curr.Opin.In CPNS InvestigationalDrugs 1999，1，587.Greenberg，D.A.Drug News Perspect 1999，12，458.Pertwee，R.G.，Progress in Neurobiology 2001，63，569)。迄今已知若干种CB1受体拮抗剂。Sanofi公开了其二芳基吡唑同类物作为选择性CB1受体拮抗剂。代表性的实例为SR-141716A(Dutta，A.K.等，Med.Chem.Res.1994，5，54.Lan，R.等，J.Med.Chem.1999，42，769.Nakamura-Palacios，E.M.等，CNS Drug Rev.1999，5，43)。CP-272871是一种吡唑衍生物，类似SR141716A，但不如SR141716A有效并且在CB1受体亚型选择性上也不如SR141716A(Meschler，J.P.等，Pharmacol.2000，60，1315)。已公开氨基烷基吲哚为CB1受体拮抗剂。代表性的实例为lodopravadoline(AM-630)，它是在1995年被提出的。AM-630为一种中等活性的CB1受体拮抗剂，但有时表现为一种弱的部分激动剂(Hosohata，K.等Life Sc.1997，61，PL115)。来自Eli Lilly的研究者描述了芳基-芳酰基取代的苯并呋喃作为选择性CB1受体拮抗剂(如LY-320135)(Felder，C.C.等，J.Pharmacol.Exp.Ther.1998，284，291)。3-烷基-5，5’-二苯基咪唑烷二酮被描述为大麻素受体配体，它被指示为大麻素拮抗剂(Kanyonyo，M.等，Biorg.Med.Chem.Lett.1999，9，2233)。Aventis Pharma要求保护二芳基亚甲基氮杂环丁烷为CB1受体拮抗剂(Mignani，S.等，专利FR2783246，2000；Chem.Abstr.2000，132，236982)。Sanofi-Synthelabo要求保护三环吡唑为CB1拮抗剂(Barth，F.等，Chem.Abstr.2001，134，340504)。有趣的是，已报道许多CB1受体拮抗剂在体外表现为相反的激动剂(Landsman，R.S.等，Eur.J.Pharmacol.1997，334，R1)。综述很好地概述了大麻素研究领域的状况(Mechoulam，R.等，Prog.Med.Chem.1998，35，199.Lambert，D.M.Curr.Med.Chem.，1999，6，635.Mechoulam，R.等，Eur.J.Pharmacol.1998，359，1.Williamson，E.M.和Evans，F.J.Drugs000，60，1303.Pertwee，R.G.Addiction Biology 2000，5，37.Robson，P.Br.J.Psychiatry 2001，178，107.Pertwee，R.G.Prog.Neurobiol.2001，63，569.Goya，P.；Jagerovic，N.Exp.Opin.Ther.Patents 2000，10，1529.Pertwee，R.G.Gut 2001，48，859)。
发明内容
现已意外地发现，对大麻素-CB1受体的有效的和选择性的拮抗作用存在于式(I)的新的4，5-二氢-1H-吡唑衍生物、其前药、其互变异构体及其盐中
Figure A20091014176600061
其中
-R和R1独立地代表苯基、噻吩基或吡啶基，所述基团可以被1、2、3或4个取代基Y取代，所述取代基可以相同或不同，选自C1-3-烷基或烷氧基、羟基、卤素、三氟甲基、三氟甲硫基、三氟甲氧基、硝基、氨基、单-或二烷基(C1-2)-氨基、单-或二烷基(C1-2)-酰氨基、(C1-3)-烷基磺酰基、二甲基磺氨基、C1-3-烷氧基羰基、羧基、三氟甲基磺酰基、氰基、氨甲酰基、氨磺酰基和乙酰基，或R和/或R1代表萘基，
-R2代表氢，羟基，C1-3-烷氧基，乙酸基或丙酸基，
-R3代表氢原子或支链或无支链C1-8烷基或C3-7环烷基，所述烷基或环烷基可以被羟基取代，
-R4代表C2-10支链或无支链杂烷基，C3-8非芳族杂环烷基或C4-10非芳族杂环烷基-烷基，所述基团含一个或多个选自(O，N，S)的杂原子或一个-SO2-基团，所述C2-10支链或无支链杂烷基，C3-8非芳族杂环烷基或C4-10非芳族杂环烷基-烷基可以被酮基、三氟甲基、C1-3烷基、羟基、氨基、单烷基氨基或二烷基氨基或氟原子取代，或R4代表氨基、羟基、苯氧基或苄氧基，或R4代表C1-8烷氧基、C3-8链烯基、C5-8环烯基或C6-9环烯基烷基，所述基团可含有一个硫原子、氮原子或氧原子、酮基或-SO2-基团，所述烷氧基、链烯基和环烯基可以被羟基、三氟甲基、氨基、单烷基氨基或二烷基氨基或氟原子取代，或R4代表C2-5烷基，所述烷基含一个氟原子，或R4代表咪唑基烷基、苄基、吡啶基甲基、苯乙基或噻吩基，或R4代表取代的苯基、苄基、吡啶基、噻吩基、吡啶基甲基或苯乙基，其中芳环被1、2或3个取代基Y取代，其中Y的含义如上所述，
或当R3是H或甲基时，R4可代表NR6R7基团，其中
-R6和R7是相同或不同的并且代表C2-4烷基，C2-4三氟烷基，或R6代表甲基，条件是R7代表C2-4烷基，或R6和R7与其所键合的氮原子一起形成具有4-8个环原子的饱和或不饱和的杂环部分，该杂环部分可含有一个氧原子或硫原子或酮基或-SO2-基团或一个额外的氮原子，该饱和或不饱和杂环部分可以被C1-4烷基取代，或
-R3和R4与其键合的氮原子一起形成具有4-10个环原子的饱和或不饱和的单环或双环杂环部分，该杂环部分可含有一个或多个选自(O、N、S)的原子或一个酮基或-SO2-基团，该部分可以被C1-4烷基、羟烷基、苯基、噻吩基、吡啶基、氨基、单烷基氨基烷基、二烷基氨基烷基、单烷基氨基、二烷基氨基、氨基烷基、氮杂环丁烷基、吡咯烷基、哌啶基或六氢-1H-氮杂
Figure A20091014176600071
基取代，
-R5代表可被1、2、3或4个取代基Y取代的苄基、苯基、噻吩基或吡啶基，其中Y的含义如上所述，可以相同或不同，或R5代表C1-8支链或无支链烷基、C3-8链烯基、C3-10环烷基、C5-10双环烷基、C6-10三环烷基或C5-8环烯基或R5代表萘基。
在式(I)化合物中存在至少一个手性中心(在4，5-二氢-1H-吡唑部分的C4位置)。本发明涉及式(I)化合物的外消旋物、非对映体混合物和各立体异构体。特别感兴趣的式(I)化合物在4，5-二氢-1H-吡唑部分的C4位置具有绝对的立体构型，如式(1a)所代表。
Figure A20091014176600072
本发明还涉及式(I)化合物的E异构体、Z异构体和E/Z混合物。
通过常规方法，使用辅助物质和/或液体或固体载体材料可将本发明化合物制成适于给药的形式。
本发明化合物因其有效的CB1拮抗活性而适用于治疗精神病学疾病如精神病、焦虑、抑郁、注意力涣散、记忆障碍、认知障碍、食欲障碍、肥胖、成瘾、癖好(appetence)、药物依赖和神经学疾病如神经变性疾病、痴呆、肌张力障碍、肌痉挛、震颤、癫痫、多发性硬化、外伤性脑损伤、中风、帕金森氏病、阿尔茨海默氏病、癫痫、亨廷顿舞蹈病、图雷特综合征、大脑局部缺血、大脑卒中、颅脑外伤、中风、脊髓损伤、神经炎性疾病、斑块硬化、病毒性脑炎、脱髓鞘相关疾病，以及用于治疗疼痛疾病包括神经性疼痛病症，和涉及大麻素神经传递的其他疾病，包括治疗脓毒性休克、青光眼、癌症、糖尿病、呕吐、恶心、哮喘、呼吸疾病、胃肠疾病、胃溃疡、腹泻和心血管疾病。
使用其中稳定转染了人大麻素CB1受体的中国仓鼠卵巢(CHO)细胞的膜制品联合作为放射性配体的[3H]CP-55940，测定本发明化合物对大麻素CB1受体的亲和力。在加入或不加入本发明化合物的情况下，将新鲜制备的细胞膜制品与[3H]-配体培育之后，通过玻璃纤维过滤器过滤而分离结合的和游离的配体。通过液体闪烁计数测定滤器上的放射性。
本发明化合物的大麻素CB1拮抗活性通过使用其中人大麻素CB1受体被稳定表达的CHO细胞的功能性研究来确定。腺苷酸环化酶采用毛喉素刺激，并通过定量蓄积的环AMP的数量而进行测定。由CB1受体激动剂(如CP-55，940或(R)-WIN-55，212-2)导致的CB1受体的伴随活化可以以浓度依赖性方式减弱毛喉素诱导的cAMP的蓄积。此CB1受体介导的反应可被CB1受体拮抗剂如本发明的化合物所拮抗。
式(II)的中间体(见下文)可通过已知的方法获得，例如：a)Francotte，E.和Tong，Z.Chem.Abstr.126，213598；b)Rempfler，H.和Kunz，W.Chem.Abstr.113，40432；c)Rempfler，H.和Kunz，W.Chem.Abstr.107，217473。
通过已知方法例如a)EP0021506；b)DE2529689；c)Grosscurt，A.C.等，J.Agric.Food Chem.1979，27，(2)，406，可以获得式(III)的中间体(见下文)，其中R2代表氢。
通过式(II)化合物与肼或水合肼反应可获得式(III)的中间体(见下文)，其中R2代表羟基
此反应优选在有机溶剂如乙醇中进行，并产生式(III)化合物
本发明化合物的适宜的合成路线如下：
合成路线A1
步骤1：式(III)化合物与式(IV)的硫代异氰酸酯衍生物反应，
Figure A20091014176600093
反应优选在有机溶剂如乙腈中进行。此反应产生式(V)的硫代羧酰胺衍生物，其中R、R1、R2和R5的含义如上述化合物(I)中所述。
Figure A20091014176600094
步骤2：式(V)化合物与化合物R3R4NH在汞(II)盐例如HgCl2的存在下反应，产生式(I)化合物。此反应优选在有机溶剂如乙腈中进行。
合成路线A2
步骤1：式(III)化合物
Figure A20091014176600095
与式(VI)的氨基甲酸酯衍生物反应。
其中R8代表低级烷基，例如甲基。此反应优选在有机溶剂例如1，4-二烷中进行，并产生式(VII)的4，5-二氢吡唑-1-甲酰胺衍生物，其中R、R1、R2和R5的含义如上述化合物(I)中所述。
Figure A20091014176600102
步骤2：优选在惰性有机溶剂例如氯苯中，式(VII)化合物与卤化剂如PCl5反应，产生式(VIII)的4，5-二氢吡唑-1-甲亚氨酰卤化物衍生物，其中R、R1、R2和R5的含义如上述化合物(I)中所述，其中R9代表卤素原子，例如Cl。
Figure A20091014176600103
步骤3：式(VIII)的化合物与化合物R3R4NH反应，反应优选在惰性有机溶剂如二氯甲烷中进行，产生式(I)化合物。
作为选择，将含额外的亲核氮原子的化合物R3R4NH与式(VIII)化合物反应，反应方式使得上述额外的亲核氮原子被保护基例如叔丁氧基羰基(Boc)等保护起来。随后按照已知方法除去保护基，产生式(I)化合物(见例如：T.W.Greene和P.G.M.Wuts，“Protective Groups inOrganic Synthesis”，第三版，John Wiley & Sons，Inc.，纽约，1999)。
合成路线A3
步骤1：式(III)化合物
Figure A20091014176600111
与式(IX)的二硫代亚氨碳酸酯衍生物反应。
Figure A20091014176600112
其中R10代表C1-3烷基。此反应优选在有机溶剂例如乙腈或甲苯中进行，并产生式(X)的亚胺硫代酸酯，其中R、R1、R2和R5的含义如上述化合物(I)中所述，并且R10代表C1-3烷基。
Figure A20091014176600113
作为选择，可通过式(V)化合物与R10-X化合物反应获得式(X)化合物，在R10-X中X代表离去基如碘基，R10的含义如上述(X)中所述。
步骤2：优选在有机溶剂如甲醇中，式(X)化合物与化合物R3R4NH进行反应，产生式(I)化合物。
具体实施方式
上述化合物的制备在下列实施例中举例说明。
实施例1
3-(4-氯苯基)-N’-((4-氯苯基)磺酰基)-N-(哌啶-1-基)-4-苯基-4，5-二氢-1H-吡唑-1-甲脒
部分A：向N-((4-氯苯基)磺酰基)氨基甲酸甲酯(CAS：34543-04-9)(2.99g，12.0mmol)和吡啶(4ml)的1，4-二烷(20ml)溶液中添加3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑(3.39g，13.2mmol)，将所得混合物在100℃搅拌4小时。真空浓缩后，将残余物溶解于二氯甲烷中，依次用水、1N HCl和水洗，过无水硫酸钠干燥，过滤并真空浓缩至20ml体积。添加甲基-叔丁基醚(60ml)，所得溶液浓缩至20ml体积。通过过滤收集形成的晶体，并从甲基-叔丁基醚中重结晶，产生3-(4-氯苯基)-N-((4-氯苯基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(4.75g，76％产率)，熔点：211-214℃。
部分B：将3-(4-氯苯基)-N-((4-氯苯基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(1.42g，3.00mmol)和五氯化磷(PCl5)(0.63g，3.03mmol)在氯苯(15ml)中的混合物在回流温度下加热1小时。真空彻底浓缩后，将形成的3-(4-氯苯基)-N-((4-氯苯基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲亚氨酰氯悬浮于无水二氯甲烷(30ml)中，并与1-氨基哌啶(1.08ml，10.0mmol)反应。在室温下搅拌16小时后，混合物用水洗两次，真空浓缩。残余物从甲基-叔丁基醚(MTBE)中重结晶，产生纯的3-(4-氯苯基)-N’-((4-氯苯基)磺酰基)-N-(哌啶-1-基)-4-苯基-4，5-二氢-1H-吡唑-1-甲脒(0.57g，34％产率)。熔点(MP)：213-214℃。MSESI+：556(MH+)。
类似于实施例1的合成，制备了总共57个具有式(XI)的化合物。列于下表1和目录1中。
Figure A20091014176600121
表1
实施例 R3 R4 R11 熔点(℃)  MS ESI+(MH+)   盐形式
  2   H 哌啶-1-基  F   189-190  540
Figure A20091014176600131
  31   H  2-氨基氧乙基   Cl   532
  32   H  2-(二甲基氨基)乙氧基   Cl   201   560
  33   H  2-(二乙基氨基)乙氧基   Cl   210   588
  34   H  2-(甲氧基)乙基   Cl   99-102
  35   CH3  2-(乙酸基)乙基   Cl   157-158   573
  36   H  2-羟基乙基   F   501
  37   H  2-羟基乙基   Cl   517
  38   H  2-羟基-2-甲基丙基   Cl
  39   H  3-羟基丙基   Cl   129-132
  40   CH3  羟基   Cl   208-211
  41   H  甲氧基   CF3   178-180
  42   H  2-氟乙基   Cl   100-103
  43   H  2-氟乙基   CF3   132-134
目录1
44.3-(4-氯苯基)-N-甲氧基-N’-((3-甲基苯基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲脒。MP：151-152℃.
45.3-(4-氯苯基)-N-甲氧基-N’-((2-甲基苯基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲脒。MP：145-146℃.
46.3-(4-氯苯基)-N-甲氧基-N’-((2，4，5-三氟苯基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲脒。MP：160-162℃.
47.3-(5-氯噻吩-2-基)-N’-((4-氯苯基)磺酰基)-N-甲氧基-4-苯基-4，5-二氢-1H-吡唑-1-甲脒。MP：180-181℃.
48.N’-((4-氯苯基)磺酰基)-3-(4-氟苯基)-N-甲氧基-4-苯基-4，5-二氢-1H-吡唑-1-甲脒。MP：201-203℃.
49.3-(4-氯苯基)-N’-((4-氯苯基)磺酰基)-N-甲氧基-4-(3-(三氟甲基)苯基)-4，5-二氢-1H-吡唑-1-甲脒。MP：80-83℃.
50.3-(4-氯苯基)-N’-((4-氯苯基)磺酰基)-N-甲氧基-4-(2，6-二氟苯基)-4，5-二氢-1H-吡唑-1-甲脒。MP：174-177℃.
51.3-(4-氯苯基)-N’-((4-氯苯基)磺酰基)-N-(2-氟乙基)-4-(2，6-二氟苯基)-4，5-二氢-1H-吡唑-1-甲脒。MP：153-155℃.
52.3-(4-氯苯基)-N’-((4-氯苯基)磺酰基)-N-(2-氟乙基)-4-(3-氟苯基)-4，5-二氢-1H-吡唑-1-甲脒。MP：130℃.
53.3-(4-氯苯基)-N-(2-氟乙基)-4-(3-氟苯基)-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲脒。MP：155℃.
54.3-(4-氯苯基)-N’-((4-氯苯基)磺酰基)-4-(3-氟苯基)-N-(甲氧基)-4，5-二氢-1H-吡唑-1-甲脒.无定形的.
55.3-(4-氯苯基)-4-(3-氟苯基)-N-(甲氧基)-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲脒。MP：＞260℃.
56.3-(4-氯苯基)-N’-((4-氯苯基)磺酰基)-4-(2-氟苯基)-N-(甲氧基)-4，5-二氢-1H-吡唑-1-甲脒。MP：162-164℃.
57.3-(4-氯苯基)-4-(2-氟苯基)-N-(甲氧基)-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲脒。MP：147-149℃.
以类似的方式制备了具有式(XII)的29个化合物。列于下表2和目录2中。
Figure A20091014176600151
表2
实施例 R11 R12 熔点(℃)  MS ESI+(MH+) 盐形式
  58   Cl 1，2，3，4-四氢异喹林-2-基  589
  59   F 1，2，3，4-四氢异喹啉-2-基  573
  60   F 吡咯烷-1-基  511
Figure A20091014176600161
目录2
86.N-[(3-(4-氯苯基)-4-(3-(三氟甲基)苯基)-4，5-二氢-1H-吡唑-1-基)(4-甲基哌嗪-1-基)亚甲基]-4-氯苯磺酰胺。MP：97-100℃。
以类似的方式制备出具有式(XIII)的化合物。列于表3或下文详述：
Figure A20091014176600171
表3
实施例 R3 R4 R13 熔点(℃)   MS ESI+(MH+)
  87   H   3-(二甲基氨基)丙基   CH3   136-138
  88   H   N-甲基哌啶-4-基   i-C3H7
实施例89
N-[(4-苯基-3-(吡啶-3-基)-4，5-二氢-1H-吡唑-1-基)(4-甲基哌嗪-1-基)亚甲基]-4-氟苯磺酰胺
部分A：将3-吡啶基苄基酮(参见Burger等，J.Am.Chem.Soc.1950，72，1988-1990)(30.2g，0.153mol)溶解于甲醇(400ml)中，并依次加入乙酸(1.5ml)、哌啶(1.5ml)和福尔马林(35ml，37％水溶液)。所得混合物在回流温度下加热210分钟。令得到的混合物达到室温并真空浓缩。添加水和2N NaOH溶液，接着用甲基-叔丁基醚(MTBE)萃取。有机层用水洗两次，经硫酸钠干燥，过滤和真空浓缩。急骤层析纯化(洗脱剂：MTBE)产生2-苯基-1-吡啶-3-基丙烯酮(21.4g，67％产率)，为一种油。ESI-MS(MH+)210。
部分B：将2-苯基-1-吡啶-3-基丙烯酮(21.4g，0.102mol)溶解于乙醇(150ml)中，并添加水合肼(10.4ml)。所得混合物在回流温度下加热3小时。令得到的混合物达到室温并真空浓缩。添加水，接着用二氯甲烷萃取。有机层用水洗，经硫酸钠干燥，过滤和真空浓缩，形成粗的4-苯基-3-(吡啶-3-基)-4，5-二氢-1H-吡唑(23g，约100％产率)。ESI-MS(MH+)224。
部分C：将粗的4-苯基-3-(吡啶-3-基)-4，5-二氢-1H-吡唑(9.81g，0.044mol)、[(4-氯苯基)磺酰基]二硫代亚氨碳酸二甲酯(12.99g，0.044mol)和三乙胺(47ml)依次溶解于乙腈中。所得混合物回流加热70小时。令得到的混合物达到室温并真空浓缩。残余物溶解于二氯甲烷中。有机层用水洗，经硫酸钠干燥，过滤和真空浓缩。急骤层析纯化(洗脱剂：甲醇/二氯甲烷＝5/95(v/v))产生N-((4-氯苯基)磺酰基)-4-苯基-3-(吡啶-3-基)-4，5-二氢-1H-吡唑-1-甲亚氨硫代酸甲酯(7.15g，35％产率)。ESI-MS(MH+)471。
部分D：将N-((4-氯苯基)磺酰基)-4-苯基-3-(吡啶-3-基)-4，5-二氢-1H-吡唑-1-甲亚氨硫代酸甲酯(1.50g，0.0033mol)悬浮于甲苯(25ml)中并添加4-甲基哌嗪(5ml)。所得混合物在60℃加热70小时。令得到的黄色溶液达到室温并真空浓缩。所得残余物从MTBE中结晶，产生N-[(4-苯基-3-(吡啶-3-基)-4，5-二氢-1H-吡唑-1-基)(4-甲基哌嗪-1-基)亚甲基]-4-氟苯-磺酰胺(1.39g，83％产率)。MP：169-170℃。
实施例90
(-)-(4S)-3-(4-氯苯基)-N’-((4-氯苯基)磺酰基)-N-甲氧基-4-苯基-4，5-二氢-1H-吡唑-1-甲脒
通过手性色谱分离外消旋的3-(4-氯苯基)-N’-((4-氯苯基)磺酰基)-N-甲氧基-4-苯基-4，5-二氢-1H-吡唑-1-甲脒(手性固定相：Chiralpak AD)获得(-)-(4S)-3-(4-氯苯基)-N’-((4-氯苯基)磺酰基)-N-甲氧基-4-苯基-4，5-二氢-1H-吡唑-1-甲脒([α25 D]＝-165°，c＝0.01，甲醇)无定形固体。流动相由乙醇组成。

Claims (2)

1.通式(I)的化合物及其互变异构体、前药、立体异构体和盐
Figure A2009101417660002C1
其中
-R和R1独立地代表苯基、噻吩基或吡啶基，所述基团可以被1、2、3或4个取代基Y取代，所述取代基可以相同或不同，选自C1-3-烷基或烷氧基、羟基、卤素、三氟甲基、三氟甲硫基、三氟甲氧基、硝基、氨基、单-或二烷基(C1-2)-氨基、单-或二烷基(C1-2)-酰氨基、(C1-3)-烷基磺酰基、二甲基磺氨基、C1-3-烷氧基羰基、羧基、三氟甲基磺酰基、氰基、氨甲酰基、氨磺酰基和乙酰基，或R和/或R1代表萘基，
-R2代表氢，羟基，C1-3-烷氧基，乙酸基或丙酸基，
-R3代表氢原子或支链或无支链C1-8烷基或C3-7环烷基，所述烷基或环烷基可以被羟基取代，
-R4代表C2-10支链或无支链杂烷基，C3-8非芳族杂环烷基或C4-10非芳族杂环烷基-烷基，所述基团含一个或多个选自(O，N，S)的杂原子或一个-SO2-基团，所述C2-10支链或无支链杂烷基，C3-8非芳族杂环烷基或C4-10非芳族杂环烷基-烷基可以被酮基、三氟甲基、C1-3烷基、羟基、氨基、单烷基氨基或二烷基氨基或氟原子取代，或R4代表氨基、羟基、苯氧基或苄氧基，或R4代表C1-8烷氧基、C3-8链烯基、C5-8环烯基或C6-9环烯基烷基，所述基团可含有一个硫原子、氮原子或氧原子、酮基或-SO2-基团，所述烷氧基、链烯基和环烯基可以被羟基、三氟甲基、氨基、单烷基氨基或二烷基氨基或氟原子取代，或R4代表C2-5烷基，所述烷基含一个氟原子，或R4代表咪唑基烷基、苄基、吡啶基甲基、苯乙基或噻吩基，或R4代表取代的苯基、苄基、吡啶基、噻吩基、吡啶基甲基或苯乙基，其中芳环被1、2或3个取代基Y取代，其中Y的含义如上所述，
或当R3是H或甲基时，R4可代表NR6R7基团，其中
-R6和R7是相同或不同的并且代表C2-4烷基，C2-4三氟烷基，或R6代表甲基，条件是R7代表C2-4烷基，或R6和R7与其所键合的氮原子一起形成具有4-8个环原子的饱和或不饱和的杂环部分，该杂环部分可含有一个氧原子或硫原子或酮基或-SO2-基团或一个额外的氮原子，该饱和或不饱和杂环部分可以被C1-4烷基取代，或者
-R3和R4与其所键合的氮原子一起形成具有4-10个环原子的饱和或不饱和的单环或双环杂环部分，该杂环部分可含有一个或多个选自(O、N、S)的原子或一个酮基或-SO2-基团，该部分可以被C1-4烷基、羟烷基、苯基、噻吩基、吡啶基、氨基、单烷基氨基烷基、二烷基氨基烷基、单烷基氨基、二烷基氨基、氨基烷基、氮杂环丁烷基、吡咯烷基、哌啶基或六氢-1H-氮杂
Figure A2009101417660003C1
基取代，
-R5代表可被1、2、3或4个取代基Y取代的苄基、苯基、噻吩基或吡啶基，其中Y的含义如上所述，可以相同或不同，或R5代表C1-8支链或无支链烷基、C3-8链烯基、C3-10环烷基、C5-10双环烷基、C6-10三环烷基或C5-8环烯基或R5代表萘基。
2.权利要求1中所要求保护的化合物的用途，用作被取代的3，4-二苯基-4，5-二氢-1H-吡唑衍生物的合成、纯化和分析中的化学标准化合物。
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