CN1205188C - 具有cb1-拮抗活性的4,5-二氢-1h-吡唑衍生物 - Google Patents
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Abstract
本发明涉及一组新的4,5-二氢-1H-吡唑衍生物,所述化合物是大麻CB1-受体的有效拮抗剂。所述化合物具有通式(I),其中R和R1相同或不同,并代表苯基、噻吩基或吡啶基,所述基团可被1、2或3个取代基Y取代,或者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,Aa代表基团(i)、(ii)、(iii)、(iv)或(v)之一,Bb代表磺酰基或羰基;而R3代表苄基、苯基、噻吩基或吡啶基,所述基团可被1、2或3个取代基Y取代,或者R3代表C1-8支链或无支链烷基或C3-8环烷基,或者R3代表萘基。
Description
本发明涉及一组新的4,5-二氢-1H-吡唑衍生物,这些化合物的制备方法,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。
上述的4,5-二氢-1H-吡唑是可以用于治疗精神病和神经病的有效的大麻-1(CB1)受体拮抗剂。
大麻素存在于印度大麻Cannabis Sativa L.中,并已持续数百年被用作药剂(Mechoulam,R.;Feigenbaum,J.J.Prog.Med.Chem.1987,24,159)。但是,仅在过去的10年中,大麻素领域的研究才揭示大麻素受体及其(内源性)激动剂和拮抗剂的关键信息。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.;Thomas,K.L.;Abu-Shaar,M.《自然》(Nature)1993,365,61.Matsuda,L.A.;Bonner,T.I.《大麻素受体》(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异常有关疾病的大麻素药物发生兴趣。脑中CB1受体的广泛分布与CB2受体的精确的外周定位使CB1受体成为精神病和神经病领域中CNS导向药物发现的一个非常令人感兴趣的分子靶体(Consroe,P.《疾病神经生物学》(Neurobiology of Disease)1998,5,534.Pop,E.《CPNS研究药物中的最新观点》(Curr.Opin.In CPNS InvestigationalDrugs)1999,1,587.Greenberg,D.A.《药物新闻透视》(Drug NewsPerspect.)1999,12,458)。迄今已知三种不同类型的CB1受体拮抗剂。Sanofi公开了它们的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,它目前正进行对精神疾病的II期临床研究(Dutta,A.K.;Sard,H.;Ryan,W.;Razdan,R.K.;Compton,D.R.;Martin,B.R.《药物化学研究》(Med.Chem.Res.)1994,5,54.Lan,R.;Liu,Q.;Fan,P.;Lin,S.;Fernando,S.R.;McCallion,D.;Pertwee,R.;Makriyannis,A.《药物化学杂志》(J.Med.Chem..)1999,42,769.Nakamura-Palacios,E.M.;Moerschbaecher,J.M.;Barker,L.A.《CNS药物综述》(CNS DrugRev.)1999,5,43)。已公开氨烷基吲哚为CB1受体拮抗剂。代表性的实例为lodopravadoline(AM-630),它是在1995年被引入的。AM-630为一种CB1受体拮抗剂,但有时表现为一种弱的部分激动剂(Hosohata,K.;Quock,R.M.;Hosohata,Y.;Burkey,T.H.;Makriyannis,A.;Consroe,P.;Roeske,W.R.;Yamamura,H.I.《生命科学》(LifeSc.)1997,61,PL115)。更为最近,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.;Joyce,K.E.;Briley,E.J.;Glass,M.;Mackie,K.P.;Fahey,K.J.;Cullinan,G.J.;Hunden,D.C.;Johnson,D.W.;Chaney,M.O.;Koppel,G.A.;Brownstein,M.《药物试验治疗杂志》(J.Pharmacol.Exp.Ther.)1998,284,291)。最近,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.;Govaerts,S.J.;Hermans,E.;Poupaert,J.H.,Lambert,D.M.《生物体药物化学通讯》(Biorg.Med.Chem.Lett.)1999,9,2233)。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.;Burkey,T.H.;Consroe,P.;Roeske,W.R.;Yamamura,H.I.《欧洲药学杂志》(Eur.J.Pharmacol.)1997,334,R1)。最近的综述很好地概述了目前大麻素研究领域的状况(Mechoulam,R.;Hanus,L.;Fride,E.《药物化学进展》(Prog.Med.Chem.)1998,35,199.Lambert,D.M.《最新药物化学》(Curr.Med.Chem.)1999,6,635.Mechoulam,R.;Fride,E.;Di Marzo,V.《欧洲药学杂志》(Eur.J.Pharmacol.)1998,359,1)。
现已意外地发现,式(I)的新的4,5-二氢-1H-吡唑衍生物、其前药、其互变体及其盐是有效的和选择性的大麻CB1-受体拮抗剂
其中,
-R和R1相同或不同,并代表苯基、噻吩基或吡啶基,所述基团可被1、2或3个取代基Y取代,所述取代基Y可以相同或不同,来自基团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(dimethylsulfamido)、C1-3-烷氧羰基、羧基、三氟甲基磺酰基、氰基、氨基甲酰基、氨磺酰和乙酰基,或者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,
-Aa代表基团(i)、(ii)、(iii)、(iv)或(v)之一,
其中,
-R4和R5彼此独立地代表氢或C1-8支链或无支链烷基或C3-8环烷基,或者R4代表乙酰氨基或二甲氨基或2,2,2-三氟乙基或苯基或吡啶基,附带条件是R5代表氢,
-R6代表氢或C1-3无支链烷基,
-Bb代表磺酰基或羰基,
-R3代表苄基、苯基、噻吩基或吡啶基,所述基团可以被1、2或3个取代基Y取代,所述取代基Y可以相同或不同,或者R3代表C1-8支链或无支链烷基或C3-8环烷基,或者R3代表萘基。
本发明的化合物由于其有效的CB1拮抗活性而适用于治疗精神疾病如精神病、焦虑、抑郁、注意涣散、记忆障碍和食欲障碍、肥胖、神经病如痴呆、肌张力障碍、帕金森病、阿尔茨海默氏病、癫痫、亨廷顿舞蹈病、图雷特综合征、大脑局部缺血以及用于治疗疼痛和其它涉及大麻素神经传递的中枢神经系统疾病,并用于治疗胃肠疾病和心血管疾病。
使用中国仓鼠卵巢(CHO)细胞的膜制剂测定本发明的化合物对大麻素CB1受体的亲合力,其中,人大麻CB1受体与作为放射配体的[3H]CP-55,940一起被稳定转染。在加入或不加入本发明化合物的情况下与所述[3H]-配体一起培养新鲜制备的细胞膜制剂之后,用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。
本发明的化合物的大麻素CB1拮抗活性由使用其中人大麻素CB1受体被稳定表达的CHO细胞的功能研究来测定。腺苷酸环化酶采用毛喉素刺激,并通过对蓄积的环AMP的定量而进行测定。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。该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。
在式(I)的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)。本发明涉及具有式(I)的化合物的外消旋物、非对映体混合物和各立体异构体。
本发明还涉及具有式(I)的化合物的E异构体、Z异构体和E/Z混合物,其中,Aa具有上述的含义(i)或(ii)。
可以通过常规方法,使用辅助物质和/或液体或固体载体材料将本发明的化合物制成适于给药的形式。
可以根据已知的方法,如a)EP 0021506;b)DE 2529689,得到其中R2代表氢的式(III)的本发明化合物(参见下文)。
本发明化合物的适宜的合成如下:
合成路线A(对于具有式(I)的化合物,其中,Aa具有上述的含义(i)或(ii))。
路线A的步骤1
具有式(II)的化合物
与肼或水合肼反应。此反应得到具有式(III)的化合物
其中,R2代表羟基。此反应优选在极性溶剂如乙醇中进行。具有式(III)(其中R2代表羟基,且其中R和R1具有以上关于化合物(I)所述的含义)的化合物是新的。
路线A的步骤2
具有式(III)的化合物与具有式(IVa)的化合物或具有式(IVb)的化合物或者其适宜的盐形式在碱存在下反应
其中,R7代表低碳烷基,如2-甲基-2-硫代假脲。此反应得到具有式(V)的4,5-二氢-1H-吡唑-1-甲脒衍生物:
其中,Aa具有上述含义(i)或(ii)。具有式(V)(其中Aa具有上述含义(i)或(ii),且其中R、R1和R2具有以上关于化合物(I)所述的含义)的化合物是新的。
可选择地,具有式(III)的化合物与所谓的鸟苷酸化剂反应。这些鸟苷酸化剂的实例为1H-吡唑-1-甲脒及其盐(例如盐酸盐)和3,5-二甲基-1H-吡唑-1-甲脒及其盐(例如硝酸盐)等等。此反应得到具有式(V)的甲脒衍生物。
可选择地,具有式(III)的化合物与所谓的受保护的鸟苷酸化剂反应。这些受保护的鸟苷酸化剂的实例为N-(苄氧羰基)-1H-吡唑-1-甲脒、N-(叔丁氧羰基)-1H-吡唑-1-甲脒和N,N’-双-(叔丁氧羰基)-1H-吡唑-1-甲脒等等。此反应物在去保护后得到具有式(V)的化合物。
路线A的步骤3
具有式(V)的化合物与任选取代的式R3-SO2X或R3-COX的化合物反应,其中R3具有上述含义,而X代表卤原子。此反应优选在碱例如三乙胺存在下在非质子溶剂如乙腈中完成。此反应得到化合物(I),其中,Bb分别代表磺酰基或羰基。
合成路线A1(对于具有式(I)的化合物,其中,Aa具上述含义(i)或(ii))
路线A1的步骤1
具有式(III)的化合物
与具有式(VI)的硫代异氰酸酯衍生物反应
此反应优选在惰性有机溶剂如乙腈中完成。
此反应得到具有式(VII)的硫代甲酰胺衍生物。具有式(VII)(其中R、R1、R2、R3和Bb具有以上关于化合物(I)所述的含义)的化合物是新的。
路线A1的步骤2
具有式(VII)的化合物与胺在汞(II)盐如HgCl2存在下反应,得到具有式(I)的化合物,其中Aa具有上述的含义(i)或(ii)。
此反应优选在极性有机溶剂如乙腈中完成。
合成路线A2(对于具有式(I)的化合物,其中Aa具上述含义(i)或(ii))
路线A2的步骤1
具有式(III)的化合物
与具有式(VIII)的氨基甲酸酯衍生物反应
其中,R7代表低碳烷基,如甲基。
此反应优选在惰性有机溶剂如1,4-二噁烷中完成。
此反应得到具有式(IX)的4,5-二氢吡唑-1-甲酰胺衍生物。具有式(IX)(其中R、R1、R2、R3和Bb具有以上关于化合物(I)所述的含义)的化合物是新的。
路线2的步骤2
具有式(IX)的化合物与卤化剂如PCl5反应得到具有式(X)的4,5-二氢吡唑-1-亚氨酰卤化物(carboximidoyl halogenide)衍生物
其中,R8代表卤原子,如氯。此反应优选在惰性有机溶剂如氯苯中完成。
具有式(X)(其中R、R1、R2、R3和Bb具有以上关于化合物(I)所述的含义,且其中R8代表卤原子)的化合物是新的。
路线A2的步骤3
具有式(X)的化合物与胺反应得到具有式(I)的化合物,其中,Aa具有上述的含义(i)或(ii)。
此反应优选在惰性有机溶剂如二氯甲烷中完成。
合成路线A3(对于具有式(I)的化合物,其中,Aa具有上述含义(i)或(ii))
路线A3的步骤1
具有式III的化合物
与具有式(XI)的二硫代亚氨碳酸酯衍生物反应。
其中,R9代表C1-3烷基。
此反应优选在极性有机溶剂如乙腈中完成。
此反应得到具有式(XII)的硫代亚胺酸酯(carboximidothioicester)衍生物。
其中,R9代表C1-3烷基。具有式(XII)(其中R、R1、R2、R3和Bb具有以上关于化合物(I)所述的含义,且其中R9代表C1-3烷基)的化合物是新的。
路线A3的步骤2
具有式(XII)的化合物与胺反应得到具有式(I)的化合物,其中,Aa具有上述含义(i)或(ii)。
此反应优选在极性有机溶剂如甲醇中完成。
合成路线B(对于具有式(I)的化合物,其中Aa具有上述含义(iii)或(iv))
路线B的步骤1
具有式(III)的化合物
分别与具有式(XIII)的化合物或具有式(XIV)的化合物反应
其中,Bb、R3和R6具有上述含义,且Z代表所谓的离去基团。
这些反应得到具有式(I)的化合物,其中,Aa分别具有上述含义(iii)或(iv)。
合成路线C(对于具有式(I)的化合物,其中,Aa具有上述含义(v))
路线C的步骤1
具有式(III)的化合物
分别与具有式(XV)的氮丙啶衍生物或具有式(XVI)的化合物反应
其中,R6具有上述含义,Z代表所谓的离去基团,而Prot代表所谓的保护基如叔丁氧羰基、苄氧羰基等等。
这些反应得到具有式(XVII)的化合物
其中,Aa具有上述含义(v)。具有式(XVII)(其中R、R1和R2具有以上关于化合物(I)所述的含义,且其中Aa具有上述含义(v),且其中Prot代表所谓的保护基)的化合物是新的。
然后根据已知方法除去所谓的保护基(例如,参见T.W.Greene,P.G.M.Wuts,“有机合成中的保护基(Protective Groups inOrganic Synthesis)”,第三版,John Wiley & Sons,Inc.,纽约,1999)得到式(V)的化合物,其中,Aa具有上述含义(v)。具有式(V)(其中R、R1和R2具有以上关于式(I)的化合物所述的含义,且其中Aa具有上述含义(v))的化合物是新的。
路线C的步骤2
使具有式(V)的化合物(其中Aa具有上述含义(v))与任选取代的式R3-SO2X或R3-COX的化合物(其中R3具有上述含义,而X为卤素)反应。此反应优选在碱如三乙胺存在下在非质子溶剂如乙腈中完成。此反应得到化合物(I),其中,Bb分别代表磺酰基或羰基。
可选择地,上述具有式(V)的化合物可以与式R3-COOH的化合物通过形成活性酯或在所谓的偶合试剂存在下进行反应。
这些化合物的制备如以下实施例所例示。
实施例I
3-(4-氯苯基)-4,5-二氢-4-羟基-4-苯基-1H-吡唑
35℃下将2-(4-氯苯甲酰)-2-苯基环氧乙烷(112克,0.43mol)溶于乙醇(650ml)。往所得的搅拌的溶液中加入N2H4·H2O(42ml),所形成的3-(4-氯苯基)-4,5-二氢-4-羟基-4-苯基-1H-吡唑缓慢沉淀。静置16小时后,过滤收集结晶物,并连续地用乙醇、水和乙醇洗涤,然后干燥得到3-(4-氯苯基)-4,5-二氢-4-羟基-4-苯基-1H-吡唑(92克,78%产率)。熔点:195-196℃。
实施例II
3-(4-氯苯基)-4,5-二氢-N-((4-氟苯基)磺酰基)-4-苯基-1H-吡唑-1-甲脒
部分A:将搅拌的3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑(5.13克,20.0mmol)、2-甲基-2-硫代假脲氢碘化物(5.00克,23.0mmol)和吡啶(10ml)的混合物于100℃加热1小时。室温下静置一夜后,加入乙醚并过滤收集沉淀。用乙醚部分将该沉淀洗涤三次得到一种固体(9克)。熔点:~230℃。将此固体溶于甲醇(20ml)。往所得的溶液连续加入2N氢氧化钠溶液(12ml)和水(200ml)。过滤收集所形成的沉淀,用乙醚洗涤两次,并连续用二异丙醚洗涤。真空干燥所得的固体得到3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒(5.1克,88%产率)。熔点:187-189℃。
部分B:往搅拌的在乙腈(10ml)中的3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒(0.50克,1.68mmol)和4-氟苯磺酰氯(0.34克,1.75mmol)混合物中加入N,N-二甲基-4-氨基吡啶(0.020克,0.175mmol)和三乙胺(1ml)。室温下将所得的溶液搅拌30分钟。加入2N氢氧化钠溶液并用乙酸乙酯(400ml)萃取,然后真空浓缩乙酸乙酯层。通过急骤层析法(石油醚/乙醚=1/1(v/v),然后用乙酸乙酯)进一步纯化所得的粗残余物。然后真空浓缩得到固体3-(4-氯苯基)-4,5-二氢-N-((4-氟苯基)磺酰基)-4-苯基-1H-吡唑-1-甲脒(0.55克,72%产率)。熔点:214-215℃。
以类似的方式制备下列具有式(I)的化合物:
4,5-二氢-N-((4-氟苯基)磺酰基)-3-(4-甲氧苯基)-4-(4-甲氧苯基)-1H-吡唑-1-甲脒:熔点:155-156℃。
4,5-二氢-3-(4-甲氧苯基)-4-(4-甲氧苯基)-N-((4-甲氧苯基)磺酰基)-1H-吡唑-1-甲脒:熔点:148-150℃。
3-(4-氯苯基)-4,5-二氢-4-苯基-N-((2,4,6-三甲苯基)磺酰基)-1H-吡唑-1-甲脒:熔点:221-222℃。
3-(4-氯苯基)-4,5-二氢-N-((4-氟苯基)磺酰基)-4-羟基-4-苯基-1H-吡唑-1-甲脒:熔点:227-228℃。
实施例III
3-(4-氯苯基)-4,5-二氢-N-(1-萘甲酰基)-4-苯基-1H-吡唑-1-甲脒
往在乙腈(15ml)中的3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒(0.75克,2.50mmol)和1-萘甲酰氯(0.4ml,2.70mmol)的搅拌的混合物中加入三乙胺(1ml)。室温下将所得的混合物搅拌1小时。加入2N氢氧化钠溶液并用乙酸乙酯萃取,然后真空浓缩乙酸乙酯层。再用急骤层析法(石油醚/乙醚=3/1(v/v),然后用乙酸乙酯)进一步纯化所得的粗残余物。然后真空浓缩得到3-(4-氯苯基)-4,5-二氢-N-(1-萘甲酰基)-4-苯基-1H-吡唑-1-甲脒(0.94克,83%产率)。熔点:206-207℃。
以类似的方式制备下列具有式(I)的化合物:
3-(4-氯苯基)-4,5-二氢-4-苯基-N-(2-吡啶酰基)-1H-吡唑-1-甲脒。熔点:118℃(分解)。
实施例IV
N1,N1-二甲基-N2-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒
部分A:将在乙腈(200ml)中的3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑(12.0克,46.8mmol)、[(4-氯苯基)磺酰基]二硫代亚氨碳酸二甲酯(CAS:13068-12-7)(9.20克,31.1mmol)和三乙胺(15ml)的搅拌的混合物于回流温度下加热20小时。再加入额外部分的3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑(12.0克,46.8mmol),并将所得的混合物于回流温度下再加热16小时。真空浓缩后,加入二氯甲烷,用水将所得的溶液洗涤两次,并经无水Na2SO4干燥。过滤和真空蒸发后,用急骤层析法(乙醚/石油醚=1/1(v/v))进一步纯化残余物,得到3-(4-氯苯基)-N-((4-氯苯基)磺酰基)-4,5-二氢-4-苯基-1H-吡唑-1-硫代亚胺酸甲酯(12.5克,80%产率基于[(4-氯苯基)磺酰基]二硫代亚氨碳酸二甲酯),为一种无晶形固体。
部分B:往在甲醇(75ml)中的3-(4-氯苯基)-N-((4-氯苯基)磺酰基)-4,5-二氢-4-苯基-1H-吡唑-1-硫代亚胺酸甲酯(4.20克,8.30mmol)的搅拌的混合物中加入二甲胺(10ml)和二氯甲烷(75ml),并在室温下将所得的溶液搅拌6小时。真空蒸发然后进行急骤层析纯化(乙醚/石油醚=1/1(v/v),然后用乙醚)得到一种固体,通过从二异丙醚重结晶而进一步纯化此固体,得到N1,N1-二甲基-N2-((4-氯-苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒(2.63克,63%产率)。熔点:182℃。
以类似的方式制备下列具有式(I)的化合物:
N-甲基-N’-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-(3-吡啶基)-1H-吡唑-1-甲脒。熔点:101-105℃。
N-甲基-N’-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-(4-吡啶基)-1H-吡唑-1-甲脒。熔点:112-115℃。
N1,N1-二甲基-N2-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-羟基-4-苯基-1H-吡唑-1-甲脒。熔点:无定形。
N-乙基-N’-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-羟基-4-苯基-1H-吡唑-1-甲脒。熔点:183-185℃。
实施例V
N-甲基-N’-(3-(三氟甲基)苯甲酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒
部分A:0℃下往在乙腈(80ml)中的3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑(5.13克,20.0mmol)加入3-(三氟甲基)苯甲酰基异硫氰酸酯(4.62克,20.0mmol),并将所得的混合物搅拌1小时。过滤收集所形成的黄色沉淀,并分别用少部分的乙腈和水洗涤,然后真空干燥得到3-(4-氯苯基)-4,5-二氢-4-苯基-N-((3-三氟甲基)苯甲酰基)-1H-吡唑-1-硫代甲酰胺(8.26克,85%产率)。熔点:180-182℃。
部分B:往在乙腈(50ml)中的3-(4-氯苯基)-4,5-二氢-4-苯基-N-((3-三氟甲基)苯甲酰基)-1H-吡唑-1-硫代甲酰胺(4.88克,10.0mmol)的搅拌悬浮物中加入冷甲胺(5ml)得到一种绿色溶液。加入在25ml乙腈中的HgCl2(3.0克,11mmol)溶液后,将所得的混合物搅拌3小时。用硅藻土(hyflo)过滤除去沉淀,收集滤液并真空浓缩。加入乙酸乙酯和0.5N NaOH后,收集乙酸乙酯层,用饱和NaCl水溶液洗涤,并用无水Na2SO4干燥,过滤并真空浓缩。色谱处理(二氯甲烷/丙酮=9/1(v/v))得到N-甲基-N’-(3-(三氟甲基)苯甲酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒(0.99克,20%产率),为一种泡沫。熔点:无定形。Rf(硅胶:二氯甲烷/丙酮=9/1(v/v))=0.3。
实施例VI
N-甲基-N’-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒
部分A:往在1,4-二噁烷(20ml)中的N-((4-氯苯基)磺酰基)氨基甲酸甲酯(CAS:34543-04-9)(2.99克,12.0mmol)和吡啶(4ml)的溶液中加入3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑(3.39克,13.2mmol),并在100℃下将所得的混合物搅拌4小时。真空浓缩后,将残余物溶于二氯甲烷,连续用水、1N HCl和水洗涤,用无水Na2SO4干燥,过滤并真空浓缩至体积为20ml。加入甲基-叔丁基醚(60ml),并将所得的溶液浓缩至20ml体积。过滤收集形成的晶体,并从甲基-叔丁基醚重结晶得到3-(4-氯苯基)-N-((4-氯苯基)磺酰基)-4,5-二氢-4-苯基-1H-吡唑-1-甲酰胺(4.75克,76%产率)。熔点:211-214℃。
部分B:将在氯苯(40ml)中的3-(4-氯苯基)-N-((4-氯苯基)磺酰基)-4,5-二氢-4-苯基-1H-吡唑-1-甲酰胺(3.67克,7.75mmol)和五氯化磷(1.69克,8.14mmol)的混合物回流加热1小时。完全真空浓缩后,将所形成的N-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-亚氨酰氯悬浮于二氯甲烷中,并与冷甲胺(1.5ml)反应。室温下搅拌1小时后,真空浓缩混合物。从乙醚结晶残余物得到N-甲基-N’-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒(2.29克,61%产率)。熔点:96-98℃(分解)。
以类似的方式制备下列具有式(I)的化合物:
N-甲基-N’-((3-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:156-160℃。
N-甲基-N’-((4-氯苯基)磺酰基)-3-(5-氯-2-噻吩基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:无定形。
N-丙基-N’-((4-氟苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:129-138℃。
N-(2-丙基)-N’-((4-氟苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:110-112℃。
N-甲基-N’-((2-丙基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:无定形。
N-(2-丙基)-N’-((4-氯苯基)磺酰基)-3-(4-吡啶基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:无定形。
N1-乙基-N1-甲基-N2-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:184℃。
N1-乙基-N1-甲基-N2-((4-氟苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:173-176℃。
N1,N1-二甲基-N2-((4-(三氟甲基)苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:195-196℃。
N1,N1-二甲基-N2-((3-甲基苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:195-198℃。
N1,N1-二甲基-N2-((3-甲氧苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:204-206℃。
N-乙基-N’-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:无定形。
N-二甲氨基-N’-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:155-159℃。
N-甲基-N’-((4-(三氟甲基)苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:无定形。
N1,N1-二甲基-N2-((2-甲基苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:148-151℃。
N-甲基-N’-((2,4-二氟苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:85℃。
N-乙酰氨基-N’-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:无定形。
N-(2,2,2-三氟乙基)-N’-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:无定形。
N-(2-吡啶基)-N’-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:142-146℃。
N-(4-吡啶基)-N’-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:204-206℃。
N-苯基-N’-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-甲脒。熔点:158-160℃。
实施例VII
3-(4-氯苯基)-1-[3-((4-氯苯基)磺酰基)丁酰基]-4,5-二氢-4-苯基-1H-吡唑
往3-((4-氯苯基)磺酰基)丁酸(1.85克,7.00mmol)、二异丙基乙胺(3ml)和1-乙基-3-(3-二甲氨基丙基)碳二亚胺氢氯化物(1.50克,15.7mmol)的搅拌的混合物中加入3-(4-氯苯基)-4-苯基-4,5-二氢-1H-吡唑(3.00克,11.7mmol),并在室温下将所得的混合物搅拌16小时。真空浓缩后,通过急骤层析法(石油醚/乙醚=1/2(v/v),然后用乙醚)纯化所得的残余物,得到3-(4-氯苯基)-1-[3-((4-氯苯基)磺酰)丁酰基]-4,5-二氢-4-苯基-1H-吡唑(3.69克,63%产率),为一种非对映体混合物。熔点:无定形。
以类似的方式制备下列具有式(I)的化合物:
3-(4-氯苯基)-1-[3-(苯基磺酰基)丙酰基]-4,5-二氢-4-苯基-1H-吡唑。熔点:122-123℃。
3-(4-氯苯基)-1-[3-((4-氯苯基)磺酰基)丙酰基]-4,5-二氢-4-苯基-1H-吡唑。熔点:178-181℃。
实施例VIII
3-(4-氯苯基)-4,5-二氢-4-苯基-1-[2-((3-(三氟甲基)苯基)-磺酰基)乙基]-1H-吡唑
往在乙腈(25ml)中的3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑(1.7克,6.60mmol)和可力丁(2ml)的搅拌的混合物中缓慢加入在乙腈(20ml)中的2-((3-(三氟甲基)苯基)磺酰基)乙基氯(1.5克,5.50mmol)的溶液,并将所得的溶液于回流温度下加热16小时。真空浓缩后,将残余物溶于乙酸乙酯,并用碳酸氢钠水溶液洗涤。连续用1N盐酸溶液和碳酸氢钠水溶液洗涤所得的乙酸乙酯层。
然后进行急骤层析纯化(石油醚/乙醚=1/2(v/v))得到一种油,用二异丙醚结晶此油得到3-(4-氯苯基)-4,5-二氢-4-苯基-1-[2-((3-(三氟甲基)苯基)磺酰基)乙基]-1H-吡唑(0.52克,19%产率)。熔点:118-119℃。
以类似的方式制备下列具有式(I)的化合物:
3-(4-氯苯基)-1-[2-(苄基磺酰基)乙基]-4,5-二氢-4-苯基-1H-吡唑。熔点:161℃。
3-(4-氯苯基)-1-[2-((4-氯苯基)磺酰基)乙基]-4,5-二氢-4-苯基-1H-吡唑。熔点:无定形。
3-(4-氯苯基)-1-[2-((4-氯苯基)磺酰基)乙基]-4,5-二氢-4-羟基-4-苯基-1H-吡唑。熔点:127-128℃。
实施例IX
N-[2-(3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-基)乙基]-3-(三氟甲基)苯磺酰胺
部分A:将在甲苯(100ml)中的3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑(5.00克,19.5mmol)和N-(叔丁氧羰基)氮丙啶(2.00克,14.0mmol)的搅拌的溶液于回流温度下加热16小时。真空浓缩后,通过急骤层析法(石油醚/乙醚=3/1(v/v),然后用石油醚/乙醚=1/1(v/v))纯化残余物。真空浓缩后,用二异丙醚结晶剩余的油状残余物,得到1-[2-((叔丁氧羰基)氨基)乙基]-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑(1.91克,34%)。从母液中反复结晶得到额外量的结晶1-[2-((叔丁氧羰基)氨基)乙基]-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑(1.19克)。
部分B:往在二氯甲烷(50ml)中的1-[2-((叔丁氧羰基)氨基)乙基]-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑(1.91克,4.8mmol)溶液中加入三氟乙酸(5ml),并在室温下将所得的溶液搅拌5小时。真空浓缩后,将残余物溶于乙酸乙酯,并用2N氢氧化钠溶液洗涤。用硫酸镁干燥乙酸乙酯层,过滤并真空浓缩得到1-(2-氨乙基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑(1.44克,定量产率),为一种油。
部分C:往在乙腈(20ml)中的1-(2-氨乙基)-3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑(0.56克,1.87mmol)和二异丙基乙胺的溶液中加入3-(三氟甲基)苯基磺酰氯(0.35ml,2.18mmol),并在室温下将所得的溶液搅拌20分钟。真空浓缩后,将残余物溶于乙酸乙酯并用2N氢氧化钠溶液洗涤。真空浓缩乙酸乙酯层。用少量的二异丙醚结晶所得的油,得到结晶N-[2-(3-(4-氯苯基)-4,5-二氢-4-苯基-1H-吡唑-1-基)乙基]-3-(三氟甲基)苯磺酰胺(0.44克,46%产率)。熔点:94-96℃。
Claims (14)
1.式(I)的化合物及其互变体和盐:
其中,
-R和R1相同或不同,并代表苯基、噻吩基或吡啶基,所述基团可被1、2或3个取代基Y取代,所述取代基Y可以相同或不同,来自基团C1-3-烷基或烷氧基、卤素或三氟甲基,或者R和/或R1代表萘基,
-R2代表氢或羟基,
-Aa代表基团(i)、(ii)、(iii)、(iv)或(v)之一,
其中,
-R4和R5彼此独立地代表氢或C1-8支链或无支链烷基或C3-8环烷基,或者R4代表乙酰氨基或二甲氨基或2,2,2-三氟乙基或苯基或吡啶基,附带条件是R5代表氢,
-R6代表氢或C1-3无支链烷基,
-Bb代表磺酰基或羰基,
-R3代表苄基、苯基、噻吩基或吡啶基,所述基团可以被1、2或3个取代基Y取代,所述取代基Y可以相同或不同,或者R3代表C1-8支链或无支链烷基或C3-8环烷基,或者R3代表萘基。
2.如权利要求1所述的具有式(I)的化合物及其盐,其中,R为4-氯苯基,R1为苯基,R2为氢,Aa为其中R4为氢而R5为甲基的基团(i),Bb为磺酰基,而R3代表4-氯苯基。
3.含有至少一种如权利要求1所述的化合物作为活性成分的药物组合物。
4.制备权利要求1的式I化合物的方法,其特征在于:
a)通过以下方法制备一种化合物,其中,R、R1-R3和Bb具有如权利要求1给出的含义,而Aa为权利要求1所定义的式(i)或(ii)的基团:
1)使具有式(II)的化合物
其中R和R1具有如权利要求1给出的含义,
与肼或水合肼反应得到具有式(III)的化合物,
其中R、R1和R2具有如权利要求1给出的含义,
将此化合物与具有式(IVa)或(IVb)的化合物反应
其中R4和R5具有如权利要求1给出的含义,
其中R7代表甲基,得到具有式(V)的化合物,
其中R、R1和R2具有如权利要求1给出的含义,而Aa为权利要求1所定义的式(i)或(ii)的基团,
将此化合物与其中X为卤素的式R3-SO2X或R3-COX的化合物反应,或者
2)使具有式(III)的化合物与式(VI)的硫代异氰酸酯反应
其中R3和Bb具有如权利要求1给出的含义,
以生产式(VII)的化合物,
其中R、R1、R2、R3和Bb具有如权利要求1给出的含义,
将此化合物与胺在汞(II)盐存在下反应,或
3)使具有式(III)的化合物与式(VIII)的化合物反应
其中R3和Bb具有如权利要求1给出的含义,
其中R7代表甲基,得到式(IX)的化合物,
其中R、R1、R2、R3和Bb具有如权利要求1给出的含义,
将此化合物与卤化剂反应得到具有式(X)的化合物,
其中R、R1、R2、R3和Bb具有如权利要求1给出的含义,
其中R8代表卤素原子,将此化合物与胺反应,或者
4)使具有式(III)的化合物与式(XI)的化合物反应
其中R3和Bb具有如权利要求1给出的含义,
其中R9代表C1-3烷基,得到具有式(XII)的化合物,
其中R、R1、R2、R3和Bb具有如权利要求1给出的含义,
其中R9代表C1-3烷基,将此化合物与胺反应,或者
b)通过将式(III)的化合物与式(XIII)或(XIV)的化合物反应而制备一种化合物,其中,R、R1-R3和Bb具有如权利要求1给出的含义,而Aa为权利要求1所定义的式(iii)或(iv)的基团,
其中Bb、R3和R6具有如权利要求1给出的含义而Z代表离去基团,或者
c)通过以下方法制备一种化合物,其中,R、R1-R3和Bb具有如权利要求1给出的含义,而Aa为权利要求1所定义的式(v)的基团:使具有式(III)的化合物与具有式(XV)或(XVI)的化合物反应
其中R6具有如权利要求1给出的含义,Z代表离去基团而Prot代表保护基团,得到具有式(XVII)的化合物,
其中R、R1和R2具有如权利要求1给出的含义,Aa为权利要求1所定义的式(v)的基团,而Prot代表保护基团,
将此化合物去保护得到具有式(V)的化合物,将此化合物与其中X为卤素的式R3-SO2X或R3-COX的化合物反应,或与式R3-COOH的化合物反应。
5.式(III)的化合物
其中,R2代表羟基,且其中R和R1具有如权利要求1所给出的含义。
6.式(V)的化合物
其中,Aa具有如权利要求1所给出的含义(i)、(ii)或(v),且其中R、R1和R2具有权利要求1给出的含义。
8.式(IX)的化合物
其中,R、R1、R2、R3和Bb具有权利要求1给出的含义。
10.式(XII)的化合物
其中,R、R1、R2、R3和Bb具有权利要求1给出的含义,且其中R9代表C1-3烷基。
11.式(XVII)的化合物
其中,R、R1和R2具有权利要求1给出的含义,且其中Aa具有如权利要求1给出的含义(v),且其中Prot代表所谓的保护基。
12.权利要求1的化合物在制备用于治疗精神疾病的药物组合物中的用途。
13.权利要求1的化合物在制备用于治疗涉及大麻素神经传递的胃肠疾病的药物组合物中的用途。
14.权利要求1的化合物在制备用于治疗涉及大麻素神经传递的心血管疾病的药物组合物中的用途。
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