CN100366614C - 具有cb1－拮抗活性的4,5－二氢－1h－吡唑衍生物 - Google Patents

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

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CN100366614C
CN100366614C CNB028017773A CN02801777A CN100366614C CN 100366614 C CN100366614 C CN 100366614C CN B028017773 A CNB028017773 A CN B028017773A CN 02801777 A CN02801777 A CN 02801777A CN 100366614 C CN100366614 C CN 100366614C
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J·H·M·兰格
C·G·克鲁斯
J·蒂普克
J·胡格多恩
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Abstract

本发明是有关于一种在4，5-二氢吡唑环的第4位置具有S构型之新颖4，5-二氢-1H-吡唑衍生物，其为大麻CB1-受体的强效拮抗剂。此化合物具有下列通式(I)其中-R和R1可为相同或不同且代表3-吡啶基或4-吡啶基、或可经卤素或甲氧基取代之苯基，-R2和R3可为相同或不同且代表氢、烷基(1-3C)或二甲胺基，-R4代表可经1或2个选自卤原子、三氟甲基、甲氧基及烷基(1-3C)所成组群之取代基取代之苯基，及其互变体、前体药物和盐。该对映体比另一对映体为更强效且更具选择性之大麻CB1-受体的拮抗剂。

Description

具有CB1-拮抗活性的4，5-二氢-1H-吡唑衍生物
本发明系有关于一种在4，5-二氢吡唑环的第4位置具有S构型之4，5-二氢-1H-吡唑衍生物的新颖对映体及有关制备该等化合物之方法，及含有一或多种此化合物作为活性成份之医药组合物。
上述(4S)-4，5-二氢-1H-吡唑为强效大麻-1(CB1)受体拮抗剂，具有治疗精神病学及神经病学疾病之利用性。
类大麻(cannabinoids)存在於印度大麻(Cannabis Sativa L.)，并使用作为药用剂已有数世纪之久(Mechoulam，R.；Feigenbaum，J.J.Prog.Med.Chem.1987，24，159)。然而仅在过去数十年中，类大麻领域之研究揭露类大麻受体和其(内生的)促效剂和拮抗剂的重要资讯。该发现和随后选殖两种不同亚型的类大麻受体(CB1和CB2)，激发了新颖类大麻受体拮抗剂之研究(Munro，S.；Thomas，K.L.；Abu-Shaar，M.Nature 1993，365，61.Matsuda，L.A.；Bonner，T.I.Cannabinoid Receptors，Pertwee，R.G.编辑1995，117，伦敦学院出版社)。另外，制药公司开始有兴趣发展类大麻药物，作为治疗类大麻系统失调相关的疾病。脑中广泛分布之CB1受体组合以极末梢定值之CB2受体，使CB1受体成为精神及神经疾病两者领域中极受注目之CNS-导向药物发现之分子标的(Consroe，P.Neurobiology ofDisease 1998，5，534.Pop，E，Curr.Opin.In CPNS Investigatiga-tional Drugs 1999，1，587.Greenberg，D.A.Drug News Perspect.1999，12，458.)。迄今，已知有三种不同的CB1受体体抗剂。Sanofi揭露基二芳基吡唑同质物作为选择性CB1受体拮抗剂。代表性实例为SR-141716A，其目前进行精神病学的II其临床研究(Dutta，A.K.；Sard，H.；Ryan，W.；Razdan，R.K.；Compton，D.R.；Martin，B.R.Med.Chem.Res.1994，5，54.Lan，R.；Liu，Q.；Fan，p.；Lin，S.；Fernando，S.R.；McCallion，D.；Pertwee，R.；Makriyannis，A.J.Med.Chem.1999，42，769.Nakamura-Palacios，E.M.；Moerschbaecher，J.M.；Barker，L.A.CNS Drug Rev.1999，5，43)。胺烷基吲哚已揭示可作为CB1受体拮抗剂。代表性实例为在1995年介纽之碘普瓦多啉(Iodopravadoline)(AM-630).AM-630为CB1受体拮抗剂，但有时呈现弱的部份促效剂(Hosohata，K.；Quock，R.M.；Hosohata，Y.；Burkey，T.H.；Makriyannis，A.；Consroe，P.；Roeske，W.R.；Yamamura，H.I.Life Sc.1997，61，PL115)。更最近之研究员提出芳基-芳酰基取代之苯并呋喃为选择性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.J.Pharmacol.Exp.Ther.1998，284，291)。最近，提出3-烷基-5，5’-二苯基咪唑啶二酮为类大麻受体配位体，其预示为类大麻拮抗剂(Kanyonyo，M.；Govaerts，S.J.；Hermans，E.；Poupaert，J.H.；Lambert，D.M.Biorg.Med.Chem.Lett.1999，9，2233)有趣的是许多CB1受体拮抗剂已被报道为活体外之反促效剂(Landsman，R.S.；Burkey，T.H.；Consroe，P.；Roeske，W.R.；Yamamura，，H.I.Eur.J.Pharmacol.1997，334，R1)。最近的回顾提供类大麻研究。领域现阶段状况之良好综述(Mechoulam，R.；Hanus，L.；Fride，E.Prog.Med.Chem.1998，35，199.Lambert，D.M. Curr. Med. Chem.1999，6，635.Mechoulam，R.；Fride，E.；Di Marzo.V. Eur.J.Pharmacol.1998，359，1)。
目前，意外地发现在其下式(1)的4，5-二氢吡唑环的第4位置具有S构型之4，5-二氢-1H-吡唑衍生物的新颖对映体，其前体药物、互变体及盐比对应之R-对映体为更具强效及选择性之大麻CB1-受体之拮抗剂；
Figure C0280177700061
其中
-R和R1可为相同或不同且代表相同或不同且代表3-吡啶基或4-吡啶基，或可经卤素或甲氧基取代之苯基，
-R2和R3可为相同或不同且代表氢可为相同或不同且代表氢、烷基(1-3C)或二甲胺基，
-R4代表可经1，2或3个选自卤原子、三氟甲基、甲氧基及烷基(1-3C)所成组群之取代基取代之苯基，
及其互变体、前体药物及盐。
本发明化合物由于具有强效CB1拮抗活性而适用于治疗精神疾病如精神病、焦虑、抑郁、注意力不足、记意疾病及食欲疾病、肥胖症，神经疾病如痴呆、双口畸形、帕金森氏症、阿尔茨海默症、癫痫病、亨丁顿氏舞蹈病、杜莱德氏病、脑缺血，以及用以治疗疼痛疾病和其他涉及类大麻神经传达之CNS-疾病，及治疗胃肠疾病及心血管疾病。
本发明化合物对类大麻CB1受体之亲和性系利用中国苍鼠卵巢(CHO)细胞的膜制剂测定，其中人类大麻CB1受体以[3H]CP-55，940作为放射配位体稳定地转染。添加或未添加本发明化合物以[3H]-配位体培育新制作之细胞膜制剂后，利用玻璃纤维滤纸过滤分离结合及游离之配位体。利用液体闪烁计数测定滤液上之放射活性。
本发明化合物之类大麻CB1拮抗活性系利用CHO细胞之功能研究加以测定，其中人类类大麻CB1受体已稳定表现。使用forskolin刺激腺酰基环酶及利用定量积之还状AMP量而测定。在浓度依存方法中，因CB1受受体促放剂(如CP-55，940)或(R)-WIN-55，212-2)活化CB1受体，可减弱forskolin-诱发之cAMP累积。此CB1受体调节之反应可藉CB1受体拮抗剂如本发明化合物拮抗。
本发明有关式(I)化合物E-异构物、Z-异构物及E/Z混合物。
该化合物可利用一般制程，使用辅助物质液体或固体载体物质制成适于投药之剂型。
具有式(III)之本发明化合物(参见如下)可依据例如a)EP0021506；b)DE 2529689之知方法获得。
本发明消旋化合物之适当合成如下：
合成路径A
路径A之步骤1
式(III)化合物：
Figure C0280177700071
与式(IV)化合物或其适当盐在碱存在下反应：
Figure C0280177700072
其中R5代表低级烷基，例如2-甲基-2-硫代假脲。此反应获得式(V)之4，5-二氢-1H-吡唑-1-甲脒衍生物：
Figure C0280177700073
其中各符号如上述定义。其中R、R1、R2及R3具有化合物(I)定义之式(V)化合物为新颖。
或者，式(III)化合物与所谓脒化剂反应。脒化剂实例为1H-吡唑-1-甲脒及其盐(例如盐酸盐)，和3，5-二甲基-1H-吡唑-1-甲脒衍生物及其盐(例如硝酸盐)等。该反应得出式(V)的甲脒衍生物。
或者，式(III)化合物与所谓经保护之脒化剂反应。经保护脒化剂实例为N-(苄氧基羰基)-1H-吡唑-1-甲脒、N-(叔-丁氧基羰基)-1H-吡唑-1-甲脒和N，N′-双(叔-丁氧基羰基)-1H-吡唑-1-甲脒等。
此反应去保护后获得式(V)化合物。
路径A之步聚2
式(V)化合物与式R4-SO2X之选择性取代之化合物反应，其中R4如前述定义及X代表卤原子。此反应较好在碱如三乙胺存在下于非质子性溶液如乙腈中进行。
合成路径A1
路径A1之步骤1
式(III)化合物：
Figure C0280177700081
与式(VI)之硫代异氰酸酯衍生物反应：
Figure C0280177700082
此反应较好在惰性有机溶液如乙腈中进行。
此反应获得式(VII)之硫代甲酰胺衍生物，其中R、R1及R4具有化合物(I)定义之式(VII)合物为新颖。
Figure C0280177700091
路径A1之步骤2
式(VII)化合物与胺在汞(II)监例如HgCl2存在下反应，得到式(I)化合物。
此反应较好在极性有机溶液中例如乙腈中进行。
合成路径A2
路径A2之步骤1
式(III)之化合物：
与式(VIII)之胺基甲酸酯衍生物反应：
Figure C0280177700101
其中R6代表低级烷基，例如甲基。
此反应较好于惰性有机溶液如1，4-二氧杂环己烷中进行。
此反应得到式(IX)之4，5-二氢吡唑-1-甲酰胺衍生物。其中R、R1和R4具有化合物(I)所述定义之式(IX)化合物为新颖。
Figure C0280177700102
路径A2之步骤2
式(IX)化合物于卤化剂例如PCl5反应，得到式(X)之4，5-二氢吡唑-1-甲酰亚胺酰基卤化物(carboximidoyl halogenide)衍生物：
其中R7代表卤原子，例如氯。上反应较好于惰性有机溶液例如氯苯中进行。
其中R、R1和R4如化合物(I)之定义及R7代表卤原子之式(X)化合物为新颖。
路径A2之步骤3
式(X)化合物与胺反应，得到式(I)化合物。
此反应较好惰性有机溶液如二氯甲烷中进行。
合成路径A3
路径A3之步骤1
式(III)化合物：
Figure C0280177700111
与式(XI)之二硫代亚胺碳酸酯衍生物反应：
Figure C0280177700112
其中R8代表C1-3烷基。
此反应较好与极性有机溶液如乙腈中进行。
此反应得到式(XII)之甲酰亚胺硫代酸酯。
Figure C0280177700121
其中R、R1和R4具有化合物(I)定义且其中R8代表C1-3烷基之式(XII)化合物为新颖。
路径A3之步骤2
式(XII)化合物与胺反应得到式(I)化合物。
此反应较好于极性有机溶液如甲醇中进行。
实施例I
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
A部份：3-(4-氯苯基)-4，5-二氢-4-苯基-1H-吡唑(5.13克，20.0毫摩尔)、2-甲基-2-硫代假脲氢碘盐(5.00克，23.0毫摩尔)及吡啶(10毫升)之搅拌混合在110℃加热1小时。室温置放隔夜后，添加二乙基醚，利用过滤法收集沉淀物。沉淀物以二乙基醚清洗三次得到固体(9克)，熔点：～230℃。此固体物溶于甲醇(20毫升)中。
依序添加2N氢氧化钠溶液(12毫升)和水(200毫升)至所得溶液中。利用过滤法收集沉淀物，以二乙基醚清洗二次及随后以二丙基醚清洗。所得固体加经真空干燥得到3-(4-氯苯基)-4，5-二氢-4-苯基-1H-吡唑-1甲脒(5.1克，产率88％)，熔点：187-189℃。
B部分：3-(4-氯苯基)-4，5-二氢-4-苯基-1H-吡唑-1-甲脒(0.50克，1.68毫摩尔)及4-氟苯基磺酰氯(0.34克，1.75毫摩尔)之乙腈(10毫升)搅拌混合物中，添加N，N-二甲基-4-胺基吡啶(0.020克，0.175毫摩尔)及三乙胺(1毫升)。所得溶液于室温搅拌30分钟。添加2N氢氧化钠溶液及以乙酸乙酯(400毫升)萃取后，真空浓缩乙酸乙酯层。所得粗残留物进一步用快速层析法(石油醚/二乙基醚＝1/1(v/v)，接著乙酸乙酯)方式纯化。接着真空浓缩得到固体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，产率72％)，熔点：214-215℃。
依类似方式制作下列之式(I)化合物：
4，5-二氢-N-((4-氟苯基)磺酰基)-3-(4-甲氧苯基)-4-(4-甲氧基苯基)-1H-吡唑-1-甲脒，熔点155-156℃。
4，5-二氢-3-(4-甲氧基苯基)-4-(4-甲氧苯基)-N-((4-甲氧基苯基)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-((2，4，6-三甲基苯基)磺酰基)-1H-吡唑-1-甲脒，熔点221-222℃。
实例II
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
A部份：3-(4-氯苯基)-4，5-二氢-4-苯基-1H-吡唑(12.0克，46.8毫摩尔)、[(4-氯苯基)磺酰基]二硫代亚胺碳酸二甲酯(CAS：13068-12-7)(9.20克，31.1毫摩尔)、及三乙基胺(15毫升)之乙腈(200毫升)搅拌混合回流加热20小时。再添加3-(4-氯苯基)-4，5-二氢-4-苯基-1H-吡唑(12.0克，46.8毫摩尔)，及所得混合物再回流加热16小时。真空浓缩后，加入二氯甲烷，所得溶液以水清洗二次，以无水Na2SO4脱水。过滤和真空蒸发后，残留物进一步利用快速层析法(二乙基醚/石油醚＝1/1(v/v))纯化，得到非晶形固体之3-(4-氯苯基)-N-((4-氯苯基)磺酰基)-4，5-二氢-4-苯基-1H-吡唑-1-甲酰亚胺基硫代酸甲酯(12.5克以[(4-氯苯基)磺酰基]二硫代亚胺碳酸二甲酯计，产率80％)。
B部份：于3-(4-氯苯基)-N-((4-氯苯基)磺酰基)-4，5-二氯-4-苯基-1H-吡唑-1-甲酰亚胺基硫代酸甲酯(4.20克，8.30毫摩尔之甲醇(75毫升)，搅拌混合物中，添加二甲基胺(10毫升)及二氯甲烷(75毫升)，所得溶液于室温搅拌6小时。真空蒸发及接著进行快速层析(二乙基醚/石油醚＝1/1(v/v)，接著二乙基醚)纯化，得到固体，其进一步自二异丙基醚再结晶纯化，得到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℃。
依类似方法，制作下列式(I)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℃。
实例III
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
A部分：N-((4-氯苯基)磺酰基胺基甲酸甲酯(CAS：34543-04-9)(2.99克，12.0毫摩尔)及吡啶(4毫升)之1，4-二氧杂环己烷(20毫升)溶液中，添加3-(4-氯苯基)-4，5-二氢-4-苯基-1H-吡唑(3.39克，13.2毫摩尔)，所得混合溶液在100℃搅拌4小时。真空浓缩后，残留物溶于二氯甲烷中，再依序用水、1N HCl和水清洗，以无水Na2SO4脱水，过滤及真空缩体只成为20毫升。添加甲基-叔-丁基醚(60毫升)及所得溶液浓缩体积成为20毫升。过滤收集所形成之结晶及自甲基-叔-丁基醚再结晶，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-甲脒(4.75克，76％产率)，熔点：211-214℃。
B部份：3-(4-氯苯基)-N-((4-氯苯基)磺酰基)-4，5-二氢-4-苯基-1H-吡唑-1-甲脒(3.67克，7.75毫摩尔)及五氯化磷(1.69克，8.14毫摩尔)之氯苯(40毫升)摩尔)混合加热回流1小时。真空浓缩后，所形成之N-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4，5-二氢-4-苯基-1H-吡唑-1-甲亚酰胺基氯悬浮于二氯甲烷中，并于冷却甲基胺(1.5毫升)反应。在室温搅拌1小时后，混合物真空浓缩。残留物自二乙基醚结晶，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℃。
依类似方式制作下列式(1)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-丙基-N’-((4-氟苯基)磺酰基)-3-(4-吡啶基)-4，5-二氢-4-苯基-1H-吡唑-1-甲脒，熔点：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-(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：非晶型。
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-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：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)磺酰盐)-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-甲氧基苯基)磺酰盐)-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-N1-((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：非晶型。
N-二甲胺基-N1-((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-N1-((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-羧脒，熔点：非晶型。
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℃。
实例IV
(-)-(4S)-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
使用Chiralpak AD，20微米手性固定相，分离消旋N-甲基N’-((4-氯苯基)磺酰基)-3-(4-氯苯基)-4，5-二氢苯基-4-苯基-1H-吡唑-1-甲脒(18克，0.037摩尔)，得到(-)-(4S)-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(7.16克，0.0147摩尔)([α25 D]＝-150°，c＝0.01，MeOH)(熔点：169-170℃。移动相由己烷/乙醇(80/20(v/v)及0.1％氢氧化铵(25％水溶液)之混合所构成。
依类似方式自对应消旋物制作下列光学纯化合物：
(-)-(4S)-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：([α25 D]＝-126°，c＝0.01，CHCl3)，熔点：172-175℃，固定相：Chiralcel OD。移动相；庚烷/2-丙醇(85/15(v/v))混合溶液。
(-)-(4S)-N-二甲胺基-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：([α25 D]＝-132°，c＝0.01，CHCl3，熔点218-224℃，固定相：Chiralcel OD。移动相：庚烷/2-丙醇(85/15(v/v))混合溶液。
(-)-(4S)-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；([α25 D]＝-131°，c＝0.01，CHCl3)，熔点：157-160℃，固定相：Chiralcel OD。移动相：庚烷/2-丙醇(85/15(v/v))混合溶液。
(-)-(4S)-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：[α25 D]＝-88°，c＝0.01，MeOH)，熔点：非晶型，固定相：Chiralpak AD。移动相：乙醇。
(-)-(4S)-N-甲基-N’-((2，4-二氟苯基)磺酰基)-3-(4-氯苯基)-4，5-二氯-4-苯基1H-吡唑-H-羧脒：：[α25 D]＝-129°，c＝0.01，MeOH，熔点：非晶型，固定相：Chiralpak AD。移动相：甲醇。

Claims (8)

1.一种在其4，5-二氢吡唑环的4位置具有S构型的式(I)化合物的对映体，
Figure C028017770002C1
其中
-R和R1可为相同或不同且代表3-吡啶基或4-吡啶基或可经卤素或甲氧基取代之苯基，
-R2和R3可为相同或不同且代表氢、(C1-C3)烷基或二甲胺基，
-R4代表可经1，2或3个选自卤素、三氟甲基、甲氧基和(C1-C3)烷基之取代基取代之苯基，
及其盐类。
2.如权利要求1之式(I)化合物，其中R为4-氯苯基，R1为苯基，R2为氢，R3为甲基及R4为4-氯苯基；及基盐类。
3.一种医药组合物，含有如权利要求1之至少一种化合物作为活性成份。
4.一种制备医药组合物之方法，其特征在于使权利要求1之化合物制成适于给药之剂型。
5.一种制备权利要求1的式I化合物之方法，其特征在于使式I化合物的消旋混合物分离成左旋及右旋对映体。
6.权利要求1的化合物在制备治疗精神疾病的药物中的用途，其中该精神疾病选自精神病、焦虑、抑郁、注意力不足、记忆疾病及食欲疾病，肥胖症，选自帕金森氏症、痴呆、肌张力障碍、阿尔茨海默症、癫病、亨丁顿氏舞蹈病、杜莱德氏病、脑缺血、疼痛疾病的神经疾病和其他涉及类大麻神经传达之CNS-疾病。
7.权利要求1的化合物在制备治疗涉及类大麻神经传达之胃肠疾病的药物中的用途。
8.权利要求1的化合物在制备治疗涉及类大麻神经传达之心血管疾病的药物中的用途。
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Families Citing this family (123)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI231757B (en) 2001-09-21 2005-05-01 Solvay Pharm Bv 1H-Imidazole derivatives having CB1 agonistic, CB1 partial agonistic or CB1-antagonistic activity
CA2478183C (en) 2002-03-12 2010-02-16 Merck & Co. Inc. Substituted amides
US7105526B2 (en) 2002-06-28 2006-09-12 Banyu Pharmaceuticals Co., Ltd. Benzimidazole derivatives
US7129239B2 (en) 2002-10-28 2006-10-31 Pfizer Inc. Purine compounds and uses thereof
US7247628B2 (en) 2002-12-12 2007-07-24 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
US7772188B2 (en) 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
US7329658B2 (en) * 2003-02-06 2008-02-12 Pfizer Inc Cannabinoid receptor ligands and uses thereof
US7176210B2 (en) 2003-02-10 2007-02-13 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7141669B2 (en) 2003-04-23 2006-11-28 Pfizer Inc. Cannabiniod receptor ligands and uses thereof
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7268133B2 (en) 2003-04-23 2007-09-11 Pfizer, Inc. Patent Department Cannabinoid receptor ligands and uses thereof
US7232823B2 (en) 2003-06-09 2007-06-19 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
TW200511990A (en) * 2003-09-02 2005-04-01 Solvay Pharm Gmbh Novel medical uses of 4, 5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity
WO2005028438A1 (ja) 2003-09-22 2005-03-31 Banyu Pharmaceutical Co., Ltd. 新規ピペリジン誘導体
WO2005039550A2 (en) * 2003-10-24 2005-05-06 Solvay Pharmaceuticals Gmbh Novel medical uses of compounds showing cb1-antagonistic activity and combination treatment involving said compounds
AR046132A1 (es) * 2003-10-24 2005-11-23 Solvay Pharm Gmbh Composicin farmaceutica que contiene al menos un compuesto con actividad de receptor de cb1, o un profarmaco , tautomero o sal del mismo, como componente activo adecuado para el tratamiento y/o profilaxis de enfermedades relacionadas con el receptor cb1 en pacientes juveniles y/o para el tratamiento
WO2005049615A1 (en) * 2003-11-21 2005-06-02 Pfizer Products Inc. Pyrazolo`1,5-a!`1,3,5! triazin -4-one derivatives as cb1 receptor antagonists
ATE478856T1 (de) 2004-01-28 2010-09-15 Hoffmann La Roche Spirobenzodioxole und deren verwendung als cb1- antagonisten
MXPA06008593A (es) * 2004-01-30 2006-08-28 Solvay Pharm Bv Derivados 1,3,5-trisustituidos de 4,5-dihidro-1h-pirazol que tienen actividad antagonista del receptor canabinoide 1.
US7649002B2 (en) 2004-02-04 2010-01-19 Pfizer Inc (3,5-dimethylpiperidin-1yl)(4-phenylpyrrolidin-3-yl)methanone derivatives as MCR4 agonists
WO2005097759A1 (en) 2004-03-29 2005-10-20 Merck & Co., Inc. Diaryltriazoles as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1
US20080125403A1 (en) 2004-04-02 2008-05-29 Merck & Co., Inc. Method of Treating Men with Metabolic and Anthropometric Disorders
US20060025448A1 (en) 2004-07-22 2006-02-02 Cadila Healthcare Limited Hair growth stimulators
JP2008509146A (ja) 2004-08-06 2008-03-27 メルク エンド カムパニー インコーポレーテッド １１−ベータ−ヒドロキシステロイドデヒドロゲナーゼ−１の阻害剤としてのスルホニル化合物
EP1784390A2 (en) 2004-08-13 2007-05-16 Amgen Inc. Substituted benzofused heterocycles
EP1807063A2 (en) * 2004-10-25 2007-07-18 Solvay Pharmaceuticals GmbH Pharmaceutical compositions comprising cb1 cannabinoid receptor antagonists and potassium channel openers for the treatment of diabetes mellitus type i, obesity and related conditions
US8394765B2 (en) 2004-11-01 2013-03-12 Amylin Pharmaceuticals Llc Methods of treating obesity with two different anti-obesity agents
US20090156474A1 (en) 2004-11-01 2009-06-18 Amylin Pharmaceuticals, Inc. Methods for treating obesity and obesity related diseases and disorders
ES2351348T3 (es) 2004-11-09 2011-02-03 F. Hoffmann-La Roche Ag Derivados de la dibenzosuberona.
WO2006060186A2 (en) * 2004-11-30 2006-06-08 Bayer Pharmaceuticals Corporation Pyrazole derivatives for the treatment of dementia and related disorders
WO2006060201A2 (en) * 2004-11-30 2006-06-08 Bayer Pharmaceuticals Corporation Pyrazole derivatives for the treatment of psychiatric disorders
PA8660701A1 (es) 2005-02-04 2006-09-22 Pfizer Prod Inc Agonistas de pyy y sus usos
US7737155B2 (en) 2005-05-17 2010-06-15 Schering Corporation Nitrogen-containing heterocyclic compounds and methods of use thereof
KR101397913B1 (ko) 2005-05-30 2014-05-26 엠에스디 가부시키가이샤 신규 피페리딘 유도체
JP2008545739A (ja) 2005-06-02 2008-12-18 グレンマーク・ファーマシューティカルズ・エスエー 新規なカンナビノイド受容体リガンド、それらを含む薬剤組成物、およびそれらの調製方法
US7923465B2 (en) 2005-06-02 2011-04-12 Glenmark Pharmaceuticals S.A. Cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
EP1757587A1 (en) * 2005-07-15 2007-02-28 Laboratorios Del Dr. Esteve, S.A. Substituted pyrazoline compounds, their preparation and use as medicaments
WO2007018248A1 (ja) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. ピリドン化合物
CA2617649A1 (en) 2005-08-11 2007-02-22 Amylin Pharmaceuticals, Inc. Hybrid polypeptides with selectable properties
BRPI0614649A2 (pt) 2005-08-11 2011-04-12 Amylin Pharmaceuticals Inc polipeptìdeos hìbridos com propriedades selecionáveis
AU2006282260A1 (en) 2005-08-24 2007-03-01 Msd K.K. Phenylpyridone derivative
EP1940842B1 (en) 2005-09-29 2012-05-30 Merck Sharp & Dohme Corp. Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
US7741317B2 (en) 2005-10-21 2010-06-22 Bristol-Myers Squibb Company LXR modulators
US8163770B2 (en) 2005-10-27 2012-04-24 Msd. K. K. Benzoxathiin derivative
KR101318127B1 (ko) 2005-11-10 2013-10-16 엠에스디 가부시키가이샤 아자 치환된 스피로 유도체
US7888376B2 (en) 2005-11-23 2011-02-15 Bristol-Myers Squibb Company Heterocyclic CETP inhibitors
EP1801098A1 (en) 2005-12-16 2007-06-27 Merck Sante 2-Adamantylurea derivatives as selective 11B-HSD1 inhibitors
KR101036981B1 (ko) 2006-02-23 2011-05-25 화이자 리미티드 멜라노코르틴 제４형 수용체 효능제 피페리디노일피롤리딘
US7763607B2 (en) 2006-04-27 2010-07-27 Solvay Pharmaceuticals Gmbh Pharmaceutical compositions comprising CBx cannabinoid receptor modulators and potassium channel modulators
CN101431998A (zh) * 2006-04-27 2009-05-13 索尔瓦药物有限公司 含有CBx大麻素受体调节剂和钾通道调节剂的药物组合物
MX2009001043A (es) 2006-08-08 2009-02-06 Sanofi Aventis Imidazolidina-2,4-dionas sustituidas con arilaminoarilalquilo, procedimiento para preparalas, medicamentos que comprenden estos compuestos y su uso.
WO2008039327A2 (en) 2006-09-22 2008-04-03 Merck & Co., Inc. Method of treatment using fatty acid synthesis inhibitors
EP2072519A4 (en) 2006-09-28 2009-10-21 Banyu Pharma Co Ltd DIARYLKETIMINDERIVAT
KR20090064478A (ko) 2006-11-13 2009-06-18 화이자 프로덕츠 인크. 디아릴, 디피리디닐 및 아릴-피리디닐 유도체, 및 이들의 용도
US8404896B2 (en) 2006-12-01 2013-03-26 Bristol-Myers Squibb Company N-((3-benzyl)-2,2-(bis-phenyl)-propan-1-amine derivatives as CETP inhibitors for the treatment of atherosclerosis and cardiovascular diseases
EP1935420A1 (en) 2006-12-21 2008-06-25 Merck Sante 2-Adamantyl-butyramide derivatives as selective 11beta-HSD1 inhibitors
US8106086B2 (en) 2007-04-02 2012-01-31 Msd K.K. Indoledione derivative
WO2008151257A2 (en) 2007-06-04 2008-12-11 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
CN101318931B (zh) * 2007-06-04 2010-05-19 上海阳帆医药科技有限公司 二芳基取代吡唑衍生物、其制备方法和用途
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
EP2025674A1 (de) 2007-08-15 2009-02-18 sanofi-aventis Substituierte Tetrahydronaphthaline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
GB2456183A (en) * 2008-01-04 2009-07-08 Gw Pharma Ltd Anti-psychotic composition comprising cannabinoids and anti-psychotic medicament
CA2714617A1 (en) 2008-03-06 2009-09-11 Banyu Pharmaceutical Co., Ltd. Alkylaminopyridine derivative
CN101981025A (zh) 2008-03-28 2011-02-23 万有制药株式会社 具有黑色素浓缩激素受体拮抗作用的二芳基甲基酰胺衍生物
EP2110374A1 (en) 2008-04-18 2009-10-21 Merck Sante Benzofurane, benzothiophene, benzothiazol derivatives as FXR modulators
WO2009149279A2 (en) 2008-06-04 2009-12-10 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
JPWO2009154132A1 (ja) 2008-06-19 2011-12-01 Ｍｓｄ株式会社 スピロジアミン−ジアリールケトオキシム誘導体
AR072707A1 (es) 2008-07-09 2010-09-15 Sanofi Aventis Compuestos heterociclicos, procesos para su preparacion, medicamentos que comprenden estos compuestos y el uso de los mismos
WO2010009319A2 (en) 2008-07-16 2010-01-21 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
EP2319841A1 (en) 2008-07-30 2011-05-11 Msd K.K. (5-membered)-(5-membered) or (5-membered)-(6-membered) fused ring cycloalkylamine derivative
ES2421920T3 (es) 2008-08-06 2013-09-06 Pfizer Ltd Compuestos de diazepina y diazocano como agonistas de MC4
WO2010047982A1 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
EA201170624A1 (ru) 2008-10-30 2011-12-30 Мерк Шарп Энд Домэ Корп. Изоникотинамидные антагонисты рецепторов орексинов
WO2010051206A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
JP5514831B2 (ja) 2008-11-17 2014-06-04 メルク・シャープ・アンド・ドーム・コーポレーション 糖尿病の治療のための置換二環式アミン
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
EP2379547A1 (en) 2008-12-16 2011-10-26 Schering Corporation Pyridopyrimidine derivatives and methods of use thereof
EP2379562A1 (en) 2008-12-16 2011-10-26 Schering Corporation Bicyclic pyranone derivatives as nicotinic acid receptor agonists
WO2010079241A1 (es) 2009-01-12 2010-07-15 Fundacion Hospital Nacional De Paraplejicos Para La Investigacion Y La Integracion Uso de antagonistas y/o agonistas inversos de los receptores cb1 para la preparación de medicamentos que incrementen la excitabilidad de las motoneuronas
WO2011011506A1 (en) 2009-07-23 2011-01-27 Schering Corporation Spirocyclic oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors
US20120220567A1 (en) 2009-07-23 2012-08-30 Shipps Jr Gerald W Benzo-fused oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors
ES2443016T3 (es) 2009-08-26 2014-02-17 Sanofi Nuevos hidratos cristalinos de fluoroglicósidos heteroaromáticos, productos farmacéuticos que comprenden estos compuestos, y su empleo
CN102812011A (zh) 2009-11-16 2012-12-05 梅利科技公司 [1,5]-二氮杂环辛间四烯衍生物
US8648073B2 (en) 2009-12-30 2014-02-11 Fochon Pharma, Inc. Certain dipeptidyl peptidase inhibitors
AR079935A1 (es) 2010-01-29 2012-02-29 Abbott Healthcare Products Bv Sintesis de derivados de pirazolin carboxamidina sustituida
AU2011218830B2 (en) 2010-02-25 2014-07-24 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
US8785634B2 (en) 2010-04-26 2014-07-22 Merck Sharp & Dohme Corp Spiropiperidine prolylcarboxypeptidase inhibitors
WO2011143057A1 (en) 2010-05-11 2011-11-17 Merck Sharp & Dohme Corp. Novel prolylcarboxypeptidase inhibitors
US9006268B2 (en) 2010-06-11 2015-04-14 Merck Sharp & Dohme Corp. Prolylcarboxypeptidase inhibitors
WO2011157827A1 (de) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-on-derivate als inhibitoren von lipasen und phospholipasen
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
CN103476258B (zh) 2011-02-25 2017-04-26 默沙东公司 用作抗糖尿病药剂的新的环状氮杂苯并咪唑衍生物
US8846666B2 (en) 2011-03-08 2014-09-30 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
EP2683702B1 (de) 2011-03-08 2014-12-24 Sanofi Neue substituierte phenyl-oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
EP2683700B1 (de) 2011-03-08 2015-02-18 Sanofi Tetrasubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
EP2683705B1 (de) 2011-03-08 2015-04-22 Sanofi Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
WO2012120057A1 (de) 2011-03-08 2012-09-13 Sanofi Neue substituierte phenyl-oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
WO2012120051A1 (de) 2011-03-08 2012-09-13 Sanofi Mit adamantan- oder noradamantan substituierte benzyl-oxathiazinderivate, diese verbindungen enthaltende arzneimittel und deren verwendung
WO2012120052A1 (de) 2011-03-08 2012-09-13 Sanofi Mit carbozyklen oder heterozyklen substituierte oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
US8828995B2 (en) 2011-03-08 2014-09-09 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120055A1 (de) 2011-03-08 2012-09-13 Sanofi Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
AR088352A1 (es) 2011-10-19 2014-05-28 Merck Sharp & Dohme Antagonistas del receptor de 2-piridiloxi-4-nitrilo orexina
US8680131B2 (en) * 2012-07-25 2014-03-25 Jenrin Discovery, Inc. Cannabinoid receptor antagonists/inverse agonists useful for treating disease conditions, including metabolic disorders and cancers
EP2880028B1 (en) 2012-08-02 2020-09-30 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US11155521B2 (en) 2012-11-13 2021-10-26 The United States Of America As Represented By The Secretary, Department Of Health And Human Services Cannabinoid receptor mediating compounds
CN104884057B (zh) 2012-11-13 2019-08-20 美国政府(由卫生和人类服务部的部长所代表) 大麻素受体介导的化合物
CA2898482A1 (en) 2013-02-22 2014-08-28 Linda L. Brockunier Antidiabetic bicyclic compounds
EP2970119B1 (en) 2013-03-14 2021-11-03 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
JP2016514671A (ja) 2013-03-15 2016-05-23 シナジー ファーマシューティカルズ インコーポレイテッド グアニル酸シクラーゼのアゴニストおよびその使用
EP2968439A2 (en) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
CA2913737A1 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
WO2015051496A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
CA2948349C (en) 2014-05-09 2023-03-28 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Pyrazole derivatives and their use as cannabinoid receptor mediators
KR102431436B1 (ko) 2014-08-29 2022-08-10 테스 파마 에스.알.엘. α-아미노-β-카복시뮤콘산 세미알데히드 데카복실라제의 억제제
CN108699043A (zh) * 2016-03-04 2018-10-23 美国政府(由卫生和人类服务部的部长所代表) 大麻素受体介导化合物
WO2018069532A1 (en) 2016-10-14 2018-04-19 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
EP3551176A4 (en) 2016-12-06 2020-06-24 Merck Sharp & Dohme Corp. ANTIDIABETIC HETEROCYCLIC COMPOUNDS
AU2019385644A1 (en) 2018-11-20 2021-06-03 Tes Pharma S.R.L. Inhibitors of α-Amino-β-carboxymuconic acid semialdehyde decarboxylase
EP3924058A1 (en) 2019-02-13 2021-12-22 Merck Sharp & Dohme Corp. 5-alkyl pyrrolidine orexin receptor agonists
US20230018413A1 (en) 2019-08-08 2023-01-19 Merck Sharp & Dohme Corp. Heteroaryl pyrrolidine and piperidine orexin receptor agonists
TW202227417A (zh) 2020-08-18 2022-07-16 美商默沙東藥廠 雙環庚烷吡咯啶之食慾素受體促效劑
EP4341246A1 (en) * 2021-05-17 2024-03-27 The United States of America, as represented by The Secretary, Department of Health and Human Services A facile and odor-free approach to convert sulfonyl urea derivatives to chalcogenide sulfonyl urea derivatives
WO2023196556A1 (en) * 2022-04-07 2023-10-12 Corbus Pharmaceuticals, Inc. Cannabinoid receptor 1 antagonists/inverse agonists and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4070365A (en) * 1974-07-12 1978-01-24 U.S. Philips Corporation Pyrazoline compounds
EP0173323A1 (de) * 1984-08-30 1986-03-05 Bayer Ag Amidinoazole
US5624941A (en) * 1992-06-23 1997-04-29 Sanofi Pyrazole derivatives, method of preparing them and pharmaceutical compositions in which they are present

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA02009258A (es) * 2000-03-23 2005-04-19 Solvay Pharm Bv Derivados de 4,5-dihidro-1h-pirazol que tienen actividad antagonistica de cannabis-1.
PE20021046A1 (es) * 2000-09-30 2002-12-14 Gruenenthal Chemie Sulfonilguanidina que tiene afinidad al punto de fijacion de gabapentina

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4070365A (en) * 1974-07-12 1978-01-24 U.S. Philips Corporation Pyrazoline compounds
EP0173323A1 (de) * 1984-08-30 1986-03-05 Bayer Ag Amidinoazole
US5624941A (en) * 1992-06-23 1997-04-29 Sanofi Pyrazole derivatives, method of preparing them and pharmaceutical compositions in which they are present

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