CN101146786A - 作为脂肪酸酰胺水解酶调节剂的哌嗪基脲和哌啶基脲 - Google Patents
作为脂肪酸酰胺水解酶调节剂的哌嗪基脲和哌啶基脲 Download PDFInfo
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- CN101146786A CN101146786A CNA2005800488137A CN200580048813A CN101146786A CN 101146786 A CN101146786 A CN 101146786A CN A2005800488137 A CNA2005800488137 A CN A2005800488137A CN 200580048813 A CN200580048813 A CN 200580048813A CN 101146786 A CN101146786 A CN 101146786A
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- China
- Prior art keywords
- piperazine
- phenyl
- carboxylic acid
- acid amides
- ylmethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 piperidinyl ureas Chemical class 0.000 title claims abstract description 541
- 108010046094 fatty-acid amide hydrolase Proteins 0.000 title abstract description 46
- 102100029111 Fatty-acid amide hydrolase 1 Human genes 0.000 title abstract description 44
- 125000004193 piperazinyl group Chemical group 0.000 title description 4
- 235000013877 carbamide Nutrition 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 386
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 132
- 238000000034 method Methods 0.000 claims abstract description 53
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 51
- 238000011282 treatment Methods 0.000 claims abstract description 48
- 201000010099 disease Diseases 0.000 claims abstract description 39
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 28
- 208000002193 Pain Diseases 0.000 claims abstract description 28
- 230000036407 pain Effects 0.000 claims abstract description 28
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 20
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 20
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- 230000000694 effects Effects 0.000 claims abstract description 16
- 208000035475 disorder Diseases 0.000 claims abstract description 12
- 206010061218 Inflammation Diseases 0.000 claims abstract description 11
- 230000004054 inflammatory process Effects 0.000 claims abstract description 11
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 11
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 9
- 230000036506 anxiety Effects 0.000 claims abstract description 9
- 230000001404 mediated effect Effects 0.000 claims abstract description 9
- FWEOQOXTVHGIFQ-UHFFFAOYSA-N 8-anilinonaphthalene-1-sulfonic acid Chemical compound C=12C(S(=O)(=O)O)=CC=CC2=CC=CC=1NC1=CC=CC=C1 FWEOQOXTVHGIFQ-UHFFFAOYSA-N 0.000 claims description 708
- 150000001408 amides Chemical class 0.000 claims description 295
- 229910052799 carbon Inorganic materials 0.000 claims description 207
- 125000006278 bromobenzyl group Chemical group 0.000 claims description 161
- RAUXNKACEUBXKS-UHFFFAOYSA-N 4-(quinolin-3-ylmethyl)piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1CC1=CN=C(C=CC=C2)C2=C1 RAUXNKACEUBXKS-UHFFFAOYSA-N 0.000 claims description 98
- 150000001721 carbon Chemical group 0.000 claims description 81
- 229910052760 oxygen Inorganic materials 0.000 claims description 79
- 229910052736 halogen Inorganic materials 0.000 claims description 66
- 150000002367 halogens Chemical class 0.000 claims description 66
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 51
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 50
- 229910052717 sulfur Inorganic materials 0.000 claims description 47
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 46
- 239000003814 drug Substances 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 45
- 208000024891 symptom Diseases 0.000 claims description 40
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 36
- 229940095102 methyl benzoate Drugs 0.000 claims description 34
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 32
- 239000001301 oxygen Substances 0.000 claims description 32
- 239000000651 prodrug Substances 0.000 claims description 32
- 229940002612 prodrug Drugs 0.000 claims description 32
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 claims description 28
- 125000006413 ring segment Chemical group 0.000 claims description 26
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 125000005842 heteroatom Chemical group 0.000 claims description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 125000005561 phenanthryl group Chemical group 0.000 claims description 21
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 20
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 20
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000004429 atom Chemical group 0.000 claims description 19
- 239000002207 metabolite Substances 0.000 claims description 19
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 16
- IYNZSSLLSBFZKE-UHFFFAOYSA-N 4-(quinolin-2-ylmethyl)piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1CC1=CC=C(C=CC=C2)C2=N1 IYNZSSLLSBFZKE-UHFFFAOYSA-N 0.000 claims description 15
- LWYZHUFJMSGJGM-UHFFFAOYSA-N 4-(naphthalen-2-ylmethyl)piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1CC1=CC=C(C=CC=C2)C2=C1 LWYZHUFJMSGJGM-UHFFFAOYSA-N 0.000 claims description 14
- 125000001624 naphthyl group Chemical group 0.000 claims description 14
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 13
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 13
- BRALMXUMVXRHIP-UHFFFAOYSA-N 4-(1,3-benzodioxol-5-ylmethyl)piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1CC1=CC=C(OCO2)C2=C1 BRALMXUMVXRHIP-UHFFFAOYSA-N 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 13
- 125000002837 carbocyclic group Chemical group 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 10
- NPDLYUOYAGBHFB-WDSKDSINSA-N Asn-Arg Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CCCN=C(N)N NPDLYUOYAGBHFB-WDSKDSINSA-N 0.000 claims description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 10
- 125000001725 pyrenyl group Chemical group 0.000 claims description 10
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 8
- 125000005605 benzo group Chemical group 0.000 claims description 8
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 8
- 230000037406 food intake Effects 0.000 claims description 8
- 235000012631 food intake Nutrition 0.000 claims description 8
- 125000001072 heteroaryl group Chemical class 0.000 claims description 8
- NNZKEXVNOITCIW-UHFFFAOYSA-N 2-[[4-(quinolin-3-ylmethyl)piperazine-1-carbonyl]amino]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1NC(=O)N1CCN(CC=2C=C3C=CC=CC3=NC=2)CC1 NNZKEXVNOITCIW-UHFFFAOYSA-N 0.000 claims description 7
- CHDLHDMNVISUIK-UHFFFAOYSA-N 3-[[4-(quinolin-3-ylmethyl)piperazine-1-carbonyl]amino]benzoic acid Chemical compound OC(=O)C1=CC=CC(NC(=O)N2CCN(CC=3C=C4C=CC=CC4=NC=3)CC2)=C1 CHDLHDMNVISUIK-UHFFFAOYSA-N 0.000 claims description 7
- CPSZTOKIORABMF-UHFFFAOYSA-N 4-(1,3-benzodioxol-4-ylmethyl)piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1CC1=CC=CC2=C1OCO2 CPSZTOKIORABMF-UHFFFAOYSA-N 0.000 claims description 7
- IQELBKHBGGWXRW-UHFFFAOYSA-N 4-(1-benzothiophen-2-ylmethyl)piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1CC1=CC2=CC=CC=C2S1 IQELBKHBGGWXRW-UHFFFAOYSA-N 0.000 claims description 7
- MSBPUMMMHLFWND-UHFFFAOYSA-N 4-(naphthalen-1-ylmethyl)piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1CC1=CC=CC2=CC=CC=C12 MSBPUMMMHLFWND-UHFFFAOYSA-N 0.000 claims description 7
- RDHGAGRIDQIHRO-UHFFFAOYSA-N 4-(pyren-1-ylmethyl)piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1CC1=CC=C(C=C2)C3=C4C2=CC=CC4=CC=C13 RDHGAGRIDQIHRO-UHFFFAOYSA-N 0.000 claims description 7
- DIMNSNBAOROORJ-UHFFFAOYSA-N 4-(pyridin-2-ylmethyl)piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1CC1=CC=CC=N1 DIMNSNBAOROORJ-UHFFFAOYSA-N 0.000 claims description 7
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- BPEZNTFUUBJDLQ-UHFFFAOYSA-N 4-[(2-hydroxyphenyl)methyl]piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1CC1=CC=CC=C1O BPEZNTFUUBJDLQ-UHFFFAOYSA-N 0.000 claims description 7
- LGYCFNVMHKTQKO-UHFFFAOYSA-N 4-[(3-phenylmethoxyphenyl)methyl]piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1CC1=CC=CC(OCC=2C=CC=CC=2)=C1 LGYCFNVMHKTQKO-UHFFFAOYSA-N 0.000 claims description 7
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Classifications
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Abstract
式(I)的化合物可用作FAAH抑制剂:其中,Z是-N或>CH;R1是-H或C1-4烷基;Ar1是2-噻唑基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基或苯基,每个基团均是未取代的或者在碳环成员上被一个或两个Ra部分所取代;其中每个Ra部分独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自独立地选自-H或-C1-4烷基;且Ar2在权利要求中限定。这种化合物可以在用于治疗由脂肪酸酰胺水解酶(FAAH)活性介导的疾病状态、障碍和病症的药物组合物和方法中使用。因此,可以给予该化合物以治疗,例如,焦虑、疼痛、炎症、睡眠障碍、摄食障碍或移动障碍(如多发性硬化)。
Description
相关申请的交叉引用
本申请要求于2004年12月30日提交的美国临时申请60/640,869的优先权
技术领域
本发明涉及某些哌嗪脲(piperazinyl urea)和哌啶脲(peperidinylurea)化合物、含有它们的药物组合物、以及使用它们治疗由脂肪酸酰胺水解酶(FAAH)活性介导的疾病状态、障碍和病症的方法。
背景技术
大麻属植物医用益处为人所知已经有几个世纪了。大麻的主要生物活性成分是△9-四氢-大麻酚(THC)。THC的发现最终导致识别了两种对其药理学作用负责的内源性大麻素(cannabinoid)受体,即CB1和CB2(Goya,Exp.Opin.TherPatents 2000,10,1529)。这些发现不仅确立了THC的作用位点,还对这些受体的内源性激动剂或“内源性大麻素”进行了探询。所识别的第一种内源性大麻素是脂肪酸酰胺花生四烯酰乙醇胺(anandamide)(AEA)。AEA自身引起许多外源性大麻素的药理学效果(Piomelli,Nat.Rev.Neurosci.2003,4(11),873)。
AEA的分解代谢主要归因于膜本体束缚蛋白脂肪酸酰胺水解酶(FAAH),其将AEA水解为花生四烯酸。FAAH于1996年被Cravatt及其合作者所表征(Cravatt,Nature1996,384,83)。随后确定了FAAH还对大量重要的脂质信号脂肪酸酰胺的分解代谢负责:这些脂肪酸酰胺包括另一种主要的外源性大麻素,2-花生四烯酰丙三醇(2-AG)(Science1992,258,1946-1949);睡眠诱导物质,油酰胺(OEA)(Science1995,268,1506);食欲抑制剂,N-油酰乙醇胺(Rodriguez de Fonesca,Nature 2001,414,209);以及消炎药,棕榈酰乙醇酰胺(PEA)(Lambert,Curr.Med.Chem.2002,9(6),663)。
FAAH的小分子抑制剂应当提高这些外源性信号脂质的浓度,从而得到其相关的有益药理学效果。已经有一些关于各种FAAH抑制剂在预临床模型中的效果的报道。
特别是,据报道两种氨基甲酸酯基FAAH抑制剂在动物模型中具有止痛效果。据报道,在大鼠中,结构如下所示的BMS-1(参见WO02/087569)在神经性疼痛的Chung脊神经结扎模型中和灵敏热伤害感受的Hargraves试验中具有止痛效果。据报道,URB-597在大鼠焦虑的零加迷宫模型(zero plus maze model)中有效,并且在大鼠的热板和福尔马林试验中具有止痛效果(Kathuria,Nat.Med.2003,9(1),76)。磺酰氟化物AM374也显示了在慢性复发性实验性自身免疫性脑脊髓炎(CREAE)小鼠(一种多发性硬化的动物模型)中显著减轻痉挛(Baker,EASEB J.2001,15(2),300)。
此外,据报道,唑并吡啶酮OL-135是FAAH的有效抑制剂,并且在大鼠中在热伤害感受的热板和尾部浸水实验中具有止痛活性(WO04/033652)。
对某些外源性大麻素效果的研究结果说明,FAAH抑制剂可以用于治疗各种病症、疾病、障碍或症状。这些包括疼痛、恶心/呕吐、厌食、痉挛、移动障碍、癫痫和青光眼。迄今,已经证实的大麻素的治疗用途包括减轻癌症患者因化疗剂诱发的恶心和呕吐、以及增进因消耗综合征而经历厌食的HIV/AIDs患者的食欲。对于这些适应症,在一些国家中两种产品是市售的,即,屈大麻酚(Marinol)和大麻隆。
除了已证实的适应症之外,大麻素的使用受到很多关注的治疗领域是止痛,即,治疗疼痛。五个小型随机控制实验显示,THC在产生剂量相关的止痛效果时优于安慰剂(Robson,Br.J.Psychiatry 2001,178,107-115)。据报道,Atlantic Pharmaceuticals公司正在开发一种合成大麻素CT-3(一种四氢大麻酚的羧酸代谢产物的1,1-二甲基-庚基衍生物)作为口服的活性止痛和消炎药。据报道,CT-3在慢性神经痛方面的中试二期实验已经于2002年5月在德国启动。
小型控制实验证明,多个患有多发性硬化的个体已经从大麻中得到了在与疾病相关的疼痛和痉挛方面的好处(Svendsen,Br.Med.J.2004,329,253)。类似地,据报道,在吸食大麻烟之后,多个脊髓损伤患者已经减轻了其疼痛痉挛。报道显示,大麻素看来在多发性硬化的CREAE模型中控制痉挛和震颤,这证实了这些影响是由CB1和CB2受体介导的(Baker,Nature 2000,404,84-87)。已经用四氢大麻酚/大麻酚(THC/CBD)的窄比率混合物在多发性硬化和脊髓损伤患者中进行了三期临床实验。
进行小规模控制实验以调查大麻素的其它潜在商业用途的报道已经做出。据报道,在志愿者中的实验已经证实,口服、注射和吸食大麻素能够与剂量相关地减轻眼压(IPO),因此可以减轻青光眼症状。眼科医师已经为其它药物不足以控制眼压的青光眼患者开出大麻处方(Robson,2001)。
与用直接作用的CB1激动剂治疗相比,使用小分子抑制剂来抑制FAAH是有优势的。外源性CB1激动剂的给药可以产生范围响应,包括减轻伤害感受、强直性昏厥、低温、以及增强进食行为。具体的说,这四项被称为“大麻素四联法(cannabinoid tetrad)”。用FAAH-/-小鼠进行的实验在伤害感受实验中显示减轻的反应,但是未显示强直性昏厥、低温或增强进食行为(Cravatt,Proc.Natl.Acad.Sci.USA 2001,98(16),9371)。禁食导致大鼠前脑中的AEA水平提高,但是在其它脑部区域则未见,这提供了AEA生物合成激励可以在解剖学上区域化到目标CNS通道的证据(Kirkham,Br.J.Pharmacol.2002,136,550)。AEA升高在大脑内局部发生而不是全面发生的发现暗示,用小分子抑制FAAH能够增强AEA和其它脂肪酸酰胺在下述组织区域中的作用:在该组织区域中,在特定病理学条件下发生这些信号分子的合成和释放(Piomelli,2003)。
除了FAAH抑制剂对AEA和其它外源性大麻素的效果之外,其它脂质介质的FAAH分解代谢的抑制剂可以用于处理其它治疗征兆。例如,PEA已经显示了在炎症、免疫抑制、止痛和神经保护的动物模型中的效果(Ueda,J.Biol.Chem.2001,276(38),35552)。油酰胺(另一种FAAH基体)诱导睡眠(Boger,Proc.Natl.Acad.Sci.USA 2000,97(10),5044;Mendelson,Neuropsychopharamacology 2001,25,S36)。
在文献中已经公开了一些不同用途的哌嗪基和哌啶基衍生物。例如,JP 11139969描述了某些苯酚衍生物作为抗氧化剂和ACAT抑制剂;WO 96/21648公开了各种哌嗪衍生物作为抗肿瘤剂;JP 48010160描述了某些哌嗪衍生物作为消炎药;WO 04/072025公开了某些取代的N-芳基杂环作为肥胖、糖尿病以及药物滥用药剂;DE 2123784和美国专利3,813,395公开了各种哌嗪基噻唑并苯并硫氮杂(piperazinylthieno-benzothiazepine)作为精神药物和麻醉药;wO98/37077和WO 99/42107描述了某些基于哌嗪的混合物作为治疗骨亏失的降钙素模拟物。此外,WO 97/42230描述了某些哌嗪脲的固相合成。WO 97/23458公开了某些哌啶衍生物作为NMDA受体配体的中间体。此外,已经报道了各种小分子FAAH调节剂,例如,在WO04/033652、US 6,462,054、US 6,096,784、WO 99/26584、WO 97/49667和wO 96/09817中。然而,仍然需要具有理想药学性质的其它有效的FAAH调节剂。
发明内容
现在,已经发现了某些哌嗪基或哌啶基衍生物具有FAAH-调节活性。
特别是,在一个一般方面,本发明涉及下式(I)的化合物或其药学可接受的盐、药学可接受的前药或所述化合物的药学活性代谢产物:
其中:
·Z是-N-或>CH;
·R1是-H或-C1-4烷基;
·Ar1是2-噻唑基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基或苯基,每个基团是未取代的或者在碳环成员上被一个或两个Ra部分所取代;
其中每个Ra部分独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自独立地是-H或-C1-4烷基;且
·Ar2是:
(a)未取代的1-萘基;或者菲基、芘基、芴基、2-萘基或N-Rd-9H-咔唑基部分,其中Rd选自-H、-C1-4烷基和苯基,每个所述部分均是未取代的或者被1个、2个或3个Re取代基所取代,
其中每个Re取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自如前所定义(每个均独立地选自-H或-C1-4烷基);
(b)在两个相邻的环碳原子处与选自下述的基团稠合形成稠环结构的苯基:具有0或1个双键的-(CH2)3-5-、-(CH2)2-3O-、-OCH2CH2O-和-OCF2O-;或者在相邻的碳原子上被-OCH2O-所取代的苯基(形成4-苯并[1,3]二氧戊环基);每个苯基部分进一步是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(c)Ar6,在这里Ar6是6-元单环杂芳基,其具有作为连接点的碳原子,具有一个或两个氮杂原子(-N=),是未取代的或者被1个、2个或3个如前所定义的Re取代基所取代;
(d)Ar5,在这里Ar5是5-元单环杂芳基,其具有作为连接点的碳原子,具有一个选自O、S、>NH和>NRf的杂原子,其中Rf是C1-8烷基或C0-3苯基烷基,其具有0个、1个、2个或3个另外的氮杂原子(-N=),是未取代的或者被1个、2个或3个如前所定义的Re取代基所取代;
(e)具有一个选自N、O和S的杂原子的9-元或10-元稠合二环杂芳基,其具有作为连接点的碳原子,并任选具有多达四个另外的被氮置换的碳原子,所述稠合二环杂芳基具有不多于5个杂原子,其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(f)在3-位或4-位上被Rg取代的苯基,其任选地进一步被1个、2个或3个取代基Rh所取代,
其中每个Rg独立地选自任选被-NRiRj取代的-C2-8烷基、-C2-8烯基、-OC3-8环烷基、-OC3-8杂环烷基和-O-C2-10烷基,其中Ri和Rj各自独立地是-H或-C1-8烷基,或者Ri和Rj与所连接的氮环原子一起形成5-元、6-元或7-元杂环烷基环,该杂环烷基环上一个另外的碳环原子任选被O、S、>NH或者>NC1-4烷基代替;并且
每个Rh取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(g)在3位或4位上被-L-Ar3取代的苯基,其中:
·L是选自-(CH2)1-3-、-CH=CH-、-O-、-OCH2、-CH2O-、NH、>NC1-4烷基、>S(=O)0-2、-OSO2、-C≡C-、-C(=O)-和共价键的连接子;且
·Ar3是选自下列的部分:
(1)苯基、萘基和菲基,
(2)Ar6’,其中Ar6’是具有作为连接点的碳原子的6-元单环杂芳基,其具有一个或两个氮杂原子(-N=),
(3)Ar5’,其中Ar5’是具有作为连接点的碳原子的5-元单环杂芳基,其具有一个选自O、S、>NH和>NRf的杂原子,其中Rf是-C1-8烷基或-C0-3苯烷基,且Ar5’具有0个、1个、2个或3个另外的氮杂原子(-N=),以及
(4)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有作为连接点的碳,该杂芳基任选具有多达四个被氮代替的另外的碳环原子,所述稠合双环杂芳基具有不多于5个杂原子;
其中部分(1)-(4)中的每个均任选在相邻的碳上被下述基团双取代以形成稠环结构:-OC1-4亚烷基-O-、-(CH2)2-3NH-、-(CH2)1-2NH(CH2)-、-(CH2)2-3N(C1-4烷基)-或-(CH2)1-2N(C1-4烷基)(CH2)-端,并且进一步任选地被1个、2个或3个取代基Rk所取代,
其中每个Rk取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(h)2-羟基苯基或2-甲氧基苯基,其是未取代的或者被1个、2个或3个R1取代
其中每个R1取代基独立地选自-CH3、6-C2-4烷基、6-C2-4烯基、-OH、-OCH3、6-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(i)4-卤代苯基,其是未取代的或者被一个、两个或三个Rm取代基所取代,
其中每个Rm取代基独立地选自-CH3、2-C2-4烷基、2-C2-4烯基、3-羟基、4-羟基、-OCH3、2-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;或者
(j)2-溴苯基、3-甲基苯基、3-甲氧基苯基、4-甲氧基苯基或3,4-二甲氧基苯基;
其中当Ar2是4-氟苯基、3,4-二氟苯基、4-氯苯基或3-甲氧基苯基时,Ar1不是未取代的苯基或者被4-C1、-NO2、-CF3或4-CO2Et取代的苯基;并且
当Ar2是3,4-二氯苯基时,Ar1不是被4-Cl、-NOC2-CF3或4-CO2Et取代的苯基。
在优选实施方式中,式(I)的化合物是以下详细说明中具体描述或例举的化合物。
在另一个一般方面,本发明涉及各自包括下述成分的药物组合物:(a)有效量的选自式(I)的化合物及其药学可接受的盐、药学可接受的前药和药学活性代谢产物的药剂;以及(b)药学可接受的赋形剂。
在另一个一般方面,本发明涉及一种治疗患有或被诊断有由FAAH活性介导的疾病、障碍或医学症状的方法,该方法包括对需要这种治疗的对象给予有效量的式(I)的化合物或其药学可接受的盐、药学可接受的前药或这种化合物的化学活性代谢产物,其中:
·Z如前所定义;
·R1如前所定义;
·Ar1如前所定义;且
·Ar2是:
(a)菲基、芘基、芴基、萘基或N-Rd-9H-咔唑基部分,其中Rd选自-H、-C1-4烷基和苯基,每个所述部分是未取代的,或者被1个、2个或3个Re取代基所取代,
其中每个Re取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义(各自独立地是-H或-C1-4烷基);
(b)在两个相邻的碳原子处与选自下列的基团稠合以形成稠环结构的苯基:具有0或1个双键的-(CH2)3-5-、-(CH2)2-3O-、-OCH2CH2O-、-OCF2O-和-OCH2O-,其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(c)Ar6,其中Ar6是具有碳作为连接点的6-元单环杂芳基,其具有1个或2个氮杂原子(-N=),其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(d)Ar5,其中Ar5具有碳作为连接点的5-元单环杂芳基,其具有1个选自O、S、>NH和>NRf的杂原子,其中Rf是C1-8烷基或C0-3苯基烷基,该杂芳基具有0个、1个、2个或3个另外的氮杂原子(-N=),其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(e)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有碳原子作为连接点,并任选具有多达四个另外的被氮置换的碳环原子,所述稠合二环杂芳基具有不多于5个杂原子,其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(f)在3-位或4-位上被Rg代的苯基,其任选地被1个、2个或3个取代基Rh所取代,
其中每个Rg独立地选自任选被-NRiRj代的-C2-8烷基、-C2-8烯基、-OC3-8环烷基、-OC3-8杂环烷基和-O-C2-10烷基,其中Ri和Rj各自独立地是-H或-C1-8烷基,或者Ri和Rj与所连接的氮环原子一起形成5-元、6-元或7-元杂环烷基环,该杂环烷基环上一个另外的碳环原子任选被O、S、>NH或者>NC1-4烷基代替;并且
每个Rh取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(g)在3位或4位上被-L-Ar3取代的苯基,其中:
·L是选自-(CH2)1-3-、-CH=CH-、-O-、-OCH2、-CH2O-、NH、>NC1-4烷基、>S(=O)0-2、-C≡C-、-C(=O)-和共价键的连接子;且
·Ar3是选自下列的部分:
(1)苯基、萘基和菲基,
(2)Ar6’,其中Ar6’是具有作为连接点的碳原子的6-元单环杂芳基,其具有一个或两个氮杂原子(-N=),
(3)Ar5’,其中Ar5’是具有作为连接点的碳原子的5-元单环杂芳基,其具有一个选自O、S、>NH和>NRf的杂原子,其中Rf是-C1-8烷基或C0-3苯烷基,且Ar5’具有0个、1个、2个或3个另外的氮杂原子(-N=),以及
(4)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有作为连接点的碳,该杂芳基还任选具有多达四个被氮代替的另外的碳环原子,所述稠合双环杂芳基具有不多于5个杂原子;
其中部分(1)-(4)中的每个均任选在相邻的碳上被下述基团双取代以形成稠环结构:-OC1-4亚烷基-O-、-(CH2)2-3NH-、-(CH2)1-2NH(CH2)-、-(CH2)2-3N(C1-4烷基)-或-(CH2)1-2N(C1-4烷基)(CH2)-,并且进一步任选地被1个、2个或3个取代基Rk所取代,
其中每个Rk取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(h)2-羟基苯基或2-甲氧基苯基,其是未取代的或者被1个、2个或3个R1取代,
其中每个R1取代基独立地选自-CH3、6-C2-4烷基、6-C2-4烯基、-OH、-OCH3、6-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(i)4-卤代苯基,其是未取代的或者被一个、两个或三个Rm取代基所取代,
其中每个Rm取代基独立地选自-CH3、2-C2-4烷基、2-C2-4烯基、3-羟基、4-羟基、-OCH3、2-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;或者
(j)2-溴苯基、3-甲基苯基、3-甲氧基苯基、4-甲氧基苯基或3,4-二甲氧基苯基。
在本发明的方法的某个具体实施方式中,疾病、障碍或医学症状选自:焦虑、疼痛、睡眠障碍、摄食障碍、炎症、多发性硬化和其它移动障碍、HIV消耗综合征、封闭型颅脑损伤、中风、阿尔茨海姆氏症、癫痫、抽动秽语综合征、尼曼-匹克病、帕金森氏病、亨廷顿舞蹈病、视神经炎、自体免疫性葡萄膜炎、药物戒断的症状、恶心、呕吐、性功能障碍、创伤后应激障碍、脑血管痉挛、青光眼、肠易激综合征、炎性肠病、免疫抑制、胃肠道逆流疾病、麻痹性肠梗阻、分泌性腹泻、胃溃疡、类风湿性关节炎、意外妊娠、高血压、癌、肝炎、过敏性气管病、自体免疫性糖尿病、顽固性瘙痒、以及神经炎。
通过以下详细说明以及所附权利要求,本发明的其它实施方式、特征和优点将会是显而易见的。
具体实施方式
参考以下说明,包括以下术语词汇表和所包含的实施例,可以更全面地理解本发明。为简单起见,本说明书所引用的公开出版物的公开内容通过引用并入本文。
如这里所使用的,术语“包括”、“包含”和“含有”在这里以起开放的、无限制的方式使用。
术语“烷基”是指链中具有1至12个碳原子的直链或支链烷基。示例性的烷基包括甲基(Me,其在结构上也可以用“/”描绘)、乙基(Et)、正丙基、异丙基、丁基、异丁基、仲丁基、叔丁基(tBu)、戊基、异戊基、叔戊基、己基、异己基等。
术语“亚烷基”是指链中具有1至12个碳原子的二价直链或支链烷基。示例性的亚烷基包括亚甲基、亚乙基、亚丙基等。
术语“烯基”是指链中具有2至12个碳原子的直链或支链烯基。(烯基的双键由两个sp2杂化的碳原子形成。)说明性的烯基包括丙-2-烯基、丁-2-烯基、丁-3-烯基、2-甲基丙-2-烯基、己-2-烯基等。
术语“炔基”是指链中具有2至12个碳原子的直链或支链炔基。(炔基的三键由两个sp杂化的碳原子形成。)说明性的炔基包括丙-2-炔基、丁-2-炔基、丁-3-炔基、2-甲基丁-2-炔基、己-2-炔基等。
术语“芳基”是指每个环具有3到12个环原子的单环或者稠多环或螺多环的芳族碳环(环结构中的环原子全都是碳)。(芳基中的碳原子是sp2杂化的。)说明性的芳基例子包括下述部分等:
术语“杂芳基”是指每个环具有3到12个环原子的单环或者稠双环或螺双环或者稠多环或螺多环的芳族杂环(环结构中的环原子选自碳原子以及氮、氧和硫杂原子。)说明性的杂原子例子包括下述部分等:
术语“环烷基”是指每个环具有3到12个环原子的饱和或部分饱和的单环或者稠多环或螺多环的碳环。说明性的环烷基例子包括下述部分等:
“杂环烷基”是指每个环具有3到12个环原子的饱和或部分饱和的单环或者稠多环或螺多环的环结构,其中的环原子选自C原子以及N、O和S杂原子。说明性的杂环烷基例子包括下述基团等:
术语“卤素”表示氯、氟、溴或碘。术语“卤代”表示氯代、氟代、溴代或碘代。
术语“取代”是指特定基团或部分带有一个或多个取代基。术语“未取代”表示特定基团不带有取代基。术语“任选取代”表示特定基团是未取代的或者被一个或多个取代基取代。当术语“取代”用于描述结构系统时,可以在结构上任何化合价允许的位置发生取代。
式(I)意欲表示具有结构式所描绘的结构的化合物以及某些变体或形式。特别是,式(I)的化合物可以具有不对称中心,因此存在不同的对映异构形式。该通式的化合物的所有光学异构体和立体异构体及其混合物均被视为处于该式的范围内。因此,式(I)意欲表示外消旋体、一种或更多种对映异构形式、一种或更多种非对映形式、以及它们的混合物。
而且,式(I)所描绘的某些结构可以作为几何异构体或(即,顺式和反式异构体)或者互变体存在。此外,式(I)意欲表示这种化合物的水合物、溶剂合物和多晶型物及其混合物。
式(I)还意欲表示该化合物的未标记形式以及同位素标记形式。除了一个或更多个原子被原子量或质量数与自然界中通常发现的原子量或质量数不同的原子代替之外,同位素标记的化合物具有式(I)所描绘的结构。可以加入到本发明的化合物中的同位素的例子分别包括氢、碳、氮、氧、硫、磷、氟和氯的同位素,例如2H、3H、11C、13C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。各种同位素标记的本发明的化合物,例如其中加入了放射性同位素如3H、11C和14C的化合物,可用于药物或基体组织分布分析。特别优选氚(即,3H)和碳-14(即,14C)同位素,因为它们容易制备和检测。此外,用较重的同位素如氘(即,2H)取代可以提供由更大的代谢稳定性所带来的治疗优势,例如体内半衰期延长或需要的剂量减少。同位素标记的本发明的化合物及其前药通常可以通过下述方式制备:进行实施方式或实施例中公开的过程,或通过用容易获得的同位素标记试剂取代非同位素标记试剂而进行下述制备。
当参考式(I)时,为指定变量,从可能物种的列表中选择具体部分不意味限定出现在其它位置的变量的部分(moiety)。换句话说,当一个变量出现多于一次时,从指定列表选择物种与为式中其它位置的相同变量选择物种无关。
在式(I)的化合物的优选实施方式中,变量Z是-N-。
在另一个优选实施方式中,变量R1是-H、甲基、乙基、异丙基、丙基或叔丁基。更优选,R1是-H。或者,R1是甲基。
优选Ar1是2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基或4-嘧啶基,它们各自是未取代的、或者被如前所定义的一个或两个Ra在环碳原子上取代。或者,Ar1是2-噻唑基。在一个可选实施方式中,Ar1是未取代的苯基或者被一个或两个如前所定义的Ra在碳环原子上取代的苯基。当Ar1是被一个或更多个Ra取代的2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基或苯基时,优选每个Ra独立地选自甲基、乙基、异丙基、叔丁基、乙烯基、烯丙基、羟基、甲氧基、乙氧基、异丙氧基、氟、溴、氯、碘、-CF3、-OCF3、甲基硫烷基、甲基亚磺酰基、甲基磺酰基、乙基磺酰基、异丙基磺酰基、甲磺酰氧基、甲酯基、-CO2H、乙酰基、丙酰基、氨基、甲基氨基、二甲基氨基、乙基甲基氨基、-SO2NH2、-SO2NHCH3、-NHSO2CH3、-C(=O)NH2、-C(=O)NHCH3、-NO2和CN。更优选,Ra独立地选自氟、溴、碘、甲氧基、甲基、甲酯基和羧基。在一些优选实施方式中,Ar1是2-氟苯基、3-氟苯基、4-氟苯基、2,4-二氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-甲苯基、3-甲苯基、4-甲苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-甲酯基苯基、3-甲酯基苯基、4-甲酯基苯基、2-羧基苯基、3-羧基苯基或未取代的苯基。
优选变量Ar2上被指定为“Re”的取代基是甲基、乙基、异丙基、叔丁基、乙烯基、烯丙基、羟基、甲氧基、乙氧基、异丙氧基、氟、溴、氯、碘、-CF3、-OCF3、甲基硫烷基、甲基亚磺酰基、甲基磺酰基、乙基磺酰基、异丙基磺酰基、甲磺酰氧基、甲酯基、-CO2H、乙酰基、丙酰基、氨基、甲基氨基、二甲基氨基、乙基甲基氨基、-SO2NH2、-SO2NHCH3、-NHSO2CH3、-C(=O)NH2、-C(=O)NHCH3、-NO2或CN。
优选Ar2是菲-9-基、芘-1-基、9H-芴-2-基、1-萘基、2-萘基、1-羟基萘-2-基、6-甲氧基萘-2-基、9-乙基-9H-咔唑-3-基、呋喃基、唑基、异唑基、1,2,3-二唑基、1,2,4-二唑基、1,2,5-二唑基、1,3,4-二唑基、噻吩基、噻唑基、异噻唑基、吡咯基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、四唑基、吲哚基、苯并呋喃基、苯并噻吩基、苯并唑基、苯并噻唑基、苯并咪唑基、吲唑基、咪唑并[1,2-a]吡啶基、吡咯并[1,5-a]吡啶基、1H-吡咯并[3,2-b]吡啶基、1H-吡咯并[2,3-b]吡啶基、1H-吡咯并[3,2-c]吡啶基、1H-吡咯并[2,3-c]吡啶基、1H-吡咯并[3,2-b]吡啶基、异喹啉基、喹啉基、喹噁啉基、喹唑啉基、茚满基、茚基、四氢化萘基、2,3-二氢-苯并呋喃基、苯并二氢吡喃基、2,3-二氢-苯并[1,4]二噁烯基(dioxinyl)、以及2,2-二氟-苯并[1,3]间二氧杂环戊烯基(dioxolyl)、嘧啶基、吡嗪基或吡啶基,它们各自是为取代的或者被一个、两个或三个如前所定义的Re取代。
更优选,Ar2是1-苯基-1H-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基或6-溴-吡啶-2-基,它们各自是未取代的或者被一个、两个或三个如前所定义的Re取代基所取代。在其它更优选的实施方案中,Ar2是未取代的2,2-二氟-苯并[1,3]间二氧杂环戊烯基或未取代的4-苯并[1,3]间二氧杂环戊烯基。更优选,Ar2是2-吲哚基、3-吲哚基、2-喹啉基、3-喹啉基或2-喹啉基,它们各自是未取代的或者被一个、两个或三个如前所定义的Re取代基所取代。甚至更优选,Ar2是2-喹啉基或3-喹啉基。
在另外可选的实施方式中,Ar2是在3-位或4-位被选自下述基团的部分取代的苯基:乙基、丙基、异丙基、丁基、异丁基、戊基、己基、辛基、乙烯基、烯丙基、环丙氧基、环丁氧基、环戊氧基、环己氧基、环庚氧基、2-二甲基氨基乙氧基、2-二甲基氨基丙氧基、4-哌啶氧基、乙氧基、丙氧基、异丙氧基、异丁氧基、戊氧基、己氧基、庚氧基、辛氧基、壬氧基、癸氧基、2-哌啶-1-基乙氧基和3-哌啶-1-基丙氧基。
优选Ri和Rj各自独立地选自氢、甲基、乙基、丙基、异丙基、丁基、异丁基和叔丁基。
或者,Ri和Rj与所连接的氮原子一起形成选自下述基团的环:吡咯烷基、吡唑啉基、哌啶基、高哌啶基、azepanyl、四氢呋喃基、四氢吡喃基、哌嗪基、吗啉基和硫代吗啉基。
优选Ar2是4-乙苯基、4-异丙苯基、3-乙烯苯基、3-乙氧基苯基、4-乙氧基苯基、3-丙氧基苯基、4-丙氧基苯基、3-异丁氧基苯基、4-异丙氧基苯基、3-异丁氧基苯基、4-异丁氧基苯基、4-环己氧基苯基、3-(2-二甲基氨基乙氧基)苯基、3-(2-哌啶-1-基乙氧基)苯基、3-(3-二甲氧基氨基丙氧基)苯基、或3-(3-哌啶-1-基丙氧基)苯基。
优选L是亚甲基、亚乙基、亚丙基、链亚烯基、-O-、亚甲基氧基、-NH->NC1-4烷基、-S-、-S(=O)-、-S(=O)2-、-OSO2-、链亚炔基或共价键。更优选L是-CH=CH-、-O-、-OCH2-、-SO2-、-OSO2-或共价键。
优选Ar3是苯基、萘基、菲基、吡啶基、嘧啶基、吡嗪基、呋喃基、噁唑基、异噁唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噻吩基、噻唑基、异噻唑基、吡咯基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、四唑基、吲哚基、苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并咪唑基、吲唑基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、1H-吡咯并[3,2-b]吡啶基、1H-吡咯并[2,3-b]吡啶基、1H-吡咯并[3,2-c]吡啶基、1H-吡咯并[2,3-c]吡啶基、1H-吡咯并[3,2-b]吡啶基、异喹啉基、喹啉基、喹噁啉基或喹唑啉基。
更优选A3是苯基、4-氯苯基、3,4-二氯苯基、4-甲苯基、4-叔丁苯基、3-三氟甲基苯基、4-甲氧基苯基、3,5-二氯苯基、1-萘基、2-萘基、3-氯苯基、9-菲基、4-甲酯基苯基、4-甲磺酰基苯基、3-甲氧基苯基或苯并[1,3]二氧戊环-5-基。
优选Ar2是未取代的2-羟基苯基,或者是被选自下列基团的部分所取代的2-羟基苯基:甲基、6-乙基、6-异丙基、6-叔丁基、6-乙烯基、6-烯丙基、羟基、甲氧基、6-乙氧基、6-异丙氧基、氟、溴、氯、碘、-CF3、-OCF3、甲基硫烷基、甲基亚磺酰基、甲基磺酰基、乙基磺酰基、异丙基磺酰基、甲酯基、-CO2H-、乙酰基、丙酰基、氨基、甲基氨基、二甲基氨基、乙基甲基氨基、-SO2NH2、-SO2NHCH3、-NHSO2CH3-、-C(=O)NH2-、-C(=O)NHCH3-、-NO2-和-CN。或者,Ar2是任选如上取代的2-甲氧基苯基。
更优选,Ar2是2-羟基苯基、5-溴-2-羟基-3-甲氧基苯基、或5-溴-2-羟基苯基。
优选Ar2是未取代或者被选自下述基团的部分取代的4-卤代苯基:甲基、2-乙基、2-异丙基、2-叔丁基、2-乙烯基、2-烯丙基、3-羟基、4-羟基、甲氧基、2-乙氧基、2-异丙氧基、氟、溴、氯、碘、-CF3、-OCF3、甲基硫烷基、甲基亚磺酰基、甲基磺酰基、乙基磺酰基、异丙基磺酰基、甲酯基、-CO2H-、乙酰基、丙酰基、氨基、甲基氨基、二甲基氨基、乙基甲基氨基、-SO2NH2、-SO2NHCH3、-NHSO2CH3-、-C(=O)NH2-、-C(=O)NHCH3-、-NO2-和-CN;且Ar1是苯基。
更优选Ar2是3,4-二溴苯基、3-溴-4-氟苯基、或4-氯-3-三氟甲基。或者Ar2是3,4-二氯苯基。
甚至更优选,Ar2是3,4-二溴苯基。
本发明优选的化合物包括下列:
4-萘-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[b]噻吩-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-碘-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(5-溴-2-羟基-3-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-溴-4-氟-苄基)-哌嗪-1-羧酸苯基酰胺;
4-茚满-5-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[b]噻吩-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-异丙基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-乙基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(5-溴-2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2,3-二氢-苯并[1,4]二氧芑-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2,3-二氢-苯并呋喃-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(3-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-萘-1-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-甲基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-吡啶-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-吡啶-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-吡啶-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-异丙氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-联苯-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-喹啉-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[1,3]二氧戊环-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(6-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(8-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(2-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-萘-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺;;
4-(1-羟基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(3-对甲苯氧基苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-叔丁基苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-三氟甲基-苯氧基)苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-甲氧基-苯氧基)-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(6-甲氧基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(菲-9-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-芘-1-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(6-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-联苯-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(6-溴-吡啶-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-氯-苯磺酰基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2-氯-8-甲基-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(3,5-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(9H-芴-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(9-乙基-9H-咔唑-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苯乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-氯-3-三氟甲基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[2,5-二甲基-1-(3-三氟甲基-苯基)-1H-吡咯-3-基甲基]-哌嗪-1-羧酸苯基酰胺;
4-(2-溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸间甲苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-甲氧基-苯基)酰胺;
4-(3,4-二-溴-苄基)-哌嗪-1-羧酸(2-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸对甲苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸邻甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸邻甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸对甲苯基酰胺;
2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸间甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2,4-二氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氟-苯基)酰胺;
4-苄基-哌啶-1-羧酸对甲苯基酰胺;
4-苄基-哌啶-1-羧酸间甲苯基酰胺;
4-苄基-哌啶-1-羧酸(2-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-4-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-2-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-3-基酰胺;
4-(4-环己氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-丙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-异丁氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-乙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(4-丙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(4-异丁氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-[3-(2-二甲基氨基-乙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(2-哌啶-1-基-乙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-二甲基氨基-丙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(4-乙氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(菲-9-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)苯氧基]-苯甲酸甲酯;
4-[3-(4-甲磺酰基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(苯并[1,3]二氧戊环-5-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
甲磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
4-氯-苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸钾盐;
3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸钾盐;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺;
4-喹啉-3-基甲基-哌嗪-l-羧酸吡啶-4-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-l-羧酸吡啶-4-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡啶-3-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡啶-4-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
4-喹喔啉-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二氯-苄基)-哌嗪-1-羧酸苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸噻唑-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸噻唑-2-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸甲基苯基酰胺;
4-(2-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-苯并呋喃-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-硝基苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-三氟甲基-苯基)酰胺;
4-(5-溴-2-羟基-3-甲氧基-苯基)-哌嗪-1-羧酸苯基酰胺盐酸盐;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸苯基酰胺盐酸盐;
4-喹啉-2-基甲基-哌嗪-1-羧酸苯基酰胺二盐酸盐;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸苯基酰胺盐酸盐;以及
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸(4-氟-苯基)酰胺。
本发明还包括式(I)所表示的化合物(例如上述那些化合物)的药学可接受的盐。特别优选这里列举的具体化合物的药学可接受的盐。
“药学可接受的盐”是指式(I)的化合物的游离酸或碱盐,其不是有毒的、生理学不可耐的、或者其它生物学不期望的情况。一般参见,例如,S.M.Berge等,“Pharmaceutical Salts”,J.Pharm.Sci.,1977,66:1-19,以及Handbook of Pharmaceutical Salts,Propertions,Selection,and Use;Stah1,P.H.,Wermuch,C.G.,Eds;Wiley-VCH and VHCA;Zurich,2002。优选的药学可接受的盐是那些药理学有效且适于与患者组织接触而不会有过分毒性、刺激或变态反应的盐。式(I)的化合物可以具有足够酸性的基团和/或足够碱性的基团,从而与多种无机或有机碱、以及无机或有机酸反应,形成药学可接受的盐。示例性的药学可接受的盐包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯代苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、γ-羟丁酸盐、羟乙酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐和杏仁酸盐。
如果式(I)的化合物含有碱性氮,则理想的药学可接受的盐可以通过本领域可用的任何合适方法制备,例如,用下述酸处理游离碱:无机酸,例如盐酸、氢溴酸、硫酸、氨基磺酸、硝酸、硼酸、磷酸等;有机酸,例如乙酸、苯乙酸、丙酸、硬脂酸、乳酸、抗坏血酸、马来酸、羟基马来酸、羟基乙磺酸、琥珀酸、戊酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、油酸、棕榈酸、月桂酸。吡喃糖苷(pyranosidyl)酸例如葡糖醛酸或半乳糖醛酸,α-羟基酸,例如杏仁酸、柠檬酸或酒石酸,氨基酸,例如天冬氨酸或谷氨酸,芳香酸,例如苯甲酸、2-乙酰苯甲酸、萘甲酸或肉桂酸,磺酸,例如月桂基磺酸、对甲苯磺酸、甲磺酸或乙磺酸;等等。
如果式(I)的化合物是酸,例如羧酸或磺酸,则理想的药学可接受的盐可以通过任何合适的方法制备,例如用无机或有机碱来处理游离酸,例如胺(伯胺、仲胺或叔胺)、碱金属氢氧化物或碱土金属氢氧化物等。合适的盐的说明性例子包括衍生自下述物质的有机盐,例如,氨基酸如甘氨酸和精氨酸、氨、碳酸盐、碳酸氢盐、伯胺、仲胺、叔胺、以及环胺如苯甲胺、吡咯烷、哌啶、吗啉和哌嗪;以及衍生自下列物质的无机盐:钠、钙、钾、镁、锰、铁、铜、锌、铝和锂。
本发明还涉及采用式(I)化合物的药学可接受的前药的治疗方法。术语“前药”是指特指化合物的前体,其在对个体给药后,在体内经由化学或生理学过程如溶剂分解或经生理学条件得到该化合物(例如,前药在生理pH下转化为式(I)的化合物)。“药学可接受的前体”是这样的前体:其不是有毒的、生理学不可耐的、或者其它方式在生理学上不适于对个体给药的物质。选择和制备合适的前药衍生物的说明性程序如,例如,“Design of Prodrugs”,ed.H.Bundgaard,ElseVier,1985。
示例性的前药包括具有通过酰胺或酯键共价连接到式(I)的化合物的游离氨基酸、羟基或羧酸基团上的氨基酸残基、或者两个或更多个(例如,两个、三个或四个)氨基酸残基的多肽链的化合物。氨基酸残基的例子包括通常用三个字母符号标识的二十种天然氨基酸以及4-羟基脯氨酸、羟基赖氨酸、锁链素(demosine)、异锁链素(isodemosine)、3-甲基组氨酸、正缬氨酸、β-丙氨酸、γ-氨基丁酸、瓜氨酸高半胱氨酸、高丝氨酸、鸟氨酸和甲硫氨酸砜。
其它类型的前药可以通过,例如,将式(I)结构的游离羧基衍生为酰胺或烷基酯来制备。示例性的酰胺包括那些衍生自氨、C1-6烷基伯胺和二(C1-6烷基)仲胺的酰胺。仲胺包括具有1-3个杂原子的5-元或6-元杂环烷基或杂芳基环部分,这些杂原子中至少有一个是氮原子。优选的酰胺衍生自氨、C1-3烷基伯胺和二(C1-2)烷基仲胺的酰胺。本发明示例性的酯包括C1-7烷基酯、C5-7碳环基酯、苯基酯和苯基(C1-6烷基)酯。优选的酯包括甲酯。前药还可以通过下述方式制备:按照在例如Adv.Drug Delivery Rev.1996,19,115中列出的那些程序,使用包括半琥珀酸酯、磷酸酯、二甲基氨基乙酸酯和磷酰氧基甲氧基羰基的基团来衍生游离羟基。羟基和氨基基团的氨基甲酸衍生物也可以得到前药。羟基的碳酸酯衍生物、磺酸酯和硫酸酯也可以提供前药。羟基的下述衍生物也可以用于得到前药:如(酰氧基)甲基醚和(酰氧基)乙基醚,其中酰基可以是任选被一个或更多个醚、胺或羧酸官能团取代的烷基酯、或者酰基是如上所述的氨基酸酯。这种类型的前药可以如J.Med.Chem.1996,39,10所述地制备。游离胺也可以衍生为酰胺、磺酰胺或磷酰胺。所有这些前药部分可以加入包括醚、胺和羧酸官能团的基团。
药学活性的代谢产物也可以用于本发明的方法中。“药学活性的代谢产物”是指式(I)化合物或其盐的体内代谢的药学活性产物。化合物的前药和活性代谢产物可以使用本领域公知或可用的常规技术来确定。参见,例如,Bertolini等,J.Med.Chem.1997,40,2011-2016;Shan等,J.Pharm.Sci.1997,86(7),765-767;Bagshawe,Drug Dev.Res.1995,34,220-230:Bodor,Adv.Drug Res.1984,13,224-331:Bundgaard,Design of Prodrugs(Elsevier Press,1985);和Larsen,Design andApplication of Prodrugs,Drug Design and Development(Krogsgaard-Larsen等,eds.,Harwood Academic Publishers,1991)。
本发明的式(I)的化合物及其药学可接受的盐、药学可接受的前药和药学活性的代谢产物(统称为“药剂”)在本发明的方法中可用作FAAH抑制剂。这些药剂可以在本发明用于治疗或预防通过抑制或调节FAAH而介导的医学症状、疾病或障碍的方法中使用,例如这里所述的那些医学症状、疾病或障碍。因此,根据本发明的药剂可以用作作为止痛剂、神经保护剂、镇静剂、食欲刺激剂或避孕药。
示例性的医学症状、疾病和障碍包括焦虑、疼痛、睡眠障碍、摄食障碍、炎症、多发性硬化和其它移动障碍、HIV消耗综合征、封闭型颅脑损伤、中风、阿尔茨海姆氏症、癫痫、抽动秽语综合征、癫痫、尼曼-匹克病、帕金森氏病、亨廷顿舞蹈病、视神经炎、自体免疫性葡萄膜炎、药物戒断的症状、恶心、呕吐、性功能障碍、创伤后应激障碍或脑血管痉挛。
因此,该药剂可以用于治疗被诊断有或患有通过FAAH活性介导的障碍或症状的受试者。这里所使用的术语“治疗(treat)”或“治疗(treating)”是指为了通过调节FAAH活性而得到治疗或预防益处的目的而对受试者给予本发明的药剂或组合物。治疗包括恢复、改善、减轻、抑制进展、降低严重程度或预防通过调节FAAH活性而介导的疾病、障碍或症状、或者这些疾病、障碍或症状的一个或更多个病征。术语“受试者”是指需要这种治疗的哺乳动物患者,例如人。“调节剂”包括抑制剂和致活剂,其中“抑制剂”是指降低、阻止、灭活、减敏或者向下调节FAAH表达或活性的化合物,而“致活剂”是提高、激活、促进、敏化或向上调节FAAH表达或活性的化合物。
因此,本发明涉及使用这里所述的药剂来治疗被诊断有或患有通过FAAH活性介导的障碍或症状的方法,这些障碍或症状例如:焦虑、疼痛、睡眠障碍、摄食障碍、炎症或移动障碍(例如,多发性硬化)。
病征或疾病状态意欲被包含在“医学症状、障碍或疾病”中。例如,疼痛可能与多种疾病和障碍有关,并且可能包括多种病因。可用根据本发明的FAAH调节剂治疗的说明性疼痛类型包括癌痛、手术后疼痛、GI tract疼痛、脊髓损伤痛、内脏痛觉过敏、丘脑性疼痛、头痛(包括应激头痛和偏头痛)、下腰痛、颈痛、肌骨痛、末梢神经痛、中枢神经痛、神经发生障碍相关的疼痛、以及痛经。HIV消耗综合征包括例如食欲丧失和恶心的相关病征。帕金森氏病包括,例如,左旋多巴诱导的运动功能障碍。多发性硬化的治疗可以包括对下述病征的治疗:痉挛、神经性疼痛、中枢性疼痛或膀胱功能障碍。药物戒断的症状可以由,例如,鸦片或尼古丁癖而导致。恶心或呕吐可能归因于化疗、术后或与阿片相关的诱因。性功能障碍的治疗可以包括改善性欲或延迟射精。癌症的治疗可以包括治疗神经胶质瘤。睡眠障碍包括,例如,睡眠呼吸暂停、失眠、以及因使用具有镇静或麻醉型作用的药剂进行治疗而导致的障碍。摄食障碍包括,例如,厌食症或与例如癌症或HIV感染/AIDS相关的食欲丧失。
在根据本发明的一个治疗方法中,对患有或被诊断有这样的疾病、障碍或病症的受试者给予有效量的根据本发明的药剂。“有效量”是指足以为需要这种治疗的患者大致带来所需治疗或预防益处的量或剂量。
本发明药剂的有效量或剂量可以通过常规方法(例如建模、剂量应变研究或临床实验)并考虑常规因素(例如,给药或药物输送的模式或途径、药剂的药代动力学、障碍或症状的严重程度和进程、受试者先前或正在进行的治疗、受试者的健康状况和对药物的响应、以及治疗医生的判断)来确定。示例性的剂量范围是每天每千克受试者体重为大约0.001到大约200mg药剂,优选大约0.05到大约100mg/kg/天,或者大约1到大约35mg/kg/天,一次给药或者分剂量给药(例如,BID,TID,QID)。对于70kg的人,合适剂量的说明性范围是大约0.05到大约7g/天,或者大约0.2到大约2.5g/天。
一旦患者的病症有所改善,可以将剂量调整为预防或维持治疗性的。例如,给药的剂量和/或频率可以作为病征的函数而降低到维持所需治疗或预防效果的水平。当然,如果病征已经减轻到合适水平,可以终止治疗。但是,患者可能因病征的任何复发而需要长期的间歇性治疗。
此外,在上述病征的治疗中,本发明的药剂可以与其它活性化合物组合使用。其它化合物可以与式(I)的药剂独立地进行共同给药,或者与这些药剂一起包含而作为本发明的药物组合物中的其它活性成分来共同给药。在一个示例性实施方式中,其它活性化合物是那些已知或被发现在由FAAH介导的病症、障碍或疾病的治疗中有效的化合物,例如另一种FAAH调节剂或对与特定病症、障碍或疾病有关的另一个目标有活性的化合物。组合给药可以用于提高效力(例如,通过在组合中包括强化本发明药剂的效能或有效性的化合物)、降低一种或更多种副作用、或者减少根据本发明的药剂的所需剂量。在一个说明性实施方式中,根据本发明的组合物可以含有一种或更多种选自阿片、NSAID(例如,布洛芬、环氧合酶-2(COX-2)抑制剂和萘普生、加巴喷丁、普瑞巴林、反胺苯环醇、对乙酰氨基酚和阿司匹林的其它活性成分。
本发明的药剂可以单独使用,或者与一种或更多种其它活性成分组合使用。本发明的药物组合物包括:有效量的本发明药剂;以及药学可接受的赋形剂。
“药学可接受的赋形剂”是指这样的物质:其不是有毒的、生理学不可耐的、或者其它方式在生理学上不适于对受试者给药的物质,例如被加入到药物组合物中或以其它方式用作媒介物、载体或稀释剂以促进药剂给药并与其相容的惰性物质。赋形剂的例子包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
含有一个或更多个剂量单位药剂的药物组合物的输送形式可以使用本领域技术人员现在或稍后已知或可用的合适的药物赋形剂和合成技术来制备。组合物在本发明的方法中可以通过口腹、肠胃外、直肠、局部或眼部途径给药,或者通过吸入给药。
制剂可以是片剂、胶囊、药袋、糖衣丸、粉末、颗粒、锭剂、重建用粉末(powder for reconstitution)、液体制剂或栓剂。优选该组合物调制为静脉输注、局部给药或口服给药。
对于口服给药,本发明的化合物可以以片剂或胶囊的形式提供,或者作为溶液、乳剂或悬浮剂提供。为制备口服组合物,药剂可以调制为,例如,每天大约0.05到大约50mg/kg的剂量,或者每天大约0.05到大约20mg/kg的剂量,或者每天大约0.1到大约10mg/kg的剂量。
口服片剂可以包括与药学可接受的赋形剂混合的活性成分,该赋形剂例如惰性稀释剂、崩解剂、粘合剂、润滑剂、甜味剂、香味剂、着色剂和防腐剂。合适的惰性填料包括碳酸钠和碳酸钙、磷酸钠和磷酸钙、乳糖、淀粉、糖、葡萄糖、甲基纤维素、硬脂酸镁、甘露醇、山梨醇等。示例性的液体口服赋形剂包括乙醇、甘油、水等。淀粉、聚乙烯吡咯烷酮(PVP)、羟乙酸淀粉钠、微晶纤维素和藻酸是合适的崩解剂。粘合剂可以包括淀粉和明胶。润滑剂,如果存在,可以是硬脂酸镁、硬脂酸或滑石。如果需要,片剂可以用例如甘油单硬脂酸酯或甘油二硬脂酸酯包被,以延迟在肠胃管中的吸收,或者可以用肠溶衣包被。
口服给药用胶囊包括硬胶囊和软胶囊。为制备硬胶囊,活性成分可以与固体、半固体或液体稀释剂混合。软胶囊可以通过将活性成分与下述物质混合而制备:水、油例如花生油或橄榄油、液体石蜡、短链脂肪酸的单甘油酯或二甘油酯的混合物、聚乙二醇400或丙二醇。
口服给药用液体可以是悬浮剂、溶液、乳剂或糖浆形式,或者可以在使用前用水或其它合适媒介物重新组成的干产品形式操作。这种液体组合物可以任选含有:药学可接受的赋形剂如悬浮剂(例如,山梨醇、甲基纤维素、藻酸钠、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶等);非水媒介物,例如,油(例如,扁桃仁油或精炼椰子油)、丙二醇、乙醇或水;防腐剂(例如,对羟基苯甲酸甲酯或丙酯或者山梨酸甲酯或丙酯);湿润剂,例如卵磷脂;以及,如果需要,香味剂或甜味剂。
本发明的药剂还可以通过非口服途径给药。例如,组合物可以调制为栓剂以直肠给药。对于肠胃外给药(包括静脉、肌内、腹腔内或皮下途径)来说,本发明的药剂可以以被缓冲到合适pH和等渗性的无菌水溶液或悬浮剂形式提供,或者在肠胃外可接受的油中提供。合适的水性媒介物包括林格溶液和等渗氯化钠。这种形式将以单位剂量形式如安瓿或一次性注射装置呈现,或者以多剂量形式如可以从其中抽出合适剂量的小瓶存在,或者作为可用于制备注射制剂的固体形式或预浓缩液而存在。说明性的浸剂剂量范围可以是大约1到1000μg/kg/分钟的药剂,与药物载体在几分钟到几天的时间范围中混合。
对于局部给药,药剂可以与药物载体混合,浓度为大约0.1%到大约10%的药物/媒介物。本发明的药剂的另一种给药模式可以利用贴剂来进行透皮输送。
或者,药剂在本发明的方法中可经由鼻或口途径通过吸入给药,例如,还含有合适载体的喷雾剂。
现在将参考下面的说明性一般制备合成方案以及随后的具体实施例来描述可用于本发明方法的示例性药剂。技术人员将意识到,为获得这里的各种化合物,可以适当地选择起始物料,这样最终希望的取代基将通过根据需要进行或不进行保护的反应方案来实现,从而得到希望的产品。或者,可能必须或需要采用合适的基团来代替最终希望的取代基,这种合适的基团可以通过反应方案获得,并根据需要用希望的取代基取代。除非另外指明,变量如上述对式(I)的定义。
方案A:
参考方案A,式(IV)的化合物可以通过使式(II)的化合物和式(III)的化合物在氯甲酸酯缩合条件下反应而获得,其中Q1表示芳基。在一个优选实施方式中,Q1是取代或未取代的苯基,且反应在碱的存在下在溶剂中在0℃到50℃的温度进行。在特别优选的实施方式中,Q1是苯基,且反应在吡啶的存在下在二氯甲烷中在0℃然后回暖到室温的温度进行。
方案B:
参考方案B,式(VII)的化合物由式(V)的化合物制备。基团Q2是CH2Ar2,或者当Z是N时其是氮保护基Q3。式(VII)的化合物通过使式(v)的化合物与式(VI)的化合物在异氰酸酯加成条件下反应而获得。在优选实施方式中,反应在溶剂中在0℃到100℃的温度进行。优选条件采用室温的二氯甲烷。或者,式(VII)的化合物通过使式(V)的化合物与式(IV)的化合物在氨基甲酸芳基酯缩合条件下反应而获得。在优选实施方式中,反应在温度为室温到120℃的温度在溶剂中发生。在特别优选的实施方式中,Q1是苯基,且反应在DMSO中在微波反应器中在l00℃进行。
方案C:
参考方案C,式(XV)的化合物由式(XI)化合物制备。在方案C中选择与转换相容的合适保护基Q3。优选Q3是叔丁基氨基甲酰基。式(X)的化合物是通过使式(XI)的化合物与式(VI)的化合物或者与式(IV)的化合物反应(如方案B所述地)而获得。式(XIV)的胺是通过在合适的Q3脱保护条件下用试剂对式(X)的化合物脱保护而获得。在特别优选的实施方式中,式(X)的化合物(其中Q3是叔丁基氨基甲酰基)与醚制氯化氢在存在或不存在甲醇的条件下在室温进行。式(XV)的化合物式通过使式(XIV)的化合物与式(XII)的化合物在还原性胺化条件下在还原剂的存在下在溶剂中在0℃到80℃的温度反应而得到的,该还原剂例如三乙酰氧基硼氢化钠、氰基硼氢化钠或苯基甲硅烷,该溶剂例如THF、DCE、DCM、甲醇、乙醇或二乙醚。使用酸性特性的促进剂或催化剂如有机金属配合物或羧酸可以提高反应速度和/或减少副产品的形成。在特别优选的实施方式中,在室温下使用DCE中的三乙酰氧基硼氰化钠。
或者,式(XIII)的化合物通过使式(XI)的化合物与式(XII)的化合物在上述还原性胺化条件下反应而获得。式(XVI)的化合物是通过如上所述在脱保护条件下从式(XIII)的化合物上除去Q3而得到。式(XV)的化合物是通过使式(XVI)的化合物与方案B中所述的式(IV)的化合物或与式(VI)的化合物反应而得到。
方案D:
参考方案D,式(XIXI)的化合物由式(XVII)的化合物制备,其中Q4是CONR1Ar1或氮保护基Q3。式(XVII)的化合物类似于方案C而制备。式(XIX)的化合物是通过使式(XVII)的化合物与式(XVIII)的化合物在Mitsunobu条件下在膦和偶氮二羧酸盐的存在下在有机溶剂中反应而获得,该膦例如三苯基膦或聚合物负载的三苯基膦,该偶氮二羧酸盐例如DBAD或DEAD,该有机溶剂例如DCM、THF等。
方案E:
参考方案E,类似于方案C而制备的式(XVII)的化合物被转化为式(XXI)的化合物,其中Q4是CONR1Ar1或氮保护基Q3。式(XXI)的化合物通过使式(XVII)的化合物与硼酸(XX)在干燥剂如4的粉状分子筛、促进剂如乙酸铜(II)和碱如吡啶或三乙胺的存在下在溶剂如DCM或DCE中反应而得到,其中Ar4是如式(I)所定义的部分Ar3,且直接结合到连接氧原子上。或者,式(XXI)的化合物通过使酚(XVII)与式(XXII)的化合物在如方案D所述的Mitsunobu条件下反应而得到,其中Ar4含有直接结合到连接氧原子上的sp3杂化的碳原子。
方案F:
参考方案F,式(XXIV)的化合物(其中Q4如上所定义)是通过使式(XVII)的化合物(其中Ar3是如式(I)所定义的部分)与式(XXIII)的化合物在碱如吡啶或三乙胺的存在下在溶剂如DCM中在0℃到室温的温度反应而获得的。
方案G:
参考方案G,式(XXV)的化合物(其中Q4如上所定义,且Ar3如式(I)所定义)如方案C中描述地获得。化合物(XXV)通过与式(XXVI)的化合物(其中X1是碘、溴、率或三氟甲磺酸酯)在Heck条件下、在钯源如乙酸钯(II)、膦配体如三苯基膦、任选的促进剂如四丁基氯化铵、以及碱如碳酸钾水溶液的存在下、在溶剂如DMF中反应而转化为式(XXVI)的化合物。
方案H:
参考方案H,式(XXX)的化合物(其中Q4如上所定义)由式(XXVIII)或式(XXXI)(二者均可由方案C制备)的化合物制备。Ar3和X1如上所定义。式(XXX)的化合物通过使式(XXVIII)的化合物与式(XXIX)的化合物在Sonogashira条件下、在含钯实体和碱的存在下在溶剂中在0℃到100℃的温度反应而制备,其中的含钯实体例如钯/碳、Pd2(dba)3、Pd2(dba)3·CHCl3、Pd(PtBu3)2、Pd2(dba)3·CHCl3/Pd(PtBu3)2、Pd(OAc)2、Pd(PhCN)2Cl2或PdCl2,碱例如三乙胺、DIEA、二异丙胺、碳酸钠、碳酸钾或碳酸铯,溶剂例如THF、DME、二氧六环、DCE、DCM、甲苯和乙腈。使用次化学计量(substoichiometric)量的铜盐如CuI和膦配体如PPh3或P(tBu)3可能是必要的或理想的。另外,使用水作为共溶剂可以促进反应和防止形成副产品。
另外,式(XXX)的化合物是通过使式(XXXI)的化合物与式(XXXVI)的化合物使用Sonogashira条件反应而制备的。
方案I:
如上所示,类似于方案C所制备的式(XXXII)的化合物(其中Q4如上所定义)与式(XXXIII)的化合物在碱如氢化钠、以及钯源如四(三苯基膦)钯(0)的存在下、在溶剂如正丁醇中、在室温到116℃的温度反应。
方案J:
参考方案J,式(XL)的化合物由式(XXXV)的化合物制备,其中Q3是氮保护基。选择与方案J所概括的方法相容的保护基Q3,例如苄基。式(XXXVI)的化合物可以由商业来源获得,或者可以遵循本领域已知的方法由合适的溴化物、醇、醛或其他前体制备。式(XXXVII)的化合物是通过用碱如氢化钠在溶剂如DMSO中处理、然后用式(XXXV)的化合物处理式(XXXVI)的化合物而制备的。式(XXXVIII)的化合物是通过在溶剂如甲醇中、在10-100psi氢气的存在下用催化剂如氧化钯(II)处理式(XXXVII)的化合物而制备的。式(XXXIX)的化合物是通过使式(XXXVIII)的化合物与能够除去保护基Q3的试剂反应而制备的。在优选实施方式中,其中Q3是苄基,合适的条件包括在20-100psi氢气的存在下在溶剂如乙醇中的催化剂如钯/碳。式(XL)的化合物是通过使式(XXXIX)的化合物与如方案B所述的式(IV)的化合物或式(VI)的化合物反应而制备的。
提供下述具体实施例以进一步说明本发明和各种优选实施方式。
实施例
化学:
在获得以下实施例所述的特性数据中,如指出的遵循下述分析规约。
在下述条件下进行制备级反相HPLC:设备,Waters;柱,WatersXterra C-18,5μm,19×50mm;流速,30ml/min;检测,λ=254nm;梯度,5%到100%乙腈/水(0.1%甲酸),经8分钟。
在下述条件下进行分析级反相HPLC:设备,Shimadzu;柱,Princeton SPHER HTS,5μm,3×50mm;流速,2.2ml/min;检测,与Finnigan AQA电喷质谱耦联的Sedex 75 ELS;梯度,0.1到100%乙腈/水(0.1%三氟乙酸),经8分钟。
除非另外指明,柱色谱在硅胶上进行,用在MeOH/DCM中的2MNH3洗脱。
质谱在Finnigan AQA上使用电喷离子化(ESI)、根据指示在正模式或负模式中获得。
NMR谱在Varian型号VXR-300S(300MHz)分光计上获得。以下1HNMR数据的格式是:以ppm记的四甲基硅烷参比低磁场中的化学位移(多重峰,以Hz记的耦联常数J,积分)。
当溶液要“浓缩”时,其在旋转蒸发仪中减压浓缩。
实施例1-17描述了用于制备本发明的某些化合物的中间体的合成。
实施例1:4-苯基氨基甲酰基-哌嗪-1-羧酸叔丁酯(中间体)
将哌嗪-1-羧酸叔丁酯(114g)的DCM(500ml)溶液在冰浴中冷却,并用异氰酸苯酯(65ml)处理。1小时(h)后,移开冰浴。15小时后,过滤得到的混和物,并用二氯甲烷(DCM,2×100ml)洗涤固体,得到题述化合物,其是白色无定形固体(95g)。
实施例2:哌嗪-1-羧酸苯基酰胺(中间体)
用2M HCL/Et2O(164ml)处理4-苯基氨基甲酰基-哌嗪-1-羧酸叔丁酯(50g)的MeOH(1L)溶液。48小时后,用Et2O(1L)稀释得到的悬浮液并过滤。用Et2O(3×100ml)洗涤固体并真空干燥,得到白色粉末(32g)。该粉末在DCM(400ml)和10%KOH水溶液(400ml)之间分配。用DCM(2×400ml)萃取水相。合并有机相,干燥(MgSO4)并浓缩,得到题述化合物,其为白色无定形固体(26g)。
实施例3:4-(4-氟-苯基氨基甲酰基)-哌嗪-1-羧酸叔丁酯(中间体)
类似于实施例1,使用异氰酸4-氟苯酯制备题述化合物。
实施例4:哌嗪-1-羧酸(4-氟-苯基)酰胺(中间体)
类似于实施例2,使用4-(4-氟-苯基氨基甲酰基)-哌嗪-1-羧酸叔丁酯制备题述化合物。
实施例5:4-(3,4-二溴-苄基)-哌嗪-1-羧酸叔丁酯(中间体)
用NaB(OAc)3H处理哌嗪-1-羧酸叔丁酯(3.5g)和3,4-二溴苯甲醛(5.0g)的DCM(80ml)溶液。16小时后,用10%KOH水溶液(80ml)处理得到的混和物。用DCM(1×80ml)萃取水相。合并有机提取物并干燥(MgSO4)。浓缩除去大部分溶剂。静置过夜,过滤所得混和物产生的晶体并用DCM(1×5ml)洗涤,得到题述化合物,其是白色晶状固体(6.0g)。
实施例6:1-(3,4-二溴-苄基)-哌嗪(中间体)
用2M HCl/Et2O(28ml)处理4-(3,4-二溴-苄基)哌嗪-1-羧酸叔丁酯(6.0g)的MeOH(100ml)悬浮液。16小时后,用Et2O(100ml)稀释得到的悬浮液并过滤。用Et2O(2×20ml)洗涤固体,并真空干燥,得到白色固体(5.0g)。该固体在10%KOH水溶液(50ml)和DCM(3×50ml)之间分配。合并有机萃取物并干燥(MgSO4),浓缩得到题述化合物,其是无色透明的油。
实施例7:4-喹啉-3-基甲基-哌嗪-1-羧酸-叔丁酯(中间体)
类似于实施例5,使用喹啉-3-甲醛(carbaldehyde)制备题述化合物。
实施例8:3-哌嗪-1-基甲基-喹啉(中间体)
类似于实施例6,使用4-喹啉-3-基甲基-哌嗪-1-羧酸叔丁酯制备题述化合物。
实施例9:4-(3-羟基-苄基)-噻嗪-1-羧酸苯基酰胺(中间体)
向哌嗪-1-羧酸苯基酰胺(2.0g)和3-羟基苯甲醛(3.0g)的DCM(200ml)溶液中加入乙酸(1.1ml),然后分批加入NaB(OAc)3H(6.0g)。反应混和物搅拌过夜。加入10%NaOH水溶液(30ml),直到水相的pH为11。然后加入1N HCl,直到水相pH为6-7。用DCM(200ml)萃取水相。合并有机层,干燥(MgSO4)并浓缩。残留物经色谱得到题述化合物,其是白色固体(2.5g)。
实施例10:4-(4-羟基-苄基)-哌嗪-1-羧酸苯基酰胺(中间体)
类似于实施例9,使用4-羟基苯甲醛制备题述化合物。
实施例11:6-氯-喹啉-2-甲醛(中间体)
将6-氯-2-甲基-喹啉(355mg)和SeO2(233mg)的1,4-二氧六环(3ml)悬浮液在80℃加热16小时。通过硅藻土过滤得到的黑色混和物。浓缩滤液,得到题述化合物为黄色粉末(324mg)。
实施例12:8-氯-喹啉-2-甲醛(中间体)
类似于实施例11,使用8-氯-2-甲基-喹啉制备题述化合物。
实施例13:1-甲基-1H-吲哚-5-甲醛(中间体)
用1,4-二氮杂-二环[2.2.2]辛烷(38mg)处理吲哚-5-甲醛(0.5g)的碳酸二甲酯(5ml)溶液。将得到的混和物加热到90℃并保持5小时,然后冷却到室温(rt)。加入EtOAc(10ml)和水(10ml),并用EtOAc(3×10ml)萃取水相。合并有机萃取物,用盐水(1×20ml)洗涤、干燥(MgSO4)、并浓缩。残留物经色谱(0-50%EtOAc-己烷),得到题述化合物,其是白色固体(46%)。
实施例14:1-甲基-1H-吲哚-6-甲醛(中间体)
类似于实施例13,使用吲哚-6-甲醛制备题述化合物。
实施例15:吡啶-2-基-氨基甲酸苯酯(中间体)
在0℃,向2-氨基吡啶(3.0g)的干THF(30ml)溶液中滴加入氯甲酸苯酯(1.0g,0.8ml),然后再滴入另一批氯甲酸苯酯(1.0g,0.8ml)。使反应混和物回暖到室温。18小时后,用EtOAc(100ml)稀释混和物,并用饱和NaHCO3水溶液(20ml)洗涤。干燥有机相(MgSO4)并浓缩。残留物经色谱得到白色固体(1.7g)。
实施例16:吡啶-3-基-氨基甲酸苯酯(中间体)
类似于实施例15,使用3-氨基吡啶制备题述化合物。
实施例17:吡啶-4-基-氨基甲酸苯酯(中间体)
类似于实施例15,使用4-氨基吡啶制备题述化合物。
实施例18:4-萘-2-基甲基-哌嗪-1-羧酸苯基酰胺
用NaB(OAc)3H(148ml)处理哌嗪-1-羧酸苯基酰胺(103mg)和2-萘甲醛(94mg)的DCM(2ml)溶液。16小时后,用10%KOH水溶液(2ml)处理得到的混和物。用DCM(2×3ml)萃取水相。合并的萃取物干燥(MgSO4)并浓缩。残留物经色谱得到题述化合物,其是白色泡沫(111mg)。
1H NMR(400MHz,CDCl3):7.85-7.80(m,3H),7.74(s,1H),7.52-7.45(m,3H),7.35-7.25(m,4H),7,05-7.00(m,1H),6.37(br s,1H),3.69(s,2H),3.53-3.48(m,4H),2.55-2.49(m,4H)。
类似于实施例18,由哌嗪-1-羧酸苯基酰胺和具体的羰基化合物制备实施例19-84。产品通过过滤反应混和物或者柱色谱分离。
实施例19:4-喹啉-2-基甲基-哌嗪-1-羧酸苯基酰胺
从2-喹啉甲醛制备题述化合物。
1HNMR(400MHz,CDCl3):8.16(d,J=8.4Hz,1H),8.08(d,J=8.4Hz,1H),7.82(d,J=8.1Hz,1H),7.74-7.69(m,1H),7.63(d,J=8.6Hz,1H),7.56-7.51(m,1H),7.36-7.21(m,4H),7.05-7.00(m,1H),6.37(br s,1H),3.89(s,2H),3.55-3.53(m,4H),2.63-2.58(m,4H).
实施例20:4-苯并[b]噻吩-2-基甲基-哌嗪-1-羧酸苯基酰胺
从苯并[b]噻吩-2-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.81-7.79(m,1H),7.71-7.69(m,1H),7.36-7.26(m,6H),7.16(s,1H),7.05-7.01(m,1H),6.32(s,1H),3.83-3.83(m,2H),3.54-3.52(m,4H),2.60-2.57(m,4H)。
实施例2l:4-(3,4-二溴-苄基)-哌嗪-1-羧酸苯基酰胺
从3,4-二溴苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.62(d,J=1.8Hz,1H),7.57(d,J=8.1Hz,1H),7.36-7.25(m,4H),7.14(dd,J=8.0,2.0Hz,1H),7.06-7.01(m,1H),6.36(br s,1H),3.52-3.48(m,4H),3.45(s,2H),2,48-2.44(m,4H)。
实施例22:4-(1-甲基-1H-吲哚-2-基甲基)-哌嗪-1-羧酸苯基酰胺
从1-甲基-1H-吲哚-2-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.56(d,J=7.6Hz,1H),7.34-7.18(m,6H),7.11-7.06(m,1H),7.02-6.98(m,1H),6.49(br s,1H),6.36(s,1H),3.78(s,3H),3.63(s,2H),3,44-3.39(m,4H),2,47-2.42(m,4H),
实施例23:4-喹啉-3-基甲基-哌嗪-1-羧酸苯基酰胺
从3-喹啉甲醛(carboxaldehyde)制备题述化合物。
1HNMR(400MHz,CDCl3):8.91(d,J=2.0Hz,1H),8.15-8.05(m,2H),7.83-7.80(m,1H),7.73-7.68(m,1H),7.59-7.53(m,1H),7.36-7.24(m,4H),7.05-7.00(m,1H),6.50(br s,1H),3.72(s,2H),3.53-3.28(m,4H),2.55-2.50(m,4H)。
实施例24:4-(4-碘-苄基)-哌嗪-1-羧酸苯基酰胺
从4-碘苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.67-7.64(m,2H),7.35-7.26(m,4H),7.10-7.01(m,3H),6.32(s,1H),3.51-3,48(m,6H),2.48-2.45(m,4H)。
实施例25:4-(3-苄氧基-苄基-哌嗪-1-羧酸苯基酰胺
从3-苄氧基苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.45-7,22(m,10H),7.05-6.88(m,4H),6.31(s,1H),5.08(s,2H),3.51-3.47(m,6H),2.48-2.46(m,4H).
实施例26:4-(5-溴-2-羟基-3-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从5-溴-2-羟基-3-甲氧基-苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):10.7(br s,1H),7,32-7,25(7.35-7.25,m,4H),7.06-7.01(m,1H),6.94(d,J=2.0Hz,1H),6.76(d,J=2.0Hz,1H),6.50(br s,1H),3.86(s,3H),3.70(s,2H),3.56-3.50(m,4H),2.60-2.55(m,4H)。
实施例27:4-(4-溴-苄基)-哌嗪-1-羧酸苯基酰胺
从4-溴苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7,47-7.43(m,2H),7.35-7.20(m,6H),7.05-7.00(m,1H),6.35(s,1H),3.51-3.47(m,6H),2.48-2.44(m,4H).
实施例28:4-(3-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从3-苯氧基苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.36-7,26(m,7H),7.13-6.99(m,6H),6.92-6.89(m,1H),6.30(s,1H),3.52-3.48(m,6H),2.49-2.47(m,4H).
实施例29:4-(3-溴-4-氟-苄基)-哌嗪-1-羧酸苯基酰胺
从3-溴-4-氟苯甲醛制备题述化合物。
1HNMR(400MHz,CDCl3):7.55(dd,J=6.6,2.1Hz,1H),7.35-7,21(m,5H),7.07(t,J=8.4Hz,1H),7.05-7.00(m,1H),6.43(br s,1H),3.50-3.45(m,6H),2.47-2.42(m,4H)。
实施例30:4-茚满-5-基甲基-哌嗪-1-羧酸苯基酰胺
从茚满-5-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7,35-7.00(m,8H),6.30(s,1H),3.51-3.47(m,6H),2.92-2.88(m,4H),2.50-2.47(m,4H),2.12-2.04(m,2H).
实施例31:4-苯并[b]噻吩-3-基甲基-哌嗪-1-羧酸苯基酰胺
从苯并[b]噻吩-3-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.00-7.98(m,1H),7.88-7.85(m,1H),7.42-7.28(m,7H),7.05-7.01(m,1H),6.32(s,1H),3.78(d,J=0.8Hz,2H),3.51-3.49(m,4H),2.56-2.53(m,4H)。
实施例32:4-(4-异丙基-苄基)-哌嗪-1-羧酸苯基酰胺
从4-异丙基苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.35-7.18(m,8H),7.05-7.01(m,1H),6.30(s,1H),3.50-3.49(m,6H),2.94-2.87(m,1H),2.50-2.47(m,4H),1.25(d,J=6.9Hz,6H)。
实施例33:4-(4-乙基-苄基)-哌嗪-1-羧酸苯基酰胺
从4-乙基苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.35-7.00(m,9H),6.32(s,1H),3.62-3.48(m,6H),2.68-2.62(m,2H),2.49-2.47(m,4H),1.26-1.22(m,3H)。
实施例34:4-(5-溴-2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺
从5-溴-2-羟基-苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):10.54(br s,1H),7.35-7.25(m,5H),7.12-7.02(m,2H),6.73(d,J=8.6Hz,1H),6.42(br s,1H),3.70(s,2H),3.55(br s,4H),2.58(brs,4H)。
实施例35:4-(2,3-二氢-苯并[1,4]二氧芑-6-基甲基)哌嗪-1-羧酸苯基
酰胺
从2,3-二氢-苯并[1,4]二氧杂环己烯-6-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.36-7.25(m,4H),7.05-7.00(m,1H),6.85-6.76(m,H),6.33(br s,1H),4.26(s,4H),3.51-3.46(m,4H),3.42(s,2H),2.49-2.45(m,4H)。
实施例36:4-(4-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从4-甲氧基苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7,35-7.21(m,6H),7.04-6.99(m,1H),6.89-6.84(m,2H),6.43(br s,1H),3.80(s,3H),3.50-3.45(m,6H),2.46-2.42(m,4H)
实施例37:4-(3-乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺
从3-乙烯基苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3),7.36-7.23(m,7H),7.21-6.99(m,1H),6.76-6.69(m,1H),6.49(s,1H),5.79-5.74(m,1H),5.27-5.24(m,1H),3.52-3.45(m,6H),2.47-2.45(m,4H)。
实施例38:4-(2,3-二氢-苯并呋喃-5-基甲基)-哌嗪-1-羧酸苯基酰胺
从2,3-二氢-苯并呋喃-5-基甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.36-7.28(m,4H),7.17(s,1H),7.06-7.01(m,1H),6.73(d,J=8.1Hz,1H),6.30(s,1H),4.60-4.55(m,2H),3.51-3.46(m,6H),3.23-3.19(m,2H),2.49-2.47(m,4H)。
实施例39:4-(3-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从3-甲氧基苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.35-7.32(m,2H),7.28-7.22(m,3H),7.03-6.98(m,1H),6.92-6.89(m,2H),6.83-6.79(m,1H),6.49(br s,1H),3.81(s,3H),3.50-3.45(m,6H),2.47-2.43(m,4H).
实施例40:4-萘-1-基甲基-哌嗪-1-羧酸苯基酰胺
从1-萘甲醛制备题述化合物。
1HNMR(400MHz,CDCl3):8.31-8.27(m,1H),7.88-7.77(m,2H),7.55-7.47(m,2H),7.43-7.24(m,6H),7.04-6.99(m,1H),6.37(br s,1H),3.93(s,2H),3.49-3.44(m,4H),2.55-2.51(m,4H)。
实施例41:4-(2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺
从2-羟基苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):10.42(br s,1H),7.36-7.17(m,5H),7.07-6.97(m,2H),6.88-6.77(m,2H),6.50(br s,1H),3.73(s,2H),3.53(br s,4H),2.57(br s,4H)。
实施例42:4-(3-甲基-苄基)-哌嗪-1-羧酸苯基酰胺
从3-甲基苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.35-7.00(m,9H),6.34(s,1H),3.51-3,49(m,6H),2.49-2.47(m,4H),2.36(s,3H)。
实施例43:4-(1H-吲哚-5-基甲基)哌嗪-1-羧酸苯基酰胺
从5-吲哚甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.55(br s,1H),7.40-7.20(m,6H),7.15(dd,J=8.2Hz,1.6,1H),7.05-6.99(m,1H),6.50(dd,J=3.0,0.9Hz,1H),3.65(m,2H),3.53-3.47(m,4H),2.55-2.50(m,4H)。
实施例44:4-(3,4-二甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从3,4-二甲氧基苯甲醛制备题述化合物。
1HNMR(400MHz,CDCl3):7.36-7.32(m,2H),7.28-7.23(m,2H),7.04-6.98(m,1H),6.90-6.80(m,3H),6.53(br s,1H),3.89(s,3H),3.87(s,3H),3.50-3.45(m,6H),2.46-2.42(m,4H)。
实施例45:4-吡啶-4-基甲基-哌嗪-1-羧酸苯基酰胺
从4-吡啶甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.57-8.56(m,2H),7.36-7.27(m,6H),7.06-7.02(m,1H),6.34(s,1H),3.55-3.51(m,6H),2.51-2.49(m,4H)。
实施例46:4-吡啶-2-基甲基-哌嗪-1-羧酸苯基酰胺
从2-吡啶甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.60-8.58(m,1H),7.70-7.52(m,1H),7.42-7.18(m,6H),7.05-7.00(m,1H),6,32(s,1H),3.71(s,2H),3.55-3.53(m,4H),2.58-2.55(m,4H)。
实施例47:4-吡啶-3-基甲基-哌嗪-1-羧酸苯基酰胺
从3-吡啶甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.56-8.53(m,2H),7.70-7.67(m,1H),7.36-7.26(m,5H),7.06-7.01(m,1H),6.33(s,1H),3.56(s,2H),3.52-3.50(m,4H),2.51-2.49(m,4H)。
实施例48:4-(4-异丙基-苯基)-哌嗪-1-羧酸苯基酰胺
从4-异丙基苯甲醛制备题述化合物。
1HNMR(400MHz,CDCl3):7,35-7.20(m,7H),7.05-7.00(m,1H),6.86-6.83(m,1H),6.32(br m,1H),4.57-4.50(m,1H),3.51-347(m,6H),2.50-2.45(m,4H),1.34(d,J=6.0Hz,6H)。
实施例49:4-联苯基-4-基甲基-哌嗪-1-羧酸苯基酰胺
从4-苯基苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.61-7.55(m,4H),7.46-7.25(m,9H),7.05-7.00(m,1H),6.44(br s,1H),3.59(s,2H),3.54-3.49(m,4H),2.55-2.50(m,4H).
实施例50:4-喹啉-4-基甲基-哌嗪-1-羧酸苯基酰胺
从4-喹啉甲醛制备题述化合物。
1HNMR(400MHz,CDCl3):8.87(d,J=4.3Hz,1H),8.24(d,J=8.4Hz,1H),8.14(d,J=8.5Hz,1H),7.75-7.70(m,1H),7.61-7.55(m,1H),7.43(d,J=4.3Hz,1H),7.36-7.25(m,4H),7.05-7.00(m,1H),6.44(br s,1H),3.55-3.50(m,4H),2.60-2.55(m,4H)。
实施例51:4-苯并[1,3]二氧戊环(dioxol)-4-基甲基-哌嗪-1-羧酸苯基
酰胺
从苯并[1,3]二氧戊环-4-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.36-7.25(m,4H),7.06-7.00(m,1H),6.85-6.75(m,3H),6.30(s,1H),3.57(s,2H),3.54-3.49(m,4H),2.56-2.50(m,4H)。
实施例52:4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸苯基
酰胺
从2,2-二氟-苯并[1,3]间二氧杂环戊烯-5-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.37-7.25(m,4H),7.12(s,1H),7.06-6,98(m,3H),6.32(s,1H),3.54-3.46(m,6H),2.50-2.45(m,4H)。
实施例53:4-(1-甲基-1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺
从1-甲基-1H-吲哚-5-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.55(s,1H),7.36-7.25(m,5H),7.21(dd,J=8.4,1.6Hz,1H),7.06-7.00(m,2H),6.46(dd,J=3.0,0.8Hz,1H),6.29(br s,1H),3.80(s,3H),3.65(s,2H),3.50(t,J=5.1Hz,4H),2.51(t,J=5.1hz,4H)。
实施例54:4-(6-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺
从6-氯-喹啉-2-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.07(d,J=8.4Hz,1H),8.01(d,J=8.8Hz,1H),7.80(d,J=2.2Hz,1H),7.67-7.62(m,2H),7.36-7.26(m,4H),7.05-7.00(m,1H),6.38(s,1H),3.86(s,2H),3.54(t,J=5.1Hz,4H),2.60(t,J=5.1Hz,4H)。
实施例55:4-(8-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺
从8-氯-喹啉-2-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.17(d,J=8.4Hz,1H),7.82(dd,J=7.5,1.3Hz,1H),7.75,7.71(m,2H),7.44(t,J=7.7Hz,1H),7.37-7.34(m,2H),7.30-7.25(m,2H),7.05-7.00(m,1H),6.40(s,1H),3.97(s,2H),3.55(t,J=5.1Hz,4H),2.64(t,J=5.1Hz,4H)。
实施例56:4-(2-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺
从2-氯-喹啉-3-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.23(s,1H),8,02(d,J=8.1Hz,1H),7.84(d,J=8.3Hz,1H),7.75-7.70(m,1H),7,60-7.55(m,1H),7.37-7.25(m,4H),7.05-7.00(m,1H),6.42(s,1H),3.79(s,2H),3.56(t,J=5.0Hz,4H),2.63(t,J=5.1Hz,4H)。
实施例57:4-萘-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺
从哌嗪-1-羧酸(4-氟-苯基)酰胺和2-萘甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.85-7.80(m,3H),7.74(s,1H),7.52-7.45(m,3H),7.30-7.25(m,2H),6.98-6.92(m,2H),6.36(s,1H),3.69(s,2H),3.49(t,J=5.1Hz,4H),2.51(t,J=5.1Hz,4H)。
实施例58:4-喹啉-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺
从哌嗪-1-羧酸(4-氟-苯基)-酰胺和2-喹啉甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.16(d,J=8.3Hz,1H),8.08(d,J=8.6Hz,1H),7.82(d,J=7.6Hz,1H),7.74-6.69(m,1H),7.63(d,J=8.3Hz,1H),7.56-7.52(m,1H),7.32-7.25(m,2H),6.99-6.94(m,2H),6.38(s,1H),3.88(s,2H),3.52(t,J=5.1Hz,4H),2.60(t,J=5.1Hz,4H)。
实施例59:4-(1-羟基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺
从1-羟基-萘-2-基甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.26-8.22(m,1H),7.78-774(m,1H),7.49-7.45(m,2H),7.35-7.26(m,5H),7.10-7.01(m,2H),6.42(s,1H),3.89(s,2H),3.70-3.40(br s,4H),2.80-2.50(br s,4H)。
实施例60:4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺
从3-(4-氯-苯氧基)-苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.36-7.25(m,7H),7.11-6.87(m,6H),6.31(s,1H),3.55-3,47(m,6H),2.51-2.46(m,4H)。
实施例61:4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺
从3-(3,4-二氯-苯氧基)-苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.40-7.25(m,6H),7.15-7.00(m,4H),6.94-6.84(m,2H),6.29(s,1H),3.56-3.48(m,6H),2.52-2,47(m,10H)。
实施例62:4-(,3-对甲苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从3-对甲苯氧基-苯甲醛制备题述化合物。
1HNMR(400MHz,CDCl3):7.36-7,24(m,5H),7.16-7,12(m,2H),7.06-6,98(m,3H),6.94-6.85(m,3H),6.31(s,1H),3,53-3.46(m,6H),2.51-2.45(m,4H)。
实施例63:4-[3-(4-叔丁基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺
从3-(4-叔丁基-苯氧基)-苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.37-7.24(m,7H),7.09-7.00(m,3H),6.96-6.85(m,3H),6.31(s,1H),3.55-3.45(m,6H),2.53-2.45(m,4H),1.33(s,9H)。
实施例64:4-[3-(3-三氟甲基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺
从3-(3-三氟甲基-苯氧基)-苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.50-6.90(m,13H),6.31(s,1H),3.56-3.46(m,6H),2.53-2.45(m,4H)。
实施例65:4-[3-(4-甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺
从3-(4-甲氧基-苯氧基)-苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.36-7.21(m,6H),7.06-6.80(m,7H),6.30(s,1H),3.81(s,3H),3.52-3.45(m,6H),2.51-2.45(m,4H)。
实施例66:4-(,6-甲氧基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺
从6-甲氧基-萘-2-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.72(d,J=8.3Hz,2H),7.66(s,1H),7,45(dd,J=8.4,1.6Hz,1H),7.35-7,24(m,4H),7,17-7.13(m,2H),7.05-6.99(m,1H),6.37(s,1H),3.92(s,3H),3.65(s,2H),3.50(t,J=5.1Hz,4H),2.50(t,J=5.1Hz,4H)。
实施例67:4-菲-9-基甲基-哌嗪-1-羧酸苯基酰胺
从菲-9-甲醛制备题述化合物。
1HNMR(400MHz,CDCl3):8.75-8.66(m,2H),8.41-8.38(m,1H),7.87(dd,J=7.7,1.3Hz,1H),7.70-7.57(m,5H),7.36-7.26(m,4H),7.05-7.00(m,1H),6.30(s,1H),3.98(s,2H),3.50(t,J=5.1Hz,4H),2.61(t,J=5.1Hz,4H)。
实施例68:4-芘-1-基甲基-哌嗪-1-羧酸苯基酰胺
从芘-1-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.53(d,J=9.1Hz,1H),8.22-8.12(m,4H),8.06(s,2H),8.04-7.96(m,2H),7.36-7.25(m,4H),7.05-7.00(m,1H),6.30(s,1H),4.22(s,2H),3.50(t,J=5.1Hz,4H),2.62(t,J=5.1Hz,4H)。
实施例69:4-(6-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺
从6-氯-喹啉-3-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.13(d,J=8.6Hz,1H),8.09(d,J=2.0Hz,1H),7.75(d,J=8.4Hz,1H),7.63(d,J=8.4Hz,1H),7.49(dd,J=8.4,2.0Hz,1H),7.36-7.26(m,4H),7.05-7.00(m,1H),6.35(s,1H),3.87(s,H),3.55(d,J=5.1Hz,4H),2.61(d,J=5.1Hz,4H)。
实施例70:4-联苯-3-基甲基-哌嗪-1-羧酸苯基酰胺
从联苯-3-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.65-7.25(m,13H),7,06-7.00(m,1H),6.31(s,1H),3.61(s,2H),3.55-3.49(m,4H),2.58-2.50(m,4H)。
实施例71:4-(6-溴-吡啶-2-基甲基)-哌嗪-1-羧酸苯基酰胺
从6-溴-吡啶-2-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.57-7.26(m,7H),7.06-7.01(m,1H),6.32(s,1H),3.70(s.2H),3.54(t,J=5.1Hz,4H),2.57(t,J=5.1Hz,4H)。
实施例72:4-[3-(4-氯-苯磺酰基)-苄基]-哌嗪-1-羧酸苯基酰胺
从3-(4-氯-苯磺酰基)-苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.94-7.85(m,6H),7.54-7.45(m,6H),7.06-7.00(m,1H),6.29(s,1H),3,58(s,2H),3.53-3,47(m,4H),2,50-2.49(m,4H)。
实施例73:4-(1H-吲哚--6-基甲基)-哌嗪-1-羧酸苯基酰胺
从吲哚-6-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.15(s,1H),7.62-7.58(m,1H),7.40-7.19(m,6H),7.12-6.99(m,2H),6,53-6.56(m,1H),6.29(s,1H),3.66(s,2H),3.54-3.47(m,4H),2.55-2.50(m,4H)。
实施例74:4-(4-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从4-苯氧基苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.40-7.25(m,8H),7.15-6.95(m,6H),6.31(s,1H),3.55-3.48(m,6H),2.55-2.45(m,4H)。
实施例75:4-(2-氯-8-甲基-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺
从2-氯-8-甲基-喹啉-3-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.17(s,1H),7.67(d,J=7.8Hz,1H),7.56(d,J=6.8Hz,1H),7.45(t,J=7.5Hz,1H),7.37-7.33(m,2H),7.30-7.25(m,2H),7.05-7.00(m,1H),6.46(s,1H),3.77(s,2H),3.54(t,J=5.1Hz,4H),2.77(s,3H),2.61(t,J=5.0Hz,4H)。
实施例76:4-(1-甲基-1H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺
从1-甲基-1H-吲哚-6-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.57(d,J=8.1Hz,1H),7.38-7.24(m,5H),7.11-7.00(m,3H),6.49-6.47(dd,J=3.1,0.8Hz,1H),6.31(s,1H),3.80(s,3H),3.68(s,2H),3.54-3.48(m,4H),2.56-2.50(m,4H)。
实施例77:4-(4-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从4-苄氧基苯甲醛制备题述化合物。
1H NMR(400MHz,CDC13):7.47-7.20(m,11H),7.05-6.98(m,1H),6.97-6.91(m,2H),5.05(s,2H),3.50-3.42(m,6H),2.47-2.40(m,4H)。
实施例78:4-[3-(3,5-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺
从3-(3,5-二氯-苯氧基)-苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.37-7.25(m,5H),7.16(d,J=7.7Hz,1H),7.10-7.00(m,3H),6.97-6.91(m,1H),6.86(d,J=1.8Hz,2H),6.31(s,1H),3.57-3.47(m,6H),2.53-2.45(m,4H)。
实施例79:4-(9H-芴-2-基甲基)-哌嗪-1-羧酸苯基酰胺
从9H-芴-2-甲醛制备题述化合物。
1HNMR(400MHz,CDCl3):7.79-7.72(m,2H),7.55-7.50(m,2H),7.40-7.23(m,7H),7.04-6.99(m,1H),6.40(s,1H),3.90(s,2H),3.60(s,2H),3.50(t,J=5.1Hz,4H),2.50(t,J=5.1Hz,4H)。
实施例80:4-(9-乙基-9H-咔唑-3-基甲基)-哌嗪-1-羧酸苯基酰胺
从9-乙基-9H-咔唑-3-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.10(d,7.6Hz,1H),8.03(s,1H),7.49-7.21(m,9H),7.04-6.99(m,1H),6.35(s,1H),4.37(q,7.2Hz,2H),3.72(s,2H),3.51(t,J=5.1Hz,4H),2.54(t,J=5.1Hz,4H),1.44(t,J=7.2Hz,3H).
实施例81:4-(4-苯乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺
从4-苯乙烯基-苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.54-7.47(m,4H),7.39-7.25(m,9H),7.11(s,2H),7.05-7.00(m,7.00,1H),6.37(s,1H),3.54(s,2H),3.50(t,J=5.0Hz,4H),2.49(t,J=5.0Hz,4H)。
实施例82:4-(4-氯-3-三氟甲基-苄基基)-哌嗪-1-羧酸苯基酰胺
从4-氯-3-三氟甲基-苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.67(s,1H),7.46(s,2H),7.35-7.25(m,4H),7.05-7.00(m,1H),6.42(s,1H),3.54(s,2H),3.50(t,J=5.1Hz,4H),2.46(t,J=5.1Hz,4H)。
实施例83:4-[2,5-二甲基-1-(3-三氟甲基-苯基)-1H-吡咯-3-基甲基]-哌
嗪-1-羧酸苯基酰胺
从2,5-二甲基-1-(3-三氟甲基-苯基)-1H-吡咯-3-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.69-7.58(m,2H),7.47(s,1H),7.42-7.25(m,5H),7.04-7.00(m,1H),6.45(s,1H),6.94(s,1H),3.52(t,J=5.1Hz,4H),3.41(s,2H),2.52(t,J=5.1Hz,4H),2.02(s,3H),1.98(s,3H)。
实施例84:4-(2-溴-苄基)-哌嗪-1-羧酸苯基酰胺
从2-溴苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.56(dd,J=8.0,1.3Hz,1H),7.46(dd,J=7.8,1.6Hz,1H),7.36-7.24(m,5H),7.13(td,J=7.7,1.7Hz,1H),7.04-6.99(m,1H),6.37(br s,1H),3.63(s,2H),3.51-3.47(m,4H),2.56-2.52(m,4H)。
实施例85:4-(3,4-二溴-苄基)-哌嗪-1-羧酸(,3-氟-苯基)酰胺
用3-氟苯基异氰酸酯(0.07ml)处理1-(3,4-二溴-苄基)-哌嗪(167mg)的DCM(2ml)溶液。16小时后,用色谱处理得到的混合物,得到题述化合物,其是白色泡沫(188mg)。
1H NMR(400MHz,CDCl3):7.61(d,J=2.0Hz,1H),7.56(d,J=8.1Hz,1H),7.31-7.12(m,3H),7.01-6.97(m,1H),6.75-6.99(m,1H),6.47(br m,1H),3.51-3.47(m,4H),3.45(s,2H),2.48-2.43(m,4H)。
类似于实施例85,实施例86-96是由1-(3,4-二溴-苄基)-哌嗪和特定的异氰酸酯类制备的。产物通过过滤反应混合物或者通过色谱分离。
实施例86;4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氟-苯基)-酰胺
从4-氟苯基异氰酸酯制备题述化合物。
1H NMR(400MHz,CDCl3):7.62(d,J=2.0Hz,1H),7.57(d,J=8.0Hz,1H),7.31-7.27(m,2H),7.15(dd,J=8.0.2.0Hz,1H),7.01-6.95(m,2H),6.28(br s,1H),3.51-3.47(m,4H),3.46(s,2H),2.50-2.45(m,4H)。
实施例87:4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-甲氧基-苯基)-酰胺
从3-甲氧基苯基异氰酸酯制备题述化合物。
1HNMR(400MHz,CDCl3):7.65-7.55(m,2H),7.20-7.10(m.3H),6.85-6.79(m,1H),6.62-6.56(m,1H),6.32(s,1H),3.80(s,3H),3.55-3.45(m,6H),2.51-2.44(m,4H)。
实施例88:4-(3,4-二溴-苄基)-哌嗪-1-羧酸间甲苯基酰胺
从3-甲基苯基异氰酸酯制备题述化合物。
1HNMR(400MHz,CDCl3):7.65-7.55(m,2H),7.25-7.07(m,4H),6.86(d,J=7.4Hz,1H),6.26(s,1H),3.55-3.44(m,6H),2.50-2.44(m,4H),2.32(s,3H)。
实施例89:4-[3,4-二溴-苄基]-哌嗪-1-羧酸(,2-氟-苯基)-酰胺
从异氰酸2-氟苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):8.08(td,J=8.2,1.6Hz,1H),7.62(d,J=1.8Hz,1H),7.57(d,J=8.0Hz,1H),7.17-6.93(m,4H),6.58(br s,1H),3.55-3.50(m,4H),3.47(s,2H),2.51-2.46(m,4H)。
实施例90:4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-甲氧基苯基)酰胺
从异氰酸4-甲氧基苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):7.63-7.62(m,1H),7.57(d,J=8.0Hz,1H),7.25-7.22(m,2H),7.16-7.13(m,1H),6.85-6.82(m,2H),6.19(s,1H),3.78(s,3H),3.50-3.46(m,6H),2.48-2.46(m,4H)。
实施例91:4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-甲氧基苯基)-酰胺
从2-甲氧基苯基异氰酸酯制备题述化合物。
1HNMR(400MHz,CDCl3):8.15-8.13(m,1H),7.63-7.56(m,2H),7.16-7.09(m,2H),6.96-6.93(m,2H),6.86-6.83(m,1H),3.87(s,3H),3.53-3.51(m,4H),3.46(s,2H),2.50-2.47(m,4H)。
实施例92:4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-氯-苯基)-酰胺
从异氰酸3-氯苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):7.62(d,1.9Hz,1H),7.57(d,J=8.2Hz,2H),7.20-7.13(m,3H),7.02-6,99(m,1H),6.34(s,1H),3,51-3.47(m,6H),2.49-2.46(m,4H)。
实施例93:4-(2,3-二溴-苄基)-哌嗪-1-羧酸(2-氯-苯基)-酰胺
从异氰酸2-氯苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):8.20-8.18(m,1H),7.63-7.56(m,2H),7.34-7.14(m,3H),7.00-6.93(m,2H),3.56-3.54(m,4H),3.48(s,2H),2.51-2.49(m,4H)。
实施例94:4-(3,4-二溴-苄基)-哌嗪-1-羧酸对甲苯基酰胺
从异氰酸4-甲基苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):7.62-7.55(m,2H),7.23-7.07(m,5H),6.25(s,1H),3.50-3.46(m,6H),2.48-2.45(m,4H),2.29(s,3H)。
实施例95:4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氯-苯基)-酰胺
从异氰酸4-氯苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):7.63-7.56(m,2H),7.31-7.23(m,4H),7.16-7.13(m,1H),6.29(s,1H),3.51-3.47(m,6H),2.49-2.46(m,4H)。
实施例96:4-(3,4-二溴-苄基)-哌嗪-1-羧酸邻甲苯基酰胺
从异氰酸2-甲基苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):7.63-7.56(m,3H),7.21-7.13(m,3H),7.04-6.99(m,1H),6.10(s,1H),3.52-3.47(m,6H),2.50-2.47(m,4H)。
类似于实施例85,实施例97-115是由3-哌嗪-1-基甲基-喹啉(除非另有指明)和特定的异氰酸酯类制备的。产物通过过滤反应混合物或者通过色谱分离。
实施例97:4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氟-苯基)-酰胺
从异氰酸3-氟苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):7.41-7.25(m,9H),7.05-7.00(m,1H),6.33(s,1H),3.69(s,2H),3.49(t,J=5.1Hz,4H),2.54(t,J=5.1Hz,4H)。
实施例98:4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺
从异氰酸4-氟苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):8.92(s,1H),8.12-8.07(m,1H),7.83-7.80(m,1H),7.71(ddd,J=8.4,6.9,1.5Hz,1H),7.52(ddd,J=8.0,7.0,1.1Hz,1H),7.30-7.27(m,2H),6.99-6.95(m,2H),6.38(s,1H),3.74(s,2H),3.50-3.52(m,4H),2.55-2.54(m,4H)
实施例99:4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氯-苯基)-酰胺
从异氰酸2-氯苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):8.76(d,J=2.1Hz,1H),8.02(dd,J=8.3.1.4Hz,1H),7.97-7.90(m,2H),7.67-7.64(m,1H),7.55(ddd,J=8.4,7.0,1.4Hz,1H),7.40(ddd,J=8.0,7.0.1.1Hz,1H),7.15(dd,J=8.0.1.5Hz,1H),7.08-7.05(m,1H),6.83(s,1H),6.80-6.76(m,1H),3.41(m,4H),2.43-2.40(m,4H)。
实施例100:4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氯-苯基)-酰胺
从异氰酸3-氯苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):8.93(d,J=2.1Hz,1H),8.12-8.08(m,2H),7.82(d,J=8.1Hz),7.72(ddd,J=8.4,6.9,1.4Hz,1H),7.57(ddd,J=8.1,7.0.1.1Hz,1H),7.48-7.46(m,1H),7.19-7.18(m,2H),7.01-6.98(m,1H),6.36(s,1H),3.75(s,1H),3.54-3.51(m,4H),2.57-2.55(m,4H)。
实施例101:4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氯-苯基)-酰胺
从异氰酸4-氯苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):8.92(d,J=2.1Hz,1H),8.12-8.07(m,2H),7.82(dd,J=8.2,1.0Hz,1H),7.72(ddd,J=8.4,6.9.1.4Hz,1H),7.56(ddd,J=8.1.7.0.1.1Hz,1H),7.32-7.30(m,1H),7.29-7.28(m,1H),7.25-7.23(m,1H),7.22-7.21(m,1H),6.39(s,1H),3.74(s,2H),3.53-3.50(m,4H),2.56-2.53(m,4H)。
实施例102:4-喹啉-3-基甲基-哌嗪-1-羧酸(2-甲氧基-苯基)-酰胺
从异氰酸2-甲氧基苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):8.93(d,J=2.0Hz,1H),8.14-8.11(m,3H),7.82(d,J=8.4Hz,1H),7.74-7.70(m,1H),7.58-7.55(m,1H),7.10(s,1H),6.97-6.92(m,2H),6.86-6.83(m,1H),3.86(s,3H),3.76(s,2H),3.56(s,4H),2.58(s,4H)。
实施例103:4-喹啉-3-基甲基-哌嗪-1-羧酸邻甲苯基酰胺
从异氰酸2-甲基苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):8.92(d,J=2.0Hz,1H),8.12(d,J=8.4Hz,1H),7.82(d,J=8.4Hz,1H),7.74-7.70(m,2H),7.62-7.55(m,2H),7.20-7.14(m,2H),7.03-6.99(m,1H),6.10(s,1H),3.56(s,2H),3.52(s,4H),2.58(s,4H),2.23(s,3H)。
实施例104:4-喹啉-3-基甲基-哌嗪-1-羧酸对甲苯基酰胺
从异氰酸4-甲基苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):8.92(d,J=2.0Hz,1H),8.12-8.09(m,2H),7.82(dd,J=8.2,0.8Hz,1H),7.72(ddd,J=8.4,7.0.1.4Hz,1H),7.56(ddd,J=8.0,6.8.1.0Hz,1H),7.23-7.20(m,2H),7.09-7.07(m,2H),6.25(s,1H),3.75(s,2H),3.53-3.51(m,4H),2.58-2.54(m,4H),2.22(s,3H)。
实施例105:2-[4-(喹啉-3-基甲基-哌嗪-1-羰基)-氨基]苯甲酸甲酯
从异氰酸2-甲酯基苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):10.77(s,1H),8.94(d,J=2.1Hz,1H),8.56(dd,J=8.6,0.9Hz,1H),8.13-8.11(m,2H),8.00(dd,J=8.1.1.6Hz,1H),7.83(d,J=8.0Hz,1H),7.74-7.70(m,1H),7.59-7.55(m,1H),7.51(ddd,J=8.8,7.3,1.7Hz,1H),6.99-6.95(m,1H),3.89(s,3H),3.77(s,2H),3.66-3.64(m,4H),2.62-2.59(m,4H)。
实施例106:3-[4-(喹啉-3-基甲基-哌嗪-1-羰基)-氨基]苯甲酸甲酯
从异氰酸3-甲酯基苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):8.92(d,J=2.1Hz,1H),8.13-8.10(m,2H),7.89(t,J=2.2Hz,1H),7.83(dd,J=8.1,1.1Hz,1H),7.75-7.68(m,3H),7.59-7.54(m,1H),7.38-7.32(m,1H),6.60(s,1H),3.88(s,3H),3.77(s,2H),3,56(t,J=4.8Hz,4H),2.58(t,J=4.6Hz,4H)。
实施例107:4-[4-(喹啉-3-基甲基-哌嗪-1-羰基)-氨基]苯甲酸甲酯
从异氰酸4-甲酯基苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):8.92(d,J=2.1Hz,1H),8.12-8.05(m,2H),7.97-7.94(m,2H),7.83-7.80(m,1H),7.71(ddd,J=8.4.6.9,1.4Hz,1H),7.56(ddd,J=8.1,6.9,1.1Hz,1H),7.46-7.42(m,2H),6.64(s,1H),3.87(s,3H),3.73(s,2H),3.54(t,J=5.0Hz,4H),2.55(t,J=5.0Hz,4H)。
实施例108:4-喹啉-3-基甲基-哌嗪-1-羧酸(4-甲氧基-苯基)-酰胺
从异氰酸4-甲氧基苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):8.92(d,J=2.1Hz,1H),8.12-8.08(m,2H),7.82(d,J=7.2Hz,1H),7.71(ddd,J=8.4,6.9,1.4Hz,1H),7.56(ddd,J=8.1,7.0.1.1Hz,1H),7.25-7.22(m,2H),6.86-6.81(m,2H),6.19(s,1H),3.77(s,3H),3.74(s,2H),3.51(t,J=5.0Hz,4H),2.56(t,J=4.8Hz,4H)。
实施例109:4-喹啉-3-基甲基-哌嗪-1-羧酸间甲苯基酰胺
从异氰酸3-甲基苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):8.92(d,J=2.1Hz,1H),8.15-8.10(m,2H),7.83(dd,J=8.2,1.0Hz,1H),7.72(ddd,J=8.4,6.9,1.4Hz,1H),7.60-7.54(m,1H),7.22(s,1H),7.18-7.13(m,1H),7.12-7.07(m,1H),6.85(d,J=7.3Hz,1H),6.27(s,1H),3.76(s,2H),3.56-3.51(m,4H),2.60-2.54(m,4H),2.31(s,3H)。
实施例110:4-喹啉-3-基甲基-哌嗪-1-羧酸(3-甲氧基-苯基)-酰胺
从异氰酸3-甲氧基苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):8.93(d,J=2.0Hz,1H),8.13-8.07(m,2H),7.82(d,J=8.1Hz,1H),7.72(ddd,J=8,4,7.0,1.4Hz,1H),7.59-7.54(m,1H),7.19-7.14(m,1H),7.13(t,J=2.2Hz,1H),6.81(dd,J=7.7.1.6Hz,1H),6.59(dd,J=8.0,2.1Hz,1H),6.31(s,1H),3.79(s,3H),3.74(s,2H),3.52(t,J=4.8Hz,4H),2.56(t,J=4.8Hz,4H)。
实施例111:4-喹啉-3-基甲基-哌嗪-1-羧酸(2,4-二氟-苯基)-酰胺
从异氰酸2,4-二氟苯酯制备题述化合物。
1HNMR(400MHz,CDCl3):8.92(d,J=2.0Hz,1H),8.11(d,J=8.6Hz,1H),8.06(s,1H),7.99-7.92(m,1H),7.82(dd,J=8.3.1.1Hz,1H),7.73-7.69(m,1H),7.58-7.54(m,1H),6.87-7.79(m,2H),6.52(s,1H),3.73(s,2H),3.53(t,J=5.1Hz,4H),2.55(t,J=5.1Hz,4H)。
实施例112:4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氟-苯基)-酰胺
从异氰酸2-氟苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):8.92(d,J=2.0Hz,1H),8.13-8.05(m,3H),7.82(dd,J=8.1,1.3Hz,1H),7.74-7.69(m,1H),7.58-7.54(m,1H),7.12-7.01(m,2H),6.98-6.92(m,1H),6.61(d,J=3.5Hz,1H),3.74(s,2H),3.55(t,J=5.1Hz,4H),2.56(t,J=5.1Hz,4H)。
实施例113:4-苄基-哌嗪-1-羧酸对甲苯基酰胺
从4-苄基哌嗪和异氰酸4-苯基苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):7.31-7.12(m,7H).7.07(d,J=8.0Hz,2H),6.32(s,1H),4.06-4.00(m,2H),2.79(td,J=13,2.5Hz,2H),2.56(d,J=6.8Hz,2H),2.28(s,3H),1.79-,165(m,3H),1.30-1.18(m,2H)。
实施例114:4-苄基-哌嗪-1-羧酸间甲苯基酰胺
从4-苄基哌嗪和异氰酸3-甲基苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):7.32-7.07(m,8H),6.84-6.80(m,1H),6.41(br s,1H),4.06-4.00(m,2H),2.78(td,J=13Hz,2.4Hz,2H),2.55(d,J=7,0Hz,2H),2.30(s,3H),1.77-1.64(m,3H),1.28-1.16(m,2H)。
实施例115:4-苄基-哌嗪-1-羧酸(2-氯-苯基)酰胺
从4-苄基哌嗪和异氰酸2-氯苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):8.19(dd,J=8.3,1.5Hz,1H),7.33-7.12(m,7H),7.03(br s,1H),6.96-6.90(m,1H),4.12-4.05(m,2H),2.85(td,J=13,2.3Hz,2H),2.57(d,J=6.8Hz,2H),1.82-1.69(m,3H),1.34-1.20(m,2H)。
实施例116:4-(3,4-二-溴-苄基)-哌嗪-1-羧酸吡啶-4-基酰胺
1-(3,4-二溴-苄基)-哌嗪(316mg)和吡啶-4-氨基甲酸苯酯(204mg)在DMSO(4ml)中的混合物在室温下搅拌16小时。得到的混合物用EtOAc(20ml)稀释,并用饱和NaHCO3水溶液(2ml)洗涤。干燥有机层(MgSO4)并浓缩。残留物经色谱得到白色固体(370mg)。
1H NMR(400MHz,CDCl3):8.45-8.40(m,2H),7.62(d,J=1.9Hz,1H),7.57(d,J=8.2Hz,1H),7.35-7.30(m,2H),7.16-7.12(m,1H),6.59(s,1H),3.56-3.50(m,4H),3.47(s,2H),2.51-2.45(m,4H)。
类似于实施例116,从1-(3,4-二溴-苄基)-哌嗪和特定的氨基甲酸芳基酯制备实施例117-118。
实施例117:4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-2-基酰胺
从吡啶-2-基氨基甲酸苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):8.22-8.18(m,1H),8.05-8.01(m,1H),7.70-7.55(m,3H),7.16-7.12(m,1H),6.98-6.90(m,2H),3.56-3.50(m,4H),3.46(s,2H),2.49-2.46(m,4H)。
实施例118:4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-3-基酰胺
从吡啶-3-基氨基甲酸苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):8.44-8.41(m,1H),8.29-8.27(m,1H),8.01-7.96(m,1H),7.65-7.52(m,2H),7.26-7.21(m,1H),7.17-7.11(m,1H),6.43(s,1H),3.56-3.51(m,4H),3.48(s,2H),2.53-2.46(m,4H)。
实施例119:4-(4-环己氧基-苄基)-哌嗪-1-羧酸苯基酰胺
向4-(4-羟基-苄基)-哌嗪-1-羧酸苯基酰胺(311mg)和环己醇(150mg)在DCM(4ml)中的混合物中加入聚合物负载的Ph3P(500mg),然后加入偶氮二碳酸二叔丁酯(345mg)。反应混合物振荡过夜,然后过滤。滤液经色谱得到题述化合物,其是白色固体(110mg)。
1H NMR(400MHz,CDCl3):7.36-7.19(m,6H),7.05-7.00(m,1H),6.88-6.84(m,2H),6.30(s,1H),4.25-4.20(m,1H),3.50-3.47(m,6H),2.48-2.46(m,4H),2.01-1.97(m,2H),1.82-1.80(m,2H),1.60-1.29(m,6H)。
类似于实施例119,从4-(3-羟基-苄基)-哌嗪-1-羧酸苯基酰胺或4-(4-羟基-苄基)-哌嗪-1-羧酸苯基酰胺与特定的醇制备实施例120-129。
实施例120:4-(3-丙氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从1-丙醇制备题述化合物。
1H NMR(400MHz,CDCl3):7.36-7.21(m,5H),7.05-6.90(m,1H),6.88-6.80(m,3H),6.32(s,1H),3.94-3.91(m,2H),3.51-3.49(m,6H),2.50-2.48(m,4H),1.86-1.77(m,2H),1.06-0.98(m,3H)。
实施例121:4-(3-异丁氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从异丁醇制备题述化合物。
1H NMR(400MHz,CDCl3):7.36-7.21(m,5H),7.05-7.01(m,1H),6.90-6.88(m,2H),6.82-6.80(m,1H),6.33(s,1H),3.72(d,J=6.6Hz,2H),3.21-3.49(m,6H),2.50-2.48(m,4H),2.12-2.05(m,1H),1.03(d,J=6.7Hz,3H)。
实施例122:4-(3-乙氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从乙醇制备题述化合物。
1H NMR(400MHz,CDCl3):7.36-7.21(m,5H),7.05-7.01(m,1H),6.91-6,89(m,2H),6.82-6.79(m,1H),6.30(s,1H),4.07-4.02(m,2H),3.51-3.49(m,6H),2.50-2.48(m,4H),1.43-1.40(m,3H)。
实施例123:4-(4-丙氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从1-丙醇制备题述化合物。
1H NMR(400MHz,CDCl3):7.36-7.20(m,6H),7.05-7.01(m,1H),6.88-6.84(m,2H),6.30(s,1H),3.93-3.90(m,2H),3.50-3.48(m,6H),2.48-2.46(m,4H),1.85-1.76(m,2H),1.06-1.02(m,3H)。
实施例124:4-(4-异丁氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从异丁醇制备题述化合物。
1H NMR(400MHz,CDCl3):7.35-7.20(m,6H),7.05-7.00(m,1H),6.88-6.84(m,2H),6.31(s,1H),3.71(d,J=6.6Hz,2H),3.50-3.47(m,6H),2.48-2.45(m,4H),2.11-2.05(m,1H),1.02(d,J=6.7Hz,6H)。
实施例125:4-[3-(2-二甲基氨基-乙氧基)-苄基)]-哌嗪-1-羧酸苯基酰胺
从2-二甲基氨基-乙醇制备题述化合物。
1H NMR(400MHz,CDC13):7.39-7.20(m,5H),7.06-6.99(m,1H),6.96-6.88(m,2H),6.86-6.80(m,1H),6.32(s,1H),4.08(t,J=5.7Hz,2H),3.56-3.46(m,6H),2.75(t,J=5.7Hz,2H),2.52-2.45(m,4H),2.36(s,6H)。
实施例126:4-[3-(2-哌啶-1-基-乙氧基)-苄基)]-哌嗪-1-羧酸苯基酰胺
从2-哌啶-1-基-乙醇制备题述化合物。
1H NMR(400MHz,CDCl3):7.40-7.20(m,5H),7.06-6.99(m,1H),6.94-6.79(m,3H),6.34(s,1H),4.11(t,J=6.1Hz,2H),3.55-3.45(m,6H),2.78(t,J=6.1Hz,2H),2.57-2.40(m,8H),1.68-1.51(m,4H),1.50-1.40(m,2H)。
实施例127:4-[3-(3-二甲基氨基-丙氧基)-苄基)]-哌嗪-1-羧酸苯基酰胺
从3-二甲基氨基-丙-1-醇制备题述化合物。
1HNMR(400MHz,CDCl3):7.40-7.19(m,5H),7.06-7.00(m,1H),6.92-6.79(m,3H),6.33(s,1H),4.02(t,J=6.4Hz,2H),3.55-3.45(m,6H),2.51-2.45(m,6H),2.57(s,6H),2.02-1.92(m,2H)。
实施例128:4-[3-(,3-哌啶-1-基-丙氧基)-苄基)]-哌嗪-1-羧酸苯基酰胺
从3-哌啶-1-基-丙-1-醇制备题述化合物。
1HNMR(400MHz,CDCl3):7.37-7.19(m,5H),7.07-7.00(m,1H),6.93-6.77(m,3H),6.32(s,1H),4.01(t,J=6.4Hz,2H),3.55-3.45(m,6H),2.60-2.30(m,10H),2.04-1.94(m,2H),1.79-1.39(m,6H)。
实施例129:4-(4-乙氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从乙醇制备题述化合物。
1H NMR(400MHz,CDCl3):7.36-7.21(m,6H),7.05-7.01(m,1H),6.88-6,85(m,2H),6.30(s,1H),4.06-4.00(m,2H),3.50-3.48(m,6H),2.48-2.46(m,4H),1.43-1.40(m,3H)。
实施例130:4-[3-(3-氯-苯氧基)-苄基)]-哌嗪-1-羧酸苯基酰胺
向4-(3-羟基-苄基)-哌嗪-1-羧酸苯基酰胺(311mg)、3-氯苯基硼酸(313mg)、Cu(OAc)2(182mg)和粉末状
分子筛(300mg)在DCM(10ml)中的混合物中加入吡啶(0.403ml)。得到的混合物在室温和环境大气压下搅拌16小时,过滤,然后用DCM洗涤。浓缩滤液,残留物经色谱得到棕色固体(350mg)。
1H NMR(400MHz,CDCl3):7.36-7.22(m,6H),7.15-6.85(m,7H),6.37(m,1H),3.56-346(m,6H),2.55-2.45(m,4H)。
类似于实施例130,从4-(3-羟基-苄基)-哌嗪-1-羧酸苯基酰胺和特定的芳烃硼酸制备实施例131-136。
实施例131:4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺
从2-萘基硼酸制备题述化合物。
1H NMR(400MHz,CDCl3):7.86-7.81(m,2H),7.73-7.65(m,1H),7.50-7.38(m,2H),7.36-7.24(m,7H),7.14-6.95(m,4H),6.30(s,1H),3.55-3.45(m,6H),2.55-2.45(m,4H)。
实施例132:4-[3-(菲-9-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺
从9-菲硼酸制备题述化合物。
1HNMR(400MHz,CDCl3):8.71-8.60(m,2H),8.35-8.31(m,1H),7.76-7.50(m,7H),7.36-7.25(m,3H),7.16-7.00(m,5H),6.33(s,1H),3.54(s,2H),3.48-3.43(m,4H),2.51-2.45(m,4H)。
实施例133:4-[3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯氧基]-苯甲酸
甲酯
从4-甲酯基苯基硼酸制备题述化合物。
1H NMR(400MHz,CDCl3):8.65-8.60(m,2H),8.05-7.97(m,2H),7.75-7.68(m,1H),7.28-7.25(m,2H),7.17-7.13(m,1H),7.10-6.95(m.5H),6.40(s,1H),3.91(s,3H),3.57-3.47(m,6H),2.54-2.47(m,4H).
实施例134:4-[3-(4-甲磺酰基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺
从4-甲磺酰基硼酸制备题述化合物。
1HNMR(400MHz,CDCl3):7.92-7.86(m,2H),7.41-7.18(m,6H),7.12-6.93(m,5H),6.31(s,1H),3.57(s,2H),3,54-3.48(m,4H),3.06(s,3H),2.55-2.47(m,4H)。
实施例135:4-[3-(3-甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺
从3-甲氧基苯基硼酸制备题述化合物。
1HNMR(400MHz,CDCl3):7.36-7.20(m,6H),7.10-7.00(m,3H),6.95-6.90(m,1H),6.68-6.55(m,3H),6.30(s,1H),3.78(s,3H),3.55-3,45(m,6H),2.53-2.46(m,4H)。
实施例136:4-[3-(苯并[1,3]二氧戊环-5-基氧基)-苄基]-哌嗪-1-羧酸苯
基酰胺
从苯并[1,3]二氧戊环-5-硼酸制备题述化合物。
1H NMR(400MHz,CDCl3):7.36-7.22(m,5H),7.06-6.95(m,3H),6.88-6.82(m,1H),6.76(d,J=8.4Hz,1H),6.58(d,J=2.4Hz,1H),6.49(dd,J=8.4,2.4Hz,1H),6.34(s,1H),3.55-3.45(m,6H),2.53-2.46(m,4H)。
实施例137:甲磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯
向4-(3-羟基-苄基)-哌嗪-1-羧酸苯基酰胺(50mg)在DCM(1ml)中的0℃溶液中加入甲磺酰氯(0.015ml),然后加入Et3N(0.029ml)。得到的混合物在室温搅拌2小时,然后经色谱得到无色的油(80mg)。
1H NMR(400MHz,CDCl3):7.42-7.22(m,7H),7.22-7.16(m,1H),7.07-7.01(m,1H),3.65-3.46(m,6H),3.22-3.15(m,3H),2.60-2.45(m,4H)。
类似于实施例137,使用特定的磺酰氯从4-(3-羟基-苄基)-哌嗪-1-羧酸苯基酰胺制备实施例138-139。
实施例138:苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯
从苯磺酰氯制备题述化合物。
1H NM R(400MHz,CDCl3):7.87-7.82(m,2H).7.71-7.65(m,1H),7.56-7.50(m,2H),7.37-7.18(m,6H),7.07-6.98(m,2H),6.95-6.89(m,1H),6.30(s,1H),3.50-3.43(m,6H),2.45-2.35(m,4H)。
实施例139:4-氯-苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯
从4-氯苯磺酰氯制备题述化合物。
1H NMR(400MHz,CDCl3):7.81-7.79(m,2H),7.54-7.49(m,2H),7.40-7.20(m,6H),7.09-6.89(m,3H),6.30(s,1H),3.52-2.45(m,6H),2.45-2.37(m,4H)。
实施例140:2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸(钾盐)
在N2下向2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-羰基]-苯甲酸甲酯(26mg)的THF(0.5ml)溶液中一次性加入三甲基硅烷酸钾(potassiumtrimethyl silanoate)(9mg),然后将混合物在室温搅拌14小时。浓缩混合物,得到题述化合物,其是白色无定形固体(22mg)。
1H NMR(400MHz,CD3OD):8.81(d,J=2.1Hz,1H),8.23-8.21(m,1H),8.14(dd,J=8.4,0.9Hz,1H),7.96-7.93(m,1H),7.91(dd,J=7.9,1.6Hz,1H),7.88-7.85(m,1H),7.68(ddd,J=8.4,6.9,1.4Hz,1H),7.54(ddd,J=8.1.7.0,1.1Hz,1H),7.19-7.23(m,1H),6.81-6.85(m,1H),3.71(s,2H),3.51-3.54(m,4H),2.49-2.51(m,4H)。
实施例141:3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]苯甲酸(钾盐)
类似于实施例140,从3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸甲酯制备题述化合物。
1HNMR(400MHz,CD3OD):8.86(d,J=2.0Hz,1H),8.28(s,1H),7.99(d.J=8.4Hz,1H),7.92(d,J=8.2Hz,1H),7.75-7.71(m,1H),7.66(m,1H),7.61-7.56(m,2H),7.53(d,J=8.0Hz,1H),7.24-7.20(m,1H),3.77(s,2H),3.56-3.53(m,4H),2.56-2.53(m,4H)。
实施例142:4-喹啉-3-基甲基-哌嗪-1-羧酸哌啶-3-基酰胺
在微波反应器中,在100℃,将吡啶-3-基氨基甲酸苯酯(0.3g)和3-哌嗪-1-基甲基-喹啉(0.32g)的DMSO(0.5ml)溶液加热0.5小时。反应混合物在DCM和水之间分配。合并的有机层用盐水(3×)洗涤,干燥(Na2SO4),并浓缩。残留物用柱色谱提纯,得到题述化合物,其是米色固体(80%)。
1H NMR(400MHz,CDCl3):8.92(d,J=2.3Hz,1H),8.72(d,J=2.3Hz,1H),8.28(d,J=8.1Hz,1H),8.23-8.21(m,1H),8.13-8.10(m,2H),7.84-7.82(m,1H),7.74-7.70(m,1H),7.59-7.55(m,1H),7.37-7.34(m,2H),3.77(s,2H),3,64-3.62(m,4H),2.62-2.59(m,4H)。
类似于实施例142,从3-哌嗪-1-基甲基-喹啉和特定的氨基甲酸苯酯制备实施例143-145。
实施例143:4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺
从吡啶-2-基-氨基甲酸苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):8.91(d,J=2.3Hz,1H),8.18-8.16(m,1H),8.12-8.00(m,3H),7.82-7.80(m,1H),7.73-7.62(m,2H),7.58-7.54(m,1H),6.95-6.92(m,1H),3.73(s,2H),3.57-3.55(m,4H),2.56-2.54(m,4H)。
实施例144:4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-4-基酰胺
从吡啶-4-基氨基甲酸苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):8.88(d,J=2,3Hz,1H),8.36-8.34(m,2H),8.10-8.05(m,2H),7.82-779(m,1H),7.73-7.68(m,1H),7.58-7.54(m,1H),7,40-7.38(m,2H),3.71(s,2H),3.57-3.54(m,4H),2.52-2.49(m,4H)。
实施例145:4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺
步骤1:嘧啶-2-基氨基甲酸苯酯。类似于实施例15,使用2-氨基嘧啶制备题述化合物。
步骤2.类似于实施例142,从嘧啶-2-基-氨基甲酸苯酯和3-哌嗪-1-基甲基-喹啉制备题述化合物。
1H NMR(400MHz,CDCl3):8.72(s,1H),8.10-8.02(m,1H),8.43-8.41(m,2H),7.69-7.66(m,2H),7.50-7.40(m,2H),6.82-7.70(m,1H),3,81(s,2H),3.42-3.38(m,4H),2.41-2.36(m,4H)。
实施例146:4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺
步骤1:4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸叔丁酯。类似于实施例5,从苯并[1,3]二氧戊环-5-甲醛制备题述化合物。
步骤2:1-苯并[1,3]二氧戊环-5-基甲基-哌嗪。类似于实施例6,从4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸叔丁酯制备题述化合物。
步骤3.类似于实施例142,从1-苯并[1,3]二氧戊环-5-基甲基-哌嗪和吡啶-3-基-氨基甲酸苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):8.44-8.43(m,1H),8.19-8.17(m,1H),7.98-7.95(m,1H),7.18-7.16(m,1H),6.83-6,80(m,2H),6.70(s,1H),5.89(s,2H),3.55-3.52(m,4H),3,47(s,2H),2.51-2.48(m,4H)。
类似于实施例142,制备实施例147-149。
实施例147:4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-4-基酰胺
从吡啶-4-基氨基甲酸苯酯和1-苯并[1,3]二氧戊环-5-基甲基-哌嗪制备题述化合物。
1H NMR(400MHz,CDCl3):8.33(d,J=5.3Hz,2H),7.35-7.34(m,2H),6.79(s,1H),6.68-6.67(m,2H),5.89(s,2H),3,48-3.45(m,4H),3.39(s,2H),2,43-2.40(m,4H)。
实施例148:4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺
从嘧啶-2-基氨基甲酸苯酯和1-苯并[1,3]二氧戊环-5-基甲基-哌嗪制备题述化合物。
1H NMR(400MHz.CDCl3):8.46(d,J=5.3Hz,2H),7.31(br s,1H),6.85-6.83(m,2H),6.72-6.68(m,2H),5.89(s,2H),3.56(br s,4H),3.45(bs,2H),2.48(br s,4H)。
实施例149:4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺
从吡啶-2-基氨基甲酸苯酯和1-苯并[1,3]二氧戊环-5-基甲基-哌嗪制备题述化合物。
1H NMR(400MHz,CDCl3):8.18(d,J=3.9Hz,1H),7.67-7.64(m,1H),6.66-6.64(m,2H),6.54-6.51(m,3H),5.94(s,2H),3.80(s,2H),3.53(t,J=4.9Hz,4H),2.36(t,J=4.8Hz,4H)。
实施例150:4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡
啶-3-基酰胺
步骤1:4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸叔 丁酯。类似于实施例5,从2,2-二氟-苯并[1,3]二氧戊环-5-甲醛制备题述化合物。
步骤2:1-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)哌嗪。类似于实施例6,从4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸叔丁酯制备题述化合物。
步骤3.类似于实施例142,从吡啶-3-基氨基甲酸苯酯和1-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪制备题述化合物。
1H NMR(400MHz,CDCl3):8.46(d,J=2.5Hz,1H),8.23-8.21(m,1H),7.99-7.96(m,1H),7.22-7.19(m,2H),7.11(s,1H),6.99-6.98(m,2H),3.54-3.52(m,4H),3.49(s,2H),2.46-2.44(m,4H)。
实施例151:4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡
啶-4-基酰胺
类似于实施例142,从吡啶-4-基氨基甲酸苯酯和1-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪制备题述化合物。
1H NMR(400MHz,CDCl3):8.36-8.34(d,J=6.8Hz,2H),7.41-7.39(d,J=5.8Hz,2H),7.10(s,1H),6.99(s,2H),3.55-3.53(m,4H),3.49(s,2H),2.47-2.44(m,4H)。
实施例152:4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-4-基酰胺
步骤1:嘧啶-4-基-氨基甲酸苯酯。类似于实施例15,从嘧啶-4-基胺制备题述化合物。
步骤2.类似于实施例142,从嘧啶-4-基-氨基甲酸苯酯和3-哌嗪-1-基甲基-喹啉制备题述化合物。
1H NM R(400MHz,CDCl3):8.94(d,J=2,0Hz,1H),8.76(s,1H),8.54(d,J=6.1Hz,1H),8.25(s,1H),8.20(d,J=8.8Hz,1H),7.99(d,J=5.8Hz,1H),7.87(d,J=7.8Hz,1H),7.79-7.75(m,1H),7.64-7.60(m,1H),7.38(br s,1H),3.85(s,2H),3.64(br s,4H),2.66(bs,4H)。
实施例153:4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸嘧
啶-4-基酰胺
类似于实施例142,从嘧啶-4-基-氨基甲酸苯酯和1-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪制备题述化合物。
1H NMR(400MHz,CDCl3):8.76(s,1H),8.54(d,J=6.1Hz,1H),7.97(d,J=5.3Hz,1H),7.65-7.39(m,2H),7.19-7.01(m,2H),4.03-3.55(m,6H),2.91-2.49(m,4H)。
实施例154:4-(3,4-二溴-苄基)-哌嗪-1-羧酸嘧啶-4-基酰胺
类似于实施例142,从嘧啶-4-基-氨基甲酸苯酯和1-(3,4-二溴-苄基)-哌嗪制备题述化合物。
1HNMR(400MHz,CDCl3):8.40(s,1H),8.10-7.80(m,1H),7.70-7.50(m,1H),7.58-7.45(m,1H),7.14-7.10(m,1H),6,55-6.40(m,1H),3.40(s,2H),2.87(t,J=4.8Hz,4H),2.38(t,J=4.8Hz,4H)。
实施例155:4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸
类似于实施例140,从4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸甲酯制备题述化合物。
1HNMR(400MHz,CD3OD):8.89(d,J=1,8Hz,1H),8.31(d,J=1.3Hz,1H),8.03(d,J=8.8Hz,1H),7.97-7.95(m,1H),7.90-7.87(m,2H),7.79-7.75(m,1H),7.65-7.61(m,1H),7.42-7.40(m,2H),3.81(s,2H),3.60-3.57(m,4H),2.59-2.57(m,4H)。
实施例156:4-喹喔啉-2-基甲基-哌嗪-1-羧酸苯基酰胺
类似于实施例18,从哌嗪-1-羧酸苯基酰胺和2-喹喔啉-甲醛制备题述化合物。
1HNMR(400MHz,CDCl3):8.96(s,1H),8.06-7.98(m,2H),7.72-7.66(m,2H),7.28-7.16(m,4H),7.96-7.92(m,1H),6.42(s,1H),3.85(s,2H),3.48-3.45(m,4H),3.55-3.52(m,4H)。
实施例157:4-(3,4-二氯-苄基)-哌嗪-1-羧酸苯基酰胺
类似于实施例18,从哌嗪-1-羧酸苯基酰胺和3,4-二氯苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):8.82-8.81(m,2H),7.98-7.96(m,2H),7.65-7.57(m,3H),7.16-7.13(m,1H),3.88-3.81(m,4H),3.50(s,2H),2.60-2.53(m,4H)。
实施例158:4-喹啉-2-基甲基-哌嗪-1-羧酸噻唑-2-基酰胺
步骤1:噻唑-2-基-氨基甲酸苯酯。类似于实施例15,使用2-氨基噻唑制备题述化合物。
步骤2.类似于实施例142,从噻唑-2-基-氨基甲酸苯酯和3-哌嗪-1-基甲基-喹啉制备题述化合物。
1H NMR(400MHz,CDCl3):9.03(d,J=2.0Hz,1H),8.24-8.20(m,2H),7.94(d,J=8.1Hz,1H),7.86-7.81(m,1H),7.70-7.66(m,1H),7.43(d,J=3.3Hz,1H),6.98(d,J=3.5Hz,1H),3.87(s,2H),3.73-3.69(m,4H),2.68(bs,4H)。
实施例159:4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸噻唑-2-基酰胺
类似于实施例142,从1-苯并[1,3]二氧戊环-5-基甲基-哌嗪和噻唑-2-基-氨基甲酸苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):7.30(d,J=4.0Hz,1H),6.89(s,1H),6.85(d,J=3.8Hz,1H),6.77(s,2H),5.97(s,1H),5.96(s,2H),3.62(bs,4H),3.53(s,2H),2.54(bs,4H)。
实施例160:4-(3,4-二溴-苄基)-哌嗪-1-羧酸甲基-苯基酰胺
向4-(3,4-二溴-苄基)-哌嗪-1-羧酸苯基酰胺(0.02g)的DMF(0.6ml)溶液中一次性加入NaH(60%的油分散液;3mg)。将得到的混合物搅拌30分钟,然后用MeI(0.005ml)处理,并且在室温搅拌12小时。浓缩混合物,残留物经柱色谱纯化(5%MeOH/DCM),得到产物,其是白色固体(0.015g)。
1H NMR(400MHz,CDCl3):7.54-7.50(m,2H),7.33-7.31(m,2H),7.12-7.05(m,4H),3.34(s,2H),3.22-3.20(m,6H),2.23-2.21(m,4H),1.63(s,3H)。
实施例161:4-(5-溴-2-羟基-3-甲氧基-苄基)-哌嗪-1-基-羧酸苯基酰胺
盐酸盐
向4-(5-溴-2-羟基-3-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺(1.2g)的Et2O(16ml)溶液中加入HCl(在Et2O中,2M,3.5ml)。1小时后,浓缩混合物,得到题述化合物,其是白色固体。
1H NMR(400MHz,CD3OD):7.40-7.20(m,6H),7.10-7.05(m,1H),4.37(s,2H),3.94(s,3H)。
类似于实施例161制备实施例162-163的化合物。
实施例162:4-(3,4-二溴-苄基)-哌嗪-1-羧酸苯基酰胺盐酸盐
1H NMR(400MHz,CD3OD):7.93(d,J=2.0Hz,1H),7.85(d,J=8.1Hz,1H),7.45-7.42(m,1H),7.73-7.34(m,2H),7.30-7.25(m,2H),7.07-7.02(m,1H),4.30(br s,2H),3.55-3.10(br m,8H)。
实施例163:4-喹啉-2-基甲基-哌嗪-1-羧酸苯基酰胺二盐酸盐
1H NMR(400MHz,CD3OD):8.73(s,1HH,8.42(d,J=8.4Hz,2H),8.01-7.94(m,2H),7.77-7.72(m,1.2H),7,65-7.56(m,2H),7.36-7.32(m,2H),7,16-7.10(m,2H),6.87-6.82(m,1H),4.63(s,2H),3.70(br s,4H)。
以下实施例164-167中的化合物可以使用类似于前述实施例中所述的方法进行制备。
实施例164:4-(2-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺
实施例165:4-苯并呋喃-2-基甲基-哌嗪-1-羧酸苯基酰胺
实施例166:4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-硝基苯基)-酰胺
实施例167:4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-三氟甲基-苯基)-酰胺
实施例A-J的题述化合物本身是公知的,并且可以从商业来源获得。实施例K和L中所述的化合物提供用于比较目的。实施例A-L中的所有化合物均是根据上述一般程序制备的。
实施例A:4-(3-碘-苄基)-哌嗪-1-羧酸苯基酰胺
从哌嗪-1-羧酸苯基酰胺和3-碘苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.71(s,1H),7.62-7.60(m,1H),7.36-7.26(m,5H),7.09-7.01(m,2H),6.33(s,1H),3.52-3.48(m,6H),2.49-2.46(m,4H)。
实施例B:4-苯并[1,31二氧戊环-5-基甲基-哌嗪-1-羧酸苯基酰胺
从哌嗪-1-羧酸苯基酰胺和苯并[1,3]二氧戊环-5-甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.36-7.24(m,4H),7.05-6.99(m,1H),6.86(br s,1H),6.77-6.72(m,2H),6.43(brs,1H),5.95(s,2H),3.50-3.46(m,4H),3.43(s,2H),2.46-2.42(m,4H)。
实施例B1.类似于实施例161,制备题述化合物的盐酸盐。
1H NMR(400MHz,CD3OD):7.37-7.27(m,4H),7.09-7.00(m,3H),6.90(d,J=7.8Hz,1H),6.05(s,2H),4.40-4,26(br m,2H),4.25(s,2H),3.50-3.38(br m,4H),3.10-3.00(br m,2H).
实施例C:4-(3-溴-苄基)-哌嗪-1-羧酸苯基酰胺
从哌嗪-1-羧酸苯基酰胺和3-溴苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.50(br s,1H),7.43-7.17(m,7H),7.05-7.00(m,1H),6.47(br s,1H),3.52-3,45(m,6H),2.48-2.42(m,4H)。
实施例D:4-(3,4-二甲基-苄基)-哌嗪-1-羧酸苯基酰胺
从哌嗪-1-羧酸苯基酰胺和3,4-二甲基苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.35-7.26(m,4H),7.11-7.00(m,4H),6.31(s,1H),3.51-3,48(m,6H),2.49-2.26(m,4H),2.26(d,J=3.8Hz,6H)。
实施例E:4-(4-甲基-苄基)-哌嗪-1-羧酸苯基酰胺
从哌嗪-1-羧酸苯基酰胺和4-甲基苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.35-7.00(m,9H),6.32(s,1H),3.50-3.48(m,6H),2.49-2.46(m,4H),2.35(s,3H)。
实施例F:4-苯乙基-哌嗪-1-羧酸苯基酰胺
从哌嗪-1-羧酸苯基酰胺和苯乙醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.37-7.19(m,9H),7.06-7.02(m,1H),6.31(s,1H),3.55-3.53(m,4H),2.85-2.81(m,2H),2.67-2.56(m,6H)。
实施例G:4-苯并[1,4]二氧戊环-5-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰
胺
从哌嗪-1-羧酸(4-氟-苯基)-酰胺和胡椒醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.29-7.24(m,2H),6.98-6.92(m,2H),6.85(s,1H),6.77-6.71(m,2H),6.56(s,1H),5.95(s,2H),3.50-3.45(m,6H),2.45(t,J=5.1Hz,4H)。
实施例H:4-苄基-哌啶-1-羧酸苯基酰胺
从4-苄基哌啶和异氰酸苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):7.35-7.10(m,9H),7.02-6.97(m,1H),6.50(br s,1H),4.07-4.00(m,2H),2.77(td,J=13,2.4Hz,2H),2.54(d,J=6.8Hz,2H),1.76-1.64(m,3H),1.28-1.15(m,2H)。
实施例I:4-(3-苯基-丙基)-哌嗪-1-羧酸苯基酰胺
从哌嗪-1-羧酸苯基酰胺和3-苯丙醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.36-7.16(m,9H),7.05-7.00(m,1H),6.40(br s,1H),3.52-3.47(m,4H),2.65(t,J=7.6Hz,2H),2.47-2,38(m,4H),2.39(t,J=7.4Hz,2H),1,88-1.79(m,2H)。
实施例J:4-苄基-哌嗪-1-羧酸苯基酰胺
从1-苄基哌嗪和异氰酸苯酯制备题述化合物。
1H NMR(400MHz,CDCl3):7.35-7.22(m,9H),7.02-6.97(m,1H),6.55(br s,1H),3.56(s,2H),3.48-3.45(m,4H),2,45-2.41(m,4H)。
实施例K:4-(2-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺
从哌嗪-1-羧酸苯基酰胺和2-苄氧基苯甲醛制备题述化合物。
1H NMR(400MHz,CDCl3):7.49-7.20(m,11H),7.05-6.92(m,3H),6.41(s,1H),5.08(s,2H),3.65(s,2H),3.51-3.45(m,4H),2.55-2.49(m,4H)。
实施例L:4-(6-溴-1、2,3,4-四氢-萘-2-基)-哌嗪-1-羧酸苯基酰胺
从哌嗪-1-羧酸苯基酰胺和6-溴-3,4-二氢-1H-萘-2-酮制备题述化合物。
1H NMR(400MHz,CDCl3):7.37-7.21(m,6H),7.06-7.02(m,1H),6.96-6.94(m,1H),6.33(s,1H),3.55-3.53(m,4H),2.94-2.64(m,9H),2.12-2.08(m,1H),1.69-1.61(m,1H)。
生物方法
检定方法1
T84冷冻团粒(pellet)(包含在1-4×15cm培养皿中)在300ml的FAAH检定缓冲液(125mM Tris、1mM EDTA、0.2%甘油、0.02%TritonX-100、0.4mM Hepes,pH9)中均化。从50μL细胞匀浆、10μL测试化合物和40μL花生四烯酸乙醇胺[1-3H-乙醇胺](3H-AEA;Perkin-Elmer,10.3Ci/mmol)制备检定混合物,后者最后加入且最终的示踪浓度为200nM。反应混合物在室温培养1小时。在培养过程中,用25μL活性炭(多层筛柱负载物(Multiscreen column loader),目录号MACL09625,Millipore)装填96-孔多层筛(Multiscreen)滤板(目录号MAFCNOB50;Millipore,Bedford,Massachussetts,USA),然后用100μL MeOH洗涤一次。同样在培养过程中,用100μL的MicroScint40(目录号6013641,Packard Bioscience,Meriden,Connecticut,USA)装填96-孔DYNEX Microlite板(目录号NL510410)。培养1小时后,将60μL反应混合物转移到炭板上,然后使用离心配准框(Centrifuge AlignmentFrames)(目录号MACF09604,Millipore)将其装配到DYNEX板的顶部。未结合的标记乙醇胺被离心到下面的板内(2000rpm,5分钟),该板如上所述地预装填了闪烁体。将板密封,然后在室温放置1小时,然后在Hewlett Packard TopCount上计数。在此检定中,所测试的化合物的结果在表1中列出
表1
实施例 | IC50(nM) | 实施例 | IC50(nM) | Ex. | IC50(nM) | ||
18 | 17 | 63 | 69 | 111 | 250 | ||
19 | 19 | 64 | 220 | 112 | 61 | ||
20 | 19 | 65 | 9 | 113 | 8000 | ||
21 | 31 | 66 | 1600 | 114 | 2300 | ||
22 | 26 | 67 | 8000 | 115 | 4000 | ||
23 | 73 | 68 | 95 | 116 | 240 | ||
24 | 52 | 69 | 23 | 117 | 360 | ||
25 | 57 | 70 | 410 | 118 | 27 | ||
26 | 79 | 71 | 6000 | 119 | 1000 | ||
27 | 69 | 72 | 110 | 120 | 170 | ||
28 | 80 | 73 | 29 | 121 | 210 | ||
29 | 120 | 74 | 2000 | 122 | 220 | ||
30 | 180 | 75 | 24 | 123 | 1500 | ||
31 | 200 | 76 | 350 | 124 | 1800 | ||
32 | 220 | 77 | 32 | 125 | 10000 | ||
33 | 280 | 78 | 5000 | 126 | 2000 |
34 | 290 | 79 | 8000 | 127 | 2000 | ||
35 | 460 | 80 | 330 | 128 | 2000 | ||
36 | 470 | 81 | 6000 | 129 | 2000 | ||
37 | 590 | 82 | 80 | 130 | 160 | ||
38 | 620 | 83 | 480 | 131 | 33 | ||
39 | 1100 | 84 | 2500 | 132 | 3000 | ||
40 | 1100 | 85 | 19 | 133 | 50 | ||
41 | 1300 | 86 | 21 | 134 | 65 | ||
42 | 2000 | 87 | 48 | 135 | 83 | ||
43 | 4000 | 88 | 100 | 136 | 67 | ||
44 | 4000 | 89 | 22 | 137 | 1000 | ||
45 | >10000 | 90 | 75 | 138 | 59 | ||
46 | >10000 | 91 | 130 | 139 | 380 | ||
47 | >10000 | 92 | 240 | 161 | 210 | ||
48 | 3500 | 93 | 460 | 162 | 38 | ||
49 | 4500 | 94 | 470 | 163 | 23 | ||
50 | 3000 | 95 | 500 | A | 120 | ||
51 | 6000 | 96 | >10000 | B | 350 | ||
52 | 87 | 97 | 120 | B1 | 1200 | ||
53 | 230 | 98 | 130 | C | 280 | ||
54 | 170 | 99 | 1600 | D | 630 | ||
55 | 28 | 100 | 200 | E | 1300 | ||
56 | 9000 | 101 | 360 | F | >10000 | ||
57 | 54 | 102 | 540 | G | 1600 | ||
58 | 100 | 103 | 6000 | H | 270 | ||
59 | 21 | 104 | 690 | I | 1700 | ||
60 | 9 | 108 | 270 | J | 2000 | ||
61 | 20 | 109 | 200 | K | >10000 | ||
62 | 18 | 110 | 200 | L | 370 |
检定方法2
A.带有人FAAH的细胞的转染
在转染之前,将带有融合(confluent)的单层SK-N-MC细胞的10-cm组织培养皿分裂两天。使用无菌技术,除去培养基,并加入胰蛋白酶将细胞从培养皿中移出。然后将五分之一细胞放置到新的10-cm培养皿中。细胞在37℃培养皿中、在含有5%CO2的含10%小牛血清的Eagle最小必需培养基(Minimal Essential Media Eagle)中生长。两天后,细胞大约融合80%。用胰蛋白酶将这些细胞从培养皿中移出,然后在临床离心机(clinical centrifuge)压成团粒。将团粒重新悬浮在400μL完全培养基中,然后转移到电极间隙为0.4cm的细胞电穿孔管中。将超螺旋的人FAAH cDNA(1μg)加入到细胞中并混合。细胞电穿孔的电压设定为0.25kV,且电容设定为960μF。细胞电穿孔后,将细胞用完全培养基(10ml)稀释,然后涂到4个10-cm培养皿上。由于细胞电穿孔功效的可变性,涂成4种不同的细胞浓度。所使用的比率是1∶20、1∶10和1∶5,剩余的细胞加入到第四培养皿。在加入选择培养基(含有600μg/ml G418的完全培养基)之前,使细胞恢复24小时。10天后,分析培养皿中存活的细胞群数。使用细胞群良好分隔的培养皿。将来自独立细胞群的细胞分离并测试。当通过花生四烯酸乙醇胺水解测量时,显示最大FAAH活性的细胞用于进一步研究。
B.FAAH检定
将T84冷冻细胞团粒或转染的SK-N-MC细胞(包含在1×15cm培养皿中)在50ml FAAH检定缓冲液(125mM Tris、1mM EDTA、0.2%甘油、0.02%Triton X-100、0.4mM Hepes,pH9)中均化。检定混合物由50μL细胞匀浆、10μL测试化合物和40μL花生四烯酸乙醇胺[1-3H-乙醇胺](3H-AEA,Perkin-E1mer,10.3Ci/mmol)组成,后者最后加入且最终示踪浓度为80nM。反应混合物在室温培养1小时。在培养过程中,用25μL活性炭(多层筛柱负载物,目录号MACL09625,Millipore)装填96-孔多层筛(Multiscreen)滤板(目录号MAFCNOB50;Millipore,Bedford,Massachussetts,USA),然后用100μLMeOH洗涤一次。同样在培养过程中,用100μL MicroScint40(目录号6013641,Packard Bioscience,Meriden,Connecticut,USA)装填96-孔DYNEXMicrolite板(目录号NL510410)。培养1小时后,将60μL反应混合物转移到炭板上,然后使用离心配准框(目录号MACF09604,Millipore)将其装配到DYNEX板的顶部。未结合的标记乙醇胺被离心到下面的板内(2000rpm,5分钟),该板如上所述地预装填了闪烁体。将板密封,然后在室温放置1小时,然后在Hewlett Packard TopCount上计数。在此检定中,所测试的化合物的结果在表2中列出。
表2
实施例 | IC50(nM) | 实施例 | IC50(nM) | |
18 | 23 | 145 | 8000 | |
21 | 19 | 146 | 380 | |
32 | 380 | 147 | 3000 | |
34 | 330 | 148 | >10000 | |
41 | 3000 | 149 | 4000 | |
52 | 100 | 150 | 130 | |
59 | 16 | 151 | 1700 | |
98 | 220 | 152 | 4000 | |
105 | >10000 | 153 | 1000 | |
106 | 230 | 154 | 282 | |
107 | 650 | 155 | 8000 | |
140 | >10000 | 156 | 840 | |
141 | 5000 | 157 | 65 | |
142 | 4100 | 158 | >10000 |
143 | 1800 | 159 | >10000 | |
144 | 2000 | 160 | >10000 |
检定方法3
A.带有大鼠FAAH的细胞的转染
在转染之前,将带有融合的单层SK-N-MC细胞的10-cm组织培养皿分裂两天。使用无菌技术,除去培养基,并加入胰蛋白酶将细胞从培养皿中移出。然后将五分之一细胞放置到新的10-cm培养皿中。细胞在37℃培养皿中、在含有5%CO2的含10%小牛血清的Eagle最小必需培养基中生长。两天后,细胞大约融合80%。用胰蛋白酶将这些细胞从培养皿中移出,然后在临床离心机中压成团粒。将团粒重新悬浮在400μL完全培养基中,然后转移到电极间隙为0.4cm的细胞电穿孔管中。将超螺旋的大鼠FAAH cDNA(1μg)加入到细胞中并混合。细胞电穿孔的电压设定为0.25kV,且电容设定为960μF。细胞电穿孔后,将细胞用完全培养基(10ml)稀释,然后涂到4个10-cm培养皿上。由于细胞电穿孔功效的可变性,涂成4种不同的细胞浓度。所使用的比率是1∶20、1∶10和1∶5,剩余的细胞加入到第四培养皿。在加入选择培养基(含有600μg/ml G418的完全培养基)之前,使细胞恢复24小时。10天后,分析培养皿中存活的细胞群数。使用细胞群良好分隔的培养皿。将来自个体细胞群的细胞分离并测试。当通过花生四烯酸乙醇胺水解测量时,显示最大FAAH活性的细胞用于进一步研究。
B.FAAH检定
将T84冷冻细胞团粒或转染的SK-N-MC细胞(包含在1×15cm培养皿中)在50ml FAAH检定缓冲液(125mM Tris、1mM EDTA、0.2%甘油、0.02%Triton X-100、0.4mM Hepes,pH9)中均化。检定混合物由50μL细胞匀浆、10μL测试化合物和40μL花生四烯酸乙醇胺[1-3H-乙醇胺](3H-AEA,Perkin-Elmer,10.3Ci/mmol)组成,后者最后加入且最终示踪浓度为80nM。反应混合物在室温培养1小时。在培养过程中,用25μL活性炭(多层筛柱负载物,目录号MACL09625,Millipore)装填96-孔多层筛滤板(目录号MAFCNOB50;Millipore,Bedford,MA,USA),然后用100μLMeOH洗涤一次。同样在培养过程中,用100μLMicroScint40(目录号6013641,Packard Bioscience,Meriden,CT,USA)装填96-孔DYNEX Microlite板(目录号NL510410)。培养1小时后,将60μL反应混合物转移到炭板上,然后使用离心配准框(目录号MACF09604,Millipore)将其装配到DYNEX板的顶部。未结合的标记乙醇胺被离心到下面的板内(2000rpm,5分钟),该板如上所述地预装填了闪烁体。将板密封,然后在室温放置1小时,然后在Hewlett Packard TopCount上计数。在此检定中,所测试的化合物的结果在表3中列出。
表3
实施例 | IC50(nM) | 实施例 | IC50(nM) | |
18 | 265 | 143 | 8000 | |
19 | 350 | 144 | 10000 | |
21 | 180 | 145 | 10000 | |
22 | 1400 | 146 | 6500 | |
26 | 130 | 147 | 10000 | |
32 | 10000 | 148 | 10000 | |
34 | 410 | 149 | 10000 | |
41 | 10000 | 150 | 290 | |
52 | 290 | 151 | 2000 | |
57 | 430 | 152 | 10000 | |
59 | 50 | 153 | 60000 |
68 | 610 | 154 | 2000 | |
98 | 6500 | 155 | 10000 | |
105 | 10000 | 156 | 8000 | |
106 | 2000 | 157 | 350 | |
107 | 8000 | 158 | 10000 | |
111 | 2000 | 159 | 10000 | |
112 | 370 | 160 | 10000 | |
140 | 10000 | 162 | 270 | |
141 | 8000 | B | 8000 | |
142 | 4000 | G | 10000 |
尽管本发明已经参考示例性和优选实施方式进行了说明,要理解的是,本发明不意味着限于前述具体描述,而是通过按照专利法原则正确解释的所附权利要求来限定。
权利要求书(按照条约第19条的修改)
1.一种式(I)的化合物,或者这种化合物的药学可接受的盐、药学可接受的前药或药学活性的代谢产物:
其中:
·Z是-N-或>CH;
·R1是-H或-C1-4烷基;
·Ar1是2-噻唑基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基或苯基,每个基团是未取代的、或者在碳环成员上被一个或两个Ra部分所取代;
其中每个Ra部分独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自独立地是-H或-C1-4烷基;且
·Ar2是:
(a)未取代的1-萘基;或者菲基、芘基、芴基、2-萘基或N-Rd-9H-咔唑基部分,其中Rd选自-H、-C1-4烷基和苯基,每个所述部分是未取代的,或者被1个、2个或3个Re取代基所取代,
其中每个Re取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(b)在两个相邻的环碳原子处与选自下述的基团稠合形成稠环结构的苯基:具有0或1个双键的-(CH2)3-5-、-OCH2CH2O-和-OCF2O-;或者在相邻的环碳原子上被-OCH2O-取代形成4-苯并[1,3]二氧戊环基的苯基;每个苯基部分进一步是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(c)Ar6,在这里Ar6是6-元单环杂芳基,其具有作为连接点的碳原子且具有一个或两个氮杂原子,其是未取代的或者被1个、2个或3个如前所定义的Re取代基所取代;
(d)具有一个选自N、O和S的杂原子的9-元或10-元稠合二环杂芳基,其具有作为连接点的碳原子并任选具有至多四个另外的被氮置换的碳原子,所述稠合二环杂芳基具有不多于5个杂原子,其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(e)在3-位或4-位上被Rg取代的苯基,其任选地进一步被1个、2个或3个取代基Rh所取代,
其中每个Rg独立地选自任选被-NRiRj取代的-C2-8烷基、-C2-8烯基、-OC3-8环烷基、-OC3-8杂环烷基和-O-C2-10烷基,其中Ri和Rj各自独立地是-H或-C1-8烷基,或者Ri和Rj与所连接的氮环原子一起形成5-元、6-元或7-元杂环烷基环,该杂环烷基环上一个另外的碳环原子任选被O、S、>NH或者>NC1-4烷基代替;并且
每个Rh取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(f)在3位或4位上被-L-Ar3取代的苯基,其中:
□L是选自-(CH2)1-3-、-CH=CH-、-O-、-OCH2、-CH2O-、-NH-、>NC1-4烷基、>S(=O)0-2、-OSO2-、-C≡C-、-C(=O)-和共价键的连接子;且
□Ar3是选自下列的部分:
(1)苯基、萘基和菲基,
(2)Ar6’,其中Ar6’是具有作为连接点的碳原子的6-元单环杂芳基,其具有一个或两个氮杂原子,
(3)Ar5’,其中Ar5’是具有作为连接点的碳原子的5-元单环杂芳基,其具有一个选自O、S、>NH和>NRf的杂原子,其中Rf是-C1-8烷基或-C0-3苯烷基,且Ar5’具有0个、1个、2个或3个另外的氮杂原子,以及
(4)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有作为连接点的碳,该杂芳基还任选具有至多四个被氮代替的另外的碳环原子,所述稠合双环杂芳基具有不多于5个杂原子;
其中部分(1)-(4)中的每个均任选在相邻的碳上被下述基团双取代以形成稠环结构:-OC1-4亚烷基-O-、-(CH2)2-3NH-、-(CH2)1-2NH(CH2)-、-(CH2)2-3N(C1-4烷基)-或-(CH2)1-2N(C1-4烷基)(CH2)-,并且进一步任选地被1个、2个或3个取代基Rk所取代,
其中每个Rk取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(g)2-羟基苯基或2-甲氧基苯基,其是未取代的或者被1个、2个或3个R1取代
其中每个R1取代基独立地选自-CH3、6-C2-4烷基、6-C2-4烯基、-OH、-OCH3、6-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(h)4-卤代苯基,其是未取代的、或者被一个、两个或三个Rm取代基所取代,
其中每个Rm取代基独立地选自-CH3、2-C2-4烷基、2-C2-4烯基、3-羟基、4-羟基、-OCH3、2-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;或者
(i)2-溴苯基、3-甲基苯基、3-甲氧基苯基、4-甲氧基苯基或3,4-二甲氧基苯基;
其中当Ar2是4-氟苯基、3,4-二氟苯基、4-氯苯基或3-甲氧基苯基时,Ar1不是未取代的苯基或者被4-Cl、-NO2、-CF3或4-CO2Et取代的苯基;并且
当Ar2是3,4-二氯苯基时,Ar1不是被4-Cl、-NO2、-CF3或4-CO2Et取代的苯基。
2.根据权利要求1所述的化合物,其中R1是甲基。
3,根据权利要求1所述的化合物,其中Ar1是2-噻唑基。
4.根据权利要求1所述的化合物,其中Ar2是2-甲氧基苯基,其是未取代的或者被1个、2个或三个取代基R1所取代。
5.根据权利要求1所述的化合物,其中Ar2是3,4-二氯苯基。
6.根据权利要求1所述的化合物,或者这种化合物的药学可接受的盐、药学可接受的前药或药学活性的代谢产物,其中
·Z是-N-或>CH;
·R1是-H或-C1-4烷基;
·Ar1是2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基或苯基,每个基团是未取代的或者在碳环成员上被一个或两个Ra部分所取代;
其中每个Ra部分独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自独立地是-H或-C1-4烷基;且
·Ar2是:
(a)未取代的1-萘基;或者菲基、芘基、芴基、2-萘基或N-Rd-9H-咔唑基部分,其中Rd选自-H、-C1-4烷基和苯基,每个所述部分是未取代的,或者被1个、2个或3个Re取代基所取代,
其中每个Re取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自如前所定义;
(b)在两个相邻的环碳原子处与选自下述的基团稠合形成稠环结构的苯基:具有0或1个双键的-(CH2)3-5-、-OCH2CH2O-和-OCF2O-;或者在相邻的环碳原子上被-OCH2O-取代形成4-苯并[1,3]二氧戊环基的苯基;每个苯基部分进一步是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(c)Ar6,在这里Ar6是6-元单环杂芳基,其具有作为连接点的碳原子且具有一个或两个氮杂原子,其是未取代的或者被1个、2个或3个如前所定义的Re取代基所取代;
(d)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有作为连接点的碳原子并任选具有至多四个另外的被氮置换的碳原子,所述稠合双环杂芳基具有不多于5个杂原子,其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(e)在3-位或4-位上被Rg取代的苯基,其任选地进一步被1个、2个或3个取代基Rh所取代,
其中每个Rg独立地选自任选被--NRiRj取代的-C2-8烷基、-C2-8烯基、-OC3-8环烷基、-OC3-8杂环烷基和-O-C2-10烷基,其中Ri和Rj各自独立地是-H或-C1-8烷基,或者Ri和Rj与所连接的氮环原子一起形成5-元、6-元或7-元杂环烷基环,该杂环烷基环上一个另外的碳环原子任选被O、S、>NH或者>NC1-4烷基代替;并且
每个Rh取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(f)在3位或4位上被-L-Ar3取代的苯基,其中:
□L是选自-(CH2)1-3-、-CH=CH-、-O-、-OCH2、-CH2O-、-NH-、>NC1-4烷基、>S(=O)0-2、-OSO2-、-C≡C-、-C(=O)-和共价键的连接子;且
□Ar3是选自下列的部分:
(1)苯基、萘基和菲基,
(2)Ar6’,其中Ar6’是具有作为连接点的碳原子的6-元单环杂芳基,其具有一个或两个氮杂原子,
(3)Ar5’,其中Ar5’是具有作为连接点的碳原子的5-元单环杂芳基,其具有一个选自O、S、>NH和>NRf的杂原子,其中Rf是-C1-8烷基或C0-3苯烷基,且Ar5’具有0个、1个、2个或3个另外的氮杂原子,以及
(4)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有作为连接点的碳,该杂芳基还任选具有至多四个被氮代替的另外的碳环原子,所述稠合双环杂芳基具有不多于5个杂原子;
其中部分(1)-(4)中的每个均任选在相邻的碳上被下述基团双取代以形成稠环结构:-OC1-4亚烷基-O-、-(CH2)2-3NH-、-(CH2)1-2NH(CH2)-、-(CH2)2-3N(C1-4烷基)-或-(CH2)1-2N(C1-4烷基)(CH2)-,并且进一步任选地被1个、2个或3个取代基Rk所取代,
其中每个Rk取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(g)2-羟基苯基,其是未取代的或者被1个、2个或3个R1取代
其中每个R1取代基独立地选自-CH3、6-C2-4烷基、6-C2-4烯基、-OH、-OCH3、6-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义
(h)4-卤代苯基,其是未取代的或者被一个、两个或三个Rm取代基所取代,
其中每个Rm取代基独立地选自-CH3、2-C2-4烷基、2-C2-4烯基、3-羟基、4-羟基、-OCH3、2-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;或者
(i)2-溴苯基、3-甲基苯基、3-甲氧基苯基、4-甲氧基苯基或3,4-二甲氧基苯基;
其中当Ar2是4-氟苯基、3,4-二氟苯基、4-氯苯基或3-甲氧基苯基时,Ar1不是未取代的苯基或者被4-Cl、-NO2、-CF3或4-CO2Et取代的苯基;并且
当Ar2是3,4-二氯苯基时,Ar1不是被4-Cl、-NO2、-CF3或4-CO2Et取代的苯基。
7.根据权利要求6所述的化合物,其中Z是-N-。
8.根据权利要求7所述的化合物,其中R1是H。
9.根据权利要求7所述的化合物,其中Ar2是菲-9-基、芘-1-基、9H-芴-2-基、1-萘基、2-萘基、1-羟基萘-2-基、6-甲氧基萘-2-基或9-乙基-9H-咔唑-3-基,这些基团的每个均是未取代的或者被一个、两个或三个如前所述的Re取代基所取代。
10.根据权利要求7所述的化合物,其中Ar2是茚满基、茚基、四氢化萘基、2,3-二氢-苯并呋喃基、苯并二氢吡喃基、2,3-二氢-苯并[1,4]二氧芑基或2,2-二氟-苯并[1,3]二氧戊环基,这些基团的每个均是未取代的或者被一个、两个或三个如前所述的Re取代基所取代。
11.根据权利要求7所述的权利要求,其中Ar2是苯基-1H-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基或6-溴-吡啶-2-基,这些基团的每个均是未取代的或者被一个、两个或三个如前所述的Re取代基所取代。
12.根据权利要求7所述的权利要求,其中Ar2是在3-位或4-位上被-L-Ar3取代的苯基,在这里L是-CH=CH-、-O-、-OCH2-、-SO2-、-OSO2-或共价键。
13.根据权利要求7所述的化合物,其中Ar2是2-羟基苯基、5-溴-2-羟基-3-甲氧基苯基或5-溴-2-羟基苯基。
14.根据权利要求8所述的化合物,其中Ar1是2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基或4-嘧啶基,这些基团的每个均是未取代的或者在碳环原子处被一个或两个如前所述的Ra取代基所取代。
15.根据权利要求8所述的化合物,其中Ar1是未取代的苯基或者在碳环原子上被一个或两个如前所述的Ra部分取代的苯基。
16.根据权利要求8所述的化合物,其中Ar1是2-氟苯基、3-氟苯基、4-氟苯基、2,4-二氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-甲酯基苯基、3-甲酯基苯基、4-甲酯基苯基、2-羧基苯基、3-羧基苯基或未取代的苯基。
17.根据权利要求16所述的化合物,其中Ar2是未取代的2,2-二氟-苯并[1,3]二氧戊环基。
18.根据权利要求16所述的化合物,其中Ar2是未取代的4-苯并[1,3]二氧戊环基。
19.根据权利要求16所述的化合物,其中Ar2是2-吲哚基、3-吲哚基、2-喹啉基、3-喹啉基或2-喹喔啉基,这些基团的每个均是未取代的或者被一个、两个或三个如前所述的Re取代基所取代。
20.根据权利要求16所述的化合物,其中Ar2是2-喹啉基或3-喹啉基。
21.根据权利要求16所述的化合物,其中Ar2是4-乙基苯基、4-异丙基苯基、3-乙烯基苯基、3-乙氧基苯基、4-乙氧基苯基、3-丙氧基苯基、4-丙氧基苯基、3-异丁氧基苯基、4-异丁氧基苯基、3-异丁氧基苯基、4-异丁氧基苯基、4-环己氧基苯基、3-(2-二甲基氨基乙氧基)苯基、3-(2-哌啶-1-基乙氧基)、3-(3-二甲基氨基丙氧基)苯基或3-(3-哌啶-1-基-丙氧基)苯基。
22.根据权利要求16所述的化合物,其中Ar3是4-氯苯基、3,4-二氯苯基、4-甲基苯基、4-叔丁基苯基、3-三氟甲基苯基、4-甲氧基苯基、3,5-二氯苯基、1-萘基、2-萘基、3-氯苯基、9-菲基、4-甲酯基苯基、4-甲磺酰基苯基、3-甲氧基苯基、苯并[1,3]二氧戊环-5-基或未取代的苯基。
23.根据权利要求16所述的化合物,其中Ar2是3,4-二溴苯基、3-溴-4-氟苯基或4-氯-3-三氟甲基。
24.根据权利要求16所述的化合物,其中Ar2是3,4-二溴苯基。
25.一种式(I)的化合物或者这种化合物的药学可接受的盐、药学可接受的前药或药学活性的代谢产物:
其中:
·Z是-N-或>CH;
·R1是-H或-C1-4烷基;
·Ar1是2-噻唑基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基或苯基,这些基团的每个均是未取代的或者在碳环成员上被一个或两个Re部分所取代;
其中,每个Re部分独立地选自乙基、异丙基、叔丁基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自独立地是-H或-OC1-4烷基;并且
·Ar2是:
(a)在两个相邻的环碳原子处与选自-OCH2O-的基团稠合形成稠环结构的苯基;每个苯基部分进一步是未取代的,或者被1个、2个或3个Re取代基所取代;
其中每个Re取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;或者
(b)Ar5,其中Ar5是呋喃基、噁唑基、异噁唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、噻吩基、噻唑基、异噻唑基、吡咯基、吡唑基、1,2,3-三唑基、1,2,4-三唑基或四唑基,这些基团的每个均是未取代的或者被一个、两个或三个如前所述的Re取代基所取代。
26.一种选自下述的化合物及其药学可接受的盐:
4-萘-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[b]噻吩-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-碘-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(5-溴-2-羟基-3-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-溴-4-氟-苄基)-哌嗪-1-羧酸苯基酰胺;
4-茚满-5-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[b]噻吩-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-异丙基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-乙基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(5-溴-2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2,3-二氢-苯并[1,4]二氧芑-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(3-乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2,3-二氢-苯并呋喃-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-萘-1-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-吡啶-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-吡啶-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-吡啶-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-异丙氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-联苯-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-喹啉-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[1,3]二氧戊环-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(6-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(8-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(2-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-萘-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺;;
4-(1-羟基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(3-对甲苯氧基苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-叔丁基苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-三氟甲基-苯氧基)苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-甲氧基-苯氧基)-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(6-甲氧基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(菲-9-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-芘-1-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(6-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-联苯-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(6-溴-吡啶-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-氯-苯磺酰基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2-氯-8-甲基-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(3,5-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(9H-芴-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(9-乙基-9H-咔唑-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苯乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-氯-3-三氟甲基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[2,5-二甲基-1-(3-三氟甲基-苯基)-1H-吡咯-3-基甲基]-哌嗪-1-羧酸苯基酰胺;
4-(2-溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸间甲苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸对甲苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸邻甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸邻甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸对甲苯基酰胺;
2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸间甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2,4-二氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氟-苯基)酰胺;
4-苄基-哌啶-1-羧酸对甲苯基酰胺;
4-苄基-哌啶-1-羧酸间甲苯基酰胺;
4-苄基-哌啶-1-羧酸(2-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-4-基酰胺;、
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-2-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-3-基酰胺;
4-(4-环己氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-丙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-异丁氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-乙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(4-丙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(4-异丁氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-[3-(2-二甲基氨基-乙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(2-哌啶-1-基-乙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-二甲基氨基-丙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(4-乙氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-氟-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(菲-9-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)苯氧基]-苯甲酸甲酯;
4-[3-(4-甲磺酰基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(苯并[1,3]二氧戊环-5-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
甲磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
4-氯-苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-4-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-4-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡啶-3-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡啶-4-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;和
4-喹喔啉-2-基甲基-哌嗪-1-羧酸苯基酰胺。
27.一种选自下述的化合物及其药学可接受的盐:
4-(3,4-二氯-苄基)-哌嗪-1-羧酸苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸噻唑-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸噻唑-2-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸甲基-苯基-酰胺;
4-(2-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-苯并呋喃-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-硝基苯基)酰胺;和
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-三氟甲基-苯基)酰胺。
28.一种治疗患有或被诊断有由FAAH活性介导的疾病、障碍或医学症状的方法,该方法包括对需要这种治疗的个体给予有效量的式(I)的化合物,或者这种化合物的药学可接受的盐、药学可接受的前药或药学活性的代谢产物:
其中:
·Z是-N-或>CH;
·R1是-H或-C1-4烷基;
·Ar1是2-噻唑基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基或苯基,每个基团是未取代的、或者在碳环成员上被一个或两个Ra部分所取代;
其中每个Ra部分独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自独立地是-H或-C1-4烷基;且
·Ar2是:
(a)菲基、芘基、芴基、萘基或N-Rd-9H-咔唑基部分,其中Rd选自-H、-C1-4烷基和苯基,每个所述部分是未取代的,或者被1个、2个或3个Re取代基所取代,
其中每个Re取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自如前所定义;
(b)在两个相邻的环碳原子处与选自下述的基团稠合形成稠环结构的苯基:具有0或1个双键的-(CH2)3-5-、-OCH2CH2O-、-OCF2O-和-OCH2O-,其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(c)Ar6,在这里Ar6是6-元单环杂芳基,其具有作为连接点的碳原子且具有一个或两个氮杂原子,其是未取代的或者被1个、2个或3个如前所定义的Re取代基所取代;
(d)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有作为连接点的碳原子并任选具有至多四个另外的被氮置换的碳原子,所述稠合双环杂芳基具有不多于5个杂原子,其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(e)在3-位或4-位上被Rg取代的苯基,其任选地进一步被1个、2个或3个取代基Rh所取代,
其中每个Rg独立地选自任选被-NRiRj取代的-C2-8烷基、-C2-8烯基、-OC3-8环烷基、-OC3-8杂环烷基和-O-C2-10烷基,其中Rj和Rj各自独立地是-H或-C1-8烷基,或者Ri和Rj与所连接的氮环原子一起形成5-元、6-元或7-元杂环烷基环,该杂环烷基环上一个另外的碳环原子任选被O、S、>NH或者>NC1-4烷基代替;并且
每个Rh取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(f)在3位或4位上被-L-Ar3取代的苯基,其中:
·L是选自-(CH2)1-3-、-CH=CH-、-O-、-OCH2、-CH2O-、-NH-、>NC1-4烷基、>S(=O)0-2、-OSO2-、-C≡C-、-C(=O)-和共价键的连接子;且
·Ar3是选自下列的部分:
(1)苯基、萘基和菲基,
(2)Ar6’,其中Ar6’是具有作为连接点的碳原子的6-元单环杂芳基,其具有一个或两个氮杂原子,
(3)Ar5’,其中Ar5’是具有作为连接点的碳原子的5-元单环杂芳基,其具有一个选自O、S、>NH和>NRf的杂原子,其中R1是-C1-8烷基或-C0-3苯烷基,且Ar5’具有0个、1个、2个或3个另外的氮杂原子,以及
(4)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有作为连接点的碳,并任选具有至多四个被氮代替的另外的碳环原子,所述稠合双环杂芳基具有不多于5个杂原子;
其中部分(1)-(4)中的每个均任选在相邻的碳上被下述基团双取代以形成稠环结构:-OC1-4亚烷基O-、-(CH2)2-3NH-、-(CH2)1-2NH(CH2)-、-(CH2)2-3N(C1-4烷基)-或-(CH2)1-2N(C1-4烷基)(CH2)-,并且进一步任选地被1个、2个或3个取代基Rk所取代,
其中每个Rk取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(g)2-羟基苯基或2-甲氧基苯基,其是未取代的或者被1个、2个或3个R1取代
其中每个R1取代基独立地选自-CH3、6-C2-4烷基、6-C2-4烯基、-OH、-OCH3、6-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(h)4-卤代苯基,其是未取代的或者被一个、两个或三个Rm取代基所取代,
其中每个Rm取代基独立地选自-CH3、2-C2-4烷基、2-C2-4烯基、3-羟基、4-羟基、-OCH3、2-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、SC1-4烷基、SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;或者
(i)2-溴苯基、3-甲基苯基、3-甲氧基苯基、4-甲氧基苯基或3,4-二甲氧基苯基。
29.一种治疗患有或被诊断有由FAAH活性介导的疾病、障碍或医学症状的方法,该方法包括对需要这种治疗的个体给予有效量的式(I)的化合物,或者这种化合物的药学可接受的盐、药学可接受的前药或药学活性的代谢产物:
其中:
·Z是-N-或>CH;
·R1是-H或-C1-4烷基;
·Ar1是2-噻唑基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基或苯基,这些基团的每个均是未取代的或者在碳环成员上被一个或两个Re部分所取代;
其中,每个Re部分独立地选自乙基、异丙基、叔丁基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和CN,其中Rb和Rc各自独立地是-H或-OC1-4烷基;并且
·Ar2是:
(a)在两个相邻的环碳原子处与选自-OCH2O-的基团稠合形成稠环结构的苯基;每个苯基部分进一步是未取代的,或者被1个、2个或3个Re取代基所取代;
其中每个Re取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;或者
(b)Ar6,其中Ar6是呋喃基、噁唑基、异噁唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、噻吩基、噻唑基、异噻唑基、吡咯基、吡唑基、1,2,3-三唑基、1,2,4-三唑基或四唑基,这些基团的每个均是未取代的或者被一个、两个或三个如前所述的Re取代基所取代。
30.一种治疗患有或被诊断有由FAAH活性介导的疾病、障碍或医学症状的方法,该方法包括对需要这种治疗的个体给予有效量的式(I)的化合物,以及这种化合物的药学可接受的盐:
4-萘-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[b]噻吩-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-碘-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(5-溴-2-羟基-3-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-溴-4-氟-苄基)-哌嗪-1-羧酸苯基酰胺;
4-茚满-5-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[b]噻吩-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-异丙基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-乙基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(5-溴-2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2,3-二氢-苯并[1,4]二氧芑-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2,3-二氢-苯并呋喃-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(3-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-萘-1-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-甲基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-吡啶-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-吡啶-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-吡啶-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-异丙氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-联苯-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-喹啉-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[1,3]二氧戊环-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(6-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(8-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(2-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-萘-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺;;
4-(1-羟基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(3-对甲苯氧基苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-叔丁基苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-三氟甲基-苯氧基)苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-甲氧基-苯氧基)-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(6-甲氧基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(菲-9-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-芘-1-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(6-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-联苯-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(6-溴-吡啶-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-氯-苯磺酰基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2-氯-8-甲基-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(3,5-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(9H-芴-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(9-乙基-9H-咔唑-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苯乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-氯-3-三氟甲基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[2,5-二甲基-1-(3-三氟甲基-苯基)-1H-吡咯-3-基甲基]-哌嗪-1-羧酸苯基酰胺;
4-(2-溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-氟-苯基)酰胺;
4-(3,4-二-溴-苄基)-哌嗪-1-羧酸(4-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸间甲苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸对甲苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸邻甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸邻甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸对甲苯基酰胺;
2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸间甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2,4-二氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氟-苯基)酰胺;
4-苄基-哌啶-1-羧酸对甲苯基酰胺;
4-苄基-哌啶-1-羧酸间甲苯基酰胺;
4-苄基-哌啶-1-羧酸(2-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-4-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-2-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-3-基酰胺;
4-(4-环己氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-丙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-异丁氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-乙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(4-丙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(4-异丁氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-[3-(2-二甲基氨基-乙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(2-哌啶-1-基-乙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-二甲基氨基-丙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(4-乙氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(菲-9-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)苯氧基]-苯甲酸甲酯;
4-[3-(4-甲磺酰基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(苯并[1,3]二氧戊环-5-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
甲磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
4-氯-苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-4-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-4-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡啶-3-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡啶-4-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
4-喹喔啉-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二氯-苄基)-哌嗪-1-羧酸苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸噻唑-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸噻唑-2-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸甲基-苯基-酰胺;
4-(2-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-苯并呋喃-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-硝基苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-三氟甲基-苯基)酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸苯基酰胺;以及
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸(4-氟-苯基)酰胺。
31.根据权利要求28或29所述的方法,其中所述的疾病、障碍或医学症状选自:焦虑、疼痛、睡眠障碍、摄食障碍、炎症、移动障碍、HIV消耗综合征、封闭型颅脑损伤、中风、阿尔茨海姆氏症、癫痫、抽动秽语综合征、尼曼-匹克病、帕金森氏病、亨廷顿舞蹈病、视神经炎、自体免疫性葡萄膜炎、药物戒断、恶心、呕吐、性功能障碍、创伤后应激障碍、脑血管痉挛、青光眼、肠易激综合征、炎性肠病、免疫抑制、胃肠道逆流疾病、麻痹性肠梗阻、分泌性腹泻、胃溃疡、类风湿性关节炎、意外妊娠、高血压、癌、肝炎、过敏性气管病、自体免疫性糖尿病、顽固性瘙痒、以及神经炎。
32.根据权利要求28或29所述的方法,其中所述的疾病、障碍或医学症状选自焦虑、疼痛、炎症、睡眠障碍、摄食障碍和移动障碍。
33.根据权利要求28或29所述的方法,其中所述的疾病、障碍或医学症状是多发性硬化。
34.根据权利要求28或29所述的方法,其中所述的疾病、障碍或医学症状是炎症中的疼痛。
35.一种用于治疗由FAAH活性介导的疾病、障碍或医学症状的药物组合物,该药物组合物包括:
(a)有效量的选自下列物质的药剂:式(I)的化合物,及其药学可接受的盐、药学可接受的前药和药学活性的代谢产物:
其中:
·Z是-N-或>CH;
·R1是-H或-C1-4烷基;
.Ar1是2-噻唑基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基或苯基,每个基团是未取代的或者在碳环成员上被一个或两个Ra部分所取代;
其中每个Ra部分独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自独立地是-H或-C1-4烷基;且
·Ar2是:
(a)未取代的1-萘基;或者菲基、芘基、芴基、2-萘基或N-Rd-9H-咔唑基部分,其中Rd选自-H、-C1-4烷基和苯基,每个所述部分均是未取代的或者被1个、2个或3个Re取代基所取代,
其中每个Re取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自如前所定义;
(b)在两个相邻的环碳原子处与选自下述的基团稠合形成稠环结构的苯基:具有0或1个双键的-(CH2)3-5-、-OCH2CH2O-和-OCF2O-;或者在相邻的环碳原子上被-OCH2O-所取代形成4-苯并[1,3]二氧戊环的苯基;每个苯基部分进一步是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(c)Ar6,在这里Ar6是6-元单环杂芳基,其具有作为连接点的碳原子,具有一个或两个氮杂原子,是未取代的或者被1个、2个或3个如前所定义的Re取代基所取代;
(d)具有一个选自N、O和S的杂原子的9-元或10-元稠合二环杂芳基,其具有作为连接点的碳原子,并任选具有至多四个另外的被氮置换的碳原子,所述稠合二环杂芳基具有不多于5个杂原子,其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(e)在3-位或4-位上被Rg取代的苯基,其任选地进一步被1个、2个或3个取代基Rh所取代,
其中每个Rg独立地选自任选被-NRiRj取代的-C2-8烷基、-C2-8烯基、-OC3-8环烷基、-OC3-8杂环烷基和-O-C2-10烷基,其中Ri和Rj各自独立地是-H或-C1-8烷基,或者Ri和Rj与所连接的氮环原子一起形成5-元、6-元或7-元杂环烷基环,该杂环烷基环上一个另外的碳环原子任选被O、S、>NH或者>NC1-4烷基代替;并且
每个Rh取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(f)在3位或4位上被-L-Ar3取代的苯基,其中:
·L是选自-(CH2)1-3-、-CH=CH-、-O-、-OCH2、-CH2O-、-NH-、>NC1-4烷基、>S(=O)0-2、-OSO-2-、-C≡C-、-C(=O)-和共价键的连接子;且
·Ar3是选自下列的部分:
(1)苯基、萘基和菲基,
(2)Ar6’,其中Ar6’是具有作为连接点的碳原子的6-元单环杂芳基,其具有一个或两个氮杂原子,
(3)Ar5’,其中Ar5’是具有作为连接点的碳原子的5-元单环杂芳基,其具有一个选自O、S、>NH和>NRf的杂原子,其中Rf是-C1-8烷基或C0-3苯烷基,且Ar5’具有0个、1个、2个或3个另外的氮杂原子,以及
(4)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有作为连接点的碳,并任选具有至多四个被氮代替的另外的碳环原子,所述稠合双环杂芳基具有不多于5个杂原子;
其中部分(1)-(4)中的每个均任选在相邻的碳上被下述基团双取代以形成稠环结构:-OC1-4亚烷基O-、-(CH2)2-3NH-、-(CH2)1-2NH(CH2)-、-(CH2)2-3N(C1-4烷基)-或-(CH2)1-2N(C1-4烷基)(CH2)-,并且进一步任选地被1个、2个或3个取代基Rk所取代,
其中每个Rk取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(g)2-羟基苯基或2-甲氧基苯基,其是未取代的或者被1个、2个或3个R1取代
其中每个R1取代基独立地选自-CH3、6-C2-4烷基、6-C2-4烯基、-OH、-OCH3、6-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRe、-NO2和-CN,其中Rb和Rc如前所定义;
(h)4-卤代苯基,其是未取代的或者被一个、两个或三个Rm取代基所取代,
其中每个Rm取代基独立地选自-CH3、2-C2-4烷基、2-C2-4烯基、3-羟基、4-羟基、-OCH3、2-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;或者
(i)2-溴苯基、3-甲基苯基、3-甲氧基苯基、4-甲氧基苯基或3,4-二甲氧基苯基;
其中当Ar2是4-氟苯基、3,4-二氟苯基、4-氯苯基或3-甲氧基苯基时,Ar1不是未取代的苯基或者被4-Cl、-NO2、-CF3或4-CO2Et取代的苯基;并且
当Ar2是3,4-二氯苯基时,Ar1不是被4-Cl、-NO2、-CF3或4-CO2Et取代的苯基;以及
(b)药学可接受的赋形剂。
36.一种用于治疗由FAAH活性介导的疾病、障碍或医学症状的药物组合物,该药物组合物包括:
(a)有效量的选自下列物质的药剂:式(I)的化合物,及其药学可接受的盐、药学可接受的前药和药学活性的代谢产物:
其中:
·Z是-N-或>CH;
R1是-H或-C1-4烷基;
·Ar1是2-噻唑基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基或苯基,这些基团的每个均是未取代的或者在碳环成员上被一个或两个Re部分所取代;
其中,每个Re部分独立地选自乙基、异丙基、叔丁基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自独立地是-H或-OC1-4烷基;并且
·Ar2是:
(a)在两个相邻的环碳原子处与选自-OCH2O-的基团稠合形成稠环结构的苯基;每个苯基部分进一步是未取代的,或者被1个、2个或3个Re取代基所取代;
其中每个Re取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;或者
(b)Ar5,其中Ar5是呋喃基、噁唑基、异噁唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、噻吩基、噻唑基、异噻唑基、吡咯基、吡唑基、1,2,3-三唑基、1,2,4-三唑基或四唑基,这些基团的每个均是未取代的或者被一个、两个或三个如前所述的Re取代基所取代;以及
(b)药学可接受的赋形剂。
37.一种用于治疗由FAAH活性介导的疾病、障碍或医学症状的药物组合物,该药物组合物包括:
(a)有效量的选自下列物质的药剂:式(I)的化合物,及其药学可接受的盐:
4-萘-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[b]噻吩-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-碘-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(5-溴-2-羟基-3-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-溴-4-氟-苄基)-哌嗪-1-羧酸苯基酰胺;
4-茚满-5-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[b]噻吩-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-异丙基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-乙基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(5-溴-2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2,3-二氢-苯并[1,4]二氧芑-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(3-乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2,3-二氢-苯并呋喃-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-萘-1-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-吡啶-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-吡啶-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-吡啶-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-异丙氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-联苯-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-喹啉-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[1,3]二氧戊环-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(6-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(8-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(2-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-萘-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺;;
4-(1-羟基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(3-对甲苯氧基苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-叔丁基苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-三氟甲基-苯氧基)苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-甲氧基-苯氧基)-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(6-甲氧基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(菲-9-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-芘-1-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(6-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-联苯-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(6-溴-吡啶-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-氯-苯磺酰基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2-氯-8-甲基-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(3,5-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(9H-芴-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(9-乙基-9H-咔唑-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苯乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-氯-3-三氟甲基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[2,5-二甲基-1-(3-三氟甲基-苯基)-1H-吡咯-3-基甲基]-哌嗪-1-羧酸苯基酰胺;
4-(2-溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸间甲苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸对甲苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸邻甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸邻甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸对甲苯基酰胺;
2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸间甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2,4-二氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氟-苯基)酰胺;
4-苄基-哌啶-1-羧酸对甲苯基酰胺;
4-苄基-哌啶-1-羧酸间甲苯基酰胺;
4-苄基-哌啶-1-羧酸(2-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-4-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-2-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-3-基酰胺;
4-(4-环己氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-丙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-异丁氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-乙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(4-丙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(4-异丁氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-[3-(2-二甲基氨基-乙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(2-哌啶-1-基-乙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-二甲基氨基-丙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(4-乙氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(菲-9-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)苯氧基]-苯甲酸甲酯;
4-[3-(4-甲磺酰基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(苯并[1,3]二氧戊环-5-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
甲磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
4-氯-苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-4-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-4-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡啶-3-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡啶-4-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;和
4-喹喔啉-2-基甲基-哌嗪-1-羧酸苯基酰胺;以及
(b)药学可接受的赋形剂。
38.根据权利要求35或36所述的药物组合物,其进一步包括:选自阿片和非甾体消炎药的止痛剂。
39.根据权利要求35或36所述的药物组合物,其进一步包括:选自阿斯匹林、对乙酰氨基酚、阿片、布洛芬、萘普生、COx-2抑制剂、加巴喷丁、普瑞巴林和反胺苯环醇的其它活性成分。
40.根据权利要求1所定义的式(I)的化合物或这种化合物的药学可接受的盐。
41.根据权利要求25所定义的式(I)的化合物或这种化合物的药学可接受的盐。
Claims (38)
1.一种式(I)的化合物,或者这种化合物的药学可接受的盐、药学可接受的前药或药学活性的代谢产物:
其中:
·Z是-N-或>CH;
·R1是-H或-C1-4烷基;
·Ar1是2-噻唑基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基或苯基,每个基团是未取代的或者在碳环成员上被一个或两个Ra部分所取代;
其中每个Ra部分独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自独立地是-H或-C1-4烷基;且
·Ar2是:
(a)未取代的1-萘基;或者菲基、芘基、芴基、2-萘基或N-Rd-9H-咔唑基部分,其中Rd选自-H、-C1-4烷基和苯基,每个所述部分均是未取代的或者被1个、2个或3个Re取代基所取代,
其中每个Re取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自如前所定义;
(b)在两个相邻的环碳原子处与选自下述的基团稠合形成稠环结构的苯基:具有0或1个双键的-(CH2)3-5-、-(CH2)2-3O-、-OCH2CH2O-和-OCF2O-;或者在相邻的环碳原子上被-OCH2O-取代形成4-苯并[1,3]二氧戊环的苯基;每个苯基部分进一步是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(c)Ar6,在这里Ar6是6-元单环杂芳基,其具有作为连接点的碳原子,具有一个或两个氮杂原子,是未取代的或者被1个、2个或3个如前所定义的Re取代基所取代;
(d)Ar5,在这里Ar5是5-元单环杂芳基,其具有作为连接点的碳原子,具有一个选自O、S、>NH和>NRf的杂原子,其中Rf是C1-8烷基或C0-3苯基烷基,其具有0个、1个、2个或3个另外的氮杂原子,是未取代的或者被1个、2个或3个如前所定义的Re取代基所取代;
(e)具有一个选自N、O和S的杂原子的9-元或10-元稠合二环杂芳基,其具有作为连接点的碳原子,并任选具有至多四个另外的被氮置换的碳原子,所述稠合二环杂芳基具有不多于5个杂原子,其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(f)在3-位或4-位上被Rg取代的苯基,其任选地进一步被1个、2个或3个取代基Rh所取代,
其中每个Rg独立地选自任选被-NRiRj取代的-C2-8烷基、-C2-8烯基、-OC3-8环烷基、-OC3-8杂环烷基和-O-C2-10烷基,其中Ri和Rj各自独立地是-H或-C1-8烷基,或者Ri和Rj与所连接的氮环原子一起形成5-元、6-元或7-元杂环烷基环,该杂环烷基环上一个另外的碳环原子任选被O、S、>NH或者>NC1-4烷基代替;并且
每个Rh取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(g)在3位或4位上被-L-Ar3取代的苯基,其中:
·L是选自-(CH2)1-3-、-CH=CH-、-O-、-OCH2、-CH2O-、-NH-、>NC1-4烷基、>S(=O)0-2、-OSO2-、-C≡C-、-C(=O)-和共价键的连接子;且
·Ar3是选自下列的部分:
(1)苯基、萘基和菲基,
(2)Ar6’,其中Ar6’是具有作为连接点的碳原子的6-元单环杂芳基,其具有一个或两个氮杂原子,
(3)Ar5’,其中Ar5’是具有作为连接点的碳原子的5-元单环杂芳基,其具有一个选自O、S、>NH和>NRf的杂原子,其中Rf是-C1-8烷基或-C0-3苯烷基,且Ar5’具有0个、1个、2个或3个另外的氮杂原子,以及
(4)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有作为连接点的碳,并任选具有至多四个被氮代替的另外的碳环原子,所述稠合双环杂芳基具有不多于5个杂原子;
其中部分(1)-(4)中的每个均任选在相邻的碳上被下述基团双取代以形成稠环结构:-OC1-4亚烷基O-、-(CH2)2-3NH-、-(CH2)1-2NH(CH2)-、 -(CH2)2-3N(C1-4烷基)-或-(CH2)1-2N(C1-4烷基)(CH2)-,并且进一步任选地被1个、2个或3个取代基Rk所取代,
其中每个Rk取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(h)2-羟基苯基或2-甲氧基苯基,其是未取代的或者被1个、2个或3个R1取代
其中每个R1取代基独立地选自-CH3、6-C2-4烷基、6-C2-4烯基、-OH、-OCH3、6-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(i)4-卤代苯基,其是未取代的或者被一个、两个或三个Rm取代基所取代,
其中每个Rm取代基独立地选自-CH3、2-C2-4烷基、2-C2-4烯基、3-羟基、4-羟基、-OCH3、 2-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;或者
(j)2-溴苯基、3-甲基苯基、3-甲氧基苯基、4-甲氧基苯基或3,4-二甲氧基苯基;
其中当Ar2是4-氟苯基、3,4-二氟苯基、4-氯苯基或3-甲氧基苯基时,Ar1不是未取代的苯基或者被4-Cl、-NO2、-CF3或4-CO2Et取代的苯基;并且
当Ar2是3,4-二氯苯基时,Ar1不是被4-Cl、-NO2、-CF3或4-CO2Et取代的苯基。
2.根据权利要求1所述的化合物,其中R1是甲基。
3.根据权利要求1所述的化合物,其中Ar1是2-噻唑基。
4.根据权利要求1所述的化合物,其中Ar2是2-甲氧基苯基,其是未取代的或者被1个、2个或三个取代基R1所取代。
5.根据权利要求1所述的化合物,其中Ar2是3,4-二氯苯基。
6.根据权利要求1所述的化合物,或者这种化合物的药学可接受的盐、药学可接受的前药或药学活性的代谢产物,其中
·Z是-N-或>CH;
·R1是-H或-C1-4烷基;
·Ar1是2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基或苯基,每个基团是未取代的或者在碳环成员上被一个或两个Ra部分所取代;
其中每个Ra部分独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自独立地是-H或-C1-4烷基;且
·Ar2是:
(a)未取代的1-萘基;或者菲基、芘基、芴基、2-萘基或N-Rd-9H-咔唑基部分,其中Rd选自-H、-C1-4烷基和苯基,每个所述部分是未取代的,或者被1个、2个或3个Re取代基所取代,
其中每个Re取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自如前所定义;
(b)在两个相邻的环碳原子处与选自下述的基团稠合形成稠环结构的苯基:具有0或1个双键的-(CH2)3-5-、-(CH2)2-3O-、-OCH2CH2O-和-OCF2O-;或者在相邻的环碳原子上被-OCH2O-取代形成4-苯并[1,3]二氧戊环基的苯基;每个苯基部分进一步是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(c)Ar6,在这里Ar6是6-元单环杂芳基,其具有作为连接点的碳原子且具有一个或两个氮杂原子,其是未取代的或者被1个、2个或3个如前所定义的Re取代基所取代;
(d)Ar5,在这里Ar5是5-元单环杂芳基,其具有作为连接点的碳原子且具有一个选自O、S、>NH和>NRf的杂原子,其中Rf是C1-8烷基或C0-3苯基烷基,其具有0个、1个、2个或3个另外的氮杂原子,是未取代的或者被1个、2个或3个如前所定义的Re取代基所取代;
(e)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有作为连接点的碳原子并任选具有至多四个另外的被氮置换的碳原子,所述稠合双环杂芳基具有不多于5个杂原子,其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(f)在3-位或4-位上被Rg取代的苯基,其任选地进一步被1个、2个或3个取代基Rh所取代,
其中每个Rg独立地选自任选被-NRiRj取代的-C2-8烷基、-C2-8烯基、-OC3-8环烷基、-OC3-8杂环烷基和-O-C2-10烷基,其中Ri和Rj各自独立地是-H或-C1-8烷基,或者Ri和Rj与所连接的氮环原子一起形成5-元、6-元或7-元杂环烷基环,该杂环烷基环上一个另外的碳环原子任选被O、S、>NH或者>NC1-4烷基代替;并且
每个Rh取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(g)在3位或4位上被-L-Ar3取代的苯基,其中:
□L是选自-(CH2)1-3-、-CH=CH-、-O-、-OCH2、-CH2O-、-NH-、>NC1-4烷基、>S(=O)0-2、-OSO2-、-C≡C-、-C(=O)-和共价键的连接子;且
□Ar3是选自下列的部分:
(1)苯基、萘基和菲基,
(2)Ar6’,其中Ar6’是具有作为连接点的碳原子的6-元单环杂芳基,其具有一个或两个氮杂原子,
(3)Ar5’,其中Ar5’是具有作为连接点的碳原子的5-元单环杂芳基,其具有一个选自O、S、>NH和>NRf的杂原子,其中Rf是-C1-8烷基或C0-3苯烷基,且Ar5’具有0个、1个、2个或3个另外的氮杂原子,以及
(4)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有作为连接点的碳,该杂芳基还任选具有至多四个被氮代替的另外的碳环原子,所述稠合双环杂芳基具有不多于5个杂原子;
其中部分(1)-(4)中的每个均任选在相邻的碳上被下述基团双取代以形成稠环结构:-OC1-4亚烷基O-、-(CH2)2-3NH-、-(CH2)1-2NH(CH2)-、-(CH2)2-3N(C1-4烷基)-或-(CH2)1-2N(C1-4烷基)(CH2)-,并且进一步任选地被1个、2个或3个取代基Rk所取代,
其中每个Rk取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(h)2-羟基苯基,其是未取代的或者被1个、2个或3个R1取代其中每个R1取代基独立地选自-CH3、6-C2-4烷基、6-C2-4烯基、-OH、-OCH3、6-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义
(i)4-卤代苯基,其是未取代的或者被一个、两个或三个Rm取代基所取代,
其中每个Rm取代基独立地选自-CH3、2-C2-4烷基、2-C2-4烯基、3-羟基、4-羟基、-OCH3、 2-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;或者
(j)2-溴苯基、3-甲基苯基、3-甲氧基苯基、4-甲氧基苯基或3,4-二甲氧基苯基;
其中当Ar2是4-氟苯基、3,4-二氟苯基、4-氯苯基或3-甲氧基苯基时,Ar1不是未取代的苯基或者被4-Cl、-NO2、-CF3或4-CO2Et取代的苯基;并且
当Ar2是3,4-二氯苯基时,Ar1不是被4-C1、-NO2、-CF3或4-CO2Et取代的苯基。
7.根据权利要求6所述的化合物,其中Z是-N-。
8.根据权利要求7所述的化合物,其中R1是H。
9.根据权利要求7所述的化合物,其中Ar2是菲-9-基、芘-1-基、9H-芴-2-基、1-萘基、2-萘基、1-羟基萘-2-基、6-甲氧基萘-2-基或9-乙基-9H-咔唑-3-基,这些基团的每个均是未取代的或者被一个、两个或三个如前所述的Re取代基所取代。
10.根据权利要求7所述的化合物,其中Ar2是茚满基、茚基、四氢化萘基、2,3-二氢-苯并呋喃基、苯并二氢吡喃基、2,3-二氢-苯并[1,4]二氧芑基或2,2-二氟-苯并[1,3]二氧戊环基,这些基团的每个均是未取代的或者被一个、两个或三个如前所述的Re取代基所取代。
11.根据权利要求7所述的权利要求,其中Ar2是苯基-1H-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基或6-溴-吡啶-2-基,这些基团的每个均是未取代的或者被一个、两个或三个如前所述的Re取代基所取代。
12.根据权利要求7所述的权利要求,其中Ar2是在3-位或4-位上被-L-Ar3取代的苯基,在这里L是-CH=CH-、-O-、-OCH2-、-SO2-、-OSO2-或共价键。
13.根据权利要求7所述的化合物,其中Ar2是2-羟基苯基、5-溴-2-羟基-3-甲氧基苯基或5-溴-2-羟基苯基。
14.根据权利要求8所述的化合物,其中Ar1是2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基或4-嘧啶基,这些基团的每个均是未取代的或者在碳环原子处被一个或两个如前所述的Ra取代基所取代。
15.根据权利要求8所述的化合物,其中Ar1是未取代的苯基或者在碳环原子上被一个或两个如前所述的Ra部分取代的苯基。
16.根据权利要求8所述的化合物,其中Ar1是2-氟苯基、3-氟苯基、4-氟苯基、2,4-二氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-甲酯基苯基、3-甲酯基苯基、4-甲酯基苯基、2-羧基苯基、3-羧基苯基或未取代的苯基。
17.根据权利要求16所述的化合物,其中Ar2是未取代的2,2-二氟-苯并[1,3]二氧戊环基。
18.根据权利要求16所述的化合物,其中Ar2是未取代的4-苯并[1,3]二氧戊环基。
19.根据权利要求16所述的化合物,其中Ar2是2-吲哚基、3-吲哚基、2-喹啉基、3-喹啉基或2-喹喔啉基,这些基团的每个均是未取代的或者被一个、两个或三个如前所述的Re取代基所取代。
20.根据权利要求16所述的化合物,其中Ar2是2-喹啉基或3-喹啉基。
21.根据权利要求16所述的化合物,其中Ar2是4-乙基苯基、4-异丙基苯基、3-乙烯基苯基、3-乙氧基苯基、4-乙氧基苯基、3-丙氧基苯基、4-丙氧基苯基、3-异丁氧基苯基、4-异丁氧基苯基、3-异丁氧基苯基、4-异丁氧基苯基、4-环己氧基苯基、3-(2-二甲基氨基乙氧基)苯基、3-(2-哌啶-1-基乙氧基)、3-(3-二甲基氨基丙氧基)苯基或3-(3-哌啶-1-基-丙氧基)苯基。
22.根据权利要求16所述的化合物,其中Ar3是4-氯苯基、3,4-二氯苯基、4-甲基苯基、4-叔丁基苯基、3-三氟甲基苯基、4-甲氧基苯基、3,5-二氯苯基、1-萘基、2-萘基、3-氯苯基、9-菲基、4-甲酯基苯基、4-甲磺酰基苯基、3-甲氧基苯基、苯并[1,3]二氧戊环-5-基或未取代的苯基。
23.根据权利要求16所述的化合物,其中Ar2是3,4-二溴苯基、3-溴-4-氟苯基或4-氯-3-三氟甲基。
24.根据权利要求16所述的化合物,其中Ar2是3,4-二溴苯基。
25.一种选自下述的化合物及其药学可接受的盐:
4-萘-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[b]噻吩-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-碘-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(5-溴-2-羟基-3-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-溴-4-氟-苄基)-哌嗪-1-羧酸苯基酰胺;
4-茚满-5-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[b]噻吩-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-异丙基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-乙基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(5-溴-2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2,3-二氢-苯并[1,4]二氧芑-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(3-乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2,3-二氢-苯并呋喃-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-萘-1-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-吡啶-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-吡啶-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-吡啶-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-异丙氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-联苯-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-喹啉-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[1,3]二氧戊环-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(6-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(8-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(2-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-萘-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺;;
4-(1-羟基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(3-对甲苯氧基苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-叔丁基苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-三氟甲基-苯氧基)苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-甲氧基-苯氧基)-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(6-甲氧基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(菲-9-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-芘-1-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(6-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-联苯-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(6-溴-吡啶-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-氯-苯磺酰基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2-氯-8-甲基-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(3,5-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(9H-芴-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(9-乙基-9H-咔唑-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苯乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-氯-3-三氟甲基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[2,5-二甲基-1-(3-三氟甲基-苯基)-1H-吡咯-3-基甲基]-哌嗪-1-羧酸苯基酰胺;
4-(2-溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸间甲苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸对甲苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸邻甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸邻甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸对甲苯基酰胺;
2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸间甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2,4-二氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氟-苯基)酰胺;
4-苄基-哌啶-1-羧酸对甲苯基酰胺;
4-苄基-哌啶-1-羧酸间甲苯基酰胺;
4-苄基-哌啶-1-羧酸(2-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-4-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-2-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-3-基酰胺;
4-(4-环己氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-丙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-异丁氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-乙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(4-丙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(4-异丁氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-[3-(2-二甲基氨基-乙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(2-哌啶-1-基-乙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-二甲基氨基-丙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(4-乙氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(菲-9-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)苯氧基]-苯甲酸甲酯;
4-[3-(4-甲磺酰基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(苯并[1,3]二氧戊环-5-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
甲磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
4-氯-苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-4-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-4-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡啶-3-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡啶-4-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;和
4-喹喔啉-2-基甲基-哌嗪-1-羧酸苯基酰胺。
26.一种选自下述的化合物及其药学可接受的盐:
4-(3,4-二氯-苄基)-哌嗪-1-羧酸苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸噻唑-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸噻唑-2-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸甲基-苯基-酰胺;
4-(2-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-苯并呋喃-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-硝基苯基)酰胺;和
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-三氟甲基-苯基)酰胺。
27.一种治疗患有或被诊断有由FAAH活性介导的疾病、障碍或医学症状的方法,该方法包括对需要这种治疗的个体给予有效量的式(I)的化合物,或者这种化合物的药学可接受的盐、药学可接受的前药或药学活性的代谢产物:
其中:
·Z是-N-或>CH;
·R1是-H或C1-4烷基;
·Ar1是2-噻唑基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基或苯基,每个基团是未取代的、或者在碳环成员上被一个或两个Ra部分所取代;
其中每个Ra部分独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自独立地是-H或-C1-4烷基;且
·Ar2是:
(a)菲基、芘基、芴基、萘基或N-Rd-9H-咔唑基部分,其中Rd选自-H、-C1-4烷基和苯基,每个所述部分是未取代的,或者被1个、2个或3个Re取代基所取代,
其中每个Re取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自如前所定义;
(b)在两个相邻的环碳原子处与选自下述的基团稠合形成稠环结构的苯基:具有0或1个双键的-(CH2)3-5-、-(CH2)2-3O-、-OCH2CH2O-、-OCF2O-和-OCH2O-,其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(c)Ar6,在这里Ar6是6-元单环杂芳基,其具有作为连接点的碳原子且具有一个或两个氮杂原子,其是未取代的或者被1个、2个或3个如前所定义的Re取代基所取代;
(d)Ar5,在这里Ar5是5-元单环杂芳基,其具有作为连接点的碳原子且具有一个选自O、S、>NH和>NRf的杂原子,其中Rf是C1-8烷基或C0-3苯基烷基,其具有0个、1个、2个或3个另外的氮杂原子,其是未取代的或者被1个、2个或3个如前所定义的Re取代基所取代;
(e)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有作为连接点的碳原子并任选具有至多四个另外的被氮置换的碳原子,所述稠合双环杂芳基具有不多于5个杂原子,其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(f)在3-位或4-位上被Rg取代的苯基,其任选地被1个、2个或3个取代基Rh所取代,
其中每个Rg独立地选自任选被-NRiRj取代的-C2-8烷基、-C2-6烯基、-OC3-8环烷基、-OC3-8杂环烷基和-O-C2-10烷基,其中Ri和Rj各自独立地是-H或-C1-8烷基,或者Ri和Rj与所连接的氮环原子一起形成5-元、6-元或7-元杂环烷基环,该杂环烷基环上一个另外的碳环原子任选被O、S、>NH或者>NC1-4烷基代替;并且
每个Rh取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(g)在3位或4位上被-L-Ar3取代的苯基,其中:
·L是选自-(CH2)1-3-、-CH=CH-、-O-、-OCH2、-CH2O-、-NH-、>NC1-4烷基、>S(=O)0-2、-OSO2-、-C≡C-、-C(=O)-和共价键的连接子;且
·Ar3是选自下列的部分:
(1)苯基、萘基和菲基,
(2)Ar6’,其中Ar6’是具有作为连接点的碳原子的6-元单环杂芳基,其具有一个或两个氮杂原子,
(3)Ar5’,其中Ar5’是具有作为连接点的碳原子的5-元单环杂芳基,其具有一个选自O、S、>NH和>NRf的杂原子,其中Rf是-C1-8烷基或-C0-3苯烷基,且Ar5’具有0个、1个、2个或3个另外的氮杂原子,以及
(4)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有作为连接点的碳,并任选具有至多四个被氮代替的另外的碳环原子,所述稠合双环杂芳基具有不多于5个杂原子;
其中部分(1)-(4)中的每个均任选在相邻的碳上被下述基团双取代以形成稠环结构:-OC1-4亚烷基O-、-(CH2)2-3NH-、-(CH2)1-2NH(CH2)-、-(CH2)2-3N(C1-4烷基)-或-(CH2)1-2N(C1-4烷基)(CH2)-,并且进一步任选地被1个、2个或3个取代基Rk所取代,
其中每个Rk取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(h)2-羟基苯基或2-甲氧基苯基,其是未取代的或者被1个、2个或3个R1取代
其中每个R1取代基独立地选自-CH3、6-C2-4烷基、6-C2-4烯基、-OH、-OCH3、6-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(i)4-卤代苯基,其是未取代的或者被一个、两个或三个Rm取代基所取代,
其中每个Rm取代基独立地选自-CH3、2-C2-4烷基、2-C2-4烯基、3-羟基、4-羟基、-OCH3、2-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;或者
(j)2-溴苯基、3-甲基苯基、3-甲氧基苯基、4-甲氧基苯基或3,4-二甲氧基苯基。
28.根据权利要求27所述的方法,其中所述的化合物选自下列化合物及其药学可接受的盐:
4-萘-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[b]噻吩-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-碘-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(5-溴-2-羟基-3-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-溴-4-氟-苄基)-哌嗪-1-羧酸苯基酰胺;
4-茚满-5-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[b]噻吩-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-异丙基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-乙基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(5-溴-2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2,3-二氢-苯并[1,4]二氧芑-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2,3-二氢-苯并呋喃-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(3-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-萘-1-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-甲基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-吡啶-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-吡啶-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-吡啶-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-异丙氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-联苯-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-喹啉-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[1,3]二氧戊环-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(6-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(8-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(2-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-萘-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺;;
4-(1-羟基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3,4--二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(3-对甲苯氧基苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-叔丁基苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-三氟甲基-苯氧基)苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-甲氧基-苯氧基)-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(6-甲氧基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(菲-9-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-芘-1-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(6-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-联苯-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(6-溴-吡啶-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-氯-苯磺酰基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2-氯-8-甲基-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(3,5-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(9H-芴-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(9-乙基-9H-咔唑-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苯乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-氯-3-三氟甲基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[2,5-二甲基-1-(3-三氟甲基-苯基)-1H-吡咯-3-基甲基]-哌嗪-1-羧酸苯基酰胺;
4-(2-溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二-溴-苄基)-哌嗪-1-羧酸(3-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸间甲苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸对甲苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸邻甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸邻甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸对甲苯基酰胺;
2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸间甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2,4-二氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氟-苯基)酰胺;
4-苄基-哌啶-1-羧酸对甲苯基酰胺;
4-苄基-哌啶-1-羧酸间甲苯基酰胺;
4-苄基-哌啶-1-羧酸(2-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-4-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-2-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-3-基酰胺;
4-(4-环己氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-丙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-异丁氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-乙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(4-丙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(4-异丁氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-[3-(2-二甲基氨基-乙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(2-哌啶-1-基-乙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-二甲基氨基-丙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(4-乙氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(菲-9-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)苯氧基]-苯甲酸甲酯;
4-[3-(4-甲磺酰基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(苯并[1,3]二氧戊环-5-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
甲磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
4-氯-苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-4-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-4-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡啶-3-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡啶-4-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
4-喹喔啉-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二氯-苄基)-哌嗪-1-羧酸苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸噻唑-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸噻唑-2-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸甲基-苯基-酰胺;
4-(2-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-苯并呋喃-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-硝基苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-三氟甲基-苯基)酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸苯基酰胺;以及
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸(4-氟-苯基)酰胺。
29.根据权利要求27所述的方法,其中所述的疾病、障碍或医学症状选自:焦虑、疼痛、睡眠障碍、摄食障碍、炎症、移动障碍、HIV消耗综合征、封闭型颅脑损伤、中风、阿尔茨海姆氏症、癫痫、抽动秽语综合征、尼曼-匹克病、帕金森氏病、亨廷顿舞蹈病、视神经炎、自体免疫性葡萄膜炎、药物戒断、恶心、呕吐、性功能障碍、创伤后应激障碍、脑血管痉挛、青光眼、肠易激综合征、炎性肠病、免疫抑制、胃肠道逆流疾病、麻痹性肠梗阻、分泌性腹泻、胃溃疡、类风湿性关节炎、意外妊娠、高血压、癌、肝炎、过敏性气管病、自体免疫性糖尿病、顽固性瘙痒、以及神经炎。
30.根据权利要求27所述的方法,其中所述的疾病、障碍或医学症状选自焦虑、疼痛、炎症、睡眠障碍、摄食障碍和移动障碍。
31.根据权利要求27所述的方法,其中所述的疾病、障碍或医学症状是多发性硬化。
32.根据权利要求27所述的方法,其中所述的疾病、障碍或医学症状是炎症中的疼痛。
33.一种用于治疗由FAAH活性介导的疾病、障碍或医学症状的药物组合物,该药物组合物包括:
(a)有效量的选自下列物质的药剂:式(I)的化合物,及其药学可接受的盐、药学可接受的前药和药学活性的代谢产物:
其中:
·Z是-N-或>CH;
·R1是-H或-C1-4烷基;
·Ar1是2-噻唑基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基或苯基,每个基团是未取代的或者在碳环成员上被一个或两个Ra部分所取代;
其中每个Ra部分独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自独立地是-H或-C1-4烷基;且
·Ar2是:
(a)未取代的1-萘基;或者菲基、芘基、芴基、2-萘基或N-Rd-9H-咔唑基部分,其中Rd选自-H、-C1-4烷基和苯基,每个所述部分均是未取代的或者被1个、2个或3个Re取代基所取代,
其中每个Re取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc各自如前所定义;
(b)在两个相邻的环碳原子处与选自下述的基团稠合形成稠环结构的苯基:具有0或1个双键的-(CH2)3-5、-(CH2)2-3O-、-OCH2CH2O-和-OCF2O-;或者在相邻的碳原子上被-OCH2O-取代形成4-苯并[1,3]二氧戊环的苯基;每个苯基部分进一步是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(c)Ar6,在这里Ar6是6-元单环杂芳基,其具有作为连接点的碳原子,具有一个或两个氮杂原子,是未取代的或者被1个、2个或3个如前所定义的Re取代基所取代;
(d)Ar5,在这里Ar5是5-元单环杂芳基,其具有作为连接点的碳原子,具有一个选自O、S、>NH和>NRf的杂原子,其中Rf是C1-8烷基或C0-3苯基烷基,其具有0个、1个、2个或3个另外的氮杂原子,是未取代的或者被1个、2个或3个如前所定义的Re取代基所取代;
(e)具有一个选自N、O和S的杂原子的9-元或10-元稠合二环杂芳基,其具有作为连接点的碳原子,并任选具有至多四个另外的被氮置换的碳原子,所述稠合二环杂芳基具有不多于5个杂原子,其是未取代的,或者被1个、2个或3个如前所定义的Re取代基所取代;
(f)在3-位或4-位上被Rg取代的苯基,其任选地进一步被1个、2个或3个取代基Rh所取代,
其中每个Rg独立地选自任选被-NRiRj取代的-C2-8烷基、-C2-8烯基、-OC3-8环烷基、-OC3-8杂环烷基和-O-C2-10烷基,其中Ri和Rj各自独立地是-H或-C1-8烷基,或者Ri和Rj与所连接的氮环原子一起形成5-元、6-元或7-元杂环烷基环,该杂环烷基环上一个另外的碳环原子任选被O、S、>NH或者>NC1-4烷基代替;并且
每个Rh取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(g)在3位或4位上被-L-Ar3取代的苯基,其中:
·L是选自-(CH2)1-3-、-CH=CH-、-O-、-OCH2、-CH2O-、-NH-、>NC1-4烷基、>S(=O)0-2、-OSO-2-、-C≡C-、-C(=O)-和共价键的连接子;且
·Ar3是选自下列的部分:
(1)苯基、萘基和菲基,
(2)Ar6’,其中Ar6’是具有作为连接点的碳原子的6-元单环杂芳基,其具有一个或两个氮杂原子,
(3)Ar5’,其中Ar5’是具有作为连接点的碳原子的5-元单环杂芳基,其具有一个选自O、S、>NH和>NRf的杂原子,其中Rf是-C1-8烷基或C0-3苯烷基,且Ar5’具有0个、1个、2个或3个另外的氮杂原子,以及
(4)具有一个选自N、O和S的杂原子的9-元或10-元稠合双环杂芳基,其具有作为连接点的碳,并任选具有至多四个被氮代替的另外的碳环原子,所述稠合双环杂芳基具有不多于5个杂原子;
其中部分(1)-(4)中的每个均任选在相邻的碳上被下述基团双取代以形成稠环结构:-OC1-4亚烷基O-、-(CH2)2-3NH-、-(CH2)1-2NH(CH2)-、-(CH2)2-3N(C1-4烷基)-或-(CH2)1-2N(C1-4烷基)(CH2)-,并且进一步任选地被1个、2个或3个取代基Rk所取代,
其中每个Rk取代基独立地选自-C1-4烷基、-C2-4烯基、-OH、-OC1-4烷基、卤素、-CF3、-OCF3,-SCF3、-SH、-S(O)0-2C1-4烷基、-OSO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(h)2-羟基苯基或2-甲氧基苯基,其是未取代的或者被1个、2个或3个R1取代
其中每个R1取代基独立地选自-CH3、6-C2-4烷基、6-C2-4烯基、-OH、-OCH3、6-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;
(i)4-卤代苯基,其是未取代的或者被一个、两个或三个Rm取代基所取代,
其中每个Rm取代基独立地选自-CH3、2-C2-4烷基、2-C2-4烯基、3-羟基、4-羟基、-OCH3、2-OC2-6烷基、卤素、-CF3、-OCF3、-SCF3、-SH、-SC1-4烷基、-SO2C1-4烷基、-CO2C1-4烷基、-CO2H、-COC1-4烷基、-N(Rb)Rc、-SO2NRbRc、-NRbSO2Rc、-C(=O)NRbRc、-NO2和-CN,其中Rb和Rc如前所定义;或者
(j)2-溴苯基、3-甲基苯基、3-甲氧基苯基、4-甲氧基苯基或3,4-二甲氧基苯基;
其中当Ar2是4-氟苯基、3,4-二氟苯基、4-氯苯基或3-甲氧基苯基时,Ar1不是未取代的苯基或者被4-Cl、-NO2、-CF3或4-CO2Et取代的苯基;并且
当Ar2是3,4-二氯苯基时,Ar1不是被4-Cl、-NO2、-CF3或4-CO2Et取代的苯基;以及
(b)药学可接受的赋形剂。
34.根据权利要求33所述的药物组合物,其中所述药剂选自下列化合物及其药学可接受的盐:
4-萘-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[b]噻吩-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-碘-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(5-溴-2-羟基-3-甲氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3-溴-4-氟-苄基)-哌嗪-1-羧酸苯基酰胺;
4-茚满-5-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[b]噻吩-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-异丙基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-乙基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(5-溴-2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2,3-二氢-苯并[1,4]二氧芑-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(3-乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2,3-二氢-苯并呋喃-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-萘-1-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(2-羟基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-吡啶-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-吡啶-2-基甲基-哌嗪-1-羧酸苯基酰胺;
4-吡啶-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(4-异丙氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-联苯-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-喹啉-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-苯并[1,3]二氧戊环-4-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1H-吲哚-5-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(6-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(8-氯-喹啉-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(2-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-萘-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺;
4-喹啉-2-基甲基-哌嗪-1-羧酸(4-氟-苯基)-酰胺;;
4-(1-羟基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3,4-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(3-对甲苯氧基苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-叔丁基苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-三氟甲基-苯氧基)苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-甲氧基-苯氧基)-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(6-甲氧基-萘-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(菲-9-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-芘-1-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(6-氯-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-联苯-3-基甲基-哌嗪-1-羧酸苯基酰胺;
4-(6-溴-吡啶-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-氯-苯磺酰基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(1H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苯氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(2-氯-8-甲基-喹啉-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(1-甲基-1 H-吲哚-6-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苄氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(3,5-二氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(9H-芴-2-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(9-乙基-9H-咔唑-3-基甲基)-哌嗪-1-羧酸苯基酰胺;
4-(4-苯乙烯基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(4-氯-3-三氟甲基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[2,5-二甲基-1-(3-三氟甲基-苯基)-1H-吡咯-3-基甲基]-哌嗪-1-羧酸苯基酰胺;
4-(2-溴-苄基)-哌嗪-1-羧酸苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸间甲苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-氟-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-甲氧基-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(3-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(2-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸对甲苯基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸(4-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸邻甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-氯-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸邻甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸对甲苯基酰胺;
2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)氨基]苯甲酸甲酯;
4-喹啉-3-基甲基-哌嗪-1-羧酸(4-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸间甲苯基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(3-甲氧基-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2,4-二氟-苯基)酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸(2-氟-苯基)酰胺;
4-苄基-哌啶-1-羧酸对甲苯基酰胺;
4-苄基-哌啶-1-羧酸间甲苯基酰胺;
4-苄基-哌啶-1-羧酸(2-氯-苯基)酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-4-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-2-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸吡啶-3-基酰胺;
4-(4-环己氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-丙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-异丁氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(3-乙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(4-丙氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-(4-异丁氧基-苄基)哌嗪-1-羧酸苯基酰胺;
4-[3-(2-二甲基氨基-乙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(2-哌啶-1-基-乙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-二甲基氨基-丙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-哌啶-1-基-丙氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-(4-乙氧基-苄基)-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-氯-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(萘-2-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(菲-9-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)苯氧基]-苯甲酸甲酯;
4-[3-(4-甲磺酰基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(3-甲氧基-苯氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
4-[3-(苯并[1,3]二氧戊环-5-基氧基)-苄基]-哌嗪-1-羧酸苯基酰胺;
甲磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
4-氯-苯磺酸3-(4-苯基氨基甲酰基-哌嗪-1-基甲基)-苯酯;
2-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
3-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸吡啶-4-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-3-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-4-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸嘧啶-2-基酰胺;
4-苯并[1,3]二氧戊环-5-基甲基-哌嗪-1-羧酸吡啶-2-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡啶-3-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸吡啶-4-基酰胺;
4-喹啉-3-基甲基-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-(2,2-二氟-苯并[1,3]二氧戊环-5-基甲基)-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-(3,4-二溴-苄基)-哌嗪-1-羧酸嘧啶-4-基酰胺;
4-[(4-喹啉-3-基甲基-哌嗪-1-羰基)-氨基]-苯甲酸;和
4-喹喔啉-2-基甲基-哌嗪-1-羧酸苯基酰胺。
35.根据权利要求33所述的药物组合物,其进一步包括:选自阿片和非甾体消炎药的止痛剂。
36.根据权利要求33所述的药物组合物,其进一步包括:选自阿斯匹林、对乙酰氨基酚、阿片、布洛芬、萘普生、COX-2抑制剂、加巴喷丁、普瑞巴林和反胺苯环醇的其它活性成分。
37.根据权利要求1所定义的式(I)的化合物或这种化合物的药学可接受的盐。
38.根据权利要求2所定义的式(I)的化合物或这种化合物的药学可接受的盐。
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CN102858338A (zh) * | 2010-01-28 | 2013-01-02 | 默沙东公司 | 治疗疼痛及其它适应症的药物组合物 |
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CN102869658B (zh) * | 2010-05-03 | 2015-09-02 | 詹森药业有限公司 | 脂肪酸酰胺水解酶的调节剂 |
CN105263910A (zh) * | 2013-02-18 | 2016-01-20 | 斯克利普斯研究所 | 具有治疗潜力的血管加压素受体调节剂 |
CN109661392A (zh) * | 2016-06-30 | 2019-04-19 | 巴斯利尔药物国际股份公司 | 用于治疗增殖性障碍的线粒体抑制剂 |
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