CN1972914A - 作为组胺h3受体配合体的非咪唑杂环化合物 - Google Patents
作为组胺h3受体配合体的非咪唑杂环化合物 Download PDFInfo
- Publication number
- CN1972914A CN1972914A CNA2005800176690A CN200580017669A CN1972914A CN 1972914 A CN1972914 A CN 1972914A CN A2005800176690 A CNA2005800176690 A CN A2005800176690A CN 200580017669 A CN200580017669 A CN 200580017669A CN 1972914 A CN1972914 A CN 1972914A
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- CN
- China
- Prior art keywords
- alkyl
- piperidines
- yuan
- propyl
- heterocycle
- 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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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title abstract description 5
- 102000004384 Histamine H3 receptors Human genes 0.000 title abstract 2
- 108090000981 Histamine H3 receptors Proteins 0.000 title abstract 2
- 239000003446 ligand Substances 0.000 title description 3
- -1 imidazole heterocyclic compounds Chemical class 0.000 claims abstract description 146
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims abstract description 88
- 229960001340 histamine Drugs 0.000 claims abstract description 45
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 31
- 238000011282 treatment Methods 0.000 claims abstract description 27
- 201000010099 disease Diseases 0.000 claims abstract description 16
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 13
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 158
- 125000000623 heterocyclic group Chemical class 0.000 claims description 74
- 125000005842 heteroatom Chemical group 0.000 claims description 71
- 239000000203 mixture Substances 0.000 claims description 60
- 229910052760 oxygen Inorganic materials 0.000 claims description 53
- 229910052799 carbon Inorganic materials 0.000 claims description 52
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 50
- 229910052717 sulfur Inorganic materials 0.000 claims description 50
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 48
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 48
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 47
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 40
- 125000004076 pyridyl group Chemical group 0.000 claims description 38
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- 125000001544 thienyl group Chemical group 0.000 claims description 35
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- 125000002541 furyl group Chemical group 0.000 claims description 30
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- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 30
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 125000004122 cyclic group Chemical group 0.000 claims description 20
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 claims description 20
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 17
- 239000002585 base Substances 0.000 claims description 16
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- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 10
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- 125000003725 azepanyl group Chemical group 0.000 claims description 8
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 8
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 4
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 4
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/12—Oxygen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明公开了下式(I)的某些非咪唑杂环化合物,其是H3受体调节剂,用于治疗组胺H3受体介导的疾病,式中在含有A-和B-的环中,1)A,B1和B2为CH;2)A为CH,B1和B2中一个为N,另一个为CH;或者3)没有A,B1为CH,B2为O;L为C1-4亚烷基或是一个共价键;Q为-(CH2) mO-,-(CH2) nC≡C-(此处的-O-和-C≡C-部分直接联在环上),羰基或硫羰基;n为1,2,3或4。
Description
本发明的范围
本发明涉及一系列含氮的5元和6元杂环,以及它们的合成和在治疗由组胺H3受体介导的病症和症状中的应用。
本发明的背景
组胺{2-(咪唑-4-基)乙胺}是一种传导物质。组胺通过多distinct G-蛋白受体发挥一种生理作用。它在直接过敏反应中起作用,随抗原IgE抗体相互作用而由杆状细胞释放。由脉管和平滑肌系统释放的组胺导致出现变态反应症状。释放组胺的活动是在H1受体中发生的(Ash,A.S.F.and Schild,H.O.,Br.J.Pharmac.Chemother.1966,27:427-439),经典的抗组胺剂(例如联苯醇胺)可阻断这种活动。组胺通过其在壁细胞的活动还是胃酸分泌的一种重要的调节剂。组胺的这种作用是由H2受体介导的(Black,J.W.et al.Nature 1972,236:385-390),而H2受体拮抗剂(例如甲氰咪胺)可阻断这种作用。第三种组胺受体-H3-最初被描述为中枢神经系统(CNS)中控制组胺的合成和释放的一种突触前的自身受体(Arrang,J.-M.et al.Nature 1983,302:832-837)。近来的证据表明,作为异种受体,H3受体也位于突触前的5-羟色胺能神经元、去甲肾上腺素能神经元、多巴胺能神经元、胆碱能神经元和(含γ-氨基丁酸的)γ-氨基丁酸能神经元中。最近也从外围组织例如血管平滑肌中发现有这些H3受体。因此,H3的激动剂、抑制剂和反向激动剂在治疗方面存在着潜在的用途。(见:“The histamine H3Receptor-A Target for New Drugs”,Leurs,R.,and Timmerman,H.,(Eds.),Elsevier,1998;Morisset,S.et al.,Nature 2000,408:860-864.)最近Oda,T.etal.描述了组胺的第四种受体-H4(J.Biol.Chem.2000,275(47):36781-36786)。
基于动物实验的结果,提出组胺H3激动剂在医治入睡/即醒和醒后难再入睡症状中有潜在的用途(Lin,J.-S.et al.,Brain Res.1990,523:325-330;Monti,J.M.et al.,Eur.J.Pharmacol.1991,205:283-287)。由于组胺H3激动剂能抑制神经性炎症,还提出可将其用于治疗偏头痛(McLeod,R.L.et al.,Soc.Neurosci.Abstr.1996,22:2010).其他的用途包括对心肌缺血和高血压(在此病症中阻断去甲肾上腺素的释放是有益的)的保护作用(Imamura,M.et al.,J.Pharmacol.Exp.Ther.1994,271(3):1259-1266)。基于组胺H3激动剂能够减少非肾上腺素能及非胆碱能(NANC)在气道中的神经传导以及减少微血管的渗漏,故可用于治疗哮喘(Ichinose,M.and Barnes,P.J.,Eur.J.Pharmacol.1989,174:49-55)。
基于用已知的组胺H3拮抗剂(例如硫丙酰胺)所做的动物药理学实验结果,对组胺H3拮抗剂和反向激动剂也提出了在许多类似的适应症上的应用。这些适应症包括痴呆症,阿尔茨海默氏病(Panula,P.etal.,Soc.Neurosci.Abstr.1995,21:1977),癫痫(Yokoyama,H.et al.,Eur.J.Pharmacol.1993,234:129-133),并发或不并发猝倒的嗜眠症,入睡/即醒自身稳定症,自发嗜睡症,昼间嗜睡症(EDS),昼夜节律紊乱,睡眠/疲劳症,疲劳,伴有睡眠窒息的瞌睡,围绝经期因激素分泌活动的改变导致的睡眠减少,喷射迟滞,与帕金森氏症相关的疲劳,与多发性硬化症(MS)相关的疲劳,与抑郁症相关的疲劳,化疗导致的疲劳,进食障碍(Machidori,H.et al.,Brain Res.1992,590:180-186),运动障碍,眩晕,不能专注多动症(ADHD),学习与记忆障碍(Barnes,J.C.et al.,Soc.Neurosci.Abstr.1993,19:1813),以及精神分裂症(Schlicker,E.and Marr,I.,Naunyn-Schmiedeberg’s Arch.Pharmacol.1996,353:290-294)。(又见:Stark,H.et al.,Drugs Future1996,21(5):507-520;and leurs,R.et al.,Prog.Drug Res.1995,45:107-165及此处引证的参考文献)。据报道,组胺H3拮抗剂单独或与一种组胺H1拮抗剂一起可用于治疗上呼吸道的变态反应(U.S.专利5,217,986号,5,352,707号和5,869,479号)。最近鉴定出了一种组胺H3拮抗剂(GT-2331),Gliatech公司正在开发其在治疗中枢神经系统疾病方面的用途(Gliatech Inc.Press Release Nov.5,1998;Bioworld Today,March 2,1999).
业已提到,有关组胺H3配体的文献已有综合性的述评(“TheHistamine H3 Receptor-A Target for New Drugs”,Leurs,R.andTimmerman,H.,(Eds.),Elsevier,1998)。这篇文献综述了组胺H3激动剂和拮抗剂的药物化学性质(各见:Krause,M.et al.,and Phillips,J.G.and Ali,S.M.)。注意到仅在咪唑部分的4号位置上有一个取代基对其活性的重要性,而另外的取代基会损害其活性。特别是,咪唑环中其他未被取代的位置的甲基化会严重损害其活性.其他的报道支持这样一种假设,即高亲和力的组胺H3受体的配体具有咪唑的一种基本功能(见Ali,S.M.et al.,J.Med.Chem.1999,42:903-909,和Stark,H.et al.,以及此处引证的参考文献)。然而,许多含咪唑的化合物是人体内主要的组胺代谢酶-组胺转甲基酶-的酶解底物,这就导致了其半衰期的缩短和降低了其生物活性(见Rouleau,A.et al.,J.Pharmacol.Exp.Tber.1997,281(3):1085-1094).此外,由于酶的诱导或酶的抑制作用,含咪唑的药物通过与细胞色素P450单氧酶系统的相互作用会参与到不适宜的生物转化过程中来(见:kapetanovic,I.M.and kupferberg,H.J.,Drug Metab.Dispos.1984,12(5):560-564;Sheets,J.J.and mason,J.I.,Drug Metab.Dispos.1984,12(5):603-606;Back,D.J.and Tjia,J.F.,Br.J.Pharmacol.1985,85:121-126;Lavrijsen,K.et al.,Biochem.Pharmacol.1986,35(11):1867-1878;Albengres,E.et al.,Drug Safety1998,18(2):83-97)。组胺H3受体能够较早的穿过薄弱的血脑屏障可能也与(药物中的)咪唑片段有关(Ganellin,C.R.et al.,Arch.Pharm.Pharm.Med.Chem.(Weinheim,Ger.)1998,331:395-404)。
最近有许多文献描述了不含咪唑部分的组胺H3配体,例如:Ganellin,C.R.et al.;Walczynski,K.et al.,Arch.Pharm.Pharm.Med.Chem.(Weinheim,Ger.)1999,332:389-398;Walczynski,K.et al.,Farmaco 1999,54:684-694;Linney,I.D.et al.,J.Med.Chem.2000,43:2362-2370;Tozer,M.J.and Kalindjian,S.B.,Exp.Opin.Ther.Patents2000,10:1045-1055;U.S.Patent 5,352,707;PCT Application WO99/42458,Aug.26,1999;PCT Application WO 02/076925;以及European Patent Application 0978512,Feb.9,2000.
另外,有关这个话题最近还有一个综述(Tozer,M.T.andKalindjian,S.B.Exp.Opin.Ther.Patents 2000,10:1045).自从Leurs的专集发表以来,有关组胺H3激动剂和拮抗剂还出现了一些文献和专利。最值得关注的是不含咪唑的组胺H3拮抗剂的开发应用(Apodaca etal.WO 02/12214;Apodaca et al. WO 02/12190;Bogenstaetter et al.02/12224;Carruthers et al. WO 01/74810;Chai et al.WO 01/74814;Breitenbucher et al.WO 01/74815;Breitenbucher et al.WO 01/74813;Breitenbucher et al. WO 01/74773;Bennani et al. WO 02/06223;Bennani et al. WO 01/66534;Schwartz et al.EP 0978512 A1;Schwartzet al. WO 00/06254;Linney et al. J.Med.Chem.2000,43,2362;以及Ganellin et al. Arch.Pharm.Pharm.Med.Chem.1998,331,395)。
本发明的化合物不含咪唑部分,没有咪唑部分原有的不利作用,一如结合在人的组胺H3受体上的受体所确定的,这些化合物在人的H3受体上保留着其潜在的功能(见Lovenberg,T.W.et al.,Mol.Pharmacol.1999,55:1101-1107)。用人的受体进行筛查来鉴定治疗人的疾病的新疗法非常重要。用大鼠的突触体(Garbarg,M.et al.,J.Pharmacol.Exp.Ther.1992,263(1):304-310),大鼠的皮质膜(West,R.E.et al.,Mol. Pharmacol.1990,38:610-613),以及豚鼠的脑(Korte,A.et al.,Biochem.Biophys.Res.Commun.1990,168(3):979-986)做了常规的结合分析。以前只有少数几次是用人的组织做的实验,但却表明这些与鼠的和灵长类的受体在药理学上有明显的不同(West,R.E.etal.,Eur.J.Pharmacol.1999,377:233-239).
这里描述的是一系列含氮的5元和6元芳族杂环化合物,这些化合物能够调节组胺受体,特别是H3受体的活性,而没有与咪唑部分的存在相关的固有问题。
本发明概述
本发明描述式(1)所示的一种杂环化合物:
其中
在含有A-和B-的环中
1)A,B1和B2为CH;
2)A为CH,B1和B2中一个为N,另一个为CH;或者
3)没有A,B1为CH,B2为O;
L为C1-4亚烷基或是一个共价键;
Q为-(CH2)mO-,-(CH2)nC≡C-(此处的-O-和-C≡C-部分直接联在环上),羰基或硫羰基;
m为2,3或4;
n为1,2,3或4;
R1可任意地被一个或两个RP取代,独立地为下列基团:-H,-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环有0,1或2个双键,带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分;
R2可任意地被一个或两个RP取代,独立地为下列基团:-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环有0,1或2个双键,带有1或2个
诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分;
或者,
R1和R2与所连接的N原子共同构成一个环,这个环可以是下列基团:
i)一个4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0,1或2个双键,有1或2个碳原子是具有0,1或2个Rq取代基的羰基碳;
ii)苯并或吡啶并稠合的4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0或1个另外的双键,有1或2个碳原于是具有0,1或2个Rq取代基的羰基碳;
Rp独立地为下列基团:-C1-6烷基,-C2-6链烯基,-C3-6环烷基,苯基,吡啶基,呋喃基,噻吩基,苄基,嘧啶基,吡咯基,卤素,-OH,-OC1-6烷基,-OC3-6环烷基,-O苯基,-O苄基,-SH,-SC1-6烷基,-SC3-6环烷基,-S苯基,-S苄基,-CN,-NO2,-N(RY)RZ(此处的RY和RZ可以独立地为H和-C1-4烷基;或者
RY和RZ可与所连接的N共同构成一个含5-,6-或7元的单环状杂环,这个杂环上有另外的1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分,这个环可被-C1-4烷基,-OH,-OC1-4烷基,卤素或者-COOC1-4烷基任意取代),-(C=O)N(RY)RZ,-(C=O)C1-4烷基,-SCF3,-OCF3,-CF3和-COOC1-4烷基,以及-COOH;
Rq独立地为下列基团:-C1-6烷基,卤素,-OH,-OC1-6烷基,-CN,-NO2,-CF3和-COOC1-4烷基;
R3可任意地被一个或两个RS取代,独立地为下列基团:-H,-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子,0,1或2个双键;
R4可任意地被一个或两个RS取代,独立地为下列基团:-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子,0,1或2个双键;
RS可独立地为下列基团:-C1-6烷基,-C2-6链烯基,-C3-6环烷基,苯基,吡啶基,呋喃基,噻吩基,苄基,嘧啶基,吡咯基,卤素,-OH,-OC1-6烷基,-OC3-6环烷基,苯氧基,苄氧基,-SH,-SC1-6烷基,-SC3-6环烷基,苯硫基,苄硫基,-CN,-NO2,-N(RY)RZ(此处的RY和RZ可以独立地为H和-C1-4烷基;或者RY和RZ可与所连接的N共同构成一个含5-,6-或7元的单环状杂环,这个杂环上有另外的1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分,这个环可被-C1-4烷基,-OH,-OC1-4烷基,卤素或者-COOC1-4烷基任意取代),-(C=O)N(RY)RZ,-(C=O)C1-4烷基,-SCF3,-OCF3,-CF3和-COOC1-4烷基,以及-COOH;
或者
R3和R4与所连接的N原子共同构成一个环,这个环可以是下列基团:
i)一个4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0,1或2个双键,有0,1或2个碳原子是具有0,1或2个R1取代基的羰基碳;
ii)苯并或吡啶并稠合的4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0或1个另外的双键,有0,1或2个碳原子是具有0,1或2个R1取代基的羰基碳;
R1独立地为下列基团:-C1-6烷基,卤素,-OH,-OC1-6烷基,-CH,-NO2,-CF3和-COOC1-4烷基;
以及对映体,非对映体,水合物,溶剂化物和它们在药学上可采用的盐,酯和酰胺。
同样地,式(1)化合物的异构形式及其在药学上可采用的盐,酯和酰胺也包括在本发明中,本发明中的这类异构形式至少可以是其中的一种异构形式。一个普通的专业人员将认识到,本发明的化合物可以单一的异构体形式存在,而其他的化合物可以一种区域异构的混合形式存在。
含有本发明的化合物的药物组分以及使用这些药物组分来治疗或预防因组胺H3受体的活性而致的病症,也是本发明的特色。
含有本发明的化合物的药物组分和一种药学上可采用的载体,以及制备或配制这种组分的方法则是本发明的另一特色。本发明的组分可以含有一种以上的本发明的化合物,或者一种联合治疗(联合配方或者联合施用不同配制的有活性的制剂)。
本发明还提出了治疗某些病状和疾病的方法,其中的每种方法都包括给需要这种治疗的患者投以有效治疗量(或总和有效)的一种本发明的化合物或组分。这些公开的化合物在治疗或预防下列神经病症的方法中是有用的:入睡/即醒和醒后难再入睡症状(例如失眠症和喷射迟滞),不能专注多动症(ADHD),学习与记忆障碍,认知功能障碍,偏头痛,神经原性炎症,痴呆,轻度的认知功能减弱(痴呆前兆),阿尔茨海默氏病,癫痫,并发或不并发猝倒的嗜眠症,猝倒,入睡/即醒后自身稳定性障碍,自发的嗜眠症,白昼嗜睡症(EDS),昼夜节律紊乱,睡眠/疲劳症,疲劳,伴有睡眠时呼吸暂停的瞌睡,围绝经期激素分泌改变导致的睡眠减少,与帕金森氏症相关的疲劳,与多发性硬化症(MS)相关的疲劳,与抑郁症相关的疲劳,化疗导致的疲劳,进食障碍,肥胖症,运动障碍,眩晕,精神分裂症,物质滥用,双极细胞疾病,燥狂型疾病和抑郁症,以及由组胺H3受体介导的其他病症,如上呼吸道变态反应性疾病,气喘,瘙痒,鼻腔充血和变态反应性鼻炎。例如,做为本发明特色的方法可以预防、抑制下列疾病的发展,或可治疗下列疾病:上呼吸道变态反应性疾病,气喘,瘙痒,鼻腔充血和过敏性鼻炎。
本发明另外体现在所公开的化合物可用于一种联合治疗方法中,包括投以总和有效剂量的一种H3拮抗剂及投以总和有效剂量的一种组胺H1拮抗剂[例如loratidine(CLARITINTM),desloratidine(CLARINEXTM),fexofenadine(ALLEGRATM)和cetirizine(ZYRTECTM)]来治疗过敏性鼻炎,鼻充血和过敏性充血。
本发明另外还体现在所公开的化合物可用于一种联合治疗方法中,包括投以总和有效剂量的一种H3拮抗剂及投以总和有效剂量的一种神经递质再吸收阻断剂[例如一种选择性的血清素再吸收抑制剂(SSRI),一种血清素-去甲肾上腺素再吸收抑制剂,一种去甲肾上腺素能再吸收抑制剂,或者一种非选择性的血清素,多巴胺或去甲肾上腺素再吸收抑制剂,包括fluoxetine(PROZACTM),sertraline(ZOLOFTTM),paroxetine(PAXILTM)和amitryptyline]来治疗抑郁症,情绪疾病或精神分裂症。本发明另外还体现在所公开的化合物可用于一种联合治疗方法中,包括投以总和有效剂量的一种H3拮抗剂及投以总和有效剂量的一种modafinil来治疗嗜眠症,白昼嗜睡症(EDS),阿尔茨海默氏症,抑郁症,注意力难以集中,与多发性硬化症(MS)相关的疲劳,麻醉后的头昏眼花、脚步踉跄,认知力减弱,精神分裂症,脑瘫相关的痉挛状态,年龄相关的记忆力减退,自发性嗜眠症,或喷射迟滞。
下面有关本发明的详细描述和例证以及所附的权利要求将使本发明的特点和优点更加明显和突出。
详细描述
优选地,含有A-和B-的环状结构为吡啶,吡嗪和异唑。
优选地,A,B1和B2为CH;为B1N,B2和A为CH;或者没有A,B1为CH,为B2O。
更优选地,含有A-和B-的环状结构为吡啶。
更优选地,含有A-和B-的环状结构为一个3,6-双取代的吡啶。
更优选地,含有A-和B-的环状结构为一个2,5-双取代的吡啶。
更优选地,含有A-和B-的环状结构为一个2,5-双取代的吡嗪。
更优选地,含有A-和B-的环状结构为一个3,5-双取代的异唑。
越加优选地,A为CH,或A阙如。
越加优选地,B1为CN或N。
越加优选地,B2为CN或O。
优选地,L为亚甲基。
优选地,Q为如下基团:丙烯氧基,乙烯氧基,亚丙炔-1-基,亚丁炔-1-基,羰基和硫羰基。
优选地,Q为丙烯氧基,亚丁炔-1-基,或羰基。
优选地,Q为羰基。
优选地,R1独立地选自下列基团:-H,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,羟基乙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,二乙氨基乙基,丙烯基,炔丙基,环丙基,环戊基,环己基,苯基,苄基,吡啶基,吡咯基,吡咯烷基,哌啶基,吗啉基,硫基吗啉基和azepanyl。
更优选地,R1独立地选自下列基团:-H,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,环丙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,和二乙氨基乙基。
越加优选地,R1独立地选自下列基团:-H,甲基,和甲氧基乙基。
优选地,R2独立地选自下列基团:甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,羟基乙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,二乙氨基乙基,丙烯基,炔丙基,环丙基,环戊基,环己基,苯基,苄基,吡啶基,吡咯基,吡咯烷基,哌啶基,吗啉基,硫基吗啉基和azepanyl。
更优选地,R2独立地选自下列基团:甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,环丙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,和二乙氨基乙基。
越加优选地,R2独立地选自下列基团:甲基,和甲氧基乙基。
优选地,R1和R2一起与所连接的氮原子共同组成一个环,这个环可以是哌啶环,吗啉环,硫代吗啉环,哌嗪环和吡咯烷环。
更优选地,R1和R2一起与所连接的氮原子共同组成一个环,这个环可以是哌啶环,吗啉环和哌嗪环。
作为另一选项,R1和R2一起与所连接的氮原子共同形成4-氟哌啶。越加优选地,R1和R2一起与所连接的氮原子共同组成一个环,这个环可以是哌啶环和吗啉环。
优选地,R3独立地选自下列基团:-H,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,羟基乙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,二乙氨基乙基,丙烯基,炔丙基,环丙基,环戊基,环己基,苯基,苄基,吡啶基,吡咯基,吡咯烷基,哌啶基,吗啉基,硫基吗啉基和azepanyl。
更优选地,R3独立地选自下列基团:-H,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,环丙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,和二乙氨基乙基。
越加优选地,R3独立地选自下列基团:-H,甲基,和甲氧基乙基。
优选地,R4独立地选自下列基团:甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,羟基乙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,二乙氨基乙基,丙烯基,炔丙基,环丙基,环戊基,环己基,苯基,苄基,吡啶基,吡咯基,吡咯烷基,哌啶基,吗啉基,硫基吗啉基和azepanyl。
更优选地,R4独立地选自下列基团:甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,环丙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,和二乙氨基乙基。
越加优选地,R4独立地选自下列基团:甲基,和甲氧基乙基。
优选地,R3和R4一起与所连接的氮原子共同组成一个环,这个环可以是哌啶环,吗啉环,硫代吗啉环,哌嗪环和吡咯烷环。
更优选地,R3和R4一起与所连接的氮原子共同组成一个环,这个环可以是哌啶环,吗啉环和哌嗪环。
作为另一选项,R3和R4一起与所连接的氮原子共同形成4-氟哌啶。越加优选地,R3和R4一起与所连接的氮原子共同组成一个环,这个环可以是哌啶环和哌嗪环。
按式(1),可以任意被RP、Rq、RS或R1中的任一个进一步取代的上述任何优选的取代基都可以被任意取代。
人们知道,这里提出的一些化合物是手性的和/或有几何异构中心,例如E-和Z-异构体。本发明包含所有这些光学异构体,包括具有本发明中的化合物特有活性的立体异构体和外消旋混合物,非对映异构体和几何异构体。本发明的化合物可以单一对映体、对映体的混合物或外消旋混合物的形式存在。在某些实例中,一个单一对映体的完全构型可能还不清楚。另外,这里提到的一些化合物可以溶剂化以及非溶剂化的形式存在。人们知道,本发明包含具有本发明中的化合物特有活性的所有这些溶剂化以及非溶剂化的形式。
已被改性成可被一些分析技术检测的本发明的化合物也包括在本发明的范围之内。本发明的化合物可用125I,18F,11C,64Cu等放射性元素标记以用于显像或用于对患者的放射性治疗。这类同位素标记的化合物,例如18F同位素标记的化合物可在检测和/或显像技术[例如正电子发射断层扫描术(PET)和单光子发射计算机断层扫描术(SPECT)]中用做探针。优选地,用18F或11C标记的本发明的化合物可在PET中做为分子探针用做研究因组胺H3受体和血清素递质引起的病症。这类化合物的另一个例证是一种同位素标记的化合物,例如用氘(2H)和/或氚(3H)标记的化合物可用于反应动力学研究中。这里所描述的化合物可用常规的化学方法与一种合适的功能化放射性试剂反应,生成放射性标记的化合物。
药学上可采用的盐,酯和胺,包括以一种合适的药效/副作用比,接触患者组织后在药理学上是有效的和合适的而没有太大的毒性、刺激性或变态反应的羧酸盐(例如C1-8烷基,C3-8环烷基,芳基,C2-10杂芳基或C2-10非芳族杂环),氨基加成盐,酸加成盐,酯和胺。表现有碱性功能的式(1)化合物的有代表性的盐包括氢溴酸盐,盐酸盐,硫酸盐,酸式硫酸盐,硝酸盐,乙酸盐,草酸盐,戊酸盐,油酸盐,棕榈酸盐,硬脂酸盐,月桂酸盐,硼酸盐,苯甲酸盐,乳酸盐,磷酸盐,甲苯磺酸盐,柠檬酸盐,马来酸盐,富马酸盐,琥珀酸盐,酒石酸盐,萘酸盐,甲磺酸盐,葡庚糖酸盐,乳二糖酸盐和十二烷基磺酸盐。表现有酸性功能的式(1)化合物的有代表性的加成盐为与这些化合物形成没有毒性的碱式盐。这些盐包括碱金属和碱土离子,例如钠,钾,钙和镁盐,以及非毒性的铵盐,季铵盐,和胺离子盐,例如四甲胺盐,甲铵盐,三甲铵盐和乙铵盐。参见S.M.Berge,et al.,“PharmaceuticalSalts”,J.Pharm.Sci.,1977,66:1-19,该篇文献也做为本文的参考文献。
本发明的化合物的前体药物也包括在本发明的范围之内。一般来说,这些药物前体将是这些化合物的功能性衍生物,它们可以在体内转化成所需要的化合物。因此,在本发明的治疗方法中,“给药”一词将包含对所描述的各种病症的治疗,而在治疗中使用了特别公开的化合物,或所使用的化合物虽未特别公开,但在投给患者后可在患者体内转化成特定的化合物。描述了选择和制备合适的前体药物衍生物的常规方法,例如,H.Bundgaard编“Design of Prodrugs”,1985。除了盐以外,本发明还提供了所描述的化合物的酯,胺和其它保护的或衍生的形式。
本发明中有代表性的药物学上可采用的胺类包括氨的衍生物,C1-6烷基伯胺和二(C1-6烷基)仲胺的衍生物。仲胺包括5元或6元的杂环或杂芳环部分,这些环状部分中含有至少一个氮原子和1或2个另外的杂原子。优选的胺为氨、C1-3烷基伯胺和二(C1-2烷基)仲胺的衍生物。本发明中有代表性的药物学上可采用的酯类包括C1-7烷基、C5-7环烷基、苯基、和苯基(C1-6)烷基酯。优选的酯为甲基酯。
本发明的化合物的前体药物也包括在本发明的范围之内。一般来说,这些药物前体将是这些化合物的功能性衍生物,它们可以在体内转化成所需要的化合物。因此,在本发明的治疗方法中,“给药”一词将包含对所描述的各种病症的治疗,而在治疗中使用了特别公开的化合物,或所使用的化合物虽未特别公开,但在投给患者后可在患者体内转化成特定的化合物。描述了选择和制备合适的前体药物衍生物的常规方法,例如,H.Bundgaard编“Design of Prodrugs”,1985。除了盐以外,本发明还提供了所描述的化合物的酯,胺和其它保护的或衍生的形式。
本发明中优选的化合物包括下列基团:
例 | 化合物 |
1 | (4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲烷酮; |
2 | (4-异丙基-哌嗪-1-基)-(6-吗啉-4-基甲基-吡啶-3-基)-甲烷酮; |
3 | (4-异丙基-哌嗪-1-基)-(5-哌啶-1-基甲基-吡啶-2-基)-甲烷酮; |
4 | 2-哌啶-1-基甲基-5-(3-哌啶-1-基-丙氧基)-吡啶; |
5 | 4-[5-(3-哌啶-1-基-丙氧基)-吡啶-2-基甲基]-吗啉; |
6 | 5-哌啶-1-基甲基-2-(3-哌啶-1-基-丙氧基)-吡啶; |
7 | 4-[6-(3-哌啶-1-基-丙氧基)-吡啶-3-基甲基]-吗啉; |
8 | 2-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶; |
9 | (4-异丙基-哌嗪-1-基)-[6-(2-哌啶-1-基-乙基氨基)-吡啶-3-基]-甲烷酮; |
10 | (4-异丙基-哌嗪-1-基)-[6-(2-吗啉-4-基-乙基氨基)-吡啶-3-基]-甲烷酮; |
11 | (4-异丙基-哌嗪-1-基)-[6-(2-吡啶-2-基-乙基氨基)-吡啶-3-基]-甲烷酮; |
12 | {6-[(2-二乙氨基-乙基)-甲基-氨基]-吡啶-3-基}-(4-异丙基-哌嗪-1-基)-甲烷酮; |
13 | (4-异丙基-哌嗪-1-基)-[6-(4-异丙基-哌嗪-1-基)-吡啶-3-基]-甲烷酮; |
14 | 4-[5-(4-异丙基-哌嗪-1-羰基)-吡啶-2-基]-哌嗪-1-羟基酸乙酯; |
15 | (4-异丙基-哌嗪-1-基)-[6-(4-甲基-哌嗪-1-基)-吡啶-3-基]-甲烷酮; |
16 | (4-异丙基-哌嗪-1-基)-[2-(2-哌啶-1-基-乙基氨基)-吡啶-4-基]-甲烷酮;- |
17 | (4-异丙基-哌嗪-1-基)-[2-(2-哌啶-1-基-乙基氨基)-吡啶-3-基]-甲烷酮;- |
18 | 3-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶; |
19 | 4-[5-(4-哌啶-1-基-丁-1-炔基)-吡啶-3-基甲基]-吗啉; |
20 | 2-(4-哌啶-1-基-丁-1-炔基)-6-哌啶-1-基甲基-吡啶; |
21 | 4-[6-(4-哌啶-1-基-丁-1-炔基)-吡啶-2-基甲基]-吗啉; |
22 | (2-甲氧基-乙基)-[6-(4-哌啶-1-基-丁-1-炔基)-吡啶-2-基甲基]-胺; |
23 | (4-异丙基-哌嗪-1-基)-(5-哌啶-1-基甲基-哌嗪-2-基)甲烷酮; |
24 | (4-异丙基-哌嗪-1-基)-(5-吗啉-4-基甲基-哌嗪-2-基)甲烷酮; |
25 | 4-[3-(3-哌啶-1-基-丙氧基)-异恶唑-5-基甲基]-哌啶; |
26 | 4-[3-(3-哌啶-1-基-丙氧基)-异恶唑-5-基甲基]-吗啉; |
27 | (2-甲氧基-乙基)-[3-(3-哌啶-1-基-丙氧基)-异恶唑-5-基甲基]-胺;和 |
28 | (4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲硫醇 |
做为一个优选的方案,本发明的化合物包括下列基团:
例 | 化合物 |
1 | (4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲烷酮; |
2 | (4-异丙基-哌嗪-1-基)-(6-吗啉-4-基甲基-吡啶-3-基)-甲烷酮; |
3 | (4-异丙基-哌嗪-1-基)-(5-哌啶-1-基甲基-吡啶-2-基)-甲烷酮; |
4 | 2-哌啶-1-基甲基-5-(3-哌啶-1-基-丙氧基)-吡啶; |
5 | 4-[5-(3-哌啶-1-基-丙氧基)-吡啶-2-基甲基]-吗啉; |
8 | 2-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶; |
9 | (4-异丙基-哌嗪-1-基)-[6-(2-哌啶-1-基-乙基氨基)-吡啶-3-基]-甲烷酮; |
10 | (4-异丙基-哌嗪-1-基)-[6-(2-吗啉-4-基-乙基氨基)-吡啶-3-基]-甲烷酮; |
12 | {6-[(2-二乙氨基-乙基)-甲基-氨基]-吡啶-3-基}-(4-异丙基-哌嗪-1-基)-甲烷酮; |
13 | (4-异丙基-哌嗪-1-基)-[6-(4-异丙基-哌嗪-1-基)-吡啶-3-基]-甲烷酮; |
例 | 化合物 |
15 | (4-异丙基-哌嗪-1-基)-[6-(4-甲基-哌嗪-1-基)-吡啶-3-基]-甲烷酮; |
16 | (4-异丙基-哌嗪-1-基)-[2-(2-哌啶-1-基-乙基氨基)-吡啶-4-基]-甲烷酮;- |
18 | 3-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶; |
19 | 4-[5-(4-哌啶-1-基-丁-1-炔基)-吡啶-3-基甲基]-吗啉; |
20 | 2-(4-哌啶-1-基-丁-1-炔基)-6-哌啶-1-基甲基-吡啶; |
21 | 4-[6-(4-哌啶-1-基-丁-1-炔基)-吡啶-2-基甲基]-吗啉; |
22 | (2-甲氧基-乙基)-[6-(4-哌啶-1-基-丁-1-炔基)-吡啶-2-基甲基]-胺; |
23 | (4-异丙基-哌嗪-1-基)-(5-哌啶-1-基甲基-哌嗪-2-基)甲烷酮; |
24 | (4-异丙基-哌嗪-1-基)-(5-吗啉-4-基甲基-哌嗪-2-基)甲烷酮; |
25 | 4-[3-(3-哌啶-1-基-丙氧基)-异唑-5-基甲基]-哌啶; |
28 | (4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲硫醇 |
做为另一个优选的方案,本发明的化合物包括下列基团:
例 | 化合物 |
1 | (4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲烷酮; |
3 | (4-异丙基-哌嗪-1-基)-(5-哌啶-1-基甲基-吡啶-2-基)-甲烷酮; |
4 | 2-哌啶-1-基甲基-5-(3-哌啶-1-基-丙氧基)-吡啶; |
8 | 2-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶; |
9 | (4-异丙基-哌嗪-1-基)-[6-(2-哌啶-1-基-乙基氨基)-吡啶-3-基]-甲烷酮; |
12 | {6-[(2-二乙氨基-乙基)-甲基-氨基]-吡啶-3-基}-(4-异丙基-哌嗪-1-基)-甲烷酮; |
13 | (4-异丙基-哌嗪-1-基)-[6-(4-异丙基-哌嗪-1-基)-吡啶-3-基]-甲烷酮; |
15 | (4-异丙基-哌嗪-1-基)-[6-(4-甲基-哌嗪-1-基)-吡啶-3-基]-甲烷酮; |
16 | (4-异丙基-哌嗪-1-基)-[2-(2-哌啶-1-基-乙基氨基)-吡啶-4-基]-甲烷酮;- |
18 | 3-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶; |
20 | 2-(4-哌啶-1-基-丁-1-炔基)-6-哌啶-1-基甲基-吡啶; |
23 | (4-异丙基-哌嗪-1-基)-(5-哌啶-1-基甲基-哌嗪-2-基)甲烷酮; |
25 | 4-[3-(3-哌啶-1-基-丙氧基)-异唑-5-基甲基]-哌啶; |
28 | (4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲硫醇 |
对于本专业普通的技术人员来说,本发明的特色和优点是明显的。基于此处公开的信息,包括摘要,详细描述,背景,实施例和权利要求,本专业一个普通的技术人员面对各种条件和用途将能做出修改和适度的变化。此处所述的出版物以参考文献的形式全文收编在此。在使用化学符号的地方,人们知道是从左向右读,否则它们的空间位置就没有意义。
上述化合物可按本专业的方法和/或下述方案和实施例中的方法制备。为获取此处所述的化合物,不管反应方案中有或没有适当的保护措施,都可用带有最终所希望的取代基的的化合物做为起始物。用常规的保护基团就可以做到这一点,如下列文献中所述:“ProtectiveGroups in Organic Chemistry”,ed.J.F.W.McOmie,Plenum Press,1973;和T.W.Greene&P.G.M.Wuts,“Protective Groups in OrganicSynthesis”,3rded.,John Wiley&Sons,1999.在接下来方便的时候可以用本专业已知的方法将保护基团去掉。另一个方案中,在最终所希望的取代基的地方,要用到一个合适的基团,该基团通过这个反应方案被所希望的取代基取代。这些化合物,母体,或药物前体也包括在本发明的范围内。上述化合物可按下述A-G方案制备。本专业的人员将会识别出,与其他方案相比,用哪一种方案能更好地制备某些化合物。
方案A
可按方案A和下列提示制备式(I)的化合物。用I2,叔丁基氯,三氟乙酸和二甲基亚砜可将市售的杂环酯类衍生物(II)在苄甲基位置上氧化成醛(III)。这种转化也可用两步反应完成,即用N-溴代琥珀酰亚胺和过氧化二苯甲酰将甲基取代基二溴化,然后将此二溴胺与硝酸银在乙醇中加热反应生成醛。然后在还原的胺化作用下使该醛的官能度反应生成式(IV)的化合物。该醛可用一个合适的胺来处理,处理时可以用(或不用)一种活化剂,例如protic酸或路易斯酸,及一种合适的还原剂,例如三乙酸氢硼化钠。该醛还可还原成醇,转换成如氯化物这样一种离去基团,以及如下面的方案G所示用一个合适的胺取代。这个氯化物也可以被氰化物的阴离子取代,生成的还原的腈以一个另外的碳原子确定这种连接。或者,这个醛可用Horner-Emmons化学法反应,然后在双键处加氢,导入一个含有另外两个碳原子的烷链。这个酯可用一个伯胺或仲胺在有一种路易斯酸活化剂(如MgBr2)存在的条件下转化成如式(I)的胺的形式。用P2S5或Lawesson氏剂处理可将此羟胺转化成式(I)相应的硫代酰胺。
方案B
式(I)的化合物也可按方案B和下列提示制备。在标准的肽偶合条件下,用一个合适的伯胺或仲胺,在有偶合剂存在的情况下可将酸衍生物(V)转换成相应的胺(VI),偶合剂包括1-羟基苯并三唑水合物(HOBt),1-[3-(二甲基氨基)丙基]-3-乙基碳化二亚胺盐酸盐(EDCI)和N-甲基吗啉。用DIBAL-H可将酯基选择性地还原为醛(VII),或者可用一种两步序列法,用一种氢化剂如LiAIH(otBu)3或NaBH4然后再用MnO2、Dess-Martin periodinane或Swern氧化将酯还原成醇。用方案A的方法将这个醛转化成式(I)的化合物,这里的Q为羰基或硫羰基。
方案C
或者,式(I)的化合物也可按方案C和下列提示制备。在肽偶合的条件下杂环羟酸(VIII)可如上述与一个伯胺或仲胺反应生成胺(IX)。用一种合适的还原剂如甲硼烷-二甲基硫醚可将胺的官能度还原为相应的胺(X)。用一种合适的烷基化剂设置上一个烃键(XI),例如1-溴-3-氯丙烷或1-溴-4-氯丙烷,并在一种合适的碱(如K2CO3)存在的条件下可将这个羟基的官能度烷基化。为使烷剂化产物具有所希望的区域选择性,可用Ag2CO3。在有一种合适的碱(如Na2CO3)存在的条件下,加或不加催化的KI,可用一个伯胺或仲胺取代这个被束缚的离去基团。或者,在Mitsunobu条件下,用一种胺-官能度的醇(例如3-哌啶-1-基丙醇),标准的或聚合物支持的三苯膦以及二-叔丁基偶氮二羧酸盐,在一种溶剂中(例如二氯甲烷)可将式(X)的化合物直接转化为式(I)的化合物。
方案D
式(I)的化合物也可按方案D和下列提示制备。用一种有机锂试剂(例如n-BuLi),并用DMF淬炼锂阴离子,可将式(XII)的化合物(其X为溴化物)转化成溴代醛(XIII)。通过用n-BuMgCl处理,可将中间的锂类原位转化成相应的格利雅试剂。溴代醛可用市售的羧酸以熟悉本专业的技术人员知道的方法制备。用上述还原的胺化反应可将该醛(XIII)转换成胺(XIV)。或者,在有一种叔胺碱(例如三乙胺)存在的条件下,用N-苯基三氟甲烷-磺酰胺或三氟代醛可将式(X)的醇转化成相应的三氟酸盐(XIV,X=OTf)。这种三氟酸盐和溴代醛可以偶合,偶合作用是在钯催化剂的作用下用一种胺取代基[例如1-丁-3-炔基-哌啶(Turner,S.C.et al.Bioorg.Med.Chem.Lett.2003,13(13):2131-2136)]在有一种钯催化剂[例如(PPh3)2PdCl2]存在的条件下,用或不用添加剂(如CuI,三苯基膦和三乙胺),使末端炔烃官能化而生成式(I)的化合物。
方案E
式(I)的化合物也可按方案E和下列提示制备。按方案D所述制备的式(XIV)的2-溴代杂环可被转换成式(I)的化合物,方法是用一种合适的醇盐试剂进行取代,由所希望的亚单位(如3-哌啶-1-基-丙-1-醇)和溴化物在有一种强碱(如氢化钠)存在的条件下反应生成。
方案F
式(I)的化合物也可按方案F和下列提示制备。如上所述,带有2-氯取代基的杂环的酸(XV)可被转换成相应的胺(XVI)。在加热或不加热的条件下,这个氯在一种溶剂中(如n-BuOH)可被一个合适的伯胺或仲胺取代,生成式(I)的化合物,这个化合物中没有L。
方案G
关于方案G,提出以下几点:用一种合适的官能化的氨基醇,例如3-哌啶-1-基-丙-1-醇,聚合物支持的三苯基膦和二叔丁基偶氮二羧酸盐,在一种溶剂,例如二氯甲烷中,可在Mitsunobu条件下使异唑(XVII)中的自由羟基烷基化。按上述的烷基化和置换步骤也可将这个醇转化为胺(XVIII)。酯的官能度可以还原成式(XIX)的醇。可用亚硫酰氯将这个醇转换成相应的氯化物,其后再用一种合适的伯胺或仲胺置换,生成式(I)的化合物。或者,将这个醇氧化成相应的醛,并按上述方法在还原胺化作用的条件下转化。
按上述方案制备的化合物可能是单一的对映体,或对映体的混合物,或外消旋混合物。如果得到的是对映体的外消旋混合物(1∶1)和非外消旋混合物(非1∶1),可以用本专业熟知的常规方法将单一的对映体分离出来。特别有用的分离方法包括手性色谱法,再结晶法,再次溶解法,非对映体盐生成法,或者衍生成非对映体的加合物后再分离。
本发明的化合物是组胺H3受体的调谐剂,因此在治疗组胺H3介导的病症方面是有用的。
本发明的化合物可以药物组分的形式用于治疗由H3受体介导的疾病患者(人和其他哺乳动物)。此处公开的化合物,单独或与其他药剂(如组胺H1受体拮抗剂)合用,在治疗或预防神经性疾病方面是有用的,这些神经性疾病包括入睡/即醒症和醒后难再入睡症(如失眠症和喷射迟滞),不能专注多动症(ADHD),学习和记忆障碍,认知功能障碍,偏头痛,神经原性炎症,痴呆,轻度认知功能减弱(痴呆前兆),阿尔茨海默氏症,癫痫,伴有或不伴有猝倒的嗜眠症,猝倒,入睡/即醒后自身稳定性病症,自发的嗜眠症,白昼嗜睡症(EDS),昼夜节律紊乱,睡眠/疲劳症,疲劳,伴有睡眠时呼吸暂停的瞌睡,围绝经期激素分泌改变导致的睡眠减少,与帕金森氏症相关的疲劳,与多发性硬化症(MS)相关的疲劳,与抑郁症相关的疲劳,化疗导致的疲劳,进食障碍,肥胖症,运动障碍,眩晕,精神分裂症,物质滥用,双极细胞疾病,燥狂型疾病和抑郁症,以及由组胺H3受体介导的其他病症,如上呼吸道变态反应性疾病,气喘,瘙痒,鼻腔充血和过敏性鼻炎。白昼嗜睡症(EDS)可发生也可不发生呼吸暂停,shift work,纤维性肌痛,多发性硬化症等等。
本发明还提供了含有一种或多种本发明化合物的,伴有药学上可采用的载体和任意选择添加的药物制剂(如H1拮抗剂,SSRIs,或modafinil)的药物组分。这些药物组分可用常规的药物赋形剂和熟悉剂型的人都知道的合成方法制备。预期本发明的化合物可用做口服,肠胃道外途径、直肠途径、局部或经眼途径给药,或做成吸入剂。也可将有效成分制备成缓释剂。制备的剂型可以是片剂,胶囊,药囊,小瓶,粉剂,颗粒剂,锭剂,原粉,水制剂或栓剂。优选的给药途径是静脉输入或局部给药,更优选的是口服给药。
为能口服,本发明的化合物可做成片剂或胶囊,或者制成溶液、乳液或悬液。口服用的片剂可用有效成分与药学上可采用的赋形剂混合制成,赋形剂包括惰性的稀释剂,崩解剂,粘合剂,润滑剂,甜味剂,调味剂,着色剂和防腐剂。适宜的惰性填充物包括碳酸钠和碳酸钙,磷酸钠和磷酸钙,乳糖,淀粉,蔗糖,葡萄糖,甲基纤维素,硬脂酸镁,甘露糖醇,山梨糖醇等等;淀粉,聚乙烯吡咯烷酮,钠淀粉甘醇酸酯,微晶纤维素和藻酸是合适的崩解剂。粘合剂包括淀粉和明胶。润滑剂,如果需要的话,一般包括硬脂酸镁,硬脂酸或滑石。如果希望的话,可用甘油一硬脂酸酯或甘油二硬脂酸酯这样一些物质给片剂挂上糖衣,或用肠衣包裹,以延缓药物在胃肠道内的吸收。口服的胶囊包括硬的明胶胶囊,在这种胶囊中有效成分与一种固体的,半固体的或液体的稀释剂混合在一起,而在软的明胶胶囊中,与有效成分混合在一起的是水,一种油(例如花生油或橄榄油),液体石蜡,一种短链脂肪酸的一甘油酯和二甘油酯,聚乙烯甘醇400或丙烯甘醇。
液体的口服剂可以是悬液,溶液,乳液或糖浆,或者是一种干物质,在口服前用水或其他合适的载体再调制成液态。这类液态的组分可以含有药学上可采用的赋形剂,如悬浮剂(例如山梨糖醇,甲基纤维素,藻酸钠,明胶,羟乙基纤维素,羰甲基纤维素,硬脂酸铝胶等等),非液态载体,包括油类(例如杏仁油或分馏的椰子油),丙烯甘醇,乙醇或水;防腐剂(例如甲基或丙基对羟基苯甲酸盐或山梨酸);保湿剂如卵磷脂;以及,如果需要,还包括调味剂和着色剂。
本发明的化合物还可以通过非口服的途径给药。可将药物组分配制成栓剂通过直肠给药。为了通过胃肠道外的途径给药,包括静脉内输液、肌肉内注射、腹膜内或皮下途径给药,一般将本发明的化合物制备成灭活的水溶液或悬液,缓冲成适当的pH和等渗性,或者用胃肠道外途径给药可采用的油配制。合适的液体载体包括林格氏液和等渗的氯化钠。制成单一剂量形式的这种剂型将装在安瓶或一次性输液装置中,多剂量的药装在管形瓶中,从瓶中可抽取适当的剂量,或者制成固体形式或浓缩形式,用这种固态的和浓缩剂可配制注射用的剂型。本发明化合物的另外的给药模式是利用一种块状配方,涂在皮肤上,经皮肤给药。本发明的化合物还可以制成吸入剂的形式给药,用一种由本发明的化合物和一种合适的载体制成的喷射剂型通过鼻腔或口腔的途径给药。
本发明化合物的有效剂量可用常规方法确定。特殊患者所需的特定剂量决定于许多因素,包括所治疗的病症的严重程度,给药途径,和患者的体重。然而,一般说来,预期每日剂量(不管是一次给药还是分几次给药)为0.01mg/d~1000mg/d,更常用的剂量是1mg/d~500mg/d,最常用的剂量是10mg/d~200mg/d.用单位体重所需剂量表示,典型的剂量是0.0001mg/kg~15mg/kg,特别是0.01mg/kg~7mg/kg,尤其特别是0.15mg/kg~2.5mg/kg。
优选地,口服剂量范围为每天0.05mg/kg~200mg/kg,分1次~4次给药。一些本发明的化合物口服剂量的范围为每天0.05mg/kg~50mg/kg,其他的为每天0.05mg/kg~20mg/kg,还有一些其他的为每天0.1mg/kg~10mg/kg。灌注的剂量范围为1~1000μg/kg/min抑制剂,与一种药物载体掺和在一起,灌注的时间范围为几分钟到几天。做局部用药时,本发明的化合物可与一种药物载体混合起来,制成1%~10%浓度的药物施用。
所公开的化合物可与其他治疗剂合用,包括H1受体拮抗剂,H2受体拮抗剂,和神经传导调谐剂,如SSRIs,血清素-去甲肾上腺素再吸收抑制剂,去甲肾上腺素能再吸收抑制剂,非选择性血清素再吸收抑制剂(NSSRIs),或其他神经活性剂,如modafinil。
确定所公开的药物组分或所公开的合用药(不论其是否以相同的组分配方)的有效治疗剂量或有效预防剂量的方法是本专业的人员已知的。做治疗用时,此处所用的“联合有效剂量”一词表示每一种活性化合物或药剂单独使用或与其他合用时的剂量,这个剂量被研究人员、兽医、医生或其他医务人员认为能够在一种组织系统,动物或人中引起生物学的或医学层面的反应,这些反应包括所治疗的疾病或损伤症状的减轻。做预防用时(即抑制一种病症的发生或发展),“联合有效剂量”一词表示每一种活性化合物或药剂单独使用或与其他合用时的剂量,这个剂量被研究人员、兽医、医生或其他医务人员认为能够抑制一种病症在某一客体内的发生或发展,而这种被延缓的病症至少部分是由于一种或多种组胺受体的调谐引起的。因此,本发明提出了两种或多种药物的联合使用,例如,(a)每种药物独立地以治疗剂量或预防剂量投药;(b)在合剂中至少有一种药物如果单独投药,则以亚治疗量或亚预防量投药,但若按照本发明与第二种或其他的药物合用,则须按全治疗量或全预防量投药;(c)两种药物若单独使用,则均须以亚治疗量或亚预防量投药,但若合用,则须按全治疗量或全预防量投药。三种或三种以上的药物合用也同样是可能的。联合用药的治疗方法包括按含有全部有效成分的单一配方投药;一种以上的配方基本上同时投药;以及投以分别配方的两种或两种以上有效药剂。
实施例
为了说明本发明,给出了下列实施例。这些实施例并非本发明的限定域。它们仅仅意味着为实现本发明所推荐的一种方法。熟悉本专业的人员可以找到其他的方法来实现本发明,这对他们来说是很显然的。但那些方法被认为也包括在本发明的范围之内。
预备性的反相高效液相色谱(HPLC)方案
Gilson装置
柱:YMC-Pack ODS-A,5μm,75×30mm
流速:10mL/min
检测:λ=220&254nm
梯度(乙腈/H2O,0.05%三氟乙酸)
1)0.0min 20%乙腈/80%H2O
2)20.0min 99%乙腈/1%H2O
反相高效液相色谱(HPLC)方案
Hewlett Packard Series 1100
柱:Agilent ZORBAXC8,5μm,4.6×150mm
流速:1mL/min
检测:λ=220&254nm
梯度(乙腈/H2O,0.05%三氟乙酸)
1)0.0min 1%乙腈/99%H2O
2)20.0min 99%乙腈/1%H2O
用电子喷雾电离化作用(ESI)在所指定的阳性或阴性模式下获得Agilent系列1100 MSD的质谱。
用Bruker型DP×400(400MHz)或DP×500(500MHz)分光光度计测得核磁共振(NMR)谱。以下的1H NMR数据为:ppm量级的四甲基硅烷参比的低磁场的化学位移[峰裂数,偶合常数j(单位:Hz),积分]。
实施例1
(4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲烷酮
步骤A 6-甲酰烟酸甲酯 将6-甲基烟酸甲酯(1.00g,6.62mmol),碘(1.68 g,6.62mmol),2-碘代-2-甲基丙烷(0.478g,2.60mmol)和三氟乙酸(2.26g,19.8mmol)的无水DMSO溶液在160℃加热3h。将反应混合物冷却到室温(rt),用50ml 1N有水的亚硫酸钠处理。用碳酸氢钠将反应混合物的pH调为10。将反应混合物用乙酸乙酯(3×100ml)提取三次。用无水硫酸钠使合并的有机相干燥,过滤,浓缩。用色谱法层析滤渣(SiO2;0-3%EtOH∶DCM),得到固态的6-甲酰烟酸甲酯(0.506g,46%)。
步骤B 6-哌啶-1-基甲基-烟酸甲酯 在6-甲酰烟酸甲酯(0.200g,1.21mmol)和哌啶(0.14mL,1.33mmol)的DCM(15mL)溶液中加入NaB(OAc)3H(0.380g,1.80mmol)。18h后,将反应物用1N的NaOH(10mL)稀释,用DCM(2×50mL)提取两次。将有机层合并,用硫酸钠干燥,浓缩。用色谱法层析滤渣(SiO2;MeOH/DCM中的1-3%2M NH3),得到油状的6-哌啶-1-基甲基=烟酸甲酯(0.210g,74%)。
步骤C (4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲烷酮将6-哌啶-1-基甲基-烟酸甲酯(0.300g,1.28mmol)和MgBr2 OEt2(0.900g,3.84mmol)的THF(15mL)溶液搅拌15min.然后向反应物中滴加1-异丙基-哌嗪(0.325g,2.56mmol)的THF(2mL)溶液,将混合物回流加热48h。将反应混合物冷却到室温,浓缩,用50mL有水的1N碳酸氢钠处理,用乙酸乙酯(3×50mL)提取三次。将有机层合并,用硫酸钠干燥,浓缩。用色谱法层析滤渣(SiO2;MeOH/DCM中的1-3%2 M NH3),得到油状的(4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲烷酮(0.210g,74%)。
MS(ESI):精确的分子量计算值C19H30N4O,330.2;m/z测定值,331.2[M+H]+.1H NMR(400MHz,CDCl3):8.55(d,J=2.2,1H),7.87(dd,J=7.8,2.0,1H),7.62(d,J=7.6,1H),3.78(br s,2H),3.67(s,2H),3.48(br s,2H),2.77-2.73(m,1H),2.65-2.48(m,8H),1.65-1.59(m,4H),1.49-1.48(m,2H),1.09(d,J=6.6,6H),
实施例2
(4-异丙基-哌嗪-1-基)-(6-吗啉-4-基甲基-吡啶-3-基)-甲烷酮该化合物的合成方法与实施例1相同,只是在步骤B中用吗啉替代哌啶。
MS(ESI):精确的分子量计算值C18H28N4O2,332.2;m/z测定值,333.2[M+H]+,1H NMR(400MHz,CDCl3):8.60(d,J=2.3,1H),7.72(dd,J=7.8,2.3,1H),7.48(d,J=7.8,1H),3.79-3.72(m,6H),3.67(s,2H),3.44(br s,2H),2.75-2.72(m,1H),2.60(br s,2H),2.52-2.48(m,6H),1.05(d,J=6.6,6H),
实施例3
(4-异丙基-哌嗪-1-基)-(5-哌啶-1-基甲基-吡啶-2-基)-甲烷酮
步骤A 6-(4-异丙基-哌嗪-1-羰基)-烟酸甲酯 在哌啶-2,5-二羧酸5-甲酯(1.00g,5.50mmol)和1-异丙基-哌嗪二盐酸(1.20g,6.10mmol)的DCM(100mL)溶液中加入1-羟基苯并三唑水合物(HOBt,1.10g,8.30mmol),1-[3-(二甲基氨基)丙基]-3-乙基碳化二亚胺盐酸盐(EDC,1.60g,8.30mmol)和N-甲基吗啉(2.9mL,27.0mmol)。18h后,用50mL有水的1N碳酸氢钠使反应混合物骤冷,用DCM(3×50mL)提取三次。合并有机层,用硫酸钠干燥,浓缩。用色谱法层析滤渣(SiO2;MeOH/DCM中的2-5%2 M NH3),得到6-(4-异丙基-哌嗪-1-羰基)-烟酸甲酯(1.20g,74%)。
步骤B (5-羟甲基-吡啶-2-基)-(4-异丙基-哌嗪-1-基)-甲烷酮 用一个干冰浴将6-(4-异丙基-哌嗪-1-羰基)-烟酸甲酯(0.500g,1.72mmol)的THF(15mL)溶液冷却到-78℃。然后在反应混合物中滴加1M三-叔丁氧基氢铝锂的THF溶液(3.44mL)。将生成的溶液放置到室温,搅拌18h。用satd.aq.酒石酸钾钠(Rochelle氏盐,15mL)使反应物骤冷,用DCM(3×50mL)提取三次。合并有机层,用硫酸钠干燥,浓缩,生成0.275g(5-羟甲基-吡啶-2-基)-(4-异丙基-哌嗪-1-基)-甲烷酮(61%)。
步骤C 6-(4-异丙基-哌嗪-1-羰基)-哌啶-3-羰醛 在(5-羟甲基-吡啶-2-基)-(4-异丙基-哌嗪-1-基)-甲烷酮(0.275g,1.10mmol)的DCM(30mL)溶液中加入MnO2(0.400g,5.20mmol).将反应物搅拌6h,用一个硅藻土垫板过滤,浓缩,生成6-(4-异丙基-哌嗪-1-羰基)-哌啶-3-羰醛(0.250g,95%)。
步骤D (4-异丙基-哌嗪-1-羰基)-(5-哌啶-1-基甲基-吡啶-2-基)-甲烷酮在6-(4-异丙基-哌嗪-1-羰基)-哌啶-3-羰醛(0.250g,0.96mmol)和哌啶(0.11mL,1.10mmol)DCM(20mL)溶液中加入NaB(OAc)3H(0.300g,1.44mmol)。18h后加入15mL 1N的NaOH,用DCM(3×25mL)提取三次。合并有机层,用硫酸钠干燥,浓缩。用色谱法层析生成的残渣(SiO2;MeOH/DCM中的4-8%2 M NH3),得到油状的(4-异丙基-哌嗪-1-羰基)-(5-哌啶-1-基甲基-吡啶-2-基)-甲烷酮(0.030g,9%)。
MS(ESI):精确的分子量计算值C19H30N4O,330.2;m/z测定值,331.5[M+H]+.1H NMR(400MHz,CDCl3):8.49(s,1H),7.77(dd,J=7.8,2.0,1H),7.58(d,J=7.8,1H),3.82 (t,J=5.0,2H),3.61(t,J=5.0,2H),3.49(s,2H),2.75-2.72(m,1H),2.62(t,J=5.0,2H),2.51(t,J=5.0,2H),2.37(br s,4H),1.60-1.54(m,4H),1.45-1.43(m,2H),1.05(d,J=6.6,6H).
实施例4
2-哌啶-1-基甲基-5-(3-哌啶-1-基-丙氧基)-吡啶
步骤A (5-羟基-吡啶-2-基)-哌啶-1-基-甲烷酮 在5-羟基-2-吡啶羧酸(2.00g,14.0mmol)和哌啶(1.5mL,15mmol)的DCM(150mL)溶液中加入HOBt(2.80g,21.0mmol),EDC(4.00g,21.0mmol)和N-甲基吗啉(8.5mL,94mmol)。18h后将反应混合物浓缩。用色谱法层析残渣(SiO2;MeOH/DCM中的5-10%2 M NH3),得到固态的(5-羟基-吡啶-2-基)-哌啶-1-基-甲烷酮(1.30g,43%)。
步骤B 6-哌啶-1-基甲基-吡啶-3-醇 在(5-羟基-吡啶-2-基)-哌啶-1-基-甲烷酮(1.30g,6.31mmol)的THF(100mL)溶液中加入甲硼烷-甲硫醚混合物(1.75mL,18.9mmol).18h后除去溶剂,用MeOH(50mL)稀释残渣,加热到60℃。2h后将溶剂蒸发掉,色谱法层析残渣(SiO2;MeOH/DCM中的4-8%2 M NH3),得到油状的6-哌啶-1-基甲基-吡啶-3-醇(0.225g,17%)。
步骤C 5-(3-氯-丙氧基)-2-哌啶-1-基甲基-吡啶 将6-哌啶-1-基甲基-吡啶-3-醇(0.225g,1.17mmol),1-溴-3-氯-丙烷(0.23mL,2.34mmol)和碳酸钾(0.483g,3.50mmol)的丙酮(10mL)溶液加热到回流温度。10h后将反应混合物冷却到室温,用50mL丙酮稀释,用一块硅藻土垫板过滤。将过滤物浓缩,生成油状的5-(3-氯-丙氧基)-2-哌啶-1-基甲基-吡啶粗品(0.250g,80%)。
步骤D 2-哌啶-1-基甲基-5-(3-哌啶-1-基-丙氧基)-吡啶 将5-(3-氯-丙氧基)-2-哌啶-1-基甲基-吡啶(0.25g,0.86mmol),哌啶(0.09mL,0.94mmol),碘化钾(0.003g,0.017mmol)和碳酸钠(0.045g,0.43mmol)的1-丁醇(5mL)溶液加热到95℃。18h后将反应混合物浓缩,用50mL DCM稀释,用一块硅藻土垫板过滤。将滤物浓缩,用色谱法层析残渣(SiO2;MeOH/DCM中的3-8%2 M NH3),得到油状的2-哌啶-1-基甲基-5-(3-哌啶-1-基-丙氧基)-吡啶(0.025g,10%).
MS(ESI):精确的分子量计算值C19H31N3O,317.3;m/z测定值,318.5.1H NMR(400MHz,CDCl3):8.23(d,J=2.8,1H),7.29(d,J=8.1,1H),7.16(dd,J=8.6,3.0,1H),4.03(t,J=6.3,2H),3.55(s,2H),2.48-2.40(m,10H),2.01-1.96(m,2H),1.61-1.46(m,8H),1.43(br s,4H).
实施例5
4-[5-(3-哌啶-1-基-丙氧基)-吡啶-2基甲基]-吗啉
该化合物的合成方法与实施例4相同,只是在步骤A中用吗啉替代哌啶。
MS(ESI):精确的分子量计算值C18H29N3O2,319.2;m/z测定值,320.5[M+H]+,1H NMR(400MHz,CDGl3):8.24(d,J=2.5,1H),7.28(d,J=8.6,1H),7.16(dd,J=8.3,2.8,1H),4.04(t,J=6.3,2H),3.72(t,J=4.7,4H),3.58(s,2H),2.49-2.46(m,6H),2.39(br s,4H),2.01-1.96(m,2H),1.61-1.55(m,4H),1.45-1.43(br s,2H).
实施例6
5-哌啶-1-基甲基-2-(3-哌啶-1-基-丙氧基)-吡啶
步骤A (6-溴-吡啶-3-基)-哌啶-1-基-甲烷酮 该中间介质的制备方法与实施例4的步骤A相同,只是用6-溴-3-吡啶羧酸替代5-羟基-2-吡啶羧酸。
步骤B 2-溴-5-哌啶-1-基甲基-吡啶 该中间介质的制备方法与实施例4的步骤B相同,只是用(6-溴-吡啶-3-基)-哌啶-1-基-甲烷酮替代(5-羟基-吡啶-2-基)-哌啶-1-基-甲烷酮。
步骤C 5-哌啶-1-基甲基-2-(3-哌啶-1-基-丙氧基)-吡啶 在NaH(1.5mmol)的DMF悬液中加入3-哌啶-1-基-丙-1-醇(1.1mmol)。30min后在此混合物中加入2-溴-5-哌啶-1-基甲基-吡啶(1mmol)。18h后用乙酸乙酯(100mL)将此反应物提取一次,用1N碳酸氢钠(50mL)和水(3×50mL)洗涤。将有机层干燥,浓缩,用二氧化硅做色谱分析,生成5-哌啶-1-基甲基-2-(3-哌啶-1-基-丙氧基)-吡啶。
实施例7
4-[6-(3-哌啶-1-基-丙氧基)-吡啶-3-基甲基]-吗啉
该化合物的合成方法同实施例6,只是在步骤A中用吗啉替代哌啶。
实施例8
2-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶
步骤A 三氟-甲磺酸5-哌啶-1-基甲基-吡啶-2-基酯 将6-哌啶-1-基甲基-吡啶-3-醇(0.225g,1.17mmol),N-苯三氟甲磺酰胺(0.50g,1.41mmol)和TEA(0.50mL,3.50mmol)的DCM(20mL)溶液回流加热18h。除去溶剂,用色谱法层析残渣(SiO2;MeOH/DCM中的0-3%2 M NH3),得到固态的三氟-甲磺酸5-哌啶-1-基甲基-吡啶-2-基酯(0.036g,95%)。
步骤B 2-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶 在三氟-甲磺酸5-哌啶-1-基甲基-吡啶-2-基酯(0.10g,0.31mmol),1-丁-3-炔基-哌啶(0.051g,0.37mmol)和TEA(2mL)的干DMF(1mL)溶液中加入二氯双(三苯基膦)-钯(II)(0.004g,0.006mmol)和碘化铜(I)(0.004g,0.016mmol)。将反应混合物在80℃加热4h,冷却到室温,用25mL DCM稀释,通过一个硅藻土垫板过滤。将混合物用25mL 1N NaOH稀释,用DCM(3×25mL)提取三次。合并有机层,用硫酸钠干燥,浓缩,用色谱法层析生成的残渣(SiO2;MeOH/DCM中的3-6%2 M NH3),得到2-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶(0.01g,10%)。
MS(ESI):精确的分子量计算值 C20H29N3,311.2;m/z测定值,312.5 [M+H]+,1H NMR(400MHz,CDCl3):8.45(d,J=2.0,1H),7.62(d,J = 8.3,1H),7.25(d,J = 8.1,1H),3.47(s,2H),2.74-2.70(m,4H),2.62-2.59(m,4H),2.37(br s,4H),1.65-1.55(m,8H),1.46-1.44(m,4H).
实施例9
(4-异丙基-哌嗪-1-基)-[6-(2-哌啶-1-基-乙氨基)-吡啶-3-基]-甲烷酮
步骤A (6-氨-吡啶-3-基)-(4-异丙基-哌嗪-1-基)-甲烷酮 在6-氯烟酸(0.985g,6025mmol)和1-异丙基-哌嗪(1.50g,7.50mmol)的DCM(100mL)溶液中加入DOBt(1.20g,9.40mmol),EDC(1.80g,9.40mmol)和N-甲基吗啉(3.4mL,31.3mmol)。18h后将反应物用1N NaOH(50mL)稀释,用EDM(3×50 mL)提取三次。将有机提取物合并,用硫酸钠干燥,浓缩。用色谱法层析残渣(SiO2;MeOH/DCM中的2-4%2 M NH3),得到(6-氯-吡啶-3-基)-(4-异丙基-哌嗪-1-基)-甲烷酮(0.934g,56%)。
步骤B (4-异丙基-哌嗪-1-基)-[6-(2-哌啶-1-基-乙氨基)-吡啶-3-基]-甲 烷酮 将(6-氯-吡啶-3-基)-(4-异丙基-哌嗪-1-基)-甲烷酮(0.20g,0.75mmol)和1-(2-氨基乙基)-哌啶(0.16mL,1.13mmol)的1-丁醇(10mL)溶液在回流温度加热。18h后将反应物浓缩,用1N水合碳酸氢钠(25mL)处理,用EDM(3×25mL)提取三次。将有机层合并,用硫酸钠干燥,浓缩。用色谱法层析残渣(SiO2;MeOH/DCM中的2-5%2 M NH3),得到油状的(4-异丙基-哌嗪-1-基)-[6-(2-哌啶-1-基-乙氨基)-吡啶-3-基]-甲烷酮(0.050g,20%)。
MS(ESI):精确的分子量计算值C20H33N5O,359.3;m/z测定值,360.2 [M+H]+.1HNMR(400MHz,CDCl3):8.20(d,J=1.8,1H),7.54(dd,J=8.6,2.3,1H),6.40(d,J=9.0,1H),5.49(br s,1H),3.65(br s,4H),3.39-3.35(m,2H),2.74-2.70(m,1H),2.59-2.57(m,2H),2.53(br s,4H),2.42(br s,4H),1.62-1.56(m,4H),1.46-1.45(m,2H),1.04(d,6.5,6H).
实施例10
(4-异丙基-哌嗪-1-基)-[6-(2-吗啉-4-基-乙氨基)-吡啶-3-基]-甲烷酮
该化合物的制备与实施例9相同,只是在步骤B中用2-吗啉-4-基-乙胺替代1-(2-氨基乙基)-哌啶。
MS(ESI):精确的分子量计算值C19H31N5O2,361.3;m/z测定值,362.2[M+H]+,1HNMR(400MHz,CDCl3):8.20(d,J=1.9,1H),7.55(dd,J=8.6,2.3,1H),6.40(d,J=9.0,1H),5.36(br s,1H),3.73-3.71(m,4H),3.66-3.62(m,4H),3.41-3.37(m,2H),2.73-2.70(m,1H),2.64-2.60(m,2H),2.52-2.47(m,8H),1.04(d,J=6.5,6H),
实施例11
(4-异丙基-哌嗪-1-基)-[6-(2-吡啶-2-基-乙氨基)-吡啶-3-基]-甲烷酮
该化合物的制备与实施例9相同,只是在步骤B中用2-吡啶-2-基-乙胺替代1-(2-氨基乙基)-哌啶。
MS(ESI):精确的分子量计算值C20H27N5O,353.46;m/z测定值,354.2[M+H]+,1HNMR(400MHz,CDCl3):8.57-8.54(m,1H),8.20(s,1H),7.63-7.59(m,1H),7.53(dd,J=8.6,2.3,1H),7.18-7.14(m,2H),6.39(d,J=9.2,1H),5.43 (br s,1H),3.78-3.73(m,2H),3.65(br s,4H),3.10(t,J = 6.5,2H),2.74-2.70(m,1H),2.52(brs,4H),1.05(d,6.4,6H).
实施例12
{6-[(2-二乙氨基-乙基)-甲基-氨基]-吡啶-3-基}-(4-异丙基-哌嗪-1-基)-甲烷酮
该化合物的制备与实施例9相同,只是在步骤B中用N,N-二乙基-N’-甲基-乙烷-1,2-二胺替代1-(2-氨基乙基)-哌啶。
MS(ESI):精确的分子量计算值C20H35N5O,361.2;m/z测定值,362.2[M+H]+.1H NMR(400MHz,CDCl3):8.26(s,1H),7.58(dd,J=8.8,2.3,1H),6.47(d,J=9.3,1H),3.66-3.63(m,6H),3.10(s,3H),2.74-2.71(m,1H),2.64-2.52(m,10H),1.06-1.01(m,12H).
实施例13
(4-异丙基-哌嗪-1-基)-[6-(4-异丙基-哌嗪-1-基)-吡啶-3-基]-甲烷酮
该化合物的制备与实施例9相同,只是在步骤B中用1-异丙基-哌嗪替代1-(2-氨基乙基)-哌啶。
MS(ESI):精确的分子量计算值C20H33N5O,359.5;m/z测定值,360.2[M+H]+.1HNMR(400MHz,CDCl3):8.27(s,1H),7.60(dd,J=8.8,2.3,1H),6.62(d,J=8.8,1H),3.63-3.60(m,8H),2.74-2.70(m,2H),2.62-2.60(m,4H),2.53(br s,4H),1.07-1.04(m,12H).
实施例14
4-[5-(4-异丙基-哌嗪-1-羰基)-吡啶-2-基]-哌嗪-1-羧酸乙酯
该化合物的制备与实施例9相同,只是在步骤B中用哌嗪-1-羧酸乙酯替代1-(2-氨基乙基)-哌啶。
MS (ESI):精确的分子量计算值C20H31N5O3,389.2;m/z测定值,390.2 [M+H]+.1H NMR(400MHz,CDCl3):8.28(s,1H),7.60(dd,J=8.8,2.3,1H),6.62(d,J=8.8,1H),4 20-4.16(m,2H),3.63-3.60(m,10H),2.73(br s,1H),2.54(br s,4H),1.60(br s,2H),1.31-1.28(m,3H),1.06(d,6.5,6H)。
实施例15
(4-异丙基-哌嗪-1-基)-[6-(4-甲基-哌嗪-1-基)-吡啶-3-基]-甲烷酮
该化合物的制备与实施例9相同,只是在步骤B中用1-甲基-哌嗪替代1-(2-氨基乙基)-哌啶。
MS(ESI):精确的分子量计算值C18H29N5O,331.2;m/z测定值,332.2[M+H]+.1H NMR(400MHz,CDCl3):8.28(s,1H),7.60(dd,J=8.8,2.3,1H),6.62 (d,J=8.8,1H),3.63-3.60(m,8H),2.74-2.70(m,1H),2.52-2.48(m,8H),2.35(s,3H),1.05(d,J=6.5,6H).
实施例16
(4-异丙基-哌嗪-1-基)-[2-(2-哌啶-1-基-乙氨基)-吡啶-4-基]-甲烷酮
步骤A (2-氯-吡啶-4-基)-(4-异丙基-哌嗪-1-基)-甲烷酮 该化合物的制备方法与实施例9的步骤A相同,用2-氯-异烟酸和1-异丙基-哌嗪。
步骤B (4-异丙基-哌嗪-1-基)-[2-(2-哌啶-1-基-乙氨基)-吡啶-4-基]-甲 烷酮 该化合物的制备方法与实施例9的步骤B相同,用(2-氯-吡啶-4-基)-哌啶-1-基-甲烷酮和2-哌啶-1-基-乙胺。
MS(ESI):精确的分子量计算值C20H33N5O,359.3;m/z测定值,360.1[M+H]+.1H NMR(400MHz,CDCl3):8.11(d,J=5.1,1H),6.48(dd,J=5.1,1.3,1H),6.37(s,1H),5.34(br s,1H),3.75(br s,2H),3.40-3.32(m,4H),2.73-2.71(m,1 H),2.59-2.54(m,4H),2.45-2.40(m,6H),1.59-1.55(m,4H),1.45-1.44(m,2H),1.05(d,J=6.5,6H).
实施例17
(4-异丙基-哌嗪-1-基)-[2-(2-哌啶-1-基-乙氨基)-吡啶-3-基]-甲烷酮
步骤A (2-氯-吡啶-3-基)-(4-异丙基-哌嗪-1-基)-甲烷酮 该化合物的制备方法与实施例9的步骤A相同,用2-氯-烟酸和1-异丙基-哌嗪。
步骤B (4-异丙基-哌嗪-1-基)-[2-(2-哌啶-1-基-乙氨基)-吡啶-3-基]-甲 烷酮 该化合物的制备方法与实施例9的步骤B相同,用(2-氯-吡啶-3-基)-哌啶-1-基-甲烷酮和2-哌啶-1-基-乙胺。
MS:精确的分子量计算值C20H33N5O,359.3;m/z测定值,360.3[M+H]+.1H NMR(400MHz,CDCl3):8.11(d,J=5.1,1H),6.48(dd,J=5.1,1.3,1H),6.37(s,1H),5.34(br s,1H),3.75(br s,2H),3.40-3.32(m,4H),2.73-2.71(m,1H),2.59-2.54(m,4H),2.45-2.40(m,6H),1.59-1.55(m,4H),1.45-1.44(m,2H),1.05(d,J=6.5,6H).
实施例18
3-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶
步骤A (5-溴-吡啶-3-基)-甲醇 于室温下在1h的时间里在5-溴烟酸(20.00g,97.00mmol)的无水THF(250mL)溶液中缓慢加入BH3(1MinTHF,197mL)的溶液。在室温下将反应混合物搅拌1h,然后在回流温度下加热5h。使反应混合物冷却到室温,滴加1M盐酸(100mL)。将生成的混合物搅拌1h,用10%水合NaOH处理,将pH调到10。然后将此溶液用乙酸乙酯(4×200mL)提取四次。将有机提取物合并,用水洗涤,用无水硫酸钠干燥,过滤,浓缩,生成粗制醇(10.71g)。将此粗制化合物提纯(SiO2;MeOH/DCM中的0-5%2 M NH3),得到(5-溴-吡啶-3-基)-甲醇(4.14g,22%)。
步骤B 5-溴-吡啶-3-碳化醛 将(5-溴-吡啶-3-基)-甲醇(1.13g,6.00mmol)溶解在40mL氯仿中,用MnO2(3.60g)处理。将反应混合物在回流温度下加热3h。用一块硅藻土板过滤此热的反应混合物,将滤物浓缩,生成5-溴-吡啶-3-碳化醛(0.570g,51%)。
步骤C 3-溴-5-哌啶-1-基甲基-吡啶 将5-溴-吡啶-3-碳化醛(0.190g,1mmol),NaB(OAc)3H(0.320g,1.50mmol)和哌啶(0.090g,1.05mmol)悬于DCM(8mL)中,将此反应混合物在室温下搅拌过夜。添加5mL 1MNaOH溶液使反应物骤冷,然后将此混合物搅拌1h。用DCM(3×15mL)将此反应混合物提取三次。将有机提取物合并,用硫酸钠使之干燥,过滤,浓缩,生成一种油质的粗产物(0.18g,71%)。将此粗产物用到下一步反应中。
步骤D 3-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶 在通氮条件下将3-溴-5-哌啶-1-基甲基-吡啶(0.353g,1.38mmol),1-丁-3-炔基-哌啶(0.380g,2.77mmol),二氯双(三苯膦)钯(II)(0.097g,0.14mmol),碘化铜(I)(0.027g,0.14mmol)和Ph3P(0.131g,0.50mmol)加到DMF(0.50mL)和Et2N(3.00mL)的混合物中。将此系统真空脱气,充氮三次,然后在120-125℃温度下加热2h。使反应混合物冷却,用标准的水合碳酸氢钠(15mL)处理,搅拌30min。将反应混合物用DCM(3×30mL)提取三次,将合并的有机相用水(2×20mL)洗两次,用无水硫酸钠使之干燥,浓缩。将浓缩的残渣提纯(SiO2:MeOH/DCM中的0-7%2 M NH3),生成3-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶(0.018g,8%).
MS(ESI):精确的分子量计算值C20H29N3,311.46;m/z测定值,312.5[M+H]+,1H NMR(500 MHz,CDCl3):8.48(d,J=1.9,1H),8.39(d,J=1.6,1H),7.66-7.64(m,1H),3.42(s,2H),2.69-2.59(m,4H),2.51-2.41(m,4H),2.40-2.30(m,4H),1.64-1.51(m,8H),1.48-1.37(m,4H).
实施例19
4-[5-(4-哌啶-1-基-丁-1-炔基)-吡啶-3-基甲基]-吗啉
步骤A 4-(5-溴-吡啶-3-基甲基)-吗啉 该化合物的制备方法与实施例18的步骤C相同,用5-溴-吡啶-3-碳化醛和吗啉。将粗产品纯化(SiO2;MeOH/DCM中的0-3%2 M NH3)得到4-(5-溴-吡啶-3-基甲基)-吗啉(61%)。
步骤B 4-[5-(4-哌啶-1-基-丁-1-炔基)-吡啶-3-基甲基]-吗啉 该化合物的制备方法与实施例18的步骤D相同,用4-(5-哌啶-3-基甲基)-吗啉和1-丁-3-炔基-哌啶(57%)。
MS(ESl):精确的分子量计算值C18H27N3O,313.45;m/z 测定值,314.5[M+H]+,1H NMR(500MHz,CDCl3):8.49(d,J=1.9,1H),8.40(d,J=1.6,1H),7.66-7.64(m,1H),3.68(t,J=4.5,4H),3.45(s,2H),2.67-2.58(m,4H),2.49-2.38(m,8H),1.62-1.52(m,4H),1.46-1.40(m,2H),
实施例20
2-(4-哌啶-1-基-丁-1-炔基)-6-哌啶-1-基甲基-吡啶
步骤A 6-溴-吡啶-2-碳化醛 在超过20 min的时间里,向-10℃的n-BuLi(2.5M的己烷溶液,5.6mL,14mmol)的无水甲苯(20mL)溶液中加入n-BuMgCl(2M的THF溶液,3.5mL),将温度保持在-10℃~0℃之间。在-10℃下将混合物搅拌30min。在30min的时间里滴加2,6-二溴-吡啶(4.74g,20mmol)的甲苯(20mL)溶液,同时将温度保持在-5℃以下。将生成的悬液在-10℃下搅拌2.5h.通过套管将混合物转到-10℃的DMF(1.9g,26mmol)的甲苯(10mL)溶液中。将此溶液在-5℃~10℃放置30min,然后转到柠檬酸(8.00g)的水(15mL)溶液中,温度保持在20℃以下。将生成的溶液搅拌10min,将不同的层分开。有机层用硫酸钠干燥,过滤,浓缩。将此残渣纯化(SiO2:10%乙酸乙酯/己烷),产生6-溴-吡啶-2-碳化醛(1.94g,52%)。
步骤B 2-溴-6-哌啶-1-基甲基-吡啶 该化合物的制备方法与实施例18的步骤C相同,用6-溴-吡啶-2-碳化醛(0.406g,2.18mmol)和哌啶(0.186g,2.18mmol)。将粗产物纯化(SiO2:MeOH/DCM中的0-4%2 MNH3),生成2-溴-6-哌啶-1-基甲基-吡啶(0.46g,83%)。
步骤C 2-(4-哌啶-1-基-丁-1-炔基)-6-哌啶-1-基甲基-吡啶 该化合物的制备方法与实施例18的步骤D相同,用2-溴-6-哌啶-1-基甲基-吡啶和1-丁-3-炔基哌啶(56%)。
MS(ESI):精确的分子量计算值C20H29N3,311.46:m/z测定值,312.5[M+H]+.1H NMR(500MHz,CDCl3):7.54(1,J=7.7,1H),7.38(d,J=7.7,1H),7.20(d,J=7.4,1H),3.58(s,2H),2.67-2.57(m,4H),2.46-2.34(m,8H),1.60-1.50(m,8H),1.44-1.36(m,4H),
实施例21
4-[6-(4-哌啶-1-基-丁-1-炔基)-吡啶-2-基甲基]-吗啉
步骤A 4-(6-溴-吡啶-2-基甲基)-吗啉 该化合物的制备方法与实施例18的步骤C相同,用6-溴-吡啶-2-碳化醛(0.415g,2.23mmol)和吗啉(0.195g,2.23mmol)。将粗产物纯化(SiO2:MeOH/DCM中的0-3%2 MNH3),生成4-(6-溴-吡啶-2-基甲基)-吗啉(0.352g,61%)。
步骤B 4-[6-(4-哌啶-1-基-丁-1-炔基)-吡啶-2-基甲基]-吗啉 该化合物(19%)的制备方法与实施例18的步骤D相同,用4-(6-溴-吡啶-2-基甲基)-吗啉(0.278g,1.08mmol)和1-丁-3-炔基哌啶(0.297g,2.16mmol).
MS(ESI):精确的分子量计算值C19H27N3O,313.45;m/z测定值,314.4[M+H]+.1H NMR(500MHz,CDCl3):7.52(t,J=7.8,1H),7.32(dd,J=8.0,1.1,1H),7.20(dd,J=7.1,1.1,1H),3.65(t,J=4.6,4H),3.58(s,2H),2.65-2.55(m,4H),2.46-2.37(m,8H),1.57-1.49(m,4H),1.41-1.34(m,2H).
实施例22
(2-甲氧基-乙基)-[6-(4-哌啶-1-基-丁-1-炔基)-吡啶-2-基甲基]-胺
步骤A (6-溴-吡啶-2-基甲基)-(2-甲氧基-乙基)-胺 该化合物的制备方法与实施例18的步骤C相同,用6-溴-吡啶-2-碳化醛(0.275g,1.48mmol)和2-甲氧基-乙胺(0.111g,1.48mmol)。将粗产物纯化(SiO2:MeOH/DCM中的0-5%2 M NH3),生成(6-溴-吡啶-2-基甲基)-(2-甲氧基-乙基)-胺(0.34g,94%)。
步骤B (2-甲氧基-乙基)-[6-(4-哌啶-1-基-丁-1-炔基)-吡啶-2-基甲基]- 胺 该化合物(13%)的制备方法与实施例18的步骤D相同,用(6-溴-吡啶-2-基甲基)-(2-甲氧基-乙基)-胺(0.300g,1.23mmol)和1-丁-3-炔基-哌啶(0.336g,2.45mmol)。
MS(ESI):精确的分子量计算值C18H27N3O,301.44;m/z测定值,302.4[M+H]+.1H NMR(500MHz,CDCl3):7.56(t,7.7,1H),7.26(d,J=7.1,1H),7.23(d,J=7.7,1H),3.90(s,2H),3.52-3.45(m,2H),3.34(s,3H),2.80(t,J=5.2,2H),2.70-2.59(m,4H),2.48-2.40(m,4H),1.67-1.54(m,5H),1.46-1.38(m,2H).
实施例23
(4-异丙基-哌嗪-基)-(5-哌啶-1-基甲基-哌嗪-基)-甲烷酮
步骤A 5-二溴甲基-吡嗪-2-羧酸甲酯 将5-甲基-哌嗪-2-羧酸甲酯(1.60g,10.5mmol;S.J.F.et al. J.Med.Chem.2002,45(18):3878-3890),N-溴丁二酰亚胺(5.62g,31.6mmol)和过氧化二苯酰(0.255g,1.05mmol)溶解在CCl4(80mL)中。将混合物回流加热18h。将反应混合物冷却,用10%水合亚硫酸钠(2×20mL)洗两次,用水(1×30mL)洗一次。用硫酸钠使有机相干燥,过滤,浓缩,生成棕色的油状粗产物(2.41g)。将此粗产物纯化(SiO2:0-20%乙酸乙酯/己烷),生成5-二溴甲基-吡嗪-2-羧酸甲酯(1.00g,31%)。
步骤B 5-甲酰-吡嗪-2-羧酸甲酯 将5-二溴甲基-吡嗪-2-羧酸甲酯(1.00g,3.23mmol)溶解在乙醇(20mL)和THF(10mL)的混合物中,加热到80℃。加入硝酸银(2.20g,12.9mmol)的水(4mL)溶液。将此反应混合物加热到80℃1.25h,趁热过滤。将滤液浓缩产生1.36g 5-甲酰-吡嗪-2-羧酸甲酯。此物不必纯化,直接用到下一步反应。
步骤C 5-哌啶-1-基甲基-吡嗪-2-羧酸甲酯 在室温下将5-甲酰-吡嗪-2-羧酸甲酯(0.400g,2.40mmol),哌啶(0.204g,2.40mmol)和NaB(OAc)3H(1.40g,3.60mmol)的DCM(10mL)混合物搅拌18h.加入10%水合NaOH(10mL)使反应骤冷,再将此混合物搅拌30min.用DCM(3×20mL)将此混合物提取三次。将有机提取物合并,用硫酸钠干燥,过滤,浓缩产生5-哌啶-1-基甲基-吡嗪-2-羧酸甲酯(0.130g,2%)。
步骤D 5-哌啶-1-基甲基-吡嗪-2-羧酸 用1M水合氢氧化锂(0.53mL,0.53mmol)处理5-哌啶-1-基甲基-吡嗪-2-羧酸甲酯(0.125g,0.53mmol)的二烷(3mL)混合物,搅拌18h。将此混合物浓缩,产生5-哌啶-1-基甲基-吡嗪-2-羧酸的锂盐(0.120g)。
步骤E (4-异丙基-哌嗪-1-基)-(5-哌啶-1-基甲基-吡嗪-2-基)-甲烷酮将5-哌啶-1-基甲基-吡嗪-2-羧酸(0.125g,0.53mmol),1-异丙基-哌嗪二盐酸盐(0.117g,0.58mmol),HOBt(0.086g,0.64mmol)和N-甲基吗啉(0.323g,3.19mmol)的DCM(7mL)混合物搅拌1h。然后用EDC(0.122g,0.64mmol)处理此混合物,继续搅拌18h。加入10mL 1N NaOH使反应骤冷,再搅拌30min。用10mL水稀释此混合物,用DCM(3×15mL)提取三次。将有机层合并,用硫酸钠干燥,过滤,浓缩产生粗产物(0.145g)。将此粗产物纯化(SiO2:MeOH/DCM中的0-5%2 M NH3),生成(4-异丙基-哌嗪-基)-(5-哌啶-1-基甲基-哌嗪-基)-甲烷酮(0.05g,26%)。
MS(ESI):精确的分子量计算值C18H29N5O,331.46;m/z测定值,332.5[M+H]+.1HNMR(500MHz,CDCl3):8.85(d,J=1.4,1H),8.64(d,J=1.4,1H),3.82(t,J=4.9,2H),3.68(s,2H),3.63(t,J=4.9,2H),2.77-2.70(m,1H),2.62(t,J=4.9,2H),2.53(t,J=4.9,2H),2.48-2.42(m,4H),1.63-1.57(m,4H),1.49-1.42(m,2H),1.05(d,J=6.6,6H).
实施例24
(4-异丙基-哌嗪-1-基)-(5-吗啉-4-基甲基-吡嗪-2-基)-甲烷酮
步骤A 5-吗啉-4-基甲基-吡嗪-2-羧酸甲酯 该化合物的制备方法与实施例23步骤C所述相同,但用的是5-甲酰-吡嗪-2-羧酸甲酯(0.78g,4.7mmol)和吗啉(0.44g,5.2mmol).
步骤B 5-吗啉-4-基甲基-吡嗪-2-羧酸 用实施例23步骤D所述方法水解5-吗啉-4-基甲基-吡嗪-2-羧酸甲酯,生成5-吗啉-4-基甲基-吡嗪-2-羧酸的粗锂盐(0.224g)。
步骤C (4-异丙基-哌嗪-1-基)-(5-吗啉-4-基甲基-吡嗪-2-基)-甲烷酮
该化合物(0.022g,7%)的制备方法与实施例23步骤E所述相同。
MS(ESI):精确的分子量计算值C17H27N5O,333.44;m/z测定值,334.5[M+H]+.1H NMR(500MHz,CDCl3):8.87(d,J=1.4,1H),8.64(d,J=1.4,1H),3.84-3.79(m,2H),3.76-3.71(m,6H),3.63-3.59(m,2H),2.77-2.71(m,1H),2.64-2.60(m,2H),2.55-2.44(m,6H),1.05(d,J=6.6,6H).
实施例25
4-[3-(3-哌啶-1-基-丙氧基)-异唑-5-基甲基]-哌啶
步骤A 3-(3-哌啶-1-基-丙氧基)-异唑-5-羧酸甲酯 将3-羟基-异唑-5-羧酸甲酯(0.859g,6.00mmol)和3-哌啶-1-基-丙-1-醇(0.860g,6.00mmol)溶解在DCM(30mL)中,加入多聚物支持的Ph3P树脂(3mmol/g,3.1g,9.30mmol)。将混合物搅拌10min,然后加入二-叔丁基偶氮羧酸盐(2.14g,9.30mmol)。将反应混合物通氮搅拌18h。用1N NaOH(20mL)使反应骤冷,然后再搅拌30min。将生成的混合物用DCM(3×30mL)提取三次。将有机提取物合并,用硫酸钠使之干燥,过滤,浓缩,产生一种油状的粗产物(3.1g),将此粗产物提纯(SiO2:MeOH/DCM中的5%2 M NH3),产生3-(3-哌啶-1-基-丙氧基)-异唑-5-羧酸甲酯(0.88g,58%)。
MS(ESI):精确的分子量计算值C13H20N2O4,268.14;m/z测定值,269.4 [M+H]+.1H NMR(500MHz,CDCl3):6.53(s,1H),4.34-4.30(m,2H),3.94(s,3H),2.47-2.34(m,6H),2.02.1.94(m,2H),1.61-1.54(m,4H),1.47-1.39(m,2H).
步骤B [3-(3-哌啶-1-基-丙氧基)-异唑-5-基]-甲醇 在30min的时间里向3-(3-哌啶-1-基-丙氧基)-异唑-5-羧酸甲酯(0.200g,0.750mmol)的EtOH(15mL)溶液中慢慢加入NaBH4(0.358g,11.2mmol)。将反应混合物回流加热过夜,然后冷却到室温,假如1N NaOH(10mL)使反应骤冷。将混合物搅拌1h,然后用DCM(3×30mL)提取三次。将有机提取物合并,用硫酸钠使之干燥,过滤,浓缩,产生所希望的醇(0.177g,99%)。
MS(ESI):精确的分子量计算值C12H20N2O3,240.15;m/z测定值,241.3[M+H]+.
步骤C 1-[3-(5-氯甲基-异唑-3-基氧基)-丙基]-哌啶 将[3-(3-哌啶-1-基-丙氧基)-异唑-5-基]-甲醇(0.150g,0.625mmol)和纯净的亚硫酰氯(4mL)的混合物回流加热3h。使反应混合物冷却到室温,浓缩产生所希望的氯化物,将此氯化物直接用做下一步反应而不必进行进一步的纯化。
步骤D 4-[3-(3-哌啶-1-基-丙氧基)-异唑-5-基甲基]-哌啶 将1-[3-(5-氯甲基-异唑-3-基氧基)-丙基]-哌啶(0.15g,0.80mmol)溶解在5mLDCM中,缓慢加入哌啶(0.24mL,2.4mmol)。将反应混合物在室温下搅拌过夜,然后浓缩,产生粗产物(0.140g)。将此粗产物纯化(SiO2:MeOH/DCM中的0-5%2 M NH3)生成最终产物(0.118g,47.6%)。
MS(ESI):精确的分子量计算值C17H29N3O2,307.23;m/z测定值,308.4[M+H]+,1H NMR(500MHz,CDCl3):5.75(s,1H),4.25-4.20(m,2H),3.53(s,2H),2.47-2.31(m,10H),1.98-1.90(m,2H),1.61-1.52(m,8H),1.45-1.35(m,4H).
实施例26
4-[3-(3-哌啶-1-基-丙氧基)-异唑-5-基甲基]-吗啉
该化合物的制备方法与实施例25的步骤D所述相同。
MS(ESI):精确的分子量计算值C16H27N3O3,309,21;m/z测定值,310.5[M+H]+,1H NMR(500MHz,CDCl3):5.80(s,1H),4.27-4.21(m,2H),3.70(t,J=4.7,4H),3.54(s,2H),2.53-2.32(m,10H),2.00-1.92(m,2H),1.61-1.54(m,4H),1.46-1.38(m,2H).
实施例27
(2-甲氧基-乙基)-[3-(3-哌啶-1-基-丙氧基)-异唑-5-基甲基]-胺
该化合物的制备方法与实施例25的步骤D所述相同。
MS(ESI):精确的分子量计算值C16H27N3O3,297.21;m/z测定值,298.5[M+H]+.1H NMR(500MHz,CDCl3):5.78(s,1H),4.26-4.22(m,2H),3.81(br s,2H),3.50-3.46(m,2H),3.35 (s,3H),2.82-2.79(m,2H),2.45-2.40(m,2H),2.40-2.33(m,3H),1.99-1.92(m,2H),1.87-1.76(m,2H),1.60-1.54(m,4H),1.46-1.39(m,2H).
实施例28
(4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲硫酮
将(4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲烷酮(实施例1,80mg,0.24mmol)和Lawesson氏剂(210mg,0.50mmol)的THF溶液回流加热48h。使反应物冷却到室温,真空除去溶剂。将残渣做色谱分析(SiO2:MeOH/DCM中的1-6%2 M NH3),产生油状的(4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲硫酮。
MS(ESI):精确的分子量计算值C19H30N4S,346.22;m/z测定值,347.5[M中H]+,
生物学实施例
A.人组胺受体的细胞传导
使细胞生长成大约70%~80%融合状,用胰蛋白酶将细胞从平板上移出,用临床用离心机使之成小团状。然后再将这个小团悬于400μL完全培养基内,移至一个电通道管中(Bio-Rad#165-2088),使与两个电极之间留有0.4cm的空隙。在此细胞团中轻轻加入1μg高度盘绕的H3受体cDNA。电通道电压设定为0.25kV,电容设定为960μF。电通道作用后用10mL完全培养基将细胞稀释,按以下比例接种在4个10cm的培养皿中:1∶20,1∶10,1∶5和1∶2。使细胞恢复生长24h,然后加入600μgG-418。让挑选出的细胞株生长并用做试验。用SK-N-MC细胞,因为它们能高效结合来抑制腺苷酸环化酶。在与组胺的反应中对腺苷酸环化酶表现出最强有力抑制作用的细胞株被用来做进一步的研究。
B.[3H]-N-甲基组胺的结合
用50 mM TrisHCl/0.5mM EDTA将表达组胺H3受体的SK-N-MC细胞的细胞团匀浆。800g离心,收集上清,将上清以30000g离心30min。再用50mM Tris/5mM EDTA(pH 7.4)将细胞团匀浆。将细胞膜用0.8nM [3H]-N-甲基组胺加/减试验化合物在25℃下培养60min,用GF/C玻璃纤维滤器快速过滤收获培养物(用0.3%聚氮杂环丙烷做预处理),用缓冲液洗涤4次。将滤物加到5mL闪烁液,然后用一个液体闪烁计数器计数信号。用10μM组胺来确定非特异性的结合。根据公式Ki=(IC50)/(1+([L]/(KD)),用0.8nM KD和0.8nM的配位体浓度([L])来计算pKi值。数据如表1所示。
表1 生物学数据
EX | K1(nM) | EX | K1(nM) | |
1 | 1 | 16 | 6 | |
2 | 18 | 17 | 141 | |
3 | 2 | 18 | 2 | |
4 | 0.8 | 19 | 15 | |
5 | 13 | 20 | 8 | |
8 | 5 | 21 | 38 | |
9 | 2 | 22 | 29 | |
10 | 14 | 23 | 2 | |
11 | 84 | 24 | 39 | |
12 | 3 | 25 | 7 | |
13 | 4 | 26 | 89 | |
14 | 79 | 27 | 169 | |
15 | 3 | 28 | 7 |
Claims (51)
1.式(I)所示的具有组胺H3受体调节活性的化合物以及其对映体、非对映体、水合物、溶剂化物和它们在药学上可采用的盐、酯和酰胺:
其中
在含A-和B-的环中,
1)A,B1和B2为CH;
2)A为CH,B1和B2中一个为N,另一个为CH;或者
3)没有A,B1为CH,B2为O;
L为C1-4亚烷基或是一个共价键;
Q为-(CH2)mO-,-(CH2)nC≡C-(此处的-O-和-C≡C-部分直接联在环上),羰基或硫羰基;
m为2,3或4;
n为1,2,3或4;
R1可任意地被一个或两个RP取代,独立地为下列基团:-H,-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环有0,1或2个双键,带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分;
R2可任意地被一个或两个RP取代,独立地为下列基团:-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环有0,1或2个双键,带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分;
或者,
R1和R2与所连接的N原子共同构成一个环,这个环可以是下列基团:
i)一个4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0,1或2个双键,有1或2个碳原子是具有0,1或2个Rq取代基的羰基碳;
ii)苯并或吡啶并稠合的4-7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0或1个另外的双键,有1或2个碳原子是具有0,1或2个Rq取代基的羰基碳;
RP独立地为下列基团:-C1-6烷基,-C2-6链烯基,-C3-6环烷基,苯基,吡啶基,呋喃基,噻吩基,苄基,嘧啶基,吡咯基,卤素,-OH,-OC1-6烷基,-OC3-6环烷基,-O苯基,-O苄基,-SH,-SC1-6烷基,-SC3-6环烷基,-S苯基,-S苄基,-CN,-NO2,-N(RY)RZ(此处的RY和RZ可以独立地为H和-C1-4烷基;或者RY和RZ可与所连接的N共同构成一个含5-,6-或7元的单环状杂环,这个杂环上有另外的1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分,这个环可被-C1-4烷基,-OH,-OC1-4烷基,卤素或者-COOC1-4烷基任意取代),-(C=O)N(RY)RZ,-(C=O)C1-4烷基,-SCF3,-OCF3,-CF3和-COOC1-4烷基,以及-COOH;
Rq独立地为下列基团:-C1-6烷基,卤素,-OH,-OC1-6烷基,-CN,-NO2,-CF3和-COOC1-4烷基;
R3 可任意地被一个或两个RS取代,独立地为下列基团:-H,-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子,0,1或2个双键;
R4可任意地被一个或两个RS取代,独立地为下列基团:-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子,0,1或2个双键;
RS可独立地为下列基团:-C1-6烷基,-C2-6链烯基,-C3-6环烷基,苯基,吡啶基,呋喃基,噻吩基,苄基,嘧啶基,吡咯基,卤素,-OH,-OC1-6烷基,-OC3-6环烷基,苯氧基,苄氧基,-SH,-SC1-6烷基,-SC3-6环烷基,苯硫基,苄硫基,-CN,-NO2,-N(RY)RZ(此处的RY和RZ可以独立地为H和-C1-4烷基;或者RY和RZ可与所连接的N共同构成一个含5-,6-或7元的单环状杂环,这个杂环上有另外的1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分,这个环可被-C1-4烷基,-OH,-OC1-4烷基,卤素或者-COOC1-4烷基任意取代),-(C=O)N(RY)RZ,-(C=O)C1-4烷基,-SCF3,-OCF3,-CF3和-COOC1-4烷基,以及-COOH;
或者
R3和R4与所连接的N原子共同构成一个环,这个环可以是下列基团:
i)一个4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0,1或2个双键,有0,1或2个碳原子是具有0,1或2个R1取代基的羰基碳;
ii)苯并或吡啶并稠合的4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0或1个另外的双键,有0,1或2个碳原子是具有0,1或2个R1取代基的羰基碳;
R1独立地为下列基团:-C1-6烷基,卤素,-OH,-OC1-6基,-CH,-NO2,-CF3和-COOC1-4烷基。
2.权利要求1的化合物,其中含A-和B-的环选自吡啶,吡嗪和异唑。
3.权利要求1的化合物,其中A,B1和B2为CH;B1为N,B2和A为CH;或者没有A,B1为CH,B2为O。
4.权利要求1的化合物,其中含A-和B-的环为吡啶。
5.权利要求1的化合物,其中含A-和B-的环为一个3,6-位双取代的吡啶。
6.权利要求1的化合物,其中含A-和B-的环为一个2,5-位双取代的吡啶。
7.权利要求1的化合物,其中含A-和B-的环为一个2,5-位双取代的吡嗪。
8.权利要求1的化合物,其中含A-和B-的环为一个3,5-位双取代的异唑。
9.权利要求1的化合物,其中的A为CH。
10.权利要求1的化合物,其中的A不存在。
11.权利要求1的化合物,其中的B1为CH。
12.权利要求1的化合物,其中的B1为N。
13.权利要求1的化合物,其中的B2为CH。
14.权利要求1的化合物,其中的B2为O。
15.权利要求1的化合物,其中的B1为亚甲基。
16.权利要求1的化合物,其中的Q为丙烯氧基,乙烯氧基,亚丙炔-1-基,亚丁炔-1-基,羰基和硫羰基。
17.权利要求1的化合物,其中的Q为丙烯氧基,亚丁炔-1-基,或羰基。
18.权利要求1的化合物,其中的Q为羰基。
19.权利要求1的化合物,其中的R1独立地为-H,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,羟基乙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,二乙基氨基乙基,丙烯基,炔丙基,环丙基,环戊基,环己基,苯基,苄基,pyridinyl,吡咯基,吡咯烷基,哌啶基,吗啉基,硫代吗啉基,和azepanyl。
20.权利要求1的化合物,其中的R1独立地为-H,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,环丙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,和二乙基氨基乙基。
21.权利要求1的化合物,其中的R1独立地为-H,甲基,和甲氧基乙基。
22.权利要求1的化合物,其中的R2独立地为甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,羟基乙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,二乙基氨基乙基,丙烯基,炔丙基,环丙基,环戊基,环己基,苯基,苄基,吡啶基,吡咯基,吡咯烷基,哌啶基,吗啉基,硫代吗啉基,和azepanyl。
23.权利要求1的化合物,其中的R2独立地为甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,环丙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,和二乙基氨基乙基。
24.权利要求1的化合物,其中的R2独立地为甲基和甲氧基乙基。
25.权利要求1的化合物,其中的R1和R2与它们所连接的N原子共同构成一个环,这个环可以是哌啶,吗啉,硫代吗啉,哌嗪,和吡咯烷。
26.权利要求1的化合物,其中的R1和R2与它们所连接的N原子共同构成一个环,这个环可以是哌啶,吗啉,和哌嗪。
27.权利要求1的化合物,其中的R1和R2与它们所连接的N原子共同构成4-氟哌啶。
28.权利要求1的化合物,其中的R1和R2与它们所连接的N原子共同构成一个环,这个环可以是哌啶和吗啉。
29.权利要求1的化合物,其中的R3独立地为-H,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,羟基乙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,二乙基氨基乙基,丙烯基,炔丙基,环丙基,环戊基,环己基,苯基,苄基,吡啶基,吡咯基,吡咯烷基,哌啶基,吗啉基,硫代吗啉基,和azepanyl。
30.权利要求1的化合物,其中的R3独立地为-H,甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,环丙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,和二乙基氨基乙基。
31.权利要求1的化合物,其中的R3独立地为-H,甲基,和甲氧基乙基。
32.权利要求1的化合物,其中的R4独立地为甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,羟基乙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,二乙基氨基乙基,丙烯基,炔丙基,环丙基,环戊基,环己基,苯基,苄基,吡啶基,吡咯基,吡咯烷基,哌啶基,吗啉基,硫代吗啉基,和azepanyl。
33.权利要求1的化合物,其中的R4独立地为甲基,乙基,丙基,异丙基,丁基,异丁基,甲氧基乙基,环丙基,哌啶基乙基,吗啉基乙基,吡啶基乙基,和二乙基氨基乙基。
34.权利要求1的化合物,其中的R4独立地为甲基和甲氧基乙基。
35.权利要求1的化合物,其中的R3和R4与它们所连接的N原子共同构成一个环,这个环可以是是哌啶,吗啉,硫代吗啉,哌嗪,和吡咯烷。
36.权利要求1的化合物,其中的R3和R4与它们所连接的N原子共同构成一个环,这个环可以是是哌啶,吗啉,和哌嗪。
37.权利要求1的化合物,其中的R3和R4与它们所连接的N原子共同构成4-氟哌啶。
38.权利要求1的化合物,其中的R3和R4与它们所连接的N原子共同构成一个环,这个环可以是是哌啶和哌嗪。
39.一种选自下列的化合物:
(4-异丙基-哌嗪-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲烷酮;
(4-异丙基-哌嗪-基)-(6-吗啉-4-基甲基-吡啶-3-基)-甲烷酮;
(4-异丙基-哌嗪-基)-(5-哌啶-1-基甲基-吡啶-2-基)-甲烷酮;
2-哌啶-1-基甲基-5-(3-哌啶-1-基-丙氧基)-吡啶;
4-[5-(3-哌啶-1-基-丙氧基)-吡啶-2-基甲基]-吗啉;
5-哌啶-1-基甲基-2-(3-哌啶-1-基-丙氧基)-吡啶;
4-[6-(3-哌啶-1-基-丙氧基)-吡啶-3-基甲基]-吗啉;
2-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶;
(4-异丙基-哌嗪-1-基)-[6-(2-哌啶-1-基-乙基氨基)-吡啶-3-基]-甲烷酮;
(4-异丙基-哌嗪-1-基)-[6-(2-吗啉-4-基-乙基氨基)-吡啶-3-基]-甲烷酮;
(4-异丙基-哌嗪-1-基)-[6-(2-吡啶-2-基-乙基氨基)-吡啶-3-基]-甲烷酮;
{6-[(2-二乙基氨基-乙基)-甲基-氨基]-吡啶-3-基}-(4-异丙基-哌嗪-1-基)-甲烷酮;
(4-异丙基-哌嗪-1-基)-[6-(4-异丙基-哌嗪-1-基)-吡啶-3-基]-甲烷酮;
4-[5-(4-异丙基-哌嗪-1-羰基)-吡啶-2-基]-哌嗪-1-羧酸乙酯;
(4-异丙基-哌嗪-1-基)-[6-(4-甲基-哌嗪-1-基)-吡啶-3-基]-甲烷酮;
(4-异丙基-哌嗪-1-基)-[2-(2-哌啶-1-基-乙基氨基)-吡啶-4-基]-甲烷酮;
(4-异丙基-哌嗪-1-基)-[2-(2-哌啶-1-基-乙基氨基)-吡啶-3-基]-甲烷酮;
3-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶;
4-[5-(4-哌啶-1-基-丁-1-炔基)-吡啶-3-基甲基]-吗啉;
2-(4-哌啶-1-基-丁-1-炔基)-6-哌啶-1-基甲基-吡啶;
4-[6-(4-哌啶-1-基-丁-1-炔基)-吡啶-2-基甲基]-吗啉;
(2-甲氧基-乙基)-[6-(4-哌啶-1-基-丁-1-炔基)-吡啶-2-基甲基]-胺;
(4-异丙基-哌嗪-1-基)-(5-哌啶-1-基甲基-哌嗪-2-基)甲烷酮;
(4-异丙基-哌嗪-1-基)-(5-吗啉-4-基甲基-哌嗪-2-基)甲烷酮;
4-[3-(3-哌啶-1-基-丙氧基)-异唑-5-基甲基]-哌啶;
4-[3-(3-哌啶-1-基-丙氧基)-异唑-5-基甲基]-吗啉;
(2-甲氧基-乙基)-[3-(3-哌啶-1-基-丙氧基)-异唑-5-基甲基]-胺;和
(4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲硫酮。
40.下列中的一种化合物:
(4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲烷酮;
(4-异丙基-哌嗪-1-基)-(6-吗啉-4-基甲基-吡啶-3-基)-甲烷酮;
(4-异丙基-哌嗪-1-基)-(5-哌啶-1-基甲基-吡啶-2-基)-甲烷酮;
2-哌啶-1-基甲基-5-(3-哌啶-1-基-丙氧基)-吡啶;
4-[5-(3-哌啶-1-基-丙氧基)-吡啶-2-基甲基]-吗啉;
2-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶;
(4-异丙基-哌嗪-1-基)-[6-(2-哌啶-1-基-乙基氨基)-吡啶-3-基]-甲烷酮;
(4-异丙基-哌嗪-1-基)-[6-(2-吗啉-4-基-乙基氨基)-吡啶-3-基]-甲烷酮;
{6-[(2-二乙基氨基-乙基)-甲基-氨基]-吡啶-3-基}-(4-异丙基-哌嗪-1-基)-甲烷酮;
(4-异丙基-哌嗪-1-基)-[6-(4-异丙基-哌嗪-1-基)-吡啶-3-基]-甲烷酮;
(4-异丙基-哌嗪-1-基)-[6-(4-甲基-哌嗪-1-基)-吡啶-3-基]-甲烷酮;
(4-异丙基-哌嗪-1-基)-[2-(2-哌啶-1-基-乙基氨基)-吡啶-4-基]-甲烷酮;
3-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶;
4-[5-(4-哌啶-1-基-丁-1-炔基)-吡啶-3-基甲基]-吗啉;
2-(4-哌啶-1-基-丁-1-炔基)-6-哌啶-1-基甲基-吡啶;
4-[6-(4-哌啶-1-基-丁-1-炔基)-吡啶-2-基甲基]-吗啉;
(2-甲氧基-乙基)-[6-(4-哌啶-1-基-丁-1-炔基)-吡啶-2-基甲基]-胺;
(4-异丙基-哌嗪-1-基)-(5-哌啶-1-基甲基-吡嗪-2-基)-甲烷酮;
(4-异丙基-哌嗪-1-基)-(5-吗啉-4-基甲基-吡嗪-2-基)-甲烷酮;
4-[3-(3-哌啶-1-基-丙氧基)-异唑-5-基甲基]-哌啶;和
(4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲硫酮。
41.一种选自下列的化合物:
(4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲烷酮;
(4-异丙基-哌嗪-1-基)-(5-哌啶-1-基甲基-吡啶-2-基)-甲烷酮;
2-哌啶-1-基甲基-5-(3-哌啶-1-基-丙氧基)-吡啶;
2-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶;
(4-异丙基-哌嗪-1-基)-[6-(2-哌啶-1-基-乙基氨基)-吡啶-3-基]-甲烷酮;
{6-[(2-二乙基氨基-乙基)-甲基-氨基]-吡啶-3-基}-(4-异丙基-哌嗪-1-基)-甲烷酮;
(4-异丙基-哌嗪-1-基)-[6-(4-异丙基-哌嗪-1-基)-吡啶-3-基]-甲烷酮;
(4-异丙基-哌嗪-1-基)-[6-(4-甲基-哌嗪-1-基)-吡啶-3-基]-甲烷酮;
(4-异丙基-哌嗪-1-基)-[2-(2-哌啶-1-基-乙基氨基)-吡啶-4-基]-甲烷酮;
3-(4-哌啶-1-基-丁-1-炔基)-5-哌啶-1-基甲基-吡啶;
2-(4-哌啶-1-基-丁-1-炔基)-6-哌啶-1-基甲基-吡啶;
(4-异丙基-哌嗪-1-基)-(5-哌啶-1-基甲基-吡嗪-2-基)-甲烷酮;
4-[3-(3-哌啶-1-基-丙氧基)-异唑-5-基甲基]-哌啶;和
(4-异丙基-哌嗪-1-基)-(6-哌啶-1-基甲基-吡啶-3-基)-甲硫酮。
42.权利要求1中的化合物,其中所说的药学上可用的盐为有效的氨基加成盐。
43.权利要求1中的化合物,其中所说的药学上可用的盐为氢溴酸盐,盐酸盐,硫酸盐,二硫酸盐,硝酸盐,乙酸盐,草酸盐,戊酸盐,油酸盐,棕榈酸盐,硬脂酸盐,月桂酸盐,硼酸盐,苯甲酸盐,乳酸盐,磷酸盐,甲苯磺酸盐,柠檬酸盐,马来酸盐,富马酸盐,琥珀酸盐,酒石酸盐,萘酸盐,甲磺酸盐,葡庚糖酸盐,乳糖酸盐,和十二烷基磺酸盐。
44.一种药物组合物,含有药学上可用的载体和有效治疗量的具有组胺H3受体调节活性的式(I)化合物:
其中
在含有A-和B-的环中,
1)A,B1和B2为CH;
2)A为CH,B1和B2中一个为N,另一个为CH;或者
3)没有A,B1为CH,B2为O;
L为C1-4亚烷基或是一个共价键;
Q为-(CH2)mO-,-(CH2)nC≡C-(此处的-O-和-C≡C-部分直接连在环上),羰基或硫羰基;
m为2,3或4;
n为1,2,3或4;
R1可任意地被一个或两个RP取代,独立地为下列基团:-H,-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环有0,1或2个双键,带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分;
R2可任意地被一个或两个RP取代,独立地为下列基团:-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环有0,1或2个双键,带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分;或者,
R1和R2与所连接的N原子共同构成一个环,这个环可以是下列基团:
i)一个4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0,1或2个双键,有1或2个碳原子是具有0,1或2个Rq取代基的羰基碳;
ii)苯并或吡啶并稠合的4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0或1个另外的双键,有1或2个碳原子是具有0,1或2个Rq取代基的羰基碳;
RP独立地为下列基团:-C1-6烷基,-C2-6链烯基,-C3-6环烷基,苯基,吡啶基,呋喃基,噻吩基,苄基,嘧啶基,吡咯基,卤素,-OH,-OC1-6烷基,-OC3-6环烷基,-O苯基,-O苄基,-SH,-SC1-6烷基,-SC3-6环烷基,-S苯基,-S苄基,-CN,-NO2,-N(RY)RZ(此处的RY和RZ可以独立地为H和-C1-4烷基;或者RY和RZ可与所连接的N共同构成一个含5-,6-或7元的单环状杂环,这个杂环上有另外的1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分,这个环可被-C1-4烷基,-OH,-OC1-4烷基,卤素或者-COOC1-4烷基任意取代),-(C=O)N(RY)RZ,-(C=O)C1-4烷基,-SCF3,-OCF3,-CF3和-COOC1-4烷基,以及-COOH;
Rq独立地为下列基团:-C1-6烷基,卤素,-OH,-OC1-6烷基,-CN,-NO2,-CF3和-COOC1-4烷基;
R3可任意地被一个或两个RS取代,独立地为下列基团:-H,-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子,0,1或2个双键;
R4可任意地被一个或两个RS取代,独立地为下列基团:-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子,0,1或2个双键;
RS可独立地为下列基团:-C1-6烷基,-C2-6链烯基,-C3-6环烷基,苯基,吡啶基,呋喃基,噻吩基,苄基,嘧啶基,吡咯基,卤素,-OH,-OC1-6烷基,-OC3-6环烷基,苯氧基,苄氧基,-SH,-SC1-6烷基,-SC3-6环烷基,苯硫基,苄硫基,-CN,-NO2,-N(RY)RZ(此处的RY和RZ可以独立地为H和-C1-4烷基;或者RY和RZ可与所连接的N共同构成一个含5-,6-或7元的单环状杂环,这个杂环上有另外的1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分,这个环可被-C1-4烷基,-OH,-OC1-4烷基,卤素或者-COOC1-4烷基任意取代),-(C=O)N(RY)RZ,-(C=O)C1-4烷基,-SCF3,-OCF3,-CF3和-COOC1-4烷基,以及-COOH;
或者
R3和R4与所连接的N原子共同构成一个环,这个环可以是下列基团:
i)一个4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0,1或2个双键,有0,1或2个碳原子是具有0,1或2个R1取代基的羰基碳;
ii)苯并或吡啶并稠合的4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0或1个另外的双键,有0,1或2个碳原子是具有0,1或2个R1取代基的羰基碳;
R1独立地为下列基团:-C1-6烷基,卤素,-OH,-OC1-6烷基,-CH,-NO2,-CF3和-COOC1-4烷基;
及其对映体、非对映体、水合物、溶剂化物和它们在药学上可用的酯和酰胺。
45.一种治疗或预防神经系统病症的方法,这些病症包括:神经性病症,如入睡/即醒和醒后难再入睡症状(例如失眠症和喷射迟滞),不能专注多动症(ADHD),学习与记忆障碍,认知功能障碍,偏头痛,神经原性炎症,痴呆,轻度的认知功能减弱(痴呆前兆),阿尔茨海默氏病,癫痫,并发或不并发猝倒的嗜眠症,猝倒,入睡/即醒后自身稳定性障碍,自发的嗜眠症,白昼嗜睡症(EDS),昼夜节律紊乱,睡眠/疲劳症,疲劳,伴有睡眠时呼吸暂停的瞌睡,围绝经期激素分泌改变导致的睡眠减少,与帕金森氏症相关的疲劳,与多发性硬化症(MS)相关的疲劳,与抑郁症相关的疲劳,化疗导致的疲劳,进食障碍,肥胖症,运动障碍,眩晕,精神分裂症,物质滥用,双极细胞疾病,燥狂性病症和哺乳类的抑郁症,这种方法包括这样的步骤,即给患有上述病症的哺乳动物投以有效治疗量的具有组胺H3受体调谐活性的式(I)化合物:
其中
在含有A-和B-的环中,
1)A,B1和B2为CH;
2)A为CH,B1和B2中一个为N,另一个为CH;或者
3)没有A,B1为CH,B2为O;
L为C1-4亚烷基或是一个共价键;
Q为-(CH2)mO-,-(CH2)nC≡C-(此处的-O-和-C≡C-部分直接连在环上),羰基或硫羰基;
m为2,3或4;
n为1,2,3或4;
R1可任意地被一个或两个RP取代,独立地为下列基团:-H,-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环有0,1或2个双键,带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分;
R2可任意地被一个或两个RP取代,独立地为下列基团:-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环有0,1或2个双键,带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分;
或者,
R1和R2与所连接的N原子共同构成一个环,这个环可以是下列基团:
i)一个4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0,1或2个双键,有1或2个碳原子是具有0,1或2个Rq取代基的羰基碳;
ii)苯并或吡啶并稠合的4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0或1个另外的双键,有1或2个碳原子是具有0,1或2个Rq取代基的羰基碳;
RP独立地为下列基团:-C1-6烷基,-C2-6链烯基,-C3-6环烷基,苯基,吡啶基,呋喃基,噻吩基,苄基,嘧啶基,吡咯基,卤素,-OH,-OC1-6烷基,-OC3-6环烷基,-O苯基,-O苄基,-SH,-SC1-6烷基,-SC3-6环烷基,-S苯基,-S苄基,-CN,-NO2,-N(RY)RZ(此处的RY和RZ可以独立地为H和-C1-4烷基;或者RY和RZ可与所连接的N共同构成一个含5-,6-或7元的单环状杂环,这个杂环上有另外的1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分,这个环可被-C1-4烷基,-OH,-OC1-4烷基,卤素或者-COOC1-4烷基任意取代),-(C=O)N(RY)RZ,-(C=O)C1-4烷基,-SCF3,-OCF3,-CF3和-COOC1-4烷基,以及-COOH;
Rq独立地为下列基团:-C1-6烷基,卤素,-OH,-OC1-6烷基,-CN,-NO2,-CF3和-COOC1-4烷基;
R3可任意地被一个或两个RS取代,独立地为下列基团:-H,-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子,0,1或2个双键;
R4可任意地被一个或两个RS取代,独立地为下列基团:-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子,0,1或2个双键;
RS可独立地为下列基团:-C1-6烷基,-C2-6链烯基,-C3-6环烷基,苯基,吡啶基,呋喃基,噻吩基,苄基,嘧啶基,吡咯基,卤素,-OH,-OC1-6烷基,-OC3-6环烷基,苯氧基,苄氧基,-SH,-SC1-6烷基,-SC3-6环烷基,苯硫基,苄硫基,-CN,-NO2,-N(RY)RZ(此处的RY和RZ可以独立地为H和-C1-4烷基;或者RY和RZ可与所连接的N共同构成一个含5-,6-或7元的单环状杂环,这个杂环上有另外的1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分,这个环可被-C1-4烷基,-OH,-OC1-4烷基,卤素或者-COOC1-4烷基任意取代),-(C=O)N(RY)RZ,-(C=O)C1-4烷基,-SCF3,-OCF3,-CF3和-COOC1-4烷基,以及-COOH;
或者
R3和R4与所连接的N原子共同构成一个环,这个环可以是下列基团:
i)一个4-7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0,1或2个双键,有0,1或2个碳原子是具有0,1或2个R1取代基的羰基碳;
ii)苯并或吡啶并稠合的4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0或1个另外的双键,有0,1或2个碳原子是具有0,1或2个R1取代基的羰基碳;
R1独立地为下列基团:-C1-6烷基,卤素,-OH,-OC1-6烷基,-CN,-NO2,-CF3和-COOC1-4烷基;
以及对映体,非对映体,水合物,溶剂化物和它们在药学上可采用的盐,酯和酰胺。
46.一种治疗或预防因组胺H3受体导致的病症的方法,这些病症包括哺乳类的上呼吸道变态反应性病症,气喘,瘙痒,鼻充血和过敏性鼻炎,这种方法是给患有上述病症的哺乳类投以有效治疗量的具有组胺H3受体调谐活性的式(I)所示的化合物:
其中
在含有A-和B-的环中,
1)A,B1和B2为CH;
2)A为CH,B1和B2中一个为N,另一个为CH;或者
3)没有A,B1为CH,B2为O;
L为C1-4亚烷基或是一个共价键;
Q为-(CH2)mO-,-(CH2)nC≡C-(此处的-O-和-C≡C-部分直接连在环上),羰基或硫羰基;
m为2,3或4;
n为1,2,3或4;
R1可任意地被一个或两个RP取代,独立地为下列基团:-H,-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环有0,1或2个双键,带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分;
R2可任意地被一个或两个RP取代,独立地为下列基团:-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环有0,1或2个双键,带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分;
或者,
R1和R2与所连接的N原子共同构成一个环,这个环可以是下列基团:
i)一个4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0,1或2个双键,有1或2个碳原子是具有0,1或2个Rq取代基的羰基碳;
ii)苯并或吡啶并稠合的4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0或1个另外的双键,有1或2个碳原子是具有0,1或2个Rq取代基的羰基碳;
RP独立地为下列基团:-C1-6烷基,-C2-6链烯基,-C3-6环烷基,苯基,吡啶基,呋喃基,噻吩基,苄基,嘧啶基,吡咯基,卤素,-OH,-OC1-6烷基,-OC3-6环烷基,-O苯基,-O苄基,-SH,-SC1-6烷基,-SC3-6环烷基,-S苯基,-S苄基,-CN,-NO2,-N(RY)RZ(此处的RY和RZ可以独立地为H和-C1-4烷基;或者RY和RZ可与所连接的N共同构成一个含5-,6-或7元的单环状杂环,这个杂环上有另外的1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分,这个环可被-C1-4烷基,-OH,-OC1-4烷基,卤素或者-COOC1-4烷基任意取代),-(C=O)N(RY)RZ,-(C=O)C1-4烷基,-SCF3,-OCF3,-CF3和-COOC1-4烷基,以及-COOH;
Rq独立地为下列基团:-C1-6烷基,卤素,-OH,-OC1-6烷基,-CN,-NO2,-CF3和-COOC1-4烷基;
R3可任意地被一个或两个RS取代,独立地为下列基团:-H,-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子,0,1或2个双键;
R4可任意地被一个或两个RS取代,独立地为下列基团:-C1-7烷基,-C2-7链烯基,-C2-7炔基,-C3-7环烷基,苯基,苄基,吡啶基,嘧啶基,呋喃基,噻吩基,吡咯基,以及一个5元、6元或7元的单环状的非芳族杂环,这个杂环带有1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子,0,1或2个双键;
RS可独立地为下列基团:-C1-6烷基,-C2-6链烯基,-C3-6环烷基,苯基,吡啶基,呋喃基,噻吩基,苄基,嘧啶基,吡咯基,卤素,-OH,-OC1-6烷基,-OC3-6环烷基,苯氧基,苄氧基,-SH,-SC1-6烷基,-SC3-6环烷基,苯硫基,苄硫基,-CN,-NO2,-N(RY)RZ(此处的RY和RZ可以独立地为H和-C1-4烷基;或者RY和RZ可与所连接的N共同构成一个含5-,6-或7元的单环状杂环,这个杂环上有另外的1或2个诸如O,S,-N=,>NH和>NC1-4烷基这样的杂原子成分,这个环可被-C1-4烷基,-OH,-OC1-4烷基,卤素或者-COOC1-4烷基任意取代),-(C=O)N(RY)RZ,-(C=O)C1-4烷基,-SCF3,-OCF3,-CF3
和-COOC1-4烷基,以及-COOH;
或者
R3和R4与所连接的N原子共同构成一个环,这个环可以是下列基团:
i)一个4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0,1或2个双键,有0,1或2个碳原子是具有0,1或2个R1取代基的羰基碳;
ii)苯并或吡啶并稠合的4~7元的非芳族杂环,这个杂环中有0或1个用至少1个碳原子与所连接的N原子隔开的杂原子,这个杂原子可以是O,S,-N=,>NH和>NC1-4烷基,这个杂环可以有0或1个另外的双键,有0,1或2个碳原子是具有0,1或2个R1取代基的羰基碳;
R1独立地为下列基团:-C1-6烷基,卤素,-OH,-OC1-6烷基,-CN,-NO2,-CF3和-COOC1-4烷基;
以及对映体,非对映体,水合物,溶剂化物和它们在药学上可采用的盐,酯和酰胺。
47.一种可用正电子发射断层扫描术(PET)和单光子发射断层扫描术(SPECT)检测的用同位素标记的权利要求1的化合物。
48.一种研究因组胺导致的病症的方法,包括这样一个步骤,即用18F标记的或用11C标记的权利要求1的化合物做为正电子发射断层扫描术(PET)的分子探针。
49.一种治疗过敏性鼻炎,鼻充血,或变态反应性充血的方法,包括(a)给患者投以联合有效量的权利要求1的化合物,和(b)给患者投以联合有效量的一种组胺H1拮抗剂。
50.一种治疗抑郁,情绪低下或精神分裂症的方法,包括(a)给患者投以联合有效量的权利要求1的化合物,和(b)给患者投以联合有效量的一种选择的血清素再吸收抑制剂。
51.一种治疗嗜眠症,白昼嗜眠症(EDS),阿尔茨海默氏病,抑郁,注意力涣散,与多发性硬化症(MS)相关的疲劳,麻醉后头晕,认知功能减弱,精神分裂症,脑瘫痪导致的痉挛,与年龄相关的记忆力减退,自发的瞌睡,或喷射迟滞的方法,包括(a)给患者投以联合有效量的权利要求1的化合物,和(b)给患者投以联合有效量的一种调节剂(modafinil)。
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US20040110802A1 (en) * | 2002-08-23 | 2004-06-10 | Atli Thorarensen | Antibacterial benzoic acid derivatives |
GB0224084D0 (en) * | 2002-10-16 | 2002-11-27 | Glaxo Group Ltd | Novel compounds |
AU2003274053A1 (en) * | 2002-10-22 | 2004-05-13 | Glaxo Group Limited | Aryloxyalkylamine derivates as h3 receptor ligands |
CN100558718C (zh) * | 2002-10-23 | 2009-11-11 | 詹森药业有限公司 | 哌嗪基和二氮杂环庚基苯甲酰胺和硫代苯甲酰胺 |
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AU2004259263B2 (en) | 2003-07-29 | 2010-12-16 | High Point Pharmaceuticals, Llc | Pyridazinyl- piperazines and their use as histamine H3 receptor ligands |
WO2005023247A1 (en) * | 2003-09-03 | 2005-03-17 | Smithkline Beecham Corporation | Compounds and methods |
GB0324159D0 (en) | 2003-10-15 | 2003-11-19 | Glaxo Group Ltd | Novel compounds |
MXPA06011414A (es) * | 2004-03-31 | 2007-04-20 | Johnson & Johnson | Compuestos heterociclicos sin imidazol como ligandos del receptor de h3 histamina. |
JP4637595B2 (ja) | 2005-01-21 | 2011-02-23 | 日立オートモティブシステムズ株式会社 | マスタシリンダ |
JP4420347B2 (ja) | 2005-03-03 | 2010-02-24 | ヤンマー株式会社 | 走行型芝刈機 |
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CN101426777A (zh) * | 2005-12-21 | 2009-05-06 | 先灵公司 | 用作组胺h3拮抗剂的苯氧基哌啶及其类似物 |
CA2645731A1 (en) * | 2006-03-15 | 2007-09-27 | Wyeth | N-substituted-azacyclylamines as histamine-3 antagonists |
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-
2005
- 2005-03-31 MX MXPA06011414A patent/MXPA06011414A/es active IP Right Grant
- 2005-03-31 WO PCT/US2005/010570 patent/WO2005097751A2/en active Application Filing
- 2005-03-31 AU AU2005230902A patent/AU2005230902A1/en not_active Abandoned
- 2005-03-31 US US11/095,398 patent/US7423147B2/en active Active
- 2005-03-31 CN CNA2005800176690A patent/CN1972914A/zh active Pending
- 2005-03-31 CA CA002561791A patent/CA2561791A1/en not_active Abandoned
- 2005-03-31 EP EP05735453A patent/EP1761496A2/en not_active Withdrawn
- 2005-03-31 JP JP2007506483A patent/JP2007531753A/ja not_active Withdrawn
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2008
- 2008-08-06 US US12/186,927 patent/US20080306066A1/en not_active Abandoned
-
2009
- 2009-09-15 US US12/559,823 patent/US7947718B2/en not_active Expired - Fee Related
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105452222A (zh) * | 2013-03-06 | 2016-03-30 | 吉瑞工厂 | 包含苯氧基哌啶核结构的h3拮抗剂 |
CN105452222B (zh) * | 2013-03-06 | 2018-10-02 | 吉瑞工厂 | 包含苯氧基哌啶核结构的h3拮抗剂 |
Also Published As
Publication number | Publication date |
---|---|
MXPA06011414A (es) | 2007-04-20 |
US20050222151A1 (en) | 2005-10-06 |
US7423147B2 (en) | 2008-09-09 |
US20080306066A1 (en) | 2008-12-11 |
CA2561791A1 (en) | 2005-10-20 |
EP1761496A2 (en) | 2007-03-14 |
AU2005230902A1 (en) | 2005-10-20 |
WO2005097751A3 (en) | 2006-03-09 |
WO2005097751A2 (en) | 2005-10-20 |
JP2007531753A (ja) | 2007-11-08 |
US7947718B2 (en) | 2011-05-24 |
US20100022539A1 (en) | 2010-01-28 |
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