CN1816541A - Vr-1拮抗剂取代-1-酞嗪胺 - Google Patents
Vr-1拮抗剂取代-1-酞嗪胺 Download PDFInfo
- Publication number
- CN1816541A CN1816541A CNA2004800191817A CN200480019181A CN1816541A CN 1816541 A CN1816541 A CN 1816541A CN A2004800191817 A CNA2004800191817 A CN A2004800191817A CN 200480019181 A CN200480019181 A CN 200480019181A CN 1816541 A CN1816541 A CN 1816541A
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- CN
- China
- Prior art keywords
- trifluoromethyl
- pyridyl
- amine
- alkyl
- phthalazines
- 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.)
- Pending
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- -1 Substituted-1-phthalazinamines Chemical class 0.000 title claims description 44
- 239000005557 antagonist Substances 0.000 title abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 208000002193 Pain Diseases 0.000 claims abstract description 26
- 239000001257 hydrogen Substances 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 15
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 13
- 206010061218 Inflammation Diseases 0.000 claims abstract description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 12
- 230000004054 inflammatory process Effects 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000001412 amines Chemical class 0.000 claims description 93
- 239000000203 mixture Substances 0.000 claims description 48
- 125000005843 halogen group Chemical group 0.000 claims description 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 239000001301 oxygen Substances 0.000 claims description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 239000005864 Sulphur Substances 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- BEHDOQLVERUTFJ-UHFFFAOYSA-N pyrido[2,3-d]pyridazin-5-amine Chemical compound C1=CC=C2C(N)=NN=CC2=N1 BEHDOQLVERUTFJ-UHFFFAOYSA-N 0.000 claims description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 230000007794 irritation Effects 0.000 claims description 5
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 4
- DOCGKTLITWQZAO-UHFFFAOYSA-N 2-[3-(trifluoromethyl)pyridin-2-yl]-n-[5-(trifluoromethyl)pyridin-2-yl]pyrido[2,3-d]pyridazin-5-amine Chemical compound N1=CC(C(F)(F)F)=CC=C1NC1=NN=CC2=NC(C=3C(=CC=CN=3)C(F)(F)F)=CC=C12 DOCGKTLITWQZAO-UHFFFAOYSA-N 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- BPQXQUFVBYWNTC-UHFFFAOYSA-N pyrido[2,3-d]pyridazin-8-amine Chemical compound C1=CN=C2C(N)=NN=CC2=C1 BPQXQUFVBYWNTC-UHFFFAOYSA-N 0.000 claims description 3
- IXBOICORUSEGPZ-UHFFFAOYSA-N pyrido[3,4-d]pyridazin-4-amine Chemical compound Nc1nncc2ccncc12 IXBOICORUSEGPZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 230000036541 health Effects 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract 1
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- 239000002585 base Substances 0.000 description 25
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- 229910052801 chlorine Inorganic materials 0.000 description 9
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- 239000011737 fluorine Substances 0.000 description 9
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- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 9
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
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- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 7
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- 229910052763 palladium Inorganic materials 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 5
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- 235000005074 zinc chloride Nutrition 0.000 description 1
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Abstract
本发明提供为VR-1拮抗剂的式(I)化合物或其药学上可接受的盐:其中Ar和R1为苯基或杂芳基,R2一般为氢,R3为氢或烷基,且X、Y和Z一般为CH或N;包含该化合物的药用组合物;化合物在治疗中的用途;化合物在制备用于治疗疼痛或炎症的药物中的用途;以及治疗疼痛或炎症的方法。
Description
本发明涉及N,6-二芳基或杂芳基取代-1-酞嗪胺及其类似物和衍生物,以及其药学上可接受的盐和前药,这些化合物用作治疗化合物,特别是用于治疗疼痛和其它经调节香草素-1受体(VR1)功能可改善的病症。
认识到红辣椒的药理活性成分是酚酰胺辣椒素已有一段时间。将辣椒素应用到粘膜或皮内注射时,可引起人剧烈的烧灼样疼痛。辣椒素作为镇痛药局部给药的有利作用也已得到充分确认。然而,对于介导这些对辣椒素反应的潜在分子药理学的了解也是最近才有所进展。
辣椒素的受体被称为香草素VR1受体,由Caterina和同事于1997年在UCSF克隆(Nature,398:816,1997)。VR1受体是在分布于皮肤、内脏、外周组织和脊髓的感觉神经上发现的阳离子通道。VR1的激活在最后产生痛觉的感觉纤维中引起动作电位。重要的是,不仅辣椒素能激活VR1受体,而且酸性pH和有害的热刺激也能激活VR1受体。许多炎症介质也使VR1受体变得敏感,这样看来它是疼痛刺激的多型整合受体。
原型VR1拮抗剂为capsazepine(Walpole等,J.Med.Chem.,37:1942,1994)-VR1 IC50为420nM。最近也已报导了一系列新的亚微摩尔级拮抗剂(Lee等,Bioorg.Med.Chem.,9:1713,2001),但是这些报导没有提供体内功效的证据。目前已经从‘超强’激动剂树胶脂毒素(resiniferatoxin)衍生出更高亲和力的拮抗剂。碘-树胶脂毒素(Wah1等,Mol.Pharmacol.,59:9,2001)为VR1的纳摩尔级拮抗剂,但不具有适合口服药物的特征。最后由Garcia-Martinez(Proc.Natl.Acad.Sci.,USA,99:2374,2002)描述的微摩尔级肽拮抗剂也是真实的。最近,国际(PCT)专利公布号WO 02/08221描述了一系列新的VR1拮抗剂,并说明在许多动物模型中显示有效。我们在本文中描述另一系列新的VR1调节剂。这些调节剂主要包含VR1拮抗剂,但也包含VR1部分拮抗剂和VR1部分激动剂。这些化合物在动物疼痛模型中显示有效。其它VR1拮抗剂在WO 03/062209(Neurogen Corporation)中公开。
本发明提供式(I)化合物或其药学上可接受的盐:
其中Ar为苯基、含1、2或3个氮原子的六元杂芳基、或含1、2、3或4个选自氧、氮和硫的杂原子且最多一个杂原子为氧或硫的五元杂芳基,Ar任选被1、2或3个独立选自以下的基团取代:卤素、羟基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基、氨基、卤代C1-6烷基、卤代C2-6烯基、卤代C2-6炔基、羟基C1-6烷基、羟基C2-6烯基、羟基C2-6炔基、氰基、硝基、氨基C1-6烷基、氨基C2-6烯基、氨基C2-6炔基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷基硫基、C1-6烷氧羰基、卤代C1-6烷氧基、卤代C2-6烯氧基、卤代C2-6炔氧基、NR4R5、CONR4R5或CO2NR4R5,其中各R4和R5独立为氢或C1-6烷基;
R1为苯基、含1、2或3个氮原子的六元杂芳基、或含1、2、3或4个选自氧、氮和硫的杂原子且最多一个杂原子为氧或硫的五元杂芳基,Ar任选被1、2或3个独立选自以下的基团取代:卤素、羟基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基、氨基、卤代C1-6烷基、卤代C2-6烯基、卤代C2-6炔基、羟基C1-6烷基、羟基C2-6烯基、羟基C2-6炔基、氰基、硝基、氨基C1-6烷基、氨基C2-6烯基、氨基C2-6炔基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷基硫基、C1-6烷氧羰基、卤代C1-6烷氧基、卤代C2-6烯氧基、卤代C2-6炔氧基、NR4R5、CONR4R5或CO2NR4R5,其中R4和R5定义同上;
R2为氢、卤素、羟基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基、NR6R7,其中R6和R7独立为氢、C1-6烷基或C1-6羟烷基,或R6和R7与它们所连接的氮原子一起形成任选含氧环原子的4、5或6-元稳定杂环;
R3为氢或C1-6烷基;
各X、Y和Z为N或CR8,其中R8为氢、卤素或C1-6烷基。
Ar优选未取代或被1或2个基团取代。Ar可以被1个基团取代。Ar可以未取代。
优选Ar上任何取代基独立选自卤素、羟基、C1-6烷基、羟基C1-6烷基、卤代C1-6烷基、C1-6烷氧基、氰基和C1-6烷氧羰基。更优选任何取代基为氟、C1-4烷基、羟基C1-4烷基、卤代C1-4烷基、C1-4烷氧基、氰基或C1-4烷氧羰基。取代基的实例为三氟甲基、氟、甲基、甲氧基、2-羟基异丙基、氰基、乙氧羰基和2-氟异丙基。
Ar优选为苯基或6-元杂芳环。Ar特别为苯基、吡啶基、咪唑基、吡嗪基、哒嗪基或嘧啶基。
Ar的具体实施方案包括3-三氟甲基吡啶-2-基、3-氟吡啶-2-基、3-甲基吡啶-2-基、吡啶-2-基、1-甲基咪唑-2-基、3-甲氧基吡啶-2-基、3-(2-羟基异丙基)吡啶-2-基、5-三氟甲基吡啶-2-基、6-三氟甲基吡啶-2-基、4-三氟甲基吡啶-2-基、4-甲基哒嗪-3-基、5-甲基嘧啶-4-基、2-甲基吡嗪-3-基、4-三氟甲基哒嗪-3-基、2-甲氧基苯基、2-氰基苯基、3,5-二氟吡啶-2-基、3-氰基吡啶-2-基、3-乙氧羰基吡啶-2-基和3-(2-氟异丙基)吡啶-2-基。
优选Ar为吡啶基,且优选被单取代。
优选Ar在Ar与分子其余部分的连接位点相邻的环位置被单取代。
优选R1未取代或被卤素、C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基或C1-6烷氧羰基取代。更优选R1上的取代基为氟、C1-4烷基、卤代C1-4烷基、卤代C1-4烷氧基或C1-4烷氧羰基。取代基的实例包括三氟甲基、叔丁基、三氟甲氧基、氟和乙氧羰基。
R1优选苯基或吡啶基,特别为苯基。
R1优选被单取代。优选取代基在R1与分子其余部分的连接位点的对位。
R1的具体实施方案包括4-三氟甲基苯基、4-叔丁基苯基、4-三氟甲氧基苯基、4-氟苯基、4-乙氧羰基苯基和5-三氟甲基吡啶-2-基。
优选R2为氢、C1-6烷氧基或NR6R7。更优选R2为氢、C1-4烷氧基、二(C1-4烷基)氨基或吗啉代。R2可为氢、甲氧基、二甲基氨基或吗啉代。R2可为氢。
R3优选为氢。
R4和R5优选为氢或甲基,特别为氢。
优选X、Y和Z均不为N,或X、Y和Z中的一个为N,且其余为CR8。R8优选为氢。优选Z为N且X和Y为CH。
优选的亚类化合物如下所示:
其中R1、R2和Ar定义同上,包括优选的定义。
因此,式IA、IB、IC和ID的化合物中:
Ar为任选被一个或两个取代基取代的苯基或六元杂芳环,这些取代基独立选自卤素、羟基、C1-6烷基、羟基C1-6烷基、卤代C1-6烷基、C1-6烷氧基、氰基和C1-6烷基羰基;
R1为苯基或吡啶基尤其为苯基,被卤素、C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基或C1-6烷氧羰基单取代;且
R2为氢、C1-4烷氧基、二(C1-4烷基)氨基或吗啉代。
在一个实施方案中,式I化合物为游离碱。
本发明的具体实施方案包括以下化合物或其药学上可接受的盐:
1)N-(4-三氟甲基苯基)-6-(3-三氟甲基-2-吡啶基)-1-酞嗪胺;
2)6-(3-氟-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
3)N-(4-(叔丁基苯基)-6-(3-三氟甲基-2-吡啶基)-1-酞嗪胺;
4)6-(3-甲基-2-吡啶基)-N-(4-(三氟甲基苯基)-1-酞嗪胺;
5)6-(3-甲基-2-吡啶基)-N-(4-三氟甲氧基苯基)-1-酞嗪胺;
6)6-(2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
7)N-(4-三氟甲基苯基)-2-(3-三氟甲基-2-吡啶基)吡啶并[2,3-d]哒嗪-5-胺;
8)6-(1-甲基-1H-咪唑-2-基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
9)4-甲氧基-6-(3-甲基-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
10)7-(3-甲基-2-吡啶基)-N-(4-三氟甲基苯基)吡啶并[3,4-d]哒嗪-4-胺;
11)4-二甲基氨基-6-(3-甲基吡啶-2-基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
12)6-(3-甲基吡啶-2-基)-4-(吗啉-4-基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
13)6-(3-甲氧基-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
14)2-{2-[1-(4-三氟甲基苯基氨基)酞嗪-6-基]吡啶-3-基}丙-2-醇;
15)N-(4-三氟甲基苯基)-6-(5-三氟甲基-2-吡啶基)-1-酞嗪胺;
16)N-(4-三氟甲基苯基)-6-(6-三氟甲基-2-吡啶基)-1-酞嗪胺;
17)N-(4-三氟甲基苯基)-6-(4-三氟甲基-2-吡啶基)-1-酞嗪胺;
18)6-(4-甲基-3-哒嗪基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
19)6-(5-甲基-4-嘧啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
20)6-(3-甲基-2-吡嗪基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
21)N-(4-三氟甲基苯基)-6-(4-三氟甲基-3-哒嗪基)-1-酞嗪胺;
22)N-(4-叔丁基苯基)-6-(3-甲基-2-吡啶基)-1-酞嗪胺盐酸盐;
23)N-(4-氟苯基)-6-(3-甲基-2-吡啶基)-1-酞嗪胺;
24)6-(2-甲氧基苯基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
25)6-(2-氰基苯基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
26)3-(3-甲基吡啶-2-基)-N-(4-三氟甲基苯基)吡啶并[2,3-d]哒嗪-8-胺;
27)N-(4-乙氧羰基苯基)-6-(3-甲基-2-吡啶基)-1-酞嗪胺;
28)6-(3,5-二氟-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
29)6-(3-氰基-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
30)6-(3-乙氧羰基-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
31)6-(3-(1-氟-1-甲基乙基)-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
32)N-(4-三氟甲基苯基)-2-(3-氯-2-吡啶基)吡啶并[2,3-d]哒嗪-5-胺;和
33)N-(5-三氟甲基-2-吡啶基)-2-(3-三氟甲基-2-吡啶基)吡啶并[2,3-d]哒嗪-5-胺。
本文作为基团或基团的一部分使用的术语“烷基”或“烷氧基”表示直链或支链基团。合适的烷基实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基和叔丁基。合适的烷氧基实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基和叔丁氧基。“烷基硫基”应按类似方式理解。
本文使用的术语“羟基C1-6烷基”指其中一个或多个(特别是1-3个,更尤其为1个)氢原子被羟基替换的C1-6烷基。特别优选羟基C1-3烷基,例如CH2OH、CH2CH2OH、CH(CH3)OH或C(CH3)2OH,最特别是CH2OH。“氨基烷基”应按类似方式理解。
本文使用的术语“卤代C1-6烷基”和“卤代C1-6烷氧基”指其中一个或多个(特别是1-3个)氢原子被卤原子尤其氟原子或氯原子替换的C1-6烷基或C1-6烷氧基。优选氟代C1-6烷基和氟代C1-6烷氧基,特别是氟代C1-3烷基和氟代C1-3烷氧基,例如CF3、CH2CH2F、CH2CHF2、CH2CF3、OCF3、OCH2CH2F、OCH2CHF2或OCH2CF3,最特别是CF3和OCF3。
本文作为基团或基团的一部分使用的术语“烯基”和“炔基”指直链或支链基团。合适的烯基实例包括乙烯基和烯丙基。合适的炔基为乙炔基或炔丙基。
在本文中使用时,术语“卤素”指氟、氯、溴和碘。最优选的卤素为氟和氯,尤其为氟。
在本文中使用时,术语“C1-6烷氧羰基”指通过其氧原子连接至羰基(C=O)从而形成C1-6烷氧羰基或卤代C1-6烷氧羰基的C1-6烷氧基或卤代C1-6烷氧基。合适的这种酯化羧基实例包括如甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基和叔丁氧羰基。
6-元杂环的实例为吡啶、嘧啶、吡嗪、哒嗪和三嗪。
5-元杂环的实例为噻吩、呋喃、吡咯、咪唑、吡唑、噁唑、异噁唑、噻唑、异噻唑、1,2,3-三唑、1,2,4-三唑、噁二唑、噻二唑和四唑。
在本发明再一方面,式(I)化合物可以药学上可接受的盐、尤其以酸加成盐的形式制备。
为了药用,式(I)化合物的盐应为无毒的药学上可接受的盐。然而,其它盐可用于制备本发明化合物或其无毒的药学上可接受的盐。本发明化合物中合适的药学上可接受的盐包括酸加成盐,例如,这些盐可通过混合本发明化合物溶液和药学上可接受的酸溶液而形成,这类酸有如盐酸、反丁烯二酸、对甲苯磺酸、马来酸、琥珀酸、乙酸、柠檬酸、酒石酸、碳酸、磷酸或硫酸。胺基盐也可包含季铵盐,其中氨基氮原子连接合适的有机基团如烷基、烯基、炔基或芳烷基部分。而且,本发明化合物连接酸性部分时,其合适的药学上可接受的盐可包括金属盐例如碱金属盐,如钠盐或钾盐;和碱土金属盐,如钙盐或镁盐。特别优选盐酸盐和苯磺酸盐,尤其为苯磺酸盐。
这些盐可用常规方法制备,例如将游离碱形式的式(I)化合物与一个或多个当量的合适酸在溶剂或介质中反应制备,所得盐在所用溶剂或介质中是不溶的;或在溶剂如水中反应制备,其在真空中或经冷冻干燥除去,或通过在合适的离子交换树脂上将已有盐的阴离子交换为另一种阴离子而除去。
本发明范围也包括上述式(I)化合物的N-氧化物。通常,这些N-氧化物可在任何可用的氮原子上形成。这些N-氧化物可经常规方法制备,例如在湿氧化铝存在下,使式(I)化合物与过硫酸氢钾制剂反应制备。
本发明范围包括上述式(I)化合物的前药。通常,这些前药是式(I)化合物的官能衍生物,在体内容易转化为必需的式(I)化合物。用于选择和制备合适前药衍生物的常规方法已在如″Design of Prodrugs″,ed.H.Bundgaard,Elsevier,1985中描述。
前药可以为生物活性物质(″母体药物″或″母体分子″)的药理非活性衍生物,需要在体内转化以释放活性药物,且较母体药物分子有改善的释放特性。例如,体内转化可以为某些代谢过程的结果,如羧酸酯、磷酸酯或硫酸酯的化学水解或酶水解,或易受影响官能团的还原或氧化。
本发明范围包括式(I)化合物及其盐的溶剂化物,例如水化物。
本发明化合物可有一个或多个不对称中心,因而既可以对映体存在又可以非对映异构体存在。应理解,所有这些异构体和它们的混合物均包含在本发明范围内。此外,式(I)化合物也可以互变异构体形式存在,且本发明范围包括独立的单一互变异构体及混合物。
本发明还提供包含一种或多种式(I)化合物与药学上可接受载体或赋形剂组合的药用组合物。
优选本发明组合物为单位剂型如片剂、丸剂、胶囊剂、散剂、颗粒剂、无菌肠胃外溶液或混悬剂、定量气雾剂或液体喷雾剂、滴剂、安瓿剂、自动注射装置、栓剂、软膏剂或凝胶剂;用于经口给药、肠胃外给药、鞘内给药、鼻内给药、舌下给药、直肠给药或局部给药,或用于吸入或吹入给药。尤其优选口服组合物如片剂、丸剂、胶囊剂或糯米纸囊剂。为了制备固体组合物如片剂,将主要活性成分与药用载体和其它药用稀释剂如水混合,形成包含本发明化合物或其药学上可接受盐的均匀混合物的固体预制剂组合物,所用药用载体有如常规压片组分,如玉米淀粉、乳糖、蔗糖、山梨醇、滑石粉、硬脂酸、硬脂酸镁、磷酸二钙或胶。当提及均匀预制剂组合物时,它是指活性成分均匀分散在组合物中,以便组合物可以容易地细分成相等的有效单位剂型如片剂、丸剂和胶囊剂。然后将固体预制剂组合物细分成上面所述含有0.1至约500mg本发明活性成分的单位剂型。有利的单位剂型包含1至500mg活性成分,例如1、5、10、25、50、100、300或500mg。新组合物的片剂或丸剂可通过包衣或其它组合方式提供具有延长作用时间的优点的剂型。例如,片剂或丸剂可以包含内部剂量和外部剂量组分,后者以包封的形式包在前者上。这两种组分可以用防止胃中崩解的肠衣层隔开,从而使得内部组分完整地进入十二指肠或延迟释放。许多材料可用于这种肠衣层或包衣,这些材料包括许多聚合物酸和聚合物酸与如虫胶、鲸蜡醇以及醋酸纤维素酯这类材料的混合物。
其中可以加入本发明的新组合物用于口服给药或注射给药的液体形式包括水溶液剂、合适矫味的糖浆剂、水或油混悬剂和用食用油如棉子油、芝麻油、椰子油或花生油矫味的乳剂、以及酏剂和类似药用溶媒。用于水混悬剂的合适分散剂或悬浮剂包括合成胶和天然胶如黄芪胶、阿拉伯胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯-吡咯烷酮或明胶。
在如下所列的疼痛病症的治疗中,合适剂量水平为每天约1.0mg至15g,优选每天约5.0mg至1g,更优选每天约5mg至500mg,尤其是每天10mg至100mg。这些化合物可以每天1-4次的方案给药。
可认识到,用于任何治疗中所需式(I)化合物的量不仅根据所选具体化合物或组合物而变化,而且根据给药途径、治疗的病症性质、患者的年龄和状况而变化,最终将由医师决定。
本发明还提供用于治疗人或动物身体的如上述定义的式(I)化合物或其药学上可接受的盐。优选所述治疗用于可通过VR1受体调节(优选拮抗剂)治疗的病症。
本发明化合物将用于预防或治疗疼痛和/或炎症为主的疾病和病症,包括慢性和急性疼痛病症。这些病症包括类风湿性关节炎;骨关节炎;术后疼痛;肌骨痛,尤其是创伤后的肌骨痛;脊椎痛;肌筋膜疼痛综合征;头痛,包括偏头痛、急性或慢性紧张性头痛、丛集性头痛、颞下颌疼痛和上颌窦疼痛;耳痛;外阴切开手术疼痛;灼伤,尤其是主要与痛觉过敏相关的灼伤;深部痛和内脏痛,如心痛、肌肉痛、眼痛、口面痛如牙痛、腹痛、妇科疼痛如痛经、与膀胱炎和分娩(labour)痛相关的疼痛、慢性盆腔痛、慢性前列腺炎和子宫内膜异位;与神经和神经根损伤相关的疼痛,如外周神经紊乱相关的疼痛,例如神经受累和臂丛神经撕脱、神经切断、外周神经病、三叉神经痛、非典型面部疼痛、神经根损伤和蛛网膜炎;瘙痒病症包括搔痒症(pruritis)、由血液透析引起的瘙痒和接触性皮炎;由粘膜暴露于(如通过食入、吸入或眼睛接触)辣椒素和相关刺激物如催泪气、辣椒或椒雾引起的疼痛(以及支气管收缩和炎症);神经病性疼痛病症如糖尿病性神经病、化学疗法引发的神经病和带状疱疹后神经痛;“非疼痛性”神经病;复杂的局部疼痛综合征;与癌相关的疼痛,经常指癌性痛;中枢神经系统疼痛,如由脊髓或脑干损害引起的疼痛、腰背痛、坐骨神经痛和强直性脊柱炎;痛风;瘢痕疼痛;过敏性肠综合征;炎性肠病;尿失禁包括膀胱逼尿肌反射过度(hyper-reflexia)和膀胱过敏;呼吸道疾病包括慢性阻塞性肺病(COPD)、慢性支气管炎、囊性纤维化、哮喘和鼻炎,包括过敏性鼻炎如季节性和常年性鼻炎,以及非过敏性鼻炎;自身免疫性疾病;和免疫缺陷疾病。
因此,再一方面,本发明提供式(I)化合物,用于制备治疗或预防经调节VR1活性可得到改善的生理疾病的药物。
本发明也提供用于治疗或预防生理疾病的方法,这些病症可通过调节VR1活性而得到改善,这种方法包括给予有需要的患者有效量的式(I)化合物或包含式(I)化合物的组合物。
再一方面或另一方面,本发明提供式(I)化合物,用于制备治疗或预防疼痛和/或炎症为主的疾病或病症的药物。
本发明也提供用于治疗或预防疼痛和/或炎症为主的疾病或病症的方法,该方法包括给予有需要的患者有效量的式(I)化合物或包含式(I)化合物的组合物。
本发明再一方面,将本发明化合物和一种或多种其它适用于治疗具体病症的药理活性药物联合使用治疗上述任一病症可能比较理想。式(I)化合物和其它药理活性药物可以同时、序贯或组合给予患者。因此,例如为了治疗或预防疼痛和/或炎症,本发明化合物可以与其他镇痛药、NR2B拮抗剂、缓激肽拮抗剂、抗偏头痛药、抗惊厥药如奥卡西平和卡马西平、抗抑郁剂(如TCA、SSRI、SNRI、P物质拮抗剂等)、脊髓阻滞剂、加巴喷丁、普加巴林和哮喘治疗药(如θ2-肾上腺素能受体激动剂或白三烯D4拮抗剂(如孟鲁司特)联合使用,其他镇痛药有如对乙酰氨基酚(扑热息痛)、阿司匹林以及包括选择性环氧合酶-2(COX-2)抑制剂的其它NSAID和阿片类镇痛药,尤其是吗啡。
具体抗炎药物包括双氯酚酸、布洛芬、消炎痛、萘丁美酮、酮洛芬、萘普生、吡罗昔康和舒林酸、依托度酸、美洛昔康、罗非考昔、塞来考昔、艾托考昔、帕瑞考昔、伐地考昔和tilicoxib。与本发明化合物联合使用的合适阿片类镇痛药包括吗啡、可待因、双氢可待因、二乙酰吗啡、氢可酮、氢吗啡酮、左吗啡、羟吗啡酮、阿芬太尼、丁丙诺啡、布托啡诺、芬太尼、舒芬太尼(sufentanyl)、哌替啶、美沙酮、纳布啡、丙氧芬和喷他佐辛;或其药学上可接受的盐。与本发明化合物联合使用的合适抗偏头痛药物包括CGRP-拮抗剂、麦角胺或5-HT1激动剂尤其是舒马曲坦、那拉曲坦、zolmatriptan或利扎曲普坦。
因此,在本发明的再一方面,提供包含本发明化合物、镇痛药与至少一种药学上可接受载体或赋形剂的药用组合物。
在本发明的再一方面或另一方面,提供包含本发明化合物和镇痛药的产品,该产品作为联合制剂在治疗或预防以疼痛和/或炎症为主的疾病或病症时同时、分别或序贯使用。
式1化合物可以通过式II化合物与式III化合物反应形成:
Ar-L1
(II) (III)
其中Ar、R1、R2、R3、X、Y和Z定义同上,L和L1的一个为Cl或Sn(烷基)3例如Sn(甲基)3或Sn(正丁基)3,另一个为溴或氯。当L或L1为Cl时,它可在适用于Suzuki偶合反应的条件下最初就转化成基团B(OH)2(综述见例如A.Suzuki,Pure Appl.Chem.,1991,63,419-422),例如,在钯催化剂如四(三苯基膦)合钯(O)、三(二亚苄基丙酮)二钯(O)、(1,1′-二(二苯基膦基)二茂铁)二氯化钯或二氯化(1,4-二(二苯基膦基)丁烷)钯的存在下;在合适溶剂如醚中,例如二甲氧基乙烷或二噁烷,或芳烃如甲苯;在升高的温度和在碱如碳酸钠的存在下。当L或L1为Sn(烷基)3,该反应在适用于Stille偶合反应的条件下方便地实现(综述见例如J.K.Stille,Angew.Chem.Int.Ed.,1986,25,508-524),例如,在钯催化剂如四(三苯基膦)合钯(O)或二(三苯基膦)氯化钯(II)的存在下,在合适溶剂如醚中,例如二噁烷,或芳烃如甲苯,在升高的温度和在催化剂如LiCl和CuI的存在下。
式II化合物可以通过式IV化合物与式HNR1R3化合物反应形成:
其中L为Br且X、Y、Z、R1、R2和R3定义同上。该反应通常在酸如盐酸的存在下,在溶剂如二噁烷中回流约30-60分钟完成。
式I化合物也可通过式V化合物与式HNR1R3化合物反应形成:
其中Ar、X、Y、Z、R1、R2和R3如定义,反应条件类似于前述反应。
式V化合物可通过稠合哒嗪-5(6H)-酮前体与磷酰氯回流或于100℃反应约1-5小时制得。
该化合物可通过式VI化合物反应形成:
其中Ar、R2、X、Y和Z定义同上。反应如下:在光存在下,于非质子性溶剂如四氯化碳中,使用如N-溴琥珀酰亚胺和AIBN或过氧化苯甲酰,通过溴自由基加成反应将式VI化合物回流约10-48小时,接着用水合肼在溶剂如乙醇中回流约18小时处理。
式VI化合物,其中R2为H、Z为N且X和Y为CH,可按如下方法制得:于约室温、惰性气氛下,通常在溶剂如四氢呋喃中,将式ArCN化合物(其中Ar定义同上)与甲基碘化镁反应约1小时得到式ArC(O)CH3化合物;接着通常于约160℃,将该化合物与二甲基甲酰胺二甲基缩醛在微波中反应约5分钟,然后与3-氨基巴豆酸乙酯在溶剂如冰醋酸中回流约6小时。
式IV化合物,其中R2为氯,可按如下方法制得:通常在乙酸的存在下,于约80℃,将式VII化合物:
其中L为溴且X、Y和Z定义同上,
与水合肼反应几小时,接着通常在碱如二异丙胺的存在下,与一当量磷酰氯回流反应约3小时。
式II化合物,其中R2为C1-6烷氧基,可通过式II化合物(其中R2为氯)与C1-6醇钠在相应醇中回流约5小时而制得。式II化合物,其中R2为NR6R7(其中R6和R7定义同上),可通过通常在溶剂如乙醇中,于约100℃,使式II化合物(其中R2为氯)与式HNR6R7化合物反应约24小时而制得。
式V化合物,其中R2为氢、Y为N且X和Z为CR8,可按如下方法制得:通常于约-78℃温度,使式VIII化合物
依次与强碱如混有正丁基锂的2,2,6,6-四甲基哌啶在溶剂如四氢呋喃中反应约90分钟,然后通常于约室温下与二甲基甲酰胺反应几小时,接着通常也在溶剂如四氢呋喃中与肼反应,随后在碱如乙酸钾的存在下加热回流。将Ar基团加成至所得溴吡啶并哒嗪酮可以通过上述Stille偶合实现。如上所述使用磷酰氯将所得化合物转化成式V化合物。
式I化合物可以通过标准方法转化成式I的其它化合物。
本文中没有描述中间体和起始原料的合成,这些化合物可以购买到或可以通过标准方法由购买的化合物制得。
在任何上述合成顺序中,可能需要和/或必需保护任一有关分子上的敏感基团或活性基团。这可以通过常规保护基团而实现,如Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,PlenumPress,1973;和T.W.Greene and P.G.M.Wuts,Protective Groups inOrganic Synthesis,John Wiley & Sons,1991中所述那些保护基团。这些保护基团可以使用本领域熟知的方法在后来方便的反应步骤中除去。
以下实施例用于举例说明本发明化合物的制备。
中间体
中间体I
6-溴-1-氯酞嗪的制备
已在WO-A-0281474中描述。
中间体II
6-溴-N-(4-三氟甲基苯基)-1-酞嗪胺
向中间体I(2g,8.21mmol)和4-氨基三氟甲苯(1.32g,1.024mL,8.21mmol)的1,4-二噁烷(20mL)溶液中加入1滴浓HCL。将反应混合物加热回流1h。冷却至室温后,将不溶物过滤收集,用1,4-二噁烷洗涤并干燥。将该固体溶于乙酸乙酯中,用饱和碳酸钠洗涤。将乙酸乙酯萃取液合并,用盐水洗涤,用硫酸镁干燥,过滤并减压蒸发得到固体。该固体用乙醇冲洗,将不溶物过滤收集并在真空下于60℃干燥,得到1.1g产物。
1H NMR(400MHz)DMSO-d6δ:7.72(2H,d,J8.6),8.18-8.23(3H,m),8.39(1H,d,J2.0),8.58(1H,d,J9.0),9.20(1H,s),9.61(1H,s).
类似地制备:
中间体III
6-溴-N-(4-三氟甲氧基苯基)-1-酞嗪胺
1H NMR(400MHz)DMSO-d6δ:7.38(2H,d,J8.2),8.02(2H,dd,J2.0 and 8.2),8.21(1H,dd,J1.8 and 8.8),8.36(1H,d,J1.6),8.55(1H,d,J9.0),9.13(1H,s),9.39-9.60(1H,m);MS(ES M+1)384/386.
中间体IV
6-溴-N-(4-叔丁基苯基)-1-酞嗪胺
1H NMR(400MHz)DMSO-d6δ:1.31(9H,s),7.38(2H,d,J8.6),7.79(2H,d,J7.8),8.16(1H,dd,J1.6 and 9.0),8.31(1H,d,J1.6),8.54(1H,d,J9.0),9.07(1H,s),9.20(1H,s);MS(ES M+1)356/358.
中间体V
6-溴-N-(4-乙氧羰基苯基)-1-酞嗪胺
1H NMR(400MHz)DMSO-d6δ:1.33(3H,t,J7.0Hz),4.32(2H,q,J7.0Hz),7.97(2H,d,J9.0Hz),8.12(2H,d,J9.0Hz),8.23(1H,dd,J2.0 and 9.0Hz),8.39(1H,d,J2.0Hz),8.59(1H,d,J9.0Hz),9.21(1H,s),9.62(1H,s).
中间体VI
6-溴-14-二氯酞嗪
将5-溴-1,3-异苯并呋喃二酮(14.8g,65.4mmol)悬浮在乙酸(150mL)中,用水合肼(10mL)于80℃处理过夜。将混合物冷却,过滤,残渣用甲醇洗涤。用4M NaOH(约250mL)将残渣研磨,过滤。将浅黄色滤液用浓HCl酸化,过滤。将残渣与甲苯(×4)共沸,悬浮在POCL3(75mL)中。缓缓加入N,N-二异丙基乙胺(10mL),将混合物加热回流3h,然后减压浓缩,悬浮在氯仿中,过滤。将滤液倾于冰上,有机相用碳酸氢钠溶液洗涤,接着用盐水洗涤。有机相用硫酸钠干燥,经二氧化硅垫过滤,用氯仿洗脱,蒸发后得到灰白色固体(6.5g,36%)。
1H NMR(400MHz)CDCl3δ:8.14-8.20(2H,m),8.48(1H,d,J0.4);MS(ES M+1)279.
中间体VII
6-溴-4-氯-N-(4-三氟甲基苯基)-1-酞嗪胺盐酸盐
将中间体VI(3.29g,11.8mmol)和4-氨基三氟甲苯(1.91g,11.84mmol)悬浮在乙醇中,加热回流3h。将该混合物过滤,得到浅黄色固体(3.0g);MS(ES M+1)404。
中间体VIII
6-溴-4-甲氧基-N-(4-三氟甲基苯基)-1-酞嗪胺
将中间体VII(1.8g,3.96mmol)和甲醇钠(2.14g,39.6mmol)悬浮在无水甲醇(15mL)中,加热回流5h。将混合物减压浓缩,将残渣在EtOAc/氯化铵之间分配,水相用EtOAc(×2)萃取。将有机相合并,用盐水洗涤,用硫酸钠干燥,经浓缩得到浅黄色固体,用DCM重结晶得到白色固体(175mg,46%)。
1H NMR(400MHz)DMSO-d6δ:4.14(3H,s),7.67(2H,d,J8.8),8.10(2H,d,J8.8),8.22-8.28(2H,m),8.51(1H,d,J8.4),9.38(1H,s);MS(ES M+1)398/400.
中间体IX
6-溴-4-二甲基氨基-N-(4-三氟甲基苯基)-1-酞嗪胺
于100℃,将中间体VII(107mg,0.24mmol)在密封管中用二甲胺(30%乙醇溶液,3mL)处理24h。混合物减压浓缩,将所得残渣在DCM/碳酸氢钠溶液间分配。用DCM萃取水相,将有机相合并,用硫酸钠干燥,经浓缩得到黄色油(87mg),用于偶合步骤时不需进一步纯化。MS(ESM+1)411/413.
中间体X
6-溴-4-(吗啉-4-基)-N-(4-三氟甲基苯基)-1-酞嗪胺
将中间体VII(100mg,0.23mmol)悬浮在乙醇(2mL)中,于100℃在密封管中用吗啉(0.099mL,1.14mmol)处理24h。将所得混合物减压浓缩,将所得残渣在DCM/碳酸氢钠溶液间分配。用DCM萃取水相,将有机相合并,用硫酸钠干燥,经浓缩得到黄色油,该油使用时不需进一步纯化。MS(ES M+1)453/455。
中间体XI
7-溴-3H-吡啶并[3,4-d]哒嗪-4-酮
将2,2,6,6-四甲基哌啶(9.58mL,56.4mmol)溶于无水THF(100mL)中,冷却至0℃,同时于15min内加入正丁基锂(1.6M己烷溶液,35.2mL,56.43mmol)。将所得溶液冷却至-78℃,在10min内边搅拌边加入四等份的固体6-溴烟酸(3.8g,18.8mmol)。于该温度继续搅拌1.5h,将所得深红色溶液用无水DMF(10mL)处理,升温至室温过夜。将混合物倾入水(200mL)中并用1M HCl酸化,用EtOAc(×4)萃取水相。将有机相合并,用盐水洗涤,用硫酸钠干燥,经浓缩得到黄色油,将该油溶于THF(25mL)中,用肼(1M THF溶液,19mL)处理。将沉淀过滤,溶于乙醇(50mL)中,在乙酸钾(5g)的存在下加热回流。混合物减压浓缩,将褐色油状固体用乙醚研磨,将该醚溶液经快速层析(50%乙酸乙酯/异己烷)得到白色固体(0.5g,12%)。
1H NMR(400MHz)DMSO-d6δ:8.21(1H,s),8.36(1H,s),9.20(1H,s),13.09,(1H,s).MS(ES M+1)226/228.
中间体XII
7-(3-甲基吡啶-2-基)-3H-吡啶并[3.4-d]哒嗪-4-酮
将中间体XI(104mg,0.46mmol)、无水氯化锂(59mg,1.38mmol)、3-甲基-2-三丁基甲锡烷基吡啶(264mg,0.69mmol)、CuI(8.8mg,0.05mmol)和Pd(PPh3)4(26.6,0.02mmol)悬浮在二噁烷(4mL)中,于160℃用微波辐射照射15min。将混合物过滤,用EtOAc洗涤残渣。将该残渣用热甲醇研磨,过滤,将滤液浓缩得到白色固体(83mg,76%)。
1H NMR(360MHz)DMSO-d6δ:2.56(3H,s),6.68(1H,br),7.06(1H,d,J6.3Hz),7.31(1H,br),7.62-7.90(2H,brm),8.82(1H,br).MS(ES M+1)239.
中间体XIII
6-(4,4,5,5-四甲基[1,3,2]二氧杂硼杂环戊烷-2-基)-N-(4-三氟甲基苯基)-1-酞嗪胺
于100℃,将中间体II(1.5g,4.07mmol)、双戊酰二硼(1.14g,4.48mmol)、乙酸钾(0.80g,8.15mmol)和[1,1′-二(二苯膦基)二茂铁]氯化钯(II)(0.15g;0.20mmol)的1,4-二噁烷(50mL)溶液加热18h。将溶剂减压蒸发,并将残渣在乙酸乙酯和水之间分配。合并乙酸乙酯萃取液,用盐水洗涤,用硫酸镁干燥,经Hyflo过滤,减压蒸发得到固体。将该固体用己烷研磨,过滤收集并干燥得到1.8g题述化合物。
1H NMR(360MHz)DMSO-d6δ:1.37(12H,s),7.71(2H,d,J8.6),8.22(3H,m),8.43(1H,s),8.62(1H,d,J8.2Hz),9.33(1H,s),9.59(1H,s).MS(ESM+1)416.
中间体XIV
2-氯-3-(1-氟-1-甲基乙基)吡啶
向冷却至-70℃的2-(2-氯-3-吡啶基)丙-2-醇(1g,5.83mmol)的二氯甲烷(10mL)溶液中逐滴加入三氟化二乙基氨基硫(1.1272g,0.857mL,6.993mmol)。加完后,将反应混合物升温至室温并搅拌30min。TLC显示起始原料消耗完。将反应混合物倾入碳酸钠溶液中,并用二氯甲烷萃取。将二氯甲烷萃取液合并,用水洗涤,用硫酸镁干燥,经过滤并减压蒸发得到油。产量=0.9g。
1H NMR(360MHz)DMSO-d6δ:1.83(3H,s),1.89(3H,s),7.30(1H,dd,J 4.6 and 7.7Hz),8.00(1H,dd,J1.9 and 7.9Hz),8.34(1H,dd,J1.9 and4.7Hz).
中间体XV
2-(3-三氟甲基-2-吡啶基)吡啶并[2,3-d]哒嗪-5-酮
将3M甲基碘化镁的乙醚(100mL,0.3mol)溶液加至冰浴冷却的无水THF(300mL)中。然后,于N2下加入3-三氟甲基-2-氰基吡啶(41g,0.24mol)的无水THF(100mL)溶液,加入时内部温度不超过10℃。加完(20min)后,于室温搅拌混合物1h。然后依次用饱和氯化铵水溶液(100mL)、2N HCl(200mL)将混合物猝灭。将产物1-(3-三氟甲基-2-吡啶基)乙酮萃取至乙醚(3×200mL),然后分离得到褐色油(34g)。TLC:硅胶,EtAc:己烷1∶3;Rf,0.6。
1H NMR(360MHz)CDCl3δ:2.62(3H,s),7.45-7.49(1H,m),8.01(1H,dd,J0.8 and 8.1 Hz),8.71(1H,dd,J0.8 and 8.1Hz).
于160℃,将乙酮(2.8g,0.015mol)和二甲基甲酰胺二甲基缩醛(2.0mL,0.015mol)的混合物在微波仪器中加热10min。重复该过程(×12),将所得黑色油加至3-氨基丁烯酸乙酯(40g,0.31mol)的冰醋酸(500mL)溶液中,常规加热回流18h。然后,将混合物浓缩并在乙醚(3×300mL)和2N NaOH溶液(200mL)之间分配。将有机相用盐水(200mL)洗涤,用MgSO4干燥,经浓缩得到褐色油,经硅胶柱层析纯化,以EtAc∶己烷1∶3->1∶1为洗脱剂,得到2-甲基-6-(3-三氟甲基-2-吡啶基)吡啶-3-甲酸乙酯,为油(36g)。TLC:硅胶,EtAc∶己烷1∶1;Rf,0.5。
1H NMR(360MHz)CDCl3δ:1.43(3H,t,J7.2Hz),2.90(3H,s),4.42(2H,q,J7.2Hz),7.48-7.51(1H,m),7.60(1H,d,J 8.0),8.13(1H,dd,J0.8 and 8.1Hz),8.33(1H,d,J8.0Hz),8.85(1H,d,J8.1Hz).
将甲酸乙酯(36g,0.12mol)、N-溴琥珀酰亚胺(72g,0.4mol)和过氧化二苯甲酰(1g)的四氯化碳(700mL)溶液加热回流72h,并用台灯照明。然后,将混合物过滤,用2M KOH溶液(100mL)洗涤母液。将有机相用MgSO4干燥,浓缩得到单溴甲基衍生物和二溴甲基衍生物的1∶9混合物(50g)。将该混合物溶于乙醇(250mL)中,加入水合肼(25mL),将混合物加热回流18h。浓缩混合物,将残渣用水研磨,经过滤收集中间体XV,为黄色固体(16g)。TLC:硅胶,EtAc;Rf,0.5。
1H NMR(400MHz)DMSO-d6δ:7.80-7.85(1H,m),8.20(1H,d,J8.3Hz),8.41(1H,s),8.44(1H,dd,J1.1and 8.0Hz),8.74(1H,d,J8.3Hz),8.01(1H,d,J8.0Hz).
中间体XVI
2-(3-三氟甲基-2-吡啶基)吡啶并[2,3-d]哒嗪-5-胺
将中间体XV(0.4g,0.0014mol)在POCl3中加热回流1h。然后真空除去过量POCl3并用甲苯(×2)驱除(chase)。将150mg残渣溶于33%氨水(3ml)中,于140℃在Smith微波反应器中加热30min,得到中间体XVI。
1H NMR(400MHz),DMSO-d6δ:8.83(1H,dd,J4.8,0.8Hz),8.77(1H,d,J0.4Hz),8.69(1H,dd,J8.4,0.8Hz),8.27(1H,dd,J8.4,1.6Hz),8.05(1H,d,J,8.4Hz),7.66-7.63(1H,m),7.21(2H,s).
实施例
实施例1
N-(4-三氟甲基苯基)-6-(3-三氟甲基-2-吡啶基)-1-酞嗪胺
于氮气下,将中间体II(300.g,0.815mmol)、双戊酰二硼(227mg,0.90mmol)、乙酸钾(159.96mg,1.63mmol)和[1,1′-二(二苯膦基)二茂铁]氯化钯(II)(29.81mg,0.041mmol)搅拌10分钟,向该混合物中加入1,4-二噁烷(10mL)。将反应混合物加热回流18h。冷却后,加入2-氯-3-三氟甲基吡啶(148mg,0.8149mmol)、2M碳酸钠溶液(1mL)和[1,1′-二(二苯膦基)二茂铁]氯化钯(II)(29.81mg,0.041mmol),将反应混合物于100℃加热6h。MS显示产物形成。将反应混合物经硅藻土过滤并用乙酸乙酯洗涤。将有机溶液用盐水洗涤,用硫酸镁干燥,过滤并减压蒸发得到油。将该油经硅胶柱纯化,用己烷/乙酸乙酯梯度洗脱。合并合适组分并减压蒸发得到固体。将该固体用己烷研磨,经过滤收集得到题述化合物,产量=135mg(38%)。
1H NMR(400MHz)DMSO-d6δ:7.73(1H,g),7.75(1H,s),7.80(1H,dd,J4.9and 7.6),8.13(1H,d,J8.6),8.19-8.24(3H,m),8.44(1H,dd,J1.2 and 8.2),8.74(1H,d,J8.6),9.01(1H,d,J4.3),9.33(1H,s),9.66(1H,s);MS(ES M+1)435.
类似地制备:
实施例2
6-(3-氟-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺
1H NMR(400MHz)DMSO-d6δ:7.61-7.65(1H,m),7.73(2H,d,J 8.6),7.96(1H,d,J1.2),7.99(2H,dd,J1.4 and 3.3),8.01(1H,d,J1.2),8.23(2H,d,J8.6),8.56-8.58(1H,m),8.63(1H,s),8.67-8.69(1H,m),8.75(1H,s),8.77(1H,s),9.38(1H,s),9.64(1H,s);MS(ES M+1)385.
实施例3
N-(4-(叔丁基苯基)-6-(3-三氟甲基-2-吡啶基)-1-酞嗪胺
1H NMR(360MHz)DMSO-d6δ:1.32(9H,s),7.40(2H,d,J 8.8),7.79(1H,dd,J4.7 and 7.9),7.84(2H,d,J 8.4),8.05-8.12(2H,m),8.42(1H,dd,J 0.7 and 7.4),8.69(1H,d,J8.8),9.00(1H,d,J4.6),9.18(1H,s),9.22(1H,s);MS(ES M+1)423.
实施例4
6-(3-甲基-2-吡啶基)-N-(4-(三氟甲基苯基)-1-酞嗪胺
向中间体II(300mg,0.815mmol)、3-甲基-2-(三丁基甲锡烷基)吡啶(467mg,1.22mmol)、无水氯化锂(77.mg,1.83mmol)和碘化铜(I)(5.8mg,0.03mmol)的二噁烷(3mL)溶液中加入四(三苯基膦)合钯(O)(35mg,0.03mmol)。将反应混合物于150℃在Smith微波反应器中加热15min。经硅藻土垫过滤收集催化剂并用乙酸乙酯洗涤。将滤液用盐水洗涤,合并乙酸乙酯萃取液,用硫酸镁干燥,过滤并减压蒸发得到油。将该油经快速层析纯化,用己烷/乙酸乙酯(10∶1)至乙酸乙酯的梯度洗脱。合并合适组分并减压蒸发得到固体。将该固体用乙腈重结晶,经过滤收集固体并干燥。产量=150mg(48%)。
1H NMR(400MHz)DMSO·d6δ:2.43(3H,s),7.43(1H,dd,J4.7and 7.8Hz),7.73(2H,d,J8.6Hz),7.84(1H,dd,J1.0 and 7.6Hz),8.23-8.28(4H,m),8.59(1H,dd,J1.0 and 4.5Hz),8.72(1H,d,J8.6Hz),9.31(1H,s),9.62(1H,s);MS(ES M+1)381.
类似地制备:
实施例5
6-(3-甲基-2-吡啶基)-N-(4-三氟甲氧基苯基)-1-酞嗪胺
1H NMR(400MHz)DMSO-d6δ:2.43(3H,s),7.42-7.45(3H,m),7.86(1H,dd,J0.8 and 7.8Hz),8.00(2H,d,J9.0Hz),8.31-8.36(2H,m),8.61(1H,dd,J 0.8 and4.7Hz),8.80(1H,d,J8.6Hz),9.31(1H,s);MS(ES M+1)397.
实施例6
6-(2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺
1H NMR(400MHz)DMSO-d6δ:7.58(1H,dd,J1.2 and 2.7),7.88(2H,d,J8.6),8.03(2H,d,J8.6),8.07-8.12(1H,m),8.33(1H,d,J8.2),8.84-8.85(1H,m),9.04(1H,dd,J2.0 and 8.6),9.17(2H,dd,J1.6 and 7.4),9.70(1H,s),11.05-11.26(1H,br s);MS(ES M+1)367.
实施例7
N-(4-三氟甲基苯基)-2-(3-三氟甲基-2-吡啶基)吡啶并[2,3-d]哒嗪-5-胺
将中间体XV(0.4g,0.0014mol)在POCl3中加热回流1h。然后真空除去过量POCl3并用甲苯(×2)驱除。将残渣溶于二噁烷(10mL)中,加入4-氨基三氟甲苯(0.45g,0.0028mol)并将混合物加热回流30min。将该混合物浓缩并经硅胶层析纯化,以EtOAc:己烷->EtOAc为洗脱剂,用乙醇重结晶所得产物,得到题述化合物,为灰白色固体(50mg)。
1H NMR(360MHz),DMSO-d6δ:7.76(2H,d,J8.5Hz),7.8-7.9(1H,m),8.23(2H,d,J8.5Hz),8.43(1H,d,J 8.5Hz),8.48(1H,d,J,8.5Hz),9.05(1H,s),9.29-9.24(2H,m),9.84(1H,s).
实施例7a
N-(4-三氟甲基苯基)-2-(3-三氟甲基-2-吡啶基)吡啶并[2,3-d]哒嗪-5-胺苯磺酸盐
于室温将实施例7产物溶于DMF中,加入苯磺酸(1.2eq)。将该溶液老化1h,然后于90min内用乙酸异丙基酯缓慢稀释。老化4h后,过滤浆状物,滤饼用乙酸异丙基酯洗涤。于室温真空干燥黄色结晶固体至恒重。产率94%。
实施例7b
N-(4-三氟甲基苯基)-2-(3-三氟甲基-2-吡啶基)吡啶并[2,3-d]哒嗪-5-胺盐酸盐
将实施例7产物溶于热乙醇中并加入2M HCL乙醚(过量)溶液。将该悬浮液老化1h,过滤浆状物并将滤饼用乙醇和乙醚洗涤。于室温真空干燥固体至恒重。产率90%。
1H NMR(360MHz)DMSO-d6δ:7.84(2H,d,8.6Hz),7.85-7.80(1H,m),8.11(1H,dd,J8.4Hz),8.5(2H,m),9.05(1H,d,J3.8Hz),9.33(1H,s),9.49(1H,J8.6Hz).
实施例8
6-(1-甲基-1H-味唑-2-基)-N-(4-三氟甲基苯基)-1-酞嗪胺:
于-78℃,搅拌N-甲基咪唑(97μL,1.23mmol)的四氢呋喃(2mL)溶液,逐滴加入正丁基锂(1.6M己烷溶液,0.82mL,1.30mmol)。搅拌该无色溶液30mins,然后通过导管加入氯化锌(500mg,3.6mmol)的四氢呋喃(3mL)溶液。于1h内将反应物升温至0℃,然后再于1h内升温至室温。将中间体II(150mg,0.408mmol)和四(三苯基膦)合钯(23mg,8.16μmol)溶于四氢呋喃(2ml)中,并通过导管加至反应混合物中。然后向混合物鼓泡通入氮气,将基加热回流并搅拌16h。冷却后,将反应混合物倾入至乙二胺四乙酸二钠盐(11g)的100mL水溶液中。然后加入固体碳酸氢钠将混合物碱化,用乙酸乙酯萃取三次并用硫酸钠干燥。过滤后,将混合物预吸附至硅胶上,用柱层析(5%甲醇/二氯甲烷)纯化。
1H NMR(400MHz,DMSO-d6)δ:9.60(1H,s)9.31(1H,s),8.69(1H,d J9.0Hz),8.42-8.40(2H,m),8.22(2H,d,J8.6Hz),7.72(2H,d,J8.6Hz),7.41(1H,s),7.11(1H,s),3.94(3H,s);MS(MH+)370.
实施例9
4-甲氧基-6-(3-甲基-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺
将中间体VIII(100mg,0.25mmol)、无水氯化锂(31mg,0.75mmol)、3-甲基-2-三丁基甲锡烷基-吡啶(144mg,0.38mmol)、CuI(4.9mg,0.03mmol.)和Pd(PPh3)4(14.5mg,0.01mmol)悬浮在二噁烷(3mL)中,于160℃用微波辐射照射15min。将混合物过滤并浓缩得到深褐色油,将该油经快速层析(25->50%乙酸乙酯-异己烷)纯化得到灰白色固体(24mg,23%)。
1H NMR(500MHz,DMSO-d6)δ:2.41(3H,s),4.13(3H,s),7.41(1H,dd,J4.5and 7.5Hz),7.67(2H,d,J8.4Hz),7.82(1H,d,J7.6Hz),8.13(2H,d,J8.7Hz),8.26(1H,dd,J1.7 and 8.6Hz),8.29(1H,s),8.58(1H,d,J3.9Hz),8.64(1H,8.6Hz),9.40(1H,s);MS(ES M+1)411.
实施例10
7-(3-甲基-2-吡啶基)-N-(4-三氟甲基苯基)吡啶并[3,4-d]哒嗪-4-胺
将中间体XII(83mg,0.35mmol)悬浮在POCl3(5mL)中,加热至100℃保持5h,并浓缩至干。将残渣悬浮在二噁烷(4ml)中,加入甲醇(4ml)以溶解混合物,然后于100℃用4-三氟甲基苯胺(0.217mL,1.74mmol.)处理过夜。将残渣过滤,在NaHCO3(饱和水溶液)/DCM之间分配,用DCM(×2)萃取水相。将有机相合并,用硫酸钠干燥,浓缩得到褐色油状残渣。经快速层析(洗脱剂:20->100%乙酸乙酯/异己烷)纯化得到灰白色固体(10mg,7%)。
1H NMR(500MHz,DMSO-d6)δ:2.57(3H,s),7.46(1H,dd,J4.5 and 7.5Hz),7.77(2H,d,J8.5Hz),7.84(1H,d,J8.5Hz),8.25(2H,d,J8.5Hz),8.46(1H,s),8.60(1H,d,J4.0Hz),9.44(1H,s),9.96(1H,s),10.07(1H,s);MS(ES M+1)382.
实施例11
4-二甲基氨基-6-(3-甲基吡啶-2-基)-N-(4-三氟甲基苯基)-1-酞嗪胺:
按实施例4中所述方法从中间体IX制备。经反相HPLC纯化;MS(ES M+1)424。
实施例12
6-(3-甲基吡啶-2-基)-4-(吗啉-4-基)-N-(4-三氟甲基苯基)-1-酞嗪胺
按实施例4中所述方法从中间体X制备。经反相HPLC纯化;MS(ES M+1)466。
实施例13
6-(3-甲氧基-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺
向中间体XIII(250mg,0.60mmol)、2-氯-3-甲氧基吡啶(95mg,0.66mmol)、1,1′-二(二苯膦基)二茂铁氯化钯(II)(22mg,0.030mmol)的1,4-二噁烷(4mL)溶液中加入碳酸钠溶液(1mL)。将反应混合物于150℃在Smith微波反应器中加热15min。将反应混合物倾入水中并用乙酸乙酯萃取。合并乙酸乙酯萃取液,用盐水洗涤,用硫酸镁干燥,过滤并减压蒸发。残渣经快速层析纯化,用乙酸乙酯为洗脱剂。合并合适组分,减压蒸发得到固体。将该固体用乙腈重结晶,过滤收集并干燥得到题述化合物。产量=55mg(23%)。
1H NMR(500MHz,DMSO-d6)δ:3.96(3H,s),7.51(1H,m),7.71(1H,d,J8.8Hz),7.73(2H d J8.6Hz)8.24(2H,d,J8.6Hz)8.38(1H,dd J4.6 and 1.0Hz),8.5(1H,d,8.4)8.62(1H,s),8.67(1H,d,J8.8)9.33(1H,s),9.60(1H,s);MS(ES M+1)397.
类似地制备:
实施例14
2-{2-[1-(4-三氟甲基苯基氨基)酞嗪-6-基]吡啶-3-基}丙-2-醇
1H NMR(500MHz,DMSO-d6)δ:1.33(6H,s),2.07(1H,s),5.00(1H,s),7.48(1H,dd,J4.6 and 8.1Hz),7.73(2H,d,J8.6Hz),8.00(1H,s),8.01(1H,s),8.16(1H,dd,J1.3 and 8.2Hz),8.24(2H,d,J8.6Hz),8.52(1H,dd,J1.1 and 4.5Hz),8.61(1H,d,J9.0Hz),9.26(1H,s),9.58(1H,s);MS(ES M+1)425.
实施例15
N-(4-三氟甲基苯基)-6-(5-三氟甲基-2-吡啶基)-1-酞嗪胺
1H NMR(400MHz,DMSO-d6)δ:7.73(2H,d,J8.6Hz),8.23(2H,d,J8.6Hz),8.43-8.50(2H,m),8.78(2H,dd,J2.3 and 1.6Hz),8.90(1H,s),9.17(1H,d,J1.2Hz),9.36(1H,s),9.63(1H,s);MS(ES M+1)435.
实施例16
N-(4-三氯甲基苯基)-6-(6-三氟甲基-2-吡啶基)-1-酞嗪胺
1H NMR(400MHz,DMSO-d6)δ:7.74(2H,d,J8.6Hz),8.02(1H,d,J7.4Hz),8.23(2H,d,J8.6Hz),8.33(1H,t,J7.8Hz),8.58(1H,d,J7.8Hz),8.73-8.79(2H,m),8.84(1H,d,J1.2Hz),9.39(1H,s),9.65(1H,s);MS(ES M+1)435.
实施例17
N-(4-三氟甲基苯基)-6-(4-三氟甲基-2-吡啶基)-1-酞嗪胺
1H NMR(400MHz,DMSO-d6)δ:7.73(2H,d,J8.6Hz),7.90(1H,dd,J0.8 and 5.1Hz),8.24(2H,d,J8.2Hz),8.62(1H,s),8.78(1H,s),8.84-8.86(1H,m),8.96(1H,d,J1.6Hz),9.07(1H,d,J5.1Hz),9.35(1H,s),9.65(1H,s);MS(ES M+1)435.
实施例18
6-(4-甲基-3-哒嗪基)-N-(4-三氟甲基苯基)-1-酞嗪胺
1H NMR(500MHz,DMSO-d6)δ:2.43(3H,s),7.73-7.77(3H,m),8.25(2H,d,J8.6Hz)8.32(1H,m),8.39(1H,s),8.78(1H,d,J8.8Hz),9.18(1H,d,J5.1Hz),9.34(1H,s),9.66(1H,s).
实施例19
6-(5-甲基-4-嘧啶基)-N-(4-三氯甲基苯基)-1-酞嗪胺
1H NMR(500MHz,DMSO-d6)δ:2.61(3H,s),7.73(2H,d,J8.6Hz),8.23(2H,d,J8.3Hz),8.28(1H,s),8.79(2H,s),8.94(1H,s),9.23(1H,s),9.36(1H,s),9.65(1H,s).
实施例20
6-(3-甲基-2-吡嗪基)-N-(4-三氟甲基苯基)-1-酞嗪胺
1H NMR(500MHz,DMSO-d6)δ:2.67(3H,s),7.73(2H,d,J8.8Hz),8.23(2H,d,J8.6Hz),8.32(1H,m),8.39(1H,s),8.65(2H,m),8.75(1H,d,J8.6Hz),9.33(1H,s),9.64(1H,s).
实施例21
N-(4-三氟甲基苯基)-6-(4-三氟甲基-3-哒嗪基)-1-酞嗪胺
1H NMR(500MHz,DMSO-d6)δ:7.66(2H,d,J8.6Hz),8.1(2H,d,J8.6Hz),8.21(1H,d,J8.6Hz),8.24(1H,d,J5.4Hz),8.29(1H,s),8.66(1H,d,J8.6Hz),9.22(1H,s),9.61(1H,d,J5.5Hz).
实施例22
N-(4-叔丁基苯基)-6-(3-甲基-2-吡啶基)-1-酞嗪胺盐酸盐
将1-氯-6-(3-甲基-2-吡啶基)酞嗪(200mg,0.78mmol)和4-叔丁基苯胺(117mg,0.125mL,0.78mmol)的1,4-二噁烷溶液加热回流2h。冷却至室温后,过滤收集沉淀,用1,4-二噁烷洗涤并干燥得到题述化合物(135mg)(43%)。
1H NMR(500MHz,DMSO-d6)δ:1.35(9H,s),7.48(1H,dd,J4.9 and 7.6Hz),7.55-7.61(4H,m),7.90(1H,dd,J0.8 and 7.8Hz),8.47(1H,dd,J1.6 and 8.6Hz),8.52(1H,d,J2.0Hz),8.63(1H,dd,J1.2 and 4.7Hz),9.09(1H,d,J 8.6),9.32(1H,s);MS(ES M+1)369.
类似地制备:
实施例23
N-(4-氟苯基)-6-(3-甲基-2-吡啶基)-1-酞嗪胺
1H NMR(500MHz,DMSO-d6)δ:2.42(3H,s),7.22(2H,t,J 8.8),7.42(1H,dd,J4.7 and 7.4),7.83(1H,d,J7.8),7.98(2H,dd,J5.1 and 8.2),8.19-8.22(2H,m),8.58(1H,d,J3.9),8.66(1H,d,J8.6),9.20(1H,s),9.28(1H,s).
实施例24
6-(2-甲氧基苯基)-N-(4-三氟甲基苯基)-1-酞嗪胺
向中间体II(200mg,0.54mmol)、2-甲氧基苯基硼酸(123.8mg,0.814mmol)和[1,1′-二(二苯膦基)二茂铁]氯化钯(II)(0.0199g,0.027mmol)中加入碳酸钠溶液(1mL)和1,4-二噁烷(4mL)。将反应混合物于150℃在Smith微波反应器中加热15min,得到MS(ES M+1)396的产物。将反应混合物倾入水中并用二氯甲烷萃取。合并二氯甲烷萃取液,用硫酸镁干燥,过滤并减压蒸发得到油。该油经快速层析纯化,以(90->50%)异己烷/乙酸乙酯(1∶1)梯度洗脱。合并合适组分并减压蒸发得到固体。将该固体用乙腈重结晶,过滤收集并干燥得到题述化合物(0.095g,44%)。
1H NMR(400MHz,DMSO-d6)δ:3.83(3H,s),7.11-7.15(1H,m),7.22(1H,d,J8.2Hz),7.45-7.51(2H,m),7.72(2H,d,J8.6Hz),8.17(1H,s),8.23(2H,d,J8.2Hz),8.63(1H,d,J8.6),9.26(1H,s),9.56(1H,s);MS(ES M+1)396.
实施例25
6-(2-氰基苯基)-N-(4-三氟甲基苯基)-1-酞嗪胺
使用实施例24所述方法由2-(4,4,5,5-四甲基[1,3,2]二氧杂硼杂环戊烷-2-基)苯甲腈和中间体II制备题述化合物。
1H NMR(400MHz,DMSO-d6)δ:7.69-7.75(3H,m,),7.83(1H,d,J7.0Hz),7.91(1H,m),8.08(1H,dd,J0.8 and 7.8Hz),8.24(1H,d,J8.6Hz),8.27(1H,dd,J1.95 and 8.6Hz),8.32(1H d,J1.2Hz)8.78(1H,d,J8.6Hz),9.33(1H,s),9.66(1H,s);MS(ES M+1)391.
实施例26
3-(3-甲基吡啶-2-基)-N-(4-三氟甲基苯基)吡啶并[2,3-d]哒嗪-8-胺
向5-溴-3-甲基吡啶-2-甲酸乙酯(1.6g,6.95mmol)和过氧化苯甲酰(84.23mg,0.347mmol)的四氯化碳(20mL)溶液中加入N-溴琥珀酰亚胺(2.47g,13.91mmol)。将反应混合物加热回流3h。再加入等量N-溴琥珀酰亚胺和过氧化苯甲酰(85mg),再继续回流7h。由MS监测反应。10h后,产物为主峰。将反应混合物冷却,经硅藻土过滤并用四氯化碳洗涤。将滤液减压蒸发得到油2.7g。将该油(2.7g,6.9615mmol)和水合肼(2.4mL)的乙醇溶液加热回流过夜。减压蒸发溶剂,将残渣溶入用2NHCl酸化的水中得到固体,将该固体过滤收集并用水洗涤,用甲苯共沸干燥。产量=0.9g。将粗产物和磷酰氯于60℃加热1h。减压蒸发过量的磷酰氯得到固体3-溴-8-氯吡啶并[2,3-d]哒嗪(0.97g)。将该物质与甲苯共沸,然后用4-氨基三氟甲苯(0.64g,0.495mL,3.97mmol)的1,4-二噁烷(20ml)溶液处理,于40℃加热1h。减压蒸发溶剂,将残渣在乙酸乙酯和碳酸钠溶液之间分配。将乙酸乙酯萃取液合并,用盐水洗涤,用硫酸镁干燥,过滤并减压蒸发得到油。将该油经快速层析纯化,以(90->50%)异己烷/乙酸乙酯梯度洗脱。合并合适组分并减压蒸发得到3-溴-N-(4-(三氟甲基)苯基)吡啶并[2,3-d]哒嗪-8-胺(100mg)。
1H NMR(500MHz,DMSO-d6)δ:7.73(2H,d,J8.6Hz),8.41(2H,d,J8.8Hz),8.91(1H,d,J2.2Hz),9.25(1H,s),9.33(1H,d,J2.2Hz),10.05(1H,s).
将该胺按实施例4反应得到题述化合物。
1H NMR(500MHz,DMSO-d6)δ:2.49(3H,s),7.49(1H,dd,J4.8 and 7.7Hz),7.76(2H,d,J8.6Hz),7.90(1H,dd,J0.5 and 7.1Hz),8.47(2H,d,J8.6Hz),8.66(1H,dd,J0.5 and4.2Hz),8.80(1H,d,J2.0Hz),9.39(1H,s),9.48(1H,d,J2.0Hz),10.10(1H,s);MS(ES M+1)382.
以下化合物按上述方法制备:
实施例27
N-(4-乙氧羰基苯基)-6-(3-甲基-2-吡啶基)-1-酞嗪胺
1H NMR(500MHz,DMSO-d6)δ:1.34(3H,t,J7.1Hz),2.43(3H,s),4.33(2H,q,J7.1Hz),7.42(1H,dd,J4.8 and 7.7Hz),7.84(1H,dd,J0.7 and 7.6Hz),7.98(2H,d,J8.8Hz),8.17(2H,d,J8.8Hz),8.24(1H,dd,J1.5 and 8.3Hz),8.28(1H,s),8.59(1H,dd,J1.1 and 4.8Hz),8.72(1H,d,J8.8Hz),9.32(1H,s),9.63(1H,s).
实施例28
6-(3,5-二氟-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺
1H NMR(500MHz,DMSO-d6)δ:7.73(2H,d,J8.6Hz),8.20-8.25(3H,m),8.52(1H,d,J8.6Hz),8.59(1H,s),8.76(2H,dd,J6.7 and 2.0Hz),9.38(1H,s),9.64(1H,s).
实施例29
6-(3-氰基-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺
1H NMR(400MHz,DMSO-d6)δ:7.73-7.77(3H,m),8.24(2H,d,J8.2Hz),8.50(1H,dd,J 1.8 and 8.8Hz),8.55-8.59(2H,m),8.81(1H,d,J8.6Hz)9.06(1H,dd,J1.8 and 4.9Hz)9.38(1H,s),9.69(1H,s).
实施例30
6-(3-乙氧羰基-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺
1H NMR(500MHz,DMSO-d6)δ:0.98(3H,t,J7.1Hz),4.15(2H,q,J7.1Hz),7.67(1H,dd,J4.9 and 7.8Hz),7.73(2H,d,J8.8Hz),8.16(1H,dd,J2.0 and 8.6Hz),8.21-8.25(3H,m),8.33(1H,dd,J1.7 and 7.8Hz),8.69(1H,d,J8.6Hz),8.92(1H,dd,J1.6 and 4.8Hz),9.33(1H,s),9.63(1H,s).
实施例31
6-(3-(1-氟-1-甲基乙基)-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺
1H NMR(500MHz,DMSO-d6)δ:1.58(3H,s),1.62(3H,s),7.54-7.57(1H,m),7.73(2H,d,J8.6Hz),8.01-8.04(3H,m),8.23(2H,d,J8.6Hz),8.64(2H,dd,J1.6 and4.8Hz),9.27(1H,s),9.60(1H,s).
实施例32
N-(4-三氟甲基苯基)-2-(3-氯-2-吡啶基)吡啶并[2,3-d]哒嗪-5-胺
1H NMR(400MHz),CDCl3δ:7.08-7.18(1H,m),7.38-7.43(1H,m),7.68(2H,d,J6.3Hz),7.92(2H,d,J6.6Hz),8.06-8.21(1H,m),8.70(1H,d,J3Hz),8.78-8.88(1H,m),8.94-9.01(1H,m).
实施例33
N-(5-三氟甲基-2-吡啶基)-2-(3-三氟甲基-2-吡啶基)吡啶并[2,3-d]哒嗪-5-胺
将中间体XVI(56.9mg,1.96×10-4mol)溶于二噁烷(4ml)中,加入2-溴-5-三氟甲基吡啶(44mg,196μmol)、碳酸铯(90mg)、Xantphos(6.3mg)和三(二亚苄基丙酮)二钯(O)(4.2mg)。将反应物脱气(鼓泡通入N2)并加热回流。搅拌16h后,将反应物冷却至室温,经硅藻土过滤(用乙酸乙酯洗涤)。然后将该反应物用饱和碳酸氢钠猝灭,用乙酸乙酯萃取三次,用硫酸钠干燥,过滤并浓缩。柱层析(30%乙酸乙酯/己烷),然后甲醇研磨,得到产物(63mg,73%)。
1H NMR(400MHz),DMSO-d6δ:7.93-7.91(1H,m),8.24(1H,dd,J8.4,2.4Hz),8.39(1H,d,J8.4Hz),8.42(1H,d,J8.1Hz),8.55(1H,dd,J8.0,1.2Hz),8.60(1H,d,J8.1Hz),8.85(1H,s),9.0(1H,s),9.10(1H,dd,J4.4,0.8Hz),9.23(1H,d,J8.8Hz).
Claims (10)
1.一种式(I)化合物或其药学上可接受的盐:
其中Ar为苯基、含1、2或3个氮原子的六元杂芳基、或含1、2、3或4个选自氧、氮和硫的杂原子且最多一个杂原子为氧或硫的五元杂芳基,Ar任选被1、2或3个独立选自以下的基团取代:卤素、羟基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基、氨基、卤代C1-6烷基、卤代C2-6烯基、卤代C2-6炔基、羟基C1-6烷基、羟基C2-6烯基、羟基C2-6炔基、氰基、硝基、氨基C1-6烷基、氨基C2-6烯基、氨基C2-6炔基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷基硫基、C1-6烷氧羰基、卤代C1-6烷氧基、卤代C2-6烯氧基、卤代C2-6炔氧基、NR4R5、CONR4R5或CO2NR4R5,其中各R4和R5独立为氢或C1-6烷基;
R1为苯基、含1、2或3个氮原子的六元杂芳基、或含1、2、3或4个选自氧、氮和硫的杂原子且最多一个杂原子为氧或硫的五元杂芳基,Ar任选被1、2或3个独立选自以下的基团取代:卤素、羟基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基、氨基、卤代C1-6烷基、卤代C2-6烯基、卤代C2-6炔基、羟基C1-6烷基、羟基C2-6烯基、羟基C2-6炔基、氰基、硝基、氨基C1-6烷基、氨基C2-6烯基、氨基C2-6炔基、C1-6烷基磺酰基、C1-6烷基亚磺酰基、C1-6烷基硫基、C1-6烷氧羰基、卤代C1-6烷氧基、卤代C2-6烯氧基、卤代C2-6炔氧基、NR4R5、CONR4R5或CO2NR4R5,其中R4和R5定义同上;
R2为氢、卤素、羟基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基、NR6R7,其中R6和R7独立为氢、C1-6烷基或C1-6羟烷基,或R6和R7与它们所连接的氮原子一起形成任选含氧环原子的4、5或6-元稳定杂环;
R3为氢或C1-6烷基;
各X、Y和Z为N或CR8,其中R8为氢、卤素或C1-6烷基。
2.权利要求1的化合物,其中Z为N,且X和Y为CH。
3.权利要求1或2的化合物,其中R1为对位取代的苯基或吡啶基。
4.权利要求1、2或3的化合物,其中Ar为在Ar与该分子其余部分的连接位点相邻的环位置被单取代的吡啶基。
5.前述权利要求中任一项的化合物,其中R2为氢、二甲氨基或吗啉代。
6.权利要求1的化合物或其药学上可接受的盐,所述化合物为:
1)N-(4-三氟甲基苯基)-6-(3-三氟甲基-2-吡啶基)-1-酞嗪胺;
2)6-(3-氟-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
3)N-(4-(叔丁基苯基)-6-(3-三氟甲基-2-吡啶基)-1-酞嗪胺;
4)6-(3-甲基-2-吡啶基)-N-(4-(三氟甲基苯基)-1-酞嗪胺;
5)6-(3-甲基-2-吡啶基)-N-(4-三氟甲氧基苯基)-1-酞嗪胺;
6)6-(2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
7)N-(4-三氟甲基苯基)-2-(3-三氟甲基-2-吡啶基)吡啶并[2,3-d]哒嗪-5-胺;
8)6-(1-甲基-1H-咪唑-2-基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
9)4-甲氧基-6-(3-甲基-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
10)7-(3-甲基-2-吡啶基)-N-(4-三氟甲基苯基)吡啶并[3,4-d]哒嗪-4-胺;
11)4-二甲基氨基-6-(3-甲基吡啶-2-基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
12)6-(3-甲基吡啶-2-基)-4-(吗啉-4-基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
13)6-(3-甲氧基-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
14)2-{2-[1-(4-三氟甲基苯基氨基)酞嗪-6-基]吡啶-3-基}丙-2-醇;
15)N-(4-三氟甲基苯基)-6-(5-三氟甲基-2-吡啶基)-1-酞嗪胺;
16)N-(4-三氟甲基苯基)-6-(6-三氟甲基-2-吡啶基)-1-酞嗪胺;
17)N-(4-三氟甲基苯基)-6-(4-三氟甲基-2-吡啶基)-1-酞嗪胺;
18)6-(4-甲基-3-哒嗪基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
19)6-(5-甲基-4-嘧啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
20)6-(3-甲基-2-吡嗪基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
21)N-(4-三氟甲基苯基)-6-(4-三氟甲基-3-哒嗪基)-1-酞嗪胺;
22)N-(4-叔丁基苯基)-6-(3-甲基-2-吡啶基)-1-酞嗪胺盐酸盐;
23)N-(4-氟苯基)-6-(3-甲基-2-吡啶基)-1-酞嗪胺;
24)6-(2-甲氧基苯基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
25)6-(2-氰基苯基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
26)3-(3-甲基吡啶-2-基)-N-(4-三氟甲基苯基)吡啶并[2,3-d]哒嗪-8-胺;
27)N-(4-乙氧羰基苯基)-6-(3-甲基-2-吡啶基)-1-酞嗪胺;
28)6-(3,5-二氟-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
29)6-(3-氰基-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
30)6-(3-乙氧羰基-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
31)6-(3-(1-氟-1-甲基乙基)-2-吡啶基)-N-(4-三氟甲基苯基)-1-酞嗪胺;
32)N-(4-三氟甲基苯基)-2-(3-氯-2-吡啶基)吡啶并[2,3-d]哒嗪-5-胺;和
33)N-(5-三氟甲基-2-吡啶基)-2-(3-三氟甲基-2-吡啶基)吡啶并[2,3-d]哒嗪-5-胺。
7.一种药用组合物,所述组合物包含权利要求1-6中任一项的化合物或其药学上可接受的盐和药学上可接受的赋形剂。
8.权利要求1-6中任一项的化合物或其药学上可接受的盐,所述化合物或其药学上可接受的盐用于治疗人或动物身体的治疗方法中。
9.权利要求1-6中任一项的化合物或其药学上可接受的盐在制备用于治疗或预防疼痛和/或炎症的药物中的用途。
10.一种在患有疼痛和/或炎症或有疼痛和/或炎症倾向的患者中治疗或预防疼痛和/或炎症的方法,所述方法包括给予该患者治疗有效量的权利要求1的化合物或其药学上可接受的盐。
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GBGB0310726.5A GB0310726D0 (en) | 2003-05-09 | 2003-05-09 | Therapeutic agents |
GB0310726.5 | 2003-05-09 |
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US (1) | US7329659B2 (zh) |
EP (1) | EP1625119B1 (zh) |
JP (1) | JP2006525984A (zh) |
CN (1) | CN1816541A (zh) |
AT (1) | ATE402166T1 (zh) |
AU (1) | AU2004236014A1 (zh) |
CA (1) | CA2524622A1 (zh) |
DE (1) | DE602004015277D1 (zh) |
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WO (1) | WO2004099177A1 (zh) |
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US7759337B2 (en) * | 2005-03-03 | 2010-07-20 | Amgen Inc. | Phthalazine compounds and methods of use |
JP2008532956A (ja) * | 2005-03-05 | 2008-08-21 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | ヒドロキシテトラヒドロ−ナフタレン誘導体の使用 |
TWI392670B (zh) * | 2006-06-22 | 2013-04-11 | Ucb Pharma Gmbh | 經取代的2-胺基萘滿之於製造用於預防、減緩及/或治療各種類型疼痛之藥物上的用途 |
CA2661436A1 (en) * | 2006-08-24 | 2008-02-28 | Serenex, Inc. | Isoquinoline, quinazoline and phthalazine derivatives |
EP2131656A4 (en) | 2006-11-15 | 2011-12-07 | Forest Lab Holdings Ltd | phthalazine |
JP2010043063A (ja) * | 2008-05-09 | 2010-02-25 | Agency For Science Technology & Research | 川崎病の診断及び治療 |
US8772481B2 (en) | 2008-10-10 | 2014-07-08 | Amgen Inc. | Aza- and diaza-phthalazine compounds as P38 map kinase modulators and methods of use thereof |
WO2010042649A2 (en) | 2008-10-10 | 2010-04-15 | Amgen Inc. | PHTHALAZINE COMPOUNDS AS p38 MAP KINASE MODULATORS AND METHODS OF USE THEREOF |
US8546388B2 (en) * | 2008-10-24 | 2013-10-01 | Purdue Pharma L.P. | Heterocyclic TRPV1 receptor ligands |
US11083199B2 (en) | 2017-01-10 | 2021-08-10 | Bayer Aktiengesellschaft | Heterocycle derivatives as pesticides |
TWI820231B (zh) | 2018-10-11 | 2023-11-01 | 德商拜耳廠股份有限公司 | 用於製備經取代咪唑衍生物之方法 |
US20230247994A1 (en) | 2020-07-02 | 2023-08-10 | Bayer Aktiengesellschaft | Heterocyclene derivatives as pest control agents |
US20230312482A1 (en) * | 2020-07-28 | 2023-10-05 | Mirati Therapeutics, Inc. | Sos1 inhibitors |
DE102022104759A1 (de) | 2022-02-28 | 2023-08-31 | SCi Kontor GmbH | Co-Kristall-Screening Verfahren, insbesondere zur Herstellung von Co-Kristallen |
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US3240781A (en) | 1965-01-06 | 1966-03-15 | Vantorex Ltd | 1-lower alkyl-4-anilinophthalazines |
GB1293565A (en) | 1969-05-03 | 1972-10-18 | Aspro Nicholas Ltd | Aminophthalazines and pharmaceutical compositions thereof |
GB9707693D0 (en) | 1997-04-16 | 1997-06-04 | Smithkline Beecham Plc | Novel method of treatment |
WO2003062209A2 (en) | 2002-01-17 | 2003-07-31 | Neurogen Corporation | Substituted quinazolin-4-ylamine analogues as modulators of capsaicin |
DE60335635D1 (de) | 2002-05-22 | 2011-02-17 | Amgen Inc | Aminopyrimidin-derivate zur verwendung als vanilloid-rezeptor-liganden zur behandlung von schmerzen |
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- 2004-05-04 AU AU2004236014A patent/AU2004236014A1/en not_active Abandoned
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EP1625119A1 (en) | 2006-02-15 |
DE602004015277D1 (de) | 2008-09-04 |
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EP1625119B1 (en) | 2008-07-23 |
US7329659B2 (en) | 2008-02-12 |
CA2524622A1 (en) | 2004-11-18 |
JP2006525984A (ja) | 2006-11-16 |
GB0310726D0 (en) | 2003-06-11 |
AU2004236014A1 (en) | 2004-11-18 |
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WO2004099177A1 (en) | 2004-11-18 |
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