CN1856473A - 异喹啉酮钾通道抑制剂 - Google Patents
异喹啉酮钾通道抑制剂 Download PDFInfo
- Publication number
- CN1856473A CN1856473A CNA2004800273785A CN200480027378A CN1856473A CN 1856473 A CN1856473 A CN 1856473A CN A2004800273785 A CNA2004800273785 A CN A2004800273785A CN 200480027378 A CN200480027378 A CN 200480027378A CN 1856473 A CN1856473 A CN 1856473A
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- CN
- China
- Prior art keywords
- group
- compound
- following composition
- alkyl
- isoquinoline
- 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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- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 22
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- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 208000003663 ventricular fibrillation Diseases 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 229950003419 zatebradine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
本发明涉及结构式(I)的化合物,该化合物可用来作为治疗心律不齐等的钾通道抑制剂。
Description
技术领域
本发明广泛涉及可用来作为钾通道抑制剂的化合物。这一类化合物可以用来作为治疗和预防心律不齐等的Kv1.5拮抗剂,和作为治疗免疫抑制、自免疫疾病等的Kv1.3抑制剂。
背景技术
电压启闭的钾通道(Kv)是多体膜蛋白,由4种α子单元组成,而且往往与副β子单元相联系。Kv通道典型地在休止膜电位关闭,但在膜去极化时打开。它们参与动作电位的再极化、从而参与神经纤维和肌肉纤维的电应激性。Kv1类钾通道包含至少7个家族成员,即Kv1.1、Kv1.3、Kv1.5等。功能性电压启闭的K+通道可以要么作为由相同子单元组成的均低聚物、要么作为有不同子单元组成的杂低聚物存在。人们认为这个现象解释了K+通道的广泛多样性。然而,天然K+通道的子单元组成和特定通道所发挥的生理作用在大多数情况下仍然是不清楚的。
Kv1.3电压启闭的钾通道是在神经元、血细胞、破骨细胞和T-淋巴细胞中发现的。有人显示Kv1.3抑制引起的膜去极化是防止T细胞增殖的有效方法,因而在很多自免疫病症中得到应用。有人假设人T-淋巴细胞的质膜中K+通道的抑制在通过调节胞内Ca++稳衡作用来引起免疫抑制反应方面发挥一定作用,已经发现这在T-细胞激活方面是重要的。已经有人提出Kv1.3通道的阻塞作为一种诱发免疫抑制反应的新机理(Chandy等,J.Exp.Med.160:369,1984;Decoursey等,Nature,307:465,1984)。然而,这些早期研究中采用的K+通道阻塞剂是非选择性的。在稍后的研究中,有人显示出只阻塞T细胞中的Kv1.3的Margatoxin在离体模型和活体模型都显示免疫抑制活性(Lin等,J.Exp.Med.177:637,1993)。然而,这种化合物的治疗效用受到其剧烈毒性的限制。最近,有人报告了一类化合物可能是上述药物的引人瞩目替代物(美国专利Nos.5,670,504;5,631,282;5,696,156;5,679,705;和5,696,156)。虽然解决了以上药物的一些活性/毒性问题,但这些化合物倾向于有大分子量而且一般是由天然产物的合成操作生产的,其分离是麻烦和费劳力的。
心房纤维性颤动(AF)是临床实践中最常见的持续心律不齐,而且其流行随人口老化而增加。保守的估计指出AF影响200多万美国人,占心血管病总住院人数的5%以上,并导致中风风险增加3~5倍(Kannel等,Am.J.Cardiol.,82:2N-9N,1998)。虽然AF很少致命,但它会损害心脏功能并导致并发症例如充血性心力衰竭、血栓栓塞、或心室纤维性颤动的发展。
已经有人显示再进入激发(再活动)是一种奠定人室上心律不齐的重要机理(Nattel,S.,Nature,415:219-226,2002)。再进入激发需要缓慢输导速度与充分简短不应期之间的临界平衡,使得能启动和维持多个再活动回路,以使AF同时共存和维持。通过延长动作电位持续期(APD)增加心肌不应性预防和/或终止再活动心律不齐。动作电位持续期决定于再极化钾电流IKr、IKs、和IKur、以及瞬间朝外电流Ito的分布。因此,这些电流中任何一种的阻塞剂都可望增加APD和产生抗心律不齐效应。
目前可供利用的抗心律不齐剂是为治疗心室和心房/室上心律不齐开发的。恶性心室心律不齐是立即威胁生命的并需要紧急护理。心室心律不齐的药物疗法包括类别Ia(例如普鲁卡因酰胺、奎尼丁)、类别Ic(例如氟卡尼、普罗帕酮)、类别III(胺碘酮)药剂,这些引起前心律不齐的显著风险。这些类别I和III药物已被证实会使AF转化成窦性心律和防止AF复发(Mounsey,JP,DiMarco,JP,Circulation,102:2665-2670),但引起潜在致死性心室前心律不齐的不可接受风险,从而可能增加死亡率(Pratt,CM,Moye,LA,Am J.Cardiol.,65:20B-29B,1990;Waldo等,Lancet,348:7-12,1996;Torp-Pedersen等,Expert Opin.Invest.Drugs,9:2695-2704,2000)。这些观察证实发展心房心律不齐治疗用的更安全和更有效药物的一种清楚的、未得到满足的医学需要。
类别IU抗心律不齐药剂引起APD的选择性延长而不显著抑制心脏传导或抑制功能。已证明临床上用于心房纤维性颤动的唯一选择性类别III药物是多非利特,它通过阻塞IKr传递其抗心律不齐效应,在人的心房和心室中都发现IK的迅速激活成分(Mounsey,JP,Circulation,102:2665-2670)。由于IKr阻塞剂增加心房和心室中的APD和不应性而不影响传导本身,理论上它们代表AF等心律不齐的治疗的潜在有用药剂(Torp-Pedersen等,Expert Opin.Invest.Drugs,9:2695-2704,2000)。然而,这些有在慢心率时提高前心率不齐风险的重大倾向。例如,当利用这些化合物时,已经观察到Torsades de点(Roden,D.M.“类别III抗心律不齐药物治疗现状”,Am J.Cardiol.,72:44B-49B,1993)。这种在慢心率时加剧的效应称为“逆频率依赖性”,而且与频率依赖作用或正向频率依赖作用成鲜明对照(Hondeghem,L.M.“类别III抗心律不齐剂的发展”,J.Cardiovasc.Cardiol.,20(Suppl.2):S17-S22)。胺碘酮已被显示具有令人感兴趣的类别III性能(Singh B.N.,Vaughan Williams E.M.“第三类抗心律不齐作用:MJ1999和AH3747对心房和心室胞内电位的影响和对心肌的其它药理学作用”Br.J.Pharmacol.39:675-689,1970;Singh B.N.,Vaughan Williams E.M,“胺碘酮—一种新型抗心绞痛药物—对心肌的影响”,Br.J.Pharmacol.,39:657-667,1970),尽管它不是一种选择性类别III药剂,因为它影响多种离子通道;此外,由于其副作用形象,其用途受到严格限制(Nademanee,K.“The AmiodaroneOdyssey”,J.Am.Coll.Cardiol.,20:1063-1065,1992;Fuster等,Circulation,104:2118-2150;Bril,A.Curr.Opin.Pharmacol.2:154-159,2002)。因此,当前可供利用的药剂例如胺碘酮和类别III药物产生有害效应的显著风险,包括发展潜在致死性心室前心律不齐。
在人心房而不是在心室中,尤其已经观察到超速延迟的整流器K+电流IKur。人心房中IKur的分子相关是指定为Kv1.5的钾通道。Kv1.5mRNA(Bertaso,Sharpe,Hendry,和James,Basic Res.Cardiol.,97:424-433,2002)和蛋白质(Mays,Foose,Philipson,和Tamkun,J.Clin.Invest.,96:282-292,1995)已经在人心房组织中检测到。在完整的人心房肌细胞中,已经确认了也称为持久性外向电流Isus或Iso的超速激活延迟整流器K+电流(IKur),这种电流具有与由人K+通道纯系(hKv1.5,HK2)表达的那些相同的性能和动力学[Wang,Fermini和Nattel,Circ.Res.73:1061-1076,1993;Fedida等,Cire.Res.73:210-216,1993;Snyders,Tamkun和Bennett,J.Gen.Physiol.,101:513-543,1993],来自大鼠大脑的类似纯系也如此(Swanson等,Neuron,4:929-939,1990)。进而,由于其激活迅速和有限的缓慢失活,相信IKur对人心房的再极化有显著贡献。因此,IKur的特定阻塞剂,即能阻塞Kv1.5的化合物,会通过人心房再极化的推迟来延长不应性而克服其它化合物的缺点,不引起成为心律不齐性后去极化的基础的心室再极化延迟,并获得用当前类别III药物治疗期间观察到的长QT综合征。显示这些性能的Kv1.5阻塞剂的描述见(Peukert等,J.Med.Chem.,46:486-498,2003;Knobloch等,Naunyn-Schmedieberg’sArch.Pharmacol.366:482-287,2002;Merck & Co.,Inc.WOO224655,2002)。
本发明中描述的化合物代表一类新颖结构的Kv1.5拮抗剂。
发明内容
本发明涉及通用结构式I的钾通道抑制剂
本发明的化合物可用于治疗和预防心律不齐等。也在本发明范围内的是包含式I化合物和药物载体的药物制剂。
具体实施方式
本发明是式I的化合物
或药物上可接受盐、结晶形式、或水合物,式中
A是
a)一种芳基环,其中任何一个稳定的芳基环原子都独立地是无取代的或有下列基团取代
1)卤素,
2)NO2,
3)CN,
4)CR46=C(R47R48)2,
5)C≡CR46,
6)(CRiRj)rOR46,
7)(CRiRj)rN(R46R47),
8)(CRiRj)rC(O)R46,
9)(CRiRj)rC(O)OR46,
10)(CRiRj)rR46,
11)(CRiRj)rS(O)0-2R61,
12)(CRiRj)rS(O)0-2N(R46R47),
13)OS(O)0-2R61,
14)N(R46)C(O)R47,
15)N(R46)S(O)0-2R61,
16)(CRiRj)rN(R46)R61,
17)(CRiRj)rN(R46)R61OR47,
18)(CRiRj)rN(R46)(CRkRl)sC(O)N(R47R48),
19)N(R46)(CRiRj)rR61,
20)N(R46)(CRiRj)rN(R47R48),
21)(CRiRj)rC(O)N(R47R48),或
22)氧代,或
b)一种杂芳基环,选自下列组成的一组:
一个5员不饱和单环式环,有1、2、3或4个选自N、O或S组成的一组的杂原子环原子,
一个6员不饱和单环式环,有1、2、3或4个选自N、O或S组成的一组的杂原子环原子,和
一个9员或10员员不饱和双环式环,有1、2、3或4个选自N、O或S组成的一组的杂原子环原子;
其中,任何稳定的S杂芳基环原子是无取代的或者有氧代一取代或二取代的,和任何稳定的C或N杂芳基环原子独立地是无取代的或有下列基团取代:
1)卤素,
2)NO2,
3)CN,
4)CR46=C(R47R48)2,
5)C≡CR46,
6)(CRiRj)rOR46,
7)(CRiRj)rN(R46R47),
8)(CRiRj)rC(O)R46,
9)(CRiRj)rC(O)OR46,
10)(CRiRj)rR46,
11)(CRiRj)rS(O)0-2R61,
12)(CRiRj)rS(O)0-2N(R46R47),
13)OS(O)0-2R61,
14)N(R46)C(O)R47,
15)N(R46)S(O)0-2R61,
16)(CRiRj)rN(R46)R61,
17)(CRiRj)rN(R46)R61OR47,
18)(CRiRj)rN(R46)(CRkRl)sC(O)N(R47R48),
19)N(R46)(CRiRj)rR61,
20)N(R46)(CRiRj)rN(R47R48),
21)(CRiRj)rC(O)N(R47R48),或
22)氧代;
R1选自下列组成的一组:
1)氢,
2)(CRaRb)nR40
3)(CRaRb)nOR40,
4)(CRaRb)nN(R40R41),
5)(CRaRb)nN(R40)C(O)OR41,
6)(CRaRb)nN(R40)(CRcRd)2N(R41)C(O)R49,
7)C3-8环烷基,
8)(CRaRb)nC(O)OR40,
9)(CRaRb)nN(R40)(CRcRd)1-3R41,
10)(CRaRb)nS(O)0-2R6,
11)(CRaRb)nS(O)0-2N(R40R41),
12)(CRaRb)nN(R40)R6OR41,
13)(CRaRb)nN(R40)(CRcRd)0-6C(O)N(R41R42);
R5选自下列组成的一组:
1)C(O)N(R55R50),
2)C(O)OR55,和
3)C(O)R82;
R2、R8、R9和R10独立地选自:
1)氢,
2)卤素,
3)NO2,
4)CN,
5)CR43=C(R44R45),
6)C≡CR43,
7)(CReRf)pOR43,
8)(CReRf)pN(R43R44),
9)(CReRf)pC(O)R43,
10)(CReRf)pC(O)OR43,
11)(CReRf)pR43,
12)(CReRf)pS(O)O-2R60,
13)(CReRf)pS(O)0-2N(R43R44),
14)OS(O)0-2R60,
15)N(R43)C(O)R44,
16)N(R43)S(O)0-2R60,
17)(CReRf)pN(R43)R60,
18)(CReRf)pN(R43)R60OR44,
19)(CReRf)pN(R43)(CRgRh)qC(O)N(R44R45),
20)N(R43)(CReRf)pR60,
21)N(R43)(CReRf)pN(R44R45),和
22)(CReRf)pC(O)N(R43R44),
Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh、Ri、Rj、Rk和Rl独立地选自下列组成的一组:
1)氢,
2)C1-C6烷基,
3)卤素,
4)芳基,
5)R80,
6)C3-C10环烷基,和
7)OR4,
所述烷基、芳基、和环烷基是无取代的,有R7一取代的,有R7和R15二取代的,有R7、R15和R16三取代的,或有R7、R15、R16和R17四取代的;
R4、R40、R41、R42、R43、R44、R45、R46、R47、R48、R49、R50、R51、R52、和R55独立地选自下列组成的一组:
1)氢,
2)C1-C6烷基,
3)C3-C10环烷基,
4)芳基,
5)R81,
6)CF3,
7)C2-C6链烯基,和
8)C2-C6链炔基,
所述烷基、芳基、和环烷基是无取代的,有R18一取代的,有R18和R19二取代的,有R18、R19和R20三取代的,或有R18、R19、R20和R21四取代的;
R6、R60、R61、和R62独立地选自下列组成的一组:
1)C1-C6烷基,
2)芳基,
3)R83,和
4)C3-C10环烷基;
所述烷基、芳基、和环烷基是无取代的,有R26一取代的,有R26和R27二取代的,有R26、R27和R28三取代的,或有R26、R27、R28和R29四取代的;
R7、R15、R16、R17、R18、R19、R20、R21、R26、R27、R28、和R29独立地选自下列组成的一组:
1)C1-C6烷基,
2)卤素,
3)OR51,
4)CF3,
5)芳基,
6)C3-C10环烷基,
7)R84,
8)S(O)0-2N(R51R52),
9)C(O)OR51,
10)C(O)R51,
11)CN,
12)C(O)N(R51R52),
13)N(R51)C(O)R52,
14)S(O)0-2R62,
15)NO2,和
16)N(R51R52);
R80、R81、R82、R83、和R84独立地选自下列一组:由有1、2、3或4个选自N、O和S组成的一组的杂原子环原子的4~6员不饱和或饱和的单环式环组成的无取代或有取代杂环式环,和有1、2、3或4个选自N、O或S组成的一组的杂原子环原子的9员或10员不饱和或饱和双环式环;且
n、p、q、r、和s独立地是0、1、2、3、4、5或6。
在本发明的一类化合物或其药物上可接受盐中,
A是一个选自如以上定义的无取代或有取代的苯基的芳基环,或如以上定义的无取代或有取代的杂芳基环,选自下列组成的一组:吡啶、嘧啶、吡嗪、哒嗪、吲哚、吡咯并吡啶、苯并咪唑、苯并唑、苯并噻唑、和苯并二唑;
R2、R8、R9和R10独立地选自下列组成的一组:
1)氢,
2)卤素,
3)OR43,和
4)(CReRf)pR43,
R1选自下列组成的一组:
1)氢,
2)(CRaRb)1-2R40
3)(CRaRb)1-2OR40,
4)(CRaRb)1-2N(R40R41),
5)(CRaRb)1-2N(R40)C(O)OR41,
6)(CRaRb)1-2N(R40)(CRcRd)2N(R41)C(O)R49,
7)(CRaRb)1-2C(O)OR40,
8)(CRaRb)1-2N(R40)(CRcRd)1-3R41,和
9)环丙基。
在这一类化合物的一个小类或其药物上可接受盐中,
R2、R8、R9和R10独立地选自下列组成的一组:
1)氢,
2)卤素,和
3)(CReRf)pOR43。
在这一小类化合物的一群或其药物上可接受盐中,
R1选自下列组成的一组:
1)氢,
2)(CRaRb)nR40,和
3)(CRaRb)nOR40。
在这一群化合物的一个小群或其药物上可接受盐中,
A是一个芳基环,其中该芳基环原子是无取代的或有卤素取代的;且
R5选自下列组成的一组:
1)C(O)N(R55R50),
2)C(O)OR55,和
3)C(O)R82。
在这一小群化合物的一个家族或其药物上可接受盐中,
R1是-CH3、-CH2CHCH2、或环丙基;
R2和R10是氢;
R8是氢或-OCH3;
R9是氢或-OCH3;和
R5选自下列组成的一组:
一种较好的实施方案是一种选自下列组成的一组的化合物:
4-(3-氟苯基)-6-甲氧基-N,N,2-三甲基-1-氧代-1,2-二氢异喹啉-3-羧酰胺,
4-(3-氟苯基)-6-甲氧基-2-甲基-3-(吡咯烷-1-基羰基)异喹啉-1(2H)-酮,
2-烯丙基-6-甲氧基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酰胺,
6-甲氧基-2-甲基-4-苯基-3-吡啶-2-基异喹啉-1(2H)-酮,
2-环丙基-6-甲氧基-4-苯基-3-(1,3-噻唑-2-基)异喹啉-1(2H)-酮,
4-(3-氟苯基)-6-甲氧基-2-甲基-1-氧代-1,2-二氢异喹啉-3-羧酸甲酯,
6-甲氧基-2-甲基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸甲酯,
7-甲氧基-2-甲基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸,
7-甲氧基-2-甲基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸甲酯,和
2-甲基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸乙酯,
或其药物上可接受盐。
以上所列化合物是在以下所述一种或多种Kv1.5试验中有活性的。
本发明的另一种实施方案是哺乳动物中病症的治疗或预防方法,该病症的治疗或预防是通过Kv1.5抑制进行或促进的,该方法包含给药Kv1.5抑制有效量的式I化合物。
一种较好的实施方案是哺乳动物中心律不齐例如心房纤维性颤动、心房扑动、心房心律不齐、和室上性心搏过速的治疗或预防方法,该方法包含给药治疗有效量的式I化合物。
另一种较好的实施方案是血栓栓塞事件例如中风的预防方法。
另一种较好的实施方案是充血性心力衰竭的预防方法。
另一种较好的实施方案是免疫抑制或涉及免疫抑制的病症例如艾滋病、癌症、老年性痴呆、创伤(包括伤口愈合、外科和休克)慢性细菌感染、某些中枢神经系统疾病、和器官或组织移植引起的包括抗性的病症、骨髓移植引起的移植物对宿主疾病的治疗或预防方法。这种实施方案内,有通过给药本发明化合物和免疫抑制化合物治疗或预防免疫抑制的方法。
另一种较好的实施方案是神经质瘤的治疗或预防方法,包括低级和高级恶性肿瘤的治疗或预防方法,较好高级恶性肿瘤的治疗或预防方法。
另一种较好的实施方案是有心房纤维性颤动的患者中诱发标准窦性心律病症的方法,其中诱发的心律对应于会被认为对于与该患者有类似块头和年龄特征的个体来说是正常的心律,该方法包含用本发明化合物治疗该患者。
另一种较好的实施方案是患者中心动过速(即快心率,例如100次/分钟)的治疗方法,该方法包含用抗心动过速器具(例如去纤颤器或起搏器)与权利要求1的化合物组合治疗该患者。
本发明也涵盖一种药物制剂,包含药物上可接受载体和式I的化合物或其药物上可接受晶体形式或其水合物。一种较好的实施方案是式I化合物的药物组合物,该组合物还包含一种第二药剂。
本发明的化合物可以有不对称中心或不对称轴,而且本发明包括所有旋光异构体及其混合物。除非另外专门提及,否则对一种异构体的参照适用于两种异构体。
此外,有碳-碳双键的化合物可以以Z-形式和E-形式存在,该化合物的所有异构体形式都包括在本发明中。
如本文中所使用的,除另有说明者外,“烷基”意在包括有规定碳原子数的支化链和直链饱和脂肪族烃基,包括所有异构体。在本说明书全文中都使用烷基的常用缩略语,例如,甲基可以由“Me”或CH3代表,乙基可以由“Et”或CH2CH3,丙基可以由“Pr”或CH2CH2CH3,丁基可以由“Bu”或CH2CH2CH2CH3代表等。“C1-6烷基”(或“C1-C6烷基”),例如,系指有规定碳原子数的直链或支化链烷基,包括所有异构体。C1-6烷基包括己基烷基和戊基烷基的所有异构体以及正丁基、异丁基、仲丁基和叔丁基、正丙基和异丙基、乙基和甲基。“C1-4烷基”系指正丁基、异丁基、仲丁基和叔丁基,正丙基和异丙基,乙基和甲基。“烷氧基”这一术语代表经由氧桥连接的所指出碳原子数的直链或支化链烷基。
“链烯基”这一术语包括含有至少两个由双键连接的碳原子的支化链和直链不饱和烃基。链烯烃乙烯,例如,由“CH2CH2”或替而代之由“H2C=CH2”代替。“C2-5链烯基”(或“C2-C5链烯基”),例如,系指有2~5个碳原子的直链或支化链链烯基,而且包括戊烯基的所有异构体以及1-丁烯基、2-丁烯基、3-丁烯基、1-丙烯基、2-丙烯基、和乙烯基。类似的术语“C2-3链烯基”有相似的含义。
“链炔基”这一术语包括含有至少两个由三键连接的碳原子的支化链和直链不饱和烃基。链炔烃乙炔,例如,由“CHCH”或替而代之由“HC≡CH”代表。“C2-5链炔基”(或“C2-C5链炔基”),例如,系指有2~5个碳原子的直链或支化链链炔基,而且包括戊炔基的所有异构体以及1-丁炔基、2-丁炔基、3-丁炔基、1-丙炔基、2-丙炔基、和乙炔基。类似的术语“C2-3链炔基”有相似的含义。
除非另有说明,否则烷基、链烯基和链炔基是无取代的或者在每个碳原子上有1~3个取代基取代,取代基包括卤素、C1-C20烷基、CF3、NH2、N(C1-C6烷基)2、NO2、氧代、CN、N3、-OH、-O(C1-C6烷基)、C3-C10环烷基、C2-C6链烯基、C2-C6链炔基、(C0-C6烷基)S(O)0-2、(C0-C6烷基)S(O)0-2(C0-C6烷基)-、(C0-C6烷基)C(O)NH-、H2N-C(NH)-、-O(C1-C6烷基)CF3、(C0-C6烷基)C(O)-、(C0-C6烷基)OC(O)-、(C0-C6烷基)O(C1-C6烷基)、(C0-C6烷基)C(O)1-2(C0-C6烷基)-、(C0-C6烷基)OC(O)NH-、芳基、芳烷基、杂环、杂环基烷基、卤芳基、卤芳烷基、卤杂环、卤杂环基烷基、氰芳基、氰芳烷基、氰杂环、和氰杂环基烷基。
“C0”这一术语当用于“C0-6烷基”等表达中时系指直连共价键。类似地,当定义一个基团中某一数目原子的存在的整数等于零时,它系指与其相邻的原子是由一个键直接连接的。例如,在结构
中,式中w是等于零、1或2的整数,当w为零时该结构是
“C3-8环烷基”(或“C3-C8环烷基”)这一术语系指一种有总共3~8个碳原子的链烷的环状环(即环丙基、环丁基、环戊基、环己基、环庚基、或环辛基)。“C3-7环烷基”、“C3-6环烷基”、“C5-7环烷基”等术语有相似的含义。
“卤素”(或“卤”)这一术语系指氟、氯、溴和碘(替而代之,简称为氟(F)、氯(Cl)、溴(Br)、和碘(I))。
“C1-6卤烷基”(还可以简称为“C1-C6卤烷基”或“卤化C1-C6烷基”)这一术语系指有一个或多个卤素取代基的如以上定义的C1-C6直链或支化链烷基。“C1-4卤烷基”这一术语有相似的含义。“C1-6氟烷基”这一术语除卤素取代基限定于氟外有相似的含义。适用的氟烷基包括(CH2)0-4CF3这一系列(即三氟甲基、2,2,2-三氟乙基、3,3,3-三氟正丙基等)。
本文中使用的“碳环”(及其变异例如“碳环的”或“碳环基”)这一术语,除非另有指出,否则系指(I)C3-C8单环的饱和或不饱和环或(ii)C7-C12双环的饱和或不饱和环系。(ii)中的每个环都要么独立于要么稠合于另一个环,而且每个环都是饱和的或不饱和的。该碳环可以连接到该分子的其余部分任何一个能导致一种稳定化合物的碳原子。稠合的双环式碳环是碳环的一个子集;即,“稠合双环式碳环”这一术语一般地系指一种C7-C10双环式环系,其中每个环都是饱和的或不饱和的而且两个相邻碳原子是由该环系中每个环共享的。一个环是饱和环、另一个环也是饱和环的稠合双环式碳环是饱和双环式环系。一个环是苯环、另一个环是饱和环的稠合双环式碳环是不饱和双环式环系。一个环是苯环、另一个是不饱和环的稠合双环式碳环是不饱和环系。饱和碳环式环也简称为环烷基环,例如环丙基、环丁基等。除非另有说明,否则碳环是无取代的或有C1-6烷基、C1-6链烯基、C1-6链炔基、芳基、卤素、NH2或OH取代的。稠合双环式不饱和碳环的一个子集是一个环为苯环、另一个环为饱和环或不饱和环并经由任何一个能导致一种稳定化合物的碳原子连接的双环式碳环。这个子集的代表性实例包括下列:
“芳基”这一术语系指芳香族单碳环和多碳环环系,其中,多环系中各个碳环式环是稠合的或经由单键相互连接的。适用的芳基包括苯基、萘基、和联苯基。
“杂环”(及其变异,例如“杂环的”或“杂环基”)这一术语广义地指(i)稳定的4~8员饱和或不饱和单环式环,或(ii)稳定的7~12员双环式环系,其中(ii)中每个环都独立于或稠合于另外一个或多个环,且每个环都是饱和的或不饱和的,而且单环式环或双环式环系含有一个或多个选自N、O和S的杂原子(例如1~6个杂原子、或1~4个杂原子)和碳原子余额(单环式环典型地含有至少一个碳原子,而环系典型地含有至少两个碳原子);且其中氮和硫杂原子中任何一个或多个任选地是氧化的,氮杂原子中任何一个或多个任选地是季铵化的。该杂环式环可以连接在任何一个杂原子或碳原子上,先决条件是该连接导致一种稳定结构的产生。当该杂环式环有取代基时,要理解的是,该取代基可以连接到该环上任何一个原子,无论杂原子还是碳原子,先决条件是产生一个稳定的化学结构。
如本文中使用的,“有取代C3-C10环烷基”、“有取代芳基”和“有取代杂环”这些术语意在包括除与该化合物的其余部分的连接点外含有1~3个取代基的环状基团。较好,该取代基选自包括但不限于下列的基团:卤素、C1-C20烷基、CF3、NH2、N(C1-C6烷基)2、NO2、氧代、CN、N3、-OH、-O(C1-C6烷基)、C3-C10环烷基、C2-C6链烯基、C2-C6链炔基、(C0-C6烷基)S(O)0-2-、(C0-C6烷基)S(O)0-2(C0-C6烷基)-、(C0-C6烷基)C(O)NH-、H2N-C(NH)-、-O(C1-C6烷基)CF3、(C0-C6烷基)C(O)-、(C0-C6烷基)OC(O)-、(C0-C6烷基)O(C1-C6烷基)-、(C0-C6烷基)C(O)1-2(C0-C6烷基)-、(C0-C6烷基)OC(O)NH-、芳基、芳烷基、杂芳基、杂环基烷基、卤芳基、卤芳烷基、卤杂环、卤杂环基烷基、氰芳基、氰芳烷基、氰杂环和氰杂环基烷基。
饱和杂环族化合物形成杂环的一个子集;即“饱和杂环的”这一术语一般地指如以上定义的杂环,其中整个环系(无论单环的还是多环的)是饱和的。“饱和杂环式环”这一术语系指4~8员饱和单环式环或稳定的7~12员双环式环系,该环系由碳原子和一个或多个选自N、O和S的杂原子组成。代表性实例包括哌啶基、哌嗪基、azepanyl、吡咯烷基、吡唑烷基、咪唑烷基、唑烷基、异唑烷基、吗啉基、噻吗啉基、噻唑烷基、异噻唑烷基、和四氢呋喃基。
杂芳香族化合物形成杂环的另一个子集;即,“杂芳香族”(替而代之“杂芳基”)一般地指以上定义的杂环,其中整个环系(无论单环的还是多环的)是一种芳香族环系。“杂芳香族环”这一术语系指5员或6员单环式芳香族环或7~12员双环式芳香族环系,后者由碳原子和一个或多个选自N、O和S的杂原子组成。杂芳香族环的代表性实例包括吡啶基、吡咯基、吡嗪基、嘧啶基、哒嗪基、噻吩基(或苯硫基)、噻唑基、呋喃基、咪唑基、吡唑基、三唑基、四唑基、唑基、异唑基、二唑、噻唑基、异噻唑基、和噻二唑基。
双环式杂环的代表性实例包括苯并三唑基、吲哚基、异吲哚基、吲唑基、二氢吲哚基、异二氢吲哚基、喹喔啉基、喹唑啉基、噌啉基、苯并二氢吡喃基、异苯并二氢吡喃基、四氢喹啉基、喹啉基、四氢异喹啉基、异喹啉基、2,3-二氢苯并呋喃基、2,3-二氢苯并1,4-二氧芑基(即
)、咪唑并(2,1-b)(1,3)噻唑(即
)、和苯并-1,3-二氧杂环戊烯基(即
)。在本文中的某些范畴内,
替而代之地简称为有连接到两个相邻碳原子上的亚甲二氧基作为取代基的苯基。
除非明确地作出相反陈述,否则“不饱和”环是一种部分不饱和或完全不饱和的环。例如,“不饱和单环式C6碳环”系指环己烯、环己二烯、和苯。
除非明确地作出相反陈述,否则本文中提到的所有范围都是包括所指出极限的。例如,描述为含有“1~4个杂原子”的杂环系指该杂环可以含有1、2、3或4个杂原子。
当在描绘和描述本发明的化合物的任何成分中或任何化学式中任何变量出现不止一次时,其每次出现时的定义独立于其每另外一次出现时的定义。此外,取代基和/或变量的组合只有当这样的组合导致稳定化合物时才是许可的。
“有取代的”(例如,像在“任选地有一个或多个取代基取代的芳基...”中那样)这一术语包括所列举取代基的一取代和多取代,达到化学上允许这样的单一取代和多次取代(包括同一部位上的多次取代)的程度。
在有吡啶基N-氧化物片断的本发明化合物中,该吡啶基N-氧化物部分在结构上是使用有等效含义的
等惯常表述来描述的。
对于含有有重复项例如(CRiRj)r式中r是整数2、Ri是一个所定义的变量、Rj也是一个所定义的变量的项的可变定义来说,Ri的值在它出现的每一种情况下可以是不同的,Rj的值在它出现的每一种情况下也可以是不同的。例如,当Ri和Rj独立地选自甲基、乙基、丙基和丁基组成的一组时,(CRiRj)2可以是
药物上可接受盐包括金属(无机)盐和有机盐;其清单见Remington’s Pharmaceutical Sciences,17th Edition,p1418(1985)。业内技术人员众所周知的是,适当的盐形式是根据物理的和化学的稳定性、流动性、吸湿性和溶解性选择的。如同业内技术人员会理解的那样,药物上可接受盐包括但不限于无机酸的盐例如盐酸盐、硫酸盐、磷酸盐、二磷酸盐、氢溴酸盐、和硝酸盐,或有机酸的盐例如苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乙酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐或棕榈酸盐、水杨酸盐、和硬脂酸盐。类似地药物上可接受阳离子包括但不限于钠、钾、钙、铝、锂和铵(尤其与仲胺的铵盐)。由于以上提到的理由,本发明的较好盐包括钾、钠、钙和铵盐。本发明范围内也包括的是式I化合物的晶体形式、水合物和溶剂合物。
本发明化合物的制备方法用以下流程说明,其中变量R是氢或C1-C6烷基,R1、R49、和R50如以上定义,而变量R3是一个取代基,选自以上作为当A是有取代芳基环时可能的取代基所列的一组取代基。其它合成方案对于业内技术人员来说将是显而易见的。
流程1
流程2
流程3
以下实施例说明式I化合物的制备,但不要认为这些实施例是对本文所附权利要求书中提出的本发明的限制。
实施例I
7-甲氧基-2-甲基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸甲酯(5)的制备
步骤A 三氟甲磺酸4-甲氧基-2-苯甲酰基-5-甲氧基苯酯(1)
将三氟甲磺酸酐(9.6ml,57mmol)添加到(2-羟基-4-甲氧基苯基)(苯基)甲酮(10g,44mmol)和三乙胺(10.7ml,61mmol)的二氯甲烷(200ml)0℃溶液中。让反应混合物逐渐回升到室温过夜。然后,将混合物倾到冰上,用乙醚(500ml)萃取。萃取液用1N HCl洗涤、然后用水洗涤、然后用10%Na2CO3洗涤、用Na2SO4干燥。过滤、浓缩,得到一种暗棕色油。当添加4∶1己烷/EtOAc(意向色谱法溶剂)时,形成一种白色结晶固体。将其滤出、用少量乙醚充分洗涤、然后用一些己烷洗涤。干燥给出7.27g白色结晶固体状产品。将合并的滤液蒸发,残渣用乙醚和己烷同样处理,进一步给出5.95g乳油色结晶固体状产品。总产率13.22g,84%。
步骤B 2-苯甲酰基-5-甲氧基苄腈(2)
起始三氟甲磺酸酯2(5.95g,16.5mmol)、Zn(CN)2(1.36g,11.6mol)和(Ph3P)4Pd(0.76g,0.6mmol)在DMF(20ml)中的混合物在80℃加热过夜。然后,让反应应冷却到室温,用甲苯稀释。该混合物用20%氨水溶液洗涤2次、用食盐水洗涤1次、然后干燥(MgSO4)。浓缩给出一种黄色油,后者用闪急色谱法(7∶3己烷/EtOAc)精制,给出白色结晶固体状产品2。产率3.48g,89%。
步骤C 2-苯甲酰基-5-甲氧基苯甲酸(3)
将6M HCl(20ml)添加到腈2(3g,12.6mmol)的二烷(20ml)溶液中。所得到的无色混合物在100℃加热3小时。然后将反应混合物冷却到室温,在减压下脱除二烷,给出一种白色悬浮液。这种悬浮液用冰冷却、用2N NaOH碱化。用二氯甲烷萃取、用冰再冷却、用6M HCl酸化。所得到的白色悬浮液用二氯甲烷、然后用氯仿、然后用EtOAc萃取。合并的萃取液干燥(Na2SO4)、浓缩,给出白色粉末状酸3(3.2g,99%)。
步骤D [(2-苯甲酰基-5-甲氧基苯甲酰基)(甲基)氨基]乙酸甲酯(4)
将Hunig’s碱(1.7ml,9.8mmol)添加到酸(0.5g,2.0mmol)、胺HCl(0.42g,3.9mmol)和BOP试剂(1g,2.3mmol)的DMF(6ml)室温溶液中。1小时后,完全转化成酰胺。将反应混合物倾到冰上、用乙醚萃取。萃取液用NaHCO3水溶液、水、1N HCl、水、然后食盐水洗涤,干燥(Na2SO4)、浓缩,给出浅黄色粘性固体状酰胺4。
步骤E 7-甲氧基-2-甲基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸甲酯(5)
将来自上一步骤的酰胺4溶解在甲醇(10ml)中,用25%NaOMe甲醇溶液(1ml)处理。然后,所得到的黄色混合物在65℃加热1小时。冷却到室温后,反应混合物用1M HCl二烷溶液酸化。所得到的混合物过滤去除NaCl。滤液浓缩、残渣用自动闪急色谱法精制。MS[M+H]+324.2
实施例II
7-甲氧基-2-甲基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸(6)的制备
将酯
5(180mg,0.56mmol)悬浮在乙醇(5ml)中。添加1M KOH(1ml),所得到的混合物在80℃加热。在数分钟内得到一种均匀溶液。2小时后,将反应混合物冷却、用1M HCl酸化。在减压下脱除乙醇,向残渣中加水。混合物过滤、残渣用水充分洗涤、干燥,给出酸
6。MS[M+H]+310.2
实施例III
4-(3-氟苯基)-6-甲氧基-2-甲基-1-氧代-1,2-二氢异喹啉-3-羧酸甲酯(8)的制备
步骤A 2-(3-氟苯甲酰基)-5-甲氧基苯甲酸(7)
将-78℃用90分钟时间将仲丁基锂(52ml,1.4M戊烷溶液,72mmol)添加到大茴香酸(5g,33mmol)和TMEDA(11ml,72mmol)的THF(80ml)溶液中。搅拌15分钟后,一次添加3-氟苯甲酸乙酯(5ml,40mmol)。将反应混合物搅拌15分钟,然后用水(20ml)使反应终止。然后使反应混合物回升到室温、倾入水(1.5L)中、添加1N NaOH(30ml)、然后反应混合物用EtOAc萃取。将萃取液抛弃。然后,水相用浓HCl酸化到pH 1,用EtOAc萃取。干燥(Na2SO4)和浓缩给出一种残渣,后者用己烷/EtOAc重结晶,给出白色固体状标题化合物。
步骤B 4-(3-氟苯基)-6-甲氧基-2-甲基-1-氧代-1,2-二氢异喹啉-3-羧酸甲酯(8)
酯
8是从酸
7基本上按照实施例I步骤D和E中为酯
5所述的程序制备的。
MS[M+H]+342.2
实施例IV
6-甲氧基-2-甲基-4-苯基-3-吡啶-2-基异喹啉-1(2H)-酮(10)的制备
步骤A 2-苄基-4-甲氧基-N-甲基苯甲酰胺(9)
酰胺
9是从大茴香酰氯按照公开的程序(WO 02/24655)制备的。
步骤B 6-甲氧基-2-甲基-4-苯基-3-吡啶-2-基异喹啉-1(2H)-酮(10)
将n-BuLi(1.6M己烷溶液,17.6ml,28mmol)添加到酰胺
9(3g,12mmol)的THF(70ml)-78℃溶液中。搅拌30分钟之后,添加2-皮考基氯HCl(3.1g,8.8mmol)。搅拌30分钟之后,反应混合物用水终止反应、然后回升到室温。将反应混合物浓缩、残渣在水与EtOAc之间分配。有机相干燥(Na2SO4)、浓缩。残渣用闪急色谱法精制。
C22H18N2O2的HRMS(ES):理论值343.1441,实测值343.1449。
实施例V
4-(3-氟苯基)-6-甲氧基-2-甲基-1-氧代-1,2-二氢异喹啉-3-羧酸(11)的制备
酸(11)是基本上按照实施例II中酸
6的程序制备的。
实施例VI
4-(3-氟苯基)-6-甲氧基-N,N,2-三甲基-1-氧代-1,2-二氢异喹啉-3-羧酰胺(12)的制备
将
11的酰氯(80mg,0.mmol mmol)添加到含有催化量DMAP的过量二甲胺在二氯乙烷中的室温溶液中。搅拌30分钟后,反应混合物用1M HCl、然后用食盐水洗涤。干燥(Na2SO4)和浓缩给出酰胺12。
C20H19N2O3F的HRMS(ES):理论值355.1453,实测值355.1476。
实施例VII
4-(3-氟苯基)-6-甲氧基-2-甲基-3-(吡咯烷-1-基羰基)异喹啉-1(2H)-酮(13)的制备
酰胺13是基本上按照前面的程序制备的。
C22H21N2O3F的HRMS(ES):理论值381.1609,实测值381.1579。
实施例VIII
2-环丙基-6-甲氧基-4-苯基-3-(1,3-噻唑-2-基)异喹啉-1(2H)-酮(17)的制备
步骤A N-(1,3-噻唑-2-基甲基)环丙胺(14)
将呋喃-2-醛(0.37g,3.9mmol)添加到环丙胺(0.2g,3.5mmol)的甲醇(6ml)溶液中。搅拌1小时之后,将反应混合物冷却到0℃,添加乙酸(少数几滴)和NaBH3CN(1.5eq)。搅拌1小时之后,反应混合物浓缩,残渣在EtOAc与NaHCO3之间分配。将有机层干燥(MgSO4)、浓缩,产物用闪急色谱法(10~25%EtOAc/己烷)精制。
步骤B 2-苯甲酰基-N-环丙基-4-甲氧基-N-(1,3-噻唑-2-基甲基)苯甲酰胺(15)
酰胺
15是从胺
14基本上按照实施例I步骤D使用对应的酸制备的。
步骤C 2-环丙基-4-羟基-6-甲氧基-4-苯基-3-(1,3-噻唑-2-基)-3,4-二氢异喹啉-1(2H)-酮(16)
化合物
16是基本上按照实施例I步骤E中所述程序通过酰胺
15的环化制备的。在这些条件下未观察到水的自发消除。
步骤D 2-环丙基-6-甲氧基-4-苯基-3-(1,3-噻唑-2-基)异喹啉-1(2H)-酮(17)
化合物
17是从化合物
16制备如下。将吡啶(1.2eq)和三氟甲磺酸酐(1.2eq)按顺序添加到
17(75mg,0.19mmol)的二氯甲烷-78℃溶液中。让反应混合物逐渐回升到室温。然后,反应混合物用水洗涤、干燥(MgSO4)。浓缩给出一种残渣,后者用自动闪急色谱法精制。MS[M+H]+375.2。
使用以下所述方法学评估本发明的代表性化合物,并发现其在Kv1.5试验中显示出活性,从而证实和确认本发明化合物作为Kv1.5抑制剂和抗心律不齐药的效用。这种类型的化合物可以显示出正向心律依赖性,在更快的去极化速率或心律时在更大程度上或优先阻塞外向K+电流。这样一种化合物可以在如下所述的电生理学研究中得到确认。例如,在以1Hz和3Hz的频率输送的一系列去极化期间,若在3Hz的10秒系列期间观察到的阻塞量大于1Hz的该阻塞量,则该阻塞是“速率依赖”的。Kv1.5阻塞剂也可以显示出使用依赖性,在此期间外向K+电流的阻塞随使用而增加,或在心细胞重复去极化期间亦然。在给定速率或频率的一系列或序列脉冲或去极化中,每个相继去极化都会在更大程度上发生阻塞的使用依赖性。例如,在频率为1Hz的一系列10个去极化期间,若该系列的第10个脉冲的阻塞量大于第1个脉冲的阻塞量,则该阻塞是“使用依赖”的。Kv1.5阻塞剂可以同时显示出使用依赖性和速率依赖性。
Kv1.5阻塞剂也可以通过使用来自各种不同物种包括但不限于人、大鼠、小鼠、狗、猴、雪貂、兔、豚鼠、或山羊的心肌细胞或其它组织进行的天然IKur的电生理学研究来确认。在天然组织中,Kv1.5可以作均低聚物或作为杂低聚物与其它Kv家族成员一起存在,也可以存在于与β-子单元的复合物中。本发明的化合物可以阻塞Kv1.5均低聚物或杂低聚物或与β-子单元的复合物中的Kv1.5。
Kv1.5试验
高通过量Kv1.5平面斑点夹持试验是一种系统的初步筛选。它证实活性,并提供专门影响Kv1.5钾通道的药剂的药效的功能尺度。Kiss等(Assay and Drug Dev.Tech.,1(1-2):127-135,2003)和Schroeder等(J.Of Biomo.Screen.,8(1),50-64,2003)描述了这种仪器对Kv1.5以及其它电压启闭离子通道的用途。
让稳定地表达从人心脏克隆的人Kv1.5钾通道α-子单元的中国鼠卵细胞(CHO)在补加了10%FBS、100U/ml青霉素、100μg/ml链霉素、1000μg/ml G418硫酸盐的Ham’s F12培养基中生长到90-100%合生。细胞通过用Versene处理分培、然后悬浮于磷酸盐缓冲的食盐水(PBS)中和离心分离。将细胞片状沉淀物再悬浮于PBS中,所得到的悬浮液放进Ion WorksTM HT仪器的细胞储槽中。
电生理学记录是用含有下列成分(mM)的胞内溶液进行的:K-葡糖酸盐100、KCl 40、MgCl2 3.2、EGTA 3、N-2-羟基乙基哌嗪-N1-2-乙磺酸(HEPES)5,调整到pH 7.3。两性霉素(Sigma公司)配制成30mg/ml储备溶液,再用内缓冲溶液稀释到0.1mg/ml的最终工作浓度。外溶液是Dulbecco’s PBS(Invitrogen公司),而且含有(mM):CaCl2 0.90,KCl 2.67,KPO4 1.47,MgCl2 0.50,NaCl 138,NaPO4 8.10,其pH为7.4。所有化合物都用DMSO配制成10mM储备溶液。在该实验期间,将化合物稀释到外缓冲剂中,然后从药物平皿转移到斑点式平皿(Patchplate)上(最终DMSO浓度<0.66vol%)。
Kv1.5离子电流是在室温记录的。将膜电流放大(RMS~10pA)并以10kHz采样。在所有实验中,漏减(leak subtraction)都是通过在试验脉冲前200ms施加一个160ms超极化(10mV)前脉冲以测定漏电导进行的。补片夹持刺激实验方案如下:
1.斑点式平皿孔中加入3.5μL外缓冲剂。
2.通过跨每个孔施加一个10mV 160ms电位差,测定平面微量移液管孔电阻(Rp)(孔试验)。
3.用移液管将细胞移至斑点式平皿上,并在每个斑点式平皿孔底部形成有1~2μm孔的高电阻密封。进行密封试验扫描,以确定该斑点式平皿孔中多少有形成了密封的细胞。
4.为了获得对细胞的电输入,让含有两性霉素的胞内溶液在该斑点式平皿底侧循环4分钟。
5.对该斑点式平皿上每个孔施加化合物添加前试验脉冲。实验方案:将细胞在-80mV的膜持有电位用电压钳夹持15秒。随后,施加一个5Hz刺激系列(27×150ms去极化到+40mV)。膜电位上升至+40mV,从而诱发外向(正)离子电流。
6.向该斑点式平皿的每个孔中添加化合物。让化合物培养5分钟。
7.运用化合物添加后试验脉冲实验方案。实验方案:将细胞在-80mV的膜持有电位用电压钳夹持15秒。随后,施加一个5Hz刺激系列(27×150ms去极化到+40mV)。
脱机进行数据分析。利用药物添加前与药物添加后之间的配对比较,确定每种化合物的抑制效果。将(5Hz系列中)第27次去极化到+40mV期间峰值对照电流的%抑制作为拮抗浓度的函数作图。通过Hill方程对浓度反应数据的拟合,确定使电流抑制50%所需要的药物浓度(IC50):
对照组的%=100×(1+([药物]/IC50)p)-1
对每个细胞都得到4个算术量度:
1)密封电阻,
2)基线量度(第一次去极化到+40mV之前5~45ms在-70mV的平均电流),
3)电流起转量度(第1次去极化到+40mV期间的化合物添加前平均电流幅度减第27次去极化到+40mV期间的化合物添加前平均电流幅度),
4)峰值电流(该5Hz系列中第27次去极化到+40mV期间的最大电流幅度)。
所有量度都是在化合物添加前轨迹和化合物添加后轨迹期间得到的。当出现下列情况时细胞不再进一步分析:
1)密封电阻<50MΩ,
2)在化合物添加前期间基线量度>±100pA,
3)电流起转量>-0.2nA,
4)读前峰值量度<400pA。
以上所列化合物在以上所述高通过量Kv1.5平面斑点夹持试验中在33μM或更低的浓度时提供≥20%抑制。
原子吸收光谱法实验方案
本试验使用火焰原子吸收光谱法(FAAS)确认专门阻塞CHO细胞中非均匀表达的人Kv1.5K+通道的药剂,如Rb+流量所量度的。FAAS对测定离子通道活性的应用是从Terstappen等,Anal.Biochem.,272:149-155,1999改进而来的。
表达人Kv1.5的CHO细胞是像以上所述那样培养、然后用胰蛋白酶-EDTA收割、用培养基洗涤的。
1.将40,000细胞/孔接种于一种96孔细胞培养板(试验板)上,让该细胞在37℃生长48小时。
2.将培养基去除,并在5%CO2下、在37℃、用3小时时间添加200μl Rb负荷缓冲剂(Aurora Biomed公司,加拿大不列颠哥伦比亚省温哥华)。
3.该细胞用200μl Hank’s平衡盐溶液(HBSS)洗涤5次,随后添加100μl含试验化合物或0.5%DMSO的HBSS。
4.10分钟后,添加100μl含有140mM KCl的HEPES缓冲食盐水,培养板在室温培养5分钟并缓缓摇荡。
5.此后立即将150μl上清液转移到一种新鲜的96孔培养板上,将其余上清液吸出。
6.将120μl溶胞缓冲剂(Aurora Biomed公司,加拿大不列颠哥伦比亚省温哥华)添加到试验板上、摇荡10分钟、然后分析。
7.用一台ICR-8000自动AAS仪器(Aurora Biomed公司,加拿大不列颠哥伦比亚省温哥华)测定上清液(SUP)和溶胞产物(LYS)样品中的Rb含量。
%FLUX=100%*(SUP/(LYS+SUP))。%INH=100%*(1-(A-B)/(C-B)),式中A是试验化合物存在下的%FLUX,B是10mM氯化(6-甲氧基-2-甲基-1-氧代-4-苯基-1,2-二氢异喹啉-3-基)-N,N-二甲基甲胺存在下的%FLUX,C是0.25%DMSO存在下的%FLUX。
以上所列化合物在以上所述AAS试验中在25μM或更小的浓度时提供≥25%抑制。
本发明的化合物可以通过任何一种能使有效成分化合物与温血动物体内的作用部位接触的手段,为按照本发明的病痛、疾病和病症的治疗或预防而给药。例如,给药可以是经口的,局部的,包括经皮的、经眼的、经颊的、经鼻内的、吸入的、经阴道内的、经直肠、经脑池内的和非经肠的。本文中使用的“非经肠”这一术语系指给药方式,包括皮下的、静脉内的、肌肉内的、关节内的、脑池内的和腹膜内的注射或输注。
这些化合物可以用任何一种可用于与医药配合使用的惯常手段,要么作为单个治疗剂、要么作为治疗剂组合给药。它们可以单独给药、但一般与根据所选择的给药途径和标准医药实践选择的药物载体一起给药。
为了本发明之目的,温血动物是具有体内平衡机理的动物王国的一员,包括哺乳动物和鸟类。
给药剂量将取决于受体的年龄、健康和体重、疾病程度,同时进行的治疗(如果有的话)的种类、治疗的频率、和所希望的效果的性质。通常,有效成分化合物的日剂量将是每日约1~500mg。一般来说,一次或多次施用的每日10~100mg就能有效地得到所希望的结果。这些剂量就是治疗和预防以上所述病痛、疾病和病症例如心律不齐如心房纤维性颤动、心房扑动、心房心律不齐、和室上心动过速、血栓栓塞事件如中风和充血性心力衰竭、和免疫抑制的有效量。
有效成分可以以固体剂型例如胶囊剂、片剂、糖锭、糖衣丸、颗粒剂和散剂或液体剂型例如酏剂、糖浆剂、乳状液剂、分散液剂、和悬浮液剂经口给药。该有效成分也可以以无菌液体剂型例如分散液剂、悬浮液剂、或溶液剂非经肠给药。也可以用来给药有效成分的其它剂型有局部给药用的软膏剂、霜剂、滴剂、经皮贴剂、或散剂,经眼给药用的眼科用溶液或悬浊液配方即滴眼药,吸入或经鼻内给药用的气雾剂喷雾或粉末组合物,或者经直肠或经阴道给药用的霜剂、软膏剂、喷雾剂或栓剂。
胶囊剂含有有效成分和粉末状载体例如乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸等。类似的稀释剂可以用来制作压缩片剂。片剂和胶囊剂都可以制造成缓释产品,以提供药剂在数小时时间内的连续释放。压缩片剂可以是糖包衣的或薄膜包衣的,以掩盖任何令人不快的味道和防止该片剂暴露于大气,或用于在胃肠道中选择性崩解的肠溶包衣。
经口给药用液体剂型可以含有着色剂和矫臭矫味剂以增加患者接受度。
一般来说,水、适用油、食盐水、右旋糖(葡萄糖)水溶液、和相关的糖溶剂以及二醇如丙二醇或聚乙二醇是非经肠溶液用适用载体。非经肠给药用溶液较好含有有效成分的水溶性盐、适用的稳定剂、和必要时缓冲物质。抗氧化剂例如亚硫酸氢钠、亚硫酸钠、或抗坏血酸,要么单独地要么组合地,是适用稳定剂。也使用的是柠檬酸及其盐和EDTA钠。此外,非经肠溶液可以含有防腐剂,例如氯化苯甲烃铵、羟基苯甲酸甲酯或丙酯、和氯丁醇。
适用的药物载体的描述见Remington’s Pharmaceutical Sciences,A.Osol,即本领域的一份标准参考文献。
对吸入法给药来说,本发明的化合物可以方便地以来自加压罐或喷雾器的气雾剂喷雾制剂形式输送。该化合物也可以作为可以配制的粉末输送,而该粉末组合物可以借助于吸入法粉末吸入器具吸入。较好的吸入输送系统是一种计量剂量吸入(MDI)气雾剂,可以将其配制成式I化合物在适用推进剂例如氟烃或烃类中的悬浮液或溶液。
对于经眼给药来说,眼科用制剂可以用式I化合物在适当眼科用载体中的适当wt%溶液或悬浮液配制,使得该化合物能与眼睛表面保持接触一段足够长时间,从而使该化合物能穿透角膜和眼睛的内部区域。
本发明化合物给药的有用医药剂型包括但不限于硬胶囊和软胶囊、片剂、非经肠注射剂、和经口悬浮液剂。
大量单元胶囊是通过灌装标准两件套硬胶囊制备的,每套灌装100mg粉末状有效成分、150mg乳糖、50mg纤维素、和6mg硬脂酸镁。
有效成分在可消化油例如大豆油、棉籽油或橄榄油中的混合物是借助于一种正置换泵制备并注射到明胶中的,形成含有100mg有效成分的软胶囊剂的。将该胶囊剂洗涤、干燥。
大量片剂是用惯常程序制备的,使得该剂量单元是100mg有效成分、0.2mg胶态二氧化硅、5mg硬脂酸镁、275mg微晶纤维素、11mg淀粉和98.8mg乳糖。可以施加适当包衣以提高适口性或延缓吸收。
适用于通过注射给药的非经肠组合物是通过在10vol%丙二醇中搅拌1.5wt%有效成分制备的。该溶液以注射用水稀释到规定体积、灭菌。
经口给药的水性悬浮液是这样配制的,使得每5ml含有mg微细有效成分、100mg羧甲基纤维素钠、5mg苯甲酸钠、1.0g山梨糖醇溶液(美国药典)、和0.025ml香草醛。
当本发明化合物是分步给药或与另一种治疗剂配合给药时,一般可以使用同样剂型。当医药以物理组合给药时,剂型和给药途径应当因所组合医药的兼容性而异加以选择。因此,共给药这一术语要理解为包括这两种药剂同时或顺序给药,或替而代之,作为这两种有效成分的固定剂量组合给药。
本发明化合物可以作为唯一有效成分或与一种第二有效成分的组合给药,该第二有效成分包括其它有Kv1.5阻塞活性的抗心律不齐药剂例如奎尼丁、普罗帕酮、氨巴利特、胺碘酮、氟卡尼、索他洛尔、溴苄铵、多非利特、阿莫兰特、苄普地尔、氯非铵,其它有Kv1.5阻塞活性的化合物例如克霉唑、酮康唑、布比卡因、红霉素、维拉帕米、硝苯地平、扎替雷定、双吲哚基马来酰亚胺,或其它心血管药剂例如但不限于ACE抑制剂,例如贝那普利、卡托普利、依那普利、福辛普利、赖诺普利、莫昔普利erbumine、喹那普利、雷米普利、和群多普利,血管紧张素II拮抗药例如坎得沙坦(candesartan)、依普沙坦(eprosartan)、irbesartan、氯沙坦、olmesartan、和缬沙坦,心苷例如地谷新、L-型钙通道阻塞剂、T-型钙通道阻塞剂、选择性和非选择性β阻塞剂,免疫抑制剂化合物、endothlin拮抗药、凝血酶抑制剂、阿司匹林、除阿司匹林外的非选择性NSAID例如萘普生、华法林、因子Xa抑制剂、低分子量肝素、未分馏肝素、氯吡格雷、噻氯匹啶、IIb/IIIa受体拮抗剂例如替罗非班(tirofiban)、5HT受体拮抗剂、氧基哌吲哚(integrin)受体拮抗剂、血栓烷(thromboxane)受体拮抗剂、TAFI抑制剂和P2T受体拮抗剂。本发明化合物也可以作为唯一有效成分或与起搏器或除纤颤器组合给药。
Claims (23)
1.以下结构的化合物
或药物上可接受盐、结晶形式、或水合物,式中
A是
a)一种芳基环,其中任何一个稳定的芳基环原子都独立地是无取代的或有下列基团取代
1)卤素,
2)NO2,
3)CN,
4)CR46=C(R47R48)2,
5)C≡CR46,
6)(CRiRj)rOR46,
7)(CRiRj)rN(R46R47),
8)(CRiRj)rC(O)R46,
9)(CRiRj)rC(O)OR46,
10)(CRiRj)rR46,
11)(CRiRj)rS(O)0-2R61,
12)(CRiRj)rS(O)0-2N(R46R47),
13)OS(O)0-2R61,
14)N(R46)C(O)R47,
15)N(R46)S(O)0-2R61,
16)(CRiRj)rN(R46)R61,
17)(CRiRj)rN(R46)R61OR47,
18)(CRiRj)rN(R46)(CRkRl)sC(O)N(R47R48),
19)N(R46)(CRiRj)rR61,
20)N(R46)(CRiRj)rN(R47R48),
21)(CRiRj)rC(O)N(R47R48),或
22)氧代,或
b)一种杂芳基环,选自下列组成的一组:
一个5员不饱和单环式环,有1、2、3或4个选自N、O或S组成的一组的杂原子环原子,
一个6员不饱和单环式环,有1、2、3或4个选自N、O或S组成的一组的杂原子环原子,和
一个9员或10员员不饱和双环式环,有1、2、3或4个选自N、O或S组成的一组的杂原子环原子;
其中,任何稳定的S杂芳基环原子是无取代的或者有氧代一取代或二取代的,和任何稳定的C或N杂芳基环原子独立地是无取代的或有下列基团取代:
1)卤素,
2)NO2,
3)CN,
4)CR46=C(R47R48)2,
5)C≡CR46,
6)(CRiRj)rOR46,
7)(CRiRj)rN(R46R47),
8)(CRiRj)rC(O)R46,
9)(CRiRj)rC(O)OR46,
10)(CRiRj)rR46,
11)(CRiRj)rS(O)0-2R61,
12)(CRiRj)rS(O)0-2N(R46R47),
13)OS(O)0-2R61,
14)N(R46)C(O)R47,
15)N(R46)S(O)0-2R61,
16)(CRiRj)rN(R46)R61,
17)(CRiRj)rN(R46)R61OR47,
18)(CRiRj)rN(R46)(CRkRl)sC(O)N(R47R48),
19)N(R46)(CRiRj)rR61,
20)N(R46)(CRiRj)rN(R47R48),
21)(CRiRj)rC(O)N(R47R48),或
22)氧代;
R1选自下列组成的一组:
1)氢,
2)(CRaRb)nR40
3)(CRaRb)nOR40,
4)(CRaRb)nN(R40R41),
5)(CRaRb)nN(R40)C(O)OR41,
6)(CRaRb)nN(R40)(CRcRd)2N(R41)C(O)R49,
7)C3-8环烷基,
8)(CRaRb)nC(O)OR40,
9)(CRaRb)nN(R40)(CRcRd)1-3R41,
10)(CRaRb)nS(O)0-2R6,
11)(CRaRb)nS(O)0-2N(R40R41),
12)(CRaRb)nN(R40)R6OR41,
13)(CRaRb)nN(R40)(CRcRd)0-6C(O)N(R41R42);
R5选自下列组成的一组:
1)C(O)N(R55R50),
2)C(O)OR55,和
3)C(O)R82;
R2、R8、R9和R10独立地选自:
1)氢,
2)卤素,
3)NO2,
4)CN,
5)CR43=C(R44R45),
6)C≡CR43,
7)(CReRf)pOR43,
8)(CReRf)pN(R43R44),
9)(CReRf)pC(O)R43,
10)(CReRf)pC(O)OR43,
11)(CReRf)pR43,
12)(CReRf)pS(O)0-2R60,
13)(CReRf)pS(O)0-2N(R43R44),
14)OS(O)0-2R60,
15)N(R43)C(O)R44,
16)N(R43)S(O)0-2R60,
17)(CReRf)pN(R43)R60,
18)(CReRf)pN(R43)R60OR44,
19)(CReRf)pN(R43)(CRgRh)qC(O)N(R44R45),
20)N(R43)(CReRf)R60,
21)N(R43)(CReRf)pN(R44R45),和
22)(CReRf)pC(O)N(R43R44),
或者R2和R8独立地如以上所定义,且R9和R10连同它们所连接的原子一起形成如下的环
Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh、Ri、Rj、Rk和Rl独立地选自下列组成的一组:
1)氢,
2)C1-C6烷基,
3)卤素,
4)芳基,
5)R80,
6)C3-C10环烷基,和
7)OR4,
所述烷基、芳基、和环烷基是无取代的,有R7一取代的,有R7和R15二取代的,有R7、R15和R16三取代的,或有R7、R15、R16和R17四取代的;
R4、R40、R41、R42、R43、R44、R45、R46、R47、R48、R49、R50、R51、R52、和R55独立地选自下列组成的一组:
1)氢,
2)C1-C6烷基,
3)C3-C10环烷基,
4)芳基,
5)R81,
6)CF3,
7)C2-C6链烯基,和
8)C2-C6链炔基,
所述烷基、芳基、和环烷基是无取代的,有R18一取代的,有R18和R19二取代的,有R18、R19和R20三取代的,或有R18、R19、R20和R21四取代的;
R6、R60、R61、和R62独立地选自下列组成的一组:
1)C1-C6烷基,
2)芳基,
3)R83,和
4)C3-C10环烷基;
所述烷基、芳基、和环烷基是无取代的,有R26一取代的,有R26和R27二取代的,有R26、R27和R28三取代的,或有R26、R27、R28和R29四取代的;
R7、R15、R16、R17、R18、R19、R20、R21、R26、R27、R28、和R29独立地选自下列组成的一组:
1)C1-C6烷基,
2)卤素,
3)OR51,
4)CF3,
5)芳基,
6)C3-C10环烷基,
7)R84,
8)S(O)0-2N(R51R52),
9)C(O)OR51,
10)C(O)R51,
11)CN,
12)C(O)N(R51R52),
13)N(R51)C(O)R52,
14)S(O)0-2R62,
15)NO2,和
16)N(R51R52);
R80、R81、R82、R83、和R84独立地选自下列一组:由有1、2、3或4个选自N、O和S组成的一组的杂原子环原子的4~6员不饱和或饱和的单环式环组成的无取代或有取代杂环式环,和有1、2、3或4个选自N、O或S组成的一组的杂原子环原子的9员或10员不饱和或饱和双环式环;且
n、p、q、r、和s独立地是0、1、2、3、4、5或6。
2.权利要求1的化合物或其药物上可接受盐,其中
A是一个选自如权利要求1中定义的无取代或有取代的苯基的芳基环,或如权利要求1中定义的无取代或有取代的杂芳基环,选自下列组成的一组:吡啶、嘧啶、吡嗪、哒嗪、吲哚、吡咯并吡啶、苯并咪唑、苯并唑、苯并噻唑、和苯并二唑;
R2、R8、R9和R10独立地选自下列组成的一组:
1)氢,
2)卤素,
3)OR43,和
4)(CReRf)pR43,
或者R2和R8独立地如以上所定义,且R9和R10连同它们所连接的原子一起形成如下的环
式中Rm是C1-C6烷基;
R1选自下列组成的一组:
1)氢,
2)(CRaRb)1-2R40
3)(CRaRb)1-2OR40,
4)(CRaRb)1-2N(R40R41),
5)(CRaRb)1-2N(R40)C(O)OR41,
6)(CRaRb)1-2N(R40)(CRcRd)2N(R41)C(O)R49,
7)(CRaRb)1-2C(O)OR40,
8)(CRaRb)1-2N(R40)(CRcRd)1-3R41,和
9)环丙基。
3.权利要求2的化合物或其药物上可接受盐,其中
R2、R8、R9和R10独立地选自下列组成的一组:
1)氢,
2)卤素,和
3)(CReRf)pOR43。
4.权利要求3的化合物或其药物上可接受盐,其中
R1选自下列组成的一组:
1)氢,
2)(CRaRb)nR40,和
3)(CRaRb)nOR40。
5.权利要求4的化合物或其药物上可接受盐,其中
A是一个芳基环,其中该芳基环原子是无取代的或有卤素取代的;且
R5选自下列组成的一组:
1)C(O)N(R55R50),
2)C(O)OR55,和
3)C(O)R82。
7.权利要求6的化合物或其药物上可接受盐,选自下列组成的一组:
4-(3-氟苯基)-6-甲氧基-N,N,2-三甲基-1-氧代-1,2-二氢异喹啉-3-羧酰胺,
4-(3-氟苯基)-6-甲氧基-2-甲基-3-(吡咯烷-1-基羰基)异喹啉-1(2H)-酮,
2-烯丙基-6-甲氧基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酰胺,
6-甲氧基-2-甲基-4-苯基-3-吡啶-2-基异喹啉-1(2H)-酮,
2-环丙基-6-甲氧基-4-苯基-3-(1,3-噻唑-2-基)异喹啉-1(2H)-酮,
4-(3-氟苯基)-6-甲氧基-2-甲基-1-氧代-1,2-二氢异喹啉-3-羧酸甲酯,
6-甲氧基-2-甲基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸甲酯,
7-甲氧基-2-甲基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸,
7-甲氧基-2-甲基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸甲酯,和
2-甲基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸乙酯。
8.哺乳动物中病症的治疗方法,其治疗是通过Kv1.5的抑制进行或促进的,该方法包含以能有效抑制Kv1.5的数量给药权利要求1的化合物。
9.权利要求8的方法,其中该病症是心律不齐。
10.权利要求9的方法,其中该心律不齐是心房纤维性颤动。
11.权利要求9的方法,其中该心律不齐选自下列组成的一组:心房扑动、心房心律不齐和室上性心动过速。
12.哺乳动物中病症的预防方法,其预防是通过Kv1.5的抑制进行或促进的,该方法包含以能有效抑制Kv1.5的数量给药权利要求1的化合物。
13.权利要求12的方法,其中该病症是心律不齐。
14.权利要求13的方法,其中该心律不齐是心房纤维性颤动。
15.权利要求13的方法,其中该心律不齐选自下列组成的一组:心房扑动、心房心律不齐和室上性心动过速。
16.权利要求12的方法,其中该病症是血栓栓塞事件。
17.权利要求16的方法,其中该该血栓栓塞事件是中风。
18.权利要求12的方法,其中该病症是充血性心力衰竭。
19.一种药物制剂,包含药物上可接受载体和权利要求1的化合物或其药物上可接受结晶形式或水合物。
20.一种药物组合物,是通过合并权利要求1的化合物和药物上可接受载体制造的。
21.心律不齐的治疗方法,包含给药权利要求1的化合物和一种选自下列组成的各类化合物之一的化合物:有Kv1.5阻塞活性的抗心律不齐药剂,ACE抑制剂,血管紧张素II拮抗剂,心苷,L-型钙通道阻塞剂,T-型钙通道阻塞剂,选择性和非选择性β阻塞剂,endothelin拮抗剂,凝血酶抑制剂,阿司匹林,非选择性NSAID,华法林,因子Xa抑制剂,低分子量肝素,未分馏肝素,氯吡格雷,噻氯匹啶,IIb/IIIa受体拮抗剂,5HT受体拮抗剂,integrin受体拮抗剂,thromboxane受体拮抗剂,TAFI抑制剂和P2T受体拮抗剂。
22.在有心房纤维性颤动的患者中诱发正常窦性心律病症的方法,包含用权利要求1的化合物治疗该患者。
23.患者中心动过速的治疗方法,包含用与权利要求1的化合物组合的抗心动过速器具治疗该患者。
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EP (1) | EP1667977A4 (zh) |
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CN (1) | CN1856473A (zh) |
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CN103864684A (zh) * | 2012-12-07 | 2014-06-18 | 天津科技大学 | 一种新颖的3,4-二氢-1(2h)异喹啉类衍生物的合成与抗肿瘤药物的应用 |
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WO2005030726A1 (en) * | 2003-09-23 | 2005-04-07 | Merck & Co., Inc. | Isoquinolinone potassium channel inhibitors |
US7709476B2 (en) * | 2003-09-23 | 2010-05-04 | Merck Sharp & Dohme Corp. | Isoquinolinone potassium channel inhibitors |
AU2004276236B2 (en) * | 2003-09-23 | 2008-01-24 | Merck Sharp & Dohme Corp. | Isoquinolinone potassium channel inhibitors |
JP4824563B2 (ja) * | 2003-09-23 | 2011-11-30 | メルク・シャープ・エンド・ドーム・コーポレイション | イソキノリンカリウムチャネル阻害剤 |
US7569589B2 (en) | 2004-07-29 | 2009-08-04 | Merck & Co., Inc. | Potassium channel inhibitors |
JP4719745B2 (ja) | 2004-07-29 | 2011-07-06 | メルク・シャープ・エンド・ドーム・コーポレイション | カリウムチャンネル阻害剤 |
WO2007030582A2 (en) | 2005-09-09 | 2007-03-15 | Bristol-Myers Squibb Company | Acyclic ikur inhibitors |
WO2007121453A2 (en) * | 2006-04-17 | 2007-10-25 | The Regents Of The University Of California | 2-hydroxy-1-oxo 1,2 dihydro isoquinoline chelating agents |
DE102006019589A1 (de) * | 2006-04-27 | 2007-10-31 | Sanofi-Aventis Deutschland Gmbh | Inhibitoren des TASK-1 und Task-3 Ionenkanals |
NZ572231A (en) * | 2006-04-27 | 2010-12-24 | Sanofi Aventis Deutschland | Inhibitors of the task-1 and task-3 ion channel |
CA2659251C (en) | 2006-07-10 | 2016-06-14 | The Regents Of The University Of California | Luminescent 1-hydroxy-2-pyridinone chelates of lanthanides |
US9623021B2 (en) * | 2007-01-22 | 2017-04-18 | Gtx, Inc. | Nuclear receptor binding agents |
CN101641013B (zh) | 2007-01-22 | 2014-07-30 | Gtx公司 | 核受体结合剂 |
US9604931B2 (en) | 2007-01-22 | 2017-03-28 | Gtx, Inc. | Nuclear receptor binding agents |
US8513295B2 (en) | 2008-09-23 | 2013-08-20 | Georgetown University | Viral and fungal inhibitors |
US8563580B2 (en) | 2008-09-23 | 2013-10-22 | Georgetown University | Flavivirus inhibitors and methods for their use |
WO2011025790A1 (en) | 2009-08-24 | 2011-03-03 | Lumiphore, Inc. | Macrocyclic hopo chelators |
MX2013002295A (es) * | 2010-09-01 | 2013-05-09 | Gruenenthal Gmbh | 1-oxo-dihidroisoquinolin-3-carboxamidas sustituidas como moduladores de kcnq2/3. |
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JPH10298164A (ja) * | 1997-02-27 | 1998-11-10 | Tanabe Seiyaku Co Ltd | イソキノリノン誘導体、その製法及びその合成中間体 |
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JP2000072751A (ja) | 1998-08-26 | 2000-03-07 | Tanabe Seiyaku Co Ltd | イソキノリノン誘導体 |
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AU2004276236B2 (en) * | 2003-09-23 | 2008-01-24 | Merck Sharp & Dohme Corp. | Isoquinolinone potassium channel inhibitors |
US7709476B2 (en) * | 2003-09-23 | 2010-05-04 | Merck Sharp & Dohme Corp. | Isoquinolinone potassium channel inhibitors |
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