CN1301154A - 酰胺衍生物和nociceptin拮抗剂 - Google Patents
酰胺衍生物和nociceptin拮抗剂 Download PDFInfo
- Publication number
- CN1301154A CN1301154A CN99806429A CN99806429A CN1301154A CN 1301154 A CN1301154 A CN 1301154A CN 99806429 A CN99806429 A CN 99806429A CN 99806429 A CN99806429 A CN 99806429A CN 1301154 A CN1301154 A CN 1301154A
- Authority
- CN
- China
- Prior art keywords
- methyl
- amino
- quinolyl
- hydrochloride salt
- benzamide hydrochloride
- 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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- 150000001408 amides Chemical class 0.000 title claims abstract description 47
- PULGYDLMFSFVBL-SMFNREODSA-N nociceptin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 PULGYDLMFSFVBL-SMFNREODSA-N 0.000 title claims abstract description 28
- 108090000622 Nociceptin Proteins 0.000 title claims abstract description 24
- 102000048266 Nociceptin Human genes 0.000 title claims abstract 5
- 239000005557 antagonist Substances 0.000 title description 3
- -1 hydroxy, amino Chemical group 0.000 claims abstract description 132
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 52
- 208000002193 Pain Diseases 0.000 claims abstract description 45
- 230000036407 pain Effects 0.000 claims abstract description 41
- 230000000202 analgesic effect Effects 0.000 claims abstract description 26
- 239000002764 nociceptin receptor antagonist Substances 0.000 claims abstract description 19
- 125000005843 halogen group Chemical group 0.000 claims abstract description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 17
- 125000003118 aryl group Chemical group 0.000 claims abstract description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 4
- DERJYEZSLHIUKF-UHFFFAOYSA-N procarbazine hydrochloride Chemical class Cl.CNNCC1=CC=C(C(=O)NC(C)C)C=C1 DERJYEZSLHIUKF-UHFFFAOYSA-N 0.000 claims description 70
- 150000003839 salts Chemical class 0.000 claims description 54
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 239000000730 antalgic agent Substances 0.000 claims description 26
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 26
- 229940035676 analgesics Drugs 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 239000000463 material Substances 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- 230000008485 antagonism Effects 0.000 claims description 11
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000005493 quinolyl group Chemical group 0.000 claims description 9
- SNIABFMMCKVXSY-UHFFFAOYSA-N benzoylazanium;chloride Chemical compound Cl.NC(=O)C1=CC=CC=C1 SNIABFMMCKVXSY-UHFFFAOYSA-N 0.000 claims description 8
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- ZFNYKZIQYSIJMK-UHFFFAOYSA-N C(#N)C1=CC=CC=C1.[O] Chemical compound C(#N)C1=CC=CC=C1.[O] ZFNYKZIQYSIJMK-UHFFFAOYSA-N 0.000 claims description 4
- UDSRUCAJZSIRHZ-UHFFFAOYSA-N benzamide dihydrochloride Chemical compound Cl.Cl.NC(=O)C1=CC=CC=C1.NC(=O)C1=CC=CC=C1 UDSRUCAJZSIRHZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- XLHUBROMZOAQMV-UHFFFAOYSA-N 1,4-benzosemiquinone Chemical group [O]C1=CC=C(O)C=C1 XLHUBROMZOAQMV-UHFFFAOYSA-N 0.000 claims description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims description 2
- YVNRUPSDZZZUQJ-UHFFFAOYSA-N [O].NC1=CC=CC=C1 Chemical compound [O].NC1=CC=CC=C1 YVNRUPSDZZZUQJ-UHFFFAOYSA-N 0.000 claims description 2
- RMDVXEIUMGVSCC-UHFFFAOYSA-N benzamide;hydrate;hydrochloride Chemical compound O.Cl.NC(=O)C1=CC=CC=C1 RMDVXEIUMGVSCC-UHFFFAOYSA-N 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 2
- ROPXGSNDFUBQHF-UHFFFAOYSA-N n-(4-amino-2-methylquinolin-6-yl)-2-[(3-methylphenoxy)methyl]benzamide Chemical compound CC1=CC=CC(OCC=2C(=CC=CC=2)C(=O)NC=2C=C3C(N)=CC(C)=NC3=CC=2)=C1 ROPXGSNDFUBQHF-UHFFFAOYSA-N 0.000 claims description 2
- MKKYFRVDLLFKRX-UHFFFAOYSA-N n-(4-amino-2-methylquinolin-6-yl)-2-[(4-chloro-3-methylphenoxy)methyl]benzamide Chemical compound C1=CC2=NC(C)=CC(N)=C2C=C1NC(=O)C1=CC=CC=C1COC1=CC=C(Cl)C(C)=C1 MKKYFRVDLLFKRX-UHFFFAOYSA-N 0.000 claims description 2
- BDDMAWARYNEZHN-UHFFFAOYSA-N n-(4-amino-2-methylquinolin-6-yl)-2-[(4-nitrophenoxy)methyl]benzamide Chemical compound C1=CC2=NC(C)=CC(N)=C2C=C1NC(=O)C1=CC=CC=C1COC1=CC=C([N+]([O-])=O)C=C1 BDDMAWARYNEZHN-UHFFFAOYSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
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- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- 230000003042 antagnostic effect Effects 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 101
- 239000000203 mixture Substances 0.000 description 91
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 46
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 44
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- 230000002829 reductive effect Effects 0.000 description 39
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- 238000010438 heat treatment Methods 0.000 description 35
- 239000000243 solution Substances 0.000 description 33
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
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- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 16
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Abstract
由通式[1’]代表的化合物和含有作为活性成分的化合物[1’]的nociceptin拮抗剂,其中R2表示任选羟基化的低级烷基、氨基等;B环表示苯基、噻吩基等;E表示单键、-O-、-S-等;G环表示芳基、杂环基等;R5表示卤代、羟基、由例如卤代等任选取代的低级烷基等;t是0或1—5的整数,前提是当t是2—5时,则各R5可以相同或不同;m是0或1—8的整数;及n是0或1—4的整数。化合物[1’]通过nociceptin抑制作用而发挥出对剧痛如手术后疼痛的止痛作用。具体酰胺衍生物的利用包括作为nociceptin拮抗剂或镇痛剂的化合物[1’]。
Description
技术领域
本发明涉及含有新的酰胺衍生物或其药学上可接受的盐的nociceptin拮抗剂。更具体地说,本发明涉及含有作为活性成分的新的酰胺衍生物或其药学上可接受的盐的镇痛剂,其作为nociceptin拮抗剂是通过选择性地作用于阿片样物质受体样-1受体而显示其止痛作用的,因而可用于治疗疼痛,特别是剧痛或由感觉神经异常(如痛觉过敏和异常性疼痛)引起的疼痛。本发明还涉及某些酰胺类衍生物作为nociceptin拮抗剂和镇痛剂的新用途。
背景技术
疼痛是任何个体感受到的一种感觉,是一种重要的生命信号或预警信号。
由伤害、手术、炎症等引起的疼痛,以及因伤害、受伤恢复后神经功能障碍等产生的慢性疼痛是主要的临床问题之一。慢性疼痛有时引起自发性疾病、运动障碍或精神错乱,其中疼痛本身就是各种不同疾病的病因。
还已知存在因感觉神经异常,例如与应答于普通疼痛刺激、异常性疼痛等的反应增强有关的痛觉过敏引起的疼痛,其中疼痛是在正常不引起疼痛的刺激的应答中感觉到的。
镇痛剂根据其作用的主要部位分成中枢镇痛剂和外周镇痛剂。由于疼痛的原因是自发的神经反应、感觉等的错综复杂综合因素,所以镇静剂、抗焦虑剂、抗抑郁剂、安眠药、解痉剂、血管舒张剂等可用作止痛辅助药物。
中枢镇痛剂可粗略分为麻醉镇痛剂、非麻醉(anarcotic)镇痛剂和解热镇痛剂。
麻醉的和非麻醉阿片样物质已被用于治疗诸如手术后疼痛、心肌梗塞、烧伤等剧痛。
这些镇痛剂显示出由强烈的止痛作用以及消除疼痛恐惧的作用所产生的显著效果。另一方面,麻醉镇痛剂伴有身体依赖性和精神依赖性,表现为药物依赖性所致的戒除综合征。呼吸抑制、恶心、呕吐、便秘、排尿困难等限制了其用途。
解热镇痛剂对浅表疼痛,如牙痛、肌痛等是有效的,但被认为对内脏痛无效。它的解热作用被认为是集中在下丘脑体温调节中枢上,而止痛作用是通过外周神经而发挥作用的。然而,在其中枢作用机制方面,仍有许多未知部分。它的止痛作用一般比麻醉的和非麻醉的阿片样物质提供的止痛作用弱。因此,临床上治疗剧痛时,必须以引起较少副作用的程度谨慎使用麻醉的和非麻醉的阿片样物质。
尽管自从通过鞘内给予人吗啡的镇痛效果被证实和吗啡首次应用于临床已有20多年了,就各种副作用、对脊柱等的组织毒性而言,优于吗啡且具有吗啡止痛作用的药物尚未发现。
某些因伤害和神经功能紊乱等引起的疼痛对目前临床使用的镇痛剂,如解热镇痛剂和麻醉镇痛剂有抗药性,因而不能显示明显的镇痛效果。
因此,仍存在对安全有效的镇痛剂的需求,尤其是对无成瘾性的强效镇痛剂以及治疗因感觉神经异常如痛觉过敏、异常性疼痛等引起疼痛的镇痛剂的需求。
当疼痛物质兴奋感觉神经末梢的伤害性感受器(游离神经末端)时,就引起疼痛,所述疼痛物质是因感受伤害的刺激(化学刺激、机械刺激、热刺激)所致组织疾病的发生而释放的,疼痛感觉的信息传到大脑皮层并被识别为疼痛。此外,内脏痛被认为是由内脏平滑肌收缩(即机械延长和兴奋感觉神经)引起的。
疼痛感觉主要是由两种细神经纤维Aδ和C纤维传递的,其中急剧的机械刺激沿有髓Aδ纤维传导,而隐痛沿无髓C纤维传导。典型的疼痛物质包括作用于神经末梢的伤害性感受器的缓激肽、血清素、组胺等。有一种加强疼痛物质作用的物质,如外周组织的炎症部位合成的前列腺素。这样的疼痛传入纤维(主传入纤维)形成脊柱背角(dorsico rnu)表层上的突触。主传入纤维通过神经递质如兴奋性氨基酸、P物质等激发伤害感受神经元,而信息从脊柱背角传到延髓、丘脑及大脑皮层。
压力和触觉主要是通过较粗的Aβ纤维传递的,与疼痛传入纤维类似,它将信息从感觉神经末梢传入脊柱背角、延髓、丘脑及大脑皮层。
阿片样物质受体与存在于这些脊髓丘脑束中各部分的痛觉有关。呼吸抑制作用、恶心作用等产生于对延髓的阿片样受体的作用。阿片样物质作用于脊髓、延髓、丘脑及大脑皮层以显示出强烈的止痛作用,但丘脑和大脑皮层的抑制不是主要作用。脊髓背角神经元的阿片样受体的直接抑制和降低通过中脑和延髓抑制所致的脊髓背角神经元的抑制被认为是主要作用。
触觉对持续施加同样强度刺激趋向于变得迟钝。这种适应在疼痛的情况下是不可行的,但因长期刺激感觉神经所致神经递质的持续释放被认为可诱导通过改变神经细胞的兴奋性或信息传递效率所致的慢性疼痛。此外,抑制性神经递质如γ-氨基丁酸(GABA),甘氨酸等抑制激活的每个受体的神经兴奋。虽然认为异常性疼痛部分是神经传递的减弱的抑制(因反复刺激施加于感觉神经所致)引起的,但慢性疼痛、痛觉过敏和异常性疼痛发作的机制仍只有限程度的了解。
如同所述的,感觉神经传递受兴奋性神经纤维和抑制性神经纤维彼此之间错综复杂的关系的控制,已发现存在许多与此有关的神经递质。因而,有许多目标可用来发现显示出有效止痛作用的药物。
随着脑吗啡受体在1973年被发现,在1975年首次发现并分离出脑啡肽,其为一种具有止痛作用的内源性五肽。已知有20多种拟吗啡肽属于阿片样肽,其抑制痛觉信息的传递。
包括吗啡在内的这些阿片样物质作用于阿片样受体。已知阿片样受体包括几种亚型,其中吗啡对μ受体显示出高亲和力,脑啡肽对δ受体显示出高亲和力,而强啡肽则对κ受体显示出高亲和力,这些构成其基础。
早已发现其中的μ受体对于止痛作用是重要的,其机制已得到充分阐明。使用阿片样拮抗剂对每种亚型的戒除综合征的诱导能力等的研究揭示,吗啡成瘾性主要归因于通过μ受体的作用。
阿片样受体样-1(ORL-1)受体具有与阿片样受体的高度同源性,但不与常规的阿片样配体结合。该受体已于1993年被克隆(*1*2)。在1995年,分离出为ORL-1受体的内源性配体的由17个氨基酸组成的肽,且对其结构进行了鉴定并命名为Nociceptin或Orphanin FQ(*3*4)(*1;FEBS Lett.,341,33-38,1994)(*2;FEBS Lett.,347,284-288,1994)(*3;Nature,377,532-535,1995)(*4;Science,270,792-794,1995)。
nociceptin的氨基酸序列与为内源性阿片样肽的强啡肽A的氨基酸序列相类似。强啡肽A为显示止痛作用的κ受体兴奋剂,但与ORL-1受体的结合很弱,据说没有活性(*5)。Nociceptin与阿片样受体的结合极弱(*6),痛觉实验包括使用小鼠的热板实验(*7)、小鼠两后爪对下腹部的抓痕实验、咬和舔后爪(SBL)行为诱导实验(*8)等揭示了它对疼痛信息传递的促进作用。这些报道说明nociceptin和ORL-1受体彼此之间具有特异的亲和力,nociceptin是一种诱导或加强疼痛的肽,与阿片样肽的情况相反。它们的作用机理的研究正在进行中。(*5;Eur.J.Pharmacol.,321,97,1997)(*6;J.Biol.Chem.,271,23642,1996)(*7;Anesthesia,45,1060-1066,1996)(*8;18th Analgesic·Opioid PeptideSymposium Abstract,11-14,1997)。
已报道ORL-1受体多表达于中枢神经系统,如大脑皮层、下丘脑、脊髓等(*9),已表明nociceptin多分布于其中疼痛主传入纤维终止的脊髓背角的表层(*10)和nociceptin的痛觉传递被认为主要是通过中枢神经系统进行的(*9;J.Neurochemistry,64,34-40,1995)(*10;NeuroReport 7,3021-3025,1996)。
还报道了给予nociceptin会引起伤害感受的超敏感性(痛觉过敏(*3*4),异常性疼痛(*11))并且它放大了因热和触觉引起的兴奋性刺激(*11;Molecular Brain Research,43,96-104,1996)。
既然如此,报道显示出nociceptin拮抗剂作用的物质仅仅是nociceptin-样多肽和为具有吗啡样结构的κ受体拮抗剂的纳洛酮苯甲酰基腙,两者均具有ORL-1受体亲和力,但具有对ORL-1受体的特异性的拮抗作用的药物尚未开发出来。
具有喹啉骨架的已知镇痛剂包括阿片样或麻醉的拮抗剂镇痛剂[日本专利未审查公布号63-264460(EP277794;BOC Inc.)],具有不同作用机制的镇痛剂[日本专利未审查公布号62-503030(US5104884;Alkaloida Vegyeszeti Gyar,抗真菌作用),WO96/13485(EP 807105;Fujisawa Pharmaceutical Industries,Ltd.,缓激肽拮抗剂),WO96/11930(Smithkline beecham P.L.C.,血清素受体拮抗剂),日本专利未审查公布号59-210084(US 4839366;Chiesi Farmaceutici S.p.A.,前列腺素合成的抑制),日本专利未审查公布号54-73784(US4293549;LeoPharmaceutical Products Limited A/S),FR 1557928和FR 1543405(M.Robert ARIES)等。这些并不包括具有本发明化合物结构的化合物,它们并未如本发明这样公开了关于nociceptin或ORL-1受体的作用。
DE 831100和DE 947552(抗血内寄生物药)、WO97/14681(骨代谢异常治疗剂),日本专利未审查公布号63-99069(US4753951;精神抑制药),日本专利未审查公布号2-167265(US 5019574;精神神经功能改善剂),Journal of American Chemistry Society(76,3703-3708,1956)(抗菌药),HU34479{用作合成咪唑并[4,5-c]喹啉衍生物(镇痛剂)的中间体的喹啉骨架的公开}等中显示了具有结构上类似于本发明化合物的喹啉骨架的化合物,以及并非作为止痛作用来使用的其它疗效的化合物,这些文献中均未公开作为镇痛剂的疗效。
本发明公开
根据前述的结果,具有nociceptin拮抗作用的药物可用作治疗疼痛的有效药物,特别是用于治疗剧痛如手术后疼痛等或因感觉神经异常(如痛觉过敏、异常性疼痛等)引起的疼痛,以及用作对ORL-1受体显示选择性作用而无显著副作用的安全药物。
因此,本发明的一个目的是提供具有不同于已知镇痛剂的作用机制(通过nociceptin拮抗作用)的药物。
本发明的另一个目的是提供具有nociceptin拮抗作用的新化合物,其可用作镇痛剂。
由于本发明者试图解决上述问题的广泛研究,本发明现在提供具有止痛作用的新化合物。
本发明特别提供下列(1)-(20)的化合物。
(1)包含作为活性成分的式[1]的酰胺衍生物或其药学上可接受的盐的nociceptin拮抗剂其中R1和R2可相同或不同,各自为氢原子、由羟基、氨基、低级烷基氨基或二(低级)烷基氨基任选取代的低级烷基;R3和R4可相同或不同,各自为氢原子、卤原子或低级烷基;A环为芳基或杂环基;B环为苯基、噻吩基、呋喃基、吡咯基、吡咯烷基、噁唑基或环己烯基;及X为氢原子、卤原子、由低级烷氧基、低级链烯基、氨基、氰基或下式的基团任选取代的低级烷基:其中E为单键、羰基、亚磺酰基、-O-、-S-、-NHCO-、-CH=CR6-,其中R6为氢原子或芳基或-NR7-,其中R7为氢原子、低级烷基或低级烷氧基羰基;G环为芳基、杂环基、环烷基或稠合的芳基;R5为卤原子、羟基、由任一卤原子、羟基、低级链烷酰基氧基和由低级烷氧基任选取代的低级烷氧基任选取代的低级烷基、由低级烷氧基任选取代的低级烷氧基、氨基、低级烷基氨基、二(低级)烷基氨基、硝基、氰基、低级链烷酰基、低级链烷酰基氧基、羧基、低级烷氧基羰基、低级烷基磺酰基或苯基;t是0或1-5的整数,其表示G环上取代基的数目,其中当t是2-5的整数时,每个R5可以相同或不同;m是0或1-8的整数;及n是0或1-4的整数。
(2)含有作为活性成分的上面(1)的酰胺衍生物或其药学上可接受的盐的nociceptin拮抗剂,其中A环为喹啉基。
(6)上面(5)的酰胺衍生物或其药学上可接受的盐,其中B环为苯基,R2为低级烷基。
(7)上面(6)的酰胺衍生物或其药学上可接受的盐,其中氨基在喹啉骨架的4-位取代,R2为在喹啉骨架的2-位上取代的甲基,E为-O-,B环苯基在2-位上具有下式的取代基其中G环、R5、t、m和n如(1)中所定义。
(8)上面(7)的酰胺衍生物或其药学上可接受的盐,其选自N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-乙基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(2,4-二氯苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-(苯氧基甲基)苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-甲氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3,5-二甲基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3,4-二甲氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-硝基苯氧基)甲基]苯甲酰胺,N-(4-氨基-2-甲基-6-喹啉基)-2-[(2,3-二甲氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3-甲基苯氧基)甲基]苯甲酰胺,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3,5-二甲氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-氯代苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-乙酰基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-羟基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-甲氧基甲氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3-甲氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-氰基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-甲基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-三氟甲基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3-硝基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(2-硝基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-乙酰氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(2-甲氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-氨基苯氧基)甲基]苯甲酰胺二盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3-氯代苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-氟代苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3,4-二氯苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(2-氯代苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-二甲基氨基苯氧基)甲基]苯甲酰胺二盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-叔丁基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-(4-联苯基氧基甲基)苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-异丙基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-硝基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-溴代苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-丙基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3-氟代苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3-三氟甲基苯氧基)甲基]苯甲酰胺盐酸盐,4-[2-{N-(4-氨基-2-甲基-6-喹啉基)氨基甲酰基}苄氧基]苯甲酸甲酯盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-碘代苯氧基)甲基]苯甲酰胺,N-(4-氨基-2-甲基-6-喹啉基)-2-(3-吡啶基氧基甲基)苯甲酰胺盐酸盐,4-[2-{(4-氨基-2-甲基-6-喹啉基)氨基甲酰基}苄氧基]苯甲酸酯盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3-氰基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-甲磺酰基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(2-氯代-4-乙基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-氯代-3-甲基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(2-氯代-4-甲基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-乙基苯氧基)甲基]苯甲酰胺,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-氯代-3-甲基苯氧基)甲基]苯甲酰胺,4-[2-{(4-氨基-2-甲基-6-喹啉基)氨基甲酰基}苄氧基]苄基乙酸酯盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-羟甲基苯氧基)甲基]苯甲酰胺盐酸盐和N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-乙基苯氧基)甲基]苯甲酰胺盐酸盐一水合物。
(9)式[1”]的酰胺衍生物或其药学上可接受的盐其中A环、R2、R5和t如(1)中所定义。
(10)含有(5)-(9)中的任何酰胺衍生物或其药学上可接受的盐和药学上可接受的载体的药用组合物。
(11)含有作为活性成分的(5)-(9)中的任何酰胺衍生物或其药学上可接受的盐的nociceptin拮抗剂。
(12)含有作为活性成分的(1)-(9)中的任何酰胺衍生物或其药学上可接受的盐的镇痛剂。
(13)发挥nociceptin拮抗作用的方法,包括给予(1)-(9)中的任何酰胺衍生物或其药学上可接受的盐。
(14)治疗疼痛的方法,包括给予(1)-(9)中的任何酰胺衍生物或其药学上可接受的盐。
(15)(1)-(9)中的任何酰胺衍生物或其药学上可接受的盐在nociceptin拮抗剂的生产中的用途。
(16)(1)-(9)中的任何酰胺衍生物或其药学上可接受的盐在镇痛剂的生产中的用途。
(17)用于拮抗nociceptin的药用组合物,它包含(1)-(9)中的任何酰胺衍生物或其药学上可接受的盐和药学上可接受的载体。
(18)包括(17)的药用组合物和与此有关的书面材料的市售包装物,所述书面材料说明该药用组合物可以或应该用于拮抗nociceptin的用法。
(19)用于止痛用途的药用组合物,它包括(1)-(9)中的任何酰胺衍生物或其药学上可接受的盐和药学上可接受的载体。
(20)包括(19)的药用组合物和与此有关的书面材料的市售包装物,所述书面材料说明该药用组合物可以或应该用于止痛的用法。
本说明书中使用的各取代基和部分定义如下。
卤原子为氟原子、氯原子、溴原子或碘原子。在R3、R4、R5和R5”中,优选氯原子。
低级烷基具有1-6个碳原子的线性或支链。其具体实例包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、叔戊基、己基等。
优选具有1-4个碳原子的线性或支链烷基。在R3、R4、R7、R9、R10、R11和R12中,更优选甲基,在R5’中,更优选甲基或乙基。
低级烷氧基具有如上对低级烷基定义的烷基部分。具体的实例包括甲氧基、乙氧基、丙氧基、异丙氧基、叔丁氧基等
低级烷硫基具有如上对低级烷基定义的烷基部分。具体的实例包括甲硫基、乙硫基、丙硫基、异丙硫基、叔丁硫基等。
优选它的烷基部分为具有1-4个碳原子的线性或支链烷基。在R8中,更优选其为甲硫基。
低级链烷酰基具有如上对低级烷基定义的烷基部分。具体的实例包括乙酰基、丙酰基、丁酰基、异丁酰基、新戊酰基等。
优选它的烷基部分为具有1-4个碳原子的线性或支链烷基。在R5中,更优选其为乙酰基。
低级烷基磺酰基具有如上对低级烷基定义的烷基部分。具体的实例包括甲磺酰基、乙磺酰基、丙磺酰基、异丙磺酰基、叔丁基磺酰基等。
优选它的烷基部分为具有1-4个碳原子的线性或支链烷基。在R5中,更优选其为甲磺酰基。
低级链烷酰基氧基具有如上对低级烷基定义的烷基部分。具体的实例包括乙酰氧基、丙酰氧基、丁酰氧基、异丁酰氧基、新戊酰氧基等。
优选它的烷基部分为具有1-4个碳原子的线性或支链烷基。在R5中,更优选其为乙酰氧基。
低级烷氧基羰基具有如上对低级烷基定义的烷基部分。具体的实例包括甲氧基羰基、乙氧基羰基、丙氧基羰基、异丙氧基羰基、叔丁氧基羰基等。
优选它的烷基部分为具有1-4个碳原子的线性或支链烷基。在R5中,更优选其为甲氧基羰基,在R7中,更优选其为叔丁氧基羰基。
由羟基任选取代的低级烷基意指如上定义的低级烷基任选由一个或多个羟基取代,所述低级烷基可以是未取代的。具体的实例包括甲基、乙基、丙基、异丙基、羟甲基、1,2-二羟基乙基、2-(羟甲基)丁基等。
R1和R2优选为甲基,乙基、丙基、异丙基或羟甲基,但更优选为甲基或乙基。
由低级烷氧基任选取代的低级烷基意指任选由如上定义的低级烷氧基取代的如上定义的低级烷基,包括未取代的烷基。具体的实例包括甲基、乙基、甲氧基甲基、乙氧基甲基、2-(甲氧基甲基)丁基等。
优选它的基础烷基部分为具有1-4个碳原子的线性烷基。在X中,更优选其为甲氧基甲基。
由低级烷氧基任选取代的低级烷氧基意指任选由如上定义的低级烷氧基取代的如上定义的低级烷氧基,包括未取代的烷氧基。具体的实例包括甲氧基、乙氧基、甲氧基甲氧基、甲氧基乙氧基、2-(甲氧基甲基)丁氧基等。
优选它的基础烷基部分为具有1-4个碳原子的线性或分支烷基。在R5中,更优选其为甲氧基或甲氧基甲氧基。
由卤原子、羟基、低级链烷酰基氧基和由低级烷氧基任选取代的低级烷氧基中的任何基团任选取代的低级烷基意指如上定义的低级烷基任选由一个或多个如上定义的卤原子、羟基、如上定义的低级链烷酰基氧基和如上定义的由低级烷氧基任选取代的低级烷氧基取代(其中每一个可以相同或不同),并且低级烷基可以未被取代。具体的实例包括甲基、乙基、丙基、异丙基、叔丁基、羟甲基、2-羟乙基、1,2-二羟基乙基、乙酰氧基甲基、新戊酰氧基甲基、溴代甲基、三氟甲基、甲氧基甲氧基甲基、甲氧基乙氧基甲基等。
优选它的基础烷基部分为具有1-4个碳原子的线性或分支烷基。在R5中,更优选其为甲基、乙基、丙基、异丙基、叔丁基、羟甲基、乙酰氧基甲基、三氟甲基或甲氧基甲氧基甲基,更优选乙基。
低级烷基氨基为其中烷基部分如同上面对低级烷基定义的一烷基氨基。具体的实例包括甲基氨基、乙基氨基、丙基氨基、异丙基氨基、叔丁基氨基等。
优选它的烷基部分为具有1-4个碳原子的线性或分支烷基。在R1和R2中,更优选其为甲基氨基。
二(低级)烷基氨基为其中烷基部分为相同或不同且如同上面对低级烷基定义的二烷基氨基。具体的实例包括二甲基氨基、二乙基氨基、甲基乙基氨基、N-异丙基N-异丁基氨基等。
优选它的烷基部分为具有1-4个碳原子的线性或分支烷基。在R1、R1和R5中,更优选其为二甲基氨基。
低级链烯基为具有1-6个碳原子的线性链烯基。具体的实例包括乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1,3-丁二烯基、2,4-丁二烯基、1-戊烯基、1,3-戊二烯基和1,3,5-己三烯基等。
X优选为乙烯基。
芳基为具有6-18个碳原子的芳族烃基。其实例包括苯基、萘基、蒽基、茚基、薁基、芴基、菲基、芘基等。
优选A环为苯基和萘基,更优选为苯基。优选G环和R6为苯基。
当G环为苯基时,取代基R5优选连接在对位上。
杂环为具有一个或多个选自作为杂原子的氧原子、氮原子和硫原子的环状化合物基团,其中可以含有多个杂原子,构成所述环的原子数为5-20。其具体实例包括吡啶基、吡嗪基、嘧啶基、吡咯基、噻吩基、呋喃基、咪唑基、吡唑基、噁唑基、噻唑基、喹啉基、异喹啉基、吲哚基、苯并呋喃基、苯并咪唑基、咪唑烷基、二氢吲哚基、吡咯烷基、吡咯啉基、哌啶基、哌嗪基、苯并二氢吡喃基、吗啉基、2,3-二氮杂萘基、1,5-二氮杂萘基、喹唑啉基、喹喔啉基、肉啉基、蝶啶基、4H-喹嗪基、咔唑基、1,3,5-三嗪基、2,3-二氢苯并呋喃基、5,6,7,8-四氢喹啉基、5,6,7,8-四氢吖啶基、2,3-二氢-1H-环戊并[b]喹啉基等。
优选G环为吡啶基、苯并呋喃基或2,3-二氢苯并呋喃基,更优选为2,3-二氢苯并呋喃基。
优选A环为含有一个或多个作为杂原子的氮原子的环状化合物基团,构成所述环的原子数为9-14。更优选其为喹啉基、异喹啉基、喹喔啉基、苯并咪唑基、5,6,7,8-四氢喹啉基、5,6,7,8-四氢吖啶基或2,3-二氢-1H-环戊并[b]喹啉基,最优选为喹啉基、5,6,7,8-四氢吖啶基或2,3-二氢-1H-环戊并[b]喹啉基。
当A环为喹啉基时,优选R1为在4-位取代的氨基,R2为在2-位取代的低级烷基和在6-位取代的-NHCO-。
环烷基为具有3-8个碳原子的饱和环烷基,其实例有环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
G环优选为环己基。
稠合的芳基为上面定义的芳基,其中上面定义的环烷基是稠合的,其为构成该环的原子数为5-18的环状化合物基团。具体实例包括2,3-二氢化茚基、5,6,7,8-四氢-2-萘基、5,6,7,8-四氢-3-萘基、1,2,3,4-四氢-2-萘基、5,6,7,8-四氢-2-蒽基、1,2,3-三氢薁基等。
G环优选为5,6,7,8-四氢-2-萘基。
保护的氨基为在典型的化学合成中使用的氨基保护基团保护的氨基。氨基保护基团的具体实例包括甲酰基、乙酰基、苯甲酰基、苄氧基羰基、甲氧基羰基、叔丁氧基羰基、邻苯二甲酰基、苄基、甲苯磺酰基等。
羧基保护基团为用于典型的化学合成中的羧基保护基团。其具体实例包括甲基、甲氧基乙氧基甲基、苯甲酰甲基、邻苯二甲酰亚氨基甲基、乙基、2,2,2-三氟乙基、2-甲硫基乙基、叔丁基、苄基、对-硝基苄基、对甲氧基苄基、叔丁基二甲基甲硅烷基等。
羟基保护基团为用于典型的化学合成中的羟基保护基团。其具体实例包括三甲基甲硅烷基、叔丁基二甲基甲硅烷基、甲基、苄基、对-甲氧基苄基、叔丁基、三苯甲基、四氢吡喃基、甲氧基甲基、甲氧基乙氧基乙基、乙酰基、苯甲酰基等。
在上述的式[1]、[1’]和[1”]中,每个符号优选指下列基团。
G环优选为芳基。
R5优选为卤原子;由任何卤原子、羟基、低级链烷酰基氧基和被低级烷氧基任选取代的低级烷氧基任选取代的低级烷基;被低级烷氧基任选取代的低级烷氧基;硝基;氰基;或低级链烷酰基,更优选为由任何卤原子、羟基、低级链烷酰基氧基和被低级烷氧基任选取代的低级烷氧基任选取代的低级烷基。
t优选是0或1或2的整数,更优选是1。
优选E为单键或-O-,更优选为-O-。
当E为-O-时,m优选是1-7的整数,更优选是1,及n优选是0。当E是单键时,m+n优选是2。
式[1]化合物包括各种异构体。例如,存在E-和Z-几何异构体。当存在不对称碳原子时,则存在立体异构体(如对映体和非对映体)。根据情况,本发明可存在互变异构体。因此,本发明包含所有这些异构体及其混合物。
它们的药学上可接受的盐可以是任何盐,只要它能与上述的式[1]、[1’]或[1”]化合物形成非毒性的盐即可。其实例包括与无机酸所成的盐,如盐酸、硫酸、磷酸、氢溴酸等的盐,与有机酸所成的盐,如草酸、丙二酸、柠檬酸、富马酸、乳酸、苹果酸、琥珀酸、酒石酸、乙酸、葡糖酸、抗坏血酸、甲磺酸、苯甲磺酸等的盐,与无机碱所成的盐,如氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、氢氧化铵等的盐,与有机碱所成的盐,如甲胺、二乙胺、三乙胺、三乙醇胺、乙二胺、三(羟甲基)甲胺、胍、胆碱、辛可宁等的盐,或与氨基酸所成的盐,如赖氨酸、精氨酸、丙氨酸等成的盐。本发明进一步包括每一化合物的含水化合物、水合物和溶剂化物。
本发明还包括每一化合物的前药和代谢物。前药是本发明化合物的衍生物,它具有化学上或代谢上可分解的基团,以及在给药到体内后,在恢复其原始形式时显示出疗效,其中包括无共价键的复合物和盐。
当本发明化合物用作药用制剂时,一般将其与已知的、常规药学上可接受的载体、赋形剂、稀释剂、增量剂、崩解剂、稳定剂、防腐剂、缓中剂、乳化剂、芳香剂、着色剂、甜味剂、粘合剂、调味剂、增溶剂及其它添加剂混合,具体地说是,通过常规方法与水、植物油、醇(如乙醇、苄基醇等)、聚乙二醇、三乙酸甘油酯、明胶、碳水化合物(如乳糖、淀粉等)、硬脂酸镁、滑石、羊毛脂、凡士林等混合并配制成片剂、丸剂、散剂、颗粒剂、栓剂、注射剂、眼用滴剂、液体剂、胶囊、锭剂、气溶胶、酏剂、悬浮液、乳剂、糖浆剂等,它们可通过口服或胃肠外给予而全身给药或局部给药。
剂量根据年龄、体重、症状、疗效、给药途径等而变化,一般对于成人为每剂量0.01mg-1g,可每日一至数次给药。
实施本发明的制备所述化合物的方法的一个实例解释如下,本发明化合物的制备方法并不限定于此。
在每一步骤中,反应物的处理可以是常规的处理,例如,分离和纯化、结晶、重结晶、硅胶柱层析、制备性HPLC等,这些处理可以适当地选择和组合进行。需要时,可以将保护基团引入官能团中并在制备中去保护。制备方法1
下式[Ⅰ]化合物的合成方法示于下文中:其中A环、R1、R2和R3如上定义。
当A环为喹啉环时,可以使用Camps的喹啉合成方法、Combes的喹啉合成方法、Friedlander的喹啉合成方法、Knorr的喹啉合成方法、Niementowski的喹啉合成方法等进行合成。部分化合物可作为市售的试剂而获得。
具有取代基的喹啉环的制备方法如下所示。制备方法1-1
于室温或加热的条件下,使化合物[Ⅰ-1]和化合物[Ⅰ-2]在诸如甲醇、乙醇、正丙醇、异丙醇等醇溶剂中缩合得到化合物[Ⅰ-3]。步骤2
将按制备方法1-1,步骤1获得的化合物[Ⅰ-3]分次加入加热的溶剂中并环合得到化合物[Ⅰ-4]。
优选溶剂为二苯基醚或二苯基醚和二苯基化合物如Dowtherm A(商标名Fluka)的混合物。
可将该制备方法运用于化合物[Ⅰ-1],其中β-酮酸酯的α-位由低级烷基取代。制备方法1-2
在加压及加热下,使化合物[Ⅰ-5]、丙酮和氨水反应得到化合物[Ⅰ-6]。步骤2
在氧化剂如次氯酸钠、次溴酸钠等的存在下,在冷却下,使按制备方法1-2,步骤1获得的化合物[Ⅰ-6]反应,将获得的反应混合物滴加到热水中并进一步加热而得到化合物[Ⅰ-7]。
采用下面的制备方法引入特定的取代基或引入到特定的取代部位。制备方法1-3
根据本制备方法,由乙炔二羧酸酯化合物和苯胺化合物获得4-羟基-2-甲氧基羰基喹啉化合物。通过在后一步骤中还原,可使该混合物的甲氧基羰基转化为羟甲基:其中R3和Y如上定义。步骤1
按照与制备方法1-1,步骤1的相同方法,使化合物[Ⅰ-8]和化合物[Ⅰ-9]缩合得到化合物[Ⅰ-10]。步骤2
按照与制备方法1-1,步骤2的相同方法,使按制备方法1-3,步骤1获得的化合物[Ⅰ-10]环合而得到化合物[Ⅰ-11]。制备方法1-4
根据本制备方法,由4-硝基喹啉N-氧化物化合物获得4,6-二氨基喹啉化合物。步骤1
在加热下,使化合物[Ⅰ-12]与金属铁在诸如盐酸、乙酸等的酸性溶剂中反应,使生成的溶液呈碱性得到化合物[Ⅰ-13]。
或者,可以使用利用锡或氯化锡(Ⅱ)和浓盐酸的典型还原、碱性金属硫化物如硫化钠水溶液的还原,催化还原等。步骤2
在冷却或室温下,用在乙酸中的溴处理按制备方法1-4,步骤1获得的化合物[Ⅰ-13],以卤化得到化合物[Ⅰ-14]。
或者,可以使用卤化剂如次卤酸盐(如次氯酸盐等)、N-溴代琥珀酰亚胺等代替卤化用的溴。步骤3
在冷却下,通过加入浓硝酸使按制备方法1-4,步骤2获得的化合物[Ⅰ-14]经在硫酸溶剂中硝化得到化合物[Ⅰ-15]。
可以使用硝酸或无机硝酸盐-硫酸代替用于硝化的硝酸-硫酸混合液。步骤4
于室温或在常压至高压下加热,在诸如甲醇、乙醇、正丙醇、异丙醇等的醇溶剂中,通过加入盐酸或溴化氢-乙酸溶液,使按制备方法1-4,步骤3获得的化合物[Ⅰ-15]经催化还原(使用氢化催化剂)得到化合物[Ⅰ-16]。
氢化催化剂的实例包括钯炭、氢氧化钯、钯黑、阮内镍、氧化铂等。
当A环为异喹啉环时,合成的实施例如下所示。制备方法1-5
按照如制备方法1-4,步骤3的相同方法,使化合物[Ⅰ-17]经硝化得到化合物[Ⅰ-18]。步骤2
于室温下,在4%碳酸钠水溶液中,用Fremy’s盐使按制备方法1-5,步骤1获得的化合物[Ⅰ-18]经脱氢作用数天得到化合物[Ⅰ-19]。步骤3
于室温下,在卤代溶剂如二氯甲烷、氯仿、四氯化碳等中,使按制备方法1-5,步骤2获得的化合物[Ⅰ-19]与间氯过苯甲酸反应以进行N-氧化作用,得到化合物[Ⅰ-20]。步骤4
在加热下,使按制备方法1-5,步骤3获得的化合物[Ⅰ-20]与磷酰氯在烃溶剂如甲苯、二甲苯等中反应,得到化合物[Ⅰ-21]。制备方法1-6
在适于缩合的加热条件下,将酸催化剂如Lewis酸(如氯化锌)加入化合物[Ⅰ-22]和化合物[Ⅰ-23]的混合物中得到化合物[Ⅰ-24]。制备方法1-7
根据本制备方法,化合物的取代基由氨基或取代的氨基取代:其中A环、R2、R3和Y如上定义,R9为氢原子或低级烷基和R10为低级烷基。步骤1
在加热下,使按制备方法1-1获得的化合物[Ⅰ-25]或市售获得的试剂与氯代磺酰基异氰酸酯在乙腈或二氯乙烷中反应,得到化合物[Ⅰ-26]。步骤2
于加热或室温下,使按制备方法1-1获得的化合物[Ⅰ-25]或市售获得的试剂与烷基化试剂在溶剂中反应,得到化合物[Ⅰ-27]。
使用作为烷基化试剂的硫酸二甲酯或对甲苯磺酸甲酯,以引入流程中的甲氧基。
优选的溶剂的实例包括烃溶剂如苯、甲苯、己烷、二甲苯等,其它的溶剂如1,4-二氧六环、乙醚、1,2-二甲氧基乙烷、四氢呋喃等。步骤3
在加热下,使按制备方法1-1获得的化合物[Ⅰ-25]或市售获得的试剂与卤化剂如磷酰氯、五氯化磷等反应,使该反应混合物呈碱性,得到化合物[Ⅰ-28]。步骤4
在加热下,使按制备方法1-5或制备方法1-7,步骤3获得的化合物[Ⅰ-28]或市售获得的试剂与金属醇盐在醇溶剂如甲醇、乙醇、丙醇、丁醇等中反应,得到化合物[Ⅰ-27]。
使用作为金属醇盐的甲醇钠,以及作为溶剂的甲醇被用作相应的醇溶剂,以引入流程中所示的甲氧基。步骤5
在加热下,使按制备方法1-7,步骤2或制备方法1-7,步骤4获得的化合物[Ⅰ-27]或市售获得的试剂与胺化剂如乙酸铵等反应,得到化合物[Ⅰ-26]。步骤6
在加热下,使按制备方法1-7,步骤3获得的化合物[Ⅰ-28]或市售获得的试剂与化合物[Ⅰ-29]在诸如碳酸钾、碳酸钠、氢氧化钠、氢氧化钾、氢氧化锂等碱的存在下反应,得到化合物[Ⅰ-30]。
在制备方法1-7中获得的化合物[Ⅰ-25]可以是在制备方法1-3中获得的化合物[Ⅰ-11]。制备方法1-8
当Y为保护的氨基时,使用与该保护基团相对应的常用去保护方法。
例如,当保护基团为乙酰基时,将浓盐酸加入按制备方法1-7获得的化合物[Ⅰ-31]或市售获得的试剂中,将该混合物加热以进行脱乙酰作用,得到化合物[Ⅰ]。
可使用在浓氨、氢氧化钾处理等中加热,以代替浓盐酸的处理。
当Y为硝基时,使用经还原硝基转化为胺的常用方法。例如,于室温或加热下,在常压或高压下,用氢化催化剂使按制备方法1-7获得的化合物[Ⅰ-31]或市售获得的试剂在溶剂中经催化还原,得到化合物[Ⅰ]。
所述溶剂的实例包括醚溶剂如1,4-二氧六环、乙醚、1,2-二甲氧基乙烷、四氢呋喃等,极性溶剂如二甲基甲酰胺、二甲亚砜、乙腈、丙酮等,醇溶剂如甲醇、乙醇、丙醇、丁醇等,酯如甲酸乙酯、乙酸乙酯、乙酸丁酯等,水或它们的溶剂混合物。
氢化催化剂的实例有钯炭、氢氧化钯、钯黑、阮内镍、氧化铂等。制备方法2
使化合物[Ⅱ-1]与自由基引发剂如过氧化苯甲酰、偶氮双异丁腈等和N-溴代琥珀酰亚胺反应,得到化合物[Ⅱ-2]。步骤2
在加热下,在诸如碳酸钾、碳酸钠、氢氧化锂、氢氧化钠、氢氧化钾、氢化锂、氢化钠、氢化钾等的碱存在下,使按制备方法2-1,步骤1获得的化合物[Ⅱ-2]与化合物[Ⅱ-3]在溶剂中反应,得到化合物[Ⅱ4]。
所述溶剂的实例包括烃溶剂如苯、甲苯、己烷、二甲苯等,醚溶剂如1,4-二氧六环、乙醚、1,2-二甲氧基乙烷、四氢呋喃等,极性溶剂如二甲基甲酰胺、二甲亚砜、乙腈、丙酮等,醇溶剂如甲醇、乙醇、丙醇、丁醇等。
大多数[Ⅱ-3]化合物可以容易地作为市售的试剂获得,虽然难于获得的化合物可通过以下制备方法合成。制备方法2-2
根据本制备方法,具有取代基的环状化合物可由卤原子取代其中G环如上定义,R5’为低级烷基和R5”为卤原子。
在与制备方法1-4,步骤2相同的方法中,使化合物[Ⅱ-5]氢化得到化合物[Ⅱ-6]。
用硫酰氯作为卤化剂,使化合物在卤代溶剂如二氯甲烷、氯仿、四氯化碳、四氯乙烯等中卤化,以取代4-烷基取代酚的邻位上的氯原子。制备方法2-3
根据本制备方法,环状化合物可由烷基磺酰基取代,其中G环如上定义,Q为羟基保护基团,R11为低级烷基。步骤1
在加热下,使化合物[Ⅱ-7]与烷基磺酸酐在卤代溶剂如二氯甲烷、氯仿、四氯化碳、四氢乙烯等中反应得到化合物[Ⅱ-8]。步骤2
通过常规方法,使按制备方法2-3,步骤1获得的化合物[Ⅱ-8]去保护得到化合物[Ⅱ-9]。
例如,当R11为甲基时,加入溴化氢水溶液并加热,或与氢化钠在二甲亚砜中加热,使去保护。制备方法2-4
在加热下,在诸如碳酸钾、碳酸钠、氢氧化锂、氢氧化钠、氢氧化钾、氢化锂、氢化钠、氢化钾等的碱存在下,使化合物[Ⅱ-10]与化合物[Ⅱ-11]在极性溶剂如二甲基甲酰胺、二甲亚砜、乙腈、丙酮等中缩合得到化合物[Ⅱ-12]。步骤2
在加热下,在烃溶剂如苯、甲苯、己烷、二甲苯等中,用缩合剂如多磷酸等,使按制备方法2-4,步骤1获得的化合物[Ⅱ-12]环合而得到化合物[Ⅱ-13]。步骤3
按照与制备方法1-4,步骤4相同的方法,使按制备方法2-4,步骤2获得的化合物[Ⅱ-13]经催化还原,得到化合物[Ⅱ-14]和[Ⅱ-15]。
所述溶剂的实例,除醇溶剂外,还包括醚溶剂如1,4-二氧六环、乙醚、1,2-二甲氧基乙烷、四氢呋喃等及其混合溶剂等。制备方法2-5
根据保护基团的类型,可通过常规去保护方法脱去羧基保护基团。
例如,当Z为甲基时,在适于去保护的加热条件下,在诸如碳酸钾、碳酸钠、氢氧化锂、氢氧化钠、氢氧化钾等的碱存在下,使化合物[Ⅱ-16]在醇溶剂如甲醇、乙醇、正丙醇、异丙醇等中反应,将生成的溶液酸化得到化合物[Ⅱ]。制备方法3
通过经缩合形成酰胺的常规方法,使按制备方法1获得的化合物[Ⅰ]或市售获得的试剂和按制备方法2获得的化合物[Ⅱ]或市售获得的试剂缩合。
例如,于室温下,用卤化剂如草酰氯、亚硫酰氯、磷酰氯、五氯化磷等在溶剂中处理化合物[Ⅱ],得到相应的酰氯。然后,于室温或冷却下,在叔胺如三乙胺等或吡啶的存在下,使该化合物与化合物[Ⅰ]缩合得到化合物[1]。
优选的溶剂实例包括卤代溶剂如二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷等,醚溶剂如1,4-二氧六环、乙醚、1,2-二甲氧基乙烷、四氢呋喃等。
或者,于室温下,在缩合剂存在下,使化合物[Ⅰ]和化合物[Ⅱ]在溶剂中反应得到化合物[1]。为使反应顺利进行,可使用增强剂。
缩合剂的实例包括N,N’-羰基二咪唑、N,N’-二环己基碳二亚胺、N,N’-二异丙基碳二亚胺、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)等,增强剂的实例包括羟基琥珀酰亚胺、1-羟基苯并三唑等。
优选溶剂的实例包括烃溶剂如苯、甲苯、己烷、二甲苯等,卤代溶剂如二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷等,醚溶剂如1,4-二氧六环、乙醚、1,2-二甲氧基乙烷、四氢呋喃等,极性溶剂如二甲基甲酰胺、二甲亚砜、乙腈等,及其混合溶剂。
为改进收率,降低成本等以提高生产效率,还原、去保护等可以在经缩合形成酰胺后进行。
例如,当化合物[Ⅰ]或化合物[Ⅱ]具有硝基时,该硝基可以在经缩合形成酰胺后被还原,或者,当化合物[Ⅰ]和化合物[Ⅱ]具有官能团如羟基等时,可以在经缩合形成酰胺后去保护。
或者,在用于还原的冷却条件下,在氩气流中,将按制备方法1-3和制备方法3获得的甲氧基羰基-取代的化合物加入醚溶剂如1,4-二氧六环、乙醚、1,2-二甲氧基乙烷、四氢呋喃等中,分次加入四氢硼酸锂,得到羟甲基-取代的化合物。
实施例
通过以下实施例具体说明本发明的式[1]化合物及其制备方法。不用说,本发明并不受这些实施例的限制。制备实施例1-14,6-二氨基-2-甲基喹啉的合成
根据参考出版物(Journal of the American Chemical Society,70,4065,1948)进行合成。步骤1
将4-氨基乙酰苯胺(150.2g,1mol)加入乙酰乙酸甲酯(136.8g,1.1mol)的甲醇(450ml)溶液中,加热回流该混合物17小时。将反应容器冷却至0℃,过滤收集生成的白色沉淀得到β-(对-乙酰氨基苯基氨基)巴豆酸甲酯(231.5g,93%,白色结晶)。步骤2
将在制备实施例1-1,步骤1中获得的β-(对-乙酰氨基苯基氨基)巴豆酸甲酯(231.5g,0.93mol)少量分批加入在加热下回流中的Dowtherm A(商标名,600ml)中。加热回流该混合物10分钟,使该反应混合物冷却至室温。过滤收集生成的沉淀并用乙酸乙酯洗涤。将获得的粗制结晶悬浮于甲醇中,过滤收集得到N-(4-羟基-2-甲基-6-喹啉基)乙酰胺(178.3g,88%,深黄色结晶)。步骤3
向在制备实施例1-1,步骤2中获得的N-(4-羟基-2-甲基-6-喹啉基)乙酰胺(100g,0.46mol)在甲苯(490ml)的悬浮液中加入硫酸二甲酯(75ml,0.79mol),将该混合物加热回流8小时。过滤收集生成的沉淀,使溶于水(1350ml)中,加热至70℃。过滤该溶液,将35%氢氧化钠水溶液(100ml)加入该滤液中。过滤收集生成的沉淀,得到N-(4-甲氧基-2-甲基-6-喹啉基)乙酰胺(55.3g,52%,浅棕色结晶)。步骤4
将在制备实施例1-1,步骤3中获得的N-(4-甲氧基-2-甲基-6-喹啉基)乙酰胺(55.6g,0.24mol)与乙酸铵(279.4g,3.62mol)混合,在加热至135℃下搅拌该混合物4小时。向该反应混合物中加入水(280ml)和浓盐酸(450ml),在加热至90℃下搅拌该混合物5小时。使该反应混合物冷却至0℃,过滤收集生成的沉淀。使获得的结晶溶于热水中,用活性炭处理并过滤。将35%氢氧化钠水溶液加入该滤液中,同时用冰冷却。过滤收集生成的沉淀,用水洗涤,于100℃减压干燥得到标题化合物(28.4g,68%,淡黄色结晶)。制备实施例1-24,6-二氨基-2-甲基喹啉的合成步骤1
向5-硝基靛红(19.21g,0.1mol)中加入丙酮(36.7ml,0.5mol)和氨水(100ml),将该混合物在高压釜中于100℃加热12小时。使该反应混合物冷却至室温,过滤收集生成的结晶,用水洗涤。经减压加热干燥获得的结晶,得到2-甲基-6-硝基喹啉-4-甲酰胺(18.30g,79%)。步骤2
向在制备实施例1-2,步骤1中获得的2-甲基-6-硝基喹啉-4-甲酰胺(231mg,1mmol)中加入次氯酸钠水溶液(0.851ml,1.2mmol),于0℃搅拌该混合物2.5小时。将该反应混合物滴加到加热回流的热水(10ml)中,并将该混合物加热回流20分钟。使该反应混合物冷却至室温,过滤收集生成的结晶并通过减压加热干燥,得到4-氨基-2-甲基-6-硝基喹啉(177mg,87%)。步骤3
将以制备实施例1-2,步骤2的相同方式获得的4-氨基-2-甲基-6-硝基喹啉(337mg,1.7mmol)溶于甲醇(15ml)中,向其中加入10%钯炭(200mg),于室温及3个大气压氢气下搅拌该混合物15小时。通过硅藻土经抽吸过滤该反应混合物,减压浓缩滤液,得到标题化合物(200mg,70%)。制备实施例1-36-氨基-2-甲基-4-甲基氨基喹啉的合成步骤1
将N-(4-羟基-2-甲基-6-喹啉基)乙酰胺(4.32g,20mmol)和磷酰氯(9.32ml,100mmol)于100℃加热15分钟。使该反应混合物冷却至室温,倾入冰水中。向其中加入28%氨水使该溶液呈碱性。过滤收集生成的不溶物,用醚和水洗涤,于80℃减压干燥,得到N-(4-氯代-2-甲基-6-喹啉基)乙酰胺(6.85g,粗品,黄色固体)。步骤2
将在制备实施例1-3,步骤1中获得的N-(4-氯代-2-甲基-6-喹啉基)乙酰胺(4.0g,粗品)和85%氢氧化钾(6.6g,100mmol)的N-甲基甲酰胺(100ml)的悬浮液于170℃加热3小时20分钟。将该反应混合物冷却至室温,用氯仿和水稀释该反应混合物。顺序用饱和碳酸氢钠水溶液、水和饱和盐水洗涤氯仿层,经硫酸钠干燥并减压浓缩。生成的黑色油状物经硅胶柱层析纯化(氯仿∶甲醇=85∶15→氯仿∶甲醇∶28%氨水=85∶15∶0.1),得到N-(2-甲基-4-甲基氨基-6-喹啉基)乙酰胺(255mg,9.5%得自N-(4-羟基-2-甲基-6-喹啉基)乙酰胺),为浅棕色固体。步骤3
将在制备实施例1-3,步骤2中获得的N-(2-甲基-4-甲基氨基-6-喹啉基)乙酰胺(248mg,1.08mmol)在6N盐酸(10ml)中加热回流2小时。将该反应混合物冷却至室温,加入4N氢氧化钠水溶液使pH不低于13,接着用冰冷却。过滤收集生成的不溶物,于60℃减压干燥,得到标题化合物(202mg,99.7%,淡黄色固体)。制备实施例1-44,6-二氨基喹啉二氢溴酸盐的合成
根据参考出版物的方法(Yakugaku Zasshi,72,665,1952),由步骤2至步骤4合成。步骤1
在110℃加热下,将4-硝基喹啉N-氧化物(10g,52.5mmol)和金属铁(26.4g,0.47mol)在乙酸(500ml)中的悬浮液搅拌3小时。过滤该反应混合物,减压浓缩滤液。向残留物中加入氢氧化钠水溶液,以使该溶液呈碱性,接着用氯仿(50ml×6)萃取之。用水和饱和盐水洗涤有机层,经硫酸钠干燥,减压浓缩得到4-氨基喹啉(6.0g,79%,棕色结晶)。步骤2
在冰冷却及搅拌下,向在制备实施例1-4,步骤1中获得的4-氨基喹啉(2.28g,15.8mmol)的乙酸(30ml)溶液中加入溴(2.78g,17.4mmol),于室温下搅拌该混合物30分钟。加入乙醚,过滤收集生成的沉淀,得到4-氨基-3-溴代喹啉氢溴酸盐(4.39g,91%)。使获得的结晶溶于水中,加入1N氢氧化钠水溶液,以使该溶液呈碱性,过滤收集生成的沉淀,用水洗涤,减压干燥得到4-氨基-3-溴代喹啉(2.91g,82%,浅灰色结晶)。步骤3
在冰冷却及搅拌下,向在制备实施例1-4,步骤2中获得的4-氨基-3-溴代喹啉(2.90g,13mmol)的浓硫酸(25ml)溶液中加入60%硝酸(1.5ml,20mmol),搅拌该混合物1小时。在冰冷却下,向该反应混合物中加入氢氧化钠(40g),过滤收集生成的沉淀。使获得的结晶溶于丙酮中,用活性炭处理,重结晶得到4-氨基-3-溴代-6-硝基喹啉(1.65g,47%,黄色结晶)。步骤4
向在制备实施例1-4,步骤3中获得的4-氨基-3-溴代-6-硝基喹啉(0.82g,3.05mmol)的乙醇(30ml)溶液中加入25%溴化氢-乙酸溶液(0.7ml,3.05mmol)和10%钯炭催化剂,于室温下,使该混合物经催化还原6小时。滤除催化剂并用水洗涤。减压浓缩滤液。从水-乙醇-乙酸乙酯中重结晶所得的残留物,得到标题化合物(0.92g,94%,棕绿色结晶)。制备实施例1-51,7-二氨基异喹啉的合成步骤1
在适于溶解的冰冷却下,将浓硫酸(80ml)少量分批加入四氢异喹啉(24.4g,183mmol)中。然后经加液漏斗滴加60%硝酸(18ml),在冰冷却下搅拌该混合物3小时。于室温下搅拌该混合物18小时。在冰冷却下,用水稀释该反应混合物,加入35%氢氧化钠水溶液,以调节该溶液至pH12。用氯仿提取后,用水洗涤有机层,经无水硫酸镁干燥并减压浓缩。使残留物溶于乙醇(180ml)中,在冰冷却下加入浓盐酸(20ml)。抽滤收集沉淀的棕色结晶,得到7-硝基四氢异喹啉盐酸盐(7.18g,22%)。步骤2
向在制备实施例1-5,步骤1中获得的7-硝基四氢异喹啉盐酸盐(7.18g,33mmol)中加入在4%碳酸钠水溶液(1.5L)中的Fremy’s盐(100g,280mmol)。于室温下搅拌该混合物7天,用氯仿提取该反应混合物,经无水硫酸镁干燥并减压浓缩。使残留物经中性氧化铝柱层析纯化(己烷∶乙酸乙酯=3∶2),得到7-硝基异喹啉(3.21g,55%)。步骤3
向在制备实施例1-5,步骤2中获得的7-硝基异喹啉(2.38g,14mmol)的氯仿(68ml)溶液中加入间氯过苯甲酸(3.54g,21mmol),于室温下搅拌该混合物21小时。抽滤除去氯仿中的不溶物,用氯仿洗涤。用碳酸氢钠水溶液和饱和盐水洗涤滤液,经无水硫酸镁干燥并减压浓缩,得到7-硝基异喹啉N-氧化物。获得的化合物可无需纯化而用于下一步骤。步骤4
在制备实施例1-5,步骤3中获得的7-硝基异喹啉N-氧化物的甲苯(185ml)的悬浮液中加入磷酰氯(3.5ml,37mmol),于90℃加热下,搅拌该混合物2小时。使该反应混合物冷却至室温,将该反应混合物倾入碳酸氢钠水溶液中。用乙酸乙酯提取水层。用饱和盐水洗涤有机层,经无水硫酸镁干燥并减压浓缩。残留物经硅胶柱层析纯化(氯仿∶丙酮=30∶1),得到1-氯-7-硝基异喹啉(540mg,14%)。步骤5
向在制备实施例1-5,步骤4中获得的1-氯-7-硝基异喹啉(670mg,3.21mmol)的甲醇(100ml)的悬浮液中加入1M甲醇钠溶液(6.5ml,6.5mmol),将该混合物加热回流3小时并减压浓缩。使残留物溶于乙酸乙酯中,用饱和盐水洗涤,经无水硫酸镁干燥并减压浓缩。残留物经硅胶柱层析纯化(氯仿∶丙酮=30∶1),得到1-甲氧基-7-硝基异喹啉(530mg,81%)。步骤6
将在制备实施例1-5,步骤5中获得的1-甲氧基-7-硝基异喹啉(530mg,2.60mmol)和乙酸铵(3g,39.0mmol)的混合物于135℃加热下搅拌4小时。将该反应混合物加入碳酸氢钠水溶液中,用氯仿提取。用饱和盐水洗涤有机层,经无水硫酸镁干燥并减压浓缩。残留物经硅胶柱层析纯化(己烷∶乙酸乙酯=2∶3),得到1-氨基-7-硝基异喹啉(246mg,50%)。步骤7
将在制备实施例1-5,步骤6中获得的1-氨基-7-硝基异喹啉(246mg,1.3mmol)和5%钯炭(100mg)在甲醇(100ml)中的混合物于室温下及常压氢气下搅拌8小时。将该反应混合物通过硅藻土抽滤,减压浓缩滤液得到标题化合物(203mg,99%)。制备实施例1-67,9-二氨基-1,2,3,4-四氢吖啶的合成步骤1
向5-硝基氨基苯甲腈(1.63g,10mmol)和环己酮(10.3ml,100mmol)的混合物中加入氯化锌(1.36g,10mmol),将该混合物加热回流20分钟。将该反应混合物冷却至室温,用乙酸乙酯稀释,滤除不溶物。减压浓缩滤液,将氯仿加入获得的棕色油状物中。过滤收集生成的黄色沉淀,于80℃减压干燥。用乙酸乙酯和1N氢氧化钠水溶液稀释该固体(1.56g),加入乙醚。过滤收集不溶物,于80℃减压干燥,得到9-氨基-7-硝基-1,2,3,4-四氢吖啶(810mg,33%),为黄色固体。步骤2
将在制备实施例1-6,步骤1中获得的9-氨基-7-硝基-1,2,3,4-四氢吖啶(773mg,3.18mmol)溶解于四氢呋喃(5ml)和乙醇(5ml)的混合溶剂中,加入5%钯炭(500mg),其后于室温和常压下氢化。7小时后,使该反应混合物通过硅藻土。浓缩滤液得到标题化合物(665mg,98%),为黄色油状物。制备实施例2-12-[(4-乙基苯氧基)甲基]苯甲酸的合成步骤1
向邻-甲苯甲酸甲酯(15.0g,0.1mol)的四氯化碳(200ml)溶液中加入N-溴代琥珀酰亚胺(18.7g,0.1mol)和过氧化苯甲酰(催化量),将该混合物加热回流2小时。使该反应混合物冷却至室温,滤除生成的沉淀。减压浓缩滤液,得到α-溴代-邻甲苯甲酸甲酯(黄色油状物)。得到的油状物可无需纯化而用于下一步骤。步骤2
向在制备实施例2-1,步骤1中获得的α-溴代-邻甲苯甲酸甲酯(2.29g,10mmol)和4-乙基苯酚(1.28g,10.5mmol)的二甲基甲酰胺(50ml)溶液中加入碳酸钾(4.15g,30mmol)。于100℃加热下搅拌该混合物1小时。将该反应混合物加入乙酸乙酯(100ml)中并用水和饱和盐水洗涤。经硫酸钠干燥有机层,减压蒸发溶剂。残留物经硅胶柱层析纯化(己烷∶乙酸乙酯=100∶5),得到2-[(4-乙基苯氧基)甲基]苯甲酸甲酯(1.96g,73%)。步骤3
向在制备实施例2-1,步骤2中获得的2-[(4-乙基苯氧基)甲基]苯甲酸甲酯(1.96g,7.3mmol)的乙醇(20ml)溶液中加入2N氢氧化钾水溶液(11ml,21.8mmol),加热回流下搅拌该混合物2小时。向该反应混合物中加入水(70ml)和6N盐酸(5ml),过滤收集生成的沉淀并用水洗涤。获得的固体经减压干燥得到标题化合物(1.75g,94%,白色结晶)。制备实施例2-22-氯代-4-乙基苯酚的合成
将4-乙基苯酚(25.4g,0.21mol)和硫酰氯(18.5ml,0.23mmol)的四氯化碳(40ml)溶液在70℃加热下搅拌3小时。用氯仿稀释该反应混合物,用水洗涤。经硫酸镁干燥有机层,减压蒸发溶剂。残留物经硅胶柱层析纯化(己烷∶乙酸乙酯=9∶1),得到2-氯代-4-乙基苯酚(25.1g,77%)。制备实施例2-34-甲基磺酰基苯酚的合成步骤1
向苯甲醚(3.3ml,30mmol)的四氯乙烯(30ml)溶液中加入甲磺酸酐(5.75g,33mmol),在145℃加热下搅拌该混合物18小时。加水至该反应混合物中,用乙醚提取该混合物。用饱和盐水洗涤有机层,经硫酸镁干燥,减压蒸发溶剂。残留物经硅胶柱层析纯化(己烷∶乙酸乙酯=1∶1),得到的结晶自己烷-乙酸乙酯中重结晶两次,得到4-甲基磺酰基苯甲醚(505mg,9%,无色结晶)。步骤2
向在制备实施例2-3,步骤1中获得的4-甲基磺酰基苯甲醚(505mg,2.7mmol)中加入48%溴化氢水溶液(3ml),将该混合物加热回流10小时。加水至该反应混合物中,用氯仿提取该混合物。经硫酸镁干燥有机层,减压蒸发溶剂,得到标题化合物(256mg,55%,无色结晶)。获得的化合物可无需纯化而用于下一步反应。制备实施例2-42-[(5-苯并呋喃基氧基)甲基]苯甲酸甲酯和2-[(2,3-二氢苯并呋喃-5-基氧基)甲基]苯甲酸甲酯的合成步骤1
向4-(苄氧基)苯酚(10.01g,50mmol)和溴代乙醛缩二乙醇(7.52ml,50mmol)的二甲基甲酰胺(100ml)溶液中加入碳酸钾(10.37g,75mmol),于170℃加热该混合物。2.5小时后,将该反应混合物冷却至室温。用水和乙酸乙酯稀释该混合物,移去水层。用饱和碳酸氢钠水溶液和饱和盐水洗涤有机层,经硫酸钠干燥并减压浓缩。残留物经硅胶柱层析纯化(己烷∶乙酸乙酯=9∶1),得到2-[4-(苄氧基)苯氧基]乙醛缩二乙醇(11.902g,75%,浅棕色油状物)。步骤2
将在制备实施例24,步骤1中获得的2-[4-(苄氧基)苯氧基]乙醛缩二乙醇(3.16g,10mmol)和多磷酸(3.16g)在甲苯(30ml)中于100℃加热。40分钟后,使该混合物冷却至室温,用乙醚稀释该反应混合物,通过倾析分离上清液。减压浓缩上清液,残留物经硅胶柱层析纯化(己烷∶乙酸乙酯=20∶1),得到5-(苄氧基)苯并呋喃(1.032g,46%,淡黄色油状物)。步骤3
将在制备实施例2-4,步骤2中获得的5-(苄氧基)苯并呋喃(1.02g,4.55mmol)溶解于乙醇(5ml)和乙酸乙酯(5ml)的混合溶剂中,加入5%钯炭(500mg),其后于室温和常压下氢化。2小时后,使该反应混合物通过硅藻土,减压浓缩滤液。使残留物溶于二甲基甲酰胺(20ml)中,加入α-溴代-邻甲苯甲酸甲酯(1.042g,4.55mmol)和碳酸钾(1.26g,9.10mmol)。于100℃加热该混合物1.25小时,冷却至室温。用水和乙酸乙酯稀释该反应混合物,以分离各层。用饱和碳酸氢钠水溶液和饱和盐水洗涤有机层,经硫酸钠干燥并减压浓缩。残留物经硅胶柱层析纯化(己烷∶乙酸乙酯=9∶1),得到2-[(5-苯并呋喃基氧基)甲基]苯甲酸甲酯(352mg,27%,白色结晶)和2-[(2,3-二氢苯并呋喃-5-基氧基)甲基]苯甲酸甲酯(220mg,17%,淡黄色油状物)。实施例1N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-乙基苯氧基)甲基]苯甲酰胺盐酸盐的合成
向在制备实施例2-1中获得的2-[(4-乙基苯氧基)甲基]苯甲酸(1.13g,4.4mmol)的氯仿(20ml)溶液中加入草酰氯(0.6ml,6.8mmol),于室温下搅拌该混合物1小时。然后减压浓缩该反应混合物。向获得的酰氯中加入吡啶(20ml)和在制备实施例1-1中获得的4,6-二氨基-2-甲基喹啉(623mg,4mmol),于室温下搅拌该混合物10小时。向该反应混合物中加入碳酸氢钠水溶液,用乙酸乙酯提取该混合物。用水和饱和盐水洗涤有机层,经硫酸钠干燥并蒸发溶剂。使获得的粗产物溶于乙醇中,用活性炭处理,蒸发溶剂。使获得的残留物溶于乙酸乙酯中,加入1N盐酸-乙醚溶液。过滤收集生成的沉淀。加热获得的固体,减压干燥,得到标题化合物(1.06g,59%,淡黄色结晶)。对于C26H25N3O2·HCl的元素分析
计算值:C:69.71%,H:5.85%,N:9.38%
实测值:C:69.77%,H:5.78%,N:9.41%
熔点:235℃实施例131N-(4-氨基-2-羟甲基-6-喹啉基)-2-[(4-甲基苯氧基)甲基]苯甲酰胺盐酸盐的合成步骤1
将4-硝基苯胺(6.91g,50mmol)和乙炔二羧酸二甲酯(7.82g,55mmol)的甲醇(100ml)溶液加热回流24.5小时。将反应容器冷却至室温并静置1天。过滤收集生成的结晶,得到2-[(4-硝基苯基)氨基]-2-丁烯二酸二甲酯(6.43g,46%,黄色结晶)。步骤2
用5分钟将在制备实施例131,步骤1中获得的2-[(4-硝基苯基)氨基]-2-丁烯二酸二甲酯(6.32g,22.6mmol)少量分批加入在加热下回流中的Dowtherm A(商标名,30ml)中。加热回流该混合物25分钟,使该反应混合物冷却至室温。用乙醚稀释该反应混合物,过滤生成的沉淀。使获得的粗制结晶悬浮于甲醇中,过滤收集得到1,4-二氢-6-硝基-4-氧代-2-喹啉甲酸甲酯(4.75g,85%,深棕色结晶)。步骤3
向在实施例131,步骤2中获得的1,4-二氢-6-硝基-4-氧代-2-喹啉甲酸甲酯(3.72g,15mmol)在乙腈(50ml)的悬浮液中加入氯代磺酰基异氰酸酯(1.30ml,15mol),将该混合物加热回流1小时。使该反应混合物冷却至室温,加入甲醇,其后减压浓缩。向该残留物中加入2mol/l碳酸钠水溶液使悬浮,过滤收集不溶物。于80℃减压干燥该不溶物,得到为粗品棕色结晶的4-氨基-6-硝基-2-喹啉甲酸甲酯(3.23g)。该化合物可无需纯化而用于下一步反应。步骤4
将在实施例131,步骤3中获得的4-氨基-6-硝基-2-喹啉甲酸甲酯的粗品结晶(494mg)和5%钯炭(500mg)在乙醇(10ml)中的悬浮液于室温及常压下氢化。2.5小时后,使该反应混合物通过硅藻土。减压浓缩滤液,得到4,6-二氨基-2-喹啉甲酸甲酯粗品(275mg,黄色泡沫状固体)。该化合物可无需纯化而用于下一步反应。步骤5
按照如实施例1相同的方法,使在实施例131,步骤4中获得的4,6-二氨基-2-喹啉甲酸甲酯的粗产物(270mg)和如制备实施例2-1的相同方法获得的2-[(4-甲基苯氧基)甲基]苯甲酸(363mg,1.5mmol)缩合为酰胺,得到N-(4-氨基-2-甲氧基羰基-6-喹啉基)-2-[(4-甲基苯氧基)甲基]苯甲酰胺(175mg,17%得自1,4-二氢-6-硝基-4-氧代-2-喹啉甲酸甲酯),为黄色固体。步骤6
在冰冷却下及氩气流中,向在实施例131,步骤5中获得的N-(4-氨基-2-甲氧基羰基-6-喹啉基)-2-[(4-甲基苯氧基)甲基]苯甲酰胺(170mg,0.385mmol)的四氢呋喃(10ml)溶液中少量分次加入四氢硼酸锂(42mg,1.927mmol)。10分钟后,使该混合物温热至室温,搅拌该混合物2小时。用饱和盐水和乙酸乙酯稀释该反应混合物以分离各层。用饱和盐水洗涤有机层,经无水硫酸钠干燥并减压浓缩。使获得的黄色残留物溶于乙酸乙酯中,加入4N盐酸-二氧六环溶液(0.5ml)以便沉淀盐酸盐。过滤收集该盐,于80℃减压干燥,得到标题化合物(116mg,67%,淡黄色结晶)。
按照如实施例1或131相同的方法处理如在制备实施例1-1至1-6的相同方法中获得的氨基-取代的化合物或市售获得的氨基-取代的化合物和如制备实施例2-1至2-4的相同方法获得的羧酸衍生物或市售获得的羧酸衍生物,得到实施例2至实施例130和实施例132的化合物。特征值示于表1至表44中。实施例133N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-乙基苯氧基)甲基]苯甲酰胺盐酸盐一水合物的合成
向N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-乙基苯氧基)甲基]苯甲酰胺盐酸盐的粗制结晶(24.0g,53.7mmol)(按照如实施例1相同的方法获得)中加入乙醇(120ml),将该混合物加热至55-60℃以便溶解。过滤该溶液,在加热至55-60℃及搅拌下,将水(120ml)滴加到滤液中。使该反应混合物冷却至室温,过滤生成的沉淀。于60℃及1mmHg下,将获得的固体干燥3天,得到标题化合物(22.6g,94%,无色结晶)。对于C26H25N3O2·HCl·H2O的元素分析
计算值:C:67.02%,H:6.06%,N:9.02%
实测值:C:66.64%,H:6.06%,N:8.99%
熔点:130℃ 表1 表2 表3 表4 表5 表6 表7 表8 表9 表10 表11 表12 表13 表14 表15 表16 表17 表18 表19 表20 表21 表22 表23 表24 表25 表26 表27 表28 表29 表30 表31 表32 表33 表34 表35 表36 表37 表38 表39 表40 表41 表42 表43 表44
评价本发明化合物的止痛效果的方法解释如下。
对于体外评价来说,可进行ORL-1受体结合测定,而进行μ受体结合测定以评价选择性。对于体内评价来说,进行早已知道的热板实验和弹尾实验用作止痛效果的实验方法,采用异常性疼痛模型进行触觉刺激实验以评价异常性疼痛。实验实施例[1]:ORL-1受体结合测定
使用Tris缓冲液[50mM Tris,2mM EDTA,0.1mM(对脒基苯基)甲磺酰氟盐酸盐(p-APMSF),2mg/ml BSA],将得自人ORL-1表达细胞的细胞膜悬浮液调节至约25μg/ml(2.5μg/孔)的膜蛋白量。将其与[3H]nociceptin(用Tris缓冲液稀释至终浓度0.5nM)和试验化合物(用Tris缓冲液稀释至终浓度10nM-10μM)混合,将该混合物于室温下孵育60分钟。使用细胞收获器在G/F-B滤膜(Packard,Unifilter 96GF/B)上回收所述膜并终止反应。洗涤3次后,于42℃干燥滤膜1小时。加入闪烁液(Packard,microscint-20),测定放射活性(Packard,Top countA99 12V)。
非特异性结合为在1μM nociceptin存在下的结合,用总结合与非特异性结合之差作为特异性结合。由每一浓度的化合物的特异性结合的抑制计算IC50,试验化合物的Ki值由该值和[3H]nociceptin的Kd值计算。实验实施例[2] μ受体结合测定
将大鼠大脑膜标准样品(终浓度0.755mg·蛋白/ml)、[3H]DAMGO(Try-D-Ala-Gly-NMe-Phe-Gly-ol)[用Tris缓冲液(50mM Tris-HCl,0.1mM p-APMSF,2mg/ml BSA(pH=7.4))稀释至终浓度1nM]和试验化合物(用Tris缓冲液稀释至终浓度10nM-10μM)混合,该混合物于室温下孵育90分钟。使用细胞收获器在G/F-B滤膜(与上述相同)上回收所述膜并终止反应。洗涤3次后,于42℃干燥滤膜1小时。加入闪烁液(与上述相同),测定放射活性(与上述相同)。
非特异性结合为在10μM纳洛酮存在下的结合,用总结合与非特异性结合之差作为特异性结合。由每一浓度的化合物的特异性结合的抑制计算IC50,试验化合物的Ki值由该值和[3H]DAMGO的Kd值计算。实验实施例[3] 热板实验
将小鼠(Crj,ICR,4周龄,雄性)置于热板(温度55.5±0.5℃)上,记录直至小鼠跳起并试图逃离的时间。根据该时间和体重给小鼠分组,以使各组具有大致平均的成员。将试验化合物悬浮于0.5%甲基纤维素(MC)溶液中,口服给予小鼠。60分钟后,将小鼠再次置于热板上,记录直至小鼠舔它们的后爪或跳起并试图逃离的时间。采用ANOVA,接着通过Dunnett双尾检验分析与给予溶剂组的显著差异。实验实施例[4] 弹尾实验
在大鼠(Crj,SD,7或8-周龄,雄性)尾端周围,从下面用暖光束照射大鼠,用弹尾止痛效果测量装置(由UGO BASILE制造)测定直至大鼠移开尾巴并逃离的时间。在给予试验化合物前,重复测量3次,根据该时间和体重给大鼠分组,以使各组具有大致平均的成员。将试验化合物悬浮于0.5%MC溶液中,口服给予大鼠。给药30、60、90、120和180分钟后,重复同样的测量。采用ANOVA,接着通过Dunnett双尾检验分析与给予溶剂组的显著差异。实验实施例[5] 异常性疼痛实验
不用麻醉,鞘内给予小鼠(Crj,ICR,4周龄,雄性)nociceptin(50pg/5μl)。在给药后20分钟的时间内,间隔5分钟,用刷子擦小鼠尾部外侧区域,观察小鼠的反应。根据以下标准进行评价:0:无变化,1:跑开或对触觉刺激叫唤,2:大声叫唤或对触觉刺激急忙逃开。将试验化合物悬浮于0.5%MC溶液中,给予nociceptin前60分钟口服给予小鼠试验化合物。用Mann-Whitny U-试验分析各给药组在给予nociceptin后20分钟的分值与给予溶剂组分值的显著性差异。
实验实施例[1]-[5]的结果示于表45-47中。
从以上实验结果证实,本发明化合物显示出因nociceptin拮抗作用所致的强的止痛效果,与阿片样受体(μ、κ、δ受体)包括μ受体相比,其部分显示出对ORL-1受体的选择性作用。
因此,本发明化合物可使药物有效地缓解疼痛,尤其是剧痛如手术后疼痛等或由感觉神经异常如痛觉过敏和异常性疼痛等引起的疼痛。此外,由于所述化合物显示出对ORL-1受体的选择性作用,它可能是没有显著副作用的安全的药物。
本申请以在日本提交的申请号100029/1998的申请为基础,其内容通过引用结合到本文中。
Claims (20)
1.包含作为活性成分的式[1]的酰胺衍生物或其药学上可接受的盐的nociceptin拮抗剂:其中R1和R2可相同或不同,各自为氢原子、由羟基、氨基、低级烷基氨基或二(低级)烷基氨基任选取代的低级烷基;R3和R4可相同或不同,各自为氢原子、卤原子或低级烷基;A环为芳基或杂环基;B环为苯基、噻吩基、呋喃基、吡咯基、吡咯烷基、噁唑剂或环己烯基;及X为氢原子、卤原子、由低级烷氧基、低级链烯基、氨基、氰基或下式的基团任选取代的低级烷基:其中E为单键、羰基、亚磺酰基、-O-、-S-、-NHCO-、-CH=CR6-,其中R6为氢原子或芳基或-NR7-,其中R7为氢原子、低级烷基或低级烷氧基羰基;G环为芳基、杂环基、环烷基或稠合的芳基;R5为卤原子、羟基、由任一卤原子、羟基、低级链烷酰基氧基和由低级烷氧基任选取代的低级烷氧基任选取代的低级烷基、由低级烷氧基任选取代的低级烷氧基、氨基、低级烷基氨基、二(低级)烷基氨基、硝基、氰基、低级链烷酰基、低级链烷酰基氧基、羧基、低级烷氧基羰基、低级烷基磺酰基或苯基;t是0或1-5的整数,其表示G环上取代基的数目,其中当t是2-5的整数时,每个R5可以相同或不同;m是0或1-8的整数;及n是0或1-4的整数。
2.包含作为活性成分的权利要求1的酰胺衍生物或其药学上可接受的盐的nociceptin拮抗剂,其中A环为喹啉基。
5.式[1’]的酰胺衍生物或其药学上可接受的盐,其中R2、B环、E、G环、R5、t、m和n如权利要求1所定义。
6.权利要求5的酰胺衍生物或其药学上可接受的盐,其中B环为苯基,R2为低级烷基。
7.权利要求6的酰胺衍生物或其药学上可接受的盐,其中氨基在喹啉骨架的4-位取代,R2为在喹啉骨架的2-位上取代的甲基,E为-O-,B环苯基在2-位上具有下式的取代基其中G环、R5、t、m和n如权利要求1所定义。
8.权利要求7的酰胺衍生物或其药学上可接受的盐,其选自:N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-乙基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(2,4-二氯苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-(苯氧基甲基)苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-甲氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3,5-二甲基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3,4-二甲氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-硝基苯氧基)甲基]苯甲酰胺,N-(4-氨基-2-甲基-6-喹啉基)-2-[(2,3-二甲氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3-甲基苯氧基)甲基]苯甲酰胺,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3,5-二甲氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-氯代苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-乙酰基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-羟基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-甲氧基甲氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3-甲氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-氰基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-甲基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-三氟甲基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3-硝基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(2-硝基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-乙酰氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(2-甲氧基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-氨基苯氧基)甲基]苯甲酰胺二盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3-氯代苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-氟代苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3,4-二氯苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(2-氯代苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-二甲基氨基苯氧基)甲基]苯甲酰胺二盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-叔丁基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-(4-联苯基氧基甲基)苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-异丙基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-硝基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-溴代苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-丙基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3-氟代苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3-三氟甲基苯氧基)甲基]苯甲酰胺盐酸盐,4-[2-{N-(4-氨基-2-甲基-6-喹啉基)氨基甲酰基}苄氧基]苯甲酸甲酯盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-碘代苯氧基)甲基]苯甲酰胺,N-(4-氨基-2-甲基-6-喹啉基)-2-(3-吡啶基氧基甲基)苯甲酰胺盐酸盐,4-[2-{(4-氨基-2-甲基-6-喹啉基)氨基甲酰基}苄氧基]苯甲酸酯盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(3-氰基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-甲磺酰基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(2-氯代-4-乙基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-氯代-3-甲基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(2-氯代-4-甲基苯氧基)甲基]苯甲酰胺盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-乙基苯氧基)甲基]苯甲酰胺,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-氯代-3-甲基苯氧基)甲基]苯甲酰胺,4-[2-{(4-氨基-2-甲基-6-喹啉基)氨基甲酰基}苄氧基]苄基乙酸酯盐酸盐,N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-羟甲基苯氧基)甲基]苯甲酰胺盐酸盐和N-(4-氨基-2-甲基-6-喹啉基)-2-[(4-乙基苯氧基)甲基]苯甲酰胺盐酸盐一水合物。
10.含有权利要求5-9中任一项的酰胺衍生物或其药学上可接受的盐和药学上可接受的载体的药用组合物。
11.含有作为活性成分的权利要求5-9中任一项的酰胺衍生物或其药学上可接受的盐的nociceptin拮抗剂。
12.含有作为活性成分的权利要求1-9中任一项的酰胺衍生物或其药学上可接受的盐的镇痛剂。
13.发挥nociceptin拮抗作用的方法,包括给予权利要求1-9中任一项的酰胺衍生物或其药学上可接受的盐。
14.治疗疼痛的方法,包括给予权利要求1-9中任一项的酰胺衍生物或其药学上可接受的盐。
15权利要求1-9中任一项的酰胺衍生物或其药学上可接受的盐在nociceptin拮抗剂的生产中的用途。
16.权利要求1-9中任一项的酰胺衍生物或其药学上可接受的盐在镇痛剂的生产中的用途。
17.用于拮抗nociceptin的药用组合物,它包含权利要求1-9中任一项的酰胺衍生物或其药学上可接受的盐和药学上可接受的载体。
18.包括权利要求17的药用组合物和与此有关的书面材料的市售包装物,所述书面材料说明该药用组合物可以或应该用于拮抗nociceptin的用法。
19.用于止痛用途的药用组合物,它包括权利要求1-9中任一项的酰胺衍生物或其药学上可接受的盐和药学上可接受的载体。
20.包括权利要求19的药用组合物和与此有关的书面材料的市售包装物,所述书面材料说明该药用组合物可以或应该用于止痛的用法。
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JP10002998 | 1998-03-26 | ||
JP100029/1998 | 1998-03-26 |
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CN99806429A Pending CN1301154A (zh) | 1998-03-26 | 1999-03-23 | 酰胺衍生物和nociceptin拮抗剂 |
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US (3) | US6410561B1 (zh) |
EP (1) | EP1072263A4 (zh) |
KR (1) | KR20010042161A (zh) |
CN (1) | CN1301154A (zh) |
AR (1) | AR018168A1 (zh) |
AU (1) | AU754716B2 (zh) |
BR (1) | BR9909666A (zh) |
CA (1) | CA2325638A1 (zh) |
CO (1) | CO5080780A1 (zh) |
FI (1) | FI20002103A (zh) |
HU (1) | HUP0101275A3 (zh) |
ID (1) | ID26099A (zh) |
IL (1) | IL138573A0 (zh) |
NO (1) | NO20004778L (zh) |
NZ (1) | NZ507760A (zh) |
RU (1) | RU2202344C2 (zh) |
SK (1) | SK14272000A3 (zh) |
TR (1) | TR200003598T2 (zh) |
TW (1) | TW487571B (zh) |
WO (1) | WO1999048492A1 (zh) |
ZA (1) | ZA200005881B (zh) |
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- 1999-03-23 KR KR1020007010601A patent/KR20010042161A/ko not_active Application Discontinuation
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- 1999-03-23 TR TR2000/03598T patent/TR200003598T2/xx unknown
- 1999-03-23 WO PCT/JP1999/001462 patent/WO1999048492A1/ja not_active Application Discontinuation
- 1999-03-24 TW TW088104619A patent/TW487571B/zh not_active IP Right Cessation
- 1999-03-26 CO CO99018458A patent/CO5080780A1/es unknown
- 1999-03-26 AR ARP990101349A patent/AR018168A1/es not_active Application Discontinuation
-
2000
- 2000-09-25 NO NO20004778A patent/NO20004778L/no unknown
- 2000-09-25 FI FI20002103A patent/FI20002103A/fi unknown
- 2000-10-20 ZA ZA200005881A patent/ZA200005881B/en unknown
-
2002
- 2002-05-10 US US10/141,866 patent/US6903094B2/en not_active Expired - Fee Related
-
2005
- 2005-06-06 US US11/145,169 patent/US20060030565A1/en not_active Abandoned
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105461623A (zh) * | 2015-12-29 | 2016-04-06 | 江苏理工学院 | 4-氨基-6-硝基-3-溴喹啉合成方法 |
Also Published As
Publication number | Publication date |
---|---|
WO1999048492A1 (fr) | 1999-09-30 |
CO5080780A1 (es) | 2001-09-25 |
EP1072263A1 (en) | 2001-01-31 |
HUP0101275A2 (hu) | 2001-09-28 |
CA2325638A1 (en) | 1999-09-30 |
NO20004778D0 (no) | 2000-09-25 |
RU2202344C2 (ru) | 2003-04-20 |
EP1072263A4 (en) | 2004-03-31 |
HUP0101275A3 (en) | 2002-12-28 |
TW487571B (en) | 2002-05-21 |
US20060030565A1 (en) | 2006-02-09 |
IL138573A0 (en) | 2001-10-31 |
KR20010042161A (ko) | 2001-05-25 |
ZA200005881B (en) | 2001-08-23 |
NZ507760A (en) | 2002-10-25 |
AR018168A1 (es) | 2001-10-31 |
FI20002103A (fi) | 2000-11-17 |
SK14272000A3 (sk) | 2001-05-10 |
NO20004778L (no) | 2000-11-27 |
US6903094B2 (en) | 2005-06-07 |
US6410561B1 (en) | 2002-06-25 |
BR9909666A (pt) | 2001-09-11 |
ID26099A (id) | 2000-11-23 |
AU2855899A (en) | 1999-10-18 |
AU754716B2 (en) | 2002-11-21 |
US20030055087A1 (en) | 2003-03-20 |
TR200003598T2 (tr) | 2001-06-21 |
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