CN114702428A - 连双环结构sigma-1受体抑制剂 - Google Patents
连双环结构sigma-1受体抑制剂 Download PDFInfo
- Publication number
- CN114702428A CN114702428A CN202210273347.8A CN202210273347A CN114702428A CN 114702428 A CN114702428 A CN 114702428A CN 202210273347 A CN202210273347 A CN 202210273347A CN 114702428 A CN114702428 A CN 114702428A
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- Prior art keywords
- formula
- alkyl
- methyl
- hydrochloride
- morpholine
- 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.)
- Granted
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- 102100028656 Sigma non-opioid intracellular receptor 1 Human genes 0.000 title abstract description 32
- 101710104750 Sigma non-opioid intracellular receptor 1 Proteins 0.000 title abstract description 27
- 239000003112 inhibitor Substances 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 99
- 239000003814 drug Substances 0.000 claims abstract description 14
- 239000000126 substance Substances 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 95
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 80
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 69
- 229910052799 carbon Inorganic materials 0.000 claims description 66
- -1 hydroxy, methyl Chemical group 0.000 claims description 62
- 229910052757 nitrogen Inorganic materials 0.000 claims description 60
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- 239000001257 hydrogen Substances 0.000 claims description 43
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 37
- 125000001188 haloalkyl group Chemical group 0.000 claims description 34
- 150000002431 hydrogen Chemical class 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
- 125000001624 naphthyl group Chemical group 0.000 claims description 32
- 150000001408 amides Chemical class 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 25
- 229910052717 sulfur Inorganic materials 0.000 claims description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 18
- 208000002193 Pain Diseases 0.000 claims description 17
- 230000036407 pain Effects 0.000 claims description 17
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical group CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 14
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 13
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 10
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000004550 quinolin-6-yl group Chemical group N1=CC=CC2=CC(=CC=C12)* 0.000 claims description 10
- 108010085082 sigma receptors Proteins 0.000 claims description 10
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 239000011630 iodine Substances 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 9
- 229940047889 isobutyramide Drugs 0.000 claims description 9
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 7
- 229940080818 propionamide Drugs 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- OCQJTPOBDCTHIW-UHFFFAOYSA-N CC(C1=C(C=CN2C3=CC=C4N=CC=CC4=C3)C2=CC=C1)N1CCOCC1 Chemical compound CC(C1=C(C=CN2C3=CC=C4N=CC=CC4=C3)C2=CC=C1)N1CCOCC1 OCQJTPOBDCTHIW-UHFFFAOYSA-N 0.000 claims description 5
- OMSRDOAESQHRKH-UHFFFAOYSA-N C(CN1CCOCC1)C1=C(C=CN2C3=CC=C4N=CC=CC4=C3)C2=CC=C1 Chemical compound C(CN1CCOCC1)C1=C(C=CN2C3=CC=C4N=CC=CC4=C3)C2=CC=C1 OMSRDOAESQHRKH-UHFFFAOYSA-N 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- ZAIDVSUVEHFYIA-UHFFFAOYSA-N C(C1=C(C=CN2C3=CC=C4N=CC=CC4=C3)C2=CC=C1)N1CCSCC1 Chemical compound C(C1=C(C=CN2C3=CC=C4N=CC=CC4=C3)C2=CC=C1)N1CCSCC1 ZAIDVSUVEHFYIA-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- BVXNJDDADPYTBP-UHFFFAOYSA-N C(C(C1=CC=C2)=CC=CC1=C2C1=CC=C2N=CC=CC2=C1)N1CCOCC1 Chemical compound C(C(C1=CC=C2)=CC=CC1=C2C1=CC=C2N=CC=CC2=C1)N1CCOCC1 BVXNJDDADPYTBP-UHFFFAOYSA-N 0.000 claims description 2
- ZONDHBYGEHDTBC-UHFFFAOYSA-N C(C(C=C1C=C2)=CC=C1N2C1=CC=C2N=CC=CC2=C1)N1CCOCC1 Chemical compound C(C(C=C1C=C2)=CC=C1N2C1=CC=C2N=CC=CC2=C1)N1CCOCC1 ZONDHBYGEHDTBC-UHFFFAOYSA-N 0.000 claims description 2
- OPZZZWKUAIXVBU-UHFFFAOYSA-N C(C1=C(C=CN2C3=CC4=CC=CC=C4C=C3)C2=CC=C1)N1CCSCC1 Chemical compound C(C1=C(C=CN2C3=CC4=CC=CC=C4C=C3)C2=CC=C1)N1CCSCC1 OPZZZWKUAIXVBU-UHFFFAOYSA-N 0.000 claims description 2
- HCAPVIQCGCTYKF-UHFFFAOYSA-N C(C1=C(C=CN2C3=CC=C(C=CC=N4)C4=C3)C2=CC=C1)N1CCOCC1 Chemical compound C(C1=C(C=CN2C3=CC=C(C=CC=N4)C4=C3)C2=CC=C1)N1CCOCC1 HCAPVIQCGCTYKF-UHFFFAOYSA-N 0.000 claims description 2
- GPEZHQLUOONJPM-UHFFFAOYSA-N C(C1=C(C=CN2C3=CC=C(C=NC=C4)C4=C3)C2=CC=C1)N1CCOCC1 Chemical compound C(C1=C(C=CN2C3=CC=C(C=NC=C4)C4=C3)C2=CC=C1)N1CCOCC1 GPEZHQLUOONJPM-UHFFFAOYSA-N 0.000 claims description 2
- JHVFQOIEUBGCRW-UHFFFAOYSA-N C(C1=C(C=CN2C3=CC=C4N=CC=CC4=C3)C2=CC=C1)N1CCOCC1 Chemical compound C(C1=C(C=CN2C3=CC=C4N=CC=CC4=C3)C2=CC=C1)N1CCOCC1 JHVFQOIEUBGCRW-UHFFFAOYSA-N 0.000 claims description 2
- YLGRVMTUBACDTM-UHFFFAOYSA-N C(C1=C(C=CN2C3=CC=C4N=CC=NC4=C3)C2=CC=C1)N1CCOCC1 Chemical compound C(C1=C(C=CN2C3=CC=C4N=CC=NC4=C3)C2=CC=C1)N1CCOCC1 YLGRVMTUBACDTM-UHFFFAOYSA-N 0.000 claims description 2
- KWTJJNSIXCFFJF-UHFFFAOYSA-N C(C1=C(C=CN2C3=CC=C4N=CN=CC4=C3)C2=CC=C1)N1CCOCC1 Chemical compound C(C1=C(C=CN2C3=CC=C4N=CN=CC4=C3)C2=CC=C1)N1CCOCC1 KWTJJNSIXCFFJF-UHFFFAOYSA-N 0.000 claims description 2
- GMCYLERUZQQLSE-UHFFFAOYSA-N C(C1=C(C=CN2C3=NC4=CC=CC=C4C=N3)C2=CC=C1)N1CCOCC1 Chemical compound C(C1=C(C=CN2C3=NC4=CC=CC=C4C=N3)C2=CC=C1)N1CCOCC1 GMCYLERUZQQLSE-UHFFFAOYSA-N 0.000 claims description 2
- YSNONYZDJOXFKA-UHFFFAOYSA-N C(CN1CCOCC1)N1C(C=CC=C2C3=CC4=CC=CC=C4C=C3)=C2N=C1 Chemical compound C(CN1CCOCC1)N1C(C=CC=C2C3=CC4=CC=CC=C4C=C3)=C2N=C1 YSNONYZDJOXFKA-UHFFFAOYSA-N 0.000 claims description 2
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- VLWFLODCIKGTEJ-UHFFFAOYSA-N CC(C1=C(C=CN2C3=CC=C4N=CC=CC4=C3)C2=CC=C1)N(CC1)CCC1(C)O Chemical compound CC(C1=C(C=CN2C3=CC=C4N=CC=CC4=C3)C2=CC=C1)N(CC1)CCC1(C)O VLWFLODCIKGTEJ-UHFFFAOYSA-N 0.000 claims description 2
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- IUYRZUBLBMRHEM-UHFFFAOYSA-N CN1CCN(CC2=C(C=CN3C4=CC5=CC=CC=C5C=C4)C3=CC=C2)CC1 Chemical compound CN1CCN(CC2=C(C=CN3C4=CC5=CC=CC=C5C=C4)C3=CC=C2)CC1 IUYRZUBLBMRHEM-UHFFFAOYSA-N 0.000 claims description 2
- 206010058019 Cancer Pain Diseases 0.000 claims description 2
- 206010065390 Inflammatory pain Diseases 0.000 claims description 2
- PCOPFXSREFOXJM-UHFFFAOYSA-N OC1(CCN(CCC2=C(C=CN3C4=CC=C5N=CC=CC5=C4)C3=CC=C2)CC1)C(F)(F)F Chemical compound OC1(CCN(CCC2=C(C=CN3C4=CC=C5N=CC=CC5=C4)C3=CC=C2)CC1)C(F)(F)F PCOPFXSREFOXJM-UHFFFAOYSA-N 0.000 claims description 2
- 208000004983 Phantom Limb Diseases 0.000 claims description 2
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- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 claims description 2
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- 125000003118 aryl group Chemical group 0.000 abstract description 8
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- 238000006243 chemical reaction Methods 0.000 description 53
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Abstract
本发明涉及化学医药领域,尤其涉及一种连双环结构sigma‑1受体抑制剂。具体提供一种结构独特的连双环结构化合物,其具有良好的σ1受体亲和力和选择性,是σ1受体的强选择性抑制剂。所述连双环结构化合物具有连双芳香环基本基团结构,中间芳香双环异侧斜对称位分别被另一双芳香环和以及与芳环直接相连的烷基胺所取代为特征。
Description
本申请为2020年11月25日提交的,发明名称为“连双环结构sigma-1受体抑制剂”的中国专利申请202011345740.0的分案申请。
技术领域
本发明涉及化学医药领域,尤其涉及一种连双环结构sigma-1受体抑制剂。
背景技术
Sigma-1受体(σ1受体)是近年来新兴的药物靶点,是多种特异中枢神经类药物的结合蛋白,其作为受体型分子伴侣发挥生理功能。在中枢神经系统中sigma-1受体主要生理功能包括镇痛、保护神经、调节认知、改善药物成瘾及运动障碍等,而外周sigma-1受体参与调节机体免疫功能。
σ1受体在中枢神经系统与外周神经均有高度表达,在中枢神经中主要分布于细胞膜,内质网(ER)膜和线粒体膜,而在外周神经系统中主要分布于淋巴组织、肺脏、肝脏、肾脏、胰脏、脾脏、肾上腺以及心脏等组织。
Sigma受体与阿片受体无同源性,存在σ1和σ2两种亚型。他们与配体结合方式十分独特:σ1受体对右旋类药物的亲和力要强于左旋类药物;σ2受体对左旋类药物的亲和力要高于对右旋类药物。SKF10047对σ1位点具有纳摩尔的亲和力,对σ2位点具有微摩尔的亲和力。
sigma-1受体(σ1受体)于1996年被成功克隆,为29-kDa的单链蛋白,含有223个氨基酸残基,相对分子量为26000。Sigma-1受体蛋白的活性结合位点主要是在氨基酸116到氨基酸223这一氨基酸链上,长链C-端的疏水性部分常与两个疏水的跨膜部分中的一个或两个共同结合sigma-1受体配体。
σ1是一种配体调节型蛋白分子伴侣,通过与NMDA以及阿片受体相互作用来发挥其分子伴侣的作用。在正常生理条件下,sigma-1受体以非活性状态存在于线粒体相关的内质网膜,与另一个分子伴侣葡萄糖调节蛋白78(GRP78)又称免疫球蛋白重链结合蛋白(Bip)形成Ca2+敏感复合物。病理状态下,σ1和Bip分离,游离到细胞质和细胞膜,和其他蛋白结合,参与调节多种生理功能。当ER中Ca2+浓度降低或特异性激动剂作用于σ1受体时,σ1受体与Bip分离并激活,再分布至细胞膜脂质筏,调节离子通道、蛋白激酶以及G蛋白偶联受体(GPCR),启动多条下游信号转导通路。Sigma-1受体可能通过以下机制发挥其生理作用:σ1受体与Bip分离后,即变为激动状态,发生再分布,并与IP3受体结合,稳定IP3受体,引起胞内Ca2+通过电压门控离子通道进入线粒体,启动线粒体内三羧酸循环,促进细胞新陈代谢,从而产生神经保护及轴突生长促进作用。
sigma-1受体(σ1受体)的生理功能主要包括镇痛、保护神经、调节认知、改善药物上瘾及运动障碍。从σ受体的生物和功能研究来看,已经有证据表明σ受体配体可能用于治疗精神疾病(如精神分裂症、抑郁症、焦虑症等)和神经类疾病(如阿尔茨海默症、疼痛等)以及诸如张力障碍和迟发性运动障碍等的运动失调,与亨延顿舞蹈病或图雷特综合症相关的运动障碍以及帕金森病。已经报道了已知的σ受体配体林卡唑在临床上显示了治疗精神病方面的效果。σ结合位点对诸如SKF10047,(+)-环唑辛和(+)-戊唑辛等的某些鸦片剂苯并吗啡烷的右旋异构体和诸如氟哌啶醇等的某些发作性睡病药具有优先的亲和力。
当前,现有技术公开了不同的σ受体的配体。其中专利WO2012072791公开了sigma受体类似物的结构及CNS相关疾病用途;然而这些结构与本专利结构并不一样。
考虑到σ受体拮抗剂或激动剂在痛疼、精神等CNS领域的潜在应用,因此,寻找对σ1受体具有有效的和选择性的药理活性并具有良好“可药用性”的化合物对临床应用具有重要意义,所述可药用性即与给药、分布、代谢和排泄相关的良好的药物性质。
发明概述
本发明旨在至少解决现有技术中存在的技术问题之一,为此,本发明的一个目的在于,提出一种结构独特的连双环结构化合物,其具有良好的σ1受体亲和力和选择性,是σ1受体的强选择性抑制剂。所述化合物具有连双芳香环基本基团结构,中间芳香双环异侧斜对称位分别被另一双芳香环和以及与芳环直接相连的烷基胺所取代为特征。
一方面,本发明涉及式I所示的化合物或其药学可接受的盐:
式I为式VI、VI-1、VII、或VIII结构,
其中,A为取代或未取代的萘基、式II-1、式III、式IV、或式V,所述取代的萘基的取代基选自取代或未取代的C1-5的烷基和卤素;所述取代的C1-5的烷基的取代基选自卤素;
式II-1、III、IV、V结构如下:
式II-1中,Q1、Q2、Q3、Q4、Q5、Q6独立地选自N或C;
式IV中,R4为烷基,式V中,R5为烷基,式III中,R10为烷基;
B为IX结构:
在式IX中,n1为0-3的整数,n2为0-6的整数;Z4为C、O、S或N;Z5选自O或CH2或CR8R9;R2、R3独立地选自氢、卤代烷基、羟基、烷基、环烷基、酰胺;R8和R9独立地选自氢、卤代烷基、羟基、烷基、环烷基,并且R8和R9不同时为氢。
进一步的,本发明涉及式I所示的化合物或其药学可接受的盐:
式I为式VI、VII、或VIII结构,
其中,A为取代或未取代的萘基、式II、式IV、或式V,所述取代的萘基的取代基选自C1-5的烷基或卤素;
式II、IV、V结构如下:
式II中,Q1、Q2、Q3、Q4、Q5独立地选自N或C;
式IV中,R4为烷基,式V中,R5为烷基;
B为IX结构:
在式IX中,n1为0-3的整数,n2为0-6的整数,Z4为C、O、S或N;Z5选自O或CH2或CR8R9;R2、R3独立地选自氢、卤代烷基、羟基、烷基、环烷基、酰胺;R8和R9独立地选自氢、卤代烷基、羟基、烷基、环烷基,并且R8和R9不同时为氢。优选,在式IX中,n1为0-3的整数、n2为0-4的整数,Z4为C、O或S;Z5选自O或CH2;R2、R3独立地选自氢、卤代烷基、羟基、烷基、酰胺。
进一步的,所述式I化合物或其药学可接受的盐为式VI结构:
其中,Z1、Z2、Z3、W独立地选自N或C;
其中,A为取代或未取代的萘基、式II、式IV、或式V,所述取代的萘基的取代基为C1-5的烷基或卤素;
式II,IV,V结构如下:
式II中,Q1、Q2、Q3、Q4、Q5独立地为N或C;
式IV中,R4为烷基,式V中,R5为烷基;
B为IX-1结构:
在式IX-1中,n1、n2独立地为0-3的整数,Z4选自C、O、S、N中的一种;R2、R3独立的选自氢、卤代烷基、羟基、烷基、环烷基、酰胺。优选,在式IX-1中,n1、n2独立地为0-3的整数,Z4选自C、O、S中的一种;R2、R3独立的选自氢、卤代烷基、羟基、烷基、酰胺。
进一步的,所述式I化合物或其药学可接受的盐为式VI结构:
其中,Z1、Z2、Z3、W独立地选自N或C;
其中,A为式II-2结构:
式II-2中,Q1、Q2、Q3、Q6独立地为N或C;
B为IX-1结构:
在式IX-1中,n1、n2独立地为0-3的整数,Z4选自C、O、S、N中的一种;R2、R3独立的选自氢、卤代烷基、羟基、烷基、环烷基、酰胺。
进一步的,所述式I化合物或其药学可接受的盐为式VI结构:
其中,Z1、Z2、Z3、W独立地选自N或C;
其中,A为取代或未取代的萘基、式II、式IV、或式V,所述取代的萘基的取代基为C1-5的烷基或卤素;
式II,IV,V结构如下:
式II中,Q1、Q2、Q3、Q4、Q5独立地为N或C;
式IV中,R4为烷基,式V中,R5为烷基;
B为IX结构:
在式IX中,n1、n2独立地为0-3的整数,Z4为C、O、S或N;Z5为CR8R9;R2、R3独立的选自氢、卤代烷基、羟基、烷基、环烷基、酰胺;R8和R9独立的选自氢、卤代烷基、羟基、烷基、环烷基,并且R8和R9不同时为氢。
进一步的,所述式I化合物或其药学可接受的盐为式VI-1结构:
其中,Z1、Z2、Z3、W独立地选自N或C;
其中,A为取代或未取代的萘基、式II、式IV、或式V,所述取代的萘基的取代基为C1-5的烷基或卤素;
式II,IV,V结构如下:
式II中,Q1、Q2、Q3、Q4、Q5独立地为N或C;
式IV中,R4为烷基,式V中,R5为烷基;
B为IX-1结构:
在式IX-1中,n1、n2独立地为0-3的整数,Z4选自C、O、S或N中的一种;R2、R3独立的选自氢、卤代烷基、羟基、烷基、环烷基、酰胺。
进一步的,所述式I化合物或其药学可接受的盐为如式VII结构:
其中,A为取代或未取代的萘基,所述取代的萘基的取代基选自C1-5的烷基或卤素;
B为IX-1结构:
在式IX-1中,n1、n2独立地为0-3的整数,Z4选自C或O;R2、R3独立的选自氢、卤代烷基、羟基、烷基。
进一步的,所述式I化合物或其药学可接受的盐为如下结构:
K6选自N或C;
其中,A为取代或未取代的萘基、式II结构,所述取代的萘基的取代基选自C1-5的烷基或卤素;
式II结构如下:
式II中,Q1、Q2、Q3、Q4、Q5独立地选自N或C;
B为IX结构:
在式IX中,n1、n2独立地为0-3的整数,Z4为C、O、S或N;Z5选自O或CH2或CR8R9;R2、R3独立的选自氢、卤代烷基、羟基、烷基、环烷基、酰胺;R8和R9独立的选自氢、卤代烷基、羟基、烷基、环烷基,并且R8和R9不同时为氢。优选,在式IX中,n1、n2为0-3的整数,Z4为C、O或S;Z5选自O或CH2;R2、R3独立的选自氢、卤代烷基、羟基、烷基、酰胺。
优选,式I化合物或其药学可接受的盐中,取代的萘基上取代基数目为1-7个,例如1、2、3、4、5、6、或7个,取代基在萘基的任意能被取代的位置上,更优选取代基的数目为1个;所述的烷基选自C1-C5的烷基;所述环烷基选自C3-C5的环烷基;所述卤代烷基选自C1-C5的卤代烷基;所述卤素选自氟、氯、溴或碘;所述氨基为-NH2、-NHRa或-NRaRb,其中Ra、Rb是烷基基团,烷基基团选自C1-5的直链或支链烷基;所述的酰胺选自乙酰胺、三氟乙酰胺,丙酰胺、异丁酰胺。进一步的,所述C1-C5的烷基选自甲基、乙基、丙基、丁基或戊基;所述的C3-C5的环烷基选自环丙基、环丁基、环戊基;C1-C5的卤代烷基选自三氟甲基,二氟甲基。
进一步的,所述式I化合物或其药学可接受的盐为如下结构:
式I为式VI、VII、VIII结构,
其中,VI结构中,Z1为N,Z2、Z3、W独立地选自N或C;
VII与VIII结构中,K1、K2、K3、K4、K5、K6独立地选自N或C;
其中,A为未取代的萘基、式II、式IV、或式V;
式II、IV、V结构如下:
式II中,Q1、Q2、Q3、Q4、Q5独立地选自N或C;
式IV中,R4选自甲基、乙基、丙基中的一种;
式V中,R5选自甲基、乙基、丙基中一种;
B为IX结构:
在式IX中,n1、n2独立地为0、1、2、3;Z4选自C、O、S中的一种;Z5选自CH2或O;R2、R3独立地选自氢、三氟甲基、羟基、甲基、乙基、丙基、异丁酰胺。
进一步的,所述式I化合物或其药学可接受的盐为如下式XII结构:
所述取代的萘基的取代基为C1-5的烷基或卤素;
式IV中,R4为甲基、乙基或丙基;
式V中,R5为甲基、乙基或丙基;
B为IX-1结构:
在式IX-1中,n1、n2独立地为0-3的整数,Z4选自C、O、S、N中的一种;R2和R3独立的选自氢、卤代烷基、羟基、烷基、环烷基和酰胺。优选,在式IX-1中,n2为1-3的整数,n1为2,Z4选自C、O、S、N中的一种;R2和R3独立的选自氢、三氟甲基、羟基、甲基。
进一步的,所述式I化合物或其药学可接受的盐为如下式XI结构:
其中,n3为0-3的整数,R7选自氢、取代或未取代的C1-5的烷基和卤素,所述取代的C1-5的烷基的取代基选自卤素;所述的卤素为氟、氯、溴、碘;优选,所述C1-C5的烷基选自甲基、乙基、丙基、丁基或戊基;键为键或不存在中的任意一种;
K1、K2、K3、K4、K5选自N或C。
进一步的,所述式I化合物或其药学可接受的盐为如下式X结构:
其中
Q3、Q4独立地选自N或C;K6选自N或C;n4选自0-3的整数,Z6选自O或CH2。优选,K6为C,Z6为CH2。
更进一步的,任一所述的式I所示的化合物或其药学可接受的盐,选自如下所示任意一个化合物:
4-((1-(萘-2-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐
4-((4-甲基哌嗪-1-基)甲基)-1-(萘-2-基)-1氢-吲哚或其盐酸盐
4-((4-环丙基哌嗪-1-基)甲基)-1-(萘-2-基)-1氢-吲哚或其盐酸盐
2-甲基-1-(4-((1-(萘-2-基)-1氢-吲哚-4-基)甲基)哌嗪-1基)丙烷-1-酮或其盐酸盐
4-((1-异喹啉-3-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐
4-((1-(喹唑啉-2-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐
4-((1-(喹啉-7-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐
4-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐
4-((1-(异喹啉-6-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐
4-((1-(喹唑林-6-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐
4-((1-(喹喔啉-6-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐
4-((1-(1-甲基-1氢-吲唑-5-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐
4-((1-(2-甲基-1氢-吲唑-5-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐
4-((1-(萘-2-基)-1氢-吡咯[2,3]吡啶-4-基)甲基)吗啉或其盐酸盐
4-((1-(萘-2-基)-1氢-吲唑-4-基)甲基)吗啉或其盐酸盐
4-((1-(喹啉-6-基)-1氢-吲唑-4-基)甲基)吗啉或其盐酸盐
4-((1-(萘-2-基)-1氢-苯并咪唑-4-基)甲基)吗啉或其盐酸盐
4-((1-(喹啉-6-基)-1氢-苯并咪唑-4-基)甲基)吗啉或其盐酸盐
4-((1-(喹啉-6-基)-1氢-吲哚-5-基)甲基)吗啉或其盐酸盐
4-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)硫代吗啉或其盐酸盐
4-((1-(萘-2-基)-1氢-吲哚-4-基)甲基)硫代吗啉或其盐酸盐
4-甲基-1-((1-萘-2-基)-1氢-吲哚-4-基)甲基)哌啶-4-羟基或其盐酸盐
1-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)-4-(三氟甲基)哌啶-4-羟基或其盐酸盐
4-甲基-1-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)哌啶-4-羟基或其盐酸盐
3-甲基-1-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)吡咯烷-3-羟基或其盐酸盐
4-(1-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙基)吗啉或其盐酸盐
4-甲基-1-(1-(1-(喹啉-6-基)-1氢-吲哚-4基)乙基)哌啶-4-醇或其盐酸盐
4-(1-(1-(喹啉-6-基)-1氢-吲唑-4-基)乙基)吗啉或其盐酸盐
4-((7-萘-2-基)-1氢-吲哚-3-基)甲基)吗啉或其盐酸盐
4-(([1,2’-双萘]-5-基)甲基)吗啉或其盐酸盐
4-((5-(喹啉-6-基)萘-1-基)甲基)吗啉或其盐酸盐
4-(2-(4-萘-2-基)-1氢-吲唑-1-基)乙基)吗啉或其盐酸盐
4-(2-(4-(萘-2-基)-1氢-苯并咪唑-1-基)乙基)吗啉或其盐酸盐
4-(2-(4-萘-2-基)-7氢-吡咯[2,3-d]嘧啶-7-基)乙基)吗啉或其盐酸盐
4-(2-((8-(萘-2-基)喹啉-4-基)氧)乙基)吗啉或其盐酸盐
4-(2-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙基)吗啉或其盐酸盐
1-(2-(1-(喹啉-6-基)-1氢-吲哚-4基)乙基)-4(三氟甲基)哌啶-4-醇或其盐酸盐
另一方面,本发明提供一种药物组合物,包含治疗有效量的上述式I所示的化合物或其可药用的盐和医学上可接受的载体。
另一方面,本发明提供一种式I所述化合物或其可药用盐,及含有其的药物组合物在制备治疗和预防sigma受体相关疾病或疾病状态的药物中的用途。进一步的,所述治疗和预防sigma受体相关疾病为疼痛,优选神经性疼痛或炎性疼痛、术后疼痛、癌症疼痛,三叉神经痛,骨关节炎疼痛,烧伤疼痛,幻肢疼痛。
具体实施方式
术语“任选”、“任选地”或“任选存在”是指随后描述的事件或情形可以但不一定出现,并且该描述包括其中所述事件或情形出现的情况和不出现的情况。例如,“任选存在的键”是指该键可以存在或可以不存在,并且该描述包括单键、双键或三键等。
术语“包含”为开放式表达,即包括本发明所指明的内容,但并不排除其他方面的内容。应当理解,术语“包含”可以涵盖封闭式的含义,即“由…组成”。
像本发明所描述的,本发明的化合物可以任选地被一个或多个取代基所取代,如上面的通式化合物或者像实施例中特定的实例、子类。应了解术语“任选取代的”与术语“取代或未取代的”可以交换使用。一般而言,术语“取代的”表示所给结构中的一个或多个氢原子被特定取代基所取代。除非其他方面表明,任选取代的基团可以在该基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自特定基团的一个或多个取代基所取代时,那么取代基可以相同或不同地在各个位置取代。
另外,需要说明的是,除非以其他方式明确指出,在本发明中所采用的描述方式“分别独立地为”应做广义理解,其既可以是指在不同基团中,相同符号之间所表达的具体选项之间互相不影响,也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分,本发明公开化合物的取代基按照基团种类或范围公开。特别指出,本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如,术语“C1-C5烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基。烷基基团的实例包括但不限于甲基(Me、-CH3),乙基(Et、-CH2CH3),正丙基(n-Pr、-CH2CH2CH3)、异丙基(i-Pr、-CH(CH3)2),正丁基(n-Bu、-CH2CH2CH2CH3)、异丁基(i-Bu、-CH2CH(CH3)2)、仲丁基(s-Bu、-CH(CH3)CH2CH3)、叔丁基(t-Bu、-C(CH3)3)、正戊基(-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)等。
本文列举的范围(如数值范围)可以涵盖其范围中的每一个值以及由各个值形成的各个亚范围。因此,例如表述“n2为0~3之间的任意一个整数”包括例如0~2的任意一个整数、2~3的任意一个整数等,例如1、2、3。
表述“一个或多个”可以表示1、2、3、4、5、6个或更多个。
术语“氢(H)”表示单个氢原子。这样的原子团可以与其他基团连接,譬如与氧原子相连,形成羟基基团。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“可药用盐”是指通过式I化合物与酸混合所制备的盐,其中,通常认为酸的阴离子适合于人类使用,其通常利用游离碱与合适的有机或无机酸的反应来制备。在用于药物时,本发明化合物的盐是无毒的“可药用盐”。如果可能的话,本发明化合物的合适的可药用酸加成盐包括衍生自无机酸的那些盐,例如,盐酸、氢溴酸、氢氟酸、硼酸、氟硼酸、磷酸、偏磷酸、硝酸、碳酸、磺酸和硫酸,以及衍生自有机酸的那些盐,例如,乙酸、苯磺酸、苯甲酸、柠檬酸、乙磺酸、富马酸、葡糖酸、乙醇酸、异硫羰酸、乳酸、乳糖酸、马来酸、苹果酸、甲磺酸、三氟甲磺酸、琥珀酸、甲苯磺酸、酒石酸和三氟乙酸。
本发明有益的技术效果
本发明提供的化合物为一种连双环结构sigma-1受体抑制剂,对sigma-1受体具有药理活性以及受体选择性的连双环结构化合物,以及这些化合物的制备方法、及其在中枢神经疾病治疗、预防之用途。该系列化合物具有较好的sigma-1受体抑制活性,且与吗啡联合使用,可以显著提高吗啡的增效作用,且对福尔马林模型诱导的I-相与II-相疼痛均有效。
附图说明:
图1:吗啡疼痛抑制率
图2:福尔马林-I相疼痛试验结果
图3:福尔马林-II相疼痛试验结果
实施例
下面详细描述本发明的实施例。下面描述的实施例是示例性的,仅用于解释本发明,而不能理解为对本发明的限制。除非另外指明,本文所指的比例、百分比等均以重量计。
合成的一般方案:
下面的实施例只是以说明为目的而不作为本发明的限制。
合成方案1:实施例1-19的化合物可通过还原胺化、以及C-N键偶联反应获得
合成方案2:实施例20-25的化合物可通过本合成方案获得
合成方案3:
实施例26-28按以下合成路线,Buckwald coupling反应、还原、取代得到目标产物
合成方案4:
实施例29按以下合成路线,通过酰胺化、Buckwald coupling、还原得到目标产物
合成方案5:
实施例30,31按以下合成路线,通过酰胺化、Buckwald coupling、还原得到目标产物
合成方案6:
实施例32-34按以下合成路线,通过取代、Buckwald coupling反应得到目标产物
合成方案7:
实施例35按以下合成路线,通过取代、Buckwald coupling反应得到目标产物
合成方案8:
如果需要,所得到的反应产物可采用诸如结晶、层析和研磨等常规方法纯化。当上述本发明的化合物的方法产生了区域异构体的混合物,可以通过诸如制备色谱等常规技术分离这些异构体。如果存在手性中心,那么可以制备消旋形式的化合物,或者可以通过对应转移性合成或拆分来制备单一的对映异构体。
术语“药理学工具”指本发明化合物的性质,通过该性质,所述化合物是σ受体的高选择性配体,其表明本发明所述的式I的化合物可以被用作测试作为σ配体的其它化合物,例如放射性配体被替换,并且还可以被用作建立与σ受体相关的生理学活性的模型。
本发明还提供对患者给药的药物组合物,所述药物组合物包含本发明的化合物、其药物可接受的盐、衍生物、前药或立体异构体和药物可接受的载体、辅剂或介质。
在优选实施方案中,药物组合物为固体或液体的口服形式。用于口服给药的合适剂型可以是片剂、胶囊、糖浆或溶液,并且可以含有本领域已知的常规赋形剂,如结合剂,例如糖浆、阿拉伯胶、明胶、山梨糖醇、黄芪胶或聚乙烯吡咯酮;充填剂,例如乳糖、蔗糖、玉米淀粉、磷酸钙、山梨糖醇或甘氨酸;压片润滑剂,例如硬脂酸镁;崩解剂,例如淀粉、聚乙烯吡咯酮、淀粉乙醇酸钠或微晶纤维素;或药物可接受的湿润剂,例如十二烷基硫酸钠。
固体口服组合物可通过混合、充填、压片的常规方法制备。重复混合操作可用于将活性剂分布在那些使用大量填充剂的组合物的各处。这类操作在本领域中是常规的。片剂可例如由湿法或干法制粒制备,根据在通常药物实践中公知的方法任选地包有包衣,尤其是使用肠溶衣进行包被。
药物组合物还可以适于胃肠道外给药,如以合适的单位剂型存在的无菌溶液、混悬液或低压冻干产品。可以使用适当的赋形剂,例如填充剂、缓冲剂或表面活性剂。
采用诸如在西班牙和美国药典及类似参考文件中所描述或指出的标准方法制备所提及的制剂。
本发明所述化合物或组合物的给药可以以任何合适的方法进行,例如静脉注射、口服制剂、腹膜内和静脉内给药。因为方便患者及待治疗疾病的慢性特点,所以优选口服给药。
通常本发明化合物的有效给药量取决于所选化合物的相对有效性、所治疗病症的严重度及患者的体重。然而,活性化合物通常以0.1-1000mg/kg/天的总日剂量每天一次或数次给药,例如每天1、2、3或4次给药。
本发明的化合物和组合物可与其它药物一起使用以提供联合治疗。所述其它药物可以形成同一组合物的一部分,或作为同时或不同时给药的单独的组合物。
给出以下实施例仅仅是为了进一步解释本发明,它们不应被视为限制本发明的范围。
下面的实施例只是以说明为目的而不作为本发明的限制。
合成方案1:
实施例1-19的化合物可通过本合成方案获得
实施例1:4-((1-(萘-2-基)-1氢-吲哚-4-基)甲基)吗啉盐酸盐
1H NMR(400MHz,CDCl3)δ:8.00(d,J=8.8Hz,1H),7.95–7.86(m,3H),7.67(dd,J=8.7,2.2Hz,1H),7.60–7.50(m,3H),7.46(d,J=3.3Hz,1H),7.24–7.15(m,2H),6.95–6.92(m,1H),3.85(s,2H),3.79–3.70(m,4H),2.65–2.49(m,4H).MS(ESI)m/z 343.2([M+H]+).
步骤1.吲哚-4甲基吗啉的合成
将吲哚-4甲醛(250mg,1.72mmol)和吗啉(449.54mg,5.16mmol)溶于DCM(10mL)中,室温反应1h后加入NaBH(OAc)3(729.07mg,3.44mmol),常温搅拌反应12h;加入水(30mL)淬灭反应,用DCM(30mLx2)萃取,有机相用饱和食盐水洗涤(10mLx3),有机相用无水硫酸钠干燥、过滤、浓缩得粗品,经柱层析(PE/EA=2/1)得吲哚-4甲基吗啉300mg,收率:80.6%
步骤2. 4-((1-(萘-2-基)-1氢-吲哚-4-基)甲基)吗啉的合成
将吲哚-4甲基吗啉(250.0mg,1.16mmol)、2-溴基萘(265.86mg,1.28mmol)、BINAP(143.21mg,0.23mmol)、Pd(dba)2(69.0mg,0.12mmol)溶于对二甲苯(10.0mL)中,加入叔丁醇钾(155.97mg,1.39mmol),98℃反应12h;加入水(80mL)淬灭反应,EA(80mL)萃取,有机相用饱和食盐水洗涤(30mLx3),无水硫酸钠干燥、过滤、浓缩得粗品,经柱层析(DCM/MeOH=40:1)得150mg 4-((1-(萘-2-基)-1氢-吲哚-4-基)甲基)吗啉,收率:37.8%
步骤3. 4-((1-(萘-2-基)-1氢-吲哚-4-基)甲基)吗啉盐酸盐合成
将1-萘基-吲哚-4甲基吗啉(140.0mg,0.4mmol)溶于DCM(2mL)中,加入HCl/EA(5.0mL),析出白色固体;浓缩、干燥后得到1-萘基-吲哚-4甲基吗啉盐酸盐(140.0mg,收率:92.4%)。
实施例2:4-((4-甲基哌嗪-1-基)甲基)-1-(萘-2-基)-1氢-吲哚盐酸盐
将吗啉换成4-甲基哌嗪,按实施例1的方法制备目标化合物。
1H NMR(400MHz,CDCl3)δ:7.99(d,J=8.7Hz,1H),7.95–7.85(m,3H),7.66(dd,J=8.7,2.1Hz,1H),7.58–7.50(m,3H),7.45(d,J=3.3Hz,1H),7.24–7.14(m,2H),6.92(dd,J=3.3,0.8Hz,1H),3.87(s,2H),2.79–2.41(m,8H),2.34(s,3H).MS(ESI)m/z 356.2([M+H]+).
实施例3:4-((4-环丙基哌嗪-1-基)甲基)-1-(萘-2-基)-1氢-吲哚盐酸盐
将吗啉换成4-环丙基哌嗪,按实施例1的方法制备目标化合物。
1H NMR(400MHz,CDCl3)δ:8.00(d,J=8.7Hz,1H),7.95–7.85(m,3H),7.65(dd,J=8.7,2.2Hz,1H),7.62–7.49(m,3H),7.47(d,J=3.3Hz,1H),7.23(d,J=6.4Hz,2H),6.88(d,J=3.3Hz,1H),4.02(s,2H),3.08–2.46(m,9H),0.48(d,J=6.3Hz,4H).MS(ESI)m/z 382.2([M+H]+).
实施例4:2-甲基-1-(4-((1-(萘-2-基)-1氢-吲哚-4-基)甲基)哌嗪-1基)丙烷-1-酮盐酸盐
将吗啉换成异丁酰胺哌嗪,按实施例1的方法制备目标化合物。
1H NMR(400MHz,CDCl3)δ:8.00(d,J=8.7Hz,1H),7.97–7.85(m,3H),7.67(dd,J=8.7,2.2Hz,1H),7.61–7.50(m,3H),7.46(d,J=3.3Hz,1H),7.25–7.12(m,2H),6.91(dd,J=3.3,0.9Hz,1H),3.87(s,2H),3.74–3.48(m,4H),2.79(hept,J=6.8Hz,1H),2.59–2.48(m,4H),1.13(d,J=6.7Hz,6H).MS(ESI)m/z 412.25([M+H]+).
实施例5:4-((1-异喹啉-3-基)-1氢-吲哚-4-基)甲基)吗啉盐酸盐
将2-溴基萘换成3-溴异喹啉,按实施例1的方法制备目标化合物。
1H NMR(400MHz,CDCl3)δ:9.26(d,J=0.9Hz,1H),8.09–8.00(m,2H),7.89–7.83(m,2H),7.81–7.80(m,1H),7.73(ddd,J=8.3,6.8,1.2Hz,1H),7.58(ddd,J=8.1,6.8,1.1Hz,1H),7.29–7.24(m,1H),7.19(dd,J=7.2,0.9Hz,1H),6.97(dd,J=3.4,0.8Hz,1H),3.84(s,2H),3.78–3.69(m,4H),2.60–2.48(m,4H).MS(ESI)m/z344.1([M+H]+).
实施例6:4-((1-(喹唑啉-2-基)-1氢-吲哚-4-基)甲基)吗啉盐酸盐
将2-溴基萘换成2-溴喹唑啉,按实施例1的方法制备目标化合物
1H NMR(400MHz,CDCl3)δ:9.37(s,1H),9.00(d,J=8.3Hz,1H),8.45(d,J=3.7Hz,1H),8.02(d,J=8.6Hz,1H),7.95–7.85(m,2H),7.59–7.49(m,1H),7.35(t,J=7.8Hz,1H),7.24(d,J=7.4Hz,1H),6.96(d,J=3.7Hz,1H),3.83(s,2H),3.78–3.65(m,4H),2.61–2.46(m,4H).MS(ESI)m/z 345.1([M+H]+).
实施例7:4-((1-(喹啉-7-基)-1氢-吲哚-4-基)甲基)吗啉盐酸盐
将2-溴基萘换成7-溴喹啉,按实施例1的方法制备目标化合物
1H NMR(400MHz,CDCl3)δ:8.98(dd,J=4.2,1.7Hz,1H),8.23(dt,J=6.9,1.1Hz,2H),7.97(d,J=8.7Hz,1H),7.78(dd,J=8.7,2.2Hz,1H),7.66(dt,J=7.9,1.0Hz,1H),7.50(d,J=3.3Hz,1H),7.45(dd,J=8.3,4.3Hz,1H),7.25-7.16(m,2H),6.97(dd,J=3.3,0.8Hz,1H),3.84(s,2H),3.80-3.69(m,4H),2.65-2.47(m,4H).MS(ESI)m/z 442.2([M+H]+).
实施例8:4-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)吗啉盐酸盐
将2-溴基萘换成6-溴喹啉,按实施例1的方法制备目标化合物
1H NMR(400MHz,CDCl3)δ:8.96(dd,J=4.2,1.7Hz,1H),8.30–8.24(m,1H),8.20(dd,J=8.3,1.0Hz,1H),7.95–7.88(m,2H),7.57(dt,J=7.9,1.1Hz,1H),7.51–7.43(m,2H),7.25–7.16(m,2H),6.96(dd,J=3.3,0.9Hz,1H),3.85(s,2H),3.78–3.70(m,4H),2.56(t,J=4.7Hz,4H).MS(ESI)m/z 344.1([M+H]+).
实施例9:4-((1-(异喹啉-6-基)-1氢-吲哚-4-基)甲基)吗啉盐酸盐
将2-溴基萘换成6-溴异喹啉,按实施例1的方法制备目标化合物
1H NMR(400MHz,CDCl3)δ:9.31(t,J=1.0Hz,1H),8.59(d,J=5.8Hz,1H),8.14(d,J=8.7Hz,1H),7.91(d,J=2.0Hz,1H),7.82(dd,J=8.7,2.1Hz,1H),7.73-7.66(m,1H),7.61(dt,J=7.9,1.0Hz,1H),7.47(d,J=3.4Hz,1H),7.26-7.17(m,2H),6.99(dd,J=3.4,0.8Hz,1H),3.84(s,2H),3.77-3.71(m,4H),2.55(t,J=4.6Hz,4H).MS(ESI)m/z 344.2([M+H]+).
实施例10:4-((1-(喹唑林-6-基)-1氢-吲哚-4-基)甲基)吗啉盐酸盐
将2-溴基萘换成6-溴喹唑啉,按实施例1的方法制备目标化合物
1H NMR(400MHz,CDCl3)δ:9.47(d,J=0.8Hz,1H),9.38(s,1H),8.23(d,J=8.9Hz,1H),8.15(dd,J=9.0,2.4Hz,1H),8.02(d,J=2.3Hz,1H),7.61–7.52(m,1H),7.45(d,J=3.3Hz,1H),7.25–7.18(m,2H),7.00(dd,J=3.3,0.9Hz,1H),3.84(s,2H),3.77–3.71(m,4H),2.58–2.50(m,4H).MS(ESI)m/z 345.15([M+H]+).
实施例11:4-((1-(喹喔啉-6-基)-1氢-吲哚-4-基)甲基)吗啉盐酸盐
将2-溴基萘换成6-溴喹喔啉,按实施例1的方法制备目标化合物
1H NMR(400MHz,CDCl3)δ:8.90(d,J=1.9Hz,1H),8.88(d,J=1.8Hz,1H),8.27(d,J=9.0Hz,1H),8.23(d,J=2.4Hz,1H),8.02(dd,J=9.0,2.5Hz,1H),7.67(dt,J=8.2,1.0Hz,1H),7.50(d,J=3.3Hz,1H),7.27–7.16(m,2H),7.01(dd,J=3.5,0.9Hz,1H),3.84(s,2H),3.78–3.71(m,4H),2.59–2.51(m,4H).MS(ESI)m/z 345.2([M+H]+).
实施例12:4-((1-(1-甲基-1氢-吲唑-5-基)-1氢-吲哚-4-基)甲基)吗啉盐酸盐
将2-溴基萘换成1-甲基-5-溴吲唑,按实施例1的方法制备目标化合物
1H NMR(400MHz,CDCl3)δ:8.05(s,1H),7.80(t,J=1.3Hz,1H),7.53(d,J=1.4Hz,2H),7.44-7.33(m,2H),7.23-7.12(m,2H),6.89(dd,J=3.2,0.8Hz,1H),4.15(s,3H),3.87(s,2H),3.76(t,J=4.7Hz,4H),2.58(t,J=4.6Hz,4H).MS(ESI)m/z 347.2([M+H]+).
实施例13:4-((1-(2-甲基-1氢-吲唑-5-基)-1氢-吲哚-4-基)甲基)吗啉盐酸盐
将2-溴基萘换成2-甲基-5-溴吲唑,按实施例1的方法制备目标化合物
1H NMR(400MHz,CDCl3)δ:7.97(s,1H),7.82(dt,J=9.1,0.9Hz,1H),7.70(dd,J=2.1,0.8Hz,1H),7.43(dd,J=9.1,2.0Hz,2H),7.37(d,J=3.2Hz,1H),7.20–7.11(m,2H),6.87(dd,J=3.2,0.9Hz,1H),4.27(s,3H),3.84(s,2H),3.78–3.70(m,4H),2.55(dd,J=5.8,3.5Hz,4H).MS(ESI)m/z 347.2([M+H]+).
实施例14:4-((1-(萘-2-基)-1氢-吡咯[2,3]吡啶-4-基)甲基)吗啉盐酸盐
将吲哚-4-甲醛换成吡咯[2,3]吡啶-4甲醛,按实施例1的方法制备目标化合物
1H NMR(400MHz,CDCl3)δ:8.35(d,J=4.8Hz,1H),8.16(d,J=2.0Hz,1H),8.03–7.86(m,4H),7.62(d,J=3.6Hz,1H),7.57–7.46(m,2H),7.18(d,J=4.8Hz,1H),6.88(d,J=3.6Hz,1H),3.85(s,2H),3.78–3.73(m,4H),2.56(t,J=4.7Hz,4H).MS(ESI)m/z 344.2([M+H]+).
实施例15:4-((1-(萘-2-基)-1氢-吲唑-4-基)甲基)吗啉盐酸盐
将吲哚-4-甲醛换成吲唑-4-甲醛,按实施例1的方法制备目标化合物
1H NMR(400MHz,CDCl3)δ:8.55(s,1H),8.15(d,J=2.0Hz,1H),8.02(d,J=8.8Hz,1H),7.97–7.87(m,3H),7.77(d,J=8.4Hz,1H),7.61–7.48(m,2H),7.39(t,J=7.8Hz,1H),7.18(d,J=6.9Hz,1H),3.87(s,2H),3.76(t,J=4.6Hz,4H),2.54(t,J=4.6Hz,4H).
MS(ESI)m/z 344.2([M+H]+).
实施例16:4-((1-(喹啉-6-基)-1氢-吲唑-4-基)甲基)吗啉盐酸盐
将2-溴基萘换成6-溴喹啉,吲哚-4甲醛换成吲唑-4-甲醛,按实施例1的方法制备目标化合物
1H NMR(400MHz,Methanol-d4)δ9.48-9.16(m,2H),8.95-8.63(m,3H),8.49(d,J=9.1Hz,1H),8.32(d,J=8.5Hz,1H),8.18(dd,J=8.5,5.4Hz,1H),7.84-7.59(m,2H),4.85(s,2H),4.15-4.00(m,2H),3.83(t,J=12.4Hz,2H),3.55-3.34(m,4H).MS(ESI)m/z 345.2([M+H]+).
实施例17:4-((1-(萘-2-基)-1氢-苯并咪唑-4-基)甲基)吗啉盐酸盐
将吲哚-4甲醛换成苯并咪唑-4-甲醛,按实施例1的方法制备目标化合物
1H NMR(400MHz,CDCl3)δ:8.05-7.82(m,6H),7.64-7.53(m,3H),7.29-7.23(m,1H),7.13(d,J=7.2Hz,1H),3.29(s,2H),3.26-3.10(m,4H),1.73(t,J=4.6Hz,4H).MS(ESI)m/z 344.2([M+H]+)
实施例18:4-((1-(喹啉-6-基)-1氢-苯并咪唑-4-基)甲基)吗啉盐酸盐
将2-溴基萘换成6-溴喹啉,吲哚-4甲醛换成苯并咪唑-4-甲醛,按实施例1的方法制备目标化合物
1H NMR(400MHz,Chloroform-d)δ9.02(dd,J=4.3,1.7Hz,1H),8.40-8.20(m,3H),8.05-7.84(m,2H),7.54(dd,J=8.4,4.5Hz,2H),7.47-7.31(m,2H),4.10(s,2H),3.77(t,J=4.6Hz,4H),2.64(t,J=4.6Hz,4H).MS(ESI)m/z 345.2([M+H]+).
实施例19:4-((1-(喹啉-6-基)-1氢-吲哚-5-基)甲基)吗啉盐酸盐
将2-溴基萘换成6-溴喹啉,吲哚-4甲醛换成吲哚-5-甲醛,按实施例1的方法制备目标化合物
1H NMR(400MHz,CDCl3)δ:8.96(dd,J=4.3,1.7Hz,1H),8.26(d,J=9.7Hz,1H),8.21(dd,J=8.4,1.7Hz,1H),7.96–7.89(m,2H),7.57(d,J=8.0Hz,1H),7.52–7.43(m,2H),7.27–7.15(m,2H),6.96(d,J=3.4Hz,1H),3.85(s,2H),3.77–3.71(m,4H),2.56(t,J=4.6Hz,4H).MS(ESI)m/z 344.2([M+H]+).
合成方案2:
实施例20-25的化合物可通过本合成方案获得
实施例20:4-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)硫代吗啉盐酸盐
1H NMR(400MHz,Methanol-d4)δ:9.26(d,J=6.8Hz,2H),8.56(d,J=1.6Hz,1H),8.47(d,J=1.4Hz,2H),8.19-8.13(m,1H),7.97-7.90(m,2H),7.52-7.42(m,2H),7.18(d,J=3.4Hz,1H),4.74(s,2H),3.93-3.78(m,2H),3.41(t,J=11.8Hz,2H),3.14(td,J=13.8,12.5,2.4Hz,2H),2.88(t,J=14.5Hz,2H).MS(ESI)m/z 360.2([M+H]+).
步骤1. 1-(喹啉-6基)-1氢-吲哚-甲醛的合成
200mL单口烧瓶中依次加入吲哚-4-甲醛(100%,1.45g,10mmol)、6-bromoquinoline(,2.08g,10.00mmol)、Cs2CO3(6.52g,20.00mmol)、Pd2(dba)3(0.92g,1.00mmol)、X-Phos(0.48g,1.00mmol)、KI(0.17g,1.00mmol)和二甲苯(40mL),N2保护油浴加热至90℃搅拌反应4h。TLC监测反应完成后,反应液冷却至室温、过滤、浓缩得2.2g粗品,柱层析(洗脱剂:EA/PE+DCM=10%-50%)得淡黄色泡沫状固体1-(喹啉-6基)-1氢-吲哚-甲醛(820mg),收率:30.1%。
步骤2. 4-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)硫代吗啉的合成
将1-(喹啉-6基)-1氢-吲哚-甲醛(272mg,1.0mmol)和巯基吗啉(309.5mg,3.0mmol)混合,溶于DCM(10.0mL)中,室温反应1h后加入NaBH(OAc)3(423.9mg,2.0mmol),常温搅拌反应12h;加入水(30mL)淬灭反应,DCM(30mL)萃取,饱和食盐水洗涤(10mL想),无水硫酸钠干燥、过滤、浓缩得粗品,经柱层析(PE/EA=2/1)得300mg产品,收率:83.4%
步骤3. 4-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)硫代吗啉盐酸盐的合成
将4-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)硫代吗啉(300mg,0.83mmol),溶于二氯甲烷(10mL),加入盐酸乙酸乙酯溶液(1mL,1M),室温下反应10分钟;减压浓缩、干燥得325mg 4-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)硫代吗啉盐酸盐,黄色固体,收率:98.4%.
实施例21:4-((1-(萘-2-基)-1氢-吲哚-4-基)甲基)硫代吗啉盐酸盐
将6-溴喹啉换成2-溴萘,按实施例20的方法制备目标化合物。
1H NMR(400MHz,CDCl3)δ:7.99(d,J=8.7Hz,1H),7.95–7.86(m,3H),7.66(dd,J=8.7,2.2Hz,1H),7.59–7.52(m,3H),7.46(d,J=3.3Hz,1H),7.24–7.15(m,2H),6.90(dd,J=3.4,0.8Hz,1H),3.91(s,2H),2.95–2.67(m,8H).MS(ESI)m/z 359.15([M+H]+).
实施例22:4-甲基-1-((1-萘-2-基)-1氢-吲哚-4-基)甲基)哌啶-4-羟基盐酸盐
将硫代吗啉换成4-甲基-4羟基哌啶,6-溴喹啉换成2-溴萘,按实施例20的方法制备目标化合物
1H NMR(400MHz,CDCl3)δ:8.00(d,J=8.7Hz,1H),7.96–7.84(m,3H),7.67-7.60(m,2H),7.60-7.45(m,4H),7.32-7.26(m,1H),6.88(dd,J=3.4,0.9Hz,1H),4.40(s,2H),3.33-2.99(m,4H),2.32(s,2H),1.72(d,J=14.3Hz,3H),1.33(s,3H).MS(ESI)m/z 371.2([M+H]+).
实施例23:1-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)-4-(三氟甲基)哌啶-4-羟基盐酸盐
将硫代吗啉换成4-三氟甲基-4-羟基哌啶,按实施例20的方法制备目标化合物
1H NMR(400MHz,Methanol-d4)δ9.27(t,J=6.0Hz,2H),8.57(s,1H),8.52-8.45(m,2H),8.17(dd,J=8.4,5.4Hz,1H),7.93(dd,J=8.2,5.7Hz,2H),7.55-7.41(m,2H),7.21(d,J=3.4Hz,1H),4.76(s,2H),3.65-3.55(m,2H),3.54-3.39(m,2H),2.15(td,J=14.0,4.2Hz,2H),2.07-1.96(m,2H).MS(ESI)m/z 426.2([M+H]+).
实施例24:4-甲基-1-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)哌啶-4-羟基盐酸盐
将硫代吗啉换成4-甲基-4-羟基哌啶,按实施例20的方法制备目标化合物
1H NMR(400MHz,Methanol-d4)δ9.39-9.23(m,2H),8.59(t,J=1.4Hz,1H),8.50(d,J=1.4Hz,2H),8.20(dd,J=8.4,5.4Hz,1H),8.00-7.87(m,2H),7.57-7.37(m,2H),7.19(d,J=3.4Hz,1H),4.70(s,2H),3.42(dd,J=7.5,3.1Hz,4H),1.97-1.73(m,4H),1.28(s,3H).MS(ESI)m/z 372.2([M+H]+).
实施例25:3-甲基-1-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)吡咯烷-3-羟基盐酸盐
将硫代吗啉换成3-甲基-3-羟基吡咯烷,按实施例20的方法制备目标化合物
1H NMR(400MHz,Methanol-d4)δ9.38-9.20(m,2H),8.57(d,J=1.7Hz,1H),8.48(d,J=2.0Hz,2H),8.17(dd,J=8.4,5.4Hz,1H),7.90(q,J=2.8Hz,2H),7.58-7.36(m,2H),7.18(dd,J=20.4,3.4Hz,1H),4.84-4.69(m,2H),3.90-3.49(m,2H),3.42-3.34(m,1H),3.29-3.23(m,1H),2.33-2.01(m,2H),1.44(d,J=7.3Hz,3H).MS(ESI)m/z 358.2([M+H]+).
合成方案3:
实施例26-28按以下合成路线,Buckwald coupling、还原、取代得到目标产物
实施例26:4-(1-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙基)吗啉盐酸盐的合成
1H NMR(400MHz,Methanol-d4)δ9.40–9.21(m,2H),8.55(dd,J=35.3,1.5Hz,3H),8.20(dd,J=8.4,5.4Hz,1H),7.99–7.86(m,2H),7.66–7.44(m,2H),7.22(dd,J=3.6,0.9Hz,1H),5.06(m,1H),4.19–4.08(m,1H),3.95(m,3H),3.82–3.69(m,1H),3.32(s,1H),3.19–3.05(m,2H),1.94(d,J=6.9Hz,3H).MS:[M+1]=358.2
步骤1. 1-(喹啉-6基)-1氢-吲哚-甲醛的合成
200mL单口烧瓶中依次加入吲哚-4-甲醛(1.45g,10mmol)、6-溴喹啉(2.08g,10.00mmol)、Cs2CO3(6.52g,20.00mmol)、Pd2(dba)3(0.92g,1.00mmol)、X-Phos(0.48g,1.00mmol)、KI(0.17g,1.00mmol)和二甲苯(40mL),N2保护下90℃搅拌反应4h。TLC监测反应完全后,降至室温、反应液过滤、浓缩得2.2g粗品经柱层析(洗脱剂:EA/PE+DCM=10%-50%)得淡黄色泡沫状固体1-(喹啉-6基)-1氢-吲哚-甲醛(820mg);收率:30.1%。
步骤2. 1-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙烷-1-醇的合成
将1-(喹啉-6基)-1氢-吲哚-甲醛(820mg,3.01mmol)溶于THF(20mL),降温至-20℃搅拌反应10min,加入bromo(methyl)magnesium(1.0ml,3M in THF),-20℃搅拌反应1.0h。TLC监测反应完全后,加入饱和氯化铵溶液(80mL)淬灭反应,乙酸乙酯萃取(80mLx2),收集有机相、干燥、浓缩得获得淡黄色泡沫状固体1-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙烷-1-醇(910mg),粗产品未经纯化直接用于下步反应。
步骤3. 1-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙基甲磺酸酯的合成
将1-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙烷-1-醇(288.3mg,1mmol)、TEA(151.8mg,1.50mmol)和乙腈(30mL)加入100mL反应瓶中,在0-20℃加入氯甲基磺酸(137.5mg,1.20mmol),加入完毕,在20℃搅拌反应2h。反应结束后,反应液直接用于下一步反应。
步骤4. 4-(1-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙基)吗啉的合成
在上述反应液中加入4-吗啉(230.4mg,2.00mmol),油浴加热至75℃,此温度下搅拌反应过夜。TLC检测检测反应完全后,加入饱和氯化钠溶液(80mL)淬灭反应,乙酸乙酯萃取(50mLx2),无水硫酸钠干燥、浓缩得420mg粗品,经pre-TLC提纯(展开剂:MeOH/DCM=8%得61mg 4-(1-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙基)吗啉,收率:15.8%。
步骤5. 4-(1-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙基)吗啉盐酸盐的合成
将4-(1-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙基)吗啉(61mg,0.16mmol)溶于二氯甲烷(8mL)中,加入盐酸乙酸乙酯溶液(0.1mL,0.16mmol),室温下超声反应完全10min。减压浓缩、干燥得黄色固体4-(1-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙基)吗啉盐酸盐(68mg),收率:97.7%.
实施例27:4-甲基-1-(1-(1-(喹啉-6-基)-1氢-吲哚-4基)乙基)哌啶-4-醇盐酸盐
将吗啉替换成4-甲基哌啶-4-醇,按方案3合成得到目标产物
1H NMR(400MHz,Methanol-d4)δ9.29–9.25(m,2H),8.57(d,J=1.5Hz,1H),8.47(d,J=1.4Hz,2H),8.17(dd,J=8.4,5.4Hz,1H),7.92–7.87(m,2H),7.55–7.43(m,2H),7.18(d,J=3.5Hz,1H),5.04(q,J=6.9Hz,1H),2.08–1.99(m,1H),1.92(d,J=6.9Hz,3H),1.88–1.77(m,2H),1.74–1.67(m,1H),1.36(m,4H),1.26(s,3H).MS:[M+1]=386.2
实施例28:4-(1-(1-(喹啉-6-基)-1氢-吲唑-4-基)乙基)吗啉盐酸盐
将吲哚-4甲醛替换成吲唑-4-甲醛,按方案3合成得到目标产物
1H NMR(400MHz,Methanol-d4)δ9.34(d,J=8.5Hz,1H),9.25(dd,J=5.4,1.3Hz,1H),8.83–8.71(m,3H),8.47(d,J=9.2Hz,1H),8.28(d,J=8.4Hz,1H),8.21–8.14(m,1H),7.78(t,J=7.9Hz,1H),7.74–7.68(m,1H),4.15–4.06(m,1H),3.92(q,J=16.6,15.3Hz,3H),3.74(t,J=12.1Hz,1H),3.19–3.05(m,2H),2.03–1.96(m,1H),1.94(d,J=6.9Hz,3H),1.27(d,J=3.8Hz,1H).
合成方案4:
实施例29按以下合成路线,Buckwald coupling、还原、取代得到目标产物
实施例29:4-((7-萘-2-基)-1氢-吲哚-3-基)甲基)吗啉盐酸盐
1H NMR(400MHz,CDCl3)δ:8.09(d,J=1.5Hz,1H),7.99(d,J=8.5Hz,1H),7.94–7.87(m,2H),7.80–7.73(m,2H),7.57–7.50(m,2H),7.35(dd,J=7.3,1.1Hz,1H),7.31–7.26(m,2H),3.82(s,2H),3.76(t,J=4.7Hz,4H),2.66–2.53(m,4H).MS(ESI)m/z 343.2([M+H]+).
步骤1.(7-氯-1氢-吲哚-3-基)(吗啉基)甲酮的合成
将7-氯-1氢-吲哚-3-甲酸(700.0mg,3.58mmol)和草酰氯(1.36g,10.74mmol)溶于DCM(10.0mL)和催化量DMF,室温下氮气保护下反应1h,浓缩;将吗啉(623.78mg,7.16mmol)和Et3N(724.52mg,7.16mmol)溶于DCM(10.0mL),将上述酰氯稀释于DCM(20mL)并缓慢滴加入反应瓶中,常温反应2h;反应完毕,加入饱和氯化铵溶液(20mL),DCM萃取(20mLx3),合并的有机相用饱和食盐水洗涤(20mLx2),无水硫酸钠干燥、过滤、浓缩得粗品700.0mg,经柱层析(PE/EtOAc=15/1)得(7-氯-1氢-吲哚-3-基)(吗啉基)甲酮(400mg,收率:42.2%)。
步骤2.吗啉(7-(萘-2-基)-1氢-吲哚-3-基)甲酮的合成
将(7-氯-1氢-吲哚-3-基)(吗啉基)甲酮(400.0mg,1.51mmol)、2-萘硼酸(519.41mg,3.02mmol)、氟化铯(688.11mg,4.53mmol)、TEBA(68.79mg,0.30mmol)和Pd(dppf)2Cl2(123.31mg,0.15mmol),溶于40.0mL Toluene/H2O中,氮气保护下,100℃搅拌反应12h;反应完毕,加入水(40mL),EA萃取(30mLx3),有机相饱和食盐水洗涤(20mLx2),无水硫酸钠干燥、过滤、浓缩得粗品,经柱层析(PE/EA=3/1)得吗啉(7-(萘-2-基)-1氢-吲哚-3-基)甲酮(400.0mg,收率:74.3%)。
步骤3. 4-((7-(萘-2-基)-1氢-吲哚-3-基)甲基)吗啉的合成
将吗啉(7-(萘-2-基)-1氢-吲哚-3-基)甲酮(200.0mg,0.56mmol)溶于THF(10mL)中,加入LAH(85.0mg,1.12mmol),氮气保护下60℃搅拌反应12h;反应完毕,加入40mL水,EA萃取(30mLx3),合并有机相,有机相用饱和食盐水洗涤(30mLx2),有机相用无水硫酸钠干燥、过滤、浓缩得粗品,经柱层析(PE/EA=1/1)得4-((7-(萘-2-基)-1氢-吲哚-3-基)甲基)吗啉(90.0mg,收率:46.9%)。
步骤4. 4-((7-(萘-2-基)-1氢-吲哚-3-基)甲基)吗啉盐酸盐合成
将4-((7-(萘-2-基)-1氢-吲哚-3-基)甲基)吗啉(60.0mg,0.18mmol)加入DCM(2mL)中,磁力搅拌溶解澄清,加入HCl/EA溶液(4.0mL),超声反应5mins;浓缩、干燥得4-((7-(萘-2-基)-1氢-吲哚-3-基)甲基)吗啉盐酸盐(67.0mg,收率:98.2%)。
合成方案5:
实施例30,31按以下合成路线,Buckwald coupling、还原、取代得到目标产物
实施例30:4-(([1,2’-双萘]-5-基)甲基)吗啉盐酸盐
1H NMR(400MHz,CDCl3)δ:8.39(dt,J=8.5,1.2Hz,1H),7.98–7.84(m,5H),7.66–7.58(m,2H),7.57–7.50(m,3H),7.48–7.42(m,1H),7.34(dd,J=8.5,6.8Hz,1H),3.96(s,2H),3.78–3.67(m,4H),2.56(t,J=4.7Hz,4H).MS(ESI)m/z 354.2([M+H]+).
步骤1.(5-溴基萘-1-基)(吗啉)甲基酮的合成
将5-溴-1萘甲酸(300.0mg,1.19mmol)和草酰氯(453.14mg,3.57mmol)溶于DCM(10.0mL)中,常温反应2h,浓缩,加入吗啉(124.58mg,1.43mmol)和Et3N(240.83mg,2.38mmol)的DCM(10.0mL)溶液,常温反应12h;反应完毕,加入水(80mL)淬灭,EA萃取(50mLx3),合并有机相,有机相用饱和食盐水洗涤(50mLx3),无水硫酸钠干燥、过滤、浓缩得油状粗品,经柱层析得到(5-溴基萘-1-基)(吗啉)甲基酮(50mg,收率:13.1%)。
步骤2.[1,2’-双萘]-5-基(吗啉)甲基酮的合成
加入(5-溴基萘-1-基)-(吗啉)甲基酮(50.0mg,0.16mmol)、2-萘硼酸(55.04mg,0.32mmol)、氟化铯(72.9 1mg,0.48mmol)、TEBA(3.64mg,0.016mmol)和Pd(dppf)2Cl2(13.07mg,0.016mmol),加入Toluene/H2O(10.0mL),溶解,98℃搅拌反应12h;反应完毕,EA萃取(50mLx3),合并有机相,有机相用饱和食盐水洗涤(50mLx3),无水硫酸钠干燥、过滤、浓缩得油状粗品,经柱层析得到[1,2’-双萘]-5-基(吗啉)甲基酮(50mg,收率:85.0%)。
步骤3. 4-[1,2’-双萘]-5-基甲基吗啉的合成
将[1,2’-双萘]-5-基(吗啉)甲基酮(220.0mg,0.60mmol)和CAH(56.93mg,1.5mmol)溶于THF(10.0mL),60℃搅拌反应12h;反应完毕,加入水(80mL)淬灭,EA萃取(50mLx3),合并有机相,有机相用饱和食盐水洗涤(50mLx3),有机相用无水硫酸钠干燥、过滤、浓缩得油状粗品,经柱层析(PE/EA=5/1)得到4-[1,2’-双萘]-5-基甲基吗啉(40.0mg,收率:18.9%)。
步骤4. 4-[1,2’-双萘]-5-基甲基吗啉盐酸盐的成盐
加入HCl/EA(4.0mL)到4-[1,2’-双萘]-5-基甲基吗啉(45.0mg,0.13mmol)的DCM(2mL)溶液中,搅拌溶解澄清,超声反应5min;浓缩、干燥后得到4-[1,2’-双萘]-5-基甲基吗啉盐酸盐(50mg,收率:98.7%)。
实施例31:4-((5-(喹啉-6-基)萘-1-基)甲基)吗啉盐酸盐
将2-萘硼酸换成6-硼酸喹啉,按实施例30的方法制备目标化合物。
1H NMR(400MHz,Methanol-d4)δ9.39-9.23(m,2H),8.54-8.45(m,2H),8.45-8.25(m,2H),8.24-8.14(m,1H),7.99(dt,J=8.6,1.1Hz,1H),7.94-7.83(m,2H),7.80-7.55(m,2H),5.01(s,2H),4.16-3.99(m,3H),3.80(td,J=13.1,11.8,3.7Hz,2H),3.46(dd,J=10.6,3.4Hz,4H).MS(ESI)m/z 355.2([M+H]+)。
合成方案6:
实施例32-34按以下合成路线,Buckwald coupling、还原、取代得到目标产物
实施例32:4-(2-(4-萘-2-基)-1氢-吲唑-1-基)乙基)吗啉盐酸盐
1H NMR(400MHz,CDCl3)δ:8.20(d,J=0.9Hz,1H),8.16(d,J=1.6Hz,1H),7.99(d,J=8.5Hz,1H),7.92(td,J=8.3,7.9,3.0Hz,2H),7.84(dd,J=8.5,1.8Hz,1H),7.57–7.42(m,4H),7.35(dd,J=6.9,1.1Hz,1H),4.58(t,J=7.0Hz,2H),3.74–3.65(m,4H),2.93(t,J=7.0Hz,2H),2.61–2.48(m,4H).MS(ESI)m/z 358.15([M+H]+).
步骤1. 4-(2-(4-溴-1氢-吲唑-1-基)乙基)吗啉的合成
将4-溴吲唑(300.0mg,1.52mmol)、4-(2-氯乙基)吗啉盐酸盐(339.9mg,1.83mmol)、K2CO3(631.3mg,4.56mmol)和KI(252.7mg,1.52mmol)溶于DMF(5.0mL),78℃搅拌反应12-18h;反应完毕,EA萃取(50mLx3),合并有机相,有机相用饱和食盐水洗涤(50mLx3),无水硫酸钠干燥、过滤、浓缩得油状粗品,经柱层析(EA/PE=1/2-1/1)得到4-(2-(4-溴-1氢-吲唑-1-基)乙基)吗啉(240.0mg,收率:50.9%)。
步骤2. 4-(2-(4-(萘-2-基)-1氢-吲唑-1-基)乙基)吗啉的合成
将4-(2-(4-溴-1氢-吲唑-1-基)乙基)吗啉(240.0mg,0.77mmol)、2-萘硼酸(266.6mg,1.55mmol)、K2CO3(268.12mg,1.94mmol)和Pd(dppf)2Cl2(20.0mg,0.077mmol)溶于10.0mL 1,4-dioxane/H2O,90℃搅拌反应12-18h;EA萃取(50mLx3),合并有机相,有机相用饱和食盐水洗涤(50mLx3),无水硫酸钠干燥、过滤、浓缩得油状粗品,经柱层析(EA/PE=1/2-1/1)得4-(2-(4-(萘-2-基)-1氢-吲唑-1-基)乙基)吗啉(80.0mg,收率:29.1%)。
步骤3. 4-(2-(4-(萘-2-基)-1氢-吲唑-1-基)乙基)吗啉盐酸盐合成
将4-(2-(4-(萘-2-基)-1氢-吲唑-1-基)乙基)吗啉(80.0mg,0.22mol)溶于2mLDCM,加入4.0mL HCl/EA,析出白色固体;浓缩、干燥后得到4-(2-(4-(萘-2-基)-1氢-吲唑-1-基)乙基)吗啉盐酸盐(65.0mg,收率:75.0%)。
实施例33:4-(2-(4-(萘-2-基)-1氢-苯并咪唑-1-基)乙基)吗啉盐酸盐
将4-溴吲唑换成4-溴苯并咪唑,按实施例32的方法制备目标化合物。
1H NMR(400MHz,CDCl3)δ:8.46(d,J=1.7Hz,1H),8.17(dd,J=8.6,1.8Hz,1H),8.11(s,1H),7.99–7.93(m,2H),7.90–7.85(m,1H),7.57(dd,J=5.1,3.4Hz,1H),7.52–7.46(m,2H),7.45–7.40(m,2H),4.33(t,J=6.3Hz,2H),3.76–3.66(m,4H),2.83(t,J=6.3Hz,2H),2.58–2.47(m,4H).MS(ESI)m/z 358.2([M+H]+)。
实施例34:4-(2-(4-萘-2-基)-7氢-吡咯[2,3-d]嘧啶-7-基)乙基)吗啉盐酸盐
将4-溴吲唑换成4-溴-7氢-吡咯[2,3-d]嘧啶,按实施例32的方法制备目标化合物。
1H NMR(400MHz,Chloroform-d)δ:9.00(s,1H),8.72–8.60(m,1H),8.26(dd,J=8.5,1.8Hz,1H),8.00(t,J=8.9Hz,2H),7.92(d,J=9.7Hz,1H),7.61–7.50(m,2H),7.41(d,J=3.6Hz,1H),6.92(d,J=3.6Hz,1H),4.46(t,J=6.4Hz,2H),3.76–3.64(m,4H),2.83(t,J=6.4Hz,2H),2.55(dd,J=5.7,3.7Hz,4H).MS(ESI)m/z359.2([M+H]+).
合成方案7:
实施例35按以下合成路线,Buckwald coupling、还原、取代得到目标产物
实施例35:4-(2-((8-(萘-2-基)喹啉-4-基)氧)乙基)吗啉盐酸盐
1H NMR(400MHz,CDCl3)δ:8.78(d,J=5.1Hz,1H),8.26(dd,J=8.3,1.5Hz,1H),8.09(d,J=1.6Hz,1H),7.96–7.79(m,5H),7.60(dd,J=8.3,7.1Hz,1H),7.49(dt,J=6.2,3.4Hz,2H),6.77(d,J=5.2Hz,1H),4.39(t,J=5.6Hz,2H),3.82–3.73(m,4H),3.02(t,J=5.6Hz,2H),2.70(t,J=4.7Hz,4H).MS(ESI)m/z 385.2([M+H]+).
步骤1. 4-(2-((8-溴喹啉-4-基)氧)乙基)吗啉的合成
将8-溴-4-羟基喹啉(300.0mg,1.34mmol)、4-(2-氯乙基)吗啉盐酸盐(299.59mg,1.61mmol)、K2CO3(463.0mg,3.35mmol)和KI(222.44mg,1.34mmol)溶于DMF(5.0mL),78℃反应12h;反应完毕,EA萃取(50mLx3),合并有机相,有机相用饱和食盐水洗涤(50mLx3),无水硫酸钠干燥、过滤、浓缩得油状粗品355.8mg,经柱层析(DCM/MeOH=20:1)得4-(2-))((8-溴喹啉-4-基)氧)乙基)吗啉(160.0mg,收率:35.4%)。
步骤2. 4-(2-((8-萘-2-基)喹啉-4-基)氧)乙基)吗啉的合成
将4-(2-((8-溴喹啉-4-基)氧)乙基)吗啉(160.0mg,0.47mmol)、2-萘硼酸(161.67mg,0.94mmol)、氟化铯(214.18mg,1.41mmol)、TEBA(11.39mg,0.05mmol)和Pd(dppf)2Cl2(40.83mg,0.05mmol)溶于Toluene/H2O(20.0mL),98℃搅拌反应15h;反应完毕,EA萃取(50mLx3),合并有机相,有机相用饱和食盐水洗涤(50mLx3),无水硫酸钠干燥、过滤、浓缩得油状粗品,经柱层析(DCM/MeOH=40/1)得4-(2-((8-萘-2-基)喹啉-4-基)氧)乙基)吗啉(88.0mg,收率:48.7%)。
步骤3. 4-(2-((8-萘-2-基)喹啉-4-基)氧)乙基)吗啉盐酸盐的合成
将4-(2-((8-萘-2-基)喹啉-4-基)氧)乙基)吗啉(75.0mg,0.19mol),溶于DCM(2mL)中,加入HCl/EA(1.0mL),超声反应5mins;浓缩、干燥后得到4-(2-((8-萘-2-基)喹啉-4-基)氧)乙基)吗啉盐酸盐(77.6mg,收率:94.6%)。
合成方案8:
实施例36-37按以下合成路线,Buckwald coupling、wittig反应、还原胺化得到目标产物
实施例36:4-(2-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙基)吗啉盐酸盐
1H NMR(400MHz,Methanol-d4)δ9.34–9.17(m,2H),8.53(d,J=2.1Hz,1H),8.50–8.41(m,2H),8.15(dd,J=8.4,5.4Hz,1H),7.80(d,J=3.5Hz,1H),7.73(d,J=8.3Hz,1H),7.30(dd,J=8.4,7.3Hz,1H),7.18(d,J=7.2Hz,1H),7.06(m,1H),4.11(m,2H),3.87(m,2H),3.66(d,J=12.6Hz,2H),3.49(m,2.9Hz,4H),3.26(m,2H).MS(ESI)m/z 358.2([M+H]+).
步骤1. 1-(喹啉-6-基)-1氢-吲哚-4-甲醛的合成
200mL单口烧瓶中依次加入吲哚-4-甲醛(1.45g,10mmol)、6-溴喹啉(2.08g,10.00mmol)、Cs2CO3(6.52g,20.00mmol)、Pd2(dba)3(0.92g,1.00mmol)、X-Phos(0.48g,1.00mmol)、KI(0.17g,1.00mmol)和二甲苯(40mL),N2保护下90℃搅拌反应4h。TLC监测反应完全后,降至室温、反应液过滤、浓缩得2.2g粗品经柱层析(洗脱剂:EA/PE+DCM=10%-50%)得淡黄色泡沫状固体1-(喹啉-6基)-1氢-吲哚-甲醛(820mg);收率:30.1%。
步骤2. 6-(4-[(E)-2-甲氧基乙烯基)-1氢-吲哚-1-基]喹啉的合成
100ml三口烧瓶中加入(甲氧基甲基)三苯基氯化磷(4.34g,12.67mmol)、t-BuONa(1.42g,12.67mmol)和ACN(40ml),氮气保护下,-30℃搅拌反应1.0h,加入1-(喹啉-6基)-1氢-吲哚-甲醛(2.3g,8.45mmol),控温20℃搅拌反应3.0。TLC监测反应完成,加入饱和氯化铵(100mL)淬灭反应,乙酸乙酯(80mL)萃取,干燥、浓缩得棕色油状粗品。经柱层析(Ea/Pe=0%-50%),获得棕色油状物6-(4-[(E)-2-甲氧基乙烯基)-1氢-吲哚-1-基]喹啉(4.4g),产品中含有三苯基氧膦,直接用于下步反应.
步骤3. 2-(1-(喹啉-6-基)-1氢-吲哚-基)乙醛的合成
将粗品6-(4-[(E)-2-甲氧基乙烯基)-1氢-吲哚-1-基]喹啉(2.2g,8mmol),盐酸(0.58g,16.00mmol),THF(60mL),H2O(15mL)先后加入100mL反应瓶中,70℃下回流反应30分钟,TLC(PE:EA=1:1+2%MeOH)检测反应完全后,加入大量饱和碳酸氢钠(20mL)淬灭反应液至中性,EA萃取(30mLx3),分出有机相,无水硫酸镁干燥、浓缩得黄色油状粗产物4g,直接进行下一步反应。
步骤4. 4-(2(吗啉-4-基)乙基)-1-(喹啉-6-基)-1氢-吲哚的合成
称取上述粗品2-(1-(喹啉-6-基)-1氢-吲哚-基)乙醛(0.24g,1mmol),吗啉(0.13g,1.50mmol),TFA(0.01g,0.10mmol)室温下搅拌15分钟后,在低温(0-5℃)下加入NaHB(OAc)3(0.85g,4.00mmol),10分钟后自然升温至室温,此温度下反应40分钟。反应完全后,饱和碳酸氢钠(10mL)淬灭反应,DCM(20mLx2)萃取,分出有机相,无水硫酸镁干燥,浓缩得黄色油状粗品,经pre-TLC(DCM:MeOH=20:1)提纯得无色油状产物50mg。
步骤5. 4-(2(吗啉-4-基)乙基)-1-(喹啉-6-基)-1氢-吲哚盐酸盐的合成
将4-(2(吗啉-4-基)乙基)-1-(喹啉-6-基)-1氢-吲哚(50mg,0.16mmol)溶于EA,充分溶解后加入盐酸乙酸乙酯溶液(0.03g,0.32mmol),浓缩、真空干燥。得淡黄色固体65mg,纯度收率100%。
实施例37:1-(2-(1-(喹啉-6-基)-1氢-吲哚-4基)乙基)-4(三氟甲基)哌啶-4-醇盐酸盐
将吗啉替换成4-(三氟甲基)哌啶-4-醇,按实施例36的方法合成得到目标化合物
1H NMR(400MHz,Methanol-d4)δ9.38–9.12(m,2H),8.53(d,J=2.1Hz,1H),8.51–8.36(m,2H),8.15(dd,J=8.5,5.4Hz,1H),7.78(d,J=3.5Hz,1H),7.72(d,J=8.3Hz,1H),7.28(m,1H),7.17(m,1H),7.06(m,1H),3.81–3.64(m,2H),3.59–3.31(m,6H),2.22(m,2H),2.12–1.97(m,2H).MS(ESI)m/z 440.2([M+H]+).
表(I)
生物活性实施例:
测试了本发明某些有代表性的化合物作为sigma(σ-1和σ-2)抑制剂的活性,具体试验方案如下:
受试化合物配制:供试品全部使用终浓度为1%DMSO溶解,如溶解不好或混悬不均匀,适当加入HCl(10%,10μL),起始浓度为1.0×10-5M(即10μM),然后依次为1μM、333nM、100nM、33nM、10nM、3.3nM、1nM、0.33nM、0.1nM、0.01nM,备用。
σ-1抑制剂活性测试:
受体膜制备:使用含320mM蔗糖pH=7.4的10mM Tris-HCl缓冲液将豚鼠全脑匀浆,调整重量,1000g离心10min,取上层液加入含蔗糖pH=7.4的10mM Tris-HCl缓冲液匀浆,然后1000g、4℃离心10min,取上清液,50000g、4℃再离心25min,取沉淀加入不含蔗糖pH=7.4的10mM Tris-HC缓冲液匀浆,50000g、4℃离心25min、取沉淀重复上一操作,最后将沉淀于-80℃储存备用。
结合试验:将制备好的受体膜用不含蔗糖pH=7.4的10mM Tris-HCl缓冲液制成220mg/ml膜的混悬液,备用。各反应管分别加入膜制备物100μL。总结合管总结合管(TB)加入100μL不含蔗糖pH=7.4的10mM Tris-HC缓冲液,非特异性结合管(NSB)加入氟哌啶醇100μL(终浓度1.0×10-5M),各受试化合物管(CB)加入100μL受试化合物。所有反应管分别加入放射性配体4nM[3H]-Pentazocine 10μL。将各反应管25℃温孵135min,反应完毕后,结合的配基通过减压快速过滤,Whatman GF/C试纸提前用0.5%PEI浸泡1h以上,用冰冷的试验缓冲液充分洗涤,将滤片取出放到4mL闪烁杯中,加入1mL的甲苯闪烁液并混匀,最后,将闪烁瓶放入HIDEX液闪计数仪计数。
σ-2抑制剂活性测试
受体膜制备:同上述σ-1受体膜制备方法。
结合试验:将制备好的受体膜用不含蔗糖10mM Tris-HCl缓冲液制成220mg/mL膜混悬液,备用。各反应管分别加入膜制备物100μL、总结合管(TB)加入100μl不含蔗糖pH 7.4的10mM Tris-HC缓冲液,非特异性结合管(NSB)加入DTG 100μL(终浓度1.0×10-5M),各受试化合物结合管(CB)加入100μL受试化合物(终浓度1.0×10-5M),并加入100nM(+)-NANM屏蔽sigma-1受体;各反应管分别加入放射性配体3H-DTG 10μL,终浓度5nM。将各反应管25℃温孵135min,反应完毕后,结合的配基通过减压快速过滤,Whatman GF/C试纸用0.5%PEI浸泡1h以上,用冰冷的试验缓冲液充分洗涤,将滤片取出放到4mL闪烁杯中,加入1mL的甲苯闪烁液并混匀。最后,将闪烁杯放入芬兰HIDEX液闪计数仪计数。
Ki值计算:
logit法计算各化合物IC50;
通过Scatchard作图得出各放射性配基Kd值及Bmax;
表(II)显示了一些得到的结果:
表(II)
药效试验实施例:
ICR小鼠热板试验
采用雄性小鼠,体重介于18-22g之间,室温约25℃,设定热板温度为55℃,热痛阈值最大设为60s,记录从放置至舔后足或跳跃的时间作为痛阈值。所有小鼠先测2次基础痛阈值,以基础痛阈5-30s为合格,淘汰不合格的小鼠。
合格的小鼠按基础痛阈值随机分为溶媒对照组、吗啡组(1.25、2.5、5、10mg/kg)和E52862 40mg/kg+吗啡组(1.25、2.5、5、10mg/kg)组。所有受试组吗啡均为SC,E52862(参考文献J.Med.Chem.2012,55,8211-8224进行合成)为IP给予溶媒或受试化合物(剂量0.1ml/10g),检测药后0.5、2h的痛阈值,计算受试化合物可能的最大镇痛效应(MPE%):MPE%=(给药后-给药前)*100/(60-给药前)。
结果
ICR小鼠热板模型试验结果表明,实施例8(EP003-D5-C020简称C020)能明显降低吗啡用量,增效作用达到2.5倍。
ICR小鼠热板模型试验结果表明,阳性化合物E-52862能明显降低吗啡用量,增效作用达到1.9倍。
详细信息如下表,图1:
上表结果表明:吗啡和待测化合物联合使用,吗啡和E52862联合使用,与吗啡单用相比,ED50均可降低,说明在该模型中,待测化合物和吗啡联用组,吗啡和E52862联合组均可增强吗啡药效。其中吗啡和E52862联合使用后,与吗啡单用相比,ED50降低1.9倍;吗啡和待测化合物联合使用后,与吗啡单用相比,ED50降低2.5倍。说明待测化合物与E52862相比,增效作用优于E52862。
福尔马林试验
具体操作如下:采用生理盐水作为溶媒,分别进行IP给药。模型组给药体积为1.3ml/只,其他各给药组给药体积为5ml/kg。受试药的给药时间为造模测试前15min。实验测试前,给药后大鼠要在实验装置内适应5-10min。适应后大鼠右后足背皮下注射5%的福尔马林溶液(含1.85%甲醛)100μL造模,以形成皮丘为造模型成功标准,若注射足出血,则该只动物舍去不用。软件自动记录造模后第0-60min之间以1min为时间段的抬足次数。
数据分析:I相,0-10min,II相,10-60min,Ⅱ-a相,10-40min,Ⅱ-b相,40-60min。使用t检验检测组间统计学差异。镇痛效应%=(溶媒组舔咬次数-给药组舔咬次数)*100%/溶媒组舔咬次数。
结果
阳性药物E52862(160mpk)和实施例8(EP003-D5-C020简称C020)(160mpk)在高剂量组该模型均有效;C020对I、II相疼痛均显示出有效,药效结果见图2、3。其中图2为I相疼痛药效图,图3为II相疼痛药效图。
Claims (11)
1.式I所示的化合物或其药学可接受的盐:
式I为式VI、VI-1、VII、或VIII结构,
其中,A为取代或未取代的萘基、式II-1、式IV、或式V,所述取代的萘基的取代基选自取代或未取代的C1-5的烷基和卤素;所述取代的C1-5的烷基的取代基选自卤素;
式II-1、IV、V结构如下:
式II-1中,Q1、Q2、Q3、Q4、Q5、Q6独立地选自N或C;
式IV中,R4为烷基,式V中,R5为烷基;
B为IX结构:
在式IX中,n1为0-3的整数,n2为0-6的整数;Z4为C、O、S或N;Z5选自O或CH2或CR8R9;R2、R3独立地选自氢、卤代烷基、羟基、烷基、环烷基、酰胺;R8和R9独立地选自氢、卤代烷基、羟基、烷基、环烷基,并且R8和R9不同时为氢;所述的烷基为C1-C5的烷基;所述环烷基为C3-C5的环烷基;所述卤代烷基为C1-C5的卤代烷基;所述卤素为氟、氯、溴或碘;所述酰胺为乙酰胺、三氟乙酰胺,丙酰胺或异丁酰胺。
2.如权利要求1所述的式I所示的化合物或其药学可接受的盐:
式I为式VI、VII、或VIII结构,
其中,A为取代或未取代的萘基、式II、式IV、或式V,所述取代的萘基的取代基选自C1-5的烷基或卤素;
式II、IV、V结构如下:
式II中,Q1、Q2、Q3、Q4、Q5独立地选自N或C;
式IV中,R4为烷基,式V中,R5为烷基;
B为IX结构:
在式IX中,n1为0-3的整数,n2为0-6的整数,Z4为C、O、S或N;Z5选自O或CH2或CR8R9;R2、R3独立地选自氢、卤代烷基、羟基、烷基、环烷基、酰胺;R8和R9独立地选自氢、卤代烷基、羟基、烷基、环烷基,并且R8和R9不同时为氢;
优选,在式IX中,n1为0-3的整数、n2为0-4的整数,Z4为C、O或S;Z5选自O或CH2;R2、R3独立地选自氢、卤代烷基、羟基、烷基、酰胺;
所述的烷基为C1-C5的烷基;所述环烷基为C3-C5的环烷基;所述卤代烷基为C1-C5的卤代烷基;所述卤素为氟、氯、溴或碘;所述酰胺为乙酰胺、三氟乙酰胺,丙酰胺或异丁酰胺。
3.如权利要求1所述的式I化合物或其药学可接受的盐,其特征在于结构为式VI:
其中,Z1、Z2、Z3、W独立地选自N或C;
其中,A为取代或未取代的萘基、式II、式IV、或式V,所述取代的萘基的取代基为C1-5的烷基或卤素;
式II,IV,V结构如下:
式II中,Q1、Q2、Q3、Q4、Q5独立地为N或C;
式IV中,R4为烷基,式V中,R5为烷基;
B为IX-1结构:
在式IX-1中,n1、n2独立地为0-3的整数,Z4选自C、O、S、N中的一种;R2、R3独立的选自氢、卤代烷基、羟基、烷基、环烷基、酰胺;
优选,在式IX-1中,n1、n2独立地为0-3的整数,Z4选自C、O、S中的一种;R2、R3独立的选自氢、卤代烷基、羟基、烷基、酰胺;
所述的烷基为C1-C5的烷基;所述环烷基为C3-C5的环烷基;所述卤代烷基为C1-C5的卤代烷基;所述卤素为氟、氯、溴或碘;所述酰胺为乙酰胺、三氟乙酰胺,丙酰胺或异丁酰胺。
5.如权利要求1所述的式I化合物或其药学可接受的盐,其特征在于结构为式VI:
其中,Z1、Z2、Z3、W独立地选自N或C;
其中,A为取代或未取代的萘基、式II、式IV、或式V,所述取代的萘基的取代基为C1-5的烷基或卤素;
式II,IV,V结构如下:
式II中,Q1、Q2、Q3、Q4、Q5独立地为N或C;
式IV中,R4为烷基,式V中,R5为烷基;
B为IX结构:
在式IX中,n1、n2独立地为0-3的整数,Z4为C、O、S或N;Z5为CR8R9;R2、R3独立的选自氢、卤代烷基、羟基、烷基、环烷基、酰胺;R8和R9独立的选自氢、卤代烷基、羟基、烷基、环烷基,并且R8和R9不同时为氢;所述的烷基为C1-C5的烷基;所述环烷基为C3-C5的环烷基;所述卤代烷基为C1-C5的卤代烷基;所述卤素为氟、氯、溴或碘;所述酰胺为乙酰胺、三氟乙酰胺,丙酰胺或异丁酰胺。
K6选自N或C;
其中,A为取代或未取代的萘基、式II结构,所述取代的萘基的取代基选自C1-5的烷基或卤素;
式II结构如下:
式II中,Q1、Q2、Q3、Q4、Q5独立地选自N或C;
B为IX结构:
在式IX中,n1、n2独立地为0-3的整数,Z4为C、O、S或N;Z5选自O或CH2或CR8R9;R2、R3独立的选自氢、卤代烷基、羟基、烷基、环烷基、酰胺;R8和R9独立的选自氢、卤代烷基、羟基、烷基、环烷基,并且R8和R9不同时为氢;
优选,在式IX中,n1、n2为0-3的整数,Z4为C、O或S;Z5选自O或CH2;R2、R3独立的选自氢、卤代烷基、羟基、烷基、酰胺;
所述的烷基为C1-C5的烷基;所述环烷基为C3-C5的环烷基;所述卤代烷基为C1-C5的卤代烷基;所述卤素为氟、氯、溴或碘;所述酰胺为乙酰胺、三氟乙酰胺,丙酰胺或异丁酰胺。
8.如权利要求1所述的式I化合物或其药学可接受的盐为如下结构:
式I为式VI、VII、VIII结构,
VII与VIII结构中,K1、K2、K3、K4、K5、K6独立地选自N或C;
其中,A为未取代的萘基、式II、式IV、或式V;
式II、IV、V结构如下:
式II中,Q1、Q2、Q3、Q4、Q5独立地选自N或C;
式IV中,R4选自甲基、乙基、丙基中的一种;
式V中,R5选自甲基、乙基、丙基中一种;
B为IX结构:
在式IX中,n1、n2独立地为0、1、2、3;Z4选自C、O、S中的一种;Z5选自CH2或O;R2、R3独立地选自氢、三氟甲基、羟基、甲基、乙基、丙基、异丁酰胺。
9.如权利要求1所述的式I所示的化合物或其药学可接受的盐,其特征在于,选自如下所示任意一个化合物:
4-((1-(萘-2-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐,
4-((4-甲基哌嗪-1-基)甲基)-1-(萘-2-基)-1氢-吲哚或其盐酸盐,
4-((4-环丙基哌嗪-1-基)甲基)-1-(萘-2-基)-1氢-吲哚或其盐酸盐,
2-甲基-1-(4-((1-(萘-2-基)-1氢-吲哚-4-基)甲基)哌嗪-1基)丙烷-1-酮或其盐酸盐,
4-((1-异喹啉-3-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐,
4-((1-(喹唑啉-2-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐,
4-((1-(喹啉-7-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐,
4-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐,
4-((1-(异喹啉-6-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐,
4-((1-(喹唑林-6-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐,
4-((1-(喹喔啉-6-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐,
4-((1-(1-甲基-1氢-吲唑-5-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐,
4-((1-(2-甲基-1氢-吲唑-5-基)-1氢-吲哚-4-基)甲基)吗啉或其盐酸盐,
4-((1-(萘-2-基)-1氢-吡咯[2,3]吡啶-4-基)甲基)吗啉或其盐酸盐,
4-((1-(萘-2-基)-1氢-吲唑-4-基)甲基)吗啉或其盐酸盐,
4-((1-(喹啉-6-基)-1氢-吲唑-4-基)甲基)吗啉或其盐酸盐,
4-((1-(萘-2-基)-1氢-苯并咪唑-4-基)甲基)吗啉或其盐酸盐,
4-((1-(喹啉-6-基)-1氢-苯并咪唑-4-基)甲基)吗啉或其盐酸盐,
4-((1-(喹啉-6-基)-1氢-吲哚-5-基)甲基)吗啉或其盐酸盐,
4-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)硫代吗啉或其盐酸盐,
4-((1-(萘-2-基)-1氢-吲哚-4-基)甲基)硫代吗啉或其盐酸盐,
4-甲基-1-((1-萘-2-基)-1氢-吲哚-4-基)甲基)哌啶-4-羟基或其盐酸盐,
1-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)-4-(三氟甲基)哌啶-4-羟基或其盐酸盐,
4-甲基-1-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)哌啶-4-羟基或其盐酸盐,
3-甲基-1-((1-(喹啉-6-基)-1氢-吲哚-4-基)甲基)吡咯烷-3-羟基或其盐酸盐,
4-(1-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙基)吗啉或其盐酸盐,
4-甲基-1-(1-(1-(喹啉-6-基)-1氢-吲哚-4基)乙基)哌啶-4-醇或其盐酸盐,
4-(1-(1-(喹啉-6-基)-1氢-吲唑-4-基)乙基)吗啉或其盐酸盐,
4-((7-萘-2-基)-1氢-吲哚-3-基)甲基)吗啉或其盐酸盐,
4-(([1,2’-双萘]-5-基)甲基)吗啉或其盐酸盐,
4-((5-(喹啉-6-基)萘-1-基)甲基)吗啉或其盐酸盐,
4-(2-(4-萘-2-基)-1氢-吲唑-1-基)乙基)吗啉或其盐酸盐,
4-(2-(4-(萘-2-基)-1氢-苯并咪唑-1-基)乙基)吗啉或其盐酸盐,
4-(2-(4-萘-2-基)-7氢-吡咯[2,3-d]嘧啶-7-基)乙基)吗啉或其盐酸盐,
4-(2-((8-(萘-2-基)喹啉-4-基)氧)乙基)吗啉或其盐酸盐,
4-(2-(1-(喹啉-6-基)-1氢-吲哚-4-基)乙基)吗啉或其盐酸盐,
1-(2-(1-(喹啉-6-基)-1氢-吲哚-4基)乙基)-4(三氟甲基)哌啶-4-醇或其盐酸盐。
10.一种药物组合物,其特征在于包含治疗有效量的权利要求1-9任一项所述的式I所示的化合物或其可药用的盐,和医学上可接受的载体。
11.权利要求1-9任一项所述式I化合物或其可药用盐或权利要求10所述的药物组合物在制备治疗和预防sigma受体相关疾病或疾病状态的药物中的用途;优选所述sigma受体相关疾病为疼痛;进一步优选所述疼痛选自神经性疼痛或炎性疼痛、术后疼痛、癌症疼痛,三叉神经痛,骨关节炎疼痛,烧伤疼痛,幻肢疼痛。
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