CN1118456C - 1,2-二氢-2-氧代喹啉衍生物 - Google Patents
1,2-二氢-2-氧代喹啉衍生物 Download PDFInfo
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- CN1118456C CN1118456C CN98811798A CN98811798A CN1118456C CN 1118456 C CN1118456 C CN 1118456C CN 98811798 A CN98811798 A CN 98811798A CN 98811798 A CN98811798 A CN 98811798A CN 1118456 C CN1118456 C CN 1118456C
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title claims abstract 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 10
- 125000005843 halogen group Chemical group 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims abstract description 5
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 11
- 125000000217 alkyl group Chemical group 0.000 abstract description 3
- 125000004122 cyclic group Chemical group 0.000 abstract description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 abstract description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract 1
- 125000003277 amino group Chemical group 0.000 abstract 1
- -1 methoxyl group Chemical group 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
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- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
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- MLIOSACVBPHZSA-UHFFFAOYSA-N 4-benzyl-3-oxoquinoxaline-2-carboxylic acid Chemical compound O=C1C(C(=O)O)=NC2=CC=CC=C2N1CC1=CC=CC=C1 MLIOSACVBPHZSA-UHFFFAOYSA-N 0.000 description 2
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
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- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
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- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000006233 propoxy propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006225 propoxyethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 230000003236 psychic effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
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- 230000002557 soporific effect Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical group FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines 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 hetero ring
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Abstract
本发明提供下式表示的1,2-二氢-2-氧代喹啉衍生物或其可药用盐。〔式中,Ar表示吡啶基或下式所示基团,(式中,X3、X4相同或不同,表示氢原子、卤素原子、C1-5的烷基、C1-5的烷氧基、羟基或三氟甲基),Y表示氮原子、CH或C(OH)。R1和R2相同或不同,表示氢原子、C1-10的烷基、C3-15的烷氧基烷基或C3-15的烷基氨基烷基,或者R1和R2与相邻的氮原子一同形成环状氨基。X1和X2相同或不同,表示氢原子、C1-5的烷基、C1-5的烷氧基或卤素原子,或X1、X2连在一起形成亚烷二氧基。n表示1~3的整数。〕
Description
技术领域
本发明涉及对线粒体地西泮结合抑制剂受体(mitochondrialdiazepam binding inhibitor receptor,简称MDR)具有较高亲和性的化合物。
背景技术
镇静催眠药的作用部位之一苯二氮(BZ)受体可以分为存在于GABAA受体/氯化物通道复合体上的中心苯并二氮受体(centralbenzodiazepine receptor,简称CBR)以及存在于中枢神经系统(神经胶质细胞)或肾上腺上的MDR 2种(Clin.Neuropharmacol.,16,401-417,1993)。安定所代表的CBR激动剂作为镇静催眠药被广泛应用,但由于CBR激动剂直接作用于GABAA受体/氯化物通道复合体,在表现出镇静催眠作用的同时,也表现出过度镇静或精神依赖性等副作用。另一方面,MDR激动剂由于通过内因性神经活性类固醇(内因性镇静催眠物质)——神经胆固醇的合成,间接作用于GABAA受体/氯化物通道,在表现出镇静催眠作用的同时,也表现出过度的镇静或神经依赖性等副作用(J.Pharmacol.Exp.Ther.,267,462-471,1993;ibid.,265,649-656,1993)。
因此,期望开发一种MDR激动剂,作为对于以前BZ类不能充分发挥疗效的症状(强迫症、恐慌症)的治疗药,以及减轻了以前BZ类的副作用的镇静催眠药。
另外,对MDR作用的化合物由于通过GABAA受体作用,有可能成为失眠障碍、癫痫、伴有肌肉僵直的运动障碍、摄食障碍、循环障碍、认识学习障碍、药物依赖性的治疗药(Progress inNeurobiology,38,379-395,1992;ibid,49,73-97,1996,J.Neurochem.58,1589-1601;Neuropharmacol.30,1435-1440,1991)。而且,从MDR的生理机能来看,有可能成为癌(Biochimica et BIOphysica Acta,1241,453-470,1995)、脂质代谢障碍(Eur.J.Pharmacol.,294,601-607,1995)、精神分裂症(Neuropharmacology,35,1075-1079,1996)、脑梗塞(J.Neurosci.,15,5263-5274,1995)、ADIS(Abstracts of thefifth international conference on AIDS,P458,1989)、阿耳茨海默氏病(Alzheimer Dis.As Soc.Disotd.2,331-336,1988)或亨庭顿氏舞蹈病(Brain Res.,248,396-401,1982)的治疗药。
另一方面,作为对MDR有亲和性的化合物,有在特表平6-501030号中公开的吲哚类化合物。
发明的描述
本发明人对于与MDR有较高亲和性的化合物进行了悉心的研究,结果发现特定的1,2-二氢-2-氧代喹啉衍生物达到了该目的,从而完成了本发明。如上所述已知吲哚类化合物是对MDR具有亲和性的化合物,但是并没有报道指出1,2-二氢-2-氧代喹啉衍生物对MDR具有亲和性。
(式中,X3、X4相同或不同,表示氢原子、卤素原子、C1-5的烷基、C1-5的烷氧基、羟基或三氟甲基),Y表示氮原子、CH。R1和R2相同或不同,表示氢原子、C1-10的烷基、C3-15的烷氧基烷基或C3-15的烷基氨基烷基,或者R1和R2与相邻的氮原子一同形成环状氨基。X1和X2相同或不同,表示氢原子、C1-5的烷基、C1-5的烷氧基或卤素原子,或X1、X2连在一起形成亚烷二氧基。n表示1~3的整数。但是R1、R2、X1、X2、X3和X4同时表示氢原子的场合,Y不为CH。〕
在本发明中,X3、X4的卤素原子是氟原子、氯原子、溴原子或碘原子。X3、X4的C1-5烷基表示直链状或支链状烷基,例如甲基、乙基、丙基、异丙基等。X3、X4的C1-5烷氧基表示直链或支链上的烷氧基,例如甲氧基、乙氧基等。R1、R2的C1-10烷基表示直链状、支链状或环状烷基,例如甲基、乙基、丙基、异丙基、环丙基、丁基、异丁基、环丁基、环丙基甲基、戊基、异戊基、环戊基、环丁基甲基、1-乙基丙基、己基、异己基、环己基、环戊基甲基、1-乙基丁基、庚基、异庚基、环己基甲基、辛基、壬基、癸基等。R1、R2的C3-5烷氧基烷基表示直链状、支链状或环状的C1-13烷氧基-C2-14烷基,例如甲氧基乙基、甲氧基丙基、甲氧基丁基、乙氧基乙基、乙氧基丙基、乙氧基丁基、乙氧基戊基、乙氧基己基、乙氧基庚基、丙氧基乙基、丙氧基丙基、丙氧基丁基、异丙氧基乙基、环丙基甲氧基乙基等。R1、R2的C3-5烷基氨基烷基表示直链状、支链状或环状的C1-13烷基氨基-C2-14烷基,例如甲氨基乙基、二甲氨基乙基、甲氨基丙基、二甲氨基丙基、甲氨基丁基、乙氨基乙基、乙氨基丙基、乙氨基丁基、乙氨基戊基、乙氨基己基、乙氨基庚基、乙氨基辛基、丙氨基乙基、丙氨基丙基、丙氨基丁基、异丙氨基乙基、环丙基甲氨基乙基、吡咯烷基乙基等。R1、R2以及与其相邻的氮原子形成的环状氨基例如吡咯烷基、哌啶基、高哌啶基、吗啉基、哌嗪基、N-甲基哌嗪基、3,5-二甲基哌嗪基等。X1、X2的C1-5烷基表示直链状、支链状或环状烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、戊基等。X1、X2的C1-5烷氧基表示直链状、支链状或环状烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、环丙基甲氧基、戊氧基、异戊氧基等。X1、X2的卤素原子表示氟原子、氯原子、溴原子或碘原子。X1、X2连在一起形成的亚烷基二氧基例如亚甲基二氧基、亚乙基二氧基、亚丙基二氧基等。另外,本发明中的可药用盐是与硫酸、盐酸、磷酸等无机酸形成的盐,与醋酸、草酸、乳酸、酒石酸、富马酸、马来酸、甲磺酸、苯磺酸等有机酸形成的盐。
式〔I〕的化合物可以采用以下的常规制备方法1~3制备(以下反应式中,Ar、Y、R1、R2、X1、X2和n与上述相同,Y1表示氮原子或CH,R3和R4相同或不同,表示C1-5的烷基或苯甲基,X5表示氯原子、溴原子或碘原子)。〔常规制备方法1〕
步骤A:使1,2-二氢-2-氧代喹啉甲酸酯衍生物(1)与卤代芳烷基(2)在惰性溶剂中,碱存在条件下进行反应,必要时使用相间移动催化剂,可以得到1-芳烷基-1,2-二氢-2-氧代喹啉甲酸酯衍生物(3)。
这里的惰性溶剂例如甲醇、乙醇等醇类;1,2-二甲氧基乙烷、四氢呋喃等醚类;甲苯、苯等烃类;氯仿、二氯甲烷等卤代烃类溶剂;乙腈、N,N-二甲基甲酰胺、水或其混合溶剂等。相间移动催化剂例如苯甲基三乙基铵溴化物等季铵盐;18-冠-6-醚等冠醚等。碱例如碳酸钾、氢氧化钠、氢化钠、金属钠等无机碱;叔丁醇钾、乙醇钠等醇化物等。
步骤B:1-芳烷基-1,2-二氢-2-氧代喹啉甲酸酯衍生物(3)在惰性溶剂中通过碱或酸水解,得到1-芳烷基-1,2-二氢-2-氧代喹啉甲酸衍生物(4)。
这里惰性溶剂例如甲醇、乙醇等醇类;丙酮等酮类;1,2-二甲氧基乙烷、四氢呋喃等醚类;甲苯、苯等烃类;氯仿、二氯甲烷等卤代烃类溶剂;乙腈、N,N-二甲基甲酰胺或这些溶剂与水的混合溶剂。碱例如碳酸钾、碳酸钠、氢氧化钾、氢氧化钠等无机碱,酸例如盐酸、硫酸、磷酸等。
步骤C:本发明化合物(6)可以由1-芳烷基-1,2-二氢-2-氧代喹啉甲酸衍生物(4)经由酰卤或混合酸酐合成。
这里酰卤表示酰氯、酰溴等,可以通过亚硫酰氯、亚磺酰溴、乙二酰氯、四氯化碳-三苯基磷化氢、四溴化碳-三苯基磷化氢等卤化剂在惰性溶剂中反应制得。所述惰性溶剂是四氢呋喃等醚类;甲苯、苯等烃类;氯仿、二氯甲烷等卤代烃类溶剂;乙腈、N,N-二甲基甲酰胺等。
混合酸酐表示羧酸与碳酸形成的酸酐等,可以通过氯碳酸乙酯、氯碳酸异丁酯等卤代碳酸酯在三乙胺、二异丙基乙胺、N-甲基吗啉、吡啶等有机碱或氢氧化钠等无机碱存在下,在惰性溶剂中反应制得。所述惰性溶剂是四氢呋喃等醚类;甲苯、苯等烃类;氯仿、二氯甲烷等卤代烃类溶剂;乙腈、N,N-二甲基甲酰胺等。
另外,本发明化合物(6)也可以通过使1-芳烷基-1,2-二氢-2-氧代喹啉甲酸与缩合剂以及胺(5)在惰性溶剂中反应制得。
这里的缩合剂表示通常使用的酰胺化试剂,例如二苯基磷酰胺、氰基磷酸二乙酯、羰基二咪唑、N,N’-二环己基碳化二亚胺、N-乙基-N’-二甲氨基丙基碳化二亚胺盐酸盐等。惰性溶剂例如1,2-二甲氧基乙烷、四氢呋喃等醚类;甲苯、苯等烃类;氯仿、二氯甲烷等卤代烃类溶剂;乙腈、N,N-二甲基甲酰胺等。另外,本反应在必要时可以添加N-羟基琥珀酰亚胺、1-羟基苯并三唑、3-羟基-4-氧代-3,4-二氢-1,2,3-苯并三嗪等作为活化剂。〔常规制备方法2〕
1,2-二氢-2-氧代喹啉羧酸衍生物(7)通过步骤C酰胺化,得到本发明化合物(8),再通过步骤A进行1-芳烷基化,得到本发明化合物(6)。〔常规制备方法3〕
步骤D:通过在惰性溶剂中使靛红酸酐衍生物(9)与丙二酸酯(10)在碱存在下反应可以制得4-羟基-1,2-二氢-2-氧代喹啉甲酸酯衍生物(11)。
这里的惰性溶剂例如甲醇、乙醇等醇类;1,2-二甲氧基乙烷、四氢呋喃等醚类;甲苯、苯等烃类;氯仿、二氯甲烷等卤代烃类溶剂;乙腈、N,N-二甲基甲酰胺、水或其混合溶剂等。碱例如碳酸钾、氢氧化钠、氢化钠、金属钠等无机碱类;叔丁醇钾、乙醇钠等醇化物等。
步骤E:4-羟基-1,2-二氢-2-氧代喹啉甲酸酯衍生物(11)在惰性溶剂中与胺衍生物(5)反应可以得到本发明化合物(12)。
这里惰性溶剂例如甲醇、乙醇等醇类;1,2-二甲氧基乙烷、四氢呋喃等醚类;甲苯、苯等烃类;氯仿、二氯甲烷等卤代烃类溶剂;乙腈、N,N-二甲基甲酰胺、水或其混合溶剂等。工业实用性
本发明的化合物对MDR具有较高的亲和性。因此,作为不安或与之相关连的疾病、抑郁病、癫痫、睡眠障碍、认识学习障碍、精神分裂症等中枢性疾病、伴有肌肉僵直的运动障碍、摄食障碍、循环障碍、药物依赖性、癌、脂质代谢障碍、脑梗塞、AIDS、阿耳茨海默氏病或亨庭顿氏舞蹈病的治疗或预防药是有效的。
发明的最佳实施方式
以下结合实施例和实验例具体说明本发明。
实施例1
(1)N,N-二己基-1-苯甲基-1,2-二氢-2-氧代喹喔啉-3-甲酰胺的制备
将1,2-二氢-2-氧代喹喔啉-3-甲酸乙酯3.90g溶解于N,N-二甲基甲酰胺25ml,在室温下用30分钟将其滴加到60%氢化钠/油0.79g的N,N-二甲基甲酰胺10ml悬浊液中。再在室温下搅拌30分钟后,用10分钟滴加溴化苯甲基3.36g,再在室温下搅拌1夜。减压浓缩反应液,在残渣中加入乙酸乙酯,用水、1N盐酸、饱和碳酸氢钠水溶液、饱和食盐水洗涤,用无水硫酸钠干燥后,过滤除去干燥剂,在减压条件下浓缩滤液,采用色谱法(硅胶:Wacogel C200(和光纯药生产),展开溶剂:己烷-乙酸乙酯=10∶1~2∶1)精制残渣后,用乙酸乙酯-己烷重结晶,得到1-苯甲基-1,2-二氢-2-氧代喹喔啉-3-甲酸乙酯3.77g。
(2)向1-苯甲基-1,2-二氢-2-氧代喹喔啉-3-甲酸乙酯2.00g中加入乙醇10ml和10%氢氧化钠水溶液20ml,在室温下搅拌1小时。向反应溶液中滴加3N盐酸,调节为酸性(pH=3.0),过滤收集析出的晶体。用水、乙醚洗涤该晶体,得到1-苯甲基-1,2-二氢-2-氧代喹喔啉-3-甲酸1.73g。
(3)将1-苯甲基-1,2-二氢-2-氧代喹喔啉-3-甲酸0.50g与三乙胺0.87ml溶解于四氢呋喃30ml中,冷却到-40℃,用5分钟滴加氯碳酸乙酯0.19ml。-40℃下搅拌10分钟后,用1小时升高到室温,再在室温下搅拌1夜。减压条件下浓缩反应混合物,在残渣中加入乙酸乙酯,用水、1N盐酸、饱和碳酸氢钠水溶液、饱和食盐水洗涤,用无水硫酸钠干燥后,过滤除去干燥剂,减压条件下浓缩滤液,采用色谱法(硅胶:Wacogel(和光纯药生产),展开溶剂:氯仿)精制残渣,用己烷重结晶,得到N,N-二己基-1-苯甲基-1,2-二氢-2-氧代喹喔啉-3-甲酰胺0.53g。
该化合物以及采用相同方法得到的化合物的结构和物理数据如表1、2所示。
实施例2
N,N-二己基-1-(3-吡啶甲基)-1,2-二氢-2-氧代喹啉-3-甲酰胺的制备
(1)将1,2-二氢-2-氧代喹啉-3-甲酸9.46g与N-甲基吗啉5.06g溶解于四氢呋喃50ml和N,N-二甲基甲酰胺250ml的混合溶剂中,冷却到-15℃,用10分钟滴加氯碳酸异丁酯6.83g。在-15℃下搅拌10分钟后,用5分钟滴加二己基胺9.73g。在-15℃下搅拌4小时,再在室温下搅拌1夜后,在减压条件下浓缩反应混合物,在残渣中加入乙酸乙酯,用水、1N盐酸、饱和碳酸氢钠水溶液、饱和食盐水洗涤,用无水硫酸钠干燥后,过滤除去干燥剂,减压条件下浓缩滤液。将残渣用己烷重结晶,得到N,N-二己基-1,2-二氢-2-氧代喹啉-3-甲酰胺13.51g。
(2)在N,N-二己基-1,2-二氢-2-氧代喹啉-3-甲酰胺1.01g的N,N-二甲基甲酰胺13ml的溶液中加入60%氢化钠/油136mg,在室温下搅拌1小时。在该反应液中加入3-氯代甲基吡啶434mg,在室温下搅拌4小时。将反应混合物注入水中,用乙酸乙酯萃取,用水、饱和碳酸氢钠水溶液、饱和食盐水洗涤,用无水硫酸钠干燥后,过滤除去干燥剂,减压条件下浓缩滤液。采用色谱法(硅胶:Wacogel C200(和光纯药生产),展开溶剂∶己烷-乙酸乙酯=7∶13~1∶19)精制残渣后,用乙酸乙酯重结晶,得到N,N-二己基-1-(3-吡啶甲基)-1,2-二氢-2-氧代喹啉-3-甲酰胺0.47g。
该化合物以及采用相同方法得到的化合物的结构和物理数据如表1、2所示。
实施例3
N,N-二己基-1-苯甲基-4-羟基-1,2-二氢-2-氧代喹啉-3-甲酰胺的制备
(1)将丙二酸二乙酯4.50g溶解于N,N-二甲基甲酰胺20ml中,在室温下一点一点加入62.4%的氢化钠1.10g。在室温下搅拌直到不再产生氢后,将反应液加热到80℃,滴加将N-苯甲基靛红酸酐6.70g溶解于N,N-二甲基甲酰胺20ml得到的溶液。滴加后在120℃加热搅拌反应混合物7小时。冷却到室温后,将反应化合物注入到冰水中,用乙酸乙酯洗涤。用1N盐酸将水相调节为酸性后,用乙酸乙酯萃取。用饱和食盐水洗涤有机相后,用无水硫酸镁干燥,过滤除去干燥剂后,减压条件下浓缩滤液。在残渣中加入乙醇使之结晶,得到1-苯甲基-4-羟基-1,2-二氢-2-氧代喹啉-3-甲酸乙酯5.88g。
(2)在130℃下将1-苯甲基-4-羟基-1,2-二氢-2-氧代喹啉-3-甲酸乙酯0.30g与二己基胺2ml的混合物加热搅拌2小时。冷却到室温后,在反应液中加入氯仿和1N盐酸,分离出有机相,用1N盐酸、水洗涤。用无水硫酸镁干燥有机相后,过滤除去干燥剂,在减压条件下浓缩滤液。采用色谱法(硅胶:默克硅胶230-4000目(默克公司生产),展开溶剂:氯仿)精制残渣后,放置使之结晶,得到N,N-二己基-1-苯甲基-4-羟基-1,2-二氢-2-氧代喹啉-3-甲酰胺0.36g。
该化合物以及采用相同方法得到的化合物的结构和物理数据如表2所示。表1Comp.*1 Exp.*2 R1 R2 X1 X2 Y n Ar m.p.(Recry.sol.*3)No. No. (℃)01 1 H H H H CH 1 Ph 229.0~231.0(CH2Cl2/Hex)02 1 Me H H H CH 1 Ph 177.0~177.5(AcOEt/Hex)03 1 Me Me H H CH 1 Ph 219.0~220.0(AcOEt)04 1 n-Pr n-Pr H H CH 1 Ph 135.0~136.0(AcOEt/Hex)05 1 n-Hex n-Hex H H CH 1 Ph 118.5~120.0(AcOEt/Hex)06 1 n-Dec n-Dec H H CH 1 Ph 78.5~80.0(AcOEt/Hex)07 1 (CH3)2N(CH2)3 (CH3)2N(CH2)3 H H CH 1 Ph 84.0~86.0(Hex)08 1 (CH2CHMc)2NH*4 H H CH 1 Ph 199.5~201.0(Hex)09 2 n-Hex n-Hex H H CH 1 2-F-Ph 93.0~94.0(放置*5)10 2 n-Hex n-Hex H H CH 1 2-Cl-Ph 108.5~109.0(放置*5)11 2 n-Hex n-Hex H H CH 1 4-Cl-Ph 150.0~151.0(放置*5)12 2 n-Hex n-Hex H H CH 1 2-P-Ph 115.5~116.5(放置*5)13 2 n-Hex n-Hex H H CH 1 4-Me-Ph 145.0~146.0(IPE)14 2 n-Hex n-Hex H H CH 1 2-MeO-Ph 99.0~100.0(放置*5)15 2 n-Hex n-Hex H H CH 1 3-MeO-Ph 107.5~108.0(放置*5)*1:化合物序号*2:化合物合成所使用的实施例序号*3:重结晶溶剂:CH2Cl2=二氯甲烷,Hex=己烷,AcOEt=乙酸乙酯,IPE=二异丙基醚*4:3,5-二甲基哌嗪基*5:采用硅胶柱色谱法精制,干燥后,放置,使之结晶。
另外,R1、R2、Ar中n-Hex=正己基、n-Dec=正癸基、n-Pr=正丙基、Ph=苯基表2Comp.*1 Exp.*2 R1 R2 X1 X2 Y n Ar m.p.(Recry.sol.*3)No. No. (℃)16 2 n-Hex n-Hex H H CH 1 2.5-(MeO)2-Ph 124.0~124.5(放置*4)17 2 n-Hex n-Hex H H CH 1 3.5-(MeO)2-Ph 94.5~95.5(放置*4)18 2 n-Hex n-Hex H H CH 1 2-Py 98.5~99.0(AcOEt)19 2 n-Hex n-Hex H H CH 1 3-Py 123.0~123.5(AcOEt)20 2 n-Hex n-Hex H H CH 1 4-Py 107.5~108.0(AcOEt)21 2 n-Hex n-Hex H H CH 2 Ph 75.0~77.0(Hex)22 1 n-Hex n-Hex 6-Cl H CH 1 Ph 145.0~146.0(AcOEt/Hex)23 1 n-Hex n-Hex 7-Cl H CH 1 Ph 119.0~119.5(AcOEt/Hex)24 1 n-Hex n-Hex OCH2O*5 CH 1 Ph 123.0~124.0(AcOEt/Hex)25 1 n-Hex n-Hex 6-OMe 7-OMe CH 1 Ph 122.5~123.5(AcOEt/Hex)26 3 n-Hex n-Hex H H COH 1 Ph 106.0~108.0(放置*4)27 1 n-Hex n-Hex H H N 1 Ph 53.5~55.5(Hex)*1:化合物序号*2:化合物合成所使用的实施例序号*3:重结晶溶剂:Hex=己烷,AcOEt=乙酸乙酯*4:采用硅胶柱色谱法精制,干燥后,放置,使之结晶。*5:6,7-亚甲二氧基
另外,R1、R2、Ar中n-Hex=正己基、Py=吡啶基、Ph-苯基。试验例〔MDR受体结合试验〕
使用从大鼠大脑皮层制得的粗线粒体部分作为受体标准品。
使用[3H]PK11195作为[3H]标识配体。
使用[3H]标识配体的结合试验按照Journal of Pharmacologyand Experimental Therapeutics,262,971(1992年)记载的下述方法进行。
受体标准品的配制:使用聚四氟乙烯匀化器,用含有其湿重量10倍容量的0.32M蔗糖的10mM Hepes缓冲液(pH7.4),将大脑皮层匀化。以900×g将匀浆离心分离10分钟。将得到的上清液以9000×g离心分离10分钟。将沉渣悬浊于Hepes缓冲液中,使蛋白质浓度达到1mg/ml,以12000×g离心分离10分钟。将得到的沉渣悬浊于50mM Hepes缓冲液(pH7.4)中,得到粗线粒体部分。
MDR结合试验:使线粒体标准品(1.0mg蛋白质/ml)、[3H]PK11195(2nM)和被测药物在4℃下反应90分钟。
反应结束后,用经0.3%聚乙烯亚胺处理过的玻璃滤器(GF/B)抽滤,用液体闪烁计测定滤纸的反射能。
以10μMPK11195存在下反应时的结合作为[3H]PK11195的非特异结合,以总结合与非特异结合的差作为特异结合。通过使一定浓度的[3H]PK11195(2nM)与浓度改变的被测药物在上述条件下反应得到抑制曲线,由该抑制曲线求出50%抑制[3H]PK11195结合的被测药物浓度(IC50),结果如表3所示。
表3
Comp.No. | MDRIC50(nM) |
0405061819202123 | 1.710.15953.40.4040.3680.1926.580.132 |
Claims (2)
2、下式表示的1,2-二氢-2-氧代喹啉衍生物或其可药用盐,式中,Ar表示吡啶基或下式所示基团
式中,X3、X4相同或不同,表示氢原子、卤素原子、C1-5的烷基、C1-5的烷氧基、羟基或三氟甲基;
Y表示氮原子、CH;
R1和R2相同或不同,表示C1-10的烷基、C3-15的烷氧基烷基或C3-15的烷基氨基烷基,或者R1和R2与相邻的氮原子一同形成环状氨基;
X1和X2相同或不同,表示氢原子、C1-5的烷基、C1-5的烷氧基或卤素原子,或X1、X2连在一起形成亚烷二氧基;
n表示1~3的整数。
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JPS63146872A (ja) * | 1986-07-08 | 1988-06-18 | Yoshitomi Pharmaceut Ind Ltd | ピリミジニルピペラジン化合物 |
JPH07278068A (ja) * | 1994-03-11 | 1995-10-24 | Adir | 新規アルキルアミノインダン化合物、その製造方法及びそれを含有する医薬組成物 |
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JPH07278068A (ja) * | 1994-03-11 | 1995-10-24 | Adir | 新規アルキルアミノインダン化合物、その製造方法及びそれを含有する医薬組成物 |
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