CN1136215C - 异喹啉衍生物或其盐 - Google Patents
异喹啉衍生物或其盐 Download PDFInfo
- Publication number
- CN1136215C CN1136215C CNB008082707A CN00808270A CN1136215C CN 1136215 C CN1136215 C CN 1136215C CN B008082707 A CNB008082707 A CN B008082707A CN 00808270 A CN00808270 A CN 00808270A CN 1136215 C CN1136215 C CN 1136215C
- Authority
- CN
- China
- Prior art keywords
- alkyl
- dimethoxy
- carbonyl
- tetrahydroisoquinoline
- compound
- 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.)
- Expired - Fee Related
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 20
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title abstract 2
- 230000000694 effects Effects 0.000 claims abstract description 25
- 230000000747 cardiac effect Effects 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 18
- 230000002401 inhibitory effect Effects 0.000 claims abstract 3
- -1 4-methylenedioxyphenyl Chemical group 0.000 claims description 52
- 238000002360 preparation method Methods 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000000468 ketone group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 6
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- VKPLPDIMEREJJF-UHFFFAOYSA-N 3-methoxybenzamide Chemical compound COC1=CC=CC(C(N)=O)=C1 VKPLPDIMEREJJF-UHFFFAOYSA-N 0.000 claims 1
- VNDHYTGVCGVETQ-UHFFFAOYSA-N 4-fluorobenzamide Chemical compound NC(=O)C1=CC=C(F)C=C1 VNDHYTGVCGVETQ-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 76
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- 230000006793 arrhythmia Effects 0.000 abstract description 7
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- 239000000243 solution Substances 0.000 description 43
- 238000000034 method Methods 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 19
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- 125000000217 alkyl group Chemical group 0.000 description 18
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
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- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 125000005936 piperidyl group Chemical group 0.000 description 8
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- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 7
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- 239000012044 organic layer Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
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- 229910052739 hydrogen Inorganic materials 0.000 description 6
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- 239000007924 injection Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
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- 230000008030 elimination Effects 0.000 description 5
- 238000003379 elimination reaction Methods 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 230000002102 hyperpolarization Effects 0.000 description 5
- IYRMNDOLPONSCJ-UHFFFAOYSA-N isoquinolin-2-ium;chloride Chemical compound Cl.C1=NC=CC2=CC=CC=C21 IYRMNDOLPONSCJ-UHFFFAOYSA-N 0.000 description 5
- 230000028161 membrane depolarization Effects 0.000 description 5
- 208000010125 myocardial infarction Diseases 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 238000007670 refining Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- 229940059260 amidate Drugs 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 210000001013 sinoatrial node Anatomy 0.000 description 4
- KEDQCFRVSHYKLR-UHFFFAOYSA-N 3-[3-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-one Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCN1C(=O)CC2=CC(OC)=C(OC)C=C2CC1 KEDQCFRVSHYKLR-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
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- 150000001408 amides Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 238000005984 hydrogenation reaction Methods 0.000 description 3
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- BPCNEKWROYSOLT-UHFFFAOYSA-N n-phenylprop-2-enamide Chemical compound C=CC(=O)NC1=CC=CC=C1 BPCNEKWROYSOLT-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- VHWJSJBTUWUEAL-UHFFFAOYSA-N propanamide;hydrochloride Chemical compound Cl.CCC(N)=O VHWJSJBTUWUEAL-UHFFFAOYSA-N 0.000 description 3
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Vascular Medicine (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
以下通式(I)表示的本发明化合物是一种医药品,具有If电流抑制作用,且不伴有痉挛等严重的副作用。本发明涉及异喹啉衍生物或其盐,以这些化合物为有效组分的医药品,特别是降心搏率药物。即,涉及具有If电流抑制作用的降心搏率药物对于心绞痛和心肌梗塞等缺血性心脏疾病,血栓性心力衰竭及心律不齐等循环系统疾病的预防有效。本发明涉及二烷氧基-1,2,3,4-四氢喹啉-2-羰基哌啶子基-3,4-二烷氧基丙酰苯胺衍生物等。
Description
技术领域
本发明涉及医药,具体涉及具有If电流抑制作用、且不伴有痉挛等严重副作用的异喹啉衍生物或其盐,以这些化合物为有效组分的医药,特别涉及降心搏率药物。
背景技术
以往公知的具有降心搏率作用的药物包括作用于神经传递物质受体及离子通道的药物。前者包括腺苷受体激动剂、M2毒蕈碱受体激动剂及β肾上腺素能受体拮抗剂等。后者包括钙离子通道抑制剂为代表的药物。使心搏率下降的药物对因心肌中氧的供给和需求的平衡失调而导致的各种临床症状,例如,心绞痛、心肌梗塞等缺血性心脏疾病,或心律不齐、心力衰竭等循环系统疾病的预防和治疗有用。但是,这些药物不仅可使心搏率下降,还会对房室传导和心脏收缩功能产生过度的抑制作用等或具有降血压作用,有时会导致心搏完全停止,因此,如果用于心脏机能低下的患者可能会出现危险。
另一方面,具有心脏起搏功能的窦房结、构成刺激传递系统的房室结、希斯束和兴奋传导纤维等的细胞会自发地产生电兴奋。具有心脏起搏功能的细胞对钠离子和钾离子等阳离子的透过无选择性,由于膜电位的过极化被活化,此外,还确认了存在受β受体刺激而活化的离子电流,被称为If电流(Difrancesco D.等,J.Physiol.377:61-88,1986,Irisawa H等,Physiol.Rev.73:197-227,1993;Difracessco D.等,Annu.Rev.Physiol.,55:455-472,1993)。心脏中的If电流有利于具有起搏功能的细胞的舒张期脱极化的形成,可调节心搏率。
因此,希望通过抑制促进舒张期脱极化的If电流来降低心搏率。实际上最近已有关于抑制If电流使心搏率下降的新药物的报道。这种If电流抑制剂不会过度抑制房室传导及心脏收缩功能,选择性地使心搏率有所下降,还可减少心肌的耗氧量,所以这种If电流抑制剂在不会过度抑制房室传导及心脏收缩功能或无心搏停止作用方面和以往的各种受体激动剂和钙通道抑制剂等的活性有所区别。因此,If电流抑制剂可以作为副作用较少的缺血性心脏疾病(例如,心绞痛和心肌梗塞等)和循环系统疾病(心律不齐和心力衰竭等)的预防和治疗剂使用。此外,在使用了麻醉的手术时,可抑制心搏率过度上升,将心搏率控制在一定范围内。
不仅是具有起搏功能的细胞,一般无起搏功能的心肌细胞原体,即心房肌和心室肌细胞中也有性质类似If电流(对阳离子透过无选择性,因过极化而活化,因β受体刺激而活化)的离子电流存在(Hangang Yu,Circ,Res.72:232-236,1993)。心力衰竭或高血压等病症中的心肌细胞原体也会出现自发的电兴奋,记录这些细胞的动作电位,可观察到活动电位再极化后的电舒张期膜电位慢慢脱极化,舒张期脱极化。可以确认这些病症中的If电流有所增加,If电流有利于舒张期脱极化的形成,导致异位自动能亢进或触发活力(Elisabetta,C.等,Circulation.94:1674-1681,1996;Elisabetta,C.等.,Circulation.95:568-571,1997)。因此,If电流抑制剂对这些病症中的自动能亢进或触发活力有抑制作用。
已知的能够使心搏率下降的化合物Zatebradine的基本作用是抑制If电流。但是,有报道认为Zatebradine在使心搏率下降的同时也产生视障碍(William H.Frishman,J.Am.Coll.Cardiol,26:305-312,1995;StephenP.Glasser等.,The American Journal of Cardiology,79:1401-1405,1997)。这是因为视细胞中存在性质和If电流类似的电流(Ih电流)(ShaulHestrin,J.Physiol.390:319-333,1987),由于Zatebradine在抑制If电流的同时会抑制Ih电流,所以会出现视障碍。和Ih电流抑制作用分开也是If电流抑制剂的研究课题之一。
发明的揭示
本发明者们对If电流抑制剂进行认真研究后确认,以下通式(I)表示的异喹啉衍生物能够抑制If电流,具有使心脏的心搏率下降的作用,且不伴有痉挛等严重的副作用,从而完成了本发明。
即,本发明涉及以下通式(I)表示的异喹啉衍生物或其盐,以该衍生物或其盐为有效组分的医药,具体涉及If电流抑制剂,特别涉及其中的降心搏率剂、心力衰竭治疗剂及心律不齐治疗剂等药物。上述式中符号含义如下所述。A表示低级亚烷基,B表示-C(=O)-NR5-或-NR5-C(=O)-,R1及R2表示相同或不同的氢原子、低级烷基、-O-低级烷基,R3、R4及R5表示相同或不同的氢原子、低级烷基,D环表示可取代的烃环或可取代的杂环,m表示1、2或3,n表示0或1,q表示1或2。
本发明化合物在化学结构上的特征是必定具备酰胺部分,显现出较强的If电流抑制作用,且不伴有痉挛等副作用。
以下,对本发明化合物(I)进行详细说明。
对本发明通式的定义无特别限定,“低级”表示碳原子数1~6的直链或支链碳链。
“烃环”为饱和或不饱和的单环或稠合烃环。包括“芳基”或“环烷基”,特别好的是“芳基”。
“芳基”较好为碳原子数6~14的芳基,还包括芳基的任意碳原子和氢原子发生加成反应而获得的二氢体、四氢体及六氢体等。更好的是苯基或萘基。
“杂环”表示含有1~4个氧原子、硫原子或氮原子等杂原子的杂芳基或饱和杂环。杂芳基包括呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、噻二唑基、吡啶基、嘧啶基、吡嗪基等5~6元单环杂芳基,以及由2个5~6元杂芳基稠合而成的萘啶基、苯并呋喃基、吲哚基、苯并咪唑基、苯并噻二唑基、苯并噁嗪基、苯并噻唑基、吡啶并吲哚基等二环式杂芳基,对它们无特别限定。饱和杂环较好为5~7元环,特别好的是哌啶基和哌嗪基。
“可取代的烃环”或“可取代的杂环”中的“取代基”只要是一般可取代这些环的基团即可。较好的是F、Cl、Br和I等卤原子,低级烷基,乙烯基等低级链烯基,乙炔基等低级炔基,-OH、-SH、三氟甲基等卤代低级烷基,-O-卤代低级烷基,-O-低级烷基,-S-低级烷基,-CO-O-低级烷基,-O-低级链烯基-CO-O-低级烷基,-COOH,-SO2-低级烷基,-SO-低级烷基,-CO-低级烷基,-CO-NH2,-CO-NH-低级烷基,-CO-N(低级烷基)2,-NO2-,-CN、-NH2、-NH-低级烷基,-N(低级烷基)2、-O-低级亚烷基-O-,-NH-CO-低级烷基及酮基(=O)等。可使用1~5个取代基,较好是使用1~3个取代基。
本发明化合物(I)具有至少1个手性碳,存在以此为基础的(R)体、(S)体等光学异构体、外消旋体和非对映立体异构体等。此外,由于不同取代基种类,还存在几何异构体或互变异构体。本发明包括这些异构体的分离物或混合物。
本发明化合物(I)可与酸形成盐。所述盐包括与盐酸、氢溴酸、氢碘酸、硫酸、硝酸和磷酸等无机酸,与甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、酒石酸、碳酸、苦味酸、甲磺酸、乙磺酸、谷氨酸等有机酸形成的酸加成盐。本发明还包括化合物(I)的水合物、乙醇等溶剂合物和多晶型物质。
本发明化合物还包括在生物体内代谢转变为前述通式(I)表示的化合物或其盐的化合物,即所谓的预抑制剂(prodrad)。形成本发明化合物的预抑制剂(prodrad)的基团包括Prog.Med.5;2157-2161(1985)中记载的基团,广川书店1990年刊《医药品开发》第7卷分子设计163~198页记载的基团。
制备方法
本发明化合物(I)可通过各种制备方法制得。下面,对具有代表性的制备方法进行说明。
本制备方法是使氨基化合物(II)和丙烯酸进行酰胺化反应,获得化合物(III)。然后,使化合物(III)和环状氨基化合物(IV)进行迈克尔加成反应,获得本发明化合物(I)。
酰胺反应可采用酰氯、酰溴等酰卤,酰基叠氮,N-羟基苯并三唑(HOBT),对硝基苯酚和N-羟基琥珀酰亚胺等的活性酯,用二环己基碳二亚胺(DCC)和碳二咪唑(CDI)等缩合剂等。迈克尔加成反应可在甲苯、苯、四氢呋喃、二氯乙烷、乙醇、二噁烷等溶剂中,在冰冷却下或室温下或加温条件下进行。此外,可添加三乙胺、三通B(triton B,氢氧化四烃铵R4NOH)和氢氧化钾等。
本制备方法是使环状氨基化合物(IV)和化合物(V)进行常规的烷基化反应后,脱去羧酸的保护基,获得化合物(VI)。然后,使化合物(VI)和氨基化合物(II)按照常规的酰胺化反应进行缩合。或者使环状氨基化合物(IV)和另外合成的化合物(VII)进行烷基化反应。
本制备方法是使环状氨基化合物(IV)和化合物(VIII)进行常规的烷基化反应后,脱去氨基的保护基,获得化合物(IX),然后按照常规方法使化合物(IX)和羧酸(X)或其衍生物进行烷基化反应。
本制备方法是使环状氨基化合物(IV)和化合物(XII)进行常规的还原烷基化反应后,脱去氨基的保护基,获得化合物(XIII),然后按照常规的酰胺化反应使化合物(XIII)和羧酸(X)或其衍生物进行缩合。或者使环状氨基化合物(IV)和另外合成的化合物(XIV)进行常规的还原烷基化反应。还原烷基化反应是使环状氨基化合物(IV)和化合物(XII)或(XIV)反应,分离出生成的席夫碱或不分离,然后还原该席夫碱的方法。还原时可采用金属氢化物的配合物,如硼氢化钠、硼氢化锂、氰基硼氢化钠、三乙酰氧基硼氢化钠等或硼烷等还原剂,或通过加氢来完成。
由上述制备方法制得的反应生成物可被分离精制,形成游离化合物、其盐或水合物等各种溶剂合物。利用常规的成盐处理可获得盐。
分离精制可采用萃取、浓缩、蒸馏、结晶化、过滤、重结晶、各种色谱法等常规化学操作完成。
利用异构体间的物理化学差异,通过常规方法可分离出各种异构体。采用一般的旋光拆分法,例如,分步结晶化或色谱法等可分离出光学异构体。此外,也可由适当的具有光学活性的原料化合物合成光学异构体。
进行分步结晶化时可采用酒石酸衍生物、苦杏仁酸衍生物、樟脑磺酸衍生物等具有光学活性的有机酸。溶剂则采用可使旋光拆分顺利进行的溶剂。
产业上利用的可能性
本发明化合物显现出具有If电流抑制作用,可选择性地使心搏率下降,减少心肌的耗氧量等特异活性,可作为心绞痛和心肌梗塞等缺血性心脏疾病,充血性心力衰竭和心律不齐等循环系统疾病的预防·治疗剂使用。
本发明化合物对因心肌中氧的供给和消耗的平衡失调而导致的各种临床症状,例如,胸部心绞痛、心肌梗塞及随之出现的心律不齐的预防或治疗,心律不齐,特别是上室性心律不齐的预防或治疗的效果非常好。
此外,本发明化合物通过对血管中血流的压迫的缓解,可减少粥样硬化症,特别是冠状动脉粥样硬化症的并发症的发生。本发明化合物是能够抑制过度上升的心搏率,在一般的外科手术时等可将心搏率控制在一定状态下的有用的药物。
由于本发明化合物的使心搏率下降的作用可直接抑制If电流,所以不会抑制房室传导和心脏收缩功能,相对于视障碍而言的心搏率下降作用的选择性高。此外,心脏中除了作为有利于形成活动电位的离子电流的If电流之外,还存在透过Na通道、K通道及Ca通道的电流等。本发明化合物的可抑制If电流的用量对心脏中存在的If电流以外的上述离子电流不会产生明显的抑制作用,所以因If电流以外的电流抑制而出现的副作用较少。此外,本发明化合物不会导致痉挛等严重的副作用。因此,本发明化合物是一种对前述各种疾病的预防和治疗有用的副作用较少的降心搏率药物。此外,本发明化合物还可作为心肌梗塞或高血压等病症中因If电流而导致的异位自动能亢进或触发活力的抑制剂使用。
由于本发明化合物通过抑制If电流使心搏率下降,所以也可作为心力衰竭或心律不齐的治疗剂使用。
本发明化合物所具备的药理作用可通过以下试验方法确认。
试验方法
1.If电流抑制作用试验
按照Robert E等在Br.J.Pharmacol.110:343-349,1993中记载的方法进行If电流抑制作用试验。
心肌分离
打击重量约为200~400g的雄性Hartley系豚鼠头部使其气绝后,切断其颈动脉一边放血一边快速地摘取心脏。将心脏转移到导入了足够的95%氧气和5%二氧化碳气体的混合气体的Tyrode’s液中,切出窦房结(起搏)部位(约3×5mm)。在37℃的温度下,用1.5mg/ml含有胶原酶(Yakult株式会社制)的除Ca2+Tyrode’s液对切出的窦房结进行约30分钟的酶处理后,于4℃在富K+溶液(KB回收溶液)中静置1小时以上。最后,用注射针揉碎处理结束后的窦房结部位,再通过移液获得分离的心脏细胞。
电流测定
将以上获得的分离的心肌撤在专用容器中,对于自行收缩的纺锤型细胞适合采用全细胞模式。以-40mV为定电位,从该电位开始依次在-10、-20、-30……-80mV给予过极化脉冲(1秒),激起If电流。由于在-80mV的过极化脉冲激起的If电流最大,所以在药效评估时测定被检化合物对-80mV的脉冲激起的If电流的作用。
药效评估
从灌流含有被检化合物的细胞外液(Tyrode液)开始,每隔5秒用-80mV的过极化脉冲激起If电流,记录约100次脉冲(约8分钟),确认药物作用在90次脉冲以上达到饱和。分别测定灌流药液前及90次脉冲后获得的If电流,通过50%的If电流被抑制时的物质浓度(IC50)比较被检化合物的If电流抑制作用。
结果:本发明的实施例化合物的IC50值为10-8M~10-5M。
2.降心搏率作用试验
按照Walter K.等在Eur.J.Pharmacol.104(1-2):9-18,1984中记载的方法进行降心搏率作用试验。
打击重量约为250~400g的雄性Hartley系豚鼠头部使其气绝后,放血致死,摘取心脏。在导入了足够的95%氧气和5%二氧化碳气体的混合气体的Tyrode’s液中制作右心房标本。将标本放置在不锈钢制挂钩
上,悬挂在负荷张力为1.0g的导入了足够的95%氧气和5%二氧化碳气体的混合气体的Tyrode’s液的马格纳斯管内,记录自动振动的心搏数。悬挂标本后稳定放置1小时以上,然后每隔30~45分钟在马格纳斯管内累积添加被验化合物,从被验化合物投入30分钟后的值求得浓度-作用曲线,评估效果。在被验化合物投入前自动心搏数减少30%的物质浓度(EC30)下比较降心搏率作用。其结果是,本发明化合物显现出较强的降心搏率作用。本试验的结果如表A所示。
表A
本发明化合物 | 降心搏率作用(EC30μM) | 本发明化合物 | 降心搏率作用(EC30μM) |
实施例2 | 0.30 | 实施例26 | 0.24 |
实施例4 | 0.57 | 实施例27 | 0.41 |
实施例5 | 0.38 | 实施例29 | 0.29 |
实施例6 | 0.32 | 实施例37 | 0.30 |
实施例9 | 0.27 | 实施例38 | 0.29 |
实施例10 | 0.27 | 实施例40 | 0.33 |
实施例12 | 0.27 | 实施例49 | 0.29 |
实施例14 | 0.47 | 实施例50 | 0.31 |
3.痉挛现象试验
在觉醒状态下,将重量为250~350g的雄性Wister系大鼠固定在笼子中,从其尾静脉投入被检化合物。对各只豚鼠静脉注射20mg/kg或40mg/kg的被检化合物后,观察动物在非拘束下的行动约1小时。根据观察过程中被检化合物对大鼠自发行动的影响评估是否出现痉挛现象。
其结果是,本发明化合物通过静脉给药40mg/kg也不会诱发痉挛,而在背景技术中引用的日本专利公开公报平2-138172号的实施例8的化合物、WO98/13364号的实施例24及33的化合物在其一半的给药量,即20mg/kg下就会诱发痉挛(表B)。
表B
本申请实施例化合物及对照化合物 | 给药量 | 现象 |
实施例2 | 40mg/kg | 未见异常 |
实施例4 | 40mg/kg | 未见异常 |
实施例5 | 40mg/kg | 未见异常 |
实施例6 | 40mg/kg | 未见异常 |
实施例9 | 40mg/kg | 未见异常 |
实施例10 | 40mg/kg | 未见异常 |
实施例14 | 40mg/kg | 未见异常 |
实施例26 | 40mg/kg | 未见异常 |
实施例27 | 40mg/kg | 未见异常 |
实施例28 | 40mg/kg | 未见异常 |
实施例29 | 40mg/kg | 未见异常 |
实施例30 | 40mg/kg | 未见异常 |
实施例37 | 40mg/kg | 未见异常 |
实施例38 | 40mg/kg | 未见异常 |
实施例40 | 40mg/kg | 未见异常 |
实施例47 | 40mg/kg | 未见异常 |
实施例49 | 40mg/kg | 未见异常 |
实施例50 | 40mg/kg | 未见异常 |
日本专利公开公报平2-138172号的实施例8(对照化合物) | 20mg/kg | 痉挛 |
WO98/13364号的实施例24(对照化合物) | 20mg/kg | 痉挛 |
WO98/13364号的实施例33(对照化合物) | 20mg/kg | 痉挛 |
从上述结果可出,本发明化合物在结构上的特征显现在导入的酰胺部分,本发明化合物不会引发痉挛,且能够有效抑制If电流,并可使心搏率下降。
用一般制药学上允许的载体可调制出含有1种或2种以上本发明化合物或其盐的医药组合物。
本发明的医药组合物的给药途径包括经口给药或注射剂、栓剂、经皮剂、吸入剂或膀胱内注入等非经口给药方式。
给药量可考虑给药对象的年龄、性别等根据不同情况决定,通常的给药量是成人1天0.1mg/kg~100mg/kg左右,可1次给药也可分2~4次给药。此外,根据症状静脉给药时,一般成人1天0.01mg/kg~10mg/kg,可1次注射也可分数次注射。
制剂用载体包括固体或液体非毒性医药用物质。
本发明的经口给药的固体组合物包括片剂、丸剂、胶囊剂、散剂和颗粒剂等。这种固体组合物中的至少1种活性物质和至少1种惰性稀释剂混合,例如,乳糖、甘露糖醇、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯吡咯烷酮、琼脂、果胶、偏硅酸铝酸镁。按照常规方法,该组合物中还可含有上述惰性稀释剂以外的添加剂,例如,硬脂酸镁等润滑剂,纤维素乙醇酸钙等崩解剂,乳糖等稳定剂,谷氨酸或天冬氨酸等助溶剂。还可根据需要,在片剂或丸剂外包裹蔗糖、明胶、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯等的糖衣或胃溶性、肠溶性薄膜。
非经口给药的注射剂包括无菌水性或非水性溶液剂、悬浮剂和乳浊剂。水性溶液剂、悬浮剂包括注射剂用蒸馏水及生理食盐水。非水溶性溶液剂和悬浮剂包括乙二醇、丙二醇、聚乙二醇、可可油、橄榄油、蓖麻油等植物油,乙醇等醇类,阿拉伯胶和吐温80等。上述组合物中还可包含等张剂,防腐剂,湿润剂,乳化剂,分散剂,乳糖等稳定剂,谷氨酸、天冬氨酸等助溶剂等添加剂。组合物可通过滤菌膜的过滤及配合使用杀菌剂或光照实现无菌化。制得的组合物或无菌固体组合物可在使用前用无菌水或无菌注射用溶剂溶解后再使用。
实施发明的最佳状态
以下,通过实施例对本发明的目的化合物及制备方法进行说明,但本发明并不仅限于这些实施例。本发明化合物的原料化合物的制备方法如参考例所述。
参考例1
以30ml的3,4-二甲氧基苯胺4.6g的四氢呋喃溶液、5.0ml三乙胺和2.68ml丙烯酰氯为原料,按照常规方法进行酰化反应,制得5.22g为白色结晶的3,4-二甲氧基丙烯酰苯胺。
与参考例1同样合成的参考例1-1~1-9的化合物见后述的表1。
参考例2
以40ml的(±)-6,7-二甲氧基-1,2,3,4-四氢异喹啉2.53g的二氯甲烷溶液、3.0g的N-(叔丁氧基羰基)-3-哌啶甲酸、3.0g的1-乙基-3-[3-(二甲基氨基)丙基]碳二亚胺的盐酸盐、0.89g的1-羟基苯并三唑为原料,按照常规方法进行酰胺化反应,制得3.77g(±)-6,7-二甲氧基-2-{[1-(叔丁氧基羰基)-3-哌啶基]羰基}-1,2,3,4-四氢异喹啉。然后,按照常规方法,用10ml含有4N盐酸的乙酸乙酯溶液对3.77g的(±)-6,7-二甲氧基-2-{[1-(叔丁氧基羰基)-3-哌啶基]羰基}-1,2,3,4-四氢异喹啉进行脱保护处理,获得2.30g为无色结晶的(±)-6,7-二甲氧基-2-[(3-哌啶基)羰基]-1,2,3,4-四氢异喹啉盐酸盐。
与参考例2同样合成的参考例2-1~2-11的化合物见后述的表1。
参考例3
按照常规方法使3.19g的(±)-6,7-二甲氧基-2-[(3-哌啶基)羰基]-1,2,3,4-四氢异喹啉盐酸盐脱盐后,使30ml所得残渣的乙腈溶液和2.85g的N-(2-溴乙基)邻苯二甲酰亚胺及1.55g碳酸钾按照常规方法进行烷基化反应,获得3.83g的(±)-6,7-二甲氧基-2-{[3-(2-邻苯二甲酰亚胺乙基)哌啶基]羰基}-1,2,3,4-四氢异喹啉。然后,按照常规方法,用45ml含有40%甲胺的甲醇溶液对以上获得的3.83g的(±)-6,7-二甲氧基-2-{[3-(2-邻苯二甲酰亚胺乙基)哌啶基]羰基}-1,2,3,4-四氢异喹啉进行脱保护处理,获得2.67g黄色泡沫状的(±)-2-{[3-(2-氨基乙基)哌啶基]羰基}-6,7-二甲氧基-1,2,3,4-四氢异喹啉。
与参考例3同样合成的参考例3-1~3-4的化合物见后述的表1。
参考例4
按照常规方法,使10ml的2-(3,4-二甲氧基苯基)乙腈1.77g的二甲基甲酰胺溶液、1.00g氢化钠和4.26g碘甲烷进行烷基化反应,获得1.78g的2-(3,4-二甲氧基苯基)-2-甲基丙腈。然后,按照常规方法,使30ml的2-(3,4-二甲氧基苯基)-2-甲基丙腈1.75g的乙醇溶液和3.0ml的28%的氨水溶液及4.3g拉奈镍进行接触加氢反应,获得1.59g的2-(3,4-二甲氧基苯基)-2-甲基丙胺。接着,按照常规方法,使8ml的2-(3,4-二甲氧基苯基)-2-甲基丙胺1.58g的甲酸溶液和0.252g多聚甲醛进行环化反应,获得1.34g淡黄色油状6,7-二甲氧基-4,4-二甲基-1,2,3,4-四氢异喹啉。按照常规方法,使10ml的2-(3,4-二甲氧基苯基)乙腈1.77g的二甲基甲酰胺溶液和1.00g氢化钠及4.26g甲基碘进行烷基化反应,获得1.78g的2-(3,4-二甲氧基苯基)-2-甲基丙腈。然后,按照常规方法,使30ml的2-(3,4-二甲氧基苯基)-2-甲基丙腈1.75g的乙醇溶液和3.0ml的28%的氨水溶液及4.3g拉奈镍进行接触加氢反应,获得1.59g的2-(3,4-二甲氧基苯基)-2-甲基丙胺。接着,按照常规方法,使8ml的2-(3,4-二甲氧基苯基)-2-甲基丙胺1.58g的甲酸溶液和0.252g多聚甲醛进行环化反应,获得1.34g淡黄色油状6,7-二甲氧基-4,4-二甲基-1,2,3,4-四氢异喹啉。
实施例1
在加热回流下,对0.268g的(±)-6,7-二甲氧基-2-[(3-哌啶基)羰基]-1,2,3,4-四氢异喹啉和0.166g的3,4-二甲氧基丙烯酰苯胺的甲苯悬浮液3ml搅拌一晚。减压蒸去反应液,在所得残渣中加入1N氢氧化钠水溶液,使反应液呈碱性后,用氯仿萃取,再用无水硫酸镁干燥有机层。滤去干燥剂后,减压蒸馏,所得残渣用硅胶柱色谱法(氯仿∶甲醇=100∶4)精制。在所得油状物的乙酸乙酯溶液8ml中加入含有4N盐酸的乙酸乙酯溶液0.227ml后,减压蒸馏溶剂。所得残渣用乙酸乙酯-乙醇结晶,获得0.337g为无色结晶的(±)-3-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]-N-(3,4-二甲氧基苯基)丙酰胺盐酸盐。
实施例2
用3.35g的(±)-6,7-二甲氧基-2-[(3-哌啶基)羰基]-1,2,3,4-四氢异喹啉和1.91g的3,4-亚甲二氧基丙烯酰苯胺,按照实施例1的方法制得4.95g为无色结晶的(±)-3-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]-N-(3,4-亚甲二氧基苯基)丙酰胺盐酸盐。
实施例3
用0.264g的(±)-6,7-二甲氧基-2-[(3-哌啶基)羰基]-1,2,3,4-四氢异喹啉和0.150g的3,5-二甲氧基丙烯酰苯胺,按照实施例1的方法制得0.243g为无色结晶的(±)-3-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]-N-(3,5-二甲氧基苯基)丙酰胺1/2草酸盐。
实施例4
用0.270g的(±)-6,7-二甲氧基-2-[(3-哌啶基)羰基]-1,2,3,4-四氢异喹啉和0.132g的4-甲氧基丙烯酰苯胺,按照实施例1的方法制得0.281g为无色结晶的(±)-3-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]-N-(4-甲氧基苯基)丙酰胺盐酸盐。
实施例5
用7.80g的(R)-6,7-二甲氧基-2-[(3-哌啶基)羰基]-1,2,3,4-四氢异喹啉和3.66g的3,4-亚甲二氧基丙烯酰苯胺,按照实施例1的方法制得11.2g为无色结晶的(-)-3-[(R)-3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]-N-(3,4-亚甲二氧基苯基)丙酰胺-L-酒石酸盐。
实施例6
用10.9g的(S)-6,7-二甲氧基-2-[(3-哌啶基)羰基]-1,2,3,4-四氢异喹啉和5.24g的3,4-亚甲二氧基丙烯酰苯胺,按照实施例1的方法制得15.6g为无色结晶的(+)-3-[(S)-3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]-N-(3,4-亚甲二氧基苯基)丙酰胺-D-酒石酸盐。
实施例7
在0.65g的(±)-6,7-二甲氧基-2-[(3-哌啶基)羰基]-1,2,3,4-四氢异喹啉盐酸盐中加入1N氢氧化钠水溶液,使溶液呈碱性后,用氯仿萃取。有机层用无水硫酸镁干燥后,减压蒸去溶剂,将所得残渣溶于20ml乙腈中。然后,加入4-溴丁酸乙酯0.32ml和碳酸钾0.32g,于80℃搅拌8小时。反应液冷却至室温后,减压蒸去溶剂,所得残渣用氯仿萃取。有机层用饱和食盐水洗涤后,用无水硫酸镁干燥。滤去干燥剂后减压浓缩,所得残渣用硅胶柱色谱法(氯仿∶甲醇=97∶3)精制,在所得0.78g油状物的乙醇溶液7ml中加入1N的氢氧化钠水溶液3.7ml,室温下搅拌3小时。用1N的盐酸中和后,减压蒸馏反应液,所得残渣和甲苯共沸2次后,在所得残渣和8ml的3,4-亚甲二氧基苯胺0.24g的四氢呋喃-8ml的DMF混合溶液中加入0.37g 1-乙基-3-[3-(二甲基氨基)丙基]碳二亚胺盐酸盐和1-羟基苯并三唑0.12g,室温下搅拌一晚。然后,减压蒸馏反应液,在所得残渣中加入1N氢氧化钠水溶液,使反应液呈碱性后,用氯仿萃取,有机层用无水硫酸镁干燥。过滤干燥剂后减压浓缩,所得残渣用硅胶柱色谱法(氯仿∶甲醇=93∶7)精制。在所得残渣的甲醇溶液中加入0.12g草酸形成草酸盐,然后用乙酸乙酯-甲醇的混合溶剂结晶化,获得0.50g为无色结晶的(±)-4-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]-N-(3,4-亚甲二氧基苯基)丁酰胺草酸盐。
实施例8
用0.69g的(±)-2-[(3-哌啶基)羰基]-6,7-二甲氧基-1,2,3,4-四氢异喹啉盐酸盐和0.27ml溴代乙酸乙酯,按照实施例7的方法制得0.04g为无色结晶的(±)-2-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]-N-(3,4-亚甲二氧基苯基)乙酰胺草酸盐。
实施例9
在(±)-2-{[3-(2-氨基乙基)哌啶基]羰基}-6,7-二甲氧基-1,2,3,4-四氢异喹啉0.410g的四氢呋喃(10ml)溶液中加入0.220g胡椒基酸、0.300g的1-乙基-3-[3-(二甲基氨基)丙基]碳二亚胺盐酸盐和0.090g的1-羟基苯并三唑,室温下搅拌一晚。减压蒸馏反应液,在所得残渣中加入1N氢氧化钠水溶液,使反应液呈碱性后,用氯仿萃取,有机层用无水硫酸镁干燥后,滤去干燥剂,减压浓缩,所得残渣用硅胶柱色谱法(氯仿∶甲醇=50∶1)精制后,在所得残渣的甲醇溶液中加入含有4N盐酸的乙酸乙酯溶液0.40ml形成盐酸盐。用丙酮使之结晶,获得0.240g为无色结晶的(±)-N-{2-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]乙基}-3,4-亚甲二氧基苯甲酰胺盐酸盐。
实施例10
用0.500g的(±)-2-{[3-(2-氨基乙基)哌啶基]羰基}-6,7-二甲氧基-1,2,3,4-四氢异喹啉和0.330g的3-甲氧基苯甲酸,按照实施例9的方法制得0.437g为无色结晶的(±)-N-{2-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]乙基}-3-甲氧基苯甲酰胺草酸盐。
实施例11
用0.720g的(±)-2-{[3-(2-氨基乙基)哌啶基]羰基}-6,7-二甲氧基-1,2,3,4-四氢异喹啉和0.380g的3,4-二甲氧基苯甲酸,按照实施例9的方法制得0.520g为无色结晶的(±)-N-{2-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]乙基}-3,4-二甲氧基苯甲酰胺草酸盐。
与实施例1同样合成的实施例12~25的化合物见后述的表2。
与实施例9同样合成的实施例26~51的化合物见后述的表2。
实施例52
于-78℃,在N-(3,4-亚甲二氧基苯甲酰基)-N-甲基甘氨酸乙酯0.32g的四氢呋喃(10ml)溶液中滴加2.8ml氢化二异丁基铝(0.95M己烷溶液),在氩气氛围气中,于-78℃搅拌2小时后,在反应液中加入1N氯化胺水溶液(3ml),使温度回复到室温后,用乙酸乙酯萃取。有机层用无水硫酸钠干燥。滤去干燥剂后减压浓缩,获得粗制的N-(3,4-亚甲二氧基苯甲酰基)-N-甲基甘氨醛。然后,在冰冷却下,在0.34g的(±)-2-[(3-哌啶基)羰基]-6,7-二甲氧基-1,2,3,4-四氢异喹啉盐酸盐的四氢呋喃(5ml)悬浮液中加入0.14ml三乙胺,在冰冷却下搅拌10分钟。在反应液中依次加入粗制的N-(3,4-亚甲二氧基苯甲酰基)-N-甲基甘氨醛的四氢呋喃(5ml)溶液、0.057ml乙酸、0.25g三乙酰氧基硼氢化钠,室温搅拌一晚。接着,在反应液中加入1N氢氧化钠水溶液,使反应液呈碱性后,用氯仿萃取,有机层用无水硫酸钠干燥。滤去干燥剂后减压浓缩,所得残渣用硅胶柱色谱法(氯仿∶甲醇=24∶1)精制后,在所得残渣的甲醇溶液中加入0.028g草酸形成作为草酸盐的0.075g淡黄色非晶体固体(±)-N-{2-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]乙基}-N-甲基-(3,4-亚甲二氧基)苯甲酰胺草酸盐。
实施例53
在9.32g的(+)-3-[(S)-3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]-N-(3,4-亚甲二氧基苯基)丙酰胺的乙醇溶液中加入2.07g富马酸,减压蒸馏后,由乙醇/2-丁酮获得9.38g为无色结晶的(+)-3-[(S)-3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]-N-(3,4-亚甲二氧基苯基)丙酰胺富马酸盐。
以下,表1所示为参考例的化学结构式及其物理化学性状。表2所示为实施例的化学结构式及其物理化学性状。采用与前述实施例或制备方法中记载的方法几乎相同的方法或本领域的技术人员对上述方法略加改变,都能够容易地制得具有表3所示化学结构式的化合物。
表中符号的含有如下。Rf:参考例,Structure:结构,Data:数据,Ex:实施例,Salt:盐,m.p.:熔点,NMR:核磁共振光谱(以TMS为内标),[α]D:旋光度,OMe:甲氧基,OEt:乙氧基,OiPr:异丙氧基,Me:甲基,L-TA:(L)-酒石酸,D-TA:(D)-酒石酸,Fu:富马酸
表2(续)
Claims (6)
1.通式(I)表示的异喹啉衍生物或其盐,上述式中符号含义如下所述:A表示C1-6亚烷基,B表示-C(=O)-NR5-或-NR5-C(=O)-,R1及R2表示相同或不同的氢原子、C1-6烷基、-O-C1-6烷基,R3、R4及R5表示相同或不同的氢原子、C1-6烷基,D环表示可取代的烃环或可取代的杂环,m表示1、2或3,n表示0或1,q表示1或2,其中,所述烃环为饱和或不饱和的单环或稠合烃环;所述杂环为含有1~4个氧原子、硫原子或氮原子的杂芳基或饱和杂环;所述取代基选自:卤原子、C1-6烷基、C1-6链烯基、C1-6炔基、-OH、-SH、卤代C1-6烷基、-O-卤代C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、-CO-O-C1-6烷基、-O-C1-6链烯基-CO-O-C1-6烷基、-COOH、-SO2-C1-6烷基、-SO-C1-6烷基、-CO-C1-6烷基、-CO-NH2、-CO-NH-C1-6烷基、-CO-N(C1-6烷基)2、-NO2-、-CN、-NH2、-NH-C1-6烷基,-N(C1-6烷基)2、-O-C1-6亚烷基-O-,-NH-CO-C1-6烷基、或酮基。
2.如权利要求1所述的异喹啉衍生物或其盐,它是由以下通式(I’)表示的:上述式中符号含义如下所述:A表示C1-6亚烷基,B表示-C(=O)-NR5-或-NR5-C(=O)-,R1及R2表示相同或不同的氢原子、C1-6烷基、-O-C1-6烷基,R3、R4及R5表示相同或不同的氢原子、C1-6烷基,D环表示可取代的烃环或可取代的杂环,其中,所述烃环为饱和或不饱和的单环或稠合烃环;所述杂环为含有1~4个氧原子、硫原子或氮原子的杂芳基或饱和杂环;所述取代基选自:卤原子、C1-6烷基、C1-6链烯基、C1-6炔基、-OH、-SH、卤代C1-6烷基、-O-卤代C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、-CO-O-C1-6烷基、-O-C1-6链烯基-CO-O-C1-6烷基、-COOH、-SO2-C1-6烷基、-SO-C1-6烷基、-CO-C1-6烷基、-CO-NH2、-CO-NH-C1-6烷基、-CO-N(C1-6烷基)2、-NO2-、-CN、-NH2、-NH-C1-6烷基,-N(C1-6烷基)2、-O-C1-6亚烷基-O-,-NH-CO-C1-6烷基、或酮基。
3.如权利要求1所述的异喹啉衍生物或其盐,它选自:N-{2-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]乙基}-4-氟苯甲酰胺,N-{2-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]乙基}-3,4-亚甲二氧基苯甲酰胺,(3-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]-N-(3,4-亚甲二氧基苯基)丙酰胺,N-{2-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]乙基}-4-甲氧基-3-甲基苯甲酰胺,N-{2-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]乙基}-3-甲氧基苯甲酰胺、N-{2-[3-(6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-羰基)哌啶子基]乙基}-3,4-二氟苯甲酰胺或它们的盐。
4.以权利要求1所述的异喹啉衍生物或其盐为有效组分的医药组合物。
5.如权利要求4所述的医药组合物在制备具有If电流抑制作用的药物中的应用。
6.如权利要求4所述的医药组合物在制备具有降心搏率作用的药物中的应用。
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US (1) | US6573279B1 (zh) |
EP (1) | EP1186601B1 (zh) |
JP (1) | JP3741042B2 (zh) |
KR (1) | KR100664893B1 (zh) |
CN (1) | CN1136215C (zh) |
AT (1) | ATE262518T1 (zh) |
AU (1) | AU4952800A (zh) |
CA (1) | CA2373880C (zh) |
DE (1) | DE60009287T2 (zh) |
DK (1) | DK1186601T3 (zh) |
ES (1) | ES2214276T3 (zh) |
MX (1) | MXPA01012392A (zh) |
PT (1) | PT1186601E (zh) |
WO (1) | WO2000075133A1 (zh) |
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DE60200160T2 (de) * | 2002-07-25 | 2004-11-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von Cilobradine oder pharmazeutisch akzeptablen Salze zur Behandlung oder Prävention von Herzversagen |
US20040138306A1 (en) * | 2002-07-25 | 2004-07-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of a specific cyclic amine derivative or the pharmaceutically acceptable salts thereof for the treatment or prevention of heart failure |
CA2511989A1 (en) * | 2002-12-25 | 2004-07-15 | Astellas Pharma Inc. | Novel benzamide derivatives and process for producing the same |
KR20060029209A (ko) * | 2003-04-02 | 2006-04-05 | 아스텔라스세이야쿠 가부시키가이샤 | 플루오로벤즈아미드 유도체의 신규 결정 |
WO2007023775A1 (ja) * | 2005-08-23 | 2007-03-01 | Astellas Pharma Inc. | 心房細動治療剤 |
TW200831497A (en) * | 2006-10-12 | 2008-08-01 | Epix Delaware Inc | Carboxamide compounds and their use |
PT2149560E (pt) * | 2007-05-22 | 2015-07-13 | Astellas Pharma Inc | Composto de tetra-hidroisoquinolina substituído na posição 1 |
WO2009076404A1 (en) * | 2007-12-10 | 2009-06-18 | Epix Delaware, Inc. | Carboxamide compounds and their use as antagonists of the chemokine ccr2 receptor |
JP2011506466A (ja) * | 2007-12-11 | 2011-03-03 | 株式会社サイトパスファインダー | カルボキサミド化合物ならびにケモカイン受容体アゴニストとしてのそれらの使用 |
JP2014521714A (ja) | 2011-08-12 | 2014-08-28 | ベーリンガー インゲルハイム フェトメディカ ゲゼルシャフト ミット ベシュレンクテル ハフツング | ネコ科動物の心不全を治療および予防する方法において使用するための奇異性電流(If)阻害薬 |
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US4059583A (en) * | 1975-11-13 | 1977-11-22 | Mcneil Laboratories, Incorporated | Substituted indoles |
JPH02138172A (ja) * | 1988-11-19 | 1990-05-28 | Mitsubishi Kasei Corp | β−アミノ酸アミド誘導体 |
WO1998013364A1 (fr) | 1996-09-25 | 1998-04-02 | Yamanouchi Pharmaceutical Co., Ltd. | Derives de 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline ou compositions medicinales obtenues |
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2000
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- 2000-06-01 ES ES00931652T patent/ES2214276T3/es not_active Expired - Lifetime
- 2000-06-01 DE DE60009287T patent/DE60009287T2/de not_active Expired - Lifetime
- 2000-06-01 DK DK00931652T patent/DK1186601T3/da active
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- 2000-06-01 EP EP00931652A patent/EP1186601B1/en not_active Expired - Lifetime
- 2000-06-01 CN CNB008082707A patent/CN1136215C/zh not_active Expired - Fee Related
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DE60009287T2 (de) | 2005-02-17 |
CA2373880C (en) | 2009-04-07 |
DK1186601T3 (da) | 2004-06-01 |
PT1186601E (pt) | 2004-06-30 |
EP1186601A4 (en) | 2002-10-30 |
DE60009287D1 (de) | 2004-04-29 |
EP1186601B1 (en) | 2004-03-24 |
CN1379773A (zh) | 2002-11-13 |
KR20020005765A (ko) | 2002-01-17 |
KR100664893B1 (ko) | 2007-01-09 |
ATE262518T1 (de) | 2004-04-15 |
CA2373880A1 (en) | 2000-12-14 |
JP3741042B2 (ja) | 2006-02-01 |
MXPA01012392A (es) | 2002-07-30 |
ES2214276T3 (es) | 2004-09-16 |
WO2000075133A1 (fr) | 2000-12-14 |
AU4952800A (en) | 2000-12-28 |
US6573279B1 (en) | 2003-06-03 |
EP1186601A1 (en) | 2002-03-13 |
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