CN1791594A - 2-氨基喹啉衍生物 - Google Patents
2-氨基喹啉衍生物 Download PDFInfo
- Publication number
- CN1791594A CN1791594A CNA2004800137780A CN200480013778A CN1791594A CN 1791594 A CN1791594 A CN 1791594A CN A2004800137780 A CNA2004800137780 A CN A2004800137780A CN 200480013778 A CN200480013778 A CN 200480013778A CN 1791594 A CN1791594 A CN 1791594A
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- China
- Prior art keywords
- amino
- methyl
- compound
- alkyl group
- low alkyl
- 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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- 150000005013 2-aminoquinolines Chemical class 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 208
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 93
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 32
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 14
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 8
- -1 alkyl amino formyl radical Chemical compound 0.000 claims description 181
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 100
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 69
- 238000006243 chemical reaction Methods 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 52
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
- 201000010099 disease Diseases 0.000 claims description 33
- 239000001301 oxygen Substances 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
- 125000005843 halogen group Chemical group 0.000 claims description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 16
- FUXJMHXHGDAHPD-UHFFFAOYSA-N pyrimidine-2-carboxamide Chemical compound NC(=O)C1=NC=CC=N1 FUXJMHXHGDAHPD-UHFFFAOYSA-N 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
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- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 8
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- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 7
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- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 6
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- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- 229960005181 morphine Drugs 0.000 claims description 6
- 208000027232 peripheral nervous system disease Diseases 0.000 claims description 6
- 230000019612 pigmentation Effects 0.000 claims description 6
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- 208000017194 Affective disease Diseases 0.000 claims description 5
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- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 4
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- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 4
- HVGQWHMSVYODLJ-GFCCVEGCSA-N melanochrome Natural products CC1(C)Oc2cc3OC(=CC(=O)c3c(O)c2C[C@H]1O)CO HVGQWHMSVYODLJ-GFCCVEGCSA-N 0.000 claims description 4
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- 125000003003 spiro group Chemical group 0.000 claims description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
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- 239000003814 drug Substances 0.000 abstract description 35
- 239000001257 hydrogen Substances 0.000 abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 8
- 208000030159 metabolic disease Diseases 0.000 abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 208000024172 Cardiovascular disease Diseases 0.000 abstract 1
- 229940122023 Melanin concentrating hormone receptor antagonist Drugs 0.000 abstract 1
- 208000015114 central nervous system disease Diseases 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 81
- 239000002585 base Substances 0.000 description 65
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 102400001132 Melanin-concentrating hormone Human genes 0.000 description 38
- 101800002739 Melanin-concentrating hormone Proteins 0.000 description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- 230000006837 decompression Effects 0.000 description 29
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 238000001035 drying Methods 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 101150106280 Mchr1 gene Proteins 0.000 description 17
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- 238000003756 stirring Methods 0.000 description 16
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
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Abstract
本发明提供2-氨基喹啉衍生物,其由通式[I]表示[式中,R1及R2表示低级烷基、低级环烷基,或R1与R2一起与它们结合的氮原子一起形成脂肪族含氮杂环,R3、R4、R6及R7表示氢原子、低级烷基等,R8表示低级烷基、低级烷氧基等,n表示0~4的整数]。该化合物作为黑色素聚集激素受体的拮抗剂起作用,作为中枢性疾病、循环***疾病、代谢性疾病用的医药品有用。
Description
技术领域
本发明涉及医药领域中有用的2-氨基喹啉衍生物。该化合物,作为黑色素聚集激素受体拮抗物质起作用,作为各种循环***疾病、神经***疾病、代谢***疾病、呼吸***疾病、消化***疾病等的预防剂或治疗剂有用。
背景技术
黑色素聚集激素(Melanin Concentrating Hormone;下面称作“MCH”)是1983年由川内等人从鲑鱼的下垂体首次分离出的环状肽激素/神经肽[自然(nature),305卷,321页(1983年)]。已知在鱼类中功能性的拮抗黑色素细胞刺激激素,引起黑色素胞内的黑色素颗粒的聚集,参与体色的变化[(International Review Of Cytology),126卷,1页(1991年);(Trends in Endocrinology and Metabolism),5卷,120页(1994年)]。另外,在哺乳动物中,含有MCH的神经元的细胞体局部存在于外侧下丘脑和未定带区,其神经纤维在大脑内有着广泛的投射(The Journal of Comparative Neurology),319卷,218页(1992年)],MCH在生物体中负责各种中枢机能。
外侧下丘脑,以前作为摄食中枢为人所知,近年来揭示MCH参与控制能量守恒性的分子生物学、药理学的见解逐渐增加。即,有报告[自然(Nature),380卷,243页(1996年);Diabetes,47卷,294页(1998年);Biochemical and Biophysical ResearchCommunications,268卷,88页(2000年);Molecular Brain Research],92卷,43页(2001年)]指出:在作为遗传性肥胖模型动物的ob/ob小鼠、db/db小鼠、Ay/a小鼠、Zucker fatty大鼠和绝食小鼠的脑内,MCH前体的mRNA的表达亢进。
在大鼠的脑室内急性给予MCH可观察到摄食的亢进[自然(Nature),380卷,243页(1996年)],慢性给药则伴随着贪食出现肥胖[Proceedings of the National Academy of Sciences of the UnitedStates of America,99卷,3240页(2002年)]。缺失MCH前体基因的小鼠,与野生型小鼠相比,可见摄食量的降低和平均体重的氧消耗量的上升,可观察到体脂肪的减少引起的低体重[自然(Nature),396卷,670页(1998年)]。
相反,过渡表达MCH前体的转基因小鼠呈现出伴随着贪食的肥胖与胰岛素抵抗性(The Journal of Clinical Investigation),107卷,379页(2001年)]。结果,揭示了MCH为肥胖形成中的重要因素,同时肥胖也作为风险因素参与代谢异常疾病和呼吸器官疾病。此外,已知MCH参与引起不安的作用、癫痫、记忆·学习、利尿作用、钠·钾的***作用、催产素分泌作用、或生殖·性功能等[Peptides,17卷,171页(1996年);Peptides,18卷,1095页(1997年);Peptides,15卷,757页(1994年);Journal of Neuroendocrinology,8卷,57页(1996年);Critical Reviews in Neurobiology,8卷,221页(1994年)]。
MCH主要通过存在于中枢神经***中的MCH受体引发多种药理作用。作为MCH受体已知1型受体(MCH-1R或SLC-1)及2型受体(MCH-2R或SLT)至少2种受体[Nature,400卷,261(1999年);Nature,400卷,265(1999年);Biochemical and Biophysical ResearchCommunications,261卷,622页(1999年);Nature Cell Biology,1卷,267页(1999年);FBS Letters,457卷,522页(1999年);Biochemicaland Biophysical Research Communications,283卷,1013页(2001年);The Journal of Biological Chemistry,276卷,20125页(2001年);Proceedings of the National Academy of Sciences of the United Statesof America,98卷,7564页(2001年);Proceedings of the NationalAcademy of Sciences of the United States of America,98卷,7576页(2001年);The Journal of Biological Chemistry,276卷,34664页(2001年);Molecular Pharmacology,60卷,632页(2001年)]。
其中,在嗫齿类中观察到的药理作用主要是通过MCH-1R来引发[Genomics,79卷,785(2002年)]。即使对MCH-1R的基因缺失小鼠慢性给予MCH也观察不到贪食及肥胖,因此已知通过MCH-1R来引发MCH造成的能量代谢抑制。而且,已知MCH-1R的缺失使小鼠的活动量亢进[Proceedings of the National Academy of Sciences of theUnited States of America,99卷,3240页(2002页)],强烈揭示其参与伴有行动异常的中枢性疾病,例如多动症、精神***症、抑郁症等[Molecular Medicine Today,6卷,43页(2000年);Trends inNeuroscience,24卷,527页(2001年)]。
另外,有报告指出白癜风患者中存在对MCH-1的自我抗体[TheJournal of Clinical Investigation,109卷,923页(2002年)]。另外,有报告指出MCH-1R在某种癌细胞中表达,MCH及MCH-1R在生物体内的表达部位也揭示了其参与癌、睡眠·觉醒、药物依赖性、消化道疾病[Biochemical and Biophysical Research Communications,289卷,44页(2001年);Neuroendocrinology,61卷,348页(1995年);Endocrinology,137卷,561页(1996年);The Journal of ComparativeNeurology,435卷,26页(2001年)]。
MCH的功能通过MCH与MCH受体相结合来表达。因此,若阻断MCH的受体结合,可阻止MCH的作用表达。结果,拮抗MCH的受体结合的物质,作为MCH参与的下列各种疾病的预防药物或治疗药物有用,例如,肥胖症、糖尿病、激素分泌异常、高脂血症、痛风、脂肪肝、肝炎、肝硬化等代谢***疾病;心绞痛、急性·充血性心衰、心肌梗塞、环状动脉硬化症、高血压、肾病、电解质异常等循环***疾病;贪食症、情感障碍、抑郁症、不安、癫痫、谵妄、痴呆、精神***症、多动症、记忆障碍、睡眠障碍、认知障碍、运动障碍、感觉异常、嗅觉障碍、***耐受、毒品依赖性、酒精依赖症等中枢及末梢神经***疾病;***症、早产、性功能障碍等生殖***疾病;消化道疾病、呼吸道疾病、癌或皮肤色素沉着等。
作为以往公知的黑色素聚集激素受体拮抗剂,例如在国际公报WO0l/21577号、国际公报WO02/06245号、国际公报WO02/02744号、国际公报WO01/82925号、特开2002-3370号等中有所记载。
例如,在特开2002-3370号中公开了下列化合物。
但是,上述说明书中不包括Ar部分为单环芳香环的、作为本发明的二环芳香环的喹啉环。也没有公开在相当于Ar1的部位上的本发明的特征的苯基嘧啶环,与本发明化合物结构不同。而且,由上述说明书也不容易得出Ar为二环芳香族的喹啉环,且Ar1部分上为苯基嘧啶环骨架的组合。
国际公报WO01/82925号中公开了下述化合物。
但是,此处Ar与氨基之间存在Y(碳数1~6的间隔物),与本发明化合物结构不同。
本发明提供具有拮抗MCH与MCH-1R相结合作用的2-氨基喹啉衍生物,同时目的在于提供使用其来预防或治疗下列疾病的药物:糖尿病、激素分泌异常、高脂血症、痛风、脂肪肝、肝炎、肝硬化等的代谢***疾病;心绞痛、急性·充血性心衰、心肌梗塞、环状动脉硬化症、高血压、肾病、电解质异常等循环***疾病;贪食症、情感障碍、抑郁症、不安、癫痫、谵妄、痴呆、精神***症、多动症、记忆障碍、睡眠障碍、认知障碍、运动障碍、感觉异常、嗅觉障碍、***耐受、毒品依赖性、酒精依赖症等中枢及末梢神经***疾病;***症、早产、性功能障碍等生殖***疾病;消化道疾病、呼吸道疾病、癌或皮肤色素沉着等。
发明内容
本发明者为了开发阻断MCH与MCH-1R的结合的化合物,进行了锐意探讨,结果发现2位上具有氨基的喹啉骨架的6位上,通过酰氨基具有特定的苯基嘧啶基的化合物为新型化合物,具有MCH-1R拮抗作用,且药物动态优良,从而基于该发现完成了本发明。
即,本发明
(1)提供通式[I]表示的2-氨基喹啉衍生物或可药用盐,
[式中,R1及R2各自独立地表示选自下列的取代基,
1)可被羟基或卤原子取代的低级烷基、
2)可被R9取代的3~6元环烷基、及
3)可被R9取代的4~6元杂环烷基,或
4)R1与R2一起与它们结合的氮原子一起形成4~11元的交联、非交联或螺环的脂肪族含氮杂环,该脂肪族含氮杂环中的1个或2个的任意氢原子可被R9取代,
R3、R4、R6及R7各自独立地表示选自下列的取代基,
1)氢原子、
2)羟基、
3)卤原子、及
4)可被卤原子取代的低级烷基,
R5表示
1)氢原子、或
2)可被卤原子取代的低级烷基,
R8表示选自下列的取代基
1)卤原子、
2)低级烷基、及
3)低级烷氧基,
R9表示选自下列的取代基:羟基、氨基、单低级烷氨基、二低级烷氨基、可被羟基或卤原子取代的低级烷基、(低级烷氧基羰基)氨基、低级烷氧基羰基(低级烷基)氨基、低级烷基羰基氨基、低级烷基羰基(低级烷基)氨基、单低级烷氨基甲酰基(低级烷基)氨基、二低级烷氨基甲酰基(低级烷基)氨基、低级烷基磺酰基氨基、低级烷基磺酰基(低级烷基)氨基、氧基及2-氧代吡咯烷基,
N表示0、1、2、3或4。]。
本发明还提供
(2)以(1)记载的化合物为有效成分的黑色素聚集激素受体拮抗剂,
(3)以(1)记载的化合物为有效成分的以肥胖症、糖尿病、激素分泌异常、高脂血症、痛风、脂肪肝、肝炎及肝硬化为代表的代谢***疾病;以心绞痛、急性·充血性心衰、心肌梗塞、冠状动脉硬化症、高血压、肾病、电解质异常为代表的循环***疾病;以贪食症、情感障碍、抑郁症、不安、癫痫、谵妄、痴呆、精神***症、多动症、记忆障碍、睡眠障碍、认知障碍、运动障碍、感觉异常、嗅觉障碍、***耐受、毒品依赖性及酒精依赖症为代表的中枢及末梢神经***疾病;以***症、早产及性功能障碍为代表的生殖***疾病;消化道疾病;呼吸道疾病;癌或皮肤色素沉着的预防剂或治疗剂,
(4)含有(1)中记载的化合物或可药用盐、及医药上允许的载体的医药组合物,
(5)包括酰胺化通式[II]表示的化合物和通式[III]表示的化合物的反应工序的方法,
[式中,R1、R2、R3、R4及R5的的定义与(1)中的记载相同。],
[式中,R6、R7、R8及n的定义与(1)中的记载相同。],
其中,该方法为通式[I]表示的化合物的制造方法,
[式中,R1、R2、R3、R4、R5、R6、R7、R8及n的定义与(1)中的记载相同。]。
下面,对于本说明书中记载的符号及用语进行说明。
“卤原子”可列举出氟原子、氯原子、溴原子、碘原子。
“低级烷基”中包括碳数1~6的烷基、即碳数1~6的直链或碳数3~6的支链烷基,具体可列举出甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、1-甲基丁基、2-甲基丁基、1,2-二甲基丙基、1-乙基丙基、正己基、异己基、1-乙基戊基、2-甲基戊基、3-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1-乙基丁基、1,1,2-三甲基丙基、1,2,2-三甲基丙基、1-乙基-2-甲基丙基、1-乙基-1甲基丙基等。
“低级环烷基”中包括碳数3~6的环烷基,具体可列举出环丙基、环丁基、环戊基及环己基。
“低级环烷氧基”为氧原子上结合了碳数3~6的环烷基的基团,具体可列举出环丙氧基、环丁氧基、环戊氧基及环己氧基。
“低级杂环烷基”是指碳数3~6的环烷基中任意碳原子的1或2个被氮原子、氧原子或硫原子取代的基团,具体可列举出吖丁啶基、吡咯烷基、哌啶基、哌嗪基、四氢呋喃基、四氢吡喃基、吗啉基、1-硫-4-氮杂环己基等。
“氧基”是指2个取代基与结合在它们上的碳原子一起形成羰基,例如指R5时,2个R5与结合在它们上的碳原子形成羰基的情况。
“可被氟原子取代的低级烷基”中包括低级烷基或被氟原子取代的低级烷基,具体可列举出上述低级烷基,以及氟甲基、二氟甲基、三氟甲基、1,2-二氟乙基等。
“可被卤原子取代的低级烷基”中包括低级烷基或被卤原子取代的低级烷基,具体可列举出上述低级烷基,以及氟甲基、二氟甲基、三氟甲基、1,2-二氟乙基、氯甲基、二氯甲基、三氯甲基、1,2-二氯乙基等。
“可被氟原子取代的低级烷氧基”包括氧原子取代低级烷基或被氟原子取代的低级烷基的基团,具体可列举出作为低级烷氧基的甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基等,或作为被氟原子取代的低级烷氧基的氟甲氧基、二氟甲氧基、三氟甲氧基、1,2-二氟乙氧基等。
“单低级烷氨基”为氨基的1个氢原子被低级烷基取代的基团,具体可列举出甲氨基、乙氨基、正丙氨基、异丙氨基、正丁氨基、仲丁氨基、叔丁氨基等。
“二低级烷氨基”为氨基的2个氢原子被低级烷基取代的基团,具体可列举出二甲氨基、二乙氨基、乙基甲氨基、二(正丙基)氨基、甲基丙氨基、二异丙氨基等。
“低级烷氧基羰基”为羰基上取代有低级烷氧基的基团,可列举出碳数1~6的烷氧基羰基,具体可列举出甲氧基羰基、乙氧基羰基、正丙氧基羰基、异丙氧基羰基、正丁氧基羰基、异丁氧基羰基、叔丁氧基羰基、正戊氧基羰基等。
“低级烷氧基羰基氨基”为氨基与低级烷氧基羰基结合的基团,可列举出碳数1~6的烷氧基羰基氨基,具体可列举出甲氧基羰基氨基、乙氧基羰基氨基、正丙氧基羰基氨基、异丙氧基羰基氨基、正丁氧基羰基氨基、异丁氧基羰基氨基、叔丁氧基羰基氨基、正戊氧基羰基氨基等。
“低级烷氧基羰基(低级烷基)氨基”为单低级烷氨基的氮原子上结合了低级烷氧基羰基来代替氢原子的基团,具体可列举出甲氧基羰基(甲基)氨基、乙氧基羰基(甲基)氨基、正丙氧基羰基(甲基)氨基等。
“低级烷基羰基”为羰基上结合有低级烷基的基团,可列举出碳数1~6的烷基羰基,具体可列举出乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、特戊酰基等。
“低级烷基羰基氨基”为氨基上结合有低级烷基羰基的基团,具体可列举出乙酰氨基、丙酰氨基、异丁酰氨基、戊酰氨基、异戊酰氨基、特戊酰氨基等。
“低级烷基羰基(低级烷基)氨基”为低级烷氨基的氮原子上的氢原子被低级烷基羰基取代的基团,具体可列举出甲基羰基(甲基)氨基、乙基羰基(甲基)氨基、正丙基羰基(甲基)氨基等。
“低级烷基羰基氧基”是指氧原子上结合有低级烷基羰基的基团,具体可列举出乙酰氧基、丙酰氧基、戊酰氧基、异戊酰氧基、特戊酰氧基等。
“单低级烷基氨基甲酰基”为氨基甲酰基的一个氢原子被低级烷基取代的基团,具体可列举出甲基氨基甲酰基、乙基氨基甲酰基、正丙基氨基甲酰基、异丙基氨基甲酰基、正丁基氨基甲酰基、仲丁基氨基甲酰基、叔丁基氨基甲酰基等。
“二低级烷基氨基甲酰基”为氨基甲酰基的两个氢原子被低级烷基取代的基团,具体可列举出二甲基氨基甲酰基、二乙基氨基甲酰基、乙基甲基氨基甲酰基、二(正丙基)氨基甲酰基、甲基丙基氨基甲酰基、二异丙基氨基甲酰基等。
“单低级烷基氨基甲酰基氨基”为氨基的一个氢原子被单低级烷基氨基甲酰基取代的基团,具体可列举出甲基氨基甲酰基氨基、乙基氨基甲酰基氨基、正丙基氨基甲酰基氨基、异丙基氨基甲酰基氨基、正丁基氨基甲酰基氨基、仲丁基氨基甲酰基氨基、叔丁基氨基甲酰基氨基等。
“二低级烷基氨基甲酰基氨基”为氨基的一个氢原子被二低级烷基氨基甲酰基取代的基团,具体可列举出二甲基氨基甲酰基氨基、二乙基氨基甲酰基氨基、二(正丙基)氨基甲酰基氨基、二异丙基氨基甲酰基氨基、二(正丁基)氨基甲酰基氨基、二(仲丁基)氨基甲酰基氨基、二(叔丁基)氨基甲酰基氨基等。
“单低级烷基氨基甲酰基(低级烷基)氨基”为低级烷氨基的氮原子上的1一个氢原子上取代有单低级烷基氨基甲酰基的基团,具体可列举出单甲基氨基甲酰基(甲基)氨基、单乙基氨基甲酰基(甲基)氨基、单(正丙基)氨基甲酰基(甲基)氨基等。
“二低级烷基氨基甲酰基(低级烷基)氨基”为低级烷氨基的氮原子上的1一个氢原子上取代有二低级烷基氨基甲酰基的基团,具体可列举出二甲基氨基甲酰基(甲基)氨基、二乙基氨基甲酰基(甲基)氨基、二(正丙基)氨基甲酰基(甲基)氨基等。
“单低级烷基氨基甲酰基氧基”为氧原子上结合有单低级烷基氨基甲酰基的基团,具体可列举出甲基氨基甲酰基氧基、乙基氨基甲酰基氧基、正丙基氨基甲酰基氧基、异丙基氨基甲酰基氧基、正丁基氨基甲酰基氧基、仲丁基氨基甲酰基氧基、叔丁基氨基甲酰基氧基等。
“二低级烷基氨基甲酰基氧基”为氧原子上结合有二低级烷基氨基甲酰基的基团,具体可列举出二甲基氨基甲酰基氧基、二乙基氨基甲酰基氧基、乙基甲基氨基甲酰基氧基、二(正丙基)氨基甲酰基氧基、甲基丙基氨基甲酰基氧基、二异丙基氨基甲酰基氧基等。
“低级烷基磺酰基”为磺酰基上结合有低级烷基的基团,具体可列举出甲磺酰基、乙磺酰基、正丙磺酰基、异丙磺酰基、正丁磺酰基、仲丁磺酰基、叔丁磺酰基等。
“低级烷基磺酰氨基”为氨基的一个氢原子被低级烷基磺酰基取代的基团,具体可列举出甲磺酰氨基、乙磺酰氨基、正丙磺酰氨基、异丙磺酰氨基、正丁磺酰氨基、仲丁磺酰氨基、叔丁磺酰氨基等。
“单低级烷基氨磺酰基”为氨磺酰基的一个氢原子被低级烷基取代的基团,具体可列举出单甲基氨磺酰基、单乙基氨磺酰基、单(正丙基)氨磺酰基、单异丙基氨磺酰基、单(正丁基)氨磺酰基、单(仲丁基)氨磺酰基、单(叔丁基)氨磺酰基等。
“二低级烷基氨磺酰基”为氨磺酰基的两个氢原子被低级烷基取代的基团,具体可列举出二甲基氨磺酰基、二乙基氨磺酰基、二(正丙基)氨磺酰基、二异丙基氨磺酰基、二(正丁基)氨磺酰基、二(仲丁基)氨磺酰基、二(叔丁基)氨磺酰基等。
“单低级烷基氨磺酰氨基”为氨基的一个氢原子被低级烷基氨磺酰基取代的基团,具体可列举出单甲基氨磺酰氨基、单乙基氨磺酰氨基、单(正丙基)氨磺酰氨基、单异丙基氨磺酰氨基、单(正丁基)氨磺酰氨基、单(仲丁基)氨磺酰氨基、叔丁基氨磺酰氨基等。
“二低级烷基氨磺酰氨基”为氨基的一个氢原子被二低级烷基氨磺酰基取代的基团,具体可列举出二甲基氨磺酰氨基、二乙基氨磺酰氨基、乙基甲基氨磺酰氨基、二(正丙基)氨磺酰氨基、甲基丙基氨磺酰氨基、二异丙基氨磺酰氨基等。
“单低级烷基氨磺酰基(低级烷基)氨基”为“单低级烷氨基”的氮原子上的氢原子被低级烷基氨磺酰基取代的基团,具体可列举出单甲基氨磺酰基(甲基)氨基、单乙基氨磺酰基(甲基)氨基、单(正丙基)氨磺酰基(甲基)氨基等。
“二低级烷基氨磺酰基(低级烷基)氨基”为“单低级烷氨基“的氮原子上的氢原子被二低级烷基氨磺酰基取代的基团,具体可列举出二甲基氨磺酰基(甲基)氨基、二乙基氨磺酰基(甲基)氨基、二(正丙基)氨磺酰基(甲基)氨基等。
“4~11元联、非交联或螺环的脂肪族含单杂环”可列举出,作为交联的脂肪族含氮杂环的2,5-二氮杂二环[2.2.1]庚烷、2,5-二氮杂二环[2.2.2]辛烷、七氢吡咯并[3.4-b]吡咯、七氢吡咯并[3.4-c]吡咯、3-氮杂二环[3.1.0]己烷、十氢吡咯并[3.4-d]氮杂等。
非交联的脂肪族含氮杂环可列举出,吖丁啶环、吡咯烷环、哌啶环、六亚甲基亚胺环、八亚甲基亚胺环、吗啉环等。
螺环的脂肪族含氮杂环可列举出,2-氮杂螺[4.4]壬烷、1-氧杂-7-氮杂螺[4.4]壬烷、2-氧杂-7-氮杂螺[4.4]壬烷、1,7-二氮杂螺[4.4]壬烷、3-氧杂-1,7-二氮杂螺[4.4]壬烷、2,7-二氮杂螺[4.4]壬烷、2,7-二氮杂螺[3.5]壬烷、2-氮杂螺[3.3]庚烷、2-氧杂-6-氮杂螺[3.3]庚烷、2,8-二氮杂螺[4.5]癸烷等。
通式[I]表示的化合物的“可药用盐“是指医药上允许的惯用的物质,可列举出氨基中的酸加成盐或含氮杂环中的酸加成盐。
该酸加成盐可列举出盐酸盐、硫酸盐、磷酸盐、高氯酸盐等无机酸盐,马来酸盐、酒石酸盐、柠檬酸盐、天冬氨酸盐、三氟乙酸盐等有机酸盐,甲磺酸盐、羟乙基磺酸盐、苯磺酸盐、对甲苯磺酸盐等磺酸盐等。
通式[I]表示的化合物
通式[I]表示的化合物中,R1或R2各自独立地表示选自下列的取代基,
1)可被羟基或卤原子取代的低级烷基、
2)可被R9取代的3~6元环烷基、及
3)可被R9取代的4~6元杂环烷基,或
4)R1与R2一起与它们结合的氮原子一起形成4~11元的交联、非交联或螺环的含氮脂肪族杂环,该含氮脂肪族杂环中的1个或2个的任意氢原子可被R9取代。
R1或R2可具体列举出甲基、乙基、正丙基、异丙基、羟甲基、2-羟乙基、3-羟丙基、氯甲基、氟甲基、二氟甲基、三氟甲基、2-氟乙基、2-氯乙基、环丁基、环戊基、环己基、四氢呋喃-2-基、吡咯烷-3-基、N-乙酰基吡咯烷-3-基、N-甲氧基羰基吡咯烷-3-基、N-异丙基羰基吡咯烷-3-基、N-甲磺酰基吡咯烷-3-基等。
R1与R2一起与它们结合的氮原子一起形成4~11元的交联、非交联或螺环的含氮脂肪族杂环时的环可列举出,吖丁啶基、吡咯烷基、哌啶、吗啉、2-氮杂螺[4.4]壬烷、1-氧杂-7-氮杂螺[4.4]壬烷、2-氧杂-7-氮杂螺[4.4]壬烷、1,7-二氮杂螺[4.4]壬烷、3-氧杂-1,7-二氮杂螺[4.4]壬烷、2,7-二氮杂螺[4.4]壬烷、2,7-二氮杂螺[3.5]壬烷、四氢吡咯并[3.4-d]氮杂、2-氮杂螺[3.3]庚烷、2-氧杂-6-氮杂螺[3.3]庚烷、2,5-二氮杂环[2.2.1]庚烷、七氢吡咯并[3.4-b]吡咯、七氢吡咯并[3.2-b]吡咯、3-氮杂环[3.1.0]己烷、七氢吡咯并[1.2-a]吡嗪、七氢吡咯并[3.4-d]氮杂、2,8-二氮杂螺[4.5]癸烷等。
R9表示选自下列的取代基:羟基、氨基、单低级烷氨基、二低级烷氨基、可被羟基或卤原子取代的低级烷基、低级烷基羰基羰基氨基、低级烷氧基羰基羰基(低级烷基)氨基、低级烷基羰基氨基、低级烷基羰基(低级烷基)氨基、单低级烷氨基甲酰基(低级烷基)氨基、二低级烷氨基甲酰基(低级烷基)氨基、低级烷基磺酰基氨基、低级烷基磺酰基(低级烷基)氨基及2-氧代吡咯烷基。
R9优选甲基、乙基、羟甲基、羟乙基、氨基、叔丁基羰基氨基、叔丁基羰基(甲基)氨基、甲氨基、乙氨基、异丙基(甲基)氨基、1-甲基-1-氨基乙基、1-甲基-1-羟乙基、甲基羰基(甲基)氨基、甲基羰基(乙基)氨基、乙基羰基(甲基)氨基、乙基羰基(乙基)氨基、异丙基羰基(甲基)氨基、异丙基羰基(乙基)氨基、甲氧基羰基(甲基)氨基、乙氧基羰基(甲基)氨基、叔丁氧基羰基氨基、甲磺酰基(甲基)氨基、甲磺酰基(乙基)氨基、乙磺酰基(甲基)氨基、二甲基氨基甲酰基、二甲基氨基甲酰基(甲基)氨基、2-氧代吡咯烷基、2-氧代-噁唑烷-3-基等。
R1或R2优选甲基、乙基、正丙基、异丙基、羟甲基、2-羟乙基、3-羟丙基、四氢呋喃-2-基、吡咯烷-3-基、N-乙酰基吡咯烷-3-基、N-甲氧基羰基吡咯烷-3-基、N-异丙基羰基吡咯烷-3-基、N-甲磺酰基吡咯烷-3-基等。
R1与R2一起与它们结合的氮原子一起形成的脂肪族含氮杂环优选式[A]表示的取代基
[式中,Ra表示R9、或两个Ra一起形成-(CH2)x-(NH)-(CH2)y-,该取代中的任意氢原子可被低级烷基、低级烷基羰基或氧基取代,x及y独立地表示0、1、2、3或4,且满足3≤x+y≤4,m表示0、1、或2。]。
Ra优选低级烷基羰基(低级烷基)氨基、低级烷基磺酰基(低级烷基)氨基、低级烷氧基羰基(低级烷基)氨基、二低级烷基氨基甲酰基(低级烷基)氨基等。
m=2时,两个Ra各自独立,也可两个Ra一起形成选自下列的基团,
此处,R10可列举出低级烷基或低级烷基羰基等。
Ra优选甲基羰基(甲基)氨基、乙基羰基(甲基)氨基、甲基羰基(乙基)氨基、乙基羰基(乙基)氨基、异丙基羰基(甲基)氨基、异丙基羰基(乙基)氨基、甲磺酰基(甲基)氨基、乙磺酰基(甲基)氨基、甲氧羰基(甲基)氨基、乙氧羰基(甲基)氨基、2-吡咯烷酮-1-基等,R10优选甲基、乙基、甲基羰基、乙基羰基等。
R1或R2的组合优选:
R1:低级烷基、R2:可被羟基取代的低级烷基,
R1:低级烷基、R2:四氢呋喃基,
R1:低级烷基、R2:可被R9取代的吡咯烷基,
R1:甲基、R2:异丙基,
R1:甲基、R2:四氢呋喃基,
R1:甲基、R2:N-乙酰基吡咯烷-3-基,
R1:甲基、R2:N-甲基吡咯酮-4-基,
R1:甲基、R2:N-甲磺酰基吡咯烷-3-基等。
式[A]表示的取代基优选1-甲基-2-氧代-1,7-二氮杂螺[4.4]壬烷-7-基、7-甲基-8-氧代-2,7-二氮杂螺[4.4]壬烷-2-基、3-[乙酰基(甲基)氨基]吡咯烷-1-基、3-[丙酰基(甲基)氨基]吡咯烷-1-基、3-[异丁酰基(甲基)氨基]吡咯烷-1-基、3-[甲磺酰基(甲基)氨基]吡咯烷-1-基、3-[甲氧基羰基(甲基)氨基]吡咯烷-1-基、3-{[(二甲氨基)羰基](甲基)氨基}吡咯烷-1-基、6-乙酰基十氢吡咯并[3.4-d]氮杂-2-基、2-氧代[1.3’]二吡咯烷基-1’-基等。
特别优选的式[A]表示的取代基如下
R3、R4、R6及R7各自独立地表示选自下列的取代基,
1)氢原子、
2)羟基、
3)卤原子、及
4)可被卤原子取代的低级烷基。
R3、R4、R6或R7优选氢原子、氟原子或甲基,更优选均为氢原子。
R5表示氢原子或可被卤原子取代的低级烷基,优选氢原子、甲基、乙基等。
R8在n为2、3或4时,各自独立地表示选自下列的取代基
1)卤原子、
2)低级烷基、及
3)低级烷氧基,
优选氟原子、甲基、乙基、甲氧基等,更优选氟原子或甲氧基。
N优选0、1或2。
通式[I]表示的化合物中,特别优选通式[I-1]表示的化合物,
[式中,R3、R4、R5、R6、R7、R8、Ra、m及n的定义与上述相同。]。
通式[I-1]表示的化合物现实出优良的MCH-1R拮抗作用,且口服吸收性及脑摄取性优良。而且对其他的受体选择性也高,作为药品具有优良的效果。
通式[I]表示的化合物具体优选,
5-(4-氟苯基)-N-[2-(1-甲基-2-氧代-1,7-二氮杂螺[4,4]壬烷-7-基)-6-喹啉基]-2-嘧啶甲酰胺、
5-(4-氟苯基)-N-[2-(7-甲基-8-氧代-2,7-二氮杂螺[4,4]壬烷-2-基)-6-喹啉基]-2-嘧啶甲酰胺、
N-(2-[(3R)-3-[异丁酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺、
N-[2-(6-乙酰基十氢吡咯并[3,4-d]氮杂-2-基)-6-喹啉基]-5-苯基-2-嘧啶甲酰胺、
N-(2-[(3R)-3-[乙酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺、
5-苯基-N-(2-[(3R)-3-[丙酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-2-嘧啶甲酰胺、
N-(2-[(3R)-3-[甲磺酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺、
N-(2-[(3R)-3-[甲氧基羰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺、
N-(2-[(3R)-3-[[(二甲氨基)羰基]](甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺、
N-(2-[异丙基(甲基)氨基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺、
5-(4-氟苯基)-N-(2-[(3R)-3-[异丁酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-2-嘧啶甲酰胺、
N-(2-[(3R)-3-[乙酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-(4-氟苯基)-2-嘧啶甲酰胺、
5-(4-氟苯基)-N-(2-[甲基(四氢-3-呋喃基)氨基]-6-喹啉基)-2-嘧啶甲酰胺、
5-(3-氟苯基)-N-(2-[(3R)-3-[异丁酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-2-嘧啶甲酰胺等。
表1中具体列出通式[I]表示的化合物。
表1
通式[I]表示的化合物的制造方法
通式[I]表示的化合物例如可通过适当组合以下制造方法来制造。
制造方法1
反应式1
[式中,R1、R2、R3、R4、R5、R6、R7、R8及n的定义与上述相同。]。
即,可通过酰胺化通式[II]表示的化合物和通式[III]表示的化合物来获得通式[I]表示的化合物。
酰胺化可利用以往公知的方法来进行,可列举出下列方法:在缩合剂的存在下使通式[II]表示的化合物和通式[III]表示的化合物反应的方法;或利用以往公知的方法活化通式[III]表示的化合物的羧酸部分制成反应性衍生物,然后酰胺化该衍生物和通式[II]表示的化合物的方法(两种方法均参照《肽合成的基础和实验》(泉屋信夫等,丸善株式会社,1983年)。
1)在缩合剂的存在下酰胺化的方法
可列举出例如在N-羟基苯丙***(下面有时称作“HoBt”)存在或不存在下,使用1,3-二环己基碳二亚胺、1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(下面有时称作“EDCl”)等的缩合剂,酰胺化通式[II]表示的化合物和通式[III]表示的化合物的方法。
通式[III]表示的化合物的用量可列举出相对于1摩尔通式[II]表示的化合物为0.9摩尔~2.0摩尔,优选1.0摩尔~1.5摩尔。
缩合剂的用量可列举出相对于1摩尔通式[III]表示的化合物为1.0摩尔~2.0摩尔,优选1.0摩尔~1.5摩尔。
使用HoBt时的用量可列举出相对于1摩尔通式[II]表示的化合物为0.9摩尔~2.0摩尔,优选1.0摩尔~1.2摩尔。
为了促进反应,相对于1摩尔通式[II]表示的化合物,也可添加0.1摩尔~1.0摩尔、优选0.1摩尔~0.5摩尔的二甲氨基吡啶。
酰胺化反应优选在有机溶剂中进行,该溶剂可列举出,例如1,4-二噁烷(下面称作“二噁烷”)、四氢呋喃(下面称作“THF”)、二***等醚;苯、甲苯、二甲苯、氯苯等芳香烃;二氯乙烷、氯仿、二氯甲烷、四氯化碳等卤代烃;吡啶、乙酸乙酯、N,N-二甲基甲酰胺(下面称作“DMF”)、二甲基亚砜(下面称作“DMSO”)等。
反应温度可列举出0℃~80℃,优选20℃~50℃,反应时间可列举出1小时~48小时。
2)经过反应性衍生物进行酰胺化的方法
利用下述方法将通式[III]表示的化合物(羧酸)制成“反应性衍生物”后,分离或不分离得到的反应性衍生物,使其与通式[II]表示的化合物进行酰胺化反应可得到目标化合物。需要说明的是,反应性衍生物的配制可基于例如《肽合成的基础和实验》(泉屋信夫等,丸善株式会社,1983年)记载的方法进行,
a)利用亚硫酰氯、草酰氯、***等氯化剂制备酰基氯的方法(酰基氯法)、
b)使用氯甲酸异丁酯、氯甲酸甲酯等制备混合酸酐的方法(混酸酐)、或
c)制备对硝基苯酯、N-羟基琥珀酰亚胺酯等活性酯的方法(活性酯)等。
反应性衍生物的用量可列举出相对于1摩尔通式[II]表示的化合物为0.8摩尔~3.0摩尔,优选1.1摩尔~1.3摩尔。
在碱性催化剂的存在下进行本反应可加速反应。该碱性催化剂可列举出碳酸锂、碳酸钠、碳酸钾等碱金属碳酸盐;碳酸氢钠、碳酸氢钾等碱金属碳酸氢盐;三乙胺、二异丙基乙胺、三正丁基胺、1,5-二氮杂二环[4.3.0]-5-壬烷、1,8-二氮杂二环[5.4.0]-7-十一碳烯、吡啶、N,N-二甲氨基吡啶等有机碱等。
碱性催化剂的用量可列举出相对于1摩尔上述反应性衍生物为0.1摩尔~2.0摩尔,优选0.1摩尔~1.2摩尔。
反应溶剂可使用上述记载的物质,反应温度可列举出-50℃~80℃,优选0℃~30℃。反应时间可列举出约30分钟~24小时,优选30分钟~15小时。
在使用反应性衍生物的酰胺化反应中,也可以使用二甲氨基吡啶。
利用以往公知的方法,通过提取、精制含有利用上述方法得到的通式[I]表示的化合物的混合溶液,可分离通式[I]表示的化合物。
制造方法2
制造方法2为通式(II)表示的化合物的制造方法。
反应式2
[式中,X表示卤原子、三氟甲烷磺酰氧基等,R1、R2、R3、R4及R5与上述相同。]。
工序2-1
优选在惰性溶剂的存在下,20℃~200℃、优选50℃~150℃下,加热10分钟~48小时、优选1小时~24小时化合物
1和化合物
2,由此得到化合物
3。该反应可在密封管(sealed tube)中进行。
惰性溶剂可列举出,例如二噁烷、THF、乙腈、DMF、DMSO、丙酮等,优选二噁烷、DMF、DMSO等。
化合物
3的用量可列举出相对于1摩尔化合物
2为1摩尔~50摩尔,优选1摩尔~10摩尔。
接着由含有化合物
3的反应混合物利用以往公知的方法,优选分离精制化合物
3,进入下一工序。在此,分离精制的方法可列举出例如溶剂提取、重结晶、柱层析、液相色谱、制备薄层色谱(制备TLC)等。另外,在以下工序中也相同。
工序2-2
还原化合物
3的硝基,得到化合物
4。还原方法可使用例如WO02/40019号公开的方法。需要说明的是,R5为氢原子时,化合物4相当于通式[II]表示的化合物。
工序2-3
该工序经由1)在化合物4上导入Boc基(叔丁氧基羰基化t-butyloxy carbonylation)的工序、2)在NaH等碱的存在下使得到的化合物与R5-X反应的工序、3)脱保护得到的化合物的Boc基的工序,得到通式[II]表示的化合物。任一工序均可利用以往公知的方法来进行。
需要说明的是,可利用公知的方法[Heterocycles,48卷,2637页(1998年)、或基于其的方法制备化合物
1。另一方面,作为化合物
2,可使用市售的化合物,也可利用实施例记载的方法来制备。
制造方法3
制造方法3为通式[III]表示的化合物的制造方法。
反应式3
[式中,L表示羟基、低级烷氧基等,X表示卤原子、三氟甲烷磺酰氧基等,R6、R7、R8及n与上述相同。]。
在溶剂中,在钯催化剂及碱存在下,使化合物
5和化合物
6反应,可制造通式[III]表示的化合物。该反应(铃木偶联)可参照例如Tetrahedron,58卷,9633页(2002年)记载的方法。
钯催化剂可列举出,例如,四(三苯基膦)钯、乙酸钯、二氯二(三苯基膦)钯、[1,1’-二(二苯基膦)二茂铁]二氯钯等,碱可列举出碳酸钾、碳酸钠、磷酸钾等。
溶剂优选叔丁醇、乙醇等醇;THF、1,2-二甲氧基乙烷(DME)等醚;苯、丙酮等芳香烃或它们的混合溶剂。
化合物
6的用量,可列举出相对于1摩尔化合物
5为0.9摩尔~2.0摩尔,优选1.0摩尔~1.5摩尔。钯催化剂的用量可列举出相对于1摩尔化合物
5为0.01摩尔~0.5摩尔,碱的用量可列举出相对于1摩尔化合物5为1摩尔~5摩尔。
反应温度可列举出室温~150℃,优选70℃~150℃。反应时间可列举出通常为1小时~24小时。
需要说明的是,化合物
5,可使用市售品,另一方面,化合物
6,可使用市售品,也可利用公知的方法[例如Journal of ChemicalSociety,3219页(1953年)]来制备。
在上述的各制造方法中,当反应物质中存在不参与反应的氨基、羟基、羧基、氧基、羰基等时,该氨基、羟基、羧基、氧基、羰基,可在用氨基的保护基、羟基的保护基、羧基的保护基或者氧基或羰基的保护基保护后进行制造方法1~3中任一反应,在反应后除去相应保护基。
“氨基的保护基”可列举出苄基、对甲氧基苄基、3,4-二甲氧基苄基、邻硝基苄基、对硝基苄基、二苯甲基、三苯基等芳烷基;甲酰基、乙酰基、丙酰基、丁酰基、戊酰基等低级烷酰基;苯甲酰基;苯基乙酰基、苯氧基乙酰基等芳基烷氧基;甲氧基羰基、乙氧基羰基、丙氧基羰基、叔丁氧基羰基等低级烷氧基羰基;苄氧基羰基、对硝基苄氧基羰基、苯乙氧基羰基、芴甲氧基羰基等芳烷氧基羰基;三甲基甲硅烷基、叔丁基二甲基甲硅烷基等低级烷基甲硅烷基;邻苯二甲酰基等,特别优选乙酰基、戊酰基、苯甲酰基、乙氧基羰基、叔丁氧基羰基、邻苯二甲酰基等。
“羟基的保护基”可列举出,例如甲基、乙基、丙基、异丙基、叔丁基等低级烷基、三甲基甲硅烷基、叔丁基二甲基甲硅烷基等低级烷基甲硅烷基;甲氧基甲基、2-甲氧基乙氧基甲基等低级烷氧基甲基;四氢吡喃基;例如三甲基甲硅烷基乙氧基甲基;苄基、对甲氧基苄基、2,3-二甲氧基苄基、间硝基苄基、对硝基苄基、三苯基等芳烷基;甲酰基、乙酰基等酰基等,特别优选甲基、甲氧基甲基、四氢吡喃基、三苯基、三甲基甲硅烷基乙氧基甲基、叔丁基二甲基甲硅烷基、乙酰基等。
“羰基的保护基”可列举出,例如甲基、乙基、丙基、异丙基、叔丁基等低级烷基;2,2,2-三氯乙基等低级卤代烷基;2-丙烯基等低级烯基;苄基、对甲氧基苄基、对硝基苄基、二苯甲基、三苯基等芳烷基等,特别优选甲基、乙基、叔丁基、2-丙烯基、苄基、对甲氧基苄基、二苯甲基等。
“氧基或羰基的保护基”可列举出亚乙基二氧基(エチレンケタ一ル)、トリメ。
保护基的除去方法根据保护基的种类及通式[I]表示的化合物的稳定性等不同而不同,可根据例如文献记载的方法[参照(ProtectiveGroups in Organic Synthesis)、T.W.Green著,John Wiley & Sons公司(1981年)]或基于其的方法,利用例如使用酸或碱的加溶剂分解,即例如使其与远过量于0.01摩尔的酸、优选三氟乙酸、甲酸、盐酸等,或远过量于等摩尔的碱、优选氢氧化钾、氢氧化钙等的方法;使用氢化金属配合物的化学还原或钯-碳催化剂、拉奈镍催化剂等的接触还原等进行。
由上述方法得到的化合物可利用以往公知的分离方法分离精制。所述方法可列举出溶剂提取、重结晶、柱层析、液相色谱、制备薄层色谱等。
本发明的化合物根据其取代基的形态存在光学异构体、非对映异构体、几何异构体等立体异构体或互变异构体时,本发明的化合物也包括这些所有的立体异构体、互变异构体及它们的混合物。
含有通式[I]表示的化合物的医药组合物
通式[I]表示的化合物可经口或非经口给药,通过制剂化为适于其给药的方式,可提供下列疾病的预防剂或治疗剂,特别是肥胖症的预防剂或治疗剂:肥胖症、糖尿病、激素分泌异常、高脂血症、痛风、脂肪肝、肝炎、肝硬化等的代谢性疾病;如心绞痛、急性·充血性心衰、心肌梗塞、环状动脉硬化症、高血压、肾病、电解质异常等循环***疾病;如贪食症、情感障碍、抑郁症、不安、癫痫、谵妄、痴呆、精神***症、多动症、记忆障碍、睡眠障碍、认知障碍、运动障碍、感觉异常、嗅觉障碍、***耐受、毒品依赖性、酒精依赖症等中枢及末梢神经***疾病;如***症、早产、性功能障碍等生殖***疾病;消化道疾病、呼吸道疾病、癌或皮肤色素沉着等。
临床使用本发明的化合物时,可根据其给药方式加入医药上允许的载体制剂化后来给药。此时,可使用制剂领域中以往公知的各种添加剂作为载体,可列举出,例如明胶、乳糖、白糖、氧化钛、淀粉、结晶纤维素、羟丙甲基纤维素、羧甲基纤维素、玉米淀粉、微晶蜡、白色凡士林、偏硅酸镁铝、无水磷酸钙、柠檬酸、柠檬酸三钠、羟丙基纤维素、山梨糖醇、脂肪酸山梨糖酐酯、聚山梨糖醇、脂肪酸蔗糖酯、聚氧乙烯、硬化蓖麻油、聚乙烯吡咯烷酮、硬脂酸镁、轻质二氧化硅、滑石、植物油、苄醇、***树胶、丙二醇、聚烷二醇、环糊精或羟丙基环糊精等。
作为这些载体与本发明的化合物的混合物来制剂化的剂型可列举出,例如,片剂、胶囊剂、颗粒剂、散剂或栓剂等固形制剂;或例如糖浆剂、酏剂或注射剂等液体制剂等,这些可根据制剂领域中的以往公知的方法来配制。需要说明的是,液体制剂也可以在使用时以溶解或混悬于其他适当的溶剂中的形式来使用。特别是为注射剂时,根据需要可溶解或混悬在生理盐水或葡萄糖溶液中,还可进一步添加缓冲液或保存剂。
这些制剂可以以1.0~100重量%、优选1.0~60重量%的比例含有本发明的化合物,或含有0~99.0重量%、优选40~99.0重量%的医药上允许的载体。这些制剂也可含有治疗上有效的其他化合物,例如糖尿病治疗剂、高血压治疗剂、动脉硬化症治疗剂等。
将本发明的化合物作为上述疾病的预防剂或治疗剂来使用时,其给药量及给药次数根据患者的性别、年龄、体重、症状的程度及所要达到的治疗效果的种类及范围等不同而不同,一般在经口给药时,优选成人每日0.1~400mg,一次或分次给药,或非经口给药时,成人每日0.002~100mg,一次或分次给药。依症状也可预防性给药。
联合疗法
本发明的化合物可组合对下列疾病有效的药物来使用(以下称作“并用用药物”):高血压、与肥胖相关的高血压、高血压相关疾病、心脏肥大、左心室肥大、代谢性疾病、肥胖、肥胖相关疾病等。在上述疾病的预防或治疗中,可同时、分别、或依次给予所述药物。同时使用本发明的化合物与1或2种以上的并用用药物时,可制成作为单一给药方式的医药组合物。但是,在联合疗法中,可相对于给药对象,将含有本发明的化合物组合物和并用用药物制成不同的包装,同时、分别、或依次给药。它们也可以留出时间差来给药。
并用用药剂的给药量可根据临床上使用的给药量,可根据给药对象、给药途径、疾病、组合等适当选择。并用用药物的给药方式无特别限定,给药时也可以组合本发明的化合物和并用用药物。这种给药方式可列举出,例如1)同时制剂化本发明的化合物和并用用药物得到的单一制剂的给药;2)分别制剂化本发明的化合物和并用用药物得到的两种制剂以同一给药途径同时给药;3)分别制剂化本发明的化合物和并用用药物得到的两种制剂以同一给药途径按时间差给药;4)分别制剂化本发明的化合物和并用用药物得到的两种制剂以不同给药途径同时给药;5)分别制剂化本发明的化合物和并用用药物得到的两种制剂以不同给药途径按时间差给药(例如,本发明的化合物;并用用药物的依次给药、或倒序给药)等。本发明的化合物与并用用药物的配合比可根据给药对象、给药途径、疾病等适当选择。
本发明中使用的并用用药物可列举出,例如“糖尿病治疗药”、“高脂血症治疗药”、“高血压治疗药”、“减肥药”等。这些并用用药物也可适当组合两种以上以适当的比例来使用。
上述“糖尿病治疗药”可列举出,例如,1)格列酮类(glitazones)[例如,环格列酮(ciglitazone)、达格列酮(darglitazone)、恩格列酮(englitazone)、依萨格列酮(isaglitazone)(MCC-555)等],吡格列酮(pioglitazone)、罗格列酮(rosiglitazone)、曲格列酮(troglitazone)、BRL49653、CLX-0921、5-BTZD、GW-0207、LG-100641、LY-300512等PPARγ激动剂;2)甲福明(metformin)、Buformin(丁福明)、苯福明(pheformin)等双胍剂;3)蛋白酪氨酸磷酸酯酶-1B阻断剂;4)醋磺己脲、氯磺丙脲、特泌胰(diabinese)、格列本脲(glibenclamide)、格列吡嗪(glipizide)、优降糖(glyburide)、格列美脲(glimepiride)、格列齐特(gliclazide)、格列戊脲(glipentide)、格列喹酮(gliquidone)、格列索脲(glisolamide)、妥拉磺脲、甲苯磺丁脲等磺酰脲;5)瑞格列奈(repaglinide)、那格列奈(nateglinide)等氯茴苯酸(meglitinides)类;6)阿卡波糖(Acarbose)、脂解素(adiposine)、卡格列波糖(camiglibose)、乙格列酯(emiglitate)、米格列醇(miglitol)、伏格列波糖(voglibose)、普拉米西-Q(pradimicin-Q)、salbostatin、CLD-711、MDL-25,673、MDL-73,945、MOR14等α-葡糖苷羟化酶阻断药;7)淀粉酶抑肽(tendamistat)、曲他丁(trestatin)、Al 3688等α-淀粉酶阻断剂;8)利诺格列(linogliride)、A-4166等胰岛素分泌促进剂;9)氯莫克舍(clomoxir)、乙莫克舍(etomoxir)等脂肪酸氧化抑制剂;10)咪格列唑(midaglizole)、伊格列哚(isaglidole)、德格列哚(deriglidole)、咪唑克生(idazoxan)、earoxan、氟洛克生(fluparoxan)等A2拮抗剂;11)biota、LP-100、诺和锐(novarapid)、地特胰岛素(Insulin detemir)、赖脯胰岛素(insulin lispro)、甘精胰岛素(insulin glargine)、锌胰岛素、赖脯胰岛素(Lys-Pro-insulin)、GLP-1(73-7)、GLPl酰胺(7-36)等胰岛素或类胰岛素;12)JT-501、法格列酮(Farglitazar)等非噻唑啉二酮;13)CLX-0904、GW-1536、GW-1929、GW-2433、KRP-297、L-796449、LR-90及SB219994等PPARα/γ双激动剂等。
上述“高脂血症治疗药”可列举出,例如,1)消胆胺、コレセブエレム(colesevelem)、考来替泊(colestipol)、交叉葡聚糖的二烷氨基烷基衍生物、盐酸考来替泊(注册商标Colestid)、ロコレスト(注册商标LoCholest)、キエストラン(注册商标Questran)等胆汁酸吸收促进剂;2)阿伐他汀(atorvastatin)、伊伐他汀(itavastatin)、氟伐他汀(fluvastatin)、洛伐他丁(lovastatin)、普伐他汀(pravastatin)、利伐他汀(rivastatin)、罗苏伐他汀(rosuvastatin)、辛伐他汀(simvastatin)、ZD-4522等HMG-CoA还原酶阻断药;3)HMG-CoA合成阻断剂;4)スナト-ルエステル、β-谷甾醇、固醇葡萄糖苷、依泽替米贝(ezetimibe)等胆甾醇吸收阻断剂;5)阿伐麦布(avasimibe)、エフルシミベ(eflucimibe)、KY-505、SMP-709等酰基辅酶A胆甾醇酰基转移酶阻断剂;6)JTT705、托切普(torcetrapib)、CP532632、BAY-63-2149、SC-591、SC-795等CETP阻断剂;7)鲨烯合成阻断剂、8)丙丁酚等抗氧化剂、9)苄氯贝特、苯扎贝特、环丙贝特、氯贝特、依托贝特、非诺贝特、ジエンカベン(gemcabene)、吉非罗齐(gemfibrozil)、GW-7647、BW-170744、LY-518674、苯氧酸衍生物[例如安妥明(注册商标Atromid)、洛必(注册商标Lopid)、Tricor(注册商标等)]等PPARα激动剂;10)GW-4064、SR-103912等FXR受体拮抗剂;11)GW3965、T9013137、XTCO-179628等LXR受体激动剂;12)烟酸等脂蛋白合成阻断剂;13)肾素-血管紧张素***阻断剂;14)微粒体性甘油三酯输送阻断剂;15)BARA1453、SC435、PHA384640、S-435、AZD7706等胆汁酸再吸收阻断剂;16)GW501516、GW590735等PPARδ激动剂;17)甘油三酯合成阻断剂;18)LAB687、CP346086等MTTP阻断剂;19)低密度脂蛋白受体诱发因子;20)鲨烯环氧酶阻断剂;21)血小板凝集阻断剂;22)MK-591等5-脂加氧酶活化蛋白质阻断剂等。
上述“高血压治疗药”可列举出,例如,1)クロロチアリドン、***、二氯苯磺胺、氢氟噻嗪、吲达帕胺(indapamide)、氢***等噻嗪类;布美他尼(bumetanide)、依他尼酸(ethacrynic acid)、速尿、トルセミド等袢类,阿米洛利、氨苯碟啶等钠类,螺内酯、エピレノン等醛固酮拮抗剂类等利尿剂;2)醋丁洛尔(acebutolol)、阿替洛尔、倍他洛尔(betaxolol)、贝凡洛尔(bevantolol)、比索洛尔(bisoprolol)、波吲洛尔(bopindolol)、卡替洛尔(carteolol)、卡维地洛(carvedilol)、噻利洛尔(celiprolol)、艾司洛尔(esmolol)、茚诺洛尔(indenolol)、美多洛尔(metaprolol)、纳多洛尔(nadolol)、萘必洛尔(nebivolol)、喷布洛尔(penbutolol)、品多洛尔、***、索他洛尔、特他洛尔(tertatolol)、替利洛尔(tilisolol)、噻吗洛尔等β-肾上腺素阻断剂;3)氨氯地平(amlodipine)、阿雷地平(aranidipine)、阿折地平(azelnidipine)、巴尼地平(banidipine)、贝尼地平(benidipine)、苄普地尔(bepridil)、西那地平(cinaldipine)、氯维地平(clevidipine)、地尔硫(diltiazem)、依福地平(efonidipine)、非洛地平(felodipine)、加洛帕米(gallopamil)、伊拉地平(isradipine)、拉西地平(lacidipine)、来米地平(lemildipine)、乐卡地平(lercanidipine)、尼卡地平(nicardipine)、尼非地平(nifedipine)、尼伐地平(nilVadipine)、尼莫地平(nimodipine)、尼索地平(nisoldipine)、尼群地平(nitrendipine)、马尼地平(manidipine)、普拉地平(pranidipine)、维拉帕米(verapamil)等钙通道阻断剂;4)苯那普利、卡托普利、西拉普利(cilazapril)、地拉普利(delapril)、依那普利、福辛普利(fosinopril)、咪达普利、罗西普利、莫西普利(moexipril)、喹那普利(quinapril)、喹普利拉(quinaprilat)、雷米普利(ramipril)、培哚普利(perindopril)、ペリンドロプリル(perindropri)、夸尼普利(quanipril)、螺普利(spirapril)、泰诺普利(tenocapril)、群多普利(trandolapril)、佐芬普利(zofenopril)等血管紧张素转换酶阻断药;5)奥马曲拉(omapatrilat)、卡多曲尔(cadoxatril)、依卡曲尔、氟西曲尔(fosidotril)、山帕曲拉(Sampatrilat)、AVE7688、ER4030等中枢内肽酶阻断剂:6)替唑生坦(tezosentan)、A308165、YM62899等内皮素拮抗剂;7)肼屈嗪、可乐定、长压定、烟酰醇等血管扩张剂;8)坎地沙坦、依普罗沙坦、依贝沙坦、罗沙坦、普拉托沙坦(pratosartan)、他索沙坦(tasosartan)、替米沙坦(telmisartan)、缬沙坦、EXP-3137、FI6828K、RNH6270等血管紧张素II拮抗药;9)尼普地洛、阿罗洛尔、氨磺洛尔等α/β肾上腺素阻断剂;10)特拉唑嗪、乌拉地尔(urapidil)、哌唑嗪、布那唑嗪、曲马唑嗪、多沙唑嗪、萘哌地尔、吲哚拉明、WHIP164、XEN010等α1阻断剂;11)洛非西丁(lofexidine)、噻美尼定(tiamenidine)、莫索尼定(moxonidine)、利美尼定(rilmenidine)、グアノベンズ(guanobenz)等α2激动剂;12)醛甾酮阻断剂等。
上述“减肥药”可列举出,例如1)帕罗西汀(paroxetine)、氟西汀(fluoxetine)、芬氟拉明(fenfluramine)、氟伏沙明(fluvoxamine)、舍曲林(sertraline)、米帕明等5HT(血清素)转运蛋白阻断剂;2)GW320659、地昔帕明、他舒普仑(talsupram)、诺米芬新等去甲肾上腺素转运蛋白阻断剂;3)利莫那班(Sanofi Synthelabo)、SR-147778(Sanofi Synthelabo)、BAY-65-2520(バイエル)、SLV-319(ソルベイ),此外还有,USP5,532,237、USP4,973,587、USPS,013,837、USP5,081,122、USP5,112,820、USP5,292,736、USPS,624,941、USP6,028,084、WO96/33159、WO98/33765、WO98/43636、WO98/43635、WO01/09120、WO01/96330、WO98/31227、WO98/41519、WO98/37061、WO00/10967、WO00/10968、WO97/29079、WO99/02499、WO01/58869、WO02/076949、WO01/64632、WO01/64633、WO01/64634、WO03/006007、WO03/007887及EP-658546中公开的化合物等***碱1受体1(CB-1)拮抗剂/反向激动剂;4)WO01/87355、WO02/08250等中公开的化合物等的血浆饥饿激素拮抗剂;5)氨砜拉嗪、3-(1H-咪唑-4-基)丙基N-(戊烯基)碳酸酯、クロベンプロビツト(clobenpropit)、ヨ一ドフエンプロピット、イモプロキシフエン、GT2395、A331440、WO02/15905中公开的化合物、O-[3-(1H-咪唑-4-基)丙醇]氨基甲酸酯、含哌嗪的H3受体拮抗剂(Lazewska,D.et al.,Phamazie,56:927-32(2001)、二苯甲酮衍生物(Sasse,A.et al.,Arch.Pharm.(Weinheim)334:45-52(2001))、取代N-苯基氨基甲酸酯(Reidemeister,S.et al.,Pharmazie,55:83-6(2000))、百利普芬衍生物(Sasse,A.et al.,J.Med.Chem..43:3335-43(2000))等组胺(H3)拮抗剂/反向激动剂;6)T-226296(Takeda)、SNAP-7941(Synaptic)、此外还有WO01/82925、WO01/87834、WO02/051809、WO02/06245、WO02/076929、WO02/076947、WO02/04433、WO02/51809、WO02/083134、WO02/094799、WO03/004027及特开2001-226269号中公开的化合物等MCH-1R拮抗剂;7)MCH-2R激动剂/拮抗剂;8)3-氯-5-(1-(6-[2-(5-乙基-4-甲基-噻唑-2-基)-乙基]-4-吗啉代-4-基-吡啶-2-基氨基)-乙基)苯基]氨基甲酸异丙酯、BIBP3226、BIBO3304、LY-357897、CP-671906、GI-264879、此外还有、USP6001836、WO96/14307、WO01/23387、WO99/51600、WO01/85690、WO/01/85098、WO01/85173及WO01/89528中公开的化合物等的NPY1拮抗剂;9)L-152804、GW-569180A、GW-594884A、GW-587081X、GW-548118X、FR235,208、FR226928、FR240662、FR252384、1229U91、GI-264879A、CGP71683A、LY-377897、LY366377、PD-160170、SR-120562A、SR-120819A、JCF-104、H409/22、此外还有USP6,140,354、USP6,191,160、USP6,258,837、USP6,313,298、USP6,337,332、USP6,329,395、USP340,683、USP6,326,375、USP6,329,395、USP6,337,332、USP6,335,345、EP-01010691、EP-01044970、WO97/19682、WO97/20820、WO97/20821、WO97/20822、WO97/20823、WO98/27063、WO00/107409、WO00/185714、WO00/185730、WO00/64880、WO00/68197、WO00/69849、WO01/09120、WO01/14376、WO01/85714、WO1/85730、WO01/07409、WO01/02379、WO01/02379、WO01/23388、WO01/23389、WO01/44201、WO01/62737、WO01/82738、WO01/0912O、WO02/20488、WO02/22592、WO02/48152、WO02/49648、WO02/094789及Norman et al.,J.Med.Chem.43:4288-4312(2000)中公开的化合物等的NPY5拮抗剂;10)人重组瘦体素(PEG-OB,Hoffman La Roche)、重组甲硫氨酰基瘦体素(Amgen)等瘦体素;11)USP5,552,524、USP5,552,523、USP5,552,522、USP5,521,283、WO96/23513、WO96/23514、WO96/23515、WO96/23516、WO96/23517、WO96/23518、WO96/23519及WO96/23520中公开的化合物等瘦体素衍生物;12)纳美芬(注册商标Revex)、3-甲氧基纳曲酮、纳洛酮、纳曲酮、WO00/21509公开的化合物等类***拮抗剂;13)SB-334867A、此外还有、WO01/96302、WO01/68609、WO02/51232、WO02/51838及WO03/023561中公开的化合物等阿立新拮抗剂;14)蛙皮素受体亚型3激动剂;15)AR-R15849、GI-181771、JMV-180、A-71378、A-71623、SR-146131、此外还有USP-5739106中公开的化合物等缩胆囊素A(CCK-A)激动剂;16)GI-181771(Glaxo-SmithKline)、SR146131(Sanofi Synthelabo)、butabindide、PD170,292、PD149164(フアイザ一)等CNTF(睫状神经营养因子ciliary neurotrophic factors);17)axokine(Regeneron)、此外还有WO94/09134、WO98/22128、WO99/43813中公开的化合物等CNTF衍生物;18)NN703、海沙瑞林(hexarelin)、MK-0677、SM-130686、CP-424,391、L-692,429、L-163,255、USP6358951、美国专利局申请号2002/049196、同2002/022637、WO01/56592、WO02/32888中公开的化合物等生长激素分泌受体激动剂;19)BVT933、DPCA37215、IK264、PNU22394、WAY161503、R-1065、YM348、此外还有USP3,914,250、WO02/36596、WO02/48124、WO02/10169、WO01/66548、WO02/44152、WO02/51844、WO02/40456及WO02/40457中公开的化合物等血清素受体2激动剂;20)黑皮质素3受体激动剂;21)CHIR86036(Chiron)、ME-10142、ME-10145(Melacure)、此外还有WO99/64002、WO00/74679、WO01/991752、WO01/74844、WO01/70708、WO01/70337、WO01/91752、WO02/059095、WO02/059107、WO02/059108、WO02/059117、WO02/12116、WO02/11715、WO02/12178、WO02/15909、WO02/068387、WO02/068388、WO02/067869、WO03/007949及WO03/009847中公开的化合物等黑皮质素4受体激动剂;22)***(注册商标Meridia/注册商标Reductil)及其盐,此外还有USP4,746,680、USP4,806,570、USP5,436,272、美国专利局申请号2002/0006964、WO01/27068及WO01/62341中公开的衍生物单胺再吸收阻断剂;23)右芬氟拉明(dexfenfluramine)、氟西汀(fluoxetine)、此外还有USP6,365,633、WO01/27060及WO01/162341中公开的血清素再摄取阻断剂;24)高血糖素样肽1(glucagon likepeptide 1)激动剂;25)托吡酯(Topiramate)(注册商标Topimax);26)植物药化合物57(phytopharm)(例如,CP644,673);27)乙酰辅酶A羧化酶2(ACC2)阻断剂;28)AD9677/TAK677(大日本制药/武田药品)、CL-316,243、SB-418790、BRL-37344、L-796568、BMS-196085、BRL-35135A、CGP12177A、BTA-243、W427353、曲卡君(Trecadrine)、ZenecaD7114、SR59119A、此外还有USP5705515、USP5451677、WO01/74782及WO02/32897中公开的化合物等β肾上腺素受体3激动剂;29)二酰基甘油酰基转移酶1阻断剂;30)二酰基甘油酰基转移酶2阻断剂;31)浅蓝菌素(Cerulenin)、C75等脂肪酸合成阻断剂;32)茶碱、己酮可可碱(Pentoxifylline)、托普司特(Zaprinast)、西地那非(Sildenafil)、氨利酮(Amrinone)、米利酮(Milrinone)、西洛酰胺(Cilostamide)、咯利普兰(Rolipram)、及西洛司特(cilomilast)等磷酸二酯酶阻断剂;32)KB-2611(KaroBioBMS)、此外还有WO02/15845、特开2000-256190中公开的化合物等甲状腺激素β激动剂;33)植烷酸、4-[(E)-2-(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)-1-丙烯基]安息香酸(TTNPB)、视黄酸(retinoic acid)、此外还有WO99/00123中公开的化合物等植烷酸(Phytanic Acid);34)油酰雌酮、此外还有del Mar-Grasa,M.et al.,Obesity Research,9:202-9(2001)中公开的化合物等酰化***;35)糖皮质激素拮抗剂;36)BVT3498、BVT2733、此外还有WO01/90091、WO01/90090、WO01/90092中公开的化合物等11-β羟基甾醇脱氢酶1型阻断剂;37)硬脂酰辅酶A去饱和酶1阻断剂(stearoyl-CoA desaturase-1);38)异亮氨酸噻唑烷(isoleucine thiazolidide)、缬氨酸吡咯烷(valinepyrrolidide)、NVP-DPP728、AF237、P93/01、TSL225、TMC-2A/2B/2C、FE999011、P9310/K364、VIP0177、SDZ274-444、此外还有WO03/004498、WO03/004496、EP1258476、WO02/083128、WO02/062764、WO03/000250、WO03/002530、WO03/002531、WO03/002553、WO03/002593、WO03/000180及WO03/000181中公开的化合物等二肽酰肽酶IV阻断剂;39)テトラヒドロリプタチン(注册商标orlistat/Xenical)、TritonWR1339、RHC80267、リプスタチン、茶皂素(Tea saponin)、diethylumbellifery phosphate、FL-386、WAY-121898、BaV-N-3176、valilactone、esteracin、ebelactone A、ebelactone B、RHC80267、此外还有WO01/77094、USP4,598,089、USP4,452,813、USP5,512,565、USP5,391,571、USP5,602,151、USP4,405,644、USP4,189,438及USP4,242,453中公开的化合物等脂肪酶阻断剂;39)脂肪酸转运蛋白阻断剂;40)二羧酸酯转运蛋白阻断剂;41)葡萄糖转运蛋白阻断剂;42)磷酸酯转运蛋白阻断剂等。
并用本发明的化合物与上述并用药物的1种或2种以上,可得到上述组合药物。另外,通过组合选自糖尿病治疗药及高脂血症治疗药的1种或2种以上的药物,上述组合药物对代谢性疾病的预防或治疗有用。特别是含有高血压治疗药及减肥药的组合,通过加入糖尿病治疗药和/或高脂血症治疗药,具有协同效果,对于代谢性疾病的预防或治疗有用。
附图说明
图1为经口给予饱食了高脂肪食物的大鼠本发明的化合物,1小时后向脑室内给予MCH,之后2小时的大鼠摄食量的示意图。
具体实施方式
下面,列举实施例对本发明进行详细地说明,但本发明并不限于实施例。需要说明的是,实施例中使用的各种试剂若无特别说明,使用的是市售品。质谱利用电喷雾离子化法(ESI)来测定。
参考例1
1-甲基-7-(6-硝基-2-喹啉基)-2-氧代-1,7-二氮杂螺[4,4]壬烷
(1)冰浴下,向二异丙胺(12ml)的THF(200ml)溶液中,加入正丁基锂(2.6M己烷溶液,32ml),同温度下搅拌20分钟。冷却该溶液到-78℃后,滴加1-(叔丁基)3-甲基1,3-吡咯烷二羧酸酯(13.0g)的THF溶液(30ml),同温度下搅拌1小时。接着在反应液中加入烯丙基溴(10ml),-78℃下搅拌1小时,进而在室温下搅拌1小时。在反应液中加入饱和氯化铵水溶液,用乙酸乙酯提取,用无水硫酸钠干燥乙酸乙酯层后,减压下浓缩。将残渣上柱层析(己烷∶乙酸乙酯=15∶1),得到黄色油状的1-(叔丁基)3-甲基3-烯丙基-1,3-吡咯烷二羧酸酯(13.3g)。
(2)在4N氢氧化钠水溶液(20ml)中加入上述(1)中得到的化合物(13.3g,49mmol)的THF-甲醇(50ml-50ml)溶液,50℃下搅拌1小时。用5N盐酸水溶液中和反应液,用氯仿提取,用无水硫酸钠干燥后,减压下浓缩。在甲苯(100ml)中溶解得到的残渣,在该溶液中加入叠氮磷酸二苯酯(13.5g)、三乙胺(6.9ml),80℃下搅拌1小时。接着在反应液中加入苄醇(6.6ml),100℃下搅拌一夜。减压下蒸馏除去反应液后,将得到的残渣上柱层析(己烷∶乙酸乙酯=6∶1),得到黄色油状的3-烯丙基-3-[(苄氧基)羰基]氨基-1-吡咯烷羧酸叔丁酯(13.0g)。
(3)冰浴下,在上述(2)中得到的化合物(10.2g)的THF(130ml)溶液中加入9-BBN(2M THF溶液,113ml),室温下搅拌一夜。进而,冰浴下在反应液中依次加入甲醇(2ml)、3N氢氧化钠水溶液(20ml)、30%双氧水(20ml),室温下搅拌3小时。接着在反应液中加入饱和碳酸氢钠水溶液,用二***提取,用无水硫酸钠干燥二***层后,减压下浓缩。将得到的残渣上柱层析(己烷∶乙酸乙酯=3∶2),得到无色油状的3-[(苄氧基)羰基]氨基-3-(3-羟丙基)-1-吡咯烷羧酸叔丁酯(7.9g)。
(4)冰浴下,在上述(3)中得到的化合物(3.2g)的DMF(30ml)溶液中加入咪唑(860mg)、叔丁基二甲基氯硅烷(1.5g),室温下搅拌4小时。在反应液中加入水,用乙酸乙酯提取,用无水硫酸钠干燥乙酸乙酯层后,减压下浓缩。将残渣溶解于DMF(30ml),冰浴下,在该溶液中加入氢氧化钠(60%油状,50mg),同温度下搅拌1小时。再在反应液中加入碘甲烷(1.3ml),室温下搅拌2小时。在水中注入反应液,加入饱和氯化铵水溶液,用乙酸乙酯提取,用无水硫酸钠干燥乙酸乙酯层后,减压下浓缩。在残渣中加入四丁基氟化铵(1M TMF溶液,15ml),室温下搅拌1小时。进而在反应液中加入饱和氯化铵水溶液,用乙酸乙酯提取,用无水硫酸钠干燥乙酸乙酯层后,减压下浓缩。将残渣上柱层析(己烷∶乙酸乙酯=3∶2),得到无色油状的3-[[(苄氧基)羰基](甲基)氨基]-3-(3-羟丙基)-1-吡咯烷羧酸叔丁酯(3.4g)。
(5)将草酰氯(1.5ml)的二氯甲烷(100ml)溶液冷却到-78℃后,加入DMSO(1.5ml),同温度下搅拌30分钟。接着,在该溶液中滴入上述(4)中得到的化合物(3.4g)的二氯甲烷(15ml)溶液,加入三乙胺(7ml),室温下搅拌1小时。在反应液中加入氯化铵水溶液,用乙酸乙酯提取,用无水硫酸钠干燥乙酸乙酯后,减压下浓缩。将残渣用叔丁醇水溶液(75%,200ml)溶解,冰浴下,在该溶液中依次加入2-甲基-2-丁烯(4.5ml)、磷酸二氢钠(2.0g)、亚氯酸钠(2.8g),室温下搅拌1小时。在反应液中加入饱和氯化铵水溶液,用乙酸乙酯提取,用无水硫酸钠干燥后,减压下浓缩。将残渣溶解于甲醇(30ml),在该溶液中加入三甲基甲硅烷基重氮甲烷-己烷溶液(2M己烷溶液,20ml),室温下搅拌30分钟。减压蒸馏除去反应液后,将残渣上柱层析(己烷∶乙酸乙酯=5∶1),得到无色油状的3-([(苄氧基)羰基](甲基)氨基)-3-(3-甲氧基-3-氧基丙基)-l-吡咯烷羧酸叔丁酯(3.2g)。
(6)在上述(5)中得到的化合物(1.0g)的甲醇(30ml)溶液中加入氢氧化钯(200ml),在氢气氛下室温下搅拌2小时。过滤反应液,减压蒸馏除去溶剂后,在残渣中加入甲苯(60ml),100℃下搅拌2小时。减压蒸馏除去甲苯后,加入4N盐酸-二噁烷溶液(20ml),室温下搅拌2小时。减压蒸馏除去反应液后,在残渣中加入2-氯-6-硝基喹啉(620mg)、碳酸钾(830mg)、异丙醇(20ml),100℃下搅拌得到的混合物一晚。在反应液中加入水,用乙酸乙酯提取,用无水硫酸钠干燥乙酸乙酯层后,减压下浓缩。将残渣上柱层析(乙酸乙酯),得到黄色固体的标题化合物(740mg)。
ESI-MS Found:m/z 327[M+H]+
参考例2
7-甲基-2-(6-硝基-2-喹啉基)-8-氧代-2,7-二氮杂螺[4,4]壬烷
(1)将3-吡咯烷醇(4.0g)的二噁烷-水(10∶1,50ml)混合溶液冷却到5℃,边保持pH8~9边滴加4-硝基苄基氯甲酸酯(10.9g)的二噁烷(20ml)溶液。5℃下搅拌10分钟后,减压下蒸馏除去溶剂。用乙酸乙酯提取残渣,用无水硫酸镁干燥有机层后,减压下蒸馏除去溶剂。用乙酸乙酯干燥得到的残渣,洗涤,得到淡黄色固体的3-羟基-1(对硝基苄氧基羰基)吡咯烷(6.6g)。
(2)将上述(1)中得到的化合物(6.3g)和三乙胺(26.5mg)的DMSO(87ml)溶液冷却到10℃,加入吡啶三氧化硫配合物(11.3g)。室温下终夜搅拌后,在反应液中加入水,用二氯甲烷提取。用无水硫酸镁干燥有机层后,减压下蒸馏除去溶剂。将得到的残渣上硅胶柱层析(己烷∶乙酸乙酯=3∶2~2∶3),得到1-(对硝基苄氧基羰基)-3-吡咯烷(4.5g)。
1H-NMR(300MHz,CDCl3,δppm):2.65(2H,m),3.88(4H,m),5.24(2H,s),7.53(2H,d,J=7.5Hz),8.22(2H,d,J=7.5Hz).
(3)在THF(50ml)中混悬氢氧化钠(60%油状,1.6g),冷却至0℃。10℃以下,在该混悬液中滴入三乙基膦酰乙酸酯(9.7g)的THF(10ml)溶液。0~5℃下搅拌30分钟后,10℃以下,在反应液中滴加上述(2)中得到的化合物(3.5g)的THF(10ml)溶液。室温下搅拌4小时后,在反应液中加入水,减压下蒸馏除去。用乙酸乙酯提取残渣,用饱和食盐水洗涤。用无水硫酸镁干燥有机层后,减压下蒸馏除去溶剂。将得到的残渣上硅胶柱层析(己烷∶乙酸乙酯=4∶1~3∶2),得到3-(2-甲氧基-2-氧代乙基)-3-(硝基甲基)-1-吡咯烷羧酸对硝基苄酯(4.2g)。
1H-NMR(300MHz,CDCl3,δppm):1.28(3H,t,J=7.5Hz),2.73(1H,m),3.19(2H,m),3.65(1H,m),4.14(2H,q,J=7.5Hz),4.21(2H,brs),5.21(2H,s),5.67(1H,m),7.52(2H,d,J=7.5Hz),8.22(2H,d,J=7.5Hz).
(4)在上述(3)中得到的化合物(3.9g)的硝基甲烷(160ml)溶液中加入1,1,3,3-四甲基胍(0.8ml),终夜加热回流。减压下浓缩反应液,将得到的残渣上硅胶柱层析(己烷∶乙酸乙酯=4∶1~3∶2),得到3-(2-甲氧基-2-氧代乙基)-3-(硝基甲基)-1-吡咯烷羧酸对硝基苄酯(1.37g)。
1H-NMR(300MHz,CDCl3,δppm):1.28(3H,t,J=7.5Hz),2.04(2H,m),2.63(2H,m),3.60(4H,m),4.18(2H,q,J=7.5Hz),4.70(2H,m),5.21(2H,s),7.51(2H,d,J=7.5Hz),8.22(2H,d,J=7.5Hz).
(5)在上述(4)中得到的化合物(500mg)的50%甲醇水溶液(80ml)中加入铁粉(425mg)及氯化铵(815mg),加热回流50分钟。冷却反应液至室温后,用硅藻土过滤。减压下浓缩滤液,加入丙酮(20ml),通过倾析除去上清液。在残渣中加入DMF(20ml),用硅藻土过滤。减压下浓缩滤液,得到3-氧代-2,7-二氮杂螺[4,4]壬烷。对其不进行精制,用于下面的反应。
(6)在上述(5)中得到的化合物的DMF(10ml)溶液中加入2-氯-6-硝基喹啉(250mg)及碳酸钾(248mg),90℃下终夜搅拌。减压下蒸馏除去溶剂,将得到的残渣上硅胶柱层析(氯仿:甲醇=10∶1),得到2-(6-硝基-2-喹啉基)-8-氧代-2,7-二氮杂螺[4,4]壬烷(44mg)。
1H-NMR(300MHz,CDCl3,δppm):2.17(1H,d,J=8.3Hz),2.21(1H,d,J=8.3Hz),2.43(1H,d,J=15Hz),2.51(1H,d,J=15Hz),3.41(1H,d,J=11Hz),3.47(1H,d,J=11Hz),3.73(4H,m),6.82(1H,d,J=8.2Hz),7.68(1H,d,J=9.0Hz),7.97(1H,d,J=9.0Hz),8.31(1H,dd,J=8.2,2.2Hz),8.55(1H,d,J=2.2Hz).
ESI-MS Found:m/z 313[M+H]+
(7)氮气流下,在上述(6)中得到的化合物的DMF(4ml)溶液中加入氢氧化钠(60%油状,17mg),室温下搅拌25分钟。在反应液中碘甲烷(99mg)的DMF(1ml)溶液,搅拌30分钟。接着,在反应液中加入水,用氯仿-甲醇(10∶1)混合溶剂提取。用无水硫酸镁干燥有机层,减压下蒸馏除去溶剂。将得到的残渣上制备TLC(氯仿∶甲醇=10∶1),得到标题化合物(27mg)。
1H-NMR(300MHz,CDC13,δppm):2.14(1H,d,J=8.3Hz),2.18(1H,d,J=8.3Hz),2.49(1H,d,J=15Hz),2.56(1H,d,J=15Hz),2.81(3H,s),3.39(1H,d,J=11Hz),3.55(1H,d,J=11Hz),3.75(4H,m),6.79(1H,d,J=8.2Hz),7.65(1H,d,J=9.0Hz),7.95(1H,d,J=9.0Hz),8.28(1H,dd,J=8.2,2.2Hz),8.51(1H,d,J=2.2Hz).
ESI-MS Found:m/z 327[M+H]+
参考例3
(3R)-N-甲基-N-[1-(6-硝基-2-喹啉基)-3-吡咯烷基]异丁酰胺
(1)0℃下,在(3R)-(-)-1-苄基-3-(甲氨基)吡咯烷(20.0g)的四氢呋喃(200ml)溶液中加入三乙胺(29.3ml)及二碳酸二叔丁酯(34.4g),室温下终夜搅拌。在反应液中加入水,用二***提取。用饱和食盐水洗涤有机层,用无水硫酸钠干燥后,减压下浓缩。在残渣中加入4N盐酸-乙酸乙酯溶液(29.0ml),用二异丙醚洗涤生成的白色结晶后,过滤。干燥生成物,得到白色结晶的(3R)-N-(1-苄基-3-吡咯烷基)-N-甲基氨基甲酸叔丁酯盐酸盐(24.2g)。
ESI-MS Found:m/z 235[M+H]+
(2)氮气氛下,在上述(1)中得到的化合物(22.0g)的甲醇(225ml)溶液中加入10%钯碳(7.2g),1气压的氢气氛下,搅拌终夜。通过氮气置换反应体系使反应停止,用硅藻土过滤反应液,减压浓缩。干燥生成物,得到白色结晶的(3R)-N-甲基-N-(3-吡咯烷基)氨基甲酸叔丁酯盐酸盐(15.9g)。
ESI-MS Found:m/z 201[M+H]+
(3)在2-氯-6-硝基氨基喹啉(7.13g)的DMF(110ml)溶液中加入碳酸钾(14.2g)及上述(2)中得到的化合物(8.90g),90℃下终夜搅拌。在反应液中加入水(400ml),过滤生成的结晶。干燥生成物,得到黄色结晶的(3R)-N-甲基-N-[1-(6-硝基-2-喹啉基)-3-吡咯烷基]氨基甲酸叔丁酯盐酸盐(11.4g)。
ESI-MS Found:m/z 273[M+H]+
(4)在三氟乙酸(110ml)中溶解上述(3)中得到的化合物(11.2g),搅拌20分钟。减压浓缩反应液后,在残渣中加入2N氢氧化钠水溶液,用氯仿提取。用饱和食盐水洗涤有机层,用无水硫酸钠干燥后,减压下浓缩。在残渣的氯仿(60ml)溶液中0℃下加入三乙胺(8.4ml)及异丁酰氯(3.8ml),搅拌1小时。在反应液中加入碳酸氢钠水,用氯仿提取。用饱和食盐水洗涤有机层,用无水硫酸钠干燥后,减压下浓缩。将残渣上硅胶柱层析(氯仿∶甲醇=95∶5),得到黄色结晶的标题化合物(10.3g)。
ESI-MS Found:m/z 243[M+H]+
参考例4
2-(6-硝基-2-喹啉基)-6-乙酰基十氢吡咯并[3,4-d]氮杂
在2-(叔丁氧基羰基)-6-苄基十氢吡咯并[3,4-d]氮杂(用WO99/40070号中记载的方法制备了该化合物。)(680mg)的甲醇(15ml)溶液中加入钯碳(500mg),在氢气流下(50psi),室温下终夜搅拌。用硅藻土过滤钯碳,减压下浓缩滤液。将得到的残渣溶解于氯仿(10ml),加入三乙胺(516ml)及乙酰氯(200mg),室温下搅拌1小时。用饱和碳酸钠水溶液洗涤反应液,用无水硫酸镁干燥有机层。减压下蒸馏除去溶剂,将得到的残渣溶解于三氟乙酸(5ml)中,室温下搅拌2小时。减压下减压蒸馏除去溶剂,在DMF(10ml)溶液中溶解残渣,在该溶液中加入2-氯-6-硝基喹啉(283mg)及碳酸钾(1.17g),90℃下终夜搅拌。减压下蒸馏除去溶剂,将残渣上硅胶柱层析(氯仿∶甲醇=10∶1),得到标题化合物(424mg)。
ESI-MS Found:m/z 355[M+H]+
参考例5
(3R)-N-甲基-N-[1-(6-硝基-2-喹啉基)-3-吡咯烷基]乙酰胺
使用乙酰氯代替参考例3-(4)中使用的异丁酰氯,其他与参考例3相同,得到标题化合物。
1H-NMR(300MHz,CDCl3,δppm):2.05-2.40(5H,m),2.85-3.05(3H,m),3.40-4.10(4H,m),4.50-5.55(1H,m),6.75-6.90(1H,m),7.60-7.75(1H,m),7.90-8.05(1H,m),8.20-8.40(1H,m),8.50-8.65(1H,m).
参考例6
(3R)-N-甲基-N-[1-(6-硝基-2-喹啉基)-3-吡咯烷基]丙酰胺
使用丙酰氯代替参考例3-(4)中使用的异丁酰氯,其他与参考例3相同,得到标题化合物。
1H-NMR(300MHz,CDCl3,δppm):1.10-1.30(3H,m),2.10-2.60(4H,m),2.85-3.05(3H,m),3.40-4.10(4H,m),4.50-5.55(1H,m),6.75-6.90(1H,m),7.60-7.75(1H,m),7.90-8.05(1H,m),8.20-8.40(1H,m),8.50-8.65(1H,m).
参考例7
(3R)-N-甲基-N-[1-(6-硝基-2-喹啉基)-3-吡咯烷基]甲磺酰胺
使用甲磺酰氯代替参考例3-(4)中使用的异丁酰氯,其他与参考例3相同,得到标题化合物。
1H-NMR(300MHz,CDCl3,δppm):2.15-2.45(2H,m),2.85-3.00(3H,m),3.55-3.75(4H,m),3.80-4.10(2H,m),4.65-4.80(1H,m),6.75-6.90(1H,m),7.60-7.75(1H,m),7.90-8.05(1H,m),8.20-8.35(1H,m),8.50-8.60(1H,m).
参考例8
2-[异丙基(甲基)氨基]-6-硝基喹啉
使用N-异丙基(甲基)胺代替3-氧代-2,7-二氮杂螺[4,4]壬烷,其他与参考例2-(6)相同,得到标题化合物。
ESI-MS Found:m/z 246[M+H]+
参考例9
N-2-[甲基(四氢-3-呋喃基)氨基]-6-硝基喹啉
使用N-甲基(四氢-3-呋喃基)胺代替3-氧代-2,7-二氮杂螺[4,4]壬烷,其他与参考例2-(6)相同,得到标题化合物。
ESI-MS Found:m/z 274[M+H]+
参考例10
5-苯基嘧啶-2-羧酸
在5-溴嘧啶-2-羧酸(5.01g)及苯基硼酸(3.61g)的乙二醇二甲醚(150ml)溶液中加入2M碳酸钠水溶液(100ml)及四三苯基膦钯(1.42g),80℃下搅拌5小时。反应液中加入碳酸氢钠水,用水稀释,用二***洗涤。在水层中加入10%磷酸水溶液,使pH为4后,用乙酸乙酯提取,用饱和食盐水洗涤。用无水硫酸钠干燥,减压下浓缩,得到白色的标题化合物(3.66g)。
ESI-MS Found:m/z 201[M+H]+
ESI-MS Found:m/z 199[M-H]-
参考例11
5-(4-氟苯基)嘧啶-2-羧酸
使用4-氟苯基硼酸代替苯基硼酸,其他与参考例10相同,得到标题化合物。
ESI-MS Found:m/z 219[M+H]+
ESI-MS Found:m/z 217[M-H]-
参考例12
5-(3-氟苯基)嘧啶-2-羧酸
使用3-氟苯基硼酸代替苯基硼酸,其他与参考例10相同,得到标题化合物。
ESI-MS Found:m/z 219[M+H]+
ESI-MS Found:m/z 217[M-H]-
实施例1
5-(4-氟苯基)-N-[2-(1-甲基-2-氧代-1,7-二氮杂螺[4,4]壬烷-7-基)-6-喹啉基]-2-嘧啶甲酰胺
在参考例1中得到的化合物(80mg)的甲醇(5ml)溶液中加入钯碳(10mg),氢气氛下室温下搅拌1小时。过滤反应液,减压蒸馏除去反应液后,将残渣溶解于氯仿(10mg),在该溶液中加入参考例11中得到的化合物(53mg)、三乙胺(70μl)、2-氯-1,3-二甲基咪唑鎓氯化物(41mg),室温下搅拌得到的混合物一晚。在反应液中加入水,用乙酸乙酯提取,用无水硫酸钠干燥乙酸乙酯层后,减压下浓缩。将残渣上柱层析(氯仿∶甲醇=100∶1),得到黄色固体的标题化合物(64mg)。
1H-NMR(400MHz,CDCl3,δppm):1.95-2.10(2H,m),2.13-2.24(1H,m),2.36-2.55(3H,m),2.87(3H,s),3.60-3.78(3H,m),3.85-3.94(1H,m),6.74(1H,d,J=9.2Hz),7.22-7.30(2H,m),7.60-7.75(4H,m),7.96(1H,d,J=9.2Hz),9.07(2H,s),10.01(1H,s).
实施例2
5-(4-氟苯基)-N-[2-(7-甲基-8-氧代-2,7-二氮杂螺[4,4]壬烷-2-基)-6-喹啉基]-2-嘧啶甲酰胺盐酸盐
除使用参考例2中得到的化合物代替参考例1中得到的化合物外,其他与实施例1的操作相同,之后用4N盐酸-乙酸乙酯处理得到的化合物,得到标题化合物。
1H-NMR(300MHz,d6-DMSO,δppm):2.15(2H,m),2.44(2H,brs),2.75(3H,s),3.56(2H,m),3.85(4H,m),7.27(1H,m),7.45(2H,m),8.01(2H,m),8.17(2H,m),8.46(1H,m),8.62(1H、brs),9.36(2H、s),11.18(1H、s).
ESI-MS Found:m/z 497[M+H]+
实施例3
N-(2-[(3R)-3-[异丁酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺
在参考例3中得到的化合物(10.2g)的四氢呋喃(150ml)溶液中氮气氛下加入20%氢氧化钯碳(4.19g),1气压的氢气氛下终夜搅拌。氮取代反应体系使反应停止后,硅藻土过滤反应液,减压浓缩滤液。0℃下,在残渣的二甲基甲酰胺(70ml)溶液中加入参考例10中得到的嘧啶羧酸苯酯(5.97g)及三乙胺(8.3ml)后,再滴入2-氯-1,3-二甲基咪唑鎓氯化物(6.55g)的二甲基甲酰胺(30ml)溶液,搅拌1小时。在反应液中加入碳酸氢钠水后,用水稀释,过滤生成的固体。将得到的固体上硅胶柱层析(氯仿∶甲醇=95∶5),通过乙酸乙酯重结晶,得到黄色结晶的标题化合物(7.65g)。
1H-NMR(400MHz,d6-DMSO,δppm):1.05-1.08(6H,m),2.05-2.25(2H,m),2.78(3/2H,s),2.96(3/2H,s),2.82-3.10(1H,m),3.35-3.55(2H,m),3.65-3.87(2H,m),4.78-4.89(1/2H,m),5.13-5.25(1/2H,m),6.88-6.93(1H,m),7.51-7.60(4H,m),7.90-7.92(3H,m),8.01(1H,d,J=8.8H z),8.36(1H,d,J=2.4Hz),9.34(2H,s),10.85(1H,s).
ESI-MS Found:m/z 496[M+H]+
实施例4
N-[2-(6-乙酰基十氢吡咯并[3,4-d]氮杂-2-基)-6-喹啉基]-5-苯基-2-嘧啶甲酰胺
除使用参考例4中得到的化合物代替参考例3中得到的化合物外,其他与实施例3的操作相同,得到标题化合物。
1H-NMR(300MHz,d6-DMSO,δppm):1.70-1.82(5H,m),2.01(3H,s),2.48 and 3.18(4H,m),3.32-3.67(5H,m),6.84(1H,d,J=8.7Hz),7.54(4H,m),7.91(3H,m),8.30(2H,m),9.34(2H,s),10.83(1H,s).
ESI-MS Found:m/z 507[M+H]+
实施例5
N-(2-[(3R)-3-[乙酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺
除使用参考例5中得到的化合物代替参考例3中得到的化合物外,其他与实施例3的操作相同,得到标题化合物。
1H-NMR(300MHz,d6-DMSO,δppm):1.95-2.30(5H,m),2.70-2.95(3H,m),3.25-3.35(3H.m),3.35-3.60(2H,m),3.60-3.90(2H,m),4.60-5.25(1H,m),6.85-6.95(1H,m),7.45-7.65(4H,m),7.85-8.10(4H,m),8.36(1H,s),9.36(2H,s),10.85(1H,s).
ESI-MS Found:m/z 467[M+H]+
实施例6
5-苯基-N-(2-[(3R)-3-[丙酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-2-嘧啶甲酰胺
除使用参考例6中得到的化合物代替参考例3中得到的化合物外,其他与实施例3的操作相同,得到标题化合物。
1H-NMR(300MHz,d6-DMSO,δppm):0.95-1.10(3H,m),2.00-2.25(2H,m),2.25-2.50(2H,m),2.70-2.95(3H,m),3.35-3.60(2H,m),3.60-3.85(2H,m),4.65-5.30(1H,m),6.85-6.95(1H,m),7.45-7.65(4H,m),7.85-8.10(4H,m),8.36(1H,s),9.36(2H,s),10.84(1H,s).
ESI-MS Found:m/z 481[M+H]+
实施例7
N-(2-[(3R)-3-[甲磺酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺
除使用参考例7中得到的化合物代替参考例3中得到的化合物外,其他与实施例3的操作相同,得到标题化合物。
1H-NMR(300MHz,d6-DMSO,δppm):2.10-2.30(2H,m),2.79(3H,s),2.99(3H,s),3.40-3.60(2H,m),3.70-3.90(2H,m),4.45-4.60(1H,m),6.85-6.95(1H,m),7.45-7.65(4H,m),7.85-8.10(4H,m),8.36(1H,s),9.36(2H,s),10.85(1H,s).
ESI-MS Found:m/z 503[M+H]+
实施例8
N-(2-[(3R)-3-[甲氧基羰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺
(1)N-(2-[(3R)-3-[叔丁氧基羰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺
除使用参考例3-(3)中得到的(3R)-N-甲基-N-[1-(6-硝基-2-喹啉基)-3-吡咯烷基]氨基甲酸叔丁酯代替参考例3中得到的化合物外,其他与实施例3的操作相同,得到标题化合物。
(2)N-(2-[(3R)-3-[甲氧基羰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺
除使用上述(1)中得到的化合物代替参考例3-(3)中得到的化合物、使用氯碳酸甲酯代替异丁酰氯外,其他与参考例3-(4)的操作相同,得到标题化合物。
1H-NMR(400MHz,CDCl3,δppm):2.18-2.27(2H,m),2.90(3H,s),3.53-3.61(2H,m),3.75(3H,s),3.82-3.90(2H,m),5.00(1H,br.s),6.75(1H,d,J=9.2Hz),7.52-7.59(3H,m),7.65-7.74(4H,m),7.94(1H,d,J=9.2Hz),8.43(1H,s),9.12(2H,s),10.04(1H,s).
ESI-MS Found:m/z 483[M+H]+
实施例9
N-(2-[(3R)-3-[[(二甲氨基)羰基]](甲基)氨基]-1-吡咯烷基)-6-喹啉基)-5-苯基-2-嘧啶甲酰胺
除使用实施例8-(1)中得到的化合物代替参考例3-(3)中得到的化合物、使用二甲基氨基甲酰氯代替异丁酰氯外,其他与参考例3-(4)的操作相同,得到标题化合物。
1H-NMR(400MHz,CDCl3,δppm):1.59(6H,s),2.12-2.21(1H,m),2.24-2.35(1H,m),2.82(3H,s),3.49-3.62(2H,m),3.82-3.90(1H,m),3.92-4.00(1H,m),4.46-4.54(1H,m),6.75(1H,d,J=9.2Hz),7.50-7.57(3H,m),7.64-7.72(4H,m),7.92(1H,d,J=8.8Hz),8.40(1H,brs),9.11(2H,s),10.02(1H,s).
ESI-MS Found:m/z 496[M+H]+
实施例10
N-(2-[异丙基(甲基)氨基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺
除使用参考例8中得到的化合物代替参考例3中得到的化合物外,其他与实施例3的操作相同,得到标题化合物。
1H-NMR(400MHz,CDCl3,δppm):1.24(6H,d,J=6.8Hz),3.01(3H,s),4.98(1H,septet,J=6.8Hz),6.91(1H,d,J=9.2Hz),7.49-7.57(3H,m),7.62-7.69(4H,m),7.89(1H,d,J=9.2Hz),8.38(1H,s),9.10(2H,s),10.00(1H,s).
ESI-MS Found:m/z 398[M+H]+
实施例11
5-(4-氟苯基)-N-(2-[(3R)-3-[异丁酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-2-嘧啶甲酰胺
除使用参考例3中得到的化合物代替参考例1中得到的化合物外,其他与实施例1的操作相同,得到标题化合物。
1H-NMR(400MHz,d6-DMSO,δppm):1.00-1.07(6H,m),2.06-2.25(2H,m),2.77(3/2H,s),2.82-2.91(1/2H,m),2.96(3/2H,s),3.00-3.11(1/2H,m),3.37-3.57(2H,m),3.66-3.84(2H,m),4.78-4.88(1/2H,m),5.12-5.23(1/2H,m),6.88-6.94(1H,m),7.40-7.44(2H,m),7.54(1H,d,J=9.2Hz),7.90(1H,dd,J=9.2,2.0Hz),7.96-8.02(3H,m),8.34(1H,d,J=2.0Hz),9.33(2H,s),10.83(1H,s).
ESI-MS Found:m/z 513[M+H]+
实施例12
N-(2-[(3R)-3-[乙酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-(4-氟苯基)-2-嘧啶甲酰胺
除使用参考例5中得到的化合物代替参考例1中得到的化合物外,其他与实施例1的操作相同,得到标题化合物。
1H-NMR(300MHz,d6-DMSO,δppm):1.95-2.25(5H,m),2.70-2.95(3H,m),3.25-3.35(3H,m),3.35-3.60(2H,m),3.60-3.90(2H,m),4.60-5.30(1H,m),6.85-6.95(1H,m),7.35-7.60(3H,m),7.85-8.10(4H,m),8.36(1H,s),9.35(2H,s),10.85(1H,s).
ESI-MS Found:m/z 485[M+H]+
实施例13
5-(4-氟苯基)-N-(2-[甲基(四氢-3-呋喃基)氨基]-6-喹啉基)-2-嘧啶甲酰胺
除使用参考例9中得到的化合物代替参考例1中得到的化合物外,其他与实施例1的操作相同,得到标题化合物。
1H-NMR(400MHz,CDCl3,δppm):1.94-2.04(1H,m),2.32-2.42(1H,m),3.10(3H,s),3.75-3.96(3H,m),4.08-4.15(1H,m),5.64-5.74(1H,m),6.94(1H,d,J=9.2Hz),7.22-7.30(2H,m),7.60-7.74(4H,m),7.94(1H,d,J=9.2Hz),8.41(1H,s),9.06(2H,s),10.00(1H,s).
ESI-MS Found:m/z 444[M+H]+
实施例14
5-(3-氟苯基)-N-(2-[(3R)-3-[异丁酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-2-嘧啶甲酰胺
除使用参考例12中得到的化合物代替5-苯基嘧啶-2-羧酸外,其他与实施例3的操作相同,得到标题化合物。
1H-NMR(400MHz,d6-DMSO,δppm):1.01-1.07(6H,m),2.07-2.25(2H,m),2.77(3/2H,s),2.83-2.91(1/2H,m),2.95(3/2H,s),3.00-3.08(1/2H,m),3.38-3.56(2H,m),3.66-3.85(2H,m),4.78-4.88(1/2H,m),5.12-5.23(1/2H,m),6.89-6.94(1H,m),7.34-7.39(1H,m),7.54(1H,d,J=8.8Hz)7.62(1H,dd,J=8.0,6.0Hz),7.78(1H,d,J=8.0Hz),7.85(1H,dt,J=10.4,2.0Hz),7.90(1H,dd,J=9.2,2.0Hz),8.01(1H,d,J=8.8Hz),8.34(1H,d,J=2.0Hz),9.38(2H,s),10.84(1H,s).
ESI-MS Found:m/z 513[M+H]+
药理试验例
本发明的化合物作为药品的有用性可用例如下述药理试验例来证明。
试验例1:MCH结合阻断试验
用质体媒介pEF/mic/cyto(インビトロジエン公司制)克隆编码人MCH-1R的cDNA序列[(FEBs Letters),398卷,253页(1996年),Biophisica Acta,1401卷,216页(1998年)]。使用Lipofectamine Plus试剂(Life Technology公司制)将得到的表达媒介转染为宿主细胞CHO-K1(American Type Culture Collection),得到MCH-1R表达细胞。
将由该表达MCH-1R的细胞配制的膜标准品,与供试化合物及50pM的[125I]MCH(NEN公司制)一起,在Assay缓冲液(10mM氯化镁、2mM乙二胺四乙酸、0.01%杆菌肽及含有0.2%牛血清白蛋白的50mM Tris缓冲液,pH7.4)中,25℃下培养1小时后,用玻璃过滤器GF/C(ワットマン公司制)过滤。用10mM氯化镁、2mM乙二胺四乙酸及含有0.04%Tween-20的50mM Tris缓冲液、pH7.4洗涤玻璃过滤器后,求出玻璃过滤器上的放射活性。非特异性结合在1μM人MCH存在下测定,求出对特异性[125I]MCH结合的供试化合物的50%阻断浓度(IC50值)。结果见表2。
表2
供试化合物 | IC50(nM) |
实施例1 | 8.0 |
实施例3 | 4.1 |
实施例9 | 3.7 |
试验例2(对由MCH诱发的摄食行为的拮抗试验)
***、甲苯噻嗪麻醉下(74及11mg、kg腹腔内单次给药),在雄性SD大鼠(9-12周龄)的第3脑室中脑定位固定下***慢性引导插管(26号),用牙科用树脂固定。使引导插管的前端位于前卤电后方2.2mm、正中线上、距头盖表面深8mm。2周恢复期过后,给予大鼠高脂肪食物约4小时,使其饱食。之后,在引导套管内***接着微量注射器的内针(33号),在第3脑室内给予黑色素聚集素(MCH,5μg/1μL/头,溶解于人工脑脊液)。在给予MCH的1小时前在0.5%甲基纤维素水溶液中混悬实施例3的化合物(10或30mg/kg),经口给药。接着给予大鼠高脂肪食物,测定MCH给药后2小时的摄食量。
图1为经口给予饱食了高脂肪食物的大鼠本发明的化合物,之后1小时后向脑室内给予MCH,之后2小时的大鼠摄食量的示意图。即,显示了下列各情况时每2小时的大鼠摄食量(g):1)不给予实施例3的化合物时,2)给予10mg/kg实施例3的化合物时,3)给予30mg/kg实施例3的化合物时。
如图1所示,本发明的化合物与用量相关地抑制了在第3脑室内给予了MCH引起的摄食量的增加。需要说明的是,将代替MCH及本发明的化合物仅给予人工脊液(aCSF)时的摄食量作为对照。
工业实用性
本发明的化合物具有MCH-1R拮抗作用,作为下列疾病的预防药物或治疗药物有用,例如,肥胖症、糖尿病、激素分泌异常、高脂血症、痛风、脂肪肝、肝炎、肝硬化等代谢性疾病;例如,心绞痛、急性·充血性心衰、心肌梗塞、环状动脉硬化症、高血压、肾病、电解质异常等循环***疾病;例如,贪食症、情感障碍、抑郁症、不安、癫痫、谵妄、痴呆、精神***症、多动症、记忆障碍、睡眠障碍、认知障碍、运动障碍、感觉异常、嗅觉障碍、***耐受、毒品依赖性、酒精依赖症等中枢及末梢神经***疾病;例如,***症、早产、性功能障碍等生殖***疾病;消化道疾病、呼吸道疾病、癌或皮肤色素沉着等。
Claims (13)
1.2-氨基喹啉衍生物或可药用的盐,其由通式[I]表示,
[式中,R1及R2各自独立地表示选自下列的取代基,
1)可被羟基或卤原子取代的低级烷基、
2)可被R9取代的3~6元环烷基、及
3)可被R9取代的4~6元杂环烷基,或
4)R1与R2一起与它们结合的氮原子一起形成4~11元的交联、非交联或螺环的脂肪族含氮杂环,该脂肪族含氮杂环中的1个或2个的任意氢原子可被R9取代,
R3、R4、R6及R7各自独立地表示选自下列的取代基,
1)氢原子、
2)羟基、
3)卤原子、及
4)可被卤原子取代的低级烷基,
R5表示
1)氢原子、或
2)可被卤原子取代的低级烷基,
R8各自独立地表示选自下列的取代基,
1)卤原子、
2)低级烷基、及
3)低级烷氧基,
R9表示选自下列的取代基:羟基、氨基、单低级烷氨基、二低级烷氨基、可被羟基或卤原子取代的低级烷基、(低级烷氧基羰基)氨基、低级烷氧基羰基(低级烷基)氨基、低级烷基羰基氨基、低级烷基羰基(低级烷基)氨基、单低级烷氨基甲酰基(低级烷基)氨基、二低级烷氨基甲酰基(低级烷基)氨基、低级烷基磺酰基氨基、低级烷基磺酰基(低级烷基)氨基、氧基及2-氧代吡咯烷基,
N表示0、1、2、3或4。]。
2.如权利要求1所述的化合物或可药用的盐,其中,R1为低级烷基;R2选自:可被羟基取代的低级烷基、四氢呋喃基、及可被R9取代的吡咯烷基。
3.如权利要求1所述的化合物或可药用的盐,其中,R1与R2一起与它们结合的氮原子一起形成4~11元的交联、非交联或螺环的脂肪族含氮杂环,由式[A]表示
[式中,Ra表示R9、或两个Ra一起形成-(CH2)x-(NH)-(CH2)y-,该取代中的任意氢原子可被低级烷基、低级烷基羰基或氧基取代,x及y独立地表示0、1、2、3或4,且满足3≤x+y≤4,m表示0、1、或2。]。
4.如权利要求3所述的化合物或可药用的盐,其中,Ra选自低级烷基羰基(低级烷基)氨基、低级烷基磺酰基(低级烷基)氨基、低级烷氧基羰基(低级烷基)氨基及二低级烷基氨基甲酰基(低级烷基)氨基,m=1。
6.如权利要求3所述的化合物或可药用的盐,其中,式[A]表示脂肪族含氮杂环选自1-甲基-2-氧代-1,7-二氮杂螺[4.4]壬烷-7-基、7-甲基-8-氧代-2,7-二氮杂螺[4.4]壬烷-2-基、3-[乙酰基(甲基)氨基]吡咯烷-1-基、3-[丙酰基(甲基)氨基]吡咯烷-1-基、3-[异丁酰基(甲基)氨基]吡咯烷-1-基、3-[甲磺酰基(甲基)氨基]吡咯烷-1-基、3-[甲氧基羰基(甲基)氨基]吡咯烷-1-基、3-{[(二甲氨基)羰基](甲基)氨基}吡咯烷-1-基、6-乙酰基十氢吡咯并[3.4-d]氮杂-2-基、2-氧代[1.3’]二吡咯烷基-1’-基。
7.如权利要求1所述的化合物或可药用的盐,其中,R8为氟原子或甲氧基。
8.如权利要求3所述的化合物或可药用的盐,其中,通式[I]表示的化合物选自:
5-(4-氟苯基)-N-[2-(1-甲基-2-氧代-1,7-二氮杂螺[4,4]壬烷-7-基)-6-喹啉基]-2-嘧啶甲酰胺、
5-(4-氟苯基)-N-[2-(7-甲基-8-氧代-2,7-二氮杂螺[4,4]壬烷-2-基)-6-喹啉基]-2-嘧啶甲酰胺、
N-(2-[(3R)-3-[异丁酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺、
N-[2-(6-乙酰基十氢吡咯并[3,4-d]氮杂-2-基)-6-喹啉基]-5-苯基-2-嘧啶甲酰胺、
N-(2-[(3R)-3-[乙酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺、
5-苯基-N-(2-[(3R)-3-[丙酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-2-嘧啶甲酰胺、
N-(2-[(3R)-3-[甲磺酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺、
N-(2-[(3R)-3-[甲氧基羰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺、
N-(2-[(3R)-3-[[(二甲氨基)羰基)](甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺、
N-(2-[异丙基(甲基)氨基]-6-喹啉基)-5-苯基-2-嘧啶甲酰胺、
5-(4-氟苯基)-N-(2-[(3R)-3-[异丁酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-2-嘧啶甲酰胺、
N-(2-[(3R)-3-[乙酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-5-(4-氟苯基)-2-嘧啶甲酰胺、
5-(4-氟苯基)-N-(2-[甲基(四氢-3-呋喃基)氨基]-6-喹啉基)-2-嘧啶甲酰胺、及
5-(3-氟苯基)-N-(2-[(3R)-3-[异丁酰基(甲基)氨基]-1-吡咯烷基]-6-喹啉基)-2-嘧啶甲酰胺。
9.黑色素聚集激素拮抗剂,其以权利要求1~8中所述的化合物为有效成分。
10.预防剂或治疗剂,其以权利要求1~8中所述的化合物为有效成分,用于预防或治疗下列疾病:以肥胖症、糖尿病、激素分泌异常、高脂血症、痛风、脂肪肝、肝炎及肝硬化为代表的代谢***疾病;以心绞痛、急性·充血性心衰、心肌梗塞、冠状动脉硬化症、高血压、肾病及电解质异常为代表的循环***疾病;以贪食症、情感障碍、抑郁症、不安、癫痫、谵妄、痴呆、精神***症、多动症、记忆障碍、睡眠障碍、认知障碍、运动障碍、感觉异常、嗅觉障碍、***耐受、毒品依赖性及酒精依赖症为代表的中枢及末梢神经***疾病;以***症、早产及性功能障碍为代表的生殖***疾病;消化道疾病;呼吸道疾病;癌或皮肤色素沉着。
11.如权利要求10所述的预防剂或治疗剂,其为肥胖症的预防剂或治疗剂。
12.医药组合物,其含有权利要求1~8中记载的化合物或可药用盐、及可药用载体。
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AU2009261248A1 (en) * | 2008-06-19 | 2009-12-23 | Banyu Pharmaceutical Co., Ltd. | Spirodiamine-diarylketoxime derivative |
WO2010147234A1 (en) * | 2009-06-18 | 2010-12-23 | Banyu Pharmaceutical Co.,Ltd. | Diarylamide-spirodiamine derivative |
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WO1995032967A1 (en) * | 1994-05-28 | 1995-12-07 | Smithkline Beecham Plc | Amide derivatives having 5ht1d-antagonist activity |
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JP2002003370A (ja) * | 1999-09-20 | 2002-01-09 | Takeda Chem Ind Ltd | メラニン凝集ホルモン拮抗剤 |
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CA2384358A1 (en) | 2000-07-05 | 2002-01-10 | Synaptic Pharmaceutical Corporation | Dna encoding a human melanin concentrating hormone receptor (mch1) and uses thereof |
PL366624A1 (en) * | 2001-07-05 | 2005-02-07 | Synaptic Pharmaceutical Corporation | Substituted anilinic piperidines as mch selective antagonists |
AU2002352878B2 (en) | 2001-11-27 | 2007-11-22 | Merck Sharp & Dohme Corp. | 2-Aminoquinoline compounds |
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2004
- 2004-05-20 JP JP2005506399A patent/JP4552854B2/ja not_active Expired - Fee Related
- 2004-05-20 WO PCT/JP2004/007217 patent/WO2004103992A1/ja active Application Filing
- 2004-05-20 US US10/556,932 patent/US7485647B2/en not_active Expired - Fee Related
- 2004-05-20 CA CA002526374A patent/CA2526374A1/en not_active Abandoned
- 2004-05-20 CN CNB2004800137780A patent/CN100448870C/zh not_active Expired - Fee Related
- 2004-05-20 EP EP04734111A patent/EP1630162A4/en not_active Withdrawn
- 2004-05-20 AU AU2004241213A patent/AU2004241213B2/en not_active Ceased
Cited By (12)
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CN107108601A (zh) * | 2014-08-28 | 2017-08-29 | 阿森纽荣股份公司 | 糖苷酶抑制剂 |
US11046712B2 (en) | 2014-08-28 | 2021-06-29 | Asceneuron Sa | Glycosidase inhibitors |
CN107108601B (zh) * | 2014-08-28 | 2021-08-20 | 阿森纽荣股份公司 | 糖苷酶抑制剂 |
CN109071526A (zh) * | 2016-02-25 | 2018-12-21 | 阿森纽荣股份公司 | 哌嗪衍生物的酸加成盐 |
US10995090B2 (en) | 2016-02-25 | 2021-05-04 | Asceneuron Sa | Substituted dihydrobenzofuran glycosidase inhibitors |
US11261183B2 (en) | 2016-02-25 | 2022-03-01 | Asceneuron Sa | Sulfoximine glycosidase inhibitors |
CN109071526B (zh) * | 2016-02-25 | 2023-02-28 | 阿森纽荣股份公司 | 哌嗪衍生物的酸加成盐 |
US11612599B2 (en) | 2016-02-25 | 2023-03-28 | Asceneuron Sa | Glycosidase inhibitors |
US11213525B2 (en) | 2017-08-24 | 2022-01-04 | Asceneuron Sa | Linear glycosidase inhibitors |
US11731972B2 (en) | 2018-08-22 | 2023-08-22 | Asceneuron Sa | Spiro compounds as glycosidase inhibitors |
US11795165B2 (en) | 2018-08-22 | 2023-10-24 | Asceneuron Sa | Tetrahydro-benzoazepine glycosidase inhibitors |
US12016852B2 (en) | 2018-08-22 | 2024-06-25 | Asceneuron Sa | Pyrrolidine glycosidase inhibitors |
Also Published As
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JPWO2004103992A1 (ja) | 2006-07-20 |
AU2004241213B2 (en) | 2009-04-23 |
US20060287340A1 (en) | 2006-12-21 |
JP4552854B2 (ja) | 2010-09-29 |
CA2526374A1 (en) | 2004-12-02 |
US7485647B2 (en) | 2009-02-03 |
EP1630162A1 (en) | 2006-03-01 |
WO2004103992A1 (ja) | 2004-12-02 |
CN100448870C (zh) | 2009-01-07 |
EP1630162A4 (en) | 2010-06-09 |
AU2004241213A1 (en) | 2004-12-02 |
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