CN1196671C - 单和双取代的3-丙基-γ-氨基丁酸 - Google Patents
单和双取代的3-丙基-γ-氨基丁酸 Download PDFInfo
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- CN1196671C CN1196671C CNB00808730XA CN00808730A CN1196671C CN 1196671 C CN1196671 C CN 1196671C CN B00808730X A CNB00808730X A CN B00808730XA CN 00808730 A CN00808730 A CN 00808730A CN 1196671 C CN1196671 C CN 1196671C
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- Prior art keywords
- methyl
- aminomethyl
- acid
- hexanoic acid
- compound
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- SIRQBZJUYVPMIC-UHFFFAOYSA-N 3-(aminomethyl)-5-methylheptanoic acid Chemical compound CCC(C)CC(CN)CC(O)=O SIRQBZJUYVPMIC-UHFFFAOYSA-N 0.000 claims description 15
- 208000014674 injury Diseases 0.000 claims description 14
- KKXFMWXZXDUYBF-UHFFFAOYSA-N 3-(aminomethyl)-5-methyloctanoic acid Chemical compound CCCC(C)CC(CN)CC(O)=O KKXFMWXZXDUYBF-UHFFFAOYSA-N 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
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- SIRQBZJUYVPMIC-SFYZADRCSA-N (3s,5r)-3-(aminomethyl)-5-methylheptanoic acid Chemical compound CC[C@@H](C)C[C@H](CN)CC(O)=O SIRQBZJUYVPMIC-SFYZADRCSA-N 0.000 claims description 9
- JETOEPZFEWLXBK-MNOVXSKESA-N (3s,5r)-3-(aminomethyl)-5-methyldecanoic acid Chemical compound CCCCC[C@@H](C)C[C@H](CN)CC(O)=O JETOEPZFEWLXBK-MNOVXSKESA-N 0.000 claims description 7
- KUSIIZRBOLFILF-UHFFFAOYSA-N 3-(aminomethyl)-5-methylnonanoic acid Chemical compound CCCCC(C)CC(CN)CC(O)=O KUSIIZRBOLFILF-UHFFFAOYSA-N 0.000 claims description 5
- HLRPRVFNTZZSHY-UHFFFAOYSA-N 3-(aminomethyl)-5-methylundecanoic acid Chemical compound CCCCCCC(C)CC(CN)CC(O)=O HLRPRVFNTZZSHY-UHFFFAOYSA-N 0.000 claims description 5
- KUSIIZRBOLFILF-ZJUUUORDSA-N (3s,5r)-3-(aminomethyl)-5-methylnonanoic acid Chemical compound CCCC[C@@H](C)C[C@H](CN)CC(O)=O KUSIIZRBOLFILF-ZJUUUORDSA-N 0.000 claims description 4
- KKXFMWXZXDUYBF-BDAKNGLRSA-N (3s,5r)-3-(aminomethyl)-5-methyloctanoic acid Chemical compound CCC[C@@H](C)C[C@H](CN)CC(O)=O KKXFMWXZXDUYBF-BDAKNGLRSA-N 0.000 claims description 4
- JETOEPZFEWLXBK-UHFFFAOYSA-N 3-(aminomethyl)-5-methyldecanoic acid Chemical compound CCCCCC(C)CC(CN)CC(O)=O JETOEPZFEWLXBK-UHFFFAOYSA-N 0.000 claims description 4
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- IASDTUBNBCYCJG-YUMQZZPRSA-N (3r,4s)-3-(azaniumylmethyl)-4,5-dimethylhexanoate Chemical compound CC(C)[C@H](C)[C@H](CN)CC(O)=O IASDTUBNBCYCJG-YUMQZZPRSA-N 0.000 description 17
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- YJIQCMGSESZZHA-ROUUACIJSA-N tert-butyl (3s,5s)-5-methyl-3-[(4-methylphenyl)sulfonyloxymethyl]octanoate Chemical compound CCC[C@H](C)C[C@@H](CC(=O)OC(C)(C)C)COS(=O)(=O)C1=CC=C(C)C=C1 YJIQCMGSESZZHA-ROUUACIJSA-N 0.000 description 1
- GSRQMHFGGNGJCU-JROBLHLSSA-N tert-butyl (3s,5s)-5-methyl-3-[(4r,5s)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidine-3-carbonyl]decanoate Chemical compound O1C(=O)N(C(=O)[C@H](CC(=O)OC(C)(C)C)C[C@@H](C)CCCCC)[C@H](C)[C@@H]1C1=CC=CC=C1 GSRQMHFGGNGJCU-JROBLHLSSA-N 0.000 description 1
- GSRYOMXTHAIEMA-WBQJQJEBSA-N tert-butyl (3s,5s)-5-methyl-3-[(4r,5s)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidine-3-carbonyl]heptanoate Chemical compound O1C(=O)N(C(=O)[C@H](CC(=O)OC(C)(C)C)C[C@@H](C)CC)[C@H](C)[C@@H]1C1=CC=CC=C1 GSRYOMXTHAIEMA-WBQJQJEBSA-N 0.000 description 1
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Abstract
本发明为式I的一系列新的单和双取代的3-丙基γ氨基丁酸。该化合物用作治疗癫痫症、晕厥发作、运动机能减退、颅病症、神经变性病症、抑郁、焦虑、恐慌、疼痛、神经病理学病症、关节炎、睡眠障碍、IBS、和胃损伤的治疗剂。制备该化合物和有用中间产物的方法也是本发明的部分。
Description
发明背景
在美国专利号4,024,175及其分案美国专利号中已知下式的化合物:
其中,R1为氢或低级烷基而n为4、5或6。其用途公开如下:对氨基硫脲诱发的痛性痉挛的预防作用;对卡地阿唑痛性痉挛的预防作用;脑病、癫痫症晕厥发作、运动机能减退和颅的损伤;和改善大脑功能。该化合物用于老年病患者。本文引用该专利作为参考。
在美国专利号5,563,175和它的各分案中已知下式的化合物
或其药学上可接受的盐,其中R1为具有1-6个碳原子的直链或支链烷基、苯基或具有3-6个碳原子的环烷基;R2为氢或甲基;而R3为氢或羧基。据此引用这些专利作为参考。
发明概述
式I的化合物
或其药学上可接受的盐,其中:
R1为氢、1-6个碳原子的直链或支链烷基或苯基;
R2为1-8个碳原子的直链或支链烷基、2-8个碳原子的直链或支链链烯基、3-7个碳原子的环烷基、1-6个碳原子的烷氧基、-烷基环烷基、-烷基烷氧基、-烷基OH、-烷基苯基、-烷基苯氧基、-苯基或取代的苯基;和
当R2为甲基时,R1为1-6个碳原子的直链或支链烷基或苯基。
在优选的式I的化合物中,R1为氢而R2为烷基。
在其它优选的式I的化合物中,R1为甲基而R2为烷基。
在其它优选的式I的化合物中,R1为甲基而R2为甲基或乙基。
特别优选的化合物选自:
3-氨基甲基-5-甲基-庚酸;
3-氨基甲基-5-甲基-辛酸;
3-氨基甲基-5-甲基-壬酸;
3-氨基甲基-5-甲基-癸酸;
3-氨基甲基-5-甲基-十一酸;
3-氨基甲基-5-甲基-月桂酸;
3-氨基甲基-5-甲基-十三酸;
3-氨基甲基-5-环丙基-己酸;3-氨基甲基-5-环丁基-己酸;
3-氨基甲基-5-环戊基-己酸;3-氨基甲基-5-环己基-己酸;
3-氨基甲基-5-三氟甲基-己酸;
3-氨基甲基-5-苯基-己酸;
3-氨基甲基-5-(2-氯苯基)-己酸;
3-氨基甲基-5-(3-氯苯基)-己酸;
3-氨基甲基-5-(4-氯苯基)-己酸;
3-氨基甲基-5-(2-甲氧基苯基)-己酸;
3-氨基甲基-5-(3-甲氧基苯基)-己酸;
3-氨基甲基-5-(4-甲氧基苯基)-己酸;和
3-氨基甲基-5-(苯基甲基)-己酸。
其它特别优选的化合物选自:
(3R,4S)-3-氨基甲基-4,5-二甲基-己酸;
3-氨基甲基-4,5-二甲基-己酸;
(3R,4S)-3-氨基甲基-4,5-二甲基-己酸MP;
(3S,4S)-3-氨基甲基-4,5-二甲基-己酸;
(3R,4R)-3-氨基甲基-4,5-二甲基-己酸MP;
3-氨基甲基-4-异丙基-己酸;
3-氨基甲基-4-异丙基-庚酸;
3-氨基甲基-4-异丙基-辛酸;
3-氨基甲基-4-异丙基-壬酸;
3-氨基甲基-4-异丙基-癸酸;和
3-氨基甲基-4-苯基-5-甲基-己酸。
其它优选的化合物选自
(3S,5S)-3-氨基甲基-5-甲氧基-己酸;
(3S,5S)-3-氨基甲基-5-乙氧基-己酸;
(3S,5S)-3-氨基甲基-5-丙氧基-己酸;
(3S,5S)-3-氨基甲基-5-异丙氧基-己酸;
(3S,5S)-3-氨基甲基-5-叔丁氧基-己酸;
(3S,5S)-3-氨基甲基-5-氟甲氧基-己酸;
(3S,5S)-3-氨基甲基-5-(2-氟-乙氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3,3,3-三氟-丙氧基)-己酸;
(3S,5S)-3-氨基甲基-5-苯氧基-己酸;
(3S,5S)-3-氨基甲基-5-(4-氯-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3-氯-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(2-氯-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(4-氟-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3-氟-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(2-氟-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(4-甲氧基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3-甲氧基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(2-甲氧基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(4-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(2-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-6-羟基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-甲氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-乙氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-丙氧基-己酸;
(3S,5S)-3-氨基甲基-6-异丙氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-叔丁氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-氟甲氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氟-乙氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(3,3,3-三氟-丙氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-苯氧基-己酸;
(3S,5S)-3-氨基甲基-6-(4-氯-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-氯-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氯-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(4-氟-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-氟-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氟-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(4-甲氧基-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-甲氧基-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-甲氧基-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(4-三氟甲基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(3-三氟甲基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基6-(2-三氟甲基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(4-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(3-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(2-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-6-苄氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-7-羟基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-甲氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-乙氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-丙氧基-庚酸;
(3S,5S)-3-氨基甲基-7-异丙氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-叔丁氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-氟甲氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(2-氟-乙氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(3,3,3-三氟-丙氧基)-庚酸;
(3S,5S)-3-氨基甲基-7-苄氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-苯氧基-庚酸;
(3S,5S)-3-氨基甲基-7-(4-氯-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(3-氯-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(2-氯-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(4-氟-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(3-氟-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(2-氟-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(4-甲氧基-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(3-甲氧基-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(2-甲氧基-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(4-三氟甲基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(3-三氟甲基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(2-三氟甲基-苯氧基)庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(4-硝基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(3-硝基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(2-硝基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-6-苯基-己酸;
(3S,5S)-3-氨基甲基-6-(4-氯-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-氯-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氯-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(4-甲氧基-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-甲氧基-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-甲氧基-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(4-氟-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-氟-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氟-苯基)-5-甲基-己酸;
(3S,5R)-3-氨基甲基-5-甲基-7-苯基-庚酸;
(3S,5R)-3-氨基甲基-7-(4-氯-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(3-氯-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(2-氯-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(4-甲氧基-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(3-甲氧基-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(2-甲氧基-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(4-氟-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(3-氟-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(2-氟-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-5-甲基-辛-7-烯酸;
(3S,5R)-3-氨基甲基-5-甲基-壬-8-烯酸;
(E)-(3S,5S)-3-氨基甲基-5-甲基-辛-6-烯酸;
(Z)-(3S,5S)-3-氨基甲基-5-甲基-辛-6-烯酸;
(Z)-(3S,5S)-3-氨基甲基-5-甲基-壬-6-烯酸;
(E)-(3S,5S)-3-氨基甲基-5-甲基-壬-6-烯酸;
(E)-(3S,5R)-3-氨基甲基-5-甲基-壬-7-烯酸;
(Z)-(3S,5R)-3-氨基甲基-5-甲基-壬-7-烯酸;
(Z)-(3S,5R)-3-氨基甲基-5-甲基-癸-7-烯酸;
(E)-(3S,5R)-3-氨基甲基-5-甲基-十一碳-7-烯酸;
(3S,5S)-3-氨基甲基-5,6,6-三甲基-庚酸;
(3S,5S)-3-氨基甲基-5,6-二甲基-庚酸;
(3S,5S)-3-氨基甲基-5-环丙基-己酸;
(3S,5S)-3-氨基甲基-5-环丁基-己酸;
(3S,5S)-3-氨基甲基-5-环戊基-己酸;和
(3S,5S)-3-氨基甲基-5-环己基-己酸。
进一步的其它更为优选的化合物为:
(3S,5R)-3-氨基甲基-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-5-甲基-壬酸;
(3S,5R)-3-氨基甲基-5-甲基-癸酸;
(3S,5R)-3-氨基甲基-5-甲基-十一酸;
(3S,5R)-3-氨基甲基-5-甲基-月桂酸;
(3S,5R)-3-氨基甲基-5,9-二甲基-癸酸;
(3S,5R)-3-氨基甲基-5,7-二甲基-辛酸;
(3S,5R)-3-氨基甲基-5,8-二甲基-壬酸;
(3S,5R)-3-氨基甲基-6-环丙基-5-甲基-己酸;
(3S,5R)-3-氨基甲基-6-环丁基-5-甲基-己酸;
(3S,5R)-3-氨基甲基-6-环戊基-5-甲基-己酸;
(3S,5R)-3-氨基甲基-6-环己基-5-甲基-己酸;
(3S,5R)-3-氨基甲基-7-环丙基-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-环丁基-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-环戊基-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-环己基-5-甲基-庚酸;
(3S,SR)-3-氨基甲基-8-环丙基-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-8-环丁基-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-8-环戊基-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-8-环己基-5-甲基-辛酸;
(3S,5S)-3-氨基甲基-6-氟-5-甲基-己酸;
(3S,5S)-3-氨基甲基-7-氟-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-8-氟-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-9-氟-5-甲基-壬酸;
(3S,5S)-3-氨基甲基-7,7,7-三氟-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-8,8,8-三氟-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-5-甲基-8-苯基-辛酸;
(3S,5S)-3-氨基甲基-5-甲基-6-苯基-己酸;和
(3S,5R)-3-氨基甲基-5-甲基-7-苯基-庚酸。
本发明还为包括治疗有效量的一或多种式I的化合物和药学可接受的载体的药物组合物。
本发明化合物用于治疗癫痫症、晕厥发作、运动机能减退、颅病症、神经变性病症、抑郁、焦虑、恐慌、疼痛、神经病理学病症、关节炎、睡眠障碍、过敏性肠综合症(IBS)和胃损伤。
发明详述
本发明的化合物为以上式I所示的单和双取代的3-丙基γ-氨基丁酸。
术语如以下所述或者它们出现在说明书中。
术语烷基或链烯基为具有1-8个碳原子的直链或支链,包括但不限于甲基、乙基、丙基、正丙基、异丙基、丁基、2-丁基、叔丁基和辛基。烷基可以是未被取代的或被1-3个氟原子取代。优选的基团为甲基和乙基。
环烷基为具有3-7个碳原子的环基。
苄基和苯基可以未被取代的或被1-3个各自独立地选自卤素,特别是氟、烷氧基、烷基和氨基的基团取代。
卤素包括氟、氯、溴和碘。
烷氧基为如以上关于烷基所述。
由于氨基酸为两性,因此当R为氢时,药理学相容盐可以是适当的无机或有机酸如盐酸、硫酸、磷酸、乙酸、草酸、乳酸、柠檬酸、苹果酸、水杨酸、丙二酸、马来酸、琥珀酸和抗坏血酸的盐。碱金属或碱土金属如钠、钾、镁或钙的盐的形成起始于对应的氢氧化物或碳酸盐。还可以用四甲基铵离子制备季铵离子盐。
化合物I-VIII的前体药物包括在本发明的范围内。氨基酰基-乙醇酸和-乳酸酯为已知的氨基酸前体药物(Wermuth C.G.,化学和工业(Chemistry and Industry),1980:433-435)。可以通过已知的方法将氨基酸的羰基酯化。前体药物和软药物在现在技术中是已知的(Palomino E.,未来的药物(Drugs of the Future),1990;15(4):361368)。据些引用上两篇引文作为参考。
口服药物的有效性取决于药物有效地转运穿过粘膜上皮和其在肠肝循环中的稳定性。在肠道外给药有效但口服效果较低或被认为血浆半衰期太短的药物可以被化学修饰成前体药物的形式。
前体药物是已被化学修饰的药物,它在作用部位可能无生物活性,但可以被一或多种酶或者其他体过过程降解或修饰成母生物活性形式。
这种化学修饰的药物或前体药物应该具有与其母形式不同的药代动力学曲线,从而使其更易于吸收通过粘膜上皮,更好地形成盐和/溶解,改进系统稳定性(例如增大血浆半衰期)。这些化学修饰可以是:
1)可被酯酶或脂肪酶分解的酯或酰胺衍生物。对于酯衍生物,可通过已知方法从该药物分子的羧酸部分得到酯。对于酰胺衍生物,可通过已知方法从该药物分子的羧酸部分和胺部分得到酰胺。
2)可被特异性或非特异性蛋白酶识别的肽。肽可以通过已知方法与药物分子的胺或羧酸部分形成酰胺键而结合到药物分子上。
3)通过膜选择前体药物形式或修饰的前体药物形式而在作用部位蓄积的衍生物。
4)1-3的任意组合。
目前的动物实验研究已表明通过制备“软”季盐可以增加某些药物的口服吸收度。将季盐称为“软”季盐是因为它与常规的季盐如R-N+(CH3)3不同,可以在水解时释放出活性药物。
与基本药物或其盐相比,“软”季盐具有有用的物理性质。其水溶性相比于其它盐如盐酸盐得到增大,但更为重要的是它们可以增大药物的肠吸收。增加吸收可能是因为“软”季盐具有表面活性剂性性质并能与胆酸等形成微团和未离子化的离子对,从而能穿透肠上皮释放出活性母体药物。
本发明的某些化合物可以未溶剂化形式和溶剂化形式包括水合形式存在。一般而言,包括水合形式的溶剂化形式等同于未溶剂化形式,并被认为包含在本发明的范围内。
本发明的化合物包括所有的对映异构体和差向异构体形式以及其适宜的混合物。例如,实施例1的化合物为所有四种可能立体异构体的混合物。实施例6的化合物为异构体的一种。在可以形成某种构型的这些化合物中,环己烷环碳中心的构型可以是R或S。
采用来自猪脑组织的[3H]加巴喷丁和α2δ亚基的放射配基结合测定(Gee N.S.,Brown J.P.,Dissanayake V.U.K.,Offord J.,ThurlowR.,Woodruff G.N.,″新的抗惊厥药,加巴喷丁,结合到钙通道的α2δ亚基,″生物化学杂志(J.Biol.Chem.),1996;271:5879-5776)。
表1
结构 [3H]GBP 抗惊厥剂
结合 %保护
(IC50,nM) 1hr 2hr
0.218 100
1.8 0 0
0.04 80 100
0.206 0 20
0.092 60 100
以上的表1显示了现有技术中以及本发明化合物对α2δ亚基的结合亲合力的比较。
比较本发明的化合物与Neurontin,一种有效治疗诸如癫痫症等疾病的上市药物。Neurontin为以下结构式的1-(氨基甲基)-环己烷乙酸。
在该测定中加巴喷丁(Neurontin)约为0.10-0.12μM。因此预期本发明化合物表现出与加巴喷丁相当或更好的药理学性质,例如作为惊厥、焦虑和疼痛的药剂。
本发明涉及一模拟化合物作为神经变性病症药剂的医疗用途。这种神经变性病症如阿耳茨海默氏病、杭廷顿氏舞蹈病、帕金森氏病和肌萎缩性侧索硬化症。
本发明还涉及治疗称为急性脑损伤的神经变性病症。它们包括但不限于:中风、头外伤和窒息。
中风指小脑血管疾病,还指小脑血管事故(CVA),包括急性血栓栓塞中风。中风包括病灶和普遍局部缺血。还包括瞬间小脑局部缺血发作和其它伴有小脑局部缺血的小脑血管问题。接受特定的颈动脉动脉内膜切除术或其它脑血管或一般血管外科操作,或者包括小脑血管造影术等的诊断血管步骤的患者。
其它的事故为头外伤、脊柱和索外伤,或者由于一般性缺氧损伤、低氧症、低血糖、低血压和类似的在关节复位、超融合术和低氧症的过程中可见的损伤。
本发明可用于一定范围的事故,例如在心脏旁路外科手术过程中,在颅内出血事故中,在产期窒息中,在心脏停止和癫痫持续状态中。
疼痛指急性和慢性疼痛。
急性疼痛通常短期存在并与交感神经系统的机能亢进有关。实例为术后疼痛和异常性疼痛。
通常将慢性疼痛定义为持续3-6个月的疼痛,它包括体因性疼痛和精神性疼痛。其它的疼痛为感受损伤。
其它的疼痛为由损伤或外周感觉神感染而导致的。它包括但不限于外周神经外伤疼痛、疱疹病毒感染、糖尿病、灼痛、帕尼扎氏丛抽出术、神经瘤、截肢和结节性脉管炎。神经病性疼痛还由慢性酒精中毒引起的神经损伤、人类免疫缺陷病毒感染、甲状腺功能减退、尿毒症或维生素缺乏导致。神经病疼痛包括但不限于由于外伤引起的疼痛,如糖尿病疼痛。
精神性疼痛的出现没有器官来源,如下背疼痛、非典型表面疼痛和慢性头痛。
其它类型的疼痛为:炎性疼痛、骨关节炎疼痛、三叉神经痛、癌痛、糖尿病性神经病、不安腿综合症、急性疱疹和带状疱疹神经痛、灼痛、臂丛抽出术、枕骨神经痛、痛风、幻肢、烧伤和其它形式的神经痛、神经病性和自发性疼痛综合症。
熟练的内科医生能够测定受试者易感或有危险的中风和中风疼痛的确切情况,以通过本发明方法进行给药。
本发明化合物还预期用于治疗抑郁。抑郁可以是与个人损失有关的压力继发的器官疾病的结果,或者自发性发生。某些形式的抑郁存在家族事件的趋势表明至少某些形式的抑郁的机械原因。抑郁的诊断主要通过量化患者心情的变化。一般通过内科医师进行心情评估或通过神经心理学医生采用验证的评价量度如Hamilton抑郁评价量度(HamiltonRating Scale)或Brief精神病学评价量度(Brief PsychiatricRating Scale)来量化。已提出其它多种量度以量化和测定抑郁患者心情变化的程度,如失眠症、精神难以集中、缺乏活力、没劲和罪过的感觉。在1994年由美国精神病学协会(the American PsychiatricAssociation)出版的被指定为DSM-IV-R手册的《精神异常诊断和统计手册》(the Diagnostic and Statistical Manual of MentalDisorders)(第四版)中收集了抑郁的诊断和所有精神病学诊断标准。
GABA为中枢神经系统的抑制性神经递质。在一般的抑制作用的含义中,似乎可能GABA-模拟物可能降低或抑制小脑功能并可能因而减缓机能和减少心境,其导致抑郁。
本发明的化合物可以通过增加突触接点的新生GABA而产生抗惊厥作用。如果加巴喷丁的确增加突触接点的GABA的水平或GABA的效力,则可以将它归为GABA-模拟物并可能降低或抑制小脑功能,因而可能减缓机能并减少心情,其导致抑郁。
与目前GABA活性的主流观点不同,GABA激动剂或GABA-模拟物可能恰恰以相反的方式通过提高心境而是抗抑郁剂的事实已成为一个新概念。
通过标准的药理学方法证明本发明化合物还预期用于治疗焦虑和恐慌。
本发明的化合物还预期用于治疗睡眠障碍。睡眠障碍是影响入睡和沉睡能力的障碍,它极大地影响了睡眠或导致与睡眠有关的异常行为。这些异常包括如失眠症、与药物有关的失眠、睡眠过度、嗜眠发作、睡眠呼吸暂停综合症和深眠状态。
本发明的化合物还用于治疗关节炎。
生物学活性
表2
实施例 [3H]Gbp结合 抗焦虑活性* 抗惊厥
(IC50,μM) %Preg.活性 %保护*
1h 2h
Pregabali 0.218 100 100
(3S,4R)3-氨基甲基-4,5-二甲基-己酸 2.2 12 20 20
(3R,4S)3-氨基甲基-4,5-二甲基-己 1.7 58 20 0
酸
(3R,4R)3-氨基甲基-4,5-二甲基-己 0.022 204 100 100
酸
3-氨基甲基-5-甲基庚 0.092 79 60 100
3-氨基甲基-5-甲基辛酸 0.019 NT 40 100
3-氨基甲基-5-甲基癸 0.150 NT 0 0
3-氨基甲基-5-甲基壬酸 0.178 NT 40 80
3-氨基甲基-5-甲基十一酸 0.163 NT NT
(3S,5R)-3-氨基甲基-5-甲基-庚酸 在测试 在测试 80 100
表2(续)
实施例 [3H]Gbp结合 抗焦虑活性* 抗惊厥
(IC50,μM) %Preg.活性 %保护*
1h 2h
(3S,5R)-3-氨基甲基-5-甲基-辛 0.012 160 100 100
酸盐酸盐
(3S,5R)-3-氨基甲基-5-甲基-壬 0.026 125.94 100 100
酸盐酸盐
(3S,5R)-3-氨基甲基-5-甲基-癸 0.0297 105.59 100 100
酸
(3S,5S)-3-氨基甲基-5-甲基-庚 在测试 在测试 0 0
酸
(3S,5S)-3-氨基甲基-5-甲基-辛 1.2 15.6 0 20
酸
(3S,5S)-3-氨基甲基-5-甲基-壬 在测试 在测试 0 0
酸
3-氨基甲基-5-甲基-6-苯基己酸 9.08 NT 0 0
3-氨基甲基-5,7,7-三甲基-辛酸 >10 NT NT
(S)-3-氨基甲基-5-甲基-辛酸 0.0126 135.38 100 100
3-氨基甲基-5,7-二甲基-辛酸 0.359 NT NT
表2(续)
实施例 [3H]Gbp结合 抗焦虑活性* 抗惊厥
(IC50,μM) %Preg.活性 %保护*
1h 2h
3-氨基甲基-6,6,6-三氟-5-甲基 4.69 NT 0 0
己酸
3-氨基甲基-5-甲基-辛-7-烯酸 >10 NT 0 0
(S)-3-氨基甲基-6-甲氧基-5-甲 在测试 在测试 0 0
基己酸
3-氨基甲基-4-异丙基-庚酸 0.671 NT NT
3-氨基甲基-4-异丙基-辛酸 5.4 NT 0 0
3-氨基甲基-4-异丙基-己酸 0.49 NT 0 0
3-氨基甲基-5-甲基-4-苯基己酸 NT 0 0
(S)-3-氨基甲基-6-氟-5-甲基己 0.605 NT NT
酸
3-氨基甲基-5-环己基-己酸 7.3 NT NT
表2(续)
实施例 [3H]Gbp结合 抗焦虑活性* 抗惊厥
(IC50,μM) %Preg.活性 %保护*
1h 2h
3-氨基甲基-5-环戊基-己酸 >10
3-氨基甲基-5-苯基-己酸 10.1 NT NT
(3S,5S)-3-氨基甲基-5-甲基- 在测试 在测试 0 20
癸酸
*剂量为30mg/kg PO化合物
NT未测试。
如以上的表2所示,本发明的化合物用作抗焦虑剂和抗惊厥剂。将它们与pregabalin比较,pregabalin为以下式的异丁基γ氨基丁酸或(S)-3-(氨基甲基)-5-甲基己酸。
材料和方法
角叉菜胶诱发的痛觉过敏
在鼠爪试验中,采用测痛仪(analgesimeter)(Randall-Selittomethod:Randall L.O.和Selitto J.J.,″在炎性组织中沉淀止痛活性的方法,″国际药效学通讯(Arch.Int.Pharmacodyn.),1957;4:409-419)测定损伤压力阈值。在试验日前在该仪器上训练雄性Sprague-Dawley大鼠。慢慢地往各大鼠的后爪加压并测定损伤压力阈值为引起缩爪所需的压力(g)。采用250g的截止点防止对爪的任何组织损伤。在试验日,进行两至三次基线测定,然后通过胸膜腔注射100μl 20%角叉菜胶至右后爪而对动物给药。在角叉菜胶实现动物表现出痛觉过敏的3小时后再次测定损伤阈值。在角叉菜胶后用加巴喷丁(3-300mg,s.c.)、吗啡(3mg/kg,s.c.)或盐水对动物给药,并在角叉菜胶后的4、4.5和5小时检查损伤阈值。
在以上角叉菜胶诱发的痛觉过敏模型中测试(R)-2-氮杂-螺[4.5]癸烷-4-羧酸盐酸盐。该化合物的口服剂量为30mg/kg,而在给药1小进后获得53%的最大可能作用(MPE)百分率。在给药2小时后,仅获得4.6%MPE。
氨基脲诱发的强直性发作
通过皮下给予氨基脲(750mg/kg)而诱发小鼠强直性发作。注意到前爪强直性拉伸的潜伏期。考虑对任何在氨基脲后2小时内不惊厥的小鼠是被保护的,并得到最大潜伏期分值为120分钟。
动物
从Interfauna(Huntingdon,UK)获得雄性Hooded Lister大鼠(200-250g),从Bantin和Kingman(Hull,UK)获得雄性TO小鼠(20-25g)。将两啮齿动物种分六组饲养。在将曼彻斯特大学药学院(Manchester University Medical School)(Manchester,UK)饲养的10只重量为280-360g的普通狨(Callithrix Jacchus)成对饲养。在12-小时亮/暗循环(在07.00钟天亮)下饲养所有的动物并用水和随意喂养。
给药
在试验前40分钟以1mL/kg的体积对大鼠和狨和10ml/kg对小鼠腹膜内(IP)或皮下(SC)给药。
小鼠亮/暗箱
该容器为顶部开口箱,长45cm,宽27cm,高27cm,通过伸到壁上方20cm的隔断将其分为一个小的(2/5)和1个大的(3/5)区域(Costall B.,等人,″在暗和亮箱中研究小鼠:确认为焦虑模型,″药理生化行为(Pharmacol.Biochem.Behav.),1989;32:777-785)。
在底部平面的隔断中心处有一个7.5×7.5cm的开口。小隔室着黑色而大隔室着白色。用60-W钨灯泡迷照射该白隔室。实验室用红光照射。各小鼠的试验通过将其放置在白色区域的中间并使其暴露于新环境中5分钟。测定在照明侧所用时间(Kilfoil T.,等人,″抗焦虑和致焦虑药物对简单的小鼠焦虑模型中研究的活性的作用,″神经药理学(Neuropharmacol.),1989;28:901-905)。
大鼠高级X-迷宫
按前述(Field,等人,″测试焦虑的大鼠高级X迷宫的自动化,″Br.J.Pharmacol.,1991;102(Suppl.):304P)已将标准高级X-迷路(Handley S.L.,等人,″α-肾上腺能受体激动剂和拮抗剂在“吓”引发的行为的迷宫-研究模型中的作用,″Naunyn-Schiedeberg’s Arch.Pharmacol.,1984;327:1-5)自动化。将动物置于X-迷路的中间面对一个开口臂。为了测定抗焦虑效果,在5分钟的试验期内测定进入和在开口臂的后半段上所用的时间(Costall,等人,″用高级+迷宫评价大鼠中的抗焦虑潜能,″Br.J.Pharmacol.,1989;96(Suppl.):312p)。
狨人恐吓试验
在2分钟的试验期记录动物对恐吓刺激(人站在大约距狨笼0.5m远并瞪着狨眼)表现出的体恣的总数。体恣打分为眯噔眼、尾姿、笼/栖所的气味标记、毛竖起、后退和背成弓状。在试验日在药物治疗之前和之后使每一动物接触恐吓刺激两次。采用单向方差分析分析两个得分之间的差异,然后进行Dunnett’s t-检验。所有的药物治疗至少在第一次(对照)恐吓的2小时后以SC进行。每一化合物的预治疗时间为40分钟。
大鼠冲突试验
在操作室内训练大鼠压杠杆以获得食物奖赏。时间表由交替的可变间期为30秒而信号为打开室内光线的不受惩罚的4分钟和固定比率为5(与取食伴随的足颤)而信号为关闭室内光线的受惩罚的3分钟组成。将每只大鼠的足颤程度调节至与不受处罚的反应相比获得大约80%-90%的反应抑制。在训练日大鼠接受盐水赋形剂。
DBA2小鼠抗惊厥效力模型
所有过程根据Parke-Davis动物应用委员会批准的协议下的实验动物的护理和应用NIH指南(NIH Guide for the Care and Use ofLaboratory Animals)进行。从Jackson实验室,Bar Harbour,缅因州获得雌性3-4周龄的DBA/2小鼠。将小鼠置于4平方英寸的悬挂在钢杆的丝网上,然后立即进行抗惊厥试验。将平面缓慢反转180并观察小鼠30秒。将任何从丝网上掉下的小鼠记为运动失调(Coughenour L.L.,McLean J.R.,Parker R.B.,″一种新型的快速测量小鼠损伤的运动功能的装置,″Pharm.Biochem.Behav.,1977;6(3):351-3)。将小鼠放置于在顶盖中间有一个高频扬声器(4cm直径)的封闭丙烯酸塑料室内(高21cm,直径约30cm)。用声频信号发生器(Protek型B-810)产生持续的在8kHz和16kHz之间每10毫秒振荡一次的正弦曲线音调。在刺激期间室底的平均声压水平(SPL)大约为100dB。将小鼠置于室内并使其适应数分钟。赋形剂治疗组的DBA/2小鼠对声音刺激(应用直至强直性拉伸发生或最多60秒)的反应具有特征性的惊厥发作顺序,它由猛烈地奔跑、随后的慢性惊厥发作,接着的强直性拉伸和最后的呼吸停止和80%或更多的小鼠死亡组成。在赋形剂治疗小鼠中,惊厥发作到呼吸停止的整个顺序持续大约15-20秒。记录药物治疗和赋形剂治疗小鼠的所有惊厥发作期的发生,强直性惊厥发作的发生用于通过机率单位分析计算抗惊厥ED50值(Litchfield J.T.,Wilcoxon F.″评价剂量-效应实验的简单方法,″J.Pharmacol.,1949;96:99-113)。在每个剂量点仅用小鼠试验一次。测试DBA/2小鼠(n=5-10每剂量)组在口部给药后小时(先前测定的最大效果时间)的声致惊厥发作反应。将该研究中的所有药物溶于蒸馏水中并通过口管饲法以10mL体积/kg体重给药。不溶的药物将悬浮在1%羧甲基纤维素。剂量表示为活性药物部分的重量。
本发明化合物还预期用于治疗疼痛和恐惧症(Am.J.Pain Manag,1995;5:7-9)。
本发明化合物还预期用于治疗躁狂综合症、急性或慢性、单向上部(single upside)或复发性抑郁。它们还预期用于治疗和/或预防双相性精神障碍(美国专利号5,510,381)。
本发明化合物还预期用于睡眠障碍。其评价如在药物研发(DrugDev Res)1988;14:151-159中所述。
可以制得本发明化合物并以宽泛的各种口服或肠道外剂型给药。因此本发明化合物可以通过注射即静脉内、肌内、皮内、皮下、十二指肠内或腹膜内给药。而且,本发明化合物可以通过吸入例如鼻内给药。此外,本发明化合物可以经眼给药。对本领域技术人员来说显然以下的剂型可以包括作为活性成分的式I的化合物或对应的式I化合物的药学上可接受的盐。
为了由本发明化合物制备药物组合物,药学上可接受的载体可以是固体或液体。固体形式的制剂包括散剂、片剂、丸剂、胶囊、扁囊剂、栓剂和可分散的颗粒。固体载体可以是一或多种还可用作稀释剂、调味剂、粘合剂、防腐剂、片剂崩解剂或成囊材料的物质。
在散剂中,该载体为细分的与细分的活性成分混合的固体。
在片剂中,活性成分以适当的比例与具有必要粘合性质的载体混合并被压制成预期的形状和大小。
散剂和片剂优选含有5或10到约70百分比的活性化合物。适宜的载体为碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、黄芪胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可油等等。术语″制剂″意指包括活性化合物和作为提供胶囊的载体的成囊材料的制剂,其中该具有或不具有其它载体的活性成分被载体包围,而该载体因此与它相关。类似地包括扁囊剂和锭剂。片剂、散剂、胶囊、丸剂、扁囊剂和锭剂可以用作适于口服的剂型。
为了制备栓剂,首先将低熔点蜡如脂肪酸甘油酯或可可油的混合物熔解并通过搅拌将活性成分均匀地分散于其中。然后将熔解的均匀混合物倾入适宜大小的模具中,使其冷却并借此凝固。
液体形式的制剂包括溶液、悬浮液和乳剂如水或水丙二醇溶液。对于肠道外注射液体制剂,可以在含水聚乙二醇溶液中制备。
适于口用的水溶液的制备可以通过将活性成分溶于水,并加入期望的适宜着色剂、调味剂、稳定剂和增稠剂。
适于口用的含水悬液的制备可以通过采用粘性材料如天然或合成树胶、树脂、甲基纤维素、羧甲基纤维素钠和其它已知助悬剂将细分的活性成分分散在水中。
还包括固体形式的制剂,设计使其在使用前立即转化成液体形式的口服制剂。这种液体形式包括溶液、悬浮液和乳剂。除了该活性成分,这些制剂可以包含着色剂、调味剂、稳定剂、缓冲剂、人工和天然甜料、分散剂、增稠剂、稳定剂等等。
药学制剂优选单元剂型。在这些剂型中,将该制剂再分成含有适量的该活性成分的单元剂量。该单元剂型可以是包装制剂,该包装含有分散量的制剂如小包装的片剂、胶囊和装入小瓶或安瓿的散剂。而且,该单元剂型本身可以是胶囊、片剂、扁囊剂或锭剂,或者它可以是适量的这些包装形式的任一种。
单元剂量制剂中活性成分的数量可以根据特定的应用和活性成分的效力而在0.1mg-1g内变化或调节。在医药应用中,这种药物可以每天给药三次,如作为100或300mg的胶囊。如果需要,该组合物还可以含有其它相容的治疗剂。
在治疗应用中,在本发明药学方法中所用的该化合物的最初给药剂量约为每日0.01mg-100mg/kg。优选日剂量范围约为0.01mg-100mg/kg。但是该剂量的变化取决于患者的需要、治疗病症的严重性和所使用的化合物。为特定病症确定适宜剂量在本领域技术范围内。一般来说,最初用比化合物的最佳剂量小的较小剂量治疗。然后通过少量增加而增大剂量直至获得该情况下的最佳效果。为方便起见,如果需要可以将总日剂量分开并在当天分部分给药。
以下的实施例例举了本发明,但它们不是意图限定范围。
一般合成方案
一般性描述
方法1
a)LiAlH4;
b)重咯酸吡啶鎓;
c)膦酰基乙酸三乙酯,NaH;
d)硝基甲烷DBU;
e)i.H2Pd/C;ii.HCl;iii离子交换色谱法。
方法2
X=OEt或手性噁唑烷辅剂。
a)膦酰基乙酸三乙酯,NaH;
b)i.NaOH,ii.新戊酰氯,Et3N,XH;
c)R1MgBr,CuBr2 DMS;
d)NaHMDS,BrCH2CO2tBu;
e)R=tBu i.LiOH,H2O2;ii.BH3,iii.TsCl,Et3N,iv.NaN3,DMSO;
f)R=Et i.LiOH,H2O2;ii.BH3,iii.PTSA,THF;iv HBr EtOH,v.NaN3 DMSO;
g)i.H2Pd/C;ii.HCI,iii.离子交换色谱法.
具体实施例
合成实施例1:3-氨基甲基-5-甲基-庚酸
a)PDC,CH2Cl2;
b)NaH,膦酰基乙酸三乙酯;
c)DBU,CH3NO2;
d)H2,10% Pd/C;
e)6N HCl,回流,离子交换树脂(Dowex 50WX8,强酸性)。
3-甲基-1-戊醛11
将3-甲基-1-戊醇10(15g,146.79mmol)加到搅拌的处在500ml二氯甲烷中的重铬酸吡啶鎓(112.17g,298.1mmol)。搅拌2.5小时,然后400ml的醚,并继续搅拌另外5分钟。将混合物中的滤液浓缩至小体积并将其应用于Florisil柱。用石油醚洗脱该化合物,进一步用在石油醚中的10%的醚作为洗脱剂在硅胶柱上色谱分析得到11(6.5g,44%)。
1H-NMR(CDCl3)δ9.72,(d,-CHO),2.38(dd,1H,-CH2CHO),2.19(dd,1H,-CH2CHO),1.95(m,1H,C2H5(CH3)CHCH2-),1.4-1.0(m),0.9-0.8(m)。
5-甲基-2-庚烯酸乙酯12
用己烷洗涤氢化钠(60%分散,2.4g,65mmol)并将其悬浮在60mL二甲氧基乙烷中。在冰水浴上冷却,同时缓慢加入膦酰基乙酸三乙酯,计时5分钟。0℃下搅拌反应物15分钟并加入20ml处在二甲氧基乙烷中的3-甲基-1-戊醛11(6.5g,65mmol)溶液。回流过夜后,将其浓缩,加入水和己烷,分离有机相,并弃去含水部分。用盐水洗涤两次并在硫酸镁上干燥。蒸发溶剂得到12(6.75g,61%)。
1H-NMR(CDCl3)δ6.89(m,1H,-CH2CH:CHCOOEt),5.77(d,1H,-CH2CH:CHCOOEt),4.16(q,2H,-COOCH2CH3),2.15和1.98(各1H和一个多重峰;-CH2CH:CHCOOEt),1.48(m,1H,C2H5(CH3)CHCH2),1.30-1.10(m),和0.83。
5-甲基-3-硝基甲基庚酸乙酯13
室温下将处在80ml乙腈中的5-甲基-2-庚酸乙酯12(6.75g,39.70mmol)、DBU(6.0g,39.7mmol)、硝基甲烷(21.97g,359.9mmol)于氮气氛下搅拌过夜。将混合物浓缩成油。用1N的HCl、盐水洗涤在醚中的油溶液并干燥。将其蒸发得到轻油,在硅胶上色谱分析,用在石油醚中的5%-10%醚洗脱得到13(3.6g,42%)。
1H-NMR(CDCl3)δ4.49-4.39(m),4.12-4.07(m),3.61(m),2.36(m),1.36-1.18(m),0.86-0.79。
3-氨基甲基-5-甲基-庚酸(实施例1)
在乙醇中在20% Pd/C的存在下将5-甲基-3-硝基甲基庚酸乙酯13(3.6g)氢化,并蒸发得到14。加入六份30ml常规盐酸并回流过夜。减压蒸发溶剂,将残留物与甲苯共沸。将含水残留物溶液用于已被HPLC等级水洗至中性PH的Dowex 50WX 8-100离子交换树脂。用水洗脱柱直到洗脱剂为中性PH,然后用0.5N的NH4OH溶液洗脱得到含有3-氨基甲基-5-甲基-庚酸的部分。合并这些部分并进一步在C18柱上色谱分析。用在甲醇中的40%的水洗脱该化合物并从甲醇-醚中结晶得到630mg的实施例1。
1H-NMR(CD3OD)δ2.83(m,1H),2.75(m,1H),2.35(m,1H),2.15(m,1H),1.95(1H,bs),1.38(1H,m),1.3-1.15(m,2H),1.14-0.95(m,2H).0.80(m,2CH3)。MS发现在(M+1)174处的分子离子,在156、139和102处的其它离子,分析计算C9H19NO2:C,62.39;H 11.05;N 8.08。实测C,62.00;H,10.83;N,7.98。
可以类似的方法制备以下的实施例。
3-氨基甲基-5-甲基-庚酸;
3-氨基甲基-5-甲基-辛酸;
3-氨基甲基-5-甲基-壬酸;
3-氨基甲基-5-甲基-癸酸;
3-氨基甲基-5-甲基-十一酸;
3-氨基甲基-5-甲基-月桂酸;
3-氨基甲基-5-甲基-十三酸;
3-氨基甲基-5-环丙基-己酸;
3-氨基甲基-5-环丁基-己酸;
3-氨基甲基-5-环戊基-己酸;
3-氨基甲基-5-环己基-己酸;
3-氨基甲基-5-三氟甲基-己酸;
3-氨基甲基-5-苯基-己酸;
3-氨基甲基-5-(2-氯苯基)-己酸;
3-氨基甲基-5-(3-氯苯基)-己酸;
3-氨基甲基-5-(4-氯苯基)-己酸;
3-氨基甲基-5-(2-甲氧基苯基)-己酸;
3-氨基甲基-5-(3-甲氧基苯基)-己酸;
3-氨基甲基-5-(4-甲氧基苯基)-己酸;和
3-氨基甲基-5-(苯基甲基)-己酸。
合成实施例2:(3R,4S)3-氨基甲基-4,5-二甲基-己酸
实施例2
反应剂和条件:
a)(R)-(-)-4-苯基-2-噁唑烷酮,(CH3)3CCOCl,Et3N,LiCl,THF,-20到23℃;
b)MeMgCl,CuBrSMe2,THF,-35C;
c)NaHMDS,BrCH2CO2tBu,THF,-78℃到-40℃;
d)LiOH,H2O2,THF,H2O,25C;
e)BH3SMe2,THF,0到25℃;
f)pTsCl,吡啶,25C;
g)NaN3,DMSO,60C;
h)阮内镍,MeOH,H2;i)3M HCl,回流,离子交换树脂(Dowex50WX8,强酸性)。
[R-(E)]3-(4-甲基-戊-2-烯酰)-4-苯基-噁唑烷-2-酮16
-20℃下将三甲基乙酰氯化物(7.8g,0.065mol)加到酸14(6.9g,0.06mol)和在THF(200mL)中的三乙胺(18g,0.187mol)。1小时后,加入氯化锂(2.35g,0.55mol)和(R)-(-)-4-苯基-2-噁唑烷酮(8.15g,0.05mol)并将稠悬浮液加热至室温。20小时后,将悬浮液过滤并将滤液浓缩。从己烷/乙酸乙酯(5∶1)中重结晶所得的固体而得到噁唑烷酮16,它是一种白色固体(8.83g,68%)。1H NMR(CDCl3)δ7.35(m,5H),7.18(dd,1H,J=15.4和1.2Hz),7.02(dd,1H,J=15.4和6.8Hz),5.45(dd,1H,J=8.8和3.9Hz),4.68(t,1H,J=8.8Hz),4.22(dd,1H,J=8.8和3.9Hz),2.50(m,1H),1.04(d,1H,J=1.4Hz),1.02(d,1H,J=1.4Hz)。MS,m/z(相对强度):260[M+H,100%]。
(3R,3R*)3-(3,4-二甲基-戊酰)-4-苯基-噁唑烷-2-酮17
-20℃下往在THF(45mL)中的溴化铜(I)-二甲基硫化物配合物加入氯化甲基镁(为在THF中的3M溶液)。20分钟后,在10分钟内滴加入在THF(20mL)中的噁唑烷酮16(3.69g,0.014mol)。2.5小时后,加入饱和氯化铵水溶液将反应猝灭。分离所得到的两层并用醚提取含水相。用1M盐酸洗涤合并的有机相,然后用含水氢氧化铵洗涤。将有机相干燥(MgSO4)并浓缩得到噁唑烷酮17,为白色固体(3.39g,88%)。1H NMR(CDCl3)δ
7.30(m,1H),5.40(dd,1H,J=8.8和3.7Hz),4.63(t,1H,J=8.8Hz),4.21(dd,1H,J=8.8和3.7Hz),2.85(dd,1H,J=16.1和5.6Hz),2.8(dd,1H,J=16.1和8.5Hz),1.90(m,1H),1.56(m,2H),0.83(d,3H,J=6.8Hz),0.78(d,3H,J=6.8Hz),0.75(d,3H,J=6.8Hz)。MS,m/z(相对强度):
276[M+H,100%]。
[3R-(3R*(R*),4S*)]-4,5-二甲基-3-(2-氧代-4-苯基-噁唑烷-3-羰基)-己酸叔丁酯18
-78℃下将双(三甲基甲硅烷基)酰胺钠(14.4mL,0.014mol,在THF中的1M溶液)加到在THF(35mL)中的噁唑烷酮17(3.37g,0.012mol)溶液。35分钟后,加入溴乙酸叔丁酯(3.5g,0.018mol)并立即将溶液加热到-40℃。3小时后,加入饱氯化铵水溶液猝灭反应。分离所得的两层并和醚提以含水相。将合并的有机相干燥并浓缩。快速色谱法(9∶1-5∶1己烷/乙酸乙酯梯度)得到酯18(3.81g,82%),为白色固体。1H NMR(CDCl3)δ7.35(m,5H),5.37(dd,1H,J=8.4和3.1Hz),4.67(t,1H,J=8.7Hz),4.41(dt,1H,J=12.0和3.5Hz),4.25(dd,1H,J=8.68和3.1Hz),2.65(dd,1H,J=16.9和12.0Hz),2.25(dd,1H,J=16.9和3.5Hz),1.6(m,1H),1.45(m,1H),1.23(s,9H),1.02(d,1H,J=6.5Hz),0.93(d,1H,J=6.7Hz),0.80(d,1H,J=7.0Hz)。MS,m/z(相对强度):429[M-H+CH3CN,100%],388[M-H,20%]。
(3R,4S)-2-(1,2-二甲基-丙基)-琥珀酸4-叔丁酯19
向在THF(54mL)/水(15mL)中的噁唑烷酮18(3.62g,9.3mmol)加入预混合的氢氧化锂溶液(20mL 0.8M水溶液,0.016mol)/H2O2(5.76mL 30%水溶液)。7小时后,用水稀释该溶液并加入重亚硫酸钠(~10g)。进一步搅拌0.5小时,然后分离两层并用醚提取含水相。然后用1M盐酸使有机相呈酸性(pH2)并用醚提取。将合并的有机相干燥(MgSO4)并浓缩。快速色谱法(5∶1己烷/乙酸乙酯)得到酸19(2.1g,95%),为无色油。
1H NMR(CDCl3)δ3.0(m,1H),2.55(dd,1H,J=16.6和11.2Hz),2.27(dd,1H,J=16.6和3.4Hz),1.70(m,1H),1.53(m,1H),1.45(m,1H),1.43(s,9H),0.95(d,1H,J=6.8Hz),0.90(d,1H,J=6.6Hz),0.83(d,1H,J=6.8Hz)。MS,m/z(相对强度):243[M-H,100%]。
(3R,4S)-3-羟基甲基-4,5-二甲基-己酸叔丁酯20
0℃下将硼烷-甲基硫化物配合物(16mL,0.032mol在THF中的2M溶液)加到在THF(20mL)中的酸19(1.96g,8mmol)的搅拌溶液中。20小时后,加入甲醇直至泡腾中止并浓缩溶液。快速色谱法(5∶1己烷/乙酸乙酯梯度)得到醇20(1.29g,70%),为无色油。
1HNMR(CDCl3)δ
3.62(m,1H),2.32(m,1H),2.14(m,1H),1.6(m,1H),1.45(s,9H),1.35(m,1H),0.93(d,1H,J=6.8Hz),0.86(d,1H,J=6.8Hz),0.77(d,1H,J=6.9Hz)。MS,
m/z(相对强度):175[M-tBu,100%]。
(3R,4S)-4,5-二甲基-3-(甲苯-4-磺酰氧基甲基)-己酸叔丁酯21
0℃下将对甲苯磺酰氯(847mg,4.4mmol)加到搅拌的处在CH2Cl2(20mL)中的醇6(850mg,3.7mmol)、DMAP(10mg,0.08mmol)和三乙胺(1.23mL,8.88mmol)溶液,将该溶液加热至室温。15小时后,用1N盐酸洗涤该溶液,然后用盐水洗涤。干燥合并的有机相(MgSO4)并浓缩。快速色谱法(100 to 92%己烷/乙酸乙酯梯度)得到甲苯磺酸酯7(1.22g,86%),为稠树胶。 1H NMR
(CDCl3)δ 7.80(d,2H,J=8.2Hz),7.25(d,2H,J=8.2Hz),3.92(m,1H),2.38(s,3H),2.20(m,2H),1.95(m,1H),1.40(m,1H),1.32(s,9H),1.27(m,1H),0.78(d,1H,J=6.6Hz),0.73(d,1H,J=6.6Hz),0.63(d,1H,J=7.1Hz)。MS,m/z(相对强度):311[85%],198[100%],157[95%]。
(3R,4S)-3-叠氮基甲基-4,5-二甲基-己酸叔丁酯22
将在DMSO(15mL)中的甲苯磺酸酯21(1.19g,3.1mmol)和叠氮化钠(402mg,6.2mmol)溶液加热到60℃,持续2.5小时。加入水(100mL)并用醚提取该溶液。干燥合并的有机相(MgSO4)并浓缩。快速色谱法(9∶1己烷/乙酸乙酯)得到该叠氮化物22(628mg,80%),为无色油。1H NMR
(CDCl3)δ3.4(dd,1H,J=12.21和6.11Hz),3.3(dd,1H,J=21.11和6.59Hz),2.30(dd,1H,J=15.14和3.66Hz),2.25(m,1H),2.05(dd,1H,J=15.14和9.04Hz),1.55(m,1H),1.45(s,9H),1.35(m,1H),0.95(d,1H,J=6.59Hz),0.90(d,1H,J=6.83Hz),0.80(d,1H,J=7.08Hz)。MS(m/z):(相对强度):228[M-N2,35%],172[M-N2-tBu,100%]。
(3R,4S)-3-氨基甲基-4,5-二甲基-己酸叔丁酯23和[4R-[4R*(S*)]]-4-(1,2-二甲基-丙基)-吡咯烷-2-酮24
在氢气氛下摇晃在甲醇(50mL)中的叠氮化物8(640mg,2.5mmol)和阮内镍(1g)4小时。过滤溶液并将滤液浓缩得到胺23和内酰胺24的混合物,将其不经纯化用于下一步骤。
(3R,4S)-3-氨基甲基-4,5-二甲基-己酸(实施例2)
将在3 M盐酸中的胺23和内酰胺24(500mg)溶液加热回流9小时,然后在室温下搅拌15小时。浓缩溶液并依次纯化固体,该纯化包括离子交换色谱法(Dowex 50WX8,强酸性),草酸盐形成,然后进一步通过离子交换色谱法(Dowex 50WX8,强酸性)纯化,得到实施例2(343mg),为白色固体。1H NMR(D2O)δ2.87(m,2H),2.22(dd,
1H,J=15.4和3.4Hz),2.12(m,1H),1.93(dd,1H,J=15.4和9.5Hz),1.38(m,1H),1.12(m,1H),0.77(d,1H,J=6.6Hz),0.74(d,1H,J=6.6Hz),0.70(d,1H,J=6.8Hz)。MS,m/z(相对强度):174[M+H,100%]。
类似地制备以下的实施例:
3-氨基甲基-4,5-二甲基-己酸;
(3R,4S)-3-氨基甲基-4,5-二甲基-己酸MP;
(3S,4S)-3-氨基甲基-4,5-二甲基-己酸;
(3R,4R)-3-氨基甲基-4,5-二甲基-己酸MP;
3-氨基甲基-4-异丙基-己酸;
3-氨基甲基-4-异丙基-庚酸;
3-氨基甲基-4-异丙基-辛酸;
3-氨基甲基-4-异丙基-壬酸;
3-氨基甲基-4-异丙基-癸酸;和
3-氨基甲基-4-苯基-5-甲基-己酸。
方法3
其中,
R3=0Me或H
R4=Me,Et
n=0-2
可用含水酸如盐酸等在室温和回流温度之间处理结构29的化合物而制得结构30的化合物。可选择用在溶剂如CH2Cl2或EtOAc等中的三氟乙酸处理结构32的化合物而制备结构30的化合物。可通过Boc保护的内酰胺如化合物31的碱水解而制备化合物30,而化合物31本身可用在溶剂如THF等中的重碳酸二叔丁酯处理结构29的化合物而制备。例如,用含水氢氧化钠处理Boc-内酰胺31将产生酸32。
可以用在氨水中的钠或锂金属处理结构28的化合物(n=0)而制备结构29的化合物。优选用在氨水中的钠金属进行反应。或者,在乙腈和水的混合物中的硝酸铈氨处理结构28的化合物(n=1或2)而制备结构29的化合物。其它在文献中已知用于在从氮上除去取代的烷氧基苄基的方法如Green,有机合成中的保护基(Protective Groups inOrganic Synthesis),Wiley,2ed,1991所述,并可以使用它们。
可通过现有技术中已知的碳-碳键形成反应由结构27的化合物(其中LG为适宜的离去基团如卤化物或烷基磺酸盐,优选使用碘化物)的化合物制备结构28的化合物。文献中有多种用于在各种金属盐的存在下偶合有机卤化物或有机烷基磺酸盐和有机金属反应剂的方法,如在综合有机合成(Comprehensive Organic Synthesis),栏3:413所总结的。例如,可以在处于溶剂如四氢呋喃等的镁金属、碘和溴化铜二甲基硫化物的存在下,用适宜的次卤化物(氯化物或碘化物)处理结构27的化合物而制备结构28的化合物。可选择使用El Marini,Synthesis,1992:1104的方法。因此,可以在处于溶剂如四氢呋喃等的镁、碘和四氯铜酸锂的存在下,用适宜的甲基取代的次卤化物如碘化物处理结构27的化合物(其中LG为碘化物)而制备结构28的化合物。
结构27的化合物结合适宜的离去基团,它可以与适宜的亲核试剂发生亲核取代。离去基团的实例包括卤化物如氯化物、溴化物或碘化,磺酸酯如甲磺酸酯、甲苯磺酸酯、三氟甲磺酸酯、nosylate等等。可以用处在溶剂如甲苯等中的碘、三苯苯磷化氢和咪唑处理结构26的化合物而制备结构27的化合物(其中LG=碘化物)。
可以用处在溶剂如四氢呋喃或DME等中的金属硼氢化物如硼氢化钠处理结构25的化合物而制备结构26的化合物。
化合物25的制备可以类似于Zoretic等人,有机化学杂志(J.OrgChem.)1980;45:810-814或Nielsen等人医药化学杂志(J.Med.Chem.),1990;33:71-77,采用适宜的苄基胺例如但不限于苄基胺,4-甲氧基苄基胺或2,4-二甲氧基苄基胺。
作为一种可选择的方法,可以用金属钠和氨水处理结构26的化合物得到4-羟基甲基-吡咯烷酮,并可以将其碘化得以4-碘甲基-吡咯烷酮。然后可以根据以上避免内酰胺氮保护的方法将4-碘甲基吡咯烷酮与有机金属反应剂偶合,方法如下。
与上述方法类似,可以使用结构33的内酰胺(见Nielsen等人,J.Med.Chem.,1990;33:71-77用于一般制备方法)以在最终氨基酸的C3上构建固定的立体化学。
以这种方式制备的化合物包括:
3-氨基甲基-5-甲基-6-苯基-己酸;
3-氨基甲基-6-(4-氯-苯基)-5-甲基-己酸;
3-氨基甲基-6-(3-氯-苯基)-5-甲基-己酸;
3-氨基甲基-6-(2-氯-苯基)-5-甲基-己酸;
3-氨基甲基-6-(4-氟-苯基)-5-甲基-己酸;
3-氨基甲基-6-(3-氟-苯基)-5-甲基-己酸;
3-氨基甲基-6-(2-氟-苯基)-5-甲基-己酸;
3-氨基甲基-5-甲基-7-苯基-庚酸;
3-氨基甲基-7-(4-氯-苯基)-5-甲基-庚酸;
3-氨基甲基-7-(3-氯-苯基)-5-甲基-庚酸;
3-氨基甲基-7-(2-氯-苯基)-5-甲基-庚酸;
3-氨基甲基-7-(4-氟-苯基)-5-甲基-庚酸;
3-氨基甲基-7-(3-氟-苯基)-5-甲基-庚酸;
3-氨基甲基-7-(2-氟-苯基)-5-甲基-庚酸;
(3S)-3-氨基甲基-6-环丙基-5-甲基-己酸;
(3S)-3-氨基甲基-6-环丁基-5-甲基-己酸;
(3S)-3-氨基甲基-6-环戊基-5-甲基-己酸;
(3S)-3-氨基甲基-6-环己基-5-甲基-己酸;
(3S)-3-氨基甲基-7-环丙基-5-甲基-庚酸;
(3S)-3-氨基甲基-7-环丁基-5-甲基-庚酸;
(3S)-3-氨基甲基-7-环戊基-5-甲基-庚酸;
(3S)-3-氨基甲基-7-环己基-5-甲基-庚酸;
(3S)-3-氨基甲基-8-环丙基-5-甲基-辛酸;
(3S)-3-氨基甲基-8-环丁基-5-甲基-辛酸;
(3S)-3-氨基甲基-8-环戊基-5-甲基-辛酸;
(3S)-3-氨基甲基-8-环己基-5-甲基-辛酸;
(3S)-3-氨基甲基-5-甲基-庚酸;
(3S)-3-氨基甲基-5-甲基-辛酸;
(3S)-3-氨基甲基-5-甲基-壬酸;
(3S)-3-氨基甲基-5-甲基-癸酸;
(3S)-3-氨基甲基-5-甲基-十-酸;
(3S)-3-氨基甲基-5,7-二甲基-辛酸;
(3S)-3-氨基甲基-5,8-二甲基-壬酸;
(3S)-3-氨基甲基-5,9-二甲基-癸酸;
(3S)-3-氨基甲基-5,6-二甲基-庚酸;
(3S)-3-氨基甲基-5,6,6-三甲基-庚酸;
(3S)-3-氨基甲基-5-环丙基-己酸;
(3S)-3-氨基甲基-6-氟-5-甲基-己酸;
(3S)-3-氨基甲基-7-氟-5-甲基-庚酸;
(3S)-3-氨基甲基-8-氟-5-甲基-辛酸;
(3S)-3-氨基甲基-7,7,7-三氟-5-甲基-庚酸;
(3S)-3-氨基甲基-8,8,8-三氟-5-甲基-辛酸;
(3S)-3-氨基甲基-5-甲基-庚-6-烯酸;
(3S)-3-氨基甲基-5-甲基-辛-7-烯酸;
(3S)-3-氨基甲基-5-甲基-壬-8-烯酸;
(E)-(3S)-3-氨基甲基-5-甲基-辛-6-烯酸;
(Z)-(3S)-3-氨基甲基-5-甲基-辛-6-烯酸;
(E)-(3S)-3-氨基甲基-5-甲基-壬-6-烯酸;
(Z)-(3S)-3-氨基甲基-5-甲基-壬-6-烯酸;
(E)-(3S)-3-氨基甲基-5-甲基-壬-7-烯酸;
(Z)-(3S)-3-氨基甲基-5-甲基-壬-7-烯酸;
(E)-(3S)-3-氨基甲基-5-甲基-癸-7-烯酸;
(Z)-(3S)-3-氨基甲基-5-甲基-癸-7-烯酸;
3-氨基甲基-6-环丙基-5-甲基-己酸;
3-氨基甲基-6-环丁基-5-甲基-己酸;
3-氨基甲基-6-环戊基-5-甲基-己酸;
3-氨基甲基-6-环己基-5-甲基-己酸;
3-氨基甲基-7-环丙基-5-甲基-庚酸;
3-氨基甲基-7-环丁基-5-甲基-庚酸;
3-氨基甲基-7-环戊基-5-甲基-庚酸;
3-氨基甲基-7-环己基-5-甲基-庚酸;
3-氨基甲基-8-环丙基-5-甲基-辛酸;
3-氨基甲基-8-环丁基-5-甲基-辛酸;
3-氨基甲基-8-环戊基-5-甲基-辛酸;
3-氨基甲基-8-环己基-5-甲基-辛酸;
3-氨基甲基-5-甲基-庚酸;
3-氨基甲基-5-甲基-辛酸;
3-氨基甲基-5-甲基-壬酸;
3-氨基甲基-5-甲基-癸酸;
3-氨基甲基-5-甲基-十一酸;
3-氨基甲基-5,7-二甲基-辛酸;
3-氨基甲基-5,8-二甲基-壬酸;
3-氨基甲基-5,9-二甲基-癸酸;
3-氨基甲基-5,6-二甲基-庚酸;
3-氨基甲基-5,6,6-三甲基-庚酸;
3-氨基甲基-5-环丙基-己酸;
3-氨基甲基-6-氟-5-甲基-己酸;
3-氨基甲基-7-氟-5-甲基-庚酸;
3-氨基甲基-8-氟-5-甲基-辛酸;
3-氨基甲基-7,7,7-三氟-5-甲基-庚酸;
3-氨基甲基-8,8,8-三氟-5-甲基-辛酸;
3-氨基甲基-5-甲基-庚-6-烯酸;
3-氨基甲基-5-甲基-辛-7-烯酸;
3-氨基甲基-5-甲基-壬-8-烯酸;
(E)-3-氨基甲基-5-甲基-辛-6-烯酸;
(Z)-3-氨基甲基-5-甲基-辛-6-烯酸;
(E)-3-氨基甲基-5-甲基-壬-6-烯酸;
(Z)-3-氨基甲基-5-甲基-壬-6-烯酸;
(E)-3-氨基甲基-5-甲基-壬-7-烯酸;
(Z)-3-氨基甲基-5-甲基-壬-7-烯酸;
(E)-3-氨基甲基-5-甲基-癸-7-烯酸;和
(Z)-3-氨基甲基-5-甲基-癸-7-烯酸。
方法4
可在-78℃和室温之间的温度下,通过采用处在溶剂如二氯甲烷中的二乙基氨基硫三氟化物处理结构39的化合物而制备结构40的化合物。其它用于氟化醇的方法是已知的和可以使用的,如在Wilkinson,Chem.Rev.1992;92:505-519中所例举的。可以如以上方法所述的方法将结构40的化合物转化成所需的γ-氨基酸。
可以通过采用处在溶剂如THF和水中的四氧化锇和高碘酸钠进行处理,和采用处在溶剂如乙醇中的硼氢化钠还原所得的中间产物而制备结构39的化合物。
结构38和34的化合物可以根据方法3所述的原则由结构3的化合物制得。
另一种可选择的用于合成醇39(n=0)的方法包括用金属硼氢化物如处在溶剂如四氢呋喃或DME等中的硼氢化钠处理结构36的化合物而得到结构37的化合物,其中的氟化作用可以与结构40的化合物的制备相类似的方式实现。可以在室温和回流之间的温度下用处在含水DMSO中的氯化钠或锂处理结构35的化合物而制备结构36的化合物。优选在回流下采用处在含水DMSO中的氯化钠进行反应。可以用适宜的甲基丙二酸二酯如二甲基甲丙二酸酯等与在溶剂如DMSO或THF等中的氢化钠处理结构34的化合物而制备结构35的化合物。优选通过以下方法进行反应:将NaH加到处在DMSO中的二甲基甲基丙二酸酯溶液,然后加入预溶于DMSO中的内酰胺34(其中LG优选为碘化或如在方法3中所定义)。
可以通过上述的方法将化合物39和37转化成具有羟基的游离氨基酸。
以下的化合物可以这种方式制备:
(3S)-3-氨基甲基-6-氟-5-甲基-己酸;
(3S)-3-氨基甲基-6-氟-5-甲基-己酸;
(3S)-3-氨基甲基-7-氟-5-甲基-庚酸;
(3S)-3-氨基甲基-8-氟-5-甲基-辛酸;
(3S)-3-氨基甲基-9-氟-5-甲基-壬酸;
(3S)-3-氨基甲基-7-羟基-5-甲基-庚酸;和
(3S)-3-氨基甲基-6-羟基-5-甲基-己酸。
可以用处在溶剂如DMSO或THF等中的适宜的烷基碘化物(或烷基磺酸盐)如甲基碘化物等和碱如正丁基锂或氢化钠等处理结构39的化合物而制备结构41的化合物。优选通过以下方法进行该反应:将NaH加到处在DMSO中的醇溶液,然后加入烷基碘化物并在室温和回流之间的温度加热反应混合物。结构41的化合物到γ-氨基酸的转化如以上所述。
或者,结构41的化合物可以来自结构42的化合物(其中LG-碘化物、溴化物或磺酸酯,如方法3中所例举),通过处在溶剂如DMSO或THF等中的适宜的烷氧基阴离子的处理。结构42的化合物还用作方法中所列的碳-碳键形成方法的反应物。
以这种方式制备的化合物包括:
(3S)-3-氨基甲基-7-羟基-5-甲基-庚酸;
(3S)-3-氨基甲基-7-甲氧基-5-甲基-庚酸;
(3S)-3-氨基甲基-7-乙氧基-5-甲基-庚酸;
(3S)-3-氨基甲基-5-甲基-7-丙氧基-庚酸;
(3S)-3-氨基甲基-7-氟甲氧基-5-甲基-庚酸;
(3S)-3-氨基甲基-7-(2-氟-乙氧基)-5-甲基-庚酸;
(3S)-3-氨基甲基-5-甲基-7-(3,3,3-三氟-丙氧基)-庚酸;
(3S)-3-氨基甲基-6-羟基-5-甲基-己酸;
(3S)-3-氨基甲基-6-甲氧基-5-甲基-己酸;
(3S)-3-氨基甲基-6-乙氧基-5-甲基-己酸;
(3S)-3-氨基甲基-5-甲基-6-丙氧基-己酸;
(3S)-3-氨基甲基-6-氟甲氧基-5-甲基-己酸;
(3S)-3-氨基甲基-6-(2-氟-乙氧基)-5-甲基-己酸;和
(3S)-3-氨基甲基-5-甲基-6-(3,3,3-三氟-丙氧基)-己酸。
方法6
可以通过在Hoekstra等人,有机方法的开发(Organic ProcessResearch and Development),1997;1:26-38所述的一般方法由以上所示的结构45的化合物制备结构53的化合物。
可以用处在水/硫酸中的三氧化铬溶液处理结构44的化合物而制备结构45的化合物。可选择使用在Hudlicky,有机化学中的氧化(Oxidations in Organic Chemistry),ACS Monograph 186,ACS1990:77中所述的裂解44中的烯的方法。
可以通过现有技术中已知的和方法3中所述的碳碳形成反应由(S)-香茅基溴化物制备结构44的化合物(其中R2=烷基,支链烷基,环烷基,烷基-环烷基)。还可以采用以烷氧基阴离子取代(S)-香茅基溴化物卤化物提供结构44的化合物,其中R=烷氧基或苯氧基醚(和根据式I的其适宜取代)。可选择采用(S)-香茅醇通过用碱如氢化钠处理(S)-香茅醇,用适宜的烷基卤化物处理所得醇盐以提供醚,从而提供结构44的化合物。在另一方法中,可以用适宜的金属硼氢化物或氢化铝类如LAH还原(S)-香茅基溴化物(或适宜的硫酸酯,例如但不限于甲烷磺酸(S)-3,7-二甲基-辛-6-烯基酯)以提供(R)-2,6-二甲基-辛-2-烯。
对于本领域技术人员来说,可考虑任意选择R-或S-香茅醇或R-或S-香茅基溴化物得到所需的在最终氨基酸的C5处的异构体。
以这种方式制备的化合物包括:
(3S,5S)-3-氨基甲基-7-甲氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-乙氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-丙氧基-庚酸;
(3S,5S)-3-氨基甲基-7-异丙氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-叔丁氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-氟甲氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(2-氟-乙氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(3,3,3-三氟-丙氧基)-庚酸;
(3S,5S)-3-氨基甲基-7-苄氧基-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-苯氧基-庚酸;
(3S,5S)-3-氨基甲基-7-(4-氯-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(3-氯-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(2-氯-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(4-氟-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(3-氟-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(2-氟-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(4-甲氧基-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(3-甲氧基-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-7-(2-甲氧基-苯氧基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(4-三氟甲基-苯氧基)庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(3-三氟甲基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(2-三氟甲基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(4-硝基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(3-硝基-苯氧基)-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-7-(2-硝基-苯氧基)-庚酸;
(3S,5R)-3-氨基甲基-7-环丙基-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-环丁基-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-环戊基-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-环己基-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-8-环丙基-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-8-环丁基-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-8-环戊基-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-8-环己基-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-5-甲基-壬酸;
(3S,5R)-3-氨基甲基-5-甲基-癸酸;
(3S,5R)-3-氨基甲基-5-甲基-十一酸;
(3S,5R)-3-氨基甲基-5,9-二甲基-癸酸;
(3S,5R)-3-氨基甲基-5,8-二甲基-壬酸;
(3S,5S)-3-氨基甲基-7-氟-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-8-氟-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-8,8,8-三氟-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-5-甲基-7-苯基-庚酸;
(3S,5R)-3-氨基甲基-7-(4-氯-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(3-氯-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(2-氯-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(4-甲氧基-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(3-甲氧基-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(2-甲氧基-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(4-氟-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(3-氟-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(2-氟-苯基)-5-甲基-庚酸;和
(3S,5R)-3-氨基甲基-5,10-二甲基-十一酸。
方法7
可以用处在溶剂如CH2Cl2中的硼三氟化物二乙基醚合物和三乙基硅烷处理结构57的化合物而制备结构58的化合物。可使用在Meyers,J.Org.Chem.,1993;58:36-42中所述的另一可选择方法,因而采用处在溶剂如含有处于甲醇的3% HCl的THF/甲醇中的氰基硼氢化钠处理结构57的化合物。
可以根据Koot,四面体通讯(Tetrahedron Lett.),1992;33:7969-7972的方法,用处在溶剂如DMF等中的二甲基胺处理结构56的化合物而制备结构57的化合物。
结构56的化合物的制备可以采用适宜的伯卤化物55(碘化物、溴化物或氯化物)在采用tBuLi标准反式金属取代的条件下处理结构54的化合物,用适宜的铜盐处理所得的有机金属反应剂,这些铜盐例如但不限于溴化铜或碘化铜。将所得的有机铜酸盐加到处在溶剂如THF等中的内酰胺(参见Koot等人,J.Org.Chem.,1992;57:1059-1061,用于制备手性内酰胺54)。Koot,Tetrahedron Lett.,1992;33:7969-7972的过程例举该方法。
对于本领域技术人员来说,可以考虑合理选择R-或S-伯卤化物55以在最终氨基酸的C5处产生所需的异构体。
以这种方式制备的化合物包括:
(3S,5S)-3-氨基甲基-5-甲氧基-己酸;
(3S,5S)-3-氨基甲基-5-乙氧基-己酸;
(3S,5S)-3-氨基甲基-5-丙氧基-己酸;
(3S,5S)-3-氨基甲基-5-异丙氧基-己酸;
(3S,5S)-3-氨基甲基-5-叔丁氧基-己酸;
(3S,5S)-3-氨基甲基-5-氟甲氧基-己酸;
(3S,5S)-3-氨基甲基-5-(2-氟-乙氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3,3,3-三氟-丙氧基)-己酸;
(3S,5S)-3-氨基甲基-5-苯氧基-己酸;
(3S,5S)-3-氨基甲基-5-(4-氯-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3-氯-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(2-氯-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(4-氟-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3-氟-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(2-氟-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(4-甲氧基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3-甲氧基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(2-甲氧基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(4-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(3-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-(2-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-6-甲氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-乙氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-丙氧基-己酸;
(3S,5S)-3-氨基甲基-6-异丙氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-叔丁氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-氟甲氧基-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氟-乙氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(3,3,3-三氟-丙氧基)-己酸;
(3S,SS)-3-氨基甲基-5-甲基-6-苯氧基-己酸;
(3S,5S)-3-氨基甲基-6-(4-氯-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-氯-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氯-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(4-氟-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-氟-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氟-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(4-甲氧基-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-甲氧基-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-甲氧基-苯氧基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-5-甲基6-(4-三氟甲基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(3-三氟甲基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基6-(2-三氟甲基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(4-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(3-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-5-甲基-6-(2-硝基-苯氧基)-己酸;
(3S,5S)-3-氨基甲基-6-苄氧基-5-甲基-己酸;
(3S,5R)-3-氨基甲基-6-环丙基-5-甲基-己酸;
(3S,5R)-3-氨基甲基-6-环丁基-5-甲基-己酸;
(3S,5R)-3-氨基甲基-6-环戊基-5-甲基-己酸;
(3S,5R)-3-氨基甲基-6-环己基-5-甲基-己酸;
(3S,5R)-3-氨基甲基-5-甲基-庚酸;
(3S,SR)-3-氨基甲基-5-甲基-辛酸;
(3S,5R)-3-氨基甲基-5-甲基-壬酸;
(3S,5R)-3-氨基甲基-5-甲基-癸酸;
(3S,5R)-3-氨基甲基-5-甲基-十一酸;
(3S,5R)-3-氨基甲基-5-甲基-月桂酸;
(3S,5R)-3-氨基甲基-5,7-二甲基-辛酸;
(3S,5R)-3-氨基甲基-5,8-二甲基-壬酸;
(3S,5R)-3-氨基甲基-5,9-二甲基-癸酸;
(3S,5R)-3-氨基甲基-5,10-二甲基-十一酸;
(3S,5S)-3-氨基甲基-5,6-二甲基-庚酸;
(3S,5S)-3-氨基甲基-5,6,6-三甲基-庚酸;
(3S,5S)-3-氨基甲基-5-环丙基-己酸;
(3S,5S)-3-氨基甲基-6-氟-5-甲基-己酸;
(3S,5S)-3-氨基甲基-7-氟-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-8-氟-5-甲基-辛酸;
(3S,5S)-3-氨基甲基-7,7,7-三氟-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-8,8,8-三氟-5-甲基-辛酸;
(3S,5S)-3-氨基甲基-5-甲基-6-苯基-己酸;
(3S,5S)-3-氨基甲基-6-(4-氯-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-氯-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氯-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(4-甲氧基-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-甲氧基-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-甲氧基-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(4-氟-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(3-氟-苯基)-5-甲基-己酸;
(3S,5S)-3-氨基甲基-6-(2-氟-苯基)-5-甲基-己酸;
(3S,5R)-3-氨基甲基-5-甲基-7-苯基-庚酸;
(3S,5R)-3-氨基甲基-7-(4-氯-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(3-氯-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(2-氯-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(4-甲氧基-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(3-甲氧基-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(2-甲氧基-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(4-氟-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(3-氟-苯基)-5-甲基-庚酸;
(3S,5R)-3-氨基甲基-7-(2-氟-苯基)-5-甲基-庚酸;
(3S,5S)-3-氨基甲基-5-甲基-庚-6-烯酸;
(3S,5R)-3-氨基甲基-5-甲基-辛-7-烯酸;
(3S,5R)-3-氨基甲基-5-甲基-壬-8-烯酸;
(E)-(3S,5S)-3-氨基甲基-5-甲基-辛-6-烯酸;
(Z)-(3S,5S)-3-氨基甲基-5-甲基-辛-6-烯酸;
(Z)-(3S,5S)-3-氨基甲基-5-甲基-壬-6-烯酸;
(E)-(3S,5S)-3-氨基甲基-5-甲基-壬-6-烯酸;
(E)-(3S,5R)-3-氨基甲基-5-甲基-壬-7-烯酸;
(Z)-(3S,5R)-3-氨基甲基-5-甲基-壬-7-烯酸;
(Z)-(3S,5R)-3-氨基甲基-5-甲基-癸-7-烯酸;和
(E)-(3S,5R)-3-氨基甲基-5-甲基-十一碳-7-烯酸。
方法8
可以在Mitsunobu,合成(Synthesis),1981:1所述的条件下,用适宜取代的酚(包括酚本身)处理结构59的化合物而制备结构60的化合物。
可以用在氨水中的钠或锂金属等处理结构39的化合物而制备结构59的化合物。优选用在氨水中的钠金属进行该反应。
直接水解化合物60将产生期望的氨基酸或者可以采用通过水解Boc保护的内酰胺的方法。
以这种方式制备的化合物包括:
(3S)-3-氨基甲基-5-甲基-7-苯氧基-庚酸;
(3S)-3-氨基甲基-7-(4-氯-苯氧基)-5-甲基-庚酸;
(3S)-3-氨基甲基-7-(3-氯-苯氧基)-5-甲基-庚酸;
(3S)-3-氨基甲基-7-(2-氯-苯氧基)-5-甲基-庚酸;
(3S)-3-氨基甲基-7-(4-氟-苯氧基)-5-甲基-庚酸;
(3S)-3-氨基甲基-7-(3-氟-苯氧基)-5-甲基-庚酸;
(3S)-3-氨基甲基-7-(2-氟-苯氧基)-5-甲基-庚酸;
(3S)-3-氨基甲基-7-(4-甲氧基-苯氧基)-5-甲基-庚酸;
(3S)-3-氨基甲基-7-(3-甲氧基-苯氧基)-5-甲基-庚酸;
(3S,)-3-氨基甲基-7-(2-甲氧基-苯氧基)-5-甲基-庚酸;
(3S)-3-氨基甲基-5-甲基-7-(4-三氟甲基-苯氧基)-庚酸;
(3S)-3-氨基甲基-5-甲基-7-(3-三氟甲基-苯氧基)-庚酸;
(3S)-3-氨基甲基-5-甲基-7-(2-三氟甲基-苯氧基)-庚酸;
(3S)-3-氨基甲基-5-甲基-7-(4-硝基-苯氧基)-庚酸;
(3S)-3-氨基甲基-5-甲基-7-(3-硝基-苯氧基)-庚酸;
(3S)-3-氨基甲基-5-甲基-7-(2-硝基-苯氧基)-庚酸;
(3S)-3-氨基甲基-6-(3-氯-苯氧基)-5-甲基-己酸;
(3S)-3-氨基甲基-6-(2-氯-苯氧基)-5-甲基-己酸;
(3S)-3-氨基甲基-6-(4-氟-苯氧基)-5-甲基-己酸;
(3S)-3-氨基甲基-6-(3-氟-苯氧基)-5-甲基-己酸;
(3S)-3-氨基甲基-6-(2-氟-苯氧基)-5-甲基-己酸;
(3S)-3-氨基甲基-6-(4-甲氧基-苯氧基)-5-甲基-己酸;
(3S)-3-氨基甲基-6-(3-甲氧基-苯氧基)-5-甲基-己酸;
(3S)-3-氨基甲基-6-(2-甲氧基-苯氧基)-5-甲基-己酸;
(3S)-3-氨基甲基-5-甲基-6-(4-三氟甲基-苯氧基)-己酸;
(3S)-3-氨基甲基-5-甲基-6-(3-三氟甲基-苯氧基)-己酸;
(3S)-3-氨基甲基-5-甲基-6-(2-三氟甲基-苯氧基)-己酸;
(3S)-3-氨基甲基-5-甲基-6-(4-硝基-苯氧基)-己酸;
(3S)-3-氨基甲基-5-甲基-6-(3-硝基-苯氧基)-己酸;
(3S)-3-氨基甲基-5-甲基-6-(2-硝基-苯氧基)-己酸;
(3S)-3-氨基甲基-5-甲基-6-苯氧基-己酸;和
(3S)-3-氨基甲基-6-(4-氯-苯氧基)-5-甲基-己酸。
方法9合成C-4取代的类似物
可以在催化剂如存在碱如位于有机溶剂如甲醇中的三乙胺的阮内镍的存在下用50psi的氢处理结构63的化合物而制备结构64的化合物。然后在室温和回流之间的温度下用含水酸如6N HCl处理所得的产物。所得的产物接受离子交换色谱法以分离产物64。
可以用适宜的碱如但不限于氢化钠、正丁基锂等,和烷基化反应剂如但不限于处在溶剂如DMSO或THF等中的溴乙酸叔丁酯或溴乙酸苄基酯处理结构62B的化合物而制备结构63的化合物。优选用氢化钠处理处在THF中的结构62B的化合物并用溴乙酸叔丁酯将所得的阴离子烷基化而进行该反应。
可以在50℃和回流之间的温度下用处在溶剂如含水DMSO中的氯化钠处理结构62A的化合物制备结构62B的化合物。
结构62A的化合物可以在铜盐如但不限于碘化铜、溴化铜二甲基硫化物的存在下,用处在溶剂如THF或醚中的适宜的烷基金属卤化物如烷基锂反应剂或有机镁卤化物处理结构61的化合物而制备结构62A的化合物。或者,在室温处或以下用氯化烷基镁处理溶剂如醚中的腈而进行该反应。
可以根据在异丁基酐和氰基乙酸甲酯之间的缩合的已知文献方法制备诸如61的化合物。
方法10:C-4取代
可以由叠氮化物71经两个步骤制备双重分枝的3-取代GABA类似物72:在贵金属催化剂如碳上的5%钯的存在下将叠氮化物71氢化,用强酸如6 N Hcl在回流下水解所得的内酰胺。然后用离子交换色谱法分离最终产物72。
可以在以下两个步骤中制备化合物71:在如0℃的温度下用在溶剂如乙醇中的HBr处理内酯如70,在10℃和80℃之间的温度下,用在溶剂如二甲基亚砜中的叠氮化钠与所得的溴化物反应。
可以在以下两步中制备内70:在0℃和100℃的温度下,在催化量的处在溶剂如乙腈中的三氯化钌的存在下,用氧化剂如高碘酸钠氧化化合物如69并用在甲醇中的碳酸钾处理所得的化合物,然后在25℃和70℃的温度下进行,接着在外周温度下,在回流下用在溶剂如THF中的酸如对甲苯磺酸或含水酸如在水中的HCl处理。
可以通过以下方法制备化合物如69:采用在溶剂如醚或THF中的氢化物还原剂如氢化锂铝还原化合物如68,并在碱如三乙胺或吡啶等的存在下将所得的醇与酰化试剂如乙酐反应。
可以通过以下方法制备结构68的化合物:在处在溶剂如乙醇中的贵金属催化剂如5%碳上的钯的存在下,将化合物如67与约50psi的氢反应。可以通过结构66的化合物与用溴化氢气体饱和的乙醇溶液反应而制备式67的化合物。可以通过以下方法由化合物如65制备化合物如66:在-78℃的温度下用强碱如在溶液如THF中的二异丙基胺处理化合物,并使所得的阴离子与化合物如溴化苄或碘苄反应。可以由文献(Davies,有机化学杂志(J.Org Chem.),1999;64(23):8501-8508;Koch J.Org.Chem.,1993;58(10):2725-37;Afonso,四面体(Tetrahedron),1993;49(20):4283-92;Bertus,Tetrahedron,Asymmetry 1999;10(7):1369-1380;Yamamoto,美国化学学会杂志(J.Am.Chem.Soc.),1992;114(20):7652-60)中已知的方法制备旋光形式的结构66的化合物(R=H或低级烷基)。
具体实施例
实施例3:合成3-氨基甲基-5-甲基-辛酸
1-苄基-4-羟基甲基-吡咯烷-2-酮74
将硼氢化钠(8.0g,0.211mol)加到处在1,2-二甲氧基乙烷(600mL)中的1-苄基-5-氧-3-吡咯烷羧酸甲酯73(See Zoretic等人,J.Org.Chem.,1980;45:810-814一般合成方法)(32.0g,0.137mol)并回流19小时。将反应物冷却至室温并加入200ml的水。用1M的柠檬酸猝来反应并减压浓缩。用二氯甲烷提取残留物,在硫酸镁上干燥,并蒸发至干得到17.47g,62%的醇74,为澄清的油。
1H NMR(CDCl3)δ 7.30(m,5H),4.38(d,1H,J=14.7),4.46(d,1H,J=14.7),3.56(m,2H),3.36(m,1H),3.10(m,1H),2.52(m,2H),2.26(m,1H)。MS,m/z(相对强度):207[M+2H,66%]。IR(KBr)3345,2946,2866,1651,1445,1025,737,和698cm-1。
1-苄基-4-碘甲基-吡咯烷-2-酮75
往在210ml甲苯中的醇内酰胺74(11.18g,0.056mol)依次加入三苯基磷化氢(20.0g,0.076mol)、咪唑(10.8g,0.159mol)和碘(19.0g,0.075mol)。搅拌悬浮液1.5小时,然后将上清液倾入另一烧瓶中。用醚洗涤该粘性黄色残留物两次并合并溶液。蒸发溶剂并在二氧化硅上色谱分析,用1∶1丙酮/己烷洗脱得到7.92g,46%的碘内酰胺75,为黄色油。1H NMR(CDCl3)δ 7.25(m,5H),4.38(d,1H,J=14.6),4.46(d,1H,J=14.6),3.38(dd,1H,J=7.8和2.2),3.20(dd,1H,J=5.6和4.4),3.12(dd,1H,J=7.3和2.4),2.96(dd,1H,J=5.8和4.4),2.60(m,2H),2.22(dd,1H,J=10.5和9.7)。MS,m/z(相对强度):224[M-H-Bn,94%],317[M+2H,64%]。IR 3027,2917,1688,1438,1267,和701cm-1。
1-苄基-4-(2-甲基-戊基)-吡咯烷-2-酮76
在氮气下将碘晶体和2-溴戊烷(2.88g,0.019mol)加到处在15ml干燥THF中的镁车削(0.50g,0.021mol)悬浮液中。在冰浴中间歇冷却放热反应,然后在室温下搅拌2小时。0℃下加入8毫升Li2CuCl4(由在10ml的干THF中的84mg LiCl和134mg CuCl2制成),然后滴加入在15ml干THF中的1-苄基-4-碘甲基吡咯烷-2-酮75,0℃下搅拌所得的悬浮液3小时。用饱和氯化铵溶液猝灭反应,然后室温下继续搅拌1小时。加入水以溶解形成的沉淀,用醚提取该溶液和在硫酸镁.上干燥。真空蒸了该溶剂并在二氧化硅上色谱分析,用1∶1丙酮/己烷洗脱得到1.13g,69%的1-苄基-4-(2-甲基-戊基)-吡咯烷-2-酮76。1HNMR(CDCl3)
δ 7.30(m,5H),4.44(m,2H),3.32(m,1H),2.86(m,1H),2.56(m,1H),2.40(m,1H),2.10(m,1H),1.30(m,6H),1.10(m,1H),0.90(m,6H)。MS,m/z(相对强度):261[M+2H,100%],301[M-H+CH3CN,82%],260[M+H,72%]。
4-(2-甲基-戊基)-吡咯烷-2-酮77
将配备干冰冷凝器的250ml三颈烧瓶冷却至-78℃。将氨水(80mL)浓缩至该烧瓶并加入处在15mL THF中的的1-苄基-4-(2-甲基-戊基)-吡咯烷-2-酮76(1.67g,0.006mol)。加入新切的钠珠直至持续深蓝颜色。除去冷却浴并在回流(-33℃)下搅拌该反应物1小时。用氯化铵猝灭该反应并蒸发过量的氨水。用水洗涤所得的残留物,用二氯甲烷提取,并在硫酸镁上干燥。蒸发溶剂,然后在二氧化硅上进行色谱层析,用1∶1丙酮/己烷洗脱得到0.94g,86%的4-(2-甲基-戊基)-吡咯烷-2-酮77。1H NMR(CDCl3)
δ6.25(br,1H),3.44(m,1H),2.95(m,1H),2.54(m,1H),2.40(m,1H),1.98(m,1H),1.30(m,6H),0.80(m,6H)。MS,m/z(相对强度):212[M+2H+CH3CN,100%],171[M+2H,72%],170[M+1H,65%]。
3-氨基甲基-5-甲基-辛酸(实施例3)
将4-(2-甲基-戊基)-吡咯烷-2-酮77(0.94g,0.007mol)溶于70mL 6N HCl并回流20小时。真空蒸发溶液并将残留物水溶液应用于已用HPLC等级洗涤的Dowex 50WX 8-100(强酸性)离子交换树脂。洗脱柱,首先用水洗脱至洗脱剂为常数pH,然后用5%的氢氧化铵溶液洗脱。将氢氧化铵部分蒸发并与甲苯共沸。用丙酮洗涤白色固体,过滤并真空干燥24小时得到氨基酸0.61g,59%。
1H NMR(CD3OD)δ3.00(m,1H),
2.85(m,1H),2.48(m,1H),2.30(m,1H),2.14(brm,1H),1.60 (brm,1H),1.38(m,4H),1.18(m,2H),0.60(m,6H)。MS,m/z(相对强度):188[M+H,100%]。
实施例4:合成3-氨基甲基-5,7-二甲基-辛酸
实施例4
1-(4-甲氧基-苄基)-5-氧代-吡咯烷-3-羧酸甲酯79
0℃下将在甲醇(13mL)中的衣康酸二甲酯(48g,0.306mol)加到在甲醇(40mL)中的4-甲氧基苄基胺(42g,0.306mol)。室温下搅拌该溶液4天。往该溶液中加入IN HCl,然后加入醚。分离双层并用醚提取含水相。干燥合并的有机相(MgSO4)。在过滤干燥剂时,从溶液中沉淀出期望的物质79,将其收集并真空干燥。23.26g,29%。MS,m/z(相对强度):264[M+H,100%]。分析计算C14H17N1O4:C,63.87;H,6.51;N,5.32。发现:C,63.96;H,6.55;N,5.29。
4-羟基甲基-1-(4-甲氧基-苄基)-吡咯烷-2-酮80
室温下将NaBH4(15g,0.081mol)部分加到在乙醇中的酯79(600mL)。4.5小时后,小心地将水(~200mL)加到反应物中,并在室温下搅拌溶液过夜。过滤除去所得的固体并将滤液浓缩得到醇80,为一种油。15.33g,81%。MS,m/z(相对强度):235[M+H,100%]。
4-碘甲基-1-(4-甲氧基-苄基)-吡咯烷-2-酮81
将三苯基磷化氢(20g,0.077mol)、咪唑(10.8g,0.16mol)和碘(19g,0.075mol)加到处在PhMe中的醇80(12.9g,0.055mol)。室温下搅拌该悬浮液5小时。加入饱和的硫代硫酸钠溶液并分离双层。用醚提取含水相,用盐水洗涤合并的有机相,干燥(MgSO4)和浓缩。对残留物进行快速色谱法(6∶1-4∶1甲苯/丙酮)得到碘化物81,为一种油。11.9g,63%.MS,m/z(相对强度):346[M+H,100%]。
4-(2,4-二甲基-戊基)-1-(4-甲氧基-苄基)-吡咯烷-2-酮82
采用与1-苄基-4-(2-甲基-戊基)吡咯烷-2-酮76的制备类似的方法得到4-(2,4-二甲基-戊基)-1-(4-甲氧基-苄基)-吡咯烷-2-酮,为一种油。1.22g,29%.MS,m/z(相对强度):304[M+H,100%]。
4-(2,4-二甲基-戊基)-吡咯烷-2-酮83
0℃下将在H2O(10mL)中的硝酸铈铵加到在MeCN(20mL)中的内酰胺(1.17g,3.86mmol)。50分钟后进一步加入部分硝酸铈铵(2.1g,3.86mmol),1小时后将该混合物吸收到二氧化硅上,并用色谱法分析得到一种油。MS,m/z(相对强度):183[M+H,100%]。
3-氨基甲基-5,7-二甲基-辛酸(实施例4)
采用与3-氨基甲基-5-甲基辛酸(实施例3)的制备类似的方法得到氨基酸,为一种固体。MS,m/z(相对强度):202[M+H,100%]。
实施例5:合成(S)-3-氨基甲基-5-甲基-辛酸
实施例5
(S)-4-羟基甲基-1-((S)-1-苯基-乙基)-吡咯烷-2-酮84
将硼氢化钠(22g,0.595mol)加到在EtOH(600mL)中的酯33(49g,0.198mol)。7小时后,小心地加入1M柠檬酸,并在泡腾结束之后,加入水以完全猝来该反应。减压除去乙醇并加入乙酸乙酯。分离所得的双层,用EtOAc提取含水相,干燥合并的有机相(MgSO4)并浓缩得到一种重油。MS,m/z(相对强度):[M+H,100%]。
(S)-4-碘甲基-1-((S)-1-苯基-乙基)-吡咯烷-2-酮85
采用与化合物80的碘化类似的方法得到碘化物85,为一种油。35.2g,56%。分析计算C13H16I1N1O1:C,47.43;H,4.90;N,4.25。发现:C,47.41;H,4.83;N,4.17。
4-(2-甲基-戊基)-1-((S)-1-苯基-乙基)-吡咯烷-2-酮86
采用与1-苄基-4-(2-甲基-戊基)-吡咯烷-2-酮的制备类似的方法得到2.71g,81.0%的86,为一种油。MS,m/z(相对强度):274[M+1H,100%],315[M+H+CH3CN,65%]。
(S)-4-(2-甲基-戊基)-吡咯烷-2-酮87
采用与4-(2-甲基-戊基)-吡咯烷-2-酮77的制备类似的方法得到1.14g,72.8%的87,为一种油。MS,m/z(相对强度):170[M+1H,10%],211[M+1H+CH3CN,90%]。
实施例5:(S)-3-氨基甲基-5-甲基-辛酸
采用与3-氨基甲基-5-甲基辛酸(实施例3)的制备类似的方法得到氨基酸(实施例5)0.88g,74.3%。
1H NMR(CD3OD)δ2.95(m,1H),2.80(m,1H),2.40(m,1H),2.25(m,1H),2.05(brm,1H),1.50(brm,1H),1.30(m,4H),1.10(m,2H),0.90(m,6H)。MS,m/z(相对强度):188[M+1H,100%],186[M-1H,100%],229[M+1H+CH3CN,30%]。
实施例6:合成(S)-3-氨基甲基-7-甲氧基-5-甲基-庚酸
(S)-4-(2-甲基-戊-4-烯基)-1-((S)-1-苯基-乙基)-吡咯烷-2-酮88
根据与1-苄基-4-(2-甲基-戊基)-吡咯烷-2-酮76的制备类似的方法得到加合物88,为一种油,6g,74%。MS,m/z(相对强度):272[M+H,100%]。
(S)-4-(4-羟基-2-甲基-丁基)-1-((S)-1-苯基-乙基)-吡咯烷-2-酮89
将OsO4(在t-BuOH中的2mL 4%wt的溶液)加到在THF/H2O(3∶1,100mL)中。1小时后,加入高碘酸钠(11.4g,0.053mol)。2小时后,过滤该悬浮液并用二氯甲烷洗涤该固体。浓缩滤液并用甲苯共沸。残留物在室温下搅拌过夜。加入1N柠檬酸并用醚稀释混合物。分离所得的两层并用醚萃取含水相,干燥(MgSO4)并浓缩合并的有机相。快速色谱层析(1∶1己烷/EtOAc)残留物得到一种油。4.2g,73%。MS,m/z(相对强度):276[M+H,100%]。
(S)-4-(4-甲氧基-2-甲基-丁基)-1-((S)-1-苯基-乙基)-吡咯烷-2-酮90
室温下将NaH(368mg,60%在油中)加到处在DMSO(60mL)中的醇89(2g,7.66mmol)。30分钟后,加入碘甲烷(1.08g,7.66mmol)并在室温下搅拌该溶液过夜,同时用水(500mL)稀释反应物。用醚提取该溶液,干燥(MgSO4)合并的有机提取物并浓缩。快速色谱层析(90%to 50%己烷/丙酮)残留物得到产物90,为一种油(1.1g,52%)。MSm/z 290(M+H,100%)。
(S)-4-(4-甲氧基-2-甲基-丁基)-吡咯烷-2-酮91
采用与4-(2-甲基-戊基)-吡咯烷-2-酮77的合成类似的方法得到内酰胺91,为一种油。MS m/z 186(M+H,100%)。
实施例6:(S)-3-氨基甲基-7-甲氧基-5-甲基-庚酸
根据与合成实施例3类似的方法。由离子-交换色谱法分离所得的氨基酸,并由甲醇/乙酸乙酯重结得到实施例6,为一种白色固体。MSm/z 204(M+H,100%)。分析计算C10H21N1O3:C,59.09;H,10.41;N,6.89.发现:C,58.71;H,10.21;N,6.67。
实施例7:合成(S)-3-氨基甲基-6-氟-5-甲基-己酸
实施例7
2-甲基-2-[(S)-5-氧代-1-((S)-1-苯基-乙基)-吡咯烷-3-基甲基]-丙二酸二甲酯92
室温下将NaH(291mg 60%分散在油中)加到在DMSO(7mL)中的二甲基甲基丙二酸酯(1.06g,7.29mmol)。在泡腾终止后,加入在DMSO(5mL)中的内酰胺85(2g,7.29mol)。1小时后加入水并用醚提到水溶液。干燥(MgSO4)合并的有机相并浓缩。快速色谱分析(1∶1己烷/丙酮)残留物得到产物,为一种油(1.7g,81%)。MS m/z 348(M+H,100%)。
2-甲基-3-[(S)-5-氧代-1-((S)-1-苯基-乙基)-吡咯烷-3-基]-丙酸甲酯93
将酯92(483mg,1.4mmol)、NaCl(104mg,1.8mmol)、水(105μL)和DMSO(5mL)回流加热2小时。将该溶液冷却至室温,加入水并用醚提取水溶液。干燥(MgSO4)合并的有机相并浓缩。快速色谱层析(80%-66%己烷/丙酮)残留物得到产物,为一种油(160mg,40%)。MS m/z 290(M+H,100%)。
(S)-4-(3-羟基-2-甲基-丙基)-1-((S)-1-苯基-乙基)-吡咯烷-2-酮37
将NaBH4(3.7g,0.10mol)加到在EtOH(100mL)中的酯93(4.82g,0.017mol),并回流加热该混合物2.5小时。将溶液冷却到0℃并小心加入1M柠檬酸,然后加入水。浓缩该溶液至半体积,加入醚提取。干燥(MgSO4)合并的有机提取物并浓缩。快速色谱层析(1∶1己烷/丙酮)残留物得到产物,为一种油(2.6g,59%)。MS m/z 262(M+H,100%)。
(S)-4-(3-氟-2-甲基-丙基)-1-((S)-1-苯基-乙基)-吡咯烷-2-酮94
-78℃下将在CH2Cl2(10mL)中的醇37加到在CH2Cl2(20mL)中的DAST(1g,6.2mmol)。1小时后于-78℃下将溶液加热至室温。7小时后,小心用饱和碳酸氢钠水溶液猝灭反应并分离双层。干燥(MgSO4)该有机相并浓缩。快速色谱层析(90%-66%己烷/丙酮)残留物得到产物,为一种油(600mg,37%)。 MS m/z 264(M+H,100%)。
(S)-4-(3-氟-2-甲基-丙基)-吡咯烷-2-酮95
采用与4-(2-甲基-戊基)-吡咯烷-2-酮77的制备类似的方法得到内酰胺,为一种油(242mg,68%)。MS m/z 159(M,100%)。
实施例7(S)-3-氨基甲基-6-氟-5-甲基-己酸
根据合成实施例3类似的方法。从甲醇/乙酸乙酯中重结晶由离子-交换色谱法分离所得的氨基酸得到实施例7,为一种白色固体。MS m/z177(M,100%).分析计算C8H16F1N1O2:0.02H2O:C,54.11;H,9.10;N,7.89。发现:C,53.75;H,9.24;N,7.72。
实施例8:合成(S)-3-氨基甲基-6-甲氧基-5-甲基-己酸
实施例8
(S)-4-(3-甲氧基-2-甲基-丙基)-1-((S)-1-苯基-乙基)-吡咯烷-2-酮96
采用与(S)-4-(4-甲氧基-2-甲基-丁基)-1-((S)-1-苯基-乙基)-吡咯烷-2-酮90的合成类似的方法得到醚96,为一种油(90mg,37%)。MS m/z 276(M+H,100%)。
(S)-4-(3-甲氧基-2-甲基-丙基)-吡咯烷-2-酮97
采用与4-(2-甲基-戊基)-吡咯烷-2-酮77的合成类似的方法得到97,为一种油(760mg,93%)。MS m/z 171(M+H,100%)。
实施例8(S)-3-氨基甲基-6-甲氧基-5-甲基-己酸
根据与合成实施例3类似的方法。从甲醇/乙酸乙酯中重结晶由离子-交换色谱法分离所得的氨基酸,得到实施例8,为一种白色固体。MS m/z 190(M+H,100%)。分析计算C9H19N1O3:C,57.12;H,10.12;N,7.40。发现:C,57.04;H,10.37;N,7.30。从母液中进行第二批沉淀(1H NMR测得1∶5比率的C5异构体)。MS m/z 190(M+H,100%)。
实施例9:合成(3S,5R)-3-氨基甲基-5-甲基-辛酸盐酸盐
(R)-2,6-二甲基-壬-2-烯98
0℃下往处在THF(800mL)中的(S)-香茅基溴化物(50g,0.228mol)加入LiCI(4.3g),然后加入CuCl2(6.8g)。30分钟后,加入氯化甲基镁(在THF中的152mL 3M溶液,Aldrich)并将溶液加热至室温。10小时后,将溶液冷却至0℃并小心加入饱和的氨化铵水溶液。分离所得的两层并用醚提取含水相。干燥(MgSO4)合并的有机相并浓缩得到一种油。32.6g;93%。不经进一步纯化而使用。
13C NMR(100MHz;CDCl3)131.13,125.28,39.50,37.35,32.35,25.92,25.77,20.31,19.74,17.81,14.60。
(R)-4-甲基-庚酸99
50分钟内将在H2SO4(33mL)/H2O(146mL)中的CrO3(39g,0.39mol)溶液加到在丙酮(433mL)中的烯烃98(20g,0.13mol)。60小时后,加入进一步量的在H2SO4(22mL)/H2O(100mL)中的CrO3(26g,0.26mol)。12小时后,用盐水稀释该溶液并用醚提取该溶液。干燥(MgSO4)合并的有机相并浓缩。快速色谱层析(6∶1 to 2∶1己烷/EtOAc的梯度)得到产物99,为一种油。12.1g;65%。MS,m/z(相对强度):143[M-H,100%]。
(4R,5S)-4-甲基-3-((R)-4-甲基-庚酰基)-5-苯基-噁唑烷-2-酮100
0℃下将三甲基乙酰氯化物(20g,0.17mol)加到在THF(500mL)中的酸99(19g,0.132mol)和三乙胺(49.9g,0.494mol)。1小时后加入LiCl(7.1g,0.17mol),然后加入噁唑烷酮(30g,0.17mol)。将混合物加热至室温,在16小时后过滤除去滤液并减压浓缩该溶液。快速色谱法(7∶1己烷/EtOAc)得到产物100,为一种油。31.5g;79%。[α]D=5.5(c1在CHCl3中)。MS,m/z(相对强度):304[M+H,100%]。
(3S,5R)-5-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯101
-50℃下将NaHMDS(在THF中的48mL 1M溶液)加到在THF(200ml)中的噁唑烷酮100(12.1g,0.04mol)。30分钟后加入溴乙酸叔丁酯(15.6g,0.08mol)。-50℃下搅拌该溶液4小时,然后加热到室温。16小时后,加入饱和氯化铵水溶液并分离双层。用醚提取含水相,干燥(MgSO4)合并的有机相并浓缩。快速色谱法(9∶1己烷/EtOAc)得到产物101,为白色固体12g;72%。[α]D=30.2(c1在CHCl3中)。
13C NMR(100MHz;
CDCl3)176.47,171.24,152.72,133.63,128.87,125.86,80.85,78.88,55.34,39.98,38.77,38.15,37.58,30.60,28.23,20.38,20.13,14.50,14.28。
(S)-2-((R)-2-甲基-戊基)-琥珀酸4-叔丁酯102
0℃下将预混合的LiOH(51.2mL 0.8M溶液)和H2O2(14.6mL 30%溶液)的溶液加到在in H2O(73mL)和THF(244mL)中的酯101(10.8g,0.025mol)。24小时后,进一步加入12.8mL LiOH(0.8M溶液)和3.65mL H2O2(30%溶液)。30分钟后,加入酸式亚硫酸钠(7g)、亚硫酸钠(13g)和水(60mL),然后加入己烷(100mL)和醚(100mL)。分离双层并用醚提取含水层。将合并的有机相浓缩至溶于(300mL)庚烷的油。滤出所得的固体,干燥(MgSO4)滤液并浓缩得到一种油(6g,93%),产物不经进一步纯化使用。MS,m/z(相对强度):257[M+H,100%]。
(3S,5R)-3-羟基甲基-5-甲基-辛酸叔丁酯103
0℃下将BH3.Me2(在THF中的36mL 2M溶液,Aldrich)加到在THF(100mL)中的酸102(3.68g,0.014mol),同时将该溶液加热到室温。15分钟后,往溶液中小心加入冰(以控制泡腾),然后加入盐水。用醚提取该溶液,干燥(MgSO4)并的有机相并减压浓缩。快速色谱法(4∶1己烷/EtOAc)得到醇103,为一种油(2.0g,59%)。
13C NMR(100MHz;CDCl3)173.56,80.85,65.91,39.74,39.20,38.90,35.65,29.99,28.31,20.18,19.99,14.56。
(3S,5R)-5-甲基-3-(甲苯-4-磺酰氧基甲基)-辛酸叔丁酯104
室温下将三乙胺(2.4g,0.024mol)、DMAP(20mg)和甲苯磺酰氯(2.3g,0.012mol)加到在CH2Cl2(40mL)中的醇103(1.98g,8.1mmol)。14小时后加入1N的HCl并分离双层。用醚提取含水相,干燥(MgSO4)并的有机相并浓缩。快速色谱法(95%己烷/EtOAc)得到甲苯磺酸酯104,为一种油(2.94g,91%)。13C NMR(100MHz;
CDCl3)171.60,144.92,133.07,130.02,128.12,80.80,72.15,39.73,38.09,37.89,32.67,29.71,28.22,21.83,20.10,19.54,14.49。
(3S,5R)-3-叠氮基甲基-5-甲基-辛酸叔丁酯105
在DMSO(30mL)中将甲苯磺酸酯104(2.92g,7.3mmol)和叠氮化钠(1.43g,0.02mol)加热到~50℃。2小时后,将溶液冷却至室温并用水稀释。用醚提取该溶液,干燥(MgSO4)并的有机相并浓缩得到一种油1.54g,79%。进一步用快速色谱法(95%己烷/EtOAc)纯化得到一种油。[α]D=-8.3(在CHCl3中的c1)。13C NMR(100MHz;CDCl3)
13C NMR(100MHz;CDCl3)172.01,
80.73,54.89,39.73,39.46,39.00,33.40,29.85,28.30,20.15,19.82,14.52。
(S)-4-((R)-2-甲基-戊基)-吡咯烷-2-酮107和(3S,5R)-3-氨基甲基-5-甲基-辛酸叔丁酯106
用5% Pd/C处理叠氮化物105并在氢气氛下摇晃20小时,由此进一步加入200mg 5%Pd/C。6小时后,浓缩滤液得到一种油,由1H NMR发现该油为伯胺106和内酰胺107(1.75g)的混合物,产物不经进一步纯化而使用。
实施例9(3S,5R)-3-氨基甲基-5-甲基-辛酸盐酸盐
用3N HCl(40mL)处理胺 106和内酰胺107(1.74g)的混合物,并将该溶液加热到50℃4小时,然后冷却到室温。12小时后,浓缩溶液并从乙酸乙酯中重结晶残留物得到氨基酸,为一种白色固体605mg。MS,m/z(相对强度):188[M+H,100%]。分析计算C10H21N1O2:H1Cl1C,53.68;H,9.91;N,6.26。发现:C,53.83;H,10.12;N,6.07。
实施例10:合成(3S,5R)-3-氨基甲基-5-甲基-庚酸
甲烷磺酸(S)-3,7-二甲基-辛-6-烯酯108
0℃下将在CH2Cl2(200mL)中的甲烷磺酰氯(26mL,0.329mol)加到在CH2Cl2(800mL)中的S-(-)-香茅醇(42.8g,0.274mol)和三乙胺(91mL,0.657mol)。2小时后于0℃下用1N Hcl洗涤该溶液,然后用盐水洗涤。干燥(MgSO4)有机相并浓缩得到一种油(60.5g,94%),该油不经进一步纯化而使用。
1H NMR(400MHz;CDCl3)5.05(1H,m),4.2(2H,m),2.95(3H,s),1.98(2H,m),1.75(1H,m),1.6(3H,s),1.5(4H,m),1.35(2H,m),1.2(1H,m),0.91(3H,d,J=6.5Hz)。
(R)-2,6-二甲基-辛-2-烯109
0℃下将氢化锂铝(3.8g,0.128mol)加到在THF(1L)中的烯烃108(60g,0.256mol)。7小时后,进一步加入3.8g氢化锂铝,并将溶液加热到室温。1 8小时后,进一步加入3.8g氢化锂铝。在进一步的21小时后,小心地用1N柠檬酸猝灭该反应并进一步用盐水稀释该溶液。分离所得的两层,干燥(MgSO4)有机相并浓缩得到一种油,该油不经进一步纯化而使用。MS,m/z(相对强度):139[M-H,100%]。
(R)-4-甲基-己酸110
采用与(R)-4-甲基-庚酸99的合成类似的方法得到酸,为一种油(9.3g,56%)。MS,m/z(相对强度):129[M-H,100%]。
(4R,5S)-4-甲基-3-((R)-4-甲基-己酰基)-5-苯基-噁唑烷-2-酮111
采用与(4R,5S)-4-甲基-3-((R)-4-甲基庚酰)-5-苯基-噁唑烷-2-酮100的合成类似的方法得到噁唑烷酮111,为一种油(35.7g,95%)。MS,m/z(相对强度):290[M+H,100%]。
(3S,5R)-5-甲基-3-[1-((4R,SS)-4-甲基-2-氧代-5-苯基-噁唑烷-3-基)-甲酰氧基]-庚酸叔丁酯112
根据与(3S,5R)-5-甲基-3-((4R,5S)-4-甲基-2-氧-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯101的制备类似的方法得到112,为一种油(7.48g;31%)。
(S)-2-((R)-2-甲基-丁基)-琥珀酸4-叔丁酯113
将预混合的LiOH(37mL 0.8M溶液)和H2O2(10.57mL 30%溶液)加到在H2O(53mL)和THF(176mL)中的酯112并将该溶液加热到室温。2小时后,加入酸式亚硫酸钠(7g)、亚硫酸钠(13g)和水(60mL),分离双层并用醚提取含水层。将合并的有机相浓缩至一种溶于庚烷(200mL)的油。滤出所得的固体,干燥(MgSO4)滤液并浓缩得到一种油(4.4g),该油不经进一步纯化而使用。
(3S,5R)-3-羟基甲基-5-甲基-庚酸叔丁酯114
采用与(3S,5R)-3-羟基甲基-5甲基-辛酸叔丁酯103的制备类似的方法得到醇114,为一种油(2.68g,69%)。MS,m/z(相对强度):216[89%],174[M-(CH3)3C,100%]。
(3S,5R)-5-甲基-3-(甲苯-4-磺酰氧基甲基)-庚酸叔丁酯115
0℃下将吡啶(2.6g,0.033mol)、DMAP(100mg)和甲苯磺酰氯(3.15g,0.016mol)加到在CH2Cl2(140mL)中的114醇(2.53g,0.011mmol)并将该溶液加热到室温3.5小时,由此再加入DMAP和TsCI(3.15g)。14小时后,加入1N HCl并分离双层。用盐水洗涤有机相,然后或干燥(MgSO4)和浓缩。快速色谱法(95%到86%己烷/EtOAc)得到甲苯磺酸酯115,为一种油(1.53g,36%)。13C NMR(100MHz;
CDCl3)130.03,128.12,72.18,37.89,37.71,32.67,31.49,29.88,28.22,21.83,19.07,11.37。
(3S,5R)-3-叠氮基甲基-5-甲基-庚酸叔丁酯116
采用与(3S,5R)-3-叠氮基甲基-5-甲基-辛酸叔丁酯105的制备类似的方法得到一种油0.956g,97%。MS,m/z(相对强度):228[M-N2,80%]。
(S)-4-((R)-2-甲基-丁基)-吡咯烷-2-酮118和(3S,5R)-3-氨基甲基-5-甲基-庚酸叔丁酯117
用在THF(20mL)中的20% Pd/C(90mg)处理叠氮化物116(689mg)并在氢气下摇晃36小时。过滤除去催化剂并将所得的油不经进一步纯化而使用。
实施例10(3S,5R)-3-氨基甲基-5-甲基-庚酸
用6N HCl处理胺117和内酰胺118的混合物并将溶液加热到50℃17小时然后冷却至室温并浓缩。采用5%氢氧化铵对所得的油进行离子-交换色谱法(Dowex,强酸性树脂)得到膏状固体,从甲醇/乙酸乙酯中将其重结晶得到(3S,5R)-3-氨基甲基-5-甲基-庚酸,实施例10。MS,m/z(相对强度):174[M+H,100%]。分析计算C19H19N1O2。C,62.39;H,11.05;N,8.08。发现:C,62.23;H,11.33;N,7.89。
实施例11:合成(3S,5S)-3-氨基甲基-5-甲基-辛酸
实施例11
(S)-2,6-二甲基-壬-2-烯119
将CuCl2(5.36g,39.7mmol)和LiCl(3.36,80.0mmol)一起在干THF(40mL)中搅拌15分钟。0℃下在氮气氛下将所得的溶液加到在THF(168 mL)中的3.0M氯化甲基镁,并在室温下搅拌15分钟。将在在THF(100mL)中的(R)-(-)-香茅基溴化物(55.16g,251.8mmol)缓慢地加到该反应悬浮液中,并在0℃下搅拌2.5小时。加热到室温并继续搅拌另一小时。将该混合物冷却至0℃并用饱和氯化铵溶液猝灭。然后将该悬浮液提取至醚,用水洗涤,并在MgSO4上干燥。减压浓缩该溶液得到36.3g;94%的(S)-2,6-二甲基-壬-2-烯,为一种油。MS,m/z(相对强度):153[M-1H,100%],194[M-1H+CH3CN,45%]。
(S)-4-甲基-庚酸120
0℃下在1.5小时内将Jones反应剂(2.7M,600mL)滴加到在丙酮(1L)中的(S)-2,6-二甲基-壬-2-烯119(39.0g,253.2mmol)并在室温下搅拌18小时。将该反应混合物倾入到饱和Na2SO4溶液中并提取到醚中。用盐水洗涤并真空浓缩。将油状残留物溶于甲醇(70mL)和1M NaOH(700mL),然后搅拌30分钟。用CH2Cl2洗涤该水溶液,用10% HCl酸化并提取到CH2Cl2。在MgSO4上干燥该溶液并浓缩至干得到24.22g;66%的(S)-4-甲基-庚酸,为一种油。MS,m/z(相对强度):143[M-1H,100%]。
(4R,5S)-4-甲基-3-((S)-4-甲基-庚酰基)-5-苯基-噁唑烷-2-酮121
采用与(4R,5S)-4-甲基-3-((R)-4甲基-庚酰)-5-苯基-噁唑烷-2-酮100的制备类似的方法得到(4R,SS)-4-甲基-3-((S)-4-甲基-庚酰)-5-苯基-噁唑烷-2-酮121,6.2g;80.0%,为一种油。MS,m/z(相对强度):304[M+1H,90%],355[M+1H+CH3CN,60%]。
(3S,5S)-5-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯122
-5℃下在氮下将在己烷(18.0mL,30.1mmol)中的正BuLi,1.6M滴加到在干THF(50mL)中的二异丙基胺(4.6mL,32.6mmol),在加入期间保持温度低于0℃。-5℃下搅拌该混合物20分钟,然后冷却到-78℃。将在THF(12mL)中的121(7.6g,25.1mmol)加到LDA溶液中并在-78℃下搅拌30分钟。将乙酸叔丁酯(4.8mL,32.6mmol)加到该反应物中并在-78℃下持续搅拌2小时。加热到室温,然后搅拌另外18小时。用饱和NaH2PO4溶液猝灭该反应,将其提取至乙酸乙酯,并在MgSO4上干燥。将该溶液浓缩得到一种溶于热己烷中的固体残留物。将该己烷溶液冷却至室温,然后进一步在冰浴上冷却。收集所得的沉淀物并风干得到122,为一种绒毛状白色固体。4.3g;41%。MS,m/z(相对强度):362[M-C(CH3)3+1H,100%],418[M+1H,20%]。
(S)-2-((S)-2-甲基-戊基)-琥珀酸4-叔丁酯和(3S,5S)-3-羟基甲基-5-甲基-辛酸叔丁酯123
0℃下将预混合的30% H2O2(12.2mL)和LiOH(0.8M,42.7mL)溶液加到与THF(203.0mL)和水(61.0mL)混合的酯122。0℃下搅拌所得的溶液4小时。将酸式亚硫酸钠(7g)、亚硫酸钠(13g)和水(60mL)加到该反应物中。然后加入1∶1混合的醚/己烷(200mL)并分离有机相。用醚提取含水相,在MgSO4上干燥合并的有机提取物并真空浓缩。将残留物溶于庚烷并搅拌5分钟。过滤所得的沉淀并将滤液浓缩至干得到一种油。
(3S,5S)-3-羟基甲基-5-甲基-辛酸叔丁酯123
根据与(3S,5R)-3-羟基甲基-5甲基-辛酸叔丁酯103的制备类似的方法得到123,为一种油。4.0g;76.0%。MS,m/z(相对强度):230[M-C(CH3)3+1H+CH3CN,100%],189[M-C(CH3)3+1H,70%]。
(3S,5S)-5-甲基-3-(甲苯-4-磺酰氧甲基)-辛酸叔丁酯124
根据与(3S,5R)-5-甲基-3-(甲苯-4-磺酰氧甲基)-辛酸104的制备类似的方法得到6.9克124。
MS,m/z(相对强度):343[M-C(CH3)3+1H,70%],384[M-C(CH3)3+1H+CH3CN,100%]。
(3S,5S)-3-叠氮基甲基-5-甲基-庚酸叔丁酯125
根据与(3S,5R)-3-叠氮基甲基-5甲基-辛酸叔丁酯105的制备类似的方法得到2.9g;66%的125,为一种油。MS,m/z(相对强度):212[M-C(CH3)3-1H,45%]。
(3S,5S)-3-氨基甲基-5-甲基-辛酸叔丁酯126
在41 PSI下将在甲醇(50.0mL)中的125(2.8g,10.4mmol)和10% Pd/C(1.0g)的混合物氢化96小时。过滤该溶液得到1.7g粗制的126,将其不经进一步纯化而使用。MS,m/z(相对强度):244[M+1H,100%],285[M+1H+CH3CN,25%]。
实施例11(3S,5S)-3-氨基甲基-5-甲基-辛酸
根据与实施例10(3S,5R)-3-氨基甲基-5-甲基-庚酸的制备的类似的方法得到实施例11.380mg;29.0%。
1H NMR(CD3OD)δ2.90(dd,J=3.9,8.8Hz,1H),2.80(dd,J=7.6,5.1Hz,1H),2.40(dd,J=3.2,12.51Hz,1H),2.20(dd,J=8.8,6.8Hz,1H),2.05(m,1H),1.55(m,1H),1.30(m,3H),1.10(m,2H),0.85(m,6H);MS,m/z(相对强度):187[M+1H,100%],211[M+1H+CH3CN,30%]。
实施例12:合成(3S,5S)-3-氨基甲基-5-甲基-庚酸
实施例12
(S)-2,6-二甲基-辛-2-烯127
0℃下在45分钟内将(R)-(-)-香茅基溴化物(49.1g,224.2mmol)滴加到在THF(336mL,336mmol)中的1.0M LAH。0℃下继续搅拌另外4小进。用饱和化铵溶液缓慢地猝灭反应然后加入醚(100mL)。过滤所得的白色结晶浆液并在MgSO4上干燥滤液。减压浓缩溶液得到26.2g;83%的127,为一种油。MS,m/z(相对强度):180[M-1H+CH3CN,100%],139[M-1H,90%]。
(S)-4-甲基-己酸128
采用与化合物120的制备类似的方法得到15.9g的128,为一种油。MS,m/z(相对强度):129[M-1H,100%],170[M-1H+CH3CN,70%]。
(4R,5S)-4-甲基-3-((S)-4-甲基-己酰基)-5-苯基-噁唑烷-2-酮129
采用与用于(4R,5S)-4-甲基-3-((S)-4甲基-庚酰)-5-苯基-噁唑烷-2-酮121的制备类似的方法得到35.0g粗品(4R,5S)-4-甲基-3-((S)-4-甲基-己酰)-5-苯基-噁唑烷-2-酮129,为一种油。将其不经进一步纯化使用。MS,m/z(相对强度):290[M+1H,100%],331[M+1H+CH3CN,20%]。
(3S,5S)-5-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-庚酸叔丁酯130
采用与用于(3S,5S)-5-甲基-3-((4R,5S)-4-甲基-2-氧-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯122的制备类似的方法得到4.6.0g,25.4%的130,为一种白色固体。MS,m/z(相对强度):348[M-C(CH3)3+1H,100%],443[M-1H+CH3CN,100%],402[M-1H,55%],404[M+1H,45%]。
(3S,5S)-3-羟基甲基-5-甲基-庚酸叔丁酯131
与用于制备(3S,5S)-3-羟基甲基-5甲基-辛酸叔丁酯123类似的方法得到1.2g,52.1%的131,为一种油。MS,m/z(相对强度):175[M-C(CH3)3+1H,100%],173[M-C(CH3)3-1H,100%],216[M-C(CH3)3+1H+CH3CN,95%]。
(3S,5S)-5-甲基-3-(甲苯-4-磺酰氧基甲基)-庚酸叔丁酯132
根据与(3S,5R)-5-甲基-3-(甲苯-4磺酰氧基甲基)-辛酸叔丁酯104的制备类似的方法得到2.1g的132,为一种油。产物不经进一步纯化用于下一步骤。MS,m/z(相对强度):329[M-C(CH3)3+1H,85%],370[M-C(CH3)3+1H+CH3CN,65%]。
(3S,5S)-3-叠氮基甲基-5-甲基-庚酸叔丁酯133
根据与(3S,5R)-3-叠氮基甲基-5甲基-辛酸叔丁酯105的制备类似的方法得到0.76g,54.0%的133,为一种油。MS,m/z(相对强度):198[M-C(CH3)3-1H,100%]。
(3S,5S)-3-氨基甲基-5-甲基-庚酸叔丁酯134
采用与用于(3S,5S)-3-氨基甲基-5-甲基辛酸叔丁酯126的类似的方法得到0.62g的134,为一种油。产物不经进一步纯化而用于下一步骤。MS,m/z(相对强度):230[M+1H,100%],271[M+1H+CH3CN,45%]。
实施例12(3S,5S)-3-氨基甲基-5-甲基-庚酸
采用与用于实施例11的类似方法得到(3S,5S)-3-氨基甲基-5-甲基-庚酸(0.3g,65.1%),为白色固体。1H NMR
(CD3OD)δ2.80-3.00(m,2H),2.40(m,1H),2.20(dd,J=8.2,7.1Hz,1H),2.05(m,1H),1.30-1.50(m,3H),1.00-1.20(m,2H),0.9(m,6H);MS,m/z(相对强度):187[M+1H,100%],211[M+1H+CH3CN,30%]。MS,m/z(相对强度):174[M+1H,100%],172[M-1H,100%],215[M+1H+CH3CN,20%]。
实施例13:合成(3S,5R)-3-氨基甲基-5-甲基-壬酸盐酸盐
(R)-4-甲基-辛酸136
外周温度下在45ml THF中合并氯化锂(0.39g,9.12mmol)和氯化铜(I)(0.61g,4.56mmol)并搅拌15分钟,然后冷却至0℃,此时加入溴化乙基镁(在THF中的1M溶液,45mL,45mmol)。滴加入(S)-香茅基溴化物(5.0g,22.8mmol)并将该溶液缓慢加热到外周温度搅拌过夜。小心加入盐NH4Cl(aq)猝灭该反应,并用Et2O和盐NH4Cl(aq)搅拌30分钟。分离相,干燥该有机相(MgSO4)并浓缩。粗产物不经纯化而使用。
0℃下将Jones’反应剂(在H2SO4(aq)中2.7M,40mL,108mmol)加到在50mL丙酮中的烯烃135(3.8g,22.8mmol)溶液并将溶液缓慢加热至外周温度搅拌过夜。在Et2O和H2O之间分离该混合物,分离相,用盐水洗涤有机相,干燥(MgSO4),并浓缩。残留物用快速色谱法(8∶1己烷∶EtOAc)纯化得到2.14g(59%)的酸136,为一种无色油:LRMS:m/z 156.9(M+);1H NMR(CDCl3):δ2.33(m,2H),1.66(m,1H),1.43(m,2H),1.23(m,5H),1.10(m,1H),0.86(m,6H)。合并26.7g CrO3、23mL H2SO4,并用水稀释至100ml而制备Jones’反应剂为2.7M的溶液。
(4R,5S)-4-甲基-3-((R)-4-甲基-辛酰基)-5-苯基-噁唑烷-2-酮137
0℃下向在25mL CH2Cl2中的酸136(2.14g,13.5mmol)加入3滴DMF,然后加入草酰氯(1.42mL,16.2mmol),导致剧烈的气体放出。将该溶液直接加热到外周温度,搅拌30分钟,并浓缩。同时,在-78℃下将正丁基锂(1.6M溶于己烷,9.3mL,14.9mmol)滴加到在40mL的THF中的噁唑烷酮(2.64g,14.9mmol)。搅拌该混合物10分钟,此时滴加入在10ml的THF中的酰基氯。-78℃搅拌反应物30分钟,然后直接加热至外周温度并用盐NH4Cl猝灭反应。在Et2O和盐NH4Cl(aq)之间分离该混合物。分离相,干燥(MgSO4)有机相,并浓缩至提供3.2g的噁唑烷酮137,为无色油。LRMS:m/z 318.2(M+);1H NMR(CDCl3):δ7.34(m,5H),5.64(d,J=7.3Hz,1H),4.73(五重峰,J=6.8Hz,1H),2.96(m,1H),2.86(m,1H),1.66(m,1H),1.47(m,2H),1.26(m,5H),1.13(m,1H),0.88(m,9H)。粗产物不经进一步纯化而使用。
(3S,5R)-5-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-壬酸叔丁酯138
-78℃下将正丁基锂(1.6M溶于己烷,7.6mL,12.1mmol)加到在30mL THF中的二异丙基胺(1.8mL,12.6mmol),搅拌混合物10分钟,此时滴加入在10mL THF中的噁唑烷酮137(3.2g,10.1mmol)。搅拌该溶液30分钟,-50℃下快速滴加入溴乙酸叔丁酯(1.8mL,12.1mmol),3小时内将该混合物缓慢加热至10℃。在Et2O和盐NH4Cl(aq)之间分离该混合物,分离相,干燥有机相(MgSO4),并浓缩。残留物用快速色谱法(16∶1-8∶1己烷s:EtOAc)纯化得到2.65g(61%)酯138,为无色晶状固体,mp=84-86℃。
[α]D 23+17.1(c=1.00,CHCl3);1H NMR(CDCl3):δ7.34(m,5H),5.62(d,J=7.3Hz,1H),4.73(五重峰,J=6.8Hz,1H),4.29(m,1H),2.67(dd,J=9.8,16.4Hz,1H),2.40(dd,J=5.1,16.4Hz,1H),1.69(m,1H),1.38(s,9H),1.28(m,7H),1.08(m,1H),0.88(m,9H);13C NMR(CDCl3)δ 176.45,171.22,152.71,133.64,128.86,125.86,80.83,78.87,55.33,40.02,38.21,37.59,36.31,30.86,29.29,28.22,23.14,20.41,14.36,14.26。分析计算C25H37NO5:C,69.58;H,8.64;N,3.25。实测:C,69.37;H,8.68;N,3.05。
(S)-2-((R)-2-甲基-己基)-琥珀酸4-叔丁酯139
0℃下将预冷却(0℃)的在10ml H2O中的LiOH一水合物(1.0g,23.8mmol)和过氧化氢(30wt%水溶液,5.0mL)溶液加到在20mL THF中的酯38(2.65g,6.14mmol)的溶液。剧烈搅拌混合物90分钟,然后加热至外周温度并搅拌90分钟。0℃下加入100mL 10%NaHSO3(aq)猝灭反应,然后用Et2O提取。分离各相,用盐水洗涤有机相,干燥(MgSO4),并浓缩。粗品酸139不经纯化而使用。
(3S,5R)-3-羟基甲基-5-甲基-壬酸叔丁酯140
0℃下将硼烷-二甲基硫化物配合物(2.0M soln in THF,4.6mL,9.2mmol)加以在30mL THF中的粗品酸139(6.14mmol)的溶液,将溶液缓慢加热到外周温度过夜。加入额外的BH3-DMS直至该酸被完全消耗(计算5mL)。加入MeOH猝灭反应,然后在Et2O和盐NaHCO3(aq)之间分离。分离相,用盐水洗涤有机相,干燥(MgSO4),并浓缩得到醇140。LRMS:m/z 226.1;1H NMR(CDCl3):δ3.63(dd,J=11.0,4.2Hz,1H),3.42(dd,J=11.0,6.8Hz,1H),2.30(dd,J=14.9,7.6Hz,1H),2.20(dd,J=14.9,5.6Hz,1H),2.03(m,2H),1.42(s,9H),1.24(m,6H),1.02(m,2H),0.85(m,6H)。粗产物不经纯化使用。
(3S,5R)-5-甲基-3-(甲苯-4-磺酰氧基甲基)-壬酸叔丁酯141
0℃下向在30mL CH2Cl2中的醇140(6.14mmol)加入DMAP(0.1g)、对甲苯磺酰氯(1.37g,7.2mmol),然后快速滴加入三乙胺(1.8mL,13mmol)。在加入并搅拌过夜后立即将混合物加热到外周温度,并不要进行完全。Et2O和1N HCl(aq)之间分离该混合物,分离相并用盐NaHCO3(aq)洗涤有机相,干燥(MgSO4)并浓缩得到甲苯磺酸酯141。产物不经进一步纯化而使用。
(3S,5R)-3-叠氮基甲基-5-甲基-壬酸叔丁酯142
根据与(3S,5R)-3-叠氮基甲基-5-甲基-辛酸叔丁酯105的制备类似的方法得到叠氮化142,为一种无色油。
LRMS:m/z 200.1;1H NMR(CDCl3):δ3.31(dd,J=12.2,4.2Hz,1H),3.19(dd,J=12.2,5.9Hz,1H),2.22(m,1H),2.10(m,1H),1.39(s,9H),1.21(m,8H),1.00(m,2H),0.81(m,6H)。
实施例13(3S,5R)-3-氨基甲基-5-甲基-壬酸盐酸盐
在20% Pd/C、EtOH的存在下,在45psi的H2下将叠氮化物142(1.0g)氢化15小时得到粗品氨基酯143,然后将其浓缩并不经纯化而使用。将6mL 6N HCl(aq)加到氨基酯143并将该混合物加热到回流90分钟,冷却并浓缩。从EtOAc∶己烷中重结晶得到0.38g(45%自叠氮化物)的(3S,5R)-3-氨基甲基-5-甲基-壬酸盐酸盐,为一种无色晶状固体(HCl盐),第二次收取82mg(10%自叠氮化物)。
mp=146-156℃.LRMS:m/z 200.1(M+);1H NMR
(CDCl3):δ2.87(dd,J=13.2,5.4Hz,1H),2.79(dd,J=13.2,7.3Hz,1H),2.29(d,J=6.8Hz,2H),2.08(m,1H),1.31(m,1H),1.09(m,7H0,0.92(m,1H),0.68(m,6H)。分析计算C11H24NO2Cl:C,55.57;H,10.17;N,5.89.实测:C,55.69;H,10.10;N,5.86。
实施例14:合成(3S,5S)-3-氨基甲基-5-甲基-壬酸
根据以上用于(R)-4-甲基-辛酸136所列的方案由(R)-香茅基溴化物制备(S)-酸145。产量相当,且1H NMR光谱与(R)-酸对映体的光谱相同。LRMS:M/z 158.9(M+1)。
如以上关于(4R,5S)-4-甲基-3-((R)-4-甲基-辛酰)-5-苯基-噁唑烷-2-酮137所述由酸145制备噁唑烷酮146。
LRMS:m/z 290.1(M-27);1H NMR(CDCl3):δ7.38(m,3H),7.28(m,2H),5.64(d,J=7.1Hz,1H),4.74(五重峰,J=6.8Hz,1H),2.92(m,2H),1.71(m,1H),1.42(m,7H),1.18(m,1H),0.88(m,9H)。
如以上关于化合物138所述由噁唑烷酮146制备叔丁酯147。LRMS:m/z 348.1(M-83)。
如以上关于(3S,5R)-3-羟基甲基-5-甲基-壬酸叔丁酯140所述由叔丁酯147制备醇149。LRMS:
m/z 156.9(M-100);1H NMR(CDCl3):δ3.60(dd,J=11.0,4.6Hz,1H),3.45(dd,J=11.0,6.8Hz,1H),2.24(m,2H),2.04(m,2H),1.42(s,9H),1.17-1.38(m,7H),1.11(m,1H),0.84(m,6H)。
实施例14:(3S,5S)-3-氨基甲基-5-甲基-壬酸
如以上关于(3S,5R)-3-氨基甲基-5-甲基-壬酸盐酸盐所述由147得到(3S,5S)-3-氨基甲基-5-甲基-壬酸。通过在Dowex 50WX8 50-100筛目、H-形式树脂上的离子交换色谱法纯化如此得到的粗品HCl盐,采用10% NH4OH作为洗脱剂得到游离碱。用Et2O洗涤蜡状固体两次并干燥得到一种无定形白色固体,mp 144-146℃。LRMS:
m/z 172.0(M-28);1H NMR(CDCl3):δ2.76(d,J=5.9Hz,2H),2.14(m,1H),1.96(m,2H),1.25(m,1H),1.12(m,6H),0.96(m,2H),0.66(m,6H)。
实施例15:合成(3S,5R)-3-氨基甲基-5-甲基-癸酸
(R)-2,6-二甲基十一碳-2-烯153
采用与(S)-2,6-二甲基-壬-2-烯119的制备类似的方法得到153,为一种无色油(20.16g,98%)。1H NMR(400MHz,
CDCl3)δ5.10-5.06(m,1H),2.10-1.89(m,2H),1.66(s,3H),1.58(s,3H),1.34-1.23(m,4H),1.15-1.06(m,2H),0.88-0.81(m,11H)。
(R)-4-甲基壬酸154
将(R)-2,6-二甲基十一碳-2-烯153(10.03g,55.03mmol)溶于丙酮(270mL)并冷却到0℃。滴加入Jones反应剂(CrO3/H2SO4)(2.7M,120mL),然后加热到室温18小时。将反应物倾入水/Na2SO4(200mL),用乙酸乙酯(4×100mL)提取含水层。在MgSO4上干燥合并的有机物,过滤并旋转蒸得到一种油。将粗品油溶于CH2Cl2(400mL)并冷却至-78℃。使臭氧冒泡进入反应直至变蓝以除去痕量的杂质(6E)(3S)-3,7二甲基辛-1,6-二烯。加入二甲基硫化物(5mL),在室温下搅拌反应物2小时。除去溶剂,在二氧化硅上色谱层析粗品,用20% EtOAc/己烷洗脱得到一种油。将该油溶于醚(100mL)并用10%NaOH(2×25mL)提取。合并含水层并用醚(50mL)提取。将含水层冷却至0℃并用HCl酸化。用EtOAc(3×100mL)提取酸性层,在MgSO4上提取合并的提取物,过滤并旋转蒸发得到154,为一种油(6.86g,54%)。1H NMR
(400MHz,CDCl3)δ2.40-2.25(m,4H),1.70-1.62(m,2H),1.47-1.11(m,8H),0.87-0.84(m,6H);[α]D=-11.4(c1 in CHCl3)。
(4R,5S)-4-甲基-3-((R)-4-甲基-壬酰基)-5-苯基-噁唑烷-2-酮155
将化合物154(6.504g,37.76mmol)溶于THF(95mL)并冷却至0℃。滴加入三乙胺(19.74mL,141.6mmol),然后滴加入三甲基乙酰氯化物(6.98mL,56.64mmol)。0℃下搅拌稠白悬浮液90分钟。加入LiCl(1.86g,41.54mmol)、(4R)-4-甲基-5-苯基-1,3-噁唑烷-2-酮(6.824g,38.51mmol)和THF(70mL),将反应物加热到室温过夜。蒸发溶剂。将固体置于EtOAc,滤出,并用EtOAc大量洗涤。用水(2×50mL)和盐水洗涤滤液。在MgSO4上干燥有机物,过滤并旋转蒸发。在二氧化硅上色谱层析粗品,用10% EtOAc/己烷洗脱得到155,为一种油(10.974g,88%)。1H NMR(400MHz,
CDCl3)δ7.44-7.35(m,3H),7.31-7.26(m,2H),5.66(d,J=7.33Hz,1H),4.76(五重峰,J=7.03Hz,1H),3.04-2.96(m,1H),2.93-2.86(m,1H),1.74-1.66(m,1H),1.52-1.47(m,1H),1.46-1.36(m,2H),1.27-1.16(m,2H),0.92-0.87(m,8H);[α]D=+34.1(c1 in CHCl3)。
(3S,5R)-5-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-癸酸叔丁酯156
根据与(3S,5S)-5-甲基-3-((4R,5S)-4-甲基-2-氧-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯122的制备类似的方法得到(3S,5R)-5-甲基-3-((4R,5S)-4-甲基-2-氧-5-苯基-噁唑烷-3-羰基)-癸酸叔丁156,为一种油(0.668g,90%)。
1H NMR(400MHz,CDCl3)δ7.41-7.28(m,5H),5.63(d,J=7.33Hz,1H),4.74(五重峰,J=6.84Hz,1H),4.33-4.26(m,1H),2.68(dd,J=16.4,9.77Hz,1H),2.41(dd,J=16.6,4.88Hz,1H),1.68(五重峰,J=6.6Hz,1H),1.50-1.32(m,10H),1.28-1.21(m,1H),1.15-1.08(m,1H),0.90-0.86(m,9H);MS(APCI)m/z348(M+-97,100%);[α]D=+18.8(c1 in CHCl3)。
(S)-2-((R)-2-甲基-庚基)-琥珀酸4-叔丁酯157
将化合物156(5.608b,12.59mmol)溶于THF/H2O(60mL/14mL)并冷却至0℃。合并LiOH(1N,18.89mL)和H2O2(35%,4.45mL,50.4mmol),然后滴加到反应物中保持T<5℃。0℃下搅拌反应物4小时,用滴加的在50mLH2O中的Na2SO3(6.3g)和NaHSO3(3.4g)来猝灭反应。搅拌反应物15分钟,分层。用EtOAc(3×100mL)提取含水层,在MgSO4上干燥合并的提取物,过滤,并旋转蒸发得到一种油。将粗品溶于EtOAc(10mL)并滴加至庚烷(250mL)。搅拌悬浮液20分钟,过滤该固体并用庚烷洗涤。用60℃H2O(100mL)洗涤滤液,在MgSO4上干燥,过滤并旋转蒸发得到157,为一种油(3.52g)。将该物质直接用于下一步骤。
(3S,5R)-3-羟基甲基-5-甲基-癸酸叔丁酯158
将化合物157(3.52g,12.3mmol)溶于无水THF(123mL)并冷却至0℃。滴加硼烷二甲基硫化物配合物(10M,3.69mL),加热反应物至室温并搅拌1小时。将反应物冷却至0℃,用滴加的MeOH(20mL)猝灭反应。搅拌反应物18小时,旋转蒸掉溶剂。在二氧化硅上色谱层析粗品,用20% EtOAc/己烷洗脱得到158(2.28g,68%),为一种油。
1H NMR(400MHz,
CDCl3)δ3.65-3.59(m,1H),3.43(dd,J=11.1,6.96Hz,1H),2.31(dd,J=14.9,7.57Hz,1H),2.21(dd,J=15.1,5.62Hz,1H),2.06-2.02(m,1H),1.43(s,9H),1.40-1.25(m,4H),1.07-1.13(m,1H),1.03-0.96(m,1H),0.86-0.84(m,6H);MS(APCI)m/z 216(M+-56,100%)。
(3S,5R)-5-甲基-3-(甲苯-4-磺酰氧基甲基)-癸酸叔丁酯159
将化合物158(2.27g,8.33mmol)溶于CH2Cl2(30mL)并冷却至0℃。加入甲苯磺酰氯(1.91g,10.0mmol)和催化剂DMAP,然后滴加入三乙胺(2.55mL,18.33mmol)。然后在0℃下搅拌反应物18小时。旋转蒸发掉溶剂(减压下除去),用EtOAc洗涤粗品并过滤。用EtOAc洗涤固体,并用0.5N HCl(20mL)、盐水(30mL)洗涤滤液,在MgSO4上干燥,过滤并旋转蒸发。在二氧化硅上色谱层析该油,用5% EtOAc/己烷梯度洗脱至10% EtOAc/己烷得到159(3.399g,96%),为一种油。1H NMR(400MHz,
CDCl3)δ7.75(d,J=8.30Hz,2H),7.31(d,J=8.30Hz,2H),3.99(dd,J=9.65,3.54Hz,1H),3.89(dd,J=9.52,5.37Hz,1H),2.42(s,3H),2.28(dd,J=14.7,6.23Hz,1H),2.19-2.14(m,1H),2.10(dd,J=14.9,6.35Hz,1H),1.38(s,9H),1.31-1.17(m,3H),1.08-0.81(m,2H),0.79-0.76(m,6H);[α]D=-10.1(c1 inCHCl3)。
(3S,5R)-3-叠氮基甲基-5-甲基-癸酸叔丁酯160
合并化合物159(3.01g,7.05mmol)、叠氮化钠(1.26g,19.40mmol)和DMSO(12mL)并加热到60℃30分钟。将EtOAc(100mL)加到反应物并过滤。用EtOAc(20mL)洗涤固体,并过滤蒸发。在二氧化硅上色谱层析粗品,用5% EtOAc/己烷洗脱得到160,为一种油(1.86g,89%)。
(3S,5R)-3-氨基甲基-5-甲基-癸酸叔丁酯161
在5% Pd/C上在氢下摇晃在THF(50mL)中的化合物(1.86g,6.25mmol)的溶液8小时,同时用氢净化三次。滤出催化剂并蒸发滤液。在二氧化硅上色谱层析粗品,用甲醇洗脱得到161,为一种油(1.21g,71%)。
1H NMR(400MHz,CDCl3)δ2.70(dd,J=12.9,4.40Hz,1H),2.54(dd,J=12.7,6.59Hz,1H),2.26(dd,J=14.5,6.96,1H),2.12(dd,J=14.5,6.47Hz,1H),1.91(m,1H),1.91(m,1H),1.43(s,12H),1.39-1.25(m,4H),1.14-1.07(m,1H),1.03-0.97(m,1H),0.86-0.82(m,6H)。
实施例15(3S,5R)-3-氨基甲基-5-甲基-癸酸
在3N HCl(30mL)中将化合物161(1.20g,4.44mmol)加热到50℃ 4小时。蒸发溶剂,用甲苯洗涤该油,并蒸发。粗品经过离子交换柱(Dowex 50WX8-100,强酸性),用水洗脱,然后用0.5N NH4OH洗脱。分离(3S,5R)-3-氨基甲基-5-甲基-癸酸为一种白色固体(0.725g,75%):
mp=174-175℃;1H NMR(400MHz,CDCl3)δ2.83(dd,J=12.69,4.88Hz,1H),2.70(dd,J=13.1,7.45Hz,1H),2.08(d,J=6.59Hz,2H),1.98(m,1H),1.28-1.20(m,1H),1.19-1.09(m,2H),0.99-0.91(m,2H),0.66(m,6H);MS(APCI)m/z 215(M+,10%),174(M+-41,100%);[α]D=-5.7(c1.025 in H2O)。
实施例16:合成(3S,5S)-3-氨基甲基-5-甲基-癸酸
(S)-2,6-二甲基-十一碳-2-烯162
在N2气氛下将氯化正丙基镁/醚溶液(2.0M,228mL)冷却到-20℃。合并LiCl(3.87g,91.25mmol)、CuCl2(6.13g,45.63mmol)和蒸馏的THF(456mL)并搅拌30分钟。通过套管将Li2CuCl溶液加到格利雅反应剂,-20℃下搅拌所得的溶液30分钟。将R-(-)香茅基溴化物(50g,228.1mmol)溶于THF(60mL)并滴加至格利雅溶液中。0℃下搅拌反应物1小时。将反应物冷却至-40℃并用滴加的NH4Cl(sat’d,200mL)猝灭。分层并用醚(3×100mL)提取含水层。在MgSO4上干燥合并的有机物,过滤,并旋转蒸发得到一种油。在二氧化硅上色谱层析粗品,用己烷洗脱得到162,为无色油(9.15g,22%)。1H NMR(400MHz,CDCl3)δ5.10-5.06(m,1H),2.10-1.89(m,2H),1.66(s,3H),1.58(s,3H),1.34-1.23(m,4H),1.15-1.06(m,2H),0.88-0.81(m,11H)。
(S)-4-甲基壬酸163
将化合物162(7.97g,43.7mmol)溶于丙酮(214mL)并冷却到0℃。滴加Jones反应剂(CrO3/H2SO4)(2.7M,95mL),并将反应物加热至室温18小时。将反应物倾入水/Na2SO4(200mL),用乙酸乙酯(4×100mL)提以含水层。在MgSO4上干燥合并的有机物,过滤,并旋转蒸发得到一种油。在二氧化硅上色谱层析粗品油,用己烷洗脱得到163,为一种油(5.56g,74%)。
1H NMR(400MHz,CDCl3)δ2.40-2.25(m,4H),1.70-1.62(m,2H),1.47-1.11(m,8H),0.87-0.84(m,6H);MS APCI m/z 170.9(M-1,100%)。
(4R,5S)-4-甲基-3-((S)-4-甲基-壬酰基)-5-苯基-噁唑烷-2-酮164
采用与用于制备化合物155的类似方法,除了将(S)-4-甲基壬酸163(5.56g,32.27mmol)用作反应剂,得到164,为一种油(10.70g100%)。1H NMR(400MHz,CDCl3)δ7.42-7.34(m,3H),7.28(d,J=6.59Hz,2H),5.64(d,J=7.33Hz,1H),4.74(五重峰,J=6.78Hz,1H),2.94-2.85(m,2H),1.73-1.67(m,1H),1.47-1.43(m,1H),1.39-1.22(m,7H),0.90-0.84(m,8H)。
(3S,5S)-5-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-癸酸叔丁酯165
采用与用于制备化合物156类似的方法得到165,为一种固体(4.25g,61%)。MS(APCI)m/z 446(M++1,10%),390(M+-55,100%,-tBu)。
(S)-2-((S)-2-甲基-庚基)-琥珀酸4-叔丁酯166
采用用于化合物157的类似的方法,除了将酯165(8.42g,18.89mmol)用作反应剂得到166,为一种油(5.81g)。将该物质直接用于下一步骤。MS(APCI)m/z 285(M-1,100%)。
(3S,5S)-3-羟基甲基-5-甲基-癸酸叔丁酯167
采用与制备化合物158类似的方法,除了将(S)-2-((S)-2-甲基-庚基)-琥珀酸4-叔丁酯166(5.78g,20.18mmol)用作反应剂,得到167,为一种油(4.18g,76%)。1H NMR(400MHz,CDCl3)δ3.64-3.58(m,1H),3.84-3.42(m,1H),2.28-2.20(m,1H),2.09-2.02(m,1H),1.43(s,9H),1.26-1.18(m,8H),1.11-1.04(m,2H),0.87-0.83(m,6H);MS(APCI)m/z 217(M+-55,50%,-tBu)。
(3S,5S)-5-甲基-3-(甲苯-4-磺酰氧基甲基)-癸酸叔丁酯168
采用与用于制备化合物159的类似的方法,除了将(3S,5S)-3-羟基甲基-5-甲基-癸酸叔丁酯167(4.164g,15.29mmol)用作反应剂,得到168,为一种油(4.17g,64%)。
1H NMR(400MHz,CDCl3)δ7.75(d,J=8.30Hz,2H),7.31(d,J=8.30Hz,2H),3.97(dd,J=9.52,4.15Hz,1H),3.90(dd,J=9.52,5.13Hz,1H),2.42(s,3H),2.28,2.19-2.13(m,2H),1.37(s,9H),1.27-1.01(m,11H),0.85(t,J=7.08Hz,3H),0.76(d,J=6.35Hz,3H)。
(3S,5S)-3-叠氮基甲基-5-甲基-癸酸叔丁酯169
采用与用于制备化合物160的类似方法,除了将(3S,5S)-5-甲基-3-(甲苯-4-磺酰氧基甲基)-癸酸叔丁酯168(4.155g,9.74mmol)用作反应剂,得到169,为一种油(2.77g,96%)。MS(APCI)m/z270(M+-27,30%,-N2),214(M+-87,100%,-tBu,-N2)。
(3S,5S)-3-氨基甲基-5-甲基-癸酸叔丁酯170
采用与用于制备化合物161类似的方法,除了将(3S,5S)-3-叠氮基甲基-5-甲基-癸酸叔丁酯169(2.50g,8.405mmol)用为反应剂,得到170,为一种油(1.648g,72%)。MS(APCI)m/z 272(M++1,100%)。
实施例14(3S,5S)-3-氨基甲基-5-甲基-癸酸
采用与用于实施例15的类似的方法,除了将(3S,5S)-3-(氨基甲基)-5-甲基癸酸叔丁酯170(1.6g,6.00mmol)用作反应剂,得到实施例16,为一种白色固体(72%)。MS(APCI)m/z 272(M++1,100%)。mp=174-175℃;1H NMR(400MHz,CD3OD)δ2.91(dd,J=12.9,3.91Hz,1H),2.83(dd,J=12.7,7.57Hz,1H),2.43(dd,J=15.6,3.17Hz,1H),2.19(dd,J=15.6,8.80Hz,1H),2.08-2.04(m,1H),1.53(m,1H),1.38-1.27(m,7H),1.78-1.03(m,2H),0.90-0.86(m,6H),0.66(m,6H);MS(APCI)m/z 216(M++1,100%),214(M-1,100%);[α]D=+21.4(c1 in MeOH)。
实施例17:合成(3R,4R)-3-氨基甲基-4,5-二甲基-己酸
实施例17
(S)-2-苄基-3-甲基-丁-1-醇172
参照JACS 1997;119:6510.酰胺(Amide)171。
由171大规模合成乙酸(S)-2-苄基-3-甲基丁酯173的方法
-78℃下将正丁基锂(10M在己烷中,100mL,1000mmol,3.9当量)加到在THF(600mL)中的二异丙基胺(108.9g,150.9mL,1.076mol,4.20当量)。搅拌所得的溶液10分钟并加热到0℃,在该温度下放置10分钟。将硼烷-氨水配合物(31.65g,1.025mmol,和4.0当量)部分加入,0℃下搅拌该悬浮液15分钟,在23℃下搅拌15分钟,然后冷却至0℃。3分钟内通过套管将在THF中的酰胺171(86g,256.41mmol,1当量)的溶液加到冷的氢化物中。23℃下搅拌反应物过夜,然后冷却至0℃。通过缓慢加入3N HCl(700mL)而猝灭过量的氢化物。用更多的含水HCl(3N,200mL)和盐水洗涤反应混合物,然后用醚(4×15mL)提取。浓缩醚溶液至小体积,加入200mL 2N的NaOH,并在23℃下搅拌2.5小时。加入更多的醚并分层。用盐饱和含水层,并用醚(3×200mL)提取。用盐水洗涤合并的有机物,并在硫酸钠上干燥。快速色谱层析(石油醚-25%醚-TEA)残留物得到醇172,50g。NMR(CDCl3)δ7.35-7.16(m,5H,C6H5),3.55(app.t,2H,-CH2OH),2.71(dd,1H,ArCH2CH-),2.52(dd,1H,ArCH2CH),1.87(m,1H,CHCH(Me),1.67(m,1H,CH(Me)2),0.98(d,3H,CH3)和0.96(d,3H,CH3)。
保存3.3g试样用于表征,剩余的立即在室温下乙酰化(三乙胺50mL,DMAP 4.6g,乙酐32mL)过夜。然后在硅胶上进行色谱层析,用石油醚洗脱,然后用在石油醚中的10%的醚洗脱得到62g有173。NMR(CDCl3)δ7.30-7.14(m,5H,C6H5),3.98(m,2H,-CH2OAc),2.71(dd,1H,ArCH2CH-),2.51(dd,1H,ArCH2CH),1.99(s,3H,CH3C=O),1.82(m,1H,CHCH(Me)和CH(Me)2),0.97(d,3H,CH3)和0.95(d,3H,CH3)。
(S)-乙酰氧基甲基-4-甲基-戊酸174和(S)-4-异丙基-二氢呋喃-2-酮175
将乙酸酯173(15g,68.18mmol)溶于CH3CN(150mL)、四氯化碳(150mL)和HPLC等级水(300mL),并搅拌。加入高碘酸钠(262.50g,1220mmol),然后加入氯化钌(650mg,3.136mmol)。过夜搅拌后,用醚和水稀释,通过才利特垫过滤。分离有机部分,含水相进一步用醚提取。在硫酸镁上干燥,然后蒸发溶剂。将碳酸钾加到残留物中,在甲醇(250mL)中回流过夜并冷却至室温。蒸发后,加入水以溶解固体,并加入浓HCl将PH调至2。加入氯仿并提取过夜。分离有机相,进一步用氯仿提取含水相。干燥合并的有机提取物,在硅胶柱上纯化产物并用在二氯化乙烯中的20%醚洗脱化合物。用薄层色谱法监测馏分,用I2/KI溶液检测斑点。合并馏并得到4.6g内酯175。
NMR(CDCl3)δ4.38(dd,1H,CHaHbO),3.93(app.t,1H,CHaHbO),2.54(dd,1H,CHcHd C=O),2.23(m,2H,CHCH(Me)和CHcHd C=O),1.60(m,1H,CH(Me)2),0.92(d,3H,CH3)和0.85(d,3H,CH3)。
(3R,4R)-3-苄基-4-异丙基-二氢呋喃-2-酮176
3-5分钟内,-78℃下于氩气氛下将双(三甲基甲硅烷基)酰胺锂(1.0M溶液在THF中,92mL,92mmol)加到在100mL干THF中的(S)-β-(2-丙基)-γ-丁内酯175(11.68g,91.25mmol)溶液中。搅拌1小时,快速加入处在干THF中的苄基碘化物(21.87g,100.37mmol)溶液。继续搅拌1.5小时并在-78℃下加入盐水溶液,然后加入乙酸乙酯来猝灭反应。分离有机相,并进一步用醚提取含水相。在硅胶上色谱层析,首先用在石油醚中的5%二氯甲烷洗脱,最后用在石油醚中的10%醚洗脱,得到期望的化合物11.6g,58%。
NMR(CDCl3)δ7.19(m,5H,C6H5),4.02(app.t,1H,CHaHbO),3.87(dd,1H,CHaHbO),2.98(d,2H,ArCH2),2.57(q,1H,BnCHC=O),2.05(m,1H,CHCH(Me)2,1.55(m,1H,CH(Me)2),0.81(d,3H,CH3)和0.72(d,3H,CH3)。
(2R,3R)-2-苄基-3-溴甲基-4-甲基-戊酸乙酯177
将内酯176(6.5g,29.8mmol)溶于绝对乙醇(80mL)并在冷浴中冷却。无水HBr冒泡通过溶液1小时并在室温下搅拌过夜,同时在干气氛下保持反应。将其倾入到冰冷的醚和盐水的混合物。分离有机相,并进一步用石油醚提取含水相。反复用冷水洗涤合并的有机溶液并干燥。真空除去溶剂得到粗品化合物7.0g。NMR(CDCl3)
δ7.27(m,5H,C6H5),4.02(m,2H,CH3CH2O),3.70(dd,1H,CHaHbBr),3.55(dd,1H,CHaHbBr),2.97(m,2H,ArCH2),2.83(q,1H,BnCHC=O),2.11(m,1H,CHCH(Me)2,1.97(m,1H,CH(Me)2),1.10(t,3H,CH3CH2O),0.96(d,3H,CH3)和0.93(d,3H,CH3)。
(2R,3R)-2-苄基-3,4-二甲基-戊酸乙酯178
在20% Pd/C(1.0g)的存在下,在含有三乙胺(3.2mL)的乙醇(100mL)中将溴酯177(7.25g,约80%纯度)氢化过夜。通过才利特垫过滤,用乙醇洗涤滤饼。蒸发溶剂,将残留物置于醚中,此时分离固体(Et3N.HCl)。过滤除去固体。浓缩滤液并重复该过程以除去所有的盐酸盐。在硅胶柱上色谱层析产物,用石油醚洗胶得到期望的去溴化的化合物3.35g。NMR(CDCl3)δ7.21(m,5H,C6H5),3.95(m,2H,CH3CH2O),2.85(m,2H,ArCH2),2.64(q,1H,BnCHC=O),1.85(m,1H,CHCH(Me)2,1.62(m,1H,CH(Me)2),1.05(t,3H,CH3CH2O),0.95(d,3H,CH3)0.84(d,3H,CH3)和0.82(d,3H,CH3)。MS给出290(M+CH3CN),249(M+1),和其它在203处。进一步用醚洗脱得到从上一步骤中带出的内酯(2.25g)。
乙酸(2R,3R)-2-苄基-3,4-二甲基-戊基-酯179
将乙酯178(3.20g,12.85mmol)溶于无水醚中并在冰浴中在惰气氛下冷却。加入氢化锂铝(500mg,13.15mmol),并在室温下搅拌该悬浮液过夜。小心加入乙酸乙酯破坏过量的LAH,同时在冰浴上搅拌反应物。小心加入饱和硫酸钠以凝结氧化铝,在常温下分离成为白色沉淀物。用二氯甲烷稀释该反应混合物,加入无水硫酸钠以干燥该混合物。过滤后浓缩溶液得到一种油3.0g。
将该物质(3.0g)溶于二氯甲烷(30mL),并加入三乙胺(2.5mL)、DMAP(200mg)和乙酐(1.5mL)。室温下搅拌3小时,并用醚稀释。用水、1N HCl、饱和碳酸氢钠、盐水洗涤该醚溶液并干燥。真空浓缩该溶液得到乙酰氧基化合物179 3.16g。
NMR(CDCl3)δ7.19(m,5H,C6H5),4.03(m,2H,CH3CH2O),2.69(m,2H,ArCH2),2.09(m,1H,BnCHCH2O),2.02(s,3H,CH3C=O),1.68(m,1H,CH3CHCH(Me)2,1.23(m,1H,CH(Me)2),0.87(d,3H,CH3),0.84(d,3H,CH3)和0.81(d,3H,CH3)。
(R)-4-((R)-1,2-二甲基-丙基)-二氢呋喃-2-酮180
将高碘酸钠(86.24g,403.32mmol,20当量)加到在HPLC等级乙腈(60mL)、四氯化碳(60mL)和水(120mL)中的芳香化合物179(5.0g,20.16mmol)溶液中。室温下剧烈搅拌该混合物过夜,并用二氯甲烷(400mL)稀释。通过才利特垫过滤该混合物以除去固体沉淀物。分离有机部分,进一步用二氯甲烷提取含水相。浓缩合并的有机部分,然后将残留物溶于醚,并将其用于Florisil柱。用在醚中的3%甲醇洗脱该化合物,蒸发至糊剂,将其溶于甲醇(100mL)。加入碳酸钾(8.0g),混合物回流6小时。蒸发溶剂,将该固体残留物溶于水。小心加入浓HCl将pH调节2,同时在冰水浴上冷却并搅拌。将氯仿(200mL)加到该溶液并在室温下搅拌过夜。分离有机相,进一步用氯仿提取含水部分。干燥后,蒸发溶剂得到内酯180 5.0g。NMR(CDCl3)δ4.36(app.t,1H,CHaHbO),3.85(app.t,1H,CHaHbO),2.46(m,2H,CHcHdC=O),2.13(m,2H,CHCH2C=O),1.60(m,1H,CH(Me)2),1.35(m,1H,CH3CHCH(Me)2),0.86(d,3H,CH3)和0.72(t,3H,CH3)。
(3R,4R)-3-溴甲基-4,5-二甲基-己酸乙酯181
将内酯180(5.0g)溶于绝对乙醇(25mL)并用氩冲洗。在冰水浴上冷却,同时使无水HBr冒泡通过该混合物45分钟并在室温下静置过夜。将混合物倾入到冰-盐水和和乙烷中。分离有机相,进一步用己烷提取含水相。干燥合并的有机提取物并蒸发。在硅胶柱上用在石油醚中的10%醚的快速色谱层析得到溴酯181 3.54g。
NMR(CDCl3)δ4.14(q,2H,CH3H2O),3.60(dd,1H,CHaHbBr),3.41(dd,1H,CHcHbBr),2.54(dd,1H,CHaHbC=O),2.44(dd,1H,CHaHbC=O),2.22(m,1H,O=CCH2CHCH2Br),1.67(m,1H,CHCH3CH(Me)2,1.37(m,1H,CH(Me)2),1.26(t,3H,CH3CH2O),0.94(d,3H,CHCH3CH(Me)2,0.81(d,3H,((CH3)2)CHCH3CH)和0.79(d,3H,((CH3)2)CHCH3CH)。
(3R,4R)-3-叠氮基甲基-4,5-二甲基-己酸乙酯182和实施例17(3R,4R)-3-氨基甲基-4,5-二甲基-己酸
室温下搅拌在无水DMF(8.0mL)中的溴酯181(3.54g,13.34mmol)、叠氮化钠(1.04g,16.13mmol)过夜。加入水(16mL)和己烷,分离有机部分,用己烷进一步提取含水部分。干燥并蒸发得到叠氮基酯3.0g。NMR(CDCl3)δ 4.14(q,2H,CH3H2O),3.48(dd,1H,CHaHbN3),3.21(dd,1H,CHcHbN3),2.34(m 2H,CHaHbC=O),2.20(m,1H,O=CCH2CHCH2N3),1.60(m,1H,CHCH3CH(Me)2。将化合物氢化(HPL,66480×100)。将氢化粗品溶于6N HCl并回流过夜。真空蒸发溶剂,残留物与甲苯共沸。进一步将残留物装载到离子交换柱色谱层析(Dowex 50Wbx 8-100)来对其进行纯化,用HPLC等级水洗涤至中性,然后用0.5N NH4OH溶液洗脱化合物。从甲醇中重结晶得到720mg。
NMR(CD3OD)δ3.04(dd,1H,CHaHbNH2),2.82(dd,1H,CHcHbNH2),2.52(dd,1H,CHaHbC=O),2.40(dd,1H,CHaHbC=O),2.07(m,1H,O=CCH2CHCH2NH2),1.67(m,1H,CHCH3CH(Me)2,1.35(m,1H,CH(Me)2),0.97(d,3H,CHCH3CH(Me)2,0.88(d,3H,((CH3)2)CHCH3CH)and 0.83(d,3H,((CH3)2)CHCH3CH)。[α]D-5.3(c,MeOH,1.9mg/mL)。分析计算C9H19NO2:C 62.39,H 11.05,N 8.08。实测C 62.01,H 11.35,N 7.88。
MS显示离子在215(M+CH3CN),197(M+Na+),174(M+H+)。通过反相HPLC,Hypersil BDS C185微米和流动相含有0.1%TFA的50/50CH3CN-水分析衍生物得到在8.21分钟的保留时间处的纯度99.93%。
实施例18-20:合成3-氨基甲基-4-异丙基-庚酸
2-氰基-4-甲基-2-戊烯酸甲酯61
在Dean-Stark收集器下将在500ml甲苯中的异丁醛(30.0g,416mmol)、甲基-氰基-乙酸盐(20.6g,208mmol)、氢氧化铵(3.2g,41.6mmol)和乙酸(5.0g,83.2)加热至回流12小时。将混合物冷却至室温并用饱和NaHSO3(3×100mL)、饱和NaHCO3(3×100mL)和100mL盐水提取。在Na2SO4上干燥有机层,并蒸发溶剂。在高度真空(0.5mmHg,B.P.=115-120℃)下蒸馏残留的油得到28.8g的2-氰基-4-甲基-2-戊烯酸甲酯61,为一种油(90%产率)。
2-氰基-3-异丙基-己酸甲酯183
将在Et2O(9.8mL,19.6mmol)中的2.0M的氯化丙基镁溶液加到在50mL的THF中的2-氰基-4-甲基-2-戊烯酸(3.0g,19.6mmol)溶液,在IPA/冰浴上于氩下将此溶液冷却至-40℃。搅拌该溶液4小时,并加入50ml饱和KH2PO4。蒸发THF,在中等压力下在硅胶上用50%CH2Cl2/己烷色谱层析残留的油。产量=1.9g(50%)的2-氰基-3-异丙基-己酸甲酯,为一种油。
2-氰基-2-(1-异丙基-丁基)-琥珀酸4-叔丁酯1-甲酯184
将在10ml的THF中的2-氰基-3-异丙基-己酸甲酯(1.9g,9.6mmol)溶液加到在20mL的THF中的NaH(用己烷洗涤,0.23g,9.6mmol),在冰水浴中在氩下冷却。搅拌该溶液10分钟,加入溴乙酸叔丁酯(2.1g,10.6mmol)。将该溶液加热至室温。12小时后,加入50ml饱和KH2PO4猝灭反应并蒸发THF。将有机产物提取至Et2O(3×50mL),并在MgSO4上干燥合并的有机层。蒸发溶剂,在中等压力下,在硅胶上以25%己烷/CH2Cl2色谱层析残留油。得到2-氰基-2-(1-异丙基-丁基)-琥珀酸4-叔丁酯1-甲酯=1.3g(42%),为一种油。
3-氰基-4-异丙基-庚酸叔丁酯185
将在25mL的DMSO中的2-氰基-2-(1-异丙基-丁基)-琥珀酸4-叔丁酯1-甲酯(1.3g,4.2mmol)、NaCl(0.25g,4.2mmol),和H2O(0.15g,8.3mmol)的混合物加热至℃12小时。将混合物冷却至室温并用100ml的盐水稀释。将有机产物提取至Et2O(3×50mL)。合并有机层并用50mL的H2O和50mL的盐水洗涤。在Na2SO4上干燥并蒸发溶剂得到0.8g(75%产率)的3-氰基-4-异丙基庚酸叔丁酯,为一种油。
4-(1-异丙基-丁基)-2-吡咯烷酮186
在50psi的H2下,在含有TEA和Ra Ni的MeOH中还原3-氰基-4-异丙基-庚酸叔丁酯(0.8g,3.2mmol)。当使用理论量的H2时,过滤除去催化剂,并蒸发溶剂得到0.6g(100%产率)的4-(1-异丙基-丁基)-2-吡咯烷酮,为一种油。
实施例18:3-氨基甲基-4-异丙基-庚酸
在50mL的6.0M HCl中将4-(1-异丙基-丁基)-2-吡咯烷酮(0.6g,2.3mmol)加热至回流12小时。将溶液冷却至室温并通过才利特过滤。蒸发滤液,从MeOH/EtOAc中重结晶残留固体。产量:0.035g(6%产率)的3-氨基甲基-4异丙基-庚酸,为一种盐酸盐,mp 160-170℃。
1HNMR(CD3OD)δ0.9(m,9H),1.30(m,5H),1.78(m,1H),2.30(m,2H),2.45(m,1H),2.95(m,2H)。MS(APCI,CH3 CN,H2O)201(M+,100%)。
实施例19:3-氨基甲基-4-异丙基-辛酸
根据实施例18的方法制备。产量=0.13g(15%)的3-氨基甲基-4-异丙基-辛酸。mp=160-170℃。1H NMR(CD3OD)δ0.9(m,9H),1.30(m,7H),1.78(m,1H),2.30(m,1H),2.45(m,2H),2.95(m,2H)。MS(APCI,CH3CN,H2O)198(M-17,100%),216(M+,50%)。
实施例20:3-氨基甲基-4-异丙基-己酸
根据实施例18制备。产量=0.11g(42%)的3-氨基甲基-4-异丙基-己酸。mp=170-180℃。1H NMR(CD3OD)δ0.9(m,9H),1.18(m,1H),1.39(m,3H),1.78(m,1H),2.30(m,1H),2.45(m,1H),2.95(m,2H)。MS(APCI,CH3CN,H2O)188(M+,100%)。
实施例21
(i)MeO2CCH=PPh3,THF,40℃;(ii)MeNO2,DBU;(iii)阮内镍,H2,MeOH;(iv)Pd-C,MeOH,H2;(v)6N HCl
合成不饱和酯188
40℃下在干四氢呋喃(30mL)中用三苯基正磷烯乙酸甲酯(3.69g,11.03mmol)搅拌(S)-(-)-香茅醛187(2.0mL,11.03mmol)。8小时后,将混合物冷却至室温并搅拌过夜。真空除去溶剂并用正戊烷(50mL)搅拌残留物。1小时后,过滤除去固体并真空除去溶剂得到一种油,由快速色谱法(二氧化硅,乙酸乙酯∶庚烷1∶9)纯化得到2.05g(88%)的188,为一种澄清的油。
1H NMR(400MHz)(CDCl3)δ0.90(3H,d,J=6Hz);1.12-1.40(2H,m);1.60(3H,s);1.62(1H,m);1.68(3H,s);2.01(3H,m);2.21(1H,m);3.73(3H,s);5.08(1H,m);5.82(1H,d,J=16 Hz);6.94(1H,m)。MS(CI+)(m/z):211(MH+,75%),179(78%),151(100%)。IR(thin film)(cm-1)ν:1271,1436,1728,2917。
合成硝基酯189
用1,8-二氮杂二环[5,4,0]十一碳-7-烯(1.44mL,9.6mmol)将酯188(2.02g,9.6mmol)溶于硝基甲烷(25mL)并在室温下搅拌。23小时后,用二乙醚(150mL)稀释该混合物,用水(50mL)洗涤然后用2N HCl(50mL)洗涤。收集有机相,干燥(MgSO4),并真空除去溶剂。通过快速色谱法(二氧化硅,乙酸乙酯∶庚烷3∶7)纯化残留物得到2.26g(87%)的189,为一种澄清的油。注意这里的和其后所有的化合物为2种非对映异构体的等摩尔混合物。1H NMR(400MHz)(CDCl3)δ0.90(2×3H,each d,J=6Hz);1.09-1.58(10H,m);1.602(6H,s);1.685(6H,s);1.94(4H,m);2.42(4H,m);2.66(2H,m);3.70(6H,s);4.42(4H,m);5.07(2H,m)。
MS(CI+)(m/z):272(MH+,90%),240(100%),151(100%)。
IR(薄膜)(cm-1)ν:1554,1739,2918。
合成内酰胺191
将硝基酯189(2.09g,7.7mmol)溶于甲醇(75mL),并于35℃下在氢气(39psi)下在阮内镍(催化剂,用水,随后用甲醇预洗涤)中摇晃。17小时后,通过才利特过滤该混合物。真空除去溶剂得到一种油。1H NMR表明已有部分双键还原因此不进一步纯化而继续处理。将部分还原产物试样(440mg,2.1mmol)溶于甲醇(40mL)并在氢气氛下在5% Pd-C上摇晃。18小时后,通过才利特过滤除去催化剂得到442mg(99%来自部分还原的物质),为一种澄清的油,它不需要纯化。
注意这里的和其后所有的化合物为2种非对映异构体的等摩尔混合物。
1H NMR(400MHz)(CDCl3)δ:0.88(18H,m);1.04-1.58(20H,m);1.96(2H,m);2.40(2H,m);2.58(2H,m);2.98(2H,m);(3.45(2H,m),5.82(2H,br s)。
MS(CI+)(m/z):212(MH+,100%)。
合成实施例21
在6N HCl(20mL)中将内酰胺191(428mg,2.0mmol)加热至回流。15小时后,将该混合物冷却至室温,并用二氯甲烷(2×10mL)洗涤。收集含水相并真空除去溶剂。将残留物溶于水(10mL)并冷冻干燥得到382mg(71%)的实施例34,为一种白色固体。注意这里的和其后所有的化合物为2种非对映异构体的等摩尔混合物。1H NMR(400MHz)(d6-DMSO)δ0.82(18H,m);0.95-1.55(20H,m);2.05-2.45(6H,m);2.75(4H,m);7.98(6H,brs)。MS(CI+)(m/z):230([MH-HCl]+,90%),212(100%)。
微量分析:计算C13H28NO2Cl:
C 58.74;H 10.62;N 5.27。
实测:C 58.46;H 10.50;N 5.33。
对本领域技术人员来说,使用(R)-(+)-香茅醛将提供与实施例21相反C5-立体化学的化合物。
Claims (10)
1.式I的化合物
或其药学上可接受的盐,其中:
R1为氢或1-6个碳原子的直链或支链烷基;
R2为4-8个碳原子的直链或支链烷基。
2.根据权利要求1的化合物,其中R1为氢,并且R2为4-8个碳原子的直链或支链烷基。
3.根据权利要求1的化合物及其药学上可接受盐,选自:
3-氨基甲基-5-甲基-壬酸;
3-氨基甲基-5-甲基-癸酸;以及
3-氨基甲基-5-甲基-十一酸。
4.化合物或其药学上可接受的盐,其为:
(3S,5R)-3-氨基甲基-5-甲基-庚酸。
5.化合物或其药学上可接受的盐,其为:
(3S,5R)-3-氨基甲基-5-甲基-辛酸。
6.根据权利要求1的化合物及其药学上可接受的盐,其为:
(3S,5R)-3-氨基甲基-5-甲基-壬酸;或
(3S,5R)-3-氨基甲基-5-甲基-癸酸。
7.化合物或其药学上可接受的盐,其中所述化合物选自:
3-氨基甲基-5-甲基-庚酸;和
3-氨基甲基-5-甲基-辛酸。
8.含有有效治疗量的权利要求1,4,5或7任一项中化合物和药学上可接受载体的药物组合物。
9.权利要求1,4,5或7任一项中的化合物用于制备治疗癫痫症、晕厥发作、运动机能减退、颅病症、神经变性病症、抑郁、焦虑、恐慌、疼痛、神经病理学病症、睡眠障碍、过敏性肠综合症或胃损伤的药物的用途。
10.权利要求1,4,5或7任一项的化合物用于制备治疗癫痫症、焦虑、恐慌、疼痛、睡眠障碍、过敏性肠综合症或胃损伤的药物的用途。
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US7164034B2 (en) | 1999-06-10 | 2007-01-16 | Pfizer Inc. | Alpha2delta ligands for fibromyalgia and other disorders |
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ES2296956T5 (es) * | 2001-06-11 | 2011-07-12 | Xenoport, Inc. | Profármacos de análogos de gaba, composiciones y sus usos. |
US8048917B2 (en) | 2005-04-06 | 2011-11-01 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
ITMI20011308A1 (it) | 2001-06-21 | 2002-12-21 | Nicox Sa | Farmaci per il dolore cronico |
JP2005521664A (ja) | 2002-01-31 | 2005-07-21 | ワーナー−ランバート カンパニー リミティド ライアビリティー カンパニー | 耳鳴を治療するためのアルファ2デルタ・リガンド |
NI200300043A (es) * | 2002-03-28 | 2003-11-05 | Warner Lambert Co | AMINOACIDOS CON AFINIDAD POR LA PROTEINA a2DELTA. |
US20030225149A1 (en) | 2002-04-30 | 2003-12-04 | Blazecka Peter G. | Process for preparing highly functionalized gamma-butyrolactams and gamma-amino acids |
US7071339B2 (en) | 2002-08-29 | 2006-07-04 | Warner Lambert Company Llc | Process for preparing functionalized γ-butyrolactones from mucohalic acid |
WO2004054566A1 (en) | 2002-12-13 | 2004-07-01 | Warner-Lambert Company Llc | Pregabalin derivatives for the treatment of fibromyalgia and other disorders |
CA2451267A1 (en) | 2002-12-13 | 2004-06-13 | Warner-Lambert Company Llc | Pharmaceutical uses for alpha2delta ligands |
DE60332387D1 (de) | 2002-12-13 | 2010-06-10 | Warner Lambert Co | Alpha-2-delta-ligand zur behandlung vonsymptomen der unteren harnwege |
CA2508297A1 (en) * | 2002-12-13 | 2004-07-01 | Warner-Lambert Company Llc | Pregabalin and derivates thereof for the treatment of fibromyalgia and other related disorders |
ITMI20022658A1 (it) | 2002-12-17 | 2004-06-18 | Nicox Sa | Farmaci per il dolore cronico. |
WO2005002585A1 (en) * | 2003-07-02 | 2005-01-13 | Warner-Lambert Company Llc | Combination of an allosteric inhibitor of matrix metalloproteinase-13 and a ligand to an alpha-2-delta receptor |
CN1849153A (zh) | 2003-09-12 | 2006-10-18 | 辉瑞大药厂 | 含有α-2-δ配体和5-羟色胺/去甲肾上腺素重摄取抑制剂的组合物 |
EP1670750A1 (en) | 2003-09-25 | 2006-06-21 | Warner-Lambert Company LLC | Prodrugs of amino acids with affinity for the alpha2delta- protein |
EA200600467A1 (ru) * | 2003-09-25 | 2006-08-25 | Уорнер-Ламберт Компани Ллс | АМИНОКИСЛОТЫ СО СРОДСТВОМ К α2δ-БЕЛКУ |
WO2006043171A2 (en) * | 2004-10-23 | 2006-04-27 | Warner-Lambert Company Llc | Methods of using alpha2delta-1 selective compounds |
EP1926710B1 (en) * | 2005-09-15 | 2014-11-12 | UCB Pharma S.A. | 4-Substituted pyrrolidin-2-ones and their use |
US20070141684A1 (en) * | 2005-12-21 | 2007-06-21 | Pfizer Inc | Preparation of gamma-amino acids having affinity for the alpha-2-delta protein |
AR061728A1 (es) * | 2006-06-30 | 2008-09-17 | Pfizer Prod Inc | Composicion para tratamiento usando compuestos selectivos alfa-2-delta-1 |
RS51940B (en) | 2006-12-22 | 2012-02-29 | Recordati Ireland Limited | Combined TH2δ LIGANAD THERAPY AND NSAID FOR LOWER URINARY TRACT DISORDERS |
WO2009136375A1 (en) * | 2008-05-08 | 2009-11-12 | Pfizer Inc | Treatment of interstitial cystitis |
JP5815552B2 (ja) | 2009-12-08 | 2015-11-17 | ケース ウェスタン リザーブ ユニバーシティCase Westernreserve University | 眼疾患を治療する化合物および方法 |
CN101914031B (zh) * | 2010-07-30 | 2013-08-28 | 中国广州分析测试中心 | 普瑞巴林衍生物及其应用 |
FI3364958T3 (fi) * | 2015-10-23 | 2023-04-06 | Navitor Pharm Inc | Sestriinin ja gator2:n vuorovaikutuksen modulaattoreita ja niiden käyttötapoja |
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US4087544A (en) * | 1974-12-21 | 1978-05-02 | Warner-Lambert Company | Treatment of cranial dysfunctions using novel cyclic amino acids |
DE2460891C2 (de) * | 1974-12-21 | 1982-09-23 | Gödecke AG, 1000 Berlin | 1-Aminomethyl-1-cycloalkanessigsäuren und deren Ester, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
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WO1992009560A1 (en) * | 1990-11-27 | 1992-06-11 | Northwestern University | Gaba and l-glutamic acid analogs for antiseizure treatment |
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CN1094757C (zh) * | 1996-07-24 | 2002-11-27 | 沃尼尔·朗伯公司 | 用于治疗疼痛的异丁基γ-氨基丁酸及其衍生物 |
WO1998017627A1 (en) * | 1996-10-23 | 1998-04-30 | Warner-Lambert Company | Substituted gamma aminobutyric acids as pharmaceutical agents |
DE69834204T2 (de) * | 1997-10-27 | 2007-03-29 | Warner-Lambert Co. Llc | Zyklische aminosäuren und deren derivate als arzneimittel |
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