CN1495160A - 1-取代-1-氨基甲基-环烷衍生物(=加巴喷丁类似物)、其制备及其在治疗神经病方面的用途 - Google Patents
1-取代-1-氨基甲基-环烷衍生物(=加巴喷丁类似物)、其制备及其在治疗神经病方面的用途 Download PDFInfo
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- CN1495160A CN1495160A CNA2003101142270A CN200310114227A CN1495160A CN 1495160 A CN1495160 A CN 1495160A CN A2003101142270 A CNA2003101142270 A CN A2003101142270A CN 200310114227 A CN200310114227 A CN 200310114227A CN 1495160 A CN1495160 A CN 1495160A
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- Prior art keywords
- methyl
- cyclopentyl
- amino methyl
- dimethyl
- amino
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Classifications
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- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C239/14—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
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- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C311/09—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton the carbon skeleton being further substituted by at least two halogen atoms
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- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/31—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
- C07C311/33—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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Abstract
公开了式(1),(1C),(1F),(1G)和(1H)的新的胺,或其药用盐,其中n是0-2的整数;m是0-3的整数;R是磺酰胺,酰胺,膦酸,杂环,磺酸,异羟肟酸;A’是桥环,选自(1),(2),(3),(4),(5),其中是连接点;Z1到Z4各自独立地选自氢和甲基;O是1-4的整数;和p是0-2的整数;在上式(1)中,当m是2而n是1时,R不能是磺酸,以及其用作癫痫、晕厥发作、少动症、颅疾病、神经变性疾病、抑郁、焦虑、恐慌、疼痛、神经病理紊乱、炎症以及胃肠道紊乱,特别是应激性肠综合征的治疗剂。
Description
本发明是申请号为98811481.X、发明名称为“1-取代-1-氨基甲基-环烷衍生物(=加巴喷丁类似物)、其制备及其在治疗神经病方面的用途”的中国专利申请的分案申请。
技术领域
本发明涉及1-取代-1-氨基甲基-环烷衍生物(=加巴喷丁类似物)、其制备及其在治疗神经病方面的用途。
背景技术
下式的化合物
其中R1是氢或低级烷基而n是4、5或6,已知于美国专利号4024175及其分案的美国专利号4087544。公开的用途是:对氨基硫脲引起的痉挛的保护作用;对卡地阿唑痉挛的保护作用;脑疾病、癫痫、晕厥发作、少动症及颅外伤;并改善脑功能。这些化合物有用于老年病患者。将上述专用引入作为参考。
下式的化合物
其中R1是含1至6个碳原子的直链或支链烷基、苯基或含3至6个碳原子的环烷基;R2是氢或甲基;而R3是氢、甲基或羧基,已知于美国专利号5563175及其多个分案申请。将这些专利引入作为参考。
发明内容
本发明的化合物是用于多种疾病的新的胺及其药用盐。这些疾病包括:癫痫、晕厥发作、少动症、颅部疾病、神经变性疾病、抑郁、焦虑、恐慌、疼痛、神经病理性疾病、炎症及胃肠疾病,特别是应激性肠综合征。
本发明的化合物为下式1,1C,1F,1G,和1H的化合物。
优选的化合物是如下的化合物,其中R是选自-NHSO2R15或-SO2NHR15的磺酰胺,其中R15是直链或支链烷基或三氟甲基。
特别优选的是N-[2-(1-氨基甲基-环己基)-乙基]-甲磺酰胺。
其它优选的化合物是这样的化合物,其中R是膦酸,-PO3H2。
特别优选的是(1-氨基甲基-环己基甲基)-膦酸和(2-氨基甲基-4-甲基-戊基)-膦酸。
其它优选的化合物是那些的化合物,其中R选自:
特别优选的是C-[1-(1H-四唑-5-基甲基)环己基]-甲胺和4-甲基-2-(1H-四唑-5-基甲基)-戊胺。
发明详述
本发明的胺是式1,1C,1F,1G,和1H的化合物及其药用盐。
本发明的化合物是下式的化合物及其药用盐:
其中:
N是0-2的整数;
m是0-3的整数;
R是磺酰胺,酰胺,膦酸,杂环,磺酸,异羟肟酸;
A’是桥环,选自:
其中:
是连接点;
Z1到Z4各自独立地选自氢和甲基;
o是1-4的整数;和
p是0-2的整数。
在上式1中,当m是2而n是1时,R不能是磺酸。(Suman-ChaulanN.等,欧洲药学杂志,1993;244:293-301.)
优选的本发明的化合物是;
(1-氨基甲基-环己基甲基)-膦酸;
(1R-反式)(1-氨基甲基-3-甲基-环己基甲基)-膦酸;
(反式)(1-氨基甲基-3,4-二甲基-环戊基甲基)-膦酸;
(1R-反式)(1-氨基甲基-3-甲基-环戊基甲基)-膦酸;
(1S-顺式)(1-氨基甲基-3-甲基-环戊基甲基)-膦酸;
(1S-反式)(1-氨基甲基-3-甲基-环戊基甲基)-膦酸;
(1R-顺式)(1-氨基甲基-3-甲基-环戊基甲基)-膦酸;
(1α,3α,4α)(1-氨基甲基-3,4-二甲基-环戊基甲基)-膦酸;
(1α,3β,4β)(1-氨基甲基-3,4-二甲基-环戊基甲基)-膦酸;
(R)(1-氨基甲基-3,3-二甲基-环戊基甲基)-膦酸;
(S)(1-氨基甲基-3,3-二甲基-环戊基甲基)-膦酸;
(1-氨基甲基-3,3-二甲基-环丁基甲基)-膦酸;
2-(1-氨基甲基-环己基)-N-羟基-乙酰胺;
(1S-反式)2-(1-氨基甲基-3-甲基-环己基)-N-羟基-乙酰胺;
(反式)2-(1-氨基甲基-3,4-二甲基-环戊基)-N-羟基-乙酰胺;
(1S-顺式)2-(1-氨基甲基-3-甲基-环戊基)-N-羟基-乙酰胺;
(1R-反式)2-(1-氨基甲基-3-甲基-环戊基)-N-羟基-乙酰胺;
(1R-顺式)2-(1-氨基甲基-3-甲基-环戊基)-N-羟基-乙酰胺;
(1-反式)2-(1-氨基甲基-3-甲基-环戊基)-N-羟基-乙酰胺;
(1α,3α,4α)2-(1-氨基甲基-3,4-二甲基-环戊基)-N-羟基-乙酰胺;
(1α,3β,4β)2-(1-氨基甲基-3,4-二甲基-环戊基)-N-羟基-乙酰胺;
(S)2-(1-氨基甲基-3,3-二甲基-环戊基)-N-羟基-乙酰胺;
(R)2-(1-氨基甲基-3,3-二甲基-环戊基)-N-羟基-乙酰胺;
2-(1-氨基甲基-3,3-二甲基-环丁基)-N-羟基-乙酰胺;
N-[2-(1-氨基甲基-环己基)-乙基]-甲磺酰胺;
(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环己基)-乙基]-甲磺酰胺;
(反式)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-甲磺酰胺;
(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-甲磺酰胺;
(1R-反式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-甲磺酰胺;
(1R-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-甲磺酰胺;
(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-甲磺酰胺;
(1α,3α,4α)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-甲磺酰胺;
(1α,3β,4β)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-甲磺酰胺;
(S)N-[2-(1-氨基甲基-3,3-二甲基-环戊基)-乙基]-甲磺酰胺;
(R)N-[2-(1-氨基甲基-3,3-二甲基-环戊基)-乙基1-甲磺酰胺;
N-[2-(1-氨基甲基-3,3-二甲基-环丁基)-乙基]-甲磺酰胺;
3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮;
(反式)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1S-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1R-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1R-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1α,3α,4α)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1α,3β,4β)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(S)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(R)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(1-氨基甲基-3,3-二甲基-环丁基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(反式)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1R-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1R-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1S-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1α,3α,4α)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1α,3β,4β)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(S)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(R)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
3-(1-氨基甲基-3,3-二甲基-环丁基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
C-[1-(1H-四唑-5-基甲基)-环己基]-甲胺;
(1S-顺式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环己基]-甲胺;
(反式)C-[3,4-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1S-顺式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1R-反式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1R-顺式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1S-反式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1α,3α,4α)C-[3,4-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-胺;
(1α,3β,4β)C-[3,4-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(S)C-[3,3-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(R)C-[3,3-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
C-[3,3-二甲基-1-(1H-四唑-5-基甲基)-环丁基]-甲胺;
N-[2-(1-氨基甲基-环己基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环己基)-乙基]-C,C,C-三氟-甲磺酰胺;
(反式)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1R-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1S-反式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1R-反式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1α,3α,4α)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1α,3β,4β)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(S)N-[2-(1-氨基甲基-3,3-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(R)N-[2-(1-氨基甲基-3,3-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
N-[2-(1-氨基甲基-3,3-二甲基-环丁基)-乙基]-C,C,C-三氟-甲磺酰胺;
3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环己基甲基)-4H-[1,2,4]噻二唑-5-酮;
(反式)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1R-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1S-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1R-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1α,3α,4α)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1α,3β,4β)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(S)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(R)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
3-(1-氨基甲基-3,3-二甲基-环丁基甲基)-4H-[1,2,4]噻二唑-5-酮;
C-[1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)环己基]甲胺;
(1S-顺式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)环己基]甲胺;
(反式)C-[3,4-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(1S-顺式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(1R-反式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(1R-顺式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(1S-反式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(1α,3α,4α)C-[3,4-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)环戊基]甲胺;
(1α,3β,4β)C-[3,4-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(S)C-[3,3-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(R)C-[3,3-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
C-[3,3-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环丁基]甲胺;
(1-氨基甲基-环己基)-甲磺酰胺;
(1R-反式)(1-氨基甲基-3-甲基-环己基)-甲磺酰胺;
(反式)(1-氨基甲基-3,4-二甲基-环戊基)甲磺酰胺;
(1S-反式)(1-氨基甲基-3-甲基-环戊基)-甲磺酰胺;
(1R-顺式)(1-氨基甲基-3-甲基-环戊基)-甲磺酰胺;
(1R-反式)(1-氨基甲基-3-甲基-环戊基)-甲磺酰胺;
(1S-顺式)(1-氨基甲基-3-甲基-环戊基)-甲磺酰胺;
(1α,3β,4β)(1-氨基甲基-3,4-二甲基-环戊基)-甲磺酰胺;
(1α,3α,4α)(1-氨基甲基-3,4-二甲基-环戊基)-甲磺酰胺;
(R)(1-氨基甲基-3,3-二甲基-环戊基)-甲磺酰胺;
(S)(1-氨基甲基-3,3-二甲基-环戊基)-甲磺酰胺;
(1-氨基甲基-3,3-二甲基-环丁基)-甲磺酰胺;
(1-氨基甲基-环己基)-甲磺酸;
(1R-反式)(1-氨基甲基-3-甲基-环己基)-甲磺酸;
(反式)(1-氨基甲基-3,4-二甲基-环戊基)甲磺酸;
(1S-反式)(1-氨基甲基-3-甲基-环戊基)-甲磺酸;
(1S-顺式)(1-氨基甲基-3-甲基-环戊基)-甲磺酸;
(1R-反式)(1-氨基甲基-3-甲基-环戊基)-甲磺酸;
(1R-顺式)(1-氨基甲基-3-甲基-环戊基)-甲磺酸;
(1α,3β,4β)(1-氨基甲基-3,4-二甲基-环戊基)-甲磺酸;
(1α,3α,4α)(1-氨基甲基-3,4-二甲基-环戊基)-甲磺酸;
(R)(1-氨基甲基-3,3-二甲基-环戊基)-甲磺酸;
(S)(1-氨基甲基-3,3-二甲基-环戊基)-甲磺酸;
(1-氨基甲基-3,3-二甲基-环丁基)-甲磺酸;
(1-氨基甲基-环戊基甲基)-膦酸;
2-(1-氨基甲基-环戊基)-N-羟基-乙酰胺;
N-[2-(1-氨基甲基-环戊基)-乙基]-甲磺酰胺;
3-(1-氨基甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(1-氨基甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
C-[1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
N-[2-(1-氨基甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
3-(1-氨基甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
C-[1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(1-氨基甲基-环戊基)-甲磺酰胺;
(1-氨基甲基-环戊基)-甲磺酸;
(9-氨基甲基-二环[3,3,1]壬-9-基甲基)-膦酸;
2-(9-氨基甲基-二环[3,3,1]壬-9-基)-N-羟基-乙酰胺;
N-[2-(9-氨基甲基-二环[3,3,1]壬-9-基)-乙基]-甲磺酰胺;
3-(9-氨基甲基--二环[3,3,1]壬-9-基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(9-氨基甲基--二环[3,3,1]壬-9-基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
C-[9-(1H-四唑-5-基甲基)-二环[3,3,1]壬-9-基]-甲胺;
N-[2-(9-氨基甲基--二环[3,3,1]壬-9-基)-乙基]-C,C,C-三氟-甲磺酰胺;
3-(9-氨基甲基-二环[3,3,1]壬-9-基甲基)-4H-[1,2,4]噻二唑-5-酮;
C-[9-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-二环[3,3,1]壬-9-基]甲胺;
(9-氨基甲基-二环[3,3,1]壬-9-基)-甲磺酰胺;
(9-氨基甲基--二环[3,3,1]壬-9-基)-甲磺酸;
(2-氨基甲基-金刚烷-2-基甲基)-膦酸;
2-(2-氨基甲基-金刚烷-2-基)-N-羟基-乙酰胺;
N-[2-(2-氨基甲基-金刚烷-2-基)-乙基]-甲磺酰胺;
3-(2-氨基甲基-金刚烷-2-基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(2-氨基甲基-金刚烷-2-基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
C-[1-(1H-四唑-5-基甲基)-金刚烷-2-基]-甲胺;
N-[2-(2-氨基甲基-金刚烷-2-基)-乙基]-C,C,C-三氟-甲磺酰胺;
3-(2-氨基甲基-金刚烷-2-基甲基)-4H-[1,2,4]噻二唑-5-酮;
C-[2-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-金刚烷-2-基]甲胺;
(2-氨基甲基-金刚烷-2-基)-甲磺酰胺;
(2-氨基甲基-金刚烷-2-基)-甲磺酸;
(1-氨基甲基-环庚基甲基)-膦酸;
2-(1-氨基甲基-环庚基)-N-羟基-乙酰胺;
N-[2-(1-氨基甲基-环庚基)-乙基]-甲磺酰胺;
3-(1-氨基甲基-环庚基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(1-氨基甲基-环庚基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
C-[1-(1H-四唑-5-基甲基)-环庚基]-甲胺;
N-[2-(1-氨基甲基-环庚基)-乙基]-C,C,C-三氟-甲磺酰胺;
C-[1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环庚基]甲胺;
(1-氨基甲基-环庚基)-甲磺酰胺;和
(1-氨基甲基-环庚基-)-甲磺酸。
因为氨基是两性的,故药用盐可以是适当的无机酸或有机酸的盐,例如,盐酸、硫酸、磷酸、乙酸、草酸、乳酸、枸橼酸、苹果酸、水杨酸、丙二酸、马来酸、琥珀酸、甲磺酸和抗坏血酸。
从相应的氢氧化物或碳酸盐开始,可以制备与碱金属或碱土金属的盐,例如,形成钠、钾、镁或钙盐。还可以用如四甲基铵离子制备季铵盐。氨基酸的羧基可以通过已知方法酯化。
本发明的某些化合物可以以非溶剂化及溶剂化的形式存在,包括水合物形式。一般来说,溶剂化形式,包括水合物形式,与非溶剂化形式是等价的,并包括在本发明的范围内。
用于制备终化合物的新中间体包括在本发明中。
用于限定本发明的术语描述如下。
磺酰胺是-NHSO2R15或-SO2NHR15的磺酰胺,其中R15是含1至6个碳原子的直链或支链烷基,或三氟甲基。
酰胺是式-NHCOR12的化合物,其中R12是含1至6个碳原子的直链或支链烷基、苄基和苯基。
膦酸是-PO3H2。
磺酸是-SO3H。
异羟肟酸是
杂环为1至2个环基,其中含1至6个杂原子,其选自氧原子、氮原子和硫原子。
优选的杂环为
术语烷基除非另外说明,指含1至11个碳原子的直链或支链烷基,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、戊基、己基、正己基、庚基、辛基、壬基、癸基和十一烷基。
环烷基除非另外说明,含3至8个碳原子,并且是环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
苄基和苯基可以无取代或被1至3个选自羟基、羧基、烷氧羰基、卤素、CF3、硝基、烷基和烷氧基的取代基取代。优选是卤素。
烷氧基中的烷基定义如上所述。
卤素是氟、氯和溴,并优选氟和氯。
烷氧羰基是-COO烷基,其中烷基定义如上。优选甲氧羰基和乙氧羰基。
本发明的某些化合物可以以非溶剂化及溶剂化的形式存在,包括水合物形式。一般来说,溶剂化形式,包括水合物形式,与非溶剂化形式是等价的,并包括在本发明的范围内。
本发明的某些化合物具有一个或多个手性中心,并且每个中心可存在R(D)或S(L)构型。本发明包括了所有对映体和差向异构体以及其适当的混合物。
采用[3H]加巴喷丁和得自猪脑组织的α2δ亚单位进行放射性配体结合检测(“新的结合到钙通道的α2δ亚单元的抗惊厥药物,加巴喷丁”,Gee N.S.等,J.Bio Chem,1996;271(10):5768-5776)。
本发明的化合物对α2δ亚单位显示出了良好的结合亲和力。在此检测中加巴喷丁(Neutontin)的浓度约为0.10至0.12μM。由于本发明的化合物也结合此亚单位,预计它们会发挥与加巴喷丁可比的药理性质。例如,作为治疗惊厥、焦虑和疼痛的药剂。
表1
实施例 | α2δ 疼痛模型 |
测试 %MPE | |
IC50(nM) 1小时 2小时 1小时 2小时 | |
C-[1-(1H-四唑-5-基甲基)-环己基]-甲胺;盐酸 | 0.203 na na 60 100 |
3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮;盐酸 | 0.17 80.6 76.1 20 40 |
C-[9-(1H-四唑-5-基甲基)-2-金刚烷基]-甲胺;盐酸 | 4.37 |
C-[9-(1H-四唑-5-基甲基)-二环[3,3,1]壬-9-基甲胺;盐酸 | 3.7 |
3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-硫酮;盐酸 | 4.22 0 0 |
反式C-[1-(1H-四唑-5-基甲基)-3,4-二甲基环戊基]-甲胺;盐酸 | 0.108 |
N-[2-(1-氨基甲基)-环己基]-乙基]-甲磺酰胺 | >10 0.3 -0.9 0 |
N-[2-(1-氨基甲基-环己基)-乙基]-叔丁酰胺 | >10 1.6 -4.8 0 |
N-[2-(1-氨基甲基-环己基)-乙基]-丙酰胺酸 | >10 |
N-[2-(1-氨基甲基-环己基)-乙基]-3-苯基-丙酰胺;盐酸 | >10 |
N-[2-(1-氨基甲基-环己基)-乙基]-2-苯基-乙酰胺;盐酸 | >10 |
加巴喷丁 | 0.14 49.9 19.9 100 100 |
3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮;盐酸在角叉菜胶引起的痛觉过敏检测中是活性的。当以30mg/kg的剂量对大鼠口服时,该化合物在1小时时增加爪缩回潜伏期80.6%,在2小时时增加爪缩回潜伏期76%。为了比较,此剂量的加巴喷丁在1小时时引起49.9%的增加,而在2小时时仅引起1 9.9%的增加。因此,前者化合物表现出比加巴喷丁的抗痛觉过敏的作用时间更长。
当C-[1-(1H-四唑-5-甲基)-环己基]-甲胺盐酸在DBA2听原性癫痫模型中试验以10mg/kg的剂量口服给药时,在给药后1小时,给出60%的保护,在给药后2小时,给出100%的保护,在给药后4小时,给出100%的保护,在给药后6小时,给出80%的保护。在同样的测试中,以10mg/kg的剂量口服给药没有产生显著的反应。在30mg/kg的剂量,其在给药后2小时,给出100%的保护。
本发明的化合物还涉及有效用于治疗癫痫的一种市售的药物Neutontin。Neutontin是1-(氨基甲基)-环己烷基乙酸,其结构式如下:
本发明的化合物还预计用于治疗癫痫。
本发明还涉及模拟的化合物作为治疗神经变性疾病的药剂的治疗用途。
这些神经变性疾病为,例如,早老性痴呆、杭廷顿氏舞蹈病、帕金森氏病、肌萎缩性侧硬化(Amyotrophic Lateral Sclerosis)和癫痫。
本发明还涉及治疗称为急性脑损伤的神经变性疾病。其中包括但不限于中风、脑外伤和窒息。
中风指脑血管疾病,并还可以指脑血管事件(CVA),并包括急性血栓栓塞中风。中风包括病灶和系统局部缺血。还包括暂时脑局部缺血发作及其它伴随脑局部缺血的脑血管问题,如特别是进行颈动脉动脉内膜切除术,或其它一般的脑血管或血管手术方法的患者,或者进行包括脑血管造影术等的诊断血管方法的患者。
疼痛指急性及慢性疼痛。
急性疼痛通常时间短并与交感神经系统的机能亢进有关。实例为手术后和异常性疼痛。
慢性疼痛通常定义为持续3至6个月的疼痛,并包括躯体原性的疼痛和精神性的疼痛。其它疼痛是感受伤害。
其它疼痛由外周感觉神经损伤或感染。它包括但不限于由外周神经外伤、疱疹病毒感染、糖尿病、灼痛、血管或神经丛撕脱、神经瘤、截肢和脉管炎引起的疼痛。神经性疼痛还由慢性酒精中毒、人免疫缺陷病毒感染、甲状腺功能减退、尿毒症或维生素缺乏造成的神经损伤引起。神经性疼痛包括但不限于由神经损伤引起的疼痛,如糖尿病患者的疼痛。
精神性疼痛是无器质性原由而发生的,如腰痛、非典型面部疼痛和慢性头痛。
其它类型的疼痛为:炎症疼痛、骨关节疼痛、三叉神经痛、癌症疼痛、糖尿病神经病、腿多动综合征、急性疱疹和疱疹后神经痛、灼痛、臂血管神经丛撕脱、枕部神经痛、痛风、幻肢、烧伤及其它形式的神经痛、神经性和自发性疼痛综合征。
其它事件为头外伤、脊髓外伤或由普通缺氧症、低氧症、低血糖和低血压引起的损伤,以及在关节复位、高融合术和低氧症过程中观察到的类似损伤。
本发明的化合物可用于治疗胃肠紊乱,特别是应激性肠综合症(IBS)
本发明将有利于各种突发事件,例如,在心脏分流术中,在颅内出血中,在产期窒息中,在心搏停止和癫痫持续状态中。
通过本发明的方法,熟练的医师将能确定给药的适宜状态,其中患者易于患有或有患有例如中风的危险以及患有中风。
还预计本发明的化合物用于治疗抑郁。抑郁可以是器质性病的结果、继发于个人损失有关的紧张状态后或是自发的。一些形式的抑郁存在很强家族发病倾向,这暗示了至少一些形式的抑郁的发病机理。抑郁的诊断主要是通过对患者情绪改变的定量测定。情绪的评价一般由医生进行或由神经心理学医生用验证的检定标度,如Hamilton抑郁检定程序表或简要精神病学检定标度进行定量。其它一些标度已被开发用于定量和检测抑郁患者情绪的改变程度,如失眠、注意力难于集中、乏力、无用感及内疚感。抑郁的诊断标准以及精神病诊断标准收集于精神病诊断和标准手册(Diagnostic and Statistical Manual of Mental Disorders)(第5版),称为DSM-IV-R手册,由美国精神病协会(AmericanPsychiatric Association)在1994年出版。
GABA是中枢神经系统的抑制性神经递质。就抑制的总概念而言,似乎GABA-模拟物可降低或抑制脑功能并因此可使功能减慢并降低心境,其导致抑郁。
本发明的化合物可以通过在突触接点增加新产生的GABA来造成抗惊厥作用。如果加巴喷丁确实在突触接点增加了GABA水平或增加了GABA的作用,则可将其分类为GABA-模拟物,并可能降低或抑制脑功能,并因此可使功能减慢并降低心境,其导致抑郁。
GABA激动剂或GABA-模拟物可能就通过提高心境的相反的方式起作用,并因此可作为抗抑郁剂的事实是一个新概念,与以前流行的GABA活性不同。
通过标准的药理学方法证明,本发明的化合物还预计可用来治疗焦虑和恐慌。
材料和方法
角叉菜胶引起的痛觉过敏
在大鼠爪压力实验中用疼痛检测器(Randall-Sellito法:Randall L.O.,Sellitto J.J.,对发炎组织止痛活性的检测方法,Arch.Int.Pharmacodyn.,4:409-419(1957))检测感受伤害压力阈。实验日前在此仪器上训练雄性Sprague-Dawley鼠(70-90g)。给每只鼠的后爪逐渐施加压力并将感受伤害阈确定为引起爪缩回需要的压力(g)。截止点为250g,以防止对爪造成的任何组织损伤。在实验的当天,在给动物右后爪足底内注射100μL2%角叉菜胶前检测两至三个基线值。角叉菜胶给药后3小时再测定感受伤害阈,以确定这些动物表现了痛觉过敏。在注射角叉菜胶后3.5小时给动物施用加巴喷丁(3-300mg/kg,s.c.)、吗啡(3mg/kg,s.c.)或盐水,并在注射角叉菜胶后4、4.5和5小时检测感受伤害阈值。
氨基脲引起的强直癫痫发作
由皮下施用氨基脲(750mg/kg)引起小鼠强直癫痫发作。注意前爪强直延伸的潜伏期。将使用氨基脲后2.0小时不产生惊厥的任何小鼠视为受到了保护,并给出最大潜伏期记录为120分钟。
动物
雄性Hooded Lister大鼠(200-250g)得自Interfauna(Huntingdon,UK),而雄性TO小鼠(20-25g)得自Bantin和Kingman(Hull,UK)。这两种啮齿类每六只一组被关在笼中。重280至360g的普通狨(Callithrix Jacchus)在Manchester大学医学院(Manchester,UK)饲养,成对关在笼中。将所有动物关在12小时亮/暗循环的环境(在07.00小时照明)中,并任意食用食物和水。
给药
在实验前40分钟,腹膜内(IP)或皮下(SC)给药,对于大鼠和狨为1ml/kg,而对于小鼠为10ml/kg。
小鼠亮/暗箱
此仪器是顶部开口的箱,长45厘米、宽27厘米、高27厘米,通过延伸在墙的20厘米上方的分隔将其分为小区域(2/5)和大区域(3/5)(Costall B.等,在黑和白箱中探查小鼠:确定为焦虑的模型,Pharmacol.Biochem.Behav.,32:777-785(1989))。
在分隔中央地板上有7.5×7.5厘米的开口。小室被漆为黑色而大室被漆为白色。白色室用60W钨灯照明。实验室用红灯照明。将每只小鼠放置在白色区域的中央并允许其探查新环境5分钟。检测在照明一侧花费的时间(Kilfoil T.等,在小鼠焦虑的简单模型中抗焦虑药和焦虑产生药对探查活性的作用,Neuropharmacol.28:901-905(1989))。
大鼠升高的X-迷宫
将标准的升高的迷宫(Handley S.L.等,α-肾上腺素受体激动剂和拮抗剂在“恐惧”激发的行为的迷宫研究模型中的效果,Naunyn-Schiedeberg′s Arch.Pharmacol.,327:1-5(1984))按照以前的描述自动化(Field等,大鼠升高的X-迷宫焦虑测试的自动化,Br.J.Pharmacol.,102(suppl):304P(1991))。将动物置于X-迷宫的中央,面对一个开口的狭长弯道。为了检测抗焦虑作用,在5分钟实验期间检测最后在开放狭长弯道的一半通过的次数和花费的时间(Costall等,使用高标准迷宫评价抗焦虑剂在大鼠中的效能,Br.J.Pharmacol.,96(Suppl):312P(1989))。
狨被人威胁实验
在2分钟的实验期间内记录动物对威胁刺激(人站立在离狨笼0.5m处并凝视狨的眼睛)表现出的体态的总次数。记录的体态为缝凝视、尾部姿势、嗅笼/杆的气味、立毛、退避和弓背。在药物处理前和后,在实验的当天每只动物接触威胁刺激2次。通过Dunnett′st检验用变量单侧分析法分析两组评分的差异。所有的药物处理在第一次(对照)威胁后至少2小时SC进行。每个化合物的预处理时间为40分钟。
大鼠冲突实验
在操作室内训练大鼠压杆来获取食物。此方案由通过开室内灯为信号的30秒的可变间隔4个4分钟无处罚期以及以室内灯关掉为信号的固定的变换系数5(通过给食物时伴随爪电击)的3个3分钟处罚期的改变组成。调整对每只鼠的爪电击程度,让其与无处罚的响应相比获得约80%至90%的响应抑制。在训练期大鼠接受盐水载体。
本发明的化合物也预计可用于治疗疼痛和恐怖紊乱(Am.J.Pain Manag.,5:7-9(1995))。
本发明的化合物还预计可用于治疗躁狂、急慢性、单侧或复发抑郁的症状。它们还预计用于治疗和/或预防两极紊乱(美国专利5510381)。
TNBS诱导的大鼠慢性内脏异常性疼痛
已发现给结肠注射三硝基苯磺酸(TNBS)引起慢性结肠炎。在人中,消化紊乱经常与内脏疼痛有关。在这些疾病中,内脏疼痛阈值降低表明内脏超敏。结果,设计此实验来评价在结肠扩张实验模型中给经肠注射TNBS对内脏疼痛阈值的作用。
动物和手术
使用重340-400g雄性的Sprague-Dawley大鼠(Janvier,LeGene st-St-Ilse,法国)。在调节的环境(20±1℃,50±5%湿度,早8:00至晚8:00光照)每个笼中关3只动物。麻醉下(氯胺酮80mg/kg i.p.;乙酰丙嗪12mg/kgip),给结肠的近端(距盲肠1厘米)进行TNBS(50mg/kg)或盐水(1.5ml/kg)注射。手术后,将动物单独关在聚丙烯笼中,并在调节的环境(20±1℃,50±5%湿度,早8:00至晚8:00光照)中关7天。
实验方法
TNBS给药后第7天,通过肛门插入气球(5-6厘米长)并通过轻击插管至尾部根部保持在此位置(气球尖端距肛门5厘米)。逐渐给此气球充气,每次5mmHg,从0至75mmHg,每次充气持续30秒。通过标准气压补偿器(ABS,St-Die,法国)控制结肠扩张的每个循环。阈值相应于产生第一次腹部收缩并停止扩张循环的压力。对同一动物进行4个循环的扩张后确定此结肠阈值(以mmHg表示的压力)。
化合物活性的检测
通过比较被测化合物治疗组与TNBS治疗组及对照组来分析数据。计算每组的平均值和SEM。化合物的抗异常活性计算如下:
活性(%)=(组C-组T)/(组A-组T)
组C:对照组结肠阈值的平均值
组T:TNBS治疗组的结肠阈值的平均值
组A:被测化合物治疗组的结肠阈值的平均值
统计分析
用单侧ANOVA再用Student不成对t检验确定每组之间的统计学显著性。在p<0.05下认为差异是统计学显著性的。
化合物
TNBS溶解于30%乙醇中,并以0.5ml/大鼠的体积注射。TNBS购自Fluka。
在结肠扩张循环前1小时进行被测化合物或其载体的口服给药。
在结肠扩张循环前30分钟进行被测化合物或其载体的皮下给药。
本发明的化合物可以以多种口服和非肠道给药剂型制备并给药。因此,本发明的化合物可以通过注射给药,即静脉内、肌肉内、皮内、皮下、十二指肠内或腹膜内给药。本发明的化合物还可以通过吸入给药,例如,鼻内吸入。此外,本发明的化合物可以透皮给药。本领域技术人员显而易见下列剂型可以含有式I的化合物或式I化合物的相应药用盐作为活性组分。
为了由本发明的化合物制备药物组合物,药用载体可以是固体或液体。固体制剂包括散剂、片剂、丸剂、胶囊、扁囊剂、栓剂和可分散颗粒剂。固体载体可以是一种或多种物质,它们也可以作为稀释剂、矫味剂、粘合剂、防腐剂、片剂崩解剂或包囊材料。
在散剂中,载体是细分的固体,其与细分的活性组分存在于混合物中。
在片剂中,此活性组分与具有需要的粘合性质的载体以适当比例混合,并压制为所需的形状和大小。
散剂和片剂优选含有5或10至约70%活性化合物。适宜的载体是碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。术语“制剂”旨在包括以包囊材料为载体提供胶囊的活性化合物的制剂,其中活性化合物与其它载体或无其它载体被包在载体中,该化合物于是与该载体联合。同样,包括扁囊剂和锭剂。片剂、散剂、胶囊、丸剂、扁囊剂和锭剂可以是适于口服给药的固体剂型。
为了制备栓剂,先将低熔点蜡如脂肪酸甘油酯或可可脂的混合物熔化,并通过搅拌将此活性组分均匀地分散在其中。然后,将熔化的均匀混合物倒入大小合适的模中,让其冷却,并由此固化。
液体形式的制剂包括溶液剂、混悬剂和乳剂,例如,水或含水丙二醇溶液。对于非肠道注射液体制剂,可以在含水聚乙二醇溶液中制备。
适于口服的含水溶液剂可以通过将活性组分溶解于水中,并按照需要加入适宜的着色剂、矫味剂、稳定和增稠剂制备。
适于口服的含水混悬剂可以通过将细分的活性组分分散于含水粘性物质中制备,如天然或合成胶、树脂、甲基纤维素、羧甲基纤维素钠及其它熟知的混悬剂。
还包括在使用前短不久转变为口服给药的液体制剂的固体形式的制剂。这些液体形式包括溶液剂、混悬剂和乳剂。除活性组分外这些制剂可含有着色剂、矫味剂、稳定剂、缓冲剂、合成或天然甜味剂、分散剂、增稠剂、助溶剂等。
此药物制剂优选是单位剂型。在此剂型中,此制剂被再分为含适量活性组分的单位剂量。此单位剂量可以是包装的制剂,该包装含可分量的制剂,如包装的片剂、胶囊和在小瓶或安瓿中的散剂。此单位剂型还可以是胶囊、片剂、扁囊剂或锭剂本身,或其可以是存在于包装形式中的适当数量的任何这些剂型。
单位剂量制剂中活性组分的量可根据具体的应用和活性组分的效力而变化或调节自0.1mg至约1g。在医药用途中,该药物以例如100或300mg的胶囊每天给药三次。必要时,该组合物还可含其他相容的治疗剂。
在治疗用途中,用于本发明药学方法的化合物以起始剂量每天约0.01mg至约100mg/kg给药。日剂量范围优选约0.01mg至约100mg/kg。但是,这些剂量可以根据患者的需要、被治疗病症的严重性以及使用的化合物变化。对特定情况下适当剂量的确定是本领域技术人员的一般知识。一般来说,开始以小于该化合物最佳剂量的较小剂量治疗。此后,小量增加此剂量直到达到在此环境下的最佳效果。方便起见,如果需要可将总日剂量再细分并在该天内分次给药。
本发明的磺酰胺可通过方案1所示的一般途径而合成。
方案1
试剂:
(i)膦酸二乙基氰基甲基酯,NaH,四氢呋喃;
(ii)硝基甲烷,氟化四丁基铵,四氢呋喃;
(iii)硼烷·甲基硫,甲苯;
(iv)三乙胺,R15SO2Cl,四氢呋喃;
(v)10%Pd-C,氢气,甲醇。
四唑可通过方案2所示的一般途径而合成。
方案2
试剂:
(i)三甲基硅烷叠氮,三甲基铝(2M,在己烷中),甲苯;
(ii)阮内镍,甲醇。
酰胺可通过方案3所示的一般途径而合成。
方案3
试剂:
(i)膦酸二乙基氰基甲基酯,NaH,四氢呋喃;
(ii)硝基甲烷,氟化四丁基铵,四氢呋喃;
(iii)硼烷·甲基硫,甲苯;
(iv)三乙胺,R15SO2Cl,四氢呋喃;
(v)10%Pd-C,氢气,甲醇。
诸如下式的杂环
可通过方案4所示的一般途径而合成。
(i)NH2OH·HCl,Et3N;
(ii)iBuOCOCl,吡啶,随后在二甲苯中回流;
(iii)Fe/HCl.
化合物1[(1-硝基甲基-环己基)乙腈]可在诸如三乙胺的碱存在下用盐酸羟胺处理而得到化合物2。
杂环化合物3可在诸如吡啶的碱存在下用氯甲酸异丁酯处理,随后通过在诸如二甲苯的溶剂中回流而制备于化合物2。硝基化合物(化合物3)可通过例如用铁和盐酸还原而转变成所需的胺。杂环化合物如
可通过方案5a所示的一般途径而合成。
方案5a
可通过方案5b所示的一般途径而合成。
方案5b
可通过方案6所示的一般途径而合成。
方案6
(i)NH2OH·HCl,Et3N;
(ii)1,1’-硫代羰基二咪唑,随后通过DBU或DBN;
(iii)Fe/HCl.
化合物1[(硝基甲基-环己基)乙腈]可在诸如三乙胺的碱存在下用盐酸羟胺处理而得到化合物2。
杂环化合物3可在诸如1,8-二氮二环-[4,5,0]-十一碳-7-烯(DBU)或1,5-二氮二环-[2,2,2]-辛烷(DBN)的碱存在下用1,1’-硫代羰基二咪唑处理而制备于化合物2。
硝基化合物(化合物3)可通过例如用铁和盐酸还原而转变成所需的胺。
杂环化合物如
可通过方案7所示的一般途径而合成。
(i)NH2OH·HCl,Et3N;
(ii)1,1’-硫代羰基二咪唑,随后通过硅胶或BF3·OEt2;
(iii)Fe/HCl.
化合物1[(硝基甲基-环己基)乙腈]可在诸如三乙胺的碱存在下用盐酸羟胺处理而得到化合物2。
杂环化合物3可用1,1’-硫代羰基二咪唑处理,随后通过硅胶或乙醚合三氟化硼处理而制备于化合物2。
硝基化合物(化合物3)可通过例如用铁和盐酸还原而转变成所需的胺。
杂环化合物如
可通过方案8所示的一般途径而合成。
方案8
(i)NH2OH·HCl,Et3N;
(ii)吡啶,SOCl2;
(iii)Fe/HCl.
化合物1[(硝基甲基-环己基)乙腈]可在诸如三乙胺的碱存在下用盐酸羟胺处理而得到化合物2。
杂环化合物3可在诸如吡啶的碱存在下用亚硫酰氯处理而制备于化合物2。
硝基化合物(化合物3)可通过例如用铁和盐酸还原而转变成所需的胺。
以下实施例是本发明的举例说明而不是想限制本发明的范围。
试剂:
(i)膦酸二乙基氰基甲基酯,NaH,四氢呋喃;
(ii)硝基甲烷,氟化四丁基铵,四氢呋喃;
(iii)硼烷·甲基硫,甲苯;
(iv)三乙胺,甲磺酰氯,四氢呋喃;
(v)10%Pd-C,氢气,甲醇然后HCL.
亚环己基-乙腈(2)
将氢化钠(在油中,60%,0.80g,20mmol)悬浮于50mL四氢呋喃中并在氮气下于冰中冷却。在10mL四氢呋喃中滴加二乙基氰基甲基膦酸酯(3.85g,22mmol)并连续搅拌15分钟得到清液。
在5mL四氢呋喃中加入环己酮并让该反应混合物温至室温。倾析该溶液并用醚洗涤该残余物三次。合并该溶液和洗涤液,用稀盐酸和水洗涤,硫酸镁干燥,过滤,并蒸干。硅色谱纯化该残余物,用庚烷/乙酸乙酯4∶1洗脱得到所需的无色油状的产物(1.5g,67%)。
1H NMR 400MHz(CDCl3):δ1.50(m,6H),2.25(t,J=5.6Hz,2H),2.49(t,J=6.8Hz,2H),5.04(s,1H).
IR νmax 2933,2859,2217,1633,1449
(1-硝基甲基-环己基)-乙腈(3)
在20mL四氢呋喃中加热腈(化合物2,0.78g,6.44mmol),硝基甲烷(0.80g,13.11mmol)和氟化四丁基铵(在四氢呋喃中,20mL,10mmol)到70℃过夜。用乙酸乙酯稀释该反应混合物并用稀盐酸和水洗涤,硫酸镁干燥,过滤,并蒸干。硅色谱纯化该残余物,用庚烷/乙酸乙酯3∶1洗脱得到所需的黄色油状的产物(0.83g,71%)。
1H NMR 400MHz(CDCl3):δ1.57(s,10H),2.63(s,2H),4.52(s,2H).
计算分析 C9H13N2O2:
C,59.32;H,7.74;N,15.37.
测定值: C,59.40;H,7.65;N,15.18.
2-(1-硝基甲基-环己基)-乙胺(4)
在氮气下加入硼烷.甲基硫(2.0M,在甲苯中,1.3mL,2.6mmol)到化合物3(0.4g,2.2mmol)的甲苯(10mL)溶液中。加热到60℃三小时,让该化合物冷却,加入15mL甲醇,随后加入15mL 4M HCL的二噁烷溶液。回流1小时后,蒸干该混合物。自乙酸乙酯结晶得到所需的无色晶体的产物(0.23g,47%);mp170-173℃。
1H NMR 400MHz(d6-DMSO):δ1.30-1.50(m,10H),1.64-1.69(m,2H),2.82-2.86(m,2H),4.57(s,2H),7.89(s,3H).
计算分析 C9H18N2O2·HCl·0.2H2O:
C,47.77;H,8.64:N,12.38.
测定值:C,47.80;H,8.66;N,12.64.
N-[2-(1-硝基甲基-环己基)-乙基]-甲磺酰胺(5)
滴加三乙胺(0.64g,6.3mmol)到盐酸胺盐(化合物4,0.70g,3.1mmol)和甲磺酰氯(0.36g,6.3mmol)在四氢呋喃(20mL)中的混合物中。室温下搅拌2小时后,过滤该混合物,用乙酸乙酯稀释,并用稀盐酸,饱和的碳酸氢钠溶液和水洗涤,硫酸镁干燥,过滤,并蒸干。自乙酸乙酯/庚烷结晶得到无色晶体(0.39g,47%);mp86-88℃。1H NMR 400MHz(d6-DMSO):δ1.35-1.50(m,10H),1.55-1.60(m,2H),2.89(s,3H),2.99-3.06(m,2H),4.55(s,2H),6.93(t,J=6Hz,1H).
计算分析 C10H20N2O4S:
C,45.44;H,7.63;N,10.60;S,12.13.
测定值:C,45.77;H,7.64;N,10.58;S,12.17.
N-[2-(1-硝基甲基-环己基)-乙基]-甲磺酰胺盐酸盐(6)
在氮气下加入10%的钯碳到化合物5(0.35g,1.3mmol)的甲醇(50mL)溶液中。在40psi氢气下振摇该混合物6小时并通过keiselguhr过滤。蒸干该滤液。加入4N HCL的二噁烷溶液,随后加入醚,得到无色晶状固体的产物(0.33g,92%);mp196-199℃。
1H NMR 400MHz(d6-DMSO):δ1.25-1.45(m,10H),1.55-1.60(m,5H),2.70-2.75(m,2H),2.90-2.95(m,5H),6.86(t,J=6.0Hz,1H),7.86(bs,3H).
计算分析 C10H22N2O2S·HCl·0.25H2O:
C,43.63;H,8.60;N,10.17.
测定值:C,43.43;H,8.64;N,9.95.
实施例2
试剂:
(i)三甲基硅烷叠氮,三甲基铝(2M,在己烷中),甲苯;
(ii)阮内镍,氢气,甲醇,然后HCL。
1-(1H-四唑-5-基甲基)-环己烷甲腈(2)
在氮气下向双腈(Griffiths G.,Mettle H.,MILLS L.S.,和Previdoli F.,Helv.Chim.Acta,74:309(1991))(1.48g,10mmol)的甲苯(20ml)溶液中加入三甲硅烷叠氮(1.15g,10mmol),随后加入三甲基铝(5mL,2.0M,在甲苯中,10mmol)。加热至90℃过夜后让该混合物冷却并小心加到乙酸乙酯,冰和6N盐酸中。用乙酸乙酯萃取水相,用水洗涤该萃取液,硫酸镁干燥,过滤,并蒸干。结晶得到所需的化合物(158mg,8%)。
C-[1-(1H-四唑-5-基甲基)-环己烷]-甲胺盐酸盐(3)
加入四唑(化合物8,158g,0.83mmol)的甲醇溶液到阮内镍的甲醇洗悬浮液。在40psi氢气下振摇该混合物3.5小时,并滤去催化剂,蒸干。残留物在乙酸乙酯和稀盐酸中分配。分离水相并蒸干。自甲醇/乙醚中结晶得到所需的化合物(44mg,23%);mp 176-179℃。
1H NMR 400MHz(d6-DMSO):δ1.20-1.60(m,10H),2.84(s,2H),3.07(s,2H),8.06(bs,3H).
实施例3
试剂:
(i)膦酸二乙基氰基甲基酯,NaH,四氢呋喃;
(ii)硝基甲烷,氟化四丁基铵,四氢呋喃;
(iii)硼烷.甲基硫,甲苯;
(iv)三乙胺,乙酰氯,四氢呋喃;
(v)10%Pd-C,氢气,甲醇然后HCL。
亚环己基-乙腈(2)
将氢化钠(在油中,60%,0.80g,20mmol)悬浮于50mL四氢呋喃中并在氮气下于冰中冷却。在10mL四氢呋喃中滴加二乙基氰基甲基膦酸酯(3.85g,22mmol)并连续搅拌15分钟得到清液。在5mL四氢呋喃中加入环己酮(1.90g,19mmol)并让该反应混合物温至室温。倾析该溶液并用乙醚洗涤该残余物三次。合并该溶液和洗涤液,用稀盐酸和水洗涤,硫酸镁干燥,过滤,并蒸干。硅色谱纯化该残余物,用庚烷/乙酸乙酯4∶1洗脱得到所需的无色油状的产物(1.5g,67%)。
1H NMR 400MHz(CDCl3):δ1.50(m,6H),2.25(t,J=5.6Hz,2H),2.49(t,J=6.8Hz,2H),5.04(s,1H).
IRνmax 2933,2859,2217,1633,1449.
(1-硝基甲基-环己基)-乙腈(3)
在20mL四氢呋喃中加热腈(化合物2,0.78g,6.44mmol),硝基甲烷(0.80g,13.11mmol)和氟化四丁基铵(在四氢呋喃中,20mL,l0mmol)到70℃过夜。用乙酸乙酯稀释该反应混合物并用稀盐酸和水洗涤,硫酸镁干燥,过滤,并蒸干。硅色谱纯化该残余物,用庚烷/乙酸乙酯3∶1洗脱得到所需的黄色油状的产物(0.83g,71%)。
1H NMR 400MHz(CDCl3):δ1.57(s,10H),2.63(s,2H),4.52(s,2H).
计算分析 C9H13N2O2:
C,59.32;H,7.74;N,15.37.
测定值:C,59.40;H,7.65;N,15.18.
2-(1-硝基甲基-环己基)-乙胺(4)
在氮气下加入硼烷·甲基硫(2.0M,在甲苯中,1.3mL,2.6mmol)到化合物3(0.4g,2.2mmol)的甲苯(10mL)溶液中。加热到60℃三小时,让该化合物冷却,加入15mL甲醇,随后加入15mL 4M HCL的二噁烷溶液。回流1小时后,蒸干该混合物。自乙酸乙酯结晶得到所需的无色晶体的产物(0.23g,47%);mp170-173℃。
1H NMR 400MHz(d6-DMSO):δ1.30-1.50(m,10H),1.64-1.69(m,2H),2.82-2.86(m,2H),4.57(s,2H),7.89(s,3H).
计算分析 C9H18N2O2·HCl·0.2H2O:
C,47.77;H,8.64;N,12.38.
测定值:C,47.80;H,8.66;N,12.64.
N-[2-(1-硝基甲基-环己基)-乙基]-乙酰胺(5)
在实施例1,步骤4后,胺盐酸盐(化合物4,0.50g,2.25mmol)与乙酰氯(0.20g,2.55mmol)和三乙胺(0.45g,4.45mmol)在四氢呋喃中反应。硅色谱纯化,其中用乙酸乙酯洗脱得到所需的晶体状固体的产物(0.35g,69%);mp 68-70℃。
1H NMR 400MHz(CDCl3):δ1.40-1.60(m,10H),1.60-1.65(m,2H),1.98(s,3H),3.30-3.40(m,2H),4.40(s,2H),5.59(bs,1H).
N-[2-(1-氨基甲基-环己基)-乙基]-乙酰胺盐酸盐(6)
在实施例1,步骤5后,在10%的钯碳存在下氢化化合物5(0.30g,1.3mmol)得到作为盐酸盐的产物(0.35g,100%)。
1H NMR 400MHz(d6-DMSO):δ1.20-1.40(m,10H),1.40-1.50(m,2H),1.81(s,3H),2.75(q,J=6.0Hz,2H),2.95-3.05(m,2H),7.99(bs,3H),8.06(t,J=4.8Hz,1H).
IRνmax 3265,2929,1628,1553,1446,1373,1298.
实施例4
3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮;盐酸盐
[1-(叔-丁氧羰基氨基-甲基)-环己基]-乙酸(2)
冷却Gabapentin(1)(9.37g,0.0547mol)在125mL 1N NaOH和50mL THF中的溶液并缓慢加入二碳酸二叔丁酯(13.1g,0.06mol)在200mL THF中的溶液。在室温下搅拌该反应混合物两小时并在旋转蒸发器中浓缩除去THF。用KH2PO4饱和该浓缩物并用3X EtOAc萃取。用2X盐水洗涤EtOAc萃取液,硫酸镁干燥。蒸干得到14.8g(100%)白色固体,mp109-111℃。
1HNMR(CDCl3)δ1.2-1.4(m,19H),2.27(s,2H),3.11(d,2H,J=6.84Hz),4.95(宽,1H).
MS(APCI)m/z272(M+1).
计算分析 C14H25NO4:
C,61.97;H,9.29;N,5.16.
测定值:C,62.36;H,9.27;N,5.19.
(1-氨基甲酰甲基-环己基甲基)-氨基甲酸叔丁酯(3)
将[1-(叔-丁氧羰基氨基-甲基)-环己基]-乙酸(2)(152g,0.56mol)置于1L THF和三乙胺(66.2g,0.65mol)中并冷却至-10℃。在1小时的时间内,加入异丁醛(84.7g,0.62mol),并在0℃下搅拌不均匀的混合物15分钟。将氨气通入该冷反应混合物30分钟,并让其温至室温。搅拌16小时后,在旋转蒸发器上蒸干反应混合物,并将残留物置于水中,用3X EtOAc萃取,用2X盐水洗涤,硫酸镁干燥。蒸干得到油状物,自戊烷结晶得到116.5g(77%)白色晶体,mp123-125℃。
1HNMR(CDCl3)δ 1.2-1.6(m,19H),2.12(s,2H),3.13(d,2H,J=7.08Hz),4.97(s,IH),5.43(s,1H),7.34(s,1H).
MS(APCI)271m/z.(M+1).
计算分析 C14H26N2O3:
C,62.19;H,9.69;N,10.36.
测定值:C,62.00;H,9.72;N,9.96.
(1-氰基甲基-环己基甲基)-氨基甲酸叔丁酯(4)
加入氰尿酰氯(39.5g,0.214mol)到(1-氨基甲酰甲基-环己基甲基)-氨基甲酸叔丁酯(3)(116g,0.429mol)的400mLDMF溶液中。用冰水浴缓和防热,并在室温下搅拌该反应混合物1.5小时。将混合物倾注入含有120g(1.43mol)NaHCO3的冰水中并用4X EtOAc萃取。用1X水,2X盐水洗涤,硫酸钠干燥。蒸干得到油状物,溶解在3∶1己烷/EtOAc并硅胶过滤。蒸发得到白色晶体(86.5g,80%),mp 54-58℃。
1HNMR(CDCl3)δ1.3-1.5(m,19H),2.30(s,2H),3.15(d,2h,J=7.00Hz),4.60(宽,1H).
MS(APCI)m/z 253(M+1).
计算分析 C14H24N2O2:
C,66.63;H,9.59;N,11.10.
测定值:C,66.64;H,9.52;N,10.80.
[1-(N-羟基脲基甲基(N-Hydroxycarbamimidoylmethyl))-环己基甲基]-氨基甲酸叔丁酯(5)
在冰水中冷却羟胺盐酸盐(69.5g,1.00mol)在DMSO(300mL)中的悬浮液,加入三乙胺(106.7g,1.05mol)。产生的放热使温度到20℃。在此温度下搅拌混合物15分钟,并过滤三乙胺盐酸盐,用THF洗涤。浓缩滤液以除去THF,并加入(1-氰基甲基-环己基甲基)-氨基甲酸叔丁酯(4)(50.4g,0.2mol),75℃下加热混合物15小时。冷却后,用水(1L)稀释该反应混合物并用3X EtOAc萃取。用1X饱和的KH2PO4,1X饱和的NaHCO3,2X盐水洗涤,硫酸钠干燥。蒸干得到胶质固体,Et2O中研制得到白色晶体25.2g(44%);mp125-127℃。
1HNMR(CDCl3)δ1.3-1.5(m 19H),1.99(s,2H),3.12(d,2H J=6.84Hz),4.93(t,1H,J=6.84Hz),5.40(s,1H).
MS(APCI)m/z 286(M+1).
计算分析 C14H27N3O3:
C,58.92;H,9.54;N,14.72.
测定值C,58.96;H,9.80;N,14.65.
BOC-加巴喷丁偕胺肟氨基甲酸酯(6)
在冰水中冷却[1-(N-羟基脲基(carbamimidoyl)甲基)-环己基甲基]-氨基甲酸叔丁酯(5)(25.1g,0.088mol)和吡啶(7.82g,0.099mol)在DMF(200mL)中的溶液,同时滴加异丁醛(12.32g,0.09mol)。15分钟后,撤去水浴并在室温下搅拌该反应混合物2小时,用水稀释并用3X EtOAc萃取。用1X水,2X盐水洗涤,硫酸钠干燥。蒸干得到油状物,34g(100%),无需进一步纯化即可使用。MS(APCI)M/Z386(m+1)。
[1-(5-氧代-4,5-二氢-[1,2,4]噁二唑-3-基甲基)-环己基甲基]-氨基甲酸叔丁酯(7)
将BOC-加巴喷丁(Gabapentin)偕胺肟氨基甲酸酯(33.88g,0.088mol)溶解于甲苯(250mL)并在回流下加热2.5小时。蒸去甲苯,在Et2O中溶解残留物,3X 75mL 1N NaOH萃取。用饱和的KH2PO4酸化该碱性萃取液并用3X Et2O萃取。用1X饱和的KH2PO4,2X盐水洗涤,硫酸钠干燥。蒸干得到奶油色固体,17.9g(65%);mp140-143℃。
1HNMR(CDCl3)δ1.0-1.6(m,19H),2.42(s,2H),3.00(d,2H,J=7.32Hz),4.86(t,1H,J=7.08Hz),11.30(s,1H).
MS(APCI)m/z 312(M+1).
计算分析 C15H25N3O4:
C,57.86;H,8.09;N,13.49.
测定值:C,58.21;H,8.31;N,13.30.
3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮;盐酸盐(8)
让BOC-加巴喷丁噁二唑酮(17.7g,0.0568mol)在4M的HCl的二噁烷(200mL)溶液中的溶液静置1.5小时。浓缩至一半体积,随后加入Et2O得到沉淀,过滤并自MeOH重结晶得到白色晶体(12.98g,92.7%);mp209-212℃。
1HNMR(DMSO-d6)δ1.2-1.5(m,10H),2.64(s,4H),2.79(s,2H),7.98(s,3H),12.35(s,1H).
MS(APCI)m/z 212(M+1).
计算分析 C10H17N3O2·HCl:
C,48.49;H,7.32;N,16.96;Cl,14.31.
测定值:C,48.71;H,7.18;N,17.03;Cl,14.32.
实施例5
[1-(5-硫代-4,5-二氢-[1,2,4]噁二唑-3-基甲基)-环己基甲]-氨基甲酸叔丁酯(9)
在室温下搅拌[1-(N-羟基脲基(carbamimidoyl)甲基)-环己基甲基]-氨基甲酸叔丁酯(4.85g,0.017mol),90%1,1’硫代羰基二咪唑(3.96g,0.02mol)和DBU(10.39g,0.068mol)在MeCN(150mL)中的混合物19小时。蒸干该反应混合物,悬浮于饱和的KH2PO4中并用3X Et2O萃取。用2X饱和的KH2PO4,2X盐水洗涤,硫酸钠干燥。蒸发,随后硅胶过滤,其中以3∶1 EtOAc/己烷洗脱,蒸发得到固体,自EtOAc/己烷重结晶得到浅桃红色固体,2.6g(47%);mp160-161℃。
1HNMR(CDCl3)δ1.1-1.6(m,19H),2.53(s,2H),3.00(d,2H,J=7.33Hz),4.90(t,1H,J=7.08Hz),12.88(s,1H).
MS(APCI)m/z 328(M+1).
计算分析 C15H25N3O3S:
C,55.02;H,7.70;N,12.83;S,9.79.
测定值:C,55.34;H,7.80;N,12.72;S,9.43.
3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-硫酮;盐酸盐(10)
将[1-(5-硫代-4,5-二氢-[1,2,4]噁二唑-3-基甲基)-环己基甲基]-氨基甲酸叔丁酯(9)(2.5g,0.0076mol)溶解于在4M的HCl的1,4-二噁烷(75mL)溶液中并在室温下搅拌。过滤形成的沉淀并自EtOAc-Et2O重结晶得到白色固体,1.31g(66%);mp 210-212℃。
1HNMR(DMSO-d6)δ1.2-1.5(m,10H),2.79-2.85(m,4H),7.99(s,3H).MS(APCI)m/z 228(M+1).
计算分析 C10H17N3OS·HCl:
C,45.53;H,6.88;N,15.93;S,12.16;Cl,13.44.
测定值:C,45.92;H,6.71;N,15.83;S,11.81;Cl,13.48.
实施例6
试剂:
(i)三甲基硅烷叠氮,氧化二丁基锡,甲苯;
(ii)镍催化剂,甲醇。
合成9-(1H-四唑-5-基甲基)-二环[3,3,1]壬烷-9-甲腈(2)
向双腈(参照WO9733859)(1.2g,6.38mmol)的甲苯(10ml)溶液中加入三甲硅烷叠氮(1.48g,12.87mmol),随后加入三丁基氧化锡(1.48g,0.64mmol)。加热至95℃三天后,用乙酸乙酯稀释该混合物,用1N盐酸和水洗涤,硫酸镁干燥,过滤,并蒸干。结晶得到所需的化合物(0.3g,20%);mp 189-191℃。
400MHz NMR(d6-DMSO)δ1.50-1.70(m,4H),1.75-2.10(m,10H),3.48(s,2H).
合成C-[9-(1H-四唑-5-基甲基)-二环[3,3,1]壬-9-基-甲胺盐酸盐(3)
加入步骤1所得的四唑(0.60g,2.59mmol)的甲醇(100mL)溶液到镍催化剂的甲醇洗悬浮液。在40psi氢气下振摇该混合物过夜,并滤去催化剂,蒸干。残留物溶解于加入的甲醇和醚盐酸中。加入乙醚并过滤得到所需的产物(0.19g,22%);mp232-236℃。
400MHz NMR(d6-DMSO)δ1.40-1.70(m,8H),1.75-1.95(m,4H),2.05-2.15(m,2H),3.13(s,2H),3.29(s,2H),8.0(bs,3H).
实施例7
试剂:
(i)氰基乙酸乙酯,NaH,四氢呋喃;
(ii)KCN,EtOH,水,回流(reflux);
(iii)三甲基硅烷叠氮,氧化二丁基锡,甲苯;
(iv)镍催化剂,甲醇。
合成2-(1H-四唑-5-基甲基)-金刚烷-2-甲腈(4)
按实施例4中9-(1H-四唑-5-基甲基)-二环[3,3,1]壬烷-9-甲腈的相同的方法制备。
合成C-[2-(1H-四唑-5-基甲基)-金刚烷-2-基-甲胺盐酸盐(3)
以类似方法准备步骤3所得的腈(0.47g,1.9mmol),用镍催化剂(一满刮勺,洗过的)在50psi氢气下振摇该混合物过夜。通过硅藻土过滤并蒸发,随后用甲醇和盐酸乙酯(ethereal hydrogenchloride)处理得到所需的产物,自甲醇和丙腈中结晶(25mg,5%);mp 250-252℃。
400MHz NMR δ1.49(s,2H),1.54(d,J=13.7Hz,2H),1.59(d,J=13.7Hz),1.67(s,2H),1.83(s,1H),1.90(s,1H),1.97(d,J=12.9Hz,2H),2.19(d,J=12.7Hz,2H),3.15(s,2H),3.34(s,被水掩盖了),7.99(bs,3H).
质谱 ES+248(100%,(M+H)+).
试剂:
(i)氰基乙酸乙酯,乙酸铵,乙酸,甲苯;
(ii)KCN,含水乙醇;
(iii)三甲基硅烷叠氮,氧化二丁基锡,甲苯;
(iv)镍催化剂,甲醇。
合成(反式)氰基-(3,4-二甲基-亚环戊基)-乙酸乙酯(2)
将反式-3,4-二甲基环戊酮(2.91g,25.94mmol),氰基乙酸乙酯(2.93g,25.93mmol),乙酸铵(0.20g,2.60mmol),和乙酸(0.31g,5.17mmol)在迪安-斯达克榻分水器下的回流的甲苯中一起加热24小时。冷却并通过硅藻土过滤后,蒸发得到所需的灰白色固体产物(5.0g,93%)。
400MHz NMR δ1.08(d,J=6.0Hz,3H),1.09(d,J=6.4Hz,3H),1.34(t,J=7.2Hz,3H),1.55-1.70(m,2H),2.30-2.45(m,2H),3.08(dd,J=20.0Hz,8.0Hz,1H),3.43(dd,J=20.0Hz,7.0Hz,1H),4.26(q,J=7.1Hz,2H).
质谱 ES+208.19(M+H)+,225.19,230.16(100%,(M+Na)+).
合成(反式)1-氰基甲基-3,4-二甲基-环戊烷甲腈(3)
在乙醇/10%水(50mL)中回流步骤1的产物(1.57g,24.1mmol)和氰化钾(1.57g,24.2mmol)过夜。蒸干并通过用乙酸乙酯/庚烷1∶1洗脱的色谱纯化得到所需的黄色油状产物,2.9g(74%);薄层色谱比移值0.45乙酸乙酯/庚烷1∶1。
400MHz NMR δ1.05(d,J=8.4Hz,3H),1.07(d,J=8.8Hz,3H),1.49(dd,J=13.2,11.6Hz,1H),1.60-1.70(m,1H),1.75-1.90(m,1H),1.96(dd,J=13.6,14.8Hz,1H),2.19(dd,J=14.0,8.4Hz,1H),2.48(dd,J=13.2,6.4Hz,1H),2.73(s,2H).
合成(反式)3,4-二甲基-1-(1H-四唑-5-基甲基)-环戊烷甲腈(4)
在甲苯(50m1)中加热双腈(1.62g,10mmol)和三甲硅烷叠氮(2.84g,24.7mmol)以及二丁基氧化锡(0.24g,0.96mmol)到100℃过夜。用乙酸乙酯稀释该反应混合物并用稀盐酸和水洗涤。硫酸镁干燥该溶液并蒸干。通过用乙酸乙酯洗脱的色谱纯化得到所需的无色油状产物,0.94g,(46%)。
质谱ES+ 206.23(M+H)+,228.26(M+Na)+.
400MHz NMR CDCl3δ1.04(d,J=7.2Hz,3H),1.05(d,J=6.4Hz),1.56(dd,J=11.6,11.6Hz,1H),1.55-1.65(m,1H),1.65-1.75(m,1H),1.83(dd,J=13.6,9.2Hz,1H),2.27(dd,J=14.0,8.0Hz),2.35(dd,J=13.0,6.8Hz,1H),3.36(s,2H).
合成(反式)C-[3,4-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺盐酸盐(5)
在甲醇中将步骤3所得的四唑(0.90g,0.44mmol)和镍催化剂(一满刮勺,洗过的)一起振摇过夜。通过硅藻土过滤并蒸干。用甲醇和乙醚盐酸处理残留物,然后在二噁烷(1∶1,20ml)中与二碳酸二-叔丁酯(0.80g,3.67mmol)和碳酸氢钠(0.80g,9.52mmol)一起搅拌过夜。用乙酸乙酯稀释该混合物,分离水相,酸化,并用3X乙酸乙酯萃取。硫酸镁干燥该萃取液,过滤并蒸发得到所需的无色油。将此油与4M盐酸在二噁烷(5ml)中搅拌过夜,然后蒸干得到所需的产物0.24mg(76%)。
400MHz d6-DMSO δ0.88(d,J=6.4Hz,3H),0.89(d,J=5.6z,3H),1.15-1.25(m,3H),1.35-1.45(m,1H),1.70-1.80(m,2H),2.82(d,J=13.2Hz,1H),2.89(d,J=13.2Hz,1H),3.04(d,J=15.2Hz,1H),3.05(d,J=15.2Hz,1H).
质谱ES+210 100%,(M+H)+.
计算的元素分析 C10H19N5·HCl·0.5H2O:
C,47.14;H,8.31;N,27.49.
测定值:C,47.23;H,7.97;N,27.16.
Claims (19)
2.权利要求1的化合物,其中R是磺酰胺,其选自-NHSO2R15或-SO2NHR15,其中R15是直链或支链烷基或三氟甲基。
3.权利要求1的化合物,名称为是N-[2-(1-氨基甲基-环己基)-乙基]-甲磺酰胺。
4.权利要求1的化合物,其中R是膦酸,-PO3H2。
5.权利要求1的化合物,选自(1-氨基甲基-环己基甲基)-膦酸和(2-氨基甲基-4-甲基-戊基)-膦酸。
6.权利要求1的化合物,其中R是选自如下的杂环:
和
7.权利要求1的化合物,选自:
(1-氨基甲基-环己基甲基)-膦酸;
(1R-反式)(1-氨基甲基-3-甲基-环己基甲基)-膦酸;
(反式)(1-氨基甲基-3,4-二甲基-环戊基甲基)-膦酸;
(1R-反式)(1-氨基甲基-3-甲基-环戊基甲基)-膦酸;
(1S-顺式)(1-氨基甲基-3-甲基-环戊基甲基)-膦酸;
(1S-反式)(1-氨基甲基-3-甲基-环戊基甲基)-膦酸;
(1R-顺式)(1-氨基甲基-3-甲基-环戊基甲基)-膦酸;
(1α,3α,4α)(1-氨基甲基-3,4-二甲基-环戊基甲基)-膦酸;
(1α,3β,4β)(1-氨基甲基-3,4-二甲基-环戊基甲基)-膦酸;
(R)(1-氨基甲基-3,3-二甲基-环戊基甲基)-膦酸;
(S)(1-氨基甲基-3,3-二甲基-环戊基甲基)-膦酸;
(1-氨基甲基-3,3-二甲基-环丁基甲基)-膦酸;
2-(1-氨基甲基-环己基)-N-羟基-乙酰胺;
(1S-反式)2-(1-氨基甲基-3-甲基-环己基)-N-羟基-乙酰胺;
(反式)2-(1-氨基甲基-3,4-二甲基-环戊基)-N-羟基-乙酰胺;
(1S-顺式)2-(1-氨基甲基-3-甲基-环戊基)-N-羟基-乙酰胺;
(1R-反式)2-(1-氨基甲基-3-甲基-环戊基)-N-羟基-乙酰胺;
(1R-顺式)2-(1-氨基甲基-3-甲基-环戊基)-N-羟基-乙酰胺;
(1-反式)2-(1-氨基甲基-3-甲基-环戊基)-N-羟基-乙酰胺;
(1α,3α,4α)2-(1-氨基甲基-3,4-二甲基-环戊基)-N-羟基-乙酰胺;
(1α,3β,4β)2-(1-氨基甲基-3,4-二甲基-环戊基)-N-羟基-乙酰胺;
(S)2-(1-氨基甲基-3,3-二甲基-环戊基)-N-羟基-乙酰胺;
(R)2-(1-氨基甲基-3,3-二甲基-环戊基)-N-羟基-乙酰胺;
2-(1-氨基甲基-3,3-二甲基-环丁基)-N-羟基-乙酰胺;
N-[2-(1-氨基甲基-环己基)-乙基]-甲磺酰胺;
(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环己基)-乙基]-甲磺酰胺;
(反式)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-甲磺酰胺;
(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-甲磺酰胺;
(1R-反式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-甲磺酰胺;
(1R-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-甲磺酰胺;
(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-甲磺酰胺;
(1α,3α,4α)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-甲磺酰胺;
(1α,3β,4β)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-甲磺酰胺;
(S)N-[2-(1-氨基甲基-3,3-二甲基-环戊基)-乙基]-甲磺酰胺;
(R)N-[2-(1-氨基甲基-3,3-二甲基-环戊基)-乙基]-甲磺酰胺;
N-[2-(1-氨基甲基-3,3-二甲基-环丁基)-乙基]-甲磺酰胺;
(1S-顺式)3-(1-氨基甲基-3-甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮;
(反式)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1R-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1R-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1S-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1α,3α,4α)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(1α,3β,4β)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(S)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
(R)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(1-氨基甲基-3,3-二甲基-环丁基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(反式)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1R-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1R-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1S-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1α,3 α,4α)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1α,3β,4β)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(S)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(R)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
3-(1-氨基甲基-3,3-二甲基-环丁基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
(1S-顺式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环己基]-甲胺;(反式)C-[3,4-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1S-顺式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1R-反式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1R-顺式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1S-反式)C-[3-甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1α,3α,4α)C-[3,4-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(1α,3β,4β)C-[3,4-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(S)C-[3,3-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
(R)C-[3,3-二甲基-1-(1H-四唑-5-基甲基)-环戊基]-甲胺;
C-[3,3-二甲基-1-(1H-四唑-5-基甲基)-环丁基]-甲胺;
N-[2-(1-氨基甲基-环己基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环己基)-乙基]-C,C,C-三氟-甲磺酰胺;
(反式)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1R-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1S-反式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1S-顺式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1R-反式)N-[2-(1-氨基甲基-3-甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1α,3α,4α)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1α,3β,4β)N-[2-(1-氨基甲基-3,4-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(S)N-[2-(1-氨基甲基-3,3-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(R)N-[2-(1-氨基甲基-3,3-二甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
N-[2-(1-氨基甲基-3,3-二甲基-环丁基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1S-顺式)3-(1-氨基甲基-3-甲基-环己基甲基)-4H-[1,2,4]噻二唑-5-酮;
(反式)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1R-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1S-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1S-顺式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1R-反式)3-(1-氨基甲基-3-甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1α,3α,4α)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1α,3β,4β)3-(1-氨基甲基-3,4-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(S)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
(R)3-(1-氨基甲基-3,3-二甲基-环戊基甲基)-4H-[1,2,4]噻二唑-5-酮;
3-(1-氨基甲基-3,3-二甲基-环丁基甲基)-4H-[1,2,4]噻二唑-5-酮;
(1S-顺式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)环己基]甲胺;
(反式)C-[3,4-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(1S-顺式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(1R-反式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(1R-顺式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(1S-反式)C-[3-甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(1α,3α,4α)C-[3,4-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)环戊基]甲胺;
(1α,3β,4β)C-[3,4-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(S)C-[3,3-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
(R)C-[3,3-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环戊基]甲胺;
C-[3,3-二甲基-1-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-环丁基]甲胺;
(1-氨基甲基-环己基)-甲磺酰胺;
(1R-反式)(1-氨基甲基-3-甲基-环己基)-甲磺酰胺;
(反式)(1-氨基甲基-3,4-二甲基-环戊基)甲磺酰胺;
(1S-反式)(1-氨基甲基-3-甲基-环戊基)-甲磺酰胺;
(1R-顺式)(1-氨基甲基-3-甲基-环戊基)-甲磺酰胺;
(1R-反式)(1-氨基甲基-3-甲基-环戊基)-甲磺酰胺;
(1S-顺式)(1-氨基甲基-3-甲基-环戊基)-甲磺酰胺;
(1α,3β,4β)(1-氨基甲基-3,4-二甲基-环戊基)-甲磺酰胺;
(1α,3α,4α)(1-氨基甲基-3,4-二甲基-环戊基)-甲磺酰胺;
(R)(1-氨基甲基-3,3-二甲基-环戊基)-甲磺酰胺;
(S)(1-氨基甲基-3,3-二甲基-环戊基)-甲磺酰胺;
(1-氨基甲基-3,3-二甲基-环丁基)-甲磺酰胺;
(1-氨基甲基-环己基)-甲磺酸;
(1R-反式)(1-氨基甲基-3-甲基-环己基)-甲磺酸;
(反式)(1-氨基甲基-3,4-二甲基-环戊基)甲磺酸;
(1S-反式)(1-氨基甲基-3-甲基-环戊基)-甲磺酸;
(1S-顺式)(1-氨基甲基-3-甲基-环戊基)-甲磺酸;
(1R-反式)(1-氨基甲基-3-甲基-环戊基)-甲磺酸;
(1R-顺式)(1-氨基甲基-3-甲基-环戊基)-甲磺酸;
(1α,3β,4β)(1-氨基甲基-3,4-二甲基-环戊基)-甲磺酸;
(1α,3α,4α)(1-氨基甲基-3,4-二甲基-环戊基)-甲磺酸;
(R)(1-氨基甲基-3,3-二甲基-环戊基)-甲磺酸;
(S)(1-氨基甲基-3,3-二甲基-环戊基)-甲磺酸;
(1-氨基甲基-3,3-二甲基-环丁基)-甲磺酸;
(1-氨基甲基-环戊基甲基)-膦酸;
2-(1-氨基甲基-环戊基)-N-羟基-乙酰胺;
N-[2-(1-氨基甲基-环戊基)-乙基]-磺酰胺;
N-[2-(1-氨基甲基-环戊基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1-氨基甲基-环戊基)-甲磺酰胺;
(1-氨基甲基-环戊基)-甲磺酸;
(9-氨基甲基-二环[3,3,1]壬-9-基甲基)-膦酸;
2-(9-氨基甲基-二环[3,3,1]壬-9-基)-N-羟基-乙酰胺;
N-[2-(9-氨基甲基--二环[3,3,1]壬-9-基)-乙基]]-甲磺酰胺;
3-(9-氨基甲基--二环[3,3,1]壬-9-基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(9-氨基甲基--二环[3,3,1]壬-9-基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
C-[9-(1H-四唑-5-基甲基)-二环[3,3,1]壬-9-基]-甲胺;
N-[2-(9-氨基甲基--二环[3,3,1]壬-9-基)-乙基]-C,C,C-三氟-甲磺酰胺;
3-(9-氨基甲基--二环[3,3,1]壬-9-基甲基)-4H-[1,2,4]噻二唑-5-酮;
C-[9-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-二环[3,3,1]壬-9-基]甲胺;
(9-氨基甲基-二环[3,3,1]壬-9-基)-甲磺酰胺;
(9-氨基甲基--二环[3,3,1]壬-9-基)-甲磺酸;
(2-氨基甲基-金刚烷-2-基甲基)-膦酸;
2-(2-氨基甲基-金刚烷-2-基)-N-羟基-乙酰胺;
N-[2-(2-氨基甲基-金刚烷-2-基)-乙基]-甲磺酰胺;
3-(2-氨基甲基-金刚烷-2-基甲基)-4H-[1,2,4]噁二唑-5-酮;
3-(2-氨基甲基-金刚烷-2-基甲基)-4H-[1,2,4]噁二唑-5-硫酮;
C-[1-(1H-四唑-5-基甲基)-金刚烷-2-基]-甲胺;
N-[2-(2-氨基甲基-金刚烷-2-基)-乙基]-C,C,C-三氟-甲磺酰胺;
3-(2-氨基甲基-金刚烷-2-基甲基)-4H-[1,2,4]噻二唑-5-酮;
C-[2-(2-氧代-2,3-二氢-2λ4-[1,2,3,5]噁噻二唑-4-基甲基)-金刚烷-2-基]甲胺;
(2-氨基甲基-金刚烷-2-基)-甲磺酰胺;
(2-氨基甲基-金刚烷-2-基)-甲磺酸;
(1-氨基甲基-环庚基甲基)-膦酸;
2-(1-氨基甲基-环庚基)-N-羟基-乙酰胺;
N-[2-(1-氨基甲基-环庚基)-乙基]-甲磺酰胺;
N-[2-(1-氨基甲基-环庚基)-乙基]-C,C,C-三氟-甲磺酰胺;
(1-氨基甲基-环庚基)-甲磺酰胺;和
(1-氨基甲基-环庚基-)-甲磺酸。
8.一种药物组合物,其中含有治疗有效量的权利要求1所述的化合物和药用载体。
9.权利要求1所述的化合物用于制备治疗癫痫的药物的用途。
10.权利要求1所述的化合物用于制备治疗晕厥发作、少动症和颅疾病的药物的用途。
11.权利要求1所述的化合物用于制备治疗神经变性疾病的药物的用途。
12.权利要求1所述的化合物用于制备治疗抑郁的药物的用途。
13.权利要求1所述的化合物用于制备治疗焦虑的药物的用途。
14.权利要求1所述的化合物用于制备治疗恐慌的药物的用途。
15.权利要求1所述的化合物用于制备治疗疼痛的药物的用途。
16.权利要求1所述的化合物用于制备治疗神经病理紊乱的药物的用途。
17.权利要求1所述的化合物用于制备治疗胃肠道损伤的药物的用途。
18.权利要求1所述的化合物用于制备治疗炎症的药物的用途。
19.权利要求1所述的化合物用于制备治疗应激性肠综合征的药物的用途。
Applications Claiming Priority (4)
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US6977397P | 1997-12-16 | 1997-12-16 | |
US60/069,773 | 1997-12-16 | ||
US10500598P | 1998-10-20 | 1998-10-20 | |
US60/105,005 | 1998-10-20 |
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CN98811481XA Division CN1131855C (zh) | 1997-12-16 | 1998-11-10 | 1-取代-1-氨基甲基-环烷衍生物(=加巴喷丁类似物)、其制备及其在治疗神经病方面的用途 |
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CNA2003101142270A Pending CN1495160A (zh) | 1997-12-16 | 1998-11-10 | 1-取代-1-氨基甲基-环烷衍生物(=加巴喷丁类似物)、其制备及其在治疗神经病方面的用途 |
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AR105592A1 (es) | 2015-08-03 | 2017-10-18 | Quadriga Biosciences Inc | b-AMINOÁCIDOS b-SUSTITUIDOS Y ANÁLOGOS COMO AGENTES QUIMIOTERAPÉUTICOS Y USOS DE LOS MISMOS |
WO2019219000A1 (en) | 2018-05-14 | 2019-11-21 | Xgene Pharmaceutical Inc. | Crystalline forms of 1-(acyloxy)-alkyl carbamate drug conjugates of naproxen and pregabalin |
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NL6804065A (zh) * | 1968-03-22 | 1969-09-24 | ||
BE789025A (fr) * | 1971-09-23 | 1973-03-20 | Allen & Hanburys Ltd | Nouvelles ethylene diamines substituees |
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 |
NO146671C (no) * | 1978-10-13 | 1982-11-17 | Janssen Pharmaceutica Nv | (1-arylcykloalkylmetyl)isotiocyanater med fungicid, baktericid og insekticid virkning |
DE3300774A1 (de) * | 1983-01-12 | 1984-07-12 | Hoechst Ag, 6230 Frankfurt | Neue spirocyclische aminosaeuren, verfahren zu ihrer herstellung, diese enthaltende mittel und deren verwendung sowie neue spirocyclische aminosaeuren als zwischenprodukte und verfahren zu deren herstellung |
DE3327318C1 (de) * | 1983-07-29 | 1985-03-14 | Gödecke AG, 1000 Berlin | 1-Aminomethylcyclohexylmethan-sulfonsaeure,Verfahren zu deren Herstellung und deren Verwendung |
US4755594A (en) * | 1986-01-31 | 1988-07-05 | Warner-Lambert Company | N6 -substituted adenosines |
DE3634066A1 (de) * | 1986-10-07 | 1988-04-21 | Boehringer Mannheim Gmbh | Neue 5-alkylbenzimidazole, verfahren zu ihrer herstellung sowie arzneimittel |
US5015644A (en) * | 1987-06-02 | 1991-05-14 | Warner-Lambert Company | Antihyperlipidemic and antiatherosclerotic urea and carbamate compounds |
US6197819B1 (en) | 1990-11-27 | 2001-03-06 | Northwestern University | Gamma amino butyric acid analogs and optical isomers |
FR2674522B1 (fr) * | 1991-03-26 | 1993-07-16 | Lipha | Nouveaux derives de l'indole, procedes de preparation et medicaments les contenant. |
FR2687402B1 (fr) * | 1992-02-14 | 1995-06-30 | Lipha | Nouveaux azaindoles, procedes de preparation et medicaments les contenant. |
CA2123728A1 (en) * | 1993-05-21 | 1994-11-22 | Noriyoshi Sueda | Urea derivatives and their use as acat inhibitors |
JPH07101929A (ja) * | 1993-10-01 | 1995-04-18 | Fujisawa Pharmaceut Co Ltd | 尿素誘導体およびその製造法 |
DE69709070T2 (de) * | 1996-03-14 | 2002-06-20 | Warner Lambert Co | Verbrückte zyklische aminosäuren als pharmazeutische mittel |
IL125544A (en) * | 1996-03-14 | 2002-03-10 | Warner Lambert Co | Transformed cyclic amino acids and pharmaceutical preparations containing them |
ATE311383T1 (de) * | 1996-08-22 | 2005-12-15 | Warner Lambert Co | Nicht-peptidische bombesin rezeptor antagonisten |
-
1998
- 1998-11-10 NZ NZ503963A patent/NZ503963A/xx unknown
- 1998-11-10 BR BR9814286-0A patent/BR9814286A/pt not_active Application Discontinuation
- 1998-11-10 CN CN98811481XA patent/CN1131855C/zh not_active Expired - Fee Related
- 1998-11-10 HU HU0004439A patent/HUP0004439A3/hu unknown
- 1998-11-10 IL IL13531398A patent/IL135313A0/xx unknown
- 1998-11-10 TR TR2000/01795T patent/TR200001795T2/xx unknown
- 1998-11-10 WO PCT/US1998/023918 patent/WO1999031075A1/en not_active Application Discontinuation
- 1998-11-10 PL PL98341291A patent/PL341291A1/xx unknown
- 1998-11-10 CN CNA2003101142270A patent/CN1495160A/zh active Pending
- 1998-11-10 AU AU13929/99A patent/AU765802B2/en not_active Ceased
- 1998-11-10 KR KR1020007006535A patent/KR20010033158A/ko not_active Application Discontinuation
- 1998-11-10 EP EP04006036A patent/EP1475371A1/en not_active Withdrawn
- 1998-11-10 AT AT98957745T patent/ATE275552T1/de not_active IP Right Cessation
- 1998-11-10 EP EP98957745A patent/EP1047678B1/en not_active Expired - Lifetime
- 1998-11-10 ES ES98957745T patent/ES2227896T3/es not_active Expired - Lifetime
- 1998-11-10 US US09/509,905 patent/US6518289B1/en not_active Expired - Fee Related
- 1998-11-10 DE DE69826151T patent/DE69826151T2/de not_active Expired - Fee Related
- 1998-11-10 PT PT98957745T patent/PT1047678E/pt unknown
- 1998-11-10 SI SI9830690T patent/SI1047678T1/xx unknown
- 1998-11-10 JP JP2000539002A patent/JP2002508362A/ja active Pending
- 1998-11-10 CA CA002304974A patent/CA2304974C/en not_active Expired - Fee Related
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2000
- 2000-04-07 IS IS5435A patent/IS5435A/is unknown
- 2000-06-14 NO NO20003039A patent/NO317252B1/no not_active IP Right Cessation
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2001
- 2001-05-23 HK HK01103570A patent/HK1032966A1/xx not_active IP Right Cessation
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2004
- 2004-03-17 NO NO20041112A patent/NO20041112L/no not_active Application Discontinuation
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KR20010033158A (ko) | 2001-04-25 |
HUP0004439A2 (hu) | 2001-10-28 |
IS5435A (is) | 2000-04-07 |
HUP0004439A3 (en) | 2001-12-28 |
HK1032966A1 (en) | 2001-08-10 |
ATE275552T1 (de) | 2004-09-15 |
ES2227896T3 (es) | 2005-04-01 |
EP1047678A1 (en) | 2000-11-02 |
CN1131855C (zh) | 2003-12-24 |
EP1047678B1 (en) | 2004-09-08 |
AU765802B2 (en) | 2003-10-02 |
DE69826151D1 (de) | 2004-10-14 |
BR9814286A (pt) | 2000-10-03 |
CN1279674A (zh) | 2001-01-10 |
US6518289B1 (en) | 2003-02-11 |
PT1047678E (pt) | 2004-12-31 |
JP2002508362A (ja) | 2002-03-19 |
CA2304974C (en) | 2005-10-25 |
NO20003039D0 (no) | 2000-06-14 |
IL135313A0 (en) | 2001-05-20 |
PL341291A1 (en) | 2001-04-09 |
TR200001795T2 (tr) | 2000-11-21 |
CA2304974A1 (en) | 1999-06-24 |
WO1999031075A1 (en) | 1999-06-24 |
NO20003039L (no) | 2000-06-14 |
EP1475371A1 (en) | 2004-11-10 |
AU1392999A (en) | 1999-07-05 |
SI1047678T1 (en) | 2005-02-28 |
NZ503963A (en) | 2002-09-27 |
NO317252B1 (no) | 2004-09-27 |
NO20041112L (no) | 2000-06-14 |
DE69826151T2 (de) | 2005-01-27 |
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