CN1817854A - 对α2δ-蛋白质具有亲和性的氨基酸 - Google Patents
对α2δ-蛋白质具有亲和性的氨基酸 Download PDFInfo
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- CN1817854A CN1817854A CNA2006100070283A CN200610007028A CN1817854A CN 1817854 A CN1817854 A CN 1817854A CN A2006100070283 A CNA2006100070283 A CN A2006100070283A CN 200610007028 A CN200610007028 A CN 200610007028A CN 1817854 A CN1817854 A CN 1817854A
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- Prior art keywords
- methyl
- amino
- acid
- amino methyl
- phenyl
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- 150000001413 amino acids Chemical class 0.000 title description 7
- 108090000623 proteins and genes Proteins 0.000 title description 3
- 102000004169 proteins and genes Human genes 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 188
- 150000003839 salts Chemical class 0.000 claims abstract description 72
- 208000002193 Pain Diseases 0.000 claims abstract description 48
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims description 78
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 70
- 239000000460 chlorine Substances 0.000 claims description 45
- 229910052731 fluorine Inorganic materials 0.000 claims description 36
- 238000002360 preparation method Methods 0.000 claims description 36
- 125000001153 fluoro group Chemical group F* 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 26
- 201000010099 disease Diseases 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 20
- 208000024891 symptom Diseases 0.000 claims description 20
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 208000004296 neuralgia Diseases 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 208000021722 neuropathic pain Diseases 0.000 claims description 12
- 208000019901 Anxiety disease Diseases 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- SRZDSMJOERDWMK-VXNVDRBHSA-N CCC[C@@H](C)C[C@](C)(C(=O)O)N Chemical compound CCC[C@@H](C)C[C@](C)(C(=O)O)N SRZDSMJOERDWMK-VXNVDRBHSA-N 0.000 claims description 6
- 208000001640 Fibromyalgia Diseases 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 208000000094 Chronic Pain Diseases 0.000 claims description 5
- 208000005298 acute pain Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- WSLCICSXJCXJEN-UHFFFAOYSA-N 2-amino-2,8-dimethylnonanoic acid Chemical compound NC(C(=O)O)(CCCCCC(C)C)C WSLCICSXJCXJEN-UHFFFAOYSA-N 0.000 claims description 4
- 206010060800 Hot flush Diseases 0.000 claims description 4
- 206010065390 Inflammatory pain Diseases 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- VHWJJTKKTVOZNB-UHFFFAOYSA-N 2-amino-2,5-dimethylheptanoic acid Chemical compound CCC(C)CCC(C)(N)C(O)=O VHWJJTKKTVOZNB-UHFFFAOYSA-N 0.000 claims description 3
- BNXWQZYKBIAXNX-UHFFFAOYSA-N 2-amino-2-methyl-3-(1-methylcyclopropyl)propanoic acid Chemical compound NC(C(=O)O)(CC1(CC1)C)C BNXWQZYKBIAXNX-UHFFFAOYSA-N 0.000 claims description 3
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- MIYYJJOPLHOQFD-SMDDNHRTSA-N C[C@@H](CCC1CCCCC1)C[C@](C)(C(=O)O)N Chemical compound C[C@@H](CCC1CCCCC1)C[C@](C)(C(=O)O)N MIYYJJOPLHOQFD-SMDDNHRTSA-N 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- VBDSGELZVDFWLA-GMSGAONNSA-N (2R,4R)-2-amino-5-cyclopropyl-2,4-dimethylpentanoic acid Chemical compound C[C@](C(=O)O)(C[C@@H](CC1CC1)C)N VBDSGELZVDFWLA-GMSGAONNSA-N 0.000 claims description 2
- VBDSGELZVDFWLA-OIBJUYFYSA-N (2R,4S)-2-amino-5-cyclopropyl-2,4-dimethylpentanoic acid Chemical compound C[C@](C(=O)O)(C[C@H](CC1CC1)C)N VBDSGELZVDFWLA-OIBJUYFYSA-N 0.000 claims description 2
- YWAJMILGBXVJTJ-UHFFFAOYSA-N 2-amino-2,4-dimethylhexanoic acid Chemical compound CCC(C)CC(C)(N)C(O)=O YWAJMILGBXVJTJ-UHFFFAOYSA-N 0.000 claims description 2
- CUPGTCAJLARWFC-UHFFFAOYSA-N 2-amino-2,5-dimethylnonanoic acid Chemical compound CC(C(=O)O)(CCC(CCCC)C)N CUPGTCAJLARWFC-UHFFFAOYSA-N 0.000 claims description 2
- WWRRQCYJQMVGIQ-UHFFFAOYSA-N 2-amino-4-ethyl-2,5-dimethylhexanoic acid Chemical compound NC(C(=O)O)(CC(C(C)C)CC)C WWRRQCYJQMVGIQ-UHFFFAOYSA-N 0.000 claims description 2
- FSIIXUWFCWHWNI-UHFFFAOYSA-N 2-amino-4-ethyl-2,8-dimethylnonanoic acid Chemical compound NC(C(=O)O)(CC(CCCC(C)C)CC)C FSIIXUWFCWHWNI-UHFFFAOYSA-N 0.000 claims description 2
- QMSQCBHHTVJEMZ-UHFFFAOYSA-N 2-amino-5-ethyl-2-methylnonanoic acid Chemical compound NC(C(=O)O)(CCC(CCCC)CC)C QMSQCBHHTVJEMZ-UHFFFAOYSA-N 0.000 claims description 2
- OOGXYXOEPLKVST-UHFFFAOYSA-N 2-amino-6-cyclobutyl-2,5-dimethylhexanoic acid Chemical compound NC(C(=O)O)(CCC(CC1CCC1)C)C OOGXYXOEPLKVST-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明涉及一类结合钙通道的α-2-δ(α2δ)亚单元的β-氨基酸。这些化合物及其可药用盐可用于治疗各种精神病、疼痛以及其它疾病。
Description
本申请是申请日为2003年3月17日、申请号为03811269.8,发明名称为“对α2δ-蛋白质具有亲和性的氨基酸”的中国发明专利申请的分案申请。
背景技术
本发明涉及一些结合钙通道的α-2-δ(α2δ)亚单元的β-氨基酸。这些化合物及其可药用盐可用于治疗各种精神病、疼痛以及其它疾病。
发明概述
本发明涉及通式I化合物以及这些化合物的可药用盐:
其中R1是氢或任选被1-5个氟原子取代的(C1-C6)烷基;
R2是氢或任选被1-5个氟原子取代的(C1-C6)烷基;或者
R1和R2与它们所连接的碳一起形成3-6元环烷基环;
R3是(C1-C6)烷基、(C3-C6)环烷基、(C3-C6)环烷基-(C1-C3)烷基、苯基、苯基-(C1-C3)烷基、吡啶基、吡啶基-(C1-C3)烷基、苯基-N(H)-、或吡啶基-N(H)-,其中每个前述的烷基部分可以任选被1-5个氟原子、优选被0-3个氟原子取代,其中所述苯基和所述吡啶基以及所述苯基-(C1-C3)烷基和所述吡啶基-(C1-C3)烷基中的苯基和吡啶基可以分别任选被1-3个取代基、优选被0-2个取代基取代,所述取代基独立地选自氯、氟、氨基、硝基、氰基、(C1-C3)烷基氨基、任选被1-3个氟原子取代的(C1-C3)烷基以及任选被1-3个氟原子取代的(C1-C3)烷氧基;
R4是氢或任选被1-5个氟原子取代的(C1-C6)烷基;
R5是氢或任选被1-5个氟原子取代的(C1-C6)烷基;
R6是氢或(C1-C6)烷基。
本发明的具体实施方案包括下面的通式I化合物及其可药用盐:
3-氨基-5,8-二甲基-壬酸;
3-氨基-5,5,7-三甲基-辛酸;
3-氨基-5,5,8-三甲基-壬酸;
3-氨基-5,5,6-三甲基-庚酸;
(3S,5S)-3-氨基-5,8-二甲基-壬酸;
(3S,5R)-3-氨基-5,8-二甲基-壬酸;
(3S)-3-氨基-5,5,6-三甲基-庚酸;
(3S)-3-氨基-5,5,7-三甲基-辛酸;
(3S)-3-氨基-5,5,8-三甲基-壬酸;以及
(3S)-3-氨基-5,5,9-三甲基-癸酸。
本发明具体实施方案的其它实施例是下面的通式I化合物及其可药用盐:
3-氨基-6-环丁基-5-甲基-己酸;
3-氨基-7-环丙基-5-甲基-庚酸;
3-氨基-7-环丁基-5-甲基-庚酸;
3-氨基-7-环戊基-5-甲基-庚酸;
3-氨基-7-环己基-5-甲基-庚酸;
3-氨基-8-环丙基-5-甲基-辛酸;
3-氨基-8-环丁基-5-甲基-辛酸;
3-氨基-8-环戊基-5-甲基-辛酸;
3-氨基-8-环己基-5-甲基-辛酸;
3-氨基-6-环丙基-5,5-二甲基-己酸;
3-氨基-6-环丁基-5,5-二甲基-己酸;
3-氨基-6-环戊基-5,5-二甲基-己酸;
3-氨基-6-环己基-5,5-二甲基-己酸;
3-氨基-7-环丙基-5,5-二甲基-庚酸;
3-氨基-7-环丁基-5,5-二甲基-庚酸;
3-氨基-7-环戊基-5,5-二甲基-庚酸;
3-氨基-7-环己基-5,5-二甲基-庚酸;
(3S,5R)-3-氨基-6-环丁基-5-甲基-己酸;
(3S,5R)-3-氨基-7-环丙基-5-甲基-庚酸;
(3S,5R)-3-氨基-7-环丁基-5-甲基-庚酸;
(3S,5R)-3-氨基-7-环戊基-5-甲基-庚酸;
(3S,5R)-3-氨基-7-环己基-5-甲基-庚酸;
(3S,5R)-3-氨基-8-环丙基-5-甲基-辛酸;
(3S,5R)-3-氨基-8-环丁基-5-甲基-辛酸;
(3S,5R)-3-氨基-8-环戊基-5-甲基-辛酸;
(3S,5R)-3-氨基-8-环己基-5-甲基-辛酸;
(3S,5S)-3-氨基-6-环丁基-5-甲基-己酸;
(3S,5S)-3-氨基-7-环丙基-5-甲基-庚酸;
(3S,5S)-3-氨基-7-环丁基-5-甲基-庚酸;
(3S,5S)-3-氨基-7-环戊基-5-甲基-庚酸;
(3S,5S)-3-氨基-7-环己基-5-甲基-庚酸;
(3S,5S)-3-氨基-8-环丙基-5-甲基-辛酸;
(3S,5S)-3-氨基-8-环丁基-5-甲基-辛酸;
(3S,5S)-3-氨基-8-环戊基-5-甲基-辛酸;
(3S,5S)-3-氨基-8-环己基-5-甲基-辛酸;
(3S)-3-氨基-6-环丙基-5,5-二甲基-己酸;
(3S)-3-氨基-6-环丁基-5,5-二甲基-己酸;
(3S)-3-氨基-6-环戊基-5,5-二甲基-己酸;
(3S)-3-氨基-6-环己基-5,5-二甲基-己酸;
(3S)-3-氨基-7-环丙基-5,5-二甲基-庚酸;
(3S)-3-氨基-7-环丁基-5,5-二甲基-庚酸;
(3S)-3-氨基-7-环戊基-5,5-二甲基-庚酸;以及
(3S)-3-氨基-7-环己基-5,5-二甲基-庚酸;
本发明其它的具体实施方案包括下面的通式I化合物及其可药用盐:
3-氨基-5-甲基-庚酸;
3-氨基-5-甲基-辛酸;
3-氨基-5-甲基-壬酸;
3-氨基-5,5-二甲基-壬酸;
3-氨基-5,5-二甲基-癸酸;
(3S)-3-氨基-5,5-二甲基-壬酸;以及
(3S)-3-氨基-5,5-二甲基-癸酸。
本发明还涉及通式IA化合物以及这类化合物的可药用盐:
其中R1是氢或任选被1-5个氟原子取代的(C1-C3)烷基;
R2是氢或任选被1-5个氟原子取代的(C1-C3)烷基;或者
R1和R2与它们所连接的碳一起形成3-6元环烷基环;
R3是(C1-C6)烷基、(C3-C6)环烷基、(C3-C6)环烷基-(C1-C3)烷基、苯基、苯基-(C1-C3)烷基、吡啶基、吡啶基-(C1-C3)烷基、苯基-N(H)-、或吡啶基-N(H)-,其中每个前述的烷基部分可以任选被1-5个氟原子、优选被0-3个氟原子取代,其中所述苯基和所述吡啶基以及所述苯基-(C1-C3)烷基和所述吡啶基-(C1-C3)烷基中的苯基和吡啶基可以分别任选被1-3个取代基、优选被0-2个取代基取代,所述取代基独立地选自氯、氟、氨基、硝基、氰基、(C1-C3)烷基氨基、任选被1-3个氟原子取代的(C1-C3)烷基以及任选被1-3个氟原子取代的(C1-C3)烷氧基;
满足的条件是,当R1是氢时,R2不是氢。
本发明还涉及通式IA-1化合物
其中R3与上述通式I中定义相同,以及这类化合物的可药用盐。
本发明其它的具体实施方案包括下面的通式IA化合物及其可药用盐:
3-氨基-5-甲基-8-苯基氨基-辛酸;
3-氨基-5-甲基-7-苯基氨基-庚酸;
3-氨基-5-甲基-6-苯基氨基-己酸;
(3S,5R)-3-氨基-5-甲基-8-苯基氨基-辛酸;
(3S,5R)-3-氨基-5-甲基-7-苯基氨基-庚酸;
(3S,5R)-3-氨基-5-甲基-6-苯基氨基-己酸;
(3S,5S)-3-氨基-5-甲基-8-苯基氨基-辛酸;
(3S,5S)-3-氨基-5-甲基-7-苯基氨基-庚酸;
(3S,5S)-3-氨基-5-甲基-6-苯基氨基-己酸;
3-氨基-5-甲基-8-苯基-辛酸;
3-氨基-8-(2-氟-苯基)-5-甲基-辛酸;
3-氨基-8-(3-氟-苯基)-5-甲基-辛酸;
3-氨基-8-(4-氟-苯基)-5-甲基-辛酸;
3-氨基-8-(2-三氟-苯基)-5-甲基-辛酸;
3-氨基-8-(3-三氟-苯基)-5-甲基-辛酸;
3-氨基-8-(4-三氟-苯基)-5-甲基-辛酸;
3-氨基-5-甲基-8-邻甲苯基-辛酸;
3-氨基-5-甲基-8-间甲苯基-辛酸;
3-氨基-5-甲基-8-对甲苯基-辛酸;
3-氨基-5-甲基-8-对甲苯基-辛酸;
3-氨基-8-(2,3-二氟-苯基)-5-甲基-辛酸;
3-氨基-8-(2,4-二氟-苯基)-5-甲基-辛酸;
3-氨基-8-(2,5-二氟-苯基)-5-甲基-辛酸;
3-氨基-8-(2,6-二氟-苯基)-5-甲基-辛酸;
(3S,5R)-3-氨基-5-甲基-8-苯基-辛酸;
(3S,5S)-3-氨基-5-甲基-8-苯基-辛酸;
(3S,5R)-3-氨基-8-(2-氟-苯基)-5-甲基-辛酸;
(3S,5S)-3-氨基-8-(2-氟-苯基)-5-甲基-辛酸;
(3S,5R)-3-氨基-8-(3-氟-苯基)-5-甲基-辛酸;
(3S,5S)-3-氨基-8-(3-氟-苯基)-5-甲基-辛酸;
(3S,5R)-3-氨基-8-(4-氟-苯基)-5-甲基-辛酸;
(3S,5S)-3-氨基-8-(4-氟-苯基)-5-甲基-辛酸;
(3S,5R)-3-氨基-8-(2-三氟-苯基)-5-甲基-辛酸;
(3S,5S)-3-氨基-8-(2-三氟-苯基)-5-甲基-辛酸;
(3S,5R)-3-氨基-8-(3-三氟-苯基)-5-甲基-辛酸;
(3S,5S)-3-氨基-8-(3-三氟-苯基)-5-甲基-辛酸;
(3S,5R)-3-氨基-8-(4-三氟-苯基)-5-甲基-辛酸;
(3S,5S)-3-氨基-8-(4-三氟-苯基)-5-甲基-辛酸;
(3S,5R)-3-氨基-5-甲基-8-邻甲苯基-辛酸;
(3S,5S)-3-氨基-5-甲基-8-邻甲苯基-辛酸;
(3S,5R)-3-氨基-5-甲基-8-间甲苯基-辛酸;
(3S,5S)-3-氨基-5-甲基-8-间甲苯基-辛酸;
(3S,5R)-3-氨基-5-甲基-8-对甲苯基-辛酸;
(3S,5S)-3-氨基-5-甲基-8-对甲苯基-辛酸;
(3S,5R)-3-氨基-8-(2,3-二氟-苯基)-5-甲基-辛酸;
(3S,5S)-3-氨基-8-(2,3-二氟-苯基)-5-甲基-辛酸;
(3S,5R)-3-氨基-8-(2,4-二氟-苯基)-5-甲基-辛酸;
(3S,5S)-3-氨基-8-(2,4-二氟-苯基)-5-甲基-辛酸;
(3S,5R)-3-氨基-8-(2,5-二氟-苯基)-5-甲基-辛酸;
(3S,5S)-3-氨基-8-(2,5-二氟-苯基)-5-甲基-辛酸;
(3S,5R)-3-氨基-8-(2,6-二氟-苯基)-5-甲基-辛酸;以及
(3S,5S)-3-氨基-8-(2,6-二氟-苯基)-5-甲基-辛酸。
本发明优选的化合物包括通式IA-2化合物,
IA-2
其中R1,R2和R3与上述通式I中定义相同。
本发明更优选的化合物实例是通式IA-2化合物,其中R1是氢,R2是甲基,R3与上述通式I中定义相同。
本发明具体实施方案的实施例是下面的通式IA-2化合物及其可药用盐:
(3S,5R)-3-氨基-5-甲基-庚酸;
(3S,5R)-3-氨基-5-甲基-辛酸;以及
(3S,5R)-3-氨基-5-甲基-壬酸。
本发明还涉及通式IB化合物及其可药用盐,
其中R3定义同上,所述化合物选自下述化合物及其可药用盐:
3-氨基-4,5-二甲基-己酸;
3-氨基-4,6-二甲基-庚酸;
3-氨基-4,7-二甲基-辛酸;
3-氨基-4,8-二甲基-壬酸;
3-氨基-4,9-二甲基-癸酸;
3-氨基-4-环丙基-戊酸;
3-氨基-4-环丁基-戊酸;
3-氨基-4-环戊基-戊酸;
3-氨基-4-环己基-戊酸;
3-氨基-5-环丙基-4-甲基-戊酸;
3-氨基-5-环丁基-4-甲基-戊酸;
3-氨基-5-环戊基-4-甲基-戊酸;
3-氨基-5-环己基-4-甲基-戊酸;
3-氨基-6-环丙基-4-甲基-己酸;
3-氨基-6-环丁基-4-甲基-己酸;
3-氨基-6-环戊基-4-甲基-己酸;
3-氨基-6-环己基-4-甲基-己酸;
3-氨基-7-环丙基-4-甲基-庚酸;
3-氨基-7-环丁基-4-甲基-庚酸;
3-氨基-7-环戊基-4-甲基-庚酸;
3-氨基-7-环己基-4-甲基-庚酸;
3-氨基-8-环丙基-4-甲基-辛酸;
3-氨基-8-环丁基-4-甲基-辛酸;
3-氨基-8-环戊基-4-甲基-辛酸;
3-氨基-8-环己基-4-甲基-辛酸;
3-氨基-9-环丙基-4-甲基-壬酸;
3-氨基-9-环丁基-4-甲基-壬酸;
3-氨基-9-环戊基-4-甲基-壬酸;
3-氨基-9-环己基-4-甲基-壬酸;
3-氨基-4-甲基-辛酸;
3-氨基-4-甲基-壬酸;
3-氨基-4-甲基-癸酸;
(3R,4R)-3-氨基-4,5-二甲基-己酸;
(3R,4R)-3-氨基-4,6-二甲基-庚酸;
(3R,4R)-3-氨基-4,7-二甲基-辛酸;
(3R,4R)-3-氨基-4,8-二甲基-壬酸;
(3R,4R)-3-氨基-4,9-二甲基-癸酸;
(3R,4R)-3-氨基-4-环丙基-戊酸;
(3R,4R)-3-氨基-4-环丁基-戊酸;
(3R,4R)-3-氨基-4-环戊基-戊酸;
(3R,4R)-3-氨基-4-环己基-戊酸;
(3R,4R)-3-氨基-5-环丙基-4-甲基-戊酸;
(3R,4R)-3-氨基-5-环丁基-4-甲基-戊酸;
(3R,4R)-3-氨基-5-环戊基-4-甲基-戊酸;
(3R,4R)-3-氨基-5-环己基-4-甲基-戊酸;
(3R,4R)-3-氨基-6-环丙基-4-甲基-己酸;
(3R,4R)-3-氨基-6-环丁基-4-甲基-己酸;
(3R,4R)-3-氨基-6-环戊基-4-甲基-己酸;
(3R,4R)-3-氨基-6-环己基-4-甲基-己酸;
(3R,4R)-3-氨基-7-环丙基-4-甲基-庚酸;
(3R,4R)-3-氨基-7-环丁基-4-甲基-庚酸;
(3R,4R)-3-氨基-7-环戊基-4-甲基-庚酸;
(3R,4R)-3-氨基-7-环己基-4-甲基-庚酸;
(3R,4R)-3-氨基-8-环丙基-4-甲基-辛酸;
(3R,4R)-3-氨基-8-环丁基-4-甲基-辛酸;
(3R,4R)-3-氨基-8-环戊基-4-甲基-辛酸;
(3R,4R)-3-氨基-8-环己基-4-甲基-辛酸;
(3R,4R)-3-氨基-9-环丙基-4-甲基-壬酸;
(3R,4R)-3-氨基-9-环丁基-4-甲基-壬酸;
(3R,4R)-3-氨基-9-环戊基-4-甲基-壬酸;
(3R,4R)-3-氨基-9-环己基-4-甲基-壬酸;
(3R,4R)-3-氨基-4-甲基-辛酸;
(3R,4R)-3-氨基-4-甲基-壬酸;
(3R,4R)-3-氨基-4-甲基-癸酸;
(3R,4S)-3-氨基-4,5-二甲基-己酸;
(3R,4S)-3-氨基-4,6-二甲基-庚酸;
(3R,4S)-3-氨基-4,7-二甲基-辛酸;
(3R,4S)-3-氨基-4,8-二甲基-壬酸;
(3R,4S)-3-氨基-4,9-二甲基-癸酸;
(3R,4S)-3-氨基-4-环丙基-戊酸;
(3R,4S)-3-氨基-4-环丁基-戊酸;
(3R,4S)-3-氨基-4-环戊基-戊酸;
(3R,4S)-3-氨基-4-环己基-戊酸;
(3R,4S)-3-氨基-5-环丙基-4-甲基-戊酸;
(3R,4S)-3-氨基-5-环丁基-4-甲基-戊酸;
(3R,4S)-3-氨基-5-环戊基-4-甲基-戊酸;
(3R,4S)-3-氨基-5-环己基-4-甲基-戊酸;
(3R,4S)-3-氨基-6-环丙基-4-甲基-己酸;
(3R,4S)-3-氨基-6-环丁基-4-甲基-己酸;
(3R,4S)-3-氨基-6-环戊基-4-甲基-己酸;
(3R,4S)-3-氨基-6-环己基-4-甲基-己酸;
(3R,4S)-3-氨基-7-环丙基-4-甲基-庚酸;
(3R,4S)-3-氨基-7-环丁基-4-甲基-庚酸;
(3R,4S)-3-氨基-7-环戊基-4-甲基-庚酸;
(3R,4S)-3-氨基-7-环己基-4-甲基-庚酸;
(3R,4S)-3-氨基-8-环丙基-4-甲基-辛酸;
(3R,4S)-3-氨基-8-环丁基-4-甲基-辛酸;
(3R,4S)-3-氨基-8-环戊基-4-甲基-辛酸;
(3R,4S)-3-氨基-8-环己基-4-甲基-辛酸;
(3R,4S)-3-氨基-9-环丙基-4-甲基-壬酸;
(3R,4S)-3-氨基-9-环丁基-4-甲基-壬酸;
(3R,4S)-3-氨基-9-环戊基-4-甲基-壬酸;
(3R,4S)-3-氨基-9-环己基-4-甲基-壬酸;
(3R,4S)-3-氨基-4-甲基-辛酸;
(3R,4S)-3-氨基-4-甲基-壬酸;以及
(3R,4S)-3-氨基-4-甲基-癸酸。
本发明还涉及通式IC化合物及其可药用盐,
其中R3定义同上,所述化合物选自下述化合物及其可药用盐:
3-氨基-6-甲基-癸酸;
3-氨基-6-环丙基-庚酸;
3-氨基-6-环丁基-庚酸;
3-氨基-6-环戊基-庚酸;
3-氨基-6-环己基-庚酸;
3-氨基-7-环丙基-6-甲基-庚酸;
3-氨基-7-环丁基-6-甲基-庚酸;
3-氨基-7-环戊基-6-甲基-庚酸;
3-氨基-7-环己基-6-甲基-庚酸;
3-氨基-8-环丙基-6-甲基-辛酸;
3-氨基-8-环丁基-6-甲基-辛酸;
3-氨基-8-环戊基-6-甲基-辛酸;
3-氨基-8-环己基-6-甲基-辛酸;
3-氨基-9-环丙基-6-甲基-壬酸;
3-氨基-9-环丁基-6-甲基-壬酸;
3-氨基-9-环戊基-6-甲基-壬酸;
3-氨基-9-环己基-6-甲基-壬酸;
3-氨基-10-环丙基-6-甲基-癸酸;
3-氨基-10-环丁基-6-甲基-癸酸;
3-氨基-10-环戊基-6-甲基-癸酸;
3-氨基-10-环己基-6-甲基-癸酸;
3-氨基-6-异丙基-庚酸;
3-氨基-6,8-二甲基-壬酸;
3-氨基-6,9-二甲基-癸酸;
(3S,6R)-3-氨基-6-甲基-癸酸;
(3S,6R)-3-氨基-6-环丙基-庚酸;
(3S,6R)-3-氨基-6-环丁基-庚酸;
(3S,6R)-3-氨基-6-环戊基-庚酸;
(3S,6R)-3-氨基-6-环己基-庚酸;
(3S,6R)-3-氨基-7-环丙基-6-甲基-庚酸;
(3S,6R)-3-氨基-7-环丁基-6-甲基-庚酸;
(3S,6R)-3-氨基-7-环戊基-6-甲基-庚酸;
(3S,6R)-3-氨基-7-环己基-6-甲基-庚酸;
(3S,6R)-3-氨基-8-环丙基-6-甲基-辛酸;
(3S,6R)-3-氨基-8-环丁基-6-甲基-辛酸;
(3S,6R)-3-氨基-8-环戊基-6-甲基-辛酸;
(3S,6R)-3-氨基-8-环己基-6-甲基-辛酸;
(3S,6R)-3-氨基-9-环丙基-6-甲基-壬酸;
(3S,6R)-3-氨基-9-环丁基-6-甲基-壬酸;
(3S,6R)-3-氨基-9-环戊基-6-甲基-壬酸;
(3S,6R)-3-氨基-9-环己基-6-甲基-壬酸;
(3S,6R)-3-氨基-10-环丙基-6-甲基-癸酸;
(3S,6R)-3-氨基-10-环丁基-6-甲基-癸酸;
(3S,6R)-3-氨基-10-环戊基-6-甲基-癸酸;
(3S,6R)-3-氨基-10-环己基-6-甲基-癸酸;
(3S,6R)-3-氨基-6-异丙基-庚酸;
(3S,6R)-3-氨基-6,8-二甲基-壬酸;
(3S,6R)-3-氨基-6,9-二甲基-癸酸;
(3S,6S)-3-氨基-6-甲基-辛酸;
(3S,6S)-3-氨基-6-甲基-壬酸;
(3S,6S)-3-氨基-6-甲基-癸酸;
(3S,6S)-3-氨基-6-环丙基-庚酸;
(3S,6S)-3-氨基-6-环丁基-庚酸;
(3S,6S)-3-氨基-6-环戊基-庚酸;
(3S,6S)-3-氨基-6-环己基-庚酸;
(3S,6S)-3-氨基-7-环丙基-6-甲基-庚酸;
(3S,6S)-3-氨基-7-环丁基-6-甲基-庚酸;
(3S,6S)-3-氨基-7-环戊基-6-甲基-庚酸;
(3S,6S)-3-氨基-7-环己基-6-甲基-庚酸;
(3S,6S)-3-氨基-8-环丙基-6-甲基-辛酸;
(3S,6S)-3-氨基-8-环丁基-6-甲基-辛酸;
(3S,6S)-3-氨基-8-环戊基-6-甲基-辛酸;
(3S,6S)-3-氨基-8-环己基-6-甲基-辛酸;
(3S,6S)-3-氨基-9-环丙基-6-甲基-壬酸;
(3S,6S)-3-氨基-9-环丁基-6-甲基-壬酸;
(3S,6S)-3-氨基-9-环戊基-6-甲基-壬酸;
(3S,6S)-3-氨基-9-环己基-6-甲基-壬酸;
(3S,6S)-3-氨基-10-环丙基-6-甲基-癸酸;
(3S,6S)-3-氨基-10-环丁基-6-甲基-癸酸;
(3S,6S)-3-氨基-10-环戊基-6-甲基-癸酸;
(3S,6S)-3-氨基-10-环己基-6-甲基-癸酸;
(3S,6S)-3-氨基-6-异丙基-庚酸;
(3S,6S)-3-氨基-6,8-二甲基-壬酸;以及
(3S,6S)-3-氨基-6,9-二甲基-癸酸。
本发明还涉及通式II化合物以及这类化合物的可药用盐:
其中R1、R2和R3与上述通式I中定义相同。
本发明具体实施方案的实施例是下面的通式IV化合物及其可药用盐:2-氨基甲基-4-丙基-庚酸。
本发明还涉及通式IIA化合物以及这类化合物的可药用盐:
其中R3与上述通式I中定义相同。
本发明其它的具体实施方案包括下面的通式IIA化合物及其可药用盐:
2-氨基甲基-4-甲基-7-苯基-庚酸;
2-氨基甲基-4-甲基-6-苯基-己酸;
2-氨基甲基-7-(4-氟-苯基)-4-甲基-庚酸;
2-氨基甲基-7-(3-氟-苯基)-4-甲基-庚酸;
2-氨基甲基-7-(2-氟-苯基)-4-甲基-庚酸;
2-氨基甲基-7-(2,4-二氟-苯基)-4-甲基-庚酸;
2-氨基甲基-7-(3,4-二氟-苯基)-4-甲基-庚酸;
2-氨基甲基-4-甲基-7-(2-三氟甲基-苯基)-庚酸;
2-氨基甲基-4-甲基-7-(3-三氟甲基-苯基)-庚酸;
2-氨基甲基-4-甲基-7-(4-三氟甲基-苯基)-庚酸;
2-氨基甲基-4-甲基-6-苯基氨基-己酸;
2-氨基甲基-4-甲基-7-苯基氨基-庚酸;
2-氨基甲基-4-甲基-8-苯基氨基-辛酸;
(2R,4R)-2-氨基甲基-4-甲基-7-苯基-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-6-苯基-己酸;
(2R,4R)-2-氨基甲基-7-(4-氟-苯基)-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-7-(3-氟-苯基)-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-7-(2-氟-苯基)-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-7-(2,4-二氟-苯基)-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-7-(3,4-二氟-苯基)-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-7-(2-三氟甲基-苯基)-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-7-(3-三氟甲基-苯基)-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-7-(4-三氟甲基-苯基)-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-6-苯基氨基-己酸;
(2R,4R)-2-氨基甲基-4-甲基-7-苯基氨基-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-8-苯基氨基-辛酸;
(2R,4S)-2-氨基甲基-4-甲基-7-苯基-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-6-苯基-己酸;
(2R,4S)-2-氨基甲基-7-(4-氟-苯基)-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-7-(3-氟-苯基)-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-7-(2-氟-苯基)-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-7-(2,4-二氟-苯基)-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-7-(3,4-二氟-苯基)-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-7-(2-三氟甲基-苯基)-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-7-(3-三氟甲基-苯基)-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-7-(4-三氟甲基-苯基)-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-6-苯基氨基-己酸;
(2R,4S)-2-氨基甲基-4-甲基-7-苯基氨基-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-8-苯基氨基-辛酸;
(2R,4S)-2-氨基甲基-6-环己基-4-乙基-己酸;
2-氨基甲基-3-(1-甲基-环丙基)-丙酸;
2-氨基甲基-3-(1-乙基-环丙基)-丙酸;
2-氨基甲基-3-(1-丙基-环丙基)-丙酸;
2-氨基甲基-3-(1-异丙基-环丙基)-丙酸;
2-氨基甲基-3-(1-丁基-环丙基)-丙酸;
2-氨基甲基-3-(1-异丁基-环丙基)-丙酸;
2-氨基甲基-3-[1-(4-甲基-戊基)-环丙基]-丙酸;
2-氨基甲基-3-(1-甲基-环丁基)-丙酸;
2-氨基甲基-3-(1-乙基-环丁基)-丙酸;
2-氨基甲基-3-(1-丙基-环丁基)-丙酸;
2-氨基甲基-3-(1-甲基-环戊基)-丙酸;
2-氨基甲基-3-(1-乙基-环戊基)-丙酸;
2-氨基甲基-3-(1-丙基-环戊基)-丙酸;
2-氨基甲基-3-(1-甲基-环己基)-丙酸;
2-氨基甲基-3-(1-乙基-环己基)-丙酸;
2-氨基甲基-3-(1-丙基-环己基)-丙酸;
2-氨基甲基-4-乙基-己酸;
2-氨基甲基-4-乙基-5-甲基-己酸;
2-氨基甲基-4-乙基-庚酸;
2-氨基甲基-4-乙基-6-甲基-庚酸;
2-氨基甲基-4-乙基-辛酸;
2-氨基甲基-4-乙基-7-甲基-辛酸;
2-氨基甲基-4-乙基-壬酸;
2-氨基甲基-4-乙基-8-甲基-壬酸;
2-氨基甲基-4,4-二甲基-庚酸;
2-氨基甲基-4,4,8-三甲基-壬酸;
2-氨基甲基-5-乙基-庚酸;
2-氨基甲基-5-乙基-6-甲基-庚酸;
2-氨基甲基-7-环丙基-5-乙基-庚酸;
2-氨基甲基-7-环丁基-5-乙基-庚酸;
2-氨基甲基-7-环戊基-5-乙基-庚酸;
2-氨基甲基-7-环己基-5-乙基-庚酸;
2-氨基甲基-5-乙基-辛酸;
2-氨基甲基-5-乙基-7-甲基-辛酸;
2-氨基甲基-5-乙基-壬酸;
2-氨基甲基-5-乙基-8-甲基-壬酸;
2-氨基甲基-4-环丙基-丁酸;
2-氨基甲基-4-(1-甲基-环丙基)-丁酸;
2-氨基甲基-4-(1-乙基-环丙基)-丁酸;
2-氨基甲基-4-环丁基-丁酸;
2-氨基甲基-4-(1-甲基-环丁基)-丁酸;
2-氨基甲基-4-(1-乙基-环丁基)-丁酸;
2-氨基甲基-4-环戊基-丁酸;
2-氨基甲基-4-(1-甲基-环戊基)-丁酸;
2-氨基甲基-4-(1-乙基-环戊基)-丁酸;
2-氨基甲基-4-环己基-丁酸;
2-氨基甲基-4-(1-甲基-环己基)-丁酸;
2-氨基甲基-4-(1-乙基-环己基)-丁酸;
(2R,4S)-2-氨基甲基-6-环戊基-4-乙基-己酸;
(2R,4S)-2-氨基甲基-6-环丁基-4-乙基-己酸;和
(2R,4S)-2-氨基甲基-6-环丙基-4-乙基-己酸。
本发明其它的具体实施方案包括下面的通式IIA化合物及其可药用盐:
2-氨基甲基-4-甲基-己酸;
2-氨基甲基-4-甲基-庚酸;
2-氨基甲基-4-甲基-辛酸;
2-氨基甲基-4-甲基-壬酸;
2-氨基甲基-4-甲基-癸酸;
(2R,4R)-2-氨基甲基-4-甲基-己酸;
(2R,4R)-2-氨基甲基-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-辛酸;
(2R,4R)-2-氨基甲基-4-甲基-壬酸;
(2R,4R)-2-氨基甲基-4-甲基-癸酸;
(2R,4S)-2-氨基甲基-4-甲基-己酸;
(2R,4S)-2-氨基甲基-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-辛酸;
(2R,4S)-2-氨基甲基-4-甲基-壬酸;
(2R,4S)-2-氨基甲基-4-甲基-癸酸;
2-氨基甲基-5-环丙基-4-甲基-戊酸;
2-氨基甲基-5-环丁基-4-甲基-戊酸;
2-氨基甲基-5-环戊基-4-甲基-戊酸;
2-氨基甲基-5-环己基-4-甲基-戊酸;
2-氨基甲基-6-环丙基-4-甲基-己酸;
2-氨基甲基-6-环丁基-4-甲基-己酸;
2-氨基甲基-6-环戊基-4-甲基-己酸;
2-氨基甲基-6-环己基-4-甲基-己酸;
2-氨基甲基-7-环丙基-4-甲基-庚酸;
2-氨基甲基-7-环丁基-4-甲基-庚酸;
2-氨基甲基-7-环戊基-4-甲基-庚酸;
2-氨基甲基-7-环己基-4-甲基-庚酸;
2-氨基甲基-8-环丙基-4-甲基-辛酸;
2-氨基甲基-8-环丁基-4-甲基-辛酸;
2-氨基甲基-8-环戊基-4-甲基-辛酸;
2-氨基甲基-8-环己基-4-甲基-辛酸;
(2R,4S)-2-氨基甲基-5-环丙基-4-甲基-戊酸;
(2R,4S)-2-氨基甲基-5-环丁基-4-甲基-戊酸;
(2R,4S)-2-氨基甲基-5-环戊基-4-甲基-戊酸;
(2R,4S)-2-氨基甲基-5-环己基-4-甲基-戊酸;
(2R,4S)-2-氨基甲基-6-环丙基-4-甲基-己酸;
(2R,4S)-2-氨基甲基-6-环丁基-4-甲基-己酸;
(2R,4S)-2-氨基甲基-6-环戊基-4-甲基-己酸;
(2R,4S)-2-氨基甲基-6-环己基-4-甲基-己酸;
(2R,4S)-2-氨基甲基-7-环丙基-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-7-环丁基-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-7-环戊基-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-7-环己基-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-8-环丙基-4-甲基-辛酸;
(2R,4S)-2-氨基甲基-8-环丁基-4-甲基-辛酸;
(2R,4S)-2-氨基甲基-8-环戊基-4-甲基-辛酸;
(2R,4S)-2-氨基甲基-8-环己基-4-甲基-辛酸;
(2R,4R)-2-氨基甲基-5-环丙基-4-甲基-戊酸;
(2R,4R)-2-氨基甲基-5-环丁基-4-甲基-戊酸;
(2R,4R)-2-氨基甲基-5-环戊基-4-甲基-戊酸;
(2R,4R)-2-氨基甲基-5-环己基-4-甲基-戊酸;
(2R,4R)-2-氨基甲基-6-环丙基-4-甲基-己酸;
(2R,4R)-2-氨基甲基-6-环丁基-4-甲基-己酸;
(2R,4R)-2-氨基甲基-6-环戊基-4-甲基-己酸;
(2R,4R)-2-氨基甲基-6-环己基-4-甲基-己酸;
(2R,4R)-2-氨基甲基-7-环丙基-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-7-环丁基-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-7-环戊基-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-7-环己基-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-8-环丙基-4-甲基-辛酸;
(2R,4R)-2-氨基甲基-8-环丁基-4-甲基-辛酸;
(2R,4R)-2-氨基甲基-8-环戊基-4-甲基-辛酸;以及
(2R,4R)-2-氨基甲基-8-环己基-4-甲基-辛酸。
本发明还涉及通式III化合物及其可药用盐,
其中R3与通式I中定义相同。
本发明还涉及通式IV化合物及其可药用盐,
其中R1和R3与通式I中定义相同。
本发明其它的具体实施方案包括下面的通式IV化合物及其可药用盐:
2-氨基甲基-6-环丙基-5-甲基-己酸;
2-氨基甲基-6-环丁基-5-甲基-己酸;
2-氨基甲基-6-环戊基-5-甲基-己酸;
2-氨基甲基-6-环己基-5-甲基-己酸;
2-氨基甲基-7-环丙基-5-甲基-庚酸;
2-氨基甲基-7-环丁基-5-甲基-庚酸;
2-氨基甲基-7-环戊基-5-甲基-庚酸;
2-氨基甲基-7-环己基-5-甲基-庚酸;
2-氨基甲基-8-环丙基-5-甲基-辛酸;
2-氨基甲基-8-环丁基-5-甲基-辛酸;
2-氨基甲基-8-环戊基-5-甲基-辛酸;
2-氨基甲基-8-环己基-5-甲基-辛酸;
2-氨基甲基-5-甲基-庚酸;
2-氨基甲基-5-甲基-辛酸;
2-氨基甲基-5-甲基-庚酸;
2-氨基甲基-5-甲基-壬酸;
(2R,6S)-2-氨基甲基-6-环丙基-5-甲基-己酸;
(2R,6S)-2-氨基甲基-6-环丁基-5-甲基-己酸;
(2R,6S)-2-氨基甲基-6-环戊基-5-甲基-己酸;
(2R,6S)-2-氨基甲基-6-环己基-5-甲基-己酸;
(2R,6S)-2-氨基甲基-7-环丙基-5-甲基-庚酸;
(2R,6S)-2-氨基甲基-7-环丁基-5-甲基-庚酸;
(2R,6S)-2-氨基甲基-7-环戊基-5-甲基-庚酸;
(2R,6S)-2-氨基甲基-7-环己基-5-甲基-庚酸;
(2R,6S)-2-氨基甲基-8-环丙基-5-甲基-辛酸;
(2R,6S)-2-氨基甲基-8-环丁基-5-甲基-辛酸;
(2R,6S)-2-氨基甲基-8-环戊基-5-甲基-辛酸;
(2R,6S)-2-氨基甲基-8-环己基-5-甲基-辛酸;
(2R,6S)-2-氨基甲基-5-甲基-庚酸;
(2R,6S)-2-氨基甲基-5-甲基-辛酸;
(2R,6S)-2-氨基甲基-5-甲基-庚酸;
(2R,6S)-2-氨基甲基-5-甲基-壬酸;
(2R,6R)-2-氨基甲基-6-环丙基-5-甲基-己酸;
(2R,6R)-2-氨基甲基-6-环丁基-5-甲基-己酸;
(2R,6R)-2-氨基甲基-6-环戊基-5-甲基-己酸;
(2R,6R)-2-氨基甲基-6-环己基-5-甲基-己酸;
(2R,6R)-2-氨基甲基-7-环丙基-5-甲基-庚酸;
(2R,6R)-2-氨基甲基-7-环丁基-5-甲基-庚酸;
(2R,6R)-2-氨基甲基-7-环戊基-5-甲基-庚酸;
(2R,6R)-2-氨基甲基-7-环己基-5-甲基-庚酸;
(2R,6R)-2-氨基甲基-8-环丙基-5-甲基-辛酸;
(2R,6R)-2-氨基甲基-8-环丁基-5-甲基-辛酸;
(2R,6R)-2-氨基甲基-8-环戊基-5-甲基-辛酸;
(2R,6R)-2-氨基甲基-8-环己基-5-甲基-辛酸;
(2R,6R)-2-氨基甲基-5-甲基-庚酸;
(2R,6R)-2-氨基甲基-5-甲基-辛酸;
(2R,6R)-2-氨基甲基-5-甲基-庚酸;以及
(2R,6R)-2-氨基甲基-5-甲基-壬酸。
本发明还涉及含有治疗有效量的通式I、IA、IA-1、IA-2、IB、IC、II、IIA、III或IV化合物或其可药用盐以及可药用载体的药物组合物。
本发明还涉及治疗哺乳动物包括人的疾病或症状的方法,它包括向需要接受该治疗的哺乳动物施用治疗有效量的通式I、IA、IA-1、IA-2、IB、IC、II、IIA、III或IV化合物或其可药用盐,其中所述疾病或症状选自癫痫、昏厥发作、纤维肌痛(fibromyalgia)、运动功能减退(hypokinesia)、颅疾病、热潮红(hot flashes)、特发性震颤(essential tremor)、化学药品依赖性和成瘾性(例如对酒精、苯丙胺(或者苯丙胺类似物质)、咖啡因、大麻、可卡因、海洛因、致幻剂、烟草、吸入剂和气溶胶喷射剂(propellants)、烟碱、类罂粟碱(opioids)、苯基甘氨酸(phenylglycidine)衍生物、镇静药、催眠药、苯并二氮以及其它抗焦虑药的依赖性和成瘾性)、以及与上述依赖性或成瘾性相关的撤退症状(withdrawalsymptoms),上瘾行为例如赌博;偏头痛、痉挛状态(spasticity)、关节炎、肠易激综合症(IBS)、慢性痛、急性痛、神经性疼痛(neuropathic pain)、血管性头痛、窦性头痛、炎性疾病(inflammatory disorders)(例如类风湿性关节炎、骨关节炎、牛皮癣)、多尿(diuresis)、经期前综合症、经期前焦虑症、耳鸣(tinnitis)以及胃损伤。
本发明还包括称为急性脑损伤的神经变性疾病类的治疗。其包括但不仅仅限制于:中风、头部创伤和昏厥。
中风与脑血管疾病有关,因而又被称作脑血管意外(cerebral vascularincident)(CVA),它包括急性脑血栓中风。中风包括局部性和全身性缺血。另外,还包括短暂的脑缺血发作以及其它伴随有脑缺血的脑血管疾病,例如那些正在接受颈动脉内膜切除手术或其它脑血管或血管外科手术或者血管诊断治疗包括脑血管造影手术等的患者所表现出的疾病症状。
通式I、IA、IA-1、IA-2、IB、IC、II、IIA、III以及IV化合物还可用于治疗头部创伤、脊髓创伤或由常见的缺氧症、组织缺氧、血糖过低、血压过低所引起的损伤、以及在关节复位(embole)、过度滴注(hyperfusion)、组织缺氧过程中所出现的类似损伤。上述化合物还可用于预防在心脏旁路手术过程中或者在发生颅内出血、产期昏厥、心博停止以及癫痫状态时所出现的神经元损伤。
本发明还涉及治疗哺乳动物包括人的疾病或症状的方法,它包括向所述哺乳动物施用治疗这类疾病或症状的有效量的通式I、IA、IA-1、IA-2、IB、IC、II、IIA、III或IV化合物或其可药用盐,其中所述疾病或症状选自谵妄(delerium)、痴呆和健忘以及其它认知性或神经变性疾病,例如帕金森病(PD)、亨廷顿病(HD)、阿尔茨海默病、老年性痴呆、阿尔茨海默氏类型痴呆(dementia of theAlzheimer’s type)、记忆障碍(memory disorder)、血管性痴呆、以及其它类型的痴呆,例如由HIV疾病、头部创伤、帕金森病、亨廷顿病、皮克病、克-雅病(Creutzfeldt-Jakob disease)、或者由多种病因引起的痴呆;运动疾病例如运动不能、运动障碍,包括家族性阵发性运动障碍、痉挛状态(spasticities)、图雷特氏综合症(Tourette’s syndrome)、Scott综合症、PALSYS以及运动不能-强直综合症(akinetic-rigid syndrome);锥体束外运动失调例如由治疗药物引起的运动失调,例如由安定药引起的帕金森综合征(neuroleptic-induced Parkinsonism)、安定药恶性综合症、由安定药引起的急性肌张力障碍(neuroleptic-induced acute dystonia)、由安定药引起的急性静坐不能、由安定药引起的迟发性运动障碍以及由治疗药物引起的姿势性震颤;唐氏综合症;脱髓鞘疾病例如多发性硬化症(MS)和肌萎缩性侧索硬化症(amylolateral sclerosis)(ALS),外周神经病例如糖尿病和由化学治疗引起的神经病,和疱疹后神经痛,三叉神经痛,节段性(segmental)或肋间神经痛以及其它神经痛;由于急性或慢性脑血管损伤引起的脑血管紊乱,例如脑梗塞、蛛网膜下出血或脑水肿。
疼痛既指急性痛又指慢性痛。急性痛通常发作时间短同时伴随着交感神经系统极度活跃。这样的实例有手术后疼痛和异常性疼痛。慢性痛通常被定义为持续3-6个月的疼痛,包括体因性疼痛和精神性疼痛。其它的疼痛是指可以感觉到痛觉的疼痛。
本发明的通式I、IA、IA-1、IA-2、IB、IC、II、IIA、III和IV化合物或其可药用盐可以治疗的疼痛类型实例包括由软组织和外周损伤引起的疼痛,例如急性创伤,与骨关节炎和类风湿性关节炎有关的疼痛,肌-骨骼疼痛,例如创伤后疼痛;脊椎疼痛,牙疼,肌筋膜疼痛综合症,外阴切开手术疼痛,以及由烧伤引起的疼痛;深度和内脏疼痛,例如心脏疼痛,肌肉疼痛,眼睛疼痛,口面疼痛,例如牙痛,腹部疼痛,妇科疼痛,例如痛经,劳动疼痛以及与子宫内膜异位相关的疼痛;与神经和根器官损伤有关的疼痛,例如与外周神经失调有关的疼痛,例如压迫性神经损害(nerve entrapment)和臂丛抽出术,截肢术,外周神经病,三叉神经痛(tic douloureux),非典型面部疼痛,神经根损伤,三叉神经痛,神经性下背疼痛,与HIV相关的神经性疼痛,与癌症相关的神经性疼痛,糖尿病性神经痛,以及蛛网膜炎;与肿瘤有关的神经性和非神经性疼痛,通常也被称作癌症性疼痛;中枢神经系统疼痛,例如由脊髓或脑干损伤引起的疼痛;下背疼痛;坐骨神经痛;幻肢痛,头痛,包括偏头痛以及其它的血管性头痛,急性或慢性紧张性头痛,丛集性头痛,颞下颌(temperomandibular)疼痛以及上颌窦疼痛;由强直性脊椎炎引起和痛风引起的疼痛;由膀胱(blader)收缩增强引起的疼痛;手术后疼痛;疤痕痛;以及慢性非神经性疼痛例如与纤维肌痛、HIV、风湿病和骨关节炎、anthralgia和肌痛、扭伤、过度疲劳和创伤例如骨折相关的疼痛;以及外科手术后疼痛。
其它一些疼痛也是由外周感觉神经损伤或感染引起的。它包括但不仅仅限制于外周神经创伤疼痛、疱疹病毒感染、糖尿病、纤维肌痛、灼痛、丛性抽出术(plexus avulsion)、神经瘤、截肢手术以及血管炎。神经性疼痛也是由源于慢性酒精中毒的神经损伤、人类免疫缺陷病毒感染、甲状腺机能减退、尿毒症或者维生素缺乏引起的。神经性疼痛包括但不仅仅限制于由神经损伤引起的疼痛,例如糖尿病患者所忍受的疼痛。
精神性疼痛是指不存在器官病因而出现的疼痛,例如下背疼痛、非典型面部疼痛以及慢性头痛。
其它类型的疼痛有:炎性疼痛(inflammatory pain)、骨关节炎疼痛、三叉神经痛、癌性疼痛、糖尿病神经病变、下肢不宁综合症、急性疱疹和疱疹后神经痛、灼痛、臂丛抽出术、枕骨神经痛、痛风、幻肢、烧伤以及其它形式的神经痛、神经性和特发性疼痛综合症(idiopathic pain syndrome)。
本发明化合物还可用于治疗抑郁症。抑郁症可能起源于器官疾病,继发于与个人损失有关的应激反应,或者就是起源于特发性的。目前有一种明显的趋势就是发现整个家族出现某种形式的抑郁症,这暗示了至少某些抑郁症的致病机理。抑郁症的诊断主要是根据对患者情绪的变化进行量化。上述这种对情绪进行评价通常是由医师完成或者由神经心理学家使用有效的等级量表例如汉密尔顿抑郁等级量表(Hamilton Depression Rating Scale)或者简要精神病学等级量表(Brief Psychiatric Rating Scale)来进行量化。已经开发出很多其它类型的量表用于量化和评价抑郁症患者情绪变化的程度,这些抑郁症患者表现有例如失眠、注意力不易集中、精力不济、感觉无用以及内疚。抑郁症以及所有精神病的诊断标准汇集在由美国精神病协会于1994年出版的精神紊乱的诊断和统计手册(Diagnostic and Statistical Manual of Mental Disorders)(第四版)中,其又名DSM-IV-R手册。
本发明还涉及治疗哺乳动物包括人的疾病或症状的方法,它包括向所述哺乳动物施用治疗这类疾病或症状的有效量的通式I、IA、IA-1、IA-2、IB、IC、II、IIA、III或IV化合物或其可药用盐,其中所述疾病或症状选自情绪失调(mooddisorders),例如抑郁(depression),或者更尤其是抑郁症(depressive disorders),例如单次发作(single episodic)的或复发性严重抑郁症(recurrent major depressivedisorders)、心境恶劣障碍、抑郁性神经症和神经症性抑郁症(neurotic depression),忧郁性抑郁症,包括厌食、体重减轻、失眠、清晨早醒(early moming waking)和精神性运动延迟,非典型抑郁症(或者反应性抑郁症),包括食欲增加、睡眠过度、精神性运动兴奋(psychomotor agitation)或过敏、季节性情绪失调(seasonalaffective disorder)以及儿童抑郁症;或者两极失调或躁狂抑郁症,例如两极I型失调、两极II型失调和循环情感性疾病;品行障碍和破坏行为疾病;焦虑症,例如表现有或不表现有广场恐怖症的恐慌症、没有恐慌病史的广场恐怖症、特殊恐怖症,例如特定动物恐怖症、社会焦虑症、社会恐怖症、强迫症,应激失调,包括创伤后应激失调和急性应激失调,以及普通的焦虑症;边缘型人格障碍;精神分裂症以及其它精神病,例如精神分裂症样疾病、分裂情感性障碍、妄想症、短暂精神病症(brief psychotic disorders)、分担类精神病症(sharedpsychotic disorders)、表现有妄想或幻觉的精神病、焦虑症的精神病发作(psychoticepisodes of anxiety)、伴有精神病的焦虑症、精神病性情绪失调例如严重的主要抑郁症(severe major depressive disorder);伴有精神病的情绪失调例如急性躁狂症以及伴有两极失调(bipolar disorder)的抑郁症,伴有精神分裂症的情绪失调;伴有思维延迟的行为错乱症,孤独症,品行障碍。
本发明化合物还可用于治疗睡眠障碍。睡眠障碍是指影响入睡和/或睡眠能力的干扰现象,包括睡眠过度或者引起与睡眠相关的异常现象。这种疾病包括例如失眠、与药物有关的失眠、睡眠过度、昏睡病、睡眠呼吸暂停综合症以及深眠状态。
本发明还涉及治疗哺乳动物包括人的疾病或症状的方法,它包括向所述哺乳动物施用治疗这类疾病或症状的有效量的通式I、IA、IA-1、IA-2、IB、IC、II、IIA、III或IV化合物或其可药用盐,其中所述疾病或症状选自睡眠障碍(sleepdisorders)(例如失眠、与药物有关的失眠、REM睡眠障碍、睡眠过度、昏睡病、睡眠-觉醒循环失调、睡眠呼吸暂停综合症、深眠状态以及与换班工作和不规律工作时间有关的睡眠障碍)。
通式I、IA、IA-1、IA-2、IB、IC、II、IIA、III和IV化合物含有至少一个手性中心,因而可能存在不同的对映异构和非对映异构形式。本发明涉及通式I、IA、IA-1、IA-2、IB、IC、II、IIA、III和IV化合物的所有的光学异构体和所有的立体异构体,包括这些化合物的外消旋混合物形式和单独的对映异构体和非对映异构体形式以及它们的混合物,本发明还涉及分别含有或使用这些化合物的药物组合物以及上述治疗方法。通过已知的方法,例如光学拆解、光学有择反应或者在终产物或其中间体的制备过程中使用色谱分离法可以获得单独的异构体。在治疗各种疾病或症状方面,本发明化合物的单独对映异构体相对于这些化合物的外消旋混合物可能更具有优势。
本发明还包括同位素标记化合物,它们与上述通式I、IA、IA-1、IA-2、IB、IC、II、IIA、III和IV相同,除了其中一个或多个原子被与自然界所常见的原子质量或原子数不同的原子质量或质量数的原子替代之外。可以引入至本发明化合物中的同位素实例包括氢、碳、氮、氧、磷、硫、氟以及氯的同位素,分别例如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F以及36Cl。含有前述同位素和/或其它原子的其它同位素的本发明的化合物、其前药、所述化合物或所述前药的可药用盐均落入本发明范围之内。本发明某些同位素标记的化合物,例如那些其中引入了放射性同位素例如3H和14C的化合物可用作药物和/或底物供进行组织分布分析。含氚的也就是3H和碳-14也就是14C由于很容易制备和检测,因此特别优选这些同位素。另外,利用重同位素例如氘也就是2H进行取代还可以获得由于具有更高的代谢稳定性而带来的治疗优势,例如增加了体内半衰期或降低了所需剂量,因此在某些情况下它们是优选的。同位素标记的本发明通式I化合物及其前药通常可以按照如下面流程图和/或实施例和制备例中所公开的方法进行制备,利用可方便得到的同位素标记试剂取代非同位素标记试剂。
除非另有说明,本文中所使用的术语“烷基”包括具有直链、支链或环状基团或者它们的组合的饱和一价烃基。“烷基”的实例包括但不仅仅限于甲基,乙基,丙基,异丙基,丁基,异、仲和叔丁基,戊基,己基、庚基,3-乙基丁基,环丙基,环丁基,环戊基,环己基,环庚基,降冰片基等。
除非另有说明,本文中所使用的术语“烷氧基”指“烷基-O-”,其中“烷基”定义同上。“烷氧基”基团的实例包括但不仅仅限于甲氧基、乙氧基、丙氧基、丁氧基和戊氧基。
本文中所使用的术语“治疗”是指逆转、减轻、抑制该术语所指的疾病或病症的恶化,或者预防该术语所指的疾病或病症,或者预防一种或多种这类病症或疾病的症状。本文中所使用的术语“治疗”指治疗作用,与前边所定义的“治疗”含义相同。
由于氨基酸具有两性,因此其药理学可相容盐可以为适宜的无机酸或有机酸的盐,例如盐酸、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、琥珀酸以及抗坏血酸的盐。由相应的氢氧化物或碳酸盐(carbonates)出发,可以形成与碱金属或碱土金属例如钠、钾、镁或钙的盐。与季铵离子的盐还可以使用例如四甲基-铵离子制备得到。
口服药物的疗效取决于药物透过粘膜上皮细胞的有效转运以及它在肠-肝循环中的稳定性。经非肠道给药后有效而口服疗效低的或者其血浆半衰期被认为太短的药物可以通过化学方法转化成前药形式。
前药就是经过化学修饰在其作用位置不具有生理活性的药物,但是它可以通过一种或多种酶或者其它的体内途径降解或者修饰成母体的生物活性形式。
这种化学修饰药物或前药应该具有与其母体药物不同的药代动力学曲线,透过粘膜上皮细胞它更容易被吸收,形成更好的盐和/或溶解度更好,系统稳定性得到改善(例如延长了血浆半衰期)。上述化学修饰方法可以是
1)可以被例如酯酶或脂肪酶裂解的酯或酰胺衍生物。对于酯衍生物,这种酯是由药物分子的羧酸基团通过已知方法衍生而来的。对于酰胺衍生物,这种酰胺可以由药物分子的羧酸基团或胺基团通过已知方法衍生得到。
2)可以被特定或非特定蛋白酶识别的肽类。肽可以按照已知方法通过与药物分子的胺或羧酸基团形成酰胺键而被偶联到药物分子上。
3)通过对前药形式或修饰前药形式进行膜选择作用而在其作用位置形成堆积的衍生物。
4)1-3的任意形式组合。
目前动物试验研究表明,通过制备成“软性”季盐可以提高某些药物的口服吸收度。这种季盐之所以称为“软性”季盐,是因为它与一般的季盐例如R-N+(CH3)3不同,它可以通过水解释放出活性药物。
“软性”季盐相对于原药或其盐具有更有用的物理特性。与其它盐例如盐酸盐相比,“软性”季盐可以增加水溶性,更重要的是它可以改善药物的透肠吸收度。吸收度增加可能是因为“软性”季盐具有表面活性而适合与胆汁酸等形成胶束和未离子化离子对,这些胶束和未离子化离子对能够更有效地穿透肠上皮细胞。所述前药经吸收之后很快水解释放出活性母体药物。
通式I、IA、IA-1、IA-2、IB、IC、II、IIA、III以及IV化合物的前药包括在本发明范围之内。前药和软药(soft drugs)是本领域所已知的(Palomino E.,Drugsof the Future,1990;15(4):361-368)。最后两篇引证文献在此引作参考。
本发明的某些化合物可以以非溶剂化物形式和溶剂化物形式包括水合物形式存在。一般来说,溶剂化物形式包括水化物形式是与非溶剂化物形式等价的,因而也被包括在本发明范围之内。
发明详述
本发明化合物可以按照下述方法制备。在反应流程图以及其后的描述中,除非另有说明,结构式I、IA、IA-1、IA-2、IB、IC、II、IIA、III和IV以及基团R1、R2、R3、R4、R5和R6定义同上。
有很多不同的方法用于制备手性和外消旋β-氨基酸。这些方法可以参见″Enantioselective Synthesis of β-amino Acids″,Juaristi,Eusebio;Editor.USA,1997,Wiley-VCH,New York,N.Y.。
下面所描述的方法是可用于制备这类化合物的方法的示例,它们并不构成对发明范围的限制。
方法A
根据Lazar等人,Synth.Commun,1998,28(2),219-224中的步骤,通过将通式1化合物在醇类溶剂例如乙醇中、在丙二酸和醋酸铵存在下加热至回流可以制备得到通式IA化合物。通式1的醛可以由商购得到的原料利用本领域技术人员所熟知的方法制备得到。
按照上述方法可以制备得到的化合物包括但不仅仅限制于下述化合物:
3-氨基-6-环丙基-5-甲基-己酸;
3-氨基-6-环丁基-5-甲基-己酸;
3-氨基-6-环戊基-5-甲基-己酸;
3-氨基-6-环己基-5-甲基-己酸;
3-氨基-7-环丙基-5-甲基-庚酸;
3-氨基-7-环丁基-5-甲基-庚酸;
3-氨基-7-环戊基-5-甲基-庚酸;
3-氨基-7-环己基-5-甲基-庚酸;
3-氨基-8-环丙基-5-甲基-辛酸;
3-氨基-8-环丁基-5-甲基-辛酸;
3-氨基-8-环戊基-5-甲基-辛酸;
3-氨基-8-环己基-5-甲基-辛酸;
3-氨基-6-环丙基-5,5-二甲基-己酸;
3-氨基-6-环丁基-5,5-二甲基-己酸;
3-氨基-6-环戊基-5,5-二甲基-己酸;
3-氨基-6-环己基-5,5-二甲基-己酸;
3-氨基-7-环丙基-5,5-二甲基-庚酸;
3-氨基-7-环丁基-5,5-二甲基-庚酸;
3-氨基-7-环戊基-5,5-二甲基-庚酸;以及
3-氨基-7-环己基-5,5-二甲基-庚酸。
方法B
如上面的方法B所述,使用将手性胺加成至α,β-不饱和体系上的方法作为获得β-氨基酸的合成途径已经在现有技术中描述过(参见例如S.G.Davies等人,J.Chem.Soc.Chem.Commun,1153,1993;S.G.Davies,Synlett,1994,117;Ishikawa等人,Synlett,1998,1291;Hawkins,J.Org.Chem.,1985,51,2820)。对照上述的方法B,通式IA化合物可以由相应的通式7化合物制备得到,其中PG表示适宜的酯保护基团,它可以使用本领域技术人员所熟知的条件通过水解或氢解除去(参见T.W.Greene和P.G.M.Wuts.,″Protective groups in organic synthesis″,Wiley,1991中有关形成和除去适宜的保护基团的详细描述)。例如,该反应可以这样进行:在水解条件下,在室温至反应混合物回流温度附近的温度下、优选在回流温度下通过用适宜的酸例如盐酸或硫酸进行处理,或者在室温附近至回流温度附近的温度下、优选在室温附近通过用适宜的无机碱例如氢氧化钠、氢氧化钾或氢氧化锂优选氢氧化钠进行处理。优选在回流温度下使用盐酸完成该反应。然而,如果PG为叔丁基,优选在三氟乙酸(TFA)中完成反应。如果PG为碱性基团,那么可以在碱性条件下使用本领域技术人员所熟知的方法,例如使用氢氧化钠或氢氧化钾完成水解。
通式7化合物可以由相应的通式6化合物利用本领域技术人员所熟知的氢解条件制备得到。例如,可以在氢气氛(大约为1-5个大气压)下、在例如甲醇、乙醇或四氢呋喃的溶剂中,通过使用钯金属催化剂例如氢氧化钯-碳或钯-碳或者使用阮内镍处理通式6化合物而制备得到所需的通式7化合物,进而完成该反应。优选在约1个大气压下的氢气氛下、在乙醇中使用钯-碳催化剂完成该反应。
通式6化合物可以这样制备得到:将相应的通式4化合物使用适宜的碱例如二异丙基氨基化锂、正丁基锂或者双(三甲基甲硅烷基)氨基化锂或钾,在例如乙醚或者优选四氢呋喃(THF)的溶剂中,在大约-80℃至大约25℃的温度下进行处理之后,再使用适宜的胺例如(R)-(+)-N-苄基-α-甲基苄基胺、(S)-(-)-N-苄基-α-甲基苄基胺进行处理,然后再加入适宜的通式4化合物。胺上氮的立体化学将决定终产物上氮的立体化学。优选该反应是这样完成的:根据Bull,Steven D.;Davies,Stephen G.;以及Smith,Andrew D,J.Chem.Soc.,Perkin Trans.1,2001,22,2931-2938中所描述的方法,使用(R)-(+)-N-苄基-α-甲基苄基胺或(S)-(-)-N-苄基-α-甲基苄基胺在使用正丁基锂在四氢呋喃中、于大约-78℃的温度下去质子化之后进行。
通式4化合物可以由相应的通式3化合物通过将其用适宜的膦酸酯在适宜的碱例如氢化钠、二异丙基氨基化锂或三乙胺以及氯化锂或溴化锂的存在下、在例如乙醚或THF的溶剂中进行处理而制备得到。优选地,将通式3化合物与磷酸酯(ALK=甲基、乙基、异丙基、苄基等)在溴化锂和三乙胺存在下、在四氢呋喃中于室温左右下进行反应。通式3化合物可以由商购得到的原料利用本领域技术人员所熟知的方法制备得到。应该理解的是,通式3化合物具有一个或多个立体异构中心。利用上述方法可以制备得到各种具有特定立体化学构型的化合物。
按照上述方法可以制备得到的化合物包括但不仅仅限制于下述化合物:
(3S,5R)-3-氨基-6-环丙基-5-甲基-己酸;
(3S,5R)-3-氨基-6-环丁基-5-甲基-己酸;
(3S,5R)-3-氨基-6-环戊基-5-甲基-己酸;
(3S,5R)-3-氨基-6-环己基-5-甲基-己酸;
(3S,5R)-3-氨基-8-环丙基-5-甲基-辛酸;
(3S,5R)-3-氨基-8-环丁基-5-甲基-辛酸;
(3S,5R)-3-氨基-8-环戊基-5-甲基-辛酸;
(3S,5R)-3-氨基-8-环己基-5-甲基-辛酸;
(3S,5S)-3-氨基-6-环丙基-5-甲基-己酸;
(3S,5S)-3-氨基-6-环丁基-5-甲基-己酸;
(3S,5S)-3-氨基-6-环戊基-5-甲基-己酸;
(3S,5S)-3-氨基-6-环己基-5-甲基-己酸;
(3S,5S)-3-氨基-8-环丙基-5-甲基-辛酸;
(3S,5S)-3-氨基-8-环丁基-5-甲基-辛酸;
(3S,5S)-3-氨基-8-环戊基-5-甲基-辛酸;
(3S,5S)-3-氨基-8-环己基-5-甲基-辛酸;
(3S)-3-氨基-6-环丙基-5,5-二甲基-己酸;
(3S)-3-氨基-6-环丁基-5,5-二甲基-己酸;
(3S)-3-氨基-6-环戊基-5,5-二甲基-己酸;
(3S)-3-氨基-6-环己基-5,5-二甲基-己酸;
(3S)-3-氨基-7-环丙基-5,5-二甲基-庚酸;
(3S)-3-氨基-7-环丁基-5,5-二甲基-庚酸;
(3S)-3-氨基-7-环戊基-5,5-二甲基-庚酸;以及
(3S)-3-氨基-7-环己基-5,5-二甲基-庚酸。
方法C
作为制备得到β-氨基酸的一种方法,将例如通式10的酰亚胺进行非对映烷基化得到例如通式11的手性琥珀酸酯类似物已经在现有技术中描述过(参见例如Evans等人,J.Org.Chem.,1999,64,6411;Sibi and Deshpande,J.Chem.Soc.Perkin Trans 1.,2000,1461;Arvanitis等人,J.Chem.Soc.Perkin Trans 1.,1998,521)。
结构11的化合物可以由结构10的化合物在适宜的酯衍生物(PG定义同上,LG=Br和I或Cl)例如溴代乙酸叔丁酯、溴代乙酸苄基酯存在下、与有机金属碱例如二异丙基氨基化锂或双(三甲基甲硅烷基)氨基化锂或双(三甲基甲硅烷基)氨基化钠等在例如四氢呋喃、乙醚等的溶剂中制备得到。完成该反应可以在-78℃的四氢呋喃中使用双(三甲基甲硅烷基)氨基化钠进行,然后于-78℃至-30℃下将所得到的阴离子中间体用溴代乙酸叔丁酯进行处理。
通式12化合物可以通过将相应的通式11化合物在氢氧化锂和过氧化氢存在下、在例如水或THF的溶剂中于约0℃-室温左右的温度下进行水解而制备得到。优选使用过氧化氢和氢氧化锂在含水的四氢呋喃中于大约0℃下,根据现有文献(参见Yuen P-W.,Kanter G.D.,Taylor C.P.,以及Vartanian M.G.,Bioorganicand Medicinal Chem.Lett.,1994;4(6):823-826)中所描述的方法完成。
使用二苯基磷酰基叠氮化物将通式12化合物在适宜醇类例如叔丁醇、苄醇或对甲氧基苄醇存在下、在适宜的溶剂例如甲苯、苯或THF中于约50℃至反应混合物回流温度左右的温度下进行处理,得到相应的通式13化合物,其中R5为甲基、乙基、叔丁基、苄基或对甲氧基苄基。R5取决于所使用的醇。优选使用甲苯溶剂在对甲氧基苄醇存在下、在回流条件下完成该反应。
使用本领域技术人员所熟知的条件,通过水解或氢解可以将通式13化合物转化为所需的通式IA化合物。(参见T.W.Greene和P.G.M.Wuts.,″Protectivegroups in organic synthesis″,Wiley,1991中有关形成和除去适宜保护基团的详细描述)。例如,该反应可以这样进行:在水解条件下,在约室温至反应混合物回流温度附近的温度下、优选在回流温度下通过用适宜的酸例如盐酸或硫酸进行处理,或者在室温附近至回流温度附近的温度下、优选在室温附近通过用适宜的无机碱例如氢氧化钠、氢氧化钾或氢氧化锂优选氢氧化钠进行处理。优选在回流温度下使用盐酸完成该反应。然而,如果PG为叔丁基,优选在三氟乙酸(TFA)中完成反应。如果PG为碱性基团,那么可以在碱性条件下使用本领域技术人员所熟知的方法,例如使用氢氧化钠或氢氧化钾完成水解。
通式10化合物可以这样制备得到:通过将相应的通式8化合物利用胺碱例如三乙胺、在三甲基乙酰氯存在下在醚溶剂例如THF中进行处理,然后利用通式9的手性噁唑烷酮处理上步反应原位形成的中间体。可以在上述方法中使用的其它噁唑烷酮实例有:(4S)-(-)-4-异丙基-2-噁唑烷酮;(S)-(-)-4-苄基-2-噁唑烷酮;(4S,5R)-(-)-4-甲基-5-苯基-2-噁唑烷酮;(R)-(+)-4-苄基-2-噁唑烷酮;(S)-(+)-4-苯基-2-噁唑烷酮;(R)-(-)-4-苯基-2-噁唑烷酮;(R)-4-异丙基-2-噁唑烷酮;以及(4R,5S)-(+)-4-甲基-5-苯基-2-噁唑烷酮以及氯化锂。优选该反应是这样完成的:将通式8的酸用三甲基乙酰氯和三乙胺在四氢呋喃中于大约-20℃下进行处理,然后根据文献方法(参见Ho G-J.和Mathre D.J.,J.Org.Chem.,1995;60:2271-2273),将在上述反应中形成的中间体用通式9的噁唑烷酮和氯化锂在室温附近进行处理。
作为替代方式,通式10化合物还可以通过将相应的通式9化合物利用由使用草酰氯处理相应的通式8化合物而衍生得到的酰基氯在例如二氯甲烷的溶剂中、在二甲基甲酰胺(DMF)存在下进行处理而制备得到。通式8的酸可以由商购得到的原料利用本领域技术人员已知的方法制备得到。这些酸可能具有一个或多个手性中心。在本申请实施例1、2和3中描述了使用香茅基溴化物和香茅醇来合成这类酸。
按照上述方法C可以制备得到的化合物包括但不仅仅限制于下述化合物:
(3S,5R)-3-氨基-5-甲基-庚酸;
(3S,5R)-3-氨基-5-甲基-辛酸;
(3S,5R)-3-氨基-5-甲基-壬酸;
(3S,5R)-3-氨基-5-甲基-癸酸;
(3S,5S)-3-氨基-5-甲基-庚酸;
(3S,5S)-3-氨基-5-甲基-辛酸;
(3S,5S)-3-氨基-5-甲基-壬酸;
(3S,5S)-3-氨基-5-甲基-癸酸;
(3S)-3-氨基-5,5-二甲基-庚酸;
(3S)-3-氨基-5,5-二甲基-辛酸;
(3S)-3-氨基-5,5-二甲基-壬酸;
(3S)-3-氨基-5,5-二甲基-癸酸;
(3S,5R)-3-氨基-7-环丙基-5-甲基-庚酸;
(3S,5R)-3-氨基-7-环丁基-5-甲基-庚酸;
(3S,5R)-3-氨基-7-环戊基-5-甲基-庚酸;
(3S,5R)-3-氨基-7-环己基-5-甲基-庚酸;
(3S,5S)-3-氨基-7-环丙基-5-甲基-庚酸;
(3S,5S)-3-氨基-7-环丁基-5-甲基-庚酸;
(3S,5S)-3-氨基-7-环戊基-5-甲基-庚酸;以及
(3S,5S)-3-氨基-7-环己基-5-甲基-庚酸。
作为替代方式,参照下面的反应流程图(方法D),使用适宜的酸(当使用叔丁基酯时,例如三氟乙酸(TFA))处理通式11化合物可以得到相应的通式14化合物,然后将其经库尔提斯重排(其中R5定义同上)得到相应的通式15化合物(参见Arvanitis等人,J.Chem.Soc.Perkin Trans 1.,1998,521有关该方法的描述)。进一步水解酰亚胺基团(得到相应的通式16化合物)和氨基甲酸酯基团,得到通式11的目标氨基酸。
根据上述通式11化合物转化为通式12化合物的步骤,可以由化合物15衍生得到化合物16。通式17化合物可以由相应的通式16化合物通过使用强酸例如盐酸等或强碱例如氢氧化钠或氢氧化钾,或者当R5为苄基或对甲氧基苄基时通过氢化条件,使用钯-碳在乙醇或THF中于氢气氛下进行处理而制备得到。在本申请实施例4中描述了这种方法,它保留了通式11化合物中手性中心的立体化学,该手性中心同样出现在产物通式II中。
方法D
按照上述方法可以制备得到的化合物包括但不仅仅限制于下述化合物:
(2R,4R)-2-氨基甲基-4-甲基-己酸;
(2R,4R)-2-氨基甲基-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-辛酸;
(2R,4R)-2-氨基甲基-4-甲基-壬酸;
(2R,4R)-2-氨基甲基-4-甲基-癸酸;
(2R,4S)-2-氨基甲基-4-甲基-己酸;
(2R,4S)-2-氨基甲基-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-辛酸;
(2R,4S)-2-氨基甲基-4-甲基-壬酸;
(2R,4S)-2-氨基甲基-4-甲基-癸酸;
(2R,4S)-2-氨基甲基-6-环丙基-4-甲基-己酸;
(2R,4S)-2-氨基甲基-6-环丁基-4-甲基-己酸;
(2R,4S)-2-氨基甲基-6-环戊基-4-甲基-己酸;以及
(2R,4S)-2-氨基甲基-6-环己基-4-甲基-己酸。
可用于制备本发明化合物的其它合成α-取代的β-氨基酸的替代方法包括下面文献中描述的方法:Juaristi等人,Tetrahedron Asymm.,7,(8),1996,2233和Seebach等人,Eur.J.Org.Chem.,1999,335,或者Arvanitis等人,J.Chem.Soc.Perkin Trans 1.,1998,521,如下面的方法E所示:
方法E
下面的方法F描述了制备通式II化合物的替代方法。
方法F
根据Hoffmann-La Roche(FR 1377736 19641106)所公开的方法,通式3化合物可以由通式2的不饱和氰基酯通过还原和水解制备得到。而氰基酯2可以通过将醛1与氰基乙酸酯进行Knoevenagel缩合而制备得到(例如Paine,J.B.;Woodward,R.B.;Dolphin,D.,J.Org.Chem.1976,41,2826)。通式1的醛可以由商购得到的原料利用本领域技术人员所熟知的方法制备得到。
通式III和IV化合物可以使用对于本领域技术人员而言为显而易见的类似于方法F的步骤制备得到。如果合成通式III化合物,起始原料应该是与方法F中通式1相似的化合物,只是其中与通式1中羰基相连的氢用甲基替换。
如下面的方法G所述,使用手性亚胺得到β-氨基酸的方法已经在现有技术中描述过(参见例如Tang,T.P.;Ellman,J.A.J.Org.Chem.1999,64,12-13)。
方法G
在上述流程图中最后一步是同时将磺酰胺和酯基进行水解。通常是使用强酸例如盐酸、氢溴酸或硫酸在溶剂例如水或二噁烷或者水和二噁烷的混合物中于大约20℃至大约50℃的温度下、优选在室温下完成该反应的。
在前述试验部分中没有进行具体描述的本发明化合物的制备方法可以通过联合使用上述的反应方法来完成,这样的联合手段对于本领域技术人员而言是显而易见的。
在上面所讨论和描述的每步反应中,压力并不是很重要,除非另有说明。大约0.5大气压至大约5大气压的压力是通常情况下可以接受的,为了方便优选环境气压也就是大约1大气压。
通式1化合物和基团A化合物、以及上述反应流程图中的中间体可以通过常规方法例如重结晶法或色谱分离法进行分离和纯化。
本发明化合物对钙通道α2δ-亚单元的结合能力可以使用下面的结合测定法进行测定。
使用利用[3H]-加巴喷丁的放射配基结合试验以及取自猪脑组织的α2δ-亚单元(参见Gee,Nicolas S等人.′The novel anticonvulsant drug,gabapentin(Neurontin),binds to the α2δ subunit of a calcium channel″J.Biol.Chem.(1996),271(10),5768-76)。本发明化合物对于α2δ蛋白质具有纳摩尔至微摩尔级的亲和力。例如,R-3-氨基-5,9-二甲基-癸酸对α2δ蛋白质具有527nM的亲和力,(3S,5S)-3-氨基-5-甲基-辛酸具有1uM的亲和力,(2R,4R)-2-氨基甲基-4-甲基-庚酸具有29nM的亲和力,2-氨基甲基-4,4-二甲基-庚酸具有83nM的亲和力。
本发明化合物的体内活性可以在痛觉过敏的动物模型中测量(参见Sluka,K.等人.2001,″Unilateral Intramuscular Injections Of Acidic Saline Produce A Bilateral,Long-Lasting Hyperalgesia″,Muscle Nerve 24:37-46;Dixon,W.,1980,″Efficientanalysis of experimental observations″.Ann Rev Pharmacol Toxicol 20:441-462;Randall L.O.and Selitto J.J.,″A Method For Measurement Of Analgesic Activity OnInflamed Tissue,″Arch.Int.Pharmacodyn,1957;4:409-419;Hargreaves K.,DubnerR.,Brown F.,Flores C.,以及Joris J.″A New And Sensitive Method For MeasuringThermal Nociception In Cutaneous Hyperalgesia″.Pain.32:77-88,1988.)、焦虑症(Vogel JR,Beer B,以及Clody DE,″A Simple And Reliable Conflict Procedure ForTesting Anti-Anxiety Agents″,Psychopharmacologia 21:1-7,1971)。
本发明化合物及其可药用盐可以通过口服、非肠道(例如皮下、静脉内、肌肉内、细胞内和滴注方法)、直肠、口腔或者鼻内给药方式向哺乳动物给药。
本发明的新化合物可以通过前述任意一种方法进行单独给药或者与可药用载体或稀释剂进行联合(combination)给药,并且还可以分成单剂量或多剂量给药。更具体地说,本发明的新治疗剂可以以各种不同的剂型给药,也就是说它们可以与各种可药用惰性载体混合成片剂、胶囊剂、锭剂、药片、硬糖果、栓剂、胶冻剂、凝胶剂、糊剂、软膏剂、含水混悬剂、注射溶液剂、酏剂、糖浆剂等剂型。这类载体包括固体稀释剂或填充剂、无菌含水介质以及各种无毒有机溶剂等。此外,口服药物组合物还适宜加入糖和/或加入香料。一般来说,本发明的新化合物与可药用载体的重量比例可以为大约1∶6至大约2∶1,优选为大约1∶4至大约1∶1。
对于口服给药,含有各种赋形剂例如微晶纤维素、柠檬酸钠、碳酸钙、磷酸二钙和甘氨酸的片剂可以与各种崩解剂例如淀粉(优选玉米、马铃薯或木薯淀粉)、褐藻酸和某些硅酸盐络合物以及各种粒化粘合剂例如聚乙烯吡咯烷酮、蔗糖、明胶以及阿拉伯树胶联合使用。此外,润滑剂例如硬脂酸镁、十二烷基硫酸钠和滑石对于压片目的通常也是非常有用的。类似类型的固体组合物还可用作凝胶胶囊剂中的填充剂;连接口优选的材料还包括乳糖或奶糖以及高分子量的聚乙二醇。如果含水混悬剂和/或酏剂适合口服给药的话,那么活性成分可以联合有各种甜味剂或芳香剂、着色物质或染料,如果若需要的话,活性成分可以联合有乳化剂和/或悬浮剂和稀释剂例如水、乙醇、丙二醇、甘油以及它们的混合物。
对于非肠道给药,可以使用本发明化合物的芝麻或花生油或者含水丙二醇溶液。如果必要的话,水溶液应该适合于缓冲(优选pH大于8),并且液体稀释剂首先还应该是等渗的。这些水溶液适合于静脉注射用。油溶液适合于关节内、肌内和皮下注射用。根据本领域技术人员所熟知的常规药学手段很容易完成这些溶液剂在无菌条件下的制备。
对于鼻内给药或吸入给药,借助于适宜的推进剂例如二氯二氟甲烷、三氯氟代甲烷、二氯四氟乙烷、二氧化碳或者其它适宜的气体,本发明的新化合物可以很方便地以溶液或混悬液的形式从经患者挤压或抽吸后的泵式喷雾器中释放出来或者以喷雾的形式从密闭容器或喷雾器中释放出来。在加压喷雾的情况中,剂量单元可以通过所提供的释放计量药物的阀门来控制。加压容器或喷雾器可以含有活性化合物的溶液或混悬液。用于吸入器或吹药器的胶囊剂和药筒(例如由凝胶制成)可以制成含有本发明化合物的粉末混合物和适宜的粉末基质例如乳糖或淀粉的制剂。优选将用于治疗普通成年人上面所提及到症状的本发明活性化合物的制剂设计为每一计量剂量或“每次”喷雾含有20μg至1000μg活性化合物。对于气雾剂而言其总的日剂量可以为100μg至10mg。可以每天几次给药,例如2、3、4或8次,还比如每次1、2或3个剂量。
本发明化合物可以以各种各样的口服和非肠道给药剂型进行配制和给药。因此,本发明化合物可以注射给药,也就是经脉内给药、肌内给药、皮内给药、皮下给药、十二指肠内给药或腹膜内给药。另外,本发明化合物还可以吸入给药,例如鼻内给药。此外,本发明化合物还可以进行透皮给药。对本领域技术人员来说显而易见的是,下面的各种剂型均可以含有作为活性成分的通式I、IA、IA-1、IA-2、IB、IC、II、IIA、III或IV化合物或者这些化合物相应的可药用盐。
对于从本发明化合物到药物组合物的制备而言,可药用载体可以为固体也可以为液体。固体形式的制剂包括散剂、片剂、胶囊剂、扁囊剂、栓剂以及分散性颗粒剂。固体载体可以为一种或多种可用作稀释剂、芳香剂、粘合剂、防腐剂、片剂崩解剂或者包囊材料的物质。在散剂中,载体为混合有细分活性成分的细分固体。在片剂中,活性成分与具有足够粘合特性的载体按照适当的比例进行混合,然后压制成所需的形状和大小。
散剂和片剂优选含有5%或10%至大约70%的活性化合物。适宜的载体有碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、凝胶、西黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点石蜡、可可油等。术语“制剂”包括含有活性化合物以及作为提供胶囊的载体的包囊材料的制剂,其中有或没有其它载体的这种活性成分被载体包围起来,而载体又与活性成分结合起来。类似地,还包括扁囊剂和锭剂。片剂、散剂、胶囊剂、丸剂、扁囊剂以及锭剂可用作适合口服的固体剂型。
为了制备栓剂,首先将低熔点石蜡例如脂肪酸甘油酯或可可油的混合物熔化,然后向其中均匀分散入活性成分,接着搅拌。随后该熔融均质混合物被倾入具有适宜尺寸的模具中,冷却,使之凝固。
液体形式制剂包括溶液剂、混悬剂、以及乳剂,例如水或水-丙二醇溶液剂。非肠道用注射液体制剂可以在含水聚乙二醇溶液中制成溶液剂。通过将活性成分溶解于水中,然后若需要加入适宜的着色剂、芳香剂、稳定剂和增稠剂,这样可以制备得到适合口服的水溶液剂。通过将细分活性成分和粘性材料例如天然或合成树胶、树脂、甲基纤维素、羧甲基纤维素钠以及其它已知的悬浮剂一起分散于水中,这样可以制备得到适合口服的水混悬剂。
另外还包括在使用之前可以很快调配成口服用液体制剂的固体形式的制剂。这样的液体制剂包括溶液剂、混悬剂和乳剂。这些制剂除了含有活性成分之外,还可以含有着色剂、芳香剂、稳定剂、缓冲剂、人造和天然甜味剂、分散剂、增稠剂、增溶剂等。
药物制剂优选为单元剂型的形式。在这种剂型中,制剂被再分成含有适宜用量的活性成分的单元剂量。单元剂型可以为每包含有独立量制剂的小包装制剂,例如包装片剂、胶囊剂、装在小瓶或安瓿中的散剂。另外,单元剂型本身可为胶囊剂、片剂、扁囊剂或锭剂,或者也可以是含有适当数目的任意一种上述剂型的包装形式。
根据某些特定应用以及活性成分的效力,可以将单元制剂中的活性成分含量调整或调节为0.01mg至1g。在临床应用中,这种药物例如100或300mg的胶囊每天可以服用三次。如果需要的话,这种药物组合物还可以含有其它能够配伍的治疗剂。
在治疗应用中,本发明药物方法中所用的化合物最初按照每天0.1mg至大约1g的剂量服用。当然,根据患者要求、所治疗症状的严重程度以及所使用的化合物可以对该剂量进行调整。决定适合于具体情形的适宜剂量属于本领域的技术范畴。一般来说,治疗最初是以小于化合物最佳剂量的较低剂量开始的。然后逐渐小增量增加剂量直到达到该情形下的最佳效果。为了方便,如果需要的话,总的日剂量在当天可以分成几份服用。
下面的实施例对本发明化合物的制备方法进行了描述。它们并不意味着对范围构成限制。熔点未经校正。NMR数据是以百万分之几给出的,并且所参照的是来自样本溶剂中的氘示踪信号。
实施例
实施例1.(3S,5R)-3-氨基-5-甲基-辛酸盐酸盐
(R)-2,6-二甲基-壬-2-烯。
在0℃下,向(S)-香茅基溴化物(50g,0.228mol)的THF(800mL)溶液中先后加入LiCl(4.3g)和CuCl2(6.8g)。30分钟后加入氯化甲基镁(152mL的3M THF溶液,Aldrich),溶液加热至室温。10小时后将溶液冷却至0℃,小心加入氯化铵的饱和水溶液。分离所得到的两层,水相用乙醚萃取。将合并的有机相干燥(MgSO4),浓缩得到(R)-2,6-二甲基-壬-2-烯。32.6g;93%。不纯化直接使用。1HNMR(400MHz;CDCl3)δ5.1(m,1H),1.95(m,2H),1.62(s,3H),1.6(s,3H),1.3(m,4H),1.2(m,2H),0.8(s,6H);13C NMR(100MHz;CDCl3)δ131.13,125.28,39.50,37.35,32.35,25.92,25.77,20.31,19.74,17.81,14.60。
(R)-4-甲基-庚酸。
在50分钟内,向(R)-2,6-二甲基-壬-2-烯(20g,0.13mol)的丙酮(433mL)溶液中加入CrO3(39g,0.39mol)的H2SO4(33mL)/H2O(146mL)溶液。6小时后,再加入一定量的CrO3(26g,0.26mol)的H2SO4(22mL)/H2O(100mL)溶液。12小时后溶液用盐水稀释,再用乙醚萃取。将合并的有机相干燥(MgSO4)并浓缩。快速色谱分离(梯度为6∶1至2∶1的己烷/EtOAc)得到(R)-4-甲基-庚酸油状物。12.1g;65%。MS,m/z(相对强度):143[M-H,100%];1H NMR(400MHz;CDCl3)δ2.35(m,2H),1.6(m,1H),1.4(m,1H),1.3(m,4H),1.1(m,1H),0.85(s,6H)。
(4R,5S)-4-甲基-3-((R)-4-甲基-庚酰基)-5-苯基-噁唑烷-2-酮。
在0℃下,向(R)-4-甲基-庚酸(19g,0.132mol)和三乙胺(49.9g,0.494mol)的THF(500mL)溶液中加入三甲基乙酰氯(20g,0.17mol)。1小时后先后加入LiCl(7.1g,0.17mol)和(4R,5S)-(+)-4-甲基-5-苯基-2-噁唑烷酮)3(30g,0.17mol)。将混合物加热至室温,16小时后通过过滤除去滤液,溶液在减压下浓缩。快速色谱分离(7∶1 己烷/EtOAc)得到(4R,5S)-4-甲基-3-((R)-4-甲基-庚酰基)-5-苯基-噁唑烷-2-酮油状物。31.5g;79%。[α]D=+5.5(c 1CHCl3溶液)。MS,m/z(相对强度):304[M+H,100%];1H NMR(400MHz;CDCl3)δ7.4-7.2(m,5H),5.6(d,J=7.32Hz,1H),4.75(m,1H),2.96(m,1H),2.86(m,1H),1.62(m,1H),1.43(m,1H),1.25(m,4H),1.12(m,1H),0.85(m,9H);13C NMR(100MHz;CDCl3)δ173.70,153.23,133.81,133.59,128.92,128.88,128.92,128.88,125.83,79.12,54.93,39.24,33.66,32.32,31.47,27.18,26.52,20.25,19.57,14.75,14.52。
(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。
在-50℃下,向(4R,5S)-4-甲基-3-((R)-4-甲基-庚酰基)-5-苯基-噁唑烷-2-酮(12.1g,0.04mol)的THF(200ml)溶液中加入双(三甲基甲硅烷基)氨基化钠(48mL的1M THF溶液)。30分钟后,加入溴代乙酸叔丁酯(15.6g,0.08mol)。溶液在-50℃下搅拌4小时,然后加热至室温。16小时后,加入氯化铵的饱和水溶液,分离两层。水相用乙醚萃取,将合并的有机相干燥(MgSO4)并浓缩。快速色谱处理(9∶1己烷/EtOAc)得到为白色固体的(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12g;72%。[α]D=+30.2(c1 CHCl3溶液)。13C NMR(100MHz;CDCl3)δ176.47,171.24,152.72,133.63,128.87,125.86,80.85,78.88,55.34,39.98,38.77,38.15,37.58,30.60,28.23,20.38,20.13,14.50,14.28。
(S)-2-((R)-2-甲基-戊基)-琥珀酸4-叔丁酯。
在0℃下,向(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(10.8g,0.025mol)的H2O(73mL)和THF(244mL)溶液中加入含有LiOH(51.2mL的0.8M溶液)和H2O2(14.6mL的30%溶液)的预混溶液。4小时后,再加入12.8mL LiOH(0.8M溶液)和3.65mL的H2O2(30%溶液)。30分钟后加入亚硫酸氢钠(7g)、硫酸钠(13g)和水(60mL),然后加入己烷(100mL)和乙醚(100mL)。分离两层,水层用乙醚萃取。合并的有机相浓缩得到油状物,将其溶解于庚烷(300mL)中。过滤除去所得到的固体,滤液干燥(MgSO4)并浓缩得到(S)-2-((R)-2-甲基-戊基)-琥珀酸4-叔丁酯(6g,93%),其直接使用不纯化。MS,m/z(相对强度):257[M+H,100%]。
(3S,5R)-3-苄氧基羰基氨基-5-甲基-辛酸,叔丁酯。
将(S)-2-((R)-2-甲基-戊基)-琥珀酸4-叔丁酯(6.0g,23.22mmol)和三乙胺(3.64mL,26.19mmol)的甲苯(200mL)溶液用二苯基磷酰基叠氮化物(5.0mL,23.22mL)处理,然后在室温下搅拌0.5小时。反应混合物在回流状态下加热3小时后,简单冷却,加入苄醇(7.2mL,69.7mmol),溶液继续加热3小时。待反应混合物冷却之后,将其用乙醚(200mL)稀释,用饱和NaHCO3和盐水洗涤合并的有机层,干燥(Na2SO4)。浓缩的有机成分通过色谱(MPLC)纯化,用8∶1的己烷∶乙酸乙酯洗脱得到(3S,5R)-3-苄氧基羰基氨基-5-甲基-辛酸,叔丁酯(6.4g,75.8%)。MS:M+1:364.2,308.2。1HNMR(400MHz,CDCl3)δ0.83(t,3H,J=6.59Hz),0.87(d,3H,J=6.59Hz),1.08-1.34(m,6H),1.39(s,9H),1.41-1.52(m,2H),2.39(m,2H),4.02(m,1H),5.05(s,2H),5.09(m,1H),和7.24-7.32(m,5H)ppm。
(3S,5R)-3-氨基-5-甲基-辛酸,叔丁酯。
将(3S,5R)-3-苄氧基羰基氨基-5-甲基-辛酸,叔丁酯(2.14g,5.88mmol)的THF(50mL)溶液在50psi的H2下用Pd/C(0.2g)处理2小时。然后反应混合物过滤并真空浓缩成油状物,得到定量产率的(3S,5R)-3-氨基-5-甲基-辛酸,叔丁酯。MS:M+1:230.2,174.1。1HNMR(400MHz,CDCl3)δ0.85-0.86(t和d重叠,6H),1.13-1.40(m,6H),1.44(s,9H),1.60(m,1H),2.31(dd,1H,J=7.81和15.86Hz),2.38(dd,1H,J=5.13和15.86Hz),3.31(m,1H),以及3.45(br s,2H)ppm。
(3S,5R)-3-氨基-5-甲基-辛酸盐酸盐。
将(3S,5R)-氨基-5-甲基-辛酸,叔丁酯(2.59g,11.3mmol)的6N HCl(100mL)浆状物加热回流18小时,冷却,用硅藻土过滤。滤液真空浓缩得到25mL,收集所得到的结晶,干燥得到(3S,5R)-3-氨基-5-甲基-辛酸盐酸盐,mp 142.5-142.7℃(1.2g,50.56%)。由滤液中得到第二批产物(0.91g)。对C9H19NO2·HCl的分析计算值为:C:51.55,H:9.61,N:6.68,Cl:16.91。实测值:C:51.69,H:9.72,N:6.56,Cl:16.63。MS:M+1:174.1。1HNMR(CD3OD)δ0.89(t,3H,J=7.32Hz),0.92(d,3H,J=6.35Hz),1.12-1.18(m,1H),1.25-1.35(m,2H),1.35-1.42(m,2H),1.54-1.64(m,2H),2.50(dd,1H,J=7.81和17.33Hz),2.65(dd,1H,J=4.64和17.32Hz),以及3.52(m,1H)ppm。
实施例2.(3S,5R)-氨基-5-甲基-庚酸
甲磺酸(S)-3,7-二甲基-辛-6-烯基酯。
在0℃下,向S-(-)-香茅醇(42.8g,0.274mol)和三乙胺(91mL,0.657mol)的CH2Cl2(800mL)的溶液中加入甲磺酰氯(26mL,0.329mol)的CH2Cl2(200mL)溶液。2小时后,溶液在0℃下先后用1N HCl和盐水洗涤。将有机相干燥(MgSO4)并浓缩得到为油状物的标题化合物(60.5g,94%),其直接使用不纯化。MS,m/z(相对强度):139[100%],143[100%]。1H NMR(400MHz;CDCl3)δ5.05(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。
在0℃下,向甲磺酸(S)-3,7-二甲基-辛-6-烯基酯(60g,0.256mol)的THF(1L)溶液中加入氢化铝锂(3.8g,0.128mol)。7小时后,再次加入3.8g氢化铝锂,溶液温热至室温。18小时后,再加入3.8g氢化铝锂。再过21小时后,用1N柠檬酸小心猝灭反应,溶液继续用盐水洗涤。分离所得到的两相,将有机相干燥(MgSO4)并浓缩得到为油状物的标题化合物,其直接使用不纯化。MS,m/z(相对强度):139[M+H,100%]。
(R)-4-甲基-己酸。
利用类似于合成(R)-4-甲基-庚酸的步骤,得到为油状物的酸(9.3g,56%)。IR(薄膜)2963,2931,2877,2675,1107,1461,1414cm-1;MS,m/z(相对强度):129[M-H,100%];1H NMR(400MHz;CDCl3)δ2.35(m,2H),1.66(m,1H),1.37(m,4H),1.29(m,1H),0.86(m,6H);13C NMR(100MHz;CDCl3)δ181.02,34.09,32.12,31.39,29.29,18.94,11.44。
(4R,5S)-4-甲基-3-((R)-4-甲基-己酰基)-5-苯基-噁唑烷-2-酮。
利用类似于合成(4R,5S)-4-甲基-3-((R)-4-甲基-庚酰基)-5-苯基-噁唑烷-2-酮的步骤,得到为油状物的标题化合物(35.7g,95%)。MS,m/z(相对强度):290[M+H,100%];1H NMR(400MHz;CDCl3)δ7.4-7.25(m,5H),5.6(d,J=7.32Hz,1H),4.75(m,1H),2.97(m,1H),2.85(m,1H),1.68(m,1H),1.43(m,2H),1.12(m,2H),0.87(m,9H);13C NMR(100MHz;CDCl3)δ173.71,153.24,133.56,128.94,128.90,125.83,79.14,54.95,34.22,33.72,31.07,29.45,27.20,26.52,19.19,19.15,14.77,14.53,11.54。
(3S,5R)-5-甲基-3-[1-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-基)-甲酰基(methanoyl)]-庚酸叔丁酯。
利用类似于制备(3S,5R)-5-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯的步骤,得到为油状物的标题化合物(7.48g;31%)。IR(薄膜)2967,2934,1770,1716,1696,1344,1148,1121,1068,1037,947cm-1;MS,m/z(相对强度):178[100%],169[100%];[α]D=+21.6(c1 CHCl3溶液)。
(S)-2-((R)-2-甲基-丁基)-琥珀酸4-叔丁酯。
在0℃下,向(3S,5R)-5-甲基-3-[1-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-基)-甲酰基(methanoyl)]-庚酸叔丁酯(7.26g,0.018mol)的H2O(53mL)和THF(176mL)溶液中加入含有LiOH(37mL的0.8M溶液)和H2O2(10.57mL的30%溶液)的预混溶液,溶液温热至室温。2小时后,加入亚硫酸氢钠(7g)、硫酸钠(13g)、和水(60mL),分离两层,水层用乙醚萃取。合并的有机相浓缩成油状物,将其溶解于庚烷(200mL)中。过滤除去所得到的固体,干燥滤液(MgSO4)并浓缩得到为油状物的标题化合物(4.4g),其直接使用不纯化。MS,m/z(相对强度):243[100%];1HNMR(400MHz;CDCl3)δ2.88(m,1H),2.59(m,1H),2.36(m,1H),1.65(m,1H),1.41(s,9H),1.20(m,4H),0.84(m,6H)。
(3S,5R)-3-苄氧基羰基氨基-5-甲基-庚酸,叔丁酯。
该化合物按照前面描述的方法制备,由(S)-2-((R)-2-甲基-丁基)琥珀酸,4-叔丁酯开始,得到为油状物的(3S,5R)-3-苄氧基羰基氨基-5-甲基-庚酸,叔丁酯(产率为73.3%)。1H NMR(400MHz;CDCl3)δ0.84(t,3H,J=7.33Hz),0.89(d,3H,J=6.60Hz),1.12-1.38(m,4H),1.41(s,9H),1.43-1.59(m,2H),2.42(m,2H),4.05(m,1H),5.07(t,2H J=12.95Hz),以及7.28-7.34(m,5H)。
(3S,5R)-氨基-5-甲基-庚酸,叔丁酯。
该化合物按照前面描述的方法制备,由(3S,5R)-3-苄氧基羰基氨基-5-甲基-庚酸,叔丁酯而不是(3S,5R)-3-苄氧基羰基氨基-5-甲基-辛酸,叔丁酯开始,得到标题化合物。1H NMR(400MHz;CDCl3)δ0.84(t和d重叠,6H),1.08-1.16(m,2H),1.27-1.30(m,2H),1.42(s,9H),1.62(br s,2H),2.15(dd,1H,J=8.54和15.62Hz),2.29(dd,1H,J=4.15和15.37Hz),以及3.20(br s,2H)。
(3S,5R)-氨基-5-甲基-庚酸盐酸盐。
将(3S,5R)-氨基-5-甲基-庚酸,叔丁酯(1.44g,6.69mmol)在3N HCl中的浆状物加热回流3小时,硅藻土过滤,浓缩至干。将所得到的固体粉碎于乙醚中得到(3S,5R)-3-氨基-5-甲基-庚酸盐酸盐,(0.95g,85%)mp 126.3-128.3℃。1HNMR(400MHz;CD3OD)δ0.92(t,3H,J=7.32Hz),0.92(d,3H,J=6.35Hz),1.15-1.24(m,1H),1.33-1.43(m,2H),1.44-1.52(m,1H),1.60-1.67(m,1H),2.57(ddd,1H,J=7.3217.67和5.12Hz),2.69(ddd,1H,J=0.97,4.88和17.32Hz),以及3.28(m,1H)。对C8H17NO2·HCl·0.1H2O的分析计算值:C:48.65,H:9.29,N:7.09,Cl:17.95。实测值:C:48.61,H:9.10,N:7.27,Cl:17.87MS:M+1:160.2。
实施例3.(3S,5R)-3-氨基-5-甲基-壬酸
(R)-4-甲基-辛酸。
在环境温度下,将氯化锂(0.39g,9.12mmol)和氯化亚铜(I)(0.61g,4.56mmol)一起溶解于45ml THF中,搅拌15分钟,然后冷却至0℃,此时加入溴化乙基镁(1M的THF溶液,45mL,45mmol)。逐滴加入(S)-香茅基溴化物(5.0g,22.8mmol),溶液慢慢温热至环境温度,搅拌过夜。通过小心加入饱和NH4Cl(aq)使反应猝灭,用Et2O和饱和NH4Cl(aq)搅拌30分钟。分离两相,将有机相干燥(MgSO4)并浓缩。粗产物(R)-2,6-二甲基-癸-2-烯直接使用不纯化。在0℃下,向(R)-2,6-二甲基-癸-2-烯(3.8g,22.8mmol)的50mL丙酮溶液中加入琼斯试剂(2.7M的H2SO4(aq)溶液,40mL,108mmol),溶液慢慢温热至室温,搅拌过夜。混合物在Et2O和H2O之间分层,分离两相,有机相用盐水洗涤,干燥(MgSO4),然后浓缩。残余物经快速色谱纯化(8∶1己烷∶EtOAc)得到2.14g(59%)为无色油状物的标题化合物:LRMS:m/z 156.9(M+);1H NMR(400MHz;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)。通过将26.7g CrO3、23mL H2SO4进行混合,然后用H2O稀释至100mL,制备得到琼斯试剂的2.7M溶液。
(4R,5S)-4-甲基-3-((R)-4-甲基-辛酰基)-5-苯基-噁唑烷-2-酮。
在0℃下,向(R)-4-甲基-辛酸(2.14g,13.5mmol)的25mL CH2Cl2溶液中慢慢加入3滴DMF,接着再加入草酰氯(1.42mL,16.2mmol)逸出剧烈的气体流。将溶液直接温热至环境温度,搅拌30分钟,浓缩。同时,在-78℃下向噁唑烷酮(2.64g,14.9mmol)的40mL THF溶液中逐滴加入正丁基锂(1.6M的己烷溶液,9.3mL,14.9mmol)。混合物搅拌10分钟,此时逐滴加入酰基氯的10mL THF溶液。在-78℃下搅拌反应30分钟,然后直接温热至室温,用饱和NH4Cl猝灭。混合物在Et2O和饱和NH4Cl(aq)之间分层,分离两相,干燥有机相(MgSO4),然后浓缩得到3.2g为无色油状物的标题化合物。LRMS:m/z 318.2(M+);1H NMR(400MHz;CDCl3):7.34(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)。该粗产物直接使用不纯化。
(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。
在-78℃下,向二异丙基胺(1.8mL,12.6mmol)的30mL THF溶液中加入正丁基锂(1.6M的己烷溶液,7.6mL,12.1mmol),混合物搅拌10分钟,此时逐滴加入(4R,5S)-4-甲基-3-((R)-4-甲基-辛酰基)-5-苯基-噁唑烷-2-酮(3.2g,10.1mmol)的10mL THF溶液。溶液搅拌30分钟,在-50℃下迅速逐滴加入溴代乙酸叔丁酯(1.8mL,12.1mmol),用3小时将混合物慢慢温热至10℃。混合物在Et2O和饱和NH4Cl(aq)之间分层,分离两相,干燥有机相(MgSO4)并浓缩。残余物经快速色谱纯化(16∶1至8∶1的己烷∶EtOAc)得到2.65g(61%)为无色晶状固体的标题化合物,mp=84-86℃。[α]D 23+17.1(c=1.00,CHCl3);1H NMR(400MHz;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(400MHz;CDCl3)δ176.45,171.22,152.71,133.64,128.86,125.86,80.83,78.87,55.33,40.02,38.21,37.59,36.31,30.86,29.29,28.22,23.14,20.41,14.36,14.26。对C25H37NO5的分析计算值:C,69.58;H,8.64;N,3.25。实测值:C,69.37;H,8.68;N,3.05。
(S)-2-((R)-2-甲基-己基)-琥珀酸4-叔丁酯。
在0℃下,向(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(2.65g,6.14mmol)的20mL THF溶液中加入预冷的(0℃)LiOH一水合物(1.0g,23.8mmol)和过氧化氢(30重量%水溶液,5.0mL)的10mL H2O溶液。混合物剧烈搅拌90分钟,然后温热至环境温度,搅拌90分钟。在0℃下通过加入100mL 10% NaHSO3(aq)使反应猝灭,然后用Et2O萃取。分离两相,有机相用盐水洗涤,干燥(MgSO4),浓缩。标题化合物直接使用不纯化。
(3S,5R)-3-苄氧基羰基氨基-5-甲基壬酸,叔丁酯。
该化合物按照类似于前面所描述的方法制备,由(S)-2-((R)-2-甲基己基)琥珀酸,4-叔丁酯而不是(S)-2-((R)-2-甲基戊基)琥珀酸,4-叔丁酯开始,得到为油状物的标题化合物(产率为71.6%)。1HNMR(400MHz;CDCl3)δ0.81(t,3H,J=4.40Hz),0.85(d,3H,J=6.55Hz),1.06-1.20(m,7H),1.36(s,9H),1.38-1.50(m,2H),2.36(m,2H),3.99(m,1H),5.02(m+s,3H),以及7.28-7.28(m,5H)。
(3S,5R)-3-氨基-5-甲基-壬酸,叔丁酯。
该化合物按照前面所描述的方法制备,只是由(3S,5R)-苄氧基羰基氨基-5-甲基-壬酸,叔丁酯而不是(3S,5R)-3-苄氧基羰基氨基-5-甲基-辛酸,叔丁酯开始。产率=97%。1HNMR(400MHz;CDCl3)δ0.82(d和t重叠,6H),1.02-1.08(m,1H),1.09-1.36(m,6H),1.39(s,9H),1.47(br s,1H),1.80(s,2H),2.13(dd,1H,J=8.54和15.61Hz),以及2.27(dd,1H,J=4.15和15.38Hz)。
(3S,5R)-3-氨基-5-甲基-壬酸盐酸盐。
将(3S,5R)-3-氨基-5-甲基-壬酸,叔丁酯(1.50g,6.16mmol)在3N HCl(100mL)中的混合物加热回流3小时,经硅藻土热过滤,真空浓缩成30mL。收集所得到的结晶,再用3N HCl洗涤,干燥得到标题化合物,mp 142.5-143.3℃。由滤液得到另一份产物1.03g(70.4%)。1HNMR(400MHz;CD3OD)δ=0.91(t,3H,J=6.84Hz),0.92(d,3H,J=6.35Hz),1.16-1.26(m,1H),1.27-1.35(m,4H),1.38-1.45(m,1H),1.61(br s,1H),1.63-1.68(m,1H),2.58(dd,1H,J=7.32和17.34Hz),2.69(dd,1H,J=5.13和17.59Hz),以及3.59(m,1H)。对C10H21NO2·HCl的分析计算值:C:53.68,H:9.91,N:6.26,Cl:15.85。实测值:C:53.89,H:10.11,N:6.13.MS:M+1:188.1。
实施例4.(2R,4R)-2-氨基甲基-4-甲基-庚酸
5R-甲基-3R-(4S-甲基-2-氧代-5R-苯基噁唑烷-3-羰基)辛酸。
将(3R,5R)-5-甲基-3-((4S,5R)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯(3.9g,9.34mmol)的二氯甲烷(150mL)溶液用三氟乙酸(7.21mL,93.4mL)处理,在环境温度下搅拌18小时。真空除去溶剂和试剂之后,将所得到的残余物在100mL己烷中进行研磨得到3.38g标题化合物(100%)mp 142-143℃。MS M+1=362.1。1H NMR(400MHz;CDCl3)δ0.85(2t,6H,J=7.1Hz),0.93(d,3H,J=6.1Hz),1.14(m,1H),1.2-1.49(m,6H),2.56(dd,1H,J=4.15和17.57Hz),2.81(dd,1h,J=17.33和10.74Hz),4.28(m,1H),4.74(五重峰,1H,J=6.84Hz),5.64(d,1H,J=7.32Hz),7.29-7.43(m,5H)。
[4R-甲基-2R-(4S-甲基-2-氧代-5R-苯基噁唑烷-3-羰基)庚基]氨基甲酸苄基酯。
将5R-甲基-3R-(4S-甲基-2-氧代-5R-苯基噁唑烷-3-羰基)辛酸(1.98g,5.48mmol)和三乙胺(0.92mL,6.57mmol)的溶液用二苯基膦酰基叠氮化物(1.2mL,5.48mmol)处理,在环境温度下搅拌30分钟,然后加热回流3小时。短暂冷却之后,将反应混合物用苄醇(2.8mL,27.4mmol)处理,继续加热回流3小时。反应混合物冷却,用乙醚(150mL)稀释,先后用饱和NaHCO3和盐水洗涤,干燥(MgSO4)并真空浓缩得到油状物。色谱处理(MPLC,用4∶1的己烷∶乙酸乙酯洗脱)得到为油状物的标题化合物(2.0g,78.3%)。MS M+1=467.1。1H NMR(400MHz;CDCl3)δ0.86(2t,6H,J=7.1Hz),0.93(d,3H,J=5.9Hz),1.14(m,1H),1.09-1.36(m,6H),1.50(d,1H,J=5.2Hz),3.49(t,1H,J=6.1Hz),4.10(m,1H),4.71(五重峰,1H,J=6.61Hz),5.06(d,2H,J=3.42Hz),5.20(t,1H,J=5.61Hz),5.64(d,1H,J=7.08Hz),7.29-7.43(m,10H)。
2R-(苄氧基羰基氨基甲基)-4R-甲基庚酸。
将4R-甲基-2R-(4S-甲基-2-氧代-5R-苯基噁唑烷-3-羰基)庚基]氨基甲酸苄基酯(4.12g,8.83mmol)在3∶1的THF∶水(100mL)的溶液冷却至0℃,然后用含有0.8N LiOH(17.5mL,14mmol)和30%H2O2(4.94mL,44mmol)的混合物处理。反应混合物置冷搅拌3小时之后,使用NaHSO3(2.37g)和Na2SO3(4.53g)在水(30mL)中的浆状物来猝灭,搅拌1小时。反应混合物用乙醚(200mL)稀释,分层,有机层用盐水洗涤,干燥(MgSO4)。浓缩后的有机萃取物经色谱(MPLC)处理,用乙酸乙酯洗脱得到1.25g 2R-(苄氧基羰基氨基甲基)-4R-甲基庚酸(46%)。MSM+1=308.1。1H NMR(400MHz;CDCl3)δ0.83(t,3H,J=6.84Hz),0.87(t,3H,J=6.35Hz),1.14(m,1H),1.06-1.54(m,7H),2.7(br s,1H),3.30(m,2H),5.05(q,2H,J=12.2Hz),5.14(t,1H,J=5.61Hz),7.30(br s,5H)。
(2R,4R)-2-氨基-4-甲基-庚酸盐酸盐。
将2R-(苄氧基羰基氨基甲基)-4R-甲基-庚酸(1.25g,4.07mmol)和Pd/C(20%,0.11g)在甲醇(50mL)中的混合物在50psi下氢化18小时。过滤除去催化剂之后,真空除去溶剂,将所得到的固体在乙醚中研磨得到(2S,4R)-2-氨基-4-甲基-庚酸盐酸盐(0.28g,40%)mp 226.3-228.0℃。MS M+1=174.0。1H NMR(400MHz;CD3OD)δ0.89(t+d,6H,J=6.35Hz),1.11(m,1H),1.25-1.40(m,4H),1.47-1.62(m,2H),2.48(br s,1H),2.93(m,2H)。对C9H19NO2·0.1 H2O的分析计算值:C:61.75 H:11.06 N:8.00。实测值:C:61.85 H:10.83 N:8.01。
实施例5.2-氨基甲基-4,4-二甲基-庚酸盐酸盐
2-氰基-4,4-二甲基-庚-2,6-二烯酸乙酯。
将2,2-二甲基-戊-4-烯醛(5.0g,44mmol)、氰基-乙酸乙酯(5.12mL,48mmol)、哌啶(1.3mL,14mmol)以及乙酸(4.52mL,80mmol)在170mL甲苯中的溶液在装备有迪安-斯达克榻分水器的烧瓶中加热回流18小时。在汽水阀中收集几毫升水。冷却反应,然后依次用1N HCl、NaHCO3和盐水洗涤。有机层用Na2SO4干燥并浓缩得到油状物。该油状物经色谱处理,用20%EtOAc的己烷溶液洗脱得到两部分的混合物,总重8.3g(91%)。1H NMR(400MHz;CDCl3)1.28(s,6H),1.32(t,3H,J=7Hz),2.26(d,2H,J=7.6Hz),4.27(q,2H,J=7.2Hz),5.08(d,1H,J=12Hz),5.10(d,1H,J=4Hz),5.72(m,1H)。
2-氨基甲基-4,4-二甲基-庚酸盐酸盐。
将2-氰基-4,4-二甲基-庚-2,6-二烯酸乙酯(5.88g,28mmol)溶解于含有91mL乙醇和6mL HCl的混合物中,然后用0.4g PtO2处理。在100psi氢气压和室温下反应15小时。过滤除去催化剂,浓缩滤液得到3.8g为油状物的所需产物2-氨基甲基-4,4-二甲基-庚酸乙酯。MS(APCI):216.2(M+1)+。将该油状物在75mL的6N HCl中回流18小时。在反应冷却的同时,形成沉淀。过滤固体,用另外的HCl溶液洗涤,乙醚研磨得到洁净的标题化合物。MS(APCI):188.1(M+1)+。186.1(M-1)+。1H NMR(400MHz;CD3OD):0.91(9H,m),1.30(5H,m),1.81(dd,1H,J=7.2Hz,14.4Hz),2.72(1H,m),3.04(2H,m);对C10H21NO2·HCl的分析计算值:C:53.68,H:9.91,N:6.26,Cl:15.85;实测值:C:53.83,H:10.15,N:6.22,Cl:15.40。MP:229.5-231.0℃。
实施例6.(S)-3-氨基-5,5-二甲基-辛酸
3-(4,4-二甲基-庚酰基)-(R)-4-甲基-(S)-5-苯基-噁唑烷-2-酮:将4,4-二甲基-庚酸(1.58g,10mmol)和三乙胺(4.6mL)在50mL THF中的溶液冷却至0℃,然后用2,2-二甲基-丙酰氯(1.36mL)处理。1小时后,加入4R-甲基-5S-苯基-噁唑烷-2-酮(1.95g,11mmol)和氯化锂(0.47g,11mmol),混合物搅拌18小时。过滤沉淀,用另外的THF充分洗涤。滤液真空浓缩得到油状固体。将该固体溶解于200mLEt2O中,依次用饱和NaHCO3、0.5N HCl和饱和NaCl洗涤,干燥(MgSO4)并真空浓缩得到为油状物的标题化合物(3.0g,95%)。1HNMR(400MHz;CDCl3):0.73-0.84(m,2H),1.10-1.22(m,4H),1.46-1.54(m,2H),2.75-2.87(m,2H),4.70(m,1H,J=7Hz),5.59(d,1H,J=7Hz),7.22-7.37(m,5H)。
5,5-二甲基-(S)-3-((R)-4-甲基-2-氧代-(S)-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯:根据实施例1,由5.07g(16mmol)3-(4,4-二甲基-庚酰基)-4-甲基-5-苯基-噁唑烷-2-酮、18mL(1N,18mmol)NaHMDS溶液以及4.72mL(32mmol)溴代乙酸叔丁酯得到3.40g(49.3%)为晶状固体的标题化合物。1HNMR(400MHz;CDCl3):0.85-0.89(m,12H),1.18-1.32(m,6H),1.41(s,9H),1.88(dd,1H,J=6Hz,8.4Hz),2.41(dd,1H,J=6Hz,16Hz),2.62(dd,1H,J=8.4Hz,16Hz),4.30-4.40(m,1H),4.72(m,1H),5.62(d,1H,J=7Hz),7.30-7.40(m,5H)。m.p.:83-85℃。
(S)-2-(2,2-二甲基-戊基)-琥珀酸4-叔丁酯:根据实施例1,由3.4g(7.9mmol)5,5-二甲基-3-(4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯、16mL(12.8mmol)0.8N LiOH以及4.5mL 30% H2O2得到2.42g(>100%)为油状物的标题化合物。1HNMR(400MHz;CDCl3):0.77-0.82(m,9H),1.14-1.29(m,5H),1.42(s,9H),1.77(dd,1H,J=8Hz,16Hz),2.36(dd,1H,J=6Hz,16Hz),2.59(dd,1H,J=8Hz,16Hz),2.75-2.85(m,1H)。
(S)-3-苄氧基羰基氨基-5,5-二甲基-辛酸叔丁酯:根据实施例1,由2.14g(7.9mmol)2-(2,2-二甲基-戊基)-琥珀酸4-叔丁酯、1.7mL DPPA、1.1mL Et3N以及2.44mL BnOH得到1.63g(54.8%,在两步中)为油状物的标题化合物。1HNMR(400MHz;CDCl3):0.78-0.89(m,9H),1.10-1.30(m,5H),1.36(s,9H),2.39(t,2H,J=5Hz),4.95-4.05(m,1H),5.00(s,2H),5.09(d,1H,J=9.6Hz),7.22-7.30(m,5H)。
(S)-3-氨基-5,5-二甲基-辛酸叔丁酯:根据实施例1,由1.63g 3-苄氧基羰基氨基-5,5-二甲基-辛酸叔丁酯和0.2g 20% Pd/C得到标题化合物。1HNMR(400MHz;CDCl3):0.84-0.89(m,9H),1.13-1.39(m,6H),1.43(s,9H),2.25(dd,1H,J=8.4Hz,15.6Hz),2.35(dd,1H,J=4.4Hz,15.6Hz),2.79(s,br,2H),3.25-3.35(m,1H)。MS,m/z,244.2(M+1)+。
(S)-3-氨基-5,5-二甲基-辛酸盐酸盐:根据实施例1,将3-氨基-5,5-二甲基-辛酸叔丁酯用3N HCl处理得到286mg为固体的标题化合物。1HNMR(400MHz;CD3OD):0.87-0.93(m,9H),1.18-1.31(m,4H),1.51(dd,1H,J=4Hz,14.4Hz),1.62(dd,1H,J=6.8Hz,14.4Hz),2.60(dd,1H,J=8Hz,17.6Hz),2.73(dd,1H,J=4Hz,7.6Hz),3.55-3.60(m,1H)。MS(APCI),m/z:188.1(M+1)+,186.1(M-1)+。对C10H21NO2·HCl·0.12H2O的分析计算值:C:53.17,H:9.92,N:6.20,Cl:15.69;实测值:C:53.19,H:10.00,N:6.08,Cl:15.25。α=+20°(MeOH)。MP:194.2-195.2℃。
实施例7.2-氨基甲基-3-(1-甲基-环丙基)-丙酸
2-氰基-3-(1-甲基-环丙基)-丙烯酸乙酯。
向1-甲基环丙烷-甲醇(Aldrich,1.13mL,11.6mmol)的50mL CH2Cl2溶液中加入中性铝(2.5g),再加入PCC(2.5g,11.6mmol),混合物在环境温度下搅拌3小时。将混合物用1cm塞径的硅胶真空过滤,用Et2O冲洗。滤液浓缩至总体积大约为5mL。向残余物中加入THF(10mL)、氰基乙酸乙酯(1.2mL,11.3mmol)、哌啶(5滴),最后加入乙酸(5滴)。全部混合物在环境温度下搅拌过夜,然后在Et2O和饱和NaHCO3水溶液之间分层。分离两相,有机相用盐水洗涤,干燥(MgSO4),浓缩。残余物经快速色谱处理(10-15%EtOAc/己烷)得到0.53g(25%)为无色油状物的酯,其静置结晶,mp35-37℃。1H NMR(CDCl3)δ6.99(s,1H),4.27(q,J=7.3Hz,2H),1.55(s,3H),1.32(t,J=7.3Hz,3H),1.14(s,2H),1.07(s,2H)。13C NMR δ170.44,162.90,115.17,103.69,62.52,21.24,21.07(2C),20.71,14.35。对C10H13NO2的分析计算值:C,67.02;H,7.31;N,7.82。实测值:C,66.86;H,7.47;N,7.70。
2-氨基甲基-3-(1-甲基-环丙基)-丙酸乙酯。
向2-氰基-3-(1-甲基-环丙基)-丙烯酸乙酯(0.45g,2.51mmol)的16mLEtOH∶THF(1∶1)溶液中加入RaNi(0.4g),混合物在帕尔摇动器中于48psi下氢化15.5小时。然后加入Pearlman氏催化剂(0.5g),继续氢化15小时。过滤混合物并浓缩,残余物经快速色谱处理,用2→3→4→5→6→8%的MeOH/CH2Cl2洗脱得到0.25g(54%)为无色油状物的氨基酯。1H NMR(CDCl3)δ3.97(m,2H),2.67(m,2H),2.46(m,1H),1.28(d,J=7.3Hz,2H),1.19(bs,2H),1.09(t,J=7.3Hz,3H),0.85(s,3H),0.04(m,4H)。LRMS:m/z 186.1(M+1)。
2-氨基甲基-3-(1-甲基-环丙基)-丙酸。
在0℃下,向2-氨基甲基-3-(1-甲基-环丙基)-丙酸乙酯(0.25g,1.35mmol)的10mL甲醇中加入10% NaOH溶液(10mL)。混合物在环境温度下搅拌过夜,然后浓缩除去甲醇。残余物冷却至0℃,用浓HCl酸化至pH为2。温热至室温后,将混合物装填在DOWEX-50WX8-100离子交换树脂上,用H2O洗脱直到对石蕊显示中性。继续用5% NH4OH(100mL)溶液洗脱,浓缩碱性馏分得到0.15g(71%)为无色固体的氨基酸。1H NMR(CDCl3)δ2.72(m,2H),2.42(m,1H),1.34(dd,J=8.5,13.9Hz,1H),1.19(dd,J=6.1,13.9Hz,1H),0.82(s,3H),0.05(m,4H)。LRMS:m/z 158.0(M+1)。
实施例8.(3S,5R)-3-氨基-5-甲基-辛酸
(5S)-5-甲基-辛-2,6-二烯酸叔丁酯。
在-78℃下,在5分钟之内逐滴向(S)-3-甲基-己-4-烯酸乙酯*(1.0g,6.4mmol)的30mL甲苯溶液中加入DIBAH(1.0M THF溶液,6.4mL)。混合物在-78℃下搅拌45分钟,同时加入5滴甲醇,使得选出剧烈的H2流。加入甲醇直到观察不到再有气体逸出(大约5mL)。此时除去冷水浴,加入大约5mL饱和的酒石酸的Na+K+盐溶液。当混合物达到室温时,再加入另外的饱和的酒石酸的Na+K+盐溶液和Et2O,继续搅拌直到两相基本上透明(大约1小时)。分离两相,有机相用盐水洗涤,干燥(MgSO4),借助挥发作用将其浓缩至总体积为大约10mL。该粗品混合物与另外一份由10mmol酯按照上述方法制备得到的醛进行混合,整份混合物直接使用不纯化。在1小时内向氢化钠(60%的矿物油分散液)在25mLTHF中的混悬液中逐滴加入P,P-二甲基膦酰基乙酸叔丁酯(3.0mL,15mmol),使得可以控制H2的逸出。完成加料之后,迅速逐滴加入该粗产物醛的甲苯(总体积为大约20mL)溶液,混合物在室温下搅拌过夜。将混合物在Et2O和饱和NH4Cl溶液之间分层,分离两相,有机相用盐水洗涤,干燥(MgSO4)并浓缩。残余物经快速色谱处理(0→3→5%EtOAc/己烷),得到1.0g(29%,两步)为浅黄色油状物的不饱和酯:1H NMR(CDCl3)δ6.75(m,1H),5.66(m,1H),5.30(m,2H),2.03-2.29(m,3H),1.58(d,J=6.1Hz,3H),1.41(s,9H),0.91(d,J=6.6Hz,3H)。
*(S)-3-甲基-己-4-烯酸乙酯由(S)-反式-3-戊烯-2-醇[Liang,J.;Hoard,D.W.;Van Khau,V.;Martinelli,M.J.;Moher,E.D.;Moore,R.E.;Tius,M.A.J.Org.Chem.,1999,64,1459]通过Johnson-Claisen重排与三乙基原乙酸酯根据文献方法[Hill,R.K.;Soman,R.;Sawada,S.,J.Org.Chem.,1972,37,3737]制备得到。
(3R,5S)-3-[苄基-(1-苯基-乙基)-氨基]-5-甲基-辛-6-烯酸叔丁酯。
在-78℃下,向(S)-(-)-N-苄基-α-甲基苄基胺(0.6ml,2.85mmol)的9.0mL THF溶液中迅速逐滴加入正丁基锂(1.6M己烷溶液,1.6mL),出现深粉红色。混合物在-78℃搅拌30分钟,同时缓慢逐滴加入(5S)-5-甲基-辛-2,6-二烯酸叔丁酯(0.5g,2.38mmol)的1.0mL THF溶液,得到浅褐色,将其置于暗处3小时。混合物在-78℃搅拌3小时,然后用饱和NH4Cl溶液猝灭。混合物温热至室温,搅拌过夜,然后在EtOAc和饱和NH4Cl溶液之间分层。浓缩两相,将有机相干燥(MgSO4)并浓缩。残余物经快速色谱处理(3→5% EtOAc/己烷)得到0.52g(52%)为黄色油状物的氨基酯。1H NMR(CDCl3)δ7.34(m,2H),7.20(m,8H),5.27(m,2H),3.74(m,1H),3.72(d,J=15.9Hz,1H),3.41(d,J=14.9Hz,1H),3.27(m,1H),2.38(m,1H),1.98(dd,J=3.7,14.2Hz,1H),1.81(dd,J=9.3,14.4Hz,1H),1.54(d,J=4.9Hz,3H),1.32(s,9H),1.24(d,J=7.1Hz,3H),0.99(m,2H),0.74(d,J=6.6Hz,3H)。
(3S,5R)-3-氨基-5-甲基-辛酸。
向(3R,5S)-3-[苄基-(1-苯基-乙基)-氨基]-5-甲基-辛-6-烯酸叔丁酯(0.92g,2.18mmol)的50mL MeOH溶液中加入20% Pd/C(0.20g),混合物在帕尔摇动器中于48psi氢化23小时。过滤混合物并浓缩。向该粗产物氨基酯的10mL CH2Cl2溶液中加入1.0mL三氟乙酸,溶液在环境温度下搅拌过夜。浓缩混合物,将残余物溶解于少量H2O中,装填在DOWEX-50WX8-100离子交换树脂上。柱子用H2O洗脱直到对石蕊显示中性,再继续用5% NH4OH(100mL)溶液洗脱。浓缩碱性馏分得到0.25g(66%,两步)为灰白色固体的氨基酸。1H NMR(CD3OD)δ3.41(m,1H),2.36(dd,J=5.1,16.6Hz,1H),2.25(dd,J=8.1,16.6Hz,1H),1.42(m,2H),1.24(m,1H),1.12(m,2H),1.00(m,1H),0.73(d,J=6.4Hz,3H),0.68(t,J=6.8Hz,3H)。LRMS:m/z 172.1(M-1)。
实施例9.2-氨基甲基-8-甲基-壬酸
利用类似于制备2-氨基甲基-4,4,8-三甲基-壬酸的方法由6-甲基-1-庚醇制备得到2-氨基甲基-8-甲基-壬酸,m/z 202.1(M+)。
2-氨基甲基-4,8-二甲基-壬酸
(R)-2,6-二甲基庚-1-醇:将镁屑(2.04g,84mmol)和碘结晶悬浮于5mL THF中,然后加入1-溴-3-甲基丁烷(0.3mL,纯的)。加热混合物开始Grignard形成反应。将残留的1-溴-3-甲基丁烷(8.63mL,72mmol)稀释在THF(60mL)中,然后逐滴加入。混合物在环境温度下搅拌2小时,冷却至-5℃。逐滴加入氯化铜(1.21g,9mmol)和LiCl(0.76g,18mmol)的THF(50mL)溶液,同时保持温度低于0℃。所得到的混合物搅拌20分钟,逐滴加入(R)-3-溴-2-甲基丙醇的THF(20mL)溶液,同时保持温度低于0℃。使混合物慢慢达到环境温度,过夜。反应混合物用氢氧化铵和水猝灭。将混合物用EtOAc稀释,3×20mL EtOAc萃取。有机相用盐水洗涤,干燥(MgSO4),过滤并浓缩。残余油状物经硅胶色谱纯化(90/10己烷/EtOAc)得到2.67g(R)-2,6-二甲基庚-1-醇。
(R)-1-碘-2,6-二甲基庚烷:在0℃下,向溶解于CH2Cl2中的载体三苯基膦(6.55g,19.67mmol)的混合物中加入碘(4.99g,19.67mmol)和咪唑(1.33g,19.67mmol)。混合物温热至环境温度,搅拌1小时,再冷却至0℃,逐滴加入(R)-2,6-二甲基庚-1-醇的CH2Cl2(5mL)的溶液。使混合物达到环境温度,搅拌1小时,同时通过硅藻土垫将其过滤,固体用CH2Cl2洗涤。浓缩滤液,粗产物经硅胶色谱纯化得到(R)-1-碘-2,6-二甲基庚烷(2.44g)。
(4R)-4,8-二甲基壬酸叔丁酯:在-78℃下,向二异丙基胺(0.827mL,5.9mmol)的THF(8mL)溶液中加入正丁基锂(2.65mL的2.6M戊烷溶液)。溶液在-78℃下搅拌30分钟,接着加入乙酸正丁酯(0.8mL,5.9mmol)。混合物在-78℃下搅拌2小时,然后加入(R)-1-碘-2,6-二甲基庚烷(0.3g,1.18mmol)和HMPA(1.5mL)的THF(1mL)溶液。在-78℃下搅拌反应,慢慢达到环境温度过夜,然后加热至35℃结束反应。反应通过加入氯化铵(饱和的水溶液)猝灭,混合物用EtOAc萃取(2×10mL)。合并有机相,用水洗涤,干燥(MgSO4),过滤并浓缩。硅胶色谱处理(98/2己烷/EtOAc)得到0.25g(4R)-4,8-二甲基壬酸叔丁酯。
(4R)-4,8-二甲基壬酸:在0℃下,将(4R)-4,8-二甲基壬酸叔丁酯在25mLCH2Cl2中的溶液用TFA(6mL)处理。混合物放置至环境温度,搅拌过夜。通过旋转蒸发除去溶剂,混合物经硅胶色谱处理(95/5己烷/EtOAc)得到0.962g(4R)-4,8-二甲基壬酸。m/z 185(M-)。
3-(4R,8-二甲基-壬酰基)-4-(S)-甲基-5(R)-苯基-噁唑烷-2-酮:利用类似于(4R,5S)-4-甲基-3-(R)-4-甲基-庚酰基)-5-噁唑烷-2-酮的步骤,得到3-(4R,8-二甲基-壬酰基)-4-(S)-甲基-5(R)-苯基-噁唑烷-2-酮(1.35g)m/z 346.5(M+)。
[4R,8-二甲基-2R-(4R-甲基-2-氧代-5R-苯基-噁唑烷-3-羰基)-壬基]-氨基甲酸苄基酯:在-20℃下,向3-(4(R),8-二甲基-壬酰基)-4(S)-甲基-5(R)-苯基-噁唑烷-2-酮(1.05g,3.04mmol)在CH2Cl2(12mL)和TiCl4(3.04mL的1M CH2Cl2溶液)中的溶液中加入二异丙基乙基胺(0.55mL,3.19mmol)。将所得到的暗红色溶液在-20℃下搅拌30分钟,然后加入N-甲氧基甲基苄基氨基甲酸酯(0.652g,3.34mmol)在CH2Cl2(3.5mL)和TiCl4(3.34mL)中的溶液。在0℃下搅拌混合物4小时。通过加入饱和的氯化铵水溶液使反应猝灭。混合物用CH2Cl2(3×15mL)萃取。收集有机相,用1N HCl洗涤,NaOH中和,接着再用盐水洗涤。干燥有机相(MgSO4),过滤,浓缩并用硅胶色谱纯化(95/5己烷/EtOAc)得到0.555g[4R,8-二甲基-2R-(4R-甲基-2-氧代-5R-苯基-噁唑烷-3-羰基)-壬基]-氨基甲酸苄基酯。
2(R)-(苄氧基羰基氨基-甲基)-4(R),8-二甲基-壬酸:利用类似于制备(S)-2-((R)-2-甲基-戊基)琥珀酸叔丁酯的方法,得到0.198g 2(R)-(苄氧基羰基氨基-甲基)-4(R),8-二甲基-壬酸。
2-氨基甲基-4,8-二甲基壬酸:将2(R)-(苄氧基羰基氨基-甲基)-4(R),8-二甲基-壬酸(0.148g,0.566mmol)用氢气在20%pd/C存在下处理得到0.082g 2-氨基甲基-4,8-二甲基壬酸,过滤后通过硅胶色谱纯化(85/15CH2Cl2/MeOH)。M/z 216.3(M+)。
实施例10.2-氨基甲基-4,4,8-三甲基-壬酸
2,2,6-三甲基-庚酸甲酯:在-78℃下,向二异丙基胺(1.54mL,11.03mmol)的THF(22mL)溶液中加入正丁基锂(6.89mL的1.6M己烷溶液)。溶液在-78℃下搅拌30分钟,接着加入异丁酸甲酯(0.97mL,8.48mmol)。混合物在-78℃下搅拌2小时,然后加入1-碘-4-甲基戊烷(1.8g,8.48mmol)和DMPU(0.55mL,4.24mmol)在THF(6mL)中的溶液。在-78℃下搅拌反应,慢慢放置16小时至环境温度。反应通过加入氯化铵(饱和的水溶液)猝灭,混合物用EtOAc(2×10mL)萃取。合并有机相,用水洗涤,干燥(MgSO4),过滤并浓缩。硅胶色谱处理(99/1己烷/EtOAc)得到1.57g 2,2,6-三甲基-庚酸甲酯。
2,2,6-三甲基-庚-1-醇:将2,2,6-三甲基-庚酸甲酯(1.97g,10.6mmol)溶解于甲苯(65mL)中,冷却至-78℃。逐滴加入DiBALH(12.7mL的1N甲苯溶液)。45分钟后,加入1.5mL DiBALH。2小时后,通过在-78℃下加入15mL MeOH使反应猝灭。混合物温热至环境温度,然后再次冷却至-78℃,然后加入10mL 1NHCl。混合物用EtOAc(3×15mL)萃取。合并的有机相用盐水洗涤,干燥(MgSO4),过滤并浓缩。残余油状物通过硅胶色谱处理(95/5己烷/EtOAc)得到2,2,6-三甲基-庚-1-醇(0.88g)。m/z 159(M+)。
2,2,6-三甲基-庚醛:将氯铬酸吡啶鎓(PCC,4.17g,19.4mmol)和中性铝(14.6g)的CH2Cl2溶液混合,并在环境温度下搅拌15分钟。将醇用CH2Cl2稀释,混合物在环境温度下搅拌2小时。溶液通过二氧化硅垫板过滤,固体用CH2Cl2洗涤。滤液蒸发得到1.05g 2,2,6-三甲基庚醛m/z 157(M+)。其直接使用不纯化。
2-氰基-4,4,8-三甲基-壬-2-烯酸苄基酯:向含有2,2,6-三甲基-庚醛(1.05g,6.73mmol)、哌啶(0.19mL,2.01mmol)以及氰基乙酸苄基酯(1.29g,7.4mmol)的混合物的甲苯(50mL)溶液中,加入冰醋酸(0.72g,12.1mmol)。将烧瓶装配上迪安-斯达克榻分水器,加热混合物回流18。混合物冷却后,用稀盐酸处理,分离各层。有机层依次用饱和碳酸氢钠溶液和盐水洗涤,干燥(MgSO4),过滤并浓缩。残余油状物通过硅胶色谱纯化(98/2己烷/EtOAc)得到1.3g 2-氰基-4,4,8-三甲基-壬-2-烯酸苄基酯m/z 314(M+)。
2-氨基甲基-4,4,8-三甲基-壬酸:将2-氰基-4,4,8-三甲基-壬-2-烯酸苄基酯(1.3g,4.14mmol)的THF(50mL)溶液用氢气在20% Pd/C存在下处理得到氰基酸和氰基甲酯的混合物。该混合物通过硅胶色谱纯化得到278mg 80105×41-1-2。该酸用氢气在阮内镍的MeOH/NH4OH的溶液中处理得到0.16g 2-氨基甲基-4,4,8-三甲基-壬酸。m/z 230.3(M+)。
实施例11.2-氨基甲基-4-乙基-辛酸
利用类似于制备2-氨基甲基-4,4,8-三甲基-壬酸的步骤,由2-乙基己醛制备2-氨基甲基-4-乙基-辛酸。m/z 202.1(M+)。
实施例12.2-氨基甲基-4-乙基-8-甲基-壬酸
利用类似于制备2-氨基甲基-4,4,8-三甲基-壬酸的步骤,由2,6-二叔丁基-4-甲基苯基环丙基羧酸酯制备2-氨基甲基-8-甲基-壬酸。m/z 230.2(M+)。
实施例13.3-氨基-2-[1-(4-甲基-戊基)-环丙基甲基]-丙酸
利用类似于制备2-氨基甲基-4,4,8-三甲基-壬酸的步骤,由2,6-二叔丁基-4-甲基苯基环丙基羧酸酯制备2-氨基甲基-8-甲基-壬酸。M/z 228.2(M+)。
实施例14.2-氨基甲基-4-乙基-己酸
利用类似于制备2-氨基甲基-4,8-二甲基-壬酸的步骤,由4-乙基己酸制备2-氨基甲基-4-乙基-己酸。m/z 174.1。
实施例15.3(S)-氨基-3,5-二甲基-庚酸
2-甲基-丙烷-2(S)-亚磺酸(1,3-二甲基-亚戊基)-酰胺:将(S)-(-)-2-甲基-2-丙烷磺酰胺(500mg,4.1mmol)、4-甲基-2-己酮(470mg,4.1mmol)以及乙氧基钛(IV)(1.7mL,8.3mmol)的溶液加热回流18小时。反应混合物倾入20mL盐水中,迅速搅拌。所得到的溶液通过硅藻土过滤,分离有机层。水层用乙酸乙酯(2×20mL)萃取。干燥合并的有机层(Na2SO4),过滤并浓缩。所得到的油状物通过硅胶色谱纯化(25% EtOAc的己烷溶液)得到575mg为黄色油状物的2-甲基-丙烷-2(S)-亚磺酸(1,3-二甲基-亚戊基)-酰胺。
3,5-二甲基-3-(2-甲基-丙烷-2(S)-亚磺酰基氨基)-庚酸甲酯:向-78℃的双(三甲基甲硅烷基)氨基化锂(5.1ml的1M THF溶液)的THF(6mL)溶液中逐滴加入乙酸甲酯(0.41mL,5.1mmol)。搅拌20分钟后,逐滴加入三异丙基氧化氯钛(chlorotitanium triisopropoxide)(2.5ml,10mmol)的THF(3mL)溶液。1小时后,在-78℃逐滴加入2-甲基-丙烷-2(S)-亚磺酸(1,3-二甲基-亚戊基)-酰胺(560mg,2.6mmol)的THF(3mL)溶液。反应在-78℃搅拌5小时,然后通过加入10mL氯化铵猝灭,温热至室温。混合物用10mL水稀释,过滤。水层用乙酸乙酯萃取(2×20mL)。合并的有机层用盐水洗涤,干燥(Na2SO4),过滤并浓缩。所得到的油状物通过硅胶色谱纯化(30% EtOAc的己烷溶液)得到360mg 3,5-二甲基-3-(2-甲基-丙烷-2(S)-亚磺酰基氨基)-庚酸甲酯。
3(S)-氨基-3,5-二甲基-庚酸:将3,5-二甲基-3-(2-甲基-丙烷-2(S)-亚磺酰基氨基)-庚酸甲酯(360mg,1.2mmol)溶解于6N HCl(2mL)和二噁烷(2mL)中,在100℃下加热6小时。混合物冷却至室温,用水稀释,EtOAc(15mL)萃取。有机相通过离子交换色谱纯化得到3(S)-氨基-3,5-二甲基-庚酸(270mg),然后再通过硅胶色谱纯化(70∶25∶5 CH2Cl2/MeOH/NH4OH)得到203mg为白色固体的3(S)-氨基-3,5-二甲基-庚酸。m/z 174(C9H19NO2+H)。
实施例16.3(S)-氨基-3,5-二甲基-壬酸
利用类似于制备3(S)-氨基-3,5-二甲基-庚酸的方法制备3(S)-氨基-3,5-二甲基-壬酸。m/z 202.1(C11H23NO2+H)。
实施例17.3(S)-氨基-3,5-二甲基-辛酸
使用类似于制备3(S)-氨基-3,5-二甲基-庚酸的方法制备3(S)-氨基-3,5-二甲基-壬酸。m/z 188.1(C10H21NO2+H)。
Claims (12)
1.通式II化合物或其可药用盐:
其中R1是氢或任选被1-5个氟原子取代的(C1-C3)烷基;
R2是氢或任选被1-5个氟原子取代的(C1-C3)烷基;
R3是(C1-C6)烷基、(C3-C6)环烷基、(C3-C6)环烷基-(C1-C3)烷基、苯基、苯基-(C1-C3)烷基、吡啶基、吡啶基-(C1-C3)烷基、苯基-N(H)-、或吡啶基-N(H)-,其中每个前述的烷基部分可以任选被1-5个氟原子取代,并且其中每个前述的苯基和吡啶基部分任选被1-3个取代基取代,所述取代基独立地选自氯、氟、氨基、硝基、氰基、(C1-C3)烷基氨基、任选被1-3个氟原子取代的(C1-C3)烷基以及任选被1-3个氟原子取代的(C1-C3)烷氧基;
条件是,当R1是氢时,R2不是氢。
2.通式IIA所代表的根据权利要求1的化合物,包括其可药用盐:
其中R3是(C1-C6)烷基、(C3-C6)环烷基、(C3-C6)环烷基-(C1-C3)烷基、苯基、苯基-(C1-C3)烷基、吡啶基、吡啶基-(C1-C3)烷基、苯基-N(H)-、或吡啶基-N(H)-,其中每个前述的烷基部分任选被1-5个氟原子取代,并且其中每个前述的苯基和吡啶基部分任选被1-3个取代基取代,所述取代基独立地选自氯、氟、氨基、硝基、氰基、(C1-C3)烷基氨基、任选被1-3个氟原子取代的(C1-C3)烷基以及任选被1-3个氟原子取代的(C1-C3)烷氧基。
3.根据权利要求1的化合物,该化合物选自下述化合物及它们的可药用盐:
2-氨基甲基-4-甲基-7-苯基-庚酸;
2-氨基甲基-4-甲基-6-苯基-己酸;
2-氨基甲基-7-(4-氟-苯基)-4-甲基-庚酸;
2-氨基甲基-7-(3-氟-苯基)-4-甲基-庚酸;
2-氨基甲基-7-(2-氟-苯基)-4-甲基-庚酸;
2-氨基甲基-7-(2,4-二氟-苯基)-4-甲基-庚酸;
2-氨基甲基-7-(3,4-二氟-苯基)-4-甲基-庚酸;
2-氨基甲基-4-甲基-7-(2-三氟甲基-苯基)-庚酸;
2-氨基甲基-4-甲基-7-(3-三氟甲基-苯基)-庚酸;
2-氨基甲基-4-甲基-7-(4-三氟甲基-苯基)-庚酸;
2-氨基甲基-4-甲基-6-苯基氨基-己酸;
2-氨基甲基-4-甲基-7-苯基氨基-庚酸;
2-氨基甲基-4-甲基-8-苯基氨基-辛酸;
(2R,4R)-2-氨基甲基-4-甲基-7-苯基-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-6-苯基-己酸;
(2R,4R)-2-氨基甲基-7-(4-氟-苯基)-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-7-(3-氟-苯基)-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-7-(2-氟-苯基)-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-7-(2,4-二氟-苯基)-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-7-(3,4-二氟-苯基)-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-7-(2-三氟甲基-苯基)-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-7-(3-三氟甲基-苯基)-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-7-(4-三氟甲基-苯基)-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-6-苯基氨基-己酸;
(2R,4R)-2-氨基甲基-4-甲基-7-苯基氨基-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-8-苯基氨基-辛酸;
(2R,4S)-2-氨基甲基-4-甲基-7-苯基-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-6-苯基-己酸;
(2R,4S)-2-氨基甲基-7-(4-氟-苯基)-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-7-(3-氟-苯基)-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-7-(2-氟-苯基)-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-7-(2,4-二氟-苯基)-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-7-(3,4-二氟-苯基)-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-7-(2-三氟甲基-苯基)-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-7-(3-三氟甲基-苯基)-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-7-(4-三氟甲基-苯基)-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-6-苯基氨基-己酸;
(2R,4S)-2-氨基甲基-4-甲基-7-苯基氨基-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-8-苯基氨基-辛酸;
(2R,4S)-2-氨基甲基-6-环己基-4-乙基-己酸;
2-氨基甲基-4-乙基-己酸;
2-氨基甲基-4-乙基-5-甲基-己酸;
2-氨基甲基-4-乙基-庚酸;
2-氨基甲基-4-乙基-6-甲基-庚酸;
2-氨基甲基-4-乙基-辛酸;
2-氨基甲基-4-乙基-7-甲基-辛酸;
2-氨基甲基-4-乙基-壬酸;
2-氨基甲基-4-乙基-8-甲基-壬酸;
2-氨基甲基-4,4-二甲基-庚酸;
2-氨基甲基-4,6-二甲基-庚酸;
2-氨基甲基-4,4,8-三甲基-壬酸;
(2R,4S)-2-氨基甲基-6-环戊基-4-乙基-己酸;
(2R,4S)-2-氨基甲基-6-环丁基-4-乙基-己酸;
(2R,4S)-2-氨基甲基-6-环丙基-4-乙基-己酸;
2-氨基甲基-4-甲基-己酸;
2-氨基甲基-4-甲基-庚酸;
2-氨基甲基-4-甲基-辛酸;
2-氨基甲基-4-甲基-壬酸;
2-氨基甲基-4-甲基-癸酸;
(2R,4R)-2-氨基甲基-4-甲基-己酸;
(2R,4R)-2-氨基甲基-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-4-甲基-辛酸;
(2R,4R)-2-氨基甲基-4-甲基-壬酸;
(2R,4R)-2-氨基甲基-4-甲基-癸酸;
(2R,4S)-2-氨基甲基-4-甲基-己酸;
(2R,4S)-2-氨基甲基-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-4-甲基-辛酸;
(2R,4S)-2-氨基甲基-4-甲基-壬酸;
(2R,4S)-2-氨基甲基-4-甲基-癸酸;
2-氨基甲基-5-环丙基-4-甲基-戊酸;
2-氨基甲基-5-环丁基-4-甲基-戊酸;
2-氨基甲基-5-环戊基-4-甲基-戊酸;
2-氨基甲基-5-环己基-4-甲基-戊酸;
2-氨基甲基-6-环丙基-4-甲基-己酸;
2-氨基甲基-6-环丁基-4-甲基-己酸;
2-氨基甲基-6-环戊基-4-甲基-己酸;
2-氨基甲基-6-环己基-4-甲基-己酸;
2-氨基甲基-7-环丙基-4-甲基-庚酸;
2-氨基甲基-7-环丁基-4-甲基-庚酸;
2-氨基甲基-7-环戊基-4-甲基-庚酸;
2-氨基甲基-7-环己基-4-甲基-庚酸;
2-氨基甲基-8-环丙基-4-甲基-辛酸;
2-氨基甲基-8-环丁基-4-甲基-辛酸;
2-氨基甲基-8-环戊基-4-甲基-辛酸;
2-氨基甲基-8-环己基-4-甲基-辛酸;
(2R,4S)-2-氨基甲基-5-环丙基-4-甲基-戊酸;
(2R,4S)-2-氨基甲基-5-环丁基-4-甲基-戊酸;
(2R,4S)-2-氨基甲基-5-环戊基-4-甲基-戊酸;
(2R,4S)-2-氨基甲基-5-环己基-4-甲基-戊酸;
(2R,4S)-2-氨基甲基-6-环丙基-4-甲基-己酸;
(2R,4S)-2-氨基甲基-6-环丁基-4-甲基-己酸;
(2R,4S)-2-氨基甲基-6-环戊基-4-甲基-己酸;
(2R,4S)-2-氨基甲基-6-环己基-4-甲基-己酸;
(2R,4S)-2-氨基甲基-7-环丙基-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-7-环丁基-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-7-环戊基-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-7-环己基-4-甲基-庚酸;
(2R,4S)-2-氨基甲基-8-环丙基-4-甲基-辛酸;
(2R,4S)-2-氨基甲基-8-环丁基-4-甲基-辛酸;
(2R,4S)-2-氨基甲基-8-环戊基-4-甲基-辛酸;
(2R,4S)-2-氨基甲基-8-环己基-4-甲基-辛酸;
(2R,4R)-2-氨基甲基-5-环丙基-4-甲基-戊酸;
(2R,4R)-2-氨基甲基-5-环丁基-4-甲基-戊酸;
(2R,4R)-2-氨基甲基-5-环戊基-4-甲基-戊酸;
(2R,4R)-2-氨基甲基-5-环己基-4-甲基-戊酸;
(2R,4R)-2-氨基甲基-6-环丙基-4-甲基-己酸;
(2R,4R)-2-氨基甲基-6-环丁基-4-甲基-己酸;
(2R,4R)-2-氨基甲基-6-环戊基-4-甲基-己酸;
(2R,4R)-2-氨基甲基-6-环己基-4-甲基-己酸;
(2R,4R)-2-氨基甲基-7-环丙基-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-7-环丁基-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-7-环戊基-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-7-环己基-4-甲基-庚酸;
(2R,4R)-2-氨基甲基-8-环丙基-4-甲基-辛酸;
(2R,4R)-2-氨基甲基-8-环丁基-4-甲基-辛酸;
(2R,4R)-2-氨基甲基-8-环戊基-4-甲基-辛酸;以及
(2R,4R)-2-氨基甲基-8-环己基-4-甲基-辛酸。
4.通式III化合物或其可药用盐:
其中R3是(C1-C6)烷基、(C3-C6)环烷基、(C3-C6)环烷基-(C1-C3)烷基、苯基、苯基-(C1-C3)烷基、吡啶基、吡啶基-(C1-C3)烷基、苯基-N(H)-、或吡啶基-N(H)-,其中每个前述的烷基部分任选被1-5个氟原子取代,并且其中每个前述的苯基和吡啶基部分任选被1-3个取代基取代,所述取代基独立地选自氯、氟、氨基、硝基、氰基、(C1-C3)烷基氨基、任选被1-3个氟原子取代的(C1-C3)烷基以及任选被1-3个氟原子取代的(C1-C3)烷氧基。
5.通式IV化合物或其可药用盐:
其中R1是氢或任选被1-5个氟原子取代的(C1-C6)烷基;以及
R3是(C1-C6)烷基、(C3-C6)环烷基、(C3-C6)环烷基-(C1-C3)烷基、苯基、苯基-(C1-C3)烷基、吡啶基、吡啶基-(C1-C3)烷基、苯基-N(H)-、或吡啶基-N(H)-,其中每个前述的烷基部分任选被1-5个氟原子取代,并且其中每个前述的苯基和吡啶基部分任选被1-3个取代基取代,所述取代基独立地选自氯、氟、氨基、硝基、氰基、(C1-C3)烷基氨基、任选被1-3个氟原子取代的(C1-C3)烷基以及任选被1-3个氟原子取代的(C1-C3)烷氧基。
6.根据权利要求5的化合物,该化合物选自下述化合物及它们的可药用盐:
2-氨基甲基-5-乙基-庚酸;
2-氨基甲基-5-乙基-6-甲基-庚酸;
2-氨基甲基-7-环丙基-5-乙基-庚酸;
2-氨基甲基-7-环丁基-5-乙基-庚酸;
2-氨基甲基-7-环戊基-5-乙基-庚酸;
2-氨基甲基-7-环己基-5-乙基-庚酸;
2-氨基甲基-5-乙基-辛酸;
2-氨基甲基-5-乙基-7-甲基-辛酸;
2-氨基甲基-5-乙基-壬酸;
2-氨基甲基-5-乙基-8-甲基-壬酸;
2-氨基甲基-6-环丙基-5-甲基-己酸;
2-氨基甲基-6-环丁基-5-甲基-己酸;
2-氨基甲基-6-环戊基-5-甲基-己酸;
2-氨基甲基-6-环己基-5-甲基-己酸;
2-氨基甲基-7-环丙基-5-甲基-庚酸;
2-氨基甲基-7-环丁基-5-甲基-庚酸;
2-氨基甲基-7-环戊基-5-甲基-庚酸;
2-氨基甲基-7-环己基-5-甲基-庚酸;
2-氨基甲基-8-环丙基-5-甲基-辛酸;
2-氨基甲基-8-环丁基-5-甲基-辛酸;
2-氨基甲基-8-环戊基-5-甲基-辛酸;
2-氨基甲基-8-环己基-5-甲基-辛酸;
2-氨基甲基-5-甲基-庚酸;
2-氨基甲基-5-甲基-辛酸;
2-氨基甲基-5-甲基-壬酸;
2-氨基甲基-8-甲基-壬酸;
(2R,6S)-2-氨基甲基-6-环丙基-5-甲基-己酸;
(2R,6S)-2-氨基甲基-6-环丁基-5-甲基-己酸;
(2R,6S)-2-氨基甲基-6-环戊基-5-甲基-己酸;
(2R,6S)-2-氨基甲基-6-环己基-5-甲基-己酸;
(2R,6S)-2-氨基甲基-7-环丙基-5-甲基-庚酸;
(2R,6S)-2-氨基甲基-7-环丁基-5-甲基-庚酸;
(2R,6S)-2-氨基甲基-7-环戊基-5-甲基-庚酸;
(2R,6S)-2-氨基甲基-7-环己基-5-甲基-庚酸;
(2R,6S)-2-氨基甲基-8-环丙基-5-甲基-辛酸;
(2R,6S)-2-氨基甲基-8-环丁基-5-甲基-辛酸;
(2R,6S)-2-氨基甲基-8-环戊基-5-甲基-辛酸;
(2R,6S)-2-氨基甲基-8-环己基-5-甲基-辛酸;
(2R,6S)-2-氨基甲基-5-甲基-庚酸;
(2R,6S)-2-氨基甲基-5-甲基-辛酸;
(2R,6S)-2-氨基甲基-5-甲基-壬酸;
(2R,6R)-2-氨基甲基-6-环丙基-5-甲基-己酸;
(2R,6R)-2-氨基甲基-6-环丁基-5-甲基-己酸;
(2R,6R)-2-氨基甲基-6-环戊基-5-甲基-己酸;
(2R,6R)-2-氨基甲基-6-环己基-5-甲基-己酸;
(2R,6R)-2-氨基甲基-7-环丙基-5-甲基-庚酸;
(2R,6R)-2-氨基甲基-7-环丁基-5-甲基-庚酸;
(2R,6R)-2-氨基甲基-7-环戊基-5-甲基-庚酸;
(2R,6R)-2-氨基甲基-7-环己基-5-甲基-庚酸;
(2R,6R)-2-氨基甲基-8-环丙基-5-甲基-辛酸;
(2R,6R)-2-氨基甲基-8-环丁基-5-甲基-辛酸;
(2R,6R)-2-氨基甲基-8-环戊基-5-甲基-辛酸;
(2R,6R)-2-氨基甲基-8-环己基-5-甲基-辛酸;
(2R,6R)-2-氨基甲基-5-甲基-庚酸;
(2R,6R)-2-氨基甲基-5-甲基-辛酸;以及
(2R,6R)-2-氨基甲基-5-甲基-壬酸。
7.化合物,其选自下述的化合物及它们的可药用盐:
2-氨基甲基-3-(1-甲基-环丙基)-丙酸;
2-氨基甲基-3-(1-乙基-环丙基)-丙酸;
2-氨基甲基-3-(1-丙基-环丙基)-丙酸;
2-氨基甲基-3-(1-异丙基-环丙基)-丙酸;
2-氨基甲基-3-(1-丁基-环丙基)-丙酸;
2-氨基甲基-3-(1-异丁基-环丙基)-丙酸;
2-氨基甲基-3-[1-(4-甲基-戊基)-环丙基]-丙酸;
2-氨基甲基-3-(1-甲基-环丁基)-丙酸;
2-氨基甲基-3-(1-乙基-环丁基)-丙酸;
2-氨基甲基-3-(1-丙基-环丁基)-丙酸;
2-氨基甲基-3-(1-甲基-环戊基)-丙酸;
2-氨基甲基-3-(1-乙基-环戊基)-丙酸;
2-氨基甲基-3-(1-丙基-环戊基)-丙酸;
2-氨基甲基-3-(1-甲基-环己基)-丙酸;
2-氨基甲基-3-(1-乙基-环己基)-丙酸;
2-氨基甲基-3-(1-丙基-环己基)-丙酸;
2-氨基甲基-4-环丙基-丁酸;
2-氨基甲基-4-(1-甲基-环丙基)-丁酸;
2-氨基甲基-4-(1-乙基-环丙基)-丁酸;
2-氨基甲基-4-环丁基-丁酸;
2-氨基甲基-4-(1-甲基-环丁基)-丁酸;
2-氨基甲基-4-(1-乙基-环丁基)-丁酸;
2-氨基甲基-4-环戊基-丁酸;
2-氨基甲基-4-(1-甲基-环戊基)-丁酸;
2-氨基甲基-4-(1-乙基-环戊基)-丁酸;
2-氨基甲基-4-环己基-丁酸;
2-氨基甲基-4-(1-甲基-环己基)-丁酸;和
2-氨基甲基-4-(1-乙基-环己基)-丁酸。
8.药物组合物,它含有治疗有效量的根据权利要求1-7中任意一项的化合物或其可药用盐;以及可药用载体。
9.治疗哺乳动物包括人的疾病或症状的方法,所述方法包括向需要该治疗的哺乳动物给药治疗有效量的根据权利要求1-7中任意一项的化合物或其可药用盐,其中所述疾病或症状选自炎性疼痛、慢性痛、急性痛、神经性疼痛、睡眠障碍、热潮红、纤维肌痛和焦虑。
10.根据权利要求9的方法,其中所述疾病或症状为神经性疼痛。
11.根据权利要求1-7中任意一项的化合物或其可药用盐在制备用于治疗炎性疼痛、慢性痛、急性痛、神经性疼痛、睡眠障碍、热潮红、纤维肌痛或焦虑的药物中的用途。
12.根据权利要求11的用途,其中所述药物用于治疗神经性疼痛。
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Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10129693A1 (de) * | 2001-06-22 | 2003-01-02 | Jan Loock | Verfahren zur extrakorporalen qualitativen und/oder quantitativen Erfassung neurotoxischer Substanzen im Blutplasma eines Individuums |
NI200300043A (es) * | 2002-03-28 | 2003-11-05 | Warner Lambert Co | AMINOACIDOS CON AFINIDAD POR LA PROTEINA a2DELTA. |
US7419981B2 (en) | 2002-08-15 | 2008-09-02 | Pfizer Inc. | Synergistic combinations of an alpha-2-delta ligand and a cGMP phosphodieterse 5 inhibitor |
CA2451267A1 (en) | 2002-12-13 | 2004-06-13 | Warner-Lambert Company Llc | Pharmaceutical uses for alpha2delta ligands |
CA2572324A1 (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 |
AU2004276072A1 (en) * | 2003-09-25 | 2005-04-07 | Warner-Lambert Company Llc | Amino acids with affinity for the alpha2delta-protein |
CN1856301A (zh) * | 2003-09-25 | 2006-11-01 | 沃尼尔·朗伯有限责任公司 | 治疗性β-氨基酸 |
JP2007528893A (ja) * | 2004-03-12 | 2007-10-18 | ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー | C1対称ビスホスフィンリガンド及びプレガバリンの不斉合成におけるそれらの使用 |
EP1768952A2 (en) * | 2004-07-09 | 2007-04-04 | Warner-Lambert Company LLC | Preparation of beta-amino acids having affinity for the alpha-2-delta protein |
WO2006092692A1 (en) * | 2005-03-01 | 2006-09-08 | Pfizer Limited | Use of combinations of pde7 inhibitors and alpha-2-delty ligands for the treatment of neuropathic pain |
WO2006100568A1 (en) * | 2005-03-24 | 2006-09-28 | Pharmacia & Upjohn Company Llc | Preparation of optically pure beta-amino acids having affinity for the alpha-2-delta protein |
WO2007052134A1 (en) * | 2005-11-04 | 2007-05-10 | Pfizer Limited | (2s)-2-aminomethyl-5-ethyl heptanoic acid its pharmaceutical use |
JP2009516675A (ja) * | 2005-11-17 | 2009-04-23 | ファイザー・リミテッド | 疼痛を治療するためのイソシステイン誘導体 |
MX2008011396A (es) * | 2006-03-06 | 2008-09-18 | Pfizer Prod Inc | Ligandos alfa-2-delta para sueño no reconstituyente. |
AR061728A1 (es) * | 2006-06-30 | 2008-09-17 | Pfizer Prod Inc | Composicion para tratamiento usando compuestos selectivos alfa-2-delta-1 |
US20110124705A1 (en) * | 2009-11-24 | 2011-05-26 | Xenoport, Inc. | Prodrugs of alpha-2-delta ligands, pharmaceutical compositions and uses thereof |
KR102027598B1 (ko) | 2011-05-17 | 2019-10-01 | 프린시피아 바이오파마, 인코퍼레이티드 | 타이로신 키나아제 저해제 |
AU2012255759B2 (en) | 2011-05-17 | 2017-08-10 | Principia Biopharma, Inc. | Kinase inhibitors |
WO2012158795A1 (en) | 2011-05-17 | 2012-11-22 | Principia Biopharma Inc. | Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors |
CN103164756A (zh) * | 2011-12-12 | 2013-06-19 | 苏州艾隆科技有限公司 | 贵重药品的管理方法及其系统 |
MX361815B (es) | 2012-09-10 | 2018-12-17 | Principia Biopharma Inc | Compuestos pirazolopirimidinicos como inhibidores de cinasas. |
US8957080B2 (en) | 2013-04-09 | 2015-02-17 | Principia Biopharma Inc. | Tyrosine kinase inhibitors |
MX2016010754A (es) | 2014-02-21 | 2017-03-03 | Principia Biopharma Inc | Sales y forma solida de un inhibidor btk. |
US10485797B2 (en) | 2014-12-18 | 2019-11-26 | Principia Biopharma Inc. | Treatment of pemphigus |
EP3313839A1 (en) | 2015-06-24 | 2018-05-02 | Principia Biopharma Inc. | Tyrosine kinase inhibitors |
BR112018077503A2 (pt) | 2016-06-29 | 2019-04-09 | Principia Biopharma Inc. | formulações de liberação modificada de 2-[3-[4-amino-3-(2-fluoro-4- fenoxi-fenil)pirazolo [3,4-d]pirimidin-1-il]piperidino-1- carbonil]-4-metil-4-[4-(oxetan-3-il)piperazin-1-il] pent-2-enenitrila |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1377736A (fr) * | 1962-12-21 | 1964-11-06 | Hoffmann La Roche | Procédé pour la préparation d'acides amino-carboxyliques |
FR1377366A (fr) | 1963-08-19 | 1964-11-06 | Dispositif de protection de sécurité pour appareils électriques | |
KR880007441A (ko) * | 1986-12-11 | 1988-08-27 | 알렌 제이.스피겔 | 스피로-치환된 글루타르아미드 이뇨제 |
AU7168091A (en) | 1989-12-22 | 1991-07-24 | Schering Corporation | Mercaptocycloacyl aminoacid endopeptidase inhibitors |
US5614498A (en) | 1990-06-07 | 1997-03-25 | Banyu Pharmaceutical Co., Ltd. | Endothelin antagonistic substance |
US5011066A (en) * | 1990-07-27 | 1991-04-30 | Motorola, Inc. | Enhanced collapse solder interconnection |
US5239113A (en) | 1991-10-15 | 1993-08-24 | Monsanto Company | Substituted β-amino acid derivatives useful as platelet aggregation inhibitors and intermediates thereof |
EP0561758A3 (en) | 1992-03-18 | 1995-04-05 | Monsanto Co | Method of preparing optically active homo-beta-amino acids |
US5578606A (en) * | 1992-10-30 | 1996-11-26 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors |
AU684878B2 (en) | 1993-11-24 | 1998-01-08 | Merck & Co., Inc. | Compounds and the use thereof to promote the release of growth hormone(s) |
WO1995015684A1 (en) | 1993-12-12 | 1995-06-15 | Agrogene, Ltd. | A novel method to protect plants from fungal infection |
US5472830A (en) | 1994-04-18 | 1995-12-05 | Ocg Microelectronic Materials, Inc. | Non-corrosion photoresist stripping composition |
DE69709742T2 (de) | 1996-07-12 | 2002-08-08 | Searle & Co | Asymmetrische synthese von chiralen beta-aminosäuren |
DE69737719D1 (de) * | 1996-10-23 | 2007-06-21 | Warner Lambert Co | Substituierte gamma-aminobuttersäurederivate als arzneimittel |
US6306909B1 (en) * | 1997-03-12 | 2001-10-23 | Queen's University At Kingston | Anti-epileptogenic agents |
GB2323594A (en) | 1997-03-25 | 1998-09-30 | Victor Martin | 2-amino-alkanoic acid derivatives, 2-amino alcohols and diamines |
US6201023B1 (en) | 1997-06-10 | 2001-03-13 | Agrogene Ltd. | Methods and compositions to protect crops against plant parasitic nematodes |
US6011066A (en) | 1998-02-02 | 2000-01-04 | Veterans General Hospital-Taipei | Method for treating septic shock |
US6153591A (en) | 1998-03-16 | 2000-11-28 | Cytovia, Inc. | Dipeptide caspase inhibitors and the use thereof |
EP1013769A1 (en) | 1998-12-22 | 2000-06-28 | Dsm N.V. | Process for the enzymatic preparation of amino acid derivatives with enhanced optical purity |
FR2791982B1 (fr) | 1999-04-06 | 2002-12-27 | Inst Nat Sante Rech Med | Inhibiteurs de lta4 hydrolase et leurs applications therapeutiques. |
DZ3253A1 (fr) * | 1999-06-10 | 2000-12-21 | Warner Lambert Co | Acides 3-propyle gamma-aminobutyriques monosubstitues et disubstitues |
AU2001259627A1 (en) * | 2000-05-16 | 2001-11-26 | Warner Lambert Company | Cell line for the expression of an alpha2delta2 calcium channel subunit |
US20030171434A1 (en) | 2000-05-17 | 2003-09-11 | Jackson Richard Francis William | Branched amino acids |
EP1317426B1 (de) | 2000-09-14 | 2005-11-16 | Grünenthal GmbH | Beta-thio-aminosäuren |
DE10048715A1 (de) | 2000-09-30 | 2004-05-19 | Grünenthal GmbH | Verwendung von Aminosäure zur Behandlung von Schmerz |
WO2002073208A2 (en) * | 2001-03-13 | 2002-09-19 | Queen's University At Kingston | Anti-epileptogenic agents |
NI200300043A (es) * | 2002-03-28 | 2003-11-05 | Warner Lambert Co | AMINOACIDOS CON AFINIDAD POR LA PROTEINA a2DELTA. |
GB0219024D0 (en) * | 2002-08-15 | 2002-09-25 | Pfizer Ltd | Synergistic combinations |
CN1228312C (zh) * | 2002-12-27 | 2005-11-23 | 中国科学院化学研究所 | 以酮为原料合成β—氨基酸的方法 |
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