CN109071392B - 苯环衍生物及其制备方法和在医药上的应用 - Google Patents
苯环衍生物及其制备方法和在医药上的应用 Download PDFInfo
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- CN109071392B CN109071392B CN201780020343.6A CN201780020343A CN109071392B CN 109071392 B CN109071392 B CN 109071392B CN 201780020343 A CN201780020343 A CN 201780020343A CN 109071392 B CN109071392 B CN 109071392B
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- Prior art keywords
- cyclopropylethyl
- compound
- hydroxy
- isopropyl
- phenyl
- Prior art date
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 206010002091 Anaesthesia Diseases 0.000 claims description 19
- 230000037005 anaesthesia Effects 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 15
- 241001465754 Metazoa Species 0.000 claims description 14
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 12
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 8
- 208000019901 Anxiety disease Diseases 0.000 claims description 5
- 230000036506 anxiety Effects 0.000 claims description 5
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- 206010028813 Nausea Diseases 0.000 claims description 4
- 206010047700 Vomiting Diseases 0.000 claims description 4
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- 230000000147 hypnotic effect Effects 0.000 claims description 4
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- 229910003827 NRaRb Chemical group 0.000 claims description 2
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- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000932 sedative agent Substances 0.000 claims 1
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- 229940002612 prodrug Drugs 0.000 abstract description 17
- 239000000651 prodrug Substances 0.000 abstract description 17
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- 230000005496 eutectics Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
- 238000006243 chemical reaction Methods 0.000 description 58
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 52
- 125000000623 heterocyclic group Chemical group 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 230000002829 reductive effect Effects 0.000 description 36
- 229910052731 fluorine Inorganic materials 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 239000000460 chlorine Substances 0.000 description 31
- 229910052739 hydrogen Inorganic materials 0.000 description 31
- 229910052801 chlorine Inorganic materials 0.000 description 30
- 229910052794 bromium Inorganic materials 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
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- 125000000217 alkyl group Chemical group 0.000 description 25
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
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- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 239000001257 hydrogen Substances 0.000 description 13
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 13
- 229960004134 propofol Drugs 0.000 description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
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- 238000003756 stirring Methods 0.000 description 10
- CFBALVDNCZBXAM-UHFFFAOYSA-N 2,6-bis(1-cyclopropylethenyl)aniline Chemical compound C1(CC1)C(=C)C1=C(N)C(=CC=C1)C(=C)C1CC1 CFBALVDNCZBXAM-UHFFFAOYSA-N 0.000 description 9
- YNXOPVFLVURFBJ-GHMZBOCLSA-N 3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxybenzaldehyde Chemical compound C1(CC1)[C@@H](C)C=1C=C(C=O)C=C(C=1O)[C@H](C)C1CC1 YNXOPVFLVURFBJ-GHMZBOCLSA-N 0.000 description 9
- WKMUTGGKHZJGQU-SNVBAGLBSA-N 3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-propan-2-ylbenzaldehyde Chemical compound C1(CC1)[C@@H](C)C=1C=C(C=O)C=C(C=1O)C(C)C WKMUTGGKHZJGQU-SNVBAGLBSA-N 0.000 description 9
- HFGWURPIPFWSMT-VXGBXAGGSA-N 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxyphenyl]propanoic acid Chemical compound C1(CC1)[C@@H](C)C=1C=C(C=C(C=1O)[C@H](C)C1CC1)CCC(=O)O HFGWURPIPFWSMT-VXGBXAGGSA-N 0.000 description 9
- WCMCKSSGIRVCPR-LLVKDONJSA-N 3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-propan-2-ylphenyl]propanoic acid Chemical compound C1(CC1)[C@@H](C)C=1C=C(C=C(C=1O)C(C)C)CCC(=O)O WCMCKSSGIRVCPR-LLVKDONJSA-N 0.000 description 9
- YUABFMHBHPKCMI-NXEZZACHSA-N 4-amino-2,6-bis[(1R)-1-cyclopropylethyl]phenol Chemical compound NC1=CC(=C(C(=C1)[C@H](C)C1CC1)O)[C@H](C)C1CC1 YUABFMHBHPKCMI-NXEZZACHSA-N 0.000 description 9
- HQVWIWRRLZPGOA-SECBINFHSA-N 4-amino-2-[(1R)-1-cyclopropylethyl]-6-propan-2-ylphenol Chemical compound NC1=CC(=C(C(=C1)C(C)C)O)[C@H](C)C1CC1 HQVWIWRRLZPGOA-SECBINFHSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 125000003545 alkoxy group Chemical group 0.000 description 9
- HWWWRHHBNVGLJC-UHFFFAOYSA-N 2-(1-cyclopropylethyl)-6-propan-2-ylaniline Chemical compound C1(CC1)C(C)C1=C(N)C(=CC=C1)C(C)C HWWWRHHBNVGLJC-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- AYELTTQNFGMJLE-GHMZBOCLSA-N N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxyphenyl]acetamide Chemical compound C1(CC1)[C@@H](C)C=1C=C(C=C(C=1O)[C@H](C)C1CC1)NC(C)=O AYELTTQNFGMJLE-GHMZBOCLSA-N 0.000 description 8
- QYKSUMFJELUCDK-HUUCEWRRSA-N N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxyphenyl]benzamide Chemical compound C1(CC1)[C@@H](C)C=1C=C(C=C(C=1O)[C@H](C)C1CC1)NC(C1=CC=CC=C1)=O QYKSUMFJELUCDK-HUUCEWRRSA-N 0.000 description 8
- PZUGGGMHTYKRTR-SNVBAGLBSA-N N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-propan-2-ylphenyl]acetamide Chemical compound C1(CC1)[C@@H](C)C=1C=C(C=C(C=1O)C(C)C)NC(C)=O PZUGGGMHTYKRTR-SNVBAGLBSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 230000008034 disappearance Effects 0.000 description 7
- CCCFFHFAVPIPNL-GHMZBOCLSA-N 2,6-bis[(1R)-1-cyclopropylethyl]aniline Chemical compound C1(CC1)[C@@H](C)C1=C(N)C(=CC=C1)[C@H](C)C1CC1 CCCFFHFAVPIPNL-GHMZBOCLSA-N 0.000 description 6
- CCCFFHFAVPIPNL-QWRGUYRKSA-N 2,6-bis[(1S)-1-cyclopropylethyl]aniline Chemical compound C1(CC1)[C@H](C)C1=C(N)C(=CC=C1)[C@@H](C)C1CC1 CCCFFHFAVPIPNL-QWRGUYRKSA-N 0.000 description 6
- HWWWRHHBNVGLJC-SNVBAGLBSA-N 2-[(1R)-1-cyclopropylethyl]-6-propan-2-ylaniline Chemical compound C1(CC1)[C@@H](C)C1=C(N)C(=CC=C1)C(C)C HWWWRHHBNVGLJC-SNVBAGLBSA-N 0.000 description 6
- HWWWRHHBNVGLJC-JTQLQIEISA-N 2-[(1S)-1-cyclopropylethyl]-6-propan-2-ylaniline Chemical compound C1(CC1)[C@H](C)C1=C(N)C(=CC=C1)C(C)C HWWWRHHBNVGLJC-JTQLQIEISA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 5
- WJBLTOCHTFVENE-GHMZBOCLSA-N [3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxyphenyl] formate Chemical compound C(=O)OC1=CC(=C(C(=C1)[C@H](C)C1CC1)O)[C@H](C)C1CC1 WJBLTOCHTFVENE-GHMZBOCLSA-N 0.000 description 5
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- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 4
- 125000006706 (C3-C6) carbocyclyl group Chemical group 0.000 description 4
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- KQNJKMNZDVSXAI-LLVKDONJSA-N N-[2-[(1R)-1-cyclopropylethyl]-6-propan-2-ylphenyl]acetamide Chemical compound C1(CC1)[C@@H](C)C1=C(C(=CC=C1)C(C)C)NC(C)=O KQNJKMNZDVSXAI-LLVKDONJSA-N 0.000 description 4
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- AXZSNQXORDPYIA-CHWSQXEVSA-N methyl 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxyphenyl]propanoate Chemical compound C1(CC1)[C@@H](C)C=1C=C(C=C(C=1O)[C@H](C)C1CC1)CCC(=O)OC AXZSNQXORDPYIA-CHWSQXEVSA-N 0.000 description 4
- LDPVRDBJTIFXJX-GFCCVEGCSA-N methyl 3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-propan-2-ylphenyl]propanoate Chemical compound COC(CCC1=CC(=C(C(=C1)C(C)C)O)[C@H](C)C1CC1)=O LDPVRDBJTIFXJX-GFCCVEGCSA-N 0.000 description 4
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- A—HUMAN NECESSITIES
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Abstract
涉及一种苯环衍生物及其制备方法和在医药上的应用,具体而言涉及如通式(A)所示的苯环衍生物,或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶,其制备方法、包含其的药物组合物以及化合物或者组合物在中枢神经领域的用途,其中,通式(A)中各取代基的定义与说明书的定义相同。
Description
技术领域
本发明涉及一种通式(A)所示的苯环衍生物,或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或者共晶,其制备方法、药物组合物以及本发明化合物在中枢神经领域的用途。
背景技术
GABAA受体是中枢神经系统中主要的抑制性神经递质受体。GABAA受体由跨膜多肽亚基的五聚体构成,19种不同的亚基组成了多种不同的GABAA受体亚型。GABAA受体涉及麻醉、抑郁、焦虑、癫痫、记忆障碍、药物依赖等多种疾病的发病机制和诊断治疗。因此,GABAA受体是药理学和临床上重要的药物作用靶点。丙泊酚及其衍生物即是一类重要的以GABAA为靶点的化合物。
丙泊酚可激活多种GABAA受体亚型,是一个临床上成熟的静脉麻醉药,广泛用于全身麻醉的诱导和维持。临床剂量相关的丙泊酚可直接激活哺乳动物神经元中的GABAA受体-氯离子通道复合体,增加氯离子传导,降低神经网络的兴奋性,进而引起全身麻醉(ManamiHara等(1993).Anesthesiology,79,781-788)。丙泊酚的显著药代动力学和药效学性质是起效快,维持时间短和快速可逆。静脉给药后,丙泊酚迅速从血液进入心、肺和肝等高灌注区,高脂溶性使丙泊酚容易跨越血脑屏障进入大脑发挥全身麻醉作用。
然而,丙泊酚也有显而易见的局限性和缺点。据报道,约70%的病人在注射丙泊酚时有一定程度的疼痛或者不适(Pascale Picard(2000).Anesthesia&Analgesia,90,963-969),有报道认为是脂质乳剂水相中的丙泊酚导致的注射疼痛(Klement W等,1991,Br JAnaesth 67,281),几项研究报道了与DIPRIVAN的水相中的丙泊酚含量相比,当丙泊酚的水相浓度降低时注射疼痛显著降低(Doenicke AW等,1996,Anesth Analg 82,472;Ueki R等,2007,J Anesth 21,325)。虽然有报道用其他药物预处理或者联合用药的方法可降低丙泊酚注射疼痛的发生率和严重程度(C.H.Tan等(1998).Anaesthesia,53,302-305),但这种疼痛仍难以避免。丙泊酚已被证明可降低收缩压,舒张压和平均动脉血压,因此在临床上会引起低血压。同时,呼吸抑制也是使用丙泊酚时不可忽视的风险。这些不良反应很大程度上阻碍了丙泊酚在一些临床病例中的应用,如心血管疾病,脑损伤和慢性低血压。
鉴于丙泊酚的局限性和缺点,需要开发新的具有更好药代动力学和药效学特性,且有较少副作用的GABAA受体激动剂。
发明内容
本发明的目的在于提供一种结构新颖、药效好、安全、可口服的GABAA受体激动剂,或者其立体异构体、药学上可接受的盐或前药,制备方法、药物组合物以及其在中枢神经领域上的用途,以便促进镇静催眠,治疗和预防焦虑、恶心、呕吐、偏头痛、惊厥、癫痫、神经变性疾病、脑保护以及中枢神经系统相关的疾病提供更多更优的药物选择途径。
本发明涉及一种通式(A)所示的化合物,或者其所有的立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶:
其中:
R1、R2、R3、R8、R9、R10和R11各自独立选自H、F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基,所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代,所述的杂环基含有1至2个选自N、O或者S的杂原子,且R1、R2和R3不同时为H;
作为选择,R1与R2、R2与R3、R1与R3、R8与R9或者R10与R11任意一组可以与同其相连接的碳原子形成一个3至8元碳环基或者3至8元杂环基,所述3至8元碳环基或者3至8元杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基取代,所述的杂环基含有1至2个选自N、O或者S的杂原子;
R4选自H、C2-8烷基、3至8元碳环基或者3至8元杂环基,所述的烷基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代,所述的杂环基含有1至2个选自N、O或者S的杂原子;
R5或者R6各自独立选自H、F、Cl、Br、I、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基,所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至8元碳环基或者3至8元杂环基的取代基所取代,所述的杂环基含有1至2个选自N、O或者S的杂原子,且R5和R6不同时为H;
作为选择,R5与R6可以与同其相连接的碳原子形成一个3至8元环,所述3至8元环可以含有0至2个选自N、O或者S的杂原子,且形成的3至8元环可以任选进一步被0至4个R12所取代;
R7选自H、F、Cl、Br、I、羟基或者C1-8烷氧基;
R12选自F、Cl、Br、I、C1-8烷基、C1-8烷氧基、羟基、-COOH、氨基、羧酸酯基、酰胺基、3至8元碳环基或者3至8元杂环基,所述的杂环基含有1至2个选自N、O或者S的杂原子;
X选自羟基或者NRaRb;
Y选自H、F或者-(CRyaRyb)m-(W1)-C(=O)(W2Ryc),且X为羟基时,Y不为H、F或者-COOH;
Ra或者Rb各自独立地选自H、C1-8烷基或者-C(=O)(W2Ryc);
W1或者W2各自独立地选自NRyc、O、S或者不存在;
Rya或者Ryb各自独立的选自H或者C1-6烷基;
Ryc选自H、C1-6烷基、C3-8碳环基或者3至8元杂环基,所述的烷基、碳环基或者杂环基可以任选进一步被0至5个选自H、F、Cl、Br、I、羟基、氨基、氰基、-COOH、C1-6烷基、C1-6烷氧基、C3-8碳环基或者3至8元杂环基的取代基所取代,所述的杂环基含有1至2个选自N、O或者S的杂原子;
m选自0、1、2或者3;
n选自1、2或者3,优选1或者2,更优选1。
本发明优选方案,包括通式(A-I)或者(A-II)所示的化合物,或者其所有的立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶:
其中:
R1、R2、R3、R8、R9、R10和R11各自独立选自H、F、Cl、Br、I、羟基、C1-6烷基、C1-6烷氧基、3至6元碳环基或者3至6元杂环基,优选H、F、Cl、C1-6烷基或者3至6元碳环基,所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-8烷基、C1-8烷氧基、3至6元碳环基或者3至6元杂环基的取代基所取代,所述的杂环基含有1至2个选自N、O或者S的杂原子,且R1、R2和R3不同时为H;
作为选择,R1与R2、R2与R3、R1与R3、R8与R9或者R10与R11任意一组可以与同其相连接的碳原子形成一个3至6元碳环基或者3至6元杂环基,所述3至6元碳环基或者3至6元杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-6烷基、C1-6烷氧基、3至6元碳环基或者3至6元杂环基所取代,优选进一步被0至5个选自F、Cl、Br、C1-6烷基、C1-6烷氧基或者3至6元碳环基所取代,所述的杂环基含有1至2个选自N、O或者S;
R4选自H、C2-6烷基、3至6元碳环基或者3至6元杂环基,所述的烷基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-6烷基、C1-6烷氧基、3至6元碳环基或者3至6元杂环基的取代基所取代,所述的杂环基含有1至2个选自N、O或者S的杂原子;
R5或者R6各自独立选自H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、3至6元碳环基或者3至6元杂环基,所述的烷基、烷氧基、碳环基或者杂环基任选进一步被0至5个选自F、Cl、Br、I、羟基、C1-6烷基、C1-6烷氧基、3至6元碳环基或者3至6元杂环基的取代基所取代,所述的杂环基含有1至2个选自N、O或者S的杂原子,且R5和R6不同时为H;
作为选择,R5与R6可以与同其相连接的碳原子形成一个3至6元环,所述3至6元环可以含有0至2个选自N、O或者S的杂原子,且形成的3至6元环可以任选进一步被0至4个R12所取代;
R7选自H、F、Cl、Br、I、羟基或者C1-6烷氧基;
R12选自F、Cl、Br、I、C1-6烷基、C1-6烷氧基、羟基、-COOH、氨基、羧酸酯基、酰胺基、3至6元碳环基或者3至6元杂环基,所述的杂环基含有1至2个选自N、O或者S的杂原子;
Y’选自-(CRyaRyb)m-(W1)-C(=O)(W2Ryc),且Y’不为-COOH;
Y选自H、F或者-(CRyaRyb)m-(W1)-C(=O)(W2Ryc);
Ra、Rb各自独立地选自H、C1-6烷基或者-C(=O)(W2Ryc);
W1、W2各自独立地选自NRyc、O、S或者不存在;
Rya、Ryb各自独立的选自H或者C1-6烷基;
Ryc选自H、C1-6烷基、C3-6碳环基或者3至6元杂环基,所述的烷基、碳环基或者杂环基可以任选进一步被0至5个选自H、F、Cl、Br、I、羟基、氨基、氰基、-COOH、C1-6烷基、C1-6烷氧基、C3-6碳环基或者3至6元杂环基的取代基所取代,所述的杂环基含有1至2个选自N、O或者S的杂原子;
m选自0、1、2或者3;
n选自1、2或者3,优选1或者2,更优选1。
本发明优选方案,包括通式(A-I)或者(A-II)所示的化合物,或者其所有的立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶:
其中:
R1、R2、R3、R8、R9、R10和R11各自独立地选自H、F、Cl、Br、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、羟基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、羟基甲基、羟基乙基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、环丙基、环丁基、环戊基或者环己基,且R1、R2和R3不同时为H;
作为选择,R1与R2、R2与R3、R1与R3、R8与R9或者R10与R11任意一组可以与同其相连接的碳原子形成环丙基、环丁基、环戊基或者环己基;
R4选自H、CH2CH2F、CHFCH3、CHFCH2F、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、羟基乙基、环丙基、环丁基、环戊基或者环己基;
R5和R6各自独立选自H、F、Cl、Br、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、羟基甲基、羟基乙基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、环丙基、环丁基、环戊基或者环己基,且R5和R6不同时为H;
作为选择,R5与R6可以与同其相连接的碳原子形成环丙基、环丁基、环戊基或者环己基;
R7选自H、F、Cl、Br、I、羟基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基或者叔丁氧基;
R12选自F、Cl、Br、I、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、羟基、-COOH、氨基、羧酸酯基、酰胺基、环丙基、环丁基、环戊基或者环己基;
Y’选自-C(=O)(Ryc)、-CH(CH3)C(=O)(Ryc)、-CH2CH2C(=O)(Ryc)、-OC(=O)(Ryc)、-CH2OC(=O)(Ryc)、-CH(CH3)OC(=O)(Ryc)、-CH2CH2OC(=O)(Ryc)、-NRycC(=O)(Ryc)、-CH2NRycC(=O)(Ryc)、-CH(CH3)NRycC(=O)(Ryc)、-CH2CH2NRycC(=O)(Ryc)、-C(=O)(ORyc)、-CH2C(=O)(ORyc)、-CH(CH3)C(=O)(ORyc)、-CH2CH2C(=O)(ORyc)、-C(=O)(NRycRyc)、-CH2C(=O)(NRycRyc)、-CH(CH3)C(=O)(NRycRyc)或者-CH2CH2C(=O)(NRycRyc),且Y’不为-COOH;
Y选自H、F、-C(=O)(Ryc)、-CH(CH3)C(=O)(Ryc)、-CH2CH2C(=O)(Ryc)、-OC(=O)(Ryc)、-CH2OC(=O)(Ryc)、-CH(CH3)OC(=O)(Ryc)、-CH2CH2OC(=O)(Ryc)、-NRycC(=O)(Ryc)、-CH2NRycC(=O)(Ryc)、-CH(CH3)NRycC(=O)(Ryc)、-CH2CH2NRycC(=O)(Ryc)、-C(=O)(ORyc)、-CH2C(=O)(ORyc)、-CH(CH3)C(=O)(ORyc)、-CH2CH2C(=O)(ORyc)、-C(=O)(NRycRyc)、-CH2C(=O)(NRycRyc)、-CH(CH3)C(=O)(NRycRyc)或者-CH2CH2C(=O)(NRycRyc);
Ra、Rb各自独立地选自H、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、或者-C(=O)(Ryc);
Ryc选自H、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基、苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、3-甲氧基苯基或者4-甲氧基苯基;
m选自0、1、2或者3;
n选自1、2或者3,优选1或者2,更优选1。
本发明优选方案,包括通式(A-I)或者(A-II)所示的化合物,或者其所有的立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶:
其中:
R1、R2、R3、R8、R9、R10和R11各自独立地选自H、甲基、乙基、正丙基、异丙基、环丙基或者环丁基,且R1、R2和R3不同时为H;
R5和R6各自独立选自H、甲基、乙基、正丙基或异丙基,且R5和R6不同时为H;
R7选自H;
Y’选自-(CRyaRyb)m-(W1)-C(=O)(W2Ryc),且Y’不为-COOH;
Y选自H、F或者-(CRyaRyb)m-(W1)-C(=O)(W2Ryc);
Ra、Rb各自独立地选自H、C1-6烷基或者-C(=O)(W2Ryc);
W1、W2各自独立地选自NRyc、O、S或者不存在;
Rya、Ryb各自独立的选自H或者C1-6烷基;
Ryc选自H、C1-6烷基、C3-6碳环基或者3至6元杂环基,所述的烷基、碳环基或者杂环基可以任选进一步被0至5个选自H、F、Cl、Br、I、羟基、氨基、氰基、-COOH、C1-6烷基、C1-6烷氧基、C3-6碳环基或者3至6元杂环基的取代基所取代,所述的杂环基含有1至2个选自N、O或者S的杂原子;
m选自0、1、2或者3;
n选自1。
本发明优选方案,包括通式(A-I)或者(A-II)所示的化合物,或者其所有的立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶:
其中:
R1、R2、R3、R8、R9、R10和R11各自独立地选自H、甲基、乙基、正丙基、异丙基、环丙基或者环丁基,且R1、R2和R3不同时为H;
R5和R6各自独立选自H、甲基、乙基、正丙基或异丙基,且R5和R6不同时为H;
R7选自H;
Y’选自-OC(=O)(Ryc)、-NRycC(=O)(Ryc)或-CH2CH2C(=O)(ORyc);
Y选自H;
Ryc选自H、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、环丙基、苯基;
n选自1。
本发明优选方案,包括通式(A-I)或者(A-II)所示的化合物,或者其所有的立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或者共晶:
其中:
R1、R2、R3、R8、R9、R10和R11各自独立地选自H、甲基、或者环丙基,且R1、R2和R3不同时为H;
R5和R6各自独立选自H或者甲基,且R5和R6不同时为H;
R7选自H;
Y’选自-OC(=O)(Ryc)、-NRycC(=O)(Ryc)或-CH2CH2C(=O)(ORyc);
Y选自H;
Ryc选自H、甲基或者苯基;
n选自1。
本发明优选方案,本发明涉及的前药化合物选自,但不限于:
本发明涉及一种药物组合物,所述的药物组合物包括通式通式(A)所述的化合物或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药,和一种或者多种药学上可接受的载体和/或者赋形剂。
本发明涉及一种通式(A)所示的化合物,或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药,在制备诱导和维持动物或者人类的麻醉、促进动物或者人类的镇静催眠、脑保护、脑卒中、治疗和/或者预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神分裂、惊厥或者癫痫药物中的用途,优选在制备诱导和维持动物或者人类的麻醉药物中的用途。
本发明使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或者F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或者氮任选进一步被一个或者多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素包括17F和19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”是指1至20个碳原子的直链或者支链饱和脂肪族烃基,优选为1至8个碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体。
“烷氧基”是指-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。。
“氨基”是指-NH2。
“烷基氨基”是指具有一个或者两个烷基取代基的氨基基团。
“羟基”是指-OH。
“羧基”是指-COOH。
“羰基”是指-(C=O)-。
“羧酸酯基”是指-COOR14,其中R14为C1-6烷基。
“酰胺基”是指-CONR15R16,其中R15和R16各自独立选自H、烷基或者碳环基。
“=O”为本领域通常习惯用法,是指以双键相连的氧原子,譬如羰基中与碳原子相连的双键氧原子。
“碳环基”是指饱和或者不饱和的芳香环或者非芳香环,芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系,碳环基可以连接有桥环或者螺环,非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基和环十二烷基、环己烯、
“杂环基”是指取代的或者未取代的饱和或者不饱和的芳香环或者非芳香环,芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系,且包含1至3个选自N、O或者S的杂原子,优选3至8元杂环基,杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上,杂环基可以连接有桥环或者螺环,非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。所述的无机碱的非限制性实施例包括Al、Ca、Li、Mg、K、Na和Zn;所述的有机碱的非限制性实施例包括氨、异丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、四甲基胺、二乙醇胺、乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、咖啡碱、普鲁卡因、胆碱、甜菜碱、苯明青霉素、乙二胺、葡萄糖胺、N-甲基甲基葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶和聚胺树脂;所述的无机酸和有机酸的非限制性实施例包括硫酸、磷酸、硝酸、氢溴酸、盐酸、甲酸、乙酸、丙酸、苯磺酸、苯甲酸、苯乙酸、水杨酸、褐藻酸、氨茴酸、樟脑酸、柠檬酸、乙烯磺酸、蚁酸、富马酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、乙醇酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘液酸、双羟萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、对甲苯磺酸、丙二酸、2-羟基丙酸、草酸、羟乙酸、葡萄糖醛酸、半乳糖醛酸、枸橼酸、赖氨酸、精氨酸、门冬氨酸、肉桂酸、对甲苯磺酸、甲磺酸、乙磺酸和三氟甲磺酸。
“药物组合物”是指一种或者多种本发明所述化合物、其药学上可接受的盐或者前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或者一种或者多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的酚基团来制备,该修饰可以通过常规的操作或者在体内被除去,而得到母体化合物。当本发明的前药被施予哺乳动物个体时,前药被割裂形成游离的羟基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或者其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或者溶剂化物形成的多元共晶。
“动物”是指包括哺乳动物,例如人、陪伴动物、动物园动物和家畜,优选人、马或者犬。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“任选”或者“任选地”或者“选择性的”或者“选择性地”是指随后所述的事件或者状况可以但未必发生,该描述包括其中发生该事件或者状况的情况及其中未发生的情况。例如,“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
本文所述“作为选择”是指一种并列的存在关系,比如“Ra与Rb各自独立选自烷基、烷氧基;作为选择,Ra与Rb形成芳环”,表示的Ra与Rb形成芳环与Ra与Rb各自独立选自烷基或烷氧基是一种并列的关系,不受彼此定义的限制。
麻醉诱导时间和麻醉维持时间:给药后开始计时,密切观察动物一般症状和给药局部、呼吸的变化。如正常动物将其推倒或者呈背位仰卧时,能立即翻正过来,这种反射判为翻正反射。反之,则视为翻正反射消失,记录反射消失时间,待动物重新出现翻正反射时,记录反射恢复时间。将给药结束至翻正反射的时间记为麻醉起效时间,自翻正反射消失至反射恢复时间记为麻醉维持时间。
具体实施方式
以下结合附图及实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或者(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或者青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm;
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体;
本发明的己知起始原料可以采用或者按照本领域已知的方法来合成,或者可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司;
氮气氛是指反应瓶连接一个约1L容积的氮气气球;
氢气氛是指反应瓶连接一个约1L容积的氢气气球;
氢化反应通常抽真空,充入氢气,反复操作3次;
实施例中无特殊说明,反应在氮气氛下进行;
实施例中无特殊说明,溶液是指水溶液;
实施例中无特殊说明,反应的温度为室温,室温最适宜的反应温度,为20℃~30℃;
DMSO,二甲基亚砜。
实施例1
[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]甲酸酯(化合物1)
[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]formate
第一步:3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯甲醛(1B)
3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-benzaldehyde
反应瓶加入2-[(1R)-1-环丙基乙基]-6-异丙基-苯酚(1A)(10g,48.94mmol)和醋酸(100mL),搅拌均匀后分批加入乌洛托品(54.89g,391.56mmol),加完后加热到100℃反应20小时。向反应液中加入水(500mL),用乙酸乙酯(100mL x 3)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=20∶1)得到黄色固体产物3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯甲醛(1B)(3.5g,收率:30.78%)。
第二步:[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]甲酸酯(化合物1)
[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]formate
向反应瓶加入加入3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯甲醛(1B)(10.0g,43.04mmol)和二氯甲烷(200mL),搅拌均匀后分批加间氯过氧苯甲酸(11.14g,64.57mmol),加完后室温反应4小时。向反应液中加入水(500mL),分液,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=20∶1)得到黄色固体[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]甲酸酯(化合物1)(7.5g,收率:70.17%)。
MS m/z(ESI):247.1(M-1).
1HNMR:(400MHz,CDCl3):δ8.30(s,1H),6.89(d,1H),6.81(d,1H),4.92(s,1H),3.19-3.12(m,1H),2.50-2.46(m,1H),1.29(d,3H),1.25(dd,6H),1.04-0.96(m,1H),0.62-0.45(m,2H),0.26-0.14(m,1H).
实施例2
[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]甲酸酯(化合物2)
[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]formate
第一步:3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯甲醛(2B)
3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-benzaldehyde
反应瓶中加入2,6-二[(1R)-1-环丙基乙基]苯酚(2A)(4.0g,17.36mmol)和醋酸(50mL),搅拌均匀后分批加入乌洛托品(19.47g,138.92mmol),加完后加热到100℃反应20小时。向反应液中加入水(100mL),用乙酸乙酯(50mL x 3)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=20∶1)得到黄色固体3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯甲醛(2B)(1.5g,收率:33.43%)。
第二步:[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]甲酸酯(化合物2)
[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]formate
反应瓶中加入加入3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯甲醛(2B)(1.0g,3.87mmol)和二氯甲烷(20mL),搅拌均匀后分批加入间氯过氧苯甲酸(1.0g,5.81mmol),加完后室温反应4小时。向反应液中加入水(50mL),分液,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=20∶1)得到黄色固体[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]甲酸酯(化合物2)(0.7g,收率:65.92%)。
MS m/z(ESI):273.1(M-1).
1HNMR:(400MHz,CDCl3):δ8.31(s,1H),6.90(d,2H),5.03(s,1H),2.50-2.45(m,2H),1.28(d,6H),1.01-0.97(m,2H),0.58-0.45(m,4H),0.24-0.16(m,4H).
实施例3
3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙酸甲酯(化合物3)
Methyl-3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoate
第一步:3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙烯酸甲酯(3B)
methyl-3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]prop-2-enoate
反应瓶中加入3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯甲醛(1B)(0.7g,3.0mmol),甲苯(10mL)和甲氧甲酰基亚甲基三苯基膦(3.0g,9.0mmol),升温至100℃反应14小时,冷却至室温后将反应液浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=30∶1)得到无色油状液体3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙烯酸甲酯(3B)(0.8g,产率:90%)。
第二步:3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙酸甲酯(化合物3)
Methyl-3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoate
反应瓶中依次加入3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙烯酸甲酯(3B)(0.8g,2.8mmol),甲醇(8mL)和Pd/C(0.24g,30%(w%)),室温反应4小时。反应液经硅藻土过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=20∶1)得到无色油状液体3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙酸甲酯(化合物3)(0.75g,产率:93%)。
MS m/z(ESI):289.1(M-1).
1HNMR(400MHz,CDCl3):δ6.93(d,1H,J=2.4Hz),6.88(d,1H,J=2.0Hz),4.82(brs,1H),3.68(s,3H),3.15-3.12(m,1H),2.89(t,2H,J=7.8Hz),2.63-2.59(m,2H),2.48-2.45(m,1H),1.29-1.24(m,9H),1.04-1.02(m,1H),0.56-0.45(m,2H),0.22-0.15(m,2H).
实施例4
3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙酸(化合物4)
3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoicacid
第一步:3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙酸(化合物4)
3-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]propanoicacid
反应瓶中放入3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙酸甲酯(化合物3)(0.75g,2.6mmol),甲醇(5mL)和水(2mL),加入NaOH(0.31g,7.7mmol),于70℃反应3小时,将反应液冷却后浓缩,残留物中加入水(10mL),用4M的HCl调节pH为5至6,用二氯甲烷(10mL x 2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(二氯甲烷/乙酸乙酯(V/V)=30∶1)得到无色油状液体3-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]丙酸(化合物4)(0.55g,产率:77%)。
MS m/z(ESI):275.1(M-1).
1HNMR(400MHz,CDCl3):δ6.95(d,1H,J=2.0Hz),6.89(d,1H,J=2.4Hz),3.17-3.10(m,1H),2.90(t,2H,J=8.0Hz),2.67-2.64(m,2H,),2.48-2.45(m,1H),1.29-1.24(m,9H),1.05-1.03(m,1H),0.57-0.46(m,2H),0.21-0.15(m,2H).
实施例5
3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙酸甲酯(化合物5)
methyl 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoate
第一步:3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙烯酸甲酯(5B)
Methyl 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]prop-2-enoate
反应瓶中放入3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯甲醛(2B)(1.1g,4.3mmol)和甲苯(6mL),加入甲氧甲酰基亚甲基三苯基膦(4.3g,13.0mmol),升温至100℃反应14小时。冷却至室温后将反应液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=30∶1)得到无色油状液体3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙烯酸甲酯(5B)(1.0g,产率:75%)。
第二步:3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙酸甲酯(化合物5)
methyl 3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoate
反应中依次加入3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙烯酸甲酯(5B)(1.0g,3.2mmol),甲醇(8mL)和Pd/C(0.3g,30%(w%)),室温搅拌4小时。反应液经硅藻土过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=20∶1)得到无色油状液体3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙酸甲酯(化合物5)(0.9g,产率:90%)。
MS m/z(ESI):315.3(M-1).
1HNMR(400MHz,CDCl3):δ6.94(s,2H),4.97(s,1H),3.68(s,3H),2.91-2.87(m,2H),2.64-2.60(m,2H),2.50-2.43(m,2H),1.28(d,6H,J=7.2Hz),1.05-1.00(m,2H),0.55-0.54(m,2H),0.46-0.44(m,2H),0.20-0.15(m,4H).
实施例6
3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙酸(化合物6)
3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoic acid
第一步:3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙酸(化合物6)
3-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]propanoic acid
反应瓶中加入3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙酸甲酯(化合物5)(0.4g,1.3mmol),甲醇(5mL),水(2mL)和氢氧化钠(0.15g,3.8mmol),70℃反应3小时。将反应液冷却后浓缩,加入水(10mL),用4M的HCl调节pH为5至6,用二氯甲烷(10mL x 2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(二氯甲烷/乙酸乙酯(V/V)=30∶1)得到无色油状液体3-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]丙酸(化合物6)(0.35g,产率:92%)。
MS m/z(ESI):301.2(M-1).
1HNMR(400MHz,CDCl3):δ6.96(s,2H),2.92-2.88(m,2H),2.69-2.65(m,2H),2.50-2.43(m,2H),1.28(d,6H,J=7.2Hz),1.06-1.00(m,2H),0.56-0.55(m,2H),0.46-0.45(m,2H),0.20-0.14(m,4H).
实施例7
N-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]乙酰胺(化合物7)
N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]acetamide
第一步:2,6-二[(1R)-1-环丙基乙基]-4-异亚硝基-2,5-二烯环己酮(7B)
2,6-bis[(1R)-1-cyclopropylethyl]-4-hydroxyimino-cyclohexa-2,5-dien-1-one
反应瓶中加入2,6-二[(1R)-1-环丙基乙基]苯酚(2A)(2.0g,8.7mmol)和无水乙醇(18mL),将体系冷却至-10℃,加入浓盐酸(1.2mL,14.8mmol),搅拌下滴加亚硝酸钠(0.66g,9.6mmol)溶于水(3.3mL)的溶液,加毕缓慢升至0℃反应5小时。向反应液中加入饱和碳酸氢钠溶液以调节pH为8至9,减压浓缩除去乙醇,加入水(20mL),用二氯甲烷(20mL x 2)萃取,无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=5∶1)得到浅棕色固体2,6-二[(1R)-1-环丙基乙基]-4-异亚硝基-2,5-二烯环己酮(7B)(1.8g,产率:80%)。
MS m/z(ESI):260.2(M+1).
第二步:4-胺基-2,6-二[(1R)-1-环丙基乙基]苯酚(7C)
4-amino-2,6-bis[(1R)-1-cyclopropylethyl]phenol
反应瓶中加入2,6-二[(1R)-1-环丙基乙基]-4-异亚硝基-2,5-二烯环己酮(7B)(0.67g,2.6mmol),甲醇(10mL)和Pd/C(0.2g,30%(w%)),体系用氢气置换3次,常温下氢化4小时。反应液经硅藻土过滤,滤液减压浓缩得棕色固体粗品4-胺基-2,6-二[(1R)-1-环丙基乙基]苯酚(7C)(0.63g),所得粗品直接用于下步反应。
MS m/z(ESI):246.3(M+1).
第三步:N-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]乙酰胺(化合物7)
N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]acetamide
反应瓶中加入粗品4-胺基-2,6-二[(1R)-1-环丙基乙基]苯酚(7C)(0.63g,2.6mmol)和二氯甲烷(5mL),加入三乙胺(1.1mL,7.7mmol),缓慢滴加乙酸酐(0.58g,5.6mmol),加完后室温搅拌16小时。反应液用水(5mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=10∶1-3∶1)得到白色固体粗品(1.8g),加入甲醇(5mL)使之溶解,加入碳酸钾(0.3g,4.9mmol),室温搅拌16小时。减压浓缩除去甲醇,加入水(20mL),用二氯甲烷(20mL x 2)萃取,无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=10∶1)得到白色固体N-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]乙酰胺(化合物7)(0.57g,产率:82%)。
MS m/z(ESI):288.2(M+1).
1HNMR(400MHz,CDCl3):δ7.26(s,1H),7.14(s,1H),2.51-2.44(m,2H),2.14(s,3H),1.28(d,6H,J=6.8Hz),1.04-1.00(m,2H),0.56-0.55(m,2H),0.46-0.45(m,2H),0.21-0.16(m,4H).
实施例8
N-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]苯甲酰胺(化合物8)
N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]benzamide
第一步:N-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]苯甲酰胺(化合物8)
N-[3,5-bis[(1R)-1-cyclopropylethyl]-4-hydroxy-phenyl]benzamide
反应瓶中加入4-胺基-2,6-二[(1R)-1-环丙基乙基]苯酚(7C)(0.82g,3.3mmol),二氯甲烷(10mL)和三乙胺(0.9mL,6.7mmol),缓慢滴加苯甲酰氯(0.52g,3.7mmol),加完后室温反应16小时。反应液用水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=10∶1-3∶1)得到白色固体粗品(1.2g),加入甲醇(6mL)和碳酸钾(1.0g,7.2mmol),50℃搅拌5小时。减压浓缩除去甲醇,加入水(20mL),用二氯甲烷(30mL x 2)萃取,无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=3∶1)得到类白色固体N-[3,5-二[(1R)-1-环丙基乙基]-4-羟基-苯基]苯甲酰胺(化合物8)(0.35g,产率:30%)。
MS m/z(ESI):350.2(M+1).
1HNMR(400MHz,CDCl3):δ7.88(d,2H,J=7.2Hz),7.72(s,1H),7.55-7.42(m,5H),5.00(s,1H),2.54-2.47(m,2H),1.31(d,6H,J=6.8Hz),1.09-1.03(m,2H),0.58-0.57(m,2H),0.49-0.48(m,2H),0.23-0.19(m,4H).
实施例9
N-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]乙酰胺(化合物9)
N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]acetamide
第一步:2-[(1R)-1-环丙基乙基]-4-异亚硝基-6-异丙基-2,5-二烯环己酮(9B)
2-[(1R)-1-cyclopropylethyl]-4-hydroxyimino-6-isopropyl-cyclohexa-2,5-dien-1-one
反应瓶中加入2-[(1R)-1-环丙基乙基]-6-异丙基-苯酚(1A)(5.0g,24.5mmol)和无水乙醇(25mL),体系降至-10℃,加入浓盐酸(3.5mL,41.6mmol),搅拌下滴加亚硝酸钠(1.9g,26.9mmol)溶于水(10mL)的溶液,加完后缓慢升至0℃反应5小时。反应液中加入饱和碳酸氢钠溶液调节pH为8至9,减压浓缩除去乙醇,加入水(20mL),用二氯甲烷(20mL x 2)萃取,无水硫酸钠干燥,过滤,滤液减压浓缩得到浅棕色固体2-[(1R)-1-环丙基乙基]-4-异亚硝基-6-异丙基-2,5-二烯环己酮(9B)(5.5g,产率:96%),直接用于下一步反应。
第二步:4-胺基-2-[(1R)-1-环丙基乙基]-6-异丙基苯酚(9C)
4-amino-2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenol
反应瓶中加入2-[(1R)-1-环丙基乙基]-4-异亚硝基-6-异丙基-2,5-二烯环己酮(9B)(1.5g,6.4mmol),甲醇(20mL),Pd/C(0.45g,30%(w%)),体系用氢气置换3次,常温下氢化反应4小时。反应液经硅藻土过滤,滤液减压浓缩得到棕色固体粗品4-胺基-2-[(1R)-1-环丙基乙基]-6-异丙基苯酚(9C)(1.4g),所得粗品直接用于下步反应。
第三步:N-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]乙酰胺(化合物9)
N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]acetamide
反应瓶中加入4-胺基-2-[(1R)-1-环丙基乙基]-6-异丙基苯酚(9C)(1.4g,6.4mmol),二氯甲烷(10mL)和三乙胺(2.7mL,19.2mmol),缓慢滴加乙酸酐(1.4g,14.0mmol),加毕于室温搅拌16小时。反应液用水(15mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=10∶1-3∶1)得到白色固体粗品(1.0g),加入甲醇(10mL)和碳酸钾(1.0g,7.2mmol),室温下搅拌16小时。减压浓缩除去甲醇,加入水(30mL),用4M的HCl调节pH为7,用二氯甲烷(20mL x 2)萃取,水相中析出白色固体,抽滤,得到N-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]乙酰胺(化合物9)(0.61g,产率:71%)。
MS m/z(ESI):262.2(M+1).
1HNMR(400MHz,CD3OD):δ7.16(d,1H,J=2.8Hz),7.08(d,1H,J=2.4Hz),3.20-3.14(m,1H),2.40-2.33(m,1H),1.97(s,3H),1.15-1.08(m,9H),0.91-0.89(m,1H),0.43-0.41(m,1H),0.26-0.25(m,1H),0.08-0.05(m,2H).
实施例10
N-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]苯甲酰胺(化合物10)
N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]benzamide
第一步:N-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]苯甲酰胺(化合物10)
N-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]benzamide
反应瓶中依次加入4-胺基-2-[(1R)-1-环丙基乙基]-6-异丙基苯酚(9C)(1.4g,2.6mmol),二氯甲烷(10mL)和三乙胺(1.8mL,13.0mmol),缓慢滴加苯甲酰氯(1.0g,7.0mmol),加完后室温搅拌16小时。反应液用水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=10∶1-3∶1)得到得白色固体粗品(2.0g),加入甲醇(10mL)和碳酸钾(1.0g,7.2mmol),升温至50℃搅拌5小时。减压浓缩除去甲醇,加入水(20mL),用二氯甲烷(30mL x 2)萃取,无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(V/V)=3∶1)得到类白色固体N-[3-[(1R)-1-环丙基乙基]-4-羟基-5-异丙基-苯基]苯甲酰胺(化合物10)(0.61g,产率:40%)。
MS m/z(ESI):324.2(M+1).
1HNMR(400MHz,CDCl3):δ7.89(d,2H,J=7.2Hz),7.71(s,1H),7.54-7.46(m,3H),7.41(s,1H),7.33(s,1H),4.87(s,1H),3.22-3.15(m,1H),2.54-2.47(m,1H),1.32-1.26(m,9H),1.09-1.06(m,1H),0.57-0.50(m,2H),0.23-0.19(m,2H).
实施例11
2,6-双[(1R)-1-环丙基乙基]苯胺(化合物11)
2,6-bis[(1R)-1-cyclopropylethyl]aniline
第一步:2,6-双(1-环丙基乙烯基)苯胺(11B)
2,6-bis(1-cyclopropylvinyl)aniline
向反应瓶中依次加入2,6-二溴苯胺(11A)(10.0g,39.9mmol),2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(23.2g,120.0mmol),七水磷酸钾(40.5g,120.0mmol),甲苯(100mL)和水(50mL),用水泵抽真空,氮气置换3次,加入醋酸钯(0.45g,2.0mmol)和2-二环己基磷-2′,6′-二异丙氧基-1,1′-联苯(Ruphos,1.86g,4.0mmol),再次用水泵抽真空,氮气置换3次,升温至90℃,氮气氛围下反应8小时。冷却至室温,过滤后分液,水相用乙酸乙酯(50mL x 3)萃取,合并有机相,用水(150mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)=50∶1-20∶1)得到淡黄色油状液体2,6-双(1-环丙基乙烯基)苯胺(11B)(7.58g,产率:84.4%)。
1HNMR(400MHz,CDCl3):δ6.87(d,2H),6.64(dd,1H),5.19(d,2H),4.94(d,2H),4.00(s,2H),1.68-1.62(m,2H),0.74-0.69(m,4H),0.48-0.45(m,4H).
第二步:2,6-双[(1R)-1-环丙基乙基]苯胺(化合物11)
2,6-bis[(1R)-1-cyclopropylethyl]aniline
室温下,向250mL的高压反应釜中加入2,6-双(1-环丙基乙烯基)苯胺(11B)(4.0g,17.8mmol)和二氯甲烷(30mL),加入催化剂[(R)-2,2′-双(二苯基膦)-1,1′-联萘]二乙酸钌(0.7g,0.83mmol),加完后将高压釜装置拧紧密封,用氢气置换3次,充入氢气,高压釜上的压力表压力显示为22atm,室温下反应30小时。减压浓缩除去溶剂,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)=30∶1)得到白色固体2,6-双[(1R)-1-环丙基乙基]苯胺(化合物11)(3.2g,产率:78.6%,手性HPLC:93.0%)。
MS m/z(ESI):230.2(M+1).
1HNMR(400MHz,CDCl3):δ7.14(d,2H),6.80(t,1H),3.62(s,2H),2.27-2.34(m,2H),1.29(d,6H),1.04-1.12(m,2H),0.52-0.59(m,2H),0.41-0.48(m,2H),0.06-0.17(m,4H).
实施例12
2,6-双[(1S)-1-环丙基乙基]苯胺(化合物12)
2,6-bis[(1S)-1-cyclopropylethyl]aniline
第一步:2,6-双[(1S)-1-环丙基乙基]苯胺(化合物12)
2,6-bis[(1S)-1-cyclopropylethyl]aniline
250mL的高压反应釜中室温下加入2,6-双(1-环丙基乙烯基)苯胺(11B)(4.0g,17.8mmol),二氯甲烷(30mL)和[(S)-2,2′-双(二苯基膦)-1,1′-联萘]二乙酸钌(0.7g,0.83mmol),加毕将高压釜装置拧紧密封,用氢气置换3次后充入氢气,高压釜上的压力表压力显示为22atm,室温下反应30小时。减压浓缩除去溶剂,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)=30∶1)得到淡黄色油状液体2,6-双[(1S)-1-环丙基乙基]苯胺(化合物12)(3.3g,产率:81.0%,手性HPLC:92.7%)。
MS m/z(ESI):230.2(M+1).
1HNMR(400MHz,CDCl3):δ7.14(d,2H),6.82(t,1H),3.62(s,2H),2.27-2.34(m,2H),1.31(d,6H),1.04-1.12(m,2H),0.52-0.59(m,2H),0.41-0.48(m,2H),0.06-0.17(m,4H).
实施例13
2-[(1R)-1-环丙基乙基]-6-异丙基苯胺(化合物13)
2-[(1R)-1-cyclopropylethyl]-6-isopropyl-aniline
第一步:2-(1-环丙基乙基)-6-异丙基苯胺(13B)
2-(1-cyclopropylvinyl)-6-isopropyl-aniline
向反应瓶中依次加入2-溴-6-异丙基苯胺(13A)(6.70g,31.29mmol),2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(9.10g,46.88mmol)),七水磷酸钾(31.76g,93.87mmol),甲苯(100mL)和水(50mL),用水泵抽真空,氮气置换3次,加入醋酸钯(0.35g,1.56mmol)和2-二环己基磷-2′,6′-二异丙氧基-1,1′-联苯(Ruphos,1.46g,3.12mmol),再次用水泵抽真空,氮气置换3次,升温至90℃,氮气氛围下反应4小时。冷却至室温,过滤后分液,水相用乙酸乙酯(50mL x 3)萃取,合并有机相,用水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)=50∶1-20∶1)得到淡黄色油状液体2-(1-环丙基乙基)-6-异丙基苯胺(13B)(4.86g,产率:77.1%)。
MS m/z(ESI):202.2(M+1).
1HNMR(400MHz,CDCl3):δ7.07(dd,1H),6.82(dd,1H),6.72(dd,1H),5.22(dd,1H),4.94(d,1H),3.83(s,2H),2.95-2.84(m,1H),1.68-1.62(m,1H),1.26(d,6H),0.73-0.68(m,2H),0.47-0.43(m,2H).
第二步:2-[(1R)-1-环丙基乙基]-6-异丙基苯胺(化合物13)
2-[(1R)-1-cyclopropylethyl]-6-isopropyl-aniline
250mL的高压反应釜中室温下加入2-(1-环丙基乙基)-6-异丙基苯胺(13B)(2.0g,9.94mmol),二氯甲烷(20mL)和[(R)-2,2′-双(二苯基膦)-1,1′-联萘]二乙酸钌(0.34g,0.40mmol),加毕将高压釜装置拧紧密封,用氢气置换3次,充入氢气,高压釜上的压力表压力显示为20atm,室温下反应30小时。减压浓缩除去溶剂,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)=30∶1)得到淡黄色油状液体2-[(1R)-1-环丙基乙基]-6-异丙基苯胺(化合物13)(1.52g,产率:75.3%,手性HPLC:98.53%)。
MS m/z(ESI):204.2(M+1).
1HNMR(400MHz,CDCl3):δ7.14(dd,1H),7.04(dd,1H),6.81(dd,1H),3.74(s,2H),2.98-2.90(m,1H),2.36-2.29(m,1H),1.30(d,3H),1.27(d,6H),1.12-1.04(m,1H),0.59-0.52(m,1H),0.48-0.41(m,1H),0.18-0.07(m,2H).
实施例14
2-[(1S)-1-环丙基乙基]-6-异丙基苯胺(化合物14)
2-[(1S)-1-cyclopropylethyl]-6-isopropyl-aniline
第一步:2-[(1S)-1-环丙基乙基]-6-异丙基苯胺(化合物14)
2-[(1S)-1-cyclopropylethyl]-6-isopropyl-aniline
室温下,250mL的高压反应釜中室温下加入2-(1-环丙基乙基)-6-异丙基苯胺(13B)(2.0g,9.94mmol),二氯甲烷(20mL)和[(S)-2,2′-双(二苯基膦)-1,1′-联萘]二乙酸钌(0.34g,0.40mmol),加毕将高压釜装置拧紧密封,置换氢气3次后充入氢气,高压釜上的压力表压力显示为20atm,室温下反应30小时。减压浓缩除去溶剂,残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(V/V)=30∶1)得到淡黄色油状液体2-[(1S)-1-环丙基乙基]-6-异丙基苯胺(化合物14)(1.54g,产率:76.2%,手性HPLC:96.95%)。
MS m/z(ESI):204.2(M+1).
1HNMR(400MHz,CDCl3):δ7.14(dd,1H),7.03(dd,1H),6.80(dd,1H),3.74(s,2H),2.98-2.89(m,1H),2.36-2.29(m,1H),1.30(d,3H),1.27(d,6H),1.15-1.04(m,1H),0.59-0.52(m,1H),0.48-0.41(m,1H),0.18-0.07(m,2H).
实施例15
N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]乙酰胺(化合物15)
N-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamide
第一步:N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]乙酰胺(化合物15)
N-[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamide
反应瓶中加入2-[(1R)-1-环丙基乙基]-6-异丙基苯胺(化合物13)(0.61g,3.0mmol)和干燥的二氯甲烷(20mL),冷却至0℃,加入三乙胺(0.46g,4.50mmol),滴加乙酰氯(0.26g,3.30mmol),自然升至室温反应1小时。加入水(20mL),分液,水相用二氯甲烷(20mL x 2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用石油醚(20mL)打浆,过滤后得到白色固体N-[2-[(1R)-1-环丙基乙基]-6-异丙基-苯基]乙酰胺(化合物15)(0.45g,产率:61.4%)。
MS m/z(ESI):246.1(M+1).
1HNMR(400MHz,DMSO-d6):δ9.09(s,1H),7.28-7.22(dd,2H),7.15-7.12(dd,1H),3.09-3.00(m,1H),2.21-2.14(m,1H),2.01(s,3H),1.25-1.12(m,9H),1.04-0.94(m,1H),0.52-0.45(m,1H),0.28-0.22(m,1H),0.15-0.08(m,2H).
实施例16
N-[2-[(1S)-1-环丙基乙基]-6-异丙基-苯基]乙酰胺(化合物16)
N-[2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamide
第一步:N-[2-[(1S)-1-环丙基乙基]-6-异丙基-苯基]乙酰胺(化合物16)
N-[2-[(1S)-1-cyclopropylethyl]-6-isopropyl-phenyl]acetamide
反应瓶中加入2-[(1S)-1-环丙基乙基]-6-异丙基苯胺(化合物14)(0.61g,3.0mmol)和干燥的二氯甲烷(20mL)中,冷却至0℃,加入三乙胺(0.46g,4.50mmol)后滴加乙酰氯(0.26g,3.30mmol),自然升至室温反应1小时,加水(20mL),分液,水相用二氯甲烷(20mL x 2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用石油醚(20mL)打浆,过滤得到白色固体N-[2-[(1S)-1-环丙基乙基]-6-异丙基-苯基]乙酰胺(化合物16)(0.56g,产率:76.1%)。
MS m/z(ESI):246.2(M+1).
1HNMR(400MHz,DMSO-d6):δ9.08(s,1H),7.27-7.24(dd,2H),7.15-7.12(dd,1H),3.08-3.00(m,1H),2.19-2.13(m,1H),2.01(s,3H),1.23-1.12(m,9H),1.03-0.95(m,1H),0.51-0.45(m,1H),0.27-0.22(m,1H),0.14-0.07(m,2H).
实施例17
N-[2,6-双[(1R)-1-环丙基乙基]苯基]乙酰胺(化合物17)
N-[2,6-bis[(1R)-1-cyclopropylethyl]phenyl]acetamide
将2,6-双[(1R)-1-环丙基乙基]苯胺(化合物11)(0.700g,3.0mmol)溶于10mL干燥的二氯甲烷中,加入干燥的三乙胺(0.52mL,3.7mmol),O℃氮气保护下滴加乙酰氯(0.25mL,3.5mmol),加完后自然升至室温反应5个小时。加入20mL水,搅拌1分钟后倒入分液漏斗中分层,水层用二氯甲烷萃取(10mLx2),合并有机相,饱和氯化钠洗(10mLx1),无水硫酸钠干燥,过滤,减压浓缩后柱层析(石油醚∶乙酸乙酯(V/V)=20∶1)得白色固体化合物N-[2,6-双[(1R)-1-环丙基乙基]苯基]乙酰胺(化合物17)及其互变异构(0.69g,收率83.3%,HPLC:95.53%)。
化合物17与化合物17-1为互变异构体。
MS m/z(ESI):270.1[M-1]-.
1H NMR(400MHz,CDCl3):δ7.40-7.35(m,1H),7.31-7.27(m,2H),6.79(s,0.4H),6.72(brs,0.6H),2.49-2.41(m,0.6H),2.28-2.21(m,1.4H),2.14(s,1.8H),1.70(s,1.2H),1.30(d,J=7.0Hz,1.2H),1.24-1.19(m,4.8H),1.10-0.95(m,1.6H),0.93-0.84(m,0.4H),0.67-0.60(m,0.4H),0.57-0.45(m,2H),0.47-0.25(m,2H),0.19-0.05(m,3H),[0.03-(-0.04)](m,0.6H).
实施例18
N-[2,6-双[(1S)-1-环丙基乙基]苯基]乙酰胺(化合物18)
N-[2,6-bis[(1S)-1-cyclopropylethyl]phenyl]acetamide
将2,6-双[(1S)-1-环丙基乙基]苯胺(化合物12)(0.700g,3.0mmol)溶于10mL干燥的二氯甲烷中,加入干燥的三乙胺(0.52mL,3.7mmol),0℃氮气保护下滴加乙酰氯(0.25mL,3.5mmol),加完后自然升至室温反应5个小时。加入20mL水,搅拌1分钟后倒入分液漏斗中分层,水层用二氯甲烷萃取(10mLx 2),合并有机相,饱和氯化钠洗(10mLx 1),无水硫酸钠干燥,过滤,减压浓缩后柱层析(石油醚∶乙酸乙酯(V/V)=20∶1)得白色固体化合物N-[2,6-双[(1S)-1-环丙基乙基]苯基]乙酰胺(化合物18)及其互变异构体(0.69g,收率83.3%,HPLC:99.81%)。
化合物18与化合物18-1为互变异构体。
MS m/z(ESI):270.1[M-1]-.
1H NMR(400MHz,CDCl3):δ7.41-7.32(m,1H),7.31-7.22(m,2H),6.77(brs,0.4H),6.72(brs,0.6H),2.48-2.41(m,0.4H),2.29-2.16(m,1.6H),2.14(s,1.8H),1.70(s,1.2H),1.30(d,J=7.0Hz,1.2H),1.24-1.17(m,4.8H),1.10-0.96(m,1.6H),0.93-0.84(m,0.6H),0.66-0.59(m,0.4H),0.57-0.45(m,2H),0.41-0.25(m,2H),0.17-0.05(m,3H),[0.01-(-0.02)](m,0.4H).
生物测试例
1、小鼠翻正反射实验
SPF级ICR小鼠(SCXY(川)-2008-24-成都达硕生物科技有限公司),18-22g,雌雄各半。利用成熟的小鼠麻醉模型研究受试化合物的全身麻醉效果(Ratnakumari Lingamaneni等(2001).Anesthesiology,2001,94,1050-7)。用生理盐水将待测化合物配制为所需浓度备用。将实验动物在实验室环境中适应后禁食12小时。次日以50、100mg/kg口服给药后,记录翻正反射消失时间,给药后到翻正反射消失的时间为麻醉诱导时间,翻正反射消失到翻正反射恢复的时间为麻醉持续时间,以麻醉诱导时间和麻醉持续时间表示麻醉作用的强弱。以麻醉诱导时间、麻醉维持时间、翻正反射消失率等指标评价麻醉效果。
翻正反射消失时间:翻正反射消失,使之处于仰卧位并能够持续60s的时间;
翻正反射恢复时间:翻正反射能力恢复,使之处于仰卧位翻正时间小于2s。
实验结果如表1所示:
表1小鼠翻正反射实验数据
结论:小鼠通过口服给药后能够产生明显的麻醉效果,表明本发明化合物具有良好的药效活性和口服特性。
Claims (8)
6.一种药物组合物,所述药物组合物包含权利要求1-5中任一项所述的化合物或者其立体异构体或者其药学上可接受的盐,和一种或者多种药学上可接受的载体和/或者赋形剂。
7.根据权利要求1-5中任一项所述的化合物、或者其立体异构体、或者其药学上可接受的盐在制备诱导和维持动物或者人类的麻醉、促进动物或者人类的镇静催眠、治疗和/或者预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神分裂、惊厥和癫痫药物中的用途。
8.根据权利要求7所述的在制备诱导和维持动物或者人类的麻醉、促进动物或者人类的镇静催眠、治疗和/或者预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神分裂、惊厥和癫痫药物中的用途,其特征在于通过口服给药。
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WO2016034079A1 (zh) * | 2014-09-04 | 2016-03-10 | 四川海思科制药有限公司 | 一种gabaa受体增强剂用于制备镇静麻醉的药物中的用途 |
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