CN101595094B - 环烷基胺取代的异喹诺酮衍生物 - Google Patents
环烷基胺取代的异喹诺酮衍生物 Download PDFInfo
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- CN101595094B CN101595094B CN2007800485284A CN200780048528A CN101595094B CN 101595094 B CN101595094 B CN 101595094B CN 2007800485284 A CN2007800485284 A CN 2007800485284A CN 200780048528 A CN200780048528 A CN 200780048528A CN 101595094 B CN101595094 B CN 101595094B
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- Prior art keywords
- alkyl
- isoquinoline
- ketone
- group
- chloro
- Prior art date
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- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 title abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 133
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 125000001118 alkylidene group Chemical group 0.000 claims description 179
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 176
- -1 pyrrolidyl Chemical group 0.000 claims description 134
- 229910052760 oxygen Inorganic materials 0.000 claims description 95
- 239000001301 oxygen Substances 0.000 claims description 91
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 68
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 61
- 229910052736 halogen Inorganic materials 0.000 claims description 57
- 150000002367 halogens Chemical class 0.000 claims description 57
- 150000003839 salts Chemical class 0.000 claims description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 206010020772 Hypertension Diseases 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000004193 piperazinyl group Chemical group 0.000 claims description 9
- 125000005936 piperidyl group Chemical group 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- YWUCOQGBXQHOJM-UHFFFAOYSA-N 7-chloro-2h-isoquinolin-1-one Chemical compound C1=C(Cl)C=C2C(O)=NC=CC2=C1 YWUCOQGBXQHOJM-UHFFFAOYSA-N 0.000 claims description 7
- 208000002249 Diabetes Complications Diseases 0.000 claims description 7
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical group NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 7
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- 239000000654 additive Substances 0.000 claims description 5
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 5
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- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 4
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- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 3
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- 208000006399 Premature Obstetric Labor Diseases 0.000 claims description 3
- 206010036600 Premature labour Diseases 0.000 claims description 3
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- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 3
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 3
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- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 3
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- 239000000203 mixture Substances 0.000 abstract description 46
- 108010041788 rho-Associated Kinases Proteins 0.000 abstract description 15
- 102000000568 rho-Associated Kinases Human genes 0.000 abstract description 15
- 230000026731 phosphorylation Effects 0.000 abstract description 6
- 238000006366 phosphorylation reaction Methods 0.000 abstract description 6
- 102000011131 Myosin-Light-Chain Phosphatase Human genes 0.000 abstract description 5
- 108010037801 Myosin-Light-Chain Phosphatase Proteins 0.000 abstract description 5
- 230000001404 mediated effect Effects 0.000 abstract description 4
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- 239000002585 base Substances 0.000 description 149
- 238000000034 method Methods 0.000 description 94
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
- 239000000243 solution Substances 0.000 description 75
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 62
- 238000005259 measurement Methods 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- 238000003756 stirring Methods 0.000 description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 32
- 238000001704 evaporation Methods 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 29
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 230000008020 evaporation Effects 0.000 description 26
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
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- 239000012043 crude product Substances 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 125000003118 aryl group Chemical group 0.000 description 19
- SOKKGFZWZZLHEK-UHFFFAOYSA-N butoxy(dimethyl)silane Chemical group CCCCO[SiH](C)C SOKKGFZWZZLHEK-UHFFFAOYSA-N 0.000 description 19
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
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- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 14
- 238000000605 extraction Methods 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 13
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 125000000753 cycloalkyl group Chemical group 0.000 description 12
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 12
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- 230000005526 G1 to G0 transition Effects 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
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Classifications
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Abstract
本发明涉及式(I)的6-取代的异喹诺酮衍生物,其可用于治疗和/或预防与Rho-激酶和/或Rho-激酶介导的肌球蛋白轻链磷酸酶磷酸化相关的疾病,以及涉及包含该化合物的组合物。
Description
本发明涉及权利要求中所述的新的异喹诺酮衍生物、它们的制备和它们在治疗和/或预防与Rho-激酶抑制和/或Rho-激酶介导的肌球蛋白轻链磷酸酶磷酸化抑制相关的疾病中的用途。
小GTPase RhoA经激动剂刺激而活化,导致RhoA从无活性的GDP-结合形式转化为活性GTP-结合形式,随后结合并活化Rho-激酶。已知两种同工型Rho-激酶1和Rho-激酶2。Rho-激酶2在血管平滑肌细胞和内皮细胞中表达。Rho-激酶2经活性GTP-结合的RhoA活化,导致平滑肌细胞通过磷酸化介导的肌球蛋白轻链磷酸酶活性抑制以及由此肌球蛋白调节轻链活性的上调而钙敏感化(Uehata等人,Nature 1997,389,990-994)。
已知Rho-激酶参与血管收缩,包括肌源紧张和平滑肌过收缩的发生(Gokina等人,J.Appl.Physiol.2005,98,1940-1948)、支气管平滑肌收缩(Yoshii等人,Am.J.Resp.Cell Mol.Biol.20,1190-1200)、哮喘(Setoguchi等人,Br J Pharmacol.2001,132,111-118;Nakahara等人,Eur J 2000,389,103)和慢性阻塞性肺病(COPD,Maruoka,Nippon Rinsho,1999,57,1982-1987)、高血压、肺动脉高压(Fukumoto等人,Heart,91,391-392,2005,Mukai等人,Nature 1997,389,990-4)和眼高压和眼内压调节(Honjo等人,Invest.Ophthalmol.Visual Sci.2001,42,137-144)、内皮功能障碍(Steioff等人,Eur.J.Pharmacol.2005,512,247-249)、绞痛(Masumoto等人,Circ2002,105,1545-1547,Shimokawa等人,JCP,2002,40,751-761)、肾病、包括高血压诱导的、非高血压诱导的和糖尿病性肾病、肾衰竭和周围动脉闭塞疾病(PAOD)(Wakino等人,Drug News Perspect.2005,18,639-643)、心肌梗塞(Demiryurek等人,Eur J Pharmacol.2005,527,129-140,Hattori等人,Circulation,2004,109,2234-2239)、心脏肥大和衰竭(Yamakawa等人,Hypertension 2000,35,313-318,Liao等人,Am J Physiol Cell Physiol.2006,290,C661-668,Kishi等人,Circ 2005,111,2741-2747)、冠心病、动脉粥样硬化、再狭窄(Pacaud等人,Arch.Mal.Coeur 2005,98,249-254,Retzer等人,FEBS Lett 2000,466,70,Negoro等人,Biochem Biophys ResCommun 1999,262,211)、糖尿病、糖尿病并发症、葡萄糖利用和代谢综合征(Sandu等人,Diabetes 2000,49,2178,Maeda等人,Cell Metab.2005,2,119-129)、性功能障碍、例如阴茎勃起功能障碍(Chitaley等人,NatureMedicine 2001,7,119-122)、视网膜病、炎症、免疫疾病、AIDS、骨质疏松、内分泌功能障碍、例如醛固酮过多症、中枢神经系统障碍如神经元变性和脊髓损伤(Hara等人,J Neurosurg 2000,93,94)、脑缺血(Uehata等人,Nature 1997,389,990;Satoh等人,Life Sci.2001,69,1441-53;Hitomi等人,Life Sci 2000,67,1929;Yamamoto等人,J Cardiovasc Pharmacol.2000,35,203-11)、脑血管痉挛(Sato等人,Circ Res 2000,87,195;Kim等人,Neurosurgery 2000,46,440)、疼痛、例如神经性疼痛(Tatsumi等人,Neuroscience 2005,131,491;Inoue等人,Nature medicine 2004,10,712)、消化道细菌感染(WO 98/06433)、癌症发生和进展、其中Rho激酶抑制已经显示抑制肿瘤细胞生长和转移的瘤形成(Itoh等人,Nature Medicine1999,5,221;Somlyo等人,Res Commun 2000,269,652)、血管生成(Uchida等人,Biochem Biophys Res 2000,269,633-640;Gingras等人,Biochem J2000,348,273)、血管平滑肌细胞增殖和运动(Tammy等人,Circ.Res.1999,84,1186-1193;Tangkijvanich等人,Atherosclerosis 2001,155,321-327)、内皮细胞增殖、内皮细胞收缩和运动(Oikawa等人,Biochem.Biophys.Res.Commun.2000,269,633-640)、应力纤维形成(Kimura等人,Science 1997,275,1308-1311;Yamashiro等人,J.Cell Biol.2000,150,797-806)、血栓形成性障碍(Kikkawa等人,FEBS Lett.2000,466,70-74;Bauer等人,Blood1999,94,1665-1672,Klages等人,J Cell Biol 1999,144,745;Retzer等人,Cell Signal 2000,12,645)和白细胞聚集(Kawaguchi等人,Eur J Pharmacol.2000,403:203-8;Sanchez-Madrid等人,J Immunol.2003,171:1023-1034,Sanchez-Madrid等人,J Immunol.2002,168:400-410)和骨吸收(Chellaiah等人,J Biol Chem.2003,278:29086-97)。Na/H交换转运系统活化(Kawaguchi等人,Eur J Pharmacol.2000,403:203-208)、阿尔茨海默病(Zhou等人,Science 2003,302,1215-1217)、内吸蛋白活化(Fukata等人,J.Biol.Chem.,1998,273,5542-5548)以及SREB(甾醇应答元件结合蛋白)信号传导及其对脂质代谢的作用(Lin等人,Circ.Res.,2003,92,1296-1304)。
因此,对Rho-激酶和/或Rho-激酶介导的肌球蛋白轻链磷酸酶磷酸化具有抑制作用的化合物可用于治疗和/或预防涉及Rho-激酶作为主要或次级病因的心血管和非心血管疾病,如高血压、肺动脉高压、高眼压症、视网膜病和青光眼、周围循环障碍、周围动脉闭塞疾病(PAOD)、冠心病、心绞痛、心脏肥大、心力衰竭、局部缺血性疾病、局部缺血性器官衰竭(终端器官损伤)、纤维化肺、纤维化肝、肝衰竭、肾病、包括高血压诱导的、非高血压诱导的和糖尿病性肾病、肾衰竭、纤维化肾、肾小球硬化、器官肥大、哮喘、慢性阻塞性肺病(COPD)、成人呼吸窘迫综合征、血栓形成性障碍、中风、脑血管痉挛、脑缺血、疼痛、例如神经性疼痛、神经元变性、脊髓损伤、阿尔茨海默病、早产、勃起功能障碍、内分泌功能障碍、动脉硬化、前列腺肥大、糖尿病和糖尿病并发症、代谢综合征、血管再狭窄、动脉粥样硬化、炎症、自身免疫疾病、AIDS、骨病如骨质疏松、消化道细菌感染、脓毒病、癌症发展和进展、例如乳房、结肠、前列腺、卵巢、脑和肺的癌症及其转移。
WO 01/64238描述了可用作神经保护剂的任选被
-(CH2)1-6-O-(CH2)0-6-、-(CH2)0-6-S-(CH2)0-6-或-(CH2)0-6-连接的杂环基取代的异喹啉-5-磺酰胺衍生物。
WO 2004/106325(Schering AG)描述了在异喹啉环1位携带醚或酯基团的Rho-激酶抑制剂法舒地尔的前药。
WO 2001/039726概括地描述了可用于治疗微生物感染的-O-(C0-C10)烷基-杂芳基取代的环己基衍生物。
JP 10087629 A描述了可用于治疗由幽门螺旋杆菌(Heliobacter pylori)引起的疾病如胃炎癌症或溃疡的异喹啉衍生物。该异喹啉衍生物可被OH在1位取代和优选被X-[(C1-C6)亚烷基)]0-1-Y进行5-取代,其中X可以是氧且Y可以是芳基或杂环基。
Hagihara等人(Bioorg.Med.Chem.1999,7,2647-2666)公开了用于治疗由幽门螺旋杆菌所引起感染的6-苄氧基-异喹啉。
US 5,480,883概括地公开了作为EGF和/或PDGF受体抑制剂、可用于抑制细胞增殖的式“Ar I-X-Ar II”化合物,其中X可以是(CHR1)m-Z-(CHR1)n,例如Z-CH2,其中Z可以是O,R1是氢或烷基,ArI可尤其是任选取代的异喹诺酮,Ar II可尤其是任选取代的C3-7单环饱和杂环系统。
WO 2005/030791(Merck & Co.)概括地描述了作为钾通道抑制剂、用于治疗心律失常、中风、充血性心力衰竭等的异喹诺酮衍生物,其任选在6位被基团(CReRf)pOR43取代,其中p可以是零,R43是例如任选被NR51R52取代的(C3-C10)环烷基,其中R51和R52可以是氢、(C1-C6)烷基等;或者R43是定义为具有1、2、3或4个杂原子的4-6元不饱和或饱和单环杂环的基团R81;且在4位被直接键合的任选取代的芳基或杂芳基取代。
WO 2005/030130(Merck & Co.)概括地描述了作为钾通道抑制剂、用于治疗心律失常、中风、充血性心力衰竭等的异喹啉衍生物,其可以在1位被羟基取代且在6位任选被基团(CReRf)pOR43取代,其中p可以是零,R43是例如任选被NR51R52取代的(C3-C10)环烷基,其中R51和R52可以是氢、(C1-C6)烷基等;或者R43是定义为具有1、2、3或4个杂原子的4-6元不饱和或饱和单环杂环的基团R81;且在4位被直接键合的任选取代的芳基或杂芳基取代。
WO 03/053330(Ube)概括地描述了作为Rho-激酶抑制剂的下式的异喹诺酮衍生物
本发明的一项实施方案是式(I)化合物,
其中
R2是H、卤素或(C1-C6)烷基;
R3是
H,
卤素,
(C1-C6)烷基,
(C1-C6)亚烷基-R’,
OH,
O-R”,
NH2,
NHR”,
NR”R”或
NH-C(O)-R”,
R4是
H,
卤素,
羟基,
CN,
(C1-C6)烷基,
R’,
(C1-C6)亚烷基-R’;
R5是
H,
卤素,
CN,
NO2,
(C1-C6)烷基,
(C2-C6)链烯基,
R’,
(C1-C6)亚烷基-(C6-C10)芳基,
(C1-C6)亚烯基-(C6-C10)芳基,
(C1-C6)亚烷基-(C5-C10)杂环基,
CH(OH)-(C1-C6)烷基,
NH2,
NH-R’,
NH-SO2H,
NH-SO2-(C1-C6)烷基,
NH-SO2-R’,
NH-C(O)-(C1-C6)烷基,
NH-C(O)-R’,
C(O)N[(C1-C6)烷基]2,
C(O)OH,或
C(O)O-(C1-C6)烷基;
R6和R6’相互独立地是
H,
R’,
(C1-C8)烷基,
(C1-C6)亚烷基-R’,
(C1-C6)亚烷基-O-(C1-C6)烷基,
(C1-C6)亚烷基-O-R’,
(C1-C6)亚烷基-CH[R’]2,
(C1-C6)亚烷基-C(O)-R’,
(C1-C6)亚烷基-C(O)NH2,
(C1-C6)亚烷基-C(O)NH-R’,
(C1-C6)亚烷基-C(O)NH-(C1-C6)烷基,
(C1-C6)亚烷基-C(O)N[(C1-C6)烷基]2,
(C1-C6)亚烷基-C(O)N[R’]2;
(C1-C6)亚烷基-C(O)O-(C1-C6)烷基,
C(O)O-(C1-C6)烷基,
C(O)OR’
C(O)(C1-C6)烷基,
C(O)R’,
C(O)NH-(C1-C6)烷基,
C(O)NHR’,
C(O)N[(C1-C6)烷基]R’
C(O)N[(C1-C6)烷基]2,
C(O)-(C1-C6)亚烷基-R’,
C(O)O(C1-C6)亚烷基-R’,
或者R6和R6’与它们所连接的N-原子一起形成(C5-C10)杂环基;
R7是
H,
卤素,
CN,
NO2,
(C1-C6)烷基,
O-(C1-C6)烷基,
(C2-C6)链烯基,
R’,
(C1-C6)亚烯基-(C6-C10)芳基,
(C1-C6)亚烷基-R’,
CH(OH)-(C1-C6)烷基,
NH2,
NH-R’,
NH-SO2H,
NH-SO2-(C1-C6)烷基,
NH-SO2-R’,
SO2-NH2,
SO2-NHR’,
NH-C(O)-(C1-C6)烷基,
NH-C(O)-R’,
C(O)N[(C1-C6)烷基]2,
C(O)OH,或
C(O)O-(C1-C6)烷基;
R8是H、卤素或(C1-C6)烷基;
n是1、2、3或4;
m是1、2、3、4或5,且
L是O或O-(C1-C6)亚烷基;
其中
R’是
(C3-C8)环烷基,
(C5-C10)杂环基,
(C6-C10)芳基;且
R”是
(C3-C8)环烷基,
(C5-C10)杂环基,
(C6-C10)芳基,
(C1-C6)烷基,
(C1-C6)亚烷基-R’,
(C1-C6)亚烷基-O-(C1-C6)烷基,
(C1-C6)亚烷基-O-R’,或
(C1-C6)亚烷基-NRxRy;且
其中Rx和Ry相互独立地是
(C1-C6)烷基,
(C5-C10)杂环基,
(C6-C10)芳基,
(C1-C4)亚烷基-(C5-C10)杂环基,
(C1-C4)亚烷基-(C6-C10)芳基,
(C1-C4)亚烷基-NH(C1-C6)烷基,
(C1-C4)亚烷基-N[(C1-C6)烷基]2,
(C1-C4)亚烷基-N[(C6-C10)芳基]2,或
(C1-C4)亚烷基-N[(C5-C10)杂环基]2;
其中在基团R4、R5、R6、R6’、R7和R8中,烷基、亚烷基或环烷基可以任选被如下基团取代一次或多次:OH、OCH3、COOH、COOCH3、NH2、NHCH3、N(CH3)2、CONHCH3或CON(CH3)2;
其中在基团R2至R8中,烷基或亚烷基可以任选被卤素取代一次或多次;
其中在基团R3至R8中,(C6-C10)芳基和(C5-C10)杂环基是未取代的或者被独立地选自如下的适宜基团取代一次或多次:OH、卤素、NO2、N3、CN、C(O)-(C1-C6)烷基、C(O)-(C1-C6)芳基、COOH、COO(C1-C6)烷基、CONH2、CONH(C1-C6)烷基、CON[(C1-C6)烷基]2、(C3-C8)环烷基、(C1-C6)烷基、(C1-C6)亚烷基-OH、(C1-C6)亚烷基-NH2、(C1-C6)亚烷基-NH(C1-C6)烷基、(C1-C6)亚烷基-N[(C1-C6)烷基]2、(C2-C6)链烯基、(C2-C6)炔基、O-(C1-C6)烷基、O-C(O)-(C1-C6)烷基、PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6)烷基、SO2N[(C1-C6)烷基]2、S-(C1-C6)烷基、SO-(C1-C6)烷基、SO2-(C1-C6)烷基、SO2-N=CH-N[(C1-C6)烷基]2、C(NH)(NH2)、NH2、NH-(C1-C6)烷基、N[(C1-C6)烷基]2、NH-C(O)-(C1-C6)烷基、NH-C(O)O-(C1-C6)烷基、NH-SO2-(C1-C6)烷基、NH-SO2-(C6-C10)芳基、NH-SO2-(C5-C10)杂环基、N(C1-C6)烷基-C(O)-(C1-C6)烷基、N(C1-C6)烷基-C(O)O-(C1-C6)烷基、N(C1-C6)烷基-C(O)-NH-(C1-C6)烷基]、(C6-C10)芳基、(C1-C6)亚烷基-(C6-C10)芳基、O-(C6-C10)芳基、O-(C1-C6)亚烷基-(C6-C10)芳基、(C5-C10)杂环基、(C1-C6)亚烷基-(C5-C10)杂环基或O-(C1-C6)亚烷基-(C5-C10)杂环基,其中(C6-C10)芳基或(C5-C10)杂环基可以被独立地选自如下的基团取代一次至三次:卤素、OH、NO2、CN、O-(C1-C6)烷基、(C1-C6)烷基、NH2、NH(C1-C6)烷基、N[(C1-C6)烷基]2、SO2CH3、COOH、C(O)O-(C1-C6)烷基、CONH2、(C1-C6)亚烷基-O-(C1-C6)烷基、(C1-C6)亚烷基-O-(C6-C10)芳基或O-(C1-C6)亚烷基-(C6-C10)芳基;
或者其中(C6-C10)芳基在连位上被O-(C1-C4)亚烷基-O基团取代,由此与氧原子所连接的碳原子一起形成5-至8-元环;
以及其中(C6-C10)芳基和(C5-C10)杂环基的芳基或杂环基取代基不可以进一步被含有芳基或杂环基的基团所取代;
并且其中如果m是3,则R6不是H、(C5-C10)杂环基或(C6-C10)芳基;和其中如果m是3,则R6是选自如下的基团:
(C1-C8)烷基,
(C3-C8)环烷基,
(C1-C6)亚烷基-R’,
(C1-C6)亚烷基-O-(C1-C6)烷基,
(C1-C6)亚烷基-O-R’,
(C1-C6)亚烷基-CH[R’]2,
(C1-C6)亚烷基-C(O)-R’,
(C1-C6)亚烷基-C(O)NH2,
(C1-C6)亚烷基-C(O)NH-R’,或
(C1-C6)亚烷基-C(O)N[R’]2;
所述基团中的烷基、亚烷基或环烷基被如下基团取代一次或多次、优选一次至三次:OH、OCH3、COOH、COOCH3、NH2、NHCH3、N(CH3)2、CONHCH3或CON(CH3)2;
或它们的立体异构和/或互变异构形式和/或它们的可药用盐。
在另一项实施方案中,式(I)化合物以式(I’)化合物表征:
式(I)和(I’)化合物相互是互变异构形式,并且是本发明的一部分。下述实施方案涉及式(I)和(I’)化合物。
R3优选是H、卤素、(C1-C4)亚烷基-R’、O-R”或NHR”。更优选R3是H或NHR”。最优选R3是H、NH-(C5-C6)杂环基或NH-苯基,尤其优选的是H、NH-含有一个或多个N原子的(C5-C6)杂芳基或NH-苯基。最尤其优选R3是H。
R3取代基的实例有
优选R4是H、卤素或(C1-C6)烷基。更优选R4是H、卤素或(C1-C4)烷基。最优选R4是H。
优选R5是H、卤素、CN、(C1-C6)烷基、(C2-C6)链烯基、R’、NH-(C6-C10)芳基或(C1-C6)亚烷基-R’。更优选R5是H、卤素、(C1-C6)烷基、(C2-C6)链烯基、R’、NH-(C6-C10)芳基或(C1-C6)亚烷基-R’。最优选R5是H、卤素、(C1-C6)烷基、(C2-C6)链烯基、(C6-C10)芳基、NH-(C6-C10)芳基、(C1-C2)烷基-(C6-C10)芳基或(C5-C10)杂芳基。尤其优选R5是H、卤素、苯基、(C1-C6)烷基、(C2-C6)链烯基、(C6-C10)芳基或(C5-C6)杂芳基。最尤其优选R5是H、卤素、甲基、乙基、乙烯基、苯基、噻吩基或吡啶基。
R5的实例有氢、氟、氯、溴、碘、甲基、乙基、乙烯基、苯基、噻吩基或吡啶基、腈、硝基、(对甲氧基)-苯基、N-苯胺,苄基、2-丙烯基、仲丁烯基、环丙基、四唑、氨基、4-甲氧基-苯胺或N-乙酰基,优选氢、氟、氯、溴、碘、甲基、乙基、乙烯基、苯基、噻吩基或吡啶基。更优选R5是H、卤素、甲基或乙基,最优选R5是H。
优选R6和R6’相互独立地是H、(C1-C6)烷基、R’、(C1-C4)亚烷基-(C3-C8)环烷基、(C1-C4)亚烷基-(C5-C10)杂环基、(C1-C4)亚烷基-(C6-C10)芳基、(C1-C6)亚烷基-O-(C1-C6)烷基、(C1-C4)亚烷基-C(O)-(C5-C10)杂环基、(C1-C4)亚烷基-C(O)-(C6-C10)芳基、(C1-C6)亚烷基-C(O)N[(C1-C6)烷基]2、(C1-C6)亚烷基-C(O)NH-(C1-C6)烷基、(C1-C6)亚烷基-C(O)O-(C1-C6)烷基、C(O)R’、C(O)(C1-C6)烷基、C(O)O-(C1-C6)烷基、C(O)NH-(C1-C6)烷基、C(O)N[(C1-C6)烷基]2或C(O)(C1-C6)亚烷基-R’,或R6和R6’与它们所连接的N-原子一起形成(C5-C10)杂环基。
在进一步优选的实施方案中,R6和R6’相互独立地是H、(C1-C6)烷基、(C5-C10)杂环基、(C3-C8)环烷基、(C6-C10)芳基、(C1-C4)亚烷基-(C3-C8)环烷基、(C1-C4)亚烷基-(C5-C10)杂环基、(C1-C4)亚烷基-(C6-C10)芳基、(C1-C6)亚烷基-O-(C1-C6)烷基、(C1-C6)亚烷基-C(O)N[(C1-C6)烷基]2、(C1-C6)亚烷基-C(O)NH-(C1-C6)烷基、(C1-C6)亚烷基-C(O)O-(C1-C6)烷基、C(O)O-(C1-C6)烷基、C(O)(C1-C6)烷基、C(O)(C3-C8)环烷基、C(O)NH-(C1-C6)烷基、C(O)N[(C1-C6)烷基]2、C(O)(C1-C6)亚烷基-(C3-C8)环烷基、C(O)(C1-C6)亚烷基-(C5-C10)杂环基、C(O)(C1-C6)亚烷基-(C6-C10)芳基,或R6和R6’与它们所连接的N-原子一起形成(C5-C10)杂环基。
在更优选的实施方案中,R6是H、(C1-C6)烷基、(C3-C6)环烷基或(C1-C4)亚烷基-(C3-C6)环烷基,且R6’是H、(C1-C6)烷基、(C3-C8)环烷基、(C5-C10)杂环基、(C5-C10)芳基、(C1-C4)亚烷基-(C3-C8)环烷基、(C1-C4)亚烷基-(C5-C10)杂环基、(C1-C4)亚烷基-(C6-C10)芳基、(C1-C6)亚烷基-O-(C1-C6)烷基、(C1-C6)亚烷基-C(O)NH-(C1-C6)烷基、(C1-C6)亚烷基-C(O)N[(C1-C6)烷基]2、(C1-C6)亚烷基-C(O)O-(C1-C6)烷基、C(O)O-(C1-C6)烷基、C(O)(C1-C6)烷基、C(O)(C3-C8)环烷基、C(O)NH-(C1-C6)烷基、C(O)N[(C1-C6)烷基]2、C(O)(C1-C6)亚烷基-(C3-C8)环烷基、C(O)(C1-C6)亚烷基-(C5-C10)杂环基、C(O)(C1-C6)亚烷基-(C6-C10)芳基,或者R6和R6’与它们所连接的N-原子一起形成(C5-C10)杂环基。
在进一步更优选的实施方案中,R6是H、(C1-C6)烷基,且R6’是H、(C1-C6)烷基、(C3-C8)环烷基、(C6-C10)芳基、(C5-C10)杂环基、(C1-C4)亚烷基-(C3-C8)环烷基、(C1-C4)亚烷基-(C5-C10)杂环基、(C1-C6)亚烷基-(C6-C10)芳基、(C1-C4)亚烷基-O-(C1-C4)烷基、(C1-C4)亚烷基-C(O)N[(C1-C4)烷基]2、(C1-C6)亚烷基-C(O)NH-(C1-C6)烷基、C(O)(C1-C6)烷基、C(O)(C1-C6)亚烷基-(C5-C10)杂环基,或者R6和R6’与它们所连接的N-原子一起形成(C5-C10)杂环基。
在进一步甚至更优选的实施方案中,R6是H、(C1-C6)烷基,且R6’是H,
(C1-C6)烷基;
(C3-C8)环烷基;
(C1-C4)亚烷基-(C3-C8)环烷基;
(C1-C4)亚烷基-O-(C1-C4)烷基;
(C1-C4)亚烷基-C(O)N[(C1-C4)烷基]2;
(C1-C4)亚烷基-(C5-C10)杂环基,其中杂环基是未取代的或者被独立地选自(C1-C4)烷基、O(C1-C4)烷基、卤素或苯基的基团取代一次或多次、优选一次至三次、更优选一次或两次,或者被(C5-C6)杂环基取代一次,其中苯基或(C5-C6)杂环基是未取代的或者被卤素、(C1-C4)烷基或O(C1-C4)烷基取代一次至三次;或者
(C1-C4)亚烷基-(C6-C10)芳基,其中芳基是未取代的或者被独立地选自如下的基团取代一次或多次、优选一次至三次:卤素、(C1-C4)烷基且优选CH3或CF3、O-(C1-C4)烷基、CN、SO2-NH2;SO2-(C1-C4)烷基且优选SO2-CH3或SO2-CF3;SO2-N=CH-N[(C1-C4)烷基]2且优选SO2-N=N-N(CH3)2、NH-CO-(C1-C4)烷基且优选NH-CO-CH3或者CO-O-(C1-C4)烷基,或者(C6-C10)芳基被未取代的苯基、未取代的O-苯基或未取代的(C5-C6)杂环基取代一次;
C(O)(C1-C4)烷基;
C(O)(C1-C4)亚烷基-(C5-C10)杂环基;
或者R6和R6’与它们所连接的N-原子一起形成(C5-C6)杂环基,它是未取代的或者被(C1-C4)烷基或C(O)O(C1-C4)烷基取代一次至三次、优选一次;其中(C1-C4)烷基或(C1-C6)烷基基团是未取代的或者被卤素、优选被氟取代一次至三次。
优选所形成的杂环基是吗啉(代)基、哌啶(子)基、吡咯烷(子)基或哌嗪(子)基,它们是未取代的或者如上文所述的那样被取代。更优选杂环基是吗啉(代)基或4-乙基哌嗪基。
在最优选的实施方案中,R6是H、(C1-C6)烷基和R6’是H、(C1-C6)烷基、(C3-C8)环烷基。
在进一步最优选的实施方案中,R6是且R6’是H、优选未取代的(C1-C6)烷基或优选未取代的(C3-C8)环烷基。尤其优选R6和R6’是H。
在一项实施方案中,R6不是叔丁氧羰基,尤其是如果m为3的话。
作为这些实施方案的实例,R6或R6’相互独立地是氢、甲基、乙基、丙基、异丙基、3-甲基-丁基、2-甲基-丙基、丁基、戊基、3,3,3-三氟丙基、4,4,4-三氟丁基或选自如下的取代基:
所示例取代基中的星号(*)表示价键与N-原子的连接处。
NR6和NR6’形成杂环的基团的实例有:
所示例取代基中的星号(*)表示价键与羰基碳原子的连接处。
优选R7是H、卤素、CN、(C1-C6)烷基、O-(C1-C6)烷基、(C2-C6)链烯基、R’或(C1-C6)亚烷基-(C3-C8)环烷基。更优选R7是H、卤素、CN、(C1-C4)烷基、O-(C1-C4)烷基、(C1-C4)链烯基、苯基、环丙基或(C5-C6)杂芳基。最优选R7是H、氟、氯、溴、甲基、乙基、甲氧基、苯基、腈、环丙基、噻吩基或乙烯基,尤其最优选R7是H、氟、氯、甲基或甲氧基。更特别优选R7是H。
R8优选是H、卤素或(C1-C4)烷基。更优选R8是H、Cl、F、甲基或乙基。最优选R8是H。
优选R2是H、卤素或(C1-C4)烷基。优选R2是H或(C1-C2)烷基。更优选R2是H、甲基或乙基。最优选R2是H。R2可以与环的任意碳原子连接,包括连接基团L所连接的位置。
优选n是1、2或3。更优选n是1或2。最优选n是1。
优选m是2、3或4。更优选m是3。在另一项实施方案中,m是1、2、4或5。
连接基团L可以在任意位置经由环碳原子与环连接。在优选的实施方案中,m是3和,以所有立体化学形式,L与氨基环己烷环的4-位连接,
或者L与氨基环己烷环的3-位连接
在尤其优选的实施方案中,L与氨基环己烷环的4-位连接。
在另一项优选的实施方案中,L是O-亚甲基、O-亚乙基或优选是O。更优选m为3且L是与氨基环己烷环的4-位连接的O-亚甲基、O-亚乙基或O。
在基团R2至R8中,烷基或亚烷基可以任选地被卤素取代一次或多次。优选烷基或亚烷基被选自氯或溴的卤素取代一次至三次,还可以被氟取代一次或多次,例如可以是全氟化的。优选卤素是氟。更优选烷基或亚烷基不是卤素化的。
在基团R4、R5、R6、R6’、R7和R8中,烷基、亚烷基或环烷基可以任选被独立地选自如下的基团取代一次或多次:OH、OCH3、COOH、COOCH3、NH2、NHCH3、N(CH3)2、CONHCH3或CON(CH3)2。如果被取代,取代基的数目优选是1、2、3或4,更优选1或2,甚至更优选1。优选亚烷基或环烷基是未取代的。更优选烷基、亚烷基或环烷基是未取代的。优选R4、R5、R7和R8中的烷基、亚烷基或环烷基是未取代的。在另一项实施方案中,R4、R5、R6、R7和R8中的烷基、亚烷基或环烷基是未取代的。
在本发明的优选实施方案中,式(I)或(I’)化合物中所含的一个或多个或所有基团可彼此独立地具有以上示出的任意优选、更优选或最优选的基团定义或任意一个或一些由以上示出基团定义所涵盖的具体指示,优选的定义、更优选或最优选和/或具体指示的所有组合是本发明的主题。此外,就所有优选实施方案而言,本发明包括式(I)或(I’)化合物的所有立体异构形式和所有比例的立体异构形式的混合物以及它们的可药用盐。
在所示例取代基(参见上文)中的术语“*-”标记了取代基所连接的位置,例如,
优选的实施方案是如下定义的式(I)化合物,其中:
R2是氢、卤素或(C1-C6)烷基;
R3是H、卤素、(C1-C4)亚烷基-R’、O-R”或NHR”;
R4是H、卤素或(C1-C6)烷基;
R5是H、(C1-C6)烷基、卤素、CN、(C2-C6)链烯基、(C6-C10)芳基、NH-(C6-C10)芳基、(C1-C6)亚烷基-(C6-C10)芳基、(C5-C10)杂环基或(C1-C6)亚烷基-(C5-C10)杂环基;
R6和R6’相互独立地是H、R’、(C1-C8)烷基、(C1-C6)亚烷基-R’、(C1-C6)亚烷基-O-(C1-C6)烷基、(C1-C6)亚烷基-O-R’、(C1-C6)亚烷基-CH[R’]2、(C1-C6)亚烷基-C(O)NH2、(C1-C6)亚烷基-C(O)NH-R’、(C1-C6)亚烷基-C(O)N[(C1-C4)烷基]2、(C1-C6)亚烷基-C(O)N[R’]2、C(O)O-(C1-C6)烷基、C(O)(C1-C6)烷基、C(O)(C3-C8)环烷基、C(O)(C5-C10)杂环基、C(O)NH-(C1-C6)烷基、C(O)N[(C1-C6)烷基]2、C(O)-(C1-C6)亚烷基-C3-C8)环烷基、C(O)(C1-C6)亚烷基-(C5-C10)杂环基、C(O)(C1-C6)亚烷基-(C6-C10)芳基,或者R6和R6’与它们所连接的N-原子一起形成(C5-C6)杂环基;
R7是H、卤素、CN、(C1-C6)烷基,O-(C1-C6)烷基,(C2-C6)链烯基或R’;
R8是H、卤素或(C1-C6)烷基;
m是2、3或4
n是1、2或3,且
L是O、O-亚甲基或O-亚乙基;
和它们的可药用盐。
另一项优选的实施方案是如下定义的式(I)化合物,其中:
R2是H或(C1-C4)烷基;
R3是H、卤素或NHR”,其中R”如上文所定义;
R4是H、卤素或(C1-C4)烷基;
R5是H、(C1-C6)烷基、卤素、(C2-C4)链烯基、(C6-C10)芳基、(C1-C6)亚烷基-(C6-C10)芳基或(C5-C10)杂环基;
R6和R6’相互独立地是H、(C3-C8)环烷基、(C1-C8)烷基、(C1-C6)亚烷基-O-(C1-C6)烷基、(C1-C3)亚烷基-R’;C(O)(C1-C6)烷基、C(O)(C3-C8)环烷基、C(O)(C5-C10)杂环基、C(O)(C1-C6)亚烷基-(C3-C8)环烷基、C(O)(C1-C6)亚烷基-(C5-C10)杂环基或C(O)(C1-C6)亚烷基-(C6-C10)芳基;
R7是H、卤素、CN、(C1-C6)烷基、O(C1-C6)烷基、(C2-C6)链烯基或R’;
R8是H、卤素或(C1-C6)烷基;
m是2、3或4
n是1、2或3;且
L是O;
和它们的可药用盐。
尤其优选的实施方案是如下定义的式(I)化合物,其中:
R2是H、(C1-C4)烷基;
R3是H、NH-(C5-C6)杂芳基或NH-苯基;
R4是H、卤素或(C1-C4)烷基;
R5是H、(C1-C4)烷基、卤素、(C1-C4)链烯基、(C6-C10)芳基、(C1-C2)烷基-(C6-C10)芳基或(C5-C6)杂芳基;
R6是H、(C3-C6)环烷基或(C1-C4)烷基;
R6’是H、(C3-C8)环烷基、(C1-C8)烷基、(C1-C3)亚烷基-R’、C(O)O-(C1-C6)烷基、C(O)(C1-C6)烷基、C(O)(C3-C6)环烷基、C(O)(C5-C6)杂环基、C(O)(C1-C3)亚烷基-(C3-C6)环烷基、C(O)(C1-C3)亚烷基-(C5-C6)杂环基或C(O)(C1-C3)亚烷基-苯基;
R7是H、卤素、CN、(C1-C4)烷基、O(C1-C4)烷基、(C1-C4)链烯基、苯基、环丙基、(C5-C6)杂芳基;
R8是H、卤素或(C1-C4)烷基;
m是3;
n是1;且
L是O;
和它们的可药用盐。
在实施方案中,本发明涉及独立地选自如下的式(I)或(I’)化合物:
15 1-[4-(7-氯-1-氧代-1,2-二氢-异喹啉-6-基氧基)-环己基]-哌啶-4-甲酸酰胺,
16 7-氯-6-(4-哌啶-1-基-环己基氧基)-2H-异喹啉-1-酮,
17 7-氯-6-(4-吗啉-4-基-环己基氧基)-2H-异喹啉-1-酮,
19 7-氯-6-(4-吡咯烷-1-基-环己基氧基)-2H-异喹啉-1-酮,
21 7-氯-6-[4-(4-甲基-哌嗪-1-基)-环己基氧基]-2H-异喹啉-1-酮,
23 [4-(7-氯-1-氧代-1,2-二氢-异喹啉-6-基氧基)-顺式-环己基氨基]-乙酸乙基酯,
24 [4-(7-氯-1-氧代-1,2-二氢-异喹啉-6-基氧基)-顺式-环己基氨基]-乙酸,
27 7-甲基-6-(4-吡咯烷-1-基-环己基氧基)-2H-异喹啉-1-酮,
28 N-[4-(7-甲基-1-氧代-1,2-二氢-异喹啉-6-基氧基)-反式-环己基]-3-哌啶-4-基-丙酰胺,
29 N-[4-(7-甲基-1-氧代-1,2-二氢-异喹啉-6-基氧基)-反式-环己基]-2-哌啶-4-基-乙酰胺,
30 N-[4-(7-氯-1-氧代-1,2-二氢-异喹啉-6-基氧基)-顺式-环己基]-3-哌啶-4-基-丙酰胺,
31 N-[4-(7-氯-1-氧代-1,2-二氢-异喹啉-6-基氧基)-顺式-环己基]-2-哌啶-4-基-乙酰胺,
43 6-((1S,3S)-3-氨基-环戊基氧基)-2H-异喹啉-1-酮,
44 6-((1S,3S)-3-氨基-环戊基氧基)-7-氯-2H-异喹啉-1-酮,
45 6-((1S,3R)-3-氨基-环戊基氧基)-2H-异喹啉-1-酮,
46 6-((1S,3R)-3-氨基-环戊基氧基)-7-氯-2H-异喹啉-1-酮,
47 6-((顺式-4-氨基-环庚基氧基)-7-甲基-2H-异喹啉-1-酮,或
48 7-氯-6-(顺式-4-氨基-环庚基氧基)-2H-异喹啉-1-酮,
或它们的立体异构形式和/或它们的可药用盐。
在另一项实施方案中,本发明涉及独立地选自如下的式(I)或(I’)化合物:
49 6-(顺式-4-氨基-环庚基氧基)-2H-异喹啉-1-酮,
54 6-(3-氨基-环丁氧基)-7-氯-2H-异喹啉-1-酮,
55 顺式-6-(3-氨基-环丁基甲氧基)-7-氯-2H-异喹啉-1-酮,
56 反式-6-(3-氨基-环丁基甲氧基)-7-氯-2H-异喹啉-1-酮,
62 6-(5-氨基-环辛基氧基)-7-氯-2H-异喹啉-1-酮,
65 5-(1-苄基氧基-7-氯-异喹啉-6-基氧基)-1-丙基-环辛胺,
66 6-(5-氨基-5-丙基-环辛基氧基)-7-氯-2H-异喹啉-1-酮,
68 6-(5-苄基-氨基-5-丙基-环辛基氧基)-7-氯-2H-异喹啉-1-酮,
69 7-氯-6-(5-乙基氨基-5-丙基-环辛基氧基)-2H-异喹啉-1-酮,
70 7-氯-6-(顺式-3-异丙基氨基-环丁氧基)-2H-异喹啉-1-酮,
71 6-(3-顺式-苄基氨基-环丁氧基)-7-氯-2H-异喹啉-1-酮,
72 6-(3-反式-苄基氨基-环丁氧基)-7-氯-2H-异喹啉-1-酮,
73 7-氯-6-(3-顺式-二苄基氨基-环丁氧基)-2H-异喹啉-1-酮,
74 7-氯-6-(3-反式-二苄基氨基-环丁氧基)-2H-异喹啉-1-酮,或
75 7-氯-6-(3-反式-二乙基氨基-环丁氧基)-2H-异喹啉-1-酮,
或它们的立体异构形式和/或它们的可药用盐(给出化合物编号以供引用)。
如本发明任意实施方案中、在含有本发明化合物优选的、更优选的、最优选的或示例性定义的前述实施方案中,一个或多个或所有基团可具有任意上述优选的、更优选的、最优选的定义或由以上示出的由其定义所涵盖的任意一个或一些具体指示。
异喹啉的取代模式是按照IUPAC规则来进行编号的:
以下所有对“式(I)或(I’)化合物”的称谓指如上所述的一种或多种式(I)或(I’)化合物以及它们的可药用盐和/或它们的立体异构形式、多晶型物和溶剂合物。也包括如本文所述的生理学功能衍生物。
式(I)或(I’)化合物的可药用盐指它们的有机和无机盐,如Remington′sPharmaceutical Sciences(第17版,第1418页(1985))所述。由于物理和化学稳定性和溶解度,对于酸性基团尤其优选钠、钾、钙和铵盐,对于碱性基团尤其优选马来酸、富马酸、琥珀酸、苹果酸、酒石酸、甲基磺酸、盐酸、硫酸、磷酸或羧酸或磺酸的盐,如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、甲磺酸盐、乙酸盐、乳酸盐、马来酸盐、富马酸盐、苹果酸盐、葡糖酸盐,和氨基酸、天然碱或羧酸的盐。由能够成盐的式(I)或(I’)化合物、包括它们的立体异构形式制备可药用盐以本身已知的方式进行。式(I)化合物与碱性试剂形成稳定的碱金属、碱土金属或任选取代的铵盐,碱性试剂如氢氧化物、碳酸盐、碳酸氢盐、醇化物和氨或有机碱,如三甲基胺或三乙基胺、乙醇胺、二乙醇胺或三乙醇胺、氨丁三醇,或其它碱性氨基酸如赖氨酸、鸟氨酸或精氨酸。当式(I)或(I’)具有碱性基团时,也可以用强酸制备稳定的酸加成盐。适合的本发明化合物的可药用酸加成盐是无机酸和有机酸的盐,无机酸如盐酸、氢溴酸、磷酸、偏磷酸、硝酸和硫酸,有机酸如乙酸、苯磺酸、苯甲酸、柠檬酸、乙磺酸、富马酸、葡糖酸、乙醇酸、羟乙磺酸、乳酸、乳糖酸、马来酸、苹果酸、甲磺酸、琥珀酸、对甲苯磺酸和酒石酸。
与不可药用的阴离子的盐如三氟乙酸盐作为有用中间体用于制备或纯化可药用盐和/或用于非治疗应用如体外应用同样属于本发明的框架内。
本文使用的术语“生理学功能衍生物”指本发明的式(I)或(I’)化合物的任意生理学上耐受的衍生物,例如N-氧化物,其在施用于哺乳动物、例如人时能够(直接或间接)形成式(I)或(I’)化合物或其活性代谢物。
生理学功能衍生物包括本发明化合物的前药,如例如H.Okada等人,Chem.Pharm.Bull.1994,42,57-61所述。这类前药可在体内代谢为本发明化合物。这些前药本身可以有活性或无活性。
本发明涉及式(I)或(I’)化合物的立体异构形式、包括外消旋物、外消旋混合物、纯的对映异构体和非对映异构体及其混合物。
本发明化合物也可以以各种多晶型形式存在,例如作为无定形和晶体多晶型形式。本发明化合物的所有多晶型形式属于本发明的框架内并且是本发明的另一方面。
如果基团或取代基在式(I)或(I’)化合物中可以出现一次以上,它们可以全部彼此独立地具有所示含义并且可以相同或不同。
术语(C1-C2)烷基、(C1-C4)烷基、(C1-C6)烷基、(C1-C8)烷基和相应的亚烷基取代基应理解为烃基残基,其分别可以是线性、例如直链的,或是支链的,且具有1、2、3、4、5、6、7或8个碳原子。这在烷基作为另一基团的取代基时也适用,例如在烷氧基(O-烷基)、S-烷基或-O(C1-C6)亚烷基-O-、烷氧基羰基或芳基烷基中。烷基的实例有甲基、乙基、丙基、丁基、戊基或己基、所有这些基团的n-异构体、异丙基、异丁基、1-甲基丁基、异戊基、新戊基、2,2-二甲基丁基、2-甲基戊基、3-甲基戊基、异己基、仲丁基、叔丁基或叔戊基。如果没有另外示出,烷基或亚烷基可以被卤代一次或多次,例如烷基可以被氟代,例如全氟代。卤代烷基的实例有CF3和CH2CF3、OCF3、SCF3或-O-(CF2)2-O-。
链烯基例如有乙烯基、1-丙稀基、2-丙稀基(=烯丙基)、2-丁烯基、3-丁烯基、2-甲基-2-丁烯基、3-甲基-2-丁烯基、5-己烯基或1,3-戊二烯基。
炔基例如有乙炔基、1-丙炔基、2-丙炔基(=炔丙基)或2-丁炔基。
卤素指氟、氯、溴或碘。
(C3-C8)环烷基是含有3、4、5、6、7或8个环碳原子的环状烷基,如环丙基、环丁基、环戊基、环己基或环辛基,其也可以被取代和/或含有1或2条双键(不饱和环烷基),例如环戊烯基或环己烯基,可以经由任意碳原子键合。
(C6-C10)芳基指芳族环或包含两个稠合或以其它方式连接的芳族环的环系,例如苯基、萘基、联苯基、四氢萘基、α-或β-四氢萘酮-、茚满基-或茚满-1-酮基。优选的(C6-C10)芳基是苯基。
(C5-C10)杂环基指其中一个或多个碳原子可以被一个或多个杂原子如1、2或3个氮原子、1或2个氧原子、1或2个硫原子或不同杂原子的组合所替换的单-或双环环系。杂环基残基可以在任意位置键合,例如1-位、2-位、3-位、4-位、5-位、6-位、7-位或8-位。(C5-C10)杂环基可以是(1)芳族的[=杂芳基]或(2)饱和的或(3)混合芳族/饱和的。
适宜的(C5-C10)杂环基包括吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并吗啉基、苯并噻吩基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、咔唑基、4aH-咔唑基、咔啉基、呋喃基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、色满基、色烯基、色烯-2-酮基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]-四氢呋喃、呋喃基、呋咱基、高吗啉基、高哌嗪基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基(苯并咪唑基)、异噻唑基、异噁唑基、吗啉基、萘啶基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑烷基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、氧硫杂蒽基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、脯氨酰基(prolinyl)、蝶啶基、purynyl、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶酮基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、噻唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻吩基、三唑基、四唑基和呫吨基。吡啶基代表2-、3-和4-吡啶基。噻吩基代表2-和3-噻吩基。呋喃基代表2-和3-呋喃基。还包括这些化合物的相应N-氧化物,例如1-氧基-2-、3-或4-吡啶基。
(C5-C10)杂环基残基的取代可在游离碳原子上或氮原子上发生。
(C5-C10)杂环基残基的优选实例是吡嗪基、吡啶基、嘧啶基、吡唑基、吗啉基、吡咯烷基、哌嗪基、哌啶基、噻吩基、苯并呋喃基、喹啉基、四唑基和三唑基。优选的(C5-C10)杂环基是(C5-C6)杂环基。
(C6-C10)芳基和(C5-C10)杂环基未被取代或若无另外指出的话被独立地选自以下的适宜基团取代一次或多次、优选取代一次至三次:卤素、OH、NO2、N3、CN、C(O)-(C1-C6)烷基、C(O)-(C1-C6)芳基、COOH、COO(C1-C6)烷基、CONH2、CONH(C1-C6)烷基、CON[(C1-C6)烷基]2、(C3-C8)环烷基、(C1-C6)烷基、(C1-C6)亚烷基-OH、(C1-C6)亚烷基-NH2、(C1-C6)亚烷基-NH(C1-C6)烷基、(C1-C6)亚烷基-N[(C1-C6)烷基]2、(C2-C6)链烯基、(C2-C6)炔基、O-(C1-C6)烷基、O-C(O)-(C1-C6)烷基、PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6)烷基、SO2N[(C1-C6)烷基]2、S-(C1-C6)烷基;SO-(C1-C6)烷基、SO2-(C1-C6)烷基、SO2-N=CH-N[(C1-C6)烷基]2、C(NH)(NH2)、NH2、NH-(C1-C6)烷基、N[(C1-C6)烷基]2、NH-C(O)-(C1-C6)烷基、NH-C(O)O-(C1-C6)烷基、NH-SO2-(C1-C6)烷基、NH-SO2-(C6-C10)芳基、NH-SO2-(C5-C10)杂环基、N(C1-C6)烷基-C(O)-(C1-C6)烷基、N(C1-C6)烷基-C(O)O-(C1-C6)烷基、N(C1-C6)烷基-C(O)-NH-(C1-C6)烷基]、(C6-C10)芳基、(C1-C6)亚烷基-(C6-C10)芳基、O-(C6-C10)芳基、O-(C1-C6)亚烷基-(C6-C10)芳基、(C5-C10)杂环基、(C1-C6)亚烷基-(C5-C10)杂环基、O-(C1-C6)亚烷基-(C5-C10)杂环基,其中(C6-C10)芳基或(C5-C10)杂环基可以被独立地选自如下的基团取代一次至三次:卤素、OH、NO2、CN、O-(C1-C6)烷基、(C1-C6)烷基、NH2、NH(C1-C6)烷基、N[(C1-C6)烷基]2、SO2CH3、COOH、C(O)O-(C1-C6)烷基、CONH2、(C1-C6)亚烷基-O-(C1-C6)烷基、(C1-C6)亚烷基-O-(C6-C10)芳基、O-(C1-C6)亚烷基-(C6-C10)芳基;或其中(C6-C10)芳基在连位上被O-(C1-C4)亚烷基-O取代,由此与氧原子所连接的碳原子一起形成5-至8-元环。(C6-C10)芳基和(C5-C10)杂环基的芳基或杂环基取代基不可以进一步被含芳基或杂环基的基团取代。
对(C6-C10)芳基而言优选的取代基有(C1-C4)烷基、O-(C1-C4)烷基、O-苯基、苯基、C(O)O-(C1-C6)烷基、C(O)OH、C(O)-(C1-C4)烷基、卤素、NO2、SO2NH2、CN、SO2-(C1-C4)烷基、SO2-N=CH-N[(C1-C6)烷基]2、NH-SO2-(C1-C4)烷基、NH2、NH-C(O)-(C1-C4)烷基、(C3-C8)环烷基、(C1-C4)烷基-OH、C(O)N[(C1-C4)烷基]2、CONH(C1-C6)烷基、C(O)NH2、N[(C1-C4)烷基]2、(C1-C4)亚烷基-(C6-C10)芳基,其中(C6-C10)芳基可以进一步被如下基团取代一次至三次、优选一次:(C1-C4)烷基、(C1-C4)亚烷基-O-(C1-C6)烷基、(C6-C10)芳基O-(C1-C6)烷基-(C6-C10)芳基,或可以在连位上被O-(C1-C4)亚烷基-O取代,由此与氧原子所连接的碳原子一起形成5-至8-元环。对(C6-C10)芳基而言更优选的取代基有卤素、CN、苯基、O-苯基、NH-C(O)-(C1-C4)烷基且尤其是NH-C(O)-CH3、C(O)-(C1-C4)烷基且尤其是C(O)-CH3、C(O)-O(C1-C4)烷基且尤其是C(O)-OCH3、(C1-C4)烷基且尤其是CH3或CF3、O-(C1-C4)烷基且尤其是O-CH3、SO2-NH2、SO2-(C1-C4)烷基且尤其是SO2-CH3或SO2-CF3;或SO2-N=CH-N[(C1-C4)烷基]2且尤其是SO2-N=CH-N[(CH3)2。
在单取代的苯基中,取代基可位于2-位、3-位或4-位,优选3-位和4-位。如果苯基携带两个取代基,它们可以位于2,3-位、2,4-位、2,5-位、2,6-位、3,4-位或3,5-位。在携带三个取代基的苯基中,取代基可位于2,3,4-位、2,3,5-位、2,3,6-位、2,4,5-位、2,4,6-位或3,4,5-位。
以上涉及苯基的描述相应地适用于衍生自苯基的二价基团,即可以是未取代或取代的亚苯基,如1,2-亚苯基、1,3-亚苯基或1,4-亚苯基。以上描述还相应地适用于芳基亚烷基中的芳基亚基团。芳基亚烷基可以是未取代的或在芳基亚基团和亚烷基亚基团上被取代,其实例有苄基、1-苯基亚乙基、2-苯基亚乙基、3-苯基亚丙基、4-苯基亚丁基、1-甲基-3-苯基-亚丙基。
对(C5-C10)杂环基而言优选的取代基有(C1-C4)烷基、O-(C1-C4)烷基、(C1-C4)亚烷基-苯基、卤素、(C1-C4)亚烷基-O-(C1-C4)烷基、(C5-C10)杂环基、(C1-C4)亚烷基-N[(C1-C4)烷基]2或(C6-C10)芳基,其中(C6-C10)芳基可以进一步被卤素、(C1-C4)烷基、O(C1-C4)烷基、(C1-C4)亚烷基-O-(C1-C6)烷基、O-(C1-C6)烷基-(C6-C10)芳基取代,或者可以在连位上被O-(C1-C4)亚烷基-O取代,由此与氧原子所连接的碳原子一起形成5-至8-元环。对(C5-C10)杂环基而言更优选的取代基有(C1-C4)烷基、O(C1-C4)烷基、卤素或苯基,其中苯基可以进一步被卤素、(C1-C4)烷基或O-(C1-C4)烷基取代一次至三次、优选一次。
(C6-C10)芳基和(C5-C10)杂环基的一般和优选的取代基可以与以上所述R1、R2、R3、R4、R5、R6、R6’、R7、R8、n、m和L的一般和优选定义组合。
本发明因此还涉及用作药物(或药剂)的式(I)或(I’)化合物和/或它们的可药用盐和/或它们的前药、式(I)或(I’)化合物和/或它们的可药用盐和/或它们的前药在制备用于治疗和/或预防与Rho-激酶和/或Rho-激酶介导的肌球蛋白轻链磷酸酶磷酸化相关的疾病的药物中的用途,即用于治疗和/或预防高血压、肺动脉高压、高眼压症、视网膜病、青光眼、周围循环障碍、周围动脉闭塞疾病(PAOD)、冠心病、心绞痛、心脏肥大、心力衰竭、局部缺血性疾病、局部缺血性器官衰竭(终端器官损伤)、纤维化肺、纤维化肝、肝衰竭、肾病、包括高血压诱导的、非高血压诱导的和糖尿病性肾病、肾衰竭、纤维化肾、肾小球硬化、器官肥大、哮喘、慢性阻塞性肺病(COPD)、成人呼吸窘迫综合征、血栓形成性障碍、中风、脑血管痉挛、脑缺血、疼痛、例如神经性疼痛、神经元变性、脊髓损伤、阿尔茨海默病、早产、勃起功能障碍、内分泌功能障碍、动脉硬化、前列腺肥大、糖尿病和糖尿病并发症、代谢综合征、血管再狭窄、动脉粥样硬化、炎症、自身免疫疾病、AIDS、骨病如骨质疏松、消化道细菌感染、脓毒病、癌症发展和进展、例如乳房、结肠、前列腺、卵巢、脑和肺的癌症及其转移。
本发明还涉及药物制剂(或药物组合物),其含有有效量的至少一种式(I)或(I’)化合物和/或其可药用盐以及可药用载体、即一种或多种可药用载体物质(或介质)和/或添加剂(或赋形剂)。
药物可口服施用,例如以丸剂、片剂、喷涂片(lacquered tablets)、包衣片、颗粒、硬和软明胶胶囊、溶液、糖浆、乳剂、混悬剂或气雾混合物形式。但是,施用也可以如下进行:经直肠、例如以栓剂形式,或经胃肠道外、例如经静脉内、肌肉内或皮下以注射溶液或输注溶液、微囊、植入剂或植入棒形式,或经皮或局部、例如以软膏、溶液或酊剂形式,或以其它途径、例如以气雾剂或鼻喷雾剂形式。
根据本发明的药物制剂以本身已知且为本领域技术人员熟悉的方式制备,除了式(I)或(I’)化合物和/或其可药用盐和/或其前药外,使用可药用的惰性无机和/或有机载体物质和/或添加剂。对于丸剂、片剂、包衣片和硬明胶胶囊的制备而言,可能使用例如乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐等。软明胶胶囊和栓剂的载体物质有例如脂肪、蜡、半固体和液体多元醇、天然或硬化油等。适宜于制备溶液、例如注射溶液或乳剂或糖浆剂的载体物质有例如水、盐水、醇、甘油、多元醇、蔗糖、转化糖、葡萄糖、植物油等。适宜用于微囊、植入剂或植入棒的载体物质有例如乙醇酸和乳酸的共聚物。药物制剂通常含有约0.5至约90%重量的式(I)或(I’)化合物和/或它们的可药用盐和/或它们的前药。药物制剂中的式(I)或(I’)活性成分和/或其可药用盐和/或其前药的量通常约0.5至约1000mg、优选约1至约500mg。
除了式(I)或(I’)活性成分和/或它们的可药用盐以及载体物质外,药物制剂可含有一种或多种添加剂,如填充剂、崩解剂、粘合剂、润滑剂、润湿剂、稳定剂、乳化剂、防腐剂、甜味剂、着色剂、矫味剂、芳香剂、增稠剂、稀释剂、缓冲物质、溶剂、增溶剂、获得储库效果的试剂、改变渗透压的盐、包衣剂或抗氧化剂。它们也可以含有两种或更多种式(I)或(I’)化合物和/或它们的可药用盐。在药物组合物含有两种或更多种式(I)化合物时,对个体化合物的选择可依据药物制剂的特定总体药理学性质。例如,作用持续时间较短的高度强效化合物可以与功效较低的长效化合物组合。就式(I)或(I’)化合物中取代基选择而言所允许的灵活性使得能够对化合物的生物学和物理化学性质进行众多控制,由此能够选择这类所需化合物。此外,除了至少一种式(I)化合物和/或其可药用盐外,药物制剂还可含有一种或多种其它治疗或预防活性成分。
当使用式(I)或(I’)化合物时,剂量可在宽限度内变化,且按照常规和如医生已知的那样,剂量应适宜于每种个例的个体情况。其取决于例如所应用的具体化合物、所治疗疾病的性质和严重程度、施用方式和方案或所治疗的是急性还是慢性病症或是否进行预防。适当的剂量可利用医学领域已知的临床方法建立。一般而言,在重约75kg的成人中获得预期结果的日剂量是约0.01至约100mg/kg、优选约0.1至约50mg/kg、特别是约0.1至约10mg/kg(每种情况下以mg/公斤体重计)。日剂量可以分为若干、例如2、3或4部分施用,特别在施用较大量的情况下如此。通常根据个体行为,可能有必要向上或向下偏离所指示的日剂量。
此外,式(I)化合物可用作用于制备其它化合物的合成中间体、特别是可由式I化合物获得、例如通过引入取代基或修饰官能团获得的其它药学活性成分。
一般而言,然后通过标准方法除去仍然存在于偶联反应所获得的产物中的保护基。例如,作为氨基保护形式的叔丁基保护基、特别是叔丁氧羰基可通过用三氟乙酸处理而脱保护、即转化为氨基。如已经解释的那样,偶联反应后还可能由适宜的前体基团生成官能团。此外,然后可以通过已知方法转化为式(I)或(I’)化合物的可药用盐或前药。
一般而言,对含有最终的式(I)或(I’)化合物或中间体的反应混合物进行处理,如果需要的话,然后将产物通过本领域技术人员已知的常规方法进行纯化。例如,所合成化合物可利用熟知的方法如结晶、色谱法或反相高效液相色谱法(RP-HPLC)或基于例如化合物大小、电荷或疏水性的其它分离方法纯化。类似地,熟知的方法如氨基酸序列分析、NMR、IR和质谱法(MS)可用于表征本发明化合物。
异喹啉酮类可经由多种方法合成。以下通用流程阐释了一些获得异喹诺酮类的可能方法,但并不限制本发明。
流程1
可使适宜取代的醛、例如被连接于适宜位置的、彼此独立地为氢、烷基、烷氧基或卤素的X或Y取代的醛与适宜的化合物如氨基乙醛的缩醛例如在溶剂如THF、氯仿或甲苯中、在甲苯磺酸或其它适宜酸的酸催化下反应,得到其中Q’可以是例如甲基或乙基的亚胺(ii),其然后可通过不同方法环化为异喹啉(iii)。例如,这可通过用适宜路易斯酸如四氯化肽、卤化铁、卤化铝等进行的路易斯酸催化、在环境温度至100℃的温度下进行,或通过适宜还原剂如硼氢化钠的作用将亚胺还原为相应的胺、将胺通过与适宜的酰氯反应转化为酰胺或磺酰胺以及随后通过适当路易斯酸的作用环化为异喹啉来进行。然后,异喹啉(iii)自身可通过适宜氧化剂如过氧化氢、间氯过苯甲酸等的作用在室温或升高的温度下转化为相应的N-氧化物(iv)。N-氧化物(iv)然后可通过与试剂如氧氯化磷在有或无五氯化磷的存在下反应而转化为1-氯-异喹啉衍生物(v)。该衍生物(v)然后可通过与各种醇Q-OH如甲醇、乙醇或苄醇在适宜碱如氢化钠的存在下、在适宜溶剂如二甲基甲酰胺、二甲基乙酰胺等中反应而转化为适宜的1-烷氧基-衍生物。或者,(v)可通过与试剂如乙酸铵反应而直接转化为异喹啉酮衍生物(vii)。
流程2
或者,异喹啉酮可如下获得:使适宜的其中Z是例如H或烷基如甲基或乙基的3-甲酰化或乙酰化氟苯(viii)与试剂如膦酸乙酸三乙酯(triethylphosphono acetate)在适宜碱如氢化钠的存在下反应,得到相应的肉桂酸酯,其随后通过适宜碱如氢氧化钾、氢氧化钠或氢氧化锂的作用、在适宜的溶剂中裂解,得到酸(ix)。然后(ix)可通过已知方法转化为相应的酰氯,酰氯可通过与叠氮化钠在适宜溶剂如醚、氯仿或丙酮中、在有或无水的存在下反应而转化为酰基叠氮。然后,可将相应的叠氮化物通过在适宜溶剂如二苯基甲烷或二苯醚中、在适宜的温度下反应而转化为异喹啉酮(x)。
流程3
以上获得的6-氟-异喹诺酮、例如(vi)可与适宜的其中P1/P2相互独立地是例如氢、烷基或保护基如Boc或邻苯二甲酰基的P1/P2-取代的氨基醇在碱如DBU、碳酸铯或氢化钠的存在下反应,得到相应的烷氧基取代的衍生物(xi)。最后,该转化可以已经在合成的早期阶段进行(例如通过适宜中间体的反应)。应当理解:在未保护的异喹诺酮的情况下,这可能需要通过适宜的方法如与适宜取代的烷基或苄基卤在碱存在下反应而在异喹诺酮部分的氮或氧上进行保护。
然后可以释放出经由该方法获得的产物如(xi),或者如果存在适宜的氨基官能团的话,可以与适宜的醛或酮在还原剂如三乙酰氧基硼氢化钠、硼氢化钠或氰基硼氢化钠的存在下、在适宜的溶剂中、在吸水剂如分子筛或适宜原酸酯的存在下反应。该氨基可能必须在初始步骤释放出,例如在酸性条件下除去Boc-基团。此外,氨基可以通过与适宜的酰氯在碱如三乙胺或Hünig’氏碱的存在下反应或者通过与适宜羧酸在碱如三乙胺或Hünig’氏碱和偶联剂如EDC、PyBOP或TOTU的存在下反应而被酰化。
在使用被保护的异喹诺酮的情况下,需要裂解所用的保护基以释放出所需的异喹诺酮(xii)。但是,该释放可以在还原性胺化步骤之前或之后进行,这取决于所用醛/酮的性质和所用的保护基。
异喹诺酮衍生物如(xii)可作为游离碱或各种盐获得,如盐酸盐、氢溴酸盐、磷酸盐、三氟乙酸盐、硫酸盐或富马酸盐。所得的盐可转化为相应的游离碱,例如对它们进行离子交换色谱法或例如通过用碱水溶液处理、随后用适宜的有机溶剂如甲基叔丁基醚、氯仿、乙酸乙酯或异丙醇/二氯甲烷混合物处理、随后蒸发至干。
如上所述用于制备异喹啉酮衍生物的通用方法可容易地调整以制备式(I)或(I’)化合物。在以下实施例中,更为详细地显示了本发明化合物的制备。
因此,下述实施例是本发明的一部分,其用于解释而非限制本发明。
可以理解,实质上不影响本发明的各种实施方案的活性的变通包括在本文公开的发明范围内。
LC/MS-方法:
方法A:
固定相: Col YMC Jsphere 33×2
梯度: ACN+0.05%TFA∶H2O+0.05%TFA
5∶95(0min)至95∶5(3.4min)至95∶5(4.4min)
流速 1mL/min
方法B:
固定相: Col YMC Jsphere 33×2
梯度: ACN+0.05%TFA∶H2O+0.05%TFA
5∶95(0min)至95∶5(2.5min)至95∶5(3.0min)
流速 1mL/min
方法C:
固定相: Col YMC Jsphere ODS H80 20×2
梯度: ACN∶H2O+0.05%TFA
4∶96(0min)至95∶5(2.0min)至95∶5(2.4min)
流速 1mL/min
方法D:
固定相: Col YMC Jsphere 33×2.1
梯度: ACN+0.08%FA∶H2O+0.1%FA(甲酸)
5∶95(0min)至95∶5(2.5min)至95∶5(3min)
流速 1.3mL/min
方法E:
固定相: Col YMC Jsphere 33×2
梯度: ACN+0.05%TFA∶H2O+0.05%TFA
5∶95(0min)至95∶5(2.5min)至95∶5(3.2min)
流速 1.3mL/min
方法F:
固定相: Col YMC-Pack Pro C18 RS 33×2.1
梯度: ACN+0.1%FA∶H2O+0.1%FA(甲酸)
5∶95(0min)至95∶5(2.5min)至95∶5(3min)
流速 1.3mL/min
方法G:
固定相: Col YMC Jsphere 33×2.1
梯度: ACN+0.05%TFA∶H2O+0.05%TFA
2∶98(0min)至2∶98(1min)至95∶5(5min)至95∶5(6.25min)
流速 1mL/min
方法H:
固定相: Col YMC Jsphere ODS H80 20×2
梯度: ACN∶H2O+0.05%TFA
7∶93(0min)至95∶5(1.2min)至95∶5(1.4min)
流速 1.1mL/min
方法I:
固定相: Waters XBridge C184
梯度: ACN+0.05%TFA∶H2O+0.05%TFA
5∶95(0min)至5∶95(0.3min)至95∶5(3.5min)至95∶5(4min)
流速 1.3mL/min
方法J:
固定相: Col YMC Jsphere 33×2
梯度: ACN+0.05%TFA∶H2O+0.05%TFA
5∶95(0min)至5∶95(0.5min)至95∶5(3.5min)至95∶5(4min)
流速 1.3mL/min
(2,2-二甲氧基-乙基)-(4-氟-苄基)-胺(1)
将12.4g 4-氟苯甲醛溶于100ml甲苯中,与10.5g 2-氨基乙醛二甲基缩醛和1.90g对甲苯磺酸一水合物在迪安-斯达克(Dean Stark)装置中反应2小时。使溶液冷却,用饱和碳酸氢钠溶液、水和盐水萃取,经硫酸镁干燥,蒸发至干。将粗产物溶于100ml乙醇中。分批加入1.89g硼氢化钠。继续搅拌过夜。对于后处理,加入乙酸直至没有观察到气体逸出。然后将溶液蒸发至干,加入二氯甲烷中,用水洗涤两次。将有机层用盐水萃取,经硫酸镁干燥,蒸发至干。将所得粗产物(20g)未经纯化用于进一步的反应。Rt=0.86分钟(方法B)。实测质量:182.1(M-OMe-),214.2(M+H+)。
N-(2,2-二甲氧基-乙基)-N-(4-氟-苄基)-4-甲基-苯磺酰胺(2)
将20g(2,2-二甲氧基-乙基)-(4-氟-苄基)-胺(1)溶于120ml二氯甲烷中。加入20ml吡啶。于0℃滴加23.8g对甲苯磺酰氯在二氯甲烷中的溶液。使反应物温热至室温,继续搅拌直至转化完全。对于后处理,将反应混合物用2M盐酸洗涤两次、用碳酸氢钠溶液洗涤两次和用盐水洗涤一次。将有机层经硫酸镁干燥,蒸发至干,将所得粗产物经硅胶色谱法纯化,得到22.95g化合物2,为橙色油。Rt=1.71分钟(方法C)。实测质量:336.1(M-OMe-)。
6-氟-异喹啉(3)
将41.6g AlCl3混悬于400ml二氯甲烷中。于室温加入22.95g N-(2,2-二甲氧基-乙基)-N-(4-氟-苄基)-4-甲基-苯磺酰胺(2)在150ml二氯甲烷中的溶液。于室温继续搅拌过夜,将溶液倒在冰上,分离各层,水相用二氯甲烷萃取两次,然后将所合并的有机层用碳酸氢钠溶液萃取两次。有机层经硫酸镁干燥,蒸发至干,将所得粗产物(8.75g)经硅胶色谱法纯化,得到2.74g化合物3。Rt=0.30分钟(方法C)。实测质量:148.1(M+H+)。
7-氯-6-氟-异喹啉(4)
以3-氯-4-氟-苯甲醛为原料,通过与合成6-氟-异喹啉(3)相同的反应序列制得标题化合物。Rt=0.77分钟(方法A)。实测质量:182.1/184.1(M+H+)。
7-氯-6-氟-异喹啉2-氧化物(5)
将25g(137.7mmol)7-氯-6-氟-异喹啉(4)溶于500ml二氯甲烷中。于室温加入50.9g(206.5mmol)间氯过苯甲酸(70%),将混合物于室温搅拌直至转化完全。对于后处理,滤出沉淀物,用二氯甲烷洗涤。将滤液用碳酸氢钠溶液洗涤两次。分离各层,水相用二氯甲烷萃取两次。有机相用硫酸镁干燥,蒸发。如此获得的固体物质(18.4g)未经进一步纯化进行使用。Rt=0.87分钟(方法C)。实测质量:198.1/200.1(M+H+)。
1,7-二氯-6-氟-异喹啉(6)
将2.6g(12.0mmol)7-氯-6-氟-异喹啉2-氧化物(5)在40ml POCl3中于回流加热4小时。将混合物冷却至室温后,将其倒在冰上。将水性溶液用二氯甲烷萃取三次。所合并的有机层用硫酸镁干燥,蒸发,得到2.91g标题化合物,将其未经进一步纯化进行使用。Rt=2.34分钟(方法A)。实测质量:216.0/218.0(M+H+)。
7-氯-6-氟-2H-异喹啉-1-酮(7)
将41.13g(190.4mmol)1,7-二氯-6-氟-异喹啉(6)溶于670ml乙酸中。加入148.8g(1.90mol)乙酸铵后,将溶液于100℃搅拌。3小时后,在减压下除去溶剂,将残余物倒入水中。水相用二氯甲烷萃取三次,所合并的有机层用饱和碳酸氢钠溶液和盐水洗涤,经硫酸钠干燥,蒸发至干。将粗产物从乙酸乙酯/庚烷中结晶,得到14.85g预期产物。通过将母液蒸发和进行硅胶色谱法可以获得另外4.5g预期产物。将沉淀物过滤和干燥,得到9.91g标题化合物。Rt=1.33分钟(方法B)。实测质量:198.0(M+H+)。
6-氟-异喹啉酮(8)
将4.8ml(90.3mmol,1.5当量)亚硫酰氯分批加入10g(60.2mmol)3-氟肉桂酸在44ml氯仿和1ml DMF中的溶液中。将反应物回流加热2.5小时。然后蒸馏溶剂,得到11.4g酰氯粗品,将其未经进一步纯化进行使用。
将酰氯溶于45ml丙酮中。于0℃分批加入8.03g(123.5mmol,2当量)NaN3。然后加入41ml水,同时维持温度低于5℃。将反应物另外搅拌1.5小时。然后加入55ml氯仿。将混合物用80ml水、然后用40ml盐水洗涤。经Na2SO4干燥和过滤后,加入14ml二苯醚,真空除去大部分氯仿(未加热)。应当避免完全除去氯仿。
历经15分钟将含有叠氮化物、二苯醚和剩余氯仿的溶液于260℃滴加入10ml三丁胺在97ml二苯醚中的溶液中。在加入期间可观察到剧烈反应。将反应物于260℃反应另外20分钟。冷却至室温后,加入270ml正庚烷。过滤出所沉淀的产物,用乙醚洗涤,得到5.65g标题化合物。MS(DCI)实测质量:164.0(M+H+)。
6-氟-2-(4-甲氧基-苄基)-2H-异喹啉-1-酮(9)
将169μL(1.24mmol,1.1当量)对甲氧基苄基氯加入200mg(1.13mmol)6-氟-异喹啉酮(8)和368mg(1.36mmol,1.2当量)Cs2CO3在3ml DMF中的混悬液中。将混合物搅拌2小时,然后倒在冰上。过滤出沉淀,用水洗涤,干燥,得到300mg标题化合物。Rt=1.76分钟(方法B)。实测质量:284.14(M+H+)。
7-氯-6-氟-2-(4-甲氧基-苄基)-2H-异喹啉-1-酮(10)
以7-氯-6-氟-2H-异喹啉-1-酮(7)为原料,按照对6-氟-2-(4-甲氧基-苄基)-2H-异喹啉-1-酮(9)所述的方案制得标题化合物。Rt=1.66分钟(方法C)。实测质量:318.3(M+H+)。
1-苄基氧基-7-氯-6-氟-异喹啉(11)
将14.74g(74.6mmol)7-氯-6-氟-2H-异喹啉-1-酮(7)溶于150ml甲苯中。加入30.86g(111.9mmol)碳酸银和15.31g(89.5mmol)苄基溴后,将混合物于80℃搅拌3小时。冷却至室温后,将反应混合物过滤,将滤液蒸发。将残余物溶于二氯甲烷中,用水洗涤,用硫酸镁干燥,蒸发。最后通过制备型HPLC进行纯化,得到11.63g标题化合物。Rt=2.51分钟(方法B)。实测质量:288.1/290.1(M+H+)。
6-(顺式-4-氨基-环己基氧基)-7-氯-2H-异喹啉-1-酮(12)
将2.19g(10.2mmol)顺式-(4-羟基-环己基)-氨基甲酸叔丁酯溶于20ml二甲基乙酰胺中。在氩气氛围下,加入814mg(20.4mmol)氢化钠(60%),将混合物于室温搅拌。30分钟后,加入2.0g(9.26mmol)1,7-二氯-6-氟-异喹啉(6)在5ml二甲基乙酰胺中的溶液,于室温继续搅拌。1小时后,加入2.0g(18.5mmol)苄醇和740mg(18.5mmol)氢化钠(60%)。将反应物于室温搅拌2小时,于80℃搅拌30分钟,以使得转化完全。真空除去溶剂,将残余物加入二氯甲烷中,用水洗涤两次。经硫酸镁干燥后,蒸发有机层,得到4.44g粗的中间体顺式-[4-(1-苄基氧基-7-氯-异喹啉-6-基氧基)-环己基]-氨基甲酸叔丁酯。将中间体溶于甲醇中,于室温用2N HCl进行处理。搅拌2天后,通过添加氢氧化钠将反应混合物调节至碱性。真空除去溶剂,将残余物在乙醇中搅拌。过滤和蒸发滤液后,得到固体物质,将其通过制备型HPLC进行纯化。将所得三氟乙酸盐溶于2N HCl中。最后进行冷冻干燥,获得433mg标题化合物,为盐酸盐。Rt=0.89分钟(方法B)。实测质量:293.2/295.2(M+H+)。
1-苄基氧基-7-氯-6-(1,4-二氧杂-螺[4.5]癸烷-8-基氧基)-异喹啉(13)
将1.26g(8.34mmol)二氧杂-螺[4.5]癸烷-8-醇溶于50ml二甲基乙酰胺中,加入695.2mg(17.4mmol)氢化钠(60%)。于室温搅拌30分钟后,加入2.0g(6.95mmol)1-苄基氧基-7-氯-6-氟-异喹啉(11)在50ml二甲基乙酰胺中的溶液,继续于室温搅拌。1小时后在减压下除去溶剂。将残余物溶于二氯甲烷中,用水洗涤。有机层用硫酸镁干燥,蒸发,得到3.30g粗产物,将其未经进一步纯化进行使用。Rt=2.05分钟(方法C)。实测质量:426.5(M+H+)。
7-氯-6-(4-氧代-环己基氧基)-2H-异喹啉-1-酮(14)
将3.30g 1-苄基氧基-7-氯-6-(1,4-二氧杂-螺[4.5]癸烷-8-基氧基)-异喹啉(13,粗产物)在30ml 6N HCl/丙酮(1∶2)于室温进行搅拌。3小时后,将反应混合物倒入饱和碳酸氢钠溶液中,用二氯甲烷萃取。有机层用硫酸镁干燥,蒸发。粗产物通过制备型HPLC进行纯化。Rt=1.34分钟(方法B)。实测质量:292.0(M+H+)。
以7-氯-6-(4-氧代-环己基氧基)-2H-异喹啉-1-酮(14)为原料,类似于下文所述的通用方法合成下述化合物,为盐酸盐:
还原性胺化反应的通用方法:
将0.46mmol适宜的胺溶于10ml甲醇中。加入分子筛92.3mg(0.57mmol)三乙胺、273.8mg(4.56mmol)乙酸和0.57mmol酮(14)后,滴加86.0mg(1.37mmol)氰基硼氢化钠溶液,将混合物于室温搅拌直至转化完全。在一些情况下,需要将混合物加热至70℃以使转化完全。对于产物的分离,将溶液过滤,在减压下除去溶剂。将残余物溶于二氯甲烷中,用1NNaOH和饱和氯化钠溶液洗涤,用硫酸镁干燥,蒸发。如果获得单-和二烷基化产物,将其通过制备型HPLC纯化,或者从甲醇HCl中沉淀出。将所得三氟乙酸盐在2N HCl/甲醇中搅拌,蒸发,溶于水中,冷冻干燥,得到预期产物,为盐酸盐。
在含有0.1%TFA的HPLC-产物级分的蒸发期间或者在随后在2NHCl/甲醇中搅拌期间,Boc-保护的产物被脱保护。参见表1。
[4-(7-氯-1-氧代-1,2-二氢-异喹啉-6-基氧基)-顺式-环己基氨基]-乙酸乙基酯(23)
将300mg(0.91mmol)6-顺式-(4-氨基-环己基氧基)-7-氯-2H-异喹啉-1-酮(12)溶于20ml甲醇中,用258mg(1.14mmol)乙醛酸乙酯按照还原胺化的通用方法进行处理。为了使转化完全,历经34小时分批加入另外的5.0当量乙醛酸乙酯和0.5当量氰基硼氢化钠,5小时反应时间后使温度增加至60℃直至反应完全。过滤后,蒸发反应溶液。将残余物溶于二氯甲烷中,用1N NaOH和饱和NaCl-溶液洗涤,经MgSO4干燥,蒸发。将如此所得的粗产物未经进一步纯化用于下一步反应。Rt=0.81分钟(方法C)。实测质量:365.4(M+H+,甲基酯,因为使用甲醇作为溶剂),0.87分钟(方法C)。实测质量:379.4(M+H+,乙基酯,标题化合物)。
[4-(7-氯-1-氧代-1,2-二氢-异喹啉-6-基氧基)-顺式-环己基氨基]-乙酸(24)
将185mg[4-(7-氯-1-氧代-1,2-二氢-异喹啉-6-基氧基)-顺式-环己基氨基]-乙酸乙基酯(23,粗产物)溶于2ml甲醇中。加入.2ml 2N NaCO3-溶液后,将溶液于室温搅拌1.5小时。真空蒸发溶剂,将残余物通过制备型HPLC进行纯化,得到标题化合物,为三氟乙酸盐。Rt=0.91分钟(方法B)。实测质量:351.3(M+H+)。
6-(反式-4-氨基-环己基氧基)-7-甲基-2H-异喹啉-1-酮(25)
a)6-氟-7-甲基-2H-异喹啉-1-酮
于0℃向10.0g(55.5mmol)3-氟-4-甲基-肉桂酸在80ml丙酮中的溶液中依次加入6.74g(66.6mmol)三乙胺在10ml丙酮中的溶液,然后加入7.83g(72.2mmol)氯甲酸乙酯。于0至5℃搅拌2小时后,加入4.0g(61.1mmol)叠氮化钠在9.5ml水中的溶液。另外搅拌1小时后,将反应混合物倒入200ml冰水中,用氯仿萃取两次。将有机相经硫酸镁干燥,加入40ml二苯醚,在真空下小心除去氯仿。然后将残余物滴加入已经预先加热至245℃的50ml二苯醚中。加入完成后,将其于230-250℃另外搅拌1小时。冷却至150℃后,将反应混合物倒入270ml庚烷中,在冰浴中进一步冷却后,抽滤出沉淀的产物,获得4.1g 6-氟-7-甲基-2H-异喹啉-1-酮。
b)6-氟-2-(4-甲氧基-苄基)-7-甲基-2H-异喹啉-1-酮
向9.17g(51.8mmol)6-氟-7-甲基-2H-异喹啉-1-酮在80ml DMF中的溶液中加入20.2g(62.1mmol)碳酸铯,然后加入8.92g(56.9mmol)4-甲氧基苄基氯。于室温搅拌90分钟后,将反应混合物倒入600ml水中,搅拌1小时,然后通过抽滤分离出沉淀的产物。由母液通过采用庚烷/乙酸乙酯(80∶20)的色谱法分离出另外的产物。将所合并的产物从乙酸乙酯中进行重结晶,获得8.39g 6-氟-2-(4-甲氧基-苄基)-7-甲基-2H-异喹啉-1-酮。
c)6-(反式-4-氨基-环己基氧基)-2-(4-甲氧基-苄基)-7-甲基-2H-异喹啉-1-酮
向1.48g(9.75mmol)反式-4-氨基环己醇盐酸盐在20ml二甲基乙酰胺中的溶液中加入1.95g(48.77mmol)氢化钠(60%),将混合物搅拌15分钟。然后加入2.90g(9.75mmol)6-氟-2-(4-甲氧基-苄基)-7-甲基-2H-异喹啉-1-酮在30ml二甲基乙酰胺中的溶液,将反应混合物于80℃加热2天。冷却后,将混合物倒入300ml冰水中,通过色谱法将沉淀的粗产物进行纯化。首先用乙酸乙酯/庚烷(2∶1)洗脱出剩余的原料,最后用纯甲醇洗脱出预期产物,得到1.98g 6-(反式-4-氨基-环己基氧基)-2-(4-甲氧基-苄基)-7-甲基-2H-异喹啉-1-酮。
d)6-(反式-4-氨基-环己基氧基)-7-甲基-2H-异喹啉-1-酮(25)
将2.64g(6.7mmol)6-(反式-4-氨基-环己基氧基)-2-(4-甲氧基-苄基)-7-甲基-2H-异喹啉-1-酮和15.3g(134.5mmol)三氟乙酸在微波炉中于150℃加热2小时。然后真空蒸馏出过量的三氟乙酸,将残余物用130ml 1M盐酸稀释。水相用二氯甲烷洗涤3次,然后将其冷冻干燥,得到盐酸盐,将其从异丙醇中重结晶。得到1.1g 6-(反式-4-氨基-环己基氧基)-7-甲基-2H-异喹啉-1-酮(25),为盐酸盐。Rt=0.92分钟(方法B)。实测质量:273.22(M+H+)。
6-(顺式-4-氨基-环己基氧基)-7-甲基-2H-异喹啉-1-酮(26)
a)顺式-4-氨基环己醇
于0℃向30.0g(0.265mol)环己酮肟在300ml二氯甲烷和38ml乙醇中的溶液中缓慢加入34.5g(0.318mol)次氯酸叔丁基酯。将所得深蓝色溶液冷却至-20℃,然后加入31.9g(0.398mol)1,3-环己二烯,将混合物于5℃在冰箱中存贮2天直至蓝色消失。将反应混合物浓缩至其体积的50%,然后缓慢加入600ml二乙醚。搅拌过夜后,通过抽滤分离出所得沉淀物,得到29.0g2-氧杂-3-氮杂-二环[2.2.2]辛烷-5-烯,为盐酸盐。将5.0g(0.045mol)该物质用3.0g(0.013mol)氧化铂于2巴氢气压力下进行氢化2小时。7小时后,过滤出催化剂,加入20ml 4M盐酸在二噁烷中的溶液。蒸发后,将残余物从30ml异丙醇中重结晶出,得到3.1g顺式-4-氨基环己醇,为盐酸盐。
b)6-(顺式-4-氨基环己基氧基)-7-甲基-2H-异喹啉-1-酮(26)
由2.55g(16.8mmol)顺式-4-氨基环己醇盐酸盐和5.0g(16.8mmol)6-氟-2-(4-甲氧基-苄基)-7-甲基-2H-异喹啉-1-酮(25,步骤b),如实施例25(步骤c和d)中所述制得0.98g 6-(顺式-4-氨基-环己基氧基)-7-甲基-2H-异喹啉-1-酮盐酸盐。Rt=0.99分钟(方法B)。实测质量:273.18(M+H+)。
7-甲基-6-(4-吡咯烷-1-基-环己基氧基)-2H-异喹啉-1-酮(27)
a)2-(4-甲氧基-苄基)-7-甲基-6-(4-吡咯烷-1-基-环己基氧基)-2H-异喹啉-1-酮
向0.4g(1mmol)6-(顺式-4-氨基-环己基氧基)-2-(4-甲氧基-苄基)-7-甲基-2H-异喹啉-1-酮(26,步骤b)、0.31g(2mmol)碘化钠和0.35g(2.5mmol)碳酸钾在40ml DMF中的溶液中滴加0.24g(1.1mmol)1,4-二溴丁烷。于室温搅拌2天后,将混合物用水稀释,用乙酸乙酯萃取。干燥和蒸发后,将残余物通过色谱法进行纯化,得到182mg 2-(4-甲氧基-苄基)-7-甲基-6-(4-吡咯烷-1-基-环己基氧基)-2H-异喹啉-1-酮。
b)7-甲基-6-(4-吡咯烷-1-基-环己基氧基)-2H-异喹啉-1-酮(27)
将180mg(0.4mmol)2-(4-甲氧基-苄基)-7-甲基-6-(4-吡咯烷-1-基-环己基氧基)-2H-异喹啉-1-酮和0.9g三氟乙酸在微波炉中于150℃加热。进行水性处理后,获得58mg 7-甲基-6-(4-吡咯烷-1-基-环己基氧基)-2H-异喹啉-1-酮,为盐酸盐。Rt=1.07分钟(方法B)。实测质量:327.2(M+H+)。
酰胺形成的通用方法:
将0.6mmol适宜的胺(作为盐酸盐)混悬于7.5ml无水DMF中。冷却至0℃后,加入0.6mmol三乙胺和0.6mmol O-((乙氧羰基)氰基亚甲基氨基)-N,N,N’,N’-四甲基脲鎓四氟硼酸盐)。将该溶液加入相应的甲酸(0.6mmol)和1当量三乙胺在7.5ml DMF中的溶液中。将混合物温热至室温,搅拌2小时。通过HPLC监测反应进程,如果需要的话加入另外当量的TOTU和三乙胺。蒸发混合物,将粗产物加入乙酸乙酯中,经硅藻土过滤,蒸发溶剂。通过硅胶色谱法纯化产物。
将所得产物溶于10ml二氯甲烷中,加入三氟乙酸(1mL)。将混合物于环境温度搅拌2小时,蒸发,加入1M HCl中,冷冻干燥。将粗产物最后溶于两倍水中,然后冷冻干燥,得到预期产物,为盐酸盐。
(1R,3S)-3-(叔丁基-二甲基-甲硅烷基氧基)-环戊醇(32)
将2.0g(9.33mmol)(1S,4R)-4-(叔丁基-二甲基-甲硅烷基氧基)-环戊-2-烯醇(Curran等人.Tetrahedron 1997,53,1983-2004)在10ml乙酸乙酯中的溶液用66mg 20%在活性碳上的氢氧化钯进行处理,将混合物于室温在氢气氛围(1atm)下搅拌过夜。滤除催化剂,将滤液真空蒸发,得到2.0g标题化合物(32)。Rt=1.72分钟(方法C)。实测质量:217.2(M+H+)。
(1S,3S)-3-(叔丁基-二甲基-甲硅烷基氧基)-环戊基胺(33)
将720mg(3.33mmol)(1R,3S)-3-(叔丁基-二甲基-甲硅烷基氧基)-环戊醇(32)和2.18g(8.32mmol)三苯膦溶于15ml四氢呋喃中,冷却至-20℃。然后滴加1.05ml(6.65mmol)偶氮二甲酸二乙酯,3分钟后滴加717μL(3.33mmol)二苯基磷酰基叠氮化物,将混合物于室温搅拌过夜。加入二乙醚和饱和氯化钠溶液,水相用二乙醚萃取三次。所合并的有机层经硫酸钠干燥,过滤,蒸发。
将粗产物溶于15ml四氢呋喃中,加入1.47g(1.80mmol)在聚苯乙烯上的三苯膦(1.2mmol/g)。加入2ml水后,将反应混合物于室温搅拌直至反应完全。滤除树脂,将滤液真空蒸发。所得产物、即256mg标题化合物(33)对于进一步转化而言是足够纯的。Rt=1.11分钟(方法C)。实测质量:216.2(M+H+)。
(1S,3S)-3-氨基-环戊醇(34)
向95mg(0.44mmol)(1S,3S)-3-(叔丁基-二甲基-甲硅烷基氧基)-环戊基胺(33)在1ml 2-丙醇中的溶液中加入1ml 2N盐酸,将混合物于室温搅拌直至转化完全。将反应混合物用二乙醚洗涤三次,将水相在真空中浓缩,冷冻干燥。将残余物加入水中,再次冷冻干燥,得到68mg(1S,3S)-3-氨基-环戊醇(34),为盐酸盐。Rt=0.13分钟(方法C)。实测质量:102.3(M+H+)。((1R,4S)-4-叠氮基-环戊-2烯基氧基)-叔丁基-二甲基-甲硅烷(35)
通过将630mg(2.46mmol)乙酸(1S,4R)-4-(叔丁基-二甲基-甲硅烷基氧基)-环戊-2烯基酯[通过使可自市售途径获得的乙酸(1S,4R)-4-羟基-环戊-2烯基酯进行硅烷基化而合成(Curran等人,Tetrahedron 1997,53,1983-2004)]在6ml四氢呋喃中的溶液与320mg(4.91mmol)叠氮化钠在1.3ml水中的溶液合并,制得标题化合物。向该双相混合物中加入112mg(0.12mmol)三(双亚苄基丙酮)双钯(0)和258mg(0.98mmol)三苯膦在2ml四氢呋喃中的溶液,将反应混合物于50℃加热6小时,此时反应完全。加入饱和氯化钠溶液,将水相反复用乙醚萃取。将所合并的有机相经硫酸钠干燥,过滤,蒸发。粗物质经硅胶色谱法纯化,得到475mg标题化合物(35).1H NMR(400MHz,DMSO)δ=0.09(s,3H),0.10(s,3H),0.88(s,9H),1.49(dt,J=3.9,14.0Hz,1H),2.69(dt,J=7.4,14.1Hz,1H),4.22-4.26(m,1H),4.75-4.79(m,1H),5.92-5.95(m,1H),6.05(dt,J=1.8,5.4Hz,1H)
(1S,4R)-4-(叔丁基-二甲基-甲硅烷基氧基)-环戊-2烯基胺(36)
将934mg(3.90mmol)((1R,4S)-4-叠氮基-环戊-2烯基氧基)-叔丁基-二甲基-甲硅烷(35)溶于16ml四氢呋喃中,加入1.13g(4.29mmol)三苯膦。加入2ml水后,将反应混合物于室温搅拌直至反应完全。加入氯化钠溶液,分离各层,将有机层真空蒸发。粗产物通过硅胶色谱法进行纯化,得到890mg标题化合物(36)。Rt=1.02分钟(方法C)。实测质量:214.3(M+H+)。
(1R,3S)-3-(叔丁基-二甲基-甲硅烷基氧基)-环戊基胺(37)
方法A
向135mg(0.56mmol)((1R,4S)-4-叠氮基-环戊-2烯基氧基)-叔丁基-二甲基-甲硅烷(35)在2ml甲醇中的溶液中加入60mg 5%钯/活性炭,将混悬液在氢气氛围(1atm)下于室温搅拌过夜。滤除催化剂,真空蒸发滤液。将残余物经硅胶色谱法纯化,得到98mg标题化合物(37)。Rt=1.15分钟(方法C)。实测质量:216.3(M+H+)。
方法B
将330mg(1.55mmol)(1S,4R)-4-(叔丁基-二甲基-甲硅烷基氧基)-环戊-2烯基胺(36)在4ml乙醇中的溶液用164mg 5%钯/活性炭进行处理,将混合物在氢气氛围(1atm)下于室温搅拌5小时。滤除催化剂,蒸发滤液,得到227mg标题化合物(37),其纯度对于进一步的转化而言是足够的。
(1S,3R)-3-氨基-环戊醇(38)
以486mg(2.26mmol)(1R,3S)-3-(叔丁基-二甲基-甲硅烷基氧基)-环戊基胺(37)为原料,按照对(1S,3S)-3-氨基-环戊醇(34)所述的方法合成229mg标题化合物,为盐酸盐。Rt=0.14分钟(方法C)。实测质量:102.3(M+H+)。
2-(4-甲氧基-苄基)-6-((1S,3S)-3-氨基-环戊基氧基)-2H-异喹啉-1-酮(39)
将106mg(4.20mmol)氢化钠(95%)混悬于3ml二甲基乙酰胺中,滴加溶于1ml二甲基乙酰胺中的193mg(1.40mmol)(1S,3S)-3-氨基-环戊醇(34)。1小时后,加入溶于另外3ml二甲基乙酰胺中的402mg(1.42mmol)2-(4-甲氧基-苄基)-6-氟-2H-异喹啉-1-酮(9)。将反应混合物于80℃搅拌直至反应完全。将混合物倒入水中,用二氯甲烷和2-丙醇(3∶1)的混合物萃取三次,将所合并的有机层蒸发。加入水,将粗产物进行冷冻干燥以除去残余的二甲基乙酰胺。将所得粗产物通过硅胶色谱法进行纯化,得到250mg标题化合物(39)。Rt=1.20分钟(方法E)。实测质量:365.2(M+H+)。
通过与合成39相同的方法,采用相应的2-(4-甲氧基-苄基)-6-氟-2H-异喹啉-1-酮和3-氨基-环戊醇,获得下述三种产物(表3)。
6-((1S,3S)-3-氨基-环戊基氧基)-2H-异喹啉-1-酮(43)
将125mg(0.34mmol)2-(4-甲氧基-苄基)-6-((1S,3S)-3-氨基-环戊基氧基)-2H-异喹啉-1-酮(39)溶于1ml TFA中,在微波炉中于150℃加热3小时。加入甲醇,蒸发反应混合物。将溶液加入1N HCl中,用二氯甲烷萃取三次。将所合并的二氯甲烷层用1N HCl萃取两次,将所合并的HCl层冷冻干燥。将残余物溶于水中,再次冷冻干燥,得到42mg 6-((1S,3S)-3-氨基-环戊基氧基)-2H-异喹啉-1-酮(43),为盐酸盐。Rt=0.86分钟(方法E)。实测质量:245.1(M+H+)。
通过与合成43相同的方法,以相应的2-(4-甲氧基-苄基)-2H-异喹啉-1-酮为原料,获得下述三种产物,为盐酸盐(表4)。
6-(顺式-4-氨基-环庚基氧基)-7-甲基-2H-异喹啉-1-酮(47)
a)顺式-4-氨基-环庚醇
于0℃向16.8g(0.149mol)环己酮肟在240ml二氯甲烷中的溶液中缓慢加入19.4g(0.178mol)次氯酸叔丁酯。将所得深蓝色溶液冷却至-20℃,然后加入30ml乙醇和20.0g(0.212mol)1,3-环庚二烯,将混合物在冰箱中于5℃储存2天,直至蓝色已经消失。将反应混合物加入30ml异丙醇中,然后加入300ml二乙醚,搅拌3小时后,通过抽滤分离出所得沉淀,得到18.6g6-氧杂-7-氮杂-二环[3.2.2]壬烷-8-烯盐酸盐。将9.0g(0.072mol)该物质用钯/活性炭在5巴氢气下进行氢化。转化完全后过滤除去催化剂,加入30ml 4M盐酸在二噁烷中的溶液。蒸发后,将残余物从20ml异丙醇和500ml二乙醚中结晶,得到7.5g顺式-4-氨基-环庚醇,为盐酸盐。
b)6-(顺式-4-氨基-环庚基氧基)-2-(4-甲氧基-苄基)-7-甲基-2H-异喹啉-1-酮
将223mg(1.35mmol)顺式-4-氨基-环庚醇在5ml二甲基乙酰胺中的溶液与242mg(8.1mmol)80%氢化钠一起于室温搅拌15分钟。然后加入0.4g(1.35mmol)6-氟-2-(4-甲氧基-苄基)-7-甲基-2H-异喹啉-1-酮(25,步骤b)在10ml二甲基乙酰胺中的溶液。将反应混合物于80℃加热8小时,然后加入另外的原始量的30%的顺式-4-氨基-环庚醇和氢化钠。于80℃另外1小时后,将反应混合物加入水中,用二氯甲烷萃取。将粗产物通过色谱法用二氯甲烷/甲醇(100∶0-97∶3)进行纯化,得到134mg 6-(顺式-4-氨基-环庚基氧基)-2-(4-甲氧基-苄基)-7-甲基-2H-异喹啉-1-酮。
c)6-(顺式-4-氨基-环庚基氧基)-7-甲基-2H-异喹啉-1-酮(47)
将130mg(0.32mmol)6-(顺式-4-氨基-环庚基氧基)-2-(4-甲氧基-苄基)-7-甲基-2H-异喹啉-1-酮溶于730mg(6.4mmol)三氟乙酸中,将混合物在微波炉中于150℃加热2小时。然后真空蒸馏出过量三氟乙酸,将残余物用水稀释,将溶液制成碱性。用二氯甲烷萃取后,经硫酸镁干燥,蒸发,获得24mg 6-(顺式-4-氨基-环庚基氧基)-7-甲基-2H-异喹啉-1-酮(47)。Rt=0.96分钟(方法B)。实测质量:287.3(M+H+)。
7-氯-6-(顺式-4-氨基-环庚基氧基)-2H-异喹啉-1-酮(48)
采用顺式-4-氨基-环庚醇盐酸盐(47,步骤a)和7-氯-6-氟-2-(4-甲氧基-苄基)-2H-异喹啉-1-酮(10),按照与合成6-(顺式-4-氨基-环庚基氧基)-7-甲基-2H-异喹啉-1-酮(47)类似的方式,获得标题产物,为盐酸盐。Rt=1.05分钟(方法B)。实测质量:307.12(M+H+)。
6-(顺式-4-氨基-环庚基氧基)-2H-异喹啉-1-酮(49)
采用顺式-4-氨基-环庚醇盐酸盐(47,步骤a)和6-氟-2-(4-甲氧基-苄基)-2H-异喹啉-1-酮(9),按照与合成6-(顺式-4-氨基-环庚基氧基)-7-甲基-2H-异喹啉-1-酮(47)类似的方式,获得标题产物,为盐酸盐。Rt=0.81分钟(方法C)。实测质量:273.2(M+H+)。
3-氨基-环丁醇(50)
向2.00g(10.8mmol)(3-氧代-环丁基)-氨基甲酸叔丁酯在20ml乙醇中的0℃冷溶液中分批加入204mg(5.40mmol)硼氢化钠。将反应混合物于室温搅拌直至转化完全。蒸发溶剂,将粗产物加入二氯甲烷中,用饱和碳酸氢钠溶液进行处理。分离各相,水相用二氯甲烷萃取两次。合并有机相,经硫酸镁干燥,浓缩,得到粗(3-羟基-环丁基)-氨基甲酸叔丁酯。Rt=0.76分钟(方法C)。实测质量:132.2(M-tBu+H+)。
将粗的醇溶于90ml二氯甲烷中,加入11ml三氟乙酸。于室温搅拌过夜后,加入100ml 2N盐酸,分离各相,将水相真空浓缩。两次将残余物溶于水和随后冷冻干燥后,分离出980mg标题化合物50,为盐酸盐,为非对映异构体的混合物。Rt=0.19分钟(方法C)。实测质量:88.35(M+H+)。
3-(1-苄基氧基-7-氯-异喹啉-6-基氧基)-环丁基胺(51)
向459mg(11.5mmol)氢化钠(60%)在16ml二甲基乙酰胺中的混悬液中加入333mg(3.82mmol)3-氨基-环丁醇(50)在8ml二甲基乙酰胺中的溶液。于室温搅拌60分钟后,加入1.00g(3.48mmol)1-苄基氧基-7-氯-6-氟-异喹啉(11)在16ml二甲基乙酰胺中的溶液,首先于室温继续搅拌,然后于50℃搅拌2小时直至反应完全。通过添加水使反应物淬灭,将反应混合物用二氯甲烷和2-丙醇(3∶1)混合物萃取三次。将所合并的有机层蒸发,加入水,使粗产物进行冷冻干燥以除去剩余的二甲基乙酰胺。将所得粗产物通过硅胶色谱法进行纯化,得到377mg标题化合物(51),为非对映异构体的混合物。Rt=0.85分钟(方法H)。实测质量:355.1(M+H+)。
通过与合成51相同的方法,采用1-苄基氧基-7-氯-6-氟-异喹啉(11)和相应的(3-氨基-环丁基)-甲醇,获得下述两种产物。
6-(3-氨基-环丁氧基)-7-氯-2H-异喹啉-1-酮(54)
将377mg(1.06mmol)3-(1-苄基氧基-7-氯-异喹啉-6-基氧基)-环丁基胺(51)在8ml 2-丙醇中的溶液用8ml 2N盐酸水溶液进行处理,搅拌直至转化完全。将反应混合物蒸发,从水中冷冻干燥两次,从2-丙醇中重结晶。可以分离出195mg标题化合物,为盐酸盐,为不可分离的非对映异构体混合物。Rt=1.92分钟(方法G)。实测质量:265.1(M+H+)。
通过对合成6-(3-氨基-环丁氧基)-7-氯-2H-异喹啉-1-酮(54)所述相同的方式、分别采用相应的3-氨基-环丁醇(50)的顺式-或反式-异构体,可以获得纯的顺式-和反式-异构体。顺式-异构体(54a):Rt=1.85分钟(方法I)。实测质量:265.1(M+H+);反式-异构体(54b):Rt=1.90分钟(方法I)。实测质量:265.1(M+H+)。
顺式-6-(3-氨基-环丁基甲氧基)-7-氯-2H-异喹啉-1-酮(55)
以756mg(2.05mmol)顺式-6-(3-氨基-环丁基甲氧基)-7-氯-2H-异喹啉-1-酮(52)为原料,如对化合物54所述可以获得460mg顺式-6-(3-氨基-环丁基甲氧基)-7-氯-2H-异喹啉-1-酮(55),为盐酸盐。Rt=1.91分钟(方法I)。实测质量:279.1(M+H+)。
反式-6-(3-氨基-环丁基甲氧基)-7-氯-2H-异喹啉-1-酮(56)
以778mg(2.11mmol)反式-6-(3-氨基-环丁基甲氧基)-7-氯-2H-异喹啉-1-酮(53)为原料,如对化合物54所述可以获得353mg反式-6-(3-氨基-环丁基甲氧基)-7-氯-2H-异喹啉-1-酮(56),为盐酸盐。Rt=1.87分钟(方法I)。实测质量:279.2(M+H+)。
顺式-5-(叔丁基-二甲基-甲硅烷基氧基)-环辛醇(57)
将21.4g(312mmol)咪唑、34.5g(229mmol)叔丁基二甲基甲硅烷基氯和10mg DMAP加入顺式-1,5-环辛烷二醇在500ml THF中的溶液中。将反应混合物搅拌2小时,然后用水淬灭,然后用乙酸乙酯萃取。将有机相用饱和氯化钠溶液洗涤,经硫酸镁干燥。过滤和在减压下蒸发,获得粗产物,将其经硅胶色谱法纯化(正庚烷/乙酸乙酯,4∶1),得到26.0g无色油状的预期产物。Rt=3.00分钟(方法J)。实测质量:259.2(M+H+)。
5-(叔丁基-二甲基-甲硅烷基氧基)-环辛酮(58)
于-78℃将4.5g(58mmol)二甲亚砜在25ml二氯甲烷中的溶液滴加至3.7g(29mmol)草酰氯在50ml二氯甲烷中的搅拌溶液中。将溶液于-78℃搅拌30分钟,然后滴加5.0g(19.3mmol)顺式-5-(叔丁基-二甲基-甲硅烷基氧基)-环辛醇(57)在30ml二氯甲烷中的溶液,同时保持温度为78℃。搅拌30分钟后,滴加9.8g(97mmol)三乙胺,使温度温热至-30℃。加入另外50ml二氯甲烷,将溶液于-30℃搅拌1小时。在搅拌下分批加入300ml饱和氯化铵溶液,然后分离有机层。用另外的氯化铵溶液洗涤后,将有机相经硫酸镁干燥,过滤,蒸发,得到5.0g黄色油状的预期产物,将其未经纯化进行使用。Rt=1.96分钟(方法C)。实测质量:257.3(M+H+)。
5-(叔丁基-二甲基-甲硅烷基氧基)-环辛胺(59)
将11.0g(38.6mmol)异丙醇钛加入5.0g(19.3mmol)5-(叔丁基-二甲基-甲硅烷基氧基)-环辛酮(58)在48.3ml(96.5mmol)2M氨-乙醇溶液中的溶液中,搅拌6小时。加入1.1g(29mmol)硼氢化钠后,将混合物于室温搅拌4天。通过添加50ml 2M氨水溶液淬灭反应物。将白色沉淀过滤除去,用乙酸乙酯洗涤。将滤液用乙酸乙酯萃取,所合并的有机层经硫酸镁干燥,过滤,蒸发,得到黄色油状的4.5g 5-(叔丁基-二甲基-甲硅烷基氧基)-环辛胺(59),为非对映异构体混合物,将其未经纯化进行使用。Rt=2.14分钟(方法J)。实测质量:258.2(M+H+)。
5-氨基-环辛醇(60)
将35ml 2N盐酸水溶液加入3.5g(13.6mmol)5-(叔丁基-二甲基-甲硅烷基氧基)-环辛胺(59)在35ml 2-丙醇中的溶液中,将所得溶液于室温搅拌过夜。在减压下除去异丙醇,将所得水性溶液用叔丁基甲基醚洗涤。通过将水层冷冻干燥,获得2.7g粗的5-氨基-环辛醇(60),为非对映异构体的混合物,为盐酸盐,将其未经进一步纯化进行使用。Rt=0.18分钟(方法C)。实测质量:144.2(M+H+)。
5-(1-苄基氧基-7-氯-异喹啉-6-基氧基)-环辛胺(61)
以0.8g(2.78mmol)1-苄基氧基-7-氯-6-氟-异喹啉(11)、417mg(14.4mmol)氢化钠(60%)和0.63g(3.5mmol)5-氨基-环辛醇(60)为原料,按照对3-(1-苄基氧基-7-氯-异喹啉-6-基氧基)-环丁基胺(51)所述的方式,合成了1.3g标题化合物。通过硅胶色谱法纯化(二氯甲烷∶甲醇∶氨水-100∶7∶0.75),得到0.35g预期产物,为非对映异构体的混合物。Rt=1.41分钟(方法C)。实测质量:413.1(M+H+)。
6-(5-氨基-环辛基氧基)-7-氯-2H-异喹啉-1-酮(62)
以0.22g(0.54mmol)5-(1-苄基氧基-7-氯-异喹啉-6-基氧基)-环辛胺(61)为原料,采用对制备化合物54所述的方法,可以获得124mg 6-(5-氨基-环辛基氧基)-7-氯-2H-异喹啉-1-酮(62),为盐酸盐。Rt=1.85分钟(方法I)。实测质量:321.1(M+H+)。
1-烯丙基-5-(叔丁基-二甲基-甲硅烷基氧基)-环辛胺(63)
向1.5g(5.85mmol)5-(叔丁基二甲基甲硅烷基氧基)环辛酮在8.4ml(58.5mmol)预先于室温搅拌15分钟的17N氨的甲醇溶液中滴加1.7ml(9.36mmol)2-烯丙基-4,4,5,5-四甲基-1,3,2-二氧杂-硼杂环戊烷(borolane)。将反应混合物于室温搅拌18小时。真空除去挥发物,将残余物重新溶于100ml二乙醚中。然后滴加100ml 1N盐酸水溶液,将所得双相混合物搅拌30分钟。分离各层,将水层用二乙醚洗涤,通过添加氢氧化钠使pH调节至9。然后将混悬液用二氯甲烷和2-丙醇的3∶1混合物萃取,将所合并的有机萃取物真空浓缩,获得0.89g标题化合物,为非对映异构体的混合物。Rt=0.44min,0.49分钟(方法C)。实测质量:184.3(M+H+)。
5-氨基-5-丙基-环辛醇(64)
将895mg(4.88mmol)1-烯丙基-5-(叔丁基-二甲基-甲硅烷基氧基)-环辛胺(63)在15ml甲醇中的溶液用52mg 10%钯/活性炭进行处理,将混合物在氢气氛围(1atm)下于室温过夜。滤除催化剂,将滤液真空蒸发,得到0.794g标题化合物(64)。Rt=0.56min,0.62min(方法C)。实测质量:186.3(M+H+)。
5-(1-苄基氧基-7-氯-异喹啉-6-基氧基)-1-丙基-环辛胺(65)
以1.11g(3.86mmol)1-苄基氧基-7-氯-6-氟-异喹啉(11)、514mg(12.9mmol)氢化钠(60%)和794mg(4.29mmol)5-氨基-5-丙基-环辛醇(64)为原料,按照对3-(1-苄基氧基-7-氯-异喹啉-6-基氧基)-环丁基胺(51)所述的方案,合成了572mg标题化合物,为非对映异构体的混合物。Rt=1.52min,1.56分钟(方法C)。实测质量:453.3(M+H+)。
6-(顺式-5-氨基-5-丙基-环辛基氧基)-7-氯-2H-异喹啉-1-酮和6-(反式-5-氨基-5-丙基-环辛基氧基)-7-氯-2H-异喹啉-1-酮(66/67)
以396mg(0.87mmol)5-(1-苄基氧基-7-氯-异喹啉-6-基氧基)-1-丙基-环辛胺(65)为原料,采用对制备化合物54所述的方法,可以获得6-(5-氨基-5-丙基-环辛基氧基)-7-氯-2H-异喹啉-1-酮,为盐酸盐。通过将混合物经制备型HPLC分析和将残余物从2N HCl和水中进行冷冻干燥,分别获得182mg和86mg纯的非对映异构体66和67。立体异构体1(66):Rt=2.31分钟(方法I)。实测质量:363.2(M+H+),346.2(M-NH3+H+)。立体异构体2(67):Rt=2.52分钟(方法G)。实测质量:363.2(M+H+),346.2(M-NH3+H+)。任意指定两种衍生物的相对立体化学。
通过对合成化合物15-22所描述的用于还原性胺化反应的通用方法,采用相应的异喹啉酮和醛或酮,获得盐酸盐形式的下述化合物(表6):
Rho激酶抑制的测定
为测量Rho-激酶抑制,根据以下方案确定IC50值:
从阿普斯德特公司(Upstate Ltd.,Dundee,UK)购得活性人重组ROCKII(N-末端His6-标记的重组人ROCK-II残基11-552)。从JPT肽技术公司(JPT Peptide Technologies,德国柏林)获得肽底物-荧光素-AKRRRLSSLRA-COOH。从西格玛-奥尔德里奇(Sigma-Aldrich,德国慕尼黑)购得腺苷-5′-三磷酸(ATP)、牛血清白蛋白(BSA)、二甲基亚砜(DMSO)、4-(2-羟基乙基)哌嗪-1-乙磺酸(Hepes)、苄泽-35和二硫苏糖醇(DTT)。从默克生物公司(Merck Biosciences,Darmstadt,德国)获得三(羟基甲基)-氨基甲烷(Tris)、氯化镁、NaOH、1M HCl和EDTA。从罗氏诊断公司(Roche Diagnostics,德国曼海姆)获得“完全”蛋白酶抑制剂。
将测试化合物在缓冲液1(25mM Tris-HCl,pH 7.4,5mM MgCl2,2mMDTT,0.02%(w/v)BSA和3%DMSO)中稀释至适当的浓度。将ROCK II酶在缓冲液2(25mM Tris-HCl,pH 7.4,5mM MgCl2,2mM DTT和0.02%(w/v)BSA)中稀释至100ng/ml的浓度。将肽底物和ATP在缓冲液2中分别稀释至3μM和120μM的浓度。将2μl化合物溶液与2μl稀释的酶在384-孔小体积微量滴定板(Greiner,Bio-One,Frickenhausen,德国)中混合,通过加入2μl含有肽底物和ATP的溶液引发激酶反应。于32℃温育60分钟后,通过加入20μl含有100mM Hepes-NaOH,pH 7.4,0.015%(v/v)苄泽-35,45mM EDTA和0.227%薄片涂布试剂1(chip coating reagent 1)(开立普生命科学公司(Caliper Lifescience Inc),Hopkinton,MA)的溶液终止反应。然后在Caliper 3000仪器上基本上如Pommereau等人(J.Biomol.Screening 9(5),409-416,2004)所述检测底物肽的磷酸化。分离条件如下:压力-1.3psi,上游电压-1562V,下游电压-500V,吸样品时间200ms。在每块板上平行地进行阳性对照(缓冲液1代替化合物)和阴性对照(缓冲液1代替化合物和缓冲液2代替ROCK II)。
在所述测定法中,利用上述实施例中所得的各种形式(盐或游离碱)测定了以下产物/化合物并测量了以下活性:
化合物编号 | pIC50 |
15 | +++++ |
16 | +++++ |
17 | +++++ |
18 | +++++ |
19 | +++++ |
20 | +++++ |
21 | +++++ |
22 | +++++ |
24 | +++++ |
28 | ++++ |
29 | ++++ |
30 | +++++ |
化合物编号 | pIC50 |
31 | +++++ |
44 | +++++ |
45 | +++++ |
47 | +++++ |
48 | +++++ |
54 | +++++ |
56 | +++++ |
66 | +++++ |
67 | +++++ |
所给出的活性表示为如下的IC50的以10为底的负对数(pIC50):
+: pIC50≤3.0
++: 3.0≤pIC50<4.0
+++ 4.0≤pIC50<5.0
++++: 5.0≤pIC50<6.0
+++++:6.0≤pIC50
Claims (33)
1.式(I)化合物
其中
R2是H或(C1-C6)烷基;
R3是H,
R4是H,
R5是H,
R6和R6’相互独立地是
H、(C1-C6)烷基、(C1-C6)亚烷基-苯基、(C1-C6)亚烷基-C(O)O-(C1-C6)烷基、C(O)-(C1-C6)亚烷基-哌啶基,
或者R6和R6’与它们所连接的N-原子一起形成哌啶基、吗啉基、吡咯烷基或哌嗪基;
R7是H、Cl、(C1-C4)烷基,
R8是H;
n是1、2、3或4;
m是1、2、3、4或5,且
L是O或O-(C1-C6)亚烷基;
其中在基团R6、R6’和R7中,烷基或亚烷基可以任选被如下基团取代一次或多次:COOH;
其中在基团R2、R3、R6、R6’和R7中,烷基或亚烷基可以任选被卤素取代一次或多次;
其中在基团R6和R6’中,所述苯基和哌啶基、吗啉基、吡咯烷基或哌嗪基是未取代的或者被独立地选自如下的适宜基团取代一次或多次:CONH2或(C1-C6)烷基;
并且其中如果m是3,则R6不是H;和
其中如果m是3,且R6是(C1-C6)烷基时,所述烷基被如下基团取代一次或多次:COOH;和
其中排除化合物(1S,3S)-6-(3-氨基环戊基氧基)-2H-异喹啉-1-酮和(1R,3R)-6-(3-氨基环戊基氧基)-2H-异喹啉-1-酮;
或它们的立体异构形式和/或它们的可药用盐。
2.根据权利要求1的化合物,其中当m是3且R6是(C1-C6)烷基时,所述烷基被如下基团取代一次至三次:COOH。
3.根据权利要求1的化合物,其中R7是H、氯、甲基、乙基。
4.根据权利要求1的化合物,其中R7是H、氯、甲基。
5.根据权利要求1的化合物,其中R7是H。
6.根据权利要求1的化合物,其中m是2、3或4。
7.根据权利要求1的化合物,其中m是3。
8.根据权利要求1的化合物,其中R2是H或(C1-C4)烷基。
9.根据权利要求1的化合物,其中R2是H或(C1-C2)烷基。
10.根据权利要求1的化合物,其中R2是H、甲基或乙基。
11.根据权利要求1的化合物,其中n是1、2或3。
12.根据权利要求1的化合物,其中n是1或2。
13.根据权利要求1的化合物,其中n是1。
14.根据权利要求1的化合物,其中
R6和R6’相互独立地是
H,
(C1-C6)烷基,
(C1-C4)亚烷基-苯基,
(C1-C6)亚烷基-C(O)O-(C1-C6)烷基,
或
C(O)(C1-C6)亚烷基-哌啶基,
或者R6和R6’与它们所连接的N-原子一起形成哌啶基、吗啉基、吡咯烷基或哌嗪基。
15.根据权利要求1的化合物,其中
R6是H或(C1-C6)烷基,且
R6’是H,
(C1-C6)烷基,
(C1-C4)亚烷基-苯基,
(C1-C6)亚烷基-C(O)O-(C1-C6)烷基,
C(O)(C1-C6)亚烷基-哌啶基,
或者
R6和R6’与它们所连接的N-原子一起形成哌啶基、吗啉基、吡咯烷基或哌嗪基。
16.根据权利要求1的化合物,其中
R6是H、(C1-C6)烷基,且
R6’是H,
(C1-C6)烷基,
(C1-C6)亚烷基-苯基,
C(O)(C1-C6)亚烷基-哌啶基,或
R6和R6’与它们所连接的N-原子一起形成哌啶基、吗啉基、吡咯烷基或哌嗪基。
17.根据权利要求1的化合物,其中
R6是H、(C1-C6)烷基且
R6’是H;
(C1-C6)烷基;
(C1-C4)亚烷基-苯基,其中苯基是未取代的或者被独立地选自如下的基团取代一次至多次:(C1-C4)烷基;
C(O)(C1-C6)亚烷基-哌啶基;
或者R6和R6’与它们所连接的N-原子一起形成哌啶基、吗啉基、吡咯烷基或哌嗪基,它是未取代的或者被(C1-C4)烷基取代一次至三次;
其中(C1-C4)烷基或(C1-C6)烷基基团是未取代的或者被卤素取代一次至三次。
18.根据权利要求1的化合物,其中R6是H、(C1-C6)烷基且R6’是H、(C1-C6)烷基。
19.根据权利要求1的化合物,其中R6是H且R6’是H、(C1-C6)烷基。
20.根据权利要求1的化合物,其中R6和R6’是H。
21.根据权利要求1的化合物,其中m是3且L与氨基环己烷环的3-位或4-位连接。
22.根据权利要求1的化合物,其中m是3且L与氨基环己烷环的4-位连接。
23.根据权利要求1的化合物,其中L是O-亚甲基、O-亚乙基或O。
24.根据权利要求1的化合物,其中L是O。
25.根据权利要求1的化合物,其中
R2是氢或(C1-C6)烷基;
R3是H;
R4是H;
R5是H;
R6和R6’相互独立地是H、(C1-C6)烷基、(C1-C6)亚烷基-苯基、C(O)(C1-C6)亚烷基-哌啶基,或者R6和R6’与它们所连接的N-原子一起形成哌啶基、吗啉基、吡咯烷基或哌嗪基;
R7是H、Cl、(C1-C4)烷基;
R8是H;
m是2、3或4
n是1、2或3,且
L是O、O-亚甲基或O-亚乙基。
26.根据权利要求1的化合物,其中
R2是H或(C1-C4)烷基;
R3是H;
R4是H;
R5是H;
R6和R6’相互独立地是H、(C1-C6)烷基、(C1-C3)亚烷基-苯基、C(O)(C1-C6)亚烷基-哌啶基;
R7是H、Cl、(C1-C4)烷基;
R8是H;
m是2、3或4
n是1、2或3;且
L是O。
27.根据权利要求1的化合物,其中
R2是H、(C1-C4)烷基;
R3是H;
R4是H;
R5是H;
R6是H或(C1-C4)烷基;
R6’是H、(C1-C6)烷基、(C1-C3)亚烷基-苯基、C(O)(C1-C3)亚烷基-哌啶基;
R7是H、Cl、(C1-C4)烷基;
R8是H;
m是3;
n是1;且
L是O。
28.根据权利要求1的化合物,所述化合物独立地选自:
1-[4-(7-氯-1-氧代-1,2-二氢-异喹啉-6-基氧基)-环己基]-哌啶-4-甲酸酰胺,
7-氯-6-(4-哌啶-1-基-环己基氧基)-2H-异喹啉-1-酮,
7-氯-6-(4-吗啉-4-基-环己基氧基)-2H-异喹啉-1-酮,
7-氯-6-(4-吡咯烷-1-基-环己基氧基)-2H-异喹啉-1-酮,
7-氯-6-[4-(4-甲基-哌嗪-1-基)-环己基氧基]-2H-异喹啉-1-酮,
[4-(7-氯-1-氧代-1,2-二氢-异喹啉-6-基氧基)-顺式-环己基氨基]-乙酸乙基酯,
[4-(7-氯-1-氧代-1,2-二氢-异喹啉-6-基氧基)-顺式-环己基氨基]-乙酸,
7-甲基-6-(4-吡咯烷-1-基-环己基氧基)-2H-异喹啉-1-酮,
N-[4-(7-甲基-1-氧代-1,2-二氢-异喹啉-6-基氧基)-反式-环己基]-3-哌啶-4-基-丙酰胺,
N-[4-(7-甲基-1-氧代-1,2-二氢-异喹啉-6-基氧基)-反式-环己基]-2-哌啶-4-基-乙酰胺,
N-[4-(7-氯-1-氧代-1,2-二氢-异喹啉-6-基氧基)-顺式-环己基]-3-哌啶-4-基-丙酰胺,
N-[4-(7-氯-1-氧代-1,2-二氢-异喹啉-6-基氧基)-顺式-环己基]-2-哌啶-4-基-乙酰胺,
6-((1S,3S)-3-氨基-环戊基氧基)-7-氯-2H-异喹啉-1-酮,
6-((1S,3R)-3-氨基-环戊基氧基)-2H-异喹啉-1-酮,
6-((1S,3R)-3-氨基-环戊基氧基)-7-氯-2H-异喹啉-1-酮,
6-((顺式-4-氨基-环庚基氧基)-7-甲基-2H-异喹啉-1-酮,或
7-氯-6-(顺式-4-氨基-环庚基氧基)-2H-异喹啉-1-酮,
或它们的立体异构形式和/或它们的可药用盐。
29.根据权利要求1的化合物,所述化合物独立地选自:
6-(顺式-4-氨基-环庚基氧基)-2H-异喹啉-1-酮,
6-(3-氨基-环丁氧基)-7-氯-2H-异喹啉-1-酮,
顺式-6-(3-氨基-环丁基甲氧基)-7-氯-2H-异喹啉-1-酮,
反式-6-(3-氨基-环丁基甲氧基)-7-氯-2H-异喹啉-1-酮,
6-(5-氨基-环辛基氧基)-7-氯-2H-异喹啉-1-酮,
6-(5-氨基-5-丙基-环辛基氧基)-7-氯-2H-异喹啉-1-酮,
6-(5-苄基-氨基-5-丙基-环辛基氧基)-7-氯-2H-异喹啉-1-酮,
7-氯-6-(5-乙基氨基-5-丙基-环辛基氧基)-2H-异喹啉-1-酮,
7-氯-6-(顺式-3-异丙基氨基-环丁氧基)-2H-异喹啉-1-酮,
6-(3-顺式-苄基氨基-环丁氧基)-7-氯-2H-异喹啉-1-酮,
6-(3-反式-苄基氨基-环丁氧基)-7-氯-2H-异喹啉-1-酮,
7-氯-6-(3-顺式-二苄基氨基-环丁氧基)-2H-异喹啉-1-酮,
7-氯-6-(3-反式-二苄基氨基-环丁氧基)-2H-异喹啉-1-酮,或
7-氯-6-(3-反式-二乙基氨基-环丁氧基)-2H-异喹啉-1-酮,
或它们的立体异构形式和/或它们的可药用盐。
30.至少一种权利要求1至29之一所述的式(I)化合物和/或它们的可药用盐在制备药剂中的用途,所述药剂用于治疗和/或预防高血压、高眼压症、视网膜病、青光眼、周围循环障碍、冠心病、心绞痛、心力衰竭、局部缺血性疾病、纤维化肺、纤维化肝、肝衰竭、肾病、器官肥大、哮喘、慢性阻塞性肺病(COPD)、成人呼吸窘迫综合征、血栓形成性障碍、中风、脑血管痉挛、脑缺血、疼痛、神经元变性、脊髓损伤、阿尔茨海默病、早产、勃起功能障碍、内分泌功能障碍、动脉硬化、前列腺肥大、糖尿病和糖尿病并发症、代谢综合征、血管再狭窄、炎症、自身免疫疾病、AIDS、骨病、消化道细菌感染、脓毒病或者癌症发展和进展。
31.权利要求30的用途,其中所述药剂用于治疗和/或预防肺动脉高压、周围动脉闭塞疾病(PAOD)、心脏肥大、肾衰竭、纤维化肾、肾小球硬化、动脉粥样硬化或者局部缺血性器官衰竭。
32.权利要求31的用途,其中所述局部缺血性器官衰竭为终端器官损伤。
33.药剂,包含有效量的至少一种权利要求1至29任一项所述的化合物和/或其药理学上可接受的盐、药学上耐受的赋形剂和载体以及酌情包含其它添加剂和/或其它活性成分。
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