CN1034075C - 苯并硫氮杂䓬衍生物的制备方法 - Google Patents
苯并硫氮杂䓬衍生物的制备方法 Download PDFInfo
- Publication number
- CN1034075C CN1034075C CN92113330A CN92113330A CN1034075C CN 1034075 C CN1034075 C CN 1034075C CN 92113330 A CN92113330 A CN 92113330A CN 92113330 A CN92113330 A CN 92113330A CN 1034075 C CN1034075 C CN 1034075C
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- CN
- China
- Prior art keywords
- methoxyphenyl
- ketone
- compound
- benzothiazepine
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 229940085242 benzothiazepine derivative selective calcium channel blockers with direct cardiac effects Drugs 0.000 title description 2
- 150000007657 benzothiazepines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002252 acyl group Chemical group 0.000 claims abstract description 4
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 40
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 36
- -1 Methoxyphenyl Chemical group 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- YFNCATAIYKQPOO-UHFFFAOYSA-N thiophanate Chemical compound CCOC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OCC YFNCATAIYKQPOO-UHFFFAOYSA-N 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 10
- 150000002367 halogens Chemical group 0.000 abstract description 4
- 150000002431 hydrogen Chemical class 0.000 abstract description 4
- 206010020772 Hypertension Diseases 0.000 abstract description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 abstract description 3
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 2
- 208000019622 heart disease Diseases 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 abstract 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
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- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- PFRUBEOIWWEFOL-UHFFFAOYSA-N [N].[S] Chemical compound [N].[S] PFRUBEOIWWEFOL-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 230000002107 myocardial effect Effects 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
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- FHGWEHGZBUBQKL-UHFFFAOYSA-N 1,2-benzothiazepine Chemical compound S1N=CC=CC2=CC=CC=C12 FHGWEHGZBUBQKL-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
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- 239000003814 drug Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000012188 paraffin wax Substances 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 150000001298 alcohols Chemical group 0.000 description 4
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 4
- 150000008046 alkali metal hydrides Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
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- 239000002184 metal Substances 0.000 description 4
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- 150000002825 nitriles Chemical class 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
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- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
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- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 3
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Abstract
下式化合物及其药学上可接受的盐:其中x是=N-A-R1或=C(R1)R2;A是单键,多亚甲基或-CO-;R1和R2分别是氢、C1-C6烷基、C3-C7环烷基、未取代或取代的苯基、任意取代的二苯甲基或任意取代的5至6元杂环基、Y是氢、卤素,C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、任意取代的苯氧基、任意取代的苄氧基或任意取代的苄基、Z是氢或酰基;n是2-6的整数。本发明还提供了含有此化合物的组合物;其可用于治疗高血压和心脏病。
其中x是=N-A-R1或=C(R1)R2;A是单键,多亚甲基或-CO-;R1和R2分别是氢、C1-C6烷基、C3-C7环烷基、未取代或取代的苯基、任意取代的二苯甲基或任意取代的5至6元杂环基、Y是氢、卤素,C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、任意取代的苯氧基、任意取代的苄氧基或任意取代的苄基、Z是氢或酰基;n是2-6的整数。本发明还提供了含有此化合物的组合物;其可用于治疗高血压和心脏病。
Description
本发明涉及新的硫氮杂_衍生物。特别是本发明涉及用作Ca-拮抗剂以及冠状血管舒张药的5-(哌啶基烷基或哌嗪基烷基)苯并硫氮杂_衍生物。
美国专利3,562,257公开了用作冠状血管舒张药的苯并硫氮杂_衍生物。虽然在美国专利4,584,131和日本专利公开(未审查)号292271/1989中公开了另一些苯并硫氮杂_衍生物,例如硫氮_酮衍生物,但并没有报道可用作冠状血管舒张药并也可用作Ca-拮抗剂,即心肌保护剂的特定的一组苯并硫氮杂_衍生物,即本发明的5-(哌啶基烷基或哌嗪基烷基)苯并硫氮杂。
众所周知,心肌或血管平滑肌的收缩与钙离子穿透到细胞内有关,因之,给患者施用Ca-拮抗剂能抑制心脏收缩和使冠状血管舒张。因此,Ca-拮抗剂可用作如心胶痛,心肌梗塞和心律失常的心脏疾病,高血压和脑血管挛缩的治疗剂。硫氮_酮已广泛地用于心胶痛和原发性高血压的治疗,但由硫氮_酮引起的心脏收缩抑制的反弹作用过于剧烈。因此,长期以来一直需要一种无此反弹作用的新的药物。
本发明发现,当使用培养的心肌细胞时,式(1)的苯并硫氮杂_衍生物:其中X是=N-A-R1或=C(R1)R2;A是单键,多亚甲基或-CO-;R1和R2分别是氢、C1-C6烷基,C3-C7环烷基,未取代或取代的苯基、任意取代的二苯甲基或任意取代的5至6元杂环基;Y是氢、卤素、C1-C6烷基、C3-C7环烷基、C1-C5烷氧基、任意取代的苯氧基,任意取代的苄氧基或任意取代的苄基;z是氢或酰基;n是2-6的整数,及其药学上可接受的盐对分离的血管显示出显著的血管舒张作用并对局部缺血的心肌显示出很强的保护作用。发明人还发现式(1)化合物仅对心脏功能有轻微的抑制作用,并且本发明化合物可用于短暂的局部缺血疾病如冠状动脉血栓形成、脑血栓等以及原发性高血压的治疗或预防。上述限定的本发明式(1)化合物包括旋光异构体和外消旋物。
此外所用的术语“多亚甲基”意思是指具有一个或多个碳原子的亚烷基,包括亚甲基、1,2-亚乙基、1,3-亚丙基和1,4-亚丁基。
术语“C1-C6烷基”意思是指具有1-6个碳原子的直链或支链烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、2-甲基丁基、正己基和异己基。
术语“C3-C7环烷基”意思是指具有3-7个碳原子的环烷基,包括环丙基、环丁基、环戊基和环己基。
术语“5-6元杂环基”意思是指环中含一个或多个氮原子并任意地含有一个或多个氧原子和/或硫原子的饱和或未饱和的5-6元杂环基。此杂环基具体的例子是吡咯基、咪唑基、吡唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、1,3,5-三嗪基、1,2,4-三嗪基、1,2,3-三嗪基、异噁唑基、噁唑基、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、异噻唑基、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、呋喃基、噻吩基等。其中优选的是吡啶基。
“卤素”意思是指氟、氯、溴或碘,优选是的氟和氯。
术语“C1-C6烷氧基”意思是指其中烷基部分可以是直链或支链的烷氧基,包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、权丁氧基、正戊氧基、异戊氧基、新戊氧基、仲戊氧基、叔戊氧基、正己氧基、新己氧基、异己氧基、仲己氧基、叔己氧基等。
苯基、二苯甲基、5-6元杂环基、苯氧基或苄氧基环上可以具有的一个或多个取代基选自上述定义的C1-C6烷基、C1-C6烷氧基、卤素和亚烷基二氧基。
术语“酰基”意思是指具有2-7个碳原子的脂族酰基如乙酰基,丙酰基、丁酰基、异丁酰基、戊酰基和己酰基,具有4-7个碳原子的环烷基羰基如环丙羰基,环丁羰基、环戊羰基和环己羰基,以及具有7-11个碳原子的芳基羰基如苯甲酰基、对甲基苯甲酰基和萘酰基,优选的酰基基团是如乙酰基和丙酰基的脂族酰基、环丙羰基、环丁羰基和苯甲酰基,最优选的是乙酰基和丙酰基。式(I)表示的本发明化合物可根据下列反应路线制备。
原料化合物(IV)可以根据日本专利公开(未审查)号43785/1971,Chem.Pham Bull,18 2028,1970,及2192,1973等中公开的方法制备。上述反应路线详述如下。
步聚1
令原料化合物(IV)与化合物(V)反应得到化合物(III)。反应所用溶剂为醇类如甲醇、乙醇、丙醇和异丙醇,腈类如乙腈和丙腈,烃类如苯和甲苯,醚类如四氢呋喃和二噁烷,酮类如丙酮和甲乙酮,酰胺类如N,N-二甲基甲酰胺和N-甲基-2-吡啶酮、亚砜类如二甲亚砜。优选的溶剂是醇类、醚类、酰胺类和腈类,最优选的是异丙醇和乙腈。
反应中所用的碱可以选自金属碳酸盐如碳酸钠和碳酸钾,金属碳酸氢盐如碳酸氢钠和碳酸氢钾,碱金属氢化物如氢化钠和氢化锂,有机碱如1,5-二氮杂双环[4,3,0]壬-5-烯和1.8-二氮杂双环[5,4,0]+一碳-7-烯,优选的碱是金属碳酸盐如碳酸钠和碳酸钾,碱金属氢化物如氢化钠。反应温度和反应时间根据所用的特定的碱和溶剂而不同,但是,反应通常是在0-120℃,优选地是在0-80℃下进行一小时——四天。当反应中使用无机碱时,可加入催化量的吡啶如4-二甲氨基吡啶或冠醚如18-冠-6以加速反应。通过用有机溶剂萃取,用水洗涤萃取液,用无水硫酸镁干燥萃取液并蒸发溶剂可以得到目的产物。如果需要,可以通过常规方法如重结晶,柱层析等将产物进一步纯化。
步骤2
令化合物(III)与化合物(VI)反应得化合物(II)。反应所用溶剂为醇类如甲醇、乙醇、丙醇和异丙醇,腈类如乙腈和丙腈,烃类如苯和甲苯,醚类如四氢呋喃和二噁烷,酮类如丙酮和甲乙酮,酰胺类如N,N-二甲基甲酰胺和N-甲基-2-吡啶酮,亚砜类如二甲亚砜。优选的溶剂是醇类如甲醇、乙醇、丙醇和异丙醇,以及腈类如乙腈和丙腈,最优选的是乙醇,异丙醇和乙腈。
反应所用的碱可以选自金属碳酸盐如碳酸钠和碳酸钾,金属碳酸氢盐如碳酸氢钠和碳酸氢钾,碱金属氢化物如氢化钠和氢化锂,有机碱如1,5-二氮杂双环[4,3,0]壬-5-烯和1,8-二氮杂双环[5,4,0]+一碳-7-烯。优选的碱是金属碳酸盐如碳酸钠和碳酸钾,碱金属氢化物如氢化钠。反应温度和反应时间根据所用的特定的碱和溶剂而不同。但是,反应通常是在0-120℃,优选地是在0-80℃下进行一小时——四天。当反应中使用无机碱时,可以加入催化量的吡啶如4-二甲氨基吡啶或冠醚如18-冠-6以加速反应。通过用有机溶剂萃取,用水洗涤萃取液,用无水硫酸镁干燥萃取液并蒸发溶剂可得到目的产物。如果需要,可以通过常规方法如重结晶、柱层析将产物进一步纯化。
步骤3
令化合物(II)与化合物(VII)反应得到化合物(I)。只要不影响反应的任何溶剂都可用于本反应中,例如可以使用烃类如己烷、苯、甲苯、二甲苯和环己烷,卤代烃类如二氯甲烷、氯仿和1,2-二氯乙烷,醚类如乙醚和四氢呋喃,酯类如乙酸乙酯。优选的溶剂是卤代烃类,最优选的是二氯甲烷。
反应所用的碱包括有机碱如三乙胺、吡啶、二甲氨基吡啶和N-甲基吗啉。如同溶剂一样,反应中也可以使用过量较多的碱。
反应温度可以在0℃-80℃,优选地是在0℃-50℃的范围内,反应时间依反应温度而不同,但反应应在1-24小时,优选地是在3-20小时内完成。通过用如乙酸乙酯这样的有机溶剂萃取产物,用水洗涤萃取液,用无水硫酸镁干燥洗过的萃取液并由干燥的萃取液中蒸发溶剂可得到目的产物。通过常规方法如重结晶、柱层析等可以将产物进一步纯化。
本发明化合物(I)及其药学上可接受的盐可以用作治疗循环疾病的治疗剂。此化合物及其盐可以在药理上可接受的载体、赋形剂和稀释剂的辅助下配制成粉剂、颗粒剂、片剂、胶囊,注射剂等等,并且可以通过口服或非肠道将它们施用给患者。剂量依特定的患者的情况及施药途径而不同。但通常当口服时,日剂量在1mg至1000mg,优选的是在1mg至100mg内变化,而当静脉内给药时,日剂量在0.1-100mg,优选的是在0.5-30mg内变化。根据患者的情况,此剂量可以以一次或分为两次给药。
下列给出的详述实施例意在说明本发明的某些具体实施方案。
实施例1
3-乙酰氧基-5[3-(4-苯基-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-1)
(1)将8.395g(25.0mmol)的2-(4-甲氧苯基)-3-羟基-8-氯-2,3-二氢-1,5苯并硫氮杂_-4(5H)-酮(IV-1)、4.723g(30.0mmol)的1-溴-3-氯丙烷(V-1)和4.1 46g(30.0mmol)的K2CO3溶于168ml丙酮中,并将混合物回流20小时。减压下将反应混合物蒸发得一残余物,将其于硅胶上进行层析,由二氯甲烷馏份中得10.96g的顺-2-(4-甲氧苯基)-3-羟基-5-(3-氯丙基)-8-氯-2,3-二氢-1,5苯并硫氮杂_-4(5H)-酮(III-1),将获得的化合物于乙酸乙酯中重结晶得9.146g无色棱晶,产率88.7%。
Mp.:103-106℃
元素分析(%)C19H19NO3SCl2:
计算值:C,55.35;H,4.64;N,3.40
实测值:C,55.31;H,4.70;N,3.38
IRγmax(石蜡):3452,1652cm-1
NMR(CDCl3)δ:2.19(2H,m),2.84(OH),3.69(3H,m),4.63(1H,m),
3.82(3H,s),4.31(1H,d,d),4.93(1H,d),6.90-7.75(7H,m)
(2)将412mg(1mmol)得到的化合物(III-1)和324mg(2mmol)的4-苯基哌嗪(VI-1)溶于4ml乙腈中,向混合物中加入166ml(1mmol)碘化钾催化剂,并将混合物回流16小时,减压下将反应混合物蒸发得一残余物,将其于硅胶上进行层析,由乙酸乙酯馏份中得440mg顺-2-(4-甲氧苯基)-3-羟基-5-[3-(4-苯基哌嗪基)丙基]-8-氯-2,3-二氢-1,5-苯并硫氮杂_-4(5H)-酮(II-1)。将如此获得的化合物(II-1)于正己烷中重结晶,得400mg无色棱晶,产率74.3%。Mp.:70-71℃无素分析(%)C29H32ClN3O3S:计算值:C,64.74;H,6.00;N,7.81实测值:C,64.51;H,6.04;N,7.77IRγmax(石蜡):3460,1661,1251,1093cm-1NMR(CDCl3)δ:1.95(2H,m),2.54(6H,m),2.88(1H,d),3.16(4H,m),3.64(1H,m),3.82(3H,s),4.31(1H,d,d),4.52(1H,m),4.93(1H,d),6.88(4H,m),7.35(7H,m),7.73(1H,d)。
(3)向5ml乙酸酐中加入800mg(1.5mmol)获得的化合物(II-1)并将混合物于100℃加热3小时,减压下将反应混合物蒸发得-残余物,将其溶于10ml二氯甲烷中并用碳酸氢钠水溶夜中和二氯甲烷层用硫酸钠干燥,有机层于硅胶上进行层析,由乙酸乙酯馏份中得850mg目的化合物(I-1)。将如此获得的化合物(I-1)的盐酸化物于丙酮中重结晶,得600mg元色粒状结晶,产率61.3%。Mp.:143-146℃元素分析(%)C31H36Cl3N3O1S:计算值:C,56.97;H,5.51;N,6.43实测值:C,57.31;H,5.66;N,6.80IRγmax(石蜡):3420,1750,1684,1250,1180cm-1NMR(CDCl3)δ:1.91(3H,s),2.4(2H,m),3.34(4H,m),3.5(6H,m)3.83(3H,s),d.13(2H,m),5.05(1H,d),5,12(1H,d),6.93(2H,d),7.4(9H,m),7.76(1H,d)。
实施例2-16
按照实际上与实施例1相同的方法,制得下列化合物I-2-I-16。
(2)3-乙酰氧基-5-[3-(4-甲基-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-2)
(3)3-乙酰氧基-5-[3-(4-(2-吡啶基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-3)
(4)3-乙酰氧基-5-[3-(4-(2-甲氧苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-1,5-苯并硫氮杂_-4(5H)-酮(I-4)
(5)3-乙酰氧基-5-[3-(4-胡椒基)-1-派嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-5)
(6)3-乙酰氧基-5-[3-(4-(3,4-亚甲基二氧苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-6)
(7)3-乙酰氧基-5-[3-(4-(2-糠酰基)-1-哌嗪基)丙基]-2,3-二氧-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-7)
(8)3-乙酰氧基-5-[3-(4-(2-甲氧苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-8)
(g)3-乙酰氧基-5-[2-(4-苯基-1-哌嗪基)乙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-9)
(10)3-乙酰氧基-5-[2-(4-(2-甲氧苯基)-1-哌嗪基)乙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-10)
(11)3-乙酰氧基-5-[2-(4-苯基-1-哌嗪基)乙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-11)
(12)3-乙酰氧基-5-[3-(4-(4-氟苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-12)
(13)3-乙酰氧基-5-[2-(4-(4-氟苯基)-1-哌嗪基)乙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-13)
(14)3-乙酰氧基-5-[3-(4,4-二苯基-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-14)
(15)3-乙酰氧基-5-[3-(4-(4,4-二氟二苯甲基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-15)
(16)3-乙酰氧基-5-[3-(4-(4-氯二苯甲基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5苯并硫氮杂_-4(5H)-酮(I-16)
实施例17
(1)按照实际上与实施例1(1)相同的方法处理原料(2S-顺)-2-(4-甲氧苯基)-3-羟基-8-氯-2,3-二氢-1,5苯并硫氮杂_-4(5H)-酮。
(2)按照实际上与实施例1步骤2和步骤3相同的方法处理4-(2-甲氧苯基)哌嗪,得无色棱晶状目的化合物(I-17),产率97.0%。MP:109-111℃(于乙酸乙酯中重结晶)元素分析(%)C32H36ClN3O5S:计算值:C,62.99;H,5.95;N,6.89实测值:C,63.09;H,6.00;N,6.77IRγmax(石蜡):1746,1678cm-1NMR(CDCl3)δ:1.90(2H,m),1.91(3H,s),2.77(10H,m),3.63(1H,m),4.47(1H,m),3,83(3H,s)3.85(3H,s),5.03(1H,d),5.15(1H,d),7.28(11H,m)旋光率 :[α]D+109.3±1.5(25℃,C=1.007,MeOH)
实施例18-39
按照实际上与实施例17相同的方法,制得下列化合物I-18-I-39。
(18)(2S-顺)-3-乙酰氧基-5-[3-(4-(2-甲氧苯基-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮盐酸化物(I-18)
(19)(2S-顺)-3-乙酰氧基-5-[3-(4-(2-甲氧苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮磷酸盐(I-19)
(20)(2S-顺)-3-乙酰氧基-5-[3-(4-(2-甲氧苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮柠檬酸盐(I-20)
(21)(2S-顺)-3-乙酰氧基-5-[3-(4-(2-甲氧苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮富马酸盐(I-21)
(22)(2S-顺)-3-乙酰氧基-5-[3-(4-(4-氯二苯甲基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-22)
(23)(2S-顺)-3-乙酰氧基-5-[3-(4-(二苯甲基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-23)
(24)(2S-顺)3-乙酰氧基-5-[3-(4-(4,4’-二氯二苯甲基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-24)
(25)(2S-顺)-3-乙酰氧基-5-[3-(4-(4-氯苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-25)
(26)(2S-顺)-3-乙酰氧基-5-[3-(4-(4-甲基苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-26)
(27)(2S-顺)-3-乙酰氧基-5-[3-(4-(环己基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-27)
(28)(2S-顺)-3-乙酰氧基-5-[3-(4-(2-甲基苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-28)
(29)(2S-顺)-3-乙酰氧基-5-[3-(4-(4-甲氧苯基)-1-派嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-29)
(30)(2S-顺)-3-乙酰氧基-5-[3-(4-(2,4-二甲氧苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-30)
(31)(2S-顺)-3-乙酰氧基-5-[3-(4-(3,4-二甲氧苯基)-1-哌嗪基)丙基]-2,3-二氢.-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-31)
(32)(2S-顺)-3-乙酰氧基-5-[3-(4-(3,4,5-三甲氧苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-32)
(33)(2S-顺)-3-乙酰氧基-5-[4-(4-(2-甲氧苯基-1-哌嗪基)丁基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-33)
(34)(2S-顺)-3-乙酰氧基-5-[5-(4-(2-甲氧苯基)-1-哌嗪基)戊基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-34)
(35)(2S-顺)-3-乙酰氧基-5-[3-(4-(2-甲氧苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-甲氧基-1,5-苯并硫氮杂_-4-(5H)-酮(I-35)
(36)(2S-顺)-3-乙酰氧基-5-[3-(4-(2-甲氧苯基-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-甲基-1,5-苯并硫氮杂_-4(5H)-酮(I-36)
(37)(2S-顺)-3-羟基-5-[3-(4-(2-甲氧苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5苯并硫氮杂_-4(5H)-酮(I-37)
(38)(2R-顺)-3-乙酰氧基-5-[3-(4-(2-甲氧苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5苯并硫氮杂_-4(5H)-酮(I-38)
(39)(2S-反)-3-乙酰氧基-5-[3-(4-(2-甲氧苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮(I-39)
除化合物I-1和I-17外,上述化合物的化学结构及产率列于表1,详细的反应条件概述于表2。另外,表3例举了目的化合物的生理特性及其重结晶所用溶剂。
表1实施例号
1)X:=N-A-R1 z n Y 产率(%) 产率(%)
2)X:=C-(R1)R2 I II2 1)A: 单键 g 3 Cl 86.6a 未分离
R1: 甲基3 1)A: 单键 g 3 Cl 80.5f 90.2
R1: 2-吡啶基4 1)A: 单键 g 3 H 81.0a 89.8
R1: 邻甲氧苯基5 1)A: -CH2- g 3 Cl 98.3f 77.1
R1: 3,4-亚甲二氧基
苯基6 1)A: -CH2- g 3 Cl 96.0a 41.9
R1: 3,4-亚甲二氧基
苯基7 1)A: -CO- g 3 Cl 64.5f 98.0
R1: 2-呋喃基8 1)A: 单键 g 3 Cl 99.3f 84.5
R1: 邻甲氧苯基9 1)A: 单键 g 2 Cl 20.3a 未分离
R1: 苯基10 1)A: 单键 g 2 Cl 21.3a 未分离
R1: 邻甲氧苯基11 2)A: 苯基 g 2 Cl 21.1f 未分离
R2: H12 1)A: 单键 g 3 Cl 96.3a 81.1
R1: 对氟苯基13 1)A: 单键 g 2 Cl 22.3a 未分离
R1: 对氟苯基14 2)R1: 苯基 g 3 Cl 99.0a 87.4
R2: 苯基15 1)A: 单键 g 3 Cl 85.3a 91.4
R1:4,4’-二氟二苯甲基16 1)A: 单键 g 3 Cl 99.0a 77.1
R1: 4-氯二苯甲基18 1)A: 单键 g 3 Cl 46.2a 92.7
R1: 邻甲氧苯基19 1)A:单键 g 3 Cl 82.2b 92.7
R:邻甲氧苯基20 1)A:单键 g 3 Cl 81.5c 92.7
R1:邻甲氧苯基21 1)A:单键 g 3 Cl 84.7d 92.7
R1:邻甲氧苯基22 1)A:单键 g 3 Cl 74.5e 73.0
R1:4-氯二苯甲基23 1)A:单键 g 3 Cl 59.8a 68.8
R:二苯甲基24 1)A:单键 g 3 Cl 85.1a 71.9
R1:4,4’-二氯
二苯甲基25 1)A:单键 g 3 Cl 78.6e 65.7
R1:4-氯苯基26 1)A:单键 g 3 Cl 65.7d 94.7
R1:4-甲苯基27 1)A:单键 g 3 Cl 71.1e 98.2
R1:环己基28 1)A:单键 g 3 Cl 58.0 79.0
R1:邻甲苯基29 1)A:单键 g 3 Cl 80.0c 79.0
R1:对甲氧苯基30 1)A:单键 g 3 Cl 77.0f 未分离
R1:2,4-二甲氧苯基31 1)A:单键 g 3 Cl 64.0 未分离
R1:3,4-二甲氧苯基32 1)A:单键 g 3 Cl 55.0 未分离
R1:3,4,5-三甲氧
苯基33 1)A:单键 g 4 Cl 75.2 84.6
R1:邻甲氧苯基34 1)A:单键 g 5 Cl 92.1a 91.9
R1:邻甲氧苯基35 1)A:单键 g 3 CH3O- 88.0a 85.0
R1:邻甲氧苯基36 1)A:单键 g 3 CH3- 93.0a 94.0
R1:邻甲氧苯基37 1)A:单键 h 3 Cl --- 85.5a
R1:邻甲氧苯基38 1)A:单键 g 3 Cl 69.8 84.7
R1:邻甲氧苯基39 1)A:单键 g 3 Cl 47.0c 未分离
R1:邻甲氧苯基a:盐酸化物 b:磷酸盐 c:柠檬酸盐d:富马酸盐 e:马来酸盐 f:草酸盐g:乙酰基 h:氢
表2
(步骤1)实施例号 原料化合物mg(mmol) 溶剂 碘化钾 反应温度 反应时间
化合物(III) 化合物(IV) (ml) mg(mmol) (℃) (小时)2 412(1) 301(3) i 5 33(0.2) 83 243 412(1) 326(2) i 5 166(1) 83 164 270(0.71) 275(1.43) i 5 24(0.15) 83 195 412(1) 440(2) i 5 166(1) 83 166 1340(3.25) 1340(6.50) i 14 108(0.65) 83 15
412(1) 360(2) i 5 166(1) 83 168 412(1) 384(2) a 4 166(1) 82 169 797(2) 2600(16) a 8 --- 40 9610 398(1) 461(2.4) i 4 50(0.3) 83 1611 398(1) 387(2.4) a 4 50(0.3) 40 1612 341(0.83) 307(1.7) a 6 28(0.17) 82 1013 398(1) 433(2.4) i 4 50(0.3) 83 1614 283(0.69) 326(1.37) i 4 23(0.14) 83 1915 310(0.75) 433(1.5) i 6 25(0.15) 83 2016 412(1) 574(2) i 5 166(1) 83 16
表2(续)
(步骤1)实施例号 原料化合物mg(mmol) 溶剂 碘化钾 反应温度 反应时间 碳酸钾
化合物(III) 化合物(IV) (ml) mg(mmol) (℃) (小时) mg(mmol)16 412(1) 384(2) a 4 166(1) 82 16 ---19 412(1) 384(2) a 4 166(1) 82 16 ---20 412(1) 384(2) a 4 166(1) 82 16 ---21 412(1) 384(2) a 4 166(1) 82 16 ---22 412(1) 574(2) i 8 166(1) 83 20 ---23 412(1) 505(2) i 8 33(0.2) 83 21 ---24 412(1) 642(2) i 8 33(0.2) 83 20 ---25 412(1) 539(2) i 8 33(0.2) 83 21 ---26 412(1) 498(2) d 8 332(2) 100 3 ---27 412(1) 337(2) d 8 332(2) 100 3 ---28 2060(5) 1270(6) d 5 1250(7.5) 100 1 1650(12)29 1030(2.5) 793(3)b d 5 625(3.8) 100 1.5 1240(9)30 1030(2.5) 776(3)b d 5 625(3.8) 100 2 825(6)31 1440(3.5) 1200(4.2)b d 10 875(5.3) 100 2 825(6)32 2060(5) 1580(5.5)b d 10 1250(7.5) 100 2 1510(11)33 613(1.44) 395(1.73) d 6 239(1.4) 100 2 ---34 642(1.46) 400(1.75) d 6 242(1.46) 100 2 ---35 490(1.2) 460(2.4) d 10 400(2.4) 100 2.5 ---36 340(0.87) 335(1.74) d 7 289(1.74) 100 2.5 ---37 412(1) 284(2) a 4 166(1) 82 16 ---38 1120(2.7) 652(2.9) d 5.6 451(2.7) 100 2 ---39 1120(2.7) 652(2.9) d 5.6 451(2.7) 100 2 ---a: 乙腈 i:异丙醇 d:二甲基甲酰胺b: 盐酸化物
表2(续)
步骤3实施例号 原料化合物mg(mmol) Ac2O 反应温度 反应时间 碱
化合物(II) (ml) (℃) (小时) mg
(mmol)2 280(0.58) 5 110 33 486(0.90) 4.9 100 34 342(0.64) 3.4 100 35 400(0.67) 3 100 36 792(1.36) 8 100 37 878(1.58) 8.8 100 38 400(0.71) 10 100 39 619(1.18) 6.2 100 310 159(0.29) 1.6 100 311 283(0.54) 2.3 100 312 800(1.44) 10 110 413 163(0.3) 1.6 100 314 361(0.6) 3.6 100 315 456(0.69) 4.5 100 2.516 480(0.72) 6 100 418 400(0.71) 10 100 319 400(0.71) 10 100 320 400(0.71) 10 100 321 400(0.71) 10 100 322 483(0.73) 4.8 100 423 432(0.69) 4.3 100 324 501(0.72) 5 100 325 376(0.66) 2 30 2126 523(0.95) 2.7 30 1327 534(0.98) 5 30 1428 2040(3.7) 10 30 15 m 22(0.18)29 1640(2.66) 5 30 15 m 20(0.17)30 1500(2.5) 5 30 48 m 20(0.17)31 2030(3.39) 7 30 2 m 30(0.24)32 3140(5.0) 8 30 2 m 23(0.18)33 708(1.22) 7 30 4 m 7.5(0.06)34 799(1.34) 8 30 4 m 7.5(0.06)35 570(1.01) 5.7 40 16 p 100(1.26)36 330(0.6) 3.3 30 1 m 20(0.06)37 --- -- -- -- ----38 1307(2.3) 6.5 30 16.5 m 14.1(0.12)39 1245(2.2) 6.2 30 16 m 13.4(0.11)
m:二甲氨基吡啶 p:吡啶
表3实施例号 表观 重结晶溶剂 MP(℃) 旋光率 IR(vcm-1 max)
[α]25 DMeOH 石蜡2-Ia CP 甲醇 250-252(d) 1746,16562-IIb CG 丙酮 230-231 1724,16643-Ib CP 丙酮 142-145 1759,16843-II oil - -4-Ia CP 丙酮 138-140 1732,16874-II CG 己烷 75-76 16625-Ib YG 甲醇 212-214(d) 1745,16855-II oil - 16616-Ia CP 丙酮 160-162 1737,16776-II oil - -7-Ib CP 丙酮 196-197 1738,1688-II oil - -8-Ib CG 丙酮 183-185 1749,16868-II CP 己烷 75-76 16629-Ib CP 丙酮 154-156 1742,16839-II - - -10-Ia YP 丙酮 153-157 1742,165510-II - - -11-Ib CP 丙酮 141-144 1748,170511-II - - -12-Ia CN 乙醇 144-145 1738,1675
乙醚12-II CP 己烷 70-71 166413-Ia CP 丙酮 153-155 1753,167913-II - - -14-Ia CP 丙酮 225-230 1746,167814-II oil - -15-Ia CP 丙酮 157-159 1748,167115-II oil - -16-Ia CP 丙酮 149-152 1750,167316-II CP 己烷 108-109 -48-Ia CP 丙酮 147-150+67.9±1.1(c=1.012) 3374,2282,
1245,167718-II oil 甲醇 - - -19-Ic CP 甲醇 140-143+69.9±1.1(c=1.005) 2350,1742,
168020-Id CP 甲醇 187-189+65.0±1.0(c=1.007) 3430,2620,
1737,167421-Ie CP 乙醇 115-117+69.6±1.1(c=1.003) 3276,2506,
1741,167222-If CA 乙醚 - +56.2±1.0(c=1.015) 3324,2394,
1744,167822-II oil - - -23-Ia CA - +64.1±1.0(c=1.005) *3410,2392,
167623-II CA - - - -24-Ia CA - - +54.5±0.9(c=1.003) *3488,166124-II oil - - - -25-If CA - - +65.3±1.0(c=1.014) *3500,2394,
1744,167825-II oil - - - -26-Ie CA - - +73.8±1.1(c=1.009) 3428,2606,
1743,167726-II oil - - - -27-If CP 乙醇 195-202 +73.9±1.1(c=1.013) 3260,2348,
1752,168527-II oil - - -28-I CP 乙醇 187-188 +110.8±1.5(c=1.006) -28-II oil - - -29-Id CP 乙醇 197-198 +58.8±1.0(c=1.004) -1-II oil - - -50-Ib CP 乙醇 175-176 +66.8±1.1(c=1.01) -30-II oil - - -31-I CP 乙醇 170-171 +101.8±1.4(c=1.011) -31-II oil - - -32-I CP 乙醇 162-163 +93.9±1.3(c=1.016) -32-II oil - - -33-I CP 己烷 139-140 +90.9±1.3(c=1.013) 1743,167633-II oil - - -34-Ia CA - +76.2±1.2(c=1.008) *3486,2390,
1739,167634-II CA - - -35-Ia CA - +70.1±1.1(c=1.003) -35-II oil - - -36-Ia CA - +80.5±1.2(c=1.005) -36-II oil - - -37-IIa CP 丙酮 135-137 +83.8±1.2(c=1.007) 3380,2360,
166038-I CP 己烷 109-111 -110.1±1.5(c=1.018) 1746,167838-II CN 己烷 175-178 - -39-Id CP 甲醇 191-192 +275.8±3.1(c=1.018) 3446,2542,
1736,164039-II oil - -a:盐酸化物 b:草酸盐 c:磷酸盐d:柠檬酸盐 e:富马酸盐 f:马来酸盐*:在二氯甲烷中CP:无色棱晶 YG:黄色粒状结晶YP:黄色棱晶 CN:无色针状结晶CA:无色无定形物
以下进行本发明化合物(I)的药理试验。
试验1
钙离子通道拮抗剂和α-阻滞作用(对分离血管的松弛作用)
通过静脉注射巴比妥(50mg/kg)将体重2-3kg的雄兔(Ra-biton日本albino种)麻醉,并通过割开腋窝动脉放血处死。分出股动脉,除去动脉周围的连接组织,并制成螺旋形标本。将标本悬浮于装有37℃Krebs-Henseleit营养溶液并吹入95%O2+5%CO2混合气体的容器(20cc)中,令股动脉承受1.5g静止张力,通过F-D传感器(Nippon Koden)(TB-611T)和前置放大器(Nippon Koden)于热敏记录仪(Nippon koden WT-685G)上记录标本张力的等量变化。通过观察化合物的累积加入量对由用50mM KCl引起的收缩的松驰作用来评价试验化合物的Ca-拮抗作用。相似地,通过观察对由1μM去甲肾上腺素(NE)引起的收缩的这种松驰作用来评价α-阻滞作用。将使用0.1mM罂粟碱时所观察到的血管松驰反应定义成血管的最大松驰能力,利用上述系统,测定获得50%最大松驰时所需化合物的浓度(IC50)。结果如表4所示。
表4
血管的松驰作用化合物号I IC50(×0.1μM)
50mM-KCl 1μM-NEI-5 2.5I-8 2.8 0.6I-11 2.0I-14 1.0I-15 0.57 6.0I-16 2.4I-18 2.5 0.37I-22 3.4I-35 1.2 0.3I-36 1.4 0.2硫氮_酮 4.2 133
试验2
对培养的心肌细胞的抗缺氧作用
通过它们对心肌细胞保护作用的研究来研究本发明化合物的抗缺氧作用。
由新生的Crj-SD鼠(2-3天龄)制得心肌细胞的最初培养物并用于本试验。根据Jones R.L.等于Am.J.Pathol,135,54-556(1989)中描述的方法制得最初培养物。用胶原酶和胰酶由心室肌中分离心肌细胞,然后通过Percoll密度一梯度离心法将心肌细胞与细胞碎片、红细胞和纤维细胞分开并纯化。将细以2-3×105细胞/3.5cm皿的比率散布于培养皿上,并将细胞于含10%牛胎血清(FBS)的Dulbecco改进的Eagle培养基(DMEM)(Dulbeccos Modified Eagles Medium)中于37℃恒温箱(5%CO2/95%空气)中培养两天。当生长出足够的心肌细胞后,将培养基换成不含有FBS的DMEM,并再继续培养一天。将如此获得的细胞用于本试验。
利用Gas PakTM厌氧房(BBL)(Gas PakTM AraerobicChamber)产生缺氧,此厌氧房是通过捕捉剩余的O2并利用H2/CO2生成袋和催化剂的作用将其转变成H2O而产生缺氧。将其中培养基已经变成不含FBS和葡萄糖的DMEM的心肌细胞培养皿置于厌氧房中,并将此厌氧房置于恒温箱中,通过测定释放到培养基中的肌酸磷酸激酶活性的抑制率测定试验化合物的抗缺氧活性。
用HCO-50作促溶剂将试验化合物全部溶于DMSO中(DMSO∶HCO-50=9∶1),并直接放到培养皿中。分别将在培养基中的DMSO和HCO-50的最终浓度调至0.09%和0.01%。通过由Oliver法改进的比色法(Wako kit)测定CPK活性。试验结果总结于表5中。
表5
抗缺氧活性(%)化合物号
1μM 10μMI-1 - 66I-3 34I-5 - 66I-7 36I-8 17 70I-12 10 87I-13 15 61I-14 - 83.6I-15 - 76I-16 18.4 57I-18 23.7 73.9I-22 25.7 73.9I-23 36.4 87I-24 14.1 88I-25 25.2 89I-29 30I-32 - 66.1I-33 36.9 87I-34 - 80.0硫氮_酮 10 29
用当CPK释放量为负对照(未加入试验化合物)时测定的试验化合物对CPK释放的抑制率(%)定义为100%,表中数值表明了试验化合物的心肌细胞保护活性。表5明显地表明本发明化合物较正对照(硫氮_酮)具有较高的保护活性。
试验3
本发明化合物对未麻醉下自生高血压鼠(SHR)的血压和心率的作用。
将日本Charles-River雄性SHR(13-17周龄)用于本试验(S.Matsuda,J.Pharmacol.Method17361,1987)。用药前和用药后2和4小时,未侵害下(间接地)用尾动脉压血压测量表(5管型)测量动物的收缩压(SBP)和心率,试验化合物溶于DMSO(100%)并口服给药。服药后2和4小时测量的SBP和心率与服药前测量比较,其减少量以百分比(%)的形式列于下表。
表6化合物号
抗高血压活性(%) 心率的减低(%)(30mg/kg PO)I-8 15 3.2I-14 14 9.8I-15a 17 6.5I-16 19 15I-18 18 7.0I-22 18 9.4I-23 16 12硫氮_酮a 11 15a:60mg/kg po
试验4
抗坏死活性
将体重200-250g雄性Slc Wistar鼠用乌拉坦(1g/kg)麻醉,并将在冠状血管下行支结扎20分钟,然后按照Hock等(Hock C.E.Ribeiro,L.G.,Tand Lefer,A.M.Am,Heart J.,109222,1985)描述的方法再灌注。将试验化合物溶于生理盐水,或者首先溶于DMSO/HCO-50(9∶1)混合液中,然后用生理盐水或0.25M蔗糖水溶液稀释,并于结扎前以0.15ml/kg/min的速率向右颈静脉内灌注10分钟。再灌注后3小时,将鼠于热垫上进行热隔离。120分钟后,分离出心脏,并将游离的左心室壁冰冻并贮存直至测定CPK活性。
CPK活性是根据经很小的改进后的Bernauer W.的方法(Arch.int.Pharmacodyn.,23190,1978)测定。将分离的组织于含1mM巯基乙醇的10倍体积0.1M Tris/HCl(pH7.5)中搅匀,并于20,000g下离心分离20分钟。上清液用于测定CPK活性,其可以用商用急救箱处理(CPK-Test,Wako)。用血清CPK作标准测定CPK并用“u/mg蛋白”表示。
将施用试验化合物时获得的由于局部缺血引起的心肌损伤抑制作用与施用活性对照(硫氮_酮)时获得抑制作用相比较。根据左心室所保留的CPK活性测定抑制程度,试验结果列于表7,其中每一剂量的保留百分比(%)根据下式计算。
保留值(%)=[(施用试验化合物时保留的CPK活性)-(只施用介质时保留的CPK活性)]/[(完整的动物具有的CPK活性)-(只施用介质时保留的CPK活性)]
表7
保留值(%)(抗坏死活性)化合物号 mg/kg(iv)
0.1 0.3 1I-8 29I-12 23I-18 30 42I-22 45I-23 45I-24 35I-35 37I-36 30硫氧_酮 13
Claims (3)
2.根据权利要求1所述的方法,其中所述式(I)表示的化合物是3-乙酰氧基-5-[3-(4-(2-甲氧苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮杂_-4(5H)-酮。
3.根据权利要求1所述的方法,其中所述式(I)表示的化合物是(2S-顺)-3-乙酰氧基-5-[3-(4-(2-甲氧苯基)-1-哌嗪基)丙基]-2,3-二氢-2-(4-甲氧苯基)-8-氯-1,5-苯并硫氮_-4(5H)-酮。
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AU709280B2 (en) * | 1996-02-23 | 1999-08-26 | Tanabe Seiyaku Co., Ltd. | Process for preparing 1,5-benzothiazepine derivative |
IL123352A0 (en) * | 1997-02-27 | 1998-09-24 | Tanabe Seiyaku Co | Process for preparing an optically active trans-3-substituted glycidic acid ester |
UA67760C2 (uk) * | 1997-12-11 | 2004-07-15 | Міннесота Майнінг Енд Мануфакчурінг Компані | Імідазонафтиридин та тетрагідроімідазонафтиридин, фармацевтична композиція, спосіб індукування біосинтезу цитокінів та спосіб лікування вірусної інфекції, проміжні сполуки |
US6897305B2 (en) * | 1998-06-08 | 2005-05-24 | Theravance, Inc. | Calcium channel drugs and uses |
US7101909B2 (en) * | 1998-10-12 | 2006-09-05 | Theravance, Inc. | Calcium channel drugs and uses |
CN1872846B (zh) * | 1999-07-09 | 2010-06-16 | 宇部兴产株式会社 | 二苯并硫氮*衍生物的制备方法 |
AU2001267844A1 (en) * | 2000-06-28 | 2002-01-08 | Takeda Chemical Industries Ltd. | Method of preparing heart muscle cells and method of searching for remedy for heart diseases |
US7550459B2 (en) | 2001-12-28 | 2009-06-23 | Acadia Pharmaceuticals, Inc. | Tetrahydroquinoline analogues as muscarinic agonists |
BR0215430A (pt) * | 2001-12-28 | 2004-12-14 | Acadia Pharm Inc | Composto e seus usos, composição, método de tratamento, método de aumento d atividade de um receptor colinérgico, método de tratamento e prevenção ou redução dos sintomas associados à disfunção em mamìferos |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3075967A (en) * | 1961-06-12 | 1963-01-29 | Olin Mathieson | Benzothiazines |
US4567175A (en) * | 1983-06-03 | 1986-01-28 | Tanabe Seiyaku Co., Ltd. | 8-Chloro-1,5-benzothiazepine derivatives |
US4594342A (en) * | 1984-04-10 | 1986-06-10 | Tanabe Seiyaku Co., Ltd. | 1,5-benzothiazepine derivative |
US4584131A (en) * | 1985-06-20 | 1986-04-22 | E. R. Squibb & Sons, Inc. | Benzothiazepine derivatives |
US5028610A (en) * | 1987-03-18 | 1991-07-02 | Sankyo Company Limited | N-benzhydryl-substituted heterocyclic derivatives, their preparation and their use |
US4963545A (en) * | 1988-05-24 | 1990-10-16 | Marion Laboratories, Inc. | Benzothiazepine anti-seizure method |
US4879289A (en) * | 1988-05-24 | 1989-11-07 | Marion Laboratories, Inc. | Method of ameliorating epileptic seizures |
FR2645744B1 (fr) * | 1989-04-13 | 1994-01-21 | Roussel Uclaf | Derives de la benzothiazepine, leur procede de preparation et les intermediaires ainsi obtenus, leur application comme medicaments et les compositions les renfermant |
CA2030159A1 (en) * | 1989-11-22 | 1991-05-23 | Nahed K. Ahmed | Anti-cancer drug potentiators |
US5001236A (en) * | 1989-11-22 | 1991-03-19 | Marion Laboratories, Inc. | Benzothiazepines |
-
1992
- 1992-10-14 US US07/960,851 patent/US5378698A/en not_active Expired - Fee Related
- 1992-10-15 CA CA002080671A patent/CA2080671A1/en not_active Abandoned
- 1992-10-16 DE DE69201184T patent/DE69201184T2/de not_active Expired - Fee Related
- 1992-10-16 DK DK92309474.2T patent/DK0541263T3/da active
- 1992-10-16 DE DE69221634T patent/DE69221634T2/de not_active Expired - Fee Related
- 1992-10-16 TW TW081108253A patent/TW221429B/zh active
- 1992-10-16 EP EP94201425A patent/EP0615971B1/en not_active Expired - Lifetime
- 1992-10-16 AT AT92309474T patent/ATE116974T1/de not_active IP Right Cessation
- 1992-10-16 EP EP92309474A patent/EP0541263B1/en not_active Expired - Lifetime
- 1992-10-16 DK DK94201425.9T patent/DK0615971T3/da active
- 1992-10-16 ES ES94201425T patent/ES2106439T3/es not_active Expired - Lifetime
- 1992-10-16 ES ES92309474T patent/ES2069967T3/es not_active Expired - Lifetime
- 1992-10-16 AT AT94201425T patent/ATE156821T1/de not_active IP Right Cessation
- 1992-10-20 KR KR1019920019273A patent/KR100214902B1/ko not_active IP Right Cessation
- 1992-10-21 CN CN92113330A patent/CN1034075C/zh not_active Expired - Fee Related
- 1992-10-21 JP JP4282874A patent/JP2818082B2/ja not_active Expired - Fee Related
-
1994
- 1994-08-22 US US08/292,226 patent/US5462936A/en not_active Expired - Fee Related
-
1997
- 1997-08-14 GR GR970401977T patent/GR3024453T3/el unknown
Also Published As
Publication number | Publication date |
---|---|
ATE156821T1 (de) | 1997-08-15 |
GR3024453T3 (en) | 1997-11-28 |
DE69201184D1 (de) | 1995-02-23 |
CA2080671A1 (en) | 1993-04-22 |
DE69221634T2 (de) | 1998-01-15 |
US5378698A (en) | 1995-01-03 |
DE69221634D1 (de) | 1997-09-18 |
EP0615971A1 (en) | 1994-09-21 |
EP0541263A1 (en) | 1993-05-12 |
EP0541263B1 (en) | 1995-01-11 |
ES2106439T3 (es) | 1997-11-01 |
US5462936A (en) | 1995-10-31 |
DK0615971T3 (da) | 1997-10-06 |
DK0541263T3 (da) | 1995-04-18 |
JPH05201865A (ja) | 1993-08-10 |
DE69201184T2 (de) | 1995-06-08 |
JP2818082B2 (ja) | 1998-10-30 |
EP0615971B1 (en) | 1997-08-13 |
KR100214902B1 (ko) | 1999-08-02 |
ATE116974T1 (de) | 1995-01-15 |
TW221429B (zh) | 1994-03-01 |
ES2069967T3 (es) | 1995-05-16 |
KR930007943A (ko) | 1993-05-20 |
CN1073168A (zh) | 1993-06-16 |
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