CN1118783A - 新的吡啶并[3,2-b][1,5]苯并硫代吖庚因的制备方法 - Google Patents
新的吡啶并[3,2-b][1,5]苯并硫代吖庚因的制备方法 Download PDFInfo
- Publication number
- CN1118783A CN1118783A CN95109346A CN95109346A CN1118783A CN 1118783 A CN1118783 A CN 1118783A CN 95109346 A CN95109346 A CN 95109346A CN 95109346 A CN95109346 A CN 95109346A CN 1118783 A CN1118783 A CN 1118783A
- Authority
- CN
- China
- Prior art keywords
- ethyl
- dioxo
- benzothiazepines
- hydrogen
- benzyl
- 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.)
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- BYUYCWQSIZPKCS-UHFFFAOYSA-N pyrido[3,2-b][1,5]benzothiazepine Chemical class C1=NC2=CC=CC=C2SC2=CC=CN=C21 BYUYCWQSIZPKCS-UHFFFAOYSA-N 0.000 title abstract description 6
- 238000004519 manufacturing process Methods 0.000 title 1
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- 238000000034 method Methods 0.000 claims abstract description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 46
- -1 benzoyloxy, benzyl methyl Chemical group 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 16
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Abstract
本发明披露了新的吡啶并[3,2-b][1,5]苯并硫代吖庚因及其制备方法。这些化合物适宜用作具有心血管,抗气喘和抗支气管狭窄活性的钙通道拮抗剂。
Description
本申请是CN91103594.X的分案申请。原申请的发明名称为“新的吡啶并[2,3-f][1,4]硫代吖庚因和吡啶并[3,2-b][1,5]苯并硫代吖庚因”;原申请的申请日为1991年5月3日。
本发明涉及新的吡啶并〔2,3—f〕〔1,4〕—硫代吖庚因和新的吡啶并〔3,2—b〕〔1,5〕苯并硫代吖庚因。这些化合物是钙离子吸入平滑肌肉组织的抑制剂,并可弛缓或防止钙机理调解的组织收缩。这些化合物是有效的抗高血压药和支气管扩张药。
这些化合物适宜于治疗心血管疾病,如高血压、局部缺血、咽峡炎、充血心力衰竭、偏头痛、心肌梗塞和发作。这些化合物也适用于治疗其他疾病,如过敏、变态反应、气喘、痛经、食管痉挛、胃肠能动性疾病、青光眼、早熟分娩和尿道疾病。本发明还涉及制备这些化合物和其组合物的方法,使用方法和新的中间体。
US4,285,955和US4,483,985(前一专利的分案专利)披露了具有钙通道拮抗活性的结构简单的二氢吡啶上的无环砜取代物。然而,这些化合物在化学性质上是不同于本发明的化合物。
Pagani,G.P.A在J.Chem。Soc.,PerkinTrans.2,1392(1974)中公开了10—苯基—2H—噻喃醇〔3,2—b〕喹啉类化合物,然而这些化合物不是钙通道拮抗药。
US4,532,248披露了一类二氢吡啶,其中包括环砜稠合在二氢吡啶环上,声称该类化合物具有强心活性。另一方面,与US4,523,248披露的相反,本发明的化合物是具含药理活性的潜在的钙拮抗药。
本发明提了具有下述结构式的吡啶并〔2,3—f〕〔1,4〕硫代吖庚因和吡啶〔3,2—b〕〔1,5〕苯并硫代吖庚因和旋光对映体(对映体或非对映体)或其药学上可接受的有机或无机酸(如氢氯酸、氢溴酸、富马酸、马来酸、对甲苯磺酸、甲基磺酸等)的盐。其中:
Y和Z可为CH2,或Y和Z一起形成一个稠合苯环;
R1是氢、氨基、C1—C3直链或支链烷基、三氟甲基或烷氧基甲基;
R2是C1—C3直链或支链烷基、苄基、3—哌啶基、N取代的3—哌啶基、N取代的2—吡咯烷基亚甲基或取代的烷基;
其中所说N—取代的3—哌啶基和所说的N—取代的2—吡咯烷基亚甲基可为C1—C8直链或支链烷基或苄基,所说取代的烷基可被C1—C8烷氧基、C2—C3链烷酰氧基、苯基乙酰氧基、苯甲酰氧基、羟基、卤素、对—甲苯磺酰氧基、甲基磺酰氧基、氨基、羰烷氧基或NR5R6所取代;
R3可以是2—吡啶基、3—吡啶基、2—噻吩基、3—噻吩基、2,1,3—苯并噁二唑基、2,1,3—苯并噻二唑基或取代的苯基;
其中所说的取代的苯基可以在其2—6位置上任一位上被氢、C1—C8直链或支链烷基、C1—C8烷氧基、氰基、C1—C4羰烷氧基、C1—C8烷硫基、二氟甲氧基、二氟甲硫基C1—C8烷磺酰基、卤素、硝基或三氟甲基所取代;
R4可以是氢、C1—C8直链或支链烷基、C3—C7环烷基、苯基、苄基、取代的苄基、甲酰基、乙酰基、特丁氧羰基、丙酰基、取代烷基或R7CH2C=O;
其中所说取代的苄基可以被卤素、三氟甲基C1—C8直链或支链烷基或C1—C8烷氧基取代;所说取代的烷基可以被氨基、C1—C4二烷基氨基、C1—C8烷氧基、羟基或卤素取代;
R5和R6可以是相同或不同的,可以是氢、C1—C8直链或支链烷基、C3—C7环烷基、苯基、苄基、苯乙基或R5和R6一起形成从由哌啶子基、吡咯烷基、吗啉代、硫代吗啉代、哌嗪代或哌啶的N4—取代的衍生物组成的一组基团中选出的杂环。
其中所说的N—取代的杂环可被氢、C1—C8直链或支链烷基、苄基、二苯甲基、苯基或取代的苯基所取代;
其中所说的取代的苯基可被氢、C1—C8烷氧基、卤素、C1—C8直链或支链烷基、硝基或三氟甲基所取代;
R7可为氨基、C1—C4二烷基氨基、C1—C8烷氧基,羟基或卤素;
n可以是1—4;
本发明还提供了制备上述化合物的方法,这些方法将在下面详细介绍。本发明也提供了某些中间体和其制备方法。
上述结构式的化合物抑制钙离子吸入平滑肌,因此具有弛缓或防止钙离子调解的平滑肌组织的收缩。这些化合物也适合于治疗心血管疾病(其中包括高血压、局部缺血、咽峡炎、充血心力衰竭、心肌梗塞和发作)。该化合物也适用于治疗其他疾病,例如过敏、变态反应、气喘、支气管痉挛、痛经、食管痉挛、胃肠能动性疾病、青光眼、早期分娩和尿道疾病。
本发明主要涉及吡啶并〔2,3—f〕〔1,4〕硫代吖庚因和吡啶并〔3,2—b〕〔1,5〕苯并硫代吖庚因,这些化合物能抑制钙离子吸入平滑肌组织,具有此活性的化合物结构式如前所示。
本发明的优选化合物是其中的具有下述定义的化合物和旋光对映体(对映或非对映体或其药学上所接受的盐);
R1是甲基;
R2是乙基或取代(取代基为乙酰氧基、氨基或NR5R6,R5和R6的定义同前)的C1—C8烷基;
R3是取代的苯基;
R4是氢、C1—C8直链或支链烷基、苄基、甲酰基、R7CH2C=O或叔丁氧基羰基;
R7是氨基;和
n为1。
本发明特别优选的化合物是:
1. 9—(2,3—二氯苯基)—1,1—二氧代—2,3,4,5,6,9—六氢—7—甲基吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸2—(N—苄基—N—甲基氨基)乙酯;
2. 9—(2,3—二氯苯基)—4,7—二甲基—1,1—二氧代—2,3,4,5,6,9—六氢吡啶〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸2—(N—苄基—N—甲基氨基)乙酯;
3. 9—(2,3—二氯苯基)—1,1—二氧代—2,3,4,5,6,9—六氢—7—甲基—吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸乙酯;
4. 9—(2,3—二氯苯基)—1,1—二氧代—4—乙基—2,3,4,5,6,9—六氢—7—甲基—吡啶并〔2,3—f〕〔1,4〕—硫代吖庚因—8—甲酸乙酯;
5. 9—(2,3—二氯苯基)—4,7—二甲基—1,1—二氧代—2,3,4,5,6,9—六氢吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸乙酯;
6. 4,7—二甲基—1,1—二氧代—2,3,4,5,6,9—六氢—9—(2,3,4,5,6—五氟苯基)—吡啶并〔2,3—f〕〔1,4〕—硫代吖庚因—8—甲酸乙酯;
7. 1,1—二氧代—2,3,4,5,6,9—六氢—7—甲基—9—(2,3,4,5,6—五氟苯基)—吡啶并〔2,3—f〕〔1,4〕—硫代吖庚因—8—甲酸乙酯;
8. 1,1—二氧代—4—乙基—2,3,4,5,6,9—六氢—7—甲基—9—(3—硝基苯基)—吡啶并〔2,3—f〕〔 1,4〕—硫代吖庚因—8—甲酸乙酯;
9. 4—(2,3—二氯苯基)—5,5—二氧代—10—甲酰基—2—甲基—1,4,10,11—四氢吡啶并〔3,2—b〕〔1,5〕—苯并硫代吖庚因—3—甲酸乙酯;
10. 9—(2,3—二氯苯基)—4,7—二甲基—1,1—二氧代—2,3,4,5,6,9—六氢吡啶并〔2,3—f〕〔1,4〕—硫代吖庚因—8—甲酸2—乙酰氧基乙酯;
11. 9—(2,3—二氯苯基)—4,7—二甲基—1,1—二氧代—2,3,4,5,6,9—六氢吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸2—新戊酰氧基乙酯;
12. 4—(2,3—二氯苯基)—2,10—二甲基—5,5—二氧代—1,4,10,11—四氢吡啶并〔3,2—b〕〔1,5〕—苯并硫代吖庚因—3—甲酸乙酯;
13. 4—(2,3—二氯苯基)—2,10—二甲基—5,5—二氧代—1,4,10,11—四氢吡啶并〔3,2—b〕〔1,5〕苯并硫代吖庚因—3—甲酸2—(N—苄基—N—甲氨基)乙酯;
14. 4—(2,3—二氯苯基)—4,7—二甲基—1,1—二氧代—2,3,4,5,6,9—六氢吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸2—(N,N—二苄氨基)乙酯;
15. 4—(2—3—二氯苯基)—4—乙基—1,1—二氧代—2,3,4,5,6,9—六氢—7—甲基吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸2—(N—苄基—N—甲氨基)乙酯;
16. 9—(2,3—二氯苯基)—4,7—二甲基—1,1—二氧代—2,3,4,5,6,9—六氢吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸(N—苄基—2—吡咯烷基)甲酯。
其中的Y和Z是CH2的本发明的化合物(即吡啶并〔2,3—f〕〔1,4〕硫代吖庚因)的化合物可按如下合成途径1制备。
硫代吖庚因酮(6)是合成某些二氢吡啶的关键中间体,(6)的制备方法如下:将Boc保护的胱胺(1)(按如上所述的二步。实施例1和2所描述的方法得到的)与表氯醇反应,接着将中间体氯乙醇(2)环化得到硫代吖庚因醇(4)。氯乙醇(2)环化经过环氧化物(3)。氨基甲酸酯阴离子的亲核进攻,则从位阻较小的一侧使环氧化合打开而形成硫代吖庚因醇(4)。如果仅用1当量的碱,此中间体环氧化物即可分离出来,或加入2当量的碱,氯乙醇(2)便可直接环化为(4)。先用间氯代过氧苯甲酸将硫代吖庚因醇(4)氧化得到1,1—二氧代—硫代吖庚因醇(5),再用琼斯试剂将(5)氧化得到1,1—二氧代硫代吖庚因酮(6)。
将此氧代砜(6)与适当取代的醛和取代的3—氨基丙烯酸酯衍生物反应得到二氢吡啶(7)。把二氢吡啶(7)曝露于酸性条件下以除去叔丁氧基保护基团得到产物(8)。然后借助苄基溴或取代的苄基溴将(8)的自由氨基官能团进行烷基化得到(9)(如果Z为卤、烷基烷氧基、烷氧基、硝基或三氟甲基),或将(8)的自由氨基用醛或酮还原胺化得到(10)(如X1和X2为氢、烷基、环烷基或一起形成一碳环或杂环)。此外也可用多种羧酸将胺(8)酰化(其中X3为氢、烷基、氨基、二取代氨基、烷氧基、羟基或卤素)得到可还原为相应胺(11b)的酰胺(11a)。在烷氧基基团存在于如(12)的酯侧链上时,该烷氧基可被酰化。保护基团叔BOC可被除去得到可用类似(8)的方法将其被苄化,烷基化或酰化的化合物(13)。
其中Y和Z一起形成苯环(而吡啶并〔3,2—b〕〔1,5〕苯并硫代吖庚因)的本发明的化合物的合成途径2如下所示:
1,1—二氧代—苯并硫代吖庚因酮(15)可用如公知技术(Federsel,H.J.et al.,TetrahedronLetters 21,2229(1986))中所述的方法由已知的苯并硫代吖庚因酮(14)经三步制成。二氢吡啶(16)是由(15)与适宜的醛和取代的3—氨基丙烯酸酯反应制得的。
在与药物载体中充分混合的混合物中,含本发明的化合物作为活性成分的的药用组合物,可用惯常的药物配制技术制备。所说载体可以采用多种形式,但这取决于制剂的给药途径,例如静脉给药、口服或肠胃外给药。如制备口服剂型,则可将任何常用药用介质(如水、乙二醇、油类、醇类、香味剂、防腐剂、着色剂等)用于口服液体制剂(如悬浮剂、酏剂和溶液);如为口服固形制剂(如粉剂、胶囊和片剂)时,可以使用载体如淀粉、糖、稀释剂、颗粒剂、润滑剂、粘结剂、崩解剂等。鉴于给药容易,片剂和胶囊剂为最适宜的口服剂型,此时自然要用固形药物载体。如需要的话,可用标准技术将片剂包以糖衣或肠溶衣。对于肠胃外给药而言,虽然也可使用其他成分(如促进溶解的或作防腐用的)也可以使用,但一般使用的载体是无菌水。也可配制注射用的悬浮液,这时可以使用适宜的液形载体、悬浮剂等。本发明的化合物也可制成烟雾剂型给药。对于每一剂量(如片剂、胶囊剂、粉剂、注射液、一茶匙等),本发明的药物组合物所含所说活性成分的量为大约0.001—100mg/kg左右,优选大约0.001—20mg/kg。
用下述实施例来对本发明作更具体的描述,但仅用于说明本发明,而不是用于限制本发明。
实施例1
双—N—(叔丁氧基羰基)胱胺
用碳酸氢二叔丁基酯(100.0g,0.458mole)对由胱胺二氢氯化物(46.95g,0.285mole)的四氢呋喃(1升THF)溶液和氢氧化钠(33.33g,0.833mole)的水(500ml)溶液配制的混合物加以处理,室温下搅拌2小时。分离出的水相用2×500ml乙醚进行萃取。合并的有机相用盐水和MgSO4干燥,减压蒸发得到白色固体产品78.2g,产率78%,D.C.I.M.S.(M+H)325。
实施例2
N—(叔—丁氧基羰基)—2—氨基乙硫醇
用NaBH4(32.5g,0.859mmole)对实施例1制得的双N—(叔—丁氧基羰基)—胱胺(77.37g,0.220mole)在1L乙醇中的溶液进行处理,猛烈放出气体,在40分钟内慢慢停止,再将反应物搅拌30分钟后,倒入2.5升的冷的稀柠檬酸(pH6)溶液中。用氯仿萃取(3×1升)此混合物,用MgSO4干燥合并的有机萃取液,减压蒸发除去溶剂,66℃—73℃、0.25托下蒸馏所得的残余物得到41.5g产物,产率53%。
实施例3
(2—(叔—丁氧基羰基—氨基)—乙基)—(3—氯—2—羟基丙基—硫醚
把实施例2中制的N—(叔丁氧基羰基)—氨基乙硫醇(40g,225mmole)和表氯醇(35.4g,383mmole)的乙醇(300ml)溶液的混合物冷却到0℃后,用碳酸钾(35.4g)对其处理,将此反应温热到室温90分钟以上,用硅藻土过滤,减压除去挥发性物质,得到透明的油状物62.09克,产率100%,D.C.I.M.S.270(M+H)。
实施例4
4—N—(叔丁氧基羰基)—6—羟基—2,3,4,5,6,7—六氢—1,4—硫代吖庚因
0℃下,把实施例3制得的(2—(叔丁氧基羰基—氨基)—乙基)—(3—氯—2—羟基丙基)—硫醚(30g,111.52mmole)溶解在500ml二甲基甲酰胺中。用氢化钠(9.81g,245mmole),分成三份对所得溶液处理15分钟以上。让此反应物料温热到室温1小时15分钟以上,倒入2。5升冰水中,用氯仿(3×1升)对其萃取。用盐水和Na2SO4对合并的有机萃取物予以干燥、蒸发,把所得残余物进行色谱纯化(3∶1的己烷∶乙酸乙酯作洗脱液,硅胶吸附)得到白色固形产物12.47g,产率48%D.C.I.M.S.234(M+H)。M.P(熔点)80—82℃。
实施例5
4—N—(叔丁氧基羰基)—1,1—二氧代—6—羟基—2,3,4,5,6,7—六氢—1,4—硫代吖庚因
1小时以上,把实施例4制得的4—N—(叔丁氧基羰基)—6—羟基—2,3,4,5,6,7—六氢—1,4—硫代吖庚因(11.7g,50.6mmole)的氯仿(100ml)溶液滴加到间氯过苯甲酸(19.2g,111mmole)的氯仿(130ml)溶液中,加完后室温下搅拌此反应物2小时,过滤反应混合物,减压浓缩滤液,得到的残余物用乙酸乙酯、己烷进行重结晶,获得产品11.37g,产率85%D.C.I.M.S.266(M+H)M.P.123—124℃。
实施例6
4—N—(叔—丁氧基羰基)—1,1—二氧代—2.3,4,5,6,7—六氢—1,4—硫代吖庚因—6—酮
把实施例5制得的4—N—(叔—丁氧基羰基)—1,1—二氧代—6—羟基—2,3,4,5,6,7—六氢—1,4—硫代吖庚因(10.0g,37.7mmole)溶解在110ml丙酮中,冷却到零度后,用新制的琼斯试剂18.8ml进行处理。室温下将反应物搅拌3小时,然后用5ml甲醇处理。15分钟后,用硫酸镁过滤反应物,对滤液立即加以浓缩,残余物用硅胶填料过滤,氯仿∶乙酸乙酯(3∶1)作洗脱液得到9.67g产物,产率87%。D.C.I.M.S.264(M+H),M.P172—173℃。
实施例7
9—(2,3—二氯苯基)—4—(叔丁氧基羰基)—1,1—二氧代—2,3,4,5,6,9—六氢—7—甲基吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸乙酯
于40ml乙醇中,把由实施例6制得的4—N—(叔丁氧基羰基)—1,1—二氧代—2,3,4,5,6,7—六氢—1,4—硫代吖庚因—6—酮(2.00g,7.60mmole)、2,3—二氯苯甲醛(1.33g,7.60mmole)和3—氨基巴豆酸乙酯(0.98g,7.60mmole)组成的混合物加热回流24小时。减压除去乙醇后,再用85ml甲苯进行置换。把此混合物加热回流2小时,冷却到室温,过滤得到2.45g产物,产率61%。
实施例8
9—(2,3—二氯苯基)—1,1—二氧代—2,3,4,5,6,9—六氢—7—甲基吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸乙酯
把实施例7制的9—(2,3—二氯苯基)—4—(叔丁氧基羰基)—1,1—二氧代—2,3,4,5,6,9—六氢—7—甲基吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸乙酯(2.45g,4.6mmole)和乙酸乙酯(150ml)组成的混合物冷却到0℃。用氯化氢气体将其饱和。混合物温热到室温。再将反应物冷却到零度,与200ml冷的4N NaOH一起振荡,分离出的液层,用2×100ml氯仿进行萃取。乙酸乙酯层用盐水干燥,合并的有机相用硫酸钠干燥。减压蒸发除去溶剂。残余物用乙醚研制得到1.86g产物,产率94%。
实施例9
9—(2,3—二氯苯基)—4,7—二甲基—1,1—二氧代—2,3,4,5,6,9—六氢吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸乙酯
用甲醛(0.240g,37%水溶液)和氢氰硼化钠(0.062g,1.16mmole)把由实施例8制得的9—(2,3—二氯苯基)—1,1—二氧代—2,3,4,5,6,9—六氢—7—甲基吡啶并—〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸乙酯(0.500g,1.16mmol)的乙腈(10ml)的混合物进行处理,15分钟后,滴加6滴AcOH,搅拌此反应物1小时。加入30ml水,反应混合物用氯仿(3×40ml)萃取,第一次萃取后,把pH调至8,合并的有机相用盐水和Na2SO4干燥。再3ml三乙胺处理。放置1.5小时后,减压除去挥发物,残余物用硅胶色谱纯化(1.5%MeOH、0.1%NH3的CHCl3液体作洗脱液。得到用乙醚研制即可凝固的油状物0.479g,产率92%。
实施例10
4—N—苄基—9—(2,3—二氯苯基)—1,1—二氧代—2,3,4,5,6,9—六氢—7—甲基吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸乙酯
于乙腈(10ml)中,把由9—(2,3—二氯苯基)—1,1—二氧代—2,3,4,5,6,9—六氢—7—甲基吡啶并〔2,3—f〕〔1,4〕—硫代吖庚因—8—甲酸乙酯(0.400g,0.92mmole)、苄基溴(0.190g,1.11mmole)和碳酸钾(0.213g,1.55mmole)组成的混合物加热3小时。冷却此反应物料,滤出固体,减压蒸发除去溶剂,残余物用硅胶柱色谱纯化(己烷∶乙酸乙酯(2∶1)作洗脱液)用乙醚重结晶得到产物(0.313g,产率65%)。
实施例11
4—叔丁氧基羰基—9—(2,3—二氯苯基)—1,1—二氧代—5a—羟基—2,3,4,5,5a,6,9,9a—八氢—7—甲基吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸2—(N—苄基—N—甲氨基)乙酯
于40ml乙醇中,把由实施例6制取的4—N—(叔丁氧基羰基)—1,1—二氧代—2,3,4,5,6,7—六氢—1,4—硫代吖庚因—6—酮(8.39g,31.9mmole)、2,3——二氯苯甲醛(5.58g,31.9mmole)和3—氨基巴豆酸2—(N—苄基—N—甲氨基)乙酯(7.91g,31.9mmole)组成的混合物加热回流17小时。把此反应物料冷却到室温,滤出的固体用50ml乙醚洗涤,得到标题化合物10.72g,产率50%D.C.I.M.S(M+H)668。
实施例12
9—(2,3—二氯苯基)—4,7—二甲基—1,1—二氧代—5a—羟基—2,3,4,5,6,9—六氢—7—吡啶并—〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸2—(N—苄基—N—甲氨基)乙酯
按如实施例8和9的方法把实施例6制得的4—N—(规—丁氧基羰基)—1,1—二氧代—2,3,4,5,6,7—六氢—1,4—硫代吖庚因—6—酮(2.10g,3.2mmole)进行处理后用异丙醇重结晶得到1.23克产物,产率70%。
实施例13
旋光拆分9—(2,3—二氯苯基)—1,1—二氧代—2,3,4,5,6,9—六氢—7—甲吡啶并〔2,3—f〕〔1,4〕—硫代吖庚因—8—甲酸乙酯
把实施例8制得的外消旋9—(2,3—二氯苯基)—1,1—二氧代—2,3,4,5,6,9—六氢—7—甲基吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸乙酯(2,41g,5.59mmole)溶解在100ml热甲醇中,将此溶液与D—二苯甲酰酒石酸酯(2.10g,5.59mmole)合并。减压除去溶剂,把此残余物用乙酸乙酯结晶3次,用氨水萃取该盐的氯仿溶液以使此盐转变为游离的碱。〔α〕D=+7.7°(C,0.41,CHCl3),按类似方式用L—二苯甲酰酒石酸得到(一)异构体,〔a〕D=-8.0(C,0.40,CHCl3)。
实施例14
5—N—甲酰基—3—羟基—2,3,4,5—四氢—〔1,5〕—苯并硫代吖庚因
于用公知方法(Federsel,H.J.et al.,Tetrahedron Letters 21,2229(1986))制得的5—N—甲酰—3—羟基—2,3,4,5—四氢—〔1,5〕苯并硫代吖庚因—3—酮(0.480g,2.31mmole)的乙醇(10ml)溶液中,加入NaBH4(0.090g,2.38mmole)。室温下搅拌此反应物料1小时。把此反应物料分配于饱和NH4Cl溶液和氯仿间。有机层用水洗涤、盐水洗涤,MgSO4干燥。减压除去溶剂得到油状产物0.452g,产率94%D.C.I.M.S.210〔M+H〕。
实施例15
1,1—二氧代—5—N—甲酰基—3—羟基—2,3,4,5—四氢—〔1,5〕—苯并硫代吖庚因
于10ml氯仿中。用由实施例14制得的5—N—甲酰基—3—羟基—2,3,4,5—四氢—〔1,5〕—苯并硫代吖庚因(0.450g,1.93mmole)对间氯过氧苯甲酸(0.946g,5.5mmole)的氯仿(20ml)溶液进行处理。室温下将此反应物料搅拌16小时,减压除去溶剂,残余物用2×10ml水研制,蒸去水得到产物0.443g,产率95%D.C.I.M.S.242〔M+H〕。
实施例16
1,1—二氧代—5—N—甲酰基—2,3,4,5—四氢—〔1,5〕—苯并硫代吖庚因—3—酮
用琼斯试剂(0.54ml,1.40mmole)对实施例15的1,1—二氧代—5—N—甲酰基—3—羟基—2,3,4,5—四氢—〔1,5〕—苯并硫代吖庚因(0.443g,1.83mmole)的丙酮(5ml)溶液进行处理。将此溶液加热回流15分钟。加入0.15ml琼斯试剂。加热反应物20分钟以上。用MgSO4过滤此冷却的溶液,减压除去溶齐,残余物用氯仿研制并过滤,蒸发滤液得到产物0.418g,产率95%D.C.I.M.S.240〔M+H〕。
实施例17
4—(2,3—二氯苯基)—5,5—二氧代—10—甲酰基—2—甲基—1,4,10,11—四氢吡啶并〔3,2—b〕—〔1,5〕—苯并硫代吖庚因—3—甲酸乙酯
将1,1—二氧代—5—N—甲酰基—2,3,4,5—四氢—〔1,5〕—苯并硫代吖庚因—3—酮(实施例16的)(0.410g,1.71mmole)、2,3—二氯苯甲醛(0.297g,1.71mmole)和3—氨基巴豆酸乙酯(0.219g,1.71mmole)的乙醇(7ml)溶液加热回流18小时。减压除去溶剂。残余物用硅胶色谱纯化(用1∶1的己烷∶乙酸乙酯作洗脱液)得到油状产物0.75g,产率86%。将此产品用氯仿—乙醚进行重结晶。
实施例18
4—叔丁氧基羰基—9—(2,3—二氯苯基)—1,1—二氧代—5a—羟基—2,3,4,5,5a,6,9,9a—八氢—7—甲吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸2—羟基乙酯
于200ml乙醇中,把由实施例6的4—N—(叔—丁氧羰基)—1,1—二氧代—2,3,4,5,6,7—六氢—1,4—硫代吖庚因—6—酮(9.06g,34.5mmole)、2,3—二氯苯甲醛(6.03g,34.5mmole)和3—氨基巴豆酸2—羟基乙酯(5.00g,34.5mmole)组成的混合物加热回流24小时。减压除去乙醇,在回流甲苯中加热残余物2小时,冷却后滤出沉淀得到6.75g标题化合物。蒸发滤液并进行色谱纯化(2.5∶1的乙酸乙酯∶己烷作洗脱液)得到3.78克产物。
实施例19
9—(2,3—二氯苯基)—1,1—二氧代—2,3,4,5,6,9—六氢—7—甲基吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸2—乙酰氧基乙酯
于5ml吡啶和5ml乙酸酐中溶解实施例18的4—叔丁氧基羰基—9—(2,3—二氯苯基)—1,1—二氧代—5a—羟基—2,3,4,5,5a,6,9,9a—八氢—7—甲基—吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸2—羟基乙酯(0.500g,0.97mmole),搅拌2小时,减压除去溶剂。残余物用25ml乙酸乙酯制成浆料并冷却至0℃其后用HCl气体使此混合物饱和,90分钟后,把此反应物料倒入30ml4NNaOH中,分离出的乙酸乙酯层用盐水干燥,水相用氯仿萃取(2×30ml)。合并的有机萃取液用硫酸钠干燥并予蒸发,残余物用硅胶色谱纯化(2%甲醇,0.1%氨的氯仿液作洗脱液)得到白色固体产物0.351g,产率89%。
实施例20
9—(2,3—二氯苯基)—4,7—二甲基—1,1—二氧代—2,3,4,5,6,9—六氢吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸—2—乙酰氧基乙酯
用氢氰硼化钠(0.070g,1.69mmole)处理由9—(2,3—二氯苯基)—1,1—二氧代—2,3,4,5,6,9—六氢—7—甲基—吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸2—乙酰氧基乙酯(实施例19的)(0.880g,1.69mmole)和甲醛水溶液(1ml,38%)的乙腈(20ml)溶液组成的混合物,搅拌1小时后,加入0.5ml乙酸,再搅拌此反应物料2小时,加40ml水和用6N NaOH把pH调到9后,用氯仿萃取(3×30ml)。合并的有机萃取物用Na2SO4干燥,减压除去溶剂,残余物用硅胶色谱纯化(2%甲醇、0.1%氨的氯仿溶液作洗脱液)得到标题化合物0.743g,产率82%。
本发明这些二氢吡啶例子和其他有代表性的化合物的物理常数列于下表1中:
D.C.I.M.S. M.P.R3=苯基取代 R4 R2 分子式 〔M+H〕 ℃2,3—二氯 H 乙基 C18H20C12N2O4S. 145—7
HCl·3/2H2O 4312,3—二氯 BOC 乙基 C23H28C12N2O4S 531 228—30五氟 BOC 乙基 C23H25F5N2O4S 553 224—62,3—二氯 Bz 乙基 C25H26C12N2O4S 521 219(d)五氟 H 乙基 C18H17F5N2O4S 453 211—32,3—二氯 Me 乙基 C19H22C12N2O4S 445 206—82—CF3 BOC 乙基 C25H29F3N2O4S 531 213—5
表1(续)其他代表性化合物
D.C.I.M.S. M.P.R3=苯基取代 R4 R2 分子式 〔M+H〕 ℃2—CF3 H 乙基 C19H21F3N2O4S 431 125(d)五氟 Me 乙基 C19H19F5N2O4S 467 212—52,3—二氯 CHO 乙基 C23H20Cl2N2O5S* 507 185—72,3—二氯 Et 乙基 C20H24Cl2N2O4S·HCl·3/2H2O 459 185—82—Cl,6—F H 乙基 C18H20ClFN2O4S 415 118—203—硝基 H 乙基 C18H21N3O6S 408 186—82,3—二氯 Pr 乙基 C21H26Cl2N2O4S 473 196—82—硝基 H 乙基 C18H21N3O6S 408 171—32,3—二氯 iPr 乙基 C21H28Cl2N2O4S 473 217—82,3—二氯 庚基 乙基 C25H34Cl2N2O4S 529 142—4*苯并硫代吖庚因环系统
表1(续)其他代表性化合物
D.C.I.M.S. M.P.R3=苯基取代 R4 R2 分子式 〔M+H〕 ℃2,3—(213噁二唑) H 乙基 C18H20N4O5S·HCl 405 216—93—硝基 Et 乙基 C20H25N2O6S·HCl·3/2H2O 436 195(d)2,3—二氯 H 乙基 C18H20Cl2N2O4S(-) 431 190(d)2,3—二氯 H 乙基 C18H20Cl2N2O4S(+) 431 193(d)2,3—二氯NH2CH2CO 乙基 C20H23Cl2N3O5S 488 166(d)2,3—二氯 H N—Bz—N—Me—乙基 C26H29N3O4Cl2S 550 132—52,3—二氯 Me N—Bz—N—Me—乙基 C27H31N3O4Cl2S 564 166—82,3—二氯 Me N—Bz—N C27H31N3O4Cl2S·—Me—乙基 2HCl·H2O 564 173(d)
表1(续)其他代表性化合物
D.C.I.M.S. M.P.R3=苯基取代 R4 R2 分子式 〔M+H〕 ℃2,3—二氯 Me 2—乙酰氧基 C21H24Cl2N2O4S 503 168—70—乙基2,3—二氯 Me 2—羟基— C19H22Cl2N2O5S 461 203—4乙基2,3—二氯 H 2—乙酰氧基—乙基 C20H24Cl2N2O4S 489 179—812,3—二氯 2—羟基—乙基 C18H20Cl2N2O5S 447 197—92,3—二氯 H 环丙基甲基 C20H22Cl2N2O4S 457 199—2002,3—二氯 H 环丙基甲基 C21H24Cl2N2O4S 471 177—92,3—二氯 H 2—i—丁酰氧基—乙基 C23H28Cl2N2O4S 531 185—5
表1(续)其他代表性化合物
D.C.I.M.S. M.P.R3=苯基取代 R4 R2 分子式 〔M+H〕 ℃2,3—二氯 Me 2—苯甲酰氧基— C26H26Cl2N2O6S 565 108—10
乙基2,3—二氯 Et 2—NBz(Me)— C28H33Cl2N3O4S·
乙基 2HCl·H2O 578 171—33—硝基 Me 2—NBz(Me)— C27H32Cl2N4O6S·
乙基 2HCl·H2O 541 148(d)2,3—二氯 Me 2—NBz2— C33H35Cl2N3O4S·
乙基 2HCl·H2O 640 175(d)2,3—二氯 Me 3—Ph—丙基 C33H35Cl2N3O4S·
HCl 535 173(d)2—氯—3—NO2 Me 乙基 C19H23ClN2O4S 456 199—201
表1(续)其他有代表性化合物
D.C.I.M.S. M.P.R3=苯基取代 R4 R2 分子式 〔M+H〕 ℃2,3—二氯 i—Pr 2—乙酰氧乙基 C23H28Cl2N2O6S 531 181—32,3—二氯 Et 2—乙酰氧乙基 C22H26Cl2N2O6S 517 187—92,3—二氯 Bz+ 2—乙酰氧乙基 C27H28Cl2N2O6S 579 102—42—氯 Me 乙基 C19H23ClN2O4S 411 223—4+Bz=苄基
表2列出了许多有代表性的本发明的化合物以抑制百分数表示的对硝吡乙甲酯(Nitrendipine,硝苯乙吡啶)结合及与钙有关的平滑肌收缩的抑制。
表2钙通道拮抗活性
P#166 P#176气管 P#176主动脉R3=苯基取代 R4 R2 硝吡乙甲酯.结合 抑制%/μM 抑制%/μM2,3—二氯 H 乙基 99,105nM 73/1.0;43/0.1 96/1.0;85/0.1
21/0.012,3—二氯 BOC 乙基 32%@1.0μM 0/2.0 18/1.0;4/0.3五氟 BOC 乙基 24%@1μM 7/2.0 37/1.0;0/0.12,3—二氯 Bz 乙基 210nM 32/2.0;10/0.1 79/1.0五氟 H 乙基 90nM 98/2.0;63/0.1;95/1.0;89/0.1;
13/0.01 61/0.01
表2(续)钙通道拮抗活性
P#166 P#176气管 P#176主动脉R3=苯基取代 R4 R2 硝吡乙甲酯.结合 抑制%/μM 抑制%/μM2,3—二氯 Me 乙基 120nM 98/2.0;80/0.1; 97/1.0;96/0.1;
55/0.01 67/0.012—CF3 BOC 乙基 7%@1.0μM 50/2.0;24/0.3 47/1.0;37/0.12—CF3 H 乙基 360nM 73/2.0;35/0.3; 83/1.0;68/0.1
38/0.1 37/0.01五氟 Me 乙基 53nM 95/1.0;73/0.1;
35/0.01 97/1.0;50/0.012,3—二氯 Et 乙基 60nM 90/1.0;70/0.3; 96/1.0;76/0.1;
33/0.01 19/0.012—Cl,6—F H 乙基 870nM 88/2.0;56/0.3 86/1.0;4.8/0.013—硝基 H 乙基 240nM 93/2.0;58/0.03 100/1.0;24/0.012,3—二氯 Pr 乙基 145nM 68/2.0;53/0.3; 100/1.0;88/0.1;
44/0.1;30/0.03 53/0.01
表2(续)钙通道拮抗活性
P#166 P#176气管 P#176主动脉R3=苯基取代 R4 R2 硝吡乙甲酯.结合 抑制%/μM 抑制%/μM2—硝基 H 乙基 75/2.0;45/0.3; 77/1.0;47/0.1;
12/0.10 27/0.012,3—二氯 ipr 乙基 72nM 86/2.0;61/0.3; 95/1.0;83/0.1;
37/0.1 38/0.012,3—二氯 hept 乙基 27/2.0 44/1.0;4/0.12,3—(2,1, H 乙基 660nM 68/2.0;22/0.3 83/1.0;22/0.13噁二唑)3—硝基 Et 乙基 92/0.3;73/0.1; 73/0.10;5/0.01
50/0.032,3—二氯 H 乙基 54/2.0;24/0.3; 69/1.0;0/0.1;
2/0.1 0/.012,3—二氯 H 乙基 96/2.0;47/0.1; 97/1.0;67/0.1;
25/0.03 14/0.012,3—二氯 NH2CH2CO乙基 36/2.0;6/0.3 20/1.0
表2(续)钙通道拮抗活性
P#166硝吡 P#176气管 P#176主动脉R3=苯基取代 R4 R2 乙甲酯.结合 #抑制/μM 抑制%/μM2,3—二氯 H N—Bz—N—
Me—乙基
380nM 86/2.0;62/0.3;
23/0.1 93/1.0;48/0.1;
20/0.032,3—二氯 Me N—Bz—N—
Me—乙基 150nM 88/2.0;71/0.3;
54/0.1;28/0.032,3—二氯 Me 2—乙酰氧 89/1.0;26/0.1;
乙基 0/0.012,3—二氯 Me 2—羟乙基 95/10;77/3.0;
62/1.0;14/0.1
表2(续)钙通道拮抗活性
P#166
硝吡乙甲酯 P#176气管 P#176主动脉R3=苯基取代 R4 R2 结合 #抑制/μM 抑制%/μM2,3—二氯 H 2—乙酰氧乙基 72/1.0;62/0.3;
18/0.12,3—二氯 H 2—羟乙基 56/10;0/1.02,3—二氯 H 环丙甲基2,3—二氯 H 环丙甲基 93/10;86/3.0;
17/0.01
R#176气管 P#176主动脉R3=苯基取代 R4 R2 #抑制/μM 抑制%/μM2,3—二氯 CHO 乙基 73/2.0;35/0.3; 74/1.0;50/0.1;
38/0.01 33/0.01
对抑制硝吡乙甲酯结合的实验是按下述步骤进行的:
用颈脱位使雌新Zealand白兔(1—2kg)致死,立即取出心脏、洗净、切片,用5倍体积的Hepes缓冲液(0.05M,PH7.4)均化该组织。在(4000×g)的力下离心此均浆10分钟,再于(42000×g)力下离心悬浮液90分钟。所得的小膜片再悬浮于(0.05M Hepes)缓冲液(PH7.4)中(0.7ml/g重),-70℃下贮藏到使用。每结合实验管中,1.0ml总的体积中含3H—硝吡乙甲酯(0.05—0.50nM),缓冲液,膜(0.10ml)和实验化合物。4℃下90分钟后,用whatman GF/C过滤器过滤使结合的硝吡乙甲酯和未结合的硝吡乙甲酯分离,漂清后,干燥过滤的样品,并用液闪烁计数器进行测量。
从总的结合的硝吡乙甲酯中扣除未有效结合的3H—硝吡乙甲酯(在有过量的未标记的硝吡乙甲酯的情况下结合的量)即得有效结合的放射性同位素示踪(标记)硝吡乙甲酯。把在试验化合物存在下的有效结合的硝吡乙甲酯的量同无化合物时结合的量进行比较。即可获得百分移位(或抑制)。
对抑制钙有关的平滑肌收缩试验是按下述步骤进行测定的:
于4℃下,把注射过量kcl致死的狗的气管和主动脉贮存于氧化克一汉(krebs—Henseleit)二氏缓冲液中过夜。从支气管端开始切下气管环即一个软骨节宽(5—10mm),也制成同样宽度主动脉组织环。切下软骨节后,37℃下,用氧化克一汉二氏缓冲溶液把气管肌肉组织和主动脉组织悬浮于25ml组织浴中。60分钟平衡后,用10μM氯化氨甲酰胆碱试验此组织。5分钟后,漂洗此组织。让其放置50分钟。然后再用50mM kcl试验此组织。30分钟后测量其收缩。漂洗该组织后再平衡50分钟。再加试验化合物10分钟,用50mM kcl试验该组织,30分钟后,再测定其收缩,并用以测定对照组的抑制百分数。
根据计算的抑制百分数实验对化合物进行评价。
Claims (3)
1.下式所示的的化合物及其旋光对映体或其医学上可接受的盐的合成方法,该式为:其中:
Y和Z一起形成苯环;
R1是氢或低级烷基;
R2是未取代的或由羟基、C1-8烷酰氧基、环丙基、苯基、苯甲酰氧基、苄甲基或N-苄基-N-甲基取代的低级烷基;
R3是氢、由卤素、硝基、CF3或噁二唑基取代的苯基;
R4是氢、C1-8直链或支链烷基、低级烷酰基、NH2CH2CO、叔丁氧基羰基、卤素取代的苯基,或苄基;
n为1;
该方法包括:
2.按照权利要求1的方法,其中使用的原料化合物和制得的化合物中的
R1是甲基;
R2是乙基或由乙酰氧基或N-苄基-N-甲基取代的乙基;
R3的定义同权利要求1所述;
R4是氢、C1—C8直链或支链烷基、苄基、甲酰基、叔丁氧羰基或NH2CH2CO;
n为1。
3.按照权利要求1的方法,其中制得的化合物为:
9—(2,3—二氯苯基)—4,7—二甲基—1,1—二氧代—2,3,4,5,6,9—六氢吡啶并〔2,3—f〕〔1,4〕硫代吖庚因—8—甲酸2—新戊酰氧基乙酯;
4—(2,3—二氯苯基)—2,10—二甲基—5,5—二氧代—1,4,10,11—四氢吡啶并〔3,2—b〕〔1,5〕苯并硫代吖庚因—3—甲酸乙酯;或
4—(2,3—二氯苯基)—2,10—二甲基—5,5—二氧代—1,4,10,11—四氢吡啶并〔3,2—b〕〔1,5〕—苯并硫代吖庚因—3—甲酸2—(N—苄基—N—甲氨基)乙酯。
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US6472530B1 (en) | 1999-09-22 | 2002-10-29 | Ortho-Mcneil Pharmaceutical, Inc. | Benzo-fused dithiepino[6,5-b]pyridines, and related compositions and methods |
ES2254258T3 (es) * | 2000-01-12 | 2006-06-16 | Ortho-Mcneil Pharmaceutical, Inc. | Benzosulfonas con una actividad antagonista del calcio. |
US6410552B1 (en) | 2000-01-27 | 2002-06-25 | Ortho-Mcneil Pharmaceutical, Inc. | Benzoether and related compositions and methods |
JP2003528104A (ja) | 2000-03-23 | 2003-09-24 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | チエピノ[3,2−b]ジヒドロピリジンおよび関連組成物ならびに方法 |
EP1296990A2 (en) | 2000-05-30 | 2003-04-02 | Ortho-McNeil Pharmaceutical, Inc. | Dihydropyridine compounds for the inhibition of calcium-influx |
KR101233139B1 (ko) | 2011-04-21 | 2013-02-21 | 주식회사 한서켐 | 라세믹 1,4-티아제핀 화합물의 분할 방법 |
CA2971869A1 (en) * | 2014-12-30 | 2016-07-07 | Myotherix, Inc. | Novel calcium modulators |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1587128A (en) * | 1977-04-07 | 1981-04-01 | Hexachimie | Benzothiazepine derivatives |
US4285955A (en) * | 1978-10-31 | 1981-08-25 | Bayer Aktiengesellschaft | 1,4-Dihydropyridinecarboxylic acids |
NZ201395A (en) * | 1981-07-30 | 1987-02-20 | Bayer Ag | Pharmaceutical compositions containing 1,4-dihydropyridines and certain of these dihydropyridines |
FR2511683A1 (fr) * | 1981-08-20 | 1983-02-25 | Hexachimie | Nouveaux derives de la pyrido (2,3-b) benzothiazepine(1,5) substituee en 5 par une carboxypiperazine, leur procede de preparation, leur application en therapeutique |
EP0225175A3 (en) * | 1985-11-28 | 1988-12-28 | FISONS plc | Dihydropyridine derivatives, processes for their preparation and pharmaceutical compositions thereof |
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1990
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