CN1056101A - 1,5-苯并硫杂吖庚酮衍生物的制备和用途 - Google Patents
1,5-苯并硫杂吖庚酮衍生物的制备和用途 Download PDFInfo
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- CN1056101A CN1056101A CN91102741A CN91102741A CN1056101A CN 1056101 A CN1056101 A CN 1056101A CN 91102741 A CN91102741 A CN 91102741A CN 91102741 A CN91102741 A CN 91102741A CN 1056101 A CN1056101 A CN 1056101A
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- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
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- 239000000203 mixture Substances 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
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- 125000005605 benzo group Chemical group 0.000 claims description 2
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- 229910052736 halogen Inorganic materials 0.000 description 1
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- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- 230000002085 persistent effect Effects 0.000 description 1
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- AAZYNPCMLRQUHI-UHFFFAOYSA-N propan-2-one;2-propan-2-yloxypropane Chemical compound CC(C)=O.CC(C)OC(C)C AAZYNPCMLRQUHI-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
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- 235000017550 sodium carbonate Nutrition 0.000 description 1
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- 239000000725 suspension Substances 0.000 description 1
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Endocrinology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
本发明涉及通式I的化合物和其药物上可接受
的盐、其制备方法以及含此类化合物的药物组合物。
新化合物的特征在于其氮原子上至少有一个支链烷
基或环烷基和/或烷基链上有取代物。与diltiazem
相比,新化合物具有钙-拮抗性质并有较长的持续作
用。所说化合物可用于几种血管疾病,如高血压和心
脏缺血等。
Description
本发明涉及diltiazem同类物和其制备方法以及其药物组合物。
Diltiazem于U.S.3562257中公开,为1,5-苯并硫杂吖庚酮(1,5-benzothiazepinone)衍生物,由于它有钙-拮抗性质,可在心血管病理学中使用。然而,diltiazem在人体内的药物动力学特征在于其半衰期较短,因此必须每4-6小时给药一次,还应考虑病人的顺应性和极易变的血浆浓度。
现已惊人地发现,通式Ⅰ的1,5-苯并硫杂吖庚酮衍生物与diltiazem相比,作用时间较长,同时具有类似或较高的钙-拮抗性质。
本发明的化合物具有下述的化学式:
式中的R为氢或R5CO基(R5为C1-C4直链或支链烷基,或为一苯基,可被卤原子、甲氧基或硝基取代);R1和R2(相同或不相同)为C1-C4直链或支链烷基或C3-C7环烷基;R3为C1-C4直链或支链烷基;R4为氢、氯、甲氧基;n为1或2;m为0或1,条件是当m为0时,R1和R2至少有一个是支链烷基或环烷基。
本发明也涉及式Ⅰ化合物的非对映异构体、对映异构体或者它们的混合物。
2位和3位上的基团是顺式,其构型是2S,3S。
US3562257公开的式Ⅰ化合物,其中的m为0,R1和R2相同并代表低级烷基;所有的实施例均涉及R1和R2为甲基的化合物。
其他diltiazem类似物公开于GB2143532、EP256888或WO8912633。
本发明也涉及式Ⅰ化合物与药物上可接受的无机酸(如氢氯酸、氢溴酸、硝酸、磷酸、硫酸等)生成的盐和与药物上可接受的有机酸(如乙酸、丙酸、马来酸、富马酸、苹果酸、草酸、酒石酸、甲磺酸等)生成的盐。
特别优先选择的式Ⅰ化合物是下面的化合物:
-式中m为0,n为1,R1和R2之一为异丙基、叔丁基、环丙基、环己基,另一为甲基或异丙基;
-式中m为1,n为1,R3为甲基,R1和R2如上所限定;
-式中m为1,n为1,R3为氢,R1和R3如上所限定;
特别优先选择的化合物是R4为氢并且R为乙酰基的化合物。
C3-C7环烷基之例有环丙基、环戊基、环己基。
R为氢或R5CO(R5定义如上)基的本发明的化合物的制备是用式Ⅱ
的苯并硫杂吖庚酮衍生物与式Ⅲ化合物
(式中m,n,R1,R2,R3,R4定义如上,X为卤素)进行反应。
如此制得的R为H的式Ⅰ化合物可以转变成R为R5CO的式Ⅰ化合物,其方法是与式Ⅳ化合物或其反应性衍生物
(式中R5的定义如上)进行反应。
另外,R为R5CO(R5定义如上)基的化合物还可以用式Ⅴ化合物
与式Ⅵ的胺
(式中m,n,R1,R2,R3,R4定义如上,Z为氯、溴或甲苯磺酰氧基)进行反应来制取。
式Ⅴ的中间体可由式Ⅱ的相应化合物与式Ⅶ化合物
(式中X为氯、溴,m、n、z和R3定义如上)进行反应而制取。
式Ⅱ化合物与式Ⅲ化合物(可以成盐)的缩合反应通常是在溶剂中在一碱性试剂(如KOH、NaOH、K2CO3、NaH)存在下进行的。
式Ⅲ的盐有氢氯酸盐、氢溴酸盐等。
溶剂可在脂肪酮(丙酮、甲乙酮等)、乙醋乙酯、二甲亚砜、二甲基甲酰胺,乙腈、四氢呋喃和二噁烷中选择。
进行反应的温度为0至100℃,特别是20至70℃,R为氢的式Ⅰ化合物与式Ⅳ化合物或其活性衍生物的缩合反应可在溶剂中于有或无酸接受剂存在下进行。式Ⅳ化合物的活性衍生物可以是一酸酐(例如乙酸酐或丙酸酐)或一氯化物(乙酰氯、丙酰氯等)。吡啶、三乙胺、N-甲基吗啉等可用作酸接受剂。适合的溶剂是乙酸、氯仿、二氯甲烷、二甲基甲酰胺、四氢呋喃。反应温度范围为20至140℃。
制备式Ⅴ化合物的反应可在极性或非极性溶剂中进行,如甲醇、乙醇、二噁烷、乙腈、四氢呋喃、N,N-二甲基甲酰胺、二氯甲烷、二甲基亚砜。
反应温度范围为0至150℃,视溶剂的沸点而定。
为中和反应所放出的有机或无机酸HX,可以使用过量的碱Ⅵ或如碳酸钾或碳酸钠之类的无机碱。
当上述反应产生非对映异构体时,可用一般方法进行分离(分步结晶法,色谱法)。
式Ⅰ化合物和其药物上可接受的盐具有好的钙-拮抗性质。
这些性质是将3H-diltiazenn从其在心脏组织的结合点上移置出来(按H.Glossmam等方法,FEBS 160,226(1983))或用在家兔分离心房中诱导的强直收缩的抑制(按M.Spedding方法,Arch、Pharmacol.318,234(1982))在体外进行研究的。
本发明的一些化合物的PIC50和PA2值高于7。式Ⅰ化合物的体内试验证明它有明显的和长时持久的抗心绞痛的性质,如加压素诱导的大鼠心绞痛所示(按M.Leitold,H.Laufen的方法,Arzneim.Forsch.33,1117(1983))。一些化合物的DE50与diltiazem的相比拟,但持续时间较长。对清醒性无套管大鼠进行的药物动力学研究,一些化合物口服给药后的半衰期高于diltiazem的半衰期。式Ⅰ化合物的自发性高血压大鼠(SHR)试验也显示较好的和持续时间长的抗高血压活性。
现将顺(+)-3-乙酰氧基-2,3-二氢-3-〔2-(N-异丙基-N-甲基氨基乙基〕-2-(4-甲氧苯基)-1,5-苯并硫杂吖庚酮-4(5H)-酮)(化合物A)(实例1)和顺-(+)-3-乙酰氧基-2,3-二氢-5-(2-甲基-3-二甲基氨基丙基)-2-(4-甲氧基苯基)-1,5-苯并硫杂吖庚-4(5H)-酮(化合物B)(非对映异构体B,实例3)的生物性质与diltiazem进行比较如下:
式Ⅰ化合物或其药物上可接受的盐可用药物组合物的形式,适于口服或非胃肠道给药。
可以使用常用的赋形剂,如淀粉、乳糖、葡糖、阿拉伯胶、硬脂酸等。药物组合物可以用片、丸、胶囊或栓剂等固体形式或如溶液、悬浮液或乳液等的液体形式。
另外,如以非胃肠道给药则可用消毒溶液的形式。
对于心血管病理学如心律不齐、高血压、心脏缺血的患者,式Ⅰ化合物的常用给药单位剂量为1至100mg。
下面的实例将对本发明进一步说明。
化合物的熔点不正确,化合物的鉴定和纯度测定是用元素分析(C,H,N)和IR,UV,NMR和MS法进行的。
实例1
顺(+)-3-乙酰氧基-2,3-二氢-5-(2-N-异丙基-N-甲基氨基乙基)-2-(4-甲氧基苯基)-1,5-苯并硫杂吖庚-4(5H)-酮,氢溴酸盐
(a)将顺(+)-2,3-二氢-3-羟基-2-(4-甲氧基苯基)-1,5-苯并磺杂吖庚-4(5H)-酮(3.3g)、N-异丙基-N-甲基氨基乙基氯化物。氢氯酸盐(1.5g)和K2CO3(1.5g)悬浮于30ml甲乙酮中,回流12小时。用乙醚处理残渣:然后以盐酸(1∶1)稀释。分离有机相。酸性水相用10% NaOH碱化,用乙醚提取数次。合并有机相,蒸发至干。得油状残渣(3.1g)直接用于下步反应。
(b)将(a)所得产物溶于31ml乙酸酐,放置12小时。真空蒸去乙酸酐。残渣溶于32ml乙醚,用6N之HBr于异丙醇中的溶液处理至呈酸性。过滤出沉淀,在丙酮-乙醚中结晶。得到2.4g白色固体m.p.137-140℃。
按上述步骤制得了下述的化合物:
-顺(+)-3-乙酰氧基-5-(2-N-乙基-N-甲基氨基乙基)-2,3-二氢-2-(4-甲氧苯基)-1,5-苯并硫杂吖庚-4(5H)-酮·草酸盐-水合物m.p.105-108℃(乙酸乙酯)
-顺(+)-3-乙酰氧基-5-(2-N-叔丁基-N-甲基氨乙基-2,3-二氢-2(4-甲氧苯基)-1,5-苯并硫杂吖庚-4(5H)-酮·草酸盐;m.p.86-89℃(异丙醇-乙醚)
-顺(+)-3-乙酰氧基-5-(2-N-环丙基-N-甲基氨基乙基)-2,3-二氢-2-(4-甲氧基苯基)-1,5-苯并硫杂吖庚-4(5H)-酮;
-顺(+)-3-乙酰氧基-5-(2-N-环己基-N-甲基氨基乙基)-2,3-二氢-2-(4-甲氧基苯基)-1,5-苯并硫杂吖庚-4(5H)-酮;
-顺(+)-3-乙酰氧基-5-(2-N-二异丙基-N-甲基氨基乙基)2,3-二氢-2(4-甲氧基苯基)-1,5-苯并硫杂吖庚-4(5H)-酮·草酸盐;m.p.86-89℃(异丙醇-乙醚)
实例2
顺(+)-3-乙酰氧基-2,3-二氢-5-(2-甲基-3-二甲基氨基丙基)-2-(4-甲氧苯基)-1,5-苯并硫杂吖庚-4(5H)-酮·草酸盐(非对映异构体A)
(a)顺(+)-3-乙酰氧基-5-(3-氯-2-甲丙基)-2,3-二氢-2-(4-甲氧苯基)-1,5-苯并硫杂吖庚-4(5H)-酮。
将顺(+)-3-乙酰氧基-2,3-二氢-2-(4-甲氧基苯基)-1,5-苯并硫杂吖庚-4(5H)-酮(5g)溶于30ml二甲基甲酰胺中,在-7℃下冷却,缓慢加入1.4g 88%KOH,10分钟后,再缓慢加入3.8g 1-溴-3-氯-2-甲基丙烷。反应温度升至0℃,将此混合物搅拌4小时。然后将反应混合物倾入250ml 0.6N NH4Cl溶液中,用CH2Cl2提取。合并有机相,用水洗涤,以Na2SO4干燥,减压蒸馏,得到6g浓厚橙色油状物,溶于热异丙醇,冷却时析出结晶,m.p.100-103℃。
按照上述方法制得了下列的化合物:
-顺(+)-3-乙酰氧基-5-(3-氯-2-乙丙基)-2,3-二氢-2-(4-甲氧基苯基)-1,5-苯并硫杂吖庚-4(5H)-酮;
-顺(+)-3-乙酰氧基-5-(3-氯-2-异丙基)-2,3-二氢-2-(4-甲氧苯基)-1,5-苯并硫杂吖庚-4(5H)-酮;
(b)由(a)所得的5g氯代衍生物溶于30ml二甲基甲酰胺,向溶液中加入10g二甲胺和0.05g KI,将此溶液加热至80℃4小时。反应混合物倾入300ml H2O,将分离的固体用乙醚提取。有机相蒸发至干,残渣在室温下与35ml乙酸酐反应。48小时后,除去过量的乙酸酐,残渣用乙醚处理。分离出白色固体并在异丙醇中用草酸成盐。经用异丙醇结晶纯化后,得到3.5g产物,m.p.177-179℃。〔α〕20 D=148(H2O)
按照上述步骤制得了下列化合物:
-顺(+)-3-乙酰氧基-2,3-二氢-5-〔2-甲基-3-(N-环丙基-N-甲基氨基)丙基〕2-(4-甲氧苯基)1,5-苯并硫杂吖庚-4(5H)-酮;
-顺(+)-3-乙酰氧基-2,3-二氢-5-〔2-甲基-3-(N-环己基-N-甲基氨基)丙基〕-2(4-甲氧基苯基)-1,5-苯并硫杂吖庚-4(5H)-酮;
-顺(+)-3-乙酰氧基-2,3-二氢-5-〔2-甲基-3-(N-二甲基氨基)丙基〕-2-〔4-甲氧苯基)-1,5-苯并硫杂吖庚-4(5H)-酮。
实例3
顺(+)-3-乙酰氧基-2,3-二氢-5-(2-甲基-3-二甲基氨基丙基)-2-(4-甲氧基苯基)-1,5-苯并硫杂吖庚-4(5H)-酮·草酸盐(非对映异构体B)
将5g 顺(+)-2,3-二氢-3-羟基-2-(4-甲氧苯基-1,5-苯并硫杂吖庚-4(5H)-酮、2.9g 2-甲基-3-二甲基氨基丙基氯化物、氢氯酸盐、5.7g K2CO3、1.4ml水在75ml丙酮中按实例1的步骤进行反应,再与70ml乙酸酐反应(见实例1(b))。粗产物用乙醚处理,滤出所得到的固体,蒸干溶液,重复此步骤。得到的4.3g残渣溶于异丙醇,并用草酸处理。在丙酮-乙醚中结晶得到的固体,其熔点m.p.84~89℃,〔α〕20 D=+119.3(H2O)。
按上述步骤制得了下列的化合物:
-顺(+)-3-乙酰氧基-7-氯-2,3-二氢-5-(2-甲基-3-二甲基氨基丙基)-2-(4-甲氧基苯基)-1,5-苯并硫杂吖庚-4(5H)-酮(以顺(+)-2,3-二氢-7-氯-3-羟基-2-(4-甲氧基苯基)-1,5-苯并硫杂吖庚-4(5M)-酮为起始原料)
实例4
顺(+)-2,3-二氢-5-(2-N-异丙基-N-甲基氨基乙基)-3-(2,2-二甲基丙酰氧基)-2-(4-甲氧基苯基-1,5-苯并硫杂吖庚-4(5H)-酮与其药物上可接受的盐
将原料(按实例1(a)公开的方法制得)溶于15ml无水吡啶,用0.23g氯化新戊基处理。24小时后,将反应混合物倾入水中,用二氯甲烷提取,收集有机相,蒸发至干。将0.9g残渣转变成相应的马来酸盐,m.p.128-130℃(丙酮-异丙醚)
Claims (4)
3、权利要求1或2的方法,其特征在于该方法起始化合物的R为乙酰基,R1为异丙基,R2为甲基,R4为氢,m为0,n为1得到的式Ⅰ化合物为顺(+)-3-乙酰氧基-2,3-二氢-5-(2-N-异丙基-N-甲基氨基乙基)-2-(4-甲氧基苯基)-1,5-苯并硫杂吖庚-4(5H)-酮和其药物上可接受的盐。
4、权利要求1或2的方法,其特征在于该方法起始化合物的R为乙酰基,R1和R2为甲基,R3为甲基,R4为氢,m为1,n为1,得到的式Ⅰ化合物为顺(+)-3-乙酰氧基-2,3-二氢-5-(2-甲基-3-二甲基氨丙基)-2-(4-甲氧基苯基)-1,5-苯并硫杂吖庚-4(5H)-酮和其药物上可接受的盐。
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IT20160A IT1240686B (it) | 1990-04-27 | 1990-04-27 | Derivati 1,5-benzotiazepinonici, loro preparazione e uso farmaceutico |
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EP (1) | EP0526495A1 (zh) |
JP (1) | JPH05506654A (zh) |
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IT (1) | IT1240686B (zh) |
MA (1) | MA22143A1 (zh) |
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WO1996038429A1 (en) * | 1995-06-01 | 1996-12-05 | Acic (Canada) Inc. | Method for the manufacture of benzothiazepine derivatives |
US5559229A (en) * | 1995-06-01 | 1996-09-24 | Acic (Canada) Inc. | Method for the manufacture of benzothiazepine |
WO2006079077A2 (en) * | 2005-01-20 | 2006-07-27 | Acadia Pharmaceuticals Inc. | Use of diltiazem or analogs thereof as modulators of ghrelin receptor |
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US3562257A (en) * | 1967-10-28 | 1971-02-09 | Tanabe Seiyaku Co | Benzothiazepine derivatives |
IT1206505B (it) * | 1983-07-22 | 1989-04-27 | Schiapparelli Farma | Nuovi derivati benzotiazepinonici, metodo per la loro preparazione e composizioni farmaceutiche che licontengono. |
ES2038668T3 (es) * | 1986-08-20 | 1993-08-01 | Mcneilab, Inc. | Vasodilatadores de benzotiazepina dotados de sustitucion aralquilica. |
US4902684A (en) * | 1988-06-20 | 1990-02-20 | E. R. Squibb & Sons, Inc. | Benzazepine and benzothiazepine derivatives |
US4902687A (en) * | 1989-03-27 | 1990-02-20 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
DE69015682T2 (de) * | 1989-04-28 | 1995-05-11 | Tanabe Seiyaku Co | Verfahren zur Herstellung von 1,5-Benzothiazepinderivaten. |
JPH085869B2 (ja) * | 1990-03-08 | 1996-01-24 | 田辺製薬株式会社 | 1,5−ベンゾチアゼピン誘導体の製法 |
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- 1991-04-18 RO RO92-01339A patent/RO111269B1/ro unknown
- 1991-04-18 HU HU923326A patent/HU9203326D0/hu unknown
- 1991-04-18 CA CA002081204A patent/CA2081204A1/en not_active Abandoned
- 1991-04-26 MA MA22413A patent/MA22143A1/fr unknown
- 1991-04-26 PT PT97508A patent/PT97508A/pt not_active Application Discontinuation
- 1991-04-26 ZA ZA913171A patent/ZA913171B/xx unknown
- 1991-04-26 IE IE141191A patent/IE71033B1/en not_active IP Right Cessation
- 1991-04-26 CS CS911209A patent/CS120991A2/cs unknown
- 1991-04-27 CN CN91102741A patent/CN1056101A/zh active Pending
-
1992
- 1992-10-20 FI FI924756A patent/FI924756A0/fi not_active Application Discontinuation
-
1995
- 1995-03-31 US US08/397,904 patent/US5571807A/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
AU7695491A (en) | 1991-11-27 |
CA2081204A1 (en) | 1991-10-28 |
IT9020160A0 (it) | 1990-04-27 |
AU645317B2 (en) | 1994-01-13 |
IE911411A1 (en) | 1991-11-06 |
BR9106372A (pt) | 1993-04-27 |
FI924756A (fi) | 1992-10-20 |
HU9203326D0 (en) | 1993-01-28 |
FI924756A0 (fi) | 1992-10-20 |
JPH05506654A (ja) | 1993-09-30 |
IT1240686B (it) | 1993-12-17 |
US5571807A (en) | 1996-11-05 |
IE71033B1 (en) | 1997-01-15 |
CS120991A2 (en) | 1991-12-17 |
EP0526495A1 (en) | 1993-02-10 |
ZA913171B (en) | 1992-02-26 |
PT97508A (pt) | 1992-01-31 |
IT9020160A1 (it) | 1991-10-27 |
IN172160B (zh) | 1993-04-17 |
RO111269B1 (ro) | 1996-08-30 |
IL97859A0 (en) | 1992-06-21 |
MA22143A1 (fr) | 1991-12-31 |
WO1991017153A1 (en) | 1991-11-14 |
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