CN1021442C - 噻喃并二吡唑的制备方法 - Google Patents
噻喃并二吡唑的制备方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
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- Animal Behavior & Ethology (AREA)
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- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
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Abstract
本发明是指一组各种不同的甲基化噻喃并二吡唑类化合物及该类化合物的硫-氧化物和硫二氧化物。该类化合物用作支气管扩张药，并可用合适的5-取代噻喃并[3，4-c]吡唑-4(1H)-酮与肼反应制得。
Description
本发明是指一组甲基化的噻喃并二吡唑类化合物及其硫-氧化物。本发明尤指一组具有式（Ⅰ）所示的化合物。
其中R1、R2、R3和R4分别为氢或甲基，且R1和R2位于它们各自所处环中的一个氮原子上，而另一个氮原子则以双键与邻近的碳原子相连;虚线表明存在两个共轭双键，该双键的特定位置以R1或R3取代基的位置来决定;n为0、1或2。本发明进一步包括上述化合物的可供药用的酸加成盐。
上述化合物与可供药用的酸组成的酸加成盐与作为本发明目的上述胺类化合物是等效的。这种盐类的例子有与无机酸生成的盐，例如盐酸、氢溴酸、硫酸、磷酸等;与有机羧酸生成的盐，例如乙酸、丙酸、羟基乙酸、乳酸、丙酮酸、丙二酸、丁二酸、富马酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸和二羟基马来酸、苯甲酸、苯乙酸、4-氨基苯甲酸、4-羟基苯甲酸、邻氨基苯甲酸、肉桂酸、水杨酸、4-氨基水杨酸、2-苯氧基苯甲酸、2-乙酰氧基苯甲酸、苦杏仁酸等;以及与有机磺酸例如甲磺酸和对-甲苯
磺酸组成的盐。
本发明较好的具体化合物是n为0的那些化合物。
本发明化合物可通过式（Ⅱ）所示的肼与式（Ⅲ）所示的1，3-二酮反应制备。
其中R1是氢或甲基
其中R2、R3和R4分别为氢或甲基。该反应可在加热下在一种惰性溶剂例如醇中进行，用甲醇较好。得到的产物（其中n为0）可用过氧苯甲酸氧化得n为1或2的那些化合物。当R1或R3是氢时，该产物可在惰性溶剂例如二甲基甲酰胺中进一步用氢化钠和碘甲烷处理得相应的R1或R3为甲基的化合物。当用该方法制得的是一取代基在环中任一氮原子上的混合产物时，得到的混合物可用层析法分离。
上述用作起始原料的1，3-二酮可从式（Ⅳ）所示的噻喃并吡唑酮制取。将这种酮与强碱和
一种合适的羰基化合物反应可得二酮。特别是可用氢化钠和甲酸乙酯或用二异丙基胺，正-丁基锂和乙酰氯的混合物。
此处所述的取代的二吡唑类化合物是支气管扩张药，因此用于治疗支气管疾患例如支气管哮喘。本发明进一步是指一种有效的扩张支气管的方法。
在应用本发明方法时，本发明的单或多取代的二吡唑类以一种支气管扩张的有效剂量给哺乳类动物体内给药，需要通过一种使化合物与哺乳类动物的支气管及气管组织能接触的有效途径。可通过非肠道途径给药，例如静脉、腹腔内或肌肉注射，或将药物经口或直肠导入胃肠道，以便通过血流产生这种接触，或者以吸入溶液进行气管内给药，例如喷雾。
该化合物支气管扩张的有效用量也即抑制或减轻支气管痉挛的用量取决于多种因素，例如被治疗动物的大小、种类和年龄，所用的特定化合物或可供药用的盐，给药途径和次数，痉挛的严重程度和引起发作的原因，还有给药时间等。在特殊情况下，给药剂量可根据现有技术的常规剂量范围来确定，例如通过观察在不同剂量比例下产生的支气管扩张活性，特别是这些化合物可在0.2到100毫克取代的二吡唑化合物/每公斤动物体重的剂量范围给药，其它剂量范围为0.5到20毫克或1到5毫克/每公斤。
通常单次剂量以与常用剂量方案中防止支气管痉挛的最低用量一致为宜。适合于口服给药的剂型以片剂、胶囊、锭剂、酏剂、糖浆等较好，且活性化合物可按常规配制成定时释放的胶囊或片剂，但当要求迅速作用时，用注射的配方或吸入的喷雾剂和气雾剂较好。在单一的剂量单位的例子中，每片含200毫克活性成分，每天给药1到6
次，或者最好是每天给药2到4次。
在本发明方法的应用中，最好将活性成分掺入含有药物载体的配方中，取代二吡唑化合物或其可供药用盐按重量含5到90%。术语“药物载体”系指已知的一些赋形剂，用于配制动物体内给药的药用活性化合物，这些赋形剂在使用条件下基本无毒和不敏感。该配方可按已知制备片剂、胶囊、锭剂、糖锭剂、栓剂、酏剂、糖浆、乳剂、散剂、可湿的和泡腾粉末，无菌注射液和喷雾剂溶液的技术配制，同时可含有合适的赋形剂，这些赋形剂已知用于制备所希望的特殊类型的配方。合适的药物载体和制剂技术可在标准教科书中找到，例如雷明顿制药科学（Remington′s pharmaceutical Sciences），Mack出版公司，Easton，宾夕法尼亚。
在评价支气管扩张药的活性时，将试验化合物经腹腔内注射或口服给予豚鼠，然后将这些豚鼠置于组织胺气雾中处理15分钟到4小时。当置于组织胺气雾中时，未给药的动物显得萎陷。操作时，观察动物并记录萎陷时间。然后将所观察到的萎陷时间与单用水处理的对照组动物作统计学比较对照组动物通常是长期积累对照的。所给试验化合物的正确剂量一般是腹腔给药LD50的30%。试验中使用的一些化合物的特殊剂量如下：
5，6-二氢-6-甲基-1H-噻喃并〔3，2-C：5，4-C′〕二吡唑;110毫克/公斤。
5，6-二氢-6-甲基-1H-噻喃并〔3，2-O：5，4-C′〕二吡唑4-氧化物;163毫克/公斤。
5，6-二氢-6-甲基-1H-噻喃并〔3，2-C：5，4-C′〕二吡唑4，4-二氧化物;163毫克/公斤。
当用上述方法进行试验时，发现本发明化合物可产生支气管扩张作用。
为了阐明本发明将介绍下列例子，但在任何方法中，不应把它们看作是一种限制。
实例1
将氢化钠（60%矿物油悬浮液8.8克），8.9毫升甲酸乙酯，3滴乙醇和400毫升四氢呋喃配制成一混合物，在搅拌下将18.5克1-甲基-5.7-二氢噻喃并〔3，4-C〕吡唑-4（1H）-酮在100毫升四氢呋喃中的溶液滴入此混合物中。将混合物加热回流4小时然后冷却。用200毫升水和100毫升乙醚稀释并短暂搅拌，分出水层，并用二氯甲烷洗涤，然后用盐酸水溶液酸化。经过滤分离出生成的固体，干燥，得灰白色固体1，4，5，7-四氢-1-甲基-4-氧代噻喃并〔3，4-C〕吡唑-5-羰基醛，熔点约158～160℃。从乙醚和二氯甲烷中重结晶可得分析样品，熔点约158～159℃。
若用1，3-二甲基-5，7-二氢噻喃并〔3，4-C〕吡唑-4（1H）-酮重复上述操作，则得到的产物为1，4，5，7-四氢-1，3-二甲基-4-氧代噻喃并〔3，4-C〕吡唑-5-羰基醛。〔所需的起始原料可按G.Menozzi等人，杂环化学（J.Het.chem），21，1437（1984）和H.Sminth英国化学会志（J.Chem.Soe），803（1953）中描述的操作程序制得。〕
若用二异丙胺、正-丁基锂的己烷溶液，并用乙酰氯代替氢化钠和甲酸乙酯重复第一节中的操作程序，则得到的产物是5-乙酰基-
5，7-二氢-1-甲基噻喃并〔3，4-C〕吡唑-4（1H）-酮。
实例2
将肼（3.5毫升）滴加到1，4，5，7-四氢-1-甲基-4-氧代噻喃并〔3，4-C〕吡唑-5-羰基醛在250毫升甲醇的溶液中。将得到的溶液加热回流45分钟，然后在室温搅拌16小时，减压除去溶剂，残余物用乙醚研磨得一橙色固体（收率93%），熔点约196～200℃。此固体从乙醇和水的混合物中重结晶得5，6-二氢-6-甲基-1H-噻喃并〔3，2-C：5，4-C′〕二吡唑，熔点约224～226℃。
若用肼和相应的二酮类化合物重复上述操作，则得5，6-二氢-6，8-二甲基-1H-噻喃并〔3，2-C：5，4-C′〕二吡唑及5，6-二氢-3，6-二甲基-1H-噻喃并〔3，2-C：5，4-C′〕二吡唑。
若用同样的羰基醛但用甲基肼代替肼重复第一节中的操作，则得到的产物为一异构体混合物。用层析法分离得5，6-二氢-1，6-二甲基-1H-噻喃并〔3，2-C：5，4-C′〕二吡唑和5，6-二氢-2，6-二甲基-2H-噻喃并〔3，2-C：5，4-C′〕二吡唑。
实例3
将1.06克3-氯过氧苯甲酸在30毫升四氢呋喃中的溶液滴加到维持在-15℃的5，6-二氢-6-甲基-1H-噻喃并〔3，2-C：5，4-C′〕二吡唑在20毫升四氢呋喃中的溶液中。将该混合物在-15℃搅拌3小时，经过滤将生成的固体分出、干燥，得黄色粉末状结晶（收率93%）。此固体从乙醇中重结晶得5，6-二氢-6-甲基-1H-噻喃并〔3，2-C：5，4-C′〕二吡唑4-氧化物，熔点高于270℃。
实例4
将7.9克85%3-氯过氧苯甲酸在50毫升二氯甲烷中的溶液滴加到冰冷的5，6-二氢-6-甲基-1H-噻喃并〔3，2-C：5，4-C′〕二吡唑在100毫升二氯甲烷中的溶液中。将该混合物在室温搅拌24小时，减压除去溶剂，残余物用四氢呋喃研磨，得一桔黄色固体（收率67%），约在238℃熔融并分解。此固体从甲醇中重结晶得5，6-二氢-6-甲基-1H-噻喃并〔3，2-C：5，4-C′〕二吡唑4，4-二氧化物，熔点高于270℃。
Claims (3)
1、一种制备式(Ⅰ)所示化合物
(其中，R1、R2、R3和R4分别为氢或甲基，且R1和R3位于它们各自所处环中的一个氮原子上，而另一个氮原子则以双键与邻近的碳原子相连；虚线表明存在两个共轭双键，该双键的特定位置由取代基R1或R3的位置所决定，n为0、1或2)的方法，该方法包括将式(Ⅱ)所示的肼
(其中，R1为氢或甲基)与式(Ⅲ)所示的1，3-二酮
(其中，R2、R3和R4的定义同上)进行反应，得n为0的化合物，然后可将该化合物用过氧化物氧化，得n为1或2的化合物。
2、按照权利要求1的方法，其特征在于制备式（Ⅴ）所示化合物
（其中，R1、R2、R3和R4分别为氢或甲基，且R1和R3位于它们各自所处环中的一个氮原子上，而另一个氮原子则以双键与邻近的碳原子相连;虚线表明存在两个共轭双键，该双键的特定位置可由取代基R1或R3的位置来决定），该制备方法包括将式（Ⅱ）所示的肼
R1NHNH2（Ⅱ）
（其中，R1为氢或甲基）与式（Ⅲ）所示的1，3-二酮
（其中，R2、R3和R4的定义同上）进行反应。
3、按照权利要求1的方法，其特征在于制备5，6-二氢-6-甲基-1H-噻喃并〔3，2-C：5，4-C″〕二吡唑，该制备方法包括将肼与1，4，5，7-四氢-1-甲基-4-氧代噻喃并〔3，4-C〕吡唑-5-羰基醛进行反应。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US007,308 | 1987-01-27 | ||
| US07/007,308 US4734431A (en) | 1987-01-27 | 1987-01-27 | Thiopyranodipyrazoles and their use as bronchodilators |
| US007.308 | 1987-01-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN88100342A CN88100342A (zh) | 1988-09-14 |
| CN1021442C true CN1021442C (zh) | 1993-06-30 |
Family
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| Application Number | Title | Priority Date | Filing Date |
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| CN88100342A Expired - Fee Related CN1021442C (zh) | 1987-01-27 | 1988-01-26 | 噻喃并二吡唑的制备方法 |
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| Country | Link |
|---|---|
| US (1) | US4734431A (zh) |
| EP (1) | EP0276835B1 (zh) |
| JP (1) | JP2562642B2 (zh) |
| KR (1) | KR960010456B1 (zh) |
| CN (1) | CN1021442C (zh) |
| AT (1) | ATE86999T1 (zh) |
| AU (1) | AU595091B2 (zh) |
| CA (1) | CA1324606C (zh) |
| DE (1) | DE3879235T2 (zh) |
| DK (1) | DK35288A (zh) |
| ES (1) | ES2054711T3 (zh) |
| FI (1) | FI87217C (zh) |
| GR (1) | GR3007404T3 (zh) |
| HU (1) | HU198724B (zh) |
| IE (1) | IE880194L (zh) |
| IL (1) | IL85186A (zh) |
| NO (1) | NO166368C (zh) |
| NZ (1) | NZ223258A (zh) |
| PH (1) | PH24997A (zh) |
| PT (1) | PT86626B (zh) |
| ZA (1) | ZA88528B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3158619A (en) * | 1962-06-14 | 1964-11-24 | Searle & Co | Certain sulfur-containing ortho-fused polycyclic pyrazole derivatives |
| US4042373A (en) * | 1976-06-02 | 1977-08-16 | E. I. Du Pont De Nemours And Company | 2-Aryl-3-chloro-2,4,6,7-tetrahydrothiopyrano[4,3-c]-pyrazoles |
| US4077956A (en) * | 1976-08-30 | 1978-03-07 | E. R. Squibb & Sons, Inc. | 5-Substituted derivatives of dipyrazolo[1,5-a:4',3'-e]pyrazine-6-carboxylic acids and esters |
| US4355164A (en) * | 1981-05-18 | 1982-10-19 | Usv Pharmaceutical Corporation | Pyridothienopyridazine anti-allergy compounds |
-
1987
- 1987-01-27 US US07/007,308 patent/US4734431A/en not_active Expired - Lifetime
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1988
- 1988-01-21 PH PH36377A patent/PH24997A/en unknown
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- 1988-01-21 NZ NZ223258A patent/NZ223258A/xx unknown
- 1988-01-22 FI FI880285A patent/FI87217C/fi not_active IP Right Cessation
- 1988-01-22 AU AU10726/88A patent/AU595091B2/en not_active Ceased
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- 1988-01-26 IE IE880194A patent/IE880194L/xx unknown
- 1988-01-26 PT PT86626A patent/PT86626B/pt not_active IP Right Cessation
- 1988-01-26 KR KR1019880000563A patent/KR960010456B1/ko not_active IP Right Cessation
- 1988-01-26 HU HU88295A patent/HU198724B/hu not_active IP Right Cessation
- 1988-01-26 CN CN88100342A patent/CN1021442C/zh not_active Expired - Fee Related
- 1988-01-26 ZA ZA88528A patent/ZA88528B/xx unknown
- 1988-01-26 NO NO880340A patent/NO166368C/no unknown
- 1988-01-26 DK DK035288A patent/DK35288A/da not_active Application Discontinuation
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- 1988-01-27 DE DE8888101182T patent/DE3879235T2/de not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| IE880194L (en) | 1988-07-27 |
| DK35288D0 (da) | 1988-01-26 |
| AU595091B2 (en) | 1990-03-22 |
| PT86626A (pt) | 1988-02-01 |
| AU1072688A (en) | 1988-07-28 |
| KR960010456B1 (ko) | 1996-08-01 |
| PH24997A (en) | 1990-12-26 |
| ZA88528B (en) | 1988-09-28 |
| ATE86999T1 (de) | 1993-04-15 |
| JPS63192779A (ja) | 1988-08-10 |
| US4734431A (en) | 1988-03-29 |
| IL85186A0 (en) | 1988-07-31 |
| DE3879235T2 (de) | 1993-06-24 |
| NZ223258A (en) | 1989-11-28 |
| KR880009028A (ko) | 1988-09-13 |
| FI87217C (fi) | 1992-12-10 |
| GR3007404T3 (zh) | 1993-07-30 |
| HUT48630A (en) | 1989-06-28 |
| DK35288A (da) | 1988-07-28 |
| DE3879235D1 (en) | 1993-04-22 |
| ES2054711T3 (es) | 1994-08-16 |
| PT86626B (pt) | 1991-12-31 |
| NO166368C (no) | 1991-07-10 |
| JP2562642B2 (ja) | 1996-12-11 |
| FI87217B (fi) | 1992-08-31 |
| EP0276835B1 (en) | 1993-03-17 |
| NO880340D0 (no) | 1988-01-26 |
| NO880340L (no) | 1988-07-28 |
| IL85186A (en) | 1992-02-16 |
| CA1324606C (en) | 1993-11-23 |
| HU198724B (en) | 1989-11-28 |
| CN88100342A (zh) | 1988-09-14 |
| FI880285A (fi) | 1988-07-28 |
| FI880285A0 (fi) | 1988-01-22 |
| EP0276835A1 (en) | 1988-08-03 |
| NO166368B (no) | 1991-04-02 |
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