CN86100849A - 抗过敏药的制备方法 - Google Patents
抗过敏药的制备方法 Download PDFInfo
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- 125000005359 phenoxyalkyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
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- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- 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
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- A61P27/16—Otologicals
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/28—Sulfur atoms
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Abstract
本发明涉及某些新型的抗过敏药及其制备方法。
Description
本发明涉及一些具有抗过敏活性的新型的化合物及其制造方法。
某些类型的细胞(例如肥大细胞)会释放几种化学传递质,这些化学传递质可传递对抗原抗体反应而作出反应的应变性反应。由于化学传递质参加直接的变应性反应,组织胺和SRS-A(过敏性的低作用物质)被认为是重要的。但后者对支气管性哮喘是最重要的。SRS-A是白细胞三烯(Leukotriene)C4(LTC4)、白细胞三烯D4(LTD4)和白细胞三烯E4(LTE4)的混合物,它是通过脂(肪)氧合酶途径得到的廿碳四烯酸的代谢物。通常,预防、减轻和清除变应性反应的症状的药物研究对准开发一些能抑制化学传递质释放或者拮抗其作用的药物。结果是抗组织胺剂[例如,苯海拉明(diphenhy dramine)和氯苯吡胺(chlorpheniramine)等]、SRS-A释放抑制剂[色过酸二钠(diso dium cromoglycate)]等上市了。但是,前者的抗支气管性哮喘的效果不可靠,而后者只有预防作用,而且在内服时没有效果。
因此,一些能拮抗SRS-A作用的药物可期望用作抗过敏药,此时,人们知道只有少数药物具有这种活性,而且知道其中没有一种在内服时是具有这种活性的。
作为对具有抗变应性作用的化合物进行广泛研究的结果,本发明者发现,由化学式(Ⅰ)所表示的一类新型化合物具有优良的抗变应性作用,尤其是对由SRS-A所引起的过敏性具有极其强烈的抑制作用,即使内服也是如此。
[其中,Ar代表吡唑(Pyzazolo)[1,5-a]吡啶-3-基环,它可具有或不具有1~4个碳原子的直链或支链烷基的取代基,或代表苯并咪唑-2-基团,而n表示0~2之间的一个整数]。
根据本发明,通式(Ⅰ)所示的化合物可通过各种途径来制造。(1).通过让通式(Ⅱ)的化合物与通式(Ⅳ)的苯氧基烷基衍生物进行反应可以制造出通式(Ⅰ)中n为0的化合物。在典型情况下它们可以通过让通式(Ⅱ)的化合物在一种合适的溶剂(例如,甲醇、乙醇、四氢呋喃等)中,并在有碱或无碱(例如,氢氧化钾、氢化钠等等)的存在下与通式(Ⅲ)的苯氧基烷基衍生物进行反应来进行制造。
Ar-SCN (Ⅳ)
[其中,Ar与上文所描述的相同]。
[其中,X是卤原子]。
(2).由通式(Ⅰ)所表示的其中n为0的化合物也可通过把通式(Ⅳ)的化合物转化成通式(Ⅱ)的化合物之后,然后再按照与(1)相同的方法将通式(Ⅱ)的化合物与通式(Ⅲ)的化合物进行反应来制造。典型情况下采用一种适合的试剂(例如,锌一盐酸、氢硼化钠、氢氧化钾等)在一种合适的溶剂(例如,甲醇,乙醇等)中,使通式(N)的化合物转化成通式(Ⅱ)的化合物。
Ar-SH (Ⅱ)
[其中,Ar所代表的是与上文所描述的相同]。
(3).通式(Ⅰ)所示的n为1的化合物可通过使通式(Ⅰ)所表示的n为0的化合物与氧化剂进行反应来制造。在典型情况下,它们可通过使通式(Ⅰ)所表示的其中n为0的化合物与一个或几个体积摩尔当量的温和的氧化剂(例如,在甲醇中的过氧化氢、在二氯甲烷中的m-氯过苯甲酸等)进行反应来加以制造。
(4).通式(Ⅰ)表示的但n为2的化合物可按照与(3)中所述的同样方法通过使通式(Ⅰ)所表示的其中n为0的化合物与氧化剂进行反应来制造。在典型情况下它们也可以通过使通式(Ⅰ)所表示的其中n为0的化合物按照与(3)中所述的同样方法,与二个或多个摩尔当量的适度的氧化剂进行反应来加以制造。
在下面,本发明将通过一些具体例来进行说明,但本发明不受这些例子的限制。
参考例子1
2-异丙基-3-氰硫基吡唑[1,5-a]-吡啶的制造。在56毫升的甲醇中的3克2-异丙基吡唑[1,5-a]吡啶的溶液中加入5.74克的硫氰酸钠,并在室温下搅拌。再把3.3克溴溶解在13毫升的被溴化钾饱和的甲醇中,然后一滴一滴地加入到上述溶液中。然后该混合物在室温下搅拌1小时,随后倒入130毫升的水中,再把所生成的沉淀物过滤出来,并进行干燥。然后再用甲醇对这种粗糙的沉淀物加以再结晶从而获得了3.53(得率为87%)的目的化合物,它是一种苍黄色的三棱形晶体。溶点为91~92.5℃。
参考例子2
2-甲基-3-氢硫基吡唑[1,5-a]吡啶的制造。该化合物是通过与参考例1中所述的同样方法采用2-甲基吡唑[1.5-a]吡啶,而不是使用2-异丙基吡唑[1,5-a]吡啶来合成的。它是一种浅黄色的粉末(得率为50%)。熔点为111~113℃。
实施例1
2-[3-(4-乙酰基-3-羟基-2-丙基苯氧基)-丙基硫]苯并咪唑的制造。
在30毫升乙醇中的1.2克2-巯基苯并咪唑的悬浮液中在搅拌下加入580毫克的氢氧化钾,然后再在室温下搅拌10分钟。接着,再往这种溶液一次地加入2.8克的3-(4-乙酰基-3-羟基-2-丙基苯氧基)丙基溴,并在室温下搅拌4小时。然后,在减压的条件下,把该溶剂蒸馏掉并用二氯甲烷对残留物进行稀释,此后再用二氯甲烷萃取三次。将三次所得的有机层混合在一起,然后用被氯化钠饱和了的水进行洗涤,并在无水硫酸钠上加以干燥。接着,又在减压的条件下把溶剂蒸馏掉,并用二氯甲烷-n-己烷对所生成的残留物进行再结晶从而得到了2.5克(得率为81%)的目的化合物,这是一种无色粉末。熔点为149~150℃。
对C24H24N2O3S进行的分析(%):计算值(实测值);C,65.60(65.71);H,6.29(6.29);N,7.29(7.24)。
实施例2
3-[3-(4-乙酰基-3-羟基-2-丙基苯氧基)丙基硫]-2-异丙基吡唑[1,5-a]吡啶的制造。
在25毫升的甲醇中1克的2-异丙基-3-氢硫基吡唑[1,5-a]吡啶(参考例子1中所描述的)悬浮液中加入2.6毫升的浓盐酸,并在室温下搅拌。然后再在该溶液中一点一点地加入1.3克的锌粉,并在室温下搅拌1小时。此后该溶液用40毫升的水进行稀释,并用二氯甲烷萃取2次,然后将二次所得有机层混合起来,并在无水硫酸钠上进行干燥,再在减压的条件下把溶剂蒸馏掉。接着,按照与实施例1相同的方法对生成的残留物进行处理,再通过闪蒸塔色层分离(二氯甲烷∶苯=2∶1)对这些粗糙的产物加以净化,最后用n-己烷进行再结晶从而获得了750毫克(得率为38%)的目的化合物,这是一种无色的针状体。熔点为99~95.5℃。
对C24H30N2O3S的分析(%):计算值(实测值);C,67.58(67.70);H,7.09(7.19);N,6.57(6.43)。
实施例3
3-[3-(4-乙酰基-3-羟基-2-丙基苯氧基)丙基硫]-2-异丙基吡唑[1,5-a]吡啶-S-氧化物的制备。
往25毫升的二氯甲烷中的800毫克3-[3-(4-乙酰基-3-羟基-2-丙基苯氧基)丙基硫]-2-异丙基吡唑[1,5-a]吡啶(实施例2中所描述的)的溶液(用冰-盐-水浴冷却到0℃以下)加入405毫克的m-氯过苯甲酸,并在0℃下搅拌15分钟。接着,把4克氢氧化钙加入到该反应混合物中,并在室温下搅拌10分钟,然后用寅式盐把悬浮液中的沉淀物过滤掉。滤液用5%碳酸氢钠的水溶液进一步洗涤,并在无水硫酸钠上进行干燥。然后在减压的条件下把溶剂蒸馏掉。最后,结晶的残留物用二氯甲烷-n-己烷进行再结晶,就可获得770毫克(得率为93%)的目的化合物,这是一种无色粉末。熔点为145~146℃。
对C24H30N2O4S的分析(%):计算值(实测值);C,65.13(65.17);H,6.83(6.79);N,6.33(6.23)。
实施例4
3-[3-(4-乙酰基-3-羟基-2-丙基苯氧基)丙基磺酸]-2-异丙基吡唑[1.5-a]吡啶的制造。
在50毫升二氯甲烷中的2克3-[3-(4-乙酰基-3-羟基-2-丙基苯氧基)丙基硫]-2-异丙基吡唑[1,5-a]吡啶(实施例2中所描述的)溶液中(水浴冷却至15℃以下)加入2.22克的m-氯过苯甲酸,并在室温下搅拌2小时。净化程序仍与实施例3中所描述的相同。生成的残留物用二氯甲烷-n-己烷进一步再结晶之后就获得了1.93克(得率为92%)的目的化合物,这是一种浅黄色的粉末。熔点为169.5~170.5℃。
对C24H30N2O5S的分析(%):计算值(实测值);C,62.86(62.70);H,6.59(6.66);N,6.11(6.01)。
表1所示的化合物是采用实施例1~4中所描述的方法合成的。
这里所给出的化合物对分离的豚鼠回肠的LTD4-诱发的收缩显示出具有很强的拮抗作用。值得注意的是,所有这些化合物在支气管性哮喘的实验模型中,口服是有效的。雾化了的抗原被预先用消炎痛和吡甲胺处理过的十分敏感的豚鼠吸入之后就会引起过敏性支气管缩小,其中,内源性地释放的SRS_A起了主要作用。本发明的化合物以20毫克/公斤的口服剂量可有效地抑制这种过敏性支气管缩小(表2)。据报道,一种很有名的SRS_A拮抗物:FPL712:即,钠7-[3-(4-乙酰基-3-羟基-2-丙基苯氧基)-2-羟基丙氧基]-4-氧代-8-丙基-4H-1-苯并吡喃-2-羧酸酯口服是无效的(P.Shead et al.:Monogr Allergy,PP.244~248.S Karger 1977)。于是,本发明的化合物是一类具有有效的抗SRS-A(白细胞三烯)活性的抗过敏药。这些化合物被认为是对变应性疾病(例如,支气管哮喘、变应性鼻炎和荨麻诊)具有预防和治疗价值的。
Claims (3)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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JP27267/85 | 1985-02-14 | ||
JP60-27267 | 1985-02-14 | ||
JP60027267A JPS61186368A (ja) | 1985-02-14 | 1985-02-14 | 新規な抗アレルギ−薬およびその製造方法 |
Publications (2)
Publication Number | Publication Date |
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CN86100849A true CN86100849A (zh) | 1986-10-08 |
CN1019890C CN1019890C (zh) | 1993-02-10 |
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CN86100849A Expired - Fee Related CN1019890C (zh) | 1985-02-14 | 1986-02-07 | 新颖的4-杂环磺酰(或硫代)丙氧基-2-羟基-3-丙基苯乙酮衍生物的制备方法 |
Country Status (13)
Country | Link |
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US (1) | US4680398A (zh) |
EP (1) | EP0191401B1 (zh) |
JP (1) | JPS61186368A (zh) |
KR (1) | KR900003652B1 (zh) |
CN (1) | CN1019890C (zh) |
AU (1) | AU591091B2 (zh) |
CA (1) | CA1297106C (zh) |
DE (1) | DE3677794D1 (zh) |
DK (1) | DK159779C (zh) |
ES (3) | ES8706641A1 (zh) |
FI (1) | FI83314C (zh) |
HU (1) | HU195508B (zh) |
NO (1) | NO162820C (zh) |
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US5182291A (en) * | 1986-02-14 | 1993-01-26 | Sanofi | Pyrozala-pyridyl aminoabkoxyphenol compounds |
US4691630A (en) * | 1986-03-14 | 1987-09-08 | Asano Tekkosho Co., Ltd. | Ink-applying mechanism of a printing machine having a reciprocative printing roll |
US4942245A (en) * | 1987-04-20 | 1990-07-17 | Kyorin Pharmaceutical Co., Ltd. | Benzimidazole Derivatives |
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GB1384530A (en) * | 1971-07-29 | 1975-02-19 | Fisons Ltd | Chromone derivatives |
DE3265715D1 (en) * | 1981-03-24 | 1985-10-03 | Fisons Plc | Anti srs-a carboxylic acid derivatives, processes for their production and pharmaceutical formulations containing them |
DE3275295D1 (en) * | 1981-11-12 | 1987-03-05 | Fisons Plc | Anti-srs-a carboxylic acid derivatives, processes for their production, and pharmaceutical formulation containing them |
JPH0613515B2 (ja) * | 1983-03-14 | 1994-02-23 | 杏林製薬株式会社 | ピラゾロ〔1,5−a〕ピリジン誘導体及びそれを含有する治療剤 |
PH22520A (en) * | 1984-11-12 | 1988-10-17 | Yamanouchi Pharma Co Ltd | Heterocyclic compounds having 4-lover alkyl-3-hydroxy-2-lower alkyl phenoxy-lower alkylene-y-group, and process of producing them |
ZA858493B (en) * | 1984-11-12 | 1986-07-30 | Yamanouchi Pharma Co Ltd | Heterocyclic compounds and process of producing them |
-
1985
- 1985-02-14 JP JP60027267A patent/JPS61186368A/ja active Granted
-
1986
- 1986-01-30 US US06/824,099 patent/US4680398A/en not_active Expired - Fee Related
- 1986-02-03 AU AU52954/86A patent/AU591091B2/en not_active Ceased
- 1986-02-04 EP EP86101417A patent/EP0191401B1/en not_active Expired - Lifetime
- 1986-02-04 DE DE8686101417T patent/DE3677794D1/de not_active Expired - Lifetime
- 1986-02-07 FI FI860571A patent/FI83314C/fi not_active IP Right Cessation
- 1986-02-07 CN CN86100849A patent/CN1019890C/zh not_active Expired - Fee Related
- 1986-02-12 CA CA000501712A patent/CA1297106C/en not_active Expired - Lifetime
- 1986-02-13 NO NO860538A patent/NO162820C/no unknown
- 1986-02-13 HU HU86623A patent/HU195508B/hu not_active IP Right Cessation
- 1986-02-13 DK DK069886A patent/DK159779C/da active
- 1986-02-13 KR KR1019860001000A patent/KR900003652B1/ko not_active IP Right Cessation
- 1986-02-14 ES ES552000A patent/ES8706641A1/es not_active Expired
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1987
- 1987-03-27 ES ES557468A patent/ES8801798A1/es not_active Expired
- 1987-03-27 ES ES557469A patent/ES8802500A1/es not_active Expired
Also Published As
Publication number | Publication date |
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ES8801798A1 (es) | 1988-02-16 |
JPS61186368A (ja) | 1986-08-20 |
FI860571A0 (fi) | 1986-02-07 |
DK159779B (da) | 1990-12-03 |
ES8706641A1 (es) | 1987-07-01 |
KR900003652B1 (ko) | 1990-05-28 |
EP0191401A3 (en) | 1988-01-07 |
CN1019890C (zh) | 1993-02-10 |
CA1297106C (en) | 1992-03-10 |
US4680398A (en) | 1987-07-14 |
DE3677794D1 (de) | 1991-04-11 |
HU195508B (en) | 1988-05-30 |
NO162820B (no) | 1989-11-13 |
FI860571A (fi) | 1986-08-15 |
NO162820C (no) | 1990-02-21 |
ES552000A0 (es) | 1987-07-01 |
DK159779C (da) | 1991-04-22 |
ES557468A0 (es) | 1988-02-16 |
DK69886D0 (da) | 1986-02-13 |
EP0191401A2 (en) | 1986-08-20 |
NO860538L (no) | 1986-08-15 |
HUT40654A (en) | 1987-01-28 |
EP0191401B1 (en) | 1991-03-06 |
AU5295486A (en) | 1986-08-21 |
FI83314C (fi) | 1991-06-25 |
DK69886A (da) | 1986-08-15 |
FI83314B (fi) | 1991-03-15 |
JPH058705B2 (zh) | 1993-02-02 |
AU591091B2 (en) | 1989-11-30 |
ES557469A0 (es) | 1988-07-16 |
KR860006461A (ko) | 1986-09-11 |
ES8802500A1 (es) | 1988-07-16 |
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