CN1040983A - 噻吩并(3′,4′-4,5)咪唑并(2,1-b)噻唑类衍生物、其制备方法及医药用途 - Google Patents
噻吩并(3′,4′-4,5)咪唑并(2,1-b)噻唑类衍生物、其制备方法及医药用途 Download PDFInfo
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Abstract
本发明涉及式I的新的噻吩并(3′,4′-4,5)咪唑并(2,1-b)噻唑衍生物和当R2为氢的药用盐,式中R1为氢、卤素或CF3;R2为氢或(1-4)碳烷基,制备这些化合物的方法和用于治疗癌症或由于免疫系统缺陷而造成的风湿性关节炎。
Description
本发明涉及噻吩并(3′,4′-4,5)咪唑并(2,1-b)噻唑类衍生物、它们的制备方法及其作为免疫系统刺激药物的应用。
于《药剂与作用》(Agents and Actions)Vol.17,1(1985)文中S.C.Gilman等叙述了作为抗炎和免疫调节物质的3-(对-氯苯基)噻唑并(3,2-a)-苯并咪唑-2-乙酸。
现在发现,噻吩并(3′,4′-4,5)咪唑并(2,1-b)噻唑类衍生物具有比上述内容更好的药理作用。
因此,本发明涉及式Ⅰ的化合物及R2为氢时的药用盐。
式中,R1为氢,卤素或三氟甲基,R2为氢或(1-4)碳烷基。
“(1-4)碳烷基”在本说明书中是指含1-4个碳原子的直链或支链饱和烷基,例如甲基,乙基,丙基,异丙基,丁基,异丁基或叔丁基,“卤素”是指氯、溴或氟。
式Ⅰ的优选化合物是R1为氯,R2为氢或甲基时的化合物。
特别优选的诸化合物为:
3-(4-氯苯基)-噻吩并(3′,4′-4,5)咪唑并(2,1-b)噻唑-2-乙酸甲酯:
3-(4-氯苯基)-噻吩并(3′,4′,-4,5)咪唑并(2,1-b)-噻唑-2-乙酸。
制备本发明如式Ⅰ所示的噻吩并(3′,4′,-4,5)咪唑并(2,1-b)噻唑类衍生物及其盐的方法是
a)在脱水剂的存在下,式Ⅱ的化合物或其酸加成盐发生环化
式中R1的定义同前,R2为(1-4)碳烷基;
b)若需要时,得到的式Ⅰ的化合物(R2为(1-4)碳烷基基)在碱性条件下水解,生成式Ⅰ的化合物(R2为氢);以及
c)如若需要,由b)法得到的R2为氢的式Ⅰ的游离酸用无机或有机碱转变成药用盐。
常规用的所有的脱水剂都可用作式Ⅱ化合物的环化反应的脱水剂,最好是用多磷酸或磷酰氯,它们可同时作为溶剂。环化温度大约为60℃到110℃。用磷酰氯时,环化反应最好是在回流温度下进行。反应时间取决于温度和环化剂,大约在10分钟到4小时之间。
如若需要,式Ⅰ的酯与碱共加热沸腾,可使其水解,最好是用等当量的碱金属氢氧化物溶液,加入助溶剂如甲醇或乙醇,有利于生成式Ⅰ的化合物,式中R2为氢。收率几近定量。
用b)法反应得到的含游离羧基的式Ⅰ化合物,可用常规方法与无机或有机碱反应转化成药用盐。生成盐的方法,例如可将上述式Ⅰ化合物(R2=H)溶解于适当的溶剂,例如水或低级脂肪醇,再加入等当量的适宜的碱,充分混合。完全生成盐后,真空下蒸除溶剂,如若需要,分离出的盐可重结晶。
药用盐可以是金属盐,尤其是碱金属或碱土金属盐,例如钠盐、钾盐、镁盐或钙盐。也可用其它药用盐,例如容易结晶的铵盐。后者是由氨或有机胺制成的,例如一、二或三低碳-(烷基、环烷基或羟烷基)胺,低碳亚烷二胺,或(羟基代低碳烷基或芳基代低碳烷基)低碳烷基铵的碱,例如,甲胺,二乙胺,三乙胺,二环己胺,三乙醇胺,亚乙基二胺(ethylenediamine),三(羟甲基)氨基甲烷,苄基-三甲基氢氧化铵等等。
由文献已知的式Ⅲ化合物(F.Outerquin和C Paulmier法国化学会志5-6,159~163(1983))和式Ⅴ化合物(W.G.Dauben,H.Tilles,有机化学杂志15,785-789(1950)起始,按本专业领域的人熟知的常规化学操作,通式Ⅱ的化合物可按如下的反应方程式合成:
式Ⅰ的新化合物及其药用盐对体外模型的免疫系统有卓越的刺激作用,这种对免疫系统的刺激作用可以测定,例如,用辅药诱发的大鼠多关节炎模型测定受试化合物的抗炎活性。
用这个试验系统测定本申请中的实例2化合物(化合物A)的抗炎作用,与3-(4-氯苯基)-噻唑并(3,2-a)苯并咪唑-2-乙酸(噻氯咪索)(tilomisole)(实例3)比较,表明本发明的化合物明显比噻氯咪索好(tilomisole)。
这些新化合物基于其药理性质可单独用作药用,或与其它活性物质制成通常的格林制剂,用于治疗由于免疫系统的缺陷,例如癌或风湿性关节炎造成的疾患。
式Ⅰ化合物拟用于人,可按常规方法给药,例如口服或非经胃肠给药。最好是口服,每日剂量为0.1~100mg/kg体重,最好是0.2~20mg/kg体重。不过,医生可根据患者的体征、年龄,式Ⅰ化合物的种类、疾病类型和剂型情况,处方剂量可酌情增减。
本发明物质若用于预防,剂量与治疗量大致范围相同,用于预防最好也是口服。
式Ⅰ化合物可以单用,也可与其它药质合用,此时式Ⅰ化合物的含有量为0.1~99%。这些药用活性物质通常与适宜的助剂和/或赋形剂或稀释剂混合,例如,像药用溶剂,明胶,阿拉伯胶,乳糖,淀粉,硬脂酸镁,滑石粉,植物油,聚亚烷基二醇、矿脂等等。药物剂型可以是固体形式,例如片剂,包衣片、栓剂,胶囊等等;或半固体形式,例如软膏剂;或液体形式,例如溶液,悬浮液或乳化液。如若处理适当,药物是无菌的,含有助剂例如有,防腐剂,稳定剂或乳化剂,以及为改善渗透压加入的盐类等等。
药物制剂尤其可由本发明的化合物与其它有治疗价值的物质合併应用。本发明的化合物,可与这些化合物,例如上述的助剂和/或赋形剂和稀释剂制成剂型,成为合并药物制剂。
实例1:
3-(4-氯苯基)噻吩并(3′,4′-4,5)咪唑并(2,1-b)-噻唑-2-乙酸甲酯
4-(4-氯苯基)-4-氧代-3-(1H-噻吩并(3,4-d)-咪唑-2-基)硫代丁酸甲酯氢溴酸盐8.00g(17.3mmol)悬浮于75ml磷酰氯中,加热沸腾10分钟。蒸馏除去过量的磷酰氯,残留物用饱和碳酸氢钠溶液中和。然后用总量为500ml的乙酸乙酯分三次萃取混合物。有机相合并,无水硫酸钠干燥,过滤,蒸去溶剂,残留物用丙酮重结晶,产量2.00g(收率:31.8%);mp:188-190℃(丙酮)1H-NMR(DMSO)δ(ppm):7.68(S,4H,pH-H);7.22;7.19;6.54;6.51(AB,2H,Th-H);3.81(S,2H,-CH2-COO-),3.67(S,3H,-COOCH3)
原料的制备如下:
3-溴-4-(4-氯苯基)-4-氧代丁酸甲酯
4-(4-氯苯基)-4-氧代丁酸甲酯50.0g(0.221mol)(C.F.H.Allen,J.B.Normington和C.V.Wilson,加拿大研究杂志11,382(1934))溶于250ml冰乙酸,并滴入三滴溴化氢于冰乙酸的溶液。搅拌下滴入溴素35.3g(0.221mol),速度是不要使反应混合物中有可见的溴素颜色,加毕,再搅拌混合物15分钟,将大部分乙酸蒸掉后,残留物用饱和碳酸氢钠溶液中和,用总量为600ml二氯甲烷分三次萃取,合并有机相,无水硫酸钠干燥,过滤后蒸干(6.(67.2g黄色油状物)。后者在甲醇中磨碎,并从甲醇中重结晶,产量:65.2g(收率97%),无色结晶,mp48~49℃(甲醇)。
4-(4-氯苯基)-4-氧代-3-(1H-噻吩并(3,4-d)咪噻-2-基)硫代丁酸甲酯氢溴酸盐
1,3-二氢噻吩并(3,4-d)咪唑-2-硫酮4.00g(25.6mmol)和3-溴-4-(4-氯苯基)-4-氧代丁酸甲酯7.11g(23.3mmol)溶于无水甲醇100ml,加热回流1.5小时。然后加1g活性碳到溶液中,过滤,蒸干。得到的残留物用乙醚处理。产量9.10g(收率84.6%),为淡褐色结晶,mp180~185℃(分解)(丙酮)。
实例2:
3-(4-氯苯基)噻吩(3′,4′-4,5)咪唑并(2,1-b)噻唑-2-乙酸
3-(4-氯苯基)噻吩并(3′,4′-4,5)咪唑并(2,1-b)噻唑-2-乙酸甲酯2.00g(5.51mmol)悬浮于甲醇20ml,加入2N氢氧化钠溶液3ml,加热回流15分钟。将反应物浓缩到大约10ml,加入2N盐酸酸化。沉淀物减压过滤,蒸馏水洗涤三次,甲醇重结晶,产量1.50g(收率:78%),无色结晶,mp200~210℃分解(甲醇)。
1H-NMR(DMSO)δ(ppm):8.87(S,宽峰,1H,-COOH)7.72(s,4H,ph-H);7.42;7.3;6.77;6.74(AB,2H,Th-H);3.83(S,2H,-CH2-COO-)
实例3
用辅药诱发的大鼠多关节炎模型研究免疫调节作用
3-(4-氯苯基)噻吩并(3′,4′,-4,5)-咪唑并(2,1-b)噻唑-2-乙酸盐(化合物A=本申请的实例2化合物)的药理作用是用辅药诱发的大鼠多关节炎模型测定的,并与3-(4-氯苯基)噻唑并(3,2-a)苯并咪唑-2-乙酸盐(噻氯咪索,化合物B)作比较。
本测定是将受试物质腹腔注射,浓度为10mg/kg体重,每日一次,连续16天,注射到有先天免疫缺陷的雌性Lewis大鼠。每种物质使用6只动物。对照组动物腹腔注射0.5%的羧甲基纤维素,而不注射活性物质。在第零日(即给受试物质开始的前一日)在受试动物的右脚下蹠处注射0.75mg丁酸杆菌于0.1ml的Freund辅药的溶液。于第11天到第14天,于未注射杆菌的左脚发生了次级反应,因而肿胀。由于这种肿胀是由于免疫反应引起的,凡能减退这种遗传造成的病理反应的物质称作免疫调节剂。肿胀的大小每天用充盈计测定,用ml表示。
表1和图1总结了该实验结果。
表1
脚体积(ml)
日 对照组 噻氯咪索组 化合物A
(0.5%CMC) 10mg/kg(腹腔注射) 10mg/kg(腹腔注射)
0 0.39±0.02 0.39±0.02 0.39±0.02
11 0.41±0.02 0.45±0.02ooo0.38±0.02**
12 0.41±0.03 0.46±0.02oo0.39±0.02
13 0.41±0.02 0.45±0.02oo0.39±0.01*
14 0.47±0.07 0.45±0.01 0.44±0.02
16 0.50±0.05 0.53±0.05 0.46±0.03*
o显著性增加*显著性减低 CMC:羧甲基纤维素
由表1和图1可看出,在所有观测的时间点上,只有化合物A可抑制次级反应回到免疫反应。
Claims (5)
1、式Ⅰ化合物和式Ⅰ中R2为氢的药用盐
式中R1为氢、卤素或CF3;R2为氢或(1-4)碳烷基。
2、依权利要求1的式Ⅰ化合物及其盐,其中R1为氯,R2为氢或甲基。
3、3-(4-氯苯基)-噻吩并(3′,4′-4,5)咪唑并(2,1-b)噻唑-2-乙酸甲酯;
3-(4-氯苯基)-噻吩并(3′,4′-4,5)咪唑并(2,1-b)噻唑-2-乙酸。
5、一种药用组合物,其特征是含有一种权利要求1所要求的式Ⅰ化合物或其盐,以治疗风湿性关节炎的有效量与药用载体或稀释剂构成。
6、一种治疗风湿性关节炎的方法,其特征是患有风湿性关节炎的患者服用权利要求1所要求的式Ⅰ化合物或其盐的有效量。
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Application Number | Priority Date | Filing Date | Title |
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AT2202/88 | 1988-09-08 | ||
AT0220288A AT394046B (de) | 1988-09-08 | 1988-09-08 | Neue thieno(3',4'-4,5)imidazo(2,1-b)thiazolderivate, verfahren zu ihrer herstellung und ihre verwendung |
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CN1040983A true CN1040983A (zh) | 1990-04-04 |
CN1025197C CN1025197C (zh) | 1994-06-29 |
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US (1) | US4978671A (zh) |
EP (1) | EP0358116A3 (zh) |
JP (1) | JPH02115189A (zh) |
KR (1) | KR900004747A (zh) |
CN (1) | CN1025197C (zh) |
AT (1) | AT394046B (zh) |
AU (1) | AU616301B2 (zh) |
CS (1) | CS8905106A3 (zh) |
DD (1) | DD284236A5 (zh) |
DK (1) | DK441689A (zh) |
FI (1) | FI89363C (zh) |
HU (1) | HU201330B (zh) |
IL (1) | IL91544A0 (zh) |
LT (1) | LT3946B (zh) |
MY (1) | MY105044A (zh) |
NO (1) | NO893428L (zh) |
NZ (1) | NZ230555A (zh) |
PH (1) | PH26102A (zh) |
PT (1) | PT91656B (zh) |
SU (1) | SU1739851A3 (zh) |
UA (1) | UA13480A (zh) |
YU (1) | YU171789A (zh) |
ZA (1) | ZA896682B (zh) |
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US4214089A (en) * | 1978-07-18 | 1980-07-22 | American Home Products Corporation | Thiazolo[3,2-a]benzimidazoles, imidazo [2,1-b]thiazoles, and related compounds as antineoplastic agents, and enhancers of the immune response |
CA1131226A (en) * | 1978-09-28 | 1982-09-07 | Tomohiko Munakata | Heterocyclic compounds |
US4293696A (en) * | 1980-12-22 | 1981-10-06 | American Home Products Corporation | 3-Substituted phenylthiazolo[3'2':1,2]imidazo[4,5-b]pyridine-2-alkanoic acids |
EP0284893A3 (de) * | 1987-04-03 | 1990-04-18 | Hafslund Nycomed Pharma Aktiengesellschaft | Neue Thieno-imidazo(2,1-b)thiazol-Derivate, ein Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Präparate |
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1988
- 1988-09-08 AT AT0220288A patent/AT394046B/de not_active IP Right Cessation
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- 1989-08-31 EP EP19890116131 patent/EP0358116A3/de not_active Withdrawn
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- 1989-09-05 AU AU41098/89A patent/AU616301B2/en not_active Ceased
- 1989-09-06 KR KR1019890012853A patent/KR900004747A/ko not_active Application Discontinuation
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- 1989-09-07 JP JP1230584A patent/JPH02115189A/ja active Pending
- 1989-09-07 PT PT91656A patent/PT91656B/pt not_active IP Right Cessation
- 1989-09-07 DK DK441689A patent/DK441689A/da not_active Application Discontinuation
- 1989-09-07 CN CN89106978A patent/CN1025197C/zh not_active Expired - Fee Related
- 1989-09-07 HU HU894730A patent/HU201330B/hu not_active IP Right Cessation
- 1989-09-08 SU SU894742029A patent/SU1739851A3/ru active
- 1989-09-08 UA UA4742029A patent/UA13480A/uk unknown
-
1994
- 1994-01-27 LT LTIP1811A patent/LT3946B/lt not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
JPH02115189A (ja) | 1990-04-27 |
AT394046B (de) | 1992-01-27 |
LT3946B (en) | 1996-05-27 |
AU4109889A (en) | 1990-03-15 |
ATA220288A (de) | 1991-07-15 |
FI894193A0 (fi) | 1989-09-06 |
DK441689D0 (da) | 1989-09-07 |
NO893428D0 (no) | 1989-08-25 |
AU616301B2 (en) | 1991-10-24 |
US4978671A (en) | 1990-12-18 |
NO893428L (no) | 1990-03-09 |
KR900004747A (ko) | 1990-04-12 |
UA13480A (uk) | 1997-04-25 |
ZA896682B (en) | 1990-08-29 |
FI894193A (fi) | 1990-03-09 |
PT91656A (pt) | 1990-03-30 |
MY105044A (en) | 1994-07-30 |
CS275035B2 (en) | 1992-01-15 |
NZ230555A (en) | 1991-02-26 |
PT91656B (pt) | 1995-05-31 |
DK441689A (da) | 1990-03-12 |
FI89363B (fi) | 1993-06-15 |
PH26102A (en) | 1992-02-06 |
HU201330B (en) | 1990-10-28 |
CS8905106A3 (en) | 1992-01-15 |
FI89363C (fi) | 1993-09-27 |
YU171789A (en) | 1991-04-30 |
IL91544A0 (en) | 1990-04-29 |
HUT51631A (en) | 1990-05-28 |
EP0358116A3 (de) | 1991-08-21 |
SU1739851A3 (ru) | 1992-06-07 |
EP0358116A2 (de) | 1990-03-14 |
DD284236A5 (de) | 1990-11-07 |
CN1025197C (zh) | 1994-06-29 |
LTIP1811A (en) | 1995-08-25 |
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