CN1028367C - 苯并咪唑衍生物的制备方法 - Google Patents
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Abstract
本发明涉及以通式I表示的新的苯并咪唑衍生物及其治疗上可接受的盐及其制备方法,其中R1R2,n,m,x,y,z和w的定义详见说明书。
Description
本发明涉及新的苯并咪唑衍生物,它们的制备方法和它们作为药品的应用。
本发明主题化合物可以通式Ⅰ表示
其中:
-R1和R2各表示氢,
-n可取0或1,
-m可取2-4,
X,Y,Z和W相同或不同,其中一个表示氮原子,而其余的表示连接有氢原子,卤素,低级烷基或羧基的碳原子。
从科学文献中已知苯并咪唑衍生物具有各种生物学活性,例如镇痛和抗炎活性(日本专利公开75,126,682);抗胃泌活性(EP246,126和EP5129);抗组胺活性(J.Jilek et al.,Collect,Czech.Chem.Cmmun.1988,53,870-83;美国专利4,200,641;Drugs of the Future,Ⅶ,10-1.1982;R.Iemura et al.,J.M.Chem.,1986,29,1178-1183;R.Iemura et al.,J.Heteroxycyclic Chem.,
1987,24,31-37;法国专利申请FR90/09563)。本发明主题化合物是新的苯并咪唑衍生物,即1-(2-乙氧乙基)-2-{ω[ω(吡咯-1-基)烷基]外氢-1,4-二氮杂
-1-基烷基}苯并咪唑,其在本发明中被命名为1-(2-乙氧乙基)-2-{ω[ω(吡咯-1-基)烷基]高哌嗪-1-基烷基}苯并咪唑。本发明人发现这些新的衍生物具有极好的抗组胺活性并且对中枢神经系统没有副作用。
通式Ⅰ的新衍生物可按照本发明,用下列任一种方法进行制备:
方法A.一使通式Ⅱa的化合物
或通式Ⅱb的化合物
其中R1,R2,n和m具有上述意义,A代表卤原子或选自甲苯磺酰氧基或甲磺酰氧基的良好“离去基团”,与通式Ⅲ的化合物
-其中X,y,z和w具有上述意义一一反应。
反应是在合适的溶剂,例如二甲基亚砜、二甲基甲酰胺、醇类、芳香或非芳香烃类、醚类如二噁烷或二苯基醚、或这些溶剂的混合物存在下进行的。这个反应最好在碱,例如碱金属氢氧化物、碳酸盐或碳酸氢盐、或这些碱的混合物存在下进行。也可使用碱金属氢化物。最适温度可在室温至溶剂的回流温度间变化,反应时间为1至24小时。
方法B.一使通式Ⅱa的化合物-其中A代表-NH2基团-与2,5-二甲基四氢呋喃反应。
反应是在合适的溶剂,例如乙酸、水、醇类、酮类或这些溶剂的混合物存在下进行的。最适温度可在室温至溶剂的回流温度间变化,反应时间为几分钟至24小时。
方法C.一使通式Ⅳ的化合物
-其中R1,R2和n具有上述意义一与通式Ⅴ的化合物
-其中x,y,z,w和m具有上述意义,B代表卤原子或选自甲苯磺酰氧基或甲磺酰氧基的良好“离去基团”-反应。
反应在合适的溶剂,例如二甲亚砜、二甲基甲酰胺、醇类、芳香或非芳香烃类、醚类如二烷或二苯基醚,或这些溶剂的混合物存在下进行的。这个反应最好在碱,例如碱金属的氢氧化物、碳酸盐或碳酸氢盐,或这些碱的混合物存在下进行。最适温度可在室温至溶剂的回流温度间变化,反应时间为1至24小时。
按照本发明所述的新衍生物的制备方法在下列实施例中给出。
下面的实施例是以说明的方式简单给出的,但不应以任何方式限制本发明的范围。
方法A
实施例1.1-(2-乙氧乙基)-2-{4-[4-(吡唑-1-基)丁基]高哌嗪-1-基甲基}苯并咪唑的制备
a)1-(2-乙氧乙基)-2-(4-苄基-1H-高哌嗪-1-基甲基)苯并咪唑
将13.6g(42.5mmol)1H-2-(4-苄基-1H-高哌嗪-1-基-甲基)苯并咪唑在20ml二甲基甲酰胺(DMF)中的溶液缓慢加入到2.04g(46.7mmol)NaN的悬浮液(55%,在矿物油中)中。将混合物加热至60-70℃保持1小时,然后加入5.1g(46.7mmol)1-氯-2-乙氧乙烷在5mlDMF中的溶液。
将混合物在同样条件下连续搅拌5小时。将它倒入水中并用乙酸乙酯萃取,用水洗涤,有机相用Na2SO4干燥,过滤并蒸发。在硅胶色谱柱上纯化所得到的油状物。用氯仿-甲醇(99∶1)洗脱后,得到5.65g(50%)1-(2-乙氧乙基)-2-(4-苄基-1H-高哌嗪-1-基-甲基)苯并咪唑,用氯仿-甲醇(97∶3)洗脱后,得到4.3g(32%)未反应的起始产物。
1H-NMR(CDCl3):& 1.12(t,3H);1.79(m,2H);2.69(m,8H);3.41(q,2H);3.63(s,2H);3.76(t,2H);3.98(s,2H);4.55(t,2H);7.25(m,8H);7.7(m,1H).
b)1-(2-乙氧乙基)-2-(高哌嗪-1-基甲基)苯并咪唑
在5大气压的氢气环境下,将5.94g(15.15mmol)1-(2-乙氧乙基)-2-(4-苄基-1H-高哌嗪-1-基甲基)苯并咪唑在80ml80%乙酸中的溶液与4.02g5%Pd/C(含水量:50%)一起在60℃下加热16小时。将混合物过滤并蒸发至干。残余物用氯仿浸溶并用20%NaOH洗涤,再用水洗涤,然后用Na2SO4干燥,过滤并蒸发后得到3.65g(80%)1-(2-乙氧乙基)-2-(高哌嗪-1-基-甲基)苯并咪唑。
1H-NMR(CDCl3);& 1.12(t,3H);1.78(m,2H);2.28(broad s,1H);2.74-3.05(m,8H);3.41(q,2H);3.76(t,2H);4.02(s,2H);4.56(t,2H);7.25(m,3H);7.7(m,1H),IR(film):3312,1463,1119,744cm-1
c)1-(2-乙氧乙基)-2-(8-甲基氮杂-5-氮鎓螺环[4,6]十一烷)苯并咪唑
将4g(13.24mmol)1-(2-乙氧乙基)-2-(高哌嗪-1-基-甲基)苯并咪唑,3.29g(15.23mmol)1,4-二溴丁烷和2.5g(18.1mmol)碳酸钾在40ml氯仿中的混合物回流16小时。将混合物冷却,过滤并蒸发。用乙醚研制残余物,得到5.6g(97%)吸湿固体,该固体物不必进一步纯化即可使用。
1H-NMR(CDCl3):& 1.06(t,3H);2.24(m,6H);2.96-3.51(m,8H);3.72-3.90(m,8H);4.15(s,2H);4.53(t,2H);7.30(m,3H);7.74(m,1H),
d)1-(2-乙氧乙基)-2-{4-[4-(吡唑-1-基)丁基]高哌嗪-1-基-甲基}苯并咪唑
将3g(6.86mmol)1-(2-乙氧乙基)-2-(8-甲基氮杂-5-氮鎓螺环[4,6]十一烷)苯并咪唑溴化物、0.56g(8.24mmole)吡唑、1.8g(13mmol)碳酸钾和30ml二甲基甲酰胺的混合物回流16小时。将混合物冷却、过滤并蒸发滤液至干。残余物用氯仿浸溶并用水洗。用机相用Na2SO4干燥、过滤并蒸发。在硅胶色谱柱上纯化所得到的油状物(洗脱剂∶氯仿-甲醇9∶1)。如此得到1.40g(48%)油状1-(2-乙氧乙基)-2-{4-[4-(吡唑-1-基)丁基]高哌嗪-1-基-甲基}苯并咪唑。
用于鉴定该化合物的光谱数据示于表1和表2中。
实施例3.1-(2-乙氧乙基)-2-{4-[4-(4,5-二氯-2-甲基咪唑-1-基)丁基]高哌嗪-1-基-甲基}苯并咪唑的制备
其制备方法与实施例1所示的方法很相似,产率为36%。
用于鉴定该化合物的光谱数据示于表1和表2中。
实施例5.1-(2-乙氧乙基)-2-{4-[4-(4-羧基吡唑-1-基)丁基]高哌嗪-1-基}苯并咪唑的制备
a)1-(2-乙氧乙基)-2-(8-氮杂-5-氮螺环[4,6]十一烷)苯并咪唑
其制备方法与实施例1c所示的方法相同,产率为97%。
1H-NMR(CDCl3):& 1.09(t,3H);1.9-2.4(m,6H);3.42(q,2H);3.82(t,2H);3.9-4.1(m,12H);4.26(t,2H);7.20(m,3H);7.50(m,1H).
b)1-(2-乙氧乙基)-2-{4-[4-(4-乙氧羰基吡唑-1-基)丁基]高哌嗪-1-基}苯并咪唑
其制备方法与实施例1d所示的方法相同,得到的粗产物在硅胶色谱柱上纯化(洗脱剂∶氯仿-甲醇95∶5)。产率为35%。
1H-NMR(CDCl3):& 1.13(t,3H);1.33(t,3H);1.93(m,6H);2.6(t,2H);2.8(m,4H);3.35-3.82(m,8H);4.07-4.4(m,6H);7.1-7.25(m,3H);7.5(m,1H);7.85(s,2H).
在室温下用10%氢氧化钠将如上制得的酯在乙醇中的溶液处理15小时进行水解。蒸发除去醇并用盐酸中和水溶液将其蒸发至干并通过用异丙醇消化从残余物中提取酸。产率87%。熔点>300℃。
用于鉴定该化合物的光谱数据示于表1和表2中。
方法B
实施例2:1-(2-乙氧乙基)-2-{4-[4-(吡咯-1-基)丁基]高哌嗪-1-基-甲基}苯并咪唑的制备
将2.98g(8mmol)1-(2-乙氧乙基)-2-{4-(4-氨基丁基)高哌嗪-1-基-甲基}苯并咪唑和1.06g(8mmol)2,5-二甲氧基四氢呋喃在30ml乙酸中的溶液回流25分钟。将混合物冷却,倒入冰冷的水中,用NaHCO3中和并用氯仿提取。用Na2SO4干燥之并在真空下蒸发至干。将如此得到的3.2g粗化合物在硅胶色谱柱上纯化(洗脱剂∶氯仿-甲醇92∶8)。产率51%。
用于鉴定该化合物的光谱数据与方法C)实施例2中所示的数据相同。
方法C
实施例2.1-(2-乙氧乙基)-2-{4-[4-(吡咯-1-基)丁基]高哌嗪-1-基-甲基}苯并咪唑的制备
将2.42g(8mmol)1-(2-乙氧乙基)-2-(高哌嗪-1-基-甲基)苯并咪唑、1.39g(8.8mmol)1-(4-氯丁基)吡咯1.65g(12mmol)碳酸钾和1.65g(11mmol)碘化钠在40ml甲乙酮中的混合物回流16小时。将混合物冷却、过滤并将滤液蒸发至干。用氯仿浸溶残余物并用水洗涤、干燥、过滤并在真空下蒸发。得到的产物在硅胶色谱柱上纯化(洗脱剂∶氯仿-甲醇92∶8),得到1.9g(56%)1-(2-乙氧乙基)-2-{4-[4-(吡咯-1-基)丁基]高哌嗪-1-基-甲基}苯并咪唑。
用于鉴定该化合物的光谱数据示于表1和表2中。
实施例4.1-(2-乙氧乙基)-2-{4-[4-(吡咯-1-基)丁基]高哌嗪-1-基-}苯并咪唑的制备
其制备方法与上例中的方法极为相似,以49%的产率得到该化合物,其与马来酸所形成的盐具有102-105℃的熔点。
表Ⅰ、2见文后
药理学活性
本发明的目的产物是有效的抗组胺剂,其特征在于它们无镇静作用,这与已知的抗组胺剂是截然不同的。
“体内”抗组胺活性
通过确定对于由产品48/80引起大鼠致死的保护作用研究了抗组胺活性。该试验是按照C.J.E.Niemegeers等人所述的方法(Arch.Int.Pharmacodyn.,234,164-176(1978)进行的。通过腹膜内途径将本发明的目的产物注射给大鼠。60分钟后,给予化合物48/80(0.5mg/kg,静脉内给药)。保护活性被定义为静脉注射化合物48/80后4小时大鼠的存活率。
为了确定能够保护50%动物的剂量(ED-50),以几种不同的剂量研究了产物的活性。
最后,给出实施例1的产物的抗组胺活性。将该活性与difen-hidramine(一种参比抗组胺剂)的活性作比较。
“体内”抗组胺活性:防止48/80诱导的死亡
实施例号 ED 50(mg/kg,i.p.)
1 0.04
Difenhidramine 5.4
镇静作用:1)Irwin试验
为了研究本发明的目的产物是否没有镇静作用,通过腹腔内途径将它们注射给大鼠并按照在SIrwin试验中所述的标准(Science,136.123-128(1962))观察动物的行为。
以下面的两种反映镇静作用的评估试验显示了对实施例1的产物进行检测的结果:
-Pas:被动性、镇静、衰竭。在0至3之间作定量评价。
于处理后1,2和3小时进行。
Atax:共济失调,评估运动协调性的改变。在
0-3之间进行评价。于处理后1,2和3小时进行。
对于本发明实施例1的产物之镇静作用的研究结果以实例方式归纳如下。将该活性与difenhidramine(一种参比抗组胺剂)的活性作比较。该产物有弱的镇静作用,而difenhidramine由于对中枢神经系统的抑制作用,已证明在剂量为80mg/kg(i.p.)时即产生毒性。
镇静作用:1)Irwin试验
实施例号 剂量 作用
Pas Atax
1 (80) 0 0.2
Difenhidramine (40) 0 0.9
(80) 有毒性
镇静作用:2)对戊巴比妥诱导的睡眠持续时间的强化作用
按照L.E.Allen等人所述的方法(Arz.Forsh.24,(6),(1974))进行有关本发明目的产物延长戊巴比妥诱导之睡眠持续时间的研究。口服所研究的产物。1小时后皮下注射戊巴比妥钠(35mg/kg)并测定在动物醒来之前的时间长短。将该睡眠持续时间与只用戊巴比妥钠处理的对照组动物作比较。
为了完成证实本发明的目的产物缺乏镇静作用的研究,在这一试验中将产物之一(实施例1)的活性与参比抗组胺剂difenhidramine进行了比较。用实施例1的产物和difenhidramine所做试验的结果如下所示。显然,difenhidramine在20mg/kg的剂量下可显著延长睡眠持续时间,而实施例1的产物即使在160mg/kg(测得的最大剂量)下也不能延长戊巴比妥诱导的睡眠持续时间。
镇静作用:2)对戊巴比妥诱导的睡眠持续时间的强化作用
实施例号 剂量 睡眠时间的延长
(mg/kg,P.O)
1 80 8%N.S.
160 1%N.S.
Difenhidramine 10 22%N.S.
20 38%*
N.S.:不显著
*:与对照组有显著性差异(P<0.05)
本发明的主题衍生物的特定药物剂型举例如下。
片剂
每片配方
实施例1的化合物 10.00mg
乳糖 54.00mg
玉米淀粉 26.00mg
微晶纤维素 18.00,g
聚乙烯吡咯烷酮 6.00mg
Croscarmellose sodium 3.60mg
胶体二氧化硅 0.60mg
硬脂酸镁 1.20mg
120.00mg
表Ⅰ
实施例号 R1R2n m R 方法 IR(cm-1)
(薄膜)
1 H H 1 4
A 2938,2869,1464,1119,
C 748,619
2 H H 1 4
B 2936,2870,1463,1120,
C 745,725
1120,746
4 H H 0 4
C 马来酸盐(KBr):
3000,2890,1619,1579,
1470,1358
670
1040,750
表2
1.11(t,3H);1.41(m,2H);1.79(m,4H);2.37-2.74
1 (m,10H);3.39(q,2H);3.75(t,2H);3.96(s,2H);
4.12(t,2H);4.55(t,2H);6.22(broad s,1H);
7.2-7.4(m,5H);7.68(m,1H)
1.11(t,3H);1.47(m,2H);1.82(m,4H);2.48
2 (t,2H);2.73(m,8H);3.39(q,2H);3.75(t,2H);
3.87(t,2H);3.97(s,2H);4.53(t,2H);6.11(m,2H);
6.63(m,2H);7.25(m,3H);7.67(m,1H)
1.11(t,3H);1.5-1.9(m,6H);2.36(s,3H);
3 2.5-2.9(m,10H);3.39(q,2H);3.7-3.9(dt,4H);
3.99(s,2H);4.54(t,2H);7.26(m,3H);7.68
(m,1H)
1.13(t,3H);1.46(m,2H);1.95(m,4H);2.52
4 (t,2H);2.79(m,4H);3.34-3.81(m,8H);4.05-4.19
(2t,4H);6.20(m,1H);7.0-7.5(m,6H)
D2O:0.93(t,3H);1.3-2.0(m,6H);2.6(m,2H);
5 2.95(m,4H);3.17-3.62(m,8H);4.11(m,4H);
7.1(m,3H);7.4(m,1H);7.87(s,1H);7.97(s,1m)
1.13(t,3H);1.33(t,3H);1.93(m,6H);2.6
6 (t,2H);2.8(m,4H);3.35-3.82(m,8H);4.07-4.4
(m,6H);7.1-7.25(m,3H);7.5(m,1H);7.85(s,2H)
(m,3H)
Claims (1)
1、制备式Ⅰ的苯并咪唑衍生物的方法,
其中
R1和R2各表示氢,
n可取0或1,
m可取2-4的整数,
X,Y,Z和W相同或不同,其中一个表示氮原子,而其余的表示连接有氢原子,卤素,低级烷基或羧基的碳原子,
所述方法包括:
方法A:使通式Ⅱa的化合物
或通式Ⅱb的化合物
其中R1,R2,n和m具有上述意义,A代表卤原子或选自甲苯磺酰氧基或甲磺酰氧基的离去基团,与通式Ⅲ的化合物反应,
其中X,Y,Z和W具有上述意义;
方法B:使通式Ⅱa的化合物,其中A代表-NH2,R,R2,n和m的定义同上,与2,5-二甲氧基四氢呋喃反应;
方法C:使通式Ⅳ的化合物
其中R1,R2和n具有上述意义,与通式Ⅴ的化合物反应,
其中X,Y,Z,W和m具有上述意义,B代表卤原子或选自甲苯磺酰氧基或甲磺酰氧基的离去基团。
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FR9104171A FR2674856B1 (fr) | 1991-04-05 | 1991-04-05 | Nouveaux antihistaminiques non sedatifs, derives de benzimidazole, leur procede de preparation et leur utilisation en tant que medicaments. |
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IT1264456B1 (it) * | 1993-05-14 | 1996-09-23 | Dompe Farmaceutici Spa | Derivati del 2-(benzimidazol-2-il)-1,3-diaminopropano farmacologicamente attivi. |
FR2727865B1 (fr) * | 1994-12-08 | 1997-07-18 | Esteve Labor Dr | Utilisation des derives de 2-(4-(azolybutyl)-piperazinyl- (methyl))-benzimidazole et analogues ainsi que de leurs sels, pour la preparation de medicaments destines au traitement ou a la prophylaxie de l'asthme |
US5773616A (en) * | 1995-02-15 | 1998-06-30 | Neurogen Corporation | Certain bridged 4-phenyl-2-aminomethylimidazoles; new dopamine receptor subtype specific ligands |
EP0809641A1 (en) * | 1995-02-15 | 1997-12-03 | Neurogen Corporation | Certain bridged 4-phenyl-2-aminomethylimidazoles; new dopamine receptor subtype specific ligands |
FR2731618B1 (fr) * | 1995-03-14 | 1997-08-01 | Esteve Labor Dr | Composition ophtalmique topique comprenant un derive de 2-(4-(azolylbutyl)-piperazinyl-methyl)-benzimidazole, notamment pour le traitement de la conjonctivite allergique |
US6211199B1 (en) | 1995-11-17 | 2001-04-03 | Aventis Pharmaceuticals Inc. | Substituted 4-(1H-benzimidazol-2-yl-amino)piperidines useful for the treatment of allergic diseases |
US6194406B1 (en) | 1995-12-20 | 2001-02-27 | Aventis Pharmaceuticals Inc. | Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic disease |
US6423704B2 (en) | 1995-12-20 | 2002-07-23 | Aventis Pharmaceuticals Inc. | Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic diseases |
US5998439A (en) * | 1996-02-21 | 1999-12-07 | Hoescht Marion Roussel, Inc. | Substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamides useful for the treatment of allergic diseases |
US5932571A (en) * | 1996-02-21 | 1999-08-03 | Hoechst Marion Roussel, Inc. | Substituted N-methyl-N-(4-(4-(1H-benzimidazol-2-yl) {1,4}diazepan-1-yl)-2-(aryl) butyl) benzamides useful for the treatment of allergic diseases |
US5922737A (en) * | 1996-02-21 | 1999-07-13 | Hoechst Marion Roussel, Inc. | Substituted N-methyl-N-(4-(4-(1H-Benzimidazol-2-YL-amino) piperidin-1-YL)-2-(arlyl) butyl) benzamides useful for the treatment of allergic diseases |
TWI225488B (en) * | 1999-12-21 | 2004-12-21 | Janssen Pharmaceutica Nv | Derivatives of homopiperidinyl substituted benzimidazole analogues |
EE05082B1 (et) * | 2000-01-19 | 2008-10-15 | Cadila Healthcare Ltd. | Pürroolirea ühend, selle valmistamine ja kasutamine lipiidi- ja kolesteroolitaset alandava ravimi valmistamiseks ning seda sisaldav farmatseutiline kompositsioon |
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CN101089000B (zh) * | 2006-06-16 | 2011-01-05 | 北京大学 | 螺环哌嗪季铵盐类化合物及其制备方法和应用 |
CA2765114A1 (en) * | 2009-06-11 | 2010-12-16 | Siena Biotech S.P.A. | Hedgehog pathway antagonists and therapeutic applications thereof |
KR102115060B1 (ko) * | 2012-12-27 | 2020-05-25 | 알즈프로텍트 | N-(3-(4-(3-(디이소부틸아미노)프로필)피페라진-1-일)프로필)-1H-벤조[d]이미다졸-2-아민의 황산염들, 이들의 제조 방법 및 그것의 용도 |
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DE3336409A1 (de) * | 1983-10-06 | 1985-04-18 | Ludwig Heumann & Co GmbH, 8500 Nürnberg | Chinazolinderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
US5010075A (en) * | 1987-04-24 | 1991-04-23 | Syntex Pharmaceuticals Ltd. | Substituted imidazolyl-alkyl-piperazine and -diazepine derivatives |
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