CN112010925B - Gde及羟甲基修饰的苯并咪唑喹唑啉，其合成，活性和应用 - Google Patents
Gde及羟甲基修饰的苯并咪唑喹唑啉，其合成，活性和应用 Download PDFInfo
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Abstract
GDE及羟甲基修饰的苯并咪唑喹唑啉,其合成,活性和应用。本发明公开了下式的6‑羟甲基‑6‑(Glu‑Asp‑Gly‑OCH2)‑5,6‑二氢苯并[4,5]咪唑[1,2‑c]喹唑啉,公开了它的制备方法,公开了它的免疫抑制活性，公开了它可延长小鼠耳后移植心肌的存活时间，因而本发明公开了它在制备免疫抑制剂中的应用。
。
Description
技术领域
本发明涉及6-羟甲基-6-(Glu-Asp-Gly-OCH2)-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉,涉及它的制备方法，涉及它的免疫抑制活性。因而本发明涉及该化合物在制备免疫抑制药物中的应用。本发明属于生物医药领域。
背景技术
上世纪60年代,第一例器官移植手术的成功。经过数十年发展,使丧失器官功能的患者得到救治。可是,人体自身免疫系统对异体器官的免疫排斥反应严重影响患者近期和远期健康。最终,免疫排斥反应影响移植术后患者的生存时间。如何避免这种免疫排斥反应至关重要。虽然临床实施了各种措施,但是成效并不理想。以肾移植为例,虽然通过血浆置换和使用强效免疫抑制剂干预急性的细胞排斥和体液排斥可得到有效控制,但这种治疗对慢性排斥反应疗效果尚不理想。这样一来,发明新型免疫抑制剂受到广泛重视。同样, 发明新型免疫抑制剂的效果也不理想。出于对发明新型免疫抑制剂的兴趣,发明人一直致力于用肽修饰含N杂环。经过3年探索,发明人发现,发明人设计该化合物的目的是将两个具有免疫抑制活性的结构进行拼合,得到一种新型免疫抑制剂。发明人发现用羟甲基和 Glu-Asp-Gly-OCH2修饰5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉生成的下式的6-羟甲基 -6-(Glu-Asp-Gly-OCH2)-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉在小鼠耳后心肌移植实验模型中显示优秀的活性。根据这个发现,发明人提了出本发明。
发明内容
本发明的第一个内容是提供6-羟甲基-6-(Glu-Asp-Gly-OCH2)-5,6-二氢苯并[4,5]咪唑 [1,2-c]喹唑啉。
本发明的第二个内容是提供6-羟甲基-6-(Glu-Asp-Gly-OCH2)-5,6-二氢苯并[4,5]咪唑 [1,2-c]喹唑啉的制备方法，该方法包括：
1)合成(6,6-二羟甲基-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
2)合成6-羟甲基-6-[Boc-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
3)合成6-羟甲基-6-[Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
4)合成6-羟甲基-6-[Boc-Asp(OBzl)-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
5)合成6-羟甲基-6-[Asp(OBzl)-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
6)合成6-羟甲基-6-[Boc-Glu(OBzl)-Asp(OBzl)-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
7)合成6-羟甲基-6-[Boc-Glu-Asp-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
8)合成6-羟甲基-6-(Glu-Asp-Gly-OCH2)-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
本发明的第三个内容是评价6-羟甲基-6-(Glu-Asp-Gly-OCH2)-5,6-二氢苯并[4,5]咪唑 [1,2-c]喹唑啉免疫抑制的作用。
附图说明
图1.6-羟甲基-6-(Glu-Asp-Gly-OCH2)-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉的合成路线.(i)2M 盐酸溶液,1,3-二羟基丙酮；(ii)二环己基碳二亚胺,1-羟基苯并三唑,Boc-Gly,N-甲基吗啉；(iii)4M氯化氢的乙酸乙酯溶液；(iv)二环己基碳二亚胺,1-羟基苯并三唑,Boc-Asp(OBzl),N-甲基吗啉；(v)二环己基碳二亚胺,1-羟基苯并三唑,Boc-Glu(OBzl),N-甲基吗啉；(vi)Pd/C,H2。
具体实施方式
为了进一步阐述本发明，下面给出一系列实施例。这些实施例完全是例证性的，它们仅用来对本发明进行具体描述，不应当理解为对本发明的限制。
实施例1制备(6,6-二羟甲基-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉(1)
将6.40g(30.6mmol)2-(2-氨基苯基)-1H-苯并咪唑与100mL甲醇悬浮,向该悬浮液加入2.76g(30.7mmol)1,3二羟基丙酮。反应混合物用2M盐酸调pH为2,此时反应液变为绿色。反应混合物室温搅拌12小时,TLC(二氯甲烷/甲醇＝20/1)显示原料点消失,并有大量黄绿色固体析出。终止反应,向反应液中滴加4M氢氧化钠水溶液将反应液的pH调至中性,过滤,得到7.03g标题化合物,为黄绿色固体。滤液减压浓缩并过滤,再得到2.52g 标题化合物,为深绿色固体。本步反应的产率为100％。ESI-MS(m/e):282[M+H]+。[α]2D5 ＝-10.00(c＝0.1CH3OH)。Mp＝214-215℃。1H-NMR(300MHz,DMSO-d6):δ/ppm＝7.86(d,J＝ 7.2Hz,1H),7.69(m,1H),7.59(m,1H),7.15(m,3H),6.85(d,J＝8.1Hz,1H),6.70(m,2H), 5.26(t,J＝5.4,2H),4.08(dd,J1＝6.0Hz,J2＝5.7Hz,2H),3.82(dd,J1＝5.7Hz,J2＝6.0Hz, 2H)。
实施例2制备6-羟甲基-6-[Boc-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉(2)
将525mg(3.00mmol)Boc-Gly,741mg(3.60mmol)二环己基碳二亚胺和405mg(3.00mmol)1-羟基苯并三唑用40mL DMF溶解。得到的溶液于冰浴搅拌30分钟,之后加1.12g(4.00mmol)6,6-二羟甲基-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉(1)。反应混合物用N-甲基吗啉调pH为7-8。之后,反应混合物室温搅拌12小时,TLC(二氯甲烷/甲醇＝20/1)显示Boc-Gly消失。反应混合物减压浓缩,残留物用50mL乙酸乙酯溶解,过滤,滤液用饱和碳酸氢钠水溶液洗(30mL×3),饱和氯化钠水溶液洗(30mL×3),用无水硫酸钠干燥12小时, 过滤,滤液减压浓缩,残留物用二氯甲烷稀释,超声,过滤,滤液减压浓缩,残留物经硅胶柱层析纯化(二氯甲烷/甲醇＝80/1),得到1.15g(87.2％)标题化合物,为淡黄绿色固体。 ESI-MS(m/e):439[M+H]+。1H-NMR(300MHz,DMSO-d6):δ/ppm＝7.87(d,J＝7.5Hz,1 H),7.70(m,1H),7.61(m,1H),7.17(m,3H),7.10(t,J＝5.7Hz,1H),6.95(s,1H),6.84(d,J ＝7.8Hz,1H),6.77(t,J＝7.5Hz,1H),5.54(t,J＝5.7Hz,1H),4.70(d,J＝11.7Hz,1H), 4.50(d,J＝12.0Hz,1H),4.41(dd,J1＝6.6Hz,J2＝5.1Hz,1H),3.93(dd,J1＝6.6Hz,J2＝ 5.1Hz,1H),3.40(m,2H),1.33(s,8H),1.22(s,1H)。
实施例3制备6-羟甲基-6-[Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉(3)
将581mg(1.30mmol)6-羟甲基-6-[Boc-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉 (2)用1mL无水乙酸乙酯溶解,冰浴下加10mL氯化氢乙酸乙酯溶液(4M),反应4小时后 TLC(二氯甲烷/甲醇＝20/1)显示化合物2消失,反应液减压浓缩,残留物用无水乙酸乙酯溶解,再减压浓缩,残留物再用无水乙酸乙酯溶解。该操作重复3次。残留物分散在10mL无水乙醚中,静置,弃乙醚,得到490mg(100％)标题化合物,为绿色固体。ESI-MS(m/e)： 339[M+H]+。
实施例4制备6-羟甲基-6-[Boc-Asp(OBzl)-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉(4)
将517mg(1.60mmol)的Boc-Asp(OBzl),330mg(1.60mmol)二环己基碳二亚胺和216mg(1.60mmol)1-羟基苯并三唑用20mL无水四氢呋喃溶解。得到的溶液于冰浴搅拌30分钟,之后加450mg(1.30mmol)的6-羟甲基-6-[Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉(3)。反应混合物用N-甲基吗啉调pH为7-8。之后,反应混合物室温搅拌12小时,TLC(二氯甲烷/甲醇＝20/1)显示化合物3消失。反应混合物减压浓缩,残留物用50mL乙酸乙酯溶解,过滤,滤液用饱和碳酸氢钠水溶液洗(30mL×3),饱和氯化钠水溶液洗(30mL×3),用无水硫酸钠干燥12小时,过滤,滤液减压浓缩,残留物用二氯甲烷稀释,超声,过滤,滤液减压浓缩,残留物经硅胶柱层析纯化(二氯甲烷/甲醇＝80/1),得到546mg(65.3％)标题化合物,为淡黄色固体。ESI-MS(m/e):644[M+H]+。1H-NMR(300MHz,DMSO-d6):δ/ppm＝8.13 (m,1H),7.89(d,J＝7.2Hz,1H),7.71(m,1H),7.62(m,1H),7.35(s,5H),7.19(m,4H), 6.94(s,1H),6.86(d,J＝8.1Hz,1H),7.77(t,J＝7.5Hz,1H),5.55(t,J＝6.6,1H),5.07(s,2 H),4.68(d,J＝11.7Hz,1H),4.51(d,J＝11.7Hz,1H),4.36(m,1H),4.15(dd,J1＝6.6Hz,J2＝4.8Hz,1H),3.96(dd,J1＝6.6Hz,J2＝4.8Hz,1H),3.58(m,2H),2.58(m,2H),1.36(s,9 H)。
实施例5制备6-羟甲基-6-[Asp(OBzl)-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉(5)
188mg(0.300mmol)的6-羟甲基-6-[Boc-Asp(OBzl)-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑 [1,2-c]喹唑啉(4)用1mL无水乙酸乙酯溶解,冰浴下加10mL氯化氢乙酸乙酯溶液(4M), 反应4小时后TLC(二氯甲烷/甲醇＝20/1)显示化合物4消失,反应液减压浓缩,残留物用无水乙酸乙酯溶解,再减压浓缩,残留物再用无水乙酸乙酯溶解。该操作重复3次。残留物分散在10mL无水乙醚中,静置,弃乙醚,得到175mg(100％)标题化合物,为绿色固体。ESI-MS(m/e):544[M+H]+。
实施例6制备6-羟甲基-6-[Boc-Glu(OBzl)-Asp(OBzl)-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑 [1,2-c]喹唑啉(6)
将120mg(0.350mmol)的Boc-Glu(OBzl)-OH,70mg mg(0.350mmol)二环己基碳二亚胺和47mg(0.350mmol)1-羟基苯并三唑用15mL无水四氢呋喃溶解。得到的溶液于冰浴搅拌30分钟,之后加175mg(0.300mmol)的6-羟甲基-6-[Asp(OBzl)-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉(5)。反应混合物用N-甲基吗啉调pH为7-8。之后,反应混合物室温搅拌12小时,TLC(二氯甲烷/甲醇＝20/1)显示化合物5消失。反应混合物减压浓缩,残留物用50mL乙酸乙酯溶解,过滤,滤液用饱和碳酸氢钠水溶液洗(30mL×3),饱和氯化钠水溶液洗(30mL×3),用无水硫酸钠干燥12小时,过滤,滤液减压浓缩,残留物用二氯甲烷稀释,超声,过滤,滤液减压浓缩,残留物经硅胶柱层析纯化(二氯甲烷/甲醇＝80/1),得到 81.0mg(32.3％)标题化合物,为淡黄色固体。ESI-MS(m/e):863[M+H]+。
＝+6.6(c＝0.1CH3OH)。Mp＝101-103℃。1H-NMR(300MHz,DMSO-d6):δ/ppm＝8.18(m,2H),7.89(d,J＝4.5Hz,1H),7.71(m,1H),7.62(m,1H),7.33(s,10H),7.18(m,3H),7.04(d,J＝7.2Hz,1 H),6.94(m,1H),6.87(d,J＝9.9Hz,1H),6.77(t,J＝7.5Hz,1H),5.06(d,J＝5.1Hz,4H), 4.65(d,J＝11.7Hz,2H),4.51(d,J＝11.7Hz,1H),4.17(m,1H),3.96(m,2H),3.60(m,2 H),2.73(m,2H),2.37(t,J＝6.9Hz,2H),1.86(m,2H),1.34(s,9H)。13C-NMR(300MHz, DMSO-d6):δ/ppm＝172.7,171.9,171.0,170.3,169.4,155.9,147.9,144.4,143.4,136.7,136.4,131.9,128.8,128.4,128.2,125.0,122.6,122.3,119.2,118.3,114.8,113.0,111.6,78.9,76.3, 66.2,65.9,65.4,63.6,54.1,49.6,36.6,30.5,28.6,27.4。
实施例7制备6-羟甲基-6-[Boc-Glu-Asp-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉 (7)
将150mg(0.170mmoL)的6-羟甲基-6-[Boc-Glu(OBzl)-Asp(OBzl)-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉(6)用5mL甲醇溶解,向得到的溶液中加15mg Pd/C,通氢气,室温搅拌2小时,TLC(二氯甲烷/甲醇＝20/1)显示反应完全。反应液过滤,滤液减压浓缩, 得到120mg(100％)标题化合物,为绿色固体。ESI-MS(m/e)：683[M+H]+。
实施例8制备6-羟甲基-6-[Glu-Asp-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉(8)
将120mg(0.170mmol)6-羟甲基-6-[Boc-Glu-Asp-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑 [1,2-c]喹唑啉(7)用1mL无水乙酸乙酯分散,冰浴下加10mL氯化氢乙酸乙酯溶液(4M), 反应4小时后TLC(乙酸乙酯/水/冰醋酸＝2/1/1)显示化合物7消失,反应液减压浓缩,残留物用无水乙酸乙酯溶解,再减压浓缩,残留物再用无水乙酸乙酯溶解。该操作重复3次。残留物分散在10mL无水乙醚中,静置,弃乙醚,得到绿色固体用C18柱纯化(水/甲醇＝75/25),馏分冻干得到42mg(42.5％)标题化合物,为绿色固体。ESI-MS(m/e):582[M+H]+。
＝-9.9(c＝0.1CH3OH)。Mp＝181-182℃。IR(cm-1):3301.90,307.53,2947.56,2112.83,1750.18,1668.76,1614.41,1561.24,1480.50,1449.44,1386.32,1313.97,1270.31,1178.70, 1065.65,1015.65,823.89,741.95,699.44。1H-NMR(300MHz,DMSO-d6):δ/ppm＝12.3(s,2 H),8.82(m,1H),8.35(m,4H),8.11(d,J＝7.8Hz,1H),8.00(d,J＝6.9Hz,1H),7.77(d,J＝ 7.2Hz,1H),7.71(s,1H),7.43(m,3H),6.94(d,J＝8.1Hz,1H),6.86(t,J＝7.5Hz,1H), 4.80(d,J＝12.3Hz,1H),4.55(d,J＝12.6Hz,1H),4.49(s,1H),4.30(d,J＝12.3Hz,1H), 4.00(m,2H),3.78(s,1H),3.61(m,2H),2.62(m,2H),2.37(t,J＝0.6Hz,2H),1.94(m,2 H)。13C-NMR(300MHz,DMSO-d6):δ/ppm＝174.8,172.4,171.6,169.5,147.9,144.4,143.4, 133.5,131.9,125.0,122.6,122.4,119.2,118.2,114.9,112.9,111.5,76.4,65.2,63.5,53.6,49.8, 37.3,31.2,28.9。
实施例9评价化合物8的免疫抑制作用
雄性Balb/c小鼠(20±2g)用10％乌拉坦(10mg/10g体重)腹腔注射麻醉。用75％酒精为小鼠耳廓局部消毒。于耳廓背侧中线约1/3处剪开一个与耳廓中线垂直的长3-4毫米口, 注意不要损伤耳廓静脉。通过该开口向耳尖方向钝性分离皮下组织使之成一人工管腔。将 C57bl/6j供心乳鼠于碎冰中冻一分钟,用75％酒精消毒皮肤,剖胸后摘取心脏。将心脏置于铺有生理盐水润湿纱布的表面皿中内搏动,使排净心腔中的余血。将供乳鼠心脏纵向剖成基本等大的肌纤维呈斜面的两瓣心肌。将心肌填入Balb/c受体鼠的人工管腔。操作时心肌组织离体时间不超过2分钟。轻按填有心肌的人工管腔,排出多余的生理盐水及气泡, 使移植心肌贴紧受体鼠耳部周围组织。心肌移植术的当天开始口服化合物8(剂量为0.1μmol/kg/天)或口服环孢菌素A(剂量为2.5μmol/kg/天)或口服生理盐水。连续给药至移植心肌的心电图消失。
心肌移植术的第七日起,每天用生物信号二道仪测量移植心肌组织的心电信号(若第七日至以后都没有心电信号则判定心肌移植手术失败)。测量异位心电图时,正负电极分别置于移植心肌组织的两侧,接地极连接在小鼠后肢。移植心肌组织心电信号全部消失后结束异位心电图测量,统计移植心肌存活时间(均值±SD),结果见表1。可见在0.1μmol/kg/天剂量下化合物8延长移植心肌存活的活性与生理盐水具有差异，本发明具有一定的技术效果。
表1化合物8对小鼠耳后心肌移植存活时间的影响
a)与生理盐水相比P<0.01；b)与生理盐水相比P<0.05；n＝12。
Claims (3)
1.下式的6-羟甲基-6-(Glu-Asp-Gly-OCH2)-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉,
2.权利要求1的6-羟甲基-6-(Glu-Asp-Gly-OCH2)-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉的制备方法,该方法包括:
2.1.合成(6,6-二羟甲基-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
2.2.合成6-羟甲基-6-[Boc-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
2.3.合成6-羟甲基-6-[Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
2.4.合成6-羟甲基-6-[Boc-Asp(OBzl)-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
2.5.合成6-羟甲基-6-[Asp(OBzl)-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
2.6.合成6-羟甲基-6-[Boc-Glu(OBzl)-Asp(OBzl)-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
2.7.合成6-羟甲基-6-[Boc-Glu-Asp-Gly-OCH2]-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉；
2.8.合成6-羟甲基-6-(Glu-Asp-Gly-OCH2)-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉。
3.权利要求1的6-羟甲基-6-(Glu-Asp-Gly-OCH2)-5,6-二氢苯并[4,5]咪唑[1,2-c]喹唑啉在制备免疫抑制剂中的应用。
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| DE2058185A1 (de) * | 1969-11-24 | 1971-06-03 | Lilly Co Eli | Immunosuppressive Mittel aus Benzimidazo[2,1-b]chinazolin-12(6H)onen und neue Benzimidazo[2,1-b] chinazolin-12(6H)one |
| DE602007005356D1 (de) * | 2006-01-13 | 2010-04-29 | Crysoptix Kk | 6,7-dihydrobenzimidazoä1,2-cüchinazolin-6-oncarbonsäuren, ihre ester und verfahren zu ihrer synthese |
| CN106349244A (zh) * | 2015-07-13 | 2017-01-25 | 首都医科大学 | 苯并咪唑并喹唑啉二甲氧苯氧乙酰-AA-OBzl，其合成，活性和应用 |
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| DE2058185A1 (de) * | 1969-11-24 | 1971-06-03 | Lilly Co Eli | Immunosuppressive Mittel aus Benzimidazo[2,1-b]chinazolin-12(6H)onen und neue Benzimidazo[2,1-b] chinazolin-12(6H)one |
| DE602007005356D1 (de) * | 2006-01-13 | 2010-04-29 | Crysoptix Kk | 6,7-dihydrobenzimidazoä1,2-cüchinazolin-6-oncarbonsäuren, ihre ester und verfahren zu ihrer synthese |
| CN106349244A (zh) * | 2015-07-13 | 2017-01-25 | 首都医科大学 | 苯并咪唑并喹唑啉二甲氧苯氧乙酰-AA-OBzl，其合成，活性和应用 |
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