CN108148085B - 具有抑制磷酸二酯酶4的化合物、制法及其药物用途 - Google Patents
具有抑制磷酸二酯酶4的化合物、制法及其药物用途 Download PDFInfo
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- CN108148085B CN108148085B CN201810007608.5A CN201810007608A CN108148085B CN 108148085 B CN108148085 B CN 108148085B CN 201810007608 A CN201810007608 A CN 201810007608A CN 108148085 B CN108148085 B CN 108148085B
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- C—CHEMISTRY; METALLURGY
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/027—Organoboranes and organoborohydrides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
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Abstract
本发明涉及药物化学领域,具体涉及一类具有抑制磷酸二酯酶4的小分子化合物(I)、制备方法及含有该化合物的药物组合物,药效学试验证明,本发明的化合物具有PDE‑4酶的抑制活性和炎症治疗功效。
Description
技术领域
本发明涉及药物化学领域,具体涉及一类具有抑制磷酸二酯酶4的小分子化合物、制备方法及含有该化合物的药物组合物和治疗用途。
背景技术
炎症是一种常见的病理过程,体表的外伤感染和各器官的大部分常见病和多发病(如疖、痈、肺炎、肝炎、肾炎等)都属于炎症性疾病[Cruz-Migoni S,J.Fat-Associated Lymphoid Clusters in Inflammation and Immunity[J].FrontImmunol.2016,7:612]。目前临床针对炎症性疾病的治疗主要手段是外用或者全身激素类药物,这类药物具有明显的副作用。寻找和发现抗炎活性更强的非激素类药物一直是药物开发者的目标。
磷酸二酯酶4(PDE4)是在中性粒细胞和T细胞中表达的主要的PDE,这启示PDE4抑制剂能够有效地控制炎症。抑制炎症细胞中的PDE4能影响各种特异性应答,例如促炎介体包括细胞因子和活性氧的产生或释放,在哮喘、COPD、炎性肠病、特应性皮炎、银屑病和类风湿性关节炎的治疗中具有显著的效果。但是目前临床使用的PDE4同工酶抑制剂,例如咯利普兰、吡拉米司特、CDP-840和艾利福等,都或多或少存在呕吐、肝毒性、皮肤刺激性等副作用,药物临床试验失败,要么临床应用受到限制。寻找新的高效低毒的磷酸二酯酶-4抑制剂,用于治疗炎症性疾病仍然十分必要。
US20060234981公开了一类含硼的小分子化合物1(Crisaborole),具有抑制PDE4酶和抗炎活性。本人前期公布专利CN106831840中的化合物2(Y5),展现出了优于Crisaborole的抗炎活性。本发明设计并合成了一系列新的化合物,并意外发现这些化合物表现出显著优于Crisaborole和Y5的效果和作用。
发明内容
本发明在前期研究的基础上,设计并合成了一类通式(I)的化合物,药效学实验证明,本发明的化合物具有抑制磷酸二酯酶4的活性,具有预防和治疗炎症相关疾病的用途。
下面详细描述本发明。
本发明公开了通式(I)的化合物:
其中
R1、R2、R3代表任意取代的卤素、C1~C6的烷基、三氟甲基、氰基、氨基、C(O)ORa、CORa或ORa;
Ra代表H、C1~C6的烷基、氨基或三氟甲基;
X为N或CH。
本发明优选下列结构化合物:
其中R1、R2的定义同前。
本发明还优选下列化合物:
其中R1、R2的定义同前。
部分优选的化合物如下:
本发明化合物及其药用盐选择碱金属或者碱土金属,氨基酸或者含有氨基的碱性化合物形成的盐,或者医药上允许的无机酸或者有机酸形成的盐,优选为钾盐,钠盐,铵盐,盐酸、硫酸、磷酸盐、氢溴酸、马来酸、富马酸、枸橼酸、甲磺酸、对甲苯磺酸、酒石酸或醋酸盐。
本发明的化合物或其药用盐和药学上可接受载体的药物组合物在制备治疗炎症性疾病中的应用。
含有本发明化合物治疗或预防炎症性疾病的药物组合物,其中含有治疗有效量的式I化合物或其药用盐和药学上可接受的载体。所述药物组合物可以是普通片剂或胶囊、缓释片剂或胶囊、控释片剂或胶囊、颗粒剂、口服液、糖浆剂、栓剂、透皮制剂、注射剂等制剂学上常规的制剂形式。
本发明化合物制备方法如下:
步骤1:在碱催化剂和氮气保护存在下,缩合化合物1和2-溴-5羟基苯甲醛,所用碱例如碳酸钾、碳酸铯、碳酸钠、氢化钠、叔丁醇钾等。溶剂可用DMF、DMA等,反应温度100℃~120℃。
步骤2:将化合物2用二氧六环溶解,然后加入频哪醇硼酸酯、乙酸钾、钯试剂,氮气氛围下100℃搅拌2小时反应完全得到化合物3
步骤3:将化合物3用甲醇溶解,缓慢加入硼氢化钠,室温搅拌0.5h。再加入3M盐酸,白色固体析出,得到化合物4。
其他化合物的制备可参考上述方法。
生物学评价通过以下实验数据说明本发明化合物的有益效果。
本发明化合物对PDE4酶的抑制作用
使用从Sf9昆虫细胞中使用N-末端GST标记由杆状病毒表达的PDE4A酶。在新制备的pH7.5Tris缓冲液中加入指定的PDE4A酶和1mM cAMP,将酶溶液输送到反应孔中,将化合物在DMSO中超声溶解然后加入至酶溶液中,在室温下孵育10分钟,将底物溶液倒入反应孔中以引发反应,在室温下孵育1小时,加入检测示踪剂(AMP2/GMP2AlexaFluor 633Tracer)和抗体(AMP2/GMP2Antibody)以终止反应,并温和混合孵育90分钟。在Ex/Em620/688处测量荧光偏振,1、0.1、0.01Μm浓度下测试实验物。酶活性小于50%,视作具有显著抑制活性。
实验结果见下表1,
表1本发明化合物对PDE4酶的抑制活性
(与Crisaborole相比,*P<0.05,**P<0.01;与Y5比较:#P<0.01,##P<0.01)
通过检测本发明化合物对PDE4酶的抑制活性,结果发现,本发明化合物在各浓度下对PDE4酶的抑制活性均优于Crisaborole和Y5,其中化合物PD-4~PD-9、PD-14~PD-25、PD-28在三个浓度下对PDE4酶的抑制率超过90%。
本发明化合物对DNCB诱导皮炎小鼠模型
选取雌性BALB/C小鼠,体重18-22g,动物适应性饲养7天后,随机分为空白组、模型组、阳性药Crisaborole组、地塞米松组、各化合物组,每组8只。除空白组小鼠外,其余小鼠用100μL 1%DNCB溶液[丙酮:橄榄油=4:1(V/V)]涂抹于剃毛处小鼠背部皮肤,连续涂抹3天,每天一次。随后小鼠饲养4天后开始给药治疗,各组动物背部涂抹受试药物,空白组、模型组动物涂抹相应溶媒,阳性药Crisaborole组、地塞米松组动物涂抹50mg/mL相应药物,给药组涂抹50mg/mL相应化合物,每只小鼠100μL,涂抹药物4小时后在涂抹0.5%DNCB溶液进行二次激发,重复给药及激发处理11次,每天一次。末次给药24小时后,处死动物取背部皮肤(1×0.4cm2),于10%福尔马林缓冲液中固定,制作病理切片,进行HE染色,100倍电镜下观察分别观察表皮层及真皮层,分别选5个区域进行检测并记录皮肤厚度,取平均值分别表示最终表皮层厚度及真皮层厚度。
结果可知,与模型组比较,本发明的化合物、地塞米松及Crisaborole、化合物Y5均能显著的降低DNCB诱导的特应性皮炎小鼠皮肤表皮及真皮层厚度(P<0.01);
具体结果见表2:
表2本发明化合物对DNCB诱导特应性皮炎小鼠皮肤厚度的影响(Mean±SD,n=8)
(注:△P<0.05,△△P<0.01,vs.空白组;*P<0.05,**P<0.01,vs.模型组;#P<0.05,##P<0.01,vs.Crisaborole组;aP<0.05,aaP<0.01,vs.化合物Y5组)
与Crisaborole比较,化合物PD-1、PD-4、PD-6、PD-7、PD-8、PD-10、PD-12、PD-14、PD-15、PD-16、PD-17、PD-21、PD-29、PD-30能极显著降低表皮厚度(P<0.01),PD-9、PD-24、PD-25、PD-26、PD-31、PD-32、PD-33、化合物Y5能显著降低皮炎小鼠表皮厚度(P<0.05);化合物PD-1、PD-4、PD-6、PD-7、PD-8、PD-10、PD-12、PD-14、PD-15、PD-16、PD-17、PD-21、PD-26、PD-29、PD-30、PD-31、PD-33、化合物Y5能极显著降低皮炎小鼠真皮厚度(P<0.01),PD-3、PD-9、PD-24、PD-25、PD-32能显著降低皮炎小鼠真皮厚度(P<0.05)。
与化合物Y5比较,化合物PD-1、PD-4、PD-6、PD-7、PD-8、PD-12、PD-14、PD-15、PD-21、PD-29能极显著降低表皮厚度(P<0.01),化合物PD-16能显著降低表皮厚度(P<0.05);化合物PD-4、PD-6、PD-7、PD-12、PD-14、PD-15、PD-17、PD-29能极显著降低皮炎小鼠真皮厚度(P<0.01),PD-1、PD-8、PD-16、PD-21、PD-33能显著降低皮炎小鼠真皮厚度(P<0.05)。
提示所发明的化合物具有较好的抗特应性皮炎作用,部分化合物作用活性优于Crisaborole及化合物Y5,具有良好的开发前景。
具体实施方式
实施例1
PD-1的制备
步骤1中间体2的制备
50mL单口瓶加入1(4.5g,21.7mmol),碘甲烷(4.58g,32.55mmol),加入30mLDMF溶解。再加入碳酸钾(6.03g,43.4mmol),100℃搅拌2h,TLC检测反应完全,乙酸乙酯萃取,饱和食盐水洗涤三次,有机层干燥,过滤,浓缩,得产物4.2g,收率87.5%。
步骤2中间体3的制备
50mL单口瓶加入2(4.2g,20mmol),2-溴-5羟基苯甲醛(4g,20mmol),加入50mLDMF溶解。再加入碳酸钾(2.56g,8mmol),氮气氛围下100℃搅拌过夜,TLC检测反应完全,乙酸乙酯萃取,饱和食盐水洗涤三次,有机层干燥,过滤,浓缩,柱层析得产物1.5g,收率20%。
步骤3中间体4的制备
50mL单口瓶加入3(1.46g,3.79mmol),频那醇硼酸酯(1.16g,4.55mmol),加入20mL二氧六环溶解。再加入乙酸钾(1.3g,7.58mmol),钯试剂(277mg,0.38mmol),氮气氛围下100℃搅拌2小时,TLC检测反应完全,乙酸乙酯萃取,饱和食盐水洗涤三次,有机层干燥,过滤,浓缩,柱层析得产物1.6g,收率97%。
步骤4PD-1的制备
50mL单口瓶加入4(1.6g,3.79mmol),加入20mL甲醇溶解,缓慢加入硼氢化钠(168mg,4.55mmol),室温搅拌0.5h。再加入3M盐酸,白色固体析出,继续反应2小时,抽滤,水洗三遍,烘干得产物PD1(0.8g,63%)。1HNMR 400MHz(DMSO-d6)δ:9.20-9.22(m,2H),8.10-8.12(m,1H),7.74-7.90(m,3H),7.44-7.46(s,1H),7.32(d,1H),7.22-7.25(m,1H),5.01(s,2H),3.96(s,3H).
实施例2
PD-2的合成
参照实施例1的方法,以2-氯喹啉-5-羧酸为原料,制得PD-2(70mg,收率13%)。1HNMR400MHz(DMSO-d6)δ:13.42(s,1H),9.33-9.35(d,1H),9.22(s,1H),8.08-8.14(m,1H),7.81-7.88(m,2H),7.73-7.77(m,1H),7.42-7.44(d,1H),7.32(s,1H),7.23-7.25(m,1H),5.02(s,2H).
实施例3
PD-3的合成
参照实施例1的方法,以2-氯喹啉-5-羧酸乙酯为原料,制得PD-3(70mg,13%),1HNMR400MHz(DMSO-d6)δ:9.20-9.22(m,2H),8.11-8.14(d,1H),7.74-7.90(m,3H),7.44-7.46(d,1H),7.32(s,1H),7.23-7.25(m,1H),5.01(s,2H),4.41-4.46(m,2H),1.38-1.42(m,3H)。
实施例4
化合物PD-4的合成
参照实施例1的方法,以2-氯-6-氰基喹啉为原料,制得PD-4(56mg,10%)。1HNMR400MHz(DMSO-d6)δ:9.24(s,1H),8.86(s,1H),8.53-8.55(d,1H),7.94-7.97(m,1H),7.82-7.84(d,1H),7.75-7.77(d,1H),7.46-7.48(d,1H),7.34(s,1H),7.24-7.26(d,1H),5.03(s,2H)。
实施例5
PD-5的合成
参照实施例1的方法,以2-氯喹啉-4-羧酸甲酯为原料,制得PD-5(34.0mg,62.8%)。1HNMR 400MHz(DMSO-d6)δ:9.22(s,1H),8.49(d,J=8.28Hz,1H),7.82(d,J=7.78Hz,1H),7.71-7.77(m,2H),7.67(s,1H),7.56-7.63(m,1H),7.33(s,1H),7.25(dd,J=8.03,1.51Hz,1H),5.02(s,2H),4.00(s,3H)。
实施例6
化合物PD-6的合成
参照实施例1的方法,以2-氯-6-三氟甲基喹啉为原料,制得PD-6(104mg,77.6%)。1HNMR400MHz(DMSO-d6)δ:9.24(s,1H),8.63-8.65(d,1H),8.49(s,1H),7.90-7.93(m,1H),7.81-7.84(m,1H),7.46-7.48(d,1H),7.34(s,1H),7.24-7.27(m,1H),5.03(s,2H)。
实施例7
化合物PD-7的合成
参照实施例1的方法,以2-氯-5-三氟甲基喹啉为原料,制得PD-7(105.0mg,59.9%)。1HNMR 400MHz(DMSO-d6)δ:9.23(s,1H),8.54(d,J=9.03Hz,1H),7.93-8.00(m,2H),7.79-7.86(m,2H),7.52(d,J=9.29Hz,1H),7.35(s,1H),7.26(d,J=7.78Hz,1H),5.03(s,2H)。
实施例8
参照实施例1的方法,以2,7-氯-5-三氟甲基喹啉为原料,制得PD-8(33.5mg,39.9%)。1HNMR 400MHz(DMSO-d6)δ:9.23(s,1H),8.54(d,J=9.03Hz,1H),7.93-8.00(m,2H),7.79-7.86(m,2H),7.52(d,J=9.29Hz,1H),7.35(s,1H),7.26(d,J=7.78Hz,1H),5.03(s,2H)。
实施例9
化合物PD-9的合成
参照实施例1的方法,以2-氯-4-三氟甲基-6-氰基-喹啉为原料,制得PD-9(87mg,48%)。1HNMR 400MHz(DMSO-d6)δ:9.27(s,1H),8.49(s,1H),8.12-8.14(d,1H),7.99(s,1H),7.84-7.92(m,2H),7.40(s,1H),7.30-7.32(m,1H),5.04(s,2H)。
实施例10
PD-10的合成
按照实施例1的方法,以2-氯喹啉-6-羧酸甲脂为原料,制得PD-12(43mg,41%)。1HNMR(400MHz,DMSO)δ9.22(s,1H),8.70–8.58(m,2H),8.12(dd,J=8.8,1.7Hz,1H),7.82(d,J=7.9Hz,1H),7.71(d,J=8.8Hz,1H),7.40(d,J=8.8Hz,1H),7.33(s,1H),7.24(d,J=8.0Hz,1H),5.02(s,2H),3.91(s,3H)。
实施例11
PD-11的合成
按照实施例1的方法,以2-氯喹啉-5-酰胺为原料,制得PD-13(37mg,32%)。1H NMR(400MHz,DMSO)δ9.24(s,1H),8.83(d,J=9.1Hz,1H),8.12(s,1H),7.82(d,J=8.0Hz,1H),7.76–7.59(m,4H),7.40–7.29(m,2H),7.23(d,J=7.9Hz,1H),5.02(s,2H)。
实施例12
PD-12的合成
按照实施例1的方法,以2-氯-5-乙酰基喹啉为原料,制得PD-12(35mg,31%)。1HNMR(400MHz,DMSO)δ9.21(s,1H),9.07(d,J=9.2Hz,1H),8.15(dd,J=7.2,1.2Hz,1H),7.79(dd,J=12.3,7.8Hz,3H),7.40(d,J=9.3Hz,1H),7.30(d,J=1.4Hz,1H),7.22(dd,J=8.0,2.0Hz,1H),5.01(s,2H),2.74(s,3H)。
实施例13
PD-13的合成
按照实施例1的方法,以2-氯-6-酰胺基喹啉为原料,制得PD-13(55mg,45%)。1HNMR(400MHz,DMSO)δ9.22(s,1H),8.51(d,J=8.8Hz,2H),8.12(d,J=10.3Hz,2H),7.83(d,J=7.9Hz,1H),7.68(d,J=8.8Hz,1H),7.48(s,1H),7.40–7.29(m,2H),7.24(d,J=9.1Hz,1H),5.03(s,2H)。
实施例14
PD-14的合成
按照实施例1的方法,以2-氯-6-乙酰基喹啉为原料,制得PD-14(60mg,51%)。1HNMR(400MHz,DMSO)δ9.23(s,1H),8.71(d,J=1.9Hz,1H),8.62(d,J=8.8Hz,1H),8.14(dd,J=8.8,2.0Hz,1H),7.83(d,J=8.0Hz,1H),7.70(d,J=8.8Hz,1H),7.41(d,J=8.8Hz,1H),7.34(d,J=1.4Hz,1H),7.25(dd,J=7.9,2.0Hz,1H),5.03(s,2H),2.70(s,3H)。
实施例15
PD-15的合成
按照实施例1的方法,以2,7-二氯-6-三氟甲基喹啉为原料,制得PD-15(35mg,33.2%)。1HNMR 400MHz(DMSO-d6)δ:9.27(s,1H),8.01(d,J=8.8Hz,1H),7.84(d,J=7.9Hz,1H),7.64(d,J=8.9Hz,1H),7.35(m,2H),6.97(d,J=7.9Hz,1H),6.48(d,J=8.0Hz,1H),5.03(s,2H)。
实施例16
PD-16的合成
按照实施例1的方法,以2,7-二氯-6-氰基喹啉为原料,制得PD-16(57mg,38%)。1HNMR(400MHz,DMSO)δ9.24(s,1H),8.76(s,1H),8.54(d,J=8.9Hz,1H),7.94(s,1H),7.82(d,J=7.9Hz,1H),7.48(d,J=8.9Hz,1H),7.34(s,1H),7.25(dd,J=8.0,2.0Hz,1H),5.02(s,2H)。
实施例17
PD-17的合成
按照实施例1的方法,以2-氯-4,6-三氟甲基喹啉为原料,制得PD-17(57mg,38%)。1HNMR(400MHz,DMSO)δ9.21(s,1H),8.76-8.73(m,1H),8.54(d,J=8.9Hz,1H),7.94(s,1H),7.82-7.73(m,1H),7.43(d,J=8.9Hz,1H),7.30(s,1H),7.19(dd,J=8.0,2.0Hz,1H),5.02(s,2H)。
实施例18
PD-18的合成
按照实施例1的方法,以2-氯-4-三氟甲基喹啉-6羧酸甲脂为原料,制得PD-18(37mg,38%)。1H NMR(400MHz,DMSO)δ9.11(s,1H),8.46(s,1H),8.10(d,J=8.8Hz,1H),7.77(s,1H),7.72–7.65(m,2H),7.15(d,J=8.0Hz,1H),4.89(s,2H),3.79(s,3H)。
实施例19
PD-19的合成
按照实施例1的方法,以2-氯-4-三氟甲基-6-乙酰基喹啉为原料,制得PD-19(107mg,68%)。1H NMR(400MHz,DMSO)δ9.26(s,1H),8.54(s,1H),8.30(d,J=8.8Hz,1H),7.95–7.82(m,3H),7.40(s,1H),7.31(dd,J=8.0,1.4Hz,1H),5.05(s,2H),2.72(s,3H)。
实施例20
PD-20的合成
按照实施例1的方法,以2-氯-4-氟喹啉-6-羧酸甲脂为原料,制得PD-20(43mg,41%)。1HNMR 400MHz(DMSO-d6)δ:9.30(s,1H),8.06-8.08(d,1H),7.81-7.84(d,1H),7.62-7.64(d,1H),7.28-7.34(m,2H),6.97-6.99(m,2H),5.04(s,2H),3.45(s,3H)。
实施例21
PD-21的合成
按照实施例1的方法,以2-氯-4-氟-6-三氟甲基喹啉为原料,制得PD-21(67mg,48%)。1HNMR 400MHz(DMSO-d6)δ:9.26(s,1H),8.03(d,J=8.8Hz,1H),7.81-7.84(m,2H),7.68-7.63(m,1H),7.28-7.34(m,2H),6.48(d,J=8.0Hz,1H),5.03(m,1H)。
实施例22
PD-22的合成
按照实施例1的方法,以2-氯-4-氟-6-氰基喹啉为原料,制得PD-22(51mg,31%)。1HNMR400MHz(DMSO-d6)δ:9.24(s,1H),8.08(d,J=8.8Hz,1H),7.83(d,J=8.8Hz,1H),7.67-7.62(m,1H),7.34(d,J=8.0Hz,2H),6.99(d,J=8.0Hz,1H),6.48(d,J=8.0Hz,1H),5.01(m,1H)。
实施例23
PD-23的合成
按照实施例1的方法,以2-氯-6-(三氟甲基)萘为原料,制得PD-23(72mg,52%)。1HNMR400MHz(DMSO-d6),9.24(s,1H),8.08(d,J=8.8Hz,1H),7.83(d,J=8.8Hz,1H),7.67-7.53(m,2H),7.34(d,J=8.0Hz,2H),6.99-6.93(m,2H),6.43(d,J=8.0Hz,1H),5.02(m,1H)。
实施例24
PD-24的合成
按照实施例1的方法,以2-氯-萘-5羧酸甲脂为原料,制得PD-24(57mg,38%)1HNMR(400MHz,DMSO)δ9.15(s,1H),8.81(d,J=9.4Hz,1H),8.16–8.04(m,2H),7.77(d,J=8.6Hz,1H),7.64–7.55(m,2H),7.47(dd,J=9.3,2.7Hz,1H),7.16–7.05(m,2H),4.94(s,2H),3.94(s,3H)。
实施例25
PD-25的合成
按照实施例1的方法,以2-氯-6-氰基萘为原料,制得PD-25(37mg,28%)。1H NMR(400MHz,DMSO)δ9.22(s,1H),8.59(s,1H),8.15(d,J=9.0Hz,1H),8.03(d,J=8.6Hz,1H),7.84–7.73(m,2H),7.58–7.46(m,2H),7.20–7.09(m,2H),4.98(s,2H)。
实施例26
PD-26的合成
按照实施例1的方法,以2,4-二氯-6-氰基喹啉为原料,制得PD-26(43mg,36%)。1HNMR400MHz(DMSO-d6)δ:9.23(s,1H),8.35(d,J=9.2Hz,1H),7.81(d,J=8.8Hz,1H),7.62(d,J=8.0Hz,1H),6.92(d,J=9.2Hz,1H),6.78-6.63(m,2H),6.46(d,J=9.2Hz,1H),5.04(m,1H)。
实施例27
PD-27的合成
按照实施例1的方法,以2,4-二氯喹啉-6-羧酸甲酯为原料,制得PD-27(63mg,36%)。1H NMR(400MHz,DMSO)δ9.34(s,1H),8.91(d,J=1.8Hz,1H),8.35(dd,J=8.8,2.0Hz,1H),8.09(d,J=8.8Hz,1H),7.92(d,J=8.0Hz,1H),7.46(d,J=1.6Hz,1H),7.38(dd,J=8.0,2.1Hz,1H),6.67(s,1H),5.06(s,2H),3.96(s,3H)。
实施例28
PD-28的合成
按照实施例1的方法,以2,4-二氯-6-三氟甲基喹啉为原料,制得PD-28(23mg,16%)。1HNMR 400MHz(DMSO-d6)δ:9.22(s,1H),8.34(d,J=9.2Hz,1H),7.82(d,J=8.8Hz,1H),7.58(d,J=8.0Hz,1H),6.97(d,J=9.2Hz,1H),6.78-6.62(m,2H),6.51(d,J=9.2Hz,1H),5.04(m,1H)。
Claims (7)
1.下列通式(I)的化合物或其药学上可接受的盐:
R1、R2、R3代表任意取代的卤素、C1~C6的烷基、三氟甲基、氰基、氨基、C(O)ORa、CORa或ORa;
Ra代表H、C1~C6的烷基、氨基或三氟甲基;
X为N或CH。
2.下列任一结构式的化合物或其药学上可接受的盐:
其中R1、R2的定义同权利要求1。
3.下列结构式的化合物或其药学上可接受的盐:
其中R1、R2的定义同权利要求1。
4.权利要求1、2或3的化合物或其药学上可接受的盐,其中药学上可接受的盐是通式(I)化合物的钾盐、钠盐、铵盐、盐酸盐、硫酸盐、磷酸盐、氢溴酸盐、马来酸盐、富马酸盐、枸橼酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸盐或醋酸盐。
5.一种药物组合物,其中含有权利要求1、2或3的化合物或其药学上可接受的盐及药学上可接受的载体。
6.权利要求1、2或3的化合物或其药学上可接受的盐用于制备抑制磷酸二酯酶4的药物的用途。
7.权利要求1、2或3的化合物或其药学上可接受的盐用于制备预防或治疗炎症相关疾病的药物的用途。
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CN102014927A (zh) * | 2008-03-06 | 2011-04-13 | 安纳考尔医药公司 | 作为抗炎药的含硼的小分子 |
CN106831840A (zh) * | 2017-03-23 | 2017-06-13 | 合肥医工医药有限公司 | 一类具有抗炎活性的小分子化合物、制备方法及其药物用途 |
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