具有四氢苯并[4,5]咪唑并[1,2-a]吡嗪骨架凝血酶抑制剂的设计合成及生物活性研究

doi:10.7503/cjcu20160797

高等学校化学学报 ›› 2017, Vol. 38 ›› Issue (6): 1059.doi: 10.7503/cjcu20160797

具有四氢苯并[4,5]咪唑并[1,2-a]吡嗪骨架凝血酶抑制剂的设计合成及生物活性研究

陈东星¹, 施锦渝², 陈秋芳², 张芮², 龚国清², 徐云根^1,²(), 朱启华^1,²()

1. 中国药科大学江苏省药物分子设计与成药性优化重点实验室, 南京 210009
2. 药学院, 南京 210009

收稿日期:2016-11-16 出版日期:2017-06-10 发布日期:2017-05-23
作者简介:联系人简介: 徐云根, 男, 博士, 教授, 博士生导师, 主要从事抗肿瘤、镇痛抗炎和心血管疾病方面的研究. E-mail: xyg@cpu.edu.cn;朱启华, 男, 博士, 副教授, 主要从事抗肿瘤和心血管疾病方面的研究. E-mail: zhuqihua@cpu.edu.cn
基金资助:
国家自然科学基金(批准号: 21272277)和江苏高等学校优秀科技创新团队(2015年)资助.

Design, Synthesis and Biological Evaluation of Thrombin Inhibitors with 1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine Nucleus^†

CHEN Dongxing¹, SHI Jinyu², CHEN Qiufang², ZHANG Rui², GONG Guoqing², XU Yungen^1,^2,^*(), ZHU Qihua^1,^2,^*()

1. Jiangsu Key Laboratory of Drug Design and Optimization, Nanjing 210009, China
2. School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China

Received:2016-11-16 Online:2017-06-10 Published:2017-05-23
Contact: XU Yungen,ZHU Qihua E-mail:xyg@cpu.edu.cn;zhuqihua@cpu.edu.cn
Supported by:
† Supported by the National Natural Science Foundation of China(No. 21272277) and the Outstanding Scientific and Technological Innovation Team Projects of Jiangsu Province of China(2015).

摘要/Abstract

摘要：

以具有四氢苯并[4,5]咪唑并[1,2-a]吡嗪新骨架的凝血酶抑制剂1为先导化合物, 设计合成了14个氨基甲酸酯衍生物(2a~6a, 2b~6b和7~10). 同时, 在化合物1结构的基础上, 引入具有抗血栓活性的川芎醇(HTMP), 设计合成了新型结构的化合物11. 目标化合物的结构均经¹H NMR, ¹³C NMR和HRMS确证. 生物活性测试结果显示, 所有目标化合物对凝血酶诱导的血小板聚集均有一定的抑制活性, 其中化合物4b 的抑制活性[IC₅₀=(0.11±0.08) μmol/L]强于对照药达比加群酯[IC₅₀=(0.60±0.05) μmol/L]. 在体内抗血栓活性测试中, 化合物4b能以剂量依赖的方式减少大鼠静脉血栓的形成. 化合物11对凝血酶诱导的血小板聚集的抑制活性较弱, 但其抑制大鼠静脉血栓形成的作用与达比加群酯相当, 这可能是由于化合物11在体内水解为川芎醇和化合物1, 两者协同产生抗血栓作用所致.

关键词: 苯并咪唑, 凝血酶抑制剂, 抗血栓

Abstract:

Compound 1, a new thrombin inhibitor with 1,2,3,4-tetrahydrobenzo[4,5] imidazo[1,2-a]pyrazine nucleus, was selected as lead compound, and fourteen carbamate derivatives derivatives(2a—6a, 2b—6b, 7—10) were designed and prepared. Furthermore, a twin drug(11) was synthesized by coupling compound 1 with 2-hydroxymethyl-3,5,6-trimethylpyrazine(HTMP). The structures of all the target compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS. Preliminary biological activity test results indicated that all of the tested compounds exhibit a certain degree of inhibitory effect on thrombin-induced platelet aggregation, among which compound 4b[IC₅₀=(0.11±0.08) μmol/L] show better anti-platelet aggregation activity than dabigatran etexilate[IC₅₀=(0.60±0.05) μmol/L]. The in vivo experimental results in rat venous thrombosis model demonstrated compound 4b can significantly reduce thrombosis in a dose-response manner. Compound 11, which showed weak inhibitory effect on thrombin-induced platelet aggregation, also displayed comparable inhibitory effect on rat venous thrombosis with dabigatran etexilate. The study points out that the enhanced potency of compound 11 may be the synergetic effect of HTMP and compound 1 which are generated by hydrolysis in vivo.

Key words: Benzimidazole, Thrombin inhibitors, Antithrombosis

中图分类号:

O626

TrendMD:

陈东星, 施锦渝, 陈秋芳, 张芮, 龚国清, 徐云根, 朱启华. 具有四氢苯并[4,5]咪唑并[1,2-a]吡嗪骨架凝血酶抑制剂的设计合成及生物活性研究. 高等学校化学学报, 2017, 38(6): 1059.

CHEN Dongxing, SHI Jinyu, CHEN Qiufang, ZHANG Rui, GONG Guoqing, XU Yungen, ZHU Qihua. Design, Synthesis and Biological Evaluation of Thrombin Inhibitors with 1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine Nucleus^†. Chem. J. Chinese Universities, 2017, 38(6): 1059.

图/表 8

参考文献 20

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Compd.	Appearance	Yield(%)	m. p./℃	HRMS(calcd. ), m/z[M+H]⁺
2a	White solid	44.2	114—116	597.2823(597.2820)
2b	White solid	48.3	106—108	669.3044(669.3031)
3a	White solid	40.3	108—110	625.3148(625.3133)
3b	White solid	44.6	94—96	725.3673(725.3657)
4a	White solid	48.0	160—162	625.3141(625.3133)
4b	White solid	66.0	148—150	725.3662(725.3657)
5a	White solid	42.6	108—110	639.3287(639.3289)
5b	White solid	47.4	88—90	753.3978(753.3970)
6a	White solid	43.7	130—132	659.2979(659.2976)
6b	White solid	54.3	120—122	793.3354(793.3344)
7	White solid	29.9	> 250	511.2453(511.2452)
8	White solid	57.4	112—114	639.3295(639.3289)
9	White solid	59.6	82—84	667.3603(667.3602)
10	White solid	54.5	94—96	673.3145(673.3133)
11	Yellow solid	35.7	104—106	703.3356(703.3351)

Compd.	Appearance	Yield(%)	m. p./℃	HRMS(calcd. ), m/z[M+H]⁺
2a	White solid	44.2	114—116	597.2823(597.2820)
2b	White solid	48.3	106—108	669.3044(669.3031)
3a	White solid	40.3	108—110	625.3148(625.3133)
3b	White solid	44.6	94—96	725.3673(725.3657)
4a	White solid	48.0	160—162	625.3141(625.3133)
4b	White solid	66.0	148—150	725.3662(725.3657)
5a	White solid	42.6	108—110	639.3287(639.3289)
5b	White solid	47.4	88—90	753.3978(753.3970)
6a	White solid	43.7	130—132	659.2979(659.2976)
6b	White solid	54.3	120—122	793.3354(793.3344)
7	White solid	29.9	> 250	511.2453(511.2452)
8	White solid	57.4	112—114	639.3295(639.3289)
9	White solid	59.6	82—84	667.3603(667.3602)
10	White solid	54.5	94—96	673.3145(673.3133)
11	Yellow solid	35.7	104—106	703.3356(703.3351)

Compd.	¹H NMR(300 MHz), δ^a	¹³C NMR(75 MHz), δ^b
2a	9.14(brs, 2H), 7.87(d, J=8.3 Hz, 2H), 7.43(s, 1H), 7.38(d, J=8.3 Hz, 2H), 7.32—7.21(m, 2H), 7.21—7.06(m, 5H), 4.34—4.24(m, 1H), 4.15—3.99(m, 5H), 3.96(q, J=7.2 Hz, 2H), 3.91—3.81(m, 1H), 3.57—3.45(m, 1H), 3.29—3.20(m, 1H), 3.07—2.84(m, 2H), 2.58(t, J=7.1 Hz, 2H), 1.18(t, J=6.9 Hz, 3H), 1.11(t, J=7.1 Hz, 3H)	171.08, 170.63, 167.19, 163.87, 152.30, 142.83, 141.49, 140.86, 134.73, 132.51, 129.67, 129.05(2C), 128.78(2C), 127.33(2C), 127.28(2C), 126.19, 122.90, 119.95, 107.88, 60.78, 60.07, 55.29, 46.34, 42.50, 40.98, 38.95, 32.10, 13.93, 13.61
2b	9.59(brs, 2H), 7.85—7.59(m, 3H), 7.26—7.02(m, 9H), 5.89—5.63(m, 1H), 4.65—4.44(m, 1H), 4.41—3.80(m, 11H), 3.62—3.27(m, 2H), 2.76(t, J=7.2 Hz, 2H), 1.36(t, J=6.8 Hz, 3H), 1.32—1.18(m, 6H)	171.12, 170.38, 166.89, 164.02, 154.40, 150.11, 142.91, 141.21, 141.00, 134.20, 132.49, 130.10, 129.33(2C), 128.79(2C), 127.36(2C), 126.94(2C), 126.21, 123.18, 120.30, 107.95, 61.68, 60.89, 60.08, 53.49, 46.34, 41.36, 38.73, 36.87, 32.12, 13.91(2C), 13.62
3a	9.07(brs, 2H), 7.89(d, J=8.0 Hz, 2H), 7.46(s, 1H), 7.40(d, J=8.2 Hz, 2H), 7.34—7.21(m, 3H), 7.21—7.18(m, 2H), 7.18—7.15(m, 1H), 7.15—7.10(m, 1H), 4.38—4.19(m, 1H), 4.11(t, J=7.0 Hz, 2H), 4.07—4.03(m, 1H), 3.99(q, J=7.1 Hz, 2H), 3.94—3.85(m, 1H), 3.81(d, J=6.6 Hz, 2H), 3.60—3.44(m, 1H), 3.31—3.20(m, 1H), 3.08—2.87(m, 2H), 2.61(t, J=7.1 Hz, 2H), 1.99—1.81(m, 1H), 1.14(t, J=7.1 Hz, 3H), 0.91(d, J=6.7 Hz, 6H)	171.12, 170.64, 167.26, 164.34, 152.41, 142.93, 141.48, 140.98, 134.80, 132.90, 129.69, 129.11(2C), 128.78(2C), 127.35(2C), 127.23(2C), 126.16, 122.92, 120.06, 107.83, 71.25, 60.07, 55.42, 46.36, 42.65, 41.11, 39.04, 32.13, 27.33, 18.77(2C), 13.62
3b	9.07(brs, 2H), 7.88(s, 2H), 7.51(s, 1H), 7.35(d, J=8.6 Hz, 1H), 7.31—7.27(m, 1H), 7.27—7.21(m, 3H), 7.21—7.18(m, 2H), 7.18—7.04(m, 2H), 5.69—5.38(m, 1H), 4.45—4.27(m, 1H), 4.24—4.15(m, 1H), 4.11(t, J=7.2 Hz, 2H), 3.99(q, J=7.1 Hz, 3H), 3.81(d, J=6.6 Hz, 2H), 3.76—3.66(m, 1H), 3.60—3.51(m, 1H), 3.49—3.39(m, 1H), 3.33—3.24(m, 2H), 2.61(t, J=7.1 Hz, 2H), 1.97—1.81(m, 1H), 1.63—1.45(m, 1H), 1.14(t, J=7.1 Hz, 3H), 0.91(d, J=6.6 Hz, 6H), 0.83(s, 3H), 0.68(s, 3H)	171.10, 170.36, 166.91, 164.15, 154.56, 150.06, 142.91, 141.22, 140.77, 134.20, 132.77, 130.10, 129.32(2C), 128.79(2C), 127.36(2C), 126.98(2C), 126.21, 123.16, 120.30, 107.96, 71.85, 71.30, 60.06, 53.58, 46.33, 41.31, 39.21, 37.24, 32.11, 27.30(2C), 18.75(2C), 18.50(2C), 13.62
4a	9.03(brs, 2H), 7.83(d, J=8.2 Hz, 2H), 7.43(s, 1H), 7.36(d, J=8.2 Hz, 2H), 7.31—7.19(m, 3H), 7.18—7.15(m, 2H), 7.15—7.08(m, 2H), 4.32—4.20(m, 1H), 4.08(t, J=7.1 Hz, 2H), 4.04—4.00(m, 1H), 3.96(q, J=7.1 Hz, 2H), 3.91—3.81(m, 1H), 3.56—3.45(m, 1H), 3.28—3.18(m, 1H), 3.04—2.86(m, 2H), 2.58(t, J=7.1 Hz, 2H), 1.42(s, 9H), 1.11(t, J=7.1 Hz, 3H)	171.20, 170.63, 166.66, 162.89, 152.33, 142.95, 141.35, 140.93, 134.78, 132.98, 129.68, 129.16(2C), 128.80(2C), 127.36(2C), 127.19(2C), 126.16, 123.00, 120.11, 107.85, 79.37, 60.10, 55.42, 46.37, 42.63, 41.12, 39.01, 32.09, 27.69(3C), 13.64
4b	9.05(brs, 2H), 7.94(d,J=5.6 Hz, 2H), 7.50(s, 1H), 7.39—7.10(m, 9H), 5.60—5.43(m, 1H), 4.44—4.28(m, 1H), 4.26—4.15(m, 1H), 4.11(t, J=6.7 Hz, 2H), 3.99(q, J=7.1 Hz, 2H), 3.94—3.83(m, 1H), 3.57—3.39(m, 1H), 3.30—3.20(m, 2H), 2.61(t, J=7.2 Hz, 2H), 1.45(s, 9H), 1.34—1.19(m, 3H), 1.14(t, J=7.1 Hz, 3H), 1.12—0.99(m, 6H)	171.13, 170.40, 166.19, 162.93, 153.23, 150.49, 142.94, 141.26, 140.97, 134.26, 132.62, 130.03, 129.38(2C), 128.81(2C), 127.37(2C), 126.96(2C), 126.21, 123.15, 120.26, 107.98, 80.74, 79.50, 60.07, 53.66, 46.35, 41.43, 39.11, 36.29, 32.12, 27.69(6C), 13.63
5a	9.18(brs, 2H), 7.89(d, J=8.3 Hz, 2H), 7.46(s, 1H), 7.40(d, J=8.3 Hz, 2H), 7.35—7.21(m, 3H), 7.21—7.15(m, 3H), 7.15—7.10(m, 1H), 4.32—4.21(m, 1H), 4.10(t, J=6.9 Hz, 2H), 4.07—3.94(m, 5H), 3.94—3.82(m, 1H), 3.59—3.47(m, 1H), 3.31—3.20(m, 1H), 3.06—2.88(m, 2H), 2.61(t, J=6.9 Hz, 2H), 1.67—1.54(m, 2H), 1.37—1.27(m, 4H), 1.14(t, J=7.1 Hz, 3H), 0.88(t, J=7.0 Hz, 3H)	171.18, 170.65, 167.21, 164.06, 152.19, 142.85, 141.48, 140.88, 134.74, 132.63, 129.69, 129.18(2C), 128.81(2C), 127.35(2C), 127.28(2C), 126.21, 122.99, 120.05, 107.90, 65.19, 60.13, 55.38, 46.36, 42.49, 41.09, 38.96, 32.07, 28.03, 27.57, 21.91, 13.64, 13.50
5b	9.13(brs, 2H), 7.90(s, 2H), 7.50(s, 1H), 7.39—7.28(m, 2H), 7.28—7.22(m, 3H), 7.22—7.07(m, 4H), 5.65—5.41(m, 1H), 4.46—4.29(m, 1H), 4.28—4.16(m, 1H), 4.11(t, J=6.7 Hz, 2H), 4.05—3.86(m, 5H), 3.76—3.61(m, 1H), 3.61—3.41(m, 2H),	171.16, 170.39, 166.71, 164.36, 154.57, 150.08, 142.97, 141.28, 140.90, 134.24, 132.77, 130.15, 129.37(2C), 128.82(2C), 127.39(2C), 126.93(2C), 126.22, 123.22, 120.37, 107.95, 65.94,
Compd.	¹H NMR(300 MHz), δ^a	¹³C NMR(75 MHz), δ^b
5b	3.32—3.22(m, 2H), 2.61(t, J=7.0 Hz, 2H), 1.68—1.52(m, 2H), 1.39—1.17(m, 8H), 1.14(t, J=7.1 Hz, 3H), 1.11—0.95(m, 2H), 0.95—0.72(m, 6H)	65.18, 60.10, 53.61, 46.37, 41.37, 39.24, 37.12, 32.16, 28.05, 27.97, 27.60, 27.49, 21.91, 21.79, 13.66, 13.48, 13.45
6a	9.06(brs, 2H), 7.90(d,J=7.9 Hz, 2H), 7.46(s, 1H), 7.44—7.36(m, 5H), 7.36—7.32(m, 1H), 7.33—7.27(m, 2H), 7.27—7.21(m, 2H), 7.21—7.10(m, 4H), 5.10(s, 2H), 4.33—4.22(m, 1H), 4.10(t, J=7.0 Hz, 2H), 4.06—4.03(m, 1H), 3.99(q, J=7.0 Hz, 2H), 3.94—3.80(m, 1H), 3.59—3.47(m, 1H), 3.31—3.20(m, 1H), 3.09—2.82(m, 2H), 2.61(t, J=7.0 Hz, 2H), 1.14(t, J=7.1 Hz, 3H)	171.13, 170.64, 167.43, 163.97, 152.34, 142.95, 141.67, 140.96, 136.18, 134.78, 132.67, 129.74, 129.17(2C), 128.79(2C), 127.88(2C), 127.67(2C), 127.42, 127.36(2C), 127.23(2C), 126.16, 122.96, 120.08, 107.84, 66.66, 60.08, 55.38, 46.38, 42.61, 41.08, 39.05, 32.13, 13.64
6b	9.15(brs, 2H), 7.87(d, J=8.3 Hz, 2H), 7.50(s, 1H), 7.44—6.97(m, 19H), 5.69—5.47(m, 1H), 5.12(s, 2H), 4.97(s, 2H), 4.70—4.56(m, 1H), 4.42—4.24(m, 1H), 4.23—4.15(m, 1H), 4.11(t, J=6.8 Hz, 2H), 3.99(q, J=7.1 Hz, 2H), 3.68—3.37(m, 2H), 3.29—3.11(m, 1H), 2.61(t, J=7.2 Hz, 2H), 1.14(t, J=7.1 Hz, 3H)	171.14, 170.36, 166.19, 162.93, 153.23, 149.93, 142.92, 141.22, 140.83, 136.15, 135.79, 134.18, 132.52, 130.16, 129.30(2C), 128.80(2C), 128.03(2C), 127.89(2C), 127.69(2C), 127.63(2C), 127.59, 127.44, 127.37(2C), 126.96(2C), 126.22, 123.22, 120.33, 107.97, 66.70, 66.37, 60.09, 53.73, 46.35, 41.33, 39.19, 37.16, 32.14, 13.64
7	9.40(s, 2H), 9.20(s, 2H), 7.81(d,J=7.7 Hz, 2H), 7.62(d, J=7.9 Hz, 2H), 7.58—7.43(m, 2H), 7.32—7.24(m, 2H), 7.24—7.19(m, 2H), 7.19—7.15(m, 1H), 7.15—7.10(m, 1H), 5.11(brs, 1H), 4.42(brs, 2H), 4.10—3.99(m, 2H), 3.66(brs, 2H), 3.49(brs, 2H), 2.77(s, 3H), 2.60—2.52(m, 2H)	172.53, 169.36, 165.24, 148.40, 143.25, 143.03, 140.55, 133.80, 131.25, 129.87(2C), 129.23(2C), 128.10(2C), 127.99(2C), 126.74, 126.22, 123.82, 118.56, 110.43, 60.70, 49.68, 46.27, 38.45, 37.94, 37.90, 32.10
8	9.05(brs, 2H), 7.70(d, J=8.2 Hz, 2H), 7.47(s, 1H), 7.33—7.14(m, 9H), 4.16—4.12(m, 1H), 4.10(t, J=7.1 Hz, 2H), 4.06—4.03(m, 1H), 3.99(q, J=7.1 Hz, 2H), 3.92—3.77(m, 1H), 3.39—3.37(m, 1H),3.28—3.15(m, 2H), 2.92—2.77(m, 1H), 2.61(t, J=6.9 Hz, 2H), 2.40(s, 3H), 1.44(d, J=4.8 Hz, 9H), 1.14(t, J=7.1 Hz, 3H)	171.18, 170.63, 166.73, 160.39, 152.10, 144.01, 142.89, 141.10, 134.40, 131.26, 129.62, 129.39(2C), 128.79(2C), 127.36(2C), 126.47(2C), 126.19, 122.80, 119.94, 107.84, 79.78, 62.11, 60.09, 48.88, 46.35, 41.98, 39.94, 36.84, 32.09, 27.64(3C), 13.64
9	8.94(brs, 2H), 7.74(d, J=8.3 Hz, 2H), 7.47(s, 1H), 7.37—7.00(m, 9H), 4.17—4.05(m, 3H), 4.06—3.92(m, 5H), 3.91—3.75(m, 1H), 3.55(d, J=27.6 Hz, 1H), 3.27—3.13(m, 2H), 2.94—2.75(m, 1H), 2.61(t, J=6.8 Hz, 2H), 2.40(s, 3H),1.68—1.49(m, 2H), 1.36—1.25(m, 6H), 1.14(t, J=7.1 Hz, 3H), 0.86(t, J=6.6 Hz, 3H)	171.18, 170.58, 167.28, 161.05, 152.07, 142.97, 142.29, 141.20, 134.47, 131.79, 129.62, 129.38(2C), 128.78(2C), 127.35(2C), 126.43(2C), 126.13, 122.81, 120.06, 107.80, 65.14, 62.15, 60.08, 48.88, 46.35, 41.95, 39.84, 36.91, 32.09, 31.04, 28.30, 25.13, 22.07, 13.65, 13.55
10	9.15(brs, 2H), 7.89(d, J=8.2 Hz, 2H), 7.53—7.35(m, 4H), 7.35—7.28(m, 1H), 7.29—7.22(m, 3H), 7.22—7.17(m, 3H), 7.17—7.14(m, 2H), 7.15—7.05(m, 2H), 5.13(s, 2H), 4.34—4.23(m, 1H), 4.12(t, J=6.7 Hz, 2H), 4.08—4.04(m, 1H), 4.01(t, J=6.7 Hz, 2H), 3.94—3.85(m, 1H), 3.57—3.49(m, 2H), 3.06—2.90(m, 2H), 2.69(t, J=7.2 Hz, 2H), 2.42(s, 3H), 0.87(t, J=6.5 Hz, 3H)	171.18, 170.81, 167.63, 164.43, 152.41, 142.94, 141.60, 141.19, 137.74, 134.89, 132.95, 129.62, 129.43(2C), 128.83(2C), 127.87(2C), 127.67(2C), 127.37(2C), 127.23, 126.46(2C), 126.19, 123.10, 120.06, 107.88, 64.69, 61.82, 60.11, 48.82, 46.30, 41.93, 40.76, 37.08, 31.05, 13.56
11	9.55(brs, 2H), 7.81(d,J=7.9 Hz, 2H), 7.72(s, 1H), 7.34(d, J=8.4 Hz, 2H), 7.31(d, J=1.3 Hz, 1H), 7.25—7.18(m, 2H), 7.16—7.05(m, 4H), 5.30(s, 2H), 4.47—4.35(m, 1H), 4.34—4.22(m, 2H), 4.09(q, J=7.3 Hz, 2H), 4.05—3.96(m, 2H), 3.80—3.71(m, 1H), 3.47—3.37(m, 1H), 3.22—3.05(m, 2H), 2.80—2.71(m, 2H), 2.60(s, 3H), 2.51(s, 3H), 2.49(s, 3H), 1.23(t, J=7.1 Hz, 3H)	171.09, 170.65, 167.46, 163.62, 152.37, 150.41, 148.61, 148.19, 144.86, 142.75, 141.48, 140.82, 134.72, 132.45, 129.59, 128.96(2C), 128.79(2C), 127.36(2C), 127.32(2C), 126.22, 122.87, 119.89, 107.92, 65.43, 60.09, 55.30, 46.32, 42.49, 40.99, 38.93, 32.06, 21.09, 20.81, 20.08, 13.61

Compd.	¹H NMR(300 MHz), δ^a	¹³C NMR(75 MHz), δ^b
2a	9.14(brs, 2H), 7.87(d, J=8.3 Hz, 2H), 7.43(s, 1H), 7.38(d, J=8.3 Hz, 2H), 7.32—7.21(m, 2H), 7.21—7.06(m, 5H), 4.34—4.24(m, 1H), 4.15—3.99(m, 5H), 3.96(q, J=7.2 Hz, 2H), 3.91—3.81(m, 1H), 3.57—3.45(m, 1H), 3.29—3.20(m, 1H), 3.07—2.84(m, 2H), 2.58(t, J=7.1 Hz, 2H), 1.18(t, J=6.9 Hz, 3H), 1.11(t, J=7.1 Hz, 3H)	171.08, 170.63, 167.19, 163.87, 152.30, 142.83, 141.49, 140.86, 134.73, 132.51, 129.67, 129.05(2C), 128.78(2C), 127.33(2C), 127.28(2C), 126.19, 122.90, 119.95, 107.88, 60.78, 60.07, 55.29, 46.34, 42.50, 40.98, 38.95, 32.10, 13.93, 13.61
2b	9.59(brs, 2H), 7.85—7.59(m, 3H), 7.26—7.02(m, 9H), 5.89—5.63(m, 1H), 4.65—4.44(m, 1H), 4.41—3.80(m, 11H), 3.62—3.27(m, 2H), 2.76(t, J=7.2 Hz, 2H), 1.36(t, J=6.8 Hz, 3H), 1.32—1.18(m, 6H)	171.12, 170.38, 166.89, 164.02, 154.40, 150.11, 142.91, 141.21, 141.00, 134.20, 132.49, 130.10, 129.33(2C), 128.79(2C), 127.36(2C), 126.94(2C), 126.21, 123.18, 120.30, 107.95, 61.68, 60.89, 60.08, 53.49, 46.34, 41.36, 38.73, 36.87, 32.12, 13.91(2C), 13.62
3a	9.07(brs, 2H), 7.89(d, J=8.0 Hz, 2H), 7.46(s, 1H), 7.40(d, J=8.2 Hz, 2H), 7.34—7.21(m, 3H), 7.21—7.18(m, 2H), 7.18—7.15(m, 1H), 7.15—7.10(m, 1H), 4.38—4.19(m, 1H), 4.11(t, J=7.0 Hz, 2H), 4.07—4.03(m, 1H), 3.99(q, J=7.1 Hz, 2H), 3.94—3.85(m, 1H), 3.81(d, J=6.6 Hz, 2H), 3.60—3.44(m, 1H), 3.31—3.20(m, 1H), 3.08—2.87(m, 2H), 2.61(t, J=7.1 Hz, 2H), 1.99—1.81(m, 1H), 1.14(t, J=7.1 Hz, 3H), 0.91(d, J=6.7 Hz, 6H)	171.12, 170.64, 167.26, 164.34, 152.41, 142.93, 141.48, 140.98, 134.80, 132.90, 129.69, 129.11(2C), 128.78(2C), 127.35(2C), 127.23(2C), 126.16, 122.92, 120.06, 107.83, 71.25, 60.07, 55.42, 46.36, 42.65, 41.11, 39.04, 32.13, 27.33, 18.77(2C), 13.62
3b	9.07(brs, 2H), 7.88(s, 2H), 7.51(s, 1H), 7.35(d, J=8.6 Hz, 1H), 7.31—7.27(m, 1H), 7.27—7.21(m, 3H), 7.21—7.18(m, 2H), 7.18—7.04(m, 2H), 5.69—5.38(m, 1H), 4.45—4.27(m, 1H), 4.24—4.15(m, 1H), 4.11(t, J=7.2 Hz, 2H), 3.99(q, J=7.1 Hz, 3H), 3.81(d, J=6.6 Hz, 2H), 3.76—3.66(m, 1H), 3.60—3.51(m, 1H), 3.49—3.39(m, 1H), 3.33—3.24(m, 2H), 2.61(t, J=7.1 Hz, 2H), 1.97—1.81(m, 1H), 1.63—1.45(m, 1H), 1.14(t, J=7.1 Hz, 3H), 0.91(d, J=6.6 Hz, 6H), 0.83(s, 3H), 0.68(s, 3H)	171.10, 170.36, 166.91, 164.15, 154.56, 150.06, 142.91, 141.22, 140.77, 134.20, 132.77, 130.10, 129.32(2C), 128.79(2C), 127.36(2C), 126.98(2C), 126.21, 123.16, 120.30, 107.96, 71.85, 71.30, 60.06, 53.58, 46.33, 41.31, 39.21, 37.24, 32.11, 27.30(2C), 18.75(2C), 18.50(2C), 13.62
4a	9.03(brs, 2H), 7.83(d, J=8.2 Hz, 2H), 7.43(s, 1H), 7.36(d, J=8.2 Hz, 2H), 7.31—7.19(m, 3H), 7.18—7.15(m, 2H), 7.15—7.08(m, 2H), 4.32—4.20(m, 1H), 4.08(t, J=7.1 Hz, 2H), 4.04—4.00(m, 1H), 3.96(q, J=7.1 Hz, 2H), 3.91—3.81(m, 1H), 3.56—3.45(m, 1H), 3.28—3.18(m, 1H), 3.04—2.86(m, 2H), 2.58(t, J=7.1 Hz, 2H), 1.42(s, 9H), 1.11(t, J=7.1 Hz, 3H)	171.20, 170.63, 166.66, 162.89, 152.33, 142.95, 141.35, 140.93, 134.78, 132.98, 129.68, 129.16(2C), 128.80(2C), 127.36(2C), 127.19(2C), 126.16, 123.00, 120.11, 107.85, 79.37, 60.10, 55.42, 46.37, 42.63, 41.12, 39.01, 32.09, 27.69(3C), 13.64
4b	9.05(brs, 2H), 7.94(d,J=5.6 Hz, 2H), 7.50(s, 1H), 7.39—7.10(m, 9H), 5.60—5.43(m, 1H), 4.44—4.28(m, 1H), 4.26—4.15(m, 1H), 4.11(t, J=6.7 Hz, 2H), 3.99(q, J=7.1 Hz, 2H), 3.94—3.83(m, 1H), 3.57—3.39(m, 1H), 3.30—3.20(m, 2H), 2.61(t, J=7.2 Hz, 2H), 1.45(s, 9H), 1.34—1.19(m, 3H), 1.14(t, J=7.1 Hz, 3H), 1.12—0.99(m, 6H)	171.13, 170.40, 166.19, 162.93, 153.23, 150.49, 142.94, 141.26, 140.97, 134.26, 132.62, 130.03, 129.38(2C), 128.81(2C), 127.37(2C), 126.96(2C), 126.21, 123.15, 120.26, 107.98, 80.74, 79.50, 60.07, 53.66, 46.35, 41.43, 39.11, 36.29, 32.12, 27.69(6C), 13.63
5a	9.18(brs, 2H), 7.89(d, J=8.3 Hz, 2H), 7.46(s, 1H), 7.40(d, J=8.3 Hz, 2H), 7.35—7.21(m, 3H), 7.21—7.15(m, 3H), 7.15—7.10(m, 1H), 4.32—4.21(m, 1H), 4.10(t, J=6.9 Hz, 2H), 4.07—3.94(m, 5H), 3.94—3.82(m, 1H), 3.59—3.47(m, 1H), 3.31—3.20(m, 1H), 3.06—2.88(m, 2H), 2.61(t, J=6.9 Hz, 2H), 1.67—1.54(m, 2H), 1.37—1.27(m, 4H), 1.14(t, J=7.1 Hz, 3H), 0.88(t, J=7.0 Hz, 3H)	171.18, 170.65, 167.21, 164.06, 152.19, 142.85, 141.48, 140.88, 134.74, 132.63, 129.69, 129.18(2C), 128.81(2C), 127.35(2C), 127.28(2C), 126.21, 122.99, 120.05, 107.90, 65.19, 60.13, 55.38, 46.36, 42.49, 41.09, 38.96, 32.07, 28.03, 27.57, 21.91, 13.64, 13.50
5b	9.13(brs, 2H), 7.90(s, 2H), 7.50(s, 1H), 7.39—7.28(m, 2H), 7.28—7.22(m, 3H), 7.22—7.07(m, 4H), 5.65—5.41(m, 1H), 4.46—4.29(m, 1H), 4.28—4.16(m, 1H), 4.11(t, J=6.7 Hz, 2H), 4.05—3.86(m, 5H), 3.76—3.61(m, 1H), 3.61—3.41(m, 2H),	171.16, 170.39, 166.71, 164.36, 154.57, 150.08, 142.97, 141.28, 140.90, 134.24, 132.77, 130.15, 129.37(2C), 128.82(2C), 127.39(2C), 126.93(2C), 126.22, 123.22, 120.37, 107.95, 65.94,
Compd.	¹H NMR(300 MHz), δ^a	¹³C NMR(75 MHz), δ^b
5b	3.32—3.22(m, 2H), 2.61(t, J=7.0 Hz, 2H), 1.68—1.52(m, 2H), 1.39—1.17(m, 8H), 1.14(t, J=7.1 Hz, 3H), 1.11—0.95(m, 2H), 0.95—0.72(m, 6H)	65.18, 60.10, 53.61, 46.37, 41.37, 39.24, 37.12, 32.16, 28.05, 27.97, 27.60, 27.49, 21.91, 21.79, 13.66, 13.48, 13.45
6a	9.06(brs, 2H), 7.90(d,J=7.9 Hz, 2H), 7.46(s, 1H), 7.44—7.36(m, 5H), 7.36—7.32(m, 1H), 7.33—7.27(m, 2H), 7.27—7.21(m, 2H), 7.21—7.10(m, 4H), 5.10(s, 2H), 4.33—4.22(m, 1H), 4.10(t, J=7.0 Hz, 2H), 4.06—4.03(m, 1H), 3.99(q, J=7.0 Hz, 2H), 3.94—3.80(m, 1H), 3.59—3.47(m, 1H), 3.31—3.20(m, 1H), 3.09—2.82(m, 2H), 2.61(t, J=7.0 Hz, 2H), 1.14(t, J=7.1 Hz, 3H)	171.13, 170.64, 167.43, 163.97, 152.34, 142.95, 141.67, 140.96, 136.18, 134.78, 132.67, 129.74, 129.17(2C), 128.79(2C), 127.88(2C), 127.67(2C), 127.42, 127.36(2C), 127.23(2C), 126.16, 122.96, 120.08, 107.84, 66.66, 60.08, 55.38, 46.38, 42.61, 41.08, 39.05, 32.13, 13.64
6b	9.15(brs, 2H), 7.87(d, J=8.3 Hz, 2H), 7.50(s, 1H), 7.44—6.97(m, 19H), 5.69—5.47(m, 1H), 5.12(s, 2H), 4.97(s, 2H), 4.70—4.56(m, 1H), 4.42—4.24(m, 1H), 4.23—4.15(m, 1H), 4.11(t, J=6.8 Hz, 2H), 3.99(q, J=7.1 Hz, 2H), 3.68—3.37(m, 2H), 3.29—3.11(m, 1H), 2.61(t, J=7.2 Hz, 2H), 1.14(t, J=7.1 Hz, 3H)	171.14, 170.36, 166.19, 162.93, 153.23, 149.93, 142.92, 141.22, 140.83, 136.15, 135.79, 134.18, 132.52, 130.16, 129.30(2C), 128.80(2C), 128.03(2C), 127.89(2C), 127.69(2C), 127.63(2C), 127.59, 127.44, 127.37(2C), 126.96(2C), 126.22, 123.22, 120.33, 107.97, 66.70, 66.37, 60.09, 53.73, 46.35, 41.33, 39.19, 37.16, 32.14, 13.64
7	9.40(s, 2H), 9.20(s, 2H), 7.81(d,J=7.7 Hz, 2H), 7.62(d, J=7.9 Hz, 2H), 7.58—7.43(m, 2H), 7.32—7.24(m, 2H), 7.24—7.19(m, 2H), 7.19—7.15(m, 1H), 7.15—7.10(m, 1H), 5.11(brs, 1H), 4.42(brs, 2H), 4.10—3.99(m, 2H), 3.66(brs, 2H), 3.49(brs, 2H), 2.77(s, 3H), 2.60—2.52(m, 2H)	172.53, 169.36, 165.24, 148.40, 143.25, 143.03, 140.55, 133.80, 131.25, 129.87(2C), 129.23(2C), 128.10(2C), 127.99(2C), 126.74, 126.22, 123.82, 118.56, 110.43, 60.70, 49.68, 46.27, 38.45, 37.94, 37.90, 32.10
8	9.05(brs, 2H), 7.70(d, J=8.2 Hz, 2H), 7.47(s, 1H), 7.33—7.14(m, 9H), 4.16—4.12(m, 1H), 4.10(t, J=7.1 Hz, 2H), 4.06—4.03(m, 1H), 3.99(q, J=7.1 Hz, 2H), 3.92—3.77(m, 1H), 3.39—3.37(m, 1H),3.28—3.15(m, 2H), 2.92—2.77(m, 1H), 2.61(t, J=6.9 Hz, 2H), 2.40(s, 3H), 1.44(d, J=4.8 Hz, 9H), 1.14(t, J=7.1 Hz, 3H)	171.18, 170.63, 166.73, 160.39, 152.10, 144.01, 142.89, 141.10, 134.40, 131.26, 129.62, 129.39(2C), 128.79(2C), 127.36(2C), 126.47(2C), 126.19, 122.80, 119.94, 107.84, 79.78, 62.11, 60.09, 48.88, 46.35, 41.98, 39.94, 36.84, 32.09, 27.64(3C), 13.64
9	8.94(brs, 2H), 7.74(d, J=8.3 Hz, 2H), 7.47(s, 1H), 7.37—7.00(m, 9H), 4.17—4.05(m, 3H), 4.06—3.92(m, 5H), 3.91—3.75(m, 1H), 3.55(d, J=27.6 Hz, 1H), 3.27—3.13(m, 2H), 2.94—2.75(m, 1H), 2.61(t, J=6.8 Hz, 2H), 2.40(s, 3H),1.68—1.49(m, 2H), 1.36—1.25(m, 6H), 1.14(t, J=7.1 Hz, 3H), 0.86(t, J=6.6 Hz, 3H)	171.18, 170.58, 167.28, 161.05, 152.07, 142.97, 142.29, 141.20, 134.47, 131.79, 129.62, 129.38(2C), 128.78(2C), 127.35(2C), 126.43(2C), 126.13, 122.81, 120.06, 107.80, 65.14, 62.15, 60.08, 48.88, 46.35, 41.95, 39.84, 36.91, 32.09, 31.04, 28.30, 25.13, 22.07, 13.65, 13.55
10	9.15(brs, 2H), 7.89(d, J=8.2 Hz, 2H), 7.53—7.35(m, 4H), 7.35—7.28(m, 1H), 7.29—7.22(m, 3H), 7.22—7.17(m, 3H), 7.17—7.14(m, 2H), 7.15—7.05(m, 2H), 5.13(s, 2H), 4.34—4.23(m, 1H), 4.12(t, J=6.7 Hz, 2H), 4.08—4.04(m, 1H), 4.01(t, J=6.7 Hz, 2H), 3.94—3.85(m, 1H), 3.57—3.49(m, 2H), 3.06—2.90(m, 2H), 2.69(t, J=7.2 Hz, 2H), 2.42(s, 3H), 0.87(t, J=6.5 Hz, 3H)	171.18, 170.81, 167.63, 164.43, 152.41, 142.94, 141.60, 141.19, 137.74, 134.89, 132.95, 129.62, 129.43(2C), 128.83(2C), 127.87(2C), 127.67(2C), 127.37(2C), 127.23, 126.46(2C), 126.19, 123.10, 120.06, 107.88, 64.69, 61.82, 60.11, 48.82, 46.30, 41.93, 40.76, 37.08, 31.05, 13.56
11	9.55(brs, 2H), 7.81(d,J=7.9 Hz, 2H), 7.72(s, 1H), 7.34(d, J=8.4 Hz, 2H), 7.31(d, J=1.3 Hz, 1H), 7.25—7.18(m, 2H), 7.16—7.05(m, 4H), 5.30(s, 2H), 4.47—4.35(m, 1H), 4.34—4.22(m, 2H), 4.09(q, J=7.3 Hz, 2H), 4.05—3.96(m, 2H), 3.80—3.71(m, 1H), 3.47—3.37(m, 1H), 3.22—3.05(m, 2H), 2.80—2.71(m, 2H), 2.60(s, 3H), 2.51(s, 3H), 2.49(s, 3H), 1.23(t, J=7.1 Hz, 3H)	171.09, 170.65, 167.46, 163.62, 152.37, 150.41, 148.61, 148.19, 144.86, 142.75, 141.48, 140.82, 134.72, 132.45, 129.59, 128.96(2C), 128.79(2C), 127.36(2C), 127.32(2C), 126.22, 122.87, 119.89, 107.92, 65.43, 60.09, 55.30, 46.32, 42.49, 40.99, 38.93, 32.06, 21.09, 20.81, 20.08, 13.61

具有四氢苯并[4,5]咪唑并[1,2-a]吡嗪骨架凝血酶抑制剂的设计合成及生物活性研究

Design, Synthesis and Biological Evaluation of Thrombin Inhibitors with 1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine Nucleus^†

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