绿卡色林衍生物的合成、 体外代谢及体内活性研究

doi:10.7503/cjcu20170094

摘要/Abstract

摘要：

将选择性5-HT_2C受体激动剂类减肥药绿卡色林分子中的仲胺转化成氨基甲酸酯类前药, 设计合成了13个氨基甲酸酯类化合物. 新化合物的结构经核磁共振波谱、红外光谱及高分辨质谱确证. 通过体外代谢稳定性实验, 筛选出半衰期长且可通过代谢持续产生绿卡色林的新化合物6b. 对化合物6b的大鼠减肥药理实验结果表明, 在日剂量相同的条件下, 化合物6b给药1次/d比绿卡色林给药2次/d的减肥效果略好.

关键词: 绿卡色林, 前药, 代谢稳定, 体内活性

Abstract:

To improve oral bioavailability and metabolic stability while maintaining the activity and selectivity, 13 carbamate prodrugs of lorcaserin were designed and synthesized by the structural modification of the secondary amine group. The structure of target compounds were confirmed by ¹H NMR, ¹³C NMR, HRMS and IR. In vitro metabolic stabilities of 13 target compounds were explored by rat liver microsomes incubation experiment, among which compound 6b showed a longer half-life and can generate lorcaserin continuously by metabolism. In high-fat diet rats model, compound 6b exhibited slightly better weight loss effect than lorcaserin at the equimolar daily doses.

Key words: Lorcaserin, Prodrug, Metabolic stability, Biological activity in vivo

中图分类号:

O626.5

TrendMD:

张灵芝, 蒋敏瑞, 魏萍, 朱启华, 龚国清, 卞学国, 徐云根. 绿卡色林衍生物的合成、体外代谢及体内活性研究. 高等学校化学学报, 2017, 38(10): 1778.

ZHANG Lingzhi, JIANG Minrui, WEI Ping, ZHU Qihua, GONG Guoqing, BIAN Xueguo, XU Yungen. Synthesis, Metabolic Stability and Biological Activity in vivo of Lorcaserin Derivatives^†. Chem. J. Chinese Universities, 2017, 38(10): 1778.

图/表 13

Fig.1 Structures of lorcaserin

Scheme 1 Synthetic routes of compounds 6a—6mRegents and conditions: a. (i) CDI, dry CH2Cl2, N2, 0—20 ℃, 5 h, (ii) lorcaserin hydrochloride, triethylamine, r. t., CH2Cl2, overnight, (iii) CF3COOH, r. t., 30 min(3h and 3i); b. 2-chloroethyl chloroformate, triethylamine, dry CH2Cl2, 0 ℃, 4 h; c. K2CO3, NaI, 5a—5d; d. HCl, dry CH2Cl2 or H2C2O4, dry acetone.

Table 1 Appearances and yields of compounds 3a—3m*

Compd.	Appearance	Yield(%)	Compd.	Appearance	Yield(%)	Compd.	Appearance	Yield(%)
3a	Yellow oil	80.4	3f	Yellow oil	81.7	3j	Yellow oil	72.5
3b	Yellow oil	38.6	3g	Yellow oil	85.8	3k	Yellow oil	87.1
3c	Yellow oil	42.3	3h	Yellow oil	37.5	3l	Yellow oil	78.1
3d	Yellow oil	42.0	3i	Yellow oil	81.5	3m	Yellow oil	45.5
3e	Yellow oil	43.8

Table 2 1H NMR data of compounds 3a—3m

Compd.	¹H NMR(300 MHz, CDCl₃), δ
3a	7.13—7.11(m, 1H), 7.08(dd, J₁=8.0 Hz, J₂=2.1 Hz, 1H), 7.02—6.99(m, 1H), 4.16(t, J=6.2 Hz, 2H), 3.84—3.33(m, 4H), 3.13—3.96(m, 2H), 2.81(dd, J=15.1, 6.2 Hz, 1H), 2.70(t, J=6.3 Hz, 2H), 2.58(q, J=7.1 Hz, 4H), 1.30—1.24(m, 3H), 1.03(t, J=7.1 Hz, 6H)
3b	7.13—7.10(m, 1H), 7.09(dd, J₁=8.0 Hz, J₂=2.1 Hz, 1H), 7.02—7.01(m, 1H), 4.20(t, J=5.9 Hz, 2H), 3.77—3.35(m, 4H), 3.03—3.00(m, 2H), 2.84—2.80(m, 1H), 2.56(t, J=5.9 Hz, 2H), 2.28(s, 6H), 1.30—1.24(m, 3H)
3c	7.14—7.07(m, 2H), 7.03—7.00(m, 1H), 4.23(t, J=6.0 Hz, 2H), 3.76—3.42(m, 4H), 3.08—3.00(m, 2H), 2.82(dd, J₁=15.1 Hz, J₂= 6.5 Hz, 1H), 2.61(t, J=5.9 Hz, 2H), 2.46—2.44(m, 4H), 1.60—1.55(m, 4H), 1.46—1.43(m, 2H), 1.30—1.28(m, 3H)
3d	7.14—7.08(m, 2H), 7.04—7.00(m, 1H), 4.23(t, J=5.8 Hz, 2H), 3.76—3.72(m, 1H), 3.70(t, J=4.5 Hz, 4H), 3.64—3.36(m, 3H), 3.08—3.00(m, 2H), 2.83(dd, J₁=14.3 Hz, J₂=4.7 Hz, 1H), 2.63(t, J=5.8 Hz, 2H), 2.52(t, J=4.6 Hz, 4H), 1.29(t, J=7.0 Hz, 3H)
3e	7.13—7.07(m, 2H), 7.03—7.01(m, 1H), 4.22(t, J=5.9 Hz, 2H), 3.74—3.40(m, 4H), 3.07—2.96(m, 2H), 2.82(dd, J₁=15.2 Hz, J₂=4.0 Hz, 1H), 2.64(t, J=5.9 Hz, 2H), 2.55—2.44(m, 8H), 2.28(s, 3H), 1.29—1.27(m, 3H)
Compd.	¹H NMR(300 MHz, CDCl₃), δ
3f	7.12—7.07(m, 2H), 7.01—6.98(m, 1H), 5.00—4.97(m, 1H), 3.84—3.34(m, 4H), 3.06—3.02(m, 2H), 2.84(dd, J₁=14.0 Hz, J₂=5.5 Hz, 1H), 2.56—2.41(m, 1H), 2.33—2.29(m, 1H), 2.27(s, 3H), 2.25(s, 3H), 1.30(d, J=6.9 Hz, 3H), 1.22(d, J=6.2 Hz, 3H)
3g	7.14—7.08(m, 2H), 7.04—7.00(m, 1H), 5.00—4.91(m, 1H), 3.65—3.43(m, 4H), 3.09—3.01(m, 2H), 2.82(dd, J₁=15.0 Hz, J₂=6.5 Hz, 1H), 2.64—2.50(m, 5H), 2.45—2.40(m, 1H), 1.30(d, J=7.1 Hz, 3H), 1.22(d, J=6.3 Hz, 3H), 1.01(td, J₁=7.1 Hz, J₂=2.8 Hz, 6H)
3h	7.17—7.14(m, 1H), 7.11(dd, J₁=8.1 Hz, J₂=2.0 Hz, 1H), 7.04—7.03(m, 1H), 4.23(t, J=5.9 Hz, 2H), 3.78—3.41(m, 4H), 3.08—3.00(m, 2H), 2.96—2.91(m, 2H), 2.84(dd, J₁=14.5 Hz, J₂=5.2 Hz, 1H), 2.65—2.61(m, 4H), 2.56—2.46(m, 4H), 1.31—1.28(m, 3H), 1.25(s, 1H)
3i	7.35—7.27(m, 5H), 7.15—7.08(m, 2H), 7.04—6.99(m, 1H), 4.27—4.23(t, J=5.4 Hz, 2H), 3.85(s, 2H), 3.65—3.39(m, 4H), 3.09—3.01(m, 2H), 2.90(t, J=5.3 Hz, 2H), 2.82(dd, J₁=15.4 Hz, J₂=6.5 Hz, 1H), 1.88(s, 1H), 1.31—1.2(m, 3H)
3j	7.15—7.10(m, 2H), 7.05—7.02(m, 1H), 6.79(s, 1H), 4.28—4.17(m, 2H), 3.81—3.40(m, 4H), 3.11—2.96(m, 3H), 2.87—2.82(m, 6H), 2.45—2.40(m, 1H), 2.15—2.12(m, 1H), 1.98—1.93(m, 2H), 1.72—1.63(m, 2H), 1.51—1.24(m, 2H), 1.33—1.28(m, 3H)
3k	7.45(s, 1H), 7.16—7.11(m, 2H), 7.05—7.00(m, 1H), 4.20—4.12(m, 2H), 3.74—3.30(m, 4H), 3.28—3.02(m, 3H), 2.99—2.70(m, 6H), 2.60—2.36(m, 1H), 2.26—2.08(m, 1H), 1.92—1.78(m, 4H), 1.34—1.28(m, 3H)
3l	7.14—7.09(m, 2H), 7.04—7.01(m, 1H), 4.21(t, J=5.8 Hz, 2H), 3.91—3.88(m, 4H), 3.22—2.94(m, 4H), 2.87—2.77(m, 4H), 2.44—2.40(m, 1H), 2.00—1.98(m, 1H), 1.73—1.53(m, 3H), 1.51—1.43(m, 3H), 1.32—1.26(m, 3H)
3m	7.18—7.08(m, 2H), 7.07—7.00(m, 1H), 4.21—4.18(m, 2H), 3.94—3.90(m, 2H), 3.76—3.47(m, 6H), 3.26—3.23(m, 4H), 3.08—3.01(m, 2H), 2.84(dd, J₁=15.1 Hz, J₂=5.9 Hz, 1H), 1.30—1.29(m, 3H), 1.29(t, J=6.8 Hz, 3H)

Table 2 1H NMR data of compounds 3a—3m

Compd.	¹H NMR(300 MHz, CDCl₃), δ
3a	7.13—7.11(m, 1H), 7.08(dd, J₁=8.0 Hz, J₂=2.1 Hz, 1H), 7.02—6.99(m, 1H), 4.16(t, J=6.2 Hz, 2H), 3.84—3.33(m, 4H), 3.13—3.96(m, 2H), 2.81(dd, J=15.1, 6.2 Hz, 1H), 2.70(t, J=6.3 Hz, 2H), 2.58(q, J=7.1 Hz, 4H), 1.30—1.24(m, 3H), 1.03(t, J=7.1 Hz, 6H)
3b	7.13—7.10(m, 1H), 7.09(dd, J₁=8.0 Hz, J₂=2.1 Hz, 1H), 7.02—7.01(m, 1H), 4.20(t, J=5.9 Hz, 2H), 3.77—3.35(m, 4H), 3.03—3.00(m, 2H), 2.84—2.80(m, 1H), 2.56(t, J=5.9 Hz, 2H), 2.28(s, 6H), 1.30—1.24(m, 3H)
3c	7.14—7.07(m, 2H), 7.03—7.00(m, 1H), 4.23(t, J=6.0 Hz, 2H), 3.76—3.42(m, 4H), 3.08—3.00(m, 2H), 2.82(dd, J₁=15.1 Hz, J₂= 6.5 Hz, 1H), 2.61(t, J=5.9 Hz, 2H), 2.46—2.44(m, 4H), 1.60—1.55(m, 4H), 1.46—1.43(m, 2H), 1.30—1.28(m, 3H)
3d	7.14—7.08(m, 2H), 7.04—7.00(m, 1H), 4.23(t, J=5.8 Hz, 2H), 3.76—3.72(m, 1H), 3.70(t, J=4.5 Hz, 4H), 3.64—3.36(m, 3H), 3.08—3.00(m, 2H), 2.83(dd, J₁=14.3 Hz, J₂=4.7 Hz, 1H), 2.63(t, J=5.8 Hz, 2H), 2.52(t, J=4.6 Hz, 4H), 1.29(t, J=7.0 Hz, 3H)
3e	7.13—7.07(m, 2H), 7.03—7.01(m, 1H), 4.22(t, J=5.9 Hz, 2H), 3.74—3.40(m, 4H), 3.07—2.96(m, 2H), 2.82(dd, J₁=15.2 Hz, J₂=4.0 Hz, 1H), 2.64(t, J=5.9 Hz, 2H), 2.55—2.44(m, 8H), 2.28(s, 3H), 1.29—1.27(m, 3H)
Compd.	¹H NMR(300 MHz, CDCl₃), δ
3f	7.12—7.07(m, 2H), 7.01—6.98(m, 1H), 5.00—4.97(m, 1H), 3.84—3.34(m, 4H), 3.06—3.02(m, 2H), 2.84(dd, J₁=14.0 Hz, J₂=5.5 Hz, 1H), 2.56—2.41(m, 1H), 2.33—2.29(m, 1H), 2.27(s, 3H), 2.25(s, 3H), 1.30(d, J=6.9 Hz, 3H), 1.22(d, J=6.2 Hz, 3H)
3g	7.14—7.08(m, 2H), 7.04—7.00(m, 1H), 5.00—4.91(m, 1H), 3.65—3.43(m, 4H), 3.09—3.01(m, 2H), 2.82(dd, J₁=15.0 Hz, J₂=6.5 Hz, 1H), 2.64—2.50(m, 5H), 2.45—2.40(m, 1H), 1.30(d, J=7.1 Hz, 3H), 1.22(d, J=6.3 Hz, 3H), 1.01(td, J₁=7.1 Hz, J₂=2.8 Hz, 6H)
3h	7.17—7.14(m, 1H), 7.11(dd, J₁=8.1 Hz, J₂=2.0 Hz, 1H), 7.04—7.03(m, 1H), 4.23(t, J=5.9 Hz, 2H), 3.78—3.41(m, 4H), 3.08—3.00(m, 2H), 2.96—2.91(m, 2H), 2.84(dd, J₁=14.5 Hz, J₂=5.2 Hz, 1H), 2.65—2.61(m, 4H), 2.56—2.46(m, 4H), 1.31—1.28(m, 3H), 1.25(s, 1H)
3i	7.35—7.27(m, 5H), 7.15—7.08(m, 2H), 7.04—6.99(m, 1H), 4.27—4.23(t, J=5.4 Hz, 2H), 3.85(s, 2H), 3.65—3.39(m, 4H), 3.09—3.01(m, 2H), 2.90(t, J=5.3 Hz, 2H), 2.82(dd, J₁=15.4 Hz, J₂=6.5 Hz, 1H), 1.88(s, 1H), 1.31—1.2(m, 3H)
3j	7.15—7.10(m, 2H), 7.05—7.02(m, 1H), 6.79(s, 1H), 4.28—4.17(m, 2H), 3.81—3.40(m, 4H), 3.11—2.96(m, 3H), 2.87—2.82(m, 6H), 2.45—2.40(m, 1H), 2.15—2.12(m, 1H), 1.98—1.93(m, 2H), 1.72—1.63(m, 2H), 1.51—1.24(m, 2H), 1.33—1.28(m, 3H)
3k	7.45(s, 1H), 7.16—7.11(m, 2H), 7.05—7.00(m, 1H), 4.20—4.12(m, 2H), 3.74—3.30(m, 4H), 3.28—3.02(m, 3H), 2.99—2.70(m, 6H), 2.60—2.36(m, 1H), 2.26—2.08(m, 1H), 1.92—1.78(m, 4H), 1.34—1.28(m, 3H)
3l	7.14—7.09(m, 2H), 7.04—7.01(m, 1H), 4.21(t, J=5.8 Hz, 2H), 3.91—3.88(m, 4H), 3.22—2.94(m, 4H), 2.87—2.77(m, 4H), 2.44—2.40(m, 1H), 2.00—1.98(m, 1H), 1.73—1.53(m, 3H), 1.51—1.43(m, 3H), 1.32—1.26(m, 3H)
3m	7.18—7.08(m, 2H), 7.07—7.00(m, 1H), 4.21—4.18(m, 2H), 3.94—3.90(m, 2H), 3.76—3.47(m, 6H), 3.26—3.23(m, 4H), 3.08—3.01(m, 2H), 2.84(dd, J₁=15.1 Hz, J₂=5.9 Hz, 1H), 1.30—1.29(m, 3H), 1.29(t, J=6.8 Hz, 3H)

Table 3 Appearances, melting points, yield and HRMS data of compounds 6a—6m*

Compd.	Appearance	m. p. /℃	Yield(%)	HRMS(calcd.), m/z[M+H]⁺
6a	White solid	156—158	78.2	339.1834(339.1840)
6b	White solid	150—152	37.5	311.1521(311.1529)
6c	White solid	152—154	41.2	351.1834(351.1841)
6d	White solid	157—158	41.0	353.1626(353.1625)
6e	White solid	222—224	42.4	366.1943(366.1949)
6f	White solid	103—105	78.7	325.1677(325.1674)
6g	White solid	98—100	82.4	353.1990(353.1985)
6h	White solid	178—180	36.4	352.1786(352.1795)
6i	White solid	178—180	79.0	373.1677(373.1674)
6j	White solid	85—86	69.9	408.2048(408.2045)
6k	White solid	127—129	84.2	394.1892(394.1892)
6l	White solid		75.1	395.2096(395.2091)
6m	White solid		43.7	355.1783(355.1782)

Table 4 1H NMR and 13C NMR data of compounds 6a—6m

Compd.	¹H NMR(300 MHz), δ^*	¹³C NMR(75 MHz), δ^*
6a	12.55(bs, 1H), 7.16—7.12(m, 2H), 7.07—7.04(m, 1H), 4.62(t, J=5.0 Hz, 2H), 3.86—3.47(m, 4H), 3.28—3.02(m, 8H), 2.89—2.86(dd, J₁=15.7Hz, J₂=4.6 Hz, 1H), 1.47—1.37(m, 6H), 1.32—1.29(m, 3H)	154.91, 145.40, 136.95, 131.18, 127.77, 126.38, 115.18, 59.16, 51.72, 49.69, 47.32, 46.34, 40.57, 35.11, 17.09, 8.32
6b	12.66(bs, 1H), 7.13—7.11(m, 2H), 7.04—7.01(m, 1H), 4.62—4.55(m, 2H), 3.82—3.45(m, 4H), 3.33—3.19(m, 2H), 3.14—3.01(m, 2H), 2.96—2.75(m, 7H), 1.30(d, J=7.0 Hz, 3H)	154.37, 145.07, 136.17, 132.42, 130.70, 128.18, 125.23, 58.94, 55.51, 49.64, 45.39, 42.86, 39.52, 34.88, 17.59
6c	12.45(bs, 1H), 7.16—7.12(m, 2H), 7.07—7.03(m, 1H), 4.65—4.64(m, 2H), 3.82—3.45(m, 6H), 3.24—3.22(m, 2H), 3.18—3.00(m, 2H), 2.88—2.83(m, 1H), 2.70—2.63(m, 2H), 2.33—2.30(m, 2H), 1.95—1.85(m, 3H), 1.50—1.37(m, 1H), 1.33—1.29(m, 3H)	155.25, 145.55, 136.66, 132.35, 131.76, 127.85, 125.73, 59.43, 56.01, 53.48, 51.44, 46.30, 40.03, 34.97, 22.25, 21.44, 17.20
6d	13.39(s, 1H), 7.15—7.11(m, 2H), 7.06—7.02(m, 1H), 4.64—4.40(m, 2H), 4.36—4.28(m, 2H), 4.01—3.98(m, 2H ), 3.81—3.50(m, 4H), 3.48—3.39(m, 2H), 3.30—3.22(m, 2H), 3.17—3.03(m, 2H), 2.99—2.89(m, 3H), 1.31—1.28(m, 3H)	154.87, 145.75, 137.16, 132.16, 131.47, 128.06, 126.38, 63.92, 58.78, 56.01, 51.69, 50.95, 45.81, 39.95, 34.80, 17.11
6e	7.15(d,J=1.9 Hz, 1H), 7.07(dd, J₁=8.1 Hz, J₂=1.9 Hz, 1H), 7.02(d, J=8.1 Hz, 1H), 4.19—4.17(m, 2H), 3.60—3.55(m, 4H), 3.44—3.24(m, 10H ), 3.12—3.06(m, 2H), 2.92(s, 3H), 2.79—2.74(m, 1H), 1.12(d, J=7.1 Hz, 3H)	156.37, 145.13, 137.06, 131.19, 127.85, 126.14, 114.72, 59.43, 56.01, 50.96, 49.33, 48.83, 45.48, 42.55, 39.12, 33.26, 16.38
6f	9.01(bs, 2H), 7.14—7.11(m, 2H), 7.07—7.03(m, 1H), 5.26—5.20(m, 1H), 3.84—3.48(m, 4H), 3.44—3.30(m, 2H), 3.12—3.00(m, 3H), 2.89(d, J=6.6 Hz, 3H),2.84(d, J=4.0 Hz, 3H), 1.31—1.29(m, 3H), 1.16(d, J=6.1 Hz, 3H)	162.83, 154.43, 145.13, 136.66, 132.41, 127.84, 126.15, 68.73, 65.31, 60.25, 50.95, 46.29, 45.48, 42.55, 35.78, 22.25, 16.78
6g	12.18(bs, 2H),7.16—7.12(m, 2H), 7.08—7.03(m, 1H),5.27—5.21(m, 1H), 3.78—3.44(m, 4H), 3.41—3.23(m, 6H), 3.07—2.93(m, 3H), 1.36—1.27(m, 12H)	155.65, 145.96, 137.96, 132.01, 127.86, 126.14, 115.13, 72.97, 70.37, 58.12, 50.95, 47.60, 45.49, 40.44, 36.19, 18.91,17.35 11.73
6h	7.11(m, 1H),7.05—6.98(m, 2H), 4.19—4.17(m, 2H), 3.60—3.57(m, 1H), 3.41—3.38(m, 6H), 3.25—3.15(m, 7H), 3.08—3.02(m, 1H), 2.96—2.88(m, 1H), 2.77—2.69(m, 1H), 1.10(d, J=7.1 Hz, 3H)	145.95, 137.06, 132.71, 131.99, 127.84, 126.13, 114.72, 59.84, 56.00, 50.54, 48.43, 45.08, 41.66, 38.31, 33.25, 15.97.
6i	10.25(bs, 2H), 7.64—7.62(m, 2H), 7.43—7.41(m, 3H), 7.15—7.09(m, 2H), 7.04—7.01(m, 1H), 4.50—4.69(m, 2H), 4.19(s, 2H), 3.83—3.80(m, 1H), 3.60—3.55(m, 3H), 3.11—3.02(m, 4H), 2.91—2.79(m, 1H), 1.30—1.25(m, 3H)	155.51, 145.80, 136.60, 131.30, 129.78, 129.41, 129.15, 128.79, 127.50, 125.82, 125.73, 59.90, 51.05, 49.99, 46.18, 44.92, 40.39, 35.47,17.17
6j	11.49(bs, 0.5H), 10.83(bs, 0.5H), 9.11(bs, 0.5H), 8.79(bs, 0.5H), 7.15—7.11(m, 2H), 7.07—7.03(m, 1H), 4.60—4.37(m, 3H), 3.76—3.34(m, 7H), 3.21—3.01(m, 3H), 2.83(s, 3H), 2.72—2.61(m, 1H), 2.40—2.09(m, 3H), 1.99—1.81(m, 2H), 1.75—1.59(m, 1H), 1.36—1.30(m, 3H)	175.06, 155.65, 145.13, 137.96, 132.00, 128.66, 126.13, 114.72, 67.84, 62.77, 55.20, 51.85, 51.30, 46.79, 41.38, 40.84, 36.60, 29.02, 25.68, 24.78, 23.15, 17.61
6k	7.15—7.12(m, 1H), 7.09—7.01(m, 2H), 4.19—4.14(m, 2H), 3.69—3.63(m, 2H ), 3.53—3.36(m, 5H), 3.23—3.02(m, 3H), 3.02—2.88(m, 1H), 2.85—2.71(m, 1H), 2.63(d, J =5.6 Hz, 3H), 2.51—2.32(m, 1H), 2.09—1.93(m, 3H), 1.12(d, J=6.5 Hz, 3H)	167.89, 156.56, 146.36, 137.06, 132.00, 127.85, 126.55, 115.13, 67.42, 64.49, 60.25, 56.50, 50.13, 46.31, 39.14, 32.85, 30.15, 29.42, 26.49, 22.25, 16.38
6l	7.13—7.09(m, 2H), 7.05—7.02(m, 1H), 4.50—4.18(m, 2H), 3.91—3.30(m, 10H), 3.23—3.01(m, 3H), 2.86—2.81(m, 1H), 2.09—1.82(m, 8H), 1.33—1.25(m, 3H)	156.06, 146.36, 137.97, 132.41, 128.25, 126.13, 115.57, 69.14, 62.97, 62.37, 60.10, 53.35, 51.91, 51.25, 49.14, 46.35, 40.84, 36.20, 31.14, 27.31, 22.73, 17.19
6m	7.13—7.02(m, 3H), 4.48—4.43(m, 2H), 3.94—3.90(m, 2H), 3.76—3.47(m, 6H), 3.26—3.23(m, 4H), 3.08—3.01(m, 2H), 2.83(dd, J₁=14.6 Hz, J₂= 4.2 Hz, 1H), 1.30—1.28(m, 6H)	155.74, 146.18, 137.53, 131.42, 128.27, 125.68, 109.95, 63.09, 58.58, 55.75, 52.85, 50.63, 48.04, 46.12, 41.00, 36.17, 35.86, 17.06, 11.62

Table 4 1H NMR and 13C NMR data of compounds 6a—6m

Compd.	¹H NMR(300 MHz), δ^*	¹³C NMR(75 MHz), δ^*
6a	12.55(bs, 1H), 7.16—7.12(m, 2H), 7.07—7.04(m, 1H), 4.62(t, J=5.0 Hz, 2H), 3.86—3.47(m, 4H), 3.28—3.02(m, 8H), 2.89—2.86(dd, J₁=15.7Hz, J₂=4.6 Hz, 1H), 1.47—1.37(m, 6H), 1.32—1.29(m, 3H)	154.91, 145.40, 136.95, 131.18, 127.77, 126.38, 115.18, 59.16, 51.72, 49.69, 47.32, 46.34, 40.57, 35.11, 17.09, 8.32
6b	12.66(bs, 1H), 7.13—7.11(m, 2H), 7.04—7.01(m, 1H), 4.62—4.55(m, 2H), 3.82—3.45(m, 4H), 3.33—3.19(m, 2H), 3.14—3.01(m, 2H), 2.96—2.75(m, 7H), 1.30(d, J=7.0 Hz, 3H)	154.37, 145.07, 136.17, 132.42, 130.70, 128.18, 125.23, 58.94, 55.51, 49.64, 45.39, 42.86, 39.52, 34.88, 17.59
6c	12.45(bs, 1H), 7.16—7.12(m, 2H), 7.07—7.03(m, 1H), 4.65—4.64(m, 2H), 3.82—3.45(m, 6H), 3.24—3.22(m, 2H), 3.18—3.00(m, 2H), 2.88—2.83(m, 1H), 2.70—2.63(m, 2H), 2.33—2.30(m, 2H), 1.95—1.85(m, 3H), 1.50—1.37(m, 1H), 1.33—1.29(m, 3H)	155.25, 145.55, 136.66, 132.35, 131.76, 127.85, 125.73, 59.43, 56.01, 53.48, 51.44, 46.30, 40.03, 34.97, 22.25, 21.44, 17.20
6d	13.39(s, 1H), 7.15—7.11(m, 2H), 7.06—7.02(m, 1H), 4.64—4.40(m, 2H), 4.36—4.28(m, 2H), 4.01—3.98(m, 2H ), 3.81—3.50(m, 4H), 3.48—3.39(m, 2H), 3.30—3.22(m, 2H), 3.17—3.03(m, 2H), 2.99—2.89(m, 3H), 1.31—1.28(m, 3H)	154.87, 145.75, 137.16, 132.16, 131.47, 128.06, 126.38, 63.92, 58.78, 56.01, 51.69, 50.95, 45.81, 39.95, 34.80, 17.11
6e	7.15(d,J=1.9 Hz, 1H), 7.07(dd, J₁=8.1 Hz, J₂=1.9 Hz, 1H), 7.02(d, J=8.1 Hz, 1H), 4.19—4.17(m, 2H), 3.60—3.55(m, 4H), 3.44—3.24(m, 10H ), 3.12—3.06(m, 2H), 2.92(s, 3H), 2.79—2.74(m, 1H), 1.12(d, J=7.1 Hz, 3H)	156.37, 145.13, 137.06, 131.19, 127.85, 126.14, 114.72, 59.43, 56.01, 50.96, 49.33, 48.83, 45.48, 42.55, 39.12, 33.26, 16.38
6f	9.01(bs, 2H), 7.14—7.11(m, 2H), 7.07—7.03(m, 1H), 5.26—5.20(m, 1H), 3.84—3.48(m, 4H), 3.44—3.30(m, 2H), 3.12—3.00(m, 3H), 2.89(d, J=6.6 Hz, 3H),2.84(d, J=4.0 Hz, 3H), 1.31—1.29(m, 3H), 1.16(d, J=6.1 Hz, 3H)	162.83, 154.43, 145.13, 136.66, 132.41, 127.84, 126.15, 68.73, 65.31, 60.25, 50.95, 46.29, 45.48, 42.55, 35.78, 22.25, 16.78
6g	12.18(bs, 2H),7.16—7.12(m, 2H), 7.08—7.03(m, 1H),5.27—5.21(m, 1H), 3.78—3.44(m, 4H), 3.41—3.23(m, 6H), 3.07—2.93(m, 3H), 1.36—1.27(m, 12H)	155.65, 145.96, 137.96, 132.01, 127.86, 126.14, 115.13, 72.97, 70.37, 58.12, 50.95, 47.60, 45.49, 40.44, 36.19, 18.91,17.35 11.73
6h	7.11(m, 1H),7.05—6.98(m, 2H), 4.19—4.17(m, 2H), 3.60—3.57(m, 1H), 3.41—3.38(m, 6H), 3.25—3.15(m, 7H), 3.08—3.02(m, 1H), 2.96—2.88(m, 1H), 2.77—2.69(m, 1H), 1.10(d, J=7.1 Hz, 3H)	145.95, 137.06, 132.71, 131.99, 127.84, 126.13, 114.72, 59.84, 56.00, 50.54, 48.43, 45.08, 41.66, 38.31, 33.25, 15.97.
6i	10.25(bs, 2H), 7.64—7.62(m, 2H), 7.43—7.41(m, 3H), 7.15—7.09(m, 2H), 7.04—7.01(m, 1H), 4.50—4.69(m, 2H), 4.19(s, 2H), 3.83—3.80(m, 1H), 3.60—3.55(m, 3H), 3.11—3.02(m, 4H), 2.91—2.79(m, 1H), 1.30—1.25(m, 3H)	155.51, 145.80, 136.60, 131.30, 129.78, 129.41, 129.15, 128.79, 127.50, 125.82, 125.73, 59.90, 51.05, 49.99, 46.18, 44.92, 40.39, 35.47,17.17
6j	11.49(bs, 0.5H), 10.83(bs, 0.5H), 9.11(bs, 0.5H), 8.79(bs, 0.5H), 7.15—7.11(m, 2H), 7.07—7.03(m, 1H), 4.60—4.37(m, 3H), 3.76—3.34(m, 7H), 3.21—3.01(m, 3H), 2.83(s, 3H), 2.72—2.61(m, 1H), 2.40—2.09(m, 3H), 1.99—1.81(m, 2H), 1.75—1.59(m, 1H), 1.36—1.30(m, 3H)	175.06, 155.65, 145.13, 137.96, 132.00, 128.66, 126.13, 114.72, 67.84, 62.77, 55.20, 51.85, 51.30, 46.79, 41.38, 40.84, 36.60, 29.02, 25.68, 24.78, 23.15, 17.61
6k	7.15—7.12(m, 1H), 7.09—7.01(m, 2H), 4.19—4.14(m, 2H), 3.69—3.63(m, 2H ), 3.53—3.36(m, 5H), 3.23—3.02(m, 3H), 3.02—2.88(m, 1H), 2.85—2.71(m, 1H), 2.63(d, J =5.6 Hz, 3H), 2.51—2.32(m, 1H), 2.09—1.93(m, 3H), 1.12(d, J=6.5 Hz, 3H)	167.89, 156.56, 146.36, 137.06, 132.00, 127.85, 126.55, 115.13, 67.42, 64.49, 60.25, 56.50, 50.13, 46.31, 39.14, 32.85, 30.15, 29.42, 26.49, 22.25, 16.38
6l	7.13—7.09(m, 2H), 7.05—7.02(m, 1H), 4.50—4.18(m, 2H), 3.91—3.30(m, 10H), 3.23—3.01(m, 3H), 2.86—2.81(m, 1H), 2.09—1.82(m, 8H), 1.33—1.25(m, 3H)	156.06, 146.36, 137.97, 132.41, 128.25, 126.13, 115.57, 69.14, 62.97, 62.37, 60.10, 53.35, 51.91, 51.25, 49.14, 46.35, 40.84, 36.20, 31.14, 27.31, 22.73, 17.19
6m	7.13—7.02(m, 3H), 4.48—4.43(m, 2H), 3.94—3.90(m, 2H), 3.76—3.47(m, 6H), 3.26—3.23(m, 4H), 3.08—3.01(m, 2H), 2.83(dd, J₁=14.6 Hz, J₂= 4.2 Hz, 1H), 1.30—1.28(m, 6H)	155.74, 146.18, 137.53, 131.42, 128.27, 125.68, 109.95, 63.09, 58.58, 55.75, 52.85, 50.63, 48.04, 46.12, 41.00, 36.17, 35.86, 17.06, 11.62

Table 5 Metabolic results of compounds 6a—6m

Compd.	Metabolic results
Compd.	Regression equation (1)	$R 1 2$	Half-intial concentration/ (μmol·L^-1)	Regression equation (2)	$R 2 2$
Lorcaserin	y=0.0625x-0.1457	0.9806	7.958	y=0.0028x+0.048	0.9724
6a	y=0.0486x-0.0756	0.9850	9.946	y=0.0014x+0.0571	0.9774
6b	y=0.0607x-0.1028	0.9945	9.068	y=0.003x+0.0415	0.9788
6c	y=0.0725x+0.1009	0.9719	7.477	y=0.0725x+0.1009	0.9402
6d	y=0.0527x-0.0604	0.9896	8.429	y=0.0032x+0.0874	0.9595
6e	y=0.0757x+0.0892	0.9889	10.349	y=0.0009x+0.0664	0.9634
6f	y=0.0572x-0.1324	0.9813	8.457	y=0.0016x+0.0546	0.9935
6g	y=0.0451x-0.0776	0.9973	9.297	y=0.0115x+0.0138	0.9411
6h	y=0.0561x+0.2282	0.9960	12.253	y=0.047x-0.3031	0.9393
6i	y=0.0585x-0.0448	0.9874	8.939	y=0.0046x+0.0421	0.9655
6j	y=0.0535x-0.0584	0.9994	9.892	y=0.0035x+0.0724	0.9165
6k	y=0.0500x-0.0300	0.9988	14.680	y=0.0049x+0.0038	0.9474
6l	y=0.0623x+0.0208	0.9962	10.443	y=0.0083x-0.0347	0.9384
6m	y=0.0663x+0.2536	0.9862	9.392	y=24.877 $e - 0.078 x$	0.9806

Table 5 Metabolic results of compounds 6a—6m

Compd.	Metabolic results
Compd.	Regression equation (1)	$R 1 2$	Half-intial concentration/ (μmol·L^-1)	Regression equation (2)	$R 2 2$
Lorcaserin	y=0.0625x-0.1457	0.9806	7.958	y=0.0028x+0.048	0.9724
6a	y=0.0486x-0.0756	0.9850	9.946	y=0.0014x+0.0571	0.9774
6b	y=0.0607x-0.1028	0.9945	9.068	y=0.003x+0.0415	0.9788
6c	y=0.0725x+0.1009	0.9719	7.477	y=0.0725x+0.1009	0.9402
6d	y=0.0527x-0.0604	0.9896	8.429	y=0.0032x+0.0874	0.9595
6e	y=0.0757x+0.0892	0.9889	10.349	y=0.0009x+0.0664	0.9634
6f	y=0.0572x-0.1324	0.9813	8.457	y=0.0016x+0.0546	0.9935
6g	y=0.0451x-0.0776	0.9973	9.297	y=0.0115x+0.0138	0.9411
6h	y=0.0561x+0.2282	0.9960	12.253	y=0.047x-0.3031	0.9393
6i	y=0.0585x-0.0448	0.9874	8.939	y=0.0046x+0.0421	0.9655
6j	y=0.0535x-0.0584	0.9994	9.892	y=0.0035x+0.0724	0.9165
6k	y=0.0500x-0.0300	0.9988	14.680	y=0.0049x+0.0038	0.9474
6l	y=0.0623x+0.0208	0.9962	10.443	y=0.0083x-0.0347	0.9384
6m	y=0.0663x+0.2536	0.9862	9.392	y=24.877 $e - 0.078 x$	0.9806

Table 6 Effect of fodder on body-weigh in model rats(x?±s, n=6)

Group	Animal number	Weight/g
Group	Animal number	Before experiment^a	After experiment^b
Normal diet control	6	222.33±9.29	322.17±7.96
High fat control	6	230.83±5.11	502.50±22.83^**
Lorcaserin control	6	228.67±6.00	470.17±15.17^**
Compound 6b	6	228.33±8.56	496.00±20.67^**

Table 7 Half-life period of compounds 6a—6m

Compd.	Half-life period/min	Compd.	Half-life period/min	Compd.	Half-life period/min
Lorcaserin	27.736	6e	33.586	6j	8.198
6a	31.031	6f	39.778	6k	13.127
6b	22.926	6g	8.153	6l	15.718
6c	14.754	6h	8.185	6m	12.488
6d	9.762	6i	15.167

Fig.2 Metabolite-lorcaserin concentration of partial compounds 6 at different time points

Table 8 Effect of compound 6b on body-weigh in high-fat model rats(xˉ±s, n=6)

Group	Animal number	Weight/g		Weight increase/g
Group	Animal number	Before experiment^a		After experiment^b
Normal diet control	6	322.17±7.96	325.00±15.43	2.83±13.54
High fat control	6	502.50±22.83^**	550.33±19.00^**	47.83±15.89^**
Lorcaserin control	6	470.17±15.17^**	481.83±18.22^**##	11.67±11.67^#
Compound 6b	6	496.00±20.67^**	490.83±28.50^**##	-5.17±17.28^##

Table 9 Effect of new compound in high-fat model rats(xˉ±s, n=6)

Group	Animal number	Liver index	Lipid index	Lees index
Normal diet control	6	2.95±0.53	0.85±0.33	290.66±5.05
High fat control	6	3.89±0.27^**	3.04±0.53^**	311.77±4.18^**
Lorcaserin control	6	3.97±0.25^**	2.70±0.68^**	306.66±4.08^**
Compound 6b	6	3.61±0.34^*	2.09±0.48^**	304.45±5.20^**

Fig.3 Effect of compound 6b on blood serum T-CHO, TG, LDL-C in model rats**P<0.01 compared with the normal diet control group; ## P<0.01 compared with the high fat control group; △△ P<0.01 compared with the compound control group.

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