CN107629056B - Benzimidazole quinazoline salicyloyl amino acid benzyl ester, preparation thereof, anti-tumor activity thereof and application thereof - Google Patents

Benzimidazole quinazoline salicyloyl amino acid benzyl ester, preparation thereof, anti-tumor activity thereof and application thereof Download PDF

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CN107629056B
CN107629056B CN201510643045.5A CN201510643045A CN107629056B CN 107629056 B CN107629056 B CN 107629056B CN 201510643045 A CN201510643045 A CN 201510643045A CN 107629056 B CN107629056 B CN 107629056B
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dichloromethane
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CN107629056A (en
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赵明
彭师奇
王玉记
吴建辉
陈鹏
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Capital Medical University
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Abstract

The invention discloses 20 compounds represented by a general formula I, a preparation method thereof, and antitumor activity and antithrombotic activity thereof. The 20 compounds represented by the general formula I have double effects of resisting tumor and thrombus, and can be used for preparing anti-tumor and antithrombotic agents.
Figure DDA0000816327600000011

Description

Benzimidazole quinazoline salicyloyl amino acid benzyl ester, preparation thereof, anti-tumor activity thereof and application thereof
Technical Field
The invention discloses 20 compounds, a preparation method thereof, and antitumor activity and antithrombotic activity thereof. Therefore, the 20 compounds of the general formula I have dual effects of anti-tumor and anti-venous thrombosis, can be used for preparing anti-tumor and anti-thrombosis agents, and belongs to the field of biological medicines.
Background
Malignant tumors are a common and frequently encountered disease that seriously affects the health and life of humans, and it is expected that by 2020, the number of deaths from malignant tumors will reach as many as 1000 in the world. Venous thromboembolism is the second leading cause of death in cancer patients, and the overall mortality rate for cancer patients who develop thromboembolism is increased. It has been known since 2000 that benzimidazol [1,2-c ] quinazolines of formula II and 6-cyano-benzimidazol [1,2-c ] quinazolines of formula III exhibit inhibitory activity against tumor cell proliferation in vitro, but no analogs have been available that exhibit anti-tumor activity in vivo.
Figure BDA0000816327580000011
Through more than ten years of experimental exploration, the inventor finds that the compound obtained by substituting salicylic acid at the 6-position has the antitumor activity and the antithrombotic activity. The compound is used as a common structure, and the carboxyl of the salicylic acid is modified by amino acid benzyl ester, so that the antitumor and antithrombotic activities can be greatly improved. Based on these experimental investigations, the inventors have proposed the present invention.
Disclosure of Invention
One of the objects of the present invention is to prepare a benzyl 5- (benzimidazol [1,2-c ] -quinazolin-6-yl) -salicylamidoate having both antitumor and antithrombotic activity.
It is a further object of the present invention to provide a process for the preparation of 20 compounds represented by general formula I, which process can be described by way of figure 1, comprising the steps of:
1. reacting 5-formylsalicylic acid with 2- (2-amino-phen-1-yl) -benzimidazole to produce 5- (5, 6-dihydrobenzimidazo [1,2-c ] -quinazolin-6-yl) -salicylic acid (1) by Pictet-Spengler condensation;
2. oxidizing 5- (5, 6-dihydrobenzimidazo [1,2-c ] -quinazolin-6-yl) -salicylic acid to 5- (benzimidazo [1,2-c ] -quinazolin-6-yl) -salicylic acid (2) in the presence of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ);
3. 5- (benzimidazole [1,2-c ]) in the presence of 1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC) and 1-hydroxybenzotriazole (HOBt)]-quinazolin-6-yl) -salicylic acid with L-N6Formation of benzyl-tert-butyloxylysinate into 5- (benzimidazole [1, 2-c)]-quinazolin-6-yl) -salicyloyl N6-benzyl tert-butoxyacyl lysine (3 i');
4. in a solution of hydrogen chloride in ethyl acetate (4M), 5- (benzimidazole [1,2-c ]]-quinazolin-6-yl) -salicyloyl N6-tert-butyloxycarbonyl-lysine benzyl ester (3 i') removal of tert-butyloxycarbonyl groupTo produce 5- (benzimidazole [1,2-c ]]-quinazolin-6-yl) -salicyloyl lysine benzyl ester (3 i);
5. in the presence of 1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC) and 1-hydroxybenzotriazole (HOBt), 5- (benzimidazole [1,2-c ] -quinazoline-6-yl) -salicylic acid and L-amino acid benzyl ester generate 5- (benzimidazole [1,2-c ] -quinazoline-6-yl) -salicyloyl amino acid benzyl ester (3 a-h, j-t).
The third purpose of the invention is to investigate the activity of the compound through in vivo and in vitro model tests, and prove that the compound of the invention has antitumor activity and antithrombotic activity.
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
Description of abbreviations appearing in the present invention:
HCl EDC 1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride
EDU 1- (3-dimethylamino) -3-ethylurea
OBzl benzyloxy group
HOBt N-hydroxybenzotriazole
NMM N-methylmorpholine
CMCNa sodium carboxymethyl cellulose
Drawings
Fig. 1 is a synthesis scheme for the preparation of compounds of general formula i. In the figure i) 5-formyl salicylic acid, ethanol and acetic acid; ii) DDQ and anhydrous tetrahydrofuran; iii) EDC, HOBt, NMM and anhydrous tetrahydrofuran; iv) an ethyl acetate solution of hydrogen chloride (4M),0 ℃.3a in which AA is a L-Ala residue, 3b in which AA is a L-Cys (Bzl) residue, 3c in which AA is a L-Asp (OBzl) residue, 3d in which AA is a L-Glu (OBzl) residue, 3e in which AA is a L-Phe residue, 3f in which AA is a L-Gly residue, 3g in which AA is a L-His residue, 3h in which AA is a L-Ile residue, 3 i' in which AA is a L-Lys (OB) residue, 3i in which AA is a L-Lys residue, 3j in which AA is a L-Leu residue, 3k in which AA is a L-Met residue, 3L in which is a L-Asn residue, 3M in which AA is a L-Pro residue, 3n in which AA is a L-Gln residueResidue, AA in 3o is L-Arg (NO)2) And the AA in 3p is an L-Ser residue, the AA in 3q is an L-Thr residue, the AA in 3r is an L-Val residue, the AA in 3s is an L-Trp residue, and the AA in 3t is an L-Tyr residue.
Detailed Description
Example 15- (5, 6-dihydrobenzimidazo [1,2-c ] -quinazolin-6-yl) -salicylic acid (1)
830mg (5mmol) of 5-formyl-salicylic acid is weighed into a 100mL round-bottom flask, 40mL of absolute ethyl alcohol is added, ultrasonic treatment is carried out to dissolve the 5-formyl-salicylic acid, if the 5-formyl-salicylic acid is insoluble, 2mL of DMF is added for assisting dissolution to obtain a clear and transparent solution, 1045mg (5mmol) of 2- (2-amino-benzene-1-yl) -benzimidazole is added into the obtained solution in batches, the mixture is stirred for 8 hours at room temperature, a green solid is separated out in a reaction solution, TLC monitors that the reaction raw material point disappears (petroleum ether: acetone ═ 2:1), and a filter cake obtained by reduced pressure filtration is used for obtaining 1.76g (99%) of the title compound as a yellow-green solid. ESI-MS (M/e):358[ M + H]+,356[M-H]-.1HNMR(300MHz,DMSO-d6)δ/ppm＝7.958(d,J＝7.5Hz,1H),7.83(s,1H),7.66(d,J＝7.8Hz,1H),7.58(s,1H),7.38(d,J＝8.7Hz,1H),7.27(t,J＝7.8Hz,1H),7.20(t,J＝6.9Hz,1H),7.10(m,3H),6.87(m,3H)。
Example 25- (Benzimidazo [1,2-c ] -quinazolin-6-yl) -salicylic acid (2)
40mL of dry THF were placed in a round bottom flask, 2.27mg (10mmol) of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) were weighed into dry THF to give a brownish red solution, and 1775mg (5mmol) of 5- (5, 6-dihydrobenzimidazole [1,2-c ] -benzoquinone were weighed]-quinazolin-6-yl) -salicylic acid (1) was added in portions to the above reddish brown solution to give a suspension, stirred at room temperature for 12 hours, TLC monitored the disappearance of the reaction starting material spot (1) (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the resulting filter cake was filtered under reduced pressure, and repeatedly rinsed 3 times with methanol to give the title compound 1.7g (96%) as a colorless solid. ESI-MS (M/e):425[ M-H]-.1HNMR(300MHz,DMSO-d6)δ/ppm＝8.63(d,J＝7.8Hz,1H),8.28(s,1H),7.92(m,4H),7.76(t,J＝7.2Hz,1H),7.48(t,J＝7.8Hz,1H),7.23(m,2H),7.20(d,J＝8.4Hz,1H)。
Example 35- (Benzimidazo [1,2-c ] -quinazolin-6-yl) -salicyloylalanine benzyl ester (3a)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 421mg (1.2mmol) of TosH Ala OBzl, 250mg (1.3mmol) of 1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl EDC), 162mg (1.2mmol) of N-hydroxybenzotriazole (HOBt), 30mL of anhydrous THF was added and stirred, NMM adjusted the pH of the reaction mixture to 8, TLC monitored the disappearance of the feed point (2) after the reaction mixture was stirred for 8 hours (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off under reduced pressure and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown-yellow oil, wet-packed with dichloromethane, dry-packed, and purified (dichloromethane: methanol ═ 100:1) to give 400mg (80%) of the title compound as a colorless solid. Mp 176-;
Figure BDA0000816327580000041
IR(KBr):3243,3062,2935,1743,1647,1595,1533,1496,1448,1371,1448,1371,1338,1305,1273,1259,1153,835,759,698.ESI-MS(m/e):517[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.776(s,1H),9.228(d,J＝5.1Hz,1H),8.645(d,J＝7.8Hz,1H),7.918(m,4H),7.778(t,J＝4.5Hz,1H),7.487(t,J＝4.5Hz,1H),7.263(m,7H),6.690(d,J＝8.4Hz,1H),5.175(s,2H),4.63(t,J＝7.2Hz,1H),1.433(d,J＝7.2Hz,3H)。
example 35- (Benzimidazo [1,2-c ] -quinazolin-6-yl) -salicylic acid benzyl sulfide cysteine benzyl ester (3b)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 405mg (1.2mmol) HCl Cys (Bzl) -OBzl, 250mg (1.3mmol)1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC), 162mg (1.2mmol) N-hydroxybenzotriazole (HOBt), 30mL anhydrous THF was added and stirred, NMM adjusted to pH 8, the reaction mixture was stirred for 8 hours and then TLC monitored starting material by TLCPoint (2) disappeared (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-packed, and purified (dichloromethane: methanol ═ 100:1) to give 431mg (68%) of the title compound as a colorless solid. Mp 165-166 ℃;
Figure BDA0000816327580000042
IR(KBr):3211,3061,3008,2958,2918,1741,1647,1624,1595,1531,1490,1446,1361,1338,1303,1271,1215,1159,759,742,732.ESI-MS(m/e):639[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.504(s,1H),9.368(d,J＝6.6Hz,1H),8.340(d,J＝7.5Hz,1H),8.431(s,1H),7.925(m,4H),7.768(t,J＝7.2Hz,1H),7.475(t,J＝7.5Hz,1H),7.236(m,12H),6.724(d,J＝8.4Hz,1H),5.181(s,2H),5.181(s,2H),4.857(dd,J＝7.2,12.6Hz,1H),3.779(s,2H),2.960(m,2H)。
example 45- (Benzimidazo [1,2-c ] -quinazolin-6-yl) -salicylic acid bis-benzyl aspartate (3c)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 582mg (1.2mmol) TosH asp (OBzl) -OBzl, 250mg (1.3mmol)1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC), 162mg (1.2mmol) N-hydroxybenzotriazole (HOBt), 30mL anhydrous THF was added and stirred, NMM adjusted the reaction solution pH to 8, TLC monitored the disappearance of the feed point (2) after the reaction mixture was stirred for 8 hours (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), a saturated aqueous solution of sodium chloride (10 mL. times.3), a 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3), and saturated sodium chlorideAqueous solution (10 mL. times.3). The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-packed, and purified (dichloromethane: methanol ═ 100:1) to give 469mg (72%) of the title compound as a colorless solid. Mp 163-164 ℃;
Figure BDA0000816327580000051
IR(KBr):3257,3066,2927,1747,1647,1622,1593,1529,1496,1340,1273,1217,827,744,698.ESI-MS(m/e):651[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.544(s,1H),9.436(d,J＝7.5Hz,1H),8.640(dd,J＝0.9,7.8Hz,1H),8.378(d,J＝1.8Hz,1H),7.904(m,4H),7.769(dt,J＝0.9,7.8Hz,1H),7.479(t,J＝7.2Hz,1H),7.283(m,12H),6.700(d,J＝8.4Hz,1H),5.162(s,2H),5.109(s,2H),5.066(t,J＝6.9Hz,1H),3.103(dd,J＝5.7,16.8Hz,1H),3.027(dd,J＝7.8,16.8Hz,1H)。
example 55- (benzimidazole [1,2-c ] -quinazolin-6-yl) -salicylic acid glutamic acid bis-benzyl ester (3d)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 598mg (1.2mmol) TosH glu (OBzl) -OBzl, 250mg (1.3mmol)1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC), 162mg (1.2mmol) N-hydroxybenzotriazole (HOBt), 30mL anhydrous THF was added and stirred, NMM adjusted the reaction solution pH to 8, TLC monitored the disappearance of the feed point (2) (dichloromethane: methanol: ice HAc ═ 10:1:0.1) after the reaction mixture was stirred for 8 hours, the reaction was stopped, EDU was filtered off by filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-packed, and purified (dichloromethane: methanol ═ 100:1) to give 436mg (66%) of the title compound as a colorless solid. Mp 176-;
Figure BDA0000816327580000052
IR(KBr):3356,3188,2927,1739,1647,1624,1595,1533,1490,1448,1338,1271,1259,1215,835,759,698.ESI-MS(m/e):665[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.686(s,1H),9.178(d,J＝6.3Hz,1H),8.651(d,J＝7.8Hz,1H),8.426(s,1H),7.892(m,4H),7.784(t,J＝6.9Hz,1H),7.475(t,J＝7.5Hz,1H),7.230(m,12H),6.713(d,J＝7.5Hz,1H),5.171(s,2H),5.045(s,2H),4.657(dd,J＝9.0,12.3Hz,1H),2.471(m,2H),2.182(dd,J＝8.7,14.4Hz,1H),2.07(dd,J＝7.5,15.9Hz,1H)。
example 65- (benzimidazole [1,2-c ] -quinazolin-6-yl) -salicyloylphenylalanin benzyl ester (3e)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 349mg (1.2mmol) HCl Phe-OBzl, 250mg (1.3mmol)1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl EDC), 162mg (1.2mmol) N-hydroxybenzotriazole (HOBt), 30mL anhydrous THF added and stirred, NMM adjusted the reaction solution pH to 8, TLC monitored the disappearance of the feed point (2) after the reaction mixture was stirred for 8 hours (dichloromethane: methanol: ice HAc ═ 10:1:0.1), reaction stopped, EDU filtered off by filtration under reduced pressure, and the filtrate concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-packed, and purified (dichloromethane: methanol ═ 100:1) to give 328mg (55%) of the title compound as a colorless solid. Mp 171-172 deg.C;
Figure BDA0000816327580000061
IR(KBr):3257,3066,2927,1747,1647,1622,1593,1529,1496,1340,1273,1217,827,744,698.ESI-MS(m/e):593[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.507(s,1H),9.164(d,J＝6.3Hz,1H),8.646(dd,J＝0.6,7.5Hz,1H),8.386(s,1H),7.913(m,4H),7.777(dt,J＝1.2,8.1Hz,1H),7.498(t,J＝7.5Hz,1H),7.313(m,5H),7.217(m,7H),6.673(d,J＝8.4Hz,1H),5.151(s,2H),4.856(dd,J＝8.1,14.1Hz,1H),3.212(dd,J＝6.0,13.8Hz,1H),3.130(dd,J＝5.7,13.8Hz,1H)。
example 75- (Benzimidazo [1,2-c ] -quinazolin-6-yl) -salicyloylglycine benzyl ester (3f)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 404mg (1.2mmol) TosH Gly-OBzl, 250mg (1.3mmol)1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC), 162mg (1.2mmol) N-hydroxybenzotriazole (HOBt), 30mL dry THF was added and stirred, NMM adjusted the reaction solution pH to 8, TLC monitored the disappearance of the feed point (2) after the reaction mixture was stirred for 8 hours (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off under reduced pressure and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-packed, and purified (dichloromethane: methanol ═ 90:1) to give 396mg (79%) of the title compound as a colorless solid. Mp 144-145 ℃;
Figure BDA0000816327580000062
IR(KBr):3441,3257,3064,1747,1650,1593,1558,1496,1371,1340,1309,1230,1230,1147,1126,718,698.ESI-MS(m/e):503[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.659(s,1H),9.330(t,J＝5.4Hz,1H),8.637(d,J＝7.8Hz,1H),8.393(d,J＝1.8Hz,1H),7.909(m, 4H),7.769(t,J＝7.2Hz,1H),7.483(t,J＝7.5Hz,1H),7.332(m,7H),6.742(d,J＝8.4Hz,1H),5.18(s,2H),4.174(d,J＝5.4Hz,2H)。
example 85- (Benzimidazo [1,2-c ] -quinazolin-6-yl) -salicyloyl histidine benzyl ester (3g)
In ice bath to 100 deg.CIn a mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ]]-quinazolin-6-yl) -salicylic acid (2), 500mg (1.2mmol) TosH His OBzl, 250mg (1.3mmol)1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC), 162mg (1.2mmol) N-hydroxybenzotriazole (HOBt), 30mL anhydrous THF was added and stirred, NMM adjusted the reaction solution pH to 8, TLC monitored the disappearance of the feed point (2) after the reaction mixture was stirred for 8 hours (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off under reduced pressure and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-packed and purified (dichloromethane: methanol ═ 20:1) to give 114mg (20%) of the title compound as a yellow solid. Mp 176-;
Figure BDA0000816327580000071
IR(KBr):3361,2935,2868,1743,1647,1595,1558,1448,1338,1305,1217,1174,1122,832,744.ESI-MS(m/e):583[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝9.399(d,J＝6.3Hz,1H),8.639(dd,J＝0.9,7.8Hz,1H),8.374(d,J＝1.8,1H),7.885(m,4H),7.773(dt,J＝1.2,7.8Hz,1H),7.551(s,1H),7.489(t,J＝10.8Hz,1H),7.226(m,7H),6.821(s,1H),6.732(d,J＝8.4Hz,1H),5.140(s,2H),4.832(t,J＝6.3Hz,1H),3.095(d,J＝6.6Hz,2H)。
example 95- (Benzimidazo [1,2-c ] -quinazolin-6-yl) -salicyloyl isoleucine benzyl ester (3h)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 435mg (1.2mmol) of TosH. Ile-OBzl, 250mg (1.3mmol) of 1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC), 162mg (1.2mmol) of N-hydroxybenzotriazole (HOBt), 30mL of anhydrous THF added and stirred, NMM adjusted the reaction solution pH to 8, TLC monitored the disappearance of the starting material spot (2) after the reaction mixture was stirred for 8 hours (dichloromethane: methanol)Ice HAc 10:1:0.1), stopping the reaction, filtering to remove EDU under reduced pressure, and concentrating the filtrate under reduced pressure to dryness. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-packed and purified (dichloromethane: methanol ═ 100:1) to give 462mg (83%) of the title compound as a colorless solid. Mp 163-164 ℃;
Figure BDA0000816327580000072
IR(KBr):3361,3072,2964,2877, 1739,1647,1595,1533,1490,1446,1361,1338,1303,1271,12125,1184,1145,833,740,689.ESI-MS(m/e):559[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.570(s,1H),9.020(d,J＝6.9Hz,1H),8.638(dd,J＝0.6,7.5Hz,1H),8.473(s,1H),7.903(m,4H),7.769(dt,J＝0.9,7.8Hz,1H),7.481(t,J＝7.2Hz,1H),7.281(m,7H),6.703(d,J＝8.4Hz,1H),5.212(dd,J＝12.6,17.7Hz,1H),5.153(dd,J＝5.1,17.4Hz,1H),4.552(t,J＝6.9Hz,1H),1.972(m,1H),1.449(m,1H),1.211(m,1H),0.898(d,J＝6.6Hz,3H),0.836(d,J＝7.2Hz,3H)。
example 105- (benzimidazole [1, 2-c)]-quinazolin-6-yl) -salicyloyl-N6-tert-Butyloxylysine benzyl ester (3 i')
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 447mg (1.2mmol) of TosH lys (boc) -OBzl, 250mg (1.3mmol) of 1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC), 162mg (1.2mmol) of N-hydroxybenzotriazole (HOBt), 30mL of anhydrous THF was added and stirred, NMM adjusted to pH 8, TLC monitored disappearance of the feed spot (2) after the reaction mixture was stirred for 8 hours (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, washed with saturated aqueous sodium bicarbonate (10 mL. times.3), and then saturated sodium chlorideAqueous solution (10 mL. times.3), 5% aqueous potassium hydrogensulfate solution (10 mL. times.3), and saturated aqueous sodium chloride solution (10 mL. times.3). The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown-yellow oil, wet-packed with dichloromethane, dry-packed, and purified (dichloromethane: methanol ═ 100:1) to give 473mg (70%) of the title compound as a colorless solid. ESI-MS (M/e) 674[ M + H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.79(s,1H),9.16(s,1H),8.64(d,J＝9Hz,1H),8.45(s,1H),7.87～8.00(m,4H),7.78(t,J＝7.5Hz,1H),7.49(t,J＝7.5Hz,1H),7.18～7.35(m,7H),6.76(s,1H),6.70(d,J＝9Hz,1H),5.17(s,2H),4.54(dd,J＝6,12Hz,1H),2.84(m,2H),1.79(m,2H),1.30(m,13H)。
Example 115- (benzimidazole [1,2-c ] -quinazolin-6-yl) -salicyloyl lysine benzyl ester (3i)
680mg (1.01mmol) of 5- (benzimidazole [1,2-c ] was added to a 100mL eggplant bottle under ice-bath]-quinazolin-6-yl) -salicylic acid tert-butoxy lysine benzyl ester (3K (Boc)), add about 10mL of 4N HCl/EtOAc solution, stir for 3h in ice bath, TLC detect the disappearance of the reaction feed spot (3 i') and terminate the reaction. The mixture was concentrated to dryness under reduced pressure, and the resultant was dissolved in 20mL of an anhydrous ethyl acetate solution, concentrated again to dryness under reduced pressure, and repeated three times. Finally, the resulting mixture was mixed well with 20mL of anhydrous ether, concentrated to dryness under reduced pressure, and repeated three times to give 547mg (95%) of the title compound as a colorless solid. Mp 164-165 ℃;
Figure BDA0000816327580000081
IR(KBr):3244,2953,2912,1734,1643,1585,1533,1489,1454,1379,1240,1193,1002,840,748,698.ESI-MS(m/e):574[M+H]+.1HNMR(800MHz,DMSO-d6)δ/ppm＝8.611(dd,J＝1.6,8.0Hz, 1H),8.304(d,J＝1.6Hz,1H),7.937(d,J＝8.0Hz,1H),7.870(d,J＝0.8Hz,1H),7.855(t,J＝4.0Hz,1H),7.855(t,J＝4.0Hz,1H),7.733(dt,J＝0.8,7.2Hz,1H),7.650(d,J＝8.0Hz,1H),7.480(dt,J＝0.8,8.0Hz,1H),7.377(m,5H),7.201(t,J＝8.0Hz,1H),6.988(t,J＝9.6Hz,2H),5.18(s,2H),4.596(s,1H),2.750(t,J＝7.2Hz,1H),1.856(t,J＝8.0Hz,1H),1.809(t,J＝8.0Hz,1H),1.587(dd,J＝7.216.8Hz,2H),1.419(t,J＝8.0Hz,2H)。
example 125- (Benzimidazo [1,2-c ] -quinazolin-6-yl) -salicyloylleucine benzyl ester (3j)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 435mg (1.2mmol) of TosH Leu-OBzl, 250mg (1.3mmol) of 1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC), 162mg (1.2mmol) of N-hydroxybenzotriazole (HOBt), 30mL of anhydrous THF was added and stirred, NMM adjusted the reaction solution pH to 8, TLC monitored the disappearance of the feed point (2) after the reaction mixture was stirred for 8 hours (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off under reduced pressure and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-mixed and purified (dichloromethane: methanol ═ 100:1) to give 415mg (74%) of the title compound as a colorless solid. Mp 158-;IR(KBr):3064,2956,2927,2868,2856,1739,1647,1622,1595,1496,1448,1361,1338,1259,1217,1195,1149,831,808,759,698.ESI-MS(m/e):559[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.771(s,1H),9.139(s,1H),8.650(dd,J＝0.9,7.8Hz,1H),8.454(s,1H),7.899(m,4H),7.785(dt,J＝1.2,7.8Hz,1H),7.494(t,J＝7.8Hz,1H),7.229(m,7H),6.717(d,J＝7.8Hz,1H),5.167(s,2H),4.628(dd,J＝4.2,8.7Hz,1H),1.77(m,1H),1.618(m,2H),0.870(d,J＝5.4Hz,6H)。
example 135- (benzimidazole [1,2-c ] -quinazolin-6-yl) -salicylic-acyl-methionine benzyl ester (3k)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 493mg (1.2mmol) of TosH.Met-OBzl, 250mg (1.3mmol) of 1- (3-dimethylamino) -3-ethaneCarbodiimide hydrochloride (HCl. EDC), 162mg (1.2mmol) of N-hydroxybenzotriazole (HOBt), 30mL of anhydrous THF was added and stirred, NMM adjusted the reaction solution pH to 8, the reaction mixture was stirred for 8 hours and TLC monitored that the raw material spot (2) disappeared (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown-yellow oil, wet-packed with dichloromethane, dry-packed, and purified (dichloromethane: methanol ═ 100:1) to give 348mg (60%) of the title compound as a colorless solid. Mp 153-;
Figure BDA0000816327580000101
IR(KBr):3211,3061,3008,2958,2918,1741,1647,1624,1595,1531,1490,1446,1361,1338,1303,1271,1215,1159,759,742,732.ESI-MS(m/e):577[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.698(s,1H),9.182(s,1H),8.652(d,J＝7.5Hz,1H),8.433(s,1H),7.923(m,4H),7.786(t,J＝7.8Hz,1H),7.495(t,J＝7.5Hz,1H),7.230(m,7H),6.716(d,J＝8.4Hz,1H),5.181(s,2H),4.730(dd,J＝6.9,13.5Hz,1H),2.504(s,2H),2.10(t,J＝6.9Hz,2H),2.000(s,3H)。
example 145- (Benzimidazo [1,2-c ] -quinazolin-6-yl) -salicylanilide benzyl ester (3l)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 310mg (1.2mmol) of HCl Asn-OBzl, 250mg (1.3mmol) of 1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC), 162mg (1.2mmol) of N-hydroxybenzotriazole (HOBt), 30mL of anhydrous THF was added and stirred, NMM adjusted the pH of the reaction solution to 8, TLC monitored the disappearance of the feed point (2) after the reaction mixture was stirred for 8 hours (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off by filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane and transferred toA100 mL separatory funnel was washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), a saturated aqueous solution of sodium chloride (10 mL. times.3), a 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3), and a saturated aqueous solution of sodium chloride (10 mL. times.3), in that order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-packed, and purified (dichloromethane: methanol ═ 20:1) to give 262mg (47%) of the title compound as a colorless solid. Mp 139-140 ℃;
Figure BDA0000816327580000102
IR(KBr):3356,3188,2927,1739,1647,1624,1595,1533,1490,1448,1338,1271,1259,1215,835,759,698.ESI-MS(m/e):560[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.48(s,1H),9.383(d,J＝7.5Hz,1H),8.641(d,J＝7.8Hz,1H),8.388(d,J＝1.8Hz,1H),7.914(m,4H),7.776(t,J＝7.8Hz,1H),7.486(t,J＝7.2Hz,1H),7.486(s,1H),7.250(m,7H),6.992(s,1H),6.710(d,J＝8.4Hz,1H),5.159(s,2H),4.947(dd,J＝5.4,12.9Hz,1H),2.770(d,J＝5.1Hz,2H)。
example 155- (benzimidazole [1,2-c ] -quinazolin-6-yl) -salicylic acid proline benzyl ester (3m)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 290mg (1.2mmol) HCl Pro-OBzl, 250mg (1.3mmol)1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl EDC), 162mg (1.2mmol) N-hydroxybenzotriazole (HOBt), 30mL anhydrous THF was added and stirred, NMM adjusted the reaction solution pH to 8, TLC monitored the disappearance of the feed point (2) after the reaction mixture was stirred for 8 hours (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off under reduced pressure and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. Drying the combined dichloromethane layer with anhydrous sodium sulfate for 2 hr, filtering, concentrating the filtrate under reduced pressure to dryness to obtain brown yellow oil, wet loading with dichloromethane, and dry loadingPurification was carried out as a sample (dichloromethane: methanol 100:1) to yield 254mg (47%) of the title compound as a colorless solid. Mp 179-180 ℃;
Figure BDA0000816327580000111
IR(KBr):3244,2953,2912,1734,1643,1585,1533,1489,1454,1379,1240,1193,1002,840,748,698.ESI-MS(m/e):543[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝10.772(s,1H),8.630(d,J＝7.2Hz,1H),7.897(m,3H),7.746(m,2H),7.493(d,J＝7.2Hz,1H),7.481(d,J＝7.8Hz,1H),7.212(m,7H),6.72(d,J＝8.4Hz,1H),5.100(dd,J＝12.6,23.1Hz,1H),4.540(dd,J＝3.6,8.1Hz,1H),3.575(dd,J＝6.6,15.6Hz,1H),3.468(dd,J＝5.7,9.9Hz,1H),2.299(m,1H),1.90(m,3H)。
example 165- (benzimidazole [1,2-c ] -quinazolin-6-yl) -salicyloylglutaminebenzyl ester (3n)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 327mg (1.2mmol) of HCl Gln-OBzl, 250mg (1.3mmol) of 1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl EDC), 162mg (1.2mmol) of N-hydroxybenzotriazole (HOBt), 30mL of anhydrous THF was added and stirred, NMM adjusted the reaction solution pH to 8, TLC monitored the disappearance of the feed point (2) after the reaction mixture was stirred for 8 hours (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off under reduced pressure and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown-yellow oil, wet-packed with dichloromethane, dry-packed, and purified (dichloromethane: methanol ═ 20:1) to give 200mg (35%) of the title compound as a pale yellow solid. Mp 168-169 deg.C;
Figure BDA0000816327580000112
IR(KBr):3356,3188,2927,1739,1647,1624,1595,1533,1490,1448,1338,1271,1259,1215,835,759,698.ESI-MS(m/e):574[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.803(s,1H),9.257(s,1H),8.657(d,J＝7.8Hz,1H),8.458(s,1H),7.925(m,4H),7.787(t,J＝7.2Hz,1H),7.497(t,J＝7.5Hz,1H),7.235(m,8H),6.791(s,1H),6.710(d,J＝7.8Hz,1H),5.175(s,2H), 4.612(d,J＝6.9Hz,1H),2.157(m,3H),1.959(m,1H)。
example 175- (Benzimidazo [1,2-c ] -quinazolin-6-yl) -salicyloyl nitroarginine benzyl ester (3o)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 577mg (1.2mmol) of TosH Arg (NO)2) OBzl, 250mg (1.3mmol) of 1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC), 162mg (1.2mmol) of N-hydroxybenzotriazole (HOBt), 30mL of anhydrous THF, stirring, NMM adjusting the pH of the reaction solution to 8, stirring the reaction mixture for 8 hours, TLC monitoring the disappearance of the starting material spot (2) (dichloromethane: methanol: ice HAc ═ 10:1:0.1), stopping the reaction, filtering off EDU under reduced pressure, and concentrating the filtrate to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-mixed and purified (dichloromethane: methanol ═ 50:1) to give 367mg (57%) of the title compound as a colorless solid. Mp 148-149 deg.C;
Figure BDA0000816327580000121
IR(KBr):3313,3066,2845,1739,1645,1595,1492,1448,1361,1338,1303,1261,833,742,698.ESI-MS(m/e):647[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.704(s,1H),9.171(s,1H),8.652(d,J＝9Hz,1H),8.432(s,1H),7.923(m,5H),7.787(t,J＝6.9Hz,1H),7.494(t,J＝7.8Hz,1H),7.234(m,7H),6.72(d,J＝8.4Hz,1H),5.174(s,2H),4.606(dd,J＝8.7,12.9Hz,1H),3.152(d,J＝5.7Hz,2H),1.860(m,2H),1.582(m,2H)。
example 185- (Benzimidazo [1,2-c ] -quinazolin-6-yl) -salicylic-ylserine benzyl ester (3p)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 277mg (1.2mmol) of HCl Ser OBzl, 250mg (1.3mmol) of 1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl EDC), 162mg (1.2mmol) of N-hydroxybenzotriazole (HOBt), 30mL of anhydrous THF was added and stirred, NMM adjusted the pH of the reaction mixture to 8, TLC monitored the disappearance of the feed point (2) (dichloromethane: methanol: ice HAc ═ 10:1:0.1) after stirring the reaction mixture for 8 hours, the reaction was stopped, EDU was filtered off under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-mixed and purified (dichloromethane: methanol 80:1) to give 215mg (41%) of the title compound as a colorless solid. Mp 173-174 deg.C;
Figure BDA0000816327580000122
IR(KBr):3277,2926,2889,1749,1651,1625,1597,1531,1490,1448,1373,1352,1301,1215,1147,869,823,732,698.ESI-MS(m/e):533[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.504(s,1H),9.216(d,J＝7.2Hz,1H),8.643(d,J＝7.5Hz,1H),8.445(d,J＝1.8Hz,1H),7.906(m,4H),7.780(t,J＝7.2Hz,1H),7.491(t,J＝7.5Hz,1H),7.271(m,7H),6.71(d,J＝8.4Hz,1H),5.281(t,J＝4.8Hz,1H),5.188(s,2H),4.467(dd,J＝4.2,8.1Hz,1H),3.860(m,2H)。
example 195- (Benzimidazo [1,2-c ] -quinazolin-6-yl) -salicylic acid threonine benzyl ester (3q)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 457mg (1.2mmol) of TosH Thr-OBzl, 250mg (1.3mmol) of 1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC), 162mg (1.2mmol) of N-hydroxybenzotriazole (H)OBt), 30mL of anhydrous THF was added thereto and stirred, NMM was added to adjust the pH of the reaction solution to 8, the reaction mixture was stirred for 8 hours and then TLC was monitored for disappearance of the starting material spot (2) (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off under reduced pressure and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-mixed and purified (dichloromethane: methanol ═ 80:1) to give 353mg (65%) of the title compound as a colorless solid. Mp 160-161 deg.C;IR(KBr):3441,3257,3069,1747,1651,1593,1558,1496,1371,1340,1309,1230,1176,1126,748,698.ESI-MS(m/e):547[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.308(s,1H),9.036(d,J＝7.8Hz,1H),8.636(d,J＝7.5Hz,1H),8.450(d,J＝2.1Hz,1H),7.899(m,4H),7.767(dt,J＝0,9,7.8Hz,1H),7.482(t,J＝7.8Hz,1H),7.322(m,7H),6.734(d,J＝8.4Hz,1H),5.283(d,J＝5.4Hz,1H),5.184(s,2H),4.612(dd,J＝3.0,7.8Hz,1H),4.295(dd,J＝6.0,9.0Hz,1H),1.172(d,J＝6.3Hz,3H)。
example 205- (Benzimidazo [1,2-c ] -quinazolin-6-yl) -salicyloylvaline benzyl ester (3r)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 455mg (1.2mmol) TosH Val-OBzl, 250mg (1.3mmol)1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC), 162mg (1.2mmol) N-hydroxybenzotriazole (HOBt), 30mL anhydrous THF was added and stirred, NMM adjusted the reaction solution pH to 8, TLC monitored the disappearance of the feed point (2) after the reaction mixture was stirred for 8 hours (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and successively treated with saturated sodium bicarbonateThe washing with the solution (10 mL. times.3), the washing with a saturated aqueous solution of sodium chloride (10 mL. times.3), the washing with a 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3), and the washing with a saturated aqueous solution of sodium chloride (10 mL. times.3). The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-packed, and purified (dichloromethane: methanol ═ 100:1) to give 445mg (82%) of the title compound as a colorless solid. Mp 157-158 ℃;
Figure BDA0000816327580000141
IR(KBr):3402,3066,2964,2877,1749,1645,1595,1533,1489,1446,1338,1303,1271,1215,1192,1149,833,759.ESI-MS(m/e):545[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.567(s,1H),9.015(d,J＝7.2Hz,1H),8.642(dd,J＝0.9,7.8Hz,1H),8.474(s,1H),7.891(m,4H),7.776(dt,J＝0.9,7.8Hz,1H),7.487(t,J＝7.2Hz,1H),7.304(m,7H),6.718(d,J＝8.4Hz,1H),5.177(d J＝11.1Hz,2H),4.496(t,J＝6.6Hz,1H),2.221(m,1H),0.933(d,J＝6.6Hz,6H)。
example 215- (benzimidazole [1,2-c ] -quinazolin-6-yl) -salicylic acid tryptophan benzyl ester (3s)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 559mg (1.2mmol) of TosH · Trp-OBzl, 250mg (1.3mmol) of 1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl · EDC), 162mg (1.2mmol) of N-hydroxybenzotriazole (HOBt), 30mL of anhydrous THF was added and stirred, NMM adjusted the reaction solution pH to 8, TLC monitored the disappearance of the feed point (2) after the reaction mixture was stirred for 8 hours (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off under reduced pressure and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-packed, purified (dichloromethane: methanol 100:1),345mg (55%) of the title compound are obtained as a yellow solid. Mp 172-173 ℃;
Figure BDA0000816327580000142
IR(KBr):3410,3059,2927,2850,1745,1645,1624,1583,1496,1448,1340,1273,1219,987,910,839,738,698.ESI-MS(m/e):632[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.528(s,1H),10.893(s,1H),9.233(s,1H),8.647(d,J＝8.4Hz,1H),8.439(s,1H),7.916(m,4H),7.776(t,J＝7.8Hz,1H),7.511(d,J＝8.4Hz,1H),7.497(t,J＝8.4Hz,1H),7.235(m,4H),7.055(t,J＝6.6Hz,1H),7.055(t,J＝6.6Hz,1H),6.930(s,1H),6.687(d,J＝8.4Hz,1H),5.121(dd,J＝12.6,17.4Hz,2H),4.885(dd,J＝7.2,13.5Hz,1H),3.33(m,2H)。
example 225- (benzimidazole [1,2-c ] -quinazolin-6-yl) -benzyl salicyloyltyrosine (3t)
To a 100mL eggplant bottle was added 355mg (1mmol) of 5- (benzimidazole [1,2-c ] under ice-cooling]-quinazolin-6-yl) -salicylic acid (2), 531mg (1.2mmol) TosH Tyr-OBzl, 250mg (1.3mmol)1- (3-dimethylamino) -3-ethylcarbodiimide hydrochloride (HCl. EDC), 162mg (1.2mmol) N-hydroxybenzotriazole (HOBt), 30mL dry THF was added and stirred, NMM adjusted to pH 8, TLC monitored the disappearance of the feed point (2) after the reaction mixture was stirred for 8 hours (dichloromethane: methanol: ice HAc ═ 10:1:0.1), the reaction was stopped, EDU was filtered off under reduced pressure and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 30mL of dichloromethane, transferred to a 100mL separatory funnel, and washed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL. times.3), saturated aqueous solution of sodium chloride (10 mL. times.3), 5% aqueous solution of potassium hydrogensulfate (10 mL. times.3) and saturated aqueous solution of sodium chloride (10 mL. times.3) in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a brown yellow oil, wet-packed with dichloromethane, dry-packed, and purified (dichloromethane: methanol ═ 80:1) to give 431mg (71%) of the title compound as a colorless solid. Mp 181-183 ℃;
Figure BDA0000816327580000151
IR(KBr):3321,3061,2951,1726,1647,1597,1516,1490,1448,1369,1340,1172,1016,821,758,698.ESI-MS(m/e):609[M+H]+.1HNMR(300MHz,DMSO-d6)δ/ppm＝12.518(s,1H),9.270(s,1H),9.111(s,1H),8.642(d,J＝7.5Hz,1H),8.412(s,1H),7.915(m,4H),7.775(t,J＝7.8Hz,1H),7.494(t,J＝7.8Hz,1H),7.243(m,7H),6.990(d,J＝7.5Hz,2H),6.686(d,J＝8.4Hz,2H),6.639(d,J＝7.8Hz,1H),5.141(s,2H),4.768(dd,J＝7.2,13.5Hz,1H),3.081(dd,J＝6.0,14.1Hz,1H),3.014(dd,J＝7.8,13.8Hz,1H)。
experimental example 1 evaluation of antitumor cell proliferation Activity
Experimental methods
(1) Materials and methods
a. Test sample
All compounds in the in vitro anti-cell proliferation assay were formulated to the desired concentration in the corresponding medium containing 0.5% DMSO. The positive control was doxorubicin and the blank was the corresponding medium containing 0.5% DMSO.
b. Cell lines
A549 (human non-small cell lung cancer cell), MCF-7 (human breast cancer cell), K562 (human chronic myelocytic leukemia cell), HL60 (human promyelocytic leukemia cell), S180 (mouse anal sarcoma cell), HaCaT (human immortalized normal epidermal cell), L02 (human immortalized normal liver cancer cell).
c. Main instrument
An enzyme-labeling instrument: 450, Biorad;
an autoclave: 400Ep-Z, Bruckmanning, Inc.;
a cell incubator: INC153, memmer, INC;
low-temperature centrifuger: SPD111V, Thermo corporation;
96-well cell culture plates: costar corporation;
quartz automatic double pure water distiller: 1810-B, Jiangsu Ronghua apparatus manufacturing Co., Ltd;
d. primary reagent
MTT: tetrathiazoie blue (3- (4, 5-dimethylthiozol-2-yl) 2,5-diphenyl-tetrazolium bromide) (Fluka) dissolved in PBS at a concentration of 5mg/mL, filtered and sterilized, and stored at 4 ℃ in the dark;
PBS: each liter of the solution contains 8.2g of NaCl and 0.2g of KCl,Na2HPO4·H2O 1.56g，KH2PO40.2g, pH 7.4;
RPMI-1640 medium: gibco corporation;
DMEM medium: gibco corporation;
fetal bovine serum: hyclone company;
penicillin: shiyao Zhongnuo pharmaceutical (Shijiazhuang) Co.Ltd;
streptomycin: shiyao Zhongnuo pharmaceutical (Shijiazhuang) Co.Ltd;
DMSO, DMSO: hyclone company;
the remaining reagents were all commercially available analytical grade.
(2) Cell culture
S180 (mouse anus sarcoma cell), HL60 (human promyelocytic leukemia cell), K562 (human chronic myelocytic leukemia cell), A549 (human non-small cell lung cancer cell) 4 strain tumor cell selecting RPMI-1640 culture medium; MCF-7 (human breast cancer cells), HaCaT (human immortalized normal epidermal cells) and L02 (human immortalized normal liver cancer cells) adopt DMEM culture medium; the culture solutions all contain 10% inactivated fetal calf serum and 1 × 105U·L-1Penicillin and 100 mg.L-1Streptomycin.
(3) In vitro anti-cell proliferation Activity assay
a. Culture of suspension cells HL60 and K562
Using MTT method, HL60 and K562 tumor cells with good growth state and logarithmic growth phase were treated at 5 × 104Inoculating the strain/mL of the strain in a 96-well plate with 100 mu L of the strain per well, adding a sample to be detected and subjected to sterilization treatment according to a preset concentration gradient, and adding an equal volume of a solvent for dissolving the sample to a control group. 37 ℃ and 5% CO2After 48 hours of incubation in the incubator, 25. mu.L of 5mg/mL MTT solution was added to each well, incubation was continued at 37 ℃ for 4 hours, centrifuged (3000rpm, 15min), the supernatant was carefully aspirated, 100. mu.L DMSO was added to each well to dissolve the purple residue, the precipitate was shaken for about 10min to completely dissolve, and the O.D. value (absorbance) was measured on a microplate reader at a wavelength of 570 nm.
b. Culture of adherent cells S180 (semi-adherent semi-suspension), A549, MCF-7, HaCaT, L02
Respectively making the cells adhere to the wall in logarithmic growth phase and in good growth state at 5X 104The cells were seeded in 96-well plates at a density of 100. mu.L/well, 37 ℃ and 5% CO2Culturing for 4h in an incubator, adding the sample to be tested and sterilized according to the preset concentration, and adding the same volume of solvent for dissolving the sample into the control group. 37 ℃ and 5% CO2After further 48h of incubation in the incubator, 25. mu.L of 5mg/mL MTT solution was added to each well, incubated at 37 ℃ for 4h, the supernatant was carefully removed, 100. mu.L DMSO was added to each well, and after the precipitate was completely dissolved by shaking for about 10min, the absorbance (O.D.) value was measured on a microplate reader at a wavelength of 570 nm.
The tumor cell inhibition rate of the sample at each sample concentration was determined by the following formula:
growth inhibition rate ═ [ (control group average o.d. value-sample group average o.d. value)/blank group average o.d. value ] × 100%
Experiment was repeated 3 times, calculated IC50The values are shown in Table 1. The results show that the compound of the invention inhibits IC of A549, MCF-7, K562, HL60, S180, HaCaT and L02 cell proliferation by 50 percent50Almost all greater than 100. mu.M. It can be seen that the compounds of the present invention have little cytotoxic effect.
TABLE 13 anti-cell proliferation Activity of a-t (IC)50Expressed by mean. + -. SD. mu.M)
Figure BDA0000816327580000171
Experimental example 2 evaluation of antitumor Activity
Experimental Material
Positive control: adriamycin
Experimental animals: ICR mice (KM clean grade), male, body weight 20 + -2 g: (
Figure BDA0000816327580000172
) (ii) a The experimental animals were purchased from the company Viton, Beijing. One group of 15 mice each, and one group of blank and positive control.
Tumor source: mouse S180 sarcoma, provided by the animal experimental center of department of medicine, university of beijing, maintained by self-passaging.
Solvent: 0.5% CMCNa solution.
Experimental methods
Dose setting
The doses of 3a-t were set at (1. mu. mol/kg), all using a single administration by oral gavage. The dose of the positive control doxorubicin was set to (2. mu. mol/kg) and administered by intraperitoneal injection.
Pharmaceutical formulation
3a-t is insoluble in water, and 0.5% CMCNa solution is added during preparation to be dispersed into suspension solution by ultrasonic oscillation. The positive control adriamycin is water-soluble and can be dissolved by normal saline.
Dosage and regimen of administration
3a-t were all administered orally by gavage. The corresponding dose is 0.2mL/20g once a day for 10 days, and the dose is 10 times.
Negative controls were administered orally by gavage with equal volumes of the respective vehicle. The corresponding dose is 0.2mL/20g once a day for 10 days, and the dose is 10 times.
The positive control doxorubicin was administered intraperitoneally at a dose of 2. mu. mol/kg. The corresponding dose is 0.2mL/20g once a day for 10 days, and the dose is 10 times.
Establishment of animal model
Adopting an in vivo anti-tumor right axillary subcutaneous inoculation model: extracting and inoculating under aseptic condition, collecting S180 ascites tumor liquid with vigorous growth, diluting with normal saline to obtain liquid (1:2), mixing, staining tumor cell suspension with freshly prepared 0.2% trypan blue, mixing, and counting by leukocyte counting method[12]The blue stained cells were dead cells, while the non-stained cells were live cells, and the cell concentration and the cell viability were calculated as follows.
Cell concentration is 4 large grid viable cell number/4 × 104X dilution factor cell number/mL
The cell survival rate was live cell number/(live cell number + dead cell number) × 100%
The tumor liquid with survival rate of more than 90 percent is usedThe slurry is prepared into 1 × 107The cell suspension of each mL is inoculated into 0.2 mL/mouse subcutaneously at the axilla of the corresponding host to prepare the solid tumor animal model.
Solid tumor re-determination
After each group was administered continuously for 10 days, the weight (weight before sacrifice) was weighed on day 11, the mice were sacrificed by removing cervical vertebrae, the tumor growth sites of the right axilla of the mice were fixed with forceps, the skin was cut open, the tumors were exposed and weighed, and the tumors were weighed to
Figure BDA0000816327580000181
And (4) showing. Data were analyzed using t-test and variance.
Results of the experiment
The results are shown in Table 2. The results show that 14 compounds of 3a-t have significant inhibitory effect (P <0.05 compared to the blank control group) on S180 mouse tumors, with the strongest inhibitory effect of compounds 3e and 3 l.
TABLE 23 a-t Effect on tumor weight in S180 tumor-bearing mice
Figure BDA0000816327580000192
a) P <0.05 to 0.5% CMCNa; b) p <0.01 compared to 0.5% CMCNa, P <0.05 compared to compound 2; n is 15.
Experimental example 3 evaluation of antithrombotic Activity
To elucidate the antithrombotic activity, 2 and 3e were selected as representative compounds in the present invention, and their antithrombotic activity in a rat model was evaluated. 0.5% CMCNa was chosen as negative control and warfarin as positive control.
Experimental animals: SD rats (clean grade), male, body weight 250 ± 20 g; the experimental animals were purchased from the company Viton, Beijing. Each 15 rats were 1 group, blank and positive control were 1 group each. Solvent: 0.5% CMCNa solution. 2 and 3e are insoluble in water, and 0.5% CMCNa solution is added during preparation to be dispersed into suspension solution by ultrasonic oscillation. The positive control warfarin is water-soluble and can be dissolved by normal saline.
The 2 and 3e doses were set at 1. mu. mol/kg and were administered orally. The dose of the positive control warfarin was set to 4.87. mu. mol/kg, and oral administration was used. The drug was administered 1 time at a weight of 0.6mL/200 g. Negative controls were dosed 1 time with an equal volume of the corresponding vehicle at 0.6mL/200g body weight.
Animal model
The method comprises the following steps of adopting a sequential irrigation mode to administer the medicine to a rat according to a corresponding dose, anesthetizing after administering for half an hour, immediately performing an operation, removing hairs on the abdomen of the rat, cutting along the midline of the abdomen, peeling off the renal veins, ligating the proximal end, suturing the abdomen, recording the circulation time, and completing the operation. Circulating for 4 hr, cutting the abdomen of rat, finding out ligated renal vein, ligating two branch openings at the distal end of the rat, shearing off the outer sides of three ligation positions to obtain a section of blood vessel, taking out the formed thrombus from the blood vessel, and weighing
Figure BDA0000816327580000202
And (4) showing. Data were analyzed using t-test and variance.
Results of the experiment
The results are shown in Table 3. The results show that 2,3e and warfarin have obvious inhibition effect on the thrombus of SD rats (compared with a blank control group, P is less than 0.01) and have definite antithrombotic activity. Based on the correlation between tumor and thrombus in pathogenesis and the correlation between 2 and 3e and other compounds of the present invention in structure and antitumor activity, it can be known that 13 other compounds of 3a-t also have definite antithrombotic activity.
TABLE 32, 3e and warfarin Effect on thrombus weight in SD rats
n 15, a) P <0.01 compared to the 0.5% CMCNa group.

Claims (4)

1. The AA is selected from Cys, L-beta-carboxyl-OBzl-Asp, L-gamma-carboxyl-OBzl-Glu, L-Phe, Gly, L-His, L-Ile and L-Lys for protecting sulfhydryl, and the general formula I is 20 compounds, wherein AA is selected from L-Ala, L-Bzl protects the sulfhydryl and is Cys, L-beta-carboxyl-OBzl-Asp, L-gamma-carboxyl-OBzl-Glu, L-Phe,L-Leu,L-Met,L-Asn,L-Pro,L-Gln,L-NG-NO2-Arg, L-Ser, L-Thr, L-Val, L-Trp, L-Tyr residues
2. A process for preparing a compound represented by the general formula I, characterized by comprising the steps of:
(1) reacting 5-formylsalicylic acid with 2-amino-phen-1-yl substituted-benzimidazole to generate 5-5, 6-dihydrobenzimidazoquinazolin-6-yl substituted-salicylic acid through Pictet-Spengler condensation reaction;
(2) oxidizing 5-5, 6-dihydrobenzimidazoloquinazolin-6-yl-substituted-salicylic acid to 5-benzimidazoloquinazolin-6-yl-substituted-salicylic acid in the presence of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone;
(3) in the presence of 1-3-dimethylamino-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, 5-benzimidazoloquinazoline-6-yl substituted-salicylic acid and L-amino acid benzyl ester generate 5-benzimidazoloquinazoline-6-yl substituted-salicyloyl amino acid benzyl ester;
(4) in 4M hydrogen chloride in ethyl acetate, 5-benzimidazoloquinazolin-6-yl-substituted-salicyl-Nω-Boc-Lys-OBzl to remove tert-butoxycarbonyl to produce 5-benzimidazoloquinazolin-6-yl-substituted-benzyl salicyloyl lysine.
3. Use of 20 compounds represented by the general formula I according to claim 1 for the preparation of antitumor medicaments.
4. Use of 20 compounds represented by the general formula I according to claim 1 for the preparation of antithrombotic medicaments.
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