CN102477077A - Boc-Pro-Ala-Lys-Lys(Pro-Ala-Lys)-OCH2(CH2)nCH3, synthesis method and application thereof as thrombus dissolving agent - Google Patents
Boc-Pro-Ala-Lys-Lys(Pro-Ala-Lys)-OCH2(CH2)nCH3, synthesis method and application thereof as thrombus dissolving agent Download PDFInfo
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Abstract
The invention discloses an oligopeptide with thrombus dissolving activities and a synthesis method and application thereof. The oligopeptide has thrombus dissolving activities and has a structural formula shown in the general formula I in the specification, wherein in the formula, n is 6, 8, 10, 12, 14 or 16. The in vitro and in vivo thrombus dissolving activity experiments indicate that the oligopeptide compound shown in the general formula I has excellent thrombus dissolving activities and can be applied as a thrombus dissolving drug.
Description
Technical field
The present invention relates to oligopeptides, relate in particular to oligopeptides and compound method thereof, the invention still further relates to their application, the invention belongs to the oligopeptides field as thrombolytic agent with thrombus dissolving activity.
Background technology
P6A (ARPAK) is one of scleroproein β chain degradation product, has thrombus dissolving activity.In the metabolism research of P6A, found meta-bolites PAK.On rat arteriovenous shut intubate thrombus dissolving model, the thrombus dissolving activity of PAK is stronger than parent P6A.According to general understanding, polypeptide all can be degraded rapidly in vivo.Structural modification through PAK delays vivo degradation speed and improves thrombus dissolving activity, is the important channel of oligopeptides thrombolytic agent research.
According to general understanding, contain the amphipathic molecule of polypeptide, for example self-assembly can take place through intermolecular non-covalent interaction in aliphatic alcohol chain modified polypeptides under suitable condition, forms nanostructure.By nanostructure can improve in vivo conveying of polypeptide, delay polypeptide in vivo degradation rate and improve the activity in vivo of polypeptide.According to these understanding, the contriver has proposed the present invention.
Summary of the invention
One of the object of the invention provides the compound with thrombus dissolving activity;
Two of the object of the invention provides a kind of synthetic above-mentioned method with thrombus dissolving activity compound.
Three of the object of the invention is that above-claimed cpd is applied to prepare thrombolytic agent.
Above-mentioned purpose of the present invention realizes by the following technical programs:
Compound with thrombus dissolving activity, its structural formula are shown in the general formula I:
N=6,8,10,12,14 or 16 in the formula.
A kind of method of the synthetic said compound of above-mentioned general formula I may further comprise the steps:
1) Boc-Pro and Ala-OBzl condensation are Boc-Pro-Ala-OBzl;
2) be Boc-Pro-Ala with the Boc-Pro-Ala-OBzl hydrogenolysis;
3) Boc-Pro-Ala and Lys (Boc)-OBzl condensation is Boc-Pro-Ala-Lys (Boc)-OBzl;
4) be Boc-Pro-Ala-Lys (Boc) with Boc-Pro-Ala-Lys (Boc)-OBzl hydrogenolysis;
5) Boc-Lys (Boc) is Boc-Lys (Boc)-OCH with the saturated fatty alcohol condensation
2(CH
2) nCH
3, n=6,8,10,12,14 or 16 wherein;
6) Boc-Lys (Boc)-OCH
2(CH
2) nCH
3Slough tertiary butyloxycarbonyl, generate Lys-OCH
2(CH
2) nCH
3
7) Boc-Pro-Ala-Lys (Boc) and Lys-OCH
2(CH
2) nCH
3Condensation is Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OCH
2(CH
2) nCH
3
8) Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OCH
2(CH
2) nCH
3Remove Boc.
In order to reach better synthetic effect, step 1) preferably in the presence of DCC and HOBt Boc-Pro in anhydrous THF, be Boc-Pro-Ala-OBzl with the Ala-OBzl condensation; Step 2) in methyl alcohol, be Boc-Pro-Ala preferably with the Boc-Pro-Ala-OBzl hydrogenolysis; Step 3) preferably in the presence of DCC and HOBt Boc-Pro-Ala in anhydrous THF, be Boc-Pro-Ala-Lys (Boc)-OBzl with Lys (Boc)-OBzl condensation; Step 4) is Boc-Pro-Ala-Lys (Boc) with Boc-Pro-Ala-Lys (Boc)-OBzl hydrogenolysis in methyl alcohol preferably; Step 5) is Boc-Lys (Boc)-OCH with the saturated fatty alcohol condensation at Boc-Lys (Boc) in the presence of the DCC in anhydrous THF preferably
2(CH
2) nCH
3Step 6) is Boc-Lys (Boc)-OCH in hydrogenchloride-ethyl acetate solution preferably
2(CH
2) nCH
3Slough Boc and generate Lys-OCH
2(CH
2) nCH
3Step 7) preferably in the presence of DCC and HOBt Boc-Pro-Ala-Lys (Boc) in anhydrous THF with Lys-OCH
2(CH
2) nCH
3Condensation is Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OCH
2(CH
2) nCH
3Step 8) is Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OCH in hydrogenchloride-ethyl acetate solution preferably
2(CH
2) nCH
3Remove Boc.
External interior thrombus dissolving activity test shows that it is active that the oligopeptide compounds shown in the general formula I of the present invention has outstanding thrombus dissolving activity with body, can be used as thrombolytic agent and uses.
The breviary term
The THF THF
HOBT N-hydroxy benzo triazole
DCC dicyclohexyl carbonyl diimine
The TLC thin-layer chromatography
The Boc tertbutyloxycarbonyl
Description of drawings
The structural formula of Fig. 1 compound of Formula I of the present invention.
The synthetic route chart .i of Fig. 2 compound of Formula I of the present invention) DCC, HOBt and NMM; Ii) Pd/C, H
2Iii) HCl/EA.
The transmission electron microscope photo of Fig. 3 The compounds of this invention 4b.
Embodiment
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and are not to be understood that to be limitation of the present invention.
Embodiment 1 preparation Boc-Lys (Boc)-OCH
2(CH
2)
6CH
3(1a)
2.0g (5.78mmol) Boc-Lys (Boc) is dissolved in the anhydrous THF of 20ml.In the solution that obtains, add 1.02g (7.51mmol) N-hydroxy benzo triazole (HOBT) and dissolving fully.After 10 minutes, under ice bath, add the solution of 1.55g (7.51mmol) dicyclohexyl carbonyl diimine (DCC) and the anhydrous THF of 15ml, obtain reaction solution (I).902mg (6.94mmol) aliphatic alcohol chain is dissolved in the anhydrous THF of 5ml and stirs obtained reaction solution (II) in 30 minutes.Add in the reaction solution (I) reaction solution (II) and stirring at room 12h under the ice bath, TLC (petrol ether/ethyl acetate, 6: 1) shows that Boc-Lys (Boc) disappears.Reaction mixture removes by filter the NSC 30023 (DCU) of generation.Filtrate decompression concentrates and removes THF, and residue is used the 250ml acetic acid ethyl dissolution.The solution that obtains is used saturated NaHCO successively
3The aqueous solution is washed, the saturated NaCl aqueous solution is washed, 5%KHSO
4The aqueous solution is washed and the saturated NaCl aqueous solution is washed.ETHYLE ACETATE is used anhydrous Na mutually
2SO
4Drying, filtration, filtrate decompression are concentrated into dried, and the residue column chromatography purification obtains 1.35g (51%) target compound, is colorless oil.ESI-MS(m/e)：459[M+H]
+.
Embodiment 2 preparation Boc-Lys (Boc)-OCH
2(CH
2)
8CH
3(1b)
According to the method for embodiment 1 by 2.0g (5.78mmol) Boc-Lys (Boc) and 1.097g (6.94mmol) CH
3(CH
2)
8CH
2OH makes 1.40g (50%) target compound, is colorless oil.ESI-MS(m/e)：487[M+H]
+.
According to the method for embodiment 1 by 2.0g (5.78mmol) Boc-Lys (Boc) and 1.291g (6.94mmol) CH
3(CH
2) 10CH
2OH makes 1.37g (46%) target compound, is colorless oil.ESI-MS(m/e)：515[M+H]
+.
Embodiment 4 preparation Boc-Lys (Boc)-OCH
2(CH
2)
12CH
3(1d)
According to the method for embodiment 1 by 2.0g (5.78mmol) Boc-Lys (Boc) and 1.485g (6.94mmol) CH
3(CH
2)
12CH
2OH makes 1.63g (52%) target compound, is the colorless solid powder.ESI-MS(m/e)：543[M+H]
+.
Embodiment 5 preparation Boc-Lys (Boc)-OCH
2(CH
2)
14CH
3(1e)
According to the method for embodiment 1 by 2.0g (5.78mmol) Boc-Lys (Boc) and 1.679g (6.94mmol) CH
3(CH
2)
14CH
2OH makes 1.581g (48%) target compound, is the colorless solid powder.ESI-MS(m/e)：571[M+H]
+.
Embodiment 6 preparation Boc-Lys (Boc)-OCH
2(CH
2)
16CH
3(1f)
According to the method for embodiment 1 by 2.0g (5.78mmol) Boc-Lys (Boc) and 1.874g (6.94mmol) CH
3(CH
2)
16CH
2OH makes 1.56g (45%) target compound, is the colorless solid powder.ESI-MS(m/e)：599[M+H]
+.
Embodiment 7 preparation Lys-OCH
2(CH
2)
6CH
3(2a)
With 1.01g (2.21mmol) Boc-Lys (Boc)-OCH
2(CH
2)
6CH
3Be dissolved in 25ml 4N hydrogenchloride-ethyl acetate solution and stirring at room 1 hour, TLC (petrol ether/ethyl acetate, 6: 1) shows Boc-Lys (Boc)-OC
8H
17Disappear.Concentrating under reduced pressure is removed ETHYLE ACETATE, and residue adds a small amount of ether repeatedly and carries out concentrating under reduced pressure to remove de-chlorine hydride.Add a small amount of ether at last residue is ground to form 704mg (96%) target compound, be colourless powder.ESI-MS(m/e)：259[M+H]
+.
Embodiment 8 preparation Lys-OCH
2(CH
2)
8CH
3(2b)
According to the method for embodiment 7 by 1.4g (2.88mmol) Boc-Lys (Boc)-OCH
2(CH
2)
8CH
3Make 931mg (90%) target compound, be colourless powder.ESI-MS(m/e)：287[M+H]
+.
Embodiment 9 preparation Lys-OCH
2(CH
2)
10CH
3(2c)
According to the method for embodiment 7 by 1.37g (2.66mmol) Boc-Lys (Boc)-OCH
2(CH
2)
10CH
3Make 947mg (92%) target compound, be colourless powder.ESI-MS(m/e)：315[M+H]
+.
Embodiment 10 preparation Lys-OCH
2(CH
2)
12CH
3(2d)
According to the method for embodiment 7 by 1.63g (3.01mmol) Boc-Lys (Boc)-OCH
2(CH
2)
12CH
3Make 1.160mg (93%) target compound, be colourless powder.ESI-MS(m/e)：343[M+H]
+.
Embodiment 11 preparation Lys-OCH
2(CH
2)
14CH
3(2e)
According to the method for embodiment 7 by 1.58g (2.77mmol) Boc-Lys (Boc)-OCH
2(CH
2)
14CH
3Make 1.09mg (89%) target compound, be colourless powder.ESI-MS(m/e)：371[M+H]
+.
Embodiment 12 preparation Lys-OCH
2(CH
2)
16CH
3(2f)
According to the method for embodiment 7 by 1.56g (2.60mmol) Boc-Lys (Boc)-OCH
2(CH
2)
16CH
3Make 1.12mg (91%) target compound, be colourless powder.ESI-MS(m/e)：399[M+H]
+.
Embodiment 13 preparation Boc-Pro-Ala-OBzl
Method according to embodiment 1 makes 5.19g (99%) target compound from 3.0g (14.0mmol) Boc-Pro and 5.88g (16.7mmol) TosAla-Obzl, is yellow powder.ESI-MS(m/e)：377[M+H]
+.
Embodiment 14 preparation Boc-Pro-Ala
5.19g (13.8mmol) Boc-Pro-Ala-OBzl is used the 25ml dissolve with methanol.In solution, add 1.0gPd/C, logical H
2(0.02Mba) and stirring at room disappear to Boc-Pro-Ala-OBzl.Filtering Pd/C, filtrate decompression are concentrated into dried.Make 3.59g (91%) target compound, be yellow powder.ESI-MS(m/e)：285[M-H]
-.
Embodiment 15 preparation Boc-Pro-Ala-Lys (Boc)-OBzl
Method according to embodiment 1 makes 6.78g (57%) target compound by 6.76g (23.6mmol) Boc-Pro-Ala and 10g (19.7mmol) TosLys (Boc)-OBzl, is colourless powder.ESI-MS(m/e)：605[M+H]
+.
Embodiment 16 preparation Boc-Pro-Ala-Lys (Boc)
Method according to embodiment 14 makes 5.36g (93%) target compound by 6.78g (11.2mmol) Boc-Pro-Ala-Lys (Boc)-OBzl, is colourless powder.ESI-MS(m/e)：513[M-H]
-.
Embodiment 17 preparation Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OC
8H
17(3a)
According to the method for embodiment 1 by 1.03g (2.0mmol) Boc-Pro-Ala-Lys (Boc) and 300mg (0.91mmol) Lys-OC
8H
17Make 386mg (34%) target compound, be colourless powder.101 ℃ of Mp; [α]
D 25=-498 (c=0.70, methyl alcohol); ESI-MS (m/e): 1273 [M+Na]
+IR (KBr): 3289,3223,3206,3088,2976,2932,2872,2864,1695,1674,1651,1639,1528,1520,1477,1456,1393,1368,1308,1250,1167,1125,1090,984,777,642.
1H NMR (500MHz, CDCl
3): δ/ppm=7.48-7.33 (m, 3H), 7.19-7.08 (m, 1H), 6.95-6.81 (m, 2H), 5.12-4.97 (m, 1H); 4.51 (s, 2H), 4.38-4.26 (m, 4H), 4.19 (s, 2H), 4.12-4.07 (m, 2H); 3.69 (s, 1H), 3.48-3.37 (m, 4H), 3.20 (s, 1H), 3.07 (s, 4H); 2.56 (s, 2H), 2.14-2.00 (m, 5H), 1.90-1.81 (m, 7H), 1.73-1.59 (m, 5H); 1.45-1.37 (m, 52H), 1.28-1.25 (m, 13H), 0.88-0.85 (t, J=3.6Hz, J=4.2Hz, 3H).
Embodiment 18 preparation Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OC
10H
21(3b)
According to the method for embodiment 1 by 1.26g (2.5mmol) Boc-Pro-Ala-Lys (Boc) and 400mg (1.1mmol) Lys-OC
10H
21Make 329mg (23%) target compound, be colourless powder.104 ℃ of Mp; [α]
D 25=-638 (c=0.53, methyl alcohol); ESI-MS (m/e): 1279 [M+H]
+IR (KBr): 3283,3231,3208,2978,2932,2859,1701,1682,1639,1518,1479,1452,1393,1366,1346,1250,1165,1123.
1H NMR (300MHz, CDCl
3): δ/ppm=7.47-7.34 (m, 3H), 7.26-6.96 (m, 3H), 5.12 (s, 2H), 4.52 (s, 2H), 4.34 (s; 3H), 4.18 (s, 2H), 4.05 (d, J=4.2Hz, 2H), 3.44 (d, J=6.3Hz, 4H); 3.19 (s, 2H), 3.05 (s, 4H), 2.14-2.01 (m, 4H), 1.88-1.86 (m, 7H); 1.67-1.56 (m, 5H), 1.39-1.34 (m, 49H), 1.23-1.15 (m, 16H), 0.83 (m, 3H).
Embodiment 19 preparation Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OC
12H
25(3c)
According to the method for embodiment 1 by 1.32g (2.6mmol) Boc-Pro-Ala-Lys (Boc) and 450mg (1.2mmol) Lys-OC
12H
25Make 392mg (26%) target compound, be colourless powder.99 ℃ of Mp; [α]
D 25=-451 (c=0.79, methyl alcohol); ESI-MS (m/e): 1329 [M+Na]
+IR (KBr): 3304,3289,3067,2978,2930,2859,1643,1530,1520,1477,1452,1395,1366,1308,1271,1248,1171,1126,1090,984,775.
1H NMR (300MHz, CDCl
3): δ/ppm=7.71-7.28 (m, 3H), 7.18-6.95 (m, 3H), 5.12 (s, 2H), 4.52 (s, 2H), 4.35 (s; 3H), 4.18 (s, 2H), 4.05 (d, J=4.2Hz, 2H), 3.46-3.43 (m, 5H), 3.19 (s; 2H), 3.05 (s, 4H), 2.14-2.02 (m, 4H), 1.89-1.86 (m, 8H), 1.68-1.56 (m, 6H); 1.43-1.32 (m, 54H), 1.23-1.15 (m, 21H), 0.86-0.82 (t, J=5.7Hz, J=6.6Hz, 3H).
Embodiment 20 preparation Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OC
14H
29(3d)
According to the method for embodiment 1 by 1.36g (2.7mmol) Boc-Pro-Ala-Lys (Boc) and 500mg (1.2mmol) Lys-OC
14H
29Make 323mg (20%) target compound, be colourless powder.107 ℃ of Mp; [α]
D 25=-865 (c=0.38, methyl alcohol); ESI-MS (m/e): 1335 [M+H]
+IR (KBr): 3329,3298,3285,3219,3076,3049,2978,2928,2857,1705,1694,1678; 1663,1643,1636,1543,1522,1516,1479,1452,1389,1368,1275; 1248,1207,1165,1123,1090,1038,986,864,775,662,415.
1H NMR (300MHz, CDCl
3): δ/ppm=7.62-7.31 (m, 2H), 7.21-6.72 (m, 3H), 5.10-5.05 (m, 1H), 4.51-4.19 (m; 6H), 4.08-4.02 (m, 2H), 3.47-3.07 (m, 9H), 2.49 (s, 1H); 2.27-2.01 (m, 4H), 1.91-1.81 (m, 6H), 1.75-1.67 (m, 6H), 1.48-1.35 (m; 47H), 1.28-1.17 (m, 23H), 0.88-0.84 (t, J=5.4Hz, J=6.9Hz, 3H).
Embodiment 21 preparation Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OC
16H
33(3e)
According to the method for embodiment 1, by 1.17g (2.3mmol) Boc-Pro-Ala-Lys (Boc) and 460mg (1.0mmol) Lys-OC
16H
33Make 412mg (29%) target compound, be colourless powder.109 ℃ of Mp; [α]
D 25=-861 (c=0.38, methyl alcohol); ESI-MS (m/e): 1363 [M+H]
+IR (KBr): 3489,3298,3285,3273,3202,3078,2976,2930,2857,1705,1690,1670,1655,1638,1539,1526,1456,1395,1366,1275,1250,1169,1123,1092,1040,984,775,694.
1H-NMR (300MHz, CDCl
3): δ/ppm=7.58-7.48 (m, 2H), 7.01-6.82 (m, 3H), 5.12-5.02 (m, 2H), 4.52-4.21 (m, 7H); 4.09 (s, 2H), 3.49-3.47 (m, 4H), 3.22 (s, 1H), 3.08 (s, 4H); 2.39 (s, 1H), 2.24-2.02 (m, 4H), 1.97-1.80 (m, 7H), 1.75-1.69 (m, 6H); 1.51-1.38 (m, 49H), 1.31-1.21 (m, 30H), 0.89-0.85 (t, J=4.2Hz, J=6.6Hz, 3H).
Embodiment 22 preparation Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OC
18H
37(3f)
According to the method for embodiment 1 by 1.27g (2.5mmol) Boc-Pro-Ala-Lys (Boc) and 530mg (1.1mmol) Lys-OC
18H
37Make 296mg (19%) target compound, be colourless powder.110 ℃ of Mp; [α]
D 25=-931 (c=0.35, methyl alcohol); ESI-MS (m/e): 1391 [M+H]
+IR (KBr): 3304,3292,3078,2974,2928,2857,2288,1688,1668,1639,1634,1537,1454,1398,1369,1248,1171,1125,988,926,868,773,683,654,602.1H NMR (300MHz, CDCl
3): δ/ppm=7.62-7.34 (m, 3H), 7.21-6.94 (m, 3H), 5.13-5.03 (m, 2H), 4.52 (s, 2H), 4.35 (s; 4H), 4.19 (s, 2H), 4.07-4.01 (m, 2H), 3.51-3.42 (m, 4H), 3.21 (s, 1H); 3.06 (s, 4H), 2.61 (s, 1H), 2.13-2.04 (m, 4H), 1.92-1.84 (m, 7H), 1.74-1.58 (m; 7H), 1.51-1.35 (m, 53H), 1.26-1.19 (m, 32H), 0.88-0.84 (t, J=5.1Hz, J=6.6Hz, 3H).
Embodiment 23 preparation Pro-Ala-Lys-Lys (Pro-Ala-Lys)-OC
8H
17(4a)
According to the method for embodiment 7 by 310mg (0.25mmol) Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OC
8H
17Make 225mg (91%) target compound, be colourless powder.137 ℃ of Mp; [α]
D 25=-100 (c=0.53, water); ESI-MS (m/e): 851 [M+H]
+IR (KBr): 3887,3836,3798,3767,3732,3416,3362,3240,3059,2934; 2864,2758,2363,2334,2046,1738,1661,1545,1456; 1383,1306,1294,1250,1175,1043,995,957,897; 843,729,640,596,573,521,486,453,415.
1H NMR (300MHz, DMSO-d
6): δ/ppm=10.08 (s, 1H), 10.84 (d, J=7.2Hz, 1H), 8.56-8.30 (m, 1H), 8.14-7.98 (m, 3H); 4.35-4.29 (m, 3H), 4.28-4.16 (m, 4H), 4.03-3.95 (m, 2H), 3.62 (s, 1H), 3.22-3.19 (m; 5H), 3.02-3.00 (m, 3H), 2.73 (s, 4H), 2.32-2.23 (m, 2H), 1.91-1.87 (m, 7H); 1.66-1.55 (m, 12H), 1.36-1.25 (m, 25H), 0.86-0.83 (t, J=7.2Hz, J=6.9Hz, 3H).
Embodiment 24 preparation Pro-Ala-Lys-Lys (Pro-Ala-Lys)-OC
10H
21(4b)
According to the method for embodiment 7 by 210mg (0.16mmol) Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OC
10H
21Make 150mg (89%) target compound, be colourless powder.152 ℃ of Mp; [α]
D 25=-154 (c=0.53, water); ESI-MS (m/e): 879 [M+H]
+IR (KBr): 3468,3408,3395,3375,3352,3273,3235,3165,3040,2930,2859,2816,1736,1655,1551,1458,1393,1256,1173.
1H NMR (300MHz, DMSO-d
6): δ/ppm=8.85 (d, J=6.9Hz, 1H), 8.36 (d, J=6.9Hz, 1H), 8.14-8.05 (m, 4H), 4.36-4.32 (m; 3H), 4.23-4.16 (m, 4H), 4.07-3.93 (m, 2H), 3.28-3.13 (m, 5H), 3.02 (m, 2H); 2.75-2.70 (t, J=7.2Hz, J=6.6Hz, 4H), 2.34-2.24 (m, 2H), 1.91-1.87 (m, 6H); 1.65-1.56 (m, 12H), 1.34-1.24 (m, 28H), 0.85 (t, J=5.7Hz, J=6.6Hz, 3H).
Embodiment 25 preparation Pro-Ala-Lys-Lys (Pro-Ala-Lys)-OC
12H
25(4c)
According to the method for embodiment 7 by 300mg (0.23mmol) Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OC
12H
25Make 225mg (93%) target compound, be colourless powder.165 ℃ of Mp; [α]
D 25=-104 (c=0.79, water); ESI-MS (m/e): 907 [M+H]
+IR (KBr): 3304,3289,3067,2978,2930,2859,1643,1530,1520,1477,1452,1395,1366,1308,1271,1248,1171,1126,1090,984,775.
1H NMR (300MHz, DMSO-d
6): δ/ppm=8.87-8.81 (m, 2H), 8.42-8.32 (m, 2H), 8.16-7.96 (m, 5H); 4.35-3.99 (m, 8H), 3.20-3.18 (m, 4H), 3.01 (s, 2H); 2.73-2.71 (m, 3H), 2.31-2.29 (m, 2H), 1.86 (s, 6H); 1.67-1.56 (m, 11H), 1.46-1.24 (m, 29H), 0.84-0.82 (m, 3H).
Embodiment 26 preparation Pro-Ala-Lys-Lys (Pro-Ala-Lys)-OC
14H
29(4d)
According to the method for embodiment 7 by 250mg (0.19mmol) Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OC
14H
29Make 182mg (90%) target compound, be colourless powder.162 ℃ of Mp; [α]
D 25=-189 (c=0.38, water); ESI-MS (m/e): 935 [M+H]
+IR (KBr): 3834,3397,3381,3368,3350,3229,3202,3192,3049,2928,2855,2826,2810,2679,1738,1684,1645,1616,1533,1447,1242,1171.
1H NMR (300MHz, DMSO-d
6): δ/ppm=10.17 (s, 2H), 8.86-8.84 (d, J=3.9Hz, 2H), 8.51 (s, 2H), 8.37-8.34 (d, J=6.6Hz; 1H), and 8.12-7.99 (m, 8H), 4.38-4.32 (m, 3H), 4.20-4.11 (m, 4H), 4.02-3.94 (m, 2H); 3.20 (s, 4H), 3.04-3.03 (m, 2H), 2.73 (s, 4H), 2.34-2.23 (m, 2H), 1.91-1.87 (m; 6H), 1.65-1.56 (m, 11H), 1.34-1.24 (m, 34H), 0.87-0.83 (t, J=5.4Hz, J=6.6Hz, 3H).
Embodiment 27 preparation Pro-Ala-Lys-Lys (Pro-Ala-Lys)-OC
16H
33(4e)
According to the method for embodiment 7 by 230mg (0.17mmol) Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OC
16H
33Make 172mg (92%) target compound, be colourless powder.Mp161 ℃; [α]
D 25=-276 (c=0.38, water); ESI-MS (m/e): 963 [M+H]
+IR (KBr): 3871,3840,3447,3412,3399,3383,3250,3051,2928,2857,2758,2565,1740,1655,1545,1456,1383,1354,1248,1177,652.
1H NMR (300MHz, DMSO-d
6): δ/ppm=10.18 (s, 2H), 8.86-8.84 (d, J=6.6Hz, 2H), 8.50 (s, 2H), 8.36-8.34 (d, J=6.6Hz; 1H), and 8.12-7.98 (m, 8H), 4.38-4.30 (m, 3H), 4.19-4.13 (m, 4H), 4.04-3.98 (m, 2H); 3.20 (s, 4H), 3.04-3.03 (m, 2H), 2.74-2.67 (m, 4H), 2.32-2.29 (m, 2H), 1.94-1.83 (m; 6H), 1.71-1.49 (m, 11H), 1.42-1.19 (m, 37H), 0.87-0.83 (t, J=5.1Hz, J=6.6Hz, 3H).
Embodiment 28 preparation Pro-Ala-Lys-Lys (Pro-Ala-Lys)-OC
18H
37(4f)
According to the method for embodiment 7 by 190mg (0.14mmol) Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OC
18H
37Make 141mg (91%) target compound, be colourless powder.161 ℃ of Mp; [α]
D 25=-203 (c=0.35, water); ESI-MS (m/e): 991 [M+H]
+IR (KBr): 3431,3402,3366,3350,3256,3250,3231,3059,2928,2855,2760,2037,1742,1657,1551,1460,1385,1306,1248,1177,1040,993,961,721,584,573,523,488,409.
1H-NMR (500MHz, DMSO-d
6): δ/ppm=8.85-8.84 (d, J=6.0Hz, 1H), 8.37-8.36 (d, J=6.6Hz, 1H), 8.15-8.05 (m, 3H); 4.36-4.29 (m, 3H), 4.21-4.15 (m, 4H), 4. 04-4.02 (m, 2H), 3.22-3.18 (m, 4H); 3.05-2.99 (m, 2H), 2.75-2.71 (m, 4H), 2.33-2.30 (m, 2H), 1.93-1.87 (m, 6H); 1.66-1.55 (m, 12H), 1.38-1.18 (m, 44H), 0.86-0.84 (t, J=5.1Hz, J=6.6Hz, 3H).
Thrombus dissolving activity experiment in the body of experimental example 1 compound of Formula I of the present invention
(6ml/kg i.p.) anaesthetizes with 20% urethane solution with the 200-220g male SD rat.The anesthetized rat dorsal position is fixed, and separates RCCA, in proximal part folder bulldog clamp; Proximal part and distal end penetrate surgical thread respectively, the surgical thread of distal end are clamped with mosquito forceps in fur, in the distal end intubate; Unclamp bulldog clamp, emit about 1ml arterial blood and be contained in the EP pipe of 1ml.The Glass tubing of past vertical fixing (long 15mm, internal diameter 2.5mm, external diameter 5.0mm, the pipe end, seal with plug) and the middle 0.1ml of injection rat artery blood, the rapid thrombus standing bolt that inserts a stainless steel material in past the pipe.This thrombus fixedly spiral uses the Stainless Steel Wire coiled of diameter as 0.2mm, and the long 12mm of spiral part contains 15 bung flanges, and the diameter of bung flange is 1.0mm, and the holder handle links to each other with spiral, and long 7.0mm is the question mark type.Behind the blood coagulation 15min, open the plug of Glass tubing bottom, with the fixing fixing holder handle of spiral of thrombus of tweezers, the thrombus that taking-up is wrapped up by thrombus from Glass tubing is spiral fixedly, accurately weighs.
The bypass intubate constitutes by 3 sections, and the stage casing is a polyethylene rubber tube, long 60mm, internal diameter 3.5mm; Two ends are identical polyethylene tube, long 100mm, internal diameter 1mm; External diameter 2mm, an end of this pipe pull into point pipe (being used to insert rat carotid artery or vein), external diameter 1mm; The outer cover one segment length 7mm of the other end, the polyethylene tube of external diameter 3.5mm (overstriking is used to insert in the polyethylene rubber tube in stage casing).The equal silylanization of the inwall of 3 sections pipes.With the thrombus of thrombus parcel fixedly spiral put into the stage casing polyethylene rubber tube, the two ends of sebific duct are nested with two poly butt ends that add respectively.It is subsequent use to fill with heparin-saline solution (50IU/kg) in will managing through sharp pipe end with syringe.
The left external jugular vein of isolated from rat; Proximal part and distal end penetrate surgical thread respectively; On the left external jugular vein that exposes, cut an angle carefully; The point pipe of the bypass duct that above-prepared is good inserts the proximal part of left external jugular vein opening by angle, simultaneously away from the fixing holder handle of spiral of the interior thrombus in bypass tube stage casing (containing fixedly spiral of the thrombus of accurately weighing).Push the heparin-saline (50IU/kg) of accurate amount with syringe through the point pipe of the other end, this moment, syringe was not withdrawn polyethylene tube, clamped the flexible pipe between syringe and the polyethylene tube with mosquito forceps.Proximal part at RCCA stops blooding with bulldog clamp, RCCA is being cut an angle carefully nearby from bulldog clamp.Extract syringe from the tip of polyethylene tube, the tip of polyethylene tube is inserted the proximal part of artery angle.The two ends of bypass duct all use 4 trumpeter's art sutures and arteriovenous to fix.
With scalp acupuncture with saline water (3ml/kg); Thrust away from the fixing nearly vein place of spiral of thrombus in the stage casing of the physiological salt soln of physiological salt soln of urokinase (20000IU/kg) or different concns The compounds of this invention (embodiment 23-28 is prepared) through bypass tube (containing fixedly spiral of the thrombus of accurately weighing); Open bulldog clamp; Make blood flow flow to vein from artery through bypass duct; This is a rat arteriovenous shut Thrombolysis Model, slowly the liquid in the syringe is injected into (about 6min) in the blood, makes saline water (blank); Urokinase (positive control) or compound of the present invention are through blood circulation, and the sequential action of pressing vein-heart-artery is to thrombus.Timing during from start injection, behind the 1h from bypass duct the fixing spiral of removal of thromboses, accurately weigh.Calculate fixedly of poor quality before and after the spiral administration of thrombus in every rat bypass duct, thrombolysis activity in the body of statistics and assessing compound.Experimental result shows that The compounds of this invention 4a-f has thrombus dissolving activity (table 1) in the outstanding body.
Table 1 1nmol/kg The compounds of this invention is to the influence of rat suppository loss of weight
a
A) n=12, the thrombus loss of weight is represented with mean SD mg; B) with saline water group ratio, p＜0.01.
Experimental example 2 dosage are to the influence of thrombus dissolving activity in the The compounds of this invention 4f body
According to the experimental technique of experimental example 1, choose the best 4f of thrombolysis effect (embodiment 28 is prepared) and investigate the thrombolysis activity under 1nmol/kg, 0.01nmol/kg and three dosage of 0.0001nmol/kg.The result shows, the thrombolytic effect show dose dependency (table 2) of 4f.
The dosage of table 2 4f is to the influence of rat suppository loss of weight
a
A) n=10, the thrombus loss of weight is represented with mean SD mg; B) with saline water and 0.01nmol/kg 4f group ratio, p＜0.01; C) with saline water and 0.0001nmol/kg 4f group ratio, p＜0.01; D) compare p＞0.05 with saline water.
The external thrombus dissolving activity of experimental example 3 The compounds of this invention 4a-f
1) making of thrombosis device
With internal diameter 4mm, external diameter 5.5mm, one section Glass tubing of length 18mm is placed on the quick detachable base of plastics, and the seam crossing of Glass tubing and plastic feet seals with one section emulsion tube.Place a Stainless Steel Wire spiral, screw diameter 1mm, length 20mm in the Glass tubing; The long hook of 2mm that comprises an end; Blood promptly be set in the stainless steel spiral around, can thrombus be hung up when weighing, when hatching, can thrombus be hung in the solution of reaction flask; Do not run into wall, in order to avoid the damage thrombus.
2) making of reaction flask
10ml cillin bottle with the band rubber plug; On rubber plug, wear a Stainless Steel Wire, the end in bottle curves hook, and thrombus hangs on the hook; Be suspended in bottle interior testing compound solution; Stainless Steel Wire can move up and down on rubber plug, regulates the height of thrombus in solution, and it just is immersed in the solution to be measured.The simulation of internal milieu: estimate that according to the rat mean body weight every rat has 13ml blood, if rat thrombus in vivo model, blood that maybe about 8ml can touch thrombus, so adding 8ml solution to be measured in the reaction flask is hatched at 37 ℃ of constant temperature shaking tables.
3) preparation of thrombus
(6ml/kg i.p.), anaesthetizes with 20% urethane with the 350-400g male SD rat; It is fixing to lie on the back, and separates RCCA, and the bulldog clamp folder closes proximal part; The long polyethylene tube of 30mm is inserted in the bulldog clamp top, emits about 3-4ml blood at every turn, approximately can put 2-3 time; 5ml syringe with silylanization injects the Glass tubing that the preparation thrombus is used with the blood of emitting immediately one by one, the stainless steel spiral is put at once.Leave standstill 40min and make thrombosis, afterwards Glass tubing is carefully taken off from base, with fine needle with separating with the Glass tubing inwall around the thrombus; Removal of thromboses hangs on the rubber plug of reaction flask; Add 8ml zero(ppm) water in the reaction flask, thrombus is suspended on leaves standstill 1 hour in the water, remove thrombus surface floating blood.After 1 hour, inhale the moisture on the bolt surface of dehematizing, accurately weigh one by one with filter paper.
4) measure the external thrombolysis activity of 4a-f:
In each reaction flask, refill the physiological salt soln of 4a-f (10nM); With saline water as blank; Urokinase (100IU/ml) hangs on thrombus in the solution of The compounds of this invention to be measured as positive control again, and 37 ℃ of constant temperature shaking table 70rpm were hatched 2 hours.After hatching end, draw surface water with filter paper and accurately weigh one by one again, calculate thrombus at the weight difference that adds solution to be measured front and back, the external thrombolysis activity of statistical appraisal compound.Experimental result shows that The compounds of this invention 4a-f has outstanding external thrombus dissolving activity (table 3).
The external thrombolysis activity of table 3 10nM The compounds of this invention 4a-f
a
A) n=6, the thrombus loss of weight is represented with mean SD mg; B) with saline water group ratio, p＜0.01.
Experimental example 4 concentration are to the influence of the external thrombus dissolving activity of The compounds of this invention 4b
According to the experimental technique of experimental example 3, choose the best 4b of thrombolysis effect (embodiment 24 is prepared) and investigate 10nM, 1nM, the thrombolysis activity under four concentration of 0.1nM and 0.01nM.The result shows, the external thrombolytic effect display density dependency (table 4) of 4b.
The concentration of table 2 4b is to the influence of external thrombolysis activity
a
A) n=6, the thrombus loss of weight is represented with mean SD mg; B) with saline water and 1nM 4b group ratio, p＜0.01; C) with saline water and 0.1nM 4b group ratio, p＜0.01; D) with saline water and 0.01nM 4b group ratio, p＜0.01.
The nanometer ball experiment of experimental example 5 The compounds of this invention 4a-f
1) particle diameter of 4a-f nanometer ball in the aqueous solution
Recording the micelle-forming concentration of 4a-f in the aqueous solution earlier is 1 * 10
-12Mg/ml.On Nano-ZS90 nano particle size determinator, measure 4a-f then 1 * 10
-12The particle diameter of mg/ml.The result shows that The compounds of this invention 4a-f can be assembled into nanometer ball in the aqueous solution, and particle diameter is 196 to 260nm (table 5).
The particle diameter of the nanometer ball that table 54a-f assembles in the aqueous solution
2) form of the nanometer ball of 4a-f
It is 1 * 10 that The compounds of this invention 4a-f is made into concentration
-12The aqueous solution of mg/ml, then with this drips of solution on copper mesh, under the JEM-1230 transmission electron microscope, observe the form of nanometer ball behind the dried solvent that volatilizees.Mensuration shows, the nanometer ball of 4a-f formation rule.The transmission electron microscope photo of 4b is as representative (describing with Fig. 3).
Claims (10)
1. the oligopeptides that has thrombus dissolving activity, its structural formula are shown in the general formula I:
N=6,8,10,12,14 or 16 in the formula.
2. the method for the said compound of synthetic claim 1 comprises:
1) Boc-Pro and Ala-OBzl condensation are Boc-Pro-Ala-OBzl;
2) be Boc-Pro-Ala with the Boc-Pro-Ala-OBzl hydrogenolysis;
3) Boc-Pro-Ala and Lys (Boc)-OBzl condensation is Boc-Pro-Ala-Lys (Boc)-OBzl;
4) be Boc-Pro-Ala-Lys (Boc) with Boc-Pro-Ala-Lys (Boc)-OBzl hydrogenolysis;
5) Boc-Lys (Boc) is Boc-Lys (Boc)-OCH with the saturated fatty alcohol condensation
2(CH
2) nCH
3N=6,8,10,12,14 or 16 wherein,
6) Boc-Lys (Boc)-OCH
2(CH
2) nCH
3Slough tertiary butyloxycarbonyl, generate Lys-OCH
2(CH
2) nCH
3
7) Boc-Pro-Ala-Lys (Boc) and Lys-OCH
2(CH
2) nCH
3Condensation is Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OCH
2(CH
2) nCH
3
8) Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OCH
2(CH
2) nCH
3Remove Boc.
3. according to the described method of claim 2, it is characterized in that in the step 1) that in the presence of NSC 57182 and N-hydroxybenzotriazole Boc-Pro is Boc-Pro-Ala-OBzl with the Ala-OBzl condensation in anhydrous THF.
4. according to the described method of claim 2, it is characterized in that step 2) in methyl alcohol, be Boc-Pro-Ala with the Boc-Pro-Ala-OBzl hydrogenolysis.
5. according to the described method of claim 2, it is characterized in that in the step 3) that be Boc-Pro-Ala-Lys (Boc)-OBzl with Lys (Boc)-OBzl condensation at Boc-Pro-Ala in the presence of DCC and the HOBt in anhydrous THF.
6. according to the described method of claim 2, it is characterized in that in the step 4) in methyl alcohol with Boc-Pro-Ala-Lys (Boc)-OBzl hydrogenolysis being Boc-Pro-Ala-Lys (Boc).
7. according to the described method of claim 2, it is characterized in that in the step 5) that in the presence of DCC Boc-Lys (Boc) is Boc-Lys (Boc)-OCH with the saturated fatty alcohol condensation in anhydrous THF
2(CH
2) nCH
3
8. according to the described method of claim 2, it is characterized in that in the step 6) Boc-Lys (Boc)-OCH in hydrogenchloride-ethyl acetate solution
2(CH
2) nCH
3Slough tertbutyloxycarbonyl, generate Lys-OCH
2(CH
2) nCH
3
9. according to the described method of claim 2, it is characterized in that in the step 7) Boc-Pro-Ala-Lys (Boc) in the presence of DCC and the HOBt in anhydrous THF with Lys-OCH
2(CH
2) nCH
3Condensation is Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OCH
2(CH
2) nCH
3In the step 8) in hydrogenchloride-ethyl acetate solution Boc-Pro-Ala-Lys (Boc)-Lys [Boc-Pro-Ala-Lys (Boc)]-OCH
2(CH
2) nCH
3Remove Boc.
10. the described compound of claim 1 is in the purposes of preparation in the thrombolytic agent.
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Non-Patent Citations (4)
| Title |
|---|
| 《J. Am. Chem. SOC.》 19951231 Peter B.等 Peter B.等 "Synthetic Lipidation of Peptides and Amino Acids: Monolayer Structure and Properties" 第9515-9522页 , * |
| 《中国医药工业杂志》 20051231 金义光 等 "基于脂质前药的自组装药物传递系统" 第185-188页 第36卷, 第3期 * |
| PETER B.等: "Peter B.等 "Synthetic Lipidation of Peptides and Amino Acids: Monolayer Structure and Properties"", 《J. AM. CHEM. SOC.》 * |
| 金义光 等: ""基于脂质前药的自组装药物传递系统"", 《中国医药工业杂志》 * |
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