CN109810172A - Isoquinolin -3- formyl-PARGD (aa) aa, preparation, anti-phlebothrombosis activity and application - Google Patents

Isoquinolin -3- formyl-PARGD (aa) aa, preparation, anti-phlebothrombosis activity and application Download PDF

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CN109810172A
CN109810172A CN201711161234.4A CN201711161234A CN109810172A CN 109810172 A CN109810172 A CN 109810172A CN 201711161234 A CN201711161234 A CN 201711161234A CN 109810172 A CN109810172 A CN 109810172A
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arg
pro
asp
ala
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CN109810172B (en
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赵明
彭师奇
桂琳
张筱宜
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Capital Medical University
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Capital Medical University
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Abstract

The invention discloses isoquinolin -3- formyl-Pro-Ala-Arg-Gly-Asp (aa)-aa of following formula, aa is Phe in formula, Ser or Val residue, disclose their preparation method, their anti-phlebothrombosis activity is disclosed, thus the invention discloses them to prepare the application in anti-phlebothrombosis drug.

Description

Isoquinolin -3- formyl-PARGD (aa) aa, preparation, anti-phlebothrombosis activity and Using
Technical field
The present invention relates to isoquinolin -3- formyl-Pro-Ala-Arg-Gly-Asp (aa)-aa, are related to their preparation side Method is related to their anti-phlebothrombosis activity, thus the present invention relates to them to prepare the application in anti-phlebothrombosis drug.This Invention belongs to biomedicine field.
Background technique
Thrombosis has become disease incidence height and the high disease of the death rate.Patients with venous thrombosis number, including deep vein thrombosis Patient's number with pulmonary embolism has been more than myocardial infarction and apoplexy morbidity total number of persons, and dead total people is caused than breast cancer and AIDS Number is high.The disease incidence of thrombosis increases exponentially state with the age and increases, to the people's health of aging country as China It threatens especially serious.It is such as included in population base, Venous Thrombosis is especially serious to the negative effect of China's national economy.Venous blood The prevention and treatment of bolt disease are always one of the emphasis of field of medicaments concern.Although warfarin nineteen forty-one is just used for clinic, Its security window is narrow.Dosage is low to will lead to pulmonary embolism, and dosage height will lead to fatal hemorrhage.Although being invention peace over more than 50 years Complete anti-phlebothrombosis drug has paid a large amount of painstaking effort, but effect is little.In antithrombotic reagent research, inventor was once public It is opened in intravenous injection N- [(3S) -1,2,3,4- tetrahydroisoquinoline -3- formoxyl]-Pro-Arg-Gly- under 10nmol/kg dosage Asp (Ser)-Ser, N- [(3S) -1,2,3,4- tetrahydroisoquinoline -3- formoxyl]-Pro-Arg-Gly-Asp (Val)-Val and It is dynamic that rat can be effectively suppressed in N- [(3S) -1,2,3,4- tetrahydroisoquinoline -3- formoxyl]-Pro-Arg-Gly-Asp (Phe)-Phe Arteries and veins thrombus, to phlebothrombosis without therapeutic effect.Inventor has found isoquinolin -3- formyl-in the rat blood that they are treated Pro-Arg-Gly-Asp (Ser)-Ser, isoquinolin -3- formyl-Pro-Arg-Gly-Asp (Val)-Val and isoquinolin -3- first Acyl-Pro-Arg-Gly-Asp (Phe)-Phe (conversion type seen below).In follow-up study, inventor is further discovered that isoquinoline Quinoline -3- formyl-Pro-Arg-Gly-Asp (Ser)-Ser, isoquinolin -3- formyl-Pro-Arg-Gly-Asp (Val)-Val and different Quinoline -3- formyl-Pro-Arg-Gly-Asp (Phe)-Phe has outstanding anti-phlebothrombosis activity.Then, inventor proposes The present invention.
Summary of the invention
First content of the invention is to prepare N- [(3S) -1,2,3,4- tetrahydroisoquinoline -3- formyl according to known methods
Base]-Pro-Ala-Arg-Gly-Asp (aa)-aa (aa is Ser, Val or Phe residue in formula).
Second content of the invention is by N- [(3S) -1,2,3,4- tetrahydroisoquinoline -3- formoxyl]-Pro-Ala- Arg-Gly-Asp (aa)-aa (aa is Ser, Val or Phe residue in formula) dehydrogenation Quantitative yield in rat blood serum is isoquinolin- 3- formyl-Pro-Ala-Arg-Gly-Asp (aa)-aa (aa is Ser, Val or Phe residue in formula).
Third content of the invention is evaluation isoquinolin -3- formyl-Pro-Ala-Arg-Gly-Asp (aa)-aa (in formula Aa is Ser, Val or Phe residue) anti-phlebothrombosis activity and observe hemorrhage side effect.
Detailed description of the invention
(aa is that Ser, Val or Phe are residual to Fig. 1 isoquinolin -3- formyl-Pro-Ala-Arg-Gly-Asp (aa)-aa in formula Base) synthetic route.
Embodiment
A series of embodiments are given below in order to which the present invention is furture elucidated.It must be noted that these embodiments are entirely example Card property.The purpose for providing these embodiments is never caused to the present invention to sufficiently express meaning of the present invention and content Any type of limitation.
Embodiment 1 prepares N- [(3S) -1,2,3,4- tetrahydroisoquinoline -3- formoxyl]-Pro-Ala-Arg-Gly-Asp (aa)-aa
N- [(3S) -1,2,3,4- tetrahydroisoquinoline -3- formoxyl]-Pro-Ala- is prepared according to the method having disclosed Arg-Gly-Asp (aa)-aa (aa is Ser, Val or Phe residue in formula).
Embodiment 2 prepares isoquinolin -3- formyl-Pro-Ala-Arg-Gly-Asp- (Ser)-Ser (10a)
By 50mg (0.04mmol) N- [(3S)-N-1,2,3,4- tetrahydroisoquinoline -3- formoxyl]-Pro-Ala-Arg- Gly-Asp (Ser)-Ser 37 DEG C with 1mL rat blood serum dissolve, obtained solution 37 DEG C isothermal vibration 4 hours, TLC prison Raw material is surveyed to disappear.37 DEG C of 2mL methanol isothermal vibration 10 minutes is added into serum solution, obtained mixed solution is in 3000 revs/min Centrifugation 10 minutes.It is centrifuged obtained residue sufficiently to be extracted with ultrapure water, separates extract liquor and be centrifuged.It is centrifuged obtained supernatant It is concentrated under reduced pressure in 37 DEG C, residue is sufficiently extracted with ultrapure water, separates extract liquor.Combined extract liquor freeze-drying, obtains 33mg (96%) title compound.ESI(-)-FT-MS:842.35219[M-H]-.Mp 118-119℃.[α]D 25=-15.9 (c =1.3, CH3OH).IR(cm-1)3690,3454,3236,2932,2364,1640,1545,1455,1390,1175,1123, 1036,643,512,426.1H NMR (300MHz, DMSO) δ/ppm=10.99 (s, 2H), 9.22 (s, 1H), 8.56 (s, 1H), 8.54(s,1H),8.53(s,5H),8.04(m,6H),8.01(m,1H),7.48(m,1H),7.43(m,1H),5.10(m,5H), 4.51 (m, 2H), 4.33 (d, J=7.5Hz, 2H), 4.27 (m, 2H), 4.03 (d, J=6Hz, 1H), 3.97 (d, J=2.4Hz, 2H), 3.92 (d, J=3.6Hz, 1H), 3.86 (d, J=7.5Hz, 2H), 3.83 (d, J=3Hz, 3H), 3.73-3.65 (m, 3H),3.58(m,2H),1.95(m,4H),1.414(m,2H),1.386(s,1H)。
Embodiment 3 prepares isoquinolin -3- formyl-Pro-Ala-Arg-Gly-Asp (Val)-Val (10b)
According to the method for embodiment 1 by 50mg (0.04mmol) N- [(3S) -1,2,3,4- tetrahydroisoquinoline -3- formyl Base] obtained 33mg (96%) title compound of-Pro-Ala-Arg-Gly-Asp (Val)-Val.ESI(-)-FT-MS: 866.41722[M-H]-.Mp 142-143℃.[α]D 25=-12.7 (c=1.6, CH3OH).IR(cm-1)3442,3253, 2966,2380,1654,1542,1456,1390,1254,1171,1025,763,645,516,438.1H NMR(300MHz, DMSO) δ/ppm=10.98 (s, 2H), 9.24 (s, 1H), 8.55 (s, 1H), 8.54 (s, 1H), 8.52 (s, 1H), 8.50 (s, 1H),8.07(m,1H),8.04(m,6H),7.49(m,1H),7.44(m,1H),4.52-4.46(m,2H),4.35-4.09(m, 2H),4.07-4.03(m,2H),3.95-3.93(m,1H),3.52-3.44(m,1H),3.21-3.11(m,1H),2.81(d,J =6.3Hz, 1H), 2.40-2.31 (m, 1H), 2.03 (m, 4H), 1.90 (m, 3H), 1.65 (m, 2H), 1.38 (d, J=7.2Hz, 3H),0.87-0.77(m,12H)。
Embodiment 4 prepares isoquinolin -3- formyl-Pro-Ala-Arg-Gly-Asp (Phe)-Phe (10c)
According to the method for embodiment 1 by 50mg (0.04mmol) N- [(3S) -1,2,3,4- tetrahydroisoquinoline -3- formyl Base] obtained 38mg (97%) title compound of-Pro-Ala-Arg-Gly-Asp (Phe)-Phe.ESI(+)-FT-MS: 964.18333[M+H]+.Mp 135-137℃.[α]D 25=-13.4 (c=1.1CH3OH).IR(cm-1)3445,2937,2363, 1744,1645,1536,1452,1392,1273,1025,672,517,445.1H NMR (300MHz, DMSO) δ/ppm= 10.99 (s, 2H), 9.22 (s, 1H), 8.54 (s, 1H), 8.52 (s, 1H), 8.06 (m, 5H), 8.05 (d, J=7.5Hz, 1H), 7.50 (m, 1H), 7.34-7.26 (m, 11H), 4.81 (m, 2H), 4.62 (m, 1H), 4.51 (m, 1H), 4.45 (q, J=8.0Hz, 1H), 4.28 (m, 3H), 4.12 (m, 2H), 3.15 (m, 3H), 2.55 (dd, J=6.3Hz, J=6.9Hz, 1H), 2.01 (m, 3H), 1.97 (m, 1H), 1.77 (m, 2H), 1.55 (m, 2H), 1.49 (d, J=7.8Hz, 3H), 1.22 (d, J=8.2Hz, 3H).
Embodiment 5 evaluates the anti-phlebothrombosis activity of 10a-c
Male SD rat (250 ± 20g) adapts to environment and fasting one day, the 20% urethane solution abdominal cavity operation consent 2min Administration anesthesia, is fixed on plate.2mL blood is taken from arteria carotis, the measurement for blood index of correlation.By rat abdomen preserved skin, disappear Poison opens abdominal cavity along hunter's line (down toward solidification gland, up to one jiao of liver of exposing).Remove the organs such as intraperitoneal small intestine and with infiltration Cross the gauze package of physiological saline.Blunt separation blood vessel surrounding connective tissue, exposure inferior caval vein and its branch.Under renal vein Abdominal aorta and inferior caval vein are removed by side, and the suture then soaked with physiological saline crosses in inferior caval vein and left renal vein Place is by Ligation of inferior vena cava.The organs such as intestines are moved back to abdominal cavity by anatomical position, with suture layer-by-layer suture abdominal cavity.It is infused from tail vein The normal saline solution of 10a-c, dosage 1nmol/kg are penetrated, the dosage of positive control warfarin is 4.87 μm of ol/kg, negative right According to for physiological saline.Rat abdominal cavity is opened after recycling in 25-28 DEG C of environment 4 hours, is one by one ligatured its branch, from cavity of resorption Start to take out 2cm inferior caval vein at the ligation of the intersection of vein and left renal vein, is taken out thrombus.Thrombus weighing, is examined with t Test statistical result.Operation with every group two only alternately, every group 12.Thrombus weighing is shown in Table 1.The result shows that in 1nmol/kg 10a-c can effectively inhibit phlebothrombosis under dosage, with the N- under 10nmol/kg dosage to phlebothrombosis without therapeutic effect [(3S) -1,2,3,4- tetrahydroisoquinoline -3- formoxyl]-Pro-Arg-Gly-Asp (Ser)-Ser, N- [(3S) -1,2,3,4- Tetrahydroisoquinoline -3- formoxyl]-Pro-Arg-Gly-Asp (Val)-Val and N- [(3S) -1,2,3,4- tetrahydroisoquinoline -3- Formoxyl]-Pro-Arg-Gly-Asp (Phe)-Phe has unexpected technical effect compared to the present invention.In addition, 10a-c's has The but not no hemorrhage side effect of warfarin of imitate that dosage is warfarin 1/4870.The present invention has unexpected technical effect.
The anti-phlebothrombosis activity of 1 10a-c of table
Compound Dosage Wet weight of thrombus (mean value ± SD mg)
Physiological saline 3ml/kg 25.35±1.41
Warfarin 4.87μmol/kg 13.13±3.71
10a 1nmol/kg 13.00±2.89a
10b 1nmol/kg 12.87±2.53a
10c 1nmol/kg 13.12±2.98a
And physiological saline ratio p<0.01, a) with warfarin ratio p>0.05；N=12.

Claims (3)

1. isoquinolin -3- formyl-Pro-Ala-Arg-Gly-Asp (aa)-aa of following formula, aa is that Ser, Val or Phe are residual in formula Base,
2. the preparation method of isoquinolin -3- formyl-Pro-Ala-Arg-Gly-Asp (aa)-aa of claim 1, this method packet Include following steps:
1) N- [(3S)-N-1,2,3,4- tetrahydroisoquinoline -3- formoxyl]-Pro-Ala- is prepared according to the method having disclosed Arg-Gly-Asp(Ser)-Ser；
2) N- [(3S)-N-1,2,3,4- tetrahydroisoquinoline -3- formoxyl]-Pro-Ala- is prepared according to the method having disclosed Arg-Gly-Asp(Val)-Val；
3) N- [(3S)-N-1,2,3,4- tetrahydroisoquinoline -3- formoxyl]-Pro-Ala- is prepared according to the method having disclosed Arg-Gly-Asp(Phe)-Phe；
4) by N- [(3S)-N-1,2,3,4- tetrahydroisoquinoline -3- formoxyl]-Pro-Ala-Arg-Gly- in rat blood serum Asp (Ser)-Ser is converted into isoquinolin -3- formyl-Pro-Ala-Arg-Gly-Asp (Ser)-Ser；
5) by N- [(3S)-N-1,2,3,4- tetrahydroisoquinoline -3- formoxyl]-Pro-Ala-Arg-Gly- in rat blood serum Asp (Val)-Val is converted into isoquinolin -3- formyl-Pro-Ala-Arg-Gly-Asp (Val)-Val；
6) by N- [(3S)-N-1,2,3,4- tetrahydroisoquinoline -3- formoxyl]-Pro-Ala-Arg-Gly- in rat blood serum Asp (Phe)-Ser is converted into isoquinolin -3- formyl-Pro-Ala-Arg-Gly-Asp (Phe)-Phe.
3. isoquinolin -3- formyl-Pro-Ala-Arg-Gly-Asp (the aa)-aa of claim 1 is preparing anti-phlebothrombosis drug In application.
CN201711161234.4A 2017-11-21 2017-11-21 isoquinoline-3-formyl-PARGD (aa) aa, preparation thereof, anti-thrombus activity and application thereof Active CN109810172B (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1431199A (en) * 2003-01-22 2003-07-23 浙江大学 Method for synthesizing 1-amino isoquinoline
CN1441784A (en) * 2000-07-12 2003-09-10 阿克佐诺贝尔公司 Thrombin inhibitors comprising aminoisoquinoline group
US20120094997A1 (en) * 2010-10-18 2012-04-19 Millennium Pharmaceuticals, Inc. Substituted hydroxamic acids and uses thereof
CN103450342A (en) * 2012-06-01 2013-12-18 首都医科大学 Tetrahydroisoquinolinyl-3-carboxylic acid modified PARGD heptapeptides, and synthesis, antithrombotic activity and application thereof
JP5789252B2 (en) * 2009-05-07 2015-10-07 インテリカイン， エルエルシー Heterocyclic compounds and uses thereof
CN105218629A (en) * 2014-06-10 2016-01-06 首都医科大学 Isoquinoline 99.9-3-formyl-RC-OBzl, its preparation, nanostructure, active and application

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1441784A (en) * 2000-07-12 2003-09-10 阿克佐诺贝尔公司 Thrombin inhibitors comprising aminoisoquinoline group
CN1431199A (en) * 2003-01-22 2003-07-23 浙江大学 Method for synthesizing 1-amino isoquinoline
JP5789252B2 (en) * 2009-05-07 2015-10-07 インテリカイン， エルエルシー Heterocyclic compounds and uses thereof
US20120094997A1 (en) * 2010-10-18 2012-04-19 Millennium Pharmaceuticals, Inc. Substituted hydroxamic acids and uses thereof
CN103450342A (en) * 2012-06-01 2013-12-18 首都医科大学 Tetrahydroisoquinolinyl-3-carboxylic acid modified PARGD heptapeptides, and synthesis, antithrombotic activity and application thereof
CN105218629A (en) * 2014-06-10 2016-01-06 首都医科大学 Isoquinoline 99.9-3-formyl-RC-OBzl, its preparation, nanostructure, active and application

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