CN106608901A - Dihydroxy dimethyl tetrahydroisoquinoline-3-formyl-Lys (Ala-Lys) and synthesis, activity and application thereof - Google Patents
Dihydroxy dimethyl tetrahydroisoquinoline-3-formyl-Lys (Ala-Lys) and synthesis, activity and application thereof Download PDFInfo
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- CN106608901A CN106608901A CN201510689440.7A CN201510689440A CN106608901A CN 106608901 A CN106608901 A CN 106608901A CN 201510689440 A CN201510689440 A CN 201510689440A CN 106608901 A CN106608901 A CN 106608901A
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- lys
- dihydroxy
- tetrahydroisoquinoline
- dimethyl
- formyls
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- RVLOMLVNNBWRSR-KNIFDHDWSA-N (2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O RVLOMLVNNBWRSR-KNIFDHDWSA-N 0.000 title claims abstract description 24
- 230000000694 effects Effects 0.000 title abstract description 16
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- 238000003786 synthesis reaction Methods 0.000 title description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 title 1
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- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 17
- 230000002785 anti-thrombosis Effects 0.000 claims description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 6
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- 229960000103 thrombolytic agent Drugs 0.000 claims description 2
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- 206010008092 Cerebral artery thrombosis Diseases 0.000 claims 1
- QOOWRKBDDXQRHC-BQBZGAKWSA-N L-lysyl-L-alanine Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN QOOWRKBDDXQRHC-BQBZGAKWSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 28
- 241000700159 Rattus Species 0.000 abstract description 22
- 201000006474 Brain Ischemia Diseases 0.000 abstract description 7
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical class C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 3
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 2
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 2
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical class C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- BKYKKWZNZXJEOX-UHFFFAOYSA-N 2-hydroxy-1,1-dimethyl-3,4-dihydroisoquinolin-3-ol Chemical compound OC1N(C(C2=CC=CC=C2C1)(C)C)O BKYKKWZNZXJEOX-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
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- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
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- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention discloses N-(3S-6,7-dihydroxy-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-formyl)-Lys (Ala-Lys) and a preparation method, antithrombus activity and thrombolytic activity thereof and also discloses the effect of the compound on treatment of rats suffering from cerebral ischemia. The invention discloses application of the compound in preparation of antithrombus medicines, thrombolytic medicines and medicines for treating ischemic stroke.
Description
Technical field
The present invention relates to N- [3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls]-Lys (Ala-Lys), it is related to its preparation method, it is related to its antithrombotic acitivity, it is related to its thrombus dissolving activity, it is related to the effect that it treats rats with cerebral ischemia, thus the present invention relates to it is preparing antithrombotic reagent, the application in thrombolytic agent and treatment ishemic stroke medicine.
Background technology
Ishemic stroke is a class more typically and endangers serious cranial vascular disease, and feature is that the incidence of disease is high, case fatality rate is high, disability rate is high and high recurrence rate.At present clinical treatment ishemic stroke faces the reality without active drug, and the patient of especially more than apoplexy face 4h is non-extremely i.e. residual.Invention is clinical important need to the effective medicine of patient of more than apoplexy face 4h.Inventor once disclosed the imidazolinium compounds of Formula II on the ischemia/reperfusion in rats apoplexy model of apoplexy face 24h, showed outstanding curative effect.That is the imidazolinium compounds of 6 days Formula II of continuous intravenous injection, once a day, initial dose is 5 μm of ol/kg, and afterwards the dosage of 5 times has outstanding curative effect for 2 μm of ol/kg.Aa in formula1And aa2Can be to exist simultaneously, aa1Exist but aa2Do not exist, or while do not exist；Work as aa1And aa2In the presence of simultaneously, aa1For R (Arg), and aa2For G (Gly), A (Ala) or Q (Gln)；Work as aa1Exist but aa2When not existing, aa1For R (Arg)；aa3Can be S (Ser), V (Val) or F (Phe).Because the 2- positions of the imidazolinium compounds of Formula II are 4- oxygen acetyl-Lys.And the side-chain amino group and main-chain carboxylic group of the Lys is connected respectively with RGD antithrombotics tetrapeptide and ARPAK thrombolysis peptides, so structure is more complicated to need to simplify.
Inventor was through 3 years experimental studies; it was found that using 3S-6; 7- dihydroxy -1; 1- dimethyl -1; 2; 3,4- tetrahydroisoquinoline -3- formoxyls replace the 1- substituted-phenyl imidazolinyls in above formula, replace the long peptidyl in above formula to obtain simple structure and eutherapeutic dual unexpected technique effect with the peptidyls of Lys (Ala-Lys) three.According to this discovery, the present invention is inventors herein proposed.
The content of the invention
1. one of present disclosure is to provide N- [3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- the formyls]-Lys (Ala-Lys) of following formula
2. the two of present disclosure are to provide the preparation method of N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys (Ala-Lys), and the method is made up of following methods:
(1) 3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydro-isoquinoline -3- carboxylic acids are prepared；
(2) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys (Boc)-OBzl is prepared；
(3) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys-OBzl is prepared；
(4) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Boc-Lys (Z)]-OBzl is prepared；
(5) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Lys (Z)]-OBzl is prepared；
(6) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Boc-Ala-Lys (Z)]-OBzl is prepared；
(7) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Ala-Lys (Z)]-OBzl is prepared；
(8) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys (Ala-Lys) is prepared.
3. the three of present disclosure are the antithrombotic acitivities for evaluating N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys (Ala-Lys).
4. the four of present disclosure are the thrombus dissolving activities for evaluating N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys (Ala-Lys).
5. the five of present disclosure are to evaluate the activity that N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys (Ala-Lys) treats cerebral ischemia after cerebral ischemia 24h.
Description of the drawings
Fig. 1 is synthetic route .i of N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys (Ala-Lys)) acetone, trifluoroacetic acid, MgSO4；ii)DCC,HOBt,NMM；Iii) hydrogen chloride-ethyl acetate solution (4M), ice bath；Iv) ethanol, Pd/C.
Specific embodiment
In order to the present invention is expanded on further, a series of embodiments are given below.These embodiments are entirely illustrative, and they are only used for being specifically described the present invention, are not construed as limitation of the present invention.
The liquid phase peptide reaction of embodiment 1 leads to method
The raw material that N-terminal is protected adds N- hydroxy benzo triazoles (HOBt) with dry DMF dissolving, in the solution for obtaining.N, N- dicyclohexyls carbonyl diimine (DCC) dissolved with dry DMF is slowly added under ice bath, 0 DEG C of stirring obtains reactant liquor (I) for 15 minutes.The raw material of carboxylic end protection is also dissolved with dry DMF; pH to 9 is adjusted with N-methylmorpholine (NMM); then mix with reactant liquor (I); pH 9 is maintained with N-methylmorpholine, is stirred at room temperature 10 hours, after TLC monitoring raw material points disappear; reactant mixture is filtered; filtrate reduced in volume, obtains the dissolving of sticky mass ethyl acetate, and the solution for obtaining uses successively 5%NaHCO3The aqueous solution is washed, 5%KHSO4The aqueous solution is washed, and the saturation NaCl aqueous solution is washed, and ethyl acetate is added anhydrous sodium sulfate drying, is filtered, and to doing, (50/1) methylene chloride/methanol, obtains target compound to residue Jing column chromatographies purifying to filtrate reduced in volume.
Embodiment 2 takes off the logical methods of Boc
The peptides that Boc is protected are dissolved with a small amount of anhydrous ethyl acetate, and ice bath stirring is lower to add hydrogen chloride-ethyl acetate solution (4M).After TLC shows that raw material point disappears, reaction solution water pump is drained repeatedly, and cleared hydrogen chloride gas, residue petroleum ether grinds repeatedly, obtains target compound.
Embodiment 3 takes off the logical method of carbobenzoxy group
The peptides of benzyl protection are dissolved with appropriate ethanol, palladium carbon (the 10% of reaction volume) is added, hydrogen room temperature hydrogenolysis is passed through.Reaction is filtered after terminating, and reduced pressure concentration obtains target compound.
Embodiment 4 prepares 3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinolines -3- carboxylic acids (1)
By 5.0g (25mmol) 3,4- dihydroxy-L-phenylalanine 250mL acetone solutions.6.0g (30mmol) anhydrous magnesium sulfate is added in the solution for obtaining.After 30 minutes, 25mL trifluoracetic acids (TFA) are added under ice bath, be stirred at room temperature 96h afterwards, and TLC (methylene chloride/methanol, 1:1) show that raw material point disappears.Reacting liquid filtering, filtrate reduced in volume, residue acetone solution continuation reduced pressure concentration, 3 times repeatedly.Residue adds 200mL absolute ethers, separates out 5.8g (95%) title compound, is colorless solid.ESI-MS(m/e):238[M+H]+；1HNMR(300MHz,DMSO-d6) δ/ppm=6.61 (s, 1H), 6.45 (s, 1H), 3.70 (dd, J=3.9,11.4Hz, 1H), 2.76 (dd, J=11.7,15.3Hz, 1H), 2.62 (m, 1H), 1.41 (s, 3H), 1.32 (s, 3H).
Embodiment 5 prepares N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys (Boc)-OBzl (2)
According to the method for embodiment 1, from 1.19g (5.01mmol) 3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- carboxylic acids and 2.83g (5.53mmol) HClLys (Boc)-OBzl obtain 1.64g (59%) title compound, are lightpink powder.ESI-MS(m/e):556[M+H]+；1HNMR(300MHz,DMSO-d6) δ/ppm=8.64 (s, 1H), 8.52 (s, 1H), 8.14 (d, J=7.5Hz, 1H), 7.36 (m, 5H), 6.74 (m, 1H), 6.57 (s, 1H), 6.37 (s, 1H), 5.14 (m, 2H), 4.30 (m, 1H), 3.55 (m, 2H), 3.32 (m, 2H), 2.88 (m, 2H), 2.57 (d, J=3.9Hz, 1H), 2.27 (m, 1H), 2.15 (s, 1H), 1.69 (m, 4H), 1.36 (s, 9H), 1.33 (s, 3H), 1.25 (s, 3H).
Embodiment 6 prepares N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys-OBzl (3)
According to the logical method of embodiment 2, from 1.50g (2.73mmol) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys (Boc)-OBzl obtains 1.01g (82%) title compound, for light pink solid, next step reaction is directly used in.ESI-MS(m/e):456[M+H]+。
Embodiment 7 prepares N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Boc-Lys (Z)]-OBzl (4)
According to the method for embodiment 1, from 0.982g (2mmol) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys-OBzl and 0.836g (2.2mmol) Boc-Lys (Z) obtains 0.703g (43%) title compound, is colourless powder.ESI-MS(m/e):818[M+H]+。
Embodiment 8 prepares N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Lys (Z)]-OBzl (5)
According to the method for embodiment 2, from 0.7g (0.86mmol) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Boc-Lys (Z)]-OBzl is obtained 0.615g (95%) title compound, is buff powder.ESI-MS(m/e):718[M+H]+。
Embodiment 9 prepares N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Boc-Ala-Lys (Z)]-OBzl (6)
According to the method for embodiment 1, from 0.43g (0.6mmol) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Lys (Z)]-OBzl and 0.132g (0.7mmol) Boc-Ala obtain 0.208g (39%) title compound, are colourless powder.ESI-MS(m/e)：889[M+H]+。
Embodiment 10 prepares N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Ala-Lys (Z)]-OBzl (7)
According to the method for embodiment 2, from 177mg (0.2mmol) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Boc-Ala-Lys (Z)]-OBzl is obtained 153mg (94%) title compound, is colourless powder.ESI-MS(m/e):789[M+H]+。
Embodiment 11 prepares N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys (Ala-Lys) (8)
According to the method for embodiment 3, from 124mg (0.15mmol) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Ala-Lys (Z)]-OBzl is obtained 60mg (71%) title compound, is colourless powder.ESI-MS(m/e):565[M+H]+.1H NMR(800MHz,DMSO):δ/ppm=8.132 (b, 1H), 7.980 (m, 1H), 7.779 (d, J=7.2Hz, 1H) .6.576 (s, 1H), 6.410 (s, 1H), 4.202 (m, 1H), 3.903 (m, 1H), 3.445 (m, 2H)
3.301 (m, 1H), 2.836 (m, 2H), 2.765 (m, 1H), 2.728 (dd, J=16Hz, J=4Hz, 1H), 2.468 (dd, J=16Hz, J=4Hz, 1H), 2.150 (m, 1H), 1.677 (m, 1H), 1.606 (m, 3H), 1.500 (m, 2H), 1.385 (m, 2H), 1.350 (s, 3H), 1.260 (s, 3H), 1.247 (m, 3H), 1.175 (d, J=6.4Hz, 3H).13C NMR(125MHz,DMSO):δ/ppm=174.97,173.74,172.62,172.10,171.12,143.94,143.84,134.85,124.43,115.80,113.05,54.13,53.80,53.16,52.54,50.03,38.65,38.57,32.82,32.66,32.64,31.93,31.17,29.22,27.64,22.19,21.72,20.68.
Experimental example 1 evaluates the antithrombotic acitivity of compound 8
By male SD rat (200 ± 20g), random packet, is raised 1 day by 10 per group, stops feeding overnight.Gavage is given after the normal saline solution (dosage is 167 μm of ol/kg) or physiological saline (dosage is 10mL/kg) 30min of the normal saline solution (dosage is 1nmol/kg) of compound 8 or aspirin, rat is anaesthetized with the normal saline solution of 20% Ethylurethanm, is performed the operation afterwards.The right carotid and left neck vein of rat are separated, the silk thread of correct amount is placed in into bypass intubation, left vein is inserted in one end of pipe, and another end pipe insertion right artrial simultaneously injects 0.2mL liquaemin anti-freezings.So that blood flow flows through bypass intubation from right artrial enters left side vein, the silk thread with thrombus is taken out after 15min and is weighed, calculate the weight of silk thread before and after blood circulation, the thrombus weight for obtaining represents and represent antithrombotic acitivity with mean value ± SD mg, makees t inspections.Data list table 1 in.As a result show that oral 1nmol/kg compounds 8 can effectively inhibition thrombosis.Illustrate present invention obtains unexpected technique effect.
The antithrombotic acitivity of the 1nmol/kg compounds 8 of table 1
N=10；A) p compared with physiological saline<0.01.
Experimental example 2 evaluates the thrombus dissolving activity of compound 8
SD rats (male, 200 ± 20g) are anaesthetized by the dosage lumbar injection urethane normal saline solution of 1200mg/kg.Its dorsal position is fixed after anesthetized rat, separates its RCCA, artery clamp is clamped at proximal part, proximal part and distal end are respectively penetrated into surgical thread, the surgical thread ligation of distal end, distal end intubation, artery clamp is unclamped, about 1mL arterial bloods is taken out, in being placed in 1mL centrifuge tubes.Toward vertical fixed rubber tube (long 15mm, internal diameter 2.5mm, external diameter 5.0mm, ttom of pipe is sealed with plug, and para films are tamping) interior injection 0.1mL rat artery blood, the fixing bolt of the subsequent thrombus that a stainless steel is rapidly inserted in pipe (fix spiral and be coiled into the stainless steel wire of a diameter of 0.2mm by thrombus, the long 10mm of spiral part, includes 15 bung flanges, and a diameter of 1.0mm support handles of bung flange are connected with spiral, 7.0mm is about, in question mark type).After blood clotting 45min, the careful thrombus wrapped up by thrombus that takes out fixes spiral from glass tube, accurately claims its weight.
Bypass intubation be made up of three parts, interlude be long 60.0mm, the polyethylene rubber tube of internal diameter 3.5mm；Two ends are long 100.0mm, internal diameter 1.0mm, the identical polyethylene pipe of external diameter 2.0mm, the pipe one end pulls into spike tube, 10.0mm (for inserting rat carotid artery and vein) is about, external diameter is 1.0mm, and one section of length of outer cover of its other end is 7.0mm, external diameter is the polyethylene pipe (for inserting in the polyethylene rubber tube in stage casing) of 3.5mm, and the inwall of 3 sections of pipes is required to silanization (1% silicone oil diethyl ether solution).The thrombus that thrombus is wrapped up is fixed spiral and is placed in the polyethylene rubber tube of stage casing, and the other two ends of sebific duct are nested respectively with the butt end that adds of two polyethylene, it is ensured that blood will not be leaked during circulation.With syringe heparin-saline solution (50IU/kg) will be filled by spike tube end in pipe, exclude bubble, it is standby.
Separate the left vena jugularis externa of rat, proximal part and distal end respectively penetrate surgical thread, the blood vessel of ligation distal end, an osculum is cut on exposed left vena jugularis externa, the above-mentioned bypass duct spike tube for preparing is inserted into left vena jugularis externa opening by osculum, while fixing spiral away from shunt valve stage casing (thrombus containing accurate weighing fixes spiral) interior thrombus.The normal saline solution (50IU/kg) of the liquaemin of correct amount is injected by the spike tube of the other end with syringe, now syringe should not withdraw polyethylene pipe, and the flexible pipe between syringe and polyethylene pipe is clamped with artery clamp.Stopped blooding with artery clamp in the proximal part of RCCA, ligature distal end, nearby RCCA an osculum is being cut into from artery clamp, from the tip of polyethylene pipe syringe is extracted, the proximal part of artery angle is inserted in the tip of polyethylene pipe.The two ends of bypass duct are fixed arteriovenous with No. 4 sutures.
The stage casing that the normal saline solution (dosage is 1nmol/kg) of the normal saline solution (dosage is 20000IU/kg) of physiological saline (3mL/kg) or urokinase or compound 8 is passed through into shunt valve with scalp acupuncture (thrombus containing accurate weighing fixes spiral), penetrate the nearly vein end that spiral is fixed away from thrombus, artery clamp is unclamped, makes blood flow flow to vein from artery by bypass duct.Solution in syringe is slowly injected into into blood, by blood circulation, by the sequential action of vein-heart-artery on the thrombus of spiral.After blood circulation 1h, the spiral of fixed thrombus, accurate weighing are taken out from bypass duct.The weight difference of thrombus before and after the spiral blood circulation that thrombus is fixed in every rat bypass duct is calculated, thrombus dissolving activity is represented and represented with mean value ± SD mg, make t inspections.Data list table 2 in.As a result show that 1nmol/kg compounds 8 can effectively lysigenous thrombus.Illustrate present invention obtains unexpected technique effect.
The thrombus dissolving activity of the 1nmol/kg compounds 8 of table 2
N=10；A) p is compared with physiological saline<0.01, the p compared with urokinase>0.05.
Experimental example 3 evaluates therapeutic action of the compound 8 to ishemic stroke rat
The long otch of about 2cm is vertically opened at the positive middle part of the neck of male SD rat (300 ± 20g of body weight), fate separates out RCCA, external carotid artery and internal carotid along nutator inner side.Pressed from both sides respectively with noninvasive artery clamp and closed at internal carotid opening and arteria carotis communis proximal part, the distal end of ligation external carotid artery, in external carotid artery 1 osculum is cut, and unclamps the artery clamp of arteria carotis communis proximal part, 10 μ L blood are taken, is pressed from both sides with noninvasive artery clamp again close Carotid proximal part afterwards.The 10 μ L blood for obtaining are placed on into room temperature in 1mL EP pipes makes blood clotting in 30 minutes, is then transferred to be placed 1 hour in -20 DEG C of refrigerators, makes blood clotting solid.Rat is 400mg/kg with 10% chloraldurate intraperitoneal injection of anesthesia, dosage.Blood clotting is taken out, 1mL physiological saline is added, blood clotting is pounded uniform tiny thrombi with steel shovel, prepared the suspension of tiny thrombus and be transferred in 1mL syringes.The artery clamp of arteria carotis communis proximal part is unclamped, by 1mL thrombus suspension slowly from rat external carotid artery to proximal part through the brain of internal carotid injection rat, external carotid artery proximal part is then ligatured, is opened and artery clamp is obtained at internal carotid and arteria carotis communis, recover blood flow.Wait revival.Rat presses Zealonga methods evaluation neurological functional deficit after reviving 24 hours.0 point indicates without any neurological deficit sign, and 1 point represents and do not damage side forelimb not tensible, and 2 points represent and walk to not damaging skidding, and 3 points to represent and turn-take into shape walking of knocking into the back to not damaging side, and 4 points represent the disturbances of consciousness without autonomous, and 5 points represent dead.According to score average packet.Daily 1 dosage of compound 8 of injection is 1nmol/kg to each group rat Jing tail veins.Continuous injection 6 days, daily scoring.As a result table 3 is listed in.The as shown by data of table 3, continuously treatment can make 11 cerebral ischemias rat biology of 24 hours score as 0 point for 6 days to compound 8, and the scoring of 1 cerebral ischemia rat biology of 24 hours can be made to be 1 point for Neurobiology scoring.Because unlike disclosed compound initial dose needs 5 μm of ol/kg, afterwards 5 maintenance doses need 2 μm of ol/kg, 6 dosage of compound 8 to be 1nmol/kg.So, initial dose and maintenance dose reduce respectively 5000 times and 2000 times.
Table 3 compound, the 8 continuous treatment impact to cerebral ischemia rat biology scoring in 24 hours in 6 days
N=12, target compound dosage=1nmol/kg, tail vein injection administration.
Claims (5)
1. N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- the formyls)-Lys (Ala-Lys) of following formula
2. N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- the formyls)-Lys (Lys-Ala) of claim 1
Preparation method, the method is comprised the following steps:
(1) 3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydro-isoquinoline -3- carboxylic acids are prepared；
(2) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys (Boc)-OBzl is prepared；
(3) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys-OBzl is prepared；
(4) prepare N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls) -
Lys[Boc-Lys(Z)]-OBzl；
(5) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Lys (Z)]-OBzl is prepared；
(6) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Boc- are prepared
Ala-Lys(Z)]-OBzl；
(7) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys [Ala- are prepared
Lys(Z)]-OBzl；
(8) N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- formyls)-Lys (Ala-Lys) is prepared.
3. N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- the formyls)-Lys (Ala-Lys) of claim 1 exists
Prepare the application in antithrombotic reagent.
4. N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- the formyls)-Lys (Ala-Lys) of claim 1 exists
Prepare the application in thrombolytic agent.
5. N- (3S-6,7- dihydroxy -1,1- dimethyl -1,2,3,4- tetrahydroisoquinoline -3- the formyls)-Lys (Ala-Lys) of claim 1 exists
Prepare the application in treatment cerebral arterial thrombosis medicine.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0424670A1 (en) * | 1989-09-23 | 1991-05-02 | Hoechst Aktiengesellschaft | ZNS-active hexapeptides with antiamnestic activity |
| CN1255124A (en) * | 1997-03-18 | 2000-05-31 | 史密丝克莱恩比彻姆有限公司 | Substituted isoquinoline derivatives and their use as anticonulsants |
| CN102477066A (en) * | 2010-11-30 | 2012-05-30 | 首都医科大学 | N-(S-1,2,3,4-tetrahydro-6,7-dihydroxyisoquinolyl-3-formyl)amino acid, synthetic method thereof, and application thereof |
| CN103450330A (en) * | 2012-06-01 | 2013-12-18 | 首都医科大学 | Dihydroxyltetrahydroisoquinoline-3-formyl amino acids as well as synthesis, antithrombotic effect and application thereof |
-
2015
- 2015-10-22 CN CN201510689440.7A patent/CN106608901B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0424670A1 (en) * | 1989-09-23 | 1991-05-02 | Hoechst Aktiengesellschaft | ZNS-active hexapeptides with antiamnestic activity |
| CN1255124A (en) * | 1997-03-18 | 2000-05-31 | 史密丝克莱恩比彻姆有限公司 | Substituted isoquinoline derivatives and their use as anticonulsants |
| CN102477066A (en) * | 2010-11-30 | 2012-05-30 | 首都医科大学 | N-(S-1,2,3,4-tetrahydro-6,7-dihydroxyisoquinolyl-3-formyl)amino acid, synthetic method thereof, and application thereof |
| CN103450330A (en) * | 2012-06-01 | 2013-12-18 | 首都医科大学 | Dihydroxyltetrahydroisoquinoline-3-formyl amino acids as well as synthesis, antithrombotic effect and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| SHENLING CHENG等: "A class of novel N-(3S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-L-amino acid derivatives: their synthesis, anti-thrombotic activity evaluation,and 3D QSAR analysis", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 林琳: "四氢异喹啉类生物碱抗血小板聚集药物研究进展", 《现代中药研究与实践》 * |
| 阚全程: "《医院药学高级教程》", 28 February 2015, 人民军医出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112237576A (en) * | 2019-07-16 | 2021-01-19 | 首都医科大学 | Dihydroxydimethylisochroman-3-carboxamido acids, their preparation, their use for combating ischemic stroke and their use |
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