CN106432417A - Pentamethoxytryptamine carbonyl propionyl-RPAK, preparation, activity and applications thereof - Google Patents
Pentamethoxytryptamine carbonyl propionyl-RPAK, preparation, activity and applications thereof Download PDFInfo
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- 230000000694 effects Effects 0.000 title abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 28
- JTEJPPKMYBDEMY-UHFFFAOYSA-N 5-methoxytryptamine Chemical compound COC1=CC=C2NC=C(CCN)C2=C1 JTEJPPKMYBDEMY-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 18
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
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- WFIYPADYPQQLNN-UHFFFAOYSA-N 2-[2-(4-bromopyrazol-1-yl)ethyl]isoindole-1,3-dione Chemical compound C1=C(Br)C=NN1CCN1C(=O)C2=CC=CC=C2C1=O WFIYPADYPQQLNN-UHFFFAOYSA-N 0.000 description 1
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- FYQSMXKJYTZYRP-DCAQKATOSA-N Pro-Ala-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 FYQSMXKJYTZYRP-DCAQKATOSA-N 0.000 description 1
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention discloses a pentamethoxytryptamine carbonyl propionyl-Lys(Arg-Pro-Ala-Lys), a preparation method, and thrombolysis activity thereof, and effects of the pentamethoxytryptamine carbonyl propionyl-Lys(Arg-Pro-Ala-Lys) in treatment of stroke rats, such that the present invention discloses applications of the pentamethoxytryptamine carbonyl propionyl-Lys(Arg-Pro-Ala-Lys) in preparation of thrombolysis drugs and ischemic stroke treating drugs.
Description
Technical field
The present invention relates to five methoxytryptamines base carbonyl propionyl-Lys (Arg-Pro-Ala-Lys), it is related to its preparation method, it is related to its thrombus dissolving activity and be related to the effect that it treats cerebral infarction, thus the present invention relates to it is being prepared thrombolytic agent and is treating the application in cerebral infarction medicine.The invention belongs to biomedicine field.
Background technology
Cerebral infarction is a class more typically and endangers serious cerebrovascular disease, and feature is that sickness rate is high, case fatality rate is high, disability rate is high and high recurrence rate.Clinical treatment cerebral infarction faces the reality not having active drug at present, 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 compoundss of Formulas I on the ischemia/reperfusion in rats apoplexy model of apoplexy face 24h, showed outstanding curative effect.The i.e. imidazolinium compoundss of 6 days Formula II of continuous intravenous injection, once a day, initial dose is 5 μm of ol/kg, and the dosage of latter 5 times has outstanding curative effect for 2 μm of ol/kg.Aa in formula1And aa2Can be for existing simultaneously, aa1Exist but aa2Do not exist, or do not exist simultaneously；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- position of the imidazolinium compoundss of Formula II is 4- oxygen acetyl-Lys.And the side-chain amino group of this Lys is connected with RGD antithrombotic tetrapeptide and ARPAK thrombolytic peptide respectively with main-chain carboxylic group, so structure is more complicated needing to simplify.
Inventor was through 3 years experimentatioies; find to replace 2- (4- oxygen acetyl group) phenyl -4 of Formulas I with five methoxytryptamine base carbonyl propionos, 4,5; 5- tetramethyl -1,3- bis- Sinerol imidazolinyl replaces and can obtain that structure is simple and eutherapeutic unexpected technique effect.According to this discovery, inventors herein propose the present invention.
Content of the invention
One of present disclosure is to provide five methoxytryptamines base carbonyl propionyl-Lys (Arg-Pro-Ala-Lys) of following formula.
The two of present disclosure are the preparation methoies providing five methoxytryptamines base carbonyl propionyl-Lys (Gly-Arg-Pro-Ala-Lys), and the method comprises the following steps：
1) five methoxytryptamine base carbonyl propanoic acid are prepared；
2) prepare Boc-Pro-Ala-OBzl；
3) prepare Boc-Pro-Ala；
4) prepare Boc-Pro-Ala-Nω-Z-Lys-OBzl；
5) prepare HCl Pro-Ala-Nω-Z-Lys-OBzl；
6) prepare Boc-NG-NO2-Arg-Pro-Ala-Nω-Z-Lys-OBzl；
7) prepare Boc-NG-NO2-Arg-Pro-Ala-Nω-Z-Lys；
8) prepare Nα- five methoxytryptamine base carbonyl propionyl-Nω-Fmoc-Lys-OBzl；
9) prepare Nα- five methoxytryptamine base carbonyl propionyl-Lys-OBzl；
10) prepare Nα- five methoxytryptamine base carbonyl propionyl-Nω-Boc-NG-NO2-Arg-Pro-Ala-Nω-Z-Lys-Lys-OBzl；
11) by Nα- five methoxytryptamine base carbonyl propionyl-Nω-Boc-NG-NO2-Arg-Pro-Ala-Nω- Z-Lys-Lys-OBzl deprotection obtains Nα- five methoxytryptamine base carbonyl propionyl-Nω-Arg-Pro-Ala-Lys-Lys.
The three of present disclosure are to evaluate the thrombus dissolving activity of five methoxytryptamines base carbonyl propionyl-Lys (Arg-Pro-Ala-Lys) and the effect for the treatment of cerebral infarction.
Brief description
Fig. 1. the synthetic route of five methoxytryptamines base carbonyl propionyl-Lys (Arg-Pro-Ala-Lys). (a) DCC, HOBt, NMM, THF；(b) 2N NaOH, THF；(c) 4N hydrogen chloride-ethyl acetate solution；(d) piperidines/DMF (e) succinic anhydride；(f)TFA/TFMSA.
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 the present invention is specifically described, and are not construed as limitation of the present invention.
Embodiment 1 connects peptide and leads to method
1mmol c-terminuses compound is dissolved in dry THF, 1.2mmol N- hydroxyl benzotriazole (HOBt) and the 1.2mmol N of dry THF dissolving is sequentially added under ice bath stirring, N- dicyclohexylcarbodiimide (DCC), stirring 0.5h, 1.05mmol aminoterminal compound is dissolved in dry THF, adds in above-mentioned reactant liquor, N-methylmorpholine (NMM) is adjusted to pH9,6h, TLC (CHCl are stirred at room temperature3/CH3OH, 10/1) show that c-terminuses raw material is wholly absent, reaction terminates.It is filtered to remove DCU, dissolved with ethyl acetate after filtrate reduced in volume, the solution obtaining uses saturation NaHCO successively3Aqueous solution is washed 3 times, and saturation NaCl aqueous solution washes 3 times, 5%KHSO4Aqueous solution is washed 3 times, and saturation NaCl aqueous solution washes 3 times, 5%NaHCO3Aqueous solution is washed 3 times and saturation NaCl aqueous solution washes 3 times.The ethyl acetate layer anhydrous Na merging2SO4It is dried, filter, filtrate reduced in volume to dry, post layer (CHCl3/CH3OH, 10/1) analysis obtains target compound after purification.
Embodiment 2 removing N- tertbutyloxycarbonyl protection group leads to method
The compound that 1mmol is contained N- tertbutyloxycarbonyl protection group is dissolved with ethyl acetate is dried on a small quantity, and ice bath stirring is lower to add 10mL 4N hydrogen chloride/ethyl acetate solution, and ice bath stirs 1-2h, TLC (CHCl3/CH3OH, 10/1) show that raw material is wholly absent, reaction terminates.Reactant liquor concentrating under reduced pressure.Residue adds 5ml anhydrous ethyl acetate, and solution decompression is concentrated to dryness.This operation is repeated 3 times.Residue adds 5ml absolute ether, solution decompression is concentrated to dryness.This operation is repeated 3 times.The target compound obtaining is directly used in the next step.
Embodiment 3 hydrolysis removing benzyl ester protection group leads to method
Compound containing benzyl ester protection group is dissolved in methanol, is slowly added dropwise 2M NaOH aqueous solution under ice bath and stirring, is adjusted to pH12, react 5h, TLC (CHCl3/CH3OH, 10/1) show that raw material is wholly absent, reaction terminates.It is slowly added dropwise saturation KHSO under ice bath stirring4Aqueous solution is adjusted to pH7, and concentrating under reduced pressure removes methanol, and remaining aqueous solution is slowly added dropwise saturation KHSO under ice bath stirring4Aqueous solution is adjusted to pH3, and ethyl acetate extracts 3 times, and the ethyl acetate layer saturation NaCl aqueous solution of merging is washed 3 times, uses anhydrous Na2SO4It is dried, filter, filtrate reduced in volume, obtain target compound.
Embodiment 4 hydrogenolysis removing benzyl ester protection group leads to method
Compound containing benzyl ester protection group is dissolved in methanol, adds Pd/C (the 20% of reaction volume), the air in decompression extraction system, be passed through hydrogen, 10h, TLC (CHCl are stirred at room temperature3/CH3OH, 10/1) show that raw material is wholly absent, reaction terminates.It is filtered to remove Pd/C, filtrate reduced in volume, obtain target compound.
Embodiment 5 prepares five methoxytryptamine base carbonyl propanoic acid
Dry THF is dissolved in by 1.9g (10.0mmol) five methoxytryptamine, ice bath stirring is lower to add 1.20g (12.0mmol) succinic anhydride, is adjusted to pH9 with NMM, 6h, TLC (CHCl are stirred at room temperature3/CH3OH, 10/1) show that c-terminuses raw material is wholly absent, reaction terminates.Dissolved with ethyl acetate after filtrate reduced in volume, the solution obtaining uses 5%KHSO successively4Aqueous solution is washed 3 times, and saturation NaCl aqueous solution washes 3 times.The ethyl acetate layer anhydrous Na merging2SO4It is dried, filters, filtrate reduced in volume obtains 2.81g (96.9%) title compound to after do, and is faint yellow solid.ESI-MS(m/e)：289[M-H]-.
Embodiment 6 prepares Boc-Pro-Ala-OBzl
Connect the logical method of peptide according to embodiment 1 and 1g (72%) title compound is obtained by 0.84g (3.90mmol) Boc-Pro and 1.30g (3.7mmol) HCl Ala-OBzl, be colorless solid.ESI-MS(m/e)：377[M+H]+.
Embodiment 7 prepares Boc-Pro-Ala
Hydrolyze the logical method of removing benzyl ester protection group according to embodiment 3 and obtain 0.7g (92%) title compound from 1g (2.66mmol) Boc-Pro-Ala-OBzl, be colorless solid.ESI-MS(m/e)：285[M-H]-.
Embodiment 8 prepares Boc-Pro-Ala-Lys (Z)-OBzl
Connect the logical method of peptide according to embodiment 1 and 1.5g (76%) title compound is obtained by 1.0g (3.7mmol) Boc-Pro-Ala and 1.25g (3.10mmol) HCl Lys (Z)-OBzl, be colorless solid.ESI-MS(m/e)：639[M+H]+.
Embodiment 9 prepares HCl Pro-Ala-Lys (Z)-OBzl
It is directly used in the next step according to the target compound that the logical method of embodiment 2 removing N- tertbutyloxycarbonyl protection group obtains from 1g (1.6mmol) Boc-Pro-Ala-Lys (Z)-OBzl.ESI-MS(m/e)：639[M+H]+.
Embodiment 10 prepares Boc-Arg (NO2)-Pro-Ala-Lys(Z)-OBzl
Connect peptide according to embodiment 1 and lead to method by 1.5g (4.60mmol) Boc-Arg (NO2) and 1.30g (3.7mmol) HCl Ala-OBzl obtain 4.46g (69%) title compound, be colorless solid.ESI-MS(m/e)：841[M+H]+.
Embodiment 13 prepares Boc-Arg (NO2)-Pro-Ala-Lys(Z)
Hydrolyze removing benzyl ester protection group according to embodiment 3 and lead to method from 1g (1.19mmol) Boc-Arg (NO2)-Pro-Ala-Lys (Z)-OBzl obtains 0.89g (100%) title compound, is colorless solid.ESI-MS(m/e)：749[M-H]-.
Embodiment 14 prepares five methoxytryptamine base carbonyl propionyl-Lys (Fmoc)-OBzl
Connect the logical method of peptide according to embodiment 1 and 0.218g (48%) title compound is obtained by 207mg (0.69mmol) five methoxytryptamine base carbonyl propanoic acid and 0.283g (0.62mmol) Lys (Fmoc)-OBzl.ESI-MS(m/e)：731[M+H]+.
Embodiment 15 prepares five methoxytryptamine base carbonyl propionyl-Lys-OBzl
Under ice bath, 0.5g (0.68mmol) five methoxytryptamine base carbonyl propionyl-Lys (Fmoc)-OBzl is dissolved in 1mL 20% piperidines/DMF (DMF), reacts 30 minutes, TLC (CHCl3/CH3OH, 5/1) display raw material point disappearance.Add ether so that solid is separated out, filter to obtain title compound, be colorless solid, be directly used in next step reaction.ESI-MS(m/e)：508[M+H]+.
Embodiment 16 prepares five methoxytryptamine base carbonyl propionyl-Lys (Boc-Arg (NO2)-Pro-Ala-Lys(Z))-OBzl
Connect peptide according to embodiment 1 and lead to method by 0.188g (0.25mmol) Boc-Arg (NO2)-Pro-Ala-Lys (Z) and 0.153g (0.3mmol) five methoxytryptamine base carbonyl propionyl-Lys-OBzl obtains 0.133g (43%) title compound.ESI-MS(m/e)：1241[M+H]+.
Embodiment 17 prepares five methoxytryptamines base carbonyl propionyl-Lys (Arg-Pro-Ala-Lys) (1)
By 100mg (0.081mmol) five methoxytryptamine base carbonyl propionyl-Lys (Boc-Arg (NO under ice bath2)-Pro-Ala-Lys (Z))-OBzl mixed with 1mL trifluoroacetic acid and 0.33mL trifluoromethanesulfonic acid, stirs 40min, pours 50mL absolute ether into, so that precipitation is precipitated.Solid is with absolute ether cyclic washing and concentrating under reduced pressure, the pale yellow powder water dissolution obtaining, adjust pH8 with ammonia, through Sephadex G10 desalination, with C18 column purification (eluant=methanol: water=5: 95), the fraction lyophilizing collected, obtains 29mg (47%) title compound, is colorless solid.Mp：140.1-143.7℃；ESI-MS(m/e)：871[M+H]+.
Experimental example 1 evaluates the thrombus dissolving activity of compound 1
SD rat (male, 200 ± 20g) presses 1200mg/kg-1Dosage lumbar injection urethane normal saline solution anaesthetized.After anesthetized rat, its dorsal position is fixed, separate its right common carotid artery, at proximal part, clamp bulldog clamp, proximal part and distal end are respectively penetrated surgical thread, the surgical thread ligation of distal end, distal end intubation, bulldog clamp is unclamped, takes out about 1mL arterial blood, be placed in 1mL centrifuge tube.Toward rubber tube (the long 15mm vertically fixing, internal diameter 2.5mm, external diameter 5.0mm, ttom of pipe plug seals, para film is tamping) interior injection 0.1ml rat artery blood, (the fixing spiral of thrombosis is coiled into the fixing bolt of the subsequent thrombosis being rapidly inserted into a stainless steel in pipe with the stainless steel silk of a diameter of 0.2mm, and the long 10mm of spiral part includes 15 bung flanges, a diameter of 1.0mm of bung flange, support handle is connected with spiral, is about 7.0mm, in question mark type).After blood coagulation 45min, carefully take out the thrombosis being wrapped up by thrombosis from glass tubing and fix spiral, accurately claim its weight.
Bypass intubation is made up of three parts, and interlude is 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 tube of external diameter 2.0mm, this pipe one end pulls into spike tube, be about 10.0mm (for inserting rat carotid artery and vein), external diameter is 1.0mm, one section of the outer cover of its other end long for 7.0mm, external diameter is the polyethylene tube (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 fixing spiral of thrombosis that thrombosis are wrapped up is placed in the polyethylene rubber tube of stage casing, and the other two ends of sebific duct are nested with the overstriking end of two polyethylene respectively it is ensured that will not leak blood during circulation.With syringe, heparin-saline solution (50IU/kg) will be filled by spike tube end in pipe, exclude bubble, standby.
Separate the left external jugular vein of rat, proximal part and distal end respectively penetrate surgical thread, the blood vessel of ligation distal end, cut an osculum on the left external jugular vein exposing, the above-mentioned bypass duct spike tube preparing is inserted left external jugular vein opening by osculum, fixes spiral away from shunt valve stage casing (thrombosis containing accurate weighing fix spiral) interior thrombosis simultaneously.Inject the normal saline solution (50IU/kg) of the heparin sodium of correct amount with syringe by the spike tube of the other end, now syringe must not withdraw polyethylene tube, clamp the flexible pipe between syringe and polyethylene tube with bulldog clamp.Stopped blooding with bulldog clamp in the proximal part of right common carotid artery, ligature distal end, nearby right common carotid artery is being cut an osculum from bulldog clamp, extracting syringe from the tip of polyethylene tube, the tip of polyethylene tube is inserted the proximal part of tremulous pulse angle.Arteriovenous are all fixed by the two ends of bypass duct with No. 4 suturess.
With scalp acupuncture by the normal saline solution (dosage is 100nmol/kg) of the normal saline solution of normal saline (3ml/kg) or urokinase (dosage is 20000IU/kg) or compound 1 stage casing (thrombosis containing accurate weighing fix spiral) by shunt valve, penetrate the nearly vein end away from the fixing spiral of thrombosis, unclamp bulldog clamp, make blood flow flow to vein by bypass duct from tremulous pulse.Solution in syringe is slowly injected into blood, by blood circulation, by vein-heart-tremulous pulse sequential action on the thrombosis of spiral.From bypass duct, after blood circulation 1h, take out the spiral of fixing thrombosis, accurate weighing.Calculate the weight difference fixing thrombosis before and after the spiral blood circulation of thrombosis in every rat bypass duct, represented with mean value ± SD mg and represent thrombus dissolving activity, make t inspection.Data lists table 1 in.Result shows that 100nmol/kg compound 1 can lysigenous thrombosis effectively.The thrombolytic activity of 100nmol/kg compound 1 is suitable with 20000IU/kg urokinase.After illustrating that structure simplifies, technique effect is obvious.
The thrombolysis activity of table 1 compound 1
N=10；A) with normal saline than p ＜ 0.01, with urokinase than p ＞ 0.05.
Experimental example 2 evaluates the therapeutical effect to cerebral infarction rat for the compound 1
Vertically open the long otch of about 2cm at the positive middle part of the cervical region of male SD rat (body weight 300 ± 20g), fate separates out right common carotid artery, external carotid artery and internal carotid artery along inside sternocleidomastoid.Being pressed from both sides respectively with noinvasive bulldog clamp closes at internal carotid artery opening and common carotid artery proximal part, the distal end of ligation external carotid artery, cuts an osculum in external carotid artery, unclamps the bulldog clamp of common carotid artery proximal part, take 10 μ l blood, close Carotid proximal part with noinvasive bulldog clamp folder more afterwards.The 10 μ l blood obtaining are placed on room temperature placement in 1ml EP pipe makes blood coagulation in 30 minutes, is then transferred to place 1 hour in -20 DEG C of refrigerators, makes blood clotting solid.Rat is 400mg/kg with 10% chloral hydrate intraperitoneal injection of anesthesia, dosage.Take out blood clotting, add 1ml normal saline, with steel shovel, blood clotting is pounded uniform tiny thrombi, prepares the suspension of tiny thrombosis and be transferred in 1ml syringe.Unclamp the bulldog clamp of common carotid artery proximal part, by 1ml thrombosis suspension slowly from rat external carotid artery to proximal part through internal carotid injection rat brain, then ligature external carotid artery proximal part, open and at internal carotid artery and common carotid artery, obtain bulldog clamp, recover blood flow.Wait revival.Rat presses Zealonga method evaluation neurological functional deficit after reviving 24 hours.0 point indicate no any neurological deficit sign, 1 point represent do not damage side forelimb not tensible, 2 points represent to do not damage skidding walk, 3 points represent to do not damage side turn-take into shape walking of knocking into the back, 4 points represent disturbance of consciousness no autonomous, 5 points represent dead.According to score average packet.Each group rat injects 1 compound 1 daily through tail vein, and dosage is 100nmol/kg.Continuous injection 6 days, daily scoring.Result lists table 2 in.As shown by data compound 1 is continuously treated 3 cerebral ischemias of 6 angel rat of 24 hours and is scored as 0 point biology, so that 11 cerebral ischemias rat of 24 hours is scored as 1 point biology.Because unlike disclosed compound initial dose needs 5 μm of ol/kg, rear 5 maintenance dosies need 2 μm of ol/kg, and 6 dosage of compound 1 are 100nmol/kg.So, initial dose and maintenance dose reduce 50 times and 20 times respectively.The benefit simplifying plus structure, present invention obtains unexpected technique effect.
Table 2 compound 1 continuously treats the impact to cerebral ischemia 24 hours rat scoring biology in 6 days
N=14.
Claims (4)
1. the N of following formulaα- five methoxytryptamine base carbonyl propionyl-Nω-Arg-Pro-Ala-Lys-Lys
2. the N of claim 1α- five methoxytryptamine base carbonyl propionyl-NωThe preparation method of-Arg-Pro-Ala-Lys-Lys, the method include with
Lower step：
1) five methoxytryptamine base carbonyl propanoic acid are prepared；
2) prepare Boc-Pro-Ala-OBzl；
3) prepare Boc-Pro-Ala；
4) prepare Boc-Pro-Ala-Nω-Z-Lys-OBzl；
5) prepare HCl Pro-Ala-Nω-Z-Lys-OBzl；
6) prepare Boc-NG-NO2-Arg-Pro-Ala-Nω-Z-Lys-OBzl；
7) prepare Boc-NG-NO2-Arg-Pro-Ala-Nω-Z-Lys；
8) prepare Nα- five methoxytryptamine base carbonyl propionyl-Nω-Fmoc-Lys-OBzl；
9) prepare Nα- five methoxytryptamine base carbonyl propionyl-Lys-OBzl；
10) prepare Nα- five methoxytryptamine base carbonyl propionyl-Nω-Boc-NG-NO2-Arg-Pro-Ala-Nω-Z-Lys-Lys-OBzl；
11) by Nα- five methoxytryptamine base carbonyl propionyl-Nω-Boc-NG-NO2-Arg-Pro-Ala-Nω- Z-Lys-Lys-OBzl deprotection obtains Nα-
Five methoxytryptamine base carbonyl propionyl-Nω-Arg-Pro-Ala-Lys-Lys.
3. the N of claim 1α- five methoxytryptamine base carbonyl propionyl-Nω- Arg-Pro-Ala-Lys-Lys answering in preparing thrombolytic agent
With.
4. the N of claim 1α- five methoxytryptamine base carbonyl propionyl-Nω- Arg-Pro-Ala-Lys-Lys is in preparation treatment cerebral infarction medicine
Application in thing.
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| CN110577578A (en) * | 2018-06-08 | 2019-12-17 | 首都医科大学 | Synthesis, activity and application of 1S-methyl-beta-tetrahydrocarboline acyl-K (RPAK) |
| CN112094318A (en) * | 2019-06-18 | 2020-12-18 | 首都医科大学 | Ethyl RPAK modified bis-carbolino-piperazinediones, preparation, activity and use thereof |
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| BEATRIZ LÓPEZ-IGLESIAS等: "New Melatonin−N,N-Dibenzyl(N‑methyl)amine Hybrids: Potent Neurogenic Agents with Antioxidant, Cholinergic, and Neuroprotective Properties as Innovative Drugs for Alzheimer’s Disease", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110577578A (en) * | 2018-06-08 | 2019-12-17 | 首都医科大学 | Synthesis, activity and application of 1S-methyl-beta-tetrahydrocarboline acyl-K (RPAK) |
| CN110577578B (en) * | 2018-06-08 | 2021-06-08 | 首都医科大学 | Synthesis, activity and application of 1S-methyl-beta-tetrahydrocarboline acyl-K (RPAK) |
| CN112094318A (en) * | 2019-06-18 | 2020-12-18 | 首都医科大学 | Ethyl RPAK modified bis-carbolino-piperazinediones, preparation, activity and use thereof |
| CN112094318B (en) * | 2019-06-18 | 2022-09-02 | 首都医科大学 | Ethyl RPAK modified bis-carbolino-piperazinediones, preparation, activity and use thereof |
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