CN107722002B - The twin medicine of 4-ASA derivative and Tubastatin A that a kind of N- benzyl replaces and its application - Google Patents
The twin medicine of 4-ASA derivative and Tubastatin A that a kind of N- benzyl replaces and its application Download PDFInfo
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- CN107722002B CN107722002B CN201710739847.5A CN201710739847A CN107722002B CN 107722002 B CN107722002 B CN 107722002B CN 201710739847 A CN201710739847 A CN 201710739847A CN 107722002 B CN107722002 B CN 107722002B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The twin medicine and its application, structure of 4-ASA derivative and Tubastatin A that a kind of N- benzyl replaces meet general formula (I)Wherein: R1,R2For-Cl ,-Br or-C (CH3)3, R3For the alkyl of 1-6 carbon atom.Such drug has good drug effect to cerebral infarction, can be used for preparing the drug for the treatment of cerebral apoplexy.
Description
Technical field
The invention belongs to pharmaceutical field, the amino-salicylic acid derivatives and Tubastatin A that a kind of N- benzyl replaces are provided
Twin medicine and its medicinal usage.
Background technique
Cerebral apoplexy has the characteristics that high mortality, high relapse rate, high disability rate, seriously endangers human health, lacks at present
Satisfied therapeutic agent.Neuroprotective agent can alleviate ischemic progress, mitigate ischemical reperfusion injury, promote injured nerve function
Recovery, it is in widespread attention.
Acetylation of histone level reduces after cerebral ischemia, is the Important cause of disease of cerebral injury.Histon deacetylase (HDAC)
(HDACs) inhibitor can raise acetylation of histone level, generate cytoprotection.There are many hypotype, selections by HDACs
Property HDACs inhibitor is relatively safer.Researches show that: Tubastatin A can reduce ischemic injuries (J Am Chem
Soc.2010,132:10842-10846), but the hydroximic acid structure that its intramolecular is very big there are polarity, it is not easy to enter maincenter.
Therefore, Tubastatin A does not show significant anti-stroke effect in artery occlusion model in rats (see attached drawing 2).
NMDAR is activated after cerebral ischemia, passes through NMDAR- postsynaptic density protein-95 (PSD95)-neuron pattern nitric oxide
Synthase (nNOS) access excessively discharges nitric oxide (NO), generates neurotoxicity.Due to NMDAR and nNOS all have it is extremely important
Physiological function, serious side effect is often led to their direct intervention.NNOS-PSD95 uncoupler 4-N- (2- hydroxyl
Base -3,5- dichloro benzyl) aminosalicylic acid (ZL006), safe and effective to cerebral ischemia (Nature Medicine, 2010,
16:1439-1443).ZL006 mainly passes through the metabolism of its carboxyl glucuronidation, and the prodrug of carboxyl esterification can delay generation
It thanks, increases maincenter distribution (Bioorganic&Medicinal Chemistry Letters, 2016,26:2152-2155).But
It is the prodrug of either ZL006 or its carboxyl esterification, is only shown in artery occlusion model in rats limited anti-
Stroke effect.
There are multiple pathology links, different mechanism weave ins to result in final destructiveness for the occurrence and development of cerebral apoplexy
As a result, the drug for intervening cerebral apoplexy different mechanisms simultaneously will be more effective.We, which design, has synthesized with urethane bond as company
The twin medicine of the ZL006 and Tubastatin A of base is connect, which can obviously increase ZL006 and Tubastatin A in brain group
Distribution in knitting, it is shown that good anti-cerebral apoplexy effect, and there is biggish therapeutic window.
Summary of the invention
The technical issues of solution: the twin medicine of amino-salicylic acid derivatives and Tubastatin A that a kind of N- benzyl replaces and
It is applied, and can be used for preparing the drug for the treatment of cerebral apoplexy.
Technical solution: the twin medicine of 4-ASA derivative and Tubastatin A that a kind of N- benzyl replaces, structure
As shown in logical formula (I):
Wherein: R1,R2For-Cl ,-Br or-C (CH3)3, R3For the alkyl of 1-6 carbon atom.
The twin medicine of 4-ASA derivative and Tubastatin A that a kind of N- benzyl replaces, it is characterised in that chemical combination
Object structure is any one in following 001~003:
The application of above-mentioned twin medicine or its pharmaceutically acceptable salt in preparation treatment cerebral apoplexy drug.
A kind of drug preparing treatment cerebral apoplexy, effective component are above-mentioned twin medicine.
The utility model has the advantages that the multiple target point that such drug is nNOS-PSD-95 uncoupler ZL006 and Tubastatin A is twin
Medicine can obviously increase distribution of the ZL006 and Tubastatin A in brain tissue, have than nNOS-PSD-95 uncoupling agent,
The mono- target drug of Tubastatin A preferably treats the effect of cerebral apoplexy, can be used for preparing the drug for the treatment of cerebral apoplexy.
Detailed description of the invention
Fig. 1 is drug and Metabolites Concentration measurement chart in the brain of target compound;15 minutes (0.1mmol/ after administration
Kg), the drug concentration and ZL006 in rat brain, the concentration of Tubastatin A, twin medicine significantly improve ZL006,
Distribution of the Tubastatin A in rat brain.
Fig. 2 is influence diagram of the target compound 001 to rat cerebral infarction area, intraluminal middle cerebral artery occlusion in rats blocking experiment
In (MCAO model), the Infarction volume after target compound 001 (30mg/kg) administration compares.
Specific embodiment
The following examples can make those skilled in the art that can be fully understood by the present invention, but not limit this in any way
Invention.
The synthesis of 1 target compound of embodiment:
Compound 001-003 synthetic route involved in embodiment:
The synthesis of compound 001:
Triphosgene (150mg, 0.5mmol) is cooled to subzero under the conditions of anhydrous and oxygen-free with the dissolution of 10mL methylene chloride
78 DEG C, be added with stirring the mixed solvent (pyridine: methylene chloride volume ratio=1:9) of 10mL pyridine and methylene chloride, solution by
It is colorless and transparent gradually to present faint yellow and gradually have pale yellow precipitate generation.After continuing stirring 15 minutes, by 2- hydroxyl -4- (2-
Hydroxyl -3,5- chlorophenylmethyl) Methyl anthranilate (ZL006 methyl esters, synthetic method: Bioorganic&Medicinal
Chemistry Letters, 2016,26:2152-2155,342mg, 1mmol) with 10mL methylene chloride dissolution after in 30 minutes
In interior addition reaction flask.It continues at subzero 78 DEG C and stirs 30 minutes after to be added, be then warmed to room temperature reaction 8 hours.8
After hour, by Tubastatin A (671mg, 2mmol) system is added after the dilution of 10mL methylene chloride, triethylamine is added
(400mg, 6mmol).The reaction was continued the at room temperature 24 hours drying sand of back spin, column chromatograph to obtain product 001.
1H NMR(300MHz,CDCl3)7.96(d,1H),7.65(d,2H),7.45(s,1H),7.39-7.34(m,2H),
7.11 (s,1H),7.06-6.96(m,6H),5.38(s,2H),4.86(s,2H),3.80(s,3H),3.55(s,2H),2.72
(s,4H),2.42(s, 3H)。
The synthesis of compound 002:
001 method of reference compound, with 2- hydroxyl -4- (2- hydroxyl -3,5- di-t-butyl benzyl) aminobenzoic acid second
Ester (is closed with reference to Bioorganic&Medicinal Chemistry Letters, 2016,26:2152-2155, ZL006 methyl esters
Synthesized at method), Tubastatin A be Material synthesis.1H NMR(300MHz,CDCl3)7.99(d,1H),7.66(d,2H),
7.48(s,1H), 7.42-7.36(m,2H),7.18(s,1H),7.12-6.71(m,6H),5.41(s,2H),4.89(s,2H),
4.42-4.39(m,2H), 3.58(s,2H),2.75(s,4H),1.45(s,9H),1.42(t,3H),1.29(s,9H)。
The synthesis of compound 003:
001 method of reference compound, with 2- hydroxyl -4- (the bromo- benzyl of the chloro- 5- of 2- hydroxyl -3-) benzocaine
It (is synthesized with reference to Bioorganic&Medicinal Chemistry Letters, 2016,26:2152-2155, ZL006 methyl esters
Method synthesis), Tubastatin A be Material synthesis.1H NMR(300MHz,CDCl3)7.94(d,1H),7.62(d,2H),
7.41(s,1H), 7.36-7.32(m,2H),7.08(s,1H),7.03-6.93(m,6H),5.35(s,2H),4.83(s,2H),
4.25-4.16(m, 1H),3.53(s,2H),2.70(s,4H),1.68-1.61(m,2H),1.36-1.27(m,6H),0.86-
0.83(m,2H)。
Drug and Metabolites Concentration measurement in the brain of 2 target compound of embodiment
It is prepared to drug solns: weighing target compound 001,002,003, ZL006, each 20mg of Tubastatin A, be dissolved in
(total volume 1% is less than) in minute quantity DMSO, is added Tween 80 (being less than total volume 5%), it is rear in hot bath that physiology salt is added
Water is settled to 20mL, and being configured to concentration is 1mgmL-1Solution.
Test method
ICR mouse 30, weight 20g or so are taken, is randomly divided into 5 groups, every group 6, tail vein is administered, dosage 20mg
kg-1.Mouse is deprived of food but not water 12h, free water during experiment.Mouse is put to death respectively at 15min after administration.It is floated with physiological saline
The bloodstain on wash clean brain tissue surface, filter paper blot surface moisture, weighing.Physiological saline (the i.e. 1g brain group of weight ratio 1:3 is added
Knit and 3mL physiological saline be added), electric homogenizer is by tissue preparation at homogenate.Ultrasonic 10min excludes bubble.
It is accurate in the centrifuge tube of 1.5mL to draw 100 μ L brain tissue homogenate liquid, the accurate 10 μ L internal standards drawn then are added
Solution (Prozac, 5 μ gmL-1) and 300 μ L methanol as precipitating reagent, in mixing whirlpool 1min on turbula shaker, in centrifugation
12000rmin in machine-1, it is centrifuged 10min, accurate 150 μ L of Aspirate supernatant is added 50 μ L ultrapure waters, takes 10 μ L solution sample introductions,
Its chromatogram image is recorded, test result is shown in Fig. 1.
The anti-cerebral apoplexy effect of 3 target compound of embodiment
Using MCAO models in rats, it is control with ZL006, Tubastatin A, has investigated the anti-cerebral apoplexy of compound 001
Drug effect.
Dosage regimen: all groups iv is administered once immediately after Reperfu- sion, is administered once altogether.It puts to death within 24 hours after cerebral ischemia dynamic
Object takes brain, and dyeing calculates brain infarction area.
MCAO models in rats: after rat is anaesthetized with 7% chloral hydrate (6mL/kg), operating table is fixed in prone position
On, skin is sterilized, neck midsection separates right carotid, external carotid artery, internal carotid, gently removes vagus nerve,
External carotid artery is ligatured and cut, follows internal carotid forward, ligatures arteria pterygopalatina.Folder closes arteria carotis communis proximal part, from external carotid artery
The distal end of ligature make a kerf, the nylon wire that insertion outer diameter is 0.285mm is moved into crossing arteria carotis communis bifurcated and entering in neck
Arteries and veins blocks all blood supplies of arteria cerebri media, right side (from crotch about 20mm) until being then inserted into light resistance slowly
After cerebral ischemia 2.0h, nylon wire is gently extracted, restores blood supply and carries out Reperfu- sion, skin suture, disinfection.
The measurement of cerebral infarction degree
After animal is put to death, broken end takes brain, removal olfactory bulb, cerebellum and low brain stem, with normal saline flushing brain surface's blood
Mark sucks remained on surface water mark, in -20 DEG C of placement 20min, makees coronal cut vertically downward in sight crossing plane immediately after taking-up
Face, and cut backward every 2mm a piece of, brain piece is placed in incubation (37 DEG C of 90min) in 1%TTC dye liquor, normal cerebral tissue dyes depth
Red, ischemic tissue of brain is then in pale asphyxia, after normal saline flushing, is rapidly arranged in a row brain piece in order from front to back,
Remained on surface water mark is blotted, is taken pictures.
Photo is handled with Image J software, is calculated the corresponding area of left brain and infarct area according to formula, is found out stalk
Dead stove percentage.
Infarction volume calculating method:
V=t (A1+A2+A3+………+An)
T is slice thickness, and A is infarct size.
%I=100% × (VC-VL)/VC
%I is Infarction volume percentage, and VC is control sides (left brain hemisphere) brain volume, and VL is that infarct side (right brain hemisphere) is non-
Infarcted region volume.
Fig. 2 is shown in influence of each group to cerebral infarct size.
Claims (3)
1. the twin medicine of 4-ASA derivative and Tubastatin A that one kind N- benzyl replaces, it is characterised in that structure is such as
Shown in 001:
2. application of the twin medicine or its pharmaceutically acceptable salt described in claim 1 in preparation treatment cerebral apoplexy drug.
3. a kind of drug for preparing treatment cerebral apoplexy, it is characterised in that effective component is twin medicine described in claim 1.
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104230745A (en) * | 2014-07-10 | 2014-12-24 | 南京医科大学 | N-benzyl-substituted amide derivatives of amino salicylic acid and 4-aminobutyric acid and drug application of N-benzyl-substituted amide derivatives |
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2017
- 2017-08-25 CN CN201710739847.5A patent/CN107722002B/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104230745A (en) * | 2014-07-10 | 2014-12-24 | 南京医科大学 | N-benzyl-substituted amide derivatives of amino salicylic acid and 4-aminobutyric acid and drug application of N-benzyl-substituted amide derivatives |
Non-Patent Citations (3)
Title |
---|
Metabolic investigation on ZL006 for the discovery of a potent prodrug for the treatment of cerebral ischemia;Dongyin Chen etal.;《Bioorganic & Medicinal Chemistry Letters》;20160319;第26卷;2152-2155 * |
nNOS-PSD-95 解耦联剂和加巴喷丁、普瑞巴林孪药的设计合成;沈坤等;《南京医科大学学报(自然科学版)》;20141031;第34卷(第10期);1441-1445 * |
Rational Design and Simple Chemistry Yield a Superior,Neuroprotective HDAC6 Inhibitor, Tubastatin A;Kyle V. Butler etal.;《JACS》;20100907;第132卷;10842-10846 * |
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