CN107857712A - (R) 3 methyl 2 (3 oxo amide groups) n-butyric acie ester - Google Patents
(R) 3 methyl 2 (3 oxo amide groups) n-butyric acie ester Download PDFInfo
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- CN107857712A CN107857712A CN201610838784.4A CN201610838784A CN107857712A CN 107857712 A CN107857712 A CN 107857712A CN 201610838784 A CN201610838784 A CN 201610838784A CN 107857712 A CN107857712 A CN 107857712A
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- WOOSCPWOYYLIHS-UHFFFAOYSA-N Oxoamide Chemical group CNC(=O)CCC(=O)C1=CC=CN=C1 WOOSCPWOYYLIHS-UHFFFAOYSA-N 0.000 title abstract 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title abstract 2
- 150000002148 esters Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 230000008451 emotion Effects 0.000 claims abstract description 10
- 210000005036 nerve Anatomy 0.000 claims abstract description 9
- 206010015037 epilepsy Diseases 0.000 claims abstract description 8
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 7
- 208000001738 Nervous System Trauma Diseases 0.000 claims abstract description 6
- 210000003169 central nervous system Anatomy 0.000 claims abstract description 6
- -1 ester compounds Chemical class 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims description 16
- 210000004556 brain Anatomy 0.000 claims description 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 10
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000000926 neurological effect Effects 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 206010008118 cerebral infarction Diseases 0.000 abstract description 11
- 201000006474 Brain Ischemia Diseases 0.000 abstract description 6
- 206010008120 Cerebral ischaemia Diseases 0.000 abstract description 6
- 208000023105 Huntington disease Diseases 0.000 abstract description 5
- 230000001225 therapeutic effect Effects 0.000 abstract description 5
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 3
- 230000004224 protection Effects 0.000 abstract description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 20
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 15
- 235000013922 glutamic acid Nutrition 0.000 description 15
- 239000004220 glutamic acid Substances 0.000 description 15
- 210000002569 neuron Anatomy 0.000 description 13
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- 241000700159 Rattus Species 0.000 description 7
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 102000018899 Glutamate Receptors Human genes 0.000 description 6
- 108010027915 Glutamate Receptors Proteins 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
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- 238000001994 activation Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 description 4
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- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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- 239000012895 dilution Substances 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 230000002964 excitative effect Effects 0.000 description 2
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- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- KZSNJWFQEVHDMF-SCSAIBSYSA-N D-valine Chemical compound CC(C)[C@@H](N)C(O)=O KZSNJWFQEVHDMF-SCSAIBSYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
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- 230000001413 cellular effect Effects 0.000 description 1
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- 230000002461 excitatory amino acid Effects 0.000 description 1
- 239000003257 excitatory amino acid Substances 0.000 description 1
- 231100000318 excitotoxic Toxicity 0.000 description 1
- 231100000063 excitotoxicity Toxicity 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
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- 230000003340 mental effect Effects 0.000 description 1
- KUGLDBMQKZTXPW-JEDNCBNOSA-N methyl (2s)-2-amino-3-methylbutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)C(C)C KUGLDBMQKZTXPW-JEDNCBNOSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
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- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention provides a kind of（R）3 methyl 2（3 oxo amide groups）N-butyric acie ester compounds and preparation method thereof and medicinal usage; such compound can play the therapeutic action of protection cerebral ischemia, it may also be used for central nervous system trauma, disturbance of emotion disease, epilepsy, nerve degenerative diseases including Parkinson's, Alzheimer disease, Huntington's disease etc. etc..
Description
Technical field
The invention belongs to pharmaceutical field, there is provided a kind of（R）- 3- methyl -2-（3- oxo amide groups）N-butyric acie ester compounds
And preparation method thereof and medicinal usage, such compound can play protection cerebral ischemia therapeutic action, it may also be used for maincenter
Nervous system trauma, disturbance of emotion disease, epilepsy, including Parkinson's, Alzheimer disease, Huntington's disease etc.
Nerve degenerative diseases etc..
Background technology
Glutamic acid is the most excitatory neurotransmitter of central nervous system content, and it is with 5-HT, monoamine and GABA etc. passs
Matter is mutually adjusted, and the excitement of control axis nervous system activity is with suppressing.In cellular level, Effect of Glutamate neurodevelopment and god
Through plasticity；In behaviouristics aspect, it regulates and controls study, memory, emotion and the reaction to ambient pressure.Glutamic acid system is excessive
Activation can trigger convulsions, intense and neure damage.
In neuro-physiology, glutamic acid is the major excitatory neurotransmitter for being present in nervous system, appropriate paddy ammonia
Acid is beneficial and necessary for Normal brain physiological function.But the numerous studies have demonstrated that excitement of excessive glutamate
Property toxicity, including ischemic stroke, epilepsy, nerve degenerative diseases.In the Cerebrospinal Fluid in Patients of spinal cord injury, glutamate levels
Exception increases.Show that glutamic acid is relevant with localized cerebral hypoxic-ischemic pathomechanism, brain ischaemia causes the tired of glutamic acid
Product, and then cause death of the cell in ischemic.Oligodendroglia is vulnerable to glutamic acid poisoning by activating glutamate receptor
Damage.The excessive activation of extracellular glutamic acid accumulation and glutamate receptor is the key mechanism of cerebrum ischemia damage.
Glutamic acid activates in synaptic levels and combines a number of glutamate receptor, controls fast response ion channel and the
The behavior of two couriers mediation.Glutamate receptor is divided into two kinds：Ion dependence and metabotropic receptor, ion channel dependence acceptor
With adjusting glutamate toxicity indirectly, and metabotropic receptor has directly regulation toxic action.Its mechanism may include calcium
The activation of the enzymatic pathway and microglia cell of ionic dependent.NMDA and non-NMDA acceptors are the hypotypes of glutamate receptor,
Both acceptors of excessive activation can cause the Excitotoxicity of neuron, and NMDA receptor activations are that glutamic acid is emerging
The committed step of putting forth energy property poisoning.The type of impairment of glutamic acid includes necrosis and apoptosis.Persistently glutamate receptor is stimulated to cause
Necrosis and apoptosis；The glutamic acid of low concentration can cause apoptosis, and the glutamic acid of high concentration can cause necrosis.
Conditioned fear acquistion normal form is the main models of current research anxiety disorder mechanism, when a neutral condition thorn
Swash（conditioned stimulus, CS）With a negativity unconditioned stimulus（unconditioned stimulus,
US after) occurring, conditioned reflex is formed, and afterwards when individually giving CS, can also cause fear reaction caused by US
（conditioned response, CR）, such as endocrine, autonomic nerve and behavior change conditioned fear are formed；Work as the mankind
This conditioned fear of acquistion and by its pathologic it is extensive when, just there is the performance of anxiety disorder；Its Glutamic Acid pair
The long term potentiation of neuron（longterm potentiation, LTP）Effect plays master as the neuromechanism of frightened acquistion
The effect wanted.
For the multinomial research in terms of physiology, iconography, gene and behavior, excitatory amino acid neurotransmitter glutamate is disclosed in the mankind
Effect in anxiety disorder.The patients with OCD of drugs of mental department is not taken compared with normal control, CSF Glutamate concentration
It is significantly raised.The content of glutamic acid of social phobia patient's anterior cingutate significantly rises compared with normal control, and glutamic acid signal
Intensity is proportionate with frightened symptom.
One kind of the present invention（R）- 3- methyl -2-（3- oxo amide groups）N-butyric acie ester compounds, the excitement to neuron
Property damage, preferable neuroprotection can be played, there is wide prospect in medicine.Such medicine can play protection cerebral ischemia damage
The therapeutic action of wound, it may also be used for central nervous system trauma, disturbance of emotion disease, epilepsy including Parkinson's, A Erci
Nerve degenerative diseases including sea silent disease, Huntington's disease etc. etc..
The content of the invention
The technical problem of solution：Present invention offer one kind (R) the esterification conjunction of -3- methyl -2- (3- oxos amide groups) n-butyric acie
Thing, the characteristics of such medicine is most prominent are that have cerebral ischemia re-pouring injured protective effect and to disturbance of emotion disease
Therapeutic action, available for prepare treatment cerebral apoplexy medicine, it may also be used for central nervous system trauma, disturbance of emotion disease,
Epilepsy, nerve degenerative diseases including Parkinson's, Alzheimer disease, Huntington's disease etc. etc..
Technical scheme：A kind of (R) -3- methyl -2- (3- oxos amide groups) n-butyric acie ester compounds, structure meets formula（）
Formula I
Wherein：R1, R2 are C1-C6 alkyl, and R3, R4 are H or C1-C3 alkyl.
Preferably：R1 is C1-C3 alkyl, and R2 is C1-C6 alkyl, and R3, R4 are H or C1-C2 alkyl.
More preferably：R1, R2 are C1-C3 alkyl, R3, R4 H.
Beneficial effect：
Described in this patent one kind (R) -3- methyl -2- (3- oxos amide groups) n-butyric acie ester compounds, it is most prominent to such medicine
The characteristics of going out is that have cerebral ischemia re-pouring injured protective effect and the therapeutic action to disturbance of emotion disease, be can be used for
Prepare treatment cerebral apoplexy medicine and disturbance of emotion disease medicine, it may also be used for central nervous system trauma, epilepsy including
Nerve degenerative diseases including Parkinson's, Alzheimer disease, Huntington's disease etc. etc..
Brief description of the drawings
The effect that Fig. 1 S1, R1 damage to neuronal excitability
Average value ± standard error；One-way ANOVA, Dunnett’s multiple comparisons test；* * with
NMDA+Gly compares, p<0.001.
General formula compound of the present invention may travel to lower route synthesis：
Embodiment
The following examples can make those skilled in the art to be apparent from the present invention, but not limit this in any way
Invention.
Compound 1：（R）- 3- methyl -2-（3- oxobutanamide groups）Methyl butyl, as shown at s 1.
Control compounds：（S）- 3- methyl -2-（3- oxobutanamide groups）Methyl butyl, as shown in R1.
Embodiment 1：Compound S1 synthesis
Synthetic route：
Building-up process：
Weigh D-Val methyl ester hydrochloride（1.67 g, 10.0 mmol）And ethyl acetoacetate（1.3 g, 10.0 mmol）
Mixing, the mL of acetonitrile 50 dissolvings are added, add DMAP afterwards（122 mg, 1 mmol）And triethylamine（2.02 g, 20.0
mmol）, return stirring 5h, TLC monitoring is risen to after 15 min are stirred at room temperature, after question response is complete, is concentrated in vacuo, crude product silicagel column
Chromatography（Petroleum ether：Ethyl acetate=2:1）, separate to obtain compound S1（1.32 g）, yield 61.4%.
ESI- MS: 216.3 [M+H]+;Optical value be+28.9 ° (c 1, MeOH)
1H NMR (400 MHz, CDCl3): δ 7.39 (1H, br s), 4.54-4.58 (1H, m), 3.76 (3H,
S), 3.49 (2H, s), 2.30 (3H, s), 2.20-2.25 (1H, m), 0.97-0.99 (6H, m)
Embodiment 2：Control compounds R1 synthesis
Synthetic route：
Building-up process：
Weigh Valine methyl ester hydrochloride（1.67 g, 10.0 mmol）And ethyl acetoacetate（1.3 g, 10.0 mmol）
Mixing, the mL of acetonitrile 50 dissolvings are added, add DMAP afterwards（122 mg, 1 mmol）And triethylamine（2.02 g, 20.0
mmol）, return stirring 5h, TLC monitoring is risen to after 15 min are stirred at room temperature, after question response is complete, is concentrated in vacuo, crude product silicagel column
Chromatography（Petroleum ether：Ethyl acetate=2:1）, separate to obtain compound R 1（1.25 g）, yield 58.3%.
ESI- MS: 216.3 [M+H]+;Optical value be -30.1 ° (c 1, MeOH)
1H NMR (400 MHz, CDCl3): δ 7.39 (1H, br s), 4.53-4.56 (1H, m), 3.75 (3H,
s), 3.48 (2H, s), 2.29 (3H, s), 2.20-2.25 (1H, m), 0.97-0.99 (6H, m).
Embodiment 3：The influence that S1 damages to Primary rat neuronal excitability
1. material
Neuron complete medium：Neurobasal culture mediums+B27（2%）+L-Glutamine（0.5mM）+P/S（1%）
2. laboratory apparatus
ELIASA（PHERAstar FS）：BMG LABTECH
ELISA Plate：12 orifice plates, Costa #3513
3. experimental method
3.1 Primary cortical neurons cells prepare
Cervical dislocation is pregnant the SD pregnant rats of 18 days, separates the cerebral cortex of E18 tire mouse, shred brain tissue into<1mm3 granules, in advance
Cold DMEM cleanings, 1000rpm centrifugation 5min, abandon supernatant；Digestion is terminated with preheating pancreatin 37 DEG C of digestion 10min, 20%FBS；
1000rpm centrifuges 5min, abandons supernatant；It is resuspended with neuron complete medium, 1000rpm centrifugation 5min, abandons supernatant；Again with nerve
First complete medium is resuspended, and crosses 200 mesh cell sieves.With the cell suspension of neuron complete medium dilution sieving to 5 × 105 thin
Born of the same parents/mL, 100 μ L cell suspensions of inoculation are added 100 μ L neurons for second day and trained completely into pre-coated PDL 96 well culture plates
Base is supported, half amount changes a not good liquor, in vitro culture to the 10th day neuron differentiation and maturation, you can for testing every three days afterwards.
3.2 compounds are prepared
DMSO dissolved compounds, storing liquid concentration are 0.5M, and -20 DEG C preserve；Suitable concn is diluted to successively with DMSO before use,
Then again with neuron complete medium be diluted to final concentration of 0 μ Μ, 0.01 μ Μ, 0.04 μ Μ, 0.12 μ Μ, 0.37 μ Μ,
1.1μΜ、3.3μΜ、10μΜ（DMSO contents are 0.1%）.
3.3 Locke ' s Buffer preparation
PH to 7.4 is adjusted, 0.22 μm of filter is degerming, 4 DEG C of preservations.
3.4 S1, R1 are probed into the drug effect of Primary cortical neurons excitotoxic injury model
The Primary rat neuron that in vitro culture is broken up to maturation discards Neurobasal+B27 culture mediums, is replaced with containing not
With the culture medium of concentration compound, 30min is incubated in advance.
Neuronal excitability damage model：It will contain 100 μM of NMDA, 10 μM of Gly and various concentrations compound
Locke ' s Buffer, after being incubated neuron 30min, with 1mM Mg2+Locke ' s Buffer rinse once, be substituted for containing
Various concentrations compound complete medium, cultivate 4h.After 4h, CellTiter-Glo, cell viability is detected.According to
CellTiter-Glo specifications add 100 μ L/ holes reagents, shake 10 minutes, on multi-functional plate reader PHERAstar FS
Compound light-emitting value is read, calculates neuron relative activity, calculation formula is as follows：Neuron relative activity（%）=（Administration group-sheet
Bottom group）/（DMSO groups-background group）×100%
4. experimental result
As shown in Figure 1, neuronal excitability damage model makes cell viability be down to 40% in this research, and compound S1 is in concentration 1.1
μM -10 μM can significantly improve neuronal excitability caused by NMDA and Gly is combined and damage.Compound R 1 is equal under all concentration
Failing, which improves neuronal excitability caused by NMDA and Gly is combined, damages.
Effects of the S1 of embodiment 4 to focal cerebral reperfusion injury
1 material and method
1.1 experimental animal
Sprague-Dawley（SD）Rat, male, body weight：250-280g, SPF level
1.2 tested medicine
Compound S1,2% propane diols dissolving.Edaravone Injection, specification：5mL:10mg, the first pharmacy in Nanjing first sign east are limited
Company produces, and uses preceding normal saline dilution.
1.3 experimental method
1.3.1 prepared by Focal Cerebral Ischemia Reperfusion model.Key step：10% chloraldurate（350mg/kg）Intraperitoneal injection
Anesthetized rat, separate, ligature and cut off right side external carotid artery, the number of people is slowly inserted along neck summation internal carotid by external carotid artery stump
The nylon embolus line about 18mm expanded is held, obstruction arteria cerebri media entrance causes ischemic.Bolt line progress 24h is pulled out after ischemic 2h to fill again
Note；Sham-operation group bolt line separating blood vessel, the same model group of remaining step.Occur Homer after animal revival to seek peace to lateral body motion
Obstacle is that model is successfully prepared.
1.3.2 animal packet is randomly divided into 5 groups, i.e. model group, positive control Edaravone group with administration experimental animal
4 groups of (6 mg/kg), S1（It is 0.1mg/kg, 0.3mg/kg, 1mg/kg, 3mg/kg respectively）, every group of 10-12 is only.S1 tested materials
Tail vein injection is administered once immediately after Reperfu- sion for each group and Edaravone Injection group, is administered once altogether.Volume is administered in each group
0.6mL/100g。
1.3.3 the measure of neurologically handicapped scoring and cerebral infarct volume
Preparation method is divided to carry out neurologically handicapped symptom assessment using improvement Bederson 5.
Cerebral infarction volume determines, and for animal after last neurological deficits score, broken end takes brain.Reject rhinencephalon, low level brain
Dry and cerebellum, remainder weigh weight in wet base immediately, brain are cut into essentially identical 5 of thickness along coronal-plane on ice, in 37 DEG C
Warm bath 30min in red tetrazolium dyestuff, normal cerebral tissue are in rose-red, and white is presented in infarcted region.Then brain piece is put to 10% first
It is fixed in aldehyde, white tissues are carefully dug down and weighed, the percentage that total brain weight is accounted for using infarction tissue's weight is used as Infarction volume
Judging index.
2 results
2.1 pairs of ischemia-reperfusion cerebral Infarction volumes and the influence of neurologically handicapped scoring
Compared with model group, medicine group can be obviously reduced rats after cerebral ischemic reperfusion infarct volume（P<0.01）；Nerve is lacked
The influence of symptom is fallen into, significantly improves rat defect symptom.It the results are shown in Table 1.
The influence that table 1 scores ischemia-reperfusion cerebral Infarction volume and neurologically handicapped（±S）
| Group | Cerebral infarct volume（%） | Neurologically handicapped scores (dividing) |
| Model group | 35.35±3.52 | 3.1±1. 05 |
| Edaravone group（6 mg·kg-1） | 22.63±1.86* | 2.5±1. 02 |
| S1（0.1 mg·kg-1） | 24.11±2.66* | 2.0±0. 98 |
| S1（0.3 mg·kg-1） | 22.61±3.57* | 1.1±0. 69* |
| S1（1 mg·kg-1） | 20.13±2.33** | 0.8±0. 53* |
*P<0.05,**P<0.01, compared with model group.
Claims (10)
1. it is a kind of shown in formula I (R) -3- methyl -2- (3- oxos amide groups) n-butyric acie ester compounds or its is pharmaceutically acceptable
Salt,
Formula I
Wherein, R1, R2 are C1-C6 alkyl, and R3, R4 are H or C1-C3 alkyl.
2. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that wherein described R1 is
C1-C3 alkyl, R2 are C1-C6 alkyl, and R3, R4 are H or C1-C2 alkyl.
3. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that wherein described R1, R2
For C1-C3 alkyl, R3, R4 H.
4. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that the compound choosing
From：
Compound 1：（R）- 3- methyl -2-（3- oxobutanamide groups）Methyl butyl, as shown at s 1.
5. the compound or its pharmaceutically acceptable salt as described in any one in Claims 1 to 4 are preparing treatment brain soldier
In medicine and available for preparing treatment central nervous system trauma, epilepsy, disturbance of emotion disease and various neurologicals
Application in the medicine of property disease.
6. the compound or its pharmaceutically acceptable salt as described in any one in Claims 1 to 4 are preparing treatment brain soldier
In medicine in application.
7. the compound or its pharmaceutically acceptable salt as described in any one in Claims 1 to 4 are preparing treatment emotion
Application in obstacle disease medicine.
8. the compound or its pharmaceutically acceptable salt as described in any one in Claims 1 to 4 are preparing treatment old age
Application in dull-witted medicine.
9. the compound or its pharmaceutically acceptable salt as described in any one in Claims 1 to 4 are preparing treatment epilepsy
And the application in the medicine of various nerve degenerative diseases.
10. a kind of pharmaceutical composition, it is characterised in that include compound described in any one in Claims 1 to 4 or its pharmacy
Upper acceptable salt and pharmaceutically acceptable carrier.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114008204A (en) * | 2019-06-05 | 2022-02-01 | 德国神经退行性疾病中心 | Chimeric autoantibody receptors (CAARs) that bind autoantibodies that target the central nervous system in neuroautoimmune diseases |
| CN114763326A (en) * | 2021-01-13 | 2022-07-19 | 南京宁丹新药技术有限公司 | Amino acid ester derivatives and application thereof |
| CN114763326B (en) * | 2021-01-13 | 2026-01-02 | 南京宁丹新药技术股份有限公司 | A class of amino acid ester derivatives and their uses |
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| EP0145956A1 (en) * | 1983-11-16 | 1985-06-26 | Ciba-Geigy Ag | Composés amidés |
| US4616002A (en) * | 1984-11-09 | 1986-10-07 | Ciba-Geigy Corporation | Dihydro pyridine compounds, compositions and use |
| CN101906069A (en) * | 2009-06-02 | 2010-12-08 | 首都医科大学 | (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl)acetic acid and its preparation method and application |
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| EP0145956A1 (en) * | 1983-11-16 | 1985-06-26 | Ciba-Geigy Ag | Composés amidés |
| US4616002A (en) * | 1984-11-09 | 1986-10-07 | Ciba-Geigy Corporation | Dihydro pyridine compounds, compositions and use |
| CN101906069A (en) * | 2009-06-02 | 2010-12-08 | 首都医科大学 | (S)-2-substituted-(3'-acetyl-2'-pyridone-1'-yl)acetic acid and its preparation method and application |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114008204A (en) * | 2019-06-05 | 2022-02-01 | 德国神经退行性疾病中心 | Chimeric autoantibody receptors (CAARs) that bind autoantibodies that target the central nervous system in neuroautoimmune diseases |
| CN114763326A (en) * | 2021-01-13 | 2022-07-19 | 南京宁丹新药技术有限公司 | Amino acid ester derivatives and application thereof |
| CN114763326B (en) * | 2021-01-13 | 2026-01-02 | 南京宁丹新药技术股份有限公司 | A class of amino acid ester derivatives and their uses |
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Effective date of registration: 20231222 Address after: Room 415, 4th Floor, No. 371 Taiping South Road, Qinhuai District, Nanjing City, Jiangsu Province, 210000 Patentee after: NANJING BAIXINYU MEDICINE Co.,Ltd. Address before: No. 2, No. 32, Zhujiang Road, Economic and Technological Development Zone, Yantai City, Shandong Province, 264006 Patentee before: YANTAI YENE BIOMEDICAL TECHNOLOGY Co.,Ltd. |