CN106946866A - A kind of medicine for preventing and treating cerebral apoplexy and preparation method thereof - Google Patents
A kind of medicine for preventing and treating cerebral apoplexy and preparation method thereof Download PDFInfo
- Publication number
- CN106946866A CN106946866A CN201710247954.6A CN201710247954A CN106946866A CN 106946866 A CN106946866 A CN 106946866A CN 201710247954 A CN201710247954 A CN 201710247954A CN 106946866 A CN106946866 A CN 106946866A
- Authority
- CN
- China
- Prior art keywords
- formulas
- alkyl
- pharmaceutically acceptable
- coumarin derivative
- cerebral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The present invention relates to a kind of medicine for preventing and treating cerebral apoplexy particularly cerebral arterial thrombosis.The present invention have studied its pharmacodynamics feature in rat body by researching and analysing the design feature of the coumarin derivative shown in formula I, it was demonstrated that it has the effect of prevention and treatment cerebral apoplexy particularly cerebral arterial thrombosis.In addition, coumarin derivative shown in formula I is in Cerebral Ischemia-reperfusion in Mice experiment, show good therapeutic activity, it can significantly reduce the behavior scoring of cerebral ischemia-reperfusion in mice and can mitigate the oedema degree and water content of injured brain tissue, cerebral infarction ratio is reduced, it can be used in prevention and treatment cerebral apoplexy particularly cerebral arterial thrombosis.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to one kind is used to prevent and treat cerebral apoplexy particularly ischemic brain
The medicine of palsy, the invention further relates to the preparation method of the medicine.
Background technology
Cerebral apoplexy is broadly divided into hemorrhagic apoplexy and the class of cerebral arterial thrombosis two, and the former mainly includes cerebral hemorrhage and spider web
Film lower cavity hemorrhage etc.；The latter mainly includes transient ischemic attack, cerebral thrombosis and cerebral embolism etc..Cerebral apoplexy be in, it is old
The common disease of year people, its death rate is the first place of our the national disease causes of the death.The patient for still having 75% or so in survivor exists
Occur deformity in varying degrees, serious disabled person is up to 40% or so, become the heavy burden of family, society and country.Cause
This actively carries out primary prevention to the crowd with hazards, is extremely important to avoid cerebral apoplexy.
Cerebral arterial thrombosis accounts for 80% or so of whole Cerebral Haemorrhage Invasion Rates, and its incidence of disease increases with the growth at age
It is high.The generation of cerebral arterial thrombosis is mainly due to the formation of cerebral embolism and local thrombus, and this is probably by atherosclerosis
Caused hemadostewnosis, thromboembolism, or with blood flow to brain cause cerebral embolism from the embolus of heart；And various originals
Injury of blood vessel, vascular inflammation caused by are also one of major reason.Many reasons cause brain blood to supply obstacle, and cause
The irreversibility infringement of injured cerebral tissue so that brain tissue ischemia, anoxic cause final necrosis, and a series of god is caused to patient
Through functional impairment and obstacle.At present according to the sorting technique of the most frequently used parting standard generally acknowledged in the world, cerebral arterial thrombosis disease
Cerebral arterial thrombosis, can be divided into 5 hypotypes by sick TOAST classification systems：It is main artery atherosis type, cardiogenic embolic type, small
Arterial occlusion type and unknown cause type.
Current drug therapy cerebral apoplexy be intended to block ischemic caused by neuronal necrosis, extension tolerance Ischemia Time and
Therapeutic time window, strengthens Neuronal viability, reverses Penumbra zone, reduces Infarction volume, promotes neurological functional recovery.Although each
Plant chemical drugs and natural drug is in different conceptual phases, but generally acknowledged definite curative effect is obtained there is presently no a kind of medicine, because
This, which actively researches and develops medicine, has important clinical meaning.
The content of the invention
It is an object of the invention to provide a kind of medicine of new prevention and treatment cerebral apoplexy, the medicine spreads out for cumarin
It is biological.
Another object of the present invention is to provide a kind of method for preparing the coumarin derivative.
A further object of the present invention is to provide a kind of pharmaceutical composition containing at least one coumarin derivative.
It is particularly it is still another object of the present invention to provide such a kind of compound in preparation prevention and treatment cerebral apoplexy scarce
Application in the medicine of courageous and upright cerebral apoplexy.
The present invention can be adopted the following technical scheme that：
Specifically, the present invention relates to the coumarin derivative shown in a kind of Formulas I or its pharmaceutically acceptable salt, preceding
Medicine：
In Formulas I：
R1、R2Selected from hydrogen, hydroxyl, halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxies, C1-6 alkoxy carbonyls
Base ,-NR11R12；Wherein, R11、R12Can be with identical or different, selected from hydrogen or C1-6 alkyl, or R11、R12It can be connected with it
Nitrogen-atoms form 5 or 6 nitrogenous circle heterocycles alkyl together；
L represents-(CRARB)n-, wherein RA、RBHydrogen or C1-6 alkyl can be each independently selected from, n is with identical or different
0th, 1,2,3,4 or 5；
A is selected from O or S；
R4、R5、R6Selected from hydrogen, hydroxyl, carboxyl, halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxies, C1-6 alkane
Epoxide carbonyl, cyano group.
The method for preparing compound of the present invention, comprises the following steps：
Cyclization is obtained the o-vanillin derivative for making shown in Formula II in the presence of base with the acetoacetic ester shown in formula III
3- acetyl group coumarin derivatives shown in formula IV, then react in the presence of lithium chloride with the RMgBr shown in Formula V again,
It is dehydrated again through the concentrated sulfuric acid, finally gives the coumarin derivative shown in Formulas I.
Wherein, R1-R2、R4-R6, A, L it is as defined above；R represents C1-6 alkyl；X represents halogen, preferably chlorine and bromine；
Alkali includes alkoxide such as sodium methoxide, caustic alcohol, potassium ethoxide, triethylamine, piperidines, pyridine etc..
In a preferred embodiment of the compounds of this invention, A represents O.
In a preferred embodiment of the compounds of this invention, A represents S.
In a preferred embodiment of the compounds of this invention, R1And R2C1-6 alkyl or C1-6 alkoxies are represented, it is excellent
Select methyl or methoxy；Or R1And/or R2Expression-NR11R12
In a preferred embodiment of the compounds of this invention, R4Represent halogen, preferably fluorine.
In a preferred embodiment of the compounds of this invention, R5Represent halogen or halo C1-6 alkyl, preferably chlorine
Or trifluoromethyl.
In some preferred embodiments of the compounds of this invention, the compound is selected from：
Definition
Unless otherwise defined, all technologies used in this application and scientific terminology have and art technology people of the present invention
Member is generally understood identical implication.All patents and publication that the application is referred to are incorporated herein by reference.
Term " C1-6 alkyl " is intended to indicate that the group obtained when removing a hydrogen atom from hydrocarbon.The alkyl can be
Side chain or straight chain and can be comprising 1-6, such as 1-5 carbon atom, such as 1-4 carbon atom, such as 1-3 carbon atom, all
Such as 1-2 carbon atom.Term include subclass alkyl (n- alkyl), secondary alkyl and tertiary alkyl, such as methyl, ethyl, n-propyl,
Isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, n-hexyl.
Term " halogen " is intended to indicate that the substituent from the main group of periodic table the 7th, such as fluorine, chlorine, bromine and iodine.
Term " 5 or 6 nitrogenous circle heterocycles alkyl " be intended to indicate that comprising at least one nitrogen-atoms, 1-5 carbon atom and other
Heteroatomic 5 or 6 yuan of the monocyclic saturation ring group that optional 0-3 are selected from oxygen, sulphur and nitrogen, such as pyrrolidinyl, piperidyl, miaow
Oxazolidinyl, pyrazolidinyl, piperazinyl, homopiperazine base, oxazole alkyl, morpholinyl, thio-morpholinyl etc..
The pharmaceutically acceptable salt of coumarin derivative shown in Formulas I, refers to the coumarin derivative and medicine shown in Formulas I
The addition salts that acceptable acid is formed on.Described acid includes：Inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid
And phosphoric acid；Or organic acids such as citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, methanesulfonic acid, butanedioic acid, tartaric acid, handkerchief
Not acid, glutamic acid, aspartic acid, oxalic acid, methanesulfonic acid, ethyl sulfonic acid, 4- toluenesulfonic acids, salicylic acid, citric acid, benzoic acid and third
Diacid.
Terms used herein " prodrug " include can biological hydrolysis acid amides and can biological hydrolysis ester, and also include a)
According to the compound of the present invention include in this prodrug can biological hydrolysis degree of functionality compound, and b) can be specified
Functional group is by biological oxidation or reduces to produce the compound of the drug substance according to the present invention.
The terms used herein acid amides of biological hydrolysis " can " is drug substance (in the present invention, the cumarin shown in Formulas I
Derivative) acid amides, its does not interfere the bioactivity of parent material a), but assigns property advantageous in the material body, such as
Acting duration, effect start, or b) inactive, but in vivo easily by subject be converted into bioactivity into
Point.The advantage is, for example, can biological hydrolysis the enteral carry out oral absorption of acid amides, and Formulas I institute can be converted into blood plasma
The coumarin derivative shown.
The terms used herein ester of biological hydrolysis " can " is that (in the present invention, the cumarin shown in Formulas I spreads out drug substance
It is biological) ester, its does not interfere the bioactivity of parent material a), but assigns property advantageous in the material body, such as acts on
Duration, effect start, or b) inactive, but are easily converted into bioactive ingredients by subject in vivo.Institute
The advantage of stating is, for example, can biological hydrolysis the enteral carry out oral absorption of ester, and the perfume (or spice) shown in Formulas I can be converted into blood plasma
Legumin derivative.
Terms used herein " pharmaceutically acceptable " means to be applied to normal drug application, i.e., not drawn in patient etc.
Play adverse events.
The invention further relates to be used as activity using the coumarin derivative shown in Formulas I or its pharmaceutically acceptable salt, prodrug
The pharmaceutical composition of composition.Described pharmaceutical composition can also include pharmaceutically acceptable assistant agent or excipient.
Described pharmaceutical composition can be prepared according to method well known in the art.Can be by the way that the cumarin shown in Formulas I be derived
Thing or its pharmaceutically acceptable salt, prodrug are combined with pharmaceutically acceptable assistant agent or excipient, are made suitable for human or animal
Any formulation used.Content of the compounds of this invention in described pharmaceutical composition is usually 0.1-95 weight %.
It can apply one or many daily with appropriate intervals in the compounds of this invention of dosage unit form.Easily,
The preparation of dosage unit contains 0.1mg to 1000mg, preferably 1mg to 100mg, such as 5-50mg compound of formula I.Chemical combination of the present invention
The suitable dosage of thing will particularly depend on patient age and illness, the seriousness of disease to be treated and other medical practitioners institute it is ripe
The factor known.
The preparation include for example in suitable for oral (including sustained release or time controlled released), rectum, it is parenteral (including
Subcutaneously, intraperitoneal, intramuscular, intra-articular and intravenous), percutaneous, eye, part, skin, nose, the system of cheek or intradermal administration
Agent.
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (including
True solution and colloidal solution), emulsion (including o/w types, w/o types and emulsion), supensoid agent, injection (including liquid drugs injection, powder-injection
And transfusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, lozenge,
Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard shell capsules, soft capsule, capsulae enterosolubilis), granule, dissipate
Agent, micropill, dripping pill, suppository, film, paster, aerosol, spray etc.；Semisolid dosage form can be ointment, gel, paste
Agent etc..
As the pharmaceutically acceptable excipient and the example of assistant agent that can be contained in pharmaceutical composition, dilution can be mentioned that
Agent, adhesive, lubricant, preservative, thickener, stabilizer, disintegrant, wetting agent, emulsifying agent, buffer substance, colouring agent, rectify
Taste agent and spices, the example is water, physiological salt solution, vegetable oil, wax, alcohol, glyceryl triacetate, PVP, bright
Glue, cellulose, carbohydrate, talcum, lanolin, vaseline or their mixture etc..
The compound or composition of the present invention can individually be taken, or merge with other treatment medicine or symptomatic drugs and use.
When the compound of the present invention exists with other medicines to act synergistically, its dosage should be adjusted according to actual conditions.
Another object of the present invention, be provide Formulas I shown in coumarin derivative or its pharmaceutically acceptable salt,
Application of the prodrug in medicine is prepared, the medicine is used to prevent and treat cerebral apoplexy, particularly cerebral arterial thrombosis.
Beneficial effect
The present invention by researching and analysing the design feature of the coumarin derivative shown in formula I, and have studied its
Pharmacodynamics feature in rat body, it was demonstrated that it has the effect of prevention and treatment cerebral apoplexy particularly cerebral arterial thrombosis.In addition,
Coumarin derivative shown in formula I shows good therapeutic activity, its energy in Cerebral Ischemia-reperfusion in Mice experiment
Enough significantly reduce the behavior scoring of cerebral ischemia-reperfusion in mice and injured brain tissue and oedema degree can be mitigated and aqueous
Amount, reduces cerebral infarction ratio, therefore it can be used in prevention and treatment cerebral apoplexy particularly cerebral arterial thrombosis.
Embodiment
The present invention is described below in more detail to contribute to the understanding of the present invention.
The compounds of this invention can be prepared with many methods known to synthesis art personnel.Compound of formula I can be with
For example using the reaction and technical battery being listed below with method known to synthetic organic chemistry field or those skilled in the art institute
It is prepared by its variant understood.It is preferred that method include but is not limited to those described below method.Reaction is suitable for used
Reagent and material and be applicable to realize conversion solvent in carry out.In addition, in the synthetic method being described below, it should be understood that
The reaction condition (including solvent, reaction atmosphere, reaction temperature, selection of duration of experiment and post processor) of all suggestions
All selection is the standard conditions of the reaction, and this should easily be confirmed by organic synthesis field technical staff.And not all fall into
The compound for determining classification can be compatible with some reaction conditions needed in some methods describeds.It is pair compatible with reaction condition to take
Dai Ji these limitations will be will be obvious to those skilled in the art that and usable alternative.
Embodiment 1：(E) -3- (5- (benzofuran -7- bases) amyl- 2- alkene -2- bases) -6,7- dimethyl -2H- chromen-2-ones
(compound A)
2- hydroxyl -4,5- dimethylbenzaldehydes 1.50g is dissolved in 200ml absolute ethyl alcohols, plus 20ml ethyl acetoacetates and
2ml piperidines, agitating heating has solid appearance after several minutes, and flow back 25min, is cooled to room temperature, after filtering needed for product 3- acetyl
Base -6,7- dimethyl -2H- chromen-2-one 2.01g, yield 93.1%, content 96.5%.ESI-MS：217.08[M+H]+
By the 3- acetyl group -6,7- dimethyl -2H- chromen-2-ones 1.08g and anhydrous Lithium chloride that are obtained in above-mentioned steps
0.43g is dissolved in the tetrahydrofuran of 40ml dryings, then adds (2- (benzofuran -7- bases) ethyl) magnesium chloride of brand-new
1.53g, which is dissolved in, to be cooled down reactant mixture after the solution in 30ml tetrahydrofurans, backflow 2h and adds 20ml saturated ammonium chloride water
Solution, aqueous phase is extracted with ether (2 × 75ml), the organic phase salt water washing of merging, anhydrous sodium sulfate drying and under vacuo
Concentration.It is added into 70 DEG C of hot solutions containing the 3ml concentrated sulfuric acids and 20ml glacial acetic acid, then stirs 10min, reaction is mixed
Thing is poured into 100ml frozen water, is then extracted with n-hexane (2 × 75ml), the organic phase saturated sodium carbonate solution and salt of merging
Water washing, anhydrous sodium sulfate drying is simultaneously concentrated under vacuum.Crude product purified by silica gel column chromatography for separation (mobile phase：N-hexane:Acetic acid
Ethyl ester=6:1) (E) -3- (5- (benzofuran -7- bases) amyl- 2- alkene -2- bases) -6,7- dimethyl -2H- chromenes -2-, has been obtained
Ketone 1.02g, yield 57.1%, content 99.1%
ESI-MS：359.16[M+H]+
Elementary analysis：Theoretical value/measured value, C (80.42/80.52), H (6.19/6.17), O (13.39/13.31)
1H NMR (400MHz, CDCl3)δ7.73(d,1H),7.54(s,1H),7.49(d,1H),7.41(s,1H),7.13
(q,1H),7.01(d,1H),6.88(s,1H),6.54(d,1H),5.46(m,1H),2.56(t,2H),2.43(s,6H),2.28
(m,2H),2.12(d,3H)。
In a similar way, following compound is synthesized：
Embodiment 2：(E) -3- (5- (the fluoro- benzos of 4- [b] thiophene -7- bases) amyl- 2- alkene -2- bases) -6,7- dimethoxys -
2H- chromen-2-ones (compound B)
ESI-MS：425.11[M+H]+
Elementary analysis：Theoretical value/measured value, C (67.91/67.78), H (4.99/5.07), F (4.48/4.57), O
(15.08/15.01),S(7.55/7.57)
1H NMR (400MHz, CDCl3)δ7.78(d,1H),7.74(d,1H),7.59(s,1H),7.31(d,1H),7.13
(d,1H),6.87(s,1H),6.72(s,1H),5.42(m,1H),3.82(s,6H),2.56(t,2H),2.28(m,2H),2.12
(d,3H)。
Embodiment 3：(E) -3- (5- (the chloro- benzos of 2- [b] thiophene -7- bases) amyl- 2- alkene -2- bases) -7- (pyrrolidines -1-
Base) -2H- chromen-2-ones (compound C)
ESI-MS：450.12[M+H]+
Elementary analysis：Theoretical value/measured value, C (69.40/69.52), H (5.38/5.47), Cl (7.88/7.79), N
(3.11/3.08),O(7.11/7.14),S(7.13/7.00)
1H NMR (400MHz, CDCl3)δ7.62(d,1H),7.59(s,1H),7.47-7.32(m,3H),7.02(s,1H),
6.67(d,1H),6.51(s,1H),5.43(m,1H),3.42(t,4H),2.56(t,2H),2.28(m,2H),2.12(d,3H),
1.82(m,4H)。
Embodiment 4：(E) -7- (dimethylamino) -3- (5- (2- trifluoromethylbenzofur -7- bases) hex- 2- alkene -2- bases) -
2H- chromen-2-ones (compound D)
ESI-MS：456.17[M+H]+
Elementary analysis：Theoretical value/measured value, C (68.56/68.52), H (5.31/5.47), F (12.51/12.58), N
(3.08/3.04),O(10.54/10.39)
1H NMR (400MHz, CDCl3)δ7.72(d,1H),7.59(s,1H),7.47(d,1H),7.22(q,1H),7.02
(d,1H),6.77(s,1H),6.61(s,1H),6.52(s,1H),5.47(m,1H),3.02(s,6H),2.96(m,1H),2.34
(m,2H),2.12(d,3H),1.24(s,3H)。
Next, passing through the pharmacodynamics effect of experimental example specific explanations representative compound.
Test example 1：Coumarin derivative shown in Formulas I treats the effect of cerebral arterial thrombosis
The pharmacological evaluation that mouse line brush makes focal cerebral ischemia in rats is that checking medicine has preventing and treating ischemic cerebral apoplexy
Middle effect is conventional zoopery.Preparing ICR Cerebral Ischemia-reperfusion in Mice model with bolt collimation method, (preparation method is referred to《Western medicine
New drug preclinical study guideline collects》Pharmacy pharmacology toxicology part, Ministry of Health of the People's Republic of China's pharmaceutical control and administration pipe
Reason office, 1993：73；《Pharmacological experimental methodology》The second edition, People's Health Publisher, 1982：830th, 1113), except sham-operation group
Outside, remaining each group is tested with the model mouse.
1st, animal
ICR mouse, male, 20~22g of body weight.Every group 20, it is divided into 8 groups, compound A low dose groups：1mg/kg；Chemical combination
Thing A middle dose groups：2mg/kg；Compound A high dose groups：4mg/kg；Compound B middle dose groups：2mg/kg；Agent in compound C
Amount group：2mg/kg；Compound D middle dose groups：2mg/kg；Sham-operation group：The physiological saline given with drug study group equivalent enters
Row sham-operation；Model group：The physiological saline given with drug study group equivalent carries out cerebral ischemia re-pouring operation.
2nd, experimental method
By mouse 10% chloraldurate intraperitoneal injection of anesthesia, neck median incision, separation, the ligation nearly heart of right carotid
End, external carotid artery and its bifurcated artery.Separation right side internal carotid, wing jaw artery, root ligation are separated downwards along internal carotid
The branch.Artery clamp is placed for line, distal end in internal carotid near-end, arteria carotis communis crotch otch inserts nylon wire, and bolt line enters
Enter internal carotid, enter cranium to arteria cerebri anterior, block all blood flow sources of arteria cerebri media.Artery clamp is removed, standby line is tightened, outside
Stay the long the end of a thread of 1cm, skin suture.Ischemic is injected intravenously administration after 1 hour.Continuation ischemic Reperfu- sion after 1 hour.Reperfu- sion 8 is small
Shi Zaici drug administration by injection.Sham-operation group is in addition to not plug wire, and remaining step is ibid.
Observation Reperfu- sion is survived the following index of mouse after 24 hours：
(1) observation survival mouse Behavioral change after 24 hours, carries out neurological deficit score：With reference to Zea Longa 5 points of system scorings
Standard：0 point is normal, impassivity injury symptoms；1 point is to be unable to full extension offside fore paw；2 points are to turn-take laterally；3 points are
Topple over to offside；4 points are spontaneous to walk, the loss of consciousness.
(2) to the influence of brain water content：Every group takes the quick broken end of 10 mouse to take brain, and left and right brain hemisphere is claimed respectively
Weight in wet base, puts drying in 100 DEG C of baking boxs, claims dry weight after 24 hours, brain water content is calculated as follows：Brain water content
(%)=(weight in wet base-dry weight)/weight in wet base × 100%.
(3) to the influence of cerebral infarct volume：Every group takes 10 mouse, and execution takes brain, cuts the coronal brain pieces of thickness about 2mm,
It is placed at once in 2%TTC solution, 37 DEG C are incubated 30 minutes.White is presented in infarct, and non-infarct presents red.Digital camera
Record is shot, each area's area is measured with Computer Image Processing, and calculate the percentage (%) that infarct accounts for whole brain tissue.
3rd, experimental result
(1) influence of the test compound to cerebral ischemia-reperfusion in mice neurological deficit score
Table 1：Test the neurological deficit score after each group Cerebral Ischemia-reperfusion in Mice
| Group | Dosage (mg/kg) | Neurological deficit score (divides) |
| Sham-operation group | - | 0 |
| Model group | - | 3.7±0.5 |
| Compound A low dose groups | 1 | 2.6±0.4# |
| Compound A middle dose groups | 2 | 2.1±0.6# |
| Compound A high dose groups | 4 | 1.7±0.4# |
| Compound B middle dose groups | 2 | 2.3±0.5# |
| Compound C middle dose groups | 2 | 2.1±0.4# |
| Compound D middle dose groups | 2 | 1.9±0.6# |
Note：Compared with model group,#P<0.05
Result of the test shows：Sham-operation group mice displayed no goes out any abnormal symptom.And model group mouse occurs or outside
Turn-take or topple over or be unable to the neurotrosis symptom of full extension offside fore paw to offside in side.Basic, normal, high dose of compound A
Amount group can significantly reduce the behavior scoring of ischemia-reperfusion mouse, and the reduction degree of its behavior scoring has with compound A
Obvious dose-dependence, compound B, C and D can also significantly reduce the behavior scoring of ischemia-reperfusion mouse, result card
Bright above-mentioned test compound can be obviously improved the neurotrosis symptom caused by ischemia-reperfusion.
(2) influence of the test compound to cerebral ischemia-reperfusion in mice brain water content
Table 2：Influence to ischemia-reperfusion Mice brain tissues water content
Note：Compared with model group,#P<0.05
Result of the test shows：Sham-operation group mouse left and right sides brain tissue is without oedema.The brain group of model group mouse ischemic side
Knit water content and be significantly higher than sham-operation group, also above its left side brain water content.And compound A basic, normal, high dosage group is small
The brain water content of mouse ischemic side is substantially less than model group, and shows certain dose-dependence, compound B, C and D
The brain water content of ischemic side can also be significantly reduced, the result proves that above-mentioned test compound can mitigate ischemia-reperfusion
The oedema degree of injured brain tissue, reduces its water content.
(3) influence of the test compound to Cerebral Ischemia-reperfusion in Mice model cerebral infarct size
Table 3：Test the cerebral infarct size after each group Cerebral Ischemia-reperfusion in Mice
Note：Compared with model group,#P<0.01
Result of the test shows：Sham-operation group Mice brain tissues are without infraction.Model group mouse ischemic side brain tissue has obvious stalk
Phenomenon is filled in, cerebral infarction/full brain (%) is 49.3 ± 2.9%.And compound A basic, normal, high dosage group can significantly reduce cerebral infarction
Percentage is filled in, reduction degree has dose-dependence with medicine, and compound B, C and D can also significantly reduce cerebral infarction percentage,
The result proves that above-mentioned test compound can damage caused cerebral infarction to Cerebral Ischemia-reperfusion in Mice and play good protection
Effect.
The preferred embodiment for the present invention is the foregoing described, so it is not limited to the present invention.Those skilled in the art couple
Embodiment disclosed herein can carry out improvement and the change without departing from scope and spirit.
Claims (10)
1. the coumarin derivative shown in a kind of Formulas I, or its pharmaceutically acceptable salt, prodrug：
In Formulas I：
R1、R2Selected from hydrogen, hydroxyl, halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxies, C1-6 alkoxy carbonyls ,-
NR11R12；Wherein, R11、R12Can be with identical or different, selected from hydrogen or C1-6 alkyl, or R11、R12The nitrogen that can be connected with it
Atom forms 5 or 6 nitrogenous circle heterocycles alkyl together；
L represents-(CRARB)n-, wherein RA、RBHydrogen or C1-6 alkyl can be each independently selected from identical or different, n is 0,1,
2nd, 3,4 or 5；
A is selected from O or S；
R4、R5、R6Selected from hydrogen, hydroxyl, carboxyl, halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxies, C1-6 alkoxies
Carbonyl, cyano group.
2. coumarin derivative or its pharmaceutically acceptable salt, prodrug shown in Formulas I according to claim 1, it is special
Levy and be, the A represents O.
3. coumarin derivative or its pharmaceutically acceptable salt, prodrug shown in Formulas I according to claim 1, it is special
Levy and be, the A represents S.
4. coumarin derivative or its pharmaceutically acceptable salt, prodrug shown in Formulas I according to claim 1, it is special
Levy and be, the R1And R2Represent C1-6 alkyl or C1-6 alkoxies, preferably methyl or methoxy；Or R1And/or R2Represent-
NR11R12。
5. coumarin derivative or its pharmaceutically acceptable salt, prodrug shown in Formulas I according to claim 1, it is special
Levy and be, the R4Represent halogen, preferably fluorine.
6. coumarin derivative or its pharmaceutically acceptable salt, prodrug shown in Formulas I according to claim 1, it is special
Levy and be, the R5Represent halogen or halo C1-6 alkyl, preferably chlorine or trifluoromethyl.
7. the coumarin derivative shown in Formulas I according to claim 1, or its pharmaceutically acceptable salt, prodrug, it is selected
From：
8. a kind of pharmaceutical composition, it includes the cumarin shown at least one Formulas I according to claim any one of 1-7
Derivative or its pharmaceutically acceptable salt, prodrug, and pharmaceutically acceptable assistant agent or excipient.
9. it is coumarin derivative shown in Formulas I or its pharmaceutically acceptable salt according to claim any one of 1-7, preceding
Application of the medicine in treatment cerebral apoplexy particularly cerebral arterial thrombosis.
10. a kind of method of the coumarin derivative shown in Formulas I prepared according to claim 1, it includes following mistake
Journey：
Making o-vanillin derivative shown in Formula II, cyclization obtains formula IV in the presence of base with the acetoacetic ester shown in formula III
Shown 3- acetyl group coumarin derivatives, then react, then pass through in the presence of lithium chloride with the RMgBr shown in Formula V again
The concentrated sulfuric acid is dehydrated, and finally gives the coumarin derivative shown in Formulas I：
Wherein, R1-R2、R4-R6, A, L definition as described in the appended claim 1；R represents C1-6 alkyl；X represents halogen, preferably chlorine
And bromine；
Alkali includes alkoxide such as sodium methoxide, caustic alcohol, potassium ethoxide, triethylamine, piperidines, pyridine etc..
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710247954.6A CN106946866B (en) | 2017-04-17 | 2017-04-17 | A kind of drug and preparation method thereof preventing and treating cerebral apoplexy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710247954.6A CN106946866B (en) | 2017-04-17 | 2017-04-17 | A kind of drug and preparation method thereof preventing and treating cerebral apoplexy |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106946866A true CN106946866A (en) | 2017-07-14 |
| CN106946866B CN106946866B (en) | 2019-04-09 |
Family
ID=59476058
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710247954.6A Active CN106946866B (en) | 2017-04-17 | 2017-04-17 | A kind of drug and preparation method thereof preventing and treating cerebral apoplexy |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106946866B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108503651A (en) * | 2018-06-11 | 2018-09-07 | 黑龙江中医药大学 | A kind of spiro-compound for treating cerebral apoplexy |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103446154A (en) * | 2012-05-29 | 2013-12-18 | 中国医学科学院药物研究所 | Applications of coumarin derivatives in preventing and curing serious brain diseases |
| CN103450134A (en) * | 2012-05-31 | 2013-12-18 | 中国医学科学院药物研究所 | Preparation of coumarin derivative and application of coumarin derivative to control of serious cerebral disease |
-
2017
- 2017-04-17 CN CN201710247954.6A patent/CN106946866B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103446154A (en) * | 2012-05-29 | 2013-12-18 | 中国医学科学院药物研究所 | Applications of coumarin derivatives in preventing and curing serious brain diseases |
| CN103450134A (en) * | 2012-05-31 | 2013-12-18 | 中国医学科学院药物研究所 | Preparation of coumarin derivative and application of coumarin derivative to control of serious cerebral disease |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108503651A (en) * | 2018-06-11 | 2018-09-07 | 黑龙江中医药大学 | A kind of spiro-compound for treating cerebral apoplexy |
| CN108503651B (en) * | 2018-06-11 | 2019-04-23 | 黑龙江中医药大学 | It is a kind of for treating the spiro-compound of cerebral apoplexy |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106946866B (en) | 2019-04-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2016531909A (en) | Pharmaceutical composition for treating or preventing neuropsychiatric disorders comprising flavone-6-C-glucose derivative as an active ingredient | |
| DE19523502A1 (en) | Kappa opiate agonists for inflammatory bowel diseases | |
| JP2020503384A (en) | Use of conjugates of polyethylene glycol with a local anesthetic in non-narcotic analgesia | |
| JP2002518442A (en) | Use of valproic acid analogs for the treatment and prevention of migraine and affective illness | |
| RU2625797C2 (en) | Use of 3-n-butyl ketone isoindoline in production of drugs for prevention and treatment of cerebral infarction | |
| JP2018531961A (en) | Methods and compositions for recovery from stroke | |
| CN106946866B (en) | A kind of drug and preparation method thereof preventing and treating cerebral apoplexy | |
| ES2237625T3 (en) | USE OF A HYDANTOIN DERIVATIVE IN A PHARMACEUTICAL COMPOSITION AGAINST HYPOALBUMINEMIA. | |
| JP6051315B2 (en) | Use of pidothymod to treat psoriasis | |
| TW201902474A (en) | Compounds for treating stroke and reducing nerve damage and uses thereof | |
| CN104771409B (en) | The purposes of orientoside | |
| JPH02108688A (en) | Quinoline compound | |
| KR102196711B1 (en) | Pharmatheutical composition comprising Tenofovir disoproxil fumarate for preventing or treating of hepatic fibrosis | |
| EP1884241B1 (en) | A oral preparation comprising dyclonine hydrochloride | |
| JP6787944B2 (en) | Muscle fatigue recovery agent | |
| US4677124A (en) | Process for preparing and therapeutical applications of the "2,4,6-triiodophenol" | |
| KR20010018271A (en) | Treatment of cardio- vascular disease and Its process | |
| CN104427982B (en) | Composition for the treatment of inflammatory and immune disorders | |
| CN109350615A (en) | Stachydrine hydrochloride is in the new application for preventing and treating ischemic cerebrovascular disease | |
| CN108503651B (en) | It is a kind of for treating the spiro-compound of cerebral apoplexy | |
| EP2184284B1 (en) | Preventive, inhibitor or remedy for cerebral aneurysm comprising ibudilast as an active ingredient | |
| WO2023145735A1 (en) | New therapy and prevention for suppressing aging-related disorders including sarcopenia | |
| WO2023134732A1 (en) | Prevention or treatment of cardiovascular diseases with high penetration prodrugs of aspirin and other nsaids | |
| WO2022183480A1 (en) | Pharmaceutical composition containing ginkgolide-type compound and cannabidiol and application thereof in medicine | |
| JP6935930B2 (en) | Prophylactic or therapeutic agent for pulmonary hypertension containing crude drug ingredients |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |