CN106146444A - A kind of new compound and application thereof - Google Patents
A kind of new compound and application thereof Download PDFInfo
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- CN106146444A CN106146444A CN201510155682.8A CN201510155682A CN106146444A CN 106146444 A CN106146444 A CN 106146444A CN 201510155682 A CN201510155682 A CN 201510155682A CN 106146444 A CN106146444 A CN 106146444A
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- China
- Prior art keywords
- hydroxyl
- butylphthalide
- compound
- acid
- derivant
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- WLSFAPIGNIBNRQ-UHFFFAOYSA-N CC(CCC(c1c2cccc1)OC2=O)OS(CCN)(=O)=O Chemical compound CC(CCC(c1c2cccc1)OC2=O)OS(CCN)(=O)=O WLSFAPIGNIBNRQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
Abstract
The present invention relates to a kind of new compound and application thereof; described compound is 3-(3 '-hydroxyl)-butylphthalide taurine ester; this compound is racemoid or its optically active compound, and the present invention also provides for above-claimed cpd and salt, 3-(3 '-hydroxyl)-butylphthalide derivant taurine ester and salt thereof in preparation prevention and the treatment heart, cerebral ischemia diseases, the application that prevents and treat in brain dementia medicine.
Description
Technical field
The present invention relates to a kind of new compound and application thereof, particularly relate to 3-(3 '-hydroxyl)-butylphthalide cattle sulphur
Acid esters and salt, the taurine ester of 3-(3 '-hydroxyl)-butylphthalide derivant and salt thereof, further relate to this compounds and exist
Preparation prevention and the treatment heart, cerebral ischemia diseases；Application in prevention and treatment brain dementia medicine.
Background technology
Cerebral ischemia disease has the features such as sickness rate height, disability rate and mortality rate are big, is the commonly encountered diseases that harm human life is healthy
And frequently-occurring disease, therefore find ischemia resisting medicine and cause the extensive concern of Chinese scholars.
Butyphthalide has another name called Butylphthalide, is originally found in celery seed, and its pharmacodynamics feature covers a lot of aspect effect:
1, cerebral ischemia-reperfusion energy metabolism can be improved；2, it is obviously reduced focal cerebral ischemia in rats cerebral infarct size, improves function of nervous system and lack
Lose；3, the cerebral edema that local cerebral ischemia causes is improved；4, ischemic region local cerebral blood flow and soft bus wire are had substantially
Improvement result；5, the dysmnesia that local cerebral ischemia causes can be significantly improved.
Butyphthalide main metabolites in vivo is 3-(3 '-hydroxyl)-butylphthalide.
In urine, butyphthalide original shape is about 9:91, cerebral tissue mesarcs medicine and the ratio of metabolite with the ratio of metabolite
Value is about 44:56, but the metabolite in brain only has 3-(3 '-hydroxyl)-butylphthalide:
Owing to 3-(3'-hydroxyl) butylphthalide is water insoluble, limit its application.The present inventor is through substantial amounts of experiment
Research, has invented good water solubility, 3-(3 '-hydroxyl)-butylphthalide taurine ester that effect is more excellent and salt, 3-
The taurine ester of (3 '-hydroxyl)-butylphthalide derivant and salt thereof, meet the demand of clinic.
Summary of the invention
The purpose of the present invention, it is simply that provide a kind of new compound, specifically refers to 3-(3 '-hydroxyl)-butylphthalide cattle
Sulphonic acid ester and salt, 3-(3 '-hydroxyl)-butylphthalide derivant taurine ester and salt thereof.And this compounds is in preparation
Prevention and the treatment heart, cerebral ischemia diseases；Application in prevention and treatment brain dementia medicine.
The invention provides 3-(3'-hydroxyl) butylphthalide to react with taurine and obtain ester, because this compound contains
Chiral carbon atom, therefore this compound is racemoid or its optically active compound.
The present invention also provides for a kind of new compound, it is characterised in that described compound is following 3-(3 '-hydroxyl
Base) the taurine ester of-butylphthalide derivant, because containing chiral carbon atom in compound, therefore this compound is for disappearing
Rotation compound or its optically active compound.Its general structure is as follows:
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl or hydrogen atom.
It is preferably the taurine ester of following 3-(3 '-hydroxyl)-butylphthalide derivant, because containing chirality in compound
Carbon atom, therefore this compound is racemoid or its optically active compound, and its general structure is as follows:
A kind of new compound, described compound is the taurine of following 3-(3 '-hydroxyl)-butylphthalide derivant
Ester, because containing chiral carbon atom in compound, therefore this compound is racemoid or its optically active compound.
Its general structure is as follows:
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl or hydrogen atom,
R1 is hydroxyl carboxylic acid or contains substituent group hydroxy carboxylic acid, amino carboxylic acid or contain substituent group amino carboxylic acid, containing halogenated carboxylic acid
Or the halogenated carboxylic acid containing substituent group.
Present invention also offers the salt of 3-(3'-hydroxyl) butylphthalide taurine ester, 3-(3 '-hydroxyl)-butylphthalide spreads out
The salt of the biological ester with taurine generation.According to routine techniques by 3-(3'-hydroxyl) butylphthalide taurine ester, 3-
Ester that (3 '-hydroxyl)-butylphthalide derivant and taurine generate and mineral acid or organic acid reaction, obtain 3-(3'-
Hydroxyl) butylphthalide taurine ester salt or 3-(3 '-hydroxyl)-butylphthalide derivant taurine ester salt.
Further, described mineral acid is nitric acid, sulphuric acid, phosphoric acid or hydrochloric acid.
Preferably 3-(3 '-hydroxyl)-butylphthalide taurine ester hydrochloride.
The present inventor is proved by substantial amounts of pharmacodynamic experiment, 3-(3 '-hydroxyl)-butylphthalide taurine ester and salt thereof,
Ester that 3-(3 '-hydroxyl)-butylphthalide derivant and taurine generate and salt thereof have a preferable pharmacologically active, and water solublity,
Have good stability.
Prior art has no the report to such noval chemical compound.
Instantiation:
The preparation of 3-(3 '-hydroxyl)-butylphthalide taurine ester:
The preparation of 3-(3 '-hydroxyl)-butylphthalide taurine ester hydrochloride:
Detailed description of the invention
The present invention is described in further detail the most by way of example, provides the implementation detail of the present invention, but
It is to be not considered as limitation of the present invention.
Embodiment 1: to Middle cerebral artery thrombosis model (Middle Cerebral Artery
Thrombosis, MCAT) rat symptom and the impact of Range of Cerebral Infarction.
One, animal
SD rat, male and female half and half, body weight 190～250g.
Two, medicine and reagent
By reagent
3-(3 '-hydroxyl)-butylphthalide taurine ester, 3-(3 '-hydroxyl)-butylphthalide taurine ester hydrochloride.
Reagent
FeCl3*6H20 (A.R.), prepares with lmol/L hydrochloric acid；Red tetrazolium (TTC), (C.P.).
Three, instrument
XTT stero microscope；Water bath with thermostatic control agitator；Electronic analytical balance.
Four, test method and result
(1) impact on MCAT rat symptom
1, packet is shown in Table 1
Table 1
2, be administered: before modeling prevention be administered, every day gastric infusion 1 time, successive administration 3 days, modeling in the 4th day, after modeling
At once gavage gives one day dosage.After modeling 12 hours again gavage give one day dosage, matched group gives equivalent solvent.
3, modeling operation is implemented: rats by intraperitoneal injection 12% chloral hydrate solution (350mg/kg) is anaesthetized.On the right side of rat
Clinostatism is fixed, and makees a curved incision at paropia and external auditory meatus line midpoint, is about 1.5cm, and pinch off temporalis also cuts,
Expose temporal bone, at the 1mm of mouth side, make the bone of an a diameter of 2.5mm by dental burr at cheekbone and temporo squamosum joint
Window, clears up residue, exposes middle cerebral artery (between tractus olfactorius and inferior cerebral vein).Suction is had 50% iron chloride
The small pieces quantitative filter paper of solution (lmol/L hydrochloric acid) 10ul applies on this section of middle cerebral artery, and about 30miri treats blood vessel
Take off filter paper after color blackening, use normal saline flushing local organization, layer-by-layer suture, steam again and raise.
4, behavioral value: different time points (6h, 24h) carries out behavior scoring to animal after surgery.(1) put forward rat-tail to leave
Ground about one chi, observes forelimb flexing situation.As double forelimb symmetries stretch to ground, it is designated as 0 point；Such as offside forelimb of performing the operation
Occur that the flexing of shoulder flexing, elbow flexing, shoulder inward turning or existing wrist elbow has again inward turning person, be designated as 1 point.(2) animal is put
On smooth ground, push away both shoulders respectively to side shifting, inspection resistance.As bilateral resistance is reciprocity and is designated as 0 point effectively；
Such as drop in resistance person when operation offside promotes, it is designated as 1 point.(3) animal two forelimb is put on a wire netting, observe
The muscular tension of two forelimbs.Bilateral muscular tension equity and strong person are 0 point；Operation offside muscle of anterior limb tension force decline is designated as 1 point.
(4) putting forward rat-tail and leave ground about one chi, animal has ceaselessly to operation offside revolver, is designated as 1 point, is otherwise designated as
0 point.According to above scale, full marks are 4 points, and mark is the highest, and the behavior disorder of animal is the most serious.
Result shows, sham operated rats has no that dystropy changes, and hemiplegia all occur in model group rats 6h, 24h after surgery
Sample symptom, mainly shows as the interior receipts of offside forelimb of performing the operation, takes on inward turning, and muscle of anterior limb tension force reduces, shoulder drag decline.With mould
Type group is compared, and the nervous symptoms of each administration group rat 24h after surgery all significantly improves, and has obvious dose-effect relationship.
(2) impact on MCAT rat cerebral infarction scope
After animal via last behavior scoring, broken end takes brain.Removing olfactory bulb, cerebellum and low brain stem, residue part is at 4 DEG C
The most crown it is cut into 5.Rapidly brain sheet is placed in TTC dye liquor and (every 5ml dye liquor contains
4%TTC1.5ml, 1MK2HPO40.1ml), 37 DEG C of lucifuge temperature are incubated 30 minutes, further take out, are placed in 10%
Formalin keeps in Dark Place.After dyed, non-ischemic region is rose, and infarct is white.White tissues is carefully dug
Under weigh, account for the percentage ratio of total brain weight as Range of Cerebral Infarction using blocking tissue's weight.
Result shows, postoperative 24h is in addition to sham operated rats is without focus of infarct, and model group and administration group rat all have in various degree
Focus of infarct.Compared with model group, the cerebral tissue infarct symptoms that ischemic brain injury is caused by each administration group rat has substantially
Improvement result, and have obvious dose-effect relationship.
Embodiment 2: rat is moved the thrombotic the present embodiment that affects of a venous bypass and selects:
One, animal
SD rat, male and female half and half, body weight 190～250g.
Two, medicine and reagent
By reagent
3-(3 '-hydroxyl)-butylphthalide taurine ester, 3-(3 '-hydroxyl)-butylphthalide taurine ester hydrochloride.
Three, instrument
AEG-220 type electronic analytical balance；Df-206 type air dry oven.
Four, test method and result
1, packet is shown in Table 2
Table 2
2, it is administered
Every day gastric infusion 1 time, successive administration 3 days, thrombus model group gives equivalent solvent.Last is i.e. carried out after being administered
Operation.
2, modeling method
Being anaesthetized by rats by intraperitoneal injection 10% chloral hydrate 0.35ml/100g, dorsal position is fixed, and operation separates the right side
Common carotid artery and left external jugular vein.The 0 of a long 8cm weighed in advance is put in the polyethylene tube stage casing of 10cm length
Number surgical thread, is full of with normal saline solution, and two client links are about 3cm and are full of intubating of normal saline.The one of this pipe
After end inserts left external jugular vein, the other end inserts right common carotid artery.Blood flow in polyethylene tube from right carotid,
Backflow into left external jugular vein again, constitute loop blood flow.Herba Clinopodii in after lOmin, rapid removal of thromboses weighs, this weight
Deducting silk thread weight, paper is heavily wet weight of thrombus；Putting into 60 DEG C of dry 24h in baking oven, removal of thromboses is weighed, and this weight subtracts
Removing silk thread weight, paper is heavily thrombosis dry weight.
Result shows, compared with thrombus model group, wet weight of thrombus and the dry weight of each administration group rat all substantially reduce, and
There is obvious dose-effect relationship.
Test example 3: the impact on scopolamine cause dementia mice learning and memory behavior:
1. material
SPF level KM mice, male, 18-22 gram.
0.9% normal saline solution.
2. packet is shown in Table 3
Table 3
3. it is administered
Mice vein respectively gives said medicine, successive administration 14 days.0.9% is given raw under sham operated rats equal conditions
Reason saline.
4. the impact on mice jumping response
Mice last is administered and carried out jumping response training 1 time first 2 day every day.During training, mice to be measured is put into diving tower instrument
In, adapt to environment 5min.Then to bottom screen be energized, record mice jump off plateau time (latent time) and
In 5min, mice is jumped off the number of times (phase errors number of resurveying) shocked by electricity by plateau.With mice association meet electricity irritation time can
Escape to platform as index with correct.Last removes blank group lumbar injection 0.9% physiology salt after being administered 30min
Outside water injection, remaining each group scopolamine injection liquid injecting 5mg/kg respectively, formally test after 30min,
Resurvey phase errors number in record mice latent time and 5min.
5. statistical method
Data processing data is carried out checking between variance analysis and group by SPSS11.5 statistical software.
6 experimental results
Result shows, scopolamine model group is compared with blank group, and mice escape latency substantially shortens, mistake
Number of times substantially increases (P ＜ 0.01), illustrates that memory deficits in mice model is successfully established.Compared with model group, each dosage
Administration group all has prolongation in various degree incubation period, and errors number also significantly reduces, and is respectively provided with significant difference.
Test example 4: on study and the impact of memory behavior after Cerebral Ischemia-reperfusion in Mice:
1. material
SPF level KM mice, male, 18-22 gram.
0.9% normal saline.
2. experimental technique
The making of Cerebral Ischemia-reperfusion in Mice damage model: ip in mice (lumbar injection) 4% chloral hydrate 0.4g/kg
Anesthesia, neck medisection skin, blunt separation bilateral common carotid arteries, wear " 4-0 " operation silk thread under bilateral common carotid arteries,
Suspend in midair and block completely to bilateral common carotid arteries blood flow, extract silk thread after lh out and make its blood flow Reperfu-sion.Sham operated rats wears silk down
Line but do not suspend blocking blood flow in midair, also extract silk thread after lh out.The most all mice skin sutures, steam again and raise.
3. packet is shown in Table 4
Table 4
4. it is administered
Once a day, from the same day of performing the operation, continuous gastric infusion 21 days.Give under sham operated rats equal conditions
0.9% normal saline.
5. the impact on mice jumping response
Mice last is administered first 2 days, and after being administered, 30min carries out jumping response training.During training, by mice to be measured
Put in diving tower instrument, adapt to environment 5min.Then being energized to bottom screen, record mice jumps off the time of plateau and (hides
Time) and 5min in mice jumped off the number of times (phase errors number of resurveying) shocked by electricity by plateau.Meet with mice association
Can correctly escape to platform during electricity irritation as index.Last is formally test after being administered lh, and record mice hides
Resurvey in time and 5min phase errors number.
6. statistical method
Data processing data is carried out checking between variance analysis and group by SPSS11.5 statistical software.
7. experimental result
Result shows, the indices of model group mice all has pole significant difference (P < 0.01) with sham operated rats, says
This model success bright.Compared with model group, each dosed administration group all has prolongation in various degree incubation period, and errors number is also
Significantly reduce, be respectively provided with significant difference.
Claims (8)
1. a new compound, it is characterised in that described compound is 3-(3 '-hydroxyl)-butylphthalide
Taurine ester, this compound is racemoid or its optically active compound, and its general structure is as follows:
2. a new compound, it is characterised in that described compound is 3-(3 '-hydroxyl)-butylphthalide
The taurine ester of derivant, this compound is racemoid or its optically active compound, and its general structure is as follows:
Wherein R is halogen atom, hydroxyl, methoxyl group, nitro, amino, alkyl, amide, carboxyl or hydrogen atom.
The taurine ester of 3-the most according to claim 2 (3 '-hydroxyl)-butylphthalide derivant, it is special
Levy and be that its general structure is as follows:
4. a new compound, it is characterised in that described compound is 3-(3 '-hydroxyl)-butylphthalide
The taurine ester of derivant, this compound is racemoid or its optically active compound, and its general structure is as follows:
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl or hydrogen atom,
R1 is hydroxyl carboxylic acid or contains substituent group hydroxy carboxylic acid, amino carboxylic acid or contain substituent group amino carboxylic acid, containing halogenated carboxylic acid
Or the halogenated carboxylic acid containing substituent group.
5. according to the new compound described in any one of claim 1-3, it is characterised in that described 3-
(3 '-hydroxyl)-butylphthalide taurine ester and 3-(3 '-hydroxyl)-butylphthalide derivant taurine ester and mineral acid or
Organic acid reaction generates 3-(3 '-hydroxyl)-butylphthalide taurine ester and 3-(3 '-hydroxyl)-butylphthalide derivant cattle
The salt of sulphonic acid ester.
Compound the most according to claim 5, it is characterised in that described mineral acid be nitric acid, sulphuric acid,
Phosphoric acid or hydrochloric acid.
3-the most according to claim 5 (3 '-hydroxyl)-butylphthalide taurine ester hydrochloride, it is characterised in that
This compound is racemoid or its optically active compound, and its structural formula is
8. claim 1-4,3-(3 '-hydroxyl)-butylphthalide taurine ester according to any one of 7 and salt, 3-
(3 '-hydroxyl)-butylphthalide derivant taurine ester and salt thereof are in preparation prevention and the treatment heart, cerebral ischemia diseases, prevention
With the application in treatment brain dementia medicine.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510155682.8A CN106146444A (en) | 2015-04-03 | 2015-04-03 | A kind of new compound and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510155682.8A CN106146444A (en) | 2015-04-03 | 2015-04-03 | A kind of new compound and application thereof |
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| CN106146444A true CN106146444A (en) | 2016-11-23 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112794831A (en) * | 2021-04-06 | 2021-05-14 | 北京理工大学 | 3- (3' -hydroxybutyl) isobenzofuran-1 (3H) -one derivative, composition, preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101123878A (en) * | 2003-07-29 | 2008-02-13 | 信号研发控股有限责任公司 | L-threonine derivatives of high therapeutic index |
| CN101289438A (en) * | 2007-04-16 | 2008-10-22 | 山东绿叶天然药物研究开发有限公司 | 3-(3'-hydroxyl)-butyl phthalide ester, and preparation thereof and uses |
| CN102503919A (en) * | 2011-10-13 | 2012-06-20 | 广东中科药物研究有限公司 | Derivatives of butylphthalide and preparation method and application thereof |
-
2015
- 2015-04-03 CN CN201510155682.8A patent/CN106146444A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101123878A (en) * | 2003-07-29 | 2008-02-13 | 信号研发控股有限责任公司 | L-threonine derivatives of high therapeutic index |
| CN101289438A (en) * | 2007-04-16 | 2008-10-22 | 山东绿叶天然药物研究开发有限公司 | 3-(3'-hydroxyl)-butyl phthalide ester, and preparation thereof and uses |
| CN102503919A (en) * | 2011-10-13 | 2012-06-20 | 广东中科药物研究有限公司 | Derivatives of butylphthalide and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 赵九洋等: "3-（3’-羟基）丁基苯酞氨基酸酯衍生物的设计与合成", 《中国海洋大学学报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112794831A (en) * | 2021-04-06 | 2021-05-14 | 北京理工大学 | 3- (3' -hydroxybutyl) isobenzofuran-1 (3H) -one derivative, composition, preparation method and application thereof |
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Application publication date: 20161123 |