CN106146443A - A kind of new compound and application thereof - Google Patents
A kind of new compound and application thereof Download PDFInfo
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- CN106146443A CN106146443A CN201510155514.9A CN201510155514A CN106146443A CN 106146443 A CN106146443 A CN 106146443A CN 201510155514 A CN201510155514 A CN 201510155514A CN 106146443 A CN106146443 A CN 106146443A
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- Prior art keywords
- acid
- hydroxyl
- butylphthalide
- derivant
- ester
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- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 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
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
- C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a kind of new compound and application thereof, described compound is the ester of 3-(3'-hydroxyl)-butylphthalide derivant and acid reaction gained, acid is selected from pharmaceutically acceptable mineral acid or organic acid, containing chiral carbon atom in this compound, this compound is racemoid or its optically active compound, further relates to this compounds at preparation prevention and the treatment heart, cerebral ischemia diseases；Application in prevention and treatment brain dementia medicine.
Description
Technical field
The present invention relates to a kind of new compound and application thereof, relate particularly to 3-(3'-hydroxyl)-butylphthalide and derive
The ester of thing and acid reaction gained and salt thereof, further relate to this compounds at 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 one of ischemia resisting medicine research emphasis becoming medical personal.
The present inventor is in brain ischemia medicament research process, through substantial amounts of experimentation, has invented water solublity good,
The obvious 3-of pharmacological action (3'-hydroxyl)-butylphthalide derivant and salt thereof, meet the demand of clinic.
Summary of the invention
The invention provides a kind of new compound, i.e. 3-(3'-hydroxyl)-butylphthalide derivant and acid reaction gained
Ester, acid is selected from pharmaceutically acceptable mineral acid or organic acid.Because containing chiral carbon atom in compound, therefore should
Compound is racemoid or its optically active compound.
Formula 1:3-(3'-hydroxyl)-butylphthalide derivant,
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl.
3-(3'-hydroxyl)-butylphthalide derivant generates 3-(3'-hydroxyl)-fourth with mineral acid and organic acid chemosynthesis
Base phthalide derivant ester.Wherein mineral acid is selected from nitric acid, sulphuric acid or phosphoric acid；Organic acid is selected from aminoacid or binary acid, ammonia
Base acid: glycine, alanine, lysine, arginine, serine, phenylalanine, proline, tyrosine, aspartic acid,
Glutamic acid, histidine, leucine, methionine, threonine, pyroglutamic acid, tryptophan, taurine or valine；Binary acid:
Dextrocamphoric acid., malic acid, citric acid, maleic acid, succinic acid, oxalic acid, 1,3-propanedicarboxylic acid, ethanedioic acid, lactic acid or malonic acid；Double hydroxyl naphthalenes
Acid, hydroxynaphthoic acid, gentisic acid, salicylic acid, hydroxyacetic acid, mandelic acid, lactic acid, 4-acetaminobenzoic acid or nicotinic acid.
3-(3'-hydroxyl)-butylphthalide derivant and glycine, succinic acid, phosphoric acid, taurine react the ester generated, knot
Structure formula is as follows:
3-(3'-hydroxyl)-butylphthalide derivant glycinate
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl；
3-(3'-hydroxyl)-butylphthalide derivant succinate
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl；
3-(3'-hydroxyl)-butylphthalide derivant phosphate ester
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl；
3-(3'-hydroxyl)-butylphthalide derivant taurine ester
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl.
The ester that 3-(3'-hydroxyl)-butylphthalide derivant obtains with acid reaction, wherein 3-(3'-hydroxyl)-butylphthalide
Derivant and aminoacid react the salt that the ester obtained obtains again with sulphuric acid, phosphoric acid, hydrochloric acid or organic acid reaction；3-(3'-hydroxyl
Base)-butylphthalide derivant react with binary acid the sodium of the ester obtained, potassium, magnesium, calcium, zinc salt or again with trometamol, two
Ethanolamine, triethanolamine, glycine, lysine or arginine reaction, the salt obtained；3-(3'-hydroxyl)-butylphthalide
The sodium of the ester that derivant and phosphatase reaction obtain, potassium, magnesium, calcium, zinc salt or again with lysine, glycine, arginine, ammonia fourth three
Alcohol, diethanolamine, triethanolamine react, the salt obtained.
3-(3'-hydroxyl)-butylphthalide derivative ester salt, is preferably as follows ester salt:
3-(3'-hydroxyl)-butylphthalide derivant glycine ester hydrochloride
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl；
3-(3'-hydroxyl)-butylphthalide derivant succinate sodium salt
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl；
3-(3'-hydroxyl)-butylphthalide derivant phosphoric acid ester sodium
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl；
3-(3'-hydroxyl)-butylphthalide derivant taurine ester hydrochloride
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl.
Prior art has no the report to such noval chemical compound.
The purpose of the present invention, it is simply that provide a kind of new compound, specifically refers to noval chemical compound 3-(3'-hydroxyl)-butyl
The ester of phthalide derivant and acid reaction gained and salt thereof, further relate to this compounds in preparation prevention and the treatment heart, cerebral ischemia
Property disease；Application in prevention and treatment brain dementia medicine.
The present inventor is proved by substantial amounts of pharmacodynamic experiment, the ester of 3-(3'-hydroxyl)-butylphthalide derivant and salt thereof
During administration, there is a preferable pharmacologically active, and water solublity, have good stability.
In order to complete the purpose of the present invention, the present inventor prepares and have studied 3-(3'-hydroxyl)-butylphthalide
The ester of derivant and acid reaction gained and salt thereof, in preparation prevention and the treatment heart, cerebral ischemia diseases medicine, pharmacology is imitated
Fruit is notable.
Detailed description of the invention:
Further illustrate the present invention below by specific embodiment, but can not be used for being construed to uniquely limit the present invention.
Embodiment 1
The compounds of this invention can be prepared as follows:
3-(3'-hydroxyl)-butylphthalide derivant glycinate preparation method:
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl.
3-(3'-hydroxyl)-butylphthalide derivant succinate preparation method:
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl.
3-(3'-hydroxyl)-butylphthalide derivant phosphate preparations:
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl.
3-(3'-hydroxyl)-butylphthalide derivant taurine ester preparation method:
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl.
3-(3'-hydroxyl)-butylphthalide derivant glycine ester hydrochloride preparation method:
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl.
3-(3'-hydroxyl)-butylphthalide derivant succinate sodium salt preparation method:
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl.
3-(3'-hydroxyl)-butylphthalide derivant sodium phosphate salt production process:
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl.
3-(3'-hydroxyl)-butylphthalide derivant taurine ester hydrochloride preparation method:
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl.
Fluoro 3-(3'-hydroxyl)-butylphthalide derivant glycinate (code name F1) preparation method:
Fluoro 3-(3'-hydroxyl)-butylphthalide derivant succinate (code name F2) preparation method:
Chloro 3-(3'-hydroxyl)-butylphthalide derivant phosphate ester (code name F3) preparation method:
Chloro 3-(3'-hydroxyl)-butylphthalide derivant taurine ester (code name F4) preparation method:
Fluoro 3-(3'-hydroxyl)-butylphthalide derivant glycine ester hydrochloride (code name F1a) preparation method:
Fluoro 3-(3'-hydroxyl)-butylphthalide derivant succinate sodium salt (code name F2a) preparation method:
Chloro 3-(3'-hydroxyl)-butylphthalide derivant phosphoric acid ester sodium (code name F3a) preparation method:
Chloro 3-(3'-hydroxyl)-butylphthalide derivant taurine ester hydrochloride (code name F4a) preparation method:
Embodiment 2, F1, F2, F3, F4, F1a, F2a, F3a, F4a nervous symptoms to causing because of traumatic brain injury in rats
Impact
Laboratory animal: Male Wistar Rats
Experimental technique: freely fall from 30cm eminence with the cone-shaped metal object of weight 220g, clashes into rats with left hat
Parietal bone on rear side of shape seam, causes traumatic brain injury in rats, oral administration after 5 minutes:
F1, F2, F3, F4, F1a, F2a, F3a, F4a (20,40,80mg/kg), evaluation behavior of giving a mark after 24 hours
Change.
Experimental result: the nervous symptoms that rat causes with cerebral ischemia because of cerebral trauma, after oral administration, with solvent control
Comparing, each administration group all can be with the nervous symptoms that significantly improves of dose dependent, and cerebral trauma is caused brain to lack by trial drug
Blood and the nervous symptoms that causes all has improvement result.
What local cerebral ischemia was caused by embodiment 3, F1, F2, F1a, F2a amnemonic affects experimental apparatus: shuttle back and forth
Case, other with embodiment 1 laboratory animal with embodiment 1 experimental technique:
(1) rat is carried out memory training:
(2) cerebral arteries ligation operation: rat is implemented cerebral arteries ligation operation according to Tamura method, after 24 hours,
The experiment of replication learning and memory in rats, method is with (1).
(3) it is grouped and is administered: normal group, sham operated rats, ischemic control group,
F1, F2, F1a, F2a (15,30,60mg/kg) group.Postoperative 15 minutes oral administrations, observe medicine after 24 hours
Thing is to the rat preclinical change of actively and passively avoidance response.
Experimental result: ischemic control group compared with normal group, the obvious loss of memory of rat, active avoidance number of times reduce,
Illustrate to create dysmnesia.Compared with solvent control group, F1, F2, F1a, F2a group active avoidance number of times the most substantially increases
Add, show that trial drug all has and improve the amnemonic effect that local cerebral ischemia causes.
Embodiment 4, F2, F2a effect to spontaneous hypertensive rat apoplexy
Laboratory animal: 6 week old spontaneous hypertensive rats
Experimental technique: 6 week old spontaneous hypertensive rats, is divided into 7 groups, often group 10, every day from the 6th week old
Feeding salt 0.8-0.9g, the most progressively increases to 1.2-1.3g every day, within the 8th week, rises and starts to be administered orally respectively
F2, F2a (12.5,25,50mg/kg/d), nimodipine (37mg/kg/d), after occurring to apoplexy 3
Week only, records neurological deficits mark and death time.
Experimental result: compared with solvent control group, F2, F2a all can substantially delay the time of cerebral seizure, show it
There is the effect that preventing brain stroke shows effect；Simultaneously F2, F2a all can dose dependent dramatically increase cerebral seizure after
Survival rate and improve neurological deficits effect, shows that its apoplexy causing spontaneously hypertensive has therapeutical effect.
Embodiment 5, F1, F1a are on local rats with cerebral ischemia cerebral infarct size and the impact of neurological deficit
Laboratory animal is with embodiment 1
Experimental technique:
According to Tamura method, rat is implemented cerebral arteries ligation operation, postoperative 10min oral administration, is divided into 8 groups,
Sham operated rats, solvent control group, F1, F1a (15,30,60mg/kg) group.
Experimental result: the nervous symptoms that focal cerebral ischemia in rats causes, after oral administration, compared with operating comparison
F1, F1a group can reduce infarct size with the nervous symptoms that significantly improves of dose dependent, show that trial drug is all played a game
Portion's cerebral ischemia and the nervous symptoms that causes are significantly improved.
Embodiment 6, F2, F2a are to dull-witted preventive and therapeutic action
(1) therapeutical effect to vascular dementia
(2) instrument: Morris water maze automatic monitoring instrument
2-VO model is set up: male Wistar rat, 10 week old, body weight about 280 grams, uses pentobarbital sodium
Anesthesia, bilateral ligation.Sham operated rats accepts identical operation in addition to not ligaturing bilateral common carotid arteries.
Experiment packet and design: be divided into sham operated rats, solvent control group, F2, F2a (15,30,60mg/kg)
Group.Within postoperative 10 days, start to be administered, within postoperative 29-33 days, carry out water maze laboratory, within 34-35 days, carry out step-through test, dynamic
Thing was put to death at the 36th day.In Behaviors survey, within 40 minutes, it is administered the most on pretreatment.
Experimental result: after oral administration, the near of cerebral blood supply insufficiency rat is remembered and locus functional impairment by F2, F2a
There is obvious effect.Prompting F2, F2a have obvious treatment and prevention effect to vascular dementia.
Claims (6)
1. a new compound, it is characterised in that described compound is 3-(3'-hydroxyl)-butylphthalide
Derivant and the ester of acid reaction gained, acid, selected from pharmaceutically acceptable mineral acid or organic acid, contains in this compound
Chiral carbon atom, this compound is racemoid or its optically active compound, and its structural formula is:
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl.
Compound the most according to claim 1, it is characterised in that described mineral acid is selected from nitric acid, sulphuric acid or phosphoric acid；
Organic acid is selected from aminoacid or binary acid, aminoacid: glycine, alanine, lysine, arginine, serine, phenylpropyl alcohol ammonia
Acid, proline, tyrosine, aspartic acid, glutamic acid, histidine, leucine, methionine, threonine, pyroglutamic acid, color
Propylhomoserin, taurine or valine；Binary acid: dextrocamphoric acid., malic acid, citric acid, maleic acid, succinic acid, oxalic acid, 1,3-propanedicarboxylic acid,
Ethanedioic acid, lactic acid or malonic acid；Pamoic acid, hydroxynaphthoic acid, gentisic acid, salicylic acid, hydroxyacetic acid, mandelic acid, lactic acid,
4-acetaminobenzoic acid or nicotinic acid.
Compound the most according to claim 2, it is characterised in that described organic acid be glycine, succinic acid,
Phosphoric acid or taurine, its reaction product is:
3-(3'-hydroxyl)-butylphthalide derivant glycinate
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl；
3-(3'-hydroxyl)-butylphthalide derivant succinate
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl；
3-(3'-hydroxyl)-butylphthalide derivant phosphate ester
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl；
Or 3-(3'-hydroxyl)-butylphthalide derivant taurine ester
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl.
Compound the most according to claim 3, it is characterised in that described 3-(3'-hydroxyl)-butylphthalide
Derivant and aminoacid react the salt that the ester obtained obtains again with sulphuric acid, phosphoric acid, hydrochloric acid or organic acid reaction；
3-(3'-hydroxyl)-butylphthalide derivant react with binary acid the sodium of the ester obtained, potassium, magnesium, calcium, zinc salt or again with
Trometamol, diethanolamine, triethanolamine, glycine, lysine, arginine react, the salt obtained；
The sodium of ester that 3-(3'-hydroxyl)-butylphthalide derivant obtains with phosphatase reaction, potassium, magnesium, calcium, zinc salt or again with rely
Propylhomoserin, glycine, arginine, trometamol, diethanolamine, triethanolamine react, the salt obtained.
The salt of ester the most according to claim 3, it is characterised in that its structural formula is:
3-(3'-hydroxyl)-butylphthalide derivant glycine ester hydrochloride
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl；
3-(3'-hydroxyl)-butylphthalide derivant succinate sodium salt
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl；
3-(3'-hydroxyl)-butylphthalide derivant phosphoric acid ester sodium
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl；
3-(3'-hydroxyl)-butylphthalide derivant taurine ester hydrochloride
Wherein R is halogen atom or hydroxyl or methoxyl group or nitro or amino or alkyl or amide or carboxyl.
6. 3-(3'-hydroxyl)-butylphthalide derivant described in any one of claim 1-5, itself and acid reaction gained
Ester and salt thereof are in preparation prevention and the treatment heart, cerebral ischemia diseases, the application that prevents and treat in brain dementia medicine.
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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 and its composition, preparation method and use |
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| 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 |
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2015
- 2015-04-03 CN CN201510155514.9A patent/CN106146443A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 (2)
| Title |
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| WEI WANG等: "Synthesis and biological activity of n-butylphthalide derivatives", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 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 |
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| CN112794831A (en) * | 2021-04-06 | 2021-05-14 | 北京理工大学 | 3-(3'-Hydroxybutyl)isobenzofuran-1(3H)-one derivative and its composition, preparation method and use |
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