CN101054346A - Preparation method and use for a set of novel compound and composition thereof - Google Patents
Preparation method and use for a set of novel compound and composition thereof Download PDFInfo
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- CN101054346A CN101054346A CN 200610073077 CN200610073077A CN101054346A CN 101054346 A CN101054346 A CN 101054346A CN 200610073077 CN200610073077 CN 200610073077 CN 200610073077 A CN200610073077 A CN 200610073077A CN 101054346 A CN101054346 A CN 101054346A
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Abstract
The invention relates to a new compounds of (s)-2-(alpha-hydroxy pentyl) benzoate and preparation method therefor, and its application in medicines for treating and preventing cardio-cerebrovascular disease, aphrenia, cephalalgia, vertigo, acoasm and enhancing memorization etc, or medicinal composition containing activity component of present invention.
Description
The present invention relates to new compound (S)-2-(a-hydroxyl amyl group) benzoate, and preparation method thereof and be the pharmaceutical composition of activeconstituents with this compounds, also relate to this compound at the treatment heart, cerebral ischemia, heart and brain artery occlusion, platelet aggregation-against, anti-senile dementia, improve brain microcirculation and improve the application of aspects such as memory, treatment cerebral trauma.
Acute ischemic cerebral apoplexy is a kind of sickness rate height (119-180/10 ten thousand), the disease of mortality ratio height (62-118/10 ten thousand), and the survivor often stays the sequela that is difficult to recover, and has both influenced patient's quality of life, increases patient family and burden on society again.Though the understanding of the pathological change process after people are taken place cerebral apoplexy has now obtained very much progress, theories such as energy metabolism, excited poison, oxidative damage, calcium overload have been proposed, only related to an aspect of complicated pathological change process, with them is the compound that instructs exploitation, is difficult to receive the ideal effect naturally.Present t-PA only U.S.'s approval is used for the treatment of cerebral infarction (the back 3 hours innerlich anwendens of falling ill), though receive better effects, danger of bleeding is arranged, and treatment back mortality ratio does not descend.Therefore the new drug of research and development treatment cerebral infarction is the focus place of the world of medicine always.
Coronary heart disease is a kind of disease of serious harm human health, because the formation of coronary atherosclerosis and thrombus causes myocardial ischemic injury.Thereby seek the newtype drug that prevents coronary atherosclerosis, stops thrombosis and coronary artery dilator, be the frontier nature work of cardiovascular agent research and development always.
The object of the present invention is to provide a kind ofly to have tangible antiplatelet and condense and improve brain microcirculation, and to the heart, cerebral ischemia, the heart and brain artery occlusion has new compound (S)-2-(a-hydroxyl amyl group) benzoate of pharmaceutical activity.
Another object of the present invention provides the synthetic method of a kind of preparation (S)-2-(a-hydroxyl amyl group) benzoate.
Another object of the present invention provides a kind of prevention and treats the pharmaceutical composition of the heart, cerebrovascular disease.
Above-claimed cpd and the composition of further providing of the present invention is in preparation prevention and the treatment heart, cerebral ischemia and the heart, cerebral arteries infraction and improve application in the medicine such as brain microcirculation.
In order to finish purpose of the present invention, one group of compound provided by the invention, i.e. (S)-2-(a-hydroxyl amyl group) benzoate, it has the structure of following general formula (I):
Wherein, M can be monovalent metallic ion such as K
+, Na
+, Li
+Deng; Also can be divalent-metal ion such as Ca
2+, Mg
2+, Zn
2+Deng; Also can be Al
3+, Fe
3+Or organic base such as meglumine base, morpholinyl, aminotoluene base, anilino, dimethylin, trimethylamine groups, diethylin, triethyamino or other alkaloid base class.
The preparation method of The compounds of this invention is as follows:
1. M is The compounds of this invention (S)-2-(a-hydroxyl amyl group) benzoate preparation method of monovalent metallic ion in the general formula (I):
Different and furans-1-(3H)-equivalent or excessive slightly monovalent base of ketone adding with normal (S)-3-normal-butyl, under-5～110 ℃ temperature condition, make different and furans-1-(the 3H)-ketone generation open loop dissociation reaction of (S)-3-normal-butyl, reaction times is 0.5～8 hour, and M is The compounds of this invention (S)-2-(a-hydroxyl amyl group) benzoate of monovalent metallic ion in the general formula that can make (I).
Wherein, the solvent medium of open loop dissociation reaction is any or an arbitrary combination in water, methyl alcohol, ethanol, Virahol, the acetone.
Employed recrystallisation solvent can be any or the arbitrary combination in methyl alcohol, ethanol, propyl alcohol, Virahol, acetone, ethyl acetate, chloroform, ether, methylene dichloride, benzene, toluene, sherwood oil or the above recrystallisation solvent: monovalent base can be mineral alkali such as sodium hydroxide, potassium hydroxide, lithium hydroxide etc., or organic metal-alcoholates salt such as sodium methylate (potassium), sodium ethylate (potassium) etc.
2. M is The compounds of this invention (S)-2-(a-hydroxyl amyl group) benzoate preparation method of divalence or trivalent metal ion in the general formula (I):
With M in the general formula (I) is after The compounds of this invention (S)-2-(a-hydroxyl amyl group) benzoate (as sylvite, sodium salt) of monovalent metallic ion is dissolved in the solvent medium, add equivalent, for example chemical pure divalence or trivalent metal salt, make it that permutoid reaction takes place at ambient temperature, reaction times is 0.5～10 hour, handle and crystallization purifying through routine operation again, get final product to such an extent that the middle M of general formula (I) is The compounds of this invention (S)-2-(a-hydroxyl amyl group) benzoate of divalence or trivalent metal ion.
Wherein, solvent medium can be any or an arbitrary combination in water, methyl alcohol, ethanol, Virahol, the acetone.Employed divalent metal salt can be any in the divalent metal salts such as magnesium chloride, zinc chloride, sal epsom, zinc sulfate; Trivalent metal salt can be any in the trivalent metal salts such as aluminum chloride, iron(ic) chloride, Tai-Ace S 150, ferric sulfate.Employed recrystallisation solvent can be any or the arbitrary combination in water, methyl alcohol, ethanol, Virahol, ethyl acetate, chloroform, ether, methylene dichloride or the above recrystallisation solvent.
3. M is compound (S)-2-(a-hydroxyl amyl group) benzoate preparation method of organic base in the general formula (I):
(1) The compounds of this invention (S)-2-(a-hydroxyl amyl group) benzoate (as sylvite, sodium salt) is dissolved in solvent medium after, add mineral acid and transfer pH value to 2.0～6.0 of solution,-30～+ 30 ℃, preferably under-20～+ 20 ℃ temperature condition, make (S)-2-(a-hydroxyl amyl group) benzoate and mineral acid generation acidification reaction, generate (S)-2-(a-hydroxyl amyl group) phenylformic acid;
(2) in above-mentioned solution, add organic extraction solvent, under-20～10 ℃ condition, utilize above described extraction and separation technology, extract free (S)-2-(a-hydroxyl amyl group) phenylformic acid, get the benzoic organic solution of free (S)-2-(a-hydroxyl amyl group), this solution is preserved under-20～10 ℃ temperature condition, and preferred temperature condition is between-20～0 ℃, and is standby;
(3) under-10～0 ℃ temperature condition, in (2), add in the solution of gained with (S)-2-(a-hydroxyl amyl group) phenylformic acid equivalent or excessive a little monovalent base solution, as potassium hydroxide solution, it is The compounds of this invention (S)-2-(a-hydroxyl amyl group) benzoate of monovalent metallic ion that reaction generates M, as sylvite, after treating that it fully reacts, adopt the method for purification identical with preparation method 1, can obtain M is monovalent metallic ion The compounds of this invention (S)-2-(a-hydroxyl amyl group) benzoate;
(4) under-10～0 ℃ temperature condition, gained contains in the benzoic solution of free (S)-2-(a-hydroxyl amyl group) in step (2), add contain with (S)-2-(a-hydroxyl amyl group) phenylformic acid equivalent or excessive slightly divalence mineral alkali or divalent metal salts solution; The trivalent metal salts solution, as the zinc hydroxide aqueous solution, it is The compounds of this invention (S)-2-(a-hydroxyl amyl group) benzoate of divalence or trivalent metal ion that reaction generates M, as zinc salt, after treating that it fully reacts, adopt the method for purification identical, can make the The compounds of this invention that M is organic base (S)-2-(a-hydroxyl amyl group) benzoate with preparation method 2;
(5) under-10～0 ℃ temperature condition, gained contains in the benzoic solution of free (S)-2-(a-hydroxyl amyl group) in step (2), add contain with (S)-2-(a-hydroxyl amyl group) phenylformic acid equivalent or excessive slightly organic bases, as aniline, it is The compounds of this invention (S)-2-(a-hydroxyl amyl group) benzoate of organic base that reaction generates M, as aniline salt, after treating that it fully reacts, adopt the method for purification identical, can make the The compounds of this invention that M is organic base (S)-2-(a-hydroxyl amyl group) organic alkali salt of phenylformic acid with preparation method 2.
Wherein the employed acid of acidification reaction can be the hydrochloric acid or the sulfuric acid of any concentration; The temperature of acidification reaction is controlled between-20～+ 20 ℃; Be used for extracting the benzoic organic solvent of (S)-2-(a-hydroxyl amyl group) and can be any or arbitrary combination of ether, ethyl acetate, chloroform, methylene dichloride, benzene, toluene, sherwood oil, normal hexane, hexanaphthene; Monovalent base can be any in potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium methylate (potassium), the sodium ethylate (potassium); Divalence inorganic metal salt and divalence mineral alkali can be any one in magnesium chloride, magnesiumcarbonate, calcium chloride, lime carbonate, zinc chloride, zinc carbonate, sal epsom, calcium hydroxide, zinc hydroxide, the magnesium hydroxide; The trivalent inorganic metal salt can be any one in iron(ic) chloride, aluminum chloride, ferric sulfate, the Tai-Ace S 150; Organic bases can be any in meglumine base, morpholinyl, aminotoluene base, anilino, dimethylin, trimethylamine groups, diethylin, triethyamino or other alkaloid base class; Dissolving M is that The compounds of this invention 2-(a-hydroxyl amyl group) the employed solvent medium of phenylamino benzoic acid salt of monovalent metallic ion can be any or the arbitrary combination in water, methyl alcohol, ethanol, Virahol, the acetone.
The inventor finds that The compounds of this invention has excellent prevention and therapeutic action to the heart, cerebral ischemia, and has platelet aggregation-against, and the treatment heart, cerebral arteries infraction is improved the heart, brain microcirculation, improved memory, pharmacological action such as anti-senile dementia.
Compound of the present invention demonstrates provide protection, the antiplatelet aggregative activity of excellent heart ischemia damage and alleviates the brain tissue impairment effect that the cerebral arteries infraction causes in experimentation on animals, and does not have excitement and cause side effects such as hemorrhage.
It is activeconstituents that pharmaceutical composition of the present invention contains the The compounds of this invention for the treatment of significant quantity, and contains one or more pharmaceutically acceptable carriers.
Compound of the present invention and pharmaceutical composition can be used for preparation prevention and the treatment heart, cerebral ischemia diseases, and the heart, cerebral arteries emphraxis improve the medicine of diseases such as the heart, brain microcirculation disorder.
Pharmaceutically acceptable carrier mentioned above is meant the pharmaceutical carrier of pharmaceutical field routine, as: thinner or excipient such as starch, sucrose, lactose, N.F,USP MANNITOL etc.; Tamanori such as derivatived cellulose, alginate, gelatin and polyvinyl pyrrolidone; Wetting agent such as glycerine; Disintegrating agent such as cross-linked polyvinylpyrrolidone, Microcrystalline Cellulose, sodium starch glycolate, lime carbonate and sodium bicarbonate etc.; Tensio-active agent such as cetyl alcohol, SDS etc.; Lubricant such as talcum powder, calcium stearate and magnesium, polyoxyethylene glycol; Also can in composition, add other auxiliarys such as flavouring agent, sweeting agent etc. in addition.
The compounds of this invention can composition form be applied to the patient who needs this treatment by modes such as oral, intravenous injections.Be used for to be made into corresponding tablet, granula, capsule etc. when oral; When being used for drug administration by injection, can be made into the solution or the powder injection of injection.Preferred form is sheet, capsule and injection.
The various formulations of pharmaceutical composition of the present invention can be according to the conventional production method preparation of pharmaceutical field.Activeconstituents is mixed with one or more carriers, be made into required formulation then.
It is 3: 2 activeconstituents that drug regimen compound of the present invention preferably contains weight ratio, and most preferred weight ratio is 1: 1 a activeconstituents.
The usage quantity of The compounds of this invention can be according to variations such as the type of route of administration, patient age, body weight, the disease of being treated and severity, and its per daily dose can be 10～800 milligrams, preferred 50～400 milligrams, can once or several times use.
The following examples can help those skilled in the art more fully to understand the present invention, but do not limit the present invention in any way.
Embodiment 1:(S)-preparation of 2-(a-hydroxyl amyl group) phenylformic acid sodium salt
With 12.0g (63mmol) (S)-different and furans-1-(the 3H)-ketone of 3-normal-butyl is dissolved in the 25ml methyl alcohol, adding 15ml is dissolved with the methanol solution of 2.5g (63mmol) NaOH, reflux is 1.5 hours under constantly stirring, the thin plate chromatography detects (developping agent sherwood oil: acetone=10: 1), iodo steam displaing color does not have raw material to reaction solution.The reaction solution concentrating under reduced pressure is got yellow dope, add the about 25ml of methylene dichloride, put in 2 ℃ of environment and place crystallization.The gained crude product gets white foam shape sodium salt solid 11.9g with methyl alcohol-methylene dichloride recrystallization, and this solids is the moisture absorption very easily, productive rate 82.0%.
Embodiment 2:(S)-preparation of 2-(a-hydroxyl amyl group) phenylformic acid sodium salt
With 1.3g (68mmol) (S)-the different and furans-1-(3H) of 3-normal-butyl-ketone adds the aqueous solution that 10ml is dissolved with 2.7g (68mmol) NaOH, reflux is 1.5 hours under stirring, (the developping agent sherwood oil: acetone=10: 1), iodo steam displaing color does not have raw material to the detection of thin plate chromatography to reaction solution.The reaction solution concentrating under reduced pressure is got yellow dope, add the about 8ml of methylene dichloride, put in 2 ℃ of environment and place crystallization.The gained crude product gets white foam shape sodium salt solid 1.22g with methyl alcohol-methylene dichloride recrystallization, and this solids is the moisture absorption very easily, productive rate 78.0%.
Embodiment 3:(S)-preparation of 2-(a-hydroxyl amyl group) phenylformic acid sodium salt
With 5.6g (23mmol) (S)-2-(a-hydroxyl amyl group) phenylformic acid sylvite is dissolved in the 15ml water, is cooled to about 0 ℃.To PH2.0～3.0, use cold diethyl ether rapid extraction (4 * 25ml) with the 0.6N hcl acidifying.Merge ether solution, (2 * 10ml), ether was used 0～2 ℃ of environment of anhydrous sodium sulphate dry 2 hours down to diethyl ether solution mutually, and low temperature is filtration rapidly down with cold water (0～5 ℃) washing.In filtrate, add the 20ml methanol solution that is dissolved with the Powdered anhydrous sodium carbonate of 1.22g (11.5mmol), stir and be warming up to room temperature down gradually.White solid appears in the reaction solution, standing over night, filter white powder sodium salt solid 3.0g, productive rate 65.2%.
Embodiment 4:(S)-preparation of 2-(a-hydroxyl amyl group) phenylformic acid sodium salt
With 2.8g (12mmol) (S)-2-(a-hydroxyl amyl group) phenylformic acid sylvite is dissolved in the 10ml water, is cooled to about 0 ℃.To PH2.0～3.0, use cold diethyl ether rapid extraction (4 * 20ml) with the 0.6N hcl acidifying.Merge ether solution, (2 * 10ml), ether was used 0～2 ℃ of environment of anhydrous sodium sulphate dry 2 hours down to diethyl ether solution mutually, and low temperature is filtration rapidly down with cold water (0～5 ℃) washing.In filtrate, add the 10ml methanol solution that is dissolved with 0.48g (12mmol) sodium hydroxide, stir and be warming up to room temperature down gradually.Behind the concentrating under reduced pressure with methyl alcohol-methylene dichloride recrystallization, filter white foam shape sodium salt solid 1.73g, this solids is the moisture absorption very easily, productive rate 70.5%.
By embodiment 1,2,3,4 gained (S)-2-(a-hydroxyl amyl group) phenylformic acid sodium salt is the white powder crystallization.
Because solids is the moisture absorption very easily, its fusing point is difficult to measure.
[α]
D=+18.3 (C=1.2, methyl alcohol)
IR(KBr)
3396cm
-1(υ
OH)，2970cm
-1(υ
CH3)，1558，1395cm
-1(υ
O-O)
1H-NMR(500MHz，DMSO)δ(ppm)
7.71(dd，J＝6.8Hz，1.8Hz，1H)，7.16-7.07(m，3H)，4.39(t，1H)，
1.65-1.49(m，2H)，1.40-1.10(m，4H)，0.83(t，3H)
Ultimate analysis C
12H
15O
3Na (FW230.23)
C(％) H(％) Na(％)
Theoretical value 62.60 6.57 9.99
Measured value 62.57 6.60 10.00
Embodiment 5:(S)-preparation of 2-(a-hydroxyl amyl group) phenylformic acid sylvite
With 1.63g (8.5mmol) (S)-the different and furans-1-(3H) of 3-normal-butyl-ketone adds the aqueous solution that 10ml is dissolved with 0.49 (8.8mmol) KOH, reflux is 1.5 hours under constantly stirring, thin-layer chromatography detects (developping agent sherwood oil: acetone=10: 1), iodo steam displaing color does not have raw material to reaction solution.The reaction solution concentrating under reduced pressure is got yellow dope, add the about 8ml of methylene dichloride, put in 2 ℃ of environment and place crystallization.The gained crude product gets white granular crystallization 1.65g, productive rate 78.6% with methyl alcohol-methylene dichloride recrystallization.
Embodiment 6:(S)-preparation of 2-(a-hydroxyl amyl group) phenylformic acid sylvite
With 17.0g (90mmol) (S)-different and furans-1-(the 3H)-ketone of 3-normal-butyl is dissolved in the 30ml methyl alcohol, adding 10ml is dissolved with the methanol solution of 5.1g (91mol) KOH, reflux is 1.5 hours under constantly stirring, thin-layer chromatography detects (developping agent sherwood oil: acetone=10: 1), iodo steam displaing color does not have raw material to reaction solution.The reaction solution concentrating under reduced pressure is got yellow dope, add the about 35ml of methylene dichloride, put in 2 ℃ of environment and place crystallization.The gained crude product gets white granular crystallization 19.8g, productive rate 89.3% with methyl alcohol-methylene dichloride recrystallization.
Embodiment 7:(S)-preparation of 2-(a-hydroxyl amyl group) phenylformic acid sylvite
With 3.92g (17.0mmol) (S)-2-(a-hydroxyl amyl group) phenylformic acid sodium salt is dissolved in the 15ml water, is cooled to about 0 ℃.To PH2.0～3.0, use cold diethyl ether rapid extraction (4 * 25ml) with the 0.6N hcl acidifying.Merge ether solution, (2 * 10ml), ether was used 0～2 ℃ of environment of anhydrous sodium sulphate dry 2 hours down to diethyl ether solution mutually, and low temperature is filtration rapidly down with cold water (0～5 ℃) washing.In filtrate, drip the 25ml methanol solution that is dissolved with the Powdered Anhydrous potassium carbonate of 1.18g (8.5mmol), stir and be warming up to room temperature down gradually.Occur white solid in the reaction solution, continue standing over night, filter white solid 2.97g, productive rate 71.0%.
Embodiment 8:(S)-preparation of 2-(a-hydroxyl amyl group) phenylformic acid sylvite
With 4.6g (20mmmol) (S)-2-(a-hydroxyl amyl group) phenylformic acid sodium salt is dissolved in the 20ml water, is cooled to about 0 ℃.With 0.6N hcl acidifying PH2.0～3.0, with cold diethyl ether rapid extraction (4 * 30ml).Merge ether solution, (2 * 10ml), ether was used 0～2 ℃ of environment of anhydrous sodium sulphate dry 2 hours down to diethyl ether solution mutually, and low temperature is filtration rapidly down with cold water (0～5 ℃) washing.In filtrate, drip the 15ml methanol solution that is dissolved with 1.12g (20mmol) potassium hydroxide, stir and be warming up to room temperature down gradually.Behind the concentrating under reduced pressure with methyl alcohol-methylene dichloride crystallization, filter white solid 4.0g, productive rate 80.5%.
By embodiment 5,6,7,8 gained (S)-2-(a-hydroxyl amyl group) phenylformic acid sylvite is the white granular crystallization.
mp152-153℃
[α]
D=+16.2 (C=1.1, methyl alcohol)
IR(KBr)
3197cm
-1(ν
oH)，2935cm
-1(ν
cH3)，1576，1560(ν
co-o)
1H-NMR(500MHz，DMSO)δ(ppm)
7.66(dd，J＝6.3Hz，2.7Hz，1H)，7.18-7.04(m，
3H)，4.31(t，1H)，3.41(s，1H)，1.81-1.54(m，2H)，1.40-1.02(m，4H)，0.80(t，3H)
Ultimate analysis C
12H
15O
3K (FW246.34)
C(％) H(％) K(％)
Theoretical value 58.51 6.14 15.87
Measured value 58.30 6.18 15.80
Embodiment 9:(S)-preparation of 2-(Alpha-hydroxy amyl group) phenylformic acid calcium salt
With 3.2g (17mmol) (S)-3-normal-butyl isobenzofuran-1-(3H)-ketone is dissolved in the 25ml methyl alcohol, adding 20ml is dissolved with the aqueous solution of 0.68g (17mmol) NaOH, reflux is 3 hours under stirring, the thin plate chromatography detects (developping agent sherwood oil: acetone=10: 1), iodo steam displaing color does not have raw material to reaction solution.The aqueous solution of 0.94g calcium chloride (8.5mmol) is added dropwise in the above-mentioned reaction solution, and reaction is 3 hours in 60 ℃ of water-baths,, filters to the PH7 with the 0.6N hcl acidifying.Filtrate decompression is concentrated into 15ml, promptly separates out white solid, leaves standstill 1 hour after-filtration, and filter cake uses cold (0～5 ℃) methanol-water (1:1) mixing solutions washing to detecting less than chlorion respectively, and oven dry gets the heavy 1.18g of white solid, productive rate 30.5%.
Embodiment 10:(S)-preparation of 2-(Alpha-hydroxy amyl group) phenylformic acid calcium salt
With 4.2g (22mmol) (S)-different and furans-1-(the 3H)-ketone of 3-normal-butyl is dissolved in the 20ml methyl alcohol, adding 15ml is dissolved with the methanol solution of 0.88g (22mmol) NaOH, reflux is 1.5 hours under constantly stirring, the thin plate chromatography detects (developping agent sherwood oil: acetone=10: 1), iodo steam displaing color does not have raw material to reaction solution.After removing solvent under reduced pressure, solids is dissolved in the 20ml water, is cooled to about 0 ℃.With 0.6N hcl acidifying PH2.0～3.0, with cold diethyl ether rapid extraction (4 * 30ml).Merge ether solution, (2 * 10ml), ether was used 0～2 ℃ of environment of anhydrous sodium sulphate dry 2 hours down to diethyl ether solution mutually, and low temperature is filtration rapidly down with cold water (0～5 ℃) washing.Stir down, in filtrate, slowly add the mixture that is mixed with 0.74g (10mmol) calcium hydroxide and 10ml water in 0 ℃, stir and be warming up to room temperature down gradually.Behind the concentrating under reduced pressure with methyl alcohol-methylene dichloride crystallization, filter white solid 3.3g, productive rate 72.3%.
Embodiment 11:(S)-preparation of 2-(Alpha-hydroxy amyl group) phenylformic acid calcium salt
With 1.2g (11mmol) CaCl
2Be dissolved in the 25ml water, be heated to about 55 ℃.To contain 5.1g (22mmol) (S)-aqueous solution 15ml of 2-(Alpha-hydroxy amyl group) phenylformic acid sodium salt adds, and about 55 ℃, constantly stirs reaction down 2.5 hours, is evaporated to about 10ml, the room temperature placement is spent the night.Filter, filter cake washes the back oven dry with water, gets the heavy 3.26g of white solid, productive rate 65.2%.
By embodiment 9,10,11 gained white solids are product (S)-2-(Alpha-hydroxy amyl group) phenylformic acid calcium salt.
This compound is decomposing more than mp255 ℃.
[α]
D=+21.5 (C=1.2, methyl alcohol)
IR(KBr)
3322cm
-1(υ
OH)，2931cm
-1(υ
CH3)，1606，1401cm
-1(υ
O-O)
1H-NMR(500MHz，DMSO)δ(ppm)
7.56(d，1H)，7.25-7.05(m，3H)，4.56(t，1H)，
1.70-1.50(m，2H)，1.25-1.05(m，4H)，0.80(t，3H)
Ultimate analysis C
24H
30O
6C
a(FW454.57)
C(％) H(％) K(％)
Theoretical value 63.41 6.65 8.82
Measured value 63.32 6.67 8.80
Embodiment 12:(S)-preparation of 2-(Alpha-hydroxy amyl group) Benzyl Benzoate amine salt
With 3.2g (17mmol) (S)-different and furans-1-(the 3H)-ketone of 3-normal-butyl is dissolved in the 20ml methyl alcohol, adding 10ml is dissolved with the methanol solution of 0.68g (17mmol) NaOH, reflux is 1.5 hours under constantly stirring, the thin plate chromatography detects (developping agent sherwood oil: acetone=10: 1), iodo steam displaing color does not have raw material to reaction solution.After removing solvent under reduced pressure, solids is dissolved in the 20ml water, is cooled to about 0 ℃.With 0.6N hcl acidifying PH2.0～3.0, with cold diethyl ether rapid extraction (4 * 30ml).Merge ether solution, (2 * 10ml), ether was used 0～2 ℃ of environment of anhydrous sodium sulphate dry 2 hours down to diethyl ether solution mutually, and low temperature is filtration rapidly down with cold water (0～5 ℃) washing.Stir down, in filtrate, slowly drip benzene methanamine 2.3g (21mmol) in 0 ℃, stir down, rise to room temperature gradually, standing over night.Get yellow dope behind the concentrating under reduced pressure, get white solid 2.6g, get white crystals 1.88g with re-crystallizing in ethyl acetate, productive rate 35.1% with sherwood oil-ether crystallization.
By embodiment 12 gained white crystals is product (S)-2-(Alpha-hydroxy amyl group) Benzyl Benzoate amine salt.
mp88-90℃
IR(KBr)
3397cm
-1(υ
NH)，2926cm
-1(br，υ
OH)，1605 1638(υ
O-O)，1516cm
-1(υ
c＝c)
1HNMR(500MHz，DMSO)δ(ppm)
7.65-7.14(m，9H)，4.66(t，1H，CH)，3.90(d，2H，CH
2)
1.60-1.65(m，2H，CH
2)，1.13-1.35(m，4H，CH
2CH
2)，0.81(t，3H，CH
3)
Ultimate analysis C
19H
25NO
3(FW315.41)
C(％) H(％) N(％)
Theoretical value 72.35 7.99 4.44
Measured value 72.30 8.01 4.66
Embodiment 13: the preparation method of medicinal compositions (tablet)
| Composition | Quantity (mg) |
| Activeconstituents | 150 |
| Starch | 60 |
| Microcrystalline Cellulose | 40 |
| Magnesium Stearate | 0.6 |
| Xylo-Mucine | 6 |
Preparation method: respectively activeconstituents, starch, Microcrystalline Cellulose, Xylo-Mucine abrasive dust are crossed 100 mesh sieves, mixing, evenly wetting with an amount of water, granulate, sieve and drying,, add Magnesium Stearate after sieve, with the mixture compressing tablet, the bag film-coat promptly gets (can select Vltra tears or like product for use) then.
Embodiment 14: the preparation method of medicinal compositions (capsule)
| Composition | Quantity (mg/ capsule) |
| Activeconstituents | 50 |
| Starch or seminose | 80 |
| Methylcellulose gum | 2～8 |
| Cross-linked pvp | 0.3～2 |
The preparation method: take by weighing mentioned component by recipe quantity, granulate behind the mixing, sieve, in the common hard capsule of packing into, active component content is 50 milligrams.
Embodiment 15: the injection method for preparing freeze-dried powder
| Composition | Quantity |
| Activeconstituents | The 50mg/ bottle |
| Hydrochloric acid or sodium hydroxide are transferred pH | 7.5～9.0 |
| N.F,USP MANNITOL | In right amount |
The preparation method: take by weighing activeconstituents and N.F,USP MANNITOL is dissolved in water for injection by prescription, regulate PH8.0-9.0 with hydrochloric acid or sodium hydroxide, filter, freeze-drying promptly after the can.Time spent adds 0.9% physiological saline intravenous drip.
The preparation method of embodiment 16 injection liquids
| Composition | Quantity |
| Activeconstituents | The 25mg/ bottle |
| Sodium hydroxide or hydrochloric acid adjust pH | In right amount |
| Water for injection or salt solution | 5～250ml |
Preparation method: activeconstituents is dissolved in proper amount of water for injection or the physiological saline, filters gained solution, pH is transferred between the 7.5-9.0 sterile filling with an amount of sodium hydroxide or hydrochloric acid.
Embodiment 17: The compounds of this invention is to the influence of local rats with cerebral ischemia cerebral infarct size
(1) test materials and method: male Wistar rat, body weight 250～280g;
(S)-and 2-(Alpha-hydroxy amyl group) phenylformic acid sylvite, prepare with distilled water;
TCC (TTC).
Arteria cerebri media Interruption (MCAO): with Chloral Hydrate (350mg/kg, ip) with behind the rat anesthesia, along neck median incision, peel off interior, the external carotid artery of left side neck, the nylon wire of long 3.0cm, diameter 0.26mm is inserted the about 2.0mm of internal carotid artery by external carotid artery, until encephalic arteria cerebri media mouth place.Put back to former cage after sewing up a wound.All processes keeps 24～25 ℃ of room temperatures.
The animal grouping: 30min irritates stomach before the 1. administration group ischemic, amounts to activeconstituents 100mg/kg; 2. 30min irritates the stomach distilled water before the control group operation, and volume is suitable with the administration group.
MCAO postoperative rat behavior point system: the rat of row left side MCAO, treat that its anesthesia back carried out behavior observation in 2,24 hours, by following standard scoring: 1. carry mouse tail built on stilts 1 chi, operation offside shoulder inward turning, the interior receipts person of forelimb commented 1 fen; 2. with on the sliding floor of rat horizontalization, push away both shoulders respectively, check the resistance that opposing promotes to side shifting.The resistance descender is chosen as 2 fens when the operation offside promotes; 3. with on the sliding floor of rat horizontalization,, be chosen as 3 fens around the operation offside person of turn-taking.
Cerebral infarct size is measured in TTC dyeing: rat one side MCAO postoperative 24 hours, broken end is got brain, and brain is placed 0～4 ℃ of physiological saline, behind the 10min, remove olfactory bulb, cerebellum and low brain stem after, crownly be cut into 5.First cutter is the utmost point and optic chiasma line midpoint before brain; Second cutter is at the optic chiasma position; The 3rd cutter is at the infundibular stalk position; Four blade is between the infundibular stalk and the posterior lobe tail utmost point.Rapidly the brain sheet is placed the 5ml staining fluid (to contain TTC (4%) 0.5ml and K then
2HPO
4(1M) aqueous solution of 0.1ml), 37 ℃ of lucifuge temperature are incubated 30min, stir once every 7-8min therebetween, dyed after, normal cerebral tissue is rose, and the cerebral infarction tissue is white in color, and boundary is clearly demarcated.After temperature is incubated and finished, white cerebral infarction tissue dug down weigh, calculate the per-cent that it accounts for the hemicerebrum total area according to " by the weight area method ".
(2) test-results
(S)-2-(Alpha-hydroxy amyl group) phenylformic acid sylvite (1-PHPB) is to the influence of permanent MCAO rat cerebral infarction area:
By the visible administration group cerebral infarct size of table 1 is 19.89 ± 3.19%, and the control group cerebral infarct size is 27.65 ± 3.12%, learns by statistics and handles, and the two has significant difference.
Table 1:
| Control group Vehicle | The compounds of this invention (20mg/kg) |
| 31.20％ | 26.31％ |
| 27.62％ | 20.44％ |
| 29.81％ | 18.10％ |
| 30.16％ | 21.98％ |
| 25.51％ | 16.90％ |
| 27.96％ | 16.35％ |
| 21.32％ | 19.12％ |
| X±SD27.65±3.12％ | X±SD19.89±3.19％ |
n＝7
(3) conclusion: (S)-2-(Alpha-hydroxy amyl group) phenylformic acid sylvite (1-PHPB) can obviously alleviate the brain tissue impairment that the rat brain obstruction of artery causes, alleviate cerebral infarct size.
Claims (15)
1. one group of compound as general formula I:
Title: (S)-2-(a-hydroxyl amyl group) phenylformic acid M salt.Wherein, M is a monovalent metallic ion, or divalent-metal ion, or trivalent metal ion, or organic base.
2. according to the compound of claim 1, wherein n=1, or n=2, or n=3.
3. according to the compound of claim 1, wherein M is potassium ion, sodium ion or lithium ion.
4. according to the compound of claim 1, wherein M is calcium ion, magnesium ion or zine ion.
5. according to the compound of claim 1, wherein M is aluminum ion, iron ion.
6. according to the compound of claim 1, wherein M is meglumine base, morpholinyl, aminotoluene base, anilino, dimethylin, trimethylamine groups, diethylin, triethyamino or other alkaloid base class.
7. be the preparation method of monovalent metallic ion compound as the M in claim 1 general formula (I): normal (S)-3-normal-butyl isobenzofuran-1-(3H)-ketone is dissolved in the hydrolysis solvent medium, add equivalent or excessive slightly monovalent base, under-5～110 ℃ temperature condition, make (S)-3-normal-butyl isobenzofuran-1-(3H)-ketone generation open loop dissociation reaction, obtain the compound that M is a monovalent metallic ion (S)-2-(a-hydroxyl amyl group) benzoate.
8. preparation method according to claim 7, the solvent medium that it is characterized in that the employed open loop dissociation reaction of this method can be any or its arbitrary combination in water, methyl alcohol, ethanol, Virahol, the acetone; Monovalent base can be a mineral alkali, as in sodium hydroxide, potassium hydroxide, the lithium hydroxide any, or in organic bases such as sodium methylate (potassium), the sodium ethylate (potassium) any.
9. M is the preparation method of divalence or trivalent metal ion compound in the general formula as claimed in claim 1 (I): with M in the general formula (I) is after compound (S)-2-(a-hydroxyl amyl group) benzoate (as sylvite, sodium salt) of monovalent metallic ion is dissolved in solvent medium, add equivalent or excessive slightly divalence or trivalent metal salt, make it that permutoid reaction takes place at ambient temperature, through suitably refining, obtain that M is compound (S)-2-(a-hydroxyl amyl group) benzoate of divalence or trivalent metal ion in the general formula I.
10. preparation method according to claim 9 is characterized in that the employed solvent medium of this method can be any or its arbitrary combination in water, methyl alcohol, ethanol, Virahol, the acetone; Employed metal-salt can be any in the soluble salt of magnesium, calcium, zinc, aluminium, iron.
11. method for preparing general formula as claimed in claim 1 (I) compound:
(1) be after (S)-2-(a-hydroxyl amyl group) benzoate of monovalent metallic ion is dissolved in solvent medium with M in general formula (I) compound, add mineral acid and transfer pH value to 2.0～6.0 of solution,-30～30 ℃, preferably under-20～0 ℃ temperature condition, make (S)-2-(a-hydroxyl amyl group) benzoate and mineral acid generation acidification reaction;
(2) in above-mentioned gained solution, add organic extraction solvent, under-20～0 ℃ of condition, extract to such an extent that contain the free benzoic organic solution of 2-(a-hydroxyl amyl group), this solution is preserved under-20～10 ℃ temperature, preferably, preserve-20～0 ℃ of temperature range, standby;
(3) under-10～0 ℃ temperature condition, in above-mentioned gained solution, add contain with (S)-2-(a-hydroxyl amyl group) phenylformic acid equivalent or other excessive slightly monovalent base solution, the M that generates in the general formula (I) is compound (S)-2-(a-hydroxyl amyl group) benzoate of monovalent metallic ion;
(4) under-10～0 ℃ temperature condition, in the solution that in step (2), makes, add contain with (S)-2-(a-hydroxyl amyl group) phenylformic acid equivalent or excessive slightly divalence mineral alkali or divalent metal salts solution, trivalent metal salts solution, the M that generates in the general formula (I) is compound (S)-2-(a-hydroxyl amyl group) benzoate of divalence or trivalent metal ion;
(5) under-10～0 ℃ temperature condition, in the solution that in step (2), makes, add contain with (S)-2-(a-hydroxyl amyl group) phenylformic acid equivalent or excessive slightly organic bases, the M that generates in the general formula (I) is compound (S)-2-(a-hydroxyl amyl group) benzoate of organic base.
12. preparation method according to claim 11 is characterized in that the employed acid of acidification reaction can be the hydrochloric acid or the sulfuric acid of any concentration; The temperature of acidification reaction is controlled between-30～+ 30 ℃; Be used for extracting the benzoic organic solvent of (S)-2-(a-hydroxyl amyl group) and can be any one or arbitrary combination of ether, ethyl acetate, chloroform, methylene dichloride, benzene, toluene, sherwood oil, normal hexane, hexanaphthene; Monovalent base can be any one in potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium methylate (potassium), the sodium ethylate (potassium); Divalence inorganic metal salt and divalence mineral alkali can be any one in magnesium chloride, magnesiumcarbonate, calcium chloride, lime carbonate, zinc chloride, zinc carbonate, sal epsom, magnesium hydroxide, zinc hydroxide or the calcium hydroxide; The trivalent inorganic metal salt can be iron(ic) chloride, aluminum chloride, any one in ferric sulfate, the Tai-Ace S 150; Organic bases can be any in meglumine, aniline, benzylamine, morpholine, dimethylamine, Trimethylamine 99, diethylamine, the triethylamine; Employed solvent medium can be any one or an arbitrary combination in water, methyl alcohol, ethanol, Virahol, acetone, ether, ethyl acetate, chloroform, methylene dichloride, benzene, toluene, sherwood oil, normal hexane, the hexanaphthene.
13. be used for the prevention and the treatment heart, cerebral ischemia diseases, cerebral arteries infraction; Platelet aggregation-against, anti-senile dementia improve brain microcirculation and improve the pharmaceutical composition of memory, it is characterized in that containing the described general formula of the claim 1 for the treatment of significant quantity (I) compound and acceptable carrier pharmaceutically.
14. as compound any in the claim 1～6 at preparation prevention and the treatment heart, cerebral ischemia diseases, the application in the heart, cerebral arteries infraction, dementia, hypermnesis, headache, dizzy, tinnitus medicine or the drug regimen.
15. application as claimed in claim 14 is characterized in that this compound can be made into tablet, capsule, freeze-dried or injection.
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