CN105732412A - Amide compound for treating stroke and preparation method thereof - Google Patents
Amide compound for treating stroke and preparation method thereof Download PDFInfo
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- CN105732412A CN105732412A CN201610136456.XA CN201610136456A CN105732412A CN 105732412 A CN105732412 A CN 105732412A CN 201610136456 A CN201610136456 A CN 201610136456A CN 105732412 A CN105732412 A CN 105732412A
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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Abstract
The invention discloses an amide compound for treating stroke and a preparation method thereof. A structural formula of the amide compound is shown as follows, wherein R1-R3 independently represent hydrogen or fluorine, R4 represents hydrogen or hydroxyl, R5 represents C1-C20 alkyl or C2-C20 alkenyl, n is an integer from 0 to 4, and respectively independent configuration representation of*1-*4 is R or S. The amide compound is synthesized through esterification reaction and ammonolysis reaction and is simple to operate and high in yield and purity. The amide compound has effects of thrombolysis and promoting recovery of brain tissue and nerve function, has obvious recovery effect on ischemic brain injury and nerve injury caused by a middle cerebral artery occlusion induced by a suture-occluded method, does not present toxic and side effect and can be used as a drug for treating stroke.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to a kind of for amides compound treating apoplexy and preparation method thereof.
Background technology
Apoplexy is a kind of acute illness, there is the features such as sickness rate height, mortality rate height, disability rate height, relapse rate height, treatment length recovery time and complication are many, the physical and mental health of serious harm middle-aged and elderly people and life security, it it is the third-largest cause of the death being only second to heart disease and cancer, death toll accounts for the 10% of the total death toll in the whole world, and the stroke survivor of 75% has deformity in various degree.Therefore, apoplexy is to have a strong impact on one of physically and mentally healthy principal disease with quality of life of our people.
At present, lack efficient curing apoplexy medicine, the medication effect of the treatment apoplexy of clinical practice is unsatisfactory, thrombolytic is the method effectively treating ischemia apoplexy, but thrombolytic drug is higher to time requirement, obtains the patient of promising result less than 5% by thromboembolism treatment, except thrombolytic drug, the medicine of clinical treatment ischemia apoplexy has: (1) vasodilator, and such medicine can make the blood stream of diseased region go in healthy cerebral tissue, the cerebral tissue of damage healthy；(2) medicine of expanding blood volume, such medicine can improve microcirculation, but has the danger causing heart patient's heart failure；(3) anticoagulant and prevent platelet aggregation medicine, is only used as the adjuvant therapy medicaments of cerebral infarction at present.
Modern medicine is thought: apoplexy refers to and causes after being obstructed due to brain blood supply that local brain tissue and function of nervous system thereof are impaired, therefore promote that injured cerebral tissue and neurological functional recovery thereof are the effective ways for the treatment of apoplexy, but there is not yet the medicine simultaneously facilitating cerebral tissue and neurological functional recovery thereof.
Summary of the invention
A technical problem to be solved by this invention is in that to overcome the shortcoming treating apoplexy medicine at present, a kind of amides compound that can promote cerebral tissue and neurological functional recovery while thrombolytic is provided, line brush is caused ischemia injury that middle cerebral artery thromboembolism (MCAO) model causes and promotes that CO2 laser weld has obvious effect by this compounds, and has no toxic and side effects.
Another technical problem to be solved by this invention is in that to provide a kind of preparation method simple to operate for above-mentioned amides compound.
Solve above-mentioned technical problem and be employed technical scheme comprise that the structural formula of this amides compound is as follows:
Representative hydrogen each independent for R1～R3 in formula or fluorine；N is the integer of 0～4；*1、*2、*3Each independent expression is configured as R or S；R4Represent hydrogen or hydroxyl, and work as R4During representation hydroxy, *4Represent and be configured as R or S；R5Represent C1～C20Alkyl or C2～C20Thiazolinyl.
The preparation method of the above-mentioned amides compound for treating apoplexy is made up of following step:
1, hydroxyl protection
With dimethyl sulfoxide for solvent, it is 1:3～3.3:3～3.3 in molar ratio by the alpha-hydroxy carboxylic acid compounds shown in Formulas I, acyl chlorides, pyridine, reacts at ambient temperature 1～3 hour, separate purified product, obtain the alpha-hydroxy carboxylic acid of the protection shown in Formula II.
2, the synthesis of acyl ammonia
With oxolane for solvent; alpha-hydroxy for protection shown in Formula II carboxylic acid, dicyclohexylcarbodiimide, DMAP, formula III compound are reacted 4～6 hours at ambient temperature for 1:1～1.3:0.05～0.15:1～1.3 in molar ratio; separate purified product, obtain the amide shown in formula III.
3, hydrolysis
Amide shown in formula III is added in the oxolane that ammonia is saturated, react 3～5 hours at 30 DEG C, separate purified product, obtain the amides compound for treating apoplexy.
Amides compound provided by the invention has thrombolytic, promotes cerebral tissue and function of nervous system's repair, can blood clot dissolving (Sanguis Leporis seu oryctolagi), and line brush is caused ischemic brain injury that middle cerebral artery thromboembolism (MCAO) model causes and nerve injury has obvious repair, and have no toxic and side effects, it is possible to as the medicine for the treatment of apoplexy.
The present invention adopts esterification, aminolysis etc. that amides compound is synthesized, simple to operate, and product yield and purity are high.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in more detail, but protection scope of the present invention is not limited only to these embodiments.
Embodiment 1
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
1, hydroxyl protection
nullBy (the 2R)-3-(3 shown in 7.92g (40mmol) Formulas I-1,4-hydroxy phenyl)-2 hydroxy propanoic acid、9.58g (122mmol) chloroacetic chloride、40mL dimethyl sulfoxide adds in there-necked flask，It is stirred at room temperature，And drip the 10mL dichloromethane solution containing 9.81g (124mmol) pyridine with the rate of addition of 4～5mL/ minute，After dripping，Room temperature reaction 2 hours，Add 50mL distilled water，Separatory，Aqueous phase dichloromethane extraction three times，After reclaiming dichloromethane，Solid silica gel chromatography (with the volume ratio of ethyl acetate Yu methanol be 20:1 mixed liquor for eluent)，Reclaim eluent，Obtain (the 2S)-triacetyl 3-(3 shown in Formula II-1,4-hydroxy phenyl)-2 hydroxy propanoic acid ester，Its productivity is 95%，Concrete reaction equation is as follows:
2, the synthesis of acyl ammonia
nullBy (2R)-triacetyl-3-(3 shown in 9.78g (30mmol) Formula II-1,4-hydroxy phenyl)-2 hydroxy propanoic acid ester、6.80g (33mmol) dicyclohexylcarbodiimide (DCC)、0.37g (3mmol) dimethylamino naphthyridine (DMAP)、40mL oxolane adds in there-necked flask，And drip 20mL containing 9.53g (30mmol) (2S with the rate of addition of 4～5mL/ minute,3S,4S)-2-amino-1,3,The tetrahydrofuran solution of 4-octadecane triol，After dripping，Room temperature reaction 5 hours，Add 50mL distilled water，Separatory，Aqueous phase dichloromethane extraction three times，After reclaiming dichloromethane，Solid silica gel chromatography (with the volume ratio of ethyl acetate Yu methanol be 10:1 mixed liquor for eluent)，Reclaim eluent，Obtain (2R)-triacetyl-3-(3 shown in formula III-1,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2S,3S,4S)-2-amino-1,3,4-octadecane three alkylolamides，Its productivity is 83%，Concrete reaction equation is as follows:
3, hydrolysis
nullBy (2R)-triacetyl-3-(3 shown in 12.48g (20mmol) formula III-1,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2S,3S,4S)-2-amino-1,3,4-octadecane three alkylolamides adds in the oxolane that 20mL ammonia is saturated，React 4 hours at 30 DEG C，Add 20mL distilled water，Aqueous phase is extracted with ethyl acetate three times，After reclaiming ethyl acetate，Solid silica gel chromatography (with the volume ratio of ethyl acetate Yu methanol be 10:1 mixed liquor for eluent)，Reclaim eluent，Obtain the amides compound for treating apoplexy，Its chemical name is (2R)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2S,3S,4S)-2-amino-1,3,4-octadecane three alkylolamides，Productivity is 92%，Structural characterization data are: MS (m/z): 497.34 (100.0%)，498.34 (30.0%)，499.34 (5.9%)；1HNMR (400MHz, CDCl3+ TMS) δ (ppm): 8.02 (s, 1H), 6.73 (d, J=7.5, 1H), 6.86 (s, 1H), 6.68 (d, J=7.5, 1H), 5.35 (s, 2H), 4.55 (m, 1H), 3.91 (m, 1H), 3.75 (m, 1H) 3.65 (m, 1H), 3.58 (m, 2H), 3.50 (m, 1H), 3.29 (m, 1H), 3.25 (m, 1H), 3.11 (m, 1H), 2.83 (m, 2H), 1.44 (m, 2H), 1.31 (m, 2H), 1.26-1.30 (m, 22H), 0.88 (t, 3H)；13CNMR (100MHz, CDCl3+ TMS) δ (ppm): 172.01,146.45,145.63,129.23,123.18,116.64,116.25,75.68,74.46,71.94,61.27,57.82,41.32,33.11,32.78,30.69,29.89,29.79,29.73,29.69,29.65,29.58,29.55,29.50,26.03,23.17,14.52.
Embodiment 2
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2R)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid equimolar (2S)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid used is replaced, other steps are identical with embodiment 1, obtaining the amides compound for treating apoplexy, its chemical name is (2S)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2S, 3S, 4S)-2-amino-1,3,4-octadecane three alkylolamides.
Embodiment 3
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S, 3S used, 4S)-2-amino-1,3,4-octadecane triols are with equimolar (2R, 3S, 4S)-2-amino-1,3,4-octadecane triol is replaced, and other steps are identical with embodiment 1, obtain the amides compound for treating apoplexy, its chemical name is (2R)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2R, 3S, 4S)-2-amino-1,3,4-octadecane three alkylolamides.
Embodiment 4
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S, 3S used, 4S)-2-amino-1,3,4-octadecane triols are with equimolar (2S, 3R, 4S)-2-amino-1,3,4-octadecane triol is replaced, and other steps are identical with embodiment 1, obtain the amides compound for treating apoplexy, its chemical name is (2R)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2S, 3R, 4S)-2-amino-1,3,4-octadecane three alkylolamides.
Embodiment 5
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S, 3S used, 4S)-2-amino-1,3,4-octadecane triols are with equimolar (2S, 3S, 4R)-2-amino-1,3,4-octadecane triol is replaced, and other steps are identical with embodiment 1, obtain the amides compound for treating apoplexy, its chemical name is (2R)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2S, 3S, 4R)-2-amino-1,3,4-octadecane three alkylolamides.
Embodiment 6
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S, 3S used, 4S)-2-amino-1,3,4-octadecane triols are with equimolar (2S, 3R, 4R)-2-amino-1,3,4-octadecane triol is replaced, and other steps are identical with embodiment 1, obtain the amides compound for treating apoplexy, its chemical name is (2R)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2S, 3R, 4R)-2-amino-1,3,4-octadecane three alkylolamides.
Embodiment 7
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S, 3S used, 4S)-2-amino-1,3,4-octadecane triols are with equimolar (2R, 3S, 4R)-2-amino-1,3,4-octadecane triol is replaced, and other steps are identical with embodiment 1, obtain the amides compound for treating apoplexy, its chemical name is (2R)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2R, 3S, 4R)-2-amino-1,3,4-octadecane three alkylolamides.
Embodiment 8
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S, 3S used, 4S)-2-amino-1,3,4-octadecane triols are with equimolar (2R, 3R, 4S)-2-amino-1,3,4-octadecane triol is replaced, and other steps are identical with embodiment 1, obtain the amides compound for treating apoplexy, its chemical name is (2R)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2R, 3R, 4S)-2-amino-1,3,4-octadecane three alkylolamides.
Embodiment 9
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S, 3S used, 4S)-2-amino-1,3,4-octadecane triols are with equimolar (2R, 3R, 4R)-2-amino-1,3,4-octadecane triol is replaced, and other steps are identical with embodiment 1, obtain the amides compound for treating apoplexy, its chemical name is (2R)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2R, 3R, 4R)-2-amino-1,3,4-octadecane three alkylolamides.
Embodiment 10
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2R)-3-(3 used, 4-hydroxy phenyl) equimolar (2R)-2-(3,4-the dihydroxy phenyl)-2-hydroxyacetic acid replacement of-2 hydroxy propanoic acid, other steps are identical with embodiment 1, prepare into (2R)-2-(3,4-dihydroxy phenyl)-2-hydroxyacetic acid-(2S, 3S, 4S)-2-amino-1,3,4-octadecane three alkylolamides.
Embodiment 11
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2R)-3-(3 used, 4-hydroxy phenyl) equimolar (2S)-2-(3,4-the dihydroxy phenyl)-2-hydroxyacetic acid replacement of-2 hydroxy propanoic acid, other steps are identical with embodiment 1, prepare into (2S)-2-(3,4-dihydroxy phenyl)-2-hydroxyacetic acid--(2S, 3S, 4S)-2-amino-1,3,4-octadecane three alkylolamides.
Embodiment 12
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S, 3S used, 4S)-2-amino-1,3,4-octadecane triols are with equimolar (2R, 3R)-2-amino-4-octadecylene-1,3-glycol is replaced, and other steps are identical with embodiment 1, obtain the amides compound for treating apoplexy, its chemical name is (2R)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2R, 3R)-2-amino-4-octadecylene-1,3-bis-alkylolamides.
Embodiment 13
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S, 3S used, 4S)-2-amino-1,3,4-octadecane triols are with equimolar (2S, 3R)-2-amino-4-octadecylene-1,3-glycol is replaced, and other steps are identical with embodiment 1, obtain the amides compound for treating apoplexy, its chemical name is (2R)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2S, 3R)-2-amino-4-octadecylene-1,3-bis-alkylolamides.
Embodiment 14
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S, 3S used, 4S)-2-amino-1,3,4-octadecane triols are with equimolar (2S, 3S)-2-amino-4-octadecylene-1,3-glycol is replaced, and other steps are identical with embodiment 1, obtain the amides compound for treating apoplexy, its chemical name is (2R)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2S, 3S)-2-amino-4-octadecylene-1,3-bis-alkylolamides.
Embodiment 15
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S used, 3S, 4S)-2-amino-1,3,4-octadecane triols equimolar (2R, 3S)-2-amino-4-octadecylene-1,3-glycol is replaced, other steps are identical with embodiment 1, obtain the amides compound for treating apoplexy, and its chemical name is (2R)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2R, 3S)-2-amino-4-octadecylene-1,3-bis-alkylolamides, gross production rate is 82%, structural characterization data are: MS (m/z): 479.32 (100.0%), 480.33 (39.8%)；1HNMR (400MHz, CDCl3null+ TMS) δ (ppm): 8.04 (s，1H)，6.73(d，J=7.5，1H)，6.86(s，1H)，6.68(d，J=7.5，1H)，5.68(d，J=6.2，1H)，5.67(d，J=6.2，1H)，5.35(s，2H)，4.55(m，1H)，4.52(m，1H)，3.79(m，1H)，3.65(m，1H)，3.50(m，1H)，3.25(m，1H)，3.11(m，1H)，2.86(m，1H)，2.80(m，2H)，1.94(m，2H)，1.31(m，2H)，1.26-1.29(m，20H)，0.88(t，3H)；13CNMR (100MHz, CDCl3+ TMS) δ (ppm): 172.41,145.45,144.63,134.30,129.43,129.18,122.64,116.35,115.75,74.36,73.54,61.97,58.86,41.52,34.11,31.78,30.09,29.80,29.75,29.70,29.69,29.67,29.65,29.62,29.30,22.77,14.40.
Embodiment 16
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S, 3S used, 4S)-2-amino-1,3,4-octadecane triols equimolar (2S)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid is replaced, other steps are identical with embodiment 1, obtaining the amides compound for treating apoplexy, its chemical name is (2S)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2R, 3R)-2-amino octadecane-1,3-bis-alkylolamides.
Embodiment 17
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S, 3S, 4S)-2-amino-1 used, 3,4-octadecane triol equimolar (2S)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid is replaced, and other steps are identical with embodiment 1, prepare into (2S)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2S, 3R)-2-amino octadecane-1,3-bis-alkylolamides.
Embodiment 18
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S, 3S, 4S)-2-amino-1 used, 3,4-octadecane triol equimolar (2S)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid is replaced, and other steps are identical with embodiment 1, prepare into (2S)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2S, 3S)-2-amino octadecane-1,3-bis-alkylolamides.
Embodiment 19
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2S, 3S, 4S)-2-amino-1 used, 3,4-octadecane triol equimolar (2S)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid is replaced, and other steps are identical with embodiment 1, prepare into (2S)-3-(3,4-hydroxy phenyl)-2 hydroxy propanoic acid-(2R, 3S)-2-amino octadecane-1,3-bis-alkylolamides.
Embodiment 20
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2R)-3-(3 used, 4-hydroxy phenyl)-2 hydroxy propanoic acid equimolar (2R)-3-(2-fluoro-4,5-dihydroxy phenyl) replacement of-2 hydroxy propanoic acid, other steps are identical with embodiment 1, prepare into (2R)-3-(2-fluoro-4,5-dihydroxy phenyl)-2 hydroxy propanoic acid-(2S, 3S, 4S)-2-amino-1,3,4-octadecane three alkylolamides, gross production rate is 80%, and structural characterization data are: MS (m/z): 515.33 (100.0%), 516.33 (40.0%)；1HNMR (400MHz, CDCl3+ TMS) δ (ppm): 8.02 (s, 1H), 6.90 (s, 1H), 6.88 (s, 1H), 5.79 (s, 2H), 4.56 (m, 1H), 3.92 (m, 1H), 3.65 (m, 1H) 3.61 (m, 1H), 3.53 (m, 2H), 3.45 (m, 1H), 3.29 (m, 1H), 3.24 (m, 1H), 3.10 (m, 1H), 2.83 (m, 2H), 1.44 (m, 2H), 1.31 (m, 2H), 1.26-1.30 (m, 22H), 0.88 (t, 3H)；13CNMR (100MHz, CDCl3+ TMS) δ (ppm): 172.01,155.01,152.80 (C-F) 146.25,141.63,122.43,116.19,106.44,75.68,74.46,71.94,61.27,57.82,41.32,33.11,32.78,30.69,29.89,29.79,29.73,29.69,29.65,29.58,29.55,29.50,26.03,23.17,14.52.
Embodiment 21
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2R)-3-(3 used, 4-hydroxy phenyl)-2 hydroxy propanoic acid equimolar (2R)-2-(2-fluoro-4, 5-dihydroxy phenyl) replacement of-2-hydroxyacetic acid, other steps are identical with embodiment 1, prepare into (2R)-2-(2-fluoro-4, 5-dihydroxy phenyl)-2-hydroxyacetic acid-(2S, 3S, 4S)-2-amino-1, 3, 4-octadecane three alkylolamides, gross production rate is 85%, structural characterization data are: MS (m/z): 501.31 (100.0%), 502.31 (28.1%), 503.32 (2.7%), 503.31 (1.4%)；1HNMR (400MHz, CDCl3+ TMS) δ (ppm): 8.14 (s, 1H), 7.32 (s, 1H), 6.88 (s, 1H), 6.75 (s, 1H), 5.99 (s, 2H), 5.82 (s, 1H), 5.40 (m, 1H), 5.37 (m, 1H), 4.49 (m, 1H) 3.51 (m, 2H), 3.40 (m, 2H), 3.25 (m, 1H), 1.40 (m, 2H), 1.31 (m, 2H), 1.26-1.30 (m, 22H), 0.88 (t, 3H)；13CNMR (100MHz, CDCl3+ TMS) δ (ppm): 170.01,155.81,153.00 (C-F), 147.25,141.63,121.43,118.19,105.44,75.68,71.46,69.94,61.27,57.82,33.11,31.91,29.79,29.73,29.69,29.65,29.58,29.55,29.54,29.53,29.51,26.03,23.17,14.52.
Embodiment 22
To prepare the amides compound for treating apoplexy that structural formula is following, concrete preparation method is as follows:
In embodiment 1, (2R)-3-(3 used, 4-hydroxy phenyl) equimolar (2S)-2-(fluoro-4, the 5-dihydroxy phenyls of the 2-)-2-hydroxyacetic acid replacement of-2 hydroxy propanoic acid, other steps are identical with embodiment 1, prepare into (2S)-2-(2-fluoro-4,5-dihydroxy phenyl)-2-hydroxyacetic acid-(2S, 3S, 4S)-2-amino-1,3,4-octadecane three alkylolamides.
In order to prove beneficial effects of the present invention, the amides compound of embodiment 1,2,15,20,21 has been carried out performance test by inventor, and concrete test situation is as follows:
1, thrombolysis role in vitro
Test objective: observe the clot dissolution rate of compound 1,2,15,20,21, evaluates the thrombolytic effect of the compounds of this invention.
Laboratory animal: healthy rabbits, weight 2.2～2.5kg, male female dual-purpose.
Medicine and reagent: plasminogen (Nat'l Pharmaceutical & Biological Products Control Institute's offer).
Instrument: ALO-2104 type electronic balance (offer of Beijing Sai Duolisi instrument system company limited)；800B-33 type desk centrifuge (Anting Scientific Instrument Factory, Shanghai's offer).
Experimental technique: take the clot that 17 parts of 1mL Sanguis Leporis seu oryctolagi congeal into and be respectively charged in 17 test tubes weighed, rinse 60 minutes with normal saline, 6400 revs/min are centrifuged, precipitate 37 DEG C of vacuum dryings and weigh (W) after 6 hours.17 test tubes are separately added into normal saline (blank group), 2.5mg/mL compound 1,2,15,20,21, the compound 1,2,15,20,21 of 5.0mg/mL, 10.0mg/mL compound 1,2,15,20,21, the each 2mL of plasmin of 5mg/mL, 37 DEG C hatch 6 hours after, reacted suspension 6400 revs/min is centrifuged 5 minutes, precipitate 37 DEG C of vacuum dryings and weigh (G) after 6 hours, calculate the dissolution rate of clot according to following formula, result is in Table 1.
Dissolution rate=(W-G)/W × 100%
The thrombolysis role in vitro of table 1 compound 1,2,15,20,21
Experimental result: as can be seen from Table 1, the thrombolytic effect of 5.0mg/mL compound 1,2,15,20,21 and 5.0mg/mL plasmin is suitable.Compared with 2.5mg/mL group, 5.0mg/mL group and 10.0mg/mL group dissolution rate significantly improve, it is seen that compound 1,2,15,20,21 has thrombolytic effect.
2, rat cerebral tissue and function of nervous system's repair are promoted
Test objective: observe the compound 1,2,15,20,21 impact on MCAO rat behavior and brain infarction area, evaluates the compounds of this invention and promotes rat cerebral tissue and function of nervous system's repair.
Laboratory animal: male SpragueDawley (SD) rat 144, body weight 250～280g, ad lib and drinking-water.
Reagent reagent: compound 1,2,15,20,21,2,3,5-triphenyltetrazolium chloride (offer of TTC, Sigma-Aldrich company), dimethyl sulfoxide (offer of DMSO, Sigma-Aldrich company).
The preparation of medicine: take each 313mg of compound 1,2,15,20,21,625mg, 1350mg, add in the DMSO solution of the sodium chloride that 100mL mass fraction is 20% respectively, as low dose of sample (25mg/kg, low dosage), middle dose sample (50mg/kg, middle dosage), heavy dose of sample (100mg/kg, high dose).Sham operated rats: 0.9% sodium chloride injection；Model group: 0.9% sodium chloride injection；Model+DMSO group: the DMSO solution of 20% sodium chloride.
Experimental technique: male SD rat is randomly divided into sham operated rats, model group, model+DMSO group, the high, medium and low dosage group of compound 1,2,15,20,21, often group 8.Tremulous pulse inside and outside sham operated rats ligation common carotid artery, neck, does not insert line bolt；Each group is gastric infusion after animal is clear-headed all.The high, medium and low dosage group of compound 1,2,15,20,21 according to 25,50,100mg/kg gastric infusion.Sham operated rats, model group and model+DMSO organize gavage equivalent solvent.With 10% chloral hydrate intraperitoneal injection of anesthesia, 350mg/kg.Line brush is adopted to prepare MCAO models in rats, take neck median incision, expose right carotid, external carotid artery and internal carotid artery, ligation common carotid artery, external carotid artery, below common carotid artery bifurcated, 5mm cuts a kerf, inserts line bolt, degree of depth 18mm, and having obvious resistance sense, rat ischemia pulls out line bolt after 2 hours.Adopting laser Doppler flowmetry monitor cerebral blood flow, probe is fixed on 2mm after bregma, opens 2mm, reduce by more than 80% mark being successfully prepared for MCAO model with middle cerebral artery Cerebral Blood Flow Following by center line.
Neurological deficits: after animal is clear-headed, put back to raising, free diet.Respectively at regaining consciousness latter 24 hours, being administered latter 30 days, mono blind method is adopted to carry out neurological deficit score, standards of grading are improvement Garcia standards of grading: include autonomic activities, quadriplegia, climbing, limb motion, somesthesia and neural reflex six, each point 0,1,2,3 points, total score 18 points, mark is more low shows that damage is more serious.
TTC dyeing measures infarct size: be administered latter 30 days, puts to death and take cerebral tissue after having marked, and puts and puts into the section of brain groove in brine ice after 2 minutes, starts every 2mm coronalplane forward from lambdoid suture crotch and cuts a piece of, totally 6.37 DEG C, dye 15 minutes in 2%TTC, 4% paraformaldehyde fixes 24 hours, infarct size is calculated after taking pictures, white is infarction part, redness is normal structure part, application PhotoshopCS2 records pixel value, infarct volume=(left side normal structure-right side normal structure)/left side normal structure.
Statistical analysis: all data all adopt SPSS13.0 statistics software to be analyzed, measurement data represents with mean ± standard deviation, enumeration data represents with median ± range interquartile, employing one factor analysis of variance is compared between group, P < 0.05 thinks there is significant difference, and result of the test is in Table 2.
Table 2 compound 1,2,15,20,21 impact (n=8) on MCAO rat neurological deficit score and cerebral infarction rate
Compared with model group, 25mg/mL group, 50mg/mL group, 100mg/mL group neurological deficit score are obviously improved；Infarct size is obviously reduced.Compared with 25mg/mL group, 50mg/mL group and 100mg/mL group Neurological deficits improve；Infarct size reduces.Illustrate that the compounds of this invention 1,2,15,20,21 has promotion rat (MCAO) cerebral tissue and function of nervous system's repair.
Above-mentioned result of the test shows, the compounds of this invention has thrombolytic simultaneously, promotes rat (MCAO) cerebral tissue and function of nervous system's repair.
Claims (2)
1. the amides compound being used for treating apoplexy, it is characterised in that the structural formula of this compound is as follows:
R in formula1～R3Each independent representative hydrogen or fluorine；N is the integer of 0～4；*1、*2、*3Each independent expression is configured as R or S；R4Represent hydrogen or hydroxyl, and work as R4During representation hydroxy, *4Represent and be configured as R or S；R5Represent C1～C20Alkyl or C2～C20Thiazolinyl.
2. the preparation method of the amides compound for treating apoplexy described in a claim 1, it is characterised in that it is made up of following step:
(1) hydroxyl protection
With dimethyl sulfoxide for solvent, it is 1:3～3.3:3～3.3 in molar ratio by the alpha-hydroxy carboxylic acid compounds shown in Formulas I, acyl chlorides, pyridine, reacts at ambient temperature 1～3 hour, separate purified product, obtain the alpha-hydroxy carboxylic acid of the protection shown in Formula II；
R in formula1～R3Each independent representative hydrogen or fluorine, n is the integer of 0～4；*1Represent and be configured as R or S；R represents C1～C2Alkyl；
(2) synthesis of acyl ammonia
With oxolane for solvent; alpha-hydroxy for protection shown in Formula II carboxylic acid, dicyclohexylcarbodiimide, DMAP, formula III compound are reacted 4～6 hours at ambient temperature for 1:1～1.3:0.05～0.15:1～1.3 in molar ratio; separate purified product, obtain the amide shown in formula III；
* in formula2、*3Each independent expression is configured as R or S；R4Represent hydrogen or hydroxyl, and work as R4During representation hydroxy, *4Represent and be configured as R or S；R5Represent C1～C20Alkyl or C2～C20Thiazolinyl；
(3) hydrolysis
Amide shown in formula III is added in the oxolane that ammonia is saturated, react 3～5 hours at 30 DEG C, separate purified product, obtain the amides compound for treating apoplexy.
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| CN112830884A (en) * | 2019-11-22 | 2021-05-25 | 深圳市高盈医药科技开发有限公司 | Salvianic acid A derivative, preparation method and medical application thereof |
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