CN103819354B - The aminosallcylic acid 2-monoethanolamine ester derivative that one class N-benzyl replaces and pharmaceutical use thereof - Google Patents

The aminosallcylic acid 2-monoethanolamine ester derivative that one class N-benzyl replaces and pharmaceutical use thereof Download PDF

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CN103819354B
CN103819354B CN201410057481.XA CN201410057481A CN103819354B CN 103819354 B CN103819354 B CN 103819354B CN 201410057481 A CN201410057481 A CN 201410057481A CN 103819354 B CN103819354 B CN 103819354B
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hydroxyl
chloro
ethanol ester
benzyl
benzaminic acid
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CN103819354A (en
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李飞
张晶
戴鹏
赵婷
李婷
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Nanjing Medical University
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Nanjing Medical University
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Abstract

The aminosallcylic acid 2-monoethanolamine ester derivative that one class N-benzyl replaces and pharmaceutical use thereof, structure meets general formula such medicine had both had the distribution of good central nervous system, and had water-soluble preferably, was conducive to pharmaceutical preparation, absorbed rapidly, had good oral administration biaavailability, have good drug effect to cerebral infarction, neurogenic pain.Can be used for the medicine preparing the nerve degenerative diseases such as treatment cerebral apoplexy, neurogenic pain and senile dementia.

Description

The aminosallcylic acid 2-monoethanolamine ester derivative that one class N-benzyl replaces and pharmaceutical use thereof
Technical field
The invention belongs to pharmacy field, the aminosallcylic acid 2-monoethanolamine ester derivative providing a class N-benzyl to replace and pharmaceutical use thereof.
Background technology
Cerebral infarction (cerebral infarction) has the features such as high mortality, high disability rate, high relapse rate, serious harm human health.Because cerebral tissue fine structure is complicated, responsive especially and fragile to hypoxic-ischemic damage, the medicine of rare determined curative effect clinically so far.Research display: under cerebral ischemia condition, excitatory amino acid (as L-glutamic acid) excessively discharges, cause NMDA acceptor (NMDAR) excessive activation, by approach pathologic release nitrogen protoxide (the NO) (Science of NMDAR-PSD-95-nNOS, 1999,284,1845-1848).NO itself has stronger oxidisability, when discharging too much or remove insufficiency of function, and can coup injury peripheral cell surface lipids and internal structure.On the other hand, a large amount of oxygen anion free radical (O is generated in cerebral ischemia re-pouring process 2 -.), and NO reaction generates ultra-oxygen anion free radical (ONOO -.), the latter, as stable Strong oxdiative thing, will cause even more serious damage (Cell.Mol.Life Sci., 2004,61,657-668) to cell.Therefore, it is the critical event that neuronal excitability toxicity occurs that the nNOS of NMDAR mediation activates, many medicines are developed around these two target molecules, because NMDAR and nNOS all has very important physiological function, severe side effect (Curr.Opin.Pharmacol. is often caused to their direct intervention, 2006,6,53-60.).If not direct intervention NMDAR or nNOS, only block the coupling of NMDAR and PSD-95 or nNOS and PSD-95, the pathologic release of NO after can suppressing cerebral ischemia under the prerequisite not affecting NMDAR and nNOS physiological function, the anti-safely and effectively brain soldier medicine not having apparent side effect may be obtained, and the coupling of nNOS and PSD-95 is in the downstream of whole signal path, be even more ideal drug target (Neuropharmacology, 2003,45,738-754).
NNOS-PSD-95 uncoupling agents Bian aniline derivative 4-N-(2-hydroxyl-3; 5-dichloro Bian Ji) aminosallcylic acid (ZL006); can under the prerequisite not affecting NMDAR, nNOS physiological function; reduce the pathologic release of the NO of NMDAR mediation; obvious neuroprotective is demonstrated to the neural cell injury under L-glutamic acid stimulates; improve middle cerebral artery occlusion (MCAO) Reperfu-sion animal nerve defect symptom, reduce infarct volume (Nature Medicine2010; 16,1439 – 1443).ZL006 avoids the side effect such as learning memory disorder, dystropy that direct intervention NMDAR, nNOS may cause, there is better security, the treatment for diseased associated with cerebral ischemia injury significant (Nature.Rev.Neur., 2011,7,61.).
Neurogenic pain is a kind of " pain that infringement or disease directly cause after involving somatosensory system ".Epidemiology survey shows have the people of 7% ~ 8% to live through the puzzlement (Pain, 2008,136:380-387) of neurogenic pain in life.Be a kind of refractory and the mankind had to disease (the Physical Medicine and Rehabilitation Clinics of NorthAmerica2013 of significant damage, 24,507-520), neurogenic pain is a lasting process, the state of an illness may occur repeatedly, needs long-term treatment.The pharmacological agenies such as general first-selected lyrica (pregebalin) and tricyclic antidepressant.
In lyrica and central nervous system, there is high affinity in α 2-δ site (ancillary subunit of valtage-gated calcium channel).Lyrica is the structural derivative of inhibitory neurotransmitter γ-aminobutyric acid (GABA), but it is not directly and GABAa, GABAb or benzodiazepine receptors bind, do not increase the neuronic GABAa reaction of vitro culture, do not change GABA concentration in rat brain, GABA is absorbed or degrades without acute effect.Pregebalin is owing to acting on central nervous system, and untoward reaction is more, and tricyclic antidepressant exists more central nervous system untoward reaction equally.
Experiment shows, by micromolecular compound and PSD-95 end similar polypeptide interference PSD-95 and nNOS coupling, significantly can alleviate acute Thermal allodynia and the quick phenomenon of chronic machinery pain (the J Pain Res. of rodent, 2012,5:1-6), nNOS-PSD-95 uncoupling agents IC87201, show it at rodent pain model and there is the mechanical bitterly quick and Thermal allodynia effect of significant suppression, analgesic (the Brit.J.Pharmacol.2009 with brand-new mechanism of action may be developed into, 158,494-506).
There is a water-wet side, a hydrophobic side in ZL006 molecule, the suitable modification of the water-wet side in ZL006 molecule and hydrophobic side linking group, still can keep its anti-cerebral apoplexy effect (Chinese invention patent application: 201210403997.6).The action target spot of nNOS-PSD-95 uncoupling agents is in central nervous system, and such medicine needs to have the distribution of good central nervous system.The nNOS-PSD-95 uncoupling agentss such as ZL006 have higher wetting ability, are unfavorable for oral absorption and central nervous system distribution.ZL006 molecule and alcohol are reacted into ester, although the distribution of medicine in central nervous system can be increased, because poorly water-soluble, have impact on oral absorption, be unfavorable for again making preparation.ZL006 equimolecular and 2-monoethanolamine and analogue react by the present inventor, the aminosallcylic acid 2-monoethanolamine ester derivative that the class N-benzyl obtained replaces, both there is the distribution of good central nervous system, and have certain water-soluble, absorb rapidly, there is good bioavailability, effectively oral, to cerebral infarction, neurogenic pain, there is good drug effect.
Summary of the invention
The technical problem solved: the aminosallcylic acid 2-monoethanolamine ester derivative that a class N-benzyl replaces, both there is the distribution of good central nervous system, and have certain water-soluble, absorb rapidly, there is good bioavailability, effectively oral, to cerebral infarction, neurogenic pain, there is good drug effect.Can be used for the medicine preparing the nerve degenerative diseases such as treatment cerebral apoplexy, neurogenic pain and senile dementia.
Technical scheme:
The aminosallcylic acid 2-monoethanolamine ester derivative that one class N-benzyl replaces, structure meets general formula (I)
Wherein R 1for-Cl ,-CH 3,-Br or-C (CH 3) 3; R 2for-H ,-CH 3or-COCH 3;
R 3, R 4be-C independently of one another 2h 5; Or connect together, form ring texture with N now R 3-R 4for:
-CH 2cH 2cH 2cH 2-,-CH 2cH 2cH 2cH 2cH 2-,-CH 2cH 2o CH 2cH 2-or
-CH 2CH 2N(CH 3)CH 2CH 2-。
The preferred structure of above-claimed cpd is:
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester,
2-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester,
2-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-N, N-diethylin) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester,
2-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester,
2-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-morpholinyl) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester,
2-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester,
2-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-morpholinyl) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester,
2-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester,
2-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-piperidyl) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester,
2-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester,
2-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-piperidyl) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester,
2-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester,
2-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-pyrryl) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester,
2-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester,
2-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-pyrryl) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-2-pyrrolylethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-N, N-diethylin),
2-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol,
2-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-N, N-diethylin) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester,
2-methoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester,
2-methoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester or
2-methoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester.
The aminosallcylic acid 2-monoethanolamine ester derivative that above-mentioned N-benzyl replaces or its pharmacy acceptable salt remove the application in the medicine be coupled between nNOS and PSD-95 albumen in preparation.
The aminosallcylic acid 2-monoethanolamine ester derivative that above-mentioned N-benzyl replaces or the application of its pharmacy acceptable salt in preparation treatment cerebral apoplexy, chronic pathological pain or nerve degenerative diseases medicine.
Remove the medicine be coupled between nNOS and PSD-95 albumen, effective constituent is aminosallcylic acid 2-monoethanolamine ester derivative or its pharmacy acceptable salt of described N-benzyl replacement.
Treatment cerebral apoplexy, chronic pathological pain or nerve degenerative diseases medicine, effective constituent is aminosallcylic acid 2-monoethanolamine ester derivative or its pharmacy acceptable salt of described N-benzyl replacement.
Beneficial effect: such medicine had both had the distribution of good central nervous system, and had water-soluble preferably, was conducive to pharmaceutical preparation, absorbed rapidly, had good oral administration biaavailability, have good drug effect to cerebral infarction, neurogenic pain.Can be used for the medicine preparing the nerve degenerative diseases such as treatment cerebral apoplexy, neurogenic pain and senile dementia.
Accompanying drawing explanation
Fig. 1 is the amount effect curve of oral ZL006-105 to the analgesic activity of mouse Nerve pathological pain.Mechanical irritation contracts sufficient threshold of reaction baseline in the preoperative mensuration of SNL.Mean value ± standard error, n=10 ~ 11, * P<0.5, * * P<0.1, * * * P<0.001;
Fig. 2 is 2 hours analgesic activities to mouse Nerve pathological pain after partial target compound 3mg/kg administration.Mean value ± standard error, n=8, * P<0.5, * * P<0.1, * * * P<0.001;
Fig. 3 is the analgesic activity of oral ZL006-105 to mouse Nerve pathological pain.(A) ZL006-105 is to the Time-activity-curve of the analgesic activity of mouse Nerve pathological pain.(B) area under curve of two treated animal Time-activity-curves, is standardized as the percentage of solvent control.Mean value ± standard error, n=8, * * * P<0.001;
Fig. 4 is the cerebral protection schematic diagram of tail intravenously administrable ZL006-118 to rat acute focal cerebral ischemia, * P<0.05; Wherein (A) is the section photo of rat acute focal cerebral ischemia dyeing hindbrain sheet, and (B) is rat acute focal cerebral ischemia infarct size per-cent
Fig. 5 is that tail intravenously administrable ZL006-118 affects schematic diagram, * P<0.05 to rat acute focal cerebral ischemia neurological handicap symptom.
Embodiment
The following examples can make those skilled in the art comprehensively can understand the present invention, but do not limit the present invention in any way.
The synthesis of target compound:
Embodiment 12-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester (ZL006-101)
Ethanol 50mL is added in 100mL eggplant-shape bottle, 2-acetoxyl group-PABA-(2-N, N-diethylin) ethanol ester 2.78g, add 3-chloro-5-tertiary butyl salicylic aldehyde 2.10g, be warming up to reflux temperature, reflux 1 hour, then cooling leaves standstill under 0 degree Celsius, separate out red solid, filter to obtain red solid 3.38g, productive rate 71.6%.In 100mL eggplant-shape bottle, add ethanol 50mL, sodium borohydride 0.5g and obtained red solid, stirring reaction 2 hours, solution is clarified, and drips water 40mL, stirs half an hour, has lime color substance to separate out, filter to obtain pale powder 2.82g, productive rate 80.4%. 1H NMR(δ,ppm,300MHz):1.11-1.13(t,J=7.2Hz,6H),1.18（s,9H），2.66-2.68(q,J=7.2Hz,4H),2.88-2.30(t,J=6.2Hz,2H),4.27(s,2H),4.40-4.42(t,J=6.2Hz,2H),5.99(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.18（s,1H），7.21（s,1H）,7.54-7.56（d，J=8.85Hz,1H）。
Embodiment 22-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester (ZL006-102)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-N, N-diethylin) ethanol ester and 3,5-dichloro-salicylaldehyde for Material synthesis, off-white powder, productive rate 81.2%. 1H NMR(δ,ppm,300MHz):1.11-1.13(t,J=7.2Hz,6H),2.18(s,3H),2.67(q,J=7.2Hz,4H),2.89(t,J=6.2Hz,2H),4.30(s,2H),4.40-4.42(t,J=6.2Hz,2H),5.95(s,1H),
6.23-6.26(dd,J=8.8Hz,2.0Hz),7.10-7.11(d,J=2.5Hz),7.39-7.40(d,J=2.5Hz),7.54-7.56（d，J=8.85Hz,1H）。
Embodiment 32-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-N, N-diethylin) ethanol ester (ZL006-103)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-N, N-diethylin) ethanol ester and the chloro-5-bromosalicylaldehyde of 3-for Material synthesis, off-white powder, productive rate 80.6%. 1H NMR(δ,ppm,300MHz):1.12(t,J=7.2Hz,6H),2.67(q,J=7.2Hz,4H),2.89(t,J=6.2Hz,2H),4.41(t,J=6.2Hz,2H),4.30(s,2H),5.95(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.24-7.25（d，J=2.5Hz,1H），7.47-7.48（d,J=2.5Hz,1H）,7.54-7.56（d,J=8.85Hz,1H）。
Embodiment 42-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester (ZL006-104)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-N, N-diethylin) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 82.2%. 1H NMR(δ,ppm,300MHz):1.12(t,J=7.2Hz,6H),2.16（s,3H），2.67(q,J=7.2Hz,4H),2.89(t,J=6.2Hz,2H),4.41(t,J=6.2Hz,2H),4.25(s,2H),5.95(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),6.93(s,1H),7.08(s,1H),7.54-7.56(d,J=8.85Hz,1H）。
Embodiment 52-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester (ZL006-105)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-morpholinyl) ethanol ester and 3-chloro-5-tertiary butyl salicylic aldehyde for Material synthesis, off-white powder, productive rate 80.8%. 1H NMR(δ,ppm,300MHz):1.18（s,9H），2.63-2.74(br,4H),2.88-2.90(t,J=6.2Hz,2H),3.73-3.75(t,J=4.5Hz),4.27(s,2H),4.41(t,J=6.2Hz,2H),
5.99(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.18（s,1H），7.21（s,1H）,7.54-7.56（d，J=8.8Hz,1H）。
Embodiment 62-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid--(2-morpholinyl) ethanol ester (ZL006-106)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-morpholinyl) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 78.7%. 1H NMR(δ,ppm,300MHz):2.18(s,3H),2.63-2.74(br,4H),2.89(t,J=6.2Hz,2H),3.74(t,J=4.5Hz),4.30(s,2H),5.95(s,1H),4.41(t,J=6.2Hz,2H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.10-7.11(d,J=2.5Hz),7.39-7.40(d,J=2.5Hz),7.54-7.56（d，J=8.8Hz,1H）。
Embodiment 72-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid--(2-morpholinyl) ethanol ester (ZL006-107)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-morpholinyl) ethanol ester and the chloro-5-bromosalicylaldehyde of 3-for Material synthesis, off-white powder, productive rate 80.1%. 1HNMR(δ,ppm,300MHz):2.63-2.74(br,4H),2.89(t,J=6.2Hz,2H),3.74(t,J=4.5Hz),4.41(t,J=6.2Hz,2H),4.30(s,2H),5.95(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.24-7.25(d,J=2.5Hz,1H),7.47-7.48(d,J=2.5Hz,1H),7.54-7.56(d,J=8.85Hz,1H）。
Embodiment 82-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid--(2-morpholinyl) ethanol ester (ZL006-108)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-morpholinyl) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 81.2%. 1HNMR(δ,ppm,300MHz):2.16（s,3H），2.63-2.74(br,4H),2.89(t,J=6.2Hz,2H),3.74(t,J=4.5Hz),4.25(s,2H),4.41(t,J=6.2Hz,2H),5.95(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),6.93（s,1H），7.08（s,1H）,7.54-7.56（d，J=8.85Hz,1H）。
Embodiment 92-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid--(2-morpholinyl) ethanol ester (ZL006-109)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-morpholinyl) ethanol ester and 3-chloro-5-tertiary butyl salicylic aldehyde for Material synthesis, off-white powder, productive rate 80.3%. 1HNMR(δ,ppm,300MHz):1.18（s,9H），2.63-2.74(br,4H),2.89(t,J=6.2Hz,2H),3.74(t,J=4.5Hz),4.27(s,2H),4.41(t,J=6.2Hz,2H),5.99(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.18(s,1H),7.21(s,1H),7.45-7.49(d,J=8.85Hz,1H)。
Embodiment 102-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid--(2-morpholinyl) ethanol ester (ZL006-110)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-morpholinyl) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 79.8%. 1HNMR(δ,ppm,300MHz):2.63-2.74(br,4H),2.89(t,J=6.2Hz,2H),3.74(t,J=4.5Hz),4.30（s,2H），4.41(t,J=6.2Hz,2H),5.94（s,1H），6.21-6.24（dd,J=2.1Hz,8.8Hz,1H），7.10-7.11（d，J=2.5Hz,1H），7.39-7.40（d,J=2.5Hz,1H）,7.50-7.52（d,J=8.85Hz,1H）。
Embodiment 112-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-morpholinyl) ethanol ester (ZL006-111)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-morpholinyl) ethanol ester and the chloro-5-bromosalicylaldehyde of 3-for Material synthesis, off-white powder, productive rate 80.9%. 1HNMR(δ,ppm,300MHz):2.63-2.74(br,4H),2.89(t,J=6.2Hz,2H),3.74(t,J=4.5Hz),4.30（s,2H），4.41(t,J=6.2Hz,2H),5.94（s,1H），6.21-624（dd,J=2.1Hz,8.8Hz,1H），7.24-7.25（d，J=2.5Hz,1H），7.47-7.48（d,J=2.5Hz,1H）,7.50-7.52（d,J=8.85Hz,1H）。
Embodiment 122-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester (ZL006-112)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-morpholinyl) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 80.2%. 1HNMR(δ,ppm,300MHz):2.16（s,3H），2.63-2.74(br,4H),2.89(t,J=6.2Hz,2H),3.74(t,J=4.5Hz),4.25(s,2H),4.41(t,J=6.2Hz,2H),5.94(s,1H),6.21-6.24(dd,J=8.8Hz,2.0Hz),6.93（s,1H），7.08（s,1H）,7.50-7.52（d，J=8.8Hz,1H）。
Embodiment 132-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester (ZL006-113)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-N-methylpiperazine base) ethanol ester and 3-chloro-5-tertiary butyl salicylic aldehyde for Material synthesis, off-white powder, productive rate 78.6%. 1HNMR(δ,ppm,300MHz):1.18（s,9H），2.30(s,3H),2.40-2.60(br,8H),2.89(t,J=6.2Hz,2H),4.27(s,2H),4.41(t,J=6.2Hz,2H),5.99(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.18（s,1H），7.21（s,1H）,7.54-7.56（d，J=8.85Hz,1H）。
Embodiment 142-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester (ZL006-114)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-N-methylpiperazine base) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 80.4%. 1HNMR(δ,ppm,300MHz):2.18(s,3H),2.30(s,3H),2.40-2.60(br,8H),2.89(t,J=6.2Hz,2H),4.30(s,2H),4.41(t,J=6.2Hz,2H),5.95(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.10-7.11(d,J=2.5Hz),7.39-7.40(d,J=2.5Hz),7.54-7.56d,J=8.85Hz,1H）。
Embodiment 152-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-N-methylpiperazine base) ethanol ester (ZL006-115)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-N-methylpiperazine base) ethanol ester and the chloro-5-bromosalicylaldehyde of 3-for Material synthesis, off-white powder, productive rate 81.5%. 1HNMR(δ,ppm,300MHz):2.30(s,3H),2.40-2.60(br,8H),2.89(t,J=6.2Hz,2H),4.30(s,2H),4.41(t,J=6.2Hz,2H),5.95(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.24-7.25（d，J=2.5Hz,1H），7.47-7.48（d,J=2.5Hz,1H）,7.54-7.56（d，J=8.85Hz,1H）。
Embodiment 162-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester (ZL006-116)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-N-methylpiperazine base) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 81.0%. 1HNMR(δ,ppm,300MHz):2.16（s,3H），2.30(s,3H),2.40-2.60(br,8H),2.89(t,J=6.2Hz,2H),4.25(s,2H),4.41(t,J=6.2Hz,2H),5.95(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),6.93（s,1H），7.08（s,1H）,7.54-7.56（d，J=8.85Hz,1H）。
Embodiment 172-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester (ZL006-117)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-N-methylpiperazine base) ethanol ester and 3-chloro-5-tertiary butyl salicylic aldehyde for Material synthesis, off-white powder, productive rate 78.6%. 1HNMR(δ,ppm,300MHz):1.18（s,9H），2.30(s,3H),2.40-2.60(br,8H),2.89(t,J=6.2Hz,2H),4.27(s,2H),4.41(t,J=6.2Hz,2H),5.99(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.18（s,1H），7.21（s,1H）,7.45-7.49（d，J=8.85Hz,1H）。
Embodiment 182-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester (ZL006-118)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-N-methylpiperazine base) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 80.4%. 1HNMR(δ,ppm,300MHz):2.30(s,3H),2.40-2.60(br,8H),2.89(t,J=6.2Hz,2H),4.30（s,2H），4.41(t,J=6.2Hz,2H),5.94（s,1H），6.21-624（dd,J=8.8Hz,2.1Hz,1H），7.10-7.11（d，J=2.5Hz,1H），7.39-7.40（d,J=2.5Hz,1H）,7.50-7.52（d,J=8.8Hz,1H）。
Embodiment 192-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-N-methylpiperazine base) ethanol ester (ZL006-119)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-N-methylpiperazine base) ethanol ester and the chloro-5-bromosalicylaldehyde of 3-for Material synthesis, off-white powder, productive rate 81.5%. 1HNMR(δ,ppm,300MHz):2.30(s,3H),2.40-2.60(br,8H),2.89(t,J=6.2Hz,2H),4.30（s,2H），4.41(t,J=6.2Hz,2H),5.94（s,1H），6.21-6.24（dd,J=2.1Hz,8.8Hz,1H），7.24-7.25（d，J=2.5Hz,1H），7.47-7.48（d,J=2.5Hz,1H）,7.50-7.52（d,J=8.85Hz,1H）。
Embodiment 202-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester (ZL006-120)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-N-methylpiperazine base) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 81.0%. 1HNMR(δ,ppm,300MHz):2.16（s,3H），2.30(s,3H),2.40-2.60(br,8H),2.89(t,J=6.2Hz,2H),4.25(s,2H),4.41(t,J=6.2Hz,2H),5.94(s,1H),6.21-6.24(dd,J=8.8Hz,2.0Hz),6.93（s,1H）,7.08（s,1H）,7.50-7.52（d，J=8.8Hz,1H）。
Embodiment 212-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester (ZL006-121)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-piperidyl) ethanol ester and 3-chloro-5-tertiary butyl salicylic aldehyde for Material synthesis, off-white powder, productive rate 80.9%. 1HNMR(δ,ppm,300MHz):1.18（s,9H），1.37-1.47(m,2H),1.51-1.59(m,4H),2.30-2.40(br,2H),2.52-2.62(br,2H),2.89(t,J=6.2Hz,2H),4.27(s,2H),4.41(t,J=6.2Hz,2H),5.99(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.18（s,1H），7.21（s,1H）,7.54-7.56（d，J=8.85Hz,1H）。
Embodiment 222-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester (ZL006-122)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-piperidyl) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 81.6%. 1HNMR(δ,ppm,300MHz):1.37-1.47(m,2H),1.51-1.59(m,4H),2.18(s,3H),2.30-2.40(br,2H),2.52-2.62(br,2H),2.89(t,J=6.2Hz,2H),4.41(t,J=6.2Hz,2H),4.30(s,2H),5.95(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.10-7.11(d,J=2.5Hz),7.39-7.40(d,J=2.5Hz),7.54-7.56（d，J=8.85Hz,1H）。
Embodiment 232-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-piperidyl) ethanol ester (ZL006-123)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-piperidyl) ethanol ester and the chloro-5-bromosalicylaldehyde of 3-for Material synthesis, off-white powder, productive rate 80.3%. 1HNMR(δ,ppm,300MHz):1.37-1.47(m,2H),1.51-1.59(m,4H),2.30-2.40(br,2H),2.52-2.62(br,2H),2.89(t,J=6.2Hz,2H),4.30(s,2H),4.41(t,J=6.2Hz,2H),5.95(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.24-7.25（d，J=2.5Hz,1H），7.47-7.48（d,J=2.5Hz,1H）,7.54-7.56（d，J=8.85Hz,1H）。
Embodiment 242-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester (ZL006-124)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-piperidyl) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 81.6%. 1HNMR(δ,ppm,300MHz):1.37-1.47(m,2H),1.51-1.59(m,4H),2.16（s,3H），2.30-2.40(br,2H),2.52-2.62(br,2H),2.89(t,J=6.2Hz,2H),4.25(s,2H),4.41(t,J=6.2Hz,2H),5.95(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),6.93（s,1H），7.08（s,1H）,7.54-7.56（d，J=8.85Hz,1H）。
Embodiment 252-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester (ZL006-125)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-piperidyl) ethanol ester and 3-chloro-5-tertiary butyl salicylic aldehyde for Material synthesis, off-white powder, productive rate 82.2%. 1HNMR(δ,ppm,300MHz):1.18（s,9H），1.37-1.47(m,2H),1.51-1.59(m,4H),2.30-2.40(br,2H),2.52-2.62(br,2H),2.89(t,J=6.2Hz,2H),4.27(s,2H),4.41(t,J=6.2Hz,2H),5.99(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.18（s,1H），7.21（s,1H）,7.45-7.49（d，J=8.8Hz,1H）。
Embodiment 262-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester (ZL006-126)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-piperidyl) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 80.4%. 1HNMR(δ,ppm,300MHz):1.37-1.47(m,2H),1.51-1.59(m,4H),2.30-2.40(br,2H),2.52-2.62(br,2H),2.89(t,J=6.2Hz,2H),4.30（s,2H），4.41(t,J=6.2Hz,2H),5.94（s,1H），6.21-624（dd,J=2.1Hz,8.8Hz,1H），7.10-7.11（d，J=2.5Hz,1H），7.39-7.40（d,J=2.5Hz,1H）,7.50-7.52（d,J=8.85Hz,1H）。
Embodiment 272-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-piperidyl) ethanol ester (ZL006-127)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-piperidyl) ethanol ester and the chloro-5-bromosalicylaldehyde of 3-for Material synthesis, off-white powder, productive rate 80.9%. 1HNMR(δ,ppm,300MHz):1.37-1.47(m,2H),1.51-1.59(m,4H),2.30-2.40(br,2H),2.52-2.62(br,2H),2.89(t,J=6.2Hz,2H),4.30（s,2H），4.41(t,J=6.2Hz,2H),5.94（s,1H），6.21-624（dd,J=2.1Hz,8.8Hz,1H），7.24-7.25（d，J=2.5Hz,1H），7.47-7.48（d,J=2.5Hz,1H）,7.50-7.52（d,J=8.85Hz,1H）。
Embodiment 282-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester (ZL006-128)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-piperidyl) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 78.6%. 1HNMR(δ,ppm,300MHz):1.37-1.47(m,2H),1.51-1.59(m,4H),2.16(s,1H),2.30-2.40(br,2H),2.52-2.62(br,2H),2.89(t,J=6.2Hz,2H),4.25(s,2H),4.41(t,J=6.2Hz,2H),5.94(s,1H),6.21-6.24(dd,J=8.8Hz,2.0Hz),6.93（s,1H），7.08（s,1H）,7.50-7.52（d，J=8.8Hz,1H）。
Embodiment 292-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester (ZL006-129)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-pyrryl) ethanol ester and 3-chloro-5-tertiary butyl salicylic aldehyde for Material synthesis, off-white powder, productive rate 77.9%. 1HNMR(δ,ppm,300MHz):1.18（s,9H），1.78-1.85(br,4H),2.68-2.77(br,4H),2.89(t,J=6.2Hz,2H),4.41(t,J=6.2Hz,2H),4.27(s,2H),5.99(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.18（s,1H），7.21（s,1H）,7.54-7.56（d，J=8.85Hz,1H）。
Embodiment 302-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-2-(2-pyrryl) ethanol ester (ZL006-130)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-pyrryl) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 78.2%. 1HNMR(δ,ppm,300MHz):1.78-1.85(br,4H),2.68-2.77(br,
4H),2.89(t,J=6.2Hz,2H),4.41(t,J=6.2Hz,2H),2.18(s,3H),4.30(s,2H),5.95(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.10-7.11(d,J=2.5Hz),7.39-7.40(d,J=2.5Hz),7.54-7.56（d，J=8.85Hz,1H）。
Embodiment 312-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-2-pyrrolylethanol ester (ZL006-131)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-pyrryl) ethanol ester and the chloro-5-bromosalicylaldehyde of 3-for Material synthesis, off-white powder, productive rate 76.8%. 1HNMR(δ,ppm,300MHz):1.78-1.85(br,4H),2.68-2.77(br,4H),2.89(t,J=6.2Hz,2H),4.30(s,2H),4.41(t,J=6.2Hz,2H),5.95(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.24-7.25（d，J=2.5Hz,1H），7.47-7.48（d,J=2.5Hz,1H）,7.54-7.56（d，J=8.8Hz,1H）。
Embodiment 322-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester (ZL006-132)
With reference to the method for embodiment 1, with 2-acetoxyl group-PABA-(2-pyrryl) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 78.1%. 1HNMR(δ,ppm,300MHz):1.78-1.85(br,4H),2.16（s,3H），2.68-2.77(br,4H),2.89(t,J=6.2Hz,2H),4.25(s,2H),4.41(t,J=6.2Hz,2H),5.95(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),6.93（s,1H），7.08（s,1H）,7.54-7.56（d，J=8.85Hz,1H）。
Embodiment 332-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester (ZL006-133)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-pyrryl) ethanol ester and 3-chloro-5-tertiary butyl salicylic aldehyde for Material synthesis, off-white powder, productive rate 77.9%. 1HNMR(δ,ppm,300MHz):1.18（s,9H），1.78-1.85(br,4H),2.68-2.77(br,4H),2.89(t,J=6.2Hz,2H),4.27(s,2H),4.41(t,J=6.2Hz,2H),5.99(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.18（s,1H），7.21（s,1H）,7.45-7.49（d，J=8.85Hz,1H）。
Embodiment 342-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester (ZL006-134)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-pyrryl) ethanol ester and 3-chloro-5-tertiary butyl salicylic aldehyde for Material synthesis, off-white powder, productive rate 77.9%. 1HNMR(δ,ppm,300MHz):1.78-1.85(br,4H),2.68-2.77(br,4H),2.89(t,J=6.2Hz,2H),4.30（s,2H），4.41(t,J=6.2Hz,2H),5.94（s,1H），6.21-624（dd,J=2.1Hz,8.8Hz,1H），7.10-7.11（d，J=2.5Hz,1H），7.39-7.40（d,J=2.5Hz,1H）,7.50-7.52（d,J=8.85Hz,1H）。
Embodiment 352-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-pyrryl) ethanol ester (ZL006-135)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-pyrryl) ethanol ester and the chloro-5-bromosalicylaldehyde of 3-for Material synthesis, off-white powder, productive rate 76.8%. 1HNMR(δ,ppm,300MHz):1.78-1.85(br,4H),2.68-2.77(br,4H),2.89(t,J=6.2Hz,2H),4.41(t,J=6.2Hz,2H),4.30（s,2H），5.94（s,1H），6.21-624（dd,J=2.1Hz,8.8Hz,1H），7.24-7.25（d，J=2.5Hz,1H），7.47-7.48（d,J=2.5Hz,1H）,7.50-7.52（d,J=8.85Hz,1H）。
Embodiment 362-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester (ZL006-136)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-pyrryl) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 78.1%. 1HNMR(δ,ppm,300MHz):1.78-1.85(br,4H),2.16（s,3H），2.68-2.77(br,4H),2.89(t,J=6.2Hz,2H),4.25(s,2H),4.41(t,J=6.2Hz,2H),5.94(s,1H),6.21-6.24(dd,J=8.8Hz,2.0Hz),6.93（s,1H），7.08（s,1H）,7.50-7.52（d，J=8.8Hz,1H）。
Embodiment 372-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester (ZL006-137)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-N, N-diethylin) ethanol ester and 3-chloro-5-tertiary butyl salicylic aldehyde for Material synthesis, off-white powder, productive rate 78.4%. 1HNMR(δ,ppm,300MHz):1.10-1.12(t,J=7.2Hz,6H),1.18（s,9H），2.66-2.68(q,J=7.2Hz,4H),2.88-2.89(t,J=6.2Hz,2H),4.41-4.43(t,J=6.2Hz,2H),4.27(s,2H),5.99(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.18（s,1H），7.21（s,1H）,7.45-7.49（d，J=8.85Hz,1H）。
Embodiment 382-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester (ZL006-138)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-N, N-diethylin) ethanol ester and 3,5-dichloro-salicylaldehyde for Material synthesis, off-white powder, productive rate 79.2%. 1HNMR(δ,ppm,300MHz):1.12(t,J=7.2Hz,6H),2.67(q,J=7.2Hz,4H),2.89(t,J=6.2Hz,2H),4.30（s,2H），4.41(t,J=6.2Hz,2H),5.94（s,1H），6.21-624（dd,J=2.1Hz,8.8Hz,1H），7.10-7.11（d，J=2.5Hz,1H），7.39-7.40（d,J=2.5Hz,1H）,7.50-7.52（d,J=8.85Hz,1H）。
Embodiment 392-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-N, N-diethylin) ethanol ester (ZL006-139)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-N, N-diethylin) ethanol ester and the chloro-5-bromosalicylaldehyde of 3-for Material synthesis, off-white powder, productive rate 76.4%. 1HNMR(δ,ppm,300MHz):1.12(t,J=7.2Hz,6H),2.67(q,J=7.2Hz,4H),2.89(t,J=6.2Hz,2H),4.30（s,2H），4.41(t,J=6.2Hz,2H),5.94（s,1H），6.21-624（dd,J=2.1Hz,8.8Hz,1H），7.24-7.25（d，J=2.5Hz,1H），7.47-7.48（d,J=2.5Hz,1H）,7.50-7.52（d,J=8.85Hz,1H）。
Embodiment 402-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester (ZL006-140)
With reference to the method for embodiment 1, with 2-hydroxy-4-aminobenzoic acid-(2-N, N-diethylin) ethanol ester and 3-chloro-5-cresotinic acid aldehyde for Material synthesis, off-white powder, productive rate 81.6%. 1HNMR(δ,ppm,300MHz):1.10-1.12(t,J=7.2Hz,6H),2.16（s,3H），2.66-2.68(q,J=7.2Hz,4H),2.88-2.90(t,J=6.2Hz,2H),4.41(t,J=6.2Hz,2H),4.24(s,2H),5.94(s,1H),6.21-6.24(dd,J=8.8Hz,2.0Hz),6.93（s,1H），7.08（s,1H）,7.50-7.52（d，J=8.8Hz,1H）。
Embodiment 412-methoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester (ZL006-141)
With reference to the method for embodiment 1, with 2-methoxyl group-PABA-(2-N, N-diethylin) ethanol ester and 3,5-dichloro-salicylaldehyde for Material synthesis, off-white powder, productive rate 78.4%. 1H NMR(δ,ppm,300MHz):1.11-1.13(t,J=7.2Hz,6H),3.38(s,3H),2.67(q,J=7.2Hz,4H),2.89(t,J=6.2Hz,2H),4.30(s,2H),4.40-4.42(t,J=6.2Hz,2H),5.95(s,1H),
6.23-6.26(dd,J=8.8Hz,2.0Hz),7.10-7.11(d,J=2.5Hz),7.39-7.40(d,J=2.5Hz),7.54-7.56（d，J=8.85Hz,1H）。
Embodiment 422-methoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester (ZL006-142)
With reference to the method for embodiment 1, with 2-methoxyl group-PABA-(2-morpholinyl) ethanol ester and 3,5-dichloro-salicylaldehyde for Material synthesis, off-white powder, productive rate 80.1%. 1H NMR(δ,ppm,300MHz):2.63-2.74(br,4H),2.89(t,J=6.2Hz,2H),3.74(t,J=4.5Hz),3.88(s,3H),4.30(s,2H),5.95(s,1H),4.41(t,J=6.2Hz,2H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.10-7.11(d,J=2.5Hz),7.39-7.40(d,J=2.5Hz),7.54-7.56（d，J=8.8Hz,1H）。
Embodiment 432-methoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester (ZL006-143)
With reference to the method for embodiment 1, with 2-methoxyl group-PABA-(2-N-methylpiperazine base) ethanol ester and 3,5-dichloro-salicylaldehyde for Material synthesis, off-white powder, productive rate 81.6%. 1HNMR(δ,ppm,300MHz):3.88(s,3H),2.30(s,3H),2.40-2.60(br,8H),2.89(t,J=6.2Hz,2H),4.30(s,2H),4.41(t,J=6.2Hz,2H),5.95(s,1H),6.23-6.26(dd,J=8.8Hz,2.0Hz),7.10-7.11(d,J=2.5Hz),7.39-7.40(d,J=2.5Hz),7.54-7.56d,J=8.85Hz,1H）。
The compound structure related in above-described embodiment is as follows:
The compound structure related in table 1 embodiment
The water-soluble research of embodiment 44 target compound
Adopt 0.1mol/L hydrochloric acid water liquid to be solvent, investigate target compound water-soluble, and with ZL006 and ZL006 cyclohexyl for contrast.Get 0.1mol/L hydrochloric acid water liquid, add and wait to investigate compound 1mg, 10mg, observe dissolving situation in 25 DEG C.Result of study shows, at 25 DEG C, fails entirely molten at 0.1mol/L hydrochloric acid water liquid ZL0061mg and ZL006 cyclohexyl 1mg, and target compound 10mg water-soluble equal can be entirely molten.Compared with ZL006 and ZL006 cyclohexyl, the water-soluble obvious increase of target compound.
The compound water soluble result of study related in table 2 embodiment
Compound Solvability (mg/10mL) Compound Solvability (mg/10mL)
ZL006 Be less than 1 ZL006-123 Be greater than 10
ZL006 cyclohexyl Be less than 1 ZL006-124 Be greater than 10
ZL006-101 Be greater than 10 ZL006-125 Be greater than 10
ZL006-102 Be greater than 10 ZL006-126 Be greater than 10
ZL006-103 Be greater than 10 ZL006-127 Be greater than 10
ZL006-104 Be greater than 10 ZL006-128 Be greater than 10
ZL006-105 Be greater than 10 ZL006-129 Be greater than 10
ZL006-106 Be greater than 10 ZL006-130 Be greater than 10
ZL006-107 Be greater than 10 ZL006-131 Be greater than 10
ZL006-108 Be greater than 10 ZL006-132 Be greater than 10
ZL006-109 Be greater than 10 ZL006-133 Be greater than 10
ZL006-110 Be greater than 10 ZL006-134 Be greater than 10
ZL006-111 Be greater than 10 ZL006-135 Be greater than 10
ZL006-112 Be greater than 10 ZL006-136 Be greater than 10
ZL006-113 Be greater than 10 ZL006-137 Be greater than 10
ZL006-114 Be greater than 10 ZL006-138 Be greater than 10
ZL006-115 Be greater than 10 ZL006-139 Be greater than 10
ZL006-116 Be greater than 10 ZL006-140 Be greater than 10
ZL006-117 Be greater than 10 ZL006-141 Be greater than 10
ZL006-118 Be greater than 10 ZL006-142 Be greater than 10
ZL006-119 Be greater than 10 ZL006-143 Be greater than 10
ZL006-120 Be greater than 10 ZL006-144 Be greater than 10
ZL006-121 Be greater than 10 ZL006-145 Be greater than 10
ZL006-122 Be greater than 10 Be greater than 10
Embodiment 45 target compound oral administration biaavailability is studied
HPLC-MC is adopted to have studied the bioavailability of target compound, and compare with ZL006 cyclohexyl, research display, the mouse absolute bioavailability of target compound under 3mg/kg dosage is all more than 50%, peak time (Tmax) is 1 hours, and ZL006 cyclohexyl, bioavailability is no more than only has about 9.8%.The compound bioavailability that the present invention obtains is obviously higher.
The pharmacokinetic parameter of table 3 partial target compound
Target compound Tmax Absolute bioavailability
ZL006 cyclohexyl 1.0 9.8%
ZL006-102 0.8 52.6%
ZL006-105 0.9 50.7%
ZL006-115 1.0 52.9%
ZL006-120 1.1 55.8%
ZL006-122 0.9 58.2%
ZL006-129 0.9 56.4%
ZL006-134 1.0 57.2%
ZL006-141 1.0 55.6%
ZL006-143 0.9 60.8%
The effect of target compound neurogenic pain
The making method of embodiment 46 neuropathic pain model
Dorsal root ganglion hypodesmus (segmental spinal nerve ligation, SNL) is adopted to prepare neuropathic pain model.Abdominal injection 2% Chloral Hydrate (0.2mL/l0g) anesthetized mice, after righting reflex loss, fixing mouse is in ventricumbent position.Adopt the method analogue formation of Kim and Chung: be about the center skin incision of 3-5cm at mouse back from the horizontal blunt separation of L4-S2, be separated the other muscle of vertebra to dash forward to the 6th lumbar vertebrae, expose and excise and expose and excise right side L5/L6 zygapophysis, part stings out L6 transverse process, thus the L4-L6 spinal nerves on right side can be exposed, isolate L5 nerve gently, and with 5-0 silk thread tightly ligation L5.Then layer-by-layer suture otch, iodophor disinfection skin, continues to raise.There is abnormal gait in postoperative animal, operation rear flank limb, except slightly turning up, except toes tightly receive, changes without other deformity.
The oral ZL006-105 of embodiment 47 is to the analgesic activity-amount effect curve of neurogenic pain
ZL006-105 group and group of solvents is divided into by measuring the contract mouse of sufficient threshold of reaction baseline of 50% mechanical irritation, then SNL operation is carried out, in postoperative 7th day, gavage gives ZL006-05 or equal-volume solvent, the dosage of ZL006-105 is respectively 0.3,1,3,10mg/kg, within after administration 1 hour, 2 hours, measure mechanical irritation and to contract the sufficient threshold of reaction, result is as shown in Figure 1, ZL006-105 is that dose-dependently increases mechanical irritation and to contract the sufficient threshold of reaction, and namely 3mg/kg has remarkable drug effect.Fig. 2 was shown in the analgesic activity of neurogenic pain in 2 hours after other partial target compounds 3mg/kg administration.
The oral ZL006-105 of embodiment 48 is to the analgesic activity-Time-activity-curve of neurogenic pain
In mouse SNL postoperative 7 days, gavage gives ZL006-105, dosage is 10mg/kg, take physiological saline as contrast (Vehicle), measure its before administration after one hour (-1h) and administration the mechanical irritation of 0.5,2,4,6,12,24 hour to contract sufficient threshold of reaction changing conditions.As shown in Figure 3, ZL006-105 significantly increases mechanical irritation and to contract the sufficient threshold of reaction result, 0.5 hour existing remarkable drug effect after administration, about 6 hours of single administration duration of efficacy.
Target compound is to the provide protection of Focal Cerebral Ischemia Reperfusion
The preparation of embodiment 49 Focal Cerebral Ischemia Reperfusion model
Supine, after 2% Chloral Hydrate (0.2mL/10g, i.p.) anesthesia, is fixed on operating table by mouse, and along neck medisection skin, blunt separation musculi colli tissue, exposes right carotid (CCA) and carefully dissociate; Peel off the vagus nerve of companion's row gently, ligation also cuts off the inside and shallow External Carotid Artery Branch (ECA) showing trend; Follow internal carotid artery (ICA) forward, near basis cranii, have bifurcated artery-arteria pterygopalatina laterally, be isolated ligation.CCA proximal part is with surgical thread ligation; The far-end eye scissors of ligature cuts off osculum, operation nylon wire (mouse is with No. 8/0) one section is heated into round bead shape insert along this osculum place respectively, insert about 16-17mm(mouse) when feeling there is light resistance till, indication wire bolt front end reaches arteria cerebri anterior.So far, the blood supply of arteria cerebri media (MCA) comprise carotid artery and brain Webster ring anterior communicating branch source blood supply all block.According to the degree of depth that marker for judgment insertion line is fastened.The extravascular that line is fastened divides ligation to fix, and prevents the slippage of line bolt.After the cerebral ischemia 1h of right side, carefully pull out line bolt, the ligation broken ends of fractured bone, realize the Reperfu-sion after ischemic.Skin suture, steams again and meticulously feeds.Keep animal heat constant in 37 ± 0.5 DEG C in surgical procedure.
Embodiment 50ZL006-118 is for the cerebral protection of rat acute focal cerebral ischemia
Middle cerebral artery occlusion model brightly can cause the infarct at the positions such as ischemic side cortex and striatum, and after TTC dyeing, healthy tissues presents redness, and infarcted region is white.ZL006-118(1.5mg/kg) in cerebral ischemia re-pouring tail intravenously administrable 1 time immediately at once, within 48 hours after cerebral ischemia, evaluate neurological handicap symptom, then put to death animal, get brain, TTC dyes, and observes the infarct size of dyeing hindbrain sheet.Result is as shown in Figure 4: compared with model control group, ZL006-118 can reduce brain infarction area to a certain extent.
Embodiment 51ZL006-118 is for the impact of rat acute focal cerebral ischemia neurological handicap symptom
Adopt ZL006-118(1.5mg/kg) in cerebral ischemia re-pouring tail intravenously administrable 1 time immediately at once, within 48 hours after cerebral ischemia, evaluate neurological handicap symptom.Test-results is as shown in Figure 5: rat Reperfu-sion administration ZL006-118 (1.5mg/kg), neurological deficits score all has clear improvement.

Claims (4)

1. the aminosallcylic acid 2-monoethanolamine ester derivative of a class N-benzyl replacement, is characterized in that structure meets general formula (I)
Wherein R 1for-Cl ,-CH 3,-Br or-C (CH 3) 3; R 2for-H ,-CH 3or-COCH 3;
R 3, R 4be-C independently of one another 2h 5; Or connect together, form ring texture with N now R 3-R 4for-CH 2cH 2cH 2cH 2-,-CH 2cH 2cH 2cH 2cH 2-,-CH 2cH 2o CH 2cH 2-or
-CH 2CH 2N(CH 3)CH 2CH 2-。
2. the aminosallcylic acid 2-monoethanolamine ester derivative of a class N-benzyl replacement according to claim 1, is characterized in that being selected from:
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester,
2-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester,
2-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-N, N-diethylin) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester,
2-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester,
2-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-morpholinyl) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester,
2-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester,
2-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-morpholinyl) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester,
2-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester,
2-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-piperidyl) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester,
2-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester,
2-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-piperidyl) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-piperidyl) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester,
2-acetoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester,
2-acetoxyl group-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-pyrryl) ethanol ester,
2-acetoxyl group-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester,
2-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-pyrryl) ethanol ester,
2-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-pyrryl) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-2-pyrrolylethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-tertiary butyl benzyl) benzaminic acid-(2-N, N-diethylin),
2-hydroxyl-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol,
2-hydroxyl-4-(the chloro-5-bromine of-2-hydroxyl-3-) benzaminic acid-(2-N, N-diethylin) ethanol ester,
2-hydroxyl-4-(-2-hydroxyl-3-chloro-5-methyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester,
2-methoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N, N-diethylin) ethanol ester,
2-methoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-morpholinyl) ethanol ester or
2-methoxyl group-4-(3,5-bis-chlorine-2-hydroxyl benzyl) benzaminic acid-(2-N-methylpiperazine base) ethanol ester.
3. the aminosallcylic acid 2-monoethanolamine ester derivative that described in claim 1 or 2, a class N-benzyl replaces or the application of its pharmacy acceptable salt in preparation treatment cerebral apoplexy, chronic pathological pain or nerve degenerative diseases medicine.
4. treat cerebral apoplexy, chronic pathological pain or nerve degenerative diseases medicine, it is characterized in that effective constituent is the aminosallcylic acid 2-monoethanolamine ester derivative that replaces of N-benzyl described in claim 1 or 2 or its pharmacy acceptable salt.
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